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

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

<IP_ADDRESS>	Mode of action, metabolism, toxicokinetic data	  PAGEREF
_Toc170608532 \h  14

<IP_ADDRESS>	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

<IP_ADDRESS>	Determination of Susceptibility	  PAGEREF _Toc170608542 \h  20

<IP_ADDRESS>	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

<IP_ADDRESS>	Studies available and considered (animal, human, general
literature)  TC \l4 "<IP_ADDRESS>	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.

<IP_ADDRESS>	Mode of action, metabolism, toxicokinetic data  TC \l4 "<IP_ADDRESS>
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.

<IP_ADDRESS>	Sufficiency of studies/data  TC \l4 "<IP_ADDRESS>	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

<IP_ADDRESS>	Determination of Susceptibility  TC \l4 "<IP_ADDRESS>	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.

<IP_ADDRESS>	Degree of Concern Analysis and Residual Uncertainties  TC \l4
"<IP_ADDRESS>	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