Page 1 of 52

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

 

OFFICE OF 

PREVENTION, PESTICIDES AND 

TOXIC SUBSTANCES 

MEMORANDUM

DATE: 28-January-2010 

SUBJECT: Difenoconazole FQPA Human Health Risk Assessment to Support the 

Establishment of Import Tolerances on Mango and Waxapple (also known 

as Wax jambu) 

PC Code: 128847 DP Barcode: 371612 

Decision No.: 413927 Registration No.: N/A 

Petition No.: PP#9E7573 Regulatory Action: Section 3 

Risk Assessment 

Type: 

Single 

Chemical/Aggregate Case No.: NA 

TXR No.: NA CAS No.: 119446-68-3 

MRID No.: NA 40 CFR §180.475 

FROM: Yan Donovan, Risk Assessor 

 Registration Action Branch IV 

 Health Effects Division (HED); 7509P 

 

THROUGH: Ray Kent, Branch Chief 

 Susan V. Hummel, Senior Chemist 

 Registration Action Branch IV 

 Health Effects Division (HED); 7509P 

TO: Rosemary Kearns/Tony Kish (RM 22) 

 Fungicide Branch 

 Registration Division (7505P) 
Page 2 of 52

Table of Content 

1.0 Executive Summary .............................................................................................. 3 

2.0 Ingredient Profile .................................................................................................. 7 

2.1 Summary of Proposed Uses ............................................................................. 7 

2.2 Structure and Nomenclature ........................................................................... 8 

3.0 Hazard Characterization/Assessment ................................................................. 9 

3.1 Hazard and Dose-Response Characterization ................................................ 9 

3.1.1 Toxicological Effects and Dose-response ................................................ 9 

3.2 FQPA Considerations ..................................................................................... 12 

3.2.1. Determination of Susceptibility .................................................................. 12 

3.2.2. Adequacy of Toxicity Database .................................................................. 13 

3.2.3. Degree of Concern Analysis: ....................................................................... 13 

3.2.4. FQPA Safety Factor Recommendation ....................................................... 13 

3.3 Endocrine Disruption ..................................................................................... 14 

4.0 Public Health and Pesticide Epidemiology Data .............................................. 14 

5.0 Dietary Exposure/Risk Characterization ......................................................... 14 

5.1 Pesticide Metabolism and Environmental Degradation .............................. 14 

5.1.1 Metabolism in Primary Crops ............................................................... 14 

5.1.2 Metabolism in Rotational Crops ........................................................... 15 

5.1.3 Metabolism in Livestock ........................................................................ 15 

5.1.4 Analytical Methodology ......................................................................... 15 

5.1.5 Environmental Degradation .................................................................. 16 

5.1.6 Comparative Metabolic Profile ............................................................. 16 

5.1.7 Toxicity Profile of Major Metabolites and Degradates ....................... 16 

5.1.8 Pesticide Metabolites and Degradates of Concern ............................... 16 

5.1.9 Drinking Water Residue Profile ............................................................ 17 

5.1.10 Food Residue Profile ............................................................................... 18 

5.1.11 International Residue Limits ................................................................. 19 

5.2 Dietary Exposure and Risk ............................................................................ 19 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ................ 21 

6.1 Residential Handler Exposure and Risk Characterization ......................... 21 

7.0 Aggregate Risk Assessments and Risk Characterization ................................ 22 

7.1 Acute & Chronic Aggregate Risk .................................................................. 22 

7.2 Short- and Intermediate-Term Aggregate Risk ........................................... 22 

8.0 Cumulative Risk Characterization/Assessment ............................................... 23 

9.0 Occupational Exposure/Risk Pathway .............................................................. 24 

10.0 Data Needs and Label Recommendations ........................................................ 24 

11.0 References: .......................................................................................................... 26 

12.0 Tolerance Summary ........................................................................................... 27 

13.0 Appendices ........................................................................................................... 28 

Appendix 1: Acute Toxicity Data on Difenoconazole Technical ............................ 28 

Appendix 2: Subchronic, Chronic and Other Toxicity Profile ............................... 29 

Appendix 3. Proposed Metabolic Pathway for difenoconazole in Rats ................ 49 

Appendix 4 Environmental Fate Degradates ......................................................... 50 
Page 3 of 52

1.0 Executive Summary

Difenoconazole is a broad spectrum fungicide belonging to the triazole group of 

fungicides (Group 3). It is currently registered in the U.S. for use as a seed treatment on 

cereal grains, canola, and cotton and for foliar applications to pome fruits, sugar beets, 

fruiting vegetables, and tuberous and corm vegetables. Tolerances for difenoconazole 

are currently established under 40 CFR §180.475. Difenoconazole acts by blocking 

demethylation during sterol biosysnthesis which, in turn, disrupts membrane synthesis. 

Proposed Uses 

Under PP#9E7573, Syngenta Crop Protection, Inc. is proposing the establishment of 

import 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/on 

Mango at 0.09 ppm and on waxapple at 1.5 ppm. The end-use product (EP) for use on 

mangos grown in Brazil is Score®, an emulsifiable concentrate (EC) formulation 

containing 250 g ai/L. Up to three foliar spray applications at a target rate of 0.11 lb 

ai/A/application (0.125 kg ai/ha/application), with a 14-day retreatment interval (RTI), 

may be made to mature mango trees for a total seasonal rate of 0.33 lb ai/A (0.375 kg 

ai/ha) using ground equipment. The preharvest interval (PHI) is 7days. The EP for use 

on waxapples grown in Taiwan is a soluble concentrate (SC) formulation containing 

12.5% w/v difenoconazole and 20% w/v azoxystrobin. The information for waxapple 

use in Taiwan is incomplete, however, the submitted field trial data will support up to 

eight foliar applications of a 125 g/L SC formulation of difenoconazole at a target rate of 

0.34 lb ai/A/application (0.39 kg ai/ha/application), with 6- to 8-day RTI (re-entry 

interval), to mature waxapple trees for a total seasonal rate of 2.74 lb ai/A (3.07 kg ai/ha) 

and a 12-day PHI. Applications may be made using ground equipment. Consistent with 

the submitted field trial data, applications should be restricted to fruit protected with 

exclusion net bags or otherwise bagged fruit. The subject review addresses 

difenoconazole only. 

Toxicity/Hazard

Difenoconazole possesses low acute toxicity by the oral, dermal and inhalation routes of 

exposure. It is not considered to be an eye or skin irritant and is not a sensitizer. 

Difenoconazole exhibits some evidence of neurotoxicity in the database, but the effects 

are transient or occur at doses exceeding the limit dose. It is not mutagenic andit is not a 

developmental or reproductive toxicant. Chronic effects in rats and mice are seen as 

cumulative decreases in body weight gains. No evidence of carcinogenicity was seen in 

rats. Evidence for carcinogenicity was seen in mice where liver tumors were induced at 

doses which were considered to be excessively high for carcinogenicity testing. 

Treatment-related non-neoplastic lesions were confined to the liver. Tumors were 

observed in mice at 46 and 58 mg/kg/day ( males and females, respectively); however, 

based on excessive toxicity observed at the two highest doses, the absence of tumors at 

the lower doses and the absence of genotoxic effects, HED’s Cancer Peer Review 

Committee (CPRC) recommended for a cancer classification of C (possible human 

carcinogen). A margin-of-exposure (MOE) approach to risk assessment was advocated 
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by the CPRC in July 2007. The FQPA Safety Factor (SF) is reduced to 1x. 

The toxicological database for difenoconazole is sufficient to conduct this risk 

assessment. However, in accordance with Part 158 Toxicology Data requirements, an 

immunotoxicity study (870.7800) is required for difenoconazole. 

Endpoints and doses for risk assessment were selected for the following scenarios: Acute 

dietary (general population including infants and children), chronic dietary, short-term 

dermal and short-term inhalation.

Dietary Exposure/Risk Assessment

HED has examined the residue chemistry database for difenoconazole and concluded that 

field trial data for mango are adequate and reflect the proposed use of Score® on mango 

in Brazil. Assuming that the use directions for waxapple in Taiwan, once fully 

elucidated, will comport with the submitted field trial data, HED believes that there are 

no residue chemistry issues that would preclude granting import tolerances for residues 

of difenoconazole on mango in Brazil and waxapple in Taiwan. 

Acute and chronic dietary (food + water) risk assessments were conducted using the 

Dietary Exposure Evaluation Model - Food Consumption Intake Database (DEEMFCIDTM, ver. 2.03. This model uses food consumption data from the United States 

Department of Agriculture’s (USDA’s) Continuing Surveys of Food Intakes by 

Individuals (CSFII; 1994-1996 and 1998). 

The unrefined acute analysis assumed tolerance-level residues, 100% crop treated (CT), 

and default processing factors. The resulting acute food exposure estimates were less 

than HED’s level of concern (<100% of the acute population-adjusted dose (aPAD)) at 

the 95th percentile of the exposure distribution for the general U.S. population (7% 

aPAD) and all population sub-groups; the most highly exposed population subgroup was 

Children1-2 years old with 16% aPAD. The somewhat refined chronic analysis assumed 

tolerance-level residues for some commodities, field trial residues for the majority of 

commodities, experimental processing factor for some crops, and 100 % CT. The 

resulting chronic food exposure estimates were less than HED’s level of concern for the 

general U.S. population (17% cPAD) and all population sub-groups; the most highly 

exposed population subgroup was children 1-2 years old with 45% cPAD. 

 

A cancer dietary assessment was not conducted for difenoconazole because the cancer 

NOAEL is higher than the chronic RfD; therefore, the chronic dietary risk estimate is 

more protective. 

Residential Exposure/Risk Assessment 

No new residential uses are being requested at this time. However, adults and 

adolescents may be exposed to difenoconazole from its currently registered use on 

ornamentals. These risks have been previously assessed. It was concluded that 

residential pesticide handlers will be exposed to short-term duration (1 - 30 days) only. 

The dermal and inhalation (short-term) residential exposure was assessed for a 
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homeowner mixer/loader/applicator wearing short pants and short-sleeved shirts as well 

as shoes plus socks using a garden hose-end sprayer, “pump-up” compressed air sprayer, 

or backpack sprayer. The margin of exposures (MOEs) are >100; therefore are not of 

concern. With respect to residential post-application exposures, current HED policy (see 

ExpoSAC minutes from 8/19/99 and 10/11/01) specifies that no significant postapplication exposure is anticipated from ornamentals, either by residents or professional 

applicators; therefore, no residential post-application assessment was conducted. 

Aggregate Risk Assessment 

Acute and chronic aggregate exposures include food plus drinking water exposures. As 

stated above, acute and chronic aggregate risks are not of concern. Since a common 

endpoint has been identified for assessment of short-term oral, dermal, and inhalation 

exposures, short-term aggregate risk assessment combines chronic dietary (food and 

water) exposure estimates with residential exposure estimates. The proposed residential 

scenarios result in exposure to only adults. Aggregate MOEs are ≥180 and are not of 

concern. 

Triazole metabolites 

The requested uses of difenoconazole did not result in an increase in dietary exposure 

estimates for free triazole or conjugated triazoles. Therefore, the last dietary exposure 

analyses for the triazole metabolites (M. Negussie, 28 Oct. 2009) have not changed. 

Occupational Handler and Postapplication Exposure/Risk Assessment

Not applicable since this is an import tolerance. 

Recommendations for Tolerances and Registration

Pending submission of a revised Section B for waxapple (see Section 10.0 under 

Directions for Use) and a revised Section F (see requirements under Proposed 

Tolerances), there are no residue chemistry issues that would preclude granting import 

tolerances for residues of difenoconazole resulting from the uses on mango in Brazil and 

waxapple in Taiwan: 

Mango ..................................................................................0.07 ppm 

Waxapple .............................................................................1.5 ppm 

Notes to PM: 

1. With regards to the use on mangos in Brazil, HED notes that Mexico and not 

Brazil is the largest importer of mangos into the U.S. Since only data from Brazil were 

submitted, the registrant should be made aware that HED can not ascertain the adequacy 

of the recommended tolerance to cover residues incurred in other geographical regions of 

South America or Mexico from the same or similar use. 

2. An error was found in MRID 47760601, Section 1.3 Test Item, bottom of Page 6 

of 66. The stated nominal/actual formulation content in Amistar Top 325 SC of 

difenoconazole and azoxystrobin are reversed. According to the label, Amistar Top 325 
Page 6 of 52

SC contains 125 g/L of difenoconazole and 200 g/L azoxystrobin. The MRID should be 

corrected. 

3. The registrant should be reminded that because difenoconazole is a triazole 

compound, HED requires that samples from any metabolism, feeding, field trial, and/or 

processing studies be analyzed for the triazole metabolites triazolylalanine (TA), triazolyl 

acetic acid (TAA), and 1,2,4-triazole (1,2,4-T). Guidance has been issued concerning 

these residue chemistry data requirements for the triazole-based metabolites under DP# 

327788 (4/25/06, M. Doherty) and data submitted in support of future uses of 

difenoconazole will be accessed accordingly. 

4. The registrant should be reminded that magnitude of the residue data for papaya, 

as a representative crop of the tropical fruit crops group, have been deemed adequate to 

support the same or substantially similar use on mango (among other tropical fruits) and 

the establishment of a separate mango tolerance. An import tolerance is currently 

established under §180.475(a)(1) for residues of difenoconazole in/on papaya at 0.3 ppm.

 

Environmental Justice Considerations

Potential areas of environmental justice concerns, to the extent possible, were considered 

in this human health risk assessment, in accordance with U.S. Executive Order 12898, 

"Federal Actions to Address Environmental Justice in Minority Populations and LowIncome Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf). 

As a part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP policy, HED 

estimates risks to population subgroups from pesticide exposures that are based on 

patterns of that subgroup’s food and water consumption, and activities in and around the 

home that involve pesticide use in a residential setting. Extensive data on food 

consumption patterns are compiled by the USDA under the Continuing Survey of Food 

Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered 

food uses of a pesticide. These data are analyzed and categorized by subgroups based on 

age, season of the year, ethnic group, and region of the country. Additionally, OPP is 

able to assess dietary exposure to smaller, specialized subgroups and exposure 

assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, non-dietary exposures based on home use of pesticide products and 

associated risks for adult applicators and for toddlers, youths, and adults entering or 

playing on treated areas postapplication are evaluated. Further considerations are 

currently in development as OPP has committed resources and expertise to the 

development of specialized software and models that consider exposure to bystanders and 

farm workers as well as lifestyle and traditional dietary patterns among specific 

subgroups. 

Review of Human Research 
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This risk assessment relies in part on data from studies in which adult human subjects 

were intentionally exposed to a pesticide or other chemical. These studies, which 

comprise the Pesticide Handlers Exposure Database (PHED) and information from the 

Agricultural Re-Entry Task Force (ARTF) and the Outdoor Residential Exposure Task 

Force (ORETF), have been determined to require a review of their ethical conduct, have 

received that review, and were considered appropriate (or ethically conducted) for use in 

risk assessments. 

2.0 Ingredient Profile

2.1 Summary of Proposed Uses

(HED memo of B. Cropp-Kohlligian, 01/21/10, D366507) 

A list of the end-use products (EPs) relevant to this import tolerance petition is presented 

in Table 2.1a. A summary of the use directions for these EPs is presented in Table 2.1b. 

Table 2.1a. Summary of Difenoconazole End-Use Products Proposed for Use on Mango and Waxapple.

Trade Name Country a.i. (% of 

formulation) 

Formulation 

Type

Proposed 

Crops 

Target Pests Label 

Date 

Score® Brazil 25% 

 (250 g ai/L) 

EC Mango Powdery mildew and 

anthracnose 

10/30/02 

(Hao Jia Zan) 1

Azoxystrobin + 

Difenoconazole 

Taiwan 12.5% SC Waxapple Anthracnose undated, 

Section B 

1

 The Taiwan end-use product is a soluble concentrate formulation containing 12.5% w/v difenoconazole and 20% w/v 

azoxystrobin. 
Page 8 of 52

Table 2.1b. Summary of Proposed Directions for Use of Difenoconazole. 

Applic. Timing, 

Type, and 

Equip. 

Product 

[Formulation] 

Applic. 

Rate 

(lb ai/A) 

[g ai/ha] 

Max. No. 

Applic. per 

Season 

Max. Seasonal 

Applic. Rate 

(lb ai/A) 

[g ai/ha] 

PHI 

(days) 

Use Directions and 

Limitations 

Mango 

Foliar; 

Ground 

(500-1,000 L/ha 

spray volume) 

Score® 

[250 g ai/L 

EC] 

0.022-

0.11 

[25-125]

3 0.33 

[375] 7 

Applications must start 

immediately after the 

engorgement of floral 

gems or before flowers 

bloom, using smallest 

dose in the first 

applications to control 

powdery mildew and a 

larger dose to control 

anthracnose; 14-day RTI. 

Waxapple 

Foliar; 

equipment not 

specified (NS) 

Hao Jia Zan

[12.5% w/v 

SC] 

3,000x 

dilution1 5 NS 30 Only to be applied during 

fluorescence; 7-day RTI. 

1

 The application rate could not be determined as the Section B only reported the concentration to be 

applied. 

2.2 Structure and Nomenclature

The nomenclature of difenoconazole is summarized in Table 2.2a, and the 

physicochemical properties of difenoconazole are summarized in Table 2.2b. 

Table 2.2a. Difenoconazole Nomenclature. 

Chemical structure 

O O

O

N N Cl

N

CH3

Cl

Common name Difenoconazole 

Company experimental name CGA-169374 

IUPAC name 1-({2-[2-chloro-4-(4-chlorophenoxy)phenyl]-4-methyl-1,3-dioxolan-2-yl}methyl)-1H1,2,4-triazole 

CAS name 1-[[2-[2-chloro-4-(4-chlorophenoxy)phenyl]-4-methyl-1,3-dioxolan-2-yl]methyl]- 1H1,2,4-triazole 

CAS registry number 119446-68-3 

End-use products (EP) Score® - for mango grown in Brazil. 

‘Hao Jia Zan Azoxystrobin + Difenoconazole’ - for waxapple grown in Taiwan 
Page 9 of 52

Table 2.2a. Difenoconazole Nomenclature. 

Chemical structure of CGA205375 livestock metabolite 

O

Cl N N

N OH Cl

Table 2.2b Physicochemical Properties of Difenoconazole. 

Parameter Value Reference 

Melting point 78.6 oC DP#s 172067 and 178394, 10/26/92, R. 

Lascola pH 6-8 at 20 oC (saturated solution) 

Density 1.37 g/cm3 at 20 oC 

Water solubility 3.3 ppm at 20 oC 

Solvent solubility g/100 mL at 25 oC: 

n-hexane: 0.5 

1-octanol: 35 

toluene: 77 

acetone: 88 

ethanol: 89 

Vapor pressure 2.5 x 10-10 mm Hg at 25 oC 

Dissociation constant, pKa Reported as <0 in MRID 42090003 which was previously reviewed in DP#s 172067 

and 178394; however, questions have arisen concerning this value. Re-examination of 

MRID 42090003 found that the product chemistry data study to support the reported 

dissociation constant for the technical grade of difenoconazole was not included. 

Octanol/water partition coefficient, 

Log(KOW) 

4.2 at 25 oC DP#s 172067 and 178394, 10/26/92, R. 

Lascola 

UV/visible absorption spectrum λmax at about 200 and 238 nm 

(in methanol at 26 oC) 

PMRA Proposed Regulatory Decision 

Document on Difenoconazole, 4/14/99 

(PRDD99-01) 

3.0 Hazard Characterization/Assessment

(For detailed discussion, refer to HED memo of M. Sahafeyan, 11/09/07, D346591) 

The toxicological database for difenoconazole is complete for the purpose of this risk 

assessment. However, a new data requirement for an Immunotoxicity study is required. 

3.1 Hazard and Dose-Response Characterization

For a complete list of studies considered, see Appendix 1 and 2 under Section 13.0 of this 

document. 

3.1.1 Toxicological Effects and Dose-response

Difenoconazole possesses low acute toxicity by the oral, dermal and inhalation routes of 

exposure. It is not considered to be an eye or skin irritant and is not a sensitizer. 
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In an acute neurotoxicity study in rats, reduced fore-limb grip strength was observed on 

day 1 in males and clinical signs of neurotoxicity in females at the limit dose of 2000 

mg/kg. This effect in males is considered as transient since it was not observed at later 

observation points and toxicity in females was observed only at doses exceeding the limit 

dose. In a subchronic neurotoxicity study in rats decreased hind limb strength was 

observed only in males, which was considered as nonspecific in nature. 

It is not a developmental or reproductive toxicant. Chronic effects in the rat study are 

seen as cumulative decreases in body weight gains. Similarly, chronic feeding studies in 

mice showed decreased body-weight gains in male and female mice at termination. In 

mice, treatment-related non-neoplastic lesions were confined to the liver and were 

supported by clinical chemistry data at a level of 300 ppm (46 and 58 mg/kg/day for 

males and females, respectively). No systemic toxicity was observed at the limit dose in 

a 28-day dermal toxicity study in rats. A dermal absorption of 15.3% was observed 

through rat skin using an in vivo method. 

Difenoconazole is not mutagenic, and no evidence of carcinogenicity was seen in rats. 

Evidence for carcinogenicity was seen in mice, where liver tumors were induced at doses 

which were considered to be excessively high for carcinogenicity testing. Liver tumors 

were observed in mice at 300 ppm and higher; however, based on excessive toxicity 

observed at the two highest doses of 2500 and 4500 ppm (females terminated after two 

weeks due to excessive toxicity resulting in moribundity and death), the absence of 

tumors at two lower doses of 10 and 30 ppm and the absence of genotoxic effects, HED’s 

Cancer Peer Review Committee (CPRC) recommended for a cancer classification of C 

(possible human carcinogen). A margin-of-exposure (MOE) approach in risk 

assessment was advocated by the CPRC utilizing the no-observable-adverse-effects-level 

(NOAEL) of 30 ppm (4.7 and 5.6 mg/kg/day in males and females, respectively) and the 

lowest-observable-adverse-effects-level (LOAEL) of 300 ppm (46 and 58 mg/kg/day in 

males and females, respectively) from the mouse study using only those biological 

endpoints which were relevant to tumor development (i.e., hepatocellular hypertrophy, 

liver necrosis, fatty changes in the liver and bile stasis) (Memo, Jess Rowland and Esther 

Rinde, 27-JUL-1994; Memo, PV Shah, 1-March-2007, HED Doc. No. 005453). 

The doses and toxicological endpoints selected for various exposure scenarios applicable 

to this risk assessment are summarized in Table 3.1.3a and Table 3.1.3b. 

Table 3.1.3a. Summary of Toxicological Doses and Endpoints for Difenoconazole for Use in Dietary 

and Non-Occupational Human-Health Risk Assessments. 

Exposure 

Scenario 

Point of 

Departure 

Uncertainty/FQPA 

Safety Factors 

RfD, PAD, LOC for 

Risk Assessment 

Study and Relevant 

Toxicological Effects 

Acute 

Dietary (All 

populations) 

NOAEL = 25 

mg/kg 

UFA = 10X 

UFH = 10X 

UFFQPA = 1X 

aRfD = aPAD = 0.25 

mg/kg/day 

Acute Neurotoxicity 

Study in Rats 

LOAEL= 200 mg/kg in 

males based on reduced 

fore-limb grip strength in 

males on day 1. 

Chronic NOAEL = UFA = 10X cRfD = cPAD = Combined chronic 
Page 11 of 52

Table 3.1.3a. Summary of Toxicological Doses and Endpoints for Difenoconazole for Use in Dietary 

and Non-Occupational Human-Health Risk Assessments. 

Exposure 

Scenario 

Point of 

Departure 

Uncertainty/FQPA 

Safety Factors 

RfD, PAD, LOC for 

Risk Assessment 

Study and Relevant 

Toxicological Effects 

Dietary (All 

populations) 

0.96 

mg/kg/day 

UFH = 10X 

UFFQPA = 1X 

0.01mg/kg/day toxicity/carcinogenicity 

(rat; dietary) LOAEL = 

24.1/32.8 mg/kg/day 

(M/F) based on 

cumulative decreases in 

body-weight gains.

Incidental 

Oral 

Short- and 

IntermediateTerm (1-30 

days and 1-6 

months) 

NOAEL = 

1.25 

mg/kg/day 

UFA = 10X 

UFH = 10X 

UFFQPA = 1X 

Residential LOC for 

MOE<100 

Reproduction and 

fertility effects (rat; 

dietary) Offspring 

LOAEL = 12.5 

mg/kg/day based on 

reduction in body-weight 

of F1 males. 

Dermal 

Short- and 

IntermediateTerm (1-30 

days and 1-6 

months) 

Oral NOAEL 

= 1.25 

mg/kg/day 

Dermal 

Absorption 

factor=15.3% 

UFA = 10X 

UFH = 10X 

UFFQPA = 1X 

Residential LOC for 

MOE<100 

Reproduction and 

fertility effects (rat; 

dietary) Offspring 

LOAEL = 12.5 

mg/kg/day based on 

reduction in body-weight 

gain of F0 females prior 

to mating, gestation and 

lactation. 

Dermal 

Long-Term 

(>6 months) 

Oral NOAEL 

= 0.96 

mg/kg/day 

Dermal 

Absorption 

factor=15.3% 

UFA = 10X 

UFH = 10X 

UFFQPA = 1X 

Residential LOC for 

MOE<100 

Combined chronic 

toxicity/carcinogenicity 

(rat; dietary) LOAEL = 

24.1/32.8 mg/kg/day 

(M/F) based on 

cumulative decreases in 

body-weight gains.

Inhalation 

(Short- and 

Intermediateterm) 

Oral NOAEL 

= 1.25 

mg/kg/day 

100% 

inhalation 

absorption 

assumed 

UFA = 10X 

UFH = 10X 

UFFQPA = 1X 

Residential LOC for 

MOE<100 

Reproduction and 

fertility effects (rat; 

dietary) Offspring 

LOAEL = 12.5 

mg/kg/day based on 

reduction in body weight 

gain of F0 females prior 

to mating, gestation and 

lactation. 

Inhalation 

(Long- term) 

Oral NOAEL 

= 0.96 

mg/kg/day 

100% 

inhalation 

absorption 

assumed 

UFA = 10X 

UFH = 10X 

UFFQPA = 1X 

Residential LOC for 

MOE<100 

Combined chronic 

toxicity/carcinogenicity 

(rat; dietary) LOAEL = 

24.1/32.8 mg/kg/day 

(M/F) based on 

cumulative decreases in 

body weight gains.

Cancer (oral, 

dermal, 

inhalation) 

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 dated March 3, 2007, HED Doc. No. 0054532).

Abbreviations: UF = uncertainty factor, UFA = extrapolation from animal to human (interspecies), UFH = 

potential variation in sensitivity among members of the human population (intraspecies), UFFQPA = FQPA 

Safety Factor, NOAEL = no-observed-adverse-effect level, LOAEL = lowest-observed-adverse-effect level, 
Page 12 of 52

RfD = reference dose (a = acute, c = chronic), PAD = population-adjusted dose, MOE = margin of 

exposure, LOC = level of concern. 

Table 3.1.3b. Summary of Toxicological Doses and Endpoints for Difenoconazole for Use in 

Occupational Human-Health Risk Assessments. 

Exposure 

Scenario 

Point of 

Departure 

Uncertainty/FQPA 

Safety Factors 

RfD, PAD, Level of 

Concern for Risk 

Assessment 

Study and 

Toxicological Effects 

Dermal 

Short- and 

IntermediateTerm (1-30 

days and 1-6 

months) 

Oral NOAEL 

= 1.25 

mg/kg/day 

Dermal 

Absorption 

factor=15.3% 

UFA = 10X 

UFH = 10X 

Occupational LOC for 

MOE<100 

Reproduction and 

fertility effects (rat; 

dietary) Offspring 

LOAEL = 12.5 

mg/kg/day based on 

reduction in body-weight 

gain of F0 females prior 

to mating, gestation and 

lactation. 

Dermal 

Long-Term 

(>6 months) 

Oral NOAEL 

= 0.96 

mg/kg/day 

Dermal 

Absorption 

factor=15.3% 

UFA = 10X 

UFH = 10X 

Occupational LOC for 

MOE<100 

Combined chronic 

toxicity/carcinogenicity 

(rat; dietary) LOAEL = 

24.1/32.8 mg/kg/day 

(M/F) based on 

cumulative decreases in 

body-weight gains.

Inhalation 

(Short- and 

Intermediateterm) 

Oral NOAEL 

= 1.25 

mg/kg/day 

100% 

inhalation 

absorption 

assumed 

UFA = 10X 

UFH = 10X 

Occupational LOC for 

MOE<100 

Reproduction and 

fertility effects (rat; 

dietary) Offspring 

LOAEL = 12.5 

mg/kg/day based on 

reduction in body-weight 

gain of F0 females prior 

to mating, gestation and 

lactation. 

Inhalation 

(Long- term) 

Oral NOAEL 

= 0.96 

mg/kg/day 

100% 

inhalation 

absorption 

assumed 

UFA = 10X 

UFH = 10X 

Occupational LOC for 

MOE<100 

Combined chronic 

toxicity/carcinogenicity 

(rat; dietary) LOAEL = 

24.1/32.8 mg/kg/day 

(M/F) based on 

cumulative decreases in 

body-weight gains.

Cancer (oral, 

dermal, 

inhalation) 

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 dated March 3, 2007, HED Doc. No. 0054532).

Abbreviations: UF = uncertainty factor, UFA = extrapolation from animal to human (interspecies), UFH = 

potential variation in sensitivity among members of the human population (intraspecies), UFFQPA = FQPA 

Safety Factor, NOAEL = no-observed-adverse-effect level, LOAEL = lowest-observed-adverse-effect level, 

RfD = reference dose (a = acute, c = chronic), PAD = population-adjusted dose, MOE = margin of 

exposure, LOC = level of concern. 

3.2 FQPA Considerations

3.2.1. Determination of Susceptibility 
Page 13 of 52

The Hazard Identification Assessment Review Committee (HIARC) determined that the 

available Agency Guideline studies indicated no increased susceptibility of rats or rabbits 

to in utero and/or postnatal exposure to difenoconazole. In the prenatal developmental 

toxicity studies in rats and rabbits and the two-generation reproduction study in rats, 

toxicity to the fetuses/offspring, when observed, occurred at equivalent or higher doses 

than in the maternal/parental animals. In the prenatal developmental toxicity study in 

rats, maternal toxicity was manifested as decreased body weight gain and food 

consumption at the LOAEL of 85 mg/kg/day; the NOAEL was 16 mg/kg/day. The 

developmental toxicity was manifested as alterations in fetal ossifications at 171 

mg/kg/day; the developmental NOAEL was 85 mg/kg/day. In a developmental toxicity 

study in rabbits, maternal and developmental toxicity were seen at the same dose level 

(75 mg/kg/day). Maternal toxicity in rabbits were manifested as decreased in body 

weight gain and decreased in food consumption, while developmental toxicity was 

manifested as decreased fetal weight. In a 2-generation reproduction study in rats, there 

were decreases in maternal body weight gain and decreases in body weights of F1 males 

at the LOAEL of 12.5 mg/kg/day; the parental systemic and off spring toxicity NOAEL 

was 1.25 mg/kg/day. 

3.2.2. Adequacy of Toxicity Database 

There are no data gaps for the assessment of the effects of difenoconazole following in 

utero and/or postnatal exposure. The acute and subchronic neurotoxicity studies in rats 

are available. In an acute neurotoxicity study in rats, reduced fore-limb grip strength was 

observed on day 1 in males. This effect is considered as transient since it was not 

observed at later observation points. In a subchronic neurotoxicity study in rats 

decreased hind limb strength was observed only in males, which was considered as 

nonspecific in nature. Difenoconazole exhibits some evidence of neurotoxicity in the 

database, but the effects are transient or occur at doses exceeding the limit dose. EPA 

concluded that difenoconazole is not a neurotoxic compound. Based on the toxicity 

profile, and lack of neurotoxicity, a developmental neurotoxicity study in rats is not 

required. 

3.2.3. Degree of Concern Analysis: 

Since there is no evidence of susceptibility, there is no concern for increased 

susceptibility due to exposure to difenoconazole. 

3.2.4. FQPA Safety Factor Recommendation 

 

The FQPA factor for increased susceptibility to infant and children is reduced to 1x for 

the following considerations: 

1) toxicology data base for difenoconazole is complete; 

2) there is no indication of increased susceptibility of rats or rabbit fetuses to in utero 

and/or postnatal exposure in the developmental and reproductive toxicity data; 
Page 14 of 52

3) there are no concerns for neurotoxicity; 

4) developmental neurotoxicity study is not required; 

5) there are no residual uncertainties in the toxicology database. 

3.3 Endocrine Disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor 

Screening Program (EDSP) to determine whether certain substances (including pesticide 

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a “naturally occurring estrogen, or other such endocrine effects as the 

Administrator may designate.” The EDSP employs a two-tiered approach to making the 

statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to 

identify the potential of a chemical substance to interact with the estrogen, androgen, or 

thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and 

are found to have the potential to interact with E, A, or T hormonal systems will proceed 

to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests 

are necessary based on the available data. Tier 2 testing is designed to identify any 

adverse endocrine related effects caused by the substance, and establish a dose-response 

relationship between the dose and the E, A, or T effect. 

Between October 2009 and February 2010, EPA issued test orders/data call-ins for the 

first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert 

ingredients. This list of chemicals was selected based on the potential for human 

exposure through pathways such as food and water, residential activity, and certain postapplication agricultural scenarios. This list should not be construed as a list of known or 

likely endocrine disruptors. 

Difenoconazole is not among the group of 58 pesticide active ingredients on the initial 

list to be screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen 

all pesticide chemicals. Accordingly, EPA anticipates issuing future EDSP test 

orders/data call-ins for all pesticide active ingredients. 

For further information on the status of the EDSP, the policies and procedures, the list of 

67 chemicals, the test guidelines and the Tier 1 screening battery, please visit our 

website: http://www.epa.gov/endo/. 

4.0 Public Health and Pesticide Epidemiology Data

Not relevant since these are new uses. 

5.0 Dietary Exposure/Risk Characterization 

5.1 Pesticide Metabolism and Environmental Degradation 

5.1.1 Metabolism in Primary Crops
Page 15 of 52

The nature of the residue in plants is understood based on acceptable plant metabolism 

studies reflecting foliar applications in canola, grape, potato, tomato, and wheat and seed 

treatment in wheat. Based on the results of available plant metabolism studies, the 

petitioner has proposed that difenoconazole is metabolized in plants by the hydroxylation 

of the phenyl ring and/or cleavage of the dioxolane ring followed by cleavage of the 

carbon-carbon bridge between the phenyl and triazole rings. The metabolic pathway 

appears to proceed by hydrolysis of the ketal to the ketone followed by reduction of the 

ketone (CGA-205374) to the alkanol (CGA 205375). CGA 205375 can be conjugated 

with sugars or the bridge linking the phenyl and triazole moieties is cleaved. HED 

concluded that the residue of concern for both tolerance enforcement and risk assessment 

for crops included in this petition is difenoconazole per se. 

5.1.2 Metabolism in Rotational Crops

The nature of the residue in rotational crops is not adequately understood because 

previously conducted studies did not reflect sufficiently high application rates, and/or 

insufficient characterization/identification of residues was achieved. An additional 

confined rotational crop study reflecting phenyl-ring labeling must be conducted at 1x the 

proposed maximum seasonal foliar application rate (0.46 lb ai/A). An acceptable limited 

field rotational crop study is available; these data will be reevaluated when the 

outstanding confined rotational crop study is received. In the meantime, this subject is 

not relevant since this is an import tolerance. 

5.1.3 Metabolism in Livestock 

The nature of the residue in livestock is understood based on acceptable goat and hen 

metabolism studies. The data were originally evaluated in support of seed treatment uses 

only, and HED concluded that the residue of concern in livestock commodities was 

difenoconazole per se. When the first foliar uses of difenoconazole on crop commodities 

were proposed (DP# 340379), HED re-evaluated the livestock metabolism data and 

concluded that the residues of concern for both tolerance setting and risk assessment for 

livestock commodities are difenoconazole and metabolite CGA-205375. 

5.1.4 Analytical Methodology 

An adequate tolerance enforcement method, method AG-575B, is available for crop 

commodities. The method determines residues of difenoconazole per se in/on crop 

commodities by gas chromatography with nitrogen-phosphorus detection (GC/NPD). 

The method limits of quantitation (LOQs) are 0.01-0.05 ppm. A confirmatory GC 

method with mass-selective detection (MSD) is also available for crop commodities. 

Samples from the submitted the crop field trials were analyzed for residues of 

difenoconazole using a high performance liquid chromatography method with tandem 

mass spectrometry detection (LC/MS/MS), Syngenta REM 147.08, or a similar method. 
Page 16 of 52

The methods are adequate for data collection based on acceptable concurrent method 

recoveries. The LOQ was 0.01 ppm for difenoconazole in mango and waxapple. 

5.1.5 Environmental Degradation 

In soil environment, difenoconazole is persistent and slightly mobile. Difenoconazole 

has low potential to reach ground water, except in soils of high sand and low organic 

matter content. It is likely to reach surface sources of drinking water via spray drift and 

runoff. In the aquatic environment its main route of dissipation is partitioning into the 

bottom sediment, and potentially relatively fast to slow aqueous photolysis in clear water 

conditions. 

Major degradates include CGA 205375 which was found in lab accumulation in fish at 

51-64% applied dose, and in aerobic soil at 14.8%, in aerobic aquatic at 11.6% and 

anaerobic aquatic at 12.6% of the applied dose, and CGA 71019 (triazole) and CGA142856 (TAA). Since triazole and TAA are common metabolites from a group of 

chemicals, they should be addressed separately. (See Appendix 4 for structures) 

5.1.6 Comparative Metabolic Profile 

Rat metabolism studies (MRID 42090028 through 31, and 42710013 through14) 

indicated that difenoconazole was rapidly adsorbed and mainly eliminated vis bile. 

Three major urinary metabolites were isolated and further identified as sulfate conjugates 

of CGA 205375, isomers of CGA 205375, and the hydroxyacetic metabolite of CGA 

205375. Further metabolism formed free triazoles. The proposed metabolic pathway in 

rats is presented in Appendix 3. 

Comparisons of the metabolisms indicated that the metabolic pathways in plants, 

livestock, rats, and the environment are very similar or identical, with the formation of 

CGA 205375 and then further metabolism to form free triazole metabolites. 

5.1.7 Toxicity Profile of Major Metabolites and Degradates 

Other than the triazole metabolites, no toxicity information is available on the CGA 

205375 metabolite. Based on structural similarity, it is assumed that the CGA 205375 

shares the same toxicity as the parent. 

5.1.8 Pesticide Metabolites and Degradates of Concern 

The most recent MARC evaluation for difenoconazole was in 1994. In 2007, HED 

reviewers re-evaluated the plant and livestock metabolism studies based on new data 
Page 17 of 52

submitted in conjunction with the new uses. It was concluded that the residue of concern 

for both tolerance enforcement and risk assessment for currently registered crops is 

difenoconazole per se. For livestock, the residues of concern for both tolerance setting 

and risk assessment for livestock commodities are difenoconazole and its metabolite 

CGA-205375. With the subject petition, HED determined that previous conclusions on 

plants and livestock stand. As for drinking water assessment, HED tentatively concludes 

that the residues of concern are parent and CGA 205375. 

5.1.9 Drinking Water Residue Profile

Although the subject petition is for import tolerances and therefore does not result in 

drinking water exposure, there are existing uses of difenoconazole in the U.S. The most 

recent drinking water assessment was conducted for parent compound only. The fate and 

transport database for difenoconazole were sufficient to conduct the drinking water 

assessment. The Tier II drinking water assessment was performed using PRZM (v3.12.2; 

May 12, 2005)/EXAMS (v. 2.98.04.06; April 25, 2005) modeling with index reservoir 

(IR) scenarios and percent cropped area (PCA) adjustment factors. The assessment was 

based on difenoconazole uses on citrus fruits and grapes. These are major crops, with 

difenoconazole maximum application rate to citrus fruits being the highest of all 

agricultural uses, and grapes being the second highest. An initial simulation analysis 

showed that grapes would produce the highest EDWCs of all proposed crop uses with the 

same maximum application rate of 0.46 lb ai/A hence grapes and citrus fruits were 

modeled. 

Florida and California citrus fruit scenarios were modeled for citrus fruits, and New York 

and California grapes scenarios were modeled for grapes. Default PCA of 0.87 was used 

for surface water models. Among all the registered and proposed new uses, the highest 

estimated drinking water concentrations (EDWCs) from surface water sources were 

derived for aerial applications of difenoconazole to New York grapes at the maximum 

annual application rate of 0.46 lb ai/acre. The recommended peak and mean estimated 

drinking water concentrations (EDWCs) for the human health risk assessment are 

provided in Table 1. These estimates exceed the previously EDWCs from 2007 drinking 

water assessment (D333319). 
Page 18 of 52

Table 1. PCA Adjusted Difenoconazole EDWCs from Surface Water Sources. 

Scenario 

Application 

Type/Annual 

Fungicide 

Application Rate 

(lb ai/A) ) 

Estimated Drinking Water Concentrations (μg/L)a

1 in 10 year annual 

peak 

1 in 10 year 

annual mean 

36 year annual 

mean 

NY Grape 

aerially applied 

0.114 x 4 = 0.46 15.8 10.4 7.62 a

 EXAMS EECs multiplied by 0.87, a default PCA factor. 

The highest SCI-GROW estimated drinking water concentration of difenoconazole from 

shallow ground water sources is 1.23 x 10-2 μg/L derived for the maximum proposed 

application rate to citrus fruit (0.50 lb ai/A), i.e. agricultural uses. Based on the previous 

drinking water assessment, this estimate is lower than an estimate for non-agricultural 

uses 1.28 x 10-2 μg/L, obtained for the maximum application rate for ornamentals (0.52 lb 

ai/A; D333319). These concentrations can be considered as both the acute and chronic 

values. 

Currently, no data are available indicating whether water treatment process will increase 

dissipation and/or will form degradation products that may be more toxic than the parent. 

5.1.10 Food Residue Profile

(HED memo of B. Cropp-Kohlligian, 01/21/10, D366507) 

HED has examined the residue chemistry database for difenoconazole and no major 

residue deficiencies will prevent the establishment of permanent tolerances for the 

proposed uses. For details on data deficiencies, please see Section 10.0. 

The nature of the residue in plants is understood based on acceptable plant metabolism 

studies reflecting foliar applications in canola, grape, potato, tomato, and wheat, and seed 

treatment in wheat. HED concludes that the residue of concern for both tolerance 

enforcement and risk assessment for crops included in this petition is difenoconazole per 

se. The nature of the residue in livestock is understood based on acceptable goat and hen 

metabolism studies. The residues of concern for both tolerance setting and risk 

assessment for livestock commodities are difenoconazole per se and its metabolite CGA205375. 

An adequate tolerance enforcement method, method AG-575B, is available for crop 

commodities. The method determines residues of difenoconazole per se in/on crop 

commodities by gas chromatography with nitrogen-phosphorus detection (GC/NPD). 

The method limits of quantitation (LOQs) are 0.01-0.05 ppm. A confirmatory GC 

method with mass-selective detection (MSD) is also available for crop commodities. 

Samples from the submitted the crop field trials were analyzed for residues of 

difenoconazole using a high performance liquid chromatography method with tandem 

mass spectrometry detection (LC/MS/MS), Syngenta REM 147.08, or a similar method. 

The methods are adequate for data collection based on acceptable concurrent method 

recoveries. The LOQ was 0.01 ppm for difenoconazole in mango and waxapple. 
Page 19 of 52

The submitted field trial data for mango are adequate and reflect the proposed use of 

Score® on mango in Brazil. The residue data from the trials conducted will support the 

proposed import tolerance of 0.09 ppm for mango. A Codex MRL for residues of 

difenoconazole per se has been established at 0.07 ppm for mango. To harmonization 

with the established Codex MRL, HED recommends a tolerance of 0.07 ppm for mango. 

HED is unable to assess the adequacy of the submitted field trial data for waxapple at this 

time because the use directions have not been fully elucidated. Syngenta is required to 

provide label use information as detailed under ‘Directions for Use’ section. Assuming 

that the use directions for waxapple in Taiwan, once fully elucidated, will comport with 

the submitted field trial data, HED tentatively recommends for the proposed import 

tolerance of 1.5 ppm for waxapple. 

There are no feedstuffs associated with the foreign uses of difenoconazole on mango in 

Brazil and waxapple in Taiwan. Therefore, no livestock enforcement methods, storage 

stability data, or feeding studies are required to support this petition. 

5.1.11 International Residue Limits

A Codex MRL for residues of difenoconazole per se has been established at 0.07 ppm for 

mango. Canadian and Mexican MRLs have been established for difenoconazole; 

however, no MRLs have been established for mango. No Codex, Canadian, and Mexican 

MRLs have been established for residues of difenoconazole in/on waxapple. 

5.2 Dietary Exposure and Risk

(HED memo of T. Morton, 01/21/10, D371613)

Residue Data used for Acute and Chronic Assessments: 

The unrefined acute analysis assumed tolerance-level residues, 100% crop treated (CT), 

and the available empirical or DEEMTM (ver. 7.81) default processing factors. The 

somewhat refined chronic analysis assumed tolerance-level residues for some 

commodities, average field trial residues for the majority of commodities, the available 

empirical or DEEMTM (ver. 7.81) default processing factors, and 100 % CT. 

The estimated drinking water residues for 1-in-10 year annual peak (15.8μg/L) was used 

for the acute dietary exposure assessment, while 1-in-10 year annual mean (10.4 μg/L) 

was used for chronic. HED notes that degradate CGA 205375 was not included in the 

drinking water assessment; however, the relative amount of CGA 205375 is not 

significant in comparison to the parent. 

DEEM-FCIDTM Program and Consumption Information 

Difenoconazole acute and chronic dietary exposure assessments were conducted using 

the DEEM-FCIDTM (ver. 2.03), which incorporates consumption data from USDA’s 

CSFII (1994-1996 and 1998). The 1994-96, 98 data are based on the reported 
Page 20 of 52

consumption of more than 20,000 individuals over two non-consecutive survey days. 

Foods “as consumed” (e.g., apple pie) are linked to EPA-defined food commodities (e.g., 

apples, peeled fruit - cooked; fresh or N/S; baked; or wheat flour - cooked; fresh or N/S, 

baked) using publicly available recipe translation files developed jointly by USDA/ARS 

and EPA. For chronic exposure assessment, consumption data are averaged for the entire 

U.S. population and within population subgroups, but for acute exposure assessment are 

retained as individual consumption events. Based on analysis of the 1994-96, 98 CSFII 

consumption data, which took into account dietary patterns and survey respondents, HED 

concluded that it is most appropriate to report risk for the following population 

subgroups: the general U.S. population, all infants (<1 year old), children 1-2, children 

3-5, children 6-12, youth 13-19, adults 20-49, females 13-49, and adults 50+ years old. 

Results and Discussion 

The resulting acute food exposure estimates were less than HED’s level of concern (-

<100% of the acute population-adjusted dose (aPAD)) at the 95th percentile of the 

exposure distribution for the general U.S. population (7 % aPAD) and all population subgroups; the most highly exposed population subgroup was children1-2 years old with 16 

% aPAD. The resulting chronic food exposure estimates were less than HED’s level of 

concern (<100% of the chronic population-adjusted dose (cPAD)) for the general U.S. 

population (17 % cPAD) and all population sub-groups; the most highly exposed 

population subgroup was children 1-2 years old with 45 % cPAD. A cancer dietary 

assessment was not conducted for difenoconazole because the cancer NOAEL is higher 

than the chronic RfD; therefore, the chronic dietary risk estimate is more protective. 

Table 5.2a. Summary of Acute Dietary Exposure and Risk for Difenoconazole at the 95th Percentile.

Population Subgroup aPAD (mg/kg/day) Exposure (mg/kg/day) %aPAD 

General U.S. Population 

0.25 

0.017747 7 

All Infants (< 1 year old) 0.0255139 10 

Children 1-2 years old 0.039565 16 

Children 3-5 years old 0.031818 13 

Children 6-12 years old 0.017949 7 

Youth 13-19 years old 0.008828 4 

Adults 20-49 years old 0.013083 5 

Adults 50+ years old 0.017255 7 

Females 13-49 years old 0.013281 5 

The bolded %aPAD is the highest. 

Table 5.2b. Summary of Chronic Dietary Exposure and Risk for Difenoconazole.

Population Subgroup cPAD (mg/kg/day) Exposure (mg/kg/day) %cPAD 

General U.S. Population 0.001709 17 

All Infants (< 1 year old) 0.002445 25 
Page 21 of 52

Table 5.2b. Summary of Chronic Dietary Exposure and Risk for Difenoconazole.

Population Subgroup cPAD (mg/kg/day) Exposure (mg/kg/day) %cPAD 

Children 1-2 years old 

0.01 

0.004484 45 

Children 3-5 years old 0.003624 36 

Children 6-12 years old 0.002061 21 

Youth 13-19 years old 0.001372 14 

Adults 20-49 years old 0.001376 14 

Adults 50+ years old 0.001548 16 

Females 13-49 years old 0.001402 14 

The bolded %cPAD is the highest. 

 

The requested uses of difenoconazole did not result in an increase in dietary 

exposure estimates for free triazole or conjugated triazoles. Therefore, the last 

dietary exposure analyses for the triazole metabolites (M. Negussie, 28 Oct. 2009) 

have not changed. 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

(HED memo of M. Sahafeyan, 11/09/07, D346591) 

6.1 Residential Handler Exposure and Risk Characterization

No new residential uses are being requested at this time. However, adults and 

adolescents may be exposed to difenoconazole from its currently registered use on 

ornamentals. These risks have been previously assessed. Below are the results from 

HED’s previous assessment: 

HED believes residential pesticide handlers will be exposed to short-term duration (1 - 30 

days) only. The dermal and inhalation (short-term) residential exposure was assessed for 

"homeowners" mixer/loader/applicator wearing short pants and short-sleeved shirts as 

well as shoes plus socks using garden hose-end sprayer, “pump-up” compressed air 

sprayer, and backpack sprayer. A MOE of 100 is adequate to protect residential pesticide 

handlers from exposures to difenoconazole. MOEs are >100; therefore are not of 

concern. A summary of these exposures and risks is presented in Table 6.1. 

Table 6.1 Summary of Exposure & Risk for Homeowners Applying Difenoconazole. 

Unit Exposure1

mg ai/lb handled 

Applic. Rate2

lb ai/unit 

Units Treated3

 Avg. Daily Exposure4 

mg ai/kg bw/day 

Short-term 

MOE5

Mixer/Loader/Applicator Using Garden Hose-end Sprayer

Dermal: 

SS&SP 11 

Inhal. 0.017 

0.13 lb ai/A 

0.5 A/day 

Dermal: 

shrtsl&pants 0.00156 

Inhal. 0.0000158 

790 

Mixer/Loader/Applicator Using "Pump-Up" Compressed Air Sprayer 
Page 22 of 52

Dermal: 

SS&SP 38 

Inhal 0.0027 

0.13 lb ai/A 

0.5 A/day 

Dermal: 

shrtsl&pants 0.00539 

Inhal. 0.0000025 

230 

Mixer/Loader/Applicator Using Backpack Sprayer 

Dermal: 

SS&SP 5.1 

Inhal. 0.03 

0.13 lb ai/A 

0.5 A/day 

Dermal: 

shrtslv&pants 0.000725 

Inhal. 0.000028 

1,700 

1. Unit Exposures are taken from “PHED SURROGATE EXPOSURE GUIDE”, Estimates of Worker Exposure from The Pesticide 

Handler Exposure Database Version 1.1, August 1998. Inhal. = Inhalation. Units = mg a.i./pound of active ingredient handled. Unit 

exposures are also taken from ORETF studies OMA 004,OMA006 and from the Draft Residential SOPs, DECEMBER 1997. SS & 

SP = short sleeved shirt and short pants. LS & LP = long sleeved shirt and long pants. 

2. Applic. Rate. = Taken from the draft Inspire® label. 

3. Units Treated are taken the residential SOPs. 

4. Average Daily Dose (ADD) = Unit Exposure * Applic. Rate * Units Treated * absorption factor (15.3 % for dermal) ÷ Body 

Weight (70 kg). 

5. NOAEL = No Observable Adverse Effect Level (1.25 mg a.i./kg bw/day for short-term and intermediate-term dermal and 

inhalation). 

6. MOE = Margin of Exposure = No Observable Adverse Effect Level (NOAEL) ÷ ADD. ADD = dermal + inhalation. 

With respect to residential post-application exposures, current HED policy (see 

ExpoSAC minutes from 8/19/99 and 10/11/01) specifies that no significant postapplication exposure is anticipated from ornamentals, either by residents or 

professional applicators; therefore, no residential post-application assessment was 

conducted. 

7.0 Aggregate Risk Assessments and Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures 

and risks from three major sources: food, drinking water, and residential exposures. In an 

aggregate assessment, exposures from relevant sources are added together and compared to 

quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be 

aggregated. When aggregating exposures and risks from various sources, HED considers 

both the route and duration of exposure. 

7.1 Acute & Chronic Aggregate Risk

Acute and chronic aggregate exposures include food plus drinking water exposures. As 

demonstrated under Section 5.2. Acute and chronic aggregate risks are not of concern. 

7.2 Short- and Intermediate-Term Aggregate Risk

Short-Term Aggregate Risk Assessment: Since a common endpoint has been identified 

for assessment of short-term oral, dermal, and inhalation exposures (changes in body 

weights and body-weight gains) the short-term aggregate risk assessment considered 

exposure from food, water, and residential sources. Since the doses corresponding to the 

identified oral, dermal, and inhalation endpoints were different but the level of concern for 

all three routes of exposure are identical, the short-term aggregate exposures were 
Page 23 of 52

calculated using the 1÷MOE approach. HED combines chronic dietary (food and water) 

exposure estimates with residential exposure estimates when conducting short-term 

aggregate risk assessments. Short-term exposure has been defined as from 1- 30 days and 

HED has concluded that chronic dietary exposure estimates will more accurately reflect 

actual dietary exposure over these time periods than will high-end acute-dietary 

exposures. The proposed residential scenarios result in exposure to only adults. 

Therefore, short-term aggregate assessments were not conducted for infants and children. 

Table 7.2 is a summary of the short-term aggregate exposures and risk estimates. Since 

the aggregate MOEs are ≥180, short-term aggregate exposure to difenoconazole is not of 

concern. 

Table 7.2. Short-Term Aggregate Risk Calculations for Handlers 

Population 

Target 

Aggregate 

MOE1

dietary 

MOE2

dermal + inhalation 

MOE3

agg. MOE 

(dietary and residential)4

Youth 13-19 years old 

100 

910 

230 

180 

Adults 20-49 years old 910 180 

Adults 50+ years old 810 180 

Females 13-49 years old 890 180 1

 total uncertainty factor for all routes of exposure is 100x; therefore, the target MOE is 100. 2

 dietary MOE = short-term incidental oral NOAEL ÷ chronic dietary exposure. 3

 dermal MOE = short-term dermal NOAEL ÷(dermal + inhalation residential exposure) (see text). 4

 aggregate MOE (dietary and residential) = 1÷((1÷MOEdietary) + (1÷MOEdermal) + (1÷MOEinhalation)). 

 

8.0 Cumulative Risk Characterization/Assessment 

Difenoconazole is a member of the triazole-containing class of pesticides. Although 

conazoles act similarly in plants (fungi) by inhibiting ergosterol biosynthesis, there is not 

necessarily a relationship between their pesticidal activity and their mechanism of 

toxicity in mammals. Structural similarities do not constitute a common mechanism of 

toxicity. Evidence is needed to establish that the chemicals operate by the same, or 

essentially the same, sequence of major biochemical events (EPA, 2002). In conazoles, 

however, a variable pattern of toxicological responses is found. Some are hepatotoxic 

and hepatocarcinogenic in mice. Some induce thyroid tumors in rats. Some induce 

developmental, reproductive, and neurological effects in rodents. Furthermore, the 

conazoles produce a diverse range of biochemical events including altered cholesterol 

levels, stress responses, and altered DNA methylation. It is not clearly understood 

whether these biochemical events are directly connected to their toxicological outcomes. 

 Thus, there is currently no evidence to indicate that conazoles share common 

mechanisms of toxicity and EPA is not following a cumulative risk approach based on a 

common mechanism of toxicity for the conazoles. For information regarding EPA’s 

procedures for cumulating effects from substances found to have a common mechanism 

of toxicity, see EPA’s website at http://www.epa.gov/pesticides/cumulative. 
Page 24 of 52

Difenoconazole is a triazole-derived pesticide. This class of compounds can form the 

common metabolite 1,2,4-triazole and two triazole conjugates (triazolylalanine and 

triazolylacetic acid). To support existing tolerances and to establish new tolerances for 

triazole-derivative pesticides, including difenoconazole, U.S. EPA conducted a human 

health risk assessment for exposure to 1,2,4-triazole, triazolylalanine, and triazolylacetic 

acid resulting from the use of all current and pending uses of any triazole-derived 

fungicide. The risk assessment is a highly conservative, screening-level evaluation in 

terms of hazards associated with common metabolites (e.g., use of a maximum 

combination of uncertainty factors) and potential dietary and non-dietary exposures (i.e., 

high end estimates of both dietary and non-dietary exposures). In addition, the Agency 

retained the additional 10X FQPA safety factor for the protection of infants and children. 

 The assessment includes evaluations of risks for various subgroups, including those 

comprised of infants and children. The Agency’s complete risk assessment is found in 

the propiconazole reregistration docket at http://www.regulations.gov, Docket 

Identification (ID) Number EPA-HQ-OPP-2005-0497. 

9.0 Occupational Exposure/Risk Pathway

Not applicable since this is a import tolerance. 

10.0 Data Needs and Label Recommendations

Residue Chemistry 

860.1200 Directions for Use - Waxapple 

• Syngenta must submit a complete description of the use of difenoconazole on 

waxapple grown in Taiwan (a translated label or complete Section B). As 

required by the NAFTA Guidance Document on Data Requirements for 

Tolerances on Imported Commodities in the United States and Canada (December 

2005), it is necessary to submit copies of registered/approved label(s) translated to 

English. The information must include, but is not limited to, the maximum single 

application rate, the maximum annual application rate, application timing (as it 

relates to plant growth stage), retreatment interval, application tank-mix 

preparation, volume of spray mix per unit area, application equipment, and the 

preharvest interval. The application rates should be expressed in units of pounds 

of active ingredient per acre (or kilograms per hectare). 

• Syngenta must submit a complete description of the use of difenoconazole on 

waxapple grown in Taiwan consistent with the use profile of the submitted field 

trial data (MRID 47760601). The submitted field trial data will support eight 

foliar applications of a 125 g/L suspension concentrate (SC) formulation of 

difenoconazole at a target rate of 0.39 kg ai/ha/application (0.34 lb 

ai/A/application), with 6- to 8-day retreatment intervals, for a total rate of 3.07 kg 
Page 25 of 52

ai/ha (2.74 lb ai/A) and a 12-day PHI. Applications may be made using ground 

equipment in 2,000 L/ha spray volumes (214 gal/A which is considered a dilute 

spray volume), without an adjuvant. 

• Consistent with the submitted field trial data, applications should be restricted to 

fruit protected with exclusion net bags or otherwise bagged fruit. 

860.1550 Proposed Tolerances 

• The proposed tolerances should be revised to reflect the recommended tolerance 

levels and correct commodity definitions as specified in Table 12.0. 

Toxicity 

• Immunotoxicity study (870.7800) 

In accordance with Part 158 Toxicology Data requirements, an immunotoxicity study 

(870.7800) is required for difenoconazole. In the absence of specific immunotoxicity 

studies, EPA has evaluated the available difenoconazole toxicity data to determine 

whether an additional database uncertainty factor is needed to account for potential 

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

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

and difenoconazole does not belong to a class of chemicals (e.g., the organotins, heavy 

metals, or halogenated aromatic hydrocarbons) that would be expected to be 

immunotoxic. Therefore, EPA does not believe that conducting immunotoxicity testing 

will result in a point of departure lower than those already selected for difenoconazole 

risk assessment, and an additional database uncertainty factor is not needed to account for 

the lack of this study. 

ORE 

• none 
Page 26 of 52

11.0 References:

1. HED memo of B. Cropp-Kohlligian, 01/28/10, “Difenoconazole. Import 

Tolerance Request on Mango and Waxapple (also known as Wax jambu). 

Summary of Analytical Chemistry and Residue Data. D371612. 

2. HED memo of T. Morton, 01/21/10, “Difenoconazole. Acute and Chronic 

Aggregate Dietary Exposure and Risk Assessments for the Section 3 Registration 

Request for Mango and Wax Apple. D371613. 

3. EFED memo of I. Maher, 05/28/09, Difenoconazole (Parent Only) Drinking 

Water Assessment in Support of New Use Registration Action for Bulb 

Vegetables, Brassica (Cole) Leafy Vegetables, Cucurbit Vegetables, Citrus Fruit, 

Grapes, and Tree Nuts”. 
Page 27 of 52

12.0 Tolerance Summary

The proposed tolerances should be revised to reflect the recommended tolerance levels 

and correct commodity definitions as specified in Table 12.0. 

Table 12.0. Tolerance Summary for Difenoconazole. 

Commodity Proposed Tolerance 

(ppm) 

Recommended Tolerance 

(ppm) 

Comments; 

Correct Commodity Definition

Mango, fruit 0.09 0.07 Mango 

Waxapple, fruit 1.5 1.5 Wax jambu 
Page 28 of 52

13.0 Appendices 

Appendix 1: Acute Toxicity Data on Difenoconazole Technical 

Table 13.0a Acute Toxicity Profile - Difenoconazole

Guideline No. Study Type MRID(s) Results Toxicity Category 

870.1100 Acute oral rat 42090006 LD50 = 1450 

mg/kg 

III 

870.1200 Acute dermal rat 42090007 LD50 > 2010 

mg/kg 

III 

870.1300 Acute inhalation rat 42090008 LC50 > 3.3 mg/L III 

870.2400 Acute eye irritation rabbit 42090009 Mild ocular 

irritation 

reversible in 7 

days 

III 

870.2500 Acute dermal irritation rabbit 42090010 Slight irritation IV 

870.2600 Skin sensitization mouse 42090011, 

42710004 

Negative N/A 
Page 29 of 52

Appendix 2: Subchronic, Chronic and Other Toxicity Profile 

Table 13.0b Subchronic, Chronic and Other Toxicity Profile of Difenoconazole

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3100 90-Day oral 

toxicity (rat) 

42090022 (1987) 

Acceptable/guideline 

0, 20, 200, 750, 1500 or 

3000 ppm 

0, 1, 10, 37.5, 75 and 150 

mg/kg/d 

NOAEL = 20 ppm (1 mg/kg/day) 

LOAEL = 200 ppm (10 mg/kg/day) based on the 10% 

decrease in body weight in the 200 ppm females (as 

well as a negative trend in feed consumption) and 

Increases in absolute liver weights in both sexes 

870.3100 90-Day oral 

toxicity (mouse) 

42090021 (1987) 

Minimum/guideline 

0, 20, 200, 2500, 7500 or 

15,000 ppm 

M: 0, 2.9, 30.8, 383.6, 

1125 and 2250 mg/kg/d 

F: 0, 4.1, 41.5, 558.9, 

1125 and 2250 mg/kg/d 

NOAEL = 20 ppm (2.9 mg/kg/day) 

LOAEL = 200 ppm (30.8 mg/kg/day) based on body 

weight changes & liver histopathology. 

870.3150 26-Week oral 

toxicity 

42090012 (1987) 

Minimum/ guideline 

0, 100, 1000, 3000 or 

6000 ppm 

M: 0, 3.6, 31.3, 96.6 and 

157.8 mg/kg/d 

F: 0, 3.4, 34.8, 110.6 and 

203.7 mg/kg/d 

NOAEL = 3000 ppm (31.3 mg/kg/day in males/34.8 

mg/kg/day in females) 

LOAEL = 6000 ppm (96.6 mg/kg/day in males/110.6 

mg/kg/day in females), based primarily on microscopic 

examination of CGA 169374-related lenticular 

cataracts. 

870.3200 21/28-Day dermal 

toxicity (rat) 

42090013 (1987) 

Minimum/ guideline 

0, 10, 100 and 1000 

mg/kg/d 

NOAEL = 10 mg/kg/day 

LOAEL = 100 mg/kg/day based on statistically 

significant decrements in body weight, body weight 

gain, and food consumption. 

870.3200 21/28-Day dermal 

toxicity (rat) 

46950310 (2000) 

Acceptable/ guideline 

0, 10, 100 and 1000 

mg/kg/d 

NOAEL (systemic) = 1000 mg/kg/day 

LOAEL (systemic) was not determined. 

NOAEL (dermal) = 100 mg/kg/day 

LOAEL (dermal) = 1000 mg/kg/day based on 

hyperkeratosis at the skin application site. 

870.3700a Prenatal 

developmental in 

(rat) 

42090016, 42710007 

(1987) 

Minimum/ guideline 

0, 2, 20, 100 or 200 

mg/kg/d from GD 6-15 

(nominal doses differed 

widely from theoretical, 

this required altering 

NOAEL/LOAEL values) 

Maternal NOAEL = 16 mg/kg/day 

LOAEL = 85 mg/kg/day based on decreased body 

weight gain and food consumption. 

Developmental NOAEL = 85 mg/kg/day 

LOAEL = 171 mg/kg/day based on alterations in fetal 

ossification. 
Page 30 of 52

Table 13.0b Subchronic, Chronic and Other Toxicity Profile of Difenoconazole

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3700b Prenatal 

developmental in 

(rabbit) 

42090017, 42710008 

(1987) 

Minimum/ guideline 

0, 1, 25 or 75 mg/kg/d 

from GD 7-19 

Maternal NOAEL = 25 mg/kg/day 

LOAEL = 75 mg/kg/day based on decreased body 

weight gain and food consumption. Developmental NOAEL = 25 mg/kg/day 

LOAEL = 75 mg/kg/day based on nonsignificant 

increases in postimplantation loss and resorptions/doe 

and a significant decrease in fetal weight. 

870.3800 Reproduction and 

fertility effects 

(rat) 

42090018 (1988) 

Minimum/ guideline 

0, 25, 250 or 2500 ppm 

0, 1.25, 12.5 and 125 

mg/kg/d 

Parental/Systemic NOAEL = 25 ppm (1.25 

mg/kg/day) 

LOAEL = 250 ppm (12.5 mg/kg/day) based on 

reductions (statistically nonsignificant) in body weight 

gain which appear to be part of a dose-related trend 

days 70-77 prior to mating, days 0-7 of gestation, and 

days 7-14 of lactation 

Reproductive NOAEL = 25 ppm (1.25 mg/kg/day) 

LOAEL = 250 ppm (12.5 mg/kg/day) based on a 

significant reduction in the body weight of F1 male 

pups at day 21 in the 250 ppm group. 

870.4100b Chronic toxicity 

(dog) 

42090012, 42710005 

(1988) 

Minimum/ guideline 

0, 20, 100, 500 or 1500 

ppm 

M: 0, 0.71, 3.4, 16.4 and 

51.2 mg/kg/d 

F: 0, 0.63, 3.7, 19.4 and 

44.3 mg/kg/d 

NOAEL = 100 ppm (3.4 mg/kg/day in males/3.7 

mg/kg/day in females) 

LOAEL = 500 ppm (16.4 mg/kg/day in males/19.4 

mg/kg/day in females), based on significant inhibition 

of body weight gain in females. 

870.4200 Carcinogenicity 

(rat) 

42090019, 42710010 

(1989) 

Minimum/ guideline 

0, 10, 20, 500 or 2500 

ppm 

M: o, 0.48, 0.96, 24.12 

and 123.7 mg/kg/d 

F: 0, 0.64, 1.27, 32.79 

and 169.6 mg/kg/d 

NOAEL = 20 ppm (0.96 mg/kg/day in males/1.27 

mg/kg/day in females) 

LOAEL = 500 ppm (24.1 mg/kg/day in males/ 32.8 

mg/kg/day in females) based on reductions in 

cumulative body weight gains in the 500 and 2500 ppm 

groups. 

No evidence of carcinogenicity
Page 31 of 52

Table 13.0b Subchronic, Chronic and Other Toxicity Profile of Difenoconazole

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.4300 Carcinogenicity 

(mouse) 

42090015, 42710006 

(1989) 

Minimum/ guideline 

0, 10, 30, 300, 2500 or 

3000 ppm 

M: 0, 1.51, 4.65, 46.29, 

423.1 and 818.9 mg/kg/d 

F: 0, 1.9, 5.63, 57.79 and 

512.6 mg/kg/d 

NOAEL = 30 ppm (4.7 mg/kg/day in males/5.6 

mg/kg/day in females) 

LOAEL = 300 ppm (46.3 mg/kg/day in males/57.8 

mg/kg/day in females) based on reductions in the 

cumulative body weight gains in the 300, 2500 & 4500 

ppm groups. 

Evidence of carcinogenicity (liver 

adenoma/carcinoma in both sexes)

870.5100 In vitro bacterial 

gene mutation 

(Salmonella 

typhimurium/ E. 

coli)/ mammalian 

activation gene 

mutation assay 

42090019, 42710010 

(1989) 

Minimum/ guideline 

340 - 5447 μg/plate; 

85 - 1362 μg/plate 

(repeat assay with 

TA1537 and TA98) 

There were sufficient and valid data to conclude that 

CGA 169374 technical was negative in the microbial 

gene mutation assay. 

870.5300 in vitro mammalian 

cell gene mutation 

assay in mouse 

lymphoma cells 

42090024 (1986) 

Unacceptable/ guideline 

No conclusion can be reached from the three 

nonactivated and two S9 activated mouse lymphoma 

forward mutation assays conducted with 

difenoconazole technical. The study was seriously 

compromised. 

870.5375 In vitro

Mammalian 

Cytogenetics 

(chromosomal 

aberrations) assay 

in Chinese hamster 

CHO cells 

46950319 (2001) 

Acceptable/ guideline 

0, 21.99, 27.49, or 34.36 

μg/mL (-S9) 

0, 34.36, 53.69 or 67.11 

μg/mL (+S9) 

There was evidence of a weak induction of structural 

chromosomal aberrations over background in the 

presence of S9-mix. 

870.5375 In vitro

Mammalian 

Cytogenetics 

(chromosomal 

aberrations) assay 

in Chinese hamster 

CHO cells 

46950321 (2001) 

Acceptable/ guideline 

0, 26.3, 39.5 or 59.3 

μg/mL (-S9) 

0, 11.7 or 17.6 μg/mL 

(+S9) 

There was evidence of a weak induction of structural 

chromosomal aberrations over background. 
Page 32 of 52

Table 13.0b Subchronic, Chronic and Other Toxicity Profile of Difenoconazole

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.5375 In vitro

Mammalian 

Cytogenetics 

(chromosomal 

aberrations) assay 

in human 

lymphocytes 

46950323 (2001) 

Acceptable/ guideline 

0, 5, 30 or 75 μg/mL (-

S9) 

0, 5, 30 or 62 μg/mL

(+S9) 

There was no evidence of structural chromosomal 

aberrations induced over background. 

870.5385 In vivo mammalian 

chromosomal 

aberration test 

Assay in Mice 

42090023 (1986) 

Unacceptable/guideline 

250, 500 or 1000 mg/kg 

There was no evidence of a cytotoxic effect on the 

target organ or significant increase in the frequency of 

nuclear anomalies (micronuclei). However, the study 

was compromised. 

870.5395 In vivo mammalian 

cytogenetics - 

erythrocyte 

micronucleus assay 

in mice 

41710011 (1992) 

Acceptable/guideline 

Doses up to 1600 mg/kg 

Mice bone marrow - No increase in micronucleated 

polychromatic erythrocytes occurred with CGA-1 

69374 (91.2% a.i). 

870.5550 Unscheduled DNA 

Synthesis in 

Mammalian Cells 

in Culture 

4210012 (1992) 

Acceptable/ guideline 

Doses up to 50 μg/mL 

CGA-i69374 tech. (92.2% a.i.) was considered to be 

negative in the unscheduled DNA synthesis assay in rat 

primary hepatocytes as measured by an 

autoradiographic method at concentrations up to 50.0 

μg/mL. 

870.5550 Unscheduled DNA 

Synthesis in 

Mammalian Cells 

in Culture 

42090027 (1985) 

Unacceptable/ guideline 

0.25-31.25 μg/mL 

No conclusion can be reached from the unscheduled 

DNA synthesis (UDS) primary rat hepatocyte assay 

conducted with difenoconazole technical at 

concentrations ranging from 0.25 to 31.25 μg /mL. The 

sensitivity of the study was severely compromised. 

870.5550 Unscheduled DNA 

Synthesis in 

Mammalian Cells 

in Culture

42090026 (1985) 

Unacceptable/ guideline 

0.08-10 μg/mL 

No conclusion can be reached from the unscheduled 

DNA synthesis (UDS) human fibroblast assay 

conducted with difenoconazole tech. at conc. ranging 

from 0.08 to 10 μg /mL. 

870.6200a Acute neurotoxicity 

screening battery 

46950327 (2006) 

Acceptable/ guideline 

0, 25, 200 or 2000 

mg/kg/d 

NOAEL (M) = 25 mg/kg/day 

LOAEL (M) = 200 mg/kg/day based on reduced forelimb grip strength in males on day 1 and increased 

motor activity on Day 1. 

NOAEL (F) = 200 mg/kg/day 

LOAEL (F) = 2000 mg/kg/day based on decreased 

body weight, the following clinical signs: upward 

curvature of the spine, tip-toe gait, decreased activity, 

piloerection and sides pinched in and decreased motor 

activity.
Page 33 of 52

Table 13.0b Subchronic, Chronic and Other Toxicity Profile of Difenoconazole

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.6200b Subchronic 

neurotoxicity 

screening battery 

46950329 (2006) 

Acceptable/ guideline 

0, 40, 250, or 1500 ppm 

M; 0, 2.8, 17.3 or 107.0 

mg/kg/d 

F: 0, 3.2, 19.5, or 120.2 

mg/kg/d 

NOAEL (M) = 40 ppm (2.8 mg/kg/day) 

LOAEL (M) = 250 ppm (17.3 mg/kg/day) based on

decreased hind limb strength. 

NOAEL (F) = 250 ppm (19.5 mg/kg/day) 

LOAEL (F) = 1500 (120.2 mg/kg/day) based on

decreased body weight, body weight gain and food 

efficiency. 

870.7485 Metabolism and 

pharmacokinetics 

(rat) 

42090028 (1990) 

Acceptable/ guideline 

14 daily doses of 0.5 or 

300 mg/kg 

The absorption, distribution, metabolism, and excretion 

of CGA 169374 were studied in groups of male and 

female Sprague-Dawley rats. Animals were 

administered a single oral gavage dose of 0.5 or 300 

mg/kg [14C]CGA- 169374, or 0.5 mg/kg unlabeled 

GGA-169374 by gavage for 14 days followed by a 

single gavage dose of 0.5 mg/kg [14C)CGA-169374 on 

day 15. The test compound was labeled with C14 at 

either the phenyl or triazole ring. 

870.7485 Metabolism and 

pharmacokinetics 

(rat) 

42090031 (1988) 

Acceptable/ guideline 

0.5 or 300 mg/kg 

These studies indicate that distribution, metabolism, 

and elimination of CGA-169374 were not sex related. 

There was a slight dose difference in the metabolism 

and elimination of CGA-169374. In phenyl and triazole 

labeling studies, fecal excretion of radioactivity was 

higher in the high dose animals compared to the low 

dose animals, and an additional metabolite was found 

in the feces of the high dose animals compared to the 

low dose animals. There was no major difference in the 

distribution and excretion of radioactivity with labeling 

at the phenyl and triazole ring positions, however, there 

were some different metabolites identified. The studies 

also showed that administration of 0.5 and 300 mg/kg 

CGA- 169314 did not induce any treatment related 

clinical effects. 

870.7485 Metabolism and 

pharmacokinetics 

(rat) 

420710013, 42710014 

(1990) 

Acceptable/ guideline 

0.5 or 300 mg/kg 

These two studies described the absorption, 

distribution, and excretion as the pharmacokinetics and 

isolated and identified urinary metabolites. Issues 

raised in the previous supplementary studies were 

answered. In conjunction with these studies, the 

previous studies are upgraded. 
Page 34 of 52

Table 13.0b Subchronic, Chronic and Other Toxicity Profile of Difenoconazole

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.7485 Metabolism and 

pharmacokinetics 

(rat) 

42090029 (1987) 

Acceptable/ guideline 

[14C]CGA-169374 was rapidly and extensively 

distributed. metabolized, and excreted in rats for all 

dosing regimens. The extent of absorption is 

undetermined pending determination of the extent of 

biliary excretion. The 4-day recoveries were 97.4- 

107.75% of the administered dose for all dosing groups. 

The elimination of radioactivity in the feces (78.06- 

94.61% of administered dose) and urine (8.48-21.86%) 

were almost comparable for all oral dose groups, with 

slightly higher radioactivity found in the feces of the 

high dose group than the low dose groups. This was 

probably due to biliary excretion, poor absorption or 

saturation of the metabolic pathway. The radioactivity 

In the blood peaked at about 24-48 hours for all dosing 

groups. Half-lives of elimination appear to be 

approximately 20 hours for the low dose groups and 33 

- 48 hours for the high dose group. The study results 

also indicate that CGA-1 69374 and/or its metabolites 

do not bioaccumulate to an appreciable extent 

following oral exposure since all the tissues contained 

negligible levels (<1%) of radioactivity 7 days 

postexposure. 

870.7485 Metabolism and 

pharmacokinetics 

(rat) 

42090030 (1987) 

Acceptable/ guideline 

The metabolism of CGA-169374 appears to be 

extensive because the metabolites accounted for most 

of the recovered radioactivity in the excreta. Three 

major metabolites were identified in the feces (i.e., A, 

B, and C). Two of the metabolites were separated into 

isomers (i.e., A1, A2, B1, and B2). Metabolite C was 

detected only In the high dose groups, indicating that 

metabolism of CGA-169374 is dose related and 

involves saturation of the metabolic pathway. Free 

triazole metabolite was dete6ted in the urine of triazole 

labeled groups and its byproduct was detected In the 

liver of phenyl labeled groups only. Other urinary 

metabolites were not characterized. 
Page 35 of 52

Table A.1.3. Subchronic, Chronic and Other Toxicity Profile of Difenoconazole Metabolites 

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.5100 In vitro Bacterial 

Gene Mutation 

(Salmonella 

typhimurium/ E. 

coli)/ mammalian 

activation gene 

mutation assay 

46950314 (1991) 

Unacceptable/ guideline 

0, 31.3, 62.5, 125, 250, 

500 or 1000 μg/plate in 

strains TA100 and 

TA1537 (-S9) 

0, 31.3, 62.5, 125, 250, 

500 or 1000 μg/plate in 

all strains (+S9) 

0, 62.5, 125, 250, 500, 

1000 or 2000 μg/plate in 

strains TA1535, WP2 

uvrA and TA98 (-S9) 

0, 62.5, 125, 250, 500, 

1000 or 2000 μg/plate in 

strains WP2 uvrA (+S9) 

The number of revertants per plate was not increased 

over the concurrent solvent control value at any test 

material concentration, with or without S9-mix, in any 

tester strain. The solvent and positive controls induced 

the appropriate responses in the corresponding strains. 

There was no evidence of induced mutant colonies over 

background. 

Tested: CGA-189138 (metabolite of difenoconazole) 

870.5100 In vitro Bacterial 

Gene Mutation 

(Salmonella 

typhimurium/ E. 

coli)/ mammalian 

activation gene 

mutation assay 

46950315 (1991) 

Unacceptable/ guideline 

0, 156, 313, 625, 1250, 

2500 or 5000 μg/plate 

(±S9) 

The number of revertants per plate was not increased 

over the concurrent solvent control value at any test 

material concentration, with or without S9-mix, in any 

tester strain. The solvent and positive controls induced 

the appropriate responses in the corresponding strains. 

There was no evidence of induced mutant colonies over 

background. 

Tested: CGA205374 (metabolite of difenoconazole) 

870.5100 In vitro Bacterial 

Gene Mutation 

(Salmonella 

typhimurium/ E. 

coli)/ mammalian 

activation gene 

mutation assay 

46950317 (1991) 

Unacceptable/ guideline 

0, 2.50, 5.00, 10.0, 20.0, 

40.0 or 80.0 μg/plate in 

all strains (-S9) 

0, 5.00, 10.0, 20.0, 40.0, 

80.0 or 160 μg/plate in 

strains TA100 and 

TA1535 (+S9) 

0, 10.0, 20.0, 40.0, 80.0, 

160 or 320 μg/plate in 

strains WP2 uvrA and 

TA1537 (-S9) 

0, 2.50, 5.00, 10.0, 20.0, 

40.0, or 80.0 μg/plate in 

strain TA98 (+S9) 

The number of revertants per plate was not increased 

over the concurrent solvent control value at any test 

material concentration, with or without S9-mix, in any 

tester strain. The solvent and positive controls induced 

the appropriate responses in the corresponding strains. 

There was no evidence of induced mutant colonies 

over background.

Tested: CGA205375 (metabolite of difenoconazole) 
Page 36 of 52

EXECUTIVE SUMMARIES OF SOME STUDIES: 

STUDY TYPE: 28-Day Dermal Toxicity – Rat 

(OPPTS 870.3200 [§82-2] (rodent); OECD 410). 

CITATION: Gerspach, R. Difenoconazole: 28-Day Repeated Dose Dermal Toxicity 

Study in Rats. Novartis Crop protection AG Toxicology (Switzerland). Novartis Report 

Number: 993072; Syngenta Report Number: T002728-06. July 11, 2000, MRID 

46950310 and MRID 46950311. Unpublished. 

EXECUTIVE SUMMARY: In a 28-day dermal toxicity study (MRID 46950310) CGA 

169374 Technical (91.8% a.i., Batch No. P807002) was applied to the shaved skin of ten 

male and ten female rats at dose levels of 0, 10, 100 and 1000 mg/kg bw/day. There were 

no treatment-related effects on body weight or food consumption. Non clinical signs of 

toxicity were noted including specific indicators of neurotoxicity. The dose level of 1000 

mg/kg bw/day caused hyperkeratosis at the skin application site. A high incidence of 

follicular cell hypertrophy of the thyroid was observed in males and females of control 

and all treatment groups and variations with dose are not considered treatment-related. 

Minimal inconsequential changes were noted on clinical chemistry parameters in high 

dose males that were not relevant toxicologically. The incidence and severity was 

increased in animals in the highest dose group. There was an increase in the absolute 

(12%) and relative (16%) weight of the liver in males in the high dose group 

accompanied by an increased incidence of slight hepatocellular hypertrophy (7/10) 

compared to controls (2/10). Females in the high dose group also had an increase in the 

relative weight of the liver (10%) with an increased incidence of slight hepatocellular 

hypertrophy (7/10) compared to controls (1/10). These effects are consistent with 

adaptive responses of the liver. 

A systemic LOAEL for male and female rats was not established. The NOAEL for 

male and female rats is 1000 mg/kg bw/day. 

A dermal irritation LOAEL for male and female rats is 1000 mg/kg bw/day based 

on hyperkeratosis at the skin application site. The dermal NOAEL for male and 

female rats is 100 mg/kg bw/day. 

This 28-day dermal toxicity study in the Fischer 344 rat is Acceptable/Guideline and 

satisfies the guideline requirement for a 28-day dermal toxicity study (OPPTS 870.3200; 

OECD 410) in the rat. 

STUDY TYPE: Acute Neurotoxicity - Rats OPPTS 870.6200a [§81-8]; OECD 424. 

CITATION: Pinto, P.J. (2006) Difenoconazole Technical (CGA169374): Acute 

Neurotoxicity Study in Rats. Central Toxicology Laboratory (Cheshire, 

UK). Laboratory report number AR7517-REG-R1, July 28, 2006. MRID 
Page 37 of 52

46950327. Unpublished. 

 Pinto, P.J. (2006) Difenoconazole Technical (CGA169374): Preliminary Acute 

Neurotoxicity Study in Rats. Central Toxicology Laboratory (Cheshire, 

UK). Laboratory report number AR7518-REG, June 16, 2006. MRID 

46950325. Unpublished. 

EXECUTIVE SUMMARY: In an acute neurotoxicity study (MRID 46950327), groups 

of fasted Alpk:APfSD Wistar-derived rats (10/sex/dose), at least 42 days old, were given 

a single oral dose of difenoconazole technical (CGA169374) (94.3% w/w, batch/lot # 

WM806228) in 1% w/v aqueous carboxymethylcellulose (CMC) at doses of 0, 25, 200, 

or 2000 mg/kg bw and observed for 14 days. Dose levels selected for this study were 

based on the results of a preliminary acute neurotoxicity study (MRID 46950325). 

Neurobehavioral assessment (functional observational battery and motor activity testing) 

was performed on 10 animals/sex/group on days -7, 1, 8, and 15. Body weight and food 

consumption were measured weekly throughout the study. At study termination, 5 

animals/sex/group were euthanized and perfused in situ for neuropathological 

examination; brain weight was recorded from these animals. Of the perfused animals, 5 

animals/sex from the control and high dose groups were subjected to histopathological 

evaluation of brain and peripheral nervous system tissues. 

There were no unscheduled deaths at any dose level. Weight change on the day of dosing 

by the control, low-, mid-, and high-dose groups was -2.1, -1.0, -7.8, and -18.3 g, 

respectively, for males and 0.0, 2.1, -3.8, and -13.0 g, respectively, for females. Body 

weight for females had recovered to control levels by day 8. Food consumption for 

males given 2000 mg/kg was approximately 20% less than control during week 1 only 

(p<0.01). Food consumption for these animals recovered to control levels during week 2. 

 There were no differences from control for females at any dose level or for males at the 

lower dose levels. These effects on body weight and food consumption were not 

toxicologically significant. 

At 2000 mg/kg, a number of adverse clinical signs were observed on day 1 (at the time of 

peak effect), including: upward curvature of the spine (8 males, 9 females); tip-toe gait 

(3, 8); decreased activity (6, 7); piloerection (3, 5); sides pinched in (3, 7); and subdued 

(1, 0). Females were affected more than males. All treatment-related clinical signs 

observed on day 1 showed complete recovery by day 5 (males) or day 7 (females). 

Significant decreases in fore-limb grip strength were seen in mid- (↓23%) and high-dose 

(↓26%) males on day 1. Females dosed with 2000 mg/kg had lower motor activities on 

day 1 (37%), at the time of peak effect, and on day 8 (31%). Males dosed with 200 or 

2000 mg/kg had higher motor activities than the controls on day 1, 50% and 55%, 

respectively, at the time of peak effect. 

There were no effects on brain weight at any dose level. Neuropathological 

examination of the central and peripheral nervous system showed no effects of 

treatment at doses of 2000 mg/kg in both sexes. 
Page 38 of 52

The LOAEL for acute neurotoxicity of difenoconazole technical (CGA169374) in 

male rats is 200 mg/kg bw based on reduced fore-limb grip strength in males on 

day 1 and increased motor activity on Day 1. The NOAEL is 25 mg/kg bw. 

The LOAEL for acute neurotoxicity of difenoconazole technical (CGA169374) in 

female rats is 2000 mg/kg bw based on decreased body weight, the following 

clinical signs: upward curvature of the spine, tip-toe gait, decreased activity, 

piloerection and sides pinched in and decreased motor activity. The NOAEL is 200 

mg/kg bw. 

This acute neurotoxicity study is classified as Acceptable/Guideline and satisfies the 

guideline requirement for an acute neurotoxicity study in rats (870.6200; OECD 424). 

Positive control data have been submitted for review and were considered acceptable.

STUDY TYPE: Subchronic Neurotoxicity, OPPTS 870.6200b [§82-7] feeding - rat; 

(OECD 424). 

CITATION: Pinto, P J. (2006). Difenoconazole technical (CGA 169374) subchronic 

neurotoxicity study in rats, final report. Central Toxicology Laboratory, 

Alderley Park, Macclesfield, Cheshire, UK SK 10 4TJ. Report number 

PR1330-REG-R1. July 28, 2006. MRID 46950329. Unpublished. 

 Pinto, P.J. (2006). Difenoconazole technical (CGA 169374) 28-day dietary 

rangefinding study in rats, final report. Central Toxicology Laboratory, 

Alderley Park, Macclesfield, Cheshire, UK SK 10 4TJ. Report number 

KR1606-REG. June 13, 2006. MRID 46950326. Unpublished. 

 

 Alexander, O. (2006) Difenoconazole technical (CGA 169374) subchronic 

neurotoxicity study in rats – study profile. Syngenta Crop Protection, Inc., 

410 Swing Road, P.O. Box 18300, Greensboro, NC 27419-8300. Report 

number PR1330-REG-R1. September 19, 2006. MRID 46950330. 

Unpublished. 

EXECUTIVE SUMMARY: In a subchronic neurotoxicity study (MRID 46950329) 

difenoconazole technical (94.5% w/w, batch no. WM806228) was administered to groups 

of 12 male and 12 female Alpk:APfSD (Wistar-derived) rats at concentrations of 0, 40, 

250, or 1500 ppm in the diet for 90 days. Respective dose levels corresponded to 0, 2.8, 

17.3 or 107.0 mg/kg bw/day for males and 0, 3.2, 19.5, or 120.2 mg/kg bw/day for 

females. Neurobehavioral assessment (functional observational battery and motor 

activity testing) was performed in 12 animals/sex/group pretest and during weeks 2, 5, 9, 

and 14. Cholinesterase activity was not determined. At study termination, 5 

animals/sex/group were euthanized and perfused in situ for neuropathological 

examination. Of the perfused animals, 5/sex from the control group and 5/sex from the 

1500 ppm group were subjected to histopathological evaluation of brain and peripheral 

nervous system tissues. 
Page 39 of 52

Treatment with difenoconazole at concentrations up to 1500 ppm in the diet had no effect 

on mortality or clinical signs. Relative to respective control weight, final body weight of 

males and females in the 1500 ppm group was reduced by 9% and 7%. Body weight gain 

was reduced by 22% in males and 23% in females. Food consumption was reduced in 

this group (statistically significant only in females [7%]), and food efficiency was 

significantly reduced in males by 21% (p≤0.05) and in females by 21% (ns). Lower dose 

groups were unaffected. Absolute liver weight in males and females in the 1500 ppm 

group was increased over respective control weight by 38% and 45%. Liver was not 

weighed in lower dose groups. The increase in liver weight was considered a normal 

response to chemical treatment. 

During weeks 2, 9 and 14, hind-limb grip strength in males in the 1500 ppm group was 

reduced by 18 to 27% relative to the control values. At week 14, hind-limb grip strength 

in males in the 250 ppm group was significantly (p≤0.05) reduced by 20% relative to the 

control values. FOB observations in females were unaffected by treatment. Motor 

activity was unaffected in both sexes at all observation times. Brain weight was 

unaffected by treatment and there were no treatment-related neuropathological lesions. 

The LOAEL in male rats is 250 ppm in the diet (17.3 mg/kg bw/day), based on 

decreased hind limb strength. The NOAEL is 40 ppm (2.8 mg/kg bw/day). 

The LOAEL in female rats is 1500 ppm in the diet (120.2 mg/kg bw/day), based on 

decreased body weight, body weight gain and food efficiency. The NOAEL is 250 

ppm (19.5 mg/kg bw/day). 

The study is classified as Acceptable/Guideline and does satisfies the guideline 

requirement for a subchronic neurotoxicity study in rats (870.6200b). Positive control 

data have been submitted for review and were considered acceptable. 

STUDY TYPE: Rodent In Vivo Dermal Penetration Study – Rat 

OPPTS 870.7600 [§85-2]; OECD none.

CITATION: Hassler, S. (2003) Difenoconazole 250 EC (A7402G): Dermal absorption 

of [Triazole-U-14C] CGA 169374 formulated as Score® 250 EC (A7402G) in the rat (in vivo). Syngenta Crop Protection AG, Health 

Assessment/Animal Metabolism CH-4002 Basel, Switzerland. Syngenta 

Number T002729-06, May 6, 2003. MRID 46950333. Unpublished. 

EXECUTIVE SUMMARY: In a dermal penetration study (MRID 46950333), 

[Triazole–U-14C] CGA 169374 (radiolabled: batch # 50.2-1 and 50.2-2 contained 98 and 

99.3% a.i., respectively; nonradiolabeled: batch # AMS 255/3 contained 99.3% a.i.) 

formulated as Score® 250 EC (A-7402G) was administered to 16 male HanBrl: WIST 

(SPF) rats/dose to a skin area of 10 cm2

 at nominal dose levels of 0, 0.005, 0.0125, and 

2.5 mg/cm2

 skin. The 2.5 mg/cm2 dose was repeated because of a high variability in the 

results of the washing procedure. Measured dose levels were 0.005, 0.0130, 2.4, and 2.6 
Page 40 of 52

mg/cm2 for the low, mid, and high dose and high dose repeat groups, respectively. 

Exposure duration was 6 hours and animals were monitored for 6, 24, 48, or 72 hours. 

The remaining discussion of dermal penetration at the high dose will include only the 

“high-dose repeat” data (i.e., the results of the first high-dose exposure will not be 

discussed). Recovery of the applied dose was acceptable with group means ranging from 

95.44 to 103.67%. Results were not adjusted for incomplete recovery of the applied 

dose. The majority of the applied dose was recovered in the skin wash, accounting for 

49-69%, 73-78%, and 76-86% of the low, mid, and high dose, respectively. The amount 

of the applied dose retained at the application site was 8-12%, 3-5%, and 2-5% of the 

low, mid, and high dose, respectively. At the low and mid dose, the major part of the 

radioactivity remaining in the skin was associated with the stratum corneum (7-11% and 

2-5%, respectively), while only 1-2% of the high dose was recovered in the upper skin 

layer. Dermal absorption (sum of blood, carcass, urine, feces, skin test site, 

gastrointestinal tract, untreated skin, and cagewash) accounted for 15-38%, 7-15%, and 

3-11% of the low, mid, and high doses, respectively. Of the test substance systemically 

absorbed, excretion into the feces was generally the primary route of elimination, 

accounting for up to 18%, 8%, and 2% of the low, mid, and high doses, respectively. Of 

the radioactivity remaining in the animal 72 hours after application, the gastrointestinal 

tract contained 3.0%, 1.4%, and 0.3% of the low, mid, and high doses, respectively, and 

the carcass contained 1.5%, 0.7%, and 1.1%, respectively. Blood concentrations during 

and after the exposure period were at or below the limits of determination. Based on the 

limited blood concentration data available, maximum blood concentrations were 

measured between 6-8 hours after dose application. 

 

Based on the amount of radioactivity entering the systemic circulation within 6 hours of 

exposure, the calculated penetration rates at the low, mid, and high doses were 0.013, 

0.162, and 30.4 μg cm-2 h-1, respectively. The penetration rates increased somewhat 

proportionally with the increase of the test substance concentration at the three dose 

levels (1:26:5100 for the concentration ratio of the dose levels versus 1:12:2300 for the 

ratio of the penetration values). 

This study in the rat is unacceptable/guideline and does not satisfy the guideline 

requirement for a dermal penetration study (870.7600) in rats. Major deficiencies include 

uncertainty in the ability of the laboratory to perform the experiment, and only one 

exposure duration was tested (6 hours), despite minimum Guideline recommendations for 

durations of 1, 10, and 24 hours. See “Study Deficiencies” for listing of numerous minor 

deficiencies. 

STUDY TYPE: In Vitro Dermal Penetration Study – Rat and Human 

OPPTS 870.7600 [§85-2]; OECD none.

CITATION: Hassler, S. (2003) Difenoconazole 250 EC (A7402G): The percutaneous 

penetration of [Triazole-U-14C] CGA 169374 formulated as Score® 250 

EC (A-7402G) through rat and human split-thickness skin membranes (in 

vitro). Syngenta Crop Protection AG, Health Assessment/Animal 

Metabolism CH-402 Basel, Switzerland. Syngenta Number T002730-06, 
Page 41 of 52

April 9, 2003. MRID 46950332. Unpublished. 

EXECUTIVE SUMMARY: In an in vitro percutaneous penetration study (MRID 

46950332), [Triazole–U-14C] CGA 169374 (98% a.i., batch number 50.2-1) mixed with 

nonradiolabeled CGA 169374 (batch number AMS 255/3 containing 99.3% a.i.) 

formulated as SCORE 250® (A-7402) was applied to skin membranes prepared from rat 

[male HanBrl: WIST (SPF)] and human (cadaver) abdominal skin. Percutaneous 

absorption at low, mid, and high doses of 0.5, 12.5, or 2500 μg/cm2

 (actual applied doses 

of 0.5, 12, or 2345 μg/cm2

) was assessed over 24 hours. 

Results clearly indicate that transfer of [Triazole–U-14C] CGA 169374 across skin 

membrane was notably greater for the rat skin membrane than for human skin membrane 

as shown by flux values that were 10-, 12-, and 32-fold greater for the low, mid, and high 

concentrations, respectively. A concentration-dependent absorption was also indicated 

by greater flux values with increasing concentration: flux values at the low, mid, and high 

doses for the rat skin membranes were 0.020, 0.455, and 26.2 ug/cm2, respectively, and 

for human skin membranes were 0.002, 0.037, and 0.822 ug/cm2, respectively. The 

increasing flux values resulted in greater absolute amounts of test article being 

transferred across the skin membranes with increasing concentration: values at the low, 

mid, and high doses for the rat skin membranes were 0.35, 7.7, and 539.2 ug/cm2, 

respectively, and for human skin membranes were 0.04, 0.84, and 15.6 ug/cm2

, 

respectively. However, the percutaneous absorption was decreased, indicating saturated 

kinetics (absorption values at the low, mid, and high doses expressed as percent of 

applied dose for the rat skin membranes were 71%, 64%, and 23%, respectively, and for 

human skin membranes were 8%, 7%, and 0.7%, respectively). 

This in vitro percutaneous absorption study in the rat is acceptable/nonguideline, but 

does not satisfy the guideline requirement for a dermal penetration study (870.7600) in 

rats. The study is a specialty study and was designed to provide only supplemental 

information to the OPPTS 870.7600 requirement. Results of this study provide 

information on the differences in dermal absorption between rat and human skin 

membranes. 

STUDY TYPE: In vitro Mammalian Cytogenetics (chromosomal aberrations) assay 

in Chinese hamster CHO cells; OPPTS 870.5375 [§84-2]; OECD 

473 

CITATION: Lloyd, M. (2001) Difenoconazole Technical: Induction of chromosome 

aberrations in cultured Chinese hamster ovary (CHO)cells. Covance 

Laboratories Ltd., Otley Road, Harrogate, North Yorkshire HG3 1PY, 

England. Laboratory Project ID: Covance Number 252/293, Syngenta 

Number T002874-06, December 11, 2001. MRID 46950319. Unpublished 

EXECUTIVE SUMMARY: In a mammalian cell cytogenetics assay (Chromosomal 

aberrations) (MRID 46950319), Chinese hamster CHO cells in culture were exposed to 
Page 42 of 52

CGA 169374 Technical (94.3% w/w, Lot No. WM806228) in DMSO for three hours at 

concentrations of 0, 21.99, 27.49, or 34.36 μg/mL without metabolic activation (S9-mix) 

and at concentrations of 0, 34.36, 53.69 or 67.11 μg/mL with S9-mix. Cells were 

harvested 17 hours following the end of exposure. Cells were exposed in a second 

confirmatory study for three hours at concentrations of 0, 21.99, 27.49 or 34.36 μg/mL 

without S9-mix and for three hours at concentrations of 0, 34.36, 53.69, 67.11 or 83.89 

μg/mL with S9-mix. Cells were harvested 17 hours following exposure. Cells were 

evaluated for the presence of structural chromosomal aberrations and for numerical 

aberrations (polyploidy, endoreduplication and hyperploidy). The S9-fraction was 

obtained from Aroclor 1254 induced male Sprague-Dawley rat liver. 

CGA 169374 Technical was tested up to cytotoxic concentrations as evidenced by a 

dose-related reduction in mitotic activity seen with and without S9-mix. There was a 

statistically significant increase in the percentage of cells with structural chromosomal 

aberrations at a CGA 169374 Technical concentration of 34.36 μg/mL without S9-mix in 

the first study. The slides were rescored to determine if aberrations at the fragile X site 

were present. Aberrations at the fragile X site are not likely relevant to clastogenicity. 

Aberrations at the fragile X site were not found but the values obtained on rescoring were 

within the historical solvent control range. There was no clear reason given why the 

percent of aberrant cells was lower when the slides were rescored. Possibly the 

distribution of cells on the slides was uneven. The increase at this dose without S9-mix 

was not seen in the confirmatory assay and thus the increase was not considered 

biologically significant. A statistically significant increase in the percent of aberrant cells 

was seen in the first study at 67.11 μg/mL with S9-mix. The statistical significance 

remained upon rescoring and all values exceeded the historical solvent control range. No 

statistically significant increase was seen at this or a higher concentration in the 

confirmatory study with S9-mix. The failure to see a significant increase in the percent 

of aberrant cells in the confirmatory study makes the results equivocal. The solvent and 

positive controls (4-Nitroquinoline 1-oxide without S9-mix and cyclophosphamide with 

S9-mix) induced the appropriate responses. There was evidence of a weak induction of 

structural chromosomal aberrations over background in the presence of S9-mix.

This study is classified as Acceptable/Guideline and satisfies the guideline requirement 

for OPPTS 870.5375; OECD 473 for in vitro cytogenetic mutagenicity data. 

STUDY TYPE: In vitro Mammalian Cytogenetics (chromosomal aberrations) assay 

in Chinese hamster CHO cells; OPPTS 870.5375 [§84-2]; OECD 

473

CITATION: Ogorek, B. (2001) Difenoconazole Technical: Cytogenetic test on Chinese 

hamster cells in vitro. Syngenta Crop Protection AG, Health Assessment 2 

Stein/Genetic Toxicology, CH-4332 Stein, Switzerland. Laboratory 

Project ID: Syngenta AG Test Number 20013013, Syngenta Number 

T002875-06, December 3, 2001. MRID 46950321. Unpublished 

EXECUTIVE SUMMARY: In a mammalian cell cytogenetics assay (Chromosomal 
Page 43 of 52

aberrations) (MRID 46950321), Chinese hamster CHO cells in culture were exposed to 

CGA 169374 Technical (94.3% w/w, Lot No. WM806228) in DMSO for three hours at 

concentrations of 0, 26.3, 39.5 or 59.3 μg/mL without metabolic activation (S9-mix) and 

at concentrations of 0, 11.7 or 17.6 μg/mL with S9-mix. Cells were harvested 18 hours 

following the end of exposure. Cells were exposed in a second confirmatory study for 21 

hours at concentrations of 0, 2.3, 5.2 or 11.7 μg/mL without S9-mix and for three hours 

at concentrations of 0, 7.8, 11.7 or 17.6 μg/mL with S9-mix. Cells were harvested 

immediately following the 21-hour exposure and 18 hours after the three-hour exposure. 

Cells were evaluated for the presence of structural chromosomal aberrations and for 

polyploidy. The S9-fraction was obtained from Aroclor 1254 induced male 

HanIbm:WIST(SPF) rat liver. 

CGA 169374 Technical was tested up to cytotoxic concentrations as evidenced by a 

dose-related reduction in mitotic activity seen with and without S9-mix. There was a 

statistically significant increase in the percentage of CHO cells with structural 

chromosomal aberrations at a CGA 169374 Technical concentration of 59.3 μg/mL 

without S9-mix in the original study when aberrations at the fragile X site were included 

but not when they were excluded. Aberrations at the fragile X site are not likely relevant 

to clastogenicity. No statistically significant increase in the percent of aberrant cells was 

seen in the original study with S9-mix. An increase in the percent of aberrant cells was 

seen in the confirmatory study at 17.6 μg/mL with S9-mix and the increase was 

statistically significant (p≤0.001) when aberrations at the fragile X site were excluded. 

The value of 6.5% aberrant cells exceeded the value of >6% set as a criterion for a 

positive effect in the testing laboratory. The failure to see a significant increase in the 

percent of aberrant cells in the original study makes the results equivocal. No 

statistically significant increase in the percentage of aberrant cells was seen at any of the 

three test material concentrations without S9-mix in the confirmatory study. The solvent 

and positive controls (Mitomycin C without S9-mix and Cyclophosphamide with S9-

mix) induced the appropriate responses. There was evidence of a weak induction of 

structural chromosomal aberrations over background.

This study is classified as Acceptable/Guideline and satisfies the guideline requirement 

for OPPTS 870.5375; OECD 473 for in vitro cytogenetic mutagenicity data. 

STUDY TYPE:In vitro Mammalian Cytogenetics (chromosomal aberrations) assay 

in human lymphocytes; OPPTS 870.5375 [§84-2]; OECD 473 

CITATION: Fox, V. (2001) Difenoconazole Technical: In vitro cytogenetic assay in 

human lymphocytes. Central Toxicology Laboratory, Alderley 

Park/Macclesfield, Cheshire, UK SK10 4TJ. Laboratory Project ID: CTL 

Number SV1090, Syngenta Number T002876-06, August 29, 2001. MRID 

46950323. Unpublished 

EXECUTIVE SUMMARY: In a mammalian cell cytogenetics assay (Chromosomal 

aberrations) (MRID 46950323), human lymphocytes in culture were exposed to CGA 

169374 Technical (94.3% w/w, Lot No. WM806228) in DMSO for three hours at 
Page 44 of 52

concentrations of 0, 5, 30 or 75 μg/mL without metabolic activation (S9-mix) and at 

concentrations of 0, 5, 30 or 62 μg/mL with S9-mix. Cells were harvested 17 hours 

following the end of exposure. Cells were exposed in a second experiment for 20 hours 

at concentrations of 0, 1, 5 or 10 μg/mL without S9-mix and for three hours at 

concentrations of 0, 5, 30 or 50 μg/mL with S9-mix. Cells were harvested immediately 

following the 20-hour exposure and 17 hours after the three-hour exposure. Cells were 

evaluated for the presence of structural chromosomal aberrations. The S9-fraction was 

obtained from Phenobarbital + β-naphthoflavone induced male Sprague-Dawley rat liver. 

CGA 169374 Technical was tested up to cytotoxic concentrations as evidenced by a 

dose-related reduction in mitotic activity seen with and without S9-mix. No statistically 

significant increases in the percentage of cells with structural aberrations, excluding gaps, 

over the solvent control values were seen at any test material concentration with or 

without S9-mix in the first experiment or without S9-mix in the second experiment. A 

statistically significant increase over the solvent control value was seen at 5μg/mL with 

S9-mix in the second experiment; however, the increase was not considered biologically 

significant because the value (4.00%) was within the historical solvent control range, the 

values at the two higher concentrations were not significantly increased and no increase 

was seen in the first experiment. The solvent and positive controls (Mitomycin C without 

S9-mix and Cyclophosphamide with S9-mix) induced the appropriate responses. There 

was no evidence of structural chromosomal aberrations induced over background.

This study is classified as Acceptable/Guideline and satisfies the guideline requirement 

for OPPTS 870.5375; OECD 473 for in vitro cytogenetic mutagenicity data. 

DIFENOCONAZOLE METABOLITES: 

STUDY TYPE: In vitro Bacterial Gene Mutation (Bacterial system, Salmonella 

typhimurium and Escherichia coli)/ mammalian activation gene 

mutation assay; OPPTS 870.5100 [§84-2]; OECD 471 (formerly 

OECD 471 & 472). 

CITATION: Nakajima, M. (1991) CGA189138 (metabolite of difenoconazole): reverse 

mutation assay of CGA189138. Biosafety Research Center; Foods, Drugs 

and Pesticides (An-Pyo Center); 582-2, Arahama Shioshinden; FukudeCho Iwata-Gun.; Shizuoka 437-12; Japan. Laboratory Project ID: BRC 

Number 1809, October 21, 1991. MRID 46950314. Unpublished. 

EXECUTIVE SUMMARY: In a reverse gene mutation assay in bacteria (MRID 

46950314), strains TA98, TA100, TA1535 and TA1537 of S. typhimurium and strain 

WP2 uvrA of E. coli were exposed to CGA-189138, a metabolite of difenoconazole, 

(97.8% a.i., lot number 910806) dissolved in DMSO in two independent assays using a 

20-minute preincubation procedure and duplicate plating. In the first mutagenicity assay, 

which was alternatively called the pilot assay and the dose-finding assay, concentrations 

of 0, 51.2, 128, 320, 800, 2000 or 5000 μg/plate were tested with and without S9-mix. In 

the second assay, which was called the main assay, concentrations of 0, 31.3, 62.5, 125, 
Page 45 of 52

250, 500 or 1000 μg/plate were tested in the absence of S9-mix in strains TA100 and 

TA1537 and in the presence of S9-mix in all Salmonella strains; concentrations of 0, 

62.5, 125, 250, 500, 1000 or 2000 μg/plate were tested in the absence of S9-mix in 

strains TA1535, WP2 uvrA and TA98 and in the presence of S9-mix in strain WP2 uvrA. 

The S9 fraction was obtained from phenobarbital and 5,6-benzoflavone-induced male 

Sprague-Dawley rat liver. 

CGA-189138 was tested at concentrations up to the limit concentration for the assay in 

the pilot assay, and many of the higher concentrations tested in both assays showed 

cytotoxicity and sometimes also insolubility. In the absence of S9-mix in the pilot assay, 

the test material was cytotoxic, as judged by stereomicroscopic examination of the 

bacterial lawns, at concentrations of 800 μg/plate and higher in strains TA100 and 

TA1537 and at concentrations of 2,000 μg/plate and higher in strains TA1535, WP2 uvrA

and TA98. In the presence of S9-mix in the pilot assay, the test material was cytotoxic at 

concentrations of 800 μg/plate and higher in all four Salmonella strains and at 

concentrations of 2,000 μg/plate and higher in strain WP2 uvrA. In the absence of S9-mix 

in the main assay, the test material was cytotoxic at concentrations of 500 μg/plate and 

higher in strain TA100, at concentrations of 1,000 μg/plate and higher in strains TA1535 

and TA98, and at the maximum concentrations tested in strains WP2 uvrA and TA1537. 

In the presence of S9-mix in the main assay, the test material was cytotoxic at 

concentrations of 500 μg/plate and higher in strains TA100, TA1535 and TA1537 and at 

the maximum concentrations tested in strains WP2 uvrA and TA98. At cytotoxic 

concentrations there was often also a marked decrease in the number of revertant 

colonies found. In the pilot assay, precipitation of the white powdery test material was 

observed on the surface of the agar plates at the time of colony counting at concentrations 

of 5,000 μg/plate in the absence of S9-mix and at concentrations of 2,000 μg/plate and 

above in the presence of S9-mix. In the main assay, such precipitation was observed only 

in the presence of S9-mix and at the highest concentration tested in strain WP2 uvrA. The 

number of revertants per plate was not increased over the concurrent solvent control 

value at any test material concentration, with or without S9-mix, in any tester strain. The 

solvent and positive controls induced the appropriate responses in the corresponding 

strains. There was no evidence of induced mutant colonies over background.

This study is classified as Unacceptable/Guideline and does not satisfies the 

requirements for Test Guideline OPPTS 870.5100; OECD 471 for in vitro mutagenicity 

(bacterial reverse gene mutation) data. Five strains of S. typhimurium were not used in 

the assay. The study can not be upgraded. 

STUDY TYPE: In vitro Bacterial Gene Mutation (Bacterial system, Salmonella 

typhimurium and Escherichia coli)/ mammalian activation gene 

mutation assay; OPPTS 870.5100 [§84-2]; OECD 471 (formerly 

OECD 471 & 472). 

CITATION: Nakajima, M. (1991) CGA205374 (metabolite of difenoconazole): reverse 

mutation assay of CGA205374. Biosafety Research Center; Foods, Drugs 

and Pesticides (An-Pyo Center); 582-2, Arahama Shioshinden; Fukude-
Page 46 of 52

Cho Iwata-Gun.; Shizuoka 437-12; Japan. Laboratory Project ID: BRC 

Number 1746, August 14, 1991. MRID 46950315. Unpublished. 

EXECUTIVE SUMMARY: In a reverse gene mutation assay in bacteria (MRID 

46950315), strains TA98, TA100, TA1535 and TA1537 of S. typhimurium and strain 

WP2 uvrA of E. coli were exposed to CGA-205374, a metabolite of difenoconazole, 

(99.3% a.i., lot number 9106054) dissolved in DMSO in two independent assays using a 

20-minute preincubation procedure and duplicate plating. In the first mutagenicity assay, 

which was alternatively called the pilot assay and the dose-finding assay, concentrations 

of 0, 51.2, 128, 320, 800, 2000 or 5000 μg/plate were tested with and without S9-mix. In 

the second assay, which was called the main assay, concentrations of 0, 156, 313, 625, 

1250, 2500 or 5000 μg/plate were tested with and without S9-mix. The S9 fraction was 

obtained from phenobarbital and 5,6-benzoflavone-induced male Sprague-Dawley rat 

liver. 

CGA-205374 was tested at concentrations up to the limit concentration for the assay, but 

the effective concentrations tested were limited by insolubility. Evidence of cytotoxicity, 

which was collected by stereomicroscopic examination of the bacterial lawns, was seen 

only in strain TA1537 at the maximum concentration tested, and then only in the main 

assay in the presence of S9-mix. The test material was quite insoluble, with cloudiness of 

the preincubation mixture being observed even at 128 μg/plate. The white powdery 

precipitate of the test material was observed on the surface of the agar plates at the time 

of colony counting at concentrations of 320 μg/plate and higher in the pilot assay in the 

absence of S9-mix and at concentrations of 800 μg/plate and higher in the presence of 

S9-mix. In the main assay, this precipitate was noted at concentrations of 313 μg/plate 

and higher both in the presence and absence of S9-mix. This precipitate became heavy 

enough to make it difficult to observe the bacterial lawn at concentrations of 1250 

μg/plate or higher in the absence of S9-mix and at the concentration of 5000 μg/plate in 

the presence of S9-mix. The number of revertants per plate was not increased over the 

concurrent solvent control value at any test material concentration, with or without S9-

mix, in any tester strain. The solvent and positive controls induced the appropriate 

responses in the corresponding strains. There was no evidence of induced mutant 

colonies over background.

This study is classified as Unacceptable/Guideline and does not satisfies the 

requirements for Test Guideline OPPTS 870.5100; OECD 471 for in vitro mutagenicity 

(bacterial reverse gene mutation) data. Five strains of S. typhimurium were not used in 

the assay. The study can not be upgraded. 

STUDY TYPE: In vitro Bacterial Gene Mutation (Bacterial system, Salmonella 

typhimurium and Escherichia coli)/ mammalian activation gene 

mutation assay; OPPTS 870.5100 [§84-2]; OECD 471 (formerly 

OECD 471 & 472). 

CITATION: Nakajima, M. (1991) CGA205375 (metabolite of difenoconazole): reverse 

mutation assay of CGA205375. Biosafety Research Center; Foods, Drugs 
Page 47 of 52

and Pesticides (An-Pyo Center); 582-2, Arahama Shioshinden; FukudeCho Iwata-Gun.; Shizuoka 437-12; Japan. Laboratory Project ID: BRC 

Number 1747, August 14, 1991. MRID 46950317. Unpublished. 

EXECUTIVE SUMMARY: In a reverse gene mutation assay in bacteria (MRID 

46950317), strains TA98, TA100, TA1535 and TA1537 of S. typhimurium and strain 

WP2 uvrA of E. coli were exposed to CGA-205375, a metabolite of difenoconazole, 

(99.8% a.i., lot number 9106055) dissolved in DMSO in two independent assays using a 

20-minute preincubation procedure and duplicate plating. In the first mutagenicity assay, 

which was alternatively called the pilot assay and the dose-finding assay, concentrations 

of 0, 51.2, 128, 320, 800, 2000 or 5000 μg/plate were tested with and without S9-mix. In 

the second assay, which was called the main assay, concentrations of 0, 2.50, 5.00, 10.0, 

20.0, 40.0 or 80.0 μg/plate were tested in the absence of S9-mix in all strains; 

concentrations of 0, 5.00, 10.0, 20.0, 40.0, 80.0 or 160 μg/plate were tested in the 

presence of S9-mix in strains TA100 and TA1535; concentrations of 0, 10.0, 20.0, 40.0, 

80.0, 160 or 320 μg/plate were tested in the presence of S9-mix in strains WP2 uvrA and 

TA1537; and concentrations of 0, 2.50, 5.00, 10.0, 20.0, 40.0, or 80.0 μg/plate were 

tested in the presence of S9-mix in strain TA98. The S9 fraction was obtained from 

phenobarbital and 5,6-benzoflavone-induced male Sprague-Dawley rat liver. 

CGA-205375 was tested at concentrations up to the limit concentration for the assay in 

the pilot assay. Most of the concentrations in that assay showed cytotoxicity and some of 

the higher ones also showed insolubility. Some of the higher concentrations in the main 

assay, which used much lower concentrations, also showed cytotoxicity. In the absence 

of S9-mix in the pilot assay, the test material was cytotoxic, as judged by 

stereomicroscopic examination of the bacterial lawns, at all concentrations in strains 

TA100 and TA1537 and at concentrations of 128 μg/plate and higher in strains TA1535, 

WP2 uvrA and TA98. In the presence of S9-mix in the pilot assay, the test material was 

cytotoxic at all tested concentrations in strain TA98, at concentrations of 128 μg/plate 

and higher in strains TA100 and TA1535, and at concentrations of 320 μg/plate and 

higher in strains WP2 uvrA and TA1537. In the absence of S9-mix in the main assay, the 

test material was cytotoxic at concentrations of 40.0 μg/plate and higher in strain TA100 

and at the highest tested concentration in the other strains. In the presence of S9-mix in 

the main assay, the test material was cytotoxic at concentrations of 40.0 μg/plate and 

higher in strain TA98, at concentrations of 80.0 μg/plate and higher in strain TA100, at 

concentrations of 160 μg/plate and higher in strain TA1537 and at the maximum 

concentrations tested in strains TA1535 and WP2 uvrA. At cytotoxic concentrations there 

was often also a marked decrease in the number of revertant colonies found. Because 

cytotoxicity was excessive at most concentrations, the pilot assay provided only slight 

useful information on mutagenesis in most strains. In the pilot assay, the needle 

crystalline precipitate of the test material was observed on the surface of the agar plates 

at the time of colony counting at concentrations of 800 μg/plate and above in the absence 

of S9-mix and at concentrations of 2,000 μg/plate and above in the presence of S9-mix. 

No precipitation was observed at any of the much lower concentrations tested in the main 

assay. The number of revertants per plate was not increased over the concurrent solvent 

control value at any test material concentration, with or without S9-mix, in any tester 
Page 48 of 52

strain. The solvent and positive controls induced the appropriate responses in the 

corresponding strains. There was no evidence of induced mutant colonies over 

background.

This study is classified as Unacceptable/Guideline and does not satisfies the 

requirements for Test Guideline OPPTS 870.5100; OECD 471 for in vitro mutagenicity 

(bacterial reverse gene mutation) data. Five strains of S. typhimurium were not used in 

the assay. The study can not be upgraded. 
Page 49 of 52

Appendix 3. Proposed Metabolic Pathway for difenoconazole in Rats 
Page 50 of 52 

Appendix 4 Environmental Fate Degradates 

Table 13.0c. Summary of Difenoconazole Major Degradates and Maximum Percent Formation Observed in the Laboratory anDegradate 1

Max Degradate Concentration (% of applied) and Time (days) to Max Concentration Analyzed Degrada

Lab 

Accumulation 

in Fish

Aqueous 

Photolysis 2,3,4 Aerobic Soil

Anaerobic 

Aquatic

Aerobic Aquatic TFD 5

CGA 205375 51-64% 3.8% (4) 14.8% (360)* 12.6% (175) 11.6% (90) 4.5% (121)A

5.3% (364)B3.5% (123)C 6.9% (182) D

CGA 205374 1.1% (14) 2.1 % (272) 0.8% (247) CGA 71019 20.6% (190) 35.9% (350)* CGA-142856 41.8% (30)4* CGA-107069/ CGA-71019

12.27% (30) 4* 

12.9% (9) 4

1 Refer to Table I-2 for name and structure; 2 Difenoconazole was stable under hydrolysis; 3 No meaningful amount of degradates were formed in soil 

photolysis study (≤ 0.2% and only single replicates); 4 In sterile natural water (MRID 46950105 and MRID 42245128); 5 % of the total applied difeno

four applications; A under bare soil conditions in GA (MRID 46950126); B under potato production condition in ND (MRID 46950129); C under a bar

in CA (MRID 46950129); D in CA bare loamy sand soil (MRID 42245140); and * The max concentration was observed in the last sampling interval. 
Page 51 of 52 

Table 13.0d. Chemical Structures of Difenoconazole and Degradation Products Detected in 

Submitted Environmental Fate Studies.

Name(s) Structure 

Known Chemical 

and Fate 

Parameters

CGA-169374 

Difenoconazole 

1-[2-[2-Chloro-4-(4-

chlorophenoxy)phenyl]-4-methyl-1,3-

dioxolan-2-ylmethyl]-1H-1,2,4-triazole. 

1-[[2-[2-Chloro-4-(4-

chlorophenoxy)phenyl]-4-methyl-1,3-

dioxolan-2-yl]methyl]-1H-1,2,4-triazole. 

1-(2-[4-(4-Chlorophenyoxy)-2-

chlorophenyl-(4-methyl-1,3-dioxolan-2-yl)-

methyl])-1H-1,2,4-triazole. 

CAS #: 119446-68-3 

Cl

O

Cl

O

O

CH3

H2C

N

N N

 

CGA-205374 [CGA-176459] 

1-[2-Chloro-4-(4-chlorophenoxy)-phenyl]-

2-[1,2,4]triazol-1-yl-ethanone 

1-[2-Chloro-4-(4-chlorophenoxy)phenyl]-2-

(1H-1,2,4-triazol-1-yl)-ethanone 

CAS #: 136815-80-0 

O

N

N

N

O Cl

Cl

CGA-205375 [CGA-211391] 

1-[2-Chloro-4-(4-chlorophenoxy)-phenyl]-

2-[1,2,4]triazol-1-yl-ethanol 

alpha-[2-Chloro-4-(4-

chlorophenoxy)phenyl]-1H-1,2,4-triazole1-ethanol. 

CAS #: 117018-19-6 

N

N

N

O Cl

Cl

OH

Mobility data 

available 

CGA-142856 

[1,2,4]Triazol-1-yl-acetic acid 

1H-1,2,4-Triazole-1-acetic acid. 

CAS #: 28711-29-7 

HO

O

N

N

N DW assessment 

completed in 2006

CGA-71019 

1-H-(1,2,4)-Triazole 

1H-1,2,4-Triazole 

4H-[1,2,4]Triazole 

CAS #: 288-88-0 

N

HN N DW assessment 

completed in 2006

CGA-107069 

1-H-(1,2,4)-Triazole-1-methanol 

C

H2

N

N

N HO
Page 52 of 52 

Name(s) Structure 

Known Chemical 

and Fate 

Parameters

CAS #: 74205-82-6 

 

CGA-131013 

2-Amino-3-[1,2,4]triazol-1-yl-propionic 

acid 

alpha-Amino-1H-1,2,4-triazole-1-propanoic 

acid 

CAS #: 86362-20-1 

OH

O

NH2

N

N

N