Document ID: EPA-HQ-OPP-2007-1199-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-09-08T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460      

	OFFICE OF PREVENTION, PESTICIDE

	AND TOXIC SUBSTANCES

	

  SEQ CHAPTER \h \r 1 MEMORANDUM

Date:	3-31-2008

SUBJECT:	Ingredient:  Uniconazole-P	Title:  Uniconazole-P Human Health
Risk Assessment for Proposed Uses on Fruiting Vegetables (Except
Cucurbits), Crop Group 8

 

PC Code:  128976	DP Barcode: D346558

MRID No.:  None	Registration No.: 59639-37

Petition No.: 7E7268	Regulatory Action: Section 3 Registration

Assessment Type: Single Chemical Aggregate	Reregistration Case No.: None

TXR No.: None	CAS No.: 83657-17-4

	          	

FROM:	Edward Scollon, Ph.D., Toxicologist

		Douglas Dotson, Ph.D., Chemist

		Shih-Chi Wang, Ph.D., Biologist

		RAB2, Health Effects Division (7509P)

			And

		Stephen Dapson, Ph.D., Pharmacologist

		RRB3, Health Effects Division (7509P)

	  SEQ CHAPTER \h \r 1 

			

THROUGH:	Alan Levy, Ph.D., Toxicologist

		William Drew, Chemist

		Kelly Schumacher, Biologist

Richard Loranger, Ph.D., Senior Scientist

		Christina Swartz, Branch Chief

		RAB2, Health Effects Division (7509P)

		

		

TO:		Shaja Brothers/Barbara Madden, RM Team 5

		RIMUERB/Registration Division (7505P) 

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

		

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc195064769"  1.0	Executive
Summary	  PAGEREF _Toc195064769 \h  4  

  HYPERLINK \l "_Toc195064770"  2.0	Ingredient Profile	  PAGEREF
_Toc195064770 \h  10  

  HYPERLINK \l "_Toc195064771"  2.1	Summary of Registered/Proposed Uses	
 PAGEREF _Toc195064771 \h  11  

  HYPERLINK \l "_Toc195064772"  2.2	Structure and Nomenclature	  PAGEREF
_Toc195064772 \h  12  

  HYPERLINK \l "_Toc195064773"  2.3	Physical and Chemical Properties	 
PAGEREF _Toc195064773 \h  13  

  HYPERLINK \l "_Toc195064774"  3.0	Hazard Characterization/Assessment	 
PAGEREF _Toc195064774 \h  13  

  HYPERLINK \l "_Toc195064775"  3.1	Hazard and Dose-Response
Characterization	  PAGEREF _Toc195064775 \h  13  

  HYPERLINK \l "_Toc195064776"  3.1.1	Database Summary	  PAGEREF
_Toc195064776 \h  14  

  HYPERLINK \l "_Toc195064777"  3.1.2	Toxicological Effects	  PAGEREF
_Toc195064777 \h  14  

  HYPERLINK \l "_Toc195064778"  3.1.3	Dose-response	  PAGEREF
_Toc195064778 \h  15  

  HYPERLINK \l "_Toc195064779"  3.2	Absorption, Distribution,
Metabolism, Excretion (ADME)	  PAGEREF _Toc195064779 \h  15  

  HYPERLINK \l "_Toc195064780"  3.3	FQPA Considerations	  PAGEREF
_Toc195064780 \h  16  

  HYPERLINK \l "_Toc195064781"  3.3.1	Adequacy of the Toxicity Database	
 PAGEREF _Toc195064781 \h  16  

  HYPERLINK \l "_Toc195064782"  3.3.2	Evidence of Neurotoxicity	 
PAGEREF _Toc195064782 \h  16  

  HYPERLINK \l "_Toc195064783"  3.3.3	Developmental Toxicity Studies	 
PAGEREF _Toc195064783 \h  16  

  HYPERLINK \l "_Toc195064784"  3.3.4	Reproductive Toxicity Study	 
PAGEREF _Toc195064784 \h  17  

  HYPERLINK \l "_Toc195064785"  3.3.5	Additional Information from
Literature Sources	  PAGEREF _Toc195064785 \h  18  

  HYPERLINK \l "_Toc195064786"  3.3.6	Pre-and/or Postnatal Toxicity	 
PAGEREF _Toc195064786 \h  18  

  HYPERLINK \l "_Toc195064787"  3.3.7	Recommendation for a Developmental
Neurotoxicity Study	  PAGEREF _Toc195064787 \h  18  

  HYPERLINK \l "_Toc195064788"  3.3.8	Rationale for the UFDB (when a DNT
is recommended)	  PAGEREF _Toc195064788 \h  18  

  HYPERLINK \l "_Toc195064789"  3.4	FQPA Safety Factor for Infants and
Children	  PAGEREF _Toc195064789 \h  18  

  HYPERLINK \l "_Toc195064790"  3.5	Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc195064790 \h  19  

  HYPERLINK \l "_Toc195064791"  3.5.1	Acute Reference Dose (aRfD) -
Females age 13-49	  PAGEREF _Toc195064791 \h  19  

  HYPERLINK \l "_Toc195064792"  3.5.2	Acute Reference Dose (aRfD) -
General Population	  PAGEREF _Toc195064792 \h  20  

  HYPERLINK \l "_Toc195064793"  3.5.3	Chronic Reference Dose (cRfD)	 
PAGEREF _Toc195064793 \h  20  

  HYPERLINK \l "_Toc195064794"  3.5.4	Incidental Oral Exposure (Short-
and Intermediate-Term)	  PAGEREF _Toc195064794 \h  21  

  HYPERLINK \l "_Toc195064795"  3.5.5	Dermal Absorption	  PAGEREF
_Toc195064795 \h  22  

  HYPERLINK \l "_Toc195064796"  3.5.6	Dermal Exposure (Short- and
Intermediate-Term)	  PAGEREF _Toc195064796 \h  23  

  HYPERLINK \l "_Toc195064797"  3.5.7	Inhalation Exposure (Short-, and
Intermediate-Term)	  PAGEREF _Toc195064797 \h  24  

  HYPERLINK \l "_Toc195064798"  3.5.8	Level of Concern for Margin of
Exposure	  PAGEREF _Toc195064798 \h  25  

  HYPERLINK \l "_Toc195064799"  3.5.9	Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc195064799 \h  25  

  HYPERLINK \l "_Toc195064800"  3.5.10	Classification of Carcinogenic
Potential	  PAGEREF _Toc195064800 \h  25  

  HYPERLINK \l "_Toc195064801"  3.5.11	Summary of Toxicological Doses
and Endpoints for Use in Human Risk Assessments	  PAGEREF _Toc195064801
\h  26  

  HYPERLINK \l "_Toc195064802"  3.6	Endocrine disruption	  PAGEREF
_Toc195064802 \h  27  

  HYPERLINK \l "_Toc195064803"  4.0	Public Health and Pesticide
Epidemiology Data	  PAGEREF _Toc195064803 \h  27  

  HYPERLINK \l "_Toc195064804"  5.0	Dietary Exposure/Risk
Characterization	  PAGEREF _Toc195064804 \h  28  

  HYPERLINK \l "_Toc195064805"  5.1	Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc195064805 \h  28  

  HYPERLINK \l "_Toc195064806"  5.1.1	Metabolism in Primary Crop	 
PAGEREF _Toc195064806 \h  28  

  HYPERLINK \l "_Toc195064807"  5.1.2	Metabolism in Rotational Crops	 
PAGEREF _Toc195064807 \h  31  

  HYPERLINK \l "_Toc195064808"  5.1.3	Metabolism in Livestock	  PAGEREF
_Toc195064808 \h  31  

  HYPERLINK \l "_Toc195064809"  5.1.4	Analytical Methodology	  PAGEREF
_Toc195064809 \h  31  

  HYPERLINK \l "_Toc195064810"  5.1.5	Environmental Degradation	 
PAGEREF _Toc195064810 \h  33  

  HYPERLINK \l "_Toc195064811"  5.1.6	Comparative Metabolic Profile	 
PAGEREF _Toc195064811 \h  33  

  HYPERLINK \l "_Toc195064812"  5.1.7	Toxicity Profile of Major
Metabolites and Degradates	  PAGEREF _Toc195064812 \h  34  

  HYPERLINK \l "_Toc195064813"  5.1.8	Pesticide Metabolites and
Degradates of Concern	  PAGEREF _Toc195064813 \h  34  

  HYPERLINK \l "_Toc195064814"  5.1.9	Drinking Water Residue Profile	 
PAGEREF _Toc195064814 \h  35  

  HYPERLINK \l "_Toc195064815"  5.1.10	Food Residue Profile	  PAGEREF
_Toc195064815 \h  36  

  HYPERLINK \l "_Toc195064816"  5.1.11	International Residue Limits	 
PAGEREF _Toc195064816 \h  37  

  HYPERLINK \l "_Toc195064817"  5.2	Dietary Exposure and Risk	  PAGEREF
_Toc195064817 \h  37  

  HYPERLINK \l "_Toc195064818"  5.2.1	Acute Dietary Exposure/Risk	 
PAGEREF _Toc195064818 \h  38  

  HYPERLINK \l "_Toc195064819"  5.2.2	Chronic Dietary Exposure/Risk	 
PAGEREF _Toc195064819 \h  38  

  HYPERLINK \l "_Toc195064820"  5.2.3	Cancer Dietary Risk	  PAGEREF
_Toc195064820 \h  38  

  HYPERLINK \l "_Toc195064821"  5.3	Anticipated Residue and Percent Crop
Treated (%CT) Information	  PAGEREF _Toc195064821 \h  39  

  HYPERLINK \l "_Toc195064822"  6.0	Residential (Non-Occupational)
Exposure/Risk Characterization	  PAGEREF _Toc195064822 \h  39  

  HYPERLINK \l "_Toc195064823"  7.0	Aggregate Risk Assessments and Risk
Characterization	  PAGEREF _Toc195064823 \h  40  

  HYPERLINK \l "_Toc195064824"  7.1	Acute Aggregate Risk	  PAGEREF
_Toc195064824 \h  40  

  HYPERLINK \l "_Toc195064825"  7.2	Short-Term Aggregate Risk	  PAGEREF
_Toc195064825 \h  40  

  HYPERLINK \l "_Toc195064826"  7.3	Intermediate-Term Aggregate Risk	 
PAGEREF _Toc195064826 \h  40  

  HYPERLINK \l "_Toc195064827"  7.4	Long-Term Aggregate Risk	  PAGEREF
_Toc195064827 \h  40  

  HYPERLINK \l "_Toc195064828"  7.5	Cancer Risk	  PAGEREF _Toc195064828
\h  40  

  HYPERLINK \l "_Toc195064829"  8.0	Cumulative Risk
Characterization/Assessment	  PAGEREF _Toc195064829 \h  41  

  HYPERLINK \l "_Toc195064830"  9.0	Occupational Exposure/Risk Pathway	 
PAGEREF _Toc195064830 \h  42  

  HYPERLINK \l "_Toc195064831"  9.1  Handler Risk	  PAGEREF
_Toc195064831 \h  42  

  HYPERLINK \l "_Toc195064832"  9.2  Post-application Risk	  PAGEREF
_Toc195064832 \h  46  

  HYPERLINK \l "_Toc195064833"  10.0	Data Needs and Label
Recommendations	  PAGEREF _Toc195064833 \h  46  

  HYPERLINK \l "_Toc195064834"  10.1	Toxicology	  PAGEREF _Toc195064834
\h  46  

  HYPERLINK \l "_Toc195064836"  10.2	Residue Chemistry	  PAGEREF
_Toc195064836 \h  47  

  HYPERLINK \l "_Toc195064837"  10.3	Occupational and Residential
Exposure	  PAGEREF _Toc195064837 \h  48  

  HYPERLINK \l "_Toc195064838"  Appendix A:	Toxicology Assessment	 
PAGEREF _Toc195064838 \h  50  

  HYPERLINK \l "_Toc195064839"  A.1	Toxicology Data Requirements	 
PAGEREF _Toc195064839 \h  50  

  HYPERLINK \l "_Toc195064840"  A.2	Toxicity Profile	  PAGEREF
_Toc195064840 \h  52  

  HYPERLINK \l "_Toc195064841"  A.3	Executive Summaries	  PAGEREF
_Toc195064841 \h  58  

  HYPERLINK \l "_Toc195064842"  A.3.1	Subchronic Toxicity	  PAGEREF
_Toc195064842 \h  58  

  HYPERLINK \l "_Toc195064843"  A.3.2	Prenatal Developmental Toxicity	 
PAGEREF _Toc195064843 \h  63  

  HYPERLINK \l "_Toc195064844"  A.3.3	Reproductive Toxicity	  PAGEREF
_Toc195064844 \h  65  

  HYPERLINK \l "_Toc195064845"  A.3.4	Chronic Toxicity	  PAGEREF
_Toc195064845 \h  66  

  HYPERLINK \l "_Toc195064846"  A.3.5	Carcinogenicity	  PAGEREF
_Toc195064846 \h  67  

  HYPERLINK \l "_Toc195064847"  A.3.6	Mutagenicity	  PAGEREF
_Toc195064847 \h  70  

  HYPERLINK \l "_Toc195064848"  A.3.7	Neurotoxicity	  PAGEREF
_Toc195064848 \h  73  

  HYPERLINK \l "_Toc195064849"  A.3.8	Metabolism	  PAGEREF _Toc195064849
\h  73  

  HYPERLINK \l "_Toc195064850"  A.4. 	References (in MRID order)	 
PAGEREF _Toc195064850 \h  75  

  HYPERLINK \l "_Toc195064851"  Appendix B:  Names and Structures of
Uniconazole and Metabolites	  PAGEREF _Toc195064851 \h  82  

  HYPERLINK \l "_Toc195064852"  Appendix C:  Tolerance Summary Table	 
PAGEREF _Toc195064852 \h  84  

 

1.0	Executive Summary  TC \l1 "1.0	Executive Summary 

Background

Uniconazole-P is a triazole fungicide that the Interregional Research
Project Number 4 (IR-4) has proposed for use on Crop Group 8, Fruiting
Vegetables (Except Cucurbits).  The intended use is as a plant growth
regulator in greenhouses.  Uniconazole,
(E)-(RS)-1-(4-chlorophenyl)-4,4-dimethyl-2-(1H-1,2,4-triazol-1-yl)pent-1
-en-3-ol, is a triazole fungicide and plant growth regulator.  The
resolved S-isomer, identified as uniconazole-P, is pesticidally active
and is the active ingredient in registered products.  Uniconazole-P
reduces plant height by reducing internode elongation through inhibition
of gibberellin biosynthesis.  Currently, uniconazole-P is only
registered for greenhouse use on ornamental plants.  The proposed use of
uniconazole-P on fruiting vegetables is the first food use for this
pesticide.  IR-4 is making the request in conjunction with Valent U.S.A.
Corporation, and on behalf of the Agricultural Experiment Stations of
Georgia and Oregon. 

Use profile

In conjunction with this petition, IR-4 is requesting amended
registration of the Valent end-use product, Sumagic® Plant Growth
Regulator (EPA Reg. No. 59639-37), a 0.055% emulsifiable concentrate
(EC) formulation.  The product is proposed for use on greenhouse-grown
fruiting vegetable transplants, including eggplant, groundcherry,
pepino, pepper, tomatillo, and tomato, as foliar spray applications at
up to 10 ppm in spray volumes of 2 qt/100 sq. ft.  The application of a
10 ppm solution at the rate of 2 quarts per 100 sq. ft. is equivalent to
0.000042 lb a.i./100 sq. ft or 0.018 lb a.i./acre.  No preharvest
interval (PHI) is specified.

Toxicology/Hazard

Uniconazole-P is rapidly absorbed after oral ingestion and extensively
metabolized by the liver.  There is no accumulation in the tissues, and
the metabolites are rapidly excreted in the feces and urine.  It has
moderate acute oral toxicity (Category II) and low acute dermal
(Category III/IV rat/rabbit) and inhalation (Category III) toxicity.  It
is a slight eye irritant (Category III), but not a skin irritant or skin
sensitizer.  In mouse, rat, and dog repeated-dose studies, oral
ingestion of high doses caused an increase in the size and weight of the
liver.  Fat accumulation in the liver was also consistently observed at
high doses.  Although observed less consistently, increases in the
activity of some enzymes indicated altered liver function as a response
to uniconazole exposure.  In chronic rodent studies, there was no
evidence of an increase in spontaneous tumors in the rat; however, in
the mouse an increase in liver neoplasms was noted.  There was limited
evidence of carcinogenicity; therefore, uniconazole is classified as a
Group C Chemical; Possible Human Carcinogen (CPRC, TXR No.0052723). 
Quantification of risk using the RfD methodology will adequately account
for all chronic effects including carcinogenicity.  Mutagenicity studies
were generally negative except for the in vitro mammalian chromosome
aberration test (CHO), which was positive with metabolic activation.  In
view of the positive results obtained for chromosomal aberration and DNA
damage/repair, the HED Peer Review Committee recommended that a dominant
lethal assay be performed to assess more fully the potential of
uniconazole to induce genetic effects in germ cells.  Uniconazole had no
effects on reproductive performance of rats and no effect on fetal
development in rabbits.  At doses that were not toxic to the mother,
there were no effects on the rat fetus.  There was no evidence of
neurotoxicity in the studies submitted in support of the registration of
uniconazole-P or in the open literature.

The acute dietary endpoint (females 13-49 years) and the inhalation
endpoints are based on the increased incidence of the 14th rib in the
oral rat development study (NOAEL = 5 mg/kg/day).  Decreased maternal
body weight in the same study was chosen for the incidental oral
endpoints (NOAEL = 5 mg/kg/day).  The dermal endpoints are based on
liver effects seen in a subchronic dermal rat study (NOAEL = 5
mg/kg/day).  The chronic dietary assessment is based on liver effects in
a chronic dog study with a NOAEL of 2 mg/kg/day.  The FQPA safety factor
has been reduced to 1x based on the lack of residual uncertainties for
pre- and postnatal toxicity and the conservative nature of the exposure
assessments.

Residue Chemistry

IR-4 is proposing the establishment of a permanent tolerance for
residues of the plant growth regulator uniconazole-P in/on Crop Group 8
at 0.01 ppm.  

Because uniconazole-P is a triazole compound, the Agency requires that
samples from any metabolism, livestock feeding, field trial, and/or
processing studies be analyzed for the triazole metabolites: 
1,2,4-triazole (1,2,4-T), triazolylalanine (TA), and triazolylacetic
acid (TAA).  The Agency issued guidance on the residue chemistry data
requirements for the triazole-based metabolites under Memo, D327788, M.
Doherty, 4/25/06.  Neither the metabolism studies nor the crop field
trials submitted under the current petition reflect analysis for the
triazole metabolites.  However, the use of another triazole-derived
pesticide, myclobutanil, on fruiting vegetables at a much higher rate is
likely to result in higher residues of 1,2,4-T, TA, and TAA.  Therefore,
the absence of these data will not preclude registration of the proposed
use of uniconazole-P.

The qualitative nature of the residue in plants is adequately understood
for the purposes of this petition.  HED has determined that the residues
of concern in fruiting vegetables are uniconazole-P, its R-enantiomer,
and the Z-isomer.  In the apple and tomato metabolism studies,
uniconazole was the primary residue identified in all apple and tomato
matrices.  The geometric Z-isomer of uniconazole was identified in apple
matrices at up to 3.0% of the total radioactive residue (TRR) and in
tomato matrices at 7.5-10.9% TRR.  Remaining identified metabolites,
including CH2OH-7E, CYC-4Cl, 7KE, and 7KZ were identified at ≤7% TRR
in apple and tomato matrices.  Based on the submitted apple and tomato
metabolism studies, the petitioner concluded that the major metabolic
pathway of uniconazole in plants is initial E/Z isomerization to the
Z-isomer followed by cyclization.  The minor metabolic pathways are
oxidation of the hydroxyl group to a ketone group, hydroxylation at the
terminal carbon, and conjugation of these metabolites.

There are no livestock feedstuffs associated with the proposed use on
fruiting vegetables.  Therefore, no livestock metabolism data,
enforcement methods, storage stability data, or feeding studies are
required to support this petition.

The petitioner proposed an acceptable GC/NPD method, Method RM-25-1, for
the enforcement of tolerances in fruiting vegetables.  The method
determines residues of uniconazole.  It does not appear to distinguish
between the R- and S-enantiomers or between the E- and Z-isomers.  The
validated limit of quantitation (LOQ) is 0.01 ppm.  An acceptable
revision of the enforcement method, Method RM-25-1a was used for data
collection in the submitted crop field trials.  The proposed enforcement
method should be amended to include the confirmatory GC/MS procedures
used in the independent laboratory validation (ILV), and to incorporate
the revisions made by the ILV laboratory.  Alternatively, the petitioner
may propose the data collection method, which includes the confirmatory
procedures and the ILV recommendations, as an enforcement method.  The
proposed enforcement method was forwarded to the Analytical Chemistry
Branch of the Biological and Economic Analysis Division (BEAD) for
petition method validation.  No multiresidue methods testing data have
been submitted.

Environmental Degradation

The water modeling strategy for this assessment focused on parent
uniconazole.  The principal conazole degradate (1,2,4-triazole) was not
included in this assessment, but was previously assessed separately. 
Other degradates were identified in environmental fate studies; however,
all identified degradates were detected at less than 5% percent of the
amount applied.  These degradates were not included in the exposure
assessment.

Comparative Metabolic Profile

Uniconazole is a member of the triazole class of compounds.  As a
result, it is very likely that in plants and animals it is metabolized
to some extent into the following compounds:  1,2,4-triazole (T),
triazole alanine (TA), and triazole acetic acid (TAA).  The registrant
did not submit metabolism studies, in which the triazole ring was
radiolabeled, however.  For the purposes of this tolerance petition, HED
assumes that uniconazole is metabolized in plants and animals to these
triazole compounds.  Studies were submitted in which the phenyl ring was
radiolabeled, however.  In the tomato and apple metabolism studies, the
primary residue identified in all matrices was parent uniconazole.  The
geometric Z-isomer of uniconazole was also found in both studies.  Minor
amounts of other metabolites and conjugates were also found.  In rats,
most of the test compound (96-99%) was excreted within three days. 
Significant fractions of the administered radioactive doses were
recovered in the urine and feces.  Five metabolites were identified in
these two fractions.  Two of these metabolites were oxidation products
of the methyl moiety of the tertiary butyl group, and one was a free
triazole.

Toxicity Profile of Major Metabolites and Degradates

HED previously performed a separate human health risk assessment for the
triazole metabolites T/TA/TAA.  The hazard characterization of the
metabolites is discussed in detail in that risk assessment.  More
recently, dietary exposure analyses were performed for the triazole
metabolites in support of a human health risk assessment performed for
the triazole fungicide myclobutanil.  HED was able to make the safety
finding with respect to the metabolites.

In the tomato and apple metabolism studies, the phenyl ring was the only
ring with a radioactive label.  No major metabolites were found.  Little
information is available on the toxicities of the metabolites that were
found.  HED anticipates that the toxicities of these metabolites are
similar to the toxicity of the parent.

Pesticide Metabolites and Degradates of Concern

Uniconazole-P, its R-enantiomer, and the Z-isomer are the residues of
concern in fruiting vegetables for risk assessment and tolerance
expression.  As tolerances are not being established for rotational
crops or animal commodities, the residue of concern in these commodities
for tolerance expression is not an issue.  Parent unicazole is the
residue of concern in drinking water.  The risks from the metabolites
1,2,4-T, TA, and TAA for the proposed use are considered to be covered
by previous assessments.

Drinking Water Residue Profile

The estimated drinking water concentration (EDWC) used in the dietary
risk assessment was provided by the Environmental Fate and Effects
Division (EFED).  Typically, EFED utilizes an integrated approach for
conducting exposure assessments that relies on an analysis of both
monitoring data and modeling.  No monitoring data are available for
uniconazole.  The surface water EDWCs were generated using the FIRST
Model, and the groundwater EDWCs were generated using the SCI-GROW
Model.  EDWCs reflect exposure to parent only.  The peak surface water
value was 3.1 ppb, and the annual average surface water value was 1.5
ppb.  The groundwater value was 0.076 ppm.

Food Residue Profile

The submitted uniconazole-P crop field trials are supported by
acceptable storage stability data, demonstrating that residues are
stable in/on bell pepper and tomato stored frozen for up to 395 days (13
months).

Adequate field trial data have been submitted to support the proposed
use on fruiting vegetables, provided the petitioner amends the product
label to specify a maximum seasonal application rate of 0.000042 lb
ai/100 sq ft. (0.018 lb ai/A) and the final application may not occur
later than 14 days after the 2-4 true leaf stage.  Residues were
nondetectable (<0.005 ppm) in/on all samples of tomato and bell pepper
transplanted and harvested at maturity following greenhouse application
of the 0.055% formulation of uniconazole-P at the 0.5x, 1x, and 2x
application rates.  The available data support the proposed tolerance of
0.01 ppm for fruiting vegetables.  The tolerance spreadsheet could not
be used to determine tolerance levels because residues were
nondetectable in/on all samples.

No processing data were submitted.  Given that residues were
nondetectable in/on all samples of tomatoes treated at 1x and 2x rates
and the timing of the application (prior to transplant), the Agency has
determined that a tomato processing study is not needed.   In addition,
tomatoes treated with uniconazole as a plant growth regulator are not
likely to be processed.

Because the proposed use of uniconazole-P on fruiting vegetables is
restricted to greenhouse application to plants intended to be
transplanted, and residues were nondetectable in/on all tomato and
pepper samples, no data pertaining to rotational crops are required to
support this petition.

International Residue Limits

No U.S. tolerances are established for uniconazole, and there are
currently no established Codex, Canadian, or Mexican maximum residue
limits (MRLs).  

Dietary Exposure

ole using the Dietary Exposure Evaluation Model DEEM-FCID™, Version
2.03.  The analyses included fruiting vegetables (crop group 8) plus
okra and drinking water.  The acute dietary exposure analysis was
performed for the population subgroup Females 13-49 only because an
endpoint attributable to a single dose was not identified for any
population subgroups other than Females 13-49.  Both the acute and
chronic analyses were unrefined.  Conservative assumptions were made
with respect to food residue values (tolerances), percent crop treated
estimates (100%), and drinking water concentrations.  The acute dietary
risk estimate for the population subgroup Females 13-49 is below HED’s
level of concern.  It utilizes <1% of the acute population adjusted dose
(aPAD).  The chronic dietary risk estimates for the general U.S.
population and all population subgroups are below HED’s level of
concern.  All subgroups utilize <1% of the chronic population adjusted
dose (cPAD). 

Uniconazole-P was classified by the HED CPRC as a Group C, possible
human carcinogen (TXR No. 0052723).  The CPRC recommended the reference
dose (RfD) approach for risk assessment and concluded that the chronic
RfD would be protective of all chronic effects including
carcinogenicity.  As a result, the chronic dietary exposure analysis is
adequate to assess cancer risk.  The general U.S. population utilizes
<1% of the cPAD.  Therefore, cancer risk is not of concern to HED.

Residential

A non-occupational and residential exposure/risk assessment was not
performed as there are currently no registered or proposed
non-occupational or residential uses for uniconazole-P.

Aggregate

There are no residential uses for uniconazole-P.  As a result, aggregate
exposure is comprised of exposures that occur through food and drinking
water only.  An acute aggregate risk assessment was performed for
Females 13-49 only.  This assessment is equivalent to the acute dietary
risk assessment.  Acute aggregate risk to Females 13-49 is below HED’s
level of concern.  As there are no non-occupational/residential uses for
uniconazole-P, no short- or intermediate-term exposures are anticipated.
 As a result, short- and intermediate-term aggregate risk assessments
are not needed. TC \l2 "7.2	Short-Term Aggregate Risk   As aggregate
exposure to uniconazole will be comprised of exposures that occur
through food and drinking water only, the long-term aggregate risk
assessment is equivalent to the chronic dietary risk assessment. 
Chronic aggregate risk is below HED’s level of concern for the general
U.S. population and all population subgroups.  All population subgroups
utilize <1% of the cPAD.  Uniconazole is considered to be a possible
human carcinogen.  However, the chronic dietary exposure analysis is
adequate to assess cancer risk.  The general U.S. population utilizes
<1% of the cPAD.  Therefore, aggregate cancer risk is not of concern to
HED.

Occupational

There are 3 handler scenarios that are expected to result in the highest
exposure for the proposed uses: (1) mixing/loading/applying liquids
using low-pressure handwand sprayer, (2) mixing/loading/applying liquids
using a back-pack sprayer, and (3) mixing/loading liquids for potential
application using a greenhouse boom.  The number of exposure days per
year was not provided.  Based on the frequency/interval of applications
to the plants, EPA assumes that all exposures would be less than 6
months per year (short- and intermediate-term exposures).  

As no chemical-specific data for assessing human exposures during 
pesticide handling activities were submitted to the Agency in support of
the registration of uniconazole, HED used surrogate data from the
Pesticide Handler’s Exposure Database (PHED) Version 1.1 (PHED
Surrogate Exposure Guide, 8/98) to assess exposures.  Defaults
established by the HED Science Advisory Council for Exposure were used
for amounts treated per day and body weight.  

No margins of exposures (MOEs) for handlers (1,100~2,900,000) exceed the
level of concern at the single layer level or single layer plus gloves
level (for back-pack sprayer users).  The HED level of concern is an MOE
of <100.  The post-application exposure/risk was evaluated using a
transfer coefficient (TC) of 400 for the moving of plants.  This TC was
recommended by HED’s Science Advisory Council for Exposure (Exposure
SAC 1/31/08).  The dermal MOE (2,700) for the moving of plants after
application also does not exceed the level of concern.  Uniconazole-P
has very low vapor pressure (1.0x10-8 Pa @ 20o C / 2.3x10-8 Pa @ 25o C);
therefore, inhalation post-application exposure/risk is not of concern. 
  

The technical material has a Toxicity Category IV for skin irritation
and a Category III for eye irritation/acute dermal toxicity.  Per the
Worker Protection Standard (WPS), a 12-hour restricted entry interval
(REI) is required.  The 12 hour REI appearing on the label is
appropriate.

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 Intakes 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 studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical.  These studies, which comprise the Pesticide Handlers Exposure
Database (PHED), have been determined to require a review of their
ethical conduct, have received that review, and have been determined to
be ethical.

Recommendations and Additional Data Needs

HED concludes that the registrant has submitted adequate data for the
Agency to establish a tolerance, and grant a conditional registration
for the requested use of uniconazole-P on fruiting vegetables.  The
toxicology and occupational databases are adequate for the purposes of
the current tolerance petition.  HED has identified several data
deficiencies in the residue chemistry database, however.  These
deficiencies are discussed in detail in Section 10.2 of this document. 
Pending submission of a revised Section B (see requirements under
Directions for Use, Section 10.2), completion of method validation by
ACB/BEAD and a revised enforcement method (see requirements under
Residue Analytical Methods, Section 10.2), and a revised Section F (see
requirements under Proposed Tolerances, Section 10.2), there are no
residue chemistry issues that would preclude granting conditional
registration for the requested uses of uniconazole-P or establishment of
the following tolerance for uniconazole residues:

Vegetable, Fruiting, Group 8	0.01 ppm

HED recommends that additional information for the plant metabolism
studies and the multiresidue method data be required as a condition of
registration (see 860.1300 and 860.1360 in Section 10.2)

2.0	Ingredient Profile  TC \l1 "2.0	Ingredient Profile 

Uniconazole-P is a triazole fungicide that IR-4 has proposed for use on
Crop Group 8, Fruiting Vegetables.  The intended use is as a plant
growth regulator in greenhouses.  Uniconazole,
(E)-(RS)-1-(4-chlorophenyl)-4,4-dimethyl-2-(1H-1,2,4-triazol-1-yl)pent-1
-en-3-ol, is a triazole Group 3 fungicide and plant growth regulator. 
The resolved S-isomer, identified as uniconazole-P, is pesticidally
active and is the active ingredient in registered products.  Based on
product chemistry reviews by the Registration Division, at least two
uniconazole-P technicals contain 78-80% S-isomer and 20% R-isomer. 
Uniconazole-P reduces plant height by reducing internode elongation
through inhibition of gibberellin biosynthesis.  Currently,
uniconazole-P is only registered for greenhouse use on ornamental
plants.  Under PP#7E7268, IR-4, in conjunction with Valent U.S.A.
Corporation, and on behalf of the Agricultural Experiment Stations of
Georgia and Oregon, is proposing the establishment of a permanent
tolerance for residues of uniconazole-P in/on Crop Group 8, Fruiting
Vegetables.  The proposed use of uniconazole-P on fruiting vegetables is
the first food use for this fungicide.  

Use profile

In conjunction with this petition, IR-4 is requesting amended
registration of the Valent end-use product, Sumagic® Plant Growth
Regulator (EPA Reg. No. 59639-37), a 0.055% emulsifiable concentrate
(EC) formulation.  The product is proposed for use on greenhouse-grown
fruiting vegetable transplants, including eggplant, groundcherry,
pepino, pepper, tomatillo, and tomato, as foliar spray applications at
up to 10 ppm in spray volumes of 2 qt/100 sq. ft.  No PHI is specified. 
The application of a 10 ppm solution at the rate of 2 quarts per 100 sq.
ft. is equivalent to 0.000042 lb a.i./100 sq. ft or 0.018 lb a.i./acre.

2.1	Summary of Registered/Proposed Uses

Table 2.1.	Summary of Directions for Use of Uniconazole-P.

Applic. Timing, Type, and Equip.	Formulation

[EPA Reg. No.]	Applic. Rate 	Max. No. Applic. per Season	Max. Seasonal
Applic. Rate

(lb ai/A)	PHI

(days)	Use Directions and Limitations

Fruiting  Vegetable Transplants:  Eggplant, Groundcherry, Pepino,
Pepper, Tomatillo, and Tomato

Foliar

Broadcast

Ground	0.055% EC

[59639-37]

0.0000832 lb ai/gallon	2-10 ppm	2

(implied)*	2 qt/100 sq ft.

(implied)*

(0.000042 lb ai/100 sq ft.)

(0.018 lb ai/A)

	Not

Speci-fied	Begin applications when 2-4 true leaves are present.  Apply
in a spray volume of 2 qt/100 square feet.  A 7- to 14-day retreatment
interval is specified.  Mixing with pesticides, fertilizers, wetting
agents, spreader stickers, or other adjuvants is prohibited.

* Label allows sequential applications at lower rates, but does not
explicitly state a maximum total rate

The product is specified for use in commercial greenhouses, lathhouses,
and shadehouses (where plants are grown in containers).  Application
through any type of irrigation system is prohibited.  An REI of 12 hours
is specified.

Under Restrictions and Limitations, the draft label contains the
following statement:  “Do not apply Sumagic to any food crops.” 
This statement should be revised to prohibit application to food crops
other than those listed on the label. 

The submitted use directions are sufficient to allow evaluation of the
available residue data provided the proposed label is amended as
specified under Directions for Use in Section 10.2.  Because
applications are to be made in the greenhouse prior to transplant, a PHI
is not needed for the proposed use.

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

(βE)-β-[(4-chlorophenyl)methylene]-α-(1,1-dimethylethyl)-1H-1,2,4-tri
azole-1-ethanol
(αS,βE)-β-[(4-chlorophenyl)methylene]-α-(1,1-dimethylethyl)-1H-1,2,4
-triazole-1-ethanol

CAS registry number	83657-22-1	83657-17-4

End-use product (EP)	None	0.055% EC formulation (EPA Reg. No. 59639-37)



Physical and Chemical Properties

TABLE 2.3.	Physicochemical Properties of Uniconazole

Parameter	Value	Reference

Melting point/range	150ºC	MRID 46424905

pH	6.54 (1% suspension of uniconazole)	MRID 46424905

Density	1.256 g/mL @ 20ºC	MRID 46424905

Water solubility	11.1 mg/L at 20ºC	MRID 46424905

Solvent solubility	Not Submitted

	Vapor pressure	1.0 x 10-8 Pa @ 20ºC

2.3 x 10-8 Pa @ 25ºC 	MRID 46424907

Dissociation constant, pKa	Does not dissociate	MRID 46424905

Octanol/water partition coefficient, Log(KOW)	Log(KOW) = 3.67 @ 25ºC
MRID 46424905

UV/visible absorption spectrum	No significant differences were observed
between the spectra obtained for the acidic, alkaline, and neutral
samples.	MRID 46424905

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

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

Uniconazole-P is rapidly absorbed after oral ingestion and extensively
metabolized by the liver.  There is no accumulation in the tissues and
the metabolites are rapidly excreted in the feces and urine.  It has
moderate acute oral toxicity (Category II) and low acute dermal
(Category III/IV rat/rabbit) and inhalation (Category III) toxicity.  It
is a slight eye irritant (Category III), but not a skin irritant or skin
sensitizer.  In mouse, rat, and dog repeated-dose studies, oral
ingestion of high doses caused an increase in the size and weight of the
liver.  Fat accumulation in the liver was also consistently observed at
high doses.  Although observed less consistently, increases in the
activity of some enzymes indicated altered liver function as a response
to uniconazole exposure.  In chronic rodent studies, there was no
evidence of an increase in spontaneous tumors in the rat; however, in
the mouse, an increase in liver neoplasms was noted.  There was limited
evidence of carcinogenicity; therefore, uniconazole is classified as a
Group C Chemical; Possible Human Carcinogen (CPRC, TXR No. 0052723). 
Quantification of risk using the RfD methodology will adequately account
for all chronic effects including carcinogenicity.  Mutagenicity studies
were generally negative except for the in vitro mammalian chromosome
aberration test (CHO) which was positive with metabolic activation.  In
view of the positive results obtained for chromosomal aberration and DNA
damage/repair, the HED Peer Review Committee recommended that a dominant
lethal assay be performed to assess more fully the potential of
uniconazole to induce genetic effects in germ cells.  Uniconazole had no
effects on reproductive performance of rats and no effect on fetal
development in rabbits.  At doses that were not toxic to the mother,
there were no effects on the rat fetus.  There was no evidence of
neurotoxicity in the studies submitted in support of the registration of
uniconazole or in the open literature.

3.1.1	Database Summary  TC \l3 "3.1.1	Database Summary 

The toxicology database for uniconazole is complete for regulatory
purposes.

3.1.1.1	Studies available and considered (animal, human, general
literature)  TC \l4 "3.1.1.1	Studies available and considered (animal,
human, general literature) 

The toxicology database for uniconazole consists of acceptable/guideline
studies including a battery of acute tests for the technical as well as
for several formulations.  In addition, there are subchronic feeding
toxicity studies in the rat and dog along with a 5-week range-finding
study in the mouse, a 28-day dermal toxicity study in the rat along with
two 28-day dermal toxicity studies performed using formulations,
developmental toxicity studies in the rat and rabbit (with range-finding
studies), a multigeneration reproduction study in the rat, a dog chronic
oral toxicity study (capsule administration), a combined chronic oral
toxicity and carcinogenicity study in the rat, a mouse carcinogenicity
study, a general metabolism study in the rat, a dermal absorption study
in the rat, and a mutagenicity battery.  No relevant data were available
from the open literature (Google and National Library of Medicine
databases).

3.1.1.2	Mode of action, metabolism, toxicokinetic data  TC \l4 "3.1.1.2
Mode of action, metabolism, toxicokinetic data 

Uniconazole is one of the triazole fungicides.  It also functions as a
plant growth regulator by inhibiting gibberellin and sterol
biosynthesis, which results in the shortening of the stem internodal
length, thereby providing an overall reduction in stem elongation. 
Studies have also shown that uniconazole inhibits ethylene synthesis and
protects plants from various stresses.  Other triazole fungicides
include amitrole, azaconazole, bitertanol, bromuconazole, cyproconazole,
difenconazole, diniconazole, epoxiconazole, fenbuconazole, flusilazole,
hexaconazole, myclobutanil, paclobutrazol, propiconazole, tetraconazole,
tebuconazole, triadimefon, triadimenol, and triticonazole.

In animals, uniconazole is rapidly absorbed, extensively metabolized,
and rapidly excreted. Following an acute oral administration to rats,
96-99% of the test compound was excreted over a 3-day period. 
Radioactivity recovered in the urine, feces, and carbon dioxide in the
exhaled air was 40-66, 33-59 and 0.1 percent of the administered dose,
respectively.  Peak tissue (including plasma) concentration of
radioactivity occurred 1 to 8 hours after the administration of the test
compound.

3.1.1.3	Sufficiency of studies/data  TC \l4 "3.1.1.3	Sufficiency of
studies/data 

The provided studies are adequate for regulatory purposes for all uses
including food.  

3.1.2	Toxicological Effects  TC \l3 "3.1.2	Toxicological Effects 

	

The target organ of the toxic effects of uniconazole is the liver, with
occasional related effects on the thyroid gland.  Most observations
include increased liver weight, with liver enzyme and clinical chemistry
changes and supportive histopathological changes.  These effects
occurred in the subchronic toxicity studies (in which animals were dosed
by both by oral and dermal routes), the chronic toxicity/carcinogenicity
study, and the multigeneration reproduction study in the rat.  These
effects were also seen in the chronic toxicity study in the dog and in
the mouse carcinogenicity study.

3.1.3	Dose-response  TC \l3 "3.1.3	Dose-response 

All acceptable studies were considered in the dose-response assessment. 
There was no suitable endpoint for acute dietary assessment for the
general population.  The acute dietary risk assessment endpoint for
females 13-49 was based on the developmental toxicity study in rats.  A
NOAEL of 5 mg/kg/day and a LOAEL of 25 mg/kg/day were chosen for
developmental and maternal toxicity based on increased incidence of 14th
rib in the fetuses and decreased body weight in the dams.  This NOAEL
will be protective for all population groups.  The chronic RfD is based
on the chronic oral (capsule) study in the dog with a NOAEL of 2
mg/kg/day and a LOAEL of 20 mg/kg/day based on liver effects including
organ weight, enzyme changes, and supportive histopathological findings.
 This dose is conservative since the study was done with administration
of the test material in capsules which is more of a bolus type of dosing
and protective for target organ effects in other species (rat and mouse)
since it was lowest dose.  The liver is the major target organ of
uniconazole and the endpoint will be protective for all population
subgroups.    

The short and intermediate term incidental oral scenarios use the rat
prenatal developmental toxicity study with a NOAEL of 5 mg/kg/day and a
LOAEL of 25 mg/kg/day based on decreased maternal body weight gain. 
This NOAEL will be protective for sensitive groups including growing
children.

The short- and intermediate-term dermal scenarios are based on the
subchronic dermal toxicity study in the rat with a NOAEL of 5 mg/kg/day
and a LOAEL of 25 mg/kg/day.  This study is appropriate because the dose
was administered by the dermal route, and the target organ was affected.
 There was dermal irritation at all dose levels, but it did not progress
to more than slight irritation of the skin.  This study is protective of
developmental effects because the endpoints are equal to those
determined in the prenatal development study.

The short- and intermediate-term inhalation scenarios use the rat
prenatal developmental toxicity study with a NOAEL of 5 mg/kg/day and a
LOAEL of 25 mg/kg/day based on increased incidence of 14th rib in the
fetuses.  As there are no subchronic inhalation studies (a 28 day
inhalation study has been requested), this study will provide the most
protective endpoint.  The same endpoints are used for the occupational
exposure scenarios.  There is no apparent “most sensitive” species
noted in the database.

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

In a metabolism study (MRID 40496701),
(S)-(E)-1-1-(p-chlorophenyl)-4,4-dimethyl-2-(1,2,4-triazol-1-
y1)-1-penten-3-ol (Purity: 99.9%, E/Z=l00/0, R/S=0.2/99.8, Lot No.
LN40902) and 14C labeled uniconazole (Purity 99%, specific activity 36.1
mCi/mmol) were administered to male and female Sprague-Dawley (SD) rats
(Charles River Japan, Inc.) to determine the absorption, distribution,
metabolism, and excretion of 14C-uniconazole when administered by oral
gavage.  A “core study” was conducted with low (1 mg/kg) and high
(200 mg/kg) dose groups and a repeated dose (14 daily dose of 1 mg/kg)
group.  In a separate tissue distribution study, 18 rats were dosed with
1 mg/kg and sacrificed in sets of three, from 1 to 72 hours after
administration.  Urine, feces, expired air (CO2), and tissues were
collected and analyzed for radioactivity.  Metabolites of uniconazole
were identified in the feces and urine from the “core study” and
selected tissues from the tissue distribution study.

Uniconazole was rapidly absorbed, extensively metabolized, and rapidly
excreted.  Over a 3-day period, most (96-99 percent) of the test
compound administered was excreted from the animals.  The radioactivity
recovered in the urine, feces, and CO2 in the exhaled air was 40-66,
33-59 and 0.1 percent of the administered dose, respectively.  Peak
tissue (including plasma) concentration of radioactivity occurred 1 to 8
hours after the administration of the test compound.  Five metabolites
were identified in the urine and feces.  These represent 83-91 percent
of the administered dose.  The metabolites of uniconazole included two
oxidation products (58-75 percent of the dose) of the methyl moiety of
the tert-butyl group and a free triazole (3-15 percent of the dose)
liberated from uniconazole.  The proposed metabolic pathway of
uniconazole was provided by the investigators.

3.3	FQPA Considerations  TC \l2 "3.3	FQPA Considerations 

3.3.1	Adequacy of the Toxicity Database  TC \l3 "3.3.1	Adequacy of the
Toxicity Database 

The uniconazole database is adequate to assess pre-/postnatal toxicity.

3.3.2	Evidence of Neurotoxicity  TC \l3 "3.3.2	Evidence of Neurotoxicity

There was no evidence of neurotoxicity in the submitted studies or in
the available open literature.  

3.3.3	Developmental Toxicity Studies  TC \l3 "3.3.3	Developmental
Toxicity Studies 

In a prenatal developmental toxicity study (MRID 40462609), uniconazole
was administered orally by gavage in 0.5% carboxymethylcellulose to
pregnant female SPF Slc:SD rats at dose levels of 0, 1, 5, 25, and 50
mg/kg/day from gestation days 6 through 15, inclusive.  Maternal
toxicity was noted as decreased body weight gain at 25 mg/kg/day and
above.  At gestation day 9, maternal body weights were reduced up to 9%
at 25 mg/kg/day and 10% at 50 mg/kg/day.  Body weight gain was reduced
40% at 25 mg/kg/day, and there was no weight gain at 50 mg/kg/day which
continued with a 20% reduction in body weight gain at gestation day 12. 
Therefore, the maternal systemic toxicity NOAEL is 5 mg/kg/day, and the
maternal systemic toxicity LOAEL is 25 mg/kg/day based on decreased body
weight.  Developmental toxicity was noted as increased incidence of 14th
ribs at the two highest dose levels.  The incidence of 14th ribs was as
follows:  5 fetuses in 2 litters for the control group, none in the low
dose group, 4 fetuses in 4 litters in the 5 mg/kg/day dose group, 14
fetuses in 11 litters in the 25 mg/kg/day dose group (p < 0.01), and 28
fetuses in 14 litters in the 50 mg/kg/day dose group (p < 0.01). 
Therefore, the developmental toxicity NOAEL is 5 mg/kg/day and the
developmental toxicity LOAEL is 25 mg/kg/day based on an increased
incidence of 14th rib.

In a prenatal developmental toxicity study (MRID 4046210), uniconazole
was administered orally by gavage in 0.5% carboxymethylcellulose to
pregnant female New England White Rabbits at dose levels of 0, 1, 3, 10,
and 20 mg/kg/day from gestation days 7 through 19, inclusive.  The
maternal systemic toxicity NOAEL is 10 mg/kg/day and the maternal
systemic toxicity LOAEL is 20 mg/kg/day, based on statistically
significant reduced food consumption and marginally reduced body weight
gains.  No developmental toxicity was noted at the dose levels tested. 
Therefore, the developmental toxicity NOAEL is equal to or greater than
20 mg/kg/day (HDT).  A LOAEL was not established.  

In support of the NOAEL/LOAEL decisions for the rabbit prenatal
development toxicity study (MRID 4046210), a range finding rabbit
prenatal study was submitted.  In this study (MRID 41745801) groups of
five rabbits were tested at 0, 10, 30, 50, 100, or 300 mg/kg/day on
gestation days 7 to 19.  Does were sacrificed on day 29, and the fetuses
were removed by caesarian section.  All rabbits in groups 5 (100
mg/kg/day) and 6 (300 mg/kg/day) died or were sacrificed in extremis on
or before gestation Day 15.  One rabbit in group 4 (50 mg/kg) was found
dead on gestation Day 19 and one was sacrificed in extremis on gestation
Day 27.  Two rabbits in group 3 (30 mg/kg/day) aborted (days 25 and 28),
and one was found dead on gestation Day 19.  A dose-related increase in
the incidence of anorexia was seen during the treatment period in groups
2-6.  All rabbits in groups 4, 5, and 6 were languid on at least two
occasions during treatment.  Two animals in group 3 and three animals in
group 4 also appeared languid during the post-treatment period.  Mean
body weights during and after the treatment period were reduced compared
to the controls in pups from groups 3 and 4.  Mean body weights in group
2 were similar to the control values throughout the study, although mean
food consumption was slightly below the control levels during the last
half of treatment.  These results support, and are consistent with, the
results of the high dose tested group (20 mg/kg/day) in the main rabbit
developmental toxicity study.

3.3.4	Reproductive Toxicity Study  TC \l3 "3.3.4	Reproductive Toxicity
Study 

In the reproductive toxicity study (MRID 41162004), uniconazole was
administered to male and female Crl:CD (SD)BR albino rats at dietary
levels of 0, 15, 150, and 1500 ppm (0, 0.75, 7.5, 75 mg/kg/day by
standard conversion values for an adult rat).  The parental systemic
toxicity NOAEL is 150 ppm (7.5 mg/kg/day) and the parental systemic
toxicity LOAEL is 1500 ppm (75 mg/kg/day) based on reduced body weight
and food intake, increased liver weight, and hepatocellular enlargement
and vacuolization.  Fertility and length of gestation were unaffected by
ingestion of the test material in the diet.  Therefore, the reproductive
toxicity NOAEL is equal to or greater than 1500 ppm (75 mg/kg/day) and
the reproductive toxicity LOAEL is greater than 1500 ppm (75 mg/kg/day).
 A non-significant decrease in the viability index was noted among pups
in the high-dose group (historical control data were not submitted). 
Pup growth was adversely affected at the highest dose level for both
generations, as evidenced by decreased body weights starting on day 4 of
lactation.  Therefore, the offspring systemic/developmental toxicity
NOAEL is 150 ppm (7.5 mg/kg/day) and the offspring
systemic/developmental toxicity LOAEL is 1500 ppm (75 mg/kg/day) based
on reduced pup growth (reduced body weight during lactation).

3.3.5	Additional Information from Literature Sources  TC \l3 "3.3.5
Additional Information from Literature Sources 

There was no evidence of hyperactivity in rats treated with uniconazole
as compared to the other triazole-containing chemicals (Toxicology
Letters 84 (1996) pages155-159, A structure-activity relationship for
the neurotoxicity of triazole fungicides, KM. Crofton (EPA RTP)).

3.3.6	Pre-and/or Postnatal Toxicity  TC \l3 "3.3.6	Pre-and/or Postnatal
Toxicity 

3.3.6.1	Determination of Susceptibility  TC \l4 "3.3.6.1	Determination
of Susceptibility 

There was evidence for increased qualitative susceptibility in the rat
developmental toxicity study.  Maternal systemic toxicity, based on
decreased body weight and developmental toxicity, based on an increased
incidence of 14th ribs, were seen at the same dose level.  No evidence
of developmental toxicity was seen at the highest doses tested in the
rabbit developmental toxicity study.  There was no evidence of increased
susceptibility in the rat two-generation reproduction study. 

3.3.6.2	Degree of Concern Analysis and Residual Uncertainties for Pre-
and/or Postnatal Susceptibility  TC \l4 "3.3.6.2	Degree of Concern
Analysis and Residual Uncertainties for Pre- and/or Postnatal
Susceptibility  

The Health Effects Division (HED) Developmental and Reproductive Peer
Review Committee met on September 7, 1990, to discuss and evaluate the
weight of the evidence for uniconazole with special reference to its
developmental and reproductive potential.  There is low concern for the
fetal effects noted in the rat developmental toxicity study because this
additional rib was the only skeletal variation noted.  It occurs only at
maternally toxic levels, and in the reproduction study in the rat,
higher doses resulted only in minimal pup toxicity in the form of
slightly reduced body weight gains.  Additionally, the NOAEL for this
effect is used for assessing acute risk to the most sensitive
populations, and is therefore protective of all toxicity seen in the
database.  There are no residual uncertainties for pre- and post-natal
toxicity.

3.3.7	Recommendation for a Developmental Neurotoxicity Study  TC \l3
"3.3.7	Recommendation for a Developmental Neurotoxicity Study 

A developmental neurotoxicity study is not required because no evidence
of neurotoxicity was noted in the available studies.

3.3.8	Rationale for the UFDB (when a DNT is recommended)  TC \l3 "3.3.8
Rationale for the UFDB 

Not applicable; a DNT is not required.

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

Based on the data discussed above, there are no residual uncertainties
for pre- and post-natal toxicity.  In addition, conservative assessments
were conducted for dietary  exposure from food and drinking water. 
There are no residential uses of uniconazole.  Therefore, the FQPA
Safety Factor can be reduced to 1x.

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

3.5.1	Acute Reference Dose (aRfD) - Females age 13-49  TC \l3 "3.5.1
Acute Reference Dose (aRfD) - Females age 13-49 

Study Selected: 	Prenatal Developmental Toxicity Study – Rat 

OPPTS 870.3700 [OPP §83-3]; OECD 414.

MRID Nos.: 		40462609 and 42123201

Executive Summary:  In a prenatal developmental toxicity study (MRID
40462609, 42123201), S-3307D T.G., (Purity 97.2%, Lot No. PKG-84075) was
administered to pregnant female SPF Slc:SD rats (The Shizuoka
Prefectural Agricultural Cooperative Association for Laboratory Animals)
orally by gavage in 0.5% carboxymethylcellulose at dose levels of 0, 1,
5, 25, and 50 mg/kg/day from gestation days 6 through 15, inclusive. 
The pregnant animals were observed daily for mortality and clinical
signs, and were weighed on days 0, 6, 9, 12, 15, and 20.  Food
consumption was recorded on days 6, 9, 12, and 20.  On day 20, all
surviving females were sacrificed, and the pups were removed by
Caesarian section.  All maternal internal organs were examined grossly,
and the uterine contents, number of corpora lutea, implantation sites,
and number and position of fetuses were recorded.  Fetuses were sexed,
weighed, and examined for external abnormalities.  Half of each litter
was examined by Wilson's technique for visceral abnormalities, while
half was cleared and stained with Alizarin Red S for examination of
skeletal abnormalities by a modification of Dawson's technique. 

Maternal toxicity was noted as decreased body weight gain at 25
mg/kg/day and above.

The maternal systemic toxicity NOAEL is 5 mg/kg/day and the maternal
systemic toxicity LOAEL is 25 mg/kg/day based on decreased body weight.

Developmental toxicity was noted as increased incidence of 14th rib at
the two highest dose levels.

The developmental toxicity NOAEL is 5 mg/kg/day and the developmental
toxicity LOAEL is 25 mg/kg/day based on increased incidence of 14th rib.

This study is classified as Acceptable-Guideline and, as such, satisfies
the guideline requirements (OPPTS 870.3700; OPP §83-3; OECD 414) for a
prenatal developmental toxicity study in rats.  

Dose and Endpoint for Risk Assessment:  NOAEL = 5 mg/kg/day based on
increased incidence of 14th rib at 25 mg/kg/day (LOAEL).    

Comments about Study/Endpoint/Uncertainty Factors:  The acute dietary
endpoint for females in the 13 to 49 year age group is based on
increased incidence of the 14th rib.  This developmental effect is
presumed to occur following a single oral dose and is considered an
appropriate endpoint for this population subgroup.  No other
developmental effects were observed in the toxicology database.  A UF of
100 (UFA =10, UFH = 10) should be used.

Acute Reference Dose (aRfD) - General Population

  TC \l3 "3.5.2	Acute Reference Dose (aRfD) - General Population  

An appropriate endpoint is not available from the uniconazole database
including the developmental toxicity studies.

3.5.3	Chronic Reference Dose (cRfD)  TC \l3 "3.5.3	Chronic Reference
Dose (cRfD) 

Study Selected: 	Chronic Oral (Capsule) Toxicity - Dog; Guideline No.
OPPTS 870.4100 [OPP §83-1]; OECD 452

MRID No.: 		41162001

Executive Summary: In a chronic toxicity study (MRID 41162001), S-3307D
(Purity: 97.4%, Lot Number PYG 86112) was administered to groups of male
and female beagles (6/sex/dose, Hazleton Research Animals, Cumberland
VA) in capsules at dose levels of 0, 2, 20, and 200 mg/kg/day for 52
weeks.  Animals were inspected twice daily for mortality and signs of
toxicity.  Once per week, each animal was observed for behavior and
movement, and the limbs, head and external orifices were examined.  Dogs
were weighed before treatment and once each week thereafter.  Food
consumption was measured and recorded weekly.  An indirect
ophthalmoscopic examination was conducted for each dog prior to
treatment initiation and during weeks 26 and 52.  Blood was collected
from each dog prior to study initiation and during weeks 13, 26, 39, and
52 for hematology and serum chemistry analyses.  Dogs were fasted
overnight prior to blood collection.  Urine samples were collected prior
to treatment and during weeks 13, 26, 39, and 52 for evaluation.  All
dogs were sacrificed following 52 weeks of treatment, and complete gross
necropsies were performed.  Tissues were collected and fixed.  Selected
organs were weighed.

Absolute and relative (to body weight) liver weights were significantly
increased in male and female dogs receiving 200 mg/kg/day, and in males
receiving 20 mg/kg/day.  Changes in the liver weights of high-dose
animals corresponded with histological changes in the liver, including
hepatocellular enlargement with increased cytoplasmic homogeneity and
increased bile pigment.  Alterations in the adrenal, kidney, and thymus
weights were also seen, but there were no corresponding histological
changes in these organs.  Alkaline phosphatase activity was
significantly elevated in both sexes receiving 200 mg/kg/day.  Mean body
weight gains were significantly reduced in high-dose males and females
at weeks 0-4, and in high-dose males at weeks 0-52.  Alterations in
platelet counts were not considered to be of toxicologic significance. 
There was no effect of dosing on mortality.

The systemic toxicity NOAEL is 2 mg/kg/day and the systemic toxicity
LOAEL is 20 mg/kg/day based on the increased absolute and relative liver
weight changes in males supported by histological and enzyme changes in
the liver.

This study is classified as Acceptable-Guideline and, as such, satisfies
the guideline requirements (OPPTS 870.4100; OPP §83-1; OECD 452) for a
chronic toxicity study.

Dose and Endpoint for Risk Assessment:  NOAEL = 2 mg/kg/day based on the
increased absolute and relative liver weight changes in males supported
by histological and enzyme changes in the liver at 20 mg/kg/day (LOAEL).

Comments about Study/Endpoint/Uncertainty Factors:  The endpoint
selected is based on effects in the target organ (i.e., the liver)
observed in the most sensitive species tested with a chronic oral
exposure scenario.  The study and endpoint were selected because they
are protective of effects observed in all the other available studies. 
The endpoint is conservative, as the study was done with the
administration of the test material in capsules which is more of a bolus
type of dosing.  The chronic reference dose is 0.02 mg/kg/day.  A UF of
100 (UFA =10, UFH = 10) should be used.

3.5.4	Incidental Oral Exposure (Short- and Intermediate-Term)   TC \l3
"3.5.4	Incidental Oral Exposure (Short- and Intermediate-Term) 

Study Selected: 	Prenatal Developmental Toxicity Study – Rat 

OPPTS 870.3700 [OPP §83-3]; OECD 414.

MRID No.: 		40462609 and 42123201

Executive Summary:  In a prenatal developmental toxicity study (MRID
40462609, 42123201), S-3307D T.G., (Purity 97.2%, Lot No. PKG-84075) was
administered to pregnant female SPF Slc:SD rats (The Shizuoka
Prefectural Agricultural Cooperative Association for Laboratory Animals)
orally by gavage in 0.5% carboxymethylcellulose at dose levels of 0, 1,
5, 25, and 50 mg/kg/day from gestation days 6 through 15, inclusive. 
The pregnant animals were observed daily for mortality and clinical
signs, and were weighed on days 0, 6, 9, 12, 15, and 20.  Food
consumption was recorded on days 6, 9, 12 and 20.  On day 20, all
surviving females were sacrificed, and the pups removed by Caesarian
section.  All maternal internal organs were examined grossly, and the
uterine contents, number of corpora lutea, implantation sites, and
number and position of fetuses were recorded.  Fetuses were sexed,
weighed, and examined for external abnormalities.  Half of each litter
was examined by Wilson's technique for visceral abnormalities, while
half were cleared and stained with Alizarin Red S for examination of
skeletal abnormalities by a modification of Dawson's technique. 

Maternal toxicity was noted as decreased body weight gain at 25
mg/kg/day and above.

The maternal systemic toxicity NOAEL is 5 mg/kg/day and the maternal
systemic toxicity LOAEL is 25 mg/kg/day based on decreased body weight.

Developmental toxicity was noted as increased incidence of 14th rib at
the two highest dose levels.

The Developmental Toxicity NOAEL is 5 mg/kg/day and the Developmental
Toxicity LOAEL is 25 mg/kg/day based on increased incidence of 14th rib.

This study is classified as Acceptable-Guideline and as such satisfies
the guideline requirements (OPPTS 870.3700; OPP §83-3; OECD 414) for a
prenatal developmental toxicity study in rats.  

Dose and Endpoint for Risk Assessment: NOAEL = 5 mg/kg/day based on
decreased maternal body weight gain at 25 mg/kg/day (LOAEL).

Comments about Study/Endpoint/Uncertainty Factors:  This endpoint is
based on an oral study, which is the route of interest for an incidental
oral risk estimate.  The study and endpoint were selected because they
are protective of effects observed in all the other available studies
following short- or intermediate-term exposure.  The endpoint is
appropriate for incidental oral exposure because this type of effect
could be seen in infants and children.  A UF of 100 (UFA =10, UFH = 10)
should be used.

3.5.5	Dermal Absorption  TC \l3 "3.5.5	Dermal Absorption 

Study Selected: 	Dermal Penetration – Rat; Guideline
OPPTS 870.7600 [OPP §85-3]

MRID No.: 		40462616

Executive Summary:  In a dermal penetration (absorption) study (MRID
40462616), [14C-U-Pheny1]-XE-10l9D (99.4% radiochemical purity, 206,000
dpm/microgram specific activity) was suspended in deionized water
containing 0.5% TWEEN 80 and applied topically in single doses of 0.05
(Group I), 0.5 (Group II), and 5.0 (Group III) mg of XE-1019D per rat
onto an unabraded 10 cm2 application site on the shaved dorsal trunk of
each of 12 rats per dose group.  Following application of the test
material, groups of four male rats from each dose group were placed
individually into MetrapR restraining metabolism chambers for either 2,
10, or 24 hours, and urine, feces, and volatiles were collected.  After
each exposure period, the animals were sacrificed, and the skin from the
application site, blood, carcass, and excreta were measured for
radioactivity.  The average total recovery of 14C applied was 94 .0%
(75.6% to 111.3%) in Group I, 101.3% (88.4% to 112.8%) in Group II, and
99.9% (74.8% to 104.8%) in Group III.

Application to a 10cm2 area of the rat's back resulted in the following
percent absorption:

							

Exposure

Time

(hrs)	0.05 mg/rat	0.5 mg/rat	5.0 mg/rat

	On/In

Skin	Skin

Wash	Absorbed

%	On/In

Skin	Skin

Wash	Absorbed

%	On/In

Skin	Skin

Wash	Absorbed

%

2	33.2	47.4	2.2	36.8	64.1	0.3	12.7	90.2	0.1

10	38.9	58.0	7.2	37.7	66.3	1.8	10.8	92.2	0.3

24	23.7	52.0	17.4	42.5	51.2	3.6	14.1	76.1	0.8

This study is classified as acceptable and, as such, satisfies the
guideline requirements (OPPTS 870.7600 [OPP §85-3]; OECD none) for a
dermal penetration (absorption) study in rats.

3.5.6	Dermal Exposure (Short- and Intermediate-Term)  TC \l3 "3.5.6
Dermal Exposure (Short-, Intermediate- and Long-Term) 

Study Selected: 	Subchronic Dermal Toxicity Study – Rat – 28 Days

OPPTS 870.3200 [OPP §82-2]; OECD 410.

MRID No.: 		40462607

Executive Summary:  In a subchronic study (MRID 40462607), XDE-1019D
(Uniconazole-P, Purity 97.62%, Lot No. PYG-86047) was administered to
male and female Sprague-Dawley: Crl CD(SD)BR rats (Charles River
Breeding Laboratories, Portage MI) dermally at dose levels of 0, 5, 25,
50, 200, and 500 mg/kg/day for 28 days (20 applications).  Animals were
inspected daily for signs of toxicity and mortality.  Pupillary
responses were examined prior to study start, weekly during the study,
and on study termination day.  Skin irritation was measured by a
modified Draize scale on study day 1, weekly thereafter, and on study
termination day.  Animals were weighed at study start, prior to dosing,
then twice weekly until study termination.  Terminal body weights were
taken after overnight fasts.  Blood was collected from all animals at
study termination for hematology and clinical analysis.  All animals
that died and that were sacrificed on schedule were subject to gross
pathological examination.  Tissues were collected for histological
examination from the control and high dose animals.  In the mid-dose
animals, only kidneys and livers were examined.  Only liver and gross
lesions were examined for the animals in the satellite study.  Selected
organs were weighed.

Dermal administration of XE-1019D to SD Crl:CD(BR) rats at dose levels
of 5, 25, 50, 200 and 500 mg/kg/day for 28 days (20 applications)
resulted in no systemic toxicity at 

5 mg/kg (LTD), but produced increased liver weight, hepatocytic
vacuolation, and centrilobular hypertrophy at doses of 25 mg/kg/day and
above.  Local dermal irritation in the form of slight skin irritation
was observed at al1 doses tested.

The systemic toxicity NOAEL is 5 mg/kg/day and the systemic toxicity
LOAEL is 25 mg/kg/day based on increased liver weight and histopathology
of the liver.  The dermal toxicity NOAEL is less than 5 mg/kg/day and
the dermal toxicity LOAEL is equal to or less than 5 mg/kg/day based on
the dermal irritation noted at all dose levels tested.

This study is classified as Acceptable-Guideline and, as such, satisfies
the guideline requirements (OPPTS 870.3200; OPP §82-2; OECD 410) for a
subchronic dermal toxicity study in rodents.  The original DER has the
wrong MRID Number, 40462617 instead of 40462607, and the study type was
listed as a 21-day dermal study when the study duration was actually 28
days.

Dose and Endpoint for Risk Assessment:  NOAEL = 5 mg/kg/day based on
increased liver weight and supportive histopathology of the liver at 25
mg/kg/day (LOAEL).    

Comments about Study/Endpoint/Uncertainty Factors:  The study selected
is a 28-day dermal study, which is the appropriate type for assessing
risk from dermal exposure.  The endpoint is based on effects on the
liver, the target organ for this compound.  Additionally, these effects
are seen at the same dose level as the developmental effects seen
following short-term exposure in the rat, so the selected endpoint is
protective for all potential forms of toxicity seen in the database. 
The 28-day exposure period is an appropriate duration for both short-
and intermediate-term assessments.

Based on the other dermal exposure studies available (lower a.i., MRID
41162003 and 41162002), HED concludes that this endpoint could be used
for exposure durations longer than 30 days.  A MOE of 100 is adequate. 
Although there was no NOAEL for dermal irritation, the irritation was
slight at all dose levels.

3.5.7	Inhalation Exposure (Short-, and Intermediate-Term)  TC \l3 "3.5.7
Inhalation Exposure (Short-, Intermediate- and Long-Term) 

Study Selected: 	Prenatal Developmental Toxicity Study – Rat 

OPPTS 870.3700 [OPP §83-3]; OECD 414.

MRID No.: 		40462609 and 42123201

Executive Summary:  In a prenatal developmental toxicity study (MRID
40462609, 42123201), S-3307D T.G., (Purity 97.2%, Lot No. PKG-84075) was
administered to pregnant female SPF Slc:SD rats (The Shizuoka
Prefectural Agricultural Cooperative Association for Laboratory Animals)
orally by gavage in 0.5% carboxymethylcellulose at dose levels of 0, 1,
5, 25, and 50 mg/kg/day from gestation days 6 through 15, inclusive. 
The pregnant animals were observed daily for mortality and clinical
signs, and were weighed on days 0, 6, 9, 12, 15, and 20.  Food
consumption was recorded on days 6, 9, 12, and 20.  On day 20, all
surviving females were sacrificed, and the pups were removed by
Caesarian section.  All maternal internal organs were examined grossly,
and the uterine contents, number of corpora lutea, implantation sites,
and number and position of fetuses were recorded.  Fetuses were sexed,
weighed, and examined for external abnormalities.  Half of each litter
was examined by Wilson's technique for visceral abnormalities, while
half was cleared and stained with Alizarin Red S for examination of
skeletal abnormalities by a modification of Dawson's technique. 

Maternal toxicity was noted as decreased body weight gain at 25
mg/kg/day and above.

The maternal systemic toxicity NOAEL is 5 mg/kg/day and the maternal
systemic toxicity LOAEL is 25 mg/kg/day based on decreased body weight.

Developmental toxicity was noted as increased incidence of 14th rib at
the two highest dose levels.

The developmental toxicity NOAEL is 5 mg/kg/day and the developmental
toxicity LOAEL is 25 mg/kg/day based on increased incidence of 14th rib.

This study is classified as Acceptable-Guideline and, as such, satisfies
the guideline requirements (OPPTS 870.3700; OPP §83-3; OECD 414) for a
prenatal developmental toxicity study in rats.  

Dose and Endpoint for Risk Assessment:  NOAEL = 5 mg/kg/day based on
increased incidence of 14th rib at 25 mg/kg/day (LOAEL).    

Comments about Study/Endpoint/Uncertainty Factors:  This endpoint is
based on an oral study which is appropriate in the absence of an
inhalation study.  The study and endpoint were selected because they are
protective of effects observed in all other available studies following
short- and intermediate-term exposure.  A UF of 100 (UFA =10, UFH = 10)
should be used.

3.5.8	Level of Concern for Margin of Exposure  TC \l3 "3.5.8	Level of
Concern for Margin of Exposure 

Table 3.5.8.  Summary of Levels of Concern for Risk Assessment.

Route	Short-Term

(1 - 30 Days)	Intermediate-Term

(1 - 6 Months)	Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal	100	100	N/A

Inhalation	100	100	N/A

Residential Exposure

Dermal	100	100	N/A

Inhalation	100	100	N/A

Incidental Oral	100	100	--

Recommendation for Aggregate Exposure Risk Assessments

  TC \l3 "3.5.9	Recommendation for Aggregate Exposure Risk Assessments 

As per FQPA, 1996, when there are potential residential exposures to a
pesticide, aggregate risk assessment must consider exposures from three
major routes: oral, dermal, and inhalation.  However, an aggregate risk
assessment across the three routes of exposure is not being conducted
for uniconazole as   TC \l3 "3.5.9	Recommendation for Aggregate Exposure
Risk Assessments there are no registered or proposed residential uses. 
Exposures through the oral route include those through food and drinking
water.  The only aggregate risk assessment being conducted for
uniconazole is comprised of exposures that result from these two
sources.  For occupational assessments, the exposures from the dermal
and inhalation routes should not be combined since the endpoints are
based on different effects.  TC \l3 "3.5.9	Recommendation for Aggregate
Exposure Risk Assessments 

Classification of Carcinogenic Potential

  TC \l3 "3.5.10	Classification of Carcinogenic Potential 

Uniconazole was classified by the HED CPRC as a Group C, possible human
carcinogen.  The CPRC recommended the reference dose (RfD) approach for
risk assessment, and concluded that the chronic RfD would be protective
of all chronic effects including carcinogenicity (TXR No.0052723).

3.5.11	Summary of Toxicological Doses and Endpoints for Use in Human
Risk Assessments  TC \l3 "3.5.11	Summary of Toxicological Doses and
Endpoints for Use in Human Risk Assessments 

Table 3.5.1 Summary of Toxicological Doses and Endpoints for Uniconazole
for Use in Dietary and Non-Occupational Human Health Risk Assessments

Exposure/

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

Acute Dietary

(Females 13-49 years of age)	NOAEL = 5 mg/kg/day	UFA= 10x

UFH=10x

FQPA SF= 1x

	Acute RfD = 0.05 mg/kg/day

aPAD = 0.05 mg/kg/day	Prenatal Developmental Toxicity - rat

LOAEL = 25 mg/kg/day based on increased incidence of 14th rib

Chronic Dietary (All Populations)	NOAEL= 2 mg/kg/day	UFA= 10x

UFH= 10x

FQPA SF= 1x

	Chronic RfD = 0.02

mg/kg/day

cPAD = 0.02 mg/kg/day	Chronic Oral (Capsule) Toxicity - dog

LOAEL = 20 mg/kg/day based on the increased absolute and relative liver
weight changes in males supported by histological and enzyme changes in
the liver

Incidental Oral Short- (1-30 days) and Intermediate-Term (1-6 months)
NOAEL = 5 mg/kg/day	UFA= 10x

UFH= 10x

FQPA SF= 1x	Residential LOC for MOE = 100	Prenatal Developmental
Toxicity - rat

LOAEL = 25 mg/kg/day based on decreased maternal body weight gain

Dermal Short- (1-30 days) and Intermediate-Term  (1-6 months)	NOAEL = 5
mg/kg/day	UFA= 10x

UFH= 10x

FQPA SF= 1x

	Residential LOC for MOE = 100

	Subchronic Dermal Toxicity - rat

LOAEL = 25 mg/kg/day based on increased liver weight and histopathology
of the liver

Inhalation Short- (1-30 days) and Intermediate-Term (1-6 months)	NOAEL =
5 mg/kg/day	UFA= 10x

UFH= 10x

FQPA SF= 1x	Residential LOC for MOE = 100

	Prenatal Developmental Toxicity - rat

LOAEL = 25 mg/kg/day based on increased incidence of 14th rib 

Cancer (oral, dermal, inhalation)	Uniconazole was classified by the HED
Carcinogenicity Peer Review Committee as a Group C, possible human
carcinogen.  The CARC recommended the reference dose (RfD) approach for
risk assessment and concluded that the chronic RfD would be protective
of all chronic effects including carcinogenicity (TXR No.0052723).

	Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (interspecies).  UFH =
potential variation in sensitivity among members of the human population
(intraspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use
of a short-term study for long-term risk assessment.  UFDB = to account
for the absence of key 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.



Table 3.5.2 Summary of Toxicological Doses and Endpoints for
Uniconazole for Use in Occupational Human Health Risk Assessments

Exposure/

Scenario	Point of Departure	Uncertainty Factors	Level of Concern for
Risk Assessment	Study and Toxicological Effects

Dermal Short- and Intermediate Term (0-6 months)	NOAEL = 5 mg/kg/day
UFA=10x

UFH=10x	Occupational LOC for MOE = 100	Subchronic Dermal Toxicity - rat

LOAEL = 25 mg/kg/day based on increased liver weight and histopathology
of the liver

Inhalation Short- and Intermediate-term (0-6 months)	NOAEL = 5 mg/kg/day
UFA=10x

UFH=10x	Occupational LOC for MOE = 100	Prenatal Developmental Toxicity -
rat

LOAEL = 25 mg/kg/day based on increased incidence of 14th rib

Cancer (oral, dermal, inhalation)	Uniconazole was classified by the HED
Carcinogenicity Peer Review Committee as a Group C, possible human
carcinogen.  The CPRC recommended the reference dose (RfD) approach for
risk assessment and concluded that the chronic RfD would be protective
of all chronic effects including carcinogenicity (TXR No.0052723).

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and  used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (interspecies).  UFH =
potential variation in sensitivity among members of the human population
(intraspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use
of a short-term study for long-term risk assessment.  UFDB = to account
for the absence of key data (i.e., lack of a critical study).  MOE =
margin of exposure.  LOC = level of concern.  N/A = not applicable.

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 Screening 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).

When additional appropriate screening and/or testing protocols being
considered under the Agency’s EDSP have been developed, uniconazole
may be subjected to further screening and/or testing to characterize
more fully the effects related to endocrine disruption.

  TC \l2 "3.6	Endocrine disruption 4.0	Public Health and Pesticide
Epidemiology Data

No public health/epidemiology data were used in developing this risk
assessment.

	

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

Residue chemistry issues related to the current tolerance petition are
discussed in detail in the residue chemistry summary document prepared
for this risk assessment (Memo, D347093, D. Dotson, 3/31/2008).

Pesticide Metabolism and Environmental Degradation  TC \l2 "5.1 
Pesticide Metabolism and Environmental Degradation 

Metabolism in Primary Crop

Tomato

Valent U.S.A. Corporation submitted a report that discusses the results
of a study in which the metabolism of [phenyl-U-14C]uniconazole-P
(specific activity 27.1 mCi/mmol) in tomato was investigated.  The
radiolabeled test substance was dissolved in methanol, then applied as
two foliar broadcast applications with a 14-day retreatment interval to
tomato plants grown in one-gallon pots in a greenhouse, at a rate of
1.35 mg/plant for a reported rate of 0.125 lb ai/A per application
(total application rate of 0.25 lb ai/A).  The plants bore 1-cm fruit at
the time of treatment.  Samples of tomato foliage, stems, and fruit were
harvested at maturity, 49 days after the last application.  Following
harvest, tomatoes were rinsed with a methanol wash to remove surface
residues, then separated into juice and pulp.  Based on the reported R:S
isomer ratio, the test substance consisted of 100% of the S-isomer of
uniconazole, uniconazole-P.  Because R:S isomerization was not
investigated in the study, the term uniconazole will be used to describe
the test substance and analyte in this report.

TRR were 4.42 ppm in tomato leaves, 0.27 ppm in stems, 0.021 ppm in the
methanol surface wash, 0.15 ppm in pulp, and 0.013 ppm in juice. 
Extraction with acetone released the majority of the radioactivity from
tomato leaves, stems, and pulp:  80.2% TRR (3.545 ppm) from leaves,
80.0% TRR (0.216 ppm) from stems, and 67.1% TRR (0.101 ppm) from pulp. 
Additional residues were released from leaves, stems, and pulp by
sequential extraction with methanol (6.0-8.7% TRR), methanol/water
(3.0-4.6% TRR), and acidic methanol (1.9-3.4% TRR).  The nonextractable
residues of pulp were subjected to hydrolysis with 1 N HCl and 20% NaOH,
which released 3.5% and 7.6% TRR, respectively.  Extraction with ethyl
acetate released 44.7% TRR (0.006 ppm) from tomato juice.  Remaining
nonextractable residues were 6.8% TRR (0.301 ppm) in leaves, 9.1% TRR
(0.025 ppm) in stems, 5.5% TRR (0.008 ppm) in pulp, and 55.3% TRR (0.007
ppm) in tomato juice.  These procedures adequately extracted the
majority of residues from tomato matrices.  Extraction results were
normalized; therefore, accountabilities were 100%.

Residues were identified and quantitated by two-dimensional TLC, and
confirmed by HPLC/UV.  Representative chromatograms were included in the
submission. 

The petitioner did not provide the dates of extraction or analysis for
the study; however, sufficient information was included in the
submission to suggest that initial characterization analysis was
completed within 6 months of harvest.  The petitioner should submit the
dates of extraction and analysis to confirm this conclusion.

The primary residue identified in all matrices was parent uniconazole,
accounting for 37.4% TRR (1.651 ppm) in leaves, 44.0% TRR (0.119 ppm) in
stems, 42.1% TRR (0.063 ppm) in pulp, 13.1% TRR (0.002 ppm) in juice,
and 57.1% TRR (0.012 ppm) in the methanol wash.  The geometric Z-isomer
of uniconazole was also a significant component, accounting for 9.2% TRR
(0.404 ppm) in leaves, 10.9% TRR (0.029 ppm) in stems, 8.9% TRR (0.013
ppm) in pulp, 7.5% TRR (0.001 ppm) in juice, and 10.0% TRR (0.0021 ppm)
in the methanol wash.  Metabolite CYC-4Cl accounted for 6.1-6.7% TRR in
leaves, stems, and pulp, and for 1.5% TRR in juice, and was present at
12.9% TRR (0.003 ppm) in the methanol wash.  Metabolites CH2OH-7E, 7KE,
and 7KZ were minor metabolites, accounting for 0.7-1.4% TRR in leaves
and 1.3-2.4% TRR (7KE and 7KZ only) in the methanol wash.  Conjugates of
the following metabolites were identified in leaves (following acid
hydrolysis of polar residues):  uniconazole (4.5% TRR), Z-isomer and
CYC-4Cl (2.3% TRR each), CH2OH-7E (4.5% TRR), and CH2OH-7Z (2.7% TRR). 
Conjugates of uniconazole, the Z-isomer, and CYC-4Cl were also
identified at low levels in the nonextractable residues of juice
(following acid hydrolysis).  Unknown free metabolites (at least 2-4 in
each matrix) accounted for 11.1-11.9% TRR in leaves and stems, 2.7% TRR
in pulp, 4.8% TRR in juice, and 9.0% TRR in the methanol wash. 
Remaining radioactivity was characterized as multicomponent polar and
conjugated unknowns, and accounted for up to 7.7% TRR (0.34 ppm) in
leaves, 17.3% TRR (0.047 ppm) in stems, 19.8% TRR (0.026 ppm) in pulp,
17.7% TRR (0.002 ppm) in tomato juice, and 9.0% TRR (0.002 ppm) in the
methanol wash.

Based on the submitted tomato metabolism study, the petitioner concluded
that the major metabolic pathway of uniconazole in plants is initial E/Z
isomerization to the Z-isomer followed by cyclization.  The minor
metabolic pathways are oxidation of the hydroxyl group to a ketone
group, hydroxylation at the terminal carbon, and conjugation of these
metabolites.  The petitioner noted that the metabolic pathway observed
in tomatoes was similar to that derived from plant metabolism studies in
apple, wheat, and rice.  The Z-isomer and CYC-4Cl metabolites were not
among those identified in the rat metabolism study.

Apple

Valent U.S.A. Corporation submitted a report that discusses the results
of a study in which the metabolism of [phenyl-U-14C]uniconazole-P
(specific activity 27.1 mCi/mmol) in apple was investigated.  The
radiolabeled test substance was isotopically diluted with nonlabeled
standard, dissolved in methanol, and applied as a 25-mg stem injection
treatment to the trunks of apple trees grown outdoors in pots.  Samples
of branches, leaves, and mature apples were harvested 86 days after
treatment.  Based on the reported R:S isomer ratio, the test substance
consisted of 100% of the S-isomer of uniconazole, uniconazole-P. 
Because R:S isomerization was not investigated in the study, the term
uniconazole will be used to describe the test substance and analyte in
this report.

TRR were 9.88 ppm in leaves, 14.6 ppm in branches, 0.074 ppm in apple
pulp, and 0.011 ppm in juice.  The low residues in apples suggest that
uniconazole was very slowly translocated in apple trees.  The petitioner
noted that <1% of the [14C]uniconazole-P injected into the trunk
translocated to the fruit.

Extraction with acetone released the majority of the radioactivity
(54.4-75.5% TRR) from leaves, branches, and apple pulp.  Sequential
extraction with methanol and methanol/water released additional
radioactivity:  4.6-18.7% TRR and 3.3-9.2% TRR, respectively.  Remaining
nonextractable residues were ≤9.4% TRR (≤1.21 ppm) in leaves and
branches, and 37.7% TRR (0.028 ppm) in pulp.  The nonextractable
residues of pulp were subjected to additional acid and base hydrolysis
procedures, which released 2.4% TRR and 29.4% TRR, respectively. 
Extraction with ethyl acetate released 48.1% TRR (0.005 ppm) from juice.
 The remaining nonextractable residues of juice (51.9% TRR, 0.006 ppm)
were not further investigated.  These procedures adequately extracted
the majority of residues from apple matrices.  Extraction results were
normalized; therefore, accountabilities were 100%.  Residues were
identified and quantitated using two-dimensional TLC and confirmed by
HPLC/UV.

The petitioner did not provide the dates of sampling, extraction, or
analysis for the study; however, sufficient information was included in
the submission to suggest that initial characterization analysis was
completed within 6 months of harvest.  The petitioner needs to submit
the dates of sampling, extraction, and analysis to confirm this
conclusion.

and accounted for up to 24.5% TRR in leaves, 0.4% TRR in branches, and
≤9.9% TRR in pulp and juice. 

Based on the results of the apple metabolism study, the petitioner
concluded that the major metabolic pathway in plants was initial E/Z
isomerization to the Z-isomer followed by cyclization and hydroxylation
at the terminal carbon, followed by conjugation.  The petitioner noted
that the metabolic pathway observed in apples was similar to that
derived from plant metabolism studies in tomato, wheat, and rice.  The
wheat and rice metabolism studies have not been reviewed by HED.  The
petitioner further noted that E/Z isomerization and cyclization
reactions are associated with photoreactions that have been observed in
uniconazole analogs, and that the Z-isomer and CYC-4Cl metabolites were
not among those identified in rats.

Conclusions.  The apple and tomato metabolism data did not include
labeling/analysis for the triazole metabolites, 1,2,4-T, TA, and TAA. 
The Agency has determined that plant metabolism studies using
triazole-labeled parent compound with analysis for the triazole
metabolites are required for registrations of triazole pesticides for
uses associated with food and/or feed crops (Memo, D327788, 4/25/06, M.
Doherty).  For the proposed early season use with a low application rate
on tomato seedlings, the triazole data will not be required.  However,
information is needed pertaining to the dates of sampling and/or
extraction and analysis for the apple and tomato metabolism studies.

The submitted metabolism studies indicate that the nature of the residue
is similar in apple and tomato.  Pending submission of the required
information pertaining to sample storage durations, the nature of the
residue in fruiting vegetables is adequately understood.  For purposes
of this petition, the residues of concern for tolerance expression and
risk assessment in fruiting vegetables are uniconazole-P, its
R-enantiomer and the Z-isomer.  

Because the nature of the residue has not been investigated in three
dissimilar crops, additional plant metabolism studies might be required
to support future food/feed uses of uniconazole-P, depending on the
crops for which tolerances are being requested.

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

Because the proposed use of uniconazole-P on fruiting vegetables is
restricted to greenhouse application to plants intended to be
transplanted, and because no detectable residues of uniconazole were
found in/on any sample in any of the crop field trials, no data
pertaining to rotational crops are required to support this petition.

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

There are no livestock feedstuffs associated with the proposed use on
fruiting vegetables.  Therefore, data requirements for livestock
metabolism are not relevant to this tolerance petition. 

Analytical Methodology

Enforcement method:  Valent U.S.A Corporation submitted GC/NPD Method
RM-25-1, “Determination of XE-1019D (S-3307) In Crops” for the
determination of residues of

uniconazole in/on various crop commodities.  Valent is proposing Method
RM-25-1 as a tolerance enforcement method, and has submitted
radiovalidation data and an ILV.  

Briefly, samples of dry crops (e.g., leaves or mulch) are extracted
twice with methanol.  The combined extracts are filtered through sodium
sulfate and concentrated.  Samples of high moisture crops (e.g., tomato
or apple) are mixed with anhydrous sodium sulfate and then extracted
twice with acetone.  The combined extracts are filtered through sodium
sulfate and concentrated.  All extracts are diluted with 10% NaCl
solution and partitioned twice with dichloromethane (DCM).  The DCM
phases are filtered through sodium sulfate, combined, and evaporated to
dryness.  For dry crops, the residue is dissolved in hexane and
partitioned twice with acetonitrile (ACN).  The ACN phases are combined,
washed with hexane, and evaporated to dryness.  The resulting residue
from dry crops and the residue from high moisture crops are dissolved in
ethyl acetate, diluted with hexane, and applied to a Florisil column. 
Residues of uniconazole are eluted with ethyl acetate.  The eluate is
evaporated to dryness and dissolved in ethyl acetate for GC/NPD
analysis.  

Based on the method description, the method does not distinguish between
the R and S enantiomers of uniconazole.  In addition, the original
residue method, RM-25, reportedly does not distinguish between
uniconazole and its Z-isomer.  The registrant needs to revise Method
RM-25-1 so that it states more clearly that it does not distinguish
between the uniconazole isomers.

The reported LOQ was 0.02 ppm (based on the lowest limit of method
validation; LLMV), and the reported LOD was 0.002 ppm based on the
results of the ILV.

No method validation data were submitted for GC/NPD Method RM-25-1;
however, the method was successfully validated for tomato fortified at
0.02, 0.04, and 0.2 ppm in the ILV.  Recoveries ranged from 82.0 to
88.5%, with an overall average recovery of 86.2% and an overall standard
deviation of 2.6%.  Acceptable concurrent recovery data reflecting
fortification of bell pepper at 0.01 ppm, and tomato at 0.01 and 0.02
ppm, were also submitted for the modified data collection method, Method
RM-25-1a, in conjunction with the tomato and pepper crop field trials. 
Together the ILV and concurrent recovery data are sufficiently
representative of the expected residue levels for fruiting vegetables. 
No additional method validation data are required.

Radiovalidation data were generated for the original residue method,
Method RM-25, in conjunction with the apple and tomato metabolism
studies submitted under PP#7E7268.  The submitted data are acceptable
and indicate that the method adequately recovered weathered residues of
uniconazole from samples of apple and tomato leaves and pulp.

Data collection method:  Samples of tomato and bell pepper from the
submitted crop field trials were analyzed for residues of uniconazole
using GC/NPD Method RM-25-1a, entitled “Determination of Uniconazole-P
in Fruiting Vegetables” (revision dated 4/10/03).  Method RM-25-1a is
a modification of the proposed enforcement method, RM-25-1 which
incorporates the ILV recommendations and includes GC/MS confirmatory
procedures.  Adequate concurrent recovery data were submitted for the
method.

Conclusions.  Pending review by ACB/BEAD, the submitted residue
analytical method data are adequate to satisfy data requirements for the
tolerance petition.  The proposed enforcement method, Method RM-25-1,
needs to be revised so that it states more clearly that it does not
distinguish between the isomers.  In addition, the method should be
modified to include the confirmatory GC/MS procedures used in the ILV
and to incorporate the revisions made by the ILV laboratory. 
Alternatively, the petitioner may propose the data collection method,
revised Method RM-25-1a, as an enforcement method for fruiting
vegetables, provided the method is modified to specify the uniconazole
isomers determined by the method.  The proposed enforcement method and
the ILV recommendations were forwarded to the Analytical Chemistry
Branch of BEAD for petition method validation.

An acceptable method was used for data collection for the bell pepper
and tomato crop field trial studies submitted under this action.  When
field trial data, reflecting analysis for residues of the triazole
metabolites, are submitted, a validated data collection method capable
of achieving an LOQ of ≤0.01 ppm for these analytes should be
submitted as specified by the Agency under Memo, D327788, M. Doherty,
4/25/06.

Multiresidue Methods

No data pertaining to multiresidue methods were submitted with this
petition, and the FDA PESTDATA database (dated June 2005) does not
contain any information for uniconazole.  Data pertaining to
multiresidue methods testing for uniconazole should be submitted.

5.1.5	Environmental Degradation TC \l3 "5.1.5	Environmental Degradation 

The modeling strategy for this assessment focused on parent uniconazole.
 The triazole degradates have been assessed previously.  Other
degradates identified in environmental fate studies are
E-1-(4-chlorophenyl)-4,4-dimethyl-2-(1,2,4-triazole-1-yl)-1-pentene-3-on
e (7KE),
Z-1-(4-chlorophenyl)-4,4-dimethyl-2-(1,2,4-triazole-1-yl)-1-pentene-3-on
e (7KZ),
1-(4-chlorophenyl)-4,4-dimethyl-2-(1,2,4-triazole-1-yl)-pentan-3-ol
(7SA),
1-(4-chlorophenyl)-4,4-dimethyl-2-(1,2,4-triazole-1-yl)-pentan-3-one
(7SK),
1-(4-chlorophenyl)-4,4-dimethyl-2-(1,2,4-triazole-1-yl)-1,2-epoxypentan-
3-ol (7EP), and carbon dioxide.  All identified degradates were detected
at less than 5% of the amount applied.

Comparative Metabolic Profile

 TC \l3 "5.1.6	Comparative Metabolic Profile 

Uniconazole is a member of the triazole class of compounds.  As a
result, it is very likely that in plants and animals it is metabolized
into the following compounds:  1,2,4-triazole, triazole alanine, and
triazole acetic acid.  The registrant did not submit metabolism studies
in which the triazole ring was radiolabeled, however.  For the purposes
of this tolerance petition, HED assumes that uniconazole is metabolized
to some extent in plants and animals to these triazole compounds.

In the tomato and apple metabolism studies, the primary residue
identified in all matrices was parent uniconazole.  The geometric
Z-isomer of uniconazole was also found in both studies.  Minor amounts
of other metabolites and conjugates were also found.  Based on the two
studies, the petitioner concluded that the major metabolic pathway of
uniconazole in tomatoes and apples is initial E/Z isomerization to the
Z-isomer followed by cyclization.  The minor metabolic pathways are
oxidation of the hydroxyl group to a ketone group, hydroxylation at the
terminal carbon, and conjugation of these metabolites.

In rats, most of the test compound (96-99%) was excreted within three
days.  Significant fractions of the administered radioactive doses were
recovered in the urine and feces.  Five metabolites were identified in
these two fractions.  Two of these metabolites were oxidation products
of the methyl moiety of the tertiary butyl group and one was a free
triazole.  As stated earlier, the registrant noted that E/Z
isomerization and cyclization reactions are associated with
photoreactions that have been observed in uniconazole analogs, and that
the Z-isomer and CYC-4Cl (plant metabolites) were not among those
identified in the rat metabolism study.  Oxidation products of the
methyl moiety of the tertiary butyl group were found in rats, tomatoes
(CH2OH-7E), and apples (CH2OH-7E).

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

Uniconazole is a member of the triazole class of compounds.  As a
result, it is very likely that in plants and animals it is metabolized
to some extent into the following compounds:  1,2,4-triazole, triazole
alanine, and triazole acetic acid.  The metabolite 1,2,4-triazole is a
major metabolite in animal commodities and TA and TAA are major
metabolites in plant commodities.  HED performed a human health risk
assessment for these metabolites (Memo, D322215, M. Doherty, 2/7/2006). 
The hazard characterization is discussed in detail in this risk
assessment.  

More recently, in support of human health risk assessments, dietary
exposure analyses of the triazole metabolites (Memos, D347252 and
D347253, W. Cutchin, 12/19/2007) were performed for the triazole
fungicides myclobutanil (Memo, D341689, W. Cutchin, 11/1/2007),
fenbuconazole, ipconazole, metconazole, tebuconazole, uniconazole and
tetraconazole (M.Doherty, 3/27/08, D350314).  HED was able to make the
safety finding with respect to the metabolites.

In the tomato and apple metabolism studies, the phenyl ring was the only
ring with a radioactive label.  No major metabolites were found.  Little
information is available on the toxicities of any of the other
metabolites that were found.  HED anticipates that the toxicities of
these metabolites are similar to the toxicity of the parent.

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

Parent uniconazole-P, its R-enantiomer and the Z-isomer, are the
residues of concern for risk assessment in fruiting vegetables.  The
residues of concern in animal commodities are not an issue for this risk
assessment because there are no significant animal feed items associated
with fruiting vegetables.  The residues of concern in rotational crops
are also not an issue for this risk assessment because the proposed use
is a greenhouse use only.  

In drinking water, the residue of concern is parent uniconazole. 
Although 1,2,4-T, TA, and TAA are residues of concern in plants from the
proposed use of uniconazole, the risks from these residues are
considered to be covered by previous assessments (see Section 8.0). 
Residues of 1,2,4-T in drinking water were also covered by those earlier
assessments.

    

       

Table 5.1.8  Summary of Metabolites and Degradates to be included in the
Risk Assessment and Tolerance Expression

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Plants

	Primary Crop: Fruiting Vegetables	Uniconazole-P, R-enantiomer and
Z-isomer	Uniconazole-P, R-enantiomer and Z-isomer

	Rotational Crop	Not Applicable	Not Applicable

Livestock

	Ruminant	Not Applicable	Not Applicable

	Poultry	Not Applicable	Not Applicable

Drinking Water	Uniconazole-P, R-enantiomer 	Not Applicable

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

The Environmental Fate and Effects Division (EFED) provided a drinking
water exposure assessment for uniconazole (D346559, M. Corbin,
2/14/2008).

The EDWCs used in the dietary risk assessments were provided by EFED
(D346559, M. Corbin, 2/14/2008).  Typically, EFED utilizes an integrated
approach for conducting exposure assessments that relies on an analysis
of both monitoring data and modeled data.  No monitoring data are
available for uniconazole.  The surface water EDWCs were generated using
the FIRST Model and the groundwater EDWCs were generated using the
SCI-GROW Model.  EDWCs reflect exposure to parent only.  The peak
surface water value was 3.1 ppb and the annual average surface water
value was 1.5 ppb.  The groundwater value was 0.076 ppb.

Table 5.1.9	Summary of Estimated Surface Water and Groundwater
Concentrations for Uniconazole.

	Uniconazole

	Surface Water Conc., ppb a	Groundwater Conc., ppb b

Acute	3.1	0.076

Chronic (non-cancer)	1.5	0.076

Chronic (cancer)	1.5	0.076

a From the FIRST Model.  Input parameters are based on uniconazole use
on bedding plants and woody ornamentals.

b From the SCI-GROW Model based on uniconazole use on bedding plants and
woody ornamentals.

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

IR-4 submitted field trial data for uniconazole on fruiting vegetables
from 18 field trials conducted in the United States during the 2002
growing season.  Twelve tomato trials were conducted in Zones 2 (NJ; 1
trial), 3 (FL; 2 trials), 5 (MI; 1 trial), 6 (TX; 1 trial), and 10 (CA
and NM; 7 trials).  Six bell pepper trials were conducted in Zones 2
(NJ; 1 trial), 3 (FL; 1 trial), 5 (MI; 1 trial), 6 (TX; 1 trial), and 10
(CA and NM; 2 trials).  No non-bell pepper field trials were conducted. 

At each test location, greenhouse-grown tomato and bell pepper plants at
the 2- to 4-leaf growth stage were treated with the 0.055% EC
formulation of uniconazole-P, in a single foliar broadcast application
made to separate plots using 5 and 10 ppm solutions.  Applications were
made using backpack sprayers, in spray volumes of 1.97-4.09 qt/100 sq.
ft, without an adjuvant.  Tomato and bell pepper plants were
transplanted to the field 20-41 days after application.  Samples of
mature tomatoes and peppers were harvested at PHIs of 91-128 days for
tomatoes and 85-116 days for peppers.  In the tomato trials, 22 samples
were taken from 1x treated plots, 2 samples were taken from 0.5x treated
plots, and 2 samples were taken from 2x treated plots.  In the pepper
trials, 10 samples were taken from 1x treated plots and 2 samples were
taken from 2x treated plots.  

Samples of tomatoes and peppers from all 10-ppm treatment plots and
samples of tomatoes from one 5-ppm treatment plot were analyzed for
residues of uniconazole using GC/NPD Method RM-25-1a.  The LOQ,
determined as the LLMV, was 0.01 ppm for uniconazole in/on tomato and
pepper; the experimental LOD was 0.005 ppm.  The method is adequate for
data collection based on acceptable concurrent recovery data.  Samples
were not analyzed for the triazole metabolites, 1,2,4-T, TA, and TAA.

The maximum storage durations of crop samples, from harvest to analysis,
were 316 days (10.4 months) for tomato and 335 days (11.0 months) for
bell pepper.  To support sample storage conditions and durations, the
petitioner conducted a concurrent storage stability study which
indicated that residues of uniconazole were relatively stable during
frozen storage for up to 395 days (13 months) in/on tomato and pepper. 
These data are adequate to support the storage durations and conditions
for the fruiting vegetable field trials.

Residues of uniconazole were nondetectable (<0.005 ppm) in/on all
samples of tomato and bell pepper harvested 91-128 and 85-116 days,
respectively, following a single foliar broadcast application of the
0.055% EC formulation of uniconazole at 0.5x, 1x, and 2x the maximum
label application rate.  

No small-size tomato varieties were used in the field trials; however,
because the proposed use pattern reflects greenhouse application to
plants made prior to fruit formation and transplanting (i.e., surface
residues are not of concern), no additional tomato trials will be
required.

No residue decline data were submitted; however, no data are required
because of the long PHIs used in the study and the absence of detectable
residues in all samples.

Conclusions.  The field trials reflect the proposed use pattern for
uniconazole, provided the petitioner amends the label as specified under
Directions for Use in Section 10.2.  Geographic representation for the
submitted tomato and bell pepper field trials is adequate.  Although one
tomato trial was conducted in Region 6 instead of in Region 1, as
recommended under OPPTS Guideline 860.1500, because the proposed use is
for pretransplant application in the greenhouse, no additional data are
required.

Samples were analyzed for uniconazole; however, samples were not
analyzed for the triazole metabolites 1,2,4-T, TA, and TAA.  Crop field
trials for any new uses should be conducted reflecting analysis of
samples for the triazole metabolites as specified by the Agency under
Memo, D327788, M. Doherty, 4/25/06.  Such data are not required for the
proposed use since the registered use of the triazole fungicide
myclobutanil on fruiting vegetables is likely to produce higher residues
of these metabolites.  

No trials were conducted on non-bell peppers.  IR-4 argued that these
data are not required because, given the very early season application
and long PHI, residues would be unlikely to result regardless of variety
or fruit size.  Because residues of uniconazole were nondetectable in/on
all samples from all 18 tomato and pepper field trials, no additional
trials will be required at this time.  HED concurs with IR-4’s
argument.

The available field trial data will support a tolerance for residues of
uniconazole-P in/on Crop Group 8, Fruiting Vegetables, at the method LOQ
of 0.01 ppm provided the label is addressed per Section 10.2.

No processing study was included in the subject petition, nor was the
need for a processing study addressed.  Since residues were
nondetectable (<0.005 ppm) in/on all tomato samples from the crop field
trials and tomatoes treated with uniconazole are unlikely to be
processed, a tomato processing study is not needed to support the
proposed use of uniconazole-P on fruiting vegetables.

Because the proposed use of uniconazole-P on fruiting vegetables is
restricted to greenhouse application to plants intended to be
transplanted, and because no detectable residues of uniconazole were
found in/on any sample in any of the crop field trials, no data
pertaining to rotational crops are required to support this petition.

International Residue Limits

No Codex, Canadian, or Mexican MRLs have been established for
uniconazole.

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

Acute and chronic aggregate dietary exposure analyses were performed for
uniconazole.  The dietary exposure analyses are discussed in a dietary
exposure memo prepared for this risk assessment (Memo, D348937, D.
Dotson, 3/31/2008). 

The acute and chronic aggregate dietary exposure analyses were performed
using the Dietary Exposure Evaluation Model DEEM-FCID™, Version 2.03. 
This model uses food consumption data from the U.S. Department of
Agriculture’s Continuing Surveys of Food Intakes by Individuals
(CSFII) from 1994-1996 and a supplemental children’s survey taken in
1998.  The analyses included fruiting vegetables (crop group 8) and
drinking water.  Although okra is not yet officially a member of group
8, it was included in the assessment.  The recommended fruiting
vegetable tolerance (0.01 ppm) was used for all fruiting vegetable
commodities.  In both the acute and chronic analysis, a percent crop
treated value of 100% was used for all commodities.  

5.2.1	Acute Dietary Exposure/Risk  TC \l3 "5.2.1  Acute Dietary
Exposure/Risk 

An acute dietary exposure analysis was performed for the population
subgroup Females 13-49 only.  This population subgroup is the only one
for which an acute dietary endpoint was selected.  The acute analysis
was unrefined.  In addition to tolerance level residues and 100% crop
treated assumptions, a conservative value was also used for drinking
water.  The surface water value of 0.0031 ppm was greater than the
groundwater value of 0.000076 ppm.  As a result, the surface water
concentration was used.  The acute dietary risk estimate for Females
13-49 is 0.4% of the aPAD at the 95th percentile of exposure. 
Therefore, the dietary risk estimate for this population subgroup is
below HED’s level of concern. 

5.2.2	Chronic Dietary Exposure/Risk  TC \l3 "5.2.2  Chronic Dietary
Exposure/Risk 

The chronic dietary exposure analysis was also unrefined.  The
recommended tolerance of 0.01 ppm was used for fruiting vegetables.  In
addition to tolerance level residues and 100% crop treated assumptions,
a conservative value was also used for drinking water.  The surface
water value of 0.0015 ppm was greater than the groundwater value of
0.000076 ppm.  As a result, the surface water concentration was used. 
The chronic dietary risk estimates for the general U.S. population and
all population subgroups are below HED’s level of concern.  The
general U.S. population and all subgroups utilize <1% of the cPAD.  The
most highly exposed population subgroup is All Infants (<1 year), which
utilizes 0.6% of the cPAD.  The general U.S. population utilizes 0.2% of
the cPAD. 

5.2.3	Cancer Dietary Risk  TC \l3 "5.2.3  Cancer Dietary Risk 

Uniconazole was classified by the HED Carcinogenicity Peer Review
Committee as a Group C, possible human carcinogen.  The CPRC recommended
the RfD approach for risk assessment, and concluded that the chronic RfD
would be protective of all chronic effects including carcinogenicity. 
As a result, the chronic dietary exposure analysis is adequate to assess
cancer risk.  The general U.S. population utilizes <1% of the cPAD. 
Therefore, cancer risk is not of concern to HED.

Table 5.2.  Summary of Dietary Exposure and Risk for Uniconazole

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	N/A

	N/A

	

0.000050	0.2	

Chronic RfD is protective

of cancer effects

	Chronic RfD is protective of cancer effects

All Infants (< 1 year old)

	

0.000114	0.6

Children 1-2 years old

	

0.000091	0.5

Children 3-5 years old

	

0.000084	0.4

Children 6-12 years old

	

0.000057	0.3

Youth 13-19 years old

	

0.000042	0.2

Adults 20-49 years old

	

0.000045	0.2

Adults 50+ years old

	

0.000044	0.2

Females 13-49 years old	0.000182	0.4	

0.000044	0.2

Anticipated Residue and Percent Crop Treated (%CT) Information

As stated above, the acute and chronic dietary exposure analyses were
unrefined.  The recommended tolerance level for fruiting vegetables was
used and the assumption was made that 100% of the fruiting vegetable
crop would be treated with uniconazole-P.

		

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

A non-occupational and residential exposure/risk assessment was not
performed as there are currently no registered or newly proposed
non-occupational or residential uses (Memo, D347096, S. Wang,
3/12/2008).

Spray drift is always a potential source of exposure to residents living
in close proximity to spraying operations.  This situation is
particularly the case with aerial application.  However, to a lesser
extent, spray drift resulting from the ground application of uniconazole
could also be a potential source of exposure.  The Agency has been
working with the Spray Drift Task Force (a membership of U.S. pesticide
registrants), EPA Regional Offices, State Lead Agencies for pesticide
regulation, and other parties to develop the best spray drift management
practices.  The Agency is now requiring interim mitigation measures for
aerial applications that must be placed on product labels/labeling.  The
Agency has completed its evaluation of the new database submitted by the
Spray Drift Task Force, and is developing a policy on how to apply
appropriately the data and the AgDRIFT computer model to its risk
assessments for pesticides applied by air, orchard airblast, and ground
hydraulic methods.  After the policy is in place, the Agency may impose
further refinements in spray drift management practices to reduce
off-target drift risks associated with pesticide application.

Aggregate Risk Assessments and Risk Characterization

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

There are no residential uses for uniconazole.  As a result, aggregate
exposure will be comprised of exposures that occur through food and
drinking water only.  

7.1	Acute Aggregate Risk TC \l2 "7.1	Acute Aggregate Risk 

There are no residential uses for uniconazole-P.  As a result, aggregate
exposure is comprised of exposures that occur through food and drinking
water only.  An acute aggregate risk assessment was performed for
Females 13-49 only.  This assessment is equivalent to the acute dietary
risk assessment.  Acute dietary risk is below HED’s level of concern
for the population subgroup Females 13-49.  The subgroup utilizes <1% of
the aPAD.   TC \l2 "7.4	Long-Term Aggregate Risk 

 

Short-Term Aggregate Risk

There are no non-occupational/residential uses for uniconazole-P.  As a
result, no short-term exposures are anticipated and a short-term
aggregate risk assessment is not needed. TC \l2 "7.2	Short-Term
Aggregate Risk 

7.3	Intermediate-Term Aggregate Risk

There are no non-occupational/residential uses for uniconazole-P.  As a
result, no intermediate-term exposures are anticipated and an
intermediate-term aggregate risk assessment is not needed.

	Long-Term Aggregate Risk

As aggregate exposure to uniconazole will be comprised of exposures that
occur through food and drinking water only, the long-term aggregate risk
assessment is equivalent to the chronic dietary risk assessment. 
Chronic dietary risk is below HED’s level of concern for the general
U.S. population and all population subgroups.  All population subgroups
utilize <1% of the cPAD.   TC \l2 "7.4	Long-Term Aggregate Risk 

7.5	Cancer Risk TC \l2 "7.5	Cancer Risk 

Uniconazole-P was classified by the HED Carcinogenicity Peer Review
Committee as a Group C, possible human carcinogen.  The CPRC recommended
the reference dose (RfD) approach for risk assessment, and concluded
that the chronic RfD would be protective of all chronic effects
including carcinogenicity (TXR No. 0052723).  As a result, the chronic
dietary exposure analysis is adequate to assess cancer risk.  The
general U.S. population utilizes <1% of the cPAD.  Therefore, cancer
risk is not of concern to HED.

Cumulative Risk Characterization/Assessment

Section 408(b)(2)(D)(v) of the FFDCA requires that, when considering
whether to establish, modify, or revoke a tolerance, the Agency consider
“available information concerning the cumulative effects” of a
particular pesticide's residues and “other substances that have a
common mechanism of toxicity.”

Uniconazole is a member of the triazole-containing class of pesticides. 
Although these conazoles act similarly in plants 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.  Responses include hepatotoxicity and
hepatocarcinogenicity in mice, thyroid tumors in rats, and
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.

The triazole-derived compounds can form the common metabolites
1,2,4-triazole, TA, and TAA.  Separate dietary exposure analyses were
prepared for these metabolites (D347252 and D347253, W. Cutchin,
12/19/07, and D350314, M. Doherty, 3/27/2008).  The dietary exposure
analyses for the triazole metabolites are adequate to cover the use of
uniconazole-P on fruiting vegetable bedding plants for several reasons. 
First, the triazole fungicide myclobutanil (which was included in the
assessment) may be used on tomatoes at a rate of 0.50 lb ai/acre and on
peppers and other members of crop group 8 at a rate of 0.125 lb ai/acre.
 The molecular weights of myclobutanil and uniconazole are very
comparable (myclobutanil MW=289 g/mole and uniconazole MW=291).  The
equivalent application rates of uniconazole would be 0.50 and 0.126 lb
ai/acre on tomatoes and peppers, respectively.  However, the proposed
application rate of uniconazole to fruiting vegetables is only 0.018 lb
ai/acre.  Second, conservative drinking water concentrations of the
triazole metabolites were included in the cumulative dietary exposure
analyses.  The EDWCs used in the dietary exposure analyses were based on
myclobutanil application to golf courses (Memo, D320682, I. Maher,
2/28/2006).  The application rate is considerably higher than the
proposed application rate of uniconazole to fruiting vegetable bedding
plants (10.4 lb ai/A as opposed to 0.018 lb ai/A).  Third, the proposed
use of uniconazole is an early season application to bedding plants
prior to fruit being present.  Finally, uniconazole is proposed for
greenhouse use on bedding plants that are primarily intended for
homeowner use.  Although plants treated with uniconazole-P may be used
for commercial fruiting vegetable production, that is not their intended
use.  For these reasons, residues of the triazole metabolites will be
much lower from the greenhouse use of uniconazole than they are from the
field application of myclobutanil and, as stated above, the dietary
exposure analyses for the triazole metabolites are adequate to cover the
use of uniconazole-P on fruiting vegetable bedding plants.

Occupational Exposure/Risk Pathway

A Section 3 registration is being requested for the end-use product
containing uniconazole-P as active ingredient.  The proposed use is: 
SUMAGIC( Plant Growth Regulator (uniconazole-P 0.055%, liquid) on
pepper, tomato, and other fruiting crop vegetables (except cucurbits)
(0.0000832 lb ai/gal) in commercial greenhouses by handwand or back-pack
sprayer.

                                                                        
                                                                        
              

9.1  Handler Risk  tc \l2 "5.1   For Crop Protection Uses   5.1.1. 
Handlers  

Equations/Calculations

The following equations were used to calculate handler exposure and
risk:

Dermal Dose (mg/kg/day) 	=	Rate (lb ai/gal) x UE (mg/lb ai) x Amount
Treated (gallons/day)

BW (kg)

Inhalation Dose (mg/kg/day)	=	 Rate (lb ai/Gal) x UE (mg/lb ai) x Amount
Treated (gallons/day)

        BW (kg)

Where:

Rate (Application Rate)		=	Maximum application rate on product label (lb
ai/gallon)

UE (Unit Exposure)		=	Exposure value derived from August 1998 PHED
Surrogate Exposure Table (mg/lb ai handled)

Amount Treated			=	Maximum amount of pesticide treated per day
(Gallons/day)

               BW				=	Body weight (kg)

Dermal MOE		                             =	NOAEL (5 mg/kg/day)          
    

                                                                        
             Dermal Daily Dose (mg/kg/day)

Inhalation MOE		                             =	NOAEL (5 mg/kg/day)      
     

                                                                        
             Inhalation Daily Dose (mg/kg/day)

Exposure Scenarios

There are 3 handler scenarios that are expected to result in the highest
exposure for the proposed uses:

Mixing/Loading/Applying Liquids using Low-Pressure Handwand Sprayer
(Scenario 1)

Mixing/Loading/Applying Liquids using Back-Pack Sprayer (Scenario 2)

Mixing/Loading Liquids for Potential Application Using Greenhouse Boom
(Scenario 3)

Application Rate

The maximum application rate provided by the IR-4 Project Coordinator,
Ray Leonard, was used for all exposure assessments.  The maximum
concentration was 0.0000832 lb ai per one gallon of spray solution.

The Amount of Pesticide Treated per Day

Based on HED’s Exposure SAC Policy Number 9.1, 40 gallons/day for
applications using low-pressure handwand or back-pack sprayer, and 1,000
gallons/day for applications using greenhouse boom were assumed.

Body Weight									

The average body weight for the general population (70 kg) was used for
dermal assessments.  The female body weight (60 kg) was used for
inhalation assessments because the inhalation endpoint is based on
developmental effects.

Exposure Frequency

No data on the number of exposure days per year were provided.  For this
risk assessment, it was assumed that handlers would be exposed for less
than 6 months per year (short- and intermediate-term exposures). 
Long-term exposure is not expected.  

Unit Exposures

The unit exposures are based on the PHED Version 1.1 as presented in the
August 1998 PHED Surrogate Exposure Guide.  

There are three basic risk mitigation approaches considered appropriate
for controlling occupational exposures.  These mitigation approaches
include administrative controls, the use of personal protective
equipment (PPE), and the use of engineering controls.  For uniconazole,
occupational handler exposure assessments were completed by HED using
baseline clothing and PPE.  The baseline clothing level scenario for
occupational exposure scenarios is generally an individual wearing long
pants, a long-sleeved shirt, no chemical resistant gloves, and no
respirator.  As reflected in the calculations included herein, PPE
involves the use of chemical-resistant gloves.  

Handlers’ Exposure and Risk

No MOEs for handlers (1,100~2,900,000) exceed the level of concern at
the single layer level or single layer plus gloves level (for back-pack
sprayer users).  The HED level of concern is an MOE of <100.  A summary
of the exposures/risks for handlers is presented in Table 9.1.  

The handler exposure estimates in this assessment are based on a central
tendency estimate of unit exposure and an upper-percentile assumption
for the application rate, and are assumed to be representative of
high-end exposures.  The uncertainties associated with this assessment
stem from the use of surrogate exposure data (e.g., differences in use
scenario and data confidence), and assumptions regarding that amount of
chemical handled.  The estimated exposures are believed to be reasonable
high-end estimates based on observations from field studies and
professional judgment.

           Table 9.1.  Non-Cancer Risks for Uniconazole Handlers.

Exposure Scenario (Scenario #)	

Mitigation Levela	

Dermal Unit Exposureb (mg/lb ai)	

Inhalation Unit Exposurec   (ug/lb ai)	

Application Rate

(lb ai/Gal)	

Amount Treatedd

(Gal/day)	

Daily

Dermal

Dosee (mg/kg/day)	

Daily

Inhalation

Dosef (mg/kg/day)	

Dermal

MOEg 	

Inhalation

MOEh    

 

Mixer/Loader

Mixing/Loading       Liquids for Application  using Greenhouse Boom  (3)

	

Single Layer,

No Gloves	

2.9	

1.2	

0.0000832	

1,000	

0.0034	

0.0000017	

1,500	

2,900,000

Mixer/Loader/Applicator

Mixing/Loading/Applying Liquids using 

Low-Pressure

Handwand Sprayer (1)

	Single Layer,

No Gloves	100	30	0.0000832	40	0.0048	0.0000017	1,100	2,900,000

Mixing/Loading/Applying Liquids using

Back-Pack Sprayer (2)

	

Single Layer,

Plus Gloves	2.5	30	

0.0000832

	40	

0.00012

	

0.0000017

	

42,000

	2,900,000

a	Single layer = long-sleeve shirt + long pants, or coveralls, and no
respirator. 

b	Dermal Unit Exposure represents long pants, long sleeved shirt, no
gloves or plus gloves. 

c	Inhalation Unit Exposure represents no respiratory protection, open
mixing/loading/applying. 

d	Daily amount treated values are from EPA estimates of the amount of
pesticide that could be treated in a single day for each exposure
scenario of concern.  Exposure SAC Policy 9, 7/5/2000.  

e	Daily dermal dose (mg/kg/d) =  [unit dermal exposure (mg/lb ai) *
application rate (lb ai/gallon) * daily amount treated /  body weight
(70kg).

f	Daily inhalation dose (mg/kg/d) = (unit exposure (µg/lb ai) *
(1mg/1000 µg) conversion * application rate (lb ai/gallon) * daily
amount treated / body weight (60kg).

g	Dermal MOE = NOAEL (5 mg/kg/d) / Daily dermal dose.  UF = 100.

h	Inhalation MOE = NOAEL (5 mg/kg/d) / Daily inhalation dose.  UF = 100.



9.2  Post-application Risk

The transfer coefficients (TCs) for plants grown in greenhouses and
other enclosed structures have not been assigned in the HED’s Exposure
SAC Policy Number 3.1.  The post-application exposure/risk was evaluated
using a TC of 400 for moving plants.  This TC was recommended by HED’s
Science Advisory Council for Exposure (Exposure SAC 1/31/08).  The
dermal MOE for the moving of plants (2,700) after application does not
exceed the level of concern.  The calculations are shown in Table 9.2. 
Uniconazole has very low vapor pressure (1.0x10-8 Pa @ 20o C / 2.3x10-8
Pa @ 25o C); therefore, inhalation post-application exposure/risk is not
of concern. 

The technical material has a Toxicity Category IV for skin irritation,
and a Category III for eye irritation/acute dermal Toxicity.  Per the
Worker Protection Standard (WPS), a 12-hr REI is required.  The 12-hour
REI appearing on the label is appropriate.

Table 9.2.  Post-application Exposure and Risk for Moving Greenhouse
Plants

Crop	

Application Rate 

(lb ai/A)	

Work Activity	

Transfer Coefficientsa (cm2/hr)	

Post-application Dayb	

DFRc

(µg/cm2)	

Daily Dosed (mg/kg/day)	    MOE e

Pepper, Tomato	0.0000832 lb ai/Gal

= 0.018 lb ai/A	Moving Plants	400	0	0.040	0.0018	2,700

a	Transfer coefficient from Science Advisory Council for Exposure: 
01/31/08.

b	Day after treatment represents approximately 12 hours following
application, when sprays have dried.

c	DFR = Application Rate (lb ai/acre) x Fraction of active ingredient
that remains on the foliage when sprays have dried (20%)  x 4.54E8
µg/lb x 24.7E-9 acre/cm2.

d	Daily dose = DFR (µg/cm2) x TC (cm2/hr) x conversion factor (1
mg/1,000 µg) x exposure time (8 hrs/day) / body weight (70 kg).

e	MOE = NOAEL (5 mg/kg/day) / daily dose (mg/kg/day).

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

Toxicology

HED recommends these studies be required for any future food uses or any
uses with higher worker exposure.

A 28-day inhalation study is required for assessment of inhalation
exposure to uniconazole-P.

In view of the positive results obtained for chromosomal aberration and
DNA damage/repair, the HED Peer Review Committee recommended that a
dominant lethal assay be performed to assess more fully the potential of
uniconazole to induce genetic effects in germ cells.

10.2	Residue Chemistry

HED recommends that RD require and receive the following before granting
a conditional registration:  a revised Section B (see requirements under
Directions for Use), method review by ACB/BEAD, a revised enforcement
method (see requirements under Residue Analytical Methods), and a
revised Section F (see requirements under Proposed Tolerances).

860.1200 Directions for Use

The following statements should be added to the fruiting vegetable
section of the label:

“If multiple applications are made to the transplants, the total
amount of uniconazole-P applied may not exceed that from a single
application of a 10 ppm spray concentration at 2 qts/100 sq ft
(equivalent to 0.000042 lb ai/100 sq ft or 0.018 lb ai/acre).  The final
application may not occur later than 14 days after the 2-4 true leaf
stage.”

The statement prohibiting application to food crops should be revised to
prohibit application to food crops other than those listed on the label.

860.1340 Residue Analytical Methods

Determination by ACB/BEAD that the enforcement method is adequate.

The proposed enforcement method, Method RM-25-1, should be modified to
clarify which isomers of uniconazole are determined by the method.  In
addition, the method should be modified to include the confirmatory
GC/MS procedures used in the ILV and to incorporate the revisions made
by the ILV laboratory.  Alternatively, the petitioner may propose the
data collection method, Method RM-25-1a, as an enforcement method for
fruiting vegetables, provided the method is modified to specify the
uniconazole isomers determined by the method.

860.1550 Proposed Tolerances

The petitioner should revise the proposed tolerance expression to
reflect the residues of concern, uniconazole-P, its R-enantiomer and the
Z-isomer.  

The proposed commodity definition should be revised as follows: 
Vegetable, Fruiting, Group 8.

Conversion of conditional registration to unconditional registration for
the requested use will be considered upon submission of the following
outstanding residue chemistry data.

860.1300 Nature of the Residue - Plants

Additional storage stability information pertaining to the dates of
sampling, extraction, and analysis are required for the available apple
and tomato metabolism studies.

860.1360 Multiresidue Methods

Data pertaining to multiresidue methods testing for uniconazole should
be submitted.

The following data deficiencies are not conditions of registration. 
However, if additional food uses are proposed in the future, the
following deficiencies should be resolved.

860.1300 Nature of the Residue - Plants

Additional plant metabolism studies will be needed for uses on crops
other than fruits or fruiting vegetables.  Such studies should include
use of uniconazole-P labeled in the triazole ring for analysis of the
triazole metabolites 1,2,4-triazole, TA and TAA.

860.1340 Residue Analytical Methods

idated data collection method capable of achieving a limit of
quantitation of ≤0.01 ppm for these analytes should be submitted as
specified by the Agency under Memo, D327788, M. Doherty, 4/25/06.

860.1500 Crop Field Trials

Crop field trials for any future new uses should be conducted reflecting
analysis of samples for the triazole metabolites as specified by the
Agency under Memo, D327788, M. Doherty, 4/25/06.

10.3	Occupational and Residential Exposure  TC \l2 "10.3	Occupational
and Residential Exposure 

	None



References:  TC \l1 "References: 

Uniconazole:  Report of the Cancer Peer Review Committee, TXR# 0052723,
J. Stewart, 10/11/1990.

Uniconazole.  Petition for Establishment of a Tolerance for Use on
Fruiting Vegetables, Crop Group 8.  Summary of Analytical Chemistry and
Residue Data.  PP#7E7268, D347093, D. Dotson, 3/31/2008.

Uniconazole Acute and Chronic Aggregate Dietary (Food and Drinking
Water) Exposure Analyses for the Section 3 Registration Action. 
D348937, D. Dotson, 3/31/2008.

Occupational and Residential Exposure/Risk Assessment for Uniconazole
for New Use on Fruiting vegetables (Pepper, Tomato, Eggplant, etc.). 
D347096, S. Wang, 3/12/2008.

Drinking Water Exposure Assessment for New Uses of Uniconazole (PC Code
128976) on Ornamental Plants and Fruiting Vegetables in Shade Houses,
Lath Houses and Greenhouses.

D 346559, M. Corbin, 2/14/2008.

 

Appendix A:	Toxicology Assessment  TC \l1 "Appendix A:	Toxicology
Assessment 

A.1	Toxicology Data Requirements TC \l2 "A.1	Toxicology Data
Requirements 

The requirements (40 CFR 158.340) for non-food use of uniconazole are in
Table 1.  Use of the new guideline numbers does not imply that the new
(1998) guideline protocols were used.  

Test 

	Technical

	Required	Satisfied

870.1100    Acute Oral Toxicity	

870.1200    Acute Dermal Toxicity	

870.1300    Acute Inhalation Toxicity	

870.2400    Primary Eye Irritation	

870.2500    Primary Dermal Irritation	

870.2600    Dermal Sensitization		yes

yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

yes

870.3100    Oral Subchronic (rodent)	

870.3150    Oral Subchronic (nonrodent)	

870.3200    21/28-Day Dermal	

870.3250    90-Day Dermal	

870.3465    90-Day Inhalation		yes

yes

yes

no

yes	yes

yes

yes

-

no

870.3700    Developmental Toxicity (rodent)	

870.3700    Developmental Toxicity (nonrodent)	

870.3800    Reproduction		yes

yes

yes	yes

yes

yes

870.4100    Chronic Toxicity (rodent)	

870.4100    Chronic Toxicity (nonrodent)	

870.4200    Oncogenicity (rat)	

870.4200    Oncogenicity (mouse)	

870.4300    Chronic/Oncogenicity		yes

yes

yes

yes

-	yes

yes

yes

yes

yes

870.5100    Mutagenicity—Gene Mutation - bacterial	

870.5300    Mutagenicity—Gene Mutation - mammalian	

870.5xxx    Mutagenicity—Structural Chromosomal Aberrations	

870.5xxx    Mutagenicity—Other Genotoxic Effects		yes

yes

yes

yes	yes

yes

yes

yes

870.6100    Acute Delayed Neurotox. (hen)	

870.6100    90-Day Neurotoxicity (hen)	

870.6200    Acute Neurotox. Screening Battery (rat)	

870.6200    90-Day Neuro. Screening Battery (rat)	

870.6300    Develop. Neuro		no

no

no

no

no	-

-

-

-

-

870.7485    General Metabolism	

870.7600    Dermal Penetration		yes

yes	yes

yes

Special Studies for Ocular Effects

Acute Oral (rat)	

Subchronic Oral (rat)	

Six-month Oral (dog)		

no

no

no	

-

-

-

A.2	Toxicity Profile TC \l2 "A.2	Toxicity Profiles 

Table A.2.1	Acute Toxicity Profile - Uniconazole 

Guideline No.	Study Type	MRID(s)	Results	Toxicity Category

870.1100	Acute oral – rat

S-3307D, Lot PY-84013,  Purity 97.2%, E/Z =

96.2/3.8, R/S = 20.8/79.2	40345405	LD50 

M = 460 mg/kg

F = 430 mg/kg	II

870.1200	Acute dermal – rat

S-3307D, Lot No. PY-84013, Purity 97.2%, E/Z - 96.2/3.8; R/S = 20.8/79.2
40345408	LD50 > 2000 mg/kg	III

870.1300	Acute inhalation – rat

S-3307D, Lot PYG-86047. Purity 97.6%, E2 = 96.9/3.1, ES/ER = 80.6/19.4
40345409	LC50 > 2.75 mg/L	III

870.2400	Acute eye irritation – rabbit

S-3307D, Lot PY-84013, Purity 97.2%, E/Z = 96.2/3.8; R/S = 20.8/79.2
40345411	Minimally irritating	III

870.2500	Acute dermal irritation – rabbit

S-3307D, Lot PY-84013, Purity 97.2%, E/Z = 96.2/3.8; R/S = 20.8/79.2 
40345411	Not irritating	IV

870.2600	Skin sensitization – guinea pig

S-3307-D, Lot PY-84013, Purity 97.2%, E/Z =

96.2/3.8; R/S 20.8/79.2	40345412	Not a skin sensitizer	NA

There are several versions of the technical grade active ingredient that
were tested in the acute battery.  The technical uniconazole can contain
various quantities of related isomers which can alter the chemistry and
toxicology of the test substance.  The studies listed above that were
performed with the technical grade active ingredient are the studies
that provide the most protective toxicity categories.

Table A.2.2    Toxicity Studies Profile

Guideline No. 	MRID No. (year)/ Classification /Doses	Results

870.3100

Subchronic oral toxicity (rat)	40462605 (1986)

Acceptable/guideline

0, 30, 100, 1000, 3000 ppm

M: 0, 23, 7.5, 73.0, 228.0 mg/kg/day

F: 0, 2.4, 8.4, 79.4, 229.0 mg/kg/day	NOAEL = 7.5 mg/kg/day

LOAEL = 73.0 mg/kg/day based on based on changes in body weights,
hematology, lipid metabolism and effects on liver and thyroid.

870.3150

Subchronic oral (capsule) toxicity (dog)	40462606 (1986)

Acceptable/guideline

0, 5, 20, 80, 320 mg/kg/day in gelatin capsules	NOAEL = 20 mg/kg/day

LOAEL = 80 mg/kg/day based on increased alkaline phosphatase activity
(males and females) and increased liver weights (males).

870.3100

Subchronic Oral (Feeding) Toxicity Study (Mouse) 

5 weeks 	41442401 (1986)

Acceptable-Nonguideline

0, 100, 300, 1000, 3000, 10000 ppm

M: 0, 20, 58, 193, 622, 2673 mg/kg/day

F: 0, 27, 77, 274, 849, 3758 mg/kg/day	NOAEL = 58 mg/kg/day

LOAEL = 193 mg/kg/day based on the body weight changes, clinical
chemistry changes, hematology changes and liver effects. 

870.3200

Subchronic dermal toxicity – 28 day (rat)	40462607 (1987)

Acceptable/guideline

0, 5, 25, 50, 200, 500 mg/kg/day	Systemic Toxicity NOAEL = 5 mg/kg/day

Systemic Toxicity LOAEL = 25 mg/kg/day based on increased liver weight
and histopathology of the liver.

Dermal Toxicity NOAEL < 5 mg/kg/day

Dermal Toxicity LOAEL ≤ 5 mg/kg/day based on dermal irritation at all
dose levels tested.

870.3200

Subchronic dermal toxicity – 28 days (rat)

Formulation

2.66% a.i.	41162003 (1989)

Acceptable/guideline

0, 100, 500, 1000 mg/kg/day	Systemic Toxicity NOAEL ≥ 1000 mg/kg/day.

Systemic Toxicity LOAEL was not achieved.

Dermal Toxicity NOAEL ≥ 1000 mg/kg/day.

Dermal Toxicity LOAEL was not achieved.  However, the irritation noted
at all dose levels was slight.

870.3200

Subchronic dermal toxicity – 28 days (rat)

Formulation

0.05% a.i.	41162002 (1987)

Acceptable/guideline

0, 1000 mg/kg/day	Only a single dose tested.

Dermal Toxicity LOAEL ≥ 1000 mg/kg/day based on acanthosis noted.

No systemic toxicity was noted.

870.3700

Prenatal developmental toxicity (rat)	40462609 (1987)

42123201 (1991)

Acceptable/guideline

0, 1, 5, 25, 50 mg/kg/day in 0.5% CMC	Maternal Toxicity NOAEL = 5 
mg/kg/day

Maternal Toxicity LOAEL = 25 mg/kg/day based on decreased body weight.

Developmental Toxicity NOAEL = 5 mg/kg/day

Developmental Toxicity LOAEL = 25 mg/kg/day based on increased incidence
of 14th rib.

870.3700

Prenatal developmental toxicity (rabbit)	40462610 (1987)

Acceptable/guideline

0, 1, 3, 10, 20 mg/kg/day in 0.5% CMC	Maternal Toxicity NOAEL = 10 
mg/kg/day

Maternal Toxicity LOAEL = 20 mg/kg/day based on statistically
significant reduced food consumption and marginally reduced body weight
gains.

Developmental Toxicity NOAEL ≥ 20 mg/kg/day (HDT).

Developmental Toxicity LOAEL was not achieved.

870.3800

Reproduction and fertility effects

(rat)	41162004 (1989)

Acceptable/guideline

0, 15, 150, 1500 ppm

0, 0.75, 7.5, 75 mg/kg/day by standard conversion factor for older rats
Parental Systemic Toxicity NOAEL = 7.5 mg/kg/day

Parental Systemic Toxicity LOAEL = 75 mg/kg/day based on reduced body
weight and food intake, increased liver
weight‬湡⁤敨慰潴散汬汵牡攠汮牡敧敭瑮愠摮瘠捡潵楬
慺楴湯മ

Reproductive Toxicity NOAEL ≥ 75 mg/kg/day

Reproductive Toxicity LOAEL > 75 mg/kg/day

Offspring Systemic/Developmental Toxicity NOAEL = 7.5 mg/kg/day

Offspring Systemic/Developmental Toxicity LOAEL = 75 mg/kg/day based on
reduced pup growth (reduced body weight during lactation).  

870.4100

Chronic toxicity

	See 41162006 below	N/A

870.4100

Chronic Oral Toxicity (dog)

Capsule administration

52 weeks 	41162001 (1988)

Acceptable/guideline

0, 2, 20, 200 mg/kg/day in gelatin capsules	Systemic Toxicity NOAEL = 2
mg/kg/day

Systemic Toxicity LOAEL = 20 mg/kg/day based on the increased absolute
and relative liver weight changes in males supported by histological and
enzyme changes in the liver.

870.4200

Carcino-genicity

(mouse)

78 weeks 	41162005 (1988)

Acceptable/guideline

0, 10, 40, 200, 1500 ppm

Mean of both sexes

0, 1.5, 6, 30, 225 mg/kg/day	Systemic Toxicity NOAEL = 30 mg/kg/day

Systemic Toxicity LOAEL = 225 mg/kg/day based on liver lesions observed
in high-dose male and female mice.

evidence of carcinogenicity

Based on the increased incidence of hepatocellular neoplasms observed in
high-dose male mice, the chemical was reviewed by the HED Cancer Peer
Review Committee (CPRC document dated 10/11/1990). 

870.4300

Combined Chronic Toxicity/

Carcino-genicity

(rat)

104 weeks 	41162006 (1989)

Acceptable/guideline

0, 10, 40, 200, 1000 ppm

M: 0, 0.36, 1.48, 7,78, 39.41 mg/kg/day

F: 0, 0.43, 1.81, 9.37, 47.85 mg/kg/day	Systemic Toxicity NOAEL = 7.78
mg/kg/day

Systemic Toxicity LOAEL = 39.41 mg/kg/day based on reduced body weight
gain and/or an increased incidence of centrilobular hepatocellular
enlargement and vacuolization in male and female rats, and decreased
cholesterol levels in female rats.

no evidence of carcinogenicity

870.5100

Bacterial Reverse Mutation Test 	40462612 (1987)

Acceptable

1 to 500 µg/plate without S9 activation; 5 to 1000 ug/plate with S9
activation	No evidence of mutagenicity at concentrations up to the limit
of solubility with or without metabolic activitation in S. typhimurium
TA1535, TA1537, TA1538, TA98, and TAl00 and in E. coli WP2, uvrA

870.5375

In vitro mammalian chromosome aberration test (CHO)	40462613 (1987)

Acceptable

2 x 10-5 to 2 x 10-4 M without S9 activation; 5 x 10-5 to 3 x 10-4 M
with S9 activation	The nonactivated test material was not clastogenic;
however, in the presence of S9 activation, S-3307D induced a clear
dose-dependent clastogenic response.  S9-activated S-3307D is a
clastogen in this test system.

870.5385

Mammalian bone marrow chromosomal aberration test 	40462615 (1987)

Acceptable when combined with 42123203 (below)	Negative for in vivo
micronuclei induction

870.5385

Mammalian bone marrow chromosomal aberration test 	42123203 (1989)

Acceptable when combined with 40462615 (above)	Negative for in vivo
micronuclei induction

870.5550

Unscheduled DNA Synthesis in Mammalian Cells in Culture 	40936004 (1988)

Unacceptable	Conduct and reporting deficiencies

870.5900

In vitro sister chromatid exchange assay (CHO)	40462614 (1987)

Unacceptable	Negative for inducing sister-chromatid exchanges (SCEs) in
Chinese hamster ovary cells treated up to the cytotoxic concentration
range.  Top doses demonstrated weak genotoxic activity in the presence
of activation.

870.7485

Metabolism and pharmaco-kinetics

(rat)	40496701 (1987)

Acceptable	Uniconazole was rapidly absorbed, extensively metabolized,
and rapidly excreted. Over a 3-day period, most (96-99 percent) of the
test compound administered was excreted from the animals. The
radioactivity recovered in the urine, feces, and CO2 in the exhaled air
was 40-66, 33-59 and 0.1 percent of the administered dose, respectively.
Peak tissue (including plasma) concentration of radioactivity occurred 1
to 8 hours after the administration of the test compound. Three major
metabolites were identified in the urine and feces. These represent
83-91 percent of the administered dose. The metabolites of uniconazole
were two oxidation products (58-75 percent of the dose) of the methyl
moiety of the tert-butyl group and a free triazole (3-15 percent of the
dose) liberated from uniconazole.

870.7600

Dermal penetration

(rat)	40462616 (1987)

Acceptable

0.05, 0.5, 5.0 mg/rat	The 10 hour absorption value is 7.2%

A.3	Executive Summaries TC \l2 "A.3	Executive Summaries 

A.3.1	Subchronic Toxicity TC \l3 "A.3.1	Subchronic Toxicity 

	870.3100	90-Day Oral Toxicity - Rat

In a subchronic study (MRID 40462605), S-3307D (uniconazole-P technical,
purity 97.2%, batch No. PY-84013) was fed to male and female
Sprague-Dawley rats (Charles River Japan, Inc.) at dietary levels of 0,
30, 100, 1000 or 3000 ppm (0, 2.25, 7.48, 73.0 and 228.0 mg/kg/day for
males and 0, 2.42, 8.36, 79.4, and 229.0 mg/kg/day for females,
respectively based on actual consumption data from the investigators)
for 3 months.  Animals were inspected twice daily for signs of
moribundity, behavioral effects, and mortality.  The investigators also
performed a detailed physical examination of every animal.  Body weights
were recorded at study initiation and every week thereafter through
study week 13.  Food consumption and water intake values for 3
consecutive days were determined once a week for all animals. 
Ophthalmological examinations were performed prior to study initiation
in all animals, and 2 weeks before the study termination in all animals
of the high-dose and control groups.  Hematology and clinical
chemistries were determined for all animals after termination of the
feeding period, and urinalyses were performed 2 weeks prior to study
termination.  All animals that were sacrificed on schedule were subject
to gross pathological examination with collection of tissue for
histopathology and organ weight determinations.

Mean body weights were depressed in males (8, 16%) and females (14, 16%)
fed 1000 and 3000 ppm, respectively.  Slight anemia was exhibited in
males and females fed 3000 ppm and males fed 1000 ppm as evidenced by
decreased hemoglobin, hematocrit, and erythrocyte counts.  Effects on
the liver and lipid metabolism were reflected in clinical chemistry
changes of males or females fed 1000 and/or 3000 ppm S-3307D.  Principal
change included increased serum SGOT, SGPT, and LAP in males fed 3000
ppm, increased cholesterol and phospholipids in females fed 3000 and
1000 ppm, and decreased triglycerides in males fed 1000 and 3000 ppm. 
Liver weights of males and females fed 1000 or 3000 ppm and thyroid
weight of males fed 3000 ppm were increased.  Macroscopic liver changes
at 3000 ppm included liver enlargement and discolored liver in males and
females, and an increase of accentuated lobular pattern in the liver of
females.  In rats fed 1000 ppm (the LOAEL), liver enlargement was found
in males and accentuated lobular pattern in the liver was found in
females.  Histologically, males and females fed 1000 and 3000 ppm
exhibited an increase in the incidence of cloudy swelling in the liver
and an increase in the incidence of small follicles and cytoplasmic
vacuolation in the thyroid. 

The systemic toxicity NOAEL is 100 ppm (7.48 mg/kg/day for males and
8.36 mg/kg/day for females) and the systemic toxicity LOAEL is 1000 ppm
(73.0 mg/kg/day for males and 79.4 mg/kg/day for females) based on
changes in body weights, hematology, lipid metabolism and effects on
liver and thyroid.

This study is classified as Acceptable-Guideline and, as such, satisfies
the guideline requirements (OPPTS 870.3100; OPP §82-1; OECD 408) for a
subchronic toxicity study in rodents (rats).  

	870.3100	90-Day Oral Toxicity – Mouse (study was for 5 weeks)

In a subchronic study (MRID 41442401), S-3307D (technical uniconazole-P,
purity 87.2%, lot No. 84075) was administered to male and female
CRL:CD-(ICR)BR mice (Charles River Breeding Laboratories, Kingston, NY)
at dietary levels of 0, 100, 300, 1000, 3000, or 10000 ppm (0, 20.01,
58.02, 192.81, 621.69, and 2673.00 mg/kg/day for males and 0, 26.70,
76.54, 273.71, 848.98, and 3758.11 for females, respectively) for 5
weeks.  Animals were inspected twice daily for signs of moribundity and
mortality.  Cageside observations were made once daily for clinical
signs of toxicity.  Thorough physical examinations were made weekly. 
Animals found dead or killed in extremis were subjected to gross
pathological examination, including examination of external surfaces,
orifices, cranial cavity, nasal cavity, paranasal sinuses, thoracic,
abdominal, and pelvic cavities, cervical tissues and organs.  Animals
were weighed at the start of the study and then weekly thereafter.  Food
consumption was determined three times per week, and the mean weekly
food consumption was calculated.  Twelve animals per sex that were not
included in the study were used for hematology, and an additional 12
animals per sex were used for clinical chemistry.  These animals were
sacrificed prior to study start.  In addition, at study termination,
blood was collected from all surviving animals for hematology and
clinical chemistry.  Urine was collected from 12 fasted mice/sex prior
to study start for baseline urinalysis.  The mice used for this analysis
were sacrificed prior to study start.  In addition, at study
termination, urine was collected from all surviving mice for urinalysis.
 All animals that died or were sacrificed on schedule were subject to
gross pathological examination with tissues collected and preserved for
future histological examination.  The liver and kidneys from all animals
in the control and high dose groups, the livers from groups 3 (300 ppm),
4 (1000 ppm), and 5 (3000 ppm), and from all unscheduled sacrifices were
embedded in paraffin, sectioned, stained, and examined microscopically. 
Selected organs were weighed.

Dietary administration of 100, 300, 1000, 3000, and 10,000 ppm S-3307D
resulted in decreased body weight and body weight gain in high dose male
and female mice when compared to controls.  Administration of the test
compound also resulted in depression of hematopoiesis in high dose mice
(significant depression in hematocrit, hemoglobin, erythrocytes,
platelets, lymphocytes) and in disturbances in clinical chemistry in mid
and high dose mice (significantly reduced SGPT, SGOT, alkaline
phosphatase).  In addition, liver/gall bladder weights were
significantly increased in both sexes administered 1000, 3000, and 10000
ppm of uniconazole. The increased liver weights correlated with
increases in SGOT, SGPT, and alkaline phosphatase and with
hepatocellular enlargement, fatty changes, and focal and individual cell
necrosis. 

The systemic toxicity NOAEL was 300 ppm (58.02 mg/kg/day in males and
76.54 mg/kg/day in females) and the systemic toxicity LOAEL was 1000 ppm
(192.81 mg/kg/day in males and 273.71 mg/kg/day in females) based on the
body weight changes, clinical chemistry changes, hematology changes and
liver effects. 

This study is classified as Acceptable-Nonguideline and, as such, does
not satisfy the guideline requirements (OPPTS 870.3100; OPP §82-1; OECD
408) for a subchronic toxicity study in rodents.  The study was
performed to determine dosage levels for a mouse carcinogenicity study.

	870.3150	90-Day Oral Toxicity - Dog

In a subchronic study (MRID 40462606), S-3307D (uniconazole-P technical,
purity 98.2%, Batch No. PYG-85082) was fed to male and female beagles
(White Eagle Laboratories, Inc.) in gelatin capsules at dose levels of
0, 5, 20, 80, or 320 mg/kg/day for 3 months.  All animals were
continuously observed up to 2 hours at the time of study initiation and,
thereafter, at 1- to 2-hour intervals up to 9 hours after test compound
administration.  From day 2 onward, animals were inspected 4 times a day
for signs of toxicity, behavioral effects, physical changes, appetite,
and excretory status.  Body weights were recorded 2 weeks and 1 week
prior to study initiation and every week thereafter through study week
13.  Food consumption values of individual animals were determined 2
weeks prior to study initiation and every week thereafter.  The feed
efficiency was also calculated on a weekly basis.  Ophthalmological
examinations were performed prior to study initiation and at weeks 5 and
11 of the study.  Electrocardiographic examinations were conducted
before study initiation and at study week 12.  Hematology and clinical
chemistry parameters were determined prior to study initiation and at 4,
8, and 12 weeks after start of the study.  Special testing was also
conducted in the form of liver function test (BSP Retention Test) and
kidney function test (PAH retention test).  Urinalysis was performed
before study initiation and at weeks 6 and 12.  All animals that died or
were sacrificed on schedule were subject to gross pathological
examination with tissues collected for histological examination and
organ weights. 

sed serum alanine aminotransferase (SGPT) activity in the 80- and 320-
mg/kg groups, a mild increase of α2-globulin values in males and a
decrease in calcium level in females receiving 80 and 320 mg/kg/day. 
Furthermore, animals receiving 80 and 320 mg/kg/day were observed with
an increased bromsulfophthalein (BSP) retention rate.  Two animals in
the 320 mg/kg dose group were observed with an increased urine volume. 
There were no compound-related effects in the animals of control and
dosed groups on ophthalmologic, electrocardiographic, and fecal
examinations, as well as renal function para-aminohippurate (PAH)
retention testing. Pathological examination of the surviving animals
disclosed increased liver weights in males receiving 320 mg/kg/day, and
a yellowish liver and exaggerated lobular pattern in some males and
females receiving 80 and 320 mg/kg/day.  Histopathological findings were
hepatocellular enlargement and cytoplasmic vacuolation of hepatocytes in
the 80 and 320-mg/kg/day dose groups, and ballooning degeneration of the
liver in the 320 mg/kg/day group.  A high-dose male that died at week 12
had increased liver weight, yellowish, fragile liver, and exaggerated
lobular hepatic architecture: histological examination revealed diffuse
cytoplasmic vacuolation of hepatocytes.  

The systemic toxicity NOAEL is 20 mg/kg/day and the systemic toxicity
LOAEL is 80 mg/kg/day based on increased alkaline phosphatase activity
(males and females) and increased liver weights (males).

This study is classified as Acceptable-Guideline and as such satisfies
the guideline requirements (OPPTS 870.3150; OPP §82-1; OECD 409) for a
subchronic toxicity study in non-rodents (dogs). 

	870.3200	21/28-Day Dermal Toxicity – Rat

In a subchronic study (MRID 40462607), XDE-1019D (uniconazole-P, purity
97.62%, lot No. PYG-86047) was administered to male and female
Sprague-Dawley: Crl CD(SD)BR rats (Charles River Breeding Laboratories,
Portage MI) dermally at dose levels of 0, 5, 25, 50, 200, and 500
mg/kg/day for 28 days (20 applications).  Animals were inspected daily
for signs of toxicity and mortality.  Pupillary responses were examined
prior to study start, weekly during the study, and on study termination
day.  Skin irritation was measured by a modified Draize scale on study
day 1, weekly thereafter, and on study termination day.  Animals were
weighed at study start, prior to dosing, then twice weekly until study
termination.  Terminal body weights were taken after overnight fasts. 
Blood was collected from all animals at study termination for hematology
and clinical analysis.  All animals that died and that were sacrificed
on schedule were subject to gross pathological examination.  Tissues
were collected for histological examination from the control and high
dose animals.  In the mid-dose animals, only kidneys and livers were
examined.  Only liver and gross lesions were examined for the animals in
the satellite study.  Selected organs were weighed.

Dermal administration of XE-1019D to SD Crl:CD(BR) rats at dose levels
of 5, 25, 50, 200 and 500 mg/kg/day for 28 days (20 applications)
resulted in no systemic toxicity at 

5 mg/kg (LDT) but produced increased liver weight, hepatocytic
vacuolation, and centrilobular hypertrophy at doses of 25 mg/kg/day and
above.  Local dermal irritation in the form of slight skin irritation
was observed at al1 doses tested.

The systemic toxicity NOAEL is 5 mg/kg/day and the systemic toxicity
LOAEL is 25 mg/kg/day based on increased liver weight and histopathology
of the liver.  The dermal toxicity NOAEL is less than 5 mg/kg/day and
the dermal toxicity LOAEL is equal to or less than 5 mg/kg/day based on
the dermal irritation noted at all dose levels tested.

This study is classified as Acceptable-Guideline and, as such, satisfies
the guideline requirements (OPPTS 870.3200; OPP §82-2; OECD 410) for a
subchronic dermal toxicity study in rodents.  The original DER has the
wrong MRID Number, 40462617 instead of 40462607 and the Study Type was
listed as a 21-day dermal study when the study duration was actually 28
days.

In a subchronic satellite study (MRID 41162002), CC-15551
(uniconazole-P, purity 0.05%, No lot or batch number) was administered
to male and female Sprague-Dawley: Crl CD(SD)BR rats (Charles River
Breeding Laboratories, Portage MI) dermally at dose levels of 0 and 1000
mg/kg/day for 28 days (20 applications).  Animals were inspected daily
for signs of toxicity and mortality.  Pupillary responses were examined
prior to study start, weekly during the study, and on study termination
day.  Skin irritation was measured by a modified Draize scale on study
day 1, weekly thereafter, and on study termination day.  Animals were
weighed at study start, prior to dosing, then twice weekly until study
termination.  Terminal body weights were taken after overnight fasts. 
Blood was collected from all animals at study termination for hematology
and clinical analysis.  All animals that died or were sacrificed on
schedule were subject to gross pathological examination.  Tissues were
collected for histological examination from the control and dosed
animals.  Kidneys and livers were examined for gross lesions among the
dosed animals.  Selected organs were weighed.

In the study, CC-15551, when administered topically at doses of 1000 mg/
kg for five days a week for 28 days (a total of 20 treatments), caused
acanthosis in males and females and decreased weight gain in males. 

The systemic toxicity NOAEL is less than 1000 mg/kg/day and the systemic
toxicity LOAEL is equal to or less than 1000 mg/kg/day based on
decreased body weights in males.  The dermal toxicity NOAEL is less than
1000 mg/kg/day and the dermal toxicity LOAEL is equal to or less than
1000 mg/kg/day based on acanthosis noted.

This study is classified as Acceptable-Guideline and, as such, satisfies
the guideline requirements (OPPTS 870.3200; OPP §82-2; OECD 410) for a
subchronic dermal toxicity study in rodents.

In a third subchronic study (MRID 41162003), CC-15388 (XE-1019D
ES-isomer, purity 2.66% v/v active ingredient in isopropyl alcohol,
lot/batch No. SX-1805) was administered to male and female
Sprague-Dawley Crl: CD BR rats (Charles River Breeding Laboratories,
Portage MI) dermally at dose levels of 0, 100, 500, and 1000 mg/kg/day
for 28 days (20 applications).  Body weights were measured twice weekly
and terminal body weights were measured on the day of necropsy. Food
consumption was determined weekly.  Observations of signs of toxicity
were made daily and included examination of the skin, eyes, mucous
membranes, respiratory and circulatory systems, autonomic and central
nervous systems and behavior patterns.  Pupillary responses were checked
every Friday and on the last day of dosing.  Skin irritation was
evaluated weekly using the Draize method.  Blood from all animals was
evaluated for hematology and serum chemistry.  Complete necropsies were
performed on all animals and included the examination of all orifices,
all body cavities, and external body surfaces.

When doses of 0, 100, 500, and 1000 mg/kg of CC-15388, containing 2.66%
XE-1019D, were administered topically, no systemic or dermal toxicity
was noted up to the limit dose.

The systemic toxicity and dermal toxicity NOAEL is equal to or greater
than 1000 mg/kg/day and the systemic toxicity and dermal toxicity LOAEL
is greater than 1000 mg/kg/day. 

This study is classified as Acceptable-Guideline and, as such, satisfies
the guideline requirements (OPPTS 870.3200; OPP §82-2; OECD 410) for a
subchronic dermal toxicity study in rodents.  

A.3.2	Prenatal Developmental Toxicity TC \l3 "A.3.2	Prenatal
Developmental Toxicity 

	870.3700 Prenatal Developmental Toxicity Study - Rat

In a prenatal developmental toxicity study (MRID 40462609, 42123201),
S-3307D T.G., (Purity 97.2%, Lot No. PKG-84075) was administered to
pregnant female SPF Slc:SD rats (The Shizuoka Prefectural Agricultural
Cooperative Association for Laboratory Animals) orally by gavage in 0.5%
carboxymethylcellulose at dose levels of 0, 1, 5, 25, and 50 mg/kg/day
from gestation days 6 through 15, inclusive.  The pregnant animals were
observed daily for mortality and clinical signs, and were weighed on
days 0, 6, 9, 12, 15, and 20.  Food consumption was recorded on days 6,
9, 12 and 20.  On day 20, all surviving females were sacrificed, and the
pups removed by Caesarian section.  All maternal internal organs were
examined grossly, and the uterine contents, number of corpora lutea,
implantation sites, number and position of fetuses were recorded. 
Fetuses were sexed, weighed, and examined for external abnormalities. 
Half of each litter was examined by Wilson's technique for visceral
abnormalities, while half was cleared and stained with Alizarin Red S
for examination of skeletal abnormalities by a modification of Dawson's
technique. 

Maternal toxicity was noted as decreased body weight gain at 25
mg/kg/day and above.

The maternal systemic toxicity NOAEL is 5 mg/kg/day and the maternal
systemic toxicity LOAEL is 25 mg/kg/day based on decreased body weight.

Developmental toxicity was noted as increased incidence of 14th rib at
the two highest dose levels.

The developmental toxicity NOAEL is 5 mg/kg/day and the developmental
toxicity LOAEL is 25 mg/kg/day based on increased incidence of 14th rib.

This study is classified as Acceptable-Guideline and, as such, satisfies
the guideline requirements (OPPTS 870.3700; OPP §83-3; OECD 414) for a
prenatal developmental toxicity study in rats.  Additional data
requested in the original DER and by the Developmental Toxicity Peer
Review Committee were submitted and reviewed (TXR# 009684).  This study
was translated from the original Japanese report.

MRID:  41745802: Hirohashi, A. (1987) S-3307D Range-Finding Teratology
Study in Rats Uniconazole-P Technical 59639-GI: Lab Project Number: DEV
8602.  Unpublished study prepared by Sumitomo Chemical Company, Ltd.
(Dated 02/04/1987)

This study supported the primary study.

	870.3700 Prenatal Developmental Toxicity Study - Rabbit

In a prenatal developmental toxicity study (MRID 4042610), S-3307D T.G.,
(Purity 98.3%, Lot Number PYG 85105) was administered to groups of
pregnant female New England White Rabbits (16/dose, Hazleton Research
Products, Inc, Denver PA) orally by gavage in 0.5% methylcellulose at
dose levels of 0, 1, 3, 10, and 20 mg/kg/day from gestation days 7
through 19, inclusive.  The animals were checked for mortality or
abnormal condition twice daily throughout gestation.  Body weight and
food consumption were recorded on gestation days 0, 7, 8, 10, 13, 16,
19, 20, 23, 26, and 29.  All does that survived until study termination
(gestation day 29), and those showing signs of abortion or premature
delivery, were sacrificed and examined for visceral abnormalities,
number of corpora lutea, number and placement of implantation sites,
early and late resorptions, and the number of live and dead fetuses. 
Abnormal viscera were retained in 10% neutral buffered formalin.  All
fetuses were weighed, sexed, and examined for external, visceral and
skeletal malformations.  Fetal visceral examination was done using a
modification of Staples technique.  Malformations and representative
genetic developmental variations were photographed.  Following visceral
examination, fetuses were eviscerated, skinned, and the skeletons fixed
and stained with Alizarin Red S solution.  Skeletal anomalies, degree of
ossification, and bone alignment were evaluated and recorded as either
variations or malformations.

Maternal toxicity was noted at the 20 mg/kg/day dose level as
statistically significant reduced food consumption and marginally
reduced body weight gains. 

The maternal systemic toxicity NOAEL is 10 mg/kg/day and the maternal
systemic Toxicity LOAEL is 20 mg/kg/day based on statistically
significant reduced food consumption and marginally reduced body weight
gains.

 

No developmental toxicity was noted at the dose levels tested.

The developmental toxicity NOAEL is equal to or greater than 20
mg/kg/day and the developmental toxicity LOAEL is greater than 20
mg/kg/day.

This study is classified as Acceptable-Guideline and, as such, satisfies
the guideline requirements (OPPTS 870.3700; OPP §83-3; OECD 414) for a
prenatal developmental toxicity study in rabbits.  Additional data
requested in the original DER and by the Developmental Toxicity Peer
Review Committee were submitted and reviewed (TXR# 008136, and 008329). 

MRID:  41745801: Morseth, S.; Dyke, S. (1986) Range-Finding Rabbit
Teratology Study S-3307 Uniconazole-P Technical 59639-GI: Lab Project
Number: 343-171.  Unpublished study prepared by Hazleton Laboratories
America, Inc.  Dated 10/23/1986 

In support of the NOAEL/LOAEL decisions for the rabbit prenatal
development toxicity study (MRID 4046210), a range finding rabbit
prenatal study was submitted.  In this study (MRID 41745801) groups of
five rabbits were tested at 0, 10, 30, 50, 100, or 300 mg/kg/day on
gestation days 7 to 19.  Does were sacrificed on day 29 and the fetuses
were removed by caesarian section.  All rabbits in groups 5 (100
mg/kg/day) and 6 (300 mg/kg/day) died or were sacrificed in extremis on
or before gestation Day 15.  One rabbit in group 4 (50 mg/kg) was found
dead on gestation Day 19 and one was sacrificed in extremis on gestation
Day 27.  Two rabbits in group 3 (30 mg/kg/day) aborted (days 25 and 28)
and one was found dead on gestation Day 19. A dose-related increase in
the incidence of anorexia was seen during the treatment period in groups
2-6.  All rabbits in groups 4, 5, and 6 were languid on at least two
occasions during treatment.  Two animals in group 3 and three animals in
group 4 also appeared languid during the post-treatment period.  Mean
body weights during and after the treatment period were reduced compared
to the controls in pups from groups 3 and 4. Mean body weights in group
2 were similar to the control values throughout the study, although mean
food consumption was slightly below the control levels during the last
half of treatment.  These results support, and are consistent with, the
results of the high dose tested group (20 mg/kg/day) in the main rabbit
developmental toxicity study.

A.3.3	Reproductive Toxicity TC \l3 "A.3.3	Reproductive Toxicity 

	870.3800 Reproduction and Fertility Effects - Rat

In a reproductive toxicity study (MRID 41162004), S-3307D (Purity 98.3%,
Lot No. PYG-85105) was administered to groups of male and female Crl:CD
(SD)BR albino rats (30/sex/dose, Charles River Laboratories, Inc,
Portage MI) in the diet at dietary levels of 0, 15, 150, and 1500 ppm
(0, 0.75, 7.5, 75 mg/kg/day by standard conversion values for the older
rat, actual compound consumption was not provided by the investigators).
 After at least 8 weeks of dietary treatment for F0 and 12 weeks for F1,
parental animals, each male was cohabitated with one female from the
same group to produce one litter.  During cohabitation, the females were
examined daily to determine the presence of a copulatory plug or sperm. 
The day on which mating was confirmed by the presence of a copulatory
plug or sperm was designated day 0 of gestation.  Females were placed in
nesting boxes regardless of mating status.  Animals were observed twice
daily for mortality and moribundity and once daily for overt signs of
toxicity (cageside observations).  At the time of weighing, each animal
was thoroughly examined.  Body weights were recorded weekly during
treatment, at terminal sacrifice, weekly during mating, and on gestation
days (GD) 0, 7, 14, and 20.  Dams producing litters were weighed on days
0, 4, 7, 14, and 21 postpartum, and weekly thereafter until terminal
sacrifice.  Food consumption was recorded weekly during the premating
period for males and females and, during gestation and lactation, for
females that were presumed pregnant or had delivered a litter. 
Following the mating period, weekly food consumption was recorded for
males, females for which mating was not confirmed, and postlactation
females.  During the mating period, food consumption was not recorded. 
The following data were recorded for each litter:  number of pups alive
and dead at birth and on days 4, 7, 14, and 21 postpartum; body weights
of live pups on days 0, 4, 7, 14, and 21 postpartum; observations for
clinical signs of toxicity on days 0, 4, 7, 14, and 2 1 postpartum; and
daily cageside observations and pup counts on each litter.  On day 4 of
lactation, all litters were reduced to eight pups (four/sex if
possible).  Pups removed on day 4 postpartum and any pups found dead
during lactation were subjected to a gross examination to identify
external or visceral abnormalities.  Each litter was weaned on day 21 of
lactation.  Two male and two female pups from each litter were randomly
selected as potential Fl parental animals (final selection made on day
28).  On day 28 postpartum, the remaining F1 pups were sacrificed and
subjected to a gross examination of cervical, thoracic, and abdominal
viscera for macroscopic abnormalities.  Gross lesions from all pups
examined were preserved in 10% neutral buffered formalin.  The F2 pups
were evaluated in the same way as the F1 pups on days 21-23 of
lactation.  Following weaning and selection of the F1 pups, the F1 males
and females were weighed and sacrificed.  Liver weight from all animals
was recorded.  Reproductive organ tissues were preserved for possible
histopathological examination.  The F1 males and females were sacrificed
according to the same regimen following weaning and sacrifice of the F1
pups.  The tissues listed above from all F0 and F1 control and high-dose
rats, as well as from all males and females failing to produce a litter,
were examined microscopically.  Microscopic evaluation of gross lesions
from all animals and livers from F1 low- and mid-dose groups was
conducted.  

Parental systemic toxicity was evidenced by reduced body weight and food
intake, increased liver weight, and hepatocellular enlargement and
vacuolization at 1500 ppm.

The parental systemic toxicity NOAEL is 150 ppm (7.5 mg/kg/day) and the
parental systemic toxicity LOAEL is 1500 ppm (75 mg/kg/day) based on
reduced body weight and food intake, increased liver weight, and
hepatocellular enlargement and vacuolization.

Fertility and length of gestation were unaffected by ingestion of the
test material in the diet. 

The reproductive toxicity NOAEL is equal to or greater than 1500 ppm (75
mg/kg/day) and the reproductive toxicity LOAEL is greater than 1500 ppm
(75 mg/kg/day).  This is a change from the original DER.

A non-significant decrease in the viability index was noted among pups
in the high-dose group (historical control data were not submitted). 
Pup growth was adversely affected at the highest dose level for both
generations. Decreased body weights were seen starting on day 4 of
lactation. 

The offspring systemic/developmental toxicity NOAEL is 150 ppm (7.5
mg/kg/day) and the offspring systemic/developmental toxicity LOAEL is
1500 ppm (75 mg/kg/day) based on reduced pup growth (reduced body weight
during lactation).

This study is classified as Acceptable-Guideline and, as such, satisfies
the guideline requirements (OPPTS 870.3800; OPP §83-4; OECD 416) for a
reproduction and fertility effects study in rats

A.3.4	Chronic Toxicity TC \l3 "A.3.4	Chronic Toxicity 

	870.4100 Chronic Toxicity – Rat

	See 870.4300 below

	870.4100 Chronic Toxicity - Dog

In a chronic toxicity study (MRID 41162001), S-3307D (Purity: 97.4%, Lot
Number PYG 86112) was administered to groups of male and female beagles
(6/sex/dose, Hazleton Research Animals, Cumberland VA) in capsules at
dose levels of 0, 2, 20, and 200 mg/kg/day for 52 weeks.  Animals were
inspected twice daily for mortality and signs of toxicity.  Once per
week, each animal was observed for behavior and movement, and the limbs,
head and external orifices were examined.  Dogs were weighed before
treatment, and once each week thereafter.  Food consumption was measured
and recorded weekly.  An indirect ophthalmoscopic examination was
conducted for each dog prior to treatment initiation and during weeks 26
and 52.  Blood was collected from each dog prior to study initiation and
during weeks 13, 26, 39, and 52 for hematology and serum chemistry
analyses.  Dogs were fasted overnight prior to blood collection.  Urine
samples were collected prior to treatment and during weeks 13, 26, 39,
and 52 for evaluation.  All dogs were sacrificed following 52 weeks of
treatment, and complete gross necropsies were performed.  Tissues were
collected and fixed.  Selected organs were weighed.

Absolute and relative (to body weight) liver weights were significantly
increased in male and female dogs receiving 200 mg/kg/day, and in males
receiving 20 mg/kg/day.  Changes in the liver weights of high-dose
animals corresponded with histological changes in the liver, including
hepatocellular enlargement with increased cytoplasmic homogeneity and
increased bile pigment.  Alterations in the adrenal, kidney, and thymus
weights were also seen, but there were no corresponding histological
changes in these organs.  Alkaline phosphatase activity was
significantly elevated in both sexes receiving 200 mg/kg/day.  Mean body
weight gains were significantly reduced in high-dose males and females
at weeks 0-4, and in high-dose males at weeks 0-52.  Alterations in
platelet counts were not considered to be of toxicologic significance. 
There was no effect of dosing on mortality.

The systemic toxicity NOAEL is 2 mg/kg/day and the systemic toxicity
LOAEL is 20 mg/kg/day based on the increased absolute and relative liver
weight changes in males supported by histological and enzyme changes in
the liver.

This study is classified as Acceptable-Guideline and, as such, satisfies
the guideline requirements (OPPTS 870.4100; OPP §83-1; OECD 452) for a
chronic toxicity study.

A.3.5	Carcinogenicity TC \l3 "A.3.5	Carcinogenicity 

	870.4200 Carcinogenicity Study - rat

	

	See 870.4300 below

	870.4200 Carcinogenicity (feeding) - Mouse

In a carcinogenicity study (MRID 41162005), S-3307D (Purity: 98.3%, Lot
Number PYG 85105) was administered to groups of male and female Crl:CD-1
(ICR)BR mice (50/sex/dose, plus satellite groups of 30/sex/dose, Charles
River Laboratories, Inc., Kingston NY) at dietary levels of 0, 10, 40,
200, and 1500  ppm (a mean of both sexes of 0, 1.5, 6, 30, and 225
mg/kg/day, respectively) for 78 weeks.  Animals were inspected twice
daily for signs of morbidity and mortality.  Observations for overt
signs of toxicity were performed daily, and detailed physical
examinations were performed twice weekly.  Mice were weighed weekly from
week 1 through week 14, and once every 4 weeks thereafter.  Food and
water consumption were recorded weekly for weeks 1-14 and once every 4
weeks thereafter.  Ophthalmological examinations were not performed, but
opacity was recorded weekly.  Blood samples were collected from the
first 10 mice/sex/satellite group at week 52 and from 10 randomly
selected mice/sex/main group at termination.  Blood samples were
collected from animals sacrificed in extremis for differential leukocyte
counts.  Clinical chemistry and urinalysis parameters were not
investigated.  All animals that died, were found moribund, or sacrificed
on schedule, were subjected to gross pathological examination of
external surface, all orifices, cranial cavity, external surface of the
brain, nasal cavity and paranasal sinuses, and internal organs.  Tissues
were collected for histological examination.  Selected organs were
weighed.

Compound-related changes were noted in the livers of high-dose (1500
ppm) mice of both sexes. These changes included diffuse hepatocellular
enlargement and vacuolization, focal chronic inflammation and necrosis,
and pigmented macrophages.  The incidence of preneoplastic lesions
(hyperplasia and/or cellular alteration) was not increased in the high
dose animals.  Amyloidosis was present in 28 to 70% of the liver
sections examined.  Amyloidosis was a leading cause of death and was
noted in substantial incidences in virtually all of the tissues
examined.  The incidence of hepatocellular adenomas was significantly
increased (p <0.01) in male mice at the high dose (1500ppm) level.  The
incidence of hepatocellular carcinomas was increased, but not at a level
of statistical significance in male mice dosed at 1500 ppm.  The
significance of the increased incidence of hepatocellular neoplasms is
difficult to interpret because of the differences in survival of the
control group (45%) and high-dose (1500 ppm) males (76%) at terminal
sacrifice.  When adenomas and carcinomas were combined, the incidence
was significantly increased (p <0.01) at the high-dose level.  The
incidence of these neoplasms in female mice was similar to that observed
in the controls; hence there was no evidence of carcinogenicity in
female mice administered uniconazole at 1500 ppm in the diet. 
Historical data for hepatocellular adenomas in male CD-1 mice showed a
mean incidence of 6.3% with a range of 0-16%.  For hepatocellular
carcinomas, the mean incidence was 14.4% with a range of 6-20%. 
Historical data for the mean incidence of combined hepatocellular
adenomas/carcinomas were not given.  In the present study, the
concurrent control value is low (2%) for hepatocellular carcinomas, and
the high-dose level incidence is not above the historical mean.  There
is no apparent effect on time-to-tumor incidence; however, most
hepatocellular tumors were seen at the terminal sacrifice.  A variety of
other spontaneous disease lesions were observed, but their types and
frequencies were within the range expected for the age and strain of
mice. 

It appears that the animals might have tolerated higher doses. 
Weight-gain data showed that doses were not adequate for females.  Based
on the 10.8% decrement in weight gain in the high dose animals, the
doses may have been adequate for the males.

The systemic toxicity NOAEL is 200 ppm (30 mg/kg/day) and the systemic
toxicity LOAEL is 1500 ppm (225 mg/kg/day) based on liver lesions
observed in high-dose male and female mice.

Based on the increased incidence of hepatocellular neoplasms observed in
high-dose male mice, the chemical was a candidate for review by the HED
Cancer Peer Review Committee (CPRC document dated 10/11/1990). 

HED’s Cancer Peer Review Committee met on July 25, 1990 to discuss and
evaluate the weight-of-the-evidence for uniconazole with special
reference to its carcinogenic potential.  Based on all information
available, the Committee concluded that uniconazole should be placed in
Group C, possible human carcinogen.  This classification was based upon
increased incidence of hepatocellular adenomas, carcinomas, and
adenomas/carcinomas combined in male CD-1 mice.  Quantification of
potential human cancer risk, using the low dose extrapolation model
(Q1*) was not recommended.  Therefore, the Reference Dose (RfD) approach
will be used for the quantification of potential human risk.

The high dose tested was considered to be adequate for carcinogenicity
testing, although it appears that females could have tolerated a higher
dosage.

This study is classified as Acceptable/Guideline and, as such, satisfies
the guideline requirements (OPPTS 870.4300; OPP §83-5; OECD 453) for a
combined chronic toxicity/carcinogenicity study.

A.3.5.1	Combined Chronic Toxicity/Carcinogenicity TC \l3 "A.3.5
Carcinogenicity 

	OPPTS 870.4300 Combined Chronic Toxicity/Carcinogenicity Study - rat

In a combined chronic toxicity/carcinogenicity study (MRID 41162006),
S-3307D (Purity: 98.3%, Lot Number PYG 85105) was administered to groups
of male and female Crl:CD(BR)SD rats (50/sex/dose, plus satellite groups
of 40/sex/dose, Charles River Laboratories, Inc., Portage MI) at dietary
levels of 0, 10, 40, 200, and 1000  ppm (0, 0.36, 1.48, 7.78, and 39.1
mg/kg/day for males and 0, 0.43, 1.81, 9.37, and 47.85 mg/kg/day for
females, respectively) for 104 weeks.  Animals were inspected twice
daily for mortality and moribundity.  Detailed clinical observations
were performed weekly through week 104.  Observations for overt signs of
toxicity were performed daily.  Individual body weights, food
consumption, and water consumption were recorded weekly for weeks 1-14
and once every 4 weeks thereafter.  Ophthalmoscopic examinations were
performed on all rats prior to study initiation, on satellite groups of
10 rats per sex scheduled for interim sacrifice, and on all rats prior
to study termination.  Blood was collected at weeks 13, 26, 53, 78, and
104 for hematology and clinical analyses from 20 rats/sex/group of the
satellite animals.  Ten of the 20 rats were bled for hematological
examination.  The remaining 10 rats were bled for clinical chemistry
analysis.  Urinalyses were performed on 20 rats/sex/group at 13, 26, 53,
78, and 104 weeks.  All animals that died and that were sacrificed
(scheduled or unscheduled) were subjected to gross pathological
examination.  Tissues were collected for histological examination. 
Selected organs were weighed.

Male and female rats [stated as mice in DER] receiving 1000 ppm
exhibited increased incidences of hepatocellular vacuolation and
enlargement.  Body weight gains were decreased by more than 10% in both
sexes fed uniconazole at a dietary level of 1000 ppm for 78 weeks. 
Liver-to-body weight ratios were significantly increased in both males
and females treated with 1000 ppm uniconazole at weeks 53 and 104. 
Total cholesterol values were significantly increased, and apparently
treatment-related, in females receiving 1000 ppm at weeks 13, 26, 53,
and 104. There were no increases in neoplastic findings related to
dosing with uniconazole.  There was no effect of dosing on mortality or
food consumption. 

The systemic toxicity NOAEL is 200 ppm (7.78 mg/kg/day for males and
9.37 mg/kg/day for females) and the systemic toxicity LOAEL is 1000 ppm
(39.41 mg/kg/day for males and 47.85 mg/kg/day for females) based on
reduced body weight gain and/or an increased incidence of centrilobular
hepatocellular enlargement and centrilobular hepatocellular
vacuolization in male and female rats, and decreased cholesterol levels
in female rats. 

The study was conducted at adequate doses for assessment of
carcinogenicity potential as indicated by the decreased body weight gain
in high-dose male and female rats.

This study is classified as Acceptable/Guideline and, as such, satisfies
the guideline requirements (OPPTS 870.4300; OPP §83-5; OECD 453) for a
combined chronic toxicity/carcinogenicity study.

A.3.6	Mutagenicity TC \l3 "A.3.6	Mutagenicity 

	870.5100 – Bacterial Reverse Mutation Test 

In Salmonella typhimurium and Escherichia coli/mammalian activation
preincubation mutagenicity assays (MRID 40462612) (S-3307D, Purity:
97.2%, Lot No. PY-84013, solvent DMSO) six concentrations of S-3307D
without S9 activation (1 to 500 micrograms/plate) and six concentrations
with S9 activation (5 to 1000 micrograms/plate) were evaluated for the
ability to induce reverse mutations in S. typhimurium TA1535, TA1537,
TA1538, TA98, and TAl00 and in E. coli WP2, uvrA in two independent,
preincubation assays.

Doses greater than or equal to 1000 micrograms/plate with or without S9
activation were insoluble.  Doses greater than or equal to 500
micrograms/plate without S9 activation were cytotoxic; no cytotoxicity
was observed under S9-activated conditions. No appreciable increase in
reversion to histidine prototrophy was seen in the S. typhimurium
strains, and no increase in reversion to tryptophan prototrophy was
noted in E. coli WP2, uvrA at any assayed level with or without S9
activation. It was concluded, therefore, that S-3307D was evaluated to
an appropriate cytotoxic dose in the nonactivated tests and to the limit
of solubility in the S9-activated experiments with no indication of a
mutagenic effect.

This study is classified as Acceptable and as such satisfies the
guideline requirements (OPPTS 870.5100 [OPP §84-2]; OECD 471) for a
Bacterial Reverse Mutation Test.

870.5375 - In vitro mammalian chromosome aberration test (CHO)

In an in vitro chromosomal aberration test in Chinese hamster ovary
cells (CHO-K1) (MRID 40462613) (S-3307D, Purity: 98.2%, Lot No.
PYG-85082, solvent DMSO) four nonactivated (2 x 10-5 to 2 x 10-4 M) and
four S9-activated doses (5 x 10-5 to 3 x 10-4 M) S-3307D were evaluated
for cytogenetic effects in Chinese hamster ovary (CHO) cells. Due to
severe cytotoxicity at doses greater than or equal to 3 x 10-4 M (less
than or equal to 2% cell survival), cultures exposed to the nonactivated
doses were harvested at 24 and 48 hours. 

Results indicated that without S9 activation, S-3307D did not induce a
clastogenic response.  Under S9-activated conditions, the highest
assayed dose was cytotoxic; cell survival at this level was less than
10% and no metaphase plates were recovered. The remaining S9-activated
doses (5 x 10-5, 1 x 10-4 and 2 x 10-4 M) induced dose-related increases
in the percent of cells with structural aberrations; the increases were
significant at 1 x 10-4 M (p less than 0.05) and 2 x 10-4 M (p less than
0.01). 

It was concluded, therefore, that the nonactivated test material was not
clastoqenic; however, in the presence of S9 activation, S-3307D induced
a clear dose-dependent clastogenic response.  S9-activated S-3307D is a
clastogen in this test system.

This study is classified as Acceptable and as such satisfies the
guideline requirements (OPPTS 870.5375 [OPP §84-2]; OECD 476) for an
in vitro mammalian chromosome aberration test (CHO).

870.5385 - Mammalian bone marrow chromosomal aberration test

In a mammalian bone marrow chromosomal aberration test (MRID 40462615)
(S-3307D, Purity: 98.2%, Lot No. PYG-85082, solvent DMSO) two mouse
micronucleus assays were conducted with S-3307D. 

In the first assay, male mice (six/group) received a single
intraperitoneal (i.p.) injection of

400 mg/kg S-3307D; bone marrow cells were collected and analyzed for
micronuclei induction in polychromatic erythrocytes (PCEs) 24, 48, and
72 hours post-treatment. 

In the second experiment, groups of six male mice were administered
single i.p. doses of 100, 200, and 400 mg/kg; cells were evaluated 72
hours post-exposure. 

Results indicated that the highest assayed dose was severely toxic
(paralysis, reduced body-weight gain, and reduced food and water
consumption). Less intense signs of compound toxicity were seen in
animals treated with the low and mid doses: these levels did not induce
increases in PCEs with micronuclei (MPEs) or adversely affect
hematopoiesis. Slight but significantly increased (p less than 0.01)
MPEs were observed in bone marrow cells 72 hours after treatment with
400 mg/kg; however, increased micronuclei induction was accompanied by
marked PCE suppression. The study authors did not consider this effect
to be genotoxic and concluded that increased MPEs resulted from compound
toxicity associated with food and water deprivation. Data were furnished
from a micronucleus assay conducted on mice deprived of food and water
for 3 days to support this conclusion. Based on our review of the data,
we agree with the study authors that S-3307D was biologically active but
not likely to be genotoxic in this test system. However, the study was
not performed with female mice; therefore, the overall biological
significance of these findings cannot be established.  However, when
combined with MRID 42123203 for female mice, the assay is considered
negative for in vivo micronuclei induction.

This study is classified as Acceptable when combined with MRID 42123203
for female mice in a mammalian bone marrow chromosomal aberration test
and both studies together as such satisfies the guideline requirements
(OPPTS 870.5385 [OPP §84-2]; OECD 475), hence this category of the
mutagenicity battery is satisfactory for regulatory purposes.

In a mammalian bone marrow chromosomal aberration test (MRID 42123203)
(S-3307D, Purity: 98.2%, Lot No. PYG-85082), marginal increases over
concurrent controls in micronuclei at an i.p. dose of (400 mg/kg)
causing both severe clinical toxicity as well as cytotoxicity, but
micronuclei incidences within background values; hence the assay is
considered negative for in vivo micronuclei induction.

This study is classified as Acceptable when combined with MRID 4046215
for male mice in a mammalian bone marrow chromosomal aberration test and
both studies together as such satisfies the guideline requirements
(OPPTS 870.5385 [OPP §84-2]; OECD 475), hence this category of the
mutagenicity battery is satisfactory for regulatory purposes.

870.5550 - Unscheduled DNA Synthesis in Mammalian Cells in Culture 

In an unscheduled DNA synthesis in mammalian cells in culture assay
(MRID 40936004) (S-3307D, Purity: 97.7%, Lot No. PYG-85082), the data
presented demonstrate that under the test conditions S-3307D did not
induce unscheduled DNA synthesis in hepatocytes of male Sprague-Dawley
rats when the test chemical was administered as a single oral dose of
300 mg/kg 12, 24, or 48 hours prior to harvest of the hepatocytes. 

Data available to Toxicology Branch indicate that the rats were treated
at adequate dosage. Deficiencies noted in the Discussion portion of this
document make the study Unacceptable for regulatory purposes. 

The information presented demonstrate that administration of S-3307D to
male Sprague Dawley rats at a single oral dose of 300 mg/kg did not
result in an increase in unscheduled DNA synthesis in hepatocytes when
harvested at 12, 24, or 48 hours post compound administration. Data in
Toxicology Branch's files indicate that the acute oral LD50 in male rats
is 460 (341-621) mg/kg, and 430 (323-572) mg/kg in female rats. 

However, deficiencies in the conduct and reporting of this study render
it Unacceptable for regulatory purposes. Among the deficiencies are:
although the investigators stated that there were 5 animals/group, only
three per group were used for the UDS assay, and the others were not
accounted for; no cells were collected from one animal in the 24 how
sacrifice group; the cultures were not done in duplicate; no
acceptability or evaluation criteria were specified. 

This study is classified as Unacceptable and as such does not satisfy
the guideline requirements (OPPTS 870.5550 [OPP §84-2]; OECD 482) for
an unscheduled DNA synthesis in mammalian cells in culture assay.

870.5900 - In vitro sister chromatid exchange assay (CHO) 

In an in vitro sister chromatid exchange assay (MRID 40462614) (S-3307D,
Purity: 98.2%, Lot No. PYG-85082, solvent DMSO) 

Reported as negative for inducing sister-chromatid exchanges (SCEs) in
Chinese hamster ovary cells treated up to the cytotoxic concentration
range, the top doses of which, however, provide evidence for weak
genotoxic activity in the presence of activation.

In view of the positive results obtained for chromosomal aberration and
DNA damage/repair the HED Peer Review Committee recommends that a
dominant lethal assay be performed to further assess the potential of
uniconazole to induce genetic effects in germ cells.

This study is classified as Unacceptable and as such does not satisfy
the guideline requirements (OPPTS 870.5900 [OPP §84-2]; OECD 479) for
an in vitro sister chromatid exchange assay (CHO) pending submission of
additional data and/or information specified in the Toxicology Branch
Evaluation (TXR# 008136).								

A.3.7	Neurotoxicity TC \l3 "A.3.7	Neurotoxicity 

	870.6100 Delayed Neurotoxicity Study - Hen

	Study not required

	870.6200 Acute Neurotoxicity Screening Battery

	Study not required, no evidence of neurotoxic effects in submitted
studies.

	870.6200 Subchronic Neurotoxicity Screening Battery

	

	Study not required, no evidence of neurotoxic effects in submitted
studies.

	870.6300 Developmental Neurotoxicity Study

	Study not required, no evidence of neurotoxic effects in submitted
studies.

A.3.8	Metabolism TC \l3 "A.3.8	Metabolism 

	870.7485	Metabolism - Rat

In a metabolism study (MRID 40496701),
(S)-(E)-1-1-(p-chlorophenyl)-4,4-dimethyl-2-(1,2,4-triazol-1-
y1)-1-penten-3-ol (Purity: 99.9%, E/Z=l00/0, R/S=0.2/99.8, Lot No.
LN40902) and 14C labeled uniconazole (Purity 99%, specific activity 36.1
mCi/mmol) were administered to male and female Sprague-Dawley rats
(Charles River Japan, Inc.) to determine the absorption, distribution,
metabolism, and excretion of 14C-uniconazole when administered by oral
gavage.    A “Core Study” was conducted with low (1 mg/kg) and high
(200 mg/kg) dose groups and a repeated dose (14 daily dose of 1 mg/kg)
group.  In a separate tissue distribution study, 18 rats were dosed with
1 mg/kg and sacrificed in sets of three from 1 to 72 hours after
administration. Urine, feces, expired air (CO2), and tissues were
collected and analyzed for radioactivity.  Metabolites of uniconazole
were identified in the feces and urine from the “Core Study” and
selected tissues from the tissue distribution study.

Uniconazole was rapidly absorbed, extensively metabolized, and rapidly
excreted.  Over a 3-day period, most (96-99 percent) of the test
compound administered was excreted from the animals. The radioactivity
recovered in the urine, feces, and CO2 in the exhaled air was 40-66,
33-59 and 0.1 percent of the administered dose, respectively.  Peak
tissue (including plasma) concentration of radioactivity occurred 1 to 8
hours after the administration of the test compound.  Five metabolites
were identified in the urine and feces.  These represent 83-91 percent
of the administered dose.  The metabolites of uniconazole were two
oxidation products (58-75 percent of the dose) of the methyl moiety of
the tert-butyl group and a free triazole (3-15 percent of the dose)
liberated from uniconazole.  The proposed metabolic pathway for
uniconazole provided by the investigators is attached to the DER.

This study is classified as Acceptable and, as such, satisfies the
guideline requirements (OPPTS 870.7485 [OPP §85-1]; OECD 417) for a
metabolism and pharmacokinetic study in rats.

	870.7600	Dermal Absorption - Rat

In a dermal penetration (absorption) study (MRID 40462616),
[14C-U-Pheny1]-XE-10l9D (99.4% radiochemical purity, 206,000
dpm/microgram specific activity) was suspended in deionized water
containing 0.5% TWEEN 80 and applied topically in single doses of 0.05
(Group I), 0.5 (Group II), and 5.0 (Group III) mg of XE-1019D per rat
onto an unabraded 10 cm2 application site on the shaved dorsal trunk of
each of 12 rats per dose group.  Following application of the test
material, groups of four male rats from each dose group were placed
individually into MetrapR restraining metabolism chambers for either 2,
10, or 24 hours, and urine, feces, and volatiles were collected.  After
each exposure period, the animals were sacrificed, and the skin from the
application site, blood, carcass, and excreta were measured for
radioactivity.  The average total recovery of 14C applied was 94 .0%
(75.6% to 111.3%) in Group I, 101.3% (88.4% to 112.8%) in Group II, and
99.9% (74.8% to 104.8%) in Group III.

Application to a 10cm2 area of the rat's back resulted in the following
percent absorption:

							

Exposure

Time

(hrs)	0.05 mg/rat	0.5 mg/rat	5.0 mg/rat

	On/In

Skin	Skin

Wash	Absorbed

%	On/In

Skin	Skin

Wash	Absorbed

%	On/In

Skin	Skin

Wash	Absorbed

%

2	33.2	47.4	2.2	36.8	64.1	0.3	12.7	90.2	0.1

10	38.9	58.0	7.2	37.7	66.3	1.8	10.8	92.2	0.3

24	23.7	52.0	17.4	42.5	51.2	3.6	14.1	76.1	0.8

The 10-hour absorption value is 7.2%.

This study is classified as Acceptable and, as such, satisfies the
guideline requirements (OPPTS 870.7600 [OPP §85-3]; OECD none) for a
dermal penetration (absorption) study in rats.

A.4. 	References (in MRID order) 

40345405

Hiromori, T. (1987) Acute Oral Toxicity of S-3307D in Rats: Study No.
A-84-007.  Unpublished study prepared by Sumitomo Chemical Co., Ltd.  45
p. 

40345406

Suzuki, T. (1987) Acute Oral Toxicity of S-3307D in Rats: Study No. 491.
 Unpublished study prepared by Sumitomo Chemical Co., Ltd. 37 p. 

40345407

Kohda, A. (1987) Acute Oral Toxicity of S-3307D in Dogs: Study No. GTL
8410.  Unpublished study prepared by Sumitomo Chemical Co., Ltd.  51 p. 

40345408

Omodaka, H. (1987) Acute Dermal Toxicity of S-3307D in Rats: Lab. Proj.
ID. ACT 85010.  Unpublished study prepared by Sumitomo Chemical Co.,
Ltd.  25 p. 

40345409

Suzuki, T. (1987) Acute Inhalation Toxicity of S-3307D in Rats: Study
No. 598.  Unpublished study prepared by Sumitomo Chemical Co., Ltd.  44
p. 

40345410

Kohda, H. (1987) Acute Inhalation Toxicity of S-3307D in Rats: Study No.
401.  Unpublished study prepared by Sumitomo Chemical Co., Ltd.  36 p. 

40345411

Chazono, Y. (1987) Primary Eye and Skin Irritation Tests with S- 3307D
in Rabbits: Study No. IRI8512.  Unpublished study prepared by Sumitomo
Chemical Co., Ltd.  24 p. 

40345412

Chazono, Y. (1987) Skin Sensitization Test with S-3307D in Guinea Pigs:
Study No. ANT8504.  Unpublished study prepared by Sumitomo Chemical Co.,
Ltd.  23 p. 

40345413

Cushman, J. (1987) The Acute Oral Toxicity of CC-15399 (SX-1748) in
Adult Male and Female Rats: Study No. CEHC 2698.  Unpublished Study
prepared by Chevron Environmental Health Center, Inc. 82 p. 

40345414

Cushman, J. (1987) The Acute Dermal Toxicity of CC-15399 (SX-1748) in
Adult Male and Female Rats: Study No. CEHC 2699.  Unpublished study
prepared by Chevron Environmental Health Center, Inc. 23 p. 

40345415

Cushman, J. (1987) The Acute Eye Irritation Potential of CC-15399
(SX-1748) [on Rabbits]: Study No. CEHC 2697.  Unpublished study prepared
by Chevron Environmental Health Center, Inc.  23 p. 

40345416

Cushman, J. (1987) The Four-hour Skin Irritation Potential of CC- 15399
(SX-1748) [on Rabbits]: Lab. Proj. ID. CEHC 2696.  Unpublished study
prepared by Chevron Environmental Health Center, Inc.  11 p. 

40345417

Cushman, J. (1987) Modified Buehler Test for the Skin Sensitization
Potential of CC-15399 [on Guinea Pigs]: Lab. Proj. ID. CEHC 2700. 
Unpublished study prepared by Chevron Environmental Health Center, Inc. 
37 p. 

40462605

Murakami, M.; Nakamura, J.; Yoshioka, K; et al. (1986) Three-month
Subacute Toxicity Study of S-3307D in Rats: Laboratory Project ID
F-84-03.  Unpublished study performed by Sumitomo Chemical Company,
Japan.  364 p. 

40462606

Kohda, A.; Yamamoto, T.; Yoshioka, K.; et al. (1986) Three-Month
Subacute Oral Toxicity Study of S-3307D in Dogs: Laboratory Project ID
GLT 8505.  Unpublished study performed by Sumitomo Chemical Company. 
271 p. 

40462607

Brorby, G.; Rosenberg, D.; Wong, Z. (1987) Revised Twenty-Eight Day
Dermal Toxicity Study of XE-1019D Technical (SX-1710) in Male and Female
Rats: Laboratory Project ID CEHC 2597.  Unpublished study performed by
Chevron Environmental Health Center.  542 p. 

40462608

Morseth, S. (1987) Combined Toxicity and Oncogenicity Study in Rats with
S-3307D T. G.: One-Year Interim Report: Laboratory Project ID 343-191. 
Unpublished study performed by Hazleton Laboratories America, Inc.  1156
p. 

40462609

Hirohashi, A.; Kawamura, S.; Kato, T.; et al. (1987) Teratology Study of
S-3307D in Rats: Laboratory Project ID DEV 8603. Unpublished study
performed by Sumitomo Chemical Company. 151 p. 

40462610

Morseth, S. (1987) Teratology Study in Rabbits with S-307D T. G.:
Laboratory Project ID 343-196.  Unpublished study performed by Hazleton
Laboratories America, Inc.  166 p. 

40462611

Morseth, S. (1987) Two-Generation Reproduction Study in Rats with
S-3307D: F0 to F1 Interim Report: Laboratory Project ID 343-201.
Unpublished study performed by Hazleton Laboratories America, Inc.  460
p. 

40462612

Kogiso, S.; Hara, M.; Yoshitake, A.; et al. (1987) Bacterial
Mutagenicity Test on S-3307D: Laboratory Project ID M 84-19. Unpublished
study performed by Sumitomo Chemical Company.  21 p. 

40462613

Kogiso, S.; Hara, M.; Ito, K. (1987) In vitro Chromosomal Aberration
Test of S-3307D in Chinese Hamster Ovary Cells (CHO-kl): Laboratory
Project ID 274.  Unpublished study prepared by Sumitomo Chemical Co.  20
p. 

40462614

Kogiso, S.; Yoshitake, A.; Hara, M.; et al. (1987) In vitro Sister
Chromatid Exchange Test of S-3307 in Chinese Hamster Ovary Cells
(CHO-kl) in Culture: Laboratory Project ID 477.  Unpublished study
prepared by Sumitomo Chemical Company.  23 p. 

40462615

Kogiso, S.; Yoshitake, A.; Hara, M.; et al. (1987) Micronulceus Test of
S-3307D in Mouse Bone Marrow Cells: Laboratory Project ID 746. 
Unpublished study performed by Sumitomo Chemical Company.  21 p. 

40462616

Brorby, G.; Rosenberg, D. (1987) The Percutaneous Absorption of Carbon
14-XE 1019D Technical (SX-1710) in Male Rats: Laboratory Project ID
S-2806.  Unpublished study performed by Chevron Environmental Health
Center, Inc.  60 p. 

40462621

Auletta, C. (1987) Acute Oral Toxicity Study in Rats of CC-15551:
Laboratory Project ID 6900-86.  Unpublished study performed by
Bio/Dynamics.  40 p. 

40462622

Auletta, C. (1987) Acute Dermal Toxicity Study in Albino Rabbits of
CC-15551: Laboratory Project ID 6901-86.  Unpublished study performed by
Bio/Dynamics Inc.  42 p. 

40462623

Rosenberg, D. (1987) Acute Inhalation Toxicity of CC-15551 (SX-1743) in
Rats: Laboratory Project ID CECH 2680.  Unpublished study performed by
Chevron Environmental Center, Inc.  50 p. 

40462624

Auletta, C. (1987) Primary Eye Irritation Study in Albino Rabbits of
CC-15551: Laboratory Project ID 6903-86.  Unpublished study prepared by
Bio/Dynamics, Inc.  47 p. 

40462625

Auletta, C. (1987) Primary Dermal Irritation Study in Albino Rabbits
...?of| CC-15551: Laboratory Project ID 6902-86. Unpublished study
performed by Biodynamics Inc.  38 p. 

40462626

Cox, R. (1987) Modified Buehler Test for Skin Sensitization Potential of
CC-15551: Laboratory Project ID 2107-150. Unpublished study performed by
Hazleton Laboratories America, Inc. 54 p. 

40496701

Yoshitake, A.; Nakatsuka, I.; Isobe, N.; et al. (1987) Metabolism of
(S)-(E)-1-1-(p-chlorophenyl)-4,4-dimethyl-2-(1,2,4-triazol-1-
y1)-1-penten-3-ol in Rats: Project ID: 417 and 631.  Unpublished study
prepared by Sumitomo Chemical Co., Ltd.  192 p. 

40936003

Kodama, J. (1988) 28-Day Dermal Toxicity of Prunit Tree Growth
Regulator--Request for Waiver with Data Summary: Project ID: RHS 12188. 
Unpublished study prepared by Chevron Environmental Health Center.  3 p.

40936004

Kogiso, S. (1988) In vivo/in vitro Unscheduled DNA Synthesis (UDS) Test
of S-3307D in Rat Hepatocytes: Project ID: ITT-80-0069. Unpublished
study prepared by Sumitomo Chemical Co.  34 p. 

41162001

Cox, R. (1988) Uniconazole-P: Chronic Toxicity Study in Dogs: HLA Study
No. 343-202-CIT.  Unpublished study prepared by Hazleton Laboratories
America, Inc.  425 p. 

41162002

Rogers, B. (1987) Uniconazole-P: Twenty-eight Day Dermal Toxicity Study
of CC-15551 (SX-1728) in Male and Female Rats: Project ID CEHC 2600-CIT.
 Unpublished study prepared by Chevron Environmental Health Center, Inc.
 223 p. 

41162003

Dougherty, K. (1989) Uniconazole-P: Four-week Repeated-dose Dermal
Toxicity Study in Rats with CC-15399 (SX-1805): Project ID CEHC
2983-CIT.  Unpublished study prepared by Chevron Environmental Health
Center, Inc.  191 p. 

41162004

Morseth, S. (1989) Uniconazole-P: Two-generation Reproduction Study in
Rats with S-3307D: HLA Study No. 343-201-CIT.  Unpublished study
prepared by Hazleton Laboratories America, Inc.  950 p. 

41162005

Morseth, S. (1989) Uniconazole-P: Oncogenicity Study in Mice with
S-3307D: HLA Study No. 343-190-CIT.  Unpublished study prepared by
Hazleton Laboratories America, Inc.  3126 p. 

41162006

Morseth, S. (1989) Uniconazole-P: Combined Chronic Toxicity and
Oncogenicity Study in Rats with S-3307D: HLA Study No. 343-191- CIT. 
Unpublished study prepared by Hazleton Laboratories America, Inc.  4112
p. 

41442401

Morseth, S. (1986) 5-Week Dietary Toxicity Study in Mice S-3307D T. G.
Final Report: (Submitted as an Addendum to: Oncogenicity Study in Mice
with S-3307D): Uniconazole-P Technical: Lab Project No. 343-168. 
Unpublished study prepared by Hazleton Laboratories America, Inc.  350
p. 

41745801

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n Laboratories America, Inc.  67 p. 

41745802

Hirohashi, A. (1987) S-3307D Range-Finding Teratology Study in Rats
Uniconazole-P Technical 59639-GI: Lab Project Number: DEV 8602.
Unpublished study prepared by Sumitomo Chemical Company, Ltd. 65 p. 

42123201

Citation:  Kawamura, S. (1991) Comments on the EPA's Review of a Rat
Teratol- ogy Study Entitled "Teratology Study of S-3307D in
Rats":Addendum to MRID 40462609: Lab Project Number: IIT-10-0123. 
Unpublished study prepared by Sumitomo Chemical Co., Ltd.  13 p. 

42123202

Citation:  Hara, M; Kosigo, S. (1990) Response to the EPA's Review of
"Data Evaluation Record, Uniconazole P, Mutagenicity-In vivo
Micronucleus Assay in Mice. Addendum to MRID 40462515: Lab Project
Number: IIT-00-0115.  Unpublished study prepared by Sumitomo Chemical
Co.  11 p. 

42123203

Kosigo, S. (1989) Micronucleus Test of S-3307D in ICR Female Mice: Lab
Project Number: 1047.  Unpublished study prepared by Sumitomo Chemical
Co., Ltd.  21 p. 

42123204

Hara, M; Oka, M.; Kosigo, S. (1990) Comments on the EPA's Review of a
"Data Evaluation Report" on the Report Entitled "In-vivo/in vitro
Unscheduled DNA Synthesis (UDS) Test of S-3307D in Rat Hepatocytes":
Addendum to MRID 40936004: Lab Project Number: 792; ITT-00-0117. 
Unpublished study prepared by Sumitomo Chemical Co., Ltd.  9 p. 

46424908

Dreher, D. (2004) Uniconazole P TGAI: Acute Oral Toxicity Study in the
Female Rat (Acute Toxic Class): Final Report.  Project Number: 2242/014.
 Unpublished study prepared by Covance Laboratories, Ltd.  28 p.

46424909

Dreher, D. (2004) Uniconazole P TGAI: Acute Dermal Toxicity Study in the
Rat: Final Report.  Project Number: 2242/015.  Unpublished study
prepared by Covance Laboratories, Ltd.  26 p.

46424910

Sanders, A. (2004) Uniconazole P TGAI: Acute Eye Irritation in the
Rabbit.  Project Number: 1913/004.  Unpublished study prepared by
Safepharm Laboratories, Ltd.  18 p.

46424911

Sanders, A. (2004) Uniconazole P TGAI: Acute Dermal Irritation in the
Rabbit.  Project Number: 1913/003.  Unpublished study prepared by
Covance Laboratories, Ltd.  14 p.

46424912

Dreher, D. (2004) Uniconazole P TGAI: Local Lymph Node Assay in the
Mouse (Individual Method): Final Report.  Project Number: 2242/018. 
Unpublished study prepared by Covance Laboratories, Ltd.  30 p.

46713703

Dreher, D. (2005) Uniconazole-p SL Formulation: Acute Oral Toxicity
Study in the Female Rat (Acute Toxic Class): Final Report.  Project
Number: 2242/019.  Unpublished study prepared by Covance Laboratories,
Ltd.  24 p.

46713704

Dreher, D. (2005) Uniconazole-p SL Formulation: Acute Dermal Toxicity
Study in the Rat: Final Report.  Project Number: 22242/020.  Unpublished
study prepared by Covance Laboratories, Ltd.  24 p.

46713705

Shepherd, N. (2005) Uniconazole-p SL Formulation: Single Exposure
Inhalation (Nose-Only) Toxicity Study in the Rat: Final Report.  Project
Number: 2242/023.  Unpublished study prepared by Covance Laboratories,
Ltd.  38 p.

46713706

Dreher, D.; Watt, I. (2005) Uniconazole-p SL Formulation: Eye Irritation
Study in the Rabbit: Final Report.  Project Number: 2242/022. 
Unpublished study prepared by Covance Laboratories, Ltd.  21 p.

46713707

Dreher, D.; Watt, I. (2005) Uniconazole-p SL Formulation: Dermal
Irritation Study in the Rabbit: Final Report.  Project Number: 2242/021.
 Unpublished study prepared by Covance Laboratories, Ltd.  20 p.

46713708

Dreher, D.; Watt, I. (2005) Uniconazole-p SL Formulation: Local Lymph
Node Assay in the Mouse (Individual Method): Final Report.  Project
Number: 2242/024.  Unpublished study prepared by Covance Laboratories,
Ltd.  26 p.



Appendix B:  Names and Structures of Uniconazole and Metabolites

APPENDIX I.	Chemical Names and Structures of Uniconazole and
Metabolites.  

Common name;

Company code	Chemical name	Chemical structure

Uniconazole

CYC-4Cl

CH2OH-7E

CH2OH-7Z

7KE

7KZ

Appendix C:  Tolerance Summary Table TC \l1 "Appendix C:  Tolerance
Reassessment Summary and Table 

Table C.1. 	Tolerance Summary for Uniconazole-P.

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

Vegetable Fruiting Crop Group 8	0.01	0.01	Vegetable, Fruiting, Group 8

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