Document ID: EPA-HQ-OPP-2007-1202-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-03-25T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460      

	OFFICE OF PREVENTION, PESTICIDES

                                                                        
                   AND TOXIC SUBSTANCES

	

MEMORANDUM

Date:  		September 30, 2008  

SUBJECT:	Propiconazole  FQPA Human Health Risk Assessment for the
Section 3 Registrations on Garden Beets, Turnips, Parsley, Cilantro and
Pineapple.  Petition No.:  7E7300.

PC Code:  122101	DP Barcode:   D347905

Decision No.: 386896	Registration No.: 100-617; 100-780

Petition No.: 7E7300	Regulatory Action: Section 3

Risk Assessment Type: aggregate risk assessment	Case No.: 3125.

TXR No.: N/A	CAS No.: 60207-90-1

MRID No.: N/A	40 CFR: § 180.434

FROM:	Yan Donovan, Chemist/Risk Assessor

		Reregistration Branch 4

		Suku Oonnithan, Biologist

Registration Branch 2

Health Effects Division (7509P)

THROUGH:	Susan Hummel, Branch Senior Scientist

		Ray Kent, branch Chief

Branch/Health Effects Division (7509P)

TO:		Dan Rosenblatt/Shaja Joyner, PM#5

		RIMUERB

		Registration Division  (7509P)

Attached is the Health Effect Division’s (HED’s) human health risk
assessment for   SEQ CHAPTER \h \r 1 propiconazole new uses. 
Propiconazole is among the group of chemicals, which generate common
metabolite, called 1,2,4-triazole and its conjugates triazole alanine
and triazole acetic acid.  A separate document is available to address
the common metabolite risk issue (HED memo of M. Doherty, D355015).  
There are antimicrobial uses for propiconazole as well.  Antimicrobial
Division (AD) has conducted a risk assessment for all existing and
potential antimicrobial uses.  The present aggregate risk assessment
includes the risks from antimicrobial uses in mushroom houses (dietary)
and in treated wood in play sets and residential decks (residential
post- application exposure).

The Team Reviewers who contributed to the disciplinary chapters and the
references are listed below. 

	1) Residue Chemistry Summary Document; Yan Donovan (D348248,
7/28/2008);

2) Occupational and Residential Exposure Assessment; Suku Oonnithan
(D349727, 08/25/08);

3) Revised Occupational and Residential Exposure Assessment of the
Antimicrobial Uses; Tim Leighton (D324052, 02/01/06);

4) Amendment to the Propiconazole RED for Children’s Post-application
Exposure from Treated Structures; Tim Leighton (D330159, 06/20/06);

	5) Dietary Exposure and Risk Assessment for New uses; Yan Donovan
(D355821, 09/30/08);

6) Drinking Water Assessment; James Lin from EFED (D 347906, 07 /02/08).

7) HED re-registration eligibility document (RED), HED memo of Y.
Donovan, 06/28/06, D329668);

8) Revised Occupational and Residential Exposure Assessment; (HED memo
of James Miller, 6/15/06, D329393)



	

Table of Content  TOC \o "1-3" \h \z \u  

  HYPERLINK \l "_Toc208293954"  1.0	Executive Summary	  PAGEREF
_Toc208293954 \h  5  

  HYPERLINK \l "_Toc208293955"  2.0	Ingredient Profile	  PAGEREF
_Toc208293955 \h  9  

  HYPERLINK \l "_Toc208293956"  2.1	Summary of Proposed Uses	  PAGEREF
_Toc208293956 \h  9  

  HYPERLINK \l "_Toc208293957"  2.2	Structure and Nomenclature	  PAGEREF
_Toc208293957 \h  10  

  HYPERLINK \l "_Toc208293958"  2.3	Physical and Chemical Properties	 
PAGEREF _Toc208293958 \h  12  

  HYPERLINK \l "_Toc208293959"  3.0	Hazard Characterization/Assessment	 
PAGEREF _Toc208293959 \h  12  

  HYPERLINK \l "_Toc208293960"  3.1	Hazard and Dose-Response
Characterization	  PAGEREF _Toc208293960 \h  12  

  HYPERLINK \l "_Toc208293961"  3.1.1	Studies available and considered
(animal, human, general literature)	  PAGEREF _Toc208293961 \h  12  

  HYPERLINK \l "_Toc208293962"  3.1.2	Mode of action, metabolism,
toxicokinetic data	  PAGEREF _Toc208293962 \h  13  

  HYPERLINK \l "_Toc208293963"  3.1.3	Sufficiency of studies/data	 
PAGEREF _Toc208293963 \h  13  

  HYPERLINK \l "_Toc208293964"  3.1.4	Toxicological Effects	  PAGEREF
_Toc208293964 \h  13  

  HYPERLINK \l "_Toc208293965"  3.2	Absorption, Distribution,
Metabolism, Excretion (ADME)	  PAGEREF _Toc208293965 \h  15  

  HYPERLINK \l "_Toc208293966"  3.3	FQPA Considerations	  PAGEREF
_Toc208293966 \h  15  

  HYPERLINK \l "_Toc208293967"  3.3.1    Adequacy of the Toxicity Data
Base	  PAGEREF _Toc208293967 \h  15  

  HYPERLINK \l "_Toc208293968"  3.3.2	Evidence of Neurotoxicity	 
PAGEREF _Toc208293968 \h  15  

  HYPERLINK \l "_Toc208293969"  3.3.3    Developmental Toxicity Studies	
 PAGEREF _Toc208293969 \h  16  

  HYPERLINK \l "_Toc208293970"  3.3.4	Reproductive Toxicity Study	 
PAGEREF _Toc208293970 \h  18  

  HYPERLINK \l "_Toc208293971"  3.3.5   	Additional Information from
Literature Sources	  PAGEREF _Toc208293971 \h  19  

  HYPERLINK \l "_Toc208293972"  3.3.6    Pre-and/or Postnatal Toxicity	 
PAGEREF _Toc208293972 \h  19  

  HYPERLINK \l "_Toc208293973"  3.3.7    Recommendation for a
Developmental Neurotoxicity Study	  PAGEREF _Toc208293973 \h  20  

  HYPERLINK \l "_Toc208293974"  3.3.8	Evidence that supports requiring a
Developmental Neurotoxicity study	  PAGEREF _Toc208293974 \h  20  

  HYPERLINK \l "_Toc208293975"  3.3.9	Evidence that supports not
requiring a Developmental Neurotoxicity study	  PAGEREF _Toc208293975 \h
 21  

  HYPERLINK \l "_Toc208293976"  3.4	FQPA Safety Factor for Infants and
Children	  PAGEREF _Toc208293976 \h  21  

  HYPERLINK \l "_Toc208293977"  3.5	Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc208293977 \h  21  

  HYPERLINK \l "_Toc208293978"  3.5.1   Acute Reference Dose (aRfD) -
Females age 13-49	  PAGEREF _Toc208293978 \h  23  

  HYPERLINK \l "_Toc208293979"  	3.5.2 Acute Reference Dose (aRfD) -
General Population	  PAGEREF _Toc208293979 \h  23  

  HYPERLINK \l "_Toc208293980"  	3.5.3 Chronic Reference Dose (cRfD)	 
PAGEREF _Toc208293980 \h  23  

  HYPERLINK \l "_Toc208293981"  	 3.5.4   Incidental Oral Exposure	 
PAGEREF _Toc208293981 \h  24  

  HYPERLINK \l "_Toc208293982"  3.5.5	Dermal Absorption	  PAGEREF
_Toc208293982 \h  24  

  HYPERLINK \l "_Toc208293983"  3.5.6	Dermal Exposure	  PAGEREF
_Toc208293983 \h  24  

  HYPERLINK \l "_Toc208293984"  3.5.7 Inhalation Exposure	  PAGEREF
_Toc208293984 \h  25  

  HYPERLINK \l "_Toc208293985"  3.5.8.	Classification of Carcinogenic
Potential	  PAGEREF _Toc208293985 \h  25  

  HYPERLINK \l "_Toc208293986"  3.6	Endocrine disruption	  PAGEREF
_Toc208293986 \h  26  

  HYPERLINK \l "_Toc208293987"  4.0	Public Health and Pesticide
Epidemiology Data	  PAGEREF _Toc208293987 \h  27  

  HYPERLINK \l "_Toc208293988"  5.0	Dietary Exposure/Risk
Characterization	  PAGEREF _Toc208293988 \h  27  

  HYPERLINK \l "_Toc208293989"  5.1	Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc208293989 \h  27  

  HYPERLINK \l "_Toc208293990"  5.1.1	Metabolism in Primary Crops	 
PAGEREF _Toc208293990 \h  27  

  HYPERLINK \l "_Toc208293991"  5.1.2	Metabolism in Rotational Crops	 
PAGEREF _Toc208293991 \h  27  

  HYPERLINK \l "_Toc208293992"  5.1.3	Metabolism in Livestock	  PAGEREF
_Toc208293992 \h  27  

  HYPERLINK \l "_Toc208293993"  5.1.4	Analytical Methodology	  PAGEREF
_Toc208293993 \h  28  

  HYPERLINK \l "_Toc208293994"  5.1.5	Environmental Degradation	 
PAGEREF _Toc208293994 \h  28  

  HYPERLINK \l "_Toc208293995"  5.1.6	Comparative Metabolic Profile	 
PAGEREF _Toc208293995 \h  29  

  HYPERLINK \l "_Toc208293996"  5.1.7	Toxicity Profile of Major
Metabolites and Degradates	  PAGEREF _Toc208293996 \h  29  

  HYPERLINK \l "_Toc208293997"  5.1.8	Pesticide Metabolites and
Degradates of Concern	  PAGEREF _Toc208293997 \h  29  

  HYPERLINK \l "_Toc208293998"  5.1.9	Drinking Water Residue Profile	 
PAGEREF _Toc208293998 \h  31  

  HYPERLINK \l "_Toc208293999"  5.1.10	Food Residue Profile	  PAGEREF
_Toc208293999 \h  31  

  HYPERLINK \l "_Toc208294000"  5.2	Dietary Exposure and Risk	  PAGEREF
_Toc208294000 \h  34  

  HYPERLINK \l "_Toc208294001"  6.0	Residential (Non-Occupational)
Exposure/Risk Characterization	  PAGEREF _Toc208294001 \h  36  

  HYPERLINK \l "_Toc208294002"  6.1	Residential Handler Exposure and
Risk Characterization	  PAGEREF _Toc208294002 \h  36  

  HYPERLINK \l "_Toc208294003"  6.2	Residential Postapplication Exposure
and Risk Characterization	  PAGEREF _Toc208294003 \h  38  

  HYPERLINK \l "_Toc208294004"  7.0	Aggregate Risk Assessments and Risk
Characterization	  PAGEREF _Toc208294004 \h  40  

  HYPERLINK \l "_Toc208294005"  7.1	Acute & Chronic Aggregate Risk	 
PAGEREF _Toc208294005 \h  40  

  HYPERLINK \l "_Toc208294006"  7.2	Short- and Intermediate-Term
Aggregate Risk	  PAGEREF _Toc208294006 \h  40  

  HYPERLINK \l "_Toc208294007"  8.0	Cumulative Risk
Characterization/Assessment	  PAGEREF _Toc208294007 \h  43  

  HYPERLINK \l "_Toc208294008"  9.0	Occupational Exposure/Risk Pathway	 
PAGEREF _Toc208294008 \h  44  

  HYPERLINK \l "_Toc208294009"  9.1	Occupational Handler Exposure and
Risk	  PAGEREF _Toc208294009 \h  44  

  HYPERLINK \l "_Toc208294010"  9.2	Occupational Postapplication
Exposure and Risk	  PAGEREF _Toc208294010 \h  47  

  HYPERLINK \l "_Toc208294011"  10.0	Data Needs and Label
Recommendations	  PAGEREF _Toc208294011 \h  49  

  HYPERLINK \l "_Toc208294012"  11.0	References:	  PAGEREF _Toc208294012
\h  51  

  HYPERLINK \l "_Toc208294013"  12.0	Tolerance Summary	  PAGEREF
_Toc208294013 \h  52  

  HYPERLINK \l "_Toc208294014"  13.0	Appendix	  PAGEREF _Toc208294014 \h
 53  

  HYPERLINK \l "_Toc208294015"  13.1	Structures of Metabolites and
Degradates	  PAGEREF _Toc208294015 \h  53  

  HYPERLINK \l "_Toc208294016"  13.2  Toxicity Profile.	  PAGEREF
_Toc208294016 \h  59  

 

1.0	Executive Summary  TC \l1 "1.0	Executive Summary 

Propiconazole is a triazole-type fungicide that provides broad spectrum
disease control on a variety of crops.  Tolerances are currently
established for the combined residues of propiconazole,
1-[[2-(2,4-dichlorophenyl)-4-propyl-1,3-dioxolan-2-yl]methyl]-1H-1,2,4-t
riazole, and its metabolites determined as 2,4-dichlorobenzoic acid
(2,4-DCBA) and expressed as parent compound in 40 CFR §180.434. 
Tolerances have been established for plant commodities in 40 CFR
§180.434(a), at levels ranging from 0.1 ppm for several commodities,
including pineapple, to 40 ppm for grass straw.  Tolerances for residues
in livestock commodities are also established under 40 CFR §180.434(a),
and range from 0.05 ppm for meat and meat byproducts to 2.0 ppm for
liver and kidney of cattle, goat, horse, and sheep.  Time-limited
tolerances are established in 40 CFR §180.434(b) for nectarine and
peach (expiration date of 12/31/10); tolerances with regional
registration are established in 40 CFR §180.434(c) for cranberry and
wild rice; and tolerances for indirect or inadvertent residues are
established in 40 CFR §180.434(d) for alfalfa forage and hay.  

Proposed Uses

The Interregional Research Project No. 4 (IR-4), on behalf of the
Agricultural Experiment Stations of CA, GA, HI, MS, NJ, OH, OK, OR, SC,
TN, and TX, is proposing to amend the use pattern for the 3.6 lb/gal
emulsifiable concentrate (EC) formulation of propiconazole (Tilt®
Fungicide, EPA Reg. No. 100-617) to add uses on garden beets, turnips,
parsley, cilantro (coriander), and the leaves of the root and tuber
vegetable group (crop group 2).  IR-4 is also proposing to amend the use
pattern for the 3.6 lb/gal EC formulation to add seed piece and
postharvest dip treatments for pineapple.  A copy of the supplemental
label proposing the use of 45% WP formulation (Tilt® 45W; EPA Reg. No.
100-780) on pineapple as postapplication dipping treatment was also
provided.   

Toxicity/Hazard

Propiconazole is a member of the class of the ergosterol biosynthesis
inhibiting fungicides.  The mode of antifungal action of propiconazole
is attributed to the inhibition of CYP51 (lanosterol-14-a-demethylase). 
Propiconazole has low to moderate toxicity in experimental animals by
the oral, dermal and inhalation routes, is moderately irritating to the
eyes, and minimally irritating to the skin, and it is a dermal
sensitizer.  The primary target organ for propiconazole toxicity in
animals is the liver.    SEQ CHAPTER \h \r 1 HED’s Hazard
Identification Assessment Review Committee (HIARC) concluded that the
toxicology database for propiconazole is complete for FQPA assessment.  
 Endpoints and dose response have been selected for acute, chronic
dietary, short and intermediate- term dermal, inhalation, and incidental
oral, and long term dermal and inhalation exposures.  For the scenarios
associated with the new uses, HED concludes that the endpoints selected
by HIARC are still appropriate.

The HIARC also concluded that the database was adequate to characterize
any potential for prenatal or postnatal risk for infants and children. 
There is low concern for pre- and/or postnatal toxicity resulting from
exposure to propiconazole, and no residual uncertainties were
identified. The exposure databases (dietary food, drinking water, and
residential) are complete and the risk assessment for each potential
exposure scenario includes all metabolites and/or degradates of concern
and does not underestimate the potential risk for infants and children. 
There fore, the FQPA factor is thus 1X.  

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.

Dietary Exposure/Risk Assessment

Provided that changes are made to the proposed use directions, the
submitted field trial data on garden beets, parsley, and pineapple are
adequate and support the proposed use patterns for the 3.6 lb/gal EC
formulation of propiconazole on these crops.  With the exception of
turnip, the number and geographic distribution of the field trials are
adequate, samples were analyzed using adequate analytical methods, and
the sample storage intervals are supported by available or concurrent
storage stability data.  The field trial data for parsley may be
translated to support the proposed use on cilantro.  The submitted
turnip field trial data are not adequate because the method used for
sample analyses was not adequate.  Since turnip is one of the
representative crops for the Crop Group 2 (leaves of the root and tuber
vegetable), the proposed use on this crop group 2 needs to be removed. 
The petitioner must propose separate tolerances for garden beet tops. 
The pineapple field trial data conducted with 3.6 lb/gal EC formulation
as a postharvest dip treatment can not be translated to WP formulation
even though the application rates are the same.  Field trials on WP
formulation are needed if the registrant wants to add the use of WP
formulation on pineapples.

Acute and chronic aggregate dietary (food and drinking water) exposure
and risk assessments were conducted for parent propiconazole using the
Dietary Exposure Evaluation Model DEEM-FCID™, Version 2.03 which use
food consumption data from the U.S. Department of Agriculture’s
Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996
and 1998.  This dietary assessment is for the parent propiconazole only.
 The common metabolites- triazole, triazolylalanine (TA), and
triazolylacetic acid (TAA) are also residues of concern.  Since these
are common metabolites from several triazole pesticides, the risk
assessment for triazoles was assessed separately. The updated risk
assessment for triazole metabolites indicated that adding the new uses
of propiconazole will not result in unacceptable risk to the triazole
metabolites (HED memo of Mike Doherty, D355015)

No monitoring data of propiconazole were available.  The drinking water
residues used in the dietary risk assessment were provided by the
Environmental Fate and Effects Division (EFED) and incorporated directly
into this dietary assessment.  Water residues were incorporated in the
DEEM-FCID into the food categories “water, direct, all sources” and
“water, indirect, all sources.”

   

Acute Dietary (Food and Drinking Water) Exposure Results and
Characterization

An acute dietary analysis for propiconazole was conducted using
tolerance levels and 100 % crop treated (CT) for all existing and
proposed uses.  The acute population adjusted dose (aPAD) is 0.3
mg/kg/day for all population subgroups (includes females 13-49 years). 
The results of the analysis indicate that acute risk from dietary
exposure (food and water) to propiconazole from the requested uses did
not exceed HED’s level of concern for the U.S. population or any
population subgroup.  At the 95th percentile, the exposure to the U.S.
population is at 7 % aPAD; the highest exposed subgroup (all infants <1
yrs old) is at 16% aPAD.

Chronic Dietary (Food and Drinking Water) Exposure Results and
Characterization

A chronic dietary analysis for propiconazole was conducted using
tolerance levels and 100 %CT for all existing and proposed uses.  The
chronic population adjusted dose (cPAD) is 0.1 mg/kg/day.  Results of
the analysis indicate that chronic risk from dietary exposure (food and
water) to propiconazole from the requested use did not exceed HED’s
level of concern for the U.S. population or any population subgroup. 
The exposure to the U.S. population is at 7 % cPAD, and the most highly
exposed subgroup, Children 1-2 years old, is at 17 % cPAD.

Cancer Dietary (Food and Drinking Water) Exposure Results and
Characterization

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.

Residential Exposure/Risk Assessment

No new residential uses are being requested at this time.  However,
adults, adolescents and toddlers may be exposed to propiconazole from
its currently registered use on turf and ornamentals.  These risks have
been previously assessed.  Homeowners can be exposed to propiconazole
through dermal and inhalation routes while applying home use products. 
All risk calculations were conducted using the maximum turf application
rate (1.8 lb ai/acre).  None of the residential handler exposure
scenarios exceeded HED’s level of concern.   The residential use
patterns result in post application dermal exposures to adults, and
dermal and oral exposures to infants and children.  These exposures are
considered short term only.  In addition to using HED’s SOP for
residential assessment, chemical specific data on turf transferable
residue (TTR) was used in the calculation.   The dermal and incidental
oral exposure to infants and children were combined, and all margins of
exposures (MOEs) do not exceed the level of concern.  Risk to children
playing on propiconazole-treated structures (from antimicrobial use) was
also assessed using a screening level assessment.  This risk assessment,
based on high end screening-level assumptions, indicates no risk of
concern.  

Aggregate Risk Assessment

Aggregate risk assessments were conducted for acute, chronic, short and
intermediate term exposure duration.  The risks do not exceed HED’s
level of concern.  Acute aggregate risk included food and water only;
chronic aggregate risk also included food and water because no chronic
exposure from residential uses is expected.  Short- term aggregate risk
included food, water, and residential/antimicrobial exposures. 
Intermediate term aggregate risk included food, water, and residential
exposure to Children 1-2 years old from treated wood used in deck and
play structures.

Occupational Handler and Postapplication Exposure/Risk Assessment

For occupational handler assessment, the default values from the
Pesticide Handlers Exposure Database (PHED) and Exposure Scientific
Advisory Committee (ExpoSAC) Policy # 9 were used.  The non-cancer
short- and intermediate-term occupational risk to mixers, loaders,
applicators, and flaggers are not of concern provided the handlers wear
personal protective equipment (PPE) consisting of long-sleeved shirt,
long pants and shoes with socks plus gloves.  Post-application exposures
were estimated using chemical-specific dislodgeable foliar residue (DFR)
data from previously submitted studies and surrogate transfer
coefficient (TC) values from the Agency's database (ExpoSAC Policy No.
3.1).  The estimated short- and intermediate-term dermal MOEs for the
various farm activities are >100 (LOC) on day "0" after application and
therefore are not of concern.  The estimated short- and long-term risks
to workers from sorting and packing of treated pineapple fruits were
found to be not of concern.   Propiconazole has low eye and skin
irritation properties (Toxicity Category III and IV) and is not a dermal
sensitizer.  The registered labels of Tilt® and Tilt®45W have a
restricted entry interval (REI) of 12 hours which is adequate.

Recommendations for Tolerances

Pending the submission of label changes outlined in Section 10.0 of this
document, HED recommends the establishment of permanent tolerances for
propiconazole, expressed as parent compound, in or on the following
commodities, to be published in 40 CFR §180.434(a).

Beet, garden, roots	0.3 ppm

Beet, garden, tops	5.5 ppm

Parsley, fresh	13 ppm

Parsley, dried	35 ppm

Cilantro leaves	13 ppm

Pineapple	4.5 ppm

Pineapple, process residue	7.0 ppm

Tolerance for residues of propiconazole on turnips, and Crop Group 2
(leaves of root and tuber vegetables) must be removed, as inadequate
residue data were provided.  

Environmental Justice Considerations

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.  Extensive data on food
consumption patterns are compiled by the USDA under the Continuing
Survey of Food Intake by Individuals (CSFII) and are used in pesticide
risk assessments for all registered food uses of a pesticide.  These
data are analyzed and categorized by subgroups based on age, season of
the year, ethnic group, and region of the country.  Additionally, OPP is
able to assess dietary exposure to smaller, specialized subgroups and
exposure assessments are performed when conditions or circumstances
warrant.  Whenever appropriate, 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.

Review of Human Research

This risk assessment relies in part on data from the Pesticide Handlers
Exposure Database (PHED) and the Outdoor Residential Exposure Task Force
(ORETF) studies in which adult human subjects were intentionally exposed
to a pesticide or other chemical.  These studies have been determined to
require a review of their ethical conduct, and have received that
review.

2.0	Ingredient Profile  TC \l1 "2.0	Ingredient Profile 

Propiconazole is a triazole-type fungicide that provides broad spectrum
disease control through inhibition of sterol biosynthesis in fungi.  It
is registered to Syngenta Crop Protection for the control of fungal
diseases on a variety of crops.   IR-4 has proposed use of the 3.6
lb/gal EC formulation of propiconazole on garden beet, turnip, parsley,
cilantro, and pineapple, and use of the 45% WP formulation of
propiconazole on pineapple.  The application methods include broadcast
aerial or ground, and post harvest dip.

2.1	Summary of Proposed Uses  TC \l2 "2.1	Summary of Proposed Uses 

The proposed use directions for the two propiconazole products are
presented in Table 2.1.

IR-4 included a copy of an existing label for the 3.6 lb/gal EC
formulation (EPA Reg. No. 100-617), and provided a text description of
the proposed use patterns for garden beets, turnip, leaves of the root
and tuber vegetable group, parsley, cilantro, and pineapple.  In
addition, a copy of a proposed supplemental label for the 3.6 lb/gal EC
formulation was provided, which included use directions for garden
beets, turnip, leaves of the root and tuber vegetable group, parsley,
cilantro, and pineapple, and a copy of a proposed supplemental label for
the 45% WP formulation (Tilt® 45W; EPA Reg. No. 100-780) was provided,
which included use directions for pineapple.  The proposed use
directions are summarized in Table 2.1.

Table 2.1.	Summary of Proposed Directions for Use of Propiconazole.

Applic. Timing, Type, and Equip.	Formulation

[EPA Reg. No.]	Applic. Rate 

(lb ai/A)	Max. No. Applic. per Season	Max. Seasonal Applic. Rate

(lb ai/A)	PHI

(days)	Use Directions and Limitations

Garden Beet and Turnip

Postemergence

Broadcast foliar

Ground or aerial 	3.6 lb/gal EC

[100-617]	0.084-0.113	Not specified (NS)	0.45	7	A minimum retreatment
interval (RTI) of 14 days is proposed.

Leaves of Root and Tuber Vegetables, including leaves of: garden beet,
edible burdock, carrot, bitter and sweet cassava, celeriac,
turnip-rooted chervil, chicory, dasheen (taro), parsnip, radish,
oriental radish, rutabaga, black salsify, sweet potato, tanier, turnip
and true yam

Postemergence

Broadcast foliar

Ground or aerial 	3.6 lb/gal EC

[100-617]	0.084-0.113	NS	0.45	7	A minimum RTI of 14 days is proposed.

Parsley, Fresh and Dried, and Cilantro (Coriander)

Postemergence

Broadcast foliar

Ground or aerial 	3.6 lb/gal EC

[100-617]	0.084-0.113	NS	0.45	7	A minimum RTI of 14 days is proposed.

Pineapple

Seed-piece treatment	3.6 lb/gal EC

[100-617]1	0.084-0.113 lb/100 gal water	1	0.113 lb/100 gal water	NS
Seed-pieces are to be immersed for 30 seconds, and then allowed to dry
or planted immediately

Postharvest treatment	3.6 lb/gal EC

[100-617]

45% WP

[100-780]2	0.084-0.113 lb/100 gal water	1	0.113 lb/100 gal water	NS
Fruit are to be immersed for 30 seconds; the dipping solution may be
mixed with postharvest waxes.  

1  This proposed use was included in Section B of the petition but was
not included on the proposed supplemental labels included in the
submission.

2  This proposed use was included on the supplemental label but not
included in Section B.

The proposed uses do not include any information about spray volumes for
foliar applications and do not include any rotational crop restrictions.
 The parent label for the 3.6 lb/gal EC formulation specifies that
ground applications to crops other than tree crops be made in a minimum
of 10 gal/A, and aerial applications to crops other than tree crops be
made in a minimum of 2 gal/A.  In addition, the following rotational
crop restrictions are specified on the parent label:  other crops
intended for food, grazing, or any component of animal feed may not be
planted within 105 days of application to the preceding crop, unless the
second crop appears on this label; and alfalfa may be planted 75 days
after the last application if the application of propiconazole has not
exceeded 0.22 lb ai/A during the previous year.

2.2	Structure and Nomenclature  TC \l2 "2.2	Structure and Nomenclature 

  SEQ CHAPTER \h \r 1 All pertinent product chemistry data requirements
have been satisfied for the Novartis 95% T/TGAI, except that additional
data are required concerning stability and UV/visible absorption (OPPTS
830.6313 and 7050).  The nomenclature of propiconazole is summarized in
Table 2.2a, and the physicochemical properties of propiconazole are
summarized in Table 2.2b.  The chemical names and structures of
propiconazole and its transformation products are presented in the
Appendix .

TABLE 2.2.	Test Compound Nomenclature

Chemical Structure	

 

Empirical Formula	C15H17Cl2N3O2

Common name	Propiconazole

Company experimental name	CGA-64250

IUPAC name
1-((2-(2,4-Dichlorophenyl)-4-propyl-1,3-dioxolan-2-yl)methyl)-1H-1,2,4-t
riazole

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

CAS Registry Number	60207-90-1

End-use product/EP	Tilt®, Alamo®, Banner®, and Orbit®, Quilt,
Stratego™ Twin-Pak™ and Stratego™ .

Chemical Class	Triazole

Known Impurities of Concern	None



	Physical and Chemical Properties

TABLE 2.3.	Physicochemical Properties

Parameter	Value	Reference

Molecular Weight	342.23	MRID No.: 40583701

Boiling point/range	>250°C at 101.325 kPa, 120°C

at 1.9 Pa	MRID No.: 43698701  

pH	4.9 @ 25°C (1% aqueous

dispersion)	MRID No.: 43698701

Density	1.289 g/cm3 typical @ 20°C 	MRID No.: 43698701  

Water solubility (20 °C)	0.10 g/L at 20°C 	MRID No.: 41720301

Solvent solubility (temperature not specified)	Completely miscible in
ethanol,

acetone, toluene and n-octanol.

n-hexane = 47 g/L	MRID No.: 42030201

Vapor pressure (25°C)	4.2 x 10-7 mmHg @ 25°C	MRID No.: 41720301

Dissociation constant, pKa	pKa 1.09 	MRID No.: 43698701

Octanol/water partition coefficient,  Log (KOW) (25 °C)	3.72 @ pH 6.6 
MRID No.: 43698701

UV/visible absorption spectrum  ((max, nm)	Not available

		

3.0	Hazard Characterization/Assessment  TC \l1 "3.0	Hazard
Characterization/Assessment 

(For detailed discussions, refer to HED memo of Y. Donovan, 06/28/06,
D329668)

  SEQ CHAPTER \h \r 1 Propiconazole is a N-substituted triazole.  It is
a member of the class of the ergosterol biosynthesis inhibiting
fungicides.  It is used as a fungicide on fruits, grains, seeds,
hardwoods and conifers.  The mode of antifungal action of conazoles is
attributed to the inhibition of CYP51 (lanosterol-14-a-demethylase)
(Zarn et al, 2003: cited in Sun et al, 2005: Toxicology Letters 155:
277–287.).  However, in mammalian systems several N-substituted azoles
are able to induce mammalian hepatic cytochrome P450s in the rat
(various authors as cited by Sun et al, 2005).  Recent work have
demonstrated that propiconazole induces CYP1A2 in rat liver and CYP2B
and CYP3A families of isoforms in rat and mouse liver (Sun et al, 2005).

3.1	Hazard and Dose-Response Characterization  TC \l2 "3.1	Hazard and
Dose-Response Characterization 

3.1.1	Studies available and considered (animal, human, general
literature)

The following data are available:

Acute- Oral rat, dermal rat, inhalation rat, eye irritation rabbit,
dermal irritation rabbit, and skin sensitization guinea pig.

Subchronic- Oral 28-day rat; oral 90-day rat, oral 90-day mouse, oral
90-day dog;

Chronic- Oral rat and dog;

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

Other- Oral rat and mouse cancer studies, 21-day dermal toxicity and
dermal penetration studies, acute neurotoxicity, mutagenicity screens
and mechanistic studies.

3.1.2	Mode of action, metabolism, toxicokinetic data

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; a group of metabolites (peak U8, 11%) appearing in the
urine.  Another 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) after intravenous dosing. 
These metabolites were also detected to varying degrees in the urine of
the orally dosed groups.  In the feces, no parent material was detected
in the iv group, but detected in the other groups (6.8-17.6% of the
fecal radioactivity in males and females).  Radiolabeled materials
co-chromatographing with standards 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.  

3.1.3	Sufficiency of studies/data

The toxicity database for propiconazole is complete for the purpose of
this risk assessment (see Appendix for Toxicity Profile table).  

3.1.4	Toxicological Effects

Propiconazole has low to moderate toxicity in experimental animals by
the oral (Category III), dermal (Category III) and inhalation routes
(Category IV).  It is moderately irritating to the eyes (Category III),
and minimally irritating to the skin (Category IV).  It is a dermal
sensitizer.  Propiconazole is readily absorbed by the rat skin with
absorption within 10 hours of dermal application.



Table 4.1a : Acute Toxicity Profile - Propiconazole			

Guideline No.	Study Type	MRID #	Results	Toxicity Category

870.1100	Acute Oral - rat	00058591	LD50 =1517 mg/kg	III

870.1200	Acute Dermal-rabbit	00058596	LD50  = >4000 mg/kg	III

870.1300	Acute Inhalation - rat	41594801	LC50  = >5.84 mg/L	IV

870.2400	Primary Eye Irritation	00058597	Corneal opacity reversed in 72
hours	III

870.2500	Primary Skin Irritation	00058598	No irritation	IV

870.2600	Dermal Sensitization	44949501	Sensitizer	-

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 at doses >50 mg/kg/day.  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.  Mice appear to be more
susceptible to its toxicity than rats.  Decreased body weight gain in
experimental animals was seen in subchronic, chronic, developmental and
reproductive studies.  Dogs appeared to be more sensitive to the
localized toxicity of propiconazole as manifested by stomach irritation
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 (incomplete ossification
of the skull, caudal vertebrae and digits, extra rib (14th rib) and
missing sternebrae, malformations of the lung and kidneys) 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 in
this study.

Propiconazole was negative for mutagenicity in the in vitro BALB/ C 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. 
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 nor 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).

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)  TC \l2 "3.2
Absorption, Distribution, Metabolism, Excretion (ADME) 

Propiconazole is rapidly absorbed from the gut and is eliminated in the
urine and feces.  It is extensively metabolized through hydroxylation,
oxidation, cleavage, dechlorination and conjugation.

3.3	FQPA Considerations  TC \l2 "3.3	FQPA Considerations 

HIARC (February 13, 2003) concluded that the toxicology database for
propiconazole is complete for FQPA assessment.  The HIARC concluded that
there is low concern for pre- and/or postnatal toxicity resulting from
exposure to propiconazole.  In the developmental toxicity study in rats,
the HIARC considered the fetal effects observed in this 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, the
HIARC determined that 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, the HIARC determined that 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.  Since there was quantitative
evidence of increased susceptibility of the young following exposure to
propiconazole in the developmental rat study, 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.  The FQPA factor is thus 1X.

	3.3.1    Adequacy of the Toxicity Data Base

  tc "4.2.1	Adequacy of the Toxicity Data Base " \l 3 

HIARC (February 13, 2003) concluded that the toxicology database for
propiconazole is complete for FQPA assessment.  The database was
adequate to characterize any potential for prenatal or postnatal risk
for infants and children. 

Evidence of Neurotoxicity 

 tc "4.2.2	Evidence of Neurotoxicity " \l 3 

Although there is no evidence of neuropathology or abnormalities in the
development of the fetal nervous system from the available developmental
and reproductive studies conducted with propiconazole, neurotoxic
effects (ataxia, lethargy, salivation, rales) were noted in pregnant
rats administered high propiconazole doses (360 mg/kg/day) during
gestation period.  In view of the neurotoxic effects observed in
pregnant rats, the HIARC (February 13, 2003) determined that an acute
neurotoxicity (ACN) study was required.  HIARC determined that for acute
(single dose) and short-term exposure scenarios a 3X database
uncertainty factor (UFDB) was adequate to account for the lack of the
ACN.

In July, 2005, the ACN study in the rat was submitted and reviewed by
the Agency (MRIDs 46604601 & 46604602).  The study confirmed that
propiconazole at doses of 300 mg/kg in rats produces severe clinical
signs of toxicity as demonstrated in the developmental rat study at 360
mg/kg. This ACN study also demonstrated that the clinical signs of
toxicity were not accompanied by nervous tissue damage and
neurobehavioral effects were minimal. Therefore, the propiconazole risk
assessment team concludes that the ACN study satisfies the data gap
imposed by HIARC and the 3X factor for the data base uncertainty factor
can be removed.  

	3.3.3    Developmental Toxicity Studies  tc "4.2.3	Developmental
Toxicity Studies " \l 3 

DEVELOPMENTAL - RAT	

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.

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).

DEVELOPMENTAL - RABBIT

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. 

	3.3.4	Reproductive Toxicity Study  tc "4.2.4	Reproductive Toxicity
Study " \l 3 

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. 

	  SEQ CHAPTER \h \r 1 3.3.5   	Additional 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.

	3.3.6    Pre-and/or Postnatal Toxicity  tc "4.2.6  Pre-and/or Postnatal
Toxicity " \l 3 

The HIARC concluded that there is low concern for pre- and/or postnatal
toxicity resulting from exposure to propiconazole.  In the developmental
toxicity study in rats, the HIARC considered the fetal effects observed
in this 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, the HIARC determined that 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, the HIARC determined that 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.

		3.3.6.1    Determination of Susceptibility  tc "4.2.6.1	Determination
of Susceptibility " \l 4 

The HIARC concluded that there is low concern for pre- and/or postnatal
toxicity resulting from exposure to Propiconazole.

		3.3.6.2	   Degree of Concern Analysis and Residual Uncertainties for
Pre and/or Post-natal Susceptibility 

 tc "4.2.6.2	Degree of Concern Analysis and Residual Uncertainties for
Pre and/or Post-natal Susceptibility " \l 4 

Since there is quantitative evidence of increased susceptibility of the
young following exposure to propiconazole in the developmental rat
study, HIARC performed a Degree of Concern Analysis to: 1) determine the
level of concern for the effects observed when considered in the context
of all available toxicity data; and 2) identify any residual
uncertainties after establishing toxicity endpoints and traditional
uncertainty factors to be used in the risk assessment of this chemical. 
If residual uncertainties are identified, HIARC examines whether these
residual uncertainties can be addressed by a special FQPA safety factor
and, if so, the size of the factor needed.  In the developmental rat
study, quantitative susceptibility was evidenced as increased incidence
of rudimentary ribs, unossified sternebrae, as well as increased
incidence of shortened and absent renal papillae and increased cleft
palate at (90 mg/kg/day) a dose lower than that evoking maternal
toxicity (severe clinical toxicity at 300 mg/kg/day).  Considering the
overall toxicity profile and the doses and endpoints selected for risk
assessment for propiconazole, the HIARC characterized the degree of
concern for the effects observed in this study as low, noting that there
is a clear NOAEL and well-characterized dose response for the
developmental effects observed.  No residual uncertainties were
identified.  The NOAEL for developmental effects in this study (30
mg/kg/day) is used as the basis for the acute Reference dose (aRfD) for
the female 13-49 population subgroup as well as for short-term
incidental oral, dermal and inhalation endpoints.  For all other
toxicity endpoints established for propiconazole, a NOAEL lower than
this developmental NOAEL is used. Based upon the above-described data,
no special FQPA safety factor is needed (i.e. 1X).

	3.3.7    Recommendation for a Developmental Neurotoxicity Study  tc
"4.3	Recommendation for a Developmental Neurotoxicity Study " \l 2 

On December 11, 2001 (reaffirmed February 13, 2003 and December 9,
2003), HIARC recommended that the decision on the need for a
developmental neurotoxicity study conducted with propiconazole is held
in reserve pending submission and evaluation of an acute neurotoxicity
study in the rat.  In December, 2005, the Propiconazole RED risk
assessment team, based on all of the data available (including the acute
neurotoxicity study), recommended that a developmental neurotoxicity
study in the rat not be required

	3.3.8	Evidence that supports requiring a Developmental Neurotoxicity
study  tc "4.3.1	Evidence that supports requiring a Developmental
Neurotoxicity study " \l 3 

Neurotoxic effects (ataxia, lethargy, salivation, rales) were noted in
pregnant rats administered high propiconazole doses (360 mg/kg/day)
during gestation.  In view of this, the HIARC determined that an acute
neurotoxicity (ACN) study was required and added a 3X database
uncertainty factor (UFDB) for acute and short term exposure scenarios. 
The rat acute neurotoxicity study submitted in July, 2005, confirmed the
clinical signs seen at relatively high doses of propiconazole.

	3.3.9	Evidence that supports not requiring a Developmental
Neurotoxicity study  tc "4.3.2	Evidence that supports not requiring a
Developmental Neurotoxicity study " \l 3 

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. 

3.4	FQPA Safety Factor for Infants and Children  TC \l2 "3.4	Safety
Factor for Infants and Children 

HIARC (February 13, 2003) concluded that the toxicology database for
propiconazole is complete for FQPA assessment.  The HIARC concluded that
there is low concern for pre- and/or postnatal toxicity resulting from
exposure to propiconazole.  In the developmental toxicity study in rats,
the HIARC considered the fetal effects observed in this 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, the
HIARC determined that 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, the HIARC determined that 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.  Since there was quantitative
evidence of increased susceptibility of the young following exposure to
propiconazole in the developmental rat study, 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.  The exposure databases (dietary food, drinking water,
and residential) are complete and that the risk assessment for each
potential exposure scenario includes all metabolites and/or degradates
of concern and does not underestimate the potential risk for infants and
children.

The FQPA factor is thus 1X.

  tc "4.2.1	Adequacy of the Toxicity Data Base " \l 3 

3.5	Hazard Identification and Toxicity Endpoint Selection  TC \l2 "3.5
Hazard Identification and Toxicity Endpoint Selection 

Table 3.5  Summary of Toxicological Doses and Endpoints for
Propiconazole for Use in Dietary Exposure Risk Assessments

Exposure/

Scenario	Point of Departure	Uncertainty/FQPA Safety Factors	RfD, PAD,
Level of Concern 	Study and Toxicological Effects

Acute Dietary (General Population, including Infants and Children)
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 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 of age)	NOAEL = 30 mg/kg/day	UFA= 10x

UFH= 10x

FQPA SF= 1x

	Acute RfD = 0.3 mg/kg/day	Developmental Toxicity Study - Rats.

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 (All Populations)	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 (oral, dermal, inhalation)   	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 (intraspecies).  UFH =
potential variation in sensitivity among members of the human population
(interspecies).  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 data (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.

Summary of target Margins of Exposure (MOEs) for risk assessment as
recommended by HIARC.

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	NA

Dermal	100	100	100

Inhalation	100	100	100

Occupational exposure:  Based on the conventional uncertainty factor of
100 X (10X for interspecies extrapolation and 10X for intraspecies
variation).

Residential exposure:  Based on the conventional uncertainty factor of
100 X (10X for interspecies extrapolation and 10X for intraspecies
variation).

Recommendation for Aggregate Exposure Risk Assessments 

 tc "4.4.9	Recommendation for Aggregate Exposure Risk Assessments " \l 3

As per FQPA, 1996, when there are potential residential exposures to the
pesticide, aggregate risk assessment must consider exposures from three
major sources: oral, dermal and inhalation exposures.  The toxicity
endpoints selected for these routes of exposure may be aggregated as
follows:  	

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.

	3.5.1   Acute Reference Dose (aRfD) - Females age 13-49  tc "4.4.1  
Acute Reference Dose (aRfD) - Females age 13-49 " \l 3 

The end point selected was based on a developmental NOAEL of 30
mg/kg/day from the developmental toxicity study in rats (MRID 40425001)
where  developmental toxicity was manifested as increased incidence of
rudimentary ribs, unossified sternebrae, as well as increased incidence
of shortened and absent renal papillae and increased cleft palate at the
LOAEL of 90 mg/kg/day.  An Uncertainty Factor (UF): 100 (10X for
inter-species extrapolation, 10X for intra-species variability) was
applied.  The developmental effects are presumed to occur after a single
exposure and are appropriate for the population of concern (females
13-49).

	3.5.2	Acute Reference Dose (aRfD) - General Population 

 tc "4.4.2	Acute Reference Dose (aRfD) - General Population " \l 3 

The endpoint selected was based on a NOAEL of 30 mg/kg/day from the
acute neurotoxicity study in rats (MRID 46604601) where clinical signs
of toxicity (piloerection in one male, diarrhea in one female, tip toe
gait in 3 females) occurred after administration of 100 mg/kg/day
propiconazole.  An Uncertainty Factor (UF) of 100 (10X for inter-species
extrapolation and 10X for intra-species variability) was applied.  

	3.5.3	Chronic Reference Dose (cRfD)

A 24-month propiconazole dietary oncogenicity acceptable/guideline study
(MRIDs 00129570 and 93194037) in CD-1 mice was selected by the HIARC for
deriving the chronic RfD.  This study is described in detail at the end
of this section.  The endpoint selected for establishing the Chronic RfD
was based on non-neoplastic liver effects (increased liver weight in
males and increase in liver lesions: masses/raised areas/
swellings/nodular areas mainly) occurring at 50 mg/kg/day with a NOAEL
of 10 mg/kg/day.  An Uncertainty Factor (UF) of 100 (10X for
inter-species extrapolation, 10X for intra-species variability) was
applied.  This dose was considered appropriate since effects occurred
after chronic exposures.  The HIARC noted that the NOAEL of 2.7
mg/kg/day in a 3-month oral feeding toxicity study in mice is lower than
the 10 mg/kg/day selected for this risk assessment.  The HIARC did not
select the lower NOAEL (2.7 mg/kg/day) because: a) of the 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 this 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 HIARC
did not select the dog study 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.

	 3.5.4   Incidental Oral Exposure 

Short Term (1-30 days)

The endpoint selected was based on a NOAEL of 30 mg/kg/day from the
acute neurotoxicity study in rats (MRID 46604601) where clinical signs
of toxicity (piloerection in one male, diarrhea in one female, tip toe
gait in 3 females) occurred after administration of 100 mg/kg/day
propiconazole.  An Uncertainty Factor (UF) of 100 (10X for inter-species
extrapolation and 10X for intra-species variability) was applied.  This
endpoint is relevant to the population of concern (infants and
children).	

Intermediate Term (1-6 months)

A 24-month propiconazole dietary oncogenicity acceptable/guideline study
(MRIDs 00129570 and 93194037) in CD-1 mice was selected by the HIARC for
deriving this endpoint with a NOAEL of 10 mg/kg/day.

	3.5.5	Dermal Absorption 

 tc "4.4.5	Dermal Absorption " \l 3 

HIARC selected a 40% dermal absorption factor 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.  Since the current factor of 40% is
based on a dermal absorption study in the rat, the propiconazole risk
assessment team believes that this value is the appropriate one to use.

Dermal Exposure 

Short Term (1-30 days) tc "4.4.6.1 Dermal Exposure (Short Term 1-30 days
for females 13-50 years old) " \l 3 

HIARC had selected a developmental NOAEL of 30 mg/kg/day from the
developmental rat study (MRID 40425001) to assess short term dermal
risks to females 13-49, and a maternal NOAEL of 90 mg/kg/day from the
developmental rat study to assess dermal risks to all other population
subgroups.  The propiconazole risk assessment team recommends that the
recently submitted rat acute neurotoxicity study (MRID 46604601) with a
NOAEL of 30 mg/kg/day is appropriate for assessing risks of this
exposure duration and is applicable to all population subgroups. Since
an oral study was selected, a 40% dermal absorption factor is used for
route to route extrapolation 

Intermediate Term (1-6 months and long term > 6 months)

HIARC selected NOAEL of 10 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)) at 50 mg/kg/day
of propiconazole administration derived from a chronic/oncogenicity
study in mice (MRID 00129570 and 93194037).

	3.5.7 Inhalation Exposure 

Short Term (1-30 days)

HIARC had selected a developmental NOAEL of 30 mg/kg/day based on
increased incidence of rudimentary ribs, unossified sternebrae and
shortened and absent renal papillae, and increased cleft palate seen at
the developmental LOAEL of 90 mg/kg/day in a developmental rat study
(MRID 40425001).  The propiconazole risk assessment team recommends that
the recently submitted rat acute neurotoxicity study (MRID 46604601)
with a NOAEL of 30 mg/kg/day is appropriate for assessing inhalation
risks of this exposure duration and is applicable to all population
subgroups. An inhalation absorption factor of 100% (default value
assuming equivalent inhalation and oral absorption) will be used for
route-to-route extrapolation.

Intermediate Term (1-6 months and long term > 6 months)		

HIARC selected NOAEL of 10 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)) at 50 mg/kg/day
of propiconazole administration derived from a chronic/oncogenicity
study in mice (MRID 00129570 and 93194037).   An inhalation absorption
factor of 100% (default value assuming equivalent inhalation and oral
absorption) will be used for route-to-route extrapolation.

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 (increased
trend and pairwise comparison, p<0.01) and increased hepatocellular
carcinomas (increased trend, p<0.05) 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
other 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
(MRID 42050501 & 42050502) 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 (20 %,
p<0.05) and total hepatocellular neoplasia (adenomas and carcinomas) of
24%, p<0.05, at the 850 ppm exposure level when compared to concurrent
controls which had unusually low incidence of 2% of adenomas and a 4% of
total neoplasia .  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,
both at p < 0.01 (Memo: Feb.1, 1999 from Lori L. Brunsman, Statistician
to SanYvette Williams-Foy, Veterinary Toxicologist).  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 (the collection dates were not specified and were not
collected in the testing facility) submitted with the study report. 
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 new data demonstrated primary
neoplastic lesions including hepatocellular adenoma (6-18%) and
hepatocellular carcinoma (8-16%) corresponding to 14-30% male CD-1 mice
bearing hepatocellular neoplasia, hemangioma (2%) and hemangiosarcoma
(2%), and foci of cellular alteration (2-4%) were observed in the livers
of males.  These new 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.

3.6	Endocrine disruption  TC \l2 "3.6	Endocrine disruption 			

EPA is required under the FFDCA, as amended by FQPA, to develop a
screening program to determine whether certain substances (including all
pesticide active and other ingredients) “may have an effect in humans
that is similar to an effect produced by a naturally occurring estrogen,
or other such endocrine effects as the Administrator may designate.” 
Following recommendations of its Endocrine Disruptor and Testing
Advisory Committee (EDSTAC), EPA determined that there was a scientific
basis for including, as part of the program, the androgen and thyroid
hormone systems, in addition to the estrogen hormone system.  EPA also
adopted EDSTAC’s recommendation that the Program include evaluations
of potential effects in wildlife.  For pesticide chemicals, EPA will use
FIFRA and, to the extent that effects in wildlife may help determine
whether a substance may have an effect in humans, FFDCA authority to
require the wildlife evaluations.  As the science develops and resources
allow, screening of additional hormone systems may be added to the
Endocrine Disruptor Screening Program (EDSP).

4.0	Public Health and Pesticide Epidemiology Data  TC \l1 "4.0	Dietary
Exposure/Risk Characterization 

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

  SEQ CHAPTER \h \r 1 From the review of the Incident Data System, it
appears that a majority of 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.

5.0	Dietary Exposure/Risk Characterization  TC \l1 "4.0	Dietary
Exposure/Risk Characterization 

 Pesticide Metabolism and Environmental Degradation

5.1.1	Metabolism in Primary Crops  TC \l3 "5.1.1	Metabolism in Primary
Crops 

  SEQ CHAPTER \h \r 1 Available plant metabolism data (primary and
rotated crops) show that plants absorb, metabolize and translocate
propiconazole throughout the plant.  A major metabolic pathway in plants
appears to be hydroxylation (primarily of the beta-carbon) of the
n-propyl group on the dioxolane ring of the cis/trans isomers of
propiconazole.  These metabolites appear to readily form sugar
conjugates.  The majority of TRR was found in the stalks, such as peanut
stalk, wheat forage and straw, grape leaves, and celery stalks (See
Table 3.4 for TRRs).  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 triazole, as 1H-1,2,4-triazole, is
released.  The free triazole is readily conjugated with the amino acid,
serine/alanine, forming triazole alanine, which is further metabolized
to triazole acetic acid possibly through the intermediate formation of
triazole lactic acid.   As mentioned earlier, the triazole issue will be
addressed separately. 

5.1.2	Metabolism in Rotational Crops  TC \l3 "5.1.2	Metabolism in
Rotational Crops 

  SEQ CHAPTER \h \r 1 The nature of the residue in confined rotational
crops is understood, and no additional confined rotational crop data are
required for the purpose of reregistration.  Based on acceptable studies
reviewed by EFED, the metabolism of propiconazole in rotational crops is
similar to that in primary crops.  In a rotational crop study,
metabolites in peanut kernels were identified as triazole acetic acid
(3.8% TRR) and triazole alanine (67.9% TRR).  Metabolites identified in
the rotational crop samples included triazole acetic acid (2.4%-68.7%
TRR), triazole alanine (6.7%-79.4% TRR), triazole lactic acid
(4.9%-35.8% TRR) and polar metabolites E, F, G, H (1.0%-7.0% TRR).

5.1.3	Metabolism in Livestock  TC \l3 "5.1.3	Metabolism in Livestock 

  SEQ CHAPTER \h \r 1 For one ruminant study, three lactating goats
received [phenyl-14C] propiconazole at 67-92 ppm for four consecutive
days in feed.  The parent (1.7-13.9% TRR), and metabolites CGA-118244
(9.4-34% TRR), and CGA-91305 (15.9-31.3% TRR) were identified in the
organic extract of tissues; metabolites CGA-118244 (23% TRR) and
CGA-91305 (24% TRR) were also identified in milk.  In addition, an
unknown was quantitated (6.2-31.1% TRR) in goat tissues.  In a second
ruminant study, a single goat was fed [triazole-14C] propiconazole at
4.53 ppm (0.2x) for 10 days.  The TRR in tissues and milk ranged from
0.01 ppm in muscle to 0.96 ppm in liver; TRR in milk were 0.015 ppm.  On
further analysis of subsamples of milk and liver, sulfate and
glucuronide conjugates were found in milk, and conjugation with amino
acids was suggested in liver; propiconazole per se was not identified in
milk or liver.  

For the poultry study, four laying hens received [phenyl-14C]
propiconazole at 67 ppm for eight consecutive days in feed.  The dosing
level corresponds to 560x the maximum theoretical dietary burden to
poultry.  The parent (1.4-39.0% TRR), and metabolites CGA-118244
(1.5-50.0% TRR), and CGA-91305 (17.7-78.6% TRR) were identified in the
organic extracts of tissues and eggs.

5.1.4	Analytical Methodology  TC \l3 "5.1.4	Analytical Methodology 

For enforcing the proposed tolerances, a gas chromatography (GC) method
using flame ionization detection (Method AG-354) is available for
determining residues of propiconazole per se in/on plant commodities,
with a limit of quantitation (LOQ) of 0.05 ppm.  In addition, FDA’s
PAM 1 Multiresidue Methods Section 302 may be used to determine parent
propiconazole in both plant and livestock matrices.

Samples from the field trials and processing studies submitted to
support the current petition were analyzed for combined residues of
propiconazole and its metabolites containing the 2,4-DCBA moiety using
GC methods with electron capture detection (ECD).   The methods are
similar common moiety methods in which all residues of concern are
converted by base hydrolysis and oxidation to 2,4-DCBA, then determined
as the 2,4-DCBA methyl ester, and reported in propiconazole equivalents.
 The lower level of method validation (LLMV) was 0.05 ppm for garden
beet roots and tops, fresh and dried parsley, and pineapple fruit and
processed commodities, and was 0.20 ppm for turnip roots and tops.  Each
of the methods was validated in conjunction with the field trial and
processing studies, and acceptable method validation and concurrent
method recoveries were obtained for all crop matrices, with the
exception of turnip commodities.

5.1.5	Environmental Degradation

  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; adsorption 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 was reported
in four soils.  In supplemental 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 adsorbs to soil with
adsorption increasing with soil organic matter content          (Kd
values =1.2 on sand to 9.34 on silty clay loam soils).  	

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.

5.1.6	Comparative Metabolic Profile TC \l3 "5.1.6	Comparative Metabolic
Profile 

The metabolism of propiconazole in rotational crops is similar to that
in primary crops.   Based on metabolism studies with peanut, wheat,
grape, rice, celery, and carrot, the major metabolic pathway in plants
appears to involve 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 1,2,4-T is released.  

In rats, 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.

As indicated above, the metabolic profile in plants and in animals are
very similar.

5.1.7	Toxicity Profile of Major Metabolites and Degradates TC \l3 "5.1.7
Toxicity Profile of Major Metabolites and Degradates 

No toxicity information is available on any of the metabolites except
for the triazole metaoblites which are being addressed separately. 
Based on the structure similarity, it is assumed that the major
metabolites share the same toxicity as the parent.

5.1.8	Pesticide Metabolites and Degradates of Concern TC \l3 "5.1.8
Pesticide Metabolites and Degradates of Concern 

  SEQ CHAPTER \h \r 1 

	For Tolerance Expression

Plants 

	Parent plus all metabolites convertible to 2,4-DCBA	Parent only

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

Livestock:

	Parent plus all metabolites convertible to 2,4-DCBA	Parent only

Water	Parent only	N/A

	 Triazole is also a residue of concern, but it will be addressed
separately.

Rationale:

Plant:  The analytical method is a single moiety method, which detects
all residues convertible to 2,4-dichlorobenzoic acid (DCBA); therefore,
MARC concluded that for risk assessment, parent and all metabolites
convertible to 2,4-DCBA are residues of concern.    SEQ CHAPTER \h \r 1
The metabolites that have the basic structure of propiconazole (e.g.
alkanol, beta-hydroxy and conjugates) would likely exhibit some of the
same toxicity as the parent compound, but would not likely be more toxic
than the parent compound.  For the purposes of risk assessment HED would
assume these metabolites would have equal toxicity as the parent
compound.  (The conjugates are included because of the possibility they
could be hydrolyzed in the stomach to the unconjugated form).  For
tolerance expression, MARC recommended parent only for the following
reasons: 1) To harmonize with the Codex MRL which is parent only; 2)
There are a number of pesticides that have 2,4-DCBA as common
metabolite; and 3) FDA multiresidue method detects parent only, and that
FDA monitoring pattern likely only detects parent.

Rotational crop: As with primary crops, parent and all metabolites
convertible to 2,4-DCBA are residue of concern for risk assessment since
the analytical method is a single moiety method which detects all
residues convertible to 2,4-dichlorobenzoic acid (DCBA).  Although these
metabolites are detected at very low levels, they are of toxicological
concern and cannot be excluded from risk assessment.  For tolerance
expression, MARC recommended parent only.   SEQ CHAPTER \h \r 1 The most
obvious misuse of propiconazole would be application to unlabeled crops.
 If rotational crop tolerances were expressed in terms of parent, then
any residues of propiconazole on rotated crops would likely be due to
direct application to these crops.  While triazole acetic acid is the
major metabolite in rotational crop study, triazole and its conjugates
are common metabolites from a number of other pesticides and have been
addressed separately.

Animals:  MARC recommended that parent and all metabolites convertible
to 2,4-DCBA are residues of concern for risk assessment since the
analytical method detects all residues convertible to
2,4-dichlorobenzoic acid (DCBA). Tolerance expression will be parent
only.    SEQ CHAPTER \h \r 1 If only propiconazole per se is regulated,
there will not likely be a need for meat and milk tolerances; only meat
by-products would likely require a tolerance.  Should there be
detectable residues of the parent compound in meat and milk, it would
most certainly be as a result of a misuse.

Water:   MARC recommended that parent only is needed to be included in
the risk assessment since the parent is persistent and immobile.  There
are several minor degradates (<10% TRR) but none of them are expected to
be significantly more toxic than the parent.  Triazole is not a major
degradate in water and therefore was not included in the water modeling;
the potential for exposure to triazole in drinking water has been
addressed in a separate document.

Triazoles

Propiconazole is a member of the triazole-containing class of
pesticides.  HED has recently conducted aggregate human health risk
assessments for 1,2,4-T, TA, and TAA (DP# 322215, 2/7/06, M. Doherty et
al.).  HED generally includes 1,2,4-T, TA, and TAA as residues of
concern for risk assessment purposes for most triazole-containing
pesticides.  1,2,4-T was a major residue found in some livestock
commodities, and TA and TAA were significant residues in some plant
metabolism studies.  Since these metabolites are common to the entire
class of triazole-derivative fungicides and because of differential
toxicity between the metabolites and the various parent compounds, risks
associated with exposure to 1,2,4-T and to TA/TAA are addressed in
separate risk assessment documents.

5.1.9	Drinking Water Residue Profile TC \l3 "5.1.9	Drinking Water
Residue Profile 

The drinking water residues used in the dietary risk assessment were
provided by the Environmental Fate and Effects Division (EFED) in the
following memorandum: “Drinking Water Assessment for Propiconazole
Uses on Garden Beet, Turnip, Leaves of Root and Tuber Vegetables, Herbs,
and Pineapple – An IR-4 Action” (Jim Lin, 07/02/08, D347906) and
incorporated directly into this dietary assessment.  Water residues were
incorporated in the DEEM-FCID into the food categories “water, direct,
all sources” and “water, indirect, all sources.”

5.1.10	Food Residue Profile  TC \l3 "5.1.10	Food Residue Profile 

(HED memo of Yan Donovan, 07/28/08, D348248)

The nature of propiconazole residues in plants and animals is adequately
understood based on the available peanut, wheat, grape, rice, celery,
carrot, goat, and poultry metabolism studies.  HED has concluded that
for plants and livestock, residues of propiconazole and all its
metabolites containing the 2,4-DCBA moiety, including conjugates, are of
concern and should be included in the dietary (food) risk assessments,
and that propiconazole per se should be included in the dietary (water)
risk assessments.  For tolerance expression, HED concluded that the
current tolerance expression for propiconazole should be amended to
include residues of propiconazole per se only.  This allows for
harmonization with the residue definition for Codex.

The free triazole metabolites, 1,2,4-triazole (1,2,4-T),
triazolylalanine (TA), and triazolylacetic acid (TAA) are also residues
of concern.  Since these are common metabolites from several triazole
pesticides, the risk assessment for triazoles will be assessed
separately.  HED also issued guidance on the residue chemistry data
requirements for the triazole-based metabolites under DP# 327788
(4/25/06, M. Doherty) which specified that any field trial or processing
studies conducted after September1, 2005 to support new uses must
analyze for the triazole metabolites.  Although none of the crop field
trial and processing studies submitted with this petition included
analysis for the triazole metabolites, these field studies are accepted
at this time because these studies were initiated and analyses were
completed before the issuance of HED’s policy regarding triazole
metabolites.  A revised triazole risk assessment will be conducted by
HED to reflect the propiconazole new uses base on available data from
propiconazole metabolism studies and other conazole- pesticide residue
data.

For enforcing the proposed tolerances, a gas chromatography (GC) method
using flame ionization detection (Method AG-354) is available for
determining residues of propiconazole per se in/on plant commodities,
with a limit of quantitation (LOQ) of 0.05 ppm.  In addition, FDA’s
PAM 1 Multiresidue Methods Section 302 may be used to determine parent
propiconazole in both plant and livestock matrices.

Samples from the field trials and processing studies submitted to
support the current petition were analyzed for combined residues of
propiconazole and its metabolites containing the 2,4-DCBA moiety using
GC methods with electron capture detection (ECD).   The methods are
similar common moiety methods in which all residues of concern are
converted by base hydrolysis and oxidation to 2,4-DCBA, then determined
as the 2,4-DCBA methyl ester, and reported in propiconazole equivalents.
 The lower level of method validation (LLMV) was 0.05 ppm for garden
beet roots and tops, fresh and dried parsley, and pineapple fruit and
processed commodities, and was 0.20 ppm for turnip roots and tops.  Each
of the methods was validated in conjunction with the field trial and
processing studies, and acceptable method validation and concurrent
method recoveries were obtained for all crop matrices, with the
exception of turnip commodities.

The submitted postharvest trial data on pineapple are adequate and
support the proposed use directions of the 3.6 lb/gal EC formulation as
a postharvest dip treatment.  Samples were analyzed using adequate
analytical methods, and the sample storage intervals were supported by
concurrent storage stability data.  The proposed tolerance for pineapple
is too low; a tolerance of 4.5 ppm must be proposed.  HED determined
that the above residue data on EC formulation can not be translated to
WP formulation even though the application rate is the same.  Field
trials on WP formulation are needed if the registrant wants to add the
use of WP formulation on pineapples.

The submitted turnip field trial data are not adequate because the
method used for sample analyses was not adequate.  Readily quantifiable
residues were observed in reagent blanks and untreated turnip top
samples, and concurrent method recoveries were generally low.  A new set
of turnip crop field trial data must be submitted.  Since turnip is one
of the representative crops for the Crop Group 2- the leaves of the root
and tuber vegetable group, the proposed use on this crop group 2 needs
to be removed.  The petitioner must propose separate tolerances for
garden beet tops.  

Adequate processing studies were submitted for parsley and pineapple. 
The studies indicate that total propiconazole residues concentrate in
dried parsley leaves and pineapple process residues but do not
concentrate in pineapple juice.  The proposed tolerance for dried
parsley leaves is too high; a tolerance of 35 ppm would be appropriate. 
A tolerance must be proposed for pineapple process residue at 7.0 ppm.  

Adequate livestock feeding study data have been submitted previously for
propiconazole.  No changes in the existing tolerances for livestock
commodities are needed to support the proposed uses of propiconazole.

Adequate confined and field rotational crop studies are available
indicating that the residues in rotational crops are similar to those in
primary crops.  The studies also support the PBIs listed on product
labels of 75 days for alfalfa and 105 days for all other crops without
direct uses.  No changes to the existing rotational crop restrictions
are needed to support the proposed uses.

Provided the proposed uses are amended as requested, adequate field
trial data are available for garden beets, parsley, and pineapple. 
Adequate field trial data are not available for turnip; new field trial
data must be submitted before the requested tolerances may be approved. 
The Agency’s Guidance for Setting Pesticide Tolerances Based on Field
Trial Data was utilized for determining appropriate tolerance levels for
garden beet roots, garden beet tops, parsley leaves, and pineapple.  The
available data indicate that the proposed tolerance for parsley leaves
is adequate but the proposed tolerance for pineapple is too low.  A
tolerance of 4.5 ppm would be appropriate for pineapple.  The available
data for parsley may be translated to support use on cilantro; the
proposed tolerance, at the same level as the tolerance for parsley
leaves, is appropriate.

The petitioner has proposed a crop group tolerance for crop group 2, the
leaves of the root and tuber vegetables.  Although the representative
crops of this group are garden beet tops and turnip tops, for which the
petitioner submitted crop field trial data, a crop group tolerance is
not appropriate at this time, because crop field trial data for turnip
are not acceptable.  Based on the garden beet field trial data at 1.5x
the proposed rate, tolerance spreadsheet predicted a 0.45 ppm for garden
beet roots and 8.0 ppm for garden beet tops.  Adjusting to 1.0x the
application rate, HED is recommending a 0.30 ppm tolerance on garden
beet roots and a 5.5 ppm on garden beet tops.  

5.1.11	International Residue Limits TC \l3 "5.1.11	International Residue
Limits 

The Codex Alimentary Commission has established several maximum residue
limits (MRLs) for propiconazole in/on various raw agricultural
commodities.  In addition, both Canada and Mexico have established MRLs
for propiconazole in/on various commodities.  The Codex and Mexican MRLs
are expressed in terms of propiconazole per se.  The Canadian MRLs are
expressed in terms of combined residues of propiconazole and its
metabolites containing the 2,4-DCBA moiety.  No Codex, Mexican, or
Canadian MRLs have been established for commodities associated with this
petition.  

	

5.2	Dietary Exposure and Risk TC \l2 "5.2  Dietary Exposure and Risk 

(Dietary Exposure and Risk Assessment for New uses; HED memo of Yan
Donovan, D355821, 09/30/08)

Residue Data used for Acute and Chronic Assessments:

These acute and chronic assessments were based on the assumption of
tolerance-level residues for all commodities with existing and proposed
tolerances and 100% crop treated (%CT) for all commodities.  The
existing tolerances are listed in 40 CFR §180.434.  The proposed new
tolerance levels used in the DEEM are presented in Table 1 (3rd column
in Table 1 below).  Table 1 is from the residue chemistry summary
chapter for propiconazole by Y. Donovan, 07/28/08, D348248.  DEEM
default processing factors from DEEM (Version 7.81) were used for all
processed commodities that do not have individual tolerances, except for
pineapple juice where available processing study indicated that there is
no concentration of residues in pineapple juice.

Drinking Water data

The drinking water residues used in the dietary risk assessment were
provided by the Environmental Fate and Effects Division (EFED) in the
following memorandum: “Drinking Water Assessment for Propiconazole
Uses on Garden Beet, Turnip, Leaves of Root and Tuber Vegetables, Herbs,
and Pineapple – An IR-4 Action” (Jim Lin, 07/02/08, D347906) and
incorporated directly into this dietary assessment.  Water residues were
incorporated in the DEEM-FCID into the food categories “water, direct,
all sources” and “water, indirect, all sources.”

The proposed new use rates are much less than the existing turf use of 8
applications at a rate of 0.786 lb ai/ac with a 14-day interval. 
Therefore, the drinking water assessment was based on  turf use rate.  

The estimated surface water drinking water concentrations for
propiconazole are:  

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

0.64 μg/L

The highest estimates from surface water (acute, 55.8 ppb and chronic,
21.6 ppb) are directly entered into the exposure model to assess the
contributions from drinking water.  

The model and its description are available at the EPA internet site:  
HYPERLINK "http://www.epa.gov/oppefed1/models/water/" 
http://www.epa.gov/oppefed1/models/water/ .  

DEEM-FCID™ Program and Consumption Information

Propiconazole acute and chronic dietary exposure assessments were
conducted using the Dietary Exposure Evaluation Model software with the
Food Commodity Intake Database DEEM-FCID™, Version 2.03 which
incorporates consumption data from USDA’s Continuing Surveys of Food
Intakes by Individuals (CSFII), 1994-1996 and 1998.  The 1994-96, 98
data are based on the reported consumption of more than 20,000
individuals over two non-consecutive survey days.  Foods “as
consumed” (e.g., apple pie) are linked to EPA-defined food commodities
(e.g. apples, peeled fruit - cooked; fresh or N/S; baked; or wheat flour
- cooked; fresh or N/S, baked) using publicly available recipe
translation files developed jointly by USDA/ARS and EPA.  For chronic
exposure assessment, consumption data are averaged for the entire U.S.
population and within population subgroups, but for acute exposure
assessment are retained as individual consumption events.  Based on
analysis of the 1994-96, 98 CSFII consumption data, which took into
account dietary patterns and survey respondents, HED concluded that it
is most appropriate to report risk for the following population
subgroups: the general U.S. population, all infants (<1 year old),
children 1-2, children 3-5, children 6-12, youth 13-19, adults 20-49,
females 13-49, and adults 50+ years old.

For chronic dietary exposure assessment, an estimate of the residue
level in each food or food-form (e.g., orange or orange juice) on the
food commodity residue list is multiplied by the average daily
consumption estimate for that food/food form to produce a residue intake
estimate.  The resulting residue intake estimate for each food/food form
is summed with the residue intake estimates for all other food/food
forms on the commodity residue list to arrive at the total average
estimated exposure.  Exposure is expressed in mg/kg body weight/day and
as a percent of the cPAD.  This procedure is performed for each
population subgroup.

For acute exposure assessments, individual one-day food consumption data
are used on an individual-by-individual basis.  The reported consumption
amounts of each food item can be multiplied by a residue point estimate
and summed to obtain a total daily pesticide exposure for a
deterministic exposure assessment, or “matched” in multiple random
pairings with residue values and then summed in a probabilistic
assessment.  The resulting distribution of exposures is expressed as a
percentage of the aPAD on both a user (i.e., only those who reported
eating relevant commodities/food forms) and a per-capita (i.e., those
who reported eating the relevant commodities as well as those who did
not) basis.  In accordance with HED policy, per capita exposure and risk
are reported for all tiers of analysis.  However, for tiers 1 and 2, any
significant differences in user vs. per capita exposure and risk are
specifically identified and noted in the risk assessment.

Results and Discussion

At the 95th percentile, the acute dietary exposure (food and water) to
general US population is at 7 % of the aPAD, and the most highly exposed
subgroup, all infants <1 yrs old, is at 16 % of the aPAD.  The chronic
dietary exposure to general US population is at 7 % of the cPAD, and the
most highly exposed subgroup, Children 1-2 yrs old, is at 17 % of the
cPAD.  All the dietary risk estimates are below 100% of the PADs.

These analyses are highly conservative, Tier 1 dietary exposure
assessments.  Further refinement to the analyses could be made through
the use of anticipated residues, incorporation of percentages of crops
treated with propiconazole, and/or monitoring data that better reflect
residues at the time of consumption.  Since risk estimates are well
below HED’s level of concern, a more highly refined analysis is not
needed at this time.

These Tier 1 analyses demonstrate that the requested uses for
propiconazole will not result in dietary risk estimates that exceed
HED’s level of concern for any of the regulated population subgroups,
including those comprised of infants and children.  A summary of the
dietary exposure analyses is given in Table 5.2.  

Table 5.2.  Summary of Dietary Exposure and Risk for Propiconazole FOOD
PLUS WATER.

Population Subgroup*	

Acute Dietary

(95th Percentile)	

Chronic Dietary	

Cancer

	

Dietary Exposure (mg/kg/day)	

% aPAD	

Dietary Exposure

(mg/kg/day)	

% cPAD	

Dietary Exposure

(mg/kg/day)	

Risk

General U.S. Population	

0.020692	

7	

0.006484	

7	

N/A

All Infants (< 1 year old)	

0.046634	

16	

0.015191	

15

	

Children 1-2 years old	

0.046428	

15	

0.016800	

17

	

Children 3-5 years old	

0.036739	12	

0.013945	

14

	

Children 6-12 years old	

0.025988	

9	

0.009237	

9

	

Youth 13-19 years old	

0.017393	

6	

0.005661	

6

	

Adults 20-49 years old	

0.016768	

6	

0.005433	

5

	

Adults 50+ years old	0.012911	

4	

0.004396	

4

	

Females 13-49 years old	

0.015986	5	0.005063	5

	

6.0	Residential (Non-Occupational) Exposure/Risk Characterization  TC
\l1 "5.0	Residential (Non-Occupational) Exposure/Risk Characterization 

6.1	Residential Handler Exposure and Risk Characterization  TC \l2 "5.1
Residential Handler Exposure and Risk Characterization 

No new residential uses are being requested at this time.  However,
adults, adolescents and toddlers may be exposed to propiconazole from
its currently registered use on turf, ornamentals, and treated paints. 
These risks have been previously assessed.  

Propiconazole: Revised Occupational and Residential Exposure Assessment;
James Miller, Environmental Scientist (D329393, 6/15/06)

Propiconazole Occupational and Residential Exposure Assessment of the
Antimicrobial Uses; Timothy Leighton (D326306, 2/1/2006)

Amendment to the Propiconazole RED for Children’s Post-application
Exposure from Treated Structures; Tim Leighton (D330159, 06/20/06)

Residential Handler Exposure Assessment

The anticipated use patterns and current labeling indicate three major
residential exposure scenarios based on the types of equipment and
techniques that can potentially be used to make propiconazole
applications.  The quantitative exposure/risk assessment developed for
residential handlers is based on these scenarios:  

Mixer/Loader/applying liquids and wettable powder in water soluble
packets via 1) Low Pressure Handwand, and 2) Hose-End Sprayer.

Applying treated paint using airless sprayer and Hose-end spray.

Residential handler exposure scenarios are considered to be short-term
only due to the infrequent uses associated with homeowner products.

A series of assumptions and exposure factors served as the basis for
completing the residential handler risk assessments.  Each assumption
and factor is detailed below.  In addition to these factors, unit
exposures were used to calculate risk estimates.  Mostly, these unit
exposures were taken from the Pesticide Handlers Exposure Database
(PHED) and the Outdoor Residential Exposure Task Force (ORETF) studies.

HED believes that the scenarios assessed in this document represent
worst-case exposures and risks resulting from use of propiconazole in
residential environments.  It should also be noted that there were many
other scenarios where medium to low quality PHED data were used to
complete the assessment.  Data quality should be considered in the
interpretation of the uncertainties associated with each risk presented.

Short-term estimated risks for residential handlers are presented below
in Table 6.1.  All estimated risks are below HED’s level of concern
(i.e., MOEs are > 100) assuming handlers are wearing short-sleeve shirt,
short pants, shoes, and socks.  

Table 6.1: Summary of Residential Handler Exposure Estimates

Application. Equip.

	Crop(s)/Site

	Max Appl. Rate¹	Daily Area Treated²	Handler Scenario	

Short-Term MOE

     Lb ai/Acre or

% in paint*	Acre/day

Or gal/day*	M/L/A	Derml+Inhln

Baseline

Low Pressure                     Handwand	Ornamentals (woody and
flowering plants), Shade Trees, Woody Shrubs and Vines	0.0024	5*	
(Liquids)	4400

 (WP/WSP)	N/A

Hose-end                           Sprayer

	5*	 (Liquids)	40,000

 (WP/WSP)	N/A

Low Pressure                      Handwand	Turf                         
                               (Lawns)	1.8	0.023	 (Liquids)	1300

 (WP/WSP)	N/A

Hose-end                           Sprayer

	0.5	 (Liquids)	530

 (WP/WSP)	N/A

Brush/Roller3 	Applying treated paint	0.35%	15*	(Paint)	330

Airless Sprayer3

	2*	(Paint)	120

Notes:

¹ Application rates are the maximum rates provided for propiconazole in
all cases.

² Amount handled per day values are HED estimates of area treated or
gallons applied based on Exposure SAC SOP #12 “Recommended Revisions
to the Standard Operating Procedures for Residential Exposure 
Assessments,” HED estimates and AD Standard Assumptions. 

3 Paint exposure scenarios are from the AD Occupational and Residential
Exposure Assessment (T. Leighton, 2/1/2006, D326306).  The density of
paint is assumed to be 10 lb/gal.

None of the residential handler exposure scenarios exceeded HED’s
level of concern. [Note: Although the risk for mixing/loading/applying
propiconazole with a low pressure handwand is not a concern, (MOE =
1300) it is important to note that most labels identify a hose-end
sprayer as the method of application.  Additionally, all risk
calculations were conducted using the maximum turf application rate (1.8
lb ai/acre).  However, a turf application rate of 0.51 lb ai/acre was
identified on a residential-use product label (EPA Reg # 100-773). This
lower application rate may better represent homeowner use.

6.2	Residential Postapplication Exposure and Risk Characterization  TC
\l2 "5.2	Residential Postapplication Exposure and Risk Characterization 

The existing residential use patterns result in post application dermal
exposures to adults, and dermal and oral exposures to infants and
children.  These exposures are considered short term only, due to the
fact that post-application exposures were calculated using Propiconazole
as the parent compound, while compound specific TTR data indicates that
at the Indiana, California, and Pennsylvania test sites, average total
propiconazole residues declined to below the minimum quantifiable limit
(MQL) by DAT = 14, DAT = 10, and DAT = 8 respectively.  These
dissipation rates, combined with label specific use rates and frequency
of use specifications, reinforce the hand to mouth short-term exposure
scenario;  For short term exposure to Children 1-2 years old, the
driving factors for this risk assessment are hand to mouth, object to
mouth, and dermal exposure.  Soil ingestion is insignificant
(MOE>300,000) compared to these factors, indicating that the post
application scenario should be short term only

In addition to using HED’s SOP for residential assessment, the study
specific turf transferable residue (TTR) was used in the calculation.  
A summary of risk estimates for residential post-application risks for
adults and children is provided in the following tables.  



Table 6.2a:  Short-term Risks to Adults and Children From
Post-application Exposure to Turf . 1

Exposure scenarios	Max. appl. rate 

(lb ai/A)	Exposure  routes	TC 

 cm²/hr	Short-term      MOE 2

 Adult, high-contact activities	1.8	dermal	70,000	350

 Adult, mowing	""	dermal	500	50,000

 Toddler, high contact activities	""	dermal	25,000	210

 Toddler, hand-to-mouth activity	""	oral	N/A	1,100

 Toddler, object-to-mouth activity 	""	oral	N/A	4,500

 Toddler, incidental soil ingestion	""	oral	N/A	330,000

1. From J. Miller, D329393, June 15, 2006.

2.  Dermal exposure only.

The post-application exposure results summarized in Table 6.2 a were not
recalculated using the current TCs to bring this assessment up to
today's standards, even though chemical-specific turf transferable
residue (TTR) studies are available for such scenarios (J. Miller,
D329393, 6/15/2006).  The TTR data were generated using the Modified
California Roller Technique (ORETF roller) in all the three locations. 
According to the ExpoSAC Policy No. 12, the TTR data generated by the
ORETF roller have a lower transfer efficiency (<0.5-1%) than that for
the revised TCs (1-5%).  Therefore, the ExpoSAC Policy No. 12 guidance
document advised against using the ORETF roller TTR data in conjunction
with the revised TCs because it results in lower exposures to adults and
children than the exposures estimated according by the current
residential SOP standards. 

The aggregated risk to Toddlers from exposures to residential turf use
is illustrated in Table 6.2b.  As shown in Table 6.2b, the aggregate MOE
is 170 which is not of concern.

Table 6.2b: Toddler Residential Risk Estimates for Post-application
Exposure to Propiconazole

Exposure Scenario	TC cm²/hr	Route of Exposure	Application Rate	MOE at
Day 0	Combined MOE

Outdoors

Hand to Mouth Activity on Turf	N/A	Oral	1.8 lb ai/acre	1100	170

Object to Mouth Activity on Turf	N/A	Oral	1.8 lb ai/acre	4500

	Soil Ingestion	N/A	Oral	1.8 lb ai/acre	330,000

	Turf – General High-Contact Activities	25000	Dermal	1.8 lb ai/acre
210

	

Note: Combined MOE = NOAEL/(ADDhand-to-mouth + ADDobject-to-mouth +
ADDincidental soil ingestion + ADDdermal)

Level of Concern: MOE = 100

	

Residential post-application scenarios from antimicrobial uses were also
assessed.  No post-application exposure to adult is expected because of
propiconazole’s low vapor pressure (therefore, no inhalation exposure)
and the registrants’ deletion of the only other use (i.e., materials
preservative in fabrics, textiles, area carpet fibers).  Propiconazole
is used on many different types of wood including 1) green or fresh cut
lumber, poles, posts, and timbers; 2) manufactured wood products such as
logs (including for log home construction), wood chips/sawdust, plywood
veneer, and particle board; 3) dry lumber; and 4) finished wood products
such as millwork, shingles, shakes, siding, plywood, and structural
lumber and composites.  Except “dry lumber” uses, the other 3
groupings would result in minimal dermal and/or incidental oral
exposure.  Inhalation exposure (e.g., in log homes treated with
propiconazole) is also expected to be negligible based on the low vapor
pressure.  For “dry lumber” uses, if propiconazole-treated lumber is
used to build residential decks and/or play sets, then there is the
potential for dermal and incidental oral exposures to treated lumber
used in decks and or play sets.  AD assessed the risk to children
playing on propiconazole-treated structures using screening level
assessment.  Table 6.2c shows the result of aggregate risk from
incidental oral and dermal exposure from propiconazole treated wood. 
This risk assessment, based on high end screening-level assumptions,
indicates no risk of concern.  Confirmatory data for the surface
residues are needed to verify this screening-level assessment.   

Table 6.2 c.  Propiconazole Assessment of Children Playing on Treated
Structures.

Exposure	Dose (mg/kg/day)a	MOEs (Target =100)b

Short-term	Intermediate

Dermal Contact	0.0675	450	150

Incidental Oral	0.00563	5,300	1,800

Aggregate	0.0731	410	140

a  Aggregate dose = dermal dose + oral dose.

b  MOEs = ST and IT NOAELs (mg/kg/day) / Dose (mg/kg/day).   Where ST
NOAEL = 30 mg/kg/day and IT NOAEL = 10 mg/kg/day.  Target MOE = 100.

		

7.0	Aggregate Risk Assessments and Risk Characterization  TC \l1 "6.0
Aggregate Risk Assessments and Risk Characterization 

In accordance with the FQPA, HED must consider and aggregate (add)
pesticide exposures and risks from three major sources: food, drinking
water, and residential exposures.  In an aggregate assessment, exposures
from relevant sources are added together and compared to quantitative
estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can
be aggregated.  When aggregating exposures and risks from various
sources, HED considers both the route and duration of exposure.

7.1	Acute & Chronic Aggregate Risk  TC \l2 "6.1	Acute & Chronic
Aggregate Risk 

Acute and chronic aggregate exposures include food plus drinking water
exposures.  As demonstrated under Section 5.2.  Acute and chronic
aggregate risks are not of concern.

7.2	Short- and Intermediate-Term Aggregate Risk  TC \l2 "6.2	Short-Term
Aggregate Risk 

Short-intermediate term aggregate exposure takes into account
residential exposure plus average exposure levels to food and water
(considered to be a background exposure level).   Based on the
residential use pattern, propiconazole post- application exposures to
adults are from dermal exposure only, for infants and children are from
dermal and oral routes.   Table 7.2a aggregates the short-term risk for
Toddlers from incidental oral, dermal, and food and water (as a
background).  Although both residential and antimicrobial uses result in
incidental oral and dermal exposure to children, 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).  HED also did a back-calculation to estimate
room available in the risk cup for short- term aggregate risk.  In order
to obtain a short- term aggregate MOE ≥ 100, the MOE resulting from
additional short- term exposures to Children 1-2 (from possible dermal
and incidental oral exposure from treated wood or other sources) needs
to be ≥ 270.  As stated above in Section 6.2, the combined short-term
MOE (dermal and incidental oral) from antimicrobial use of propiconazole
in treated wood for Toddler is 410, which is greater than 270.

Table 7.2a: 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 

(As background)	N/A	Food and water	0.0168	30	1800 2	160

Hand to Mouth Activity on Turf	100 1	Oral	0.0269	30	1100 3

	Object to Mouth Activity on Turf	100 1	Oral	0.0067	30	4500 3

	Soil Ingestion	100 1	Oral	0.00009	30	330,000 3

	Turf – General High-Contact Activities	100 1	Dermal	0.1410	30	210 4

	Note:

1 Target MOE= 100, Developmental rat-severe maternal clinical toxicity. 
NOAEL=30

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

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

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

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

Table 7.2b 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, no post application
inhalation exposure is anticipated to occur.  No post-application
exposures are expected to occur with antimicrobial uses.  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 7.2b: 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	0.0065	30	4600 2	330

Residential Post-application (Residential Turf Gen. High-Contact
Activities))	100 1	Dermal	0.085	30	350 3

	Note:

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

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

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

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

7.3	Intermediate-Term Aggregate Risk 

The only residential use scenario that will result in potential
intermediate term exposure to propiconazole is post application exposure
to Children from wood treatment (antimicrobial use).   Table 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 7.3: 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 

(As background)	N/A	Food and water	0.0168	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)].

7.4	Long-Term Aggregate Risk 

Since there are no residential uses that will likely result in chronic
exposure to propiconazole, chronic aggregate includes food and water
only.   Water exposure has been included in the DEEM analysis;
therefore, the result of chronic aggregate risk assessment is as shown
in Table 5.2.  Propiconazole does not possess a separate cancer dietary
endpoint—the RfD approach is considered protective; therefore, the
results of only the acute and chronic analyses are given.

8.0	Cumulative Risk Characterization/Assessment  TC \l1 "7.0	Cumulative
Risk Characterization/Assessment 

Propiconazole is a member of the triazole-containing class of
pesticides.  Although conazoles act similarly in plants (fungi) by
inhibiting ergosterol biosynthesis, there is not necessarily a
relationship between their pesticidal activity and their mechanism of
toxicity in mammals.  Structural similarities do not constitute a common
mechanism of toxicity.  Evidence is needed to establish that the
chemicals operate by the same, or essentially the same, sequence of
major biochemical events (EPA, 2002).   In conazoles, however, a
variable pattern of toxicological responses is found.   Some are
hepatotoxic and hepatocarcinogenic in mice. Some induce thyroid tumors
in rats.  Some induce developmental, reproductive, and neurological
effects in rodents.  Furthermore, the conazoles produce a diverse range
of biochemical events including altered cholesterol levels, stress
responses, and altered DNA methylation.  It is not clearly understood
whether these biochemical events are directly connected to their
toxicological outcomes.  Thus, there is currently no evidence to
indicate that conazoles share common mechanisms of toxicity and EPA is
not following a cumulative risk approach based on a common mechanism of
toxicity for the conazoles.   For information regarding EPA’s
procedures for cumulating effects from substances found to have a common
mechanism of toxicity, see EPA’s website at
http://www.epa.gov/pesticides/cumulative.

Propiconazole is a triazole-derived pesticide.  This class of compounds
can form the common metabolite 1,2,4-triazole and two triazole
conjugates (triazolylalanine and triazolylacetic acid).  To support
existing tolerances and to establish new tolerances for
triazole-derivative pesticides, including propiconazole, U.S. EPA
conducted a human health risk assessment for exposure to 1,2,4-triazole,
triazolylalanine, and triazolylacetic acid resulting from the use of all
current and pending uses of any triazole-derived fungicide.  The risk
assessment is a highly conservative, screening-level evaluation in terms
of hazards associated with common metabolites (e.g., use of a maximum
combination of uncertainty factors) and potential dietary and
non-dietary exposures (i.e., high end estimates of both dietary and
non-dietary exposures).  In addition, the Agency retained the additional
10X FQPA safety factor for the protection of infants and children.  The
assessment includes evaluations of risks for various subgroups,
including those comprised of infants and children.  The Agency’s
complete risk assessment is found in the propiconazole reregistration
docket at http://www.regulations.gov, Docket Identification (ID) Number
EPA-HQ-OPP-2005-0497.

9.0	Occupational Exposure/Risk Pathway  TC \l1 "8.0	Occupational
Exposure/Risk Pathway 

(HED memo of 09/03/08, Suku Oonnithan, DP barcode D349727)

9.1	Occupational Handler Exposure and Risk

  TC \l1 "8.1	Occupational Handler Exposure and Risk 

The proposed new uses for Tilt® on garden beet, turnips, leaves of root
and tuber vegetables, parsley, and cilantro may result in short- and
intermediate-term exposures due to repeated applications at 14 day
intervals during the season.  Pineapples are grown throughout the year
in Hawaii and the state ranks first in total production in the U.S. (B.
S. Sipes, 2000).  Therefore, the use of Tilt® and Tilt® 45W for the
post-harvest treatment of pineapple fruits may result in short- and
long-term exposures to workers.  

For handler exposure assessment, inputs from PHED (unit exposures at
various exposure parameters) and ExpoSAC Policy # 9 (area treated/day)
along with other factors (application rate, % dermal absorption, and
endpoints) were used to calculate exposures and risks for each of the
scenarios identified.  The dermal and inhalation MOEs were combined to
derive total MOEs for each exposure scenario.

Table 9.1a summarizes the short- and intermediate-term risks to handlers
of mixing, loading, and applying Tilt® by foliar applications on garden
beets, turnip, leaves of root and tuber vegetables, parsley, and
cilantro.  All the estimated short- and intermediate-term MOEs for
handlers are >100 and hence, not of concern (LOC = 100), provided the
handlers wear baseline PPE plus gloves. 

Table 9.1b summarizes the short- and long-term risks to handlers of
Tilt® and Tilt® 45W for dip or spray treatment of pineapple fruits. 
The estimated short- and long-term MOEs of mixers/loaders are >100 and
therefore, not of concern, provided they wear baseline PPE plus gloves. 
The occupational risks to applicators of these two formulations were not
assessed because it is assumed that the pineapple fruits are treated (by
dip or spray) with automatic equipment with minimal applicator
involvement.  The State of Hawaii grows pineapple year round and ranks
first in the production of pineapples in the United States with an
annual production of 332,000 tons in 1998 (Sipes, B, 2000).  The share
of fresh fruits represents 33% of annual production combined with the
year round post-harvest treatment, it is expected that the commercial
processors in Hawaii would use automatic equipment.  Therefore dermal
and inhalation exposures to applicators from dip or spray operations are
expected to be minimal since such application equipment is operated
remotely.  According to the product labels, these workers are required
to wear PPE consisting of long-sleeved shirt, long pants, shoes plus
socks and chemical resistant gloves.

For propiconazole a Q1* for carcinogenicity was not established and the
RfD approach is considered protective; therefore, a cancer risk
assessment for handlers is not required.



Table 9.1a.  Propiconazole: Non-cancer Short- and Intermediate-term
Risks to Handlers from Use of Tilt (EC) on Proposed Vegetables.  

Scen.  No.1	Task, Max. single appl. rate 	Equipment,             Area
treated/day 	PPE &

EC 2  	Dermal dose 3	Inhalation dose 4	Total Dose 5 mg/kg/day	Total MOE
6

	Short-term	Interm.- term

1 & 3	Mixing / Loading  

0.1125 lb ai/A	Aerial & Chemigation

350 acres	Baseline,        (open) 	unit exp.  2.9 dose/day	  0.6525	unit
exp.  0.0012 dose/day	   0.00068	0.65138	46	15

	Baseline + gloves, (open)	unit exp.  0.023 dose/day	  0.00518	unit exp.
 0.0012 dose/day	  0.00068	0.00585	5,100	1,700

2

Ground boom        80 acres	Baseline,  (open)	unit exp.  2.9 dose/day	 
0.149	unit exp.  0.0012 dose/day	  0.00015	0.1493	200	67

	Baseline + gloves, (open)	unit exp.  0.023 dose/day	  0.0012	unit exp. 
0.0012 dose/day	  0.00015	0.00134	22,000	7,500

4	Applying, 0.1125 lb ai/A

	Aerial

350 acres	Baseline,           (encl. cockpit) 	unit exp.  0.005 dose/day
  0.00113	unit exp. 0.000068 dose/day	  0.00004	0.00116	26,000	8,600

5

Ground boom        80 acres	Baseline,           (open cab) 	unit exp. 
0.014 dose/day	  0.00072	unit exp.  0.00074 dose/day	  0.0001	0.00082
37,000	12,000

6

Chemigation

350 acres	Not assessed; chemigation does not involve applicator
exposure.

7	Flagging, 0.1125 lb ai/A	Aerial

350 acres	Baseline      (none) 	unit exp.  0.011 dose/day   0.00248	unit
exp.  0.00035 dose/day	  0.0002	0.00267	11,000	3,700

1. The scenario #s are from Table 7.1. Scenarios 1 and 3 were combined
because of common inputs.

2.  Personal protective equipment (PPE), Baseline = long sleeved shirt,
long pants and shoes with socks. EC = engineering controls, open = open
mixing/loading.  3.  Dermal dose (mg/kg/day) =  (appl. rate * acres
treated/day * dermal unit exposure * % dermal absorption) / body weight
(70 kg).

4.  Inhalation dose (mg/kg/day) =  (appl. rate * acres treated/day *
inhalation unit exposure * % inhal. absorption) / body weight (70 kg).

5. Total dose (mg/kg/day) = dermal + inhalation doses for the scenario.

6. MOE (short- and intermediate-term) =  NOAEL(for the duration) / total
dose (mg/kg/day).  Bolded MOEs are < LOC of 100.



Table 9.1b.  Propiconazole: Non-cancer Short-and Long-term Risks to
Handlers from Uses of  Tilt (EC) and Tilt 45W on Pineapple Fruits.

Scen.  No.1	Task, Formulation, Max. single appl. rate 	Equipment,       
             ai (lbs) handled/day	PPE & EC 2  	Dermal dose 3	Inhalation
dose 4	Total dose 5 mg/kg/day	Total MOE 6

	Short term	Long. term

8	Mixing/Loading 

Tilt (EC)	dip/spray

3.6 lbs	Baseline + gloves, (open)	unit exp	0.023              dose
0.00047	unit exp	0.0012   dose	0.00006	0.00053	56,000	19,000

9	Mixing/Loading

Tilt 45W (WP)	dip/spray

3.6 lbs	Baseline + gloves, (open)	unit exp	0.17     dose	0.00349	unit
exp	0.04342 dose 	0.00223	0.00571	5,300	1,800

10	Applying        diluted spray	dip/spray

3.6 lbs	Not assessed; since treatment of pineapple fruits is expected to
be an automated operation.

1. The scenario #s are from Table 7.1. 

2.  Personal protective equipment (PPE), Baseline = long sleeved shirt,
long pants and shoes with socks. EC = engineering controls, open = open
mixing/loading.  3.  Dermal dose (mg/kg/day) =  (appl. rate * lbs fruits
treated/day * dermal unit exposure * % dermal absorption) / body weight
(70 kg).

4.  Inhalation dose (mg/kg/day) =  (appl. rate * lbs fruits treated/day
* inhalation unit exposure * % inhal. absorption) / body weight (70 kg).

5. Total dose (mg/kg/day) = dermal + inhalation doses for the scenario.

6. MOE (short- and long-term) =  NOAEL(for the duration) / total dose
(mg/kg/day). The intermediate - and long-term MOEs are the same because
of the same NOAEL.



9.2	Occupational Postapplication Exposure and Risk  TC \l1 "8.2
Occupational Postapplication Exposure and Risk 

There is a potential for dermal and inhalation exposures of workers who
enter fields treated with a pesticide to do post-application activities
such as scouting, weeding, hand harvesting, etc.  For the agricultural
uses of propiconazole, workers may be subjected to dermal exposures
only.  Inhalation exposure is not expected because propiconazole is a
non-volatile pesticide and the fact that workers are expected to enter
the treated area after the label specified REI.  For this action,
post-application exposures from the use of propiconazole on vegetable
crops and that from the post-harvest treated pineapple fruits were
assessed.  There is no Q1* established for human carcinogenicity and the
RfD approach is considered protective; therefore, a cancer risk
assessment for post-application workers is not required.

Post-application Exposure From Vegetable Crops: According to the
proposed use pattern, dermal exposure to residues is likely when workers
enter the treated fields to do irrigation, thinning, scouting, weeding,
and/or harvesting.  Such exposures may be short- (1-30 days) or
intermediate-term (1-6 months) depending upon the duration of use.  The
intermediate-term exposures result from the multiple applications of
Tilt® at 14-day intervals.

The post-application worker exposures were estimated using
chemical-specific DFR data and default TCs from HED's Exposure SAC
Policy No. 3.1.  Four DFR studies are available for propiconazole, the
results of which are summarized in Table 9.2a.  Because none of the
available DFR values could be used as surrogate for the vegetable crops,
the DFRs were normalized with respect to application rates and the
highest DFR (0.250 µg/cm2) was selected for estimating the risks to
post-application workers entering vegetable crop fields treated with
Tilt® (Table 9.2b).  

Table 9.2a:  Propiconazole: Summary of Chemical-specific Dislodgeable
Foliar Residues Established on Different Crops.1 

Crop           (Location)	Appl. rate     (lb ai/A)	Appl.         Method
Established DFR2 (µg/cm2)	Normalized         DFR 3 (µg/cm2)	DFR T1/2

Days	% Transferred on Day 0

Corn (NC)	Tilt 3.6E (EC)

@ 0.1125	Gr. boom	0.0585	0.058	3.14	4.6

Peach (CA)	EC and WP            @ 0.1125	Air blast	0.25	0.250*	9.79	20.1

Pecan (SC)	Tilt 3.6E (EC)

@ 0.34	Air blast	0.385	0.127	5.5	10.1

Rice (AR)	Tilt 3.6E (EC)

@ 0.28	Aerial	0.184	0.074	2.25	5.9

1.  From  J. Miller (D329393, 06/15/2006).

2. Dislodgeable foliar residue (DFR) for day "0". 

3. DFR value (*) for this assessment.



Table 9.2b. Propiconazole: Non-cancer Short-and Intermediate-term Risks
to Workers Entering Propiconazole Treated Fields.

Crops &         Appl. rate	Post-appl. activity	TC 1	DFR2        µg/cm2
Daily dose  (mg/kg/day) 3	Sh. term   MOE 4   	Inter.-term MOE 4

leafy vegetables

0.1125 lb ai/A	irrigation,  scouting 	1,500 (medium)	0.250	0.00129
23,000	7,800

	thinning           hand harvesting	2,500   (high)	0.250	0.00321	9,300
3,100

1. TC values are for celery, collards, and parsley which are similar to
the proposed vegetables. 

2. Normalized DFR value from Table 8.1 above.

3. Dermal dose = [AR * TC * DFR * CF1.0E-3 * % DA * ET] / 70 BW where
AR=  application rate (0.1125 lb ai/A),  BW = 70 kg, CF (conversion
factor 1.0E-3, µg/mg), DA= dermal absorption (40 %), DFR = dislodgeable
foliar residue on day 't0' (0.250 µg/cm2), ET = exposure time (8
hours), and TC = surrogate transfer coefficient for the specific
activity.  

4. MOE = NOAEL/DD. Short- and Intermediate-term NOAELs are 30 and 10
mg/kg/day, respectively.

The post-application exposure estimated for the vegetable crops using
the highest normalized chemical-specific DFR value are provided in Table
9.2b.  The estimated non-cancer short- and intermediate-term
post-application MOEs for workers who may enter Tilt® treated vegetable
fields on day "0" after application, are greater than 100 (LOC = 100)
and therefore are not of concern.

Post-application Risk from Treated Pineapples:  The petitioner has not
provided a chemical-specific post-treatment exposure study to address
the exposure of workers who do the sorting, culling, and packing of
pineapple fruits following treatment with propiconazole.  The Agency
also has no treatment-specific data available to estimate such
exposures.  However, attempts have been made to extrapolate data from
various sources to generate surrogate data needed to address the
post-application exposure to workers resulting from handling treated
fruits and other commodities.  As stated earlier pineapple is grown year
round in Hawaii; therefore post-harvest treatment of fruits is expected
to be a year round operation resulting in short- and long-term exposure
to workers.  Using surrogate inputs and assumptions, the short- and
long-term post-application risks to workers who sort and pack pineapple
fruits following treatment with propiconazole were estimated (Table
9.2c).    

For this assessment, instead of using the application rate as an input
in the algorithm, the propiconazole residues were estimated using the
weight and surface area of the fruit.  It was assumed that the pineapple
fruit (with out the top) is cylindrical in shape and all the residues of
propiconazole following treatment with Tilt® and Tilt® 45W
formulations remain on the surface of the fruit.  Then the weight and
surface area of a pineapple fruit (w/o the top) were determined.  



of a pineapple = 2 π r2 + 2 π r * h where π = 3.14, r = 5.63 cm, and
h =14.0 cm.  Weight and surface area values are average of 2 pineapples
(purchased locally) after  the tops removed. 

2.  Surface residues on fruit = (0.0136 mg ai/g) * 1801 g (wt of fruit)
/ 694 cm 2 (surface area). 

3.  Transfer coefficient (TC) and transfer factor (TF) taken from
Jaquith, D. (D280908, Feb 7, 2002).  The TC is based on a fruit packing
study (Nigg, H.N., J.H. Stamper, and R.M. Queen (1984), The Development
and Use of a Universal Model to Predict Tree Crop Harvester Pesticide
Exposure (J. Am. Ind. Hyg. Assoc.; 45:182-186).  The transfer  factor is
from a transfer study (Brouwer, H., R. Krouse, and J. van Hemmen (1999),
Transfer of Contaminants from Surface to Hands: Experimental Assessment
of Linearity of the Exposure Process.  Adherence to the Skin, and Area
Exposed During Fixed Pressure and Repeated Contact with Surfaces
Contaminated with a Powder (Appl. Occupat. Environm. Hyg. 14: 231-239).

4. Daily dose = surface residue (mg/cm2) * TC (cm²/hr) * TF % * Hrs/day
(8) * DA (40%) / BW (70 kg)..

5. MOE = Sh. term NOAEL  (30 mg/kg/day for short- and 10 mg/kg/day for
long-term) / daily dose (mg/kg/day) . 

An MOE of 100 provides adequate protection to workers from exposures to
propiconazole.  Since the estimated short- and long-term MOEs are > 100,
sorting and packing of pineapples treated with Tilt® and Tilt® 45W do
not exceed HED's LOC.  No inhalation exposure is expected during such
post-treatment activities because propiconazole is a non-volatile
pesticide and the treated fruits are allowed to dry before packed for
shipping.

The registered labels of Tilt® (EPA Reg. No. 100-617) and Tilt® 45W
(EPA Reg. No. 100-780) have a 12-hour restricted entry interval (REI)
which is adequate considering the post-application exposures resulting
from the use of propiconazole on the proposed crops.

10.0	Data Needs and Label Recommendations  TC \l1 "9.0	Data Needs and
Label Recommendations 

Residue Chemistry

860.1200 Directions for Use

The proposed use on turnip must be removed from Section B until adequate
field trial data have been submitted.

The proposed use on the leaves of root and tuber vegetables, crop group
2 must be removed from Section B.  

The proposed use of 45% WP formulation of propiconazole on pineapple
must be removed from the supplemental label.

The proposed uses on garden beets, parsley, and cilantro must be revised
to specify PHIs of 14 days instead of 7 day, because the submitted crop
field trial data for garden beet and parsley reflected PHIs of 14 days. 

860.1550 Proposed Tolerances

The petitioner must submit a revised Section F reflecting the
recommended tolerances and commodity definitions presented above and in
Table 7.  The proposed tolerances for “Vegetables, leaves of root and
tuber, group 2” and “Turnip, roots” must be removed from Section
F.

Tolerance must be proposed for pineapple process residue at 7.0 ppm.

860.1500 Crop Field Trials

To support the proposed use on turnips, the petitioner must submit a
full set of crop field trial data in which turnips are treated at 1x the
proposed maximum seasonal rate, harvested at the proposed PHI, and
analyzed using adequate methods for residues of propiconazole per se and
the triazole metabolites, 1,2,4-T, TA, and TAA.  

Toxicity

Immunotoxicity study



11.0	References:  TC \l1 "10.0 References: 

1) Residue Chemistry Summary Document; Yan Donovan (D348248, 7/28/2008);

2) Occupational and Residential Exposure Assessment; Suku Oonnithan
(D349727, 09/03/08);

3) Revised Occupational and Residential Exposure Assessment of the
Antimicrobial Uses; Tim Leighton (D324052, 02/01/06);

4) Amendment to the Propiconazole RED for Children’s Post-application
Exposure from Treated Structures; Tim Leighton (D330159, 06/20/06);

5) Dietary Exposure and Risk Assessment for New uses; Yan Donovan
(D355821, 09/30/08);

6) Drinking Water Assessment; James Lin from EFED (D 347906, 07 /02/08).

7) HED re-registration eligibility document (RED), (HED memo of Y.
Donovan, 06/28/06, D329668)

8) Revised Occupational and Residential Exposure Assessment; (HED memo
of James Miller, 6/15/06, D329393)

12.0	Tolerance Summary  TC \l1 "11.0	Tolerance Summary 

Table 12.1	Tolerance Summary for Propiconazole

Commodity	Proposed Tolerance (ppm)	Recommended Tolerance (ppm)	Comments;
Correct Commodity Definition

Vegetables, leaves of root and tuber, group 2	8.0	Remove	Insufficient
data have been submitted to support a crop group tolerance

Beet, garden, roots	0.6	0.30	Adjusted for 1x application rate

Beet, garden, tops	None	5.5

	Turnip, roots	0.2	Remove	A new set of crop field trial data are needed
if tolerances are to be established.

Turnip, tops	None	Remove

	Parsley, fresh	13	13	Parsley, leaves

Parsley, dried 	60	35	Parsley, dried leaves

Cilantro, leaves	13	13	Coriander, leaves

Pineapple	0.91	4.5	The recommend tolerance will cover the existing
tolerance

Pineapple, process residue	None	7.0

	1  A tolerance for propiconazole residues in/on pineapple is currently
established at 0.1 ppm [40 CFR 180.434(a)].



13.0	Appendix  TC \l1 "12.0	Appendix: Toxicity Profile 

  SEQ CHAPTER \h \r 1 13.1	Structures of Metabolites and Degradates

  SEQ CHAPTER \h \r 1 (The highest %TRR is chosen when both [14C]
triazole-labeled propiconazole or [14C] phenyl-labeled studies were
conducted).  SEQ CHAPTER \h \r 1 

Table 3.4.   Tabular Summary of Metabolites and Degradates

Chemical Name (other names in parenthesis)	

Commodity	Percent TRR (PPM) 1	Structure

Matrices - Major Residue (>10%TRR)	Matrices - Minor Residue (<10%TRR)

	Parent	Wheat grain ( 0.1 lbs ai/A)

0.4	

 

	Wheat forage (0.1 lbs ai/A)

7.3

Wheat straw (0.1 lbs ai/A)

3.9

Wheat grain ( 0.5 lbs ai/A)

0.8

Wheat forage (0.5 lbs ai/A	17.2

	Wheat straw ( 0.5 lbs ai/A)

9.0

Celery, stalk	85.3

	Grape, fruit	14.6

	Grape, juice

2.0

Peanut, kernel (field)

--

Peanut, stalk (field)	54

	Peanut, shell (field)

--

Peanut, kernel (green house)

N/A

Peanut, stalk (green house)	89

	Peanut, shell (green house)

N/A

Rotational Crops

Peanut, stalk

5

Peanut, shell

--

Peanut, kernel

--

Wheat, grain

--

Wheat, mature stalk

--

Wheat, immature stalk

0.7

Lettuce, head

--

Carrot

--

Corn, kernel

--

Corn, cob

--

Corn, immature stalk

--

corn, mature stalk

--

Ruminant	1.7-13.9

	Poultry	1.4- 39

	Rat

--

Water

--

	

CGA-91304	Wheat grain (0.1 lbs ai/A)

0.1	

 

	Wheat forage (0.1 lbs ai/A)

0.3

Wheat straw (0.1 lbs ai/A)

1.2

Wheat grain ( 0.5 lbs ai/A)

0.3

Wheat forage (0.5 lbs ai/A

0.3

Wheat straw ( 0.5 lbs ai/A)

1.5

Celery, stalk

1.1

Grape, fruit	32.6

	Grape, juice	31.4

	Rotational Crops

--

Ruminant

--

Poultry

--

Rat

2 -3.6

Water

<10%

	CGA-91305	Wheat grain (0.1 lbs ai/A)

0.1	

 

	Wheat straw ( 0.5 lbs ai/A)

0.1

Celery, stalk

1.9

Grape, fruit

4.9

Grape, juice

2.9

Peanut, kernel (field)

--

Peanut, stalk (field)

3

Peanut, shell (field)

--

Peanut, kernel (green house)

8

Peanut, stalk (green house)

--

Peanut, shell (green house)

--

Rotational Crops

Peanut, stalk

2

Peanut, shell

--

Peanut, kernel

--

Wheat, grain

--

Wheat, mature stalk

--

Wheat, immature stalk

2.1

Lettuce, head

--

Carrot

--

Ruminant	15.9-31.3	--

Poultry	17.7-78.6	--

Rat

--

Water

<10%

	CGA-118244	Wheat grain ( 0.1 lbs ai/A)

0.4	

 

	Wheat forage (0.1 lbs ai/A)

0.4

Wheat straw (0.1 lbs ai/A)

1.0

Wheat grain ( 0.5 lbs ai/A)

0.2

Wheat forage (0.5 lbs ai/A

0.4

Wheat straw ( 0.5 lbs ai/A)

1.1

Celery, stalk

1.4

Rotational Crops

--

Ruminant	9.4- 34	--

Poultry	2-50	--

Rat

3.6

Water

--

	CGA-118245	Wheat grain ( 0.1 lbs ai/A)

0.4	

 

	Wheat forage (0.1 lbs ai/A)

0.2

Wheat straw (0.1 lbs ai/A)

0.4

Wheat grain ( 0.5 lbs ai/A)

0.1

Wheat forage (0.5 lbs ai/A

0.1

Wheat straw ( 0.5 lbs ai/A)

0.3

Celery, stalk

--

Rat	61.8

CGA-136735 	Wheat grain ( 0.1 lbs ai/A)

--	

 

	Wheat forage (0.1 lbs ai/A)

ND

Wheat straw (0.1 lbs ai/A)

0.1

Wheat grain ( 0.5 lbs ai/A)

ND

Wheat forage (0.5 lbs ai/

0.1

Wheat straw ( 0.5 lbs ai/A)

0.8

Celery, stalk

--

Rat

--

	

13.2 Toxicity Profile.

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

 (male 3.6, 18.1 and 96.4 ,  female 4.6, 23.3 and 100.6 
mg/kg/day)

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

870.4200

24-Month Carcinogenicity in Mice	00129570 (1982 )

Acceptable/guideline

0, 100, 500 or 2500 ppm

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

Liver tumors at 2500 ppm in male mice.

870.4200

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

Acceptable/guideline

0, 100, 500 or 850 ppm

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

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

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

870.6200 

Acute neurotoxicity in rats	46604601 (2005)

Acceptable/guideline

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

NOAEL = 30 mg/kg.

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

NOAEL for neurobehavioral toxicity = 100 mg/kg

870-5100

Bacterial reverse mutation	00058601 (1979)

Unacceptable

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 

 h€

5

6

L

W

j

k

l

m

n

o

w

6

L

l

m

n

o

ž

·

Þ

ß

ጀw

x

ß

ã

ä

¥

³

Ç

Ø	@

jk

jè

jÜ

j_

j

h

h

옍)

h:

$

葞葠ｰ摧毼§

$

葞葠ｰ摧毼§

$

葞葠ｰ摧毼§

$

$

$

$

$

÷ïéåéÞéÞéÞéÞéÞéåéåéåéåéåéåéÖéåéåéåÖÎ
ÖÃÖ¼åéÖåé´åé´åéåéåéåéåé®§®éåéå

¶

¶

Æ

¶

¶

Æ

¶

¶

Æ

¶

¶

Æ

¶

¶

Æ

¶

¶

Æ

¶

¶

Æ

¶

¶

Æ

¶

¶

Æ

¶

¶

Æ

€

萏ː␱䀀Ȧ葞ː摧屸»

옍

옍

«

®

±

æ

ç

i

j

„

«

¬

ༀ킄㄂$葞ː摧˶î

<

<

<

萏<␱䀀Ȧ葞<摧˶î

᐀㪤㄀$摧䤰ü

h÷

'

 h£F

 h£F

h

瑹㜲Ä

, h£F

 h£F

 h£F

 h£F

( h£F

摧㜲Ä

摧㜲Ä

Æ

h+

摧ソJ

&

Æ

옍

옍

옍

hx[

h

Ä

©

혈rᬅ쐀損谓鈘촞耤꤆

혈rᬅ쐀損谓鈘촞耤꤆

hx[

혈rᬅ쐀損谓鈘촞$꤇

혈rᬅ쐀損谓鈘촞$꤇

혈rᬅ쐀損谓鈘촞$꤇

혈rᬅ쐀損谓鈘촞$꤇

&

öîöîöîöîéåÝåÝåÝÕÝåÌÃå¾å¾å¸é°¬§¢˜‘Šƒ
˜}tmf h+

 h+

h+

 hx[

옍)

”ÿô

ᐆ

”ÿô

摧學

h+

h+

 h+

&

&

&

&

hÀ

ᔛ靨㨹ᘀhm

hm

hm

hm

hm

h

h

옍)

 hÿm

 hÿm

옍)

愀Ĥ摧ป

愀Ĥ摧ป

h

h

  h

 h

  h

 h

  h

$

$

攃昀Ĵ瑹毼§

瑹毼§

愀Ĥ摧毼§Ѐ

瑹毼§

愀Ĥ摧毼§

愀Ĥ摧毼§

攃昀Ĵ瑹毼§

愀Ĥ摧毼§

愀Ĥ摧毼§

愀Ĥ摧毼§

™

kd

B

摧ᠤl

摧ᠤl

摧ᠤl

摧ᠤl

摧ᠤl

摧ᠤl

摧ᠤl

摧ᠤl

摧ᠤl

摧ᠤl

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.

 of    NUMPAGES \* arabic \* MERGEFORMAT  67 

Page   PAGE  19  of   NUMPAGES  67 

Page   PAGE  45  of   NUMPAGES  67 

Page   PAGE  48  of   NUMPAGES  67 

Page   PAGE  49  of   NUMPAGES  67 

    	Chronic RfD =        10 mg/kg/day (NOAEL)    =     0.1 mg/kg/day			
		100 (UF)

 

Acute RfD (General Pop.)  =      30 mg/kg (NOAEL)    = 0.3 mg/kg

		     100 (UF)

Acute RfD (Females 13-49 years old) =      30 mg/kg (NOAEL)   = 0.3
mg/kg

		    		100 (UF)