UNITED STATES ENVIRONMENT AL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF C HEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

DATE: October 1, 2015 

SUBJECT: Difenoconazole: Human Health Risk Scoping Document in Support of 

Registration Review 

PC Code: 128847 DP Barcode: 0429075 

Decision No.: 50897 1 Registra tion No: N/A 

Petition No.: None Regulatory Action: Registration Review 

Assessment Type: Scoping Document Reregistration Case No.: 7014 

TXR No.: None CAS No.: I 19446-68-3 

MRID No.: None 40 CFR: § 180.475 

FROM: Ivan Nieves, Risk Assessor ._()4J .:__ .A Bonnie Cropp-Kohlligian, Environmental Scientis 

f . Thurston Morton, Chemist, Senior Scientist ) 

Ri

Abda

sk Assessme

llah K.hasawinah

nt Branch 

, PhD.

4 

, Toxicologist 

~ 

'/J 

// 

~ 

Health Effects Division (7509P) 

THROUGH: Elissa Reaves, PhD., Branch Chief ~7?~----~ Risk Assessment Branch 4, HED (7509P) 

TO: Rosemary Kearns/Tony Kish (RM 22) 

Fungicide Branch 

Registration Division (7505P) 

And 

Maria Piansay, Chemical Review Manager 

Risk Management and Implementation Branch 5 

Pesticide Re-evaluation Division (7508P) 

Attached in HED's human health scoping document for difenoconazole to support 

Registration Review. 
Di fenoconazole/ 12884 7 Scoping Document 0429075 

Executive Summary 

The HED difenoconazole Registration Review team has evaluated the scientific database 

for the pesticide difenoconazole 1-[2-[2-chloro-4-( 4-chloro-phenoxy)-phenyl]-4-methyl-

[1,3]dioxolan-2-ylmethyl]- 1 H-[l ,2,4]triazole to determine the scope of the work 

necessary to support the existing registrations. 

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

fungicides. [t is currently registered in the U.S. for use as a seed treatment on a number 

of cereal grain crops, cotton, canola, and potato seed pieces; for post-harvest use on 

members of tuberous and corm vegetables subgroup 1 C and pome fruit group 11-1 O; and 

for multiple foliar applications on numerous crops including potatoes, stone fruit group 

12, and tree nut group 14. Difenoconazole is also registered for use on golf course turf 

and treatment of ornamental plants in commercial and residential landscapes and interior 

plantscapes. Tolerances for difenoconazole, currently established under 40 CFR 

§ 180.475, range from 0.01-95 ppm. Difenoconazole acts by blocking demethylation 

during sterol biosynthesis which, in turn, disrupts membrane synthesis. Difenoconazole 

is available as emulsifiable concentrate, soluble concentrate, emulsion [oil] in water, 

flowable suspension, and ready-to-use formulations. As a seed treatment, it is applied 

with commercial grade seed treatment equipment. As a foliar treatment, it is applied to 

field and vegetable crops, landscape ornamentals and golf course turf by commercial 

applicators using aerial and ground appli cation methods and equipment. It is applied to 

ornamentals by residential applicators using hand held sprayers. 

The toxicology database for difenoconazole is complete for evaluating and characterizing 

toxicity and selecting endpoints for purposes of this risk assessment. No new 

toxicological data are required. HED does not anticipate the need to revise the 

toxicological endpoints, points of departure, or safety factors for difenoconazole during 

Registration Review. 

The difenoconazole residue chemistry database is complete. The most recent acute and 

chronic dietary exposure analyses were conducted in 2015 using the Dietary Exposure 

Evaluation Model software with the Food Commodity Intake Database (DEEM-FCID) 

Version 3.16. The resulting acute and chronic food plus water dietary exposure estimates 

were less than HED's Level of Concern (LOC) for the general U.S. population and aJI 

population sub-groups. Quantification of human cancer risk is not required since it was 

determined the chronic dietary exposure assessment is protective of chronic risk 

including potential cancer. HED does not anticipate the need for a revised dietary 

assessment during Registration Review unless dietary exposure models or the Estimated 

Drinking Water Concentrations (EDWCs) are updated. 

There is sufficient information available to assess residential exposure resulting from 

residential uses of difenoconazole for Registration Review. Residential handler and postapplication exposures were all re-evaluated and discussed in the most recent human 

health risk assessment dated February 24, 2015 (D421188; I. Nieves; 2/24/2015) based 

on the most current Standard Operating Procedures (SOPs) updated in 2012. All handler 

and post-application exposure scenarios identified for the registered uses (i.e., 

applications to golf course turf and treatment of ornamental plants in commercial and 

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Difenoconazole/128847 Scoping Document D429075 

residential landscapes and interior plantscapes) resulted of no concern to the Agency. 

HED does not anticipate the need for a revised residential assessment during Registration 

Review. A spray drift and volatilization risk assessment for difenoconazole will be 

completed during Registration Review. 

There is sufficient information available to assess occupational exposure resulting from 

occupational uses of difenoconazole for Registration Review. The most recent 

quantitative occupational risk assessment that discusses these use patterns was conducted 

in 2015 (D421188; I. Nieves; 2/24/2015). No estimated risks of concern were identified 

for handlers with the required Personal Protective Equipment (PPE) (i.e., long shirt, long 

pants, shoes, socks and gloves). No risk estimates of concern were identified from postapplication exposure either. The Restricted Entry Interval (REI) specified on proposed 

and registered labels is 12 hours based on difenoconazole's acute toxicity. This is 

considered adequate to protect agricultural workers from post-application exposures to 

difenoconazole. HED does not anticipate the need for a revised occupational assessment 

during Registration Review. 

The acute and chronic aggregate risk assessments take into account exposure estimates 

from dietary consumption of difenoconazole (food and drinking water). In the 2015 

assessment, the acute and chronic dietary risk estimates were not of concern to HED 

(<100% aPAD and cPAD, respectively) for the general U.S. population and all other 

population subgroups. Short term aggregate exposures account for residential exposure 

plus average exposure levels to food and water (considered to be a background exposure 

level). In the 2015 assessment, short term aggregate risk estimates ranged from MO Es of 

170 to 190 (target MOE is 100) and therefore not of concern to HED. HED does not 

anticipate the need for a revised aggregate assessment during Registration Review. 

The previous aggregate triazole human health risk assessment was recently updated for 

free triazoles and its conjugates and the aggregate estimates remain below HED's level of 

concern (T. Morton, D426493, 4/9/15). As part of Registration Review, updated 

aggregate risk assessments may be necessary to reflect revised dietary or residential 

exposure estimates. 

No data deficiencies were identified for difenoconazole however HED anticipates 

conducting the following risk assessment updates during Registration Review: 

Dietary Exposure: 

• A revised dietary assessment during Registration Review would only be 

completed if dietary exposure models or the Estimated Drinking Water 

Concentrations (EDWCs) are updated. 

Occupational and Residential Exposure: 

• The need for spray drift and volatilization risk assessments for difenoconazole 

will be completed during registration review. 

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Difenoconazole/12884 7 Scoping Document D429075 

.1 Introduction 

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

fungicides. There are currently 35 active end-use products. Syngenta Crop Protection, 

LLC, has 32of these, and the other three are registered with Albaugh, LLC (2), and 

Nu farm Americas, Inc ( 1 ). It is currently registered in the U.S. for use as a seed treatment 

on a number of cereal grain crops, cotton, canola, and potato seed pieces and for postharvest use on members of tuberous and corm vegetables subgroup IC and pome fruit 

group 11-10 and for multiple foliar applications on numerous crops including stone fruit 

group 12 and tree nut group 14. Difenoconazole is also registered for use on golf course 

turf and treatment of ornamental plants in commercial and residential landscapes and 

interior plantscapes. 

2 Hazard ldentificationff oxicology 

The toxicology database for difenoconazole is complete for evaluating and characterizing 

toxicity and selecting endpoints for risk assessment. Subchronic and chronic toxicity 

studies with difenoconazole in mice and rats showed decreased body weights and effects 

on the liver (e.g. hepatocellular hypertrophy, liver necrosis, fatty changes in the liver). 

Acute and subchronic neurotoxicity studies showed evidence of neurotoxic effects. 

However, the observed effects were transient and the dose-response was well 

characterized with identified dose levels at which no observed adverse effects were seen. 

The available developmental and reproduction toxicity studies indicated no increased 

susceptibility of rats or rabbits from in utero or postnatal exposure to difenoconazole. In 

an immunotoxicity study in mice, difenoconazole produced immunotoxicity at doses that 

caused systemic toxicity. No evidence of carcinogenicity was seen in the chronic/cancer 

rat study. Evidence for carcinogenicity was seen in mice as induction of liver tumors at 

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

Difenoconazole has been classified as "Suggestive Evidence of Carcinogenic Potential'. 

with risk quantified using a non-linear (Margin of Exposure) approach (TXR 0054532). 

The cancer classification is based on tumors occurring at excessive toxic doses in mice, 

the absence of tumors at the lower doses and the absence of genotoxic effects. The 

FQPA Safety Factor is reduced to lX. Difenoconazole exhibits low acute toxicity by the 

oral, dermal and inhalation routes of exposure. It is not an eye or skin irritant and is not a 

sensitizer. 

Endpoints/Points of Departure (PODs) for Risk Assessment. Toxicological points of 

departure (PODs) were selected for dietary and drinking water exposures risk 

assessments. An acute POD for all populations was selected from an acute neurotoxicity 

study in rats based on reduced grip strength. A chronic POD was selected from a 

chronic/carcinogenicity study in rats based on body weight effects. Short- and 

intermediate-term incidental oral, dermal and inhalation PODs were selected from an oral 

rat reproduction study based on decreased body weight effects in pups and parental 

animals. A dermal absorption factor is applied when dermal exposure endpoints are 

selected from oral toxicity studies. A dermal absorption factor of 6%, based on triple 

pack data, was used for the dermal exposure assessment. Inhalation toxicity is assumed 

to be equivalent to oral toxicity. An uncertainty factor of 1 OOX was applied endpoints 

Page 4 of29 
Difenoconazole/12884 7 Scoping Document D429075 

selected for al I exposures routes ( 1 OX for interspecies extrapolation, 1 OX for intraspecies 

variation, lX FQPA SF). 

FQPA Factor. The available Agency guideline studies indicated no increased qualitative 

or quantitative 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. 

Together, the available data support the reduction of the FQPA factor to IX. 

A summary of toxicological doses and points of departure for difenoconazole is presented 

in Table 3 in the Appendix. A toxicity profile of difenoconazole is presented in Tables 4 

and 5, and guideline data requirements in Table 6 of the Appendix. 

Conclusions for Toxicology 

The toxicology database for difenoconazole is complete. Based on a WOE approach 

considering all the available difenoconazole hazard and exposure information, the Hazard 

and Science Policy Council (HASPOC) concluded that a 28-day day inhalation study is 

not required at this time (TXR # 0054074). HED does not anticipate the need to revise 

the toxicological endpoints, points of departure, or safety factors for difenoconazole 

during Registration Review. 

Residue Chemistry 

The qualitative nature of the residue of difenoconazole in/on crops and livestock is 

adequately understood. The HED Residues of Concern Knowledgebase Sub-committee 

(ROCKS) has determined (DP# 391350) that the residues of concern for tolerance 

enforcement and risk assessment in/on crop commodities is parent only and in livestock 

commodities are parent and its metabolite, CGA-205375 (l-(2-chloro-4-(4-

chlorophenoxy)phenyl]-2-[l ,2,4]triazol-1-yl-ethanol). In addition, metabolite OH-CGA169374 should be considered as a residue of concern in milk for the dietary risk 

assessment. Metabolites CGA-205375 and OH-CGA-169374 are no more toxic than 

difenoconazole. Adequate analytical enforcement methods are available. 

The HED ROCKS also determined (DP# 391350) that the residues of concern in drinking 

water are parent and its metabolite, CGA-205375. 

Conclusions for Residue Chemistry 

The difenoconazole residue chemistry database is complete. 

Dietary Exposure and Risk Assessment 

The most recent acute and chronic dietary exposure analyses were conducted in 2015 and 

considered all currently registered uses (D42649 1, T. Morton, l-July-20 15). The 

analyses were conducted using DEEM-FCID (ver. 3.1 6) which incorporated food 

consumption data from the 2003-2008 food consumption data from the U.S. Department 

of Agriculture's (USDA's) National Health and Nutrition Examination Survey, What We 

Page 5 of29 
Difenoconazole/ 128847 Scoping Document D429075 

Eat in America, NHANES/WWEIA). The resulting unrefined (assuming tolerance level 

residues and I 00 %CT) acute food plus water dietary exposure estimates were less than 

HED's level of concern (< I 00% of the acute population-adjusted dose (aP AD)) at the 

95th percenti le of the exposure distribution for the general U.S. population (I 5% aP AD) 

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

children 1-2 years old with 49% aPAD. The somewhat refined chronic analysis assumed 

tolerance-level residues for some commodities, average field trial residues and USDA 

Pesticide Data Program monitoring samples for the remaining commodities, the available 

empirical or DEEM (ver. 7.8 1) default processing factors, and% CT assumptions for 

some commodities. The resulting chronic food plus water dietary exposure estimates 

were less than HED's level of concern (<100% of the chronic population-adjusted dose 

(cPAD)) for the general U.S. population (26% cPAD) and all population sub-groups; the 

most highly exposed population subgroup was chi ldren 1 - 2 years old with 89% cPAD. 

Conclusions for Dietwy Exposure 

HED does not anticipate the need for a revised dietary assessment during Registration 

Review unless the Estimated Drinking Water Concentrations (EDWCs) are updated. 

Residential Exposure and Risk Assessment 

Residential exposure is expected from registered uses. There is exposure from handlers 

working with ornamental plants, and residential post-application exposure from 

applications to golf course turf and treatment of ornamental plants in commercial and 

residential landscapes and interior plantscapes. Scenarios identified from these uses were 

all re-evaluated and discussed in the most recent human health risk assessment dated 

February 24, 2015 (D42 1188; I. Nieves; 2/24/201 5) based on the 2012. At this time no 

new nor proposed residential uses have been submitted to the Agency. 

The highest application rate assessed for handlers was 0 .13 1 b ail A. Exposure scenarios 

identified and assessed included mixing/loading and applying liquid formulations with 

the following equipment: manually-pressurized handwand; hose-end sprayer; backpack; 

and a ready to use hose-end sprayer. No estimated risks of concern were identified from 

residential handler exposure scenarios (MOEs>LOC of 100). Total MOEs (dermal and 

inhalation combined exposure) ranged from 3,500 to 68,000. All exposure scenarios 

were considered to be of short-term duration (1-30 days). 

Exposure scenarios were identified via the dermal route of exposure from postapplication activities. Rates of application ranged from 0.13 to 0.25 lb ai/ A. Risk 

estimates from post-application exposure scenarios resulted in MOEs above the Agency's 

LOC of 100. MOEs ranged from 250 to 31,000 (e.g., for golfers). 

In conjunction with the 2007 40 CFR Part 158 Data Requirements, HED typically 

requires submission of a turf transferable residue (TTR) study in order to determine 

exposure and risk associated with playing on treated turf. Since the estimated residenti al 

turf post-application exposure for golf course using default TTR values for 

difenoconazole is minimal in comparison to the level of concern (i.e., the calculated 

MOE is greater than 10 times higher than the level of concern, MOE= 2, 100 compared to 

Page 6 of29 
Difenoconazole/12884 7 Scoping Document D429075 

the LOC of 100); EPA is waiving the 40CFR TTR data requirement. In this instance, it is 

unlikely that chemical-specific TTR data would be needed to further refine exposure 

assessments or would add appreciably to our general understanding of the availability of 

turf transferable pesticide residues. 

In accordance with 40CFR 158, Dislodgeable Foliar Residue DFR data are required for 

residential (e.g., ornamentals) uses that could result in post-application exposure to 

foliage. Since the estimated residential post-application exposure for ornamentals using 

default DFR values for difenoconazole is minimal in comparison to the level of concern 

(i.e., the calculated MOE is greater than 2 times higher than the level of concern, MOE= 

300 compared to the LOC of 100); EPA is waiving the 40CFR DFR data requirement. In 

this instance, it is unlikely that chemical-specific DFR data would be needed to further 

refine exposure assessments or would add appreciably to our overall understanding of the 

availability of dislodgeable foliar pesticide residues for difenoconazole. 

Residential bystander exposures resulting from off-site transport (e.g., spray drift or 

volatilization) may occur as a result of applications of difenoconazole. The potential for 

spray drift will be quantitatively evaluated for each pesticide during the Registration 

Review process which ensures that all uses for that pesticide will be considered 

concurrent! y. 

In terms of volatilization, the Agency has developed a Volatilization Screening Tool and 

a subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HO-OPP-2014-0219). During 

Registration Review, the Agency will utilize this analysis to determine if data (i.e., flux 

studies, route-specific inhalation toxicological studies) or further analysis is required for 

difenoconazole. 

Conclusions of Residential Exposure Assessment 

HED does not anticipate the need for a revised residential assessment during Registration 

Review. Spray drift and volatilization risk assessment for difenoconazole will be 

completed during Registration Review. 

Aggregate Exposure and Risk Assessment 

The acute and chronic aggregate risk assessments in the 2015 risk assessment take into 

account exposure estimates from dietary consumption of difenoconazole (food and 

drinking water). The acute and chronic dietary risk estimates were not of concern to HED 

(<100% aPAD and cPAD, respectively) for the general U.S. population and all other 

population subgroups. 

Short term aggregate exposure takes into account residential exposure plus average 

exposure levels to food and water (considered to be a background exposure level). The 

short term aggregate risk included the estimated risk associated with combined risks from 

average food and drinking water exposures and dermal and inhalation exposures from 

adults handling difenoconazole with a backpack sprayer and from post-application 

exposure to children 6 to 11 years old re-entering a treated garden scenario. Short term 

Page 7 of29 
Difenoconazole/12884 7 Scoping Document 0429075 

aggregate risk estimates in the 2015 risk assessment ranged from MOEs of 170 to 190 

and therefore not of concern to HED. 

There are no residential use scenarios that will result in potential intermediate term 

exposure to difenoconazole. Therefore, an intermediate-term aggregate was not 

performed. 

Application of difenoconazole also results in potential exposures to the metabolites T 

(l ,2,4-triazole), TA (triazolylalanine), T AA (triazolylacetic acid), and THP (triazolyl 

hydroxypropionic acid). These compounds are considered to be toxicologically different 

from difenoconazole. The previous aggregate triazole human health risk assessment was 

recently updated for free triazoles and its conjugates and the aggregate estimates remain 

below HED's level of concern (T. Morton, 0426493, 4/9/15). 

Co11clusio11s for Aggregate Assessment 

HED does not anticipate the need for a revised aggregate assessment during Registration 

Review unless the Estimated Drinking Water Concentrations (EDWCs) are updated. 

Revised triazole risk assessments may be required. 

Occupational Exposure and Risk Assessment 

Occupational handler and post-application exposures are expected based on the registered 

uses of difenoconazole. The most recent quantitative occupational risk assessment that 

discuss these use patterns was conducted in 2015 (0421188; I. Nieves; 2/24/2015). 

Difenoconazole is formulated as emulsifiable concentrates, soluble concentrates, 

emulsions (oil) in water, Oowable suspensions, and ready-to-use formulations. Foliar 

agricultural applications can be made by air, groundboom, airblast, chemigation, and 

handheld equipment at application rates ranging from 0.07 pounds active ingredient per 

acre (lb ail A) to 0.13 lb ai/ A. Commercial applications with low-pressure handheld 

equipment to ornamentals can range from 0.0011 to 0.003 lb ai per gallon of solution. 

Golf course turf applications are made at a rate of 0.25 lb ail A. Seeds are treated with 

specialized equipment at rates ranging from 0.025 to 0.031 lb ai per hundred pounds of 

seed. Post-harvest application are registered at 0.00035 lb ai/100 lbs potatoes. 

Occupational exposure scenarios applicable to difenoconazole range from short-term ( I 

to 30 days) to intermediate-term (30 days to six months) duration. 

The occupational handler assessments indicate that, for the existing registered uses, all of 

the potential exposure scenarios provide dermal and inhalation margins of exposure 

(MO Es) greater than or equal to the LOC of 100 at some level of personal protection 

and/or engineering controls. The labels for most uses require gloves in addition to 

baseline clothing attire of long pants, long sleeved shirt and shoes plus socks and are 

considered adequately protective. 

Several levels of dermal post-application exposure activities have been identified ranging 

from low exposure activities such as weeding and scouting in immature plants to very 

high exposure activities such as harvesting or thinning fruit from trees. The short- and 

intermediate-term post-application assessments indicate that the MOEs reach the LOC of 

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Difenoconazole/ 12884 7 Scoping Document D429075 

100 within 1 day after application for all of the existing use scenarios. The restricted 

entry interval (REI) listed on the applicable labels is 12 hours and is adequately 

protective. 

In accordance with 40CFR158, Dislodgeable Foliar Residue DFR data are required for 

occupational (e.g., crops) uses that could result in post-application exposure to 

foliage. Since the highest estimated occupational post-application exposure using default 

DFR values for difenoconazole is minimal in comparison to the level of concern (i.e., the 

calculated MOE is greater than 2 times higher than the level of concern, MOE =370 

compared to the LOC of 100); EPA is waiving the 40CFR DFR data requirement. In this 

instance, it is unlikely that chemical-specific DFR data would be needed to further refine 

exposure assessments or would add appreciably to our overall understanding of the 

availability of dislodgeable foliar pesticide residues for difenoconazole. 

Conclusions/or Occupational Exposure 

HED does not anticipate the need for a revised occupational assessment during 

Registration Review. 

Public Health and Pesticide Epidemiology Data 

For this evaluation, both the OPP Incident Data System (IDS) and the Centers for Disease 

Control and Prevention/National Institute for Occupational Safety and Health 

(CDC/NIOSH) Sentinel Event Notification System for Occupational Risk-Pesticides 

(SENSOR) databases were consulted for pesticide incident data on the active ingredient 

difenoconazole (D429081 ). The purpose of the database search is to identify potential 

patterns in the frequency and severity of the health effects attributed to difenoconazole 

and salts exposure. Difenoconazole is not included in the AHS, and, therefore, this study 

does not provide information for this report. 

Based on the low frequency and severity of incident cases reported for difenoconazole in 

both IDS and SENSOR-Pesticides there does not appear to be a concern at this time that 

would warrant further investigation. The Agency will continue to monitor the incident 

information and if a concern is triggered, additional analysis will be included in the risk 

assessment. 

Tolerance Assessment and International Harmonization 

U.S. permanent tolerances for residues of difenoconazole are established under 40 CFR 

§ I 80.475(a)(l) in/on numerous crop commodities and U.S. permanent tolerances for 

residues of difenoconazole and its metabolite, CGA-205375, calculated as the 

stoichiometric equivalent of difenoconazole are established under 40 CFR § l 80.475(a)(2) 

in milk, egg and ruminant tissue commodities. The current tolerance expression is in 

accordance with the HED Interim Guidance on Tolerance Expressions (5/27/2009, S. 

Knizner). U.S. tolerances are harmonized with Codex and Canadian maximum residue 

limit (MRL) with regards to definition of residues as well as levels in/on a number of 

commodities. See Table 7 in the Appendix to this document for details. Additional 

harmonization of residue levels will be considered under Registration Review. 

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Difenoconazole/ 12884 7 Scoping Document D429075 

Cumulative Risk 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 the 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. 

Human Studies 

The 2002 RED and 2015risk assessment relied in part on data from studies in which adult 

human subjects were intentionally exposed to a pesticide or other chemical. These data, 

which include studies from PHED 1.1, the AHETF database, the ARTF database, and 

ExpoSAC Policy 14 (SOPs for Seed Treatment), are ( l) subject to ethics review pursuant 

to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics 

requirements. For certain studies, the ethics review may have included review by the 

Human Studies Review Board. Descriptions of data sources, as well as guidance on their 

use, can be found at the Agency website 1

• 

Data Requirements 

No data deficiencies were identified for difenoconazole however HED anticipates 

conducting the following risk assessment updates during Registration Review: 

Dietary Expousre: 

• HED does not anticipate the need for a revised dietary assessment during 

Registration Review unless dietary exposure models or the Estimated Drinking 

Water Concentrations (EDWCs) are updated. 

Occupational and Residential Exposure: 

• The need for spray drift and volatilization risk assessments for difenoconazole 

will be completed during registration review. 

1 http://www.eoa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html 

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Difenoconazole/12884 7 Scoping Document D429075 

References 

Difenoconazole: Tier I (Scoping) Review of Human Incidents and Epidemiology. S. 

Recore, 0429081 , 9/ 15/2015 

Difenoconazole. Human Health Risk Assessment for proposed new foliar uses on 

legume subgroup 6C and bushberry subgroup 13-07B; post-harvest uses on pome fruit 

group 11-1 O; and ornamental plants and vegetable transplants grown in both indoor and 

outdoor production facilities. - I. Nieves, D422992, D421429, D421216, 0421201, 

0421208, 0421188, and D413471, 2/24/2015 

Oifenoconazole. New Foliar Uses on Pea and Bean, Dried Shelled, Except Soybean, 

Subgroup 6C and Bushberry Subgroup 13-07B. Summary of Analytical Chemistry and 

Residue Data. - B. Cropp-Kohlligian, D418479 and D421194, 10115/2014 

Difenoconazole. Request to Register New Multiple Active Ingredient (MAI) End-Use 

Product (AcademyTM Fungicide) for New Post-Harvest Uses on Pome Fruit Group 11-10. 

Summary of Analytical Chemistry and Residue Data. - B. Cropp-Kohlligian, 0417611 , 

10/17/2014 

Oifenoconazole. Acute and Chronic Aggregate Dietary Exposure and Risk Assessments 

for the Petition for Use of Difenoconazole on Pea and Bean, Dried Shelled, Except 

Soybean, Subgroup 6C, Bush berry Subgroup I 3-07B and an amended use on Pome Fruit 

to add Post-Harvest Use of Difenoconazole. - T. Morton, 0421430, 2/24/15 

Drinking Water Exposure Assessment in support of the new use registration of multiple 

difenoconazole formulated products on Artichoke, Berry Bushberry Subgroup 13-07B, 

Ginseng, and Bean and Pea, Dried Shelled (except Soybean) Subgroup 6C as well as 

Conversion of Stone Fruit Crop Group 12-12 and Tree Nuts Crop Group 14-12 .. - F. 

Khan, D421092, I 1/13/14 

Difenoconazole. Occupational and Residential Exposure Assessment for a Proposed Use 

on Canela and Oilseed Subgroup 20A. - T. Nieves, 041 281 1, 09/13/2013 

Difenoconazole. Occupational and Residential Exposure Assessment to Evaluate the 

Risk from Proposed Uses on Post-Harvest Potatoes, and the Expansion of Various Crop 

Groups Including: Citrus Fruit Group 10-10; Fruiting Vegetable Subgroups 8-10; Low 

Growing Berry Subgroup 13-07G, except cranberry; Pome Fruit, Crop Group 11-10 and 

Fruiting Vegetable, Crop Group 8-10). - I. Nieves, D398608, 5/30/2012 

Difenoconazole. Occupational and Residential Exposure Assessment for the Proposed 

New Use of Difenoconazole on Strawberry, Carrot, Chickpeas, Soybean, Stone Fruit: 

Group 12 and Golf Course Turfgrass. - Rebecca Daiss; 0371037; February 24, 2011 . 

Difenoconazole. Occupational and Residential Exposure/Risk Assessment for the 

Proposed New Uses of Difenoconazole on Fruiting Vegetables, Tuberous and Conn 

Vegetables, Pome Fruit, Sugar Beets and Ornamentals - Mark I. Dow; D340044; July 27, 

2007. 

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Difenoconazole/128847 Scoping Document 0429075 

Difenoconazole: Report of the Residues of Concern Knowledgebase Subcommittee 

(ROCKS). William Irwin; 0 391350; September 19, 2011 

Interim Guidance on Tolerance Expressions. Steve Knizner; May 27, 2009. 

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Difenoconazole/12884 7 Scoping Document D429075 

Appendix A. 

Table 1. Difenoconazole Nomenclature. 

Chemical structure of parent ~ o'Q ~N I ~ I~ N I Cl 

N 0 0 

L_\ Cl 

c~ mol. wt. 406.3 

Common name Di fenoconazole 

Company experimental name CGA-169374 

IUPAC name 1-(2-(2-chloro-4-( 4-chloro-phenoxy)-pheny 1)-4-methyl-[ 1,3 ]dioxolan-2-

ylmethyl]-1H-[ 1,2,4 ]triazole 

CAS name 1-[[2-[2-ch loro-4-( 4-ch lorophenoxy )phenyl]-4-methy 1-1 ,3 -dioxolan-2-yl]methyl]-

I H-1 ,2,4-triazole 

CAS registry number I 19446-68-3 

CGA

Chemical 

-205375 

structure 

livestock 

of Ou "': 

metabolite, 1-(2-chloro-4-( 4-

0N 

I 

chlo

[ 1,2,

r

4 

o-phenoxy)phenyl]-2

]triazol-1-yl-ethanol 

- N I ~ ~ Cl 

~N OH Cl mol. wt. 349.2 

Chemical structure of 

1,2,4-Triazole (I ,2,4-T) N~ 

I N HN--...Y 

Chemical structure of 

Triazolylalanine (TA) NH2 N~ 

HO ~IN N~ 

0 

Chemical structure of 

Triazolylacetic acid (T AA) 0 N~ 

~/ N~ N 

HO 

Page 13of29 
Di fenoconazole/ 12884 7 Scoping Document D429075 

Table 2. Physicochemical Properties of Dife noconazole. 

Parameter Value Reference 

Melting point 78.6 °C DP#s 172067 and 178394, I 0/26/92, R. 

pH 6-8 at 20 °C (saturated solution) Lascola 

Density 1.37 g/cm3 at 20 °C 

Water solubility 3.3 ppm at 20 °C 

Solvent solubility g/100 mL at 25 °C: 

n-hexane: 0.5 

1-octanol: 35 

toluene: 77 

acetone: 88 

ethanol: 89 

Vapor pressure 2.5 x I 0·

10 mm Hg at 25 °C 

Dissociation constant, pK. pure grade (99.3% ± 0.3%) DP# 375159, 5/26/10, B. Croppdifenoconazole in water (with 4% Kohlligian 

methanol) at 20°C is I. I 

Octanol/water partition 4.2 at 25 °C DP#s 172067 and 178394, I 0/26/92, R. 

coeffi cient, Log(Kow) Lascola 

UV /visible absorption spectrum Amu at about 200 and 238 nm PMRA Proposed Regulatory Decision 

(in methanol at 26 °C) Document on Difenoconazole, 4/ 14/99 

( PRDD99-0 I) 

Page 14 of29 
Difenoconazole/12884 7 Scoping Document D429075 

Table 3a. Summary of Toxicological Doses and Endpoints for Difenoconazole for Use in Dietary and NonOccupational Human Health Risk Assessments D422992 Februarv 24 2015, PC Code: 128847 

Exposure Point of Uncertainty/FQPA RfD, PAD, Study and Relevant LOC for Risk Scenario Departure Safety Factors Assessment Toxicologica l Effects 

Acute Dietary NOAEL =25 UFA = IOX aRID = aPAD Acute Neurotoxicity Study in 

(All populations) mg/kg UFH = IOX = 0.25 Rats (MRJD 46950327) 

UFFQPA = IX mg/kg/day LOAEL= 200 mg/kg in males 

based on reduced fore-limb grip 

strength in males on day 1. 

Chronic Dietary NOAEL = 0.96 UFA = !OX cRfD = cPAD Combined chronic 

(All populations) mg/kg/day UFH = IOX = toxicity/carcinogenicity (rat; 

UFFQPA = IX 0.0 I mg/kg/day dietary, MRJD 42090019, 

427100 I 0) LOAEL = 24.1/32.8 

mg/kg/day (M/F) based on 

cumulative decreases in bodyweight gains. 

Incidental Oral Oral NOAEL = UFA= IOX Residential Reproduction and fertility Study 

Short-Term ( 1- 1.25 UFH = IOX LOC for (rat; dietary, MRlD 42090018) 

30 days) mg/kg/day UFFQPA = IX MOE< IOO Parental/Offspring LOAEL = 

12.5 mg/kg/day based on 

decreased pup weight in males 

on day 21 and reduction in bodyweight gain of Fo fema les prior 

to mating, gestation and 

lactation. 

Dermal Oral NOAEL = UFA = IOX Residential Reproduction and fertility Study 

Short- and 1.25 UFH = IOX LOC for (rat; dietary, MRID 42090018) 

lntem1ediate- mg/kg/day UFFQPA = IX MOE< IOO Parental/Offspring LOA EL = 

Term (1 -30 days 12.5 mg/kg/day based on 

and 1-6 months) decreased pup weight in males 

DAF =6% on day 21 and reduction in bodyweight gain of Fo females prior 

to mating, gestation and 

lactation. 

Inhalation Oral NOAEL = UFA= IOX Residential Reproduction and fertility Study 

(Short- and 1.25 UFH = IOX LOC for (rat; dietary, MRID 42090018) 

lntennediate- mg/kg/day UFFQPA = IX MOE< IOO Parental/Offspring LOAEL = 

term) 12.5 mg/kg/day based on 

Inhalation and decreased pup weight in males 

oral absorption on day 21 and reduction in bodyassumed weight gain of Fo females prior 

equivalent to mating, gestation and 

lactation. 

Cancer (oral, Difenoconazole is classified "Suggestive Evidence of Carcinogenic Potential" with a nondennal, linear (MOE) approach for human risk characterization (CPRC Document, 7/27/94, Memo, 

inhalation) P. V. Shah dated March 3, 2007, HED Doc. No. 0054532). 

Point of Departure (POD) = A data point or an estimated point that 1s derived from observed dose-response data and used to mark the 

beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOA EL = no 

observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from 

animal to human (interspecies). UF11 = potential variation in sensitivity among members of the human population (intraspecies OAF= 

Demial Absorption Factor 

Page 15 of29 
Difenoconazole/ l 28847 Scoping Document 0429075 

Table 3 b. Summary of Toxicological Doses a nd Endpoints for Difenoconazole for Use O ccupational 

Huma n Health Risk Assessments 0422992, February 24 2015, PC Code: 128847 

Exposure Point of Uncertainty/FQPA RID, PAD, Study and Toxicological 

Scenario Departure Safety Factors Level of Effects 

Concern for 

Risk 

Assessment 

Dermal Reproduction and fertility 

Short- and Study (rat; dietary, MRlD 

Intermediate- Oral UFA= IOX 42090018) Parental/Offspring 

Term ( 1-30 NOAEL = UFH = IOX Occupational LOAEL = 12.5 mg/kg/day 

days and 1-6 1.25 LOC for based on decreased pup weight 

months) mg/kg/day MOE< IOO in males on day 21 and 

OAF=6% reduction in body-weight gain 

of Fo females prior to mating, 

gestation and lactation. 

Inhalation Reproduction and fertility 

(Short- and Study (rat; dietary, MRlD 

Intermed iate- Oral UFA= IOX 420900 18) Parental/Offspring 

tenn) NOAEL = UF11 = IOX Occupational LOA EL = 12.5 mg/kg/day 

Inhalation and 1.25 LOC for based on decreased pup weight 

oral absorption mg/kg/day MOE< IOO in males on day 21 and 

assumed reduction in body-weight gai n 

equivalent of Fo females prior to mating, 

gestation and lactation. 

Cancer (oral, Difenoconazole is classified "Suggestive Evidence of Carcinogenic Potential" with a nondermal, linear (MOE) approach for human risk characterization (CPRC Document, 7/27/94, Memo, P. 

inhalation) V. Shah dated March 3, 2007, HED Doc. No. 0054532). 

Ta ble 4. Acute Toxicity Profile - Difenoconazole: February 2015 

G uideline No. Study Type MRID No. Results Toxicity Category 

870.1 100 Acute oral 42090006 ( 1987) LDso = 1450 mg/kg Ill 

870.1200 Acute dermal 42090007 ( 1987) LDso > 20 I 0 mg/kg 111 

870.1300 Acute inhalation 42090008 ( 1991) LCso > 3.3 mg/L Ill 

870.2400 Eye irritation 42090009 ( 1991 ) Mild irritation reversible in 7 days 111 

870.2500 Dermal irritation 420900 10 (199 1) Slight irritation IV 

870.2600 Skin sensitization 42090011 (1987), Negative NIA 

427 10004 (1992) 

Table 5. Subchronic, Ch ronic, Other Toxicity Profile - Difenoconazole: Februa ry 2015 

G uideline No. MRID No. (year)/ Results 

Study Type Classification !Doses 

870.3 100 42090022 ( 1987) NOA EL = 20 ppm (I mg/kg/day) 

90-Day oral toxicity Accepta ble/guideline LOA EL = 200 ppm ( IO mg/kg/day) based on the I 0% 

(rat) 0, 20, 200, 750, 1500 or 3000 decrease in body weight in the 200 ppm females (as well 

ppm as a negative trend in feed consumption) and Increases in 

0, I, 10,37.5, 75and 150 absolute liver weights in both sexes 

mg/kg/d 

870.3100 42090021 ( 1987) NOA EL = 20 ppm (2.9 mg/kg/day) 

90-Day oral toxicity Acceptable/guideline LOA EL = 200 ppm (30.8 mg/kg/day) based on body 

(mouse) 0, 20, 200, 2500, 7500 or 15,000 weight changes & liver histopathology. 

ppm 

Page 16 of29 
Difenoconazole/12884 7 Scoping Document D429075 

Table 5. Subchronic, Chronic, Other Toxicitv Profile - Difenoconazole: February 2015 

G uideline No. MRID No. (year)/ Results 

Study Type Classification /Doses 

M: 0, 2.9, 30.8, 383.6, 11 25 and 

2250 mg/kg/d 

F: 0, 4.1 , 4.1.5, 558.9, 1125 and 

2250 mg/kg/d 

870.3150 420900 12 (1987) NOAEL = 3000 ppm (3 1.3 mg/kg/day in males/34.8 

26-Week oral toxicity Acceptable I guideline mg/kg/day in females) 

0, 100, I 000, 3000 or 6000 ppm LOAEL = 6000 ppm (96.6 mg/kg/day in males/ 110.6 

M: 0, 3.6, 31.3, 96.6 and 157.8 mg/kg/day in females), based primarily on microscopic 

mg/kg/d examination of CGA 169374-related lenticular cataracts. 

F: 0, 3.4, 34.8, 110.6 and 203.7 

mg/kg/d 

870.3200 42090013 ( 1987) NOA EL = I 0 mg/kg/day 

2 1/28-Day dermal Acceptable I guideline LOAEL = I 00 mg/kg/day based on statistically 

toxicity (rat) 0, IO, 100 and 1000 mg/kg/d significant decrements in body weight, body weight gain, 

and food consumption. 

870.3200 46950310 (2000) NOAEL (systemic) = 1000 mg/kg/day 

21 /28-Day dermal Acceptable/ gu ideline LOAEL (systemic) was not determined. 

toxicity (rat) 0, I 0, I 00 and I 000 mg/kg/d NOAEL (dermal) = 100 mg/kg/day 

LOA EL (dermal) = I 000 mg/kg/day based on 

hyperkeratosis at the skin application site. 

870.3465 Waived HASPOC TXR# 0054074 

28/90-Day Inhalation 

870.3700a 42090016, 42710007 (1987) Maternal NOA EL = 16 mg/kg/day 

Prenatal Acceptable I guideline LOA EL = 85 mg/kg/day based on decreased body weight 

deve lopmental in (rat) 0, 2, 20, 100 or 200 mg/kg/d gain and food consumption. 

from GD 6-15 (nominal doses Developmenta l NOA EL = 85 mg/kg/day 

differed widely from theoretical, LOA EL = 171 mg/kg/day based on alterations in fetal 

this required altering ossification. 

NOAEL/LOAEL values) 

870.3700b 420900 17' 42710008 (1987) Materna l NOA EL = 25 mg/kg/day 

Prenatal Acceptable I guideline LOA EL = 75 mg/kg/day based on decreased body weight 

developmental in 0, I, 25 or 75 mg/kg/d from GD gain and food consumption. 

(rabbit) 7-19 Developmental NOA EL = 25 mg/kg/day 

LOA EL = 75 mg/kg/day based on nonsignificant 

increases in postimplantation loss and resorptions/doe and 

a significant decrease in fetal weiaht. 

870.3800 42090018 ( 1988) Parental/Systemic NOA EL = 25 ppm ( 1.25 mg/kg/day) 

Reproduction and Acceptable I guideline LOA EL = 250 ppm ( 12.5 mg/kg/day) based on 

fertility effects 0, 25, 250 or 2500 ppm reductions (statistically nonsignificant) in body weight 

(rat) 0, 1.25, 12.5 and 125 mg/kg/d 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 

Offspring NOA EL = 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 FI male pups 

at day 21 in the 250 ppm group. 

870.41 OOb 42090012, 42710005(1988) NOAEL = 100 ppm (3.4 mg/kg/day in males/3.7 

Chronic toxicity Acceptable I guideline mg/kg/day in females) 

(dog) 0, 20, I 00, 500 or 1500 ppm LOA EL = 500 ppm (16.4 mg/kg/day in males/19.4 

M: 0, 0.71, 3.4, 16.4 and 51.2 mg/kg/day in females), based on significant inhibition of 

mg/kg/d body weight gain in females. 

F: 0, 0.63, 3.7, 19.4 and 44.3 

mg/kg/d 

Page 17of29 
Difenoconazole/ 12884 7 Scoping Document 0 429075 

Table 5. Subchronic, Chronic, Other Toxicity Profile - Difenoconazole: February 2015 

G uideline No. MRID No. (year)/ Results 

Study Type Cla ssification /Doses 

870.4200 42090019, 427100 10( 1989) NOAEL = 20 ppm (0.96 mg/kg/day in males/ 1.27 

Carcinogenicity Acceptable I guideline mg/kg/day in females) 

(rat) 0, I 0, 20, 500 or 2500 ppm LOAEL = 500 ppm (24. I mg/kg/day in males/ 32.8 

M: o, 0.48, 0.96, 24. 12 and 123.7 mg/kg/day in fema les) based on reductions in cumulative 

mg/kg/d body weight gains in the 500 and 2500 ppm groups. 

F: 0, 0.64, 1.27, 32.79 and 169.6 

mg/kg/d No evidence of carcinogenicity 

870.4300 42090015,427 10006(1989) NOAEL = 30 ppm (4.7 mg/kg/day in males/5.6 

Carcinogenicity Acceptable I guideline mg/kg/day in fema les) 

(mouse) 0, I 0, 30, 300, 2500 or 3000 ppm LOAEL = 300 ppm (46.3 mg/kg/day in males/57.8 

M: 0, 1.51 , 4.65, 46.29, 423.1 mg/kg/day in females) based on reductions in the 

and 818.9 mg/kg/d cumulative body weight gains and hepatocellular 

F: 0, 1.9, 5.63, 57.79 and 5 12.6 hypertrophy, liver necrosis, fatty changes in the liver and 

mg/kg/d bile stasis in the 300, 2500 & 4500 ppm groups. 

Evidence of carcinogenicity (liver adenoma/carcinoma in 

both sexes) 

870.5 100 42090019,427100 10( 1989) There were sufficient and valid data to conclude that 

In vitro bacterial gene Acceptable I guideline CGA 169374 technical was negative in the microbial 

mutation (Salmonella 340 - 5447 μg/plate; gene mutation assay. 

typhimuriuml £. coli)/ 85 - 1362 μg/plate (repeat assay 

mammalian with TA l537 and TA98) 

activation gene 

mutation assay 

870.5300 42090024 ( 1986) No conc lusion can be reached from the three nonactivated 

in vitro mammalian Unacceptable/ guideline and two S9 activated mouse lymphoma forward mutation 

cell gene mutation assays conducted with difenoconazole technical. The 

assay in mouse study was seriously compromised. 

lymphoma cells 

870.5375 469503 19 (200 I) There was evidence of a weak induction of structural 

In vitro Mammalian Acceptable/ guideline chromosomal aberrations over background in the 

Cytogenetics 0, 21 .99, 27.49, or 34.36 μg/mL presence ofS9-mix. 

(chromosoma l (-S9) 

aberrations) assay in 0, 34.36, 53.69 or 67. 11 μg/m L 

Chinese hamster (+S9) 

CHO cells 

870.5375 4695032 1 (200 I) There was evidence of a weak induction of structural 

In vitro Mammalian Acceptable/ guideline chromosomal aberrations over background. 

Cytogenetics 0, 26.3, 39.5 or 59.3 μg/mL (-S9) 

(chromosomal 0, 11.7 or 17.6 μg/mL (+S9) 

aberrations) assay in 

Chinese hamster 

CHO cells 

870.5375 46950323 (200 I) There was no evidence of structural chromosomal 

In vitro Mammalian Acceptable/ guideline aberrations induced over background. 

Cytogenetics 0, 5, 30 or 75 μg/mL (-S9) 

(chromosomal 0, 5, 30 or 62 μg/mL (+S9) 

aberrations) assay in 

human lymphocytes 

870.5385 42090023 ( 1986) There was no evidence of a cytotoxic effect on the target 

In vivo mammalian U naccepta blc/guideline organ or significant increase in the frequency of nuclear 

chromosomal 250, 500 or I 000 mg/kg anomalies (micronuclci). However, the study was 

compromised. 

Page 18 of29 
Difenoconazole/12884 7 Scoping Document 0429075 

Table 5. Subchronic, Chronic, Other Toxicity Profile - Difenoconazole: February 2015 

G uideline No. MRID No. (year)/ Results 

Study Type Classification /Doses 

aberration test Assay 

in Mice 

870.5395 41710011 (1992) Mice bone marrow - No increase in micronucleated 

In vivo mammalian Acceptable/guideline polychromatic erythrocytes occurred with CGA-1 69374 

cytogenetics - Doses up to 1600 mg/kg (91.2% a.i). 

erythrocyte 

micronucleus assay in 

mice 

870.5550 4210012 ( 1992) CGA-i69374 tech. (92.2% a.i.) was considered to be 

Unscheduled DNA Acceptable/ guideline negative in the unscheduled DNA synthesis assay in rat 

Synthesis in Doses up to 50 μg/mL primary hepatocytes as measured by an autoradiographic 

Mammalian Cells in method at concentrations up to 50.0 μg/mL. 

Culture 

870.5550 42090027 ( 1985) No conclusion can be reached from the unscheduled 

Unscheduled DNA Unaccepta ble/ guideline DNA synthesis (UDS) primary rat hepatocyte assay 

Synthesis in 0.25-3 I .25 μg/mL conducted with difenoconazole technical at 

Mammalian Cells in concentrations ranging from 0.25 to 3 1.25 μg /mL. The 

Culture sensitivity of the study was severely compromised. 

870.5550 42090026 ( 1985) No conclusion can be reached from the unscheduled 

Unscheduled DNA Unaccepta ble/ guideline DNA synthesis (UDS) human fibroblast assay conducted 

Synthesis in 0.08-10 μg/mL with difenoconazole tech. at cone. ranging from 0.08 to 

Mammalian Cells in JO ~ig mL. 

Culture 

870.6200a 46950327 (2006) NOAEL (M) = 25 mg/kg/day 

Acute neurotoxicity Acceptable/ guideline LOAEL (M) = 200 mg/kg/day based on reduced forescreening battery 0, 25, 200 or 2000 mg/kg/d limb grip strength in males on day I and increased motor 

activity on Day I. 

NOA EL (F) = 200 mg/kg/day 

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

weight, the following clin ical signs: upward curvature of 

the spine, tip-toe gait, decreased activity, piloerection and 

sides pinched in and decreased motor activity. 

870.6200b 46950329 (2006) NOAEL (M) = 40 ppm (2.8 mg/kg/day) 

Subchronic Acceptable/ guideline LOA EL (M) = 250 ppm ( 17 .3 mg/kg/day) based on 

neuroroxicity 0, 40, 250, or 1500 ppm M; 0, decreased hind limb strength. 

screening battery 2.8, I 7 .3 or I 07 .0 mg/kg/d NOA EL (F) = 250 ppm ( 19.5 mg/kg/day) 

F:0, 3.2, 19.5, or 120.2 mg/kg/d LOA EL (F) = 1500 ( 120.2 mg/kg/day) based on 

decreased body weight, body weight gain and food 

efficiency. 

870.7800 48696701 (201 1) Systemic toxicity NOAEL = 200 ppm (35 mg/kg/day) 

I mmunotoxicity Acceptable/ guideline Systemic toxicity LOAEL = I 000 ppm (177 mg/kg/day) 

[dietary] - Mouse 0, 20, 200, I 000, or 1500 pm (0, based on decreased body weight gains and liver toxicity 

3, 35, I 77, or 247 mg/kg/day) for 

28 days. lmmunotoxicity NOAEL = 200 ppm (35 mg/kg/day) 

lmmunotoxicity LOAEL = 1000 ppm (177 mg/kg/day) 

based on decreased mean anti-SRBC lgM levels. 

870.7600 In vivo 47453201 (2007) See TXR 0056473 

Dermal Penetration -

rat 

870.7600 In vivo 46950333 (2003) See TXR 0056473 

Dermal Penetration -

rat 

Page 19 of29 
Difenoconazole/128847 Scoping Document D429075 

Table 5. Subchronic, Chronic, Other Toxicity Profile - Difenoconazole: Februar y 2015 

Guideline No. MRID No. (year)/ Results 

Study Type Classification /Doses 

870.7600 In virro 47453202 (2007) See TXR 0056473 

Dermal Penetration 

870.7600 In virro 47453203 (2007) See TXR 0056473 

Dermal Penetration 

870.7485 42090028 ( 1990) Male and female Sprague-Dawley rats. Animals were 

Metabolism and Acceptable/ guideline administered a single oral gavage dose of0.5 or 300 

pharmacokinet ics 14 daily doses of 0.5 or 300 mg/kg (

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

(rat) mg/kg 169374 by gavage for 14 days followed by a single 

gavage dose of 0.5 mg/kg [14C)CGA- l 69374 on day 15. 

The test compound was labeled with C14 at either the 

phenyl or triazole ring. 

870.7485 42090028 ( 1990) Male and female Sprague-Dawley rats. Animals were 

Metabolism and 42090029 ( 1987) administered a single oral gavage dose of0.5 or 300 

pharmacokinetics 42090030 ( 1987) mg/kg (

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

(rat) 42090031 ( 1988) 169374 by gavage for 14 days followed by a single 

Acceptable/ guideline gavage dose of0.5 mg/kg [14

C)CGA-169374 on day 15. 

Single oral dose 0.5 or 300 The test compound was labeled with C14 at either the 

mg/kg phenyl or triazole ring. 

14 daily doses of 0.5 or 300 

mg/kg [ 14C] CCA 169374 was rapidly and extensively 

distributed, metabolized, and excreted in rats for all 

dosing regimens. The metabolism of difenoconazole 

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. metabolites A, B, and C). Two of the 

metabolites were separated into isomers (i.e., Al, A2, BI, 

and B2). Metabolite C was detected only in the highdose groups, indicating that metabolism of 

difenoconazole is dose-related and involves saturation of 

the metabolic pathway. Free triazole metabolite was 

detected 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. 

870.7485 42090028 ( 1990) The absorption, distribution, metabolism, and excretion 

42090029 ( 1987) of CGA 169374 were studied in groups of male and 

42090030 ( 1987) female Sprague-Dawley rats. Animals were administered 

4209003 1 ( 1988) a single oral gavage dose of0.5 or 300 mg/kg [14C]CGAAcceptable/ guideline in 169374, or 0.5 mg/kg unlabeled GGA-169374 by gavage 

conjunction with MRJDs for 14 days followed by a single gavage dose of 0.5 

420710013 , 427 1001 4 listed mg/kg [14C)CGA- l 69374 on day 15. The test compound 

below was labeled with C14 at either the phenyl or triazole ring. 

Single oral dose 0.5 or 300 

mg/kg [

14CI CCA 169374 was rapidly and extensively 

14 daily doses of 0.5 or 300 distributed, metabolized, and excreted in rats fo r a ll 

mg/kg dosing regimens. The extent of absorption is 

undetermined pending determination of the extent of 

biliary excretion. The 4-day recoveries were 97.94-

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 

Page 20 of29 
Difenoconazo le/ 12 8 84 7 Scoping Document 0429075 

Table 5. Subchronic, Chronic, Other Toxicity Profile - Oifenoconazole: February 2015 

Guideline No. M RID No. (year)/ Results 

Study Type Classification /Doses 

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. 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 difenoconazole 

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 post exposure. 

The metabolism of difenoconazole 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. metabolites 

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

isomers (i.e., Al, A2, BI , and 82). Metabolite C was 

detected only in the high-dose groups, indicating that 

metabolism of difenoconazole is dose-related and 

involves saturation of the metabolic pathway. Free 

triazole metabolite was detected in the urine of triazolelabeled groups and its byproduct was detected in the liver 

of phenyl labeled groups only. Other urinary metabolites 

were not characterized. 

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 an imals 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. 

Page 21 of29 
Difenoconazole/ 12884 7 Scoping Document D429075 

Table 6. Guideline Data Requirements: Difenoconazole: February 2015 

Test Technical 

Required Satisfied 

870.1100 Acute Oral Toxicity yes yes 

870. 1200 Acute Dennal Toxicity yes yes 

870. 1300 Acute Inhalation Toxicity yes yes 

870.2400 Primary Eye Irritation yes yes 

870.2500 Primary Dennal Irritation yes yes 

870.2600 Dennal Sensitization yes ves 

870.3 100 Oral Subchronic (rodent) yes yes 

870.3 150 Oral Subchronic (non-rodent) yes yes 

870.3200 21-Day Dennal no yes 

870.3250 90-Day Dennal no - 870.3465 28/90-Day Inha lation waived* - 870.3700a Developmental Toxicity (rodent) yes yes 

870.3700b Developmental Toxicity (non-rodent) yes yes 

870.3800 Reproduction yes ves 

870.41 OOa Chronic Toxicity (rodent) yes yes 

870.41 OOb Chronic Toxicity (non-rodent) yes yes 

870.4200a carcinogenicity (rat) yes yes 

870.4200b carcinogenicity (mouse) yes yes 

870.4300 Chronic/carcinogenicity yes yes 

870.5 100 Mutagenicity-Gene Mutation - bacterial yes yes 

870.5300 Mutagenicity- Gene Mutation - mammalian yes yes 

870.5375 Mutagenicity- Srructural Chromosomal Aberrations yes yes 

870.5900 Mutagenicitv-Other Genotoxic Effects yes yes 

870.6 1 OOa Acute Delayed Neurotox. (hen) no - 870.6 1 OOb 90-Day Neurotoxicity (hen) no - 870.6200a Acute Neurotox. Screening Battery (rat) yes yes 

870.6200b 90-Day Neuro. Screening Battery (rat) yes - 870.6300 Develoo. Neuro no - 870.7485 General Metabolism yes yes 

870.7600 Dermal Penetration yes yes 

870.7800 lmmunotoxicity yes yes 

* waived per HASPOC TXR 0054074 

Page 22 of29 
Difenoconazole/12884 7 Scoping Document D429075 

Table 7. International Residue Limits 

Difenoconazole (128847; 8/3/15) 

Table 7. Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition: 

us Canada Mexico1 Codex2 

40 CFR 180.475: 1-[[2-[2-ch loro-4-( 4- Difenoconazole 

Plant: difenoconazole, l-[2-[2-chloro-4- ch lorophenoxy )phenyl]-4-

( 4-ch lorophenoxy )phenyl]-4-methyl- methyl- I ,3-dioxolan-2- The residue is fatI ,3-dioxolan-2-ylmethyl]-I H- I ,2,4- ylmethyl]-I H- I ,2,4-triazole soluble. 

triazole 

Commodity Tolerance (ppm) !Maximum Residue limit (mvk~) 

us Canada Mexico1 Codex2 

Almond, hulls 7.0 

Apple, wet pomace 25 

Aspirated grain fractions 95 

Banana' 0.2 0.2 0.1 

Barley, grain 0.1 0.0 1 

Barlev, hav 0.05 

Barley, straw 0.05 

Beet, sugar 0.3 0.2 

Beet, sugar, dried pulp 1.9 1.9 

Berry, low growing, 2.5 2.5 bearberries, bilberries, 

subgroup I 3-07G, except lowbush blueberries, 

cranberry cloudberries, lingonberries, 

muntries, partridgeberries, 

strawberries 

Brassica, head and stem, 1.9 I .9 broccoli, brussels 2 

subgroup SA sprouts, cabbages, 

cauliflowers, broccoli, 

Chinese broccoli, Chinese 

mustard cabbages, 

kohlrabies, napa Chinese 

cabbages 

Brassica, leafy green, 35 35 broccoli raab, bok choy 

subgroup SB Chinese cabbages, collards, 

kales, mustard greens, 

mustard spinach, rape 

leaves 

Bushberrv subgroup I 3-078 4.0 

Carrot 0.50 0.5 carrot roots 0.2 

Citrus, dried pulp 2.0 

Citrus, oil 25 25 

Com, sweet, forage 0.01 

Corn, sweet, kernel plus cob 0.01 0.01 

with husks removed 

Corn, sweet, stover 0.01 

Cotton, gin byproducts 0.05 

Cotton, undelinted seed 0.05 0.05 

Dragonfruit1 1.5 

Page 23 of29 
Difenoconazole/1 28847 Scoping Docwnent 0429075 

Table 7. Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition: 

us Canada Mexico1 Codex2 

Fruit, citrus, group I 0-10 0.60 0.8 Australian (desert limes, 0.6 

linger limes, round limes), 

brown river finger limes, 

calamondin, citrus citron, 

citrus hybrids, graperruits, 

kumquats, lemons, limes, 

Mediterranean Mandarin, 

Mount White lime, New 

Guinea wild limes, oranges, 

pummelos, Russell River 

limes, Satsuma mandarins 

sweet limes, tachibana 

oranges, tahiti limes, 

tangeloa, tangerines, 

tangors, trifoliate oranges, 

Uniq rruits 

Fruit, pome, group I 1-10 5.0 I apples, Asian pears, 0.8 

azaroles, Chinese quinces, 

crabapples, Japanese 

quinces, loquats, mayhaws, 

medlars, pears, quinces, 

teiocotes 

Fruits, stone, group 12 2.5 2.5 American plums, 0.2 cherries, plums 

Apricots, beach plums, (including prunes) 

black cherries, Canada 0.5 nectarines, peach 

plums, capulins, cherry 

plums, chicksaw plums, 

damson plums, fresh prune 

plums, Japanese apricots, 

Japanese plums, jujubes, 

klamath plums, nanking 

cherries. nectarines, 

peaches, plumcots, plums, 

sloes, sweet cherries, tart 

cherries 

Grape 4.0 4 .. 

.) 

Grape, raisin 6.0 6 6 dried grapes 

(=currants, raisins 

and sultanas) 

Mango• 0.07 0.09 0.07 

Page 24 of29 
Difenoconazole/128847 Scoping Document 0429075 

Table 7. Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition: 

us Canada Mexico1 Codex2 

Nut, tree, group 14 0.03 0.03 African tree nuts, 0.03 

almond nuts, beechnuts, 

black walnuts, Brazil nuts, 

Brazilian pine nuts, bunya 

nuts, bur oak nuts, 

butternuts, Cajou nuts, 

candlenuts, cashew nuts, 

chestnuts, ch inquapin nuts, 

coconuts, coquito nuts, dika 

nuts, English walnuts, 

ginkgo nuts, Guiana 

chestnuts, hazelnuts 

(filbert), heartnuts, hickory 

nuts, Japanese horsechestnuts, macadamia nuts, 

mongongo nuts, monkeypot nuts, monkey puzzle 

nuts, okari nuts, pachira 

nuts, peach palm nuts, 

pecan nuts, pequi nuts, pili 

nuts, pine nuts, pistachio 

nuts, sapucaia nuts, tropical 

almond nuts, yellow horn 

nuts 

Oat, forage 0.15 

Oat, grain 0.01 0.01 

Oat, hay 0.05 

Oat, straw 0.05 

Onion, bulb, subgroup 3-07 A 0.20 0.2 Chinese, onions, 0.02 garlic('") 

Daylilies, dry bulb onions, 0.1 onion bulb 

fritillaria bulbs, garlic, 

great-headed garlic, lilies, 

pearl onions, potato onions, 

serpent garlic, shallot bulbs 

Onion, green, subgroup 3- 6.0 6 Beltsville bunching 0.3 leek 

078 onions, elegans hosta, fresh 9 spring onion 

(Chinese chive leaves, chive 

leaves), fresh onions, 

fritillaria leaves, green 

onions, kurrats, lady's leeks, 

leeks, macrostem onions, 

shallot leaves, tree onion 

tops, Welsh onion tops, wild 

leeks 

Papaya1 0.30 0.3 0.2 

0.3 (proposed) 

Page 25 of29 
Difenoconazole/ 12884 7 Scoping Document 0429075 

Table 7. Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition: 

us Canada Mexico1 Codex2 

Pea and bean, dried shelled, 0.20 0.03 Dry (adzuki beans, 0.7 beans, except 

except soybean, subgroup 6C beans, blackeyed peas, broad bean and soya 

broad beans, catjang seeds, bean 

chickpeas, cowpea seeds, 

field peas, guar seeds, 

kidney beans, lablab beans, 

lima beans, moth beans, 

mung beans, navy beans, 

pigeon peas, pink beans, 

pinto beans, rice beans, 

soybeans, southern peas, 

tepary beans, urd beans, 

lentils) grain lupin 

Pea, field, hay 40 

Pea, field, vines 10 

Pistachio 0.03 0.03 0.03 lTee nuts 

Potato, wet peel 7.3 

Rapeseed subgroup 20A 0.10 0.1 Seeds (Borage, crambe. 0.05 rapeseed 

cuphea; echium, flax seed, 

gold of pleasure, hare's ear 

mustard, lesquerella, 

lunaria, meadowfoam, 

milkweed, mustard seed 

(condiment type and oilseed 

type), oil radish, poppy 

seed, rapeseed, sesame, 

sweet rocket) 

Rye, forage 0. 15 

Rye, grain 0.01 0.01 

Rye, straw 0.05 

Soybean, hulls 0.20 

Soybean, seed 0.15 0.15 0.02 (*)soybean 

(dry) 

Turnip, greens 35 

Vegetable, cucurbit, group 9 0.70 0.7 balsam apples, balsam 0.2 cucumber, 

pears, cantaloupes, chayotc gherkin, squash 

fruit, Chinese cucumbers, summer 

Chinese waxgourds, citron 0.7 melons, except 

melons. cucumbers, edible watermelon 

gourds, muskmelons (other 

than those listed in this 

item) pumpkins, summer 

squash, watermelons, west 

Indian gherkins, winter 

squash 

Page 26 of29 
Difenoconazole/12884 7 Scoping Document D429075 

Table 7. Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definilion: 

us Canada Mexico' Codex2 

Vegetable, fruiting, group 8- 0.60 0.6 Arrican eggplants, bell 0.6 rruiting 

10 peppers, bush tomatoes, vegetables other than 

coconas, currant tomatoes, cucurbits (except 

eggplants, garden sweet com and 

huckleberries, goji berries, mushroom) 

groundcherries, martyn ias, 5 peppers chili, dried 

naranj ill as, non bell 

peppers, okras, pea 

eggplants, pepinos, roselles, 

scarlet eggplants, 

sunberries, tomatillos, 

tomatoes, tree tomatoes 

Vegetable, tuberous and 4.0 4 arracacha, arrowroot, 4 potato 

corm, subgroup 1 C cassava roots, chayote 

roots, Chinese artichokes, 

chufa, edible canna, ginger 

roots, Jerusalem artichokes, 

lerens, potatoes, sweet 

potato roots, tanier conns, 

taro conns, true yam tubers, 

turmeric roots, yam bean 

roots 

Wax jambu 1 1.5 

Wheat, forage 0.1 

Wheat, grain 0.1 0.1 wheat 0.02 (*) 

Wheat, hav 0.05 

Wheat, straw 0.1 3 wheat straw and 

fodder, dry 

MRLs with NO US Equivalent 

Buckwheat 0.01 

Pearl millet 0.01 

Popcorn grain 0.01 

Proso millet 0.0 1 

Rice 0.01 

Sorghum 0.01 

Teosinte 0.01 

Triticale 0.01 

Wild rice 0.01 

Asparagus 0.03 

Celeriac 0.5 

Celery 3 

Ginseng 0.08 

Ginseng, dried including red 0.2 

ginseng 

Ginseng, extracts 0.6 

Lettuce, head 2 

Lettuce, leaf 2 

Olives 2 

Passion rruir 0.05 

Peas (pods and 0.7 

succulent=immature seeds) 

Sunflower seed 0.02 

Page 27 of29 
Difenoconazole/ 128847 Scoping Document 0429075 

Table 7. Summary of US and Lnternatio nal To lerances and Maximum Residue Limits 

Residue Definition: 

us Canada Mexico• Codex2 

US 40 CFR 180.475 Canada Mexico• Codex2 

Livestock: sum of d ifenoconazole. 1-[2- 1-[[2-[2-chloro-4-(4- Animal commodities: 

[2-chloro-4-( 4-chlorophenoxy )phenyl]- chlorophenoxy)phenyl)-4- sum of 

4-methyl-1,3-dioxolan-2-ylmethyl]-1 H- methyl-1 ,3-dioxolan-2- difenoconazole and 

1,2,4-triazole, and its metabolite, CGA- ylmethyl]-1 H- 1,2,4-triazole, 1-[2-chloro-4-(4-

205375, l-[2-chloro-4-(4-chloro- including the metabolite a - chloro-phenoxy)-

phenoxy)phenyl)-2-( 1,2,4)triazol- l-yl- [2-chloro-4-(4- phenyl]-2-( 1.2.4-

ethanol, calculated as the stoichiometric chlorophenoxy)phenyl]-1 H- triazol)-1-yl-ethanol), 

equivalent of difenoconazole 1,2,4-triazole-I-ethanol expressed as 

di fenoconazole. 

Commodity Tolerance (pvm) /Maximum Residue Limit (mf!/kf!) 

us Canada Mexico• Codex2 

Cattle, fat 0.10 

Canle, liver 0.40 0.1 1.5 edible offal 

mammalian 

Cattle, meat 0.05 0.05 0.2 meat (from 

mammals other than 

marine mammals) 

(fat) 

Canle, meat byproduct 0.10 0.05 1.5 edible offal 

(except liver) mammalian 

E1rn. 0.02 0.05 0.03 

Goat, fat 0.01 

Goat, liver 0.40 0.1 1.5 edible offal 

mammalian 

Goat, meat 0.05 0.05 0.2 meat (from 

mammals other than 

marine mammals) 

(fat) 

Goat, meat byproduct (except 0. 10 0.05 1.5 edible offal 

liver) mammalian 

Hog, fat 0.10 

Hog, liver 0.40 0. 1 1.5 edible offal 

mammalian 

Hog, meat 0.05 0.05 0.2 meat (from 

mammals other than 

marine mammals) 

(fat) 

Hog, meat byproduct (except 0.10 0.05 1.5 edible offal 

liver) mammalian 

Horse, fat 0.10 

Horse, liver 0.40 0.1 1.5 edible offal 

mammalian 

Horse, meat 0.05 0.05 0.2 meat (fi-orn 

mammals other than 

marine mammals) 

(fat) 

Horse, meat byproduct 0.10 0.05 1.5 edible offal 

(except liver) mammalian 

Milk 0.02 0.0 1 0.02 

Sheep, fat 0.10 

Sheep, liver 0.40 0.1 1.5 edible offal 

mammalian 

Page 28 of29 
Difenoconazole/128847 Scoping Document 0 429075 

Table 7. Summary of US and Internationa l Tolerances and Maximum Residue Limits 

Residue Definition: 

us Canada Mexico1 Codex2 

Sheep, meat 0.05 0.05 0.2 meat (from 

mammals other than 

marine mammals) 

(fat) 

Sheep, meat byproduct 0. 10 0.05 1.5 edible offal 

(except liver) mammalian 

MRLs with NO US £q11ivalent 

Poultry, meat 0.0 I (*)(fat) 

Poultry. edible offal of 0.01 (*) 

Completed: M. Negussie; 08/ 12/ 15 1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes. 

2 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP 

= processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be 

measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the 

CCPR and the CAC. 

Page 29 of29