UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION 

MEMORANDUM 

February 27, 2013 

SUBJECT: Propiconazole Human Health Risk Assessment for an Amended Section 3 

Registration on Cereal Grains. 

PC Code: 122101 

Decision No.: 460659 

Petition No.: 2F7975 

Risk Assessment e ate 

TXR No.: NA 

MRIDNo.: NA 

FROM: Thurston G. Morton, Chemist , ~ 

OP Barcode: 403631 

Registration No.: 100-617, I 00-1178, and 100-

1324 

Regulatory Action: Amended Section 3 

Re istration 

Case No.: 3125 

James S Miller, Environmental Scientist _,;r·· /1 

Abdallah Khasawinah, PhD., Toxicologis!/' ,// 

Risk Assessment Branch 4 · 

Health Effects Division (7509P) 

THROUGH: Elissa Reaves, Ph.D., Branch Chief ~~,-(...../ 7& .......... S

Risk 

usan 

Assessment 

V. Hummel

Branch 

, Branc

4, 

h Senior 

HED (7509P) 

Scientist -

~ 

A __ ,.,...,._ .V. ~ 

TO: Heather Garvie 

Fungicide Branch 

Registration Division (7505P) 

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

amended Section 3 use of propiconazole on cereal grains. The document has been revised to 

include an assessment of aggregate risk from residential exposures to propiconazole. 

Page 1 of64 
Page 2 of 64 

1.0 EXECUTIVE SUMMARY ................................................................................................ 5

2.0 HED RECOMMENDATIONS .......................................................................................... 9

2.1 Data Deficiencies/Conditions of Registration................................................................ 9

2.2 Tolerance Considerations ............................................................................................... 9

2.2.1 Enforcement Analytical Method ............................................................................. 9

2.2.2 International Harmonization ................................................................................... 9

2.2.3 Recommended Tolerances...................................................................................... 10

2.2.4 Revisions to Petitioned-For Tolerances ................................................................ 11

2.3 Label Recommendations ............................................................................................... 11

3.0 INGREDIENT PROFILE ................................................................................................ 12

3.1 Chemical Identity .......................................................................................................... 12

3.2 Physical/Chemical Characteristics ............................................................................... 12

3.3 Pesticide Use Pattern ..................................................................................................... 12

3.3.1 Registered Products ................................................................................................ 12

3.3.2 Proposed New Uses ................................................................................................. 12

3.4 Anticipated Exposure Pathways................................................................................... 13

3.5 Considerations of Environmental Justice ................................................................... 13

4.0 HAZARD CHARACTERIZATION/ASSESSMENT ................................................... 14

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

4.2 Absorption, Distribution, Metabolism and Excretion ................................................ 14

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

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

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

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

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

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

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

4.5.1 Dose-Response Assessment .................................................................................... 17

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

4.5.3 Classification of Carcinogenic Potential ............................................................... 18

4.5.4 Summary of Points of Departure Used in Risk Assessment ............................... 18

5.0 DIETARY AND DRINKING WATER EXPOSURE AND RISK ASSESSMENT .... 20

5.1 Metabolite/Degradate Residue Profile ......................................................................... 20

5.1.1 Summary of Plant and Livestock Metabolism Studies ........................................ 20
Page 3 of 64 

5.1.2 Comparison of Metabolic Pathways ...................................................................... 21

5.1.3 Environmental Fate and Transport ...................................................................... 21

5.1.4 Residues of Concern Summary and Rationale ..................................................... 22

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

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

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

5.3.1 Estimated Drinking Water Concentrations.......................................................... 27

5.4.1 Acute Dietary and Drinking Water Analysis ....................................................... 28

5.4.2 Chronic Dietary and Drinking Water Analysis ................................................... 29

6.0 RESIDENTIAL EXPOSURE AND RISK ASSESSMENT .......................................... 30

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

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

7.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT ............................................ 31

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

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

7.3 Intermediate-Term Aggregate Risk ............................................................................. 34

8.0 CUMULATIVE RISK ...................................................................................................... 35

9.0 OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION .............................. 36

9.1 Exposure Scenarios....................................................................................................... 36

9.2 Handler Exposure .......................................................................................................... 36

9.2.1 Handler Exposure Scenarios .................................................................................. 37

9.2.2 Handler Exposure Data .......................................................................................... 37

9.2.3 Handler Exposure Assumptions ............................................................................ 38

9.2.4 Handler Exposure and Risk Estimates ................................................................. 39

9.3 Post Application Exposure ............................................................................................ 40

9.3.1 Post Application Exposure Scenarios.................................................................... 42

9.3.2 Post Application Exposure Assumptions .............................................................. 42

9.3.3 Post-Application Exposure and Risk Estimates ................................................... 43

9.3.4 Restricted Entry Interval ....................................................................................... 44

10. REFERENCES .................................................................................................................. 44

A TOXICOLOGY DATA SUMMARY .............................................................................. 45

A.1 Guideline Data Requirements ................................................................................ 45

A.2 Toxicity Profiles .......................................................................................................... 46

A.3 Toxicological Endpoints ............................................................................................. 52
Page 4 of 64 

A.4 EXECUTIVE SUMMARIES .................................................................................... 57

Additional Developmental/Reproduction Toxicity Information from Literature Sources

 ................................................................................................................................................ 61

APPENDIX B. Chemical Names And Structures Of Metabolites ......................................... 63

APPENDIX C. Physical/Chemical Properties .......................................................................... 64

APPENDIX D. Studies Reviewed for Ethical Conduct .......................................................... 64
Page 5 of 64 

1.0 EXECUTIVE SUMMARY 

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

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

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

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

Under PP#2F7975, Syngenta is proposing increased tolerances along with an amended use for 

propiconazole on cereal grains. 

Use Profile 

Propiconazole 1-[[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2-yl]methyl]-1H-1,2,4-triazole) 

is a systemic triazole-type fungicide that provides broad spectrum disease control on a variety of 

food and non-food crops. Permanent tolerances are established (40 CFR §180.434) for the 

combined residues of propiconazole and its metabolites (determined as 2,4-dichlorobenzoic acid 

(2,4-DCBA)) in/on a variety of agricultural commodities at levels ranging from 0.05 ppm in/on 

meat and meat byproducts to 40 ppm in/on grass straw. Non-food uses include use on 

commercial, public and residential ornamentals, landscapes and turf. The mode of antifungal 

action of propiconazole is attributed to the inhibition of CYP51 (lanosterol-14-a-demethylase). 

Inhibition of normal sterol production disrupts cell wall formation and slows or stops the growth 

of the fungus. Agricultural applications of propiconazole are made using ground or aerial 

equipment. Propiconaizole is applied to non-food areas by both occupational and residential 

handlers. Occupational application methods for non-food uses include, seed piece dip, tree 

injection, and handheld equipment (i.e., low-pressure handwand, handgun sprayer, backpack 

sprayer). Residential applications are made with handheld equipment. 

Proposed New Uses

Syngenta has submitted an application for the registration of products containing propiconazole 

for an amended use on cereal grains. The products are manufactured by Syngenta Crop 

Protection, Inc. under the trade name Tilt® Fungicide (EPA Reg. No. 100-617), Quilt® Fungicide 

(EPA Reg. No. 100-1178) and Quilt Xcel® Fungicide (EPA Reg. No. 100-1324). Syngenta is 

amending the use by lowering the pre-harvest interval (PHI) to 7 days for forage and hay of 

cereal grains. The amended use is not proposed for residential use and residential exposures are 

not expected based on the proposed uses. 

The toxicology database for propiconazole is adequate for evaluating and characterizing toxicity 

and selecting endpoints for purposes of this risk assessment. The primary target organ for 

propiconazole toxicity in animals is the liver. Liver effects observed in subchronic and chronic 

oral studies in rats and mice include lesions, hypertrophy and necrosis. In a rat developmental 

study, fetal effects were observed at doses lower than doses at which maternal effects were seen 

demonstrating quantitative evidence of increased susceptibility of fetuses to in utero exposure to 

propiconazole. While in rabbits, developmental toxicity occurred at higher doses than 

maternally toxic doses. In the two generation reproduction study in rats, offspring toxicity 

occurred at a higher dose than the parental toxic dose suggesting lower susceptibility of the 
Page 6 of 64 

offspring to the toxic doses of propiconazole. Propiconazole does not appear to be neurotoxic 

based on an acute neurotoxicity study. The concern for susceptibility is low since clear NOAELs 

were established in the rat and rabbit developmental studies and the points of departure selected 

for the risk assessment scenarios are protective of the susceptibility observed in the rat 

developmental study. Therefore, the FQPA safety factor was reduced to 1X. 

Propiconazole is classified as a Group C possible human carcinogen with risk quantitated using a 

reference dose (RfD) approach. Propiconazole showed no significant toxicity in a battery of 

acute toxicity tests (Toxicity Category III or IV in all tests). It is not a skin irritant but is a 

dermal sensitizer. 

Dose Response Assessment 

Toxicological endpoints were selected for dietary/drinking water, occupational and residential 

exposure scenarios. Acute and chronic points of departure (PODs) were selected for assessment 

of food and drinking water exposures. An acute POD for the general population was selected 

from an acute neurotoxicity study in rats. An acute POD for females 13-49 was selected from a 

developmental toxicity study in rats. A chronic/cancer POD for the general population was 

selected from a carcinogenicity study in mice. Short and intermediate-term occupational 

exposures via the dermal and inhalation routes may occur based on the use pattern and label 

directions. Toxicological endpoints for short-term inhalation, dermal, and incidental oral 

exposures were selected from the acute neurotoxicity study in rats. Toxicological endpoints for 

intermediate-term inhalation, dermal, and incidental oral exposures were selected from a 

carcinogenicity study in mice. Since an oral study was selected for dermal exposure, a 40% 

dermal absorption factor from a dermal absorption study in rats is used for route to route 

extrapolation. An uncertainty factor of 100X was applied to endpoints selected for all exposure 

routes (10X for interspecies extrapolation, 10X for intraspecies variation). 

Exposure/Risk Assessment and Risk Characterization 

Risk assessments were conducted for dietary (food and water), and occupational exposure 

pathways based on registered uses and request for the new use of propiconazole. Worker 

exposures were assessed for handler and post-application activities. There are no new requested 

residential uses expected with this registration, therefore residential risk was not assessed for the 

proposed new use. Conservative acute and refined chronic dietary and drinking water risk 

assessments for propiconazole conclude that dietary and drinking water exposure estimates are 

below HED’s level of concern for the general population and all population subgroups. At the 

95th percentile, the exposure to the general U.S. population is 26 % of the aPAD; the highest 

exposed subgroup (Children 1-2 yrs old) is 85% of the aPAD. The exposure to the general U.S. 

population is 7 % of the cPAD, and the most highly exposed subgroup (Children 1-2 yrs old) is 

24 % of the cPAD. Additionally, the requested use of propiconazole did not result in an increase 

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

exposure analyses for the triazole metabolites did not need to be updated (T. Morton, D403618, 

8/1/12). Aggregate risks from propiconazole are not of concern. Occupational exposure and risk 

estimates indicate that worker and residential handler and post-application exposures are not of 

concern at the maximum allowable application rates for the proposed new uses provided that 
Page 7 of 64 

handlers wear chemical resistant gloves as required on the label. The only residential use 

scenario that will result in potential intermediate term exposure to propiconazole is post 

application exposure to children from wood treatment (antimicrobial use). Table 15 shows the 

aggregate risk for intermediate term exposure to Children 1-2 years old. The aggregate MOE is 

120, which is greater than the target MOE of 100. Therefore, this scenario is not of concern. 

Aggregate Assessment of Free Triazole & its Conjugates 

The addition of the new amended use does not increase the aggregate exposure to free triazoles 

and its conjugates. Therefore, the previous aggregate human health risk assessment was not 

updated for free triazoles and its conjugates and the aggregate estimates remain below HED’s 

level of concern (T. Morton, D403619, 8/1/12). 

Use of Human Studies 

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These studies, listed in Appendix 2.0, 

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

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

appropriate review. 

Environmental Justice 

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

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf). 

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

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

risks to population subgroups from pesticide exposures that are based on patterns of that 

subgroup’s food and water consumption, and activities in and around the home that involve 

pesticide use in a residential setting. Whenever appropriate, non-dietary exposures based on 

home use of pesticide products and associated risks for adult applicators and for toddlers, youths, 

and adults entering or playing on treated areas post-application are evaluated. Further 

considerations are currently in development, as OPP has committed resources and expertise to 

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

farm workers as well as lifestyle and traditional dietary patterns among specific subgroups. 
Page 8 of 64 

Tolerance Recommendation 

Pending submission of a revised Section F (see requirements under Proposed Tolerances), there 

are no residue chemistry issues that would preclude granting an amended Section 3 registration 

for the requested amended use of propiconazole on cereal grains, or establishment of the 

following tolerances for residues of propiconazole. 

Barley, hay ................................................................................................. 30 ppm 

Barley, straw .............................................................................................. 20 ppm 

Barley, grain .............................................................................................. 3.0 ppm 

Rye, forage ................................................................................................ 9.0 ppm 

Oat, forage................................................................................................. 4.0 ppm 

Oat, hay ...................................................................................................... 15 ppm 

Oat, grain................................................................................................... 3.0 ppm 

Wheat, forage ............................................................................................. 15 ppm 

Wheat, hay ................................................................................................. 30 ppm 

Wheat, straw .............................................................................................. 20 ppm 

Barley, bran ............................................................................................... 6.0 ppm 

Rye, straw .................................................................................................. 10 ppm 

Grain, aspirated fractions ......................................................................... 110 ppm 

As previously noted, permanent tolerances are currently established for the combined residues of 

propiconazole and its 2,4-DCBA containing metabolites at levels ranging from 0.1-40 ppm in/on 

plant commodities [40 CFR §180.434(a)]. HED has determined that the current tolerance 

expression should be amended to include only propiconazole per se because 1) there are a 

number of pesticides that have 2,4-DCBA as common metabolite, and an enforcement agency 

may not be able to determine if residues are due to misuse of propiconazole or the proper use of 

other pesticides containing 2,4-DCBA; 2) propiconazole per se can be detected by FDA 

multiresidue methods; and 3) inclusion of only parent allows harmonization with the residue 

definition for the Codex MRLs. 

However, the tolerance expression will not be changed to parent only at this time. The tolerance 

expression does need to be changed to reflect current HED guidance. In 2009 HED issued 

guidance on tolerance expressions (S. Knizner, 2009). We now conclude the tolerance 

expression should be as follows: Tolerances are established for residues of propiconazole, 

including its metabolites and degradates, in or on the commodities in the table below. 

Compliance with the tolerance levels specified below is to be determined by measuring only 

those propiconazole residues convertible to 2,4-dichlorobenzoic acid (2,4-DCBA), expressed as 

the stoichiometric equivalent of propiconazole, in or on the commodity in the table below. 

The Codex Alimentarius Commission has established several maximum residue limits (MRLs) 

for propiconazole in/on various raw agricultural commodities. In addition, both Canada and 

Mexico have established MRLs for propiconazole in/on various commodities. The Codex and 

Mexican MRLs are expressed in terms of propiconazole per se. The Canadian MRLs are 

expressed in terms of combined residues of propiconazole and its metabolites containing the 2,4-

DCBA moiety. Codex has MRLs for straw and fodder of barley, rye, and wheat along with 

MRL for barley grain. The U.S. cannot harmonize at this level due to the use pattern registered 

in the U.S along with the CODEX tolerance expression. Canada has MRLs for barley, grain and 

oats, grain. The U.S. cannot harmonize at this level due to the use pattern registered in the U.S 

but will be harmonized on the tolerance expression for Canada only. 
Page 9 of 64 

2.0 HED RECOMMENDATIONS 

2.1 Data Deficiencies/Conditions of Registration 

HED can recommend for registration and permanent tolerances for the proposed amended uses 

of propiconazole. Deficiencies are stated below. The specific tolerance recommendations are 

discussed in Section 2.2, and label modifications are discussed in Section 2.3. 

Note to PM: 

Immunotoxicity study remains outstanding. 

Revised Section F required. 

2.2 Tolerance Considerations

 2.2.1 Enforcement Analytical Method 

An adequate method, HPLC/UV Method AG-671A, is available for tolerance enforcement. This 

method has undergone a successful tolerance method validation by the Analytical Chemistry 

Branch of BEAD. The method was forwarded to FDA for inclusion in PAM Volume II. This 

method has an LOQ of 0.02 ppm. The method includes optional detection via HPLC/MS, giving 

a means of residue confirmation. 

 2.2.2 International Harmonization 

The Codex Alimentarius Commission has established several maximum residue limits 

(MRLs) for propiconazole in/on various raw agricultural commodities. In addition, both Canada 

and Mexico have established MRLs for propiconazole in/on various commodities. The Codex 

and Mexican MRLs are expressed in terms of propiconazole per se. The Canadian MRLs are 

expressed in terms of combined residues of propiconazole and its metabolites containing the 2,4-

DCBA moiety. Codex has MRLs for straw and fodder of barley, rye, and wheat along with an 

MRL for barley grain. The U.S. cannot harmonize at this level due to the use pattern registered 

in the U.S along with the CODEX MRL expression. Canada has MRLs for barley, grain and 

oats, grain. The U.S. cannot harmonize at this level due to the use pattern registered in the U.S 

but will be harmonized on the tolerance expression for Canada only. 
Page 10 of 64 

 2.2.3 Recommended Tolerances 

Pending submission of revised Section F, there are no residue chemistry issues that would 

preclude granting registration for the requested amended use of propiconazole. Available data 

support the following tolerances under 40 CFR 180.434 for residues of propiconazole in/on the 

following raw agricultural commodities: 

 Barley, hay ................................................................................................. 30 ppm 

Barley, straw .............................................................................................. 20 ppm 

Barley, grain .............................................................................................. 3.0 ppm 

Rye, forage ................................................................................................ 9.0 ppm 

Oat, forage................................................................................................. 4.0 ppm 

Oat, hay ...................................................................................................... 15 ppm 

Oat, grain................................................................................................... 3.0 ppm 

Wheat, forage ............................................................................................. 15 ppm 

Wheat, hay ................................................................................................. 30 ppm 

Wheat, straw .............................................................................................. 20 ppm 

Barley, bran ............................................................................................... 6.0 ppm 

Rye, straw .................................................................................................. 10 ppm 

Grain, aspirated fractions ......................................................................... 110 ppm 

As previously noted, permanent tolerances are currently established for the combined residues of 

propiconazole and its 2,4-DCBA containing metabolites at levels ranging from 0.1-40 ppm in/on 

plant commodities [40 CFR §180.434(a)]. HED has determined that the current tolerance 

expression should be amended to include only propiconazole per se because 1) there are a 

number of pesticides that have 2,4-DCBA as common metabolite, and an enforcement agency 

may not be able to determine if residues are due to misuse of propiconazole or the proper use of 

other pesticides containing 2,4-DCBA; 2) propiconazole per se can be detected by FDA 

multiresidue methods; and 3) inclusion of only parent allows harmonization with the residue 

definition for the Codex MRLs. 

However, the tolerance expression will not be changed to parent only at this time. The tolerance 

expression does need to be changed to reflect current HED guidance. In 2009 HED issued 

guidance on tolerance expressions (S. Knizner, 2009). We now conclude the tolerance 

expression should be as follows: Tolerances are established for residues of propiconazole, 

including its metabolites and degradates, in or on the commodities in the table below. 

Compliance with the tolerance levels specified below is to be determined by measuring only 

those propiconazole residues convertible to 2,4-dichlorobenzoic acid (2,4-DCBA), expressed as 

the stoichiometric equivalent of propiconazole, in or on the commodity in the table below. 

Adequate crop field trial data reflecting the proposed use patterns were submitted for purposes of 

establishing tolerances on the requested amended use. The Organization for Economic 

Cooperation and Development tolerance calculation procedures were utilized in determining the 

appropriate tolerance level for the requested amended use. Changes in recommended tolerance 

are based on the use of these calculation procedures and are shown in Table 1, along with 

rounding to the appropriate significant figures. 

The proposed and recommended tolerances for propiconazole as a result of the subject action are 

presented in Table 1. 
Page 11 of 64 

Table 1. Tolerance Summary for Propiconazole. 

Commodity Proposed Tolerance

(ppm) 

Recommended Tolerance 

(ppm) Comments 

40 CFR §180.434(a)(1) 

Barley, hay 30 30 

Barley, straw 20 20 

Barley, grain 3 3.0 

Barley, bran none 6.0 The current tolerance for 

barley, bran is 0.6 ppm. 

Rye, forage 9 9.0 

Rye, straw 9 10 

Oat, forage 4 4.0 

Oat, hay 15 15 

Oat, grain 3 3.0 

Wheat, forage 15 15 

Wheat, hay 30 30 

Wheat, straw 20 20 

Grain, aspirated fractions 108 110 

*Changes are due to rounding of significant figures, not proposing a tolerance for a processed commodity, and 

correcting commodity vocabulary. 

 2.2.4 Revisions to Petitioned-For Tolerances 

Revised Section F, proposing the following tolerances 

Barley, grain .............................................................................................. 3.0 ppm 

Rye, forage ................................................................................................ 9.0 ppm 

Oat, forage................................................................................................. 4.0 ppm 

Oat, hay ...................................................................................................... 15 ppm 

Oat, grain................................................................................................... 3.0 ppm 

Barley, bran ............................................................................................... 6.0 ppm 

Rye, straw .................................................................................................. 10 ppm 

Grain, aspirated fractions ......................................................................... 110 ppm 

The existing tolerance for Rye, straw must remain at 10 ppm. The existing 

tolerance for Barley, bran of 0.6 ppm needs to be increased to 6.0 ppm. 

2.3 Label Recommendations 

No Label Recommendations are required.
Page 12 of 64 

3.0 INGREDIENT PROFILE 

3.1 Chemical Identity 

Structure and nomenclature are reported in Table 2. 

Table 2. Nomenclature of Propiconazole

Compound 

Common name Propiconazole 

Company experimental names CGA-64250 

IUPAC name 1-[2-(2,4_dichlorophenyl)-4-propyl-1,3-dioxolan-2-ylmethyl]-1H-1,2,4_triazole 

CAS name 1-[[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2-yl]methyl]-1H-1,2,4-triazole 

CAS # 60207-90-1 

End-use products/EP 3.6 lb/gal EC (EPA Reg. Nos. 100-617 

3.2 Physical/Chemical Characteristics 

The physicochemical properties of propiconazole are reported in Appendix C. 

3.3 Pesticide Use Pattern

 3.3.1 Registered Products 

There are 155 active propiconazole registrations, 139 Section 3s, 8 Section 18s, and 8 SLNs 

(24(c)s). 

 3.3.2 Proposed New Uses 

Propiconazole is proposed for an amended use on cereal grains (Table 3). 

N

N N

O

O

Cl

Cl
Page 13 of 64 

1. 45 day for animal feed only. 

2. 7 day PHI for forage and hay only. 

3.4 Anticipated Exposure Pathways 

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

proposed amended use of propiconazole on cereal grains. For domestic uses, humans may be 

exposed to propiconazole in food and drinking water, since propiconazole may be applied 

directly to growing crops and application may result in propiconazole reaching surface and 

ground water sources of drinking water. There are also residential uses of propiconazole, so 

there is exposure in residential or non-occupational settings. In an occupational setting, 

applicators may be exposed while handling the pesticide prior to application, as well as during 

application. There is a potential for post-application exposure for workers re-entering treated 

fields. 

Risk assessments have been previously prepared for the existing uses of propiconazole. This risk 

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

uses of propiconazole, but also considers the existing uses as well, particularly for the dietary 

exposure assessment. 

3.5 Considerations of Environmental Justice

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

human health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations,” 

http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. 

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

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

risks to population subgroups from pesticide exposures that are based on patterns of that 

Table 3. Label Directions for Proposed Uses of Propiconazole 

Product 

EPA 

Reg. 

No. 

Use Site Target Application 

Methods 

Maximum 

Application 

Rate 

(lb ai/A) 

PHI 

(day) 

REI 

(hr) 

Use Directions/ 

Limitations 

Tilt®

Fungicide 

EC 

(100-

617) 

Cereal 

Grains: 

Wheat; 

Barley; 

Oats; Rye; 

Triticale 

Broadcast 

Foliar 

Aerial 

Chemigation 

Groundboom 

0.056 - 0.113 

(2 app. /season) 14 

7

(Forage 

and 

Hay)2 

12 

hr 

A minimum 

retreatment 

interval (RTI) of 

14 days is 

proposed. 

Quilt Xcel®

Fungicide 

EC 

(100-

1324) 

0.056-0.112 

(2 app. /season) 

A minimum 

retreatment 

interval (RTI) of 

14 days is 

proposed. 

Contains 

azoxystrobin 

also. 

Quilt®

Fungicide 

EC 

(100-

1178) 

0.056 - 0.114 

(2 app. /season) 
Page 14 of 64 

subgroup’s food and water consumption, and activities in and around the home that involve 

pesticide use in a residential setting. Extensive data on food consumption patterns are compiled 

by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used 

in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed 

and categorized by subgroups based on age, season of the year, ethnic group, and region of the 

country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups 

and exposure assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, nondietary exposures based on home use of pesticide products and associated risks 

for adult applicators and for toddlers, youths, and adults entering or playing on treated areas 

post-application are evaluated. Further considerations are currently in development as OPP has 

committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary 

patterns among specific subgroups. 

4.0 HAZARD CHARACTERIZATION/ASSESSMENT 

4.1 Toxicology Studies Available for Analysis

The toxicology database for propiconazole is adequate for evaluating and characterizing 

propiconazole toxicity and selecting endpoints for purposes of this risk assessment. An 

immunotoxicity is study required as part of new 40 CFR Part 158 data requirements for 

registration of a pesticide. A waiver request for a 28-day immunotoxicity study in rodents was 

submitted but denied by the Agency. 

The following data are available: 

Acute- Oral rat, dermal rat, inhalation rat, eye irritation rabbit, dermal irritation rabbit, and skin 

sensitization guinea pig. 

Subchronic- Oral 90-day rat, oral 90-day mouse (3), and oral 90-day dog; 

Chronic- Oral rat, mouse and dog; 

Reproductive/developmental- Oral developmental rabbit and rat, 2-generation reproductive rat 

Other- Oral rat and mouse cancer studies, 21-day dermal rabbit toxicity and dermal penetration 

study, acute neurotoxicity, metabolism, mutagenicity screens and mechanistic studies (3). 

4.2 Absorption, Distribution, Metabolism and Excretion

The rat metabolism study labeled with 14C at the triazole-[3,5] position indicated that parent 

compound was extensively metabolized. An intravenous (IV) study labeled with (U-14C)-Phenyl 

found several metabolites, including CGA 118245 (61.8% in males, 2.4% in females), CGA 

217495 (8.9% in males, 58.3% in females), CGA 91304 (2.3% in males only), and CGA 118244 

(3.6% in females only). No parent material was detected in the feces in the iv group. The 

metabolites seen in the iv study were detected to varying degrees in the urine and the feces of the 

orally dosed groups. Radiolabeled materials CGA 91305, CGA 118245 and CGA 177291 were 

reported ranging from 0.5% - 10.9% of the fecal radioactivity in males and females or in one sex 

alone. Most of the fecal radioactivity was not characterized. Metabolites CGA 217495 and 

CGA 177291 are not found in plant or livestock metabolism (see Appendix for structures). In 

two other (U-14C)-phenyl and 14C-triazole ring labeled propiconazole studies, the percentages of 
Page 15 of 64 

fecal metabolites extracted and distributed at various pH’s were not substantially different 

between the triazole and phenyl labeled samples, which suggest that the bridge between the 

phenyl ring and the triazole ring remained intact. The proposed metabolic pathway appears to 

involve the cleavage of the dioxolane ring through the oxidation of the propyl side chain, with 

subsequent dechlorination and conjugation. In a (U-14C)-phenyl labeled propiconazole 

metabolism study in mice, it was concluded that the major metabolic pathway in mice proceeds 

via elimination of the dioxolane ring leading to ketone formation (CGA 91304) and reduction to 

yield the corresponding alcohol (CGA 91305). Both CGA 91304 and CGA 91305 are found in 

plants and livestock. 

 

4.3 Toxicological Effects

The primary target organ for propiconazole toxicity in animals is the liver. Increased 

liver weights were seen in mice after subchronic or chronic oral exposures to propiconazole. 

Liver lesions such as vacuolation of hepatocytes, ballooned liver cells, foci of enlarged 

hepatocytes, hypertrophy and necrosis are characteristic of propiconazole toxicity in rats and 

mice. Decreased body weight gain was also seen in subchronic, chronic, developmental and 

reproductive studies in animal studies. Dogs appeared to be more sensitive to the localized 

toxicity of propiconazole as manifested by stomach irritations at 6 mg/kg/day and above. 

In rabbits, developmental toxicity occurred at a higher dose than the maternally toxic dose, while 

in rats, developmental toxicity occurred at lower doses than maternal toxic doses. Increased 

incidences of rudimentary ribs occurred in rat and rabbit fetuses. Increased cleft palate 

malformations were noted in two studies in rats. In one published study in rats, developmental 

effects (malformations of the lung and kidneys, incomplete ossification of the skull, caudal 

vertebrae and digits, extra rib (14th rib) and missing sternbrae were reported at doses that were 

not maternally toxic. In the two generation reproduction study in rats, offspring toxicity 

occurred at a higher dose than the parental toxic dose suggesting lower susceptibility of the 

offspring to the toxic doses of propiconazole. 

The acute neurotoxicity study resulted in decreased motor activity at 300 mg/kg. The current 

acute dietary assessment is based on an endpoint more sensitive than the neurotoxicity in the 

acute neurotoxicity study. Based on a weight of evidence evaluation by the HASPOC, the SCN 

was waived. 

Propiconazole was negative for mutagenicity in the in vitro BALB/3T3 cell transformation 

assay, bacterial reverse mutation assay, Chinese hamster bone marrow chromosomal aberration 

assay, unscheduled DNA synthesis studies in human fibroblasts and primary rat hepatocytes, 

mitotic gene conversion assay and the dominant lethal assay in mice. It caused proliferative 

changes in the rat liver with or without pretreatment with an initiator, like phenobarbital, a 

known liver tumor promoter. Liver enzyme induction studies with propiconazole in mice 

demonstrated that propiconazole is a strong phenobarbital type inducer of xenobiotic 

metabolizing enzymes. Hepatocellular proliferation studies in mice suggest that propiconazole 

induces cell proliferation followed by treatment-related hypertrophy in a manner similar to the 

known hypertrophic agent phenobarbital. 
Page 16 of 64 

Propiconazole has low to moderate toxicity in experimental animals by the oral (Category III), 

dermal (Category III) and inhalation routes (Category IV), is moderately irritating to the eyes 

(Category III), minimally irritating to the skin (Category IV) and is a dermal sensitizer. 

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

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

For propiconazole there are acceptable developmental toxicity studies in the rat and rabbit and an 

acceptable multi- generation reproduction study in the rat. An acceptable acute neurotoxicity 

study in the rat is also available in the database which results in effects at higher doses. Based on 

a weight of the evidence (WOE) the SCN was recently waived by the HASPOC (TXR 0056387). 

Although quantitative susceptibility was observed in the rat developmental study, a clear 

NOAEL is established for the developmental effects. Furthermore, the acute dietary for females 

13-49 years old is based on the developmental NOAEL from the study with quantitative 

susceptibility. Therefore, the risk assessment is protective of this susceptibility and there are no 

remaining uncertainties for the young. Together, the available data support the reduction of the 

FQPA factor to 1X. 

 4.4.1 Completeness of the Toxicology Database

The toxicological database for propiconazole is adequate for the purpose of this risk assessment. 

Based on a WOE approach considering all the available propiconazole hazard and exposure 

information, the HASPOC concluded that a 28-day day inhalation study and a subchronic 

neurotoxicity study are not required at this time (8/1/12, TXR #: 0056387). A previous risk 

assessment document (HED memoranda B. Daiss, 04/27/11, DP389194) contains detailed and 

up-to-date discussions of the toxicology and hazard evaluation of propiconazole. Please refer to 

these documents for further extensive details. Also, please refer to Appendix 2 of this current 

risk assessment document for the toxicity profile tables. 

 4.4.2 Evidence of Neurotoxicity 

In an acute oral neurotoxicity study, single oral administration at the high dose of 300 mg/kg 

propiconazole produced severe clinical signs of toxicity in rats within 5- 6 hours (e.g., decreased 

activity, cold, pale, piloerection, subdued, tip toe gate, staining around the nose). Limited signs 

(piloerection, diarrhea, tip toe gait) were seen in the 100 mg/kg dosed animals. No treatment 

related clinical signs were observed at the low dose (30 mg/kg). Functional observational battery 

(FOB) and motor activity tests showed reduced activity in males and females at the high dose. 

Based on weight of evidence the subchronic neurotoxicity is waived (HASPOC, TXR 0056387). 

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

The toxicology database for propiconazole is adequate for FQPA assessment. Although 

quantitative susceptibility was observed in the rat developmental study, a clear NOAEL is 

established for the developmental effects. Furthermore, the acute dietary for females 13-49 years 
Page 17 of 64 

old is based on the developmental NOAEL from the study with quantitative susceptibility. 

Therefore, the risk assessment is protective of this susceptibility and there are no remaining 

uncertainties for the young. 

There are no residual uncertainties with regard to pre- and/or postnatal toxicity. The dietary food 

exposure assessment uses conservative assumptions which result in protective estimates of 

dietary exposure. The dietary drinking water assessment uses values generated by model and 

associated modeling parameters which are designed to provide protective, high-end estimates of 

water concentrations. 

4.4.4 Residual Uncertainty in the Exposure Database 

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

conservative and will not underestimate dietary and/or non-dietary residential exposure to 

propiconazole. 

4.5 Toxicity Endpoint and Point of Departure 

4.5.1 Dose-Response Assessment 

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

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

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

An acute POD of 30 mg/kg for the general population was selected from an acute neurotoxicity 

study based on clinical signs of toxicity (piloerection, diarrhea, tip toe gait) at 100 mg/kg. An 

acute POD of 30 mg/kg (NOAEL) was selected for females age 13-49 years from a 

developmental study in rats based on increased incidence of rudimentary ribs, un-ossified 

sternebrae, as well as increased incidence of shortened and absent renal papillae and increased 

cleft palate at 90 mg/kg/day. The developmental effects of concern are presumed to occur after a 

single exposure and are relevant only to females aged 13-49 years old since they occur in utero. 

An uncertainty factor (UF) of 100x (10X to account for intraspecies extrapolation and 10X for 

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

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

(aPAD) is equivalent to the aRfD. 

A chronic POD of 10.0 mg/kg/day (NOAEL) was selected for the general population from a twoyear oncogenicity study in mice based on non-neoplastic liver effects (increased liver weight in 

males and increase in liver lesions: masses/raised areas/ swellings/nodular areas mainly at 50 

mg/kg/day. An uncertainty factor (UF) of 100x (10X to account for intraspecies extrapolation 

and 10X for intraspecies variation) was applied to the dose to obtain a chronic reference dose 

(cRfD/cPAD) of 0.1 mg/kg/day. 

Incidental oral short term exposure was assessed using a POD (NOAEL) of 30 mg/kg/day from 

an acute neurotoxicity study based on clinical signs of toxicity (piloerection, diarrhea, tip toe 

gait) at 100 mg/kg. An MOE of 100 is applied to account for the intra- and inter-species 
Page 18 of 64 

variation. Incidental oral intermediate term exposure was assessed using a POD (NOAEL) of 10 

mg/kg/day from an oncogenicity study in mice based on based on non-neoplastic liver effects 

(increased liver weight in males and increase in liver lesions: masses/raised areas/ 

swellings/nodular areas mainly at 50 mg/kg/day. An MOE of 100 is applied to account for the 

intra- and inter-species variation. 

A short-term dermal POD of 30 mg/kg/day was selected from the acute neurotoxicity study 

described above. An intermediate-term dermal POD of 10 mg/kg/day was selected from the 24 

month oncogenicity mouse study described above. An MOE of 100 is required for the short- and 

intermediate-term scenarios for dermal exposure. This includes 10X for interspecies 

extrapolation and 10X for intraspecies variation. 

A short-term inhalation POD of 30 mg/kg/day was selected from the acute neurotoxicity study 

described above. An intermediate-term inhalation POD of 10 mg/kg/day was selected from the 

24 month oncogenicity mouse study described above. An MOE of 100 is required for the shortand intermediate-term scenarios for inhalation exposure. This includes 10X for interspecies 

extrapolation and 10X for intraspecies variation. 

 4.5.2 Recommendations for Combining Exposure Routes 

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

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

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

via dermal and incidental oral routes of exposure. For the general population, including infants 

and children, the short term oral exposure can be aggregated with the short-term dermal and 

inhalation due to a common toxicological endpoint (clinical signs in the ACN study). A 

common toxicological endpoint was identified from the cancer mouse study for intermediateand long-term oral, dermal (oral equivalent) and inhalation (oral equivalent) routes. Therefore, 

these routes can be aggregated for these scenarios for the appropriate population. 

4.5.3 Classification of Carcinogenic Potential 

Propiconazole was carcinogenic to CD-1 male mice. Propiconazole was not carcinogenic to rats 

or to female mice. The HED Carcinogenicity Peer Review Committee (CPRC) classified 

propiconazole as Group C - possible human carcinogen and recommended that for the purpose of 

risk characterization the reference Dose (RfD) approach be used for quantification of human risk 

(HED Doc. No. 009771, April 15, 1992 meeting). 

 

 4.5.4 Summary of Points of Departure Used in Risk Assessment

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

Tables 4 and 5. 
Page 19 of 64 

Table 4. Summary of Toxicological Doses and Endpoints for Propiconazole for Use in Dietary Human Health Risk 

Assessments 

Exposure/Scenario Point of 

Departure 

Uncertainty/FQP

A Safety Factors 

RfD, PAD, LOC 

for Risk 

Assessment 

Study and Toxicological Effects 

Acute Dietary 

(General 

Population) 

NOAEL = 

30 

mg/kg/day 

UFA= 10X 

UFH=10X 

FQPA SF= 1X 

Acute RfD = 0.3 

mg/kg/day 

aPAD = 0.3 

mg/kg/day 

Acute neurotoxicity study Rat MRID 46604601 

LOAEL = 100 mg/kg/day based on clinical signs 

of toxicity (piloerection in one male, diarrhea in 

one female, tip toe gait in 3 females).

Acute Dietary 

(Females 13-49 

years) 

NOAEL = 

30 

mg/kg/day 

UFA= 10X. 

UFH=10X 

FQPA SF= 1X 

Acute RfD = 0.3 

mg/kg/day 

aPAD = 0.3 

mg/kg/day 

Developmental Study - Rat MRID 40425001 

LOAEL = 90 mg/kg/day based on increased 

incidence of rudimentary ribs, un-ossified 

sternebrae, as well as increased incidence of 

shortened and absent renal papillae and increased 

cleft palate.

Chronic Dietary 

(Adult Males and 

Females 50+ yrs) 

NOAEL = 

10 

mg/kg/day 

UFA= 10X 

UFH=10X 

FQPA SF= 1X 

Chronic RfD = 

0.1 

mg/kg/day 

cPAD = 

0.1mg/kg/day 

24-month oncogenicity study on CD-1 mice. 

MRID 00129918 

LOAEL = 50 mg/kg/day based on non-neoplastic 

liver effects (increased liver weight in males and 

increase in liver lesions: masses/raised areas/ 

swellings/nodular areas mainly). 

Cancer (all routes) Classification: Group C, possible human carcinogen, RfD approach for risk characterization 

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

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

LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = 

potential variation in sensitivity among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a NOAEL. UFS = 

use of a short-term study for long-term risk assessment. UFDB = to account for the absence of key date (i.e., lack of a critical study). FQPA SF = 

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

of concern. N/A = not applicable 

Table 5. Summary of Toxicological Doses and Endpoints for Propiconazole for Use in Residential and Occupational 

Human Health Risk Assessments 

Exposure/ 

Scenario 

Point of 

Departure 

Uncertainty 

Factors 

Level of Concern 

for Risk 

Assessment 

Study and Toxicological Effects 

Incidental Oral 

short-term 

NOAEL= 30 

mg/kg/day 

UFA= 10X 

UFH=10X 

Residential LOC 

for MOE = 100 

Occupational LOC 

for MOE = 100 

Acute Neurotoxicity Study-Rats MRID 46604601 

LOAEL = 100 mg/kg/day based on clinical signs 

of toxicity (piloerection in one male, diarrhea in 

one female, tip toe gait in 3 females). 

Incidental Oral 

Intermediate-term 

NOAEL= 10 

mg/kg/day 

UFA= 10X 

UFH=10X 

Residential LOC 

for MOE = 100 

Occupational LOC 

for MOE = 100 

24 Month Oncogenicity Study - Mice MRID 

00129918 

LOAEL = 50 mg/kg/day based on non-neoplastic 

liver effects (increased liver weight in males and 

increase in liver lesions: masses/raised areas/ 

swellings/nodular areas mainly). 

Dermal Short Term 

(1-30 days) 

DAF = 40% 

NOAEL= 30 

mg/kg/day 

UFA= 10X 

UFH=10X 

Residential LOC 

for MOE = 100 

Occupational LOC 

for MOE = 100 

Acute Neurotoxicity Study-Rats MRID 

46604601 

LOAEL = 100 mg/kg/day based on clinical signs 

of toxicity (piloerection in one male, diarrhea in 

one female, tip toe gait in 3 females). 
Page 20 of 64 

Table 5. Summary of Toxicological Doses and Endpoints for Propiconazole for Use in Residential and Occupational 

Human Health Risk Assessments 

Exposure/ 

Scenario 

Point of 

Departure 

Uncertainty 

Factors 

Level of Concern 

for Risk 

Assessment 

Study and Toxicological Effects 

Dermal Intermediate 

Term (1-6 months) 

DAF = 40% 

NOAEL= 10 

mg/kg/day 

UFA= 10X 

UFH=10X 

Residential LOC 

for MOE = 100 

Occupational LOC 

for MOE = 100 

24 Month Oncogenicity Study - Mice MRID 

00129918 

LOAEL = 50 mg/kg/day based on non-neoplastic 

liver effects (increased liver weight in males and 

increase in liver lesions: masses/raised areas/ 

swellings/nodular areas mainly). 

Inhalation Short 

Term (1-30 days) 

NOAEL= 30 

mg/kg/day 

UFA= 10X 

UFH=10X 

Occupational LOC 

for MOE = 100 

Acute Neurotoxicity Study-Rats MRID 

46604601 

LOAEL = 100 mg/kg/day based on clinical signs 

of toxicity (piloerection in one male, diarrhea in 

one female, tip toe gait in 3 females). 

Inhalation 

Intermediate Term 

(1-6 months) 

NOAEL= 10 

mg/kg/day 

 24 Month Oncogenicity Study - Mice MRID 

00129918 

LOAEL = 50 mg/kg/day based on non-neoplastic 

liver effects (increased liver weight in males and 

increase in liver lesions: masses/raised areas/ 

swellings/nodular areas mainly). 

Cancer (all routes) Classification: Group C, possible human carcinogen, RfD approach for risk characterization 

DAF = Dermal Absorption Factor 

Based on the available toxicity database and the Agency's current practices, the inhalation risk 

for propiconazole was assessed using an oral toxicity study. The Agency sought expert advice 

and input on issues related to this route to route extrapolation approach (i.e. the use of oral 

toxicity studies for inhalation risk assessment) from its Federal Insecticide, Fungicide, and 

Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the 

SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report and may, as appropriate, reexamine and develop new 

policies and procedures for conducting inhalation risk assessments, including route to route 

extrapolation of toxicity data. If any new policies or procedures are developed, the Agency may 

revisit the need for an inhalation toxicity study for propiconazole and/or a reexamination of the 

inhalation toxicity risk assessment. 

5.0 DIETARY AND DRINKING WATER EXPOSURE AND RISK ASSESSMENT 

5.1 Metabolite/Degradate Residue Profile 

 5.1.1 Summary of Plant and Livestock Metabolism Studies 

The nature of propiconazole residues in plants is adequately understood (DP D329394, Y. 

Donovan, 6/15/06). These data indicate that the major metabolic pathway in plants involves 

hydroxylation of the n-propyl group on the dioxolane ring of the cis/trans isomers of 

propiconazole, with subsequent conjugation to sugars. A possible alternative pathway involves 

reductive deketalization of the dioxolane ring and sugar conjugation of the resulting metabolite. 
Page 21 of 64 

The alkyl bridge between the phenyl and triazole rings is metabolized and free 1H-1,2,4-triazole 

is released. The free triazole is readily conjugated with the amino acid, serine/alanine, forming 

triazole aniline which is further metabolized to triazole acetic acid possibly through the 

intermediate formation of triazole lactic acid. HED considers free triazole, triazole alanine, and 

triazole acetic acid to be residues of concern in plants. Since these are common metabolites from 

several triazole containing pesticides, the risk assessment for triazoles has been assessed 

separately (HED memo of 11/3/10, T. Morton, D383609). 

The nature of propiconazole residues in livestock is adequately understood based on acceptable 

goat and poultry metabolism studies (DP D329394, Y. Donovan, 6/15/06). 

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

 5.1.2 Comparison of Metabolic Pathways 

The rat metabolism study indicated that parent compound was extensively metabolized. An 

intravenous study found several metabolites, including CGA 118245, CGA 217495, CGA 91304, 

and CGA 118244. No parent material was detected in the feces in the iv group. The metabolites 

seen in the iv study were detected to varying degrees in the urine and the feces of the orally 

dosed groups. Radiolabeled materials CGA 91305, CGA 118245 and CGA 177291 were 

present in the fecal radioactivity in males and females or in one sex alone. Most of the fecal 

radioactivity was not characterized. Metabolites CGA 217495 and CGA 177291 are not found in 

plant or livestock metabolism. The proposed metabolic pathway involves the cleavage of the 

dioxolane ring through the oxidation of the propyl side chain, with subsequent dechlorination 

and conjugation. In a (U-14C)-phenyl labeled propiconazole metabolism study in mice, it was 

concluded that the major metabolic pathway in mice proceeds via elimination of the dioxolane 

ring leading to ketone formation (CGA 91304) and reduction to yield the corresponding alcohol 

(CGA 91305). Both CGA 91304 and CGA 91305 are found in plants and livestock. The plant 

metabolism data indicate that the major metabolic pathway in plants involves hydroxylation of 

the n-propyl group on the dioxolane ring of the cis/trans isomers of propiconazole, with 

subsequent conjugation to sugars. A possible alternative pathway involves reductive 

deketalization of the dioxolane ring and sugar conjugation of the resulting metabolite. The alkyl 

bridge between the phenyl and triazole rings is metabolized and free 1H-1,2,4-triazole is 

released. The free triazole is readily conjugated with the amino acid, serine/alanine, forming 

triazole aniline which is further metabolized to triazole acetic acid possibly through the 

intermediate formation of triazole lactic acid. 

 5.1.3 Environmental Fate and Transport 

For propiconazole, turf, a previously registered crop, has the highest application rate (6.285 lb 

a.i./A, 8 applications of 0.786 lb a.i../A per year with a 14-day interval between applications) 

((DP 325821,328690, Dated 07/07/2006). EFED has provided EDWCs for the proposed new 

uses and has provided a comparison of these new EDWCs with the previously assessed turf use. 

The previously assessed turf EDWCs are approximately one order of magnitude higher (more 

protective), than the EDWCs for the new use and therefore, the turf EDWCs were used for the 

updated dietary risk assessment. 
Page 22 of 64 

 5.1.4 Residues of Concern Summary and Rationale 

A summary of the metabolites and degradates to be included in the risk assessment and tolerance 

expression are presented below in Table 6. Detailed rationale for these conclusions were 

presented in a previous document (DP329394, Y. Donovan, 06/15/06). 

Table 6. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance 

Expression.

Matrix For Risk Assessment For Tolerance Expression 

Plants Parent plus all metabolites convertible to 2,4-

DCBA 

Parent only 

Rotational crop Parent plus all metabolites convertible to 2,4-

DCBA 

Parent only 

Livestock: Parent plus all metabolites convertible to 2,4-

DCBA 

Parent only 

Water Parent only N/A 

Note: For all triazole-containing pesticides, the triazole-containing metabolites 1,2,4-T, TA, and TAA should also 

be included as residues of concern for risk assessment purposes only for plant and livestock commodities. Since 

these metabolites are common to the entire class of triazole-derivative fungicides and because of differential toxicity 

between the metabolites and the various parent compounds, risks associated with exposure to 1,2,4-T and to 

TA/TAA are addressed in separate risk assessment documents. 

M1 = 5-[(4-chlorophenyl)methyl]-2-methoxyl-2-methyl-1-(1H-1,2,4-triazol-1-ylmethyl)-1-cyclopentanol; M11 = 5-

[(4-chlorophenyl)methoxyl]-2,2-dimethyl-1-(1H-1,2,4-triazol-1-ylmethyl)-1-cyclopentanol; M12 = 5-[(4-

chlorophenyl)methyl]-2-carboxyl-2-methyl-1-(1H-1,2,4-triazol-1-ylmethyl)-1-cyclopentanol; M31 = 

(1S*,3R*,5S*)-3-hydroxy-cis-metconazole; 1,2,4-T = 1H-1,2,4-triazole; TAA = 1H-1,2,4-triazol-1-yl acetic acid; 

TA = 2-amino-3-(1H-1,2,4-triazol-1-yl)propanoic acid. 

5.2 Food Residue Profile 

 5.2.1 Residues in Crops 

Field trials have submitted supporting the new uses for propiconazole. The results from these 

studies are discussed in the appropriate data evaluation report (DER) and summarized in the 

following tables. 
Page 23 of 64 

TABLE 7a. Summary of Residue Data from Barley Crop Field Trials with Propiconazole.

Commodity Analyte Total App. 

Rate 

(lb ai/A) 

PHI 

(days)

Residue Levels (ppm)1

n Sample 

Min. 

Sample 

Max. 

LAFT2 HAFT2 Median Mean Std. 

Dev. 

Barley Hay Propiconazole 0.2188-

0.2311 

7 9 0.436 4.46 0.436 4.19 1.70 1.77 1.25 

Propiconazole and 

Metabolites 

9 2.08 13.1 2.08 11.9 4.27 6.13 3.95 

T 9 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A 

TA 9 <0.05 0.210 <0.056 0.197 0.070 0.089 0.045 

TAA 9 <0.02 0.065 <0.02 0.061 0.022 0.033 0.017 

Propiconazole 14 9 0.157 2.10 0.175 1.72 0.483 0.671 0.509 

Propiconazole and 

Metabolites 

9 1.73 6.61 1.78 5.87 2.85 3.53 1.42 

T 9 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A 

TA 9 <0.05 0.184 <0.05 0.180 0.065 0.084 0.047 

TAA 9 <0.02 0.077 <0.02 0.077 0.034 0.035 0.017 

Barley 

Grain 

Propiconazole 0.2213-

0.2290 

16-49 9 <0.01 1.30 <0.01 1.12 0.0103 0.170 0.363 

Propiconazole and 

Metabolites 

9 <0.05 2.22 <0.05 2.12 0.255 0.468 0.656 

T 9 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A 

TA 9 <0.06 0.274 <0.06 0.247 0.069 0.096 0.061 

TAA 9 <0.02 0.118 <0.02 0.107 0.022 0.038 0.029 

Barley 

Straw 

Propiconazole 16-49 9 0.0770 5.20 0.0821 4.99 0.287 1.50 1.91 

Propiconazole and 

Metabolites 

9 0.891 10.3 0.918 10.1 2.90 4.21 3.50 

T 9 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A 

TA 9 <0.01 0.024 <0.01 0.023 0.012 0.015 0.005 

TAA 9 <0.01 0.042 <0.01 0.038 0.013 0.019 0.011 1

 Except for sample min/max, values reflect per trial averages; n = no. of field trials. For calculation of median, mean, and 

standard deviation, the LOQ was used for any results reported as <LOQ in Table C.3. N/A = Not applicable. 2

 LAFT = lowest average field trial; HAFT = highest average field trial. 
Page 24 of 64 

TABLE 7b. Summary of Residue Data from Oat Crop Field Trials with Propiconazole.

Commodity Analyte Total App. 

Rate 

(lb ai/A) 

PHI 

(days)

Residue Levels (ppm)1

n Sample 

Min. 

Sample 

Max. 

LAFT2 HAFT2 Median Mean Std. 

Dev. 

Oat Forage Propiconazole 0.2156-

0.2290 

7 11 0.135 1.26 0.154 1.17 0.818 0.689 0.379 

Propiconazole and 

Metabolites 

11 0.431 2.46 0.499 2.31 1.48 1.40 0.584 

T 11 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A 

TA 11 0.0178 0.146 0.0184 0.128 0.0282 0.0423 0.0308

TAA 11 <0.01 0.0344 <0.01 0.0328 0.0100 0.0126 0.007 

Propiconazole 14 11 0.0316 0.480 0.0404 0.449 0.262 0.240 0.150 

Propiconazole and 

Metabolites 

11 0.303 1.51 0.389 1.39 0.975 0.919 0.378 

T 11 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A 

TA 11 0.0189 0.212 0.0236 0.212 0.0434 0.0554 0.0536

TAA 11 <0.01 0.0433 <0.01 0.0431 0.0117 0.0165 0.0103

Oat Hay Propiconazole 0.2156-

0.2290 

7 11 0.110 4.46 0.184 4.26 1.38 1.66 1.34 

Propiconazole and 

Metabolites 

11 0.629 8.54 0.798 8.00 3.23 3.47 2.31 

T 11 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A 

TA 11 <0.1 0.334 <0.1 0.325 0.100 0.133 0.0675

TAA 11 <0.01 0.0645 <0.01 0.0633 0.0145 0.0201 0.0160

Propiconazole 14 11 0.0620 2.69 0.0680 1.98 0.540 0.677 0.571 

Propiconazole and 

Metabolites 

11 0.559 5.69 0.592 4.41 1.99 2.30 1.25 

T 11 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A 

TA 11 <0.1 0.387 <0.1 0.373 0.100 0.140 0.0824

TAA 11 <0.01 0.110 <0.01 0.107 0.0239 0.0300 0.0276

Oat Grain Propiconazole 0.2188-

0.2331 

25-48 11 <0.01 0.386 <0.01 0.368 0.0392 0.100 0.121 

Propiconazole and 

Metabolites 

11 0.0630 1.61 0.0649 1.56 0.195 0.440 0.549 

T 11 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A 

TA 11 0.0480 0.362 0.0498 0.353 0.125 0.169 0.108 

TAA 11 <0.02 0.117 <0.02 0.115 0.0332 0.0476 0.0326

Oat Straw Propiconazole 25-48 11 0.0172 2.40 0.0191 1.21 0.0894 0.309 0.383 

Propiconazole and 

Metabolites 

11 0.291 6.07 0.302 5.10 2.05 2.22 1.45 

T 11 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A 

TA 11 <0.01 0.0438 <0.01 0.0435 0.0161 0.0181 0.0110

TAA 11 <0.01 0.0261 <0.01 0.0247 0.0137 0.0147 0.0052 1

 Except for sample min/max, values reflect per trial averages; n = no. of field trials. For calculation of median, mean, and 

standard deviation, the LOQ was used for any results reported as <LOQ in Tables C.3.1. and C.3.2 N/A = Not applicable. 2

 LAFT = lowest average field trial; HAFT = highest average field trial. 
Page 25 of 64 

TABLE 7c. Summary of Residue Data from Rye Crop Field Trials with Propiconazole.

Commodity Analyte Total App. 

Rate 

(lb ai/A) 

PHI 

(days)

Residue Levels (ppm)1

n Sample 

Min. 

Sample 

Max. 

LAFT2 HAFT2 Median Mean Std. 

Dev. 

Rye Forage Propiconazole 0.2222-

0.2263 

6-8 4 0.895 1.62 0.895 1.52 1.11 1.16 0.263 

Propiconazole and 

Metabolites 

4 2.29 3.99 2.37 3.75 2.85 2.95 0.677 

T 4 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A 

TA 4 <0.02 0.0775 <0.02 0.0673 0.0356 0.0396 0.0199

TAA 4 <0.01 0.0263 <0.01 0.0224 0.0101 0.0132 0.006 

Propiconazole 13-15 4 0.383 0.955 0.403 0.938 0.459 0.565 0.251 

Propiconazole and 

Metabolites 

4 1.25 3.01 1.33 2.97 2.03 2.09 0.763 

T 4 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A 

TA 4 <0.02 0.0945 <0.0207 0.0875 0.0313 0.0427 0.0303

TAA 4 <0.01 0.0272 <0.01 0.0260 0.0115 0.0147 0.0076

Rye Grain Propiconazole 0.2216-

0.2288 

34-50 4 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A 

Propiconazole and 

Metabolites 

4 <0.05 0.160 <0.05 0.144 0.0729 0.0849 0.0410

T 4 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A 

TA 4 <0.06 0.615 <0.06 0.565 0.150 0.231 0.228 

TAA 4 0.0319 0.141 0.0371 0.131 0.0764 0.0802 0.0389

Rye Straw Propiconazole 34-50 4 0.0384 0.650 0.0428 0.551 0.160 0.228 0.225 

Propiconazole and 

Metabolites 

4 0.657 4.94 0.689 4.60 1.27 1.96 1.81 

T 4 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A 

TA 4 0.0277 0.108 0.0299 0.102 0.0705 0.0682 0.0334

TAA 4 <0.03 0.0595 <0.03 0.0580 0.0329 0.0384 0.0133 1

 Except for sample min/max, values reflect per trial averages; n = no. of field trials. For calculation of median, mean, and 

standard deviation, the LOQ was used for any results reported as <LOQ in Table C.3. N/A = Not applicable. 2

 LAFT = lowest average field trial; HAFT = highest average field trial. 
Page 26 of 64 

TABLE 7d. Summary of Residue Data from Wheat Crop Field Trials with Propiconazole.

Commodity Analyte Total App. 

Rate 

(lb ai/A) 

PHI 

(days)

Residue Levels (ppm)1

n Sample 

Min. 

Sample 

Max. 

LAFT2 HAFT2 Median Mean Std. 

Dev. 

Wheat 

Forage 

Propiconazole 0.2190-

0.2306 

7 15 0.271 4.90 0.271 4.79 1.28 1.44 1.13 

Propiconazole and 

Metabolites 

15 1.18 9.00 1.23 8.47 2.16 2.88 1.90 

T 15 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A 

TA 15 <0.01 0.0975 <0.0110 0.0918 0.0193 0.0261 0.0207

TAA 15 <0.01 0.0336 <0.01 0.0324 0.0100 0.0130 0.0063

Propiconazole 14-20 15 0.0606 2.16 0.0813 2.13 0.538 0.611 0.528 

Propiconazole and 

Metabolites 

15 0.717 5.85 0.778 5.46 1.35 1.75 1.14 

T 15 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A 

TA 15 <0.01 0.0740 <0.01 0.0735 0.0190 0.0245 0.0159

TAA 15 <0.01 0.0444 <0.01 0.0442 0.0100 0.0148 0.0093

Wheat Hay Propiconazole 0.2190-

0.2306 

7 15 0.444 9.82 0.444 9.57 2.01 2.75 2.30 

Propiconazole and 

Metabolites 

15 1.98 22.5 1.98 21.6 5.31 7.22 5.01 

T 15 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A 

TA 15 0.0218 0.250 0.0218 0.236 0.0525 0.0688 0.0541

TAA 15 <0.01 0.138 <0.01 0.135 0.0182 0.0300 0.0315

Propiconazole 14-20 15 0.149 5.48 0.156 5.41 0.784 1.24 1.28 

Propiconazole and 

Metabolites 

15 1.57 18.7 1.62 17.4 3.65 4.78 4.13 

T 15 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A 

TA 15 0.0158 0.174 0.0166 0.166 0.0409 0.0527 0.0400

TAA 15 <0.01 0.128 <0.0125 0.116 0.0242 0.0331 0.0274

Wheat 

Grain 

Propiconazole 0.2140-

0.2308 

24-64 15 <0.01 0.0842 <0.01 0.0779 0.0100 0.0153 0.0176

Propiconazole and 

Metabolites 

15 <0.05 0.169 <0.05 0.145 0.0556 0.0705 0.0286

T 15 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A 

TA 15 <0.02 0.286 <0.02 0.279 0.133 0.135 0.0744

TAA 15 <0.01 0.0720 <0.01 0.0718 0.0209 0.0283 0.0172

Wheat 

Straw 

Propiconazole 24-64 15 0.0432 4.36 0.0462 4.04 0.455 1.16 1.41 

Propiconazole and 

Metabolites 

15 0.570 13.3 0.597 12.6 2.74 4.50 4.05 

T 15 <0.01 <0.01 <0.01 <0.01 0.01 0.01 N/A 

TA 15 <0.01 0.0560 <0.01 0.0515 0.0124 0.0162 0.0109

TAA 15 <0.01 0.0510 <0.01 0.0497 0.0177 0.0200 0.0114 1

 Except for sample min/max, values reflect per trial averages; n = no. of field trials. For calculation of median, mean, and 

standard deviation, the LOQ was used for any results reported as <LOQ in Tables C.3.1. and C.3.2 N/A = Not applicable. 2

 LAFT = lowest average field trial; HAFT = highest average field trial. 
Page 27 of 64 

5.3 Water Residue Profile 

 5.3.1 Estimated Drinking Water Concentrations 

For propiconazole, turf, a previously registered crop, has the highest application rate (6.285 lb 

a.i./A, 8 applications of 0.786 lb a.i../A per year with a 14-day interval between applications) 

((DP 325821,328690, Dated 07/07/2006). EFED has provided EDWCs for the proposed new 

uses and has provided a comparison of these new EDWCs with the previously assessed turf use. 

The previously assessed turf EDWCs are approximately one order of magnitude higher (more 

protective), than the EDWCs for new uses and therefore, the turf EDWCs were used for the 

updated dietary risk assessment. 

This drinking water assessment used surface water models PRZM/EXAMS and groundwater 

model (SCI-GROW). These results are based on EDWCs for Turf (DP 325821, 328690, 

07/07/2006). The proposed new use does not result in higher EDWCs than those estimated for 

turf uses. 

The estimated surface water drinking water concentrations for propiconazole are: 

55.78 ug /L for the 1 in 10 year annual peak concentration (acute) 

21.61 ug /L for the 1 in 10 year annual mean concentration (non-cancer chronic) and 

13.24 ug /L for the 30 year annual mean concentration (cancer chronic). 

The SCI-GROW estimated ground water drinking water concentrations for propiconazole are not 

expected to exceed 0.64 μg/L 

Drinking Water Data for Free Triazoles

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

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

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

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

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

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

summarized in Table 8. HED notes that there were no detects of 1,2,4-triazole in any of the 271 

water samples analyzed by PDP, with a limit of quantification of 730 parts-per-trillion (0.73 

ppb). The surface water estimates are significantly greater than those for ground water, and were 

used in the assessments for free triazole as well as the conjugated metabolites. EFED stated that 

the new metconazole uses are covered by the previous drinking water assessment for 1,2,4-

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

Table 8. Summary of Estimated Drinking Water Concentrations of 1,2,4-Triazole. 

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

Acute 0.041 0.001 

Chronic 0.011 0.001 
Page 28 of 64 

5.4 Dietary and Drinking Water Exposure and Risk 

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

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

Food Commodity Intake Database DEEM-FCIDTM, Version 3.16, which incorporates 

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

Eat in America, (NHANES/WWEIA). This dietary survey was conducted from 2003 to 2008. 

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

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

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

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

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

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

the PAD. 

 5.4.1 Acute Dietary and Drinking Water Analysis 

A new dietary assessment was conducted for the proposed amended use. The proposed amended use 

results dietary risk estimates below HED’s level of concern; see Table 9. The highest is children 1-2 

years resulting in 85% of the aPAD. 

Table 9. Results of Acute Dietary Exposure Analysis for Food and Drinking Water 

Population Subgroup aPAD (mg/kg/day) 

95th Percentile 

Exposure (mg/kg/day) % aPAD 

General U.S. Population 

0.3 

0.077562 26 

All Infants (< 1 year old) 0.108099 36 

Children 1-2 years old 0.253533 85 

Children 3-5 years old 0.194271 65 

Children 6-12 years old 0.106036 35 

Youth 13-19 years old 0.073595 25 

Adults 20-49 years old 0.061233 20 

Adults 50+ years old 0.050898 17 

Females 13-49 years old 0.060552 20 

Dietary Assessment of Free Triazole and its Conjugates

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

Address The Amended Propiconazole Section 3 Registration to Add Foliar Use on Sugarcane. T. Morton, 

DP403618.drs, 8/1/12.

The proposed amended use of propiconazole did not result in an increase in dietary exposure estimates 

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

metabolites did not need to be updated. The results from the previous dietary analysis are below 

HED’s level of concern; see Table 10. 
Page 29 of 64 

Table 10. Summary of Dietary (Food and Drinking Water) Exposure and Risk for the Common Triazole 

Metabolites (Previous Assessment). 

Population Subgroup 

Acute Dietary 

(95th Percentile) Chronic Dietary Cancer 

Dietary 

Exposure 

(mg/kg/day) 

% aPAD* 

Dietary 

Exposure 

(mg/kg/day) 

% cPAD* 

Dietary 

Exposure 

(mg/kg/day) 

Risk 

1,2,4-Triazole 

General U.S. Population 0.008282 28 0.001327 27 

Not 

Applicable 

Not 

Applicable

All Infants (< 1 year old) 0.012115 40 0.001843 37 

Children 1-2 years old 0.023117 77 0.003832 77 

Children 3-5 years old 0.018974 63 0.003064 61 

Children 6-12 years old 0.010992 37 0.001665 33 

Youth 13-19 years old 0.007222 24 0.001085 22 

Adults 20-49 years old 0.006609 23 0.001137 23 

Adults 50+ years old 0.005820 19 0.001073 22 

Females 13-49 years old 0.006747 22 0.001110 22 

Triazolylalanine + Triazolylacetic Acid+Triazolylpyruvic acid 

General U.S. Population 

Not 

Applicable 

Not 

Applicable

0.018547 21 

Not 

Applicable 

Not 

Applicable

All Infants (< 1 year old) 0.021851 24 

Children 1-2 years old 0.058600 65 

Children 3-5 years old 0.047124 52 

Children 6-12 years old 0.024837 28 

Youth 13-19 years old 0.015657 17 

Adults 20-49 years old 0.015272 17 

Adults 50+ years old 0.014323 16 

Females 13-49 years old 0.079772 80 0.014900 17 

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

 5.4.2 Chronic Dietary and Drinking Water Analysis 

A new dietary assessment was conducted for the proposed amended use of propiconazole and results 

in dietary risk estimates below HED’s level of concern; see Table 11. 

Table 11. Results of Chronic Dietary Exposure Analysis for Food and Drinking Water 

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

General U.S. Population 

0.1 

0.007432 7.4 

All Infants (< 1 year old) 0.010280 10 

Children 1-2 years old 0.023718 24 

Children 3-5 years old 0.019121 19 

Children 6-12 years old 0.009941 9.9 

Youth 13-19 years old 0.006022 6.0 

Adults 20-49 years old 0.006180 6.2 

Adults 50+ years old 0.005618 5.6 

Females 13-49 years old 0.005622 5.6 
Page 30 of 64 

6.0 RESIDENTIAL EXPOSURE AND RISK ASSESSMENT 

Residential exposures are not expected based on the proposed uses, however the proposed new 

use will affect the aggregate exposure, therefore an updated residential exposure assessment was 

conducted. The revision of residential exposures will impact the human health aggregate risk 

assessment for Propiconazole. Each assumption and factor is detailed in the 2012 Residential 

SOPs (http://www.epa.gov/pesticides/science/residential-exposure-sop.html). The residential 

handler exposure/risk characterization for cereal grains is summarized in below. 

Specifics concerning residential handler exposure and risks are provided in the most recent 

occupational and residential exposure assessment for propiconazole (D349727, S. Oonnithan, 

9/3/06). 

 

6.1 Residential Bystander Postapplication Inhalation Exposure 

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

assessment was not performed for propiconazole at this time. However, volatilization of 

pesticides may be a potential source of post-application inhalation exposure to individuals nearby 

to pesticide applications. The Agency sought expert advice and input on issues related to 

volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report 

on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html) and is 

in the process of evaluating the SAP report. The Agency may, as appropriate, develop policies 

and procedures to identify the need for and, subsequently, the way to incorporate postapplication inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative post-application 

inhalation exposure assessment for propiconazole. 

6.2 Spray Drift 

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for Propiconazole. 

The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State 

Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices (see the Agency’s Spray Drift website for more information at 

(http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the 

Agency is now requiring interim mitigation measures for aerial applications that must be placed 

on product labels/labeling. The Agency has completed its evaluation of the new database 

submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is 

developing a policy on how to appropriately apply the data and the AgDRIFT computer model to 

its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. 

After the policy is in place, the Agency may impose further refinements in spray drift 

management practices to reduce off-target drift with specific products with significant risks 

associated with drift. 
Page 31 of 64 

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

performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation 

exposure assessment was performed for flaggers. This exposure scenario is representative of a 

worse case inhalation (drift) exposure and may be considered protective of most outdoor 

agricultural and commercial post-application inhalation exposure scenarios. 

7.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT 

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

risks from three major sources: food, drinking water, and residential exposures (dermal and 

residential). In an aggregate assessment, exposures from relevant sources are added together and 

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

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

both the route and duration of exposure. 

7.1 Acute & Chronic Aggregate Risk 

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

demonstrated under Section 5.4, acute and chronic aggregate risks are not of concern. 

7.2 Short- and Intermediate-Term Aggregate Risk

Short term aggregate exposure takes into account residential exposure plus average exposure 

levels to food and water (considered to be a background exposure level). Table 12 aggregates 

the short-term risk for toddlers from incidental oral, dermal, and food and water (as a 

background). The highest incidental oral and dermal exposure scenarios are from residential use 

on turf, which were used in the short term aggregate risk assessment. The short-term 

aggregate risk MOE of 96 exceeds HED’s level of concern (LOC=100). This assessment is 

considered very conservative in that the residential incidental oral post-application exposure was 

calculated by combining three screening level assessments (which by themselves already have 

conservative estimates). 
Page 32 of 64 

Table 12: Short-term Aggregate Risk Estimates to Propiconazole for Toddler (Children 1-2years)

Exposure Scenario Target 

MOE 

Route of 

Exposure Exposure NOAELs MOE at Day 0 Combined MOE5

Average Food and Water N/A Oral 0.0237 

30 

1300 2

96 

Hand to Mouth Activity on Turf 

100 1

Oral 0.0269 2100 3

Object to Mouth Activity on Turf Oral 0.0067 68000 3

Soil Ingestion Oral 0.00009 490,000 3

Turf –High-Contact Activities Dermal 0.2827 110 4

1

 Target MOE= 100, Acute Neuortoxicity NOAEL=30 2

 MOE food = [(short-term oral NOAEL)/(chronic dietary exposure)] 3

 MOE oral = [(short -term oral NOAEL)/(hand-to-mouth residential exposure)] 4

 MOE dermal = [(short -term dermal NOAEL)/(high-end dermal residential exposure)] 5

 Aggregate Combined MOE (food, water, and residential) = 1÷ [(1÷MOE food and water) + (1÷MOE oral) + (1÷MOE 

dermal)]. 

The residential handler exposure/risk characterization for cereal grains is summarized in Table 

13. 

For all residential handler exposure scenarios, MOEs exceed HED’s LOC (Dermal LOC = 100), 

and therefore not of concern to HED. Summaries of the short- term risk estimates for residential 

handlers are included in Table 13. 

Summaries of the short-term risk estimates for residential post-application activities are included 

in Table 14. 
Page 33 of 64 

Table 13. Short-Term Residential Handler Exposure and Risk Estimates for Propiconazole. 

Exposure 

Scenario 

Target 

MOE 

Dermal 

Unit 

Exposure 

(ug/lb ai) 

Inhl. Unit 

Exposure 

(ug/lb ai) 

Maximum 

Application 

Ratea 

(lb ai/ft2) 

Or 

(lb ai/Acre)

Area 

Treated or 

Amount 

Handled 

Dailyb

Dermal Inhalation Total 

Dose 

(mg/kg/day)c MOE d Dose (mg/kg/day)e MOEf MOEg

Mixer/loader/Applicator 

Low Pressure 

Handwand/ 

Ornamentals 

100 

63,000 18 

5.5 x 10-8 1,200 ft2 

0.000021 1,400,000 5.9 x10-9 5.1 x 109 1.4 x 106 

Hose-end 

Sprayer/ 

Ornamentals 

58,000 1.4 0.000019 1,600,000 1.2 x 10-9 6.5 x 1010 1.6 x 106 

Low Pressure 

Handwand/ 

Turf/Lawns 100 

Hose-end Sprayer is protective 

Hose-end 

Sprayer/ 

Turf/Lawns 

13,400 22 1.8 0.5 Acres 0.060 500 0.000099 300,000 500 

Brush/Roller 

Applying paint 100 450,000 200 0.0035 lb ai/ 1 gal can 0.016 1,900 0.000007 4,300,00 1,900 Airless Sprayer 

Applying Paint 63,000 18 0.0033 9.100 0.00000095 32,000,000 9,100 

a. Based on registered or proposed label (0.0024 lb ai/A): [ 0.0024 lb ai/A x A/43,560 sq ft. = 5.5 x 10 -8 ] or (0.000000055 lb ai/ft2) b. Exposure Science Advisory Council Policy #9.1. c. Dermal Dose = Dermal Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gallo

kg). 

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

e. Inhalation Dose = Inhalation Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled 

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

 Total MOE = NOAEL (mg/kg/day) / (Dermal Dose + Inhalation Dose) OR Total MOE = 1/ [(1/Dermal MOE) + (1/Inhalation MOE)].
Page 34 of 64 

Table 14: Short-Term Residential Post-application/Incidental Oral Exposure and Risk Estimates for 

Propiconazole. 

Lifestage Post-application Exposure Scenario Dose MOEs 

Adult 

Turf - sprays 

Dermal 0.142785 210

Inhalation N/A N/A 

Child 

Dermal 0.282685455 110 

Inhalation N/A N/A 

Hand to Mouth 0.014490408 2,100 

Object to Mouth 0.00044 68,000 

Incidental Soil 

Ingestion 0.000061 490,000 

Table 14 aggregates the short-term risk for adults from residential post application, and average 

food and water (as a background). Based on the low vapor pressure of propiconazole, negligible 

post application inhalation exposure is anticipated to occur. The highest post application 

exposure from residential use on turf was used in the short term aggregate. The aggregate MOE 

is 200, which is greater than the target MOE of 100. This aggregate exposure assessment is 

considered very conservative because the assumptions used for each of the scenarios separately 

are already high end (i.e., time spent outdoors, dislodgeable residues). 

Table 14: Short-term Aggregate Risk Estimates to Propiconazole for Adults from Post-Application Activities

Exposure Scenario Target 

MOE 

Route of 

Exposure 

Exposure or 

Daily dose NOAELs MOE at Day 0 Combined MOE4

Average Food and Water 

(As background) 

N/A Food and 

water 0.0062 

30 

4800 2

200 Residential Post-application 

(Residential Turf Gen. HighContact Activities)) 100 1 Dermal 0.143 210 3

1

 Target MOE= 100, Developmental rat- increased incidence of rudimentary risks. NOAEL = 30 2

 MOE food and water = [(short-term oral NOAEL)/(chronic dietary exposure)] 

3

 MOE dermal = [(short -term dermal NOAEL)/(high-end dermal residential exposure)] 4

 Aggregate Combined MOE (food, water, and residential) = 1÷ [(1÷MOE food and water) + (1÷MOE post appl. dermal)]. 

7.3 Intermediate-Term Aggregate Risk 

The only residential use scenario that will result in potential intermediate term exposure to 

propiconazole is post application exposure to children from wood treatment (antimicrobial use). 

Table 15 shows the aggregate risk for intermediate term exposure to Children 1-2 years old. The 

aggregate MOE is 110, which is greater than the target MOE of 100. Therefore, this scenario is 

not of concern. 
Page 35 of 64 

Table 15. Intermediate -term Aggregate Risk Estimates to Propiconazole for Toddler (Children 1-2years)

Exposure Scenario 

Target 

MOE 

Route of 

Exposure Exposure NOAELs MOE at Day 0 Combined MOE5

Average Food and Water N/A Oral 0.0237 10 420 2

Incidental oral 100 110 1 Oral 0.0056 10 18003

Dermal Contact Activities 100 1 Dermal 0.059 10 170 4

Note:

1

 Target MOE= 100, 24 Month oncogenicity study. NOAEL=10 

2

 MOE food = [(intermediate-term oral NOAEL)/(chronic dietary exposure)] 3

 MOE oral = [(intermediate -term oral NOAEL)/(hand-to-mouth residential exposure)] 4

 MOE dermal = [(intermediate -term dermal NOAEL)/(high-end dermal residential exposure)] 5

 Aggregate Combined MOE (food, water, and residential) = 1÷ [(1÷MOE food and water) + (1÷MOE oral) + (1÷MOE 

dermal)]. 

These aggregate exposure assessments are considered conservative estimates, that should not 

underestimate risks, for the following reasons: 1) the dietary inputs used tolerance-level residues 

for many food commodities, and crop specific (turf) screening level drinking water modeling 

data (i.e., surface water modeling); 2) maximum application rates and minimum application 

intervals were used; and 3) conservative SOPs and upper level estimates of exposure were 

employed. 

Updated Aggregate Assessment of Free Triazole & its Conjugates

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

Amended Propiconazole Section 3 Registration to Add Use on Sugarcane. DP403619, T. Morton, 8/1/12.

The addition of the proposed amended use does not increase the aggregate exposure to free 

triazoles and its conjugates. Therefore, the previous aggregate human health risk assessment for 

free triazoles and its conjugates did not need updated and the aggregate estimates are below 

HED’s level of concern (DP403619, T. Morton, 8/1/12). 

8.0 CUMULATIVE RISK 

Propiconazole is a member of the triazole-containing class of pesticides. Although conazoles act 

similarly in plants (fungi) by inhibiting ergosterol biosynthesis, there is not necessarily a 

relationship between their pesticidal activity and their mechanism of toxicity in mammals. 

Structural similarities do not constitute a common mechanism of toxicity. Evidence is needed to 

establish that the chemicals operate by the same, or essentially the same, sequence of major 

biochemical events (EPA, 2002). In conazoles, however, a variable pattern of toxicological 

responses is found; some are hepatotoxic and hepatocarcinogenic in mice. Some induce thyroid 

tumors in rats. Some induce developmental, reproductive, and neurological effects in rodents. 

Furthermore, the conazoles produce a diverse range of biochemical events including altered 

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

whether these biochemical events are directly connected to their toxicological outcomes. Thus, 
Page 36 of 64 

there is currently no evidence to indicate that conazoles share common mechanisms of toxicity 

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

for the conazoles. For information regarding EPA’s procedures for cumulating effects from 

substances found to have a common mechanism of toxicity, see EPA’s website at 

http://www.epa.gov/pesticides/cumulative. 

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

metabolite 1,2,4-triazole and two triazole conjugates (triazolylalanine and triazolylacetic acid). 

To support existing tolerances and to establish new tolerances for triazole-derivative pesticides, 

including propiconazole, U.S. EPA conducted a human health risk assessment for exposure to 

1,2,4-triazole, triazolylalanine, and triazolylacetic acid resulting from the use of all current and 

pending uses of any triazole-derived fungicide. The risk assessment is a highly conservative, 

screening-level evaluation in terms of hazards associated with common metabolites (e.g., use of 

a maximum combination of uncertainty factors) and potential dietary and non-dietary exposures 

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

retained the additional 1X FQPA safety factor for the protection of infants and children. The 

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

infants and children. The Agency’s complete risk assessment is found in the propiconazole 

reregistration docket at http://www.regulations.gov, Docket Identification (ID) Number EPAHQ-OPP-2005-0497. 

9.0 OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION 

9.1 Exposure Scenarios 

Occupational handler and post-application exposure scenarios were assessed for the proposed 

amended use. Based on the product labels and information provided by the registrant, short- and 

intermediate-term exposure is assessed for handlers and post-application activities. Dermal and 

inhalation exposures are aggregated for propiconazole because the toxicity endpoints for these 

exposure routes are not based on common toxicological endpoints. Labels for the propiconazole 

proposed uses require that applicators and other handlers wear personal protective equipment 

(PPE) consisting of long-sleeved shirt, long pants and shoes with socks plus gloves. 

9.2 Handler Exposure 

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

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

activities through the dermal and inhalation routes. Propiconazole products are applied using 

aerial, airblast, groundboom and chemigation equipment. 

The quantitative exposure/risk assessment developed for occupational handlers is based on the 

following exposure scenarios: 
Page 37 of 64 

 9.2.1 Handler Exposure Scenarios 

Occupational handler exposure scenarios were assessed for the proposed use of propiconazole on 

cereal grains. For all dermal and inhalation exposure scenarios, risk estimates do not exceed 

HED’s LOC (Dermal LOC = 100; Inhalation LOC = 100) with label-specified PPE and, 

therefore, are not of concern to HED. Since the dermal and inhalation endpoints are based on 

similar effects, the doses are combined for a total MOE. See table 3 for details. 

Based on the anticipated use patterns and current labeling, types of equipment and techniques 

that can potentially be used, occupational handler exposure is expected from the proposed uses. 

The quantitative exposure/risk assessment developed for occupational handlers is based on the 

following scenarios: 

MIXER/LOADER

1. Open mixing/loading EC for aerial applications; 

2. Open mixing/loading EC for chemigation applications; 

3. Open mixing/loading EC for groundboom applications; 

APPLICATORS

1. Applying sprays with aerial equipment; 

 2. Applying sprays with groundboom equipment; 

 

Note: Chemigation is an irrigation system that does not have an applicator. It is applied 

mechanically. 

FLAGGERS

1. Flagging for aerial applications; 

 9.2.2 Handler Exposure Data 

Unit Exposures: It is the policy of HED to use the best available data to assess handler exposure. 

Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, 

include the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the Agricultural 

Handler Exposure Task Force (AHETF) database, the Outdoor Residential Exposure Task Force 

(ORETF) database, or other registrant-submitted occupational exposure studies. Some of these 

data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. 

The standard values recommended for use in predicting handler exposure that are used in this 

assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit 

Exposure Surrogate Reference Table” (http://www.epa.gov/opp00001/science/handler-exposuretable.pdf), which, along with additional information on HED policy on use of surrogate data, 

including descriptions of the various sources, can be found at 

http://www.epa.gov/pesticides/science/handler-exposure-data.html. 
Page 38 of 64 

 9.2.3 Handler Exposure Assumptions 

Based on HED ExpoSAC Policy No. 9.1, the area treated in a day was assumed to be: 

 1200 acres for mixing/loading to support aerial applications, 

 350 acres for mixing /loading chemigation applications 

 200 acres for mixing/loading to support groundboom applications, 

 1200 acres for applying with aerial equipment, 

 200 acres for applying with groundboom equipment, and 

 350 acres for flagging to support aerial applications. 

Body Weight

The average adult body weight of 80 kg was used for estimating short-, and intermediate-term 

dermal and inhalation daily dose calculations. 

Absorption Factors

The short- and intermediate-term dermal absorption factor is 40%. 

Personal Protective Equipment (PPE)

For pesticide handlers, this assessment presents “baseline” and “label specific PPE (i.e. workers 

wearing a single layer of work clothing consisting of a long sleeved shirt, long pants, shoes, plus 

socks and protective eyewear) calculations. See table 3 for specifics. 

Equations and Calculations

 

Daily Dose: 

Daily dose (dermal and inhalation) is calculated by normalizing the daily exposure (dermal or 

inhalation) value by body weight and accounting for absorption factors: 

Average Daily Dose (mg/kg/day) = Daily Exposure (mg ai/day) x {Absorption Factor } 

 Body Weight (kg) 

Where: 

Average Daily Dose = Absorbed dose received from exposure to a pesticide in a given 

 scenario (mg pesticide active ingredient/kg body weight/day), 

Daily Exposure = Amount (mg ai/day) deposited on the surface of the skin that is 

 available for dermal absorption or amount inhaled that is available 

 for inhalation absorption, 

Absorption Factor = A measure of the amount of chemical that crosses a biological 

 boundary such as the skin or lungs, and 

Body Weight = Body weight determined to represent the population of interest in a 

 risk assessment. 

Margin of Exposure (MOE):

The daily dermal and inhalation dose received by occupational handlers was compared to the 

appropriate PoD (i.e. NOAELs) to assess the risk to occupational handlers. All MOE values 
Page 39 of 64 

were calculated using the following formula: 

 MOE = NOAEL (mg/kg/day) 

 Average Daily Dose (mg/kg/day) 

 

Where: 

MOE = Margin of exposure value used by HED to represent risk or how close 

 a chemical exposure is to being a concern (unitless), 

ADD = Average daily dose (ADD) is absorbed dose received from exposure to 

 pesticide, and 

NOAEL = Dose level in a toxicity study, where no observed adverse effects occurred 

in the study. 

For all dermal and inhalation exposure scenarios, risk estimates do not exceed HED’s LOC 

(Dermal LOC = 100; Inhalation LOC = 100) with label-specified PPE and, therefore, are not of 

concern to HED. Summaries of the combined short- and intermediate-term risk estimates for 

occupational handlers are included in Table 4. 

 9.2.4 Handler Exposure and Risk Estimates 

 

Summaries of the combined, dermal plus inhalation short-, and intermediate-term risks for each 

exposure scenario are presented in Table 18. The combined dermal and inhalation exposure 

risks are not of concern (i.e., MOEs >100), provided the mixer/loaders wear chemical-resistant 

gloves as directed on the label. 

Exposure scenarios listed within (mixing/loading, applying, and flagging), risk estimates do not 

exceed HED’s LOC (MOE < 100), and therefore not of concern to HED. See Table 16 for 

details. 
Page 40 of 64 

Table 16. Agricultural Handler Exposure and Risk for Propiconazole Use on Cereal Grains 

Exposure 

Scenario 

Maxium 

App. Rate a

(lb ai/A) 

Area 

Treated 

Daily b

(acres) 

Unit Exposure 

(μg/lb ai) c

Dose 

(mg/kg/day) d

Com

Sho

Baseline 

(BL) 

Baseline + 

Label Spec. PPE 

Baseline 

(BL) 

Baseline + 

Label Spec. PPE 

Der

 Inh

Dermal Inhal. Dermal Inhal. Dermal Inhal. Dermal Inhal. BL 

 Mixing/Loading “Cereal Grains” (Emulsifiable Concentrate) 

Aerial 

0.114 

1,200 

220 0.219 37.6 0.219 

0.015 0.00037 0.0257 0.00037 200 

Chemigation 350 0.044 0.00011 0.0075 0.00011 680 

Groundboom 200 0.025 0.000062 0.0043 0.000062 1,200 

 Applying “Cereal Grains” (Emulsifiable Concentrate) 

Aerial 

(Enclosed 

Cockpit) 

0.114 

1,200 No Data 

5 

(Eng. 

Control) 

0.068 

(Eng. 

Control) 

No Data 

0.00098 

(Eng. 

Control) 

0.0001 

(Eng. 

Control) 

No Data 

Chemigation N/A 

Groundboom 

Equipment 

(Open Cab) 

200 78.6 0.34 16.1 0.34 0.009 0.000097 0.0018 0.000097 3,300 
Page 41 of 64 

Table 16. Agricultural Handler Exposure and Risk for Propiconazole Use on Cereal Grains 

Exposure 

Scenario 

Maxium 

App. Rate a

(lb ai/A) 

Area 

Treated 

Daily b

(acres) 

Unit Exposure 

(μg/lb ai) c

Dose 

(mg/kg/day) d

Com

Sho

Baseline 

(BL) 

Baseline + 

Label Spec. PPE 

Baseline 

(BL) 

Baseline + 

Label Spec. PPE 

Der

 Inh

Dermal Inhal. Dermal Inhal. Dermal Inhal. Dermal Inhal. BL 

Flagging 

Aerial 0.175 350 11 35 12 35 0.0034 0.00028 0.0037 0.00027 8,200 

a. Application rates = maximum application rates from the parent labels. 

b. Area treated daily from Science Advisory Council Policy # 9.1. 

 c. Unit Exposures are from the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table,” dated 03/12, and located at http://www.epa.gov/opp0

 exposure-table.pdf and (http://www.epa.gov/pesticides/science/handler-exposure-data.html).

d. Dermal and Inhalation Dose (mg/kg/day) daily unit exposure (μg/lb ai) x application rate (lb ai/acre) x acres treated x 1E-3 mg/μg

 / body weight (80 kg adult). 

 e. Combined MOE = NOAEL (30 mg/kg/day for ST and 10 mg/kg/day for IT) / combined dermal and inhalation daily dose (mg/kg/day). Level of concern = 100

f. LOC = Level Of Concern (target Margin of Exposure or MOE). g. Aerial application rate for Sugarcane (0.175 lb ai/A) is protective of cereal grains, therefore only flagger for sugarcane was assessed. Aerial: Enc

engineering control; therefore the unit exposures and MOEs reflect this.
Page 42 of 64 

9.3 Post Application Exposure 

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

present in an environment that has been previously treated with a pesticide (also referred to as a 

re-entry exposure). Such exposure may occur when workers enter previously treated areas to 

perform job functions, including activities related to crop production. In the case for 

propiconazole, post-application dermal exposure to field workers following ground and aerial 

applications is probable. 

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

exposure assessment was not performed for propiconazole at this time. However, there are 

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

of pesticides and re-suspension of dusts and/or particulates that contain pesticides. The Agency 

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

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

The Agency received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

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

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures, to identify the need for and, subsequently, the way to incorporate occupational 

post-application inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for propiconazole. 

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

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

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

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

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

inhalation exposure scenarios. 

 

 9.3.1 Post Application Exposure Scenarios 

Post-application propiconazole residues are expected for individuals involved in hand weeding; 

scouting; thinning; hand harvesting, and irrigation. For all dermal post-application exposure 

scenarios, risk estimates do not exceed HED’s LOC (Dermal LOC = 100), and therefore not of 

concern to HED. 

 

 9.3.2 Post Application Exposure Assumptions 

Transfer Coefficients: It is the policy of HED to use the best available data to assess postapplication exposure. Sources of generic post-application data, used as surrogate data in the 

absence of chemical-specific data, are derived from Agricultural Reentry Task Force (ARTF) 
Page 43 of 64 

exposure monitoring studies, and, as proprietary data, are subject to the data protection 

provisions of FIFRA. The standard values recommended for use in predicting post-application 

exposure that are used in this assessment, known as “transfer coefficients”, are presented in the 

“Science Advisory Council for Exposure (ExpoSAC) Policy 3” 

(http://www.epa.gov/pesticides/science/exposac_policy3.pdf), which, along with additional 

information about the ARTF data, can be found at http://www.epa.gov/pesticides/science/postapp-exposure-data.html. 

Post-application Studies: A total of six studies are described in [memorandum; (D279301, J. 

Miller, 8/18/05)] and listed in this section. These studies described propiconazole residue 

dissipation and exposure for corn, peaches, rice, pecans, ornamentals and turf. 

 MRID 42564003: Propiconazole – Dislodgeable Residue on Corn (North Carolina)

 EPA MRID 425640-03; Report dated 1991. Author Avakian, M; 

 Sponsor: Ciba-Geigy Corporation Agriculture Division. 

 Submitted by Environmental Technologies Institute, Inc. and EN-CAS Labs. 

 MRID 44959701: Dissipation of Dislodgeable Foliar Residue of Two formulations of Propicoanzole 

(OrbitTM and OrbitTM 45W) Applied to Peaches. 

 EPA MRID 44959701(0442); Report dated 1999; 

 Author; Rosenheck, L. Report: Lab report Number: 260-98: 44580: AG-561 

Performing Laboratories: ABC Laboratories., Inc. 

 MRID 45288601: Determination of Transferable Turf Residue on Turf treated with Banner 

MAXX; Report dated (2000); Authors; Rosenheck, L.; Meyer, L. Lab Project Number 990046: 179-99. 

Performing Laboratories: Central California Research Laboratories, Inc. 

 MRID 40279806: Author; Honeycutt, R. CGA 64250 (Tilt) Worker Exposure in Pecans Unpublished. 

Sponsored by: Ciba-Geigy 

 MRID 133390: Author; Honeycutt, R. (1983) CGA 64250 (Tilt) Worker Exposure in Rice: Report No. 

EIR-83011. ( Unpublished study received Dec 12, 1983 under 100-617; submitted by Ciba-Geigy Corp., 

Greensboro, NC; CDL:07222-C) 

 MRID 44959702: Dissipation of Dislodgeable Foliar Residues of Propiconazole 

(Banner MAXX); Applied to Commercial Ornamentals. Rosenheck, L.; Meyer, L.(1999) Final 

report: Lab Project Number: 1134-99. Unpublished study prepared by Novartis Crop Protection, Inc. 

 51 p. 

HED evaluated these studies and decided that for this occupational post-application assessment, 

the rice study (MRID 133390) DFR values would be used for cereal grains. 

 9.3.3 Post-Application Exposure and Risk Estimates 

For all dermal post-application exposure scenarios, risk estimates do not exceed HED’s LOC 

(Dermal LOC = 100), therefore, are not of concern to HED. 

A summary of post-application exposure and risk calculations, assumptions, and results is 

provided in Table 17. 
Page 44 of 64 

1. Maximum application rate from proposed labels. See table 2 for specifics. 

2. DAT = Days after treatment needed to reach the LOC of 100; DAT 0 = the day of treatment/ assumed to be approx. 12 hours. 

3. DFR (μg/cm2) = dislodgeable foliar residues corresponding to DAT, based on chemical specific data and application rate. 4. TC (cm2

/hr) = transfer coefficients and associated activities from ExpoSAC Policy Number 3. 

 (http://www.epa.gov/pesticides/science/exposac_policy3.pdf) 

 5. MOE on corresponding DAT. MOE = NOAEL / Daily Dose. Daily Dose = [(DFR x TC x 40% Dermal absorption x 8 hr 

Exp.TimeExp. Time)] / [(CF: 1000 μg/mg) x (80-kg Body Weight). Short-Term NOAEL = 30 mg/kg/day; Intermediate-term 

NOAEL = 1 mg/kg/day. The LOC is 100. 

 ** Cereal Grains DFR data (MRID 133390) 

 9.3.4 Restricted Entry Interval 

Propiconazole has been classified in Toxicity Category III for acute dermal and eye irritation and 

Category IV for primary skin irritation. Per the Worker Protection Standard (WPS), a 12-hr 

restricted entry interval (REI) is required for chemicals classified under Toxicity Category III/IV. 

10. REFERENCES 

Propiconazole. Amended Use on Cereal Grains. Analytical Methods and Residue Data., T. Morton, D400030,

02/27/2013

Propiconazole: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments 

for Cereal Grains, T. Morton, D403630, 02/27/2013 

Propiconazole: Assessment of Aerial; Chemigation; and Groundboom Applications to Sugarcane and Cereal Grains 

(Wheat; Barley; Oats; Rye, and Triticale). J.S. Miller, D403629, 11/15/2012 

Drinking Water Exposure Assessment for the IR-4 Petition (1E7855) that Proposes Tolerances for Residues of 

Propiconazole on Dry Bean, Succulent Bean, and Snap Bean. – I. Abdel-Sahib, D389673, 1/4/12 

Propiconazole: Summary of Hazard and Science Policy Council (HASPOC) Meeting of June 21, 2012: 

Recommendations on the need for a 28-day inhalation study and a subchronic neurotoxicity study, K. Rury, 

TXR#0056387, date. 

Table 17. Summary of Estimated Post-Application MOEs for Cereal Grains 

Crop 

Application 

Rate 

(lb ai/A) 1

DAT2 DFR 3

(μg/cm2) 

TC 4

(cm2/hr) Activity 4

MOE 5 

LOC = 100 

Short-Term IntermediateTerm 

Cereal 

Grains 0.114 0 0.184**

70 

Hand 

Weeding, 

Thinning 

5,800,000 1,900,000 

210 Scouting, 1,900,000 650,000 

1,100 Scouting, 370,000 120,000 

1,900 Irrigation 210,000 72,000 
Page 45 of 64 

APPENDICES 

A TOXICOLOGY DATA SUMMARY 

 A.1 Guideline Data Requirements 

Guideline Data Requirements 

Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity ....................................................... 

870.1200 Acute Dermal Toxicity .................................................. 

870.1300 Acute Inhalation Toxicity .............................................. 

870.2400 Primary Eye Irritation .................................................... 

870.2500 Primary Dermal Irritation .............................................. 

870.2600 Dermal Sensitization...................................................... 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

870.3100 Oral Subchronic (rodent) ............................................... 

870.3150 Oral Subchronic (nonrodent) ......................................... 

870.3200 21-Day Dermal .............................................................. 

870.3250 90-Day Dermal .............................................................. 

870.3465 28/90-Day Inhalation ..................................................... 

yes 

yes 

yes 

no 

no* 

yes 

yes 

yes 

- 

- 

870.3700a Developmental Toxicity (rodent) ................................... 

870.3700b Developmental Toxicity (nonrodent)............................. 

870.3800 Reproduction ................................................................. 

yes 

yes 

yes 

yes 

yes 

yes 

870.4100a Chronic Toxicity (rodent) .............................................. 

870.4100b Chronic Toxicity (nonrodent) ........................................ 

870.4200a Oncogenicity (rat) .......................................................... 

870.4200b Oncogenicity (mouse) .................................................... 

870.4300 Chronic/Oncogenicity .................................................... 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

870.5100 Mutagenicity—Gene Mutation - bacterial ..................... 

870.5300 Mutagenicity—Gene Mutation - mammalian ................ 

870.5375 Mutagenicity—Structural Chromosomal Aberrations ... 

870.5900 Mutagenicity—Other Genotoxic Effects ....................... 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

870.6100a Acute Delayed Neurotox. (hen) ..................................... 

870.6100b 90-Day Neurotoxicity (hen) ........................................... 

870.6200a Acute Neurotox. Screening Battery (rat) ....................... 

870.6200b 90-Day Neuro. Screening Battery (rat) .......................... 

870.6300 Develop. Neuro .............................................................. 

no 

no 

yes 

no* 

no 

- 

- 

yes 

- 

- 

870.7485 General Metabolism ...................................................... 

870.7600 Dermal Penetration ........................................................ 

870.7800 Immunotoxicity ............................................................. 

yes 

no 

yes 

yes 

- 

no 

* waived per HASPOC TXR 0056387 
Page 46 of 64 

A.2 Toxicity Profiles 

Table A.2: Propiconazole Acute Toxicity Profile 

Guideline

No. 

Study Type MRID # Results Toxicity Category

870.1100 Acute Oral Toxicity– rat 00058591 LD50 =1517 mg/kg III 

870.1200 Acute Dermal Toxicity-rabbit 00058596 LD50 = >4000 mg/kg III 

870.1300 Acute Inhalation Toxicity– rat 41594801 LC50 = >50.84 mg/L IV 

870.2400 Acute Eye Irritation 00058597 Corneal opacity reversed in 72 hrs III 

870.2500 Acute Dermal Irritation 00058598 No irritation IV 

870.2600 Skin Sensitization 44949501 confirmed sensitizer - 

Table A.3 Subchronic, Chronic and Other Toxicity Profile: Propiconazole 

Guideline No./ Study 

Type 

MRID No. (year)/ 

Classification /Doses 

Results 

870.3100 

90-Day Feeding 

Study in Rat 

00058606 (1997) 

Acceptable/Guideline 

0, 240, 1200 or 6000 ppm 

(M: 0, 15.9, 76.1, 461.7, F: 

0, 16.8, 77.6, 400.9 

mg/kg/day ) 

LOAEL = 6000 ppm in males (462 mg/kg bw /day) and 1200 ppm 

in females (77.59 mg/kg bw/day) based on reduced body weight 

gain. 

NOAEL = 1200 ppm in males (76 mg/kg bw/day) and 240 ppm in 

females (16.82 mg/kg bw/day). 

870.3100 

3-month oral toxicity 

study - mice 

42050501,(1991) 

Acceptable/Guideline 

0, 20 500 or 2500 ppm 

(M: 0, 2.7, 65, or 352, 

F: 0, 3.4, 85, 434 

mg/kg/day) Two additional 

male groups at 850, 1450 

ppm (112, 194 mg/kg/day) 

LOAEL = 500 ppm (65 mg/kg/day) in males and 2500 ppm (434 

mg/kg/day) in females based on increase in absolute and relative 

liver weights and histopathological changes (hypertrophy, necrosis). 

NOAEL is 20 ppm in males (2.7 mg/kg/day) and 500 ppm in 

females (85 mg/kg/day). 

870.3100 

3-month oral - male 

mice 

42050502 (1991) 

Acceptable/Guideline 

0, 20, 500, 850, 1450 ,2500 

ppm 

(0, 2.7, 65, 112, 194, 352 

mg/kg/day 

LOAEL = 500 ppm (65 mg/kg/day), based on increase in absolute 

and relative liver weights and histopathological liver lesions 

(hypertrophy, necrosis, vacuolation) seen at 4, 8 and 13 weeks 

sacrifices. The NOAEL is 20 ppm (2.7 mg/kg/day) 

870.3100 

3-month oral - male 

mice. 

45215801 (1997) 

Supplement to MRID 

42050502: Reexamination 

of liver 

Confirms findings in MRID 42050502. No change to NOAEL or 

LOAEL 

870.3150 

3-month dog (dietary) 

00058607(1979) 

Acceptable/Guideline 

0, 50, 250 or 1250 ppm 

(0, 1.25, 6.25, 31.25 

mg/kg/day) 

LOAEL is 250 ppm (59 mg/kg/day) based on the finding of 

lymphoid follicles in the mucous membrane of the pyloric part of 

the stomach. 

NOAEL is 50 ppm (13mg/kg/day) 
Page 47 of 64 

Table A.3 Subchronic, Chronic and Other Toxicity Profile: Propiconazole 

Guideline No./ Study 

Type 

MRID No. (year)/ 

Classification /Doses 

Results 

870.3200 

21 - Day dermal 

toxicity - rabbits 

00116591 (1982) 

Acceptable/Guideline 

0, 3, 30 or 300 mg/kg/day 

LOAEL: 3 mg/kg/day based on mild dermal irritation 

(Hyperkeratosis, acanthosis, mild dilation of blood vessels and 

mononuclear cells and/or heterophils in the proximal dermis). No 

systemic toxicity was reported. 

NOAEL for skin lesions not established 

870.3700a 

Developmental 

Toxicity- Rat 

40425001(1987) 

Acceptable/guideline 

0, 30, 90 or 300 mg/kg/day 

Maternal Toxicity LOAEL = 300 mg/kg/day based on severe 

clinical toxicity (ataxia, coma, lethargy, prostation, labored 

respiration and salivation) 

NOAEL = 90 mg/kg/day 

Developmental Toxicity LOAEL = 90 mg/kg/day based on 

increased incidence of rudimentary ribs, cleft palate malformations 

(0.3%) unossified sternebrae, as well as increased incidence of 

shortened and absent renal papillae. 

NOAEL = 30 mg/kg/day 

Non-guideline 

Developmental 

Toxicity- Rat 

40425002 (1987) 

Acceptable/non-guideline 

0 or 300 mg/kg/day 

cleft palate: 2/2064 fetuses of dosed animals vs. 0/1222 controls 

(lab.hist. control incidence: was 0/5431). This confirms findings of 

cleft palate noted in above study. 

Severe clinical toxicity in the treated animals (ataxia, coma, 

lethargy, prostation, labored respiration and salivation) 

870.3700b 

Developmental 

Toxicity- Rabbit 

40425004 (1986) 

Acceptable/guideline 

 0, 100, 250 or 400 

mg/kg/day 

Maternal Toxicity LOAEL = 250 mg/kg/day based on reduced dam 

body weight gain and decreased food consumption during the 

dosing period 

NOAEL = 100 mg/kg/day 

Developmental Toxicity 

LOAEL = 400 mg/kg/day based on increased incidence of fetuses 

/litters with 13thrib and increased abortions. 

NOAEL = 250 mg/kg/day 

870.3800 

2-Generation 

reproduction- Rat 

00151514 (1985) 

Acceptable/guideline 

0, 100. 500 or 2500 ppm 

Parental Toxicity LOAEL = 500 ppm (42 mg/kg/day) based on 

increased incidence of hepatic clear cell change 

NOAEL = 8 mg/kg/day 

Reproductive Toxicity 

LOAEL =>2500 ppm (>263 mg/kg/day, HDT) 

Offspring Toxicity 

LOAEL = 2500 ppm (192-263 mg/kg/day based on decreased 

offspring survival and body weights and an increased incidence of 

hepatic cellular swelling 

NOAEL = 500 ppm (43-52 mg/kg/day) 

870.4100 

12-Month Chronic 

Oral Toxicity 

(dietary) - Dogs 

00151515 (1985) 

Acceptable/guideline 

0, 5, 50 or 250 ppm 

(0, 0.12, 1.25, or 6.25 

mg/kg/day) 

LOAEL = 250 ppm (6.25 mg/kg/day), based on hyperemia of the 

stomach in males (indicating mild irritation of the mucosa). 

NOAEL is 50 ppm (1.25 mg/kg/day) 
Page 48 of 64 

Table A.3 Subchronic, Chronic and Other Toxicity Profile: Propiconazole 

Guideline No./ Study 

Type 

MRID No. (year)/ 

Classification /Doses 

Results 

870.4100 

24-Month 

Chronic/Carcinogenic

ity Feeding-Rats 

00129918 (1982) 

Acceptable/guideline 

0, 100, 500 or 2500 ppm 

 (male 3.6, 18.1 and 96.4 , 

female 4.6, 23.3 and 100.6 

mg/kg/day) 

 LOAEL = 2500 ppm (96.4 mg/kg/day) based on liver lesions 

(vacuolation of hepatocytes in males, ballooned cells in the liver of 

males, foci of enlarged hepatocytes in females, and increased 

incidence of luminal dilation of the uterus) and reduced body 

weight gain in both males and females. NOAEL = 500 ppm (18.1 

mg/kg/day). The test material was not carcinogenic at the doses 

tested. 

870.4200 

24-Month 

Carcinogenicity in 

Mice 

00129570 (1982 ) 

Acceptable/guideline 

0, 100, 500 or 2500 ppm 

(M: 10.0, 49.4, and 344.3 

F: 10.8, 55.6 and 340.3 

mg/kg/day 

LOAEL = 500 ppm (49.5 mg/kg/day) based on non-neoplastic liver 

effects (increased liver weight in males and increase in liver lesions 

(masses/raised areas/ swellings/nodular areas mainly)). The 

NOAEL was 100 ppm (10 mg/kg/day). 

Liver tumors at 2500 ppm in male mice. 

870.4200 

18 - month 

oncogenicity study - 

male CD-1 mice 

44381401 (1997) 

Acceptable/guideline 

0, 100, 500 or 850 ppm 

(0, 11, 59 or 108 

mg/kg/day) 

LOAEL= 500 ppm (59.0 mg/kg/day) for males, based on 

hepatotoxicity (increased liver weight, hepatocellular hypertrophy, 

liver necrosis) and body weight gain effects observed at the interim 

and terminal sacrifices. 

NOAEL= 100 ppm (11.0 mg/kg/day) for males. 

Treatment related increase in hepatocellular adenoma and total 

hepatocellular neoplasia at the 850 ppm exposure level compared to 

concurrent controls, but were within the range of the inadequate 

historical control data submitted with the study report. Adequate 

dosing based on body weight gain and hepatotoxic effects seen at 

500 and 850 ppm. Subsequently, the Registrant submitted 

additional control data on five groups of CD-1 male mice generated 

within the approximate time frame of the original study and in the 

same testing facility under similar experimental conditions (MRID 

45215804) concerning the spontaneous occurrence of liver tumors. 

The tumor incidence observed in male livers at the 850 ppm dose is 

within the range of the new historical data. 

870.6200 

Acute neurotoxicity 

in rats 

46604601 (2005) 

Acceptable/guideline 

0, 30, 100 or 300 mg/kg by 

gavage 

LOAEL = 100 mg/kg based on clinical signs of toxicity 

(piloerection, diarrhea, tiptoe gait). 

NOAEL = 30 mg/kg. 

LOAEL for neurobehavioral toxicity = 300 mg/kg based on reduced 

motor activity. 

NOAEL for neurobehavioral toxicity = 100 mg/kg 

870-5100 

Bacterial reverse 

mutation 

00058601 (1979) 

Unacceptable 

25-2025 g/plate 

Negative in Salmonella strains with or without S-9 activation. Test 

material purity not specified, not tested up to cytotoxic dose. 
Page 49 of 64 

Table A.3 Subchronic, Chronic and Other Toxicity Profile: Propiconazole 

Guideline No./ Study 

Type 

MRID No. (year)/ 

Classification /Doses 

Results 

870-5300 

In vitro cell 

transformation assay 

(BALB/3T3) 

00133349 (1982) 

Acceptable/guideline 

 1.16-18.5 g/ml 

Did not cause a measurable increase in transformation of BALB/T3 

cells. Highest dose produced 25% reduction in colony forming 

ability. 

870-5385 

(bone marrow 

chromosomal 

aberration) - Chinese 

hamsters 

00058603 (1979) 

Acceptable/guideline 

0, 251, 502 or 1004 mg/kg 

Negative for induction of micronuclei in bone marrow cells at all 

levels tested. 

870-5550 

Unscheduled DNA 

synthesis in human 

fibroblasts, 

00133347 (1982) 

Acceptable/guideline 

Negative for inducing Unscheduled DNA Synthesis at 

concentrations up to and including 9.32 μg/ml. Highest dose tested 

to allow at least 25% cell viability 

870-5550 

Unscheduled DNA 

synthesis in primary 

rat hepatocytes 

00133348 (1982) 

Acceptable/guideline 

Negative for inducing Unscheduled DNA Synthesis at 

concentrations up to and including 83.5μg/ml. Highest dose tested 

to allow at least 25% cell viability 

870-5575 

Mitotic gene 

conversion assay 

(Saccharomyces 

cerevisiae) 

00133343 (1982) 

Acceptable/guideline 

10, 30, 90 or 270 g/ml 

No increase in convertants or revertants (did not induce mutation) 

with or without activation. Concentrations of 30 g/ml had 

inhibitory effect on yeast cell growth. 

870.5450 

Dominant lethal assay 

in mice 

00058602 (1979) 

Acceptable/guideline 

165 or 495 mg/kg single 

dose oral gavage, 

No evidence of dominant lethal effects was observed in the progeny 

of mice treated with propiconazole. 

870.7485 

Metabolism and 

pharmacokinetics 

(Rat) 

42403901 (1983) 

Acceptable/guideline 

male rats: single oral 

31.4 mg/kg - 14C at the 

triazole-[3,5] position 

Rapidly metabolized: 96% excreted in urine and feces (5:4 ratio) 

after 3 days. Extensively metabolized by hydroxylation, oxidation 

and conjugation. 

870.7485 

Metabolism and 

pharmacokinetics 

(Rat) 

41326701 (1989) 

Acceptable/guideline 

0.5 mg/kg oral or iv (U14C)-Phenyl label or 0.5 

mg/kg/day unlabeled for 

14 days followed with 0.5 

mg/kg labeled or single 

oral dose 50 mg/kg labeled 

Oral or iv routes resulted in similar patterns of 14C elimination 

suggesting biliary excretion. >90% of 14C excreted after 168 hours 

mostly within the 48 hrs. Females eliminated more in the urine 

than in the feces and vice versa for males in the orally dosed 

groups. No significant differences were seen in the excretion pattern 

or were seen between the low and high dose groups or the repeated 

dosing groups. Extensively metabolized (oxidative): 24 and 47 

metabolites in urine and feces, respectively. Parent (27-30% of 

AD) only detected in the urine of iv animals. 
Page 50 of 64 

Table A.3 Subchronic, Chronic and Other Toxicity Profile: Propiconazole 

Guideline No./ Study 

Type 

MRID No. (year)/ 

Classification /Doses 

Results 

870.7485 

Metabolism and 

pharmacokinetics 

(Rat) 

00074506 (1979) 

00074507 (1981) 

Acceptable/guideline 

triazole-[3,5-14C] labeled 

single oral dose of 31.4 

mg/kg or phenyl-[U-14C] 

single oral dose of 32.5 

mg/kg to male rats. 

Study focused on urinary and fecal metabolites. Similar metabolic 

profiles for the two labels suggesting that the bridge between the 

phenyl ring and the triazole ring remained intact. Metabolic 

pathway: cleavage of dioxolane ring through the oxidation of the 

propyl side chain, with subsequent dechlorination and conjugation 

and through the oxidation of the propyl side chain. Urinary and 

fecal metabolites except the presence of parent in feces. 

870.7485 

Metabolism and 

pharmacokinetics 

(Mouse) 

00164795 (1986) 

Acceptable/non-guideline 

Male and female mice fed 

in the diet for 21 days at 5, 

100 or 2500 ppm 

propiconazole followed by 

phenyl-[U-14C] single oral 

dose at corresponding 

levels. Two male rats 

given single oral dose 9.4 

mg/kg of the phenyl-[U14C]compound 

Mice pre-treated with the unlabeled CGA 64250 excreted 83-103% 

of the administered 14C radioactivity within 96 hours (mostly within 

the first 24-48 hours) in the urine and feces (mostly in urine: 1.5-

3.7x of the feces). The male rats excreted nearly equal amounts of 

the radioactivity in urine (48%) and feces (54%). Mouse urinary 

metabolites 15-30. The major metabolic pathway in mice proceeds 

via elimination of the dioxolane ring. In males this represents 30% 

of the AD whereas in the females it represents 15% of the AD. 

Mice cleaved the dioxolane ring to a greater extent (70% & and 

40% for males and females, respectively) than do male rats (30%). 

870.7600 

Dermal penetration 

(Rat) 

42415701 (1986) 

Acceptable/guideline 

Propiconazole 14C at the 

triazole-[3,5] position 

0.01, 0.1, 1.0 mg/cm2

The average dermal absorption of propiconazole over a 10 hour 

period at an exposure level of 0.01 mg/cm2

 is approximately 40% 

870-7800 

Immunotoxicity 

MRID 48799701, 2012 Waiver request denied (D401289). Data gap remains. 

Non- guideline 

Special study 

00151517 (1984) 

Acceptable 

Tumor promotion- rat 

2000 ppm dietary up to 8 

weeks 

Propiconazole caused proliferative changes, with or without 

pretreatment with an initiator (DENA;nitrosodiethylamine), in the 

rat liver similar to phenobarbital (500 ppm), a known liver tumor 

promoter. 
Page 51 of 64 

Table A.3 Subchronic, Chronic and Other Toxicity Profile: Propiconazole 

Guideline No./ Study 

Type 

MRID No. (year)/ 

Classification /Doses 

Results 

Non- guideline 

Special study 

Mechanistic studies: 

Hepatic biochemical 

parameters - Mouse 

45215803 (1998) 

Male CD-1 mice, 6/dose 

propiconazole at 0, 850 or 

2500 ppm (0, 149, 578 

mg/kg/day) for 14 days. 

Phenobarbital 850 ppm 

(145 mg/kg/day) to one 

group 

Total cytochrome P450 activity increased significantly (3-3.9x of 

the controls) at 850 ppm propiconazole. 7-ethoxyresorufin activity, 

indicative of CYP1A1 induction was increased slightly but not to 

the extent observed following true induction. Lauric acid 

hydroxylation, specifically a result of peroxisome proliferation, was 

not induced by propiconazole. However, the activity of 7-

pentoxyresorufin-O-dealkylase, associated with CYP2B or PB-type 

induction, was clearly increased 30-55-fold by propiconazole. 

Microsomal coumarin 7-hydroxylase, associated with enzymes 

belonging to the subfamily CYP2A was also induced by 

propiconazole treatment consistent with PB-like induction. The 

microsomal activities of epoxide hydrolase and UDPGT and the 

cytosolic activity of GST were slightly increased with 

propiconazole treatment. The pattern of microsomal and cytosolic 

enzyme induction determined biochemically was entirely consistent 

with PB-type induction. Propiconazole resulted in a marked 

increase of total testosterone oxidation. 

The results from the determination of microsomal and cytosolic 

enzyme activities, testosterone hydroxylation, and immunoblot 

analyses show that propiconazole is not a 3-MC or mixed type 

inducer, but causes a pure PB-type induction of cytochrome P450 

activity. 

The effects of propiconazole treatment on mouse liver weights and 

liver enzymes were comparable to those produced by phenobarbital, 

a known liver enzyme inducer and liver tumor promoter. The 

authors concluded that propiconazole can thus be considered a 

strong phenobarbital-type inducer of xenobiotic metabolizing 

enzymes in the mouse. 
Page 52 of 64 

Table A.3 Subchronic, Chronic and Other Toxicity Profile: Propiconazole 

Guideline No./ Study 

Type 

MRID No. (year)/ 

Classification /Doses 

Results 

Non- guideline 

Special study 

Mechanistic studies: 

Hepatocellular 

proliferation - Mouse 

45215802 (1999) 

Male CD-1 mice 40/dose 

 propiconazole at 0, 850 or 

2500 ppm (0, 127, 353 

mg/kg/day) for up to 60 

days. A group of 40 mice 

given 850 ppm PB. Five 

mice/group were sacrificed 

on days 1, 2, 3, 4, 7, 28, or 

60 (IP injection of 100 

mg/kg BrdU two hours 

prior to sacrifice) 

Test material and Phenobarbital (PB) induced a dose- related 

increase in absolute and relative liver weights. All mice developed 

hepatocellular hypertrophy (primarily in the centrilobular 

hepatocytes with mild effects in the midzonal hepatocytes). Liver 

necrosis and cytoplasmic vacuolation were noted. Increased mitotic 

activity was observed in all groups. Minimal to moderate 

hepatocellular nerosis of hypertrophic single or focal cells was 

found predominately in the high dose and PB group. Treatment 

with propiconazole or PB induced a >1000% increase in BrdUstaining hepatocellular nuclei within 24 hours from the start of the 

study that peaked at a >3600% increase by 48 hours. Thereafter, 

the number of BrdU-stained nuclei decreased dramatically and was 

not biologically different from controls 7 days after the start and 

through the remainder of the study. For all treatment groups, the 

BrdU-staining nuclei were found primarily in the 

centrilobular/midzonal portions of the liver. These data support the 

conclusion that propiconazole induced an initial time- and doserelated proliferation in the liver followed by a sustained treatmentrelated hypertrophy in a manner similar to the known hypertrophic 

agent PB. The hepatomegaly was attributed to a sharp and transient 

induction of hepatocellular proliferation as well as to a time- and 

dose-related increase in the severity of hepatocellular hypertrophy. 

A.3 Toxicological Endpoints 

A.3.1 Acute Reference Dose (aRfD) - Females age 13-49 

 Selected Study: Developmental Toxicity in Rats (MRID 40425001). 

 See Section 3.2.2 and Appendix C. 

 Dose and Endpoint for Establishing an aRfD: 30 mg/kg/day - Developmental NOAEL of 

30 mg/kg/day and a LOAEL of 90 mg/kg/day based on increased incidence of rudimentary ribs, 

unossified sternebrae, as well as increased incidence of shortened and absent renal papillae and 

increased cleft palate. 

Uncertainty Factor (UF): 100 – 10X for interspecies extrapolation and 10X for 

intraspecies variation. 

Comments about Study/Endpoint: The developmental effects of concern are presumed to 

occur after a single exposure and are relevant to females aged 13-50 years old since they occur in 

utero and to young children based on post-natal effects. 
Page 53 of 64 

A.3.2

Acute 

Referen

ce Dose (aRfD) - General Population 

 Selected Study: Acute Neurotoxicity in Rats (MRID 46046401). 

 See Section 3.2.1 and Appendix C. 

 Dose and Endpoint for Establishing an aRfD: 30 mg/kg/day - NOAEL of 30 mg/kg/day 

and a LOAEL of 100 mg/kg/day based on clinical signs of toxicity (i.e., piloerection in one male, 

diarrhea in one female, tip toe gait in 3 females). 

Uncertainty Factor (UF): 100 – 10X for interspecies extrapolation and 10X for 

intraspecies variation. 

Comments about Study/Endpoint: The effects of concern are presumed to occur after a 

single exposure. 

 

A.3.3 Chronic Reference Dose (cRfD) - All Populations 

Selected Study: 24 Month Oncogenicity Study in Mice (MRIDs 00129570 & 93194037) 

 Oncogenicity Mouse Study - A 24-month propiconazole dietary oncogenicity study in 

CD-1 mice was conducted at doses of 0, 100, 500 or 2500 ppm (M: 10.0, 49.4, and 344.3 F: 

10.8, 55.6 and 340.3 mg/kg/day selected by the HIARC for deriving the chronic RfD. Nonneoplastic liver effects (increased liver weight in males and increase in liver lesions: 

masses/raised areas/ swellings/nodular areas mainly) were observed at 50 mg/kg/day. (See 

Appendix B) 

Dose and Endpoint for Establishing a cRfD: 10 mg/kg/day - NOAEL of 10 mg/kg/day 

and a LOAEL of 50 mg/kg/day based on non-neoplastic liver effects. 

Uncertainty Factor (UF): 100 – 10X for interspecies extrapolation and 10X for 

intraspecies variation. 

Comments about Study/Endpoint: The lower NOAEL of 2.7 mg/kg/day in a 3-month 

oral feeding toxicity study in mice was not selected because a) there is a wide dose spread 

 Acute RfD = 30 mg/kg (NOAEL) = 0.30 mg/kg/day 

 (Females 13-49) 100 (UF)

 Acute RfD = 30 mg/kg (NOAEL) =0.3 mg/kg/day 

 (General Population) 100 (UF)
Page 54 of 64 

between the NOAEL (2.7 mg/kg/day) and the LOAEL (65 mg/kg/day) in that study, b) the 

LOAEL (50 mg/kg/day) in the selected study is lower than the LOAEL (65 mg/kg/day) of the 3-

month mouse oral feeding study, and c) the liver toxicity seen in the 2 year mouse study is 

consistent with that seen in an 18-month mice and 2-generation reproduction studies. In an 18-

month oncogenicity study in mice, the NOAEL for liver toxicity was 11 mg/kg/day and the 

LOAEL 59 mg/kg/day). In a 24-month feeding study in rats, the NOAEL for liver toxicity was 

18 mg/kg/day and the LOAEL 96 mg/kg/day). In 2-generation reproduction study in rats, the 

NOAEL for liver toxicity was 8 mg/kg/day and the LOAEL 42 mg/kg/day). The dog study was 

not selected since stomach irritations were attributed to local effects and not systemic toxicity, 

and target organ (liver) toxicity seen in mice and rats was not seen in dogs. 

A.3.4 Incidental Oral Exposure (Short- and Intermediate-Term) 

Incidental Oral Exposure (Short-Term) 

 Selected Study: Acute Neurotoxicity in Rats (MRID 46046401). 

 See Section 3.4.2 

Dose and Endpoint for Establishing an aRfD: 30 mg/kg/day - NOAEL of 30 mg/kg/day 

and a LOAEL of 100 mg/kg/day based on clinical signs of toxicity (piloerection in one 

male, diarrhea in one female, tip toe gait in 3 females. 

Uncertainty Factor (UF)/Level of Concern = 100 – 10X for interspecies extrapolation and 

10X for intraspecies variation. FQPA 1X 

Incidental Oral Exposure (Intermediate-Term) 

Selected Study: 24 Month Oncogenicity Study in Mice (MRIDs 00129570 & 93194037) 

See Section 3.4.3 

Dose and Endpoint for Establishing a cRfD: 10 mg/kg/day - NOAEL of 10 mg/kg/day 

and a LOAEL of 50 mg/kg/day based on non-neoplastic liver effects. 

Uncertainty Factor (UF): 100 – 10X for interspecies extrapolation and 10X for 

intraspecies variation. 

 Chronic RfD = (NOAEL) 10 mg/kg = 0.1 

 (General Population) (UF) 100
Page 55 of 64 

A.3.5 Dermal Absorption 

HIARC selected a 40% dermal absorption factor (DAF) based on the average dermal absorption 

of propiconazole over a 10 hour exposure period in rats at an exposure level of 0.01 mg/cm2 

(MRID’s 42415701, 45345901). Although another dermal absorption factor for propiconazole 

of 1% was used in a recent Section 18 risk assessment, the basis for the lower absorption factor 

was not clear. Therefore, a DAF of 40% was used for this assessment. 

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

Dermal Exposure (Short-Term)

 Selected Study: Acute Neurotoxicity in Rats (MRID 46046401). 

 See Section 3.3.1 

Dose and Endpoint NOAEL of 30 mg/kg/day and a LOAEL of 100 mg/kg/day based on 

clinical signs of toxicity (piloerection in one male, diarrhea in one female, tip toe gait in 3 

females. 

Uncertainty Factor (UF)/Level of Concern= 100 – 10X for interspecies extrapolation and 

10X for intraspecies variation. FQPA 1X 

Comments about Study/Endpoint: Since an oral NOAEL was selected for dermal risk 

assessment, a dermal absorption factor of 40% based on a dermal absorption study in rats 

should be used. Although a dermal toxicity study is available, a POD from an oral study 

was selected because neurotoxicity, the primary effect of concern for short-term exposure 

is not specifically evaluated in the available dermal toxicity studies. The selected 

endpoint is protective of potential neurotoxic effects from dermal exposure. 

Dermal Exposure (Intermediate-Term)

Selected Study: 24 Month Oncogenicity Study in Mice (MRIDs 00129570 & 93194037) 

See Section 3.4.3 

Dose and Endpoint for Establishing a cRfD: 10 mg/kg/day - NOAEL of 10 mg/kg/day 

and a LOAEL of 50 mg/kg/day based on non-neoplastic liver effects. 

Uncertainty Factor (UF): )/Level of Concern: 100 – 10X for interspecies extrapolation 

and 10X for intraspecies variation. FQPA 1X 

 

Comments about Study/Endpoint: Since an oral NOAEL was selected for dermal risk 

assessment, a dermal absorption factor of 40% based on a dermal absorption study in rats 

should be used. 
Page 56 of 64 

A.3.7 Inhalation Exposure (Short and Intermediate-Term)

Inhalation Exposure (Short-Term)

 Selected Study: Neurotoxicity in Rats (MRID 46046401). 

 See Section 3.4.2 

Dose and Endpoint: . NOAEL of 30 mg/kg/day and a LOAEL of 100 mg/kg/day based 

on clinical signs of toxicity (piloerection in one male, diarrhea in one female, tip toe gait 

in 3 females. 

Uncertainty Factor (UF)/Level of Concern: 100 – 10X for interspecies extrapolation and 

10X for intraspecies variation. FQPA 1X 

Comments about Study/Endpoint: Inhalation toxicity is assumed to be equivalent to oral 

toxicity. 

Inhalation Exposure (Intermediate-Term)

Selected Study: 24 Month Oncogenicity Study in Mice (MRIDs 00129570 & 93194037) 

See Section 3.4.3 

Dose and Endpoint 10 mg/kg/day - NOAEL of 10 mg/kg/day and a LOAEL of 50 

mg/kg/day based on non-neoplastic liver effects. 

Uncertainty Factor (UF)/Level of Concern: 100 – 10X for interspecies extrapolation and 

10X for intraspecies variation. FQPA 1X 

Comments about Study/Endpoint: Inhalation toxicity is assumed to be equivalent to oral 

toxicity. 
Page 57 of 64 

A.4 EXECUTIVE SUMMARIES 

870.3200 Dermal Toxicity 

In a repeated dose dermal toxicity study (MRID 00116591 and 93194034), groups of 20 New 

Zealand rabbits received 15 daily dermal applications of 0 (11 males and 9 females), 3 (11 males 

and 9 females), 30 (10 males and 10 females), or 300 (13 males and 7 females) mg/kg/day 

propiconazole technical(90.7%, Batch No. FL-810858) over a 21-day period. The test material 

was applied on the intact and abraded skin with an impervious cuff for 6 hours for five days a 

week for three weeks. There were no treatment-related deaths or signs of systemic toxicity and 

no treatment-related effects on body weight, food consumption, or opthalmology, hematological 

and clinical chemistry parameters. One high dose female rabbit died on day 3 following 

diarrhea, decreased activity and body tone. A male rabbit in the low dose group died on day 23, 

the day of necropsy. Both deaths were not considered compound-related. Diarrhea was observed 

in one control female, 2 males and 2 females in the low dose group, and 3 males and 1 female in 

the mid dose group. Skin irritations were noted in the 30 and 1000 mg/kg/day groups beginning 

at day 2 and persisted for the remainder of the study with maximum irritation indexes of 1.0 and 

4.1, respectively. Signs of irritation were noted in the 3.0 mg/kg/day group beginning on day 15 

in males only with the highest irritation index of 0.3 at day 19. There were no compound related 

gross necropsy, organ weight effects or histopathological findings. There were mild to moderate 

skin lesions which were dose related in treated animals compared to controls. Hyperkeratosis, 

acanthosis, mild dilation of blood vessels and mononuclear cells and/or heterophils in the 

proximal dermis were noted in a dose related manner. The LOAEL for systemic effects was 

>1000 mg/kg/day (the highest dose tested). The NOAEL for systemic effects is 1000 

mg/kg/day. The LOAEL for skin effects was 3 mg/kg/day based on mild dermal irritation 

(Hyperkeratosis, acanthosis, mild dilation of blood vessels and mononuclear cells and/or 

heterophils in the proximal dermis) at 3 and 30 mg/kg/day and moderate dermal irritation at 1000 

mg/kg/day. No NOAEL for skin lesions was established. 

870.3700 Developmental Toxicity 

Rat Developmental Toxicity - Study 1 

In an acceptable/guideline developmental toxicity study (MRID 40425001), CGA 64250 

technical(92.1% purity propiconazole, Batch no. FL 850083) was administered to 24 CL:COBS 

CD (SD) BR VAF/PLUS virgin female rats/dose by oral gavage in aqueous suspensions (3% 

corn starch containing 0.5% Tween 80) at dose levels of 0, 30, 90 or 300 mg/kg/day from days 6 

through 16 of gestation. High dose animals initially received 360 mg/kg/day up to five days, but 

because of severe symptoms it was reduced to 300 mg/kg/day. Severe compound-related 

maternal toxicity was observed at the high dose level during the first five days of dosing 

beginning on day 8 of gestation at 360 mg/kg/day. These included statistically significant 

increases in the incidence of lethargy, ataxia, salivation, and biologically significant increases in 

rales, prostration, hypothermia and bradypnea. The incidence of these effects versus control is as 

follows: lethargy (9/23 vs. 0/24 in controls), salivation (4/23 vs. 0/24 in controls) and ataxia 
Page 58 of 64 

(3/23 vs. 0/24 in controls). After lowering the dose to 300 mg/kg/day on day 6, the severity and 

frequency of these effects decreased rapidly. At the lower doses with the exception of one animal 

of the 90 mg/kg/day group exhibiting rales, there were no treatment related clinical observations. 

Mean food consumption was significantly reduced (p<0.05) in the 300 mg/kg/day group on days 

7-8, 8-9 and 9-10 and in the 90 mg/kg/day group on days 8-9 and 10-11. Maternal body weights 

were not affected by the treatments. Maternal body weight gains were significantly decreased 

(p<0.05) in the 90 mg/kg/day group (44% of controls) and in the high dose group (38% of 

controls) during gestation days 6-8 only. This effect was considered to be temporary and not 

treatment related. No significant treatment-related effects on uterine weights, corpora lutea, live 

and dead fetuses, fetal weights, and resorption were reported. The maternal toxicity LOAEL 

of propiconazole is 300 mg/kg/day, based on severe clinical toxicity. The maternal toxicity 

NOAEL is 90 mg/kg/day. Fetotoxic effects observed included a high incidence of rudimentary 

ribs, though not statistically significant but part of dose related trend (0.7%, 3% and 39% in the 

30, 90 and 300 mg/kg/day groups, respectively vs. 0% in the controls), a high incidence of unossified sternebrae (57%, p< 0.05 in the 90 mg group, and 72%, p< 0.01 in the 300 mg group vs. 

38% in the controls), as well as increased incidence of shortened renal papillae (26% in the 90 

mg group (not statistically significant) and 39% in the 300 mg group, p < 0.01 vs. 23% in the 

controls) and absent renal papillae ( 5% in the 90 mg group (not statistically significant) and 11% 

in the 300 mg group, p < 0.01 vs. 3% in the controls) and dilated ureter ( 43% in the 300 mg 

group, p < 0.01 vs. 27% in the controls). External and visceral examination revealed a very low 

incidence of cleft plate malformations in the 90 mg group (0.3%) and in the 300 mg group 

(0.7%) and considered to be “probably compound related”. Historical controls in 19 teratology 

studies from this laboratory had no incidence of cleft palate. The cleft palate incidence in the 

current study was probably under reported because only half of the fetuses were examined 

viscerally. It was also concluded that the low incidence of this finding along with skeletal 

anomalies was indicative of delayed development. The cleft palate finding at 300 mg/kg/day 

was also confirmed in a separate study (MRID 40425002) where propiconazole was 

administered to pregnant rats at 0 or 300 mg/kg/day during the gestation period. The 

developmental toxicity LOAEL of propiconazole is 90 mg/kg/day, based on increased 

incidence of rudimentary ribs, un-ossified sternebrae, as well as increased incidence of 

shortened and absent renal papillae and increased cleft palate. The developmental toxicity 

NOAEL is 30 mg/kg/day.

Rat Developmental Toxicity - Study 2

In an acceptable/non-guideline developmental toxicity study (MRID 40425002), CGA 64250 

technical (92.1% purity, Batch No. FL 850083) was administered to CL:COBS CD (SD) BR 

VAF/PLUS virgin female rats by oral gavage in aqueous suspensions (3% corn starch containing 

0.5% Tween 80) at dose levels of 0 or 300 mg/kg/day from days 6 through 15 of gestation. The 

control group comprised 178 sperm positive animals and the compound treated group comprised 

189 sperm positive animals. The study was intended to confirm the finding of cleft palate in the 

previous study (MRID 40425001). The death of two dams from the treated group was 

considered incidental. Severe maternal toxicity was observed during the treatment period 

beginning on gestation day 6 and included a statistically significant increase in the incidence of 

ataxia (42% vs. 0 in controls), coma (9% vs. 0 in controls), lethargy (44% vs. 0 in controls), 
Page 59 of 64 

prostration (3% vs. 0 in controls), audible respiration (4% vs. 0 in controls), labored respiration 

(11% vs. 0 in controls), and salivation (20% vs. 0 in controls) in addition to a biologically 

significant incidence of ptosis (0.5% vs. 0 in controls), lacrimation (2% vs. 0 in controls), pale 

color (2% vs. 0 in controls) and death (1% vs. 0 in controls). Mean food consumption was 

significantly lower (60-92% of the control values, p<0.05) in the treated group during the dosing 

period. Body weight gains were significantly lower (68% of controls, p<0.05) in dosed animals 

during GD 6-16. There were no significant differences between dosed and control animals with 

respect to fetal sex ratio or mean number of corpora lutea, implantation sites and dead fetuses. 

The mean number of live fetuses was significantly (95% of controls, p<0.05) lower in dosed 

animals, due to lower mean implantation sites, and higher mean total resorption in the dosed 

animals, although not significantly different from controls. Mean fetal weights for both males 

and females (95% of controls, p<0.001) were significantly lower in dosed animals. Fetuses were 

examined for external abnormalities only and there were no statistically significant treatmentrelated, external gross observations among fetuses. Cleft palate was reported in 2/2064 fetuses 

of dosed animals and 0/1222 of control fetuses. The incidence of cleft palate in controls for all 

teratology studies (not including this one) conducted at this laboratory during 1983-1985 was 

0/5431. This study confirms the findings of cleft palate in the previous guideline study (MRID 

40425001). 

Rabbit Developmental Toxicity 

In a developmental toxicity study (MRID 00265796), CGA 64250 technical (92.1% purity 

propiconazole) was administered to groups (19/group) of artificially inseminated New Zealand 

white rabbits by oral gavage in aqueous suspensions (3% corn starch containing 0.5% Tween 80) 

at dose levels of 0, 100, 250 or 400 mg/kg/day from days 7 through 19 of gestation. One animal 

from each of the mid-dose groups was found dead. In high-dose animals, 5/19 does were 

sacrificed early due to abortion or early delivery (statistically significant, p<0.05 compared to 

control 1/19). In the mid dose (250 mg/kg/day) group, one doe aborted early. One control 

animal delivered early. Among animals of the high dose group, an increased incidence of stool 

alterations (decreased/no/soft; 18/19 vs. 11/19 in controls, p<0.05) was observed, possibly 

compound related. During the dosing period (days 7-19), the high and mid dose animals had a 

significant (p<0.05) decrease in food intake (43 - 63% of the controls and 58-78% of the controls 

in the high- and mid-dose groups, respectively) and a severe decrease in the maternal body 

weight gain, but rebounded to normal after withdrawal of the test compound. During GD 7-10, 

the maternal animals had a weight loss of 0.047 and 0.111 kg at 250 and 400 mg/kg, 

respectively, compared to a weight gain of 0.018 kg in controls. The weight gains during GD 

10-20 were 67-77% and 11-43% of controls at 250 and 400 mg/kg/day, respectively. An 

increased incidence of the formation of 13th rib was observed at 400 mg/kg/day. The incidence of 

this finding on fetuses/litter basis was 2.7, 3.9, 4.1 and 5.3 at 0, 100, 250 and 400 mg/kg/day, 

respectively. The incidence of fetuses at 400 mg/kg/day with this finding was statistically 

significant. Therefore, this finding was considered to be treatment-related. The increase in the 

number of resorptions at 400 mg/kg/day was caused by the resorption of an entire litter. At 400 

mg/kg/day there was also an increased incidence of abortions. The maternal toxicity LOAEL 

of propiconazole in the rabbit is 250 mg/kg/day, based on reduced maternal body weight 

gains and decreased food consumption during the dosing period. The maternal toxicity 
Page 60 of 64 

NOAEL is 100 mg/kg/day. The developmental toxicity LOAEL was 400 mg/kg/day based 

on increased incidence of fetuses/litters with 13th rib and increased abortions. The 

developmental toxicity NOAEL was 250 mg/kg/day. 

870.7600 Dermal Absorption Studies 

In a dermal absorption study (MRID’s 42415701, 45345901), groups (4/group) of young adult 

male, Harlan Sprague-Dawley rats (age not given) were exposed to triazole-[3,5-]14C- CGA64250 (95% radiochemical purity, specific activity 28.2 mCi/mg for low and mid-dose levels and 

2.01 mCi/mg for the high-dose level) at doses of 0.1, 1.0 or 10 mg/rat (0.01, 0.1 or 1 mg/cm2, 

respectively) to a 10 cm2 shaven dorso-lumbar area. The radioactive test compound was added to 

the 3.6EC formulated product (45.8% active ingredient and 54.2% inert substances) and applied 

as an aqueous suspension. One group of four rats/dose were exposed for 24 hours, while two 

other groups of four rats each/dose were exposed for 10 or 24 hours followed by a 72-hour 

depletion phase. This study is an addendum to an earlier study where groups of four male rats 

each were treated similarly but exposed for 2, 4 or 10 hours (MRID 00164469). In both studies, 

following the exposure period, the test compound remaining on the skin was removed with a 

soap rinse. Fecal and urinary samples were collected at the end of the exposure periods and at 24 

hour intervals (for the depletion groups) following the exposure. 

At sacrifice time rats were anesthetized and blood collected. The radioactivity present in excreta, 

blood, carcass, skin, skin washes and patch components were determined. The applied 

radioactivity was accounted for, with recoveries ranging from 82.8 to 108 % for MRID 

42415701 and 86.6 to 112.6% for MRID 00164469. 

The amount of test compound absorbed was directly proportional to the applied dose. The rate 

of absorption appeared to be saturated at the highest dose level; at the low dose level, there was a 

time dependent increase in the amount of compound absorbed. After 24 hours, 57.1, 271 and 

3010 μg/cm2

 (57.13, 27.14 and 30.10% of total dose were absorbed at the low, mid and high 

dose levels, respectively). During the 72-hour depletion phase essentially all of the compound 

was eliminated in the urine and feces; urinary elimination predominated at the mid and high dose 

levels. At the end of the 72 hour depletion phase, less than 2% of the test compound was still 

present in the carcass. The results of the earlier study (MRID 00164469) demonstrated that 26-

35% of the applied radioactivity (at all dose levels) is absorbed within the first two hours and 

remained fairly constant for the longer exposure periods of 4 and 8 hours except for the low dose 

of 0.01 mg/cm2

 where it increased to 54%. The average dermal absorption of propiconazole 

over a 10 hour period at an exposure level of 0.01 mg/cm2

 is approximately 40%. The attached 

appendix provides a summary of both studies.

870.3800 Reproduction 

Rat Reproduction Study 

In an acceptable/guideline 2-generation reproduction study (MRID 00151514), CGA 64250 

technical (89.7% purity propiconazole, FL-830377) was administered to 15 male and 30 female 
Page 61 of 64 

Charles river CD rats at dose levels of 0, 100, 500 or 2500 ppm (mean doses of 8, 42 and 192 

mg/kg/day for F0 males, 9.4, 43, 223 mg/kg/day for F0 females, 9.2, 48, 238 mg/kg/day for F1 

males and 10, 52, 263 mg/kg/day for F1 females) in the diet. Test diets were administered to 

both F0 and F1 generation rats during pre-mating period and throughout gestation and lactation 

periods. Parental Toxicity: No compound-related clinical observations or mortality were 

reported. Female body weights in the F0 and F1 generation were significantly reduced in the high 

dose group at most of the body weight intervals(82-94% of the controls, p<0.05 and 0.01); body 

weight gains were also significantly reduced during pre-mating (12 weeks)as well as gestation 

and lactation periods(77-85% of controls, p<0.01). Correspondingly, high dose females also had 

significantly reduced food intake (83-88% of controls). In the F0 and F1 generation male body 

weights were reduced in the high dose groups compared to controls (not statistically significant); 

body weight gains in this group was 91-94% of controls for the pre-mating period and during the 

entire duration of the study (7 months). Food consumption was reduced significantly in high 

dose F0 males at week 1 (65% of the control, p<0.01) and week 7 (86% of the control, p<0.01) 

and in high dose F1 males and females at week 2, 6 and 10 (84-88% of controls). Histological 

examinations revealed that hepatic “cellular swelling” was significantly increased in mid-dose 

males and high-dose males and females of the F0 generation. In the F1 parental animals, increase 

in the incidence of this finding was significant for both sexes in the mid- and high-dose groups. 

The incidence of “hepatic clear-cell change” was significantly increased in F0 high-dose males, 

F1 mid-dose and high-dose males and F1 high-dose females (p<0.05). The LOAEL for 

parental toxicity is 500 ppm (42 mg/kg/day) based on increased hepatic clear-cell change 

and the NOAEL for parental toxicity is 100 ppm (8 mg/kg/day). Reproductive parameters 

(mating, fecundity, gestation, male and female fertility indices, litter resorptions and gestation 

duration) were comparable in all groups. Offspring Toxicity: The number and percent of viable 

pups at birth and surviving through weaning were comparable between the dose groups and 

controls for both the F1a and F1b litters. In the F2a litters, however, the number of pups delivered, 

delivered viable and surviving to day 4 of lactation were significantly (p<0.01) reduced in the 

high-dose group. The percentages of high-dose pups delivered viable and surviving to day 4 

were also reduced (not statistically significant). The F2b litters of these dams had significantly 

reduced survival rates (both number and percent of surviving pups) at lactation days 7, 14, and 

21. The mean body weights of high-dose progeny were significantly reduced at days 14 and 21 

for pups of both generations (72-81% of controls). Reductions were also significant on days 4 

and 7 (except for F1b litters) and at birth (F2b litters only). At necropsy, no treatment related 

anomalies, organ weight changes and gross pathology findings were noted in pups. 

Histopathological evaluation of selected organs from F1b and F2b progeny revealed significantly 

(p<0.01) increased incidences of hepatic “cellular swelling” in high-dose males and females. 

This was considered to be a compound related effect. The LOAEL and NOAEL for offspring 

toxicity are at 2500 ppm (192-263 mg/kg/day) and 500 ppm (43-52 mg/kg/day), respectively, 

based on decreased offspring survival and body weights and an increased incidence of 

hepatic lesions (cellular swelling) at 2500 ppm. 

Additional Developmental/Reproduction Toxicity Information from Literature Sources

In a published study, propiconazole (Tilt 100 EC in the form of 10% solution) was administered 

to groups of pregnant female albino rats (15/dose) at 0, 75.85 or 151.70 mg (ai)/kg/day on days 
Page 62 of 64 

6-15 of gestation (Hassan, 1993. Embryotoxic and teratogenic effects of the organic fungicide 

tilt in albino rats. Bull. Fac. Pharm., Cairo University 31(3): 459-463). Rats were sacrificed on 

day 20 of gestation. Post-implantation deaths, resorption sites and dead fetuses were counted. 

Fetuses were examined for morphological, visceral and skeletal malformations. Propiconazole 

was fetotoxic at both doses causing significant (p<0.05) increased fetal resorptions (8 and 21% at 

the low and high dose vs. 0% in the control), increased fetal deaths (10 and 24% at the low and 

high doses vs. 2% in the control) and decreased fetal weight). The mean number of stunted 

fetuses was significantly higher (p<0.05) at both doses (1.43 and 3.57) at the low and high dose 

vs. 0.13 in the control), noting incomplete ossification of the skull, caudal vertebrae and digits, 

extra rib (14th rib) and missing sternebrae. Malformations of the lung and kidneys were reported. 

No maternal toxicity was reported at either dose. The LOAEL for developmental toxicity in 

this study is 76 mg/kg/day (the lowest dose tested). A NOAEL is not established. 

870.6200b Subchronic Neurotoxicity 

Waived by HASPOC TXR 0056387 

870.5100, 870-5300 Mutagenicity 

Propiconazole was negative in six acceptable mutagenicity studies: 

1. In vitro cell transformation assay (MRID 00133349) 

2. Bone Marrow Chromosomal Aberration (MRID 00058603) 

3. Mutagenicity: Unscheduled DNA synthesis (MRID 00133347) 

 4. Mutagenicity: Unscheduled DNA synthesis (MRID 00133348) 

 5. Mitotic Gene Conversion Assay (MRID 00133343) 

 6. Dominant Lethal Assay in Mice (MRID 00058602) 

870.7800 Immunotoxicity

CropLife America (CLA) has made available the results of a retrospective analysis on 78 

immunotoxicity studies submitted to the Agency which suggests that immunotoxicity studies 

have not provided Points of Departure (PoD) lower than other guideline studies. OPP is also 

conducting an independent retrospective analysis of more than 160 immunotoxicity studies 

submitted to Agency. Preliminary findings of OPP’s retrospective analysis also suggest that 

immunotoxicity studies have not yet provided lower PoDs than are selected from other guideline 

experimental toxicology studies and thus, so far, immunotoxicity studies would not have 

impacted the Agency’s risk assessments. The OPP retrospective analysis is anticipated to be 

completed in the summer of 2012. In the interim,OPPinterim, OPP recommends that the 

immunotoxicity continue to be required for registration and registration review chemicals. 

The complete toxicity profile for propiconazole is provided in Appendix A. 
Page 63 of 64 

APPENDIX B. Chemical Names And Structures Of Metabolites 

* N

HC

=

=

CH

N

N CH2 

 C

Cl

Cl

O O

CH2 CH 

 

CH2 CH CH3 

 

OH

 

N

HC

=

=

CH

N

N CH2 

 C

Cl

Cl

O O

CH2 CH 

 

CH2 CH2 

 OH

 

N

HC

=

=

CH

N

N CH2 

 C

Cl

Cl

O O

CH2 CH 

 

COOH 

CH2 

 C

Cl

Cl

O O

CH2 CH 

 

CH2 COOH 

N

HC

=

=

CH

N

N N

HC

=

=

CH

N

N CH2 

 C

Cl

Cl 

O

 

N

HC

=

=

CH

N

N CH2 

 CH

Cl

Cl 

OH

Cl

Cl HOOC

N

HC

=

=

CH

N

N CH2 

 C

Cl

Cl

O O

CH2 CH 

 

CH2 CH2 CH3 

 

CGA 64250 CGA 118244

CGA 118245 CGA 217495

CGA 217496 CGA 91304

CGA 91305 CGA 177291

APPENDIX: REFERENCE COMPOUNDS
Page 64 of 64 

APPENDIX C. Physical/Chemical Properties 

Table 3. Physicochemical Properties of Technical Grade Propiconazole. 

Parameter Value Reference

Boiling point 120 C at 1.9 Pa, >250 C at 101.325 kPa MRID No. 43698701 

pH 4.9 at 25 C (1% aqueous dispersion) MRID No. 43698701 

Density 1.289 g/cm3 at 20 C MRID No. 43698701 

Water solubility 0.10 g/L at 20 C MRID No. 41720301 

Solvent solubility (temperature not specified) 

Completely miscible in ethanol, acetone, 

toluene and n-octanol. hexane = 47 g/L MRID No. 42030201 

Vapor pressure 4.2 x 10-7 mm Hg at 25 C MRID No. 41720301 

Dissociation constant (pKa) 1.09 MRID No. 43698701 

Octanol/water partition coefficient Log(KOW) 3.72 at pH 6.6 and 25 C MRID No. 43698701 

UV/visible absorption spectrum (8max, nm) Not available MRID No. 40583703 

APPENDIX D. Studies Reviewed for Ethical Conduct 

This risk assessment relies in part on data from studies in which adult human subjects were intentionally 

exposed to a pesticide or other chemical. These studies were determined to require a review of their ethical 

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

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

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

Chemicals Association, released February, 1995. 

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

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