Document ID: EPA-HQ-OPP-2006-0072-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-09-28T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

     OFFICE OF	

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

DATE:		07-SEP-2007

SUBJECT:	PP#5F7009:  Tembotrione.  Human-Health Risk Assessment for
Proposed Uses on Field Corn, Sweet Corn and Popcorn.  PC Code 012808. 
DP# 325935.  Decision # 362526.

		Regulatory Action:  Section 3 Registration

		Risk Assessment Type:  Single Chemical Aggregate

FROM:	Lisa Austin, Ph.D., Toxicologist

		George F. Kramer, Ph.D., Senior Chemist

	Kelly Lowe, Environmental Scientist

	Registration Action Branch 1 (RAB1)

	Health Effects Division (HED, 7509P)

THROUGH:	PV Shah, Ph.D., Acting Branch Chief

		RAB1/HED (7509P)

		Jeffery Evans, Senior Biologist

		Chemistry and Exposure Branch (CEB)

		Michael Metzger, Branch Chief

		Reregistration Branch 1 (RRB1)

TO:		Eugene Wilson/Joanne Miller, PM Team 23

     Registration Division (RD; 7505P)

The HED of the Office of Pesticide Programs (OPP) is charged with
estimating the risk to human health from exposure to pesticides.  The RD
of OPP has requested that HED evaluate hazard and exposure data and
conduct dietary, occupational, residential and aggregate exposure
assessments, as needed, to estimate the risk to human health that will
result from the proposed uses of tembotrione,
2-[2-chloro-4-(methylsulfonyl)-3-[(2,2,2-(trifluoroethoxy)methyl]benzoyl
]-1,3-cyclohexanedione (designated by the company code AE0172747) in/on
field corn, sweet corn and popcorn.  The registrant is Bayer
CropScience.  This is the first food use request for tembotrione.  This
is a shared joint review with the Pest Management Regulatory Agency
(PMRA) in Canada.  It was recently registered in Austria for use on
corn.

A summary of the findings and an assessment of human risk resulting from
the proposed uses of tembotrione are provided in this document.  The
risk assessment and the hazard characterization were provided by Lisa
Austin (RAB1), the residue chemistry data review, and the dietary risk
assessment by George Kramer (RAB1), the occupational/residential
exposure assessment by Kelly Lowe (RAB1), and the drinking water
assessment by William Eckel of the Environmental Fate and Effects
Division (EFED).

Recommendation for Tolerances and Registration:

Pending submission of revised Sections B and F (see requirements under
Section 10.0 Data Needs and Label Recommendations) and the submission of
reference standards for tembotrione and its metabolite M5 (see
requirements under Submittal of Analytical Reference Standards), there
are no residue chemistry, occupational exposure or toxicology issues
that would preclude granting a conditional registration for the
requested uses of tembotrione on field corn, popcorn, and sweet corn. 
Registration should be made conditional pending the submission of
additional information concerning the proposed enforcement methods (see
requirements under Residue Analytical Methods), completion of a
successful petition method validation (PMV) of the proposed enforcement
methods for plant and livestock commodities by Agency chemists at the
Analytical Chemistry Branch/Biological and Economics Analysis Division
(ACB/BEAD), and chemical-specific dislodgeable foliar residue data.  

The proposed uses and the submitted data support the following permanent
tolerances for the combined residues of tembotrione and its metabolite
M5 expressed as tembotrione equivalents, in/on the following corn
commodities:

Corn, field, grain	0.02 ppm

Corn, field, forage	0.60 ppm

Corn, field, stover	0.45 ppm

Corn, sweet, kernel plus cob with husks removed	0.04 ppm

Corn, sweet, forage	1.0 ppm

Corn, sweet, stover	1.2 ppm

Corn, pop, grain	0.02 ppm

Corn, pop, stover	0.35 ppm

The proposed uses and the submitted data support the following
tolerances for the combined residues of tembotrione and its metabolite
M5, expressed as tembotrione equivalents in the following livestock
commodities:  

Cattle, liver	0.40 ppm

Cattle, meat byproducts, except liver	0.07 ppm

Goat, liver	0.40 ppm

Goat, meat byproducts, except liver	0.07 ppm

Horse, liver	0.40 ppm

Horse, meat byproducts, except liver	0.07 ppm

Sheep, liver	0.40 ppm

Sheep, meat byproducts, except liver	0.07 ppm 

Poultry, liver	0.07 ppm

Data Gaps

Toxicology:  

There are no toxicology data gaps.

Chemistry:

860.1340 Residue Analytical Methods

To be acceptable as enforcement methods, LC/MS/MS Methods AE/03/01 for
plant commodities and 00967 for livestock commodities should undergo
successful PMVs by Agency chemists at ACB/BEAD.

Both methods should be revised to include a calculation for the
conversion of residues of the metabolite(s) to parent equivalents for
quantitation.  

Separate confirmatory methods for Method AE/03/01 will not be requested
provided that two ion transitions are monitored during MS/MS analysis
for each analyte. 

  SEQ CHAPTER \h \r 1 860.1650 Submittal of Analytical Reference
Standards

Analytical standards for tembotrione and its metabolite M5 are currently
not available in the National Pesticide Standards Repository. 
Analytical reference standards of tembotrione and its metabolite
(including the deuterated internal standards) should be supplied, and
supplies replenished as requested by the Repository.  

860.1550 Proposed Tolerances

The petitioner is requested to submit a revised Section F specifying the
following:  

The tolerance expression for plant commodities should be revised to
include the combined residues of tembotrione and M5, expressed as
tembotrione equivalents.

The tolerance expression for livestock commodities should be revised to
include the combined residues of tembotrione and its metabolite M5,
expressed as tembotrione equivalents.

The revised tolerances and commodity definitions presented in Appendix
C:  Tolerance Reassessment Summary and Table (summarized above).

Occupational and Residential Exposure:  

875.2100 Chemical-specific dislodgeable foliar residue data.

Table of Contents

  TOC \f  1.0	Executive Summary	  PAGEREF _Toc170608523 \h  6 

2.0	Ingredient Profile	  PAGEREF _Toc170608524 \h  11 

2.1	Summary of Registered/Proposed Uses	  PAGEREF _Toc170608525 \h  11 

2.2	Structure and Nomenclature	  PAGEREF _Toc170608526 \h  11 

2.3	Physical and Chemical Properties	  PAGEREF _Toc170608527 \h  13 

3.0	Hazard Characterization/Assessment	  PAGEREF _Toc170608528 \h  14 

3.1	Hazard and Dose-Response Characterization	  PAGEREF _Toc170608529 \h
 14 

3.1.1	Database Summary	  PAGEREF _Toc170608530 \h  14 

3.1.1.1	Studies available and considered (animal, human, general
literature)	  PAGEREF _Toc170608531 \h  14 

3.1.1.2	Mode of action, metabolism, toxicokinetic data	  PAGEREF
_Toc170608532 \h  14 

3.1.1.3	Sufficiency of studies/data	  PAGEREF _Toc170608533 \h  15 

3.1.2	Toxicological Effects	  PAGEREF _Toc170608534 \h  15 

3.1.3	Dose response Assessment	  PAGEREF _Toc170608535 \h  17 

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)	  PAGEREF
_Toc170608536 \h  17 

3.3	FQPA Considerations	  PAGEREF _Toc170608537 \h  19 

3.3.1	Adequacy of the Toxicity Database	  PAGEREF _Toc170608538 \h  19 

3.3.2	Evidence of Neurotoxicity	  PAGEREF _Toc170608539 \h  20 

3.3.3	Additional Information from Literature Sources	  PAGEREF
_Toc170608540 \h  20 

3.3.4	Pre-and/or Postnatal Toxicity	  PAGEREF _Toc170608541 \h  20 

3.3.4.1	Determination of Susceptibility	  PAGEREF _Toc170608542 \h  20 

3.3.4.2	Degree of Concern Analysis and Residual Uncertainties	  PAGEREF
_Toc170608543 \h  21 

3.3.5	Recommendation for a Developmental Neurotoxicity Study	  PAGEREF
_Toc170608544 \h  21 

3.4	Safety Factor for Infants and Children	  PAGEREF _Toc170608545 \h 
21 

3.5	Hazard Identification and Toxicity Endpoint Selection	  PAGEREF
_Toc170608546 \h  21 

3.5.1	Acute Reference Dose (aRfD) - General Population (including
females age 13-49	  PAGEREF _Toc170608547 \h  21 

3.5.2	Chronic Reference Dose (cRfD)	  PAGEREF _Toc170608548 \h  22 

3.5.3	Incidental Oral Exposure (Short- and Intermediate-Term)	  PAGEREF
_Toc170608549 \h  22 

3.5.4	Dermal Absorption	  PAGEREF _Toc170608550 \h  23 

3.5.5	Dermal Exposure (Short-, Intermediate- and Long-Term)	  PAGEREF
_Toc170608551 \h  23 

3.5.6	Inhalation Exposure (Short-, Intermediate- and Long-Term)	 
PAGEREF _Toc170608552 \h  24 

3.5.7	Level of Concern for Margin of Exposure	  PAGEREF _Toc170608553 \h
 25 

3.5.8	Recommendation for Aggregate Exposure Risk Assessments	  PAGEREF
_Toc170608554 \h  25 

3.5.9	Classification of Carcinogenic Potential	  PAGEREF _Toc170608555
\h  25 

3.5.10	Summary of Toxicological Doses and Endpoints for tembotrione for
Use in Human Risk Assessments	  PAGEREF _Toc170608556 \h  26 

3.6	Endocrine disruption	  PAGEREF _Toc170608557 \h  28 

4.0	Public Health and Pesticide Epidemiology Data	  PAGEREF
_Toc170608558 \h  29 

5.0	Dietary Exposure/Risk Characterization	  PAGEREF _Toc170608559 \h 
29 

5.1  Pesticide Metabolism and Environmental Degradation	  PAGEREF
_Toc170608560 \h  29 

5.1.1	Metabolism in Primary Crops	  PAGEREF _Toc170608561 \h  29 

5.1.2	Metabolism in Rotational Crops	  PAGEREF _Toc170608562 \h  29 

5.1.3	Metabolism in Livestock	  PAGEREF _Toc170608563 \h  29 

5.1.4	Analytical Methodology	  PAGEREF _Toc170608564 \h  31 

5.1.5	Environmental Degradation	  PAGEREF _Toc170608565 \h  31 

5.1.6	Comparative Metabolic Profile	  PAGEREF _Toc170608566 \h  31 

5.1.7	Toxicity Profile of Major Metabolites and Degradates	  PAGEREF
_Toc170608567 \h  32 

5.1.8	Pesticide Metabolites and Degradates of Concern	  PAGEREF
_Toc170608568 \h  33 

5.1.9	Drinking Water Residue Profile	  PAGEREF _Toc170608569 \h  33 

5.1.10	Food Residue Profile	  PAGEREF _Toc170608570 \h  33 

5.1.11	International Residue Limits	  PAGEREF _Toc170608571 \h  35 

5.2  Dietary Exposure and Risk	  PAGEREF _Toc170608572 \h  35 

5.2.1  Acute Dietary Exposure/Risk	  PAGEREF _Toc170608573 \h  35 

5.2.2  Chronic Dietary Exposure/Risk	  PAGEREF _Toc170608574 \h  35 

5.2.3  Cancer Dietary Risk	  PAGEREF _Toc170608575 \h  35 

5.3 Anticipated Residue and Percent Crop Treated (%CT) Information	 
PAGEREF _Toc170608576 \h  36 

6.0	Residential (Non-Occupational) Exposure/Risk Characterization	 
PAGEREF _Toc170608577 \h  36 

6.1	Other (Spray Drift, etc.)	  PAGEREF _Toc170608578 \h  36 

7.0	Aggregate Risk Assessments and Risk Characterization	  PAGEREF
_Toc170608579 \h  37 

8.0	Cumulative Risk Characterization/Assessment	  PAGEREF _Toc170608580
\h  37 

9.0	Occupational Exposure/Risk Pathway	  PAGEREF _Toc170608581 \h  38 

9.1	Short-/Intermediate-Term Occupational Handler Risk	  PAGEREF
_Toc170608582 \h  38 

9.2	Short-/Intermediate-Term Postapplication Risk	  PAGEREF
_Toc170608583 \h  41 

10.0	Data Needs and Label Recommendations	  PAGEREF _Toc170608584 \h  43

10.1	Toxicology	  PAGEREF _Toc170608585 \h  43 

10.2	Residue Chemistry	  PAGEREF _Toc170608586 \h  43 

10.3	Occupational and Residential Exposure	  PAGEREF _Toc170608587 \h 
44 

References:	  PAGEREF _Toc170608588 \h  44 

Appendix A:  Toxicology Assessment	  PAGEREF _Toc170608589 \h  45 

A.1  Toxicology Data Requirements	  PAGEREF _Toc170608590 \h  45 

A.2  Toxicity Profiles	  PAGEREF _Toc170608591 \h  46 

A.3  Executive Summaries	  PAGEREF _Toc170608592 \h  55 

Appendix B:  Metabolism Assessment	  PAGEREF _Toc170608593 \h  101 

B.1	Metabolism Guidance and Considerations	  PAGEREF _Toc170608594 \h 
101 

Appendix B:  Metabolism Assessment	  PAGEREF _Toc170608595 \h  101 

B.1	Metabolism Guidance and Considerations	  PAGEREF _Toc170608596 \h 
101 

Appendix C:  Tolerance Reassessment Summary and Table	  PAGEREF
_Toc170608597 \h  105 

 1.0	Executive Summary  TC \l1 "1.0	Executive Summary 

Tembotrione is a broad spectrum early and mid-postemergence herbicide. 
It is applied via groundboom equipment at an application rate of 0.082
lb ai/acre.  The maximum application rate is 0.16 lb ai/acre (2
applications/season).  Tembotrione belongs to the triketone class of
herbicides and acts by inhibiting 4-hydroxyphenylpyruvate dioxygenase
(HPPD) which leads to chlorophyll destruction by photooxidation and
causes bleaching of emerging foliar tissue.  In mammals, HPPD is a key
enzyme in the catabolism of tyrosine.  It catalyzes the conversion of
4-hydroxyphenylpyruvate (HPP) to homogentisate.  Inhibition of HPPD
leads to a reconversion of HPP to tyrosine and a consequent increase in
blood tyrosine concentrations (tyrosinemia).  There are no existing
tolerances, uses, or exemptions for tembotrione.  The field corn
petition represents the first proposed use for tembotrione.  There are
currently no proposed residential uses of tembotrione.  This is a joint
shared review with PMRA in the U.S.  It is currently registered in
Austria.

Currently, there are three registered herbicides, isoxaflutole,
topramezone, and mesotrione, and one new herbicide in the review process
(pyrasulfatole) that are also HPPD inhibitors.

Toxicity/Hazard:  Tembotrione has low acute toxicity via the oral,
dermal and inhalation routes of exposure (Toxicity category III or IV). 
It is a dermal sensitizer but not an eye or dermal irritant.

The primary target organs were the eyes, liver and kidneys.  In
subchronic and chronic oral toxicity studies, corneal opacity,
neovascularization, edema of the cornea, and keratitis of the eye were
observed in the rat and dog.  Liver effects (increased weight,
hypertrophy, hyperplasia) were seen in the rat, mouse and dog.  In the
kidney, increased weight, and papillary mineralization were observed in
the rat and mouse following chronic exposure. 

The dog appeared to be more sensitive to hematological effects.  In the
subchronic and chronic dog toxicity studies hematological changes
indicative of anemia were seen [decreased mean corpuscular hemoglobin
(MCH) and mean corpuscular volume (MCV)].  Similar hematological effects
were also observed in the chronic toxicity study in the mouse.

Certain changes in multiple organs seen in the subchronic, chronic,
dermal, and reproduction studies (e.g., microscopic changes in the
thyroid gland, adrenal gland, and pancreas; increased number of corpora
lutea in the ovary, and delayed preputial separation) may be due to
various mechanisms including possible liver-pituitary-thyroid
homeostatic disruption or inhibition of steroid synthesis.

In a combined chronic/carcinogenicity study, squamous cell carcinomas of
the cornea and thyroid follicular adenomas were observed in male rats. 
The Cancer Assessment Review Committee (CARC) met on April 11, 2007 and
classified tembotrione as “Suggestive Evidence of Carcinogenic
Potential” based on the lack of carcinogenicity in mice, the
observance of tumors in male rats only and the lack of mutagenicity. 
Therefore, quantification of carcinogenic potential is not required. 
The reference dose (RfD) would be protective of cancer effects.

Evidence of neurotoxicity was seen in the subchronic and chronic
toxicity studies in the dog (uncoordinated movement, disturbance in
locomotion) and in the acute (decreased arousal, decreased body
temperature, decreased motor and locomotor activities) and developmental
neurotoxicity (brain morphometric changes, decreased acoustic startle
response) studies in the rat.  In the developmental neurotoxicity study
in rats, increased susceptibility was observed as fetal neurological
effects and occurred at a dose that was lower than the dose at which
maternal toxicity occurred (corneal opacity).  There was no evidence of
neurotoxicity in the subchronic neurotoxicity study in rats. 

There was evidence of increased susceptibility of rabbits and rats to in
utero and postnatal exposure to tembotrione in the developmental and 2
generation reproduction studies.  In the developmental study in rabbits,
fetal effects (delayed growth/skeletal development and skeletal
variations/anomalies) occurred at a dose lower than that which caused
maternal toxicity (mortality, few or no feces, abortion, decreased body
weight and food consumption).  Also, fetal effects (skeletal variations,
decreased fetal body weight, runting) were observed at a dose lower than
that which caused marginal maternal toxicity (decreased body-weight
gains and food consumption) in the developmental study in rats.  No
teratogenic effects were observed in the rat and rabbit developmental
toxicity studies.  In the 2-generation reproduction study in rats,
offspring effects (opacity, acute inflammation and neovascularization of
the cornea, increased incidences of minimal extramedullary hematopoeisis
in the spleen, delayed preputial separation, and decreased absolute
brain weight) occur at the lowest dose in the presence of maternal
toxicity (opacity, acute inflammation and neovascularization of the
cornea).  There were no reproductive effects.  

Rat metabolism data indicate that tembotrione is well absorbed.  More
than 96% of the administered dose was recovered in urine and feces in 24
hours.  Minor sex differences were observed in the routes of excretion. 
The primary routes of elimination were the urine in females and the
urine and feces in males.  The highest concentrations of radioactivity
were found in the skin followed by the liver, kidneys, stomach (and
contents) and carcass.

Males had higher mean blood, plasma maximum concentrations (Cmax) and
area under the concentration-time curves (AUC) values than females.  At
5 mg/kg, saturation of the initial elimination/biotransformation
processes was evident resulting in a slower initial elimination phase.

The parent molecule and 11 metabolites were identified and isolated from
urine and feces.  Metabolic profiles were qualitatively similar for both
radiolabeled forms; however, profiles for the high and low doses were
not the same and differences were noted between sexes.  The primary step
in the metabolism of tembotrione is the hydroxylation (oxidative
pathway) of the cyclohexyl ring of the molecule.

Dose Response and Food Quality Protection Act (FQPA) Assessments:  The
tembotrione risk assessment team recommends that the 10X FQPA safety
factor (SF) for the protection of infants and children be reduced to 1X
since there is a complete toxicity database for tembotrione and exposure
data are complete or are estimated based on data that reasonably account
for potential exposures.  The recommendation is based on the following: 
1) The established acute RfD (aRfD, 0.0008 mg/kg) and chronic RfD (cRfD,
0.0004 mg/kg/day) are protective of any developmental and neurological
effects observed at doses of 10 mg/kg/day in the developmental toxicity
and 0.8 mg/kg/day in the developmental-neurotoxicity study (DNT),
respectively.  2) There are no residual uncertainties concerning pre-
and postnatal toxicity.  3) There are no residual uncertainties with
respect to exposure data.  4) The dietary food exposure assessment
utilizes proposed tolerance-level residues and 100% crop treated (CT)
information for all proposed commodities.  By using this screening-level
assessment, the acute and chronic exposures/risks will not be
underestimated.  5) The dietary drinking water assessment utilizes
values generated by model and associated modeling parameters which are
designed to provide conservative, health-protective, high-end estimates
of water concentrations.  6) There are no registered or proposed uses of
tembotrione which would result in residential exposure.  A 100-fold
uncertainty factor (UF) (10x for interspecies extrapolation and 10x for
intraspecies variation) was incorporated into the acute and chronic RfD.
 An additional 10X UF was applied to the aRfD due to lowest-observed
adverse-effect level (LOAEL) to no-observed adverse-effect level (NOAEL)
extrapolation in the DNT study.  The acute population-adjusted dose
(aPAD) and the chronic population adjusted dose (cPAD) are equal to the
acute and chronic RfDs, respectively, divided by the FQPA SF (1X). 
Therefore, the acute and chronic PADs are equal to the acute and chronic
RfDs.  Tembotrione is classified as “suggestive evidence of
carcinogenic potential” by all relevant routes of exposure based on
adequate studies in two animal species; therefore, cancer risk
assessments are not required.  In estimating margins of exposure (MOEs),
the level of concern (LOC) is for MOEs <1000 for the dermal and
inhalation risk assessments.  A 15% dermal-absorption factor and a 100%
inhalation-absorption factor were used for use in the route-to-route
extrapolation.  The toxicological endpoints relevant to this assessment
are summarized below.

acute dietary (general population, including infants and children)	NOAEL
= 0.8 mg/kg/day	acute RfD and aPAD = 0.0008 mg/kg/day

chronic dietary	NOAEL = 0.04 mg/kg/day	chronic RfD and cPAD = 0.0004
mg/kg/day

short-term dermal	oral NOAEL = 0.8 mg/kg/day	LOC for MOEs <1000
(occupational)

intermediate-term dermal	oral NOAEL = 0.8 mg/kg/day	LOC for MOEs <1000
(occupational)

short-term inhalation	oral NOAEL = 0.8 mg/kg/day	LOC for MOEs <1000
(occupational)

intermediate-term inhalation	oral NOAEL = 0.8 mg/kg/day	LOC for MOEs
<1000 (occupational)

osure analyses.  The resulting acute dietary (food + water) risk
estimates using the DEEM-FCID™ model at the 95th percentile (<77%,
aPAD for all infants (<1 year old), the most highly-exposed population
subgroup) were not of concern (<100% aPAD).  A chronic dietary
assessment assuming tolerance-level residues, DEEM™ 7.81 default
processing factors, and 100% CT was also conducted.  The highest
estimate of chronic surface water exposure (1.05 ppb) was used for
drinking water in this analysis.  The chronic dietary risk assessment
shows that for all included commodities, the chronic dietary risk
estimates are not of concern (i.e., <100% cPAD).  For the U.S.
population the exposure for food and water utilized 22% of the cPAD. 
The chronic dietary risk estimate for the highest reported exposed
population subgroup, children 3-5 years old, is 48% of the cPAD. 
Dietary cancer risk concerns due to long-term consumption of tembotrione
residues are adequately addressed by the chronic exposure analysis using
the cPAD.

Residential Exposure:  The proposed new use is on an agricultural crop
(e.g., corn); therefore, residential exposures are not expected and were
not assessed.

Aggregate Risk:  There are no uses of tembotrione that are expected to
result in residential exposures.  Therefore, the aggregate exposure
assessment takes into consideration dietary food + water exposure only. 
The acute and chronic dietary estimates represent aggregate risk.

Occupational Exposure/Risk to Mixer/Loader and Applicators:  Tembotrione
is applied by ground equipment only (aerial application is prohibited on
the label).  Based upon the proposed use pattern, HED expects the most
highly exposed occupational pesticide handlers are likely to be:

1) Mixer/loader using open-pour loading of liquids for groundboom
applications (Pesticide Handlers Exposure Database, PHED)

2) Applicators using open-cab groundboom sprayer (PHED)

HED believes most exposure durations will be short-term (1-30 days). 
However, the HED Science Advisory Council for Exposure (ExpoSAC)
maintains it is possible for commercial applicators to be exposed to
intermediate-term exposure durations (1-6 months).  In addition, the
short- and intermediate-term toxicological endpoints are the same;
therefore, the estimates of risk for short-term duration exposures are
protective of those for intermediate-term duration exposures.  Long-term
exposures are not expected; therefore, a long-term assessment was not
conducted.

No chemical-specific data were available to assess potential exposure to
pesticide handlers.  The estimates of exposure to pesticide handlers are
based upon surrogate study data available in the PHED (Ver 1.1, 1998)
Surrogate Exposure Guide (August 1998).  The proposed product label
involved in this assessment directs applicators and other handlers to
wear a long-sleeved shirt and long pants; socks, shoes and
chemical-resistant gloves.

HED has determined that there are no risks of concern associated with
the groundboom applicator scenario at baseline.  However, HED has
determined that there are risks of concern (i.e., MOEs <1000) associated
with the mixer/loader scenarios at baseline and with the use of gloves,
as directed by the label.  If an extra layer of clothing is worn (i.e.,
a double layer), then the MOE is 910; and, if a closed mixing/loading
system is utilized (i.e., engineering control), then the MOE is 1,400. 
HED has determined that the risks associated with a mixer/loader wearing
a double layer of clothing are not of concern and recommends that a
double layer of clothing (i.e., coverall) be added to the label under
the personal-protective equipment (PPE) requirements for handlers.  

Occupation Post-application Risk:  HED expects that postapplication
exposure will occur since tembotrione is applied as a foliar spray. 
There is a potential for agricultural workers to have post-application
exposure to pesticides during the course of typical agricultural
activities in corn.  Short-term exposures are expected for hand-weeding,
scouting, and irrigation activities.

Estimates of exposure and risk result in a MOE >1000 on day 0
(restricted-entry interval (REI) = 12 hours) only for hand-weeding
activities at the lowest transfer coefficient (TC; i.e., when corn is at
a low crop height and minimal foliage development), and therefore, do
not exceed HED’s LOC.  All of the other exposure activities result in
risk that is of concern, with MOEs ranging from 250 to 630 on the day of
application.  Chemical-specific dislodgeable foliar data would be needed
to further refine these estimates as well as information on specific
re-entry activities occurring postapplication.  Currently, the label
requires a 12-hour REI; however, HED recommends a 13-day REI for
irrigation, scouting and hand-weeding activities.

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

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

Review of Human Research:  This risk assessment relies in part on data
from studies in which adult human subjects were intentionally exposed to
a pesticide or other chemical.  The database listed below has been
determined to require a review of its ethical conduct.  It has received
the appropriate review.  It was concluded it does not violate current
ethical standards.

Studies reviewed for ethical conduct:  The PHED Task Force, 1995.  The
Pesticide Handlers Exposure Database, Version 1.1.  Task Force members
Health Canada, U.S. Environmental Protection Agency, and the National
Agricultural Chemicals Association, released February, 1995.

2.0	Ingredient Profile  TC \l1 "2.0	Ingredient Profile 

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

The petitioner has submitted a draft label dated 11/5/06 for the 3.5 lb
ai/gal suspension concentrate (SC) formulation (AE 0172747 Herbicide;
File Symbol 264-xxx).  Information pertaining to the proposed end-use
product is listed in Table 2.1.1.  A summary of the proposed use pattern
on corn (field, pop, and sweet) is detailed in Table 2.1.2.  The
proposed rotational crop restrictions are listed in Table 2.1.3.

Table 2.1.1.  Summary of Proposed End-Use Product.

Trade Name	

Reg. No.	ai (% of formulation)	Formulation Type	

Target Crops	

Target Pests	

Label Date

AE 0172747 Herbicide	264-xxx	34.5% (equivalent to 3.5 lb ai/gal)	SC
Field corn, silage corn, seed corn, sweet corn, and popcorn	Various
annual broadleaf and grass weeds	Draft label submitted 11/5/06

Table 2.1.2.  Summary of Proposed Directions for Use of Tembotrione (AE
0172747 Herbicide).

Application Timing	Single Application Rate (lb ai/A)	Max. Number of
Applications per Season	Re-entry Interval (days)	Retreatment Interval 

(days)	Max. Seasonal Application Rate (lb ai/A)	

PHI

(days)

Corn (Field, Silage, Seed, Sweet, and Pop)

Postemergence

Broadcast foliar spray	0.082	2	13	14	0.16	45 days for forage;

none listed for grain and stover

Use Directions and Restrictions:  Applications must be made to corn from
emergence through the V8 stage of growth; application to corn that is
more mature than growth stage V8 (i.e., more than 8 visible leaf
collars) is prohibited.  Applications are to be made in a minimum of 10
gal/A using ground equipment.  Aerial application and/or application
through any type of irrigation system are prohibited.  Use of an
external spray adjuvant is required, and the adjuvant type is dependent
on the weed spectrum.  A 45-day pregrazing interval is proposed for corn
forage.  

Table 2.1.3.  Proposed Rotational Crop restrictions Listed on AE 0172747
Herbicide Label.

General:  If a corn crop has been destroyed by hail or other means soon
after an AE 0172747 Herbicide application, field corn, sweet corn, or
popcorn may be replanted immediately after the application.  Rotational
intervals for all other crops following an AE 0172747 Herbicide
application are presented in the chart below.

120 days	10 months	18 months

Small grains	Alfalfa	Cucurbits

	Canola	Dry beans

	Cotton	Sunflower

	Peas	Sugar beets

	Potatoes	All other crops

	Snap beans

Sorghum

Soybean

Tomato

	

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

Table 2.2.  Test Compound Nomenclature for Tembotrione and its
Metabolites M6, M5, and M2.

Compound:  Tembotrione 	Chemical Structure

Proposed Common name	Tembotrione (Parent)

Company experimental name	AE 0172747

IUPAC name
2-{2-Chloro-4-mesyl-3-[(2,2,2-trifluoroethoxy)methyl]benzoyl}cyclohexane
-1,3-dione

CAS name
2-[2-Chloro-4-(methylsulfonyl)-3-[(2,2,2-trifluoroethoxy)methyl]benzoyl]
-1,3-cyclohexanedione

CAS #	335104-84-2

End-use product/EP	AE 0172747 Herbicide, EPA Reg No. 264-xxx

Compound:  AE 0456148	Chemical Structure

Common name	Metabolite M6

Company experimental name	AE 0456148

IUPAC name	None provided

CAS name	2-Chloro-4-mesyl-3-[(2,2,2-trifluroethoxy)methyl]benzoic acid

CAS #	None provided

Compound:  AE 1417268	Chemical Structure

Common name	Metabolite M5

Company experimental name	AE 1417268

IUPAC name	None provided

CAS name
2-[2-Chloro-4-(methylsulfonyl)-3-[2,2,2-trifluoroethoxy)methyl]benzoyl]-
4,6-dihydroxycyclohexan-1,3-dione

CAS #	None provided

Compound:  AE 1392936	Chemical Structure

 

Common name	Metabolite M2

Company experimental name	AE 1392936

IUPAC name	None provided

CAS name	2-Chloro-3-hydroxymethyl-4-mesylbenzoic acid

CAS #	None provided

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

Table 2.3.  Physicochemical Properties of Technical Grade Tembotrione.

Parameter	Value	Reference (MRID#)

Melting point	117 ºC	46695402

pH @ 24 (C	3.63

	Density (g/mL @ 20 (C)	1.56

	Water solubility (mg/L @ 20 °C)	0.22 at pH 4

28.3 at pH 7

29.7 at pH 9

	Solvent solubility (g/L at 20 °C)

DMSO

Methylene Chloride

Acetone

Ethyl Acetate

Toluene

Hexane

Ethanol	

>600

>600

300-600

180.2

75.7

47.6

8.2

	Vapor pressure (Torr, 20 °C)	8.25 x 10-11

	Dissociation constant (pKa)	3.2

	Octanol/water partition coefficient 

(Pow @ 23 °C )

(Pow @ 24 °C )

(Pow @ 23 °C )	

0.0430 at pH 9.0

0.0807 at pH 7.0

144.9 at pH 2.0

	UV/visible absorption spectrum (nm)	Primary: 205

Secondary: 284

Tertiary: 240

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

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

3.1.1	Database Summary  TC \l3 "3.1.1	Database Summary 

3.1.1.1	Studies available and considered (animal, human, general
literature)  TC \l4 "3.1.1.1	Studies available and considered (animal,
human, general literature) 

Acute- oral, dermal, inhalation, eye irritation, skin irritation, dermal
sensitization, neurotoxicity.

Subchronic- 21/28-day dermal toxicity in rat, oral 90-day rat, oral
90-day mouse, oral neurotoxicity rat.

Chronic- oral rat (combined chronic/carcinogenicity), oral
carcinogenicity in mice and oral dog.

Reproductive/developmental- oral developmental rat and rabbit, rat
reproduction/fertility, rat DNT.

Other- dermal-penetration study, mutagenicity studies (in vitro and in
vivo), metabolism/pharmacokinetics studies, blood coagulation study,
tyrosine levels in pregnant rabbits study and HPPD-inhibition study
parent versus metabolites.  

3.1.1.2	Mode of action, metabolism, toxicokinetic data  TC \l4 "3.1.1.2
Mode of action, metabolism, toxicokinetic data 

Tembotrione is a broad-spectrum early and mid-postemergence herbicide
that belongs to the triketone class of herbicides.  It acts by
inhibiting 4- HPPD, which leads to chlorophyll destruction by
photooxidation and causes bleaching of emerging foliar tissue.  In
mammals, HPPD is a key enzyme in the catabolism of tyrosine.  It
catalyzes the conversion of 4-hydroxyphenylpyruvate (HPP) to
homogentisate.  Inhibition of HPPD leads to a reconversion of HPP to
tyrosine and a consequent increase in blood tyrosine concentrations
(tyrosinemia).  

Rat metabolism data indicate that tembotrione is well absorbed.  More
than 96.3% of the administered dose was recovered in urine and feces in
24 hours.  Sex differences were observed in the routes of excretion. 
The primary routes of elimination were the urine in females and the
urine and feces in males.  At the low dose, males excreted up to 24.4%
and 70.4%; females up to 79.1% and 20% of the administered dose in the
urine and feces, respectively.  At the high dose, females excreted up to
63.7% and 28.5%; males up to 44.2 % and 49.1% of the dose in the urine
and feces, respectively.  The highest mean levels of radioactivity were
extracted from the liver (1.7-3.5%) and kidneys (0.14-0.26%) at the low
dose.  At the high dose, the mean levels of radioactivity were extracted
from the skin/fur (0.22-0.33%) and carcass.  The highest concentrations
of radioactivity were found in the skin followed by the liver, kidneys,
stomach (and contents) and carcass.  

Males had higher mean blood plasma maximum concentrations (Cmax) and AUC
values than females.  In both sexes, the area under 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.  

The parent molecule and 11 metabolites were identified & isolated from
urine and feces.  Metabolic profiles were qualitatively similar for both
radiolabeled forms; however, profiles for the high and low doses were
not the same and differences were noted between sexes.  Females excreted
the greatest quantity of the parent molecule in urine (44.1-59.4%). 
While low and high dose males eliminated 1.9-3.0% and 33.8%,
respectively, in the urine.  The metabolites found in the greatest
quantities were 4-hydroxy-tembotrione and 5- hydroxy-tembotrione.  Other
identified metabolites found at <5% were the 4,5-dihydroxy, benzylic
alcohol, dihydroxy-bezophenone, 4-hydroxy-benzylic alcohol, and
ketohydroxy-hexanoic acid ([cyclohexyl-UL-14C] only).  Males excreted
greater quantities of both major metabolites than females; except, at
the high dose where 4-hydroxy-tembotrione was eliminated in
approximately equal amounts in both sexes.  The primary step in the
metabolism of tembotrione is the hydroxylation (oxidative pathway) of
the cyclohexyl ring of the molecule.

3.1.1.3	Sufficiency of studies/data  TC \l4 "3.1.1.3	Sufficiency of
studies/data 

The toxicity database is complete for tembotrione and is adequate for
the conduct of human health risk and assessment of children’s
susceptibility, as required by FQPA.  All studies evaluated were deemed
acceptable and met guideline criteria with few exceptions; however,
there was enough adequate information available for each study for
toxicity characterization that this does not constitute a data gap.

3.1.2	Toxicological Effects  TC \l3 "3.1.2	Toxicological Effects 

Tembotrione has low acute toxicity via the oral, dermal and inhalation
routes of exposure (Toxicity category III or IV).  It is a dermal
sensitizer but not an eye or dermal irritant.

The eye, liver and kidney are the primary target organs of tembotrione. 
In the subchronic, chronic and reproduction rat studies, and the
subchronic dog study, corneal opacity, edema of the cornea,
neovascularization, and keratitis were seen at various doses indicating
ocular toxicity.  Males appear to be more susceptible to ocular toxicity
than females.  Also, corneal opacity was completely reversible following
subchronic and chronic exposures in rats and some neovascularizations
were reversible following subchronic exposure in rats; but these effects
were not reversible following chronic exposure.  In the subchronic and
chronic rat and mouse toxicity studies, and subchronic dog toxicity
studies, liver toxicity was indicated at various doses by increased
liver weights, gross and microscopic pathology, and increased serum
alanine aminotransferase.  In the subchronic, chronic, reproduction and
dermal rat toxicity studies kidney toxicity (microscopic pathology,
increased urinary ketone levels, decreased pH) was observed at various
doses.  In the chronic mouse toxicity study, kidney toxicity was also
evident at the low and high dose (microscopic pathology, increased
urinary ketone levels and decreased pH).

Thyroid gland toxicity was observed in the 21/28-day dermal toxicity
study in the rat and chronic oral toxicity study in the dog.  Dermal
exposure (21/28-day study) resulted in colloid alteration and
hypertrophic follicular epithelium in the thyroid gland in the rat. 
Also observed were degenerative changes in the pancreas, increased
proteinacious material in the Ratche pouch in the pituitary gland and
basophilic tubules in the kidneys.  Pigmentation of the thyroid gland
along with hematological changes and microscopic changes in the sciatic
nerve were observed in the dog.

The dog was more susceptible than rodents to hematological effects.  In
the subchronic and chronic dog studies changes indicative of anemia were
seen (decreased MCH and MCV).  Similar effects were also observed in the
mouse.

Certain changes in multiple organs seen in the subchronic, chronic,
dermal, and reproduction studies (e.g., microscopic changes in the
thyroid gland, adrenal gland, and pancreas; increased number of corpora
lutea in the ovary, and delayed preputial separation) may be due to
various mechanisms including possible liver-pituitary-thyroid
homeostatic disruption or inhibition of steroid synthesis.

Long-term dietary administration of tembotrione resulted in an increased
incidence of thyroid adenomas and squamous cell carcinomas of the cornea
in male rats.  Since the incidence of thyroid adenomas was not
statistically significant, they were considered unrelated to treatment. 
The levels of the doses tested were adequate.  No tumors were noted in
female rats or in male and female mice after long-term dietary
administration of tembotrione.  The HED CARC (April 11, 2007) classified
tembotrione as "Suggestive Evidence of Carcinogenic Potential" by the
oral route based on the occurrence of eye tumors in male rats;
therefore, the quantification of cancer risk is not required.

Tembotrione did not show evidence of mutagenicity in in vitro or in vivo
studies.

Evidence of neurotoxicity was noted in the subchronic and chronic
toxicity studies in dogs.  Uncoordinated movement, disturbance in
locomotion and microscopic changes in the sciatic nerve were observed in
the dog at the highest dose tested in the subchronic (124/111 mg/kg/day)
and chronic studies (37.8/41.6 mg/kg/day, M/F).  Neurotoxic effects were
also seen in the acute neurotoxicity and developmental neurotoxicity
studies in rats.  In the acute neurotoxicity study, decreased arousal
was observed on day 0 in male rats at the lowest dose tested 200 mg/kg. 
In females, decreased body temperature, motor and locomotor activities
are observed on day 0 at the next dose (500 mg/kg).  In the DNT study,
brain morphometric changes and decreased acoustic startle response were
observed in offspring at the lowest dose tested (0.8 mg/kg/day).  These
effects were observed at a dose lower than that which caused maternal
toxicity (16.3 mg/kg/day, corneal opacity).

There was evidence of increased susceptibility following in utero and
postnatal exposure in the developmental and 2-generation studies.  Fetal
effects were increased skeletal variations including delayed
ossification and decreased fetal body weight and increased number of
runts.  These effects were observed at the lowest dose tested (25
mg/kg/day) and at a dose lower than that which caused marginal maternal
toxicity (125 mg/kg/day, decreased body-weight gains and food
consumption).  In the rabbit developmental study, decreased growth
and/or delayed development of the skeleton and increased incidences of
skeletal variations and anomalies in fetuses occurred at the a dose (10
mg/kg/day) lower than that which caused maternal toxicity (100
mg/kg/day, few or no feces, late abortion, decreased body weight and
food consumption).  In the 2-generation reproduction study in rats,
parental effects occur at the lowest dose tested (1.4/1.6 mg/kg/day,
M/F) and include corneal opacity, acute inflammation and
neovascularization of the cornea.  Offspring effects occurred at the
same dose and included similar eye effects as well as increased
incidences of minimal extramedullary hematopoeisis in the spleen,
delayed preputial separation, and decreased absolute brain weight. 
There were no effects on reproduction.

Rat metabolism data indicated that tembotrione is well absorbed. 
Greater than 96 % of the administered dose was recovered in urine and
feces in 24 hours.  The primary routes of elimination were the urine in
females (63.7-79.1%) and the feces in males (49.1-70.4%).  The highest
mean levels of radioactivity were extracted from the liver (1.7-3.5%)
and kidneys (0.14-0.26%) at the low dose.  At the high dose, the mean
levels of radioactivity were extracted from the skin/fur (0.22-0.33%)
and carcass.  No other tissue exceeded 0.06% of the administered dose. 
Males had higher mean blood plasma maximum concentrations (Cmax) and AUC
values than females.  At 1000 mg/kg saturation of the initial
elimination/ biotransformation processes occurred resulting in a slower
initial elimination phase in both sexes.  Metabolic profiles were
qualitatively similar for both radiolabeled forms; however, profiles for
the high and low doses were not the same and differences were noted
between sexes.  The major urinary and fecal metabolites were
4-hydroxy-tembotrione and 5- hydroxy-tembotrione.  The primary step in
the metabolism of tembotrione is the hydroxylation (oxidative pathway)
of the cyclohexyl ring of the molecule.

3.1.3	Dose-Response Assessment  TC \l3 "3.1.3	Dose response Assessment 

A summary of the toxicological endpoints and doses chosen for the
relevant exposure scenarios for dietary and occupational human health
risk assessments is provided in Tables 3.5.10a and 3.5.10b.  The
conventional interspecies extrapolation (10X) and intraspecies variation
(10X) UFs were applied for all exposure scenarios.  An additional 10X UF
was applied for LOAEL to NOAEL extrapolation in the DNT study.  The FQPA
SF for increased susceptibility was reduced to 1x for all exposures
scenarios.

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)  TC \l2 "3.2
Absorption, Distribution, Metabolism, Excretion (ADME) 

The absorption and metabolism of tembotrione was investigated with the
molecule labeled on either the phenyl or the cyclohexyl group at 5 mg/kg
or 1000 mg/kg.  Tembotrione was rapidly absorbed, extensively
metabolized, and excreted.  Total excretion of tembotrione was greater
than 96% by 24 hours regardless of dose level or position of radiolabel.
 Sex differences were observed in the routes of excretion.  The primary
routes of elimination were the urine in females and the urine and feces
in males.  Males excreted up to 24.4% and 70.4% and females up to 79.1%
and 20% of the administered dose in the urine and feces, respectively,
at the low dose.  Females excreted up to 63.7% and 28.5% and males up to
44.2 % and 49.1% of the dose in the urine and feces, respectively, at
the high dose.  The highest mean levels of radioactivity were extracted
from the liver (1.7-3.5%) and kidneys (0.14-0.26%) at the low dose.  At
the high dose, the mean levels of radioactivity were extracted from the
skin/fur (0.22-0.33%) and carcass.  The highest concentrations of
radioactivity were found in the skin followed by the liver, kidneys,
stomach (and contents) and carcass.  There was no evidence of
bioaccumulation.  

Males had higher mean blood, plasma maximum concentrations (Cmax) and
AUC values than females.  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.  

The parent molecule and 11 metabolites were identified and isolated. 
Metabolic profiles were qualitatively similar for both radiolabeled
forms; however, profiles for the high and low doses were not the same
and differences were noted between sexes.  Females excreted the greatest
quantity of the parent molecule in urine (44.1-59.4%).  While low and
high dose males eliminated 1.9-3.0% and 33.8%, respectively, in the
urine.  The metabolites found in the greatest quantities were 4- and 5-
hydroxy-tembotrione.  Other identified metabolites found at <5% were the
4,5-dihydroxy-tembotrione, benzylic alcohol, dihydroxy-benzophenone,
4-hydroxy-benzylic alcohol, and ketohydroxy-hexanoic acid
([cyclohexyl-UL-14C] only).  Males excreted greater quantities of 4- and
5- hydroxy-tembotrione than females; except, at the high dose where
4-hydroxy-tembotrione was eliminated in approximately equal amounts in
both sexes.  The primary step in the metabolism of tembotrione is the
hydroxylation (oxidative pathway) of the cyclohexyl ring of the molecule
(figure 1).  

FIGURE 1. 	Proposed Metabolic Profile of Tembotrione in Rats

3.3	FQPA Considerations  TC \l2 "3.3	FQPA Considerations 

3.3.1	Adequacy of the Toxicity Database  TC \l3 "3.3.1	Adequacy of the
Toxicity Database 

The toxicology database for tembotrione is adequate.  The following
acceptable studies are available:

Developmental toxicity in rats and rabbits (2)

Two-generation reproduction study in rats (1)

Developmental Neurotoxicity Study (1)

Acute and Subchronic Neurotoxicity Studies (2)

Executive summaries for each of these studies are provided in Appendix
A.3.

3.3.2	Evidence of Neurotoxicity  TC \l3 "3.3.2	Evidence of
Neurotoxicity 

Evidence of neurotoxicity was noted in the subchronic and chronic
toxicity studies in the dog and the acute and developmental
neurotoxicity studies in the rat.  Uncoordinated movement, disturbance
in locomotion and microscopic changes in the sciatic nerve were observed
in the dog at the highest dose tested in the subchronic (124/111
mg/kg/day) and chronic studies (37.8/41.6 mg/kg/day, M/F).  In the acute
neurotoxicity study, decreased arousal was observed on day 0 in male
rats at the lowest dose tested 200 mg/kg.  In females, decreased body
temperature, motor and locomotor activities were observed on day 0 at
the next dose (500 mg/kg).  In the DNT study, brain morphometric changes
and decreased acoustic startle response are observed in offspring at the
lowest dose tested (0.8 mg/kg/day).  

3.3.3	Additional Information from Literature Sources   TC \l3 "3.3.3
Additional Information from Literature Sources 

The literature search did not reveal relevant information.

3.3.4	Pre-and/or Postnatal Toxicity  TC \l3 "3.3.4	Pre-and/or Postnatal
Toxicity 

3.3.4.1	Determination of Susceptibility  TC \l4 "3.3.4.1	Determination
of Susceptibility 

There is evidence of increased susceptibility in rabbit and rat fetuses
to in utero exposure to tembotrione.  In a developmental toxicity study
in rabbits, decreased growth and/or delayed development of the skeleton
and increased incidences of skeletal variations and anomalies in fetuses
occurred at  a dose (10 mg/kg/day) lower than that which caused maternal
toxicity (100 mg/kg/day, few or no feces, late abortion, decreased body
weight and food consumption).  In a rat developmental toxicity study,
increased skeletal variations including delayed ossifications and
decreased growth and developmental effects as indicated by decreased
fetal body weights and an increased number of runts occurred in fetuses
at a dose (25 mg/kg/day) lower than the dose (125 mg/kg/day) that caused
marginal maternal toxicity (decreased body-weight gains and food
consumption).  In addition, decreased post-weaning body weight (males),
decreased acoustic startle response and brain morphometric changes were
seen in rat fetuses at a dose (0.8 mg/kg/day, LDT) lower than the dose
at which there was maternal toxicity (16.3 mg/kg/day, cornel opacity
during lactation) in the rat neurotoxicity DNT.  These studies indicate
evidence of increased susceptibility however, the concern for the
increased susceptibility seen in rat and rabbit developmental toxicity
is low because a well characterized NOAEL protecting fetuses has been
established.  In addition, the developmental NOAELs for these studies
are approximately 12 to 30 fold higher than the LOAEL used for the acute
RfD.  The effects seen in the developmental neurotoxicity study at the
LOAEL of 0.8 mg/kg bw/day is considered as low toxicity since there was
no clear dose response observed for morphometric changes in the
offspring at termination.  In fact, the brain morphometric measurements
were lower at the dose compared to mid and the high dose.  The decreased
accoustic startle response observed in adult rats was statistically
significant at the mid and high dose but not at the low dose.  In
addition, at the low dose there were large variations in the measurement
of the acoustic startle response.  Therefore, the FQPA factor of 10X
applied for use of LOAEL to NOAEL is considered as protective of any
residual susceptibility.  In addition, the NOAEL (0.04 mg/kg/day)
selected for the cRfD is lower (20X) than the dose at which
developmental and neurological effects were observed. 

3.3.4.2	Degree of Concern Analysis and Residual Uncertainties  TC \l4
"3.3.4.2	Degree of Concern Analysis and Residual Uncertainties  for Pre-
and/or Postnatal Susceptibility

There is evidence of increased susceptibility following in utero
exposure in the rabbit (oral) and rat (oral) developmental toxicity
studies occurring at 10 mg/kg/day and 25 mg/kg/day, respectively; and in
the rat DNT study occurring at 0.8 mg/kg/day.  However, the effects are
well characterized and an additional 10X UFL for extrapolation of the
LOAEL to NOAEL was applied, which will be protective of developmental
effects.  Therefore, there are low concerns or residual uncertainties
for pre- and post-natal toxicity.  The NOAEL (0.04 mg/kg/day) selected
for the cRfD is lower (20X) than the dose at which developmental and
neurological effects were observed. 

3.3.5	Recommendation for a Developmental Neurotoxicity Study  TC \l3
"3.3.5	Recommendation for a Developmental Neurotoxicity Study 

A DNT study was provided as part of the toxicity data package.  

3.4	FQPA SF for Infants and Children  TC \l2 "3.4	Safety Factor for
Infants and Children 

The tembotrione risk assessment team has recommended that the 10X FQPA
SF be reduced to 1X for all exposure scenarios because there is a
complete toxicity database for tembotrione and exposure data are
complete or are estimated based on data that reasonably account for
potential exposures.  There was evidence of increased susceptibility of
fetuses and offspring to developmental and neurological effects in the
developmental toxicity and DNT studies (rabbits, rats), respectively. 
However, the established aRfD (0.0008 mg/kg) and cRfD (0.0004 mg/kg/day)
are protective of any developmental and neurological effects observed at
doses as low as 0.8 mg/kg/day in these studies.  There are low concerns
or residual uncertainties concerning pre- and postnatal toxicity.  There
are also no additional residual uncertainties with respect to exposure
data.  The dietary food exposure assessment utilizes proposed tolerance
level or higher residues and 100% CT information for all commodities. 
By using these screening-level assessments, acute and chronic
exposures/risks will not be underestimated.  The dietary drinking water
assessment utilizes values generated by model and associated modeling
parameters which are designed to provide conservative, health
protective, high-end estimates of water concentrations.  There is no
potential for residential exposure.

3.5	Hazard Identification and Toxicity Endpoint Selection  TC \l2 "3.5
Hazard Identification and Toxicity Endpoint Selection 

3.5.1	aRfD - General Population (including females age 13-49)  TC \l3
"3.5.1	Acute Reference Dose (aRfD) - General Population (including
females age 13-49 

Study Selected:  Developmental Neurotoxicity/Rat

MRID No.:  46695725

Executive Summary:  See Appendix A, Guideline [§ 870.3700]

Dose and Endpoint for Establishing aRfD:  An offspring NOAEL was not
established, based on decreased post-weaning body weight (males),
decreased acoustic startle response on post-natal day (PND) 60 (males),
and brain morphometric changes on PND 75 (males and females) at 0.8
mg/kg/day (LOAEL).

Comments on Study/Endpoint/UFs:  The endpoint chosen, decreased acoustic
startle response and brain morphometric changes were presumed to occur
following a single exposure.  An UF of 100 was applied to account for
interspecies extrapolation (10X) and intraspecies variation (10X) and an
additional UF of 10X was applied to account for LOAEL to NOAEL
extrapolation.  

aRfD = 0.8 mg/kg/day (LOAEL) = 0.0008 mg/kg

                 			1000 (UF)

3.5.2	cRfD  TC \l3 "3.5.2	Chronic Reference Dose (cRfD) 

Study Selected:  Chronic Toxicity/Carcinogenicity (Feeding)/Rat

MRID No.: 46695708

Executive Summary:  See Appendix A, Guideline [§ 870.4300]

Dose and Endpoint for Establishing RfD:  The NOAEL of 0.04 mg/kg/day was
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 levels 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
observed in the male at 0.79 mg/kg/day (LOAEL).

UF(s):  An UF of 100 was applied to account for interspecies
extrapolation (10X) and intraspecies variation (10X).

Comments about Study/Endpoint/UF:  This study provided the lowest NOAEL
in the database (most sensitive endpoint) and will also provide the most
protective limits for human effects.

cRfD = 0.04 mg/kg/day (NOAEL) = 0.0004 mg/kg/day

    100 (UF)

3.5.3	Incidental Oral Exposure (Short- and Intermediate-Term)   TC \l3
"3.5.3	Incidental Oral Exposure (Short- and Intermediate-Term) 

Study Selected:  Developmental Neurotoxicity/ Rat	 

MRID No.:  46695725

Executive Summary:  See Appendix A, Guideline [§ 870.3700]

Dose and Endpoint for Establishing aRfD:  An offspring NOAEL was not
established, 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) at 0.8 mg/kg/day
(LOAEL).

Comments on Study/Endpoint/UFs:  The endpoint chosen, because it was
appropriate for the duration of exposure and the population of concern. 
An UF of 100 was applied to account for inter species extrapolation
(10X) and intraspecies variation (10X) and an additional UF of 10X was
applied to account for LOAEL to NOAEL extrapolation.

3.5.4	Dermal Absorption  TC \l3 "3.5.4	Dermal Absorption 

Study Selected:  Dermal Penetration Study/Rat

MRID No.:  46695730

Executive Summary:  See Appendix A, Guideline [§ 870.7600]

Based on the dermal penetration study in rats, a dermal-absorption
factor of 15% is appropriate for human risk assessment.

3.5.5	Dermal Exposure (Short-, Intermediate- and Long-Term)   TC \l3
"3.5.5	Dermal Exposure (Short-, Intermediate- and Long-Term) 

Short- and Intermediate-term Dermal Exposure

Study Selected:  Developmental Neurotoxicity/Rat 

MRID No.:  46695725

Executive Summary:  See Appendix A, Guideline [§ 870.3700]

Dose and Endpoint for Establishing aRfD:  An offspring NOAEL was not
established, 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) at 0.8 mg/kg/day
(LOAEL).

Comments on Study/Endpoint/UFs:  Since there is a developmental concern,
the DNT was selected instead of a dermal toxicity study for this
endpoint.  Additionally, it was appropriate for the duration of
exposure.  An UF of 100 was applied to account for interspecies
extrapolation (10X) and intraspecies variation.  The LOC for the MOE is
<1000.  The dermal-absorption factor is 15%, based on a dermal
penetration study in rats.

Long-Term Dermal Exposure

Study Selected:  Chronic Toxicity/Carcinogenicity (Feeding)/Rat

MRID No.:  46695708

Executive Summary:  See Appendix A, Guideline [§ 870. 4300]

Dose and Endpoint for Establishing RfD:  The NOAEL of 0.04 mg/kg/day was
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 levels 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
observed in the male at 0.79 mg/kg/day (LOAEL).

UF(s):  An UF of 100 was applied to account for interspecies
extrapolation (10X) and intraspecies variation (10X).

Comments about Study/Endpoint/UF:  This study provided the lowest NOAEL
in the database (most sensitive endpoint) and will also provide the most
protective limits for human effects.  The LOC for the MOE is <100.  The
dermal-absorption factor is 15%, based on a dermal penetration study in
rats.

3.5.6	Inhalation Exposure (Short-, Intermediate- and Long-Term)   TC \l3
"3.5.6	Inhalation Exposure (Short-, Intermediate- and Long-Term) 

Short- and Intermediate-Term Inhalation Exposure

Study Selected:  Developmental Neurotoxicity/Rat

MRID No.:  46695725

Executive Summary:  See Appendix A, Guideline [§ 870.3700]

Dose and Endpoint for Establishing aRfD:  An offspring NOAEL was not
established, 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) at 0.8 mg/kg/day
(LOAEL).

Comments on Study/Endpoint/UFs:  Since there is a developmental concern
and an inhalation toxicity study is not available, the DNT was selected
for this endpoint.  Additionally, it was appropriate for the duration of
exposure.  An UF of 100 was applied to account for interspecies
extrapolation (10X) and intraspecies variation (10X).  The LOC for the
MOE is <1000.  HED assumes equivalent toxicity via the oral and
inhalation routes.

Long-Term Inhalation Exposure

Study Selected:  Chronic Toxicity/Carcinogenicity (Feeding)/Rat

MRID No.:  46695708

Executive Summary:  See Appendix A, Guideline [§ 870.4300]

Dose and Endpoint for Establishing RfD:  The NOAEL of 0.04 mg/kg/day was
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 levels 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
observed in the male at 0.79 mg/kg/day (LOAEL).

UF(s):  An UF of 100 was applied to account for interspecies
extrapolation (10X) and intraspecies variation (10X).

Comments about Study/Endpoint/UF:  This study provided the lowest NOAEL
in the database (most sensitive endpoint) and will also provide the most
protective limits for human effects.  The LOC for the MOE is <100.  HED
assumes equivalent toxicity via the oral and inhalation routes.

3.5.7	Levels of Concern for Margins of Exposure

  TC \l3 "3.5.7	Level of Concern for Margin of Exposure 

Table 3.5.7.  Summary of Levels of Concern for Risk Assessment.

Route	Short-Term

(1-30 Days)	Intermediate-Term

(1-6 Months)	Long-Term

(>6 Months)

Occupational (Worker) Exposure

Dermal	1000a	1000	100b

Inhalation	1000	1000	100

Residential Exposure

Dermal	1000	1000	100

Inhalation	1000	1000	100

Incidental Oral	1000	1000	100

a LOC = Interspecies extrapolation (10X), intraspecies variation (10X)
and LOAEL to NOAEL extrapolation (10X) Ufs.

b LOC = Interspecies extrapolation (10X) and intraspecies variation
(10X) UFs.

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

As per FQPA, 1996, when there are potential residential exposures to a
pesticide, aggregate risk assessment must consider exposures from three
major sources: oral, dermal and inhalation exposures.  However, an
aggregated exposure risk assessment incorporating residential exposures
is not required since there are no residential uses for tembotrione at
this time.  

For oral exposure dietary exposure and water were aggregated.  For
occupational exposure dermal and inhalation exposure were combined since
the effects of concern are the same and identified from the same study.

3.5.9	Classification of Carcinogenic Potential  TC \l3 "3.5.9
Classification of Carcinogenic Potential 

On April 11, 2007, in accordance with the EPA Guidelines for Carcinogen
Risk Assessment (March, 2005), the HED CARC classified tembotrione as
“Suggestive Evidence of Carcinogenic Potential” based on the
occurrence of squamous cell carcinoma in male rats.  Therefore,
quantification of carcinogenic potential is not required.  The RfD is
assumed to be protective of cancer effects.

3.5.10	Summary of Toxicological Doses and Endpoints for Tembotrione for
Use in Human-Health Risk Assessments  TC \l3 "3.5.10	Summary of
Toxicological Doses and Endpoints for tembotrione for Use in Human Risk
Assessments 

Table 3.5.10a.  Summary of Toxicological Doses and Endpoints for
tembotrione for Use in Dietary and Non-Occupational Human Health Risk
Assessments.

Exposure/

Scenario	Point of Departure	Uncertainty/FQPA SF s	RfD, PAD, LOC for Risk
Assessment	Study and Toxicological Effects

Acute Dietary (General Population, including Infants and Children)
NOAEL<0.8 mg/kg

	UFA = 10X

UFH = 10X

FQPA SF = 10X

(includes UFL = 10X)	Acute RfD =

0.0008 mg/kg

aPAD = 0.0008 mg/kg	

Developmental neurotoxicity

Offspring NOAEL was not established.

Offspring LOAEL = 0.8 mg/kg/day based on decreased acoustic startle
response on PND 60 (males), and brain morphometric changes on PND 75
(males and females).

Chronic Dietary (All Populations)	

NOAEL=0.04 mg/kg/day

 	

UFA = 10X

UFH = 10X

FQPA SF = 10X

	

Chronic RfD = 0.0004 mg/kg/day

cPAD = 0.0004 mg/kg/day

	

Chronic/Carcinogenicity

LOAEL = 0.79 mg/kg/day 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 levels 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.

Incidental Oral Short- and Intermediate-Term (1-30 days and 1-6 months)	

NOAEL<0.8 mg/kg

	UFA = 10X

UFH = 10X

FQPA SF = 10X

(includes UFL = 10X)	

Residential LOC for MOE = 1000	Developmental neurotoxicity

Offspring NOAEL was not established.

Offspring LOAEL = 0.8 mg/kg/day based on decreased acoustic startle
response on PND 60 (males), and brain morphometric changes on PND 75
(males and females).

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

NOAEL<0.8 mg/kg

	UFA = 10X

UFH = 10X

FQPA SF = 10X (includes UFL = 10X)

Dermal-absorption rate = 15%	

Residential and Occupational LOC for MOE = 1000	

Developmental neurotoxicity

Offspring NOAEL was not established.

Offspring LOAEL = 0.8 mg/kg/day based on decreased acoustic startle
response on PND 60 (males), and brain morphometric changes on PND 75
(males and females).

Dermal 

Long-Term

(> 6 months)	

NOAEL=0.04 mg/kg/day

 	

UFA = 10X

UFH = 10X

FQPA SF = 1X

Dermal-absorption rate = 15%

	

Residential and Occupational LOC for MOE = 100	

Chronic/Carcinogenicity

LOAEL = 0.79 mg/kg/day 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 levels 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.

Inhalation Short- and Intermediate-Term (1-30 days and 1-6 months)
NOAEL<0.8 mg/kg

	UFA = 10X

UFH = 10X

FQPA SF = 10X

(includes UFL = 10X)

Inhalation-absorption rate = 100%	

Residential and Occupational LOC for MOE = 1000	

Developmental neurotoxicity

Offspring NOAEL was not established.

Offspring LOAEL = 0.8 mg/kg/day based on decreased acoustic startle
response on PND 60 (males), and brain morphometric changes on PND 75
(males and females).

Inhalation 

Long-Term

(> 6 months)	

NOAEL=0.04 mg/kg/day

 	

UFA = 10X

UFH = 10X

FQPA SF = 1X

Inhalation-absorption rate=100%

	

Residential and Occupational LOC for MOE = 100	

Chronic/Carcinogenicity

LOAEL = 0.79 mg/kg/day 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 levels 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.

Cancer (oral, dermal, inhalation)	Classification:  “Suggestive
Evidence of Carcinogenic Potential” based on the observance of
squamous cell carcinomas in a rat carcinogenicity study.  Quantification
of cancer risk is not required.

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



Table 3.5.10b.  Summary of Toxicological Doses and Endpoints for
tembotrione for Use in Occupational Human Health Risk Assessments.

Exposure/

Scenario	Point of Departure	UFs	LOC for Risk Assessment	Study and
Toxicological Effects

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

NOAEL<0.8 mg/kg

	UFA = 10X

UFH = 10X

FQPA SF = 1X

(includes UFL = 10X)

Dermal-absorption rate = 15%	Occupational LOC for MOE = 1000	

Developmental neurotoxicity

Offspring LOAEL = 0.8 mg/kg/day based on decreased acoustic startle
response on PND 60 (males), and brain morphometric changes on PND 75
(males and females).

Inhalation Short- and Intermediate-Term (1-30 days and 1-6 months)	

NOAEL<0.8 mg/kg

	UFA = 10X

UFH = 10X

FQPA SF = 1X

(includes UFL = 10X)

Dermal- absorption rate = 15%	Occupational LOC for MOE = 1000	

Developmental neurotoxicity

Offspring LOAEL = 0.8 mg/kg/day based on decreased acoustic startle
response on PND 60 (males), and brain morphometric changes on PND 75
(males and females).

Cancer (oral, dermal, inhalation)	Classification:  “Suggestive
Evidence of Carcinogenic Potential” based on the observance of
squamous cell carcinomas in a rat carcinogenicity study.  Quantification
of cancer risk is not required.

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and  used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no-observed adverse-effect level. 
LOAEL = lowest-observed adverse-effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (interspecies).  UFH =
potential variation in sensitivity among members of the human population
(intraspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  MOE =
margin of exposure.  LOC = level of concern.  N/A = not applicable.

3.6	Endocrine disruption  TC \l2 "3.6	Endocrine disruption 

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

When additional appropriate screening and/or testing protocols being
considered under the Agency’s EDSP have been developed, tembotrione
may be subjected to further screening and/or testing to better
characterize effects related to endocrine disruption.

Public Health and Pesticide Epidemiology Data  TC \l1 "4.0	Public Health
and Pesticide Epidemiology Data 

No public health/epidemiology data were used in developing this risk
assessment.  Since tembotrione is a new chemical, data are not
available.  

5.0	Dietary Exposure/Risk Characterization  TC \l1 "5.0	Dietary
Exposure/Risk Characterization 

The following references apply to this section: 

Residue Chemistry Summary - D325349, G. Kramer, 18-JUL-2007

Dietary Exposure - D335831, G. Kramer, 18-JUL -2007

Estimated Drinking Water Concentrations & Environmental Degradation -
D335247, W. Eckel, 01-JAN-2007

5.1	Pesticide Metabolism and Environmental Degradation  TC \l2 "5.1 
Pesticide Metabolism and Environmental Degradation 

5.1.1	Metabolism in Primary Crops  TC \l3 "5.1.1	Metabolism in Primary
Crops 

The submitted metabolism data for corn, using test substances
radiolabeled in the phenyl and cyclohexyl rings, are adequate to
elucidate the nature of the residue in the subject crop.  Tembotrione is
metabolized in corn by hydroxylation of the cyclohexyl moiety to form
the monohydroxy (M10) and dihydroxy (M5) metabolites, followed by
cleavage to the benzoic acid derivative M6 (figure 2).  The formation of
M6 directly from the parent herbicide could not be ruled out.  The
metabolite M2 is formed by the subsequent cleavage of the
trifluoroethoxy ether bond of M6.

5.1.2	Metabolism in Rotational Crops  TC \l3 "5.1.2	Metabolism in
Rotational Crops 

The metabolic profile of tembotrione in confined rotational crops
involves cleavage of the complete cyclohexyl moiety from the parent
compound leaving the benzoic acid moiety of the molecule, M6, and to a
lesser extent subsequent cleavage of the ether bond to form M2.  The two
residue components identified in the study, M6 and M2, were also
identified in the primary crop (corn) metabolism study.  The metabolism
of tembotrione in rotational crops appears to be consistent with the
pathway observed in the corn metabolism study.

5.1.3	Metabolism in Livestock  TC \l3 "5.1.3	Metabolism in Livestock 

The submitted cow and poultry metabolism data, using the parent compound
radiolabeled in the phenyl and cyclohexyl rings, and the cow metabolism
data using cyclohexyl-labeled M5 are adequate to satisfy data
requirements.  The livestock metabolism studies indicate that
tembotrione and its M5 metabolite are not extensively metabolized.  Only
the parent was identified and confirmed in cow and poultry tissues,
milk, and eggs; and only metabolite M5 was identified in the
supplementary study.  

FIGURE 2. 	Proposed Metabolic Profile of Tembotrione in Corn

Metabolites P2, P5 and P10 are presented in the text as M2, M5 and M10;
AE045148, as M6.

5.1.4	Analytical Methodology  TC \l3 "5.1.4	Analytical Methodology 

The petitioner has submitted several liquid chromatography/mass
spectroscopy (LC/MS/MS) residue analytical methods for the determination
of residues of the parent and its metabolites in/on corn and livestock
commodities.  Method AE/03/01 determines residues of tembotrione and its
metabolites M6, M5, and M2 in/on corn commodities.  Method 00967
determines residues of tembotrione and its metabolite M5 in meat, milk,
and eggs.  Method AE-003-A04-02 determines residues of tembotrione per
se in beef tissues and milk.  Method AE-004-A04-02 determines residues
of tembotrione per se in poultry tissues (skin, muscle, and liver) and
eggs (white and yolk).  The validated limit of quantitation (LOQ)
reported in the method submission is 0.010 ppm for all matrices.  These
methods were used as the data-collection methods in the analysis of
samples for residues of concern from the various studies associated with
the current petition.  Each method has been adequately validated by the
petitioner as well as by independent laboratories.  Methods AE/03/01 and
00967 were also adequately radiovalidated using weathered samples
obtained from metabolism studies.

HED has determined that Methods AE/03/01 and 00967 may be suitable
enforcement methods for corn and livestock commodities, respectively,
provided the methods pass successful PMVs by Agency chemists at ACL/BEAD
and the petitioner addresses the following issues:  The methods should
be revised to include a calculation for the conversion of residues of
the metabolite(s) to parent equivalents for quantitation.  A separate
confirmatory method for Method AE/03/01 will not be required provided
that two ion transitions are monitored during MS/MS analysis for each
analyte.  Currently, Method No. 00967 reflects measurement of a second
LC/MS/MS ion transition for each analyte.  The petitioner has indicated
that Method AE/03/01 will be superseded by Revision AE/03/01-01, in
which a second ion transition is to be monitored.

5.1.5	Environmental Degradation TC \l3 "5.1.5	Environmental Degradation 

Tembotrione is not expected to be persistent in the environment,
degrading primarily through aerobic biodegradation and photolysis.  The
primary metabolic profile of tembotrione in the environment involves
cleavage of the complete cyclohexyl moiety from the parent compound
leaving the benzoic acid moiety of the molecule, M6, and to a lesser
extent subsequent cleavage of the ether bond to form M2.  Other
metabolites observed include AE 0968400, AE 1124336, glutaric acid, and
AE 0941989 (see Appendix B:  Metabolism Assessment, Table B.3).

5.1.6	Comparative Metabolic Profile TC \l3 "5.1.6	Comparative Metabolic
Profile 

The primary route of metabolism in rats and a major route in corn was
found to be hydroxylation (oxidative pathway) of the cyclohexyl ring of
the molecule.  The 4 and 6 positions were hydroxylated in corn while the
5 and 6 positions were hydroxylated in rats.  The primary route of
metabolism in corn, rotational crops, and the environment involves
cleavage of the complete cyclohexyl moiety from the parent compound
leaving the benzoic acid moiety of the molecule, M6, and to a lesser
extent subsequent cleavage of the ether bond to form M2.  Metabolism of
tembotrione was not observed in the livestock studies.

5.1.7	Toxicity Profile of Major Metabolites and Degradates TC \l3
"5.1.7	Toxicity Profile of Major Metabolites and Degradates 

The following toxicity data were submitted for metabolites M6, M2 and
M5.

M6 has low acute toxicity via the oral and dermal routes of exposure
(Toxicity Category III).  It is an eye irritant (Toxicity Category III)
but not a dermal irritant (Toxicity Category IV).

In a subchronic oral toxicity rat study, M6 caused an increase in the
incidence of hematopoiesis of the spleen at the high dose (1436.3
mg/kg/day) in females.  Effects were not observed in males up to the
highest dose tested (1203.8 mg/kg/day).  There is no evidence of
mutagenicity in in vitro studies.  

M2 has low acute toxicity via the oral route of exposure (Toxicity
Category III).  Additional acute toxicity studies were not provided. 
There is no evidence of mutagenicity in in vitro studies.

M5 has low acute toxicity via the oral route of exposure (Toxicity
Category III).  Additional acute toxicity studies were not provided.

In a subchronic toxicity study in the rat, M5 caused pancreatic toxicity
(acinar degeneration/ apoptosis) in both sexes, hepatotoxicity (increase
weight, enlargement with prominent lobulation, hypertrophy) in males at
586 mg/kg/day (HDT) and increase serum triglycerides and eye lesions
(white area in eye, corneal opacity, neovascularization, edema of the
cornea, keratitis) in females at 718 mg/kg/day (HDT).  Also, there was
one mortality due to a hemorrhagic syndrome in a male rat.  

M5 is positive for the gene mutation assay in mouse lymphoma cells;
other assays (gene mutation assay in bacteria and chromosome aberrations
assay in human lymphocytes) are negative.  Since additional mutagenic
studies were not available, the mutagenic potential of the metabolite M5
is inconclusive.

In a special single dose oral study in rats, tembotrione and M5 caused a
20- and 5-fold increase, respectively, in plasma tyrosine levels at 10
mg/kg in male rats.  M2 and M6 did not cause elevated tyrosine levels in
the plasma.  Cleavage of the phenyl and cyclohexyl rings appears to
eliminate the ability to inhibit HPPD.

5.1.8	Pesticide Metabolites and Degradates of Concern TC \l3 "5.1.8
Pesticide Metabolites and Degradates of Concern 

Table 5.1.8.  Summary of Metabolites and Degradates to be included in
the Risk Assessment and Tolerance Expression.

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Plants

	Primary Crop	Tembotrione + M5	Tembotrione + M5

	Rotational Crop	Tembotrione + M5	Not Applicable

Livestock

	Ruminant	Tembotrione + M5	Tembotrione + M5

	Poultry	Tembotrione + M5	Tembotrione + M5

Drinking Water

	Tembotrione	Not Applicable

Plants and Livestock:  The available toxicity data for M2, M5 and M6
(the major metabolites in plants) show that the metabolites are
considerably less toxic than the parent.  Since there is limited data
for M5 and it retains some potential to inhibit HPPD due to its
structural similarity to the parent compound, the M5 metabolite is
considered as toxic as the parent in this risk assessment.  M2 and M6
were excluded as residues of concern since they lack the potential to
inhibit HPPD and are structurally unrelated to the parent compound. 
Therefore, residues of concern in the tolerance expression and risk
assessment for plants are tembotrione and its metabolite M5.  Metabolism
of tembotrione was not observed in the livestock studies.  However, M5
was included as a residue of concern in the tolerance expression and
risk assessment for livestock to account for transfer of residues from
feed commodities.

Water:  M2, AE 0968400, and M6 are the major environmental degradates. 
M2 and M6 were excluded as residues of concern for the reasons discussed
above.  AE 0968400 is structurally similar to M6 and can thus be
excluded as a residue of concern.  Therefore, the residue of concern in
the risk assessment for drinking water is tembotrione only. 

5.1.9	Drinking Water Residue Profile TC \l3 "5.1.9	Drinking Water
Residue Profile 

Table 5.1.9.  Summary of Estimated Surface Water and Groundwater
Concentrations for Tembotrione.

	Tembotrione per se

	Surface Water Conc., ppba	Groundwater Conc., ppb b

Acute	5.84	0.0139

Chronic (non-cancer)	1.05 	0.0139

Chronic (cancer)	0.72	0.0139

a From the Tier II PRZM-EXAMS - Index Reservoir model.  Input parameters
are based on 0.082 lbs a.i./acre per application with a 14 day minimum
interval between applications and two applications per season.  The
highest peak concentration came from the Florida corn scenario; the
highest yearly average and 30-year average, from the North Dakota
scenario.

b From the SCI-GROW model assuming a maximum seasonal use rate of 0.082
lbs ai/A, a Koc of 20 mL/g, and a half-life of 10.45 days.

5.1.10	Food Residue Profile  TC \l3 "5.1.10	Food Residue Profile 

The submitted magnitude of the residue data for the RACs of field corn,
popcorn, and sweet corn are adequate.  There are adequate storage
stability data to validate the storage conditions and intervals of
samples collected from the field trials.  

An acceptable corn processing study is available.  The corn study shows
that following processing of field corn grain bearing quantifiable
residues, total residues of tembotrione and its metabolite (as parent
equivalents) concentrated slightly in meal (1.2x processing factor) but
did not concentrate in oil (0.02x), flour (0.80x), grits (1.0x), or
starch (0.02x).  A tolerance for corn meal need not be established as
the recommended RAC tolerance will cover any expected residues in corn
meal as a result of the proposed use.  A processing study on rotated
wheat was also submitted.  The wheat study shows that total residues of
tembotrione and its metabolites were below the method <LOQ of 0.010 ppm
in/on rotated wheat grain following treatment of the primary crop at 5x.
 As residues in the RAC were <0.010 ppm, data on the processed
commodities of wheat as a rotated crop are not required.

Adequate dairy cow and poultry feeding studies have been submitted;
these studies are acceptable for determining tolerance levels for
livestock commodities.  Based on the submitted data, HED has concluded
that the tolerances, expressed as tembotrione and its metabolite M5, are
required for some livestock commodities (meat byproducts).  

A summary of the recommended tolerances for the current petition are
listed in Appendix C:  Tolerance Reassessment Summary.  The petitioner
should submit a revised Section F reflecting the recommended tolerances
and commodity definitions presented in Appendix C.

The Agency’s Guidance for Setting Pesticide Tolerances Based on Field
Trial Data was utilized for determining appropriate tolerance levels for
field corn forage, field corn stover, popcorn stover sweet corn forage,
and sweet corn stover; see Appendix II for tolerance calculations.  The
Agency’s tolerance spreadsheet was not used to determine tolerance
levels for the remainder of various corn commodities since greater than
95% of the treated samples bore individual or total residues below the
LOQ.  

A tolerance for corn aspirated grain fractions is not needed because the
proposed use on field corn involves applications prior to the crop’s
reproductive stage.  Tolerances for the processed commodities of corn
are not needed because the submitted corn processing study shows that
residues do not concentrate.  Residues of tembotrione and its metabolite
are not likely to concentrate in the processed commodities of rotated
wheat grain because residues of tembotrione and its metabolites were
nonquantifiable following treatments at 5x the proposed seasonal rate. 
Tolerances for inadvertent residues of tembotrione in/on rotational
crops are not needed because the limited field rotational crop trials
show that residues were below the LOQ in/on various rotational crop
commodities.

5.1.11	International Residue Limits TC \l3 "5.1.11	International
Residue Limits 

There are no Codex, Canadian, or Mexican maximum residue limits (MRLs)
established for residues of tembotrione in crops or livestock
commodities.

5.2	Dietary Exposure and Risk TC \l2 "5.2  Dietary Exposure and Risk 

5.2.1	Acute Dietary Exposure/Risk  TC \l3 "5.2.1  Acute Dietary
Exposure/Risk 

™ 7.81 default processing factors, and 100% CT were assumed.  Also,
the distribution of estimated daily drinking water exposure still
assumes 100% CT and the maximum application rate.  The 95th percentile
is thus the appropriate LOC.

5.2.2	Chronic Dietary Exposure/Risk  TC \l3 "5.2.2  Chronic Dietary
Exposure/Risk 

A conservative chronic dietary assessment assuming tolerance-level
residues, DEEM™ 7.81 default processing factors, and 100% CT was also
conducted.  The highest estimate of chronic surface water exposure (1.05
ppb) was used for drinking water in this analysis.  The chronic dietary
risk assessment shows that for all included commodities, the chronic
(non-cancer) dietary risk estimates are below HED’s LOC (i.e., <100%
cPAD).  For the U.S. population the exposure for food and water utilized
22% of the cPAD.  The chronic dietary risk estimate for the highest
reported exposed population subgroup, children 3-5 years old, is 48% of
the cPAD.

5.2.3	Cancer Dietary Risk  TC \l3 "5.2.3  Cancer Dietary Risk 

Dietary cancer risk concerns due to long-term consumption of tembotrione
residues are adequately addressed by the chronic exposure analysis using
the cPAD.  



Table 5.2.  Summary of Dietary (Food and Drinking Water) Exposure Risk
for Tembotrione.

Population Subgroup	Acute Dietary

(95th Percentile)	Chronic Dietary

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

(mg/kg/day)	% cPAD

General U.S. Population	0.000255	32	0.000090	22

All Infants (<1 year old)	0.000618	77	0.000159	40

Children 1-2 years old	0.000445	56	0.000172	43

Children 3-5 years old	0.000444	55	0.000192	48

Children 6-12 years old	0.000335	42	0.000141	35

Youth 13-19 years old	0.000261	33	0.000104	26

Adults 20-49 years old	0.000192	24	0.000075	19

Adults 50+ years old	0.000147	18	0.000056	14

Females 13-49 years old	0.000197	25	0.000075	19

The values for the highest exposed population for each type of risk
assessment are bolded.

5.3	Anticipated Residue and Percent Crop Treated (%CT) Information TC
\l2 "5.3 Anticipated Residue and Percent Crop Treated (%CT) Information 

The acute and chronic dietary exposure analyses were based on
tolerance-level residues and the assumption of 100% CT.  Anticipated
residues and percent CT estimates were not incorporated into the
assessments.

6.0	Residential (Non-Occupational) Exposure/Risk Characterization  TC
\l1 "6.0	Residential (Non-Occupational) Exposure/Risk Characterization 

The following reference applies to this section: 

Occupational and Residential Exposure - D326301, K. Lowe, 29-Mar-2007.

As tembotrione is a new active ingredient with no registered or proposed
residential uses, a quantitative non-occupational exposure assessment
was not performed.

6.1	Other (Spray Drift, etc.) TC \l2 "6.1	Other (Spray Drift, etc.) 

Spray drift is always a potential source of exposure to residents nearby
to spraying operations.  This is particularly the case with aerial
application, but, to a lesser extent, could also be a potential source
of exposure from the ground application method employed for tembotrione.
 The Agency has been working with the Spray Drift Task Force, EPA
Regional Offices and State Lead Agencies for pesticide regulation and
other parties to develop the best spray drift management practices.  On
a chemical by chemical basis, the Agency is now requiring interim
mitigation measures for aerial applications that must be placed on
product labels/labeling.  The Agency has completed its evaluation of the
new database submitted by the Spray Drift Task Force, a membership of
U.S. pesticide registrants, and is developing a policy on how to
appropriately apply the data and the AgDRIFT® computer model to its
risk assessments for pesticides applied by air, orchard airblast and
ground hydraulic methods.  After the policy is in place, the Agency may
impose further refinements in spray drift management practices to reduce
off-target drift with specific products with significant risks
associated with drift.

7.0	Aggregate Risk Assessments and Risk Characterization  TC \l1 "7.0
Aggregate Risk Assessments and Risk Characterization 

Aggregate exposure and risk assessments were assessed by incorporating
the drinking water directly into the dietary-exposure assessment for the
following scenarios:  acute and chronic aggregate exposure (food +
drinking water).  Short-, intermediate-, and long-term aggregate-risk
assessments were not performed because there are no registered or
proposed uses of which result in residential exposures.  A cancer
aggregate-risk assessment was not performed because dietary cancer risk
concerns due to long-term consumption of tembotrione residues are
adequately addressed by the chronic exposure analysis using the cPAD.

See section 8.0 for further discussion on the effects of HPPD
inhibition.

8.0	Cumulative Risk Characterization/Assessment  TC \l1 "8.0	Cumulative
Risk Characterization/Assessment 

Tembotrione, mesotrione, pyrasulfotole, isoxaflutole and topramezone
belongs to a class of herbicides that inhibit the liver enzyme HPPD,
which is involved in the catabolism (metabolic breakdown) of tyrosine
(an amino acid derived from proteins in the diet).  Inhibition of HPPD
can result in elevated tyrosine levels in the blood, a condition called
tyrosinemia.  HPPD-inhibiting herbicides have been found to cause a
number of toxicities in laboratory animal studies including ocular,
developmental, liver and kidney effects.  Of these toxicities, it is the
ocular effect (corneal opacity) that is highly correlated with the
elevated blood tyrosine levels.  In fact, rats dosed with tyrosine alone
show ocular opacities similar to those seen with HPPD inhibitors. 
Although the other toxicities may be associated with chemically-induced
tyrosinemia, other mechanisms may also be involved. 

There are marked differences among species in the ocular toxicity
associated with inhibition of HPPD.  Ocular effects following treatment
with HPPD-inhibitor herbicides are seen in the rat, but not in the
mouse.  Monkeys also seem to be recalcitrant to the ocular toxicity
induced by HPPD inhibition.  The explanation of this species-specific
response in ocular opacity is related to the species differences in the
clearance of tyrosine.  A metabolic pathway exists to remove tyrosine
from the blood that involves a liver enzyme called tyrosine
aminotransferase (TAT).  In contrast to rats where ocular toxicity is
observed following exposure to HPPD-inhibiting herbicides, mice and
humans are unlikely to achieve the levels of plasma tyrosine necessary
to produce ocular opacities because the activity of TAT in these species
is much greater compared to rats.  Thus, humans and mice have a highly
effective metabolic process for handling excess tyrosine. 

HPPD inhibitors ( e.g., Nitisinone) are used as an effective therapeutic
agent to treat patients suffering from rare genetic diseases of tyrosine
catabolism.  Treatment starts in childhood but is often sustained
throughout patient’s lifetime.  The human experience indicates that a
therapeutic dose (1 mg/kg/day dose) of Nitisinone has an excellent
safety record in infants, children and adults and that serious adverse
health outcomes have not been observed in a population followed for
approximately a decade.  Rarely, ocular effects are seen in patients
with high plasma tyrosine levels; however, these effects are transient
and can be readily reversed upon adherence to a restricted protein diet.
 This indicates that an HPPD inhibitor in it of itself cannot easily
overwhelm the tyrosine-clearance mechanism in humans. 

Therefore, exposure to environmental residues of HPPD-inhibiting
herbicides are unlikely to result in the high blood levels of tyrosine
and ocular toxicity in humans due to an efficient metabolic process to
handle excess tyrosine.  In the future, assessments of HPPD-inhibiting
herbicides willl consider more appropriate models and cross species
extrapolation methods. 

Therefore, EPA has not conducted cumulative risk assessment with other
HPPD inhibitors (HED Doc. D 341612; dated 7/02/07). 

Therefore, a cumulative risk assessment was not performed for
tembotrione.

9.0	Occupational Exposure/Risk Pathway  TC \l1 "9.0	Occupational
Exposure/Risk Pathway 

The following reference applies to this section:

Occupational and Residential Exposure Assessment - D326301, K. Lowe.,
29-March-2007

Uses are proposed in/on field corn, sweet corn and popcorn.  Tembotrione
is applied as an early (prior to the 8-leaf stage of growth)
post-emergent herbicide.  Occupational handler and post-application
exposure may occur as a result of the proposed uses.  Application
methods, rates and use pattern are described in Table 2.1.2.  Aerial
application and/or application through any type of irrigation system are
prohibited.  Use of an external spray adjuvant is required, and the
adjuvant type is dependent on the weed spectrum.  Use sites carry a
45-day PHI for forage.  Re-treatment interval is 14 days.  The label
indicates a REI of 12-hours.  Corn (field, sweet and popcorn) may be
treated twice a season. 

HED believes most exposure durations will be short-term (1-30 days). 
However, the ExpoSAC maintains it is possible for commercial applicators
to be exposed to intermediate-term exposure durations (1-6 months).  In
addition, the short- and intermediate-term toxicological endpoints are
the same; therefore, the estimates of risk for short-term duration
exposures are protective of those for intermediate-term duration
exposures.  Long-term exposures are not expected; therefore, a long-term
assessment was not conducted. 

9.1	Short-/Intermediate-Term Occupational Handler Risk  TC \l2 "9.1
Short-/Intermediate-Term Occupational Handler Risk 

Tembotrione is applied by ground equipment only (aerial application is
prohibited on the label).  Based upon the proposed agricultural uses,
HED expects the most highly exposed occupational pesticide handlers are
likely to be:

1) mixer/loader using open-pour loading of liquids for groundboom
spraying

2) applicator using open-cab ground-boom sprayer

No chemical-specific data were available with which to assess potential
exposure to pesticide handlers.  The estimates of exposure to pesticide
handlers are based upon surrogate study data available in the PHED
Surrogate Guide (August, 1998).  For pesticide handlers, it is HED
standard practice to present estimates of dermal exposure for
“baseline”; that is, for workers wearing a single layer of work
clothing consisting of a long-sleeved shirt, long pants, shoes plus
socks and no protective gloves, as well as for “baseline” and the
use of protective gloves or other PPE as might be necessary.  The
proposed product label involved in this assessment directs applicators
and other handlers to wear a long-sleeved shirt and long pants; socks,
shoes and chemical-resistant gloves.

Daily dermal or inhalation handler exposures are estimated for each
applicable handler task with the application rate, the area treated in a
day, and the applicable dermal or inhalation unit exposure using the
following formula:

Daily Exposure (mg ai/day) = UE (mg ai/lb ai handled) x AR (lbs ai/area
or volume) x AT (area or amount/day)

Where:  

Daily Exposure	=	Amount (mg ai/day) deposited on the surface of the skin
that is available for dermal absorption or amount inhaled that is
available for inhalation absorption;

UE	 		=	Unit exposure value (mg ai/lb ai) derived from August 1998 PHED
Surrogate Guide;

AR			=	application rate (lb ai/A or lb ai/gal); 0.082 lb ai/A and

	AT		 	=	Area treated (A/day) or 200A. 

The daily dermal or inhalation dose is calculated by normalizing the
daily exposure by body weight and adjusting, if necessary, with an
appropriate dermal- or inhalation- absorption factor using the following
formula:

Average Daily Dose (mg/kg/day) = Daily Exposure (mg ai/day) x
(Absorption Factor (%/100) / Body Weight (70 kg)

Where:

Average Daily Dose 		= 	Absorbed dose received from exposure to a
pesticide in a given scenario (mg pesticide active ingredient/kg body
weight/day);

Daily Exposure 		= 	Amount (mg ai/day) deposited on the surface of the
skin that is available for dermal absorption or amount inhaled that is
available for inhalation absorption;

Absorption Factor 		= 	A measure of the amount of chemical that crosses
a biological boundary such as the skin or lungs (% of the total
available absorbed); and

Body Weight 			= 	Body weight determined to represent the population of
interest in a risk assessment (kg).

Non-cancer dermal and inhalation risks for each applicable handler
scenario are represented by a MOE, which is a ratio of the NOAEL to the
daily dose.  All MOE values were calculated using the formula below:

MOE= 0.8 mg/kg/day / Average Daily Dose (mg/kg/day)

A total MOE was calculated because the dermal and inhalation
toxicological endpoints of concern are based on the same adverse effects
and dose level.  The total (dermal + inhalation) MOE values were
calculated using the formula below:

  SEQ CHAPTER \h \r 1 Total MOE = NOAEL / Dermal + Inhalation Dose

Occupational Handler Non-cancer Risk Summary 

Short- and intermediate-term handler risks were estimated.  HED assumes
inhalation toxicity as equivalent to oral toxicity and 15% dermal
absorption (based on a dermal penetration study in rats).  Short-term
dermal and inhalation exposures were summed and compared to the
short-term NOAEL of 0.8 mg/kg/day identified for short-term dermal and
inhalation risk assessment.  Intermediate-term dermal and inhalation
exposures were summed and compared to the NOAEL of 0.8 mg/kg/day
identified for intermediate-term dermal and inhalation risk assessment. 
The MOE is >1000 as a result of LOAEL to NOAEL extrapolation.  Exposure
and risk estimates are presented in Table 9.1 below.  HED has determined
that there are no risks of concern associated with the groundboom
application scenario at baseline.  However, HED has determined that
there are risks of concern (i.e., MOEs <1000) associated with the
mixer/loader scenarios at baseline.  and with the use of gloves, as
directed by the label.  If an extra layer of clothing is worn (i.e., a
double layer), the MOE is 910 and if a closed mixing/loading system is
utilized (i.e., engineering control), the MOE is 1,400.  HED has
determined that the risks associated with a mixer/loader wearing a
double layer of clothing are not of concern and recommends that a double
layer of clothing (i.e., coverall) be added to the label for PPE.  



Table 9.1.  Tembotrione Occupational Dermal and Inhalation Exposures and
Risks.

Exposure Scenario	Crop or Target	App Rate (lb ai/acre)a	Area Treated
Daily (acres)b	Unit Exposures	Doses (mg/kg/day)c	Short-and
Intermediate-term MOEs	Combined MOEsd

Dermal and

Inhalation (mg/lb ai)

	Mixer/Loader

Mixing/Loading Liquids Concentrates for Groundboom Applications

(open pour)	Field and silage corn, seed corn, sweet corn, popcorn	0.082
200	Dermal

Baselinee: 2.9

PPE – SL w/glovesg: 0.023 

PPE – DL w/glovesh: 0.017 

Engineering controli: 0.0086	Dermal 

Baseline: 0.1

PPE – SL w/gloves: 0.00081

PPE – DL w/gloves: 0.0006

Engineering control: 0.0003	Dermal 

Baseline: 7.8

PPE – SL w/gloves: 990

PPE – DL w/gloves: 1,300

Engineering control: 2,600	Baseline Dermal and Inhalation: 7.8

PPE – SL w/gloves + Baseline Inhalation:  730

PPE – DL w/gloves + Baseline Inhalation: 910

Engineering control + Baseline Inhalation: 1,400

Inhalation

Baselinef: 0.0012	Inhalation

Baseline: 0.00028	Inhalation

Baseline:  2,800

	Applicator

Applying Sprays via Ground-boom Equipment

(open cab)	Field and silage corn, seed corn, sweet corn, popcorn	0.082
200	Dermal

Baseline: 0.014	Dermal

Baseline: 0.00049	Dermal

Baseline: 1,600	Baseline Dermal + Inhalation: 1,200

Inhalation

Baseline: 0.00074	Inhalation

Baseline: 0.00017	Inhalation

Baseline: 4,600

	a	Application rate = maximum application rate from label (0.082 lb
ai/acre).

b	Amount handled per day values are HED estimates of acres treated per
day based on Exposure SAC SOP #9 “Standard Values for Daily Acres
Treated in Agriculture,” industry sources, and HED estimates.	

c	Dose (mg/kg/day) = Unit exposure(mg/lb ai) x App Rate (lb ai/acre) x
Area Treated (acres/day) x  %Absorption (15% dermal and 100% inhalation)
/ Body weight (70 kg).  

d	  SEQ CHAPTER \h \r 1 Combined MOE = NOAEL or LOAEL (mg/kg/day) /
(Dermal + Inhalation Dose (mg/kg/day))

e	Baseline Dermal:  Long-sleeve shirt, long pants, and no gloves.

f	Baseline Inhalation: no respirator.

g	PPE - SL w/ gloves: Single layer plus chemical-resistant gloves.

h	PPE – DL w/gloves: Double layer plus chemical-resistant gloves.

i	Engineering control: closed mixing/loading system

9.2	Short-/Intermediate-Term Postapplication Risk  TC \l2 "9.2
Short-/Intermediate-Term Postapplication Risk 

HED expects that postapplication exposure will occur since tembotrione
is applied as a foliar spray.  Since no postapplication data was
submitted in support of this registration action, exposures during
postapplication activities were estimated using dermal TCs from the HED
ExpoSAC Policy Number 3.1:  Agricultural TCs, August 2000, summarized in
9.2.1 below.  It is anticipated that because of the label restriction
that this product will not be applied to corn that is more mature than
the 8-leaf stage of growth, that the most likely postapplication
activities will be hand-weeding, scouting, and irrigation. In addition,
the following assumptions were also used:

Assumptions:

Application Rate	= 	0.082 lb ai/A 

Exposure Duration	=	8 hours per day

Body Weight		=	70 kg

Dermal Absorption	= 	15% 

Fraction of a.i. retained on foliage is assumed to be 20% (0.2) on day
zero (= % dislodgeable foliar residue, DFR, after initial treatment). 
This fraction is assumed to further dissipate at the rate of 10% (0.1)
per day on following days.  These are default values established by
HED’s ExpoSAC.

Daily dermal exposures were calculated on each postapplication day after
application using the following equation:

DE(t) (mg/day) = (TR(t) (µg/cm2) x TC (cm2/hr) x Hr/Day)/1000 (µg/mg)

Where:

DE(t)	=	Daily exposure or amount deposited on the surface of the skin at
time (t) attributable for activity in a previously treated area, also
referred to as potential dose (mg ai/day);

	TR(t)	=	Transferable residues that can be dislodgeable foliar residue
at time “t” (µg/cm2);

	TC	=	Transfer Coefficient (cm2/hour); and

	Hr/day	=	Exposure duration meant to represent a typical workday (8
hours).

Note that the (TR(t)) input may represent levels on the day of
application in the case of short-term risk calculations.  Once daily
exposures are calculated, the calculation of daily absorbed dose and the
resulting MOEs use the same algorithms that are described above for the
handler exposures.  These calculations are completed for each day or
appropriate block of time after application.

Occupational Postapplication Noncancer Risk Summary 

Table 9.2.2 presents a summary of occupational postapplication risks
associated with use of tembotrione.  HED has determined that risks are
not of concern (i.e., MOEs >1000) on day 0 (REI = 12 hours) only for
hand-weeding activities at the lowest TC (i.e., when corn is at a low
crop height and minimal foliage development).  All of the other exposure
activities have risks of concern, with MOEs ranging from 250 to 630 on
the day of application.  Chemical-specific dislodgeable foliar data
would be needed to further refine these estimates.  Currently, the label
requires a 12-hour REI; however, HED recommends a 13-day REI for
irrigation, scouting and hand-weeding activities.

Table 9.2.1.  Postapplication Activities and Dermal TCs.

Proposed Crops	Policy Crop Group Category	TCs (cm2/hr)	Activities

Corn	Field / row crop, tall	100	Hand-weeding

400 	Scouting

1,000	Irrigation, Scouting, Hand-weeding



Table 9.2.2.  Summary of Occupational Postapplication Risks for
Tembotrione.

Crop Grouping	Application rate

(lb ai/acre)	TC (cm2/hr)	Days after Application to Reach LOC	MOE at Day
0

	LOC = 1000

Corn	0.082	100 (Hand-weeding)	0 (12 hours)	2,500

400 (Scouting)	5	630

1,000 (Irrigation, Scouting, Hand-weeding)	13	250

10.0	Data Needs and Label Recommendations  TC \l1 "10.0	Data Needs and
Label Recommendations 

10.1	Toxicology  TC \l2 "10.1	Toxicology 

There are no toxicology data gaps.

10.2	Residue Chemistry  TC \l2 "10.2	Residue Chemistry 

860.1340 Residue Analytical Methods

To be acceptable as enforcement methods, LC/MS/MS Methods AE/03/01 for
plant commodities and 00967 for livestock commodities should undergo
successful PMVs by Agency chemists at ACL/BEAD.

Both methods should be revised to include a calculation for the
conversion of residues of the metabolite(s) to parent equivalents for
quantitation.  

Separate confirmatory methods for Method AE/03/01 will not be requested
provided that two ion transitions are monitored during MS/MS analysis
for each analyte. 

  SEQ CHAPTER \h \r 1 860.1650 Submittal of Analytical Reference
Standards

Analytical standards for tembotrione and its metabolite M5 are currently
not available in the National Pesticide Standards Repository. 
Analytical reference standards of tembotrione and its metabolite
(including the deuterated internal standards) should be supplied, and
supplies replenished as requested by the Repository.  

860.1550 Proposed Tolerances

The petitioner is requested to submit a revised Section F specifying the
following:

The tolerance expression for plant commodities should be revised to
include the combined residues of tembotrione and M5, expressed as
tembotrione equivalents.

The tolerance expression for livestock commodities should be revised to
include the combined residues of tembotrione and its metabolite M5,
expressed as tembotrione equivalents.

The appropriate levels are specified in Appendix C:  Tolerance
Reassessment Summary and Table.

10.3	Occupational and Residential Exposure  TC \l2 "10.3	Occupational
and Residential Exposure 

875.2100 Chemical-specific dislodgeable foliar residue data.

HED requests further information from the registrant on specific
re-entry activities that take place postapplication.  

HED recommends the following label changes based on the results of the
exposure assessment:

Add coveralls to the PPE requirements for handlers.

Change the REI to 13 days.

References:  TC \l1 "References: 

Tembotrione:  Section 3 Registration Request for Uses on Corn (Field,
Pop, and Sweet).  Summary of Analytical Chemistry and Residue Data. 
PP#5F7009.  G. Kramer.  D325349.

Tembotrione:  Acute and Chronic Dietary (Food and Drinking Water)
Exposure and Risk Assessment for Residues on Corn and Livestock
Commodities.  PP#5F7009.  G. Kramer.  D335831.

Tembotrione: Occupational and Residential Exposure/Risk Assessment for
the New Use on Field and Silage Corn, Seed Corn, Sweet Corn and Popcorn.
 K. Lowe.  D326301

Drinking Water Assessment for Tembotrione.  W. Eckel.  D335247.

Tembotrione:  Evaluation of the Carcinogenic Potential of Tembotrione. 
J. Kidwell.  TXR 0054606.

Appendix A:  Toxicology Assessment  TC \l1 "Appendix A:  Toxicology
Assessment 

A.1	Toxicology Data Requirements TC \l2 "A.1  Toxicology Data
Requirements  

The requirements (40 CFR 158.340) for use on food for tembotrione are in
Table 1. Use of the new guideline numbers does not imply that the new
(1998) guideline protocols were used.

Test 

	Technical

	Required	Satisfied

870.1100    Acute Oral Toxicity	

870.1200    Acute Dermal Toxicity	

870.1300    Acute Inhalation Toxicity	

870.2400    Primary Eye Irritation	

870.2500    Primary Dermal Irritation	

870.2600    Dermal Sensitization		yes

yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

yes

870.3100    Oral Subchronic (rodent)	

870.3150    Oral Subchronic (nonrodent)	

870.3200    21-Day Dermal	

870.3250    90-Day Dermal	

870.3465    90-Day Inhalation		yes

yes

yes

no

no

	yes

yes

yes

-

-

870.3700a  Developmental Toxicity (rodent)	

870.3700b  Developmental Toxicity (nonrodent)	

870.3800    Reproduction		yes

yes

yes	yes

yes

yes

870.4100a  Chronic Toxicity (rodent)	

870.4100b  Chronic Toxicity (nonrodent)	

870.4200a  Oncogenicity (rat)	

870.4200b  Oncogenicity (mouse)	

870.4300    Chronic/Oncogenicity		yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

870.5100    Mutagenicity—Gene Mutation - bacterial	

870.5300    Mutagenicity—Gene Mutation - mammalian	

870.5xxx    Mutagenicity—Structural Chromosomal Aberrations	

870.5xxx    Mutagenicity—Other Genotoxic Effects		yes

yes

yes

yes

	yes

yes

yes

yes

870.6100a  Acute Delayed Neurotox. (hen)	

870.6100b  90-Day Neurotoxicity (hen)	

870.6200a  Acute Neurotox. Screening Battery (rat)	

870.6200b  90-Day Neuro. Screening Battery (rat)	

870.6300    Develop. Neuro		no

no

no

no

no	-

-

yes

yes

yes

870.7485    General Metabolism	

870.7600    Dermal Penetration		yes

yes	yes

yes

Special Studies for Ocular Effects

Acute Oral (rat)	

Subchronic Oral (rat)	

Six-month Oral (dog)		-	-

A.2  Toxicity Profiles TC \l2 "A.2  Toxicity Profiles 

Table A.2.1	Acute Toxicity Profile - Test Substance 

Guideline No.	Study Type	MRID(s)	Results	Toxicity Category

870.1100	Acute oral [rat]	46695618 	LD50 > 2000 mg/kg	III

870.1200	Acute dermal [rat]	46695623	LD50 > 2000 mg/kg	III

870.1300	Acute inhalation [rat]	46695626	LC50 >4.57 mg/L	IV

870.2400	Acute eye irritation [rabbit]	46695628	Non-irritating	IV

870.2500	Acute dermal irritation [rabbit]	46695631	Non-irritating	IV

870.2600	Skin sensitization [Guinea Pig]	46695634	Dermal Sensitizer		N/A

Table A.2.2	Subchronic, Chronic and Other Toxicity Profile

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

870.3100

	90-Day oral toxicity (rat)	46695638 (2002)

Acceptable/guideline

0, 1.25, 75, 1500, 7000 ppm

M:  0, 0.07, 4.45, 86.4, 413 mg/kg/day

F:  0, 0.09, 5.59, 107.2, 465 mg/kg/day	NOAEL=M/F: 0.07/0.09 mg/kg/day

LOAEL=M/F: 4.45/5.59 mg/kg/day 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.

870.3100

	90-Day oral toxicity (rat)	466995639 (2005)

Acceptable/guideline

0, 6, 20, 40 ppm

M: 0, 0.30, 0.98, 2.20 mg/kg/day

F: 0, 0.35, 1.18, 2.68 mg/kg/day

	NOAEL =M/F: 0.30/0.35  mg/kg/day

LOAEL = M/F: 0.98/1.18 mg/kg/day based on snowflake-like corneal opacity
and keratitis of the eyes in males and corneal opacity,
neovascularization and edema of the cornea in females.

870.3100

	90-Day oral toxicity (mouse)	466995640 (2003)

Acceptable/non-guideline

0, 35, 350, 3500, 7000 ppm

M:  0, 5.9, 64, 631, 1317 mg/kg/day

F:  0, 7.3, 75.6, 783, 1833 mg/kg/day

	NOAEL =M/F: 64/75.6 mg/kg/day

LOAEL =M/F: 631/783 mg/kg/day based on decreased uterine weights and
increased corpora lutea in the ovary in females and serum alanine
aminotransferase activity , liver weights, hepatocellular hypertrophy,
dark livers, macroscopic erosive/ulcerative lesion in the stomach and/or
dark intestinal content in both sexes.

870.3150

	90-Day oral toxicity (dog)	46695643 (2004)

Acceptable/guideline

0, 125, 750, 4500/2250 ppm

M: 0, 4.5, 26.7, 124/111 mg/kg/day

F: 0, 4.5, 28.5, 124/111 mg/kg/day	NOAEL =M/F: 26.7/28.5 mg/kg/day

LOAEL = 124/111 mg/kg/day based on clinical signs of toxicity including
uncoordinated movement, disturbance in locomotion , decreased body
weights and body-weight gains, effects on hematology 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.

870.3200

	21/28-Day dermal toxicity (rat)	46695644 (2005)

Acceptable/guideline

0, 250, 500, 1000 mg/kg/day	NOAEL was not established

LOAEL = 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.  

870.3200

	21/28-Day dermal toxicity (rat)	46695645 (2005)

Acceptable/guideline

0, 50, 250, 1000 mg/kg/day	NOAEL was not established in males; NOAEL=F:
50 mg/kg/day 

LOAEL = M: 50 mg/kg/day based on colloid alterations in the thyroid
gland and degenerative changes in the pancreas.

LOAEL=F: 250 mg/kg/day based on degenerative changes in the pancreas.   

870.3250

	90-Day dermal toxicity (species)	N/A

	870.3465

	90-Day inhalation toxicity (species)	N/A

	870.3700a

	Prenatal developmental in (rat)	46695646 and 46695647 (2003)

Acceptable/guideline

0, 25, 125, 500 mg/kg/day	Maternal NOAEL = 25 mg/kg/day

LOAEL = 125 mg/kg/day based on decreased body-weight gains and food
consumption.

Developmental NOAEL was not established.

LOAEL = 25 mg/kg/day based on increased skeletal variations including
delayed ossifications and decreased growth and developmental as
indicated by decreased fetal body weights and an increased number of
runts.

870.3700b

	Prenatal developmental in (rabbit)	46695703 (2003)

acceptable/guideline

0, 1, 10, 100 mg/kg/day	Maternal NOAEL = 10 mg/kg/day

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

Developmental NOAEL = 1 mg/kg/day 

LOAEL = 10 mg/kg/day based on decreased or delayed growth and/or
development of the skeleton and increased incidences of other skeletal
variations and anomalies.

870.3800

	Reproduction and fertility effects

(rat)	46695704 (2005)

Acceptable/guideline

0, 20, 200, 1500 ppm

M:  0, 1.4, 13.3, 100.4 mg/kg/day

F:  0, 1.6, 15.8, 119.3 mg/kg/day	Parental/Systemic NOAEL was not
established.

LOAEL = M/F: 1.4/1.6 mg/kg/day based on effects on the eyes, including
corneal opacity, acute inflammation, and neovascularization.

Reproductive NOAEL = M/F 100.4/119.3 mg/kg/day

LOAEL was not established.

Offspring NOAEL was not established.

LOAEL = M/F:  1.4/1.6 mg/kg/day 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.

870.4100b

	Chronic toxicity

(dog)	46695705 (2005)

Acceptable/guideline

0, 75, 300, or 1200 ppm

M:  0, 2.5, 9.0, 37.8 mg/kg/day

F:  0, 2.5, 10.2, 41.6 mg/kg/day	NOAEL was not established in males.

LOAEL= M: 2.5 mg/kg/day based on the increased number of digestion
chambers of the sciatic nerve.

NOAEL=F: 10.2 mg/kg/day

LOAEL= F: 41.6 mg/kg/day based on decreases in MCH and MCV, increased
platelet counts, changes in erythrocyte morphology and pigmentation of
the thyroid gland. 

870.4300

	Chronic/ Carcinogenicity (mouse)	46695706 (2005)

Acceptable/guideline

0, 30, 300, 1000, or 3000 ppm 

M: 0, 4, 43, 146, 440 mg/kg/day 

F: 0, 5, 54, 179, 552 mg/kg/day 	NOAEL was not established.

LOAEL =M/F: 4/5 mg/kg/day based on 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.

No evidence of carcinogenicity

870.4300

	Chronic/ Carcinogenicity (rat)	46695707 (2005)

Unacceptable/guideline

0, 0.10, 1.05, 134, 280 mg/kg/day

	NOAEL =F: 0.10 mg/kg/day

LOAEL = F: 1.05 mg/kg/day based on keratitis of the eye and biliary
hyperplasia/fibrosis.

No evidence of carcinogenicity

870.4300

	Chronic/ Carcinogenicity (rat)	46695708 (2005)

Acceptable/guideline

0, 20, 200,  or 800 ppm 

M: 0, 0.04, 0.79, 8.3, 31.7 mg/kg/day	NOAEL=M: 0.04 mg/kg/day

LOAEL =M: 0.79 mg/kg/day 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 levels 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.

Evidence of carcinogenicity:

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.

870.5100 

	In vitro Bacterial Gene Mutation	46695709 (2005)

Acceptable/guideline

0, 50, 150, 500, 1500 and 5000 ug/plate	There was no evidence of induced
mutant colonies over background.

870.5300 

	In vitro Gene mutation in Chinese Hamster V79

	46695713 (2005)

Acceptable/guideline

0, 250, 500, 1000, 1400, 1500, 1600 ug/mL

	There was no evidence of induced mutant colonies over background.

870.5375 	In vitro Mammalian Cytogenetics chromosomal aberration assay
Human Lymphocytes

	46695717 (2005)

Acceptable/Guideline

0, 0.08, 0.16, 0.31, 0.63, 1.25, 2.5, 5, 10 mM	Equivocal because
structural aberrations and polyploidy observed in the absence of
excessive cytotoxicity at 3306 ug/mL with metabolic activation was not
reproduced.  

870.5395 	In Vivo Mammalian Cytogenetics - Erythrocyte Micronucleus
assay in mice	46695721 (2005)

Acceptable/Guideline

500, 1000 and 2000 mg/kg	There was no increase in the frequency of
micronucleated immature erythrocytes in mouse bone marrow.

870.5550 	Other Effects: 

Unscheduled DNA Synthesis in primary rat hepatocytes/mammalian cell
cultures

	46695722(2005)

Acceptable/Guideline

0, 1000 and 2000 mg/kg	There was no increase in the frequency of
micronucleated immature erythrocytes in mouse bone marrow.

870.6200a

	Acute neurotoxicity screening battery	46695723(2005)

Acceptable/Guideline

0, 200, 500, 2000 mg/kg	NOAEL was not established in males

LOAEL=M: 200 mg/kg based on decreased arousal (sluggish with some
exploratory movement) in the open field on day 0

NOAEL= F: 200 mg/kg

LOAEL= F: 500 mg/kg based on urine staining, red nasal discharge,
decreased body temperature on day 0, decreased motor and locomotor
activity on day 0.

870.6200b

	Subchronic neurotoxicity screening battery (rat)	46695724(2005)

Acceptable/Guideline

0, 20, 250, 2500 ppm

M:  0, 1.33, 16.4, 160 mg/kg/day

F:  0, 1.75, 21.0, 224 mg/kg/day	NOAEL= M/F: 16.4/21.0 mg/kg/day

LOAEL= M/F: 160/224 mg/kg/day based on decreased body weight and
body-weight gain in both sexes.

870.6300

	Developmental neurotoxicity (rat)	46695725(2005)

Acceptable/Guideline

0, 10, 200, or 1500 ppm

0, 0.8, 16.3, and 118 mg/kg/day	Maternal NOAEL= 0.8 mg/kg/day 

Maternal LOAEL=16.3 mg/kg/day based on corneal opacity during lactation.

Offspring NOAEL was not established.

Offspring LOAEL= 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).

870.7485

	Metabolism and pharmacokinetics

(rat)	46695726 (2005)

Acceptable/guideline

5 and 1000 mg/kg 	Tembotrione was rapidly absorbed, extensively
metabolized, and excreted.  Total excretion of tembotrione was
96.3-102.7% by 24 hours regardless of dose level or position of
radiolabel.  Sex differences were observed in the routes of excretion. 
The primary routes of elimination were the urine in females and the
urine and feces in males.  Males excreted up to 24.4% and 70.4% and
females up to 79.1% and 20% of the administered dose in the urine and
feces, respectively, at the low dose.  Females excreted up to 63.7% and
28.5% and males up to 44.2 % and 49.1% of the dose in the urine and
feces, respectively, at the high dose.  The highest mean levels of
radioactivity were extracted from the liver (1.7-3.5%) and kidneys
(0.14-0.26%) at the low dose.  At the high dose, the mean levels of
radioactivity were extracted from the skin/fur (0.22-0.33%) and carcass.
 The highest concentrations of radioactivity were found in the skin
followed by the liver, kidneys, stomach (and contents) and carcass. 
There was no evidence of bioaccumulation.  The parent molecule and 11
metabolites were identified & isolated.  Metabolic profiles were
qualitatively similar for both radiolabeled forms; however, profiles for
the high and low doses were not the same and differences were noted
between sexes.  Females excreted the greatest quantity of the parent
molecule in urine (44.1-59.4%).  While low and high dose males
eliminated 1.9-3.0% and 33.8%, respectively, in the urine.  The
metabolites found in the greatest quantities were 4-hydroxy--tembotrione
and 5- hydroxy--tembotrione.  Other identified metabolites found at <5%
were the 4,5-dihydroxy, benzylic alcohol, dihydroxy-bezophenone,
4-hydroxy-benzylic alcohol, and ketohydroxy-hexanoic acid
([cyclohexyl-UL-14C] only).  Males excreted greater quantities of both
metabolites than females; except, at the high dose where
4-hydroxy--tembotrione was eliminated in approximately equal amounts in
both sexes. The primary step in the metabolism of tembotrione is the
hydroxylation (oxidative pathway) of the cyclohexyl ring of the
molecule.

870.7600	Dermal penetration

(rat)	46695730 (2005)

Acceptable/guideline

6.6, 66, 660 ug/cm2	Dermal absorption is 15%

	Effects on blood coagulation parameters with and without vitamin K1
46695731 (2005)

Acceptable/non-guideline

1000 mg/kg

1000 mg/kg and 10 mg/kg vitamin K1	Alterations in clotting parameters
were mediated by effects on vitamin K1 clotting factors.

	Effect on blood tyrosine levels in pregnant rabbits 

	46695732 (2004)

Acceptable/non-guideline

0, 10 mg/kg/day	Blood tyrosine levels in treated animals were
significantly elevated relative to controls for all intervals measured
during treatment.

	Inhibition of 4-Hydroxyphenylpyruvate Dioxygenase in Rats and In Vitro
46695733 and 46695734 (2005)

Acceptable/non-guideline

In vivo: 0, 10 mg/kg

In vitro: 0, 30, 60, 120 uM	In vivo:  AE0172747 increased plasma
tyrosine levels by 20-fold,

AE1417286 increased plasma tyrosine levels by 5-fold,

AE0456148 and AE1392936 did not affect plasma tyrosine levels relative
to controls.

In vitro: Rank of species by their ability to produce 4- HPLA after
inhibition of HPPDase in (from most to least produced): mouse, human,
rabbit, rat and dog.

Table A.2.3	Subchronic Toxicity Profile for Metabolites of Tembotrione

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

AE 1417268

870.3100

	90-Day oral toxicity (rat)	46695641 and 46695637 (2005)

Acceptable/guideline

0, 200, 1500, 9000 ppm

M:  0, 12.7, 95.7, 586 mg/kg/d

F:  0, 15.6, 115, 718 mg/kg/d	NOAEL=M/F; 95.7/115 mg/kg/d

LOAEL=M/F: 586/718 mg/kg/d  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.

AE0456148

870.3100

	90-Day oral toxicity (rat)	46695642 (2005)

Acceptable/guideline

0, 15, 150, 1500, 15,000 ppm

M:  0, 1.19, 12.34, 120.19, 1203.8 mg/kg/d

F:  0, 1.63, 16.08, 162.49, 1436.3 mg/kg/d

	NOAEL= M: 1203.8 mg/kg/d

LOAEL was not established.

NOAEL=F: 162.49 mg/kg/d

LOAEL = F: based on increased incidence of hematopoiesis of the spleen.

A.3  Executive Summaries TC \l2 "A.3  Executive Summaries 

	870.3100	90-Day Oral Toxicity - Rat

EXECUTIVE SUMMARY:  In a 90-day oral toxicity study (MRID 46695638)
AE0172747 (97.4% a.i., batch # LE356) was administered to Wistar (AF)
Rj:WI (IOPS HAN) rats10/sex/dose in the diet at dose levels of 0, 1.25,
or 7,000 ppm (equivalent to M/F:  0/0, 0.07/0.09, or 413/465 mg/kg
bw/day) and 15/sex/ dose at 75 or 1,500 ppm (equivalent to M/F: 
4.45/5.59, or 86.4/107.2 mg/kg bw/day) for 90 days.  Five animals/sex
from the 75 and 1,500 ppm groups were maintained untreated for 4 weeks
to observe reversibility of potential ophthalmological effects. 

There were no treatment related effects observed in urinalysis.

One male in the 7000 ppm group was sacrificed moribund on day 64.
Clinical signs of toxicity included white area on the eye, ocular
discharge and damaged eyes in 1500 ppm (6/10) and 7000 ppm (8/10) males
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
(Lot/batch No. 078H06822 and 123K0376; purity >99%) for 28 days. 
(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 to the eye, kidney, liver, pancreas, and thyroid of rats.

One Group 3 female rat died during the study, but its death was
unrelated to treatment.  No treatment-related effects were noted on body
weight, body weight gain, or food consumption.  Nine of ten male and
3/10 female rats in Group 4 (2% tyrosine + 10 µg/kg bw/day NTBC)
developed white areas on the eye between Days 23-26 on one or more
occasions.  Following opthalmoscopic examination prior to sacrifice,
9/10 male rats in Group 4 had developed corneal edema and all male and
3/10 female rats had developed “snow flake” corneal opacities.  In
addition, three Group 4 male rats had developed congestive iritis.  None
of the male and female rats in Group 2 (2% tyrosine) or Group 3 (10
µg/kg bw/day NTBC) developed ocular abnormalities.  

The average plasma tyrosine concentration of Group 3 and Group 4 male
and female rats was markedly increased 18-23 fold on the day of
sacrifice, while plasma tyrosine was unaffected by treatment in Group 2
rats. 

Although the liver to body weight ratio of male and female rats in Group
4 was statistically increased, no histological correlates were found. 
No other treatment-related effects were noted on organ weight. 
Microscopic treatment-related effects were found in the pancreas,
thyroid, and eyes of Group 4 rats.  The incidences of focal/multifocal
acinar atrophy/ fibrosis and/or acinar degeneration/apoptosis, as well
as the incidence of focal/multifocal or diffuse inflammation were
increased in the pancreas of Group 4 male and female rats.  In the
thyroid, an increased incidence of colloid alteration was found in male,
but not female rats of Group 4 rats.  In the eye, the incidence of
unilateral and bilateral keratitis was markedly increased in male rats
while minimal keratitis was found in 1/10 Group 4 female rats.  No
treatment-related effects were noted in male or female Group 2 and Group
3 rats.

This study suggests that male rats are more sensitive to treatment with
2% tyrosine + 10 μg/kg bw/day NTBC than female rats and that the eye
and thyroid are target organs for toxicity.  

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

A.4	References

46695703	Wason, S. (2003) AE 0172747:  Developmental toxicity study in
the rabbit by gavage.  Bayer CropScience, Sophia Antipolis Cedex,
France.  Laboratory Study Report: SA 02056, February 24, 2003.  MRID
46695703.  Unpublished.

46695704	Young, A.D., B.L. Fickbohm (2005) Technical Grade AE0172747:  A
two-generation reproductive toxicity study in the Wistar Rat.  Bayer
CropScience LP, Toxicology, Stilwell, KS.  Report No.: 201266, August
31, 2005.  MRID 46695704.  Unpublished.

46695705	Kennel, P. (2005) AE0172747 Chronic toxicity study in the dog
by dietary administration.  Bayer CropScience, Sophia Antipolis Cedex,
France.  Study Report No.: SA 03352, September 9, 2005.  MRID 46695705. 
Unpublished.

46695706	Langrand-Lerche, C. (2005) Carcinogenicity study of AE 0172747
in the C57BL/6 Mouse by dietary administration.  Bayer CropScience,
Sophia Antipolis Cedex, France. Laboratory Study No.: SA 02256,
September 9, 2005.  MRID 46695706.  Unpublished.

46695707	Kennel, P. (2005) Chronic toxicity and carcinogenicity study of
AE 0172747 in the Wistar rat by dietary administration. Bayer
CropScience, 355, rue Dostoievski, BP 153, 06903 Sophia Antipolis Cedex,
France. Report of Study SA 02055, May 20, 2005. MRID 46695707.
Unpublished.

46695708	Kennel, P. (2005) Chronic toxicity and carcinogenicity study of
AE 0172747 in the male Wistar rat by dietary administration. Bayer
CropScience, 355, rue Dostoievski, BP 153, 06903 Sophia Antipolis Cedex,
France. Report of Study SA 02400, November 7, 2005. MRID 46695708.
Unpublished.

46695709	May, K. (2003). Technical AE0172747 Bacterial Reverse Mutation
Test. Huntingdon Life Sciences Ltd., Huntingdon, Great Britain.
Laboratory report number: AES 117/0230631, October 10, 2003. 46695709.
Unpublished.

46695710	Herbold, B. (2005). AE0456148 (Project:AE0172747)
Salmonella/microsome test -Plate incorporation and preincubation method;
Bayer HealthCare AG, Wuppertal, Germany. Report number: AT01610, June 9,
2005. MRID 46695710. Unpublished.

46695711	Wirnitzer, U. (2004). AE1417268 (Project:AE0172747)
Salmonella/Microsome Test (Plate Incorporation And Preincubation
Method); Bayer Healthcare AG, Wuppertal, Germany. Report number: AT1713,
December 16, 2004. MRID 46695711. Unpublished.

46695712	Wirnitzer, U. (2005). AE1392936 (project: AE0172747)
Salmonella/Microsome Test - Plate Incorporation and Preincubation
Method; Bayer HealthCare AG, Wuppertal, Germany. Report number: AT02552,
October 27, 2005. MRID 46695712. Unpublished.

46695713	May, K. (2005).  Technical AE0172747 – Mammalian Cell
Mutation Assay. Huntington Life Sciences Ltd., Cambridgeshire, Great
Britain. Report No.: AES119/024223.  MRID 46695713, January 25, 2005. 
Unpublished

46695714	Herbold, B. (2004).  AE0456148 (Project: AE0172747) –
V79/HPRT-in vitro for the detection of induced forward mutations.  Bayer
Healthcare AG, Wuppertal, Germany. Report number: AT01738, December 10,
2004. MRID 46695714. Unpublished.

46695715		Lloyd, M. (2005).  AE1417268 – Mutation at the Thymidine
Kinase (Tk) Locus of Mouse Lymphoma L5178Y Cells (MLA) Using the
Microtitre Fluctuation Technique.  Covance Laboratories Ltd., Harrogate,
North Yorkshire, England. Report No.: 2014/89.  October 26, 2005. MRID
46695715. Unpublished.

46695716		Herbold, B. (2005).  AE1392936 (Project: AE0172747) –
V79/HPRT-in vitro for the detection of induced forward mutations.  Bayer
Healthcare AG, Wuppertal, Germany. Report number: AT02433, August 26,
2005. MRID 46695716. Unpublished.

46695717		Mason, C. (2004). Technical AE0172747 - In Vitro Mammalian
Chromosome Aberration Test in Human Lymphocytes. Huntingdon Life
Sciences Ltd., Huntingdon, Cambridgeshire, Great Britain. Report No.:
AES118/024021. January 6, 2004. MRID 46695717. Unpublished.

46695718	Herbold, B. (2005). AE0456148 (Project: AE0172747 - In vitro
Chromosome Aberration Test with Chinese Hamster V79 Cells. Bayer
HealthCare AG, Wuppertal, Germany. Report No.: AT01906. October 4, 2005.
MRID 46695718. Unpublished.

46695719		Kumaravel, T. S. (2005). AE1417268:  Induction of Chromosome
Aberrations in Cultured Human Peripheral Blood Lymphocytes. Covance
Laboratories Ltd., Harrogate, North Yorkshire, England. Report No.:
2014/88; October, 2005. MRID 46695719. Unpublished.

46695720		Thum, M. (2005). AE1392936 00 1C94 0001 (Project AE0172747)-
In vitro Chromosome Aberration Test with Chinese Hamster V79 Cells.
Bayer HealthCare, AG, Wuppertal, Germany. Report No.: AT02214. October
12, 2005. MRID 46695720. Unpublished.

46695721	Mehmood, Z. (2003).  Technical AE0172747- Mouse Micronucleus
Test. Huntingdon Life Sciences Ltd, Cambridgeshire, Great Britain.
Report No.: AES120/023519, October 27, 2003. MRID 46695721. Unpublished.

46695722		Wirnitzer, U. (2005).  AE 0172747 (Project: AE 0172747) - 
Unscheduled DNA

				synthesis test with rat liver cells in vivo;  Bayer Healthcare AG,
Wuppertal, Germany.  Report No.: AT02169, July 1, 2005. MRID 46695722.
Unpublished.

46695723	Sheets, L.P., and R.G. Gilmore, (2005) An acute oral
neurotoxicity screening study with technical grade AE 0172747 in Wistar
rats.  Bayer CropScience LP, Stilwell, KS.  Laboratory Study No.: 
03-N12-TB, April 5, 2005.  MRID 46695723.  Unpublished.

46695724	Gilmore, R.G. (2005) A subchronic neurotoxicity screening study
with technical grade AE 0172747 in Wistar rats.  Bayer CropScience LP,
Stilwell, KS.  Laboratory Study No.: 03-N72-PK, March 28, 2005.  MRID
46695724.  Unpublished.

46695725	Sheets, L.P., R.G. Gilmore, and H.E. Hoss (2005) A
developmental neurotoxicity screening study with technical grade AE
0172747 in Wistar rats.  Bayer CropScience LP, Stilwell, KS.  Laboratory
Study No.:  04-D72-UE, September 7, 2005.  MRID 46695725.  Unpublished.

46695726	Koester, J. (2005). [Cyclohexyl-UL-14C]AE 0172747:  rat
blood/plasma kinetics study.  Bayer CropScience AG, Development,
Metabolism/Environmental Fate, Monheim am Rhein, Germany.  Laboratory
Study No.:  M01819137, March 8, 2005.  MRID 46695726.  Unpublished

46695730	Odin-Feurtet, M.  (2005) AE 0172747 and isoxadifen-ethyl SC 420
+ 210 formulation:  in vivo dermal absorption study in the male rat. 
Bayer CropScience, 355 rue Dostoïevski, Sophia Antipolis, France. 
Laboratory Project ID:  SA 04079, January 13, 2005.  MRID 46695730. 
Unpublished

46695731	Blanck, O. (2005) AE 0172747:  effects on blood coagulation
parameters with and without administration of vitamin K1.  Bayer
CropScience, 355, rue Dostoïevski, Sophia Antipolis Cedex, France. 
Laboratory Study Report:  SA 04296, April 15, 2005.  MRID 46695731. 
Unpublished.

46695732	Blanck, O. (2004) AE 0172747:  effect on blood tyrosine level
in pregnant rabbit after oral administration by gavage.  Bayer
CropScience, rue Dostoïevski, Sophia Antipolis, Cedex, France. 
Laboratory Study No.:  SA 03315, June 15, 2004.  MRID 46695732. 
Unpublished.

46695733	Totis, M. (2005) AE 1417268, AE 0456148, and AE 1392936: 
assessment of HPPDase inhibition in the rat.  Bayer CropScience, Sophia
Antipolis Cedex, France.  Laboratory Study Report:  SA 04132, March 7,
2005.  MRID 46695733.  Unpublished.

46695638	Steiblen, G. (2005) AE 0172747 - 90-day toxicity study in the
rat by dietary

	administration.  Bayer CropScience, Sophia Antipolis, France; Report
No.:  SA

	01170, January 25, 2005. MRID 46695638.  Unpublished.

46695639	Kennel, P. (2005) AE 0172747 - 90-day toxicity study in the rat
by dietary

	administration.  Bayer CropScience, Sophia Antipolis, France; Report
No.:  SA 05002, October 28, 2005. MRID 46695639.  Unpublished.

46695640	Steiblen, G., (2003) AE 0172747:  90-day toxicity study in the
mouse by dietary

		administration.  Bayer CropScience, 355, rue Dostoïevski, Sophia
Antipolis

		Cedex, France. Laboratory Study No.: SA 01431, July 9, 2003.  MRID
46695640. 

			Unpublished.

46695642	Eiben, R. (2005) AE 0456148:  Study on subchronic toxicity in
rats (administration in the diet for 3 months).  Bayer HealthCare AG,
Wuppertal, Germany.  Laboratory Study Report No.:  AT02191, July 18,
2005.  MRID 46695642.  Unpublished.

46695643	Kennel, P. (2004) AE 0172747 90-Day toxicity study in the dog
by dietary administration.  Bayer CropScience, Sophia Antipolis Cedex,
France.  Study Report No.: SA 02162, January 27, 2004.  MRID 46695643. 
Unpublished.

46695645		Krötlinger, F. and L. Schladt (2005) Subacute toxicity study
in the rat (4 weeks dermal administration).  Bayer HealthCare AG,
Wuppertal, Germany.  Laboratory Study No.: T1075496, November 9, 2005. 
MRID 46695645.  Unpublished.

47044502	Blanck, O.  (2006)  Effects of tyrosinaemia on selected organs
in rats.  Bayer CropScience 355, rud Dostoïevski, BP 153, 06903 Sophia
Antipolis Cedex, France.  Report Number SA 05330.  August 1, 2006.  MRID
47044502.  Unpublished.

47044503	Kennel, P. (2006) Effect of tyrosinaemia on pregnancy and
embryo-fetal development in the rat. Bayer CropScience, Sophia Antipolis
Cedex, France.  Laboratory study number SA 05192, January 13, 2006. MRID
47044503.  Unpublished.  

47044504	Blanck, O. (2006) Effects of diets enriched with tyrosine on
selected organs in rats.  Bayer CropScience 355, rue Dostoïevski, BP
153, 06903 Sophia Antipolis Cedex, France.  Report Number SA 05207. 
August 1, 2006.  MRID 47044504.  Unpublished.

Appendix B:  Metabolism Assessment  TC \l1 "Appendix B:  Metabolism
Assessment 

B.1	Metabolism Guidance and Considerations TC \l2 "B.1	Metabolism
Guidance and Considerations   TC \l1 "Appendix B:  Metabolism Assessment
 TC \l2 "B.1	Metabolism Guidance and Considerations 

Table B.2.		Tabular Summary of Metabolites and Degradates

Chemical Name (other names in parenthesis)	

Matrix	Percent TRR (PPM)1	Structure

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

	Tembotrione
(2-[2-Chloro-4-(methylsulfonyl)-3-[(2,2,2-trifluoroethoxy)methyl]benzoyl
]-1,3-cyclohexanedione)	Corn	-	-	

	Rotational Crops	-	-

Ruminant	Kidney, Liver

	Poultry	Tissues, Eggs

	Rat	Excreta

	Water	yes

M5

(2-[2-Chloro-4-(methylsulfonyl)-3-[2,2,2-trifluoroethoxy)methyl]benzoyl]
-4,6-dihydroxycyclohexan-1,3-dione)	Corn

Forage, Stover, Grain	

	Rotational Crops

Ruminant	-	-

Poultry	-	-

Rat	-	-

Water	-	-

	M6

(2-Chloro-4-mesyl-3-[(2,2,2-trifluoroethoxy)

methyl]benzoic acid)	Corn	Forage, Stover, Grain

	Rotational Crops	Swiss chard, Turnip tops & roots; Wheat forage, hay,
straw, & grain

	Ruminant	-	-

Poultry	-	-

Rat

Excreta

Water	maximum 96%

M10

 

	Rotational Crops	-	-

Ruminant	-	-

Poultry	-	-

Rat	Excreta

	Water	-	-

	M2

	Rotational Crops	Wheat forage, hay, straw, & grain	Turnip roots

Ruminant	-

	Poultry	-	-

Rat	-	-

Water	maximum 17%

Corn (phenyl-label), 46695530; 0.181 lb ai/A; 1.1X rate; growth stage
BBCH 12-14; 84 days (forage); and maturity, 124 days (stover and grain).

Cow (PH label); 46695532; 8.01 ppm; 6.8X MTDB; 7 days; 23 hour PSI 

Hen (PH label); 46695534; 11.33 ppm; 470X MTDB; 14 days; 24 hour PSI

Rotational Crops; 46695612; Swiss chard, turnips, and spring wheat;
1.2X, applied to bare soil;90-day PBI

Rat Metabolism; 5 or 1000 mg gavage dose; Wistar, 168-hour depuration.



	T1/2 = 10.5 days	T1/2 = 257 days	T1/2 = 5.9 days (CA)	T1/2 = 62.4 days
T1/2 = 448 days	Aqueous: stable	stable @ pH 5, 7, and 9 at 25 ºC for 30
days

	T1/2 = 72-131 days (NC)

	Soil: T1/2 = 29-32 d

	AE 0456148 (M6)

	72.4% @ 14 days	41.6% @ 120 days	maximum of 36.1% (CA)	95.2% @ 141 days
maximum of 2.4%

	maximum of 25.8% days (NC)

	Soil: 22.0% @ 9 days

AE 0968400

	14.4% @ 35 days

	maximum 4.4%

maximum 6.1% (NC)

	AE 1124336

	maximum 2.6%

	maximum 0.8% (NC)

	AE 1392936 (M2)

maximum of 17.1% (NC)

	AE 1392936 (glutaric acid)

Aqueous: 6.8% @ 10 days

	Soil: 13.8% @ 3 day

	AE 0941989

Soil: 17.9% @ 1 day; 15.3% @ 3 days

	Study MRID No.	46695414

46695416	46695420	46695425	46695422	46695423	Aqueous: 46695411

Soil: 46695412, 46695413	46695410

Appendix C:  Tolerance Reassessment Summary and Table TC \l1 "Appendix
C:  Tolerance Reassessment Summary and Table 

Table C.1.  Tolerance Summary for Tembotrione.

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0.07	0.07	Horse, meat byproducts, except liver

Horse, meat by products	0.5	0.40	Horse, liver

Additional Livestock Commodity Tolerance That Needs to be Established

Poultry, liver	None	0.07

	

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O

O

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Cl

O

C

F

3

S

O

2

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