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

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  tc \l3 "4.2.3	Developmental Toxicity
Studies  	10

3.3.2	Developmental Toxicity 	10

3.3.3  	Reproductive Toxicity	11

3.3.4	Pre-and/or Postnatal Toxicity tc \l3 "4.2.5  	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  tc \l3 "4.4.1
Acute Reference Dose - General Population 	12

3.4.2	 tc \l3 "4.4.2	 Acute Reference Dose – General Population	12

3.4.3	 tc \l3 "4.4.3	 Chronic Reference Dose – Adult Males and Females
Age 50+	13

3.4.4	 tc \l3 "4.4.3	 Incidental Oral Exposure – Short-Term	14

3.4.5	 tc \l3 "4.4.3	 Incidental Oral Exposure – Intermediate-Term	14

3.4.6	 tc \l3 "4.4.4	 Dermal Absorption	14

3.4.7	 tc \l3 "4.4.5	 Dermal Exposure – Short-Term	14

3.4.8	 tc \l3 "4.4.5	 Dermal Exposure – Intermediate-Term	15

3.4.9	 tc \l3 "4.4.6	 Inhalation Exposure – Short-Term	15

3.4.10	 tc \l3 "4.4.6	 Inhalation Exposure – Intermediate-Term	15

3.4.11	 tc \l3 "4.4.6	 Classification of Carcinogenic Potential	16

3.5	 tc \l3 "4.4.7	 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

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

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-t
riazole) 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 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 intermediate-term
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

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

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_tri
azole

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

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/cm3 at 20 C	MRID No. 43698701

Water solubility	0.10 g/L at 20 C	MRID No. 41720301

Solvent solubility (temperature not specified)	Completely miscible in
ethanol, acetone, toluene and n-octanol.  hexane = 47 g/L	MRID No.
42030201

Vapor pressure	4.2 x 10-7  mm Hg at 25 C	MRID No. 41720301

Dissociation constant (pKa)	1.09	MRID No. 43698701

Octanol/water partition coefficient Log(KOW)	3.72 at pH 6.6 and 25 C
MRID No. 43698701

UV/visible absorption spectrum (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.

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   SEQ CHAPTER \h \r 1 rat metabolism study labeled with 14C at the
triazole-[3,5] position indicated that parent compound was extensively
metabolized.  An intravenous study labeled with (U-14C)-Phenyl found
several metabolites, including CGA 118245 (61.8% in males, 2.4% in
females), CGA 217495 (8.9% in males, 58.3% in females), CGA 91304 (2.3%
in males only), and CGA 118244 (3.6% in females only).  No parent
material was detected in the feces in the iv group. The metabolites seen
in the iv study were detected to varying degrees in the urine and the
feces of the orally dosed groups.   Radiolabeled materials CGA 91305,
CGA 118245 and CGA 177291 were reported ranging from 0.5% - 10.9% of the
fecal radioactivity in males and females or in one sex alone.  Most of
the fecal radioactivity was not characterized.  Metabolites CGA 217495
and CGA 177291 are not found in plant or livestock metabolism (see
Appendix for structures).  In two other (U-14C)-phenyl and  14C-triazole
ring labeled propiconazole studies, the percentages of fecal metabolites
extracted and distributed at various pH’s were not substantially
different between the triazole and phenyl labeled samples, which suggest
that the bridge between the phenyl ring and the triazole ring remained
intact.  The proposed metabolic pathway appears to involve the cleavage
of the dioxolane ring through the oxidation of the propyl side chain,
with subsequent dechlorination and conjugation.  In a (U-14C)-phenyl
labeled propiconazole metabolism study in mice, it was concluded that
the major metabolic pathway in mice proceeds via elimination of the
dioxolane ring leading to ketone formation (CGA 91304) and reduction to
yield the corresponding alcohol (CGA 91305).  Both CGA 91304 and CGA
91305 are found in plants and livestock.

3.3	FQPA Hazard Considerations tc \l2 "4.2	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  tc \l3 "4.2.3	Developmental Toxicity
Studies

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 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  tc \l3 "4.2.4	Reproductive Toxicity Study

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 tc \l3 "4.2.6  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 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.

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.  Non-neoplastic
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 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)

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 tc \l3 "4.4.8
Classification of Carcinogenic Potential

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

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/FQPA 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

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 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   TC \l1 "4.0	Dietary Exposure/Risk
Characterization

  SEQ CHAPTER \h \r 1 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.
SEQ CHAPTER \h \r 1 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 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

	<IP_ADDRESS> 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.

	<IP_ADDRESS> 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.

	<IP_ADDRESS>	Multiresidue Method

	  SEQ CHAPTER \h \r 1  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.   SEQ CHAPTER \h \r 1   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

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

  SEQ CHAPTER \h \r 1 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 (t½ = 426 days).  Aqueous
photolysis may occur in the presence of sensitizers (t½ = <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 (t½ = <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 10-6 Torr 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

stimated ground water drinking water concentrations for propiconazole
are not expected to exceed 0.64 μg/L.  These 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

base (DEEM-FCID™).  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

6.0 	RESIDENTIAL EXPOSURE AND RISK tc "3.0	Residential and Other
Non-Occupational Exposures and Risks"

		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  TC \l2 "6.2	Short-Term Aggregate Risk

Short term aggregate exposure takes into account residential exposure
plus average exposure levels to food and water (considered to be a
background exposure level).   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)]

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 3	2300

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

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. High-Contact
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	120

Incidental oral	100 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.

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.

Handler Exposure Scenarios

<IP_ADDRESS> 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

<IP_ADDRESS>	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

-	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
chemical-resistant 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

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).

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

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

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 (Orbit™ and Orbit™  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

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

	•	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	Short- Term

MOE5	Int-Term

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 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  HYPERLINK
"http://www.epa.gov/fedrgstr/EPA_PEST/2002/January/Day_16/"
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)

APPENDICES

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

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

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)

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/Carcinogenicity Feeding-Rats

	00129918 (1982)

Acceptable/guideline

0, 100, 500 or 2500 ppm

,  female 4.6, 23.3 and 100.6  mg/kg/day)

	 LOAEL = 2500 ppm (96.4  mg/kg/day) based on liver lesions (vacuolation
of hepatocytes in males, ballooned cells in the liver of males, foci of
enlarged hepatocytes in females, and increased incidence of luminal
dilation of the uterus) and reduced body weight gain in both males and
females.  NOAEL = 500 ppm (18.1 mg/kg/day).  The test material was not
carcinogenic at the doses tested.

870.4200

24-Month Carcinogenicity in Mice	00129570 (1982 )

Acceptable/guideline

0, 100, 500 or 2500 ppm

(M: 10.0, 49.4, and 344.3  F: 10.8, 55.6 and 340.3 mg/kg/day	LOAEL = 500
ppm (49.5 mg/kg/day) based on non-neoplastic liver effects (increased
liver weight in males and increase in liver lesions (masses/raised
areas/ swellings/nodular areas mainly)).  The NOAEL was 100 ppm (10
mg/kg/day).

Liver tumors at 2500 ppm in male mice.

870.4200

18 - month oncogenicity study - male CD-1 mice	44381401 (1997)

Acceptable/guideline

0, 100, 500 or 850 ppm

(0, 11, 59 or 108 mg/kg/day)	LOAEL= 500 ppm (59.0 mg/kg/day) for males,
based on hepatotoxicity (increased liver weight, hepatocellular
hypertrophy, liver necrosis) and body weight gain effects observed at
the interim and terminal sacrifices.

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

Treatment related increase in hepatocellular adenoma and total
hepatocellular neoplasia at the 850 ppm exposure level compared to
concurrent controls, but were within the range of the inadequate
historical control data submitted with the study report.  Adequate
dosing based on body weight gain and hepatotoxic effects seen at 500 and
850 ppm.  Subsequently, the Registrant submitted additional control data
on five groups of CD-1 male mice generated within the approximate time
frame of the original study and in the same testing facility under
similar experimental conditions (MRID 45215804) concerning the
spontaneous occurrence of liver tumors.   The tumor incidence observed
in male livers at the 850 ppm dose is within the range of the new
historical data.

870.6200

Acute neurotoxicity in rats	46604601 (2005)

Acceptable/guideline

0, 30, 100 or 300 mg/kg by gavage	LOAEL = 100 mg/kg based on clinical
signs of toxicity (piloerection, diarrhea, tiptoe gait).

NOAEL = 30 mg/kg.

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

NOAEL for neurobehavioral toxicity = 100 mg/kg

870-5100

Bacterial reverse mutation	00058601 (1979)

Unacceptable

25-2025 g/plate	Negative in Salmonella strains with or without S-9
activation.  Test material purity not specified, not tested up to
cytotoxic dose.

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

g/ml	No increase in convertants or revertants (did not induce
mutation) with or without activation.  Concentrations of 30 g/ml
had inhibitory effect on yeast cell growth.

870.5450

Dominant lethal assay in mice

	00058602 (1979)

Acceptable/guideline

165 or 495 mg/kg single dose oral gavage,

	No evidence of dominant lethal effects was observed in the progeny of
mice treated with propiconazole.

870.7485

Metabolism and pharmacokinetics

(Rat)	42403901 (1983)

Acceptable/guideline

male rats: single oral

31.4 mg/kg  - 14C at the triazole-[3,5] position	Rapidly metabolized:
96% excreted in urine and feces (5:4 ratio) after 3 days.  Extensively
metabolized by hydroxylation, oxidation and conjugation.

870.7485

Metabolism and pharmacokinetics

(Rat)	41326701 (1989)

Acceptable/guideline

0.5 mg/kg oral or iv (U-14C)-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-[U-14C] single oral dose of 32.5 mg/kg to male rats.  	Study
focused on urinary and fecal metabolites.  Similar metabolic profiles
for the two labels suggesting that the bridge between the phenyl ring
and the triazole ring remained intact.  Metabolic pathway: cleavage of
dioxolane ring through the oxidation of the propyl side chain, with
subsequent dechlorination and conjugation and through the oxidation of
the propyl side chain.  Urinary and fecal metabolites except the
presence of parent in feces.

870.7485

Metabolism and pharmacokinetics

(Mouse)	00164795 (1986)

Acceptable/non-guideline

Male and female mice fed in the diet for 21 days at 5, 100 or 2500 ppm
propiconazole followed by phenyl-[U-14C] single oral dose at
corresponding levels.  Two male rats given single oral dose 9.4 mg/kg of
the phenyl-[U-14C]compound	Mice pre-treated with the unlabeled CGA 64250
excreted 83-103% of the administered 14C radioactivity within 96 hours
(mostly within the first 24-48 hours) in the urine and feces (mostly in
urine: 1.5-3.7x of the feces).   The male rats excreted nearly equal
amounts of the radioactivity in urine (48%) and feces (54%). Mouse
urinary metabolites 15-30.  The major metabolic pathway in mice proceeds
via elimination of the dioxolane ring.  In males this represents 30% of
the AD whereas in the females it represents 15% of the AD.  Mice cleaved
the dioxolane ring to a greater extent (70% & and 40% for males and
females, respectively) than do male rats (30%).

870.7600

Dermal penetration

(Rat)	42415701 (1986)

Acceptable/guideline

Propiconazole 14C at the triazole-[3,5] position

0.01, 0.1, 1.0 mg/cm2	The average dermal absorption of propiconazole
over a 10 hour period at an exposure level of 0.01 mg/cm2 is
approximately 40%

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.

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.

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 BrdU-staining
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 dose-related proliferation in the liver followed by a
sustained treatment-related 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.

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)

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 un-ossified
sternebrae (57%, p< 0.05 in the 90 mg group, and 72%, p< 0.01 in the 300
mg group vs. 38% in the controls), as well as increased incidence of
shortened renal papillae (26% in the 90 mg group (not statistically
significant) and 39% in the 300 mg group, p < 0.01 vs. 23% in the
controls) and absent renal papillae ( 5% in the 90 mg group (not
statistically significant) and 11% in the 300 mg group, p < 0.01 vs. 3%
in the controls) and dilated ureter ( 43% in the 300 mg group, p < 0.01
vs. 27% in the controls). External and visceral examination revealed a
very low incidence of cleft plate malformations in the 90 mg group
(0.3%) and in the 300 mg group (0.7%) and considered to be “probably
compound related”.  Historical controls in 19 teratology studies from
this laboratory had no incidence of cleft palate.  The cleft palate
incidence in the current study was probably under reported because only
half of the fetuses were examined viscerally.  It was also concluded
that the low incidence of this finding along with skeletal anomalies was
indicative of delayed development.  The cleft palate finding at 300
mg/kg/day was also confirmed in a separate study (MRID 40425002) where
propiconazole was administered to pregnant rats at 0 or 300 mg/kg/day
during the gestation period.  The developmental toxicity LOAEL of
propiconazole is 90 mg/kg/day, based on increased incidence of
rudimentary ribs,  un-ossified sternebrae, as well as increased
incidence of shortened and absent renal papillae and increased cleft
palate.  The developmental toxicity NOAEL is 30 mg/kg/day.

Rat Developmental Toxicity - Study 2

In an acceptable/non-guideline developmental toxicity study (MRID
40425002), CGA 64250 technical (92.1% purity, Batch No. FL 850083) was
administered to CL:COBS CD (SD) BR VAF/PLUS virgin female rats by oral
gavage in aqueous suspensions (3% corn starch containing 0.5% Tween 80)
at dose levels of 0 or 300 mg/kg/day from days 6 through 15 of
gestation.  The control group comprised 178 sperm positive animals and
the compound treated group comprised 189 sperm positive animals.  The
study was intended to confirm the finding of cleft palate in the
previous study (MRID 40425001).  The death of two dams from the treated
group was considered incidental.  Severe maternal toxicity was observed
during the treatment period beginning on gestation day 6 and included a
statistically significant increase in the incidence of ataxia (42% vs. 0
in controls), coma (9% vs. 0 in controls), lethargy (44% vs. 0 in
controls), 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
treatment- related, external gross observations among fetuses.  Cleft
palate was reported in 2/2064 fetuses of dosed animals and 0/1222 of
control fetuses.  The incidence of cleft palate in controls for all
teratology studies (not including this one) conducted at this laboratory
during 1983-1985 was 0/5431.  This study confirms the findings of cleft
palate in the previous guideline study (MRID 40425001).

Rabbit Developmental Toxicity

In a developmental toxicity study (MRID 00265796), CGA 64250 technical
(92.1% purity propiconazole) was administered to groups (19/group) of
artificially inseminated New Zealand white rabbits by oral gavage in
aqueous suspensions (3% corn starch containing 0.5% Tween 80) at dose
levels of 0, 100, 250 or 400 mg/kg/day from days 7 through 19 of
gestation.  One animal from each of the mid-dose groups was found dead.
In high-dose animals, 5/19 does were sacrificed early due to abortion or
early delivery (statistically significant, p<0.05 compared to control
1/19).  In the mid dose (250 mg/kg/day) group, one doe aborted early.
One control animal delivered early.  Among animals of the high dose
group, an increased incidence of stool alterations (decreased/no/soft;
18/19 vs. 11/19 in controls, p<0.05) was observed, possibly compound
related.  During the dosing period (days 7-19), the high and mid dose
animals had a significant (p<0.05) decrease in food intake (43 - 63% of
the controls and 58-78% of the controls in the high- and mid-dose
groups, respectively) and a severe decrease in the maternal body weight
gain, but rebounded to normal after withdrawal of the test compound.
During GD 7-10, the maternal animals had a weight loss of 0.047 and
0.111 kg at 250 and 400 mg/kg, respectively, compared to a weight gain
of 0.018 kg in controls.  The weight gains during GD 10-20 were 67-77%
and 11-43% of controls at 250 and 400 mg/kg/day, respectively.  An
increased incidence of the formation of 13th rib was observed at 400
mg/kg/day. The incidence of this finding on fetuses/litter basis was
2.7, 3.9, 4.1 and 5.3 at 0, 100, 250 and 400 mg/kg/day, respectively.
The incidence of fetuses at 400 mg/kg/day with this finding was
statistically significant.  Therefore, this finding was considered to be
treatment-related.  The increase in the number of resorptions at 400
mg/kg/day was caused by the resorption of an entire litter.  At 400
mg/kg/day there was also an increased incidence of abortions.  The
maternal toxicity LOAEL of propiconazole in the rabbit is 250 mg/kg/day,
based on reduced maternal body weight gains and decreased food
consumption during the dosing period.  The maternal toxicity 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.  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 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.

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).	 D. 	REFERENCES FOR
TOXICITY STUDIES

82-1       Subchronic Oral Toxicity: 90-Day Study

58606	Sachsse, K.; Suter, P.; Luetkemeier, H.; et al. (1979) CGA 64'250
Techn. Three Months Toxicity Study on Rats: Project No. 790014. Final
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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.
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258 p.

151511	Ciba-Geigy Corp. (1985) Response by Ciba-Geigy to EPA Review of
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Clinical, Ophthalmological, and Analytical Chemistry Data of Bayer
Report 12397]. Unpublished compilation. 41 p.

42050501	Potrepka, R.; Turnier, J. (1991) Subchronic Dietary Toxicity
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42050502	Potrepka, R.; Turnier, J. (1991) 13-Week Dietary Toxicity Study
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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
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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
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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

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

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 Ciba-Geigy 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
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40783302	Ballantine, L. (1988) Tolerance Assessment System: Routine
Chronic Analysis (Propiconazole-Celery). Unpublished study prepared by
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40783304	Anon. (1988) Tolerance Assessment System Routine Chronic
Analysis: Propiconazole-Corn. 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
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40783309	Ballantine, L. (1988) Tolerance Assessment System Routine
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41063803	Ballantine, L. (1988) Tolerance Assessment System Routine
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93194035	Gillis, J.; Tisdel, M. (1990) Ciba-Geigy Corp. Phase 3 Summary
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93194036	Gillis, J.; Tisdel, M. (1990) Ciba-Geigy Corp. Phase 3 Summary
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Prepared by Food & Drug Research Labs. Inc. 13 p.

83-2       Oncogenicity

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-
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41178301	Stevens, J. (1989) Propiconazole Technical: Perspective: Liver
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Excessive Level of Propiconazole. Unpublished study prepared by
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44381401	Gerspach, R. (1997) CGA-64250 Technical: 18-Month Oncogenicity
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45215804	Gerspach, R. (1999) 18-Month Oncogenicity Study in Mice: Final