Document ID: EPA-HQ-OPP-2005-0312-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-03-14T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF	

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: January 23, 2007

MEMORANDUM

SUBJECT:	Prothioconazole: Human Health Risk Assessment for Proposed Uses
on Barley, Canola, Chickpea, Dried Shelled Peas and Beans (except
Soybean), Lentils, Oilseed Crops (except Sunflower and Safflower),
Peanut, Wheat, and Rice. PC Code: 113961, Petition No: 4F6830, DP
Barcode: D328967.

FROM:	Barry O’Keefe, Risk Assessor/Senior Biologist

		Myron Ottley, Ph.D., Senior Toxicologist

		Sarah Winfield, Biologist

		Registration Action Branch 3

		Health Effects Division (7509P)

			AND

		Stephen Funk, Ph.D., Senior Chemist

		Immediate Office

		Health Effects Division (7509P)

			AND

		Toiya Goodlow, Chemist

		Reregistration Branch 1

		Health Effects Division (7509P)

THROUGH:	Paula Deschamp, Branch Chief

		Registration Action Branch 3

		Health Effects Division (7509P)

			AND

		William Burnam, Senior Science Advisor

		Immediate Office

		Health Effects Division (7509P)

			AND

		Mike Metzger, Branch Chief

		Reregistration Branch 1

		Health Effects Division (7509P)

TO:		Cynthia Giles-Parker/Lana Coppolino, RM Team 22 

		Fungicide Branch

		Registration Division (5705P)

The Registration Division (RD) of the Office of Pesticide Programs (OPP)
has requested that HED evaluate toxicology and residue chemistry data
and conduct dietary, aggregate, and occupational exposure and risk
assessments, as needed, to estimate the risk to human health that will
result from the proposed use of prothioconazole in/on the following
crops: barley, canola, chickpea, dried shelled peas and beans crop
subgroup, lentils, oilseed crop subgroup (rapeseed, Indian rapeseed,
Indian mustard, field mustard, black mustard, flax, crambe, and borage),
peanut, rice, and wheat (spring, durum and winter).

This chemical has been submitted by Bayer CropScience for joint review
by EPA and the Pesticide Management Regulatory Agency (PMRA) of Canada. 
The crops proposed for joint review include barley, the oilseed crop
group, the dried shell and bean subgroup, and wheat.  Uses on peanuts
and rice are being proposed for the U.S. only.

A summary of the findings and an assessment of human risk resulting from
the proposed uses of prothioconazole are provided in this document.  The
risk assessment was provided by Barry O’Keefe, the toxicology
assessment by Myron Ottley, the residue chemistry data review by Steve
Funk, the dietary assessment by Toiya Goodlow, and the occupational
assessment by Sarah Winfield.  The drinking water assessment was
provided by Roxolana Kashuba of the Environmental Fate and Effects
Division (EFED).

There are currently no permanent established tolerances for
prothioconazole in the United States (U.S.).  Additionally, there are
currently no U.S. products registered for prothioconazole.  

HED has completed a human health risk assessment for the proposed uses
of the new active ingredient prothioconazole.  For most proposed crops,
the risk estimates from acute and chronic dietary exposures (i.e., from
food and drinking water) do not exceed HED’s level of concern (LOC). 
However, for the proposed use on rice, the exposure from food and upper
bound water estimates results in risk estimates that exceed HED’s LOC
(utilized 279% of the aPAD at the 95th percentile), while exposure from
food and lower bound water estimates results in risk estimates that do
not exceed HED’s LOC (utilized 57% of the aPAD at the 95th
percentile).  Based on these dietary risk concerns, HED cannot make a
safety finding for the proposed prothioconazole agricultural use on rice
using the upper bound water estimates.  However, for all other proposed
crop uses HED can make a safety finding.  Therefore, HED does not
recommend for the establishment of tolerances for rice commodities
because of risk concerns.  Additionally, the petitioner, Bayer
CropScience, has acknowledged their intent to remove rice from their
tolerance petition.

The acute and chronic dietary assessments are moderately refined (e.g.,
average field trial values, empirical processing factors and livestock
maximum residues, and 100% crop treated were incorporated).  Risk
estimates from food residues alone are below HED’s LOC; the primary
exposure component is from drinking water.  The exposure estimates from
drinking water are based on moderately refined estimated drinking water
concentrations (EDWCs) provided by EFED; which included time series
values (distribution of water residue) for all crops, except rice
(interim rice model used), and regional default percent cropped area
(PCA) factors.  EFED provided HED with two sets of EDWC values, i.e.
upper and lower bound EDWCs, in order to address two major uncertainties
in computation of the EDWCs.  Predominantly, EFED is concerned about a
high percentage of uncharacterized unextracted/bound residues. 
Secondly, EFED is concerned about the different mobilities (Koc values)
of the two main degradates (prothioconazole-desthio and
prothioconazole-S-methyl).  To address these uncertainties, EFED
provided HED with upper and lower bound EDWC values for each crop; i.e.,
upper bound EDWCs include unextractable residues and lower Koc vales,
while lower bound EDWCs exclude unextractable residues and employ higher
Koc values.  Any concern about the uncertainties of any bound residues
or differences in Koc values are adequately addressed by regulating and
relying upon the upper bound EDWCs in the dietary risk assessment.

Additionally, one handler exposure scenario (closed mixer/loader for
aerial application to wheat) did not reach the LOC of an MOE of 1000
with engineering controls, and therefore exceeds HED’s LOC. 
Mixer/loader scenarios for aerial application for crops other than wheat
also required applying the engineering control of a closed mixer/loader
system, in order to result in MOEs of 1000 or greater.

For postapplication workers, dermal MOEs reach 1000 or greater on the
day of application for postapplication activities such as scouting in
low crops with minimal plant growth, as well as hand weeding; however,
for activities such as scouting in crops with fuller foliage plants and
irrigating crops, up to 10 days following application are required to
reach MOEs of 1000.  Recently (December 7, 2006), dislogeable foliar
residue (DFR) data on four crops were submitted which indicate an REI of
48 hours would be protective of workers conducting postapplication
activities (based on preliminary review).  HED recommends for a
conditional registration with a 48-hour REI-pending full review and
evaluation of the submitted DFR data.

HED Recommendations

Pending submission of the revised Sections B and F as specified in
Section 10.0 of this risk assessment, HED concludes there are no
toxicology or residue chemistry data requirements that would preclude
the establishment of a conditional registration and the following
permanent tolerances: 

Tolerances for combined residues of prothioconazole and its desthio
metabolite:

Barley, grain	0.35	ppm

Barley, hay	7.0	ppm

Barley, straw	4.0	ppm

Grain, aspirated grain fractions	11	ppm

Pea and bean, dried shelled, except soybean, subgroup 6C	0.90	ppm

Peanut	0.02	ppm

Peanut, hay	6.0	ppm

Rapeseed, seed	0.15	ppm

Wheat, grain	0.07	ppm

Wheat, forage	6.0	ppm

Wheat, hay	4.5	ppm

Wheat, straw	5.0	ppm

Tolerances for prothioconazole, the desthio metabolite, and conjugates
convertible to these two compounds by acid hydrolysis, calculated as
parent:

Cattle, fat	0.1	ppm

Cattle, meat	0.02	ppm

Cattle, meat byproducts	0.20	ppm

Goat, fat	0.1	ppm

Goat, meat	0.02	ppm

Goat, meat byproducts	0.20	ppm

Hog, meat byproducts	0.05	ppm

Horse, fat	0.1	ppm

Horse, meat	0.02	ppm

Horse, meat byproducts	0.20	ppm

Milk	0.02	ppm

	Poultry, liver	  0.02  	ppm

Sheep, fat	0.1	ppm

Sheep, meat	0.02	ppm

Sheep, meat byproducts	0.20	ppm

Table of Contents

  TOC \f  1.0	Executive Summary	  PAGEREF _Toc148494523 \h  7 

2.0	Ingredient Profile	  PAGEREF _Toc148494524 \h  16 

2.1	Summary of Registered/Proposed Uses	  PAGEREF _Toc148494525 \h  16 

2.2	Structure and Nomenclature	  PAGEREF _Toc148494526 \h  19 

2.3	Physical and Chemical Properties	  PAGEREF _Toc148494527 \h  20 

3.0	Hazard Characterization/Assessment	  PAGEREF _Toc148494528 \h  20 

3.1	Hazard and Dose-Response Characterization	  PAGEREF _Toc148494529 \h
 20 

3.1.1	Database Summary	  PAGEREF _Toc148494530 \h  20 

3.1.1.1	Studies available and considered (animal, human, general
literature)	  PAGEREF _Toc148494531 \h  21 

3.1.1.2	Mode of action, metabolism, toxicokinetic data	  PAGEREF
_Toc148494532 \h  21 

3.1.1.3	Sufficiency of studies/data	  PAGEREF _Toc148494533 \h  21 

3.1.2	Toxicological Effects	  PAGEREF _Toc148494534 \h  22 

3.1.3	Dose-response	  PAGEREF _Toc148494535 \h  24 

3.1.4	FQPA	  PAGEREF _Toc148494536 \h  25 

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)	  PAGEREF
_Toc148494537 \h  25 

3.3	FQPA Considerations	  PAGEREF _Toc148494538 \h  28 

3.3.1	Adequacy of the Toxicity Database	  PAGEREF _Toc148494539 \h  28 

3.3.2	Evidence of Neurotoxicity	  PAGEREF _Toc148494540 \h  28 

3.3.3	Developmental Toxicity Studies	  PAGEREF _Toc148494541 \h  32 

3.3.4	Reproductive Toxicity Study	  PAGEREF _Toc148494542 \h  38 

3.3.5	Additional Information from Literature Sources	  PAGEREF
_Toc148494543 \h  41 

3.3.6	Pre-and/or Postnatal Toxicity	  PAGEREF _Toc148494544 \h  41 

3.3.6.1	Determination of Susceptibility	  PAGEREF _Toc148494545 \h  42 

3.3.6.2	Degree of Concern Analysis and Residual Uncertainties	  PAGEREF
_Toc148494546 \h  42 

3.3.7	Recommendation for a Developmental Neurotoxicity Study	  PAGEREF
_Toc148494547 \h  43 

3.4	Safety Factor for Infants and Children	  PAGEREF _Toc148494548 \h 
43 

3.5	Hazard Identification and Toxicity Endpoint Selection	  PAGEREF
_Toc148494549 \h  44 

3.5.1	Acute Reference Dose (aRfD) Females age 13-49	  PAGEREF
_Toc148494550 \h  44 

3.5.2	Acute Reference Dose (aRfD) – General Population, including
Infants & Children	  PAGEREF _Toc148494551 \h  45 

3.5.3	Chronic Reference Dose (cRfD) - All Populations	  PAGEREF
_Toc148494552 \h  46 

3.5.4	Incidental Oral Exposure (Short- and Intermediate-Term)	  PAGEREF
_Toc148494553 \h  46 

3.5.5	Dermal Absorption	  PAGEREF _Toc148494554 \h  46 

3.5.6	Dermal Exposure (Short-, and Intermediate-Term)	  PAGEREF
_Toc148494555 \h  47 

3.5.6	Inhalation Exposure (Short-, and Intermediate-Term)	  PAGEREF
_Toc148494556 \h  48 

3.5.8	Level of Concern for Margin of Exposure	  PAGEREF _Toc148494557 \h
 49 

3.5.9	Recommendation for Aggregate Exposure Risk Assessments	  PAGEREF
_Toc148494558 \h  49 

3.5.10	Classification of Carcinogenic Potential	  PAGEREF _Toc148494559
\h  49 

3.5.10	Summary of Toxicological Doses and Endpoints for Prothioconazole
for Use in Human Risk Assessments	  PAGEREF _Toc148494560 \h  50 

3.6	Endocrine disruption	  PAGEREF _Toc148494561 \h  51 

4.0	Public Health and Pesticide Epidemiology Data	  PAGEREF
_Toc148494562 \h  52 

5.0	Dietary Exposure/Risk Characterization	  PAGEREF _Toc148494563 \h 
52 

5.1 Pesticide Metabolism and Environmental Degradation	  PAGEREF
_Toc148494564 \h  52 

5.1.1	Metabolism in Primary Crops	  PAGEREF _Toc148494565 \h  52 

5.1.2	Metabolism in Rotational Crops	  PAGEREF _Toc148494566 \h  55 

5.1.3	Metabolism in Livestock	  PAGEREF _Toc148494567 \h  56 

5.1.4	Analytical Methodology	  PAGEREF _Toc148494568 \h  58 

5.1.5	Environmental Degradation	  PAGEREF _Toc148494569 \h  60 

5.1.6	Comparative Metabolic Profile	  PAGEREF _Toc148494570 \h  62 

5.1.7	Toxicity Profile of Major Metabolites and Degradates	  PAGEREF
_Toc148494571 \h  63 

5.1.8	Pesticide Metabolites and Degradates of Concern	  PAGEREF
_Toc148494572 \h  63 

5.1.9	Drinking Water Residue Profile	  PAGEREF _Toc148494573 \h  65 

5.1.10	Food Residue Profile	  PAGEREF _Toc148494574 \h  68 

5.1.11	International Residue Limits (IRL)	  PAGEREF _Toc148494575 \h  90

5.2  Dietary Exposure and Risk	  PAGEREF _Toc148494576 \h  90 

5.2.1  Acute Dietary Exposure/Risk	  PAGEREF _Toc148494577 \h  92 

5.2.2  Chronic Dietary Exposure/Risk	  PAGEREF _Toc148494578 \h  94 

5.2.3  Cancer Dietary Risk	  PAGEREF _Toc148494579 \h  95 

6.0	Residential (Non-Occupational) Exposure/Risk Characterization	 
PAGEREF _Toc148494580 \h  96 

7.0	Aggregate Risk Assessments and Risk Characterization	  PAGEREF
_Toc148494581 \h  96 

8.0	Cumulative Risk Characterization/Assessment	  PAGEREF _Toc148494582
\h  96 

9.0	Occupational Exposure/Risk Pathway	  PAGEREF _Toc148494583 \h  97 

9.1	Short-/Intermediate-/Long-Term/Cancer (if needed) Handler Risk	 
PAGEREF _Toc148494584 \h  99 

9.2	Short-/Intermediate-/Long-Term/Cancer (if needed) Postapplication
Risk	  PAGEREF _Toc148494585 \h  103 

10.0	Data Needs and Label Requirements	  PAGEREF _Toc148494586 \h  106 

10.1	Toxicology	  PAGEREF _Toc148494587 \h  106 

10.2	Residue Chemistry	  PAGEREF _Toc148494588 \h  106 

10.3	Occupational and Residential Exposure	  PAGEREF _Toc148494589 \h 
108 

10.4	Triazole Data Requirements	  PAGEREF _Toc148494590 \h  109 

References:	  PAGEREF _Toc148494591 \h  110 

Appendix A:  Toxicology Assessment	  PAGEREF _Toc148494592 \h  113 

A.1  Toxicology Data Requirements	  PAGEREF _Toc148494593 \h  113 

A.2  Toxicity Profiles	  PAGEREF _Toc148494594 \h  115 

A.3  Executive Summaries	  PAGEREF _Toc148494595 \h  132 

Appendix B:  Metabolism Assessment	  PAGEREF _Toc148494596 \h  187 

B.1	Metabolism Guidance and Considerations	  PAGEREF _Toc148494597 \h 
187 

Appendix C:  Tolerance Reassessment Summary and Table	  PAGEREF
_Toc148494598 \h  222 

 

1.0	Executive Summary  TC \l1 "1.0	Executive Summary 

Prothioconazole,
2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl-2-hydroxypropyl]-1,2-dihydr
o-3H-1,2,4-triazole-3-thione, is a new active ingredient developed by
Bayer CropScience LP (i.e. the petitioner).  Prothioconazole is a
systemic demethylation inhibitor fungicide which belongs to the
triazolinthione class of fungicides.  The petitioner states that
prothioconazole has shown excellent protective, curative, and
eradicative performance against plant diseases caused by ascomycetes,
basidiomycetes, and deutromycetes fungi in many crops.  The petitioner
states that the principle mode of action of prothioconazole fungicide is
the inhibition of demethylation at position 14 of lanosterol or
24-methylene dihydroano-sterol, both of which are precursors of sterols
in fungi; i.e., it works through disruption of ergosterol biosynthesis
(Ergosterol, a precursor to Vitamin D2, is an important component of
fungal cell walls).

Bayer CropScience has proposed, in PP#4F6830, the establishment of
permanent tolerances for combined residues of the fungicide
prothioconazole
[2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2-dihy
dro-3H-1,2,4-triazole-3-thione] and its desthio metabolite in/on
numerous agricultural commodities.

The petitioner is currently proposing food/feed uses on the following
crops: barley, canola, chickpea, dried shelled peas and beans crop
subgroup (except soybean), lentils, oilseed crop subgroup (except
sunflower and safflower), peanut, rice, and wheat (spring, durum and
winter).

This chemical has been submitted by Bayer CropScience for joint review
by EPA and the Pesticide Management Regulatory Agency (PMRA) of Canada. 
The crops proposed for joint review include barley, canola, chickpeas,
the oilseed crop group, the dried shell and bean subgroup, lentils and
wheat.  Uses on peanuts and rice are being proposed for the U.S. only.

In conjunction with the subject tolerance petition, Bayer CropScience
has submitted an application for Section 3 registration of a 4 lb/gal
suspension concentrate (equivalent to a flowable concentrate; FlC)
formulation (Proline® 480 SC Fungicide; EPA File Symbol No. 264-IEL). 
The product is to be applied as broadcast postemergence foliar or soil
sprays (application to soil for peanuts only) using ground or aerial
equipment at 0.088-0.178 lb ai/A/application (0.100-0.200 kg
ai/ha/application).  The proposed maximum seasonal rates range
0.285-0.713 lb ai/A (0.320-0.800 kg ai/ha), and the proposed retreatment
intervals are 5-21 days.  The proposed post harvest intervals (PHIs)
range from 7 days for dried shelled peas and beans to 40 days for rice.

There are no proposed or existing residential uses of prothioconazole.

Prothioconazole is a thio-triazole, and as such, HED notes that a
separate risk assessment was conducted for the 1,2,4-triazole and its
conjugates.  Prothioconazole is a member of the triazolinthione group of
fungicides.  Triazolylalanine (TA), triazolylhydroxoypropionic acid
(THPA), and triazolylacetic acid (TAA), metabolites common to the
triazole derivative class of fungicides, were also found to be
metabolites of prothioconazole.  HED conducted an aggregate risk
assessment for the metabolite/degradate 1,2,4-triazole (also referred to
as free triazole) and its conjugates TA and TAA, including data review,
hazard identification and endpoint selection, to support the extension
of existing tolerances and the granting of new parent triazole
derivative fungicide tolerances (1,2,4-Triazole, Triazole Alanine,
Triazole Acetic Acid: Human Health Aggregate Risk Assessment in Support
of Reregistration and Registration Actions for Triazole-derivative
Fungicide Compounds. M. Doherty, et. al., 12/22/05).

Toxicity/Hazard Assessment

The toxicology database for prothioconazole (also known as JAU6476),
submitted by Bayer CropScience, is extremely large, especially the
number of complex toxicology studies.  In addition to the full
toxicology database for prothioconazole, there is a second complete
toxicology database for the major metabolite/degradate
prothioconazole-desthio (also known as SXX0665), and additional studies
on other minor metabolites/degradates.  The toxicity database for
prothioconazole (and its metabolites) is considered complete, and deemed
adequate for endpoint selection for exposure risk assessment scenarios
and for FQPA evaluation.

Acute Toxicity:  Prothioconazole has low acute toxicity by oral, dermal,
and inhalation routes.  It is not a dermal sensitizer, or a skin or eye
irritant.  Prothioconazole-desthio also has low acute toxicity by oral,
dermal, and inhalation routes.  It is not a dermal sensitizer, or a skin
irritant, but it is a slight eye irritant.

Subchronic Toxicity:  The studies show that the target organs at the
LOAEL include the liver, kidney, urinary bladder, thyroid and blood.
Significant clinical chemistry findings were also made.  NOAEL/LOAEL
values across the family of chemicals (i.e., prothioconazole, and
prothioconazole-desthio and prothioconazole sulfonic acid potassium salt
metabolites) in the toxicity database indicate that
prothioconazole-desthio is a more toxic chemical.

Chronic Toxicity:  In addition to the target organs and effects observed
in the subchronic studies (i.e., liver, kidney, urinary bladder,
thyroid, hematology and clinical chemistry), chronic toxicity at the
LOAEL also included body weight and food consumption changes, and
toxicity to the lymphatic and GI systems.  The relative potency of
prothioconazole-desthio was greater than prothioconazole.

Carcinogenicity:  Studies in the rat and mouse, using both
prothioconazole and prothioconazole-desthio, showed no evidence of
carcinogenicity.  The data show that dosing was adequate, except in the
rat cancer study using prothioconazole, where the dosing was considered
too high.

Developmental Toxicity:  The data indicated that prothioconazole and the
three metabolites evaluated (i.e., prothioconazole-desthio,
prothioconazole sulfonic acid potassium salt, and
prothioconazole-deschloro) variously produce pre-natal developmental
effects at levels equal to or below maternally toxic levels. 
Prothioconazole-desthio is the most toxic orally or dermally, with
LOAELs significantly below that of the other chemicals.  The rabbit is
the more sensitive species.  Lastly, prothioconazole-desthio is a
developmental neurotoxicant, producing changes in brain morphometrics
and increases in the occurrence of peripheral nerve lesions in the
neonate.  A NOAEL was not determined, since these observations were
looked for only at the high dose level.

Reproductive Toxicity:  Reproduction studies in the rat, conducted using
prothioconazole and prothioconazole-desthio, suggested that these
chemicals may not be primary reproductive toxicants.  Reproductive and
offspring toxicities were observed only in the presence of parental
toxicity.  Indeed, the parental LOAELs are lower.  The data show that
prothioconazole-desthio is more toxic by an order of magnitude.  The
nature of parental toxicity is similar to what was observed in the
subchronic studies, such as body weight and food consumption changes,
liver effects, etc.  Reproductive effects included decreases in
reproductive indices such as those that indicate pup survival and
growth.  Offspring toxicity was manifested by decreased pup weights and
malformations such as cleft palate.

Neurotoxicity:  Acute and subchronic neurotoxicity studies were
conducted in the rat using prothioconazole.  A developmental
neurotoxicity study was conducted in the rat using
prothioconazole-desthio.  Prothioconazole-desthio was the more potent
neurotoxicant.

Dermal Toxicity:  Acute dermal toxicity studies on prothioconazole and
prothioconazole-desthio indicate that they are not irritants (Tox
Category IV).  One subchronic dermal rat study using prothioconazole
failed to show any local or systemic toxicity.  However, a dermal
developmental toxicity study using prothioconazole-desthio showed local
effects at a high dose in the rat. 

Comparative Toxicity:  The available data show that the
prothioconazole-desthio metabolite produces toxicity at the lowest dose
levels in the areas of subchronic, developmental and reproductive
toxicities compared with prothioconazole and the two additional
metabolites that were tested.

FQPA:  There are adequate data in the prothioconazole (including
metabolites) database to characterize the potential for pre-natal or
post-natal risks to infants and children: two-generation reproduction
studies in rats; developmental studies in rats and rabbits; and a
developmental neurotoxicity study in rats.  The effects seen in these
studies suggest that pups are more susceptible: pup effects were seen at
levels below the LOAELs for maternal toxicity and, in general, were of
comparable or greater severity compared to the effects observed in
adults.  In addition, since the developmental effects seen in the
developmental neurotoxicity study (DNT) were investigated at the high
dose level only, there is uncertainty concerning the LOAEL/NOAEL for
developmental effects in this study.  Thus, the FQPA factor is retained
at 10X. 

Dose Response & Endpoint Selection:  In plants, the major
metabolite/degradate of prothioconazole is prothioconazole-desthio,
which is significantly more toxic than prothioconazole.  Therefore, the
residues of concern in plant commodities are both prothioconazole and
its metabolite prothioconazole-desthio.  Also, the residues of concern
in edible ruminant tissues and milk are prothioconazole, and its desthio
and 4-hydroxy metabolites and their conjugates.

Since exposure to prothioconazole-desthio in food and drinking water
will be significant, and will in many cases exceed that of
prothioconazole, the decision was made by HED, in conjunction with PMRA,
to use the toxicity data on prothioconazole-desthio in the hazard and
dose response characterization.

The prothioconazole risk assessment team selected the most sensitive and
protective endpoints from the prothioconazole-desthio database to employ
in the prothioconazole risk assessment.  Appropriate endpoints were
identified for the acute and chronic dietary exposure scenarios and
appropriate occupational scenarios following dermal and inhalation
exposures.  

Acute Dietary Exposure:  The endpoint from the developmental toxicity
study in rabbits was selected for the acute dietary exposure scenario to
females 13-49 years old, with a NOAEL of 2 mg/kg/day, and a
developmental toxicity LOAEL of 10 mg/kg/day, based on multiple
malformations including malformed vertebral body and ribs, and
arthrogryposis.  An uncertainty factor (UF) of 1000X (10X for
interspecies extrapolation, 10X for intraspecies variations, 10X for
database uncertainty) was applied, resulting in an aRfD/aPAD of
0.002mg/kg/day.  No dose and endpoint were set for the general
population, including infants and children, because an appropriate study
to use in this risk assessment was not identified.

Chronic Dietary Exposure:  The endpoint from the chronic/oncogenicity
study in rats was selected for the chronic dietary exposure scenario,
with a NOAEL of 1.1 mg/kg/day, and a LOAEL of 8 mg/kg/day, based on
liver histopathology in males and females [hepatocellular vacuolation
and fatty change (single cell, centrilobular, and periportal)].  An
uncertainty factor (UF) of 1000X (10X for interspecies extrapolation,
10X for intraspecies variations, 10X for database uncertainty) was
applied, resulting in an cRfD/cPAD of 0.001mg/kg/day.

Short- and Intermediate-Term Dermal Occupational Exposure:  The endpoint
from the dermal developmental toxicity study in rats was selected for
the dermal exposure scenarios, with a NOAEL of 30 mg/kg/day, and a LOAEL
of 100 mg/kg/day, based on an increase incidence of supernumerary ribs
(14th rib).  An uncertainty factor (UF) of 1000X (10X for interspecies
extrapolation, 10X for intraspecies variations, 10X for database
uncertainty) was applied, resulting in a LOC margin of exposure (MOE) of
1000.

Short- and Intermediate-Term Inhalation Occupational Exposure:  The
endpoint from the developmental toxicity study in rabbits was selected
for the inhalation exposure, with a NOAEL of 2.0 mg/kg/day, and a
developmental toxicity LOAEL of 10 mg/kg/day, based on multiple
malformations including malformed vertebral body and ribs, and
arthrogryposis.  An uncertainty factor (UF) of 1000X (10X for
interspecies extrapolation, 10X for intraspecies variations, 10X for
database uncertainty) was applied, resulting in a LOC margin of exposure
(MOE) of 1000.

The available studies in the mouse and rat show no increase in tumor
incidence.  Therefore, HED has concluded prothioconazole or its
metabolites are not carcinogenic, and are classified “Not likely to be
Carcinogenic to Humans” according to the 2005 Cancer Guidelines.

Drinking Water Exposure Assessment

The estimated drinking water concentrations (EDWCs) used in the dietary
risk assessment were provided by the Environmental Fate and Effects
Division (EFED) and incorporated directly into the dietary assessment. 
Water residues were incorporated in DEEM-FCID into the food categories
“water, direct, all sources” and “water, indirect, all sources.”
  

EDWCs were determined using the PRZM-EXAMS screening model, with the
exception of rice.    SEQ CHAPTER \h \r 1 EDWCs for rice paddies  SEQ
CHAPTER \h \r 1  were determined using the Interim Rice Model,
10/29/2002.  The Interim Rice Model is capable of calculating EDWCs for
acute exposures only.  Therefore, the chronic dietary analyses
considered water estimates based on the bean application scenario only. 
The use of the acute rice EDWC values for the chronic exposure would
result in overestimated and unrealistic exposure and risk estimates. 
The Interim Rice model is intended to be an interim measure until a more
complete rice modeling method becomes available.  

EDWC point estimates were submitted for both lower and upper bounds to
account for two major uncertainties in the drinking water modeling. 
First, some prothioconazole residues remained in the bound phase in EFED
studies used to characterize persistence.  To address this uncertainty,
modeling was bounded based on inclusion and exclusion of unextracted
residues in half-life calculations.  Secondly, the two major water
degradates of prothioconazole formed rapidly after application and have
different mobility.  To address this uncertainty, modeling was conducted
using KOCs (soil organic carbon-water partitioning coefficients) for
prothioconazole-desthio and prothioconazole-S-methyl.   The lower bound
EDWCs represent the exclusion of unextracted residues and the use of the
higher Koc.  Conversely, the higher bound estimates represent the
inclusion of unextracted residues and the use of the lower Koc.  Any
concern about the uncertainties of any bound residues or differences in
Koc values are adequately addressed by regulating and relying upon the
upper bound EDWCs in the dietary risk assessment.

EDWCs were further refined for beans and rice.  Regional default Percent
Cropped Area factors (PCA) have been applied to estimated concentrations
of these crops.  DEEM analyses were performed for both the upper and
lower bound estimates and for the rice and bean crop scenarios, since
these EDWC values were the highest reported.  

Residential Exposure/Risk Assessment

There are no proposed or existing residential uses of prothioconazole. 
Therefore, no residential exposure assessment is required.

Dietary/Aggregate Exposure/Risk Assessment

Acute and chronic dietary risk assessments were conducted using the
Dietary Exposure Evaluation Model (DEEM-FCID™, Version 2.03), which
used food consumption data from the U.S. Department of Agriculture’s
Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996
and 1998. The analyses were performed to support the registration of the
new chemical, prothioconazole.  

Acute Dietary Exposure Results and Characterization:  A moderately
refined acute dietary exposure assessment was conducted for
prothioconazole.  Empirical processing factors (PFs) and livestock
maximum residues were incorporated, and 100 percent crop treated (%CT)
was assumed for the acute assessment.  Average residue levels were also
used, since all of the plant commodities included in this assessment are
blended food forms.  No acute endpoint was identified for the general
U.S. population.  Females, 13-49 years of age, was the only population
subgroup included in the acute assessment.  Dietary risk estimates were
determined considering exposures from food alone and food plus water
using estimated drinking water concentrations (EDWCs) for surface water
sources provided by the Environmental Fate and Effects Division (EFED). 
EDWC values were submitted for both lower and upper bounds for each crop
scenario.  The acute analyses were performed incorporating the EDWC
values for beans and separate analyses were performed using the EDWCs
for rice, since these crops yielded the highest EDWC values. Ground
water sources were not included, as the EDWCs for this water source are
minimal in comparison to surface water.  

The dietary exposure analyses result in acute dietary risk estimates
that are below the Agency’s level of concern for food only, and for
food and drinking water based on the bean application scenario.  At the
95th percentile, the food only exposure for females 13-49 years old was
0.000216 mg/kg/day, which utilized 11% of the acute population adjusted
dose (aPAD).  The exposure for food plus lower bound surface water
estimates was 0.000614 mg/kg/day, which utilized 31% of the aPAD at the
95th percentile.  The exposure for food and upper bound water estimates
was 0.001192 mg/kg/day, which utilized 60% of the aPAD at the 95th
percentile for females 13-49.

Using EDWCs for rice, the dietary exposure analyses result in acute
dietary risk estimates that are below the Agency’s level of concern
for the food plus lower bound surface water analysis; however, dietary
estimates exceeded the Agency’s level of concern for food plus upper
bound surface water estimates.  For females 13-49 years old, the
exposure for food plus lower bound surface water estimates was 0.001141
mg/kg/day, which utilized 57% of the aPAD at the 95th percentile.  The
exposure for food and upper bound water estimates was 0.005573
mg/kg/day, which utilized 279% of the aPAD at the 95th percentile.  

Surface water was found to be the most significant contributor to the
risk estimates for the food plus upper bound water analysis based on the
rice application scenario. 

Chronic Dietary Exposure Results and Characterization:  A moderately
refined chronic dietary exposure assessment was also performed. 
Empirical processing factors, average residues, and livestock maximum
residues were incorporated into the chronic assessment; 100% crop
treated was also assumed.  Dietary risk estimates were determined
considering exposures from food alone and food plus upper or lower bound
surface water EDWC point estimates based on the bean application
scenario.  Chronic EDWCs for rice were not determined due to model
constraints.   The dietary exposure analyses result in chronic dietary
risk estimates that are below the Agency’s level of concern for food
alone and food plus water.  The highest exposure and risk estimates were
for all infants and children 1-2 years old.  The food only exposure was
0.000530 mg/kg/day, which utilized 48% of the chronic population
adjusted dose (cPAD) for children 1-2.  The highest exposure and risk
estimates for food plus lower bound water were also for children 1-2. 
The exposure for food plus lower surface water estimates was 0.000684
mg/kg/day, utilizing 62% of the cPAD.   The highest exposure and risk
estimates for food plus upper bound water were for the all infants
population subgroup. The exposure for food plus upper bound surface
water estimates was 0.000948mg/kg/day, which utilized 86% of the cPAD.  

Occupational Exposure/Risk Assessment

There is potential for exposure from mixing, loading, and applying of
prothioconazole on proposed use sites, and from entering areas
previously treated with prothioconazole.  Occupational exposure to
prothioconazole is limited to use of the proposed formulation PROLINE®
480 SC Fungicide on field crops.  Short- and intermediate-term dermal
and inhalation exposures are expected from handler activities, and
short- and intermediate-term dermal exposures are expected from
postapplication activities.

Handler Risk:  The registrant submitted a prothioconazole-specific
handler exposure study, which was not used, since the unit exposure
information was determined to be inappropriate for use in exposure
estimate calculations (and subsequent risk estimates) because of the
small scale of the study, the choice of activity combinations, and the
use of Bayer employees as study subjects.  The study also investigated
the likely range of percent conversion from prothioconazole to
desthio-prothioconazole during a typical agricultural workday, and this
information is used qualitatively in this document.  Note: An ethics
review of this study was completed (K.Sherman, 9/27/06). It was
concluded the study does not violate current ethical standards, and
although it was considered scientifically valid for qualitative
purposes, it did not meet HED’s scientific standards for quantitative
use in this risk assessment. Unit exposure data from the Pesticide
Handlers Exposure Database (PHED) was determined to be more applicable,
and was therefore used instead.

Handler exposure scenarios considered representative of the potential
exposures expected from the proposed prothioconazole use patterns are as
follows: mixing and loading (M/L) for aerial and groundboom equipment
and application with aerial and groundboom equipment, as well as
flagging for aerial applications.  Total Margins of Exposure (MOEs)
range from 870 to 5,000.  One exposure scenario (closed M/L for aerial
application to wheat) did not reach the LOC of an MOE of 1000 with
engineering controls.  M/L for aerial application for crops other than
wheat also required applying the engineering control of a closed M/L
system, in order to result in MOEs of 1000 or greater.  M/L exposure
scenarios for groundboom equipment reach MOEs of 1000 or greater with
baseline clothing (long-sleeved shirt, long pants, shoes and socks) and
the personal protective equipment (PPE) gloves.  Both aerial and
groundboom application exposure scenarios reach MOEs of 1000 with
baseline clothing and no gloves.  

Postapplication Risk:  Postapplication dermal MOEs reach 1000 or greater
on the day of application for postapplication activities such as
scouting in low crops with minimal plant growth, as well as hand
weeding; however, for activities such as scouting in crops with fuller
foliage plants and irrigating crops, up to 10 days following application
are required to reach MOEs of 1000.  Recently (December 7, 2006), DFR
data on four crops were submitted which indicate an REI of 48 hours
would be protective of workers conducting postapplication activities
(based on preliminary review).  HED recommends for a conditional
registration with a 48-hour REI-pending full review and evaluation of
the submitted DFR data.

Additionally, the label should be amended to explicitly state the crops
excluded in particular groups (i.e., for the oilseed crop group,
sunflower and safflower crops are excluded, and for the dried shelled
pea and bean crop subgroup, soybean crops are excluded).

HED Risk Conclusions/Recommendations

HED has completed a human health risk assessment for the proposed uses
of the new active ingredient prothioconazole.  For most proposed crops,
the risk estimates from acute and chronic dietary exposures (i.e., from
food and drinking water) do not exceed HED’s level of concern (LOC). 
However, for the proposed use on rice, the exposure from food and upper
bound water estimates results in risk estimates that exceed HED’s LOC
(utilized 279% of the aPAD at the 95th percentile), while exposure from
food and lower bound water estimates results in risk estimates that do
not exceed HED’s LOC (utilized 57% of the aPAD at the 95th
percentile).  Based on these dietary risk concerns, HED cannot make a
safety finding for the proposed prothioconazole agricultural use on rice
using the upper bound water estimates.  However, for all other proposed
crop uses HED can make a safety finding.  Therefore, HED does not
recommend for the establishment of tolerances for rice commodities
because of risk concerns.  Additionally, the petitioner, Bayer
CropScience, has acknowledged their intent to remove rice from their
tolerance petition.

The acute and chronic dietary assessments are moderately refined (e.g.,
average field trial values, empirical processing factors and livestock
maximum residues, and 100% crop treated were incorporated).  Risk
estimates from food residues alone are below HED’s LOC; the primary
exposure component is from drinking water.  The exposure estimates from
drinking water are based on moderately refined estimated drinking water
concentrations (EDWCs) provided by EFED; which included time series
values (distribution of water residue) for all crops, except rice
(interim rice model used), and regional default percent cropped area
(PCA) factors.  EFED provided HED with two sets of EDWC values, i.e.
upper and lower bound EDWCs, in order to address two major uncertainties
in computation of the EDWCs.  Predominantly, EFED is concerned about a
high percentage of uncharacterized unextracted/bound residues. 
Secondly, EFED is concerned about the different mobilities (Koc values)
of the two main degradates (prothioconazole-desthio and
prothioconazole-S-methyl).  To address these uncertainties, EFED
provided HED with upper and lower bound EDWC values for each crop; i.e.,
upper bound EDWCs include unextractable residues and lower Koc vales,
while lower bound EDWCs exclude unextractable residues and employ higher
Koc values.

Additionally, one handler exposure scenario (closed mixer/loader for
aerial application to wheat) did not reach the LOC of an MOE of 1000
with engineering controls, and therefore exceeds HED’s LOC. 
Mixer/loader for aerial application for crops other than wheat also
required applying the engineering control of a closed mixer/loader
system, in order to result in MOEs of 1000 or greater.

For postapplication workers, dermal MOEs reach 1000 or greater on the
day of application for postapplication activities such as scouting in
low crops with minimal plant growth, as well as hand weeding; however,
for activities such as scouting in crops with fuller foliage plants and
irrigating crops, up to 10 days following application are required to
reach MOEs of 1000.  Recently (December 7, 2006), DFR data on four crops
were submitted which indicate an REI of 48 hours would be protective of
workers conducting postapplication activities (based on preliminary
review).  HED recommends for a conditional registration with a 48-hour
REI-pending full review and evaluation of the submitted DFR data. 

Pending submission of the revised Sections B and F as specified in
Section 10.0 of this risk assessment, HED concludes there are no
toxicology or residue chemistry data requirements that would preclude
the establishment of a conditional registration and the following
permanent tolerances (excluding rice, grain, rice, straw and rice,
hulls): 

Tolerances for combined residues of prothioconazole and its desthio
metabolite:

Barley, grain	0.35	ppm

Barley, hay	7.0	ppm

Barley, straw	4.0	ppm

Grain, aspirated grain fractions	11	ppm

Pea and bean, dried shelled, except soybean, subgroup 6C	0.90	ppm

Peanut	0.02	ppm

Peanut, hay	6.0	ppm

Rapeseed, seed	0.15	ppm

Wheat, grain	0.07	ppm

Wheat, forage	6.0	ppm

Wheat, hay	4.5	ppm

Wheat, straw	5.0	ppm

Tolerances for prothioconazole, the desthio metabolite, and conjugates
convertible to these two compounds by acid hydrolysis, calculated as
parent:

Cattle, fat	0.1	ppm

Cattle, meat	0.02	ppm

Cattle, meat byproducts	0.20	ppm

Goat, fat	0.1	ppm

Goat, meat	0.02	ppm

Goat, meat byproducts	0.20	ppm

Hog, meat byproducts	0.05	ppm

Horse, fat	0.1	ppm

Horse, meat	0.02	ppm

Horse, meat byproducts	0.20	ppm

Milk	0.02	ppm

	Poultry, liver	  0.02  	ppm

Sheep, fat	0.1	ppm

Sheep, meat	0.02	ppm

Sheep, meat byproducts	0.20	ppm

2.0	Ingredient Profile   TC \l1 "2.0	Ingredient Profile 

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

The petitioner is currently proposing food/feed uses on the following
crops: barley, canola, chickpea, dried shelled peas and beans crop
subgroup (except soybean), lentils, oilseed crop subgroup (except
sunflower and safflower), peanut, rice, and wheat (spring, durum and
winter).

This chemical has been submitted by Bayer CropScience for joint review
by EPA and the PMRA of Canada.  The crops proposed for joint review
include barley, canola, chickpeas, the oilseed crop group, the dried
shell and bean subgroup, lentils and wheat.  Uses on peanuts and rice
are being proposed for the U.S. only.

Prothioconazole is proposed as a broad spectrum systemic fungicide for
the control of ascomycetes, basidiomycetes, and deuteromycetes diseases.
 Applications may be made alone or as a tank mix with other fungicides,
insecticides, or herbicides.  To optimize disease control, the lowest
labeled rate of spray surfactant should be tank-mixed with PROLINE ®
480 SC Fungicide.  Application through any type of irrigation system is
prohibited.  For crops not listed on this label, do not plant back
within 30 days of last application.  

In conjunction with the subject tolerance petition, Bayer CropScience
has submitted an application for Section 3 registration of a 4 lb/gal
suspension concentrate (equivalent to a flowable concentrate; FlC)
formulation (Proline® 480 SC Fungicide; EPA File Symbol No. 264-IEL;
41% active ingredient).  The product is to be applied as broadcast
postemergence foliar or soil sprays (application to soil for peanuts
only) using ground or aerial equipment at 0.088-0.178 lb
ai/A/application (0.100-0.200 kg ai/ha/application).  The proposed
maximum seasonal rates range 0.285-0.713 lb ai/A (0.320-0.800 kg ai/ha),
and the proposed retreatment intervals are 5-21 days.  The proposed post
harvest intervals (PHIs) range from 7 days for dried shelled peas and
beans to 40 days for rice.  The proposed directions for use of
prothioconazole are summarized in Table 2.1.

Table 2.1.	Summary of Directions for Use of Prothioconazole

Applic. Timing, Type, and Equip.	Applic. Rate

(lb ai/A)

[fl oz/A]	Max. No. Applic. per Season	Retreatment Interval

(days)	Max. Seasonal Applic. Rate

(lb ai/A)

[fl oz/A]	PHI (days)	Use Directions and Limitations

Barley (for Fusarium Head Blight)

Broadcast foliar spray;

Ground or aerial	0.134 -0.178

[4.3 - 5.7]	2	7 to 14	0.293

[9.37]	32	Apply as a preventative foliar spray within the time period
when 70 to 100% of the barley heads on the main stem are fully emerged
when weather conditions are favorable for disease development and up to
3 to 5 days after full head emergence.  Spray equipment must be set up
to provide good coverage to barley heads (using ground application
equipment, use forward and backward mounted nozzles or nozzles with a
two-directional spray).

Barley (for Leaf and Stem Diseases)

Broadcast foliar spray;

Ground or aerial	0.0875 – 0.134

[2.8 - 4.3]	2	7 to 14	0.269

[8.6]	32	Apply as a preventative foliar spray when the earliest disease
symptoms appear on the leaves or stems. 

Canola

Broadcast foliar spray;

Ground or aerial	0.134 -0.178

[4.3 - 5.7]	2	5 to 7	0.356

[11.4]	36	Apply when the canola crop is in the 20 to 50% bloom stage
(approximately 4-8 days after the canola crop begins to flower, not
after 50% bloom stage).  Best protection will be achieved when the
fungicide is applied prior to petals beginning to fall, and will allow
for the maximum number of petals to be protected.  The lower application
rate is recommended for most canola crops, the higher rate is
recommended for fields with a history of heavy disease pressure or for
dense crop stands.  Good spray coverage of the plants is essential. 

Chickpea

Broadcast foliar spray;

Ground or aerial	0.134 -0.178

[4.3 - 5.7]	3	10 to 14	0.534

[17.1]	7	Apply at first sign of disease.  Use higher use rate when
conditions are favorable for severe disease pressure and/or when growing
less disease resistant varieties. 

Dried Shelled Peas and Beans Subgroup 

(Grain, Sweet, White and White Sweet lupins; Field, Kidney, Dry lima,
Pinto and Tepary beans; Adzuki bean, Blackeyed pea, Catjang, Cowpea,
Crowder pea, Moth bean, Mung bean, Rice bean, Southern pea and Urd bean;
Dry broad bean; Guar; Lablab bean; Pea [including Field pea] and Pigeon
pea)

Broadcast foliar spray;

Ground or aerial	0.134 -0.178

[4.3 – 5.7]	3	5 to 14	0.534

[17.1]	7	Apply at the first sign of disease.  Use higher use rate when
conditions are favorable for severe disease pressure and/or when growing
less disease resistant varieties.

Lentils

Broadcast foliar spray;

Ground or aerial	0.134 -0.178

[4.3 – 5.7]	3	10 to 14	0.534

[17.1]	7	Apply at early flower or at the first sign of disease.  Use
higher use rate when conditions are favorable for severe disease
pressure and/or when growing less disease resistant varieties.

Oilseed Crop Subgroup

(Rapeseed, Indian rapeseed, Indian mustard, Field mustard, Black
mustard, Flax, Crambe and Borage)

Broadcast foliar spray;

Ground or aerial	0.134 -0.178

[4.3 – 5.7]	2	5 to 7	0.356

[11.4]	36	Apply when the crop is 20 to 50% bloom stage (not after the
50% bloom stage).  Utilize higher rate for fields with history of heavy
disease pressure or for dense crop stands.  Good spray coverage is
essential.

Peanut

Broadcast foliar spray;

Ground or aerial	0.156 -0.178

[5.0 – 5.7]	4	14 to 21	0.713

[22.8]	14	Soil Borne disease: Utilize the high use rate.  Make four
consecutive applications at 14 day intervals.  In a typical 7 spray
application program beginning 30-40 days after planting, PROLINE should
be applied for sprays 3, 4, 5 and 6.  For control of soil-borne diseases
when using a Leaf Spot Advisory Program schedule, begin in July and
continue at 14 day intervals.  PROLINE must be carried by rainfall or
irrigation into the root zone, drought conditions will decrease
effectiveness against the root and pod rots.

Foliar disease: Apply the specified rate in a preventive spray schedule.
 Apply up to 4 sprays using a 14 day interval.  Use higher rate when
conditions are favorable for severe disease pressure and/or when growing
less disease resistant varieties.

Rice

Broadcast foliar spray;

Ground or aerial	0.143

[4.56]	2	Not Specified	0.285

[9.12]	40	Apply at initial sign of disease.  Exact timing for rice
disease control is dependent on rice growth stage, rice variety, the
type of disease to be controlled and disease severity.  Applications
typically will occur from panicle differentiation to late boot.  Consult
with local extension personnel or Bayer Crop Science representative to
determine if treatment is needed.  Under severe disease conditions or
when conditions are favorable for continued disease development, a
second application of PROLINE may be made as late as 70% panicle
emergence from the boot (but no later than 70% panicle emergence from
boot).

Wheat (spring, durum and winter) (for Fusarium Head Blight)

Broadcast foliar spray;

Ground or aerial	0.134 -0.178

[4.3 – 5.7]	2	7 to 14	0.293

[9.37]	30	Apply within the time period from when at least 75% of the
wheat heads on the main stem are fully emerged to when 50% of the heads
on the main stem are in flower.  Optimal timing of application may be at
or around 15% flower.  Spray equipment must be set up to provide good
coverage to wheat heads (using ground application equipment, use forward
and backward mounted nozzles or nozzles with a two-directional spray).
PROLINE may be applied up to the point where wheat heads are in the full
flower growth stage.

Wheat (spring, durum and winter) (for Leaf and Stem Diseases)

Broadcast foliar spray;

Ground or aerial	0.134 -0.156

[4.3 - 5.0]	2	7 to 14	0.293

[9.37]	30	Apply as a preventative foliar spray or when the earliest
disease symptoms appear on the leaves or stems.  Wheat fields should be
observed closely for early disease symptoms, particularly when
susceptible varieties are planted and/or under prolonged conditions
favorable for disease development.  PROLINE may be applied up to the
point where wheat heads are in the full flower growth stage.

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

Table 2.2a.  Prothioconazole Nomenclature.

Chemical structure of prothioconazole	

Empirical Formula	C14H15Cl2N3OS

Common name	Prothioconazole

Company experimental name	JAU 6476

IUPAC name
2-[2-(1-Chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2-dihyd
ro-3H-1,2,4-triazole-3-thione

CAS name
2-[2-(1-Chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2-dihyd
ro-3H-1,2,4-triazole-3-thione

CAS registry number	178928-70-6

End-use product/EP	PROLINE ® 480 SC Fungicide

Chemical Class	Triazolinthione

Known Impurities of Concern	None

TABLE 2.2b.	Prothioconazole-Desthio Nomenclature

Chemical Structure	

Company experimental name	JAU 6476-desthio (SXX 0665)

2.3	Physical and Chemical Properties  TC \l2 "2.3	Physical and Chemical
Properties 

Table 2.3.  Physicochemical Properties of the Technical-Grade
Prothioconazole.

Parameter	Value	Reference

Molecular Weight	344.26 g/mol

	Melting point	139.1 - 144.5 °C	MRID 46246003

Density (g/ml at 200C)	1.36 (pure active ingredient)	MRID 46246003

	1.17 at 20 °C (end use product)	MRID 46246003

Water solubility (g/L)	5.0  pH 4 buffer at 20 °C

0.3  pH 8 buffer at 20 °C

2.0  pH 9 Buffer at 20 °C	MRID 46246003

Solvent solubility at 20 °C (g/L)	                                  
g/L at room temp

acetone	>250

acetonitrile	10-100

dichloromethane	100-250

dimethylsulfoxide	100-250

ethyl acetate	<250

n-heptane	<0.1

1-octanol	10-100

polyethylene glycol	>250

2-propanol	10-100

xylene	1-10	MRID 46246003

Vapor pressure (Pa at 20 or 25 °C)	<4 x 10-7	MRID 46246003

Dissociation constant, pKa	6.9	MRID 46246003

Octanol/water partition coefficient, Log(KOW)	at 20 °C 

unbuffered: Kow = 11300; log Kow = 4.05

pH 4: Kow = 14600; log = 4.16

pH 7: Kow = 6600; log = 3.82

pH 9: Kow = 100; log = 2.00	MRID 46246003

UV/visible absorption spectrum	Peak maxima at 275 nm.  No absorption at
>300 nm.	MRID 46246003

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 

3.1.1	Database Summary  TC \l3 "3.1.1	Database Summary 

The toxicology database for prothioconazole (also known as JAU6476),
submitted by Bayer CropScience, is extremely large, especially the
number of complex toxicology studies.  In addition to the full
toxicology database for prothioconazole, there is a second complete
toxicology database for the major metabolite/degradate
prothioconazole-desthio (also known as SXX0665), and additional studies
on other minor metabolites/degradates.  The toxicity database for
prothioconazole (and its metabolites) is considered complete, and deemed
adequate for endpoint selection for exposure risk assessment scenarios
and for FQPA evaluation.

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) 

Prothioconazole (JAU6476)

Acute- oral, dermal, inhalation, eye irritation, skin irritation, dermal
sensitization

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

Chronic- Oral rat and dog;

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

Other- Oral rat and mouse cancer studies, mutagenicity screens, and
metabolism and pharmacokinetic studies; acute and subchronic
neurotoxicity studies; dermal penetration study; immunotoxicity study;
special in vitro thyroid study; determination of enzyme activities in
the dog.

Prothioconazole-desthio  (SXX0665)

Acute- oral, dermal, inhalation, eye irritation, skin irritation, dermal
sensitization

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

Chronic- Oral rat and dog;

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

Other- Oral rat and mouse cancer studies, mutagenicity screens, and
metabolism and pharmacokinetic studies; dermal penetration study; liver
foci test; plasma kinetics in rat; ovarian finding study in rats; acute
intraperitoneal study in rat.

Prothioconazole, deschloro

Developmental – Oral in rats

Prothioconazole, sulfonic acid K salt

Subchronic – Oral 90-day in rats

Developmental – Oral in rats

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

Prothioconazole is a systemic demethylation inhibitor fungicide which
belongs to the triazolinthione class of fungicides.  The registrant
states the principle mode of action of prothioconazole fungicide is that
it acts against susceptible fungi through the inhibition of
demethylation at position 14 of lanosterol or 24-methylene
dihydroano-sterol, both of which are precursors of sterols in fungi;
i.e., it works through disruption of ergosterol biosynthesis
(Ergosterol, a precursor to Vitamin D2, is an important component of
fungal cell walls).

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

The toxicity database for prothioconazole (see Appendixes A.2 and A.3
for Toxicity Profile Tables and Executive Summaries of studies), is
deemed adequate for endpoint selection for exposure risk assessment
scenarios and for FQPA evaluation.

It should be noted that three studies were considered Unacceptable
according to Guideline standards:

	First, the oral subchronic and chronic studies in the dog using
prothioconazole-desthio were not tested at high enough dose levels, and
the chronic study had reporting deficiencies.  However, the subchronic
and chronic studies in the rat demonstrated toxicity at dose levels well
below the highest levels tested in the dog, which means that repeating
the dog studies at higher levels would not provide information useful to
this risk assessment.

Secondly, the oral cancer study in the rat using prothioconazole was
conducted at dose levels that were too high to permit meaningful
non-cancer toxicity evaluations.  However, since there was no evidence
of carcinogenicity at the excessively high dose levels, and since an
acceptable cancer study in the rat using prothioconazole-desthio (as
well as acceptable mouse studies using prothioconazole and the desthio
metabolite),  repeating this study was considered unnecessary.

In addition, it should be noted that the developmental neurotoxicity
study in the rat using prothioconazole-desthio was classified as
Acceptable Nonguideline.  The study was conducted according to guideline
standards, and has yielded valid and useful data in some areas; however,
data reporting in other areas (i.e. brain morphometry peripheral nerve
degeneration) is incomplete according to guideline standards, and HED
has requested the missing data.

HED has concluded that the available toxicity database on
prothioconazole and the desthio metabolite are sufficient to
characterize the toxicity of prothioconazole, and to identify endpoints
that will be protective of populations evaluated in the risk assessment.

3.1.2	Toxicological Effects  TC \l3 "3.1.2	Toxicological Effects 

NOAEL and LOAEL:  The NOAEL (No Observed Adverse Effect Level) is the
dose level, in a given study, at which no adverse effects were noted. 
Similarly, the LOAEL (Lowest Observed Adverse Effect Level) is the dose
level at which effects of toxicological significance were observed. 
NOAELs/LOAELs derived from the toxicity database are well characterized
[with the exception of certain endpoints in the developmental
neurotoxicity study] and are used as endpoints for appropriate risk
assessments.

Acute Toxicity:  Prothioconazole has low acute toxicity by oral, dermal,
and inhalation routes.  It is not a dermal sensitizer, or a skin or eye
irritant.  Prothioconazole-desthio also has low acute toxicity by oral,
dermal, and inhalation routes.  It is not a dermal sensitizer, or a skin
irritant, but it is a slight eye irritant.

Subchronic Toxicity:  The studies show that the target organs at the
LOAEL include the liver, kidney, urinary bladder, thyroid and blood.
Significant clinical chemistry findings were also made.  NOAEL/LOAEL
values across the family of chemicals (i.e., prothioconazole, and
prothioconazole-desthio and prothioconazole sulfonic acid potassium salt
metabolites) in the toxicity database indicate that
prothioconazole-desthio is a more toxic chemical.

Chronic Toxicity:  In addition to the target organs and effects observed
in the subchronic studies (i.e., liver, kidney, urinary bladder,
thyroid, hematology and clinical chemistry), chronic toxicity at the
LOAEL also included body weight and food consumption changes, and
toxicity to the lymphatic and GI systems.  The relative potency of
prothioconazole-desthio was greater than prothioconazole.

Carcinogenicity:  Studies in the rat and mouse, using both
prothioconazole and prothioconazole-desthio, showed no evidence of
carcinogenicity.  The data show that dosing was adequate, except in the
rat cancer study using prothioconazole, where the dosing was considered
too high.

Developmental Toxicity:  The data indicated that prothioconazole and the
three metabolites evaluated (i.e., prothioconazole-desthio,
prothioconazole sulfonic acid potassium salt, and
prothioconazole-deschloro) can be primary developmental toxicants,
producing effects including malformations in the conceptus at levels
equal to or below maternally toxic levels in some studies, particularly
those studies  conducted using prothioconazole-desthio. 
Prothioconazole-desthio is the most toxic orally or dermally, with
LOAELs significantly below that of the other chemicals.  The rabbit is
the more sensitive species, qualitatively.  Lastly,
prothioconazole-desthio is a developmental neurotoxicant, producing
malformations and such neurotoxic effects as changes in brain
morphometrics and increases in the occurrence of peripheral nerve
lesions in the neonate.  A NOAEL was not determined for the
neurotoxicity, since these observations were looked for only at the high
dose level.

Reproductive Toxicity:  Reproduction studies in the rat, conducted using
prothioconazole and prothioconazole-desthio, suggested that these
chemicals may not be primary reproductive toxicants.  Reproductive and
offspring toxicities were observed only in the presence of parental
toxicity.  Indeed, the parental LOAELs are lower.  The data show that
prothioconazole-desthio is more toxic by an order of magnitude.  The
nature of parental toxicity is similar to what was observed in the
subchronic studies, such as body weight and food consumption changes,
liver effects, etc.  Reproductive effects included decreases in
reproductive indices such as those that indicate pup survival and
growth.  Offspring toxicity was manifested by decreased pup weights and
malformations such as cleft palate.

Neurotoxicity:  Acute and subchronic neurotoxicity studies were
conducted in the rat using prothioconazole.  A developmental
neurotoxicity study was conducted in the rat using
prothioconazole-desthio.  Prothioconazole-desthio was the more potent
neurotoxicant.

Dermal Toxicity:  Acute dermal toxicity studies on prothioconazole and
prothioconazole-desthio indicate that they are not irritants (Tox
Category IV).  One subchronic dermal rat study using prothioconazole
failed to show any local or systemic toxicity.  However, a dermal
developmental toxicity study using prothioconazole-desthio showed
systemic toxicity as evidenced by an increase in supernumerary ribs at
maternally non-toxic doses.

Comparative Toxicity:  The available data show that the
prothioconazole-desthio metabolite produces toxicity at the lowest dose
levels in the areas of subchronic, developmental and reproductive
toxicities compared with prothioconazole and the two additional
metabolites that were tested.  

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

In plants, the major metabolite/degradate of prothioconazole is
prothioconazole-desthio, which is significantly more toxic than
prothioconazole.  Therefore, the residues of concern in plant
commodities are both prothioconazole and its metabolite
prothioconazole-desthio.  Also, the residues of concern in edible
ruminant tissues and milk are prothioconazole, and its desthio and
4-hydroxy metabolites and their conjugates.

Since exposure to prothioconazole-desthio in food and drinking water
will be significant, and will in many cases exceed that of
prothioconazole, the decision was made by HED, in conjunction with PMRA,
to use the toxicity data on prothioconazole-desthio in the hazard and
dose response characterization.

The prothioconazole risk assessment team selected the most sensitive and
protective endpoints from the prothioconazole-desthio database to employ
in the prothioconazole risk assessment.  Appropriate endpoints were
identified for the acute and chronic dietary exposure scenarios and
appropriate occupational scenarios following dermal and inhalation
exposures.  Residential exposure scenarios are not anticipated.  

In determining endpoints for acute dietary risk assessments, the toxic
effects in three studies were considered, as follows:

Study	NOAEL

mg/kg/day	LOAEL

mg/kg/day	Toxic Effects	Comment

Developmental Toxicity – Rat

MRID 46246321, 43246322	3	10	increased incidence of supernumerary ribs
and incomplete/delayed ossifications.	Possibly appropriate for Acute
Dietary, Females 13 – 50 years.

Quantitative susceptibility demonstrated in that the maternal
NOAEL/LOAEL are  30/100 mg/kg/day

Developmental Toxicity – Rabbit

MRID 46246327	2	10	malformed vertebral body and ribs, arthrogryposis,
and multiple malformations	Appropriate for Acute Dietary, Females 13 –
50 years

Quantitative susceptibility demonstrated in that the maternal
NOAEL/LOAEL are 10/50 mg/kg/day

Developmental Neurotoxicity – Rat

MRID 46246418	3.6	15.1	deviated snout, malocclusion	Appropriate for
Acute Dietary, Females 13 – 50 years

	15.1	43.3	Dystocia	Maternal effects.  Possibly appropriate for Acute
Dietary, General Population 

	not reported	not reported	brain morphometric changes and increased
incidence of peripheral nerve lesions	Appropriate for Acute Dietary,
General Population since effects seen in neonate, indicating the
potential for effects to occur in children and adults following a single
postnatal dose.  

The endpoints from the developmental neurotoxicity (DNT) study are
considered because they show effects that could occur in both adults and
offspring, following single or multiple exposures.  However, because
morphometric changes and peripheral nerve lesions were reported only at
the high doses level in the DNT study, a NOAEL and LOAEL could not be
established for these endpoints.  The lack of this information limits
the utilization of this study for endpoint selection.  Therefore, the
resulting database uncertainties form the basis for retaining the FQPA
factor throughout the risk assessment.

The endpoints from the rat and rabbit developmental studies are
considered because developmental endpoints are identified.  Since the
endpoints occur at levels below the maternal NOAEL, susceptibility in
the offspring is demonstrated.

The weight of evidence evaluation of these toxic effects and the doses
selected for risk assessment will be further discussed in Section 3.5.

3.1.4	FQPA  TC \l3 "3.1.4	FQPA 

There are adequate data in the prothioconazole (including metabolites)
database to characterize the potential for pre-natal or post-natal risks
to infants and children: two-generation reproduction studies in rats;
developmental studies in rats and rabbits; and a developmental
neurotoxicity study in rats.  The effects seen in these studies suggest
that pups are more susceptible: pup effects were seen at levels below
the LOAELs for maternal toxicity and, in general, were of comparable or
greater severity compared to the effects observed in adults.  In
addition, since the developmental effects seen in the developmental
neurotoxicity (DNT) study were investigated at the high dose level only,
there is uncertainty concerning the LOAEL/NOAEL for developmental
effects in this study.  Thus, the FQPA factor is retained at 10X (see
Section 3.3 for details).

It is highly unlikely that the lowest dose tested in the DNT study will
be a LOAEL.  We are regulating at doses lower than the lowest dose in
the DNT.  In order for concern to be warranted regarding HED’s
approach or position, the true NOAEL (what ever that may turn out to be)
would need to be 10 fold lower than the current lowest dose used for
regulation.  The lowest regulatory dose derived from the DNT (0.0036
mg/kg/day) is higher than the doses used for regulation (acute 0.002
mg/kg/day) and (chronic 0.001 mg/kg/day).

Moreover, it is unlikely that the lowest dose tested in the DNT would be
a LOAEL for effects seen at the highest dose tested, because that would
indicate a dose-response curve with a slope which is more shallow
(gradual) than is demonstrated in the desthio-prothioconazole database. 
The ratio of the highest to the lowest dose level in the DNT study (43.3
mg/kg/day / 3.6 mg/kg/day) is 12X, and the existing database does not
show other adverse effects occurring over such a wide dose range.

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

		Prothioconazole (JAU6476)

In a metabolism study (MRID 46246421), the absorption, distribution,
metabolism and excretion of prothioconazole were investigated.

Following single oral low dose administration, the absorption of
prothioconazole in male rats was approximately 94% for the triazole
label.  The absorption for the phenyl label was estimated to be
approximately 90% at 48 hours based on extrapolation of the course of
excretion for the triazole label at 48 hours.

Plasma radioactivity time-course data showed that absorption following
single oral low dose administration was rapid, with peak plasma
concentrations occurring between 0.33 and 0.66 hours post administration
in males and females.  Peak plasma concentrations following single oral
high dose administration occurred between 0.66 and 1.00 hours post
administration in males and females.  The absorption of the
phenyl-labelled prothioconazole was slightly more rapid, with peak
plasma concentrations occurring between 0.16 and 0.33 hours post
administration of a single oral low dose in males, and at 0.16 hours
post administration of a repeat oral low dose in males and females. 
Oscillations in the plasma time course were noted, indicating that the
radioactivity was subjected to enterohepatic circulation.  This effect
was more prominent in the female rats. A slight delay in absorption
compared to males was also noted in females. 

Residual radioactivity in the rats 168 hours after a single oral low
dose administration was low.  For the triazole label, 1.5% of the
administered dose was recovered in the tissues and carcass of males, and
0.4% was recovered in females.  The highest tissue levels were found in
liver, carcass and gastrointestinal tract.  In all other tissues
examined, residual radioactivity levels ranged from 0.0004-0.07%.  For
the phenyl label (administered to males only), 5.8% of the administered
dose was recovered in the tissues and carcass.  The highest tissue
levels were found in the gastrointestinal tract, liver and carcass.  In
all other tissues examined, residual radioactivity levels ranged from
0.0001-0.05%.  Residual radioactivity in the rats 48 hours after a
repeat oral low dose administration was also low, with 3.8% of the
administered dose recovered in the tissues and carcass of males, and
0.8% recovered in females.  The highest tissue levels were found in
liver, gastrointestinal tract and carcass. In all other tissues
examined, residual radioactivity levels ranged from 0.0002-0.05%.  Total
body accumulation as well as liver accumulation was consistently higher
in males.  Residual radioactivity in the rats 168 hours after a single
oral high dose administration was also low, with 0.11% of the
administered dose recovered in the carcass and tissues of both males and
females.  Total body accumulation was approximately the same in males
and females, with liver accumulation higher in the males. 

The primary route of excretion for both labels and both sexes was via
the feces.  Following single oral low dose administration (triazole
label), total recovery was approximately 94-95% of the administered dose
for both sexes, with 10% (males) and 16% (females) of the administered
dose eliminated in the urine, and 84% (males) and 78% (females)
eliminated in the feces. In the phenyl-labelled group (males only), 5%
of the administered dose was eliminated in the urine and 85% in the
feces, for a total recovery of approximately 90%.  In the bile
duct-cannulated triazole-label group (males only), approximately 90% of
the administered dose was eliminated in the bile within 24-48 hours.  In
the phenyl-label group (males only), approximately 81% of the
administered dose was eliminated in the bile after 24 hours and 93%
after 48 hours.

Prothioconazole was extensively metabolised in the rat following oral
administration.  Eighteen metabolites and the parent compound were
identified in urine, feces and bile.  The biotransformation of
prothioconazole consisted of three major reaction types including
desulfuration, oxidative hydroxylation of the phenyl moiety and
glucuronic acid conjugation.  Identification of the metabolites ranged
from 26-63% of the administered dose.  A higher percentage of metabolite
isolation and identification could not be achieved due to difficulties
in fecal extraction where 67-79% of the administered dose remained in
non-extractable residues in the solids.  The major route of excretion
for prothioconazole was in the feces, representing 22-53% of the
administered dose.  The parent compound prothioconazole was the most
abundant in the faeces (1-22% of the administered dose), followed by the
prothioconazole-desthio metabolite (3-16% of the administered dose). 
All other fecal metabolites represented less than 7% of the administered
dose.  The 1, 2, 4-triazole metabolite was not detected in the feces. 
The major urinary metabolite was prothioconazole-S- or O-glucuronide
(0.1-8% of the administered dose) and was preferentially excreted in
females.  The 1, 2, 4-triazole metabolite represented 0.8-2.3% of the
administered dose following administration of single oral low and/or
high doses.  The remaining urinary metabolites accounted for 0-1.4% of
the administered dose.  Prothioconazole-S- or O-glucuronide was the most
abundant metabolite in the bile, representing approximately 46% of the
administered dose.  This metabolite was excreted in females only in the
urine, however, it was noted in the bile in males.  The glucuronic acid
metabolites in the bile represented 8-10% of the administered dose. 
Parent compound represented 3-5% of the administered dose in the bile. 
The 1, 2, 4-triazole metabolite was not detected in the bile. 

μg/g in males and up to 0.97 μg/g in females), followed by kidney
(renal medulla, up to 0.64 μg/g), brown/perirenal fat (up to 0.36
μg/g), thyroid (up to 0.23 μg/g) and adrenal gland (up to 0.27 μg/g).
 All other tissues showed peak concentrations of <0.13 μg/g. 
Concentrations of radioactivity decreased rapidly from 24 to 168 hours
post-administration, indicative of continued elimination from the
tissues. 

Prothioconazole-Desthio (SXX0665)

In a metabolism study (MRID 46246422), the absorption, distribution,
metabolism and excretion of prothioconazole-desthio were investigated.  

Absorption of the radioactive test material from the gastro-intestinal
tract (GIT) commenced as early as 4 minutes following dosing.  A maximum
concentration of 0.052(μg/g was observed at 1.5 hours.  The largest
amount of radioactivity was observed in the liver and the GIT, likely
due to long-lasting enterohepatic circulation.  The remaining tissues
contained levels of radioactivity of less than 1%.  Greater than 90% of
the administered radioactive dose was excreted in the bile and urine. 
Very little of the administered radioactivity was recovered in the
expired carbon dioxide.  The majority of the radioactive administered
dose was excreted in the faeces, with a minor portion being excreted in
the urine.  The skin contained a minute amount of the recovered
radioactivity, while the carcass and GIT contained up to 4 and 2.25%,
respectively.  Excretion was not likely complete at 48 hours, as the
total body radioactive residue was 5 to 6% of the administered dose at
that time point.  The elimination half-life was found to be 44.3 hours,
and the mean residence time was 48.2 hours.  These observations indicate
that the process of redistribution of the radioactivity into the plasma
before elimination was slow, as supported by the total clearance of 10.9
mL/min kg bw and the renal clearance of 1.4 mL/min kg bw.  Following the
intraduodenal administration of the radioactive dose in bile-cannulated
animals, 84 to 85% of the administered dose was found in the bile after
24 and 48 hours, respectively.  Excretion in urine in these animals
accounted for almost 6% of the administered dose after 48 hours, while
excretion in faeces accounted for 2% of the administered dose for the
same time period.  In the pooled bile sample, 18 radioactive HPLC peaks
were observed accounting for 84.3% of the administered dose.  Five
compounds were isolated and identified, while the remaining 13
metabolites were not identified, accounting for 44.7% of the
administered dose.

In whole-body autoradiography experiments, the quick onset of absorption
of the test material was demonstrated.  Absorption was not complete
after one hour.  The autoradiograms also showed that the blood
concentration was less than the concentration present in the fatty
tissues, demonstrating the lipophilic nature of prothioconazole-desthio,
and perhaps of its metabolites.  The mucous membrane of the stomach
walls were observed with radioactivity throughout the various
observation periods, which was considered an indication of extrabiliary
secretion of the absorbed radioactivity back into the stomach lumen. 
The muscle, heart, lung, brain, thyroid, and mineral portion of the
bones showed minor concentrations of radioactivity.  The testes had a
radioactivity distribution pattern indicative of the blood circulation
in the organ.  Medium amounts of radioactivity were observed in some
glandular organs, including the preputial gland and the adrenals.  The
gums were also observed with increased radioactivity, with unknown
physiological significance.  The distributions noted at one hour were
fairly consistent for 48 hours, though declining due to excretion.  The
renal cortex contained radioactivity to a much greater extent than did
the renal pelvis, indicating that the radioactivity was reabsorbed in
the duodenum.  As well, the radioactivity that is absorbed is likely not
transformed into metabolites that are adequately polar to be eliminated
by the kidney.  This results in increased passage through the liver by
the radioactive test material.

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 database for prothioconazole (including its metabolites) is adequate
for FQPA consideration.

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

Prothioconazole demonstrated neurotoxicity in the acute neurotoxicity
battery of tests, but not in the subchronic neurotoxicity study at
levels up to the Limit Dose.  These are the only two studies conducted
with this compound designed to assess neurotoxic effects. 
Prothioconazole-desthio demonstrated neurotoxicity in the developmental
neurotoxicity study, the only neurotoxicity study conducted.  The
effects seen were changes in motor and locomotor activity in the acute
neurotoxicity study, and changes in brain morphometry and increased
incidence of lesions in the peripheral nerves in the developmental
neurotoxicity study in the neonate.

Overt neurotoxicity was not demonstrated in the other studies conducted
with these compounds.

Acute Neurotoxicity in Rats – Prothioconazole

In an acute neurotoxicity study (MRID 46246417), groups of fasted,
9-week-old Wistar rats (12/sex) were given a single oral (gavage) dose
of prothioconazole (97.6-98.8% a.i., batch# 898803005) in 0.5%
methylcellulose/0.4% Tween 80 at doses of 0 (vehicle), 200, 750, or 2000
mg/kg bw and observed for 14 days.  Neurobehavioral assessment
(functional observational battery [FOB] and motor activity testing) was
performed in 12 animals/sex/group on day 0 (four hours following
treatment, the time of peak effect) and on days 7 and 14. 
Cholinesterase activity was not determined.  At study termination, six
animals/sex/group were euthanized and perfused in situ for
neuropathological examination.  Of the perfused animals, the control and
high-dose groups were subjected to histopathological evaluation of brain
and peripheral nervous system tissues. 

There were no treatment-related effects on mortality, body weight, brain
weight or gross and histologic pathology or neuropathology.  The only
treatment-related clinical sign was brown perianal stain (graded as
slight) observed on 3/12, 7/12, 11/12, and 12/12 males and 0/12, 0/12,
8/12, and 11/12 females in the control through high-dose groups during
days 1 through 5.  This clinical sign was also observed, but at lower
incidences, during the FOB on the day of treatment.  The effect had
resolved by FOB test day 7.  Partially formed stools were also noted
during the FOB.  Although the incidences of perianal stain of 7/12
(males, 200 mg/kg) and 8/12 (females, 750 mg/kg) would appear similar,
the incidence for males was within historical control values for this
vehicle; whereas, the incidence in females showed a clear effect at the
mid and high dose.  No other parameters examined in the FOB were
affected. 

Motor activity (total beam breaks) was non-significantly reduced on the
day of treatment (by 29 and 36% in males in the 750 and 2000 mg/kg
groups, respectively, and by 45% in females in the 2000 mg/kg group). 
Sub-session data (up to approximately 50 minutes) also showed
correspondingly reduced motor activity.  This effect on motor activity
had resolved by the next test session on day 7.  The effect on locomotor
activity was similar.  It is not clear whether the observed clinical
sign and reduced motor and locomotor activity were due to transient
effects on the nervous system or were an effect on the gastrointestinal
tract resulting from administration of a noxious substance.  In the
absence of other effects, the perianal stain observed on females in the
750 mg/kg group was considered a non-adverse effect.

The LOAELs for prothioconazole in male and female rats are 750 and 2000
mg/kg, respectively, based on the transient effect of reduced motor and
locomotor activity.  The NOAELs for male and female rats are 200 and 750
mg/kg, respectively.

This neurotoxicity study is classified as Acceptable/Guideline, and
satisfies the guideline requirement for an acute neurotoxicity study in
rats (870.6200; OECD 424) provided the conducting laboratory provides
positive control data demonstrating the ability to detect major
neurotoxic endpoints, changes in motor activity, and nervous system
pathology.  Raw data on analysis for concentration, homogeneity, and
stability of the test material should also be provided.  This review is
a joint effort of the PMRA and the EPA.

Subchronic Neurotoxicity in Rats – Prothioconazole

In a subchronic neurotoxicity study (MRID 46246416) prothioconazole
(97.6-98.8% a.i., batch #s 898803005 and 6233/0031) was administered to
12 Wistar (Crl:WI(HAN)BR) rats/sex/group at nominal dose levels of 0,
100, 500, or 1000 mg/kg bw/day, five days/week, for 13 weeks
(analytically determined doses of 0, 98, 505, and 1030 mg/kg/day).  The
dose was administered by gavage in 0.5% methylcellulose/0.4% Tween 80 in
deionized water.  Neurobehavioral assessment (functional observational
battery and motor activity testing) was performed in 12
animals/sex/group pretreatment and during weeks 4, 8, and 13. 
Cholinesterase activity was not determined.  At study termination, six
animals/sex/group were euthanized and perfused in situ for
neuropathological examination.  Of the perfused animals, the control and
high-dose groups were subjected to histopathological evaluation of brain
and peripheral nervous system tissues. 

There were no treatment-related deaths.  Treatment-related clinical
signs included urine stain on 8/12 males and 9/10 females in the 500
mg/kg/day group and 12/12 males and 11/11 females in the 1000 mg/kg/day
group.  Urine stain was first observed on day 18 on males treated with
1000 mg/kg/day.  Urine stain increased in frequency with duration of
exposure.  Urine stain was considered an effect of treatment, but, in
the absence of other clinical signs or histological correlates, not an
adverse effect.  Oral stain was observed on 3/12 males (beginning on day
25) and 1/11 females in the 1000 mg/kg/day group.  Males in the mid- and
high-dose groups lost weight during the first week of the study (3-4%). 
Weight loss was not accompanied by a decrease in food consumption during
the first week.  Final body weight was slightly (non-statistically)
reduced in males treated with 500 (6%) and 1000 mg/kg/day (8%) when
compared to final control body weight.  Body weight gain was reduced by
16 and 24% in males in the 500 and 1000 mg/kg/day groups, respectively. 
The body weight effects are considered adverse at the high dose.  Body
weight and body weight gain of females were unaffected by treatment. 
Food consumption was unaffected in both sexes.  Urine stain was the only
compound-related parameter affected during the Functional Observational
Battery (FOB).  

Compared with the respective control groups, slight reductions were
observed in motor and locomotor activity (up to 26%, non-statistically
significant) in both sexes in the high-dose groups.  These reductions
occurred in males and females during week 4 and in females during weeks
4 and 13.  However, the values for females were not dose-related, and
differences in values between the control and high-dose females for all
weeks (8-15%) were less than or similar to the difference between the
pretest control and high-dose group value (14%).  Therefore, the effect
on motor activity for females cannot be considered a clear effect of
treatment.  The effect on motor activity of males is questionable for
the same reasons.  There were no compound-related ophthalmic findings or
microscopic lesions of the central or peripheral nervous system.  Brain
weight was unaffected by treatment.

Based on decreased body weight and body weight gains in males, the LOAEL
for prothioconazole was 1000 mg/kg bw/day.  The NOAEL was 500 mg/kg/day.

This neurotoxicity study is classified as Acceptable (pending submission
of homogeneity, concentration, and stability analysis and positive
control data)/Guideline, and satisfies the guideline requirement for a
subchronic neurotoxicity study in rats (870.6200b; no OECD) provided the
conducting laboratory provides positive control data demonstrating their
ability to detect major neurotoxic endpoints, changes in motor activity,
and nervous system pathology.  Raw data on analysis for concentration,
homogeneity, and stability of the test material should also be provided.
 This review is a joint effort of the PMRA and the EPA.

Developmental Neurotoxicity in Rats – Prothioconazole-Desthio

In a developmental neurotoxicity study (MRID 46246418),
prothioconazole-desthio (99.1-99.4% a.i.; batch # RUX76-105-1E), a
metabolite of prothioconazole (PC Code 113961), was administered in the
diet to 30 female mated Wistar Hannover Crl:WI (Glx/BRL/Han) IGS BR
rats/dose at nominal concentrations of 0, 40, 160 and 500 ppm from
gestation day (GD) 6 through lactation day (LD) 21.  Average doses to
the dams were 0, 3.6, 15.1 and 43.3 mg/kg/day during gestation and 0,
8.1, 35.7 and 104.6 mg/kg/day during lactation for the 0, 40, 160 and
500 ppm groups, respectively.  No data were provided regarding exposure
to the offspring.  A Functional Operational Battery (FOB) was performed
on 30 dams/dose on GDs 13 and 20, and on 10 dams/dose on LDs 11 and 21. 
On postnatal day (PND) 4, litters were culled to yield four males and
four females (as closely as possible).  Offspring were allocated for
detailed clinical observations (PNDs 4, 11, 21, 35, 45, 60) and
assessment of motor activity (PNDs 13, 17, 21, 60), auditory startle
reflex habituation (PNDs 22, 38, 60), learning and memory (passive
avoidance [PNDs 22, 29] and watermaze [PNDs 60, 67] testing), and
neuropathology and brain morphometric evaluation at PND 21
(neuropathology for CNS tissues only) and at study termination (day
75±5 of age; neuropathology for CNS and PNS tissues).  Ophthalmologic
evaluations were also performed, around PND 50-60.  Pup physical
development was evaluated by body weight.  The age of sexual maturation
(vaginal opening in females and preputial separation in males) was
assessed.

No parental females died during the study; however, three dams at the
500 ppm dose had dystocia at parturition and were sacrificed on GD 22 or
24 (date was unclear in study report).  All of the pups from these
litters were dead.  No treatment-related effects on clinical signs, body
weight, body weight gain, or food consumption were observed in dams
during gestation and lactation.  The mean duration of gestation was
increased at 500 ppm (22.1 days compared to 21.5 days for the control
group).  The mean number of pups per litter was slightly decreased at
500 ppm (10.9 vs. 11.9 in the control group).  The number of stillborn
pups was increased at 160 and 500 ppm (0, 0, 3 and 3 in the 0, 40, 160
and 500 ppm groups, respectively).

No treatment-related clinical signs were observed in offspring during
lactation.  Post-weaning, there was a progressive development of
malocclusion and a deviated snout (dorsal aspect) with associated
findings (lacrimation, lacrimal stain) at 160 (one male, two females)
and 500 ppm (three males, seven females).  The changes became evident
around PND 32 with progressively more animals developing malocclusion
and a deviated snout.  Body weight at birth was increased at 160 and 500
ppm (7 and 13-14%, respectively, in both sexes); however by PND 71
absolute body weight in adult males at 500 ppm was significantly lower
than control values (5%).  The average age of onset of preputial
separation in males and vaginal opening in females was not affected by
treatment.

Clinical signs observed during the FOB examinations were associated with
malocclusion (broken teeth or malocclusion in one female each at 160 and
500 ppm on PNDs 45 and 60) and a deviated snout (two other females at
500 ppm on PND 60).  Total motor activity was increased at 500 ppm in
both sexes at PND 13 (82-120% above control levels).  Auditory startle
response was increased in males at 500 ppm on PND 22 (53-70%).  There
were no clear treatment-related effects on learning and memory as
evaluated by passive avoidance testing on PND 22-29. Increases in
latency and errors were seen in the water maze on PND 60, in males at
160 and 500 ppm  (83-67% increase in Trial 1 errors) and in females at
500 ppm only (54% increase in errors).  Limitations in the data
presentation and high variance made interpretation of the water maze
findings unclear.

Brain weight at PND 21 and 75 necropsy was unaffected by treatment.  No
gross lesions were observed in either sex at PND 21 necropsy or in
treated males at terminal necropsy.  Malocclusion was noted in both
sexes at 160 and 500 ppm; associated skull findings included fracture of
the nasal bone and deviation of the snout (at 500 ppm in both sexes). 
Incidence was higher in females than in males.  An increase in lesions
of the peripheral nerves was also noted at 500 ppm, again more prominent
in females than in males.  Mid- and low-dose groups were not evaluated. 
Changes in brain morphometric measurements were also seen at 500 ppm;
corpus callosum measurements were increased in males at both ages
(19-25%) and frontal cortex measures were increased in adult females
(5%); low and mid-dose groups were not evaluated for either measure.

The maternal LOAEL for prothioconazole-desthio (metabolite of
prothioconazole) in rats is 500 ppm (43.3 mg/kg/day during gestation)
based on dystocia.  The maternal NOAEL is 160 ppm (15.1 mg/kg/day during
gestation).

The offspring systemic and neurotoxicity NOAEL for
prothioconazole-desthio in rats could not be determined, due to the
absence of neuropathological and brain morphometric evaluations at the
mid and low dose treatment levels.

The non-neurotoxic developmental NOAEL for prothioconazole-desthio in
rats is 3.6 mg/kg/day, and the LOAEL is 15.1 mg/kg/day based on deviated
snout and malocclusion.

This developmental neurotoxicity study is classified as
Acceptable/Nonguideline and does not satisfies the guideline requirement
for a developmental neurotoxicity study in rats (OPPTS 870.6300, (83-6).
 The classification may be upgradable pending submission of the
additional data listed [in the DER], as well as acceptable positive
control data.  This review is a joint effort of the PMRA and the EPA.

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

Developmental Toxicity in Rats -- Prothioconazole

In a developmental toxicity study (MRID 46246316), prothioconazole (99.5
to 99.8% a.i.) was administered to 26 female Hsd Cpb:WU SPF-bred Wistar
rats/dose by oral gavage at dose levels of 0, 80, 500, or 1000 mg/kg
bw/day from days 6 through 19 of gestation.

An increase in urination and water consumption was observed in the mid
and high dose dams.  This observation was likely due to kidney function
impairment, although no correlating kidney findings were noted.  The
kidneys were not subject to histopathological examination, and
therefore, kidney damage may not have been found.  There were adverse
effects on body weight gain (corrected and uncorrected) in the mid and
high dose dams.  Dams in the high dose group lost body weight during
gestation days 6 to 8, and food consumption was decreased from days 6 to
11.  Body weight gain reductions of as much as 82% were observed in the
mid and high dose group during treatment.  Hepatotoxicity was evident as
levels of the liver enzymes alanine aminotransferase and alkaline
phosphatase were increased (17 and 33% respectively) while triglyceride
levels were decreased (13%) in the high dose animals.  Liver weights
were also slightly increased (absolute: 5%; relative 6%) in the high
dose group, with accompanying observations of focal necrosis observed in
one animal each of the low and mid dose groups, and two animals in the
high dose group.  There were no gross pathological findings of note in
any dose group.  Fetal weights were decreased slightly in the high dose
group, which is likely a secondary effect of the decreased body weight
gain in this dose group.  An increased incidence of engorged placenta
was observed in the mid and high dose groups, however, there was no
significant effect on the number of live fetuses.  This finding was
considered treatment-related, but not adverse.

The maternal LOAEL is 500 mg/kg bw/day, based on increased urination and
water consumption, and decreased body weight gain.  The maternal NOAEL
is 80 mg/kg bw/day.

The malformation microphthalmia was observed at an increased incidence
in the high dose group.  This finding was accompanied by an increased
incidence of eye rudiment flat in the treated animals, a finding that is
usually the first indication of a malformed eye.  Dilation of the renal
pelvis was observed at an increased incidence in the high dose litters. 
Although the incidence was within the range of historical control, the
finding was thought to be related to the decreased fetal weights and
delayed ossification observed in the skeletal evaluations.  Numerous
incidences of incomplete or no ossification were observed in digits,
toes, Sterne brae, and the pubic bone in the mid and/or high dose group
fetuses.  These were considered indications of delayed development in
the mid and high dose fetuses.  Dysplastic pubic bone (malformation) was
observed in one fetus in each of the mid and high dose groups.  The mid
and high dose group litters showed an increased incidence of left
punctiform 14th rib, while the high dose group showed an increase in the
incidence of bilateral punctiform 14th rib.  There were no findings in
the cartilage of the treated fetuses.

The developmental LOAEL is 500 mg/kg bw/day, based on increased
incidence of delayed ossification, increased incidence of dysplastic
pubic bone, and increased incidence of left punctiform 14th rib.  The
developmental NOAEL is 80 mg/kg bw/day.

On the basis of the maternal and developmental NOAELs, there does not
appear to be an increased susceptibility of the fetus to in utero
exposure to JAU 6476 (99.5 to 99.8% a.i.).

The developmental toxicity study in the rat is classified acceptable and
satisfies the guideline requirement for a developmental toxicity study
(OPPTS 870.3700; OECD 414) in rats.

Developmental Toxicity in Rats – Prothioconazole-Desthio

When the data from the two following oral studies (MRIDs 46246321 and
46246322) are combined, Acceptable Guideline data are available to
assess developmental toxicity in the rat using prothioconazole-desthio. 

In a developmental toxicity study (MRID 46246321),
prothioconazole-desthio Technical (Purity: 97.4%) was administered to 35
female Wistar rats/dose by gavage (at 10 mL/kg bw/day in bidistilled
water with 0.5% Cremophor EL) at dose levels of 0, 10, 30, or 100 mg/kg
bw/day from days 6 through 15 of gestation.  A subgroup of 10/dose were
used for assessment of liver toxicity and sacrificed on day 16.

In the main group dams, no mortalities or treatment-related clinical
signs were observed during the study.  Body weight gain decreased in the
high dose group during treatment and post-treatment.  Body weight gain
corrected for gravid uterine weight did not show significant differences
between control and treated groups.  Food consumption was decreased at
100 mg/kg bw/day.  No abnormal findings were noted during gross
pathological examination.  No significant treatment-related differences
in pregnancy incidence, mean number of corpora lutea, mean number of
implantations, mean fetal weight, sex ratio and pre-implantation loss.

In the subgroup dams, body weight decreases were all less than 10%, and
were not considered to be an adverse treatment-related effect.  However,
body weight gain was significantly decreased in the mid and high-dose
groups during treatment (GD days 6-11), with no accompanying
treatment-related effect on food consumption.  No significant
treatment-related effect on plasma ALAT or ASAT activity was noted. 
Increased absolute and relative liver weights were noted at the high
dose.  Pathological changes in the liver were observed in the high dose
group including increased severity of inflammatory foci, centrilobular
hypertrophy and fatty change.

The NOAEL for maternal toxicity is 30 mg/kg bw/day based on decreased
body weight gain, increased liver weight and liver histopathology
(increased severity of inflammatory foci, centrilobular hypertrophy and
fatty change) at the LOAEL of 100 mg/kg bw/day. 

Significant treatment-related increases in post-implantation loss and
resorptions were noted in the high dose main group dams.  There were no
significant treatment-related effects on fetal weight. 
Post-implantation loss in subgroup dams was also increased at the high
dose.  The mean number of live fetuses was slightly reduced in the high
dose subgroup dams as well.

A definitive increase in skeletal variations was noted in the high dose
group fetuses (incompletely and non-ossified crania, vertebrae, stern
brae, and forelimb/hindlimb digits), with some variations also noted at
the low and mid-doses.  The incidence of supernumerary ribs was
significantly increased in all dose groups and exceeded the incidence in
concurrent and historical control data.  An increased incidence of cleft
palate (2 fetuses in 2 litters) was noted at the high dose, compared to
concurrent (0) and historical control incidences (0-1 fetuses in 1
litter). Visceral examination confirmed the presence of cleft palate
(palatoschisis) in one high-dose animal.  No other visceral
malformations were noted. 

A NOAEL for developmental toxicity cannot be established in this study
due to the increased incidence of supernumerary ribs at all dose levels.
 Incomplete/delayed ossifications were also noted at all dose levels in
the absence of any effects on fetal weight gain.  Increased resorptions,
decreased number of live fetuses and an increased incidence of cleft
palate were observed at the highest dose tested, 100 mg/kg bw/day.  This
compound is teratogenic at maternally toxic doses.

Two further supplementary studies were conducted to help establish a
developmental NOAEL for supernumerary ribs (MRID 46246320) and to
determine the post-natal persistence of this skeletal variant (MRID
46246319).

An increased sensitivity of the fetuses to treatment with
prothioconazole-desthio is apparent, evidenced by the increased
incidence of supernumerary ribs and incomplete/delayed ossifications at
doses of 10 mg/kg bw/day and up, in the absence of maternal toxicity. 

The developmental toxicity study in the rat is classified acceptable and
satisfies the guideline requirement for a developmental toxicity study
(OPPTS 870.3700; OECD 414) in rats. 

In a developmental toxicity study (MRID 46246322)
prothioconazole-desthio Technical (Purity 94.7%) was administered to 25
female Wistar rats/dose once daily by gavage (in a volume of 10 mL/kg
bw/day) at doses 0, 1 or 3 mg/kg bw/day from days 6 through 15 of
gestation.

No mortalities, clinical signs, gross pathology or effects on body
weight/body weight gain or food consumption were observed in dams up to
3 mg/kg bw/day.  There were no treatment-related effects on pregnancies,
number of corpora lutea, number of implantations, number and size of
litters, sex ratio of the pups and mean pup weight.  Post-implantation
loss was decreased at 3 mg/kg bw/day which correlated with an increase
in the number of live fetuses at this dose. These effects were not
considered adverse. 

The NOAEL of 30 mg/kg bw/day for maternal toxicity, as determined in the
main study (MRID 46246321), was not affected by this supplementary
study. 

There were no adverse treatment-related effects on pup survival or pup
weight.  No external or visceral malformations were observed.  An
increased incidence of supernumerary ribs was noted at the highest dose
(3 mg/kg bw/day) compared to concurrent control values, however the
incidences were within the historical control data ranges and were
similar to the control group incidences in the main rat developmental
study.  The increase in supernumerary ribs noted at 3 mg/kg bw/day is
therefore considered incidental, and not an adverse effect in the
absence of maternal toxicity. 

The NOAEL for developmental effects was determined to be 3 mg/kg bw/day
based on the absence of any adverse effects on reproductive or
developmental parameters in this supplementary study.  The developmental
LOAEL of 10 mg/kg bw/day is based on the increased incidence of
supernumerary ribs and incomplete/delayed ossifications at doses of 10
mg/kg bw/day and up, in the main study.

An increased sensitivity of the fetuses to treatment with
prothioconazole-desthio is apparent, evidenced by the increased
incidence of supernumerary ribs and incomplete/delayed ossifications at
the LOAEL of 10 mg/kg bw/day, in the absence of maternal toxicity.

The developmental toxicity study in the rat is classified as
supplementary, as it is non-guideline, but satisfies GLP requirements. 

When both studies summarized above (MRIDs 46246321, 46246322) are
combined, the maternal NOAEL is 30 mg/kg/day, and the LOAEL is 100
mg/kg/day based on decreased body weight gain, increased liver weight
and liver histopathology (increased severity of inflammatory foci,
centrilobular hypertrophy and fatty change).  The developmental NOAEL is
3 mg/kg/day, and the developmental LOAEL is 10 mg/kg/day, based on
increased incidence of supernumerary ribs and incomplete/delayed
ossifications.

Developmental Toxicity in Rats – Prothioconazole Sulfonic Acid K Salt

In a developmental toxicity study (MRID 46246324) prothioconazole
sulfonic acid K. salt (98.9% a.i.) was administered to 25 mated female
rats (Rat WIST Hanlbm: WIST (SPF Quality))/dose by gavage via
bi-distilled water vehicle, at dose levels of 0, 30, 150 or 750 mg/kg
bw/day from days 6 through 20 of gestation. 

The test-article caused severe toxicity at the highest dose tested,
including mortality and clinical signs related to treatment.  Six dams
were found dead between day 9 and 12 post coitum and the clinical signs
observed included ruffled fur observed alone, or in tandem with
irregular breathing or breathing noise.  Effects on the high dose group
were comprised of decreased body weight and body weight gain, which can
be attributed to toxicity as the dose exceeded MTD.  An increase was
reported in the incidence of non-pregnant dams in the mid-dose group
(150 mg/kg), however the results of test article administration on
reproductive parameters in this group show that reproductive fitness is
not affected.  Indices such as mean corpora lutea, live fetuses and
implantation sites were greater than those in the control and low dose
group, suggesting that the increase in non-pregnant dams may be
incidental in this dose group.  

Developmental effects were incidental for most parameters following the
administration of prothioconazole sulfonic acid K salt.  While there
were abnormal findings in the mid and high dose groups, the types of
effects seen were not related and were negligible statistically.  The
effects might be more attributed to genetic variations within dams, or
the males that they were mated with.  Further findings that were seen in
the external, visceral and skeletal examinations were for the most part
within the concurrent and historical control ranges for this strain of
rat.  A finding that was outside the previously recorded historical
control range and the concurrent control range was the incidence of
rudimentary supernumerary one ribs, on both the right and left sides. 
The incidence was statistically significantly increased on both a litter
and foetal basis.

The maternal LOAEL is 750 mg/kg bw/day, based on mortality and clinical
signs.  The maternal NOAEL is 150 mg/kg bw/day.  

The developmental LOAEL was 30 mg/kg/day, based on a statistically
significantly increased incidence of rudimentary supernumerary one ribs,
at the low dose of 30 mg/kg bw/day.  A NOAEL was not established.

The developmental toxicity in the rat is classified acceptable and
satisfies the guideline requirement for a developmental toxicity study
(OPPTS 870.3700; OECD 414; DACO No. 4.5.2) in rats.

Developmental Toxicity in Rabbits, Prothioconazole

In a developmental toxicity study (MRID 46246328) prothioconazole (94%),
in aqueous 0.5% carboxymethylcellulose sodium salt (CMC), was
administered to groups of 24 mated female Chinchilla rabbits by oral
gavage at 0, 10, 30, or 80 mg/kg bw/d from post coitum (pc) day 6 to 27.
 The animals were sacrificed on pc day 28.  The number of pregnant
females at 10 and 80 mg/kg bw/d groups was not sufficient. Therefore, 6
and 7 mated females were added to these groups, respectively.  Further,
because no clear effects of toxicity were noted up to and including 80
mg/kg bw/d, an additional dose group of 24 mated females was tested at
350 mg/kg bw/d. 

One high-dose dam was found dead on pc day 25.  Compared to the vehicle
control group, high-dose animals had a higher number of total
resorptions or abortions, lower food consumption and body weight gain,
and marginally lower placenta weights.  No treatment-related signs were
noted in the other dose groups and no abnormal changes were noted during
necropsy. Comparison of the liver and adrenal weights gave no indication
of treatment-related effects.  There was an increase in
post-implantation loss and a corresponding decrease in the total number
of fetuses in high-dose dams.  The findings included 3 dams with total
resorptions and 3 dams which aborted during the last treatment week. 
There was a decrease of fetal body weights and marginally retarded
ossification at 350 mg/kg bw/d.  None of the other fetal examinations
(external and visceral examination, examination of fetal hearts and
major blood vessels, of the heads and brains, and sex ratios) gave
indications of treatment-related changes. 

Based on these results the LOAEL and NOAEL for the maternal toxicity
were considered to be 350 and 80 mg/kg bw/d, respectively.  Treatment
with prothioconazole caused abortions and total resorptions and lower
fetal body weight at 350 mg/kg bw/d.  Therefore the LOAEL and NOAEL for
developmental toxicity were considered to be 350 and 80 mg/kg bw/d,
respectively.  There was no evidence of teratogenic potential of
prothioconazole.

The developmental toxicity study in the rabbit is acceptable and
satisfies the guideline requirement for a developmental toxicity study
(OPPTS 870.3700; OECD 414) in rabbits.

Developmental Toxicity in Rabbits – Prothioconazole-Desthio

In a developmental toxicity study (MRID 46246327) SXX 0665 (94%) was
administered to groups of 15 female Himalayan rabbits by oral gavage
(Deionized water containing 0.5% Cremorphor EL (BASF)) at 0, 2, 10, or
50 mg/kg bw/d from post coitum (pc) day 6 to 18. The animals were
sacrificed on pc day 29. There were no effects on clinical signs, water
intake, or mortality. Food intake was marginally lowered in high-dose
dams. Body weight gain of high-dose animals was adversely affected
during gestation, presumably as a result of elevated resorption rate. At
terminal sacrifice, there was no significant gross pathological
observation. Treatment-related histopathological findings were evident
in the liver of mid- and high-dose dams. The liver findings included
increased destruction of individual hepatocytes and low glycogen
mobilization. Examination of fetal parameters revealed no
treatment-related findings on fetal weight and sex, or on skeletal
system development. The placentas were normal. Due to an elevated
resorption rate (including total litter loss) and the number of fetuses
per dam were lower at 50 mg/kg bw/d group. Malformations were observed
at 10 and 50 mg/kg bw/d groups. At 10 mg/kg bw/d, alterations included
malformed vertebral body and ribs, arthrogryposis, and multiple
malformations. These malformations could arise spontaneously in
Himalayan rabbits. At 50 mg/kg bw/d, malformed alterations included
cleft plates. 

The maternal LOAEL is 50 mg/kg bw/d, based on decreased food
consumption, body weight gain, elevated resorption rate (including total
litter loss) and decreased number of fetuses per dam at this dose.  The
maternal NOAEL is 10 mg/kg bw/d.

The developmental LOAEL is 10 mg/kg bw/d, based on arthrogryposis and
multiple malformations at this dose.  The developmental NOAEL is 2 mg/kg
bw/d. SXX 0665 was teratogenic in the Himalayan rabbit at maternally
non-toxic doses.

The developmental toxicity study in the rabbit is acceptable and
satisfies the guideline requirement for a developmental toxicity study
(OPPTS 870.3700; OECD 414) in rabbits.  This review is a joint effort of
the PMRA and the EPA.

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

Prothioconazole

In a 2-generation reproduction study (MRID 46246334), prothioconazole
(98.1-98.8%) was administered by gavage to 30 Wistar rats/sex/dose in
aqueous 0.5% methylcellulose and 0.4% Tween 80 suspension at dose levels
of 0, 10, 100 or 750 mg/kg bw/day at a dosing volume of 10 mL/kg. 

There were no treatment-related mortalities or clinical findings
throughout the study in any generation in either adults or pups.  There
was a decrease in body weight gain and increase in food consumption in
the P generation males during premating at 750 mg/kg bw/day, thereby
indicating a decrease in food efficiency.  At 750 mg/kg bw/day, F1 males
body weight was consistently 14-17% lower when compared to the control
group.  This is consistent with the findings for the F1 male pups
between days 7 and 21, thereby indicating that the F1 males were
consistently 14-17% smaller than the control group from day 21 to
sacrifice.

The following reproductive parameters were noted.  At the 750 mg/kg
bw/day dose level, a treatment-related decline in the number of estrous
cycles occurred in both the P and F1 generations.  Also, a significant
increase in the length of the estrous cycle was observed in the P
generation.  There were no treatment-related effects on any sperm
parameters either generation at any dose.  There were no
treatment-related effects on mating, fertility, implanations or
gestation indices (i.e., animals mating, becoming pregnant and
maintaining a pregnancy through to parturition) in either generation at
any dose.  At 750 mg/kg bw/day, non statistical but slight increases in
time to insemination were observed in both generations.  In the ovaries,
the number of pre-antral follicles was decreased in both generations at
the 750 mg/kg bw/day dose level.  The number of corpora lutea were
significantly decreased in the P generation.  The significance of these
findings is considered equivocal.  No other significant findings were
observed in either generation during a quantitative evaluation of the
ovaries.  

There were no treatment-related effects on live birth, viability,
lactation, birth indices, mean litter size or sex ratio in pups at any
dose in either generation.  The number of days to vaginal opening was
unaffected in the F1 generation.  Preputial separation was increased at
the high dose in the F1 generation, when compared to historical
controls, but was likely due to delayed growth during lactation.  In the
F2 generation, the anogenital distance at birth was increased compared
to control in both sexes (at 100 and 750 mg/kg bw/day for males and at
750 mg/kg bw/day for females), however, this was within historical
control range in males.  The increase in anogenital distance in females
is likely due to the lengthened duration of gestation and the higher
birth weights of the pups.  Pup body weight was decreased in the high
dose between day 4 and 7 in the F1 generation and remained decreased
throughout lactation.  Both sexes showed a decrease in body weight day 4
through 21 in the F1 generation.  In the F2 generation, litter body
weight decreased day 14 through 21.  In males the decrease was seen days
14 through 21 and in females the decrease was seen day 14.

There were no notable gross pathology findings in adults or pups of
either generation. 

Absolute liver weight was increased in both sexes in the P generation
and relative liver weight was increased in both sexes in the F1
generation at 750 mg/kg bw/day.  Hepatocytomegaly was observed during
histopathology in the males of both generations and in F1 females at
this dose.  Relative kidney weight was increased in males in both
generations at 750 mg/kg bw/day.  Histopathology revealed multifocal
cortical nephrosis in both generations of males at 750 mg/kg bw/day. 
The relative weight of the seminal vesicles was decreased at 100 and 750
mg/kg bw/day in the P generation and at 750 mg/kg bw/day in the F1
generation.  While there were no histopathological findings to support
these findings, in the F1 generation, decreases in testicular, prostate,
epicauda and epididymis weight were also noted, indicating a clear
pattern of sexual organ weight decrease.  In the P and F1 generations,
the relative weight of the thymus was decreased in males at 750 mg/kg
bw/day while the absolute and relative weights of this organ were both
decreased in the P generation females at the 100 and 750 mg/kg bw/day
dose levels. No histopathological findings were observed in this organ. 
Decreases in absolute spleen weight were observed in both generations of
male pups at the high dose while decreases in absolute and relative
spleen weight were observed in female pups in both generations.  There
were no histopathological findings in the pups of either generation.

The parental LOAEL is 750 mg/kg bw/day, based on decreased body weights,
body weight gains and increased food consumption, increased liver
weights and kidney weights, decreased thymus, testicular, prostate,
epicauda and epididymis weights as well as histopathological findings in
the liver and kidney.  The NOAEL is 100 mg/kg bw/day. 

The LOAEL for reproductive effects is 750 mg/kg bw/day based on
decreased number of estrous cycles in both generations and increased
duration of estrous cycle in the P generation.  The NOAEL is 100 mg/kg
bw/day.

The LOAEL for offspring effect is 750 mg/kg bw/day based on decreased
body weight and reduced spleen weight.  The NOAEL is 100 mg/kg bw/day.

This study is acceptable and satisfies the guideline requirement for a
2-generation reproductive study (OPPTS 870.3800); OECD 416 in rat. 

Prothioconazole-Desthio

In a 2-generation reproduction study (MRID 46246333),
prothioconazole-desthio was administered to 30 Sprague-Dawley
rats/sex/dose in the diet at dose levels of 0, 40, 160, and 640 ppm. 

Parental animals: In the P parental animals, one control female and one
high-dose female died due to dystocia; three high-dose females were
killed prematurely  due to signs of dystocia; one high-dose female was
killed prematurely due to complete litter loss on lactation day 1.  In
the F1 parental animals, three high-dose female died due to dystocia,
one mid-dose female and one high-dose female were killed prematurely due
to complete litter loss on lactation day 2.  The increased incidence of
dystocia was considered to be treatment-related.  There were no
treatment-related clinical signs in either generation.

No significant treatment-related adverse effects on parental body weight
or body weight gain were noted during pre-mating or gestation for either
generation.  During lactation, high-dose P females showed increased body
weight gain accompanied by decreased food consumption (both P and F1
females), which could be associated with decreased litter size and pup
weight in the high dose groups. 

There were no treatment-related effects on estrous cycles, mating,
gestation and birth indices, or implantation sites or number of litters.

Relative liver weight was increased in high dose P and F1 adult males
and high dose F1 adult females, while absolute liver weight was
increased in high dose P males only.  Absolute and relative ovary
weights were statistically increased in 640 ppm F1 adult females.
Absolute ovary weights also were statistically increased in 160 ppm F1
adult females.  Histopathological observations in the liver consisted of
increased incidence and/or severity of multifocal hepatocellular
cytoplasmic vacuolization in both mid and high dose P and F1 males, and
in high dose P and F1 females.  These observations are consistent with
fatty change in the liver which could account for the observed increases
in liver weights.  Increased liver necrosis was additionally observed in
high dose P and F1 females.  The increased incidences of dystocia in
high dose females may be related to these histopathological changes. 
The mean number of antral follicles in the ovaries was increased in high
dose females, and statistically significant in the F1 high dose females.
 There were no significant differences in the number of preantral
follicles or corpora lutea.  The toxicological significance of this
increase is unknown; however there was a significant increase in ovary
weight in the F1 females only.  No histopathological changes were noted
in male reproductive organs. 

Offspring: Increased incidence of cannibalised and/or missing pups was
noted in the high dose for both the F1 and F2 pups.  The number of dams
with cannibalised pups was also significantly increased at the high dose
in both generations.  Additionally in the F2 pups, increased incidences
of weak and unthrifty pups were noted.  Litter size was significantly
decreased at the high dose in F1 generation, however it was still well
within the range of historical control data provided for this strain of
rat, and is not considered an adverse treatment-related effect. 
Viability index on day 4 was significantly reduced at the high dose in
both generations.

There was a significant decrease in pup body weight at the high dose
from lactation days 7-21 in the F1 litters; reduced pup body weight was
also noted in the F2 litters on lactation days 14 and 21.  These
decreases were considered to be treatment-related.  An increased
incidence of the following observations was noted in F1 pups culled on
day 4 and those who died during days 0-3: enlarged liver, cleft palate,
red kidney zones, dilated renal pelvis, dilated ureters, and distended
bladder.  Dilated renal pelvis was the only observation in the F2 pups. 
No gross lesions were noted in the 21 day weanlings. 

The LOAEL for parental effects is 640 ppm (equivalent to 40-46 or 41-73
mg/kg bw/day [M/F]) based on increased liver weight, liver
histopathology and decreased food consumption during lactation (females
only).  The NOAEL is 160 ppm (equivalent to 9.5-11 or 10-19 mg/kg bw/day
[M/F]). 

The LOAEL for reproductive effects is 640 ppm (equivalent to 40-46 or
41-73 mg/kg bw/day [M/F]) based on increased incidence of dystocia,
decreased viability and decreased pup body weight.  The NOAEL is 160 ppm
(equivalent to 9.5-11 or 10-19 mg/kg bw/day [M/F]).

The LOAEL for offspring effects is 640 ppm (equivalent to 40-46 or 41-73
mg/kg bw/day [M/F]) based on decreased pup body weight and increased
incidence of cleft palate, dilated renal pelvis, dilated ureters and
dilated bladder.  The NOAEL is 160 ppm (equivalent to 9.5-11 or 10-19
mg/kg bw/day [M/F]).

On the basis of the parental and offspring NOAELs/LOAELs, there was no
indication that the neonates were quantitatively more sensitive than the
adults following treatment.

This study is acceptable and satisfies the guideline requirement for a
2-generation reproductive study (OPPTS 870.3800); OECD 416 in rats. 

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

No additional studies from the open literature were found.

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

	Prenatal

Available evidence from rat developmental toxicity studies with
prothioconazole (oral)  and its desthio (oral and dermal) and sulfonic
acid K salt (oral) metabolites, rabbit developmental with desthio
metabolite (oral), and rat developmental neurotoxicity with desthio
metabolite (oral), as well as a multigeneration reproduction study with
the desthio metabolite, indicate that there is concern for prenatal
toxicity.  Effects include skeletal structural abnormalities such as
cleft palate, deviated snout, malocclusion, and extra ribs;
developmental delays; other effects include changes in brain
morphometry, peripheral nerve lesions, and death.

Postnatal

Available data also show that the skeletal effects such as extra ribs
are not completely reversible after birth in the rat, but persist as
development continues.  Data from the developmental neurotoxicity study
also show that brain morphometry is abnormal postnatally, and there is
an increased incidence of lesions of the peripheral nerves postnatally.

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

Susceptibility was not demonstrated in rats or rabbits exposed to
prothioconazole in developmental or reproductive toxicity studies. 
However, susceptibility was demonstrated in rats and rabbits when
exposed to prothioconazole-desthio. 

Quantitative Susceptibility.  Developmental effects were seen in the rat
offspring at levels below maternally toxic levels following both oral
and dermal exposure.  For example, an increase in extra ribs was
observed in rat offspring at levels that were not toxic to dams
[prothioconazole-desthio, prothioconazole sulfonic acid K salt].  An
increased incidence of progressive malocclusion and deviated snout was
observed in offspring in the rat DNT at levels below the maternal LOAEL.
 Developmental effects such as structural alterations and malformations
were also seen in the rabbit at levels below the maternal LOAEL.

Qualitative Susceptibility.  In the rat reproduction study, effects in
the offspring occurred at levels comparable to maternally toxic levels,
but the effects appeared to be more severe than maternal/parental
effects.  For example, changes in liver weight and liver histopathology
were noted in the parents, while decreased viability and increased
malformations (cleft palate, dilated renal pelvis, dilated ureters and
dilated bladder) were noted in the offspring.

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

The toxicology database for prothioconazole and its
prothioconazole-desthio metabolite shows evidence of increased
qualitative and quantitative susceptibility in the offspring.  There are
adequate data in the prothioconazole (including metabolites) database to
characterize the potential for pre-natal or post-natal risks to infants
and children; i.e., two-generation reproduction studies in rats;
developmental studies in rats and rabbits; and a developmental
neurotoxicity (DNT) study in rats.  The effects seen in these studies
suggest that pups are more susceptible; i.e., pup effects were seen at
levels below the LOAELs for maternal toxicity and, in general, were of
comparable or greater severity compared to the effects observed in
adults.

In addition, since the developmental effects seen in the DNT study (MRID
46246418) were investigated at the high dose level only, there is
uncertainty concerning the LOAEL/NOAEL for developmental effects in this
study.  Specifically, an increase in lesions of the peripheral nerves
was noted at the high-dose, but mid- and low-dose groups were not
evaluated.  Changes in brain morphometric measurements were also seen at
the high-dose, but mid- and low-dose groups were not evaluated.  Because
of the lack of brain measurements and examination of peripheral nerves
at the low and mid doses, it is impossible to rule out an effect at
these levels.  Thus, the FQPA factor is retained at 10X.  However, the
degree of concern for pre- and postnatal toxicity is low, because this
residual uncertainty is addressed through the use of a 10X FQPA/database
uncertainty factor.

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

A developmental neurotoxicity study [Acceptable Non-Guideline] was
submitted with the other toxicity data, which has provided useful
information.  A second study is not requested at this time, however the
current study was not adequately reported, and the missing data are
required as a condition of registration.

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

The prothioconazole risk assessment team has recommended that the 10X
FQPA Safety Factor be retained in the form of an uncertainty factor
(UFDB) for the lack of data to established a NOAEL and LOAEL for
neurotoxicity (brain morphometry and peripheral nerve lesions) observed
in the rat developmental neurotoxicity study.  This uncertainty factor
is applied to the acute and chronic aggregate dietary risk assessments

The toxicity database for prothioconazole and its metabolites is
considered complete, and deemed adequate for selection of endpoints to
be used in this risk assessment.  There is evidence of increased
qualitative susceptibility following pre-/or postnatal exposure in the
rat 2-generational studies conducted with prothioconazole-desthio such
as decreased viability and increased malformations.  These
developmental/offspring effects occurred at doses causing
maternal/parental toxicity in the form of decreased body weight and/or
changes in liver histopathology.  There is also evidence of increased
quantitative susceptibility in the developmental (oral and dermal) and
the developmental neurotoxicity studies in the rat, and the oral
developmental study in the rabbit.

There is low concern for the quantitative and qualitative susceptibility
and no additional residual uncertainties with respect to either pre-/or
postnatal toxicity because NOAELs/LOAELs derived from the toxicity
database are well characterized [with the exception of certain endpoints
in the developmental neurotoxicity study] and are used as endpoints for
appropriate risk assessments.

There are also no additional residual uncertainties with respect to the
exposure data base.  The exposure data are complete or are estimated
based on data that reasonably account for potential exposures.  The
dietary food exposure assessment utilized empirical processing factors,
100% crop treated (acute assessment), average residue levels, and
livestock maximum residues.  Results from ruminant feeding studies and
poultry metabolism studies were used to determine the maximum residue
levels for livestock commodities.  The dietary drinking water assessment
utilized health protective high-end model estimates of drinking water
concentrations (EDWCs).  EDWCs were further refined by applying regional
percent cropped area (PCA) factors for canola, beans, peanuts, and rice.
 There is no potential for residential exposure.  Based on these data
and conclusions, the 10X FQPA Safety Factor is subsumed in the form of a
database uncertainty factor (UFDB ) for lack of data to establish a
NOAEL and a LOAEL for neurotoxicity (brain morphometry and peripheral
nerve lesions) observed in the rat developmental neurotoxicity study.

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: Developmental Toxicity in Rabbits	OPPTS 870.6300  (83-6

MRID No.: 46246327  (Prothioconazole-desthio)

Executive Summary:   In a developmental toxicity study (MRID 46246327)
prothioconazole-desthio (94%) was administered to groups of 15 female
Himalayan rabbits by oral gavage at 0, 2, 10, or 50 mg/kg bw/d from post
coitum (pc) day 6 to 18.  The animals were sacrificed on pc day 29.

There were no effects on clinical signs, water intake, or mortality. 
Food intake was marginally lowered in high-dose dams.  Body weight of
high-dose animals was adversely affected during gestation, presumably as
a result of elevated resorption rate.  At terminal sacrifice, there was
no significant gross pathological observation.  Treatment-related
histopathological findings were evident in the liver of mid- and
high-dose dams.  The liver findings included increased destruction of
individual hepatocytes and low glycogen mobilization.  Examination of
fetal parameters revealed no treatment-related findings on fetal weight
and sex, or on skeletal system development.  The placentas were normal. 
Due to an elevated resorption rate, the gestation rate and the number of
fetuses were lower at 50 mg/kg bw/d group.  Malformation was observed at
10 and 50 mg/kg bw/d groups.  At 10 mg/kg bw/d, alterations included
malformed vertebral body and ribs, arthrogryposis, and multiple
malformations.  These malformations could arise spontaneously in
Himalayan rabbits.  At 50 mg/kg bw/d, malformed alterations included
cleft plates.

The maternal LOAEL is 50 mg/kg bw/d, based on decreased food
consumption, body weight gain, elevated resorption rate (including total
litter loss) and decreased number of fetuses per dam at this dose.  The
maternal NOAEL is 10 mg/kg bw/d.

The developmental LOAEL is 10 mg/kg bw/d, based on arthrogryposis and
multiple malformations at this dose.  The developmental NOAEL is 2 mg/kg
bw/d.  Prothioconazole-desthio was teratogenic in the Himalayan rabbit
at maternally non-toxic doses.

The developmental toxicity study in the rabbit is acceptable and
satisfies the guideline requirement for a developmental toxicity study
(OPPTS 870.3700; OECD 414) in rabbits.

Dose and Endpoint for Establishing aRfD: Developmental toxicity LOAEL =
10 mg/kg/day, based on multiple malformations including malformed
vertebral body and ribs, arthrogryposis .  The NOAEL is 2.0 mg/kg/day.

Uncertainty Factor (UF): 1000 (10X for interspecies extrapolation and
10X for intraspecies variations, 10X for database uncertainty.  See
Sections 3.1.3, 3.1.4)

Comments about Study/Endpoint   Please refer to the summary table in
Section 3.1.3. There is a co-critical study which reported developmental
effects in the fetus and neonate following exposure to prothioconazole
desthio, using a developmental neurotoxicity protocol (MRID 46246418). 
Deviated snout and malocclusion were observed at 15.1 mg/kg/day (NOAEL =
3.6 mg/kg/day).  Also, brain morphometrics changes and an increased
incidence of peripheral nerve lesions were observed at 43.3 mg/kg/day
(NOAEL not reported).  If the NOAEL of 3.6 mg/kg/day were used as the
endpoint, with 100X UF, the Acute RfD would be 0.036 mg/kg.  Since the
endpoint derived from the developmental neurotoxicity study is not as
low as the endpoint from the rabbit developmental study, it is not used
for this risk assessment.  Another study (MRIDs 46246321, 46246322)
showing increased incidence of supernumerary ribs and incomplete/delayed
ossifications using an oral developmental toxicity protocol in the rat,
was also considered for this endpoint.  However, the rabbit study
provided more robust endpoint on which to base a risk assessment, while
occurring at dose levels very similar to the rat study.  Therefore the
rat study was not used.

Acute RfD (females 13-49 years old)  =  2.0 mg/kg/day  = 0.002 mg/kg  

					           1000 (UF)

3.5.2	Acute Reference Dose (aRfD) - General Population, including
Infants & Children  TC \l3 "3.5.2	Acute Reference Dose (aRfD) –
General Population, including Infants & Children 

An endpoint of concern attributed to a single dose effect was not
identified in the database; therefore, acute risk to the general
population including infants and children was not quantified.  An
acceptable acute neurotoxicity study using prothioconazole is available,
which showed reduce levels of motor and locomotor activity at a
relatively high single dose (NOAEL = 200 mg/kg/day).  However, these
effects were transient and reversible; and occurred at a dose which is
two orders of magnitude higher than the levels where toxicity is
observed in the chronic studies.  Therefore; the Chronic RfD provides
more than adequate protection from these transient and reversible acute
effects.

3.5.3	Chronic Reference Dose (cRfD) - All Populations  TC \l3 "3.5.3
Chronic Reference Dose (cRfD) - All Populations 

Study Selected: Chronic/Oncogenicity Study in Rats	OPPTS 870.6300  (83-6

MRID No. 46246342  (Prothioconazole-desthio)

Executive Summary:   See Executive Summary in Section 3.3.2.

Uncertainty Factor (UF): 1000 (10X for interspecies extrapolation, 10X
for intraspecies variations, 10X for database uncertainty. See Sections
3.1.3 and 3.1.4)

Dose and Endpoint for Establishing cRfD: Chronic toxicity LOAEL = 8.0,
based on liver histopathology in males and females [hepatocellular
vacuolation and fatty change (single cell, centrilobular, and
periportal)].  The NOAEL was 1.1 mg/kg/day.

Comments about Study/Endpoint: This study showed significant effects at
dose levels lower than any other appropriate study in the database.  It
is also of an appropriate duration (chronic), and the NOAEL is expected
to be protective against the uncertainties surrounding the brain
morphometric and peripheral nerve degeneration observations in the
developmental neurotoxicity study, the number for risk assessment there
being 0.043 mg/kg/day (43.4 mg/kg/day/1000 UF).

Chronic RfD (general population)  =  1.1 mg/kg/day (LOAEL) = 0.001 mg/kg
 

						               1000 (UF)

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

Dose and Endpoint for Risk Assessment: None.  Residential exposure is
not anticipated..

3.5.5	Dermal Absorption  TC \l3 "3.5.5	Dermal Absorption 

The dermal absorption factor is based on a dermal penetration study on
prothioconazole-desthio.  In a dermal absorption study (Guideline OPPTS
870.7600 [(85-2], MRID 46246425), five male rhesus monkeys received a
dermal dose of 144 µg (6 µg/cm2) prothioconazole-desthio containing
14C prothioconazole-desthio for 8 hours.

Observed was a mean recovery of 18.61% of the dose in excreta (10.25 %
in urine, 5.79 % in feces, 1.50 % in cage debris/rinse samples, and 1.07
% in the pan wash/wipe and chair wipe) through 144 hours.  The majority
of the administered dermal dose was recovered from the application site
(mean = 73.54 %) from the washings.  The overall mean recovery of
radioactivity from the dermally dosed animals was 92.15 %.

The dermal absorption rate was 18.6%.

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

Study Selected: Dermal Developmental Toxicity in Rats	OPPTS 870.6300 
(83-6

MRID No.: 46246325 (Prothioconazole-desthio)

Executive Summary: In a developmental toxicity study (MRID 46246325,
46246326) SXX 0665 technical (93.7% a.i.) was administered by topical
application as a suspension in 1% aqueous Cremophor EL to four groups of
25 mated female Wistar rats (Bor/WISW [SPF Cpb]) at dose levels of 0,
10, 30, 100, 300 or 1000 mg/kg bw/day from day 6 to 15 post coitum.  The
applications were made for 6 hours/day, under occlusive dressings, to a
5 x 5 cm area of clipped dorsal area.

≥300 mg/kg, which persisted up to 4 days.  There was also very slight
swelling in one animal at 1000 mg/kg for one day.  There were no
treatment-related clinical findings.  There were no treatment-related
effects on body weight, body weight gain or food intake.  There were no
treatment-related findings at necropsy or in liver weight.  The maternal
NOAEL was 1000 mg/kg.  The maternal LOAEL was > 1000 mg/kg, based on
lack of adverse systemic effects in dams at doses tested.

There were no treatment-related differences in pregnancy rate, number of
corpora lutea, implantations, live fetuses, pre- or post- implantation
loss, fetal weight, sex ratio, the total number of resorptions, late
resorptions, and mean fetal weights. 

There was an increased incidence of supernumerary 14th rib in all
treatment groups (> 100 mg/kg). There was an increased incidence of
microphthalmia at 300 and 1000 mg/kg compared with concurrent and
historical controls.  There was an increased incidence of the following
malformations at 1000 mg/kg:  macroglosia, hydrocephaly and
hydronephrosis compared to concurrent and historical controls. Cleft
palate occurred in only one fetus and litter, at 1000 mg/kg, as well as
in the historical control data and is not considered treatment-related. 
There was an increased incidence of tubular bone dysplasia at 1000 mg/kg
and an increased incidence of 15th rib at >300 mg/kg relative to
concurrent controls.  The developmental NOAEL was 30 mg/kg.  The
developmental LOAEL was 100 mg/kg, based on an increased incidence of
supernumerary rib (14th rib) at this dose.  There was a quantitative
increase in pup sensitivity, with malformations occurring at
non-maternally toxic doses.  

Dose and Endpoint for Risk Assessment:  Developmental toxicity NOAEL =
30 mg/kg/day. LOAEL = 100 mg/kg/day, based on increased incidence of
supernumerary rib.  Also, because this study showed effects in the
fetus, a female-specific body weight of 60 kg should be used for dermal
exposure estimates.

Comments about Study/Endpoint:  This study is an acceptable repeated
exposure, route-specific dermal study, therefore it is deemed to be the
most appropriate study for this risk assessment.

3.5.6.2. Dermal Exposure Long Term:

Dose and Endpoint for Risk Assessment: None; long term exposure is not
expected.

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

Study Selected: Developmental Toxicity in Rabbits	OPPTS 870.6300  (83-6

MRID No.: 46246327 (Prothioconazole-desthio)

	Executive Summary:   See Section 3.5.1.1.

Dose and Endpoint for Risk Assessment: Developmental toxicity LOAEL = 10
mg/kg/day, based on multiple malformations including malformed vertebral
body and ribs, arthrogryposis.  The NOAEL is 2.0 mg/kg/day.

Uncertainty Factor (UF): 1000 (10X for interspecies extrapolation and
10X for intraspecies variations, 10X for database uncertainty.)

Comments about Study/Endpoint   Please refer to the summary table in
Section 3.1.3. There is a co-critical study which reported developmental
effects in the fetus and neonate following exposure to prothioconazole
desthio, using a developmental neurotoxicity protocol (MRID 46246418). 
Deviated snout and malocclusion were observed at 15.1 mg/kg/day (NOAEL =
3.6 mg/kg/day).  Also, brain morphometrics changes and an increased
incidence of peripheral nerve lesions were observed at 43.3 mg/kg/day
(NOAEL not reported).  If the NOAEL of 3.6 mg/kg/day were used as the
endpoint, with 100X UF, the Acute RfD would be 0.036 mg/kg.  Since the
endpoint derived from the developmental neurotoxicity study is not as
low as the endpoint from the rabbit developmental study, it is not used
for this risk assessment.  Another study (MRIDs 46246321, 46246322)
showing increased incidence of supernumerary ribs and incomplete/delayed
ossifications using an oral developmental toxicity protocol in the rat,
was also considered for this endpoint.  However, the rabbit study
provided more robust endpoint on which to base a risk assessment, while
occurring at dose levels very similar to the rat study.  Therefore the
rat study was not used.

3.5.7.1. Inhalation Exposure Long Term:

Dose and Endpoint for Risk Assessment: None; a long-term inhalation
exposure scenario has not been identified

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

A summary of the level of concern margins of exposure (MOEs) for risk
assessment purposes are presented below:

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	

1000	

1000	

None

Inhalation	

1000	

1000	

None

Residential Exposure

Dermal or Inhalation	

None	

None	

None

Occupational exposure:  Dermal and Inhalation: Based on the conventional
uncertainty factor of 1000X (10X for interspecies extrapolation, 10X for
intraspecies variation and 10X FQPA for database uncertainty).

Based on the conventional uncertainty factor of 100X (10X for
interspecies extrapolation and 10X for intraspecies variation), plus 10X
for lack of a NOAEL for brain morphometry and peripheral nerve lesions
in the oral developmental neurotoxicity study.

Residential exposure:  None expected.

3.5.9	Recommendation for Aggregate Exposure Risk Assessments  TC \l3
"3.5.9	Recommendation for Aggregate Exposure Risk Assessments 

For this assessment all dietary exposures, i.e., food and drinking
water, are aggregated.  For the proposed crops, the estimated
concentrations of prothioconazole and its degradates in drinking water,
provided by EFED, were incorporated directly into the acute and chronic
dietary assessments.

For exposures to mixers, loaders, and applicators, risk estimates for
short- and intermediate-term exposures from both inhalation and dermal
routes are added together, because the hazard/endpoint is the same. 
Because the MOEs for dermal and inhalation exposures are calculated
using different NOAELs, a total MOE approach [1/((1/MOE dermal) +
(1/MOEinhalation))] should be used to combine dermal and inhalation
risks.

3.5.10	Classification of Carcinogenic Potential  TC \l3 "3.5.10
Classification of Carcinogenic Potential 

The available studies in the mouse and rat show no increase in tumor
incidence.  Therefore, HED has concluded prothioconazole or its
metabolites are not carcinogenic, and are classified “Not likely to be
Carcinogenic to Humans” according to the 2005 Cancer Guidelines.

3.5.10	Summary of Toxicological Doses and Endpoints for Prothioconazole
for Use in Human Risk Assessments  TC \l3 "3.5.10	Summary of
Toxicological Doses and Endpoints for Prothioconazole for Use in Human
Risk Assessments 

Table 3.5.10.1  Summary of Toxicological Doses and Endpoints for
Prothioconazole desthio 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)	NOAEL = 2.0 mg/kg/day	UFA=10x

UFH=10x

FQPA SF=10x (UFDB)	Acute RfD = 0.002 mg/kg/day

aPAD = 0.002 mg/kg/day	Developmental Toxicity study in rabbits

LOAEL = 10 mg/kg/day, based on structural alterations including
malformed vertebral body and ribs, arthrogryposis, and multiple
malformations.

Acute Dietary (General Population, including infants and 	None	None	None
An appropriate study was not identified

Chronic Dietary (All Populations)	NOAEL=1.1 mg/kg/day	UFA=10x

UFH=10x

FQPA SF=10x (UFDB)	Chronic RfD = 

0.001 mg/kg/day

cPAD = 0.001 mg/kg/day	Chronic/Oncogenicity study in rats  

LOAEL = 8.0 mg/kg/day based on liver histopathology (hepatocellular
vacuolation and fatty change (single cell, centrilobular, and
periportal)).

Incidental Oral Short- and Intermediate-Term (1-30 days and 1-6 months)
N/A	N/A	N/A	Incidental oral exposure endpoint not identified because
residential exposure is not anticipated.

Dermal Short- and Intermediate-Term (1-30 days and 1-6 months)	N/A	N/A
N/A

	Dermal endpoints are not applicable because residential exposure is not
anticipated.

Inhalation Short- and Intermediate-term (1-30 days and 1-6 months)	N/A
N/A	N/A

	Inhalation endpoints are not applicable because residential exposure is
not anticipated

Cancer (oral, dermal, inhalation)	Classification:  “Not likely to be
Carcinogenic to Humans” based on the absence of significant tumor
increases in two adequate rodent carcinogenicity studies.

For acute and chronic dietary (food and water) risk assessments, the 10x
FQPA SF has been retained in the form of a UFdb (10x) for the lack of
NOAEL and a LOAEL from the developmental neurotoxicity study, regarding
some neurotoxic endpoint (peripheral nerve lesions and brain
morphometrics).

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

Table 3.5.10.2  Summary of Toxicological Doses and Endpoints for
Prothioconazole desthio 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 (1-30 days and 1-6 months)	NOAEL=30
mg/kg/day

	UFA=10x

UFH=10x

UFDB = 10x 	Occupational LOC for MOE = 1000	Dermal developmental study
in rats  

LOAEL = 100 mg/kg/day based on an increased incidence of supernumerary
rib (14th rib).

Inhalation Short- and Intermediate-term (1-30 days and 1-6 months)
NOAEL=2.0 mg/kg/day

Inhalation absorption are assumed to be 100%	UFA=10x

UFH=10x

UFDB = 10x	Occupational LOC for MOE = 1000	Developmental Toxicity study
in rabbits

LOAEL = 10 mg/kg/day, based on structural alterations including
malformed vertebral body and ribs, arthrogryposis, and multiple
malformations.

Cancer (oral, dermal, inhalation)	Classification:  “Not likely to be
Carcinogenic to Humans” based on the absence of significant tumor
increases in two adequate rodent carcinogenicity studies.

The LOC for occupational exposure to prothioconazole desthio is based on
the conventional uncertainty factor of 100x (UFA = 10x and UFH = 10x)
and an additional UFDB (10x) for the lack of NOAEL and a LOAEL from the
developmental neurotoxicity study, regarding some neurotoxic endpoint
(peripheral nerve lesions and brain morphometrics).

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

The submitted data on the toxicity of prothioconazole and its desthio,
deschloro, and sulfonic acid K salt metabolites do not suggest a concern
for endocrine disruption at this time.

4.0	Public Health and Pesticide Epidemiology Data  TC \l1 "4.0	Public
Health and Pesticide Epidemiology Data 

Prothioconazole is an unregistered, new active ingredient, and
therefore, no public health, epidemiologic data, and/or incident reports
are available.

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

The potential for dietary exposure to prothioconazole and its
metabolites and/or degradates includes consumption of food and drinking
water.  Acute and chronic dietary (food plus drinking water) exposure
analyses were conducted.  

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

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

The applicant has submitted metabolism studies on three dissimilar
crops, wheat, peanut, and sugar beet.  The crops selected for the
studies are sufficiently representative of the crops for which the
applicant is requesting registration:  barley, peanut, rice, wheat, the
dried shell and bean subgroup, and the oilseed crop group.  The
application patterns used in the studies are similar to those the
applicant is proposing (foliar applications), and bracket the preharvest
intervals that are being proposed.  The applicant submitted studies
reflecting labeling in both rings for all three crops.  Detailed
discussions are presented in the residue chemistry summary document
(Prothioconazole.  Petition for Establishment of Tolerances for Use on
Barley, Oilseed (Except Sunflower and Safflower) Crop Group, Dried
Shelled Pea and Bean (Except Soybean) Crop Subgroup, Peanut, Rice, and
Wheat. Summary of Analytical Chemistry and Residue Data. PP#4F6830.
D303508; S. Funk, 08/21/06).

The metabolism of prothioconazole was investigated in plants following
foliar spray applications of [triazole-UL-14C] prothioconazole or
[phenyl-UL-14C] prothioconazole to wheat, peanuts, and sugar beet and
seed treatment application of [phenyl-UL-14C] prothioconazole to wheat.

Bayer CropScience submitted   SEQ CHAPTER \h \r 1 eight plant metabolism
studies to support the proposed uses, seven of which were reviewed:  (1)
a wheat metabolism study reflecting foliar application of
[phenyl-14C]-prothioconazole (MRID 46246141); (2) a wheat metabolism
study reflecting seed treatment with [phenyl-14C]-prothioconazole (MRID
46246142); (3) a wheat metabolism study reflecting foliar application of
[triazole-14C]-prothioconazole (MRID 46246143); (4) a peanut metabolism
study reflecting foliar application of [phenyl-14C]-prothioconazole
(MRID 46246145); (5) a peanut metabolism study reflecting foliar
application of [triazole-14C]-prothioconazole (MRID 46246146); (6) a
sugar beet metabolism study reflecting foliar application of
[triazole-14C]-prothioconazole (MRID 46246147); and (7) a sugar beet
metabolism study reflecting foliar application of
[phenyl-14C]-prothioconazole (MRID 46246148).    SEQ CHAPTER \h \r 1 A
wheat metabolism study reflecting application of
[triazole-14C]-prothioconazole-desthio (metabolite) (MRID 46246144) was
not reviewed, because it did not provide any additional relevant
information.

The results of the plant studies showed that prothioconazole (JAU6476)
was extensively metabolized after the foliar (wheat, peanut, and sugar
beet) and seed treatment application (wheat) of [triazole-UL-14C]
prothioconazole or [phenyl-UL-14C] prothioconazole.  The parent compound
represented only <1 to 7% of the residues in all matrices.  The proposed
metabolic profile for prothioconazole in sugar beet, wheat and peanut is
presented in Appendix B., Figures B.1. and B.2.

In the phenyl label studies, the major residue found in wheat, peanut,
and sugar beet was prothioconazole-desthio (6% to 58% of the total
radioactive residue (TRRs) in wheat, peanuts, and sugar beet).  A second
major metabolic process involved hydroxylation followed by conjugation. 
Since prothioconazole has multiple positions that could potentially
undergo hydroxylation, the majority of the remaining metabolites were
simply multiple isomers of monohydroxylated prothioconazole-desthio and
their corresponding glucosides along with prothioconazole-hydroxy-diene,
dihydroxy-diene, dihydroxy-olefin, and their conjugates.  Collectively,
these conjugated and/or hydroxylated metabolites represented a major
portion (18 to 37%) of the TRRs in the crop matrices and contained both
the phenyl and the triazole rings in the molecule.  However, none of
these hydroxylated metabolites individually reached or exceeded 10% of
the TRRs in any target crop matrix.  Cleavage of the triazole moiety
occurred resulting in the formation of the label-specific metabolite
prothioconazole-benzylpropyldiol and its glucoside, which represented a
minor portion of the TRRs. 

A total of 60% to 74% of the residues from the phenyl label foliar
studies were identified.  An additional 20% to 48% of the TRRs were
characterized by extraction and/or chromatographic behaviors.  Only 1 to
8% of the residues remained unextracted.  The unextracted residues from
the wheat seed treatment study ranged from 8% to 26% of the TRRs in the
wheat forage, hay, and straw.  However, the actual ppm residue levels of
unextractable residues ranged from only 0.01 ppm to 0.02 ppm.

The triazole label plant studies showed three major metabolic processes
(desulfuration, hydroxylation, and cleavage of the triazole moiety). 
Prothioconazole-desthio (6% to 25% maximum levels in wheat, peanuts, and
sugar beet) and the label-specific triazole conjugates, triazolylalanine
(TA), triazolylacetic acid (TAA), and triazolylhydroxypropionic acid
(THP) (collectively representing a maximum of 29% to 90% of the TRRs in
wheat, peanuts, and sugar beet) were the major residues found in the
triazole label studies.  Although the triazole label studies showed
greater cleavage of the triazole moiety (compared to the phenyl label),
no free triazole was detected in any crop matrix.  As was found in the
phenyl label studies, numerous minor hydroxylated metabolites and their
conjugates comprised the majority of the remainder of the residues. 
Triazolyl-ethanol and its glucoside and triazolyethanol sulfonic acid
glucoside were minor metabolites arising from cleavage of the benzylic
group.

A total of 61% to 94% of the residues from the triazole label studies
were identified.  An additional 6% to 33% of the TRRs were characterized
by extraction and/or chromatographic behaviors.  The unextractable
residues ranged from only <1% to 6% of the TRRs in the plant matrices.

With the exception of the label-specific metabolites, the metabolic
profiles were very similar for the target crop studies with both labels.
 The triazole and phenyl label studies clearly elucidated the metabolic
fate of the prothioconazole molecule in target crops and were very much
complementary to each other.  Irrespective of the mode of application
(foliar or seed treatment) and the target crop (wheat, peanuts, or sugar
beet), the major residues found in all crops were
prothioconazole-desthio, TA, THP acid, and TAA.  The metabolic profiles
for the target crops were also similar to the profiles found in the
rotational crops.  However, the levels of the triazole-based conjugates
were much higher in the rotational crops, a finding which was consistent
with that expected for confined rotational crop studies with a
triazole-based fungicide.

Following the initial metabolism of prothioconazole to
prothioconazole-desthio (through oxidation of the sulfur to the
corresponding sulfonic acid with subsequent elimination of the sulfonic
acid group), two major metabolic processes were observed.  One major
pathway involved the hydroxylation of the phenyl ring and/or benzylic
carbon to form multiple isomers of prothioconazole-hydroxy-desthio,
prothioconazole-dihydroxy-desthio, and
prothioconazole-α-hydroxy-desthio followed by conjugation to form the
corresponding glucosides or acetate.  The other major pathway involved
the cleavage of the H2C-N bond to release the triazole moiety (and
benzylpropyldiol) leading to the formation of TA and THPA and further
metabolism of the triazole conjugates to TAA.  The fact that no free
triazole was found in any target crop matrix suggests an immediate or
very rapid conjugation of the released triazole to form the triazole
conjugates.

Minor metabolic processes involved the successive reductions of the
phenyl ring to form dienes and olefins; formation of
prothioconazole-triazolinone; and cleavage of the chlorobenzylic group
to form triazolyl-ethanol and its glucoside. 

Wheat Metabolism Summary:  The submitted wheat metabolism data are
adequate to satisfy data requirements.  Based on the results of the
wheat metabolism studies, the applicant concluded that prothioconazole
is initially metabolized in wheat by oxidation and loss of sulfur to
form prothioconazole-desthio, after which two major metabolic processes
occur:  (1) hydroxylation of the phenyl ring and/or benzylic carbon to
form isomers of prothioconazole-OH-desthio, prothioconazole-diOH
desthio, and prothioconazole-α-OH-desthio, followed by conjugation to
form the corresponding glucosides, malonyl-glucosides and acetate; and
(2) release of the triazole moiety to form triazolylalanine and THPA and
further metabolism of the triazole conjugates to form triazolylacetic
acid.  The applicant noted that the absence of free triazole in any
wheat matrix suggested that immediate or very rapid conjugation of
released triazole occurred.  The following minor metabolic pathways were
reported:  formation of prothioconazole-triazolinone and
prothioconazole-desthio-phenyl-cysteine; conjugation of
prothioconazole-desthio with glucose and malonic acid; oxidation of the
sulfur atom of prothioconazole to form prothioconazole sulfonic acid;
and cleavage of the benzylic group to form triazolyl-ethanol and its
glucoside.

A similar metabolic pathway is proposed for the metabolism of
prothioconazole in wheat following application as a seed treatment.

Peanut Metabolism Summary:  The submitted peanut metabolism data are
adequate to satisfy data requirements.  Based on the results of the
peanut metabolism studies, the applicant concluded that prothioconazole
is initially metabolized in peanut by:  (1) oxidation and loss of sulfur
to form prothioconazole-desthio; (2) hydroxylation of the chlorobenzyl
ring of prothioconazole-desthio at positions 3 and 4 to form the hydroxy
desthio metabolites; (3) conjugation of the hydroxylated metabolites;
(4) exchange of oxygen for sulfur; and (5) release of the triazole
moiety to form triazolylalanine and THPA.  Free triazole was not
detected in any peanut matrix.

Sugar beet metabolism summary:  The sugar beet metabolism data are
adequate to satisfy data requirements. Based on the results of the sugar
beet metabolism studies, the applicant concluded that prothioconazole is
extensively metabolized in sugar beet via:  (1) oxidation of the sulfur
of the triazolinethione ring to the corresponding sulfonic acid and
subsequent elimination of the sulfonic acid group to form desthio
prothioconazole; (2) hydroxylation of the phenyl ring or the benzyl
carbon to form multiple isomers, with subsequent conjugation with
glucose or further reaction to produce
prothioconazole-desthio-hydroxy-dieneyl-cysteine; (3) release of the
triazole moiety to form triazolylalanine and THPA; and (4) elimination
of the phenyl ring.  The applicant noted that free triazole was not
identified.

Based on these considerations, HED concludes that the submitted studies
are adequate to delineate the nature of prothioconazole residues in
plants.  

The residues of concern for both enforcement purposes (tolerance) and
for risk assessment in plant commodities are parent prothioconazole and
its metabolite prothioconazole-desthio, expressed as prothioconazole.

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

Bayer CropScience submitted t  SEQ CHAPTER \h \r 1 wo confined
rotational crop studies to support the proposed uses, one conducted
using [phenyl-14C]-prothioconazole (MRID 46246225) and one conducted
using [triazole-14C]-prothioconazole (MRID 46246226).  Additionally, a
limited field rotational crop study (MRID 46246227) on the
representative crops mustard greens (leafy vegetable), turnip (root
vegetable), and wheat (cereal grain) was submitted.  Detailed
discussions of the results of these studies are presented below in
section 5.1.10 and in the residue chemistry summary document (D303508;
S. Funk, 08/21/06).

The metabolism in rotational crops was found to be qualitatively similar
to that in the primary crops peanut, sugar beet and wheat, as the same
major metabolites were detected.  The presence of minor unknown polar
compounds indicated that composition of metabolites in rotational crops
was influenced by the metabolism of prothioconazole in soil.  In
addition, it appeared that conjugation was more prevalent in rotational
crop metabolism than in primary crop metabolism.

The confined study did show the potential for accumulation of residue in
rotated crops.

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

The metabolic pathway for prothioconazole was evaluated in livestock
following three consecutive daily oral doses of [phenyl-UL-14C]
prothioconazole or [triazole-UL-14C] prothioconazole to lactating goats
and laying hens.  Some qualitative and quantitative differences between
goats and laying hens were observed.  These differences were:

cleavage of prothioconazole and prothioconazole-desthio to release
1,2,4-triazole and triazolylethanol occurred in poultry, but these
metabolites were not found in goats (1,2,4-triazole was also found in
rats following an oral dose of [triazole-UL-14C] prothioconazole),

methylation of the sulfur atom of the parent compound was a major
metabolic process in poultry, but was only a minor pathway in goats,

cleavage of the triazolinthione ring to yield thiocyanate was a major
metabolic process in goats, but was only a minor pathway in poultry, and

conjugation of prothioconazole with lactose occurred only in goats.

With the exception of the above-mentioned differences, the metabolism of
prothioconazole was very similar in all livestock. Conjugation of the
unchanged parent compound with glucuronic acid forming an S-glucuronide
and desulfuration of prothioconazole yielding prothioconazole-desthio
were major metabolic processes in both poultry and goats.  However, the
majority of the metabolites found in poultry and goats were products of
hydroxylations of prothioconazole and its desthio metabolite (probably
through epoxide intermediates) leading to the formation of the
corresponding dihydroxy and dihydroxy-dienes.  Detailed discussions of
the results of the livestock metabolism studies are presented below and
in the residue chemistry summary document (D303508; S. Funk, 08/21/06). 
The proposed metabolic profile for prothioconazole in livestock is
presented in Appendix B., Figures B.3 through B.6.

In goats, the di-hydroxylated metabolites (prothioconazole-dihydroxy and
prothioconazole-desthio-dihydroxy-diene) were further conjugated with
glucuronic acid; in poultry, the sulfate and glucuronic acid conjugates
of the di-hydroxylated prothioconazole-desthio metabolites were formed. 
Sulfate and glucuronic acid conjugation of prothioconazole-3/4-hydroxy
and methylation of prothioconazole-dihydroxy-desthio occurred in both
poultry and goats.

Five livestock metabolism studies were supplied to support the proposed
uses:  (1) a goat metabolism study reflecting dosing with
[triazole-14C]-prothioconazole (MRID 46246149); (2) a goat metabolism
study reflecting dosing with [phenyl-14C]-prothioconazole (MRID
46246150); (3) a goat metabolism study reflecting dosing with
[phenyl-14C] prothioconazole-desthio (MRID 46246201), which was not
considered; (4) a hen metabolism study reflecting dosing with
[phenyl-14C]-prothioconazole (MRID 46246202); and (5) a hen metabolism
study reflecting dosing with [triazole-14C]-prothioconazole (MRID
46246203).

Goat Metabolism Summary:  The goat metabolism data are adequate to
satisfy data requirements. Based on the results of the goat metabolism
studies, it is concluded that prothioconazole is metabolized in goats
via several steps:  conjugation of the unchanged parent compound with
glucuronic acid resulting in an S- or O-glucuronide; additional
glucuronidation of the triazole-thione nitrogen atom of the parent
compound to form prothioconazole-N-glucuronide; hydroxylation of the
parent compound to form prothioconazole-4-hydroxy and a further hydroxy
isomer, followed by conjugation with glucuronic acid; oxidation of the
phenyl ring of the parent compound to form
prothioconazole-dihydroxy-diene; elimination of sulfur to form
prothioconazole-desthio; further hydroxylation of the chlorophenyl
moiety to form prothioconazole-3-hydroxy-desthio and
prothioconazole-4-hydroxy-desthio, followed by conjugation with
glucuronic acid; oxidation of the chlorophenyl moiety of
prothioconazole-desthio to form prothioconazole-desthio-dihydroxy-diene;
conjugation of the triazolinethione moiety of the parent compound with
lactose; conjugation of hydroxylated metabolites of prothioconazole with
sulfate; methylation of the triazolinethione moiety of prothioconazole
to form prothioconazole-S-methyl; and cleavage of the parent compound to
form thiocyanate.  The presence of
prothioconazole-dihydroxy-desthio-glucuronides indicated that isomers of
prothioconazole-dihydroxy-desthio were formed as intermediates. 
Methylation of prothioconazole-hydroxy-desthio-glucuronides to form
prothioconazole-hydroxymethoxy-desthio-glucuronides occurred to a small
extent, as did the glucuronidation of prothioconazole-desthio.

Hen Metabolism Summary:  The hen metabolism data are adequate to satisfy
data requirements. 

Based on the study results, the applicant concluded that prothioconazole
is metabolized in hens via several steps:  conjugation of the unchanged
parent compound with glucuronic acid to form an S- (more likely) or an
O-glucuronide; methylation of the triazolinethione moiety to form
prothioconazole-S-methyl; elimination of sulfur to form the metabolite
prothioconazole-desthio; hydroxylation of the chlorophenyl moiety of the
metabolite prothioconazole-desthio to form
prothioconazole-4-hydroxy-desthio and possibly
prothioconazole-3-hydroxy-desthio, followed by conjugation with sulfate;
oxidation of the chlorophenyl moiety of prothioconazole-desthio,
followed by conjugation with glucuronic acid, to form
prothioconazole-desthio-3,4-dihydroxy-dienyl-glucuronide; cleavage of
the aliphatic carbon chain to form 1,2,4-triazole and
prothioconazole-triazolylethanol; cleavage of the triazolinethione
moiety to form thiocyanate; hydroxylation of the parent compound to form
prothioconazole-4-hydroxy; glucuronidation of a triazolinethione
nitrogen atom of the parent compound to form
prothioconazole-N-glucuronide; and, to a small extent, methylation of
prothioconazole-hydroxy-desthio to form
prothioconazole-hydroxymethoxy-desthio-glucuronides.  The presence of
sulfate conjugates of prothioconazole-dihydroxy-desthio and
prothioconazole-hydroxymethoxy-desthio indicated that
prothioconazole-dihydroxy-desthio and
prothioconazole-hydroxymethoxy-desthio were formed as intermediates.

The residue of concern for tolerance enforcement in livestock
commodities is prothioconazole and prothioconazole-desthio and
conjugates that are converted to prothioconazole or
prothioconazole-desthio by acid hydrolysis, expressed as
prothioconazole.  The residue of concern for risk assessment in
livestock commodities is prothioconazole, prothioconazole-desthio,
prothioconazole-4-hydroxy and conjugates that are converted to
prothioconazole, prothioconazole-desthio, or prothioconazole-4-hydroxy
by acid hydrolysis, expressed as prothioconazole.

5.1.4	Analytical Methodology  TC \l3 "5.1.4	Analytical Methodology 

PP#4F6830.  New Chemical – Prothioconazole in/on Plant and Livestock
Commodities.  Tolerance Method Validation Report. (MRID #’s 462462-04,
462462-06, 462462-07, and 462462-09) Chemical # 113961.  Decision
Number:  318440.  ACB # B05-39.  DP Barcode 318440. P. Schermerhorn.
08/04/06.

Adequate analytical methods exist for the determination of the residue
as defined for both tolerance enforcement and for determination of the
residues of concern for risk assessment for both plant and livestock
commodities.  

Enforcement Method for Plant Commodities

An HPLC-MS/MS method was developed and proposed for data gathering and
enforcement purposes for plant matrices.  An oxidative extraction
procedure converts prothioconazole residues to a mixture of
prothioconazole-desthio and prothioconazole sulfonic acid. The desthio
prothioconazole metabolite remains unchanged after extraction.  The
cooled extract is spiked with an isotopically labeled internal standard,
cleaned up by C18 solid-phase extraction (SPE), and mixed with either
0.1% formic acid or 1% acetic acid for analysis by LC-MS/MS.  The
results for prothioconazole sulfonic acid and prothioconazole-desthio
are reported in prothioconazole equivalents and then totaled to yield
“total prothioconazole derived residues.”  The validated LOQs
reported for each of the two analytes in the method are 0.02 ppm for
canola seed, peanut nutmeat, and wheat grain; and 0.05 ppm for dried
peas, wheat forage, wheat hay, and wheat straw.  Adequate extraction
efficiencies were demonstrated using radiolabeled wheat forage, and
sugar beet tops analyzed with the enforcement method.  The method was
sent to the analytical chemistry laboratory (ACL) for validation.  The
Analytical Chemistry Branch (ACB) found the method meets the requirement
of the Residue Chemistry Test Guidelines, OPPTS 860.1340, for acceptable
tolerance enforcement methods.

The registrant has submitted a high performance liquid chromatography
(with electrospray ionization) and tandem mass spectrometry (LC-MS/MS)
data gathering method for the determination of residues of
1H-1,2,4-triazole and the triazole conjugates triazolylalanine (TA) and
triazolylacetic acid (TAA) in plant commodities.  Validated LOQs range
from 0.01-0.05 ppm for 1H-1,2,4-triazole and 0.01-1.5 ppm for TA and
TAA.

Enforcement Method for Livestock Commodities

The livestock analytical method (HPLC-MS/MS), similar for both data
collection and enforcement, is capable of determining prothioconazole,
prothioconazole-desthio, prothioconazole-4-hydroxy, and conjugates that
can be converted to one of these compounds via acid hydrolysis.  Samples
of bovine liver, kidney, and muscle are extracted with acetonitrile
(ACN)/water and 25% aqueous L-cysteine HCl.  An internal standard
solution is added to the extract.  The internal standard solution
consists of a mixture of [triazole-15N3-13C2]-prothioconazole,
[triazole-15N3-13C2]-prothioconazole-desthio, and
[triazole-15N3-13C2]-prothioconazole-4-hydroxy in ACN containing 50
µg/mL L-cysteine HCl.  Fat samples are extracted with n-hexane and then
with a mixture of ACN, 25% aqueous L-cysteine HCl, and acetone; the
combined extracts are allowed to separate, and internal standard
solution is added to the aqueous phase.  Samples of milk and cream are
mixed with internal standard solution directly.  For all matrices, the
extract/sample is hydrolyzed using aqueous HCl, and the hydrolysate is
partitioned with methylene chloride and acetone.  The organic phase is
concentrated to aqueous, mixed with ACN and water, and analyzed by
LC-MS/MS.  Adequate extraction efficiencies were demonstrated using
radiolabeled goat milk, goat liver, goat muscle and goat fat analyzed
with the enforcement method.  The method has been validated by an
independent laboratory for ruminant commodities only.  The limits of
quantitation (LOQ) are as follows for each of the three analytes: 0.005
ppm for milk; 0.010 ppm for skim milk, cream, and muscle; 0.010 ppm for
liver; 0.010 ppm for kidney; and 0.050 ppm for fat.  

The method was sent to the analytical chemistry laboratory (ACL) for
validation.  The Analytical Chemistry Branch (ACB) found the method
meets the requirement of the Residue Chemistry Test Guidelines, OPPTS
860.1340, for acceptable tolerance enforcement methods.

Recommendations for Methods for Plant and Livestock Commodities

ACB finds that both methods (plant and livestock) which use liquid
chromatography with tandem mass spectrometry using electrospray
ionization in both the positive and negative modes meets the
requirements of the Residue Chemistry Test Guidelines, OPPTS 860.1340,
for acceptable tolerance enforcement methods.

ACB recommends that the petitioner include a confirmatory procedure for
each method submitted. The OPP guidelines require either a confirmatory
method or an interference study to eliminate the possibility of false
positives while using the primary enforcement method.  When mass
spectrometry is used for detection in the primary enforcement method a
confirmatory method is waived as long as the detector provides enough
selectivity to eliminate false positives.  While we fully agree that
MS/MS provides excellent selectivity, expert opinion has changed over
the past several years as mass spectrometrists have gained more
experience with the instrumentation.  A single MS/MS ion transition used
to be considered sufficient for positive confirmation of analyte
residue.  However, instances of false positive interferences have led
towards consensus that two ion transitions are needed to provide
“confirmation” of residues.  The ACB recommends that future
revisions of these methods include at least two multiple reaction
monitoring (MRM) transitions.  References include the following:

a) Commission Decision 2002/657/EC, Official Journal of the European
Communities, August 12, 2002.

b) Guidance for Industry:  Mass Spectrometry for Confirmation of the
Identity of Animal Drug Residues, US FDA Center for Veterinary Medicine,
May 1, 2003.

c) Bethem, et al, Establishing the Fitness for Purpose of Mass
Spectrometric Methods, J Am Soc Mass Spectrom 2003, 14, 523-541.

ACB reviewed the Independent Laboratory Validation (ILV) reports for
both the plant and livestock methods (MRID #’s 462462-09 and
462462-07, respectively).  ACB recommends that there were successful
ILV’s.  

a) However, the first ILV trial of the plant method failed due to
incomplete mixing following the addition of internal standard and prior
to the removal of an aliquot for the C-18 SPE cartridge cleanup.  This
step may require a precautionary note in any future revisions of the
method.

b) The ILV performing the livestock method found that a quadratic
regression calibration curve with 1/x2 weighting gave the best fit for
the milk.  ACB was able to use a linear regression of y = mx + b for the
milk.  Both the ILV and ACB used a 1/x weighted least square regression
fit for the liver.  A 1/x weighted linear regression was recommended and
used by the petitioner.

Multiresidue Methods

Bayer CropScience has submitted multiresidue method data (MRID 46246210)
for prothioconazole, the metabolites prothioconazole-desthio and
prothioconazole-4-hydroxy, and the triazole-related compounds triazole,
triazolylalanine, and triazolylacetic acid.  The test substances were
analyzed according to the FDA Multi-Residue Method Test guidelines in
PAM, Vol. I (dated 1/94).  Prothioconazole, prothioconazole-desthio,
prothioconazole-4-hydroxy, triazole and triazolylacetic acid were tested
through Protocols A and C.  As a result of Protocol C testing,
prothioconazole, prothioconazole-desthio, and prothioconazole-4-hydroxy
were tested through Protocol F.  Prothioconazole-4-hydroxy and
triazolylacetic acid were tested through Protocol B.  Based on the
results of the Protocol F testing, testing under Protocols D and E was
not required for prothioconazole, and testing under Protocol E was not
required for prothioconazole-4-hydroxy.  Because the test substances are
not substituted ureas, no testing under Protocol G was required.  A
suitable solvent for triazolylalanine could not be found; therefore,
testing of this compound could not be conducted.  

Sensitivity for triazolylacetic acid was poor using Protocol A, and no
response was obtained for the other test compounds.  Protocol C testing
indicated that further testing using Protocols D, E, and F was not
required for triazolylacetic acid and triazole.  Triazolylacetic acid
and prothioconazole-4-hydroxy could not be adequately recovered under
Protocol B.  Prothioconazole and prothioconazole-4-hydroxy were not
adequately recovered using the Florisil column cleanup steps of Protocol
F, and prothioconazole-4-hydroxy did not yield adequate chromatography
using Protocol D; thus, no further testing of these compounds was
conducted.  Prothioconazole-desthio could not be adequately recovered
under Protocols D or E, using wheat hay.  Recovery of
prothioconazole-desthio was variable (66-100%) under Protocol F, using
ground beef.  

Conclusions:  The multiresidue test data will be forwarded to FDA for
further evaluation.  Based on the results of the testing, the
multiresidue methods are not appropriate for determining prothioconazole
residues of concern, or for determining residues of triazole,
triazolylalanine, or triazolylacetic acid. 

5.1.5	Environmental Degradation TC \l3 "5.1.5	Environmental Degradation 

A detailed characterization of the environmental fate and transport of
prothioconazole and its degradates is provided in the following
document: “Prothioconazole Section 3: Environmental Fate and
Ecological Risk Assessment”, DP Barcode: 324660, Decision #: 341716,
C. Salice and R. Kashuba, 06/01/06.

Based on environmental fate data submitted by the registrant,
prothioconazole is expected to degrade rapidly in the environment.  The
major transformation products (created in amounts greater than or equal
to 10% of applied radioactivity) resulting from degradation processes of
prothioconazole include: prothioconazole-desthio,
prothioconazole-S-methyl, prothioconazole-thiazocine, and
1,2,4-triazole.  The identified minor transformation products (created
in amounts less than 10% of applied radioactivity) resulting from
degradation processes of prothioconazole include:  SEQ CHAPTER \h \r 1 
prothioconazole-sulfonic acid, prothioconazole-triazolinone,
prothioconazole-3, 4, 5, and 6-hydroxy-desthio, 2-chlorobenzoic acid,
and prothioconazole-triazolylketone.

The predominant means of degradation of prothioconazole combined
residues of concern in the environment is likely to be aerobic aquatic
metabolism, with loss of prothioconazole, prothioconazole-desthio, and
prothioconazole-S-methyl attributed to the formation of 1,2,4-triazole,
prothioconazole-triazolinone, other minor unidentified degradates and
CO2.

The predominant degradate is prothioconazole-desthio, which is formed
quickly and in large amounts from all degradation processes evaluated
(maximum of 5.7% of applied in hydrolysis, 55.7% in aqueous photolysis,
39.0% in soil photolysis, 49.4% in aerobic soil metabolism, and 54.6 %
in aerobic aquatic metabolism total system).  It is the result of
desulfonation of prothioconazole parent.  Prothioconazole-S-methyl is
also formed in large amounts from anaerobic aquatic metabolism (78.2% of
applied in total system) and in lesser amounts from aerobic soil
metabolism (14.6% of applied) and aerobic aquatic metabolism (12.7 % of
applied in total system).  It is the result of methylation of the sulfur
of prothioconazole parent.  Both of these identified major
transformation products are expected to form in large concentrations in
both terrestrial and aquatic environment compartments.

Prothioconazole-desthio is expected to be persistent with moderate
mobility in the soil.  Since prothioconazole and prothioconazole-desthio
are both stable to hydrolysis, together very slowly degraded by aerobic
soil metabolism, anaerobic aquatic metabolism and aqueous photolysis,
and together moderately degraded by aerobic aquatic metabolism,
transport to surface water of the relatively persistent prothioconazole
and prothioconazole-desthio combination will occur.  Due to this
persistence and moderate mobility of prothioconazole-desthio in some
soils, transport to ground water is also likely, particularly in areas
with porous soil of low organic carbon content. 

Prothioconazole-thiazocine is formed at a maximum of 14.1% of applied
radioactivity from aqueous photolysis only.  This mode of degradation is
only likely to be influential in clear, shallow water, under clear
atmospheric conditions.  In actual environmental systems, aqueous
photolysis is likely to proceed at a much slower rate due to the
attenuation of light due to increasing depth of water bodies, light
adsorption by suspended solids, and natural obstruction of sunlight. 
Therefore, since it is likely to form only in very small amounts under
very specific circumstances in the environment, and HED has very low
concern regarding the hazard associated with this environmental
metabolite, prothioconazole-thiazocine is not considered in this
assessment.

The 1,2,4-triazole degradate was only tracked in aerobic soil
metabolism, aerobic aquatic metabolism, and aqueous photolysis studies. 
It formed in large amounts (maximum of 41.8% of applied radioactivity)
as a result of aerobic aquatic metabolism, at medium amounts (maximum of
11.9% of applied radioactivity) as a result of aqueous photolysis and at
very small, practically non-detectable amounts (maximum of <2.0% of
applied radioactivity) as a result of aerobic soil metabolism.  The
1,2,4-triazole degradate is being characterized in a separate,
cumulative triazole assessment and is, therefore, not considered
separately in this assessment.

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

The metabolism of prothioconazole was similar in all livestock (hens and
goats).  Conjugation of the unchanged parent compound with glucuronic
acid forming an S-glucuronide and desulfuration of prothioconazole
yielding prothioconazole-desthio were major metabolic processes in both
poultry and goats.  However, the majority of the metabolites found in
poultry and goats were products of hydroxylations of prothioconazole and
its desthio metabolite (probably through epoxide intermediates) leading
to the formation of the corresponding dihydroxy and dihydroxy-dienes.

Some qualitative and quantitative differences between goats and laying
hens were observed.  These differences were:

cleavage of prothioconazole and prothioconazole-desthio to release
1,2,4-triazole and triazolylethanol occurred in poultry, but these
metabolites were not found in goats (1,2,4-triazole was also found in
rats following an oral dose of [triazole-UL-14C] prothioconazole),

methylation of the sulfur atom of the parent compound was a major
metabolic process in poultry, but was only a minor pathway in goats,

cleavage of the triazolinthione ring to yield thiocyanate was a major
metabolic process in goats, but was only a minor pathway in poultry, and

conjugation of prothioconazole with lactose occurred only in goats.

The metabolism observed in livestock was similar to that observed in the
rat.  Prothioconazole and/or the O- or S-glucuronide were/was a major
component of the residue in all species.  Prothioconazole-desthio was
likewise found in the rat (bile, urine) and in livestock commodities. 
The metabolite prothioconazole-4-hydroxy and/or it glucuronide was found
in livestock and in the rat (feces).  The metabolite
prothioconazole-3-hydroxy desthio was tentatively identified as a
component in goat matrices and was a minor constituent in rat feces, but
was absent in poultry.  The metabolite prothioconazole-4-hydroxy desthio
was found in all species.  Prothioconazole triazolinone was found in rat
feces, but not in goat or poultry commodities.  Prothioconazole-S-methyl
was a major metabolite found in hen fat and rat feces, but not in goat
commodities.  Finally, desthio prothioconazole 3,4-dihydroxy dienyl
glucuronide was found in hen commodities and in rat urine.

-α-hydroxy-desthio followed by conjugation to form the corresponding
glucosides or acetate.  The other major pathway involved the cleavage of
the H2C-N bond to release the triazole moiety (and benzylpropyldiol)
leading to the formation of TA and THPA and further metabolism of the
triazole conjugates to TAA.  The fact that no free triazole was found in
any target crop matrix suggests an immediate or very rapid conjugation
of the released triazole to form the triazole conjugates.

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

As explained in detail previously in this document, prothioconazole is
rapidly metabolized by plants, livestock, and laboratory animals, and is
rapidly degraded in the environmental.  The predominant metabolite and
degradate is prothioconazole-desthio.  Prothioconazole-desthio is more
toxic than parent prothioconazole by nearly an order of magnitude.  As
explained in detail throughout section 3 of this document, the toxicity
findings for the metabolite/degradate prothioconazole-desthio are of
paramount importance to the risk assessment of prothioconazole.  In
addition to the full toxicology database for prothioconazole, there is a
second nearly complete database of studies for the major
metabolite/degradate prothioconazole-desthio (also known as SXX0665).  A
few additional toxicity studies were also submitted on other minor
metabolites/degradates, i.e. prothioconazole-deschloro and
prothioconazole sulfonic acid K salt.  The toxicity profiles for
prothioconazole and prothioconazole-desthio are available in Appendixes
A.2. and A.3. below.

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

The major constituents of the TRR in plant foliar and seed treatment
studies and in limited field rotational crop studies were
prothioconazole and prothioconazole-desthio, totaling 20–30%.   Minor
components (each <10% TRR) were hydroxylated and dihydroxylated
derivatives of these two compounds.  Limited rotational crop field
studies revealed no quantifiable residues of prothioconazole or
prothioconazole-desthio at a 30 day PBI.  Because the analytical method
converts prothioconazole to a mixture of prothioconazole sulfonic acid
and prothioconazole-desthio, it is not possible to estimate the relative
amounts of prothioconazole and prothioconazole-desthio in the numerous
field trial studies.

It is estimated that the various minor hydroxy metabolites are of no
greater toxicological concern than the parent.  Therefore, for risk
assessment purposes, the residue of concern is defined as the sum of
parent prothioconazole and the prothioconazole-desthio metabolite.

Prothioconazole underwent extensive metabolism in both ruminants and
poultry, and the pathways were generally similar.  Parent (or
glucoronide conjugate) was significant (>10% TRR) in ruminant liver,
kidney, muscle, milk, and fat and in hen liver, egg, muscle, and fat. 
The desthio-prothioconazole metabolite was present in all commodities,
but >10% only in fat (goat and hen) and eggs.  The
prothioconazole-4-hydroxy (or its glucuronide conjugate) was >10% TRR in
goat liver, goat fat, and goat kidney and was present (minor) in several
poultry commodities.

Conjugation of the unchanged parent compound with glucuronic acid
forming an S-glucuronide and desulfuration of prothioconazole yielding
prothioconazole-desthio were major metabolic processes in both poultry
and goats.  However, the majority of the metabolites found in poultry
and goats were products of hydroxylations of prothioconazole and its
desthio metabolite (probably through epoxide intermediates) leading to
the formation of the corresponding dihydroxy and dihydroxy-dienes.  In
goats, the di-hydroxylated metabolites (prothioconazole-dihydroxy and
prothioconazole-desthio-dihydroxy-diene) were further conjugated with
glucuronic acid; in poultry, the sulfate and glucuronic acid conjugates
of the di-hydroxylated prothioconazole-desthio metabolites were formed. 
Sulfate and glucuronic acid conjugation of prothioconazole-3/4-hydroxy
and methylation of prothioconazole-dihydroxy-desthio occurred in both
poultry and goats.

It is estimated that the various hydroxy and dihydroxy metabolites and
conjugates thereof of both prothioconazole and prothioconazole-desthio
are of no greater toxicological concern than the parent.  For tolerance
enforcement purposes, the residue is defined as the sum prothioconazole
and prothioconazole-desthio and conjugates that can be converted to
these two compounds by acid hydrolysis, expressed as prothioconazole. 
As the prothioconazole-4-hydroxy and its conjugates were significant
(>10% TRR) in several ruminant commodities, they will be included in the
residue of concern for dietary risk assessment.  The residue of concern
for dietary risk assessment purposes is defined as the sum of
prothioconazole, prothioconazole-desthio, prothioconazole-4-hydroxy and
conjugates that can be converted to one of these three compounds by acid
hydrolysis, expressed as prothioconazole. 

Not considered in the degradates/metabolites for risk assessment and
tolerance expression are prothioconazole-S-methyl, 20–28% TRR in hen
fat and minor amounts (<10%) in hen egg, liver, and muscle; thiocyanate
ion, 12–40% TRR in goat commodities; and prothioconazole-6-hydroxy
sulfate, 10% in goat liver.  These metabolites are of no special
toxicological concern relative to the parent prothioconazole. 

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	Prothioconazole

Desthio-prothioconazole	Prothioconazole

Desthio-prothioconazole

	Rotational Crop	Not necessary	Not necessary

Livestock

	Ruminant	Prothioconazole

Prothioconazole-Desthio

Prothioconazole-4-Hydroxy

Acid hydrolyzable conjugates of the above three	Prothioconazole

Prothioconazole-Desthio

Acid hydrolyzable conjugates of the above two

	Poultry	Prothioconazole

Prothioconazole-Desthio

Prothioconazole-4-Hydroxy

Acid hydrolyzable conjugates of the above three	Prothioconazole

Prothioconazole-Desthio

Acid hydrolyzable conjugates of the above two

Drinking Water

	Prothioconazole

Prothioconazole-Desthio

Prothioconazole-S-Methyl	Not Applicable

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

Prothioconazole has the potential to reach surface water via runoff,
erosion, and spray drift.  Prothioconazole appears to degrade relatively
quickly in the environment.  Its major degradates are
prothioconazole-desthio and prothioconazole-S-methyl.  These degradates
are detected in major amounts in almost all fate laboratory studies, and
therefore, it is assumed that these degradates are likely to result in
significant environmental concentrations.  Estimated environmental
concentrations are based on total toxic residues, i.e., the parent
prothioconazole compound plus prothioconazole-desthio and
prothioconazole-S-methyl.  Two other major degradates were not included
in this assessment:  prothioconazole-thiazocine (not considered a
degradate of concern) and 1,2,4-triazole (since it is assessed
separately as a common degradate in the conazole aggregate risk
assessment).  The prothioconazole-desthio and prothioconazole-S-methyl
degradates are persistent, moderately to slightly mobile, and may reach
ground water; because of this and their toxicity they have been included
in the drinking water exposure estimates.

The quick degradation of prothioconazole in concert with poor extraction
methods in soil and sediment metabolism studies leads to great
uncertainty in the composition and bioavailability of large amounts of
unextracted material.  It cannot be determined which portions of the
unextracted material are composed of potentially bioavailable parent
prothioconazole, which are composed of potentially bioavailable
prothioconazole-desthio or other degradates, and which are composed of
legitimately unextractable, non-bioavailable material.  Due to this
uncertainty, biotic degradation rates are unable to be calculated for
prothioconazole alone.  Therefore, a total toxic residues method,
including unextracted material, is utilized for higher bound
environmental exposure estimate modeling.  For lower bound estimate
modeling, it is assumed that unextracted material is non-bioavailable
and non-toxic.  There is evidence that the prothioconazole-desthio
degradate is moderately mobile (Kds of 4.13 to 13.38 mL/g in four soils,
stability to hydrolysis, long half-lives to other environmental
degradation processes and multiple detections at 15-30 cm and one
detection at 30-45 cm in terrestrial field dissipation studies).

Additionally, the Agency does have concern about the potential toxicity
of 1,2,4-triazole and two conjugates, triazolylalanine (TA) and
triazolylacetic acid (TAA); these metabolites are common to most of the
triazole fungicides.  To support the extension of existing tolerances
and the granting of new parent triazole-derivative fungicide tolerances,
EPA has conducted a human health risk assessment for aggregate exposure
to 1,2,4-triazole and triazole conjugates (1,2,4-Triazole, Triazole
Alanine, Triazole Acetic Acid: Human Health Aggregate Risk Assessment in
Support of Reregistration and Registration Actions for
Triazole-derivative Fungicide Compounds. M. Doherty et. al., 12/22/05).

The estimated drinking water concentration (EDWC) values used in the
dietary risk assessment were provided by the Environmental Fate and
Effects Division (EFED) in the following memo: Prothioconazole Tier II
Estimated Drinking Water Concentrations (EDWCs) for Use in the Human
Health Risk Assessment [Second Revision] (DP Barcode 330265, R. Kashuba,
6/21/06).  The EDWCs for prothioconazole and its degradates in drinking
water from the proposed uses were incorporated directly into the acute
and chronic dietary risk assessments.  Water residues were incorporated
in the DEEM-FCID( in the food categories “water, direct, all
sources” and “water, indirect, all sources.”  Ground water sources
were not included in the dietary risk assessment because the EDWCs for
this water source are minimal in comparison to surface water.

EDWCs and time series values for surface water sources were determined
using the PRZM-EXAMS screening models, with the exception of rice.   
SEQ CHAPTER \h \r 1 EDWCs for rice paddies  SEQ CHAPTER \h \r 1  were
determined using the Interim Rice Model, 10/29/2002.  The Interim Rice
Model is capable of calculating EDWCs for acute exposures only, and is
used to generate screening level rice paddy water concentrations
resulting from pesticide use on rice.  This model is intended to be an
interim measure until a more complete rice modeling method becomes
available.  

Because of the uncertainties with unextracted residues and KOC, EFED has
provided HED with upper and lower bound Tier II EDWCs in order to
characterize how this uncertainty affects the EDWCs.  Generally, upper
and lower EDWCs differed by a factor of 1.3 to 2.6 as a result of these
bounding assumptions.  Inclusion or exclusion of unextracted residues
made a larger difference in concentrations than use of a high or low
KOC.  

EDWCs and time series values were submitted for both lower and upper
bounds for each crop scenario to account for two major uncertainties in
the drinking water modeling.  First, some prothioconazole residues
remained in the bound phase in EFED studies used to characterize
persistence.  To address this uncertainty, modeling was bound based on
inclusion and exclusion of unextracted residues in half-life
calculations.  Secondly, the two, major water degradates of
prothioconazole formed rapidly after application and have different
mobility.  To address this uncertainty, modeling was conducted using
KOCs (soil organic carbon-water partitioning coefficients) for
prothioconazole-desthio and prothioconazole-S-methyl.  The lower bound
EDWC and time series values represent the exclusion of unextracted
residues and the use of the higher Koc.  Conversely, the higher bound
estimates represent the inclusion of unextracted residues and the use of
the lower Koc.  Any concern about the uncertainties of any bound
residues or differences in Koc values are adequately addressed by
regulating and relying upon the upper bound EDWCs in the dietary risk
assessment.

To further refine EDWCs for canola, beans, peanuts, and rice, regional
default Percent Cropped Area factors (PCA) have been applied to
estimated concentrations.  Because wheat is grown across the country,
and a crop-specific national PCA is available, wheat EDWCs are not
further refined with regional PCAs.  Canola is grown within a single
regional basin, and therefore, only one default regional PCA was used in
canola refinement.  Alternately, most beans and peanuts are grown in two
regional basins each and, therefore, two default regional PCAs were used
in bean and peanut refinement.  Similarly, EDWCs for rice are reported
with two (lower and higher end) regional PCAs.

Surface water EDWCs are summarized in Table 5.1.9 below.  DEEM analyses
were performed for both the upper and lower bound estimates for the rice
and bean crop scenarios, since these EDWC values (in bold) were the
highest values reported.  The EDWC values for rice were only used in the
acute assessment.

Table 5.1.9.  Ranges of Tier II EDWCs for Surface Water Based on Aerial
Application of

Prothioconazole

DRINKING WATER SOURCE    (MODEL USED)	USE SCENARIO       (rate modeled)
ESTIMATED DRINKING WATER CONCENTRATION  (EDWC)  ( ppb) 

Acute 	Chronic 

Surface water  (PRZM/EXAMS)	NATIONAL PERCENT CROPPED AREA (PCA)

	Wheat1     	5.4 – 11	2.6 – 6.0

	Canola1           	7.5 – 14	3.5 – 9.1

	Bean1               	14 – 23	6.7 – 12

	Peanut1            	21 – 29	6.2 – 10.

	Rice2	45 - 115	N/A

	REGIONAL PERCENT CROPPED AREA (PCA)

	Canola1           	7.2 – 13	3.3 – 8.7 

	Bean3               	10. – 22	4.9 – 11

	Peanut3            	9.3 – 22	2.7 – 8.1

	Rice4	21 - 112	N/A

1Represents ranges in input parameters (aerobic soil, aerobic aquatic,
and anaerobic aquatic metabolism half-lives and KOC).

2Represents range in Kd input parameter.

3Represents ranges in input parameters (aerobic soil, aerobic aquatic,
and anaerobic aquatic metabolism half-lives and KOC) as well as ranges
in regional PCAs.

4Represents range in Kd input parameter as well as ranges in regional
PCAs.

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

Based on the current prothioconazole feed items, residues of concern are
anticipated in ruminant commodities at or about the limit of
quantitation of the analytical method for all commodities, except liver
and kidney.  Finite residues are anticipated for these commodities.

Based on the current prothioconazole feed items, residues of concern are
not anticipated in poultry commodities at or about the limit of
quantitation of the analytical method for all commodities, except liver.
 Residues at the limit of quantitation may be anticipated in poultry
liver.

In general, prothioconazole/prothioconazole-desthio residues did not
concentrate appreciably in the processed fractions of grain, oil seeds,
or peanuts.  The exceptions are aspirated grain fractions (wheat) (245X)
and rice hulls (4.4X), suggesting that the residue may be concentrated
in the surface of commodities.

Magnitude of Residues in Plants

Crop field trial data were submitted for barley, canola, dried peas and
beans, peanut, rice, and wheat reflecting the proposed use pattern for
the 4 lb/gal FlC formulation.  The residue data provided is summarized
in Table 5.1.10.1, including total prothioconazole derived residues, and
residue data for 1,2,4-triazole and triazole conjugates triazolylalanine
and triazolylacetic acid.  Detailed discussions of the results of the
crop field trial studies are presented in the residue chemistry summary
document (D303508; S. Funk, 08/21/06).  Confirmatory storage stability
data will be submitted to support all crop field trials.  Adequate
processing data have been submitted for canola, peanut, rice, and wheat,
which indicate that a tolerance is needed for rice hulls; additional
storage stability data are required to support the processing studies. 
The available rotational crop data indicate that the proposed rotational
crop restrictions are appropriate; no rotational crop tolerances are
needed to support this petition.  

The petitioner included residue data for 1,2,4-triazole and triazole
conjugates triazolylalanine and triazolylacetic acid with the crop field
trial, processing, and field rotational crop studies submitted with this
petition.  The data indicate that quantifiable residues of the triazole
conjugates will occur in primary, processed, and field rotational crop
commodities following treatment of primary crops with prothioconazole. 
Radiovalidation data for the method used to collect these data and
completion of the ongoing storage stability study with these compounds
are needed to support these residue data.  

Table 5.1.10.1 Summary of Residues from Crop Field Trials with
Prothioconazole.

Crop Matrix	Applic.Rate

(lb ai/A)

[kg ai/ha]	PHI (days)	Residues (ppm)

	n	Min.	Max.	HAFT1	Median	Mean	Std. Dev.

BARLEY (proposed use = 0.293 lb ai/A [0.328 kg ai/ha] total application
rate, 30-day PHI)

Total Prothioconazole-Derived Residues

Barley grain	0.286-0.309

[0.321-0.348]	30-71	49	<0.02	0.158	0.151	0.022	0.040	0.041

Barley hay	0.286-0.309

[0.321-0.348]	12-16	49	0.317	6.59	5.95	1.22	1.72	1.39

Barley straw	0.286-0.309

[0.321-0.348]	30-71	50	<0.05	1.871	1.65	0.304	0.554	0.510

1,2,4-Triazole Residues

Barley grain	0.286-0.309

[0.321-0.348]	30-71	50	<0.01	<0.01	<0.01	0.005	0.005	0.0

Barley hay	0.286-0.309

[0.321-0.348]	12-16	49	<0.01	<0.01	<0.01	0.005	0.005	0.0

Barley straw	0.286-0.309

[0.321-0.348]	30-71	50	<0.01	<0.01	<0.01	0.005	0.005	0.0

Triazole Conjugate Residues

Barley grain	0.286-0.309

[0.321-0.348]	30-71	50	<0.10	0.915	0.909	0.239	0.300	0.215

Barley hay	0.286-0.309

[0.321-0.348]	12-16	49	<0.05	0.547	0.445	0.135	0.134	0.104

Barley straw	0.286-0.309

[0.321-0.348]	30-71	50	<0.1	0.385	0.359	0.05	0.090	0.093

CANOLA (proposed use = 0.356 lb ai/A [0.400 kg ai/ha] total application
rate, 36-day PHI)

Total Prothioconazole-Derived Residues

Canola seed	0.35-0.37 [0.39-0.42]	36-83	44	<0.020	0.097	0.086	0.010
0.015	0.0169

1,2,4-Triazole Residues

Canola seed	0.35-0.37 [0.39-0.42]	36-83	44	<0.020	<0.020	<0.020	0.010
0.010	0

Triazole Conjugate Residues

Canola seed	0.35-0.37 [0.39-0.42]	36-83	44	0.064	0.848	0.716	0.311	0.321
0.124

DRIED PEA AND BEAN (proposed use = 0.534 lb ai/A [0.600 kg ai/ha] total
application rate, 7-day PHI)

Total Prothioconazole-Derived Residues

Pea, dried shelled	0.530-0.549

[0.595-0.615]	7-8	26	<0.05	0.684	0.661	0.025	0.156	0.219

Bean, dried shelled	0.534-0.580

[0.598-0.650]	7-8	20	<0.05	0.288	0.243	0.025	0.062	0.072

1,2,4-Triazole Residues

Pea, dried shelled	0.530-0.549

[0.595-0.615]	7-8	26	<0.01	0.011	0.01	0.005	0.005	0.001

Bean, dried shelled	0.534-0.580

[0.598-0.650]	7-8	20	<0.01	<0.01	<0.01	0.005	0.005	0.0

Triazole Conjugate Residues

Pea, dried shelled	0.530-0.549

[0.595-0.615]	7-8	26	<0.05	0.789	0.775	0.085	0.177	0.213

Bean, dried shelled	0.534-0.580

[0.598-0.650]	7-8	20	<0.02	0.311	0.249	0.045	0.080	0.093

PEANUT (proposed use = 0.713 lb ai/A [0.800 kg ai/ha] total application
rate, 14-day PHI)

Total Prothioconazole-Derived Residues

Peanut nutmeat	0.707-0.734

[0.792-0.823]	13-15	24	<0.02	<0.02	<0.02	0.01	0.01	0.0

Peanut hay	0.707-0.734

[0.792-0.823]	13-15	24	0.989	4.458	3.630	2.657	2.612	0.884

1,2,4-Triazole Residues

Peanut nutmeat	0.707-0.734

[0.792-0.823]	13-15	24	<0.02	0.02	<0.02	0.01	0.01	0.0

Peanut hay	0.707-0.734

[0.792-0.823]	13-15	24	<0.02	<0.02	<0.02	0.01	0.01	0.0

Triazole Conjugate Residues

Peanut nutmeat	0.707-0.734

[0.792-0.823]	13-15	24	0.162	3.903	3.390	0.827	1.158	1.127

Peanut hay	0.707-0.734

[0.792-0.823]	13-15	24	<0.10	1.278	1.244	0.176	0.323	0.361

RICE (proposed use = 0.285 lb ai/A [0.320 kg ai/ha] total application
rate, 40-day PHI)

Total Prothioconazole-Derived Residues

Rice, grain	0.34-0.37

[0.38-0.41]	40-67	32	<0.02	0.222	0.191	0.01	0.031	0.048

Rice, straw	0.34-0.37

[0.38-0.41]	40-67	32	<0.05	1.277	1.189	0.432	0.464	0.319

1,2,4-Triazole Residues

Rice, grain	0.34-0.37

[0.38-0.41]	40-67	32	<0.01	<0.01	<0.01	0.005	0.005	0.0

Rice, straw	0.34-0.37

[0.38-0.41]	40-67	32	<0.01	<0.01	<0.01	0.005	0.005	0.0

Triazole Conjugate Residues

Rice, grain	0.34-0.37

[0.38-0.41]	40-67	32	<0.05	0.571	0.553	0.025	0.103	0.148

Rice, straw	0.34-0.37

[0.38-0.41]	40-67	32	<0.05	0.506	0.478	0.025	0.088	0.122

WHEAT (proposed use = 0.293 lb ai/A [0.328 kg ai/ha] total application
rate, 30-day PHI)

Total Prothioconazole-derived Residues

Wheat hay	0.281-0.313 2

[0.315-0.350]	12-17	66	0.288	3.571	3.543	1.269	1.420	0.970

Wheat grain	0.281-0.313 2

[0.315-0.350]	10; 30-57	66	<0.02	0.061	0.045	0.010	0.014	0.011

Wheat straw	0.281-0.313 2

[0.315-0.350]	10; 30-57	64	0.106	1.96	1.899	0.350	0.577	0.471

Wheat forage	0.286-0.299

[0.320-0.336]	7	46	0.061	6.987	5.842	1.352	1.401	1.268

1,2,4-Triazole Residues

Wheat hay	0.281-0.313 2

[0.315-0.350]	12-17	66	<0.01	<0.01	<0.01	0.005	0.005	0.0

Wheat grain	0.281-0.313 2

[0.315-0.350]	10; 30-57	66	<0.01	<0.01	<0.01	0.005	0.005	0.0

Wheat straw	0.281-0.313 2

[0.315-0.350]	10; 30-57	66	<0.01	<0.01	<0.01	0.005	0.005	0.0

Wheat forage	0.286-0.299

[0.320-0.336]	7	46	<0.01	<0.01	<0.01	0.005	0.005	0.0

Triazole Conjugate Residues

Wheat hay	0.281-0.313 2

[0.315-0.350]	12-17	66	0.018	0.665	0.631	0.204	0.220	0.124

Wheat grain	0.281-0.313 2

[0.315-0.350]	10; 30-57	66	0.098	1.76	1.76	0.460	0.534	0.320

Wheat straw	0.281-0.313 2

[0.315-0.350]	10; 30-57	64	<0.025	0.495	0.449	0.063	0.095	0.104

Wheat forage	0.286-0.299

[0.320-0.336]	7	46	<0.01	0.175	0.173	0.038	0.050	0.042

1  HAFT = Highest Average Field Trial.

2  In one field trial, the total application rate was 0.375 lb ai/A
(0.420 kg ai/ha); we note that this trial did not include maximum
residues for any of the metabolites.

Barley: Bayer CropScience has submitted field trial data on barley from
field trials conducted in the U.S. and Canada.  A total of 25 five
trials were conducted in Regions 1 (PA; 1 trial), 5 (ND; 2 trials, ON; 1
trial), 5B (QC; 1 trial), 7 (ND; 3 trials, and SK; 1 trial), 9 (AZ; 1
trial), 10 (AZ; 1 trial), 11 (ID and OR; 2 trials) and 14 (AB; 4 trials,
MB; 4 trials, and SK; 4 trials) during the 2000-2001 growing season. 
The number and locations of field trials are in accordance with OPPTS
Guideline 860.1500 and Directive 98-02; Section 9. 

At each test location, two broadcast foliar applications of the 4 lb/gal
(480 g/L) suspension concentrate formulation (flowable concentrate; FlC)
were made to barley at ~0.11-0.18 lb a.i./A (~0.123-0.202 kg a.i./ha) at
an average 12-day retreatment interval, for a total seasonal application
rate of ~0.29 lb a.i./A (~0.33 kg a.i./ha).  Applications were made in
~5-43 gal/A (~45-407 L/ha) of water using ground equipment.  An adjuvant
was not added to the spray mixture for any applications.  Barley hay was
cut at 23 test sites, 12-16 days after treatment, and was left in the
field for 1-14 days prior to collection of barley hay.  Samples of
barley grain and straw were harvested at 23 test sites 30-71 days after
the last application.  At two locations, additional samples were
collected to determine residue decline.  In the decline trial performed
in Region 7 (Northwood, ND), samples were harvested 8, 13, 22, and 28
days after treatment for barley hay and 32, 37, 44, and 47 days after
treatment for barley grain and straw.  In the decline trial performed in
Region 5 (Branchton, ON), samples were harvested  9, 14, 21, and 29 days
after treatment for barley hay and 36, 39, 45, and 49 days after
treatment for barley grain and straw.

Samples were analyzed for total prothioconazole-derived residues
(prothioconazole and the metabolite prothioconazole-desthio) using
LC-MS/MS method RPA JA/03/01.  The validated LOQs for the total
prothioconazole-derived residues were 0.02 ppm for barley grain and 0.05
ppm for barley hay and straw.  The method is adequate for data
collection for barley grain, hay and straw based on acceptable
concurrent method recovery data and method validation data. Samples were
analyzed for residues of 1H-1,2,4-triazole and the triazole conjugates
triazolylalanine and triazolylacetic acid using an LC-MS/MS method
(Bayer Report No. G200598).  The validated LOQ for 1H-1,2,4-triazole was
0.01 ppm for barley grain, hay and straw, and the validated LOQs for the
triazole conjugates were 0.10 ppm for barley grain and straw, and 0.05
ppm for hay.  The methods are adequate for data collection for barley
matrices based on acceptable concurrent method recovery data.

In barley matrices harvested 30-71 days (12-16 days for hay), total
prothioconazole-derived residues were 0.158 ppm, 6.59 ppm and 1.87 ppm,
respectively, in/on barley grain, hay, and straw.  Residues of 
1H-1,2,4-triazole were less than the LOQ (<0.01 ppm) in/on barley grain,
hay, and straw; and 0.915 ppm, 0.547 ppm and 0.385 ppm, respectively,
in/on barley grain, hay, and straw for the triazole conjugates. Total
prothioconazole-derived residues did not increase with increasing
sampling intervals in barley grain, hay, and straw, and residues of the
triazole conjugates did not increase in grain, but increased slightly
with increasing sampling intervals in samples from one trial each for
hay and straw. 

The maximum storage intervals of crop samples from harvest to analysis
for total prothioconazole-derived residues were 1234 days (40.6 months)
for barley grain and 1269 days (41.7 months) for barley hay and straw.
The degree of loss of prothioconazole-derived residues and
prothioconazole-desthio residues is not expected to exceed 30% after
41.7 months in barley grain, hay and straw.

Canola: Bayer CropScience has submitted field trial data on canola from
field trials conducted in the U.S. and Canada.  A total of 22 trials
were conducted in Regions 2 (GA; 1 trial), 5 (ND; 1 trial, and ON; 1
trial), 7 (ND; 1 trial, and SK; 1 trial), 11 (ID; 3 trials), and 14 (AB;
4 trials, MB; 5 trials, and SK; 5 trials) during the 2000 growing
season.  The number and locations of field trials were in accordance
with OPPTS Guideline 860.1500 and Directive 98-02; Section 9. 

At each test location, two broadcast foliar applications of the 4 lb/gal
(480 g/L) suspension concentrate formulation (flowable concentrate; FlC)
were made to canola at 0.17-0.19 lb a.i./A (0.19-0.21 kg a.i./ha) at an
average 16-day retreatment interval (7-44 days), for a total seasonal
application rate of 0.35-0.37 lb a.i./A (0.39-0.42 kg a.i./ha). 
Applications were made in ~11-42 gal/A (106-395 L/ha) of water using
ground equipment.  An adjuvant was not added to the spray mixture for
any applications.  Samples of canola were harvested at 20 test sites,
36-83 days after the last application.  Two locations (Ashton, ID and
Branchton, ON) were designated for residue decline studies.  Samples
were harvested 50, 54, 59, and 64 days after treatment in the decline
trial performed in ID (region 11).  In the ON trial (region 5), all
samples were cut inadvertently on day 41.  Seed samples from this site
were collected on the day of harvest, and 5, 10, and 15 days after
harvest.

Samples were analyzed for total prothioconazole-derived residues
(prothioconazole and the metabolite prothioconazole-desthio) using
LC-MS/MS method RPA JA/03/01.  The validated LOQ for total
prothioconazole-derived residues was 0.02 ppm for canola seed.  Samples
were analyzed for residues of 1H-1,2,4-triazole, and the triazole
conjugates triazolylalanine and triazolylacetic acid using an LC-MS/MS
method (Bayer Report No. G200598).  The validated LOQs were 0.02 ppm for
1H-1,2,4-triazole and 0.025 ppm for the triazole conjugates for canola
seed.  The methods were adequate for data collection based on acceptable
concurrent method recovery data.

The results from the canola field trials indicated that the maximum
residues of prothioconazole in/on canola seed harvested 36-83 days
following the last of two broadcast foliar applications were 0.097 ppm
for total prothioconazole-derived residues, <0.02 ppm for
1H-1,2,4-triazole, and 0.848 ppm for the triazole conjugates.

In the residue decline trial conducted in ID, total
prothioconazole-derived residues and residues of 1H-1,2,4-triazole were
less than the LOQ (<0.02 ppm each) at all sampling intervals.  Residues
of the triazole conjugates did not increase with increasing sampling
intervals. 

The maximum storage interval of canola seed samples from harvest to
analysis for total prothioconazole-derived residues was 1265 days (41.6
months).  Prothioconazole-derived residues and prothioconazole-desthio
residues are stable up to 12.7 months (interim report) in canola
matrices. The degree of loss of prothioconazole-derived residues and
prothioconazole-desthio residues is not expected to exceed 30% after
41.6 months. 

Dried shelled pea and bean, group 6C: Bayer CropScience has submitted
field trial data on dried peas and beans. A total of 23 field trials
were conducted during the 2002 growing season in the U.S. and Canada. 
Thirteen trials were conducted on dried peas in Regions 5 (MN and ON; 2
trials), 11 (ID; 1 trial, OR; 3 trials, and WA; 1 trial), and 14 (AB; 2
trials, MB; 1 trial, and SK; 3 trials), and 10 trials were conducted on
dried beans in Regions 5 (IL, IN, KS, and ON; 4 trials), 7 (ND;1 trial),
7A (AB; 1 trial), 8 (TX; 1 trial), 9 (MT; 1 trial), 10 (CA; 1 trial),
and 11 (WA; 1 trial).  The number and locations of field trials are in
accordance with OPPTS Guideline 860.1500 and Directive 98-02; Section 9.

At each test location, three broadcast foliar applications of the 4
lb/gal (480 g/L) suspension concentrate formulation (flowable
concentrate; FlC) were made at ~0.180 lb a.i./A (~ 0.200 kg a.i./ha) at
9- to 15-day retreatment intervals, for a total seasonal application
rate of ~0.54 lb a.i./A (~0.60 kg a.i./ha).  Applications were made in
~10-33 gal/A of water using ground equipment.  A non-ionic surfactant
was added to the spray mixture for all applications.  An additional plot
at each trial was treated with three applications at a target rate of
~0.134 lb a.i./A (~ 0.150 kg a.i./ha); however, the applicant stated
that the results from this application were not used because they did
not support the desired product label application rate.  Samples of
dried shelled peas and beans were harvested 7-8 days after the last
application from all test sites.  It should be noted that in three of
the pea field trials and five of the bean field trials, the pea and bean
plants were cut and allowed to dry in the field for 2-8 days prior to
collection.  At two locations for dried peas and one location for dried
beans, additional samples were collected to determine residue decline. 
Samples were harvested, at both locations, 0, 3-4, 7, 14-15, and 21-22
days after treatment for dried peas and 0, 7, 14, and 21 days after
treatment for dried beans.

Samples were analyzed for total prothioconazole-derived residues
(prothioconazole and the metabolite prothioconazole-desthio) using
LC-MS/MS method RPA JA/03/01.  The validated LOQ for total
prothioconazole-derived residues was 0.05 ppm for dried peas and dried
beans.  Samples were analyzed for residues of 1H-1,2,4-triazole and the
triazole conjugates triazolylalanine and triazolylacetic acid using an
LC-MS/MS method (Bayer Report No. G200598).  The validated LOQs were
0.01 ppm for 1H-1,2,4-triazole for dried peas and beans, 0.02 ppm for
the triazole conjugates for dried beans, and 0.05 ppm for the triazole
conjugates for dried peas.  The methods are adequate for data collection
based on acceptable concurrent method recovery data.

The results from the pea and bean field trials show that the maximum
residues of prothioconazole in/on dried peas and beans harvested 7-8
days following the last of three broadcast foliar applications at a
total seasonal rate of 0.530-0.580 lb a.i./A (0.595-0.650 kg a.i./ha)
were 0.684 ppm in/on dried peas and 0.288 ppm in/on dried beans for
total prothioconazole-derived residues; 0.011 ppm in/on dried peas and
less than the LOQ (<0.01 ppm) in/on dried beans for 1H-1,2,4-triazole;
and 0.789 ppm in/on dried peas and 0.311 ppm in/on dried beans for the
triazole conjugates. 

In the residue decline trials, residues of 1H-1,2,4-triazole were less
than the method LOQ (<0.01 ppm) at all sampling intervals in dried peas
and beans.  Total prothioconazole-derived residues did not increase with
increasing sampling intervals in the dried bean trial and in one dried
pea trial; in the other dried pea trial, residues increased slightly
with increasing sampling intervals (from an average of 0.31 ppm at the
7-day PHI to an average of 0.34 ppm at the 21-day PHI).  Residues of the
triazole conjugates did not increase with increasing sampling intervals
in dried peas, but increased slightly in dried beans with increasing
sampling intervals.  

The maximum storage interval of crop samples from harvest to analysis
for total prothioconazole-derived residues was 542 days (17.8 months)
for dried beans and peas.  The degree of loss of prothioconazole-derived
residues and prothioconazole-desthio residues is not expected to exceed
30% after 17.8 months in dried beans and peas.

Peanut: Bayer CropScience has submitted field trial data on peanuts. 
Twelve trials were conducted in Regions 2 (AL; 1 trial, GA; 3 trials,
NC; 3 trials, and VA; 1 trial), 3 (FL; 1 trial), 6 (TX; 2 trials), and 8
(OK; 1 trial) during the 2000 growing season.  The number and locations
of field trials are in accordance with OPPTS Guideline 860.1500 and
Directive 98-02; Section 9.

At each test location, four broadcast foliar applications of the 4
lb/gal (480 g/L) suspension concentrate formulation (flowable
concentrate; FlC) were made to peanuts at  ~0.18 lb a.i./A (~0.20 kg
a.i./ha) at 12- to 14-day retreatment intervals, for a total seasonal
application rate of ~0.72 lb a.i./A (~0.80 kg a.i./ha).  Applications
were made in ~13-37 gal/A (~119-349 L/ha) of water using ground
equipment.  An adjuvant was not added to the spray mixture for any
applications.  Peanut plants were dug up at all test sites 13-15 days
after treatment, and were left in the field for 2-8 days prior to
collection of peanuts and peanut hay.  In one field trial (GA),
additional samples were dug up at 7, 14, 21, and 28 days following the
last application to evaluate residue decline.

Samples were analyzed for total prothioconazole-derived residues
(prothioconazole and the metabolite prothioconazole-desthio) using
LC-MS/MS method RPA JA/03/01.  The validated LOQs for total
prothioconazole-derived residues were 0.02 ppm for peanut nutmeat and
0.05 ppm for hay.  Samples were analyzed for residues of
1H-1,2,4-triazole and the triazole conjugates triazolylalanine and
triazolylacetic acid using an LC-MS/MS method (Bayer Report No.
G200598).  The validated LOQ for 1H-1,2,4-triazole was 0.02 ppm for
peanut nutmeat and hay, and the validated LOQs for the triazole
conjugates were 0.125 ppm for peanut nutmeat and 0.10 ppm for hay.  The
methods were adequate for data collection based on acceptable concurrent
method recovery data.

The results from the peanut field trials indicated that the maximum
residues of prothioconazole in/on peanut matrices harvested 13-15 days
following the last of four broadcast foliar applications at a total
seasonal rate of 0.707-0.734 lb a.i./A (0.792-0.823 kg a.i./ha) were
<0.02 ppm in/on nutmeat and 4.458 ppm in/on hay for total
prothioconazole-derived residues; 0.02 ppm in/on nutmeat and less than
the LOQ (<0.02 ppm) in/on hay for 1H-1,2,4-triazole; and 3.903 ppm in/on
nutmeat and 1.278 ppm in/on hay for the triazole conjugates.

In the residue decline trial, residues of 1H-1,2,4-triazole were less
than the method LOQ (<0.02 ppm) at all sampling intervals for peanut
nutmeat and hay, and total prothioconazole-derived residues were less
than the method LOQ (<0.02 ppm) at all sampling intervals for nutmeat. 
The average total prothioconazole-derived residues in hay increased
slightly from the 7-day sampling interval to the 14-day sampling
interval and then decreased by the 28-day sampling interval.  Residues
of the triazole conjugates increased slightly in nutmeat (from an
average of 0.868 ppm to an average of 0.964 ppm) with increasing
sampling intervals; a greater increase was observed in peanut hay (from
an average of 0.117 ppm to an average of 0.355 ppm).

The maximum storage interval of crop samples from harvest to analysis
for total prothioconazole-derived residues was 1214 days (39.9 months)
for peanut nutmeat and hay.  

Prothioconazole-derived residues and prothioconazole-desthio residues
are stable up to 12.7 months (interim report).  The degree of loss of
prothioconazole-derived residues and prothioconazole-desthio residues is
not expected to exceed 30% after 39.9 months. 

Rice: Bayer CropScience has submitted field trial data on rice.  A total
of 16 trials were conducted in Regions 4 (LA; 6 trials, AR; 4 trials,
and MS; 1 trial), 5 (MI; 1 trial), 6 (TX; 2 trials), and 10 (CA; 2
trials) during the 2000 growing season.  The number and locations of
field trials are in accordance with OPPTS Guideline 860.1500 and
Directive 98-02; Section 9.

At each test location, two broadcast foliar applications of the 4 lb/gal
(480 g/L) suspension concentrate formulation (flowable concentrate; FlC)
were made to rice at  ~0.18 lb a.i./A (~0.20 kg a.i./ha) at 13- to
16-day retreatment intervals, for a total seasonal application rate of
~0.36 lb a.i./A (~0.40 kg a.i./ha).  Applications were made in ~12-23
gal/A of water using ground equipment.  An adjuvant was not added to the
spray mixture for any applications.  Samples of rice were harvested at
14 test sites 40-67 days after the last application.  At two locations,
additional samples were collected to determine residue decline.  Samples
were harvested 49, 55, 58, and 65 days after treatment for the decline
trial conducted in Benoit, MS (Region 4), and 64, 69, 74, and 80 days
after treatment for the decline trial conducted in Glen, CA (Region 10).

Samples were analyzed for total prothioconazole-derived residues
(prothioconazole and the metabolite prothioconazole-desthio) using
LC-MS/MS method RPA JA/03/01.  The validated LOQs for total
prothioconazole-derived residues were 0.02 ppm for rice grain and 0.05
ppm for rice straw.  Samples were analyzed for residues of
1H-1,2,4-triazole and the triazole conjugates triazolylalanine and
triazolylacetic acid using an LC-MS/MS method (Bayer Report No.
G200598).  The validated LOQs were 0.01 ppm for 1H-1,2,4-triazole and
0.05 ppm for the triazole conjugates for rice grain and straw.  The
methods are adequate for data collection based on acceptable concurrent
method recovery data.

The results from the rice field trials showed that the total
prothioconazole-derived residues in/on rice matrices harvested 40-67
days following the last of two broadcast foliar applications were 0.222
ppm in/on rice grain and 1.277 ppm in/on rice straw.  Residues of
1H-1,2,4-triazole were less than the LOQ (<0.01 ppm) in/on rice grain
and straw.  Maximum residues of the triazole conjugates were 0.571 ppm
(rice grain) and 0.506 ppm (rice straw).

In the residue decline trials, total prothioconazole-derived residues
in/on rice grain were <LOQ (0.02 ppm) in one trial, and did not increase
with increasing sampling intervals in/on rice grain in the other trial. 
For rice straw, total prothioconazole-derived residues increased
slightly with increasing sampling intervals in one trial.  In the other
trial, residues in/on straw increased slightly at the middle sampling
intervals, and then decreased at the final sampling interval.  Residues
of the triazole conjugates in/on rice grain were <LOQ (<0.05 ppm) for
one trial, and increased slightly in rice grain with increasing sampling
intervals in the other trial.  For rice straw, residues increased
slightly with increasing sampling intervals in one trial, while residues
did not increase in the other trial.  Residues of 1H-1,2,4-triazole
in/on rice grain and straw from both trials were less than the method
LOQs (<0.02 ppm for total prothioconazole-derived residues, <0.05 ppm
for the triazole conjugates, and <0.01 ppm for 1H-1,2,4-triazole) at all
sampling intervals. 

The maximum storage interval of crop samples from harvest to analysis
for total prothioconazole-derived residues was 1240 days (40.8 months)
for rice grain and straw.  The degree of loss of prothioconazole-derived
residues and prothioconazole-desthio residues is not expected to exceed
30% after 40.8 months in rice grain and straw. 

Wheat: Bayer CropScience has submitted field trial data on wheat from
trials conducted in the U.S. and Canada.  A total of 54 trials were
conducted in Regions 2 (GA and NC; 2 trials), 4 (MS; 2 trials), 5 (IN; 1
trial, KS; 2 trials, NE; 2 trials, and ON; 2 trials), 6 (TX; 2 trials),
7 (AB; 1 trial, ND; 5 trials, SD; 2 trials, and SK; 3 trials), 7A (AB; 2
trials), 8 (OK; 3 trials and TX; 7 trials), 11 (OR; 2 trials), and 14
(AB; 6 trials, MB; 6 trials, and SK; 4 trials) during the 2000 growing
season.  The number and locations of field trials are in accordance with
OPPTS Guideline 860.1500 and Directive 98-02; Section 9.

At each test location, two broadcast foliar applications of the 4 lb/gal
(480 g/L) suspension concentrate formulation (flowable concentrate; FlC)
were made to wheat.  The first application was made at 0.108-0.120 lb
a.i./A (0.122-0.135 kg a.i./ha) followed by a second application at
0.170-0.199 lb a.i./A (0.190-0.223 kg a.i./ha) with a 5- to 18-day
retreatment interval, for a total seasonal application rate of ~0.29 lb
a.i./A (~0.33 kg a.i./ha).  In one field trial conducted in IN, the
first application was made at 0.185 lb a.i./A (0.207 kg a.i./ha)
followed by a second application at 0.190 lb a.i./A (0.213 kg a.i./ha)
with a 14-day retreatment interval, for a total seasonal application
rate of 0.375 lb a.i./A (0.420 kg a.i./ha).  Applications were made in
11-45 gal/A of water using ground equipment.  An adjuvant was not added
to the spray mixture for any applications.

For 33 trials, including two decline trials, two treatment plots
(designated as FORAG and HGRST) were used.  The timing of the
application varied for the two treatment plots.  In the FORAG plot the
second application was made 1 day prior to the first cutting of forage
and in the HGRST plot the second application was made at full flowering.
 Wheat forage from the FORAG plots was harvested one day after
treatment, but these samples were never analyzed or reported.  Wheat hay
from the HGRST plots was cut 12-17 days after treatment and was left in
the field for 0-14 days prior to collection of wheat hay.  Samples of
wheat grain and straw from the HGRST plots were harvested at earliest
commercial harvest, 30-57 days after the last application, except in one
trial in which samples were harvested 10 days after second application. 

For 21 trials, one treatment plot (designated as TRTD) was used; the
second application was made 7 days prior to the first cutting of the
forage.  Only wheat forage was harvested from these trials. 

At two locations (ND and NE), additional samples were collected to
determine residue decline. The samples were harvested at both locations
0, 1, 7, and 14 days after treatment for wheat forage at 6 or 7, 14, 20
or 21, and 28 days after treatment for wheat hay, and at 35 or 36, 39 or
40, 44 or 46, and 49 or 50 days after treatment for wheat grain and
straw.

Samples were analyzed for total prothioconazole-derived residues
(prothioconazole and the metabolite prothioconazole-desthio) using
LC-MS/MS method RPA JA/03/01.  The validated LOQs for the total
prothioconazole-derived residues were 0.02 ppm for wheat grain and 0.05
ppm for wheat forage, hay, and straw.  The method is adequate for data
collection for wheat grain hay, forage and straw based on acceptable
concurrent method recovery data and method validation data. Samples were
analyzed for residues of 1H-1,2,4-triazole and the triazole conjugates
triazolylalanine and triazolylacetic acid using an LC-MS/MS method
(Bayer Report No. G200598).  The validated LOQ for 1H-1,2,4-triazole and
triazolylalanine was 0.01 ppm for wheat forage, hay, grain, and straw;
and the validated LOQs for triazolylacetic acid were 0.01 ppm for wheat
forage, hay, and grain and 0.025 ppm for wheat straw.  The method is
adequate for data collection in wheat matrices based on acceptable
concurrent method recovery data.

The results from the wheat field trials show that in wheat matrices
harvested 10-57 days (12-17 days for hay) following the last of two
broadcast foliar applications at a total seasonal rate of 0.281-0.375 lb
a.i./A (0.315-0.420 kg a.i./ha), the maximum residues of prothioconazole
were 0.061 ppm, 1.96 ppm, and 3.571 ppm, respectively, in/on wheat
grain, straw, and hay for the total prothioconazole-derived residues;
less than the LOQ (<0.01 ppm) in/on wheat grain, straw, and hay for
1H-1,2,4-triazole; and 0.495 ppm, 0.665 ppm, and 1.76 ppm, respectively,
in/on wheat straw, hay, and grain for the triazole conjugates.  In wheat
forage harvested 7 days following the last of two broadcast foliar
applications at a total seasonal rate of 0.286-0.299 lb a.i./A
(0.320-0.336 kg a.i./ha), the maximum residues were 6.987 ppm for the
total prothioconazole-derived residues, less than the LOQ (<0.01 ppm)
for 1H-1,2,4-triazole, and 0.175 ppm for the triazole conjugates.

In the residue decline trials, residues of 1H-1,2,4-triazole at all
sampling intervals were less than the method LOQ (<0.01 ppm) in/on wheat
hay, grain, straw, and forage for both trials (NE and ND).  Total
prothioconazole-derived residues did not increase in any wheat matrix
with increasing sampling intervals, and residues of the triazole
conjugates increased slightly in samples of wheat forage from both
trials and in wheat straw from one trial but did not increase in wheat
hay or grain with increasing sampling intervals.

The maximum storage intervals of crop samples from harvest to analysis
for total prothioconazole-derived residues were 469 days (15.4 months)
for wheat forage, 1214 days (39.9 months) for wheat grain, 1221 days
(40.1 months) for wheat hay, and 1203 days (39.5 months) for wheat
straw.  Prothioconazole-derived residues are relatively stable up to 1
year (interim report) in wheat matrices.  Corrections due to apparent
dissipation of prothioconazole-derived residues in samples stored beyond
a year are not necessary due to the low absolute (ppm) and % residue
levels in wheat matrices.  Residues of prothioconazole-desthio are
stable for up to 1 year and the degree of loss is not expected to exceed
30% after 40.1 months.  

Conclusions:  The submitted crop field trial residue data are adequate
to satisfy data requirements.  As stated under Directions for Use
(860.1200), the applicant has proposed use on an “Oilseed Crop
Subgroup” which consists of the members of the Oilseed Crop Group 20
with the exception of safflower seed and sunflower seed.  The
representative crops of Crop Group 20 are canola and sunflower. 
Currently, no crop subgroups have been defined by HED for Crop Group 20.
 The applicant has submitted crop field trial data for canola but not
for sunflower.  The available crop field trial data will support use of
prothioconazole on the following oilseed commodities:  rapeseed, canola,
Indian rapeseed, field mustard seed, and crambe.

The submitted crop field trial data support the following tolerances for
the combined residues 

of prothioconazole and its desthio metabolite:  barley grain at 0.35ppm;
barley hay at 7.0 ppm; 

barley straw at 4.0 ppm; dried shelled pea and bean, except soybean,
subgroup 6C, at 0.90 

ppm; peanut at 0.02 ppm; peanut hay at 6.0 ppm, rapeseed seed at 0.15
ppm; rice grain at 0.20 

ppm; rice straw at 1.4 ppm; wheat grain at 0.07 ppm; wheat forage at 6.0
ppm; wheat hay at 4.5 

ppm; and wheat straw 5.0 ppm.  The tolerance values were determined
using a statistical 

calculation with the available field trial data.

Residue data for wheat aspirated grain fractions were included with the
processing study (see 860.1520).  The residue data indicate that total
prothioconazole-derived residues concentrate in aspirated grain
fractions.  Based on a processing factor of 245x and a HAFT residue of
0.045 ppm for wheat grain, the expected residues in wheat aspirated
grain fractions following treatment at 1x would be 11.0 ppm.  Therefore,
a tolerance for aspirated grain fractions is needed to support the
proposed uses.  Because the applicant is not proposing use of
prothioconazole on field corn, sorghum, or soybeans, the residue data
from wheat are used to determine the tolerance level for aspirated grain
fractions; these data indicate that a tolerance of 11 ppm would be
appropriate. 

The residue data for aspirated grain fractions indicate that residues of
1,2,4-triazole and the triazole conjugates do not concentrate in wheat
aspirated grain fractions.

Magnitude of the Residue in Processed Commodities

Conclusions:  The submitted processing data for canola, peanut, rice,
and wheat are adequate to satisfy data requirements.  A summary of the
processing factors for prothioconazole residues is provided in Table
5.1.10.2.  The processing data indicate that total
prothioconazole-derived residues concentrate >7.9x in peanut meal, 4.4x
in rice hulls, 2.4x in wheat bran, and 2.0x in wheat germ.  Because
total prothioconazole-derived residues were below the LOQ in/on all
peanut nutmeat samples from the crop field trials, the actual residues
observed in peanut meal in the processing study will be used to
determine expected residues.  Total prothioconazole-derived residues
averaged 0.159 ppm in peanut meal in the processing study.  When this
value is corrected for the exaggerated rate of the study (5x) expected
residues in peanut meal following treatment at 1x are calculated to be
0.032 ppm.  Because the tolerance for peanut nutmeat will be established
at the LOQ (0.02 ppm) and because expected residues in peanut meal are
less than 2x the LOQ for peanut nutmeat, a tolerance for peanut meal is
not needed.  

Based on a processing factor of 4.4x for rice hulls and a HAFT residue
of 0.191 ppm for rice grain, the expected residues in rice hulls
following treatment at 1x would be 0.840 ppm.  Because the expected
residues are greater than the proposed tolerance of 0.60 ppm for rice
grain, a tolerance for rice hulls is needed; a tolerance of 0.90 ppm is
appropriate.  

Based on processing factors of 2.4x for wheat bran and 2.0x for wheat
germ and a HAFT residue of 0.045 ppm for wheat grain, the expected
residues in wheat bran and germ following treatment at 1x would be 0.11
and 0.09 ppm, respectively.  Because the germ residue is less than the
recommended tolerance of 0.10 ppm for wheat grain and because the bran
residue is only slightly greater than the recommended tolerance for
wheat grain, tolerances are not appropriate for germ and bran.

The HAFT total prothioconazole-derived residues in barley grain are
0.151 ppm.  Based on the 2.4x processing factor for wheat bran, the
expected residues in barley bran following treatment at 1x would be 0.36
ppm.  Because expected residues are not significantly greater than the
proposed tolerance of 0.35 ppm for barley grain, a tolerance for barley
bran is not needed.

The processing data indicate that residues of 1,2,4-triazole may
concentrate in peanut meal (>1.9x), dry roasted peanuts (>12.5x), and
peanut butter (>11.9x).  Because 1,2,4-triazole residues were below the
LOQ in/on all but one peanut nutmeat sample from the crop field trials,
the actual residues observed in peanut meal in the processing study
should be used to determine expected residues.  Residues of
1,2,4-triazole averaged 0.019, 0.125, and 0.119 ppm in peanut meal, dry
roasted peanuts, and peanut butter, respectively.  When these values are
corrected for the exaggeration rate of the study, 5x, expected residues
of 1,2,4-triazole in peanut meal, dry roasted peanuts, and peanut butter
following treatment at 1x are calculated to be 0.004, 0.025, and 0.024
ppm, respectively.  

The processing data indicate that residues of the triazole conjugates
may concentrate in canola meal (2.9x), peanut meal (1.9x), rice bran
(6.9x), wheat bran (3.1x), wheat germ (3.6x), and wheat shorts (1.5x). 
The processing factor for canola meal exceeds the theoretical
concentration factor of 1.9x; therefore, the theoretical concentration
factor will be used to determine expected residues.  Based on these
processing factors and HAFT residues of 0.716, 3.390, 0.553, and 1.76
ppm for canola seed, peanut, rice grain, and wheat grain, respectively,
the expected residues of triazole conjugates in processed commodities
following treatment at 1x would be:  1.36 ppm in canola meal; 6.44 ppm
in peanut meal; 3.82 ppm in rice bran; 5.46 ppm in wheat bran; 6.34 ppm
in wheat germ; and 2.64 ppm in wheat shorts.

Table 5.1.10.2.	Summary of Processing Factors for Prothioconazole.

RAC	Processed Commodity	Average Processing Factor

Total Prothioconazole-Derived Residues	1,2,4-Triazole	Triazole Conjugate
Residues

Canola	Meal	<0.7x	NC 1	2.9x

	Refined oil	<0.7x	NC	<0.02x

Peanut	Meal	>7.9x	>1.9x	1.9x

	Refined oil	NC	NC	<0.01x

	Dry roasted peanuts	NC	>12.5x	0.5x

	Peanut butter	NC	>11.9x	0.6x

Rice	Polished Grain	<0.1x	NC	0.5x

	Bran	0.6x	NC	6.9x

	Hulls	4.4x	NC	0.3x

Wheat	Aspirated grain fractions	245x	NC	0.3x

	Bran	2.4x	NC	3.1x

	Flour	<0.4x	NC	0.5x

	Germ	2.0x	NC	3.6x

	Middlings	0.6x	NC	0.6x

	Shorts	1.0x	NC	1.5x

1  NC = Not calculated.  The processing factor could not be calculated
because residues were below the LOQ in both the RAC and the processed
fraction.

Storage Stability in Plant Commodities

Bayer has submitted the results of three storage stability studies with
prothioconazole and the metabolite prothioconazole-desthio in plant
commodities (MRID 46477701) as well as the results of a storage
stability study with prothioconazole and the desthio metabolite in wheat
commodities (MRID 46246139). 

Storage intervals and conditions of samples from the submitted studies: 
The storage intervals and conditions of samples from the submitted crop
field trial, processing, and field rotational crop studies are presented
in Table 5.1.10.3.  The reported storage duration represents the
interval from sample collection to analysis. 

Table 5.1.10.3.	Summary of Storage Intervals and Conditions.

Matrix	Storage Temp. (°C)	Actual Storage Duration

Total Prothioconazole-Derived Residues

Crop Field Trials; MRIDs 46246215-46246217 and 46246219-46246221

Barley grain	-30.0 to -4.8	824-1234 days (27.1-40.6 months)

Barley hay	-30.0 to -4.8	859-1269 days (28.2-41.7 months)

Barley straw	-30.0 to -4.8	825-1240 days  (27.1-40.8 months

Bean, dried shelled	-24 to -22	490-536 days (16.1-17.6 months)

Canola seed	-30.0 to -4.8	867-1265 days (28.5-41.6 months)

Pea, dried shelled	-24 to -22	494-542 days (16.2-17.8 months)

Peanut nutmeat	-30.0 to -4.8	1175-1214 days (38.6-39.9 months)

Peanut hay	-30.0 to -4.8	1173-1212 days (38.6-39.8 months)

Rice grain	-30.0 to -4.8	1135-1240 days (37.3-40.8 months)

Rice straw	-30.0 to -4.8	1120-1226 days (36.8-40.3 months)

Wheat hay	-30.0 to -4.8	871-1221 days (28.6-40.1 months)

Wheat grain	-30.0 to -4.8	873-1214 days (28.7-39.9 months)

Wheat straw	-30.0 to -4.8	854-1203 days (28.1-39.5 months)

Wheat forage	-30.0 to -4.8	181-469 days (6.0-15.4 months)

Processing Studies; MRIDs 46246218 and 46246222-46246224

Canola seed	-30.0 to -4.8	1261 days (41 months)

Canola meal and refined oil

918 days (30 months)

Peanut nutmeat	-30.0 to -4.8	1090 days (36 months)

Peanut meal, refined oil, dry roasted peanuts, and peanut butter

911 days (31 months)

Rice grain	<-5	1222 days (40 months)

Rice polished grain, bran, and hulls

902 days (30 months)

Wheat grain	<-5	1285 days (42 months)

Wheat aspirated grain fractions, bran, germ, flour, middlings, and
shorts

909 days (30 months)

Field Rotational Crop Study; MRID 46246227

Mustard greens	-30.0 to -4.8	1135-1263 days (37.3-41.5 months)

Turnip tops	-30.0 to -4.8	1136-1243 days (37.3-40.8 months)

Turnip roots	-30.0 to -4.8	1136-1243 days (37.3-40.8 months)

Wheat forage	-30.0 to -4.8	952-1002 days (31.3-32.9 months)

Wheat hay	-30.0 to -4.8	893-943 days (29.3-31.0 months)

Wheat grain	-30.0 to -4.8	869-919 days (28.6-30.2 months)

Wheat straw	-30.0 to -4.8	861-911 days (28.3-29.9 months)

Conclusions:  The available storage stability data are tentatively
adequate to support the storage intervals and conditions of samples from
the submitted crop field trial, processing, and field rotational crop
studies.  The final reports of the ongoing storage stability studies
with prothioconazole and prothioconazole-desthio (interim results for
which were reported in MRID 46477701) will be submitted as confirmatory
data.  

For the storage stability data reported in MRID 46477701 for
prothioconazole and prothioconazole-desthio, RAB3 concludes that the
ongoing study (Storage Stability Study 2) will provide the most
information about any actual decline of prothioconazole or
prothioconazole-desthio residues in crop matrices because it includes
more than one sampling interval.  The results of the other two studies
reported in that submission only reflect one sampling interval.  The
applicant chose the tested matrices in Studies 1 and 2 of that
submission to be representative of five diverse crops [an oilseed
(canola), a non-oily grain (wheat), a leafy vegetable (mustard greens),
a root crop (turnip), and a fruiting vegetable (tomato)] as well as the
processed commodities of three crops [an oilseed, a fruiting vegetable,
and a non-oily grain].  Even though prothioconazole appears to be
slightly unstable in two matrices (tomato paste, wheat bran) the overall
impact on the crop residues will not be significant.  However, based on
OPPTS 860.1380, the Agency will consider corrections on a case-by-case
basis, taking into account factors such as the absolute (ppm) and
relative (% ROC) residue levels of the component that is unstable in
storage.  Therefore, correction for dissipation of
prothioconazole-derived residues during freezer storage will not be
necessary at this time. 

Because the applicant has reported that Method No. 00598 is not adequate
for determination of weathered residues of prothioconazole, the results
of the storage stability study reported in MRID 46246139 will not be
used to evaluate the stability of prothioconazole residues in wheat
commodities during frozen storage.

Magnitude of Residue in Meat, Milk, Poultry and Eggs (MMPE)

Bayer CropScience submitted two cattle feeding studies with the subject
petition, one in which cattle were dosed with prothioconazole (MRID
46246213) and one in which cattle were dosed with desthio
prothioconazole (MRID 46246214), which was not reviewed for this
petition.  

Maximum Theoretical Dietary Burdens

Using the recommended tolerances for prothioconazole residues in/on
livestock feed items, the calculated maximum theoretical dietary burden
(MTDB) of prothioconazole to livestock is presented in Table 5.1.10.4.



Table 5.1.10.4. Calculation of Maximum Dietary Burdens of
Prothioconazole to Livestock.

	Maximum % of Diet

% of Diet Used

Dietary Burden, ppm

Crop	Commodity	Residue

%DM	Beef	Dairy	Poultry	Swine

Beef	Dairy	Poultry	Swine

Beef	Dairy	Poultry	Swine

Grain	Aspirated grain fractions	11.025

85	20	20	--	20

20	20	--	20

2.59	2.59	0.00	2.21

Wheat	forage	6.987

25	25	60	--	--

25	60	--	--

6.99	16.77	0.00	0.00

Barley	Hay	6.59

88	25	60	--	--

25	20	--	--

1.87	1.50	0.00	0.00

Peanut	Hay	4.458

85	25	50	--	--

25	0	--	--

1.31	0.00	0.00	0.00

Wheat	Hay	3.571

88	25	60	--	--

5	0	--	--

0.20	0.00	0.00	0.00

Wheat	Straw	1.96

88	10	10	--	--

0	0	--	--

0.00	0.00	0.00	0.00

Barley	Straw	1.871

89	10	10	--	--

0	0	--	--

0.00	0.00	0.00	0.00

Rice	Straw	1.277

90	10	10	--	--

0	0	--	--

0.00	0.00	0.00	0.00

Rice	Hulls	0.8404

90	10	10	15	--

0	0	15	--

0.00	0.00	0.13	0.00

Cowpea	Seed	0.684

88	20	20	10	50

0	0	10	50

0.00	0.00	0.07	0.34

Pea, field	Seed	0.684

90	20	20	20	20

0	0	20	20

0.00	0.00	0.14	0.14

Rice	Bran	0.222

90	15	15	25	15

0	0	25	10

0.00	0.00	0.06	0.02

Rice	Grain	0.222

88	40	40	60	65

0	0	30	0

0.00	0.00	0.07	0.00

Barley	Grain	0.158

88	50	40	75	80

0	0	0	0

0.00	0.00	0.00	0.00

Peanut	Meal	0.158

85	15	15	25	15

0	0	0	0

0.00	0.00	0.00	0.00

Wheat	Milled byproducts	0.108

88	40	50	50	50

0	0	0	0

0.00	0.00	0.00	0.00

Canola	Meal	0.097

88	15	15	15	15

0	0	0	0

0.00	0.00	0.00	0.00

Wheat	Grain	0.061

89	50	40	80	80

0	0	0	0

0.00	0.00	0.00	0.00

Total

100	100	100	100

12.97	20.86	0.45	2.71

Magnitude of the Residue in Milk, Meat, and Meat Byproducts of Ruminants

Bayer CropScience submitted a dairy cattle feeding study with
prothioconazole (MRID 46246213).  Prothioconazole was administered
orally (via gelatin capsules) to three groups of dairy cattle (3 cows
per group) once daily for 29 consecutive days.  Dosing was made at
levels equivalent to 9.9, 29.5, and 98.4 ppm in the feed.  The dosing
levels correspond to 0.5-fold, 1.4-fold, and 4.7-fold the anticipated
dietary burden.  Milk and tissue samples were analyzed using the
proposed enforcement method for animal commodities, which was an
LC-MS/MS method (Bayer Report No. 200537).  This method determined
residues of prothioconazole, desthio prothioconazole, and
prothioconazole-4-hydroxy, plus any metabolites hydrolyzable to these
compounds.  Tissue samples (except fat) were extracted with acetonitrile
(ACN)/water and aqueous L-cysteine HCl.  Fat samples were first
extracted with n-hexane, then ACN, L-cysteine HCl and acetone.  All
samples (including milk and cream) were hydrolyzed with aqueous HCl,
then partitioned with methylene chloride and acetone before LC-MS/MS
analysis.  The method was adequate for data collection based on
acceptable concurrent method recovery data.  The storage intervals for
all matrices except fat were reported to be <30 days, therefore no
storage stability data is needed for these matrices.  Fat samples from
the lowest feeding level (0.5-fold) were stored frozen for up to 86 days
prior to analysis.  For the 1.4-fold and 4.7-fold feeding levels,
samples were stored for 43 and 37 days, respectively.  A supporting
storage stability study indicated that residues of prothioconazole,
prothioconazole-desthio, and prothioconazole-4-hydroxy were stable for
27 days (<30% decline).  After 89 days in storage, residues of
prothioconazole-4-hydroxy showed a 33% decline.  The 1.4-fold dose group
(29.5 ppm) was closest to the anticipated dietary burden (21 ppm). 
Confirmatory data will be generated to confirm the stability of the
prothioconazole-4-hydroxy in fat for a duration of 45 days.

The maximum residues of prothioconazole, prothioconazole-desthio, and
prothioconazole-4-hydroxy in milk and tissues are listed in Table
5.1.10.5 below.  Because low residue levels were observed in samples
from the mid and high dose groups, milk and muscle samples from the low
dose group (9.9 ppm) were not analyzed.  

Table 5.1.10.5.	Maximum Residues of Prothioconazole (A),
Prothioconazole-Desthio (B), and Prothioconazole-4 hydroxy (C), as
prothioconazole equivalents, by Feeding Level Following Dosing of Dairy
Cattle with Prothioconazole for 29 Days.

Matrix

	Residues (ppm)

	9.9 ppm	29.5 ppm	98.4 ppm

	A	B	C	A	B	C	A	B	C

Milk	--	--	--	<0.005	<0.005	<0.005	<0.005	<0.005	<0.005

Skim milk	--	--	--	--	--	--

<0.01	<0.01	<0.01

Cream	--	--	--	--	--	--	<0.01	<0.01	<0.01

Fat	<0.05	<0.05	<0.05	<0.05	<0.05	<0.05	0.062	<0.05	<0.05

Kidney	0.062	<0.01	0.017	0.176	<0.01	0.063	0.79	0.011	0.356

Liver	0.063	<0.01	0.127	0.054	0.011	0.181	0.467	0.030	0.518

Muscle	--	--	--	<0.01	<0.01	<0.01	<0.01	<0.01	<0.01

Quantifiable residues (of prothioconazole, 0.005 - 0.006 ppm) were
observed in only two samples of milk from the highest dosing level. 
However, detectable residues of prothioconazole were observed in several
samples.  Based on these residues, it appeared that residues had reached
a plateau by within the first week of dosing.

Conclusions:  The submitted cattle study data are adequate to satisfy
livestock feeding study data requirements for ruminants. 

The feeding study data indicate that tolerances are needed for the
combined residues of prothioconazole and desthio prothioconazole in
cattle, goat, hog, horse, and sheep commodities. 

Using the results of the prothioconazole feeding study and defining the
residue for tolerance purposes as the sum of prothioconazole,
prothioconazole-desthio, and metabolites that can be hydrolyzed to these
compounds, expressed as prothioconazole, we calculate that tolerances
should be set at the combined LOQs for milk (0.02 ppm, using LOQs for
skim milk and cream); at the combined LOQs for the fat (0.10 ppm) and
muscle (0.02 ppm) of cattle, goats, horses, and sheep; at 0.20 ppm for
the meat byproducts of cattle, goats, horses, and sheep; and at 0.05 ppm
for the meat byproducts of hogs.  The available data indicate that a
tolerance is not needed for milk fat or the fat and meat of hogs. 

Magnitude of the Residue in Eggs, Meat, and Meat Byproducts of Poultry

The applicant did not submit a poultry feeding study with the subject
petition but submitted a request for a waiver from the requirements for
a poultry feeding study.  

The applicant used a value of 0.455 ppm as the maximum theoretical
dietary burden for poultry, based on a diet consisting of 15% rice
hulls, 60% rice grain, and 25% barley grain (and using “anticipated”
tolerance values of 1.5, 0.3, and 0.2 ppm, respectively).  This agrees
with the 0.45 ppm calculated in Table 5.1.10.4 above, resulting from the
feeding of rice and pea commodities.   To determine the residues that
would be found by the proposed enforcement method for livestock
commodities, it can be assumed that residues of
prothioconazole-glucuronide (N-, S- or O- glucuronides) would be
converted to prothioconazole.  Under that assumption, the combined
residues from the metabolism studies (171 ppm and 163 ppm in diet, or
about 360X) were: liver, 1.7 and 1.8 ppm; egg, 0.014 and 0.017 ppm;
muscle, 0.031 and 0.018 ppm; fat, 0.29 and 0.14 ppm.  The residues at a
feeding level of 0.455 ppm can be estimated to be: liver, 0.005 ppm;
egg, 0.00005 ppm; muscle, 0.00009 ppm; fat, 0.0008 ppm.  The enforcement
analytical method for livestock commodities has not been validated for
poultry items.  Assuming that the method has a LOQ of 0.01 ppm for each
of the two analytes for poultry commodities (combined LOQ 0.02 ppm,
based on an LOQ of 0.01 ppm for each analyte in cattle liver), no
residue would be anticipated at the defined feeding level in any of the
poultry commodities, except liver.  Residues appeared not to have
obtained a plateau in eggs, as the TRR in the oviduct egg was about 10X
that in the eggs.  Factoring in a 10X increase in residue in the egg
would not lead to a prediction of detectable residues in eggs at a
feeding level of 0.45 ppm prothioconazole in the diet.

Under the currently proposed uses and defining the residue for tolerance
purposes as the sum of prothioconazole, prothioconazole-desthio, and
metabolites that can be hydrolyzed to these compounds, expressed as
prothioconazole, we conclude that residues are unlikely in poultry
commodities except liver and that, therefore, poultry commodity
tolerances are not needed, except for liver.  A tolerance of 0.02 ppm
should be proposed for chicken liver, based on the validated LOQ of 0.01
ppm for each of the analytes in cattle liver.  HED concludes that the
waiver request for a poultry feeding study is denied.  Additionally, a
fully validated analytical method for poultry commodities is required.

The proposed tolerance of 0.02 ppm for chicken liver is adequate.  The
extrapolation is over a very high range.  The extrapolated value for
liver is 0.005, which might have a considerable error.  Thus, it is
prudent to set a tolerance at the limit of quantitation.  Note that
liver is the only commodity with such a “large” predicted
concentration.  The proposed tolerance was derived by taking the residue
levels for the residues of concern in poultry (parent, and the desthio
metabolite) and dividing them by 360 (rate of exaggeration in the
metabolism study).  When you do this you get a result of 0.0053 ppm
(phenyl label study) and 0.00575 ppm (triazole label study).  Based on
this analysis HED would conclude that residues would not exceed 0.00575
ppm in liver.  However, this level is lower than the method limit of
quantification for those residues.  If the tolerance level were set at
0.005 ppm, this tolerance would be unenforceable as the analytical
method does not have the ability to quantify residues at this level.  In
a case like this HED adds the limits of quantification for the residues
of concern together to come up with the tolerance level.  In this
particular case the limit of quantification is 0.01 ppm for each of the
two analytes (parent and desthio-metabolite).  Thus, 2 x 0.01 ppm = 0.02
ppm (this value is the sum of the LOQs) and this is the level HED
recommends for the tolerance level.

Storage Stability in Livestock Commodities

The storage intervals for all matrices from the cattle feeding studies,
except fat from the prothioconazole feeding study, were reported to be
<30 days.  Because samples were stored frozen prior to analysis and
analyzed within 30 days of collection, supporting storage stability data
are not needed for milk and tissues except fat.  Fat samples from the
lowest feeding level (0.5-fold) were stored frozen for up to 86 days
prior to analysis.  For the 1.4-fold and 4.7-fold feeding levels,
samples were stored for 43 and 37 days, respectively.  A supporting
storage stability study indicated that residues of prothioconazole,
desthio prothioconazole, and prothioconazole-4-hydroxy were stable for
27 days (<30% decline).  After 89 days in storage, low concurrent
recoveries of prothioconazole-4-hydroxy residues were observed at the
0.5-fold feeding level indicating a 33% apparent decline.  The 1.4-fold
dose group (29.5 ppm) was closest to the anticipated dietary burden (21
ppm). 

Conclusions: The applicant will repeat a storage stability study in fat
samples for prothioconazole and the prothioconazole-4-hydroxy metabolite
for a period of 45 days at the 1.4-fold and 4.7-fold feeding level as
confirmatory data.  A report will be submitted to EPA. Therefore,
correction for dissipation of prothioconazole-derived residues and the
prothioconazole-4-OH in fat during freezer storage will not be necessary
at this time.

Confined Accumulation in Rotational Crops

Conclusions:  The submitted confined rotational crop data are adequate
to satisfy data requirements.  Based on the results of the phenyl-label
study, the applicant concluded that metabolism in rotational crops was
similar to that in the primary crops peanut and wheat, as the same major
metabolites were detected.  The presence of minor unknown polar
compounds indicated that composition of metabolites in rotational crops
was influenced by the metabolism of prothioconazole in soil.  The
applicant did not discuss prothioconazole metabolism in soil.  

The applicant did not propose a metabolic pathway for
[triazole-3,5-14C]-prothioconazole in rotational crops.  It appeared
that conjugation was more prevalent in rotational crop metabolism than
in primary crop metabolism, and that metabolism/degradation of the
triazole ring to triazole conjugates was more extensive in rotational
crops than in primary crops. 

The submitted confined rotational crop studies indicate the potential
for quantifiable prothioconazole and triazole conjugate residues in
rotated crop commodities.  No metabolites were identified in the
confined rotational crop studies that were not identified in one or more
of the primary crop metabolism studies.  The residue definition in
rotational crop commodities is the same as for primary crop commodities,
i.e., prothioconazole and the desthio metabolite.

Field Accumulation in Rotational Crops

Conclusions:  The submitted field rotational crop residue data are
adequate to satisfy data requirements.  The applicant has proposed the
following rotational crop restrictions:  crops listed on the label may
be planted as soon as practical after last application; all other crops
may be planted 30 days following last application.  The submitted field
rotational crop data, which indicated no quantifiable total
prothioconazole-derived residues in mustard greens, turnip root and top,
and wheat forage, hay grain, and straw at the 1-month PBI, are adequate
to support the proposed rotational crop restrictions.  With these
restrictions, tolerances will not be needed for rotated crops.

Proposed Tolerances

Bayer CropScience has proposed the establishment of permanent tolerances
for residues of the fungicide prothioconazole
[2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2-dihy
dro-3H-1,2,4-triazole-3-thione] and the desthio metabolite in/on raw
agricultural and processed commodities, and for residues of
prothioconazole, the desthio and 4-hydroxy metabolites, and conjugates
that can be converted to these three compounds by acid hydrolysis, in/on
cattle commodities.

The proposed tolerance expression for plant commodities should be
revised to specify that residues of the desthio metabolite are
calculated as parent.  The tolerance expression for livestock
commodities should be revised to residues of prothioconazole, desthio
prothioconazole, and conjugates that can be converted to these two
compounds by acid hydrolysis, calculated as parent.

There are currently no established Codex or Mexican MRLs for
prothioconazole.  MRLs in Canada will be established as a result of this
Joint Review project.  An International Residue Limit Status sheet is
attached to this review.  

Pending receipt of the required storage stability data, the available
crop field trial data will support tolerances for residues of
prothioconazole and the desthio metabolite in/on:  barley, grain;
barley, hay; barley, straw; grain, aspirated grain fractions; pea and
bean, dried shelled, except soybean, subgroup 6C; peanut; peanut, hay;
rapeseed, seed; rice, grain; rice, straw; rice, hulls; wheat, grain;
wheat, forage; wheat, hay; and wheat, straw.  The available data
indicate that the proposed tolerance of 0.06 ppm for wheat grain is too
low; a revised tolerance of 0.07 ppm should be proposed.  The available
crop field trial data indicate that the proposed tolerances of 13.0 ppm
for aspirated grain fractions, and 7.0 ppm for wheat forage are too
high.  Revised tolerances of 11 ppm and 6.0 ppm, respectively, should be
proposed.  The available crop field trial data indicate that the
proposed tolerances of 4.0 ppm for wheat hay and 2.3 ppm for wheat straw
are too low.  Revised tolerances of 4.5 ppm and 5.0 ppm, respectively,
should be proposed.

The available crop field trial data indicate that proposed tolerances
for barley grain of 0.2 ppm and for barley straw of 2.0 ppm are too low.
 Revised tolerances of 0.35 ppm and 4.0 ppm, respectively, should be
proposed.

The available crop field trial data indicate that proposed tolerance for
the pea and bean subgroup, dried, shelled, except soybean, of 0.8 ppm is
too low.  A revised tolerance of 0.9 ppm should be proposed.

The available crop field trial data indicate that proposed tolerance for
peanut hay of 5.0 ppm is too low.  A revised tolerance of 6.0 ppm should
be proposed.

The available crop field trial data indicate that the proposed tolerance
for rice grain of 0.25 ppm is too high.  A revised tolerance of 0.20 ppm
should be proposed.  Likewise, the available field trial data indicate
that the proposed tolerance for rice straw of 1.5 ppm is too high.  A
revised tolerance of 1.4 ppm should be proposed.  However, since the
petitioner, Bayer CropScience, has acknowledged their intent to remove
rice from their tolerance petition, HED has removed rice commodities
from the consideration for tolerances.

Additional crop field trial data are required to support the proposed
tolerances for black mustard seed, borage seed, flax seed, and Indian
mustard seed.  

The proposed tolerances for canola seed, crambe seed, field mustard
seed, and Indian rapeseed are not needed.  According to 40 CFR
§180.1(h), a tolerance for rapeseed will cover these commodities.

The ruminant feeding study will support tolerances for the combined
residue of prothioconazole, prothioconazole-desthio, and metabolites
that are acid hydrolyzed to these two compounds, calculated as parent,
in cattle, goat, hog, horse, and sheep commodities.  The applicant must
propose tolerances for the fat, meat, and meat byproducts of goat,
horse, and sheep, and must propose tolerances for the meat byproducts of
hogs.  The values proposed by the applicant are inappropriate as they
included the 4-hydroxy prothioconazole metabolite and conjugates thereof
that can be acid hydrolyzed to 4-hydroxy prothioconazole.  The
appropriate levels for the tolerances are listed in Table 5.1.10.6.  

A poultry metabolism study will support tolerances for the combined
residue of prothioconazole, prothioconazole-desthio, and metabolites
that are acid hydrolyzed to these two compounds, expressed as parent, at
the LOQs of the analytical method, for poultry liver.  The results of
the poultry metabolism study indicate that tolerances are not needed for
the remaining poultry commodities.  Note that new animal feed tolerance
petitions will not be considered until a poultry feeding study is
conducted and until the enforcement analytical method is fully validated
for poultry commodities.

Based on the results of HED’s risk assessment, the proposed tolerances
should be revised to reflect the correct commodity definitions as
specified in Table 5.1.10.6.

Table 5.1.10.6.	Tolerance Summary for Prothioconazole.

Commodity	Proposed Tolerance (ppm)	Recommended Tolerance (ppm)	Comments/

Correct commodity definition

Tolerances for residues of prothioconazole and the desthio metabolite

Barley, grain	0.2	0.35	The proposed tolerance is too low.

Barley, hay	7.0	7.0

	Barley, straw	2.0	4.0	The proposed tolerance is too low.

Barley, pearled barley	0.2	Delete, not needed	A separate tolerance is
not needed for pearled barley.

Barley, bran	0.4	Delete, not needed	A separate tolerance is not need for
barley, bran.

Black mustard, seed	0.1	Delete, not allowed at this time	Additional crop
field trial data are needed to support this tolerance.

Borage, seed	0.1	Delete, not allowed at this time	Additional crop field
trial data are needed to support this tolerance.

Canola, seed	0.1	Delete, not needed	As specified under 40 CFR
§180.1(h), a tolerance for rapeseed applies to canola seed and crambe
seed.

Crambe, seed	0.1	Delete, not needed

	Field mustard, seed	0.1	Delete, not needed	Covered under the tolerance
for rapeseed.

Flax, seed	0.1	Delete, not allowed at this time	Additional crop field
trial data are needed to support this tolerance.

Grain, aspirated fractions	13.0	11	The proposed tolerance is too high;

Grain, aspirated grain fractions

Indian mustard, seed	0.1	Delete, not allowed at this time	Additional
crop field trial data are needed to support this tolerance.

Indian rapeseed	0.1	Delete, not needed	Covered under the tolerance for
rapeseed.

Pea and bean, dried, shelled, except soybean, subgroup	0.8	0.90	The
proposed tolerance is too low.

Pea and bean, dried shelled, except soybean, subgroup 6C

Peanut, nutmeat	0.02	0.02	Peanut

Peanut, hay	5.0	6.0	The proposed tolerance is too low.

Peanut, meal	0.3	Delete, not needed	A separate tolerance is not needed
for peanut meal.

Rapeseed, seed	0.1	0.15	The proposed tolerance is too low.

Rice, grain	0.25	Delete, not needed	Petitioner intends to remove rice
from their tolerance petition.

Rice, straw	1.5	Delete, not needed	Petitioner intends to remove rice
from their tolerance petition.

Rice, hulls	1.0	Delete, not needed	Petitioner intends to remove rice
from their tolerance petition.

Wheat, grain	0.06	0.07	The proposed tolerance is too low.

Wheat, forage	7.0	6.0	The proposed tolerance is too high.

Wheat, hay	4.0	4.5	The proposed tolerance is too low.

Wheat, straw	2.3	5.0	The proposed tolerance is too low.

Wheat, bran	1.5	Delete, not needed. 	Covered under the tolerance for
wheat, grain

Wheat, germ	0.15	Delete, not needed.	Covered under the tolerance for
wheat, grain.

Tolerances for the combined residue of prothioconazole, the desthio
metabolite, and conjugates convertible to these two compounds by acid
hydrolysis, calculated as prothioconazole

Milk	0.006	0.02	The proposed tolerance is too low.

Cattle, fat	0.1	0.1

	Cattle, meat	0.01	0.02	The proposed tolerance is too low.

Cattle, meat byproducts	1.2	0.20	The proposed tolerance is too high.

Goat, fat	None	0.1	Extrapolated from cattle.

Goat, meat	None	0.02	Extrapolated from cattle.

Goat, meat byproducts	None	0.20	Extrapolated from cattle.

Hog, meat byproducts	None	0.05	Extrapolated from cattle.

Horse, fat	None	0.1	Extrapolated from cattle.

Horse, meat	None	0.02	Extrapolated from cattle.

Horse, meat byproducts	None	0.20	Extrapolated from cattle.

Sheep, fat	None	0.1	Extrapolated from cattle.

Sheep, meat	None	0.02	Extrapolated from cattle.

Sheep, meat byproducts	None	0.20	Extrapolated from cattle.

Poultry, liver	None	0.02	A tolerance is needed.	

5.1.11	International Residue Limits (IRL) TC \l3 "5.1.11	International
Residue Limits (IRL) 

There are currently no U.S., Canadian, Mexican, or international Codex
tolerances established for prothioconazole.  There are no maximum
residue limits (MRLs) established for prothioconazole in Codex or in
Mexico.  Maximum residue limits will be established in Canada as a
result of this Joint Review.  An IRL Status Sheet is attached.

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

Prothioconazole: Acute Probabilistic and Chronic Aggregate Dietary and
Drinking Water Exposure and Risk Assessments for the Section 3
Registration Action. PP #4F6830. DP Barcode 331636, T. Goodlow,
08/03/06.

Dietary risk assessment incorporates both exposure and toxicity of a
given pesticide.  For acute and chronic assessments, the risk is
expressed as a percentage of a maximum acceptable dose (i.e., the dose
which HED has concluded will result in no unreasonable adverse health
effects).  This dose is referred to as the population adjusted dose
(PAD). For acute and non-cancer chronic exposures, HED is concerned when
estimated dietary risk exceeds 100% of the PAD.  

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

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

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

Residue Data used for Acute and Chronic Assessments:

Moderately refined acute and chronic dietary assessments were performed
for prothioconazole.  The refinements used for both exposure durations
are summarized below.  

Average field trial residues were used for all plant commodities in both
the acute and chronic analyses.  Mean values used in this assessment can
be found in Stephen Funk’s Summary of Analytical Chemistry and Residue
Data document under ‘crop field trials’.  Since all of the crops
included in this assessment are blended food forms, no residue data
files (RDFs) were required.  See Change in Classification of Food Forms
with Respect to “Not Blended,” “Partially Blended,” and
“Blended” Status, HED’s ChemSAC memo, 8/20/1999 for further
details.

 x  Σ Residues

					    	    Diet in feeding study

Example:	The maximum residue for milk is calculated below using the MTDB
of 21 ppm, a diet of 29.5 ppm from the livestock feeding study, and
residues of <0.005, <0.005, and <0.005 ppm for milk.

			Maximum Residue for Milk =   21 ppm   x  0.015 ppm  =  0.011 ppm

				       		             29.5 ppm

EFED submitted modeled EDWC values.  Point estimates were used in the
acute and chronic assessments from the bean and rice application
scenarios.  See D330265, Prothioconazole Tier II Estimated Drinking
Water Concentrations (EDWCs) for Use in the Human Health Risk Assessment
[Second revision] by Roxolana Kashuba for further details.

Since there are no water monitoring data available for prothioconazole,
drinking water exposure estimates were based on PRZM-EXAMS surface water
modeling results.  The drinking water inputs may be considered
conservative for the following reasons.  The model results assume that
applications will be made at maximum application rates every year for 30
years.  The PRZM-EXAMS models are based on an actual reservoir/watershed
system in Illinois which is known to be a highly vulnerable
configuration.  Based on these considerations, it is likely that actual
exposure to prothioconazole from drinking water is somewhat lower than
the estimates provided in this assessment.  

Empirical factors generated in processing studies were also included
when appropriate in the acute and chronic assessments.  Reduction
factors were used for canola refined oil, polished rice grain, rice bran
and wheat flour.  Concentration factors were incorporated for wheat bran
and germ.  A default DEEM 7.81 processing factor was also included for
dried beef.  A processing factor could not be calculated for peanut
butter in the submitted peanut processing study because residues were
below the limit of quantification (LOQ) in both the raw agricultural
commodity (RAC) and the processed fraction; therefore, no PF was applied
for peanut butter.  See Summary of Analytical Chemistry and Residue Data
document for additional information.

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

A moderately refined acute dietary exposure assessment was conducted for
prothioconazole.  Average field trial values, empirical processing
factors, and livestock maximum residues were incorporated into the
refined acute assessment.  The assessment also assumed 100% CT.  No
acute endpoint was identified for the general U.S. population.  Females,
13-49 years of age, was the only population subgroup included in the
acute assessment.  Dietary risk estimates were determined considering
exposures from food alone and food plus water using surface water
exposures for the dry bean and rice crops, since these commodities have
the highest EDWCs.  Ground water sources were not included, as the EDWCs
for this water source are minimal in comparison to surface water.  

The dietary exposure analyses result in acute dietary risk estimates
that are below the Agency’s level of concern for food only and food
and water based on the bean application scenario.  At the 95th
percentile, the food only exposure for females 13-49 years old was
0.000216 mg/kg/day, which utilized 11% of the aPAD (see Table 5.2.1). 
The exposure for food plus lower bound surface water estimates was
0.000614 mg/kg/day, which utilized 31% of the aPAD at the 95th
percentile.  The exposure for food and upper bound water estimates was
0.001192 mg/kg/day, which utilized 60% of the aPAD at the 95th
percentile for females 13-49 (see Table 5.2.2).

Using EDWCs for rice, the dietary exposure analyses result in acute
dietary risk estimates that are below the Agency’s level of concern
for the food plus lower bound surface water analysis; dietary estimates
exceeded the Agency’s level of concern for food plus upper bound
surface water estimates.  For females 13-49 years old, the exposure for
food plus lower bound surface water estimates was 0.001141 mg/kg/day,
which utilized 57% of the aPAD at the 95th percentile.  The exposure for
food and upper bound water estimates was 0.005573 mg/kg/day, which
utilized 279% of the aPAD at the 95th percentile (see Table 5.2.2). 
Surface water was found to be the most significant contributor to the
risk estimates for the food plus upper bound water analysis based on the
rice application scenario.   

The results of the Critical Exposure Contribution analysis showed that
surface water is the most significant contributor to the risk estimates
for females 13-49 years of age in the analysis considering food plus the
upper bound surface water estimate from rice, with surface water
comprising over 95% of the total exposure.  EDWCs used in the acute
assessment have been refined by EFED with the application of regional
default Percent Cropped Area factors.  The availability of surface water
monitoring data or a more appropriate model for determining rice
estimated drinking water concentrations could greatly impact the chronic
risk estimates.  However, without such data, further refinement of
exposure estimates is not possible.  

Table 5.2.1.  Results of Acute Dietary Exposure Analysis for
Prothioconazole Using DEEM FCID at the 95th Percentile – Food Only

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

Females 13-49 years old 	0.0020	0.000216	11



Table 5.2.2.  Results of Acute Dietary Exposure Analysis for
Prothioconazole Using DEEM FCID at the 95th Percentile – Food and
Water

Population Subgroup	aPAD (mg/kg/day)	Lower Bound	Upper Bound

Exposure (mg/kg/day)	% aPAD	Exposure (mg/kg/day)	% aPAD

Females 13-49 years old 	

0.0020	USING DRY BEAN EDWC VALUES

0.000614	31	0.001192	60

USING RICE EDWC VALUES

0.001141	57	0.005573	279

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

A refined chronic dietary exposure assessment was also performed. 
Empirical processing factors, average residues, and livestock maximum
residues were incorporated into the chronic assessment; 100% crop
treated was also assumed.  Dietary risk estimates were determined
considering exposures from food alone and food plus upper or lower bound
surface water EDWC point estimates based on the bean application
scenario.  Chronic EDWCs for rice were not determined due to model
constraints.  The dietary exposure analyses result in chronic dietary
risk estimates that are below the Agency’s level of concern for food
alone and food plus water.  The highest exposure and risk estimates were
for all infants and children 1-2 years old.  The food only exposure was
0.000530 mg/kg/day, which utilized 48% of the cPAD for children 1-2 (see
Table 5.2.3).  The highest exposure and risk estimates for food plus
lower bound water were also for children 1-2.  The exposure for food
plus lower surface water estimates was 0.000684 mg/kg/day, utilizing 62%
of the cPAD.  The highest exposure and risk estimates for food plus
upper bound water were for the all infants population subgroup.  The
exposure for food plus upper bound surface water estimates was
0.000948mg/kg/day, which utilized 86% of the cPAD (see Table 5.2.4).  



Table 5.2.3.  Results of Chronic Dietary Exposure Analysis  for
Prothioconazole Using DEEM FCID-                 Food Only

Population Subgroup	cPAD (mg/kg/day)	Refined Assessment

Exposure (mg/kg/day)	% cPAD

General U.S. Population	0.0011	0.000136	12

All Infants (< 1 year old)	0.0011	0.000188	17

Children 1-2 years old	0.0011	0.000530	48

Children 3-5 years old	0.0011	0.000382	35

Children 6-12 years old	0.0011	0.000238	22

Youth 13-19 years old	0.0011	0.000120	11

Adults 20-49 years old	0.0011	0.000093	8.5

Adults 50+ years old	0.0011	0.000081	7.4

Females 13-49 years old 	0.0011	0.000084	7.7

Table 5.2.4.  Results of DEEM-FCID Chronic Dietary Exposure Analysis 
for Prothioconazole Using Lower and Upper Bound EDWC Values for Beans
– Food and Water

Population Subgroup	cPAD (mg/kg/day)	Lower Bound	Upper Bound

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

General U.S. Population	0.0011	0.000240	22	0.000368	34

All Infants (< 1 year old)	0.0011	0.000527	48	0.000948	86

Children 1-2 years old	0.0011	0.000684	62	0.000875	80

Children 3-5 years old	0.0011	0.000526	48	0.000704	64

Children 6-12 years old	0.0011	0.000337	31	0.000460	42

Youth 13-19 years old	0.0011	0.000195	18	0.000288	26

Adults 20-49 years old	0.0011	0.000189	17	0.000309	28

Adults 50+ years old	0.0011	0.000182	17	0.000309	28

Females 13-49 years old 	0.0011	0.000180	16	0.000300	27

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

The available toxicology studies in the mouse and rat showed no increase
in tumor incidence, and therefore HED concluded that prothioconazole or
its metabolites are not carcinogenic, and classified “Not Likely to be
Carcinogenic to Humans” according to the 2005 Cancer Guidelines. 
Therefore, a dietary cancer assessment was not performed. 

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

Residential exposures are not expected, since there are no proposed
residential uses.

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

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

Based on the proposed Section 3 food crop uses, dietary aggregate
exposures (i.e. food plus drinking water) are anticipated.  No
residential uses are proposed, and therefore, no residential exposures
are anticipated.  Consequently, only dietary (food plus drinking water)
exposures were aggregated for this assessment.  However, rather than
using back-calculated drinking water levels of comparison (DWLOCs),
estimates of pesticide residues in drinking water were incorporated
directly into the dietary exposure analysis to assess aggregate acute
and chronic risk.  Refer to section 5.2 for these risk estimates.  

Recent advances in dietary exposure models (DEEM/Calendex, LifeLine, and
CARES) allow EPA to incorporate actual water consumption data and body
weight data in assessing exposure to pesticides in drinking water as
well as conduct probabilistic assessments for food, water, and
residential exposures to pesticides.  These more sophisticated exposure
assessments are not possible under the DWLOC approach.

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

Prothioconazole is a member of the triazole-containing class of
pesticides, often referred to as the conazoles.  EPA is not currently
following a cumulative risk approach based on a common mechanism of
toxicity for the conazoles.  The conazole pesticides, as a whole, tend
to exhibit carcinogenic, developmental, reproductive, and/or
neurological effects in mammals.  Additionally, all the members of this
class of compounds are capable of forming, via environmental and
metabolic activities, 1,2,4-triazole, triazolylalanine and/or
triazolylacetic acid.  These metabolites have also been shown to cause
developmental, reproductive, and/or neurological effects.  Structural
similarities and sharing a common effect does 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.  Hence, the underlying basis of toxicity is
the same, or essentially the same for each chemical.” (EPA, 2002)  A
number of potential events could contribute to the toxicity of conazoles
(e.g., altered cholesterol levels, stress responses, altered DNA
methylation).  At this time, there is not sufficient evidence to
determine whether conazoles share common mechanisms of toxicity. 
Without such understanding, there is no basis to make a common mechanism
of toxicity finding for the diverse range of effects found. 
Investigations into the conazoles are currently being undertaken by the
EPA’s Office of Research and Development.  When the results of this
research are available, the Agency will make a determination of whether
there is a common mechanism of toxicity and, therefore, a basis for
assessing cumulative risk.  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.

To support existing tolerances and to establish new tolerances for
conazole pesticides, including prothioconazole, EPA conducted human
health risk assessments for exposure to 1,2 4-triazole,
triazolylalanine, and triazolylacetic acid resulting from the use of all
current and pending uses of triazole-containing pesticides (as of
9/1/05).  The risk assessment is a highly conservative, screening-level
evaluation in terms of hazards associated with the common metabolites
(e.g., use of maximum combination of uncertainty factors) and potential
dietary and non-dietary exposures (i.e., high-end estimates of both
dietary and non-dietary exposures).  Acute and chronic aggregate risk
estimates associated with these compounds are below the Agency's level
of concern for all durations of exposure and for all population
subgroups, including those of infants and children.  The Agency's risk
assessment for these common metabolites is available in the
propiconazole reregistration docket at http://www.regulations.gov,
Docket Identification (ID) Number EPA-HQ-OPP-2005-0497.

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

Prothioconazole: Occupational Exposure and Risk Assessment for Proposed
Uses on Barley, Oilseed (except Sunflower and Safflower) Crop Group,
Dried Shelled Pea and Bean (except Soybean) Subgroup, Peanut, Rice and
Wheat. PC Code: 113961, DP Barcode: D303579, 8/18/06.

Occupational exposure to prothioconazole is limited to use of the
proposed formulation PROLINE® 480 SC Fungicide, which is proposed for
application on barley, oilseed crops, dried bean and pea crops, peanuts,
rice and wheat (more detail is provided in Tables 2.1 and 2.3 under
Section 2.0).  Short- and intermediate-term dermal and inhalation
exposures are expected from handler activities, and short- and
intermediate-term dermal exposures are expected from postapplication
activities.

As discussed previously in the hazard section, the short- and
intermediate-term dermal exposure scenarios are assessed using the NOAEL
from the dermal developmental toxicity study in the rat (30 mg/kg/day,
based on an increased incidence of supernumerary rib at the LOAEL of 100
mg/kg/day); and the short- and intermediate-term inhalation exposure
scenarios are assessed using the NOAEL from the developmental toxicity
study in the rabbit (2 mg/kg/day, based on arthrogryposis and multiple
malformations).  A dermal absorption factor was not applied because the
study the endpoint was selected from was route specific.  However, for
the inhalation exposure estimates, an inhalation absorption factor of
100% was applied because the developmental study in the rabbit was an
oral study and inhalation and oral exposures are assumed to be
equivalent.  Also, a body weight of 60 kg was used in the exposure
estimates, because the endpoints were developmental (and therefore a
female-specific body weight is appropriate).

Although the inhalation and dermal exposure scenarios employ different
quantitative hazard estimates from different studies for risk
calculations – the endpoint/hazard that the quantitative hazard
estimates represent is the same.  Therefore, the respective risk
estimates are combined via the total MOE approach, resulting in a total
MOE that reflects risk resulting from exposure via the inhalation and
dermal routes, for both short- and intermediate-term exposure durations.
 As described previously, the LOC is 1000.

As part of the registration package, the registrant submitted a
prothioconazole-specific handler exposure study (Maasfeld, W. (2004)
Determination of exposure to JAU 6476 and JAU 6476-desthio (SXX 0665)
during mixing/loading and application of JAU 6476 in cereals.
Unpublished study prepared by Bayer AG under Project No. P666001501.
110p. (MRID 46246447)).  The first objective of the study aimed to
provide unit exposure information on prothioconazole and
prothioconazole-desthio.  The unit exposure information was determined
to be inappropriate for use in exposure estimate calculations (and
subsequent risk estimates) because of the small scale of the study, the
choice of activity combinations, and the use of Bayer employees as study
subjects.  The best use of the study was to ascertain the likely range
of percent conversion from prothioconazole to prothioconazole-desthio
during a typical agricultural workday (the second objective).  Only
outer dosimeters, which represent workers’ clothes, detected both
prothioconazole and prothioconazole-desthio, and therefore offered the
most information regarding percent conversion estimates (which ranged
from 0.5 to 61%).  Although percent conversions were estimated in
EPA’s secondary review of the study, they are not used quantitatively
in this assessment (only qualitatively).  Note: An ethics review of this
study was completed (K.Sherman, 9/27/06).  The conclusions of the ethics
review are as follows:  1) Although there were some gaps in the
documentation of the ethical conduct of this study, there is no clear
evidence that the research was intended to harm participants, or that is
was fundamentally unethical in other ways; 2) Deficient documentation
does not itself constitute evidence that the conduct of this study was
deficient relative to standards prevailing when is was conducted; and 3)
From the documentation available, the research did not involve
intentional exposure of any subjects who were pregnant or nursing women
or children.  It was concluded the study does not violate current
ethical standards, and although it was considered scientifically valid
for qualitative purposes, it did not meet HED’s scientific standards
for quantitative use in this risk assessment.

Rather than estimate exposure to prothioconazole and
prothioconazole-desthio separately (and then estimate separate risks),
the risk assessment team decided to estimate exposure based on
prothioconazole assuming no conversion (resulting in protective exposure
estimates), and compare these estimates to quantitative hazard estimates
from the prothioconazole-desthio toxicology database (protective
quantitative hazard estimates, because prothioconazole-desthio is
generally considered more toxic than prothioconazole).  This approach
results in a protective risk assessment.



9.1	Short-/Intermediate-Term Handler Risk  TC \l2 "9.1
Short-/Intermediate-/Long-Term/Cancer (if needed) Handler Risk 

Handlers are assumed to have potential short- (1-30 consecutive days)
and intermediate-term (31-180 consecutive days) dermal and inhalation
exposure to prothioconazole when mixing, loading and applying PROLINE®
480 SC Fungicide.  

Prothioconazole-specific handler exposure data were submitted in support
of this action, but as explained above, were used only qualitatively in
this assessment because of the small scale of the study, the choice of
activity combinations, and the use of Bayer employees as study subjects.
 It is the policy of HED to use data from PHED Version 1.1 as presented
in the PHED Surrogate Exposure Guide (8/98) to assess handler exposures
for regulatory actions when chemical-specific monitoring data are not
more-applicable, nor more scenario-specific (HED Science Advisory
Council for Exposure [ExpoSAC] Policy .007, “Use of Values from PHED
Surrogate Table and Chemical-Specific Data” HED, OPP, 1/28/99). 
Additionally, typical HED standard values were used for the amount
treated per day (ExpoSAC Policy # 9, 7/5/00).  

The daily doses presented in this assessment are characterized as mid-
to high-end exposure estimates because both upper-percentile and average
values were used in the calculations: the unit exposure values from PHED
are considered to be central tendency; the areas treated per day values
are considered typical-to-high-end; the application rates and other
treatment variables used in this assessment are upper-percentile values;
and the inhalation absorption factor and body weight values are
considered protective.

PROLINE® 480 SC is applied aerially and by ground equipment.  The
following handler scenarios were considered representative of potential
exposures expected from use of this product: mixing and loading for
aerial and groundboom equipment; and application with aerial and
groundboom equipment; as well as flagging for aerial applications.  The
following levels of PPE and engineering controls were necessary to reach
the LOC for each scenario (for M/L for aerial application to rice and
wheat, the LOC was not reached; refer to Table 9.1 for details on the
exposure and risk estimates).

Mixing and Loading for:

Aerial: with the engineering controls/PPE (closed system and gloves),
all scenarios reached the LOC of an MOE of 1000, except for wheat

Groundboom: with baseline clothing and the PPE gloves, all scenarios
reached the LOC of an MOE of 1000

Application with:

Aerial Equipment (closed cockpit): with baseline clothing (and no
gloves), all scenarios reached the LOC of an MOE of 1000

Groundboom Equipment: with baseline clothing (and no gloves), all
scenarios reached the LOC of an MOE of 1000

Flagging for aerial applications: with baseline clothing (and no
gloves), all scenarios reach the LOC of an MOE of 1000

Although the mixing and loading for aerial application to wheat does not
result in an exposure estimate 1000X less than the quantitative hazard
estimate (even with engineering controls) this estimate does involve
uncertainty regarding both hazard and exposure.  On the exposure side,
prothioconazole exposure estimates are compared to
prothioconazole-desthio endpoints (in order to be protective and prevent
separating out risks from prothioconazole and prothioconazole-desthio),
even though there are data that support prothioconazole-desthio exposure
estimates being at most about half that of prothioconazole exposure
estimates (i.e. conversion estimates of prothioconazole to
prothioconazole-desthio ranged from 0.5 to 61% in MRID 46246447).  On
the hazard side, an additional 10X has been applied to account for lack
of a NOAEL in the DNT study regarding the neurotoxic endpoint of
peripheral lesions and brain morphometrics; and had the risk assessment
team separated out risk from prothioconazole and
prothioconazole-desthio, not only would the prothioconazole-desthio
exposure estimates be lower, the prothioconazole quantitative hazard
estimate would be about 7X greater than the prothioconazole-desthio
quantitative hazard estimate employed in this assessment.

Table 9.1 summarizes the handler exposure estimates and risk resulting
from the proposed uses of prothioconazole.



Table 9.1.	Short- and Intermediate-Term Occupational Exposure and Risk
Estimates for Prothioconazole.  All estimates are at different
mitigation levels (either the 

		lowest at which the LOC is reached, or the highest available if the
LOC is not reached) listed below each scenario description.  Bolded MOEs
are those that do not 

		reach the LOC.  The S-T/I-T dermal NOAEL is 30 mg/kg/day.  S-T/I-T
inhalation NOAEL is 2.0 mg/kg/day

Exposure Scenario	Application Rate

(lb ai/acre)	Crop

	Exposure Route	Acres Treated

per Day1	PHED Unit Exposure2

(mg/lb ai) 	Daily Dose3

(mg/kg/day)

	Route-specific Short-/Inter Term MOE	Total Short-/Inter Term MOE5

Closed M/L Liquids, for Aerial

PPE/Engineering control = Closed system + gloves	0.178	Barley, canola,
chickpea, dried shelled peas and beans subgroup, lentils, oilseed crop
subgroup,  peanuts	Dermal	350	0.0086	0.0089	3,400	3,000

	Inhalation

0.000083	0.000086	23,000

0.143

	Rice	Dermal	1200	0.0086	0.025	1,200	1,000

	Inhalation

0.000083	0.00024	8,300

0.178	Wheat	Dermal	1200	0.0086	0.031	970	870

	Inhalation

0.000083	0.00030	6,700

	Open M/L Liquids, for Groundboom

PPE = single layer + gloves	0.178	Barley, canola, chickpea, dried
shelled peas and beans subgroup, lentils, oilseed crop subgroup, 
peanuts	Dermal	80	0.023	0.0055	5,500	3,100

	Inhalation

0.0012	0.00028	7,100

0.143

	Rice	Dermal	200	0.023	0.011	2,700	1,500

	Inhalation

0.0012	0.00057	3,500

0.178	Wheat	Dermal	200	0.023	0.014	2,100	1,200

	Inhalation

0.0012	0.00071	2,800

	Applying Liquid, with Aerial - fixed wing (enclosed cockpit)

Baseline (no PPE, i.e., single layer, no gloves)	0.178	Barley, canola,
chickpea, dried shelled peas and beans subgroup, lentils, oilseed crop
subgroup,  peanuts	Dermal	350	0.005	0.0052	5,800	4,800

	Inhalation

0.000068	0.000071	28,000

0.143

	Rice	Dermal	

1200	0.005	0.014	2,100	1,700

	Inhalation

0.000068	0.00019	11,000

0.178	Wheat	Dermal	1200	0.005	0.018	1,700	1,400

	Inhalation

0.000068	0.00024	8,300

	Applying Liquid, with Groundboom (open cab)

Baseline (no PPE, i.e., single layer, no gloves)	0.178	Barley, canola,
chickpea, dried shelled peas and beans subgroup, lentils, oilseed crop
subgroup,  peanuts	Dermal	80	0.014	0.0033	9,100	5,000

	Inhalation

0.00074	0.00018	11,000

0.143

	Rice	Dermal	200	0.014	0.0067	4,500	2,500

	Inhalation

0.00074	0.00035	5,700

0.178	Wheat	Dermal	200	0.014	0.0083	3,600	2,000

	Inhalation

0.00074	0.00044	4,500

	Flagging for Aerial Operations

Baseline (no PPE, i.e., single layer, no gloves)	0.178	Barley, canola,
chickpea, dried shelled peas and beans subgroup, lentils, oilseed crop
subgroup,  peanuts, wheat	Dermal	350	0.011	0.011	2,700	1,800

	Inhalation

0.00035	0.00037	5,400

0.143	Rice	Dermal	350	0.011	0.0092	3,300	2,200

	Inhalation

0.00035	0.00029	6,900

	1 Acres Treated Per Day from ExpoSAC Policy # 9, 7/5/00

2 Unit exposure values are given for PPE/Engineering controls listed
under Exposure Scenario (column 1)

3 Daily Dose = [Application Rate (lb ai/A) x Acres Treated (A/day) x
Unit Exposure (mg/lb ai handled) x Absorption Factor]/Body Weight.  A
dermal absorption factor is not applied, since the endpoint chosen is
from a dermal toxicity study.  An inhalation absorption factor of 100%
was used for inhalation risk, since the endpoint chosen is from an oral
toxicity study.  A body weight of 60 kg used for all calculations
because the endpoints are gender-specific.  Short-/Intermediate-term
Dermal NOAEL=30 mg/kg/day; LOC = 1000.  Short-/Intermediate-term
Inhalation LOAEL=2.0 mg/kg/day.  LOC = 1000

4 Total MOE = 1/[(1/Dermal MOE) + (1/Inhalation MOE)] (Risk are combined
via the total MOE approach because although the endpoints are selected
from different studies and conducted with different species, the adverse
effects are similar, and therefore merit combination)

9.2	Short-/Intermediate-Term Postapplication Risk  TC \l2 "9.2
Short-/Intermediate-/Long-Term/Cancer (if needed) Postapplication Risk 

Postapplication workers are assumed to have potential short- and
intermediate-term dermal exposure (but not inhalation exposure) from the
proposed uses of PROLINE® 480 SC Fungicide.  All of the proposed uses
are for low to medium height row crops and because of this shared
feature, the postapplication exposure expected for different crops are
similar when similar postapplication activities are conducted. 
Postapplication activities expected from the proposed uses are scouting,
irrigation, hand weeding and hand harvesting.  No chemical-specific data
relevant to postapplication exposure (i.e., dislodgeable foliar residue
[DFR] data) were submitted, therefore, postapplication exposure
estimates were calculated using standard HED Exposure SAC assumptions
(body weight, exposure duration, fraction of ai retained on foliage and
daily dissipation) and policies (SOP # 003.1).  The quantitative hazard
estimate of 30 mg/kg/day (LOAEL from the dermal developmental study in
the rat) as used in the handler assessment (see previous section) is
used in the postapplication assessment.  

The resulting exposure estimates and risks are presented below in Table
9.2.  For most activities and crops, the REI of 24 hours on the proposed
label is not adequate to protect workers.  To protect workers conducting
all postapplication activities, an REI of 10 days is adequate to protect
workers conducting most postapplication activities.  For some
postapplication activities, such as irrigation which can often be
automated, an REI of 10 days may not pose a problem.  However, for other
postapplication activities, such as harvesting peas and beans (the label
indicates a PHI of 7 days), this poses a problem.  The estimated REIs
were determined using standard values (20% ai initially retained on
foliage, 10% daily dissipation), and these assumptions may be
overestimating postapplication risk.  But these defaults may be
underestimating postapplication risk as well (e.g., in the Western US,
there is generally less rainfall, which can result in slower
dissipation).  However, in the absence of data, further refinement
cannot be executed.  The development of field data would present a more
accurate picture of postapplication risk, and therefore, DFR data are
required.  Recently (December 7, 2006), the Agency received such data
from Bayer (i.e., DFR data, MRID pending).  The data provide information
on both prothioconazole and prothioconazole-desthio dislodgeable foliar
residues from trials with peanut, dry bean, soybean and sugarbeet crops.
 An initial science screen indicates that these data will likely support
an REI much lower than HED’s currently recommended 10-day REI.  The
study appears to be conducted according to guideline requirements and to
be properly validated.    Based on the preliminary screen, HED believes
that an REI of 48 hours will be protective of workers conducting
postapplication activities.  Pending full review and evaluation of the
DFR data, HED has no objection to a conditional registration with a
48-hour REI for agricultural workers.

Again, it should be pointed out that the estimates reported in Table 9.2
(which do not include information from the newly submitted DFR data)
involve uncertainty regarding hazard and exposure: an additional 10X has
been applied to account for lack of a NOAEL in the DNT study regarding
the neurotoxic endpoint of peripheral lesions and brain morphometrics;
and for exposure, prothioconazole exposure estimates rely on default
assumptions for residues (20% of initial application remains on foliage,
and 10% daily dissipation).  In addition, the exposure estimates are
compared to prothioconazole-desthio endpoints (a protective approach,
which may overestimate risk since a prothioconazole quantitative hazard
estimate would likely be about 7X greater than the
prothioconazole-desthio quantitative hazard estimate used).



Table 9.2		Summary of Occupational Postapplication Risks for
Prothioconazole.  The S-T/I-T dermal NOAEL is 30 mg/kg/day.  

Crop 	Appl. Rate

 (lb ai/A)	Fraction of ai Retained on Foliage	Daily Dissipation Rate
Transfer 

Coefficient

(cm2/hr)1	Dislodgeable 

Foliar Residue

(ug/cm2)2	Days After Application (t)	Dermal Daily Dose3

(mg/kg/day)	Short-/Inter-Term Dermal MOE4

Barley, 

Canola

(representative oilseed crops)	0.178	0.2	0.1	Low/min: scouting (100)
0.399	0	0.0053	5,700

High or low/full: scouting (1,500)	0.399	0	0.080	380

	0.359	1	0.072	420

	0.323	2	0.065	460

	0.291	3	0.058	520

	0.155	9	0.031	970

	0.139	10	0.028	1,100

Dried shelled peas and beans subgroup	0.178

	Low/min: irrigation and scouting, Low/full or min: hand weeding (100)
0.399	0	0.0053	5,700

Low/full: irrigation and scouting (1,500)	0.399	0	0.080	380

	0.359	1	0.072	420

	0.323	2	0.065	460

	0.291	3	0.058	520

	0.155	9	0.031	970

	0.139	10	0.028	1,100

Peanuts	0.178

	Hand weeding (100)	0.399	0	0.0053	5,700

Low/full: irrigation and scouting (1500)	0.399	0	0.080	380

	0.359	1	0.072	420

	0.323	2	0.065	460

	0.291	3	0.058	520

	0.155	9	0.031	970

	0.139	10	0.028	1,100

Rice	0.143

	Low/min: scouting (100)	0.321	0	0.0043	7,000

Low/full: scouting (1,500)	0.321	0	0.064	470

	0.153	7	0.031	970

	0.138	8	0.028	1,100

Wheat	0.178

	Low/min: irrigation and scouting (100)	0.399	0	0.0053	5,700

Low/full: irrigation and scouting (1,500)	0.399	0	0.080	380

	0.359	1	0.072	420

	0.323	2	0.065	460

	0.291	3	0.058	520

	0.155	9	0.031	970

	0.139	10	0.028	1,100

1 Transfer coefficients are taken from the HED Science Advisory Council
(SAC) for Exposure SOP 003.1 (August 2000)

2 Dislodgeable Foliar Residue Postapplication day (ug/cm2) = Application
rate (lb ai/A) x Fraction of ai Retained on the Foliage (default
assumption) x (1- Fraction of Residue that Dissipates Daily [also
default assumption]) postapplication day zero x 4.54E+8 ug/lb x 2.47E-8
A/cm2

3 Daily Dose = [Dislodgeable Foliar Residue x 0.001 mg/ug x Dermal
Transfer Coefficient (cm2/hr) x Exposure Time (8 hours)]/Body weight (60
kg)

4 MOE = NOAEL/Daily Dose.   Short-/Intermediate-Term Dermal NOAEL = 30
mg/kg/day.  LOC = 1000.10.0	Data Needs and Label Recommendations  TC
\l1 "10.0	Data Needs and Label Requirements 

10.1	Toxicology  TC \l2 "10.1	Toxicology 			

The developmental neurotoxicity (DNT) study of prothioconazole-desthio
(MRID 46246418) is classified as an acceptable/non-guideline study,
because of inadequate data reporting which prevented the identification
of the developmental NOAEL.  Specifically, an increase in lesions of the
peripheral nerves was noted at the high-dose, but mid- and low-dose
groups were not evaluated.  Changes in brain morphometric measurements
were also seen at the high-dose, but mid- and low-dose groups were not
evaluated.

•	For the Developmental Neurotoxicity Study (MRID 46246418), brain
morphometric measurements from the mid and low dose animals must be
submitted as well as addressing the other deficiencies listed in the DER
to allow the reconsideration of the FQPA database uncertainty factor.

10.2	Residue Chemistry  TC \l2 "10.2	Residue Chemistry 

860.1200 Directions for Use

•	The applicant has proposed use on an “Oilseed Crop Subgroup”
which consists of the members of the Oilseed Crop Group 20 with the
exception of safflower seed and sunflower seed.  The representative
crops of Crop Group 20 are canola and sunflower.  Currently, no crop
subgroups have been defined by HED for Crop Group 20.  The applicant has
submitted crop field trial data for canola but not for sunflower.  In
the absence of crop field trial data for sunflower, the applicant must
modify the use directions to remove reference to the Oilseed Crop
Subgroup and to delete the following commodities from the label:  Indian
mustard (Brassica juncea); black mustard (Brassica nigra); flax (Linum
usitatissimum); and borage (Borago officinalis).

•	The retreatment intervals proposed by the applicant are not in
agreement with the retreatment intervals used in the crop field trials
for several crops, and the applicant did not propose a retreatment
interval for rice.  For barley, rice, wheat, and canola and the oilseed
crops of rapeseed, Indian rapeseed, field mustard seed, and crambe, the
applicant must propose a minimum retreatment interval of 14 days. 

•	Although the label specifies use of a spray adjuvant for all uses
except soil application to peanuts, the only crops for which surfactants
were used in the field trials were those in the dried pea/bean crop
subgroup.  In the absence of data supporting their use, the label must
be modified to remove the recommendation regarding spray adjuvants for
all crops except chickpea, lentils, and the dried shelled peas and beans
subgroup.

•	HED notes that the use directions for barley and wheat specify that
the maximum single application rate is 0.178 lb ai/A (200 g ai/ha) and
that a maximum of two applications may be made.  The maximum seasonal
application rate for barley and wheat is 0.293 lb ai/A (328 g ai/ha)
which is less than two times the maximum single application rate.  For
wheat and barley, the applicant may wish to note on the product label
that the maximum seasonal rate would be exceeded if two applications
were made at the maximum single application rate.

860.1340 Residue Analytical Methods

•	The proposed data collection and enforcement methods for livestock
commodities must be validated for poultry commodities.

860.1380 Storage Stability

•	The final report of the ongoing storage stability study with
prothioconazole and desthio-prothioconazole in plant commodities
(interim results for which were reported in MRID 46477701) must be
submitted.

•	To support the reported results for 1,2,4-triazole and the triazole
conjugates, the final report of the ongoing storage stability study with
triazole and triazole conjugates in plant commodities (interim results
of which were reported in MRID 46246211) must be submitted.  

860.1480 Meat, Milk, Poultry, and Eggs

•	The applicant must submit a poultry feeding study with
prothioconazole.

•	Data must be generated and submitted to confirm the degree of
stability of the prothioconazole-4-hydroxy in ruminant fat for a
duration of 45 days.

860.1500 Crop Field Trials

•	The applicant has proposed use on an “Oilseed Crop Subgroup”
which consists of the members of the Oilseed Crop Group 20 with the
exception of safflower seed and sunflower seed.  The representative
crops of Crop Group 20 are canola and sunflower.  Currently, no crop
subgroups have been defined by HED for Crop Group 20.  The applicant has
submitted crop field trial data for canola but not for sunflower.  In
order to support the proposed tolerances for Indian mustard (Brassica
juncea); black mustard (Brassica nigra); flax (Linum usitatissimum); and
borage (Borago officinalis) additional crop field trial data must be
submitted.

860.1650 Submittal of Analytical Reference Standards

•	Based on the proposed tolerance expressions and the proposed
enforcement methods, analytical reference standards of the following
compounds must be supplied and supplies replenished as requested by the
Repository:  

•	prothioconazole-desthio [JAU6476-desthio;
α-(1-chlorocyclopropyl)-α-[(2-chlorophenyl)methyl]-1H-1,2,4-triazole-1
-ethanol]

•	prothioconazole sulfonic acid potassium salt [potassium salt of
JAU6476 sulfonic acid;
1-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1H-1,2,4-
triazole sulfonic acid, potassium salt]

•	[triazole-15N-13C]prothioconazole

•	[triazole-15N-13C]prothioconazole-desthio

•	[triazole-15N-13C]prothioconazole sulfonic acid

860.1650 Proposed Tolerances

 and prothioconazole-desthio
[α-(1-chlorocyclopropyl)-α-[(2-chlorophenyl)methyl]-1H-1,2,4-triazole-
1-ethanol], calculated as parent”.

•	The proposed tolerance expression for livestock commodities should
be revised to be expressed in terms of the “combined residues of the
fungicide prothioconazole
[2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2-dihy
dro-3H-1,2,4-triazole-3-thione] and prothioconazole-desthio
[α-(1-chlorocyclopropyl)-α-[(2-chlorophenyl)methyl]-1H-1,2,4-triazole-
1-ethanol] and conjugates convertible to these two compounds by acid
hydrolysis, calculated as parent.”

•	The proposed tolerances should be revised to reflect the correct
commodity definitions as specified in Table 5.1.10.6.  In addition,
revisions to the proposed tolerance levels for certain commodities and
deletion of certain tolerances are required, as specified in Table
5.1.10.6. 

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

875.2100 Foliar Dislodgeable Residue Dissipation 

•	Dislodgeable foliar residue data to inform and refine
postapplication exposure and risk estimates (Note: Received December 7,
2006)

•	Raw data from field fortifications in MRID 46246447 (in addition to
the % conversions reported in the study)

Label Recommendations

•	State on the label that sunflower and safflower are excluded from
the oilseed crop group

•	State on the label that soybeans are excluded from the dried peas
and beans subgroup

•	Change the REI to 48 hours

10.4	Triazole Data Requirements  TC \l2 "10.4	Triazole Data Requirements

As specified in HED’s February 7, 2006 risk assessment (M. Doherty et
al, DP# 322215) for 1,2,4-triazole and its metabolites triazole alanine
and triazole acetic acid, HED recommended that resolution of various
issues be a condition of registration for new uses of
triazole-derivative fungicides and for new active ingredients which
contain the 1,2,4-triazole ring.  The requirement for a chronic
toxicity/oncogenicity study in male rats and female mice in the 2/7/2006
memo was later modified by HED to a 1-year chronic study in male and
female rats (Kit Farwell, DP# 321328, 5/10/2006).  Therefore, HED
recommends that the registration of the proposed new uses of
prothioconazole be conditioned upon resolution of the following issues:

Chemistry:

Final two-year storage stability study with 1,2,4-triazole;

Resolution of concerns regarding the prevalence of conjugated residues
of TA and the ability of the analytical method to quantify them.

Toxicology:

Free triazole:

Developmental neurotoxicity study in rats;

Chronic toxicity – 1 year chronic rat study in males and females 

Acute neurotoxicity study in rats [This study, included in the original
data requirements, was placed in reserve pending the results of the
combined subchronic/neurotoxicity study, in response to a previous
waiver request.  A new waiver request for this study was submitted in
August 2005, and is under review.];

Triazole alanine:

Developmental toxicity study in rabbits;

Chronic toxicity study in rats, conducted according to current
guidelines that include neurobehavioral assessments, with additional
neuropathology evaluations conducted according to the neurotoxicity
guidelines;

Triazole acetic acid:

Developmental toxicity study in rabbits;

Combined 90-day feeding/neurotoxicity study in rats.



References:  TC \l1 "References: 

1. Prothioconazole.  Petition for Establishment of Tolerances for Use on
Barley, Oilseed (Except Sunflower and Safflower) Crop Group, Dried
Shelled Pea and Bean (Except Soybean) Crop Subgroup, Peanut, Rice, and
Wheat.  Summary of Analytical Chemistry and Residue Data.  PP#4F6830. DP
Barcode 303508; S. Funk, 8/21/06.

2. Prothioconazole: Occupational Exposure and Risk Assessment for
Proposed Uses on Barley, Oilseed (except Sunflower and Safflower) Crop
Group, Dried Shelled Pea and Bean (except Soybean) Subgroup, Peanut,
Rice and Wheat. PC Code: 113961, DP Barcode: D303579, 8/18/06

3. Prothioconazole: Acute Probabilistic and Chronic Aggregate Dietary
and Drinking Water Exposure and Risk Assessments for the Section 3
Registration Action. PP #4F6830. DP Barcode 331636, T. Goodlow,
08/03/06.

4. Prothioconazole Tier II Estimated Drinking Water Concentrations
(EDWCs) for Use in the Human Health Risk Assessment (DP Barcode 324569,
R. Kashuba, 4/26/06)

5. Prothioconazole Tier II Estimated Drinking Water Concentrations
(EDWCs) for Use in the Human Health Risk Assessment [Second Revision]
(DP Barcode 330265, R. Kashuba, 6/21/06).  

6. PP#4F6830.  New Chemical – Prothioconazole in/on Plant and
Livestock Commodities.  Tolerance Method Validation Report. (MRID #’s
462462-04, 462462-06, 462462-07, and 462462-09) Chemical # 113961. 
Decision Number:  318440.  ACB # B05-39.

DP Barcode 318440. P. Schermerhorn. 08/04/06.

7. Prothioconazole Section 3: Environmental Fate and Ecological Risk
Assessment, DP Barcode: 324660, Decision #: 341716, C. Salice and R.
Kashuba, 06/01/06. 



INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name: 
[2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2-dihy
dro-3H-1,2,4-triazole-3-thione	Common Name:  Prothioconazole 	X Proposed
tolerance

 Reevaluated tolerance

 Other	Date:  03/09/05

Codex Status (Maximum Residue Limits)	U. S. Tolerances

X No Codex proposal step 6 or above

 No Codex proposal step 6 or above for the crops requested	Petition
Number:  PP#4F6830

DP Barcode:  D303508 and D314517

 No Limits

 No Limits for the crops requested

Limits to be established under this Joint Review project.	X No Limits

 No Limits for the crops requested

Residue definition:  N/A

	Residue definition:  N/A

Crop(s)	MRL (mg/kg)	Crop(s)	MRL (mg/kg)

	Notes/Special Instructions: S.Funk, 03/17/05

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 food use for prothioconazole and
its metabolites/degradates are presented in Table A.1.  Use of the new
guideline numbers does not imply that the new (1998) guideline protocols
were used.

Table A.1.  Toxicology Data Requirements (40 CFR 158.340) for the Food
Use of Prothioconazole (JAU6476) and its Metabolites/Degradates.

Guideline No.		Study Type 

	

Technical	

	

Required	

Submitted	

MRID No.

870.1100	Acute Oral Toxicity - Rat	

870.1100	Acute Oral Toxicity - Mouse	

870.1200	Acute Dermal Toxicity - Rat	

870.1300	Acute Inhalation Toxicity - Rat	

870.2400	Primary Eye Irritation - Rabbit	

870.2500	Primary Skin Irritation - Rabbit	

870.2600	Dermal Sensitization – Guinea Pig	

	

Y

N

Y

Y

Y

Y

Y	

Y

Y

Y

Y

Y

Y	

46246230a

46246231d

46246242 d

46246244 a

46246243 d

46246246 a

46246247 d

46246249 a

46246250 d

46246302 a

46246250 d

46246305 a

46246304 d

870.3100	Subchronic (Oral) Toxicity - Rat	

870.3100	Subchronic (Oral) Toxicity - Mouse	

870.3150	Subchronic (Oral) Toxicity - Dog	

870.3200	21/28-Day Dermal Toxicity - Rat	

870.3465	90-Day Inhalation Toxicity		

Y§

N

Y

Y

N

	

Y

Y

Y

	

46246309d

46246312b

46246310d 46246311a

46246313a

46246314d

46246315a

46246432 d 46246433 d

870.3700a	Prenatal Developmental (Oral) Toxicity -Rat	

870.3700a	Prenatal Developmental (Dermal) Tox -Rat	

	

870.3700b	Prenatal Developmental (Oral) Tox - Rabbit	

870.3800	Reproduction and Fertility Effects		

Y¶

N

Y

Y	

Y

Y

Y	

46246316a

46246321d

46246324b

46246323a

46246325d

46246328a

46246327d

46246334a 46246333d

870.4100a	Chronic (Oral) Toxicity - Rat	

870.4100b	Chronic (Oral) Toxicity - Dog	

870.4200a	Carcinogenicity - Rat	

870.4200b	Carcinogenicity - Mouse	

870.4300	Combined Chronic Toxicity /Carcinogenicity (mouse)		

Y

Y

Y

Y

Y	

Y

Y

Y

Y

Y	

46246335a

46246336a

46246337d

46246338a

46246339a

46246340d

46246341d

46246342d

870.5100	Bacterial reverse mutation test	

870.5300	In vitro mammalian cell gene mutation test	

870.5375	In vitro mammalian chromosome aberration test	

870.5395	Mammalian erythrocyte micronucleus test	

870.5550	Unscheduled DNA synthesis in mammalian cells	

	

Y

Y

Y

Y

Y

	

Y

Y

Y

Y

Y

	

46246343 a

46246344 d

46246345c

46246402b

46246404 a

46246405 d

46246406 a

46246407 d

46246408c

46246409 a

46246410 d

46246411 a

46246412 a

46246413 a

46246414 d

870.6200a	Neurotoxicity Screening Battery - Acute - Rat	

870.6200b	Neurotoxicity Screening Battery -Subchronic - Rat	

870.6300	Developmental Neurotoxicity – Rat……….

	

N

N

Y	

Y	

46246416a

46246417a

46246418d

870.7485	Metabolism – Rat	

870.7485	Dermal Penetration – Rat	

	

Y

N	

Y

	

46246421 a

46246419 a

46246420 d

46246422 d

46246423 a

46246424 d

46246425 d

46246426 a

870.7800		Immunotoxicity - Mouse	

	

N	

	

46246438 a

§	Required in rodent and non-rodent; Required in rat and rabbit

a	JAU 6476; b	JAU 6476 Sulfonic Acid K Salt; c	JAU 6476 des chloro; d
SXX 0665

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

Table A.2.1	Acute Toxicity of Prothioconazole technical and Desthio-

Prothioconazole technical

Guideline	Study	Species	Results	Tox. Category	MRID No.

Prothioconazole

870.1100	Acute oral toxicity	Rat	LD50 >= 6200 mg/kg  (M, F)	IV	46246230

870.1200	Acute dermal toxicity	Rat	LD50 >= 2000 mg/kg (M, F)	III
46246244

870.1300	Acute inhalation toxicity	Rat	LC50 >= 4.99 mg/L 

(M, F)	IV	46246246

870.2400	Primary eye irritation	Rabbit	Not an irritant	IV	46246249

870.2500	Primary skin irritation	Rabbit	Not an irritant	IV	46246302

870.2600	Dermal sensitization 	Guinea Pig	Not a sensitizer	Negative
46246305

Desthio-prothioconazole

870.1100	Acute oral toxicity	Rat	LD50  = 2806 mg/kg (M, F) (approximate)
III	46246231

870.1100	Acute oral toxicity	Mouse	LD50  = 2235 mg/kg

(Males)  

LD50  = 3459 mg/kg 

(Females)	III	46246242

870.1200	Acute dermal toxicity	Rat	LD50 >= 5000 mg/kg (M,F)

	IV	46246243

870.1300	Acute inhalation toxicity	Rat	LC50 >= 5.077 mg/L

(M,F)	IV	46246247

870.2400	Primary eye irritation	Rabbit	Slight irritant (iritis,
discharge)	III	46246250

870.2500	Primary skin irritation	Rabbit	Not an irritant	IV	46246250

870.2600	Dermal sensitization	Guinea Pig	Not a sensitizer	Negative
46246304



Table A.2.2: Toxicity Profile for Prothioconazole (JAU6476) Technical

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

870.3100

90-day oral toxicity rodents (rat)

	46246311 (1999)

0, 20, 100, 500 mg/kg/day 

Acceptable/Guideline	NOAEL = 100 mg/kg/day

LOAEL = 500 mg/kg/day based on increased water consumption (males and
females), increased cholesterol (males and females), liver effects
[increased liver weights (females), hepatocellular hypertrophy (males
and females) and cytoplasmic change (males and females)] and kidney
effects [decreased urinary volume (males and females), increased urine
protein levels (males and females), and the increased incidence and
severity of basophilic tubules of the renal cortex (males)].

870.3100

90-Day oral toxicity rodents (mouse)	46246427 (1999)

0, 25, 100, 400 mg/kg/day

Acceptable/Guideline	NOAEL =  25 mg/kg/day

LOAEL = 100 mg/kg/day based on increased cholesterol levels and
increased liver enzyme activity in females, increased liver weights in
both sexes, and increased incidence of hepatocellular hypertrophy and
cytoplasmic change in the liver of both sexes.

870.3100

28-Day oral toxicity rodents (rat)	46246429 (1998)

0, 10000 ppm in both neat or stabilized diet

0, 1000 mg/kg/day by gavage

Acceptable/Nonguideline

	No NOAEL or LOAEL were determined as this was a nonguideline study to
compare routes of administration

Observations included clinical signs of toxicity, changes in BW, BWG,
FC; liver and kidney effects (wt, histopathology), clinical chemistry
changes 

870.3100

28-Day oral toxicity rodents (rat)	46246428 (1997)

0, 400, 2000, 10000 ppm

0, 18.6/18.8, 145.7/151.0, or 951.7/1032.5 (M/F) mg/kg/day

Acceptable/Nonguideline 	No NOAEL or LOAEL were determined

Observations included changes in body wt, food consumption, liver and
kidney effects, clinical chemistry

870.3150

90-day oral toxicity nonrodents (dog)	46246435 (2000)

0, 25, 100, 300 mg/kg/day

Acceptable/Nonguideline	No NOAEL or LOAEL were determined in this study,
the specific observations included effects on liver and kidney enzyme
activities and tissues concentrations of parent and metabolites were
determined.  This study included a 4 week recovery phase.

870.3150

90-day oral toxicity nonrodents (dog)	46426313 (2001)

0, 25, 100, 300 mg/kg/day

Acceptable/Guideline	NOAEL = 25 mg/kg/day

LOAEL = 100 mg/kg/day based on kidney (histopathological) and thyroid
(T4 and TSH) findings at 100 mg/kg.  This study included a 4 week
recovery phase.

870.3200

21/28-Day dermal toxicity (rat)	46426315 (2000)

0, 100, 300, 1000 mg/kg

Acceptable/Guideline	NOAEL = 1000 mg/kg/day

LOAEL > 1000 mg/kg/day

870.3700a

Prenatal develop-mental in rats – oral	46246316 (1996)

0, 80, 500, 1000 mg/kg/day

Acceptable/Guideline	Maternal Toxicity

NOAEL = 80 mg/kg/day

LOAEL = 500 mg/kg/day based on increased urination and water
consumption, and decreased body weight gain.

Developmental Toxicity

NOAEL = 80 mg/kg/day

LOAEL = 500  mg/kg/day based on increased incidence of delayed
ossification, increased incidence of dysplastic pubic bone, and
increased incidence of left punctiform 14th rib.

870.3700a

Prenatal develop-mental in rats – oral	46246317 (2002)

0, 40, 200, 1000 mg/kg/day

Acceptable/Nonguideline	Range finding study for above, no endpoints were
determined.

870.3700a

Prenatal develop-mental in rodents 

(rat) - dermal	46246323 (2001)       

0, Technical 1000 mg/kg/day, 62.5 mg/kg/day diluted EC 250 formulation,
250 mg/kg/day EC 250 formulation

Acceptable/Nonguideline	Maternal Toxicity

NOAEL > 1000 mg/kg/day

LOAEL > 1000 mg/kg/day 

Developmental Toxicity

NOAEL = 1000 mg/kg/day

LOAEL > 1000 mg/kg/day

870.3700a

Prenatal develop-mental in rats – oral	46923601 (2004)

0, 20, 80, 750 mg/kg/day

Acceptable/Nonguideline	Maternal Toxicity

NOAEL = 80 mg/kg/day

LOAEL = 750 mg/kg/day based on increased water consumption, decreased
food consumption and decreased body weight gain.

Developmental Toxicity

NOAEL = 80 mg/kg/day

LOAEL = 750 mg/kg/day based on increased incidence of rudimentary ribs
(comma-shaped).

870.3700b

Prenatal develop-mental in nonrodents

(rabbit)	46246330 (1997)

0, 80, 100, 300, 480 mg/kg/day

pilot study

Acceptable/Nonguideline	Maternal Toxicity

NOAEL < 80 mg/kg/day

LOAEL = 80 mg/kg/day based on reduced food consumption and body wts.

Developmental NOAEL = 300 mg/kg/day

LOAEL = 480 mg/kg/day based on decreased body wt, and small fetuses.

870.3700b

Prenatal develop-mental in nonrodents

(rabbit)	46246328 (1998)

0, 10, 30, 80, 350* mg/kg/day

* Additional group added after start of study

Acceptable/Guideline	Maternal Toxicity

NOAEL = 80 mg/kg/day

LOAEL = 350 mg/kg/day based on decreased body wt and decreased food
consumption.

Developmental Toxicity

NOAEL = 80 mg/kg/day

LOAEL = 350 mg/kg/day based on abortions, total resorptions, and lower
fetal body weight

870.3800

Reproduction and fertility effects	46246331 (1999)

0, 10, 100, 250, 500 mg/kg/day 

(pilot)

Acceptable/Nonguideline	Parental Toxicity

NOAEL = 250 mg/kg/day

LOAEL = 500 mg/kg/day based on clinical signs (urine stain)

Reproductive Toxicity

NOAEL = 500 mg/kg/day

LOAEL > 500 mg/kg/day

Offspring Toxicity

NOAEL = 500 mg/kg/day

LOAEL > 500 mg/kg/day

870.3800

Reproduction and fertility effects	46246334 (2001)

0, 10, 100, 750 mg/kg/day

Combined with MRID 46246331

Acceptable/Guideline	Parental Toxicity

 NOAEL = 100 mg/kg/day

 LOAEL = 750 mg/kg/day based on decreased body weights, body weight
gains and increased food consumption, increased liver weights and kidney
weights, decreased thymus, testicular, prostate, epicauda and epididymis
weights as well as histopathological findings in the liver and kidney.

Reproductive Toxicity

NOAEL = 100 mg/kg/day

LOAEL = 750 mg/kg/day based on decreased number of estrous cycles in
both generations and  increased duration of estrous cycle in the P
generation.

Offspring Toxicity

NOAEL = 100 mg/kg/day

LOAEL = 750 mg/kg/day based on decreased pup body weight and spleen wt.

870.4100a

Chronic toxicity rodents (rat)	46246335 (2000)

0, 5, 50, 750 mg/kg/day

Rat,  53 weeks

Acceptable/Guideline	NOAEL = 50 mg/kg/day

LOAEL = 750 mg/kg/day based on decreased body weight and body weight
gain, alterations in hematology and clinical chemistry parameters
indicative of liver and kidney damage, increased liver and kidney
weights, and accompanying histopathological alterations in the liver,
kidney and urinary bladder.  FOB conducted at 27 and 52 weeks.

870.4100b

Chronic toxicity

non-rodent (dog)	46246336 (2001)

0, 5, 40, 125 mg/kg/day

one year

Acceptable/Guideline	NOAEL = 5 mg/kg/day

LOAEL = 40 mg/kg/day based on decreased T3 and T4 thyroid hormones,
increased urine volume, and increased incidence of chronic inflammation
and pigmentation in the kidneys of the male animals, and decreased T4
thyroid hormone, increased spleen weight, increased incidence of spleen
pigmentation, and increased incidence of crystals present in the kidneys
of the female animals.

870.4200

Carcinogenicity rats	46246338 (2001)

M: 0, 5, 50, 750/500 mg/kg/day

F: 0,5,50,750/625 mg/kg/day

106 weeks

Unacceptable/Guideline

for Carcinogenicity because dose levels too high.	NOAEL = 50 mg/kg/day

LOAEL = 500/625 (M/F) mg/kg/day based on  increased mortality and
decreased body weight/body weight gain, changes in clinical chemistry
(APh, creatinine, urea) and hematological parameters, increased liver
and kidney weights, and liver (hypertrophy and eosinophilic/clear cell
focus) and kidney/urinary bladder pathology.

870.4300

Carcinogenicity mice	46246339 (2001)

0, 10, 70, 500 mg/kg/day

80 weeks

Acceptable/Guideline	NOAEL = 10 mg/kg/day

LOAEL = 70 mg/kg/day based on kidney (tubular degeneration/regeneration
in males) effects.

no evidence of carcinogenicity

870.6200a

Acute neurotoxicity screening battery	46246417 (2000)

0, 200, 750, 2000 mg/kg/day

Acceptable/Guideline	NOAEL = 200/750 (M/F) mg/kg/day 

LOAEL = 750/2000 (M/F) based on the transient effect of reduced motor
and locomotor activity.

870.6200b

Subchronic neurotoxicity screening battery	46246416 (2001)

0, 100, 500, 1000 mg/kg/day

Acceptable/Guideline	Systemic Toxicity

NOAEL = 500 mg/kg/day

LOAEL = 1000 mg/kg/day based on decreased body weight & body weight gain
in males.

No neurotoxicity was noted at dose levels tested.

870.7600

Dermal Absorption	46246426 (1997)

Rat   N= 10

Pilot Study	Absorption rate

49.41%

870.7600

Dermal Absorption	46246423 (2003)

Monkey   N = 1

Pilot Study	Absorption rate

4.06%

  SEQ CHAPTER \h \r 1 870.7485

Metabolism	46246421 (2001)

Aceptable/Guideline	  SEQ CHAPTER \h \r 1 JAU6476 was extensively
metabolised in the rat following oral administration. Eighteen
metabolites and the parent compound were identified in urine, faeces and
bile. The biotransformation of JAU6476 consisted of 3 major reaction
types including desulfuration, oxidative hydroxylation of the phenyl
moiety and glucuronic acid conjugation. Identification of the
metabolites ranged from 26-63% of the administered dose. A higher
percentage of metabolite isolation and identification could not be
achieved due to difficulties in fecal extraction where 21-33% of the
administered dose remained in non-extractable residues in the solids.
The parent compound JAU6476 was the most abundant in the faeces (1-22%
of the administered dose), followed by the JAU6476-desthio metabolite
(3-18% of the administered dose). All other fecal metabolites
represented less than 8% of the administered dose. The 1, 2, 4-triazole
metabolite was not detected in the faeces. The major urinary metabolite
was JAU6476-S- or O-glucuronide (0.1-8% of the administered dose) and
was preferentially excreted in females. The 1, 2, 4-triazole metabolite
represented 0.8-2.3% of the administered dose following administration
of single oral low and/or high doses. The remaining urinary metabolites
each accounted for 0-1.4% of the administered dose. JAU6476-S- or
O-glucuronide was the most abundant metabolite in the bile, representing
approximately 46% of the administered dose. This metabolite was excreted
in females only in the urine; however it was noted in the bile in males.
 Desthio glucuronic acid metabolites in the bile represented 8-10% of
the administered dose. Parent compound represented 3-5% of the
administered dose in the bile. The 1, 2, 4-triazole metabolite was not
detected in the bile. 

  SEQ CHAPTER \h \r 1 870.7485

Metabolism	46246419 (2001)

Acceptable/Nonguideline	  SEQ CHAPTER \h \r 1 The whole body
autoradiography results are in agreement with the absorption,
distribution and excretion pattern of JAU6476 in the main metabolism
study (MRID 46246421). In summary, peak concentrations in males were
noted 1 hour post-administration and continued to decline until
sacrifice at 168 hours. In females, absorption was slightly delayed with
peak concentrations in some tissues noted at 8 hours
post-administration. The highest concentrations were noted in liver (up
to 1.78 μg/g in males and up to 0.97 μg/g in females), followed by
kidney (renal medulla, up to 0.64 μg/g), brown/perirenal fat (up to
0.36 μg/g), thyroid (up to 0.23 μg/g) and adrenal gland (up to 0.27
μg/g). All other tissues showed peak concentrations of <0.13 μg/g.
Concentrations of radioactivity decreased rapidly from 24 to 168 hours
post-administration, indicative of continued elimination from the
tissues.

  SEQ CHAPTER \h \r 1 870.7800 Immunotoxicity	46246438 (2002)

Acceptable/Nonguideline	  SEQ CHAPTER \h \r 1 Piloerection was noted in
the high-dose males from days 13-21.There were no significant effects on
body weight, food consumption or spleen weights.  Under the conditions
of this study, JAU 6476 did not suppress the humoral immune response in
a dose-dependent manner in that it did not significantly decrease the
IgM antibody-forming cell response to the T-dependent antigen (sheep
erythrocytes).   An increase in plaque-forming cells was noted in the
high-dose males (↑125%).

870.5100

Bacterial reverse mutation test	46246343 (1996)

Acceptable/Guideline	JAU 6476 is considered negative for reverse
mutation in this battery of S. typhimurium strains up to cytotoxic
concentrations.

870.5300

In vitro mammalian cell gene mutation test	46246404 (1996)

Acceptable/Guideline	JAU 6476 is considered non-mutagenic in the
V79-HGPRT forward mutation assay.

870.5375

In vitro mammalian chromosome aberration test	46246406 (1996)

Acceptable/Guideline	JAU 6476 may be considered clastogenic (i.e.,
induces increases in structural aberrations), but this mutagenic
activation may result from secondary cytotoxicity rather than direct
structural DNA damage.

870.5395

Mammalian erythrocyte micronucleus test	46246409 (1996)

Acceptable/Guideline	The one i.p. dose of 250 mg/kg JAU 6476
(prothioconazole) is considered to be non-clastogenetic in vivo.

870.5395

Mammalian erythrocyte micronucleus test	46246411 (2003)

Acceptable/Guideline	JAU 6476 (prothioconazole) is not clastogenic or
aneugenic in male mice treated up to overtly toxic and cytotoxic doses.

870.5550

Unscheduled DNA synthesis in mammalian cells	46246412 (1998) 

Acceptable/Guideline	JAU 6476 is evaluated as equivocal in this assay.  

However, these results were clarified based on the negative findings in
the in vivo UDS assay in rat hepatocytes from adult male rats exposed up
to the 5000 mg/kg with the same Batch No. of the test materials. (MRID
46246413).

870.5550

Unscheduled DNA synthesis in mammalian cells	46246413 (1999) 

Acceptable/Guideline	JAU 6476 (prothioconazole) is negative for
UDS-induction in hepatocytes drawn from male rats administered single
oral doses of 2500 and 5000 mg/kg.

Special Study

Inhibition of enzymes in liver microsomes	46246415 (1999)

Unacceptable/

Nonguideline	Inhibition was found in microsomes of both rats and mice. 
The IC50 (Inhibitory Concentration) attained for its ECOD metabolism was
5 uM JAU 6476 in rat preparations, and 9 uM in mouse microsomes.  The
inhibition of testosterone hydroxylation in rat microsomes by JAU 6476
was much weaker, since both hydroxylation and oxidation reactions
correlated with different cytochrome P450 subtypes  had to occur,
namely, 16alpha, 2alpha  6beta, and 7alpha  hydroxylation; plus
oxidation to androstendione.  The inclusive IC50 of most of these P450
subtypes was approximately 75 to 100 uM; for 7alpha hydroxylation (=
subtype 2 A1), the IC50 was about 1000 uM.

No conclusions can be reached from this study because of the numerous
study deficiencies

Special Study

  SEQ CHAPTER \h \r 1 Interaction with Thyroid Peroxidase in vitro
46246436 (1996)

Acceptable/Nonguideline	  SEQ CHAPTER \h \r 1 Thyroid peroxidase
(TPO)-catalyzed guaiacol oxidation was inhibited by compounds tested.
3-mercapto-1,2,4-triazole had the lowest IC50 value (i.e.: lowest
concentration required to inhibit the reaction by 50%), followed by PTU
then JAU 6476 and JAU 6953.  This provided initial indication that TPO
may be irreversibly inhibited. 

PTU, ETU, JAU 6476, JAU 6953 and 3-mercapto-1,2,4-triazole
dose-dependently suppressed TPO-catalyzed iodine formation temporarily. 
Following suppression, iodine reappeared.  The rate was then similar to
controls.  3-mercapto-1,2,4-triazole suppressed the rate of the
reappearing iodine formation longer than the other compounds.  

This study showed inhibition of guaiacol and iodine oxidation with the
compounds tested.

	



Table A.2.3: Toxicity Profile for Prothioconazole-Desthio (SXX0665)
Technical

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

870.3100

4-Week oral toxicity rodents

(rat)	46246430 (1992)

0, 100, 300, 1000 ppm

0, 11, 34/38, 117/ 121 (M/F) mg/kg/day

Acceptable/Guideline	NOAEL = 11 mg/kg/day for males; < 11 mg/kg/day for
females

LOAEL = 34 mg/kg/day for males and ( 11 mg/kg/day for females based
increased liver triglycerides and absolute and relative liver weights in
males and on decreased relative and absolute ovary weight with
histopathology

870.3100

90-Day oral toxicity rodents

(rat)	46246309 (1999)

0, 30, 125, 500, 2000 ppm

2.2/3.0, 9.6/12.5, 36.9/50.7, 161.9/210.8 mg/kg/d M/F

Acceptable/Guideline	NOAEL = 2.2/3.0 (M/F) mg/kg/day

LOAEL = 9.6/12.5 mg/kg/day based on histological changes in the liver of
males and increased P450 in females.

870.3100

90-Day oral toxicity rodents

(mouse)	46246310 (1999)

0, 40, 200, 1000, 5000 ppm

0, 11.5/16.0, 58.9/79.5, 294.0/392.3, 1454/2073 (M/F) mg/kg/day

Acceptable/Nonguideline	NOAEL < 11.5/16.0 (M/F) mg/kg/day

LOAEL = 11.5.16.0 (M/F) mg/kg/day based on decreased body weight gain in
both sexes.

870.3150

39-Day oral toxicity in nonrodents (dog)	46246431 (1999)

0, 10, 100/5000,  1000 ppm

0, 0.3, 3/150, 30 (M/F) mg/kg/day

Acceptable/Nonguideline	Range finding study, no NOAEL or LOAEL were
established, observations included dramatic reductions in
uterine/oviduct absolute and relative organ weights at 10 ppm. 

870.3150

90-Day oral toxicity in nonrodents (dog)	46246314 (2000)

0, 40, 200, 1000 ppm

 0, 1.58/1.62, 7.81/8.53, 37.79/42.75 (M/F/) mg/kg/day 

Unacceptable/Guideline	NOAEL = 37.79/42.75 (M/F) mg/kg/day

LOAEL > 37.79/42.75 (M/F) mg/kg/day

870.3465

90-Day inhalation toxicity

(rat)	46246432 (1991) - Pilot

46246433 (1992)

0, 11.3, 46.8, 228.4 mg/m3/day 

Unacceptable/Guideline	NOAEL = 228.4 mg/m3/day

LOAEL > 228.4 mg/m3/day

870.3700a

Prenatal develop-mental in rodents (rat) - dermal	46246326 (1991)

0, 30 mg/kg/day

Pilot study, used with 46246325

Acceptable/Nonguideline	Discussed in appendix 1 of MRID 46246325

Maternal Toxicity

NOAEL = 30 mg/kg/day

LOAEL > 30 mg/kg/day

Developmental Toxicity

NOAEL = 30 mg/kg/day

LOAEL > 30 mg/kg/day

870.3700a

Prenatal develop-mental in rodents (rat) - dermal	46246325 (1991)

0, 100, 300, 1000 mg/kg/day

Acceptable/Guideline

When combined with 46246326                	Maternal Toxicity

NOAEL = 1000 mg/kg/day

LOAEL > 1000 mg/kg/day

Developmental Toxicity

NOAEL = 30 mg/kg/day

LOAEL = 100 mg/kg/day based on structural alterations (14th rib)

870.3700a

Prenatal develop-mental in rodents (rat) - oral	46246322 (1991)

0, 1, 3 mg/kg/day

Acceptable/Nonguideline

results combined

with 46246321	Maternal Toxicity

NOAEL = 3 mg/kg/day

LOAEL > 3 mg/kg/day

Developmental Toxicity

NOAEL = 3 mg/kg/day

LOAEL > 3 mg/kg/day

Combined with 46246321

870.3700a

Prenatal develop-mental in rodents (rat) - oral	46246321 (1991)

0, 10, 30, 100 mg/kg/day

Acceptable/Guideline

results combined with 46246322	Maternal Toxicity

NOAEL = 30 mg/kg/day

LOAEL = 100 mg/kg/day based on decreased body weight gains, increased
liver weight with histopathology

Developmental Toxicity

NOAEL < 10 mg/kg/day

LOAEL < 10 mg/kg/day based on structural alterations (supernumery ribs)
and incomplete/delayed ossification at all levels.

Combined with 46346322

870.3700a

Prenatal develop-mental in rodents (rat) - oral	46246320 (1990)

0, 100 mg/kg/day

Acceptable/Nonguideline

	Maternal Toxicity

NOAEL = 100 mg/kg/day

LOAEL > 100 mg/kg/day

Developmental Toxicity

NOAEL <100 mg/kg/day

LOAEL = 100 mg/kg/day based on developmental delays

870.3700a

Prenatal develop-mental in rodents (rat) - oral	46246319 (1992)

0, 30 mg/kg/day oral

Acceptable/Nonguideline

	Maternal Toxicity

No NOAEL or LOAEL were determined

Developmental Toxicity

No NOAEL or LOAEL were determined, observations included structural
abnormalities, developmental delays, death, shows 14th rib not
completely reversible after birth.

Follow up of MRID 46246320, 46246321.

870.3700b

Prenatal 

developmental in nonrodents

(rabbit) - oral

	46246327, (1991)

0, 2, 10, 50 mg/kg/day 

Acceptable/Guideline

	Maternal Toxicity

NOAEL = 10 mg/kg/day

LOAEL = 50 mg/kg/day based on decreased body wt gain, decrease food
consumption, increased resorptions, decreased number of fetuses, liver
histopathology.

Developmental Toxicity

NOAEL = 2 mg/kg/day

LOAEL = 10 mg/kg/day based on structural alterations including malformed
vertebral body and ribs, arthrogryposis, and other multiple
malformations.

870.3700b

Prenatal 

developmental in nonrodents

(rabbit) - dermal

	46246329 (1991)

0, 100, 300, 1000 mg/kg/day dermal

pilot study

Acceptable/Nonguideline	Maternal Toxicity

NOAEL = 300 mg/kg/day

LOAEL = 1000 mg/kg/day based on local dermal toxicity

Developmental Toxicity

NOAEL = 1000 mg/kg/day

LOAEL > 1000 mg/kg/day

870.3800

Reproduction and fertility effects	46246332 (1992)

0, 0.52, 2.49, 53.0, 79.6 mg/kg/day (pilot)

Acceptable/Nonguideline

	Parental Toxicity

NOAEL = 0.52 mg/kg/day

LOAEL = 2.49 mg/kg/day based on incr. liver wt., liver discoloration

Reproductive Toxicity 

NOAEL = 2.49 mg/kg/day

LOAEL = 53.0 mg/kg/day based on decreased litter size, birth index, live
birth index and viability index

Offspring Toxicity

NOAEL = 2.49 mg/kg/day

LOAEL = 53.0 mg/kg/day based on increased liver discoloration (increased
cleft palate at 79.6)

870.3800

Reproduction and fertility effects	46246333 (2001)

0, 40, 160, 640 ppm

0, 2.7/3.0, 10.4/12.0, 42.6/49.5 (M/F) mg/kg/day - premating

0, 2.5, 10.0, 41.2

mg/kg/day - gestation

0, 4.8, 18.6, 72.6 mg/kg/day -  lactation

Acceptable/Guideline	Parental Toxicity

NOAEL = 10.4/12.0 (M/F) mg/kg/day

LOAEL = 42.6/49.5 (M/F) mg/kg/day based on increased liver wt, liver
histopathology, decreased food consumption during lactation (females
only).

Reproductive Toxicity

NOAEL = 10.4/12.0 (M/F) mg/kg/day

LOAEL = 42.6/49.5 (M/F) mg/kg/day based on increased incidence of
dystocia, decreased viability and decreased pup body weight. 

Offspring Toxicity 

NOAEL = 10.4/12.0 mg/kg/day

LOAEL = 42.6/49.5 (M/F) mg/kg/day based on decreased pup body weight and
increased incidence of cleft palate, dilated renal pelvis, dilated
ureters and dilated bladder.

870.4100b

Chronic toxicity dogs	46246337 (2001)

0, 40, 300, 2000 ppm

0, 1.35/1.55, 10.1/11.1, 69.9/77.1 (M/F)  mg/kg/day

30 weeks

Unacceptable/Guideline

Not  tested at high enough doses

GLP deficiencies	NOAEL = 69.9/77.1 (M/F) mg/kg/day 

LOAEL > 69.9/77.1 (M/F) mg/kg/day

870.4200

Carcinogenicity rats	46246342 (1999)

0, 20, 140, 980 ppm

0, 1.1/1.6, 8.0/11.2, 57.6/77.4 (M/F) mg/kg/day

Acceptable/Guideline	NOAEL = 1.1/1.6 (M/F) mg/kg/day

LOAEL = 8.0/11.2 (M/F) mg/kg/day based on clinical chemistry,
histopathology (liver).

no evidence of carcinogenicity

870.4300

Carcinogenicity mice	46246340 (2000)

46246341 (2001)

0, 12.5, 50, 200 ppm

0, 3.1/5.1, 12.8/20.3, 51.7/80.0 (M/F) mg/kg/day

105 weeks

Acceptable/Guideline	NOAEL =12.8/20.3 (M/F) mg/kg/day

LOAEL = 51.7/80.0 (M/F) mg/kg/day based on decreased body weight gain in
males, decreased triglyceride levels in both sexes, decreased
cholesterol levels in males, changes in glucose levels in males,
increased liver weights in both sexes, increased incidence of
histopathological findings in the liver hepatocytes in both sexes,
decreased blood urea levels in females, increased kidney weights in
females, and increased incidence of eosinophilic droplets in the
cortical tubules of the kidneys of females.

no evidence of carcinogenicity

870.6300

Developmental neurotoxicity rats	46246418 (2004)

0, 40, 160, 500 ppm 

0, 3.6, 15.1, 43.3 mg/kg/day during gestation

0, 8.1, 35.7, 104.6 during lactation

Acceptable/Nonguideline

	Maternal Toxicity

NOAEL = 15.1 mg/kg/day

LOAEL = 43.3 mg/kg/day based on dystocia

Developmental Toxicity

NOAEL = 3.6 mg/kg/day

LOAEL = 15.1 mg/kg/day based on deviated snout and malocclusion

Offspring Neurotoxicity potential could not be determined - Brain
morphometric changes and increased incidence of peripheral nerve lesions
were observed at high dose level, but not measured at mid- and low-dose
levels.  

870.7600

Dermal Absorption	46246425 (2003)

Monkey   N=5	Absorption rate: 

18.61%

870.7600

Dermal Absorption	46246424 (2003)

Monkey   N=1

Pilot Study	Absorption rate

7.11%

  SEQ CHAPTER \h \r 1 870.7485

Metabolism -rat	46246422 (2001)

46246420 (2001)

Pilot study and autoradiography

Acceptable/Nonguideline	  SEQ CHAPTER \h \r 1 In whole-body
autoradiography experiments, the quick onset of absorption of the test
material was demonstrated.  Absorption was not complete after one hour. 
The autoradiograms also showed that the blood concentration was less
than the concentration present in the fatty tissues, demonstrating the
lipophilic nature of SXX0665, and perhaps of its metabolites.  The
mucous membrane of the stomach walls were observed with radioactivity
throughout the various observation periods, which was considered an
indication of extrabiliary secretion of the absorbed radioactivity back
into the stomach lumen.  The muscle, heart, lung, brain, thyroid, and
mineral portion of the bones showed minor concentrations of
radioactivity.  The testes had a radioactivity distribution pattern
indicative of the blood circulation in the organ.  Medium amounts of
radioactivity were observed in some glandular organs, including the
preputial gland and the adrenals.  The gums were also observed with
increased radioactivity, with unknown physiological significance.  The
distributions noted at one hour were fairly consistent for 48 hours,
though declining due to excretion.  The renal cortex contained
radioactivity to a much greater extent than did the renal pelvis,
indicating that the radioactivity was reabsorbed in the duodenum.  As
well, the radioactivity that is absorbed is likely not transformed into
metabolites that are adequately polar to be eliminated by the kidney. 
This results in increased passage through the liver by the radioactive
test material.

  SEQ CHAPTER \h \r 1 870.7485

  SEQ CHAPTER \h \r 1 Pregnant Metabolism Study (single and multiple
oral and dermal low and high dose administration)- Rat	46246439 (2001)

Acceptable/Nonguideline	The maximum concentrations (Cmax) were
comparable between single and multiple oral administration of 1 mg/kg
and 3 mg/kg and dermal application of 30 mg/kg, respectively.  The
maximum concentration varied after single and multiple dermal
application of 100 mg/kg.  The time to achieve maximum concentration was
prolonged after dermal application compared with oral administration at
all doses tested (single and multiple) but the delay was not
dose-dependent.  The longest terminal half-life was observed in the high
dose single dermal application (100 mg/kg) which was 34.4 h.  The lowest
terminal half-life was observed in the low dose multiple dermal
application group (30 mg/kg).  The AUC values (representing an indirect
measure for the fraction of SXX 0665 absorbed) increased only slightly
after large increases in applied dose (both dermal and oral).

870.5100

Bacterial reverse mutation test	46246344 (1990)

Acceptable/Guideline	At no concentration up to cytotoxic levels in
either assay, however, were increases in revertants induced by SXX 0665,
compared to concurrent negative controls, or compared to the
laboratory’s historical control data.  Marked increases were induced
in all positive controls.

870.5300 

In vitro mammalian cell gene mutation	46246405 (1999)

	SXX 0665 is considered non-mutagenic in the V79-HGPRT Forward Mutation
Assay.

870.5375

In vitro mammalian chromosome aberration test	46246407 (1995)

Acceptable/Guideline	SXX 0665 is considered to be non-clastogenic in CHO
cells up to subcytotoxic concentrations.

870.5395

Mammalian erythrocyte micronucleus test	64246410 (1993)

Acceptable/Guideline	SXX 0665 is not considered to be a clastogen or
aneugen in mice at the i.p. administration of 350 mg/kg.

870.5550

Unscheduled DNA synthesis in mammalian cells	46246414 (1992)

Acceptable/Guideline	There was no evidence that UDS, as determined by
radioactive tracer procedures [nuclear silver grain counts], was
induced.

Special Study

  SEQ CHAPTER \h \r 1 Assessment of Ovarian Findings in Rodents	  SEQ
CHAPTER \h \r 1 46246441 (2001)

Acceptable/Non Guideline	  SEQ CHAPTER \h \r 1 Currently, the only study
where the ovary findings influence the study LOAEL is MRID 46246430
(Krotlinger, 1992).  Although there is evidence that the ovary effects
seen in this study are coincidental, the reviewers for this submission
have decided to consider this effect treatment related.  A NOAEL for
females was not achieved in this study; however, there is an adequate
margin of safety to this LOAEL from the dose levels selected during risk
assessment.

Special Study

  SEQ CHAPTER \h \r 1 Liver Foci Study- Rat	46246437 (1991)

Acceptable/Nonguideline	  SEQ CHAPTER \h \r 1 The incidences of foci of
altered hepatocytes (FAH) were slightly increased in males and females
administered the test substance (980 ppm) for 6 weeks (groups 1 and 7)
compared to their controls (groups 2 and 8).  The incidence of FAH was
slightly decreased in males and females administered the test substance
(980 ppm) for 12 weeks (groups 3 and 9) compared to their controls
(groups 6 and 12).  The incidences of FAH were higher in the control
males compared to the females.  Administration of the test substance to
animals previously treated with an initiator (NNM) and a regenerative
proliferation inducer (DGA) (groups 4 and 10) produced only slightly
elevated (no statistical significance) incidences of FAH relative to
those in the corresponding control groups (groups 5 and 11).  Severe
cytoplasmic vacuolation, particularly following the 12-week treatment,
was found in the Zone II hepatocytes of nearly all males that had been
exposed to the test substance and exhibited this increased activity
(this correlation was absent in animal no. 19).  These vacuoles appeared
void to the eye in sections that had been treated with solvents. In
native sections, these vacuoles were highly refractive. Isolated
cellular destruction and mitosis of parenchyma1 cells were also observed
in these animals.” In males administered the test substance, there was
an increase in the glucose-6 phosphate dehydrogenase activity in 3/5
animals compared to 0/5 controls after 6 weeks, and in 5/5 animals
compared to 1/5 controls after 12 weeks.  “This rise in activity was
limited to the Rappaport Zone I hepatocytes.” The enzyme induction in
the periportal hepatocytes was stronger at 13 weeks in the males
administered test substance without NNM and DGA than with.  There were
no clear patterns with the incidence or severity of enzyme induction
findings in the females.  “No evident hepatocytic vacuolation was
observed in the females of any group.  However, in animals that had been
treated with the test substance, it was noted that the stored glycogen
in perivenular cells was distributed very uniformly throughout the
cytoplasm, whereas structures having the appearance of densely packed
glycogen pools - often concentrated at the cellular periphery - were
observed in the pertinent controls.”

	



Table A.2.4: Toxicity Profile for Prothioconazole - Sulfonic Acid K Salt
Technical

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

870.3100

90-Day oral toxicity rodents (rat)	46246312 (2001)

0, 30, 125, 500, 2000 ppm

0, 2.1/2.6, 8.7/9.7, 34.3/40.4, 135.9/163.0 (M/F) mg/kg/day

Acceptable/Guideline	NOAEL = 34.3/40.4 (M/F) mg/kg/day

LOAEL = 135.9/163.0 (M/F) mg/Kg/day based on microscopic findings in the
ovary in females (cysts), and the urinary bladder (transitional cell
hyperplasia) and testes (focal degeneration germinal epithelium) in
males.

870.3700a

Prenatal develop-mental in rodents

(rat)	46246318 (2001)

0, 30, 100, 500, 1000 mg/kg/day

Range finding study

Acceptable/Nonguideline	Discussed in review of MRID 46246234

Maternal Toxicity 

NOAEL = 500 mg/kg/day

LOAEL = 1000 mg/kg/day

based on decreased FC, BW, clinical signs and high mortality.

Developmental Toxicity

NOAEL = >1000 mg/kg/day

LOAEL > 1000 mg/kg/day

870.3700a

Prenatal develop-mental in rodents

(rat)	46246324 (2001)

0, 30, 150, 750 mg/kg/day

Acceptable/Guideline	Maternal Toxicity

NOAEL = 150 mg/kg/day

LOAEL = 750 mg/kg/day based on clinical signs, decreased food
consumption, decreased body wt, mortality

Developmental Toxicity

NOAEL < 30 mg/kg/day

LOAEL ≤ 30 mg/kg/day based on increased incidence of supernumerary one
ribs.

870.5100

Bacterial reverse mutation test	46246402 (2000)

Unacceptable/Guideline	No concentration in either assay did the test
article significantly increased the number of revertants over negative
control values.  However, the spontaneous revertant counts of strain
TA100 as well as the response to the S9-activated positive control were
lower than expected.

Table A.2.5: Toxicity Profile for Prothioconazole - Des-chloro Technical

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

870.3700a

Prenatal develop-mental in rodents (rat)	46246317 (2002)

0, 40, 200, 1000 mg/kg/day

Acceptable/Nonguideline

	Maternal Toxicity

No NOAEL or LOAEL were established, observations included decreased food
consumption, body weight, body weight gain

Developmental Toxicity

No NOAEL or LOAEL were established, observations included decreased
fetal wt, increased developmental delays & structural abnormalities

870.5100

Bacterial reverse mutation test	46246345 (2003)

Acceptable/Guideline	No evidence of mutagenicity (increased revertants)
was observed in either assay up to cytotoxic levels of the test
substance.  Therefore, 6476 Des-chloro is considered non-mutagenic in
this bacterial test system.

870.5375

In vitro mammalian chromosome aberration test	46246408 (2003)

Acceptable/Guideline	JAU 6476 Des-Chloro is considered non-clastogenic
in this test system.

Table A.2.6 Supplemental: Toxicity Profile for other Prothioconazole
metabolites

870.5100

Bacterial reverse mutation test	46246346 (2002)

JAU 6476-methyl

Acceptable/Guideline	JAU 6476-methyl is considered nonmutagenic in this
battery of S. typhimurium strains up to cytotoxic levels.

870.5100

Bacterial reverse mutation test	46246347 (2002)

JAU 64760-asymmetric isomer

Acceptable/Guideline	The asymmetric isomer of JAU 6476 is considered
nonmutagenic in this battery of S. typhimurium cultures up to cytotoxic
concentrations.

870.5100

Bacterial reverse mutation test	46246348 (2001)

JAU 6476-asymmetric disulfide

Acceptable/Guideline	JAU 6476-asymmetric disulfide does not induce
reverse mutation in this bacterial test system up to cytotoxic
concentrations.

870.5100

Bacterial reverse mutation test	46246349 (2000)

JAU6476-alpha-hydroxy-desthio

Acceptable/Guideline	The alpha-hydroxy-desthio derivative of JAU 6476 is
considered non-mutagenic in this bacterial test system up to the
cytotoxic/limit concentration.

870.5100

Bacterial reverse mutation test	46246350 (2000)

JAU 6476-triazolinone

Acceptable/Guideline	JAU 6476-triazolinone is considered nonmutagenic in
this S. typhimurium test system.

870.5100

Bacterial reverse mutation test	46246401 (2000)

JAU-6476-alpha-acetoxy-desthio

Acceptable/Guideline	JAU 6476-alpha-acetoxy-desthio is considered
non-mutagenic in this bacterial test system.

870.5100

Bacterial reverse mutation test	46246403 (2000)

JAU-6476-benzylpropyldiol	JAU 6476-Benzylpropyldiol does not induce
reverse mutation in this bacterial test system up to cytotoxic
concentrations.

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

A.3.1	Subchronic Toxicity

	870.3100	90-Day Oral Toxicity - Rat

		Prothioconazole

				In a subchronic toxicity study (MRID 46246311), JAU 6476 (97.6%
a.i.) was administered to 10 Wistar Hsd Cpb:WU rats/sex/dose by gavage
at dose levels of 0, 20, 100 or 500 mg/kg bw/day with a vehicle of 0.5%
aqueous Tylose over a period of up to 14 weeks.  In addition 10
rats/sex/dose were treated likewise with JAU 6476 with doses of 0 and
500 mg/kg bw/day over 14 weeks then observed for a subsequent
treatment-free period of 4 weeks for reversibility.  An additional
satellite group of 5 rats/sex/dose was treated at 0, 20, 100 and 500
mg/kg bw/d for 4 weeks and then immunotoxicological investigations were
performed. 

There were no treatment-related clinical signs.  One female at 500 mg/kg
was killed in a moribund condition on day 96 of test, with necropsy
findings including; inflammation of the tongue (grade 1), basophilic
tubules in the kidney (grade 1), and a dilated urinary bladder.  This
death could not be ruled out as non-treatment-related.  Other deaths
were due to maladministration (2~ at 500 mg/kg/d) or blood collection
(1~ at 500, 1~ at 0 and 1~ at 100 mg/kg/d).  There were no
treatment-related effects on body weight, body weight gain or food
consumption in the study.   In the main study, water consumption was
increased in males (20-42%) and females (14-34%) at 500 mg/kg.  In the
recovery group, water consumption was increased during the treatment
weeks (16-35% in males; 20-49% in females) and returned to control
values in males or was only slightly higher than controls in females
(10%) during the recovery period.  Water consumption was increased in
the satellite groups (20-27% males, 7-25% females), but was not
statistically increased at week 4 (the last day measured).  There were
no treatment- related effects in the ophthalmological examinations or
hematology.   

There were treatment-related changes in cholesterol and triglyceride
levels.  Cholesterol levels were increased at 500 mg/kg at week 5 (18%
males; 25% females) and 14 (36% males; 31% females), but were reduced at
week 19 in the recovery groups (19% males; 7% females).  Triglyceride
levels were decreased at week 5 at ≥100 mg/kg in males (26-30%
decreased) and at 500 mg/kg in females (16%).  Triglyceride levels were
also decreased at 500 mg/kg at week 14 (37% females) and at week 19 (19%
males; 6% females).  ALAT (serum alanine amino-transferase) levels were
increased at week 5 at ≥100 mg/kg (5-22% males) and decreased (not
statistically) at 500 mg/kg at weeks 14 (males 8%; females 20%) and 19
(males 7%; females 9%).  The toxicological significance of these changes
is not known.

There was a treatment-related effect on epoxide hydrolase (both sexes),
and UDP-Glucuronyltransferase (males only).  Epoxide hydrolase levels
were statistically increased in both sexes at 500 mg/kg (14 weeks). 
UDP-Glucuronyltransferase levels were statistically increased at 500
mg/kg in males (14 weeks).  Aldrin epoxidase levels were statistically
decreased at ≥20 mg/kg in males (14 weeks), but the toxicologically
significance of this decrease is not known.  Hydroxylation of
testosterone was slightly inhibited at 16α- and 2α- positions in high
dose males and was slightly increased at the 6β-position in high dose
males and females.  Plasma concentrations of JAU 6476 were higher in
females (approximately 2X) than in males at weeks 6 and 11 but
concentrations did not increase proportionately compared to the dose. 
Plasma concentrations of SXX 0665 were low compared to the
concentrations JAU 6476.  Based on a non-GLP immunotoxicity
investigation, the test substance was not considered immunotoxic.

At 500 mg/kg, urine volume levels were decreased in males at week 4
(54%), 13 (40%) and 18 (13%) and in females at week 4 (18%) and 18
(10%).  Protein levels were increased at week 4 (93% males; 85% females)
and 13 (67% males; 37% females), but were decreased (33% males) or
comparable to control values (females) at week 18.  The effects in
urinalysis were considered toxicologically significant in combination
with histological effects noted in the kidney.  There were no
treatment-related findings in the sediment of urine in males or females
at the weeks tested. 

≥100 mg/kg in males.  Basophilic tubules of the renal cortex were
noted in male rats at all dose levels (including controls).  Severity
was increased at 500 mg/kg in males.  There were no differences between
control and treatment groups at the end of the recovery period.  Study
authors noted that hyaline droplets/inclusions were observed in
epithelial cells of the proximal tubules in the kidneys of males from
all groups and Azan-positive staining confirmed the deposits to be
proteinaceous (considered to be alpha- 2-microglobulin).  The severity
of this finding was similar in all groups. 

The liver and kidney were target organs for prothioconazole toxicity in
the rat.  

The LOAEL is 500 mg/kg, based on increased water consumption (males and
females), increased cholesterol (males and females), liver effects
[increased liver weights (females), hepatocellular hypertrophy (males
and females) and cytoplasmic change (males and females)] and kidney
effects [decreased urinary volume (males and females), increased urine
protein levels (males and females), and the increased incidence and
severity of basophilic tubules of the renal cortex (males)].  The NOAEL
is 100 mg/kg.

This subchronic toxicity study in the rat is acceptable, and satisfies
the guideline requirement for a subchronic oral study (OPPTS 870.3100;
OECD 408) in the rat.  This review is a joint effort of the PMRA and the
EPA.

__________

				In a subchronic toxicity study (MRID 46246428), JAU 6476 (99.5%
a.i.) was administered to 5 Wistar rats/sex/dose in the diet with 1%
peanut oil at dose levels of 0, 400, 2000, or 10000 ppm (equivalent to
0, 18.6, 145.7, or 951.7 mg/kg bw/day for males, and 0, 18.8, 151.0, or
1032.5 mg/kg bw/day for females) for 4 weeks.  The animals were
sacrificed and subject to gross necropsy after 4 weeks.

Due to chemical stability issues, the compound consumption was estimated
for each of the dose groups.  There were no mortalities and there were
no clinical signs associated with treatment.  Body weight was decreased
in the high dose male animals from day 7 to termination, and body weight
gain was also decreased in these animals.  Food consumption was also
decreased in these animals, which may be an indication of a palatability
issue at the high dose.  Body weight and food consumption were not
affected in the female animals.  Water consumption was increased in both
sexes at the high dose.  This may be related to the palatability of the
test compound.  Kidney function may also be affected in the high dose
groups of both sexes, as related histopathological changes of basophilic
tubules and tubule dilatation were observed, in addition to the
observation of increased water consumption with decreased urine volume. 
Two high dose males had pale, discolored, marbled kidneys.  There were
no adverse treatment- related hematology findings in either sex.  Liver
enzyme (alanine aminotransferase and alkaline phosphatase) and
cholesterol levels were increased in both sexes, with accompanying liver
weight increases and liver pathology in the female animals.  High dose
males showed decreased T3 and T4 while high dose females only had
decreased T4.

No NOAEL or LOAEL were determined, as this is a range-finding study.

This subchronic toxicity study in the rat is acceptable as a
supplementary range-finding study and satisfies the guideline
requirement (OECD 407) for a repeat-dose oral study in rats.  This
review is a joint effort of the PMRA and the EPA.

__________

				In a subchronic toxicity study in the rat (MRID 46246429) JAU 6476
(99.5% a.i.) was administered to two sets of animals.  One set of
animals (5 animals/sex/dose) was administered test material in the diet
at dose levels of 0 ppm or 10000 ppm in neat diet or 10000 ppm in
stabilized diet.  The second set of animals (5 animals/sex/dose) were
dosed by gavage at dose levels of 0 or 1000 mg/kg bw/day.  The animals
were sacrificed and subject to gross necropsy after 4 weeks.

There were no mortalities observed in the study.  Animals fed neat test
material in the diet showed piloerection for some portion of the
treatment period.  Body weight and body weight gain was reduced in the
neat diet-treated males for the duration of the study.  Total body
weight gain was decreased in the gavage males, and in the stabilized-
and neat-diet treated female animals.  Food consumption was increased
throughout the study period in the animals treated with stabilized diet.
 Water consumption was clearly increased in both sexes given test
material neat in the diet.  This observation may be related to
palatability of the test material, as this was a possible cause of a
number of observations in the 4-week dietary rat study also.  Hematology
and clinical chemistry parameters were not measured in the animals fed
treated diet.  Increased levels of alanine aminotransferase were
observed in the male and female gavaged animals.  Alkaline phosphatase
was also increased in the females.  Glutamate dehydrogenase was
increased in males and decreased in females, and albumin was decreased
in the females.  All of these observations are likely related to liver
weight and histopathological changes noted in these animals.  The
cytochrome P450 liver enzymes were increased and decreased sporadically
among the dose groups, while the conjugation liver enzymes were
increased in all treated groups, with the exception of glutathione-S-
transferase in females fed stabilized diet.  Absolute liver weight was
increased in the stabilized diet- treated males.  Slight decreases were
observed in the other male dose groups.  The female animals fed neat
diet and dosed by gavage showed increased absolute and relative liver
weight.  The neat diet-treated females also showed histopathological
changes in the liver, and the gavage animals showed changes in clinical
chemistry related to the liver, giving an indication of possible
treatment-related liver effects.  Cytoplasmic change was observed in the
liver of a male fed stabilized diet and gavaged males, and females in
each of the neat diet and gavage groups.  Single cell necrosis was
observed in one male in each of the diet dose groups.  Mononuclear cell
infiltration in the liver was observed in one female in each of the diet
dose groups.  These liver findings are likely related to the gross
changes observed in the liver, as well as to clinical chemistry
observations, indicating that the liver is likely a target organ of this
test material.  Urea levels in males were increased and may be related
to changes observed in the kidney.  Absolute and relative kidney weights
were decreased in the males dosed by gavage, along with
histopathological changes of basophilic tubules in the kidney. An
increased incidence of basophilic tubules was also observed in the males
fed neat diet, and in each of the treated female groups.  The finding
was more severe in the male animals.  Mononuclear cell infiltration in
the kidneys was also observed in the kidney in one male fed neat diet. 
These kidney findings are likely an indication that the kidney is also a
target organ of JAU 6476.  Creatinine kinase levels were decreased in
males and increased in females.  The increases could be due to muscle
injury.   Decreases were also observed in the absolute brain weights,
absolute and relative adrenal weights, and absolute and relative heart
weights were observed in the gavaged males.  These changes may be
related to the decreased body weight gain observed in these animals. 
The relative and absolute adrenal weights were increased in the gavaged
females.  One female in this group also showed histopathological
mononuclear cell infiltration in the adrenals, which may be related to
the increased adrenal weights.  There were no treatment-related findings
observed upon necropsy.  Overall, plasma levels of JAU 6476 and the
metabolite SXX 0665 were highest in the animals dosed by gavage.  In
addition, animals fed stabilized diet showed lower plasma levels of JAU
6476 and SXX 0665 than the animals fed neat diet.  Plasma levels of SXX
0665 were relatively low when compared with levels of JAU 6476 in the
plasma of both animals dosed in the diet and by gavage.  Animals dosed
by gavage showed the greatest number of treatment-related effects,
however hematology and clinical chemistry parameters were not measured
in the animals receiving treated diet.  Effects on the target organs
(liver - increased weights, cytoplasmic change; kidney - basophilic
tubules) were noted in both dosing regimes with a similar degree of
incidence.

No NOAEL or LOAEL were determined, as this is a supplemental study.

This subchronic toxicity study in the rat is acceptable as a
supplemental study and satisfies the guideline requirement (OECD 407)
for a repeat-dose oral study in rats.  This review is a joint effort of
the PMRA and the EPA.

		Prothioconazole-desthio

				In a subchronic toxicity study (MRID 46246430) SXX0665 (Purity:
93.7%) was administered to 10 Bor: WISW (Spf-Cpb) rats/sex/dose in the
diet (1% peanut oil) at dose levels of 0, 100, 300 or 1000 ppm [0, 11,
34/38 or 117/121 (M/F) mg/kg bw/day] for 4 weeks. 

↓16%) and females (↓13%) at 1000 ppm. Males in the 1000 ppm dose
group additionally showed decreased bilirubin (↓22%) and triglycerides
(↓44%), while females showed increased cholesterol (↑46%).
Significant liver enzyme induction was observed at the highest dose with
increases in N-DEM (females only) and O-DEM (males and females). P450
activity was significantly increased at 300 and 1000 ppm in males, and
at 1000 ppm in females. Liver triglycerides were significantly increased
at doses > 300 ppm (↑23-170%) in males only.

	In males, absolute and relative liver weight was significantly
increased in the mid (16%) and high dose groups (28-34%). In females,
absolute and relative liver weight was also significantly increased at
the high dose (25%), with relative liver weight increased at the low
(6%) but not mid dose group. Higher variability was noted in the mid and
high dose groups. In addition, ovary weight (both absolute and relative)
was significantly increased in all treatment groups (31-44%). In
females, adrenal weight (both absolute and relative) was increased in
the mid and high dose groups (120-122%); absolute and relative kidney
weight was increased in the high dose group (108%) only and pituitary
weight was increased in females at ≥100 ppm absolute (25%) and
relative (20-40%). 

	Enlarged ovaries were noted in all treated females, and a clear watery
fluid was noted in the ovarian follicles, corroborating the finding of
increased ovary weight in all treatment groups. Increased number of
tertiary follicles (more than 3) were noted in the ovaries of females in
the mid (2/5) and high-dose (3/5) groups. Increased incidence of stromal
edema was noted in the mid (5/5) and high dose (4/5) females compared to
control. The ovarian findings were considered to be treatment-related.
Fatty infiltration of the liver was noted in all treatment groups. This
was considered a treatment-related effect due a clear dose response in
incidence and severity (minimal to marked). The areas of fatty change
were predominantly midzonal or periportal areas of the liver lobules. 
Hepatocellular hypertrophy was also noted in one high-dose female. 

The results of this subchronic study flag the liver as a target organ.
In addition, the effects on the ovaries and adrenal gland suggest a
possible effect of SXX0665 on steroid metabolism. 

	

No NOAEL was determined for females. The LOAEL for females is 100 ppm
based on increased relative and absolute ovary weight with corroborating
histopathological findings (increased number of ovarian follicles and
stromal edema) occurring at 300 ppm. The NOAEL for males is 100 ppm, the
LOAEL for males is 300 ppm based on increased liver triglycerides and
increased relative and absolute liver weight.

This subchronic toxicity study in the rat is acceptable and satisfies
the guideline requirement (OECD 407) for a repeat-dose oral study. This
review is a joint effort of the PMRA and the EPA. 

__________

		In a subchronic toxicity study (MRID 46246309) SXX 0665 (93.1% a.i.)
was administered to 10 Wistar rats/sex/dose in diet at dose levels of 0,
30, 125, 500 or 2000 ppm (0/0, 2.2/3.0, 9.6/12.5, 36.9/50.7, or
161.9/210.8 mg/kg bw/day for males/females) for 14 weeks.  Also,
treatment and 5 weeks recovery groups were run with 10 rats/dose/group
in diet at dose levels of 0 and 2000 ppm (0/0 and 162.2/219.1 mg/kg
bw/day for males/females).

There were no treatment-related effects on mortality, clinical signs or
opthalmological parameters in either sex at any dose.  The registrant
did not report any results for the first 14 weeks of treatment of the 5
week recovery group, thereby making comparison of the treatment and
recovery group unreliable for body weight, body weight gain, haematology
and clinical chemistry parameters.  Treatment-related decreases in body
weight were observed in males between weeks 1 and 14 as well as the
overall body weight gain.  Food consumption was decreased (not
significant) in males between weeks 1 and 6.  There were no
treatment-related changes in body weight/body weight gain in the females
or in either sex of the recovery groups at any dose.  Water consumption
was decreased in males at 2000 ppm and in females at 125 ppm and 2000
ppm in the treatment group. In the recovery groups, water consumption
was decreased in males during treatment and was comparable to controls
afterwards.  Treatment-related decreases in protein excretion and the
occurrence of ketone bodies in urine were observed in the 2000 ppm males
week 4.  Signs of hepatotoxicity included: i)  increased
aminotransferases (ASAT and ALAT) and alkaline phosphatase (ALP) in
males at 2000 ppm (week 5 and 14) which did not persist in recovery
groups; ii)  increased ALAT at 2000 ppm in females (week 14) which did
not persist in recovery groups; iii) increased bilirubin at(500 ppm for
males and (30 ppm for females (week 14) which did not persist in
recovery groups; iv)  increased cholesterol at 2000 ppm in females (week
5 and 14) which did not persist in recovery groups; v)  decreased
triglycerides at (125 ppm week 5 and (500 ppm week 14 in males which did
not persist in recovery groups; vi)  increased absolute and relative
liver weight in both sexes at doses (500  ppm. (statistical significance
was observed in both sexes at 2000 ppm but in the case of the absolute
liver weight, it was not significant at 500 ppm in the females - at the
end of recovery the liver weights were comparable with control); vii) 
liver homogenate amino-N-demethylase was increased in females at doses
(500 ppm; viii)  liver homogenate P-nitroanisole-O-demethylase was
increases in males at 2000 ppm and in females at doses (500 ppm (the
recovery group female values were similar to control for these
parameters while the P-nitroanisole-O-demethylase was still increased in
the male recovery group); ix)  liver homogenate P450 was increased at
doses(500 ppm in males and (125 ppm in females; x)  liver homogenate
triglyceride values were decreased in males at 2000 ppm and at doses (30
ppm in females (recovery group triglyceride values were similar to
control values in females while the male values remained significantly
decreased); xi)  pale and/or enlarged liver in males at doses (500  ppm
and enlarged livers in females at 2000 ppm;  xii) increased incidence
and severity of hepatocellular hypertrophy, vacuolation, and
mid-zonal/centrilobular fatty change in males at doses (125 ppm; xiii)
increased incidence and severity of hepatocellular hypertrophy in
females at dose (500 ppm and: xiv) hepatocellular hypertrophy persisting
in the recovery group males but not in the females. 

The LOAEL is 125 ppm/day in both sexes, based on histological changes in
the liver of males. The NOAEL is 30 ppm.

This subchronic toxicity study in the rat is acceptable and satisfies
the guideline requirement for a subchronic oral study (OPPTS 870.3100;
OECD 408) in the rat.  This review is a joint effort of the PMRA and the
EPA.

		Prothioconazole-sulfonic acid K-salt

				In a subchronic toxicity study (MRID 46246312), JAU 6476- sulfonic
acid K-salt (98.9%) was administered to 10 Wistar rats/sex/dose in the
diet (with 1% peanut oil) at dose levels of 0, 30, 125, 500 or 2000 ppm
(0.0, 2.1, 8.7, 34.3 or 135.9 mg/kg bw/day in males or 0.0, 2.6, 9.7,
40.4 or 163.0 mg/kg bw/d in females) for 13 weeks. 

There were no treatment-related clinical signs or mortality.  One female
at 500 ppm was sacrificed moribund on day 23, examination did not show
treatment-related effects.  There were no treatment- related effects on
body weight, body weight gain, water consumption or food consumption. 
Ophthalmoscopic examination was not performed.  There were no
treatment-related effects on hematology or clinical chemistry.  There
were no treatment-related findings in the urinalysis. There were no
adverse treatment-related findings on liver enzymes in this study. 
There were no adverse treatment- related findings in absolute or
relative organ weights. 

One cyst was noted in the ovaries of high dose females at gross
examination, which correlates with cysts noted at microscopic
examination.

At microscopic examination, effects were noted in the urinary bladder
and testes in males, and the ovaries in females.  These effects are
considered treatment-related.  Transitional cell hyperplasia in the
urinary bladder (diffuse grade 1 or 2) was noted in 4/10 males at 2000
ppm.  One male had grade 3 hyperplasia with incipient papillary growth
pattern.  There was no treatment induced hyperplasia in the transitional
epithelium in females.  There was an increase in incidence and severity
of ovary cysts at 2000 ppm.  There was a reduced number of corpora lutea
in the ovaries of 2/10 high dose females, but there were no
corresponding findings in ovary weights.  Focal degeneration germinal
epithelium was noted in the testes in 3/10 males at 2000 ppm compared to
1/10 in control males, but there were no corresponding findings.  There
was an increase in proestrous in females at 2000 ppm in the vagina. 

The LOAEL is 2000 ppm (equivalent to 135.9 or 163.0 mg/kg bw/day in
males/females), based on microscopic findings in the ovary in females
(cysts), and the urinary bladder (transitional cell hyperplasia) and
testes (focal degeneration germinal epithelium) in males.  The NOAEL is
500 ppm (equivalent to 34.3 or 40.4 mg/kg bw/day in males/females).  

This subchronic toxicity study in the rat is acceptable and satisfies
the guideline requirement for a subchronic oral study (OPPTS 870.3100;
OECD 408) in the rat. This review is a joint effort of the PMRA and the
EPA.

	870.3100	90-Day Oral Toxicity - Mouse

		Prothioconazole

	

							In a subchronic toxicity range-finding study (MRID 46246427), JAU
6476 (97.6% a.i.) was administered to 10 CD-1 mice/sex/dose by gavage at
dose levels of 0, 25, 100, or 400  mg/kg bw/day in aqueous 0.5% Tylose
MH 300 P for 14 weeks.  Surviving animals were sacrificed after 14
weeks, and subject to necropsy.

There were no clinical findings related to treatment with the test
compound, and there was no treatment- related mortality observed.  Five
animals died during the study as a result of either gavage error or
blood collection.  There were no treatment-related effects on body
weight or body weight gain.  There were no treatment-related effects on
food consumption, food efficiency, or hematology.  Treatment-related
changes were observed in a number of clinical chemistry parameters. 
Increased aspartate aminotransferase and decreased albumin levels in the
high dose male animals, and increased cholesterol levels in mid and high
dose females are likely related to the other liver findings.  The
observations in the liver included increased liver weight in the mid and
high dose of both sexes, increased incidence of lobulation of the liver
and enlarged liver in the high dose males, and increased incidence of
hepatocellular hypertrophy and cytoplasmic change in the livers of the
mid and high dose animals of both sexes.  The cytochrome P450 liver
enzymes tested (ECOD, EROD, ALD) were also elevated in both sexes in the
mid and high dose groups, while the conjugation liver enzymes (GST) were
increased only in the high dose females.  Other histopathological
changes related to liver effects included increased incidence of
vacuolation and focal necrosis in the high dose males, and increased
incidence of periportal fatty change and vacuolation in the high dose
females.

The LOAEL is 100 mg/kg bw/day for males and females, based on increased
cholesterol levels and increased liver enzyme activity in females,
increased liver weights in both sexes, and increased incidence of
hepatocellular hypertrophy and cytoplasmic change in the liver of both
sexes.  The NOAEL is 25 mg/kg bw/day for male and females.

This subchronic toxicity study in the mouse is acceptable and satisfies
the guideline requirement for a subchronic oral study (OPPTS 870.3100;
OECD 408) in mice.  This review is a joint effort of the PMRA and the
EPA.

		Prothioconazole-desthio

				In a range-finding subchronic toxicity study (MRID  46246310), SXX
0665 (93.1% a.i.) was administered to 10 B6C3F1 mice/sex/dose in diet
(1% peanut oil) at dose levels of 0, 40, 200, 1000 or 5000 ppm (0/0,
11.5/16.0, 58.9/79.5, 294.0/392.3 or 1454/2073 mg/kg bw/day for
males/females- with 5000 ppm equivalent calculated by reviewer using
approximate food consumption values from the 1000 ppm group) for 13
weeks.

≥200 ppm (10-14% at 200 ppm & 73-85% at 1000 ppm) and in females at
1000 ppm (42-45%). Gross pathology revealed accentuated lobulation of
the liver in the 1000 ppm males (100% vs. 0% controls) and
histopathology revealed periacinar hepatocytic fatty vacuolation in
males at doses ≥1000 ppm (80% vs. 0% controls).  Single cell necrosis
was increased in both sexes: 60% for males at 5000 ppm; 30, 40, & 70%
for females at doses 200, 1000, & 5000 ppm.  Apoptosis was increased in
both sexes at 5000 ppm, 60% for males and 20% for females.  Increase
incidences of hepatocellular hypertrophy were seen in males treated at
200 & 1000 ppm (100% in both groups vs. 0% for controls) and in females
treated at 40, 200, and 1000 ppm (70, 80, and 100% respectively vs. 0%
for controls).  In addition, increased ploidy was observed in the livers
of males at 5000 ppm (40% vs. 0% controls). 

In males, treatment-related decreases in erythrocytes (12%) were
observed at 1000 ppm, along with decreased (14%) hematocrit and platelet
count and increases (13-15%) in mean corpuscular hemoglobin (MCH) and
mean corpuscular hemoglobin concentration (MCHC).  Leucocytes were
decreased at 1000 ppm in males (34%).  

≥200 ppm. 

At 5000 ppm (the dose at which animals died or had to be killed within
one week of treatment), abnormal contents in the caecum, colon,
duodenum, jejunum and rectum, as well as increased emaciation was
observed in the males and females.  In the stomach of one male and three
females, changed areas on the glandular mucosa of the stomach were
noted.  

The LOAEL is 40 ppm (11.5/ 16.0 mg/kg/bw) based on decreased body weight
gain in both sexes.  The NOAEL is < 40 ppm (11.5/ 16.0 mg/kg/bw). 

This range-finding subchronic toxicity study in the mouse is an
acceptable/non-guideline subchronic oral study in the mouse.  This
review is a joint effort of the PMRA and the EPA.

	870.3150	90-Day Oral Toxicity - Dog

		Prothioconazole

	

				In a subchronic toxicity study (MRID 46246435) JAU 6476 (Purity
98.1-98.8%) was administered to 4 beagle dogs/sex/dose, by gavage (in
aqueous 0.5% methylcellulose/0.4% Tween 80), at dose levels of 0, 25,
100 and 300 mg/kg bw/day.  The test compound was administered for 13
weeks (all doses) with a 4 week recovery period using the 0 and 300
mg/kg bw/day groups only.  The purpose of this non-guideline study was
to examine hepatic and renal enzyme activities in dogs following a 13
week administration of JAU 6476.

In males, no significant treatment-related effects on phase I or phase
II liver enzyme activities were observed following treatment for 13
weeks.  In females, only epoxide hydrolase (EH) activity was
significantly increased at 100 (↑58%) and 300 (↑85%) mg/kg bw/day
compared to control.  Following a 4 week recovery period, no significant
differences in enzyme activities were noted in either sex and the values
were comparable to controls.

↓36%) at 300 mg/kg bw/day.  No significant effects were observed in
females after 13 weeks.  Following a 4 week recovery period, no
significant differences in enzyme activities were noted in either sex
and the values were comparable to controls. 

Tissue concentrations of JAU 6476 and SXX 0665 were measured in the high
dose group only.  In the liver, the tissue concentration ratio of JAU
6476 to the SXX 0665 metabolite was approximately 10:1.  In kidney, the
SXX 0665 metabolite was undetectable. The concentration of JAU 6476 was
approximately 3-fold higher in females in both tissues.

This subchronic toxicity study in the dog is acceptable as a
supplemental study only as many of the guideline requirements for a
subchronic oral study (OPPTS 870.3150; OECD 409) in dogs have not been
addressed in this study.  This review is a joint effort of the PMRA and
the EPA.

________

				In a subchronic toxicity study (MRID 46246313) JAU 6476 (Purity:
98.1-98.8%; Batch No. 6233/0031) was administered to 48 Beagle dogs
(4/sex/dose by gavage 5 days/week at dose levels of 0, 25,100, and 300
mg/kg bw/day) with a recovery group dosed at 300 mg/kg/day (8-week
recovery period). The vehicle used was 0.5% methyl cellulose with 0.4%
Tween 80 in deionized water.  All animals were treated for a total of 90
days. 

There were no compound related effects on mortality, clinical
observations, blood pressure and ECG parameters, hematology,
ophthalmology and neurology. No treatment related changes were seen in
urinalysis or organ weights in any dose group. No treatment related
differences were seen in the hepatic metabolizing enzyme activity
including cytochrome P-450, N-demethylase (NDEM), O-demethylase (ODEM)
or glucuronyltransferase at study termination.

Overall body weight gain was decreased in the high dose (treated and
recovery) males and (recovery) females.  There were several clinical
chemistry parameters related to liver function (ALT, ALP, GGT) which
were elevated in both sexes but particularly females in the 100 and/or
300 mg/kg groups with subtle changes persisting in 300 mg/kg recovery
males at study termination. Additionally, there were subtle decreases in
T4 and TSH suggesting minimal thyroid effects in the 100 and 300 mg/kg
groups. 

Compound-related gross lesions were seen in the kidneys of several
animals of the 300 mg/kg dose group.  Target organ micropathology was
seen in the kidney of both sexes. The kidney changes present in males
and females of the 100 and 300 mg/kg groups were characterized by
multifocal chronic interstitial fibrosis with associated tubular
regeneration and minimal inflammatory cell infiltrate. These morphologic
chronic, focal to multi focal renal changes were not completely
reversible as evidenced by their presence in the 300 mg/kg recovery
group animals. In 300 mg/kg males, a proximal renal tubular degeneration
was also present. Significant increases in the relative organ weights of
liver, kidney and thymus were seen in the 300 mg/kg female group.

The NOAEL in beagle dogs was 25 mg/kg/day. The LOAEL was based on kidney
(histopathological) and thyroid (T4 and TSH) findings at 100 mg/kg.

 

This subchronic toxicity study in the dog is acceptable and satisfies
the guideline requirement for a subchronic oral study (OPPTS 870.3150;
OECD 409) in dogs.  This review is a joint effort of the PMRA and the
EPA.

		Prothioconazole-desthio

				In a subchronic toxicity study (MRID 46246314), SXX 0665 (94.3%
a.i.; Batch No. 1717008/90) was administered to 4 Beagle dogs/sex/dose
in diet at dose levels of 0, 40, 200 or 1000 ppm (0, 1.58, 7.81 or 37.79
and 0, 1.62, 8.53 or 42.75 mg/kg bw/day for males and females,
respectively) for 90 days.

There was no mortality and no treatment-related clinical observations. 
There were no treatment-related changes in body weight, body weight gain
and food consumption.  Liver weights (absolute and relative) were
increased at 1000 ppm in females.  The increased liver weights
correlates with an increase in enzyme induction at this dose. These
liver changes are considered an adaptive response and not adverse. There
was an increase in partial thromboplastin time in the 1000 ppm females
at the end of the study.  N- demethylase and O-demethylase activities in
liver homogenates were increased in both sexes and cytochrome P450
enzyme activities were increased in males.  Cytoplasmic change in the
liver was noted in 3/4 males and 4/4 females at 1000 ppm.

There were no significant treatment-related effects observed in the 200
ppm (7.81 and 8.53 mg/kg bw/day in males and females, respectively)
group for any of the parameters measured.  

The NOAEL is 1000 ppm.  The LOAEL is > 1000 ppm, based on the lack of
adverse effects at the doses tested in this study.  This study is
considered supplemental due to deficiencies in organ weight measurements
and deviations from GLP with respect to liver enzymology and
histopathology. 

This subchronic toxicity study is unacceptable because it does not
satisfy the guideline requirement for a subchronic oral study (OPPTS
870.3150; OECD 409) in dogs.  Liver enzymology and histopathology were
not performed according to GLP standards.  Fasting status and timing of
blood sampling was not reported, making hematology and clinical
chemistry parameters difficult to compare with historical controls. 
Several hematological, clinical chemistry and urinalysis parameters
outlined as OPPTS Guideline 870.3150 requirements were not reported. 
Uterine weights were not reported, despite dramatic reductions in
uterine/oviduct absolute and relative weight in the 39-day range-finding
dog study that preceded the current study (MRID 46246431).  This review
is a joint effort of the PMRA and the EPA

________

					In a subchronic toxicity study (MRID 46246431), SXX 0665 (94.7%
a.i., Batch No. 17005/89) was administered to 2 Beagle dogs/sex/dose in
the diet (no vehicle) at dose levels of 0, 10, 100/5000 or 1000 ppm (0,
0.3, 3/150 or 30 mg/kg bw/day) for 39 days.  Due to the lack of
observations indicating overt toxicity in the 100 ppm group, the dose
was increased to 5000 ppm on Day 26 until the end of the study.

There was no mortality and no treatment-related clinical observations. 
One female at 1000 ppm was found to be pregnant at necropsy.  There were
no treatment-related changes in body weight, body weight gain and food
consumption, with the exception of the 5000 ppm group.  After the 5000
ppm dosing regime was initiated, there was a dramatic decline in food
consumption and body weights declined to such an extent that the animals
in that groups had a mean body weight at the end of the study that was
lower than at the beginning of the study. 

Although the sample number is small and does not lend itself to proper
statistical analysis, a number of trends regarding organ weight were
observed.  Increased liver and thyroid absolute and relative weight in
both sexes in a dose-dependent manner was observed, with liver weights
affected to a greater extent in males.  The higher liver weights
coincide with increased liver enzyme (7-ethoxycoumarin deethylase
[ECOD], aldrin epoxidase [ALD], epoxide hydrolase [EH], and
UDP-Glucuronyl transferase [UDPGT]) activation (100/5000 and 1000 ppm)
and urea urinary excretion (5000 ppm only).  Reduced hepatocyte size was
seen at 100/5000 and 1000 ppm.  Increased hepatocyte optical density was
observed in all animals of the 1000 ppm group, and food consumption was
unaffected in both sexes and body weight gain was increased in males, so
it can not be attributed to glycogenolysis.  Absolute and relative
uterus/oviduct weights were dramatically decreased in all treatment
groups in a dose-dependent manner and the one high-dose female had
markedly lower absolute and relative ovarian weights. One control had a
high ovary weight and the sample size was small, so the toxicological
significance of this finding is unknown.  

Cytoplasmic changes were seen in the livers of the 100/5000 and 1000 ppm
animals.  Round cell infiltration was noted in the adrenal glands of one
female at ≥10 ppm, which the applicant attributes to stress. 
Increased iron pigmentation in the spleen was observed in both sexes at
1000 ppm group and decreased cellularity was observed in the bone marrow
of the femur and sternum in both sexes at 100/5000 and 1000 ppm. There
was an increased number of megakaryocytes was observed in one 100/5000
female; this female had shown a decreased thymus size that was
histopathologically confirmed as moderate thymic atrophy.

A NOAEL cannot be established for this study as it is a range-finding
study.  Also, marked effects on absolute and relative organ weights
(increased in thyroid in both sexes, increased in liver in males and
decreased in uterus/oviduct in females) were observed at 10 ppm (0, 0.3,
3/150 and 30 mg/kg bw/day).  The small sample size precludes proper
statistical analysis but the calculated standard error suggests that the
increased relative (to brain wt) liver weight in males is significantly
different from controls at 10 ppm.  Liver enzyme activities and urinary
creatinine and urea levels were not affected in either sex in the 10 ppm
group. 

This subchronic toxicity study in the dog is a range-finding study and
does not satisfy the guideline requirement for a subchronic oral study
(OPPTS 870.3150; OECD 409) in dogs as it was not conducted to meet GLP
standards.  This review is a joint effort of the PMRA and the EPA.

	870.3200	21/28-Day Dermal Toxicity – Rat

		Prothioconazole

	

				In a repeat-dose dermal toxicity study (MRID 46246315),
prothioconazole (98.5%) was applied neat to the shaved skin of 10
HsdCpb:WU rats/sex/dose, at dose levels of 0, 100, 300 or 1000 mg/kg
bw/day, 6 hours/day for 5 days/week during a 28-day period.

There were no mortalities, no treatment-related clinical observations
and no treatment-related water consumption, hematology, clinical
chemistry, opthalmascopic or gross pathology findings.

The NOAEL for the 28-day rat dermal toxicity study was established to be
1000 mg/kg bw/d.  The LOAEL was not determined.

This repeated dose dermal toxicity study in the rat is acceptable and
satisfies the guideline requirement for a repeated dose dermal toxicity
study (OPPTS 870.3200 (rodent); OECD 410) in rats.  This review is a
joint effort of the PMRA and the EPA.

		Prothioconazole-desthio

			No Acceptable studies are available.

	870.3465	90-Day Inhalation – Rat

		Prothioconazole

	

			No Acceptable studies are available.

		Prothioconazole-desthio

				In a subchronic inhalation toxicity study (MRID 46246433) SXX0665
(Purity: 95.4%) was administered suspended in PEG 400: alcohol to 10
Wistar rats/sex/concentration by head/nose only inhalation exposure
system at concentrations of 0, 11.3, 46.8 and 228.4 mg/m3 for 6 hours
per day, 5 days/week for a total of 28 days.  

 

Exposure conditions were monitored for concentrations, particle sizes
and temperature and humidity and the animals were observed weekly for
changes in body weight but not food consumption and early and late
ophthalmic observations.   Blood was analyzed on day 9 and at the end of
exposures for effects on hematology and clinical chemistry.  Urine was
examined during week three of the exposures.   At the end of 28 days,
the animals were sacrificed and examined for organ weight changes, gross
observations but not histopathological effects.  

No significant treatment-related effects were noted on mortality, body
weight, clinical signs, hematology, clinical biochemistry, urinalysis or
ophthalmology. No significant gross pathological findings were noted.
Decreased absolute and relative thymus weights (approx. 25%) were noted
in the vehicle control and high dose females, compared to the air
control; however, this effect is considered incidental in the absence of
a dose response, a similar effect in males or any accompanying effects
on body weight, gross pathology or clinical toxicity. 

The NOAEL is 228.4 mg/m3 (0. 228 mg/L).  No LOAEL was determined for
this study.

  

This subchronic toxicity study in the rat is considered UNACCEPTABLE and
does not satisfy the OPPTS guideline requirement (870.3465) for a
subchronic inhalation study in the rat for the following reasons, due to
several major deficiences regarding methodology and measurements.  This
review is a joint effort of the PMRA and the EPA. 

A.3.2	Prenatal Developmental Toxicity

	870.3700a Prenatal Developmental Toxicity Study - Rat

		Prothioconazole

	

				In a developmental toxicity study (MRID 46246316), prothioconazole
(99.5 to 99.8% a.i.) was administered to 26 female Hsd Cpb:WU SPF-bred
Wistar rats/dose by oral gavage at dose levels of 0, 80, 500, or 1000
mg/kg bw/day from days 6 through 19 of gestation.

An increase in urination and water consumption was observed in the mid
and high dose dams.  This observation was likely due to kidney function
impairment, although no correlating kidney findings were noted.  The
kidneys were not subject to histopathological examination, and
therefore, kidney damage may not have been found.  There were adverse
effects on body weight gain (corrected and uncorrected) in the mid and
high dose dams.  Dams in the high dose group lost body weight during
gestation days 6 to 8, and food consumption was decreased from days 6 to
11.  Body weight gain reductions of as much as 82% were observed in the
mid and high dose group during treatment.  Hepatotoxicity was evident as
levels of the liver enzymes alanine aminotransferase and alkaline
phosphatase were increased (17 and 33% respectively) while triglyceride
levels were decreased (13%) in the high dose animals.  Liver weights
were also slightly increased (absolute: 5%; relative 6%) in the high
dose group, with accompanying observations of focal necrosis observed in
one animal each of the low and mid dose groups, and two animals in the
high dose group.  There were no gross pathological findings of note in
any dose group.  Fetal weights were decreased slightly in the high dose
group, which is likely a secondary effect of the decreased body weight
gain in this dose group.  An increased incidence of engorged placenta
was observed in the mid and high dose groups, however, there was no
significant effect on the number of live fetuses.  This finding was
considered treatment-related, but not adverse.

The maternal LOAEL is 500 mg/kg bw/day, based on increased urination and
water consumption, and decreased body weight gain.  The maternal NOAEL
is 80 mg/kg bw/day.

The malformation microphthalmia was observed at an increased incidence
in the high dose group.  This finding was accompanied by an increased
incidence of eye rudiment flat in the treated animals, a finding that is
usually the first indication of a malformed eye.  Dilation of the renal
pelvis was observed at an increased incidence in the high dose litters. 
Although the incidence was within the range of historical control, the
finding was thought to be related to the decreased fetal weights and
delayed ossification observed in the skeletal evaluations.  Numerous
incidences of incomplete or no ossification were observed in digits,
toes, sternebrae, and the pubic bone in the mid and/or high dose group
fetuses.  These were considered indications of delayed development in
the mid and high dose fetuses.  Dysplastic pubic bone (malformation) was
observed in one fetus in each of the mid and high dose groups.  The mid
and high dose group litters showed an increased incidence of left
punctiform 14th rib, while the high dose group showed an increase in the
incidence of bilateral punctiform 14th rib.  There were no findings in
the cartilage of the treated fetuses.

The developmental LOAEL is 500 mg/kg bw/day, based on increased
incidence of delayed ossification, increased incidence of dysplastic
pubic bone, and increased incidence of left punctiform 14th rib.  The
developmental NOAEL is 80 mg/kg bw/day.

On the basis of the maternal and developmental NOAELs, there does not
appear to be an increased susceptibility of the fetus to in utero
exposure to JAU 6476 (99.5 to 99.8% a.i.).

The developmental toxicity study in the rat is classified acceptable and
satisfies the guideline requirement for a developmental toxicity study
(OPPTS 870.3700; OECD 414) in rats.  This review is a joint effort of
the PMRA and the EPA.

________

				In a developmental toxicity study (MRID 46246323), JAU 6476 was
administered dermally in one of three forms to groups of 29-30 mated
female Wistar rats on gestation 6 through 19.  The test material was
administered as technical prothioconazole (98.1-98.8% a.i.) at a dose
level of 1000 mg ai/kg bw/d (limit dose), as EC 250 formulation (25%
a.i.) at a dose level of 250 mg ai/kg bw/d, or as a diluted EC 250
formulation (1:3) at a dose level 62.5 mg ai/kg bw/d.  The test material
was applied for 6 hours/day, on non-occlusive dressings to an area of
clipped skin equivalent to 10% body surface area.

There were no treatment-related effects on clinical signs, body weight,
body weight gain, or food consumption.  There were no treatment-related
effects noted at necropsy and there was not a treatment-related
difference in gravid uterine weight compared with concurrent controls. 

Post-implantation loss was increased at 1000 mg/kg compared with the
controls, but the mean/animal was only slightly increased in
consideration of the standard deviation.  As a result of there only
being one dose for the technical (limit-dose), there is no dose-response
to be observed and it is difficult to make any conclusions whether the
increase in post-implantation loss at the limit-dose is
treatment-related.  The EC250 and 1:3 dilution formulations had the same
total postimplantation loss percent, but the EC250 formulation had a
higher mean/animal value.  There was no valid historical control data
provided for this study.

There were no treatment-related external, visceral or skeletal
malformations or variations.  Most treatment groups, including
concurrent controls, were above the historical control range for the
following skeletal variations: nasal incompletely ossified, frontal
suture enlarged, coronal suture enlarged and rudimentary ribs.  The
overall incidence of skeletal variations was lower in the treatment
group compared with the concurrent controls. 

The maternal NOAEL is 1000 mg a.i./kg with a LOAEL of > 1000 mg a.i./kg.

The developmental NOAEL is 1000 mg a.i./kg with a LOAEL of > 1000 mg
a.i./kg.

The dermal developmental toxicity study in the rat is classified as an
acceptable (supplementary study); and satisfies the guideline
requirement for a limit-dose dermal developmental toxicity study (OPPTS
870.3700; OECD 414) in the rat.  This review is a joint effort of the
PMRA and the EPA.

________

In a developmental toxicity study (MRID 46923601) JAU 6476 (97.8- 98.7%
purity) was administered to 25 female Wistar Hanover (Crl:WI(HAN))
rats/dose by oral gavage on Days 6-19 of gestation at nominal
concentrations of 0 (0.55 CMC and deionized water vehicle), 20, 80, or
750 mg/kg bw/day, at a dosing volume of 10 mL/kg.

There were no treatment-related effects on clinical parameters or
mortality in dams.  Body weight gains were decreased during treatment
and overall (day 0-20) at the 750 mg/kg dose level.  Food consumption
was decreased and water consumption was increased in the high dose
animals.  Urea nitrogen, alkaline phosphatase and cholesterol were
increased.

The maternal NOAEL is 80 mg/kg bw/day, based on decreased body weight
gains and food consumption and increased water consumption at 750 mg/kg
bw/day.

There were no treatment-related effects on developmental parameters. 
There was an increased incidence of rudimentary ribs at 750 mg/kg
bw/day. 

The developmental NOAEL is 80 mg/kg bw/day, based on increased
rudimentary ribs noted at 750 mg/kg bw/day.

The developmental toxicity study in the rat is classified acceptable
nonguideline.  While it does not statisfy the guideline requirement
(OPPTS 870.3700; OECD 414) for a developmental toxicity study, the data
are deemed valid and useful for toxicity assessment in the rat. This
study focused on eye and rib effects and did not perform visceral
examination on the fetuses.  This review is a joint effort of the PMRA
and the EPA.

________

		Prothioconazole-desthio

				In a developmental toxicity study (MRID 46246319) SXX 0665 (Purity:
93.9%) was administered to 30 female Wistar rats/dose, by gavage (0.5%
Cremophor EL in bidistilled water), at dose levels of 0 or 30 mg/kg
bw/day from days 6 through 15 of gestation (dose volume of 10 mL/kg
bw/day).  Both control and treatment groups were subdivided into two
groups of 15, half for cesarian section and half for rearing. Nine
additional dams were introduced to the treatment group due to the death
of one animal in the cesarian section subgroup and the high pup
mortality in the rearing subgroup.  This study was performed as a
follow-up to MRIDs 46246320 and 46246321.

There were no treatment-related adverse effects on mortality, clinical
signs, body weight, or food consumption in dams.  Pregnancy rates,
fertility and gestation indices were comparable among control and
treated groups.  A reduced rearing index was noted at 30 mg/kg bw/day
(76.2%) compared to control (92.9%) due to total litter loss of 5
litters from the rearing group dams within 6 days of birth.  No
treatment-related effects were noted on mean number of corpora lutea and
implantations, resorptions, litter size, fetal weight or sex ratio in
dams undergoing cesarian section.  Increased placental weights were
noted at 30 mg/kg bw/day, which correlates with the gross pathological
finding of engorged placentas in 2 dams in the cesarian section group. 

	Pup death was significantly increased, therefore the mean pup survival
was decreased, in the 30 mg/kg bw/day rearing group due to complete
litter loss in 5 litters (4 litters within 3 days of birth and 1 litter
within 6 days of birth).  An increased incidence of emaciated pups (9
pups vs. 2 in control) and pups with depressed body temperature (4 pups
vs. 0 in control) were observed at 30 mg/kg bw/day in the rearing group.
 No treatment-related effects on body weight were observed in the
surviving pups.

  

	All of the fetuses (100%) in the cesarian section group exhibited
skeletal dysplasias of the radius and ulna at 30 mg/kg bw/day.  In
addition, 5 fetuses (in 3 litters) exhibited humeral dysplasia and 10
fetuses (in 3 litters) exhibited cleft palate. Increased incidence of
delayed ossification was noted in the fetuses at 30 mg/kg bw/day,
specifically affecting the sternum, ribs and hyoid bone.  Supernumerary
(14th) ribs were observed in all treated fetuses (100% fetuses in 100%
litters) compared to concurrent (15.3% fetuses in 57.1% litters) and
historical controls (10-12% fetuses).  The increased supernumerary ribs
consisted mainly of “rudimentary or punctiform/comma-shaped” 14th
ribs, as opposed to fewer “extra or complete/slightly shortened”
ribs.  The incidence of both rudimentary 15th (3% fetuses in 14.3%
litters) and 16th (1.5% fetuses in 14.3% litters) ribs was increased,
with no 15th or 16th ribs observed in the concurrent control group. 

	In the rearing group, the incidence of supernumerary 14th ribs was
increased (31.9% pups in 75.0% litters) in 42-44 day old pups, in both
“rudimentary or punctiform/comma-shaped” and “extra or
complete/slightly shortened” ribs.  The incidence of rudimentary ribs
in the reared pups was 13.4% fetuses in 75.0% litters which is increased
compared to control, but significantly decreased compared to the
incidence in 20 day fetuses (84.2% fetuses in 57.1% litters).  The
incidence of extra/complete ribs in the reared pups (18.5% fetuses in
56.3% litters) was similar to the incidence observed in the 20 day
fetuses.  The incidence of 14th ribs in the concurrent control rearing
group (3.7% fetuses in 15.4% litters) was markedly reduced compared to
the concurrent control cesarian section group. No incidences of 15th or
16th ribs were noted in 42-44 day old pups.

	The persistence of the supernumerary 14th ribs classified as
“extra” or “complete/slightly shortened” in the 42-44 day old
pups indicates that the treatment-induced supernumerary rib development
does not show complete postnatal reversibility.  The persistence of
supernumerary 14th ribs appears to be influenced by the length of the
rib (punctiform vs. complete/slightly shortened) rather than the
location (14th, 15th or 16th) of the rib. 

This non-guideline developmental toxicity study in the rat is acceptable
as a supplementary study only, therefore no endpoints were determined. 
This review is a joint effort of the PMRA and the EPA.

________

				In a developmental toxicity study (MRID 46246321), SXX 0665
Technical (Purity: 97.4%) was administered to 35 female Wistar rats/dose
by gavage (at 10 mL/kg bw/day in bidistilled water with 0.5% Cremophor
EL) at dose levels of 0, 10, 30, or 100 mg/kg bw/day from days 6 through
15 of gestation.  A subgroup of 10/dose were used for assessment of
liver toxicity and sacrificed on day 16.

In the main group dams, no mortalities or treatment-related clinical
signs were observed during the study.  Body weight gain decreased in the
high dose group during treatment and post-treatment.  Body weight gain
corrected for gravid uterine weight did not show significant differences
between control and treated groups.  Food consumption was decreased at
100 mg/kg bw/day.  No abnormal findings were noted during gross
pathological examination.  No significant treatment-related differences
in pregnancy incidence, mean number of corpora lutea, mean number of
implantations, mean fetal weight, sex ratio and pre-implantation loss.

In the subgroup dams, body weight decreases were all less than 10%, and
were not considered to be an adverse treatment-related effect.  However,
body weight gain was significantly decreased in the mid and high-dose
groups during treatment (GD days 6-11), with no accompanying
treatment-related effect on food consumption.  No significant
treatment-related effect on plasma ALAT or ASAT activity were noted. 
Increased absolute and relative liver weights were noted at the high
dose.  Pathological changes in the liver were observed in the high dose
group including increased severity of inflammatory foci, centrilobular
hypertrophy and fatty change.

The NOAEL for maternal toxicity is 30 mg/kg bw/day based on decreased
body weight gain, increased liver weight and liver histopathology
(increased severity of inflammatory foci, centrilobular hypertrophy and
fatty change) at the LOAEL of 100 mg/kg bw/day. 

Significant treatment-related increases in post-implantation loss and
resorptions were noted in the high dose main group dams.  There were no
significant treatment-related effects on fetal weight.  Post-
implantation loss in subgroup dams was also increased at the high dose. 
The mean number of live fetuses was slightly reduced in the high dose
subgroup dams as well.

A definitive increase in skeletal variations was noted in the high dose
group fetuses (incompletely and non-ossified crania, vertebrae, stern
brae, and forelimb/hindlimb digits), with some variations also noted at
the low and mid-doses.  The incidence of supernumerary ribs was
significantly increased in all dose groups and exceeded the incidence in
concurrent and historical control data.  An increased incidence of cleft
palate (2 fetuses in 2 litters) was noted at the high dose, compared to
concurrent (0) and historical control incidences (0-1 fetuses in 1
litter).  Visceral examination confirmed the presence of cleft palate
(palatoschisis) in one high-dose animal.  No other visceral
malformations were noted. 

A NOAEL for developmental toxicity cannot be established in this study
due to the increased incidence of supernumerary ribs at all dose levels.
 Incomplete/delayed ossifications were also noted at all dose levels in
the absence of any effects on fetal weight gain.  Increased resorptions,
decreased number of live fetuses and an increased incidence of cleft
palate were observed at the highest dose tested, 100 mg/kg bw/day.  This
compound is teratogenic at maternally toxic doses.

Two further supplementary studies were conducted to establish a
developmental NOAEL for supernumerary ribs and to determine the
post-natal effect of this skeletal variant.

An increased sensitivity of the fetuses to treatment with SXX 0665 is
apparent, evidenced by the increased incidence of supernumerary ribs and
incomplete/delayed ossifications at doses of 10 mg/kg bw/day and up, in
the absence of maternal toxicity. 

The developmental toxicity study in the rat is classified acceptable and
satisfies the guideline requirement for a developmental toxicity study
(OPPTS 870.3700; OECD 414) in rats.  This review is a joint effort of
the PMRA and the EPA.

________

				In a developmental toxicity study (MRID 46246322) SXX 0665 Technical
(Purity 94.7%) was administered to 25 female Wistar rats/dose once daily
by gavage (in a volume of 10 mL/kg bw/day) at doses 0, 1 or 3 mg/kg
bw/day from days 6 through 15 of gestation. 

No mortalities, clinical signs, gross pathology or effects on body
weight/body weight gain or food consumption were observed in dams up to
3 mg/kg bw/day.  There were no treatment-related effects on pregnancies,
number of corpora lutea, number of implantations, number and size of
litters, sex ratio of the pups and mean pup weight.  Post-implantation
loss was decreased at 3 mg/kg bw/day which correlated with an increase
in the number of live fetuses at this dose.  These effects were not
considered adverse. 

The NOAEL of 30 mg/kg bw/day for maternal toxicity, as determined in the
main study (MRID 46246321), was not affected by this supplementary
study. 

There were no adverse treatment-related effects on pup survival or pup
weight. No external or visceral malformations were observed.  An
increased incidence of supernumerary ribs was noted at the highest dose
(3 mg/kg bw/day) compared to concurrent control values, however the
incidences were within the historical control data ranges and were
similar to the control group incidences in the main rat developmental
study.  The increase in supernumerary ribs noted at 3 mg/kg bw/day is
therefore considered incidental, and not an adverse effect in the
absence of maternal toxicity. 

The NOAEL for developmental effects was determined to be 3 mg/kg bw/day
based on the absence of any adverse effects on reproductive or
developmental parameters in this supplementary study.  The developmental
LOAEL of 10 mg/kg bw/day is based on the increased incidence of
supernumerary ribs and incomplete/delayed ossifications at doses of 10
mg/kg bw/day and up, in the main study. 

An increased sensitivity of the fetuses to treatment with SXX 0665 is
apparent, evidenced by the increased incidence of supernumerary ribs and
incomplete/delayed ossifications at the LOAEL of 10 mg/kg bw/day, in the
absence of maternal toxicity.

The developmental toxicity study in the rat is classified as
supplementary, as it is non-guideline but satisfies GLP requirements. 
This review is a joint effort of the PMRA and the EPA.

________

				In a developmental toxicity study (MRID 46246325, 46246326) SXX 0665
technical (93.7% a.i.) was administered by topical application as a
suspension in 1% aqueous Cremophor EL to four groups of 25 mated female
Wistar rats (Bor/WISW [SPF Cpb]) at dose levels of 0, 10, 30, 100, 300
or 1000 mg/kg bw/day from day 6 to 15 post coitum.  The applications
were made for 6 hours/day, under occlusive dressings, to a 5 x 5 cm area
of clipped dorsal area.

There were no deaths during the treatment at any dose level.  There was
an increased incidence of slight redness around the treatment area at
≥300 mg/kg, which persisted up to 4 days.  There was also very slight
swelling in one animal at 1000 mg/kg for one day.  There were no
treatment-related clinical findings.  There were no treatment-related
effects on body weight, body weight gain or food intake.  There were no
treatment-related findings at necropsy or in liver weight.  The maternal
NOAEL was 1000 mg/kg.  The maternal LOAEL was >1000 mg/kg, based on lack
of adverse systemic effects in dams at doses tested.

There were no treatment-related differences in pregnancy rate, number of
corpora lutea, implantations, live fetuses, pre- or post- implantation
loss, fetal weight, sex ratio, the total number of resorptions, late
resorptions, and mean fetal weights. 

≥300 mg/kg relative to concurrent controls.  The developmental NOAEL
was 30 mg/kg.  The developmental LOAEL was 100 mg/kg, based on an
increased incidence of supernumerary rib (14th rib) at this dose.  There
was a quantitative increase in pup sensitivity, with malformations
occurring at non-maternally toxic doses.  

A supplemental study (T 7037368) was performed in order to investigate
the observation of supernumerary ribs at the low dose in the main study.
 The maternal and developmental NOAELs were 30 mg/kg, based on no
treatment-related effects in pups or dams in this study.

The developmental toxicity study in the rat is classified acceptable and
satisfies the guideline requirement for a developmental toxicity study
(OPPTS 870.3700; OECD 414) in rat.  This review is a joint effort of the
PMRA and the EPA.

		Prothioconazole-Deschloro

		In a pilot developmental toxicity study (MRID 46246317), JAU 6476-
deschloro (96.9% a.i.) was administered to 8 female Wistar rats/dose, in
0.5% aqueous carboxymethylcellulose, by gavage at dose levels of 0, 40,
200 or 1000 mg/kg bw/day from days 6 through 19 of gestation. 

There were no treatment-related effects on mortality.  Clinical
observations at 1000 mg/kg included: increased urination (5/8), and
increased water consumption (8/8) but varied in the time of onset and
persistence.  There was a decrease in body weight gain at ≥200 mg/kg
for several time intervals.  There were no treatment-related
observations at gross necropsy.

There were no treatment-related effects on pregnancy rate, number of
corpora lutea, implantations, live or dead fetuses, resorptions,
placental weight, pre-implantation loss, post-implantation loss, fetal
weight or sex ratio.  There was a decrease in the total number of live
fetuses at 200 mg/kg (not at 1000 mg/kg), so it is difficult to
interpret a dose-response (or lack of) at this dose.  At 1000 mg/kg,
white spots were observed on two placentas (fetus # 282 and 283) from
the same dam (dam # 927).  The toxicological significance of this
finding is unknown since fetus 282 also had multiple malformations. 

There were no treatment-related external deviations observed.  There was
an increased incidence of visceral deviations at 1000 mg/kg relative to
concurrent and historical control data which included slight dilation of
renal pelvis and dilation of ureter.  Skeletal deviations included
retarded ossification of skull bones and wavy ribs at 1000 mg/kg.  There
was an increase in 14th rib and vertebral bodies at 1000 mg/kg relative
to concurrent controls at 1000 mg/kg. 

There was an increased incidence of macroglossia at 1000 mg/kg compared
to concurrent controls.  One fetus (#282) with macroglosia was slightly
edematous along with other malformations (skeletal) and had a placenta
with white spots.  There were no treatment-related visceral
malformations observed.  There was an increased incidence of
malformations in the scapula, humerus, sternebra and clavicle at 1000
mg/kg relative to concurrent control values.  The findings were observed
in one to two fetuses, similar to the number of fetuses with dysplasia
of forelimb bones, cleft sternebra, dysplasia of scapula in the relevant
historical control studies, so it is not considered adverse. 

The developmental toxicity study in the rat is classified supplemental
because it is a pilot study and does not satisfy the guideline
requirement for a developmental toxicity study (OPPTS 870.3700; OECD
414) in the rat (non-GLP).  No endpoints were established for this study
since it is a pilot study and there were too few animals in each dose
group.  This review is a joint effort of the PMRA and the EPA.

		Prothioconazole-Sulfonic Acid K Salt

		In a developmental toxicity study (MRID 46246324) Sulfonic Acid K.
Salt (98.9% a.i.) was administered to 25 mated female rats (Rat WIST
Hanlbm: WIST (SPF Quality))/dose by gavage via bi-distilled water
vehicle, at dose levels of 0, 30, 150 or 750 mg/kg bw/day from days 6
through 20 of gestation. 

The test-article caused severe toxicity at the highest dose tested,
including mortality and clinical signs related to treatment.  Six dams
were found dead between day 9 and 12 post coitum and the clinical signs
observed included ruffled fur observed alone, or in tandem with
irregular breathing or breathing noise.

Effects on the high dose group were comprised of decreased body weight
and body weight gain.  An increase was reported in the incidence of
non-pregnant dams in the mid-dose group (150 mg/kg), however the results
of test article administration on reproductive parameters in this group
show that reproductive fitness is not affected.  Indices such as mean
corpora lutea, live fetuses and implantation sites were greater than
those in the control and low dose group, suggesting that the increase in
non- pregnant dams may be incidental in this dose group.  

A finding that was outside the previously recorded historical control
range and the concurrent control range was the incidence of rudimentary
supernumerary one ribs, on both the right and left sides.  The incidence
was statistically significantly increased on both a litter and fetal
basis.  Since supernumerary ribs were seen in several studies, in the
absence of maternal toxicity, and were shown to be non- completely
reversible after the first few weeks of life, they were considered an
adverse effect of treatment.

The maternal LOAEL is 750 mg/kg bw/day, based on mortality and clinical
signs.  The maternal NOAEL is 150 mg/kg bw/day.

The developmental LOAEL is 30 mg/kg bw/day, based on the increased
incidence of rudimentary supernumerary one ribs.  The developmental
NOAEL is <30 mg/kg bw/day.

The developmental toxicity study in the rat is classified acceptable and
satisfies the guideline requirement for a developmental toxicity study
(OPPTS 870.3700; OECD 414; DACO No. 4.5.2) in rats.  This review is a
joint effort of the PMRA and the EPA.

	870.3700b Prenatal Developmental Toxicity Study - Rabbit

		Prothioconazole

	

								In a developmental toxicity study (MRID 46246328) JAU 6476
(94%), in aqueous 0.5% carboxymethylcellulose sodium salt (CMC), was
administered to groups of 24 mated female Chinchilla rabbits by oral
gavage at 0, 10, 30, or 80 mg/kg bw/d from post coitum (pc) day 6 to 27.
 The animals were sacrificed on pc day 28.  The number of pregnant
females at 10 and 80 mg/kg bw/d groups was not sufficient.  Therefore, 6
and 7 mated females were added to these groups, respectively.  Further,
because no clear effects of toxicity were noted up to and including 80
mg/kg bw/d, an additional dose group of 24 mated females was tested at
350 mg/kg bw/d.  One high-dose dam was found dead on pc day 25. 
Compared to the vehicle control group, high-dose animals had higher
number of total resorptions or abortions, lower food consumption and
body weight gain, and marginally lower placenta weights.  No
treatment-related signs were noted in the other dose groups and no
abnormal changes were noted during necropsy.  Comparison of the liver
and adrenal weights gave no indication of treatment- related effects. 
There was an increase in post-implantation loss and a corresponding
decrease in the total number of fetuses in high-dose dams.  The findings
included 3 dams with total resorptions and 3 dams which aborted during
the last treatment week.  There was a decrease of fetal body weights at
350 mg/kg bw/d, likely secondary to maternal body weight effects.  None
of the other fetal examinations - external and visceral examination,
examination of fetal hearts and major blood vessels, of the heads and
brains, and sex ratios - gave indications of treatment-related changes. 
Based on these results the LOAEL (lowest observed adverse effect level)
and NOAEL (no observed adverse effect level) for the maternal toxicity
were considered to be 350 and 80 mg/kg bw/d, respectively.  Treatment
with JAU 6476 caused abortions and total resorptions and lower fetal
body weight at 350 mg/kg bw/d. Therefore the LOAEL and NOAEL for
developmental toxicity were considered to be 350 and 80 mg/kg bw/d,
respectively.  There was no evidence of teratogenic potential of JAU
6476.

The developmental toxicity study in the rabbit is acceptable and
satisfies the guideline requirement for a developmental toxicity study
(OPPTS 870.3700; OECD 414) in rabbits.  This review is a joint effort of
the PMRA and the EPA.

		Prothioconazole-desthio

								In a developmental toxicity study (MRID 46246327) SXX 0665 (94%)
was administered to groups of 15 female Himalayan rabbits by oral gavage
(deionized water containing 0.5% Cremorphor EL (BASF)) at 0, 2, 10, or
50 mg/kg bw/d from post coitum (pc) day 6 to 18. The animals were
sacrificed on pc day 29. 

There were no effects on clinical signs, water intake, or mortality.
Food intake was marginally lowered in high-dose dams. Body weight gain
of high-dose animals was adversely affected during gestation, presumably
as a result of elevated resorption rate. At terminal sacrifice, there
was no significant gross pathological observation. Treatment-related
histopathological findings were evident in the liver of mid- and
high-dose dams. The liver findings included increased destruction of
individual hepatocytes and low glycogen mobilization.  The LOAEL  for
maternal toxicity was 10 mg/kg bw/day, decreased body wt gain, decrease
food consumption, increased resorptions, decreased number of fetuses,
liver histopathology; the NOAEL was 2 mg/kg bw/day.

Examination of fetal parameters revealed no treatment-related findings
on fetal weight and sex, or on skeletal system development. The
placentas were normal. Due to an elevated resorption rate, the gestation
rate and the number of fetuses were lower at 50 mg/kg bw/d group.
Malformations were observed at 10 and 50 mg/kg bw/d groups. At 10 mg/kg
bw/d, alterations included malformed vertebral body and ribs,
arthrogryposis, and multiple malformations. These malformations could
arise spontaneously in Himalayan rabbits. At 50 mg/kg bw/d, malformed
alterations included cleft plates.  The LOAEL  for developmental
toxicity was 10 mg/kg bw/day based on structural alterations including
malformed vertebral body and ribs, arthrogryposis, and other multiple
malformations; the NOAEL was 2 mg/kg bw/day.

The developmental toxicity study in the rabbit is acceptable and
satisfies the guideline requirement for a developmental toxicity study
(OPPTS 870.3700; OECD 414) in rabbits.  This review is a joint effort of
the PMRA and the EPA.

A.3.3	Reproductive Toxicity

	870.3800 Reproduction and Fertility Effects - Rat

		Prothioconazole

	

				In a 2-generation reproduction study (MRID 46246334) prothioconazole
(98.1-98.8%) was administered by gavage to 30 Wistar rats/sex/dose in
aqueous 0.5% methylcellulose and 0.4% Tween 80 suspension at dose levels
of 0, 10, 100 or 750 mg/kg bw/day at a dosing volume of 10 mL/kg.

There were no treatment-related mortalities or clinical findings
throughout the study in any generation in either adults or pups.  There
was a decrease in body weight and body weight gain (14-21%) and increase
in food consumption (5-19%) in the P generation males during premating
at 750 mg/kg bw/day, thereby indicating a decrease in food efficiency.
At 750 mg/kg bw/day, body weight in F1 males was consistently 14–17%
lower when compared to the control group.  This is consistent with the
findings for the F1 male pups between days 7 and 21, thereby indicating
that the F1 males were consistently 14–17% smaller than the control
group from day 21 to sacrifice.

The following changes in reproductive parameters were noted.  At the 750
mg/kg bw/day dose level, a treatment-related decline in the number of
estrous cycles occurred in both the P and F1 generations.  Also, a
significant increase in the length of the estrous cycle was observed in
the P generation.  There were no treatment-related effects on any sperm
parameters in either generation at any dose.  There were no
treatment-related effects on mating, fertility, implantations or
gestation indices (i.e., animals mating, becoming pregnant and
maintaining a pregnancy through to parturition) in either generation at
any dose.  At 750 mg/kg bw/day, non statistical but slight increases in
time to insemination were observed in both generations.  In the ovaries,
the number of pre-antral follicles was decreased in the P generation,
but increased in F1 at the 750 mg/kg bw/day dose level.  The
significance of these findings is considered equivocal. No other
significant findings were observed in either generation during a
quantitative evaluation of the ovaries.  

There were no treatment-related effects on live birth, viability,
lactation, birth indices, mean litter size or sex ratio in pups at any
dose in either generation.  The number of days to vaginal opening was
unaffected in the F1 generation.  Preputial separation was increased at
the high dose in the F1 generation, when compared to historical
controls, but was likely due to delayed growth during lactation.  In the
F2 generation, the anogenital distance at birth was increased compared
to control in both sexes (at 100 and 750 mg/kg bw/day for males and at
750 mg/kg bw/day for females), however, this was within historical
control range in males.  The increase in anogenital distance in females
is likely due to the lengthened duration of gestation and the higher
birth weights of the pups.  Pup body weight was decreased in the high
dose between day 4 and 7 in the F1 generation and remained decreased
throughout lactation.  Both sexes showed a decrease in body weight day 4
through 21 in the F1 generation.  In the F2 generation, litter body
weight decreased day 14 through 21.  In males the decrease was seen days
14 through 21 and in females the decrease was seen day 14.

There were no notable gross pathology findings in adults or pups of
either generation. 

Absolute liver weight was increased in both sexes in the P generation
and relative liver weight was increased in both sexes in the F1
generation at 750 mg/kg bw/day.  Hepatocytomegaly was observed during
histopathology in the males of both generations and in F1 females at
this dose.  Relative kidney weight was increased in males in both
generations at 750 mg/kg bw/day.  Histopathology revealed multifocal
cortical nephrosis in both generations of males at 750 mg/kg bw/day. 
The relative weight of the seminal vesicles was decreased at 100 and 750
mg/kg bw/day in the P generation and at 750 mg/kg bw/day in the F1
generation.  While there were no histopathological findings to support
these findings, in the F1 generation, decreases in testicular, prostate,
epicauda and epididymis weight were also noted, indicating a clear
pattern of sexual organ weight decrease, however, these findings are
likely secondary to decreased body weight.  In the P and F1 generations,
the relative weight of the thymus was decreased in males at 750 mg/kg
bw/day while the absolute and relative weights of this organ were both
decreased in the P generation females at the 100 and 750 mg/kg bw/day
dose levels.  No histopathological findings were observed in this organ.
 Decreases in absolute spleen weight were observed in both generations
of male pups at the high dose while decreases in absolute and relative
spleen weight were observed in female pups in both generations.  There
were no histopathological findings in the pups of either generation.

The parental LOAEL is 750 mg/kg bw/day, based on decreased body weights,
body weight gains and increased food consumption, increased liver
weights and kidney weights, decreased thymus, testicular, prostate,
epicauda and epididymis weights as well as histopathological findings in
the liver and kidney.  The NOAEL is 100 mg/kg bw/day.

The LOAEL for reproductive effects is 750 mg/kg bw/day based on
decreased number of estrous cycles in both generations and increased
duration of estrous cycle in the P generation.  The NOAEL is 100 mg/kg
bw/day.

The LOAEL for offspring effect is 750 mg/kg bw/day based on decreased
body weight and reduced spleen weight.  The NOAEL is 100mg/kg bw/day.

This study is acceptable and satisfies the guideline requirement for a
2-generation reproductive study (OPPTS 870.3800); OECD 416 in rat.  This
review is a joint effort of the PMRA and the EPA.

		Prothioconazole-desthio

				In a 2-generation reproduction study (MRID 46246333), SXX 0665 was
administered to 30 Sprague- Dawley rats/sex/dose in the diet (1% corn
oil) at dose levels of 0, 40, 160, and 640 ppm. 

Parental animals: In the P parental animals, one control female and one
high-dose female died due to dystocia; three high-dose females were
killed prematurely  due to signs of dystocia; one high-dose female was
killed prematurely due to complete litter loss on lactation day 1. In
the F1 parental animals, three high-dose females died due to dystocia,
one mid-dose female and one high-dose female were killed prematurely due
to complete litter loss on lactation day 2. The increased incidence of
dystocia was considered to be treatment-related. There were no
treatment-related clinical signs in either generation.

No significant treatment-related adverse effects on parental body weight
or body weight gain were noted during pre-mating or gestation for either
generation. During lactation, high-dose P females showed increased body
weight gain accompanied by decreased food consumption (both P and F1
females), which could be associated with decreased litter size and pup
weight in the high dose groups. 

There were no treatment-related effects on estrous cycles, mating,
gestation and birth indices, or implantation sites or number of litters.

Relative liver weight was increased in high dose P and F1 adult males
and high dose F1 adult females, while absolute liver weight was
increased in high dose P males only.  Absolute and relative ovary
weights were statistically increased in 640 ppm F1 adult females. 
Absolute ovary weights also were statistically increased in 160 ppm F1
adult females.  Histopathological observations in the liver consisted of
increased incidence and/or severity of multifocal hepatocellular
cytoplasmic vacuolization in both mid and high dose P and F1 males, and
in high dose P and F1 females.  These observations are consistent with
fatty change in the liver which could account for the observed increases
in liver weights.  Increased liver necrosis was additionally observed in
high dose P and F1 females.  The increased incidences of dystocia in
high dose females may be related to these histopathological changes. 
The mean number of antral follicles in the ovaries was increased in high
dose females, and statistically significant in the F1 high dose females.
 There were no significant differences in the number of preantral
follicles or corpora lutea.  The toxicological significance of this
increase is unknown; however there was a significant increase in ovary
weight in the F1 females only.  No histopathological changes were noted
in male reproductive organs. 

Offspring: Increased incidence of cannibalized and/or missing pups was
noted in the high dose for both the F1 and F2 pups.  The number of dams
with cannibalized pups was also significantly increased at the high dose
in both generations.  Additionally in the F2 pups, increased incidences
of weak and unthrifty pups were noted. Litter size was significantly
decreased at the high dose in F1 generation, however it was still well
within the range of historical control data provided for this strain of
rat, and is not considered an adverse treatment-related effect.
Viability index on day 4 was significantly reduced at the high dose in
both generations. 

There was a significant decrease in pup body weight at the high dose
from lactation days 7-21 in the F1 litters; reduced pup body weight was
also noted in the F2 litters on lactation days 14 and 21.  These
decreases were considered to be treatment-related.  An increased
incidence of the following observations was noted in F1 pups culled on
day 4 and those who died during days 0-3: enlarged liver, cleft palate,
red kidney zones, dilated renal pelvis, dilated ureters, and distended
bladder.  Dilated renal pelvis was the only observation in the F2 pups. 
No gross lesions were noted in the 21 day weanlings. 

The LOAEL for parental effects is 640 ppm (equivalent to 40-46 or 41-73
mg/kg bw/day [M/F]) based on increased liver weight, liver
histopathology and decreased food consumption during lactation (females
only).  The NOAEL is 160 ppm (equivalent to 9.5-11 or 10-19 mg/kg bw/day
[M/F]). 

The LOAEL for reproductive effects is 640 ppm (equivalent to 40-46 or
41-73 mg/kg bw/day [M/F]) based on increased incidence of dystocia,
decreased viability and decreased pup body weight.  The NOAEL is 160 ppm
(equivalent to 9.5-11 or 10-19 mg/kg bw/day [M/F]).

The LOAEL for offspring effects is 640 ppm (equivalent to 40-46 or 41-73
mg/kg bw/day [M/F]) based on decreased pup body weight and increased
incidence of cleft palate, dilated renal pelvis, dilated ureters and
dilated bladder.  The NOAEL is 160 ppm (equivalent to 9.5-11 or 10-19
mg/kg bw/day [M/F]).

On the basis of the parental and offspring NOAELs/LOAELs, there was no
indication that the neonates were quantitatively more sensitive than the
adults following treatment.

This study is acceptable and satisfies the guideline requirement for a
2-generation reproductive study (OPPTS 870.3800); OECD 416 in rats. 
This review is a joint effort of the PMRA and the EPA.

A.3.4	Chronic Toxicity

	870.4100a (870.4300) Chronic Toxicity – Rat

		Prothioconazole

	

				In a chronic toxicity study (MRID 46246335) JAU 6476 (98.8-99.4%
a.i.) was administered to 20 Wistar rats/sex/dose in an aqueous solution
of 0.5% Tylose by gavage at dose levels of 0, 5, 50 or 750 mg/kg bw/day
for 53 weeks.  A Functional Observational Battery as well as grip
strength determinations were conducted in weeks 27 and 52 with 10
rats/sex/dose.

 

An increase in the number of animals with salivation and increased urine
excretion was observed in animals of both sexes in the high dose group. 
Statistically significant decreases in body weight and body weight gain
were also observed in high dose animals of both sexes.  The magnitude of
this decreased body weight gain became more pronounced as the study
progressed, and resulted in an overall body weight gain that was 79% and
77% of controls in males and females, respectively.  The results of the
FOB did not indicate any potential for neurotoxicity.

Decreased hemoglobin levels and increased thrombocyte and leukocyte
counts were noted in animals from the highest dose level.  Alterations
in clinical chemistry and urinalysis parameters indicative of liver and
kidney damage were also observed in these animals.  Effects indicative
of liver damage included increased serum alkaline phosphatase,
bilirubin, cholesterol and triglyceride concentrations and decreased
plasma, glucose and protein concentrations. Additionally, increased
liver weights and a granular appearance of the hepatocellular cytoplasm
were observed in high dose rats.  T4 was decreased in both sexes at 750
mg/kg bw/day

Effects on the urinary system at 750 mg/kg bw/day included increased
plasma urea and creatinine concentrations, decreased urine pH, and
yellow-brown spherical crystalloids in urine sediments.  Corroborating
evidence of kidney damage included increased relative kidney weights and
an increased severity of chronic progressive nephropathy and incidence
of simple urothelial hyperplasia in urinary bladder, accompanied in most
cases by a minimal focal inflammatory infiltration.

The NOAEL in this study was 50 mg/kg bw/day.  The LOAEL was 750 mg/kg
bw/day, based on decreased body weight and body weight gain, alterations
in hematology and clinical chemistry parameters indicative of liver and
kidney damage, increased liver and kidney weights, and accompanying
histopathological alterations in the liver, kidney and urinary bladder. 

This chronic study in the rat is acceptable and satisfies the guideline
requirement for a chronic oral study (OPPTS 870.4100), OECD 452 in rats.
 This review is a joint effort of the PMRA and the EPA.

		Prothioconazole-desthio

			See Carcinogenicity – Rat (MRID 46246342)

	870.4100b Chronic Toxicity - Dog

		Prothioconazole

	

						In a 1-year dog study (MRID 46246336), JAU 6476 (98.4 to 98.8%
a.i.) was administered to 4 beagle dogs/sex/dose by gavage (0.5% methyl
cellulose with 0.4% TWEEN 80 in deionized water) at dose levels of 0, 5,
40, or 125 mg/kg bw/day for five days/week for a period of one year. 
Surviving animals were sacrificed and subject to gross necropsy and
histopathological examination.

There were no mortalities, and no compound-related clinical signs of
toxicity observed.  There were no treatment-related hematological
findings, and no neurological, body temperature, or electrocardiogram
parameter effects.  No treatment-related findings were noted in the
gross pathology during necropsy.  Behavioral observations, including
increased salivation and staining, as well as sporadic vomiting, were
noted and attributed to the mode of dosing (gavage).  Overall body
weight and body weight gain were decreased by 21 and 42%, respectively,
in the high dose female animals, and food consumption was also decreased
by as much as 47% in these animals.  In addition, overall body weight
gain in the high dose male animals was reduced by 14% of the control
value.  Mid and high dose male animals showed increased alkaline
phosphatase levels, as did the all of the treated female groups. 
O-demethylase levels were also increased in the mid and high dose males,
while cytochrome P-450 levels were elevated in all of the treated female
groups.  Absolute and relative liver weights were increased in the high
dose groups of both sexes.  Changes in liver histopathology were also
observed, including liver pigmentation (pigment in kupffer cells that is
PAS and iron positive compatible with hemosiderin and scattered pigment
compatible with bile pigment) in the high doses of both sexes, and
extramedullary hematopoiesis in a high dose female.  The liver
pigmentation could be related to hematopoiesis, but was not considered
adverse in the absence of significant red blood cell findings.  Levels
of the thyroid hormones T3 and T4 were decreased in the treated males,
and levels of T4 were decreased in the treated female animals.  These
decreases may be secondary to the liver-related effects.  Alanine
aminotransferase levels were decreased in all of the treated males, with
unknown toxicological significance.  Urine volume was increased in the
high dose groups of both sexes.  Blood levels in the urine were also
increased in the high dose male animals.   The relative kidney weights
were increased in the low and high dose female animals.  In addition,
high dose males showed crystals and mineralization in the kidney, while
mid and high dose males showed chronic inflammation and pigmentation in
the kidney.  Females in the high dose group showed fibrosis and chronic
inflammation, while females in the mid and high dose groups were
observed with crystals in the kidney.  The kidney effects were
considered adverse in the mid and high dose animals of both sexes.  Both
the liver and kidneys are considered target organs of this test
material.  Urine calcium was decreased in the treated females, the
toxicological significance of which is unknown.  Treatment-related
changes in the spleen of the female animals were observed.  Absolute and
relative spleen weights were increased in all treated females, and
pigmentation in the mid and high dose females and fibrosiderotic plaques
in high dose females were observed microscopically in the spleen.  The
spleen effects were considered adverse at the mid and high doses.

The LOAEL is 40 mg/kg bw/day for both sexes, based on decreased T3 and
T4 thyroid hormones, increased urine volume, and increased incidence of
chronic inflammation and pigmentation in the kidneys of the male
animals, and decreased T4 thyroid hormone, increased spleen weight,
increased incidence of spleen pigmentation, increased urine volume, and
increased incidence of crystals present in the kidneys of the female
animals.  The NOAEL is 5 mg/kg bw/day for both sexes.

This study in dogs is acceptable and satisfies the guideline requirement
for a 1-year oral toxicity study in dogs (OPPTS 870.4100; OECD 452). 
This review is a joint effort of the PMRA and the EPA.

		Prothioconazole-desthio

				In a chronic toxicity study (MRID 46246337), SXX 9665, (92.8% a.i.;
Batch No. 1717008/90) was administered to 4 Beagle dogs/sex/dose in diet
at dose levels of 0, 40, 300 or 2000 ppm (0, 1.35, 10.1 and 69.9 and 0,
1.55, 11.1 or 77.1 mg/kg bw/day for males and females, respectively) for
30 weeks.  The study was initially intended to be 52 weeks, but the
exposure period was truncated due to discontinuation of the development
of the test compound.

There were no treatment-related mortality and no treatment-related
clinical observations.  There were no treatment-related changes in body
weight, body weight gain and food consumption, with the exception of the
2000 ppm females that had slightly reduced body weights at the end of
the study.  

At 2000 ppm, effects were observed in both male and females.  Liver
enzymes were elevated in both sexes, as were relative liver weights. 
Histopathological examination of the livers revealed cytoplasmic changes
(increased granulation and glycogenolysis) in the centrilobular
hepatocytes in all 2000 ppm animals.  These observations coincide with
reduced thyroxine levels, suggesting that significant liver enzyme
activation occurred in both sexes at 2000 ppm.  These liver changes are
considered an adaptive response and not adverse.

The NOAEL is 2000 ppm.  The LOAEL is > 2000 ppm, based on the lack of
adverse effects at the doses tested. 

This chronic toxicity study in the dog does not satisfy the guideline
requirement for a chronic oral study (DACO 4.4.5, OPPTS 870.4100) or a
subchronic oral study (OPPTS 870.3150; OECD 409) in dogs due to a number
of investigations that did not meet GLP standards.  This study is
considered to be supplemental.  This review is a joint effort of the
PMRA and the EPA.

A.3.5	Carcinogenicity

	870.4200a Carcinogenicity Study - rat

		Prothioconazole

	

				In a carcinogenicity study (MRID 46246338), JAU 6476 (98.5 to 99.1%
a.i.) was administered to 50 Wistar Hsd Cpb:WU rats/sex/dose by gavage
(aqueous solution of 0.5% Tylose) at dose levels of 0, 5, 50, or
750/500/625 mg/kg bw/day (the high dose was reduced from 750 mg/kg
bw/day to 500 mg/kg bw/day for males at study week 84, and to 625 mg/kg
bw/day for females at study week 56) for 2 years.

↓32%/43%), 26-52 (↓32%/56%), and 52-75 (↓76%/25%).  Overall (study
week 0-105) body weight gain decreases were 29% and 20% for males and
females, respectively, compared to controls.  Food and water consumption
were significantly increased in the high dose male and female animals. 
Water clefts of the eye were observed at an increased incidence in the
high dose animals.  Several hematological parameters were affected in
the high dose males and females. Alkaline phosphatase (both sexes),
creatinine (males) and urea (males) were increased at the high dose
indicative of liver and kidney changes.  Decreases were observed in
aspartate aminotransferase and alanine aminotransferase levels, with
unknown toxicological significance.  Urine volume was increased in the
high dose group of both sexes (230-360%, males; 52-98%, females), along
with mean water intake for both males (↑124%) and females (↑57%). 
Relative liver and kidney weights were increased in the high dose male
animals, while absolute and relative liver weights and relative kidney
weights were increased in the high dose females.  Several other relative
organ weights were increased in the high dose animals, although this is
likely due to the decreased terminal body weight in these animals. 
Gross and microscopic findings indicative of liver and kidney effects
were observed in the high dose groups of both sexes.  Numerous other
non-neoplastic gross and microscopic pathological findings were noted in
the high dose male and females that are likely secondary to the poor
general condition of these animals.

The LOAEL for chronic toxicity is 500 mg/kg/day based on increased
mortality and decreased body weight/body weight gain, changes in
clinical chemistry (APh, creatinine, urea) and hematological parameters,
increased liver and kidney weights, and liver (hypertrophy and
eosinophilic/clear cell focus) and kidney/urinary bladder pathology. 
The NOAEL for chronic toxicity was 50 mg/kg bw/day for both sexes.

In this study, there is no adequate dose for the evaluation of
carcinogenicity of JAU 6476.  The high dose for both sexes (750/500
mg/kg bw/day for males and 750/625 mg/kg bw/day for females) was
considered to be excessive, as shown by the increased mortality and
decreased body weight/body weight gain in both sexes.  There was no
treatment-related increase in tumor incidence in the treatment groups
when compared with control animals up and including 625 mg/kg bw/day in
females.  At 500 mg/kg bw/day in males, malignant thymomas were
observed, but as dosing was excessive, these tumors were not considered
treatment-related. 

This carcinogenicity study in the rat is unacceptable /guideline and
does not satisfy the guideline requirement for a carcinogenicity study
(OPPTS 870.4200; OECD 451) in rats.  There is no adequate dose for the
evaluation of carcinogenicity of JAU 6476 due to excessive toxicity at
the high dose and too large dose spacing between the mid and high dose
groups.  The high dose (750/625/500 mg/kg/day) was considered excessive
based on: 1) increased mortality in both sexes which resulted in dose
reduction to 625 mg/kg/day during week 56 for females and to 500
mg/kg/day during week 84 for the males, and 2) significant decreases in
body weight/body weight gain from week 12 in males and from week 29 in
females at this dose.  No effects were seen at the mid dose of 50
mg/kg/day.  The animals in this study are compromised.  However, while
the study is considered unacceptable, a new cancer study conducted with
the parent compound is not required since an adequate rat cancer study
conducted with the metabolite is available, which is the basis for the
risk assessment.  This review is a joint effort of the PMRA and the EPA

		Prothioconazole-desthio

				In a combined chronic toxicity/carcinogenicity study (MRID
46246342), SXX 0665 (92.8-95.4% a.i.) was administered to 60, 5–6 week
old Wistar rats/sex/dose in diet (1% peanut oil) at dose levels of 0,
20, 140 or 980 ppm (0, 1.1/1.6, 8.0/11.2 or 57.6/77.4 mg/kg bw/day for
males/females).  An interim kill was performed at week 52 on 10
rats/sex/dose while the remaining 50 rats/sex/dose were dosed for 104
weeks. 

There were no treatment-related effects of clinical signs,
ophthalmology, urinalysis parameters, food consumption or water
consumption.  There were mortalities at all dose levels in both sexes,
however, these deaths were not deemed to be treatment-related as they
were spontaneous, were due to animals being in moribund state, or due to
death during blood collection.  No treatment-related decrease in body
weight/body weight gain was seen in males.  In females at 980 ppm,
decreases in body weight (↓3-9%) and body weight gain (↓16-40%),
relative to controls, were observed throughout the study, resulting in a
treatment-related overall body weight gain decrease of 14%, relative to
control.  Treatment-related liver effects included: i) absolute liver
weight was increased in males at 980 ppm (weeks 52 and 104); II)
relative liver weight was increased at 980 ppm in both sexes (weeks 52
and 104); iii) liver discoloration in males at 140 and 980 ppm (week 52)
and; iv) slightly increased incidence of enlarged livers in males at 980
ppm.  Treatment-related adverse non-neoplastic liver histopathology
effects included; i)  increased hepatocellular vacuolation in males at
140 and 980 ppm (weeks 52 and 104) in males and at 140 and 980 ppm (week
104) in females; ii) increased incidence of single cell necrosis in
males at 980 ppm (week 52); iii)  increased incidence of centrilobular
fatty change at 140 and 980 ppm (weeks 52 and 104); iv) increased
incidence of cytoplasmic change in females at 980 ppm (week 52) and then
in both sexes at 980 ppm (week 104); v) increased incidence of
periportal fatty change in females at 140 and 980 ppm (week 52); vi)
increased incidence of hepatocellular hypertrophy in both sexes at 980
ppm (week 104) and; vii) increased incidence of single cell fatty change
at 140 and 980 ppm in both sexes (week 104).

T3 was decreased in females weeks 53 and 104 at 980 ppm and T4 was
decreased in males weeks 104 at 140 ppm and 980 ppm.  In the thyroid
gland, histopathology revealed increased incidences of hypertrophy of
follicular epithelium in males at 980 ppm, week 52 and increased
colloidal mineralization in both sexes at 980 ppm, week 52, as well as
in 980 ppm females, week 104. 

≥140 ppm.  There was an increase in adrenocortical hyperplasia in
females at week 104 at 980 ppm. 

There were no neoplastic findings. 

The LOAEL is 140 ppm (8.0/11.2 mg/kg bw/day for M/F), based on liver
histopathology (hepatocellular vacuolation and fatty change (single
cell, centrilobular, and periportal)).  The NOAEL is 20 ppm (1.1/1.6
mg/kg bw/day for M/F).

														

At the doses tested, there were no treatment related increases in tumor
incidence when compared to controls.  Dosing was considered adequate
based on the liver histopathology in both sexes at 140 ppm and 980 ppm,
as well as body weight/body weight gain decreases in females and
increased liver weights in both sexes at the high dose.

This chronic toxicity/carcinogenicity study in the rat is
Acceptable/Guideline and satisfies and satisfies the guideline
requirement for a chronic/carcinogenicity study (OPPTS 870.4300); OECD
453 in rats.  This review is a joint effort of the PMRA and the EPA.

	870.4200b Carcinogenicity (feeding) - Mouse

		Prothioconazole

	

				In a carcinogenicity study (MRID 46246339), JAU 6476 (98.2-98.8%
a.i.) was administered to 60 Crl:CD-1 (ICR)BR mice/sex/dose by gavage
(with 0.5% Tylose aqueous solution) at dose levels of 0, 10, 70, 500
mg/kg bw/day for 80 weeks.  

There was no treatment-related effect on mortality.  Body weight was
decreased (5-10% in males; 4-13% in females) from week 6 to week 78 at
500 mg/kg.  At the end of the study (week 78), body weights were
decreased 9% in males and 13% in females compared with controls.  Body
weight gains were decreased compared with controls at weeks 0-13 (males
and females), 13-26 (males and females), 26-52 (females) and 52-78
(females).  There were no treatment-related adverse effects on food
consumption in male or female mice. 

Clinical chemistry, eye examinations and urinalysis were not conducted
during this study.   There were no treatment-related adverse findings in
the differential blood count. 

Absolute kidney weights were decreased in males (20%) and females (15%)
at 500 mg/kg.  Relative kidney weights were decreased in males (13%) at
500 mg/kg and were comparable to controls in females.  There were
corresponding gross and histopathological effects [tubular
degeneration/regeneration and subscapular tubular degeneration with
interstitial fibrosis] in the kidneys.  There was a statistically
significant increase in absolute liver weights in male mice at ≥70
mg/kg (12-25%) and in female mice at 500 mg/kg (21%).  Relative liver
weights were increased at ≥70 mg/kg in male (16-39%) and female mice
(10-39%).  There was a decrease in absolute (44%) and relative (37%)
uterus weights at 500 mg/kg but the biological relevance of this is not
clear. 

There was an increase in the incidence of discoloration in the kidneys
in males and females at 500 mg/kg.  There was a dramatic increase in the
incidence of surface changes in the kidneys of male mice at 500 mg/kg
compared with the other treatment groups, but there was a poor-response
in females.  There were changes in kidney weights and corresponding
histopathological effects in the kidneys at the high dose, so kidney
effects were considered treatment-related and adverse at 500 mg/kg. 
There was an increase in the incidence of distinct lobulation in the
liver of male mice at ≥70 mg/kg compared with control values.  There
was not a dose-response in females for this parameter.  There was an
increase in fluid in the body cavity at 500 mg/kg in males and at ≥70
mg/kg in females, but the toxicological significance of this finding is
not known.  There was a decrease in discoloration of seminal vesicles in
male mice in all treatment groups compared with controls, but the
toxicological significance of this finding is not known.  There was a
decrease in the incidence of consistency change in the uterus which
corresponds with doses at which there was a decrease in uterus weight,
but the toxicological significance of this finding in combination with
decreased uterus weights is not known.

There was an increased incidence of tubular degeneration/regeneration in
the kidney at ≥70 mg/kg in males and 500 mg/kg in females and an
increased incidence of subcapsular tubular degeneration with
interstitial fibrosis at 500 mg/kg in male and female mice.  This
corresponds with gross pathology in the kidney and changes in kidney
weight. There was a treatment-related increase in centrilobular
hypertrophy in male mice at ≥70 mg/kg and in female mice at 500 mg/kg.
 This finding corresponds with weight and gross pathology effects in the
liver. However, in the absence of other hepatic histopathologic changes
and absence of clinical chemistry evaluations, it can not be determined
whether these changes are adverse.  There was an increase in the
incidence of inflammation in the seminal vesicles in males at 500 mg/kg,
but the toxicological significance of this finding in combination with a
decrease in discoloration noted in gross observations is not known. 
Other effects had a poor dose-response and/or were slight, and were not
considered treatment-related.

There were no treatment-related adverse neoplastic findings.

The LOAEL is 70 mg/kg, based on kidney (tubular
degeneration/regeneration in males) effects.  The NOAEL is 10 mg/kg.

At the doses tested, there was not a treatment related increase in tumor
incidence when compared to controls.  Dosing was considered adequate
based on renal tubular toxicity at the mid dose and high dose and
decreased body weight at the high dose.

This carcinogenicity study in the mouse is acceptable (guideline) and
satisfies guideline requirement for a carcinogenicity study (OPPTS
870.4200); OECD 451 in mice.  This review is a joint effort of the PMRA
and the EPA.

		Prothioconazole-desthio

				In a carcinogenicity study (MRID 46246340, 46246341), SXX 0665
(93.1% a.i.) was administered to 50 B6C3F1 mice/sex/dose (and to 10
mice/sex/dose as satellite groups for sacrifice at 12 months) in diet
(1% peanut oil) at dose levels of 0, 12.5, 50, or 200 ppm (0, 3.1, 12.8,
or 51.7 mg/kg bw/day for males, and 0, 5.1, 20.3, or 80.0 mg/kg bw/day
for females) for 105 weeks.

There were no treatment-related mortalities or clinical signs.  Body
weight and food consumption were unaffected by treatment.  There were no
treatment-related hematological changes.  Overall body weight gain was
decreased in the high dose male animals.  Levels of cholesterol and
triglycerides were decreased in the treated male animals throughout the
study.  Glucose levels increased and decreased during Weeks 53 and 105,
respectively, in the treated male animals.  Changes in these clinical
chemistry parameters in the male animals were considered to be related
to liver changes noted in these animals, and were considered adaptive in
the low and mid dose males.  Levels of triglycerides were decreased at
the end of the study in the treated female animals.  As with the male
animals, this observation was related to liver findings noted in the
high dose females.  Absolute and relative liver weights were increased
in both the male and female high dose animals.  At interim sacrifice,
fine vesicular vacuolation in the hepatocytes and periacinar fat
staining were observed at an increased incidence in the mid and high
dose males.  Periacinar fat staining was also increased in the mid and
high dose terminal sacrifice males, and in all of the treated females at
terminal sacrifice.  Periacinar hypertrophy with cytoplasmic change in
hepatocytes was observed at an increased incidence in the mid and high
dose interim sacrifice females.  These histopathological findings
correlate to the increased liver weights and the clinical chemistry
changes.  The liver changes were, therefore, considered
treatment-related and adverse in the high dose animals of both sexes. 
Decreased urea levels in the blood were observed in the treated females
throughout the study, and were likely related to kidney changes
observed.  The high dose females showed an elevated mean absolute and
relative kidney weight.  There were also histopathological findings of
eosinophilic droplets in the cortical tubules observed in the mid and
high dose groups.  The increased mean kidney weight was, therefore,
considered treatment-related and adverse in the high dose females.

The LOAEL for chronic toxicity was 200 ppm (equal to 51.7 mg/kg bw/day
in males, and 80.0 mg/kg bw/day in females) based on decreased body
weight gain in males, decreased triglyceride levels in both sexes,
decreased cholesterol levels in males, changes in glucose levels in
males, increased liver weights in both sexes, increased incidence of
histopathological findings in the liver hepatocytes in both sexes,
decreased blood urea levels in females, increased kidney weights in
females, and increased incidence of eosinophilic droplets in the
cortical tubules of the kidneys of females.  The NOAEL for chronic
toxicity was 50 ppm (equal to 12.8 mg/kg bw/day for males, and 20.3
mg/kg bw/day for females).

At the doses tested, there was no treatment-related increase in tumor
incidence in the treatment groups when compared with control animals up
to and including 200 ppm (equal to 51.7 mg/kg bw/day in males, and 80.0
mg/kg bw/day in females), the highest dose tested.  Under the conditions
of the current study, SXX 0665 was not considered to be carcinogenic in
mice.  Dosing was considered adequate based on decreased body weight
gain (males), increased liver weights, clinical chemistry changes and
increased histopathological findings in the liver hepatocytes (both
sexes), increased kidney weights (females) and increased incidence of
eosinophilic droplets in cortical tubules of kidneys (females) at 200
ppm.  

This carcinogenicity study in the mouse is acceptable (guideline) and
satisfies the guideline requirement for a carcinogenicity study (OPPTS
870.4200; OECD 451) in mice.  This review is a joint effort of the PMRA
and the EPA.

A.3.6	Mutagenicity

	Gene Mutation

Guideline 84-2, Reverse Gene Mutation

MRID 46246343

Acceptable Guideline

JAU 6476

	dose range: 16 to 5000 ug/plate 

JAU 6476 was increasingly cytotoxic at 158 ug/plate ± S9 in all strains
treated by plate incorporation, and at the highest concentration, 500
µg/plate ±S9, in four of the five strains treated by preincubation,
but additionally at 158 ug/plate in TA102.  However, at the remaining
concentrations, no appreciable differences in the number of revertants
in test cultures compared to solvent controls were found.  In contrast,
marked increases in all positive controls were induced.

Therefore, JAU 6476 is considered negative for reverse mutation in this
battery of S. typhimurium strains up to cytotoxic concentrations.

Guideline 84-2, Reverse Gene Mutation

MRID 46246345

Acceptable Guideline

JAU 6476 Des-chloro	16 to 5000 ug/plate  in the initial plate
incorporation assay, and at six concentrations ranging from 5 to 1581
µg/plate in the subsequent preincubation modification

No evidence of mutagenicity (increased revertants) was observed in
either assay up to cytotoxic levels of the test substance.  

Therefore, 6476 Des-chloro is considered non-mutagenic in this bacterial
test system

Guideline 84-2, Reverse Gene Mutation

MRID 46246401

Acceptable Guideline

JAU 6476-alpha-acetoxy-desthio,	16 to 5000 ug/plate

At non-cytotoxic concentrations of the test article in either assay no
increases in revertant colonies (i.e., evidence of reverse mutation)
were observed, either in the presence or absence of activation. 

 

Therefore, JAU 6476-alpha-acetoxy-desthio is considered non-mutagenic in
this bacterial test system

Guideline 84-2, Reverse Gene Mutation

MRID 46246402

Unacceptable Guideline

JAU 6476 sulfonic acid K. salt	16 to 5000 ug/plate

At no concentration in either assay did the test article significantly
increase the number of revertants over negative control values. 
However, the spontaneous revertant counts of strain TA100 as well as the
response to the S9-activated positive control were lower than expected

Guideline 84-2, Reverse Gene Mutation

MRID 46246347

Acceptable Guideline

the asymmetric isomer of JAU 6476	16 to 5000 ug/plate

The asymmetric isomer of JAU 6476 is considered nonmutagenic in this
battery of S. typhimurium cultures up to cytotoxic concentrations.

Guideline 84-2, Reverse Gene Mutation

MRID 46246350

Acceptable Guideline

JAU 6476 - triazolinone	Cytotoxicity was evident at concentrations 
500 ug/plate ±S9 in both assays, compromising the useful assessment of
mutagenicity at higher concentrations.  

Non-cytotoxic concentrations of the test article provided no increases
in revertant colonies compared to negative control values, in contrast
to marked increases in all positive controls.

Therefore, JAU 6476-triazolinone is considered nonmutagenic in this S.
typhimurium test system.

Guideline 84-2, Reverse Gene Mutation

MRID 46246348

Acceptable Guideline

JAU 6476-asymmetric disulfide	six  concentrations ranging from 16 to
5000 ug/plate in both assays, in the presence and absence of metabolic
activation

The highest concentration tested, 5000 ug/plate ± S9, caused a
reduction in revertant colonies and/or cell titers.  Compound
precipitation was seen at 1581 ·µg/plate.  At no testable article
concentration 1581 ug/plate (plate incorporation) and 500
µg/plate (preincubation) up to the limit (5000 ug/plate) in either
assay did JAU 6476-asymmetric disulfide increase the numbers of
revertant colonies cultured with/without metabolic activation.  All
positive controls manifested marked increases in revertant colonies.

Therefore, JAU 6476-asymmetric disulfide does not induce reverse
mutation in this bacterial test system up to cytotoxic concentrations.

Guideline 84-2, Reverse Gene Mutation

MRID 46246344

Acceptable Guideline

SXX 0665	five  concentrations ranging from 8 to 5000 ug/plate in the
initial experiment, and five concentrations ranging from 150 to 2400
ug/plate in the repeat test, both in the presence and absence of a 
metabolic activation system

At no concentration up to cytotoxic levels in either assay, however,
were increases in revertants induced by SXX 0665, compared to concurrent
negative controls, or compared to the laboratory’s historical control
data.  Marked increases were induced in all positive controls.

Guideline 84-2, Reverse Gene Mutation

MRID 46246346

Acceptable Guideline

JAU 6476-methyl	Six concentrations ranging from 16 to 5000 ·g/plate in
the initial plate incorporation experiment, and at a lower range of six
concentrations from 16 to 512 µg/plate in the subsequent preincubation
test, in the presence and absence of an exogenous metabolic activation.

Concentrations 158 µg/plate ±S9 caused increasing bacteriotoxicity
in four of five strains treated by plate incorporation, and 256
ug/plate ±S9 in the majority of strains in the preincubation test. 
However, in neither assay at any usable concentration in cultures
with/without metabolic activation were increases in reversion to
prototrophy induced in test article-treated cultures.  Marked increases
in revertant colonies were seen in all positive controls.

Therefore, JAU 6476-methyl is considered nonmutagenic in this battery of
S. typhimurium strains up to cytotoxic levels.

Guideline 84-2, Reverse Gene Mutation

MRID 46246349

Acceptable Guideline

JAU 6476- alpha-hydroxy-desthio	six concentrations ranging from 16 to
5000 ·g/plate (both assays), in the presence and absence of metabolic
activation

The highest concentration, 5000·µg/plate, was cytotoxic in two strains
in the initial plate incorporation assay, but in all strains by
preincubation.  However, increases in revertant colonies (evidence of
reverse mutation) were not observed at any concentration in either assay
exposed up to the limit concentration, 5000·µg/plate.  In contrast,
marked increases in revertants were found in all positive control
cultures.

Therefore, this alpha-hydroxy-desthio derivative of JAU 6476 is
considered non-mutagenic in this bacterial test system up to the
cytotoxic/limit concentration.

Guideline 84-2, Forward Gene Mutation

MRID 46246404

Acceptable Guideline

JAU 6476	Six concentrations ranging from 75 to 200 ug/mL were assayed.

Increasing test article cytotoxicity (as evident by decreased survival
as well as relative population growth) was observed in both the presence
(200 ug/mL) and absence (150 ug/mL) of S9-activation.  However at no
usable concentration in either the initial or the repeat assay did JAU
6476 increase the frequency of forward mutations, ± S9).  Marked
increases were induced in both positive controls.

Therefore, JAU 6476 is considered non-mutagenic in the V79-HGPRT forward
mutation assay.

Guideline 84-2, Forward Gene Mutation

MRID 46246405

Acceptable Guideline

JAU 6476	six concentrations ranging from 16 to 5000 ug/plate

Concentrations of the test material >500 ug/plate in the initial plate
incorporation assay caused an increasingly severe strain-specific
cytotoxicity, compromising appropriate assessment of reverse mutation at
higher levels.  Slight cytotoxicity in the majority of strains occurred
in the preincubation assay at the highest concentration tested, 256
µg/plate.  At no usable test article concentration in either assay did
JAU 6476-benzylpropyldiol increase the number of revertant colonies
cultures with/without metabolic activation.  All positive controls
manifested marked increases in revertant counts. 

Therefore, JAU 6476-Benzylpropyldiol does not induce reverse mutation in
this bacterial test system up to cytotoxic concentrations.

Guideline 84-2, Forward Gene Mutation

MRID 46246403

Acceptable Guideline

JAU 6476	Seven concentrations ranging from 12.5 to 250 ug/mL - S9 (three
trials), or six concentrations ranging from 50 to 500 ug/mL +S9 (four
trials). 

200 ·µg/mL or with S9- activation at 500 ug/mL.  Further,
precipitation of the test article occurred at the highest S9- activated
concentration tested.

However, at no usable concentration in any trial ± S9 did the test
article induce mutant frequencies (MFs), as determined by increases in
forward mutation to HGPRT-/- in test cultures over negative controls. 
In contrast, both reference mutagens induced marked increases in MFs.

Therefore, SXX 0665 is considered non-mutagenic in the V79-HGPRT Forward
Mutation Assay.

	Cytogenetics

Guideline 84-2, in vitro cytogenetics

MRID 46246408

Acceptable Guideline

JAU 6476 Des-Chloro	60, 120, 180, 240 and 300 ug/mL in the presence and
absence of metabolic action

No statistically significant increases in structural chromosome
aberrations were manifested in culture treated for 4 hours at 60, 120,
and 180 ug/mL ± S9-mix or for 18 hours at 12, 24 and 36 ug/mL, both
harvested 18  hours after the onset of treatment, nor were increases
found at the 180 ·g/mL treatment and harvested at 30 hours.  Both
positive controls induced marked increases in structural aberrations.

Therefore JAU 6476 Des-Chloro is considered non-clastogenic in this test
system.

Guideline 84-2, In Vitro cytogenetics

MRID 46246406

Acceptable Guideline

JAU 6476	75, 100, and 150 ug/mL and harvested 18 hours after the
beginning of treatment in the initial assay; at a single dose of 150
ug/mL with a harvest at 30 hours in the repeat assay.

In preliminary cytotoxicity tests, decreases in cell survival and
mitotic indices were found at >50 ug/mL -S9 and 150 ug/mL +S9.  In the
main assays, significant increases in chromosome (structural)
aberrations (chromatid and chromosome breaks, fragments and exchanges)
were seen in non-activated cultures at all test article concentrations. 
These increases, however, were not concentration-related and were
statistically significant only at the highest concentration tested
(HCT), 150 ug/mL in -S9 cultures, but questionable below that
concentration.  Increases were also observed in S9-activated cultures at
150 ug/mL.  Therefore, these increases may conceivably be attributable
to excessive cytotoxic effects, especially in the early phase of culture
growth.  Both positive controls induced clearly significant increases in
structural aberrations.  There were no increases in numerical
aberrations (polyploidy) in either test article-treated cells or
positive controls.

Therefore, JAU 6476 may be considered clastogenic (i.e., induces
increases in structural aberrations), but this mutagenic activation may
result from secondary cytotoxicity rather than direct structural DNA
damage.

Guideline 84-2, In Vivo (micronucleus) cytogenetics

MRID 46246410

Acceptable Guideline

SXX 0665	SXX 0665 is not considered to be a clastogen or aneugen in mice
at the i.p. administration of 350 mg/kg.

Guideline 84-2, In Vivo cytogenetics

MRID 46246409

Acceptable Guideline

JAU 6476	Adverse clinical signs of toxicity (apathy, semi-anesthesia,
staggered gait, sternal recumbency, spasm, and breathing difficulties)
were evident in test animals (but not in either control group) up to 24
hours after administration, but subsided thereafter.

The ratio of polychromatic to normochromatic erythrocytes was not
altered by JAU 6476 administration; the single statistically significant
difference at 24 hours (1000:968) was not considered biologically
relevant.  Furthermore, no biologically-relevant or statistically
significant differences were found in the incidence of micronucleated
polychromatic erythrocytes between the test group and the negative
control.  In contrast, the positive control showed a marked increase in
micronuclei, in conjunction with a lack of effect on the ratio of
polychromatic to normochromatic erythrocytes.

Therefore, the one i.p. dose of 250 mg/kg JAU 6476 (prothioconazole) is
considered to be non- clastogenetic in vivo.

Guideline 84-2, In Vivo cytogenetics

MRID 46246411

Acceptable Guideline

JAU 6476	50, 100 and 200 mg/kg

50 mg/kg; all animals, however, survived thereafter.  A significantly
altered ratio between polychromatic (PCE) and normochromatic (NCE)
erythrocytes was found at the highest dose, 200 mg/kg.

However, no increases in structural chromosome aberrations
(clastogenicity), compared to the vehicle control, were elicited at any
dose of JAU 6476.

In contrast, marked increases were induced in the positive control
groups in the absence of any alteration in the PCE:NCE ratio.

Therefore, JAU 6476 (prothioconazole) is not clastogenic or aneugenic in
male mice treated up to overtly toxic and cytotoxic doses.

Guideline 84-2, In Vitro cytogenetics

MRID 46246407

Acceptable Guideline

SXX 0665	5, 25, and 125 ug/mL

SXX 0665 is considered to be non-clastogenic in CHO cells up to
subcytotoxic concentrations.

	

	Other Genotoxicity

Guideline 84-2, Unscheduled DNA Synthesis

MRID 46246414

Acceptable Guideline

SXX 0665	at six concentrations ranging from 5 to 60 ug/mL in the
presence of radioactive thymidine

The highest concentration caused cell damage and reduced cell number. 
However, there was no evidence that UDS, as determined by radioactive
tracer procedures [nuclear silver grain counts], was induced.

Guideline 84-2, Unscheduled DNA Synthesis

MRID 46246413

Acceptable Guideline

JAU 6476	single oral doses of 2500 or 5000 mg/kg

JAU 6476 (prothioconazole) is negative for UDS-induction in hepatocytes
drawn from male rats administered single oral doses of 2500 and 5000
mg/kg.

Guideline 84-2, Unscheduled DNA Synthesis

MRID 46246412

Acceptable Guideline

JAU 6476	seven concentrations ranging from 1.0 to 40 ug/mL in the first
trial, and 0.5 to 20 ug/mL in the repeat test, both in the presence of
tritiated-thymidine in order to monitor the number of silver grains
indicating UDS (other than scheduled synthesis during normal mitosis).

JAU 6476 produced slight non-dose-related increases (averaging
approximately 10X the vehicle control) in grain counts as well as in the
percent of cells with five nuclear grain counts (>16X vehicle
control), (cells in repair), compared to the concurrent vehicle control.
 The positive control induced marked increases in both grain counts and
percent of cells in repair.  Therefore, JAU 6476 is evaluated as
equivocal in this assay.

However, these results were clarified based on the negative findings in
the in vivo UDS assay in rat hepatocytes from adult male rats exposed up
to the 5000 mg/kg with the same Batch No. of the test materials. (MRID
46246413)

A.3.7	Neurotoxicity

	870.6100 Delayed Neurotoxicity Study - Hen

		Prothioconazole

	

			No Acceptable studies are available.

		Prothioconazole-desthio

			No Acceptable studies are available.

	870.6200 Acute Neurotoxicity Screening Battery

		Prothioconazole

	

				In an acute neurotoxicity study (MRID 46246417), groups of fasted,
9-week-old Wistar rats (12/sex) were given a single oral (gavage) dose
of JAU 6476 (97.6-98.8% a.i., batch# 898803005) in 0.5%
methylcellulose/0.4% Tween 80 at doses of 0 (vehicle), 200, 750, or 2000
mg/kg bw and observed for 14 days.  Neurobehavioral assessment
(functional observational battery [FOB] and motor activity testing) was
performed in 12 animals/sex/group on day 0 (four hours following
treatment, the time of peak effect) and on days 7 and 14. 
Cholinesterase activity was not determined.  At study termination, six
animals/sex/group were euthanized and perfused in situ for
neuropathological examination.  Of the perfused animals, the control and
high-dose groups were subjected to histopathological evaluation of brain
and peripheral nervous system tissues. 

There were no treatment-related effects on mortality, body weight, brain
weight or gross and histologic pathology or neuropathology.  The only
treatment-related clinical sign was brown perianal stain (graded as
slight) observed on 3/12, 7/12, 11/12, and 12/12 males and 0/12, 0/12,
8/12, and 11/12 females in the control through high-dose groups during
days 1 through 5.  This clinical sign was also observed, but at lower
incidences, during the FOB on the day of treatment.  The effect had
resolved by FOB test day 7.  Partially formed stools were also noted
during the FOB.  Although the incidences of perianal stain of 7/12
(males, 200 mg/kg) and 8/12 (females, 750 mg/kg) would appear similar,
the incidence for males was within historical control values for this
vehicle; whereas, the incidence in females showed a clear effect at the
mid and high dose.  No other parameters examined in the FOB were
affected. 

Motor activity (total beam breaks) was non-significantly reduced on the
day of treatment (by 29 and 36% in males in the 750 and 2000 mg/kg
groups, respectively, and by 45% in females in the 2000 mg/kg group). 
Subsession data (up to approximately 50 minutes) also showed
correspondingly reduced motor activity.  This effect on motor activity
had resolved by the next test session on day 7.  The effect on locomotor
activity was similar.  It is not clear whether the observed clinical
sign and reduced motor and locomotor activity were due to transient
effects on the nervous system or were an effect on the gastrointestinal
tract resulting from administration of a noxious substance.  In the
absence of other effects, the perianal stain observed on females in the
750 mg/kg group was considered a non-adverse effect.

The LOAELs for JAU 6476 in male and female rats are 750 and 2000 mg/kg,
respectively, based on the transient effect of reduced motor and
locomotor activity.  The NOAELs for male and female rats are 200 and 750
mg/kg, respectively.

This neurotoxicity study is classified as Acceptable/Guideline, and
satisfies the guideline requirement for an acute neurotoxicity study in
rats (870.6200; OECD 424) provided the conducting laboratory provides
positive control data demonstrating the ability to detect major
neurotoxic endpoints, changes in motor activity, and nervous system
pathology.  Raw data on analysis for concentration, homogeneity, and
stability of the test material should also be provided.  This review is
a joint effort of the PMRA and the EPA.

		Prothioconazole-desthio

			No Acceptable studies are available.

	870.6200 Subchronic Neurotoxicity Screening Battery

		Prothioconazole

	

				In n a subchronic neurotoxicity study (MRID 46246416) JAU 6476
(97.6-98.8% a.i., batch #s 898803005 and 6233/0031) was administered to
12 Wistar (Crl:WI(HAN)BR) rats/sex/group at nominal dose levels of 0,
100, 500, or 1000 mg/kg bw/day, five days/week, for 13 weeks
(analytically determined doses of 0, 98, 505, and 1030 mg/kg/day).  The
dose was administered by gavage in 0.5% methylcellulose/0.4% Tween 80 in
deionized water.  Neurobehavioral assessment (functional observational
battery and motor activity testing) was performed in 12
animals/sex/group pretreatment and during weeks 4, 8, and 13. 
Cholinesterase activity was not determined.  At study termination, six
animals/sex/group were euthanized and perfused in situ for
neuropathological examination.  Of the perfused animals, the control and
high-dose groups were subjected to histopathological evaluation of brain
and peripheral nervous system tissues. 

There were no treatment-related deaths.  Treatment-related clinical
signs included urine stain on 8/12 males and 9/10 females in the 500
mg/kg/day group and 12/12 males and 11/	11 females in the 1000 mg/kg/day
group.  Urine stain was first observed on day 18 on males treated with
1000 mg/kg/day.  Urine stain increased in frequency with duration of
exposure.  Urine stain was considered an effect of treatment, but, in
the absence of other clinical signs or histological correlates, not an
adverse effect.  Oral stain was observed on 3/12 males (beginning on day
25) and 1/11 females in the 1000 mg/kg/day group.  Males in the mid- and
high-dose groups lost weight during the first week of the study (3-4%).
Weight loss was not accompanied by a decrease in food consumption during
the first week.  Final body weight was slightly (non-statistically)
reduced in males treated with 500 (6%) and 1000 mg/kg/day (8%) when
compared to final control body weight.  Body weight gain was reduced by
16 and 24% in males in the 500 and 1000 mg/kg/day groups, respectively. 
The body weight effects are considered adverse at the high dose.  Body
weight and body weight gain of females were unaffected by treatment. 
Food consumption was unaffected in both sexes.  Urine stain was the only
compound-related parameter affected during the FOB.  

Compared with the respective control groups, slight reductions were
observed in motor and locomotor activity (up to 26%, non-statistically
significant) in both sexes in the high-dose groups.  These reductions
occurred in males and females during week 4 and in females during weeks
4 and 13.  However, the values for females were not dose-related, and
differences in values between the control and high-dose females for all
weeks (8-15%) were less than or similar to the difference between the
pretest control and high-dose group value (14%).  Therefore, the effect
on motor activity for females cannot be considered a clear effect of
treatment.  The effect on motor activity of males is questionable for
the same reasons.  There were no compound- related ophthalmic findings
or microscopic lesions of the central or peripheral nervous system. 
Brain weight was unaffected by treatment.

Based on decreased body weight and body weight gains in males, the LOAEL
for JAU 6476 was 1000 mg/kg bw/day. The NOAEL was 500 mg/kg/day. 

This neurotoxicity study is classified as Acceptable (pending submission
of homogeneity, concentration, and stability analysis and positive
control data)/Guideline, and satisfies the guideline requirement for a
subchronic neurotoxicity study in rats (870.6200b; no OECD) provided the
conducting laboratory provides positive control data demonstrating their
ability to detect major neurotoxic endpoints, changes in motor activity,
and nervous system pathology.  Raw data on analysis for concentration,
homogeneity, and stability of the test material should also be provided.
 This review is a joint effort of the PMRA and the EPA.

		Prothioconazole-desthio

			No Acceptable studies are available.

	870.6300 Developmental Neurotoxicity Study

		Prothioconazole

	

			No Acceptable studies available.

		Prothioconazole-desthio

			In a developmental neurotoxicity study (MRID 46246418), SXX 0665
(99.1-99.4% a.i.; batch # RUX76-105-1E), a metabolite of prothioconazole
(PC Code 113961), was administered in the diet to 30 female mated Wistar
Hannover Crl:WI (Glx/BRL/Han) IGS BR rats/dose at nominal concentrations
of 0, 40, 160 and 500 ppm from gestation day (GD) 6 through lactation
day (LD) 21.  Average doses to the dams were 0, 3.6, 15.1 and 43.3
mg/kg/day during gestation and 0, 8.1, 35.7 and 104.6 mg/kg/day during
lactation for the 0, 40, 160 and 500 ppm groups, respectively.  No data
were provided regarding exposure to the offspring.  A Functional
Operational Battery (FOB) was performed on 30 dams/dose on GDs 13 and
20, and on 10 dams/dose on LDs 11 and 21.  On postnatal day (PND) 4,
litters were culled to yield four males and four females (as closely as
possible).  Offspring were allocated for detailed clinical observations
(PNDs4, 11, 21, 35, 45, 60) and assessment of motor activity (PNDs13,
17, 21, 60), auditory startle reflex habituation (PNDs22, 38, 60),
learning and memory (passive avoidance [PNDs22, 29] and watermaze [PNDs
60, 67] testing), and neuropathology and brain morphometric evaluation
at PND21 (neuropathology for CNS tissues only) and at study termination
(day 75±5 of age; neuropathology for CNS and PNS tissues). 
Ophthalmologic evaluations were also performed, around PND 50-60.  Pup
physical development was evaluated by body weight.  The age of sexual
maturation (vaginal opening in females and preputial separation in
males) was assessed.

No parental females died during the study; however, three dams at 500
ppm had dystocia at parturition and were sacrificed on GD 22 or 24 (date
was unclear in study report).  All of the pups from these litters were
dead.  No treatment-related effects on clinical signs, body weight, body
weight gain, or food consumption were observed in dams during gestation
and lactation.  The mean duration of gestation was increased at 500 ppm
(22.1 days compared to 21.5 days for the control group).  The mean
number of pups per litter was slightly decreased at 500 ppm (10.9 vs.
11.9 in the control group).  The number of stillborn pups was increased
at 160 and 500 ppm (0, 0, 3 and 3 in the 0, 40, 160 and 500 ppm groups,
respectively).

No treatment-related clinical signs were observed in offspring during
lactation.  Post-weaning, there was a progressive development of
malocclusion and a deviated snout (dorsal aspect) with associated
findings (lacrimation, lacrimal stain) at 160 (one male, two females)
and 500 ppm (three males, seven females).  The changes became evident
around PND 32 with progressively more animals developing malocclusion
and a deviated snout.  Body weight at birth was increased at 160 and 500
ppm (7 and 13-14%, respectively, in both sexes); however by PND71
absolute body weight in adult males at 500 ppm was significantly lower
than control values (5%).  The average age of onset of preputial
separation in males and vaginal opening in females was not affected by
treatment.

Clinical signs observed during the FOB examinations were associated with
malocclusion (broken teeth or malocclusion in one female each at 160 and
500 ppm on PNDs 45 and 60) and a deviated snout (two other females at
500 ppm on PND 60).  Total motor activity was increased at 500 ppm in
both sexes at PND 13 (82-120% above control levels).  Auditory startle
response was increased in males at 500 ppm on PND22 (53-70%).  There
were no clear treatment-related effects on learning and memory as
evaluated by passive avoidance testing on PND22-29. Increases in latency
and errors were seen in the water maze on PND60, in males at 160 and 500
ppm (83-67% increase in Trial 1 errors) and in females at 500 ppm only
(54% increase in errors).  Limitations in the data presentation and high
variance made interpretation of the water maze findings unclear.

Brain weight at PND 21 and 75 necropsy was unaffected by treatment.  No
gross lesions were observed in either sex at PND 21 necropsy or in
treated males at terminal necropsy.  Malocclusion was noted in both
sexes at 160 and 500 ppm; associated skull findings included fracture of
the nasal bone and deviation of the snout (at 500 ppm in both sexes). 
Incidence was higher in females than in males.  An increase in lesions
of the peripheral nerves was also noted at 500 ppm, again more prominent
in females than in males.  Mid- and low-dose groups were not evaluated. 
Changes in brain morphometric measurements were also seen at 500 ppm;
corpus callosum measurements were increased in males at both ages
(19-25%) and frontal cortex measures were increased in adult females
(5%); low and mid-dose groups were not evaluated for either measure.

PMRA:

The maternal LOAEL for SXX 0665 (metabolite of prothioconazole) in rats
is 160 ppm (15.1 mg/kg/day) based on an increased incidence of stillborn
pups.  The maternal NOAEL is 40 ppm (3.6 mg/kg/day). 

The developmental LOAEL for SXX 0665 in rats is 160 ppm (15.1 mg/kg/day)
based on an increased incidence of progressive malocclusion and deviated
snout and increased incidence of stillborn pups.  The developmental
NOAEL is 40 ppm (3.6 mg/kg/day).

The offspring neurotoxicity LOAEL and NOAEL for SXX 0665 in rats could
not be determined, due to the absence of neuropathological and brain
morphometric evaluations at the mid and low dose treatment levels.

EPA:

The maternal LOAEL for prothioconazole-desthio (metabolite of
prothioconazole) in rats is 500 ppm (43.3 mg/kg/day during gestation)
based on dystocia.  The maternal NOAEL is 160 ppm (15.1 mg/kg/day during
gestation).

The offspring systemic and neurotoxicity NOAEL for
prothioconazole-desthio in rats could not be determined, due to the
absence of neuropathological and brain morphometric evaluations at the
mid and low dose treatment levels

The non-neurotoxic developmental NOAEL for prothioconazole-desthio in
rats is 3.6 mg/kg/day, and the LOAEL is 15.1 mg/kg/day based on deviated
snout and malocclusion.

This developmental neurotoxicity is classified as
Acceptable/Nonguideline and does not satisfies the guideline requirement
for a developmental neurotoxicity study in rats (OPPTS 870.6300,
§83-6).  The classification may be upgradable pending submission of the
additional data listed under ‘deficiencies’ below, as well as
acceptable positive control data.  This review is a joint effort of the
PMRA and the EPA.

A.3.8	Metabolism

	870.7485	Metabolism - Rat

		Prothioconazole

	

			In a whole body autoradiography distribution study (MRID 46246419),
triazole-labeled JAU6476 (Prothioconazole) (Purity: >99%), was
administered to 8 Wistar rats/sex/dose in a single oral administration
at dose levels of 4 mg/kg bw non-radiolabeled JAU6476 and 4 mg/kg bw
[Triazole-UL-14C] JAU6476 in 0.5% aqueous Tragacanth.  One control
animal/sex was dosed with vehicle alone.  One animal/sex was killed at
1, 4, 8, 24, 48, 72, 120 and 168 hours after dose administration.
Control animals were killed 4 hours after dose administration.  All
animals were fixed and processed for whole body autoradiography.

The whole body autoradiography results are in agreement with the
absorption, distribution and excretion pattern of JAU6476 in the main
metabolism study (MRID 46246421).  In summary, peak concentrations in
males were noted 1 hour post-administration and continued to decline
until sacrifice at 168 hours. In females, absorption was slightly
delayed with peak concentrations in some tissues noted at 8 hours post-
administration.  The highest concentrations were noted in liver (up to
1.78 ug/g in males and up to 0.97 ug/g in females), followed by kidney
(renal medulla, up to 0.64 ug/g), brown/perirenal fat (up to 0.36 ug/g),
thyroid (up to 0.23 ug/g) and adrenal gland (up to 0.27 ug/g). All other
tissues showed peak concentrations of <0.13 ug/g. Concentrations of
radioactivity decreased rapidly from 24 to 168 hours
post-administration, indicative of continued elimination from the
tissues. 

This metabolism study in the rat is classified as
Acceptable/Nonguideline and does not satisfy the guideline requirement
for a metabolism study (OPPTS 870.7485; OECD 417) in the rat.  This
guideline requirement for prothioconazole (JAU6476) was satisfied by
another rat metabolism study (MRID 46246421).  This review is a joint
effort of the PMRA and the EPA.

________

 					The absorption, distribution, metabolism and excretion (MRID
46246421) of JAU6476 (Prothioconazole) (Purity 99.4-99.8% a.i) was
investigated in male and female Wistar rats following gavage
administration of [triazole-UL-14C]- or [phenyl-UL-14C]-labelled JAU6476
in 0.5% aqueous Tragacanth solution. Single oral low dose (SOLD) studies
were conducted using 2 mg/kg bw of [triazole-UL-14C]- or
[phenyl-UL-14C]-labelled JAU6476 in males and females; 5 mg/kg bw of
[phenyl- UL-14C]-labelled JAU6476 in males only. Single oral high dose
(SOHD) studies were conducted using 150 mg/kg bw of
[triazole-UL-14C]-labelled JAU6476 in males and females.  Repeat oral
low dose (ROLD) studies were conducted using a pretreatment of 2 mg/kg
bw unlabelled JAU6476 for 14-15 days followed by a SOLD of 2 mg/kg bw of
[phenyl-UL-14C]-labelled JAU6476 in males and females.  Biliary
excretion studies were conducted using 2 mg/kg bw [triazole-UL-14C]- and
[phenyl-UL-14C]-labelled JAU6476 in males only.  The animals were
sacrificed at 168 hours post-dosing for the SOLD and SOHD groups, at 168
hours after the final dose for the ROLD groups and at 48 hours
post-dosing for the bile- cannulated [triazole-UL-14C]-labelled group.

The biokinetic behavior and metabolism of JAU6476 was adequately
outlined in this series of tests, using both triazole and phenyl labels.
 The recovery of administered radioactivity was adequate.  The results
of a preliminary test showed that a minimal amount of radioactivity
(<0.06%) was recovered in the expired air (measured as 14CO2), therefore
it was determined that it was not necessary to monitor CO2 and volatiles
in further studies.  Following single oral low dose administration, the
absorption of JAU 6476 in male rats was approximately 94% for the
triazole label.  The absorption for the phenyl label was estimated to be
approximately 90% at 48 hours based on extrapolation of the course of
excretion for the triazole label at 48 hours.

Plasma radioactivity time-course data showed that absorption following
single oral low dose administration was rapid, with peak plasma
concentrations occurring between 0.33 and 0.66 hours post administration
in males and females.  Peak plasma concentrations following single oral
high dose administration occurred between 0.66 and 1.00 hours post
administration in males and females.  The absorption of the
phenyl-labelled JAU6476 was slightly more rapid, with peak plasma
concentrations occurring between 0.16 and 0.33 hours post administration
of a single oral low dose in males, and at 0.16 hours post
administration of a repeat oral low dose in males and females. 
Oscillations in the plasma time course were noted, indicating that the
radioactivity was subjected to enterohepatic circulation.  This effect
was more prominent in the female rats.  A slight delay in absorption
compared to males was also noted in females. 

Residual radioactivity in the rats 168 hours after a single oral low
dose administration was low. For the triazole label, 1.5% of the
administered dose was recovered in the tissues and carcass of males, and
0.4% was recovered in females.  The highest tissue levels were found in
liver, carcass and gastrointestinal tract. In all other tissues
examined, residual radioactivity levels ranged from 0.0004- 0.07%.  For
the phenyl label (administered to males only), 5.8% of the administered
dose was recovered in the tissues and carcass.  The highest tissue
levels were found in the gastrointestinal tract, liver and carcass. In
all other tissues examined, residual radioactivity levels ranged from
0.0001-0.05%. Residual radioactivity in the rats 48 hours after a repeat
oral low dose administration was also low, with 3.8% of the administered
dose recovered in the tissues and carcass of males, and 0.8% recovered
in females.  The highest tissue levels were found in liver,
gastrointestinal tract and carcass.  In all other tissues examined,
residual radioactivity levels ranged from 0.0002-0.05%.Total body
accumulation as well as liver accumulation was consistently higher in
males.  Residual radioactivity in the rats 168 hours after a single oral
high dose administration was also low, with 0.11% of the administered
dose recovered in the carcass and tissues of both males and females.
Total body accumulation was approximately the same in males and females,
with liver accumulation higher in the males. 

The primary route of excretion for both labels and both sexes was via
the feces.  Following single oral low dose administration (triazole
label), total recovery was approximately 94-95% of the administered dose
for both sexes, with 10% (males) and 16% (females) of the administered
dose eliminated in the urine, and 84% (males) and 78% (females)
eliminated in the feces.  In the phenyl-labelled group (males only), 5%
of the administered dose was eliminated in the urine and 81% in the
feces, for a total recovery of approximately 90%.  In the bile
duct-cannulated triazole-label group (males only), approximately 90% of
the administered dose was eliminated in the bile within 24-48 hours. In
the phenyl-label group (males only), approximately 81% of the
administered dose was eliminated in the bile after 24 hours and 93%
after 48 hours.

JAU6476 was extensively metabolized in the rat following oral
administration.  Eighteen metabolites and the parent compound were
identified in urine, feces and bile.  The biotransformation of JAU6476
consisted of 3 major reaction types including desulfuration, oxidative
hydroxylation of the phenyl moiety and glucuronic acid conjugation. 
Identification of the metabolites ranged from 26-63% of the administered
dose.  A higher percentage of metabolite isolation and identification
could not be achieved due to difficulties in fecal extraction where
21-33% of the administered dose remained in non-extractable residues in
the solids.  The parent compound JAU6476 was the most abundant in the
feces (1-22% of the administered dose), followed by the JAU6476-desthio
metabolite (3-18% of the administered dose).  All other fecal
metabolites represented less than 8% of the administered dose. The 1, 2,
4-triazole metabolite was not detected in the feces.  The major urinary
metabolite was JAU6476-S- or O-glucuronide (0.1-8% of the administered
dose) and was preferentially excreted in females.  The 1, 2, 4-triazole
metabolite represented 0.8-2.3% of the administered dose following
administration of single oral low and/or high doses.  The remaining
urinary metabolites each accounted for 0-1.4% of the administered dose. 
JAU6476- S- or O-glucuronide was the most abundant metabolite in the
bile, representing approximately 46% of the administered dose.  This
metabolite was excreted in females only in the urine, however it was
noted in the bile in males.  Desthio glucuronic acid metabolites in the
bile represented 8-10% of the administered dose.  Parent compound
represented 3-5% of the administered dose in the bile.  The 1, 2,
4-triazole metabolite was not detected in the bile. 

This metabolism study in the rat is classified as acceptable and
satisfies the guideline requirement for a metabolism study (OPPTS
870.7485; OECD 417) in rats.  This review is a joint effort of the PMRA
and the EPA.

________

		Prothioconazole-desthio

				In a metabolism study (MRID 46246439), SXX 0665 (99.6% purity)
(uniformly labelled with carbon-14 in the benzene ring of the molecule)
was administered singly or in multiple dose levels to groups of pregnant
rats (5/dose) at 1 or 3 mg/kg orally by gavage or 30 or 100 mg/kg by the
dermal route on gestation day 6.  The multiple dose regimen was
performed with 9 doses of non-radio labelled compound followed by one
dose of the radio labelled compound at intervals of 24 hours.  For
dermal application, the exposure time was 6 hours under occlusive
conditions followed by 18 hours of non-exposure.  

The maximum concentrations (Cmax) were comparable between single and
multiple oral administration of 1 mg/kg and 3 mg/kg and dermal
application of 30 mg/kg, respectively.  The maximum concentration varied
after single and multiple dermal application of 100 mg/kg.  The time to
achieve maximum concentration was prolonged after dermal application
compared with oral administration at all doses tested (single and
multiple) but the delay was not dose-dependent.  The longest terminal
half-life was observed in the high dose single dermal application (100
mg/kg) which was 34.4 h.  The lowest terminal half-life was observed in
the low dose multiple dermal application group (30 mg/kg).  The AUC
values (representing an indirect measure for the fraction of SXX 0665
absorbed) increased only slightly after large increases in applied dose
(both dermal and oral). 

This metabolism study in the rat is classified as supplemental and does
not satisfy the guideline requirement for a metabolism study (OPPTS
870.7485); OECD 417 in the rat (see deficiency notes).  This review is a
joint effort of the PMRA and the EPA.

________

				In a metabolism study (MRID 46246422), [Phenyl-UL-14C] SXX0665 (a
metabolite of prothioconazole) (99.8% a.i.), was administered to 5 to 10
Wistar BOR/WISW (SPF Cpb) male rats/dose in 0.5% aqueous Tragacanth in a
single oral gavage dose or an intraduodenal dose at levels of 1 or 5
mg/kg bw.  The animals were immediately placed in either metabolism
cages or restraining cages following dosing.  Expired air, urine, feces,
and/or bile were collected throughout the observation period and
analyzed.  The animals were sacrificed 48 hours after dose
administration, and the carcass, skin, and gastrointestinal tract from
each animal were collected and analyzed.

Absorption of the radioactive test material from the GIT commenced as
early as 4 minutes following dosing.  A maximum concentration of 0.052
µg/g was observed at 1.5 hours.  The largest amount of radioactivity
was observed in the liver and the GIT, likely due to long-lasting
enterohepatic circulation.  The remaining tissues contained levels of
radioactivity of less than 1%.  Greater than 90% of the administered
radioactive dose was excreted in the bile and urine.  Very little of the
administered radioactivity was recovered in the expired carbon dioxide. 
The majority of the radioactive administered dose was excreted in the
feces, with a minor portion being excreted in the urine.  The skin
contained a minute amount of the recovered radioactivity, while the
carcass and GIT contained up to 4 and 2.25%, respectively.  Excretion
was not likely complete at 48 hours, as the total body radioactive
residue was 5 to 6% of the administered dose at that time point.  The
elimination half-life was found to be 44.3 hours, and the mean residence
time was 48.2 hours.  These observations indicate that the process of
redistribution of the radioactivity into the plasma before elimination
was slow, as supported by the total clearance of 10.9 mL/min•kg bw and
the renal clearance of 1.4 mL/min•kg bw.  Following the intraduodenal
administration of the radioactive dose in bile-cannulated animals, 84 to
85% of the administered dose was found in the bile after 24 and 48
hours, respectively.  Excretion in urine in these animals accounted for
almost 6% of the administered dose after 48 hours, while excretion in
feces accounted for 2% of the administered dose for the same time
period.  In the pooled bile sample, 18 radioactive HPLC peaks were
observed accounting for 84.3% of the administered dose.  Five compounds
were isolated and identified, while the remaining 13 metabolites were
not identified, accounting for 44.7% of the administered dose.

In whole-body autoradiography experiments, the quick onset of absorption
of the test material was demonstrated.  Absorption was not complete
after one hour.  The autoradiograms also showed that the blood
concentration was less than the concentration present in the fatty
tissues, demonstrating the lipophilic nature of SXX0665, and perhaps of
its metabolites.  The mucous membrane of the stomach walls were observed
with radioactivity throughout the various observation periods, which was
considered an indication of extrabiliary secretion of the absorbed
radioactivity back into the stomach lumen.  The muscle, heart, lung,
brain, thyroid, and mineral portion of the bones showed minor
concentrations of radioactivity.  The testes had a radioactivity
distribution pattern indicative of the blood circulation in the organ. 
Medium amounts of radioactivity were observed in some glandular organs,
including the preputial gland and the adrenals.  The gums were also
observed with increased radioactivity, with unknown physiological
significance.  The distributions noted at one hour were fairly
consistent for 48 hours, though declining due to excretion.  The renal
cortex contained radioactivity to a much greater extent than did the
renal pelvis, indicating that the radioactivity was reabsorbed in the
duodenum.  As well, the radioactivity that is absorbed is likely not
transformed into metabolites that are adequately polar to be eliminated
by the kidney.  This results in increased passage through the liver by
the radioactive test material.

This metabolism study in the rat is classified Acceptable/Nonguideline
and does not satisfy the guideline requirement for a metabolism study
(OPPTS 870.7485; OECD 417) in rats.  This study alone does not fulfill
the guideline requirements for a metabolism study (DACO 4.5.9), but can
be considered a supplementary study along with the other studies
submitted under DACO 4.5.9.  This review is a joint effort of the PMRA
and the EPA.

	870.7600	Dermal Absorption - Rat

		Prothioconazole

	

			This study (MRID 46246423) was submitted in support of the proposed
registration of a new end use product, Proline 480 SC Foliar Fungicide,
containing the active ingredient prothioconazole.  This is a preliminary
study performed to obtain basic information on absorption of the use
product (JAU 6476 250 EC) and a 373 fold aqueous dilution (field
dilution) thereof.  Three other dermal absorption studies conducted in
monkeys were also submitted, one on the parent compound and two on the
prothioconazole desthio metabolite. 

Two groups of five male Wistar rats were administered nominal doses of
2.5 or 0.0067 mg/cm2 of prothioconazole in 100 ·L of the respective
solutions to a 10 cm2 area of the back, and monitored up to 24 hr 
post-dosing.  The skin wash was conducted after 24-hours and all animals
were sacrificed immediately after.  Dermal absorption was calculated by
adding residues measured in the excreta (urine + cage wash + feces),
carcass (blood + GI tract + carcass) and skin bound residues (skin test
site + residual skin).  Skin bound residues were included in the
calculation of dermal absorption, as the monitoring period (24- hours)
was not long enough to characterize skin bound residues.  As the high
dose exceeds the recommended guideline dose, it is not considered to be
useful to determine dermal absorption, as saturation of the treated site
may have occurred.  Mean dermal absorption at the low dose was 49.4%
(n=5).  This value is considered to be conservative because: (1) a
portion of the active ingredient was retained at the skin site (35.3%)
and it is unlikely that all of the skin bound residues will become
systemically available, and (2) the skin wash was not performed until 24
hours after exposure and 10 hours is considered most applicable to the
typical worker exposure time.

In addition, the formation of the potential metabolite, prothioconazole
desthio was investigated in the rinsing solutions of the application
site and in the applied skin on 1 animal at each dose level.  The
rinsing solutions of the application site and the applied skin at the
end of the 24 hour exposure period were analyzed by HPLC and TLC.  At
the high dose, the degradation product amounted to 0.5% on the skin at
the application site.  The metabolite was not found in the skin extracts
(extraction efficiency = 84%).  At the low dose, 6.3% of the applied
dose was due to prothioconazole desthio in the skin rinse and 3.3% of
the applied dose was detected as the metabolite in the skin extracts
(extraction efficiency = 64%).

________

			This study (MRID 46246424) was submitted in support of the proposed
registration of a new end use product, Proline 480 SC Foliar Fungicide,
containing the active ingredient prothioconazole.  The purpose of this
study was to determine the rate and route of elimination of
radiolabelled prothioconazole following a single intravenous or dermal
administration to male rhesus monkeys.  This exploratory study was to
aid in the design of a definitive dermal absorption and mass balance
study.  Three other dermal absorption studies conducted in rats and
monkeys were also submitted, one on the parent compound and two on the
desthio metabolite. 

The purpose of this study was to determine the rate and route of
elimination of prothioconazole derived radioactivity following a single
intravenous or dermal administration to male rhesus monkeys.  A single
male rhesus monkey received either an intravenous dose of 240 g
prothioconazole-phenyl-UL-14C or a dermal dose of 240 g (10 g/cm2)
prothioconazole SC 480 containing 14C prothioconazole.

Dermal administration of prothioconazole SC 480, containing 14C
prothioconazole, for 8 hours to a male rhesus monkey resulted in
recovery of 3.30% of the dose in excreta (1.91% in urine, 0.90% in
feces, and 0.33% in cage debris/rinse samples) over 192 hours.  The
majority of the administered dermal dose was recovered from the skin was
of the application site (87.25 %).  The overall recovery of
radioactivity from the dermally dosed animal was 92.51% indicating that
7.49% of the administered dose was unaccounted for.  Total recovery of
the intravenous dosed animal through 192 hours post-dose was 35.68% in
urine, 13.91% in feces and 31.13% in cage debris/rinse samples
(attributed primarily to urinary excretion).  The overall recovery of
radioactivity for the intravenously dosed animal was 81.25%, indicating
that 18.75% may have remained in the body. 

		Prothioconazole-desthio

			This (MRID 46246425) study was submitted in support of the proposed
registration of a new end use product, Proline 480 SC Foliar Fungicide,
containing the active ingredient prothioconazole.  The purposed of this
study was to determine the rate and route of elimination of
radiolabelled prothioconazole following a single intravenous or dermal
administration to male rhesus monkeys.  This exploratory study was to
aid in the design of a definitive dermal absorption and mass balance
study.  Three other dermal absorption studies conducted in rats and
monkeys were also submitted, two on the parent compound and one on the
prothioconazole desthio metabolite. 

The purpose of this study was to determine the rate and route of
elimination of prothioconazole-desthio, a metabolite of prothioconazole,
derived radioactivity following a single intravenous or dermal
administration to male rhesus monkeys.  A single male rhesus monkey
received either an intravenous dose of 240 ug prothioconazole
desthio-phenyl-UL-14C or a dermal dose of 240 ug (10 g/cm2)
prothioconazole desthio SC 480 containing 14C prothioconazole desthio
for 8 hours.

Dermal administration of prothioconazole desthio SC 480, containing 14C
prothioconazole desthio, to a male rhesus monkey resulted in a dermally
absorbed dose of 7.11% (3.74% in urine, 2.19% in feces, 0.60% in cage
debris/rinse samples, 0.57% in the pan wash/wipe and chair wipe, and
0.01% in tape strips) through 192 hours.  However, 10.47% of the applied
dose was recovered from the non-occlusive cover and therefore not
available for absorption.  The majority of the administered dermal dose
was recovered from the application site (83.28 %) with 0.01% of the
applied dose recovered in the tape strips.  The overall recovery of
radioactivity from the dermally dosed animal was 100.92%.  The overall
recovery of radioactivity for the intravenously dosed animal was 97.54%,
indicating that 2.46% may have remained in the body.

Based on the results of this exploratory study, it was decided that only
dermal administration of prothioconazole desthio would be performed in
the definitive dermal absorption and mass balance study in monkeys.

________

			The purpose of this study (MRID 46246426) was to determine the rate
and route of elimination of prothioconazole-desthio, a metabolite of
prothioconazole, derived radioactivity following dermal administration
to male rhesus monkeys.  Five male rhesus monkeys received a dermal dose
of 144 ·g (6 ·g/cm2) prothioconazole-desthio SC 480 containing 14C
prothioconazole-desthio for 8 hours.

Dermal administration of prothioconazole-desthio SC 480, containing 14C
prothioconazole-desthio, to male rhesus monkeys resulted in a mean
recovery of 18.61% of the dose in excreta (10.25 % in urine, 5.79 % in
feces, 1.50 % in cage debris/rinse samples, and 1.07 % in the pan
wash/wipe and chair wipe) through 144 hours.  The majority of the
administered dermal dose was recovered from the application site (mean =
73.54 %).  The overall mean recovery of radioactivity from the dermally
dosed animals was 92.15 %.  In a previously conducted pilot study, the
overall recovery of radioactivity in a monkey dosed intravenously with
prothioconazole-desthio and followed for 192 hours was high (97.54 %).

In an exploratory study, dermal administration of
prothioconazole-desthio SC 480, containing 14C prothioconazole-desthio,
to a male rhesus monkey resulted in a dermally absorbed dose of 7.11%
(3.74% in urine, 2.19% in feces, 0.60% in cage debris/rinse samples, and
0.57% in the pan wash/wipe, chair wipe, and 0.01% in tape strips)
through 192 hours.  However, 10.47% of the applied dose was recovered
from the non-occlusive cover and therefore was not available for
absorption.  The majority of the administered dermal dose was recovered
from the application site (83.28 %) with 0.01% of the applied dose
recovered in the tape strips.  The overall recovery of radioactivity
from the dermally dosed animal was 100.92%.  The overall recovery of
radioactivity for the intravenously dosed animal was 97.54%, indicating
that 2.46% may have remained in the body.

A.3.9	Special Studies

In a Liver Foci study (MRID 46246437), SXX 0665 (95.4 % a.i.; Batch
No.1717008/90) was administered to 6 groups of Wistar Bor:WISW
(5/sex/group) in the diet with 1% peanut oil at a dose level of 980 ppm.
 An initiator, N-nitrosomorpholine (NNM), and a regenerative cellular
proliferation inducer, D-galactosamine (DGA), were administered to some
of the treatment groups.

The incidences of foci of altered hepatocytes (FAH) were slightly
increased in males and females administered the test substance (980 ppm)
for 6 weeks (groups 1 and 7) compared to their controls (groups 2 and
8).  The incidence of FAH was slightly decreased in males and females
administered the test substance (980 ppm) for 12 weeks (groups 3 and 9)
compared to their controls (groups 6 and 12).  The incidences of FAH
were higher in the control males compared to the females. 
Administration of the test substance to animals previously treated with
an initiator (NNM) and a regenerative proliferation inducer (DGA)
(groups 4 and 10) produced only slightly elevated (no statistical
significance) incidences of FAH relative to those in the corresponding
control groups (groups 5 and 11).  Severe cytoplasmic vacuolation,
particularly following the 12-week treatment, was found in the Zone II
hepatocytes of nearly all males that had been exposed to the test
substance and exhibited this increased activity (this correlation was
absent in animal no. 19).  These vacuoles appeared void to the eye in
sections that had been treated with solvents. In native sections, these
vacuoles were highly refractive. Isolated cellular destruction and
mitosis of parenchyma1 cells were also observed in these animals.”  In
males administered the test substance, there was an increase in the
glucose-6 phosphate dehydrogenase activity in 3/5 animals compared to
0/5 controls after 6 weeks, and in 5/5 animals compared to 1/5 controls
after 12 weeks.  “This rise in activity was limited to the Rappaport
Zone I hepatocytes.”  The enzyme induction in the periportal
hepatocytes was stronger at 13 weeks in the males administered test
substance without NNM and DGA than with.  There were no clear patterns
with the incidence or severity of enzyme induction findings in the
females.  “No evident hepatocytic vacuolation was observed in the
females of any group.  However, in animals that had been treated with
the test substance, it was noted that the stored glycogen in perivenular
cells was distributed very uniformly throughout the cytoplasm, whereas
structures having the appearance of densely packed glycogen pools -
often concentrated at the cellular periphery - were observed in the
pertinent controls.”

This study reaffirms that there were no liver tumors in the long-term
studies and supports the findings that there are other effects in the
liver (vacuolation and enzyme induction).  A NOAEL or LOAEL will not be
established on this study since it is non-guideline and supplementary. 

This study is non-guideline and is classified as supplemental.  This
review is a joint effort of the PMRA and the EPA.

________

In an acute intraperitoneal toxicity study (MRID 46246434), groups of
unfasted, 8- to 11-week-old SPF-bred Wistar Bor:WISW (SPF-Cpb)rats
(5/sex/dose, with some exceptions) were given a single intraperitoneal
dose of SXX 0665 (94.0% a.i.) in 1% v/v Cremophor EL at doses of 10,
100, 355, 400, 450, 500, 800, or 1000 mg/kg bw and observed for 14 days.

Both male and female animals at the 100 mg/kg bw dose level showed signs
of apathy and labored breathing.  The males in this dose group also
showed decreased motility, staggering gait, and atony.  Females showed
these signs at higher dose levels.  Both sexes also displayed at doses
higher than 100 mg/kg bw piloerection, poor or no reflexes, lying on the
side, spasmodic state, transient convulsions, stretched legs, and
lacrimation.  Clinical signs were not observed in either sex at 10 mg/kg
bw.  Male animals dosed with 10 and 100 mg/kg bw gained body weight
throughout the study.  Above these doses, a number of surviving males
showed initial decreases in body weight before body weight gains were
observed.  Four of five females dosed with 10 mg/kg bw gained weight
during the study period.  The majority of surviving females in the other
dose groups showed a decrease in body weight at some point during the
observation period.  A number of male animals dosed with 355 to 450
mg/kg bw or higher showed whitish liver surface in places.  Males dosed
at 500 mg/kg bw or greater showed pale organs and patchy and/or
distended lungs.  Males dosed with 800 mg/kg bw were found with mucid
contents in the small intestine.

Estimated Intraperitoneal LD50:	Males: between 450 and 500 mg/kg bw

										Females: 632 mg/kg bw

This acute intraperitoneal study is acceptable as a supplementary study
only because there is no guideline requirement for acute intraperitoneal
toxicity.  This review is a joint effort of the PMRA and the EPA.

________

In this study (MRID 46246436), JAU 6476 (purity not provided) was
studied in vitro using solubilized hog thyroid microsomes as an enzyme
source in order to determine if there is an interaction with thyroid
peroxidase (TPO).  As a source of reference, ethylenethiourea (ETU),
propylthiouracil (PTU), 3-mercapto-1,2,4-triazole (a basic thiourea
moiety of JAU 6476), and JAU 6953 (a related thiourea derivative) were
investigated under similar conditions. 

Thyroid peroxidase (TPO)-catalyzed guaiacol oxidation was inhibited by
compounds tested. 3-mercapto- 1,2,4-triazole had the lowest IC50 value
(i.e.: lowest concentration required to inhibit the reaction by 50%),
followed by PTU then JAU 6476 and JAU 6953.  This provided initial
indication that TPO may be irreversibly inhibited. 

PTU, ETU, JAU 6476, JAU 6953 and 3-mercapto-1,2,4-triazole
dose-dependently suppressed TPO- catalyzed iodine formation temporarily.
 Following suppression, iodine reappeared.  The rate was then similar to
controls.  3-mercapto-1,2,4-triazole suppressed the rate of the
reappearing iodine formation longer than the other compounds.  

This study showed inhibition of guaiacol and iodine oxidation with the
compounds tested.

This study is classified as supplementary.  This study is non-guideline.
 This review is a joint effort of the PMRA and the EPA.

________

In an immunotoxicity study (MRID 46246438) JAU 6476 (Purity: 98.4%) was
administered to 8 CRL:CDI(ICR) mice/sex/dose by gavage at dose levels of
0, 25, 100 and 400 mg/kg bw/day. Clinical observations and body weight
measurements were performed daily.  Animals were exposed to the test
substance or positive control for 28 days, then injected intravenously
with sheep erythrocytes on day 24.  On day 28 (males) or 29 (females)
(peak day of IgM response), the animals were sacrificed, spleens were
removed and weighed, then spleen cells were prepared on day 30.  The
primary response to sheep erythrocytes was measured using a plaque assay

Piloerection was noted in the high-dose males from days 13-21.There were
no significant effects on body weight, food consumption or spleen
weights.  Under the conditions of this study, JAU 6476 did not suppress
the humoral immune response in a dose-dependent manner in that it did
not significantly decrease the IgM antibody-forming cell response to the
T-dependent antigen (sheep erythrocytes).  An increase in plaque-forming
cells was noted in the high-dose males ((125%).

This immunotoxicity study is classified as supplemental and does not
satisfy the guideline requirement for an immunotoxicity study (OPPTS
870.7800) in the mouse. Thymus weights, spleen cell viability and IgM
PFC activity per spleen were not measured/reported.  The range of
historical control data for spleen cell counts was not reported and the
positive control validation study was not provided.  This review is a
joint effort of the PMRA and the EPA.

________

A review was performed of ovarian toxicity in rats and mice following
varying lengths of exposure to SXX 0665 (MRID 46246441).  These studies
were: 4-weeks, 14-weeks with 5-weeks recovery, combined chronic toxicity
and carcinogenicity, and two-generation reproduction in rats as well as
13-weeks (range-finding) and carcinogenicity in mice.

Appendix B:  Metabolism Assessment  TC \l1 "Appendix B:  Metabolism
Assessment 

B.1	Metabolism Guidance and Considerations TC \l2 "B.1	Metabolism
Guidance and Considerations 

Figure B.1. Proposed metabolic pathway for [phenyl and
triazole-14C]-prothioconazole (JAU6476) in/on sugar beet, wheat and
peanut:

Figure B.2.  Proposed metabolic pathway for
[triazole-3,5-14C]-desthio-prothioconazole (SXX 0665) in/on summer
wheat:

Figure B.3.  Proposed metabolic pathway for Prothioconazole (JAU6476)
in livestock.

P = poultry   G = goat

Figure B.4. Proposed metabolic pathway in laying hens for [triazole- or
phenyl-14C]-prothioconazole (JAU6476):

Figure B.5. Proposed metabolic pathway in lactating goat for [triazole-
or phenyl-14C]-prothioconazole (JAU6476):

Figure B.6.  Proposed metabolic pathway for
[phenyl-14C]-desthio-prothioconazole (JAU6476-desthio or SXX0665) in
lactating goat:

Figure B.7. Proposed metabolic pathway for prothioconazole (JAU6476) in
rats following oral administration (extracted from page 18 of the
registrant’s study report).



Table B.1.	Chemical Names and Structures of Prothioconazole and its
Transformation Products.

Common Name/Code

Matrix	Chemical Name	Structure

Prothioconazole; JAU6476

[Parent]

Wheat forage, hay, straw, and grain

Peanut hay

Sugar beet tops

Rotated Swiss chard, turnip tops and root, and wheat straw

Goat milk, liver, kidney, muscle, and fat

Hen egg, liver, muscle, and fat
2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2-dihyd
ro-3H-1,2,4-triazole-3-thione	

Prothioconazole-desthio; JAU6476-desthio

[included in tolerance expression for plant and animal commodities]

Wheat forage, hay, straw, and grain

Peanut hay and nutmeat

Sugar beet tops and root

Rotated Swiss chard, turnip tops and root, and wheat forage, hay, straw,
and grain

Goat milk, liver, kidney, muscle, and fat

Hen egg, liver, muscle, and fat
α-(1-chlorocyclopropyl)-α-[(2-chlorophenyl)methyl]-1H-1,2,4-triazole-1
-ethanol	

Prothioconazole-4-hydroxy; JAU6476-4-hydroxy

[included in tolerance expression for animal commodities]

Goat milk, liver, kidney, muscle, and fat

Hen liver and muscle
2-[2-(1-chlorocyclopropyl)-3-(2-chloro-4-hydroxyphenyl)-2-hydroxypropyl]
-1,2-dihydro-3H-1,2,4-triazole-3-thione	

JAU6476-α-OH-desthio

Wheat forage, hay, straw, and grain

Sugar beet tops

Rotated Swiss chard, turnip tops and root, and wheat forage, hay, straw,
and grain
2-(1-chlorocyclopropyl)-1-(2-chlorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2
-propanediol	

JAU6476-3-OH-desthio

Wheat forage, hay, and straw

Peanut hay

Rotated Swiss chard, turnip tops and root, and wheat forage, hay, straw,
and grain

Goat milk, liver, kidney, muscle, and fat

α-(1-chlorocyclopropyl)-α-[(2-chloro-3-hydroxyphenyl)-methyl]-1H-1,2,4
-triazole-1-ethanol	

JAU6476-4-OH-desthio

Wheat forage, hay, and straw

Peanut hay

Rotated Swiss chard, turnip tops and root, and wheat forage, hay, straw,
and grain

Goat liver

Hen egg and liver
α-(1-chlorocyclopropyl)-α-[(2-chloro-4-hydroxyphenyl)-methyl]-1H-1,2,4
-triazole-1-ethanol	

JAU6476-6-OH-desthio 

Wheat forage, hay, and straw

Rotated turnip tops and root and wheat forage and straw
α-(1-chlorocyclopropyl)-α-[(2-chloro-6-hydroxyphenyl)-methyl]-1H-1,2,4
-triazole-1-ethanol	

JAU6476-OH-desthio isomers

Wheat forage and straw

Sugar beet tops

JAU6476-triazolinone

Wheat forage, hay, straw, and grain

Peanut hay

Sugar beet tops and root

Rotated Swiss chard, turnip tops and root, and wheat forage, hay, and
straw
2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-2,4-dihyd
ro-3H-1,2,4-triazole-3-one	

JAU6476 sulfonic acid

Wheat forage, hay, and straw

Peanut hay and nutmeat

Sugar beet tops

Rotated Swiss chard, turnip tops, and wheat forage, hay, and straw
1-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1H-1,2,4-
triazole-5-sulfonic acid	

JAU6476-α-acetoxy-desthio

Wheat forage, hay, straw, and grain

Rotated wheat forage, hay, and straw
2-(1-chlorocyclopropyl)-1-(2-chlorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol
-1-yl)propyl acetate	

JAU6476-disulfide

Wheat forage, hay, straw, and grain

Peanut hay

Rotated Swiss chard, turnip tops and root, and wheat forage, hay, and
straw

JAU6476-benzylpropyldiol

Wheat straw

Rotated Swiss chard, turnip tops and root, and wheat straw
2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)propane-1,2-diol	

Triazolyl-ethanol

Wheat straw

Peanut hay

Sugar beet tops

Rotated Swiss chard, turnip tops and root, and wheat forage, hay, and
straw

Hen egg, liver, muscle, and fat
1-(1-chlorocyclopropyl)-2-(1H-1,2,4-triazol-1-yl)ethanol	

JAU6476-desthio-phenyl-cysteine

Wheat forage

Peanut hay

JAU6476-dihydroxy-diene sulfonic acid

Peanut hay

JAU6476-dihydroxyolefin sulfonic acid

Peanut hay

JAU6476-desthio-hydroxy-dienyl-cysteine

Peanut hay and nutmeat

Sugar beet tops and root

JAU6476-S-methyl

Goat liver

α-(1-chlorocyclopropyl)-α-[(2-chlorophenyl)methyl]-3-(methylthio)-1H-1
,2,4-triazole-1-ethanol	

JAU6476-lactoside

Goat milk

JAU6476-dihydroxy-diene

Goat milk

Hen liver and muscle
2-[2-(1-chlorocyclopropyl)-3-(2-chloro-3,4-dihydroxycyclohexa-1,5-dien-1
-yl)-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione 1	

JAU6476-desthio-dihydroxy-diene

Goat milk and liver
3-chloro-4-[2-(1-chlorocyclopropyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)p
ropyl]cyclohexa-3,5-diene-1,2-diol 1	

Triazole metabolites

1,2,4-Triazole

Hen egg, liver, muscle, and fat	1,2,4-triazole	

Triazolylalanine (TA)

Wheat forage, hay, straw, and grain

Peanut hay and nutmeat

Sugar beet tops and root

α-amino-1H-1,2,4-triazole-1-propanoic acid	

Triazolylacetic acid (TAA)

Wheat forage, hay, straw, and grain

Peanut hay and nutmeat

Rotated Swiss chard, turnip tops and root, and wheat forage, hay, straw,
and grain	1H-1,2,4-triazole-1-acetic acid	

Triazolylhydroxypropionic acid (THPA)

Wheat forage, hay, straw, and grain

Peanut hay and nutmeat

Sugar beet tops

Rotated Swiss chard, turnip tops and root, and wheat forage, hay, straw,
and grain	α-hydroxy-1H-1,2,4-triazole-1-propanoic acid	

Thiocyanate

Goat milk, liver, kidney, muscle, and fat

Hen egg, liver, muscle, and fat	thiocyanate ion	

Glucosides

JAU6476-desthio-glucoside

Wheat hay and straw

JAU6476-OH-desthio glucoside isomers 2

Wheat forage, hay, straw, and grain

Peanut nutmeat and hay

Rotated Swiss chard, turnip tops and root, and wheat forage, hay, and
straw

JAU6476-OH-desthio glucoside isomers

Sugar beet tops

or

JAU6476-desthio-malonyl-glucoside

Wheat forage and hay

JAU6476-OH-desthio-malonyl-glucoside

Wheat forage, hay, and straw

Peanut hay

JAU6476-dihydroxy-desthio-malonyl-glucoside

Wheat forage

JAU6476-benzylpropyldiol glucoside

Wheat hay, straw, and grain

Rotated turnip tops and root and wheat forage and straw
2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)propane-1,2-diol glucoside	

Triazolyl-ethanol-glucoside

Wheat forage, hay, and straw

Peanut hay

Sugar beet tops

Rotated turnip tops and root and wheat forage, hay, and straw

Triazolyl-sulfonic acid-ethanol-glucoside

Sugar beet tops

JAU6476-OH-sulfonic acid-glucoside isomers

Wheat forage and hay

Sugar beet tops

JAU6476-hydroxy-di-sulfonic acid glucoside

Sugar beet tops

JAU6476-desthio-dihydroxy-olefin glucosides

Peanut hay and nutmeat

Rotated Swiss chard, turnip tops and root, and wheat forage, hay, and
straw

Glucuronides

JAU6476-hydroxy-glucuronide 2

Goat milk, liver, kidney, muscle, and fat

Hen liver

JAU6476-S-glucuronide

Goat milk, liver, kidney, muscle, and fat

Hen egg, liver, muscle, and fat

JAU6476-O- or S-glucuronide

Goat milk, liver, kidney, muscle, and fat

Hen egg, liver, muscle, and fat

JAU6476-N-glucuronide

Goat milk, liver, kidney, muscle, and fat

Hen liver and muscle

JAU6476-desthio-3,4-dihydroxy-dienyl-glucuronide

Goat liver

Hen liver and muscle

JAU6476-4-hydroxy-desthio-glucuronide

Goat milk

JAU6476-dihydroxy-desthio-glucuronide

Goat milk

JAU6476-hydroxy-methoxy-desthio-glucuronide

Goat milk

JAU6476-desthio-glucuronide

Goat milk

Sulfate conjugates

Sulfate conjugate of JAU6476-hydroxy

Goat liver

Sulfate conjugate of JAU6476-hydroxy-desthio

Hen liver and fat

Sulfate conjugate of JAU6476-dihydroxy-desthio

Hen liver, muscle, and fat

Sulfate conjugate of JAU6476-hydroxy-methoxy-desthio

Hen liver, muscle, and fat

1  When chemical names were not provided by the petitioner, the chemical
naming feature of ISIS/Draw was used to generate the name.

2  Including 3-hydroxy and/or 4-hydroxy isomers.





Table B.2.  Tabular Summary of Metabolites & Degradates of
Prothioconazole.

Chemical Name	

Matrix	

Percent TRR	

Structure

Major Residue (>10%TRR)	

Minor Residue (<10%TRR)

	

Prothioconazole

2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2-dihyd
ro-3H-1,2,4-triazole-3-thione	

Wheat , grain	

	

Yes	

	

Wheat ,forage	

	

Yes

Wheat, hay	

	

Yes

Wheat, straw	

	

Yes

Sugar beet, root	

	

NF

Sugar beet, tops	

	

Yes

Peanut, nut meat	

	

NF

Peanut, hay	

	

Yes

Goat, milk	

	

Yes

Goat, liver	

Yes	

Goat, kidney	

Yes	

Goat, muscle	

Yes	

Goat, fat	

Yes	

Hen, egg	

Yes	

Hen, liver	

Yes	

Hen, fat	

Yes	

Hen, muscle	

Yes	

Hen, egg	

Yes	

Rat	

Yes 22% adm dose (feces)	

Water	

	

	

JAU6476-O- or S-glucuronide	

Wheat	

	

NF	

	

Sugar beet	

	

NF

Peanut	

	

NF

Goat, milk	

	

Yes

Goat, liver	

Yes	

Goat, kidney	

Yes	

Goat, muscle	

Yes	

Goat, fat	

Yes	

Hen, egg	

Yes	

Hen, liver	

Yes	

Hen, fat	

	

Yes

Hen, muscle	

Yes	

Hen, egg	

Yes	

Rat	

Yes 46% adm dose (bile)	

Yes 8% adm dose (urine)

Water	

	

	

Prothioconazole-Desthio	

Wheat , grain	

15.9% (0.0139 ppm)	

	

	

Wheat ,forage	

35.3% (3.7 ppm)	

Wheat, hay	

18.5% (1.64 ppm)	

Wheat, straw	

22.3% (5.95 ppm)	

Sugar beet, root	

41% (0.048 ppm)	

Sugar beet, tops	

26% (1.14 ppm)	

Peanut, nut meat	

	

NF

Peanut, hay	

26.7% (1.14 ppm)	

Goat, milk	

	

Yes

Goat, liver	

Yes	

Goat, kidney	

Yes (Glucuronide)	

Goat, muscle	

	

Yes

Goat, fat	

Yes (free & Glucuronide)	

Hen, egg	

Yes	

Hen, liver	

	

Yes

Hen, fat	

Yes	

Hen, muscle	

	

Yes

Hen, egg	

Yes	

Rat	

Yes 18% adm dose (feces)	

Water	

Yes	

	

1,2,4-triazole	

Wheat	

	

NF	

	

Sugar beet	

	

NF

Peanut	

	

NF

Goat	

	

NF

Hen	

Yes (egg and muscle)	

Yes (liver)

Rat	

	

Water	

Yes	

	

Triazolyalanine (TA)	

Wheat	

Yes (all except straw)	

Yes (straw)	

Not available

	

Sugar beet	

Yes (roots)	

Yes (tops)

Peanut	

Yes (nutmeat)	

Yes (hay)

Goat	

	

NF

Hen	

	

NF

Rat	

	

Water	

	

	

Triazolylacetic acid (TAA)	

Wheat	

Yes (grain)	

Yes (forage, hay, & straw)	

	

Sugar beet	

	

NF

Peanut	

	

Yes (nutmeat & hay)

Goat	

	

NF

Hen	

	

NF

Rat	

	

Water	

	

	

Thiocyanate

thiocyanate ion	

Wheat	

	

NF	

	

Sugar beet	

	

NF

Peanut	

	

NF

Goat	

Yes (milk, fat, muscle)	

Yes (liver, kidney)

Hen	

	

Yes (all tissues)

Rat	

	

Water	

	

	

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ro-3H-1,2,4-triazole-3-thione	

Wheat	

	

NF	

	

Sugar beet	

	

NF

Peanut	

	

NF

Goat	

Yes (liver) 	

Yes (milk, muscle, kidney, & fat)

Hen	

	

Yes (liver)

Rat	

	

Water	

	

	

JAU6476-4-hydroxy-glucuronide	

Wheat	

	

NF	

Structure not available

	

Sugar beet	

	

NF

Peanut	

	

NF

Goat	

Yes (muscle)	

Yes (kidney)

Hen	

	

NF

Rat	

	

Water	

	

	

Wheat:		

MRID:  46246141;  Haas, M.; Bornatsch, W. (2000) Metabolism of JAU 6476
in Spring Wheat (after foliar application).  Project Number:
M/1730851/5, 110880, MR/198/99.  Unpublished study prepared by Bayer Ag
Institut fuer Ruckstands-Analytik.  149 p.

MRID:  46246142;  Haas, M. (2001) Metabolism of JAU 6476 in Spring Wheat
after Seed Dressing.  Project Number: M/1730885/2, 110881, MR/467/99. 
Unpublished study prepared by Bayer Ag Institut fuer
Ruckstands-Analytik.  84 p.

MRID:  46246143;  Duah, F.; Lopez, R. (2004) The Metabolism of
[Triazole-3, 5-(Carbon 14)] JAU6476 in Wheat.  Project Number: J6041601,
200733.  Unpublished study prepared by Bayer Corp.  197 p.

MRID:  46246144;  Vogeler, K.; Sakamoto, H.; Brauner, A. (1993)
Metabolism of SXX 0665 in Summer Wheat.  Project Number: M/1730365/5,
MR/PF3906, PF/3906.  Unpublished study prepared by Bayer Ag Institut
fuer Ruckstands-Analytik.  114 p.

Peanut:  

MRID:  46246145;  Haas, M. (2001) Metabolism of [Phenyl-UL-(Carbon
14)]JAU6476 in Peanuts.  Project Number: M/1730984/2, MR/193/01. 
Unpublished study prepared by Bayer Ag Institut fuer
Ruckstands-Analytik.  130 p.

MRID:  46246146;  Haas, M. (2003) Metabolism of [triazole-UL-(Carbon
14)]JAU6476 in Peanuts.  Project Number: M1731145/2, MR/194/02. 
Unpublished study prepared by Bayer Ag, Institute of Product Info.  145
p.

Sugar Beet:  

MRID:  46246147;  Beedle, E.; Ying, S. (2004) The Metabolism of
[Triazole-UL-(Carbon 14)]JAU6476 in Sugar Beets.  Project Number:
J6041603, 200467.  Unpublished study prepared by Bayer Corp.  91 p.

MRID:  46246148;  Beedle, E.; Ying, S. (2004) The Metabolism of
[Phenyl-UL-(Carbon 14)]JAU6476 in Sugar Beets.  Project Number:
J6041602, 200466.  Unpublished study prepared by Bayer Corp.  86 p.

Livestock (Goat):

MRID:  46246149;  Weber, E.; Weber, H.; Spiegel, K. (2003)
[Triazole-UL-(Carbon 14)]JAU6476: Absorption, Distribution, Excretion,
and Metabolism in the Lactating Goat.  Project Number: M51819114,
MR/448/02.  Unpublished study prepared by Bayer Ag, Institute of Product
Info.  308 p.

MRID:  46246150;  Weber, H.; Spiegel, K. (2001) [Phenyl-UL-(Carbon
14)]JAU6476: Absorption, Distribution, Excretion, and Metabolism in the
Lactating Goat.  Project Number: M/91819082, MR/092/01.  Unpublished
study prepared by Bayer Ag Institut fuer Ruckstands-Analytik.  205 p.

MRID:  46246201; Weber, H.; Weber, E.; Spiegel, K. (2002)
((Phenyl-UL-(Carbon 14))JAU6476-desthio: Absorption, Distribution,
Excretion, and Metabolism in the Lactating Goat Including the Validation
of the Residue Analytical Method for the Determination of
JAU6476-desthio, JAU6476-3-hydroxy-desthio.  Project Number: M91819091,
SXX1, SXX2.  Unpublished study prepared by Bayer Ag Institut fuer
Ruckstands-Analytik.  399

Livestock (Hens):

MRID:  46246202;  Weber, H.; Spiegel, K. (2001) ((Phenyl-UL-(Carbon
14))JAU6476: Absorption, Distribution, Excretion, and Metabolism in
Laying Hens.  Project Number: M/81819090, MR/309/01.  Unpublished study
prepared by Bayer Ag Institut fuer Ruckstands-Analytik.  142 p.

MRID:  46246203; Weber, H.; Justus, K. (2003) ((Triazole-UL-(Carbon
14))JAU6476: Absorption, Distribution, Excretion, and Metabolism in
Laying Hens.  Project Number: M/91819118, MEF005/03.  Unpublished study
prepared by Bayer Ag, Institute of Product Info.  157 p.

Minor metabolites (<10% TRR) that were found in only one study or
matrices were not included in this table.

NF = not found.



Table B.3.  Summary of physical/chemical and environmental fate and
transport properties of prothioconazole combined residues of concern.

PARAMETER	VALUE(S) (units)	SOURCE MRID	COMMENT

  Chemical Name	Prothioconazole: 

  SEQ CHAPTER \h \r 1
2-[2-(1-Chlorocyclopropyl)-3-(2-chloropheny1)-2-hydroxypropyl]-1,2-dihyd
ro-3H-1,2,4-triazole-3-thione; 

Prothioconazole-desthio:  

2-[2-(1-Chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxy-propyl]-1,2-dihy
dro-3H-1,2,4-triazole 

Prothioconazole-S-methyl:  

alpha-1(1-chlorocyclopropyl)-alpha-[(2-chlorophenyl)methyl]-3-(methylthi
o)-1H-1,2,4-triazole-1-ethanol	46246003   SEQ CHAPTER \h \r 1 46477401
–

  Molecular Weight	Prothioconazole:   SEQ CHAPTER \h \r 1 344.264 

Prothioconazole-desthio: 312.2

Prothioconazole-S-methyl: 358.3	46246003 46477401	–

  Solubility 

                   (pH 4 (20 oC))

                   (pH 8 (20 oC))

                   (pH 9 (20 oC))	Prothioconazole:

5 mg/L or ppm

300 mg/L or ppm

2000 mg/L or ppm	46246003	  SEQ CHAPTER \h \r 1 Moderately solubility at
acidic pH, highly soluble at alkaline pHs.

  Vapor Pressure (20 oC and          25 oC)	Prothioconazole:   SEQ
CHAPTER \h \r 1 <<4 x 10-7 Pa	46246003	  SEQ CHAPTER \h \r 1 Relatively
non-volatile under field conditions.

  Henry’s Law constant (20 oC)	Prothioconazole: <2.96 x 10-10
atm-m3/mol	46246003	Estimated from vapor pressure and water solubility.

  pKa (20 oC)	Prothioconazole: 6.9	46246003	  SEQ CHAPTER \h \r 1 Weak
acid, anion at neutral and alkaline pHs.

 Octanol-Water Partition                                                
                   

 Coefficient (log KOW,  at 20 oC)

                 Unbuffered

                  pH 4

                  pH7

                  pH9	Prothioconazole:

4.05

4.16

3.82

2.00	46246003	  SEQ CHAPTER \h \r 1 Potential for bioaccumulation at
neutral and acidic pH.

  Hydrolysis Half-life 

  (pH 4, 7, 9; (25 oC))

	Prothioconazole and Prothioconazole-desthio: 

stable

(Prothioconazole-S-methyl is not formed from prothioconazole
hydrolysis.)	  SEQ CHAPTER \h \r 1 46246505

  SEQ CHAPTER \h \r 1 46246506	Study (46246505) conducted on
prothioconazole at 50 oC; results extrapolated to 25 oC.  Phenyl label
only.  Stable at all three pHs.  

Study (46246506) conducted on prothioconazole-desthio as “parent” at
25 oC.  Degradation slopes not significantly different from zero; phenyl
label only.

  Aqueous Photolysis Half-life 

  (pH 7, at 25 oC)	Prothioconazole:

t1/2  = 9.7 days                             

Prothioconazole-desthio:

Increasing at study termination

Prothioconazole and Prothioconazole-desthio: 

t1/2  = 101.9 days 

(Prothioconazole-S-methyl is not formed from prothioconazole aqueous
photolysis.)	46246507	Value corrected to represent natural sunlight at
40°N latitude; uncorrected laboratory half-life of 19.9 days for both
phenyl and triazole labels (continuous irradiation; xenon lamp). 
Concentration of prothioconazole-desthio was still increasing at
prothioconazole aqueous photolysis study termination.

  Soil Photolysis Half-life	Prothioconazole and Prothioconazole-desthio:

stable

(Prothioconazole-S-methyl is not formed from prothioconazole soil
photolysis.)	46246510	Half-life could not be calculated as parent
degraded faster in dark samples than in irradiated samples.  Phenyl
label only.  Concentration of prothioconazole-desthio was still
increasing at study termination.

  Aerobic Soil Metabolism 

  Half-life	Prothioconazole combined residues of concern: 

t1/2 =  533.2 days (silt; phenyl),                         866.4 days
(silt; triazole).                                   990.2 days (loamy
sand; phenyl),                   1386.3 days (loamy sand; triazole),    
               866.4 days (sandy loam; phenyl) ,                     
462.1 days (silty clay loam; phenyl).

                                                  	46246511 46246512
Half-lives are calculated via linear regression on log-transformed data,
combining amounts of prothioconazole, prothioconazole-desthio, and
prothioconazole-S-methyl per sampling interval.   Phenyl and triazole
labels treated separately, labeled accordingly.  Non-extractable
residues added in as parent.    

  Anaerobic Aquatic Metabolism   

  Half-life	Prothioconazole combined residues of concern: 

t1/2  = stable (total system); 

56.8 days (water layer).

	46246516	  SEQ CHAPTER \h \r 1 Fuquay, GA pond sediment/water system. 
Sandy clay loam/water, phenyl label only.  Half-lives are calculated via
linear regression on log-transformed data, combining amounts of
prothioconazole, prothioconazole-desthio, and prothioconazole-S-methyl
per sampling interval.  Non-extractable residues added in as parent.    

  Aerobic Aquatic Metabolism 

  Half-life	Prothioconazole combined residues of concern: 

t1/2 = 433.2 days (H, total system, p),                346.6 days (H,
total system, t),                            106.6 days (A, total
system, p),                           67.3 days (A, total system, t).

t1/2  = 17.2 days (H, water layer, p),                    16.2 days (H,
water layer, t),                               23.3 days (A, water
layer, p),                              21.7 days (A, water layer, t).

	  SEQ CHAPTER \h \r 1 46246515	Two systems tested: (H) Honniger Weiher
pond (loam/water) and (A)   SEQ CHAPTER \h \r 1 Anglerweiher lake (loamy
sand/water). Both phenyl (p) and triazole (t) labels in each system. 
Half-lives are calculated via linear regression on log-transformed data,
combining amounts of prothioconazole, prothioconazole-desthio, and
prothioconazole-S-methyl per sampling interval.  Non-extractable
residues added in as parent.    

Organic Carbon Partition

  Coefficient (KOC)	(mL/gOC)	LS	SCL	SL	S

Prothioconazole	--

	--	--	--	  SEQ CHAPTER \h \r 1 46246539   SEQ CHAPTER \h \r 1 46246504

	Parent mobility cannot be determined due to instability and low column
resolution; very high sorption estimated, lower mobility than
transformation products

	Prothioconazole-desthio	523	536	617	625	  SEQ CHAPTER \h \r 1 46246450

	Conducted on prothioconazole-desthio as “parent.”  Used four soils:
loamy sand (LS) at 0.79%OC, silty clay loam (SCL) at 1.66%OC, sandy loam
(SL) at 2.02%OC, silt (S) at 2.14%OC.

	Prothioconazole-S-methyl	1973	2484	2772	2995	  SEQ CHAPTER \h \r 1
46246501	Conducted on prothioconazole-S-methyl as “parent.”  Used
same soils as MRID: 46246450.

  Soil Partition Coefficient (Kd)	(mL/g)	LS	SCL	SL	S

Prothioconazole	--	--	--	--	  SEQ CHAPTER \h \r 1 46246539   SEQ CHAPTER
\h \r 1 46246504	Same as for KOC.

	Prothioconazole-desthio	4.13	8.90	12.46	13.38	  SEQ CHAPTER \h \r 1
46246450	Same as for KOC.

	Prothioconazole-S-methyl	15.6	41.2	56.0	64.1	  SEQ CHAPTER \h \r 1
46246501	Same as for KOC.

  Terrestrial Field Dissipation 

  Half-life1	California (sandy loam/loam):        Prothioconazole:      
                                                t1/2 (in surface soil)=
2.2 days; 

Not detected above LOD below a depth of 15 cm nor after 7DAT.           
                           Prothioconazole-desthio:                     
                      t1/2 (in surface soil)= 84.5 days; 

Detected above LOD to a depth of 45 cm and through 307DAT.

Georgia (sand/sandy loam):   

Prothioconazole:                                                        
                            t1/2 (in surface soil)= 4.7 days; 

Not detected above LOD below a depth of 15 cm nor after 14DAT.

Prothioconazole-desthio:

t1/2 (in surface soil)= 96.3 days; 

Detected above LOD to a depth of 30 cm through 7DAT. 

New York (loamy sand):

Prothioconazole:

t1/2 (in surface soil)= 96.3 days; 

Not detected above LOD below a depth of 15 cm nor after 211DAT.

Prothioconazole-desthio:                                       t1/2 (in
surface soil)= 315.1 days; 

Not detected above LOD below a depth of 15 cm (except for one sampling
interval  (211DAT) where detected above LOD to 30 cm); detected above
LOD through study completion (567DAT).	46246517

46246518

46246519	Studies conducted on prothioconazole as parent.  For   SEQ
CHAPTER \h \r 1 half-lives calculated for degradates from parent
dissipation studies, day of max concentration of degradate is used as
day zero in regression.

  Aquatic Field Dissipation 

  Half-life1	California (clay):                          
Prothioconazole:                                                    t1/2
(in sediment)= 203.9 days;                               t1/2 (in paddy
water)= 1.7 days.                Prothioconazole-desthio:               
                       t1/2 (in sediment)= 122 days.

Arkansas (loam):                                 Prothioconazole:       
                                            t1/2 (in sediment)= too few
detections;                   t1/2 (in paddy water)= 0.9 days.

Prothioconazole-desthio:                                       t1/2 (in
sediment)= 121.6 days.                           

Arkansas-cropped (loam):               Prothioconazole:                 
                                  t1/2 (in sediment)= too few
detections;                   t1/2 (in paddy water)= 0.6 days.          
                                                               
Prothioconazole-desthio:                                       t1/2 (in
sediment)= 90.0 days.	46246522 

46246523 

   

46246524	Studies conducted on prothioconazole as parent.  For   SEQ
CHAPTER \h \r 1 half-lives calculated for degradates from parent
dissipation studies, day of max concentration of degradate is used as
day zero in regression.

Bioconcentration Factor (BCF) 	Prothioconazole and
prothioconazole-desthio do not appear to bioaccumulate. 	  SEQ CHAPTER
\h \r 1 46246034   SEQ CHAPTER \h \r 1 46246035	BCF cannot be calculated
due to   SEQ CHAPTER \h \r 1 lack of a clear accumulation plateau.

1DAT= days after treatment.



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

Appendix C.	Tolerance Summary for Prothioconazole.

Commodity	Proposed Tolerance (ppm)	Recommended Tolerance (ppm)	Comments/

Correct commodity definition

Tolerances for residues of prothioconazole and the desthio metabolite

Barley, grain	0.2	0.35	The proposed tolerance is too low.

Barley, hay	7.0	7.0

	Barley, straw	2.0	4.0	The proposed tolerance is too low.

Barley, pearled barley	0.2	Delete, not needed	A separate tolerance is
not needed for pearled barley.

Barley, bran	0.4	Delete, not needed	A separate tolerance is not need for
barley, bran.

Black mustard, seed	0.1	Delete, not allowed at this time	Additional crop
field trial data are needed to support this tolerance.

Borage, seed	0.1	Delete, not allowed at this time	Additional crop field
trial data are needed to support this tolerance.

Canola, seed	0.1	Delete, not needed	As specified under 40 CFR
§180.1(h), a tolerance for rapeseed applies to canola seed and crambe
seed.

Crambe, seed	0.1	Delete, not needed

	Field mustard, seed	0.1	Delete, not needed	Covered under the tolerance
for rapeseed.

Flax, seed	0.1	Delete, not allowed at this time	Additional crop field
trial data are needed to support this tolerance.

Grain, aspirated fractions	13.0	11	The proposed tolerance is too high;

Grain, aspirated grain fractions

Indian mustard, seed	0.1	Delete, not allowed at this time	Additional
crop field trial data are needed to support this tolerance.

Indian rapeseed	0.1	Delete, not needed	Covered under the tolerance for
rapeseed.

Pea and bean, dried, shelled, except soybean, subgroup	0.8	0.90	The
proposed tolerance is too low.

Pea and bean, dried shelled, except soybean, subgroup 6C

Peanut, nutmeat	0.02	0.02	Peanut

Peanut, hay	5.0	6.0	The proposed tolerance is too low.

Peanut, meal	0.3	Delete, not needed	A separate tolerance is not needed
for peanut meal.

Rapeseed, seed	0.1	0.15	The proposed tolerance is too low.

Rice, grain	0.25	Delete, not needed	Petitioner intends to remove rice
from their tolerance petition.

Rice, straw	1.5	Delete, not needed	Petitioner intends to remove rice
from their tolerance petition.

Rice, hulls	1.0	Delete, not needed	Petitioner intends to remove rice
from their tolerance petition.

Wheat, grain	0.06	0.07	The proposed tolerance is too low.

Wheat, forage	7.0	6.0	The proposed tolerance is too high.

Wheat, hay	4.0	4.5	The proposed tolerance is too low.

Wheat, straw	2.3	5.0	The proposed tolerance is too low.

Wheat, bran	1.5	Delete, not needed. 	Covered under the tolerance for
wheat, grain

Wheat, germ	0.15	Delete, not needed.	Covered under the tolerance for
wheat, grain.

Tolerances for the combined residue of prothioconazole, the desthio
metabolite, and conjugates convertible to these two compounds by acid
hydrolysis, calculated as prothioconazole

Milk	0.006	0.02	The proposed tolerance is too low.

Cattle, fat	0.1	0.1

	Cattle, meat	0.01	0.02	The proposed tolerance is too low.

Cattle, meat byproducts	1.2	0.2	The proposed tolerance is too high.

Goat, fat	None	0.1	Extrapolated from cattle.

Goat, meat	None	0.02	Extrapolated from cattle.

Goat, meat byproducts	None	0.2	Extrapolated from cattle.

Hog, meat byproducts	None	0.05	Extrapolated from cattle.

Horse, fat	None	0.1	Extrapolated from cattle.

Horse, meat	None	0.02	Extrapolated from cattle.

Horse, meat byproducts	None	0.2	Extrapolated from cattle.

Sheep, fat	None	0.1	Extrapolated from cattle.

Sheep, meat	None	0.02	Extrapolated from cattle.

Sheep, meat byproducts	None	0.2	Extrapolated from cattle.

Poultry, liver	None	0.02	A tolerance is needed.	

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