OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON D.C., 20460

November 5, 2015

PC Code: 128847 

DP Barcode: 428500

MEMORANDUM

SUBJECT: Difenoconazole: Preliminary Problem Formulation for Environmental Fate, 

Ecological Risk, Endangered Species, and Drinking Water Exposure Assessments 

in Support of Registration Review

FROM: Michael Lowit, Ph.D., Ecologist

Faruque Khan, Ph.D., Senior Fate Scientist

Sujatha Sankula, Ph.D., Branch Chief

Environmental Risk Branch I

Environmental Fate and Effects Division (7507P)

TO: Maria Piansay, Chemical Review Manager

Jill Bloom, Team Leader

Linda Arrington, Branch Chief

Risk Management and Implementation Branch V

Pesticide Re-evaluation Division (7508P)

The Environmental Fate and Effects Division (EFED) has completed the preliminary problem 

formulation for the environmental fate, ecological risk, endangered species, and drinking water 

exposure assessments to be conducted as part of the Registration Review of the fungicide 

difenoconazole (CAS# 119446-68-3). Functioning as the first stage of the risk assessment 

process for registration review, this problem formulation provides an overview of what is 

currently known about the environmental fate and ecological effects associated with 

difenoconazole and its degradates. It also describes the preliminary ecological risk hypothesis 

and analysis plan for evaluating and characterizing risk to non-target species in support of the 

registration review of difenoconazole. This document also recommends studies that should be 

included in a generic data call-in (DCI) to address uncertainties surrounding the environmental 

fate and potential ecological effects of difenoconazole.
2

EFED recommends the following studies to reduce uncertainty in the risk assessment1:

• 850.4550: Cyanobacteria toxicity (difenoconazole; TGAI)*

• 850.4100: Terrestrial plant toxicity (seedling emergence) – (TEP)*

o Tier II testing is required for lettuce, soybean, and sugar beet. A NOAEC must be 

established at the maximum single application rate (Tier 1 test) for the other seven 

test species (those showing no effects in the available study, MRID 48453203); 

alternatively, Tier II testing may be conducted for those species.

• 850.4150 : Terrestrial plant toxicity (vegetative vigor) – (TEP)*

o A NOAEC must be established for all ten test species at the maximum single 

application rate (Tier I test). Alternatively, Tier II testing may be conducted.

• Non-guideline: Chronic toxicity to benthic invertebrates (whole sediment; 3 test species: 

freshwater amphipod, freshwater midge, and estuarine/marine amphipod) –

(difenoconazole; TGAI)*

o EFED recommends that the registrant consider Agency-wide guidelines for 

chronic testing of freshwater and estuarine/marine organisms2,3 because the 

OCSPP 850 series guidelines are in the process of being finalized. A protocol 

must be submitted for review prior to initiating the studies.

• Non-guideline Tier I: Honeybee adult acute oral exposure (difenoconazole; TGAI)

• Non-guideline Tier I: Honeybee adult chronic oral exposure (difenoconazole; TGAI)

• Non-guideline Tier I: Honeybee larval acute and chronic oral exposure (difenoconazole; 

TGAI)

• Non-guideline Tier II: Residue in pollen and nectar (recommendation pending risks 

identified in Tier I studies) (TEP)

• Non-guideline Tier II: semi-field testing for pollinators (tunnel and feeding studies) 

(recommendation pending risks identified in Tier I studies) (TEP)

• 850.3040: Tier III full-field testing for pollinators (recommendation pending risk 

identified in Tier II studies) (TEP)

• 850.6100: ILV: Independent laboratory validation report for analytical method in soil for 

difenoconazole and its metabolites (CGA-205375, CGA-142856, and CGA-71019).

• 850.6100: ECM/ILV: Environmental chemistry method and independent laboratory 

validation reports for analytical method in water for difenoconazole and its metabolites 

(CGA-205375, CGA-142856, and CGA-71019).

Toxicity data from other sources (e.g., other conazoles) may be used in the absence of data for 

difenoconazole. Use of surrogate data may over or underestimate risk of difenoconazole use.

 1 The studies marked with an asterisk (*) were recently required as a condition of registration for a PRIA label 

amendment for EPA Reg. No. 100-739 to add new uses to the label for use on Legumes Subgroup 6C and Bushberry 

Subgroup 13-07B; Related to Petition #4F8231 (May 6, 2015). 2 USEPA 2000. Methods for Measuring the Toxicity and Bioaccumulation of Sediment-associated Contaminants 

with Freshwater Invertebrates. EPA 600/R-99/064 3 USEPA 2001. Methods for Assessing the Chronic Toxicity of Marine and Estuarine Sediment-associated 

Contaminants with the Amphipod Leptocheirus plumulosus. EPA 600/R-01/020.
3

EFED recommends the following label changes to reduce uncertainty in the risk assessment:

EFED requests that the registrant provide maximum annual application rates per acre (maximum 

lb ai/A/year) on all labels in addition to the currently labeled per-crop or per-season rates. 

Potential accumulation of difenoconazole is a concern given that it is persistent and because 

many crops may have multiple crop seasons per year. In the absence of labeled maximum 

annual application rates (or labeled maximum number of crop seasons/year), EFED will assume 

multiple crop seasons for applicable crops and make conservative assumptions about the number 

of seasons based on the best available information.
4

Problem Formulation for the Environmental Fate, 

Ecological Risk, Endangered Species, and Drinking 

Water Exposure Assessments in Support of the 

Registration Review of Difenoconazole

CAS: 119446-68-3

PC Code: 128847

Environmental Fate and Effects Division

Prepared by:

Michael Lowit, Ph.D., Ecologist

Faruque Khan, Ph.D., Senior Fate Scientist

U.S. Environmental Protection Agency

Office of Pesticide Programs

Environmental Fate and Effects Division

Environmental Risk Branch I

1200 Pennsylvania Ave., NW

Mail Code 7507P

Washington, DC 20460

Reviewed by:

Ryan Mroz, Biologist

Gregory Orrick, RAPL
5

Table of Contents

1. Purpose........................................................................................................................................ 6

2. Problem Formulation .................................................................................................................. 6

2.1. Nature of Regulatory Action................................................................................................ 6

2.2. Previous Assessments.......................................................................................................... 6

2.2.1. Ecological Risk Assessments........................................................................................ 6

2.2.2. Drinking Water Exposure Assessments........................................................................ 6

3. Stressor Source and Distribution ................................................................................................ 7

3.1. Mechanism of Action.......................................................................................................... 7

3.2. Overview of Pesticide Use and Usage ................................................................................ 7

3.3. Physical, Chemical, and Environmental Fate Properties of Difenoconazole and its 

Degradates................................................................................................................................... 8

3.4. Monitoring Data................................................................................................................ 13

3.5. Clean Water Act................................................................................................................ 13

4. Receptors.................................................................................................................................. 13

4.1. Toxicity of Difenoconazole .............................................................................................. 14

4.2. Toxicity of 1,2,4-Triazole (PC 600074) ........................................................................... 18

4.3. Toxicity of Triazole Acetic Acid (PC 600082)................................................................. 19

4.4. Toxicity of CGA-205375.................................................................................................. 20

4.5. Incident Databases Review............................................................................................... 21

5. Exposure Pathways of Concern ............................................................................................... 21

6. Analysis Plan ........................................................................................................................... 21

6.1. Stressors of Concern .......................................................................................................... 22

6.2. Measures of Exposure........................................................................................................ 23

6.3. Measures of Effect ............................................................................................................. 23

6.4. Integration of Exposure and Effects .................................................................................. 24

6.5. Endangered Species Assessments...................................................................................... 24

6.6. Endocrine Disruptor Screening.......................................................................................... 25

6.7. Drinking Water Assessment .............................................................................................. 25

6.8. Preliminary Identification of Data Gaps............................................................................ 25

6.8.1. Environmental Fate Data ............................................................................................ 25

6.8.2. Ecological Effects Data............................................................................................... 27

7. References................................................................................................................................ 33

APPENDIX A. Difenoconazole Uses.......................................................................................... 34

APPENDIX B. Names and Structures of Difenoconazole and its Major and Minor Degradates 37

APPENDIX C. ECOSAR Results................................................................................................ 42

APPENDIX D. SIP v.1.0 Inputs and Outputs.............................................................................. 43

APPENDIX E. STIR v.1.0 Inputs and Outputs........................................................................... 44
6

1. Purpose

The purpose of this problem formulation is to provide an understanding of what is known about 

the environmental fate, ecological effects, and currently registered uses of difenoconazole. This 

document provides a plan for analyzing data relevant to difenoconazole and for conducting 

environmental fate, ecological risk, endangered species, and drinking water exposure 

assessments for its registered uses. Additionally, this problem formulation identifies data gaps, 

uncertainties, and potential assumptions used to address those uncertainties relative to 

characterizing the potential ecological risk associated with the registered uses of difenoconazole.

2. Problem Formulation

2.1. Nature of Regulatory Action

As part of the implementation of the Registration Review program4 pursuant to Section 3(g) of 

the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), the Agency is beginning its 

evaluation of difenoconazole to determine whether it continues to meet the FIFRA standard for 

registration. This problem formulation in support of the Registration Review of difenoconazole 

will be posted in the initial docket which will be open to the public phase of the review process.

2.2. Previous Assessments

2.2.1. Ecological Risk Assessments

Difenoconazole was first registered in the US in 1994 as systemic broad-spectrum fungicide; 

it is currently registered for use on a variety of food crops, ornamental plants, and turf. 

Previous ecological risk assessments (ERA) identified risk concerns primarily for aquatic 

invertebrates, fish, birds, and mammals on a chronic basis and on an acute basis for 

estuarine/marine invertebrates for certain uses (most recent: USEPA, 2014a). Risk concerns 

for terrestrial plants were limited to listed dicot species.

2.2.2. Drinking Water Exposure Assessments

The most recent drinking water assessment (DWA) in support of human health risk assessment 

was conducted in 2014 to support the registration of difenoconazole on numerous uses including 

artichoke, ginseng, berry and small fruits (subgroup 13-07B), legume vegetables (subgroup 6C) 

as well as conversion of use on stone fruit to crop group 12-12 and tree nuts to crop group 14-12

(USEPA, 2014b). The estimated drinking water concentrations (EDWCs) of difenoconazole and 

its major degradate, CGA-205375 (aka, M1), were generated using application rates of 0.46 to 

0.52 lb ai/A with the Surface Water Concentration Calculator model (SWCC) for surface water 

and the maximum application rate of 0.52 lb ai/A with the PRZM-GW and SCI-GROW models 

for groundwater. For surface water, the EDWCs did not exceed those recommended in the 

previous DWA for use on grapes (see USEPA, 2013), which were a peak (acute) concentration 

of 20.0 μg/L, an annual mean (non-cancer chronic) concentration of 13.6 μg/L, and a 30-year 

annual average concentration (cancer chronic) of 9.9 μg/L. PRZM-GW estimated groundwater 

concentrations were: acute = 1.77 μg/L and chronic = 0.66 μg/L for the maximum application 

rate of 0.52 lb ai/A for the FL citrus scenario.

 4 http://www2.epa.gov/pesticide-reevaluation/registration-review-process
7

3. Stressor Source and Distribution

3.1. Mechanism of Action

Difenoconazole is a broad-spectrum triazole fungicide that works by inhibiting demethylation 

and other processes in sterol biosynthesis. Difenoconazole is a penetrating systemic fungicide 

which is rapidly absorbed by leaves and is then distributed within plant tissue by translaminar 

movement.

3.2. Overview of Pesticide Use and Usage

Estimates of the actual usage of difenoconazole on agricultural crops are summarized in Table 1 

(Screening Level Usage Analysis (SLUA) provided by the Biological and Economic Analysis 

Division (BEAD) on October 2, 2014). Primary uses in terms of average weight of applied 

product of difenoconazole are wheat (seed treatment), potatoes, and sugar beet. These data 

represent usage information from 2004 to 2014.

Difenoconazole is labeled for use on a variety of food crops, ornamental plants, and turf. Most 

uses allow aerial and ground applications and in some cases chemigation. A summary of 

previously assessed uses, maximum application rates, number of applications, and minimum 

application intervals is reported in Appendix A. The registration review risk assessment will be 

based on current label information at the time of assessment as provided by BEAD.

To reduce uncertainty in the risk assessment, EFED requests that the registrant provide annual 

maximum application rates per acre (maximum lb ai/A/year) on all labels in addition to the 

currently labeled per-crop or per-season rates that remain on some labels. Potential 

accumulation of difenoconazole is a concern given that it is persistent and because many crops 

may have multiple crop seasons per year. In the absence of labeled maximum annual application 

rates (or labeled maximum numbers of crop seasons/year), EFED will assume multiple crop 

seasons for applicable crops and make conservative assumptions about the number of seasons 

based on best available information.

Table 1. Estimated Usage of Difenoconazole on Agricultural Crops

Crop Average Annual Usage

lb ai/A

Percent (%) Crop Treated

Average Maximum

Almonds 7,000 5 15

Apples 7,000 15 25

Brussels Sprouts1 <500 Not calculated

Cabbage <500 <2.5 5

Cantaloupes <500 <2.5 <2.5

Cucumbers 3,000 5 10

Garlic <500 5 5

Grapefruit <500 <2.5 <2.5

Grapes 9,000 5 10

Onions 2,000 5 10

Oranges 1,000 <2.5 <2.5
8

Crop Average Annual Usage

lb ai/A

Percent (%) Crop Treated

Average Maximum

Peaches <500 <1 <2.5

Pears <500 5 10

Pecans 1,000 <2.5 <2.5

Peppers <500 <2.5 5

Pistachios <500 <2.5 5

Potatoes 20,000 15 30

Pumpkins <500 <2.5 5

Squash <500 5 10

Strawberries <500 <2.5 <2.5

Sugar Beets 20,000 15 30

Tangerines 1,000 <2.5 <2.5

Tomatoes 7,000 25 40

Walnuts <500 <2.5 <2.5

Watermelons 2,000 5 10

Wheat (Seed Treatment) 40,000 10 15 1 Based on CA DPR data only (80% or more of U.S. acres grown are in California)

3.3. Physical, Chemical, and Environmental Fate Properties of Difenoconazole and 

its Degradates

Difenoconazole is a water soluble (15 mg/L) chemical. It has a relatively low vapor pressure 

(2.5 x 10-10 mm Hg) and Henry’s Law constant (8.9 x 10-12 atm∙m3/mol), which suggest that 

volatilization is not expected to be a major route of dissipation from soil and water. Select 

physical and chemical properties are presented in Table 2.

Table 2. Physical and Chemical Properties of Difenoconazole

Property Value Source

Common Name Difenoconazole

MRID 46950104

CAS Registry No. 119446-68-3

PC Code 128847

Structure

Chemical Name (CAS) 1-{2-[4-(chlorophenoxy)-2-chlorophenyl-(4-methyl -

1,3-dioxolan-2-yl)-methyl]} -1H-1,2,4-triazole
9

Property Value Source

SMILES notation O1CC(C)OC1(Cn2ncnc2)c3c(Cl)cc(Oc4ccc(Cl)cc4)cc3 EPI Suite, v3.12 

SMILES

Molecular Formula C19H17Cl2N3O3

Molecular Weight 406.27 MRID 46950104

Physical State Red Liquid

Vapor pressure 2.5 x 10-10 mm Hg (25 oC) MRID 46515901

Henry’s Law constant 8.9 x 10-12 atm x m3/mol MRID 46515901

Specific Gravity/ Density 1.14g/cm3 @ 25 oC MRID 46950104

Solubility in water 15.0 mg/L @ 25 oC MRID 46950104

log Kow 4.4 (25 oC) MRID 46950105

Table 3 summarizes the environmental fate data for difenoconazole. Difenoconazole was stable 

to hydrolysis at pH 5, 7, and 9 in aqueous buffered solutions. Aqueous photolysis half-lives 

ranged from 9.2 to 228 days in sterile buffer solutions. Difenoconazole may potentially undergo 

relatively fast photolysis (DT50 of 6 days) in natural aquatic environments, which may be 

attributable to indirect photolysis via irradiation absorption by organic components present in the 

natural water. However, difenoconazole was stable to soil photolysis.

Difenoconazole is relatively stable to aerobic and anaerobic soil metabolism and aerobic and

anaerobic aquatic metabolism. When applied at 0.1-0.23 ppm to a variety of European and 

domestic aerobic soils, difenoconazole degraded with half-lives ranging from 84.5 to 533 days. 

At a concentration of 10 ppm in a loam soil, difenoconazole degraded with half-lives of 1059 to 

1600 days under aerobic conditions and 947 days under anaerobic conditions.

In aquatic environments under aerobic conditions, difenoconazole degraded with half-lives 

ranging from 315 to 565 days at concentrations up to 0.17 g ai/L and 860 days at a concentration 

of 10 mg ai/L. Under anaerobic conditions, difenoconazole degraded with half-lives of 370 days 

at a concentration of 0.04 mg ai/L and 1245 days at a concentration of 10 mg ai/L. The longer 

half-life values obtained in both terrestrial and aquatic environments with higher concentrations 

may imply that the rate of microbially mediated degradation of difenoconazole may be 

concentration dependent.

During aqueous photolysis, difenoconazole breaks down to 1,2,4-triazole acetic acid (aka, 

triazole acetic acid and CGA-142856) and is further degraded to triazole methanol (aka, CGA107069), and 1,2,4-triazole (aka, CGA-71019). In aerobic soil, difenoconazole degrades slowly 

to the ketone CGA-205374, which in turn is reduced to the alcohol CGA-205375, the cleavage 

product 1,2,4-triazole, carbon dioxide, and minor compounds. CGA-205375 and 1,2,4-triazole 

were also identified as degradates in aerobic and anaerobic metabolism studies. CGA-205375 

consistently reached a maximum of 4.4% to 14.8% in biodegradation studies. The greatest 

formation of 1,2,4-triazole was observed in the anaerobic aquatic metabolism study (35.9% at 
10

study termination; 350 days). Triazole acetic acid reached a maximum of 42% at the end of the 

aquatic photolysis study (30 days) and CGA-205375 was detected at a maximum of 14% at the 

end of terrestrial field study (580 days). The non-extractable fraction (8.1% to 48.9%) was a 

major sink for the applied difenoconazole, while mineralization accounted for 0.6% to 23.4% AR 

in laboratory aerobic and anaerobic metabolism studies. Chemical names, structures, and 

formation of major and minor degradates are reported in Appendix B.

Submitted terrestrial field dissipation studies showed that difenoconazole and its degradates did 

not leach below 30 cm of soil depth except in one study where leaching was noted up to 60 cm of 

the cropped plot soil (under potato production conditions in ND; MRID 46950129). 

Difenoconazole dissipated with half-lives ranging from 136 to 462 days in the terrestrial field 

dissipation studies.

Difenoconazole appears to be slightly mobile to hardly mobile in soils (FAO, 2000). Freundlich 

adsorption coefficient (KF(ads)) values were 12.8 mL/g for sand soil, 63.0 mL/g for sandy loam 

soil, 54.8 mL/g for silt loam soil, and 47.2 mL/g for silty clay loam soil. The corresponding KFoc

values were 3867, 3518, 3471, and 7734 mL/g. KF(ads) values for difenoconazole are directly 

proportional to the soil organic carbon content. In another study, KF(ads) values were 11.6, 22.9, 

182, and 201 mL/g for the Madera loamy sand, Visalia sandy loam, North Dakota clay loam, and 

Florida sand soils, respectively; corresponding KFoc values were 3870, 4587, 4799, and 11202 

mL/g. However, this study was conducted with autoclaved soil, potentially distorting the 

mobility characteristics of difenoconazole.

The octanol water partition coefficient (log Kow of 4.4) suggests that difenoconazole has a 

potential to bioaccumulate. Difenoconazole accumulated rapidly in edible and non-edible 

bluegill sunfish tissues with bioconcentration factors of 170x for edible tissues, 570x for nonedible tissues, and 330x for whole body. Depuration was also rapid with a depuration half-life of 

approximately 1 day and 96-98% clearance after 14 days of depuration. One metabolite, CGA205375, was recovered from both edible and non-edible tissues, accounting for 51-64% of the 

applied difenoconazole.

Table 3. Summary of the Environmental Fate Properties of Difenoconazole

Property Value Source

Hydrolysis half-life

pH = 5

pH = 7

pH = 9

Stable

Stable

Stable

MRID 42245127

Photolysis half-life in water 6 days – ca. 1 ppm in in natural water 

ca. 9.2 days – 1mg ai/L sterile buffer 

solution

228 days – 1.52 mg ai/L in sterile buffer 

solution (15-day study)

Major degradates (maximum % [at day])

CGA-142856 (41.8 [30d])

CGA-107069 (12.27 [30d])

1,2,4-triazole (12.9 [9d])

MRID 42245128 

MRID 46950104

MRID 46950105

Photolysis half-life in soil 349 - 823 days1

No major degradates

MRID 469501-06 & -073
11

Property Value Source

Aerobic soil metabolism half-life 84.5 days – at 0.1 ppm concentration

1600 days – at 10 ppm in loam2

1059 days – at 10 ppm in sandy loam2

120 days – at 0.13 ppm; Swiss loam

104 days – at 0.13 ppm; Swiss loam

158 days – at 0.23 ppm; Swiss sandy loam

187 days – at 0.23 ppm; Swiss 

sandy loam/loamy sand 

198 days – at 0.23 ppm; French silty clay 

loam

408 days – at ca. 0.1 ppm in CA loamy sand 

at 25o

C

533 days – at ca. 0.1 ppm in CA loamy sand 

at 25o

C

Major degradates (maximum % [at day])

CGA-205375 (14.8 [360d]

1,2,4-triazole (20.6 [190d])

Non-extractable residue (48.9 [293d])

MRID 42245131

MRID 42245132

MRID 42245133

MRID 46950109

MRID 46950110

MRID 46950111

MRID 469501-12 & -13

MRID 469501-14 & -15

Anaerobic soil metabolism half-life 947 days – at 10 ppm in loam2

No major degradates

MRID 42245132

Aerobic aquatic metabolism halflife860 days (10 mg ai/L)2; rice paddy water

330 days (0.17 mg ai/L); Swiss pond watersilty clay loam sediment

301 days; Swiss river water-sandy loam 

sediment

565 days; water and loamy sand sediment 

from river near Porterville, CA 

Major degradate (maximum % [at day])

CGA-205375 (11.6 [90d])

Non-extractable residue (8.9 [112d])

MRID 42245134

MRID 46950116

MRID 469501-17 &-18

Anaerobic aquatic metabolism halflife 1245 days (10 mg ai/L)2; rice paddy water

433 days (0.04 mg ai/L); water and loamy 

sand sediment from river near Porterville, 

CA

Major degradates (maximum % [at day])

CGA-205375 (12.6 [175d]

CGA-71019 (35.9 [350d])

Non-extractable residue (8.1 [302d])

MRID 42245134

MRID 469501-19 & -20

Terrestrial field dissipation half-life 252 days - determined in the 0- to 3-inch 

depth – CA bare loamy sand

231 days – GA bare loamy sand (four 

applications of 0.13 lb ai/A)

139 days – CA bare plot of loam soil (four 

applications of 0.13 lb ai/A)

462 days – ND bare sandy clay loam

No major degradates

MRID 42245140

MRID 46950126

MRID 46950127

MRID 46950129 
12

Property Value Source

Soil adsorption coefficient 

KF(ads) and KFoc (L/kg)

KF(ads) and (1/n) soil

11.61 (0.80) Madera loamy sand

22.94 (0.84) Visalia sandy loam

182.4 (0.86) North Dakota clay loam

201.6 (0.91) Florida sand

KFoc (% of organic carbon) soil

3870 (0.3) Madera loamy sand

4587 (0.5) Visalia sandy loam

4799 (3.8) North Dakota clay loam

11202 (1.8) Florida sand

MRID 469501-21 & -22

KF(ads) and (1/n) soil

12.8 (0.74) Sand

63.0 (0.76 Sandy loam 

54.8 (0.85) Silt loam

47.2 (0.91) Silty clay loam

KFoc (% of organic carbon) soil

3867 (0.33) Sand

3518 (1.79) Sandy loam

3471 (1.58) Silt loam

7734 (0.61) Silty clay loam

MRID 422451353

CGA-205375

KF(ads) and (1/n) soil

9.64 (0.83) Madera loamy sand

12.35 (0.83) Visalia sandy loam

145.32 (0.73) North Dakota clay loam

115.77 (0.84) Florida sand

KFoc (% of organic carbon) soil

3214 (0.3) Madera loamy sand

2470 (0.5) Visalia sandy loam

3824 (3.8) North Dakota clay loam

6432 (1.8) Florida sand

MRID 469501-23 & -24

Bluegill sunfish (Lepomis 

macrochirus) bioconcentration 

(BCF) factor 

Depuration half-life

170x in edible tissues

570x nonedible tissues

330x for whole body

1 day

MRID 46950123

1 The soil photolysis half-life under xenon light conditions was recalculated to represent the conditions under 

natural sunlight intensity during 30-day periods between June and September (104.7-246.9 W∙min/cm2), as a result, 

a range of half-lives was obtained. 2 The test application rate was significantly higher than expected under registrant-proposed use conditions for 

difenoconazole. 

3 The test soils were autoclaved prior to conducting the study which could distort the mobility characteristic of 

difenoconazole, thus, the study results will not be used as modeling input parameters. 

Major degradates (CGA-205375, 1,2,4 triazole, and triazole acetic acid)

There are few environmental fate studies available for the major degradates of difenoconazole.

CGA-205375 has the potential to be slightly more mobile (FAO, 2000) in the soil than the parent

compound. Freundlich adsorption values for CGA-205375 are 9.6, 12.3, 145, and 116 mL/g for 

the Madera loamy sand, Visalia sandy loam, North Dakota clay loam, and Florida sand soils, 

respectively; corresponding KFoc values are 3214, 2470, 3824, and 6432 mL/g. In addition, the 

KF(ads) values for CGA-205375 are directly proportional to soil organic carbon content. 
13

The environmental fate properties of 1,2,4-triazole and triazole acetic acid were provided in a 

recent registration review problem formulation for myclobutanil (see USEPA, 2015). Abiotic 

(hydrolysis half-lives = 99 to 421 days; stable to aqueous photolysis) and biotic degradations are 

not major routes of 1,2,4-triazole degradation. Microbial degradation of 1,2,4-triazole in aerobic 

soils is highly varied (half-lives = 20 days to stable). 1,2,4-triazole is moderately persistent in 

anaerobic soil (half-life = 81 days). The major transformation products of 1,2,4-triazole are 

triazole acetic acid and hydroxytriazole. Both transformation products are formed through 

microbial degradation in aerobic soils.

3.4. Monitoring Data

EFED is aware of monitoring data for difenoconazole. Available data from sources including 

federal and state agencies will be considered in the DWA and ERA.

3.5. Clean Water Act

Difenoconazole is not identified as a cause of impairment for any water bodies listed as impaired 

under section 303(d) of the Clean Water Act.

5

 In addition, no Total Maximum Daily Loads 

(TMDL) have been developed.

6

 The Impaired Waters and Total Maximum Daily Loads website 

can be consulted for more information.

7 The Agency invites submission of water quality data for 

difenoconazole. To the extent possible, data should conform to the quality standards in the OPP 

Standard Operating Procedure: Inclusion of Impaired Water Body and Other Water Quality 

Data in OPP’s Registration Review Risk Assessment and Management Process8, in order to 

ensure they can be used quantitatively or qualitatively in pesticide risk assessments.

4. Receptors

Consistent with the process described in the Overview Document (USEPA, 2004), the risk 

assessment for difenoconazole relies on a surrogate species approach. Toxicological data 

generated from surrogate test species, which are intended to be representative of broad 

taxonomic groups, are used to extrapolate the potential effects on a variety of species (receptors) 

included under these taxonomic groupings.

Acute and chronic toxicity data from studies submitted by pesticide registrants along with the 

available open literature will be used to evaluate the potential direct and indirect effects of 

difenoconazole to aquatic and terrestrial receptors. This includes toxicity on the technical grade 

active ingredient, degradates, and when available, formulated products (e.g., “Six-Pack” studies). 

Open literature studies will be identified through EPA’s ECOTOXicology (ECOTOX) database9

, 

which employs a literature search engine for locating chemical toxicity data.

A summary of available toxicity data representing non-target organisms exposed to 

difenoconazole and major degradates (1,2,4-triazole, triazole acetic acid, and CGA-205375) is 

 5 http://iaspub.epa.gov/tmdl_waters10/attains_nation_cy.cause_detail_303d?p_cause_group_id=885

6 http://iaspub.epa.gov/tmdl_waters10/attains_nation.tmdl_pollutant_detail?p_pollutant_group_id=885&p_pollutant

_group_name=PESTICIDES

7 http://www.epa.gov/owow/tmdl/ 8 http://archive.epa.gov/pesticides/ppdc/ppdc/2006/november06/session1-sop.pdf 9 http://cfpub.epa.gov/ecotox/
14

provided in Sections 4.1, 4.2, 4.3, and 4.4. Ecological Structure Activity Relationship 

(ECOSAR) methods10 were used to estimate toxicity of the major degradates in cases where data 

are unavailable; results are discussed below and are presented in Appendix C. A review of 

ecological incidents associated with difenoconazole is provided in Section 4.5. The ECOTOX 

database will be searched when the risk assessment for difenoconazole is prepared. At that time, 

EFED will review the endpoints from open literature studies that are more sensitive than those 

from available guideline studies.

4.1. Toxicity of Difenoconazole

Table 4. Summary of Aquatic Taxa Toxicity Endpoints for Difenoconazole

Type of Study Species Toxicity Value 

(μg ai/L) MRID

Acute – Freshwater 

Fish

Rainbow trout

(Oncorhynchus mykiss)

96-hr LC50 = 810 (630-1200)1

NOAEC = 350

LOAEC = 630 based on mortality, 

darkened pigmentation, and lethargy

Other sublethal effects: decreased 

respiration

----------------------------------------------------

96-hr LC50 = 1060 (970-1130)1

Slope = 16.1 (9.0-23.3)

NOAEC < 580

LOAEC ≤ 580 based on partial loss of 

equilibrium and lethargy

Other sublethal effects: darkened 

pigmentation

42245107

------------------

42245108

Bluegill Sunfish

(Lepomis macrochirus)

96-hr LC50 = 1200 (900-1700)1

NOAEC = 520

LOAEC = 900 based on surfacing, loss of 

equilibrium, fish on the bottom, and 

quiescence

42245109

Fathead minnow

(Pimephales promelas)

96-hr LC50 = 1800 (1300-2600)1

NOAEC = 660

LOAEC = 1300 based on mortality, 

lethargy, and loss of equilibrium

Other sublethal effects: lying on the 

bottom or surface

48453201

 10 ECOSAR predictive software is available publically though the Epi SuiteTM program. 

http://www2.epa.gov/tsca-screening-tools/ecological-structure-activity-relationships-ecosar-predictive-model
15

Type of Study Species Toxicity Value 

(μg ai/L) MRID

Chronic – Freshwater 

Fish

Fathead minnow

(Pimephales promelas)

Early Life Stage

NOAEC = 8.7

LOAEC = 19 based on reduced larval 

length 30-days post-hatch

----------------------------------------------------

Life Cycle

NOAEC = 1.9

LOAEC = 3.7 based on reduced male 

length of F0-generation 12 weeks posthatch

42245115

------------------

48453205

Rainbow trout

(Oncorhynchus mykiss)

NOAEC = 0.86

Value used for risk assessment. Based on 

acute-to-chronic ratio of fathead minnow 

data to rainbow trout data (the most 

acutely sensitive species).2

-

Acute – Freshwater 

Invertebrate

Water flea 

(Daphnia magna)

48-hr EC50 = 770 (590-950) 1

Slope = 4.1 (2.5-5.7) 1

NOAEC < 520

LOAEC ≤ 520 based on mortality

Other sublethal effects: on bottom and 

quiescence

42245110

Chronic – Freshwater 

Invertebrate

Water flea

(Daphnia magna)

NOAEC = 5.6

LOAEC = 13.0 based on reduced number 

of young/adult/reproductive day and adult 

length

42245114

Chronic – Freshwater 

Invertebrate 

(Sediment)

Midge

(Chironomus riparius)

NOAEC = 5 mg ai/kg-sediment

LOAEC = 50 mg ai/kg-sediment based on 

emergence rate & development rate

476486013

Acute –

Estuarine/Marine Fish

Sheepshead minnow 

(Cyprinodon variegates)

96-hr LC50 = 819 (0-infinity)1

NOAEC = 325

LOAEC = 428 based on mortality

Other sublethal effects: lethargy and lying 

on the bottom

----------------------------------------------------

96-hr LC50 = 1100 (900-1500)1

NOAEC = 270

LOAEC = 400 based on loss of 

equilibrium

42245112

------------------

42906702
16

Type of Study Species Toxicity Value 

(μg ai/L) MRID

Chronic –

Estuarine/Marine Fish

Sheepshead minnow 

(Cyprinodon variegates)

NOAEC = 0.86

Based on acute-to-chronic ratio of fathead 

minnow data to sheepshead minnow data.4

-

Acute –

Estuarine/Marine 

Mollusk

Eastern oyster

(Crassostrea virginica)

96-hr EC50 = 424 (333-539)1

NOAEC = 180

LOAEC = 340 based on reduced shell 

growth

----------------------------------------------------

96-hr EC50 > 300

NOAEC = 210

LOAEC = 300 based on reduced shell 

growth

42906701

------------------

42245113

Acute –

Estuarine/Marine 

Invertebrate

Mysid shrimp

(Americamysis bahia)

96-hr LC50 = 150 (125-193)1

Slope = 4.7 (2.7-6.7) 1

NOAEC = 480

LOAEC = 730 based on mortality

42245111

Chronic –

Estuarine/Marine 

Invertebrate

Mysid shrimp

(Americamysis bahia)

NOAEC < 0.115

LOAEC ≤ 0.115 based on reduced number 

of young/adult/reproductive day

----------------------------------------------------

NOAEC < 0.31

LOAEC ≤ 0.31 based on reduced number 

of young/adult/reproductive day and 

number of young/adult

----------------------------------------------------

NOAEC = 4.8

LOAEC = 10 based on reduced F0 postpairing survival, offspring/female and time 

to first brood

46950133

------------------

47648603

------------------

49322901 and 

49387801

Vascular Plant –

Freshwater

Duckweed

(Lemna gibba)

7-day EC50 = 1900 (1600-2400)1,5

Slope = 1.3±0.96

EC05 = 110 (59-190) 1

NOAEC < 110

LOAEC ≤ 110 based on reduced frond 

number

46950204
17

Type of Study Species Toxicity Value 

(μg ai/L) MRID

Non-vascular Plant Freshwater Diatom

(Navicula pelliculosa)

96-hr EC50 = 98 (68-140) 1,5

Slope = 2.3±0.3 (poor fit)6

NOAEC = 53

LOAEC = 150 based on reduced cell 

density

46950208

Freshwater Algae 

(Pseudokirchneriella 

subcapitata)

96-hr EC50 = 300 (200-440) 1,5

Slope = 2.9±0.5 (poor fit)6

NOAEC = 150

LOAEC = 360 based on reduced cell 

density

46950212

Marine Diatom

(Skeletonema costatum)

96-hr EC50 = 430 (300-630) 1,5

Slope = 2.4±0.46

EC05 = 87 (39-190)1

NOAEC < 6.3

LOAEC ≤ 6.3 based on reduced cell 

density

46950210

1 Range is 95% confidence interval.

2 Acute toxicity to fathead minnow: LC50 = 1800 μg ai/L (MRID 48453201); acute toxicity to rainbow trout: LC50 = 

810 μg ai/L (MRID 42245107), and chronic toxicity to fathead minnow: NOAEC = 1.9 μg ai/L (MRID 48453205) 3 This is a range finding study and should not be used quantitatively for risk assessment.

4 Acute toxicity to fathead minnow: LC50 = 1800 μg ai/L (MRID 48453201); acute toxicity to sheepshead minnow: 

LC50 = 819 μg ai/L (MRID 42245112), and chronic toxicity to fathead minnow: NOAEC = 1.9 μg ai/L (MRID 

48453205)

5 Most sensitive endpoint (based on EC50) is reported. 6 ± standard error

Table 5. Summary of Terrestrial Taxa Toxicity Endpoints for Difenoconazole

Type of Study Species Toxicity Value MRID

Acute – Avian Oral 

Dose

Canary

(Serinus canaria)

LD50 > 2000 mg ai/kg-bw

NOAEL ≥ 2000 mg ai/kg-bw

LOAEL > 2000 mg ai/kg-bw

48453202

Mallard duck

(Anas platyrhynchos)

LD50 > 2150 mg/kg-bw

NOAEL < 2150 mg/kg-bw

LOAEL ≤ 2150 mg/kg-bw based on 

reduced body weight gain and feeding

42245105

Acute – Avian Dietary

Bobwhite quail

(Colinus virginianus)

LC50 = 4760 mg/kg-diet (4103-5522) 1

Slope = 1.2

NOAEC = 625 mg/kg-diet

LOAEC = 1250 mg/kg-diet based on 

reduced body weight and feeding

42245103

Mallard duck

(Anas platyrhynchos)

LC50 > 5000 mg/kg-diet

NOAEC = 625 mg/kg-diet

LOAEC = 1250 mg/kg-diet based 

mortality

Other sublethal effects: reduced body 

weight and feeding

42245104

Chronic – Avian 

Dietary

Bobwhite quail

(Colinus virginianus)

NOAEC = 21.9 mg ai/kg-diet

LOAEC = 108 mg ai/kg-diet based on 

reduction in hatchling body weight 

46950202
18

Type of Study Species Toxicity Value MRID

Chronic – Avian 

Dietary

Mallard duck

(Anas platyrhynchos)

NOAEC = 110.8 mg ai/kg-diet

LOAEC = 492.9 mg ai/kg-diet based on 

egg shell thinning

42245106

Acute – Mammalian 

Oral Dose

Laboratory rat

(Rattus norvegicus) LD50 = 1453 mg ai/kg-bw 42090006

Two Generation 

Reproduction –

Mammalian

Laboratory rat

(Rattus norvegicus)

NOAEC = 25 mg ai/kg-diet

LOAEC = 250 mg ai/kg-diet based on 

reduced maternal body weight gain and 

reduced pup weight

42090018

Acute Contact –

Terrestrial Invertebrate 

Honey bee

(Apis mellifera)

LD50 >100 μg ai/bee

NOAEL ≥ 100 μg ai/bee

LOAEL > 100 μg ai/bee

42245124

Acute Contact – 

Terrestrial Invertebrate

Earthworm

(Eisenia fetida)

14-day LC50 > 610 mg ai/kg-dw soil

NOAEC ≥ 610 mg ai/kg-dw soil

LOAEC > 610 mg ai/kg-dw soil

42245125

Tier I – Terrestrial 

Plants

Corn, Onion, Ryegrass, 

Wheat, Radish, Cabbage, 

Lettuce, Sugar beet, 

Soybean, and Tomato

Seedling Emergence

EC25 > 0.111/0.112 lb ai/A2

NOAEC < 0.111/0.112 lb ai/A2,3

LOAEC ≤ 0.111/0.112 lb ai/A2,3

----------------------------------------------------

Vegetative Vigor

EC25 > 0.123 lb ai/A

NOAEC ≥ 0.123 lb ai/A

LOAEC > 0.123 lb ai/A

48453203

------------------

48453204

1 Range is 95% confidence interval.

2 Some species were exposed to 0.111 lb ai/A and others were exposed to 0.112 lb ai/A.

3 Effects at 0.11 lb ai/A on lettuce, sugar beet, and soybean were considered biologically significant. Lettuce 

showed reduced emergence (21%), survival (17%), shoot length (26%), and dry weight (24%). Soybean showed 

reduced shoot length (23%). Sugar beet showed reduced survival (18%).

4.2. Toxicity of 1,2,4-Triazole (PC 600074)

Available guideline data for 1,2,4-triazole are presented in Table 6 and 7. 1,2,4-triazole is less 

toxic than difenoconazole to non-vascular plants (green algae), freshwater fish (acute basis), and 

freshwater invertebrates (acute basis). In contrast, birds are more acutely sensitive to 1,2,4-

triazole compared to difenoconazole. Finally, both 1,2,4-triazole and difenoconazole showed 

chronic effects to mammals at 250 mg ai/kg-diet; however, there is uncertainty about the relative 

chronic toxicity of the two compounds because a NOAEC was established in the difenoconazole 

study (25 mg ai/kg-diet) whereas the 1,2,4-triazole study did not test below 250 mg ai/kg-diet. 

Non-guideline, summary report data on acute oral toxicity to rats (MRID 45284001, 45284004, 

and 45284008) suggests that 1,2,4-triazole (LD50s ranging from 1375 to 3080 mg/kg-bw) and 

difenoconazole (LD50 = 1453 mg ai/kg-bw) are equally as toxic.

Table 6. Summary of Aquatic Taxa Toxicity Endpoints for 1,2,4-Triazole

Type of Study Species Toxicity Value 

(μg ai/L) MRID

Acute – Freshwater 

Fish

Rainbow trout

(Oncorhynchus mykiss) 96-hr LC50 = 498,000 48474301
19

Type of Study Species Toxicity Value 

(μg ai/L) MRID

Acute – Freshwater 

Invertebrate

Water flea 

(Daphnia magna) 48-hr EC50 > 98,100 48453206

Non-vascular Plant

Freshwater Algae 

(Pseudokirchneriella 

subcapitata)

96-hr EC50 = 14,000 45880401

Table 7. Summary of Terrestrial Taxa Toxicity Endpoints for 1,2,4-Triazole

Type of Study Species Toxicity Value MRID

Acute – Avian Oral 

Dose

Bobwhite quail

(Colinus virginianus) LD50 = 770 mg ai/kg-bw 49380701

Two Generation 

Reproduction –

Mammalian

Laboratory rat

(Rattus norvegicus)

NOAEC < 250 mg ai/kg-diet

LOAEC ≤ 250 mg ai/kg-diet based on 

reduced body weight and body weight gain 

in F1 males, reduced spleen weight in F1 

females and F2 female pups, and reduced 

body weight, body weight gain, and brain 

weight in F2 pups

46467304

Subchronic (28 day 

adult) and reproductive 

(additional 28 day 

offspring) – 

Terrestrial Invertebrate

Earthworm 

(Eisenia fetida)

LC50 > 70.81 μg/kg

NOAEC ≥ 70.81 μg/kg

LOAEC > 70.81 μg/kg

45880402

28 day – Terrestrial 

Invertebrate 

Springtails

(Folsomia candida)

28-day LC50 > 10 mg ai/kg soil

NOAEC = 1.8 mg ai/kg soil

LOAEC = 3.2 mg ai/kg soil based on 

reduced number of juveniles

45880404

ECOSAR methods were used to predict chronic toxicity of 1,2,4-triazole to fish and aquatic 

invertebrates based on its structural similarity to chemicals for which aquatic toxicity data are 

known (Appendix C). Estimates were available for freshwater organisms but not 

marine/estuarine organisms. A comparison of 1,2,4-triazole ECOSAR estimates to 

experimentally derived difenoconazole toxicity values suggests that 1,2,4-triazole is much less

toxic (two orders of magnitude) than difenoconazole on a chronic basis to freshwater 

invertebrates and fish. There is reasonable confidence in the ECOSAR estimates for 1,2,4-

triazole (at least for fish and non-vascular plants11) given that the ECOSAR estimates are within 

an order of magnitude of the available experimentally derived values. 

4.3. Toxicity of Triazole Acetic Acid (PC 600082)

Available guideline data for triazole acetic acid are presented in Table 8 and 9. Triazole acetic 

acid is less acutely toxic than difenoconazole to mammals, freshwater fish, and freshwater 

invertebrates. It is uncertain if triazole acetic acid is more or less acutely toxic to birds than 

difenoconazole because none of the available studies for either chemical showed treatmentrelated mortality up to the highest doses tested (ca. 2000 mg ai/kg-bw).12

 11 There is no basis for judging confidence in the ECOSAR estimate of acute toxicity to freshwater invertebrates due 

to a non-definitive endpoint. 12 There was one mortality in the canary study (MRID 48453202) that may not have been treatment related.
20

Table 8. Summary of Aquatic Taxa Toxicity Endpoints for Triazole Acetic Acid

Type of Study Species Toxicity Value 

(μg ai/L) MRID

Acute – Freshwater 

Fish

Rainbow trout

(Oncorhynchus mykiss)

96-hr LC50 > 101,000 48453209

Acute – Freshwater 

Invertebrate

Water flea 

(Daphnia magna) 48-hr EC50 > 108,000 48453208

Table 9. Summary of Terrestrial Taxa Toxicity Endpoints for Triazole Acetic Acid

Type of Study Species Toxicity Value MRID

Acute – Avian Oral 

Dose

Bobwhite quail

(Colinus virginianus) LD50 > 1926 mg ai/kg-bw 49412601

Acute – Mammalian 

Oral Dose

Laboratory rat

(Rattus norvegicus) LD50 > 5000 mg ai/kg-bw 45596802

A comparison of triazole acetic acid ECOSAR estimates to experimentally derived 

difenoconazole toxicity values suggests that triazole acetic acid is much less toxic (three or more 

orders of magnitude) than difenoconazole to aquatic non-vascular plants, freshwater fish (chronic 

basis), and freshwater invertebrates (chronic basis) (Appendix C). Estimates were not available 

for marine/estuarine organisms. There is no basis for judging confidence in the ECOSAR 

estimates because the ECOSAR estimates for acute toxicity to fish and invertebrates are 

substantially greater (less toxic) than the non-definitive endpoints observed in the available acute 

toxicity studies.

4.4. Toxicity of CGA-205375

On an acute oral basis, CGA-205375 and difenoconazole are of similar toxicity to mammals 

(Table 5 and 10). 

Table 10. Summary of Terrestrial Taxa Toxicity Endpoints for CGA-205375

Type of Study Species Toxicity Value MRID

Acute – Mammalian 

Oral Dose Mouse LD50 = 2309 mg ai/kg-bw1 46950303

1 LD50 = 1289 mg ai/kg-bw scaled to laboratory rat weight (350 g) based on an average mouse body weight of 34 g 

in this study and the following equation: mouse LD50 * (mouse bw/rat bw)0.25

A comparison of CGA-205375 ECOSAR estimates to experimentally derived difenoconazole 

toxicity values suggests that CGA-205375 is not more toxic than difenoconazole to aquatic 

organisms in general and is similar in toxicity (< 10 times difference) to aquatic non-vascular 

plants, fish (acute basis), and invertebrates (acute basis) (Appendix C). The available 

information also suggests that CGA-205375 and difenoconazole are similar in chronic toxicity to 

freshwater fish and invertebrates based on ECOSAR estimates of both compounds (< 10 times 

difference) and to a lesser extent when based on comparison of CGA-205375 ECOSAR 

estimates to experimentally derived difenoconazole data. Experimentally derived CGA-205375 

data are not available to judge the level of confidence in the ECOSAR estimates.
21

4.5. Incident Databases Review

Reviews were conducted of the Ecological Incident Information System (EIIS, version 2.1.1)13, 

the Agency’s Aggregated Incidents Reports database, and the Avian Incident Monitoring System 

(AIMS)14 on 7/16/2015. No incidents were reported in EIIS or AIMS. Ten minor plant damage 

incidents were reported for one difenoconazole product (Revus Top) in the aggregated incident 

database. The Revus Top label indicates that it is a dual ai product containing mandipropamid, a 

fungicide, as well as difenoconazole.

The total number of actual incidents associated with the use of difenoconazole may be higher 

than what is reported to the Agency. Incidents may go unreported since effects may not be 

immediately apparent or readily attributed to the use of a chemical. As such, the absence of 

incident reports cannot be construed as the absence of incidents.

5. Exposure Pathways of Concern

The use patterns and environmental fate properties of difenoconazole indicate that exposure to 

non-target aquatic and terrestrial organisms may occur from direct spray and offsite movement 

via spray drift and runoff. 

An additional exposure pathway that will be considered is the consumption of contaminated fish

by piscivorus animals because fate data (log Kow) of difenoconazole (4.4) and CGA-205375 

(3.79; EPISUITE estimate) suggest the potential for bioaccumulation of both compounds in the 

aquatic food web.

Screening Imbibition Program

The Screening Imbibition Program (SIP v.1.0)15 was used to calculate an upper-bound estimate 

of bird and mammal exposure to difenoconazole in drinking water. Drinking water exposure 

alone was determined not to be a potential acute concern for birds or mammals; however, the 

screen suggests that there is a potential chronic concern for birds and mammals. Appendix D

provides model results.

Screening Tool for Inhalation Risk 

The Screening Tool for Inhalation Risk (STIR v.1.0)15 was used to provide an upper-bound 

estimate of exposure of birds and mammals to pesticides through inhalation of spray drift or 

vapor. The screening suggests that difenoconazole exposure is not likely significant enough for 

an inhalation risk concern. Appendix E provides model results.

6. Analysis Plan

In order to address the risk hypothesis, the potential for adverse effects on the environment is 

estimated. The use, environmental fate, and ecological effects of difenoconazole will be 

 13 http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/technical-overview-ecological-riskassessment-risk 14 http://www.abcbirds.org/abcprograms/policy/toxins/aims/aims/index.cfm 15 http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/models-pesticide-risk-assessment
22

characterized and integrated to assess risk. This will be accomplished using a risk quotient (RQ; 

ratio of exposure concentration to effects concentration) approach. Although risk is often 

defined as the likelihood and magnitude of adverse ecological effects, the risk quotient-based 

approach does not provide a quantitative estimate of likelihood or magnitude of an adverse 

effect. However, as outlined in the Overview Document (USEPA, 2004), the likelihood of 

effects to individual organisms from particular uses of difenoconazole will be estimated using 

the probit dose-response slope and either the level of concern or actual calculated risk quotient 

value.

This analysis plan will be revisited and may be revised depending upon a full review of the data 

available in the open literature and the information submitted by the public in response to the 

opening of the Registration Review docket.

6.1. Stressors of Concern

Ecological Risk Assessment

Difenoconazole and CGA-205375 will be considered stressors of concern in the difenoconazole 

ERA. Available information suggests that CGA-205375 and difenoconazole are of similar 

toxicity. Equal toxicity of difenoconazole and CGA-205375 will be assumed in the absence of 

data. The other two major degradates, 1,2,4-triazole and triazole acetic acid, will also be 

considered stressors of concern; however, on a case by case basis. Available information 

suggests that they are equally as toxic as difenoconazole (e.g., 1,2,4-triazole acute oral toxicity to 

rats), less toxic than difenoconazole (e.g., 1,2,4-triazole and triazole acetic acid acute toxicity to 

freshwater fish and invertebrates), or more toxic than difenoconazole (e.g., 1,2,4-triazole acute 

oral toxicity to birds) depending on the taxonomic group and exposure scenario. For example, 

1,2,4-triazole will be a degradate of concern for acute toxicity to mammals and birds but will not 

be a degradate of concern for acute toxicity to freshwater fish and invertebrates.

Drinking Water Assessment

Difenoconazole and CGA-205375 will be considered the stressors of concern in the 

difenoconazole DWA, consistent with the conclusions of the Residues of Concern 

Knowledgebase Subcommittee (ROCKS) committee of the Health Effects Division (HED) 

(USEPA, 2011). The residues of concern may be reevaluated pending receipt and review of 

additional environmental fate and toxicity data. It is anticipated that the other two major 

degradates, 1,2,4-triazole and triazole acetic acid, will be addressed in an updated aggregate 

DWA.

Aggregate Risk Assessment

Aggregate risk from two of the major degradates, 1,2,4-triazole and its conjugate: triazole acetic 

acid, may be addressed in a separate ERA and DWA because they are common to the class of 

compounds known as triazoles (i.e., triazole-derivative fungicides, T-D fungicides, or 

conazoles).
23

6.2. Measures of Exposure

Difenoconazole concentrations in aquatic and terrestrial environments will be modeled using the 

maximum labeled application rates, the maximum number of applications, the minimum 

application intervals, and application methods that have the greatest potential for off-site 

transport. 

Aquatic Exposure 

There is potential for exposure to non-target organisms through run-off and spray drift. The 

most current models will be used to estimate residues in water at the time of the risk assessment

(e.g., SWCC). 16 Bioaccumulation potential in aquatic organisms will be estimated to assess 

exposure to piscivorus animals (e.g., Kow (based) Aquatic BioAccumulation Model 

(KABAM)).16 

A total toxic residue (TTR) approach will be used to estimate exposure to aquatic organisms. 

Degradate CGA-205375 will be included in the TTR of difenoconazole because it forms greater 

than 10% of applied difenoconazole in available fate studies and available information suggests 

that CGA-205375 and difenoconazole are equally toxic. 

Terrestrial Exposure

There is potential for exposure to non-target organisms through consumption of contaminated 

food items (e.g., treated insects or vegetation and contaminated fish), direct application, runoff, 

or spray drift. The most current models will be used at the time of the risk assessment. Current 

models include:

T-REX (v 1.5.2)

16 is used to estimate avian and mammal exposure residues on terrestrial food 

items. For input into T-REX, the default foliar dissipation half-life of 35 days will be used in the 

absence of acceptable foliar dissipation rate data.

TerrPlant (v 1.2.2)16 is used to calculate EECs for characterizing exposure to terrestrial and semiaquatic plants.

Terrestrial Investigation Model (TIM, v. 3.0 beta)16 is used to derive quantitative estimates of the 

probability (or likelihood) and magnitude of mortality to birds.

6.3. Measures of Effect

Toxicity effects data will be used as measures of direct and indirect effects to biological 

receptors (USEPA, 2004). As discussed previously, data will be obtained from registrantsubmitted studies and from literature studies identified in ECOTOX.

Quantitative assessment of risks will be based on study endpoints that can be directly linked to 

the Agency’s assessment endpoints of impaired survival, growth, and reproduction. Sub-lethal 

 16 http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/models-pesticide-risk-assessment
24

effects (e.g., lethargy and changes in coloration) will be evaluated qualitatively. Available 

incident data will be used to further characterize risk.

6.4. Integration of Exposure and Effects

The exposure and effects data will be integrated in order to evaluate potential adverse ecological 

effects on non-target species. The risk quotient method will be used to compare exposure and 

measured toxicity values. EECs will be divided by acute and chronic toxicity values. The 

resulting RQs will be compared to the Agency’s Levels of Concern (LOC) (USEPA, 2004). 

6.5. Endangered Species Assessments

Consistent with EPA’s responsibility under the Endangered Species Act (ESA), the Agency will 

evaluate risks to federally listed threatened and endangered (listed) species from registered uses 

of pesticides in accordance with the Joint Interim Approaches developed to implement the 

recommendations of the April 2013 National Academy of Sciences (NAS) report, Assessing 

Risks to Endangered and Threatened Species from Pesticides. The NAS report17 outlines 

recommendations on specific scientific and technical issues related to the development of 

pesticide risk assessments that EPA and the Services (U.S. Fish and Wildlife Service and 

National Marine Fisheries) must conduct in connection with their obligations under the ESA and 

FIFRA. EPA will address concerns specific to difenoconazole in connection with the 

development of its final registration review decision for difenoconazole. 

In November 2013, EPA, the Services, and USDA released a white paper containing a summary 

of their joint Interim Approaches for assessing risks to listed species from pesticides. These 

Interim Approaches were developed jointly by the agencies in response to the NAS 

recommendations, and reflect a common approach to risk assessment shared by the agencies as a 

way of addressing scientific differences between the EPA and the Services. Details of the joint 

Interim Approaches are contained in the November 1, 2013 white paper, Interim Approaches for 

National-Level Pesticide Endangered Species Act Assessments Based on the Recommendations 

of the National Academy of Sciences April 2013 Report. 18

Given that the agencies are continuing to develop and work toward implementation of the 

Interim Approaches to assess the potential risks of pesticides to listed species and their 

designated critical habitat, this ecological problem formulation supporting the Preliminary Work 

Plan for difenoconazole does not describe the specific ESA analysis, including effects 

determinations for specific listed species or designated critical habitat, to be conducted during 

registration review. While the agencies continue to develop a common method for ESA analysis, 

the planned risk assessment for the registration review of difenoconazole will describe the level 

of ESA analysis completed for this particular registration review case. This assessment will 

allow EPA to focus its future evaluations on the types of species where the potential for effects 

exists, once the scientific methods being developed by the agencies have been fully vetted. Once 

the agencies have fully developed and implemented the scientific methods necessary to complete 

 17 http://www.nap.edu/catalog/18344/assessing-risks-to-endangered-and-threatened-species-from-pesticides 18 http://www2.epa.gov/endangered-species/interim-approaches-pesticide-endangered-species-act-assessmentsbased-nas-report
25

risk assessments for listed species and their designated critical habitats, these methods will be 

applied to subsequent analyses of difenoconazole as part of completing this registration review.

6.6. Endocrine Disruptor Screening

As required by Federal Food, Drug and Cosmetic Act (FFDCA) section 408(p), difenoconazole

is subject to the endocrine screening part of the Endocrine Disruptor Screening Program 

(EDSP).

19 Difenoconazole is not in the first or second group of pesticide active ingredients to be 

screened under the EDSP. 

6.7. Drinking Water Assessment

A DWA will be conducted, if warranted, to support future human health dietary risk assessments 

of difenoconazole. The residues of concern will be difenoconazole and CGA-205375 as 

recommended by the ROCKS committee (USEPA, 2011). The residues of concern may be 

reevaluated pending receipt and review of additional environmental fate and toxicity data. 

Concentrations in surface and groundwater will be estimated using current exposure models.20 

Additionally, EFED may update the previously conducted aggregate drinking water exposure 

assessment for 1,2,4-triazole and its conjugates.

6.8. Preliminary Identification of Data Gaps

Available studies submitted to fulfill environmental fate and ecological effects guideline 

requirements, as well as outstanding data gaps for difenoconazole are defined in Sections 6.8.1 

and 6.8.2, respectively. Studies are identified that offer data for each guideline requirement, as 

well as study classifications and whether or not further data are needed in order to support the 

risk assessment.

6.8.1. Environmental Fate Data

Environmental fate data gaps for difenoconazole are indicated in the table below (Table 11). 

EFED recommends requesting the following studies to reduce uncertainty in the risk assessment:

• 850.7100: ILV: Independent laboratory validation report for analytical method in soil for 

difenoconazole and its metabolites (CGA-205375, CGA-142856, and CGA-71019).

• 850.7100: ECM/ILV: Environmental chemistry methods and independent laboratory 

validation in water for difenoconazole and its metabolites (CGA-205375, CGA-142856,

and CGA-71019).

Major degradate (CGA-205375)

There are no environmental fate studies available for CGA-205375 except for a soil batch 

equilibrium study (MRID 469501-23/24). In the absence of CGA-205375 environmental fate 

studies, needed physiochemical and environmental fate properties will be estimated using EPI 

 19 http://www2.epa.gov/endocrine-disruption 20 http://www2.epa.gov/pesticide-science-and-assessing-pesticide-risks/models-pesticide-risk-assessment
26

Suite.21 Study-sourced environmental fate and physicochemical properties of CGA-205375 may

reduce the uncertainties in the aquatic exposure and drinking water assessments.

Table 11. Environmental Fate Data and Data Gaps for Difenoconazole

Guideline Description MRID Classification Data 

Gap? Comments

835.2120 Hydrolysis 42245127 Acceptable No --

835.2240 Aqueous 

photolysis

42245128

46950104

46950105

Supplemental No --

835.2410 Soil photolysis 46950106 Supplemental No --

835.4100 Aerobic soil 

metabolism

42245131

42245132

42245133

46950109

46950110

46950111

469501-12 & -13

469501-14 & -15

Supplemental

Supplemental

Supplemental

Supplemental

Supplemental

Supplemental

Supplemental

Supplemental

No --

835.4200 Anaerobic soil 

metabolism

42245132

42245133

Supplemental

Supplemental

No Two anaerobic soil metabolism 

studies have already been 

submitted and are classified as 

supplemental. Additional data are 

required under 40 CFR Part 158 

for terrestrial outdoor uses. 

Predicted DT50s suggest that 

difenoconazole is stable under 

anaerobic conditions. Additional 

data are considered to have a low 

potential to add value to exposure 

assessments for the ecological 

risk and drinking water. 

835.4300 Aerobic aquatic 

metabolism

42245134

46950116

46950117

Supplemental

Supplemental

Supplemental

No --

835.4400 Anaerobic 

aquatic 

metabolism

42245134

46950119

Supplemental

Supplemental

No --

835.1230

835.1240

Adsorption/ 

desorption and 

leaching

42245135

42245136

46950121

Supplemental

Supplemental

Acceptable

No --

835.1410 Volatility –

laboratory

-- -- No Difenoconazole is not expected 

to be volatile under normal use 

conditions based on low vapor 

pressure and Henry’s Law 

Constant

 21 Estimation Programs Interface (EPI) SuiteTM is comprised of a set of programs that estimate fate and physical 

properties. It was developed by the EPA’s Office of Pollution Prevention Toxics and Syracuse Research 

Corporation (SRC). 
27

Guideline Description MRID Classification Data 

Gap? Comments

835.6100 Terrestrial field 

dissipation

42245140

46950126

46950127

46950129

Supplemental

Acceptable

Acceptable

No ---

850.6100 Analytical 

method in soil

46950128 

(ECM)

Not applicable Yes Independent laboratory 

validations (ILV) is required for 

difenoconazole and its 

degradates.

Analytical 

method in water

-- -- Yes Environmental chemistry method 

(ECM) and independent 

laboratory validations (ILV) are 

required for difenoconazole and 

its degradates.

850.1730 Fish 

bioconcentration

42245142 Acceptable No ---

BOLD = Recommended Studies

6.8.2. Ecological Effects Data

Data gaps for difenoconazole remain (Tables 12, 13, and 14); however, some of these studies 

are anticipated to have little impact on the risk assessment and are not recommended for a datacall in (DCI). EFED recommends requesting the following studies to reduce uncertainty in the 

risk assessment:22

• 850.4550: Cyanobacteria toxicity (difenoconazole; TGAI)*

• 850.4100: Terrestrial plant toxicity (seedling emergence) – (TEP)*

o Tier II testing is required for lettuce, soybean, and sugar beet. A NOAEC must be 

established at the maximum single application rate (Tier 1 test) for the other seven 

test species (those showing no effects in the available study, MRID 48453203); 

alternatively, Tier II testing may be conducted for those species.

• 850.4150 : Terrestrial plant toxicity (vegetative vigor) – (TEP)*

o A NOAEC must be established for all ten test species at the maximum single 

application rate (Tier I test). Alternatively, Tier II testing may be conducted.

• Non-guideline: Chronic toxicity to benthic invertebrates (whole sediment; 3 test species: 

freshwater amphipod, freshwater midge, and estuarine/marine amphipod) –

(difenoconazole; TGAI)*

o EFED recommends that the registrant consider Agency-wide guidelines for 

chronic testing of freshwater and estuarine/marine organisms23,24 because the 

OCSPP 850 series guidelines are in the process of being finalized. A protocol 

must be submitted for review prior to initiating the studies.

 22 The studies marked with an asterisk (*) were recently required as a condition of registration for a PRIA label 

amendment for EPA Reg. No. 100-739 to add new uses to the label for use on Legumes Subgroup 6C and Bushberry 

Subgroup 13-07B; Related to Petition #4F8231 (May 6, 2015). 23 USEPA 2000. Methods for Measuring the Toxicity and Bioaccumulation of Sediment-associated Contaminants 

with Freshwater Invertebrates. EPA 600/R-99/064 24 USEPA 2001. Methods for Assessing the Chronic Toxicity of Marine and Estuarine Sediment-associated 

Contaminants with the Amphipod Leptocheirus plumulosus. EPA 600/R-01/020.
28

• Non-guideline Tier I: Honeybee adult acute oral exposure (difenoconazole; TGAI)

• Non-guideline Tier I: Honeybee adult chronic oral exposure (difenoconazole; TGAI)

• Non-guideline Tier I: Honeybee larval acute and chronic oral exposure (difenoconazole; 

TGAI)

• Non-guideline Tier II: Residue in pollen and nectar (recommendation pending risks 

identified in Tier I studies) (TEP)

• Non-guideline Tier II: semi-field testing for pollinators (tunnel and feeding studies) 

(recommendation pending risks identified in Tier I studies) (TEP)

• 850.3040: Tier III full-field testing for pollinators (recommendation pending risk 

identified in Tier II studies) (TEP)

Toxicity data from other sources (e.g., other conazoles) may be used in the absence of data for 

difenoconazole. Use of surrogate data may over or underestimate risk of difenoconazole use.

Major degradates (CGA-205375, 1,2,4-triazole, and triazole acetic acid)

Data submission for CGA-205375, 1,2,4-triazole, and triazole acetic acid chronic toxicity would 

be welcomed and may reduce uncertainty in the risk assessment; however, EFED is not 

recommending degradate toxicity data at this time given that it is not anticipated that data would 

substantially change risk conclusions. Nonetheless, chronic toxicity data may be useful for 

refining risk concerns for birds, fish, and aquatic invertebrates. ECOSAR estimates suggest that 

CGA-205375 and difenoconazole are equally toxic to aquatic organisms (less than an order of 

magnitude difference in toxicity); therefore, equal toxicity will be assumed in the absence of 

data. ECOSAR estimates of 1,2,4-triazole and triazole acetic acid suggest that they are less toxic 

on a chronic basis than difenoconazole to aquatic organisms; thus, empirical data would be 

useful to confirm this assumption. Data indicate that 1,2,4-triazole is more acutely toxic to birds 

than difenoconazole, suggesting chronic toxicity of 1,2,4-triazole may be greater than 

difenoconazole as well. Although a chronic risk concern is expected for birds based on 

difenoconazole alone, 1,2,4-triazole data would be useful to confirm the assumption of greater 

toxicity and better characterize risk from difenoconazole use. 

Table 12. Ecological Effects Data Requirements (TGAI) for Aquatic Organisms Exposed 

to Difenoconazole and Data GapsA

Guideline Description MRID Classification Data 

Gap? Comments

850.1075

Acute freshwater 

fish toxicity

(cold water species)

42245107

42245108

Acceptable1

Acceptable1 No

1 In some cases an older 

classification scheme was 

reported in the DER. 

Studies classified as “core” 

are equivalent to 

“acceptable”.

 

2 Upgraded to acceptable 

with submission of MRID 

46950132.

Acute freshwater 

fish toxicity

(warm water 

species)

42245109

48453201

Acceptable1

Acceptable No

Acute estuarine/

marine fish toxicity

42245112

42906702

Acceptable1

Acceptable1 No
29

Guideline Description MRID Classification Data 

Gap? Comments

850.1010

Acute toxicity to 

freshwater 

invertebrates

42245110 Acceptable1 No 3 A definitive endpoint was 

established in MRID 

49322901/49387801 but at a 

higher concentration than 

those showing effects in the 

two previously conducted 

studies (MRID 46950133 

and 47648603). Given the 

available information, 

additional testing is unlikely 

to add substantial value to 

the risk assessment 

(conclusions) and is 

therefore not requested at 

this time. However, 

additional testing could be 

recommended in the future 

if it appears that it would 

impact the risk assessment 

(see detailed discussion in 

USEPA, 2014a).

4 There is some uncertainty 

in the results of the available 

early life stage study. A 

new study is not 

recommended because risk 

can be assessed using the 

acceptable life cycle study

(MRID 48453205).

5 Although a study 

submission would be 

welcomed, EFED is not 

recommending a study at 

this time. Toxicity can be 

estimated using an acute-tochronic ratio if data are not 

available. Available acute 

data suggest similar toxicity 

of difenoconazole to 

freshwater and 

marine/estuarine fish; thus, 

it is assumed that toxicity is 

similar on a chronic-basis 

too. It is assumed that the 

freshwater study is 

protective of marineestuarine fish. 

850.1025

Acute estuarine/

marine mollusk 

toxicity

42245113

42906701

Acceptable1

Acceptable1 No

850.1035

Acute estuarine/

marine invertebrate 

toxicity

42245111 Acceptable1 No

850.1300

Freshwater 

invertebrate life 

cycle

42245114 Acceptable2 No

850.1350

Saltwater 

invertebrate life 

cycle

46950133

47648603

49322901/49387801

Supplemental

Supplemental

Acceptable

No3

850.1400

Freshwater fish early 

life stage 42245115 Supplemental Yes4

Saltwater fish early 

life stage - - Yes

850.1500

Freshwater fish life 

cycle 48453205 Acceptable No

Saltwater fish life

cycle - - Yes5

850.1735

Whole sediment 

acute toxicity, 

freshwater 

invertebrates

47648601 Supplemental No6

850.1740

Whole sediment 

chronic toxicity, 

marine invertebrates

- - No

-

Whole sediment 

chronic toxicity, 

freshwater 

invertebrates

- - Yes7

-

Whole sediment 

chronic toxicity, 

marine-estuarine 

invertebrates

- - Yes7

850.5400B

Aquatic plant 

growth

(freshwater green 

alga)

46950212 Acceptable No

Aquatic plant 

growth (freshwater 

diatom)

46950208 Acceptable No
30

Guideline Description MRID Classification Data 

Gap? Comments

Aquatic plant 

growth (saltwater 

diatom)

46950210 Acceptable No

6 The available study is a 

non-guideline range finding 

study that does not fill the 

data requirement for 

850.1735. However, there is 

not a data gap because an 

acute study is not required.

7 Data are recommended 

because there is uncertainty 

associated with chronic risk 

to benthic invertebrates 

given that pore water EECs 

are similar to water column 

EECs and the chronic LOC 

(1.0) is exceeded for aquatic 

invertebrates based on 

comparison of water column 

species toxicity data to pore 

water EECs. Sediment 

chronic toxicity testing with 

three species is 

recommended: freshwater 

midge, freshwater 

amphipod, and 

marine/estuarine amphipod.

8 Testing with a TEP is 

typically recommended; 

however, TGAI testing is 

preferred to be consistent 

with available 

difenoconazole toxicity data 

for other aquatic plants. 

9 A study is not 

recommended at this time as 

additional data are unlikely 

to have substantial impact 

on the risk assessment.

850.5400B

Aquatic plant 

growth 

(Cyanobacteria)

46950206 Invalid Yes8

850.4400B

Aquatic plant 

growth (vascular 

plants)

46950204 Supplemental Yes9

A An invalid early life stage (ELS) study was previously submitted for freshwater fish (MRID 45137502) but was

subsequently replaced with a supplemental ELS study and an acceptable life cycle study. BAs of July 2012 the new guideline numbers are 850.4500 (Algal toxicity) and 850.4550 (Cyanobacteria toxicity)

BOLD = Recommended Studies
31

Table 13. Ecological Effects Data Requirements (TGAI) for Terrestrial Animals Exposed 

to Difenoconazole and Data GapsA

Guideline Description MRID Classification Data 

Gap?

Comments

850.2100

Avian acute oral 

toxicity

(upland game or 

waterfowl species)

42245105 Acceptable1 No2

1 In some cases an older 

classification scheme was 

reported in the DER. Studies 

classified as “core” are 

equivalent to “acceptable”.

2 Non-definitive endpoints were 

reported. Additional data are not 

needed nor recommended at this 

time. However, if the risk 

picture changes (e.g., risk 

concerns cannot be precluded 

based on the available data due to 

greater exposure than is expected 

at this time based on current 

uses) then additional data could 

be recommended in the future.

3 Upgraded to acceptable with 

submission of MRID 46950201.

4 Data are needed to assess risk 

because an exposure pathway 

exists, some of the registered 

uses are pollinator attractive 

crops (USDA, 2015), and 

incidental residues may occur on 

other flowering plants (e.g.

weeds) on or near the treatment 

site.

5 If Tier 1 screening risks are 

identified based on Tier I toxicity 

studies then Tier II studies 

(residue in pollen and nectar and 

850.3040 semi-field testing for 

pollinators) could be 

recommended and if risks are 

identified based on Tier II 

assessment then Tier III studies 

could be recommended 

(850.3040 full-field testing for 

pollinators).

Avian acute oral 

toxicity (passerine 

species)

48453202 Acceptable No2

850.2200

Avian dietary toxicity 

(upland game species) 42245103 Acceptable1 No

Avian dietary toxicity 

(waterfowl species) 42245104 Acceptable1 No2

850.2300

Avian reproduction 

(upland game species) 46950202 Acceptable No

Avian reproduction 

(waterfowl species) 42245106 Acceptable 3 No

850.3020

Adult honeybee acute 

contact toxicity 

(Tier 1)

42245124 Acceptable1 No2

NonguidelineAdult honeybee acute 

oral toxicity (Tier 1) 42245123 Invalid Yes

Nonguideline

Adult honeybee 

chronic oral toxicity 

(Tier 1)

- - Yes4,5

Nonguideline

Larval honeybee acute 

and chronic oral 

toxicity (Tier 1)

- - Yes4,5

A In some cases invalid studies were submitted [avian reproduction with an upland game species (MRID 42280601) 

and adult honeybee acute contact toxicity (MRID 42245123)] but were subsequently replaced with valid studies.

BOLD = Recommended Studies
32

Table 14. Ecological Effects Data Requirements (TEP) for Plants Exposed to 

Difenoconazole and Data Gaps

Guideline Description MRID Classification Data 

Gap? Comments

850.4100A

Terrestrial plant 

toxicity (Tier I or Tier 

II seedling emergence)

48453203 Supplemental Yes1,2

1 The available Tier I study is 

supplemental because there were 

biologically significant effects 

observed in dicots at the limit 

test concentration which is below 

the maximum labeled single 

application rate (turf; 0.26 lb 

ai/A). Tier II testing is required

for the dicot species that showed 

effects in the available study 

(lettuce, soybean, and sugar 

beet). Furthermore, a NOAEC 

must be established at the 

maximum single application rate 

(Tier 1 test) for the other seven 

test species (those showing no 

effects in the available study) to 

meet the data requirement; 

alternatively, Tier II testing may 

be conducted for those species.

2 It is EFEDs understanding that 

0.26 lb ai/A is the maximum 

single application rate for all 

currently registered uses. The 

registrant should confirm the 

maximum registered rate prior to 

conducting any Tier I studies.

3 The available Tier I study is 

supplemental because the limit 

test concentration is below the 

maximum labeled single 

application rate (turf; 0.26 lb 

ai/A). To meet the data 

requirement, a NOAEC must be 

established for all ten test species 

at the maximum single 

application rate (Tier I test). 

Alternatively, Tier II testing may 

be conducted.

850.4150B

Terrestrial plant 

toxicity (Tier I or Tier 

II vegetative vigor)

48453204 Supplemental Yes2,3

A As of July 2012 the Final Guideline 850.4100 contains both Tier I and Tier II test guidance.

B As of July 2012 the Final Guideline 850.4150 contains both Tier I and Tier II test guidance.

BOLD = Recommended Studies
33

7. References

FAO. 2000. Appendix 2. Parameters of pesticides that influence processes in the soil. In FAO 

Information Division Editorial Group (Ed.), Pesticide Disposal Series 8. Assessing Soil 

Contamination. A Reference Manual. Rome: Food & Agriculture Organization of the 

United Nations (FAO). http://www.fao.org/docrep/003/x2570e/x2570e00.htm

USDA. 2015. Attractiveness of Agricultural Crops to Pollinating Bees for the Collection of 

Nectar and/or Pollen.

USEPA. 2004. Overview of the Ecological Risk Assessment Process in the Office of Pesticide 

Programs. U.S. Environmental Protection Agency, Office of Prevention, Pesticides and 

Toxic Substances, Office of Pesticide Programs, Washington DC. January 23, 2004.

USEPA. 2011. Difenoconazole: Report of the Residues of Concern Knowledgebase Subcommittee (ROCKS). Health Effects Division, Office of Chemical Safety and Pollution 

Prevention. U. S. Environmental Protection Agency. DP 391350.

USEPA. 2013. Drinking Water Exposure Assessment in support of the new use registration of 

difenoconazole formulated product Inspire on Canola/Oilseed Subgroup 20A. 

Environmental Fate and Effects Division, Office of Chemical Safety and Pollution 

Prevention. U. S. Environmental Protection Agency. DP 412614.

USEPA. 2014a. Difenoconazole: Ecological Risk Assessment for Numerous Proposed New Uses 

and Changes to Registered Uses (Application Rate, Crop Groupings, and Additions to 

New Products). DP 417610+.

USEPA. 2014b. 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. 

Environmental Fate and Effects Division, Office of Chemical Safety and Pollution 

Prevention. U. S. Environmental Protection Agency. DP 421092. 

USEPA. 2015. Myclobutanil Problem Formulation for Registration Review. DP 421959.
34

APPENDIX A. Difenoconazole Uses

Previous assessments are listed in Table A-1. The purpose of this table is to capture the 

historical range of assessed uses and rates and is not intended to constitute a comprehensive upto-date list of currently registered uses and rates. Most uses allow aerial and ground applications 

and in some cases chemigation. In some cases a different mode of action fungicide should be 

alternated after a specified number of applications of difenoconazole containing products. The 

registration review risk assessment will be based on current label information at the time of 

assessment as provided by BEAD.

Table A-1. Previous Actions and Assessed Uses for Difenoconazole

Crop Maximum Application 

Rate (lb ai/A)

Number of 

Applications 

(Minimum 

Application 

Interval (days))

Action

DP Barcode

Single Seasonal/ (Date)

Annual

Ornamentals 0.13 0.52 /year 

(outdoor) or 

/crop 

(indoor)

4 (7) ERA

417610, 418014, 418502, 

421513, 421518, 421519, 

and 421523

(12/19/2014)

DWA

421092

(11/13/2014)

Berry and small fruit; 

bushberry subgroup 13-07B

Brassica (cole) leafy vegetables

Bulb vegetables (green onion 

limited to 3 applications or 

0.345 lb ai/A/year (outdoor 

crop) or per crop (indoor crop)

Cucurbit vegetables

Ginseng

Legume vegetables; dried 

shelled pea and bean (except 

soybean) subgroup 6C

Stone fruit (crop group 12-12)

0.115 0.46 /year 

(outdoor; all 

uses) or 

/crop 

(indoor; 

Brassica,

bulb 

vegetables, 

and cucurbit 

vegetables)

4 (7)

Artichoke

Tree nuts (crop group 14-12)

0.115 0.46 4 (14)

Cucurbit vegetables 0.114 + 

0.064

0.52 4 +1 (7)

Cucumber (greenhouse 

grown)

0.114 0.46 4 (7)

Fruiting vegetables (except 

tomato)

0.113 0.45 /year 

(outdoor) or 

/crop 

(indoor)

4 (7)

Tomato 0.0656 0.385 /year 

(outdoor) or 

/crop 

(indoor)

6 (7)

Pome fruit (crop group 11-10) Post-harvest treatment (dip, drench, flood, or 

spray)
35

Crop Maximum Application 

Rate (lb ai/A)

Number of 

Applications 

(Minimum 

Application 

Interval (days))

Action

DP Barcode

Single Seasonal/ (Date)

Annual

Canola and oilseed subgroup 

20A

0.113 NS

(assumed 

0.113)

NS

(assumed 1 

application/year)

ERA

409484 and 409488

(11/08/2013)

DWA

412614

(8/14/2013)

Potato (seed treatment) 0.062 NA NA ERA

402993 and 404403

(8/29/2012)

Citrus 0.125 0.50 4 (7) DWA - revised

395784

(12/20/2011)

Fruiting vegetable

Low growing berry subgroup 

(except cranberry)

Vegetable, tuberous and corm 

subgroup

0.114 0.46 4 (7)

Pome fruit 0.07 0.35 5 (7)

Carrot

Chickpea

Strawberry

0.114 0.46 4 (7) ERA

378927 and 384074 

(2/22/2011)

DWA

378946

(9/27/2010)

* Seed treatments were not 

included in the DWA.

Soybean 0.114 0.46 4 (7-14 

depending on the 

formulation)

Stone fruit (group 12) 0.114 0.46 4 (7-10 

depending on the 

formulation)

Oat (seed treatment) 0.023 NA NA

Rye (seed treatment) 0.034 NA NA

Golf course turf 0.26 0.52 2 (14) ERA

377719

(7/28/2010)

DWA

371044

(6/1/2010)

Citrus fruit 0.125 0.50 4 (7) ERA

361251

(8/26/2009)

DWA

361398

(5/28/2009)

DWA - revised

398836

(2/23/2012)

Bulb vegetables (green onion) 0.114 0.34 3 (7)

Brassica (cole) leafy vegetables

Bulb vegetables (dry bulb)

Cucurbit vegetables

0.114 0.46 4 (7)

Grapes 0.114 0.46 4 (10)

Almonds

Filberts

Pecans

Pistachios

Tree nuts

0.114 0.46 4 (14)

Watermelon 0.114 0.228 2 Emergency Exemption for 

Indiana

353502

(7/3/2008)
36

Crop Maximum Application 

Rate (lb ai/A)

Number of 

Applications 

(Minimum 

Application 

Interval (days))

Action

DP Barcode

Single Seasonal/ (Date)

Annual

Cucurbits- watermelons, 

cantaloupes, cucumbers 

0.114 0.46 4 Emergency Exemption for

Georgia

351238

(5/15/2008)

Almonds 0.11 N/A 2 Emergency Exemption for 

California

351716

(5/15/2008)

Ornamentals (carnations, 

gladiolus, irises, and roses)

0.13 0.561 NS (7) ERA

333319 and 340041

(7/12/2007)

DWA

333319 and 340041

(5/1/2007 and 6/19/2007)

Fruiting vegetables

Sugar beet 

Vegetables, tuberous and corm 

subgroup

0.11 0.44 NS (7)

Pome fruit 0.07 0.35 NS (7)

Barley (seed treatment)

Corn, sweet (seed treatment)

Cotton (seed treatment)

0.024

0.008

0.006

NA

NA

NA

NA

NA

NA

ERA

316708, 316620, and 

316707

(9/21/2005)

Wheat (seed treatment) 0.044 NA NA DWA

307166

(5/2/2005)

Canola (seed treatment) 0.00192 NA NA ERA and DWA

252640

(5/30/2001)

Canola (seed treatment) 0.0013 NA NA Emergency Exemption for

North Dakota

260762

(12/20/1999)

Wheat (seed treatment) 0.031 NA NA DWA

252509

(2/9/1999)

Wheat (seed treatment) 0.015 NA NA DWA

Unknown DP

(10/27/1998)

Wheat (seed treatment)

Barley (seed treatment)

0.010 NA NA ERA

194836, 194830, 194872 

and 194874

(3/29/1994)

Wheat (seed treatment) 1 oz per 100 

lb seed

NA NA Emergency Exemption for

Idaho

194787

(9/29/1993)

NA = Not applicable

NS = Not specified

1 The 2007 ERA and DWA seem to have erroneously reported the annual rate as 0.56 lb ai/A. The correct rate is 

0.52 lb ai/A
37

APPENDIX B. Names and Structures of Difenoconazole and its Major and Minor Degradates

Table B-1

Code Name 

(Synonym) Chemical Name Chemical Structure Study Type MRID Maximum %AR (day)

Final %AR 

(study length)

PARENT

Difenoconazole 

(CGA-169374)

IUPAC Name: 3-Chloro-4-[(2RS,4RS;2RS,4SR)-

4-methyl-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-

dioxolan-2-yl]phenyl 4-chlorophenyl ether.

CAS Name: 1-[2-[2-Chloro-4-(4-

chlorophenoxy)phenyl]-4-methyl-1,3-dioxolan-2-

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

CAS Number: 119446-68-3

Formula: C19H17Cl2N3O3

MW: 406.3 

SMILES: 

O1CC(C)OC1(Cn2ncnc2)c3c(Cl)cc(Oc4ccc(Cl)cc4)cc3

Hydrolysis 

pH 5

42245127

Not 

applicable

stable

Hydrolysis 

pH 7

stable

Hydrolysis 

pH 9

stable

Aqueous 

Photolysis

42245128 2.50 (30 days)

46950104 1.21 ± 0.5

(30 days)

46950105 94.1 (15 days)

Soil 

Photolysis

46950106

46950107

91.4 (30 days)

Aerobic 

Soil 

Metabolism

46950109 18.4 ± 0.1

(293 days)

46950110 14.1 

(293 days)

46950111 38.7 

(228 days)

46950112

46950113

57.6 

(360 days)

46950114

46950115

59.6 

(372 days)

Aerobic 

Aquatic 

Metabolism

46950116 71.2 

(183 days)

46950117

46950118

81.53 ± 3.22

(112 days)

Anaerobic 

Aquatic 

Metabolism

46950119

46950120

42.72 ± 0.88 

(350 days)
38

Code Name 

(Synonym) Chemical Name Chemical Structure Study Type MRID Maximum %AR (day)

Final %AR 

(study length)

Difenoconazole 

(CGA-169374)

Terrestrial 

Field 

Dissipation

46950126 Not 

applicable

44 ppb 

(531 days)

46950127 14 ppb

(535 days)

46950129 302 ppb 

(422 days)

MAJOR (>10%) TRANSFORMATION PRODUCTS

CGA-205375

(CGA-179500, 

CGA-211391,

and M1)

CAS Name: alpha-[2-Chloro-4-(4-

chlorophenoxy)phenyl]-1H-1,2,4-triazole-1-

ethanol.

1-[2-Chloro-4-(4-chlorophenoxy)phenyl]-2-

[1,2,4]-triazol-1-yl-ethanol.

CAS Number: 117018-19-6

Aqueous 

Photolysis

42245128 2.9 (5 days) 0.1 (30 days)

46950104 2.04 (14 days) 0.96 (30 days)

46950105 NA NA

Aerobic 

Soil 

metabolism

46950109 5.1 ± 1.4

(84 days)

3.7 ± 0.1

(293 days)

46950110 4.6 ± 0.1

(56 days)

3.7 ± 0.5

(293 days)

46950111 4.4 ± 1.6

(120 days)

2.7

(293 days)

46950112

46950113

14.8 ± 1.8 

(360 days)

14.8 ± 1.8

(360 days)

46950114

46950115

9.4 ± 0.1

(372 days)

9.4 ± 0.1

(372 days)

Aerobic 

Aquatic 

Metabolism

46950116 6.2 (183 days) 6.2 (183 days)

Anaerobic 

Aquatic 

Metabolism

46950119

46950120

12.60 ± 0.42

(175 days)

6.2 ± 0.76

(350 days)

Terrestrial 

Field 

Dissipation

46950126 11 ppb 

(358 days)

6.2ppb 

(531 days)

46950127 12 ppb 

(123 days)

5.6 ppb 

(531 days)

46950129 18ppb 

(364 days)

12.0 2ppb 

(535 days)

N

N

N

O Cl

Cl

OH
39

Code Name 

(Synonym) Chemical Name Chemical Structure Study Type MRID Maximum %AR (day)

Final %AR 

(study length)

1,2,4-triazole

(CGA-71019)

CAS Name: 1H-1,2,4-Triazole 

CAS Number: 288-88-0

Aqueous 

Photolysis 42245128 13.4 (9 days) 10.9 (30 days)

46950104 12.27 ± 0.7 

(30 days)

12.27 ± 0.7 

(30 days)

46950105 NA NA

Aerobic 

Soil 

Metabolism

46950110 20.6

(190 days)

17.8 ± 2.8

(293 days)

46950111 1.6 ± 0.4

(120 days)

0.9

(228 days)

46950114

46950115

7.8 ± 0.1

(372 days)

7.8 ± 0.1

(372 days)

Anaerobic 

Aquatic 

Metabolism

46950119

46950120

35.92 ± 0.71

(350 days)

35.92 ± 0.71

(350 days)

Terrestrial 

Field 

Dissipation

46950129 3.5 ppb 

(36 days)

< LOQ 

(535 days)

1,2,4-triazole 

acetic acid

(CGA-142856)

CAS Name: 1H-1,2,4-Triazole-1-acetic acid

CAS Number: 28711-29-7

Aqueous 

Photolysis

46950104 41.83 ± 0.9 

(30 days)

41.83 ± 0.9 

(30 days)

Terrestrial 

Field 

Dissipation

46950126

<LOQ 11 ppb 

(358 days)

CGA-107069 CAS Name: 1H-1,2,4-Triazole-1-methanol

CAS Number: 74205-82-6

Aqueous 

Photolysis

46950104 Reported as combined residue 

with 1,2,4-triazole

Carbon dioxide CAS Number: 124-38-9

Formula: CO2

MW: 44.1 g/mol

Aqueous 

Photolysis 46950104 2.01 (30 days) 2.01 ± 2.5(30 days)

46950105 0.01 (3 days) <0.1 (15 days)

Soil 

Photolysis

46950106

46950107

0.02 (21 days) <0.2 (30 days)

Aerobic 

Soil 

Metabolism

46950109 23.4 ± 1.9

(293 days)

23.4 ± 1.9

(293 days)

46950110 4.5 ± 2.4

(293 days)

4.5 ± 2.4

(293 days)

HO

O

N

N

N

C

H2

N

N

N HO

O C O
40

Code Name (Synonym) Chemical Name Chemical Structure Study Type MRID Maximum 

%AR (day)

Final %AR 

(study length)

Carbon dioxide Aerobic 

Soil 

Metabolism

46950111 19.2

(228 days)

19.2

(228 days)

46950112

46950113

15.0 ± 1.3

(360 days)

15.0 ± 1.3

(360 days)

46950114

46950115

4.2 ± 0.1

(372 days)

4.2 ± 0.1

(372 days)

Aerobic 

Aquatic 

Metabolism

46950116 3.0 (183 days) 3.0 (183 days)

46950117

46950118

0.59 ± 0.28

(98 days)

0.29 ± 0.03

(112 days)

Anaerobic 

Aquatic 

Metabolism

46950119

46950120

0.55 ± 0.33

(245 days)

0.25 ± 0.02

(350 days)

Non-

extractable 

Residues

Not identified Not identified Aerobic 

Soil 

Metabolism

46950109 38.0 ± 1.3

(293 days)

38.0 ± 1.3

(293 days)

46950110 48.9 ± 0.6

(293 days)

48.9 ± 0.6

(293 days)

46950111 22.9

(228 days)

22.9

(228 days)

46950112

46950113

14.4 ± 1.0

(360 days)

14.4 ± 1.0

(360 days)

46950114

46950115

18.4 ± 1.0

(360 days)

14.4 ± 1.0

(372 days)

Aerobic 

Aquatic 

Metabolism

46950116 13.9 

(183 days)

13.9 

(183 days)

46950117

46950118

8.87 ± 3.04

(112 days)

8.87 ± 3.04

(112 days)

Anaerobic 

Aquatic 

Metabolism

46950119

46950120

8.06 ± 1.24

(302 days)

7.11 ± 0.32

(350 days)

Unidentified

1

Unknowns

Not identified Not identified Aqueous 

Photolysis

42245128 20.0 (15 days) 6.5 (30 days)

46950104 29.02 ± 2.9 

(30 days)

29.02 ± 2.9

(30 days)

46950105 16.7 (15 days) 11.1 (15 days)
41

Code Name 

(Synonym) Chemical Name Chemical Structure Study Type MRID Maximum %AR (day)

Final %AR 

(study length)

Unidentified1

Unknowns

Aerobic 

Soil 

Metabolism

46950111 0.4

(228 days)

0.4

(228 days)

MINOR (<10%) TRANSFORMATION PRODUCTS

CGA-205374 

(CGA-176459)

CAS Name: 1-[2-Chloro-4-(4-

chlorophenoxy)phenyl]-2-(1H-1,2,4-triazol-1-yl)-

ethanone.

CAS Number: 136815-80-0

Aqueous 

Photolysis

42245128 1.5 (0 day) < LOQ 

(30 days)

46950104 1.11 ± 0.11

(14 days)

0.13 ± 0.1

(30 days)

46950105 NA NA

Aerobic 

Soil 

Metabolism

46950114

46950115

2.1 ± 0.4

(272 days)

1.4 ± 0.1

(293 days)

Anaerobic 

Aquatic 

Metabolism

46950119

46950120

0.77± 0.23

(245 day)

LOQ 

(350 days)

M2 Not identified Not identified Aerobic 

Soil 

Metabolism

46950109 1.5

(28 days)

1.4 ± 0.1

(293 days)

46950110 2.1 ± 1.81

(293 days)

2.1 ± 1.81

(293 days)

46950111 1.5

(228 days)

1.5

(228 days)

Anaerobic 

Aquatic 

Metabolism

46950119

46950120

5.79 ± 1.42

(245 days)

< LOQ 

(350 days)

M4 Not identified Not identified Aerobic 

Soil 

Metabolism

46950109 1.2

(190 days)

1.0 ± 0.4

(293 days)

NA = Not Analyzed

LOQ = Limit of Quantitation (1ppb)

1 Unidentified unknowns consist of M4, M5, M6, and several unidentified components ranging from 0.5% to 9.7% of the applied radioactivity at study 

termination.

O

N

N

N

O Cl

Cl
42

APPENDIX C. ECOSAR Results

Table C-1. Comparative Aquatic Toxicity of Difenoconazole and Major Degradation Products

Compound FW fish 

96-hr 

acute 

LC50

(mg/L)

FW fish 

chronic 

NOAEC

(mg/L)1

FW 

invertebrate 

48-hr acute 

EC50

(mg/L)

FW 

invertebrate 

chronic 

NOAEC

(mg/L)1

ME fish 

96-hr 

acute LC50

(mg/L)

ME fish 

chronic 

NOAEC

(mg/L)1

ME 

invertebrate 

96-hr acute 

LC50

(mg/L)

ME 

invertebrate 

chronic 

NOAEC

(mg/L)1

Nonvascular 

plant 96-hr 

EC50

(mg/L)

Difenoconazole 0.87

(0.81)

0.007

(0.0009)

0.95

(0.77)

0.030

(0.006) (0.82) (0.0009) (0.15) (<0.000115) 0.51(0.30)

2

1,2,4-triazole 722.0

(498.0) 2.2 3166.2(>98.0) 29.2 - - - - 35.7(14.0) 2

Triazole acetic 

acid

51322.1

(>101.0) 132.3 281000.0(>108.0) 2132.3 - - - - 1716.9

CGA-205375 2.79 0.022 2.6 0.179 8.363 0.099 0.870 0.252 1.33 1 ECOSAR estimated chronic value is defined as the geometric mean of the no observed effect concentration (NOEC) and the lowest observed 

effect concentration (LOEC).

2 Green algae

3 Endpoint exceeds predicted water solubility of compound.

BOLD values are ECOSAR (v1.00) toxicity estimates (lowest toxicity value if multiple ECOSAR classes are available, i.e., the most 

toxic).

Italic values are from submitted toxicity studies (most sensitive endpoint if multiple are available) 

FW = freshwater and ME = marine/estuarine
43

APPENDIX D. SIP v.1.0 Inputs and Outputs

Table D-1. Inputs

Parameter Value

Chemical name Difenoconazole

Solubility (in water at 25oC; mg/L) 15

Mammalian LD50 (mg/kg-bw) 1453

Mammalian test species laboratory rat

Body weight (g) of "other" mammalian species

Mammalian NOAEL (mg/kg-bw) 1.25

Mammalian test species laboratory rat

Body weight (g) of "other" mammalian species

Avian LD50 (mg/kg-bw) 2150

Avian test species Mallard duck

Body weight (g) of "other" avian species

Mineau scaling factor 1.15

Mallard NOAEC (mg/kg-diet) 110.8

Bobwhite quail NOAEC (mg/kg-diet) 21.9

NOAEC (mg/kg-diet) for other bird species 0

Body weight (g) of other avian species 0

NOAEC (mg/kg-diet) for 2nd other bird species 0

Body weight (g) of 2nd other avian species 0

Table D-2. Mammalian Results

Parameter Acute Chronic

Upper bound exposure (mg/kg-bw) 2.5800 2.5800

Adjusted toxicity value (mg/kg-bw) 1117.5903 0.9615

Ratio of exposure to toxicity 0.0023 2.6834

Conclusion*

Drinking water exposure 

alone is NOT a potential 

concern for mammals

Exposure through 

drinking water alone is 

a potential concern for 

mammals

Table D-3. Avian Results

Parameter Acute Chronic

Upper bound exposure (mg/kg-bw) 12.1500 12.1500

Adjusted toxicity value (mg/kg-bw) 1116.3346 2.3279

Ratio of exposure to acute toxicity 0.0109 5.2192

Conclusion*

Drinking water exposure 

alone is NOT a potential 

concern for birds

Exposure through 

drinking water alone is 

a potential concern for 

birds

*Conclusion is for drinking water exposure alone. This does not combine all routes of exposure. Therefore, when 

aggregated with other routes (i.e., diet, inhalation, dermal), pesticide exposure through drinking water may 

contribute to a total exposure that has potential for effects to non-target animals.
44

APPENDIX E. STIR v.1.0 Inputs and Outputs

 

Table E-1. Input

Application and Chemical Information

Enter Chemical Name Difenoconazole

Enter Chemical Use turf

Is the Application a Spray? (enter y or n) y

If Spray What Type (enter ground or air) ground

Enter Chemical Molecular Weight (g/mole) 406.27

Enter Chemical Vapor Pressure (mmHg) 2.50E-10

Enter Application Rate (lb ai/acre) 0.26

Toxicity Properties

Bird

Enter Lowest Bird Oral LD50 (mg/kg-bw) 2150

Enter Mineau Scaling Factor 1.15

Enter Tested Bird Weight (kg) 1.58

Mammal

Enter Lowest Rat Oral LD50 (mg/kg-bw) 1453

Enter Lowest Rat Inhalation LC50 (mg/L) >3.31

Duration of Rat Inhalation Study (hr) 4

Enter Rat Weight (kg) 0.35 1 MRID 42090008

 Table E-2. Output

Results Avian (0.020 kg )

Maximum Vapor Concentration in Air at Saturation (mg/m3) 5.47E-06

Maximum 1-hour Vapor Inhalation Dose (mg/kg) 6.87E-07

Adjusted Inhalation LD50 1.96E+01

Ratio of Vapor Dose to Adjusted Inhalation LD50 3.50E-08 Exposure not Likely Significant

Maximum Post-treatment Spray Inhalation Dose (mg/kg) 2.75E-02

Ratio of Droplet Inhalation Dose to Adjusted Inhalation LD50 1.40E-03 Exposure not Likely Significant

Results Mammalian (0.015 kg )

Maximum Vapor Concentration in Air at Saturation (mg/m3) 5.47E-06

Maximum 1-hour Vapor Inhalation Dose (mg/kg) 8.64E-07

Adjusted Inhalation LD50 1.96E+02

Ratio of Vapor Dose to Adjusted Inhalation LD50 4.40E-09 Exposure not Likely Significant

Maximum Post-treatment Spray Inhalation Dose (mg/kg) 3.45E-02

Ratio of Droplet Inhalation Dose to Adjusted Inhalation LD50 1.76E-04 Exposure not Likely Significant