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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

March 9, 2011 

SUBJECT: Revised Propiconazole Human Health Risk Assessment for a Section 3 

Registration on Mint, Bulb Vegetables, Caneberry Subgroup 13-07A, Bushberry Subgroup 13-

07B, and Low Growing Berry Subgroup 13-07G.

PC Code: 122101 DP Barcode: 385913

Decision No.: 425825 Registration No.: 100-617

Petition No.: 9E7959 Regulatory Action: Section 3 Registration 

Risk Assessment Type: Single Chemical Aggregate Case No.: 3125

TXR No.: NA CAS No.: 60207-90-1

MRID No.: NA 40 CFR: 180.434

FROM: Becky Daiss, Biologist 

Ivan Nieves, Chemist

Jerry Stokes, Chemist

Risk Assessment Branch 4

Health Effects Division (7509P)

THROUGH: Susan V. Hummel, Branch Senior Scientist

Risk Assessment Branch 4, HED (7509P)

TO: Barbara Madden, Risk Manager 

Emergency Response Branch

Registration Division (7505P)

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

the Section 3 proposed use of propiconazole on mint, bulb vegetables, caneberry subgroup 13-

07A, bushberry subgroup 13-07B, and low growing berry subgroup 13-07G. The document has 

been revised to include an assessment of aggregate risk from residential exposures to 

propiconazole. Supporting documents are listed below. 

Occupational Exposure Assessment – I. Nieves, D, 10/19/2010

Residue Chemistry Assessment – J. Stokes, D372878, 11/3/10

Dietary and Drinking Water Exposure Assessment – B. Daiss, D375283, 11/3/10

Drinking Water Exposure Assessment – R. Miller, D380135, 7/9/10
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TABLE OF CONTENTS

 pg.

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

2.0 INGREDIENT PROFILE....................................................................................................7

2.1 Registered Products and Proposed New Uses .....................................................................7

2.2 Structure, Nomenclature and Physical/Chemical Properties...............................................7

3.0 HAZARD CHARACTERIZATION/ASSESSMENT ........................................................8

3.1 Hazard Characterization ......................................................................................................8

3.2 Absorption, Distribution, Metabolism and Excretion..........................................................9

3.3 FQPA Hazard Considerations ...........................................................................................10

3.3.1 Neurotoxicity Toxicity .........................................................................................10

3.3.2 Developmental Toxicity ........................................................................................10

3.3.3 Reproductive Toxicity ...........................................................................................11

3.3.4 Pre-and/or Postnatal Toxicity ................................................................................11

3.3.5 FQPA Factor..........................................................................................................11

3.4 Toxicity Endpoint Selection ..............................................................................................12

3.4.1 Acute Reference Dose – Females Age 13-49 .......................................................12

3.4.2 Acute Reference Dose – General Population.........................................................12

3.4.3 Chronic Reference Dose – Adult Males and Females Age 50+ ............................13

3.4.4 Incidental Oral Exposure – Short-Term.................................................................14

3.4.5 Incidental Oral Exposure – Intermediate-Term .....................................................14

3.4.6 Dermal Absorption.................................................................................................14

3.4.7 Dermal Exposure – Short-Term.............................................................................14

3.4.8 Dermal Exposure – Intermediate-Term .................................................................15

3.4.9 Inhalation Exposure – Short-Term.........................................................................15

3.4.10 Inhalation Exposure – Intermediate-Term.............................................................15

3.4.11 Classification of Carcinogenic Potential................................................................16

3.5 Margins of Exposure..........................................................................................................17

3.6 Recommendation for Aggregate Exposure........................................................................17

3.7 Summary of Endpoints Selected for Risk Assessment......................................................17

3.8 Endocrine Disruption.........................................................................................................18

4.0 PUBLIC HEALTH AND EPIDEMIOLOGY ...................................................................19

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

5.1 Residue Chemistry Profile .................................................................................................19

5.1.1 Metabolism in Primary Crops and Livestock ........................................................19

5.1.2 Metabolism in Rotational Crops............................................................................20

5.1.3 Residues of Concern ..............................................................................................20

5.1.4 Residue Analytical Methods..................................................................................20

5.1.5 Residues in Crops ..................................................................................................21

5.1.6 Residues in Processed Commodities .....................................................................21
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5.1.7 Residues in Rotational Crops.................................................................................21

5.1.8 Storage Stability.....................................................................................................22

5.2 Drinking Water Profile ......................................................................................................22

5.2.1 Environmental Fate and Transport.........................................................................22

5.2.2 Estimated Drinking Water Concentrations............................................................23

5.3 Dietary and Drinking Water Exposure and Risk ...............................................................23

6.0 RESIDENTIAL EXPOSURE AND RISK ASSESSMENT ............................................24

7.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT...............................................24

7.1 Short Term Aggregate Risk ...............................................................................................24

7.2 Intermediate Term Aggregate Risk....................................................................................26

8.0 OCCUPATIONAL EXPOSURE AND RISK...................................................................26

8.1 Occupational Exposure Scenarios......................................................................................26

8.2 Occupational Handler Exposure ........................................................................................27

8.2.1 Handler Exposure Scenarios..................................................................................27

8.2.2 Handler Exposure Data ..........................................................................................27

8.2.3 Handler Exposure Assumptions.............................................................................27

8.2.4 Handler Exposure and Risk Estimates...................................................................28

8.3 Occupational Post-Application Exposure Data and Assumptions.....................................29

8.3.1 Post-Application Exposure Scenarios....................................................................29

8.3.2 Post-Application Exposure Data ...........................................................................30

8.3.3 Post-Application Exposure Assumptions ..............................................................30

8.3.4 Post-Application Exposure and Risk Estimates.....................................................31

9.0 CUMULATIVE RISK.......................................................................................................33

10.0 DATA NEEDS...................................................................................................................32

10.1 Toxicity Data Requirements..............................................................................................32

APPENDICES

A. GUIDELINE TOXICOLOGY DATA SUMMARY.........................................................33

A.1 Guideline Data Requirements................................................................................33

A.2 Toxicity Profiles.....................................................................................................34

B. STUDIES REVIEWED FOR ETHICAL CONDUCT......................................................41

C. SUMMARIES OF KEY TOXICITY STUDIES ...............................................................43

D. REFERENCES FOR TOXICITY STUDIES ....................................................................52

E. CHEMICAL NAMES AND STRUCTURES OF METABOLITES.................................58

1.0 EXECUTIVE SUMMARY
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This assessment provides information to support an amended Section 3 registration for 

the use of propiconazole on mint, bulb vegetables, caneberry subgroup 13-07A, bushberry

subgroup 13-07B, and low growing berry subgroup 13-07G. This document addresses the 

exposures and risks associated with exposures from currently registered uses and the proposed 

new uses of propiconozole. 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. Propiconizole 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

The Interregional Research Project No. 4 (IR-4) has submitted an application for the 

registration a product containing propiconazole for use on mint, bulb vegetables, caneberry

subgroup 13-07A, bushberry subgroup 13-07B, and low growing berry subgroup 13-07G. 

Registrations exist for the representative commodities of these subgroups. The IR-4 petition 

requests expansion of the tolerance to the whole subgroup. The product is manufactured by 

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

It is an emulsifiable concentrate (EC) product containing 41.8% active ingredient (ai) per gallon 

(3.6 lb ai/gal). Pre-harvest intervals (PHIs) of 30 days are proposed for caneberry, bushberry and 

mint. A 14 day PHI is proposed for bulb onion and a 0 day PHI is proposed for green onion. 

The new product is not proposed for residential use and residential exposures are not expected 

based on the proposed uses. 

Hazard Identification

The toxicology database for propiconazole is adequate for evaluating and characterizing 
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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. Propiconazole is 

not a reproductive toxicant. In a rat developmental study, fetal effects in pups were observed at 

doses lower than doses at which maternal effects were seen providing quantitative evidence of 

increased susceptibility of fetuses to in utero exposure to propiconozole. Propiconozole does not 

appear to be neurotoxic based on an acute neurotoxicity study. The FQPA safety factor was 

reduced to 1X because residual uncertainties with regard to pre- and/or postnatal toxicity are 

minimal. 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. Immunotoxicity and subchronic neurotoxicity studies are required as 

part of new 40 CFR Part 158 requirements for registration of a pesticide. 

Dose Response Assessment

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

residential exposure scenarios. Acute and chronic Population Adjusted Doses (PADs) were 

selected for assessment of food and drinking water exposures. An acute PAD for the general 

population was selected from an acute neurotoxicity study in rats. An acute PAD for females 13-

49 was selected from a developmental toxicity study in rats. A chronic/cancer PAD for the 

general population was selected from a carcinogenicity study in mice. Short and intermediateterm occupational exposures via the dermal and inhalation routes may occur based on the use 

pattern and label directions. Toxicological endpoints for inhalation, dermal, and incidental oral

exposures were selected from the acute neurotoxicity study in rats. Since an oral study was 

selected for dermal exposure, a 40% dermal absorption factor from a dermal absorption study in 

rates is used for route to route extrapolation. An uncertainty factor of 100X was applied to 

endpoints selected for all exposure routes (10x for interspecies extrapolation, 10x for intraspecies 

variation). 

Exposure/Risk Assessment and Risk Characterization

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

pathways based on registered uses and requests for new uses of propiconazole. Worker

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

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

proposed new use. Conservative acute and 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. Aggregate risks from 

propiconazole are not a concern. Occupational exposure and risk estimates indicate that worker

and residential handler and post-application exposures are not of concern at the maximum 

allowable application rates for the proposed new uses provided that handlers wear chemical 

resistant gloves as required on the label. 

Use of Human Studies
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This risk assessment relies in part on data from studies in which adult human subjects 

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

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

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

received the appropriate review.

Environmental Justice

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

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

Actions to Address Environmental Justice in Minority Populations and Low-Income 

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

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

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

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

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

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

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

and adults entering or playing on treated areas postapplication 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

Pending submission of a revised Section F (see requirements under Proposed 

Tolerances), there are no residue chemistry issues that would preclude granting conditional 

Section 3 registration for the requested use of propiconozole on mint, bulb vegetables, caneberry

subgroup 13-07A, bushberry subgroup 13-07B, and low growing berry subgroup 13-07G or 

establishment of the following tolerances for residues of propiconozole. 

Mint, spearmint, tops.....................................................10.0 ppm

Mint, peppermint, tops...................................................10.0 ppm

Onion, bulb subgroup 3-07A ............................................0.2 ppm

Onion, green, subgroup 3-07B..........................................9.0 ppm

Caneberry, subgroup 13-07A............................................1.0 ppm

Bushberry, subgroup 13-07B............................................1.0 ppm

Low growing berry subgroup 13-07G* .............................1.3 ppm

* except cranberry

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)]. However, HED has determined that the 
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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. 

Codex has established several maximum residue limits (MRLs) for propiconazole in/on 

various raw agricultural commodities. The Codex MRLs are expressed in terms of 

propiconazole per se, which is the same as the US tolerance expression. Both Canada and 

Mexico have established MRLs/tolerances on several commodities which also have U.S. 

tolerances. To the extent possible, U.S. tolerances have been harmonized with Codex, Canadian, 

and Mexican MRLs.

2.0 INGREDIENT PROFILE 

2.1 Registered and Proposed New Uses 

There are currently 264 active propiconazole registrations including 120 Section 3 

registrations and fourteen 24(c) special local needs (SLNs) and 129 Section 18 Emergency

Exemption. 

The Interregional Research Project No. 4 (IR-4) has applied for registration of a new 

emulsifiable concentrate (EC) product containing 41.8% ai. The product is proposed for use on 

mint, bulb vegetables, caneberry subgroup 13-07A, bushberry subgroup 13-07B, and low 

growing berry subgroup 13-07G (Table 1). The product is manufactured by Syngenta Crop 

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

Table 1: Propiconazole: Proposed Use for Tilt® (EPA Reg. No. 100-617)

Crops Appl. Method Maximum Application Rates

Mint Aerial

Groundboom

Chemigation

Single 0.113 lb ai/A Seasonal 0.338 lb ai/A 

Bulb Vegetables Single 0.094 lb ai/A Seasonal 0.45 lb ai/A

Caneberries & Bushberries Single 0.070 lb ai/A Seasonal 0.84 lb ai/A

Low Growing Berries Single 0.047 lb ai/A Seasonal 0.45 lb ai/A

2.2 Structure, Nomenclature, and Physical/Chemical Properties 

The nomenclature and physicochemical properties of propiconazole are provided in 

Tables 2 and 3.
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Table 2. Nomenclature of Propiconazole

Compound

N

N N

O

O

Cl

Cl

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 

Table 3. Physicochemical Properties of Technical Grade Propiconazole.

Parameter Value Reference

Boiling point 120 C at 1.9 Pa, >250 C at 101.325 kPa MRID No. 43698701

pH 4.9 at 25 C (1% aqueous dispersion) MRID No. 43698701

Density 1.289 g/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

3.0 HAZARD CHARACTERIZATION/ASSESSMENT

3.1 Hazard Characterization

The toxicology database for propiconazole is adequate for evaluating and characterizing 

toxicity and selecting endpoints for purposes of this risk assessment. Subchronic neurotoxicity

and immunotoxicity studies are required as part of new 40 CFR Part 158 data requirements for

registration of a pesticide.

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. Mice appear to be more susceptible to propiconazole 

toxicity than rats. Dogs appeared to be more sensitive to the localized toxicity of propiconazole 

as manifested by stomach irritations at 6 mg/kg/day and above.
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In rabbits, developmental toxicity occurred at a higher dose than the maternal toxic dose, 

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

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

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

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

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

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

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

offspring to the toxic doses of propiconazole. 

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

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

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

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

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

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

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

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

Immunotoxicity and subchronic neurotoxicity studies are required. These are new data 

requirements under 40 CFR Part 158 as part of the data requirements for registration of a 

pesticide (food and non-food uses). The complete toxicity profile for propiconazole is provided 

in Appendix 1.2, Tables 2 and 3. 

3.2 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 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 
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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. 

3.3 FQPA Hazard Considerations

The toxicity database for propiconazole is sufficient for a full hazard evaluation and is 

considered adequate to evaluate risks to infants and children. Acceptable developmental toxicity

studies in the rat and rabbit, acceptable multi- and single generation reproduction studies in the 

rat. An acceptable acute neurotoxicity study in the rat is also available in the database. 

Subchronic neurotoxicity and immunotoxicity studies are required under 40 CFR Part 158 as a 

part of the new data requirements for registration of a pesticide (food and non-food uses). 

Together, the available data support the reduction of the FQPA factor to 1X.

3.3.1 Neurotoxicity 

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

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

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

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

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

observational battery (FOB) and motor activity tests showed reduced activity in males and 

females at the high dose. 

3.3.2 Developmental Toxicity 

In a developmental toxicity study in rats, severe compound-related maternal toxicity was 

observed at the high dose level (360 mg/kg/day) during the first five days of dosing. The high 

dose was lowered to 300 mg/kg/day on day 6 and the severity and frequency of these effects 

decreased rapidly. There were no treatment related clinical observations in maternal animals 

with the exception of one animal exhibiting rales. Fetotoxic effects included increased incidence 

of rudimentary ribs, un-ossified sternebrae, shortened renal papillae, and dilated ureter at 90 and 

300 mg/kg/day (NOAEL of 30 mg/kg/day). In addition, cleft palate findings along with skeletal 

anomalies also seen at these doses were determined to be probable treatment related indications 
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of delayed development. Cleft palate findings were confirmed in a subsequent development 

toxicity study in rats. HED toxicologists consider the fetal effects observed in the rat study at a 

dose lower than that evoking maternal toxicity to be quantitative evidence of increased 

susceptibility of fetuses to in utero exposure to propiconazole. In the developmental toxicity

study in rabbits, neither quantitative nor qualitative evidence of increased susceptibility of 

fetuses to in utero exposure to propiconazole was observed. 

3.3.3 Reproductive Toxicity 

A 2-generation reproduction study showed no compound-related clinical observations or 

mortality in parents or off-spring. Food consumption and body weight effects were observed at 

the high dose in parents and pups. Hepatic effects (cellular swelling) were seen in mid- and 

high-dose parental animals and at the high dose in offspring. There were no signs of 

reproductive toxicity. 

3.3.4 Pre-and/or Postnatal Toxicity

The toxicology database for propiconazole is sufficient for FQPA assessment. There is 

low concern for pre- and/or post-natal toxicity resulting from exposure to propiconazole. In the 

developmental toxicity study in rats, fetal effects observed in this study at a dose lower than that 

evoking maternal toxicity are considered to be quantitative evidence of increased susceptibility

of fetuses to in utero exposure to propiconazole. In the developmental toxicity study in rabbits, 

neither quantitative nor qualitative evidence of increased susceptibility of fetuses to in utero

exposure to propiconazole was observed in this study. In the 2-generation reproduction study in 

rats, neither quantitative nor qualitative evidence of increased susceptibility of neonates (as 

compared to adults) to pre- and/or postnatal exposure to propiconazole was observed in this 

study. There is no evidence of neuropathology or abnormalities in the development of the fetal 

nervous system from the available toxicity studies conducted with propiconazole. In the rat 

acute neurotoxicity study, there was evidence of mild neurobehavioral effects at 300 mg/kg, but 

no evidence of neuropathology from propiconazole administration. Since there was quantitative 

evidence of increased susceptibility of the young following exposure to propiconazole in the 

developmental rat study, the HED Hazard Identification Assessment Review Committee 

(HIARC) performed a Degree of Concern Analysis and concluded that the degree of concern for 

the effects observed in this study was low and no residual uncertainties were identified. 

3.3.5 FQPA Factor

HED recommends the FQPA SF be reduced to 1X based on the following: 

- The toxicological data base is adequate for FQPA assessment. 

- Residual uncertainties or concerns for pre- and/or post-natal toxicity are minimal.

- Although an apparent increased quantitative susceptibility was observed in fetuses 

and offspring based on minimal toxicity at high doses of administration, clear 

NOAELs and LOAELs have been identified for all effects of concern, and a clear 

dose-response has been well defined. Since this increased susceptibility is occurring 
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at high doses and a clear dose response has been well defined for all effects of 

concern, residual uncertainties or concerns for pre- and/or post-natal toxicity are 

minimal.

3.4 Toxicity Endpoint Selection

3.4.1 Acute Reference Dose (aRfD) / aPAD – Females 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. 

 

3.4.2 Acute Reference Dose (aRfD) / aPAD – Females 13-49

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. 

 

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

 (Females 13-49) 100 (UF)

 Acute RfD = 30 mg/kg (NOAEL) =0.3 mg/kg/day

 (General Population) 100 (UF)
Page 13 of 58

3.4.3 Chronic Reference Dose (cRfD) / cPAD – All Population

Selected Study: 24 Month Oncogenicity Study in Mice (MRIDs 00129570 & 93194037)

Oncogenicity Mouse Study - A 24-month propiconazole dietary oncogenicity study in 

CD-1 mice was conducted at doses of 0, 100, 500 or 2500 ppm (M: 10.0, 49.4, and 344.3 F: 

10.8, 55.6 and 340.3 mg/kg/day selected by the HIARC for deriving the chronic RfD. Nonneoplastic liver effects (increased liver weight in males and increase in liver lesions: 

masses/raised areas/ swellings/nodular areas mainly) were observed at 50 mg/kg/day. (See 

Appendix B)

Dose and Endpoint for Establishing a cRfD: 10 mg/kg/day - NOAEL of 10 mg/kg/day

and a LOAEL of 50 mg/kg/day based on non-neoplastic liver effects. 

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

variation.

Comments about Study/Endpoint: The lower NOAEL of 2.7 mg/kg/day in a 3-month 

oral feeding toxicity study in mice was not selected because a) there is a wide dose spread 

between the NOAEL (2.7 mg/kg/day) and the LOAEL (65 mg/kg/day) in that study, b) the 

LOAEL (50 mg/kg/day) in the selected study is lower than the LOAEL (65 mg/kg/day) of the 3-

month mouse oral feeding study, and c) the liver toxicity seen in the 2 year mouse study is 

consistent with that seen in an 18-month mice and 2-generation reproduction studies. In an 18-

month oncogenicity study in mice, the NOAEL for liver toxicity was 11 mg/kg/day and the 

LOAEL 59 mg/kg/day). In a 24-month feeding study in rats, the NOAEL for liver toxicity was 

18 mg/kg/day and the LOAEL 96 mg/kg/day). In 2-generation reproduction study in rats, the 

NOAEL for liver toxicity was 8 mg/kg/day and the LOAEL 42 mg/kg/day). The dog study was 

not selected since stomach irritations were attributed to local effects and not systemic toxicity, 

and target organ (liver) toxicity seen in mice and rats was not seen in dogs.

3.4.4 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

 Chronic RfD = (NOAEL) 10 mg/kg = 0.1

 (General Population) (UF) 100
Page 14 of 58

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

3.4.5 Incidental Oral Exposure (Intermediate-Term)

Selected Study: 24 Month Oncogenicity Study in Mice (MRIDs 00129570 & 93194037)

See Section 3.4.3

Dose and Endpoint for Establishing a cRfD: 10 mg/kg/day - NOAEL of 10 mg/kg/day

and a LOAEL of 50 mg/kg/day based on non-neoplastic liver effects. 

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

variation.

3.4.6 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. 

3.4.7 Dermal Exposure (Short-Term)

Selected Study: Acute Neurotoxicity in Rats (MRID 46046401). 

See Section 3.3.1

Dose and Endpoint NOAEL of 30 mg/kg/day and a LOAEL of 100 mg/kg/day based on 

clinical signs of toxicity (piloerection in one male, diarrhea in one female, tip toe gait in 3 

females.

Uncertainty Factor (UF)/Level of Concern= 100 – 10x for interspecies extrapolation and 

10x for intraspecies variation. FQPA 1X

Comments about Study/Endpoint: Since an oral NOAEL was selected for dermal risk 

assessment, a dermal absorption factor of 40% based on a dermal absorption study in rats should 

be used. Although a dermal toxicity study is available, a POD from an oral study was selected 

because neurotoxicity, the primary effect of concern for short-term exposure is not specifically 

evaluated in the available dermal toxicity studies. The selected endpoint is protective of 

potential neurotoxic effects from dermal exposure. 

3.4.8 Dermal Exposure (Intermediate-Term)
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Selected Study: 24 Month Oncogenicity Study in Mice (MRIDs 00129570 & 93194037)

See Section 3.4.3

Dose and Endpoint for Establishing a cRfD: 10 mg/kg/day - NOAEL of 10 mg/kg/day

and a LOAEL of 50 mg/kg/day based on non-neoplastic liver effects. 

Uncertainty Factor (UF): )/Level of Concern: 100 – 10x for interspecies extrapolation and 

10x for intraspecies variation. FQPA 1X

Comments about Study/Endpoint: Since an oral NOAEL was selected for dermal risk 

assessment, a dermal absorption factor of 40% based on a dermal absorption study in rats should 

be used. 

3.4.9 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.

3.4.10 Inhalation Exposure (Intermediate-Term)

Selected Study: 24 Month Oncogenicity Study in Mice (MRIDs 00129570 & 93194037)

See Section 3.4.3

Dose and Endpoint 10 mg/kg/day - NOAEL of 10 mg/kg/day and a LOAEL of 50

mg/kg/day based on non-neoplastic liver effects. 

Uncertainty Factor (UF)/Level of Concern: 100 – 10x for interspecies extrapolation and 

10x for intraspecies variation. FQPA 1X

Comments about Study/Endpoint: Inhalation toxicity is assumed to be equivalent to oral 

toxicity.

3.4.11 Classification of Carcinogenic Potential
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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 should be used and would be protective 

(HED Doc. No. 009771, April 15, 1992 meeting). This classification was based on increased 

hepatocellular adenomas and combined adenomas/carcinomas and increased hepatocellular 

carcinomas in male mice at the high dose (2500 ppm) in an oral feeding oncogenicity study

(MRID 00129570). There was no treatment related increased tumor response in female mice. In 

a rat study conducted with acceptable doses of propiconazole (0, 100, 500, or 2500 ppm), no 

tumorogenic response was observed either (MRID 00250784). The CPRC determined that the 

high dose of 2500 used in the mouse study was excessively toxic (based on survival, liver 

clinical pathology, histopathology, and body weight and body weight gains) but that the lower

doses (100 & 500 ppm) were not adequate for assessing the carcinogenic potential of 

propiconazole. The 2500 ppm used in the oncogenicity study exceeded the MTD demonstrated 

in the 90 day study based on the endpoint of hepatic necrosis. 

Subsequently the Registrant conducted an 18-month oncogenicity study in male CD-1 

mice at 0, 100, 500 or 850 pm (MRID 44381401). There was a treatment related increase in 

hepatocellular adenoma incidences and total hepatocellular neoplasia (adenomas and 

carcinomas) of 24%, at the 850 ppm exposure level when compared to concurrent controls which 

had unusually low incidence of adenomas (2%) and total neoplasia (4%). Based on HED 

standard statistical computations, there was a significant dose-related increasing trend, and a 

significant difference in the pair-wise comparison of the 850 ppm dose group with the concurrent 

controls, for liver adenomas and/or carcinomas combined. However, this increase in the total 

neoplasm was driven primarily by the adenomas. Dosing was considered adequate based on the 

body weight gain and hepatotoxic effects seen at 500 and 850 ppm. The percentage adenomas 

and carcinomas were within the range of the inadequate historical control data initially submitted 

by the registrant. Subsequently submitted adequate control data are more consistent with 

previous historical control data for the CD mouse and indicate that the study control in the 

second mouse study may be low. The tumor incidence observed in male livers at the 850 ppm 

dose is within the range of the new historical data. However, propiconazole will continue to be 

classified as possible human carcinogen (group C) and for the purpose of risk characterization 

the reference Dose (RfD) approach will continue to be used.

3.5 Margins of Exposure

A summary of target Levels of Concern for risk assessment is provided in Table 4.

Table 4. Target Levels of Concern/Margin of Exposure for Propiconazole

Route/Duration Short-Term

(1-30 Days)

Intermediate-Term

(1 - 6 Months)

Long-Term

(> 6 Months)

Occupational (Worker) Exposure
Page 17 of 58

Table 4. Target Levels of Concern/Margin of Exposure for Propiconazole

Route/Duration Short-Term

(1-30 Days)

Intermediate-Term

(1 - 6 Months)

Long-Term

(> 6 Months)

Dermal 100 100 100

Inhalation 100 100 100

Residential (Non-Dietary) Exposure

Oral 100 100 N/A

Dermal 100 100 100

Inhalation 100 100 100

3.6 Recommendation for Aggregate Exposure Risk Assessments

When there are potential residential exposures to the pesticide, 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 for intermediate- and long-term oral, dermal (oral 

equivalent) and inhalation (oral equivalent) routes. These routes can be aggregated for these 

scenarios for the appropriate population.

3.7 Summary of Endpoints Selected for Risk Assessment

Toxicological doses/endpoints selected for the propiconazole risk assessment are 

provided in Tables 5 and 6.

Table 5. 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

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

DNT Study - Rat 

LOAEL = 90 mg/kg/day based on increased 

incidence of rudimentary ribs, un-ossified 

sternebrae, as well as increased incidence of 

shortened and absent renal papillae and increased 

cleft palate.

Chronic Dietary 

(Adult Males and 

Females 50+ yrs)

NOAEL = 

10

mg/kg/day

UFA= 10x

UFH=10x

FQPA SF= 1x

Chronic RfD = 

0.1

mg/kg/day

cPAD = 

0.1mg/kg/day

24-month oncogenicity study on CD-1 mice.

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

liver effects (increased liver weight in males and 

increase in liver lesions: masses/raised areas/ 

swellings/nodular areas mainly).

Cancer (all routes) Classification: Group C, possible human carcinogen, RfD approach for risk characterization
Page 18 of 58

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

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

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

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

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

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

of concern. N/A = not applicable

Table 6. Summary of Toxicological Doses and Endpoints for Propiconazole for Use in Residential and Occupational 

Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

Dermal 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 

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 Oncogenicity Study - Mice 

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

liver effects (increased liver weight in males and 

increase in liver lesions: masses/raised areas/ 

swellings/nodular areas mainly).

Inhalation Short 

Term (1-30 days) 

NOAEL= 30

mg/kg/day 

UFA= 10x

UFH=10x

Occupational LOC 

for MOE = 100

Acute Neurotoxicity Study-Rats 

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

of toxicity (piloerection in one male, diarrhea in 

one female, tip toe gait in 3 females).

Inhalation 

Intermediate Term

(1-6 months) 

NOAEL= 10

mg/kg/day

24 Month Oncogenicity Study - Mice 

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

liver effects (increased liver weight in males and 

increase in liver lesions: masses/raised areas/ 

swellings/nodular areas mainly).

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

DAF = Dermal Absorption Factor 

3.8 Endocrine Disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor 

Screening Program (EDSP) to determine whether certain substances (including pesticide active 

and other ingredients) may have an effect in humans or wildlife similar to an effect produced by

a “naturally occurring estrogen, or other such endocrine effects as the Administrator may

designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA issued test orders/data call-ins for the 
Page 19 of 58

first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert 

ingredients. This list of chemicals was selected based on the potential for human exposure 

through pathways such as food and water, residential activity, and certain post-application 

agricultural scenarios. This list should not be construed as a list of known or likely endocrine 

disruptors.

Propiconazole is not among the group of 58 pesticide active ingredients on the initial list 

to be screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide 

chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data call-ins for all 

pesticide active ingredients. 

For further information on the status of the EDSP, the policies and procedures, the list of 

67 chemicals, the test guidelines and the Tier 1 screening battery, please visit our website: 

http://www.epa.gov/endo/.

4.0 PUBLIC HEALTH AND EPIDEMIOLOGY 

From the review of the Incident Data System, it appears that a majority of propiconazole 

cases involved skin symptoms such as rash, itching, and skin irritation and respiratory effects 

such as difficulty breathing. Poison Control Center data would tend to support the Incident Data 

System results; dermal irritation, erythema, and difficulty breathing were among the most 

common effects reported. Measures to limit skin and respiratory exposure are recommended for 

this pesticide. Appropriate personal protective equipment to protect the skin is also 

recommended for both handlers and field workers who are likely to have substantial contact with 

propiconazole. (HED memo of J. Blondell, D319239, 07/26/05)

5.0 DIETARY AND DRINKING WATER EXPOSURE ASSESSMENT

5.1 Residue Chemistry Profile

5.1.1 Metabolism in Primary Crops and Livestock

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 assessed 

separately (HED memo of 11/3/10, T. Morton, D383609). The nature of propiconazole residues 
Page 20 of 58

in livestock is adequately understood based on acceptable goat and poultry metabolism studies 

(DP D329394, Y. Donovan, 6/15/06).

5.1.2 Metabolism in Rotational Crops

The nature of the residue in confined rotational crops is understood (D329394, Y. 

Donovan, 6/15/06). Based on acceptable studies previously reviewed by EFED, the metabolism 

of propiconazole in rotational crops is similar to that in primary crops. 

5.1.3 Residues of Concern

HED has concluded that the residues of concern should include propiconazole and all its 

metabolites containing the 2,4-DCBA moiety, including conjugates for dietary risk assessment of 

food, as virtually all the residue data have been generated using a common moiety method that 

converts parent and all of the metabolites of concern to 2,4-DCBA. 

Table 7. Compounds to be Included in the Risk Assessment and Tolerance Expression.

Matrix Residues Included in Risk Assessment Residue Included in Tolerance 

Expression for Compliance Monitoring

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 Parent only

5.1.4 Residue Analytical Methods

5.1.4.1 Enforcement Methods

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. 

5.1.4.2 Data Collection Methods

For plant commodities, samples were analyzed for propiconazole as 2,4-dichlorobenzoic 

methyl ester using the working method “Working Analytical Method for the Determination of 

Propiconazole in Mint Leaves as 2,4-Dichlorobenzoic Methyl Ester Using Gas Chromatography with 

Electron Capture Detector”. This method was adapted from “Determination of Total Residues of 

Propiconazole in Crops as 2,4-Dichlorobenzoic Acid by Capillary Gas Chromatography” (Method 

No. AG-454B). The lowest level of method validation (LLMV) in this study was 0.050 ppm. Based 

on recoveries of samples fortified at the LLMV, the limit of detection (LOD) and limit of 

quantitation (LOQ) were calculated as 0.023 ppm and 0.070 ppm, respectively. 
Page 21 of 58

5.1.4.3 Multiresidue Method

The FDA PESTDATA database (PAM Volume I, Appendix I) indicates that 

propiconazole is completely recovered (>80%) using Multiresidue Methods Section 302. The 

recovery of propiconazole metabolites CGA-91305, CGA-118244, and 1,2,4-triazole is variable 

using Section 302. Propiconazole and metabolites CGA-91305, CGA-118244, and 1,2,4-triazole 

are not recovered using Multiresidue Methods Sections 303 and 304.

5.1.5 Residues in Crops

The available field trial data are adequate and support the proposed amended use patterns 

for propiconazole on mint. The number and geographic distribution of the field trials are 

adequate, and the appropriate samples were collected at the proposed PHI. In five field trials in 

Regions 5 and 11, propiconazole (3.6 lb/gal EC) was applied 3 times to established fields of mint 

as broadcast foliar applications at 0.1125 lb ai/A/application at RTIs of 6-8 days, for a total of 

0.3375 lb ai/A/season (1x rate). The initial application was made when plants were 2-4 inches in 

height, and all applications were made using ground equipment. Duplicate control and treated 

samples of fresh mint hay were harvested from each site at 7 days after treatment (DAT). 

Samples were stored frozen from collection to analysis for an interval supported by available 

storage stability data. Total residues of propiconazole and its DCBA containing metabolites 

in/on mint were determined using a validate GC/ECD Method AG-454B (LOQ is 0.07 ppm, and 

an LOD is 0.023 ppm). Total propiconazole residues were 0.114-5.453 ppm and averaged 3.316 

ppm in/on 10 samples of mint hay harvested at 7 DAT.

The existing tolerances for berry group 13 (1.0 ppm), onion, bulb (0.2 ppm), onion, green 

(9.0 ppm), and strawberry (1.3 ppm) are adequate to cover any propiconazole residues under new 

crop groupings: onion, bulb subgroup 3-07A (0.2 ppm), onion, green subgroup 3-07B (9.0 

ppm), caneberry subgroup 13-07A (1.0 ppm), bushberry subgroup 13-07B (1.0 ppm), and low 

growing berry subgroup 13-07G (except cranberry) (1.3 ppm). 

5.1.6 Residues in Processed Commodities

Adequate data are available from two mint processing studies (DP Barcode D209468, W. 

Wassell, 4/25/95). In two field trials, propiconazole (EC) was applied to mint at rates up to 0.34 

lb ai/A (1.5x labeled rate). Samples of fresh mint hay were cut 90 DAT, air dried, and distilled 

to yield mint oil. Samples of mint hay and oil were stored for up to 224 days prior to analysis 

using an adequate GC/ECD method (AG-454B). Total propiconazole residues were 0.12 ppm in 

fresh hay from both field trials and were <0.05 and 0.08 ppm in oil from the two sites, for an 

average processing factor of 0.5x for mint oil. Therefore, a separate tolerance for mint oil is not 

required. Previously submitted processing studies, reflecting the measurement of total 

combined residues, are adequate for the proposed uses of propiconazole on other commodities. 

5.1.7 Residues in Rotational Crops
Page 22 of 58

Plant-back restrictions have been established for propiconazole products registered for 

use on rotational crops based on the confined rotational crop studies. Labels specify that any

food/feed crops not listed on the label should not be planted within 105 days of treatment. 

Tolerances for inadvertent residues of propiconazole in/on alfalfa planted in rotation with 

propiconazole-treated crops have been established at 0.1 ppm for alfalfa forage and hay. 

5.1.8 Storage Stability.

Adequate storage stability data are available indicating that residues of propiconazole and 

its metabolites determined as 2,4-DCBA are stable at ≤-15 C for up to 39 months in a variety of 

commodities. (D329394, Y. Donovan, 6/15/06). 

5.2 Drinking Water Profile

5.2.1 Environmental Fate and Transport

Acceptable and supplemental environmental fate data indicate that propiconazole is 

persistent in most soil and aqueous environments. Propiconazole is stable to hydrolysis and 

photodegradation in water. It has an aerobic soil metabolism half-life of 69 days and is 

persistent in aquatic environments (t1⁄2 = 426 days). Aqueous photolysis may occur in the 

presence of sensitizers (t1⁄2 = <1 day). Its principal route of dissipation in terrestrial environments appears to be adsorption to soil which increases with soil organic matter content (Kd

values=1.2 on sand to 9.34 on silty clay loam soils). Terrestrial field dissipation half-lives of 

about 100 days were reported in four soils. In aquatic dissipation studies in rice fields, 

propiconazole dissipated rapidly (t1⁄2 = <5 days) although the route of dissipation was not apparent. Propiconazole is moderately mobile to relatively immobile in most soil and aqueous 

environments. Propiconazole is not volatile (vapor pressure is 1.3 x 10-6Torr at 200 C). 

Propiconazole is broken down through hydroxylation of the propyl side chain and the dioxolane 

ring to give 1,2,4-triazole and other products, including particle-bound material and carbon 

dioxide. CGA-136735, CGA-118245 and CGA-71019 were identified as major degradates 

(>10% of applied) in environmental fate studies. Minor degradates include CGA-91304 and 

CGA-91305.

5.2.2 Estimated Drinking Water Concentrations 

Drinking water residues provided by the Environmental Fate and Effects Division 

(EFED) (D372880, J. Lin, 7/6/10) were incorporated directly into the acute and chronic dietary

analyses. EFED generated the surface water and ground water estimates using the Pesticide 

Root Zone Model 3 and Screening Concentration in Ground Water (SCIGROW; Tier 1) models, 

respectively. The estimated surface water drinking water concentrations (EDWCs) for 

propiconazole are 55.78 ug /L for the 1 in 10 year annual peak concentration (acute), 21.61 ug /L

for the 1 in 10 year annual mean concentration (non-cancer chronic) and 13.24 ug /L for the 30 

year annual mean concentration (cancer chronic). The SCI-GROW estimated ground water 

drinking water concentrations for propiconazole are not expected to exceed 0.64 μg/L. These 
Page 23 of 58

results are based on EDWCs for Turf (DP 325821, 328690, 07/07/2006). The proposed new uses 

do not result in higher EDWCs than those estimated for turf uses. 

5.3 Dietary and Drinking Water Exposure and Risk

HED conducted screening-level acute and chronic dietary and drinking water exposure 

and risk assessments using the Dietary Exposure Evaluation Model with the Food Commodity

Intake Database (DEEM-FCIDTM). Dietary risk assessment incorporates both exposure and 

toxicity of a given pesticide. For acute and chronic dietary assessments, the risk is expressed as 

a percentage of a maximum acceptable dose (i.e., the dose which HED has concluded will result 

in no unreasonable adverse health effects). This dose is referred to as the population adjusted 

dose (PAD). The PAD is equivalent to the reference dose (RfD) divided by the additional Safety 

Factor, if applied. For acute and non-cancer chronic exposures, HED is concerned when 

estimated dietary risk exceeds 100% of the PAD. 

The resulting acute and chronic food and water exposure estimates were less than HED’s 

level of concern (<100% aPAD) for the general U.S. population and all population sub-groups

(Tables 8 and 9). At the 95th percentile, the acute dietary exposure (food and water) to general 

US population is 7 % of the aPAD, and the most highly exposed subgroup, Children 1-2 yrs old, 

is 17 % of the aPAD. The chronic dietary exposure to general US population is 7 % of the 

cPAD, and the most highly exposed subgroup, Children 1-2 yrs old, is 18 % of the cPAD. All 

the dietary risk estimates are below 100% of the PADs.

Table 8. Results of Acute Dietary Exposure Analysis for Food and Water

Population Subgroup aPAD (mg/kg/day)

95th Percentile

Exposure (mg/kg/day) % aPAD

General U.S. Population

0.3

0.022053 7

All Infants (< 1 year old) 0.048257 16

Children 1-2 years old 0.051498 17

Children 3-5 years old 0.039652 13

Children 6-12 years old 0.027168 9

Youth 13-19 years old 0.018085 6

Adults 20-49 years old 0.017975 6

Adults 50+ years old 0.013576 5

Females 13-49 years old 0.016750 6

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

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

General U.S. Population

0.1

0.006794 7

All Infants (< 1 year old) 0.015851 16

Children 1-2 years old 0.018210 18

Children 3-5 years old 0.014763 15

Children 6-12 years old 0.009627 10

Youth 13-19 years old 0.005891 6

Adults 20-49 years old 0.005685 6

Adults 50+ years old 0.004556 5

Females 13-49 years old 0.005369 5
Page 24 of 58

6.0 RESIDENTIAL EXPOSURE AND RISK

There are no new requested residential uses expected with this registration, therefore 

risks associated to propiconazole and the product Tilt®in a residential environment was not 

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

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

Oonnithan, 9/3/06)

7.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT 

In accordance with the FQPA, when there are potential residential exposures to a 

pesticide, aggregate risk assessment must consider exposures from three major routes: oral, 

dermal, and inhalation. There are three sources for these types of exposures: food, drinking 

water, and residential uses. 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 acute and chronic 

exposure estimates provided in the Dietary Exposure Section represent aggregate risk for acute 

and chronic exposures. 

7.1 Short-Term Aggregate Risk

Short term aggregate exposure takes into account residential exposure plus average 

exposure levels to food and water (considered to be a background exposure level). Table 10

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

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

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

risk does not exceed HED’s level of concern. This assessment is considered very conservative in 

that the residential incidental oral post-application exposure was calculated by combining three 

screening level assessments (which by themselves already have conservative estimates). 

Table 10: Short-term Aggregate Risk Estimates to Propiconazole for Toddler (Children 1-2years)

Exposure Scenario Target 

MOE

Route of 

Exposure Exposure NOAELs MOE at Day 0 Combined MOE5

Average Food and Water N/A Oral 0.0182

30

1600 2

160

Hand to Mouth Activity on Turf

100 1

Oral 0.0269 1100 3

Object to Mouth Activity on Turf Oral 0.0067 4500 3

Soil Ingestion Oral 0.00009 330,000 3

Turf –High-Contact Activities Dermal 0.1410 210 4

1 Target MOE= 100, Acute Neurotoxicity NOAEL=30

2 MOE food = [(short-term oral NOAEL)/(chronic dietary exposure)]
Page 25 of 58

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 11 aggregates the short-term risk for adults from residential handler exposure, and 

average food and water exposure (as a background). The lowest aggregate MOE is 120, which is 

greater than the target MOE of 100. Adult handlers have some inhalation exposure, but there are 

no appropriate inhalation studies on propiconazole to assess their potential risk. Based on a 

recent effort to determine whether oral studies are predictive of inhalation toxicity, HED has 

concluded that the MOEs for inhalation exposure are sufficiently large that there is no concern 

for potential inhalation risk.

Table 11: Short-term Aggregate Risk Estimates to Propiconazole for Adults from Handler 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 0.0060 30 5000 2 NA

Ornamentals w Low Pressure 

Handwand

100 1

Dermal and 

Inhalation

0.0069

30

4400 32300

Ornamentals w Hose-end

Sprayer 0.0008 40000 4400

Turf w Low Pressure 

Handwand 0.0237 1300 1000

Turf w Hose-end Sprayer 0.0568 530 480

Applying Paint w Brush/ 

Roller 0.0323 330 300

Applying Paint w Airless 

Sprayer 0.2432 120 120

1 Target MOE= 100, Acute Neuortoxicity NOAEL=30

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

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

4 Aggregate Combined MOE (food, water, and residential) = 1÷ [(1÷MOE food and water) + (1÷MOE handler inhalation and

dermal)].

Table 12 aggregates the short-term risk for adults from residential post application, and 

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

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

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

aggregate MOE is 330, which is greater than the target MOE of 100. This aggregate exposure 

assessment is considered very conservative because the assumptions used for each of the 

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

Table 12: Short-term Aggregate Risk Estimates to Propiconazole for Adults from Post-Application Activities
Page 26 of 58

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 0.0060

30

5000 2

330 Residential Post-application 

(Residential Turf Gen. HighContact Activities))100 1 Dermal 0.085 350 3

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

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

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

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

7.2 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 120, which is greater than the target MOE of 100.

Table 13. Intermediate -term Aggregate Risk Estimates to Propiconazole for Toddler (Children 1-2years)

Exposure Scenario

Target 

MOE

Route of 

Exposure Exposure NOAELs MOE at Day 0 Combined MOE5

Average Food and Water N/A Oral 0.0180 10 600 2

Incidental oral 100 120 1 Oral 0.0056 10 18003

Dermal Contact Activities 100 1 Dermal 0.068 10 150 4

Note:

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

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

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

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

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

dermal)].

8.0 OCCUPATIONAL EXPOSURE AND RISK

8.1 Occupational Exposure Scenarios

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

proposed new product on mint, bulb vegetables, caneberries, bushberries, and low growing 

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

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

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

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

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

(PPE) consisting of long-sleeved shirt, long pants and shoes with socks plus gloves. 
Page 27 of 58

8.2 Occupational Handler Exposure

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

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

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

aerial, airblast, groundboom and chemigation equipment.

8.2.1 Handler Exposure Scenarios

8.2.1.1 Mixing and Loading

• Mixing/loading emulsifiable concentrates for aerial application

• Mixing/loading emulsifiable concentrates for groundboom application

• Mixing/loading emulsifiable concentrates for airblast application

• Mixing/loading emulsifiable concentrates for chemigation application

• Applying sprays aerially

8.2.1.2 Application 

• Applying sprays aerially

• Applying sprays with groundboom sprayer

• Applying sprays with airblast sprayer

• Flagging for aerial spray application

8.2.2 Handler Exposure Data

Chemical-specific data for assessing exposure during pesticide handling activities were 

not submitted to the Agency in support of this Section 3 application. Therefore, data from the 

Pesticide Handlers Exposure Database (PHED) Version 1.1 to assess handler exposures for 

regulatory actions (HED Science Advisory Council for Exposure Standard Operating Procedure 

#7, 1/28/99).

8.2.3 Handler Exposure Assumptions 

• Average body weight of an adult handler is 70 kg.

• Dermal Absorption Factor is 40%

• Exposure duration is short-term (1- 30 days) and intermediate-term (1-6 months)

• Maximum label application rates:

- 0.1125 lb ai/A for mint and low growing berries

- 0.225 lb ai A for bulb vegetables

- 0.16875 lb ai/A for bushberries

• Area treated: (ExpSAC SOP No. 9.1)

- 350 acres per day for aerial applications

- 350 acres for chemigation applications

- 80 acres for groundboom applications 
Page 28 of 58

- 40 acres for airblast applications 

8.2.4 Handler Exposure and Risk Estimates

Summaries of the combined, dermal plus inhalation short-, and intermediate-term risks 

for each exposure scenario are presented in Table 14. The combined dermal and inhalation 

exposure risks are not of concern (i.e., MOEs >100), provided the mixer/loaders wear chemicalresistant gloves as directed on the label. 

Table 14: Summary of Short- and Intermediate- Term Propiconazole Occupational Handler Non-Cancer Risks

Crops Exposure 

Scenario

Appl. 

Rate

(lb 

ai/acre)

1

Area 

Treatd

(A/day)

2

Unit Exposure

(mg/lb ai) 3

ST & IT Dose

(mg/kg/day) 4 ST MOE IT MOE

Aggregate 

ST MOE

Aggregate 

IT MOE

Dermal

Inhalation

Dermal

Inhalation

Dermal 

Inhalation

Dermal 

Inhalation

BL BL+ 

Gloves BL BL+Gloves BL* BL + 

Glove BL BL +Gloves BL BL+Gloves BL BL+Gloves

Mixer/Loader-Liquids

Mint

Aerial

0.1125

350 2.9 0.023 0.0012 0.65 0.0052 0.0007 46 5,800 44,000 15 1,900 15,000 46 5,100 15 1,700

Groundboom 80 2.9 0.023 0.0012 0.15 0.0012 0.0002 201 25,000 190,000 67 8,500 65,000 201 22,000 67 7,500

Chemigation 350 2.9 0.023 0.0012 0.65 0.0052 0.0007 46 5,800 44,000 15 1,900 15,000 46 5,100 15 1,700

Bulb 

Veg

Aerial

0.225

350 2.9 0.023 0.0012 1.31 0.0104 0.0014 23 2,900 22,000 8 970 7,400 23 2,600 8 860

Groundboom 80 2.9 0.023 0.0012 0.29 0.0024 0.0003 101 13,000 97,000 34 4,200 32,000 100 11,000 33 3,700

Chemigation 350 2.9 0.023 0.0012 1.31 0.0104 0.0014 23 2,900 22,000 8 970 7,400 23 2,600 8 860

Cane

berry

Aerial

0.16875

350 2.9 0.023 0.0012 0.98 0.0078 0.0010 31 3,900 30,000 10 1,300 9,900 31 3,400 10 1,100

Airblast 40 2.9 0.023 0.0012 0.11 0.0009 0.0001 268 34,000 260,000 89 11,000 86,000 270 30,000 89 10,000

Chemigation 350 2.9 0.023 0.0012 0.98 0.0078 0.0010 31 3,900 30,000 10 1,300 9,900 31 3,400 10 1,100

Bush

berry

Aerial

0.16875

350 2.9 0.023 0.0012 0.98 0.0078 0.0010 31 3,900 30,000 10 1,300 9,900 31 3,400 10 1,100

Airblast 40 2.9 0.023 0.0012 0.11 0.0009 0.0001 268 34,000 260,000 89 11,000 86,000 270 30,000 89 10,000

Chemigation 350 2.9 0.023 0.0012 0.98 0.0078 0.0010 31 3,900 30,000 10 1,300 9,900 31 3,400 10 1,100

Low 

Growing 

Berry

Groundboom

0.1125

350 2.9 0.023 0.0012 0.65 0.0052 0.0007 46 5,800 44,000 15 1,900 15,000 46 5,100 15 1,700

Chemigation 80 2.9 0.023 0.0012 0.15 0.0012 0.0002 201 25,000 190,000 67 8,500 65,000 201 22,000 67 7,500

Aerial 350 2.9 0.023 0.0012 0.65 0.0052 0.0007 46 5,800 44,000 15 1,900 15,000 46 5,100 15 1,700

Applicator

Mint

Aerial

0.1125

350 0.005 N/A 0.0001 0.0011 N/A 0.00004 27,000 N/A 780,000 8,900 N/A 260,000 26,000 N/A 8,600 N/A

Groundboom 80 0.014 0.014 0.0007 0.0007 0.0007 0.0001 42,000 42,000 320,000 14,000 14,000 105,000 37,000 37,000 12,000 12,000

Bulb 

Veg

Aerial

0.225

350 0.005 N/A 0.0001 0.0023 N/A 0.0001 13,000 N/A 390,000 4,000 N/A 131,000 13,000 N/A 4,300 N/A

Groundboom 80 0.014 0.014 0.0007 0.0014 0.0014 0.0002 21,000 21,000 160,000 6,900 6,900 53,000 18,000 18,000 6,100 6,100

Cane

berry

Aerial

0.16875

350 0.005 N/A 0.0001 0.0017 N/A 0.0006 18,000 N/A 520,000 5,900 N/A 170,000 17,000 N/A 5,700 N/A

Airblast 40 0.36 0.24 0.0045 0.014 0.0093 0.0004 2,200 3,200 69,000 720 1,100 23,000 2,100 3,100 700 1,030

Bush

berries

Aerial

0.16875

350 0.005 N/A 0.0001 0.0017 N/A 0.0001 18,000 N/A 520,000 5,900 N/A 170,000 17,000 N/A 5,700 N/A

Airblast 40 0.36 0.24 0.0045 0.014 0.0093 0.0004 2,200 3,200 69,000 720 1,100 23,000 2,100 3,100 700 1,030
Page 29 of 58

Table 14: Summary of Short- and Intermediate- Term Propiconazole Occupational Handler Non-Cancer Risks

Crops Exposure 

Scenario

Appl. 

Rate

(lb 

ai/acre)

1

Area 

Treatd

(A/day)

2

Unit Exposure

(mg/lb ai) 3

ST & IT Dose

(mg/kg/day) 4 ST MOE IT MOE

Aggregate 

ST MOE

Aggregate 

IT MOE

Dermal

Inhalation

Dermal

Inhalation

Dermal 

Inhalation

Dermal 

Inhalation

BL BL+ 

Gloves BL BL+Gloves BL* BL + 

Glove BL BL +Gloves BL BL+Gloves BL BL+Gloves

Low 

Growing 

Berries

Aerial

0.1125

350 0.005 N/A 0.0001 0.0011 N/A 0.00004 27,000 N/A 780,000 8,900 N/A 260,000 26,000 N/A 8,600 N/A

Groundboom 80 0.014 0.014 0.0007 0.0007 0.0007 0.0001 42,000 42,000 320,000 14,000 14,000 105,000 37,000 37,000 12,000 12,000

Flagger

Mint

Flagger

0.1125

350 0.011 N/A 0.0004

0.0025

N/A

0.0002 12,000

N/A

150,000 4,040

N/A

51,000 11,000

N/A

3,700

N/A

Bulb 

Veg 0.225 0.0050 0.0004 6,060 76,000 2,020 25,000 5,600 1,900

Cane

berry

0.16875 0.0037 0.0003 8,080 102,000 2,700 34,000 7,500 2,500

Bush

Berry

0.16875 0.0037 0.0003 8,080 102,000 2,700 34,000 7,500 2,500

Low 

Growing 

Berry

0.1125 0.0025 0.0002 12,000 150,000 4,040 51,000 11,000 3,700

1. Baseline (BL*) and PPE unit exposure values are reported in the PHED Surrogate Exposure Guide dated August 1998

2 Application rates based on proposed label rate.

3. Amount treated based on information provided ExpoSAC Policy 9

4. Dermal dose (mg/kg/event) = [unit dermal exposure (mg/lb ai) * application rate (lb ai/A) * Amount treated / body weight (70 

kg)].

5

Inhalation dose (mg/kg/event) = [unit exposure (kg/lb ai) * (1mg/1000 kg) conversion * appl. rate (lb ai/lbs seed) * Amount 

treated / body weight (70 kg)].

6. MOE = NOAEL (mg/kg/day) / Average Daily Dose (mg/kg/day)

7. Agg MOE = 1/(1/Dermal MOE + 1/Inhalation MOE).

8.3 Occupational Post-Application Exposure

8.3.1 Post-Application Exposure Scenarios

• Mint – Hedging, Irrigation, Hand Weeding, Scouting

• Caneberries – Hand Harvest, Hand Pruning, Training, Tying

• Bushberries/Low Growing Bushberries – Hand Harvest, Hand Pruning, Thinning, 

• Bulb Vegetables – Hand Harvest, Thinning

8.3.2 Post Application Exposure Data 

The post-application risk assessment for propiconazole has been developed using 

chemical-specific dislodgeable foliar residue (DFR) data on corn, peach, and rice data. The 

following studies were used to determine the dislodgeable foliar residue levels:

• MRID 42564003: Propiconazole – Dislodgeable Residue on Corn (North Carolina) EPA
Page 30 of 58

• MRID 42564003; Report dated 1991. Author Avakian, M; Sponsor: Ciba-Geigy Corporation 

Agriculture Division. Submitted by Environmental Technologies Institute, Inc. and EN-CAS 

Labs.

• MRID 44959701: Dissipation of Dislodgeable Foliar Residue of Two formulations of 

Propiconazole (OrbitTM and OrbitTM 45W) Applied to Peaches.

• MRID 44959701(0442); Report dated 1999; Author; Rosenheck, L. Report: Lab report Number: 

260-98: 44580: AG-561 Performing Laboratories: ABC Laboratories

• MRID 00133390: Worker Exposure in Rice Author; Honeycutt, R. (1983) CGA 64250 (Tilt) 

Report No. EIR-83011. ( Unpublished study received Dec 12, 1983 under 100-617; submitted by 

Ciba-Geigy Corp., Greensboro, NC; CDL:07222-C)

The available chemical/crop specific DFR data were extrapolated for the proposed uses 

based on similarities in application methods between the study and selected crop groups, the crop 

canopy, and application rates (i.e., between the study and current labels). The DFR values were 

adjusted to account for the differences in the application rate used in the study and on the 

proposed label. Corn data were used to complete all occupational assessments that were based 

on exposures to “root” vegetables. Peach data were used to complete all occupational 

assessments that were based on exposures to vine/trellis and low berries. Rice data were used to 

complete all occupational assessments that were based on exposures to low/medium field/row 

crops. DFR data used in the assessment are provided in Table 15.

Table 15. Dislogeable Foliar Residue Data

Location App. Rate

(lb ai/acre)

App. 

Method

Corr. 

Coeff.

Slope

(Ln DFR vs. t)

[T0]

(μg/cm2)

T1/2

(days)

Day 0

(% trans.)

Corn DFR Data (MRID 42564003)

NC (Tilt 3.E) 0.1125 Groundboom 0.750 -0.22061 0.0585 3.14 4.6

Peach DFR Data (MRID 449597-01)

CA (Break EC) 0.1125 Airblast 0.900 -0.0708 0.25 9.79 20.1

Rice DFR Data (MRID 00133390)

Arkansas 0.28 Aerial 0.946 -0.30837 0.184 2.25 5.9

8.3.3 Post Application Exposure Assumptions

• Average body weight of an adult handler is 70 kg.

• Dermal Absorption Factor = 40% 

• Exposure duration is 8 hrs per day for 1- 30 days

• Maximum label application rates:

- 0.1125 lb ai/A for mint and low growing berries

- 0.225 lb ai A for bulb vegetables

- 0.16875 lb ai/A for bushberries

• Transfer Coefficients:

- 1500 cm2/hour for hedging, irrigation, hand weeding, scouting mint 

- 1100 cm2/hour for hand harvesting, hand pruning, training, tying caneberries

- 1100 cm2/hour for hand harvesting, hand pruning, thinning bushberries

- 1500 cm2/hour for hand harvesting, hand pruning low growing bushberries

- 2500 cm2/hour for hand harvesting, thinning bulb vegetables
Page 31 of 58

• Initial fraction of ai retained on foliage is based on chemical/crop specific DFR data 

• Exposure is assumed to occur on the day of application (day 0) 

8.3.4 Post-Application Exposure and Risk Estimates

A summary of the postapplication risks for each crop/activity combination are shown in 

Table 16. Occupational post-application short-and intermediate- term exposure do not exceed 

HED’s level of concern (i.e., MOEs > 100) at day 0. 

Table 16: Propiconazole Non-cancer Post-application Worker Risk Estimates at Day 0

Crop Activity

Transfer 

Coeff

(cm2/hr) 1

Max

App Rate

(lb ai/A) 2

DFR0

(μg/cm2)

3

Daily Dose

(mg/kg/day) 4

ShortTerm

MOE5

IntTerm

MOE6

Mint Hedging; Irrigation; Weeding, 

Hand; Scouting 1500 0.1125 0.0739 0.0051 5,900 2,000

Caneberries Harvest, Hand; Pruning, Hand; 

Training; Tying 1100 0.16875 0.375 0.0189 1,600 530

Bushberries Harvest, Hand; Pruning, Hand; 

Thinning 1100 0.16875 0.375 0.0189 1,600 530

Low Growing 

Bushberries Harvest, Hand; Pruning, Hand 1500 0.1125 0.25 0.0171 1750 580

Bulb Vegetables Harvest, Hand; Thinning 2500 0.225 0.117 0.0134 2,200 750

1 TC cm2

/hr = Transfer coefficients and associated activities (ExpoSAC Policy Memo #003.1)

2 Application rates are based on maximum values based on proposed label.

3 DFR (mg/cm2

) = Dislodgeable Foliar Residues corresponding to day 0. Application Rate (lb ai/A) x CF (4.54E+5 mg/lb) x CF 

(2.47E-8 A/ cm2) x % initial fraction of ai retained on foliage from chemical specific DFR studies

4 Daily Dose (mg/kg/day) = DFR (mg/cm2

) x TC (cm2/hr) x 8 (hrs/day) / Body weight (70 kg).

5

ST MOE = short-term endpoint for dermal (NOAEL mg/kg/day)/Daily Dose

6

IT MOE = intermediate-term endpoint for dermal (NOAEL mg/kg/day)/Daily Dose

Since post-application risks were not a concern on day “0” (12 hours following 

application), the restricted entry interval (REI) is based on the acute toxicity of propiconazole

technical material which is classified as Category III for acute dermal, acute oral toxicity, and

eye irritation potential and Category IV for acute inhalation, and skin irritation potential. Under 

the Worker Protection Standard for Agricultural Pesticides, active ingredients classified as acute 

toxicity categories III or IV for these routes are assigned a 12-hour REI. Therefore, the 12-hour 

REI that appears on the proposed label is adequate. 

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

inhalation exposure assessment was not performed for propiconazole at this time. However, 

there are multiple potential sources of post-application inhalation exposure to individuals 

performing post-application activities in previously treated fields. These potential sources 

include volatilization of pesticides and re-suspension of dusts and/or particulates that contain 

pesticides. The Agency sought expert advice and input on issues related to volatilization of 

pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel 

(SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 

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

process of evaluating the SAP report as well as available post-application inhalation exposure 
Page 32 of 58

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures, to identify the need for and, subsequently, the way to incorporate occupational 

post-application inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for propiconazole.

9.0 CUMULATIVE RISK

Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, 

modify, or revoke a tolerance, the Agency consider “available information” concerning the 

cumulative effects of a particular pesticide's residues and “other substances that have a common 

mechanism of toxicity.”

EPA does not have, at this time, available data to determine whether propiconazole has a 

common mechanism of toxicity with other substances. Unlike other pesticides for which EPA 

has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has 

not made a common mechanism of toxicity finding as to propiconazole and any other substances 

and, propiconazole does not appear to produce a toxic metabolite produced by other substances 

which have tolerances in the U. S. For the purposes of this tolerance reassessment action, 

therefore, EPA has not assumed that propiconazole has a common mechanism of toxicity with 

other substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s OPP concerning common mechanism determinations and 

procedures for cumulating effects from substances found to have a common mechanism on 

EPA’s website at http://www.epa.gov/fedrgstr/EPA_PEST/2002/January/Day_16/.

10.0 DATA NEEDS

10.1 Toxicology Data Requirements 

- Immunotoxicity (GLN 870.7800)

- Subchronic Neurotoxicity (GLN 870.6200b)
Page 33 of 58

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

yes

yes

yes

no

yes

yes

yes

yes

-

yes

870.3700a Developmental Toxicity (rodent)...................................

870.3700b Developmental Toxicity (nonrodent).............................

870.3800 Reproduction .................................................................

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent)..............................................

870.4100b Chronic Toxicity (nonrodent)........................................

870.4200a Oncogenicity (rat)..........................................................

870.4200b Oncogenicity (mouse)....................................................

870.4300 Chronic/Oncogenicity....................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial.....................

870.5300 Mutagenicity—Gene Mutation - mammalian................

870.5375 Mutagenicity—Structural Chromosomal Aberrations...

870.5900 Mutagenicity—Other Genotoxic Effects.......................

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotox. (hen).....................................

870.6100b 90-Day Neurotoxicity (hen)...........................................

870.6200a Acute Neurotox. Screening Battery (rat) .......................

870.6200b 90-Day Neuro. Screening Battery (rat)..........................

870.6300 Develop. Neuro..............................................................

no

no

yes

yes

no

-

-

yes

no

-

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

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

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

yes

no

yes

yes

-

no
Page 34 of 58

A.2 Toxicity Profiles

A.2.1 Acute Toxicity

Table 1: 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 -

A.2.2 Subchronic, Chronic, Other Toxicity

Table 4.1b Subchronic, Chronic and Other Toxicity Profile: Propiconazole

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870.3100

90-Day Feeding 

Study in Rat

00058606 (1997)

Acceptable/Guideline

0, 240, 1200 or 6000 ppm

(M: 0, 15.9, 76.1, 461.7, F: 

0, 16.8, 77.6, 400.9 

mg/kg/day )

LOAEL = 6000 ppm in males (462 mg/kg bw /day) and 1200 ppm 

in females (77.59 mg/kg bw/day) based on reduced body weight 

gain. 

NOAEL = 1200 ppm in males (76 mg/kg bw/day) and 240 ppm in 

females (16.82 mg/kg bw/day).

870.3100

3-month oral toxicity 

study - mice

42050501,(1991)

Acceptable/Guideline

0, 20 500 or 2500 ppm 

(M: 0, 2.7, 65, or 352, 

F: 0, 3.4, 85, 434 

mg/kg/day) Two additional 

male groups at 850, 1450 

ppm (112, 194 mg/kg/day)

LOAEL = 500 ppm (65 mg/kg/day) in males and 2500 ppm (434 

mg/kg/day) in females based on increase in absolute and relative 

liver weights and histopathological changes (hypertrophy, necrosis).

NOAEL is 20 ppm in males (2.7 mg/kg/day) and 500 ppm in 

females (85 mg/kg/day).

870.3100

3-month oral - male 

mice 

42050502 (1991)

Acceptable/Guideline

0, 20, 500, 850, 1450 ,2500 

ppm

(0, 2.7, 65, 112, 194, 352 

mg/kg/day

LOAEL = 500 ppm (65 mg/kg/day), based on increase in absolute 

and relative liver weights and histopathological liver lesions 

(hypertrophy, necrosis, vacuolation) seen at 4, 8 and 13 weeks 

sacrifices. The NOAEL is 20 ppm (2.7 mg/kg/day)

870.3100

3-month oral - male 

mice. 

45215801 (1997) 

Supplement to MRID 

42050502: Reexamination 

of liver

Confirms findings in MRID 42050502. No change to NOAEL or 

LOAEL
Page 35 of 58

Table 4.1b Subchronic, Chronic and Other Toxicity Profile: Propiconazole

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

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) 

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)
Page 36 of 58

Table 4.1b Subchronic, Chronic and Other Toxicity Profile: Propiconazole

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

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)

870.4100

24-Month 

Chronic/Carcinogenic

ity Feeding-Rats

00129918 (1982)

Acceptable/guideline

0, 100, 500 or 2500 ppm

(male 3.6, 18.1 and 96.4 , 

female 4.6, 23.3 and 100.6 

mg/kg/day)

LOAEL = 2500 ppm (96.4 mg/kg/day) based on liver lesions 

(vacuolation of hepatocytes in males, ballooned cells in the liver of 

males, foci of enlarged hepatocytes in females, and increased 

incidence of luminal dilation of the uterus) and reduced body 

weight gain in both males and females. NOAEL = 500 ppm (18.1 

mg/kg/day). The test material was not carcinogenic at the doses 

tested. 

870.4200

24-Month 

Carcinogenicity in 

Mice

00129570 (1982 )

Acceptable/guideline

0, 100, 500 or 2500 ppm

(M: 10.0, 49.4, and 344.3 

F: 10.8, 55.6 and 340.3 

mg/kg/day

LOAEL = 500 ppm (49.5 mg/kg/day) based on non-neoplastic liver 

effects (increased liver weight in males and increase in liver lesions 

(masses/raised areas/ swellings/nodular areas mainly)). The 

NOAEL was 100 ppm (10 mg/kg/day).

Liver tumors at 2500 ppm in male mice.

870.4200

18 - month 

oncogenicity study -

male CD-1 mice

44381401 (1997)

Acceptable/guideline

0, 100, 500 or 850 ppm

(0, 11, 59 or 108 

mg/kg/day)

LOAEL= 500 ppm (59.0 mg/kg/day) for males, based on 

hepatotoxicity (increased liver weight, hepatocellular hypertrophy, 

liver necrosis) and body weight gain effects observed at the interim 

and terminal sacrifices. 

NOAEL= 100 ppm (11.0 mg/kg/day) for males.

Treatment related increase in hepatocellular adenoma and total 

hepatocellular neoplasia at the 850 ppm exposure level compared to 

concurrent controls, but were within the range of the inadequate 

historical control data submitted with the study report. Adequate 

dosing based on body weight gain and hepatotoxic effects seen at 

500 and 850 ppm. Subsequently, the Registrant submitted 

additional control data on five groups of CD-1 male mice generated 

within the approximate time frame of the original study and in the 

same testing facility under similar experimental conditions (MRID 

45215804) concerning the spontaneous occurrence of liver tumors. 

The tumor incidence observed in male livers at the 850 ppm dose is 

within the range of the new historical data. 

870.6200 

Acute neurotoxicity 

in rats

46604601 (2005)

Acceptable/guideline

0, 30, 100 or 300 mg/kg by 

gavage

LOAEL = 100 mg/kg based on clinical signs of toxicity 

(piloerection, diarrhea, tiptoe gait). 

NOAEL = 30 mg/kg.

LOAEL for neurobehavioral toxicity = 300 mg/kg based on reduced 

motor activity.

NOAEL for neurobehavioral toxicity = 100 mg/kg
Page 37 of 58

Table 4.1b Subchronic, Chronic and Other Toxicity Profile: Propiconazole

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

870-5100

Bacterial reverse 

mutation

00058601 (1979)

Unacceptable

25-2025 g/plate

Negative in Salmonella strains with or without S-9 activation. Test 

material purity not specified, not tested up to cytotoxic dose.

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 38 of 58

Table 4.1b 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%

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 39 of 58

Table 4.1b 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 40 of 58

Table 4.1b Subchronic, Chronic and Other Toxicity Profile: Propiconazole

Guideline No./ Study 

Type

MRID No. (year)/ 

Classification /Doses

Results

Non- guideline 

Special study

Mechanistic studies: 

Hepatocellular 

proliferation - Mouse

45215802 (1999)

Male CD-1 mice 40/dose 

propiconazole at 0, 850 or 

2500 ppm (0, 127, 353 

mg/kg/day) for up to 60 

days. A group of 40 mice 

given 850 ppm PB. Five 

mice/group were sacrificed 

on days 1, 2, 3, 4, 7, 28, or 

60 (IP injection of 100 

mg/kg BrdU two hours 

prior to sacrifice)

Test material and Phenobarbital (PB) induced a dose- related 

increase in absolute and relative liver weights. All mice developed 

hepatocellular hypertrophy (primarily in the centrilobular 

hepatocytes with mild effects in the midzonal hepatocytes). Liver 

necrosis and cytoplasmic vacuolation were noted. Increased mitotic 

activity was observed in all groups. Minimal to moderate 

hepatocellular nerosis of hypertrophic single or focal cells was 

found predominately in the high dose and PB group. Treatment 

with propiconazole or PB induced a >1000% increase in BrdUstaining hepatocellular nuclei within 24 hours from the start of the 

study that peaked at a >3600% increase by 48 hours. Thereafter, 

the number of BrdU-stained nuclei decreased dramatically and was 

not biologically different from controls 7 days after the start and 

through the remainder of the study. For all treatment groups, the 

BrdU-staining nuclei were found primarily in the 

centrilobular/midzonal portions of the liver. These data support the 

conclusion that propiconazole induced an initial time- and doserelated proliferation in the liver followed by a sustained treatmentrelated hypertrophy in a manner similar to the known hypertrophic 

agent PB. The hepatomegaly was attributed to a sharp and transient 

induction of hepatocellular proliferation as well as to a time- and 

dose-related increase in the severity of hepatocellular hypertrophy.
Page 41 of 58

B. STUDIES REVIEWED FOR ETHICAL CONDUCT

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.

Agricultural Re-entry Task Force (ARTF) data base (SOP #3.1)
Page 42 of 58

C. SUMMARIES OF KEY TOXICOLOGY STUDIES 

870.3700 Developmental Toxicity

Rat Developmental Toxicity - Study 1

In an acceptable/guideline developmental toxicity study (MRID 40425001), CGA 64250 

technical(92.1% purity propiconazole, Batch no. FL 850083) was administered to 24 CL:COBS 

CD (SD) BR VAF/PLUS virgin female rats/dose by oral gavage in aqueous suspensions (3% 

corn starch containing 0.5% Tween 80) at dose levels of 0, 30, 90 or 300 mg/kg/day from days 6 

through 16 of gestation. High dose animals initially received 360 mg/kg/day up to five days, but 

because of severe symptoms it was reduced to 300 mg/kg/day. Severe compound-related 

maternal toxicity was observed at the high dose level during the first five days of dosing 

beginning on day 8 of gestation at 360 mg/kg/day. These included statistically significant 

increases in the incidence of lethargy, ataxia, salivation, and biologically significant increases in 

rales, prostration, hypothermia and bradypnea. The incidence of these effects versus control is as 

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

(3/23 vs. 0/24 in controls). After lowering the dose to 300 mg/kg/day on day 6, the severity and 

frequency of these effects decreased rapidly. At the lower doses with the exception of one animal 

of the 90 mg/kg/day group exhibiting rales, there were no treatment related clinical observations. 

Mean food consumption was significantly reduced (p<0.05) in the 300 mg/kg/day group on days 

7-8, 8-9 and 9-10 and in the 90 mg/kg/day group on days 8-9 and 10-11. Maternal body weights 

were not affected by the treatments. Maternal body weight gains were significantly decreased 

(p<0.05) in the 90 mg/kg/day group (44% of controls) and in the high dose group (38% of 

controls) during gestation days 6-8 only. This effect was considered to be temporary and not 

treatment related. No significant treatment-related effects on uterine weights, corpora lutea, live 

and dead fetuses, fetal weights, and resorption were reported. The maternal toxicity LOAEL 

of propiconazole is 300 mg/kg/day, based on severe clinical toxicity. The maternal toxicity 

NOAEL is 90 mg/kg/day. Fetotoxic effects observed included a high incidence of rudimentary

ribs, though not statistically significant but part of dose related trend (0.7%, 3% and 39% in the 

30, 90 and 300 mg/kg/day groups, respectively vs. 0% in the controls), a high incidence of unossified sternebrae (57%, p< 0.05 in the 90 mg group, and 72%, p< 0.01 in the 300 mg group vs. 

38% in the controls), as well as increased incidence of shortened renal papillae (26% in the 90 

mg group (not statistically significant) and 39% in the 300 mg group, p < 0.01 vs. 23% in the 

controls) and absent renal papillae ( 5% in the 90 mg group (not statistically significant) and 11% 

in the 300 mg group, p < 0.01 vs. 3% in the controls) and dilated ureter ( 43% in the 300 mg 

group, p < 0.01 vs. 27% in the controls). External and visceral examination revealed a very low 

incidence of cleft plate malformations in the 90 mg group (0.3%) and in the 300 mg group 

(0.7%) and considered to be “probably compound related”. Historical controls in 19 teratology

studies from this laboratory had no incidence of cleft palate. The cleft palate incidence in the 

current study was probably under reported because only half of the fetuses were examined 

viscerally. It was also concluded that the low incidence of this finding along with skeletal 

anomalies was indicative of delayed development. The cleft palate finding at 300 mg/kg/day

was also confirmed in a separate study (MRID 40425002) where propiconazole was 

administered to pregnant rats at 0 or 300 mg/kg/day during the gestation period. The 
Page 43 of 58

developmental toxicity LOAEL of propiconazole is 90 mg/kg/day, based on increased 

incidence of rudimentary ribs, un-ossified sternebrae, as well as increased incidence of 

shortened and absent renal papillae and increased cleft palate. The developmental toxicity 

NOAEL is 30 mg/kg/day.

Rat Developmental Toxicity - Study 2

In an acceptable/non-guideline developmental toxicity study (MRID 40425002), CGA 64250 

technical (92.1% purity, Batch No. FL 850083) was administered to CL:COBS CD (SD) BR 

VAF/PLUS virgin female rats by oral gavage in aqueous suspensions (3% corn starch containing 

0.5% Tween 80) at dose levels of 0 or 300 mg/kg/day from days 6 through 15 of gestation. The 

control group comprised 178 sperm positive animals and the compound treated group comprised 

189 sperm positive animals. The study was intended to confirm the finding of cleft palate in the 

previous study (MRID 40425001). The death of two dams from the treated group was 

considered incidental. Severe maternal toxicity was observed during the treatment period 

beginning on gestation day 6 and included a statistically significant increase in the incidence of 

ataxia (42% vs. 0 in controls), coma (9% vs. 0 in controls), lethargy (44% vs. 0 in controls), 

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 
Page 44 of 58

animal delivered early. Among animals of the high dose group, an increased incidence of stool 

alterations (decreased/no/soft; 18/19 vs. 11/19 in controls, p<0.05) was observed, possibly 

compound related. During the dosing period (days 7-19), the high and mid dose animals had a 

significant (p<0.05) decrease in food intake (43 - 63% of the controls and 58-78% of the controls 

in the high- and mid-dose groups, respectively) and a severe decrease in the maternal body 

weight gain, but rebounded to normal after withdrawal of the test compound. During GD 7-10, 

the maternal animals had a weight loss of 0.047 and 0.111 kg at 250 and 400 mg/kg, 

respectively, compared to a weight gain of 0.018 kg in controls. The weight gains during GD 

10-20 were 67-77% and 11-43% of controls at 250 and 400 mg/kg/day, respectively. An 

increased incidence of the formation of 13th rib was observed at 400 mg/kg/day. The incidence of 

this finding on fetuses/litter basis was 2.7, 3.9, 4.1 and 5.3 at 0, 100, 250 and 400 mg/kg/day, 

respectively. The incidence of fetuses at 400 mg/kg/day with this finding was statistically

significant. Therefore, this finding was considered to be treatment-related. The increase in the 

number of resorptions at 400 mg/kg/day was caused by the resorption of an entire litter. At 400 

mg/kg/day there was also an increased incidence of abortions. The maternal toxicity LOAEL 

of propiconazole in the rabbit is 250 mg/kg/day, based on reduced maternal body weight 

gains and decreased food consumption during the dosing period. The maternal toxicity 

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. 

870-3800 Reproductive Toxicity 

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. 
Page 45 of 58

The incidence of “hepatic clear-cell change” was significantly increased in F0 high-dose males, 

F1 mid-dose and high-dose males and F1 high-dose females (p<0.05). The LOAEL for 

parental toxicity is 500 ppm (42 mg/kg/day) based on increased hepatic clear-cell change 

and the NOAEL for parental toxicity is 100 ppm (8 mg/kg/day). Reproductive parameters 

(mating, fecundity, gestation, male and female fertility indices, litter resorptions and gestation 

duration) were comparable in all groups. Offspring Toxicity: The number and percent of viable 

pups at birth and surviving through weaning were comparable between the dose groups and 

controls for both the F1a and F1b litters. In the F2a litters, however, the number of pups delivered, 

delivered viable and surviving to day 4 of lactation were significantly (p<0.01) reduced in the 

high-dose group. The percentages of high-dose pups delivered viable and surviving to day 4 

were also reduced (not statistically significant). The F2b litters of these dams had significantly 

reduced survival rates (both number and percent of surviving pups) at lactation days 7, 14, and 

21. The mean body weights of high-dose progeny were significantly reduced at days 14 and 21 

for pups of both generations (72-81% of controls). Reductions were also significant on days 4 

and 7 (except for F1b litters) and at birth (F2b litters only). At necropsy, no treatment related 

anomalies, organ weight changes and gross pathology findings were noted in pups. 

Histopathological evaluation of selected organs from F1b and F2b progeny revealed significantly 

(p<0.01) increased incidences of hepatic “cellular swelling” in high-dose males and females. 

This was considered to be a compound related effect. The LOAEL and NOAEL for offspring 

toxicity are at 2500 ppm (192-263 mg/kg/day) and 500 ppm (43-52 mg/kg/day), respectively, 

based on decreased offspring survival and body weights and an increased incidence of 

hepatic lesions (cellular swelling) at 2500 ppm. 

Additional Developmental/Reproduction Toxicity Information from Literature Sources

In a published study, propiconazole (Tilt 100 EC in the form of 10% solution) was administered 

to groups of pregnant female albino rats (15/dose) at 0, 75.85 or 151.70 mg (ai)/kg/day on days 

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.

870.4200b Mouse Carcinogenity Study

In a 24-month oncogenicity study (MRIDs 00129570, 00151503, 00130844 and 93194037), 

CGA 64250 technical (Batch No. P4-6, 87.2-91.9% purity) was administered to groups of CD-1 

mice (52/sex/dose) in the diet at concentrations of 0, 100, 500, or 2500 ppm (10.0, 49.4, and 
Page 46 of 58

344.3 mg/kg/day for males and 10.8, 55.6 and 340.3 mg/kg/day for females, respectively). A 

satellite group (12 mice/sex/dose) was sacrificed at one year. Diets were prepared weekly. 

During the first year of the study, the test material was ground directly into basal diet. During 

the second year, the test substance was dissolved in ethyl acetate prior to incorporation into the 

diet to improve the homogeneity of the test material in the diet. However, the EPA reviewers 

questioned the use of the ethyl acetate and its impact on the study. The results of analyses for 

purity (including identification of all impurities) and stability of the test material in the diet 

provided later by the registrant were found to be satisfactory (HED doc. No. 005352).

A review of the individual clinical observations revealed no obvious treatment-related in-life 

signs (HED doc. No. 005352). An increase in mortality was noted in males of the 2500 ppm 

group during the first 6 months. This finding is considered compound-related. Survival at 104 

weeks for the control, 100, 500 and 2500 ppm groups was 46%, 38%, 40%, and 27% for the 

males and 54%, 63%, 46% and 62% for the females, respectively. However, sufficient number 

of animals were alive at study termination to assess the carcinogenic potential of the test 

material.

Sporadic decreases in body weight gain, particularly in the high dose male and female groups 

were noted. Food consumption was increased in high dose male mice only.

There were no compound-related effects on hematological parameters examined. SGPT and 

SGOT were significantly increased in high dose males and females at 52 weeks and in high dose 

males at 100 weeks. SAP was increased in high dose males at week 100. These changes are 

considered indicative of liver damage. Urinalysis results did not reveal any treatment-related 

effects.

Increased liver weight was noted in high and mid dose males and in high dose females both at 

interim and terminal sacrifice. There was good correlation between gross and microscopic 

findings. Enlarged livers containing gross pathological changes were seen in high dose animals. 

Non-neoplastic changes in high dose males and females consisted of hepatocyte enlargement, 

vacuolation and fat deposition. Liver histopathology of low and mid dose mice was comparable 

to those of controls.

Amyloidosis occurred more frequently in treated animals compared to controls, but was not 

dose-related.

Necropsy observations at the termination of the study indicated a treatment-related increase in 

liver lesions (masses/raised areas/ swellings/nodular areas mainly) among mid- and high-dose 

males (150% and 140% of controls, respectively) and in high-dose females (367% of control).

CGA 64250 treatment was associated with early expression of malignant liver cell tumors in 

male mice. The incidences of malignant (presumably carcinomas) liver tumors at the one year 

interim sacrifice were 0/11, 0/11 1/11, and 3/9 in the control, low, mid and high dose males, 

respectively. No liver tumors were found in any of the female mice sacrificed at the 1-year 

interim sacrifice.
Page 47 of 58

The total incidences of combined liver adenomas/carcinomas in males for the control, 100, 500 

and 2500 ppm groups were 28/64, 14/64, 25/62 and 48/64, respectively. For females the 

incidence was 5/64, 1/64, 2/64 and 8/64 in the control, 100, 500 and 2500 ppm groups, 

respectively. The combined incidence of liver tumors was statistically significant (p< 0.001) at 

the high dose level for males.

Male mice given CGA 64250 technical at 2500 ppm in the diet developed liver tumors. The 

LOAEL was 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).
Page 48 of 58

D. REFERENCES FOR TOXICITY STUDIES

82-1 Subchronic Oral Toxicity: 90-Day Study

MRID Citation Reference

58606 Sachsse, K.; Suter, P.; Luetkemeier, H.; et al. (1979) CGA 64'250 Techn. Three Months 

Toxicity Study on Rats: Project No. 790014. Final rept. (Unpublished study received 

Jan 28, 1981 under 100-618; prepared by Ciba-Geigy Ltd., Switzerland, submitted by 

Ciba-Geigy Corp., Greensboro, N.C.; CDL:244271-Q) 

58607 Sachsse, K.; Bathe, R.; Luetkemeier, H.; et al. (1979) CGA 64'250 3-Month Toxicity 

Study on Dogs. Final rept. (Unpublished study received Jan 28, 1981 under 100-618; 

prepared by Ciba-Geigy Ltd., Switzerland, submitted by Ciba-Geigy Corp., Greensboro, 

N.C.; CDL:244271-R) 

146771 Maruhn, D.; Bomhard, E. (1984) Triazolylalanine (THS 2212) Study for Subchronic 

Toxicity to Rats (Three-month Feeding Study): Report No. 12397. Unpublished study 

prepared by Bayer AG Institute of Toxicology. 258 p. 

151511 Ciba-Geigy Corp. (1985) Response by Ciba-Geigy to EPA Review of the 90-day

Feeding Study in Rats with Triazole Alanine: [Includes Clinical, Ophthalmological, and 

Analytical Chemistry Data of Bayer Report 12397]. Unpublished compilation. 41 p. 

42050501 Potrepka, R.; Turnier, J. (1991) Subchronic Dietary Toxicity Study with CGA-64250 in 

Mice: Lab Project Number: F-00098. Unpublished study prepared by Ciba-Geigy Corp. 

302 p. 

42050502 Potrepka, R.; Turnier, J. (1991) 13-Week Dietary Toxicity Study with CGA-64250 in 

Male Mice: Lab Project Number: F-00107. Unpublished study prepared by Ciba-Geigy 

Corp. 226 p. 

45215801 Hardisty, J. (1997) 13-Week Dietary Toxicity Study with CGA-64250 in Male Mice: Final 

Report: (Supplement for MRID No.42050502): Lab Project Number: 140-081: F-00107: 

799-97. Unpublished study prepared by Experimental Pathology Laboratories, Inc. 51 

p. 

93194032 Gillis, J.; Tisdel, M. (1990) Ciba-Geigy Corp. Phase 3 Summary of MRID 00058606. 90-

Day Toxicity Study in Rats: Propiconazole: Study # 790014. Prepared by CIBA-CEIGY

Limited. 13 p. 

93194033 Gillis, J.; Tisdel, M. (1990) Ciba-Geigy Corp. Phase 3 Summary of MRID 00058607. 90-

Day Toxicity Study in Dogs: Study # 785751. Prepared by CIBA-GEIGY Limited. 12 p. 

93194083 Sachsse, K.; Suter, P.; Luetkemeier, H. et al. (1990) Ciba-Geigy Corp. Phase 3 

Reformat of MRID 00058606. Three Months Toxicity Study on Rats: Propiconazole: 

Study # 790014. Prepared by CBIA-GEIGY Limited. 195 p. 

93194084 Sachsse, K.; Bathe, R.; Luetkemeier, H. et al. (1990) Ciba-Geigy Corp. Phase 3 

Reformat of MRID 00058607. Three Month Toxicity Study on Dogs: Propiconazole: 

Study # 785751. Prepared by Ciba-Geigy Limited. 204 p. 

82-2 21-day dermal-rabbit/rat

MRID Citation Reference
Page 49 of 58

116591 Larson, E.; Matthews, R.; Naismith, R.; et al. (1982) 21 Day Dermal Toxicity Study in 

Rabbits: (CGA-64250 Technical): PH 430-CG-001- 82. Rev. (Unpublished study 

received Oct 4, 1982 under 100- 641; prepared by Pharmakon Research International, 

Inc., sub- mitted by Ciba-Geigy Corp., Greensboro, NC; CDL:248442-E) 

93194034 Gillis, J.; Tisdel, M. (1990) Ciba-Geigy Corp. Phase 3 Summary of MRID 00116591. 21-

Day Dermal Study in Rabbit: Study # 430-CG-001-82. Prepared by Pharmakon 

Research International. 12 p. 

83-1 Chronic Toxicity

MRID Citation Reference

74494 Hunter, B.; Slater, N.D. (1981) CGA 64 250: Potential Tumorigenic and Toxic Effects in 

Prolonged Dietary Administration to Rats (84 Week Status Report): Tox. Dispo. 78 

9023. (Unpublished study, including letter dated Apr 23, 1981 from N.D. Slater to R. 

Hess, received Jun 8, 1981 under 100-EX-69; prepared by Huntingdon Research 

Centre, England, submitted by Ciba-Geigy Corp., Greensboro, N.C.; CDL:070162-A) 

84153 Hunter, B. (1981) Letter sent to R. Hess dated Apr 23, 1981: CGA 64 250: Long term 

feeding study in mice: Test No. 78 9022. (Unpublished study received Jun 8, 1981 

under 100-EX-69; pre- pared by Huntingdon Research Centre, England, submitted by 

Ciba- Geigy Corp., Greensboro, N.C.; CDL:070162-B) 

129570 Hunter, B.; Scholey, D.; Haywood, R.; et al. (1982) CGA 64 250: Long-term Feeding 

Study in Mice: CBG/196/81827. Final rept. (Unpublished study received Jul 21, 1983 

under 100-641; prepared by Huntingdon Research Centre, Eng., submitted by CibaGeigy Corp., Greensboro, NC; CDL:250784-A; 250785; 250786) 

130844 Ciba-Geigy Corp. (19??) CGA-64250: Long-term Feeding Study in Mice: Incidence of 

Liver Tumors in Males. (Unpublished study received Sep 14, 1983 under 100-641; 

CDL:251237-A) 

151502 Ciba-Geigy Corp. (1985) Response to EPA Review of the Two-Year Dietary 

Oncogenicity and Chronic Toxicity Study with CGA-64250 Technical: [Includes 

Historical Control Data and an Addendum to the HRC Report No. CBG 193/8284]. 

Unpublished compilation. 373 p. 

151503 Ciba-Geigy Corp. (1985) Response to the EPA Review of the Long-Term Feeding 

Study in Mice with CGA-64250 Technical: [Includes Chem- istry Data of Test Material, 

Details of Diet Preparation, Summa- ry of Incidence of Clinical Signs, and Addendum to 

Report CBG 196/81827]. Unpublished compilation. 214 p. 

151515 Johnson, W.; Thompson, S. (1985) One-year Subchronic Oral Toxicity Study in Beagle 

Dogs with CGA-64250 Technical: (Final Report): FDRL Study No. 7737. Unpublished 

study prepared by Food and Drug Research Laboratories, Inc. 570 p. 

40783302 Ballantine, L. (1988) Tolerance Assessment System: Routine Chronic Analysis 

(Propiconazole-Celery). Unpublished study prepared by Ciba-Geigy Corp. 23 p. 

40783304 Anon. (1988) Tolerance Assessment System Routine Chronic Analysis: PropiconazoleCorn. Unpublished study prepared by Ciba-Geigy Corp. 24 p. 

40783307 Ballantine, L. (1988) Tolerance Assessment System Routine Chronic Analysis: 

Propiconazole-Pineapple. Unpublished study prepared by Ciba-Geigy Corp. 23 p. 
Page 50 of 58

40783309 Ballantine, L. (1988) Tolerance Assessment System Routine Chronic Analysis: 

Propiconazole--Dry Beans. Unpublished study prepared by Ciba-Geigy Corp. 28 p. 

41063803 Ballantine, L. (1988) Tolerance Assessment System Routine Chronic Analysis 

Propiconazole-Stoned Fruit. Unpublished study prepared by Ciba-Geigy Corp. 26 p. 

93194035 Gillis, J.; Tisdel, M. (1990) Ciba-Geigy Corp. Phase 3 Summary of MRID 00129918 and 

Related MRIDs 00074494, 00151502. Combined Chronic Oncogenicity/ Toxicity Study 

in Rats: Study # 193/8284. Prepared by Huntingdon Research Centre. 15 p. 

93194036 Gillis, J.; Tisdel, M. (1990) Ciba-Geigy Corp. Phase 3 Summary of MRID 00151515. 

One-Year Oral Toxicity Study in the Dog: Study # 7737. Prepared by Food & Drug 

Research Labs. Inc. 13 p. 

83-2 Oncogenicity

MRID Citation Reference

129918 Hunter, B.; Slater, N.; Heywood, R.; et al. (1982) CGA 64 250: Potential Tumorigenic 

and Toxic Effects in Prolonged Dietary Administration to Rats: CBG 193/8284 (Test No. 

789023). Final rept. (Unpublished study received Jul 21, 1983 under 100-641; prepared 

by Huntingdon Research Centre, Eng., submitted by Ciba- Geigy Corp., Greensboro, 

NC; CDL:250787-A; 250788; 250789; 250790) 

130844 Ciba-Geigy Corp. (19??) CGA-64250: Long-term Feeding Study in Mice: Incidence of 

Liver Tumors in Males. (Unpublished study received Sep 14, 1983 under 100-641; 

CDL:251237-A) 

151502 Ciba-Geigy Corp. (1985) Response to EPA Review of the Two-Year Dietary 

Oncogenicity and Chronic Toxicity Study with CGA-64250 Technical: [Includes 

Historical Control Data and an Addendum to the HRC Report No. CBG 193/8284]. 

Unpublished compilation. 373 p. 

151503 Ciba-Geigy Corp. (1985) Response to the EPA Review of the Long-Term Feeding 

Study in Mice with CGA-64250 Technical: [Includes Chem- istry Data of Test Material, 

Details of Diet Preparation, Summa- ry of Incidence of Clinical Signs, and Addendum to 

Report CBG 196/81827]. Unpublished compilation. 214 p. 

151516 Waechter, F.; Bentley, P.; Staeubli, W. (1984) The Effect of Propi- conazole on Drug 

Metabolizing Enzymes in the Liver of Male Rats and Mice. Unpublished study prepared 

by Ciba-Geigy Ltd. 22 p. 

151517 Froehlich, E.; Bentley, P.; Staeubli, W.; et al. (1984) Promo- tion Study with CGA 

64250: [Study on the Influence of CGA 64250 in the Formation of Focal Proliferative 

Changes in the Rat Li- ver]: GU Exploratory Research Project No. 834015. Unpublished 

study prepared by Ciba-Geigy Ltd. 553 p. 

41178301 Stevens, J. (1989) Propiconazole Technical: Perspective: Liver Tumor Response Noted 

in Male Mice After the Administration of an Excessive Level of Propiconazole. 

Unpublished study prepared by Ciba-Geigy Corp. 23 p. 

44381401 Gerspach, R. (1997) CGA-64250 Technical: 18-Month Oncogenicity Study in Mice: Lab 

Project Number: 943126. Unpublished study prepared by Novartis Crop Protection Ag. 

453 p. 

45215804 Gerspach, R. (1999) 18-Month Oncogenicity Study in Mice: Final Report 
Page 51 of 58

(Propiconazole): Lab Project Number: 943126: 800-97. Unpublished study prepared by 

Novartis Crop Protection AG. 64 p. {OPPTS 870.4200} 

93194035 Gillis, J.; Tisdel, M. (1990) Ciba-Geigy Corp. Phase 3 Summary of MRID 00129918 and 

Related MRIDs 00074494, 00151502. Combined Chronic Oncogenicity/ Toxicity Study 

in Rats: Study # 193/8284. Prepared by Huntingdon Research Centre. 15 p. 

93194037 Gillis, J.; Tisdel, M. (1990) Ciba-Geigy Corp. Phase 3 Summary of MRID 00129570 and 

Related MRIDs 00084153, 00151503, 00130844. Long-Term Feeding Study in Mice: 

Propiconazole: Study # 196/81827. Prepared by Huntingdon Research Centre. 14 p. 

83-3 Teratogenicity -- 2 Species

MRID Citation Reference

58604 Fritz, H.; Becker, H. (1979) Report on CGA 64'250 Tech.: Teratology Study (Seg. II) in 

Rats: Project No. 790011. (Unpublished study received Jan 28, 1981 under 100-618; 

prepared by Ciba-Geigy Ltd., Switzerland, submitted by Ciba-Geigy Corp., Greensboro, 

N.C.; CDL:244271-O) 

58605 Fritz, H.; Becker, H. (1979) Report on CGA 64'250 Tech.: Teratology Study (Seg. II) in 

Rabbits: Project No. 790009. (Unpublished study received Jan 28, 1981 under 100-618; 

prepared by Ciba- Geigy Ltd., Switzerland, submitted by Ciba-Geigy Corp., Greensboro, N.C.; CDL:244271-P) 

132915 Clapp, M.; Killick, K.; Hollis, K.; et al. (1983) Triazole Alanine: Teratogenicity Study in 

the Rat: Report No. CTL/P/875. (Unpub- lished study received Dec 12, 1983 under 100-

617; prepared by Imperial Chemical Industries Plc., U.K., submitted by Ciba-Geigy 

Corp., Greensboro, NC; CDL:072208-H) 

143454 Ciba-Geigy Corp. (1984) Response by Ciba-Geigy to the April 12, 1984 Letter 

Regarding Rat and Rabbit Teratology Studies with CGA-64250 Technical. Unpublished 

compilation. 467 p. 

163322 Conn, R. (1986) Letter sent to H. Jacoby dated Sep 4, 1986: Tilt Fungicide ...: 

Additional teratology information. Prepared by Ciba-Geigy Corp. 3 p. 

164800 Raab, D.; Youreneff, M.; Giknis, L.; et al. (1986) CGA-64250 Tech- nical: A Teratology 

Study in New Zealand White Rabbits: Toxico- logy/Pathology Report 86043 (MIN 

852172). Unpublished study prepared by Ciba-Geigy Corp. 437 p. 

40425001 Giknis, M. (1987) CGA-64250 Technical: Teratology (Segment II) Study in Rats: 

Laboratory Project ID 86004. Unpublished study prepared by Ciba-Geigy Corporation, 

Pharmaceuticals Div.. 425 p. 

40425002 Mallows, S.; Levy, E.; Goknis, M.; et al. (1987) CGA-64250: A Modified Teratology 

(Segment II) Study in Albino Rats ...: Laboratory Project ID 86189. Unpublished study 

prepared by Ciba-Geigy Corporation. 408 p. 

40425004 Raab, D.; Youreneff, M.; Giknis, M.; et al. (1987) Propiconazole: A Teratology Study in 

New Zealand Rabbits: Final Report Amendment No. 1: Laboratory Project ID 86043. 

Unpublished study prepared by Ciba-Geigy Corporation. 125 p. 

93194038 Gillis, J.; Tisdel, M. (1990) Ciba-Geigy Corp. Phase 3 Summary of MRID 40425001. 

Teratology Study in Rats: Propiconazole: Study # MIN 852148. Prepared by CIBAGEIGY Corp. 12 p. 
Page 52 of 58

93194039 Gillis, J.; Tisdel, M. (1990) Ciba-Geigy Corp. Phase 3 Summary of MRID 40425002. 

Modified Teratology Study in Rats: Propiconazole: Study # MIN 862244. Prepared by 

CIBA-GEIGY Corp. 12 p. 

93194040 Gillis, J.; Tisdel, M. (1990) Ciba-Geigy Corp. Phase 3 Summary of MRID 00164800 and 

Related MRIDs 40425004. Teratology Study in Rabbits: Propiconazole: Study # MIN 

852172. Prepared by CIBA-GEIGY Corp. 12 p. 

83-4 2-generation repro.-rat

MRID Citation Reference

132916 Birtley, R. (1983) Triazole Alanine: Preliminary Reproduction Study in the Rat: Report 

No. CTL/L/470. (Unpublished study received Dec 12, 1983 under 100-617; prepared by 

Imperial Chemical In- dustries Plc., U.K., submitted by Ciba-Geigy Corp., Greensboro, 

NC; CDL:072208-I) 

132917 Birtley, R.; Milburn, G.; Corrigan, M.; et al. (1983) Triazole Alanine: Rat Multigeneration 

Study: CTL Study No. RR0255/F0, Parental Generation and RR0255/F1, Subsequent 

Generation. Prog- ress rept., Jun 21, 1983. (Unpublished study received Dec 12, 1983 

under 100-617; prepared by Imperial Chemical Industries Plc., U.K., submitted by CibaGeigy Corp., Greensboro, NC; CDL: 072208-J) 

133350 Fritz, H.; Giese, K.; Zak, F. (1981) Report on CGA 64250 Tech.: 2- Generation Study in 

Rats: Test No. 79 0010. (Unpublished study received Dec 12, 1983 under 100-617; 

prepared by Ciba-Geigy Ltd., Switz., submitted by Ciba-Geigy Corp., Greensboro, NC; 

CDL:072206-K) 

138167 Salamon, C.; Place, M.; Mayhew, D.; et al. (1984) Two-generation Reproduction Study 

in Albino Rats with CGA-64250 Technical: Study No. 450-1202. Interim rept. 

(Unpublished study received Feb 8, 1984 under 100-617; prepared by Toxigenics, Inc., 

submit- ted by Ciba-Geigy Corp., Greensboro, NC; CDL:252368-A; 252369) 

151514 Borders, C.; Salamon, C. (1985) Two-Generation Reproduction Study in Albino Rats 

with CGA-64250 Technical: Toxigenics Study 450- 1202. Unpublished study prepared 

by Toxigenics, Inc. 1886 p. 

163164 Salamon, C. (1983) Two-generation Reproduction Study in Albino Rats Using CGA64250 Technical: Study No. 450-1202. Unpublished study prepared by ToxiGenics, Inc. 

20 p. 

93194041 Tisdel, M. (1990) Ciba-Geigy Corp. Phase 3 Summary of MRID 00138167 and Related 

MRIDs 00151514, 00163164. Two-Generation Reproduction Study in Rats: Study # 

450-1202. Prepared by Toxigenics, Inc. 12 p. 

84-2 Interaction with Gonadal DNA

MRID Citation Reference

58601 Arni, P.; Muller, D. (1979) Salmonella/Mammalian-Microsome Muta- genicity Test with 

CGA 64 250: No. of Experiment: 78/2577. (Un- published study received Jan 28, 1981 

under 100-618; prepared by Ciba-Geigy Ltd., Switzerland, submitted by Ciba-Geigy

Corp., Greensboro, N.C.; CDL:244271-L) 

58602 Hool, G. (1979) Dominant Lethal Study: CGA 64 250: Mouse: No. of Experiment: 
Page 53 of 58

790034. (Unpublished study received Jan 28, 1981 under 100-618; prepared by CibaGeigy Ltd., Switzerland, submit- ted by Ciba-Geigy Corp., Greensboro, N.C.; 

CDL:244271-M) 

58603 Hool, G.; Langauer, M. (1979) Nucleus Anomaly Test in Somatic In- terphase Nuclei: 

CGA 64 250: Chinese Hamster: No. of Experiment: 79-0805. (Unpublished study 

received Jan 28, 1981 under 100- 618; prepared by Ciba-Geigy Ltd., Switzerland, 

submitted by Ciba-Geigy Corp., Greensboro, N.C.; CDL:244271-N) 

132911 Herbold, B.; Lorke, D. (1983) THS 2212 Triazolylalanine: Salmonella/Microsome Test 

for Point Mutagenic Effect: Report No. 11388. (Unpublished study received Dec 12, 

1983 under 100-617; prepared by Bayer AG, W. Ger., submitted by Ciba-Geigy Corp., 

Greensboro, NC; CDL:072208-B) 

132912 Herbold, B.; Lorke, D. (1982) THS 2212 (Triazolylalanine): Micro- nucleus Test for 

Mutagenic Effect on Mice: Report No. 11054. (Unpublished study received Dec 12, 

1983 under 100-617; prepared by Bayer AG, W. Ger., submitted by Ciba-Geigy Corp., 

Greensboro, NC; CDL:072208-D) 

132913 Herbold, B. (1983) THS 2212 (Triazolylalanine): Pol A1 Test on E. coli during Testing 

for Effects Harmful to DNA: Report No. 11390. (Unpublished study received Dec 12, 

1983 under 100- 617; prepared by Bayer AG, W. Ger., submitted by Ciba-Geigy Corp., 

Greensboro, NC; CDL:072208-E) 

132914 Richold, M.; Allen, J.; Williams, A.; et al. (1981) Cell Trans- formation Test for Potential 

Carcinogenicity of R152056: ICI 394A/81153; CTL/C/1085. (Unpublished study 

received Dec 12, 1983 under 100-617; prepared by Huntingdon Research Centre, Eng., 

submitted by Ciba-Geigy Corp., Greensboro, NC; CDL: 072208-F) 

133342 Strasser, F. (1982) L5178Y/TK +/- Mouse Lymphoma Mutagenicity Test: CGA 64 250 

(in vitro Test for Mutagenic Properties of Chemical Substances in Mammilian Cells): 

Experiment # 811516. (Unpub- lished study received Dec 12, 1983 under 100-617; 

prepared by Ciba-Geigy Ltd., Switz., submitted by Ciba-Geigy Corp., Greens- boro, NC; 

CDL:072206-B) 

133343 Arni, P. (1982) Saccharomyces cerevisiae D7/Mammalian-microsome Mu- tagenicity 

Test in vitro with CGA 64 250 (Test for Mutagenic Properties in Yeast Cells): 

Experiment No. 811558. (Unpublished study received Dec 12, 1983 under 100-617; 

prepared by Ciba- Geigy Ltd., Switz., submitted by Ciba-Geigy Corp., Greensboro, NC; 

CDL:072206-C) 

133344 Strasser, F. (1982) Point Mutation Assay with Mouse Lymphoma Cells Host-mediated 

Assay with CGA 64 250 (Test for Mutagenic Proper- ties in Mammilian Cells): 

Experiment No. 811513. (Unpublished study received Dec 12, 1983 under 100-617; 

prepared by Ciba- Geigy Ltd., Switz., submitted by Ciba-Geigy Corp., Greensboro, NC; 

CDL:072206-D) 

133345 Hool, G. (1982) Chromosome Studies in Male Germinal Epithelium: CGA 64 250: 

Mouse (Test for Mutagenic Effects on Spermatogonia): Experiment No. 811511. 

(Unpublished study received Dec 12, 1983 under 100-617; prepared by Ciba-Geigy 

Ltd., Switz., submitted by Ciba-Geigy Corp., Greensboro, NC; CDL:072206-E) 

133346 Hool, G. (1982) Chromosome Studies in Male Germinal Epithelium: CGA 64 250: 

Mouse (Test for Mutagenic Effects on Spermatocytes): Ex- periment No. 811512. 

(Unpublished study received Dec 12, 1983 under 100-617; prepared by Ciba-Geigy 

Ltd., Switz., submitted by Ciba-Geigy Corp., Greensboro, NC; CDL:072206-F) 
Page 54 of 58

133347 Puri, E. (1982) Autoradiographic DNA Repair Test on Human Fibro- blasts: CGA 64 

250 (in vitro Test for DNA-damaging Properties): Experiment No. 811655. (Unpublished 

study received Dec 12, 1983 under 100-617; prepared by Ciba-Geigy Ltd., Switz., 

submitted by Ciba-Geigy Corp., Greensboro, NC; CDL:072206-G) 

133348 Puri, E. (1982) Autoradiographic DNA Repair Test on Rat Hepato- cytes: CGA 64 250 

(in vitro Test for DNA-damaging Properties): Experiment No. 811514. (Unpublished 

study received Dec 12, 1983 under 100-617; prepared by Ciba-Geigy Ltd., Switz., 

submitted by Ciba-Geigy Corp., Greensboro, NC; CDL:072206-H) 

133349 Strasser, F. (1982) BALB/3T3 Cell Transformation Assay: CGA 64 250 (in vitro Test for 

Transformation-inducing Properties in Mammal- ian Fibroblasts): Experiment No. 

790806. (Unpublished study re- ceived Dec 12, 1983 under 100-617; prepared by CibaGeigy Ltd., Switz., submitted by Ciba-Geigy Corp., Greensboro, NC; CDL 072206-J) 

133361 Watkins, P.; Rutty, D.; Topham, J.; et al. (1982) R152056: 3-(1,2, 4,-Triazol-1-yl)

Alanine (ICI 156,342)--Micronucleus Test in CBC Fl Mice: TOM/4. (Unpublished study 

received Dec 12, 1983 under 100-617; prepared by Imperial Chemical Industries Plc., 

U.K., submitted by Ciba-Geigy Corp., Greensboro, NC; CDL: 072208-C) 

151504 Strasser, F. (1985) L5178Y+/- Mouse Lymphoma Mutagenicity Test: CGA 64250: 

Supplement to the Report Dated August 10, 1982: Test No. 811516. Unpublished study 

prepared by Ciba-Geigy Ltd. 8 p. 

151505 Arni, P. (1985) Saccharomyces cerevisae D7/Mammalian-Microsome Mutagenicity Test 

in vitro: CGA 64250: Supplement to the Re- port Dated August 19, 1982: Test No. 

811558. Unpublished study prepared by Ciba-Geigy Ltd. 5 p. 

151506 Hool, G. (1985) Chromosome Studies on the Germinal Epithelium of Mouse 

Spermatogonia: CGA 64250: Supplement to the Report Dated August 31, 1982: Test 

No. 811511. Unpublished study prepared by Ciba-Geigy Corp. 4 p. 

151507 Hool, G. (1985) Chromosome Studies on the Germinal Epithelium of Mouse 

Spermatocytes: CGA 64250: Supplement to the Report Dated August 13, 1982: Test 

No. 811512: Test No. 811512. Unpublished study prepared by Ciba-Geigy Ltd. 3 p. 

151508 Puri, E. (1985) Autoradiographic DNA Repair Test on Human Fibro- blasts: CGA 

64250: Supplement to the Report Dated August 12, 1985: Test No. 811655. 

Unpublished study prepared by Ciba- Geigy Ltd. 10 p. 

151509 Puri, E. (1985) Autoradiographic DNA Repair Test on Rat Hepato: cytes: CGA 64250: 

Supplement to the Report Dated August 12, 1982: Test No. 811514. Unpublished study 

prepared by Ciba- Geigy Ltd. 12 p. 

151510 Hool, G. (1985) Sister Chromatid Exchange Study in Somatic Cells of Chinese Hamster 

Bone Marrow: CGA 64250: Supplement to the Re- port Dated October 18, 1982: Test 

No. 811515. Unpublished study prepared by Ciba-Geigy Ltd. 2 p. 

163163 Hool, G. (1982) Sister Chromatid Exchange Study: Test for Muta- genic Effects on 

Bone Marrow Cells: CGA 64 250: Chinese Hamster: Experiment No. 811515. 

Unpublished study prepared by Ciba-Geigy Limited. 8 p. 

165468 Strasser, F. (1985) Point Mutation Assay with Mouse Lymphoma Cells Host Mediated 

Assay: (Test for Mutagenic Properties in Mammalian Cells): CGA 64250: Supplement to 

the Report Dated August 10, 1982: Test No. 811513. Unpublished study prepared by 

Ciba-Geigy Ltd. 4 p. 
Page 55 of 58

41594802 Deparade, E. (1983) CGA-64250 Technical: Salmonella/Mammalian-Micro some 

Mutagenicity Test: Lab Project Number: 830121. Unpublished study prepared by CibaGeigy Ltd. 31 p. 

41594803 Strasser, F. (1987) CGA-64250 Technical: Micronucleus Test (Chinese Hamster): Lab 

Project Number: 860359. Unpublished study prepared by Ciba-Geigy Ltd. 28 p. 

42050504 Ogorek, B. (1983) Intrasanguine Host-Mediated Assay with S. typhim- urium: CGA64250: Lab Project Number: 830120. Unpublished study prepared by Ciba-Geigy Ltd. 

21 p. 

42050505 Strasser, F. (1984) Chromosome Studies on Human Lymphocytes in vit- ro: CGA-64 

250: Lab Project Number: 840025. Unpublished study prepared by Ciba-Geigy Ltd. 19 

p. 

45215802 Weber, E. (1999) Assessment of Hepatic Cell Proliferation in Male Mice 

(Propiconazole): Final Report: Lab Project Number: CB 97/23: 539-98. Unpublished 

study prepared by Novartis Crop Protection AG. 59 p. 

93194042 Breckenridge, C. (1990) Ciba-Geigy Corp. Phase 3 Summary of MRID 41594802. 

Salmonella/Mammalian-Microsome Mutagenicity Test: Propiconazole: Study No. 

830121. Prepared by Ciba-Geigy Limited. 12 p. 

93194043 Breckenridge, C. (1990) Ciba-Geigy Corp. Phase 3 Summary of MRID 41594803. 

Micronucleus Test - Chinese Hamster: Propiconazole: Study No. 860359. Prepared by 

Ciba-Geigy Limited. 12 p. 

93194044 Breckenridge, C. (1990) Ciba-Geigy Corp. Phase 3 Summary of MRID 00133348 and 

Related MRIDs 00151509. DNA Repair Test, Rat Hepatocytes: Propiconazole: Study # 

811514. Prepared by CIBA-GEIGY Limited. 12 p. 

85-1 General metabolism

MRID Citation Reference

74495 Marco, G.J.; Kahrs, R.A. (1981) CGA-64250--Rice and Pecans: Resi- dues Observed 

and Metabolism Data Including the Analytical Methods Used: Report No. ABR-81020. 

(Unpublished study received Jun 8, 1981 under 100-EX-69; submitted by Ciba-Geigy

Corp., Greensboro, N.C.; CDL:070163-A) 

74505 Hambock, H. (1979) Distribution, Degradation and Excretion of CGA 64 250 in the Rat: 

Project Report 24/79. (Unpublished study received Jun 8, 1981 under 100-EX-69; 

prepared by Ciba-Geigy Ltd., Switzerland, submitted by Ciba-Geigy Corp., Greensboro, 

N.C.; CDL:070164-K) 

74506 Muecke, W. (1979) Characterization of Urinary and Faecal Metabo- lites of Rats after 

Oral Application of CGA 64 250: Project Report 35/79. (Unpublished study received Jun 

8, 1981 under 100-EX-69; prepared by Ciba-Geigy Ltd., Switzerland, submitted by 

Ciba-Geigy Corp., Greensboro, N.C.; CDL:070164-L) 

74507 Mucke, W. (1981) The Major Metabolic Pathways of CGA 64 250 in the Rat: Project 

Report 9/81. (Unpublished study received Jun 8, 1981 under 100-EX-69; prepared by 

Ciba-Geigy Ltd., Switzerland, submitted by Ciba-Geigy Corp., Greensboro, N.C.; 

CDL:070164-M) 

129906 Simoneaux, B. (1983) Dermal Absorption of Triazole-14C-CGA- 64250 by Rats: Report 
Page 56 of 58

No. ABR-82068. (Unpublished study re- ceived Jul 21, 1983 under 100-641; submitted 

by Ciba-Geigy Corp., Greensboro, NC; CDL:250782-G) 

131098 Simoneaux, B. (1983) Dermal Absorption of Triazole-14C-CGA-64250 by Rats: Report 

No. ABR-82068. (Unpublished study received Sep 8, 1983 under 100-617; submitted 

by Ciba-Geigy Corp., Greensboro, NC; CDL:251239-I) 

132946 Simoneaux, B. (1983) Dermal Absorption of Triazole-14C-CGA-64250 by Rats: M5-62-

2A: Report No. ABR-82068. (Unpublished study re- ceived Dec 12, 1983 under 100-

617; submitted by Ciba-Geigy Corp., Greensboro, NC; CDL:072224-V) 

133385 Ciba-Geigy Corp. (1983) CGA-64250: Pecans. (Compilation; unpub- lished study 

received Dec 12, 1983 under 100-617; CDL:072212-A; 072213; 072214; 072215; 

072216; 072217) 

147861 Bissig, R. (19??) The Metabolism of [U-Carbon-14]-phenyl CBA 64 250 in Mice after 

Pretreatment with Unlabelled CGA 64 250: Project No. 12RB01. Unpublished study 

prepared by Agricultural Division Research and Development, Ciba-Geigy Corp. 16 p. 

164470 Wang, L. (1959) Plasma volume, cell volume, total blood volume and F cells factor in 

the normal and splenectomized Sherman rat. American Journal of Physiology 

196(1):188-192. 

164794 Ballantine, L. (1986) Propiconazole Animal Metabolism Update: Metabolism in Mice: 

Dermal Absorption in the Rat: Report No. ABR-86071. Unpublished compilation 

prepared by Ciba-Geigy Corp. 10 p. 

164795 Bissig, R. (1986) The Metabolism of [U-Carbon 14]-phenyl-CGA 64 250 in Mice after 

Pretreatment with Unlabelled CGA 64 250: Project Report 6/86. Unpublished study 

prepared by Ciba-Geigy Limited. 52 p. 

164796 Hamboeck, H. (1979) Distribution, Degradation and Excretion of CGA 64 250 in the 

Rat: Project Report 24/79. Unpublished study pre- pared by Ciba-Geigy Limited. 19 p. 

164797 Muecke, W. (1981) The Major Metabolic Pathways of CGA 64 250 in the Rat: Project 

Report 9/81. Unpublished study prepared by Ciba- Geigy Limited. 13 p. 

164798 Muecke, W. (1983) The Metabolism of CGA 64 250 in the Rats: Project Report 24/83. 

Unpublished study prepared by Ciba-Geigy Limited. 145 p. 

41326701 Cresswell, D. (1989) (U-carbon-14)-Phenyl CGA 64250: Absorption, Distribution, 

Metabolism and Excretion in the Rat: Lab Project Number: 380/105. Unpublished study 

prepared by Hazleton UK. 520 p. 

41594804 Cresswell, D. (1989) U-?carbon 14|-phenyl CGA 64250: Absorption, Distribution, 

Metabolism and Excretion in the Rat: Lab Project No. 380/105. Unpublished study 

prepared by Hazleton UK. 520 p. 

42403901 Mucke, W. (1983) The Metabolism of CGA-64250 in the Rat: Lab Project Number: 

24/83. Unpublished study prepared by Ciba-Geigy Ltd. 148 p. 

93194045 Hochman, J. (1990) Ciba-Geigy Corp. Phase 3 Summary of MRID 41326701. 

Propiconazole - Rat Metabolism: Project 380/150. Prepared by Hazleton UK. 17 p. 

85-2 Dermal penetration

MRID Citation Reference
Page 57 of 58

47154901 Schwartz, R. (2007) Studies of the Dermal Resorption of (Carbon 14)-Fenpropimorph. 

Project Number: WOL/07/2905. Unpublished study prepared by Dr. Wolman GmbH. 

125 p.

85-3 Dermal Penetration/Absorption

MRID Citation Reference

164469 Murphy, T.; Brown, K.; Doornheim, D.; et al. (1986) Dermal Absorp- tion of [Carbon 14]-

Propiconazole in Rats after a Ten-hour Ex- posure Period: Report No. ABR-86053. 

Unpublished study prepared by Ciba-Geigy Corp. 76 p. 

164794 Ballantine, L. (1986) Propiconazole Animal Metabolism Update: Metabolism in Mice: 

Dermal Absorption in the Rat: Report No. ABR-86071. Unpublished compilation 

prepared by Ciba-Geigy Corp. 10 p. 

42415701 Murphy, T. (1986) Dermal Absorption of ?carbon 14|-Propiconazole: Addendum to 

ABR-86053: Lab Project Number: ABR-86064. Unpublished study prepared by CibaGeigy Corp. 85 p. 

45345901 Murphy, T. (2001) Dermal Absorption of (carbon 14)-Propiconazole: Addendum to 

ABR-86053: MRID 42415701: Lab Project Number: 1596-01. Unpublished study 

prepared by Syngenta Crop Protection, Inc. 7 p. {OPPTS 870.7600} 
Page 58 of 58

E. 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