[Federal Register: January 15, 2009 (Volume 74, Number 10)]
[Notices]
[Page 2576-2577]
[DOCID:fr15ja09-86]

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DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

[Project No. 12107-003]

Granite County; Notice of Application Accepted for Filing and
Soliciting Motions To Intervene and Protests

January 9, 2009.
    Take notice that the following hydroelectric application has been
filed with the Commission and is available for public inspection.
    a. Type of Application: A New License. (Major Project).
    b. Project No: 12107-003.
    c. Date Filed: August 8, 2008.
    d. Applicant: Granite County.
    e. Name of Project: Flint Creek Hydroelectric Project.
    f. Location: The proposed project would be located on Flint Creek
at the Georgetown Lake Dam, near Philipsburg, in Granite County and
Deer Lodge County, Montana. The proposed project would affect about
1266.33 acres of Federal lands within the Beaverhead-Deer Lodge
National Forest.
    g. Filed Pursuant to: Federal Power Act 16 U.S.C. 791 (a)-825(r).
    h. Applicant Contact: Granite County, Maureen Connor, Chairman,
Board of County Commissioners, PO Box 925, Philipsburg, Montana 59858-
0925;<PHONE_NUMBER>, or Roger Kirk, Agent, PO Box 1136, Bozeman,
Montana 59771;<PHONE_NUMBER>.
    i. FERC Contact: Gaylord Hoisington,<PHONE_NUMBER> or
<EMAIL_ADDRESS>    j. Cooperating agencies: We are asking Federal, State, local, and
tribal agencies with jurisdiction and/or special expertise with respect
to environmental issues to cooperate with us in the preparation of the
environmental document. Agencies who would like to request cooperating
status should follow the instructions for filing such requests
described in item k below. Cooperating agencies should note the
Commission's policy that agencies that cooperate in the preparation of
the environmental document cannot also intervene. See, 94 FERC ] 61,076
(2001).
    k. Deadline for filing motions to intervene and protest and request
for cooperating agency status: 60 days from the issuance date of this
notice (March 10, 2009).
    All documents (original and eight copies) should be filed with:
Kimberly D. Bose, Secretary, Federal Energy Regulatory Commission, 888
First Street, NE., Washington, DC 20426.
    The Commission's Rules of Practice and Procedures require all
intervenors filing documents with the Commission to serve a copy of
that document on each person on the official service list for the
project. Further, if an intervenor files comments or documents with the
Commission relating to the merits of an issue that may affect the
responsibilities of a particular resource agency, they must also serve
a copy of the document on that resource agency.
    Motions to intervene and protests and requests for cooperating
agency status may be filed electronically via the Internet in lieu of
paper. The Commission strongly encourages electronic filings. See 18
CFR 385.2001(a)(1)(iii) and the instructions on the Commission's Web
site (http://www.ferc.gov) under the ``e-Filing'' link.
    l. This application has been accepted for filing, but is not ready
for environmental analysis at this time.
    m. The Flint Creek project consists of: (1) An existing 2,850 acre
reservoir with

31,034 acre-feet of storage at elevation 6,378 feet above mean sea
level; (2) an existing 330-foot-long and 44-foot-high earth with
masonry-core dam; (3) a new 36-inch-diameter by 6,282-foot-long polymer
and/or steel pipeline; (4) a surge tank; (5) a new 36-inch-diameter by
approximately 1,463-foot-long buried penstock connecting the surge tank
to the new powerhouse; (6) a new approximately 30-foot by 40-foot
powerhouse containing one Pelton turbine-generator unit rated at 2
megawatts; (7) a new approximately 95-foot-long buried tailrace; (8) a
new approximately 10-foot by 10-foot fenced substation located next to
the powerhouse; and (9) all appurtenant structures. The average annual
generation of the project is approximately 10 gigawatthours.
    n. A copy of the application is available for review at the
Commission in the Public Reference Room or may be viewed on the
Commission's Web site at http://www.ferc.gov using the ``eLibrary''
link. Enter the docket number excluding the last three digits in the
docket number field to access the document. For assistance, contact
FERC Online Support at<EMAIL_ADDRESS>or toll-free at 1-
866-208-3676, or for TTY,<PHONE_NUMBER>. A copy is also available for
inspection and reproduction at the address in item (h) above.
    You may also register online at  http://www.ferc.gov/docs-filing/
esubscription.asp to be notified via e-mail of new filings and
issuances related to this or other pending projects. For assistance,
contact FERC Online Support.
    o. Any qualified applicant desiring to file a competing application
must submit to the Commission, on or before the specified intervention
deadline date, a competing development application, or a notice of
intent to file such an application. Submission of a timely notice of
intent allows an interested person to file the competing development
application no later than 120 days after the specified intervention
deadline date. Applications for preliminary permits will not be
accepted in response to this notice.
    A notice of intent must specify the exact name, business address,
and telephone number of the prospective applicant, and must include an
unequivocal statement of intent to submit a development application. A
notice of intent must be served on the applicant(s) named in this
public notice.
    Anyone may submit a protest or a motion to intervene in accordance
with the requirements of Rules of Practice and Procedure, 18 CFR
385.210, 385.211, and 385.214. In determining the appropriate action to
take, the Commission will consider all protests filed, but only those
who file a motion to intervene in accordance with the Commission's
Rules may become a party to the proceeding. Any protests or motions to
intervene must be received on or before the specified deadline date for
the particular application.
    When the application is ready for environmental analysis, the
Commission will issue a public notice requesting comments,
recommendations, terms and conditions, or prescriptions.
    All filings must (1) Bear in all capital letters the title
``PROTEST'' or ``MOTION TO INTERVENE,'' ``NOTICE OF INTENT TO FILE
COMPETING APPLICATION,'' or ``COMPETING APPLICATION;'' (2) set forth in
the heading the name of the applicant and the project number of the
application to which the filing responds; (3) furnish the name,
address, and telephone number of the person protesting or intervening;
and (4) otherwise comply with the requirements of 18 CFR 385.2001
through 385.2005. Agencies may obtain copies of the application
directly from the applicant. A copy of any protest or motion to
intervene must be served upon each representative of the applicant
specified in the particular application.

Kimberly D. Bose,
Secretary.
[FR Doc. E9-748 Filed 1-14-09; 8:45 am]

BILLING CODE 6717-01-P


Maternal LOAEL = 37 mg/kg/day, based on ocular opacities during
lactation

Maternal NOAEL = 3.8 mg/kg/day.

Offspring LOAEL = 37 mg/kg/day based on ocular opacity (post-weaning),
decreased body weight, delayed preputial separation (males), increase in
number of trials to criterion and decreases in trial latencies (passive
avoidance; PND 22 males), retinal degeneration at ophthalmoscopy
(females), decreased brain weight (PND 21 females), decreased cerebrum
length (PND 21 females), and decreased cerebellum height (PND 21 males)

Offspring NOAEL = 3.8 mg/kg/day.	46801917 (2006)

Acceptable/Non-guideline

0, 3.8, 37, or 354 mg/kg bw/day (gestation and lactation)

870.6200

	Acute neurotoxicity (rat; gavage)

	LOAEL = 200 mg/kg bw (F) and 2000 mg/kg bw (M) based on decreased
locomotor activity on day 0

NOAEL not observed in females; 500 mg/kg bw in males.	46801915 (2005)

Acceptable/Guideline

0, 200, 500, or 2000 mg/kg bw

870.4300

	Combined chronic toxicity/carcinogenicity (rat; dietary)

	LOAEL = 10/14 mg/kg (M/F) based on corneal opacity, neovascularization
of the cornea, inflammation of the cornea, regenerative corneal
hyperplasia, corneal atrophy, and/or retinal atrophy (both sexes),
hepatocellular hypertrophy along with increased serum cholesterol
(males) and an increased incidence of chronic progressive nephropathy
(males)

NOAEL = 1.0/1.4 mg/kg (M/F).	46801910 (2006)

Acceptable/Guideline

0, 25, 250, 1000, or 2500 ppm (equivalent to 0/0, 1.0/1.4, 10/14, 41/57,
or 104/140 mg/kg bw/day [M/F])

N/A

	28-day oral toxicity (dog; dietary)

	LOAEL = 171/174 mg/kg bw/day (F/M) based on increases in serum
triglycerides and elevated liver weights (M&F), and increased midzonal
multifocal vacuolation of liver (M)

NOAEL not observed.	46801845 (2002)

Acceptable/Non-guideline

0, 5000, 13000 or 26000 ppm (equivalent to 0/0, 174/171, 469/440 or
860/782 mg/kg bw/day [M/F])

870.3150

	29/90-day oral toxicity (dog; dietary)

	N/A	46801901 (2004)

Unacceptable/Guideline

0, 1500, 9000 or 18000 ppm; study terminated on day 29

870.3150

	90-day oral toxicity (dog; dietary)

	LOAEL not established

NOAEL = 40/33 mg/kg bw/day (M/F).	46801902 (2005)

Acceptable/Guideline

0, 100, 500, or 1000 ppm (equivalent to 0/0, 3/3, 17/17, or 40/33 mg/kg
bw/day [M/F])

870.3100

	90-day oral toxicity (rat; dietary)

	LOAEL = 77 mg/kg bw/day (F) and 454 mg/kg bw/day (M), based on
increased incidences of corneal opacity (M&F), mortality, and
histopathology in the kidney, urinary bladder, thyroid, and ureters (M)

NOAEL = 2.32 mg/kg bw/day (F) and 66 mg/kg bw/day (M).	46801842 (2003)

Acceptable/Guideline

0, 2, 30, 1000, 7000, or 12000 ppm (equivalent to 0/0, 0.13/0.15,
1.96/2.32, 66/77, 454/537, or 830/956 mg/kg bw/day [M/F])

870.3700

	Prenatal developmental toxicity (rat; gavage)

	Maternal LOAEL = 100 mg/kg/day based on increased incidence of
salivation, decreased corrected body weight gain, decreased body weight
during GD 6-8 and enlarged placenta.  Maternal NOAEL = 10 mg/kg/day.

Developmental LOAEL = 100 mg/kg/day based on increased fetal and/or
litter skeletal variations; and decreased body weight (males);

Developmental NOAEL = 10 mg/kg/day.	46801905 (2006)

Acceptable/Guideline

0, 10, 100, or 300 mg/kg bw/day

870.3700

	Prenatal developmental toxicity (rabbit; gavage)

	Maternal LOAEL = 250 mg/kg bw/day based on decreased body weight gain
during GD 8-10 and decreased food consumption

Maternal NOAEL = 75 mg/kg bw/day.

Developmental LOAEL = 75 mg/kg bw/day based on increased incidences of
fetal/litter skeletal variations  Developmental NOAEL = 10 mg/kg/day.
46801906 (2006)

Acceptable/Guideline

0, 10, 75, or 250 mg/kg bw/day

870.3800

	Reproduction and fertility effects (rat; dietary)

	Parental LOAEL = 2.5/3.1 mg/kg bw/day (M/F), based on colloid
alteration and/or pigment deposition in the thyroid

Parental NOAEL not observed.

Offspring LOAEL = 26.3/32.6 mg/kg bw/day [M/F] based on corneal opacity
and/or corneal neovascularization (F1 and F2 generations)

Offspring NOAEL = 2.5/3.1 mg/kg bw/day [M/F].

Reproductive LOAEL = 26.3/32.6 mg/kg bw/day (M/F), based on delayed
balano-preputial separation in F1 pups.

Reproductive NOAEL = 2.5/3.1 mg/kg bw/day (M/F).	46801907 (2005)

Acceptable/Guideline

0, 30, 300 or 3000 ppm (equivalent to premating doses of 0/0, 2.5/3.1,
26.3/32.6, or 272.4/345.7 mg/kg bw/day [F0 M/F]; and 0/0, 3.68/4.2,
34.1/38.9 or 353.6/393.4 mg/kg bw/day [F1 M/F])

870.4100

	Chronic toxicity (dog; dietary)

	LOAEL = 34 (M) & 93 (F) mg/kg/day, based on increased incidence and
severity of kidney tubular dilatation (M) and cataracts (F).

NOAEL = 7 (M) & 33 (F) mg/kg/day.	46801908 (2006)

Acceptable/Guideline

0, 250, 1000, or 3000 ppm (equivalent to 0/0, 7/9, 34/33, or 101/93
mg/kg bw/day [M/F])

870.4200

	Carcinogenicity (mouse; dietary)

	LOAEL = 13.6/16.7 mg/kg bw/day (M/F) based on increased incidences of
gallstones

NOAEL not observed.	46801909 (2006)

Acceptable/Guideline

0/0, 13.6/16.7, 137/168 and 560/713 mg/kg bw/day (M/F)

870.5100

	Gene mutation (bacterial; in vitro)

	Negative	46801911 (2004)

Acceptable/Guideline

0, 16, 50, 158, 500, 1581 or 5000 (g/plate (+/- S9)

870.5300

	Gene
m瑵瑡潩洨浡慭楬湡※湩瘠瑩潲ഩ万来瑡癩ݥ㘴〸㤱㈱
⠠〲㐰ഩ捁散瑰扡敬䜯極敤楬敮

0, 30, 60, 120, 240, 480, or 960 μg/mL (+/- S9)

870.5375

	Chromosome aberration (mammalian; in vitro)

	Negative (chromosome isodeletions observed at cytotoxic concentration
only).	46801913 (2004)

Acceptable/Guideline

0, 200, 400, 500, 600, 800, 1000, 1500, 2000, or 2500 μg/mL (+/- S9)

870.5395

	Erythrocyte micronucleus (mouse; in vivo)

	Negative	46801914 (2003)

Acceptable/Guideline

0/0, 125/250, 250/500 or 500/1000 mg/kg bw (M/F)

870.7485

	Metabolism and Pharmacokinetics

	Following oral administration, ~60% of radioactivity absorbed and
excreted in urine in 6 hrs; ~70% of radioactivity excreted in urine and
30% in feces by 52 hrs; hydroxymethyl AE 0317309 (2%), desmethyl AE
0317309 (<9%), and AE B197555 (benzoic acid; <2%) observed as
metabolites in urine & feces; further metabolism unknown;  <2% of
administered dose remained in residual carcass and tissues after 52 hrs,
highest residues in liver and kidney.	46801918 (2005)

Acceptable/Guideline

0 or 10 mg/kg bw (single low dose; dietary and iv); high dose and
repeated dosing not tested

N/A	14-day ocular toxicity study in rat and mouse (mechanistic)

	46801922 (1995)

Acceptable/Non-guideline

N/A	Effect of tyrosinemia on pregnancy and embryo-fetal development in
rat (mechanisitic)

46801921 (2006)

Acceptable/Non-guideline

N/A	In vitro inhibition of HPPD (mechanisitic)

	46801920 (2006)

Acceptable/Non-guideline

N/A	14-day comparative toxicity feeding study in dog

	46801903 (2006)

Acceptable/Non-guideline

TOXICITY PROFILE FOR BENZOIC ACID METABOLITE AE B197555 (RPA 203328)

Guideline No. 	Study Type	Results 	MRID No. (year)/ Classification
/Doses

870.1100

	Acute oral toxicity (rat)

	LD50 > 5000 mg/kg bw (M,F; toxicity category IV)	43904812 (1995)

Acceptable/Guideline

5000 mg/kg bw

N/A	28-day oral toxicity (rat; dietary)

	LOAEL not observed

NOAEL = 1118/1269 mg/kg/day (M/F)	43904813 (1995)

Acceptable/Non-guideline

0, 150, 500, 5000, or 15000 ppm (equal to 0/0, 11.1/12.7, 37.6/42.7,
377/421, or 1118/1269 mg/kg bw/day [M/F])

870.3100

	90-day oral toxicity (rat; dietary)

	LOAEL not observed

NOAEL = 769/952 mg/kg/day (M/F)	45655903 (1998)

Acceptable/Guideline

0, 1200, 4800, or 12000 ppm (equivalent to 0, 73.2/93.1, 306/371, or
769/952 mg/kg bw/day [M/F])

870.3700

	Prenatal developmental toxicity (rat; gavage)

	Maternal LOAEL = 250 mg/kg bw/day, based on clinical signs (salivation,
piloerection, red nasal discharge around time of treatment), decreased
body weight gain, and decreased food consumption

Maternal NOAEL = 75 mg/kg bw/day

Developmental LOAEL not observed Developmental NOAEL = 750 mg/kg bw/day
45655906 (1999)

Acceptable/Guideline

0, 75, 250, or 750 mg/kg bw/day

870.5100

Gene mutation (bacterial; in vitro)	0, 100, 250, 500, 1000, 2500, or
5000 g/plate (+/- S9)

Acceptable/Guideline	Negative	43904814

870.5375

Chromosome aberration (mammalian; in vitro)	0, 924, 931, 1320, 1330,
1890, 1900, 2700, or 2710 μg/mL (+/- S9)

Acceptable/Guideline	Negative	44545301

870.5395

Erythrocyte micronucleus (mouse; in vivo)	500, 1000, or 2000 mg/kg bw

Acceptable/Guideline	Negative	44545302

870.5300

Gene mutation (mammalian; in vitro)	84.5-2700 μg/mL (-S9)

338-2700 μg/mL (+S9)

Acceptable/Guideline	Negative	44545301

A.3.	Executive Summaries  TC "A.3.	Executive Summaries" \f C \l "2"

A.3.1	Subchronic Toxicity

	870.3100	90-Day Oral Toxicity – Rat

In a 90-day oral toxicity study (MRID 46801842), AE 0317309 (97.4% w/w
ai, batch H2235) was administered in the diet to groups of 10 Rj:WI(IOPS
HAN) Wistar rats  rats/sex/dose at dose levels of 0, 2, 30, 1000, 7000
and 12000 ppm (equivalent to 0.0, 0.13, 1.96, 66, 454, and 830 mg/kg
bw/day for males and 0.0, 0.15, 2.32, 77, 537 and 956 mg/kg bw/day in
females) for a period of 90 days.

No abnormalities were detected during the neurotoxicity assessment and
there were no treatment related effects on hematological parameters.

At 12000 ppm, six male and one female were either sacrificed for humane
reasons or were found dead during the treatment period.  The group was
terminated at week 11 due to excessive toxicity.  At 7000 ppm, two males
were found dead or were sacrificed for humane reasons during the
treatment period.  Treatment related clinical signs were observed in a
large number of rats at 7000 and 12000 ppm and consisted of intensely
yellow colored urine associated on a few occasions with soiled
anogenital area, soiled fur, piloerection, general pallor and wasted
appearance.  Other clinical signs noted included: few or no feces, cold
to touch, reduced motor activity, labored respiration, hunched posture,
increased salivation and soiling around the mouth.  White areas on eyes
were noted in two males at 7000 ppm and in one male and four females at
12000 ppm.  At 1000 ppm, yellow coloured urine was noted in all males on
a few days and one female presented a white area on the eyes.

At 12000 ppm, a reduction in mean body weight gain of 70% was recorded
in males during the first week of exposure.  At this dose level, the
depressions in body weight gain ranged from 11.5 to 56% over days 22 to
70.  In females at 7000 ppm and 12000 ppm, the depressions in mean body
weight gain were 12.5 and 15.6%, respectively, relative to controls at
the end of the 90 day period.  At 12000 ppm food consumption in males
was lower than control values throughout the study.  In females at
12000, the mean food consumption was lower than control value on the
first week of treatment only (reduction of 28%) without reaching
statistical significance.  At 7000 ppm, a reduction of food consumption
was noted during the first week in males (28%) and females (15%), the
difference with controls reaching statistical significance in males
only.  Very slight reductions thereafter were also observed in both
sexes but were not statistically significant.

Neovascularization of the cornea and characteristic “snowflake”
corneal opacities were noted at 7000 and 12000 ppm in males, and at
1000, 7000, and 12000 ppm in females.

(p≤0.01) increased in males at 1000 ppm (45%) and 7000 ppm (51%).
Triglycerides were statistically significantly (p≤0.01) increased in
males at 1000 ppm (112%) and 7000 ppm (68%).  Ketone levels were
increased from 1000 ppm in both males and females.  This is likely due
to detection of the diketone structure of the test substance itself, as
the vast majority of the parent molecule is excreted in the urine
unchanged.  There was an increased incidence of occult blood,
erythrocytes, leukocytes, and epithelial cells in the urine in both
males and females at 7000 ppm and in females at 12000 ppm (males in the
12000 ppm group did not survive until the end of the study and urine was
therefore not collected).

At 1000 ppm and 7000 ppm, the relative liver to body weight in males was
statistically significantly increased by 22 and 26% respectively.  At
1000 ppm and 7000 ppm, relative kidney to body weight in males was
increased 3.5 and 38.6%, respectively, the latter increase being
statistically significant.  For females relative liver weight was
increased 8.7, 13 and 8.7% at 1000, 7000 and 12000 ppm and relative
kidney weight was increased 8, 25.4 and 30%, respectively.

At 7000 ppm and 12000 ppm, abnormal shape of the kidneys, mottled
kidneys, dilation of and gritty content in the renal pelvis, gritty
content, distension of the urinary bladder, and gritty content of the
ureters, and enlarged livers were observed in males and females.
Livers were enlarged in 3/10 males at 1000 ppm. Prominent lobulation was
noted in 1/7 male at 7000 ppm and in 2/10 males at 1000 ppm.  The
thyroid gland was enlarged in one male at 1000 ppm.

The 12000 ppm group was terminated early at 11 weeks and tissues from
animals in this group were not microscopically examined.  Histological
changes associated with the presence of calculi (urolithiasis) were
found in the kidneys/urinary bladder/ureters in 4/8 males and 6/10
females at 7000ppm.  Associated histological changes included:

pelvic dilatation (unilateral or bilateral), urinary epithelial
hyperplasia (pelvis, urinary bladder and ureters), interstitial fibrosis
of the urinary tract, cystitis and Ureteritis.   Slight to moderate
diffuse centrilobular hepatocellular hypertrophy was observed in

6/7 males at 7000 ppm, in 9/10 males at 1000 ppm and in 1/10 female at
7000 ppm.  In females, a periportal vacuolation was found in 8/10
animals at 7000 ppm and 3/10 animals at 1000 ppm.

The LOAEL is 1000 ppm (77 mg/kg bw/day) in females based on
neovascularization of the cornea and “snowflake” corneal opacity;
and 7000 ppm (454 mg/kg bw/day) in males based on mortality,
neovascularization of the cornea and “snowflake” corneal opacity,
and histopathology in the kidney, urinary bladder, thyroid, and ureters.
 The NOAEL is 30 ppm (2.32 mg/kg bw/day) in females and 1000 ppm (66
mg/kg bw/day) in males.

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 the rat.

	870.3100	90-Day Oral Toxicity – Mouse

In a 90-day oral toxicity study (MRID 46801844), pyrasulfotole (95.7%
w/w ai, batch Op. 1-4) was administered to 10 C57BL/6 J@ Ico
mice/sex/dose in the diet at dose levels of 0, 100, 1500, or 3000 ppm
(equal to 0/0, 16.5/19.7, 124/152, 259/326, or 500/617 mg/kg bw/day for
males/females).

There were no compound-related effects on mortality, clinical signs,
ophthalmology, body weight, food consumption, clinical chemistry, organ
weights, or gross and histologic pathology.  Urinary pH was slightly
increased at 3000 ppm in females (6.3, p<0.05 vs. 6.0 in controls).  Due
to the small number or volume of samples obtained, urinary pH was not
measured in 3000 ppm males.  Examination of the individual animal data
revealed that urinary pH for the other male dose groups was similar to
controls (~6.0).

The LOAEL was not observed.  The NOAEL is 3000 ppm (500/617 mg/kg/day
[M/F]).

This 90-day oral toxicity study in the mouse is Acceptable (guideline)
and satisfies the guideline requirement for a 90-day oral toxicity study
(OPPTS 870.3100; OECD 408) in rodents.

	870.3150	90-Day Oral Toxicity – Dog

In a 90-day oral toxicity study (MRID 46801902), AE 0317309 (95.7% w/w
ai, batch Op:1-4) was administered in the diet to groups of 4 Beagle
dogs/sex/dose at dose levels of 0, 100, 500, or 1000 ppm (equivalent to
0/0, 3/3, 17/17 and 40/33 mg/kg bw/day in male/female dogs,
respectively) for a period of 90 days.

There were no compound-related effects on mortality, clinical signs,
body weight, food and water consumption, hematology, clinical chemistry,
urinalysis, gross pathology and microscopic pathology.

The LOAEL was not established.   The NOAEL is 40 mg/kg bw/day for males
and 33 mg/kg bw/day for females.

This 90-day oral toxicity study in the dog is 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

In a 28-day dermal toxicity study (MRID 46801904), AE 0317309 (96.3% w/w
ai, batch Op:1-4) was applied to the shaved skin of 10 Wistar HsdCpb:WU
rats/sex/dose at dose levels of 0, 10, 100, or 1000 mg/kg bw/day, 6
hours/day for 5 days/week during a 28-day period.

 incidence and severity at ≥10 mg/kg bw/day in males.  However, since
the alteration was predominantly minimal at 10 mg/kg, it was not
considered toxicologically relevant at this dose.

The LOAEL is 100 mg/kg/day, based on focal degeneration of the pancreas
(both sexes) and alteration of thyroid colloid (males).  The NOAEL was
10 mg/kg/day.

This 28-day dermal toxicity study in the rat is Acceptable (guideline)
and satisfies the guideline requirement for a 28-day dermal toxicity
study (OPPTS 870.3200; OECD 410) in mammals.

A.3.2	Prenatal Developmental Toxicity

	870.3700a Prenatal Developmental Toxicity Study – Rat

In a developmental toxicity study (MRID 46801905), AE 0317309 (95.7%
w/w; Batch# OP. 1-4) 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, 10, 100, or 300 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, except for yellow
sediment in the kidney and gritty material in the bladder of one 300
mg/kg/day dose female..

At 300 mg/kg/day, maternal body weight decreased slightly throughout the
study, but was not statistically significant.  Body weight change was
statistically significantly decreased 53 and 84%, at 100 and 300 mg/kg
bw/day, respectively during the gestation days 6-8, compared to
controls.  Thereafter, body weight change was similar across all groups.
 Maternal corrected body weight change was statistically significantly
reduced 8.4% compared to controls at 300 mg/kg /day.

There was a treatment-related, biologically and/or statistically
significant decrease in food consumption at 300 mg/kg /day between
gestation days 6 and 16, compared to controls.  The effect was more
pronounced between GD 6-8 where there was a 15% reduction in food
consumption and 7% reduction during GD 8-10.

The maternal LOAEL is 100 mg/kg/day based on increased incidence of
salivation, decreased corrected body weight gain, decreased corrected
body weight gain during GD 6-8 and dose-related enlarged placenta.  The
maternal NOAEL is 10 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
visceral malformations.

Mean fetal body weights (combined sexes) were significantly (P ≤ 0.01)
decreased by 5.5% at 300 mg/kg/day; male fetal body weights were
decreased 2 – 5.5% at > 100 mg/kg/day.  In males the body weights were
significantly decreased (P≤0.05 or 0.01) at ≥ 100 mg/kg/day.  Fetal
body weights at and above 100 mg/kg/day is considered treatment-related.
 Additionally at 300 mg/kg/day, a total of 4 fetuses from two different
litters presented the malformation of hindpaw polydactyly.  Three of the
fetuses with hindpaw polydactyly, all from the same litter showed an
anomaly of kyphosis, forelimb hyperflexion, misshapen digits on the
forepaws, and malpositioning of the digits on both the forepaws and the
hindpaws.  Two of the four fetuses with the external observation of
hindpaw polydactyly had malformations including short tibia and femur,
supernumerary cartilaginous phalanges, fused cartilage for several
metatarsals and phalanges, and unossified 5th metatarsal (presumably the
other two fetuses with externally observed hindpaw polydactyly were not
included among those subjected to skeletal observation).  There was a
slight increase at the mid and high dose in the occurrence of 27
pre-sacral vertebrae.  Treatment-related variants observed in this study
were primarily linked to ossification.  Some of these occurred at an
increased fetal and/or litter incidence in the low dose group.  These
were 7th cervical centrum:  unossified/normal cartilage; forepaws:  3rd
and/or 4th proximal phalanges: unossified/normal cartilage; 1st
metatarsal:  unossified/normal cartilage; and less than 9 sacrocaudal
vertebrae ossified/9 first sacrocaudal vertebrae:  normal cartilage.
Since the skeletal changes at the low dose were limited to low
incidences of variations and since skeletal variations were also
observed in the rabbit developmental toxicity study at 75 mg/kg/day
(NOAEL = 10 mg/kg/day), they were not considered toxicologically
significant.

The developmental LOAEL is 100 mg/kg/day based on increased fetal and/or
litter skeletal variations and decreased body weight (males). The
developmental NOAEL is 10 mg/kg/day.

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

In a developmental toxicity study (MRID 46801906), AE 0317309Technical
(95.7% ai; Batch # Op. 1-4) in 0.5% aqueous methylcellulose was
administered daily via oral gavage to 24 time-mated New Zealand White
rabbits/group at a dose volume of 4 mL/kg at dose levels of 0, 10, 75,
or 250 mg/kg bw/day from gestation day (GD) 6 through 28 inclusive.  All
surviving rabbits were killed on GD 29; their fetuses were removed by
cesarean section and examined.  Liver weight and the number of ribs were
noted for each animal. The gravid uterine weight, number of corpora
lutea, number of implantations, resorptions (early and late), and live
and dead fetuses, and the individual weight of live fetuses, was
recorded for each animal.  Live fetuses were sacrificed and examined
externally.  The heads of approximately half the fetuses were fixed for
later examination.  All fetuses were dissected for visceral findings,
fixed, and stained for skeletal examination.

No effects of treatment were observed on mortality, number of corpora
lutea, implantation sites, early or late resorptions, number of live or
dead fetuses, or percent pre- or post-implantation losses per dam and
fetal sex ratio, fetal external, and visceral malformations at any dose
level.

g/kg bw/day maternal body weight gain decreased (↓230% or 0g gain vs
30g in control) significantly between GD 8-10 and food consumption
decreased significantly throughout the study.  At necropsy 2/25 does had
prominent liver lobulations, however, no histopathology information was
available.

The maternal LOAEL is 250 mg/kg bw/day based on decreased body weight
gain during GD 8-10 and decreased food consumption during the study.
The maternal NOAEL was 75 mg/kg bw/day.

≥ 10 mg/kg bw/day and was dose–related.  However, a follow-up
historical control analysis revealed that concurrent controls were at
the upper end of the historical control range and that body weights at
the low and mid doses were within the historical control range.  A
number of skeletal anomalies and variants were recorded at ≥75 mg/kg
bw/day; however; their incidences at 10 mg/kg/day did not exceed rates
in historical control data.

The developmental LOAEL was 75 mg/kg bw/day based on an increased
incidence of fetal/litter skeletal anomalies/variations.  The
developmental NOAEL was 10 mg/kg bw/day.

This study is classified acceptable/guideline (OPPTS 870.3700b) and
satisfy the guideline requirements for a developmental study in the
rabbit.

A.3.3	Reproductive Toxicity

	870.3800 Reproduction and Fertility Effects - Rat

In a 2-generation reproduction study (MRID 46801907) AE0317309 (95.7%
ai, batch# Op. 1-4) was administered to 25 Wistar rats/sex/dose in the
diet at dose levels of 0, 30, 300 or 3000 ppm (equivalent to 0, 2.5,
26.3, and 272.4 mg/kg bw/day for F0 males and 0, 3.1, 32.6 and 345.7
mg/kg bw/day for F0 females, and 0, 3.68, 34.1 and 353.6 mg/kg bw/day in
F1 males and 0, 4.2, 38.9 and 393.4 mg/kg bw/day in F1 females during
the premating period).

There was a dose-related increase in the incidence of either diffuse
and/or reticulate corneal opacities, and of corneal neovascularization
in both F0 and F1 males and females at 300 ppm and 3000 ppm.

There were significant increases in absolute liver (12.9%) and kidney
(12.2%) weights in F1 males in the 3000 ppm group. Absolute thyroid
weight was significantly increased in F1 males in the 300 ppm (28.6%)
and 3000 ppm (35.7%) groups. Significant increases in absolute adrenal
weights were observed in F1 females at 3000 ppm. There were significant
increases in relative liver weight (6.0 and 10.3%, respectively),
relative kidney weight (6.2% and 16.4%, respectively), and relative
thyroid weight (both 37.9%) in F1 males at 300 ppm and 3000 ppm.

Treatment related effects were observed in the eyes and thyroid of both
males and females of the F0 and F1 generations, and in pituitary,
kidneys, and liver of F0 and F1 males.  Findings in the eyes, at 300 ppm
and 3000 ppm in both males and females of the F0 and F1 generations,
included keratitis and vascularization, correlating with in-life
observations.

Thyroid findings included colloid alteration at all doses in male F0 and
F1 rats, and females of the F0 generation and from 300 ppm in F1
females, pigment deposition at all doses in F0 and F1 males and from 300
ppm in F0 and F1 females, and increased follicular cell hypertrophy in
F0 males at 3000 ppm and F1 males from 3000 ppm and F0 females at 3000
ppm.  It is noted that follicular cell hypertrophy was not observed and
that colloid alteration/pigment deposition was minimal at 30 ppm.
Eosinophilic inclusions were increased in the anterior pituitary of
males at 300 ppm and 3000 ppm in both the F0 and F1 generations.
Findings in the liver included hepatocellular hypertrophy, cellular
alteration, and slight increases in periportal fat accumulation in F0
and F1 males at 300 ppm and 3000 ppm.  The kidneys of males in the F0
and F1 generation had increased incidence and/or severity of basophilic
tubules and tubular dilation, in a dose related manner from 300 ppm.

Number of pups born dead appeared to have been elevated at all doses in
the F1 generation and at 30 ppm and 3000 ppm in F2 generation.  However,
the data did not show a clear dose-response association or any
statistical significance and the live birth index was unaffected in
either generation. Treatment related clinical signs in pups included
cold to the touch, which was increased in F1 pups at 3000 ppm only (12
pups), compared to control (5 pups). There was an increased incidence of
autolysis and no milk in the stomach in the F2 pups at 3000 ppm (4-5
pups) compared to controls (1 pup). The incidence of dilated and/or
enlarged kidneys was increased at 3000 ppm in F1 and F2 pups.  The mean
viability index was non-significantly reduced in a dose-related manner
in F2 pups at all doses as shown: 92.45±23.326, 83.79±32.046,
78.89±35.016, and 71.60±38.201 at 0, 30, 300 and 3000 ppm,
respectively.  A benchmark dose analysis for this endpoint by R. Mitkus
yielded a BDM=227.6 ppm and a BMDL=68.13 ppm.  This supported the
conclusion not to consider the decrease in viability index at the low
dose as treatment-related.  In addition, only the index at 3000 ppm of
test substance was lower than the historical data presented by the study
authors.  Examination of pups at the time of weaning on postnatal day 28
showed an increased incidence of corneal opacity and/or corneal
neovascularization at 300 ppm and 3000 ppm in both F1 and F2 pups,
showing a dose-related increase.  Both litter (mean body weight for
males and females taken together) and pup (mean body weight for males or
females, taken separately) body weights were statistically significantly
decreased in the F1 (mean liter weight decr. 7.9%) and F2 (mean liter
weight decr. 11.1%) pups at 3000 ppm at weaning on day 28.  In F2
females at 3000 ppm, body weight was also statistically significantly
decreased at lactation day 21. Statistically significant delays of
balano-preputial separation at 300 ppm and 3000 ppm, and a statistically
significant delay of vaginal opening at 3000 ppm, were observed in F1
pups.  These parameters were not assessed in F2 pups.

The parental systemic LOAEL is 30 ppm (2.5 mg/kg bw/day in males, 3.1
mg/kg bw/day in females), based on minimal colloid alteration and/or
pigment deposition in the thyroid.  The parental systemic NOAEL was not
observed.

The offspring LOAEL is 300 ppm (26.3 mg/kg bw/day in males, 32.6 mg/kg
bw/day in females), based on corneal opacity and/or corneal
neovascularization (F1 and F2 generations).  The offspring NOAEL is
30ppm (2.5 mg/kg bw/day in males, 3.1 mg/kg bw/day in females).

The reproductive LOAEL is 300 ppm (26.3 mg/kg bw/day in males, 32.6
mg/kg bw/day in females), based on delays in balano-preputial separation
in F1 pups.  The reproductive NOAEL is 30ppm (2.5 mg/kg bw/day in males,
3.1 mg/kg bw/day in females).

This study is acceptable/guideline and satisfies the guideline
requirement for a 2-generation reproduction study (OPPTS 870.3800; OECD
416) in the rat.

A.3.4	Chronic Toxicity

	870.4100b Chronic Toxicity - Dog

In a chronic toxicity study (MRID 46801908), AE 0317309 (95.7% w/w,
Batch #: OP. 1-4) was administered to 4 beagle dogs/sex/dose in the diet
for 52 weeks at doses of 0, 250, 1000, or 3000 ppm (equivalent to 0/0,
7/9, 34/33, and 101/93 mg/kg/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.  LDH levels
were decreased in the mid and high dose females at 12months.  However,
the pretest values were also low in these groups, suggesting that this
was not treatment-related.  There was no evidence of treatment-related
increased blood levels in the urine.

At 3000 ppm, APTT was significantly depressed in males (16%) and females
(14-16%) at ≥ 1000 ppm.  The prothrombin time was not significantly
effected.  Since the APTT was decreased rather than increased, the
clinical and toxicological significance is unknown.

A dose-related, non-statistically significant, increase in the absolute
and relative liver, kidney and thyroid weights increased in males and
females.  Specifically at the 3000 ppm dose, absolute and relative liver
weights in males and females (34-49%), absolute and relative kidney
weights in males (26-38%), and absolute and relative thyroid weights in
females (18-30%) increased.  Microscopically, increased incidence of
hepatocytomegaly was observed in 2/4 males and 3/4 females at the high
dose, compared to 0/4 in controls.  Hepatocytomegaly was observed as 1
(minimal) on a scale of 1 to 5.  Kidney tubular dilatation was observed
in 1/4, 1/4, 3/4, and 4/4 in the control, 250, 1000 and 3000 ppm males,
respectively with a severity grade of 2 in the mid- and high dose groups
and grade severity of 1 each in control and low dose groups.
Additionally, cataracts were observed one each in 3000 ppm males and
females; grade severity of 2.  One high-dose male showed inflammation,
hemorrhage and debris in bladder.  Increased thyroid weights were not
associated with any treatment-related micropathology observed.

The LOAEL is 1000 ppm (equivalent to 34 mg/kg/day) in males, based upon
the increased incidence and severity of kidney tubular dilatation.  The
NOAEL was 250 ppm (equivalent to 7 mg/kg/day) in males.   The LOAEL is
3000 ppm (equivalent to 93 mg/kg bw/day) in females, based on cataracts.
 The NOAEL is 1000 ppm (equivalent to 33 mg/kg/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

	870.4300 Combined chronic toxicity/Carcinogenicity Study - rat

In a combined chronic toxicity/carcinogenicity study (MRID 46801910), AE
0317309 (95.7% ai, batch Op. 1-4) was administered in the diet to 75
six-week-old Wistar Rj:WI (IOPS HAN) rats/sex/group at dose levels of 0,
25, 250, 1000, or 2500 ppm (equivalent to 0/0, 1.0/1.4, 10/14, 41/57, or
104/140 mg/kg bw/day in males/females) for 24 months.  Animals were
sacrificed at 6 (10/dose group), 12 (10/dose group), and 24 months
(55/dose group).

urine of males and females at ≥1000 ppm at all collection periods and
in males at 250 ppm at months 19 and 24 only.  Urinary pH was decreased
at ≥250 ppm in males at all time points and in females at 3 months
only.  Urinary protein was increased in males in all treatment groups
from 6 months onwards.  Decreases in urinary pH and increased urinary
protein in males were considered toxicologically significant in
conjunction with treatment-related increases in chronic progressive
nephropathy and collecting duct hyperplasia.  The increased level of
ketones may have been due to unmetabolized test substance.

Absolute and relative liver and kidney weights were elevated in males at
≥250 ppm from 6 months onwards (liver: 20%; kidney: >15%).  There were
no significant effects on organ weights in females.  At macroscopic
examination, the incidence of eye opacities was increased in males and
females at ≥250 ppm.  Enlarged liver was observed in males at 6 months
in all treated groups and at 12 months at ≥250 ppm.  At 24 months,
there was an increased incidence among males of pale kidneys and
irregular surface of the kidney at ≥1000 ppm.  Non-neoplastic
histopathology included peripheral retinal atrophy, corneal
inflammation, corneal hyperplasia, and/or corneal neovascularization at
≥250 ppm in both sexes and an increased incidence of chronic
progressive nephropathy in males at ≥250 ppm.  Histopathology observed
in several other organs at higher doses is summarized in the Australian
review (attached).  The only treatment-related neoplastic finding was
that of rare squamous cell tumors of the cornea (one papilloma, one
carcinoma) observed in two separate males at 2500 ppm.

The LOAEL was 250 ppm (10/14 mg/kg [M/F]) based on corneal opacity,
neovascularization of the cornea, inflammation of the cornea,
regenerative corneal hyperplasia, corneal atrophy, and/or retinal
atrophy (both sexes), and hepatocellular hypertrophy along with
increased serum cholesterol (males).  The NOAEL was 25 ppm (1.0/1.4
mg/kg [M/F]).

At the doses tested, there was a treatment-related increase in the
incidence of corneal squamous cell tumors when compared to controls.
Dosing was considered adequate, but not excessive, based on decreased
body weight/body weight gain and non-neoplastic lesions of the eyes,
liver, pancreas, thyroid and kidney at the high dose.

This chronic toxicity/carcinogenicity study in the rat is classified as
Acceptable (guideline) and satisfies the guideline requirement for a
chronic toxicity/carcinogenicity study (OPPTS 870.4300; OECD 453) in
rat.  Although motor activity, grip strength, and reactivity to sensory
stimuli were not assessed in the chronic phase of the study as required
by the guideline, they were assessed in other, short-term studies.

	870.4200b Carcinogenicity (feeding) - Mouse

In a carcinogenicity study (MRID 46801909), AE 0317309 (95.7% w/w ai)
(95.7% w/w ai; Batch No. OP. 1-4) was administered in the diet to
C57BL/6J mice (50/dose) at doses of 0, 100, 1000, or 4000 ppm for males.
Groups of 50 females/group received 0, 100, 1000, or 6000 ppm for the
first 10 weeks, then reduced the high-dose to 4000 ppm from week 11
onwards. The high-dose in females was considered excessive because of
increased mortality.  The concentrations resulted in doses of 0/0,
13.6/16.7, 137/168 and 560/713 mg/kg/day in males and females for up to
78 weeks.  Additionally, 10 mice/sex/dose were treated similarly for up
to 52 weeks and then scheduled for interim sacrifice.

There was no effect of treatment on food consumption.  Liver and urinary
system was identified as target system. Treatment-related effects were
observed on mortality, clinical signs, body weight body weight gains,
hematology, liver and kidney weights, urolithiasis, and gall stones in
males and females.  At 4000 ppm, survival rate at 18 months was 50 and
40%, respectively in males and females.  The survival rate is above the
guideline recommended level and is acceptable.  Survival rates at 100
and 1000 ppm were comparable to controls.

At 4000 ppm clinical signs suggested of compound administration include
hardness in the urinary bladder area, soiled fur, reduced motor
activity, labored or rapid respiration and red urine.  The study authors
presumed red urine color was due to compound excretion, however, no
urine analysis was performed to confirm.

At 4000 ppm mean body weight significantly in both males and females.
Body weight was unaffected 1000 ppm in males, however, body weight gain
was significantly decreased; the incidence was dose-related.  At this
dose, in females, body weight gains were significantly decreased during
two time periods (days 92-176 and 344-450).

Red blood cells, Hb, Hct, and MCHC were decreased in females at 4000 ppm
at 18 months (showing indications of dose-response relationships). MCV
was slightly increased in females at 4000 ppm at 18 months. In males at
4000 ppm, similar hematological effects were generally observed at 18
months. The perturbations seen at 4000 ppm were considered to be
treatment-related.  Hematological changes at 100 ppm were comparable to
controls.

The majority of statistically significant organ weight changes were
restricted to 4000 ppm mice sacrificed at 18 months. Absolute and
relative kidney weights increased in males and males at 4000 ppm dose
group at the terminal sacrifice.  Absolute brain weight was reduced at
4000 ppm at 18 months in males, although it was actually significantly
increased as a percentage of body weight. Relative liver weights were
increased in both males and females at 18 months, reaching statistical
significance in all treated males, with no clear dose-response
associated effects on absolute liver weights. Absolute and relative
spleen weights were increased in males and relative spleen weights in
females at 18 months in 4000 ppm group.

In all treatment groups (males and females) at 12 months, incidences (n=
7 - 10) of the following lesions were increased in the kidneys: (i)
large kidneys (2-7 treated vs 0 control); (ii) small kidneys (1-4
treated vs 0 controls); stones (1-4 vs 0 control); pelvic dilation (3-6
vs 0 control); pale (1-3 vs 0 control) cysts (1-2 vs 0 control) gritty
content in the bladder (6-8 vs 0 control) and distended bladder (4-8 vs
0 control).  At 18 months, the majority of those which died unscheduled
at 4000 ppm were found to have died due to acute or chronic renal
failure, due to urinary tract blockage or chronic kidney and/or urinary
bladder inflammation, respectively. Stones were found in the kidney
and/or urinary bladder of these animals; other findings at necropsy of
unscheduled deaths were enlarged or small kidneys, renal pelvic
dilation, pale kidneys, renal cyst(s), distention of the urinary
bladder, and gallbladder stones or concretions. Similar findings were
observed in animals sacrificed at 18 months.  The incidence of above
findings at 4000 ppm were higher than the incidence at 12 months of
sacrifice.

Increased incidence of gallstones was a relatively common observation in
all treated groups at scheduled sacrifice, although there was no
dose-response relationship.

Microscopic examination was not conducted at 12 months. At 18 months,
histopathologic findings included a dose-related increase in the
incidence of minor to moderate centrilobular hepatocellular hypertrophy
in males and females at 1000 and 4000 ppm; which was statistically
significant in the males at 1000 and 4000 ppm and the females at 4000
ppm. This was considered to be treatment-related. Most of the other
treatment-related findings were observed in the urinary system (kidney,
urinary bladder, and ureters) at the high dose in males and females and
were associated with stones and concretions observed in the urinary
system at the same dose.

The LOAEL is 100 ppm (equivalent to 13.6/16.7 mg/kg/day [M/F]), based on
an increased incidence of gallstones.  The NOAEL was not established.

Treatment-related neoplastic findings included urinary bladder
transitional cell carcinomas (including urethral transitional cell
carcinoma) and papillomas and carcinomas combined in males and urinary
bladder transitional cell papillomas, carcinomas, and papillomas and
carcinomas combined in females at 4000 ppm.

Dosing was considered excessive in both sexes because of significantly
increased mortality in males (53% vs 16% in controls) and females (62%
vs 30% in controls), much of which occurred in the first year of the
study.  The increased mortality was due to the presence of urinary
bladder stones.  However, the dose was considered appropriate for risk
assessment purposes because it also caused tumors in the target organ
responsible for increased mortality.  In addition, dose selection for
the long term study was reasonable based on the results of the 90-day
study where no effects were seen at 3000 ppm.

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

Please refer to toxicological profile table above.

A.3.7	Neurotoxicity

	870.6200 Acute Neurotoxicity Screening Battery

In an acute neurotoxicity study (MRID 46801915), groups of 12 unfasted,
9-week-old Wistar rats/sex/dose were given a single oral dose by gavage
of AE 0317309 (95.7% ai, batch Op. 1-4) in aqueous 0.5%
methylcellulose/0.4% Tween 80 at doses of 0, 200, 500, or 2000 mg/kg bw
and observed for 14 days.  Cage-side observations were performed at
least once daily (once daily on holidays and weekends) for mortality or
clinical signs of moribundity.  Detailed physical examinations for
clinical signs of toxicity were carried out and recorded daily.  Animals
were weighed weekly as a component of the FOB (functional observational
battery) and at sacrifice.  Neurobehavioral assessment (FOB and motor
activity testing) was performed in all animals (fasted) one week prior
to dosing, approximately 30 minutes after dosing on day 0, and on days 7
and 14 after dosing.  The 30-min evaluation time was selected based on a
preliminary disposition study wherein blood concentrations peaked at
approximately 30 minutes post dosing.  The FOB included standard
parameters including home cage and open field observations, reflex
testing, and determination of fore-limb and hind-limb grip strength, and
landing foot splay.  Motor and locomotor activity were measured over a
60-minute period for each animal.  At study termination, all animals
were euthanized and 6 rats/sex/dose were perfused in situ for
neuropathological examination.  Of the perfused animals, all were
subjected to histopathological evaluation of brain and peripheral
nervous system tissues.

.  A dose-dependent increase in red nasal stain was observed at ≥500
mg/kg in males and at ≥200 mg/kg in females.  The incidence of oral
stain or red stained forepaws was also increased in males or females at
≥200 mg/kg.  All stainings were considered to be due to excretion of
test compound and therefore not toxicologically significant.  Mean
locomotor activity was significantly decreased (P<0.01) in all treated
females on the day of dosing.  When compared to both control and
pre-test levels, the decrease was dose-dependent.  Although not
statistically significant, dose-dependent decreasing trends were
observed in motor activity (days 0 and 7) and locomotor activity (day 7)
in females.  The decreases in overall locomotor activity were
corroborated by statistically significant decreases in locomotor
activity in treated females at several subsessions across days of
testing.  A 34% (NSS) decrease in mean overall locomotor activity was
observed in males at 2000 mg/kg on day 0.  The decrease was corroborated
by decreased interval locomotor activity in males at 2000 mg/kg on day
0, which reached statistical significance during interval 3.

The LOAEL was 200 mg/kg bw in females and 2000 mg/kg bw in males based
on decreased locomotor activity on day 0.  The NOAEL was not observed in
females and was 500 mg/kg bw in males.

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

	870.6200 Subchronic Neurotoxicity Screening Battery

In a subchronic neurotoxicity study (MRID 46801916), AE 0317309 (95.7%
ai, batch Op. 1-4) was administered to 12 eight-week-old Wistar
rats/sex/group at dose levels of 0, 500, 2500, or 5000 ppm (equivalent
to 0/0, 32/42, 166/206, or 345/416 mg/kg bw/day in males/females) for 90
days.  Clinical signs were assessed twice daily on weekdays and once
daily on weekends and holidays.  Body weight and food consumption were
measured on a weekly basis.  Neurobehavioral assessment (functional
observational battery and motor activity testing) was performed in all
animals/sex/group once in the week prior to the start of the feeding
period, and once each during weeks 2, 4, 8, and 13.  The FOB included
standard parameters including home cage and open field observations,
reflex testing, and determination of fore-limb and hind-limb grip
strength, and landing foot splay.  Motor and locomotor activity were
measured over a 60-minute period for each animal.  Ophthalmoscopic
examinations were conducted in all animals prior to the start of the
study and during week 12.  At study termination, all animals were
euthanized and 6 rats/sex/dose were perfused in situ for
neuropathological examination.  Of the perfused animals, all were
subjected to histopathological evaluation of brain and peripheral
nervous system tissues.

increased (≤12%) at 5000 ppm at several intervals, but was not
considered toxicologically significant in the absence of adverse effects
on any other parameter, including body weight.  Increased incidences of
corneal opacity (2, 3, and 1 vs. 0 in controls) and corneal
neovascularization (1, 2, and 1 vs. 0 in controls) were observed in all
treated females.  Incidences of retinal degeneration were
dose-dependently increased in females (1, 2, and 3 vs. 1 in controls),
but not males.  The increased incidence of corneal neovascularisation
was considered toxicologically significant at the low dose, since the
incidence was 0 in control females at ophthalmoscopy in the 90-day
toxicity study in rat and 0 in control females at ophthalmoscopy at 6
and 12 months in the chronic toxicity study in rats.

The LOAEL was 500 ppm (42 mg/kg bw/day) in females based on increased
incidences of corneal opacity and corneal neovascularization in females
and not observed in males.  The NOAEL was not observed in females and
was 5000 ppm (345 mg/kg bw/day) in males.

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

	870.6300 Developmental Neurotoxicity Study

In a developmental neurotoxicity study (MRID 46801917), AE 0317309
(95.7% w/w ai, batch Op. 1-4) was administered from gestation day 6
through postnatal day 21 to 30 female Wistar rats per dose in the diet
at nominal concentrations of 0, 45, 450, or 4500 ppm during gestation
and 0/0/0, 24/20/16, 237/196/161, or 2368/1957/1607 ppm during weeks
1/2/3 of lactation.  These concentrations provided an average daily
intake of 0, 3.8, 37, or 354 mg/kg bw/day over gestation and lactation.
Offspring were not dosed directly in this study.  Dams were observed for
clinical signs at least once daily.  FOB (functional observational
battery) tests were conducted on GDs 13 and 20 and LDs 11 and 21.  Body
weight and food consumption were measured on GDs 6, 13, and 20 and on
LDs 0, 7, 14, and 21.  On LD 4 litters were culled to eight pups, with
four male and four female pups wherever possible.  Dams were sacrificed
on LD 21 following weaning of their litters, and a gross necropsy
examination was conducted.  Offspring were allocated for FOB and
assessment of motor activity, auditory startle reflex habituation,
learning and memory (passive avoidance and watermaze testing), and
neuropathology (including brain weights).  Offspring were monitored
daily throughout lactation for clinical signs or morbidity and were
weighed individually on LDs 0, 4, 11, 17, and 21 and weekly thereafter.
The age of sexual maturation (vaginal opening in females and preputial
separation in males) was also recorded.

There were no treatment-related effects on mortality, clinical signs
during gestation, or body weight in dams.  During lactation, ocular
opacities were observed in up to 5/21 dams from LD 9 at 37 mk/kg/day and
in up to 14/20 females from LD 10 at 354 mg/kg/day.  During the FOB,
ocular opacities were observed on LD 11 in 3/10 dams at 37 mk/kg/day and
in 7/10 dams at 354 mg/kg/day; and on LD 21 in 2/10 and 7/10 dams at 37
and 354 mg/kg/day, respectively.  Food consumption was reduced in dams
during weeks 1-2 of lactation at 37 (12-19%) and 354 (9-20%) mg/kg/day,
however without a corresponding effect on body weight.  The fertility
index was decreased (NSS) at 37 mg/kg/day (3%) and 354 mg/kg/day
(13.3%); however, this observation was not considered treatment-related,
since dosing began on GD 6.  All other reproductive parameters were
unaffected by treatment.

The maternal LOAEL is 37 mg/kg/day, based on ocular opacities during
lactation.  The maternal NOAEL is 3.8 mg/kg/day.

There were no treatment-related effects on litter size,
viability/mortality, or other litter parameters in offspring.  Clinical
signs and body weight were unaffected during lactation.  During
post-weaning, ocular opacities were observed in 6/58 males at 354
mg/kg/day on or after PND 29, as well as in 2/63 females at 37 mg/kg/day
and 1/60 females at 354 mg/kg/day on or after PND 30.  Body weight was
decreased in males and females by 6-9% and 4-8% each at 37 mg/kg/day and
by 8-13% and 8-11% each at 354 mg/kg/day.  Preputial separation was
delayed at 37 mg/kg/day (46.0 days) and 354 mg/kg/day (46.7 days, P<
0.01), compared to controls (44.1 days).  Vaginal patency was unaffected
by treatment.  During the FOB, ocular opacity was observed in 1/15
females at both 37 mg/kg/day and 354 mg/kg/day.  These changes were
first noted on postnatal days 45 and 35, respectively, and persisted in
both cases through postnatal day 60.

No treatment-related effects were observed on motor activity or auditory
startle response.  For PND 22 animals tested for passive avoidance, an
increase (P<0.05) in the number of trials to criterion, as well as
dose-dependent decreases in trials 1 and 2 latencies, were observed at
≥37 mg/kg/day during the learning session.  During the retention
session, an increase (P<0.05) in the number of trials to criterion and
reduced latency at trial 1 were observed at 354 mg/kg/day.  There were
no treatment-related effects on acquisition and retention in either
adult males or females during the water maze testing.  An increase in
the mean time required to complete trial 1 was observed in the retention
phase in males at 37 mg/kg/day; however, the result was not considered
treatment-related in the absence of dose response and treatment-related
effects on the number of trials to reach criterion.

During ophthalmoscopic examinations, retinal degeneration was observed
in 4/10 males at 354 mg/kg/day.  Retinal degeneration was also observed
in 0/13, 1/13, 3/11, and 4/10 females at 0, 3.8, 37, and 354 (P<0.05)
mg/kg/day, respectively.  The increase in one female animal at the low
dose was not considered treatment-related based on the low incidence and
lack of statistical significance in the current study and since retinal
degeneration was not observed at a similar dose in F1 or F2 offspring in
the 2-generation reproduction study.  Absolute fixed brain weight on PND
21 was statistically significantly decreased for males (8%) at 354
mg/kg/day and for females at 37 mg/kg/day (6%) and 354 mg/kg/day (11%).
Absolute fixed brain weight on PND 75 was also decreased for females at
354 mg/kg/day (5%).  At necropsy, an increased incidence of opacity was
observed in the eyes of 3/10 PND 75 males at 354 mg/kg/day.  During
macroscopic morphometry at PND 21, cerebellum length was decreased
(P<0.05) in perfused males (6%) and females (7%) at 354 mg/kg/day.
Cerebrum length was also decreased (P<0.05) in females at 37 (4%) and
354 (5%) mg/kg/day.  At PND 75, cerebellum length was decreased in males
(5%, P<0.05) and females (4%, NSS) at 354 mg/kg/day.  During microscopic
morphometry on PND 21, cerebellum height was decreased (P<0.05) in males
at 37 mg/kg/day (7%) and 354 mg/kg/day (8%) and in females at 354
mg/kg/day (10%).  The hippocampal gyrus was decreased (P<0.05) by 11%
and 9% in males and females, respectively, at 354 mg/kg/day on PND 21.
On PND 75, cerebellum height was changed at the mid and high doses in
males (↑14% and ↓6%, respectively) and females (↑13% and ↓6%);
however, in the absence of a consistent change across dose, the findings
were not considered toxicologically significant.

The offspring LOAEL is 37 mg/kg/day, based on ocular opacity
(post-weaning), decreased body weight, delayed preputial separation
(males), increase in the number of trials to criterion and decreases in
trial latencies (passive avoidance; PND 22 males), retinal degeneration
at ophthalmoscopy (females), decreased brain weight (PND 21 females),
decreased cerebrum length (PND 21 females), and decreased cerebellum
height (PND 21 males).  The offspring NOAEL was 3.8 mg/kg/day.

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

In a metabolism study (MRID 46801918), AE 0317309 (97.6-100% ai, Vial #s
C-938, C-939, C-938B, C-1024A, K-1196, K-1267), male Wistar Hanover rats
(five rats for each radiolabel) were given single oral doses of
[phenyl-UL-14C] AE 0317309 {methanone,
(5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)[2-(methylsulfonyl)-4-(trifluoro
-methyl) phenyl] [phenyl-UL-14C]} or [pyrazole-3-14C] AE 0317309
{methanone,
(5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)[2-(methylsulfonyl)-4-(trifluoro
methyl)phenyl] [pyrazole-3-14C]} at dose rates of 10.0 and 9.88 mg/kg
bw, respectively.  In two separate experiments, male Wistar Hanover rats
with surgically implanted jugular cannula were dosed intravenously with
[phenyl-UL-14C] AE 0317309 (four rats) or [pyrazole-3-14C] AE 0317309
(five rats) at dose rates of 9.81 and 9.60 mg/kg bw, respectively.

The [phenyl-UL-14C] AE 0317309 was readily absorbed following oral
dosing, with approximately 62% of the administered radioactivity dose
being recovered in the urine within 6 h post dose. A total of
approximately 73% of the administered radioactivity dose was recovered
in the urine by the time of sacrifice (52 h).

The [pyrazole-3-14C] AE 0317309 was readily absorbed following a single
oral dose, with approximately 57% of the administered radioactivity dose
being recovered in the urine within 6 h post dose. A total of
approximately 75% of the dose was recovered in the urine by the time of
sacrifice (48 h).

In the case of intravenous administration, approximately 90% of the
radioactivity was excreted in the urine and approximately 10% in the
feces by 48 h.  Most (over 80%) of the intravenous dose was excreted in
the urine within 6 h.

In all experiments, <2% of the administered dose remained in the
residual carcass and tissues at sacrifice.  In all experiments, the
highest residues were found in the liver and kidney. There was no
apparent difference between the phenyl-UL-14C label and the
pyrazole-3-14C label in the distribution of equivalents in the tissues
following intravenous dosing. However, concentrations in the tissues
were consistently higher in the case of the pyrazole-3-14C label than in
the case of the phenyl-UL-14C label following oral dosing. The
distribution of radioactivity in tissues did not differ greatly between
oral and intravenous dosing, with the exception that the concentration
in the residual carcass is somewhat higher in the latter case. Following
both oral and intravenous administration, most of the dose was excreted
unchanged as AE 0317309. Hydroxymethyl AE 0317309, desmethyl AE
0317309, and AE B197555 were observed as minor metabolites in the urine
and feces.  Following oral dosing, approximately 70% of the
radioactivity was excreted in the urine and 30% in the feces by 48 or 52
h.

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

A.3.9	Special/Mechanistic Studies

In an in vivo study (MRID 46801922), 5 Crl:CD(SD)BR rats, 5 Brown Norway
rats (BN/Crl BR), and 5 Crl:CD-1(ICR)BR mice/sex (6 weeks old) were
administered 0%, 2%, or 5% L-tyrosine (batch# 68160-123) in the diet for
14 days (equivalent to 0/0, 2240/1900, or 5600/4750 mg/kg bw/day for SD
rats; 0/0, 2443/2182, or 6107/5455 mg/kg bw/day for Brown Norway rats;
and 0/0, 4000/4800, or 10000/12000 mg/kg bw/day for mice, respectively
[M/F]).  The study was designed to determine the relative sensitivities
of SD rats, Brown Norway rats, and CD-1 mice to the development of
corneal lesions after consuming diet supplemented with tyrosine.
Clinical signs and mortality were monitored daily.  Body weights and
food consumption were measured weekly.  Ophthalmoscopic examinations
were reported for study days 2, 3, 7, 8, and 14.  Blood was collected on
study day 15 prior to necropsy for determination of plasma tyrosine
concentration.  Animals were sacrificed by exsanguination under deep
anesthesia and subjected to a gross necropsy.  Histological sections of
the eyes of selected animals were prepared.  Plasma samples from all
male rats, control and high-dose female SD rats, and control and
high-dose male mice were analyzed for tyrosine concentrations.

There were no treatment-related effects on mortality, body weight, or
food consumption or at necropsy.  Treatment-related clinical signs in SD
rats at 5% tyrosine included dark urine in all males in the second week
of the study and in 3 females on day 14 only.  Corneal opacity was
observed in 1/5 male SD rats at 5% tyrosine.  This same animal appeared
thin and showed slight ptosis and moderate piloerection from Days 10 and
13, respectively.  At ophthalmoscopic examination, all male SD rats at
5% tyrosine showed “snow flake” corneal opacities by day 7 with
progression of the opacity over time.  By day 14, two male SD rats also
showed signs of edema and vascularization of the cornea.  In 3/5 SD
males, congestion of the iris was also evident.  One male Brown Norway
rat at 5% tyrosine had a slight “snow flake” corneal opacity visible
on day 14 only.  Male SD and Brown Norway rats showed a dose-related
increase in mean plasma tyrosine concentrations.  One high-dose male
Brown Norway rat, which was observed on day 14 to have a corneal
opacity, was found to have plasma tyrosine concentrations markedly
higher than those observed in the other four male Brown Norway rats.
Male CD-1 mice showed no increase in plasma tyrosine concentrations at
5% dietary tyrosine.  No changes in plasma tyrosine concentrations were
observed in females; however, plasma tyrosine concentrations were only
determined for control and high-dose SD females rats.  In 2/2 male SD
rats at 5% tyrosine, treatment-related microscopic findings included
inflammatory reactions in the cornea, edematous or swollen nuclear
changes in the corneal epithelial cells, and corneal vacuolation.  In
1/2 Brown Norway rats treated with 5% tyrosine, microscopic findings
included inflammation of the anterior chamber and cornea.  A focal area
of moderate vacuolation of the corneal epithelial cells was observed in
1/2 male Brown Norway rats treated at 2%.  This was not observed in 2/2
control Brown Norway males or in this animal at ophthalmoscopic
examination.

The study is classified as Acceptable/Non-guideline and is acceptable
for determining the relative sensitivities of SD rats, Brown Norway
rats, and CD-1 mice to the development of corneal lesions after
consuming diet supplemented with tyrosine.

In an in vivo study (MRID 46801921), 23 pregnant female SD rats/dose
group were administered vehicle alone (demineralized water) by gavage
from GD 6-20 or 10 µg/kg bw/day NTBC, 1433 mg/kg bw/day L-tyrosine, or
NTBC (10 µg/kg bw/day) + L-tyrosine (1424 mg/kg bw/day) by gavage from
GD 6-21.  The study was designed to test the hypothesis that maternal
tyrosinemia has no effect on fetal skeletal development.  Morbidity,
mortality, and clinical signs were monitored daily throughout gestation.
 Body weights and food consumption were measured on gestation days 6, 8,
10, 12, 14, 16, 18, and 21.  Maternal plasma tyrosine concentrations
were measured at sacrifice (GD 21).  At necropsy, the reproductive tract
and livers were weighed and the number of corpora lutea, implantations,
resorptions, and live and dead fetuses, and the sex and individual body
weights of the live fetuses were recorded.  Following external
examination of all fetuses, a limited number of skeletal endpoints were
evaluated from approximately half the fetuses in each litter.

There were no treatment-related effects on maternal mortality, clinical
signs, body weight, corrected body weight, food consumption, litter
parameters, or fetal external findings.  Four of the 23 dams in the
group receiving tyrosine + NTBC showed minimal corneal opacity.  Mean
plasma tyrosine concentrations at GD 21 were 5-, 8-, and 63-fold those
of controls in the L-tyrosine, NTBC, or L-tyrosine + NTBC groups,
respectively.  Mean fetal body weight was reduced by 7% (P<0.05) in male
and female fetuses whose dams were administered tyrosine + NTBC and was
slightly but statistically non-significantly reduced by 2-3% in fetuses
whose dams were administered NTBC alone.  Increases (relative to
concurrent controls) in the incidences of the following skeletal
findings were observed in animals receiving tyrosine + NTBC: 7th
cervical centrum: unossified / normal cartilage; 6th sternebra:
incomplete ossification / normal cartilage; 5th sternebra:  unossified /
normal cartilage; Extra ossification point(s) (unilateral / bilateral)
on 14th thoracic vertebra; Forepaws:  3rd and/or 4th proximal phalanges:
 unossified / normal cartilage; 5th metacarpal: incomplete ossification
/ normal cartilage; 1st metatarsal: unossified: normal cartilage; and
Less than 9 sacrocaudal vertebrae ossified / 9 first sacrocaudal
vertebrae: normal cartilage.  Increases in the incidences of the
following skeletal findings were also observed in animals receiving
tyrosine alone and NTBC alone: 7th cervical centrum: unossified / normal
cartilage; and Extra ossification point(s) (unilateral / bilateral) on
14th thoracic vertebra.  Because historical control data were not
submitted and statistical analysis was not performed, the increased
incidences in each of these groups were considered treatment-related.

The study is classified as Acceptable/Non-guideline and is acceptable
for demonstrating an association between increased maternal blood
tyrosine concentrations, fetal skeletal anomalies, and decreased fetal
body weight.

Liverbeads™ preparations were dissolved, hepatocytes were sonicated,
and the suspension was transferred to vials for storage at -80°C.
Concentrations of L-tyrosine and of p-hydroxyphenyl lactic acid (HPLA)
were then determined by HPLC analysis.

Baseline HPLA concentrations (µg/mg protein) were below the limit of
quantitation (LOQ) at each time point for all species except mouse.
HPLA concentrations were increased in mice and human hepatocytes at 2
and 4 h following incubation with NTBC.  HPLA concentrations returned to
baseline levels when hepatocytes were exposed to basal medium
supplemented with tyrosine.  When LiverbeadsTM were incubated with
tyrosine and NTBC, HPLA concentrations were increased at 2 h in rat,
mouse, and human and at 4 h in all species except dog.  Mean tyrosine
concentrations in mouse hepatocytes incubated with L-tyrosine alone were
slightly lower than concentrations in hepatocytes measured in the other
species tested (Appendix 1).  Mean tyrosine concentrations in mouse
hepatocytes incubated with L-tyrosine + NTBC were increased over those
in mouse hepatocytes incubated with L-tyrosine alone (Appendix 1).  The
results suggest that under basal conditions more HPLA is formed in mouse
hepatocytes than in hepatocytes of the other tested species and that
inhibition of HPPD by NTBC leads to increased concentrations of HPLA in
mouse hepatocytes and detectable concentrations of HPLA in human
hepatocytes.  The results also suggest that HPLA is formed in
hepatocytes of all tested species, except dog, under conditions of
increased tyrosine concentration and inhibition of HPPD by NTBC.

The study is classified as Acceptable/Non-guideline and is acceptable
for assessing the species differences in the production of the tyrosine
metabolite HPLA following incubation of hepatocytes with NTBC.

In a comparative feeding study (MRID 46801903), 5 male Beagle dogs/group
were administered 18000 ppm AE 0317309 (batch Op. 1-4) mixed with either
dry feed (300g Purina Certified Canine Diet Etts 5006-3) or wet feed
(300g Purina Certified Canine Diet 5007 meal + 450 mL tap water) for 1.5
hrs/day for 16 days.  Untreated control groups were not included in the
study.  The study was designed to determine if administration of treated
feed with water affects the blood and urinary concentrations of AE
0317309 relative to the blood and urinary concentrations of AE0317309
following administration of treated dry feed.  Test substance intake was
318 mg/kg bw/day on days 1-7 and 479 mg/kg bw/day on days 8-16 in the
dry feed group and 272 mg/kg bw/day on days 1-7 and 388 mg/kg bw/day on
days 8-16 in the wet feed group.  Animals were examined for clinical
signs of toxicity twice daily.  Body weights were measured on study days
0, 7, and 16, and food consumption was measured on a daily basis.  Blood
urea nitrogen and creatinine, as well as standard urinalysis parameters,
were measured pre-test, and on study days 6 and 14.  Urine was also
collected at 2, 4, 6, 8, 12, and 24 h after the last feeding on day 15
for measurement of urinary AE 0317309 concentration.  Blood was
collected at 2, 4, and 6 h after the last feeding on day 15 for
measurement of plasma AE 0317309 concentration.  On study day 16, the
animals were sacrificed and subjected to a gross necropsy of the urinary
tract with kidney weight measurement.

No mortalities were observed during the study, and there was no
difference in food consumption or kidney weight between the wet-feed or
the dry-feed group.  Treatment-related clinical signs were limited to
red urine in 2/5 dogs of the dry-feed group on or after day 7.  A tan
substance was noted in the feces of all wet-feed dogs.  Mean body
weight, relative to day 0, was decreased by 4% (day 7) and 5% (day 16)
in the dry-feed group and by 6% (day 7) and 9% (day 16) in the wet-feed
group.  On days 6 and 14, blood urea nitrogen (BUN) levels were
increased 67-87% over pre-test values (15 mg/dl) in the dry-feed group
and were more than double pre-test values (11 mg/dl) in the wet-feed
group.  Blood was observed in the urine in both dietary groups, albeit
to a greater extent in the dry-feed group.  Urinary calculi were
observed in 2/5 dogs in the dry-feed group, and the urinary bladders of
these animals showed moderate thickening.  These findings were not
observed in any of the dogs in the wet-feed group.  Plasma
concentrations of test substance in the dry-feed group were increased by
52% and 64% over those in the wet-feed group at 2 and 4 hrs. post
feeding, but were similar by 6 hrs. post feeding.  Urine concentrations
of test substance in the dry-feed group were more than double those in
the wet-feed group at 12 hrs. post feeding, but were similar by 24 hrs.
post dosing.  The results of the study are inconclusive, since test
substance intake was 20% higher in dogs receiving dry feed than in those
receiving wet feed.

The study is classified as Acceptable/Non-guideline and is acceptable
for assessing the general differences in toxicological effect between
dry feed and wet feed treated with AE 0317309 in dogs.

Benzoic acid metabolite

90-Day Oral Toxicity - Rat (2)

In a 28-day oral toxicity study (MRID 43904813), RPA 203328 (99.7% w/w
ai, batch DA 938) was administered to 10 Sprague Dawley rats/sex/dose in
the diet at dose levels of 0, 150, 500, 5000, or 15000 ppm (equal to
0/0, 11.1/12.7, 37.6/42.7, 377/421, and 1118/1269 mg/kg bw/day in
males/females).

There were no compound-related effects on mortality, clinical signs,
body weight, food consumption, hematology, clinical chemistry,
ophthalmology, organ weights, or gross and histological pathology.  Mean
urinary pH was reduced in males at 15000 ppm (6.5, P<0.01 vs. 7.28 in
controls).  In the absence of corroborating evidence of toxicity in any
other parameter, the finding was not considered toxicologically
significant.

The LOAEL was not observed.  The NOAEL is 15000 ppm (1118/1269 mg/kg/day
[M/F]).

This 28-day oral toxicity study in the rat is Acceptable (non-guideline)
as a range-finding study and does not satisfy the guideline requirement
for a 90-day oral toxicity study (OPPTS 870.3100; OECD 408) in rodents.

In a 90-day oral toxicity study (MRID 45655903), RPA 203328 (99% a.i,
batch # NMI874) was administered to 10 Sprague Dawley rats/sex/dose in
the diet at dose levels of 0, 1200, 4800, or 12000 ppm (equivalent to 0,
73.2/93.1, 306/371, or 769/952 mg/kg bw/day in males/females,
respectively).

There were no compound-related effects on mortality, clinical signs
(including reflexes), ophthalmology, body weight, food consumption,
hematology, clinical chemistry, urinalysis, organ weights, or gross and
histologic pathology.  Urinary pH was slightly reduced (P<0.01) at the
mid and high doses (5.45 vs. 6.11 in controls); however, the findings
were not considered toxicologically significant in the absence of
corroborating evidence of toxicity in any other measure.  The LOAEL was
not observed.  The NOAEL is 12000 ppm (769/952 mg/kg/day in
males/females).

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 rodents.

870.3700 Prenatal Developmental Toxicity Study - Rat

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s methylcellulose at dose levels of 0, 75, 250, or 750 mg/kg bw/day from
days 6 through 20 of gestation.

) and from GD 10-14 at ≥250 mg/kg (26%).  Mean cumulative body weight
gain corrected for gravid uterine weight was reduced by 31% and 37%
(P<0.01) at 250 and 750 mg/kg, respectively.  Food consumption was
decreased throughout the treatment period by ≤15% (P<0.01) at ≥250
mg/kg.

The maternal LOAEL is 250 mg/kg bw/day, based on clinical signs
(salivation, piloerection, red nasal discharge around time of
treatment), decreased body weight gain, and decreased food consumption.
The maternal NOAEL is 75 mg/kg bw/day.

No treatment-related effects were observed on cesarean parameters or
external, visceral, or skeletal observations.

The developmental LOAEL was not observed.  The developmental NOAEL is
750 mg/kg bw/day.

The developmental toxicity study in the rat is classified Acceptable
(guideline) and satisfies the guideline requirement for a developmental
toxicity study (OPPTS 870.3700; OECD 414) in the rat.

Appendix B.	Metabolism Assessment  TC "Appendix B.	Metabolism
Assessment" \f C \l "1"

Table B.2.  Tabular Summary of Metabolites and Degradates.

Chemical Name	Commodity	Percent TRR (PPM) 1	Structure

Matrices - Major Residue  >10%TRR)	Matrices - Minor Residue (<10%TRR)

	Pyrasulfotole (AE 0317309)	Wheat	Forage	Phenyl label (wos)	28.7% (0.71
ppm)	Phenyl label (ws)		7.3% (0.18 ppm)

Hay	Phenyl label (wos)	12.1% (0.37 ppm)	Phenyl label (ws)		4.4% (0.14
ppm)

	Straw

Phenyl label (ws)		4.6% (0.13 ppm)

Phenyl label (wos)	7.5% (0.21 ppm)

Laying Hen	Muscle	Phenyl label		95.3% (0.036 ppm)

Pyrazole label		92.9% (0.018 ppm)

Fat	Phenyl label		97.1% (0.064 ppm)

Pyrazole label		97.7% (0.014 ppm)

Liver	Phenyl label		93.3% (1.456 ppm)

Pyrazole label		94.6% (1.215 ppm)

	Lactating Goat	Muscle	Phenyl label		80.2% (0.008 ppm)

Kidney	Phenyl label		99.6% (0.532 ppm)

Pyrazole label		92.4% (0.249 ppm)

Liver	Phenyl label		95.5% (1.411 ppm)

Pyrazole label		93.3% (1.603 ppm)

Milk	Phenyl label		82.7% (0.014 ppm)

Pyrazole label		38.8% (0.017 ppm)

	Rotational Crops (Wheat)	120-DAT grain

Phenyl label		0.9% (<0.001 ppm)

	301-DAT hay

Phenyl label		2% (0.001 ppm)

Table B.2.  Tabular Summary of Metabolites and Degradates.

Chemical Name	Commodity	Percent TRR (PPM) 1	Structure

Matrices - Major Residue  >10%TRR)	Matrices - Minor Residue (<10%TRR)

	Pyrasulfotole benzoic acid

(AE B197555)	Wheat	Forage	Phenyl label		26.0% (0.119 ppm)

Phenyl label (ws)		16.3% (0.39 ppm)

Phenyl label (wos)	20.1% (0.49 ppm)

Hay	Phenyl label		60.8% (0.11 ppm)

Phenyl label (ws)		24.9% (0.78 ppm)

Phenyl label (wos)	33.6% (1.06 ppm)

Straw	Phenyl label		66.0% (0.36 ppm)

Phenyl label (ws)		30.5% (0.88 ppm)

Phenyl label (wos)	37.2% (1.04 ppm)

Grain	Phenyl label 		89.5% (0.27 ppm)

Phenyl label (ws)		97.6% (0.15 ppm)

Phenyl label (wos)		97.7% (0.23 ppm)

	Rotational Crops (Wheat)	120-DAT forage	Phenyl label		90.2% (0.024 ppm)

120-DAT hay	Phenyl label		80.2% (0.049 ppm)	Pyrazole label		3% (<0.001
ppm)

	120-DAT straw	Phenyl label		49.7% (0.012 ppm)	Pyrazole label		9% (0.002
ppm)

	120-DAT grain	Phenyl label		89.4% (0.028 ppm)

301-DAT forage	Phenyl label		91.3% (0.078 ppm)

301-DAT hay	Phenyl label		58.3% (0.021 ppm)

301-DAT straw	Phenyl label		27.0% (0.004 ppm)

301-DAT grain	Phenyl label		77.0% (0.008 ppm)

Table B.2.  Tabular Summary of Metabolites and Degradates.

Chemical Name	Commodity	Percent TRR (PPM) 1	Structure

Matrices - Major Residue  >10%TRR)	Matrices - Minor Residue (<10%TRR)

	Pyrasulfotole-desmethyl-O glucoside	Wheat	Forage	Phenyl label		34.2%
(0.152 ppm)

Pyrazole label		43.4% (0.202 ppm)

Phenyl label (ws)		43.5% (1.04 ppm)

Phenyl label (wos)		30.2% (0.74 ppm)

Hay	Phenyl label 		10.4% (0.02 ppm)

Pyrazole label		25.4% (0.015 ppm)

Phenyl label (ws)		36.7% (1.16 ppm)

Phenyl label (wos)		25.7% (0.80 ppm)

Straw	Pyrazole label		21.7% (0.08 ppm)

Phenyl label (ws)		27.9% (0.81 ppm)

Phenyl label (wos)		19.6% (0.55 ppm)	Phenyl label		5.1% (0.03 ppm)

	Grain

Pyrazole label	0.7% (<0.001 ppm)

	Pyrasulfotole-desmethyl

(AE 1073910)	Laying Hen	Muscle

Phenyl label	2.2% (0.001 ppm)

Pyrazole label	2.2% (<0.001 ppm)

Fat

Phenyl label	1.8% (0.001 ppm)

	Liver

Phenyl label	6.5% (0.101 ppm)

Pyrazole label	4.8% (0.062 ppm)

	Liver	Pyrazole label		1.4% (0.025 ppm)

Milk	Phenyl label		11.7% (0.002 ppm)

Pyrasulfotole-hydroxymethyl	Lactating Goat	Muscle	Phenyl label 		8.3%
(0.001 ppm)

Milk	Phenyl label		4.4% (0.001 ppm)

Table B.2.  Tabular Summary of Metabolites and Degradates.

Chemical Name	Commodity	Percent TRR (PPM) 1	Structure

Matrices - Major Residue  >10%TRR)	Matrices - Minor Residue (<10%TRR)

	Pyrasulfotole-sulfinyl-lactate	Wheat	Forage

Phenyl label (ws)		7.8% (0.19 ppm)

Hay

Phenyl label (ws)		8.9% (0.28 ppm)

	Straw

Phenyl label (ws)		9.6% (0.28 ppm)

	Grain

	Wheat:  MRID No. 46801748 and 46801748; 0.089 lb ai/A (100 g ai/ha); 2x
the maximum proposed seasonal rate for cereal grains; PHIs = 0 days,
27-28 days (forage), 49-50 days (hay), and 89-90 days (harvest).

Wheat:  MRID No. 46801801; 0.087 lb ai/A [98 g ai/ha; phenyl-label; with
safener (ws)] and 0.086 lb ai/A [96 g ai/ha; phenyl-label; without
safener (wos)]; 2x maximum proposed seasonal rate for cereal grains; PHI
= 21 days (forage), 44 days (hay), 79 days (harvest).

Rotational crops:  MRID 46801833; 0.073 lb ai/A [82 g ai/ha;
phenyl-label and pyrazole-label]; 2.2x (phenyl) and 1.6x (pyrazole)
maximum proposed seasonal rate for cereal grains; PBI = 120 days (wheat,
swiss chard, turnips) and 301 days (wheat).

Laying Hen:  MRID Nos. 46801802 and 46801803;  8.6 ppm (phenyl-label)
and 10.5 ppm (pyrazole-label); 150x and 180x the MTDB for poultry,
respectively; 14 days of dosing; ~30 minute PSI.

Lactating Goat:  MRID Nos. 46801804 and 46801805; 52.1 ppm
(phenyl-label) and 28.1 ppm (pyrazole-label); 130x and 72x the MTDB for
beef and dairy cattle, respectively; 3 days of dosing; 24 hour PSI.

Rat Metabolism:	MRID No. 46801918; single oral doses - 10.0 mg/kg
(phenyl-label) and 9.88 mg/kg (pyrazole-label); intravenous doses –
9.81 mg/kg (phenyl-label) and 9.60 mg/kg (pyrazole-label); Wistar
Hanover rats

Table B.3.		Environmental Fate Summary for Pyrasulfotole.

Degradate Name and Structure	Report % Applied Dose, PPB, T1/2, Other
Pertinent Information	Monitoring Data

Available?	Cleaned Up

By Drinking

Water Treatment?

	Aerobic Soil Metabolism	Aerobic Aquatic Metabolism	Field Dissipation
Hydrolysis	Soil

Photolysis	Aqueous Photolysis	Anaerobic Aquatic Metabolism	Anaerobic
Soil Metabolism

Pyrasulfotole (AE 0317309; K-1196; K1267); Parent

	DT50 = 5.8 d	Stable	DT50 = 8.9 d	Stable	Stable	Stable	Stable	Stable	No
national-scale monitoring data available.	No information available on
drinking water treatment effects on pyrasulfotole.

	DT50= 63 d

DT50 = 5.7 d

Stable

DT50 = 23 d

DT50 = 5.7 d

DT50 = 9.2 – 18 d

	Pryasulfotole-benzioc acid (RPA 203328)

	12	--	6.1 ppb	--	--	--	--	9.9

	3.8

14 ppb

--

9.3

3.9 ppb

27-37 ppb

	Study MRID No(s).	46801709

46801710

46801711	46801713	46801716

46801717

46801718

46801719	46801705	46801707	46801706	46801714

46801715	46801712

Study Characterization 3	Acceptable	Acceptable	Acceptable	Acceptable
Acceptable	Acceptable	Acceptable	Acceptable

1.  % of theoretically applied based on target application rate.

Appendix C.	Tolerance Summary Table for Pyrasulfotole  TC "Appendix C.
Tolerance Summary Table for Pyrasulfotole" \f C \l "1"

Table 14.  Tolerance Summary for Pyrasulfotole.

Commodity	Proposed Tolerance (ppm)	Recommended Tolerance (ppm)	Comments

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Sheep, meat	0.01	0.02

	Sheep, fat	0.01	0.02

	Sheep, meat byproducts	0.3	0.06	Sheep, meat byproducts, except liver

Sheep, liver	-	0.35

	Horse, meat	0.01	0.02

	Horse, fat	0.01	0.02

	Horse, meat byproducts	0.3	0.06	Horse, meat byproducts, except liver

Horse, liver	-	0.35

	Poultry, meat	-	0.02

	Poultry, fat	-	0.02

	Poultry, meat byproducts	-	0.02

	Eggs	-	0.02

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