UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

Date: December 31, 2007

MEMORANDUM

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-dihyd
ro-3H-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

  TOC \f  1.0	Executive Summary	  PAGEREF _Toc187567037 \h  5

2.0	Ingredient Profile	  PAGEREF _Toc187567038 \h  14

2.1	Summary of Registered/Proposed Uses	  PAGEREF _Toc187567039 \h  15

2.2	Structure and Nomenclature	  PAGEREF _Toc187567040 \h  19

2.3	Physical and Chemical Properties	  PAGEREF _Toc187567041 \h  19

3.0	Hazard Characterization/Assessment	  PAGEREF _Toc187567042 \h  20

3.1	Hazard and Dose-Response Characterization	  PAGEREF _Toc187567043 \h
 20

3.1.1	Database Summary	  PAGEREF _Toc187567044 \h  20

3.1.2	Toxicological Effects	  PAGEREF _Toc187567045 \h  21

3.1.3	Dose-response	  PAGEREF _Toc187567046 \h  22

3.1.4	FQPA	  PAGEREF _Toc187567047 \h  23

3.2	Hazard Identification and Toxicity Endpoint Selection	  PAGEREF
_Toc187567048 \h  24

3.2.1	Summary of Dose Response and Endpoint Selection	  PAGEREF
_Toc187567049 \h  24

3.2.2	Level of Concern for Margin of Exposure	  PAGEREF _Toc187567050 \h
 25

3.2.3	Recommendation for Aggregate Exposure Risk Assessments	  PAGEREF
_Toc187567051 \h  25

3.2.4	Classification of Carcinogenic Potential	  PAGEREF _Toc187567052
\h  26

3.2.5	Summary of Toxicological Doses and Endpoints for Prothioconazole
for Use in Human Risk Assessments	  PAGEREF _Toc187567053 \h  26

3.3	Endocrine disruption	  PAGEREF _Toc187567054 \h  27

4.0	Dietary Exposure/Risk Characterization	  PAGEREF _Toc187567055 \h
28

4.1 Pesticide Metabolism and Environmental Degradation	  PAGEREF
_Toc187567056 \h  28

4.1.1	Metabolism in Primary Crops	  PAGEREF _Toc187567057 \h  28

4.1.2	Metabolism in Rotational Crops	  PAGEREF _Toc187567058 \h  29

4.1.3	Metabolism in Livestock	  PAGEREF _Toc187567059 \h  29

4.1.4	Analytical Methodology	  PAGEREF _Toc187567060 \h  30

4.1.5	Storage Stability Data	  PAGEREF _Toc187567061 \h  31

4.1.6	Magnitude of the Residue in Plants	  PAGEREF _Toc187567062 \h  32

4.1.7	Magnitude of the Residue in Processed Food/Feed	  PAGEREF
_Toc187567063 \h  35

4.1.8	Magnitude of the Residue in Meat, Milk, Poultry, and Eggs
PAGEREF _Toc187567064 \h  36

4.1.9	Confined and Field Rotational Accumulation in Rotational Crops
PAGEREF _Toc187567065 \h  39

4.1.10	Drinking Water Residue Profile	  PAGEREF _Toc187567066 \h  40

4.1.11	Proposed Tolerances	  PAGEREF _Toc187567067 \h  41

4.1.12	International Residue Limits (IRL)	  PAGEREF _Toc187567068 \h  43

4.2  Dietary Exposure and Risk	  PAGEREF _Toc187567069 \h  43

4.2.1  Acute Dietary Exposure/Risk	  PAGEREF _Toc187567070 \h  46

4.2.2  Chronic Dietary Exposure/Risk	  PAGEREF _Toc187567071 \h  47

4.2.3  Cancer Dietary Risk	  PAGEREF _Toc187567072 \h  49

5.0	Residential (Non-Occupational) Exposure/Risk Characterization
PAGEREF _Toc187567073 \h  49

6.0	Aggregate Risk Assessments and Risk Characterization	  PAGEREF
_Toc187567074 \h  49

7.0	Cumulative Risk Characterization/Assessment	  PAGEREF _Toc187567075
\h  49

8.0	Occupational Exposure/Risk Pathway	  PAGEREF _Toc187567076 \h  50

8.1	Short-/Intermediate-Term Handler Risk	  PAGEREF _Toc187567077 \h  51

8.2	Short-/Intermediate-Term Postapplication Risk	  PAGEREF
_Toc187567078 \h  54

9.0	Data Needs and Label Requirements	  PAGEREF _Toc187567079 \h  58

9.1	Toxicology	  PAGEREF _Toc187567080 \h  58

9.2	Residue Chemistry	  PAGEREF _Toc187567081 \h  58

9.3	Occupational Exposure	  PAGEREF _Toc187567082 \h  59

9.4	Triazole Data Requirements	  PAGEREF _Toc187567083 \h  60

References:	  PAGEREF _Toc187567084 \h  61

Appendix A:  Toxicology Assessment	  PAGEREF _Toc187567085 \h  63

A.  Toxicity Profiles	  PAGEREF _Toc187567086 \h  63

1.0	Executive Summary  TC \l1 "1.0	Executive Summary

Prothioconazole,
2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl-2-hydroxypropyl]-1,2-dihydr
o-3H-1,2,4-triazole-3-thione, is a 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 D2, 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-dihyd
ro-3H-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.

) 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

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

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

The available 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

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 KOCs (soil organic carbon-water partitioning coefficients) for
prothioconazole-desthio and prothioconazole-S-methyl.   The lower bound
EDWCs represent the exclusion of unextracted residues and the use of the
higher Koc (i.e. less mobility).  Conversely, the higher bound estimates
represent the inclusion of unextracted residues and the use of the lower
Koc (i.e. less mobility).  Any concern about the uncertainties of any
bound residues or differences in Koc values are adequately addressed by
regulating and relying upon the upper bound EDWCs in the dietary risk
assessment.

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

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

Dietary/Aggregate Exposure/Risk Assessment

Acute and chronic dietary risk assessments were conducted using the
Dietary Exposure Evaluation Model (DEEM-FCID™, Version 2.03), which
used food consumption data from the U.S. Department of Agriculture’s
Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996
and 1998. The analyses were performed to support the registration of 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 95th 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 95th
percentile.  The exposure for food and upper bound drinking water
estimates utilized 76% of the aPAD at the 95th 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

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, PROVOSTTM 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

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:

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

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

860.1550 Proposed Tolerances

•	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, the revised Section F should reflect the
recommended tolerances and commodity definitions presented in Table
4.1.9.

Recommendations for Labels

•	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,"   HYPERLINK
"http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf"
http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

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

Review of Human Research

This risk assessment relies in part on data from 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   TC \l1 "2.0	Ingredient Profile

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

  SEQ CHAPTER \h \r 1 Table 2.1.  Prothioconazole End-Use Products.

Trade Name	EPA Reg. No.	ai (% of formulation)	Formulation Type	Target
Crops	Target Pests	Use Directions and Limitations

PROLINE® 480 SC Fungicide	264-IEL	41%

2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2-dihyd
ro-3H-1,2,4-triazole-3-thione	Soluble concentrate (SC)	Barley, oilseed
(except sunflower and safflower) crop group, dried shelled pea and bean
(except soybean) subgroup, peanut, soybean, sugar beet, and wheat.	Broad
spectrum systemic fungicide for the control of Ascomycetes,
Basidiomycetes, and Deuteromycetes diseases	Applications may be made
alone or as a tank mix with other fungicides, insecticides, or
herbicides.  To optimize disease control, the lowest labeled rate of
spray surfactant should be tank-mixed with PROLINE ® 480 SC Fungicide.
Application through any type of irrigation system is prohibited.  For
crops not listed on this label, do not plant back within 30 days of last
application. REI – 24 hours

PROVOSTTM 433 SC Fungicide	264-IAR	12.9%

(also contains 25.8% tebuconazole)	SC	Peanuts and soybeans

Provides control or suppression of many important diseases.  When
reference is made to disease 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 0728 325 SC Fungicide	264-XXX	16.0%

(also contains 13.7% trifloxystrobin trifloxystrobin)	SC	Sugar beets
Broad spectrum fungicide, that provides control or suppression of
several important diseases of sugar beets (e.g., Cercospora Leaf Spot,
Powdery Mildew, Rhizoctonia Stem Canker, Crown Rot). 	Provides control
or suppression of many important diseases.  When reference is made to
disease 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. Contains both Group 11 and
Group 3 fungicides.  To limit the potential for development of disease
resistance: alternate each application with at least one application of
a fungicide from a different fungicide group. REI – 12 Hours

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

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 D2, 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, PROVOSTTM 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 Directions for Proposed Uses of Prothioconazole.

Application Timing, Type and Equipment	Trade Name

	Max. Single rate

(lb ai/A)	Max. number of Appl. per Season	Max. Seasonal Application Rate
(lb ai/A)	PHI

(Days)	Use Directions and Limitations

Soybean

Postemergence;

Broadcast foliar;

Provost™ 433 SC Fungicide	0.028	3	0.402	21

	Sugar Beet

Postemergence;

Broadcast foliar or Banded;

Ground and aerial	Proline® 480 SC Fungicide	0.134-0.178	3	0.534	7	For
foliar disease: apply at the first sign of disease, and use higher use
rate and shorter intervals when conditions are favorable for severe
disease pressure and/or 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   SEQ CHAPTER \h \r 1 14- 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 0728 325 SC Fungicide	0.093-0.128	3	0.530	21

Table 2.3.	Summary of Directions for Existing Uses of Prothioconazole

Appl. Type, and Equip.	Appl. Rate

(lb ai/A)

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

(days)	Max. Seasonal Appl. Rate

(lb ai/A)

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

Barley (for Fusarium Head Blight)

Broadcast foliar spray;

Ground or aerial	0.13 -0.18

[4.3 - 5.7]	2	7 to 14	0.29

[9.4]	32	Apply as a preventative foliar spray within the time period
when 70 to 100% of the barley heads on the main stem are fully emerged
when weather conditions are favorable for disease development and up to
3 to 5 days after full head emergence.  Spray equipment must be set up
to provide good coverage to barley heads (using ground application
equipment, use forward and backward mounted nozzles or nozzles with a
two-directional spray).

Barley (for Leaf and Stem Diseases)

Broadcast foliar spray;

Ground or aerial	0.088 – 0.13

[2.8 - 4.3]	2	7 to 14	0.27

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

Canola

Broadcast foliar spray;

Ground or aerial	0.13 -0.18

[4.3 - 5.7]	2	5 to 7	0.36

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

Chickpea

Broadcast foliar spray;

Ground or aerial	0.13 -0.18

[4.3 - 5.7]	3	10 to 14	0.53

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

Dried Shelled Peas and Beans Subgroup

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

Broadcast foliar spray;

Ground or aerial	0.13 -0.18

[4.3 – 5.7]	3	5 to 14	0.53

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

Lentils

Broadcast foliar spray;

Ground or aerial	0.13 -0.18

[4.3 – 5.7]	3	10 to 14	0.53

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

Oilseed Crop Subgroup

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

Broadcast foliar spray;

Ground or aerial	0.134 -0.178

[4.3 – 5.7]	2	5 to 7	0.356

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

Peanut

Broadcast foliar spray;

Ground or aerial	0.16 -0.18

[5.0 – 5.7, PROLINE]

0.038-0.10

 [4.0 – 10.7, PROVOST]	4	14 to 21	0.71

[22.8, PROLINE]

0.40

[42.8, PROVOST]	14	Soil Borne disease: Utilize the high use rate.  Make
four consecutive applications at 14 day intervals.  In a typical 7 spray
application, the formulation should be applied for sprays 3, 4, 5 and 6.
 For control of soil-borne diseases when using a Leaf Spot Advisory
Program schedule, begin in July and continue at 14 day intervals.  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)

Broadcast foliar spray;

Ground or aerial	0.13 -0.18

[4.3 – 5.7]	2	7 to 14	0.29

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

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

Broadcast foliar spray;

Ground or aerial	0.13 -0.16

[4.3 - 5.0]	2	7 to 14	0.29

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

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

Table 2.4.  Prothioconazole Nomenclature.

Chemical structure of prothioconazole

Empirical Formula	C14H15Cl2N3OS

Common name	Prothioconazole

Company experimental name	JAU 6476

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

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

CAS registry number	178928-70-6

End-use product/EP	PROLINE ® 480 SC Fungicide

Chemical Class	Triazolinthione

Known Impurities of Concern	None

Table 2.5.	Prothioconazole-Desthio Nomenclature

Chemical Structure

Company experimental name	JAU 6476-desthio (SXX 0665)

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

Table 2.6.  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 200C)	1.36 (pure active ingredient)	MRID 46246003

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

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

0.3  pH 8 buffer at 20 °C

2.0  pH 9 Buffer at 20 °C	MRID 46246003

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

acetone	>250

acetonitrile	10-100

dichloromethane	100-250

dimethylsulfoxide	100-250

ethyl acetate	<250

n-heptane	<0.1

1-octanol	10-100

polyethylene glycol	>250

2-propanol	10-100

xylene	1-10	MRID 46246003

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

Dissociation constant, pKa	6.9	MRID 46246003

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

unbuffered: Kow = 11300; log Kow = 4.05

pH 4: Kow = 14600; log = 4.16

pH 7: Kow = 6600; log = 3.82

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

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

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

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

3.1.1	Database Summary  TC \l3 "3.1.1	Database Summary

The toxicology database for prothioconazole 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  TC \l3 "3.1.2	Toxicological Effects

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

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

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

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

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

Developmental Toxicity:  The data indicated that prothioconazole and the
three metabolites evaluated (i.e., prothioconazole-desthio,
prothioconazole sulfonic acid potassium salt, and
prothioconazole-deschloro) can be primary developmental toxicants,
producing effects including malformations in the conceptus at levels
equal to or below maternally toxic levels in some studies, particularly
those studies  conducted using prothioconazole-desthio.
Prothioconazole-desthio is the most toxic orally 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  TC \l3 "3.1.3	Dose-response

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

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

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

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

Study	NOAEL

mg/kg/day	LOAEL

mg/kg/day	Toxic Effects	Comment

Developmental Toxicity – Rat

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

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

Developmental Toxicity – Rabbit

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

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

Developmental Neurotoxicity – Rat

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

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

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

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

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

The weight of evidence evaluation of these toxic effects and the doses
selected for risk assessment 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  TC \l3 "3.1.4	FQPA

There are adequate data in the prothioconazole (including metabolites)
database to characterize the potential for pre-natal or post-natal risks
to infants and children: two-generation reproduction studies in rats;
developmental studies in rats and rabbits; and a developmental
neurotoxicity study in rats.  The effects seen in these studies suggest
that pups are more susceptible: pup effects were seen at levels below
the LOAELs for maternal toxicity and, in general, were of comparable or
greater severity compared to the effects observed in adults.  In
addition, since the developmental effects seen in the developmental
neurotoxicity (DNT) study were investigated at the high dose level only,
there is uncertainty concerning the LOAEL/NOAEL for developmental
effects in this study.  Thus, the FQPA factor is retained at 10X (see
Section 3.3 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  TC \l2 "3.2
Hazard Identification and Toxicity Endpoint Selection

3.2.1.	Summary of Dose Response and Endpoint Selection  TC \l3 "3.2.1
Summary of Dose Response and Endpoint Selection

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

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

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

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

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

3.2.2	Level of Concern for Margin of Exposure  TC \l3 "3.2.2	Level of
Concern for Margin of Exposure

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

Table 3.2.2 Summary of Levels of Concern for Risk Assessment.

Route

Short-Term

(1 - 30 Days)

Intermediate-Term

(1 - 6 Months)

 Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal

1000

1000

None

Inhalation

1000

1000

None

Residential Exposure

Dermal or Inhalation

None

None

None

Occupational exposure:  Dermal and Inhalation: Based on the conventional
uncertainty factor of 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:  None expected.

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

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/MOEinhalation))] is be used to combine dermal and inhalation risks.

3.2.4	Classification of Carcinogenic Potential  TC \l3 "3.2.4
Classification of Carcinogenic Potential

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

3.2.5	Summary Tables of Toxicological Doses and Endpoints for
Prothioconazole for Use in Human Risk Assessments  TC \l3 "3.2.5	Summary
of Toxicological Doses and Endpoints for Prothioconazole for Use in
Human Risk Assessments

Table <IP_ADDRESS>  Summary of Toxicological Doses and Endpoints for
Prothioconazole desthio for Use in Dietary and Non-Occupational Human
Health Risk Assessments

Exposure/

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

Acute Dietary (Females 13 – 49)	NOAEL = 2.0 mg/kg/day	UFA=10x

UFH=10x

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

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

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

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

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

UFH=10x

FQPA SF=10x (UFDB)	Chronic RfD =

0.001 mg/kg/day

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

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

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

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

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

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

	Inhalation endpoints are not applicable because residential exposure is
not anticipated

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

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

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

Table <IP_ADDRESS>  Summary of Toxicological Doses and Endpoints for
Prothioconazole desthio for Use in Occupational Human Health Risk
Assessments

Exposure/

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

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

	UFA=10x

UFH=10x

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

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

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

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

UFH=10x

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

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

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

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

3.3	Endocrine disruption  TC \l2 "3.3	Endocrine disruption

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

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

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

4.1	Pesticide Metabolism and Environmental Degradation  TC \l2 "4.1
Pesticide Metabolism and Environmental Degradation

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  TC \l3 "4.1.1	Metabolism in Primary
Crops

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.

Conclusions:  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  TC \l3 "4.1.2	Metabolism in
Rotational Crops

Bayer CropScience previously submitted t  SEQ CHAPTER \h \r 1 wo
confined rotational crop studies to support the proposed uses, one
conducted using [phenyl-14C]-prothioconazole (MRID 46246225) and one
conducted using [triazole-14C]-prothioconazole (MRID 46246226).
Additionally, a limited field rotational crop study (MRID 46246227) on
the representative crops mustard greens (leafy vegetable), turnip (root
vegetable), and wheat (cereal grain) was 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  TC \l3 "4.1.3	Metabolism in Livestock

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  TC \l3 "4.1.4	Analytical Methodology

  SEQ CHAPTER \h \r 1 Residue Chemistry Memo DP# 318440, 7/30/07, P.
Schermerhorn (TMV Report)

  SEQ CHAPTER \h \r 1 Residue 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

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 TC \l3 "4.1.5	Storage Stability Data

Plant commodities

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.

ively 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

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.

4.1.6	Magnitude of the Residue in Plants TC \l3 "4.1.6	Magnitude of the
Residue in Plants

Soybean

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 4.1.1.  Summary of Residue Data from Soybean Field Trials with
Prothioconazole.

Matrix

Total Rate

(lb ai/A)

PHI (days)

Residues (ppm)

N

Min.

Max.

HAFT

Median (STMdR)

Mean (STMR)

st™).  A 21-day preharvest interval (PHI) is proposed for both
products.

Total Prothioconazole-Derived Residues

Forage	0.391-0.449	5-7	42	<0.05	4.45	4.25	1.37	1.39	0.95

Hay

5-7	42	1.46	18.9	18.3	5.56	5.97	3.36

Seed	0.393-0.413	19-23	42	<0.05	0.142	0.12	0.05	0.05	0.02

1,2,4-Triazole Residues

Forage	0.391-0.449	5-7	21	<0.01	0.01	NA	0.01	0.01	0.00

Hay

5-7	21	<0.01	0.01	NA	0.01	0.01	0.00

Seed	0.393-0.413	19-23	8	<0.01	<0.01	<0.01	<0.01	<0.01	0.00

Triazole Conjugate Residues

Forage	0.391-0.449	5-7	21	<0.05	0.27	NA	0.06	0.08	0.06

Hay

5-7	21	0.04	0.40	NA	0.17	0.15	0.09

Seed	0.393-0.413	19-23	8	0.04	0.08	0.08	0.06	0.06	0.01

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

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 4.1.2.  Summary of Residue Data for Sugar Beet Field Trials with
Prothioconazole.

Matrix	Total Rate

(lb ai/A) 	PHI (days)	Residues (ppm)

	n	Min.	Max.	HAFT	Median (STMdR)	Mean (STMR)	Std. Dev.

Proposed use pattern:  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).

Total Prothioconazole-Derived Residues

Tops	0.529-

0.548	6-7	24	0.39	4.18	3.87	1.64	1.80	1.17

13-14	24	0.20	1.97	1.75	1.04	1.03	0.60

Roots

6-7	24	<0.05	0.24	0.17	0.05	0.07	0.05

13-14	24	<0.05	0.14	0.11	0.05	0.07	0.06

1,2,4-Triazole Residues

Tops	0.529-

0.548	6-7	12	<0.01	<0.01	<0.01	<0.01	<0.01	--

13-14	12	<0.01	<0.01	<0.01	<0.01	<0.01	--

Roots

6-7	12	<0.01	0.012	<0.011	<0.01	<0.01	0.001

13-14	12	<0.01	<0.01	<0.01	<0.01	<0.01	--

Triazole Conjugate Residues

Tops	0.529-

0.548	6-7	12	<0.01	0.018	0.018	0.01	0.012	0.003

13-14	12	<0.01	0.021	0.021	0.01	0.012	0.004

Roots

6-7	12	<0.01	0.014	0.014	0.01	0.011	0.002

13-14	12	<0.01	0.017	0.017	0.012	0.013	0.003

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  TC \l3 "4.1.7
Magnitude of the Residue in Processed Food/Feed

Soybean

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.

  SEQ CHAPTER \h \r 1 Table 4.1.3.  Summary of Processing Factors for
Prothioconazole from the Soybean Study.

RAC	Processed Commodity	Average Processing Factor 1

Prothioconazole	1,24-Triazole	Total Triazole Conjugates 2

Soybean	Aspirated grain fractions	76x	>1.3x	2.1x

	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).

Conclusions:  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

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.

  SEQ CHAPTER \h \r 1 Table 4.1.4.  Summary of Processing Factors for
Prothioconazole from the Sugar Beet Study.

RAC	Processed Commodity	Average 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).

Conclusions:  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 TC \l3
"4.1.8	Magnitude of the Residue in Meat, Milk, Poultry, and Eggs

  SEQ CHAPTER \h \r 1 Residue Chemistry Memo DP#s 303508 & 314517,
8/21/06, S. Funk (PP#4F6830)

Livestock dietary burdens

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	Type1	% Dry Matter2	% Diet2	Recommended/

Established

Tolerance (ppm)	Dietary Contribution (ppm)3

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 fractions	CC	85	5	11.0	0.65

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

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

  SEQ CHAPTER \h \r 1 Residue 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 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.

Matrix

	Residues (ppm)

	9.9 ppm	29.5 ppm	98.4 ppm

	A	B	C	A	B	C	A	B	C

Milk

(day 29)	--	--	--	<0.005	<0.005	<0.005	<0.005	<0.005	<0.005

Skim milk	--	--	--	--	--	--	<0.01	<0.01	<0.01

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

Fat	<0.05	<0.05	<0.05	<0.05

(0.019)1	<0.05

(≈0.003)1	<0.05

(≈0.006)1	0.062	<0.05	<0.05

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

Liver	0.063	<0.01	0.054	0.120	0.011	0.181	0.467	0.030	0.518

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

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 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 are required.

4.1.9	Confined and Field Rotational Accumulation in Rotational Crops  TC
\l3 "4.1.9	Confined and Field Rotational Accumulation in Rotational
Crops

  SEQ CHAPTER \h \r 1 Residue 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 TC \l3 "4.1.10	Drinking Water
Residue Profile

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
KOCs (soil organic carbon-water partitioning coefficients) for
prothioconazole-desthio and prothioconazole-S-methyl.   The lower bound
EDWCs represent the exclusion of unextracted residues and the use of the
higher Koc (less mobility).  Conversely, the higher bound estimates
represent the inclusion of unextracted residues and the use of the lower
Koc (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 SOURCE            (MODEL USED)	USE SCENARIO       (rate
modeled)	ESTIMATED DRINKING WATER CONCENTRATION  ( ppb)

ACUTE	CHRONIC

Lower Bound	Upper Bound	Lower Bound	Upper Bound

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

	Sugar Beet	--	--	8.4	13

4.1.11	Proposed Tolerances TC \l3 "4.1.11	Proposed Tolerances

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.

e-desthio,
α-(1-chlorocyclopropyl)-α-[(2-chlorophenyl)methyl]-1H-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 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 Tolerance (ppm)	Recommended Tolerance (ppm)	Comments;
Correct Commodity Definition

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) TC \l3 "4.1.12	International
Residue Limits (IRL)

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 TC \l2 "4.2  Dietary Exposure and Risk

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

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

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

Dietary Assessment of Free Triazole and its Conjugates

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:

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.

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.

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

Empirical factors generated in processing studies were also included
when appropriate in the acute and chronic assessments.  Reduction
factors were used for canola refined oil, 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  TC \l3 "4.2.1  Acute Dietary
Exposure/Risk

A moderately refined acute dietary exposure assessment was conducted for
prothioconazole.  Average field trial values, empirical processing
factors, and livestock maximum residues were incorporated into the
refined acute assessment.  The assessment also assumed 100% CT.  No
acute endpoint was identified for the general U.S. population; females
13-49 years of age was the only population subgroup included in the
acute assessment.  Dietary risk estimates were determined considering
exposures from food alone and food plus water using 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 95th 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 95th 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 95th percentile (see Table 4.2.2).

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

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

Females 13-49 years old 	0.002	0.000167	8.4

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

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

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

Females 13-49 years old 	0.002	0.000737	37	0.001518	76

4.2.2	Chronic Dietary Exposure/Risk  TC \l3 "4.2.2  Chronic Dietary
Exposure/Risk

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 (mg/kg/day)	Refined Assessment

Exposure (mg/kg/day)	% cPAD

General U.S. Population	0.0011	0.000105	9.5

All Infants (< 1 year old)	0.0011	0.000132	12

Children 1-2 years old	0.0011	0.000338	31

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

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

General U.S. Population	0.0011	0.000282	26	0.000379	34

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

Children 1-2 years old	0.0011	0.000601	55	0.000745	68

Children 3-5 years old	0.0011	0.000521	47	0.000656	60

Children 6-12 years old	0.0011	0.000350	32	0.000443	40

Youth 13-19 years old	0.0011	0.000223	20	0.000294	27

Adults 20-49 years old	0.0011	0.000242	22	0.000333	30

Adults 50+ years old	0.0011	0.000238	22	0.000334	30

Females 13-49 years old 	0.0011	0.000234	21	0.000325	30

4.2.3	Cancer Dietary Risk  TC \l3 "4.2.3  Cancer Dietary Risk

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

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

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

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

In accordance with the FQPA, HED must consider and aggregate (add)