UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION 

MEMORANDUM 

July l, 2015 

SUBJECT: Difenoconazole: Human Health Risk Assessment for Proposed New Foliar Uses 

on Globe Artichoke, Ginseng and Greenhouse Grown Cucumbers and Conversion 

of the Established Foliar Uses/Tolerances for Stone Fruit Group 12 and Tree Nut 

Crop Group 14 to Stone Fruit Group 12-1 2 and Tree Nut Group 14-1 2. 

PC Code: 128847 

Decision No.: 491006 

OP Barcodes: 0 426020 

Registr ation Nos.: I 00-1262, I 00-1313, I 00-

1317 

Petition No.: 4E8274 Regulatory Action: Section 3 Registration 

Risk Assessment Type: Single Chemical Aggregare Case No.: 70 14 

TXR No.: NA CAS No.: 11 9446-68-3 

MRID No.: NA n 40 F~: § 180.475 

FROM: Ivan Nieves, Risk Assessor { _/J\ -----::::--,,--

Thurston Morton, Chemist, Seni S~Rlist\ r / -.....-.:.---. 

Bonnie Cropp-Kohlligian, Environmental Scifntist · 

Abdallah, Khasawinah, PhD. Toxicologist ,., ~ L° 0~ 

Risk Assessment Branch 4 · 

Health Effects Division (7509P) 

THROUGH: Charles Smith, Acting Chief S:::v Risk Assessment Branch 4 ~ Health Effects Division (7509P) 

TO: Laura Nollen and Barbara Madden, RM05 

Minor Use and Emergency Response Branch 

Registration Division (7505P) 

This document provides the Health Effects Division's (HED's) risk assessment of proposed new 

foliar uses on globe artichoke, ginseng and greenhouse grown cucumbers and conversion of the 

established foliar uses/tolerances for stone fruit group 12 and tree nut crop group 14 to stone fruit 

group 12- l 2 and tree nut group 14-12. 

Page I of 47 
Table of Contents 

1.0 EXECUTIVE SUMMARY ................................................................................................ 4 

2.0 HED RECOMMENDATIONS .......................................................................................... 7 

2.1 Data Deficiencies .............................................................................................................. 7 

2.2 Tolerance Considerations ............................................................................................... 7 

2.2.1 Enforcement Analytical Method ............................................................................. 7 

2.2.2 Recommended Tolerances ........................................................................................ 7 

2.2.3 Revisions to Petitioned-For Tolerances .................................................................. 8 

2.2.4 International Harmonization ................................................................................... 8 

2.3 Label Recommendations ................................................................................................. 8 

2.3. l Recommendations from Residue Reviews .............................................................. 8 

3.0 INGREDIENT PROFILE .................................................................................................. 9 

3.1 Chemical Identity ............................................................................................................ 9 

3.2 Physical/Chemical Characteristics ............................................................................... 10 

3.3 Pesticide Use Pattern ..................................................................................................... 10 

3.4 Anticipated Exposure Pathlvays ................................................................................... 13 

3.5 Considerations of Environmental J ustice .................................................................... 13 

4.0 HAZARD CHARACTERIZATION AND DOSE-RESPONSE ASSESSMENT ........ 14 

4.1 Toxicology Studies Available for Analysis .................................................................. 14 

4.2 Absorption, Distribution, Metabolism and Excretion (ADME) ................................ 14 

4.3 Toxicological Effects ...................................................................................................... 15 

4.4 Safety Factor for Infants and Children (FQPA Safety Factor) ................................. 16 

4.4.1 Completeness of the Toxicology Database ............................................................ 16 

4.4.2 Evidence of Neurotoxicity ...................................................................................... 16 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal. ..... 16 

4.4.4 Residual Uncertainty in the Exposure Database .................................................. 17 

4.5 Toxicity Endpoint and Point of Departure Selections ................................................ 17 

4.5.l Dose-Response Assessment .................................................................................... 17 

4.5.2 Recommendations for Combining Exposure Routes for Risk Assessment ....... 18 

4.5.3 Cancer Classification and Risk Assessment Recommendations ......................... 18 

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Risk 

Assessment ............................................................................................................................ 18 

5.0 DIET ARY EXPOSURE AND RISK ASSESSMENT ................................................... 20 

5.J Metabolite/Degradate Residue Profile ......................................................................... 20 

Page 2 of 47 
Page 3 of 47

5.1.1 Summary of Plant and Animal Metabolism Studies ........................................... 20

5.1.2 Summary of Environmental Degradation ............................................................ 21

5.1.3 Comparison of Metabolic Pathways...................................................................... 21

5.1.4 Residues of Concern Summary and Rationale..................................................... 21

5.2 Food Residue Profile ..................................................................................................... 22

5.2.1 Residues in Crops.................................................................................................... 22

5.3 Water Residue Profile ................................................................................................... 23

5.3.1 Estimated Drinking Water Concentrations.......................................................... 23

5.4 Dietary Risk Assessment............................................................................................... 24

5.4.1 Description of Residue Data Used in Dietary Assessment .................................. 24

5.4.2 Percent Crop Treated Used in Dietary Assessment............................................. 25

5.4.3 Acute Dietary Risk Assessment ............................................................................. 25

5.4.4 Chronic Dietary and Drinking Water Analysis ................................................... 26

6.0 RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE/RISK 

CHARACTERIZATION ........................................................................................................... 27

6.1 Residential Bystander Postapplication Inhalation Exposure .................................... 30

6.2 Spray Drift...................................................................................................................... 30

7.0 AGGREGATE EXPOSURE/RISK CHARACTERIZATION..................................... 30

7.1 Acute & Chronic Aggregate Risk................................................................................. 31

7.2 Short-Term Aggregate Risk ......................................................................................... 31

7.3 Intermediate-Term Aggregate Risk............................................................................. 32

8.0 Cumulative Exposure/Risk Characterization ................................................................ 32

9.0 OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION.............................. 32

9.1 Exposure Scenarios....................................................................................................... 32

9.2 Handler Exposure.......................................................................................................... 33

9.2.1 Handler Exposure Scenarios.................................................................................. 33

9.3 Post-Application Exposure ........................................................................................... 33

9.3.1 Restricted Entry Interval ....................................................................................... 34

10. REFERENCES.................................................................................................................. 35

APPENDIX A. TOXICOLOGY DATA SUMMARY ............................................................. 36

APPENDIX B. Chemical Names And Structures Of Metabolites......................................... 45

APPENDIX C. Physical/Chemical Properties.......................................................................... 46

APPENDIX D. Studies Reviewed for Ethical Conduct.......................................................... 46
Page 4 of 47

1.0 EXECUTIVE SUMMARY

The Interregional Research Project #4 (IR-4) is proposing new foliar uses of difenoconazole on 

globe artichoke, ginseng and greenhouse grown cucumbers and conversion of registered uses of 

difenoconazole on stone fruit group 12 and tree nut group 14 to stone fruit group 12-12 and tree 

nut group, respectively.

This document addresses the exposures and risks associated with exposures from currently 

registered uses and the proposed amended use of difenoconazole. It also assesses potential 

enhanced sensitivity of infants and children from dietary and/or residential exposure as required 

under the Food Quality Protection Act (FQPA) of 1996.

Use Profile

Difenoconazole is a broad spectrum fungicide belonging to the triazole group of fungicides. 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 post-harvest use on members of tuberous and corm 

vegetables subgroup 1C and pome fruit group 11-10 (pending but imminent) and for multiple 

late-season foliar applications on numerous crops including stone fruit group 12 and tree nut 

group 14. 

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 application methods and equipment. It is 

applied to ornamentals by residential applicators using hand held sprayers. 

Proposed New Uses

Under Section B of the petition 4E8274, IR-4 has submitted directions for use on artichoke 

(intended to be globe artichoke consistent with the submitted field trial data although not 

specified in the use directions), ginseng, stone fruit group 12-12 and tree nut group 14-12 for the 

2.08 lb ai/gal EC formulation of difenoconazole (InspireTM Fungicide; EPA Reg. No. 100-1262) 

and a 1.05 lb ai/gal multiple active ingredient (MAI) suspension concentrate (SC) formulation 

with azoxystrobin (Quadris TopTM Fungicide; EPA Reg. No. 100-1313). In addition, IR-4 has 

submitted directions for use on artichoke (intended to be globe artichoke consistent with the 

submitted field trial data although not specified in the use directions), stone fruit 12-12 and 

cucumber (greenhouse) for a 0.73 lb ai/gal MAI emulsion oil in water (EW) formulation with 

cyprodinil (Inspire Super TM Fungicide; EPA Reg. No. 100-1317). In addition, IR-4 submitted 

draft supplemental labels, which are substantially similar to Section B of the petition.
Page 5 of 47

This review addresses difenoconazole only. Other active ingredients and uses listed on the 

new end-use product labels will not be discussed herein. This assessment does address the 

updated aggregate assessment for free triazole and its conjugates. 

Toxicological Effects

The toxicology database for difenoconazole is complete for evaluating and characterizing 

toxicity and selecting endpoints for purposes of this 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 excessive toxicity observed at the two highest doses, the absence of 

tumors at the lower doses and the absence of genotoxic effects. The FQPA Safety Factor is 

reduced to 1X. 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.

Dose Response Assessment

Toxicological points of departure (PODs) were selected for dietary and drinking water exposures 

for the assessment of proposed new uses of difenoconazole. Acute and chronic PODs were 

selected for assessment of food and water exposures. 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 100X was applied endpoints selected for all exposures routes (10X for 

interspecies extrapolation, 10X for intraspecies variation, 1X FQPA SF). 

Exposure/Risk Assessment and Risk Characterization

Conservative acute and refined chronic dietary and drinking water risk assessments for 

difenoconazole conclude that dietary and drinking water exposure estimates are below HED’s 

level of concern for the general population and all population subgroups. At the 95th percentile, 

the acute dietary exposure to the general U.S. population is 15% of the aPAD; the highest 
Page 6 of 47

exposed subgroup (All Infants < 1 yr) is 49% of the aPAD. The chronic dietary exposure to the 

general U.S. population is 26% of the cPAD, and the most highly exposed subgroup (Children 1-

2 yrs old) is 89% of the cPAD. The previous triazole dietary exposure assessment was updated

(T. Morton, D426492, 4/9/15). A new residential assessment was not performed since there are 

no proposed new residential uses at this time. The currently registered outdoor and indoor 

residential exposure scenarios have been previously reassessed for all difenoconazole uses based 

on the Revised Residential SOPs (2012); no risk estimates of concern were identified (D421188, 

I. Nieves, 02/24/2015). Previously assessed residential exposure risk estimates were combined 

with current dietary exposure estimates for the aggregate risk assessment. Aggregate risk 

estimates were not of concern. Risk estimates for occupational handler and post-application 

exposure scenarios for all proposed uses have also been previously assessed at a similar and/or 

higher rate (D421188, I. Nieves, 02/24/2015). None of the existing or proposed new uses were 

of concern at maximum use rates with label required PPE (i.e., long shirt, long pants, shoes, 

socks and gloves).

Aggregate Assessment of Free Triazole & its Conjugates

The previous aggregate human health risk assessment was updated for free triazoles and its 

conjugates and the aggregate estimates remain below HED’s level of concern (T. Morton, 

D426493, 4/9/15). 

Use of Human Studies

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, listed in Appendix 2.0, 

have been determined to require a review of their ethical conduct. Some of these studies are also 

subject to review by the Human Studies Review Board. All of the studies used have received the 

appropriate review. 

Environmental Justice

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 Low-Income 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. 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 post-application 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. 
Page 7 of 47

2.0 HED RECOMMENDATIONS

2.1 Data Deficiencies 

Deficiencies are stated below. The specific tolerance recommendations are discussed in Section 

2.2.3 Recommended Tolerances. 

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate enforcement method, GC/NPD method AG-575B, is available for the determination 

of residues of difenoconazole per se in/on plant commodities. An adequate enforcement method, 

GC/MSD method AG-676A, is also available for the determination of residues of difenoconazole 

per se in/on canola and barley commodities. A confirmatory method, GC/MSD method AG-676, 

is also available. The LOQs are 0.01-0.05 ppm. 

2.2.2 Recommended Tolerances

HED has examined the residue chemistry database for difenoconazole. With regards to 

difenoconazole, pending submission of a revised Section B (see requirements under 860.1200 

Directions for Use) and Section F (see requirements under 860.1550 Proposed Tolerances) of 

petition 4E8274, there are no residue chemistry issues that would preclude granting the proposed 

foliar uses on globe artichoke, ginseng and greenhouse grown cucumbers or the expansion of 

existing foliar uses on stone fruit group 12 and tree nut group 14 to new crop groups fruit, stone, 

group 12-12 and nut, tree, group 14-12 or establishment of tolerances for residues of 

difenoconazole in/on the following commodities:

Artichoke, globe .......................................................................1.5 ppm

Ginseng.....................................................................................1.0 ppm

Fruit, stone, group 12-12 ..........................................................2.5 ppm

Nut, tree, group 14-12...............................................................0.03 ppm

Concomitantly, the tolerances for residues of difenoconazole in/on the following commodities

should be removed:

Fruit, stone, group 12................................................................2.5 ppm

Nut, tree, group 14 ....................................................................0.03 ppm

Pistachio....................................................................................0.03 ppm

Tolerances for plant commodities are established under §180.475(a)(1), and are expressed in 

terms of difenoconazole per se. The tolerance expression proposed by IR-4 is in terms of 

difenoconazole per se. The tolerances proposed by IR-4 are listed in Table 2.2.2 along with the 

tolerance levels recommended by HED and correct commodity definitions.
Page 8 of 47

Table 2.2.2. Tolerance Summary for Difenoconazole.

Commodity Proposed 

Tolerance 

(ppm)

Recommended 

Tolerance 

(ppm)

Correct Commodity Definition;

Comments

Artichoke, globe 1.5 1.5 Artichoke, globe

Ginseng 0.50 1.0 Ginseng

Fruit, stone, group 12-12 2.5 2.5 Fruit, stone, group 12-12

Nut, tree, group 14-12 0.03 0.03 Nut, tree, group 14-12

Fruit, stone, group 12 Remove Remove Currently established at 2.5 ppm

Nut, tree, group 14 Remove Remove Currently established at 0.03 ppm

Pistachio Remove Remove Currently established at 0.03 ppm

2.2.3 Revisions to Petitioned-For Tolerances

The recommended tolerance for residues of difenoconazole in/on ginseng (1.0 ppm) is not the 

same as the petitioned-for tolerance (0.5 ppm) due to the finding that residues of difenoconazole 

appeared to increase significantly with a PHI longer than the proposed 0-day PHI. Average 

per-trial residues increased by a factor of as much as 2.3x between the 0- and 21-day PHIs and 

based on this finding, ChemSAC (9/27/14) determined that average per-trial residues of 

difenoconazole for trials reflecting a 0-day PHI should be adjusted by a factor of 2.3x to 

account for the maximum demonstrated increase in difenoconazole residues resulting from 

PHIs longer than the proposed 0-day PHI and these adjusted residues have been used in the 

OECD tolerance calculation procedures.

2.2.4 International Harmonization

Codex maximum residue limits (MRLs) for residues of difenoconazole have been established at 

0.08 ppm for ginseng; at 0.2 ppm for ginseng, dried including red ginseng; at 0.6 ppm for 

ginseng extracts; at 0.2 ppm for cherries and plums (including prunes); at 0.5 ppm for nectarines 

and peaches; and at 0.03 ppm for tree nuts. Canadian MRLs have been established for 

difenoconazole for individually listed members of stone fruit group 12-12 and tree nut group 14-

12 at 2.5 ppm and 0.03 ppm, respectively. Mexico adopts U.S. tolerances and/or Codex MRLs 

for its export purposes. Based on the submitted/available magnitude of the residue data, 

harmonization with established Codex MRLs is not possible for ginseng, cherries, plums 

(including prunes), nectarines, peaches, because the Codex MRLs are too low. The U.S. 

tolerances for stone fruit (2.5 ppm) and tree nuts (0.03 ppm) are harmonized with the established 

Canadian MRLs for individually listed members of these groups and with the established Codex 

MRL for tree nuts. There are no established Codex, Canadian or Mexican MRLs for residues of 

difenoconazole for globe artichoke so harmonization for this commodity is not possible. 

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews
Page 9 of 47

Section B of petition 4E8274 pertaining to uses on artichoke should be revised to specify globe 

artichoke only. [Note: IR-4 submitted draft supplemental labels which are substantially similar 

to Section B of the petition and should be amended as well.]

3.0 INGREDIENT PROFILE 

3.1 Chemical Identity

The chemical structure and nomenclature of difenoconazole and its regulated livestock 

metabolite CGA-205375, is presented in Tables 3.1.1.

Table 1. Difenoconazole Nomenclature.

Chemical structure of parent

mol. wt. 406.3

Common name Difenoconazole

Company experimental name CGA-169374

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

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

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

1H-1,2,4-triazole

CAS registry number 119446-68-3

Chemical structure of 

CGA-205375 livestock 

metabolite

mol. wt. 349.2

Chemical structure of 

1,2,4-Triazole (1,2,4-T)

Chemical structure of 

Triazolyl alanine (TA)

Chemical structure of

Triazolyl acetic acid (TAA)

O O

O

N N Cl

N

CH3

Cl

O

N N Cl

N

OH Cl

HN

N

N

N

N

N

HO

NH2

O

N

N

N

HO

O
Page 10 of 47

3.2 Physical/Chemical Characteristics 

The physicochemical properties of difenoconazole are reported in Appendix C. 

3.3 Pesticide Use Pattern

Under Section B of the petition 4E8274, IR-4 has submitted directions for use on artichoke 

(intended to be globe artichoke consistent with the submitted field trial data although not 

specified in the use directions), ginseng, stone fruit group 12-12 and tree nut group 14-12 for the 

2.08 lb ai/gal EC formulation of difenoconazole (InspireTM Fungicide; EPA Reg. No. 100-1262) 

and a 1.05 lb ai/gal multiple active ingredient (MAI) suspension concentrate (SC) formulation 

with azoxystrobin (Quadris TopTM Fungicide; EPA Reg. No. 100-1313). In addition, IR-4 has 

submitted directions for use on artichoke (intended to be globe artichoke consistent with the 

submitted field trial data although not specified in the use directions), stone fruit 12-12 and 

cucumber (greenhouse) for a 0.73 lb ai/gal MAI emulsion oil in water (EW) formulation with 

cyprodinil (Inspire Super TM Fungicide; EPA Reg. No. 100-1317). In addition, IR-4 submitted 

draft supplemental labels which are substantially similar to Section B of the petition. The subject 

end-use products are identified in Table 3.3.1, and the use directions based on Section B of the 

petition are summarized in Table 3.3.2.
Page 11 of 47

Table 3.3.1. Summary of End-Use Products and Crops Under Consideration.

Trade Name EPA Reg. 

No.

ai Content Formulation 

Type

Target Crops Source of Use

Directions 

InspireTM 

Fungicide

100-1262 Difenoconazole

2.08 lb ai/gal

(23.2%)

Emulsifiable 

concentrate

(EC)

Artichoke1

Ginseng

Stone Fruit Group 12-12: 

apricot; apricot, Japanese; 

capulin; cherry, black; cherry, 

Nanking; cherry, sweet; cherry, 

tart; Jujube, Chinese; nectarine; 

peach; plum; plum, American; 

plum, beach; plum, plumcot; sloe; 

cultivars,varieties, and/or hybrids 

of these.

Tree Nuts Group 14-12: African 

nut-tree; almond2; beechnut’ 

Brazil, nut; Brazilian pine; bunya; 

bur, oak; butternut; Cajou nut; 

candlenut; cashew; chestnut; 

chinquapin; coconut; coquito nut; 

dika nut; ginkgo; Guiana 

chestnut; hazelnut (filbert)2; 

heartnut; hickory nut; Japanese 

horse-chestnut; macadamia nut; 

mongongo nut; monkey-pot; 

monkey puzzle nut; Okari nut; 

Pachira nut; peach palm nut; 

pecan2; pequi; Pili nut; pine nut; 

pistachio2; Sapucaia nut; tropical

almond; walnut, black; walnut, 

English; yellowhorn; cultivars, 

varieties, and/or hybrids of these.

Section B of 

petition which 

is consistent 

with the Draft 

Supplemental 

Label

Dated 

11/11/13

Quadris 

TopTM 

Fungicide

100-1313 Difenoconazole

1.05 lb ai/gal 

(11.4%)

Azoxystrobin

1.67 lb ai/gal 

(18.2%)

Suspension 

concentrate

(SC)

Section B of 

petition which 

is consistent 

with the Draft 

Supplemental 

Label

Dated 11/8/13

Inspire 

SuperTM 

Fungicide

100-1317 Difenoconazole

0.73 lb ai/gal

(8.4%)

Cyprodinil

2.09 lb ai/gal

(24.1%)

Emulsion oil 

in water (EW)

Artichoke1

Cucumber (Greenhouse)

Stone Fruit Group 12-12: 

apricot; apricot, Japanese; 

capulin; cherry, black; cherry, 

Nanking; cherry, sweet; cherry, 

tart; Jujube, Chinese; nectarine; 

peach; plum; plum, American; 

plum, beach; plum, plumcot; sloe; 

cultivars,varieties, and/or hybrids 

of these.

Section B of 

the Petition 

which is 

consistent with 

the Draft 

Supplemental 

Label

Dated 

12/17/13

1 Although not specified in the use directions, the use on artichoke is intended to be for globe artichoke consistent 

with the supporting data.

2 While almonds, filberts, pecans and pistachios are listed among the target crops in Section B of the petition, they 

are listed separately on the currently registered end-use product labels as indicated in Section B of the petition and 

there are specific use directions for them on the currently registered end-use product labels. Some of these specific 

use directions are less restrictive.
Page 12 of 47

Table 3.3.2. Summary of Directions for Use of Difenoconazole.

Appl. Timing, 

Type, and Equip.

Formulation

[EPA Reg. No.]

Max. Appl. 

Rate 

(lb ai/A)

Max. No. 

Appl. per 

Season

Max. 

Seasonal 

Appl. Rate

(lb ai/A)

PHI1

(days)

Use Directions 

and 

Limitations2

Ginseng 

Foliar,

Broadcast, Ground 

(≥15 gal/A), aerial 

(≥10 gal/A) or 

chemigation (0.1-

0.25 inches/A)

2.08 lb ai/gal EC

[100-1262]

0.114-0.115 Not Specified 

(NS)

0.46 0 The minimum 

retreatment 

interval is 7 

days. 

1.05 lb ai/gal 

MAI SC

[100-1313]

Artichoke3

Foliar,

Broadcast, Ground 

(≥50 gal/A), aerial 

(≥10 gal/A) or 

chemigation (0.1-

0.25 inches/A)

2.08 lb ai/gal EC

[100-1262]

0.114-0.115 NS 0.46 3 The minimum 

retreatment 

interval is 14 

days 1.05 lb ai/gal 

MAI SC

[100-1313]

0.73 lb ai/gal 

MAI EW

[100-1317]

Cucumber (Greenhouse)

Foliar,

Broadcast, Ground 

(≥15 gal/A), aerial 

(≥10 gal/A) or 

chemigation (0.1-

0.25 inches/A)

0.73 lb ai/gal 

MAI EW

[100-1317]

0.114-0.115 Not Specified 

(NS)

0.46 0 The minimum 

retreatment 

interval is 7 

days. 

Stone Fruit 12-124

Foliar,

Broadcast, Ground 

(≥15 gal/A) or 

aerial (≥10 gal/A)

2.08 lb ai/gal EC

[100-1262]

0.114-0.115 Not Specified 

(NS)

0.46 0 The minimum 

retreatment 

interval is 7 

days. 

1.05 lb ai/gal 

MAI SC

[100-1313]

0.73 lb ai/gal 

MAI EW

[100-1317]

2

Tree Nut 14-124 [Note: While almonds, filberts, pecans and pistachios are listed among the target crops in 

Section B of the petition, they are listed separately on the currently registered end-use product labels as indicated 

in Section B of the petition and there are specific use directions for them on the currently registered end-use 

product labels. Some of these specific use directions are less restrictive.]
Page 13 of 47

Table 3.3.2. Summary of Directions for Use of Difenoconazole.

Appl. Timing, 

Type, and Equip.

Formulation

[EPA Reg. No.]

Max. Appl. 

Rate 

(lb ai/A)

Max. No. 

Appl. per 

Season

Max. 

Seasonal 

Appl. Rate

(lb ai/A)

PHI1

(days)

Use Directions 

and 

Limitations2

Foliar,

Broadcast, Ground 

(≥15 gal/A) or 

aerial (≥10 gal/A)

2.08 lb ai/gal EC

[100-1262]

0.114-0.115 NS 0.46 14 The minimum 

retreatment 

interval is 14 

days. 1.05 lb ai/gal 

MAI SC

[100-1313]

45

1 PHI = pre-harvest interval.

2 All use directions include the following: Make no more than 2 sequential applications before alternating to 

another fungicide with a different mode of action.

3 Although not specified in the use directions, the use on artichoke is intended to be for globe artichoke consistent 

with the supporting data.

4 These are the same use direction currently on the labels for stone fruit group 12 and tree nuts group 14.

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the 

proposed uses of difenoconazole on new foliar uses on globe artichoke, ginseng and greenhouse 

grown cucumbers and conversion of the established foliar uses/tolerances for stone fruit group 

12 and tree nut crop group 14 to stone fruit group 12-12 and tree nut group 14-12. For domestic 

uses, humans may be exposed to difenoconazole in food and drinking water, since 

difenoconazole may be applied directly to growing crops and application may result in 

difenoconazole reaching surface and ground water sources of drinking water. There are also 

residential uses of difenoconazole, so there is exposure in residential or non-occupational 

settings. In an occupational setting, applicators may be exposed while handling the pesticide 

prior to application, as well as during application. There is a potential for post-application 

exposure for workers re-entering treated fields. 

Risk assessments have been previously conducted for the existing uses of difenoconazole. This 

risk assessment considers all of the aforementioned exposure pathways based on the proposed 

uses of difenoconazole, but also considers the existing uses as well.

3.5 Considerations of Environmental Justice

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 Low-Income 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 
Page 14 of 47

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 

post-application 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.

4.0 HAZARD CHARACTERIZATION AND DOSE-RESPONSE ASSESSMENT

4.1 Toxicology Studies Available for Analysis

The toxicology database for difenoconazole is complete for evaluating and characterizing 

difenoconazole toxicity and selecting endpoints for purposes of this risk assessment. All toxicity 

studies required in accordance with new 40 CFR Part 158 data requirements have been 

submitted. The Hazard and Science Policy Council (HASPOC) concluded that a 28-day 

inhalation toxicity study is not required at this time (TXR 0054074).

4.2 Absorption, Distribution, Metabolism and Excretion (ADME)

The absorption, distribution, metabolism, and excretion of difenoconazole were studied in rats. 

In one study, the test compound was labeled with C14 at either the phenyl or triazole ring. 

Animals were administered a single oral gavage dose of 0.5 or 300 mg/kg of radiolabeled 

compound or 0.5 mg/kg unlabeled compound by gavage for 14 days followed by a single gavage 

dose of 0.5 mg/kg [14C]-difenoconazole on day 15. In a second follow-up study [14C]-

difenoconazole (phenyl ring label) was administered as single oral gavage dose of 0.5 or 300 

mg/kg. The second study was conducted to address deficiencies in the initial study by providing 

biliary excretion and identification of metabolites. 

Difenoconazole was rapidly absorbed and extensively distributed, metabolized, and excreted in 

rats for all dosing regimens. Distribution, metabolism and elimination of difenoconazole were 

not sex related in the first study. Recovery of administered dose was 96-108%. Biliary 

excretion, examined in the second study, constituted the main route of elimination with some 

dose and sex dependency (75% at the low dose for both sexes; 56% for males and 39% for 

females at the high dose). Urinary and fecal eliminations exhibited a dose-related pattern at 48 

hours. In bile duct cannulated rats, 9-l4% of dose was eliminated in the urine at the low dose 

versus 1% in the high-dose rats. In bile duct cannulated rats, 2-4% was eliminated in the feces at 

the low dose versus 17-22% at the high dose. Half-lives of elimination are approximately 20 

hours for the low dose groups and 33-48 hours for the high dose group. Radioactivity in the 

blood peaked at 2 to 4 hours at the low and high dose respectively. 

Difenoconazole undergoes successive oxidation and conjugation reactions. Following 

administration of 300 mg/kg of (14C-phenyl) difenoconazole, three major urinary metabolites 
Page 15 of 47

were identified as CGA 205375 and HO-CGA 205375 (6% of dose), sulfate conjugates (and 

their isomers) of HO-205375 (3.9% of dose), and the hydroxyacetic metabolite of HO-CGA 

205375 (2.0% of dose). No single unknown urinary metabolite accounted for >1.1% of the dose. 

Free triazole metabolite was detected in the urine of the triazole-label groups and its byproduct 

was detected in the liver of phenyl labeled groups only.

The study results indicate that difenoconazole and/or its metabolites do not bioaccumulate 

appreciably following oral exposure since all tissues contained negligible levels (<1%) or 

radioactivity 7 days post exposure.

A dermal absorption factor of 6% was derived based on data from a triple pack of a rat in vivo

dermal absorption study and in vitro dermal absorption studies conducted with rat and human 

skin (TXR 0056473). Inhalation toxicity is assumed to be equivalent to oral toxicity. 

4.3 Toxicological Effects

Subchronic and chronic studies with difenoconazole in mice and rats showed decreased body 

weights, decreased body weight gains and effects on the liver (e.g. hepatocellular hypertrophy, 

liver necrosis, fatty changes in the liver). No systemic toxicity was observed at the limit dose in 

the most recently submitted 28-day rat dermal toxicity study. 

The available toxicity studies indicated no increased susceptibility of rats or rabbits from in utero

or postnatal exposure to difenoconazole. In prenatal developmental toxicity studies in rats and 

rabbits and in the two-generation reproduction study in rats, fetal/offspring toxicity, when 

observed, occurred at equivalent or higher doses than in the maternal/parental animals. 

In a rat developmental toxicity study, developmental effects were observed at doses higher than 

those which caused maternal toxicity. Developmental effects in the rat included increased 

incidence of ossification of the thoracic vertebrae and hyoid, decreased number of sternal centers 

of ossification, increased number of ribs and thoracic vertebrae, and decreased number of lumbar 

vertebrae. In the rabbit study, developmental effects (increases in post-implantation loss and 

resorptions and decreases in fetal body weight) were also seen at maternally toxic (decreased 

body weight gain and food consumption) doses. In 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 an acute neurotoxicity study in rats, reduced fore-limb grip strength was observed on day 1 in 

males at the LOAEL of 200 mg/kg. The effect in males is considered transient since it was not 

observed at later observation points. Toxicity in females was observed only at the limit dose

(2000 mg/kg). In a subchronic neurotoxicity study in rats, decreased hind limb strength was 

observed in males only at ≥ 17.5 mg/kg/day doses. The effects observed in acute and subchronic 

neurotoxicity studies are transient, and the dose-response is well characterized with identified 

NOAELs. Based on the toxicity profile, and lack of concern for neurotoxicity, a developmental 

neurotoxicity study in rats is not required.

In an immunotoxicity study in mice difenoconazole produced immunotoxicity at doses that 
Page 16 of 47

caused systemic toxicity. 

In accordance with HED’s current policy and EPA’s 2005 Cancer Guidelines, difenoconazole is 

classified as “Suggestive Evidence of Carcinogenic Potential” based on liver tumors observed in 

mice at 300 ppm and higher, the absence of tumors at two lower doses of 10 and 30 ppm, 

excessive toxicity observed at the two highest doses of 2500 and 4500 ppm, the absence of 

genotoxicity and no evidence of carcinogenicity in rats (TXR 0054532). HED’s Cancer Peer 

Review Committee recommended use of an MOE approach to risk assessment using the chronic 

point of departure (POD) based on effects observed in the chronic mouse study relevant to tumor 

development (i.e., hepatocellular hypertrophy, liver necrosis, fatty changes in the liver and bile 

stasis). The POD is considered protective of the cancer effects. 

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

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

The complete toxicity profile for difenoconazole is provided in Appendix A. 

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

Based on the lack of quantitative or qualitative sensitivity and complete toxicity database for 

difenoconaozle, the FQPA factor for increased susceptibility to infants and children may be 

reduced to 1x.

4.4.1 Completeness of the Toxicology Database

The toxicity database is sufficient for a full hazard evaluation and is considered adequate to 

evaluate risks to infants and children. The Hazard and Science Policy Council (HASPOC) 

concluded that a 28-day inhalation toxicity study is not required at this time (TXR 0054074). 

4.4.2 Evidence of Neurotoxicity

There are no clear signs of neurotoxicity following acute, subchronic or chronic dosing in 

multiple species in the difenoconazole database. The effects observed in acute and subchronic 

neurotoxicity studies are transient, and the dose-response is well characterized with identified 

NOAELs. 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

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. 

In a rat developmental toxicity study developmental effects were observed at doses higher than 

those which caused maternal toxicity. In the rabbit study, developmental effects (increases in 
Page 17 of 47

post-implantation loss and resorptions and decreases in fetal body weight) were also seen at 

maternally toxic doses (decreased body weight gain and food consumption). In the twogeneration reproduction study in rats, toxicity to the fetuses/offspring, when observed, occurred 

at equivalent or higher doses than in the maternal/parental animals.

4.4.4 Residual Uncertainty in the Exposure Database 

There are no residual uncertainties in the exposure database. The dietary risk assessment is 

conservative (tolerance level residues and 100% crop treated for the acute while the chronic used 

USDA Pesticide Data Program (PDP) monitoring data, average field trial residues for some 

commodities, tolerance level residues for remaining commodities, and average percent crop 

treated for some commodities) and will not underestimate dietary exposure to difenoconazole.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

Toxicity endpoints and points of departure (PODs) for dietary (food and water), occupational, 

and residential exposure scenarios are summarized below. A detailed description of the studies 

used as a basis for the selected endpoints are presented in Appendix A. 

An acute POD of 25 mg/kg/day (NOAEL) was selected from an acute neurotoxicity study in rats 

based on reduced fore-limb grip strength in males on day 1 at the LOAEL of 200 mg/kg/day. An 

uncertainty factor (UF) of 100x (10x to account for interspecies extrapolation and 10x for 

intraspecies variation) was applied to the NOAEL to obtain an acute reference dose (aRfD) of 

0.25 mg/kg/day. Since the FQPA factor has been reduced to 1X, the acute population adjusted 

dose (aPAD) is equivalent to the aRfD. The selected endpoint is considered appropriate for 

acute dietary exposure because effects were seen after a single dose. The endpoint is protective 

of the general population and all subpopulations for effects seen in the acute neurotoxicity study 

in rats. It is also protective of developmental and maternal effects observed in the rabbit 

developmental toxicity study at the LOAEL of 75 mg/kg/day (NOAEL of 25 mg/kg/day).

A chronic POD of 0.96 mg/kg/day (NOAEL) was selected from a chronic toxicity/

carcinogenicity oral study in rats based on cumulative decreases in body weight gains in males 

observed at the LOAEL of 24 mg/kg/day. A UF of 100x (10x to account for interspecies 

extrapolation and 10x for intraspecies variation) was applied to the dose to obtain a chronic 

reference dose (cRfD/cPAD) of 0.01 mg/kg/day. Since the FQPA factor has been reduced to 1X, 

the chronic population adjusted dose (cPAD) is equivalent to the cRfD. 

Short-term incidental oral and short- and intermediate term dermal and inhalation PODs of 1.25 

mg/kg/day were selected from a two generation reproduction study in rats based on decreased 

pup weight in males at 12.5 mg/kg/day (LOAEL) on day 21, and reductions in body weight gain 

in F0 females. Although dermal toxicity studies are available, a POD from an oral study was 

selected because effects in young animals (decreased pup weight) the primary effect of concern 

for short, intermediate and long term exposure is not specifically evaluated in the available 

dermal toxicity studies that only assess adult animals. The selected endpoint is protective of 
Page 18 of 47

offspring effects from dermal exposure. An MOE of 100 is the level of concern (LOC) for the 

short- and intermediate-term dermal and inhalation exposure scenarios based on the conventional 

uncertainty factor of 100 (10x for interspecies extrapolation and 10x for intraspecies variation). 

There are no residential uses for difenoconazole that would result in incidental oral exposure to 

children. 

A dermal absorption factor (DAF) is applied when dermal exposure endpoints are selected from 

oral toxicity studies. The dermal factor converts the oral dose to an equivalent dermal dose for 

the risk assessment. A DAF of 6% was selected for use in risk assessment based on available in 

vivo dermal absorption studies in rat and in vitro dermal absorption studies conducted with rat 

and human skin (TXR 0056473). 

4.5.2 Recommendations for Combining Exposure Routes for Risk Assessment

When there are potential residential exposures to the pesticide, the aggregate risk assessment 

must consider exposures from three major sources: oral, dermal and inhalation exposures. There 

are potential residential post-application exposures to adults via the dermal route and to children 

via dermal and incidental oral routes of exposure. The common toxicological effect for the oral, 

dermal, and inhalation routes is body weight. 

4.5.3 Cancer Classification and Risk Assessment Recommendations

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, 

the absence of genotoxic effects, and no evidence of carcinogenicity in rats. In accordance with 

HED’s current policy and EPA’s 2005 Cancer Guidelines, difenoconazole is classified as 

“Suggestive Evidence of Carcinogenic Potential,” based on excessive toxicity observed at the 

two highest doses, the absence of tumors at the lower doses and the absence of genotoxic effects

(TXR 0054532). Based on the CPRC recommendation, the risk assessment uses an (MOE) 

approach 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). The chronic 

POD of 0.96 mg/kg/day selected based on bodyweight effects is protective of the cancer effects. 

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Risk 

Assessment

Toxicological doses/endpoints selected for the difenoconazole risk assessment are provided in 

Tables 4.5.4.1 and 4.5.4.2.
Page 19 of 47

Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Difenoconazole for Use in Dietary and NonOccupational 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

(MRID 46950327)

LOAEL= 200 mg/kg in males based 

on reduced fore-limb grip strength 

in males on day 1.

Chronic Dietary 

(All populations)

NOAEL = 0.96

mg/kg/day

UFA = 10X

UFH = 10X

UFFQPA = 1X

cRfD = cPAD = 

0.01mg/kg/day

Combined chronic 

toxicity/carcinogenicity (rat; dietary, 

MRID 42090019, 42710010) 

LOAEL = 24.1/32.8 mg/kg/day 

(M/F) based on cumulative 

decreases in body-weight gains.

Incidental Oral 

Short-Term (1-30 

days)

Oral NOAEL = 

1.25

mg/kg/day

UFA = 10X

UFH = 10X

UFFQPA = 1X

Residential LOC 

for MOE<100

Reproduction and fertility Study 

(rat; dietary, MRID 42090018) 

Parental/Offspring LOAEL = 12.5 

mg/kg/day based on decreased pup 

weight in males on day 21 and 

reduction in body-weight gain of F0

females prior to mating, gestation 

and lactation.

Dermal

Short- and 

IntermediateTerm (1-30 days 

and 1-6 months) 

DAF = 6%

Oral NOAEL = 

1.25

mg/kg/day

UFA = 10X

UFH = 10X

UFFQPA = 1X

Residential LOC 

for MOE<100

Reproduction and fertility Study 

(rat; dietary, MRID 42090018) 

Parental/Offspring LOAEL = 12.5 

mg/kg/day based on decreased pup 

weight in males on day 21 and 

reduction in body-weight gain of F0

females prior to mating, gestation 

and lactation.

Inhalation

(Short- and 

Intermediate-term)

Inhalation and oral 

absorption 

assumed 

equivalent

Oral NOAEL = 

1.25

mg/kg/day

UFA = 10X

UFH = 10X

UFFQPA = 1X

Residential LOC 

for MOE<100

Reproduction and fertility Study 

(rat; dietary, MRID 42090018) 

Parental/Offspring LOAEL = 12.5 

mg/kg/day based on decreased pup 

weight in males on day 21 and 

reduction in body-weight gain of F0

females prior to mating, gestation 

and lactation.

Cancer (oral, 

dermal, inhalation)

Difenoconazole is classified “Suggestive Evidence of Carcinogenic Potential” 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).

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

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

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

human (interspecies). UFH = potential variation in sensitivity among members of the human population (intraspecies DAF = Dermal 

Absorption Factor

Table 4.5.4.2. Summary of Toxicological Doses and Endpoints for Difenoconazole for Use 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 

Oral NOAEL 

= 1.25

UFA = 10X

UFH = 10X

Occupational LOC 

for MOE<100

Reproduction and fertility Study 

(rat; dietary, MRID 42090018) 
Page 20 of 47

Table 4.5.4.2. Summary of Toxicological Doses and Endpoints for Difenoconazole for Use 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

IntermediateTerm (1-30 days 

and 1-6 months)

DAF = 6%

mg/kg/day Parental/Offspring LOAEL = 12.5 

mg/kg/day based on decreased pup 

weight in males on day 21 and 

reduction in body-weight gain of F0

females prior to mating, gestation 

and lactation.

Inhalation

(Short- and 

Intermediate-term)

Inhalation and oral 

absorption 

assumed 

equivalent

Oral NOAEL 

= 1.25

mg/kg/day

UFA = 10X

UFH = 10X Occupational LOC 

for MOE<100

Reproduction and fertility Study 

(rat; dietary, MRID 42090018) 

Parental/Offspring LOAEL = 12.5 

mg/kg/day based on decreased pup 

weight in males on day 21 and 

reduction in body-weight gain of F0

females prior to mating, gestation 

and lactation.

Cancer (oral, 

dermal, inhalation)

Difenoconazole is classified “Suggestive Evidence of Carcinogenic Potential” 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).

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

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

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

human (interspecies). UFH = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = 

FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. 

LOC = level of concern. N/A = not applicable.

5.0 DIETARY EXPOSURE AND RISK ASSESSMENT

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

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. The residue of concern for both tolerance enforcement and risk assessment for crops 

included in this petition is difenoconazole only. The nature of the residue in livestock is 

understood based on acceptable goat and hen metabolism studies. The residues of concern for 

both tolerance enforcement and risk assessment for livestock commodities are difenoconazole 

and its metabolite CGA-205375. In addition, metabolite OH-CGA-169374, which comprised 

15% of the TRR in goat milk from the phenyl-labeled study, should be considered as a residue of 

concern in milk for the dietary risk assessment. 

The nature of the residue in rotational crops is adequately understood. The metabolism of 

difenoconazole in rotational crops is similar to that of primary crops. The available 

difenoconazole confined and limited field rotational crop trials are deemed adequate to satisfy 

data requirements under Guidelines 860.1850 and 860.1900. Taken together, these data support 

a 30-day plantback interval (PBI) for cereal and root/tuber crops not already registered for foliar 

use with difenoconazole and a 60-day PBI for all other crops not already registered for foliar use 
Page 21 of 47

with difenoconazole. With these PBIs, tolerances for residues of difenoconazole are not needed 

for rotational crops. 

Structures and names of difenoconazole metabolites are provided in Appendix B. 

5.1.2 Summary of Environmental Degradation

Difenoconazole has potential to reach surface water via run-off, erosion, and spray drift, and is 

less likely to reach ground water except in soils of high sand and low organic matter content.

Environmental fate data indicate that difenoconazole is relatively stable to aerobic and anaerobic 

soil metabolisms and aerobic and anaerobic aquatic metabolism. When applied at 0.1-0.23 ppm 

to an aerobic soil, difenoconazole appears to degrade with half-lives ranging from 84.5 to 533 

days based on laboratory studies conducted on a variety of foreign and domestic soils. At 

concentrations of 10 ppm, difenoconazole degraded with the half-lives of 1059-1600 days in 

aerobic, and 947 days anaerobic loam soil, respectively. In aquatic environment under aerobic 

conditions, difenoconazole microbially degraded with half-lives ranging from 315 to 565 days at 

concentrations up to 0.17 mg ai/L, and 860 days in a concentration of 10 mg ai/L. Under 

anaerobic conditions, difenoconazole degraded in 370 days at a concentration of 0.04 mg ai/L, 

and 1245 days at concentrations of 10 mg ai/L. The longer half-life values obtained for those 

higher concentration rates may imply that the rate of difenoconazole microbially mediated 

degradation may be concentration dependent. In laboratory studies on difenoconazole a 

significant amount of radioactivity was nonextractable (14.4 to 48.9%) from soils. 

Considering abiotic degradation, difenoconazole is photolyzed in water (half-life of 6 to 228 

days), but stable in soil. The half-life of 228 days was extrapolated from a 15-day study in which 

difenoconazole slowly photolyzed from 100% to 91% under artificial light conditions (MRID 

46950105). Also, the compound is stable to hydrolysis at pH values from 4 to 9. 

Difenoconazole degraded with half-lives ranging from 139 to 462 days in the terrestrial field 

dissipation studies. The overall stability of the compound in the terrestrial environment suggests 

that difenoconazole may accumulate in soil with successive applications from year to year.

5.1.3 Comparison of Metabolic Pathways

Little information is available on the toxicity of the major difenoconazole metabolites. The 

CGA-205375 metabolite formed in livestock appears to be formed in the rat also and is, 

therefore, part of the total toxic exposure for these animals. 

5.1.4 Residues of Concern Summary and Rationale

Residues of concern were determined based on recommendations from the HED Residues of 

Concern Knowledgebase Sub-committee (ROCKS) (D391350, 9/19/11). The residue of concern 

for plant commodities for tolerance enforcement and risk assessment purposes is difenoconazole 

only. The HED ROCKS has determined that the parent compound and the CGA-205375 

metabolite are the residues of concern in livestock commodities for both the tolerance 

enforcement and the risk assessment. In addition, metabolite OH-CGA-169374, which 
Page 22 of 47

comprised 15% of the TRR in goat milk from the phenyl-labeled study, should be considered as 

a residue of concern in milk for the dietary risk assessment. Based on available goat metabolism 

data, total residues of concern in milk for dietary risk assessments (parent, CGA-205375 and 

OH-CGA-169374), should be calculated by multiplying the tolerance in milk by a factor of 1.5x. 

Table 5.1.4 summarizes tolerance expression and the residues of concern in plant and livestock 

commodities. 

Difenoconazole belongs to the triazole group of fungicides. The triazole metabolites common to 

the group, 1,2,4-triazole (1,2,4-T), triazolylalanine (TA) and triazolylacetic acid (TAA), are 

residues of concern for risk assessment purposes and are assessed separately from the parent 

compound.

Table 5.1.4. Difenoconazole Residues of Concern in Plants and Ruminants.

Matrix

Residues of Concern

For Risk Assessment For Tolerance Expression

Plants Primary and Rotational crops Parent Only Parent Only

Livestock Ruminant and Poultry Parent and CGA 205375 Parent and CGA 205375

Milk Parent, CGA 205375 and 

OH-CGA-169374

Parent and CGA 205375

Drinking Water Parent and CGA 205375 NA

Note: The triazole-containing metabolites 1,2,4-T, TA, and TAA should be included in the residues of concern for risk 

assessment purposes only for plant and livestock commodities. Since these metabolites are common to the entire class of 

traizole-derivative fungicides and because of differential toxicity between metabolites and the various parent compounds, risks 

associated with exposure to 1,2,4-T and to TA/TAA are addressed separately.

5.2 Food Residue Profile

5.2.1 Residues in Crops

The submitted globe artichoke field trial data conducted with an EW formulation of 

difenoconazole, the ginseng field trial data conducted with a SC formulation of difenoconazole 

and the greenhouse grown cucumber field trial data conducted with an EW formulation of 

difenoconazole are adequate to support the proposed uses of difenoconazole on globe artichoke, 

ginseng and greenhouse grown cucumber. The number and locations of field trials reflecting the 

proposed uses are in accordance with Guideline 860.1500. Using the Organization for Economic 

Cooperation and Development (OECD) tolerance calculation procedures, the recommended 

tolerances for residues of difenoconazole in/on artichoke, globe and ginseng are 1.5 ppm and 1.0 

ppm, respectively. The existing tolerance of 0.70 ppm in/on vegetable, cucurbit, group 9 will 

cover residues incurred in/on greenhouse grown cucumber at the proposed use rate. The 

recommended tolerance in/on artichoke, globe is the same as the petitioned-for tolerance; 

however, the recommended tolerance in/on ginseng (1.0 ppm) is not the same as the petitionedfor tolerance (0.50 ppm) due to the need to use an adjustment factor (2.3x) for the ginseng 

residue data reflecting the proposed 0-day PHI based on residue decline data that indicated 

that residues of difenoconazole incurred in/on ginseng could increase significantly with a 

longer PHI (ChemSAC 9/17/14).

No data were submitted in support of the proposed uses of the EC and SC formulation of 
Page 23 of 47

difenoconazole on globe artichoke or the EC formulation of difenoconazole on ginseng; 

however, having considered the available bridging data comparing residues of difenoconazole 

from use of an EC formulation with that of an SC formulation or an EW formulation and given 

that the recommended tolerances are well above the highest average field trial (HAFT) levels 

found in the supporting magnitude of the residue data, HED concludes that the recommended 

tolerances for residues of difenoconazole are likely to cover the proposed uses of the EC and SC 

formulations of difenoconazole. 

The previously submitted cherry (tart and sweet), peach, plum, almond, and pecan field trial data 

and plum processing data which are adequate to support the currently registered uses of 

difenoconazole on stone fruit and tree nuts are adequate to support the proposed expansions of 

those uses to stone fruit group 12-12 and the tree nut group 14-12. No additional data are 

required. The recommended tolerances for residues of difenoconazole in/on fruit, stone, group 

12-12 (2.5 ppm) and nut, tree, group 14-12 (0.03 ppm) are the same as the petitioned-for 

tolerances.

5.3 Water Residue Profile

5.3.1 Estimated Drinking Water Concentrations 

This assessment provides estimated drinking water concentrations (EDWCs) of difenoconazole 

and its major metabolite, CGA-205375 (M1) in surface water and groundwater in support of 

human health risk assessment on the Interregional Research Project Number 4 (IR4) proposed 

new uses on ginseng, artichoke, and conversion on stone fruit group 12-12 and tree nut group 14-

12. The Residues of Concern Knowledgebase Subcommittee (ROCKS) of the Health Effects 

Division (HED) recommended to include CGA-205375 as a residue of concern for drinking 

water (USEPA, 2011, DP 391350). Therefore, this drinking water assessment was performed 

using total toxic residue (TTR; i.e. parent plus CGA 205375) method in support of the proposed 

Section 3 new uses following the approach used in a previous drinking water assessment for 

canola (US EPA 2013a, DP412614). Foliar spray applications (both aerial and ground spray 

applications) and chemigation, are being proposed for these crops. The EDWCs of 

difenoconazole and its major metabolite, CGA-205375 (M1) were generated using application 

rates of 0.46 to 0.52 lbs a.i./A.with the Surface Water Concentration Calculator model for 

surface water as well as the maximum application rate of 0.52 lbs a.i./A with the PRZM-GW and 

SCI-GROW models for groundwater. 

The Interregional Research Project Number 4 (IR-4) also revised the existing crop groupings by 

converting stone fruit Group 12 to stone fruit Group 12-12 and nut tree Group 12 to nut tree 

Group 14-12. Since there are no changes in the application rates and methods for the revised 

crop groupings, previous drinking water assessments (stone fruit; USEPA, 2010; DP426124 and 

tree nut; USEPA 2009, DP340378) fulfill the requirement for refining EDWCs for these crops. 

EFED noticed that the application rate for cucurbit is higher in the submitted Inspire Super (EPA 

Reg. No. 100-1317) label as compared to previous label, which was stamped on August 03, 

2012. Since the maximum applicant rate of 0.52 lbs a.i./A for cucurbit is higher than previously 

assessed application rate of 0.46 lbs a.i./A (USEPA 2009; DP361398 the EDWCs for the revised 

rate of cucurbit was reassessed. 
Page 24 of 47

Surface water and groundwater modeling were conducted for the maximum annual application 

rate of 0.46 to 0.52 lbs a.i./A for aerial application only as aerial applications produce 

conservative estimates. Remaining model input parameters were chosen according to current 

guidance (USEPA, 2009 and USEPA, 2013b). For surface water, the EDWCs for new uses and 

the revised application rate for cucurbit did not exceed the previously recommended peak (acute) 

concentration of 20.0 μg/L, annual mean (non-cancer chronic) concentration of 13.6 μg/L and 

the 30 year annual average concentration (cancer chronic) of 9.9 μg/L reported in the drinking 

water assessment based on grape use (US EPA, 2013; DP 398836). Recently, PRGM-GW 

scenarios were revised and consequently the estimated PZRM-GW groundwater concentrations 

were reduced to 1.77 μg/L from 2.24 μg/L and chronic concentration of 0.66 μg/L from 0.78 

μg/L for the maximum application rate for FL citrus scenario. Recommended surface water and 

groundwater EDWCs for human health are listed in (Table 5.3.1.2). 

Table 5.3.1.2. Tier II Drinking Water Exposure Estimates for Total Toxic Residues of Difenoconazole 

Source Peak Exposure (μg/L) Annual Mean Exposure 

(μg/L)

30-year Average 

Exposure (μg/L)

Surface water 20.0 13.6 9.9

Groundwater1 2.24 --- 0.82

1 Groundwater EDWCs are based on PRZM-GW 100 years simulation and the highest application rate for 

difenoconazole

Drinking Water Data for Free Triazoles

Residues of 1,2,4-triazole in drinking water were provided to HED by the EFED (I. Maher, 

DP320682, 28 Feb 2006). Due to the inter-conversion between 1,2,4-triazole, triazole alanine, 

and triazole acetic acid that may occur in the environment, the residue estimates used in these 

assessments are a summation of all three residues and, therefore, represent an overestimate of 

actual concentrations of the common triazole metabolites in drinking water. The Tier II 

PRZM/EXAMS (surface water) and SCIGROW (ground water) residue estimates are 

summarized in Table 5.3.1.3. HED notes that there were no detects of 1,2,4-triazole in any of 

the 271 water samples analyzed by PDP, with a limit of quantification of 730 parts-per-trillion 

(0.73 ppb). The surface water estimates are significantly greater than those for ground water, 

and were used in the assessments for free triazole as well as the conjugated metabolites. EFED 

stated that the new metconazole uses are covered by the previous drinking water assessment for 

1,2,4-triazole (DP320682, I. Maher, 2/28/06).

Table 5.3.1.3. Summary of Estimated Drinking Water Concentrations of 1,2,4-Triazole.

Exposure Duration Surface Water Concentration, ppm Ground Water Concentration, ppm

Acute 0.041 0.001

Chronic 0.011 0.001

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Screening level acute and refined chronic dietary and drinking water exposure and risk 

assessments were conducted using the Dietary Exposure Evaluation Model software with the 

Food Commodity Intake Database DEEM-FCID, Version 4.02, which incorporates consumption 
Page 25 of 47

data from USDA’s National Health and Nutrition Examination Survey, What We Eat in 

America, (NHANES/WWEIA). This dietary survey was conducted from 2003 to 2010. 

Dietary risk assessment incorporates both exposure and toxicity of a given pesticide. For acute 

and chronic dietary assessments, the risk is expressed as a percentage of a maximum acceptable 

dose (i.e., the dose which HED has concluded will result in no unreasonable adverse health 

effects). This dose is referred to as the population adjusted dose (PAD). The PAD is equivalent 

to the reference dose (RfD) divided by the additional Safety Factor, if applied. For acute and 

non-cancer chronic exposures, HED is concerned when estimated dietary risk exceeds 100% of 

the PAD. 

5.4.2 Percent Crop Treated Used in Dietary Assessment

The acute dietary exposure analyses assumed 100% crop treated (CT). Average %CT was used

in the chronic dietary exposure analysis for the following crops: almond 5%, cabbage 2.5%, 

cucumbers 5%, garlic 5%, grape 5%, grapefruit 2.5%, onions 5%, orange 2.5%, pecan 2.5%, 

peach 1%, peppers 2.5%, pistachio 2.5%, pumpkin 2.5%, squash 5%, strawberry 2.5%, sugar 

beets 15%, tangerine 2.5%, tomatoes 25%, walnut 2.5%, watermelon 5%, and wheat 10%.

5.4.3 Acute Dietary Risk Assessment

A new dietary assessment was conducted for the proposed new uses. The proposed uses resulted in 

dietary risk estimates below HED’s level of concern (see Table 5.4.3.1). The highest is All Infants (<1 

year old) resulting in 49% of the aPAD. 

Table 5.4.3.1. Summary of Acute Dietary (Food plus Water) 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

0.038371 15

All Infants (< 1 year old) 0.122946 49

Children 1-2 years old 0.108065 43

Children 3-5 years old 0.074134 30

Children 6-12 years old 0.050183 20

Youth 13-19 years old 0.024840 10

Adults 20-49 years old 0.026003 10

Adults 50-99 years old 0.028849 12

Females 13-49 years old 0.025932 10

The bolded %aPAD is the highest.

Dietary Assessment of Free Triazole and its Conjugates

Reference: Common Triazole Metabolites: Updated Dietary (Food + Water) Exposure and Risk Assessment to 

Address The New Section 3 Registrations For Use of Propiconazole on Tea, Dill, Mustard Greens, Radish, and 

Watercress; Use of Difenoconazole on Globe Artichoke, Ginseng and Greenhouse Grown Cucumbers and 

Conversion of the Established Foliar Uses/Tolerances for Stone Fruit and Tree Nut Crop Groups to Fruit, Stone, 

Group 12-12 and the Nut, Tree, Group 14-12.; and Use of Flutriafol on Hops. T. Morton, DP426492.drs, 4/9/15.

The dietary exposure analyses for the triazole metabolites (D426492, T. Morton, 4/9/15) was 
Page 26 of 47

recently updated. Addition of these new uses of difenoconazole did not significantly change the 

dietary exposure for the triazole metabolites. The results from the triazole dietary analysis are 

below HED’s level of concern; see Table 5.4.3.2.

Table 5.4.3.2. Summary of Dietary (Food and Drinking Water) Exposure and Risk for the Common 

Triazole Metabolites.

Population Subgroup

Acute Dietary

(95th Percentile)

Chronic Dietary Cancer

Dietary 

Exposure 

(mg/kg/day)

% aPAD*

Dietary 

Exposure

(mg/kg/day)

% cPAD*

Dietary 

Exposure

(mg/kg/day)

Risk

1,2,4-Triazole

General U.S. Population 0.007869 26 0.001150 23

Not 

Applicable

Not 

Applicable

All Infants (< 1 year old) 0.012319 41 0.002097 42

Children 1-2 years old 0.019569 65 0.003321 66

Children 3-5 years old 0.016613 55 0.002646 53

Children 6-12 years old 0.009615 32 0.001431 29

Youth 13-19 years old 0.006804 23 0.000922 18

Adults 20-49 years old 0.006350 21 0.000979 20

Adults 50-99 years old 0.005587 19 0.000927 19

Females 13-49 years old 0.006416 21 0.000942 19

Triazolylalanine + Triazolylacetic Acid+Triazolylpyruvic acid

General U.S. Population

Not 

Applicable

Not 

Applicable

0.015819 18

Not 

Applicable

Not 

Applicable

All Infants (< 1 year old) 0.021523 24

Children 1-2 years old 0.050635 56

Children 3-5 years old 0.040816 45

Children 6-12 years old 0.021357 24

Youth 13-19 years old 0.013174 15

Adults 20-49 years old 0.012901 14

Adults 50-99 years old 0.012185 14

Females 13-49 years old 0.073349 73 0.012373 14

* The values for the highest exposed population for each type of risk assessment are bolded.

5.4.4 Chronic Dietary and Drinking Water Analysis

A new dietary assessment was conducted for the proposed uses of difenoconazole and results in 

dietary risk estimates below HED’s level of concern (see Table 5.4.2).

Table 5.4.4. Summary of Chronic Dietary (Food plus Water) Exposure and Risk for Difenoconazole.

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

General U.S. Population

0.01

0.002591 26

All Infants (< 1 year old) 0.007691 77

Children 1-2 years old 0.008894 89

Children 3-5 years old 0.006043 60

Children 6-12 years old 0.003709 37

Youth 13-19 years old 0.002016 20

Adults 20-49 years old 0.001893 19

Adults 50-99 years old 0.002095 21

Females 13-49 years old 0.001856 19
Page 27 of 47

The bolded %cPAD is the highest.

5.4.5 Summary Table

Table 5.4.5. Summary of Dietary (Food plus Water) Exposure and Risk for Difenoconazole

Population Subgroup

Acute Dietary (95th 

Percentile) Chronic Dietary Cancer

Dietary 

Exposure 

(mg/kg/day)

% aPAD

Dietary 

Exposure

(mg/kg/day)

% cPAD

Dietary 

Exposure

(mg/kg/day)

Risk

General U.S. Population 0.038371 15 0.002591 26

N/A

All Infants (< 1 year old) 0.122946 49 0.007691 77

Children 1-2 years old 0.108065 43 0.008894 89

Children 3-5 years old 0.074134 30 0.006043 60

Children 6-12 years old 0.050183 20 0.003709 37

Youth 13-19 years old 0.024840 10 0.002016 20

Adults 20-49 years old 0.026003 10 0.001893 19

Adults 50-99 years old 0.028849 12 0.002095 21

Females 13-49 years old 0.025932 10 0.001856 19

6.0 RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE/RISK 

CHARACTERIZATION

There are no proposed residential uses at this time; however, there are existing residential uses 

that have been previously reassessed to reflect updates to HED’s 2012 Residential SOPs1along 

with policy changes for body weight assumptions. The revised residential exposure estimates 

impact the human health aggregate risk assessment for difenoconazole. 

Based on the existing exposure pattern, residential exposure scenarios have been identified from 

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

Potential exposure is expected to homeowners handling the product and/or from performing 

post-application activities in treated areas. 

Representative outdoor and indoor residential handler and post-application exposure scenarios 

were previously reassessed for all difenoconazole uses using the Revised Residential SOPs

(2012), and the risk estimates were not of concern (D421188, I. Nieves, 02/24/2015). Table 

6.0.1 presents a summary of the residential handler non-cancer exposure and risk estimates for 

the registered scenarios (MOEs ranged from 3,500 to 68,000; LOC =100). Table 6.0.2

summarizes the residential post-application non-cancer exposure and risk estimates for all 

difenoconazole uses (MOEs ranged from 250 to 31,000; LOC=100).

 

1 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html
Page 28 of 47

Table 6.0.1. Residential Handler Non-cancer Exposure and Risk Estimates for Difenoconazole.

Exposure 

Scenario

Level of 

Concern

Dermal 

Unit 

Exposure 

(mg/lb ai)

Inhalation 

Unit 

Exposure 

(mg/lb ai)

Maximum 

Application 

Rate1

Area 

Treated 

or 

Amount 

Handled 

Daily2

Dermal Inhalation Total

Dose 

(mg/kg/day)3 MOE4 Dose (mg/kg/day)5 MOE6 MOE7

Mixer/Loader/Applicator on Ornamentals (Garden/Trees) with Liquid Formulation

Manuallypressurized 

handwand

100

63 0.018

3.0x10-6

lb ai/ft2

(0.13 lb ai/A)

1,200 ft2

0.00017 7,400 0.0000008 1,600,000 7,400

Hose-end 

Sprayer 58 0.0014 0.00016 8,000 0.000000063 20,000,000 8,000

Backpack 130 0.14 0.00035 3,600 0.0000063 200,000 3,500

Ready-touse Hoseend Sprayer

6.26 0.034 0.000017 74,000 0.0000015 820,000 68,000

1 Based on registered label (EPA Reg. No. 100-1262)

2 Based on HED’s 2012 Residential SOPs (http://www.epa.gov/pesticides/science/residential-exposure-sop.html).

3 Dermal Dose = Dermal Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A/day or 

gallons/day) × Dermal Absorption Factor (%) ÷ Body Weight (kg).

4 Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg/kg/day).

5 Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A/day or 

gallons/day) ÷ Body Weight (kg).

6 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

7 Total MOE = NOAEL (mg/kg/day) ÷ (Dermal Dose + Inhalation Dose).
Page 29 of 47

Table 6.0.2. Residential Post-application Non-cancer Exposure and Risk Estimates for Difenoconazole.

Lifestage Post-application Exposure Scenario Application Rate1 Dose (mg/kg/day)2 MOEs3

Use Site Route of Exposure

Adult

Gardens

Dermal 0.13 lb ai/A

0.005 250

Child

6 < 11 yrs 0.003 360

Adult Trees and Retail 

Plants

0.00046 2,700

Child

6 < 11 yrs 0.00031 4,000

Adult

Indoor Plants

0.000060 21,000

Child

6 < 11 yrs 0.000041 31,000

Adult

Golfing Dermal 0.25 lb ai/A

0.00044 2,800

Child

11 <16 years 0.00051 2,400

Child

6 < 11 yrs 0.00060 2,100

1. Based on registered or proposed label (Reg. No. 100-1262).

2. Dose (mg/kg/day) equations provided in Appendix [A].

3. MOE = POD (mg/kg/day) ÷ Dose (mg/kg/day).

Table 6.0.3 reflects the residential risk estimates that are recommended for use in the aggregate 

assessment for difenoconazole.

 The recommended residential exposure for use in the adult aggregate assessment reflects 

dermal and inhalation exposure from mixing/loading/applying difenoconazole with a 

backpack sprayer.

 The recommended residential exposure for use in the adult aggregate assessment reflects 

dermal exposure from post-application exposure to garden applications.

 The recommended residential exposure for use in the children 6 to 11 years old aggregate 

assessment reflects dermal exposure from post-application exposure to garden 

applications.

Table 6.0.3. Recommendations for the Residential Exposures for the Difenoconazole Aggregate 

Assessment.1

Lifestage

(Scenario)

Dose (mg/kg/day)2,4 MOE3,5

Dermal Inhalation Oral Total Dermal Inhalation Oral Total

Residential Handler

Adult (Backpack Sprayer) 0.00035 0.0000063 N/A 0.00036 3,600 200,000 N/A 3,500

Residential Post-application

Adult (Garden) 0.005 N/A N/A 0.0054 250 N/A N/A 250

Child 6<11 yrs

(Gardens) 0.003 N/A N/A 0.0030 360 N/A N/A 360

1 Bolded risk estimates should contribute to the residential exposure portion of the aggregate assessment. 

2 Residential Handler Dose = the highest handler dose for each applicable lifestage of all residential handler scenarios 

assessed. Total = dermal + inhalation.

3 Residential Handler MOE = the MOEs associated with the highest residential handler doses. Total = 1 ÷ (1/Dermal 
Page 30 of 47

MOE) + (1/Inhalation MOE).

4 Residential Post-application Dose = the highest post-application dose for each applicable lifestage of all postapplication scenarios assessed. Total = dermal + inhalation + incidental oral.

5 Residential Post-application MOE = the MOEs associated with the highest post-application doses. Total = Dermal 

MOE + Inhalation MOE + Incidental Oral MOE. 

6.1 Residential Bystander Postapplication Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for difenoconazole at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category III and IV), low vapor pressure (2.5 x 10-10 mm Hg at 25 

oC), and the low proposed use rate (0.13 lb ai/A). However, volatilization of pesticides may be a 

source of post-application inhalation exposure to individuals nearby pesticide applications. The 

Agency sought expert advice and input on issues related to volatilization of pesticides from its 

Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in 

December 2009, and received the SAP’s final report on March 2, 20102. The Agency is in the 

process of evaluating the SAP report and may, as appropriate, develop policies and procedures to 

identify the need for and, subsequently, the way to incorporate post-application inhalation 

exposure into the Agency's risk assessments. If new policies or procedures are developed, the 

Agency may revisit the need for a quantitative post-application inhalation exposure assessment 

for difenoconazole.

6.2 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is 

particularly the case with aerial application, but, to a lesser extent, spray drift can also be a 

potential source of exposure from the ground application methods (e.g., groundboom and 

airblast) employed for difenoconazole. The Agency has been working with the Spray Drift Task 

Force (a task force composed of various registrants which was developed as a result of a Data 

Call-In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation 

and other parties to develop the best spray drift management practices (see the Agency’s Spray 

Drift website for more information). 3 The Agency is also taking means to qualitatively and 

qualitatively address spray drift as a potential source of exposure in risk assessments for 

pesticides through existing programs such as Ag Drift and chemical specific properties of 

pesticides. 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 

concurrently. 

7.0 AGGREGATE EXPOSURE/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 (dermal and 

 

2 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html

3 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm 
Page 31 of 47

residential). 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 5.4, acute and chronic aggregate risks are not of concern.

7.2 Short-Term Aggregate Risk

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 includes the estimated risk associated with combined risks from average food and 

drinking water exposures and dermal exposures from post-application exposure to adults and 

children 6 to 11 years old re-entering a treated garden. Short term aggregate risk estimates are

provided in Table 7.2.

Table 7.2. Short-Term Aggregate Risk Calculations

Population

Short-Term Scenario

NOAEL 

mg/kg/day LOC1

Max 

Allowable 

Exposure2

mg/kg/day

Average 

Food and 

Water 

Exposure 

mg/kg/day

Residential 

Exposure 

mg/kg/day3

Total 

Exposure 

mg/kg/day4

Aggregate 

MOE (food, 

water, and 

residential)5

Adult Male

1.25 100 0.0125

0.0021 0.0054 0.0075 170

Adult Female 0.0018 0.0054 0.0072 170

Child 0.0037 0.0030 0.0067 190

1 10X for interspecies extrapolation, 10X for intraspecies variation.

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC.

3 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure]. Refer to Table 6.0.3.

4 Total Exposure = Avg Food & Water Exposure + Residential Exposure).

5 Aggregate MOE = [NOAEL/ (Avg Food & Water Exposure + Residential Exposure)].

Updated Aggregate Assessment of Free Triazole & its Conjugates

Reference: Common Triazole Metabolites: Updated Aggregate Human Health Risk Assessment to Address The 

New Section 3 Registrations For Use of Propiconazole on Tea, Dill, Mustard Greens, Radish, and Watercress; Use 

of Difenoconazole on Globe Artichoke, Ginseng and Greenhouse Grown Cucumbers and Conversion of the 

Established Foliar Uses/Tolerances for Stone Fruit and Tree Nut Crop Groups to Fruit, Stone, Group 12-12 and the 

Nut, Tree, Group 14-12.; and Use of Flutriafol on Hops. DP426493, T. Morton, xx/xx/xx.

The previous aggregate human health risk assessment for free triazoles and its conjugates was 

updated and the aggregate estimates are below HED’s level of concern (DP426493, T. Morton, 

xx/xx/xx).
Page 32 of 47

7.3 Intermediate-Term Aggregate Risk 

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

difenoconazole. Therefore, an intermediate-term aggregate was not performed.

8.0 Cumulative Exposure/Risk Characterization

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.

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 propiconazole, 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 EPAHQ-OPP-2005-0497.

9.0 OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION

9.1 Exposure Scenarios
Page 33 of 47

Occupational handler and post-application exposure scenarios have been identified for the 

proposed uses. Based on the product labels and information provided by the registrant, shortand intermediate-term exposure is expected for occupational handlers and post-application 

activities. Chronic exposure is not expected for the proposed use patterns. 

9.2 Handler Exposure 

The term “handler” applies to individuals who mix, load, and apply the pesticide product. 

There is a potential for exposure to difenoconazole during mixing, loading, and application 

activities through the dermal and inhalation routes. 

9.2.1 Handler Exposure Scenarios

Occupational handler exposure and risk estimates for the proposed new foliar uses on globe 

artichoke, ginseng, greenhouse grown cucumbers and conversion of the established foliar 

uses/tolerances for stone fruit group 12 and tree nut crop group 14 to stone fruit group 12-12 and 

tree nut group 14-12, are all expected to result in comparable/identical exposure scenarios to 

those previously assessed and discussed in a recent risk assessment for this chemical (D421188, 

I. Nieves, 02/24/2015). The application rates proposed for these new uses are identical to the 

ones previously assessed (0.11 lb ai/A), and risk estimates were quantified at higher rates, and/or 

higher amount used or area treated than the proposed uses. No risk estimates of concern were 

identified for any of the previous uses utilizing label required PPE (i.e., long shirt, long pants, 

shoes, socks and gloves). Based on the premise that all uses require the same PPE previously 

labeled, and there have been no revisions to the toxicological database/endpoints and/or to the 

occupational SOPs since the date of the recent assessment, all proposed new uses are considered 

to be not of concern to the Agency. 

9.3 Post-Application Exposure 

HED uses the term post-application to describe exposures that occur when individuals are 

present in an environment that has been previously treated with a pesticide (also referred to as reentry exposure). Such exposures may occur when workers enter previously treated areas to 

perform job functions, including activities related to crop production, such as scouting for pests 

or harvesting. Post-application exposure levels vary over time and depend on such things as the 

type of activity, the nature of the crop or target that was treated, the type of pesticide application, 

and the chemical’s degradation properties. In addition, the timing of pesticide applications, 

relative to harvest activities, can greatly reduce the potential for post-application exposure.

Dermal Exposure 

Post-application dermal exposure and risk estimates for the proposed new uses are all expected 

to result in comparable/identical exposure scenarios to those discussed and assessed in a recent 

risk assessments for this chemical (D421188, I. Nieves, 02/24/2015). The application rates 

proposed for these new uses are identical to the ones previously assessed (0.11 lb ai/A). No risk 
Page 34 of 47

estimates of concern were identified for any of the previous uses. Based on the premise that no 

new dislodgeable foliar residue (DFR) studies have been submitted, and there have been no 

revisions to the toxicological database/endpoints and/or to the occupational post-application 

SOPs since the date of the recent assesment, all post-applications activities related to the 

proposed new uses are considered to be not of concern to the Agency.

Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for difenoconazole at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category III and IV), low vapor pressure (2.5 x 10-10 mm Hg at 25 

oC), and low proposed use rates (highest proposed rate = 0.11 lb ai/A). However, there are 

multiple potential sources of post-application inhalation exposure to individuals performing postapplication activities in previously treated fields. These potential sources include volatilization 

of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency 

sought expert advice and input on issues related to volatilization of pesticides from its Federal 

Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, 

and received the SAP’s final report on March 2, 20104. The Agency is in the process of 

evaluating the SAP report as well as available post-application inhalation exposure data 

generated by the ARTF and may, as appropriate, develop policies and procedures, to identify the 

need for and, subsequently, the way to incorporate occupational post-application inhalation 

exposure into the Agency's risk assessments. If new policies or procedures are put into place, the 

Agency may revisit the need for a quantitative occupational post-application inhalation exposure 

assessment for difenoconazole.

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in 

higher exposure than post-application exposure. Therefore, it is expected that these handler 

inhalation exposure estimates would be protective of most occupational post-application 

inhalation exposure scenarios.

9.3.1 Restricted Entry Interval

The REI specified on the proposed label is based on the acute toxicity of difenoconazole. 

Difenoconazole is classified as Toxicity Category III for acute dermal toxicity and eye irriitation,

and Toxicity Category IV for skin irritation potential. It is not a skin sensitizer. Short- and 

intermediate-term post-application risk estimates were not a concern on day 0 (12 hours 

following application) for all post-application activities. Under 40 CFR 156.208 (c) (2) (iii), 

active ingredients classified as Acute III or IV for acute dermal, eye irritation and primary skin 

irritation are assigned a 12-hour REI. Therefore, the [156 subpart K] Worker Protection 

Statement interim REI of 12 hours on the proposed labels is adequate to protect agricultural 

workers from post-application exposures to difenoconazole. 

 

4 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
Page 35 of 47

10. REFERENCES

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 11-10; and ornamental plants and vegetable 

transplants grown in both indoor and outdoor production facilities – I. Nieves; D422992, D421429, D421216,

D421201, D421208, D421188, and D413471; 02/24/2015

Difenoconazole. New Foliar Uses on Globe Artichoke, Ginseng and Greenhouse Grown Cucumbers and 

Conversion of the Established Foliar Uses/Tolerances for Stone Fruit and Tree Nut Crop Groups to Fruit, Stone, 

Group 12-12 and the Nut, Tree, Group 14-12. Summary of Analytical Chemistry and Residue Data. - B. CroppKohlligian, D421089, 01/28/2015

Difenoconazole. Acute and Chronic Aggregate Dietary Exposure and Risk Assessments for the Petition for Use of 

Difenoconazole on Globe Artichoke, Ginseng and Greenhouse Grown Cucumbers and Conversion of the 

Established Foliar Uses/Tolerances for Stone Fruit and Tree Nut Crop Groups to Fruit, Stone, Group 12-12 and the 

Nut, Tree, Group 14-12. - T. Morton, D426491, 7/1/15

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, 11/13/14

Difenoconazole. Occupational and Residential Exposure Assessment for a Proposed Use on Canola and Oilseed 

Subgroup 20A. - I. Nieves, D412811, 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; 

D371037; February 24, 2011.

Difenoconazole. Occupational and Residential Exposure/Risk Assessment for the Proposed New Uses of 

Difenoconazole on Fruiting Vegetables, Tuberous and Corm Vegetables, Pome Fruit, Sugar Beets and Ornamentals 

- Mark I. Dow; D340044; July 27, 2007.
Page 36 of 47

APPENDICES

APPENDIX A. TOXICOLOGY DATA SUMMARY

A.1 Guideline Data Requirements - Difenoconazole

Guideline 

No. Study Type Technical MRID 

Required Submitted No.

870.3100

870.3150

870.3200

870.3250

870.3465

Subchronic (Oral) Toxicity - Rodent .........................................

Subchronic (Oral) Toxicity - Non-Rodent.................................

21/28-Day Dermal Toxicity.......................................................

90-Day Dermal Toxicity

90-Day Inhalation Toxicity .......................................................

Y

Y

N

N

N*

Y

Y

Y

N

N

42090022 

42090021

42090013

42090013

46950310

870.3700a

870.3700b

870.3800

Prenatal Developmental Toxicity - Rodent................................

Prenatal Developmental Toxicity - Non-Rodent........................

Reproduction and Fertility Effects.............................................

Y

Y

Y

Y

Y

Y

42090016

42710008

42090017

42710008

42090018

870.4100a

870.4100b

870.4200a

870.4200b

870.4300

Chronic (Oral) Toxicity - Rodent ..............................................

Chronic (Oral) Toxicity - Non-Rodent (Dog)............................

Carcinogenicity - Rat

Carcinogenicity - Mouse

Combined Chronic Toxicity /Carcinogenicity

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

42090015

42710006

42090012

42710005

42090019

42710010

42090015

42710006

42090019, 

42710010

870.6100a

870.6100b

870.6200a

870.6200b

870.6300

870.7485

870.7600

870.7800

Neurotoxicity - Acute Delayed Neurotox.- Hen ........................

Neurotoxicity - Subchronic - Hen.............................................

Neurotoxicity - Acute - Rat........................................................

Neurotoxicity -Subchronic - Rat................................................

Developmental Neurotoxicity..................

General Metabolism

Dermal Penetration

Immunotoxicity.................................................................

N

N

Y

Y

N

Y

Y

Y

N

N

Y

Y

N

Y

Y

Y

---

---

46950327 

46950329

--

42090028

47453201

46950333

47453202

47453203

48696701

* The Hazard and Science Policy Council (HASPOC) concluded that a 28-day inhalation toxicity study is not 

required at this time (TXR 0054074).
Page 37 of 47

A.2 Toxicity Profiles

Table A.1. Acute Toxicity Profile – Difenoconazole

Guideline No. Study Type MRID No. Results Toxicity Category

870.1100 Acute oral 42090006 LD50 = 1450 mg/kg III

870.1200 Acute dermal 42090007 LD50 > 2010 mg/kg III

870.1300 Acute inhalation 42090008 LC50 > 3.3 mg/L III

870.2400 Eye irritation 42090009 Mild irritation reversible in 7 days III

870.2500 Dermal irritation 40789807 Slight irritation IV

870.2600 Skin sensitization 42090011, 42710004 Negative N/A

Table A.2. 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)

Acceptable/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)

Acceptable / 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)

Acceptable / 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.
Page 38 of 47

Table A.2. Subchronic, Chronic and Other Toxicity Profile of Difenoconazole

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3700a Prenatal 

developmental in 

(rat)

42090016, 42710007 (1987)

Acceptable / 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.

870.3700b Prenatal 

developmental in 

(rabbit)

42090017, 42710008 (1987)

Acceptable / 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 non-significant 

increases in post-implantation loss and resorptions/doe 

and a significant decrease in fetal weight.

870.3800 Reproduction and 

fertility effects

(rat)

42090018 (1988)

Acceptable / 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 non-significant) 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

Offspring 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)

Acceptable / 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)

Acceptable / 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

870.4300 Carcinogenicity

(mouse)

42090015, 42710006 (1989)

Acceptable / 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 and hepatocellular 

hypertrophy, liver necrosis, fatty changes in the liver and 

bile stasis in the 300, 2500 & 4500 ppm groups. 

Evidence of carcinogenicity (liver adenoma/carcinoma in 

both sexes)
Page 39 of 47

Table A.2. Subchronic, Chronic and Other Toxicity Profile of Difenoconazole

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

42090019, 42710010 (1989)

Acceptable / 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.

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).
Page 40 of 47

Table A.2. Subchronic, Chronic and Other Toxicity Profile of Difenoconazole

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

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.

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. 

870.7800 Immunotoxicity 

[dietary] - Mouse

48696701 (2011)

Acceptable/ guideline 

0, 20, 200, 1000, or 1500 pm 

(0, 3, 35, 177, or 247 

mg/kg/day) for 28 days.

Systemic toxicity NOAEL = 200 ppm (35 mg/kg/day)

Systemic toxicity LOAEL = 1000 ppm (177 mg/kg/day) 

based on decreased body weight gains and liver toxicity

Immunotoxicity NOAEL = 200 ppm (35 mg/kg/day)

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

based on decreased mean anti-SRBC IgM levels.

870.7600 

Dermal 

Penetration

In vivo Dermal 

Penetration in the 

Rat, 

In vitro 

47453201 (2007) See TXR 0056473

870.7600 

Dermal 

Penetration

In vivo Dermal 

Penetration in the 

Rat, 

46950333 (2003) See TXR 0056473
Page 41 of 47

Table A.2. Subchronic, Chronic and Other Toxicity Profile of Difenoconazole

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.7600 

Dermal 

Penetration

In vitro

Absorption 

through Human 

Epidermis; 

47453202 (2007) See TXR 0056473

870.7600 

Dermal 

Penetration

In vitro

Absorption 

through Rat 

Epidermis; 

47453203 (2007) See TXR 0056473

870.7485 Metabolism and 

pharmacokinetics

(rat)

42090028 (1990)

Acceptable/ guideline

14 daily doses of 0.5 or 300 

mg/kg

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 GGA169374 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)

42090028 (1990)

42090029 (1987)

42090030 (1987)

42090031 (1988)

Acceptable/ guideline

Single oral dose 0.5 or 300 

mg/kg

14 daily doses of 0.5 or 300 

mg/kg

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 GGA169374 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.

[

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, B1, 

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. 
Page 42 of 47

870.7485 Metabolism and 

pharmacokinetics

(rat)

42090028 (1990)

42090029 (1987)

42090030 (1987)

42090031 (1988)

Acceptable/ guideline in 

conjunction with MRIDs 

420710013, 42710014 listed 

below 

Single oral dose 0.5 or 300 

mg/kg

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]CGA169374, 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.

[

14C] CCA 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 97.94-

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 

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, B1, and B2). 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 animals compared to the low dose 

animals, and an additional metabolite was found in the 
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Table A.2. Subchronic, Chronic and Other Toxicity Profile of Difenoconazole

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

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.

A.3 Toxicological Endpoints

A.3.1 Acute Population Adjusted Doses (aPAD) – All Populations

Selected Study: Acute Neurotoxicity Study in Rats 

MRID 46950327 

Dose and Endpoint for Establishing an aPAD: NOAEL is 25 mg/kg/day. LOAEL is 200 

mg/kg/day based on reduced fore-limb grip strength in males on day 1. 

Uncertainty Factor (UF): 100, this includes 10x for interspecies extrapolation and 10x for 

intraspecies variation, 1X FQPA SF.

Comments about Study/Endpoint: The selected endpoint is considered appropriate for acute 

dietary exposure because effects were seen after a single dose. The endpoint is protective of the 

general population and all subpopulations for effects seen in the acute neurotoxicity study in rats. 

It is also protective of developmental and maternal effects observed in the rabbit developmental 

toxicity study at the LOAEL of 75 mg/kg/day and NOAEL of 25 mg/kg/day.

A.3.2 Chronic Population Adjusted Dose (cPAD) – All Populations

Selected Study: Chronic/Oncogenicity Study in Rats 

MRID 42090019/20

Dose and Endpoint for establishing an cPAD: The NOAEL is 0.96 mg/kg/day. The LOAEL is 

24.12 mg/kg/day based on cumulative decreases in body weight gains at 24.12 mg/kg/day in 

males. 

General Population aPAD = (NOAEL) 25 mg/kg = 0.25 mg/kg

 (UF) 100

General Population cPAD = (NOAEL) 0.96 mg/kg/day = 0.01 mg/kg/day

 (UF) 100
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Uncertainty Factor (UF): 100: This includes 10X for interspecies extrapolation,10x for 

intraspecies variation, 1X FQPA SF.

A.3.3 Incidental Oral Exposure (Short-Term)

Selected Study: Two Generation Reproduction Study in Rats 

MRID 42090018

Dose and Endpoint for Establishing POD: The NOAEL is 1.25 mg/kg/day based on decreased 

pup weight in males at 12.5 mg/kg/day (LOAEL) on day 21, and reductions in body weight gain 

in F0 females.

Uncertainty Factor (UF): An MOE 100 is required for the short- and intermediate-term scenarios 

for dermal exposure is based on the conventional uncertainty factor of 100. This includes 10x 

for interspecies extrapolation and 10x for intraspecies variation.

Comments about Study/Endpoint: There are no residential uses for difenoconazole that would 

result in incidental oral exposure to children. However, a short term oral exposure endpoint is 

required for aggregate risk assessment. 

A.3.4 Dermal Absorption

A dermal absorption factor (DAF) is applied when dermal exposure endpoints are 

selected from oral toxicity studies. The dermal factor converts the oral dose to an equivalent 

dermal dose for the risk assessment. A DAF of 6% was selected for use in risk assessment based 

on available in vivo dermal absorption studies in rat and in vitro dermal absorption studies 

conducted with rat and human skin (TXR 0056473). 

A.3.5 Dermal Exposure (Short and Intermediate-Term)

Selected Study: Two Generation Reproduction Study in Rats (MRID 42090018)

Dose and Endpoint for Establishing POD: The NOAEL is 1.25 mg/kg/day based on 

decreased pup weight in males at 12.5 mg/kg/day (LOAEL) on day 21 and reductions in body 

weight gain in F0 females. Dermal absorption is 6%.

Uncertainty Factor (UF): An MOE 100 is required for the short- and intermediate-term 

scenarios for dermal exposure is based on the conventional uncertainty factor of 100. This 

includes 10x for interspecies extrapolation and 10x for intraspecies variation.

Comments about Study/Endpoint: Although dermal toxicity studies are available, a POD 

from an oral study was selected because effects in young animals (decreased pup weight) the 

primary effect of concern for short, intermediate and long term exposure is not specifically 

evaluated in the available dermal toxicity studies that only assess adult animals. The selected 

endpoint is protective of offspring effects from dermal exposure. A DAF of 6% is applied to the 
Page 45 of 47

POD for dermal exposure.

A.3.6 Inhalation Exposure (Short- and Intermediate-Term) 

Selected Study: Two Generation Reproduction Study in Rats (MRID 42090018)

APPENDIX B. Chemical Names And Structures Of Metabolites

B.1 Chemical Names And Structures

Difenoconazole Nomenclature.

Chemical structure

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)-1H-1,2,4-triazole

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

1H-1,2,4-triazole

CAS registry number 119446-68-3

Chemical structure of 

CGA-205375 livestock 

metabolite

Chemical structure of 

1,2,4-Triazole (1,2,4-T)

Chemical structure of 

Triazolylalanine (TA)

O O

O

N N Cl

N

CH3

Cl

O

N N Cl

N

OH Cl

HN

N

N

N

N

N

HO

NH2

O
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Difenoconazole Nomenclature.

Chemical structure of

Triazolylacetic acid (TAA)

APPENDIX C. Physical/Chemical Properties

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/cm3at 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 pure grade (99.3% ± 0.3%) 

difenoconazole in water (with 4% 

methanol) at 20oC is 1.1 

DP# 375159, 5/26/10, B. Cropp-Kohlligian

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 max at about 200 and 238 nm 

(in methanol at 26 oC)

PMRA Proposed Regulatory Decision 

Document on Difenoconazole, 4/14/99 

(PRDD99-01)

APPENDIX D. Studies Reviewed for Ethical Conduct

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 were determined to require a review of their ethical 

conduct, have received that review and have been determined to be ethical.

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. Task Force 

members Health Canada, U.S. Environmental Protection Agency, and the National Agricultural 

Chemicals Association, released February, 1995.

N

N

N

HO

O
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The Agricultural Handler Exposure Task Force (AHETF), 2011. The Occupational Handler Unit 

Exposure Surrogate Reference Table. U.S. Environmental Protection Agency. Released June 21, 2011.

Klonne, D. (1999) Integrated Report for Evaluation of Potential Exposures to Homeowners and Professional Lawn 

Care Operators Mixing, Loading, and Applying Granular and Liquid Pesticides to Residential Lawns: Lab Project 

Number: OMA005: OMA001: OMA002. Unpublished study prepared by Riceerca, Inc., and Morse Laboratories. 

2213 p. (MRID 44972201).

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. Task Force members 

Health Canada, U.S. Environmental Protection Agency, and the National Agricultural Chemicals Association, 

released February, 199