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 <IP_ADDRESS>.

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 <IP_ADDRESS>.

Table <IP_ADDRESS>.	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 <IP_ADDRESS>.  In addition,
revisions to the proposed tolerance levels for certain commodities and
deletion of certain tolerances are required, as specified in Table
<IP_ADDRESS>.

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 = <IP_ADDRESS> (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.