**UNITED STATES ENVIRONMENTAL PROTECTION AGENCY**

WASHINGTON, D.C. 20460

![](media/image1.wmf){width="0.85in" height="0.925in"}

> OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: December 31, 2007

**[MEMORANDUM]{.underline}**

SUBJECT: Prothioconazole: Human Health Risk Assessment for Proposed Uses
on Soybeans \[Petition No: 6F7073, DP Barcode: 329704\] and Sugar Beets
\[Petition No: 6F7134, DP Barcode: D335154\] PC Code: 113961.

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

Myron Ottley, Ph.D., Senior Toxicologist

Sarah Winfield, Biologist

Registration Action Branch 3

Health Effects Division (7509P)

AND

Stephen Funk, Ph.D., Senior Chemist

Immediate Office

Health Effects Division (7509P)

AND

Toiya Goodlow, Chemist

Reregistration Branch 1

Health Effects Division (7509P)

THROUGH: Paula Deschamp, Branch Chief

Registration Action Branch 3

Health Effects Division (7509P)

TO: Cynthia Giles-Parker/Tony Kish, RM Team 22

Fungicide Branch

Registration Division (5705P)

Bayer CropScience submitted separate petitions (6F7073 for soybeans and
6F7134 sugar beets) for the establishment of permanent tolerances for
residues of prothioconazole
(2-\[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl-2-hydroxypropyl\]-1,2-dihydro-3*H*-1,2,4-triazole-3-thione)
and its desthio metabolite in/or the following commodities: soybean,
seed; soybean, hay; soybean, forage; beet, sugar, tops; and beet sugar,
roots.

The Registration Division (RD) of the Office of Pesticide Programs (OPP)
has requested that HED evaluate toxicology and residue chemistry data
and conduct dietary, aggregate, and occupational exposure and risk
assessments, as needed, to estimate the risk to human health that will
result from the proposed use of prothioconazole in/on soybeans and sugar
beets.

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

Note: HED previously completed a Section 3 human health risk assessment
for the use of prothioconazole on barley, canola, chickpea, dried
shelled peas and beans crop subgroup, lentils, oilseed crop subgroup
(rapeseed, Indian rapeseed, Indian mustard, field mustard, black
mustard, flax, crambe, borage), peanut and wheat (spring, durum and
winter) (Memo B. O'Keefe, et. al., 1/23/07, DP# 328967). As there are no
new toxicity data associated with this action, the hazard
characterization and endpoint selection, from the previous risk
assessment are applied directly to this action.

> **Table of Contents**

**1.0** **Executive Summary** [5](#__RefHeading___Toc187567037)

**2.0** **Ingredient Profile** [14](#__RefHeading___Toc187567038)

2.1 Summary of Registered/Proposed Uses
[15](#__RefHeading___Toc187567039)

2.2 Structure and Nomenclature [19](#__RefHeading___Toc187567040)

2.3 Physical and Chemical Properties [19](#__RefHeading___Toc187567041)

**3.0** **Hazard Characterization/Assessment**
[20](#__RefHeading___Toc187567042)

3.1 Hazard and Dose-Response Characterization
[20](#__RefHeading___Toc187567043)

3.1.1 Database Summary [20](#__RefHeading___Toc187567044)

3.1.2 Toxicological Effects [21](#__RefHeading___Toc187567045)

3.1.3 Dose-response [22](#__RefHeading___Toc187567046)

3.1.4 FQPA [23](#__RefHeading___Toc187567047)

3.2 Hazard Identification and Toxicity Endpoint Selection
[24](#__RefHeading___Toc187567048)

3.2.1 Summary of Dose Response and Endpoint Selection
[24](#__RefHeading___Toc187567049)

3.2.2 Level of Concern for Margin of Exposure
[25](#__RefHeading___Toc187567050)

3.2.3 Recommendation for Aggregate Exposure Risk Assessments
[25](#__RefHeading___Toc187567051)

3.2.4 Classification of Carcinogenic Potential
[26](#__RefHeading___Toc187567052)

3.2.5 Summary of Toxicological Doses and Endpoints for Prothioconazole
for Use in Human Risk Assessments [26](#__RefHeading___Toc187567053)

3.3 Endocrine disruption [27](#__RefHeading___Toc187567054)

**4.0** **Dietary Exposure/Risk Characterization**
[28](#__RefHeading___Toc187567055)

4.1 Pesticide Metabolism and Environmental Degradation
[28](#__RefHeading___Toc187567056)

4.1.1 Metabolism in Primary Crops [28](#__RefHeading___Toc187567057)

4.1.2 Metabolism in Rotational Crops [29](#__RefHeading___Toc187567058)

4.1.3 Metabolism in Livestock [29](#__RefHeading___Toc187567059)

4.1.4 Analytical Methodology [30](#__RefHeading___Toc187567060)

4.1.5 Storage Stability Data [31](#__RefHeading___Toc187567061)

4.1.6 Magnitude of the Residue in Plants
[32](#__RefHeading___Toc187567062)

4.1.7 Magnitude of the Residue in Processed Food/Feed
[35](#__RefHeading___Toc187567063)

4.1.8 Magnitude of the Residue in Meat, Milk, Poultry, and Eggs
[36](#__RefHeading___Toc187567064)

4.1.9 Confined and Field Rotational Accumulation in Rotational Crops
[39](#__RefHeading___Toc187567065)

4.1.10 Drinking Water Residue Profile [40](#__RefHeading___Toc187567066)

4.1.11 Proposed Tolerances [41](#__RefHeading___Toc187567067)

4.1.12 International Residue Limits (IRL)
[43](#__RefHeading___Toc187567068)

4.2 Dietary Exposure and Risk [43](#__RefHeading___Toc187567069)

4.2.1 Acute Dietary Exposure/Risk [46](#__RefHeading___Toc187567070)

4.2.2 Chronic Dietary Exposure/Risk [47](#__RefHeading___Toc187567071)

4.2.3 Cancer Dietary Risk [49](#__RefHeading___Toc187567072)

**5.0** **Residential (Non-Occupational) Exposure/Risk
Characterization** [49](#__RefHeading___Toc187567073)

**6.0** **Aggregate Risk Assessments and Risk Characterization**
[49](#__RefHeading___Toc187567074)

**7.0** **Cumulative Risk Characterization/Assessment**
[49](#__RefHeading___Toc187567075)

**8.0** **Occupational Exposure/Risk Pathway**
[50](#__RefHeading___Toc187567076)

8.1 Short-/Intermediate-Term Handler Risk
[51](#__RefHeading___Toc187567077)

8.2 Short-/Intermediate-Term Postapplication Risk
[54](#__RefHeading___Toc187567078)

**9.0** **Data Needs and Label Requirements**
[58](#__RefHeading___Toc187567079)

9.1 Toxicology [58](#__RefHeading___Toc187567080)

9.2 Residue Chemistry [58](#__RefHeading___Toc187567081)

9.3 Occupational Exposure [59](#__RefHeading___Toc187567082)

9.4 Triazole Data Requirements [60](#__RefHeading___Toc187567083)

**References:** [61](#__RefHeading___Toc187567084)

**Appendix A: Toxicology Assessment** [63](#__RefHeading___Toc187567085)

A. Toxicity Profiles [63](#__RefHeading___Toc187567086)

**1.0 Executive Summary**[]{#__RefHeading___Toc187567037 .anchor}

Prothioconazole,
2-\[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl-2-hydroxypropyl\]-1,2-dihydro-3*H*-1,2,4-triazole-3-thione,
is a recently registered active ingredient developed by Bayer
CropScience LP (i.e. the petitioner). Prothioconazole is a systemic
demethylation inhibitor fungicide which belongs to the triazolinthione
class of fungicides.

The petitioner states that prothioconazole has shown excellent
protective, curative, and eradicative performance against plant diseases
caused by ascomycetes, basidiomycetes, and deutromycetes fungi in many
crops. The petitioner states that the principle mode of action of
prothioconazole fungicide is the inhibition of demethylation at position
14 of lanosterol or 24-methylene dihydroano-sterol, both of which are
precursors of sterols in fungi; i.e., it works through disruption of
ergosterol biosynthesis (Ergosterol, a precursor to Vitamin D~2~, is an
important component of fungal cell walls).

The petitioner is currently proposing food/feed uses on soybean and
sugar beet. Additionally, under PP#6F7073 (soybean) and PP#6F7134 (sugar
beet), the petitioner requests the establishment of permanent tolerances
for residues of the fungicide prothioconazole,
2-\[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl\]-1,2-dihydro-3*H*-1,2,4-triazole-3-thione
and its desthio metabolite in/on the following raw agricultural
commodities: soybean, seed; soybean, hay; soybean, forage; beet, sugar,
roots; and beet, sugar, tops.

The end-use products (EPs) proposed for use on soybeans are Proline® 480
SC Fungicide (EPA File Symbol 264-IEL, 4 lb ai/gal) and Provost™ 433 SC
Fungicide (EPA File Symbol 264-IAR, 1.2 lb ai/gal). It is noted that
Proline® 480 SC Fungicide was recently registered in conjunction with
PP#4F6830 and has been assigned EPA Reg. No. 264-825. The products are
proposed for multiple broadcast postemergence foliar applications using
ground or aerial equipment at maximum seasonal rates of 0.281 lb ai/A
(Proline®) or 0.402 lb ai/A (Provost™). A 21-day preharvest interval
(PHI) is proposed for both products.

The end-use products (EPs) proposed for use on sugar beets are Proline®
480 SC Fungicide and USF 0728 325 SC Fungicide (EPA File Symbol 264-XXX,
1.49 lb ai/gal). The products are proposed for multiple broadcast
postemergence foliar applications using ground or aerial equipment at a
maximum seasonal rate of 0.534 lb ai/A. The proposed PHIs are 7 days
(Proline®) or 21 days (USF 0728 325 SC Fungicide).

There are no proposed or existing residential uses of prothioconazole.

Prothioconazole is a thio-triazole, and as such, HED notes that a
separate risk assessment was conducted for the 1,2,4-triazole and its
conjugates. Triazolylalanine (TA), triazolylhydroxoypropionic acid
(THPA), and triazolylacetic acid (TAA), metabolites common to the
triazole derivative class of fungicides, were also found to be
metabolites of prothioconazole.

HED conducted an aggregate risk assessment for the metabolite/degradate
1,2,4-triazole (also referred to as free triazole) and its conjugates TA
and TAA, including data review, hazard identification and endpoint
selection, to support the extension of existing tolerances and the
granting of new parent triazole derivative fungicide tolerances (DP#
322215, 2/7/06, M. Doherty *et al.*). TA and TAA residues are primarily
associated with plant commodities whereas 1,2,4-T is associated with
rats and livestock. In that assessment, it was concluded that there are
no human health risk issues associated with 1,2,4-T or its metabolites
that would preclude reregistration of the triazole-derivative fungicides
registered at the time the risk assessment memo was issued or
conditional registration of the triazole-derivative fungicide uses that
have been proposed as of September 1, 2005. The risk assessment included
uses of prothioconazole proposed in PP#4F6830; the last prothioconazole
risk assessment. Additionally, in that aggregate triazoles risk
assessment, HED concluded that new uses for triazole pesticides (such as
the proposed prothioconazole uses addressed in this document) should be
examined in terms of potential residues of 1,2,4-T and its conjugates,
and that the risk assessment may require revision if new uses are for
sites not already addressed by the current list of registered or
proposed uses, if the formation of the metabolites exceeds the estimates
used in the previous risk assessment, or if required toxicity data raise
concerns not addressed by the current risk assessment.

Separate dietary risk assessments, based on conservative residue
estimates, have been completed for 1,2,4-T and TA+TAA (combined) and are
updated, as needed, for new triazole fungicide uses. The most recent
dietary assessments for these compounds (W. Cutchin, DP Numbers 347252
and 347253, 12/19/07) include residue estimates for soybean and sugar
beet commodities. Currently registered uses on soybean and sugar beet
from the application of other triazole fungicides result in potentially
greater residues of 1,2,4-T and TA+TAA (combined) on the resulting crop
commodities than are attributable to these proposed uses of
prothioconazole. Therefore, an updated assessment is not required to
address dietary exposure to 1,2,4-T or to TA+TAA for these new
prothioconazole petitions.

***[Toxicity/Hazard Assessment]{.underline}***

The toxicology database for prothioconazole and its metabolites,
submitted by Bayer CropScience, is extremely large, especially the
number of complex toxicology studies. In addition to the full toxicology
database for prothioconazole ( also known as JAU6476), there is a second
complete toxicology database for the major metabolite/degradate
prothioconazole-desthio (also known as SXX0665), and additional studies
on other minor metabolites/degradates. The toxicity database for
prothioconazole (and its metabolites) is considered complete, and deemed
adequate for endpoint selection for exposure risk assessment scenarios
and for FQPA evaluation. Please refer to Appendix A for the toxicity
profile tables. Please refer to the previous prothioconazole risk
assessment document for further extensive details, including the
executive summaries of the individual toxicology studies (B. O'Keefe, DP
Barcode 328967, 1/23/07).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

***[Drinking Water Exposure Assessment]{.underline}***

The Environmental Fate and Effects Division (EFED) provided estimated
drinking water concentrations (EDWCs) determined using the PRZM-EXAMS
screening model. These EDWCs were incorporated directly into the dietary
assessment. Water residues were incorporated in DEEM-FCID into the food
categories "water, direct, all sources" and "water, indirect, all
sources."

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

Estimated drinking water concentrations were further refined for peanuts
and sugar beets. Regional default Percent Cropped Area factors (PCA)
have been applied to estimated concentrations of these crops. DEEM
analyses were performed using surface water EDWCs for both the upper and
lower bound estimates for the peanut (previous registration) and sugar
beet (proposed registration) crop scenarios, since these EDWC values
were the highest reported for the respective acute (peanut, lower bound
13 ppb and upper bound 29 ppb) and chronic (sugar beet, lower bound 8.4
ppb and upper bound 13 ppb) exposure durations.

***[Residential Exposure/Risk Assessment]{.underline}***

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

***[Dietary/Aggregate Exposure/Risk Assessment]{.underline}***

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

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

The dietary exposure analyses result in acute dietary risk estimates
that are below the Agency's level of concern (LOC) for food only, and
for food and drinking water. At the 95^th^ percentile, the food only
exposure for females 13-49 years old utilized 8.4% of the acute
population adjusted dose (aPAD). The exposure for food plus lower bound
drinking water estimates represented 37% of the aPAD at the 95^th^
percentile. The exposure for food and upper bound drinking water
estimates utilized 76% of the aPAD at the 95^th^ percentile.

***Chronic Dietary Exposure Results and Characterization***: A
moderately refined chronic dietary exposure assessment was also
performed. Empirical processing factors, average residues, and livestock
maximum residues were incorporated into the chronic assessment; 100%
crop treated was also assumed. Dietary risk estimates were determined
considering exposures from food alone and food plus upper or lower bound
surface water EDWC point estimates based on the sugar beet application
scenario, since this crop yielded the highest chronic EDWC values.

The dietary exposure analyses result in chronic dietary risk estimates
that are below the Agency's LOC for food alone and food plus water. The
highest exposure and risk estimates were for children 1-2 years old and
all infants. The food only exposure represented 31% of the chronic
population adjusted dose (cPAD) for children 1-2 years old. The highest
exposure and risk estimates for food plus drinking water were for the
all infants population subgroup. The exposure for food plus lower bound
drinking water estimates utilized 65% of the cPAD; food plus upper bound
drinking water estimates utilized 94% of the cPAD.

***[Occupational Exposure/Risk Assessment]{.underline}***

There is potential for exposure from mixing, loading, and applying
prothioconazole on proposed use sites, and from entering areas
previously treated with prothioconazole. Short- and intermediate-term
dermal and inhalation exposures are expected from handler activities,
and short- and intermediate-term dermal exposures are expected from
postapplication activities.

***Handler Risk**:* Handler exposure scenarios considered representative
of the potential exposures expected from the proposed prothioconazole
use patterns on sugar beets and soybeans are as follows: mixing and
loading (M/L) for aerial and groundboom equipment and application with
aerial and groundboom equipment, as well as flagging for aerial
applications**.** Total MOEs range from 860 to 3,800. Closed M/L for
aerial application to sugar beets (at the maximum proposed rate) did not
reach the LOC of an MOE of 1000 with engineering controls. However,
closed M/L for aerial application for sugar beets at a reduced rate and
soybean at the maximum rate did reach the LOC of an MOE of 1000 with
engineering controls. M/L exposure scenarios for groundboom equipment
reach MOEs of 1000 or greater with baseline clothing (long-sleeved
shirt, long pants, shoes and socks) and the personal protective
equipment (PPE) gloves. Both aerial and groundboom application (and
flagging) exposure scenarios reach MOEs of 1000 with baseline clothing
and no gloves.

Although the M/L for aerial application to sugar beets at the maximum
proposed application rate does not result in an exposure estimate 1000X
less than the quantitative hazard estimate (even with engineering
controls) this estimate does involve potential overestimation of
exposure. As mentioned above, prothioconazole exposure estimates are
compared to prothioconazole-desthio endpoints, resulting in a highly
protective risk assessment. Had risk from prothioconazole and
prothioconazole-desthio been estimated in separate assessments, lower
prothioconazole-desthio exposure estimates would have yielded a greater
margin of exposure. Therefore, an MOE of 860 at the maximum proposed
label rate may not indicate a risk of concern.

***Postapplication Risk**:* Postapplication dermal MOEs reach 1000 or
greater on the day of application for postapplication activities such as
scouting in low crops with minimal plant growth, as well as hand
weeding; however, for activities such as scouting in crops with fuller
foliage plants, and irrigating crops, up to 2 days following application
are required to reach MOEs of 1000. Therefore, the labels, which
indicate restricted-entry intervals (REIs) of 12 and 24 hours, need to
be amended to indicate an REI of 2 days in order to be protective of the
LOC. Additionally, two formulations, PROVOST^TM^ 433 SC Fungicide (for
use on peanuts and soybeans) and USF 0728 325 SC Fungicide (for use on
sugar beets) include other active ingredients (i.e., namely,
tebuconazole and trifloxystrobin) -- the Registration Division (RD) must
ensure that the REI is also protective of these additional active
ingredients. Other label amendments are discussed below under
recommendations.

***[Recommendations for Tolerances]{.underline}***

HED has completed a human health risk assessment for the proposed new
uses on soybeans and sugar beets of the active ingredient
prothioconazole. Provided that revised Sections B and F as specified in
Section 9.0 of this document are submitted, the residue chemistry,
toxicological, and occupational databases support the establishment of a
*conditional registration* and the following permanent tolerances for
residues of prothioconazole as follows:

[Tolerances for combined residues of prothioconazole and its desthio
metabolite]{.underline}:

> Soybean, forage 4.5 ppm
>
> Soybean, seed 0.15 ppm
>
> Soybean, hay 17 ppm
>
> Beet, sugar, roots 0.25 ppm

The registration should be made conditional upon receipt of additional
data specified in Section 9.0.

[860.1200 Directions for Use]{.underline}

[• A revised Section B is required to specify a preharvest interval of 7
days for soybean forage and hay.]{.mark}

[860.1550 Proposed Tolerances]{.underline}

[• The petitioner is required to submit a revised Section F to
incorporate the CAS name of prothioconazole-desthio in the tolerance
expression and to specify that residues of the metabolite are calculated
as parent. In addition,]{.mark} the revised Section F should reflect the
recommended tolerances and commodity definitions presented in Table
4.1.9.

***[Recommendations for Labels]{.underline}***

• **PREVIOUS:** State on the label that sunflower and safflower are
excluded from the oilseed crop group

• USF 0728 325 SC Fungicide, on page 4 of the proposed label, remove the
language describing use directions for chemigation. The label states
"apply USF 0728 325 SC through irrigation equipment only to crops for
which chemigation is specified on this label." There is one crop on the
label (sugar beets), and chemigation is not specified in the use
directions (whereas aerial and ground application methods are
specified).

• USF 0728 325 SC Fungicide should specify a 30-day plant-back interval
for crops not on the label.

• USF 0728 325 SC Fungicide, for sugar beets, the retreatment intervals
are contradictory, i.e., in the restrictions section it lists 14- to
30-day spray intervals for foliar and soilborne diseases; but within the
soilborne disease section it lists a 10- to 14-day spray schedule. Since
EFED relied on a 14- to 30-day interval for the drinking water numbers
for sugar beets, HED suggests that the label should not specify 10- to
14-day intervals.

• Change the REI to 48 hours on all labels.

• Remove all references to rice on the Proline 480 SC label.

• Indicate on the labels, that hand-harvesting is prohibited.

**Environmental Justice Considerations**

Potential areas of environmental justice concerns, to the extent
possible, were considered in this human health risk assessment, in
accordance with U.S. Executive Order 12898, \"Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations,\"
<http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf>).

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures.
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup's
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting. Extensive data on food
consumption patterns are compiled by the USDA under the Continuing
Survey of Food Intake by Individuals (CSFII) and are used in pesticide
risk assessments for all registered food uses of a pesticide. These data
are analyzed and categorized by subgroups based on age, season of the
year, ethnic group, and region of the country. Additionally, OPP is able
to assess dietary exposure to smaller, specialized subgroups and
exposure assessments are performed when conditions or circumstances
warrant. Whenever appropriate, non-dietary exposures based on home use
of pesticide products and associated risks for adult applicators and for
toddlers, youths, and adults entering or playing on treated areas
postapplication are evaluated. Further considerations are currently in
development as OPP has committed resources and expertise to the
development of specialized software and models that consider exposure to
bystanders and farm workers as well as lifestyle and traditional dietary
patterns among specific subgroups.

**Review of Human Research**

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

**2.0 Ingredient Profile** []{#__RefHeading___Toc187567038 .anchor}

A summary of prothioconazole end-use products proposed for use on the
crops discussed in this document is listed in Table 2.1.

+------+----+-----------+------+-------+---------+------------------+
| Nu   |    |           |      |       |         |                  |
| mber |    |           |      |       |         |                  |
| r    |    |           |      |       |         |                  |
| ange |    |           |      |       |         |                  |
| CH   |    |           |      |       |         |                  |
| APTE |    |           |      |       |         |                  |
| R**T |    |           |      |       |         |                  |
| able |    |           |      |       |         |                  |
| 2.1. |    |           |      |       |         |                  |
| Pro  |    |           |      |       |         |                  |
| thio |    |           |      |       |         |                  |
| cona |    |           |      |       |         |                  |
| zole |    |           |      |       |         |                  |
| End  |    |           |      |       |         |                  |
| -Use |    |           |      |       |         |                  |
| Pro  |    |           |      |       |         |                  |
| duct |    |           |      |       |         |                  |
| s.** |    |           |      |       |         |                  |
+======+====+===========+======+=======+=========+==================+
| T    | E  | ai (% of  | For  | T     | Target  | Use Directions   |
| rade | PA | for       | mula | arget | Pests   | and Limitations  |
| Name | Re | mulation) | tion | Crops |         |                  |
|      | g. |           | Type |       |         |                  |
|      | N  |           |      |       |         |                  |
|      | o. |           |      |       |         |                  |
+------+----+-----------+------+-------+---------+------------------+
| PROL | 2  | 41%       | Sol  | Ba    | Broad   | Applications may |
| INE® | 64 |           | uble | rley, | s       | be made alone or |
| 480  | -I | 2-\[2-    | con  | oi    | pectrum | as a tank mix    |
| SC   | EL | (1-chloro | cent | lseed | s       | with other       |
| F    |    | cycloprop | rate | (e    | ystemic | fungicides,      |
| ungi |    | yl)-3-(2- | (SC) | xcept | fu      | insecticides, or |
| cide |    | chlorophe |      | sunf  | ngicide | herbicides. To   |
|      |    | nyl)-2-hy |      | lower | for the | optimize disease |
|      |    | droxyprop |      | and   | control | control, the     |
|      |    | yl\]-1,2- |      | saffl | of      | lowest labeled   |
|      |    | dihydro-3 |      | ower) | Ascom   | rate of spray    |
|      |    | *H*-1,2,4 |      | crop  | ycetes, | surfactant       |
|      |    | -triazole |      | g     | B       | should be        |
|      |    | -3-thione |      | roup, | asidiom | tank-mixed with  |
|      |    |           |      | dried | ycetes, | PROLINE ® 480 SC |
|      |    |           |      | sh    | and     | Fungicide.       |
|      |    |           |      | elled | Deutero | Application      |
|      |    |           |      | pea   | mycetes | through any type |
|      |    |           |      | and   | d       | of irrigation    |
|      |    |           |      | bean  | iseases | system is        |
|      |    |           |      | (e    |         | prohibited. For  |
|      |    |           |      | xcept |         | crops not listed |
|      |    |           |      | soy   |         | on this label,   |
|      |    |           |      | bean) |         | do not plant     |
|      |    |           |      | subg  |         | back within 30   |
|      |    |           |      | roup, |         | days of last     |
|      |    |           |      | pe    |         | application. REI |
|      |    |           |      | anut, |         | -- 24 hours      |
|      |    |           |      | soy   |         |                  |
|      |    |           |      | bean, |         |                  |
|      |    |           |      | sugar |         |                  |
|      |    |           |      | beet, |         |                  |
|      |    |           |      | and   |         |                  |
|      |    |           |      | w     |         |                  |
|      |    |           |      | heat. |         |                  |
+------+----+-----------+------+-------+---------+------------------+
| PRO  | 2  | 12.9%     | SC   | Pe    |         | Provides control |
| VOST | 64 |           |      | anuts |         | or suppression   |
| ^TM^ | -I | (also     |      | and   |         | of many          |
| 433  | AR | contains  |      | soy   |         | important        |
| SC   |    | 25.8%     |      | beans |         | diseases. When   |
| F    |    | **tebuco  |      |       |         | reference is     |
| ungi |    | nazole**) |      |       |         | made to disease  |
| cide |    |           |      |       |         | suppression,     |
|      |    |           |      |       |         | suppression can  |
|      |    |           |      |       |         | mean either      |
|      |    |           |      |       |         | erratic control  |
|      |    |           |      |       |         | from good to     |
|      |    |           |      |       |         | fair or          |
|      |    |           |      |       |         | consistent       |
|      |    |           |      |       |         | control at a     |
|      |    |           |      |       |         | level below that |
|      |    |           |      |       |         | obtained with    |
|      |    |           |      |       |         | the best         |
|      |    |           |      |       |         | commercial       |
|      |    |           |      |       |         | disease control  |
|      |    |           |      |       |         | products. For    |
|      |    |           |      |       |         | crops not listed |
|      |    |           |      |       |         | on this label,   |
|      |    |           |      |       |         | do not plant     |
|      |    |           |      |       |         | back within 30   |
|      |    |           |      |       |         | days of last     |
|      |    |           |      |       |         | application. REI |
|      |    |           |      |       |         | -- 24 hours      |
+------+----+-----------+------+-------+---------+------------------+
| USF  | 2  | 16.0%     | SC   | Sugar | Broad   | Provides control |
| 0728 | 64 |           |      | beets | s       | or suppression   |
| 325  | -X | (also     |      |       | pectrum | of many          |
| SC   | XX | contains  |      |       | fun     | important        |
| F    |    | 13.7%     |      |       | gicide, | diseases. When   |
| ungi |    | triflo    |      |       | that    | reference is     |
| cide |    | xystrobin |      |       | p       | made to disease  |
|      |    | **        |      |       | rovides | suppression,     |
|      |    | trifloxys |      |       | control | suppression can  |
|      |    | trobin**) |      |       | or      | mean either      |
|      |    |           |      |       | supp    | erratic control  |
|      |    |           |      |       | ression | from good to     |
|      |    |           |      |       | of      | fair or          |
|      |    |           |      |       | several | consistent       |
|      |    |           |      |       | im      | control at a     |
|      |    |           |      |       | portant | level below that |
|      |    |           |      |       | d       | obtained with    |
|      |    |           |      |       | iseases | the best         |
|      |    |           |      |       | of      | commercial       |
|      |    |           |      |       | sugar   | disease control  |
|      |    |           |      |       | beets   | products.        |
|      |    |           |      |       | (       | Contains both    |
|      |    |           |      |       | *e.g.*, | Group 11 and     |
|      |    |           |      |       | Cer     | Group 3          |
|      |    |           |      |       | cospora | fungicides. To   |
|      |    |           |      |       | Leaf    | limit the        |
|      |    |           |      |       | Spot,   | potential for    |
|      |    |           |      |       | Powdery | development of   |
|      |    |           |      |       | Mildew, | disease          |
|      |    |           |      |       | Rhiz    | resistance:      |
|      |    |           |      |       | octonia | alternate each   |
|      |    |           |      |       | Stem    | application with |
|      |    |           |      |       | Canker, | at least one     |
|      |    |           |      |       | Crown   | application of a |
|      |    |           |      |       | Rot).   | fungicide from a |
|      |    |           |      |       |         | different        |
|      |    |           |      |       |         | fungicide group. |
|      |    |           |      |       |         | REI -- 12 Hours  |
+------+----+-----------+------+-------+---------+------------------+

1.  **Summary of Registered/Proposed
    Uses**[]{#__RefHeading___Toc187567039 .anchor}

Prothioconazole is a systemic, broad spectrum fungicide in the triazole
chemical class developed by Bayer CropScience. Prothioconazole is a
demethylation-inhibitor (DMI-type) fungicide which works through
disruption of ergosterol biosynthesis (ergosterol, a precursor to
Vitamin D~2~, is an important component of fungal cell walls).
Prothioconazole fungicide is for the control of ascomycetes,
basidiomycetes, and deuteromycetes diseases. Applications may be made
alone or as a tank mix with other fungicides, insecticides, or
herbicides. To optimize disease control, the lowest labeled rate of
spray surfactant should be tank-mixed with prothioconazole formulations.
Application through any type of irrigation system is prohibited. For
crops not listed on the proposed labels, do not plantback within 30 days
of last application.

Prothioconazole, formulated as PROLINE ® 480 SC Fungicide, is currently
registered for food/feed uses on: barley, canola, chickpea, dried
shelled peas and beans crop subgroup, lentils, oilseed crop subgroup
(rapeseed, Indian rapeseed, Indian mustard, field mustard, black
mustard, flax, crambe, borage), peanut and wheat (spring, durum and
winter); and is proposed for use on soybeans and sugar beets.
Additionally, two new prothioconazole formulations, PROVOST^TM^ 433 SC
Fungicide (for use on peanuts and soybeans) and USF 0728 325 SC
Fungicide (for use on sugar beets) are being proposed for registration.
The directions for use of prothioconazole on proposed and existing crop
sites are summarized in Tables 2.2 and 2.3, respectively.

+----------+-------+-----+-------+---------+----+---+-------------------+
| **Table  |       |     |       |         |    |   |                   |
| 2.2.     |       |     |       |         |    |   |                   |
| Summary  |       |     |       |         |    |   |                   |
| of       |       |     |       |         |    |   |                   |
| Di       |       |     |       |         |    |   |                   |
| rections |       |     |       |         |    |   |                   |
| for      |       |     |       |         |    |   |                   |
| Proposed |       |     |       |         |    |   |                   |
| Uses of  |       |     |       |         |    |   |                   |
| Pr       |       |     |       |         |    |   |                   |
| othiocon |       |     |       |         |    |   |                   |
| azole.** |       |     |       |         |    |   |                   |
+==========+=======+=====+=======+=========+====+===+===================+
| App      | Trade | M   | Max.  | Max.    | P  |   | Use Directions    |
| lication | Name  | ax. | n     | S       | HI |   | and Limitations   |
| Timing,  |       | Sin | umber | easonal |    |   |                   |
| Type and |       | gle | of    | Appl    | (D |   |                   |
| E        |       | r   | Appl. | ication | ay |   |                   |
| quipment |       | ate | per   | Rate    | s) |   |                   |
|          |       |     | S     | (lb     |    |   |                   |
|          |       | (lb | eason | ai/A)   |    |   |                   |
|          |       | ai  |       |         |    |   |                   |
|          |       | /A) |       |         |    |   |                   |
+----------+-------+-----+-------+---------+----+---+-------------------+
| **S      |       |     |       |         |    |   |                   |
| oybean** |       |     |       |         |    |   |                   |
+----------+-------+-----+-------+---------+----+---+-------------------+
| Postem   | Pro   | 0.  | 3     | 0.281   | 21 | A |                   |
| ergence; | line® | 078 |       |         |    | N |                   |
|          | 480   | -0. |       |         |    | u |                   |
| B        | SC    | 094 |       |         |    | m |                   |
| roadcast | Fung  |     |       |         |    | b |                   |
| foliar;  | icide |     |       |         |    | e |                   |
|          |       |     |       |         |    | r |                   |
| Ground   |       |     |       |         |    | r |                   |
| and      |       |     |       |         |    | a |                   |
| aerial   |       |     |       |         |    | n |                   |
|          |       |     |       |         |    | g |                   |
|          |       |     |       |         |    | e |                   |
|          |       |     |       |         |    | C |                   |
|          |       |     |       |         |    | H |                   |
|          |       |     |       |         |    | A |                   |
|          |       |     |       |         |    | P |                   |
|          |       |     |       |         |    | T |                   |
|          |       |     |       |         |    | E |                   |
|          |       |     |       |         |    | R |                   |
|          |       |     |       |         |    | 1 |                   |
|          |       |     |       |         |    | 0 |                   |
|          |       |     |       |         |    | - |                   |
|          |       |     |       |         |    | t |                   |
|          |       |     |       |         |    | o |                   |
|          |       |     |       |         |    | 2 |                   |
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|          |       |     |       |         |    | - |                   |
|          |       |     |       |         |    | d |                   |
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|          |       |     |       |         |    | d |                   |
|          |       |     |       |         |    | g |                   |
|          |       |     |       |         |    | r |                   |
|          |       |     |       |         |    | o |                   |
|          |       |     |       |         |    | u |                   |
|          |       |     |       |         |    | n |                   |
|          |       |     |       |         |    | d |                   |
|          |       |     |       |         |    | e |                   |
|          |       |     |       |         |    | q |                   |
|          |       |     |       |         |    | u |                   |
|          |       |     |       |         |    | i |                   |
|          |       |     |       |         |    | p |                   |
|          |       |     |       |         |    | m |                   |
|          |       |     |       |         |    | e |                   |
|          |       |     |       |         |    | n |                   |
|          |       |     |       |         |    | t |                   |
|          |       |     |       |         |    | , |                   |
|          |       |     |       |         |    | r |                   |
|          |       |     |       |         |    | e |                   |
|          |       |     |       |         |    | s |                   |
|          |       |     |       |         |    | p |                   |
|          |       |     |       |         |    | e |                   |
|          |       |     |       |         |    | c |                   |
|          |       |     |       |         |    | t |                   |
|          |       |     |       |         |    | i |                   |
|          |       |     |       |         |    | v |                   |
|          |       |     |       |         |    | e |                   |
|          |       |     |       |         |    | l |                   |
|          |       |     |       |         |    | y |                   |
|          |       |     |       |         |    | . |                   |
+----------+-------+-----+-------+---------+----+---+-------------------+
|          | Pro   | 0.  | 3     | 0.402   | 21 |   |                   |
|          | vost™ | 028 |       |         |    |   |                   |
|          | 433   |     |       |         |    |   |                   |
|          | SC    |     |       |         |    |   |                   |
|          | Fung  |     |       |         |    |   |                   |
|          | icide |     |       |         |    |   |                   |
+----------+-------+-----+-------+---------+----+---+-------------------+
| **Sugar  |       |     |       |         |    |   |                   |
| Beet**   |       |     |       |         |    |   |                   |
+----------+-------+-----+-------+---------+----+---+-------------------+
| Postem   | Pro   | 0.  | 3     | 0.534   | 7  |   | For foliar        |
| ergence; | line® | 134 |       |         |    |   | disease: apply at |
|          | 480   | -0. |       |         |    |   | the first sign of |
| B        | SC    | 178 |       |         |    |   | disease, and use  |
| roadcast | Fung  |     |       |         |    |   | higher use rate   |
| foliar   | icide |     |       |         |    |   | and shorter       |
| or       |       |     |       |         |    |   | intervals when    |
| Banded;  |       |     |       |         |    |   | conditions are    |
|          |       |     |       |         |    |   | favorable for     |
| Ground   |       |     |       |         |    |   | severe disease    |
| and      |       |     |       |         |    |   | pressure and/or   |
| aerial   |       |     |       |         |    |   | when growing less |
|          |       |     |       |         |    |   | disease resistant |
|          |       |     |       |         |    |   | varieties.        |
|          |       |     |       |         |    |   |                   |
|          |       |     |       |         |    |   | For soil-borne    |
|          |       |     |       |         |    |   | disease control:  |
|          |       |     |       |         |    |   | apply either      |
|          |       |     |       |         |    |   | broadcast or in a |
|          |       |     |       |         |    |   | 7-inch band at    |
|          |       |     |       |         |    |   | the 4-leaf to row |
|          |       |     |       |         |    |   | closure growth    |
|          |       |     |       |         |    |   | stage.            |
|          |       |     |       |         |    |   |                   |
|          |       |     |       |         |    |   | In general, a     |
|          |       |     |       |         |    |   | Number range      |
|          |       |     |       |         |    |   | CHAPTER14- to     |
|          |       |     |       |         |    |   | 30-day            |
|          |       |     |       |         |    |   | retreatment       |
|          |       |     |       |         |    |   | interval is       |
|          |       |     |       |         |    |   | specified         |
|          |       |     |       |         |    |   | depending on the  |
|          |       |     |       |         |    |   | region. However,  |
|          |       |     |       |         |    |   | a 10 to 14 day    |
|          |       |     |       |         |    |   | retreatment       |
|          |       |     |       |         |    |   | interval is       |
|          |       |     |       |         |    |   | specified for     |
|          |       |     |       |         |    |   | soilborne         |
|          |       |     |       |         |    |   | diseases on the   |
|          |       |     |       |         |    |   | USF 0728 label    |
|          |       |     |       |         |    |   | only. Use of a    |
|          |       |     |       |         |    |   | spray surfactant  |
|          |       |     |       |         |    |   | is recommended.   |
|          |       |     |       |         |    |   | Apply in a        |
|          |       |     |       |         |    |   | minimum of 5 and  |
|          |       |     |       |         |    |   | 10 gal/A using    |
|          |       |     |       |         |    |   | aerial and ground |
|          |       |     |       |         |    |   | equipment,        |
|          |       |     |       |         |    |   | respectively.     |
+----------+-------+-----+-------+---------+----+---+-------------------+
|          | USF   | 0.  | 3     | 0.530   | 21 |   |                   |
|          | 0728  | 093 |       |         |    |   |                   |
|          | 325   | -0. |       |         |    |   |                   |
|          | SC    | 128 |       |         |    |   |                   |
|          | Fung  |     |       |         |    |   |                   |
|          | icide |     |       |         |    |   |                   |
+----------+-------+-----+-------+---------+----+---+-------------------+

+----------+-------+-----+------+-------+---+-----------------------+
| **Table  |       |     |      |       |   |                       |
| 2.3.     |       |     |      |       |   |                       |
| Summary  |       |     |      |       |   |                       |
| of       |       |     |      |       |   |                       |
| Di       |       |     |      |       |   |                       |
| rections |       |     |      |       |   |                       |
| for      |       |     |      |       |   |                       |
| Existing |       |     |      |       |   |                       |
| Uses of  |       |     |      |       |   |                       |
| P        |       |     |      |       |   |                       |
| rothioco |       |     |      |       |   |                       |
| nazole** |       |     |      |       |   |                       |
+==========+=======+=====+======+=======+===+=======================+
| Appl.    | Appl. | M   | Ret  | Max.  | P | Use Directions and    |
| Type,    | Rate  | ax. | reat | Sea   | H | Limitations           |
| and      |       | No. | ment | sonal | I |                       |
| Equip.   | (lb   | Ap  | Inte | Appl. | ( |                       |
|          | ai/A) | pl. | rval | Rate  | d |                       |
|          |       | per |      |       | a |                       |
|          | \[fl  | Sea | (d   | (lb   | y |                       |
|          | o     | son | ays) | ai/A) | s |                       |
|          | z/A\] |     |      |       | ) |                       |
|          |       |     |      | \[fl  |   |                       |
|          |       |     |      | o     |   |                       |
|          |       |     |      | z/A\] |   |                       |
+----------+-------+-----+------+-------+---+-----------------------+
| Barley   |       |     |      |       |   |                       |
| (for     |       |     |      |       |   |                       |
| Fusarium |       |     |      |       |   |                       |
| Head     |       |     |      |       |   |                       |
| Blight)  |       |     |      |       |   |                       |
+----------+-------+-----+------+-------+---+-----------------------+
| B        | 0.13  | 2   | 7 to | 0.29  | 3 | Apply as a            |
| roadcast | -0.18 |     | 14   |       | 2 | preventative foliar   |
| foliar   |       |     |      | \[    |   | spray within the time |
| spray;   | \[    |     |      | 9.4\] |   | period when 70 to     |
|          | 4.3 - |     |      |       |   | 100% of the barley    |
| Ground   | 5.7\] |     |      |       |   | heads on the main     |
| or       |       |     |      |       |   | stem are fully        |
| aerial   |       |     |      |       |   | emerged when weather  |
|          |       |     |      |       |   | conditions are        |
|          |       |     |      |       |   | favorable for disease |
|          |       |     |      |       |   | development and up to |
|          |       |     |      |       |   | 3 to 5 days after     |
|          |       |     |      |       |   | full head emergence.  |
|          |       |     |      |       |   | Spray equipment must  |
|          |       |     |      |       |   | be set up to provide  |
|          |       |     |      |       |   | good coverage to      |
|          |       |     |      |       |   | barley heads (using   |
|          |       |     |      |       |   | ground application    |
|          |       |     |      |       |   | equipment, use        |
|          |       |     |      |       |   | forward and backward  |
|          |       |     |      |       |   | mounted nozzles or    |
|          |       |     |      |       |   | nozzles with a        |
|          |       |     |      |       |   | two-directional       |
|          |       |     |      |       |   | spray).               |
+----------+-------+-----+------+-------+---+-----------------------+
| Barley   |       |     |      |       |   |                       |
| (for     |       |     |      |       |   |                       |
| Leaf and |       |     |      |       |   |                       |
| Stem     |       |     |      |       |   |                       |
| D        |       |     |      |       |   |                       |
| iseases) |       |     |      |       |   |                       |
+----------+-------+-----+------+-------+---+-----------------------+
| B        | 0.088 | 2   | 7 to | 0.27  | 3 | Apply as a            |
| roadcast | --    |     | 14   |       | 2 | preventative foliar   |
| foliar   | 0.13  |     |      | \[    |   | spray when the        |
| spray;   |       |     |      | 8.6\] |   | earliest disease      |
|          | \[    |     |      |       |   | symptoms appear on    |
| Ground   | 2.8 - |     |      |       |   | the leaves or stems.  |
| or       | 4.3\] |     |      |       |   |                       |
| aerial   |       |     |      |       |   |                       |
+----------+-------+-----+------+-------+---+-----------------------+
| Canola   |       |     |      |       |   |                       |
+----------+-------+-----+------+-------+---+-----------------------+
| B        | 0.13  | 2   | 5 to | 0.36  | 3 | Apply when the canola |
| roadcast | -0.18 |     | 7    |       | 6 | crop is in the 20 to  |
| foliar   |       |     |      | \[1   |   | 50% bloom stage       |
| spray;   | \[    |     |      | 1.4\] |   | (approximately 4-8    |
|          | 4.3 - |     |      |       |   | days after the canola |
| Ground   | 5.7\] |     |      |       |   | crop begins to        |
| or       |       |     |      |       |   | flower, not after 50% |
| aerial   |       |     |      |       |   | bloom stage). Best    |
|          |       |     |      |       |   | protection will be    |
|          |       |     |      |       |   | achieved when the     |
|          |       |     |      |       |   | fungicide is applied  |
|          |       |     |      |       |   | prior to petals       |
|          |       |     |      |       |   | beginning to fall,    |
|          |       |     |      |       |   | and will allow for    |
|          |       |     |      |       |   | the maximum number of |
|          |       |     |      |       |   | petals to be          |
|          |       |     |      |       |   | protected. The lower  |
|          |       |     |      |       |   | application rate is   |
|          |       |     |      |       |   | recommended for most  |
|          |       |     |      |       |   | canola crops, the     |
|          |       |     |      |       |   | higher rate is        |
|          |       |     |      |       |   | recommended for       |
|          |       |     |      |       |   | fields with a history |
|          |       |     |      |       |   | of heavy disease      |
|          |       |     |      |       |   | pressure or for dense |
|          |       |     |      |       |   | crop stands. Good     |
|          |       |     |      |       |   | spray coverage of the |
|          |       |     |      |       |   | plants is essential.  |
+----------+-------+-----+------+-------+---+-----------------------+
| Chickpea |       |     |      |       |   |                       |
+----------+-------+-----+------+-------+---+-----------------------+
| B        | 0.13  | 3   | 10   | 0.53  | 7 | Apply at first sign   |
| roadcast | -0.18 |     | to   |       |   | of disease. Use       |
| foliar   |       |     | 14   | \[1   |   | higher use rate when  |
| spray;   | \[    |     |      | 7.1\] |   | conditions are        |
|          | 4.3 - |     |      |       |   | favorable for severe  |
| Ground   | 5.7\] |     |      |       |   | disease pressure      |
| or       |       |     |      |       |   | and/or when growing   |
| aerial   |       |     |      |       |   | less disease          |
|          |       |     |      |       |   | resistant varieties.  |
+----------+-------+-----+------+-------+---+-----------------------+
| Dried    |       |     |      |       |   |                       |
| Shelled  |       |     |      |       |   |                       |
| Peas and |       |     |      |       |   |                       |
| Beans    |       |     |      |       |   |                       |
| Subgroup |       |     |      |       |   |                       |
|          |       |     |      |       |   |                       |
| (Grain,  |       |     |      |       |   |                       |
| Sweet,   |       |     |      |       |   |                       |
| White    |       |     |      |       |   |                       |
| and      |       |     |      |       |   |                       |
| White    |       |     |      |       |   |                       |
| Sweet    |       |     |      |       |   |                       |
| lupins;  |       |     |      |       |   |                       |
| Field,   |       |     |      |       |   |                       |
| Kidney,  |       |     |      |       |   |                       |
| Dry      |       |     |      |       |   |                       |
| lima,    |       |     |      |       |   |                       |
| Pinto    |       |     |      |       |   |                       |
| and      |       |     |      |       |   |                       |
| Tepary   |       |     |      |       |   |                       |
| beans;   |       |     |      |       |   |                       |
| Adzuki   |       |     |      |       |   |                       |
| bean,    |       |     |      |       |   |                       |
| Bl       |       |     |      |       |   |                       |
| ack-eyed |       |     |      |       |   |                       |
| pea,     |       |     |      |       |   |                       |
| Catjang, |       |     |      |       |   |                       |
| Cowpea,  |       |     |      |       |   |                       |
| Crowder  |       |     |      |       |   |                       |
| pea,     |       |     |      |       |   |                       |
| Moth     |       |     |      |       |   |                       |
| bean,    |       |     |      |       |   |                       |
| Mung     |       |     |      |       |   |                       |
| bean,    |       |     |      |       |   |                       |
| Rice     |       |     |      |       |   |                       |
| bean,    |       |     |      |       |   |                       |
| Southern |       |     |      |       |   |                       |
| pea and  |       |     |      |       |   |                       |
| Urd      |       |     |      |       |   |                       |
| bean;    |       |     |      |       |   |                       |
| Dry      |       |     |      |       |   |                       |
| broad    |       |     |      |       |   |                       |
| bean;    |       |     |      |       |   |                       |
| Guar;    |       |     |      |       |   |                       |
| Lablab   |       |     |      |       |   |                       |
| bean;    |       |     |      |       |   |                       |
| Pea      |       |     |      |       |   |                       |
| \[i      |       |     |      |       |   |                       |
| ncluding |       |     |      |       |   |                       |
| Field    |       |     |      |       |   |                       |
| pea\]    |       |     |      |       |   |                       |
| and      |       |     |      |       |   |                       |
| Pigeon   |       |     |      |       |   |                       |
| pea)     |       |     |      |       |   |                       |
+----------+-------+-----+------+-------+---+-----------------------+
| B        | 0.13  | 3   | 5 to | 0.53  | 7 | Apply at the first    |
| roadcast | -0.18 |     | 14   |       |   | sign of disease. Use  |
| foliar   |       |     |      | \[1   |   | higher use rate when  |
| spray;   | \[4.3 |     |      | 7.1\] |   | conditions are        |
|          | --    |     |      |       |   | favorable for severe  |
| Ground   | 5.7\] |     |      |       |   | disease pressure      |
| or       |       |     |      |       |   | and/or when growing   |
| aerial   |       |     |      |       |   | less disease          |
|          |       |     |      |       |   | resistant varieties.  |
+----------+-------+-----+------+-------+---+-----------------------+
| Lentils  |       |     |      |       |   |                       |
+----------+-------+-----+------+-------+---+-----------------------+
| B        | 0.13  | 3   | 10   | 0.53  | 7 | Apply at early flower |
| roadcast | -0.18 |     | to   |       |   | or at the first sign  |
| foliar   |       |     | 14   | \[1   |   | of disease. Use       |
| spray;   | \[4.3 |     |      | 7.1\] |   | higher use rate when  |
|          | --    |     |      |       |   | conditions are        |
| Ground   | 5.7\] |     |      |       |   | favorable for severe  |
| or       |       |     |      |       |   | disease pressure      |
| aerial   |       |     |      |       |   | and/or when growing   |
|          |       |     |      |       |   | less disease          |
|          |       |     |      |       |   | resistant varieties.  |
+----------+-------+-----+------+-------+---+-----------------------+
| Oilseed  |       |     |      |       |   |                       |
| Crop     |       |     |      |       |   |                       |
| Subgroup |       |     |      |       |   |                       |
|          |       |     |      |       |   |                       |
| (R       |       |     |      |       |   |                       |
| apeseed, |       |     |      |       |   |                       |
| Indian   |       |     |      |       |   |                       |
| r        |       |     |      |       |   |                       |
| apeseed, |       |     |      |       |   |                       |
| Indian   |       |     |      |       |   |                       |
| mustard, |       |     |      |       |   |                       |
| Field    |       |     |      |       |   |                       |
| mustard, |       |     |      |       |   |                       |
| Black    |       |     |      |       |   |                       |
| mustard, |       |     |      |       |   |                       |
| Flax,    |       |     |      |       |   |                       |
| Crambe   |       |     |      |       |   |                       |
| and      |       |     |      |       |   |                       |
| Borage)  |       |     |      |       |   |                       |
+----------+-------+-----+------+-------+---+-----------------------+
| B        | 0.134 | 2   | 5 to | 0.356 | 3 | Apply when the crop   |
| roadcast | -     |     | 7    |       | 6 | is 20 to 50% bloom    |
| foliar   | 0.178 |     |      | \[1   |   | stage (not after the  |
| spray;   |       |     |      | 1.4\] |   | 50% bloom stage).     |
|          | \[4.3 |     |      |       |   | Utilize higher rate   |
| Ground   | --    |     |      |       |   | for fields with       |
| or       | 5.7\] |     |      |       |   | history of heavy      |
| aerial   |       |     |      |       |   | disease pressure or   |
|          |       |     |      |       |   | for dense crop        |
|          |       |     |      |       |   | stands. Good spray    |
|          |       |     |      |       |   | coverage is           |
|          |       |     |      |       |   | essential.            |
+----------+-------+-----+------+-------+---+-----------------------+
| Peanut   |       |     |      |       |   |                       |
+----------+-------+-----+------+-------+---+-----------------------+
| B        | 0.16  | 4   | 14   | 0.71  | 1 | Soil Borne disease:   |
| roadcast | -0.18 |     | to   |       | 4 | Utilize the high use  |
| foliar   |       |     | 21   | \[    |   | rate. Make four       |
| spray;   | \[5.0 |     |      | 22.8, |   | consecutive           |
|          | --    |     |      | PROL  |   | applications at 14    |
| Ground   | 5.7,  |     |      | INE\] |   | day intervals. In a   |
| or       | PROL  |     |      |       |   | typical 7 spray       |
| aerial   | INE\] |     |      | 0.40  |   | application, the      |
|          |       |     |      |       |   | formulation should be |
|          | 0.038 |     |      | \[    |   | applied for sprays 3, |
|          | -0.10 |     |      | 42.8, |   | 4, 5 and 6. For       |
|          |       |     |      | PROV  |   | control of soil-borne |
|          | \[4.0 |     |      | OST\] |   | diseases when using a |
|          | --    |     |      |       |   | Leaf Spot Advisory    |
|          | 10.7, |     |      |       |   | Program schedule,     |
|          | PROV  |     |      |       |   | begin in July and     |
|          | OST\] |     |      |       |   | continue at 14 day    |
|          |       |     |      |       |   | intervals. The        |
|          |       |     |      |       |   | formulation must be   |
|          |       |     |      |       |   | carried by rainfall   |
|          |       |     |      |       |   | or irrigation into    |
|          |       |     |      |       |   | the root zone,        |
|          |       |     |      |       |   | drought conditions    |
|          |       |     |      |       |   | will decrease         |
|          |       |     |      |       |   | effectiveness against |
|          |       |     |      |       |   | the root and pod      |
|          |       |     |      |       |   | rots.                 |
|          |       |     |      |       |   |                       |
|          |       |     |      |       |   | Foliar disease: Apply |
|          |       |     |      |       |   | the specified rate in |
|          |       |     |      |       |   | a preventive spray    |
|          |       |     |      |       |   | schedule. Apply up to |
|          |       |     |      |       |   | 4 sprays using a 14   |
|          |       |     |      |       |   | day interval. Use     |
|          |       |     |      |       |   | higher rate when      |
|          |       |     |      |       |   | conditions are        |
|          |       |     |      |       |   | favorable for severe  |
|          |       |     |      |       |   | disease pressure      |
|          |       |     |      |       |   | and/or when growing   |
|          |       |     |      |       |   | less disease          |
|          |       |     |      |       |   | resistant varieties.  |
+----------+-------+-----+------+-------+---+-----------------------+
| Wheat    |       |     |      |       |   |                       |
| (spring, |       |     |      |       |   |                       |
| durum    |       |     |      |       |   |                       |
| and      |       |     |      |       |   |                       |
| winter)  |       |     |      |       |   |                       |
| (for     |       |     |      |       |   |                       |
| Fusarium |       |     |      |       |   |                       |
| Head     |       |     |      |       |   |                       |
| Blight)  |       |     |      |       |   |                       |
+----------+-------+-----+------+-------+---+-----------------------+
| B        | 0.13  | 2   | 7 to | 0.29  | 3 | Apply within the time |
| roadcast | -0.18 |     | 14   |       | 0 | period from when at   |
| foliar   |       |     |      | \[9   |   | least 75% of the      |
| spray;   | \[4.3 |     |      | .37\] |   | wheat heads on the    |
|          | --    |     |      |       |   | main stem are fully   |
| Ground   | 5.7\] |     |      |       |   | emerged to when 50%   |
| or       |       |     |      |       |   | of the heads on the   |
| aerial   |       |     |      |       |   | main stem are in      |
|          |       |     |      |       |   | flower. Optimal       |
|          |       |     |      |       |   | timing of application |
|          |       |     |      |       |   | may be at or around   |
|          |       |     |      |       |   | 15% flower. Spray     |
|          |       |     |      |       |   | equipment must be set |
|          |       |     |      |       |   | up to provide good    |
|          |       |     |      |       |   | coverage to wheat     |
|          |       |     |      |       |   | heads (using ground   |
|          |       |     |      |       |   | application           |
|          |       |     |      |       |   | equipment, use        |
|          |       |     |      |       |   | forward and backward  |
|          |       |     |      |       |   | mounted nozzles or    |
|          |       |     |      |       |   | nozzles with a        |
|          |       |     |      |       |   | two-directional       |
|          |       |     |      |       |   | spray). PROLINE may   |
|          |       |     |      |       |   | be applied up to the  |
|          |       |     |      |       |   | point where wheat     |
|          |       |     |      |       |   | heads are in the full |
|          |       |     |      |       |   | flower growth stage.  |
+----------+-------+-----+------+-------+---+-----------------------+
| Wheat    |       |     |      |       |   |                       |
| (spring, |       |     |      |       |   |                       |
| durum    |       |     |      |       |   |                       |
| and      |       |     |      |       |   |                       |
| winter)  |       |     |      |       |   |                       |
| (for     |       |     |      |       |   |                       |
| Leaf and |       |     |      |       |   |                       |
| Stem     |       |     |      |       |   |                       |
| D        |       |     |      |       |   |                       |
| iseases) |       |     |      |       |   |                       |
+----------+-------+-----+------+-------+---+-----------------------+
| B        | 0.13  | 2   | 7 to | 0.29  | 3 | Apply as a            |
| roadcast | -0.16 |     | 14   |       | 0 | preventative foliar   |
| foliar   |       |     |      | \[9   |   | spray or when the     |
| spray;   | \[    |     |      | .37\] |   | earliest disease      |
|          | 4.3 - |     |      |       |   | symptoms appear on    |
| Ground   | 5.0\] |     |      |       |   | the leaves or stems.  |
| or       |       |     |      |       |   | Wheat fields should   |
| aerial   |       |     |      |       |   | be observed closely   |
|          |       |     |      |       |   | for early disease     |
|          |       |     |      |       |   | symptoms,             |
|          |       |     |      |       |   | particularly when     |
|          |       |     |      |       |   | susceptible varieties |
|          |       |     |      |       |   | are planted and/or    |
|          |       |     |      |       |   | under prolonged       |
|          |       |     |      |       |   | conditions favorable  |
|          |       |     |      |       |   | for disease           |
|          |       |     |      |       |   | development. PROLINE  |
|          |       |     |      |       |   | may be applied up to  |
|          |       |     |      |       |   | the point where wheat |
|          |       |     |      |       |   | heads are in the full |
|          |       |     |      |       |   | flower growth stage.  |
+----------+-------+-----+------+-------+---+-----------------------+

**2.2 Structure and Nomenclature**[]{#__RefHeading___Toc187567040
.anchor}

  -------------------------------------------------------------------------------------------------------------------------------
  **Table 2.4.        
  Prothioconazole     
  Nomenclature.**     
  ------------------- -----------------------------------------------------------------------------------------------------------
  Chemical structure  ![](media/image2.wmf){width="1.4166666666666667in" height="1.1770833333333333in"}
  of prothioconazole  

  Empirical Formula   C~14~H~15~Cl~2~N~3~OS

  Common name         Prothioconazole

  Company             JAU 6476
  experimental name   

  IUPAC name          2-\[2-(1-Chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl\]-1,2-dihydro-3*H*-1,2,4-triazole-3-thione

  CAS name            2-\[2-(1-Chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl\]-1,2-dihydro-3*H*-1,2,4-triazole-3-thione

  CAS registry number 178928-70-6

  End-use product/EP  PROLINE ® 480 SC Fungicide

  Chemical Class      Triazolinthione

  Known Impurities of None
  Concern             
  -------------------------------------------------------------------------------------------------------------------------------

  ------------------------- ---------------------------------------------------
  **Table 2.5.              
  Prothioconazole-Desthio   
  Nomenclature**            

  Chemical Structure        ![](media/image3.wmf){width="1.148611111111111in"
                            height="1.0833333333333333in"}

  Company experimental name JAU 6476-desthio (SXX 0665)
  ------------------------- ---------------------------------------------------

**2.3 Physical and Chemical Properties**[]{#__RefHeading___Toc187567041
.anchor}

+------------------------------+--------------------------+-----------+
| **Table 2.6. Physicochemical |                          |           |
| Properties of the            |                          |           |
| Technical-Grade              |                          |           |
| Prothioconazole.**           |                          |           |
+==============================+==========================+===========+
| Parameter                    | Value                    | Reference |
+------------------------------+--------------------------+-----------+
| Molecular Weight             | 344.26 g/mol             |           |
+------------------------------+--------------------------+-----------+
| Melting point                | 139.1 - 144.5 °C         | MRID      |
|                              |                          | 46246003  |
+------------------------------+--------------------------+-----------+
| Density (g/ml at 20^0^C)     | 1.36 (pure active        | MRID      |
|                              | ingredient)              | 46246003  |
+------------------------------+--------------------------+-----------+
|                              | 1.17 at 20 °C (end use   | MRID      |
|                              | product)                 | 46246003  |
+------------------------------+--------------------------+-----------+
| Water solubility (g/L)       | 5.0 pH 4 buffer at 20 °C | MRID      |
|                              |                          | 46246003  |
|                              | 0.3 pH 8 buffer at 20 °C |           |
|                              |                          |           |
|                              | 2.0 pH 9 Buffer at 20 °C |           |
+------------------------------+--------------------------+-----------+
| Solvent solubility at 20 °C  | [g/L at room             | MRID      |
| (g/L)                        | temp]{.underline}        | 46246003  |
|                              |                          |           |
|                              | acetone \>250            |           |
|                              |                          |           |
|                              | acetonitrile 10-100      |           |
|                              |                          |           |
|                              | dichloromethane 100-250  |           |
|                              |                          |           |
|                              | dimethylsulfoxide        |           |
|                              | 100-250                  |           |
|                              |                          |           |
|                              | ethyl acetate \<250      |           |
|                              |                          |           |
|                              | n-heptane \<0.1          |           |
|                              |                          |           |
|                              | 1-octanol 10-100         |           |
|                              |                          |           |
|                              | polyethylene glycol      |           |
|                              | \>250                    |           |
|                              |                          |           |
|                              | 2-propanol 10-100        |           |
|                              |                          |           |
|                              | xylene 1-10              |           |
+------------------------------+--------------------------+-----------+
| Vapor pressure (Pa at 20 or  | \<4 x 10^-7^             | MRID      |
| 25 °C)                       |                          | 46246003  |
+------------------------------+--------------------------+-----------+
| Dissociation constant, pK~a~ | 6.9                      | MRID      |
|                              |                          | 46246003  |
+------------------------------+--------------------------+-----------+
| Octanol/water partition      | at 20 °C                 | MRID      |
| coefficient, Log(K~OW~)      |                          | 46246003  |
|                              | unbuffered: Kow = 11300; |           |
|                              | log K~ow~ = 4.05         |           |
|                              |                          |           |
|                              | pH 4: K~ow~ = 14600; log |           |
|                              | = 4.16                   |           |
|                              |                          |           |
|                              | pH 7: K~ow~ = 6600; log  |           |
|                              | = 3.82                   |           |
|                              |                          |           |
|                              | pH 9: K~ow~ = 100; log = |           |
|                              | 2.00                     |           |
+------------------------------+--------------------------+-----------+
| UV/visible absorption        | Peak maxima at 275 nm.   | MRID      |
| spectrum                     | No absorption at \>300   | 46246003  |
|                              | nm.                      |           |
+------------------------------+--------------------------+-----------+

**3.0 Hazard
Characterization/Assessment**[]{#__RefHeading___Toc187567042 .anchor}

**3.1 Hazard and Dose-Response
Characterization**[]{#__RefHeading___Toc187567043 .anchor}

**3.1.1 Database Summary**[]{#__RefHeading___Toc187567044 .anchor}

The toxicology database for prothioconazole and its metabolites, which
was previously submitted by Bayer CropScience, is extremely large,
especially the number of complex toxicology studies. In addition to the
full toxicology database for prothioconazole (also known as JAU6476),
there is a second complete toxicology database for the major
metabolite/degradate prothioconazole-desthio (also known as SXX0665),
and additional studies on other minor metabolites/degradates. The
toxicity database for prothioconazole (and its metabolites) is
considered complete, and deemed adequate for endpoint selection for
exposure risk assessment scenarios and for FQPA evaluation. Please refer
to Appendix A for the toxicity profile tables. Please refer to the
previous prothioconazole risk assessment document for further extensive
details, including the executive summaries of the individual toxicology
studies (B. O'Keefe, DP Barcode 328967, 1/23/07).

**3.1.2 Toxicological Effects**[]{#__RefHeading___Toc187567045 .anchor}

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

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

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

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

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

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

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

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

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

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

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

**3.1.3 Dose-response**[]{#__RefHeading___Toc187567046 .anchor}

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

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

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

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

+-----------+------+------+-----------------+-------------------------+
| **Study** | *    | *    | **Toxic         | **Comment**             |
|           | *NOA | *LOA | Effects**       |                         |
|           | EL** | EL** |                 |                         |
|           |      |      |                 |                         |
|           | m    | m    |                 |                         |
|           | g/kg | g/kg |                 |                         |
|           | /day | /day |                 |                         |
+-----------+------+------+-----------------+-------------------------+
| Deve      | 3    | 10   | increased       | Possibly appropriate    |
| lopmental |      |      | incidence of    | for Acute Dietary,      |
| Toxicity  |      |      | supernumerary   | Females 13 -- 50 years. |
| -- Rat    |      |      | ribs and        |                         |
|           |      |      | inc             | Quantitative            |
| MRID      |      |      | omplete/delayed | susceptibility          |
| 46246321, |      |      | ossifications.  | demonstrated in that    |
| 43246322  |      |      |                 | the maternal            |
|           |      |      |                 | NOAEL/LOAEL are 30/100  |
|           |      |      |                 | mg/kg/day               |
+-----------+------+------+-----------------+-------------------------+
| Deve      | 2    | 10   | malformed       | Appropriate for Acute   |
| lopmental |      |      | vertebral body  | Dietary, Females 13 --  |
| Toxicity  |      |      | and ribs,       | 50 years                |
| -- Rabbit |      |      | arthrogryposis, |                         |
|           |      |      | and multiple    | Quantitative            |
| MRID      |      |      | malformations   | susceptibility          |
| 46246327  |      |      |                 | demonstrated in that    |
|           |      |      |                 | the maternal            |
|           |      |      |                 | NOAEL/LOAEL are 10/50   |
|           |      |      |                 | mg/kg/day               |
+-----------+------+------+-----------------+-------------------------+
| Deve      | 3.6  | 15.1 | deviated snout, | Appropriate for Acute   |
| lopmental |      |      | malocclusion    | Dietary, Females 13 --  |
| Neur      |      |      |                 | 50 years                |
| otoxicity |      |      |                 |                         |
| -- Rat    |      |      |                 |                         |
|           |      |      |                 |                         |
| MRID      |      |      |                 |                         |
| 46246418  |      |      |                 |                         |
+-----------+------+------+-----------------+-------------------------+
|           | 15.1 | 43.3 | Dystocia        | Maternal effects.       |
|           |      |      |                 | Possibly appropriate    |
|           |      |      |                 | for Acute Dietary,      |
|           |      |      |                 | General Population      |
+-----------+------+------+-----------------+-------------------------+
|           | not  | not  | brain           | Appropriate for Acute   |
|           | repo | repo | morphometric    | Dietary, General        |
|           | rted | rted | changes and     | Population since        |
|           |      |      | increased       | effects seen in         |
|           |      |      | incidence of    | neonate, indicating the |
|           |      |      | peripheral      | potential for effects   |
|           |      |      | nerve lesions   | to occur in children    |
|           |      |      |                 | and adults following a  |
|           |      |      |                 | single postnatal dose.  |
+-----------+------+------+-----------------+-------------------------+

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

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

The weight of evidence evaluation of these toxic effects and the doses
selected for risk assessment were discussed in detail in Section 3.5 of
the previous prothioconazole risk assessment document (B. O'Keefe, DP
Barcode 328967, 1/23/07).

**3.1.4 FQPA**[]{#__RefHeading___Toc187567047 .anchor}

There are adequate data in the prothioconazole (including metabolites)
database to characterize the potential for pre-natal or post-natal risks
to infants and children: two-generation reproduction studies in rats;
developmental studies in rats and rabbits; and a developmental
neurotoxicity study in rats. The effects seen in these studies suggest
that pups are more susceptible: pup effects were seen at levels below
the LOAELs for maternal toxicity and, in general, were of comparable or
greater severity compared to the effects observed in adults. In
addition, since the developmental effects seen in the developmental
neurotoxicity (DNT) study were investigated at the high dose level only,
there is uncertainty concerning the LOAEL/NOAEL for developmental
effects in this study. Thus, the FQPA factor is retained at 10X (see
Section 3.3 of the previous prothioconazole risk assessment document (B.
O'Keefe, DP Barcode 328967, 1/23/07) for details).

**3.2 Hazard Identification and Toxicity Endpoint
Selection**[]{#__RefHeading___Toc187567048 .anchor}

**3.2.1. Summary of Dose Response and Endpoint
Selection**[]{#__RefHeading___Toc187567049 .anchor}

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

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

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

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

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

**3.2.2 Level of Concern for Margin of
Exposure**[]{#__RefHeading___Toc187567050 .anchor}

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

+-----------------------+-----------+-----------------+--------------+
| **Table 3.2.2 Summary |           |                 |              |
| of Levels of Concern  |           |                 |              |
| for Risk              |           |                 |              |
| Assessment.**         |           |                 |              |
+-----------------------+-----------+-----------------+--------------+
| **Route**             | **Sho     | **Inte          | *            |
|                       | rt-Term** | rmediate-Term** | *Long-Term** |
|                       |           |                 |              |
|                       | **(1 - 30 | **(1 - 6        | **(\> 6      |
|                       | Days)**   | Months)**       | Months)**    |
+-----------------------+-----------+-----------------+--------------+
| **Occupational        |           |                 |              |
| (Worker) Exposure**   |           |                 |              |
+-----------------------+-----------+-----------------+--------------+
| **Dermal**            | 1000      | 1000            | None         |
+-----------------------+-----------+-----------------+--------------+
| **Inhalation**        | 1000      | 1000            | None         |
+-----------------------+-----------+-----------------+--------------+
| **Residential         |           |                 |              |
| Exposure**            |           |                 |              |
+-----------------------+-----------+-----------------+--------------+
| **Dermal or           | None      | None            | None         |
| Inhalation**          |           |                 |              |
+-----------------------+-----------+-----------------+--------------+

> [Occupational exposure]{.underline}: **[Dermal]{.smallcaps}** and
> **[Inhalation]{.smallcaps}**: Based on the conventional uncertainty
> factor of 100X (10X for interspecies extrapolation and 10X for
> intraspecies variation), plus a 10X database uncertainty factor for
> lack of a NOAEL for brain morphometry and peripheral nerve lesions in
> the oral developmental neurotoxicity study.
>
> [Residential exposure:]{.underline} None expected.

**3.2.3 Recommendation for Aggregate Exposure Risk
Assessments**[]{#__RefHeading___Toc187567051 .anchor}

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

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

**3.2.4 Classification of Carcinogenic
Potential**[]{#__RefHeading___Toc187567052 .anchor}

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

**3.2.5 Summary Tables of Toxicological Doses and Endpoints for
Prothioconazole for Use in Human Risk
Assessments**[]{#__RefHeading___Toc187567053 .anchor}

+----------+--------+------------+----------+------------------------+
| **Table  |        |            |          |                        |
| 3.2.5.1  |        |            |          |                        |
| Summary  |        |            |          |                        |
| of       |        |            |          |                        |
| Toxic    |        |            |          |                        |
| ological |        |            |          |                        |
| Doses    |        |            |          |                        |
| and      |        |            |          |                        |
| E        |        |            |          |                        |
| ndpoints |        |            |          |                        |
| for      |        |            |          |                        |
| Prothio  |        |            |          |                        |
| conazole |        |            |          |                        |
| desthio  |        |            |          |                        |
| for Use  |        |            |          |                        |
| in       |        |            |          |                        |
| Dietary  |        |            |          |                        |
| and      |        |            |          |                        |
| Non-Occu |        |            |          |                        |
| pational |        |            |          |                        |
| Human    |        |            |          |                        |
| Health   |        |            |          |                        |
| Risk     |        |            |          |                        |
| Asses    |        |            |          |                        |
| sments** |        |            |          |                        |
+==========+========+============+==========+========================+
| **Exp    | *      | **Uncert   | **RfD,   | **Study and            |
| osure/** | *Point | ainty/FQPA | PAD,     | Toxicological          |
|          | of     | Safety     | Level of | Effects**              |
| **Sc     | Depar  | Factors**  | Concern  |                        |
| enario** | ture** |            | for Risk |                        |
|          |        |            | Asse     |                        |
|          |        |            | ssment** |                        |
+----------+--------+------------+----------+------------------------+
| Acute    | NOAEL  | UF~A~=10x  | Acute    | **Developmental        |
| Dietary  | = 2.0  |            | RfD =    | Toxicity study in      |
| (Females | mg/    | UF~H~=10x  | 0.002    | rabbits**              |
| 13 --    | kg/day |            | m        |                        |
| 49)      |        | FQPA       | g/kg/day | LOAEL = 10 mg/kg/day,  |
|          |        | SF=10x     |          | based on structural    |
|          |        | (UF~DB~)   | aPAD =   | alterations including  |
|          |        |            | 0.002    | malformed vertebral    |
|          |        |            | m        | body and ribs,         |
|          |        |            | g/kg/day | arthrogryposis, and    |
|          |        |            |          | multiple               |
|          |        |            |          | malformations.         |
+----------+--------+------------+----------+------------------------+
| Acute    | None   | None       | None     | **An appropriate study |
| Dietary  |        |            |          | was not identified**   |
| (General |        |            |          |                        |
| Pop      |        |            |          |                        |
| ulation, |        |            |          |                        |
| i        |        |            |          |                        |
| ncluding |        |            |          |                        |
| infants  |        |            |          |                        |
| and      |        |            |          |                        |
+----------+--------+------------+----------+------------------------+
| Chronic  | NOA    | UF~A~=10x  | Chronic  | **Chronic/Oncogenicity |
| Dietary  | EL=1.1 |            | RfD =    | study in rats**        |
| (All     | mg/    | UF~H~=10x  |          |                        |
| Popu     | kg/day |            | 0.001    | LOAEL = 8.0 mg/kg/day  |
| lations) |        | FQPA       | m        | based on liver         |
|          |        | SF=10x     | g/kg/day | histopathology         |
|          |        | (UF~DB~)   |          | (hepatocellular        |
|          |        |            | cPAD =   | vacuolation and fatty  |
|          |        |            | 0.001    | change (single cell,   |
|          |        |            | m        | centrilobular, and     |
|          |        |            | g/kg/day | periportal)).          |
+----------+--------+------------+----------+------------------------+
| In       | N/A    | N/A        | N/A      | Incidental oral        |
| cidental |        |            |          | exposure endpoint not  |
| Oral     |        |            |          | identified because     |
| Short-   |        |            |          | residential exposure   |
| and      |        |            |          | is not anticipated.    |
| I        |        |            |          |                        |
| ntermedi |        |            |          |                        |
| ate-Term |        |            |          |                        |
| (1-30    |        |            |          |                        |
| days and |        |            |          |                        |
| 1-6      |        |            |          |                        |
| months)  |        |            |          |                        |
+----------+--------+------------+----------+------------------------+
| Dermal   | N/A    | N/A        | N/A      | Dermal endpoints are   |
| Short-   |        |            |          | not applicable because |
| and      |        |            |          | residential exposure   |
| I        |        |            |          | is not anticipated.    |
| ntermedi |        |            |          |                        |
| ate-Term |        |            |          |                        |
| (1-30    |        |            |          |                        |
| days and |        |            |          |                        |
| 1-6      |        |            |          |                        |
| months)  |        |            |          |                        |
+----------+--------+------------+----------+------------------------+
| In       | N/A    | N/A        | N/A      | Inhalation endpoints   |
| halation |        |            |          | are not applicable     |
| Short-   |        |            |          | because residential    |
| and      |        |            |          | exposure is not        |
| I        |        |            |          | anticipated            |
| ntermedi |        |            |          |                        |
| ate-term |        |            |          |                        |
| (1-30    |        |            |          |                        |
| days and |        |            |          |                        |
| 1-6      |        |            |          |                        |
| months)  |        |            |          |                        |
+----------+--------+------------+----------+------------------------+
| Cancer   | Cla    |            |          |                        |
| (oral,   | ssific |            |          |                        |
| dermal,  | ation: |            |          |                        |
| inh      | "Not   |            |          |                        |
| alation) | likely |            |          |                        |
|          | to be  |            |          |                        |
|          | Carcin |            |          |                        |
|          | ogenic |            |          |                        |
|          | to     |            |          |                        |
|          | H      |            |          |                        |
|          | umans" |            |          |                        |
|          | based  |            |          |                        |
|          | on the |            |          |                        |
|          | a      |            |          |                        |
|          | bsence |            |          |                        |
|          | of     |            |          |                        |
|          | signi  |            |          |                        |
|          | ficant |            |          |                        |
|          | tumor  |            |          |                        |
|          | inc    |            |          |                        |
|          | reases |            |          |                        |
|          | in two |            |          |                        |
|          | ad     |            |          |                        |
|          | equate |            |          |                        |
|          | rodent |            |          |                        |
|          | car    |            |          |                        |
|          | cinoge |            |          |                        |
|          | nicity |            |          |                        |
|          | st     |            |          |                        |
|          | udies. |            |          |                        |
+----------+--------+------------+----------+------------------------+

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

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

+----------+--------+------------+----------+------------------------+
| **Table  |        |            |          |                        |
| 3.2.5.2  |        |            |          |                        |
| Summary  |        |            |          |                        |
| of       |        |            |          |                        |
| Toxic    |        |            |          |                        |
| ological |        |            |          |                        |
| Doses    |        |            |          |                        |
| and      |        |            |          |                        |
| E        |        |            |          |                        |
| ndpoints |        |            |          |                        |
| for      |        |            |          |                        |
| Prothio  |        |            |          |                        |
| conazole |        |            |          |                        |
| desthio  |        |            |          |                        |
| for Use  |        |            |          |                        |
| in       |        |            |          |                        |
| Occu     |        |            |          |                        |
| pational |        |            |          |                        |
| Human    |        |            |          |                        |
| Health   |        |            |          |                        |
| Risk     |        |            |          |                        |
| Asses    |        |            |          |                        |
| sments** |        |            |          |                        |
+----------+--------+------------+----------+------------------------+
| **Exp    | *      | **U        | **Level  | **Study and            |
| osure/** | *Point | ncertainty | of       | Toxicological          |
|          | of     | Factors**  | Concern  | Effects**              |
| **Sc     | Depar  |            | for Risk |                        |
| enario** | ture** |            | Asse     |                        |
|          |        |            | ssment** |                        |
+----------+--------+------------+----------+------------------------+
| Dermal   | NO     | UF~A~=10x  | Occu     | **Dermal developmental |
| Short-   | AEL=30 |            | pational | study in rats**        |
| and      | mg/    | UF~H~=10x  | LOC for  |                        |
| I        | kg/day |            | MOE =    | LOAEL = 100 mg/kg/day  |
| ntermedi |        | UF~DB~ =   | 1000     | based on an increased  |
| ate-Term |        | 10x        |          | incidence of           |
| (1-30    |        |            |          | supernumerary rib      |
| days and |        |            |          | (14th rib).            |
| 1-6      |        |            |          |                        |
| months)  |        |            |          |                        |
+----------+--------+------------+----------+------------------------+
| In       | NOA    | UF~A~=10x  | Occu     | **Developmental        |
| halation | EL=2.0 |            | pational | Toxicity study in      |
| Short-   | mg/    | UF~H~=10x  | LOC for  | rabbits**              |
| and      | kg/day |            | MOE =    |                        |
| I        |        | UF~DB~ =   | 1000     | LOAEL = 10 mg/kg/day,  |
| ntermedi | Inha   | 10x        |          | based on structural    |
| ate-term | lation |            |          | alterations including  |
| (1-30    | abso   |            |          | malformed vertebral    |
| days and | rption |            |          | body and ribs,         |
| 1-6      | are    |            |          | arthrogryposis, and    |
| months)  | a      |            |          | multiple               |
|          | ssumed |            |          | malformations.         |
|          | to be  |            |          |                        |
|          | 100%   |            |          |                        |
+----------+--------+------------+----------+------------------------+
| Cancer   | Cla    |            |          |                        |
| (oral,   | ssific |            |          |                        |
| dermal,  | ation: |            |          |                        |
| inh      | "Not   |            |          |                        |
| alation) | likely |            |          |                        |
|          | to be  |            |          |                        |
|          | Carcin |            |          |                        |
|          | ogenic |            |          |                        |
|          | to     |            |          |                        |
|          | H      |            |          |                        |
|          | umans" |            |          |                        |
|          | based  |            |          |                        |
|          | on the |            |          |                        |
|          | a      |            |          |                        |
|          | bsence |            |          |                        |
|          | of     |            |          |                        |
|          | signi  |            |          |                        |
|          | ficant |            |          |                        |
|          | tumor  |            |          |                        |
|          | inc    |            |          |                        |
|          | reases |            |          |                        |
|          | in two |            |          |                        |
|          | ad     |            |          |                        |
|          | equate |            |          |                        |
|          | rodent |            |          |                        |
|          | car    |            |          |                        |
|          | cinoge |            |          |                        |
|          | nicity |            |          |                        |
|          | st     |            |          |                        |
|          | udies. |            |          |                        |
+----------+--------+------------+----------+------------------------+

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

**3.3 Endocrine disruption**[]{#__RefHeading___Toc187567054 .anchor}

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

**4.0 Dietary Exposure/Risk
Characterization**[]{#__RefHeading___Toc187567055 .anchor}

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

**4.1 Pesticide Metabolism and Environmental
Degradation**[]{#__RefHeading___Toc187567056 .anchor}

References:

*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.
DP303508, S. Funk, 08/21/06*.

*Prothioconazole. Petitions for Establishment of Tolerances for Use on
Sugar Beet (PP#6F7134) and Soybean (PP#6F7073). Summary of Analytical
Chemistry and Residue Data. DP331663, S. Funk, 12/19/07.*

**4.1.1 Metabolism in Primary Crops**[]{#__RefHeading___Toc187567057
.anchor}

No plant metabolism studies were submitted with the subject petitions.
The petitioner has previously submitted metabolism studies with
prothioconazole (labeled in the triazole and phenyl rings) reflecting
foliar uses on wheat, peanut, and sugar beet, and seed treatment
(phenyl-ring label only) of wheat. Detailed discussions of these plant
metabolism studies are presented in the residue chemistry summary
document DP# 303508, 8/21/06, S. Funk (PP#4F6830). The data indicate
that the metabolism of prothioconazole is similar in dissimilar crops.
Prothioconazole was not found to be a major component of the residue in
plant commodities, at 1.0-7.4% TRR in wheat matrices, peanut hay, and
sugar beet tops; prothioconazole was not identified in peanut nutmeat or
sugar beet root. Prothioconazole-desthio was a major component of the
residue, at 9.3-35% TRR in wheat matrices, 24-28% TRR in peanut hay,
6.2% TRR in peanut nutmeat, and 19-58% TRR in sugar beet tops and root.
In triazole-label studies, triazolylalanine accounted for 71% TRR in
wheat grain, 4.1-25% TRR in wheat forage, hay, and straw, 50% TRR in
peanut nutmeat, 29% TRR in sugar beet root, and \<2% TRR in peanut hay
and sugar beet tops. Triazolylacetic acid accounted for 19% TRR in wheat
grain, \<5% TRR in wheat forage, hay, and straw, and peanut nutmeat and
hay, and was not identified in sugar beet root or tops. Free triazole
was not identified in any plant matrix.

*Conclusion*s: The nature of the residue in plants is adequately
understood. The residues of concern for tolerance enforcement and for
risk assessment in plant commodities are defined as the sum of
prothioconazole and its metabolite prothioconazole-desthio, calculated
as prothioconazole.

**4.1.2 Metabolism in Rotational Crops**[]{#__RefHeading___Toc187567058
.anchor}

Bayer CropScience previously submitted tNumber range CHAPTERwo confined
rotational crop studies to support the proposed uses, one conducted
using \[phenyl-^14^C\]-prothioconazole (MRID 46246225) and one conducted
using \[triazole-^14^C\]-prothioconazole (MRID 46246226). Additionally,
a limited field rotational crop study (MRID 46246227) on the
representative crops mustard greens (leafy vegetable), turnip (root
vegetable), and wheat (cereal grain) was previously submitted. Detailed
discussions of the results of these studies were presented in the
previous residue chemistry summary document (*DP# 303508; S. Funk,
08/21/06)* and in the previous risk assessment document *(DP# 328967; B.
O'Keefe, 01/23/07).*.

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

**4.1.3 Metabolism in Livestock**[]{#__RefHeading___Toc187567059
.anchor}

No animal metabolism studies were submitted with the subject petitions.
The petitioner has previously submitted metabolism studies with
prothioconazole (labeled in the triazole and phenyl rings) with goats
and hens. With the exception of some qualitative and quantitative
differences observed between goats and hens, the metabolism of
prothioconazole was very similar in all livestock. Prothioconazole was
found to be a major residue in liver, kidney (goat only) and fat, at
11-31% TRR and was identified in muscle at 2.5-13% TRR; prothioconazole
was found at lower levels in milk and egg (\<4% TRR).
Prothioconazole-desthio was a major metabolite in fat and egg, at 15-29%
TRR, but was found at lower levels in other tissues and milk (\<8% TRR).
4-Hydroxy prothioconazole was found at \~11% TRR in goat liver and at
\<8.5% TRR in other goat matrices and in hen liver and muscle. Two
co-eluting metabolites, JAU6476-O- or S-glucuronide and
JAU6476-3-hydroxy-desthio, were found to be major metabolites, at \~34%
TRR in goat kidney and 4.4%-24% TRR in goat milk and tissues, and hen
matrices. In triazole-label studies, 1,2,4-triazole accounted for a
significant portion of radioactivity in egg (11% TRR) and hen muscle
(19% TRR); 1,2,4-triazole was found at lower levels in hen liver and fat
(\<2% TRR) but was not detected in goat matrices. Thiocyanate was found
to account for a major portion of radioactivity in milk and goat kidney,
muscle, and fat, at 9.0-41% TRR; thiocyanate was found at lower levels
in goat liver (\~2% TRR) and hen matrices (\<10% TRR).
JAU6476-triazolyl-ethanol was a major metabolite in egg (16% TRR) and
hen muscle (28% TRR), was found at lower levels in hen liver and fat
(\<4% TRR), and was not detected in goat matrices. Additional
metabolites found at significant levels were JAU6476-S-methyl, at 20-28%
TRR in hen fat (found at \<7% TRR in other hen matrices and \<1% TRR in
goat liver), and JAU6476-hydroxy-glucuronide, at 11% TRR in goat fat
(\<7% TRR in other goat matrices and in hen liver).

*Conclusions*. The nature of the residue in animal commodities is
adequately understood. For the purpose of tolerance enforcement, the
residues of concern are the sum of prothioconazole, the
prothioconazole-desthio metabolite, and conjugates that can be converted
to either of these two compounds by acid hydrolysis, calculated as
prothioconazole. For purposes of risk assessment, the residues of
concern consist of prothioconazole, the prothioconazole-desthio
metabolite, the 4-hydroxy prothioconazole metabolite, and conjugates
that can be converted to any of these three compounds by acid
hydrolysis.

**4.1.4 Analytical Methodology**[]{#__RefHeading___Toc187567060 .anchor}

*Number range CHAPTERResidue Chemistry Memo DP# 318440, 7/30/07, P.
Schermerhorn (TMV Report)*

*Number range CHAPTERResidue Chemistry Memo DP#s 303508 & 314517,
8/21/06, S. Funk (PP#4F6830)*

Adequate analytical methods exist for the determination of the residue
as defined for both tolerance enforcement and for determination of the
residues of concern for risk assessment for both plant and livestock
commodities. Two methods (LC/MS/MS Method RPA JA/03/01 for plants and
LC/MS/MS Method Bayer Report No. 200537 for animals) which use liquid
chromatography with tandem mass spectrometry using electrospray
ionization in both the positive and negative modes have successfully
passed tolerance method validation at ACB/BEAD. However, ACB recommended
that revisions of these methods should be submitted to include at least
two multiple reaction monitoring (MRM) transitions to preclude the need
for a confirmatory method. In addition, we reiterate the data gap cited
in the initial prothioconazole petition (PP#4F6830) that the proposed
data collection and enforcement methods for livestock commodities must
be validated for poultry commodities.

The data-collection method used for the analysis of samples collected
from the soybean and sugar beet field and processing studies is
adequate. Samples were analyzed for total prothioconazole-derived
residues (prothioconazole and its metabolite prothioconazole-desthio)
using LC-MS/MS method (RPA JA/03/01) which is similar to the enforcement
method. The validated LOQ for total prothioconazole-derived residues was
0.05 ppm for soybean and sugar beet matrices, and 1 ppm for soybean
aspirated grain fractions. Samples were also analyzed for residues of
1,2,4-triazole and triazole conjugates (triazolylalanine and
triazolylacetic acid) using an LC/MS/MS method (Morse Meth-160). The
validated LOQ was 0.01 ppm for 1,2,4-triazole, and ranged 0.01-0.05 ppm
for the triazole conjugates.

**[Multiresidue Methods]{.underline}**

A multiresidue method testing study was previously submitted in support
of PP#4F6830. The study investigated the recovery of prothioconazole,
prothioconazole-desthio, prothioconazole-4-hydroxy, and the
triazole-related compounds (triazole, triazolylalanine and
triazolylacetic acid) through the multiresidue methods of PAM Vol. I.
Based on a cursory review of the study results, HED concluded that the
multiresidue methods are not appropriate for determining residues of
prothioconazole residues of concern, or for determining triazole
residues. The study has been forwarded to FDA for further review.

**4.1.5 Storage Stability Data**[]{#__RefHeading___Toc187567061 .anchor}

[Plant commodities]{.underline}

The interim results of several storage stability studies for
prothioconazole and its desthio metabolite in plant commodities were
previously reported in PP#4F6830. The interim results indicate that
residues of prothioconazole appear to be stable for 12.5 to 12.7 months
in canola oil (14% decomposition), canola seed (20% decomposition),
mustard green (22% decomposition), tomato fruit (14% decomposition),
turnip roots (0% decomposition), wheat flour (12% decomposition), wheat
forage (16% decomposition), wheat grain (27% decomposition), and wheat
straw (15% decomposition). Prothioconazole showed 33% and 36%
decomposition in tomato paste and wheat bran, respectively. However, the
plant metabolism studies in three dissimilar crops have shown that
prothioconazole is expected to contribute only 0 to 7% (0 to 20%
normalized) of the total residues measured in the field crop residue
studies. Therefore, the initial prothioconazole petition concluded that
the apparent slight instability of prothioconazole in tomato paste and
wheat bran would not be expected to have any significant effect on the
total prothioconazole residue levels measured in the field crop residue
studies. Prothioconazole-desthio, the major residue anticipated in crop
matrices, was found to be stable in all matrices after 12.5 to 12.7
months of freezer storage. Percent decomposition of
prothioconazole-desthio was equal to or less than 5% in all matrices.
Prothioconazole-desthio would be expected to contribute 6 to 58% (80 to
100% normalized) of the residues measured in the prothioconazole field
crop residue trials.

Additional data from a marginally acceptable study (Study 1; MRID
46477701) indicate that combined residues of prothioconazole and
prothioconazole-desthio appear to be stable in/on wheat forage, hay, and
straw stored frozen for up to \~35 months. Combined residues of
prothioconazole and prothioconazole-desthio were found to decline during
frozen storage for \~35 months by \~18% in/on canola seed, \~13% in/on
mustard greens, \~20% in/on tomato, \~17% in/on turnip root, and \~32%
in/on wheat grain.

It was also reported that 1,2,4-triazole residues are stable at ‑15 ºC
for up to 24 months in/on turnip roots, mustard greens, wheat straw and
wheat grain, but less stable in wheat forage (48% decomposition) and
canola seed (73% decomposition), and that total residues for triazole
conjugates are stable at ‑15 ºC for up to 24 months in turnip roots,
mustard greens, wheat forage, wheat straw and wheat grain, and
relatively stable in canola seed (≤36% decomposition).

*Conclusions:* The available storage stability data are tentatively
adequate to support the storage intervals and conditions of samples
analyzed for prothioconazole residues of concern from the submitted crop
field trial and processing studies. The final reports of the ongoing
storage stability studies with prothioconazole and
prothioconazole-desthio (up to 45 months) must be submitted as
confirmatory data. Storage stability data for processed commodities are
not required as processed matrices were analyzed within \~1 month of
collection in the soybean and sugar beet processing studies and storage
stability data for the RAC will support the storage conditions and
durations of AGF samples from the soybean study.

The adequacy of the triazole storage stability study to support the
requested uses of prothioconazole will be determined when the final
results of an ongoing triazole storage stability study are submitted to
the Agency (6-month interim data were submitted in MRID 46246211).

[Livestock commodities]{.underline}

Storage stability data were submitted in conjunction with the previously
submitted livestock feeding studies. The petitioner has repeated 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. The results
indicated some instability of the prothioconazole over the 45 days, but
the previously established tolerance is adequate to cover this loss.

[]{.mark}

**4.1.6 Magnitude of the Residue in
Plants**[]{#__RefHeading___Toc187567062 .anchor}

[Soybean]{.underline}

DER Reference: 46841001.der.doc

Bayer CropScience has submitted field trial data for prothioconazole on
soybeans. A summary of residue data from the soybean field trials is
presented in Table 4.1.. The maximum total prothioconazole-derived
residues were 4.45 and 18.9 ppm in/on soybean forage and hay,
respectively, harvested 5-7 days following treatment at 0.391-0.449 lb
ai/A. For mature seed harvested 19-23 days following treatment at
0.393-0.413 lb ai/A, the maximum total prothioconazole-derived residues
were 0.142 ppm.

<table>
<colgroup>
<col style="width: 8%" />
<col style="width: 14%" />
<col style="width: 8%" />
<col style="width: 5%" />
<col style="width: 10%" />
<col style="width: 10%" />
<col style="width: 10%" />
<col style="width: 10%" />
<col style="width: 10%" />
<col style="width: 8%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="10"><strong>Table 4.1.1. Summary of Residue Data from
Soybean Field Trials with Prothioconazole.</strong></td>
</tr>
<tr class="even">
<td rowspan="2">Matrix</td>
<td rowspan="2"><p>Total Rate</p>
<p>(lb ai/A)</p></td>
<td rowspan="2">PHI (days)</td>
<td colspan="7">Residues (ppm)</td>
</tr>
<tr class="odd">
<td>N</td>
<td>Min.</td>
<td>Max.</td>
<td>HAFT</td>
<td>Median (STMdR)</td>
<td>Mean (STMR)</td>
<td>Std. Dev.</td>
</tr>
<tr class="even">
<td colspan="10"><em>Proposed use pattern</em>: Multiple broadcast
postemergence foliar applications at maximum seasonal rates of 0.281 lb
ai/A (Proline®) or 0.402 lb ai/A (Provost™). A 21-day preharvest
interval (PHI) is proposed for both products.</td>
</tr>
<tr class="odd">
<td colspan="10"><strong>Total Prothioconazole-Derived
Residues</strong></td>
</tr>
<tr class="even">
<td>Forage</td>
<td rowspan="2">0.391-0.449</td>
<td>5-7</td>
<td>42</td>
<td>&lt;0.05</td>
<td>4.45</td>
<td>4.25</td>
<td>1.37</td>
<td>1.39</td>
<td>0.95</td>
</tr>
<tr class="odd">
<td>Hay</td>
<td>5-7</td>
<td>42</td>
<td>1.46</td>
<td>18.9</td>
<td>18.3</td>
<td>5.56</td>
<td>5.97</td>
<td>3.36</td>
</tr>
<tr class="even">
<td>Seed</td>
<td>0.393-0.413</td>
<td>19-23</td>
<td>42</td>
<td>&lt;0.05</td>
<td>0.142</td>
<td>0.12</td>
<td>0.05</td>
<td>0.05</td>
<td>0.02</td>
</tr>
<tr class="odd">
<td colspan="10"><strong>1,2,4-Triazole Residues</strong></td>
</tr>
<tr class="even">
<td>Forage</td>
<td rowspan="2">0.391-0.449</td>
<td>5-7</td>
<td>21</td>
<td>&lt;0.01</td>
<td>0.01</td>
<td>NA</td>
<td>0.01</td>
<td>0.01</td>
<td>0.00</td>
</tr>
<tr class="odd">
<td>Hay</td>
<td>5-7</td>
<td>21</td>
<td>&lt;0.01</td>
<td>0.01</td>
<td>NA</td>
<td>0.01</td>
<td>0.01</td>
<td>0.00</td>
</tr>
<tr class="even">
<td>Seed</td>
<td>0.393-0.413</td>
<td>19-23</td>
<td>8</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>0.00</td>
</tr>
<tr class="odd">
<td colspan="10"><strong>Triazole Conjugate Residues</strong></td>
</tr>
<tr class="even">
<td>Forage</td>
<td rowspan="2">0.391-0.449</td>
<td>5-7</td>
<td>21</td>
<td>&lt;0.05</td>
<td>0.27</td>
<td>NA</td>
<td>0.06</td>
<td>0.08</td>
<td>0.06</td>
</tr>
<tr class="odd">
<td>Hay</td>
<td>5-7</td>
<td>21</td>
<td>0.04</td>
<td>0.40</td>
<td>NA</td>
<td>0.17</td>
<td>0.15</td>
<td>0.09</td>
</tr>
<tr class="even">
<td>Seed</td>
<td>0.393-0.413</td>
<td>19-23</td>
<td>8</td>
<td>0.04</td>
<td>0.08</td>
<td>0.08</td>
<td>0.06</td>
<td>0.06</td>
<td>0.01</td>
</tr>
</tbody>
</table>

Based on the decline trial data, residues in/on soybean forage and hay
generally declined with later harvest intervals. In the two residue
decline tests, prothioconazole-derived residues in/on forage declined
from averages of 2.8 ppm and 3.7 ppm at 0 DAT to 0.35 ppm and 0.46 ppm
at 14 DAT, respectively. Prothioconazole-derived residues in/on hay
declined from averages of 16.2 ppm and 18.9 ppm at 0 DAT to 1.40 ppm and
1.81 ppm at 14 DAT. For seeds, prothioconazole-derived residues were too
low (\<0.05 ppm) to determine decline trends.

The 1,2,4-triazole residues were \<0.01-0.01 ppm for both forage and hay
samples harvested 5-7 DAT. The triazole conjugate residues were
\<0.05-0.27 ppm and 0.04-0.40 ppm in the respective forage and hay
samples. For composite samples of seed harvested 19-23 DAT, residues of
1,2,4-triazole were \<0.01 ppm, and residues of triazole conjugates were
0.04-0.08 ppm.

*Conclusions:* The submitted residue data for soybeans are adequate to
fulfill data requirements pending submission of the final study reports
from ongoing storage stability studies and revision of product labels to
specify appropriate preharvest intervals for certain soybean
commodities. The number and location of field trials are in accordance
with OPPTS Guideline 860.1500, and the conducted field trials reflect
the maximum proposed seasonal rate for Provost™ as well as the proposed
21-day PHI for soybean seed.

The field trial data for soybean forage and hay were entered into the
Agency's tolerance spreadsheet as described in a document entitled
*Statistical Basis of the NAFTA Method for Calculating Pesticide Maximum
Residue Limits from Field Trial Data* to determine appropriate tolerance
levels; see Appendix I of DP# 331663, 12/19/07, S. Funk (PP#6F7073 and
PP#6F7134). The tolerance spreadsheet was not used for soybean seed
because \>60% of treated samples bore residues below the LOQ. The
tolerance spreadsheet recommends tolerances of 4.5 ppm for soybean
forage and 17 ppm for soybean hay. Based on the maximum residues of
0.142 ppm obtained from the field trials, HED recommends a tolerance of
0.15 ppm for soybean seed which is identical to the level proposed by
the petitioner. A revised Section B is required to specify a minimum
preharvest interval of 7 days for soybean forage and hay.

[Sugar Beet]{.underline}

DER Reference: 46974608.der.doc

Bayer CropScience has submitted field trial data for prothioconazole on
sugar beets. A summary of residue data from the sugar beet field trials
is presented in Table 4.1.2. The maximum total prothioconazole-derived
residues were 4.18 and 1.97 ppm in/on sugar beet tops harvested at 6/7
and 13/14 days, respectively, following late-season foliar applications
of the 4 lb/gal FlC formulation at a total rate of 0.529-0.548 lb ai/A.
The maximum total prothioconazole-derived residues were 0.24 and 0.14
ppm in/on roots harvested 6/7 and 13/14 DAT, respectively.

<table>
<colgroup>
<col style="width: 8%" />
<col style="width: 14%" />
<col style="width: 8%" />
<col style="width: 5%" />
<col style="width: 10%" />
<col style="width: 10%" />
<col style="width: 10%" />
<col style="width: 10%" />
<col style="width: 10%" />
<col style="width: 8%" />
</colgroup>
<tbody>
<tr class="odd">
<td colspan="10"><strong>Table 4.1.2. Summary of Residue Data for Sugar
Beet Field Trials with Prothioconazole.</strong></td>
</tr>
<tr class="even">
<td rowspan="2">Matrix</td>
<td rowspan="2"><p>Total Rate</p>
<p>(lb ai/A)</p></td>
<td rowspan="2">PHI (days)</td>
<td colspan="7">Residues (ppm)</td>
</tr>
<tr class="odd">
<td>n</td>
<td>Min.</td>
<td>Max.</td>
<td>HAFT</td>
<td>Median (STMdR)</td>
<td>Mean (STMR)</td>
<td>Std. Dev.</td>
</tr>
<tr class="even">
<td colspan="10"><em>Proposed use pattern</em>: Multiple broadcast
postemergence foliar applications at a maximum seasonal rate of 0.534 lb
ai/A. The proposed PHIs are 7 days (Proline®) or 21 days (USF 0728 325
SC Fungicide).</td>
</tr>
<tr class="odd">
<td colspan="10"><strong>Total Prothioconazole-Derived
Residues</strong></td>
</tr>
<tr class="even">
<td rowspan="2">Tops</td>
<td rowspan="4"><p>0.529-</p>
<p>0.548</p></td>
<td>6-7</td>
<td>24</td>
<td>0.39</td>
<td>4.18</td>
<td>3.87</td>
<td>1.64</td>
<td>1.80</td>
<td>1.17</td>
</tr>
<tr class="odd">
<td>13-14</td>
<td>24</td>
<td>0.20</td>
<td>1.97</td>
<td>1.75</td>
<td>1.04</td>
<td>1.03</td>
<td>0.60</td>
</tr>
<tr class="even">
<td rowspan="2">Roots</td>
<td>6-7</td>
<td>24</td>
<td>&lt;0.05</td>
<td>0.24</td>
<td>0.17</td>
<td>0.05</td>
<td>0.07</td>
<td>0.05</td>
</tr>
<tr class="odd">
<td>13-14</td>
<td>24</td>
<td>&lt;0.05</td>
<td>0.14</td>
<td>0.11</td>
<td>0.05</td>
<td>0.07</td>
<td>0.06</td>
</tr>
<tr class="even">
<td colspan="10"><strong>1,2,4-Triazole Residues</strong></td>
</tr>
<tr class="odd">
<td rowspan="2">Tops</td>
<td rowspan="4"><p>0.529-</p>
<p>0.548</p></td>
<td>6-7</td>
<td>12</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>--</td>
</tr>
<tr class="even">
<td>13-14</td>
<td>12</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>--</td>
</tr>
<tr class="odd">
<td rowspan="2">Roots</td>
<td>6-7</td>
<td>12</td>
<td>&lt;0.01</td>
<td>0.012</td>
<td>&lt;0.011</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>0.001</td>
</tr>
<tr class="even">
<td>13-14</td>
<td>12</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>--</td>
</tr>
<tr class="odd">
<td colspan="10"><strong>Triazole Conjugate Residues</strong></td>
</tr>
<tr class="even">
<td rowspan="2">Tops</td>
<td rowspan="4"><p>0.529-</p>
<p>0.548</p></td>
<td>6-7</td>
<td>12</td>
<td>&lt;0.01</td>
<td>0.018</td>
<td>0.018</td>
<td>0.01</td>
<td>0.012</td>
<td>0.003</td>
</tr>
<tr class="odd">
<td>13-14</td>
<td>12</td>
<td>&lt;0.01</td>
<td>0.021</td>
<td>0.021</td>
<td>0.01</td>
<td>0.012</td>
<td>0.004</td>
</tr>
<tr class="even">
<td rowspan="2">Roots</td>
<td>6-7</td>
<td>12</td>
<td>&lt;0.01</td>
<td>0.014</td>
<td>0.014</td>
<td>0.01</td>
<td>0.011</td>
<td>0.002</td>
</tr>
<tr class="odd">
<td>13-14</td>
<td>12</td>
<td>&lt;0.01</td>
<td>0.017</td>
<td>0.017</td>
<td>0.012</td>
<td>0.013</td>
<td>0.003</td>
</tr>
</tbody>
</table>

Based on the residue decline trial data, residues in sugar beet tops and
roots generally declined with later harvest intervals.
Prothioconazole-derived residues declined from 5.0 and 0.07 ppm at the
0-day PHI to 0.74 and 0.06 ppm at the 27-day PHI in/on tops and roots,
respectively.

Residues of 1,2,4-triazole were below the LOQ (\<0.01 ppm) and
\<0.01-0.01 ppm, respectively, in/on sugar beet tops and roots harvested
6/7 and 13/14 days after treatment. Total residues of the triazole
conjugates were \<0.01-0.02 ppm in/on sugar beet tops and roots
harvested 6/7 and 13/14 DAT.

*Conclusions*: The submitted residue data for sugar beet are adequate to
fulfill data requirements pending submission of the final study reports
from ongoing storage stability studies. The number and location of field
trials are in accordance with OPPTS Guideline 860.1500, and the
conducted field trials reflect the maximum proposed seasonal rate and
the proposed 7-day PHI.

The Agency's tolerance spreadsheet was not used for sugar beet root
because \>60% of treated samples bore residues below the LOQ. Based on
the maximum residues of 0.24 ppm obtained from the field trials (7 day
PHI), HED recommends a tolerance of 0.25 ppm for sugar beet root which
is identical to the level proposed by the petitioner. According to the
Minutes of the 1/17/2007 ChemSAC meeting, a tolerance for sugar beet
tops need not be established because they are not a human food commodity
and are being eliminated from Table 1 Feedstuffs (October 2006).

**4.1.7 Magnitude of the Residue in Processed Food/Feed**
[]{#__RefHeading___Toc187567063 .anchor}

[Soybean]{.underline}

DER Reference: 46841002.der.doc

Bayer CropScience has submitted a processing study with prothioconazole
on soybeans. A summary of processing factors from the soybean processing
study is presented in Table 4.1.3.

  ----------------------------------------------------------------------------------------
  Number range                                                          
  CHAPTER**Table                                                        
  4.1.3. Summary of                                                     
  Processing                                                            
  Factors for                                                           
  Prothioconazole                                                       
  from the Soybean                                                      
  Study.**                                                              
  ----------------- ----------------- ----------------- --------------- ------------------
  RAC               Processed         Average                           
                    Commodity         Processing Factor                 
                                      ^1^                               

                                      Prothioconazole   1,24-Triazole   Total Triazole
                                                                        Conjugates ^2^

  Soybean           Aspirated grain   76x               \>1.3x          2.1x
                    fractions                                           

                    Meal              0.2x              NC              1.5x

                    Hulls             0.6x              NC              0.6x

                    Refined oil       \<0.2x            NC              \<0.1x
  ----------------------------------------------------------------------------------------

^1^ NC = Not calculated; residues were below the LOQ in the RAC and the
processed commodity.

^2^ Total triazolylalanine and triazolylacetic acid residues.

The observed processing factors do not exceed the theoretical
concentration factors of 11.3x for soybean hulls, 2.2x for meal, and
12.0x for oil (OPPTS 860.1520, Table 3, based on separation of
components).

[]{.mark}

*Conclusion*s: The soybean processing study is acceptable to satisfy
data requirements pending submission of the final study reports from
ongoing storage stability studies. The treated samples of soybean seed
(RAC) used for processing bore an average prothioconazole-derived
residue of 3.06 ppm. Following processing of the RAC, residues did not
concentrate in meal (processing factor of 0.2x), hulls (0.6x), and
refined oil (\<0.2x) but concentrated in soybean aspirated grain
fractions (76x). The maximum expected residues in soybean AGF is 9.12
ppm \[HAFT (0.12 ppm; see Table 7) X processing factor (76x)\]. The
established tolerance (11 ppm) for aspirated grain fractions (based on
barley and wheat) will cover residues of prothioconazole-derived
residues in soybean AGF as a result of the proposed use.

Processing factors could not be calculated for 1,2,4-triazole in meal,
hulls, and refined oil because residues were below the LOQ in the RAC
and processed matrices. Residues of the triazole conjugates did not
appear to concentrate in refined oil and hulls, but appeared to
concentrate in meal (1.5x). The processing factors for residues of
1,2,4-triazole and triazole conjugates in AGF were 1.3x and 2.1x,
respectively.

[Sugar Beet]{.underline}

DER Reference: 46974609.der.doc

Bayer CropScience has submitted a processing study with prothioconazole
on sugar beets. A summary of processing factors from the sugar beet
processing study is presented in Table 4.1.4.

  -----------------------------------------------------------------------------------------
  Number range                                                           
  CHAPTER**Table                                                         
  4.1.4. Summary of                                                      
  Processing                                                             
  Factors for                                                            
  Prothioconazole                                                        
  from the Sugar                                                         
  Beet Study.**                                                          
  ----------------- ----------------- ----------------- ---------------- ------------------
  RAC               Processed         Average                            
                    Commodity         Processing Factor                  
                                      ^1^                                

                                      Prothioconazole   1,2,4-Triazole   Total Triazole
                                                                         Conjugates ^2^

  Sugar beet        Refined sugar     \<0.1x            NC               \<0.7x

                    Dried pulp        \<0.1x            NC               \<0.7x

                    Molasses          0.2x              NC               5.3x
  -----------------------------------------------------------------------------------------

^1^ NC = Not calculated; residues were below the LOQ in the RAC and the
processed commodity.

^2^ Total triazolylalanine and triazolylacetic acid residues.

The observed processing factors do not exceed the theoretical
concentration factors of 12.5x for sugar beet sugar (OPPTS 860.1520,
Table 3, based on separation of components) or 20x for sugar beet dry
pulp (OPPTS 860.1520, Table 4, maximum experimental factor).

*Conclusion*s: The sugar beet processing study is acceptable to satisfy
data requirements pending submission of the final study reports from
ongoing storage stability studies. The treated samples of sugar beet
root (RAC) used for processing bore an average prothioconazole-derived
residue of 1.82 ppm. Following processing of the RAC, residues did not
concentrate in refined sugar (\<0.1x), dried pulp (\<0.1x), and molasses
(\<0.1x). The results suggest that tolerances are not needed for the
processed commodities of sugar beet.

Residues of the triazole conjugates did not appear to concentrate in
refined sugar and dried pulp (\<0.7x processing factors), but appeared
to concentrate in molasses (5.3x) with processing. Processing factors
could not be calculated for 1,2,4-triazole because residues were below
the LOQ in the RAC and processed refined sugar, dried pulp and molasses.

**4.1.8 Magnitude of the Residue in Meat, Milk, Poultry, and
Eggs**[]{#__RefHeading___Toc187567064 .anchor}

Number range CHAPTERResidue Chemistry Memo DP#s 303508 & 314517,
8/21/06, S. Funk (PP#4F6830)

[Livestock dietary burdens]{.underline}

The potential for secondary transfer of prothioconazole residues of
concern in meat, milk, poultry, and eggs exists because there are
several livestock feedstuffs (soybean seed, forage, hay, aspirated grain
fractions, meal, hulls and silage; and sugar beet dried pulp and
molasses) that are associated with the proposed uses in the current
petitions. Sugar beet tops are no longer considered a significant feed
item and have been removed from Table 1 Feedstuffs (October 2006). The
livestock dietary burdens of prothioconazole are presented in Table
4.1.5, and the calculations made reflect the most recent guidance from
HED concerning revisions of feedstuff percentages in Table 1 and
constructing reasonably balanced livestock diets (RBDs). The calculated
dietary burdens of prothioconazole are 9.24 ppm for beef cattle, 9.79
ppm for dairy cattle, 0.29 ppm for poultry, and 0.10 ppm for swine.

+------------------+------+------+-------+------------+---------------+
| **Table 4.1.5.   |      |      |       |            |               |
| Calculation of   |      |      |       |            |               |
| Dietary Burdens  |      |      |       |            |               |
| of               |      |      |       |            |               |
| Prothioconazole  |      |      |       |            |               |
| Residues to      |      |      |       |            |               |
| Livestock.**     |      |      |       |            |               |
+==================+======+======+=======+============+===============+
| Feedstuff        | Typ  | \%   | \%    | Re         | Dietary       |
|                  | e^1^ | Dry  | Di    | commended/ | Contribution  |
|                  |      | M    | et^2^ |            | (ppm)^3^      |
|                  |      | atte |       | E          |               |
|                  |      | r^2^ |       | stablished |               |
|                  |      |      |       |            |               |
|                  |      |      |       | Tolerance  |               |
|                  |      |      |       | (ppm)      |               |
+------------------+------+------+-------+------------+---------------+
| **Beef Cattle**  |      |      |       |            |               |
+------------------+------+------+-------+------------+---------------+
| Soybean hay      | R    | 85   | 30    | 17.0       | 6.00          |
+------------------+------+------+-------+------------+---------------+
| Wheat forage     | R    | 25   | 10    | 6.0        | 2.40          |
+------------------+------+------+-------+------------+---------------+
| Barley grain     | CC   | 88   | 40    | 0.35       | 0.16          |
+------------------+------+------+-------+------------+---------------+
| Aspirated grain  | CC   | 85   | 5     | 11.0       | 0.65          |
| fractions        |      |      |       |            |               |
+------------------+------+------+-------+------------+---------------+
| Soybean seed     | PC   | 89   | 15    | 0.15       | 0.03          |
+------------------+------+------+-------+------------+---------------+
| TOTAL BURDEN     | \--  | \--  | 100   | \--        | **9.24**      |
+------------------+------+------+-------+------------+---------------+
| **Dairy Cattle** |      |      |       |            |               |
+------------------+------+------+-------+------------+---------------+
| Soybean hay      | R    | 85   | 30    | 17.0       | 6.00          |
+------------------+------+------+-------+------------+---------------+
| Wheat forage     | R    | 25   | 15    | 6.0        | 3.60          |
+------------------+------+------+-------+------------+---------------+
| Barley grain     | CC   | 88   | 40    | 0.35       | 0.16          |
+------------------+------+------+-------+------------+---------------+
| Soybean seed     | PC   | 89   | 15    | 0.15       | 0.03          |
+------------------+------+------+-------+------------+---------------+
| TOTAL BURDEN     | \--  | \--  | 100   | \--        | **9.79**      |
+------------------+------+------+-------+------------+---------------+
| **Poultry**      |      |      |       |            |               |
+------------------+------+------+-------+------------+---------------+
| Barley grain     | CC   | 88   | 70    | 0.35       | 0.25          |
+------------------+------+------+-------+------------+---------------+
| Wheat grain      | CC   | 89   | 10    | 0.07       | 0.007         |
+------------------+------+------+-------+------------+---------------+
| Soybean seed     | PC   | 89   | 20    | 0.15       | 0.03          |
+------------------+------+------+-------+------------+---------------+
| TOTAL BURDEN     | \--  | \--  | 100   | \--        | **0.29**      |
+------------------+------+------+-------+------------+---------------+
| **Swine**        |      |      |       |            |               |
+------------------+------+------+-------+------------+---------------+
| Barley grain     | CC   | 88   | 20    | 0.35       | 0.07          |
+------------------+------+------+-------+------------+---------------+
| Untreated        | CC   | NA   | 60    | NA         | \--           |
+------------------+------+------+-------+------------+---------------+
| Soybean seed     | PC   | 89   | 20    | 0.15       | 0.03          |
+------------------+------+------+-------+------------+---------------+
| TOTAL BURDEN     | \--  | \--  | 100   | \--        | **0.10**      |
+------------------+------+------+-------+------------+---------------+

^1^ R: Roughage; CC: Carbohydrate concentrate; PC: Protein concentrate.

^2^ Revision of feedstuffs in OPPTS 860.1000 Table 1 referenced as
"Table 1 Feedstuffs (October 2006)."

^3^ Contribution = (\[tolerance /% DM\] X % diet) for beef and dairy
cattle; contribution = (\[tolerance\] X % diet) for poultry and swine.

[Established livestock tolerances]{.underline}

Tolerances have been established for the combined residues of
prothioconazole, prothioconazole-desthio, and conjugates that can be
converted to these two compounds by acid hydrolysis, calculated as
parent, at 0.02 ppm for milk; 0.02, 0.1, and 0.2 ppm, respectively, for
the meat, fat, and meat byproducts of cattle, goat, and sheep; 0.05 ppm
for the meat byproducts of hog; and 0.02 ppm for poultry liver.

The prothioconazole tolerances for livestock commodities were
established based on results from the submitted feeding studies and the
Agency's estimated dietary burdens for prothioconazole residues, which
were originally calculated to be 12.97 ppm for beef cattle, 20.86 ppm
for dairy cattle, 0.45 ppm for poultry, and 2.71 ppm for swine. These
values represented the maximum theoretical burden with no consideration
of a reasonably balanced diet, i.e., the diet was excessive in
forage/hay.

[Animal feeding studies]{.underline}

Number range CHAPTERResidue Chemistry Memo DP#s 303508 & 314517,
8/21/06, S. Funk (PP#4F6830)

Two cattle feeding studies were previously reviewed in PP#4F6830, one in
which cattle were dosed with prothioconazole (MRID 46246213) and one in
which cattle were dosed with prothioconazole-desthio (MRID 46246214).
The results of the first study are summarized below; the second study
was deemed supplemental.

Prothioconazole was administered orally (via gelatin capsules) to three
groups of dairy cattle (3 cows per group) once daily for 29 consecutive
days. Dosing was made at levels equivalent to 9.9, 29.5, and 98.4 ppm in
the feed. The dosing levels correspond to \~1x, 3x, and 10x the
recalculated dietary burden for dairy cattle based on a reasonably
balanced diet. Milk and tissue samples were analyzed using the proposed
enforcement method for animal commodities, which was an LC-MS/MS method
(Bayer Report No. 200537). This method determined residues of
prothioconazole, prothioconazole desthio, and prothioconazole-4-hydroxy,
plus any metabolites hydrolysable to these compounds. The maximum
residues of prothioconazole, prothioconazole-desthio, and
prothioconazole-4-hydroxy in milk and tissues are listed in Table 4.1.
below. Because low residue levels were observed in samples from the mid
and high dose groups, milk and muscle samples from the low dose group
(9.9 ppm) were not analyzed.

<table style="width:100%;">
<colgroup>
<col style="width: 12%" />
<col style="width: 9%" />
<col style="width: 10%" />
<col style="width: 8%" />
<col style="width: 10%" />
<col style="width: 9%" />
<col style="width: 9%" />
<col style="width: 11%" />
<col style="width: 7%" />
<col style="width: 8%" />
</colgroup>
<thead>
<tr class="header">
<th colspan="10"><strong>Table 4.1.6. Maximum Residues of
Prothioconazole (A), Prothioconazole-desthio (B), and
Prothioconazole-4-hydroxy (C), as prothioconazole equivalents, by
Feeding Level Following Dosing of Dairy Cattle with Prothioconazole for
29 Days.</strong></th>
</tr>
<tr class="odd">
<th rowspan="3">Matrix</th>
<th colspan="9">Residues (ppm)</th>
</tr>
<tr class="header">
<th colspan="3">9.9 ppm</th>
<th colspan="3">29.5 ppm</th>
<th colspan="3">98.4 ppm</th>
</tr>
<tr class="odd">
<th>A</th>
<th>B</th>
<th>C</th>
<th>A</th>
<th>B</th>
<th>C</th>
<th>A</th>
<th>B</th>
<th>C</th>
</tr>
</thead>
<tbody>
<tr class="odd">
<td><p>Milk</p>
<p>(day 29)</p></td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>&lt;0.005</td>
<td>&lt;0.005</td>
<td>&lt;0.005</td>
<td>&lt;0.005</td>
<td>&lt;0.005</td>
<td>&lt;0.005</td>
</tr>
<tr class="even">
<td>Skim milk</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
</tr>
<tr class="odd">
<td>Cream</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
</tr>
<tr class="even">
<td>Fat</td>
<td>&lt;0.05</td>
<td>&lt;0.05</td>
<td>&lt;0.05</td>
<td><p>&lt;0.05</p>
<p>(0.019)<sup>1</sup></p></td>
<td><p>&lt;0.05</p>
<p>(≈0.003)<sup>1</sup></p></td>
<td><p>&lt;0.05</p>
<p>(≈0.006)<sup>1</sup></p></td>
<td>0.062</td>
<td>&lt;0.05</td>
<td>&lt;0.05</td>
</tr>
<tr class="odd">
<td>Kidney</td>
<td>0.062</td>
<td>&lt;0.01</td>
<td>0.017</td>
<td>0.176</td>
<td>&lt;0.01</td>
<td>0.063</td>
<td>0.79</td>
<td>0.011</td>
<td>0.356</td>
</tr>
<tr class="even">
<td>Liver</td>
<td>0.063</td>
<td>&lt;0.01</td>
<td>0.054</td>
<td>0.120</td>
<td>0.011</td>
<td>0.181</td>
<td>0.467</td>
<td>0.030</td>
<td>0.518</td>
</tr>
<tr class="odd">
<td>Muscle</td>
<td>--</td>
<td>--</td>
<td>--</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
<td>&lt;0.01</td>
</tr>
</tbody>
</table>

^1^ At/near the limit of *detection*; in fat, 0.012 ppm for
prothioconazole, 0.005 ppm for prothioconazole desthio, 0.008 ppm for
prothioconazole-4-hydroxy.

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

A poultry feeding study is not available. HED *provisionally* concluded
in PP#4F6830 [that residues are unlikely in poultry commodities except
liver and that, therefore, poultry commodity tolerances are not needed,
except for liver. The extreme extrapolation required and the short
interval of the poultry metabolism study (3 days) makes the conclusions
on the need for poultry tolerances tentative. Therefore, a poultry
feeding study and fully validated analytical method for poultry
commodities]{.mark} are required as conditions of the registration of
prothioconazole.

*Conclusions*: Based on the dietary exposure levels and the residue data
from the ruminant feeding study, the existing prothioconazole tolerances
for animal commodities are adequate to support the proposed uses. As
requested in PP#4F6830 and to support the current petitions, [a poultry
feeding study and fully validated analytical method for poultry
commodities]{.mark} are required.

**4.1.9 Confined and Field Rotational Accumulation in Rotational Crops**
[]{#__RefHeading___Toc187567065 .anchor}

Number range CHAPTERResidue Chemistry Memo DP#s 303508 & 314517,
8/21/06, S. Funk (PP#4F6830)

Two acceptable confined crop rotation studies were previously submitted
in PP#4F6830. HED review of these studies indicate that the metabolism
of prothioconazole 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. 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 (for tolerance enforcement and for dietary
intake assessment) is the same as for primary crop commodities,
prothioconazole and the desthio metabolite.

Bayer previously submitted a limited field rotational crop study in
PP#4F6830 on the representative crops mustard greens (leafy vegetable),
turnip (root vegetable), and wheat (cereal grain). HED has determined
that these data are adequate to satisfy data requirements. The
petitioner 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 plantback interval (PBI), are adequate to support the
proposed rotational crop restrictions, provided that the required
storage stability data do not indicate significant decline of
prothioconazole residues in these commodities during storage.

**4.1.10 Drinking Water Residue Profile**[]{#__RefHeading___Toc187567066
.anchor}

Reference: *Drinking Water Assessment for the Section 3 New Use
Petitions for the Use of Prothioconazole on Soybeans and Sugar Beets.
DP#'s 341457 & 341458, C. Sutton, 10/10/07.*

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

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

EFED provided estimated drinking water concentrations (EDWCs), which
were determined using the PRZM-EXAMS screening model. EDWC point
estimates were provided for both lower and upper bounds to account for
two major uncertainties in the drinking water modeling. First, some
prothioconazole residues remained in the bound phase in EFED studies
used to characterize persistence. To address this uncertainty, modeling
was bounded based on inclusion and exclusion of unextracted residues in
half-life calculations. Secondly, the two major water degradates of
prothioconazole formed rapidly after application and have different
mobilities. To address this uncertainty, modeling was conducted using
K~OCs~ (soil organic carbon-water partitioning coefficients) for
prothioconazole-desthio and prothioconazole-S-methyl. The lower bound
EDWCs represent the exclusion of unextracted residues and the use of the
higher K~oc~ (less mobility). Conversely, the higher bound estimates
represent the inclusion of unextracted residues and the use of the lower
K~oc~ (more mobility).

EDWCs were further refined for peanuts and sugar beets. Regional default
Percent Cropped Area (PCA) factors have been applied to estimated
concentrations of these crops. Surface water EDWCs used in this
assessment are summarized in Table 4.1.7 below. DEEM analyses were
performed using both the upper and lower bound estimates and the peanut
(previous registration) and sugar beet (proposed registration) crop
scenarios shown below, since these EDWC values were the highest reported
for the respective acute and chronic exposure durations.

  ----------------- -------------- --------------- --------- --------- ---------
  **Table 4.1.7.                                                       
  Summary of                                                           
  Estimated                                                            
  Drinking Water                                                       
  Concentrations                                                       
  for                                                                  
  Prothioconazole                                                      
  Used for Dietary                                                     
  Assessment**                                                         

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

                                   ACUTE                     CHRONIC   

                                   Lower Bound     Upper     Lower     Upper
                                                   Bound     Bound     Bound

  Surface water     Peanut         13              29        \--       \--
  (PRZM/EXAMS)                                                         

                    Sugar Beet     \--             \--       8.4       13
  ----------------- -------------- --------------- --------- --------- ---------

**4.1.11 Proposed Tolerances**[]{#__RefHeading___Toc187567067 .anchor}

HED has determined that the residues of concern for tolerance
enforcement and for risk assessment in plant and rotational crop
commodities are defined as the sum of prothioconazole and its metabolite
prothioconazole-desthio, calculated as prothioconazole. The residues of
concern in livestock commodities for tolerance enforcement are defined
as the sum of prothioconazole, prothioconazole-desthio, and conjugates
that are converted to prothioconazole or prothioconazole-desthio via
acid hydrolysis, calculated as prothioconazole. The residues of concern
for risk assessment in livestock commodities are defined as the sum of
prothioconazole, prothioconazole-desthio, 4-hydroxy prothioconazole, and
conjugates that are converted to prothioconazole or
prothioconazole-desthio or 4-hydroxy prothioconazole via acid
hydrolysis, calculated as prothioconazole.

Prothioconazole tolerances for plant commodities listed in 40 CFR
§180.626(a)(1) are expressed in terms of the combined residues of the
fungicide prothioconazole,
2-\[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl\]-1,2-dihydro-3*H*-1,2,4-triazole-3-thione,
and prothioconazole-desthio,
α-(1-chlorocyclopropyl)-α-\[(2-chlorophenyl)methyl\]-1*H*-1,2,4-triazole-1-ethanol,
calculated as parent.

Prothioconazole tolerances for animal commodities are listed in 40 CFR
§180.626(a)(2) and are expressed in terms of the combined residues of
the prothioconazole and prothioconazole-desthio, and conjugates that can
be converted to these two compounds by acid hydrolysis, calculated as
parent.

The tolerance expression proposed by Bayer in #6F7073 and PP#6F7134 is
consistent with the tolerance definition for plant commodities listed in
40 CFR §180.626(a)(1). However, a revised Section F must be submitted to
incorporate the CAS name of prothioconazole-desthio in the tolerance
expression and to specify that residues of the metabolite are calculated
as parent.

The field trial data for soybean forage and hay were entered into the
Agency's tolerance spreadsheet as described in a document entitled
*Statistical Basis of the NAFTA Method for Calculating Pesticide Maximum
Residue Limits from Field Trial Data* to determine appropriate tolerance
levels; see Appendix I. The tolerance spreadsheet was not used for
soybean seed because \>60% of treated samples bore residue below the
data-collection method LOQ. The tolerance spreadsheet recommends
tolerances of 4.5 ppm for soybean forage and 17 ppm for soybean hay.
Based on the maximum residues of 0.142 ppm obtained for seed from the
field trials, HED recommends a tolerance of 0.15 ppm for soybean seed.

The field trial data for sugar beet root were not entered into the
Agency's tolerance spreadsheet because \>60% of treated samples bore
residues below the LOQ. Based on the maximum residues of 0.24 ppm
obtained from the field trials and excluding an apparent invalid value
(1.26 ppm), HED recommends a tolerance of 0.25 ppm for sugar beet root.
According to the Minutes of the 1/17/2007 ChemSAC meeting, a tolerance
for sugar beet tops need not be established because they are not a human
food commodity and are being eliminated from Table 1 Feedstuffs (October
2006).

The submitted soybean and sugar beet processing studies indicate that
tolerances are not needed for the processed commodities of these crops.
No concentration of prothioconazole-derived residues was observed in
soybean meal (0.2x), hulls (0.6x), and refined oil (\<0.2x) and in sugar
beet refined sugar (\<0.1x), dried pulp (\<0.1x), and molasses (\<0.1x).
Residues concentrated in soybean aspirated grain fractions (76x); the
established tolerance (11 ppm) for aspirated grain fractions (based on
barley and wheat) will cover residues of prothioconazole-derived
residues in soybean AGF as a result of the proposed use.

No tolerances are needed for rotational crops based on previously
submitted studies which showed no quantifiable total
prothioconazole-derived residues in/on rotated mustard greens, turnip
root and top, and wheat forage, hay grain, and straw at the 1-month PBI.
The 30-day rotational crop restriction on the proposed product labels is
appropriate.

Adequate ruminant feeding studies are available, and these data indicate
that the established tolerances for milk, and fat, meat, and meat
byproducts of cattle, goat, hog, horse, and sheep remain adequate to
support the proposed uses and the re-calculated dietary burdens.
Consistent with the determination made in PP#4F6830, HED *tentatively*
concludes that the established tolerance for [poultry liver is adequate
based on extrapolation made from the results of previously submitted
poultry metabolism studies. A poultry feeding study and fully validated
analytical methods for poultry commodities]{.mark} were requested in
PP#4F6830 as a condition for full registration, and these data gaps
apply as well for the current petitions.

A summary of the recommended tolerances for the crop commodities
discussed in this Summary Document is presented in Table 4.1.9. The
petitioner should submit a revised Section F reflecting the recommended
tolerances and correct commodity definitions presented in Table 4.1.9.

  -------------------- --------------- -------------- -----------------------
  **Table 4.1.9.                                      
  Tolerance Summary                                   
  for                                                 
  Prothioconazole.**                                  

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

  Soybean, forage      5               4.5            Tolerance
                                                      recommendation is
                                                      contingent upon label
                                                      revision to specify a
                                                      7-day PHI.

  Soybean, seed        0.15            0.15           

  Soybean, hay         22              17             Tolerance
                                                      recommendation is
                                                      contingent upon label
                                                      revision to specify a
                                                      7-day PHI.

  Beet, sugar, roots   0.25            0.25           

  Beet, sugar, tops    9               Not needed     Tolerances are not
                                                      currently required for
                                                      sugar beet tops.
  -------------------- --------------- -------------- -----------------------

**4.1.12 International Residue Limits
(IRL)**[]{#__RefHeading___Toc187567068 .anchor}

There are currently no established Codex or Mexican MRLs for
prothioconazole. Canada MRLs have been proposed (12/2006) for
prothioconazole in/on barley; dry chickpeas and dry lentils; rapeseed
(canola); mustard seed; wheat; fat and meat byproducts of cattle, goats,
horses and sheep; meat byproducts of hogs; meat of cattle, goats, horses
and sheep; milk; and liver of poultry as a result of the previous joint
review project (PP#4F6830); no Canadian MRLs are proposed or established
for soybean or sugar beet matrices. An International Residue Limit
Status sheet is attached to this review.

**4.2 Dietary Exposure and Risk**[]{#__RefHeading___Toc187567069
.anchor}

Reference: *Prothioconazole: Acute and Chronic Aggregate Dietary and
Drinking Water Exposure and Risk Assessments for the Section 3
Registration Actions on Sugar Beets (PP# 6F7134) and Soybeans (PP#
6F7073). DP Barcode 345924, T. Goodlow, 12/19/07.*

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-FCID^TM^, 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.

[Dietary Assessment of Free Triazole and its Conjugates]{.underline}

Prothioconazole is a thio-triazole, and as such, HED notes that a
separate risk assessment was conducted for the 1,2,4-triazole and its
conjugates. Triazolylalanine (TA), triazolylhydroxoypropionic acid
(THPA), and triazolylacetic acid (TAA), metabolites common to the
triazole derivative class of fungicides, were also found to be
metabolites of prothioconazole.

HED conducted an aggregate risk assessment for the metabolite/degradate
1,2,4-triazole (also referred to as free triazole) and its conjugates TA
and TAA, including data review, hazard identification and endpoint
selection, to support the extension of existing tolerances and the
granting of new parent triazole derivative fungicide tolerances (DP#
322215, 2/7/06, M. Doherty *et al.*). TA and TAA residues are primarily
associated with plant commodities whereas 1,2,4-T is associated with
rats and livestock. In that assessment, it was concluded that there are
no human health risk issues associated with 1,2,4-T or its metabolites
that would preclude reregistration of the triazole-derivative fungicides
registered at the time the risk assessment memo was issued or
conditional registration of the triazole-derivative fungicide uses that
have been proposed as of September 1, 2005. The risk assessment included
uses of prothioconazole proposed in PP#4F6830; the last prothioconazole
risk assessment. Additionally, in that aggregate triazoles risk
assessment, HED concluded that new uses for triazole pesticides (such as
the proposed prothioconazole uses addressed in this document) should be
examined in terms of potential residues of 1,2,4-T and its conjugates,
and that the risk assessment may require revision if new uses are for
sites not already addressed by the current list of registered or
proposed uses, if the formation of the metabolites exceeds the estimates
used in the previous risk assessment, or if required toxicity data raise
concerns not addressed by the current risk assessment.

Separate dietary risk assessments, based on conservative residue
estimates, have been completed for 1,2,4-T and TA+TAA (combined) and are
updated, as needed, for new triazole fungicide uses. The most recent
dietary assessments for these compounds (W. Cutchin, DP Numbers 347252
and 347253, 12/19/07) include residue estimates for soybean and sugar
beet commodities. Currently registered uses on soybean and sugar beet
from the application of other triazole fungicides result in potentially
greater residues of 1,2,4-T and TA+TAA (combined) on the resulting crop
commodities than are attributable to these proposed uses of
prothioconazole. Therefore, an updated assessment is not required to
address dietary exposure to 1,2,4-T or to TA+TAA for these new
prothioconazole petitions.

[Residue Data used for Acute and Chronic Assessments:]{.underline}

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.

-   Maximum residues were used in the assessments for livestock
    commodities. These values were determined using the previously
    submitted ruminant feeding study, poultry metabolism study, and the
    calculated reasonably balanced dietary burden (RBDB); see DP#
    331663, S. Funk for further details.

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-   EFED submitted modeled EDWC values. Point estimates were used in the
    acute and chronic assessments from the peanut and sugar beets
    application scenarios. See DP#'s 341457 and 341458, Drinking Water
    Assessment for the Section 3 New Use Petitions for the Use of
    Prothioconazole on Soybeans and Sugar Beets, by C. Sutton, 10/10/07,
    for additional information.

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-   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.

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-   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, wheat flour, soybean
    refined oil, and sugar beet molasses. 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 (PF)
    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.

**4.2.1 Acute Dietary Exposure/Risk**[]{#__RefHeading___Toc187567070
.anchor}

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 drinking water exposures for
the peanut application scenario. 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
drinking water. At the 95^th^ percentile, the food only exposure for
females 13-49 years old was 0.000167 mg/kg/day, which utilized 8.4% of
the aPAD (see Table 4.2.1). The exposure for food plus lower bound
drinking water estimates was 0.000737 mg/kg/day, which utilized 37% of
the aPAD at the 95^th^ percentile. The exposure for food and upper bound
drinking water estimates was 0.001518 mg/kg/day, which utilized 76% of
the aPAD at the 95^th^ percentile (see Table 4.2.2).

  ------------------ ----------------- -------------------- -------------
  **Table 4.2.1.                                            
  Results of Acute                                          
  Dietary Exposure                                          
  Analysis for                                              
  Prothioconazole                                           
  Using DEEM FCID at                                        
  the 95^th^                                                
  Percentile --                                             
  *Food Only***                                             

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

  Females 13-49      0.002             0.000167             8.4
  years old                                                 
  ------------------ ----------------- -------------------- -------------

  ------------------- --------------- --------------- -------- --------------- ---------
  **Table 4.2.2.                                                               
  Results of Acute                                                             
  Dietary Exposure                                                             
  Analysis for                                                                 
  Prothioconazole                                                              
  Using DEEM FCID at                                                           
  the 95^th^                                                                   
  Percentile -- *Food                                                          
  and Water* (Peanut                                                           
  EDWC value)**                                                                

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

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

  Females 13-49 years 0.002           0.000737        37       0.001518        76
  old                                                                          
  ------------------- --------------- --------------- -------- --------------- ---------

**4.2.2 Chronic Dietary Exposure/Risk**[]{#__RefHeading___Toc187567071
.anchor}

A moderately refined chronic dietary exposure assessment was also
performed. Empirical processing factors, average residues, and livestock
maximum residues were incorporated into the chronic assessment; 100%
crop treated was also assumed. Dietary risk estimates were determined
considering exposures from food alone and food plus upper or lower bound
drinking water EDWC point estimates based on the sugar beet application
scenario. 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 drinking water. The highest exposure and risk estimates
were for all infants and children 1-2 years old. The food only exposure
was 0.000338 mg/kg/day, which utilized 31% of the cPAD for children 1-2
years old (see Table 4.2.3). The highest exposure and risk estimates for
food plus drinking water were for the all infants population subgroup.
The exposure for food plus lower drinking water estimates was 0.000712
mg/kg/day, utilizing 65% of the cPAD. The exposure for food plus upper
bound drinking water estimates was 0.001030 mg/kg/day, which utilized
94% of the cPAD (see Table 4.2.4).

  ------------------------ --------------- ---------------- ---------------
  **Table 4.2.3. Results                                    
  of Chronic Dietary                                        
  Exposure Analysis for                                     
  Prothioconazole Using                                     
  DEEM FCID- *Food Only***                                  

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

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

  General U.S. Population  0.0011          0.000105         9.5

  All Infants (\< 1 year   0.0011          0.000132         12
  old)                                                      

  **Children 1-2 years     0.0011          **0.000338**     **31**
  old**                                                     

  Children 3-5 years old   0.0011          0.000275         25

  Children 6-12 years old  0.0011          0.000180         16

  Youth 13-19 years old    0.0011          0.000095         8.7

  Adults 20-49 years old   0.0011          0.000077         7.0

  Adults 50+ years old     0.0011          0.000064         5.9

  Females 13-49 years old  0.0011          0.000070         6.3
  ------------------------ --------------- ---------------- ---------------

  ------------------- --------------- --------------- --------- --------------- ---------
  **Table 4.2.4.                                                                
  Results of                                                                    
  DEEM-FCID Chronic                                                             
  Dietary Exposure                                                              
  Analysis for                                                                  
  Prothioconazole                                                               
  Using Lower and                                                               
  Upper Bound EDWC                                                              
  Values for Sugar                                                              
  Beets-- *Food and                                                             
  Water***                                                                      

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

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

  General U.S.        0.0011          0.000282        26        0.000379        34
  Population                                                                    

  **All Infants (\< 1 0.0011          **0.000712**    **65**    **0.001030**    **94**
  year old)**                                                                   

  Children 1-2 years  0.0011          0.000601        55        0.000745        68
  old                                                                           

  Children 3-5 years  0.0011          0.000521        47        0.000656        60
  old                                                                           

  Children 6-12 years 0.0011          0.000350        32        0.000443        40
  old                                                                           

  Youth 13-19 years   0.0011          0.000223        20        0.000294        27
  old                                                                           

  Adults 20-49 years  0.0011          0.000242        22        0.000333        30
  old                                                                           

  Adults 50+ years    0.0011          0.000238        22        0.000334        30
  old                                                                           

  Females 13-49 years 0.0011          0.000234        21        0.000325        30
  old                                                                           
  ------------------- --------------- --------------- --------- --------------- ---------

**4.2.3 Cancer Dietary Risk**[]{#__RefHeading___Toc187567072 .anchor}

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.

**5.0 Residential (Non-Occupational) Exposure/Risk
Characterization**[]{#__RefHeading___Toc187567073 .anchor}

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

**6.0 Aggregate Risk Assessments and Risk
Characterization**[]{#__RefHeading___Toc187567074 .anchor}

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 and existing 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. 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 4.2 for these risk estimates.**

**7.0 Cumulative Risk
Characterization/Assessment**[]{#__RefHeading___Toc187567075 .anchor}

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.

**8.0 Occupational Exposure/Risk
Pathway**[]{#__RefHeading___Toc187567076 .anchor}

*Prothioconazole: Occupational Exposure and Risk Assessment for Proposed
Uses on Soybeans and Sugar Beets and revised postapplicationassessment
for: Barley, Oilseed (except Sunflower and Safflower) Crop Group, Dried
Shelled Pea and Bean (except Soybean) Subgroup, Peanut, and Wheat. PC
Code: 113961, DP Barcode: D331662, S. Winfield, 12/31/07.*

Occupational exposure to prothioconazole is expected from registered
uses on barley, oilseed crops, dried bean and pea crops, peanuts and
wheat; as well as proposed uses on soybeans and sugar beets. 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, at the LOAEL of 10 mg/kg/day). A dermal absorption factor
was not applied because the study the endpoint was selected from was
route specific. A default inhalation absorption factor of 100% was
applied to the inhalation exposure estimates because the study the
endpoint was selected from was not route specific (*i.e.*, it was an
oral study). Also, a body weight of 60 kg was used in the exposure
estimates, because the endpoints were developmental effects (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 an MOE of less than 1000.

**8.1 Short-/Intermediate-Term Handler
Risk**[]{#__RefHeading___Toc187567077 .anchor}

Handlers are assumed to have potential short- (1-30 consecutive days)
and intermediate-term (1-6 consecutive months) dermal and inhalation
exposure to prothioconazole when mixing, loading and applying
prothioconazole formulations.

Although prothioconazole-specific handler exposure data were submitted
in support of a previous action (D303579, 8/18/06), these data are not
used quantitatively 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. In addition, rather than estimate exposure to
prothioconazole and prothioconazole-desthio separately (and then
estimate separate risks), the risk assessment team estimated exposure
based on prothioconazole assuming no conversion (resulting in protective
exposure estimates), and compared 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.

Prothioconazole is applied aerially and by ground equipment. The
following handler scenarios were considered representative of potential
exposures expected from use on the proposed crops: 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 (except for M/L for aerial application to
sugar beets, which did not reach the LOC with engineering controls).

-   Mixing and Loading (M/L) for:

    -   Aerial: with the engineering controls and PPE of a closed
        loading system and gloves, the soybean and sugar beet (at the
        minimum rate of 0.13 lb ai/A on the PROLINE label) scenarios
        reached the LOC of an MOE of 1000, but the sugar beet scenario
        (at the maximum rate of 0.18 lb ai/A on the PROLINE label) did
        not (MOE = 860)

    -   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 sugar beets at
the maximum proposed application rate does not result in an exposure
estimate 1000X less than the quantitative hazard estimate (even with
engineering controls) this estimate does involve potential
overestimation of exposure. As mentioned above, prothioconazole exposure
estimates are compared to prothioconazole-desthio endpoints, resulting
in a highly protective risk assessment. Had risk from prothioconazole
and prothioconazole-desthio been estimated in separate assessments,
lower prothioconazole-desthio exposure estimates would have yielded a
greater margin of exposure. Therefore, an MOE of 860 at the maximum
proposed label rate may not indicate a risk of concern.

Table 8.1 summarizes the handler exposure estimates and risk resulting
from the proposed uses of prothioconazole.

+-----------+--------+---------+----+----+------+------+-----+-----+
| **Table   |        |         |    |    |      |      |     |     |
| 8.1.      |        |         |    |    |      |      |     |     |
| Short-    |        |         |    |    |      |      |     |     |
| and       |        |         |    |    |      |      |     |     |
| Intermed  |        |         |    |    |      |      |     |     |
| iate-Term |        |         |    |    |      |      |     |     |
| Occ       |        |         |    |    |      |      |     |     |
| upational |        |         |    |    |      |      |     |     |
| Exposure  |        |         |    |    |      |      |     |     |
| and Risk  |        |         |    |    |      |      |     |     |
| Estimates |        |         |    |    |      |      |     |     |
| for       |        |         |    |    |      |      |     |     |
| Prothioco |        |         |    |    |      |      |     |     |
| nazole.** |        |         |    |    |      |      |     |     |
+===========+========+=========+====+====+======+======+=====+=====+
| *         | *      | *       | ** | *  | **   | **D  | *   | *   |
| *Exposure | *Appli | *Crop** | Ex | *A | PHED | aily | *Ro | *To |
| Scen      | cation |         | po | cr | Unit | D    | ute | tal |
| ario^1^** | Rate** |         | su | es | E    | ose^ | -sp | Sho |
|           |        |         | re | T  | xpos | 4^** | eci | rt- |
|           | **(lb  |         | R  | re | ure^ |      | fic | /In |
|           | ai/a   |         | ou | at | 3^** | **(  | Sho | ter |
|           | cre)** |         | te | ed |      | mg/k | rt- | T   |
|           |        |         | ** | ** | **(m | g/da | /In | erm |
|           |        |         |    |    | g/lb | y)** | ter | MOE |
|           |        |         |    | *  | a    |      | T   | ^5, |
|           |        |         |    | *p | i)** |      | erm | \ 6 |
|           |        |         |    | er |      |      | MO  | ^** |
|           |        |         |    | Da |      |      | E** |     |
|           |        |         |    | y^ |      |      |     |     |
|           |        |         |    | 2^ |      |      |     |     |
|           |        |         |    | ** |      |      |     |     |
+-----------+--------+---------+----+----+------+------+-----+-----+
| Closed    | 0.178  | Sugar   | De | 12 | 0.   | 0    | 980 | 860 |
| M/L       | (max   | beet    | rm | 00 | 0086 | .031 |     |     |
| Liquids,  | rate   |         | al |    |      |      |     |     |
| for       | on     |         |    |    |      |      |     |     |
| Aerial    | P      |         |    |    |      |      |     |     |
|           | ROLINE |         |    |    |      |      |     |     |
| PPE/En    | label) |         |    |    |      |      |     |     |
| gineering |        |         |    |    |      |      |     |     |
| control = |        |         |    |    |      |      |     |     |
| Closed    |        |         |    |    |      |      |     |     |
| system +  |        |         |    |    |      |      |     |     |
| gloves    |        |         |    |    |      |      |     |     |
+-----------+--------+---------+----+----+------+------+-----+-----+
|           |        |         | In |    | 0.00 | 0.0  | 6   |     |
|           |        |         | ha |    | 0083 | 0030 | 800 |     |
|           |        |         | la |    |      |      |     |     |
|           |        |         | ti |    |      |      |     |     |
|           |        |         | on |    |      |      |     |     |
+-----------+--------+---------+----+----+------+------+-----+-----+
|           | 0.13   | Sugar   | De | 12 | 0.   | 0    | 1   | 1   |
|           | (min   | beet    | rm | 00 | 0086 | .022 | 300 | 100 |
|           | rate   |         | al |    |      |      |     |     |
|           | on     |         |    |    |      |      |     |     |
|           | P      |         |    |    |      |      |     |     |
|           | ROLINE |         |    |    |      |      |     |     |
|           | label) |         |    |    |      |      |     |     |
+-----------+--------+---------+----+----+------+------+-----+-----+
|           |        |         | In |    | 0.00 | 0.0  | 6   |     |
|           |        |         | ha |    | 0083 | 0030 | 800 |     |
|           |        |         | la |    |      |      |     |     |
|           |        |         | ti |    |      |      |     |     |
|           |        |         | on |    |      |      |     |     |
+-----------+--------+---------+----+----+------+------+-----+-----+
|           | 0.0938 | Soybean | De | 12 | 0.   | 0    | 1   | 1   |
|           |        |         | rm | 00 | 0086 | .016 | 900 | 600 |
|           |        |         | al |    |      |      |     |     |
+-----------+--------+---------+----+----+------+------+-----+-----+
|           |        |         | In |    | 0.00 | 0.0  | 13  |     |
|           |        |         | ha |    | 0083 | 0016 | 000 |     |
|           |        |         | la |    |      |      |     |     |
|           |        |         | ti |    |      |      |     |     |
|           |        |         | on |    |      |      |     |     |
+-----------+--------+---------+----+----+------+------+-----+-----+
| Open M/L  | 0.178  | Sugar   | De | 2  | 0    | 0    | 2   | 1   |
| Liquids,  |        | beet    | rm | 00 | .023 | .014 | 200 | 200 |
| for       |        |         | al |    |      |      |     |     |
| G         |        |         |    |    |      |      |     |     |
| roundboom |        |         |    |    |      |      |     |     |
|           |        |         |    |    |      |      |     |     |
| PPE =     |        |         |    |    |      |      |     |     |
| single    |        |         |    |    |      |      |     |     |
| layer +   |        |         |    |    |      |      |     |     |
| gloves    |        |         |    |    |      |      |     |     |
+-----------+--------+---------+----+----+------+------+-----+-----+
|           |        |         | In |    | 0.   | 0.0  | 2   |     |
|           |        |         | ha |    | 0012 | 0071 | 800 |     |
|           |        |         | la |    |      |      |     |     |
|           |        |         | ti |    |      |      |     |     |
|           |        |         | on |    |      |      |     |     |
+-----------+--------+---------+----+----+------+------+-----+-----+
|           | 0.0938 | Soybean | De | 2  | 0    | 0.   | 4   | 2   |
|           |        |         | rm | 00 | .023 | 0072 | 200 | 300 |
|           |        |         | al |    |      |      |     |     |
+-----------+--------+---------+----+----+------+------+-----+-----+
|           |        |         | In |    | 0.   | 0.0  | 5   |     |
|           |        |         | ha |    | 0012 | 0038 | 300 |     |
|           |        |         | la |    |      |      |     |     |
|           |        |         | ti |    |      |      |     |     |
|           |        |         | on |    |      |      |     |     |
+-----------+--------+---------+----+----+------+------+-----+-----+
| Applying  | 0.178  | Sugar   | De | 12 | 0    | 0    | 1   | 1   |
| Liquid,   |        | beet    | rm | 00 | .005 | .018 | 700 | 400 |
| with      |        |         | al |    |      |      |     |     |
| Aerial    |        |         |    |    |      |      |     |     |
| (enclosed |        |         |    |    |      |      |     |     |
| cockpit)  |        |         |    |    |      |      |     |     |
|           |        |         |    |    |      |      |     |     |
| Baseline  |        |         |    |    |      |      |     |     |
| (no PPE,  |        |         |    |    |      |      |     |     |
| *i.e.*,   |        |         |    |    |      |      |     |     |
| single    |        |         |    |    |      |      |     |     |
| layer, no |        |         |    |    |      |      |     |     |
| gloves)   |        |         |    |    |      |      |     |     |
+-----------+--------+---------+----+----+------+------+-----+-----+
|           |        |         | In |    | 0.00 | 0.0  | 8   |     |
|           |        |         | ha |    | 0068 | 0024 | 300 |     |
|           |        |         | la |    |      |      |     |     |
|           |        |         | ti |    |      |      |     |     |
|           |        |         | on |    |      |      |     |     |
+-----------+--------+---------+----+----+------+------+-----+-----+
|           | 0.0938 | Soybean | De | 12 | 0    | 0.   | 3   | 2   |
|           |        |         | rm | 00 | .005 | 0094 | 200 | 700 |
|           |        |         | al |    |      |      |     |     |
+-----------+--------+---------+----+----+------+------+-----+-----+
|           |        |         | In |    | 0.00 | 0.0  | 16  |     |
|           |        |         | ha |    | 0068 | 0013 | 000 |     |
|           |        |         | la |    |      |      |     |     |
|           |        |         | ti |    |      |      |     |     |
|           |        |         | on |    |      |      |     |     |
+-----------+--------+---------+----+----+------+------+-----+-----+
| Applying  | 0.178  | Sugar   | De | 2  | 0    | 0.   | 3   | 2   |
| Liquid,   |        | beet    | rm | 00 | .014 | 0083 | 600 | 000 |
| with      |        |         | al |    |      |      |     |     |
| G         |        |         |    |    |      |      |     |     |
| roundboom |        |         |    |    |      |      |     |     |
| (open     |        |         |    |    |      |      |     |     |
| cab)      |        |         |    |    |      |      |     |     |
|           |        |         |    |    |      |      |     |     |
| Baseline  |        |         |    |    |      |      |     |     |
| (no PPE,  |        |         |    |    |      |      |     |     |
| *i.e.*,   |        |         |    |    |      |      |     |     |
| single    |        |         |    |    |      |      |     |     |
| layer, no |        |         |    |    |      |      |     |     |
| gloves)   |        |         |    |    |      |      |     |     |
+-----------+--------+---------+----+----+------+------+-----+-----+
|           |        |         | In |    | 0.0  | 0.0  | 4   |     |
|           |        |         | ha |    | 0074 | 0044 | 600 |     |
|           |        |         | la |    |      |      |     |     |
|           |        |         | ti |    |      |      |     |     |
|           |        |         | on |    |      |      |     |     |
+-----------+--------+---------+----+----+------+------+-----+-----+
|           | 0.0938 | Soybean | De | 2  | 0    | 0.   | 6   | 3   |
|           |        |         | rm | 00 | .014 | 0044 | 900 | 800 |
|           |        |         | al |    |      |      |     |     |
+-----------+--------+---------+----+----+------+------+-----+-----+
|           |        |         | In |    | 0.0  | 0.0  | 8   |     |
|           |        |         | ha |    | 0074 | 0023 | 600 |     |
|           |        |         | la |    |      |      |     |     |
|           |        |         | ti |    |      |      |     |     |
|           |        |         | on |    |      |      |     |     |
+-----------+--------+---------+----+----+------+------+-----+-----+
| Flagging  | 0.178  | Sugar   | De | 3  | 0    | 0    | 2   | 1   |
| for       |        | beet    | rm | 50 | .011 | .011 | 600 | 800 |
| Aerial    |        |         | al |    |      |      |     |     |
| O         |        |         |    |    |      |      |     |     |
| perations |        |         |    |    |      |      |     |     |
|           |        |         |    |    |      |      |     |     |
| Baseline  |        |         |    |    |      |      |     |     |
| (no PPE,  |        |         |    |    |      |      |     |     |
| *i.e.*,   |        |         |    |    |      |      |     |     |
| single    |        |         |    |    |      |      |     |     |
| layer, no |        |         |    |    |      |      |     |     |
| gloves)   |        |         |    |    |      |      |     |     |
+-----------+--------+---------+----+----+------+------+-----+-----+
|           |        |         | In |    | 0.0  | 0.0  | 5   |     |
|           |        |         | ha |    | 0035 | 0036 | 500 |     |
|           |        |         | la |    |      |      |     |     |
|           |        |         | ti |    |      |      |     |     |
|           |        |         | on |    |      |      |     |     |
+-----------+--------+---------+----+----+------+------+-----+-----+
|           | 0.0938 | Soybean | De | 3  | 0    | 0.   | 5   | 3   |
|           |        |         | rm | 50 | .011 | 0060 | 000 | 400 |
|           |        |         | al |    |      |      |     |     |
+-----------+--------+---------+----+----+------+------+-----+-----+
|           |        |         | In |    | 0.0  | 0.0  | 10  |     |
|           |        |         | ha |    | 0035 | 0019 | 000 |     |
|           |        |         | la |    |      |      |     |     |
|           |        |         | ti |    |      |      |     |     |
|           |        |         | on |    |      |      |     |     |
+-----------+--------+---------+----+----+------+------+-----+-----+

**^1^** 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.

**^2^** Acres Treated Per Day from ExpoSAC Policy \# 9, 7/5/00

**^3^** Unit exposure values are given for PPE/Engineering controls
listed under Exposure Scenario (column 1) and taken from PHED Version
1.1 as presented in the PHED Surrogate Exposure Guide (8/98);

**^4^** 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

**^5^** 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)

**^6^** Sugar beets: The Total MOE for single layer, gloves M/L for
aerial is 200 without a respirator and 230 with a respirator; the Total
MOE for double layer, gloves for M/L for aerial is 240 without a
respirator and 270 with a respirator. Soybeans: The Total MOE for single
layer, gloves M/L for aerial is 390 without a respirator and 430 with a
respirator; the Total MOE for double layer, gloves for M/L for aerial is
460 without a respirator and 510 with a respirator

**8.2 Short-/Intermediate-Term Postapplication
Risk**[]{#__RefHeading___Toc187567078 .anchor}

Postapplication workers are assumed to have potential short- and
intermediate-term dermal exposure (but not inhalation exposure;
prothioconazole has a low vapor pressure; therefore, after application,
although residues are expected to persist on foliage, these residues are
not expected to volatilize) from the registered and proposed uses of
prothioconazole. All of the registered and proposed uses are for low to
medium height row crops and because of this shared feature, the
postapplication exposures expected for different crops are similar when
similar postapplication activities are conducted. Postapplication
activities expected from the proposed uses are scouting, irrigation, and
hand weeding and thinning.

Chemical-specific data relevant to postapplication exposure (*i.e.*,
dislodgeable foliar residue \[DFR\] data) were submitted and determined
to be acceptable; therefore, postapplication exposure estimates were
calculated using results from the DFR studies, as well as standard HED
Exposure SAC assumptions (body weight and exposure duration) and
transfer coefficients (SOP \# 003.1). The quantitative hazard estimate
of 30 mg/kg/day (NOAEL from the dermal developmental study in the rat),
as used in the handler assessment (see previous section), is used in the
postapplication assessment.

> ***Summary of DFR study*** (***MRID 470026-01, DP Barcode: D335477)***
>
> Bayer CropScience submitted to the U.S. EPA the study: *JAU 6476 480
> SC -- Dislodgeable Foliar Residue on Various Crops* in support of the
> registrations for the fungicide prothioconazole and the
> prothioconazole formulation PROLINE 480 SC (soluble concentrate). The
> study objectives were to determine the dissipation of dislodgeable
> foliar residues (DFR) of prothioconazole and its degradation product,
> prothioconazole-desthio on the following crops:

-   **dry beans** (in Oregon and Washington; applied Proline 480 SC with
    ground-based boom spray equipment, application rate \~0.18 lb ai/A,
    3 times at 10 day application intervals);

-   **soybeans** (Nebraska and Minnesota; applied Proline 480 SC with
    hand boom and field sprayers, application rate \~0.13 lb ai/A, 3
    times at 9-10 day application intervals);

-   **sugar beets** (Minnesota; applied 480 SC with ground-based spray
    equipment, application rate 0.18 lb ai/A, 3 times at 9 day
    application intervals); and

-   **peanuts** (in Florida and Georgia; applied Proline 480 SC with
    ground-based and hand-held spray equipment, application rate \~ 0.18
    lb ai/A, 4 times at 14 day application intervals).

> The locations, formulation, application rates, number of applications
> and equipment all reflect scenarios expected based on the crops and
> usage information provided on the labels (although the labels contain
> different percentages of prothioconazole, they are all SC formulations
> and therefore applied as liquids). The study did depart from the label
> in regards to application intervals for dry beans (the minimum
> application interval on the label is 5 days, whereas the study
> employed an application interval of 10 days). Additionally, the study
> only tested 1 to 2 sites per/crop. However, results from this study
> indicate prothioconazole and prothioconazole-desthio dissipate
> quickly, and therefore, this is not a limitation of the study. The
> study indicated prothioconazole and prothioconazole-desthio do not
> persist as dislodgeable foliar residues above the LOQ (0.05 µg/cm^2^)
> for more than 3 days after the last treatment. Below the LOQ (but
> above the LOD; *i.e.*, at low levels), prothioconazole and
> prothioconazole-desthio persist as dislodgeable residues on foliage
> for a bit longer, ranging from 3-10 days after treatment. Regression
> lines were plotted using the natural logarithm (ln) of the residue
> values versus the days after the final application. HED-calculated
> R^2^ values ranged from 0.86 to 0.93, and half-lives ranged from 0.49
> to 1.8 days for total-prothiconazole (*i.e.*, combined residues of
> prothiconazole and prothioconazole-desthio converted to
> prothioconazole-equivalents). Requirements for this type of study are
> specified by the U.S. EPA OPPT Series 875, Occupational and
> Residential Exposure Test Guidelines, Group B: Dislodgeable Foliar
> Residue Dissipation: Agricultural, Guideline 875.2100. The study was
> reviewed by Versar and by the U.S. EPA.

In the absence of chemical-specific DFR data, HED assumes a default
dissipation rate of 10% per day, and that a default fraction of the
applied ai is available on the foliage on the day of application
(*i.e.*, 20%) when calculating DFR estimates (which in turn are used in
postapplication exposure estimates, see footnotes of Table 8.3).
However, the chemical-specific DFR data demonstrated that total
prothioconazole (prothioconazole and prothioconazole-desthio combined)
dissipate more quickly than 10% per day, and that the fraction of
applied ai available on the foliage as a percent of the application
rate, can be 2-fold lower than 20%. These DFR data were used to
calculate 'fraction of ai applied' and 'dissipation rate' estimates (for
use in postapplication exposure estimates) for the crops tested, and
were extrapolated to those crops for which no DFR data are available.

In order to estimate DFRs for the crops prothioconazole is
registered/proposed for use on, an average percent initial DFR value was
calculated from the DFR studies conducted on each crop. Additionally, an
average daily dissipation rate was estimated for each of the crops
tested (see Table 8.2). Although uncertainties are introduced into the
assessment when crop-specific residues are used to estimate dissipation
parameters, it is believed to be more realistic than using default
assumptions.

See Table 8.2 for a summary of these values calculated from the DFR
study.

**Table 8**.2: Results of DFR Study analysis

+---------+---------+----+-----+-----+----+-----+-----+------------+
| *       | **L     | ** | *   |     | *  |     | **H | **Maximum  |
| *Crop** | ocation | R^ | *Me |     | *D |     | alf | t          |
|         | (s      | 2^ | asu |     | is |     | l   | otal-proth |
|         | tate)** | ** | red |     | si |     | ife | ioconazole |
|         |         |    | i   |     | pa |     | (d  | (u         |
|         |         |    | nit |     | ti |     | ays | g/cm^2^)** |
|         |         |    | ial |     | on |     | )** | ^1^        |
|         |         |    | DFR |     | (% |     |     |            |
|         |         |    | (%  |     | p  |     |     |            |
|         |         |    | of  |     | er |     |     |            |
|         |         |    | ap  |     | da |     |     |            |
|         |         |    | pl. |     | y) |     |     |            |
|         |         |    | r   |     | ** |     |     |            |
|         |         |    | ate |     |    |     |     |            |
|         |         |    | )** |     |    |     |     |            |
+---------+---------+----+-----+-----+----+-----+-----+------------+
| **dry   | Oregon  | 0. | 2   | **  | 45 | **  | 1.2 | 0.442      |
| beans** |         | 87 | 2.2 | Avg | .1 | Avg |     | 0DAT3      |
|         |         |    |     | :** |    | :** |     |            |
|         |         |    |     |     |    |     |     |            |
|         |         |    |     | **  |    | **  |     |            |
|         |         |    |     | 23. |    | 48. |     |            |
|         |         |    |     | 3** |    | 4** |     |            |
+---------+---------+----+-----+-----+----+-----+-----+------------+
|         | Was     | 0. | 2   |     | 51 |     | 1.0 | 0.631      |
|         | hington | 93 | 4.5 |     | .7 |     |     | 0DAT2      |
+---------+---------+----+-----+-----+----+-----+-----+------------+
| **soy   | N       | 0. | 2.6 | **  | ** | NA  | 1.1 | 0.111      |
| beans** | ebraska | 89 |     | Avg | 46 |     |     | 0DAT1      |
|         |         |    |     | :** | .8 |     |     |            |
|         |         |    |     |     | ** |     |     |            |
|         |         |    |     | *   |    |     |     |            |
|         |         |    |     | *8. |    |     |     |            |
|         |         |    |     | 2** |    |     |     |            |
+---------+---------+----+-----+-----+----+-----+-----+------------+
|         | Mi      | 0. | 1   |     | 75 |     | 0   | 0.294      |
|         | nnesota | 86 | 3.7 |     | .8 |     | .49 | 0DAT3      |
+---------+---------+----+-----+-----+----+-----+-----+------------+
| **sugar | Mi      | 0. | **  | NA  | ** | NA  | 1.2 | 0.372      |
| beets** | nnesota | 90 | 16. | ^3^ | 43 |     |     | 0DAT2      |
|         |         |    | 7** |     | .7 |     |     |            |
|         |         |    |     |     | ** |     |     |            |
+---------+---------+----+-----+-----+----+-----+-----+------------+
| **pe    | Florida | 0. | 8.8 | **  | 32 | **  | 1.8 | 0.215      |
| anuts** |         | 93 |     | Avg | .3 | Avg |     | 0DAT1      |
|         |         |    |     | :** |    | :** |     |            |
|         |         |    |     |     |    |     |     |            |
|         |         |    |     | *   |    | **  |     |            |
|         |         |    |     | *8. |    | 32. |     |            |
|         |         |    |     | 8** |    | 9** |     |            |
+---------+---------+----+-----+-----+----+-----+-----+------------+
|         | Georgia | 0. | 8.9 |     | 33 |     | 1.7 | 0.248      |
|         |         | 92 |     |     | .5 |     |     | 0DAT3      |
+---------+---------+----+-----+-----+----+-----+-----+------------+
| **Avera |         |    | *   |     | *  |     |     |            |
| ge**^2^ |         |    | *14 |     | *4 |     |     |            |
|         |         |    | %** |     | 2% |     |     |            |
|         |         |    |     |     | ** |     |     |            |
+---------+---------+----+-----+-----+----+-----+-----+------------+

^1^ XDATY, where X indicates the number of days after treatment, and Y
indicates which treatment the residue was detected after (1-4)

^2^The MN soybean dissipation result was not considered when averaging
daily dissipation across crops and when averaging for soybeans only,
because there was a rainfall event within 24 hours of the last
treatment.

^3^ NA, not applicable

The resulting DFRs, exposure estimates and risks are presented below in
Table 8.3. For some activities and crops, the REIs of 12 and 24 hours on
the proposed labels are not adequate to reach an MOE of 1000. To protect
workers conducting all postapplication activities, an REI of 48 hours (2
days) is required (based on scouting barley, canola; and irrigating and
scouting beans/peas and sugar beets). \[Note: hand harvesting was not
evaluated because this practice is being replaced by mechanical
harvesting; the label must indicate that hand harvesting is not
permitted\].

The estimated REIs were determined using average values calculated from
the DFR study.

[]{.mark}

[]{.mark}

+-------+---+-----+-----+----------------+------+-----+-----+-----+
| **    |   |     |     |                |      |     |     |     |
| Table |   |     |     |                |      |     |     |     |
| 8.3.  |   |     |     |                |      |     |     |     |
| Su    |   |     |     |                |      |     |     |     |
| mmary |   |     |     |                |      |     |     |     |
| of    |   |     |     |                |      |     |     |     |
| Oc    |   |     |     |                |      |     |     |     |
| cupat |   |     |     |                |      |     |     |     |
| ional |   |     |     |                |      |     |     |     |
| Posta |   |     |     |                |      |     |     |     |
| pplic |   |     |     |                |      |     |     |     |
| ation |   |     |     |                |      |     |     |     |
| Risks |   |     |     |                |      |     |     |     |
| for   |   |     |     |                |      |     |     |     |
| Pro   |   |     |     |                |      |     |     |     |
| thioc |   |     |     |                |      |     |     |     |
| onazo |   |     |     |                |      |     |     |     |
| le.** |   |     |     |                |      |     |     |     |
+=======+===+=====+=====+================+======+=====+=====+=====+
| **C   | * | *   | *   | **Transfer**   | **Di | **T | **  | *   |
| rop** | * | *Fr | *Da |                | slod | ime | Der | *Sh |
|       | A | act | ily | *              | geab | Af  | mal | ort |
|       | p | ion | Di  | *Coefficient** | le** | ter | Da  | -/I |
|       | p | of  | ssi |                |      | Ap  | ily | nte |
|       | l | ai  | pat | **(            | **Fo | pli | Dos | r-T |
|       | . | Re  | ion | cm^2^/hr)^2^** | liar | cat | e^4 | erm |
|       | R | tai | Rat |                | R    | ion | ^** | Der |
|       | a | ned | e^1 |                | esid | (d  |     | mal |
|       | t | on  | ^** |                | ue** | ays | **( | MO  |
|       | e | Fol |     |                |      | )** | mg/ | E^5 |
|       | * | iag |     |                | **(  |     | kg/ | ^** |
|       | * | e^1 |     |                | ug/c |     | day |     |
|       |   | ^** |     |                | m2)^ |     | )** |     |
|       | * |     |     |                | 3^** |     |     |     |
|       | * |     |     |                |      |     |     |     |
|       | ( |     |     |                |      |     |     |     |
|       | l |     |     |                |      |     |     |     |
|       | b |     |     |                |      |     |     |     |
|       | a |     |     |                |      |     |     |     |
|       | i |     |     |                |      |     |     |     |
|       | / |     |     |                |      |     |     |     |
|       | A |     |     |                |      |     |     |     |
|       | ) |     |     |                |      |     |     |     |
|       | * |     |     |                |      |     |     |     |
|       | * |     |     |                |      |     |     |     |
+-------+---+-----+-----+----------------+------+-----+-----+-----+
| Ba    | 0 | 0   | 0   | Low/min:       | 0    | 0   | 0.0 | 4   |
| rley, | . | .23 | .48 | scouting (100) | .465 |     | 062 | 800 |
|       | 1 | ^6^ | ^6^ |                |      |     |     |     |
| C     | 7 |     |     |                |      |     |     |     |
| anola | 8 |     |     |                |      |     |     |     |
|       |   |     |     |                |      |     |     |     |
| (repr |   |     |     |                |      |     |     |     |
| esent |   |     |     |                |      |     |     |     |
| ative |   |     |     |                |      |     |     |     |
| oi    |   |     |     |                |      |     |     |     |
| lseed |   |     |     |                |      |     |     |     |
| c     |   |     |     |                |      |     |     |     |
| rops) |   |     |     |                |      |     |     |     |
+-------+---+-----+-----+----------------+------+-----+-----+-----+
|       |   |     |     | High or        | 0    | 0   | 0.0 | 320 |
|       |   |     |     | low/full:      | .465 |     | 930 |     |
|       |   |     |     | scouting       |      |     |     |     |
|       |   |     |     | (1,500)        |      |     |     |     |
+-------+---+-----+-----+----------------+------+-----+-----+-----+
|       |   |     |     |                | 0    | 1   | 0.0 | 630 |
|       |   |     |     |                | .240 |     | 480 |     |
+-------+---+-----+-----+----------------+------+-----+-----+-----+
|       |   |     |     |                | 0.13 | 2   | 0.0 | 1   |
|       |   |     |     |                |      |     | 248 | 200 |
+-------+---+-----+-----+----------------+------+-----+-----+-----+
| Dried | 0 | 0   | 0   | Low/min:       | 0    | 0   | 0.0 | 4   |
| sh    | . | .23 | .48 | irrigation and | .465 |     | 062 | 800 |
| elled | 1 |     |     | scouting,      |      |     |     |     |
| peas  | 7 |     |     | Low/full or    |      |     |     |     |
| and   | 8 |     |     | min: hand      |      |     |     |     |
| beans |   |     |     | weeding (100)  |      |     |     |     |
| sub   |   |     |     |                |      |     |     |     |
| group |   |     |     |                |      |     |     |     |
+-------+---+-----+-----+----------------+------+-----+-----+-----+
|       |   |     |     | Low/full:      | 0    | 0   | 0.0 | 320 |
|       |   |     |     | irrigation and | .465 |     | 930 |     |
|       |   |     |     | scouting       |      |     |     |     |
|       |   |     |     | (1,500)        |      |     |     |     |
+-------+---+-----+-----+----------------+------+-----+-----+-----+
|       |   |     |     |                | 0    | 1   | 0.0 | 630 |
|       |   |     |     |                | .240 |     | 480 |     |
+-------+---+-----+-----+----------------+------+-----+-----+-----+
|       |   |     |     |                | 0.13 | 2   | 0.0 | 1   |
|       |   |     |     |                |      |     | 248 | 200 |
+-------+---+-----+-----+----------------+------+-----+-----+-----+
| Pe    | 0 | 0.  | 0   | Hand weeding   | 0    | 0   | 0.0 | 13  |
| anuts | . | 088 | .33 | (100)          | .178 |     | 024 | 000 |
|       | 1 |     |     |                |      |     |     |     |
|       | 7 |     |     |                |      |     |     |     |
|       | 8 |     |     |                |      |     |     |     |
+-------+---+-----+-----+----------------+------+-----+-----+-----+
|       |   |     |     | Low/full:      | 0    | 0   | 0.  | 840 |
|       |   |     |     | irrigation and | .178 |     | 036 |     |
|       |   |     |     | scouting       |      |     |     |     |
|       |   |     |     | (1500)         |      |     |     |     |
+-------+---+-----+-----+----------------+------+-----+-----+-----+
|       |   |     |     |                | 0    | 1   | 0.  | 1   |
|       |   |     |     |                | .119 |     | 024 | 300 |
+-------+---+-----+-----+----------------+------+-----+-----+-----+
| Soy   | 0 | 0.  | 0   | Hand weeding,  | 0    | 0   | 0.0 | 26  |
| beans | . | 082 | .47 | Low/full:      | .086 |     | 012 | 000 |
|       | 0 |     |     | scouting (100) |      |     |     |     |
|       | 9 |     |     |                |      |     |     |     |
|       | 3 |     |     |                |      |     |     |     |
|       | 8 |     |     |                |      |     |     |     |
+-------+---+-----+-----+----------------+------+-----+-----+-----+
|       |   |     |     | Low/full:      | 0    | 0   | 0.0 | 1   |
|       |   |     |     | irrigation and | .086 |     | 173 | 700 |
|       |   |     |     | scouting       |      |     |     |     |
|       |   |     |     | (1500)         |      |     |     |     |
+-------+---+-----+-----+----------------+------+-----+-----+-----+
| Sugar | 0 | 0   | 0   | Thinning, Hand | 0    | 0   | 0.0 | 6   |
| beets | . | .17 | .44 | weeding,       | .343 |     | 046 | 600 |
|       | 1 |     |     | Low/full and   |      |     |     |     |
|       | 7 |     |     | min:           |      |     |     |     |
|       | 8 |     |     | irrigation     |      |     |     |     |
|       |   |     |     | (100)          |      |     |     |     |
+-------+---+-----+-----+----------------+------+-----+-----+-----+
|       |   |     |     | Low/full:      | 0    | 0   | 0.0 | 440 |
|       |   |     |     | irrigation and | .343 |     | 686 |     |
|       |   |     |     | scouting       |      |     |     |     |
|       |   |     |     | (1500)         |      |     |     |     |
+-------+---+-----+-----+----------------+------+-----+-----+-----+
|       |   |     |     |                | 0    | 1   | 0.0 | 780 |
|       |   |     |     |                | .192 |     | 384 |     |
+-------+---+-----+-----+----------------+------+-----+-----+-----+
|       |   |     |     |                | 0    | 2   | 0.0 | 1   |
|       |   |     |     |                | .108 |     | 215 | 400 |
+-------+---+-----+-----+----------------+------+-----+-----+-----+
| Wheat | 0 | 0   | 0   | Low/min:       | 0    | 0   | 0.0 | 6   |
|       | . | .17 | .44 | irrigation and | .343 |     | 046 | 600 |
|       | 1 | ^6^ | ^6^ | scouting (100) |      |     |     |     |
|       | 7 |     |     |                |      |     |     |     |
|       | 8 |     |     |                |      |     |     |     |
+-------+---+-----+-----+----------------+------+-----+-----+-----+
|       |   |     |     | Low/full:      | 0    | 0   | 0.0 | 440 |
|       |   |     |     | irrigation and | .343 |     | 686 |     |
|       |   |     |     | scouting       |      |     |     |     |
|       |   |     |     | (1,500)        |      |     |     |     |
+-------+---+-----+-----+----------------+------+-----+-----+-----+
|       |   |     |     |                | 0    | 1   | 0.0 | 780 |
|       |   |     |     |                | .192 |     | 384 |     |
+-------+---+-----+-----+----------------+------+-----+-----+-----+
|       |   |     |     |                | 0    | 2   | 0.0 | 1   |
|       |   |     |     |                | .108 |     | 215 | 400 |
+-------+---+-----+-----+----------------+------+-----+-----+-----+

^1^ Prothioconazole-specific data (MRID 47002801). See Table 5.2a

^2^ Transfer coefficients are taken from the HED Science Advisory
Council (SAC) for Exposure SOP 003.1 (August 2000)

^3^ Dislodgeable Foliar Residue ~Postapplication\ day~ (ug/cm^2^) =
Application rate (lb ai/A) x Fraction of ai Retained on the Foliage x
(1- Fraction of Residue that Dissipates Daily)
^postapplication\ day\ zero^ x 4.54E+8 ug/lb x 2.47E-8 A/cm^2^

^4^ Daily Dose = \[Dislodgeable Foliar Residue x 0.001 mg/ug x Dermal
Transfer Coefficient (cm^2^/hr) x Exposure Time (8 hours)\]/Body weight
(60 kg)

^5^ MOE = NOAEL/Daily Dose. Short-/Intermediate-Term Dermal NOAEL = 30
mg/kg/day. LOC = 1000.

^6^ Dry bean data are used as surrogate for barley, canola and oilseed
crops; and sugar beet data are used as surrogate for wheat crops.

**9.0 Data Needs and Label
Recommendations**[]{#__RefHeading___Toc187567079 .anchor}

**9.1 Toxicology**[]{#__RefHeading___Toc187567080 .anchor}

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.

**9.2 Residue Chemistry**[]{#__RefHeading___Toc187567081 .anchor}

[860.1200 Directions for Use]{.underline}

[• A revised Section B is required to specify a preharvest interval of 7
days for soybean forage and hay.]{.mark}

[860.1340 Residue Analytical Methods]{.underline}

• Revisions are suggested of the enforcement methods, LC/MS/MS Method
RPA JA/03/01 for plants and LC/MS/MS Method Bayer Report No. 200537 for
ruminants, to include at least two multiple reaction monitoring (MRM)
transitions to preclude the need for a confirmatory method.

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

[860.1380 Storage Stability]{.underline}

• 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 as confirmatory data.

[• 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.]{.mark}

[860.1480 Meat, Milk, Poultry, and Eggs]{.underline}

[• The petitioner must submit a poultry feeding study with
prothioconazole.]{.mark}

[860.1550 Proposed Tolerances]{.underline}

[• The petitioner is required to submit a revised Section F to
incorporate the CAS name of prothioconazole-desthio in the tolerance
expression and to specify that residues of the metabolite are calculated
as parent. In addition,]{.mark} the revised Section F should reflect the
recommended tolerances and commodity definitions presented in Table 11.

[860.1650 Submittal of Analytical Reference Standards]{.underline}

• 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:

> • desthio prothioconazole \[JAU6476-desthio;
> (2-(1-chlorocyclopropyl)-1-(2-chlorophenyl)-3-(1*H*-1,2,4-triazol-1-yl)-2-propanol)\]
>
> • prothioconazole sulfonic acid potassium salt \[potassium salt of
> JAU6476 sulfonic acid;
> 1-\[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl\]1*H*-1,2,4-triazole
> sulfonic acid, potassium salt\]
>
> • \[triazole-^15^N-^13^C\]prothioconazole
>
> • \[triazole-^15^N-^13^C\]JAU6476-desthio
>
> • \[triazole-^15^N-^13^C\]JAU6476 sulfonic acid

The reference standards should be sent to the Analytical Chemistry Lab,
which is located at Fort Meade, to the attention of either Theresa Cole
or Frederic Siegelman at the following address (Note that the mail will
be returned if the extended zip code is not used.) :

> USEPA
>
> National Pesticide Standards Repository/Analytical Chemistry
> Branch/OPP
>
> 701 Mapes Road
>
> Fort George G. Meade, MD 20755-5350

**9.3 Occupational Exposure**[]{#__RefHeading___Toc187567082 .anchor}

[875.1100 Dermal Exposure and 875.1300 Inhalation Exposure]{.underline}

• **PREVIOUS:** Raw data from field fortifications in MRID 46246447 (in
addition to the % conversions reported in the study)

[875.2100 Foliar Dislodgeable Residue Dissipation]{.underline}

• The registrant indicated prothioconazole-desthio residue measurements
were converted to prothioconazole-equivalents, however, they did not
specify the method employed to correct the values. HED has assumed the
same technique was used in this study, as was used in the applicator
study (submitted with a previous petition). That is, to account for
prothioconazole-desthio's lower molecular weight,
prothioconazole-desthio was converted to "prothioconazole-equivalents"
by applying a molar ratio of the two compounds. HED recommends that RD
seek confirmation from Bayer CropScience that this is indeed the
approach used in the DFR study (MRID 470026-01).

***Label Recommendations***

• **PREVIOUS:** State on the label that sunflower and safflower are
excluded from the oilseed crop group

• USF 0728 325 SC Fungicide, on page 4 of the proposed label, remove the
language describing use directions for chemigation. The label states
"apply USF 0728 325 SC through irrigation equipment only to crops for
which chemigation is specified on this label." There is one crop on the
label (sugar beets), and chemigation is not specified in the use
directions (whereas aerial and ground application methods are
specified).

• USF 0728 325 SC Fungicide should specify a 30-day plant-back interval
for crops not on the label.

• USF 0728 325 SC Fungicide specifies a 10- to 14-day spray interval for
soilborne diseases for sugar beets, but the overall restrictions specify
a 14- to 30-day spray interval. The spray interval for soilborne
diseases should reflect the overall spray interval of 14- to 30 days.

• Change the REI to 48 hours on all labels.

• Remove all references to rice on the Proline 480 SC label.

• Indicate on the labels, that hand-harvesting is prohibited.

**9.4 Triazole Data Requirements**[]{#__RefHeading___Toc187567083
.anchor}

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.

-   Toxicology:

    -   Free triazole:

        -   Developmental neurotoxicity study in rats;

        -   Chronic toxicity -- 1 year chronic rat study in males and
            females.

    -   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:**[]{#__RefHeading___Toc187567084 .anchor}

**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. Petitions for Establishment of Tolerances for
Use on Sugar Beet (PP#6F7134) and Soybean (PP#6F7073). Summary of
Analytical Chemistry and Residue Data. DP331663, S. Funk, 12/19/07.

**3.** Prothioconazole: Acute and Chronic Aggregate Dietary and Drinking
Water Exposure and Risk Assessments for the Section 3 Registration
Actions on Sugar Beets (PP# 6F7134) and Soybeans (PP# 6F7073). DP
Barcode 345924, T. Goodlow, 11/19/07.

**4.** Drinking Water Assessment for the Section 3 New Use Petitions for
the Use of Prothioconazole on Soybeans and Sugar Beets. DP#'s 341457 &
341458, C. Sutton, 10/10/07.

**5.** Prothioconazole Section 3: Environmental Fate and Ecological Risk
Assessment, DP Barcode: 324660, Decision #: 341716, C. Salice and R.
Kashuba, 06/01/06.

**6.** Prothioconazole: Occupational Exposure and Risk Assessment for
Proposed Uses on Soybeans and Sugar Beets and revised
postapplicationassessment for: Barley, Oilseed (except Sunflower and
Safflower) Crop Group, Dried Shelled Pea and Bean (except Soybean)
Subgroup, Peanut, and Wheat. PC Code: 113961, DP Barcode: D331662, S.
Winfield, 12/31/07.

**7.** PP# 4F6830. New Chemical -- Prothioconazole in/on Plant and
Livestock Commodities. Tolerance Method Validation (TMV) Report (MRID
#'s 462462-04, 462462-06, 462462-07, and 462462-09) Chemical \# 113961.
Decision Number: 318440. ACB \# B05-39. DP# 318440, 7/30/07, P.
Schermerhorn.

+-----------------+-----------------+-------------------+--------------+
| INTERNATIONAL   |                 |                   |              |
| RESIDUE LIMIT   |                 |                   |              |
| STATUS          |                 |                   |              |
+-----------------+-----------------+-------------------+--------------+
| Chemical Name:  | Common Name:    | X Proposed        | Date: 8/2007 |
| \[              | Prothioconazole | tolerance         |              |
| 2-\[2-(1-chloro |                 |                   |              |
| cyclopropyl)-3- |                 |  Reevaluated     |              |
| (2-chlorophenyl |                 | tolerance         |              |
| )-2-hydroxyprop |                 |                   |              |
| yl\]-1,2-dihydr |                 |  Other           |              |
| o-3*H*-1,2,4-tr |                 |                   |              |
| iazole-3-thione |                 |                   |              |
+-----------------+-----------------+-------------------+--------------+
| Codex Status    |                 | U. S. Tolerances  |              |
| (Maximum        |                 |                   |              |
| Residue Limits) |                 |                   |              |
+-----------------+-----------------+-------------------+--------------+
| X No Codex      |                 | Petition Number:  |              |
| proposal step 6 |                 | PP#s 6F7073 &     |              |
| or above        |                 | 6F7134            |              |
|                 |                 |                   |              |
|  No Codex      |                 | DP#s: 331663 &    |              |
| proposal step 6 |                 | 335154            |              |
| or above for    |                 |                   |              |
| the crops       |                 | Other Identifier: |              |
| requested       |                 |                   |              |
+-----------------+-----------------+-------------------+--------------+
| Residue         |                 | Reviewer/Branch:  |              |
| definition      |                 | L. Cheng/RAB3     |              |
| (step 8/CXL):   |                 |                   |              |
| N/A             |                 |                   |              |
+-----------------+-----------------+-------------------+--------------+
|                 |                 | [Residue          |              |
|                 |                 | definit           |              |
|                 |                 | ion]{.underline}: |              |
|                 |                 | Prothioconazole,  |              |
|                 |                 | 2-\               |              |
|                 |                 | [2-(1-chlorocyclo |              |
|                 |                 | propyl)-3-(2-chlo |              |
|                 |                 | rophenyl)-2-hydro |              |
|                 |                 | xypropyl\]-1,2-di |              |
|                 |                 | hydro-3*H*-1,2,4- |              |
|                 |                 | triazole-3-thione |              |
|                 |                 | and its desthio   |              |
|                 |                 | metabolite        |              |
+-----------------+-----------------+-------------------+--------------+
| Crop (s)        | MRL (mg/kg)     | Crop(s)           | Tolerance    |
|                 |                 |                   | (ppm)        |
+-----------------+-----------------+-------------------+--------------+
|                 |                 | Soybean, forage   | 4.5          |
+-----------------+-----------------+-------------------+--------------+
|                 |                 | Soybean, seed     | 0.15         |
+-----------------+-----------------+-------------------+--------------+
|                 |                 | Soybean, hay      | 17           |
+-----------------+-----------------+-------------------+--------------+
|                 |                 | Beet, sugar,      | 0.25         |
|                 |                 | roots             |              |
+-----------------+-----------------+-------------------+--------------+
|                 |                 |                   |              |
+-----------------+-----------------+-------------------+--------------+
|                 |                 |                   |              |
+-----------------+-----------------+-------------------+--------------+
| Limits for      |                 | Limits for Mexico |              |
| Canada          |                 |                   |              |
+-----------------+-----------------+-------------------+--------------+
|  No Limits     |                 | X No Limits       |              |
|                 |                 |                   |              |
| X No Limits for |                 |  No Limits for   |              |
| the crops       |                 | the crops         |              |
| requested       |                 | requested         |              |
+-----------------+-----------------+-------------------+--------------+
| Residue         |                 | Residue           |              |
| definition:     |                 | definition:       |              |
+-----------------+-----------------+-------------------+--------------+
| Crop(s)         | MRL (mg/kg)     | Crop(s)           | MRL (mg/kg)  |
+-----------------+-----------------+-------------------+--------------+
|                 |                 |                   |              |
+-----------------+-----------------+-------------------+--------------+
|                 |                 |                   |              |
+-----------------+-----------------+-------------------+--------------+
|                 |                 |                   |              |
+-----------------+-----------------+-------------------+--------------+
|                 |                 |                   |              |
+-----------------+-----------------+-------------------+--------------+
| Notes/Special   |                 |                   |              |
| Instructions:   |                 |                   |              |
| S. Funk,        |                 |                   |              |
| 10/03/2007      |                 |                   |              |
+-----------------+-----------------+-------------------+--------------+

**Appendix A: Toxicology Assessment**[]{#__RefHeading___Toc187567085
.anchor}

**A. Toxicity Profiles**[]{#__RefHeading___Toc187567086 .anchor}

**Table A.1. Acute Toxicity of Prothioconazole technical and Desthio-**

> **Prothioconazole technical**

+----------+-----------+--------+-------------------+-------+---------+
| G        | Study     | S      | Results           | Tox.  | MRID    |
| uideline |           | pecies |                   | Cat   | No.     |
|          |           |        |                   | egory |         |
+----------+-----------+--------+-------------------+-------+---------+
| Prothio  |           |        |                   |       |         |
| conazole |           |        |                   |       |         |
+----------+-----------+--------+-------------------+-------+---------+
| 870.1100 | Acute     | Rat    | LD~50~ \>= 6200   | IV    | 4       |
|          | oral      |        | mg/kg (M, F)      |       | 6246230 |
|          | toxicity  |        |                   |       |         |
+----------+-----------+--------+-------------------+-------+---------+
| 870.1200 | Acute     | Rat    | LD~50~ \>= 2000   | III   | 4       |
|          | dermal    |        | mg/kg (M, F)      |       | 6246244 |
|          | toxicity  |        |                   |       |         |
+----------+-----------+--------+-------------------+-------+---------+
| 870.1300 | Acute     | Rat    | LC~50~ \>= 4.99   | IV    | 4       |
|          | i         |        | mg/L              |       | 6246246 |
|          | nhalation |        |                   |       |         |
|          | toxicity  |        | (M, F)            |       |         |
+----------+-----------+--------+-------------------+-------+---------+
| 870.2400 | Primary   | Rabbit | Not an irritant   | IV    | 4       |
|          | eye       |        |                   |       | 6246249 |
|          | i         |        |                   |       |         |
|          | rritation |        |                   |       |         |
+----------+-----------+--------+-------------------+-------+---------+
| 870.2500 | Primary   | Rabbit | Not an irritant   | IV    | 4       |
|          | skin      |        |                   |       | 6246302 |
|          | i         |        |                   |       |         |
|          | rritation |        |                   |       |         |
+----------+-----------+--------+-------------------+-------+---------+
| 870.2600 | Dermal    | Guinea | Not a sensitizer  | Neg   | 4       |
|          | sens      | Pig    |                   | ative | 6246305 |
|          | itization |        |                   |       |         |
+----------+-----------+--------+-------------------+-------+---------+
| Desthio  |           |        |                   |       |         |
| -prothio |           |        |                   |       |         |
| conazole |           |        |                   |       |         |
+----------+-----------+--------+-------------------+-------+---------+
| 870.1100 | Acute     | Rat    | LD~50~ = 2806     | III   | 4       |
|          | oral      |        | mg/kg (M, F)      |       | 6246231 |
|          | toxicity  |        | (approximate)     |       |         |
+----------+-----------+--------+-------------------+-------+---------+
| 870.1100 | Acute     | Mouse  | LD~50~ = 2235     | III   | 4       |
|          | oral      |        | mg/kg             |       | 6246242 |
|          | toxicity  |        |                   |       |         |
|          |           |        | (Males)           |       |         |
|          |           |        |                   |       |         |
|          |           |        | LD~50~ = 3459     |       |         |
|          |           |        | mg/kg             |       |         |
|          |           |        |                   |       |         |
|          |           |        | (Females)         |       |         |
+----------+-----------+--------+-------------------+-------+---------+
| 870.1200 | Acute     | Rat    | LD~50~ \>= 5000   | IV    | 4       |
|          | dermal    |        | mg/kg (M,F)       |       | 6246243 |
|          | toxicity  |        |                   |       |         |
+----------+-----------+--------+-------------------+-------+---------+
| 870.1300 | Acute     | Rat    | LC~50~ \>= 5.077  | IV    | 4       |
|          | i         |        | mg/L              |       | 6246247 |
|          | nhalation |        |                   |       |         |
|          | toxicity  |        | (M,F)             |       |         |
+----------+-----------+--------+-------------------+-------+---------+
| 870.2400 | Primary   | Rabbit | Slight irritant   | III   | 4       |
|          | eye       |        | (iritis,          |       | 6246250 |
|          | i         |        | discharge)        |       |         |
|          | rritation |        |                   |       |         |
+----------+-----------+--------+-------------------+-------+---------+
| 870.2500 | Primary   | Rabbit | Not an irritant   | IV    | 4       |
|          | skin      |        |                   |       | 6246250 |
|          | i         |        |                   |       |         |
|          | rritation |        |                   |       |         |
+----------+-----------+--------+-------------------+-------+---------+
| 870.2600 | Dermal    | Guinea | Not a sensitizer  | Neg   | 4       |
|          | sens      | Pig    |                   | ative | 6246304 |
|          | itization |        |                   |       |         |
+----------+-----------+--------+-------------------+-------+---------+

+-------------+-----------------+--------------------------------------+
| **Table     |                 |                                      |
| A.2:        |                 |                                      |
| Toxicity    |                 |                                      |
| Profile for |                 |                                      |
| Prot        |                 |                                      |
| hioconazole |                 |                                      |
| (JAU6476)   |                 |                                      |
| Technical** |                 |                                      |
+=============+=================+======================================+
| **Guideline | **MRID No.      | **Results**                          |
| No./ Study  | (year)/         |                                      |
| Type**      | Classification  |                                      |
|             | /Doses**        |                                      |
+-------------+-----------------+--------------------------------------+
| 870.3100    | 46246311 (1999) | NOAEL = 100 mg/kg/day                |
|             |                 |                                      |
| 90-day oral | 0, 20, 100, 500 | LOAEL = 500 mg/kg/day based on       |
| toxicity    | mg/kg/day       | increased water consumption (males   |
| rodents     |                 | and females), increased cholesterol  |
| (rat)       | Accep           | (males and females), liver effects   |
|             | table/Guideline | \[increased liver weights (females), |
|             |                 | hepatocellular hypertrophy (males    |
|             |                 | and females) and cytoplasmic change  |
|             |                 | (males and females)\] 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    | 46246427 (1999) | NOAEL = 25 mg/kg/day                 |
|             |                 |                                      |
| 90-Day oral | 0, 25, 100, 400 | LOAEL = 100 mg/kg/day based on       |
| toxicity    | mg/kg/day       | increased cholesterol levels and     |
| rodents     |                 | increased liver enzyme activity in   |
| (mouse)     | Accep           | females, increased liver weights in  |
|             | table/Guideline | both sexes, and increased incidence  |
|             |                 | of hepatocellular hypertrophy and    |
|             |                 | cytoplasmic change in the liver of   |
|             |                 | both sexes.                          |
+-------------+-----------------+--------------------------------------+
| 870.3100    | 46246429 (1998) | No NOAEL or LOAEL were determined as |
|             |                 | this was a nonguideline study to     |
| 28-Day oral | 0, 10000 ppm in | compare routes of administration     |
| toxicity    | both neat or    |                                      |
| rodents     | stabilized diet | Observations included clinical signs |
| (rat)       |                 | of toxicity, changes in BW, BWG, FC; |
|             | 0, 1000         | liver and kidney effects (wt,        |
|             | mg/kg/day by    | histopathology), clinical chemistry  |
|             | gavage          | changes                              |
|             |                 |                                      |
|             | Acceptab        |                                      |
|             | le/Nonguideline |                                      |
+-------------+-----------------+--------------------------------------+
| 870.3100    | 46246428 (1997) | No NOAEL or LOAEL were determined    |
|             |                 |                                      |
| 28-Day oral | 0, 400, 2000,   | Observations included changes in     |
| toxicity    | 10000 ppm       | body wt, food consumption, liver and |
| rodents     |                 | kidney effects, clinical chemistry   |
| (rat)       | 0, 18.6/18.8,   |                                      |
|             | 145.7/151.0, or |                                      |
|             | 951.7/1032.5    |                                      |
|             | (M/F) mg/kg/day |                                      |
|             |                 |                                      |
|             | Acceptab        |                                      |
|             | le/Nonguideline |                                      |
+-------------+-----------------+--------------------------------------+
| 870.3150    | 46246435 (2000) | No NOAEL or LOAEL were determined in |
|             |                 | this study, the specific             |
| 90-day oral | 0, 25, 100, 300 | observations included effects on     |
| toxicity    | mg/kg/day       | liver and kidney enzyme activities   |
| nonrodents  |                 | and tissues concentrations of parent |
| (dog)       | Acceptab        | and metabolites were determined.     |
|             | le/Nonguideline | This study included a 4 week         |
|             |                 | recovery phase.                      |
+-------------+-----------------+--------------------------------------+
| 870.3150    | 46426313 (2001) | NOAEL = 25 mg/kg/day                 |
|             |                 |                                      |
| 90-day oral | 0, 25, 100, 300 | LOAEL = 100 mg/kg/day based on       |
| toxicity    | mg/kg/day       | kidney (histopathological) and       |
| nonrodents  |                 | thyroid (T4 and TSH) findings at 100 |
| (dog)       | Accep           | mg/kg. This study included a 4 week  |
|             | table/Guideline | recovery phase.                      |
+-------------+-----------------+--------------------------------------+
| 870.3200    | 46426315 (2000) | NOAEL = 1000 mg/kg/day               |
|             |                 |                                      |
| 21/28-Day   | 0, 100, 300,    | LOAEL \> 1000 mg/kg/day              |
| dermal      | 1000 mg/kg      |                                      |
| toxicity    |                 |                                      |
| (rat)       | Accep           |                                      |
|             | table/Guideline |                                      |
+-------------+-----------------+--------------------------------------+
| 870.3700a   | 46246316 (1996) | **Maternal Toxicity**                |
|             |                 |                                      |
| Prenatal    | 0, 80, 500,     | NOAEL = 80 mg/kg/day                 |
| dev         | 1000 mg/kg/day  |                                      |
| elop-mental |                 | LOAEL = 500 mg/kg/day based on       |
| in rats --  | Accep           | increased urination and water        |
| oral        | table/Guideline | 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 14^th^  |
|             |                 | rib.                                 |
+-------------+-----------------+--------------------------------------+
| 870.3700a   | 46246317 (2002) | Range finding study for above, no    |
|             |                 | endpoints were determined.           |
| Prenatal    | 0, 40, 200,     |                                      |
| dev         | 1000 mg/kg/day  |                                      |
| elop-mental |                 |                                      |
| in rats --  | Acceptab        |                                      |
| oral        | le/Nonguideline |                                      |
+-------------+-----------------+--------------------------------------+
| 870.3700a   | 46246323 (2001) | **Maternal Toxicity**                |
|             |                 |                                      |
| Prenatal    | 0, Technical    | NOAEL \> 1000 mg/kg/day              |
| dev         | 1000 mg/kg/day, |                                      |
| elop-mental | 62.5 mg/kg/day  | LOAEL \> 1000 mg/kg/day              |
| in rodents  | diluted EC 250  |                                      |
|             | formulation,    | **Developmental Toxicity**           |
| (rat) -     | 250 mg/kg/day   |                                      |
| dermal      | EC 250          | NOAEL = 1000 mg/kg/day               |
|             | formulation     |                                      |
|             |                 | LOAEL \> 1000 mg/kg/day              |
|             | Acceptab        |                                      |
|             | le/Nonguideline |                                      |
+-------------+-----------------+--------------------------------------+
| 870.3700a   | 46923601 (2004) | **Maternal Toxicity**                |
|             |                 |                                      |
| Prenatal    | 0, 20, 80, 750  | NOAEL = 80 mg/kg/day                 |
| dev         | mg/kg/day       |                                      |
| elop-mental |                 | LOAEL = 750 mg/kg/day based on       |
| in rats --  | Acceptab        | increased water consumption,         |
| oral        | le/Nonguideline | 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   | 46246330 (1997) | **Maternal Toxicity**                |
|             |                 |                                      |
| Prenatal    | 0, 80, 100,     | NOAEL \< 80 mg/kg/day                |
| dev         | 300, 480        |                                      |
| elop-mental | mg/kg/day       | LOAEL = 80 mg/kg/day based on        |
| in          |                 | reduced food consumption and body    |
| nonrodents  | pilot study     | wts.                                 |
|             |                 |                                      |
| (rabbit)    | Acceptab        | **Developmenta**l NOAEL = 300        |
|             | le/Nonguideline | mg/kg/day                            |
|             |                 |                                      |
|             |                 | LOAEL = 480 mg/kg/day based on       |
|             |                 | decreased body wt, and small         |
|             |                 | fetuses.                             |
+-------------+-----------------+--------------------------------------+
| 870.3700b   | 46246328 (1998) | **Maternal Toxicity**                |
|             |                 |                                      |
| Prenatal    | 0, 10, 30, 80,  | NOAEL = 80 mg/kg/day                 |
| dev         | 350\* mg/kg/day |                                      |
| elop-mental |                 | LOAEL = 350 mg/kg/day based on       |
| in          | \* Additional   | decreased body wt and decreased food |
| nonrodents  | group added     | consumption.                         |
|             | after start of  |                                      |
| (rabbit)    | study           | **Developmental Toxicity**           |
|             |                 |                                      |
|             | Accep           | NOAEL = 80 mg/kg/day                 |
|             | table/Guideline |                                      |
|             |                 | LOAEL = 350 mg/kg/day based on       |
|             |                 | abortions, total resorptions, and    |
|             |                 | lower fetal body weight              |
+-------------+-----------------+--------------------------------------+
| 870.3800    | 46246331 (1999) | **Parental Toxicity**                |
|             |                 |                                      |
| R           | 0, 10, 100,     | NOAEL = 250 mg/kg/day                |
| eproduction | 250, 500        |                                      |
| and         | mg/kg/day       | LOAEL = 500 mg/kg/day based on       |
| fertility   |                 | clinical signs (urine stain)         |
| effects     | (pilot)         |                                      |
|             |                 | **Reproductive Toxicity**            |
|             | Acceptab        |                                      |
|             | le/Nonguideline | NOAEL = 500 mg/kg/day                |
|             |                 |                                      |
|             |                 | LOAEL \> 500 mg/kg/day               |
|             |                 |                                      |
|             |                 | **Offspring Toxicity**               |
|             |                 |                                      |
|             |                 | NOAEL = 500 mg/kg/day                |
|             |                 |                                      |
|             |                 | LOAEL \> 500 mg/kg/day               |
+-------------+-----------------+--------------------------------------+
| 870.3800    | 46246334 (2001) | **Parental Toxicity**                |
|             |                 |                                      |
| R           | 0, 10, 100, 750 | NOAEL = 100 mg/kg/day                |
| eproduction | mg/kg/day       |                                      |
| and         |                 | LOAEL = 750 mg/kg/day based on       |
| fertility   | Combined with   | decreased body weights, body weight  |
| effects     | MRID 46246331   | gains and increased food             |
|             |                 | consumption, increased liver weights |
|             | Accep           | and kidney weights, decreased        |
|             | table/Guideline | 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   | 46246335 (2000) | NOAEL = 50 mg/kg/day                 |
|             |                 |                                      |
| Chronic     | 0, 5, 50, 750   | LOAEL = 750 mg/kg/day based on       |
| toxicity    | mg/kg/day       | decreased body weight and body       |
| rodents     |                 | weight gain, alterations in          |
| (rat)       | Rat, 53 weeks   | hematology and clinical chemistry    |
|             |                 | parameters indicative of liver and   |
|             | Accep           | kidney damage, increased liver and   |
|             | table/Guideline | kidney weights, and accompanying     |
|             |                 | histopathological alterations in the |
|             |                 | liver, kidney and urinary bladder.   |
|             |                 | FOB conducted at 27 and 52 weeks.    |
+-------------+-----------------+--------------------------------------+
| 870.4100b   | 46246336 (2001) | NOAEL = 5 mg/kg/day                  |
|             |                 |                                      |
| Chronic     | 0, 5, 40, 125   | LOAEL = 40 mg/kg/day based on        |
| toxicity    | mg/kg/day       | decreased T3 and T4 thyroid          |
|             |                 | hormones, increased urine volume,    |
| non-rodent  | one year        | and increased incidence of chronic   |
| (dog)       |                 | inflammation and pigmentation in the |
|             | Accep           | kidneys of the male animals, and     |
|             | table/Guideline | 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    | 46246338 (2001) | NOAEL = 50 mg/kg/day                 |
|             |                 |                                      |
| Carc        | M: 0, 5, 50,    | LOAEL = 500/625 (M/F) mg/kg/day      |
| inogenicity | 750/500         | based **on increased mortality** and |
| rats        | mg/kg/day       | decreased body weight/body weight    |
|             |                 | gain, changes in clinical chemistry  |
|             | F:              | (APh, creatinine, urea) and          |
|             | 0,5,50,750/625  | hematological parameters, increased  |
|             | mg/kg/day       | liver and kidney weights, and liver  |
|             |                 | (hypertrophy and eosinophilic/clear  |
|             | 106 weeks       | cell focus) and kidney/urinary       |
|             |                 | bladder pathology.                   |
|             | Unaccep         |                                      |
|             | table/Guideline |                                      |
|             |                 |                                      |
|             | for             |                                      |
|             | Carcinogenicity |                                      |
|             | because dose    |                                      |
|             | levels too      |                                      |
|             | high.           |                                      |
+-------------+-----------------+--------------------------------------+
| 870.4300    | 46246339 (2001) | NOAEL = 10 mg/kg/day                 |
|             |                 |                                      |
| Carc        | 0, 10, 70, 500  | LOAEL = 70 mg/kg/day based on kidney |
| inogenicity | mg/kg/day       | (tubular degeneration/regeneration   |
| mice        |                 | in males) effects.                   |
|             | 80 weeks        |                                      |
|             |                 | **no evidence of carcinogenicity**   |
|             | Accep           |                                      |
|             | table/Guideline |                                      |
+-------------+-----------------+--------------------------------------+
| 870.6200a   | 46246417 (2000) | NOAEL = 200/750 (M/F) mg/kg/day      |
|             |                 |                                      |
| Acute       | 0, 200, 750,    | LOAEL = 750/2000 (M/F) based on the  |
| ne          | 2000 mg/kg/day  | transient effect of reduced motor    |
| urotoxicity |                 | and locomotor activity.              |
| screening   | Accep           |                                      |
| battery     | table/Guideline |                                      |
+-------------+-----------------+--------------------------------------+
| 870.6200b   | 46246416 (2001) | **Systemic Toxicity**                |
|             |                 |                                      |
| Subchronic  | 0, 100, 500,    | NOAEL = 500 mg/kg/day                |
| ne          | 1000 mg/kg/day  |                                      |
| urotoxicity |                 | LOAEL = 1000 mg/kg/day based on      |
| screening   | Accep           | decreased body weight & body weight  |
| battery     | table/Guideline | gain in males.                       |
|             |                 |                                      |
|             |                 | No neurotoxicity was noted at dose   |
|             |                 | levels tested.                       |
+-------------+-----------------+--------------------------------------+
| 870.7600    | 46246426 (1997) | Absorption rate                      |
|             |                 |                                      |
| Dermal      | Rat N= 10       | 49.41%                               |
| Absorption  |                 |                                      |
|             | Pilot Study     |                                      |
+-------------+-----------------+--------------------------------------+
| 870.7600    | 46246423 (2003) | Absorption rate                      |
|             |                 |                                      |
| Dermal      | Monkey N = 1    | 4.06%                                |
| Absorption  |                 |                                      |
|             | Pilot Study     |                                      |
+-------------+-----------------+--------------------------------------+
| Number      | 46246421 (2001) | Number range CHAPTERJAU6476 was      |
| range       |                 | extensively metabolised in the rat   |
| CHAP        | Acep            | following oral administration.       |
| TER870.7485 | table/Guideline | Eighteen metabolites and the parent  |
|             |                 | compound were identified in urine,   |
| Metabolism  |                 | 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.                |
+-------------+-----------------+--------------------------------------+
| Number      | 46246419 (2001) | Number range CHAPTERThe whole body   |
| range       |                 | autoradiography results are in       |
| CHAP        | Acceptab        | agreement with the absorption,       |
| TER870.7485 | le/Nonguideline | distribution and excretion pattern   |
|             |                 | of JAU6476 in the main metabolism    |
| 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.                    |
+-------------+-----------------+--------------------------------------+
| Number      | 46246438 (2002) | Number range CHAPTERPiloerection was |
| range       |                 | noted in the high-dose males from    |
| CHAP        | Acceptab        | days 13-21.There were no significant |
| TER870.7800 | le/Nonguideline | effects on body weight, food         |
| Imm         |                 | consumption or spleen weights. Under |
| unotoxicity |                 | 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    | 46246343 (1996) | JAU 6476 is considered negative for  |
|             |                 | reverse mutation in this battery of  |
| Bacterial   | Accep           | *S. typhimurium* strains up to       |
| reverse     | table/Guideline | cytotoxic concentrations.            |
| mutation    |                 |                                      |
| test        |                 |                                      |
+-------------+-----------------+--------------------------------------+
| 870.5300    | 46246404 (1996) | JAU 6476 is considered non-mutagenic |
|             |                 | in the V79-HGPRT forward mutation    |
| In vitro    | Accep           | assay.                               |
| mammalian   | table/Guideline |                                      |
| cell gene   |                 |                                      |
| mutation    |                 |                                      |
| test        |                 |                                      |
+-------------+-----------------+--------------------------------------+
| 870.5375    | 46246406 (1996) | JAU 6476 may be considered           |
|             |                 | clastogenic (*i.e.*, induces         |
| In vitro    | Accep           | increases in structural              |
| mammalian   | table/Guideline | aberrations), but this mutagenic     |
| chromosome  |                 | activation may result from secondary |
| aberration  |                 | cytotoxicity rather than direct      |
| test        |                 | structural DNA damage.               |
+-------------+-----------------+--------------------------------------+
| 870.5395    | 46246409 (1996) | The one i.p. dose of 250 mg/kg JAU   |
|             |                 | 6476 (prothioconazole) is considered |
| Mammalian   | Accep           | to be non-clastogenetic *in vivo*.   |
| erythrocyte | table/Guideline |                                      |
| m           |                 |                                      |
| icronucleus |                 |                                      |
| test        |                 |                                      |
+-------------+-----------------+--------------------------------------+
| 870.5395    | 46246411 (2003) | JAU 6476 (prothioconazole) is not    |
|             |                 | clastogenic or aneugenic in male     |
| Mammalian   | Accep           | mice treated up to overtly toxic and |
| erythrocyte | table/Guideline | cytotoxic doses.                     |
| m           |                 |                                      |
| icronucleus |                 |                                      |
| test        |                 |                                      |
+-------------+-----------------+--------------------------------------+
| 870.5550    | 46246412 (1998) | **JAU 6476 is evaluated as equivocal |
|             |                 | in this assay.**                     |
| Unscheduled | Accep           |                                      |
| DNA         | table/Guideline | However, these results were          |
| synthesis   |                 | clarified based on the negative      |
| in          |                 | findings in the *in vivo* UDS assay  |
| mammalian   |                 | in rat hepatocytes from adult male   |
| cells       |                 | rats exposed up to the 5000 mg/kg    |
|             |                 | with the same Batch No. of the test  |
|             |                 | materials. (MRID 46246413).          |
+-------------+-----------------+--------------------------------------+
| 870.5550    | 46246413 (1999) | **JAU 6476 (prothioconazole) is      |
|             |                 | negative for UDS-induction in        |
| Unscheduled | Accep           | hepatocytes drawn from male rats     |
| DNA         | table/Guideline | administered single oral doses of    |
| synthesis   |                 | 2500 and 5000 mg/kg**.               |
| in          |                 |                                      |
| mammalian   |                 |                                      |
| cells       |                 |                                      |
+-------------+-----------------+--------------------------------------+
| Special     | 46246415 (1999) | Inhibition was found in microsomes   |
| Study       |                 | of both rats and mice. The IC50      |
|             | Unacceptable/   | (Inhibitory Concentration) attained  |
| Inhibition  |                 | for its ECOD metabolism was 5 *u*M   |
| of enzymes  | Nonguideline    | JAU 6476 in rat preparations, and 9  |
| in liver    |                 | *u*M in mouse microsomes. The        |
| microsomes  |                 | 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]{.underline},         |
|             |                 | 16alpha, 2alpha 6beta, and 7alpha    |
|             |                 | hydroxylation; plus oxidation to     |
|             |                 | androstendione. The inclusive IC50   |
|             |                 | of most of these P450 subtypes was   |
|             |                 | approximately 75 to 100 *u*M; for    |
|             |                 | 7alpha hydroxylation (= subtype 2    |
|             |                 | A1), the IC50 was about 1000 *u*M.   |
|             |                 |                                      |
|             |                 | **No conclusions can be reached from |
|             |                 | this study because of the numerous   |
|             |                 | study deficiencies**                 |
+-------------+-----------------+--------------------------------------+
| Special     | 46246436 (1996) | Number range CHAPTERThyroid          |
| Study       |                 | peroxidase (TPO)-catalyzed guaiacol  |
|             | Acceptab        | oxidation was inhibited by compounds |
| Number      | le/Nonguideline | tested. 3-mercapto-1,2,4-triazole    |
| range       |                 | had the lowest IC50 value (i.e.:     |
| CHAPTER     |                 | lowest concentration required to     |
| Interaction |                 | inhibit the reaction by 50%),        |
| with        |                 | followed by PTU then JAU 6476 and    |
| Thyroid     |                 | JAU 6953. This provided initial      |
| Peroxidase  |                 | indication that TPO may be           |
| in vitro    |                 | 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.3:        |                 |                                      |
| Toxicity    |                 |                                      |
| Profile for |                 |                                      |
| P           |                 |                                      |
| rothioconaz |                 |                                      |
| ole-Desthio |                 |                                      |
| (SXX0665)   |                 |                                      |
| Technical** |                 |                                      |
+=============+=================+======================================+
| **Guideline | **MRID No.      | **Results**                          |
| No./ Study  | (year)/         |                                      |
| Type**      | Classification  |                                      |
|             | /Doses**        |                                      |
+-------------+-----------------+--------------------------------------+
| 870.3100    | 46246430 (1992) | NOAEL = 11 mg/kg/day for males; \<   |
|             |                 | 11 mg/kg/day for females             |
| 4-Week oral | 0, 100, 300,    |                                      |
| toxicity    | 1000 ppm        | LOAEL = 34 mg/kg/day for males and ≤ |
| rodents     |                 | 11 mg/kg/day for females based       |
|             | 0, 11, 34/38,   | increased liver triglycerides and    |
| (rat)       | 117/ 121 (M/F)  | absolute and relative liver weights  |
|             | mg/kg/day       | in males and on decreased relative   |
|             |                 | and absolute ovary weight with       |
|             | Accep           | histopathology                       |
|             | table/Guideline |                                      |
+-------------+-----------------+--------------------------------------+
| 870.3100    | 46246309 (1999) | NOAEL = 2.2/3.0 (M/F) mg/kg/day      |
|             |                 |                                      |
| 90-Day oral | 0, 30, 125,     | LOAEL = 9.6/12.5 mg/kg/day based on  |
| toxicity    | 500, 2000 ppm   | histological changes in the liver of |
| rodents     |                 | males and increased P450 in females. |
|             | 2.2/3.0,        |                                      |
| (rat)       | 9.6/12.5,       |                                      |
|             | 36.9/50.7,      |                                      |
|             | 161.9/210.8     |                                      |
|             | mg/kg/d M/F     |                                      |
|             |                 |                                      |
|             | Accep           |                                      |
|             | table/Guideline |                                      |
+-------------+-----------------+--------------------------------------+
| 870.3100    | 46246310 (1999) | NOAEL \< 11.5/16.0 (M/F) mg/kg/day   |
|             |                 |                                      |
| 90-Day oral | 0, 40, 200,     | LOAEL = 11.5.16.0 (M/F) mg/kg/day    |
| toxicity    | 1000, 5000 ppm  | based on decreased body weight gain  |
| rodents     |                 | in both sexes.                       |
|             | 0, 11.5/16.0,   |                                      |
| (mouse)     | 58.9/79.5,      |                                      |
|             | 294.0/392.3,    |                                      |
|             | 1454/2073 (M/F) |                                      |
|             | mg/kg/day       |                                      |
|             |                 |                                      |
|             | Acceptab        |                                      |
|             | le/Nonguideline |                                      |
+-------------+-----------------+--------------------------------------+
| 870.3150    | 46246431 (1999) | Range finding study, no NOAEL or     |
|             |                 | LOAEL were established, observations |
| 39-Day oral | 0, 10,          | included dramatic reductions in      |
| toxicity in | 100/5000, 1000  | uterine/oviduct absolute and         |
| nonrodents  | ppm             | relative organ weights at 10 ppm.    |
| (dog)       |                 |                                      |
|             | 0, 0.3, 3/150,  |                                      |
|             | 30 (M/F)        |                                      |
|             | mg/kg/day       |                                      |
|             |                 |                                      |
|             | Acceptab        |                                      |
|             | le/Nonguideline |                                      |
+-------------+-----------------+--------------------------------------+
| 870.3150    | 46246314 (2000) | NOAEL = 37.79/42.75 (M/F) mg/kg/day  |
|             |                 |                                      |
| 90-Day oral | 0, 40, 200,     | LOAEL \> 37.79/42.75 (M/F) mg/kg/day |
| toxicity in | 1000 ppm        |                                      |
| nonrodents  |                 |                                      |
| (dog)       | 0, 1.58/1.62,   |                                      |
|             | 7.81/8.53,      |                                      |
|             | 37.79/42.75     |                                      |
|             | (M/F/)          |                                      |
|             | mg/kg/day       |                                      |
|             |                 |                                      |
|             | Unaccep         |                                      |
|             | table/Guideline |                                      |
+-------------+-----------------+--------------------------------------+
| 870.3465    | 46246432        | NOAEL = 228.4 mg/m^3^/day            |
|             | (1991) - Pilot  |                                      |
| 90-Day      |                 | LOAEL \> 228.4 mg/m^3^/day           |
| inhalation  | 46246433 (1992) |                                      |
| toxicity    |                 |                                      |
|             | 0, 11.3, 46.8,  |                                      |
| (rat)       | 228.4           |                                      |
|             | mg/m^3^/day     |                                      |
|             |                 |                                      |
|             | Unaccep         |                                      |
|             | table/Guideline |                                      |
+-------------+-----------------+--------------------------------------+
| 870.3700a   | 46246326 (1991) | **Discussed in appendix 1 of MRID    |
|             |                 | 46246325**                           |
| Prenatal    | 0, 30 mg/kg/day |                                      |
| dev         |                 | **Maternal Toxicity**                |
| elop-mental | Pilot study,    |                                      |
| in rodents  | used with       | NOAEL = 30 mg/kg/day                 |
| (rat) -     | 46246325        |                                      |
| dermal      |                 | LOAEL \> 30 mg/kg/day                |
|             | Acceptab        |                                      |
|             | le/Nonguideline | **Developmental Toxicity**           |
|             |                 |                                      |
|             |                 | NOAEL = 30 mg/kg/day                 |
|             |                 |                                      |
|             |                 | LOAEL \> 30 mg/kg/day                |
+-------------+-----------------+--------------------------------------+
| 870.3700a   | 46246325 (1991) | **Maternal Toxicity**                |
|             |                 |                                      |
| Prenatal    | 0, 100, 300,    | NOAEL = 1000 mg/kg/day               |
| dev         | 1000 mg/kg/day  |                                      |
| elop-mental |                 | LOAEL \> 1000 mg/kg/day              |
| in rodents  | Accep           |                                      |
| (rat) -     | table/Guideline | **Developmental Toxicity**           |
| dermal      |                 |                                      |
|             | When combined   | NOAEL = 30 mg/kg/day                 |
|             | with 46246326   |                                      |
|             |                 | LOAEL = 100 mg/kg/day based on       |
|             |                 | structural alterations (14^th^ rib)  |
+-------------+-----------------+--------------------------------------+
| 870.3700a   | 46246322 (1991) | **Maternal Toxicity**                |
|             |                 |                                      |
| Prenatal    | 0, 1, 3         | NOAEL = 3 mg/kg/day                  |
| dev         | mg/kg/day       |                                      |
| elop-mental |                 | LOAEL \> 3 mg/kg/day                 |
| in rodents  | Acceptab        |                                      |
| (rat) -     | le/Nonguideline | **Developmental Toxicity**           |
| oral        |                 |                                      |
|             | results         | NOAEL = 3 mg/kg/day                  |
|             | combined        |                                      |
|             |                 | LOAEL \> 3 mg/kg/day                 |
|             | with 46246321   |                                      |
|             |                 | Combined with 46246321               |
+-------------+-----------------+--------------------------------------+
| 870.3700a   | 46246321 (1991) | **Maternal Toxicity**                |
|             |                 |                                      |
| Prenatal    | 0, 10, 30, 100  | NOAEL = 30 mg/kg/day                 |
| dev         | mg/kg/day       |                                      |
| elop-mental |                 | LOAEL = 100 mg/kg/day based on       |
| in rodents  | Accep           | decreased body weight gains,         |
| (rat) -     | table/Guideline | increased liver weight with          |
| oral        |                 | histopathology                       |
|             | results         |                                      |
|             | combined with   | **Developmental Toxicity**           |
|             | 46246322        |                                      |
|             |                 | 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   | 46246320 (1990) | **Maternal Toxicity**                |
|             |                 |                                      |
| Prenatal    | 0, 100          | NOAEL = 100 mg/kg/day                |
| dev         | mg/kg/day       |                                      |
| elop-mental |                 | LOAEL \> 100 mg/kg/day               |
| in rodents  | Acceptab        |                                      |
| (rat) -     | le/Nonguideline | **Developmental Toxicity**           |
| oral        |                 |                                      |
|             |                 | NOAEL \<100 mg/kg/day                |
|             |                 |                                      |
|             |                 | LOAEL = 100 mg/kg/day based on       |
|             |                 | developmental delays                 |
+-------------+-----------------+--------------------------------------+
| 870.3700a   | 46246319 (1992) | **Maternal Toxicity**                |
|             |                 |                                      |
| Prenatal    | 0, 30 mg/kg/day | No NOAEL or LOAEL were determined    |
| dev         | oral            |                                      |
| elop-mental |                 | **Developmental Toxicity**           |
| in rodents  | Acceptab        |                                      |
| (rat) -     | le/Nonguideline | No NOAEL or LOAEL were determined,   |
| oral        |                 | observations included structural     |
|             |                 | abnormalities, developmental delays, |
|             |                 | death, shows 14^th^ rib not          |
|             |                 | completely reversible after birth.   |
|             |                 |                                      |
|             |                 | Follow up of MRID 46246320,          |
|             |                 | 46246321.                            |
+-------------+-----------------+--------------------------------------+
| 870.3700b   | 46246327,       | **Maternal Toxicity**                |
|             | (1991)          |                                      |
| Prenatal    |                 | NOAEL = 10 mg/kg/day                 |
|             | 0, 2, 10, 50    |                                      |
| de          | mg/kg/day       | LOAEL = 50 mg/kg/day based on        |
| velopmental |                 | decreased body wt gain, decrease     |
| in          | Accep           | food consumption, increased          |
| nonrodents  | table/Guideline | resorptions, decreased number of     |
|             |                 | fetuses, liver histopathology.       |
| (rabbit) -  |                 |                                      |
| oral        |                 | **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   | 46246329 (1991) | **Maternal Toxicity**                |
|             |                 |                                      |
| Prenatal    | 0, 100, 300,    | NOAEL = 300 mg/kg/day                |
|             | 1000 mg/kg/day  |                                      |
| de          | dermal          | LOAEL = 1000 mg/kg/day based on      |
| velopmental |                 | local dermal toxicity                |
| in          | pilot study     |                                      |
| nonrodents  |                 | **Developmental Toxicity**           |
|             | Acceptab        |                                      |
| (rabbit) -  | le/Nonguideline | NOAEL = 1000 mg/kg/day               |
| dermal      |                 |                                      |
|             |                 | LOAEL \> 1000 mg/kg/day              |
+-------------+-----------------+--------------------------------------+
| 870.3800    | 46246332 (1992) | **Parental Toxicity**                |
|             |                 |                                      |
| R           | 0, 0.52, 2.49,  | NOAEL = 0.52 mg/kg/day               |
| eproduction | 53.0, 79.6      |                                      |
| and         | mg/kg/day       | LOAEL = 2.49 mg/kg/day based on      |
| fertility   | (pilot)         | incr. liver wt., liver discoloration |
| effects     |                 |                                      |
|             | Acceptab        | **Reproductive Toxicity**            |
|             | le/Nonguideline |                                      |
|             |                 | 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    | 46246333 (2001) | **Parental Toxicity**                |
|             |                 |                                      |
| R           | 0, 40, 160, 640 | NOAEL = 10.4/12.0 (M/F) mg/kg/day    |
| eproduction | ppm             |                                      |
| and         |                 | LOAEL = 42.6/49.5 (M/F) mg/kg/day    |
| fertility   | 0, 2.7/3.0,     | based on increased liver wt, liver   |
| effects     | 10.4/12.0,      | histopathology, decreased food       |
|             | 42.6/49.5 (M/F) | consumption during lactation         |
|             | mg/kg/day -     | (females only).                      |
|             | premating       |                                      |
|             |                 | **Reproductive Toxicity**            |
|             | 0, 2.5, 10.0,   |                                      |
|             | 41.2            | NOAEL = 10.4/12.0 (M/F) mg/kg/day    |
|             |                 |                                      |
|             | mg/kg/day -     | LOAEL = 42.6/49.5 (M/F) mg/kg/day    |
|             | gestation       | based on increased incidence of      |
|             |                 | dystocia, decreased viability and    |
|             | 0, 4.8, 18.6,   | decreased pup body weight.           |
|             | 72.6            |                                      |
|             | mg/kg/day -     | **Offspring Toxicity**               |
|             | lactation       |                                      |
|             |                 | NOAEL = 10.4/12.0 mg/kg/day          |
|             | Accep           |                                      |
|             | table/Guideline | 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   | 46246337 (2001) | NOAEL = 69.9/77.1 (M/F) mg/kg/day    |
|             |                 |                                      |
| Chronic     | 0, 40, 300,     | LOAEL \> 69.9/77.1 (M/F) mg/kg/day   |
| toxicity    | 2000 ppm        |                                      |
| dogs        |                 |                                      |
|             | 0, 1.35/1.55,   |                                      |
|             | 10.1/11.1,      |                                      |
|             | 69.9/77.1 (M/F) |                                      |
|             | mg/kg/day       |                                      |
|             |                 |                                      |
|             | 30 weeks        |                                      |
|             |                 |                                      |
|             | Unaccep         |                                      |
|             | table/Guideline |                                      |
|             |                 |                                      |
|             | Not tested at   |                                      |
|             | high enough     |                                      |
|             | doses           |                                      |
|             |                 |                                      |
|             | GLP             |                                      |
|             | deficiencies    |                                      |
+-------------+-----------------+--------------------------------------+
| 870.4200    | 46246342 (1999) | NOAEL = 1.1/1.6 (M/F) mg/kg/day      |
|             |                 |                                      |
| Carc        | 0, 20, 140, 980 | LOAEL = 8.0/11.2 (M/F) mg/kg/day     |
| inogenicity | ppm             | based on clinical chemistry,         |
| rats        |                 | histopathology (liver).              |
|             | 0, 1.1/1.6,     |                                      |
|             | 8.0/11.2,       | **no evidence of carcinogenicity**   |
|             | 57.6/77.4 (M/F) |                                      |
|             | mg/kg/day       |                                      |
|             |                 |                                      |
|             | Accep           |                                      |
|             | table/Guideline |                                      |
+-------------+-----------------+--------------------------------------+
| 870.4300    | 46246340 (2000) | NOAEL =12.8/20.3 (M/F) mg/kg/day     |
|             |                 |                                      |
| Carc        | 46246341 (2001) | LOAEL = 51.7/80.0 (M/F) mg/kg/day    |
| inogenicity |                 | based on decreased body weight gain  |
| mice        | 0, 12.5, 50,    | in males, decreased triglyceride     |
|             | 200 ppm         | levels in both sexes, decreased      |
|             |                 | cholesterol levels in males, changes |
|             | 0, 3.1/5.1,     | in glucose levels in males,          |
|             | 12.8/20.3,      | increased liver weights in both      |
|             | 51.7/80.0 (M/F) | sexes, increased incidence of        |
|             | mg/kg/day       | histopathological findings in the    |
|             |                 | liver hepatocytes in both sexes,     |
|             | 105 weeks       | decreased blood urea levels in       |
|             |                 | females, increased kidney weights in |
|             | Accep           | females, and increased incidence of  |
|             | table/Guideline | eosinophilic droplets in the         |
|             |                 | cortical tubules of the kidneys of   |
|             |                 | females.                             |
|             |                 |                                      |
|             |                 | **no evidence of carcinogenicity**   |
+-------------+-----------------+--------------------------------------+
| 870.6300    | 46246418 (2004) | **Maternal Toxicity**                |
|             |                 |                                      |
| De          | 0, 40, 160, 500 | NOAEL = 15.1 mg/kg/day               |
| velopmental | ppm             |                                      |
| ne          |                 | LOAEL = 43.3 mg/kg/day based on      |
| urotoxicity | 0, 3.6, 15.1,   | dystocia                             |
| rats        | 43.3 mg/kg/day  |                                      |
|             | during          | **Developmental Toxicity**           |
|             | gestation       |                                      |
|             |                 | NOAEL = 3.6 mg/kg/day                |
|             | 0, 8.1, 35.7,   |                                      |
|             | 104.6 during    | LOAEL = 15.1 mg/kg/day based on      |
|             | lactation       | deviated snout and malocclusion      |
|             |                 |                                      |
|             | Acceptab        | **Offspring Neurotoxicity**          |
|             | le/Nonguideline | 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    | 46246425 (2003) | Absorption rate:                     |
|             |                 |                                      |
| Dermal      | Monkey N=5      | 18.61%                               |
| Absorption  |                 |                                      |
+-------------+-----------------+--------------------------------------+
| 870.7600    | 46246424 (2003) | Absorption rate                      |
|             |                 |                                      |
| Dermal      | Monkey N=1      | 7.11%                                |
| Absorption  |                 |                                      |
|             | Pilot Study     |                                      |
+-------------+-----------------+--------------------------------------+
| Number      | 46246422 (2001) | Number range CHAPTERIn whole-body    |
| range       |                 | autoradiography experiments, the     |
| CHAP        | 46246420 (2001) | quick onset of absorption of the     |
| TER870.7485 |                 | test material was demonstrated.      |
|             | Pilot study and | Absorption was not complete after    |
| Metabolism  | autoradiography | one hour. The autoradiograms also    |
| -rat        |                 | showed that the blood concentration  |
|             | Acceptab        | was less than the concentration      |
|             | le/Nonguideline | 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.           |
+-------------+-----------------+--------------------------------------+
| Number      | 46246439 (2001) | The maximum concentrations (Cmax)    |
| range       |                 | were comparable between single and   |
| CHAP        | Acceptab        | multiple oral administration of 1    |
| TER870.7485 | le/Nonguideline | mg/kg and 3 mg/kg and dermal         |
|             |                 | application of 30 mg/kg,             |
| Number      |                 | respectively. The maximum            |
| range       |                 | concentration varied after single    |
| CHAP        |                 | and multiple dermal application of   |
| TERPregnant |                 | 100 mg/kg. The time to achieve       |
| Metabolism  |                 | maximum concentration was prolonged  |
| Study       |                 | after dermal application compared    |
| (single and |                 | with oral administration at all      |
| multiple    |                 | doses tested (single and multiple)   |
| oral and    |                 | but the delay was not                |
| dermal low  |                 | dose-dependent. The longest terminal |
| and high    |                 | half-life was observed in the high   |
| dose        |                 | dose single dermal application (100  |
| admin       |                 | mg/kg) which was 34.4 h. The lowest  |
| istration)- |                 | terminal half-life was observed in   |
| Rat         |                 | 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    | 46246344 (1990) | At no concentration up to cytotoxic  |
|             |                 | levels in either assay, however,     |
| Bacterial   | Accep           | were increases in revertants induced |
| reverse     | table/Guideline | by SXX 0665, compared to concurrent  |
| mutation    |                 | negative controls, or compared to    |
| test        |                 | the laboratory's historical control  |
|             |                 | data. Marked increases were induced  |
|             |                 | in all positive controls.            |
+-------------+-----------------+--------------------------------------+
| 870.5300    | 46246405 (1999) | SXX 0665 is considered non-mutagenic |
|             |                 | in the V79-HGPRT Forward Mutation    |
| In vitro    |                 | Assay.                               |
| mammalian   |                 |                                      |
| cell gene   |                 |                                      |
| mutation    |                 |                                      |
+-------------+-----------------+--------------------------------------+
| 870.5375    | 46246407 (1995) | SXX 0665 is considered to be         |
|             |                 | non-clastogenic in CHO cells up to   |
| In vitro    | Accep           | subcytotoxic concentrations.         |
| mammalian   | table/Guideline |                                      |
| chromosome  |                 |                                      |
| aberration  |                 |                                      |
| test        |                 |                                      |
+-------------+-----------------+--------------------------------------+
| 870.5395    | 64246410 (1993) | SXX 0665 is not considered to be a   |
|             |                 | clastogen or aneugen in mice at the  |
| Mammalian   | Accep           | i.p. administration of 350 mg/kg.    |
| erythrocyte | table/Guideline |                                      |
| m           |                 |                                      |
| icronucleus |                 |                                      |
| test        |                 |                                      |
+-------------+-----------------+--------------------------------------+
| 870.5550    | 46246414 (1992) | There was no evidence that UDS, as   |
|             |                 | determined by radioactive tracer     |
| Unscheduled | Accep           | procedures \[nuclear silver grain    |
| DNA         | table/Guideline | counts\], was induced.               |
| synthesis   |                 |                                      |
| in          |                 |                                      |
| mammalian   |                 |                                      |
| cells       |                 |                                      |
+-------------+-----------------+--------------------------------------+
| Special     | Number range    | Number range CHAPTERCurrently, the   |
| Study       | CHAPTER46246441 | only study where the ovary findings  |
|             | (2001)          | influence the study LOAEL is MRID    |
| Number      |                 | 46246430 (Krotlinger, 1992).         |
| range       | Acceptable/Non  | Although there is evidence that the  |
| CHAPTE      | Guideline       | ovary effects seen in this study are |
| RAssessment |                 | coincidental, the reviewers for this |
| of Ovarian  |                 | submission have decided to consider  |
| Findings in |                 | this effect treatment related. A     |
| Rodents     |                 | 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     | 46246437 (1991) | Number range CHAPTERThe incidences   |
| Study       |                 | of foci of altered hepatocytes (FAH) |
|             | Acceptab        | were slightly increased in males and |
| Number      | le/Nonguideline | females administered the test        |
| range       |                 | substance (980 ppm) for 6 weeks      |
| C           |                 | (groups 1 and 7) compared to their   |
| HAPTERLiver |                 | controls (groups 2 and 8). The       |
| Foci Study- |                 | incidence of FAH was slightly        |
| Rat         |                 | 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.4:        |                 |                                      |
| Toxicity    |                 |                                      |
| Profile for |                 |                                      |
| Prothi      |                 |                                      |
| oconazole - |                 |                                      |
| Sulfonic    |                 |                                      |
| Acid K Salt |                 |                                      |
| Technical** |                 |                                      |
+=============+=================+======================================+
| **Guideline | **MRID No.      | **Results**                          |
| No./ Study  | (year)/         |                                      |
| Type**      | Classification  |                                      |
|             | /Doses**        |                                      |
+-------------+-----------------+--------------------------------------+
| 870.3100    | 46246312 (2001) | NOAEL = 34.3/40.4 (M/F) mg/kg/day    |
|             |                 |                                      |
| 90-Day oral | 0, 30, 125,     | LOAEL = 135.9/163.0 (M/F) mg/Kg/day  |
| toxicity    | 500, 2000 ppm   | based on microscopic findings in the |
| rodents     |                 | ovary in females (cysts), and the    |
| (rat)       | 0, 2.1/2.6,     | urinary bladder (transitional cell   |
|             | 8.7/9.7,        | hyperplasia) and testes (focal       |
|             | 34.3/40.4,      | degeneration germinal epithelium) in |
|             | 135.9/163.0     | males.                               |
|             | (M/F) mg/kg/day |                                      |
|             |                 |                                      |
|             | Accep           |                                      |
|             | table/Guideline |                                      |
+-------------+-----------------+--------------------------------------+
| 870.3700a   | 46246318 (2001) | **Discussed in review of MRID        |
|             |                 | 46246234**                           |
| Prenatal    | 0, 30, 100,     |                                      |
| dev         | 500, 1000       | **Maternal Toxicity**                |
| elop-mental | mg/kg/day       |                                      |
| in rodents  |                 | NOAEL = 500 mg/kg/day                |
|             | Range finding   |                                      |
| (rat)       | study           | LOAEL = 1000 mg/kg/day               |
|             |                 |                                      |
|             | Acceptab        | based on decreased FC, BW, clinical  |
|             | le/Nonguideline | signs and high mortality.            |
|             |                 |                                      |
|             |                 | **Developmental Toxicity**           |
|             |                 |                                      |
|             |                 | NOAEL = \>1000 mg/kg/day             |
|             |                 |                                      |
|             |                 | LOAEL \> 1000 mg/kg/day              |
+-------------+-----------------+--------------------------------------+
| 870.3700a   | 46246324 (2001) | **Maternal Toxicity**                |
|             |                 |                                      |
| Prenatal    | 0, 30, 150, 750 | NOAEL = 150 mg/kg/day                |
| dev         | mg/kg/day       |                                      |
| elop-mental |                 | LOAEL = 750 mg/kg/day based on       |
| in rodents  | Accep           | clinical signs, decreased food       |
|             | table/Guideline | consumption, decreased body wt,      |
| (rat)       |                 | mortality                            |
|             |                 |                                      |
|             |                 | **Developmental Toxicity**           |
|             |                 |                                      |
|             |                 | NOAEL \< 30 mg/kg/day                |
|             |                 |                                      |
|             |                 | LOAEL ≤ 30 mg/kg/day based on        |
|             |                 | increased incidence of supernumerary |
|             |                 | one ribs.                            |
+-------------+-----------------+--------------------------------------+
| 870.5100    | 46246402 (2000) | No concentration in either assay did |
|             |                 | the test article significantly       |
| Bacterial   | Unaccep         | increased the number of revertants   |
| reverse     | table/Guideline | over negative control values.        |
| mutation    |                 | However, the spontaneous revertant   |
| test        |                 | counts of strain TA100 as well as    |
|             |                 | the response to the S9-activated     |
|             |                 | positive control were lower than     |
|             |                 | expected.                            |
+-------------+-----------------+--------------------------------------+

+-------------+-----------------+--------------------------------------+
| **Table     |                 |                                      |
| A.5:        |                 |                                      |
| Toxicity    |                 |                                      |
| Profile for |                 |                                      |
| Prothi      |                 |                                      |
| oconazole - |                 |                                      |
| Des-chloro  |                 |                                      |
| Technical** |                 |                                      |
+=============+=================+======================================+
| **Guideline | **MRID No.      | **Results**                          |
| No./ Study  | (year)/         |                                      |
| Type**      | Classification  |                                      |
|             | /Doses**        |                                      |
+-------------+-----------------+--------------------------------------+
| 870.3700a   | 46246317 (2002) | **Maternal Toxicity**                |
|             |                 |                                      |
| Prenatal    | 0, 40, 200,     | No NOAEL or LOAEL were established,  |
| dev         | 1000 mg/kg/day  | observations included decreased food |
| elop-mental |                 | consumption, body weight, body       |
| in rodents  | Acceptab        | weight gain                          |
| (rat)       | le/Nonguideline |                                      |
|             |                 | **Developmental Toxicity**           |
|             |                 |                                      |
|             |                 | No NOAEL or LOAEL were established,  |
|             |                 | observations included decreased      |
|             |                 | fetal wt, increased developmental    |
|             |                 | delays & structural abnormalities    |
+-------------+-----------------+--------------------------------------+
| 870.5100    | 46246345 (2003) | No evidence of mutagenicity          |
|             |                 | (increased revertants) was observed  |
| Bacterial   | Accep           | in either assay up to cytotoxic      |
| reverse     | table/Guideline | levels of the test substance.        |
| mutation    |                 | Therefore, 6476 Des-chloro is        |
| test        |                 | considered non-mutagenic in this     |
|             |                 | bacterial test system.               |
+-------------+-----------------+--------------------------------------+
| 870.5375    | 46246408 (2003) | JAU 6476 Des-Chloro is considered    |
|             |                 | non-clastogenic in this test system. |
| In vitro    | Accep           |                                      |
| mammalian   | table/Guideline |                                      |
| chromosome  |                 |                                      |
| aberration  |                 |                                      |
| test        |                 |                                      |
+-------------+-----------------+--------------------------------------+

+-------------+-----------------+--------------------------------------+
| **Table A.6 |                 |                                      |
| Su          |                 |                                      |
| pplemental: |                 |                                      |
| Toxicity    |                 |                                      |
| Profile for |                 |                                      |
| other       |                 |                                      |
| Prot        |                 |                                      |
| hioconazole |                 |                                      |
| me          |                 |                                      |
| tabolites** |                 |                                      |
+=============+=================+======================================+
| 870.5100    | 46246346 (2002) | JAU 6476-methyl is considered        |
|             |                 | nonmutagenic in this battery of *S.  |
| Bacterial   | JAU 6476-methyl | typhimurium* strains up to cytotoxic |
| reverse     |                 | levels.                              |
| mutation    | Accep           |                                      |
| test        | table/Guideline |                                      |
+-------------+-----------------+--------------------------------------+
| 870.5100    | 46246347 (2002) | The asymmetric isomer of JAU 6476 is |
|             |                 | considered nonmutagenic in this      |
| Bacterial   | JAU             | battery of *S. typhimurium* cultures |
| reverse     | 6               | up to cytotoxic concentrations.      |
| mutation    | 4760-asymmetric |                                      |
| test        | isomer          |                                      |
|             |                 |                                      |
|             | Accep           |                                      |
|             | table/Guideline |                                      |
+-------------+-----------------+--------------------------------------+
| 870.5100    | 46246348 (2001) | JAU 6476-asymmetric disulfide does   |
|             |                 | not induce reverse mutation in this  |
| Bacterial   | JAU             | bacterial test system up to          |
| reverse     | 6476-asymmetric | cytotoxic concentrations.            |
| mutation    | disulfide       |                                      |
| test        |                 |                                      |
|             | Accep           |                                      |
|             | table/Guideline |                                      |
+-------------+-----------------+--------------------------------------+
| 870.5100    | 46246349 (2000) | The alpha-hydroxy-desthio derivative |
|             |                 | of JAU 6476 is considered            |
| Bacterial   | JAU6476-alpha-  | non-mutagenic in this bacterial test |
| reverse     | hydroxy-desthio | system up to the cytotoxic/limit     |
| mutation    |                 | concentration.                       |
| test        | Accep           |                                      |
|             | table/Guideline |                                      |
+-------------+-----------------+--------------------------------------+
| 870.5100    | 46246350 (2000) | JAU 6476-triazolinone is considered  |
|             |                 | nonmutagenic in this *S.             |
| Bacterial   | JAU             | typhimurium* test system.            |
| reverse     | 64              |                                      |
| mutation    | 76-triazolinone |                                      |
| test        |                 |                                      |
|             | Accep           |                                      |
|             | table/Guideline |                                      |
+-------------+-----------------+--------------------------------------+
| 870.5100    | 46246401 (2000) | JAU 6476-alpha-acetoxy-desthio is    |
|             |                 | considered non-mutagenic in this     |
| Bacterial   | JAU-6476-alpha- | bacterial test system.               |
| reverse     | acetoxy-desthio |                                      |
| mutation    |                 |                                      |
| test        | Accep           |                                      |
|             | table/Guideline |                                      |
+-------------+-----------------+--------------------------------------+
| 870.5100    | 46246403 (2000) | JAU 6476-Benzylpropyldiol does not   |
|             |                 | induce reverse mutation in this      |
| Bacterial   | JAU-6476-b      | bacterial test system up to          |
| reverse     | enzylpropyldiol | cytotoxic concentrations.            |
| mutation    |                 |                                      |
| test        |                 |                                      |
+-------------+-----------------+--------------------------------------+