UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION 

MEMORANDUM 

December 2, 2015 

SUBJECT: Propiconazole Human Health Risk Assessment for the New Use of 

Propiconazole on Imported Tea. 

PC Code: 122101 

Decision No.: 493436 

Petition No.:4£8300 

Risk Assessment T 

TXRNo.: NA 

MRID No.: NA 

DP Barcode:426896 

Re istration No.: I 00-6 17 

Regulatory Action: Tolerance, No US 

Reoistration 

Case No.: 3125 

CAS No.: 60207-90-1 

FROM: Thurston G. Morton, Chemist ... r, OL., '1 O' ~IA.. 

Kelly O'Rourke, Biologist · ~ j ' _ 

Abdallah Khasawinah, PhD., Toxicologist p~ Risk Assessment Branch 4 

Health Effects Division (7509P) 

THROUGH: Elissa Reaves, Ph.D., Chief 

Risk Assessment Branch 4, HE 

TO: Tamue Gibson/Shaja Joyner, RM20 

Fungicide Branch 

Registration Division (7505P) 

This document provides the Health Effects Division's (HEO's) risk assessment for the new use 

of propiconazole on imported tea. 

Page 1 of53 
1.0 EXECUTIVE SUMMARY ................................................................................................ 4 

2.0 HED RECOMMENDATIONS .......................................................................................... 8 

2.1 Data Deficiencies/Conditions of Registration ................................................................ 8 

2.2 Tolerance Considerations ............................................................................................... 8 

2.2.1 Enforcement Analytical Method ............................................................................. 8 

2.2.2 International Harmonization ................................................................................... 8 

2.2.3 Recommended Tolerances ........................................................................................ 8 

2.2.4 Revisions to Petitioned-For Tolerances .................................................................. 9 

2.3 Label Recommendations ................................................................................................. 9 

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

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

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

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

3.3.1 Proposed New Uses ................................................................................................. l 0 

3.4 Anticipated Exposure Path,vays ................................................................................... 10 

3.5 Considerations of Environmental Justice .................................................................... 11 

4.0 HAZARD CHARACTERIZATION/ASSESSMENT ................................................... 11 

4.1 Toxicology Studies Available for Analysis .................................................................. 11 

4.2 Absorption, Distribution, Metabolism and Excretion ................................................ 12 

4.3 Toxicological Effects ...................................................................................................... 12 

4.4 Safety Factor for Infants and Children (FQPA Safety Factor) ................................. 13 

4.4.1 Completeness of the Toxicology Database ............................................................ 13 

4.4.2 Evidence of Neurotoxicity ...................................................................................... 13 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal.. .... 14 

4.4.4 Residual Uncertainty in the Exposure Database .................................................. 14 

4.5 Toxicity Endpoint and Point of Departure .................................................................. 14 

4.5.1 Dose-Response Assessment .................................................................................... 14 

4.5.2 Recommendations for Combining Exposure Routes ........................................... 16 

4.5.3 Classification of Carcinogenic Potential ............................................................... 16 

4.5.4 Summary of Points of Departure Used in Risk Assessment ............................... 16 

5.0 DIETARY AND DRINKING WATER EXPOSURE AND RISKASSESSMENT .... 19 

Page 2 of 53 
Page 3 of 53

5.1 Metabolite/Degradate Residue Profile......................................................................... 19

5.1.1 Summary of Plant and Livestock Metabolism Studies........................................ 19

5.1.2 Comparison of Metabolic Pathways...................................................................... 19

5.1.3 Environmental Fate and Transport ...................................................................... 20

5.1.4 Residues of Concern Summary and Rationale..................................................... 20

5.2 Food Residue Profile ..................................................................................................... 21

5.2.1 Residues in Crops.................................................................................................... 21

5.3 Water Residue Profile ................................................................................................... 22

5.3.1 Estimated Drinking Water Concentrations.......................................................... 22

5.4.1 Acute Dietary and Drinking Water Analysis ....................................................... 23

5.4.2 Chronic Dietary and Drinking Water Analysis ................................................... 24

6.0 RESIDENTIAL EXPOSURE AND RISK ASSESSMENT .......................................... 25

6.1 Residential Bystander Postapplication Inhalation Exposure .................................... 27

6.2 Spray Drift...................................................................................................................... 27

7.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT............................................ 28

7.1 Acute & Chronic Aggregate Risk................................................................................. 28

7.2 Short- and Intermediate-Term Aggregate Risk ......................................................... 28

7.3 Intermediate-Term Aggregate Risk............................................................................. 30

8.0 CUMULATIVE RISK...................................................................................................... 30

9.0 OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION.............................. 31

10. REFERENCES.................................................................................................................. 31

A TOXICOLOGY DATA SUMMARY.............................................................................. 32

A.1 Guideline Data Requirements................................................................................ 32

A.3 Toxicological Endpoints............................................................................................. 39

A.4 EXECUTIVE SUMMARIES .................................................................................... 44

APPENDIX B. Chemical Names And Structures Of Metabolites......................................... 52

APPENDIX C. Physical/Chemical Properties.......................................................................... 53

APPENDIX D. Studies Reviewed for Ethical Conduct.......................................................... 53
Page 4 of 53

1.0 EXECUTIVE SUMMARY

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

the proposed new use of propiconazole on imported tea. A tolerance of 4.0 ppm for 

propiconazole residues in/on tea is proposed, but no registration is being proposed in the U. S. It

also assesses potential enhanced sensitivity of infants and children from dietary and/or residential 

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

Use Profile

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. Propiconazole 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

Tea Association of the USA, Inc. (TAUSA) has submitted a request for a new use of 

propiconazole for use on tea imported into the United States. A tolerance of 4.0 ppm for 

propiconazole residues in/on tea is proposed, but no registration is being proposed in the U. S. 

The use rate is 100 gr a.i./ha with a 7 day pre-harvest interval (PHI).

The toxicology database for propiconazole is complete 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. There are mixed effects 

in the developmental and reproduction rat studies. In a rat developmental study, fetal effects 

were observed at doses lower than doses at which maternal effects were seen thereby 

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 rat 

offspring to propiconazole. Propiconazole does not appear to be neurotoxic based on an acute 
Page 5 of 53

and subchronic neurotoxicity studies. 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

A new risk assessment was conducted for dietary (food and water) only. No updated 

occupational exposure assessment was required since the requested use is for imported tea. For 

the current registration action, there are no new residential uses and, therefore, residential risk 

was not assessed for this new use. However, for the aggregate assessment, the existing 

registered residential use that previously resulted in the greatest short-term exposure was utilized 

(i.e., post-application activity on treated turf). 

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 8 % 

of the cPAD, and the most highly exposed subgroup (Children 1-2 yrs old) is 24 % of the cPAD. 

A dietary exposure assessment for the free triazole or conjugated triazoles was also recently 

updated. 
Page 6 of 53

Aggregate risks from propiconazole are not of concern. For adults, the short-term residential 

dermal MOE estimated from post-application activity on treated turf, when aggregated with 

dietary exposure, is 200, which does not fall below the LOC of 100 and is therefore not of 

concern. For children, the aggregated MOE (incidental oral + dermal + dietary) MOE was 96

[note that while this falls below HED’s LOC of 100, this assessment is considered very 

conservative in that the residential incidental oral post-application exposure was calculated by 

combining screening level assessments (which by themselves already have conservative 

estimates)]. The only scenario that is expected to result in potential intermediate-term exposure 

to propiconazole is post-application exposure to children from wood treatment, which is from an 

antimicrobial use. The aggregate risk (dietary + residential exposure) for intermediate-term 

exposure to Children 1-2 years old yields an MOE of 110, which does not fall below the level of 

concern of 100 and, therefore, this scenario is not of concern.

An occupational exposure assessment is not required for imported tea.

Aggregate Assessment of Free Triazole & its Conjugates

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

conjugates. The previous aggregate human health risk assessment was updated for free triazoles 

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

D426493, 4/9/15). 

Use of Human Studies

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

intentionally exposed to a pesticide or other chemical. These data, which include [studies from 

PHED 1.1; the AHETF database; the Outdoor Residential Exposure Task Force (ORETF) 

database; and the ARTF database], are (1) subject to ethics review pursuant to 40 CFR 26, (2) 

have received that review, and (3) are compliant with applicable ethics requirements. 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.archives.gov/federal-register/executive-orders/pdf/12898.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 
Page 7 of 53

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. 

Tolerance Recommendation

There are no residue chemistry issues that would preclude granting a tolerance on imported tea. 

The proposed US tolerance for tea of 4.0 ppm is adequate to cover this new use.

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.

A new section to be added to [40 CFR §180.434 as [40 CFR §180.434(a)(2) for the tolerance 

expression for parent only.

Following is the appropriate tolerance expression:

Propiconazole; tolerances for residues

(a) General. 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 propiconazole, 1-

[[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2-yl]methyl]-1H-1,2,4-triazole, in or on the 

commodity.

The Codex Alimentarius Commission has established a 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. Canada has an MRL for tea at 4 ppm. There is no Codex MRL for tea. The U.S. is

harmonized on the MRL level for Canada. 
Page 8 of 53

2.0 HED RECOMMENDATIONS

2.1 Data Deficiencies/Conditions of Registration

HED can recommend for registration for the proposed new use of propiconazole. 

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 a 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. Canada has an MRL for tea at 4 ppm. There are no Codex MRL for tea. The U.S. is

harmonized on the MRL level for Canada. 

2.2.3 Recommended Tolerances

There are no residue chemistry issues that would preclude granting a tolerance for propiconazole

on imported tea. Available data support the proposed tolerance under 40 CFR 180.434 for 

residues of propiconazole in/on the following raw agricultural commodities:

Tea ............................................................................................................ 4.0 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.
Page 9 of 53

A new section to be added to [40 CFR §180.434 as [40 CFR §180.434(a)(2) for the tolerance 

expression for parent only.

Following is the appropriate tolerance expression:

Propiconazole; tolerances for residues

(a) General. 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 propiconazole, 1-

[[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2-yl]methyl]-1H-1,2,4-triazole, in or on the 

commodity. 

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

supporting the proposed tolerance for imported tea. 

2.2.4 Revisions to Petitioned-For Tolerances

None

2.3 Label Recommendations

None

3.0 INGREDIENT PROFILE

3.1 Chemical Identity

Structure and nomenclature are reported in Table 3.1.

Table 3.1. 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 

N

N N

O

O

Cl

Cl
Page 10 of 53

3.2 Physical/Chemical Characteristics

The physicochemical properties of propiconazole are reported in Appendix C. 

3.3 Pesticide Use Pattern

3.3.1 Proposed New Uses

Propiconazole is proposed for Tilt (EPA Reg. # 100-617) for use on imported tea (Table3.3.1). 

3.4 Anticipated Exposure Pathways

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

proposed new use of propiconazole on imported tea. For the existing 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 no residential uses associated with the 

proposed use on imported tea, however, the aggregate exposure was updated. An occupational 

exposure assessment is not required for imported tea.

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 

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

exposure assessment.

Table 3.3.1. Label Directions for Proposed New Use of the Propiconazole Product

Product EPA Reg. No. Use 

Site Target Application Methods

Maximum 

Application 

Rate

(lb ai/100 gal)

PHI

(day)

REI

(hr)

Use Directions/ 

Limitations

Tilt® 

Fungicide

EPA Reg. No. 

100-617 Tea

High volume 

spray, foliar 

sprays during 

active 

vegetative 

growth stage

Foliar 100 gr a.i/ha 7 NA
Page 11 of 53

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.archives.gov/federal-register/executive-orders/pdf/12898.pdf). As a part of 

every pesticide risk assessment, OPP considers a large variety of consumer subgroups according 

to well-established procedures. In line with OPP policy, HED estimates risks to population 

subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water 

consumption, and activities in and around the home that involve pesticide use in a residential 

setting. Extensive data on food consumption patterns are compiled by the U.S. Department of 

Agriculture’s (USDA’s) National Health and Nutrition Examination Survey/What We Eat in 

America, (NHANES/WWEIA), are used in pesticide risk assessments for all registered food uses 

of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the 

year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary 

exposure to smaller, specialized subgroups and exposure assessments are performed when 

conditions or circumstances warrant. Whenever appropriate, non-dietary exposures based on 

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

and adults entering or playing on treated areas 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 complete for evaluating and characterizing 

propiconazole toxicity and selecting endpoints for purposes of this risk assessment

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 and subchronic neurotoxicity, metabolism, mutagenicity screens 

and mechanistic studies (3).
Page 12 of 53

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 (U14C)-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 (U14C)-phenyl and 14C-triazole ring labeled propiconazole studies, the percentages 

of 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 (U14C)-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 sternebrae 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. 
Page 13 of 53

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. 

Propiconazole has low to moderate acute 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 available in the database with clinical toxicity at the high dose only with no 

microscopic changes. A subchronic neurotoxicity study in rats demonstrated no neurotoxic 

effects (clinical or pathological) at the highest dose tested. 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 complete 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). However, the 

registrant provided later an acceptable/guideline SCN study.

4.4.2 Evidence of Neurotoxicity

An acute neurotoxicity study is available for propiconazole. In this study, a 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 
Page 14 of 53

toe gate, staining around the nose). Limited clinical 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 but only at the high dose (300 mg/kg) with no 

microscopic changes to the nervous tissues. Based on weight of evidence (WOE) the subchronic 

neurotoxicity is waived (HASPOC, TXR 0056387). Although the HASPOC waived the 

subchronic neurotoxicity (HASPOC, TXR 0056387), the registrant later submitted an 

acceptable/guideline SCN study in rats. In this study, propiconazole was not neurotoxic at the 

highest dose tested of 3500 ppm (equivalent to 222 mg/kg bw/day). Both the ACN and the SCN 

studies demonstrated that propiconazole is not neurotoxic at the doses tested. Additionally, 

neurotoxic and neurobehavioral effects were not seen in the propiconazole toxicity database. The 

liver is the primary target organ of propiconazole toxicity, and decreased body weight is the most 

sensitive endpoint in repeated-dose studies.

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

The toxicology database for propiconazole is complete 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 

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 and non-dietary risk 

assessments are 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. 
Page 15 of 53

An acute POD of 30 mg/kg (NOAEL) 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 carcinogenicity 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) of0.1 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. The selected toxicity endpoint was the most sensitive to assess this exposure 

scenario. The NOAELs in the developmental rat (90 mg/kg/day) and rabbit (100 mg/kg/day) 

studies were much higher and would not be protective of the toxicity seen in the ACN study. An 

MOE of 100 is applied to account for the intra- and inter-species variation. Incidental oral 

intermediate term exposure was assessed using a POD (NOAEL) of 10 mg/kg/day from an 

carcinogenicity 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 carcinogenicity mouse study described above. An MOE of 100 is required for the shortand 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 carcinogenicity mouse study described above. An MOE of 100 is required for the 

short- and intermediate-term scenarios for inhalation exposure. This includes 10X for 

interspecies extrapolation and 10X for intraspecies variation.
Page 16 of 53

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 

(TXR No. 0009771, 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 4.5.4.1and 4.5.4.2.
Page 17 of 53

Table 4.5.4.1. 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 carcinogenicity study on CD-1 mice.

MRID 00129918

LOAEL = 50 mg/kg/day based on nonneoplastic 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, TXR No. 

0009771

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
Page 18 of 53

Table 4.5.4.2. 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 (1-30 

days)

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

(1-6 months)

NOAEL= 10 

mg/kg/day 

UFA= 10X

UFH=10X

Residential LOC 

for MOE = 100

Occupational 

LOC for MOE = 

100

24 Month carcinogenicity Study - Mice MRID 

00129918

LOAEL = 50 mg/kg/day based on nonneoplastic 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).

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 carcinogenicity Study - Mice MRID 

00129918

LOAEL = 50 mg/kg/day based on nonneoplastic 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

UFA= 10X

UFH=10X

Occupational 

LOC for MOE = 

100

24 Month carcinogenicity Study - Mice MRID 

00129918

LOAEL = 50 mg/kg/day based on nonneoplastic 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, TXR No. 

0009771

DAF = Dermal Absorption Factor 
Page 19 of 53

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. 

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 updated

separately (HED memo of 10/24/13, T. Morton, D414951). 

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 (U14C)-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 
Page 20 of 53

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 did not provide a drinking water assessment for 

the imported tea use. It was determined the previously assessed turf use resulted in the 

maximum EDWCs. 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.

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 5.1.4. Detailed rationale for these conclusions were 

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

Table 5.1.4. 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.
Page 21 of 53

5.2 Food Residue Profile

5.2.1 Residues in Crops

Reference:Propiconazole. New Use of Propiconazole on Imported Tea. Summary of Analytical Chemistry and 

Residue Data. T. Morton, D422887, 12/1/2015

Supervised trials were carried out in India in 2006-2007 to generate data on residues of 

propiconazole in made tea. In all three trials, one foliar spray application of propiconazole at 

either 100 g a.i./ha (1x Indian rate) or 200 g a.i./ha was made to tea plants. Samples were 

collected at PHIs 0-14 days. Supervised trials were carried out in Sri Lanka in 2006-2008 to 

generate data on residues of propiconazole in made tea. In all five trials, one foliar spray 

application of propiconazole at 21 g a.i./ha (1x Sri Lankan rate) was made to tea plants. Samples 

were collected at PHIs of 0 and 6-7 days. In the decline trials, the leaf samples were collected on 

Day 0 (prior to spraying), Day 1 (2 hours after spraying), and Days 3, 5, 7, 10, 14 and 21. 

Results from the field trials in India showed that, following one application of propiconazole (EC 

formulation; 250 g/L) at a rate of 100 g a.i./ha, residues were 0.42-1.8 ppm in/on black tea 

samples harvested at a PHI of 7 days.

Results from the field trials in Sri Lanka showed that, following one application of propiconazole 

(EC formulation; 250 g/L) at a rate of 21 g a.i./ha, residues were <0.01-1.1 ppm in/on black tea 

samples harvested at a PHI of 6-7 days.

The results from these studies are discussed in the appropriate data evaluation report (DER) and 

summarized in the following table. 

Table 5.2.1. Summary of Residues from Tea Trials with Propiconazole.

Matrix Appl. Rate

(g a.i./ha)

PHI

(days) n

Residues (ppm)

Min. # Max. # LAFT* HAFT* Median* Mean* SD*

INDIA (PMRA# 1955332)

Black tea

(Made tea) 100 7 3 0.42 1.8 0.42 1.66 0.64 0.907 0.662

SRI LANKA (PMRA# 2065596)

Black tea

(Made tea) 21 6-7 8 <0.01 1.1 <0.01 1.1 0.089 0.261 0.374

# Values based on total number of samples.

* Values based on per-trial averages. LAFT = Lowest Average Field Trial, HAFT = Highest Average Field Trial, SD = Standard Deviation. For computation 

of the LAFT, HAFT, median, mean and standard deviation, values < LOQ are assumed to be at the LOQ.
Page 22 of 53

5.3 Water Residue Profile

5.3.1 Estimated Drinking Water Concentrations

The drinking water residues used in the dietary risk assessment were provided by the 

Environmental Fate and Effects Division (EFED) in the following memorandum, “Drinking 

Water Exposure Assessment for the petition (1F7892) that proposes tolerances for residues of 

propiconazole on sugarcane (I. Abdel-Saheb, 09/26/12, D396031, D396034),” and incorporated 

directly into this dietary assessment. In the case of 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). The 

proposed new use does not result in higher EDWCs than those estimated for turf uses. Water 

residues were directly incorporated in the DEEM-FCID into the food categories “water, direct, 

all sources” and “water, indirect, all sources.” 

The estimated surface water drinking water concentrations for propiconazole are: 

64.1ug /L for the 1 in 10 year annual peak concentration (acute) 

24.8ug /L for the 1 in 10 year annual mean concentration (non-cancer chronic) and 

The highest estimates from surface water (acute, 64.1 ppb and chronic, 24.8 ppb) are directly 

entered into the exposure model to assess the contributions from drinking water. 

Drinking Water Data for Free Triazoles

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

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

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

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

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

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

summarized in Table 5.3.1. 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. 

Table 5.3.1. 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 23 of 53

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-FCID, 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 noncancer chronic exposures, HED is concerned when estimated dietary risk exceeds 100% of the 

PAD. 

Reference: Propiconazole: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk 

Assessments for the New Use of Propiconazole on Imported Tea. T. Morton, D426895, 12/1/2015

5.4.1 Acute Dietary and Drinking Water Analysis

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

results in dietary risk estimates below HED’s level of concern; see Table 5.4.1.1. The most highly 

exposed subgroup is children 1-2 years resulting in 85% of the aPAD. 

Table 5.4.1.1. Results of Acute Dietary Exposure Analysis for Food and Drinking Water for 

Propiconazole

Population Subgroup aPAD (mg/kg/day)

95th Percentile

Exposure (mg/kg/day) % aPAD

General U.S. Population

0.3

0.078158 26

All Infants (< 1 year old) 0.108192 36

Children 1-2 years old 0.254748 85

Children 3-5 years old 0.194251 65

Children 6-12 years old 0.106047 35

Youth 13-19 years old 0.073973 25

Adults 20-49 years old 0.061394 20

Adults 50-99 years old 0.051211 17

Females 13-49 years old 0.061027 20
Page 24 of 53

Dietary Assessment of Free Triazole and its Conjugates

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

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

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

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

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

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

recently updated. Addition of this new use of propiconazole did not significantly change the 

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

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

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

Triazole Metabolites.

Population Subgroup

Acute Dietary

(95th Percentile) Chronic Dietary Cancer

Dietary 

Exposure 

(mg/kg/day)

% aPAD*

Dietary 

Exposure

(mg/kg/day)

% cPAD*

Dietary 

Exposure

(mg/kg/day)

Risk

1,2,4-Triazole

General U.S. Population 0.007869 26 0.001150 23

Not 

Applicable

Not 

Applicable

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

Children 1-2 years old 0.019569 65 0.003321 66

Children 3-5 years old 0.016613 55 0.002646 53

Children 6-12 years old 0.009615 32 0.001431 29

Youth 13-19 years old 0.006804 23 0.000922 18

Adults 20-49 years old 0.006350 21 0.000979 20

Adults 50-99 years old 0.005587 19 0.000927 19

Females 13-49 years old 0.006416 21 0.000942 19

Triazolylalanine + Triazolylacetic Acid+Triazolylpyruvic acid

General U.S. Population

Not 

Applicable

Not 

Applicable

0.015819 18

Not 

Applicable

Not 

Applicable

All Infants (< 1 year old) 0.021523 24

Children 1-2 years old 0.050635 56

Children 3-5 years old 0.040816 45

Children 6-12 years old 0.021357 24

Youth 13-19 years old 0.013174 15

Adults 20-49 years old 0.012901 14

Adults 50-99 years old 0.012185 14

Females 13-49 years old 0.073349 73 0.012373 14

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

5.4.2 Chronic Dietary and Drinking Water Analysis

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

results in dietary risk estimates below HED’s level of concern; see Table 5.4.2.
Page 25 of 53

Table 5.4.2. Results of Chronic Dietary Exposure Analysis for Food and Drinking Water for 

Propiconazole

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

General U.S. Population

0.1

0.007703 7.7

All Infants (< 1 year old) 0.010526 11

Children 1-2 years old 0.024051 24

Children 3-5 years old 0.019424 19

Children 6-12 years old 0.010141 10

Youth 13-19 years old 0.006213 6.2

Adults 20-49 years old 0.006449 6.4

Adults 50-99 years old 0.005932 5.9

Females 13-49 years old 0.005890 5.9

6.0 RESIDENTIAL EXPOSURE AND RISK ASSESSMENT

There are no proposed residential uses associated with this action; however, there are existing 

residential uses that have been reassessed in a previous document (D403629, J. Miller, 

11/15/2012) to reflect updates to HED’s 2012 Residential SOPs 

(http://www.epa.gov/pesticides/science/residential-exposure-sop.html), along with policy 

changes for body weight assumptions. The revised Total MOEs (dermal + inhalation) for 

residential handler and post-application exposure did not fall below the LOC of 100, and 

therefore, are not of concern. Handler and Post-application estimated risks are presented in 

Tables 6.1 and 6.2, respectively.
Page 26 of 53

Table 6.1. 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 3.2 x 107 9,100

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)

Exposure Science Advisory Council Policy #9.1.

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 gallons/day) x DAF (40%)/BW (80 kg).

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

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 (A or gallons/day) /BW (kg).

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 27 of 53

Table 6.2: 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

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 
Page 28 of 53

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.

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 previously 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.

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

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

4/9/15).

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). The highest exposure 

scenarios are from post-application exposure associated with residential use on turf, which were 

used in the short-term aggregate risk assessment. 

Table 7.2.1aggregates the short-term risk for toddlers from incidental oral, dermal, and food and 

water (as a background). The short-term aggregate risk MOE of 96 exceeds HED’s level of 

concern (LOC=100). This assessment is considered conservative since the short-term endpoints 

are based on a conservative LOAEL that is 3x higher than the NOAEL. Therefore, the true 

NOAEL is likely higher and would result in MOEs greater than 100. Further, the assessment is 
Page 29 of 53

based on a combination of tolerance-level residues and reliable data on average field-trial 

residues and 100 PCT, conservative assumptions in the ground and surface water modeling, and 

conservative assumptions to assess post-application exposure of children as well as incidental 

oral exposure of toddlers. Additionally, the assessment could be further refined by using PCT 

estimates and anticipated residues for all crops. Although dietary (food and water) is not the 

aggregate exposure driver, incorporating percent crop treated would likely increase the aggregate 

MOE further above 100. For example, the Agency’s latest PCT figures indicate that the highest 

average PCT reported for propiconazole residues on crops is 55%, which is much less than the 

100 PCT the Agency used for all commodities in its assessment. Accordingly, even though this 

MOE for children 1-2 years old is slightly below the target MOE of 100, the difference is small 

and is more than offset by the conservative exposure assumptions and therefore not of concern.

Table 7.2.1. Short-term Aggregate Risk Estimates to Propiconazole for 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 0.024051

30

1200 2

Hand to Mouth Activity on Turf 96

100 1

Oral 0.0269 21003

Turf –High-Contact Activities Dermal 0.2827 1104

1 Target MOE= 100, Acute Neurotoxicity 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)].

Table 7.2.2 aggregates the short-term risk for adults from residential post-application, and 

average food and water (as a background). The aggregate MOE is 200, which does not fall 

below HED’s LOC, and therefore is not of concern. 

Table 7.2.2: 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 0.0063

30

4800 2

200 Residential Post-application 

(Residential Turf Gen. HighContact Activities))100 1 Dermal 0.143 2103

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)].
Page 30 of 53

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 7.3 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.

Table 7.3. Intermediate -term Aggregate Risk Estimates to Propiconazole for 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 0.0239 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 carcinogenicity 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 high-end 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 

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

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

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

Nut, Tree, Group 14-12.; and Use of Flutriafol on Hops. DP426493, T. Morton, 4/9/15.

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 
Page 31 of 53

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

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

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

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

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

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

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

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

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

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

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). Based on the completeness 

of the database, the Agency reduced the FQPA safety factor to 1X . The assessment includes 

evaluations of risks for various subgroups, including those comprised of infants and children. 

The Agency’s complete risk assessment is found in the propiconazole reregistration docket at 

http://www.regulations.gov, Docket Identification (ID) Number EPA-HQ-OPP-2005-0497.

9.0 OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION

This submission was for a use of propiconazole in imported tea, therefore, no occupational 

exposure assessment was performed.

10. REFERENCES

Propiconazole. New Use of Propiconazole on Imported Tea. Summary of Analytical Chemistry and Residue Data.

T. Morton, D422887, 12/1/2015

Propiconazole: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments 

for the New Use of Propiconazole on Imported Tea., T. Morton, D426895, 12/1/2015

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. 
Page 32 of 53

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 carcinogenicity (rat) ......................................................

870.4200b carcinogenicity (mouse)................................................

870.4300 Chronic/carcinogenicity ................................................

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

yes

no

-

-

yes

yes

-

870.7485 General Metabolism......................................................

870.7600 Dermal Penetration........................................................

870.7800 Immunotoxicity .............................................................

yes

no

no**

yes

-

-

* waived per HASPOC TXR 0056387

** waived per HASPOC TXR 0056761 and TXR 0056730.
Page 33 of 53

A.2 Toxicity Profiles

Table A.2: Propiconazole Acute Toxicity Profile

GuidelineNo. 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. 

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 34 of 53

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 35 of 53

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 

carcinogenicity 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
Page 36 of 53

Table A.3 Subchronic, Chronic and Other Toxicity Profile: Propiconazole

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870.6200b 

90-Day Neurotoxicity

Screening Battery 

(rat)

49300503 (2014)

Acceptable/guideline

♂ 0, 200, 600, or 3500 ppm 

0,13, 38, and 222 mg/kg 

bw/day, 

♀ 0, 200, 600, or 1500 ppm 

0, 15, 45, and 111 mg/kg 

bw/day, 

LOAEL in males = 3500 (220 mg/kg/day) based on significant 

reductions in body weight gain and food consumption

NOAEL in males = 600 ppm (38 mg/kg/day).

NOAEL in females = 1500 ppm (111/kg/day), the highest dose 

tested.

LOAEL in females was not established.

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.
Page 37 of 53

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)

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.

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-[U14C] 

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-[U14C] 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/cm2is approximately 40%

870-7800

Immunotoxicity

MRID 48799701, 2012

Waiver Request

waived (TXR 0056761 and TXR 0056730)..

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 38 of 53

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 39 of 53

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 necrosis 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 40 of 53

A.3.2 Acute Reference 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. 

aRfD (General Population) =

30 mg/kg (NOAEL)

100 (UF)

= 0.3 mg/kg

A.3.3 Chronic Reference Dose (cRfD) - All Populations

Selected Study: 24 Month carcinogenicity Study in Mice (MRIDs 00129570 & 

93194037)

Carcinogenicity Mouse Study - A 24-month propiconazole dietary carcinogenicity 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.

 Acute RfD = 30 mg/kg(NOAEL) = 0.30 mg/kg/

 (Females 13-49) 100(UF)
Page 41 of 53

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 

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 carcinogenicity 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.

cRfD (General Population) =

10 mg/kg/day (NOAEL)

100 (UF)

= 0.1 mg/kg/day

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.

Comments about Study/Endpoint: The selected toxicity endpoint was the most sensitive 

to assess this exposure scenario. The NOAELs in the developmental rat (90 mg/kg/day) 

and rabbit (100 mg/kg/day) studies were much higher and would not be protective of the 

toxicity seen in the ACN study. 

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 carcinogenicity 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. 
Page 42 of 53

Uncertainty Factor (UF): 100 – 10X for interspecies extrapolation and 10X for 

intraspecies variation.

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 with no systemic toxicity at 

300 mg/kg/day (propiconazole caused dermal irritation at 3 mg/kg/day and above dose), a 

POD from an oral study was selected because clinical toxicity, the primary effect of 

concern for short-term exposure is not specifically evaluated in the available dermal 

toxicity study. The selected endpoint is protective of potential clinical effects from 

dermal exposure. 

Dermal Exposure (Intermediate-Term)

Selected Study: 24 Month carcinogenicity 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 
Page 43 of 53

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. 

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 carcinogenicity 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 44 of 53

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 
Page 45 of 53

follows: lethargy (9/23 vs. 0/24 in controls), salivation (4/23 vs. 0/24 in controls) and ataxia 

(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 palate 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 
Page 46 of 53

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), 

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 
Page 47 of 53

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 

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 cm2shaven 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/cm2is approximately 40%. The attached 

appendix provides a summary of both studies.
Page 48 of 53

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 

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, 
Page 49 of 53

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 

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

In a subchronic neurotoxicity study (MRID 49300503), Propiconazole (95.2% a.i.) was 

administered to groups of ~6-week-old Crl-CD(SD) rats (12/sex/dose) continuously in the diet 

for 13 weeks at concentrations of 0, 200, 600, or 1500 ppm (females) or 3500 ppm (males) 

(equivalent to 0,13, 38, and 222 mg/kg bw/day, respectively, in males and 0, 15, 45, and 111 

mg/kg bw/day, respectively, in females). Dietary levels were chosen based on the findings of a 

4-week dietary range-finding neurotoxicity study (MRID 49300502). Neurobehavioral 

assessment (functional observational battery (FOB) and motor activity testing) was performed in 

12 animals/sex/group during pretest (Week -1) and Weeks 1, 3, 7, and 12. Cholinesterase 

activity was not determined. At study termination, 5 rats/sex/group were euthanized and 

perfused in situ for neuropathological examination. Of the perfused animals, 5 rats/sex each 

from the control and high-dose groups were subjected to histopathological evaluation of brain 

and peripheral nervous system tissues. 

Males at 3500 ppm had a statistically significant decrease in mean body weight gain over Days 

1-7 (83% of controls) accompanied by a reduction in food consumption (88% of controls). 

Although not statistically significant, overall body weight gain in high-dose males was reduced 

to 89% of controls, indicating that the male rats fed the high dose were not able to completely 

recover from the reduction in body weight that occurred during the first week of treatment. No 

significant changes in body weight, body weight gain, or food consumption were noted in 

females. 

Dietary treatment with up 3500 ppm in male rats and 1500 ppm in female rats did not result in 
Page 50 of 53

any signs of neurotoxicity as indicated by clinical observations, mortality, FOB observations, 

motor activity counts, or neurohistopathological evaluation, and no treatment-related effects 

were noted during ophthalmoscopic examination, gross pathology or in brain weight and brain 

dimension measurements. Positive control data were provided.

Based on the effects seen in this study, the LOAEL for Sprague-Dawley male rats was 3500 

ppm (equivalent to 222 mg/kg bw/day) based on significant reductions in body weight gain 

and food consumption, with a NOAEL of 600 ppm (equivalent to 38 mg/kg bw/day). The 

NOAEL in female Sprague-Dawley rats was 1500 ppm (equivalent to 111 mg/kg bw/day) 

and a LOAEL was not established.

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

Propiconazole is one of the conazoles that were reviewed as a class by the Hazard and Science

Policy Council (HASPOC) for the immunotoxicity test requirements (TXR 0056730). A waiver

was recommended for an immunotoxicity study for the class of conazole pesticides based on the

following considerations:

• There was no evidence of adverse effects on the immune system in mice, rats, or dogs in

the data base for any of the conazole pesticides.

• The liver, not the immune system, is generally the target organ for this chemical class,

and hepatotoxicity or body weight changes are the primary toxicological endpoints of

concern and were used in risk assessments.

• The conazoles do not belong to a class of chemicals (e.g., the organotins, heavy metals,

or halogenated aromatic hydrocarbons) that would be expected to be immunotoxic.

There was no evidence of immunotoxicity with six other structurally-related conazole

fungicides, namely, flutriafol, metconazole, tebuconazole, tetraconazole, triadimefon,

triflumizole, and triticonazole. In the Immunotoxicity study for triflumizole, the effects

on the immune system occurred only at the highest dose tested. Immunotoxicity was

demonstrated with difenoconazole, however it was observed in the presence of systemic

toxicity and at a relatively high dose.

PODs based on the most sensitive endpoints obtained via the appropriate routes of exposure in

the most sensitive species are currently used for dietary and non-dietary risk assessments.
Page 51 of 53

All these factors indicate that an immunotoxicity study would most likely not result in an adverse

effect that could be used as an endpoint for conazole risk assessment.

Based on a weight of evidence approach, the HASPOC concluded that immunotoxicity studies

are not required as this time for propiconazole (TXR 0056730). An immunotoxicity study is not

anticipated to provide a lower POD or result in a more sensitive endpoint than those already

used. Therefore the waiver request is granted (TXR 0056761).
Page 52 of 53

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 53 of 53

APPENDIX C. Physical/Chemical Properties

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/cm3at 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 (max, 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.