The LOAEL is 100 mg/kg bw/day for males and females, based on increased
cholesterol levels and increased liver enzyme activity in females,
increased liver weights in both sexes, and increased incidence of
hepatocellular hypertrophy and cytoplasmic change in the liver of both
sexes.  The NOAEL is 25 mg/kg bw/day for male and females.

This subchronic toxicity study in the mouse is acceptable and satisfies
the guideline requirement for a subchronic oral study (OPPTS 870.3100;
OECD 408) in mice.  This review is a joint effort of the PMRA and the
EPA.

		Prothioconazole-desthio

				In a range-finding subchronic toxicity study (MRID  46246310), SXX
0665 (93.1% a.i.) was administered to 10 B6C3F1 mice/sex/dose in diet
(1% peanut oil) at dose levels of 0, 40, 200, 1000 or 5000 ppm (0/0,
11.5/16.0, 58.9/79.5, 294.0/392.3 or 1454/2073 mg/kg bw/day for
males/females- with 5000 ppm equivalent calculated by reviewer using
approximate food consumption values from the 1000 ppm group) for 13
weeks.

≥200 ppm (10-14% at 200 ppm & 73-85% at 1000 ppm) and in females at
1000 ppm (42-45%). Gross pathology revealed accentuated lobulation of
the liver in the 1000 ppm males (100% vs. 0% controls) and
histopathology revealed periacinar hepatocytic fatty vacuolation in
males at doses ≥1000 ppm (80% vs. 0% controls).  Single cell necrosis
was increased in both sexes: 60% for males at 5000 ppm; 30, 40, & 70%
for females at doses 200, 1000, & 5000 ppm.  Apoptosis was increased in
both sexes at 5000 ppm, 60% for males and 20% for females.  Increase
incidences of hepatocellular hypertrophy were seen in males treated at
200 & 1000 ppm (100% in both groups vs. 0% for controls) and in females
treated at 40, 200, and 1000 ppm (70, 80, and 100% respectively vs. 0%
for controls).  In addition, increased ploidy was observed in the livers
of males at 5000 ppm (40% vs. 0% controls).

In males, treatment-related decreases in erythrocytes (12%) were
observed at 1000 ppm, along with decreased (14%) hematocrit and platelet
count and increases (13-15%) in mean corpuscular hemoglobin (MCH) and
mean corpuscular hemoglobin concentration (MCHC).  Leucocytes were
decreased at 1000 ppm in males (34%).

≥200 ppm.

At 5000 ppm (the dose at which animals died or had to be killed within
one week of treatment), abnormal contents in the caecum, colon,
duodenum, jejunum and rectum, as well as increased emaciation was
observed in the males and females.  In the stomach of one male and three
females, changed areas on the glandular mucosa of the stomach were
noted.

The LOAEL is 40 ppm (11.5/ 16.0 mg/kg/bw) based on decreased body weight
gain in both sexes.  The NOAEL is < 40 ppm (11.5/ 16.0 mg/kg/bw).

This range-finding subchronic toxicity study in the mouse is an
acceptable/non-guideline subchronic oral study in the mouse.  This
review is a joint effort of the PMRA and the EPA.

	870.3150	90-Day Oral Toxicity - Dog

		Prothioconazole

				In a subchronic toxicity study (MRID 46246435) JAU 6476 (Purity
98.1-98.8%) was administered to 4 beagle dogs/sex/dose, by gavage (in
aqueous 0.5% methylcellulose/0.4% Tween 80), at dose levels of 0, 25,
100 and 300 mg/kg bw/day.  The test compound was administered for 13
weeks (all doses) with a 4 week recovery period using the 0 and 300
mg/kg bw/day groups only.  The purpose of this non-guideline study was
to examine hepatic and renal enzyme activities in dogs following a 13
week administration of JAU 6476.

In males, no significant treatment-related effects on phase I or phase
II liver enzyme activities were observed following treatment for 13
weeks.  In females, only epoxide hydrolase (EH) activity was
significantly increased at 100 (↑58%) and 300 (↑85%) mg/kg bw/day
compared to control.  Following a 4 week recovery period, no significant
differences in enzyme activities were noted in either sex and the values
were comparable to controls.

↓36%) at 300 mg/kg bw/day.  No significant effects were observed in
females after 13 weeks.  Following a 4 week recovery period, no
significant differences in enzyme activities were noted in either sex
and the values were comparable to controls.

Tissue concentrations of JAU 6476 and SXX 0665 were measured in the high
dose group only.  In the liver, the tissue concentration ratio of JAU
6476 to the SXX 0665 metabolite was approximately 10:1.  In kidney, the
SXX 0665 metabolite was undetectable. The concentration of JAU 6476 was
approximately 3-fold higher in females in both tissues.

This subchronic toxicity study in the dog is acceptable as a
supplemental study only as many of the guideline requirements for a
subchronic oral study (OPPTS 870.3150; OECD 409) in dogs have not been
addressed in this study.  This review is a joint effort of the PMRA and
the EPA.

________

				In a subchronic toxicity study (MRID 46246313) JAU 6476 (Purity:
98.1-98.8%; Batch No. 6233/0031) was administered to 48 Beagle dogs
(4/sex/dose by gavage 5 days/week at dose levels of 0, 25,100, and 300
mg/kg bw/day) with a recovery group dosed at 300 mg/kg/day (8-week
recovery period). The vehicle used was 0.5% methyl cellulose with 0.4%
Tween 80 in deionized water.  All animals were treated for a total of 90
days.

There were no compound related effects on mortality, clinical
observations, blood pressure and ECG parameters, hematology,
ophthalmology and neurology. No treatment related changes were seen in
urinalysis or organ weights in any dose group. No treatment related
differences were seen in the hepatic metabolizing enzyme activity
including cytochrome P-450, N-demethylase (NDEM), O-demethylase (ODEM)
or glucuronyltransferase at study termination.

Overall body weight gain was decreased in the high dose (treated and
recovery) males and (recovery) females.  There were several clinical
chemistry parameters related to liver function (ALT, ALP, GGT) which
were elevated in both sexes but particularly females in the 100 and/or
300 mg/kg groups with subtle changes persisting in 300 mg/kg recovery
males at study termination. Additionally, there were subtle decreases in
T4 and TSH suggesting minimal thyroid effects in the 100 and 300 mg/kg
groups.

Compound-related gross lesions were seen in the kidneys of several
animals of the 300 mg/kg dose group.  Target organ micropathology was
seen in the kidney of both sexes. The kidney changes present in males
and females of the 100 and 300 mg/kg groups were characterized by
multifocal chronic interstitial fibrosis with associated tubular
regeneration and minimal inflammatory cell infiltrate. These morphologic
chronic, focal to multi focal renal changes were not completely
reversible as evidenced by their presence in the 300 mg/kg recovery
group animals. In 300 mg/kg males, a proximal renal tubular degeneration
was also present. Significant increases in the relative organ weights of
liver, kidney and thymus were seen in the 300 mg/kg female group.

The NOAEL in beagle dogs was 25 mg/kg/day. The LOAEL was based on kidney
(histopathological) and thyroid (T4 and TSH) findings at 100 mg/kg.

This subchronic toxicity study in the dog is acceptable and satisfies
the guideline requirement for a subchronic oral study (OPPTS 870.3150;
OECD 409) in dogs.  This review is a joint effort of the PMRA and the
EPA.

		Prothioconazole-desthio

				In a subchronic toxicity study (MRID 46246314), SXX 0665 (94.3%
a.i.; Batch No. 1717008/90) was administered to 4 Beagle dogs/sex/dose
in diet at dose levels of 0, 40, 200 or 1000 ppm (0, 1.58, 7.81 or 37.79
and 0, 1.62, 8.53 or 42.75 mg/kg bw/day for males and females,
respectively) for 90 days.

There was no mortality and no treatment-related clinical observations.
There were no treatment-related changes in body weight, body weight gain
and food consumption.  Liver weights (absolute and relative) were
increased at 1000 ppm in females.  The increased liver weights
correlates with an increase in enzyme induction at this dose. These
liver changes are considered an adaptive response and not adverse. There
was an increase in partial thromboplastin time in the 1000 ppm females
at the end of the study.  N- demethylase and O-demethylase activities in
liver homogenates were increased in both sexes and cytochrome P450
enzyme activities were increased in males.  Cytoplasmic change in the
liver was noted in 3/4 males and 4/4 females at 1000 ppm.

There were no significant treatment-related effects observed in the 200
ppm (7.81 and 8.53 mg/kg bw/day in males and females, respectively)
group for any of the parameters measured.

The NOAEL is 1000 ppm.  The LOAEL is > 1000 ppm, based on the lack of
adverse effects at the doses tested in this study.  This study is
considered supplemental due to deficiencies in organ weight measurements
and deviations from GLP with respect to liver enzymology and
histopathology.

This subchronic toxicity study is unacceptable because it does not
satisfy the guideline requirement for a subchronic oral study (OPPTS
870.3150; OECD 409) in dogs.  Liver enzymology and histopathology were
not performed according to GLP standards.  Fasting status and timing of
blood sampling was not reported, making hematology and clinical
chemistry parameters difficult to compare with historical controls.
Several hematological, clinical chemistry and urinalysis parameters
outlined as OPPTS Guideline 870.3150 requirements were not reported.
Uterine weights were not reported, despite dramatic reductions in
uterine/oviduct absolute and relative weight in the 39-day range-finding
dog study that preceded the current study (MRID 46246431).  This review
is a joint effort of the PMRA and the EPA

________

					In a subchronic toxicity study (MRID 46246431), SXX 0665 (94.7%
a.i., Batch No. 17005/89) was administered to 2 Beagle dogs/sex/dose in
the diet (no vehicle) at dose levels of 0, 10, 100/5000 or 1000 ppm (0,
0.3, 3/150 or 30 mg/kg bw/day) for 39 days.  Due to the lack of
observations indicating overt toxicity in the 100 ppm group, the dose
was increased to 5000 ppm on Day 26 until the end of the study.

There was no mortality and no treatment-related clinical observations.
One female at 1000 ppm was found to be pregnant at necropsy.  There were
no treatment-related changes in body weight, body weight gain and food
consumption, with the exception of the 5000 ppm group.  After the 5000
ppm dosing regime was initiated, there was a dramatic decline in food
consumption and body weights declined to such an extent that the animals
in that groups had a mean body weight at the end of the study that was
lower than at the beginning of the study.

Although the sample number is small and does not lend itself to proper
statistical analysis, a number of trends regarding organ weight were
observed.  Increased liver and thyroid absolute and relative weight in
both sexes in a dose-dependent manner was observed, with liver weights
affected to a greater extent in males.  The higher liver weights
coincide with increased liver enzyme (7-ethoxycoumarin deethylase
[ECOD], aldrin epoxidase [ALD], epoxide hydrolase [EH], and
UDP-Glucuronyl transferase [UDPGT]) activation (100/5000 and 1000 ppm)
and urea urinary excretion (5000 ppm only).  Reduced hepatocyte size was
seen at 100/5000 and 1000 ppm.  Increased hepatocyte optical density was
observed in all animals of the 1000 ppm group, and food consumption was
unaffected in both sexes and body weight gain was increased in males, so
it can not be attributed to glycogenolysis.  Absolute and relative
uterus/oviduct weights were dramatically decreased in all treatment
groups in a dose-dependent manner and the one high-dose female had
markedly lower absolute and relative ovarian weights. One control had a
high ovary weight and the sample size was small, so the toxicological
significance of this finding is unknown.

Cytoplasmic changes were seen in the livers of the 100/5000 and 1000 ppm
animals.  Round cell infiltration was noted in the adrenal glands of one
female at ≥10 ppm, which the applicant attributes to stress.
Increased iron pigmentation in the spleen was observed in both sexes at
1000 ppm group and decreased cellularity was observed in the bone marrow
of the femur and sternum in both sexes at 100/5000 and 1000 ppm. There
was an increased number of megakaryocytes was observed in one 100/5000
female; this female had shown a decreased thymus size that was
histopathologically confirmed as moderate thymic atrophy.

A NOAEL cannot be established for this study as it is a range-finding
study.  Also, marked effects on absolute and relative organ weights
(increased in thyroid in both sexes, increased in liver in males and
decreased in uterus/oviduct in females) were observed at 10 ppm (0, 0.3,
3/150 and 30 mg/kg bw/day).  The small sample size precludes proper
statistical analysis but the calculated standard error suggests that the
increased relative (to brain wt) liver weight in males is significantly
different from controls at 10 ppm.  Liver enzyme activities and urinary
creatinine and urea levels were not affected in either sex in the 10 ppm
group.

This subchronic toxicity study in the dog is a range-finding study and
does not satisfy the guideline requirement for a subchronic oral study
(OPPTS 870.3150; OECD 409) in dogs as it was not conducted to meet GLP
standards.  This review is a joint effort of the PMRA and the EPA.

	870.3200	21/28-Day Dermal Toxicity – Rat

		Prothioconazole

				In a repeat-dose dermal toxicity study (MRID 46246315),
prothioconazole (98.5%) was applied neat to the shaved skin of 10
HsdCpb:WU rats/sex/dose, at dose levels of 0, 100, 300 or 1000 mg/kg
bw/day, 6 hours/day for 5 days/week during a 28-day period.

There were no mortalities, no treatment-related clinical observations
and no treatment-related water consumption, hematology, clinical
chemistry, opthalmascopic or gross pathology findings.

The NOAEL for the 28-day rat dermal toxicity study was established to be
1000 mg/kg bw/d.  The LOAEL was not determined.

This repeated dose dermal toxicity study in the rat is acceptable and
satisfies the guideline requirement for a repeated dose dermal toxicity
study (OPPTS 870.3200 (rodent); OECD 410) in rats.  This review is a
joint effort of the PMRA and the EPA.

		Prothioconazole-desthio

			No Acceptable studies are available.

	870.3465	90-Day Inhalation – Rat

		Prothioconazole

			No Acceptable studies are available.

		Prothioconazole-desthio

				In a subchronic inhalation toxicity study (MRID 46246433) SXX0665
(Purity: 95.4%) was administered suspended in PEG 400: alcohol to 10
Wistar rats/sex/concentration by head/nose only inhalation exposure
system at concentrations of 0, 11.3, 46.8 and 228.4 mg/m3 for 6 hours
per day, 5 days/week for a total of 28 days.

Exposure conditions were monitored for concentrations, particle sizes
and temperature and humidity and the animals were observed weekly for
changes in body weight but not food consumption and early and late
ophthalmic observations.   Blood was analyzed on day 9 and at the end of
exposures for effects on hematology and clinical chemistry.  Urine was
examined during week three of the exposures.   At the end of 28 days,
the animals were sacrificed and examined for organ weight changes, gross
observations but not histopathological effects.

No significant treatment-related effects were noted on mortality, body
weight, clinical signs, hematology, clinical biochemistry, urinalysis or
ophthalmology. No significant gross pathological findings were noted.
Decreased absolute and relative thymus weights (approx. 25%) were noted
in the vehicle control and high dose females, compared to the air
control; however, this effect is considered incidental in the absence of
a dose response, a similar effect in males or any accompanying effects
on body weight, gross pathology or clinical toxicity.

The NOAEL is 228.4 mg/m3 (0. 228 mg/L).  No LOAEL was determined for
this study.

This subchronic toxicity study in the rat is considered UNACCEPTABLE and
does not satisfy the OPPTS guideline requirement (870.3465) for a
subchronic inhalation study in the rat for the following reasons, due to
several major deficiences regarding methodology and measurements.  This
review is a joint effort of the PMRA and the EPA.

A.3.2	Prenatal Developmental Toxicity

	870.3700a Prenatal Developmental Toxicity Study - Rat

		Prothioconazole

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

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

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

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

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

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

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

________

				In a developmental toxicity study (MRID 46246323), JAU 6476 was
administered dermally in one of three forms to groups of 29-30 mated
female Wistar rats on gestation 6 through 19.  The test material was
administered as technical prothioconazole (98.1-98.8% a.i.) at a dose
level of 1000 mg ai/kg bw/d (limit dose), as EC 250 formulation (25%
a.i.) at a dose level of 250 mg ai/kg bw/d, or as a diluted EC 250
formulation (1:3) at a dose level 62.5 mg ai/kg bw/d.  The test material
was applied for 6 hours/day, on non-occlusive dressings to an area of
clipped skin equivalent to 10% body surface area.

There were no treatment-related effects on clinical signs, body weight,
body weight gain, or food consumption.  There were no treatment-related
effects noted at necropsy and there was not a treatment-related
difference in gravid uterine weight compared with concurrent controls.

Post-implantation loss was increased at 1000 mg/kg compared with the
controls, but the mean/animal was only slightly increased in
consideration of the standard deviation.  As a result of there only
being one dose for the technical (limit-dose), there is no dose-response
to be observed and it is difficult to make any conclusions whether the
increase in post-implantation loss at the limit-dose is
treatment-related.  The EC250 and 1:3 dilution formulations had the same
total postimplantation loss percent, but the EC250 formulation had a
higher mean/animal value.  There was no valid historical control data
provided for this study.

There were no treatment-related external, visceral or skeletal
malformations or variations.  Most treatment groups, including
concurrent controls, were above the historical control range for the
following skeletal variations: nasal incompletely ossified, frontal
suture enlarged, coronal suture enlarged and rudimentary ribs.  The
overall incidence of skeletal variations was lower in the treatment
group compared with the concurrent controls.

The maternal NOAEL is 1000 mg a.i./kg with a LOAEL of > 1000 mg a.i./kg.

The developmental NOAEL is 1000 mg a.i./kg with a LOAEL of > 1000 mg
a.i./kg.

The dermal developmental toxicity study in the rat is classified as an
acceptable (supplementary study); and satisfies the guideline
requirement for a limit-dose dermal developmental toxicity study (OPPTS
870.3700; OECD 414) in the rat.  This review is a joint effort of the
PMRA and the EPA.

________

In a developmental toxicity study (MRID 46923601) JAU 6476 (97.8- 98.7%
purity) was administered to 25 female Wistar Hanover (Crl:WI(HAN))
rats/dose by oral gavage on Days 6-19 of gestation at nominal
concentrations of 0 (0.55 CMC and deionized water vehicle), 20, 80, or
750 mg/kg bw/day, at a dosing volume of 10 mL/kg.

There were no treatment-related effects on clinical parameters or
mortality in dams.  Body weight gains were decreased during treatment
and overall (day 0-20) at the 750 mg/kg dose level.  Food consumption
was decreased and water consumption was increased in the high dose
animals.  Urea nitrogen, alkaline phosphatase and cholesterol were
increased.

The maternal NOAEL is 80 mg/kg bw/day, based on decreased body weight
gains and food consumption and increased water consumption at 750 mg/kg
bw/day.

There were no treatment-related effects on developmental parameters.
There was an increased incidence of rudimentary ribs at 750 mg/kg
bw/day.

The developmental NOAEL is 80 mg/kg bw/day, based on increased
rudimentary ribs noted at 750 mg/kg bw/day.

The developmental toxicity study in the rat is classified acceptable
nonguideline.  While it does not statisfy the guideline requirement
(OPPTS 870.3700; OECD 414) for a developmental toxicity study, the data
are deemed valid and useful for toxicity assessment in the rat. This
study focused on eye and rib effects and did not perform visceral
examination on the fetuses.  This review is a joint effort of the PMRA
and the EPA.

________

		Prothioconazole-desthio

				In a developmental toxicity study (MRID 46246319) SXX 0665 (Purity:
93.9%) was administered to 30 female Wistar rats/dose, by gavage (0.5%
Cremophor EL in bidistilled water), at dose levels of 0 or 30 mg/kg
bw/day from days 6 through 15 of gestation (dose volume of 10 mL/kg
bw/day).  Both control and treatment groups were subdivided into two
groups of 15, half for cesarian section and half for rearing. Nine
additional dams were introduced to the treatment group due to the death
of one animal in the cesarian section subgroup and the high pup
mortality in the rearing subgroup.  This study was performed as a
follow-up to MRIDs 46246320 and 46246321.

There were no treatment-related adverse effects on mortality, clinical
signs, body weight, or food consumption in dams.  Pregnancy rates,
fertility and gestation indices were comparable among control and
treated groups.  A reduced rearing index was noted at 30 mg/kg bw/day
(76.2%) compared to control (92.9%) due to total litter loss of 5
litters from the rearing group dams within 6 days of birth.  No
treatment-related effects were noted on mean number of corpora lutea and
implantations, resorptions, litter size, fetal weight or sex ratio in
dams undergoing cesarian section.  Increased placental weights were
noted at 30 mg/kg bw/day, which correlates with the gross pathological
finding of engorged placentas in 2 dams in the cesarian section group.

	Pup death was significantly increased, therefore the mean pup survival
was decreased, in the 30 mg/kg bw/day rearing group due to complete
litter loss in 5 litters (4 litters within 3 days of birth and 1 litter
within 6 days of birth).  An increased incidence of emaciated pups (9
pups vs. 2 in control) and pups with depressed body temperature (4 pups
vs. 0 in control) were observed at 30 mg/kg bw/day in the rearing group.
 No treatment-related effects on body weight were observed in the
surviving pups.

	All of the fetuses (100%) in the cesarian section group exhibited
skeletal dysplasias of the radius and ulna at 30 mg/kg bw/day.  In
addition, 5 fetuses (in 3 litters) exhibited humeral dysplasia and 10
fetuses (in 3 litters) exhibited cleft palate. Increased incidence of
delayed ossification was noted in the fetuses at 30 mg/kg bw/day,
specifically affecting the sternum, ribs and hyoid bone.  Supernumerary
(14th) ribs were observed in all treated fetuses (100% fetuses in 100%
litters) compared to concurrent (15.3% fetuses in 57.1% litters) and
historical controls (10-12% fetuses).  The increased supernumerary ribs
consisted mainly of “rudimentary or punctiform/comma-shaped” 14th
ribs, as opposed to fewer “extra or complete/slightly shortened”
ribs.  The incidence of both rudimentary 15th (3% fetuses in 14.3%
litters) and 16th (1.5% fetuses in 14.3% litters) ribs was increased,
with no 15th or 16th ribs observed in the concurrent control group.

	In the rearing group, the incidence of supernumerary 14th ribs was
increased (31.9% pups in 75.0% litters) in 42-44 day old pups, in both
“rudimentary or punctiform/comma-shaped” and “extra or
complete/slightly shortened” ribs.  The incidence of rudimentary ribs
in the reared pups was 13.4% fetuses in 75.0% litters which is increased
compared to control, but significantly decreased compared to the
incidence in 20 day fetuses (84.2% fetuses in 57.1% litters).  The
incidence of extra/complete ribs in the reared pups (18.5% fetuses in
56.3% litters) was similar to the incidence observed in the 20 day
fetuses.  The incidence of 14th ribs in the concurrent control rearing
group (3.7% fetuses in 15.4% litters) was markedly reduced compared to
the concurrent control cesarian section group. No incidences of 15th or
16th ribs were noted in 42-44 day old pups.

	The persistence of the supernumerary 14th ribs classified as
“extra” or “complete/slightly shortened” in the 42-44 day old
pups indicates that the treatment-induced supernumerary rib development
does not show complete postnatal reversibility.  The persistence of
supernumerary 14th ribs appears to be influenced by the length of the
rib (punctiform vs. complete/slightly shortened) rather than the
location (14th, 15th or 16th) of the rib.

This non-guideline developmental toxicity study in the rat is acceptable
as a supplementary study only, therefore no endpoints were determined.
This review is a joint effort of the PMRA and the EPA.

________

				In a developmental toxicity study (MRID 46246321), SXX 0665
Technical (Purity: 97.4%) was administered to 35 female Wistar rats/dose
by gavage (at 10 mL/kg bw/day in bidistilled water with 0.5% Cremophor
EL) at dose levels of 0, 10, 30, or 100 mg/kg bw/day from days 6 through
15 of gestation.  A subgroup of 10/dose were used for assessment of
liver toxicity and sacrificed on day 16.

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

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

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

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

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

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

Two further supplementary studies were conducted to establish a
developmental NOAEL for supernumerary ribs and to determine the
post-natal effect of this skeletal variant.

An increased sensitivity of the fetuses to treatment with SXX 0665 is
apparent, evidenced by the increased incidence of supernumerary ribs and
incomplete/delayed ossifications at doses of 10 mg/kg bw/day and up, in
the absence of maternal toxicity.

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

________

				In a developmental toxicity study (MRID 46246322) SXX 0665 Technical
(Purity 94.7%) was administered to 25 female Wistar rats/dose once daily
by gavage (in a volume of 10 mL/kg bw/day) at doses 0, 1 or 3 mg/kg
bw/day from days 6 through 15 of gestation.

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

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

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

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

An increased sensitivity of the fetuses to treatment with SXX 0665 is
apparent, evidenced by the increased incidence of supernumerary ribs and
incomplete/delayed ossifications at the LOAEL of 10 mg/kg bw/day, in the
absence of maternal toxicity.

The developmental toxicity study in the rat is classified as
supplementary, as it is non-guideline but satisfies GLP requirements.
This review is a joint effort of the PMRA and the EPA.

________

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

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

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

≥300 mg/kg relative to concurrent controls.  The developmental NOAEL
was 30 mg/kg.  The developmental LOAEL was 100 mg/kg, based on an
increased incidence of supernumerary rib (14th rib) at this dose.  There
was a quantitative increase in pup sensitivity, with malformations
occurring at non-maternally toxic doses.

A supplemental study (T 7037368) was performed in order to investigate
the observation of supernumerary ribs at the low dose in the main study.
 The maternal and developmental NOAELs were 30 mg/kg, based on no
treatment-related effects in pups or dams in this study.

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

		Prothioconazole-Deschloro

		In a pilot developmental toxicity study (MRID 46246317), JAU 6476-
deschloro (96.9% a.i.) was administered to 8 female Wistar rats/dose, in
0.5% aqueous carboxymethylcellulose, by gavage at dose levels of 0, 40,
200 or 1000 mg/kg bw/day from days 6 through 19 of gestation.

There were no treatment-related effects on mortality.  Clinical
observations at 1000 mg/kg included: increased urination (5/8), and
increased water consumption (8/8) but varied in the time of onset and
persistence.  There was a decrease in body weight gain at ≥200 mg/kg
for several time intervals.  There were no treatment-related
observations at gross necropsy.

There were no treatment-related effects on pregnancy rate, number of
corpora lutea, implantations, live or dead fetuses, resorptions,
placental weight, pre-implantation loss, post-implantation loss, fetal
weight or sex ratio.  There was a decrease in the total number of live
fetuses at 200 mg/kg (not at 1000 mg/kg), so it is difficult to
interpret a dose-response (or lack of) at this dose.  At 1000 mg/kg,
white spots were observed on two placentas (fetus # 282 and 283) from
the same dam (dam # 927).  The toxicological significance of this
finding is unknown since fetus 282 also had multiple malformations.

There were no treatment-related external deviations observed.  There was
an increased incidence of visceral deviations at 1000 mg/kg relative to
concurrent and historical control data which included slight dilation of
renal pelvis and dilation of ureter.  Skeletal deviations included
retarded ossification of skull bones and wavy ribs at 1000 mg/kg.  There
was an increase in 14th rib and vertebral bodies at 1000 mg/kg relative
to concurrent controls at 1000 mg/kg.

There was an increased incidence of macroglossia at 1000 mg/kg compared
to concurrent controls.  One fetus (#282) with macroglosia was slightly
edematous along with other malformations (skeletal) and had a placenta
with white spots.  There were no treatment-related visceral
malformations observed.  There was an increased incidence of
malformations in the scapula, humerus, sternebra and clavicle at 1000
mg/kg relative to concurrent control values.  The findings were observed
in one to two fetuses, similar to the number of fetuses with dysplasia
of forelimb bones, cleft sternebra, dysplasia of scapula in the relevant
historical control studies, so it is not considered adverse.

The developmental toxicity study in the rat is classified supplemental
because it is a pilot study and does not satisfy the guideline
requirement for a developmental toxicity study (OPPTS 870.3700; OECD
414) in the rat (non-GLP).  No endpoints were established for this study
since it is a pilot study and there were too few animals in each dose
group.  This review is a joint effort of the PMRA and the EPA.

		Prothioconazole-Sulfonic Acid K Salt

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

The test-article caused severe toxicity at the highest dose tested,
including mortality and clinical signs related to treatment.  Six dams
were found dead between day 9 and 12 post coitum and the clinical signs
observed included ruffled fur observed alone, or in tandem with
irregular breathing or breathing noise.

Effects on the high dose group were comprised of decreased body weight
and body weight gain.  An increase was reported in the incidence of
non-pregnant dams in the mid-dose group (150 mg/kg), however the results
of test article administration on reproductive parameters in this group
show that reproductive fitness is not affected.  Indices such as mean
corpora lutea, live fetuses and implantation sites were greater than
those in the control and low dose group, suggesting that the increase in
non- pregnant dams may be incidental in this dose group.

A finding that was outside the previously recorded historical control
range and the concurrent control range was the incidence of rudimentary
supernumerary one ribs, on both the right and left sides.  The incidence
was statistically significantly increased on both a litter and fetal
basis.  Since supernumerary ribs were seen in several studies, in the
absence of maternal toxicity, and were shown to be non- completely
reversible after the first few weeks of life, they were considered an
adverse effect of treatment.

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

The developmental LOAEL is 30 mg/kg bw/day, based on the increased
incidence of rudimentary supernumerary one ribs.  The developmental
NOAEL is <30 mg/kg bw/day.

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

	870.3700b Prenatal Developmental Toxicity Study - Rabbit

		Prothioconazole

								In a developmental toxicity study (MRID 46246328) JAU 6476
(94%), in aqueous 0.5% carboxymethylcellulose sodium salt (CMC), was
administered to groups of 24 mated female Chinchilla rabbits by oral
gavage at 0, 10, 30, or 80 mg/kg bw/d from post coitum (pc) day 6 to 27.
 The animals were sacrificed on pc day 28.  The number of pregnant
females at 10 and 80 mg/kg bw/d groups was not sufficient.  Therefore, 6
and 7 mated females were added to these groups, respectively.  Further,
because no clear effects of toxicity were noted up to and including 80
mg/kg bw/d, an additional dose group of 24 mated females was tested at
350 mg/kg bw/d.  One high-dose dam was found dead on pc day 25.
Compared to the vehicle control group, high-dose animals had higher
number of total resorptions or abortions, lower food consumption and
body weight gain, and marginally lower placenta weights.  No
treatment-related signs were noted in the other dose groups and no
abnormal changes were noted during necropsy.  Comparison of the liver
and adrenal weights gave no indication of treatment- related effects.
There was an increase in post-implantation loss and a corresponding
decrease in the total number of fetuses in high-dose dams.  The findings
included 3 dams with total resorptions and 3 dams which aborted during
the last treatment week.  There was a decrease of fetal body weights at
350 mg/kg bw/d, likely secondary to maternal body weight effects.  None
of the other fetal examinations - external and visceral examination,
examination of fetal hearts and major blood vessels, of the heads and
brains, and sex ratios - gave indications of treatment-related changes.
Based on these results the LOAEL (lowest observed adverse effect level)
and NOAEL (no observed adverse effect level) for the maternal toxicity
were considered to be 350 and 80 mg/kg bw/d, respectively.  Treatment
with JAU 6476 caused abortions and total resorptions and lower fetal
body weight at 350 mg/kg bw/d. Therefore the LOAEL and NOAEL for
developmental toxicity were considered to be 350 and 80 mg/kg bw/d,
respectively.  There was no evidence of teratogenic potential of JAU
6476.

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

		Prothioconazole-desthio

								In a developmental toxicity study (MRID 46246327) SXX 0665 (94%)
was administered to groups of 15 female Himalayan rabbits by oral gavage
(deionized water containing 0.5% Cremorphor EL (BASF)) at 0, 2, 10, or
50 mg/kg bw/d from post coitum (pc) day 6 to 18. The animals were
sacrificed on pc day 29.

There were no effects on clinical signs, water intake, or mortality.
Food intake was marginally lowered in high-dose dams. Body weight gain
of high-dose animals was adversely affected during gestation, presumably
as a result of elevated resorption rate. At terminal sacrifice, there
was no significant gross pathological observation. Treatment-related
histopathological findings were evident in the liver of mid- and
high-dose dams. The liver findings included increased destruction of
individual hepatocytes and low glycogen mobilization.  The LOAEL  for
maternal toxicity was 10 mg/kg bw/day, decreased body wt gain, decrease
food consumption, increased resorptions, decreased number of fetuses,
liver histopathology; the NOAEL was 2 mg/kg bw/day.

Examination of fetal parameters revealed no treatment-related findings
on fetal weight and sex, or on skeletal system development. The
placentas were normal. Due to an elevated resorption rate, the gestation
rate and the number of fetuses were lower at 50 mg/kg bw/d group.
Malformations were observed at 10 and 50 mg/kg bw/d groups. At 10 mg/kg
bw/d, alterations included malformed vertebral body and ribs,
arthrogryposis, and multiple malformations. These malformations could
arise spontaneously in Himalayan rabbits. At 50 mg/kg bw/d, malformed
alterations included cleft plates.  The LOAEL  for developmental
toxicity was 10 mg/kg bw/day based on structural alterations including
malformed vertebral body and ribs, arthrogryposis, and other multiple
malformations; the NOAEL was 2 mg/kg bw/day.

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

A.3.3	Reproductive Toxicity

	870.3800 Reproduction and Fertility Effects - Rat

		Prothioconazole

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

There were no treatment-related mortalities or clinical findings
throughout the study in any generation in either adults or pups.  There
was a decrease in body weight and body weight gain (14-21%) and increase
in food consumption (5-19%) in the P generation males during premating
at 750 mg/kg bw/day, thereby indicating a decrease in food efficiency.
At 750 mg/kg bw/day, body weight in F1 males was consistently 14–17%
lower when compared to the control group.  This is consistent with the
findings for the F1 male pups between days 7 and 21, thereby indicating
that the F1 males were consistently 14–17% smaller than the control
group from day 21 to sacrifice.

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

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

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

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

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

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

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

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

		Prothioconazole-desthio

				In a 2-generation reproduction study (MRID 46246333), SXX 0665 was
administered to 30 Sprague- Dawley rats/sex/dose in the diet (1% corn
oil) at dose levels of 0, 40, 160, and 640 ppm.

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

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

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

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

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

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

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

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

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

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

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

A.3.4	Chronic Toxicity

	870.4100a (870.4300) Chronic Toxicity – Rat

		Prothioconazole

				In a chronic toxicity study (MRID 46246335) JAU 6476 (98.8-99.4%
a.i.) was administered to 20 Wistar rats/sex/dose in an aqueous solution
of 0.5% Tylose by gavage at dose levels of 0, 5, 50 or 750 mg/kg bw/day
for 53 weeks.  A Functional Observational Battery as well as grip
strength determinations were conducted in weeks 27 and 52 with 10
rats/sex/dose.

An increase in the number of animals with salivation and increased urine
excretion was observed in animals of both sexes in the high dose group.
Statistically significant decreases in body weight and body weight gain
were also observed in high dose animals of both sexes.  The magnitude of
this decreased body weight gain became more pronounced as the study
progressed, and resulted in an overall body weight gain that was 79% and
77% of controls in males and females, respectively.  The results of the
FOB did not indicate any potential for neurotoxicity.

Decreased hemoglobin levels and increased thrombocyte and leukocyte
counts were noted in animals from the highest dose level.  Alterations
in clinical chemistry and urinalysis parameters indicative of liver and
kidney damage were also observed in these animals.  Effects indicative
of liver damage included increased serum alkaline phosphatase,
bilirubin, cholesterol and triglyceride concentrations and decreased
plasma, glucose and protein concentrations. Additionally, increased
liver weights and a granular appearance of the hepatocellular cytoplasm
were observed in high dose rats.  T4 was decreased in both sexes at 750
mg/kg bw/day

Effects on the urinary system at 750 mg/kg bw/day included increased
plasma urea and creatinine concentrations, decreased urine pH, and
yellow-brown spherical crystalloids in urine sediments.  Corroborating
evidence of kidney damage included increased relative kidney weights and
an increased severity of chronic progressive nephropathy and incidence
of simple urothelial hyperplasia in urinary bladder, accompanied in most
cases by a minimal focal inflammatory infiltration.

The NOAEL in this study was 50 mg/kg bw/day.  The LOAEL was 750 mg/kg
bw/day, based on decreased body weight and body weight gain, alterations
in hematology and clinical chemistry parameters indicative of liver and
kidney damage, increased liver and kidney weights, and accompanying
histopathological alterations in the liver, kidney and urinary bladder.

This chronic study in the rat is acceptable and satisfies the guideline
requirement for a chronic oral study (OPPTS 870.4100), OECD 452 in rats.
 This review is a joint effort of the PMRA and the EPA.

		Prothioconazole-desthio

			See Carcinogenicity – Rat (MRID 46246342)

	870.4100b Chronic Toxicity - Dog

		Prothioconazole

						In a 1-year dog study (MRID 46246336), JAU 6476 (98.4 to 98.8%
a.i.) was administered to 4 beagle dogs/sex/dose by gavage (0.5% methyl
cellulose with 0.4% TWEEN 80 in deionized water) at dose levels of 0, 5,
40, or 125 mg/kg bw/day for five days/week for a period of one year.
Surviving animals were sacrificed and subject to gross necropsy and
histopathological examination.

There were no mortalities, and no compound-related clinical signs of
toxicity observed.  There were no treatment-related hematological
findings, and no neurological, body temperature, or electrocardiogram
parameter effects.  No treatment-related findings were noted in the
gross pathology during necropsy.  Behavioral observations, including
increased salivation and staining, as well as sporadic vomiting, were
noted and attributed to the mode of dosing (gavage).  Overall body
weight and body weight gain were decreased by 21 and 42%, respectively,
in the high dose female animals, and food consumption was also decreased
by as much as 47% in these animals.  In addition, overall body weight
gain in the high dose male animals was reduced by 14% of the control
value.  Mid and high dose male animals showed increased alkaline
phosphatase levels, as did the all of the treated female groups.
O-demethylase levels were also increased in the mid and high dose males,
while cytochrome P-450 levels were elevated in all of the treated female
groups.  Absolute and relative liver weights were increased in the high
dose groups of both sexes.  Changes in liver histopathology were also
observed, including liver pigmentation (pigment in kupffer cells that is
PAS and iron positive compatible with hemosiderin and scattered pigment
compatible with bile pigment) in the high doses of both sexes, and
extramedullary hematopoiesis in a high dose female.  The liver
pigmentation could be related to hematopoiesis, but was not considered
adverse in the absence of significant red blood cell findings.  Levels
of the thyroid hormones T3 and T4 were decreased in the treated males,
and levels of T4 were decreased in the treated female animals.  These
decreases may be secondary to the liver-related effects.  Alanine
aminotransferase levels were decreased in all of the treated males, with
unknown toxicological significance.  Urine volume was increased in the
high dose groups of both sexes.  Blood levels in the urine were also
increased in the high dose male animals.   The relative kidney weights
were increased in the low and high dose female animals.  In addition,
high dose males showed crystals and mineralization in the kidney, while
mid and high dose males showed chronic inflammation and pigmentation in
the kidney.  Females in the high dose group showed fibrosis and chronic
inflammation, while females in the mid and high dose groups were
observed with crystals in the kidney.  The kidney effects were
considered adverse in the mid and high dose animals of both sexes.  Both
the liver and kidneys are considered target organs of this test
material.  Urine calcium was decreased in the treated females, the
toxicological significance of which is unknown.  Treatment-related
changes in the spleen of the female animals were observed.  Absolute and
relative spleen weights were increased in all treated females, and
pigmentation in the mid and high dose females and fibrosiderotic plaques
in high dose females were observed microscopically in the spleen.  The
spleen effects were considered adverse at the mid and high doses.

The LOAEL is 40 mg/kg bw/day for both sexes, based on decreased T3 and
T4 thyroid hormones, increased urine volume, and increased incidence of
chronic inflammation and pigmentation in the kidneys of the male
animals, and decreased T4 thyroid hormone, increased spleen weight,
increased incidence of spleen pigmentation, increased urine volume, and
increased incidence of crystals present in the kidneys of the female
animals.  The NOAEL is 5 mg/kg bw/day for both sexes.

This study in dogs is acceptable and satisfies the guideline requirement
for a 1-year oral toxicity study in dogs (OPPTS 870.4100; OECD 452).
This review is a joint effort of the PMRA and the EPA.

		Prothioconazole-desthio

				In a chronic toxicity study (MRID 46246337), SXX 9665, (92.8% a.i.;
Batch No. 1717008/90) was administered to 4 Beagle dogs/sex/dose in diet
at dose levels of 0, 40, 300 or 2000 ppm (0, 1.35, 10.1 and 69.9 and 0,
1.55, 11.1 or 77.1 mg/kg bw/day for males and females, respectively) for
30 weeks.  The study was initially intended to be 52 weeks, but the
exposure period was truncated due to discontinuation of the development
of the test compound.

There were no treatment-related mortality and no treatment-related
clinical observations.  There were no treatment-related changes in body
weight, body weight gain and food consumption, with the exception of the
2000 ppm females that had slightly reduced body weights at the end of
the study.

At 2000 ppm, effects were observed in both male and females.  Liver
enzymes were elevated in both sexes, as were relative liver weights.
Histopathological examination of the livers revealed cytoplasmic changes
(increased granulation and glycogenolysis) in the centrilobular
hepatocytes in all 2000 ppm animals.  These observations coincide with
reduced thyroxine levels, suggesting that significant liver enzyme
activation occurred in both sexes at 2000 ppm.  These liver changes are
considered an adaptive response and not adverse.

The NOAEL is 2000 ppm.  The LOAEL is > 2000 ppm, based on the lack of
adverse effects at the doses tested.

This chronic toxicity study in the dog does not satisfy the guideline
requirement for a chronic oral study (DACO 4.4.5, OPPTS 870.4100) or a
subchronic oral study (OPPTS 870.3150; OECD 409) in dogs due to a number
of investigations that did not meet GLP standards.  This study is
considered to be supplemental.  This review is a joint effort of the
PMRA and the EPA.

A.3.5	Carcinogenicity

	870.4200a Carcinogenicity Study - rat

		Prothioconazole

				In a carcinogenicity study (MRID 46246338), JAU 6476 (98.5 to 99.1%
a.i.) was administered to 50 Wistar Hsd Cpb:WU rats/sex/dose by gavage
(aqueous solution of 0.5% Tylose) at dose levels of 0, 5, 50, or
750/500/625 mg/kg bw/day (the high dose was reduced from 750 mg/kg
bw/day to 500 mg/kg bw/day for males at study week 84, and to 625 mg/kg
bw/day for females at study week 56) for 2 years.

↓32%/43%), 26-52 (↓32%/56%), and 52-75 (↓76%/25%).  Overall (study
week 0-105) body weight gain decreases were 29% and 20% for males and
females, respectively, compared to controls.  Food and water consumption
were significantly increased in the high dose male and female animals.
Water clefts of the eye were observed at an increased incidence in the
high dose animals.  Several hematological parameters were affected in
the high dose males and females. Alkaline phosphatase (both sexes),
creatinine (males) and urea (males) were increased at the high dose
indicative of liver and kidney changes.  Decreases were observed in
aspartate aminotransferase and alanine aminotransferase levels, with
unknown toxicological significance.  Urine volume was increased in the
high dose group of both sexes (230-360%, males; 52-98%, females), along
with mean water intake for both males (↑124%) and females (↑57%).
Relative liver and kidney weights were increased in the high dose male
animals, while absolute and relative liver weights and relative kidney
weights were increased in the high dose females.  Several other relative
organ weights were increased in the high dose animals, although this is
likely due to the decreased terminal body weight in these animals.
Gross and microscopic findings indicative of liver and kidney effects
were observed in the high dose groups of both sexes.  Numerous other
non-neoplastic gross and microscopic pathological findings were noted in
the high dose male and females that are likely secondary to the poor
general condition of these animals.

The LOAEL for chronic toxicity is 500 mg/kg/day based on increased
mortality and decreased body weight/body weight gain, changes in
clinical chemistry (APh, creatinine, urea) and hematological parameters,
increased liver and kidney weights, and liver (hypertrophy and
eosinophilic/clear cell focus) and kidney/urinary bladder pathology.
The NOAEL for chronic toxicity was 50 mg/kg bw/day for both sexes.

In this study, there is no adequate dose for the evaluation of
carcinogenicity of JAU 6476.  The high dose for both sexes (750/500
mg/kg bw/day for males and 750/625 mg/kg bw/day for females) was
considered to be excessive, as shown by the increased mortality and
decreased body weight/body weight gain in both sexes.  There was no
treatment-related increase in tumor incidence in the treatment groups
when compared with control animals up and including 625 mg/kg bw/day in
females.  At 500 mg/kg bw/day in males, malignant thymomas were
observed, but as dosing was excessive, these tumors were not considered
treatment-related.

This carcinogenicity study in the rat is unacceptable /guideline and
does not satisfy the guideline requirement for a carcinogenicity study
(OPPTS 870.4200; OECD 451) in rats.  There is no adequate dose for the
evaluation of carcinogenicity of JAU 6476 due to excessive toxicity at
the high dose and too large dose spacing between the mid and high dose
groups.  The high dose (750/625/500 mg/kg/day) was considered excessive
based on: 1) increased mortality in both sexes which resulted in dose
reduction to 625 mg/kg/day during week 56 for females and to 500
mg/kg/day during week 84 for the males, and 2) significant decreases in
body weight/body weight gain from week 12 in males and from week 29 in
females at this dose.  No effects were seen at the mid dose of 50
mg/kg/day.  The animals in this study are compromised.  However, while
the study is considered unacceptable, a new cancer study conducted with
the parent compound is not required since an adequate rat cancer study
conducted with the metabolite is available, which is the basis for the
risk assessment.  This review is a joint effort of the PMRA and the EPA

		Prothioconazole-desthio

				In a combined chronic toxicity/carcinogenicity study (MRID
46246342), SXX 0665 (92.8-95.4% a.i.) was administered to 60, 5–6 week
old Wistar rats/sex/dose in diet (1% peanut oil) at dose levels of 0,
20, 140 or 980 ppm (0, 1.1/1.6, 8.0/11.2 or 57.6/77.4 mg/kg bw/day for
males/females).  An interim kill was performed at week 52 on 10
rats/sex/dose while the remaining 50 rats/sex/dose were dosed for 104
weeks.

There were no treatment-related effects of clinical signs,
ophthalmology, urinalysis parameters, food consumption or water
consumption.  There were mortalities at all dose levels in both sexes,
however, these deaths were not deemed to be treatment-related as they
were spontaneous, were due to animals being in moribund state, or due to
death during blood collection.  No treatment-related decrease in body
weight/body weight gain was seen in males.  In females at 980 ppm,
decreases in body weight (↓3-9%) and body weight gain (↓16-40%),
relative to controls, were observed throughout the study, resulting in a
treatment-related overall body weight gain decrease of 14%, relative to
control.  Treatment-related liver effects included: i) absolute liver
weight was increased in males at 980 ppm (weeks 52 and 104); II)
relative liver weight was increased at 980 ppm in both sexes (weeks 52
and 104); iii) liver discoloration in males at 140 and 980 ppm (week 52)
and; iv) slightly increased incidence of enlarged livers in males at 980
ppm.  Treatment-related adverse non-neoplastic liver histopathology
effects included; i)  increased hepatocellular vacuolation in males at
140 and 980 ppm (weeks 52 and 104) in males and at 140 and 980 ppm (week
104) in females; ii) increased incidence of single cell necrosis in
males at 980 ppm (week 52); iii)  increased incidence of centrilobular
fatty change at 140 and 980 ppm (weeks 52 and 104); iv) increased
incidence of cytoplasmic change in females at 980 ppm (week 52) and then
in both sexes at 980 ppm (week 104); v) increased incidence of
periportal fatty change in females at 140 and 980 ppm (week 52); vi)
increased incidence of hepatocellular hypertrophy in both sexes at 980
ppm (week 104) and; vii) increased incidence of single cell fatty change
at 140 and 980 ppm in both sexes (week 104).

T3 was decreased in females weeks 53 and 104 at 980 ppm and T4 was
decreased in males weeks 104 at 140 ppm and 980 ppm.  In the thyroid
gland, histopathology revealed increased incidences of hypertrophy of
follicular epithelium in males at 980 ppm, week 52 and increased
colloidal mineralization in both sexes at 980 ppm, week 52, as well as
in 980 ppm females, week 104.

≥140 ppm.  There was an increase in adrenocortical hyperplasia in
females at week 104 at 980 ppm.

There were no neoplastic findings.

The LOAEL is 140 ppm (8.0/11.2 mg/kg bw/day for M/F), based on liver
histopathology (hepatocellular vacuolation and fatty change (single
cell, centrilobular, and periportal)).  The NOAEL is 20 ppm (1.1/1.6
mg/kg bw/day for M/F).

At the doses tested, there were no treatment related increases in tumor
incidence when compared to controls.  Dosing was considered adequate
based on the liver histopathology in both sexes at 140 ppm and 980 ppm,
as well as body weight/body weight gain decreases in females and
increased liver weights in both sexes at the high dose.

This chronic toxicity/carcinogenicity study in the rat is
Acceptable/Guideline and satisfies and satisfies the guideline
requirement for a chronic/carcinogenicity study (OPPTS 870.4300); OECD
453 in rats.  This review is a joint effort of the PMRA and the EPA.

	870.4200b Carcinogenicity (feeding) - Mouse

		Prothioconazole

				In a carcinogenicity study (MRID 46246339), JAU 6476 (98.2-98.8%
a.i.) was administered to 60 Crl:CD-1 (ICR)BR mice/sex/dose by gavage
(with 0.5% Tylose aqueous solution) at dose levels of 0, 10, 70, 500
mg/kg bw/day for 80 weeks.

There was no treatment-related effect on mortality.  Body weight was
decreased (5-10% in males; 4-13% in females) from week 6 to week 78 at
500 mg/kg.  At the end of the study (week 78), body weights were
decreased 9% in males and 13% in females compared with controls.  Body
weight gains were decreased compared with controls at weeks 0-13 (males
and females), 13-26 (males and females), 26-52 (females) and 52-78
(females).  There were no treatment-related adverse effects on food
consumption in male or female mice.

Clinical chemistry, eye examinations and urinalysis were not conducted
during this study.   There were no treatment-related adverse findings in
the differential blood count.

Absolute kidney weights were decreased in males (20%) and females (15%)
at 500 mg/kg.  Relative kidney weights were decreased in males (13%) at
500 mg/kg and were comparable to controls in females.  There were
corresponding gross and histopathological effects [tubular
degeneration/regeneration and subscapular tubular degeneration with
interstitial fibrosis] in the kidneys.  There was a statistically
significant increase in absolute liver weights in male mice at ≥70
mg/kg (12-25%) and in female mice at 500 mg/kg (21%).  Relative liver
weights were increased at ≥70 mg/kg in male (16-39%) and female mice
(10-39%).  There was a decrease in absolute (44%) and relative (37%)
uterus weights at 500 mg/kg but the biological relevance of this is not
clear.

There was an increase in the incidence of discoloration in the kidneys
in males and females at 500 mg/kg.  There was a dramatic increase in the
incidence of surface changes in the kidneys of male mice at 500 mg/kg
compared with the other treatment groups, but there was a poor-response
in females.  There were changes in kidney weights and corresponding
histopathological effects in the kidneys at the high dose, so kidney
effects were considered treatment-related and adverse at 500 mg/kg.
There was an increase in the incidence of distinct lobulation in the
liver of male mice at ≥70 mg/kg compared with control values.  There
was not a dose-response in females for this parameter.  There was an
increase in fluid in the body cavity at 500 mg/kg in males and at ≥70
mg/kg in females, but the toxicological significance of this finding is
not known.  There was a decrease in discoloration of seminal vesicles in
male mice in all treatment groups compared with controls, but the
toxicological significance of this finding is not known.  There was a
decrease in the incidence of consistency change in the uterus which
corresponds with doses at which there was a decrease in uterus weight,
but the toxicological significance of this finding in combination with
decreased uterus weights is not known.

There was an increased incidence of tubular degeneration/regeneration in
the kidney at ≥70 mg/kg in males and 500 mg/kg in females and an
increased incidence of subcapsular tubular degeneration with
interstitial fibrosis at 500 mg/kg in male and female mice.  This
corresponds with gross pathology in the kidney and changes in kidney
weight. There was a treatment-related increase in centrilobular
hypertrophy in male mice at ≥70 mg/kg and in female mice at 500 mg/kg.
 This finding corresponds with weight and gross pathology effects in the
liver. However, in the absence of other hepatic histopathologic changes
and absence of clinical chemistry evaluations, it can not be determined
whether these changes are adverse.  There was an increase in the
incidence of inflammation in the seminal vesicles in males at 500 mg/kg,
but the toxicological significance of this finding in combination with a
decrease in discoloration noted in gross observations is not known.
Other effects had a poor dose-response and/or were slight, and were not
considered treatment-related.

There were no treatment-related adverse neoplastic findings.

The LOAEL is 70 mg/kg, based on kidney (tubular
degeneration/regeneration in males) effects.  The NOAEL is 10 mg/kg.

At the doses tested, there was not a treatment related increase in tumor
incidence when compared to controls.  Dosing was considered adequate
based on renal tubular toxicity at the mid dose and high dose and
decreased body weight at the high dose.

This carcinogenicity study in the mouse is acceptable (guideline) and
satisfies guideline requirement for a carcinogenicity study (OPPTS
870.4200); OECD 451 in mice.  This review is a joint effort of the PMRA
and the EPA.

		Prothioconazole-desthio

				In a carcinogenicity study (MRID 46246340, 46246341), SXX 0665
(93.1% a.i.) was administered to 50 B6C3F1 mice/sex/dose (and to 10
mice/sex/dose as satellite groups for sacrifice at 12 months) in diet
(1% peanut oil) at dose levels of 0, 12.5, 50, or 200 ppm (0, 3.1, 12.8,
or 51.7 mg/kg bw/day for males, and 0, 5.1, 20.3, or 80.0 mg/kg bw/day
for females) for 105 weeks.

There were no treatment-related mortalities or clinical signs.  Body
weight and food consumption were unaffected by treatment.  There were no
treatment-related hematological changes.  Overall body weight gain was
decreased in the high dose male animals.  Levels of cholesterol and
triglycerides were decreased in the treated male animals throughout the
study.  Glucose levels increased and decreased during Weeks 53 and 105,
respectively, in the treated male animals.  Changes in these clinical
chemistry parameters in the male animals were considered to be related
to liver changes noted in these animals, and were considered adaptive in
the low and mid dose males.  Levels of triglycerides were decreased at
the end of the study in the treated female animals.  As with the male
animals, this observation was related to liver findings noted in the
high dose females.  Absolute and relative liver weights were increased
in both the male and female high dose animals.  At interim sacrifice,
fine vesicular vacuolation in the hepatocytes and periacinar fat
staining were observed at an increased incidence in the mid and high
dose males.  Periacinar fat staining was also increased in the mid and
high dose terminal sacrifice males, and in all of the treated females at
terminal sacrifice.  Periacinar hypertrophy with cytoplasmic change in
hepatocytes was observed at an increased incidence in the mid and high
dose interim sacrifice females.  These histopathological findings
correlate to the increased liver weights and the clinical chemistry
changes.  The liver changes were, therefore, considered
treatment-related and adverse in the high dose animals of both sexes.
Decreased urea levels in the blood were observed in the treated females
throughout the study, and were likely related to kidney changes
observed.  The high dose females showed an elevated mean absolute and
relative kidney weight.  There were also histopathological findings of
eosinophilic droplets in the cortical tubules observed in the mid and
high dose groups.  The increased mean kidney weight was, therefore,
considered treatment-related and adverse in the high dose females.

The LOAEL for chronic toxicity was 200 ppm (equal to 51.7 mg/kg bw/day
in males, and 80.0 mg/kg bw/day in females) based on decreased body
weight gain in males, decreased triglyceride levels in both sexes,
decreased cholesterol levels in males, changes in glucose levels in
males, increased liver weights in both sexes, increased incidence of
histopathological findings in the liver hepatocytes in both sexes,
decreased blood urea levels in females, increased kidney weights in
females, and increased incidence of eosinophilic droplets in the
cortical tubules of the kidneys of females.  The NOAEL for chronic
toxicity was 50 ppm (equal to 12.8 mg/kg bw/day for males, and 20.3
mg/kg bw/day for females).

At the doses tested, there was no treatment-related increase in tumor
incidence in the treatment groups when compared with control animals up
to and including 200 ppm (equal to 51.7 mg/kg bw/day in males, and 80.0
mg/kg bw/day in females), the highest dose tested.  Under the conditions
of the current study, SXX 0665 was not considered to be carcinogenic in
mice.  Dosing was considered adequate based on decreased body weight
gain (males), increased liver weights, clinical chemistry changes and
increased histopathological findings in the liver hepatocytes (both
sexes), increased kidney weights (females) and increased incidence of
eosinophilic droplets in cortical tubules of kidneys (females) at 200
ppm.

This carcinogenicity study in the mouse is acceptable (guideline) and
satisfies the guideline requirement for a carcinogenicity study (OPPTS
870.4200; OECD 451) in mice.  This review is a joint effort of the PMRA
and the EPA.

A.3.6	Mutagenicity

	Gene Mutation

Guideline 84-2, Reverse Gene Mutation

MRID 46246343

Acceptable Guideline

JAU 6476

	dose range: 16 to 5000 ug/plate

JAU 6476 was increasingly cytotoxic at 158 ug/plate ± S9 in all strains
treated by plate incorporation, and at the highest concentration, 500
µg/plate ±S9, in four of the five strains treated by preincubation,
but additionally at 158 ug/plate in TA102.  However, at the remaining
concentrations, no appreciable differences in the number of revertants
in test cultures compared to solvent controls were found.  In contrast,
marked increases in all positive controls were induced.

Therefore, JAU 6476 is considered negative for reverse mutation in this
battery of S. typhimurium strains up to cytotoxic concentrations.

Guideline 84-2, Reverse Gene Mutation

MRID 46246345

Acceptable Guideline

JAU 6476 Des-chloro	16 to 5000 ug/plate  in the initial plate
incorporation assay, and at six concentrations ranging from 5 to 1581
µg/plate in the subsequent preincubation modification

No evidence of mutagenicity (increased revertants) was observed in
either assay up to cytotoxic levels of the test substance.

Therefore, 6476 Des-chloro is considered non-mutagenic in this bacterial
test system

Guideline 84-2, Reverse Gene Mutation

MRID 46246401

Acceptable Guideline

JAU 6476-alpha-acetoxy-desthio,	16 to 5000 ug/plate

At non-cytotoxic concentrations of the test article in either assay no
increases in revertant colonies (i.e., evidence of reverse mutation)
were observed, either in the presence or absence of activation.

Therefore, JAU 6476-alpha-acetoxy-desthio is considered non-mutagenic in
this bacterial test system

Guideline 84-2, Reverse Gene Mutation

MRID 46246402

Unacceptable Guideline

JAU 6476 sulfonic acid K. salt	16 to 5000 ug/plate

At no concentration in either assay did the test article significantly
increase the number of revertants over negative control values.
However, the spontaneous revertant counts of strain TA100 as well as the
response to the S9-activated positive control were lower than expected

Guideline 84-2, Reverse Gene Mutation

MRID 46246347

Acceptable Guideline

the asymmetric isomer of JAU 6476	16 to 5000 ug/plate

The asymmetric isomer of JAU 6476 is considered nonmutagenic in this
battery of S. typhimurium cultures up to cytotoxic concentrations.

Guideline 84-2, Reverse Gene Mutation

MRID 46246350

Acceptable Guideline

JAU 6476 - triazolinone	Cytotoxicity was evident at concentrations 
500 ug/plate ±S9 in both assays, compromising the useful assessment of
mutagenicity at higher concentrations.

Non-cytotoxic concentrations of the test article provided no increases
in revertant colonies compared to negative control values, in contrast
to marked increases in all positive controls.

Therefore, JAU 6476-triazolinone is considered nonmutagenic in this S.
typhimurium test system.

Guideline 84-2, Reverse Gene Mutation

MRID 46246348

Acceptable Guideline

JAU 6476-asymmetric disulfide	six  concentrations ranging from 16 to
5000 ug/plate in both assays, in the presence and absence of metabolic
activation

The highest concentration tested, 5000 ug/plate ± S9, caused a
reduction in revertant colonies and/or cell titers.  Compound
precipitation was seen at 1581 ·µg/plate.  At no testable article
concentration 1581 ug/plate (plate incorporation) and 500
µg/plate (preincubation) up to the limit (5000 ug/plate) in either
assay did JAU 6476-asymmetric disulfide increase the numbers of
revertant colonies cultured with/without metabolic activation.  All
positive controls manifested marked increases in revertant colonies.

Therefore, JAU 6476-asymmetric disulfide does not induce reverse
mutation in this bacterial test system up to cytotoxic concentrations.

Guideline 84-2, Reverse Gene Mutation

MRID 46246344

Acceptable Guideline

SXX 0665	five  concentrations ranging from 8 to 5000 ug/plate in the
initial experiment, and five concentrations ranging from 150 to 2400
ug/plate in the repeat test, both in the presence and absence of a
metabolic activation system

At no concentration up to cytotoxic levels in either assay, however,
were increases in revertants induced by SXX 0665, compared to concurrent
negative controls, or compared to the laboratory’s historical control
data.  Marked increases were induced in all positive controls.

Guideline 84-2, Reverse Gene Mutation

MRID 46246346

Acceptable Guideline

JAU 6476-methyl	Six concentrations ranging from 16 to 5000 ·g/plate in
the initial plate incorporation experiment, and at a lower range of six
concentrations from 16 to 512 µg/plate in the subsequent preincubation
test, in the presence and absence of an exogenous metabolic activation.

Concentrations 158 µg/plate ±S9 caused increasing bacteriotoxicity
in four of five strains treated by plate incorporation, and 256
ug/plate ±S9 in the majority of strains in the preincubation test.
However, in neither assay at any usable concentration in cultures
with/without metabolic activation were increases in reversion to
prototrophy induced in test article-treated cultures.  Marked increases
in revertant colonies were seen in all positive controls.

Therefore, JAU 6476-methyl is considered nonmutagenic in this battery of
S. typhimurium strains up to cytotoxic levels.

Guideline 84-2, Reverse Gene Mutation

MRID 46246349

Acceptable Guideline

JAU 6476- alpha-hydroxy-desthio	six concentrations ranging from 16 to
5000 ·g/plate (both assays), in the presence and absence of metabolic
activation

The highest concentration, 5000·µg/plate, was cytotoxic in two strains
in the initial plate incorporation assay, but in all strains by
preincubation.  However, increases in revertant colonies (evidence of
reverse mutation) were not observed at any concentration in either assay
exposed up to the limit concentration, 5000·µg/plate.  In contrast,
marked increases in revertants were found in all positive control
cultures.

Therefore, this alpha-hydroxy-desthio derivative of JAU 6476 is
considered non-mutagenic in this bacterial test system up to the
cytotoxic/limit concentration.

Guideline 84-2, Forward Gene Mutation

MRID 46246404

Acceptable Guideline

JAU 6476	Six concentrations ranging from 75 to 200 ug/mL were assayed.

Increasing test article cytotoxicity (as evident by decreased survival
as well as relative population growth) was observed in both the presence
(200 ug/mL) and absence (150 ug/mL) of S9-activation.  However at no
usable concentration in either the initial or the repeat assay did JAU
6476 increase the frequency of forward mutations, ± S9).  Marked
increases were induced in both positive controls.

Therefore, JAU 6476 is considered non-mutagenic in the V79-HGPRT forward
mutation assay.

Guideline 84-2, Forward Gene Mutation

MRID 46246405

Acceptable Guideline

JAU 6476	six concentrations ranging from 16 to 5000 ug/plate

Concentrations of the test material >500 ug/plate in the initial plate
incorporation assay caused an increasingly severe strain-specific
cytotoxicity, compromising appropriate assessment of reverse mutation at
higher levels.  Slight cytotoxicity in the majority of strains occurred
in the preincubation assay at the highest concentration tested, 256
µg/plate.  At no usable test article concentration in either assay did
JAU 6476-benzylpropyldiol increase the number of revertant colonies
cultures with/without metabolic activation.  All positive controls
manifested marked increases in revertant counts.

Therefore, JAU 6476-Benzylpropyldiol does not induce reverse mutation in
this bacterial test system up to cytotoxic concentrations.

Guideline 84-2, Forward Gene Mutation

MRID 46246403

Acceptable Guideline

JAU 6476	Seven concentrations ranging from 12.5 to 250 ug/mL - S9 (three
trials), or six concentrations ranging from 50 to 500 ug/mL +S9 (four
trials).

200 ·µg/mL or with S9- activation at 500 ug/mL.  Further,
precipitation of the test article occurred at the highest S9- activated
concentration tested.

However, at no usable concentration in any trial ± S9 did the test
article induce mutant frequencies (MFs), as determined by increases in
forward mutation to HGPRT-/- in test cultures over negative controls.
In contrast, both reference mutagens induced marked increases in MFs.

Therefore, SXX 0665 is considered non-mutagenic in the V79-HGPRT Forward
Mutation Assay.

	Cytogenetics

Guideline 84-2, in vitro cytogenetics

MRID 46246408

Acceptable Guideline

JAU 6476 Des-Chloro	60, 120, 180, 240 and 300 ug/mL in the presence and
absence of metabolic action

No statistically significant increases in structural chromosome
aberrations were manifested in culture treated for 4 hours at 60, 120,
and 180 ug/mL ± S9-mix or for 18 hours at 12, 24 and 36 ug/mL, both
harvested 18  hours after the onset of treatment, nor were increases
found at the 180 ·g/mL treatment and harvested at 30 hours.  Both
positive controls induced marked increases in structural aberrations.

Therefore JAU 6476 Des-Chloro is considered non-clastogenic in this test
system.

Guideline 84-2, In Vitro cytogenetics

MRID 46246406

Acceptable Guideline

JAU 6476	75, 100, and 150 ug/mL and harvested 18 hours after the
beginning of treatment in the initial assay; at a single dose of 150
ug/mL with a harvest at 30 hours in the repeat assay.

In preliminary cytotoxicity tests, decreases in cell survival and
mitotic indices were found at >50 ug/mL -S9 and 150 ug/mL +S9.  In the
main assays, significant increases in chromosome (structural)
aberrations (chromatid and chromosome breaks, fragments and exchanges)
were seen in non-activated cultures at all test article concentrations.
These increases, however, were not concentration-related and were
statistically significant only at the highest concentration tested
(HCT), 150 ug/mL in -S9 cultures, but questionable below that
concentration.  Increases were also observed in S9-activated cultures at
150 ug/mL.  Therefore, these increases may conceivably be attributable
to excessive cytotoxic effects, especially in the early phase of culture
growth.  Both positive controls induced clearly significant increases in
structural aberrations.  There were no increases in numerical
aberrations (polyploidy) in either test article-treated cells or
positive controls.

Therefore, JAU 6476 may be considered clastogenic (i.e., induces
increases in structural aberrations), but this mutagenic activation may
result from secondary cytotoxicity rather than direct structural DNA
damage.

Guideline 84-2, In Vivo (micronucleus) cytogenetics

MRID 46246410

Acceptable Guideline

SXX 0665	SXX 0665 is not considered to be a clastogen or aneugen in mice
at the i.p. administration of 350 mg/kg.

Guideline 84-2, In Vivo cytogenetics

MRID 46246409

Acceptable Guideline

JAU 6476	Adverse clinical signs of toxicity (apathy, semi-anesthesia,
staggered gait, sternal recumbency, spasm, and breathing difficulties)
were evident in test animals (but not in either control group) up to 24
hours after administration, but subsided thereafter.

The ratio of polychromatic to normochromatic erythrocytes was not
altered by JAU 6476 administration; the single statistically significant
difference at 24 hours (1000:968) was not considered biologically
relevant.  Furthermore, no biologically-relevant or statistically
significant differences were found in the incidence of micronucleated
polychromatic erythrocytes between the test group and the negative
control.  In contrast, the positive control showed a marked increase in
micronuclei, in conjunction with a lack of effect on the ratio of
polychromatic to normochromatic erythrocytes.

Therefore, the one i.p. dose of 250 mg/kg JAU 6476 (prothioconazole) is
considered to be non- clastogenetic in vivo.

Guideline 84-2, In Vivo cytogenetics

MRID 46246411

Acceptable Guideline

JAU 6476	50, 100 and 200 mg/kg

50 mg/kg; all animals, however, survived thereafter.  A significantly
altered ratio between polychromatic (PCE) and normochromatic (NCE)
erythrocytes was found at the highest dose, 200 mg/kg.

However, no increases in structural chromosome aberrations
(clastogenicity), compared to the vehicle control, were elicited at any
dose of JAU 6476.

In contrast, marked increases were induced in the positive control
groups in the absence of any alteration in the PCE:NCE ratio.

Therefore, JAU 6476 (prothioconazole) is not clastogenic or aneugenic in
male mice treated up to overtly toxic and cytotoxic doses.

Guideline 84-2, In Vitro cytogenetics

MRID 46246407

Acceptable Guideline

SXX 0665	5, 25, and 125 ug/mL

SXX 0665 is considered to be non-clastogenic in CHO cells up to
subcytotoxic concentrations.

	Other Genotoxicity

Guideline 84-2, Unscheduled DNA Synthesis

MRID 46246414

Acceptable Guideline

SXX 0665	at six concentrations ranging from 5 to 60 ug/mL in the
presence of radioactive thymidine

The highest concentration caused cell damage and reduced cell number.
However, there was no evidence that UDS, as determined by radioactive
tracer procedures [nuclear silver grain counts], was induced.

Guideline 84-2, Unscheduled DNA Synthesis

MRID 46246413

Acceptable Guideline

JAU 6476	single oral doses of 2500 or 5000 mg/kg

JAU 6476 (prothioconazole) is negative for UDS-induction in hepatocytes
drawn from male rats administered single oral doses of 2500 and 5000
mg/kg.

Guideline 84-2, Unscheduled DNA Synthesis

MRID 46246412

Acceptable Guideline

JAU 6476	seven concentrations ranging from 1.0 to 40 ug/mL in the first
trial, and 0.5 to 20 ug/mL in the repeat test, both in the presence of
tritiated-thymidine in order to monitor the number of silver grains
indicating UDS (other than scheduled synthesis during normal mitosis).

JAU 6476 produced slight non-dose-related increases (averaging
approximately 10X the vehicle control) in grain counts as well as in the
percent of cells with five nuclear grain counts (>16X vehicle
control), (cells in repair), compared to the concurrent vehicle control.
 The positive control induced marked increases in both grain counts and
percent of cells in repair.  Therefore, JAU 6476 is evaluated as
equivocal in this assay.

However, these results were clarified based on the negative findings in
the in vivo UDS assay in rat hepatocytes from adult male rats exposed up
to the 5000 mg/kg with the same Batch No. of the test materials. (MRID
46246413)

A.3.7	Neurotoxicity

	870.6100 Delayed Neurotoxicity Study - Hen

		Prothioconazole

			No Acceptable studies are available.

		Prothioconazole-desthio

			No Acceptable studies are available.

	870.6200 Acute Neurotoxicity Screening Battery

		Prothioconazole

				In an acute neurotoxicity study (MRID 46246417), groups of fasted,
9-week-old Wistar rats (12/sex) were given a single oral (gavage) dose
of JAU 6476 (97.6-98.8% a.i., batch# 898803005) in 0.5%
methylcellulose/0.4% Tween 80 at doses of 0 (vehicle), 200, 750, or 2000
mg/kg bw and observed for 14 days.  Neurobehavioral assessment
(functional observational battery [FOB] and motor activity testing) was
performed in 12 animals/sex/group on day 0 (four hours following
treatment, the time of peak effect) and on days 7 and 14.
Cholinesterase activity was not determined.  At study termination, six
animals/sex/group were euthanized and perfused in situ for
neuropathological examination.  Of the perfused animals, the control and
high-dose groups were subjected to histopathological evaluation of brain
and peripheral nervous system tissues.

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

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

The LOAELs for JAU 6476 in male and female rats are 750 and 2000 mg/kg,
respectively, based on the transient effect of reduced motor and
locomotor activity.  The NOAELs for male and female rats are 200 and 750
mg/kg, respectively.

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

		Prothioconazole-desthio

			No Acceptable studies are available.

	870.6200 Subchronic Neurotoxicity Screening Battery

		Prothioconazole

				In n a subchronic neurotoxicity study (MRID 46246416) JAU 6476
(97.6-98.8% a.i., batch #s 898803005 and 6233/0031) was administered to
12 Wistar (Crl:WI(HAN)BR) rats/sex/group at nominal dose levels of 0,
100, 500, or 1000 mg/kg bw/day, five days/week, for 13 weeks
(analytically determined doses of 0, 98, 505, and 1030 mg/kg/day).  The
dose was administered by gavage in 0.5% methylcellulose/0.4% Tween 80 in
deionized water.  Neurobehavioral assessment (functional observational
battery and motor activity testing) was performed in 12
animals/sex/group pretreatment and during weeks 4, 8, and 13.
Cholinesterase activity was not determined.  At study termination, six
animals/sex/group were euthanized and perfused in situ for
neuropathological examination.  Of the perfused animals, the control and
high-dose groups were subjected to histopathological evaluation of brain
and peripheral nervous system tissues.

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

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

Based on decreased body weight and body weight gains in males, the LOAEL
for JAU 6476 was 1000 mg/kg bw/day. The NOAEL was 500 mg/kg/day.

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

		Prothioconazole-desthio

			No Acceptable studies are available.

	870.6300 Developmental Neurotoxicity Study

		Prothioconazole

			No Acceptable studies available.

		Prothioconazole-desthio

			In a developmental neurotoxicity study (MRID 46246418), SXX 0665
(99.1-99.4% a.i.; batch # RUX76-105-1E), a metabolite of prothioconazole
(PC Code 113961), was administered in the diet to 30 female mated Wistar
Hannover Crl:WI (Glx/BRL/Han) IGS BR rats/dose at nominal concentrations
of 0, 40, 160 and 500 ppm from gestation day (GD) 6 through lactation
day (LD) 21.  Average doses to the dams were 0, 3.6, 15.1 and 43.3
mg/kg/day during gestation and 0, 8.1, 35.7 and 104.6 mg/kg/day during
lactation for the 0, 40, 160 and 500 ppm groups, respectively.  No data
were provided regarding exposure to the offspring.  A Functional
Operational Battery (FOB) was performed on 30 dams/dose on GDs 13 and
20, and on 10 dams/dose on LDs 11 and 21.  On postnatal day (PND) 4,
litters were culled to yield four males and four females (as closely as
possible).  Offspring were allocated for detailed clinical observations
(PNDs4, 11, 21, 35, 45, 60) and assessment of motor activity (PNDs13,
17, 21, 60), auditory startle reflex habituation (PNDs22, 38, 60),
learning and memory (passive avoidance [PNDs22, 29] and watermaze [PNDs
60, 67] testing), and neuropathology and brain morphometric evaluation
at PND21 (neuropathology for CNS tissues only) and at study termination
(day 75±5 of age; neuropathology for CNS and PNS tissues).
Ophthalmologic evaluations were also performed, around PND 50-60.  Pup
physical development was evaluated by body weight.  The age of sexual
maturation (vaginal opening in females and preputial separation in
males) was assessed.

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

No treatment-related clinical signs were observed in offspring during
lactation.  Post-weaning, there was a progressive development of
malocclusion and a deviated snout (dorsal aspect) with associated
findings (lacrimation, lacrimal stain) at 160 (one male, two females)
and 500 ppm (three males, seven females).  The changes became evident
around PND 32 with progressively more animals developing malocclusion
and a deviated snout.  Body weight at birth was increased at 160 and 500
ppm (7 and 13-14%, respectively, in both sexes); however by PND71
absolute body weight in adult males at 500 ppm was significantly lower
than control values (5%).  The average age of onset of preputial
separation in males and vaginal opening in females was not affected by
treatment.

Clinical signs observed during the FOB examinations were associated with
malocclusion (broken teeth or malocclusion in one female each at 160 and
500 ppm on PNDs 45 and 60) and a deviated snout (two other females at
500 ppm on PND 60).  Total motor activity was increased at 500 ppm in
both sexes at PND 13 (82-120% above control levels).  Auditory startle
response was increased in males at 500 ppm on PND22 (53-70%).  There
were no clear treatment-related effects on learning and memory as
evaluated by passive avoidance testing on PND22-29. Increases in latency
and errors were seen in the water maze on PND60, in males at 160 and 500
ppm (83-67% increase in Trial 1 errors) and in females at 500 ppm only
(54% increase in errors).  Limitations in the data presentation and high
variance made interpretation of the water maze findings unclear.

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

PMRA:

The maternal LOAEL for SXX 0665 (metabolite of prothioconazole) in rats
is 160 ppm (15.1 mg/kg/day) based on an increased incidence of stillborn
pups.  The maternal NOAEL is 40 ppm (3.6 mg/kg/day).

The developmental LOAEL for SXX 0665 in rats is 160 ppm (15.1 mg/kg/day)
based on an increased incidence of progressive malocclusion and deviated
snout and increased incidence of stillborn pups.  The developmental
NOAEL is 40 ppm (3.6 mg/kg/day).

The offspring neurotoxicity LOAEL and NOAEL for SXX 0665 in rats could
not be determined, due to the absence of neuropathological and brain
morphometric evaluations at the mid and low dose treatment levels.

EPA:

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

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

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

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

A.3.8	Metabolism

	870.7485	Metabolism - Rat

		Prothioconazole

			In a whole body autoradiography distribution study (MRID 46246419),
triazole-labeled JAU6476 (Prothioconazole) (Purity: >99%), was
administered to 8 Wistar rats/sex/dose in a single oral administration
at dose levels of 4 mg/kg bw non-radiolabeled JAU6476 and 4 mg/kg bw
[Triazole-UL-14C] JAU6476 in 0.5% aqueous Tragacanth.  One control
animal/sex was dosed with vehicle alone.  One animal/sex was killed at
1, 4, 8, 24, 48, 72, 120 and 168 hours after dose administration.
Control animals were killed 4 hours after dose administration.  All
animals were fixed and processed for whole body autoradiography.

The whole body autoradiography results are in agreement with the
absorption, distribution and excretion pattern of JAU6476 in the main
metabolism study (MRID 46246421).  In summary, peak concentrations in
males were noted 1 hour post-administration and continued to decline
until sacrifice at 168 hours. In females, absorption was slightly
delayed with peak concentrations in some tissues noted at 8 hours post-
administration.  The highest concentrations were noted in liver (up to
1.78 ug/g in males and up to 0.97 ug/g in females), followed by kidney
(renal medulla, up to 0.64 ug/g), brown/perirenal fat (up to 0.36 ug/g),
thyroid (up to 0.23 ug/g) and adrenal gland (up to 0.27 ug/g). All other
tissues showed peak concentrations of <0.13 ug/g. Concentrations of
radioactivity decreased rapidly from 24 to 168 hours
post-administration, indicative of continued elimination from the
tissues.

This metabolism study in the rat is classified as
Acceptable/Nonguideline and does not satisfy the guideline requirement
for a metabolism study (OPPTS 870.7485; OECD 417) in the rat.  This
guideline requirement for prothioconazole (JAU6476) was satisfied by
another rat metabolism study (MRID 46246421).  This review is a joint
effort of the PMRA and the EPA.

________

 					The absorption, distribution, metabolism and excretion (MRID
46246421) of JAU6476 (Prothioconazole) (Purity 99.4-99.8% a.i) was
investigated in male and female Wistar rats following gavage
administration of [triazole-UL-14C]- or [phenyl-UL-14C]-labelled JAU6476
in 0.5% aqueous Tragacanth solution. Single oral low dose (SOLD) studies
were conducted using 2 mg/kg bw of [triazole-UL-14C]- or
[phenyl-UL-14C]-labelled JAU6476 in males and females; 5 mg/kg bw of
[phenyl- UL-14C]-labelled JAU6476 in males only. Single oral high dose
(SOHD) studies were conducted using 150 mg/kg bw of
[triazole-UL-14C]-labelled JAU6476 in males and females.  Repeat oral
low dose (ROLD) studies were conducted using a pretreatment of 2 mg/kg
bw unlabelled JAU6476 for 14-15 days followed by a SOLD of 2 mg/kg bw of
[phenyl-UL-14C]-labelled JAU6476 in males and females.  Biliary
excretion studies were conducted using 2 mg/kg bw [triazole-UL-14C]- and
[phenyl-UL-14C]-labelled JAU6476 in males only.  The animals were
sacrificed at 168 hours post-dosing for the SOLD and SOHD groups, at 168
hours after the final dose for the ROLD groups and at 48 hours
post-dosing for the bile- cannulated [triazole-UL-14C]-labelled group.

The biokinetic behavior and metabolism of JAU6476 was adequately
outlined in this series of tests, using both triazole and phenyl labels.
 The recovery of administered radioactivity was adequate.  The results
of a preliminary test showed that a minimal amount of radioactivity
(<0.06%) was recovered in the expired air (measured as 14CO2), therefore
it was determined that it was not necessary to monitor CO2 and volatiles
in further studies.  Following single oral low dose administration, the
absorption of JAU 6476 in male rats was approximately 94% for the
triazole label.  The absorption for the phenyl label was estimated to be
approximately 90% at 48 hours based on extrapolation of the course of
excretion for the triazole label at 48 hours.

Plasma radioactivity time-course data showed that absorption following
single oral low dose administration was rapid, with peak plasma
concentrations occurring between 0.33 and 0.66 hours post administration
in males and females.  Peak plasma concentrations following single oral
high dose administration occurred between 0.66 and 1.00 hours post
administration in males and females.  The absorption of the
phenyl-labelled JAU6476 was slightly more rapid, with peak plasma
concentrations occurring between 0.16 and 0.33 hours post administration
of a single oral low dose in males, and at 0.16 hours post
administration of a repeat oral low dose in males and females.
Oscillations in the plasma time course were noted, indicating that the
radioactivity was subjected to enterohepatic circulation.  This effect
was more prominent in the female rats.  A slight delay in absorption
compared to males was also noted in females.

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

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

JAU6476 was extensively metabolized in the rat following oral
administration.  Eighteen metabolites and the parent compound were
identified in urine, feces and bile.  The biotransformation of JAU6476
consisted of 3 major reaction types including desulfuration, oxidative
hydroxylation of the phenyl moiety and glucuronic acid conjugation.
Identification of the metabolites ranged from 26-63% of the administered
dose.  A higher percentage of metabolite isolation and identification
could not be achieved due to difficulties in fecal extraction where
21-33% of the administered dose remained in non-extractable residues in
the solids.  The parent compound JAU6476 was the most abundant in the
feces (1-22% of the administered dose), followed by the JAU6476-desthio
metabolite (3-18% of the administered dose).  All other fecal
metabolites represented less than 8% of the administered dose. The 1, 2,
4-triazole metabolite was not detected in the feces.  The major urinary
metabolite was JAU6476-S- or O-glucuronide (0.1-8% of the administered
dose) and was preferentially excreted in females.  The 1, 2, 4-triazole
metabolite represented 0.8-2.3% of the administered dose following
administration of single oral low and/or high doses.  The remaining
urinary metabolites each accounted for 0-1.4% of the administered dose.
JAU6476- S- or O-glucuronide was the most abundant metabolite in the
bile, representing approximately 46% of the administered dose.  This
metabolite was excreted in females only in the urine, however it was
noted in the bile in males.  Desthio glucuronic acid metabolites in the
bile represented 8-10% of the administered dose.  Parent compound
represented 3-5% of the administered dose in the bile.  The 1, 2,
4-triazole metabolite was not detected in the bile.

This metabolism study in the rat is classified as acceptable and
satisfies the guideline requirement for a metabolism study (OPPTS
870.7485; OECD 417) in rats.  This review is a joint effort of the PMRA
and the EPA.

________

		Prothioconazole-desthio

				In a metabolism study (MRID 46246439), SXX 0665 (99.6% purity)
(uniformly labelled with carbon-14 in the benzene ring of the molecule)
was administered singly or in multiple dose levels to groups of pregnant
rats (5/dose) at 1 or 3 mg/kg orally by gavage or 30 or 100 mg/kg by the
dermal route on gestation day 6.  The multiple dose regimen was
performed with 9 doses of non-radio labelled compound followed by one
dose of the radio labelled compound at intervals of 24 hours.  For
dermal application, the exposure time was 6 hours under occlusive
conditions followed by 18 hours of non-exposure.

The maximum concentrations (Cmax) were comparable between single and
multiple oral administration of 1 mg/kg and 3 mg/kg and dermal
application of 30 mg/kg, respectively.  The maximum concentration varied
after single and multiple dermal application of 100 mg/kg.  The time to
achieve maximum concentration was prolonged after dermal application
compared with oral administration at all doses tested (single and
multiple) but the delay was not dose-dependent.  The longest terminal
half-life was observed in the high dose single dermal application (100
mg/kg) which was 34.4 h.  The lowest terminal half-life was observed in
the low dose multiple dermal application group (30 mg/kg).  The AUC
values (representing an indirect measure for the fraction of SXX 0665
absorbed) increased only slightly after large increases in applied dose
(both dermal and oral).

This metabolism study in the rat is classified as supplemental and does
not satisfy the guideline requirement for a metabolism study (OPPTS
870.7485); OECD 417 in the rat (see deficiency notes).  This review is a
joint effort of the PMRA and the EPA.

________

				In a metabolism study (MRID 46246422), [Phenyl-UL-14C] SXX0665 (a
metabolite of prothioconazole) (99.8% a.i.), was administered to 5 to 10
Wistar BOR/WISW (SPF Cpb) male rats/dose in 0.5% aqueous Tragacanth in a
single oral gavage dose or an intraduodenal dose at levels of 1 or 5
mg/kg bw.  The animals were immediately placed in either metabolism
cages or restraining cages following dosing.  Expired air, urine, feces,
and/or bile were collected throughout the observation period and
analyzed.  The animals were sacrificed 48 hours after dose
administration, and the carcass, skin, and gastrointestinal tract from
each animal were collected and analyzed.

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

In whole-body autoradiography experiments, the quick onset of absorption
of the test material was demonstrated.  Absorption was not complete
after one hour.  The autoradiograms also showed that the blood
concentration was less than the concentration present in the fatty
tissues, demonstrating the lipophilic nature of SXX0665, and perhaps of
its metabolites.  The mucous membrane of the stomach walls were observed
with radioactivity throughout the various observation periods, which was
considered an indication of extrabiliary secretion of the absorbed
radioactivity back into the stomach lumen.  The muscle, heart, lung,
brain, thyroid, and mineral portion of the bones showed minor
concentrations of radioactivity.  The testes had a radioactivity
distribution pattern indicative of the blood circulation in the organ.
Medium amounts of radioactivity were observed in some glandular organs,
including the preputial gland and the adrenals.  The gums were also
observed with increased radioactivity, with unknown physiological
significance.  The distributions noted at one hour were fairly
consistent for 48 hours, though declining due to excretion.  The renal
cortex contained radioactivity to a much greater extent than did the
renal pelvis, indicating that the radioactivity was reabsorbed in the
duodenum.  As well, the radioactivity that is absorbed is likely not
transformed into metabolites that are adequately polar to be eliminated
by the kidney.  This results in increased passage through the liver by
the radioactive test material.

This metabolism study in the rat is classified Acceptable/Nonguideline
and does not satisfy the guideline requirement for a metabolism study
(OPPTS 870.7485; OECD 417) in rats.  This study alone does not fulfill
the guideline requirements for a metabolism study (DACO 4.5.9), but can
be considered a supplementary study along with the other studies