and sores and/or crusts on the skin in 7000 ppm males (7/10).
Neovascularisation and corneal opacity occurred at an increased
incidence in males at 75 (2/15), 1500 (4/15) and 7000 ppm (2/10); and in
females at 75 (1/15), 1500 ppm (3-4/15) compared to 0/10 in controls.
These effects were observed at a higher frequency in males compared to
females.  Also, the frequency of appearance of corneal opacity increased
with treatment duration.  However, neovascularization (2/5 in 1500 ppm
males) observed in males and in females corneal opacity and
neovascularization were reversible following a 4 week recovery period in
the 75 and 1500 ppm groups.  Hair loss was observed in both sexes in the
7000 ppm group (7/10).

-15 (↓19%, p<0.01) and 1-29 (↓12%, p<0.05).  At 7,000 ppm in both
sexes, body weight was significantly reduced throughout treatment by
13-19% in males (p<0.001) and 9-11% in females (p<0.01).  Body-weight
gain was significantly (p<0.001) reduced by 29% in males and 24% in
females.  At 1,500 ppm, food consumption was significantly reduced for
males during the first week of treatment (↓14%, p<0.01).  Food
consumption was reduced throughout treatment by 7-36% in males and
10-32% in females at 7,000 ppm.

No hematological effects were observed in females at any dose level.
Blood clotting parameters (mean activated partial thromboplastin and
mean prothrombin times) were significantly elevated at > 1500 ppm
(21-41%).  RBC, MCH and HCT were significantly reduced in 7000 ppm males
by 9-21%.

A treatment related increase in cholesterol was observed in males in a
dose-dependent manner that reached significance at >75 ppm [1.25 ppm
(14%), 75 ppm (22%, p<0.01), 1500 ppm (32%, p<0.001), 7000 ppm (80%,
p<0.001)] and increased significantly by 34% (p<0.01) in females at 7000
ppm.

Urinary pH significantly (p<0.01) decreased at > 1500 ppm (5.95-6.00)
versus controls (6.65) in males and at 75 and 1500 ppm (5.25, 10%,
p<0.05; 5.15, 10%, p<0.01), respectively, versus controls (5.75) in
females.  A treatment related increase in ketone levels (grades 2 and 3)
was noted in both sexes at >75 ppm when compared to controls.

Relative brain weight was significantly (p<0.01) increased in both males
and females by 11 and 12%, respectively, at 7000 ppm.  Absolute brain
weight decreased significantly (p<0.001) by 6% in 7000 ppm males only
and was comparable to controls in females.  In males, absolute liver
weight was significantly increased by 20% (p<0.01) in 75 and 1500 ppm
and by 18% (p<0.05) in 7000 ppm groups.  Relative liver weight
significantly (p<0.001) increased dose-dependently by 21-38% in males;
and in 7000 ppm females by 19%.  These effects were considered treatment
related since hepatic effects were observed in other studies.  Absolute
thymus weight decreased in a dose-dependent manner that reached
significance in 7000 ppm males (34%, p<0.05).  In females, absolute and
relative thymus weight significantly decreased by 20-31% (p<0.05-0.001)
in all treated groups.  Relative Heart weight significantly increased in
7000 ppm males by 12% (p<0.05).  Relative kidney weight increased
significantly in 1500 (12%, p<.05) and 7000 ppm (25%, p<.001) males.
However, relative heart weight changes were not considered significant
toxicologically in the absence of a dose response and/or corroborating
pathological changes.

The following microscopic changes were observed at an increased
incidence in males: diffuse centrilobular hepatocellular hypertrophy at
75 (6/10), 1500 (8/10), and 7000 ppm (8/9) versus controls (0/10); and
diffuse paracortical hyperplasia in the submaxillary lymph node at 7000
ppm (5/9 vs 0/10 in controls), testicular unilateral tubular atrophy
(3/10), multifocal accumulation of golden-brown pigments in macrophages
in the epididymides (4/10) and prostates glands (3/10); and bilateral
spermatic granulomas in the epididymides (3/10) at 7000 ppm compared to
0/10 in controls.  An increased incidence of thyroid gland follicular
hypertrophy in 75 ppm (1/10) and 1500 ppm (3/10) and  colloid
condensation in 1.25 ppm (1/10), 75 ppm (4/10) and 1500 ppm (6/10) males
was observed compared to 0/10 in controls.  These effects were
considered treatment-related.  Also, there was an increased incidence of
hyaline droplets accumulation in the corticotubular epithelium of the
kidneys in males at 1.25 (4/10) 75(6/10), 1500 (7/10) 7000 ppm (8/9)
versus controls (5/10).  The increased incidence of multifocal
accumulation of hyaline droplets was due to the α2μ-globulin mechanism
which is specific to the male rat, therefore, it was not considered to
be toxicologically significant.

In females, the following microscopic changes were observed at an
increased incidence: multifocal corticotubular basal vacuolation
(slight) in the kidneys occurred in a dose-dependent manner 1-6/10 in
all treated groups compared to 0/10 in controls; diffuse hypertrophy of
the interstitial gland in the ovaries was observed in the 1500 ppm and
7000 ppm groups (3/10) compared to 0/10 in controls.  These effects were
considered treatment-related.  Multifocal accumulation of alveolar
macrophages in lungs observed in all treated groups (4-9/10 vs 1/10 in
controls) was considered a sporadic finding in the absence of a clear
dose response.

The LOAEL is M/F: 4.45/5.59 mg/kg/day (75 ppm), based on
neovascularization and opacity of the cornea and increased urinary
ketones in both sexes; increased cholesterol, absolute liver weights,
and diffuse centrilobular hepatocellular hypertrophy in males; and
decreased absolute and relative thymus weights in females.  The NOAEL is
M/F: 0.07/0.09 mg/kg/day (1.25 ppm).

This 90-day oral toxicity study in the rat is acceptable/guideline and
satisfies the guideline requirement for a 90-day oral toxicity study
(OPPTS 870.3100; OECD 408) in rats.

EXECUTIVE SUMMARY:  In a 90-day subchronic toxicity study (MRID
466995639), AE 0172747 (94-7-95.5% a.i., batch/lot # PFI 0254) was
administered to 10 Rj: WI (IOPS HAN) Wistar rats/sex/dose in the diet at
dose levels of 0, 6, 20 or 40 ppm (equivalent to 0, 0.30, 0.98 or 2.20
mg/kg bw/day in males and 0, 0.35, 1.18 or 2.68 mg/kg bw/day in females,
respectively) in the diet for at least 90 days.   No mortality occurred
throughout the course of this study at any dose level.  Body weight,
body-weight gain, food consumption, hematology and clinical chemistry
assessment were unaffected by treatment.

At 6 ppm, no toxicologically significant change was noted.

At 20 ppm, snow flake-like corneal opacity was noted at the
ophthalmological examination in the left eye of one male after 3 months
of treatment.  This male was observed with unilateral keratitis upon
microscopic examination.  Urinalysis revealed higher ketone levels in
both sexes in comparison to controls.

At 40 ppm, clinical signs were noted in a single female and consisted of
white areas on the left eye noted at the weekly physical examination on
Days 78 and 85.  The neurotoxicity assessment revealed no
treatment-related effects. At the ophthalmological examination, corneal
opacity, neovascularization and edema of the cornea in the left eye of
female was confirmed after 3 months of treatment.  Urinalysis showed
higher ketone levels in both sexes, in association with a mean pH value
lowered by 8% in males (p≤0.05), when compared to the control values.
One female was observed with unilateral keratitis at microscopic
examination.

The LOAEL is 20 ppm (0.98 mg/kg bw/day in males and 1.18 mg/kg bw/day in
females), based on snow flake-like corneal opacity and keratitis of the
eyes in males and corneal opacity, neovascularization and edema of the
cornea in females.  The NOAEL is 6 ppm (0.30 mg/kg bw/day in males and
0.35 mg/kg bw/day in females).

This 90-day subchronic toxicity study in the rat is acceptable/guideline
and satisfies the guideline requirement for a 90-day subchronic toxicity
study [(OPPTS 870.3100); OECD 408] in rats.

EXECUTIVE SUMMARY:  Metabolite AE 1417268 (M5)

In a subchronic oral toxicity study (MRIDs 46695641 and 46695637),
AE 1417268 (plant metabolite of AE 0172747; 99% purity; Batch No. NLL
7555-9) was administered to 10 Wistar rats/sex/dose in the diet at dose
levels of 0, 200, 1500, or 9000 ppm (equivalent to 0/0, 12.7/15.6,
95.7/115, and 586/718 mg/kg/day in males/females) for 90 days.

No effect was observed on clinical signs of toxicity, body weight, body
weight gain, food consumption, hematology, clinical chemistry, or
urinalysis.

One 9000 ppm male was killed moribund on Day 69, and was found to be
suffering from a hemorrhagic syndrome.

At 9000 ppm, increased incidences of slight diffuse acinar
degeneration/apoptosis in the pancreas in the males (4/10 treated vs
0/10 controls) and minimal to moderate degeneration in the females (8/10
treated vs 3/10 controls) were observed.

At 9000 ppm, a white area on the right eye of one female was noted from
Day 36 onwards.  Superficial corneal opacity was observed in one eye in
the females (3/10 treated vs 0/10 controls), and was associated with
neovascularization of the cornea in 1 of the 3 females and
neovascularization of the cornea and edema of the cornea for another of
the 3 females.  Eye opacity (gross lesion) was present in two females/10
vs 0/10 controls.  Increased incidences of slight to moderate unilateral
keratitis (2/10 treated vs 0/10 controls) and bilateral keratitis (1/10
treated vs 0/10 controls) were noted in the females.  Eye toxicity was
considered a critical neurological effect.

Absolute, relative to body, and relative to brain liver weights were
increased (p<0.01) in the >1500 ppm males (increase 17-27%). The liver
was enlarged in the >1500 ppm males (8/10 each treated vs 0/10 controls)
and had prominent lobulation in the 9000 ppm males (4/10 treated vs 1/10
controls).  Increased incidences minimal to slight centrilobular
hepatocellular hypertrophy (diffuse) were noted in the >1500 ppm males
(4-5/10 treated vs 0/10).  Also, serum triglycerides were increased by
43% in the 9000 ppm females.

The LOAEL is 9000 ppm (equivalent to 586/718 mg/kg/day in
males/females), based on acinar degeneration/apoptosis in the pancreas
of both sexes, death due to a hemorrhagic syndrome in one male,
increased absolute and relative liver weights, enlarged liver with
prominent lobulation and hepatocellular hypertrophy in males; and
increased serum triglycerides and eye lesions in females.  The NOAEL is
1500 ppm (equivalent to 95.7/115 mg/kg/day in males/females).

This study is classified as acceptable/guideline and satisfies the
guideline requirements (OPPTS 870.3100; OECD 408) for a subchronic oral
toxicity study in the rat.

EXECUTIVE SUMMARY : Metabolite AE 0456148 (M6)

In a subchronic oral toxicity study (MRID 46695642), AE 0456148 (a
metabolite of AE 0172747; 99.0% purity; Batch No. ABJ1204-PFI) was
administered to 10 Wistar rats/sex/dose in the diet at dose levels of 0,
15, 150, 1500, or 15,000 ppm (equivalent to 0/0, 1.19/1.63, 12.34/16.08,
120.19/162.49, and 1203.8/1436.3 mg/kg bw/day in males/females) for at
least 94 days.

No adverse, treatment-related effects were observed on mortality,
clinical signs, functional observational battery, motor activity,
locomotor activity, body weight, food or water consumption,
ophthalmoscopy, hematology, clinical chemistry, urinalysis, organ
weights, gross pathology, or histopathology.

At 15,000 ppm, a decrease in body weight gain during the last week of
the study (decr. 71%; p<= 0.01) resulting in decreased body weight at
Day 91 (decr. 9%; p<= 0.05) was observed in females.  This decrease in
body weights in females corresponded to a decrease in food consumption
observed during Week 13 of the study and is considered to be an indirect
effect of treatment.  Also at 15,000 ppm, mean food consumption was
decreased (NS) in females throughout the study.  However, this effect
only resulted in a minor decrease in body weight during Week 13 of the
study; therefore this effect was not considered adverse.

At >= 1500 ppm, an increase in incidence and severity of minimal to
moderate hematopoiesis of the spleen was observed in females when
compared with controls.

The LOAEL was 1500 ppm (equivalent to 162.49 mg/kg bw/day) in females,
based on an increase in the incidence in hematopoiesis of the spleen.
The NOAEL is 150 ppm (equivalent to 16.08 mg/kg bw/day) in females.
The LOAEL was not determined in males. The NOAEL is 15,000 ppm
(equivalent to 1203.8 mg/kg bw/day) in males.

This study is classified as acceptable/guideline and satisfies the
guideline requirements (OPPTS 870.3100a; OECD 408) for a subchronic oral
toxicity study in the rat.

	870.3100	90-Day Oral Toxicity - Mouse

EXECUTIVE SUMMARY: In a subchronic oral toxicity study (MRID 46695640),
AE 0172747 (95.0% w/w a.i.; Batch No. PFI 0195) was administered to 10
C57BL/6J@ Ico mice/sex/dose in the diet at dose levels of 0, 35, 350,
3500, or 7000 ppm (equivalent to 0/0, 5.9/7.3, 64.0/75.6, 631/783, and
1317/1833 mg/kg bw/day in males/females) for 90 days.  No
treatment-related ophthalmic findings were noted.

A dose-related increased incidence of intense yellow colored urine was
noted in 6-10/10 mice in each treated group.

One 7000 ppm male was killed moribund on Day 78.  This mouse had reduced
motor activity, hunched posture, and was cold to touch.  It had a dark
intestinal content, which corresponded to marked focal/multifocal
ulceration and diffuse transmural hemorrhage in the duodenum observed
microscopically.  This death was considered related to treatment.

Transient effects on body weight and body-weight gains were observed at
7000 ppm.  Overall (Days 1-90) body-weight gains were similar to
controls in both sexes.  In the males, body-weight gains were decreased
by 69% during the first two weeks, while food consumption was only
decreased by 9%.  However, body-weight gains in the males were generally
similar to controls after the first two weeks.  In the females,
decreased body weights were observed generally each week from Days
15-85.  There was no body-weight gain in the females during the first
week of treatment; however, the mice consumed 13% more food.  Cumulative
body-weight gains (Days 1-29) were decreased by 42%; however, after Day
29, the females generally gained weight faster than controls.  In the
7000 ppm females, increased food consumption was generally observed
weekly from Day 36 until termination.  Food consumption was increased
dose-dependently in females and was increased by 20% at 7000 ppm.  The
body weight and body-weight gain changes are minor and are not
considered to be adverse effects.

Indications of slight hepatotoxicity were observed at 3500 and 7000 ppm.
 Absolute, relative to body, and relative to brain liver weights were
increased (p<=0.05) in the males by 11-36%.  Relative to brain liver
weights were increased (p<=0.05) by 17-28% in the females.  The liver
was dark in both sexes (2-6/9-10 treated vs 0/10 controls).  Increased
incidences of slight to mild diffuse centrilobular hepatocellular
hypertrophy were observed in both sexes (3-10/9-10 treated vs 0/10
controls).

Slight increased corpora lutea in ovaries was noted in the >=3500 ppm
females (8-9/8-10 treated vs 0/10 controls).  Proestrus vagina was noted
at 7000 ppm (5/10 treated vs 0/10 controls).

The LOAEL is 3500 ppm (631/783 mg/kg/day in males/females), based on
decreased uterine weights and increased corpora lutea in the ovary in
females; and increased serum alanine aminotransferase activity, liver
weights, hepatocellular hypertrophy, dark liver, macroscopic
erosive/ulcerative lesions in the stomach and/or dark intestinal content
in both sexes.  The NOAEL is 350 ppm (64.0/75.6 mg/kg/day in
males/females).

This study is classified as acceptable/non-guideline and does not
satisfy the guideline requirements (OPPTS 870.3100; OECD 408) for a
subchronic oral toxicity study in the mouse.  The study can not be
upgraded due to the absence of hematology data required at the time of
study.

	870.3150	90-Day Oral Toxicity - Dog

EXECUTIVE SUMMARY:  In a subchronic oral toxicity study (MRID 46695643),
AE 0172747 (94-95.0% w/w, Batch Nos.: PFI 0195 and PFI 0215) was
administered to 4 beagle dogs/sex/dose in the diet at doses of 0, 125,
or 750 ppm (equivalent to 0/0, 4.5/4.5, and 26.7/28.5 mg/kg/day in
males/females) for 90 days.  Additionally, a high dose group was fed the
test substance in the diet at 4500 ppm (equivalent to 124/111 mg/kg/day
in males/females) for 29 days which was then reduced to 2250 ppm from
Days 30-90 due to overt signs of toxicity (uncoordinated movements and
lack of body-weight gain).

No treatment-related adverse effects were observed on urinalysis or
gross pathology at any dose, and no treatment-related effects were
observed at 125 or 750 ppm.  The following treatment-related effects
occurred at 4500/2250 ppm.

One male was killed in extremis on Day 38.  Clinical signs of toxicity
and decreased body-weight gain were observed prior to sacrifice of this
animal.

One male (on Days 29-39) and two females (on Days 30-42) had
uncoordinated movements.  Two males (on Days 41-43) had a wasted
appearance, and one of these males continued to have this appearance
during the last two weeks of the study.  Beginning on Day 34 and lasting
up to Day 90, one male and all females displayed one or more of the
following signs of toxicity:  abnormal placing, posture, hopping, or
wheel barrowing.  These signs were not observed in the remaining
treatment groups.

Body weights in males and females were decreased beginning on Days 19-22
and lasting throughout the study, resulting in decreased overall (Day
1-90) body-weight gains.  The decrease in body weights in females
corresponded to a decrease in food consumption observed during Weeks
1-5, while being dosed at 4500 ppm.  When dosing changed from 4500 ppm
to 2250 ppm at Week 5, food consumption remained decreased until Week 9
where values became comparable to or increased over controls for the
remainder of the study.

A bilateral corneal opacity was observed in one male during the Weeks 7
and 13 examinations.  No other effects were observed on ophthalmoscopy.

The following differences from controls in hematology were observed
throughout the study in both sexes:  (i) decreased MCH; (ii) increased
platelets; (iii) decreased hemoglobin; and (iv) decreased leukocytes and
neutrophils.  Additionally at this dose, the following differences were
observed:  (i) increased reticulocytes throughout the study in females;
and (ii) decreased mean corpuscular volume (MCV) at Week 13 in males.
Changes in erythrocyte morphology observed at Week 7 and/or Week 13
included:  slight to severe anisocytosis, anisochromia, and hypochromia
and slight to moderate microcytosis.  Albumin levels and
albumin/globulin ratios were decreased in both sexes at Week 7 and in
males at Week 13.  Alkaline phosphatase (ALK) activity was increased in
females at Week 7, with activity remaining increased to a lesser
magnitude on Week 13.

Absolute and relative (to body and brain) liver weights were increased
by 17-37% in males and 16-32% in females when compared with controls.
Mild diffuse hepatocellular cloudy swelling was observed in all males
(3/3), and a slight to mild effect was observed in all females (4/4)
compared with 0/4 of the respective control animals.  A slight
multifocal pigmentation of hepatocytes and Kupffer cells was observed in
all males (3/3 vs. 0/4 controls) and 2/4 females (vs. 0/4 controls).
Multifocal vacuolation of the adrenal glands was observed in all males
(3/3 vs. 0/4 controls).

In the peripheral nerves, an increased number of digestion chambers were
noted as follows (vs 0 controls):  (i) sciatic nerve of 1/4 female; (ii)
radial nerve of 3/3 females; (iii) musculocutaneous nerve of 2/3 males
and 1/3 females; and (iv) femoral nerve of 1/3 males and 1/3 females.
In the one female with increased number of digestion chambers in the
sciatic nerve, a mild atrophy/regeneration of the tibial muscle was also
noted.  These digestion chambers were a result of focal enlargement of
the myelin sheath due to myelin debris, and may account for the
neurological effects observed at this dose.

The LOAEL is 4500/2250 ppm (equivalent to 124/111 mg/kg/day M/F), based
upon clinical signs of toxicity including neurological effects,
decreased body weights and body-weight gains, effects on hematology
(including erythrocyte morphology) and clinical chemistry, increased
liver weights, and microscopic effects on the liver and peripheral
nerves in both sexes; vacuolation of the adrenal glands in males,
bilateral corneal opacity in males, and decreased food consumption in
females.  The NOAEL is 750 ppm (equivalent to 26.7/28.5 mg/kg/day M/F).

This study is classified as acceptable/guideline and satisfies the
guideline requirement for a 90-day oral toxicity study (OPPTS 870.3150;
OECD 409) in dogs.

	870.3200	21/28-Day Dermal Toxicity – Rat

EXECUTIVE SUMMARY:  In a 28-day dermal toxicity study (MRID 46695644),
AE 0172747 (95.4% w/w a.i.; Batch no. PFI0254) was applied to the shaved
skin of 10 Wistar rats/sex/dose at dose levels of 0, 250, 500, or 1000
mg/kg bw/day, 6 hours/day for 5 days/week (7 days in Week 4) during a
28-day period.

No treatment-related effects were observed on mortality, clinical signs,
neurological toxicity, dermal irritation, body weight, body-weight gain,
food consumption, water consumption, hematology, clinical chemistry,
glucose levels, organ weights, or gross pathology.  No alterations were
noted in the skin.

The target organ was the pancreas.  Increased incidences of minimal to
moderate degenerative changes/increase of apoptotic bodies of the
exocrine acinar tissue were noted in the pancreas of all treated groups
in both sexes (9-10/10 treated vs 0-2/10 controls).  A dose related
increase in severity was apparent in the males, but incidence and
severity were similar in the 500 and 1000 mg/kg/day females.
Degeneration/apoptosis in the pancreas was also noted in a concurrently
submitted 28-day dermal toxicity study (MRID 46695645) in the Wistar
rat.  Additionally in the 1000 mg/kg/day females, increased incidences
of minimal to slight ductular proliferation and inflammatory filtrate
were observed in the pancreas (3-4/10 treated vs 0/10 controls).  There
was also increased incidences of minimal to moderate colloid alteration
in the thyroid of all treated male (9-10/10 treated vs 3/10 controls)
and female (4-6/10 treated vs 0/10 controls) groups and minimal to
slight hypertrophic follicular epithelium in the thyroid of the 500 and
1000 mg/kg/day males (6-7/10 treated vs 2/10 controls).  In addition,
increased incidences of the following lesions were observed (#
affected/10 treated vs # affected/10 control): (i) basophilic tubules
were noted in the kidneys of all treated male groups (7-9 vs 6),  (ii)
minimal to slight inflammation in the prostate at 1000 mg/kg/day (3 vs
0); (iii) minimal to slight increased proteinacious material in the
Rathke pouch in the pituitary of the 1000 mg/kg/day males (4 vs 1); and
(iv) minimal mononuclear infiltrate in the kidneys of the 1000 mg/kg/day
males (3 vs 0).  These effects were considered treatment related.

The LOAEL is 250 mg/kg/day, based on colloid alterations and
hypertrophic follicular epithelium in the thyroid gland; and
degenerative changes in the pancreas in both sexes and increased
proteinacious material in the Rathke pouch in the pituitary and
basophilic tubules in the kidneys of males.  The NOAEL was not
established.

This study is classified as acceptable/guideline and satisfies the
guideline requirements (OPPTS 870.3200; OECD 410) for a 28-day dermal
toxicity study in rats.

EXECUTIVE SUMMARY:  In a 28-day dermal toxicity study (MRID 46695645),
AE 0172747 (94.7% w/w a.i.; Batch no. PFI0254) was applied to the shaved
skin of 10 Wistar rats/sex/dose at dose levels of 0, 50, 250, or 1000
mg/kg bw/day, 6 hours/day for 5 days/week (7 days in Week 4) during a
28-day period.

No treatment-related effects were observed on mortality, clinical signs,
neurological toxicity, dermal irritation, body weight, body-weight gain,
food consumption, water consumption, hematology, clinical chemistry,
organ weights, or gross pathology.

The target organ was the pancreas.  Increased incidences of minimal to
moderate degenerative changes/increase of apoptotic bodies of the
exocrine acinar tissue were noted in the pancreas of all treated male
groups (6-10/10 treated vs 1/10 controls) and >250 mg/kg/day females
(5-10/10 treated vs 1/10 controls).

The following findings were considered equivocal: minimal to slight
condensed cytoplasm in the liver in 1000 mg/kg/day males (5/10 treated
vs 2/10 controls) and minimal to moderate proteinaceous plug in the
urinary bladder in the 1000 mg/kg/day males (6/10 treated vs 0/10
controls).  These findings were not confirmed in a previously conducted
28-day dermal toxicity study (MRID 46695644) in the
楗瑳牡爠瑡愠⁴潤敳⁳灵琠〱〰洠⽧杫搯祡മ

Minimal to slight colloid alteration in ≥250 mg/kg/day females (2-4/10
treated vs 1/10 controls) and minimal to slight hypertrophic follicular
epithelium in the thyroid of the 1000 mg/kg/day females (3 vs 0) were
predominantly of minimal severity and an effect was confirmed in the
previous dermal toxicity study.  Minimal to slight hypertrophic
follicular epithelium in the thyroid was noted in the 1000 mg/kg/day
males (6/10) compared to concurrent (4/10) and historical (0-5/10
concurrent controls).  Minimal to moderate colloid alteration of the
thyroid was noted in all treated male groups (8-10 vs 0).  Moderate
severity was observed in only one 1000 mg/kg/day rat.
Erosion/neovascularization and keratitis of the eye were observed in
1000 mg/kg/day males (2/10 vs 0).  These findings were considered
adverse.

The LOAEL is 50 mg/kg/day for males, based on colloid alterations in the
thyroid gland and degenerative changes in the pancreas.  The NOAEL was
not established.  The LOAEL is 250 mg/kg/day for females, based on
degenerative changes in the pancreas.  The NOAEL is 50 mg/kg/day.

This study is classified as acceptable/guideline and satisfies the
guideline requirements (OPPTS 870.3200 ; OECD 410) for a 28-day dermal
toxicity study in rats.

A.3.2	Prenatal Developmental Toxicity

	870.3700a Prenatal Developmental Toxicity Study - Rat

EXECUTIVE SUMMARY:  In a developmental toxicity study (MRID 46695647),
AE0172747 (95.0% w/w; Batch# PFI 0195) in 0.5% methylcellulose 400 was
administered via gavage at a dose volume of 10 mL/kg to 25 Sprague
Dawley rats/dose group at dose levels of 0, 25, 125, or 500 mg/kg/day
from gestation days (GD) 6-20.  On GD 21, all dams were euthanized, and
the uterus was removed via cesarean section and its contents examined.
Fetuses were examined for external, visceral, and skeletal
malformations, anomalies, and variations.

All dams survived until scheduled termination, and there were no
treatment-related macroscopic findings at termination.

Vaginal discharge was observed in one 125 mg/kg/day female on GD 16 and
in two 500 mg/kg/day dams (#s 789 and 773) on GD 11 and 16,
respectively, compared to 0 controls.  Associated anogenital soiling was
noted in Dam # 773.  Additionally at 500 mg/kg/day, increased salivation
was observed in 18/25 dams compared to 0 controls.

Maternal body-weight gains were decreased (p<=0.05) by 52-92% at >=25
mg/kg/day during GD 6-8, and continued to be decreased (p<=0.05) by
28-32% at >=125 mg/kg/day during GD 8-10.  Body-weight gains for the
overall (GD 0-21) study were decreased (not significant) by 9% at >=125
mg/kg/day; and these decreases were still evident when corrected for
gravid uterine weight (decr.11-13%).  Food consumption was decreased
(p<=0.05) by 8-16% in the 125 and 500 mg/kg/day dams during GD 6-12 and
remained decreased (decr.11%; p<=0.01) at 500 mg/kg/day during GD 12-14.
 Because the decrease in body-weight gain in the 25 mg/kg/day group was
transient and did not affect overall body-weight gains, it was not
considered adverse.  Although not adverse to the dams, this initial
decrease in weight gain may have contributed to the decreased (decr.3%;
p<=0.01) fetal body weights at this dose.

The maternal LOAEL is 125 mg/kg/day based on decreased body-weight gains
and food consumption.  The maternal NOAEL is 25 mg/kg/day.

There were no abortions, premature deliveries, or complete litter
resorptions.  Furthermore, there were no effects of treatment on numbers
of litters, live fetuses, dead fetuses, resorptions (early or late), or
on sex ratio or post-implantation loss.  There were no treatment-related
external, visceral, or skeletal malformations.

At >=25 mg/kg/day, fetal body weights were dose-dependently decreased
(p<=0.01) by 3-16%, and a dose-related increase in the number of runts
(fetuses weighing less than 4.0 g) was observed compared to controls.
Additionally at these doses, incidences of the following skeletal
variations, indicative of altered growth and development, were increased
over controls:  (i) enlarged (poor ossification) of the anterior and/or
posterior fontanelle; (ii) unossified 7th cervical centrum; (iii)
incomplete ossification of the 5th and/or 6th sternebrae, hemisternebra
of the 5th sternebrae, or bipartite 5th sternebrae; (iv) extra
ossification points (unilateral/bilateral) on the 14th thoracic
vertebra; (v) incomplete ossification of the thoracic centrum; (vi)
unossified 3rd and/or 4th proximal phalanges on the forepaws; (vii)
incomplete ossification or unossified 5th metacarpals; (viii) unossified
1st metatarsals; and (ix) less than 9 sacrocaudal vertebrae ossified/9
first sacrocaudal vertebrae.

Additionally at >=125 mg/kg/day, incidences of the following skeletal
variations and anomalies were increased over controls:  (i) bilateral
incomplete ossification of the supraoccipital, interparietal, nasals,
frontals, and /or parietals; (ii) unossified 5th and/or 6th sternebrae;
(iii) unossified thoracic centrum; and (iv) bipartite and/or dumbbell
thoracic centrum and cartilage.

Finally at 500 mg/kg/day, incidences of the following skeletal
variations were increased over controls:  (i) unossified hyoid centrum;
(ii) unossified 7th cervical centrum, cartilage bipartite; (iii)
bipartite ossification, incomplete ossification, or unossified 1st, 2nd,
and/or 4th sternebrae.

At >=25 mg/kg/day, incidences of short unilateral/bilateral 14th
thoracic ribs were increased over controls.  Additionally at >=125
mg/kg/day, incidences of bipartite and/or dumbbell thoracic centrum and
cartilage were increased over controls.  At 500 mg/kg/day, incidences of
the following variations were increased over controls:  (i) enlarged
thymus; (ii) split, bipartite, or branched xiphoid process; (iii)
bipartite and/or dumbbell thoracic centrum; and (iv) dumbbell 1st lumbar
centrum.  Additionally at this dose, enlarged bladder and absent
(unilateral) renal papilla were noted in a single fetus.

The developmental LOAEL is 25 mg/kg/day based on increased skeletal
variations including delayed ossifications and on decreased growth and
development as indicated by decreased fetal body weights, and an
increased number of runts.  The developmental NOAEL was not observed.

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

	870.3700b Prenatal Developmental Toxicity Study - Rabbit

EXECUTIVE SUMMARY:  In a developmental toxicity study (MRIDs 46695703,
46695701, and 46695702), AE0172747 (95.0% w/w; Batch# PFI 0195) in 0.5%
methylcellulose 400 was administered via gavage at a dose volume of 4
mL/kg to 25 New Zealand White rabbits/dose group at dose levels of 0, 1,
10, or 100 mg/kg bw/day from gestation days (GD) 6-28.  On GD 29, all
surviving does were euthanized, and the uterus was removed via cesarean
section and its contents examined.  Fetuses were examined for external,
visceral, and skeletal malformations, anomalies, and variations.

At 100 mg/kg bw/day, between GD 15 and 22, five pregnant females were
either found dead or were euthanized in extremis or following abortion.
Of these five animals, one (# 530) was found dead on GD 15; three (#
529, 526, and 522) were euthanized in extremis on GD 16, 17, 22; and
another (# 517) aborted and was euthanized on GD 21.  Marked reductions
in food consumption, body-weight loss (between -0.17 and -0.55 kg), and
one or more occasions of few or no feces were observed in all five of
these does prior to death.  Additionally: Doe # 530 had no urine on one
occasion, and Doe # 522, 526, and 529 had red traces on the cage tray
prior to necropsy.  Necropsy of these animals revealed:  dark liquid
present in the uterus in Doe # 522 and 529; dark contents in the
intestine and pale appearance in Doe #522; and pale liver in Doe # 526.

 body weight) food consumption were decreased (p≤0.05) by 37-38% in
the 100 mg/kg bw/day group at the beginning of treatment from GD 6-8.
Additionally at 100 mg/kg bw/day, food consumption remained decreased
(p≤0.05) by 23% for GD 8-10 and 10-14.  The decreases at 100 mg/kg
bw/day corresponded to the significant decreases observed in body-weight
gains.  After GD 14, food consumption in these groups was comparable to
controls.

At 10 mg/kg bw/day, few feces were observed in 6/25 treated does
compared to 3/25 controls.  At 10 mg/kg bw/day, one female (# 499)
showed a marked reduction in food consumption, body-weight loss of -0.20
kg, and one or more occasions of few or no feces prior to abortion on GD
23.

Absolute and relative (to body weight) food consumption were decreased
(p≤0.05) by 17% in the 10 mg/kg bw/day group at the beginning of
treatment from GD 6-8.

At 1 mg/kg bw/day, one female (# 475) was killed in extremis on GD 21
following:  a marked reduction in food consumption; body-weight loss of
-0.35 kg; one or more occasions of few or no feces; and one occasion (GD
19) of no urine.

The maternal LOAEL is 100 mg/kg bw/day based on mortality, clinical
signs of toxicity (i.e., few or no feces), abortion and decreased body
weight and food consumption.  The maternal NOAEL is 10 mg/kg bw/day.

There were no premature deliveries and no complete litter resorptions.
Furthermore, there were no effects of treatment on numbers of live
fetuses/doe, dead fetuses/doe, resorptions (early or late),
resorptions/doe (early or late), or on fetal weights, sex ratio, or
post-implantation loss.

At 10 and 100 mg/kg/day, incidences of the following skeletal variations
and anomalies were increased over controls and indicate decreased or
delayed growth and development:  (i) enlarged (poor ossification) of the
anterior and/or posterior fontanelle; (ii) unossified atlas centrum;
(iii) extra ossification site between atlas and axis centrum; (iv)
incomplete ossification of the 1st or 2nd sternebra; (v)
unilateral/bilateral incomplete ossification of the pubis; (vi)
unossified 1st or 2nd sternebra; and (vii) extra sternebral
ossification.  Additionally at 100 mg/kg/day, the incidence of
unossified 6th sternebra was higher than controls.

At 10 and 100 mg/kg/day, incidences of the following skeletal variations
were increased over concurrent controls:  (i) cartilage of 8th rib
(unilateral/bilateral) attached to the sternum; (ii) cartilage of 1st
and 2nd rib (unilateral/bilateral) fused; (iii) presence of 27
pre-sacral vertebrae; and (iv) 13 thoracic rib(s) unilateral/bilateral
and presence of 27 pre-sacral vertebrae.  Additionally at 100 mg/kg/day,
(i) unilateral/bilateral 1st ribs short; (ii) cartilage of 1st rib
(unilateral/bilateral) not attached to the sternum; and (iii) 14
thoracic ribs (bilateral) or 14 thoracic rib (unilateral) short and/or
detached.

Additionally at 100 mg/kg/day, incidences of the following visceral
variations were increased over concurrent controls:  (i) short
innominate arteries; (ii) absent innominate arteries; and (iii) dilated
cerebral lateral ventricles (bilateral).

At 100 mg/kg/day, fused kidneys and retroesophageal aortic arch were
noted in a single fetus (each) compared to 0 controls.  Incidences of
all other malformations were unrelated to dose.

The developmental LOAEL is 10 mg/kg bw/day based on decreased or delayed
growth and/or development of the skeleton and increased incidences of
other skeletal variations and anomalies.  The developmental NOAEL is 1
mg/kg bw/day.

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

A.3.3	Reproductive Toxicity

	870.3800 Reproduction and Fertility Effects - Rat

EXECUTIVE SUMMARY:  In a two-generation reproduction toxicity study
(MRID 46695704), AE0172747 (94.0% w/w; Batch# OP2250027) was
administered in the diet to 30 Wistar Hanover (Crl:WI[GLX/BR/HAN]IGS BR)
rats/sex/dose at dose levels of 0, 20, 200, or 1500 ppm (equivalent to
0/0, 1.4/1.6, 13.3/15.8, and 100.4/119.3 mg/kg/day).  The P generation
parents were dosed for 70 days before they were mated to produce the F1
litters.  From the F1 weanlings, 30 rats/sex/dose were selected to be
parents and were fed the same test diet concentrations as their parents
for 70 days prior to mating to produce the F2 litters.

Corneal opacity was observed (vs 0 controls) in all treated groups in
both sexes and both generations during all study intervals.  With the
exception of the pre-mating, mating, and gestation periods in the 20 ppm
P generation females, these incidences were significantly (p<0.01)
increased over controls.  The incidence of corneal opacity was generally
dose-dependent, and increased in the females during lactation when
intake of the test substance approximately doubled.  The rate of this
increase over the course of the study was similar among the treated
groups.  These clinical findings were confirmed at termination, with the
eyes of both sexes and both generations at >20 ppm showing opacity
(26.7-96.7%) observed grossly and acute inflammation and
neovascularization observed microscopically (26.7-100%) compared to 0
controls.  Mean severity of these findings, presented in the study
report on a scale of 1 (minimal) to 5 (severe), ranged from 1.1-2.4 but
showed no definitive relationship to dose.

During pre-mating, minor decreases in parental body weights were
observed in the:  (i) 1500 ppm P males beginning on Day 28 through
termination; (ii) 200 and 1500 ppm P females from Days 21 through 70;
(iii) 200 and 1500 ppm F1 males throughout pre-mating; and (iv) 1500 ppm
F1 females during Days 0-14.  Body-weight gains for the pre-mating
period were decreased in the 1500 ppm P males and in the 200 and 1500
ppm F1 males.  Food consumption was decreased in the:  (i) 1500 ppm P
males from Days 7-21; (ii) P females at 200 ppm from Days 0-7 and 14-21
and at 1500 ppm from Days 0-7 and 14-56; and (iii) F1 males at 200 ppm
from Days 56-63 and at 1500 ppm from Days 35-63.  During gestation, body
weights were decreased in the P dams at 1500 ppm on GD 6 and at 200 and
1500 ppm on GD 13.  Food consumption was decreased in the 1500 ppm P
dams during GD 6-13.  During lactation, body weights in the P dams were
decreased at 1500 ppm on LD 4, 7, and 14; however, body-weight gains for
the overall (LD 0-21) lactation period were unaffected by treatment.
Food consumption was decreased in the P dams at 200 ppm during LD 7-14
and 14-21 and throughout lactation at 1500 ppm.  In the 1500 ppm F1
dams, food consumption was decreased during LD 7-14 and 14-21.

kidneys was increased at ≥20 ppm in the F1 males and females
(3.6-10.0% treated compared to 3.3% controls and 7-56.7% treated vs 3.3%
controls, respectively), and the mean severity was slightly higher at
1500 ppm (1.3) compared to controls (1.0). Chronic inflammation of the
kidneys was observed at an increased incidence in 1500 ppm F1 males
(23.3 % treated vs 0 controls).  Also, there was a dose dependent
increase in the incidence of pelvic dilatation in F1 males (13.8-53.5%)
and females (7-56.7%) relative to controls.

The LOAEL for parental toxicity is 20 ppm (equivalent to 1.4/1.6
mg/kg/day in males/females) based on effects on the eyes, including
corneal opacity, acute inflammation, and neovascularization.  The NOAEL
was not observed.

Treatment-related decreases (p<0.05) in pup body weights were observed:
in the F1 pups at 200 and 1500 ppm beginning on PND 7 and continuing
throughout the reminder of the post-natal period; and in the F2 pups at
200 ppm beginning on PND 21 and at 1500 ppm beginning on PND 14.
Body-weight gains in these groups were dose-dependently decreased.
Compared to controls, the time until preputial separation was
dose-dependently delayed in all treated groups in the F1 and F2
offspring.  This effect was considered treatment related.  Also, the
time to vaginal opening was longer in the 1500 ppm F1 offspring.

incidences of minimal extramedullary hematopoeisis in the spleen were
observed in all treated groups and reached statistical significance
(p≤0.05) at 200 ppm in the F1 female pups (19.2% treated vs 0%
controls) and at 1500 ppm in the pups of both sexes and both generations
(33.3-82.1% treated vs 0-3.8% controls).  This was considered a
treatment related effect.  Also, absolute brain weights were
dose-dependently decreased (p< 0.05) in both sexes in both generations.
In F1 male and female pups, absolute brain weights significantly
decreased 3-10% in all treatment groups.  In the F2 generation, absolute
brain weights significantly decreased 5-9% in males and females at >200
ppm.  Relative brain weights were significantly increased (p< 0.05) in
only F1 males and females by 8-9% at >200 ppm.

In the F2 juveniles, opacity was macroscopically observed in the eyes of
100% of the treated males and females.  Acute inflammation and
neovascularization were microscopically observed in the male and female
F2 juveniles at 20 ppm (50.0-88.9%) and >200 ppm (100%) compared to 0
controls.  Mean severity of these findings was slightly increased at
>200 ppm (1.9-3.0) compared to 20 ppm (1.0-2.3).

Additionally in the 1500 ppm F2 juvenile males, dilated kidney was noted
in 2/2 (100%) animals examined.

The LOAEL for offspring toxicity is 20 ppm (equivalent to 1.4/1.6
mg/kg/day in males/females) based on effects on the eyes, including
corneal opacity, acute inflammation, and neovascularization; increased
incidences of minimal extramedullary hematopoeisis in the spleen,
delayed preputial separation, and decreased absolute brain weight.  The
NOAEL was not observed.

There were no effects of treatment on any reproductive parameter in
either generation, including: the number and duration of estrous cycles;
sperm count, motility, and morphology; mating, fertility, and gestation
indices; and pre-coital and gestation durations.

The LOAEL for reproductive toxicity was not observed.  The NOAEL is 1500
ppm (equivalent to 100.4/119.3 mg/kg/day in males/females).

This study is classified as acceptable/guideline and satisfies the
guideline requirements (OPPTS 870.3800; OECD 416) for a two-generation
reproduction study in the rat.

A.3.4	Chronic Toxicity

	870.4100a (870.4300) Chronic Toxicity – Rat

EXECUTIVE SUMMARY:  In a combined chronic / carcinogenicity study (MRID
46695707) AE 0172747 (95.0% a.i., batch/lot # PFI 0195) was administered
to 60 Rj: WI (IOPS HAN) Wistar rats/sex/dose in the diet at dose levels
of 0, 2, 20, 2500 or 5000 ppm (equivalent to 0, 0.10, 1.05, 134 or 280
mg/kg bw/day) for 104 weeks.   Additional groups of 10 rats/sex were
administered the same dosing regimen, but were terminated at 52 weeks
(interim sacrifice).  Two groups of 15 rats/sex receiving 0 or 5,000 ppm
in the diet for 52 weeks were followed for an additional 13 weeks after
treatment ended in the recovery phase of the study.

Excessive toxicity and/or mortality were observed in males in the 2,500
and 5,000 ppm groups.  Therefore, males in the 5,000 ppm group were
terminated at Week 6 and males in all the other groups were terminated
at Week 43. Males in the 2 ppm showed a few incidences of corneal
opacity, neovascularization of the cornea and snow flake-like corneal
opacity after 6 months of treatment. Males and females in the 20 ppm
group exhibited corneal opacity, neovascularization of the cornea, snow
flake-like corneal opacity, and edema of the cornea (females only).
Females in the 20, 2,500 and 5,000 ppm groups exhibited keratitis of the
eye.  Hair loss, generalized or localized soiled fur and soiled
anogenital region were observed in females in the 2,500 and 5,000 ppm
groups.  At the end of the recovery phase, the only persistent
treatment-related clinical signs observed were hair loss in 1/5 animals
and white area on one eye in 1/12 animals.

[The data summary presented below addresses only the toxic effects
reported for female rats.]

Body weight was slightly decreased by 2 through 6% during the first year
of treatment for females in the 2,500 ppm group.  Cumulative body-weight
gain was decreased by 16% after one week of treatment and by 10% at the
end of the first year.  By Day 708, body weight was comparable to
controls, while cumulative body-weight gain was slightly decreased by
5%.  Body weight and cumulative body-weight gain were decreased by 5 and
36% during the first week of treatment for females in the 5,000 ppm
group, respectively, when compared to controls.  This initial loss was
maintained throughout the course of the study leading to a final
body-weight reduction on Day 708 of 5% and an overall reduction in
cumulative body-weight gain of 7%, compared to controls.  Food
consumption was decreased by up to 11% during the first six weeks of
treatment, but comparable to controls thereafter.

Clinical chemistry revealed an increase in mean total cholesterol
concentration (23-59%) on most occasions throughout the study, with
increases in triglycerides concentrations at the 5 (87%) and 7 (50%)
months and decreases (18%) in mean glucose concentrations for females
during the first year of treatment at 5,000 ppm when compared to
controls.  These changes were reversible after 13 weeks of recovery.
Urinalysis revealed increases in ketone levels and decreases in pH
values for females in the 5,000 ppm group throughout the study.  These
changes were reversible after 13 weeks of recovery.

At 2,500 ppm, the mean liver to body weight ratio was increased by 11%
when compared to controls.  Mean liver weights, liver to body-weight
ratios and liver to brain weight ratios were increased in females in the
5,000 ppm group by 19%, 23% and 22%, respectively, when compared to
controls.  Mean adrenal gland weights were decreased by 34% and 35% in
females in the 2,500 and 5,000 ppm groups, respectively, when compared
to controls.  Mean adrenal to body-weight ratios were decreased in
females in the 20, 2,500, and 5,000 ppm, by 30%, 29% and 29%,
respectively, when compared to controls.  Mean adrenal to brain weight
ratios were decreased in females in the 2,500 and 5,000 ppm groups by
33% and 34%, respectively, when compared to controls.   At the end of
the recovery period, the mean liver to body-weight ratio was increased
in females by 8% when compared to controls.

The incidence of minimal to severe keratitis of the eye was increased at
20, 2,500 and 5,000 ppm (56%, 87% and 83%, respectively) when compared
to controls (3%).

Increased incidences of sciatic nerve atrophy were noted at 2,500 and
5,000 ppm (58% and 67%, respectively, versus 28% in controls), and were
sometimes associated with a minimal to moderate chronic inflammatory
response and/or minimal to marked mineralization of vessels within the
nerve. The incidence of chronic inflammation was increased at 5,000 ppm
(33% versus 7% in controls), and the incidence of mineralization of the
vessels was increased at both 2,500 and 5,000 ppm (37% and 55%,
respectively, versus 11% in controls).  In the skeletal muscle, the
incidence of minimal to moderate atrophy was increased at 5,000 ppm
(53%) when compared to controls (31%).

In the liver, the incidence of minimal to marked biliary
hyperplasia/fibrosis was increased at 20, 2,500 and 5,000 ppm (67%, 77%
and 81%, respectively) when compared to controls (45%).  Additionally in
the liver, the incidence of minimal to marked sinusoidal dilatation was
increased at 2,500 and 5,000 ppm (58% and 64%, respectively) when
compared to controls (35%).

In the pancreas, the incidence of minimal to moderate acinar
atrophy/fibrosis was increased at 2,500 and 5,000 ppm (42% and 54%,
respectively) when compared to controls (25%).

In the adrenal gland, the incidence of minimal to marked cortical
atrophy was increased at 5,000 ppm (22%) when compared to controls (3%).

In the lung, the incidence of minimal to slight perivascular cuffing was
increased in the 2,500 and 5,000 ppm groups (23% and 34%, respectively)
when compared to controls (12%).

The LOAEL is 20 ppm (1.05 mg/kg bw/day) in females, based on keratitis
of the eye and biliary hyperplasia/fibrosis.  The NOAEL is 2 ppm (0.10
mg/kg bw/day).

At the doses tested, there was no treatment related increase in tumor
incidence in female Rj: WI (IOPS HAN) Wistar rats when compared to
controls.  Dosing was considered adequate in females only based on
decreased body-weight gain of 14% at 13 weeks, marked biliary
hyperplasia/fibrosis, minimal to moderate sciatic nerve atrophy, minimal
to moderate atrophy in the skeletal muscle, minimal to moderate acinar
atrophy/fibrosis of the pancreas and of minimal to marked cortical
atrophy of the adrenal gland at 5,000 ppm.  The study did not adequately
test for the carcinogenic potential of AE 0172747 in male Rj: WI (IOPS
HAN) Wistar rats due to the early termination at 43 (or 6) weeks of all
male groups.

This chronic/carcinogenicity study in the rat is unacceptable/guideline
and does not satisfy the guideline requirement for a chronic/
carcinogenicity study [(OPPTS 870.4300); OECD 453] in rats.  All male
groups were terminated early and only very minimal data for males were
presented.

EXECUTIVE SUMMARY:  In a combined chronic/carcinogenicity study (MRID
46695708) AE 0172747 (95.0% a.i., batch/lot # PFI 0195) was administered
to 60 Rj: WI (IOPS HAN) Wistar male rats/dose in the diet at dose levels
of 0, 1, 20, 200 or 800 ppm (equivalent to 0, 0.04, 0.79, 8.3 or 31.7
mg/kg bw/day) in the diet for 104 weeks.   Additional groups of 10
rats/sex were administered the same dosing regimen, but were terminated
at 52 weeks (interim sacrifice).  Two groups of 15 male rats receiving 0
or 800 ppm in the diet for 52 weeks were followed for an additional 13
weeks after treatment ended in the recovery phase of the study.

There were no compound related effects on mortality, food consumption or
hematology.  At 20, 200, and 800 ppm, white area on eyes was noted in
most animals.  In addition, focal swelling (principally of the hindlimb)
occurred at a slightly higher incidence at the three dietary levels
(18-24% vs. 9% in the controls), and limited use of limb was increased
at 200 ppm (21%), in comparison with the controls (9%).  At 800 ppm,
hair loss occurred.

Ophthalmological findings revealed corneal opacity, neovascularization
and edema of the cornea and snow flake-like corneal opacity were
observed at 20, 200, and 800 ppm.  After 13 weeks of recovery, corneal
opacity, edema of the cornea and snow flake-like corneal opacity were
reversible, whereas neovascularization of the cornea persisted in all
treated animals in the recovery group (800 ppm).

 800 ppm, food consumption was decreased at times by up to 7% (p≤0.01
or p≤0.05) during the first five months of the study, but was
comparable to controls during the second year of the study.

Total cholesterol concentrations were significantly increased (p≤
0.01) at 200 and 800 ppm (46 and 52%, respectively), compared to
controls during the first 18 months of treatment.  The increased total
cholesterol concentrations observed at 800 ppm during the first 18
months of treatment were still present after 3 months of recovery (43%,
p≤0.01),  compared to controls.

Urinalysis revealed increased ketone levels and lower pH values at 20,
200 and 800 ppm throughout the study.  Decreased amount of crystals
(believed to be linked to the lower pH values) was also observed.  In
addition, at 200 and 800 ppm increased protein levels were observed.
After 13 weeks of recovery, decreased crystal amount was similar between
the 800 ppm group and control group, whereas the increased ketone level,
protein level and the lower pH value were not reversible.

at 20, 200, and 800 ppm by 15, 13 and 18% (p≤ 0.05), respectively.
The kidney to body-weight ratio was increased at 20, 200, and 800 ppm by
24, 31 and 26% (p≤0.01), respectively.  The kidney to brain weight
ratio was increased at 20, 200, and 800 ppm by 20, 20 and 23% (p≤0.01
or p≤0.05), respectively.  At the end of the recovery period, mean
kidney weights were higher by between 15 to 25% (p≤ 0.01) in animals
previously treated at 800 ppm, in comparison to controls.

Gross necropsy revealed a higher incidence of ocular opacity at 20, 200,
and 800 ppm.  The incidence of minimal to marked keratitis of the eye(s)
was significantly increased (p≤0.01) in males in the 20, 200, and 800
ppm groups (97-98%) when compared to controls (3%).    Keratitis
included one or more of the following changes in the cornea: acute
inflammation, epithelial hyperplasia, keratinization, epithelial
vacuolization, erosion and/or ulceration.  Generally, the keratitis
observed in this study was a multifocal to diffuse chronic active
superficial keratitis, involving the corneal epithelium and superficial
aspects of the corneal stroma, which did not penetrate the cornea.   A
slight non-statistically significant elevation (3-5%) of hyperplastic
lesions was noted on the cornea of the eye at 200 and 800 ppm, when
compared to controls (0%).   In addition, a minimal to moderate retinal
degeneration, mostly located in the ora serrata area of the retina, was
significantly increased (p≤0.05) in the 800 ppm group (15%) when
compared to controls (3%).

In the kidney, a minimal to severe chronic nephropathy was significantly
increased (p≤0.01) in the 20, 200, and 800 ppm group, (87%, 87%, 92%
and 83%, respectively) compared to in the control group (63%).  Changes
within the kidney included one or more of the following changes: tubular
cell regeneration, thickened basement membranes (glomerular and
tubular), interstitial fibrosis, inflammation, dilated/cystic tubules,
protein casts, pigmentation, mineralization, debris, mesangial
proliferation, glomerular sclerosis, and hypertrophy/hyperplasia of
tubular epithelium.  Severity grades moderate or higher generally
reflected a kidney with most of the above-mentioned changes, some
reflecting end-stage renal disease (probable cause of death).

In the sciatic nerve, minimal to slight nerve fiber degeneration was
significantly increased (p≤0.05) in the 20, 200 and 800 ppm groups
(73%, 73% and 75%, respectively), when compared to controls (53%).  This
change was described as multiple fiber degeneration, loss of stain
intensity, decreased density and definition of the nerve fiber and/or
demyelination.  In addition, sometimes associated with sciatic nerve
atrophy was a minimal to moderate chronic inflammatory response and/or
minimal to moderate mineralization of the vessels within the nerve.  In
general, these changes were noted in animals that survived to the
terminal sacrifice, indicating a late onset of the exacerbation of this
lesion.

ntly (p≤0.01) increased in the 200 and 800 ppm groups (13% and 12%,
respectively) when compared to controls (0%).

In the pancreas, the incidence of minimal to moderate acinar
atrophy/fibrosis was significantly increased (p≤0.01) in the 200 and
800 ppm groups (63% and 67%, respectively), when compared to controls
(35%).  Pancreatic acinar atrophy/fibrosis generally is a focal or
lobular atrophy (dedifferentiation of acinar cells and an increase in
small duct-like structures), sometimes associated with a relative
increase in interstitial collagen and a small number of inflammatory
cells, but in the 200 and 800 ppm dose groups this lesion was more
diffuse in distribution.   In the skeletal muscle, the incidence of
minimal to moderate atrophy was significantly increased in the 800 ppm
group (49%) when compared to controls (32%).

The LOAEL is 20 ppm (0.79 mg/kg bw/day) in males, based on
neovascularization and edema of the cornea and snow flake-like corneal
opacity, unilateral or bilateral keratitis of the eye, decreased mean
body weight and mean body-weight gain, increased total cholesterol,
higher ketone level and lower pH values, higher protein levels,
increased kidney weight, kidney to body weight and kidney to brain
weight ratios, chronic nephropathy and atrophy of the sciatic nerve.
The NOAEL is 1 ppm (0.04 mg/kg bw/day).

There was a slight increase in neoplastic lesions; i.e., squamous cell
carcinoma of the cornea in the 200 and 800 ppm groups (7% and 3%,
respectively), when compared to controls (0%).   This change was
considered to be a result of the keratitis of the eye.  Rats appear to
be much more sensitive to tyrosinaemia than humans.

This chronic/carcinogenicity study in the rat is acceptable/guideline
and satisfies the guideline requirement for a chronic/ carcinogenicity
study [(OPPTS 870.4300); OECD 453] in rats when evaluated together with
the associative study most recently completed in females (MRID
46695707).

	870.4100b (870.4300b) Chronic Toxicity – Mouse

EXECUTIVE SUMMARY:  In a carcinogenicity study (MRID 46695706), AE
0172747 (95% w/w a.i.; Batch No. PFI 0195) was administered in the diet
to C57BL/6 J@ Ico mice (50/sex/dose) at doses of 0, 30, 300, 1000, or
3000 ppm (equivalent to 0/0, 4/5, 43/54, 146/179, and 440/552 mg/kg/day
in males/females) for up to 78 weeks.  Additionally, 10 mice/sex/dose
were treated similarly for up to 52 weeks.

No treatment-related effect was observed on mortality or ophthalmoscopic
examination.

At 30 ppm (the lowest dose tested), there was evidence of toxicity in
the gallbladder and liver in both sexes.  The toxicity became more
severe at higher doses.  In all treatment groups at 12 months,
incidences (n=10) of the following lesions were increased in the
gallbladder and liver: (i) minimal to moderate gallstones in males and
females (2-5 treated vs 1 control); (ii) minimal to marked gallstones in
females (2-7 treated vs 0 controls); and (iii) minimal to moderate
centrilobular to panlobular hepatocellular hypertrophy (diffuse) in
females (5-10 treated vs 0 controls).

In all treatment groups at 18 months, gallbladder stones were observed
in mice at necropsy in both sexes (18-36/50 treated vs 1/50 controls).
Incidences of the following microscopic lesions were increased in all
treatment groups in the gallbladder (# affected/50 treated vs #
affected/50 controls, except n=49 in male controls and 1000 ppm
females): (i) minimal to marked gallstones in both sexes (6-26 vs 0-1;
p<=0.001); (ii) minimal to marked eosinophilic cytoplasmic alteration
(focal/multifocal) in females (9-28 vs 2; p<=0.05); and (iii) minimal to
moderate subepithelial mixed cell infiltrate (focal/multifocal) in
females (15-29 vs 11; not statistically significant).  Hepatotoxicity
was indicated in all treatment groups by increased (p<=0.01) relative to
body liver weights in both sexes (incr 6-26%); increased incidences of
minimal to moderate centrilobular to panlobular hepatocellular
hypertrophy (diffuse) in females (12-47/49-50 vs 0/50; p<=0.001); and
macroscopic white foci in males (4-6/50 treated vs 1/50 control).  An
increased incidence of papillary mineralization was also observed in the
kidneys of females at 18 months.  Slight anemia was observed in all
treated female groups at 18 months, as evidenced by decreases in
hemoglobin concentration, hematocrit, and erythrocyte count.

At 300 ppm and above at 18 months, incidences of the following lesions
were increased in the liver: minimal to moderate centrilobular to
panlobular hepatocellular hypertrophy (diffuse) in the males; and
minimal to slight hepatocellular degeneration (focal/multifocal) in
females.  Minimal to marked eosinophilic cytoplasmic alteration
(focal/multifocal) in male gallbladders was considered equivocally
treatment-related because the incidence and/or severity were not clearly
related to dose.

At 1000 ppm and above, intense yellow colored urine was noted in males
and females.  This finding was first observed at the end of the third
month of treatment at 3000 ppm and the fifth month at 1000 ppm.  Once
noted, this finding continued to be observed throughout treatment.
Decreased food consumption in females was often observed beginning at
Day 22.  Food consumptions during the first 4-week period and the
following 12-week period were reduced.

 Increased incidences of dilatation of uterine horns were noted grossly
at ≥1000 ppm.

At 3000 ppm, decreased body weights were observed sporadically in
females throughout the treatment period and contributed to decreased
bodyweight gain (Days 92-344) and overall (Days 1-540) body-weight gain.
 After 18 months in the males, absolute and relative to body testicular
weights were decreased.  Increased incidences of the following gross
lesions were noted: red foci in the male liver, prominent lobulation in
the female liver, and renal pelvic dilatation in the females.

At 3000 ppm at 18 months, incidences of the following microscopic
lesions were increased in the liver: (i) minimal to slight
hepatocellular degeneration (focal/multifocal) in the males; (ii)
minimal to slight hepatocellular vacuolation (diffuse) in the males;
(iii) increased number of mitoses in the females; and (iv) minimal to
moderate eosinophilic focus(i) of altered hepatocytes (focal/multifocal)
in the females.  Additionally, an increased incidence of minimal to
moderate interstitial mixed cell infiltrate (focal/multifocal) in the
liver in males was considered equivocal because only minimal severity
was observed at 3000 ppm and the incidence and severity were not clearly
related to dose.  Minimal to marked horn dilatation (diffuse) in the
uterus at 3000 ppm was considered treatment-related.

The LOAEL is 30 ppm (equivalent to 4/5 mg/kg/day in males/females),
based on gallstones, eosinophilic cytoplasmic alteration, subepithelial
mixed cell infiltrate, and dilatation in/of the gallbladder;
hepatocellular vacuolation, hepatocellular hypertrophy, and increased
liver weight in males and females; and papillary mineralization of the
kidney and changes in hematological parameters indicative of anemia in
females.  The NOAEL was not established.

At the doses tested, there was not a treatment-related increase in tumor
incidence when compared to controls.  Dosing was considered adequate
based on toxicity noted in the gallbladder, liver, and testes, decreased
body weight and body-weight gain, and decreased food consumption.

This study is classified as acceptable/guideline and satisfies the
guideline requirements (OPPTS 870.4200b; OECD 451) for a carcinogenicity
study in mice.

	870.4100b Chronic Toxicity - Dog

EXECUTIVE SUMMARY:  In a chronic toxicity study (MRID 46695705), AE
0172747 (95.4% w/w, Batch #: PFI 0254) was administered to 4 beagle
dogs/sex/dose in the diet for 52 weeks at doses of 0, 75, 300, or 1200
ppm (equivalent to 0/0, 2.5/2.5, 9.0/10.2, and 37.8/41.6 mg/kg bw/day in
males/females).

No treatment-related adverse effects were observed on mortality, body
weights, body-weight gains, food consumption, ophthalmoscopic
examination, urinalysis, or clinical chemistry at any dose.   Increased
incidence of urinary ketone levels were observed in all treated groups
throughout the study.  This effect would seem reasonable considering
that the test substance is a herbicide of the triketone family.

At 1200 ppm, one male displayed disturbance in locomotion between Days
112 and 287, had soft or liquid feces throughout the study, and had a
general wasted appearance during Days 78-321, even though this animal
ate its entire daily food ration.

The following differences from controls were observed throughout the
study in both sexes at 1200 ppm:  (i) increased platelets (incr.
51-95%); (ii) decreased mean corpuscular hemoglobin (MCH) (decr. 8-18%);
and (iii) decreased mean corpuscular volume (MCV) (decr. 6-17%).
Additionally, erythrocytes were increased (incr. 21%) in the females at
12-13 months.  One male and all females displayed some changes in
erythrocyte morphology including:  slight to severe anisocytosis,
microcytosis, anisochromia, and hypochromia; poikilocytosis; slight to
moderate basophilic stippling; and target cells.

In the 1200 ppm males, an increased number of digestion chambers of the
sciatic nerve were observed.  Minimal to slight increased number of
digestion chambers located unilaterally/bilaterally was observed at:  75
ppm (1), 300 ppm (1), and 1200 ppm (2).  In the females, this finding
was only noted in 1/4 females each at 75 and 300 ppm.  Apparently, these
digestion chambers were a result of focal enlargement of the myelin
sheath due to myelin debris and may account for the neurological effect
(disturbances in locomotion) observed in one of the 1200 ppm males.  In
the subchronic dog study (MRID 46695643), reviewed concurrently with
this study, an increased number of digestion chambers of the sciatic
nerve were observed in the 4500/2250 ppm treatment group.

The LOAEL is 75 ppm (equivalent to 2.5 mg/kg bw/day) in males, based
upon the increased number of digestion chambers of the sciatic nerve.
The NOAEL was not determined in males.   The LOAEL is 1200 ppm
(equivalent to 41.6 mg/kg bw/day) in females, based on decreases in MCH
and MCV, increased platelet counts, changes in erythrocyte morphology
and pigmentation of the thyroid gland.  The NOAEL is 300 ppm (equivalent
to 10.2 mg/kg bw/day) in females.

This study is classified as acceptable/guideline and satisfies the
guideline requirement (OPPTS 870.4100b, OECD 452) for a chronic oral
toxicity study in dogs.

A.3.5	Carcinogenicity

	870.4200a Carcinogenicity Study – rat

EXECUTIVE SUMMARY:  In a combined chronic / carcinogenicity study (MRID
46695707) AE 0172747 (95.0% a.i., batch/lot # PFI 0195) was administered
to 60 Rj: WI (IOPS HAN) Wistar rats/sex/dose in the diet at dose levels
of 0, 2, 20, 1250 or 2,500 ppm (equivalent to 0, 0.10, 1.05, 134 or 280
mg/kg bw/day) for 104 weeks.   Additional groups of 10 rats/sex were
administered the same dosing regimen, but were terminated at 52 weeks
(interim sacrifice).  Two groups of 15 rats/sex receiving 0 or 5,000 ppm
in the diet for 52 weeks were followed for an additional 13 weeks after
treatment ended in the recovery phase of the study.

Excessive toxicity and/or mortality were observed in males in the 2,500
and 5,000 ppm groups.  Therefore, males in the 5,000 ppm group were
terminated at Week 6 and males in all the other groups were terminated
at Week 43. Males in the 2 ppm showed a few incidences of corneal
opacity, neovascularization of the cornea and snow flake-like corneal
opacity after 6 months of treatment. Males and females in the 20 ppm
group exhibited corneal opacity, neovascularization of the cornea, snow
flake-like corneal opacity, and edema of the cornea (females only).
Females in the 20, 2,500 and 5,000 ppm groups exhibited keratitis of the
eye.  Hair loss, generalized or localized soiled fur and soiled
anogenital region were observed in females in the 2,500 and 5,000 ppm
groups.  At the end of the recovery phase, the only persistent
treatment-related clinical signs observed were hair loss in 1/5 animals
and white area on one eye in 1/12 animals.

[The data summary presented below addresses only the toxic effects
reported for female rats.]

Body weight was slightly decreased by 2 through 6% during the first year
of treatment for females in the 2,500 ppm group.  Cumulative body weight
gain was decreased by 16% after one week of treatment and by 10% at the
end of the first year.  By Day 708, body weight was comparable to
controls, while cumulative body weight gain was slightly decreased by
5%.  Body weight and cumulative body weight gain were decreased by 5 and
36% during the first week of treatment for females in the 5,000 ppm
group, respectively, when compared to controls.  This initial loss was
maintained throughout the course of the study leading to a final body
weight reduction on Day 708 of 5% and an overall reduction in cumulative
body weight gain of 7%, compared to controls.  Food consumption was
decreased by up to 11% during the first six weeks of treatment, but
comparable to controls thereafter.

Clinical chemistry revealed an increase in mean total cholesterol
concentration (23-59%) on most occasions throughout the study, with
increases in triglycerides concentrations at the 5 (87%) and 7 (50%)
months and decreases (18%) in mean glucose concentrations for females
during the first year of treatment at 5,000 ppm when compared to
controls.  These changes were reversible after 13 weeks of recovery.
Urinalysis revealed increases in ketone levels and decreases in pH
values for females in the 5,000 ppm group throughout the study.  These
changes were reversible after 13 weeks of recovery.

At 2,500 ppm, the mean liver to body weight ratio was increased by 11%
when compared to controls.  Mean liver weights, liver to body weight
ratios and liver to brain weight ratios were increased in females in the
5,000 ppm group by 19%, 23% and 22%, respectively, when compared to
controls.  Mean adrenal gland weights were decreased by 34% and 35% in
females in the 2,500 and 5,000 ppm groups, respectively, when compared
to controls.  Mean adrenal to body weight ratios were decreased in
females in the 20, 2,500, and 5,000 ppm, by 30%, 29% and 29%,
respectively, when compared to controls.  Mean adrenal to brain weight
ratios were decreased in females in the 2,500 and 5,000 ppm groups by
33% and 34%, respectively, when compared to controls.   At the end of
the recovery period, the mean liver to body weight ratio was increased
in females by 8% when compared to controls.

The incidence of minimal to severe keratitis of the eye was increased at
20, 2,500 and 5,000 ppm (56%, 87% and 83%, respectively) when compared
to controls (3%).

Increased incidences of sciatic nerve atrophy were noted at 2,500 and
5,000 ppm (58% and 67%, respectively, versus 28% in controls), and were
sometimes associated with a minimal to moderate chronic inflammatory
response and/or minimal to marked mineralization of vessels within the
nerve. The incidence of chronic inflammation was increased at 5,000 ppm
(33% versus 7% in controls), and the incidence of mineralization of the
vessels was increased at both 2,500 and 5,000 ppm (37% and 55%,
respectively, versus 11% in controls).  In the skeletal muscle, the
incidence of minimal to moderate atrophy was increased at 5,000 ppm
(53%) when compared to controls (31%).

In the liver, the incidence of minimal to marked biliary
hyperplasia/fibrosis was increased at 20, 2,500 and 5,000 ppm (67%, 77%
and 81%, respectively) when compared to controls (45%).  Additionally in
the liver, the incidence of minimal to marked sinusoidal dilatation was
increased at 2,500 and 5,000 ppm (58% and 64%, respectively) when
compared to controls (35%).

In the pancreas, the incidence of minimal to moderate acinar
atrophy/fibrosis was increased at 2,500 and 5,000 ppm (42% and 54%,
respectively) when compared to controls (25%).

In the adrenal gland, the incidence of minimal to marked cortical
atrophy was increased at 5,000 ppm (22%) when compared to controls (3%).

In the lung, the incidence of minimal to slight perivascular cuffing was
increased in the 2,500 and 5,000 ppm groups (23% and 34%, respectively)
when compared to controls (12%).

The LOAEL is 20 ppm (105 mg/kg bw/day) in females, based on keratitis of
the eye and biliary hyperplasia/fibrosis.  The NOAEL is 2 ppm (0.10
mg/kg bw/day).

At the doses tested, there was no treatment related increase in tumor
incidence in female Rj: WI (IOPS HAN) Wistar rats when compared to
controls.  Dosing was considered adequate in females only based on
decreased body weight gain of 14% at 13 weeks, marked biliary
hyperplasia/fibrosis, minimal to moderate sciatic nerve atrophy, minimal
to moderate atrophy in the skeletal muscle, minimal to moderate acinar
atrophy/fibrosis of the pancreas and of minimal to marked cortical
atrophy of the adrenal gland at 5,000 ppm.  The study did not adequately
test for the carcinogenic potential of AE 0172747 in male Rj: WI (IOPS
HAN) Wistar rats due to the early termination at 43 (or 6) weeks of all
male groups.

This chronic/carcinogenicity study in the rat is unacceptable/guideline
and does not satisfy the guideline requirement for a chronic/
carcinogenicity study [(OPPTS 870.4300); OECD 453] in rats.  All male
groups were terminated early and only very minimal data for males were
presented.

EXECUTIVE SUMMARY:  In a combined chronic/carcinogenicity study (MRID
46695708) AE 0172747 (95.0% a.i., batch/lot # PFI 0195) was administered
to 60 Rj: WI (IOPS HAN) Wistar male rats/dose in the diet at dose levels
of 0, 1, 20, 200 or 800 ppm (equivalent to 0, 0.04, 0.79, 8.3 or 31.7
mg/kg bw/day) in the diet for 104 weeks.   Additional groups of 10
rats/sex were administered the same dosing regimen, but were terminated
at 52 weeks (interim sacrifice).  Two groups of 15 male rats receiving 0
or 800 ppm in the diet for 52 weeks were followed for an additional 13
weeks after treatment ended in the recovery phase of the study.

There were no compound related effects on mortality, food consumption or
hematology.  At 20, 200, and 800 ppm, white area on eyes was noted in
most animals.  In addition, focal swelling (principally of the hindlimb)
occurred at a slightly higher incidence at the three dietary levels
(18-24% vs. 9% in the controls), and limited use of limb was increased
at 200 ppm (21%), in comparison with the controls (9%).  At 800 ppm,
hair loss occurred.

Ophthalmological findings revealed corneal opacity, neovascularization
and edema of the cornea and snow flake-like corneal opacity were
observed at 20, 200, and 800 ppm.  After 13 weeks of recovery, corneal
opacity, edema of the cornea and snow flake-like corneal opacity were
reversible, whereas neovascularization of the cornea persisted in all
treated animals in the recovery group (800 ppm).

Body weight and body weight gain were decreased by 4% (p≤0.01 or
p≤0.05) during the first year of treatment for animals in the 20 ppm
group, compared to controls.  However, these parameters were
progressively reduced the last six months of treatment, and by Day 708,
body weight and body weight gain were decreased by 11% (p≤0.01) and
17% (p≤0.01), respectively, compared to controls.  At 200 ppm, body
weight and body weight gain were decreased by 5% and 7% (p≤0.01 or
p≤0.05), respectively, during the first year of treatment, compared to
controls.  By Day 708, body weight and body weight gain were decreased
by 15% (p≤0.01) and 24% (p≤0.01), respectively, compared to
controls.  At 800 ppm, by the end of the first year, body weight and
body weight gain were decreased by 6% (p≤0.01) and 8% (p≤0.01),
respectively, compared to controls.   At the end of the study, body
weight and body weight gain were decreased by 7% and 10%, respectively,
compared to controls.  At the end of the recovery period, body weight
gain body weight gain were decreased by 37% in the 800 ppm group,
compared to controls.  At 800 ppm, food consumption was decreased at
times by up to 7% (p≤0.01 or p≤0.05) during the first five months of
the study, but was comparable to controls during the second year of the
study.

Total cholesterol concentrations were significantly increased (p≤
0.01) at 200 and 800 ppm (46 and 52%, respectively), compared to
controls during the first 18 months of treatment.  The increased total
cholesterol concentrations observed at 800 ppm during the first 18
months of treatment were still present after 3 months of recovery (43%,
p≤0.01),  compared to controls.

Urinalysis revealed increased ketone levels and lower pH values at 20,
200 and 800 ppm throughout the study.  Decreased amount of crystals
(believed to be linked to the lower pH values) was also observed.  In
addition, at 200 and 800 ppm increased protein levels were observed.
After 13 weeks of recovery, decreased crystal amount was similar between
the 800 ppm group and control group, whereas the increased ketone level,
protein level and the lower pH value were not reversible.

Kidney weights were increased at 20, 200, and 800 ppm by 15, 13 and 18%
(p≤ 0.05), respectively.  The kidney to body weight ratio was
increased at 20, 200, and 800 ppm by 24, 31 and 26% (p≤0.01),
respectively.  The kidney to brain weight ratio was increased at 20,
200, and 800 ppm by 20, 20 and 23% (p≤0.01 or p≤0.05), respectively.
 At the end of the recovery period, mean kidney weights were higher by
between 15 to 25% (p≤ 0.01) in animals previously treated at 800 ppm,
in comparison to controls.

Gross necropsy revealed a higher incidence of ocular opacity at 20, 200,
and 800 ppm.  The incidence of minimal to marked keratitis of the eye(s)
was significantly increased (p≤0.01) in males in the 20, 200, and 800
ppm groups (97-98%) when compared to controls (3%).    Keratitis
included one or more of the following changes in the cornea: acute
inflammation, epithelial hyperplasia, keratinization, epithelial
vacuolization, erosion and/or ulceration.  Generally, the keratitis
observed in this study was a multifocal to diffuse chronic active
superficial keratitis, involving the corneal epithelium and superficial
aspects of the corneal stroma, which did not penetrate the cornea.   A
slight non-statistically significant elevation (3-5%) of hyperplastic
lesions was noted on the cornea of the eye at 200 and 800 ppm, when
compared to controls (0%).   In addition, a minimal to moderate retinal
degeneration, mostly located in the ora serrata area of the retina, was
significantly increased (p≤0.05) in the 800 ppm group (15%) when
compared to controls (3%).

In the kidney, a minimal to severe chronic nephropathy was significantly
increased (p≤0.01) in the 20, 200, and 800 ppm group, (87%, 87%, 92%
and 83%, respectively) compared to in the control group (63%).   Changes
within the kidney included one or more of the following changes: tubular
cell regeneration, thickened basement membranes (glomerular and
tubular), interstitial fibrosis, inflammation, dilated/cystic tubules,
protein casts, pigmentation, mineralization, debris, mesangial
proliferation, glomerular sclerosis, and hypertrophy/hyperplasia of
tubular epithelium.  Severity grades moderate or higher generally
reflected a kidney with most of the above-mentioned changes, some
reflecting end-stage renal disease (probable cause of death).

In the sciatic nerve, minimal to slight nerve fiber degeneration was
significantly increased (p≤0.05) in the 20, 200 and 800 ppm groups
(73%, 73% and 75%, respectively), when compared to controls (53%).
This change was described as multiple fiber degeneration, loss of stain
intensity, decreased density and definition of the nerve fiber and/or
demyelination.  In addition, sometimes associated with sciatic nerve
atrophy was a minimal to moderate chronic inflammatory response and/or
minimal to moderate mineralization of the vessels within the nerve.  In
general, these changes were noted in animals that survived to the
terminal sacrifice, indicating a late onset of the exacerbation of this
lesion.

ntly (p≤0.01) increased in the 200 and 800 ppm groups (13% and 12%,
respectively) when compared to controls (0%).

In the pancreas, the incidence of minimal to moderate acinar
atrophy/fibrosis was significantly increased (p≤0.01) in the 200 and
800 ppm groups (63% and 67%, respectively), when compared to controls
(35%).  Pancreatic acinar atrophy/fibrosis generally is a focal or
lobular atrophy (dedifferentiation of acinar cells and an increase in
small duct-like structures), sometimes associated with a relative
increase in interstitial collagen and a small number of inflammatory
cells, but in the 200 and 800 ppm dose groups this lesion was more
diffuse in distribution.   In the skeletal muscle, the incidence of
minimal to moderate atrophy was significantly increased in the 800 ppm
group (49%) when compared to controls (32%).

The LOAEL is 20 ppm (0.79 mg/kg bw/day) in males, based on
neovascularization and edema of the cornea and snow flake-like corneal
opacity, unilateral or bilateral keratitis of the eye, decreased mean
body weight and mean body weight gain, increased total cholesterol,
higher ketone level and lower pH values, higher protein levels,
increased kidney weight, kidney to body weight and kidney to brain
weight ratios, chronic nephropathy and atrophy of the sciatic nerve.
The NOAEL is 1 ppm (0.04 mg/kg bw/day).

There was a slight increase in neoplastic lesions; i.e., squamous cell
carcinoma of the cornea in the 200 and 800 ppm groups (7% and 3%,
respectively), when compared to controls (0%).   This change was
considered to be a result of the keratitis of the eye.  Rats appear to
be much more sensitive to tyrosinaemia than humans.

This chronic/carcinogenicity study in the rat is acceptable/guideline
and satisfies the guideline requirement for a chronic/ carcinogenicity
study [(OPPTS 870.4300); OECD 453] in rats when evaluated together with
the associative study most recently completed in females (MRID
46695707).

	870.4200b Carcinogenicity (feeding) - Mouse

EXECUTIVE SUMMARY:  In a carcinogenicity study (MRID 46695706), AE
0172747 (95% w/w a.i.; Batch No. PFI 0195) was administered in the diet
to C57BL/6 J@ Ico mice (50/sex/dose) at doses of 0, 30, 300, 1000, or
3000 ppm (equivalent to 0/0, 4/5, 43/54, 146/179, and 440/552 mg/kg/day
in males/females) for up to 78 weeks.  Additionally, 10 mice/sex/dose
were treated similarly for up to 52 weeks.

No treatment-related effect was observed on mortality or ophthalmoscopic
examination.

At 30 ppm (the lowest dose tested), there was evidence of toxicity in
the gallbladder and liver in both sexes.  The toxicity became more
severe at higher doses.  In all treatment groups at 12 months,
incidences (n=10) of the following lesions were increased in the
gallbladder and liver: (i) minimal to moderate gallstones in males and
females (2-5 treated vs 1 control); (ii) minimal to marked gallstones in
females (2-7 treated vs 0 controls); and (iii) minimal to moderate
centrilobular to panlobular hepatocellular hypertrophy (diffuse) in
females (5-10 treated vs 0 controls).

In all treatment groups at 18 months, gallbladder stones were observed
in mice at necropsy in both sexes (18-36/50 treated vs 1/50 controls).
Incidences of the following microscopic lesions were increased in all
treatment groups in the gallbladder (# affected/50 treated vs #
affected/50 controls, except n=49 in male controls and 1000 ppm
females): (i) minimal to marked gallstones in both sexes (6-26 vs 0-1;
p<=0.001); (ii) minimal to marked eosinophilic cytoplasmic alteration
(focal/multifocal) in females (9-28 vs 2; p<=0.05); and (iii) minimal to
moderate subepithelial mixed cell infiltrate (focal/multifocal) in
females (15-29 vs 11; not statistically significant).  Hepatotoxicity
was indicated in all treatment groups by increased (p<=0.01) relative to
body liver weights in both sexes (incr 6-26%); increased incidences of
minimal to moderate centrilobular to panlobular hepatocellular
hypertrophy (diffuse) in females (12-47/49-50 vs 0/50; p<=0.001); and
macroscopic white foci in males (4-6/50 treated vs 1/50 control).  An
increased incidence of papillary mineralization was also observed in the
kidneys of females at 18 months.  Slight anemia was observed in all
treated female groups at 18 months, as evidenced by decreases in
hemoglobin concentration, hematocrit, and erythrocyte count.

At 300 ppm and above at 18 months, incidences of the following lesions
were increased in the liver: minimal to moderate centrilobular to
panlobular hepatocellular hypertrophy (diffuse) in the males; and
minimal to slight hepatocellular degeneration (focal/multifocal) in
females.  Minimal to marked eosinophilic cytoplasmic alteration
(focal/multifocal) in male gallbladders was considered equivocally
treatment-related because the incidence and/or severity were not clearly
related to dose.

At 1000 ppm and above, intense yellow colored urine was noted in males
and females.  This finding was first observed at the end of the third
month of treatment at 3000 ppm and the fifth month at 1000 ppm.  Once
noted, this finding continued to be observed throughout treatment.
Decreased food consumption in females was often observed beginning at
Day 22.  Food consumptions during the first 4-week period and the
following 12-week period were reduced.

 Increased incidences of dilatation of uterine horns were noted grossly
at ≥1000 ppm.

At 3000 ppm, decreased body weights were observed sporadically in
females throughout the treatment period and contributed to decreased
bodyweight gain (Days 92-344) and overall (Days 1-540) body weight gain.
 After 18 months in the males, absolute and relative to body testicular
weights were decreased.  Increased incidences of the following gross
lesions were noted: red foci in the male liver, prominent lobulation in
the female liver, and renal pelvic dilatation in the females.

At 3000 ppm at 18 months, incidences of the following microscopic
lesions were increased in the liver: (i) minimal to slight
hepatocellular degeneration (focal/multifocal) in the males; (ii)
minimal to slight hepatocellular vacuolation (diffuse) in the males;
(iii) increased number of mitoses in the females; and (iv) minimal to
moderate eosinophilic focus(i) of altered hepatocytes (focal/multifocal)
in the females.  Additionally, an increased incidence of minimal to
moderate interstitial mixed cell infiltrate (focal/multifocal) in the
liver in males was considered equivocal because only minimal severity
was observed at 3000 ppm and the incidence and severity were not clearly
related to dose.  Minimal to marked horn dilatation (diffuse) in the
uterus at 3000 ppm was considered treatment-related.

The LOAEL is 30 ppm (equivalent to 4/5 mg/kg/day in males/females),
based on gallstones, eosinophilic cytoplasmic alteration, subepithelial
mixed cell infiltrate, and dilatation in/of the gallbladder;
hepatocellular vacuolation, hepatocellular hypertrophy, and increased
liver weight in males and females; and papillary mineralization of the
kidney and changes in hematological parameters indicative of anemia in
females.  The NOAEL was not established.

At the doses tested, there was not a treatment-related increase in tumor
incidence when compared to controls.  Dosing was considered adequate
based on toxicity noted in the gallbladder, liver, and testes, decreased
body weight and body weight gain, and decreased food consumption.

This study is classified as acceptable/guideline and satisfies the
guideline requirements (OPPTS 870.4200b; OECD 451) for a carcinogenicity
study in mice.

A.3.6	Mutagenicity

	Gene Mutation

870.5100, In vitro Bacterial Gene Mutation

MRID 46695709

Acceptable/guideline	0, 5, 15, 50, 150, 500, 1500 and 5000 ug/plate in
the presence and absence of mammalian metabolic activation in the
range-finding assay (standard plate test) and concentrations of 0, 50,
150, 500, 1500 and 5000 ug/plate in the presence and absence of
mammalian metabolic activation in the second assay (pre-incubation
test).

 Negative for inducing gene mutations in S. typhimurium strains   SEQ
CHAPTER \h \r 1 TA 1535, TA1537, TA1538, TA98 and TA100 up to 5000
(g/plate (limit concentration) in the absence and presence of metabolic
activation.

Metabolites of Tembotrione

870.5100, In vitro Bacterial Gene Mutation

MRID 46695710

Acceptable/guideline	AE0456148

0, 16, 50, 158, 500, 1581 and 5000 (g/plate in the presence and absence
of mammalian metabolic activation.

Negative for inducing gene mutations in S. typhimurium strains   SEQ
CHAPTER \h \r 1 TA 1535, TA1537, TA1538, TA98 and TA100 tested up to
5000 (g/plate (limit concentration) in the absence and presence of
metabolic activation

870.5100, In vitro Bacterial Gene Mutation

MRID 46695711

Acceptable/guideline	AE1417268

0, 16, 50, 158, 500, 1581 and 5000 (g/plate in the presence and absence
of mammalian metabolic activation.

Negative for inducing gene mutations in S. typhimurium strains   SEQ
CHAPTER \h \r 1 TA 1535, TA1537, TA1538, TA98 and TA100 tested up to
5000 (g/plate (limit concentration) in the absence and presence of
metabolic activation.

870.5100, In vitro Bacterial Gene Mutation

MRID 46695712

Acceptable/guideline	AE1392936

0, 16, 50, 158, 500, 1581 and 5000 ug/plate in the presence and absence
of mammalian metabolic activation.

Negative for inducing gene mutations in S. typhimurium strains   SEQ
CHAPTER \h \r 1 TA 1535, TA1537, TA1538, TA98 and TA100 tested up to
5000 (g/plate (limit concentration) in the absence and presence of
metabolic activation.

	Cytogenetics

870.5300, In Vitro Mammalian Cells in Culture Gene Mutation assay in
Chinese Hamster V79 Cells (HPRT Locus Assay);

MRID 46695713

Acceptable/guideline

	0, 250, 500, 1000, 1400, 1500 and 1600 μg/mL, with and without
metabolic activation.

Negative for inducing gene mutations in Chinese hamster V79 cells in the
absence and presence of metabolic activation tested up to cytotoxicity,
1600 ug/mL.

870.5375, In vitro Mammalian Cytogenetics Chromosomal Aberration Assay
in Human Lymphocytes

MRID 46695717

Unacceptable/Guideline	In the first assay, 0, 0.08, 0.16, 0.31, 0.63,
1.25, 2.5, 5 and 10 mM (equivalent to 0, 35.26, 70.53, 136.65, 278, 551,
1102, 2204 and 4408 ug/mL) with and without metabolic activation (S9).
In a second assay, 0, 1.25, 2.5, 5, 7.5 and 10 mM (equivalent to 0, 551,
1102, 2204, 3306 and 4408 ug/mL) with and without metabolic activation.

Equivocal because structural aberrations and polyploidy were observed in
the absence of excessive cytotoxicity at 3306 ug/mL with metabolic
activation.  In the first test, up to the limit concentration (4408
ug/mL); no increases were seen; therefore, clastogenicity and polyploidy
were not confirmed.

Metabolites of Tembotrione

870.5300, In Vitro Mammalian Cells in Culture Gene Mutation assay in
Chinese Hamster V79 Cells (HPRT Locus Assay);

MRID 46695714

Acceptable/guideline

	AE0456148

0, 55, 110, 220, 440, 880, 1760 and 3520 μg/mL with and without
metabolic activation.

Negative for inducing gene mutations in Chinese hamster V79 cells tested
up to 3520 ug/mL (limit concentration) in the absence and presence of
metabolic activation.

870.5300, In Vitro Mammalian Cells in Culture Gene Mutation assay in
Mouse Lymphoma L5178Y Cells (MLA) (TK Locus Assay);

MRID 46695715

Acceptable/guideline	AE1417268

0, 302, 614, 1075, 1844, 2534, and 3115 ug/mL for experiment 1 and 0,
235, 499, 1036, 1670, 2534; and 3023 ug/mL for experiment 2.

Positive for inducing weak increases in the mutant colonies over
background following 24 hours of exposure in the absence of S9 at high
concentrations (2534 and 3023 ug/mL).  There was no repeat testing for
confirmation.

870.5300, In Vitro Mammalian Cells in Culture Gene Mutation assay in
Chinese Hamster V79 Cells (HPRT Locus Assay);

MRID 46695716

Acceptable/guideline

	AE1392936

0, 45, 90, 180, 360, 720, and 1440 µg/mL with and without metabolic
activation.

Negative for inducing gene mutations in Chinese hamster V79 cells in the
absence and presence of metabolic activation tested up to its limit of
solubility, 1440 ug/mL.

870.5375, In vitro Mammalian Cytogenetics Chromosomal Aberration Assay
in Human Lymphocytes

MRID 46695718

acceptable/Guideline	AE0456148

0, 900, 1800 or 3600 μg/mL for four and 18 hours with and  without
metabolic activation (S9-mix).

Negative for inducing chromosome structural aberrations and polyploidy
in Chinese hamster V79 cells tested up to 3600 ug/mL (limit of
solubility) in the absence and presence of metabolic activation.

870.5375, In vitro Mammalian Cytogenetics Chromosomal Aberration Assay
in Human Lymphocytes

MRID 46695719

acceptable/Guideline	AE1417268

0, 10, 50, 100, 250, 500, 1000, 2000, 2500, 3000, 3500, 4000 and 4724
ug/mL for three hours with and  without metabolic activation

Negative for inducing structural aberrations or polyploidy tested up to
cytotoxic concentrations, 4724 ug/mL.

870.5375, In vitro Mammalian Cytogenetics Chromosomal Aberration Assay
in Chinese Hamster V79 Cells

MRID 46695720

acceptable/Guideline	AE1392936

0, 350, 700, and 1400 ug/mL for 4 hours with and  without metabolic
activation.

Negative for inducing chromosome structural aberrations or polyploidy up
to cytotoxic concentrations up to the solubility limit.

	Other Genotoxicity

870.5395, In Vivo Mammalian Cytogenetics - Erythrocyte Micronucleus
assay in mice

MRID 46695721

Acceptable/guideline

	500, 1000 and 2000 mg/kg body weight

Negative for the increase in frequency of micronucleated immature
erythrocytes in mouse bone marrow tested up to 2000 mg/kg (limit dose).

870.5550, Unscheduled DNA Synthesis in Primary Rat Hepatocytes/Mammalian
Cell Cultures

MRID 46695722

Acceptable/Guideline	1,000 or 2,000 mg/kg body

Negative for inducing unscheduled DNA synthesis in Wistar rat primary
hepatocytes tested up to 2000 mg/kg (limit dose).

A.3.7	Neurotoxicity

	870.6100 Delayed Neurotoxicity Study - Hen

	870.6200 Acute Neurotoxicity Screening Battery

EXECUTIVE SUMMARY:  In an acute neurotoxicity study (MRID 46695723),
groups of non-fasted, young-adult Wistar rats (12/sex/dose) were given a
single oral (gavage; 10 mL/kg) dose of AE 0172747 (94% a.i., Batch No.
PFI 0215) in aqueous 0.5% methyl cellulose/0.4% Tween 80 at doses of 0,
200, 500 or 2000 mg/kg (limit dose) and observed for 14 days.  A
functional observational battery (FOB) and motor activity testing were
performed on all animals during pre-exposure, Day 0 (at 3 hours
post-dosing, the estimated time-of-peak effect), and Days 7 and 14.  At
study termination, 6 animals/sex/group were euthanized and perfused in
situ for neuropathological examination.  The brain and peripheral
nervous system tissues collected from the perfused animals in the
control and 2000 mg/kg  groups were subjected to histopathological
evaluation.  Positive control data were not provided; however, data
previously reviewed by the Agency have been included in this DER.

No compound-related effects on mortality, body weight, body-weight gain,
brain weight, gross pathology, or neuropathology were observed at any
dose in either sex.

At 200 mg/kg and above, the following treatment-related effect was
noted: FOB effect on Day 0, decreased arousal in the open-field in the
males (2-7).

At 500 mg/kg and above, the following treatment-related effects were
noted: (i) increased incidence (# affected/12 vs. 0/12 controls) of
urine stain at 500 mg/kg (2 females) and 2000 mg/kg (8 of each sex), and
red nasal stain at 500 mg/kg (1 of each sex) and 2000 mg/kg (4 males);
(ii) FOB effects on Day 0 at 500 mg/kg included, decreased (p<=0.05)
body temperature (°C) in the females (37.4 treated vs. 38.1 controls);
and (iii) on Day 0, decreased (p<=0.05) total session motor activity in
the males (decr 41-70%) and females (decr 27-66%) and total session
locomotor activity in the males (decr 42-71%) and females (decr 29-76%).

Additional FOB effects on Day 0 noted at 2000 mg/kg included: (i)
decreased arousal in the open-field in the females (7/12 treated vs. 0
controls); (ii) decreased number of rears in the males (0.6 treated vs.
2.2 controls) and females (2.3 treated vs. 6.6 controls, p<=0.05); (iii)
decreased (p<=0.05) body temperature (°C) in the males (36.8 treated
vs. 37.2 controls) and females (36.7 treated vs. 38.1 controls); and
(iv) decreased (p<=0.05) approach response (no reaction) in the males
(6/12 treated vs. 0 controls).

All clinical signs of toxicity were initially observed on Days 0-3 and
were resolved by Day 8, and all FOB parameters and motor activity were
similar to controls on Days 7 and 14.

The LOAEL is 200 mg/kg in males based on FOB effects, decreased arousal
in the open-field on Day 0.  The NOAEL in males was not identified.  The
LOAEL is 500 mg/kg in females based on urine staining, red nasal
discharge, and on FOB effects decreased body temperature on Day 0, and
decreased motor and locomotor activity on Day 0.  The NOAEL in females
is 200 mg/kg.

This study is classified as acceptable/guideline and satisfies the
guideline requirement (870.6200; OECD 424) for an acute neurotoxicity
study in rats.

	870.6200 Subchronic Neurotoxicity Screening Battery

EXECUTIVE SUMMARY:  In a subchronic neurotoxicity study (MRID 46695724),
AE 0172747 (94% a.i., Batch No. PFI 0215) was administered in the diet
to 12 young-adult Wistar rats/sex/group at dose levels of 0, 20, 250, or
2500 ppm (equivalent to 0/0, 1.33/1.75, 16.4/21.0, and 160/224 mg/kg
bw/day [M/F], respectively) for 13 weeks.  Neurobehavioral assessment
(functional observational battery [FOB] and motor activity testing) was
performed in 12 rats/sex/group at pre-dosing and Weeks 2, 4, 8, and 13.
At study termination, 6 rats/sex/group were anesthetized and perfused in
situ for neuropathological examination.  The tissues from the perfused
animals in the control and 2500 ppm groups were subjected to
histopathological evaluation of brain and peripheral nervous system
tissues.  Positive control data were not provided; however, data
previously reviewed by the Agency have been included in this DER.

No compound-related effects were observed in mortality, clinical signs
of toxicity, ophthalmoscopic effects, FOB, motor activity, brain
weights, or gross or neuropathology.

At 2500 ppm, slight decreases (3-8%; not statistically significant) in
body weight were noted in both sexes throughout the study, and overall
(Days 0-91) body-weight gain (calculated by the reviewers) was decreased
by 18-19% in the both sexes compared to controls.

No treatment-related effects were observed at 250 ppm or lower in either
sex.

No neurological effects were observed at any dose in either sex.

The LOAEL is 2500 ppm (equivalent to 160/224 mg/kg bw/day [M/F]) based
on decreased body weight and body-weight gain in both sexes.  The NOAEL
is 250 ppm (equivalent to 16.4/21.0 mg/kg bw/day [M/F]).

The study is classified as acceptable/guideline and satisfies the
guideline requirement (OPPTS 870.6200b) for a subchronic neurotoxicity
study in rats.

	870.6300 Developmental Neurotoxicity Study

EXECUTIVE SUMMARY:  In a developmental neurotoxicity study (MRID
46695725) technical grade AE 0172747 (94% a.i., Batch #s PFI 0215 and
OP2250027) was administered to approximately 30 mated female Wistar rats
per dose in the diet at nominal dose levels (gestation) of 0, 10, 200,
or 1500 ppm from gestation day (GD) 6 through lactation day (LD) 21.
Doses were adjusted during lactation to achieve a more consistent dosage
throughout exposure.  The mean daily intake during gestation and
lactation was 0, 0.8, 16.3, and 118 mg/kg/day.  Dams were allowed to
deliver naturally and were killed on LD 21, following weaning of their
respective litters.  Any females that were found to be sperm positive
and/or with a vaginal plug, but did not deliver, were sacrificed on GD
24; eight treated dams were examined for pregnancy status.  On postnatal
day (PND) 4, litters were standardized to 8 pups/litter; the remaining
offspring and dams were sacrificed and discarded without further
examinations.  Subsequently, 1 pup/litter/group (at least 10
pups/sex/dose when available) was allocated to subsets for FOB, motor
activity, acoustic startle response, learning and memory evaluation, and
neuropathological examination.

No treatment-related effects were observed on mortality or reproductive
parameters or at necropsy in dams.  At ≥16.3 mg/kg/day, corneal
opacity was observed during lactation in dams both upon clinical
examination and during the FOB.  Body weight in dams was decreased by
5-7% during gestation and by 3-5% during lactation at ≥16.3 mg/kg/day.
 Overall body-weight gain in dams was decreased by 13-17% during
gestation at ≥16.3 mg/kg/day. Overall body-weight gain during
lactation was similar to controls at all doses.  During gestation, no
treatment-related differences in food consumption were observed.  During
lactation, food consumption in dams was decreased by 8-12% for part
(≥16.3 mg/kg/day) or all (118 mg/kg/day) of the pre-weaning period.

The maternal LOAEL is 16.3 mg/kg/day, based on corneal opacity during
lactation.  The maternal NOAEL is 0.8 mg/kg/day.

≥16.3 mg/kg/day at the time of clinical observations and during the
FOB.  Offspring pre-weaning body weights were decreased by 7-14% at
≥16.3 mg/kg/day for most days of lactation.  Body-weight gains were
also decreased by 8-32% at ≥16.3 mg/kg/day throughout most pre-weaning
intervals.  Offspring post-weaning body weights remained decreased by
5-16% in both sexes throughout the study at ≥16.3 mg/kg/day.
Decreases (5-6%) in post-weaning body weight in the 0.8 mg/kg/day males
were also considered treatment-related since they were observed many
weeks after treatment was discontinued and therefore appeared to be
delayed-onset effects.  Preputial separation was delayed by 2.1 days in
the 118 mg/kg/day males.

≥16.3 mg/kg/day.  In addition, in males on PND 60, the interval peak
amplitude values were decreased by 40-50% during most or all blocks at
≥16.3 mg/kg/day.  At 0.8 mg/kg/day, mean peak amplitude was decreased
by 38% (p<0.05) during block 2 only.  PND 21 absolute brain weights were
decreased in males by 6-9% at ≥16.3 mg/kg/day and in females by 6% at
118 mg/kg/day; terminal body weight was also decreased in both sexes.
PND 75 absolute brain weights were decreased in both sexes by 6-7% at
118 mg/kg/day either with (males) or without (females) corresponding
reductions in terminal body weights.  Changes were observed in several
morphometric parameters in adult animals at ≥0.8 mg/kg/day; however,
statistical analysis of brain morphometry data for PND 21 and 70 males
and females was inappropriate.  Measurements at each dose level were
compared separately to those in controls (i.e., 2-group comparisons)
using individual t-tests.  More appropriate is the use of Dunnett’s
test (as used for brain weights) for group comparisons against a single
control.

The offspring LOAEL is 0.8 mg/kg/day, based on decreased post-weaning
body weight (males), decreased acoustic startle response on PND 60
(males), and brain morphometric changes on PND 75 (males and females).
The offspring NOAEL was not determined.

This study is classified Acceptable/non-guideline and may be used for
regulatory purposes.  It does not, however, satisfy the guideline
requirement for a developmental neurotoxicity study in rats [OPPTS
870.6300, §83-6; OECD 426 (draft)] due to the pending review of the
positive control data.

A.3.8	Metabolism

	870.7485	Metabolism - Rat

EXECUTIVE SUMMARY:  In a series of metabolism studies (MRIDs 46695726,
46695727, 46695728, and 46695729), [phenyl-U-14C]-AE 0172747 (Batch # Z
31053-4; radiochemical purity 99.5%) or [cyclohexyl-UL-14C]-AE 0172747
(Batch #s BECH 1517 or BECH 1523; radiochemical purity >98%) in PEG 200
was administered by oral gavage to groups of four Wistar rats/sex/dose
at doses of 5 or 1000 mg/kg.  The concentration time-courses of
radioactivity in blood and plasma were calculated, the concentrations of
radioactivity in tissues and excreta were determined, and metabolites
were identified and quantified in the urine and feces.

The test compound was absorbed rapidly, as radioactivity was detected in
the blood and plasma of all animals at the first time point measured (30
min post-dosing) for both radiolabeled forms.  Males had higher mean
blood and plasma maximum concentrations (Cmax) than females.  Also,
males displayed higher AUC values than females in both blood and plasma
at both doses.  In both sexes, the AUC for both blood and plasma
indicated a disproportionally higher mean systemic exposure at 1000
mg/kg than at 5 mg/kg (>200-fold) that was apparently due to a
saturation of the initial elimination/biotransformation processes,
resulting in a slower initial elimination phase.  Other blood and plasma
parameters were generally similar across doses and radiolabeled forms.

In the 5 mg/kg animals dosed with either radiolabeled form, the liver
and kidneys contained the highest mean levels of radioactivity.  No
other tissue exceeded 0.12% of the administered dose.  In the 1000 mg/kg
animals dosed with [phenyl-U-14C]-AE 0172747, the skin/fur and carcass
contained the highest mean levels of radioactivity.  No other tissue
exceeded 0.06% of the administered dose.

In the 5 mg/kg [phenyl-U-14C] males, the highest concentrations of
radioactivity were detected in the, liver, kidneys, skin, and carcass.
In the 5 mg/kg [phenyl-U-14C] females and [cyclohexyl-UL-14C] males and
females, the highest concentrations of radioactivity were detected in
the liver, kidneys, skin, and carcass.  In the 1000 mg/kg [phenyl-U-14C]
males and females, the highest concentrations of radioactivity were
detected in the skin, liver, kidneys, stomach (and contents), and
carcass and there was no evidence of bioaccumulation.

Total recoveries ranged from 96.3-102.7% of the administered doses, with
no differences observed between dose levels or position of the
radiolabel. Substantial sex differences were observed in the routes of
excretion.  At 5 mg/kg, the majority of the radioactivity was recovered
in the feces of the males, while in the females, the majority of the
radioactivity was recovered in the urine.  At this dose, the majority of
the radioactivity in the urine was recovered during the first 6 h, while
the majority of radioactivity in the feces was recovered during the
first 24 h.

Tissues and cage wash each accounted for <5.1%.  Sex differences in the
routes of excretion were also observed in the 1000 mg/kg group.  In the
males, approximately equal proportions of radioactivity were recovered
in the feces and urine, while in the females, the majority of the
radioactivity was recovered in the urine.  At this dose, the majority of
the radioactivity in the urine was recovered during the first 24 h,
while the majority of radioactivity in the feces was recovered during
the first 48 h.  Tissues and cage wash each accounted for <10.1%.

The test compound was extensively metabolized.  The majority of
radioactivity in urine and fecal extract samples was present as parent
and up to eleven metabolites.  Metabolic profiles were qualitatively
similar for both radiolabeled forms; however, profiles for the high and
low doses were dissimilar, and major differences were noted between
sexes.  The major route of metabolism was found to be hydroxylation
(oxidative pathway) of the cyclohexyl ring of the molecule.  In excreta,
parent and identified compounds accounted for 68.1-93.2% of the
administered dose, while unidentified metabolites accounted for
2.5-13.8% of the administered dose.  The total administered dose
accounted for in the excreta was 82.3-104.9%.

Parent compound accounted for 1.9-59.9% of the total radioactivity
eliminated, and was found in greatest quantity in the urine of the
females (44.1-59.4%).  Low dose males eliminated small amounts of parent
(1.9-3.0%), while high dose males eliminated moderate amounts (33.8%).
The metabolite found in the greatest quantity at both doses was
4-hydroxy-AE 0172747, with low dose males eliminating more than low dose
females.  High dose males and females eliminated approximately equal
amounts.  The only other metabolite found at >5% of the administered
dose was 5-hydroxy-AE 0172747.  Males excreted greater quantities than
females.

This metabolism study in the rat is classified acceptable/guideline and
satisfies the guideline requirement for a Tier 1 metabolism study [OPPTS
870.7485, OECD 417] in rats.

COMPLIANCE:  Signed and dated Data Confidentiality, GLP Compliance, and
Quality Assurance statements were provided.

	870.7600	Dermal Absorption - Rat

EXECUTIVE SUMMARY:  In an in vivo dermal penetration study (MRID
46695730), [phenyl-UL-14C]-AE 0172747 (>98% radiochemical purity; batch
# BECH 0857) in a suspension concentrate formulation containing 420 g/L
AE 0172747 and 210 g/L Isoxadifen-ethyl was applied to four male Wistar
(Rj:WI[IOPS HAN]) rats/group on 2 x 6 cm2 skin areas at dose levels of
0, 6.6, 66, or 660 µg/cm2.  Exposure times were 0.5, 1, 2, 4, 10, and
24 h for each dose.  At the end of each exposure period, the skin was
swabbed, and urine, feces, treated skin, cardiac blood, kidneys, liver,
brain, spleen, and residual carcass were collected and analyzed for
radioactivity.

Recovery of the applied dose was 90.8-98.7% of the administered dose.
The distribution profile of radioactivity was qualitatively similar
between the dose groups.  The majority of the administered dose was
recovered from the skin swabs, accounting for 76-93% of the administered
doses.  A total of 76-94% of the applied doses was not absorbed. A
general trend of increasing dermal absorption with increasing time was
observed, and the amount of radioactivity found in the treated skin
generally increased with decreasing dose level.  Estimates of dermal
absorption were based on the sum of the treated skin + the total
directly absorbed (urine + feces + cage wash + carcass + brain + spleen
+ liver + kidneys + blood + non-treated skin + surrounding skin).
Dermal absorption was 8.3-14.9% (low), 4.8-12.8% (intermediate), and
1.7-4.8% (high) of the applied doses.  The amount of dermal absorption
was not proportional to dose.

All treatments (dose levels applied) were for exposure periods for up to
24 h.  The most conservative value for risk assessment is a
dermal-absorption of 15% observed at the low dose (6.6 µg/cm2) at 4 h
after application.  This value should be considered to protect
commercial applicators.

This study is acceptable/guideline and satisfies the guideline
requirements (OPPTS 870.7600; OECD none) for a dermal penetration study
in rats.

A.3.9	Special/Other Studies

Effects on Blood Coagulation Parameters - rats; Non-guideline

EXECUTIVE SUMMARY:  The purpose of this non-guideline study (MRID
46695731) was to investigate the potential effect of AE 0172747 with and
without co-administration of vitamin K1 on blood coagulation in rats.
Vitamin K1 is essential for the production of Prothrombin and Factors
VII, IX, and X by the liver.  In this study, AE 0172747 (95.4% a.i.;
Batch # PFI 0254) in 0.5% aqueous methylcellulose was administered daily
via oral gavage at a dose volume of 10 mL/kg to groups of eight male
Wistar (Rj:WI(IOPS HAN) rats for three consecutive days.  One group was
dosed with the test compound at 1000 mg/kg, while a second group was
dosed at 1000 mg/kg and also was given daily 10 mg/kg doses of vitamin
K1 by subcutaneous injection.  A third group received vehicle only via
daily gavage.  On Day 4, the rats were killed and plasma fibrinogen,
prothrombin time, activated partial thromboplastin time, and specific
coagulation factor times of the extrinsic (Factors II, V, VII, and X)
and intrinsic (Factors VIII, IX, XI, and XII) pathways were measured.

Systemic effects:

No effects of treatment were observed on mortality.

On Day 2, tilting head was observed in 2/8 rats in the 1000 mg/kg AE
0172747 group, and in 1/8 rats in the 1000 mg/kg AE 0172747 + vitamin K1
group.  Additionally in the vitamin K1 group, another animal presented
with piloerection and hunched posture on Day 2, and reduced motor
activity, increased salivation, soiling around the mouth, and hunched
posture on Day 3.  Body-weight losses of 3 and 5 g were noted during
treatment (Days 1-3) in the 1000 mg/kg AE 0172747 group and vitamin K1
group, respectively, while control rats gained 5 g during the same
period.  Food consumption was decreased by 26-42% in all treated rats
during treatment.  In the 1000 mg/kg AE 0172747 group, single or
multiple red foci were observed in the following organs (# affected/8
treated) compared to 0 controls:  stomach (6); lungs (3); testes (2);
epididymides (2); prostate (1); and thymus (1).  Additionally in this
group, unilateral or bilateral dark red epididymides were noted in 5
animals.  These changes were considered to be treatment-related
hemorrhagic foci.  These findings were not observed in the vitamin K1
group.

Coagulation effects:

The following parameters were increased (p<=0.01) in the 1000 mg/kg AE
0172747 treated group:  (i) prothrombin time (incr. 971%); (ii) Factor
II (incr. 322%); (iii) Factor VII (incr. 110%); (iv) Factor X (incr.
256%); (v) activated partial thromboplastin time (incr. 319%); and (vi)
Factor IX (incr. 46%).  These parameters were comparable to controls in
the vitamin K1 group.  These data indicate that the alterations in
clotting parameters were mediated by effects on vitamin K1 clotting
factors.

This study is acceptable/non-guideline.

Non-guideline; Blood Tyrosine Levels – Rabbit

EXECUTIVE SUMMARY:  This non-guideline study (MRID 46695732) was
performed to evaluate the effects of AE 0172747 on blood tyrosine levels
in pregnant rabbits following administration by gavage from GD 6-28.  AE
0172747 has been shown to inhibit 4-hydroxyphenylpyruvate dioxygenase
(HPPDase).  HPPDase is involved in L-tyrosine catabolism, and inhibition
of this enzyme leads to an increase in systemic L-tyrosine
concentrations.  In this study, AE 0172747 (95.0% a.i.; Batch # PFI
0195) in aqueous 0.5% methylcellulose was administered daily via oral
gavage at a dose volume of 4 mL/kg to groups of 6 presumed pregnant New
Zealand White (KBL [NZW]) rabbits/dose at dose levels of 0 or 10 mg/kg
bw/day on gestation days (GD) 6-28.  Clinical observations, body
weights, and food consumption were recorded at regular intervals during
treatment.  Blood samples were taken from each animal on GD 4, 10, 15,
22, and 29, and the levels of tyrosine were determined.  All surviving
does were killed on GD 29 for examination of their uterine contents.

Maternal toxicity:  No treatment-related effects were observed on
mortality, clinical signs of toxicity, body weights, body-weight gains,
food consumption, or gross pathology.

 to GD 4 were significantly (p≤0.01) higher than controls for all
intervals measured during treatment.

Developmental toxicity:  No effects of treatment were observed on
numbers of litters, live fetuses, or complete litter resorptions.

This study in the rabbit is classified acceptable/non-guideline.

Inhibition of 4-Hydroxyphenylpyruvate Dioxygenase in Rats and In Vitro;
Non-guideline

EXECUTIVE SUMMARY:  In two non-guideline studies (MRIDs 46695733 and
46695734), the potential of AE 0172747 and three of its metabolites (AE
1417268, AE 0456148, and

AE 1392936) to inhibit 4-hydroxyphenylpyruvate dioxygenase (HPPDase) in
vivo in the rat was examined, and the levels of tyrosine and
4-hydroxyphenyl lactic acid (4-HPLA) in suspensions of immobilized
hepatocytes from rat, dog, rabbit, mouse and human livers following
exposure to AE 0172747 in vitro were measured.  In the in vivo studies,
AE 1417268 (Batch # 2003BRP003-284), AE 0456148 (Batch # OD05/01), AE
1392936 (Batch # LSMI 1-2-34), or AE 0172747 (Batch # PFI 0195) in PEG
400 was administered once via oral gavage at a dose volume of  5 mL/kg
to groups of three male Wistar (OFA) rats at a dose level of 10 mg/kg.
Plasma tyrosine concentrations were measured prior to dosing, and at 2,
4, 8, 24, 48, and 72 h post-dosing.  The purpose of these studies was to
evaluate the potential inhibition of HPPDase by AE 1417268, AE 0456148,
and AE 1392936, and compare the results to those obtained with the
parent compound.  HPPDase is involved in L-tyrosine catabolism, and
inhibition of this enzyme leads to an increase in systemic L-tyrosine
concentrations.  In the in vitro studies, AE 0172747 (94.7% a.i.; Batch
# PFI 0254) was dissolved in dimethylsulfoxide (DMSO).  Cytotoxicity
assays were then performed on rat and mouse hepatocytes using 30, 60, or
120 µM AE 0172747 in a final concentration of 1% DMSO in the culture
medium.  Next, the test substance was added to cultures of immobilized
rat, dog, rabbit, mouse, and human hepatocytes (Liverbeads™) to a
final concentration of 120 µM in a final concentration of 1% DMSO in
the culture medium, and incubated for 0, 2, or 4 h at 37ºC.  The
concentrations of tyrosine and 4-HPLA in the Liverbeads™ were then
determined.  The purpose of these studies was to rank the different
species according to their ability to produce 4-HPLA.  When HPPDase is
inhibited, 4-HPLA is produced by an alternative pathway and helps limit
systemic tyrosine increases.

In vivo studies (MRID 46695733):  AE 0172747 had a strong effect on
plasma tyrosine levels, causing an approximately 20-fold increase at 24
h post-dosing.  AE 1417286 caused a smaller 5-fold increase in plasma
tyrosine levels that peaked at 8 h post-dosing.  AE 0456148 and AE
1392936 had no effect on plasma tyrosine levels and were similar to the
PEG 400-treated controls.

In vitro studies (MRID 46695734)

al medium at any time point in any species except the mouse.  Mouse
Liverbeads™ produced very low levels of 4-HPLA (0.10-0.12 µg/mg
protein) at all time points that did not increase with incubation time.
In basal medium with AE 0172747, 4-HPLA was detected at 2 and 4 h in
human (0.20-0.38 µg/mg protein; p<=0.05) and mouse (0.42-0.65 µg/mg
protein, p<=0.05) Liverbeads™, and the levels increased with time.
4-HPLA was not detected in rat, dog, or rabbit Liverbeads™ incubated
in basal medium with AE 0172747.  Similarly, 4-HPLA was not detected in
L-tyrosine supplemented medium at any time point in any species except
the mouse.  Mouse Liverbeads™ produced low levels of 4-HPLA (0.12-0.27
µg/mg protein) at all time points that increased with incubation time.
In L-tyrosine supplemented medium with AE 0172747, 4-HPLA was detected
at 2 and 4 h in rabbit (0.19-0.32 µg/mg protein), human (0.40-0.84
µg/mg protein), and mouse (0.94-1.40 µg/mg protein) Liverbeads™, and
the levels increased with time.  4-HPLA was also detected at 4 h in rat
(0.18 µg/mg protein) and dog (0.15 µg/mg protein) Liverbeads™.
Therefore, the ranking of species by their ability to produce 4-HPLA
after inhibition of HPPDase is (from most to least produced):  mouse,
human, rabbit, rat, and dog.

In summary, AE 1417268 has an inhibitory effect on HPPDase activity  in
vivo, but much lower than that observed with AE 0172747, while AE
0456148 and AE 1392936 had no inhibitory effect on HPPDase activity.
Human and mouse hepatocytes produced more 4-HPLA in vitro than rabbit,
dog, or rat hepatocytes under all experimental conditions.  Thus, human
and mouse hepatocytes were able to use an alternative pathway for
tyrosine catabolism when HPPDase was inhibited.  Rabbit, dog, and rat
were much less efficient under both normal and extreme conditions.

This study is acceptable/non-guideline.

Tyrosinemia Tissue Effects – Rat;  Nonguideline

EXECUTIVE SUMMARY:  In a subchronic toxicity study (MRID 47044502), two
groups of five male and five female Wistar rats (Groups 1 and 3) were
fed basal diet while two groups of five male and five female Wistar rats
(Groups 2 and 4) were fed diets supplemented with 20,000 ppm (2%)
L-tyrosine (Lot No. 114K0375, purity 98.9%) for 28 days.  (The tyrosine
supplementation was approximately three to five times the normal dietary
intake.)  Rats in Groups 3 and 4 received 10 μg/kg bw/day
2-(2-nitro-4-trifluoromethyl-benzoyl)-1,3-cyclohexanedione (NTBC), an
inhibitor of 4-hydroxyphenylpyruvate dioxygenase, daily by gavage.  The
study was done to determine the effects of increased plasma tyrosine
concentration to the eye, kidney, liver, pancreas, and thyroid of rats

No toxicologically significant effects on body weight or food intake
were noted.  All male and 1/5 female rats in Group 4 (2% dietary
tyrosine + 10 µg/kg bw/day NTBC by gavage) developed white areas on the
eye beginning on Day 24 through the end of the study.  In addition, the
eyes of 4/5 Group 4 male rats were half-closed beginning on Day 22
through the remainder of the study.

The average plasma tyrosine concentration of Group 4 male and female
rats increased with time from approximately three to five fold on Day 2
to a 24-fold increase in males and 18-fold increase in females by Day
21.  Treatment with 10 µg/kg bw/day NTBC alone had little effect on
plasma tyrosine in male and female rats until Day 29/30 when it was
increased 3-fold and 5.8-fold in males and females, respectively.  After
an overnight fast, plasma tyrosine was increased in NTBC-treated rats
18-fold in males and 27-fold in females.  Treatment with 2% dietary
tyrosine alone induced a < 5-fold increase of plasma tyrosine in male
and female rats that decreased with fasting.

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+ eye, pancreas, and thyroid.  Bilateral keratitis was observed in the
eyes of all males and one female and diffuse interstitial mixed cell
inflammation was noted in the pancreas of two males and one female rat
treated with tyrosine/ NTBC.  The pancreatic changes were associated
with an increased incidence of focal/multifocal acinar degeneration and
apoptosis.  Minimal to slight thyroid colloid alteration was noted in
3/5 Group 4 male rats.  No treatment-related effects, to the eye,
pancreas, or thyroid, were noted in rats treated only with tyrosine or
NTBC.

This study demonstrated a prolonged threshold tyrosine concentration
exists in rats, above which macroscopic and/or microscopic effects occur
to the eye, pancreas, and thyroid.  These effects occurred when rats
were fed diets containing three to five times the normal dietary intake
of tyrosine while one of the tyrosine   HYPERLINK
"http://www.answers.com/topic/catabolism-2" \t "_top"  cataboli zing
enzymes was inhibited.

This subchronic study in the rat is Acceptable/Nonguideline.  The
relevance of the study to the chemical tembotrione was not explained.

Prenatal Developmental Toxicity Study - Rat

EXECUTIVE SUMMARY:  In a non-guideline developmental toxicity study
(MRID 47044503), L-tyrosine (>99% a.i., Batch nos. 111K0888 and
078H06822) was administered in feed at dietary concentrations of 0 or
20,000 ppm (equivalent to 0 or 1404-1461 mg/kg bw/day) on gestation days
(GD) 6-21, and NTBC (99.7% a.i., batch #MKH13222-3-2) was administered
by gavage in demineralized water at dose levels of 0 or 10 ug/kg bw/day
on GD 6-20.  Four groups of 23 mated female Sprague-Dawley [Crl:CD(SD)]
rats were fed/dosed as follows: basal diet/demineralized water
(controls); treated diet/demineralized water; basal diet/NTBC; and
treated diet/NTBC.  On GD 21, blood was drawn for plasma tyrosine
measurement, and dams were sacrificed and necropsied.  All live fetuses
were weighed, sexed, and examined externally; approximately one-half
were subjected to skeletal evaluation, and visceral evaluations were not
done.  The objective of the study was to evaluate the developmental
effects of an increased blood tyrosine level produced by the
co-administration of increased dietary L-tyrosine and NTBC, an inhibitor
of 4-hydroxyphenyl–pyruvate dioxygenase, a tyrosine catabolizing
enzyme.

One female in the NTBC-only group was sacrificed on GD 13, following
weight loss (21 g during GD 10-12), reduced motor activity and head tilt
(both GD 12-13); no abnormal findings were noted at necropsy and a
definitive relationship to treatment could not be established.  Maternal
toxicity was evident in the L-tyrosine/NTBC group as an increased
incidence of corneal opacity at gross necropsy (4/23 dams vs. 0/23
controls).  One animal in the NTBC-only group had treatment-related
ocular effects noted during physical examination (a small right eye on
GD 7-21 and a white area on the right eye on GD 14-21).  There were no
treatment-related effects on body weight, food consumption, or liver
weight.  On GD 21, mean plasma tyrosine concentrations of the control,
L-tyrosine-only, NTBC– only, and combined L-tyrosine/NTBC groups were
46.04, 216.4, 388.6, and 2888 nmol/mL, respectively; thus, the mean
plasma tyrosine levels of the L-tyrosine-only, NTBC-only, and L-tyrosine
plus NTBC groups were increased 4.7-fold, 8.4-fold, and 62.7-fold,
respectively, relative to controls.

Mean fetal weight was decreased in both sexes in the group treated with
combined L-tyrosine/NTBC (-7%, p<0.01).  There were no treatment-related
effects on live litter size or postimplantation loss, including
early/late resorptions or dead fetuses, or on fetal sex ratio.  The
litter incidence of unossified 7th cervical centrum was increased in all
treated groups (control: 1/23, L-tyrosine: 6/22, NTBC: 6/20,
L-tyrosine+NTBC: 19/23).  In the L-tyrosine/NTBC-combined group, there
was an increased litter incidence of extra ossification point(s) of the
14th thoracic vertebrae (11/23 vs. 2/23 controls), along with slightly
increased litter incidences of unossified or incompletely ossified 3rd
and/or 4th proximal phalanges of the forepaw, 5th metacarpal, 1st
metatarsal, 5th sternebra, and the first 9 sacrocaudal vertebrae; these
differences are consistent with delayed fetal ossification.

This study demonstrates that co-administration of dietary L-tyrosine at
20,000 (1461 mg/kg bw/day) on GD 6-21 with oral NTBC at 10
ug/kg bw/day on GD 6-20 results in altered fetal growth in
Sprague-Dawley rats.

This developmental toxicity study in the rat is classified
Acceptable/Non-guideline.  The relevance of the study to the chemical
tembotrione was not explained.

Tyrosinemia Tissue Effects – Rat;  Nonguideline

EXECUTIVE SUMMARY:  In a subchronic toxicity study (MRID 47044504), two
groups of 10 male and 10 female Wistar rats (Groups 1 and 3) were fed
basal diet while two groups of 10 male and 10 female Wistar rats (Groups
2 and 4) were fed diets supplemented with 20,000 ppm (2%) L-tyrosine