 

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: Joanne Miller; 703-305-6224

 

Bayer CropScience

Petition # 8F7452

 Summary of Petitions

EPA has received pesticide petition 8F7452 from Bayer CropScience, 2
T.W. Alexander Drive, Research Triangle Park, NC 27709 proposing,
pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act
(FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a
revised tolerance for combined residues of tembotrione,
2-[2-chloro-4-methylsulfonyl)-3-[(2,2,2-trifluoroethoxy)methyl]benzoyl]-
1,3-cyclohexanedione, and its metabolite (M5),
2-[2-chloro-4-(methylsulfonyl)-3-[(2,2,2-trifluoroethoxy)methyl]benzoyl]
-4,6-dihydroxy-1,3-cyclohexanedione,  in or on the raw agricultural
commodities corn, sweet, forage at 0.09 parts per million (ppm), corn,
sweet, kernel plus cob with husks removed at 0.01 ppm, and corn, sweet,
stover at  0.15 ppm.  EPA has determined that the petition contains data
or information regarding the elements set forth in section 408(d)(2) of
the FFDCA; however, EPA has not fully evaluated the sufficiency of the
submitted data at this time or whether the data supports granting of the
petition.  Additional data may be needed before EPA rules on the
petition.

A. Residue Chemistry 

	1. Plant metabolism.  The metabolism of tembotrione was determined in
corn forage, stover and grain following treatment of young plants with
14C-labeled material. Hydroxylation and cleavage of the cyclohexanedione
ring were the major metabolic processes.  The major residues in corn
forage, grain, and stover were the dihydroxylated parent (AE 1417268)
and a benzoic acid cleavage product, (AE 0456148) with lesser amounts of
the benzyl alcohol (AE 1392936) formed by cleavage of the ether bond of
the benzoic acid.

	2. Analytical method.  Independently validated, analytical methods
for plants, plant products and animal matrices, suitable for enforcement
purposes, have been submitted for measuring  tembotrione and all
significant metabolites.  Typically, residues are extracted from plant
or animal using accelerated solvent extraction.  Following
concentration, quantitation is by LC/MS/MS using deuterated internal
standards.  AE 1392936 requires additional clean-up by anion exchange,
solid phase extraction prior to quantitation.  Determination of AE
1417268 in ruminant samples requires a hexane wash prior to
quantitation.

3. Magnitude of residues.  Additional field residue trials have been
conducted with only one application of tembotrione at rates of 0.067 or
0.082 lb a.i./A, in accordance with the current product label, and
support the proposed reduction in tolerances.

B. Toxicological Profile

1. Acute toxicity.  Technical tembotrione and the formulated product
show low acute toxicity (Toxicity Category III or IV) via the oral,
dermal and inhalation routes of exposure.  Tembotrione was not an eye
irritant or a dermal irritant (Toxicity Category IV), but showed
moderate potential as a contact sensitizer in a Magnusson and Kligman
maximization assay.  The formulated product was slightly irritating to
the eyes and skin, and is not a skin sensitizer via the Buehler Patch
Test with guinea pigs.  In an acute neurotoxicity screening battery in
rats, the NOAEL was 200 mg/kg body weight based on decreased motor
activity.  There was no evidence of neurotoxicity following an acute
exposure to tembotrione.

	2. Genotoxicty.  Tembotrione was tested for its genotoxic potential in
a battery of five in vitro or in vivo studies covering all required
end-points (gene mutations, chromosomal aberrations, and DNA damage and
repair).   Tembotrione showed some evidence of clastogenic activity, but
only at toxic concentrations.  All other studies were negative for
genotoxicity.  Based on the weight of evidence, tembotrione is not
genotoxic.

	3. Reproductive and developmental toxicity.  Tembotrione inhibits the
4-hydroxyphenylpyruvate dioxygenase (4-HPPD) enzyme in the metabolism of
tyrosine. Inhibition of this enzyme results in increased serum tyrosine
levels and eventually in adverse effects in the animal with increased
incidences of corneal opacity, decreased body-weight, and body-weight
gains. The reproductive and developmental toxicity of tembotrione was
investigated in a 2-generation reproductive toxicity study, as well as
in rat and rabbit teratology studies.  In the 2-generation reproductive
toxicity study a parental/systemic NOAEL was not established but the
LOAEL was 1.4 mg/kg based on corneal opacity, inflammation and
neovascularization.  An offspring NOAEL was not determined but the LOAEL
was 1.4 mg/kg based on corneal opacity, acute inflammation, and
neovascularization; increased incidences of minimal extramedullary
hematopoeisis in the spleen, delayed preputial separation, and decreased
absolute brain weight.  There was no evidence of reproductive toxicity
or offspring susceptibility.  In the rat developmental toxicity study
the maternal NOAEL was 25 mg/kg bw/day based on decreased body weight
gains and food consumption.  The developmental NOAEL was less than 25
mg/kg/day based on decreased fetal body weights, increased number of
runts, and increased skeletal variations.  In the rabbit developmental
toxicity study the maternal NOAEL was 10 mg/kg based on reduced food
consumption, few feces, abortion, and decreased body weight.  The
developmental NOAEL was 1 mg/kg bw/day based on increase incidence of
skeletal anomalies and variations in the fetuses.  Skeletal variations
have been noted with exposure to other HPPDase inhibiting compounds.  In
a developmental neurotoxicity study in rats the maternal NOAEL was 0.8
mg/kg bw/day based on decreased body weight and body weight gain and
corneal opacities.  An offspring NOAEL was not determined and the LOAEL
was 0.8 mg/kg based on decreased post-weaning body weight (males),
decreased acoustic startle response on PND 60 (males), and brain
morphometric changes on PND 75 (males and females).  The lower body
weight effects resulted in delayed preputial separation and decreased
acoustic startle response.

4. Subchronic toxicity. The subchronic toxicity of tembotrione was
investigated via the oral route in 90-day feeding studies in mouse, rat
and dog, and via the dermal route in two 28-day dermal toxicity studies
in rat.  In general, there was mild to moderate toxicity observed in
mice and dogs at high doses.  The rat is the most sensitive species,
with the male rat being more sensitive than the female rat.  Effects
were typically seen in the eye, kidney, liver, thyroid and pancreas. 
These same effects were also seen in the chronic feeding studies.  The
90-day oral NOAEL in mice was 64 mg/kg bw/day based on liver effects. 
The 90-day oral NOAEL resulting from two rat studies was 0.3 mg/kg
bw/day based on corneal opacity in a male rat.  Effects on liver and
kidney were also noted at higher doses.  The 90-day oral NOAEL in the
dog was 26.7 mg/kg bw/day based on reduced body weight, corneal
opacities, hematological changes, clinical chemistry and liver effects. 
The 28-day NOAEL resulting from two dermal toxicity studies in rat was
less than 50 mg/kg bw/day based on effects in the pancreas.  Similar
effects have been noted with other HPPDase inhibiting compounds, and
mechanistic data indicates that these effects are likely due to elevated
tyrosine levels due to HPPD inhibition.  A 90-day neurotoxicity study in
rats showed no evidence of neurotoxicity following exposure to
tembotrione.

5. Chronic toxicity.  The chronic toxicity and oncogenic potential of
tembotrione was evaluated in mice, dog and rats.  A NOAEL was not
established (<2.5 mg/kg) in the one year dog feeding study based on
increased number of digestion chambers of the sciatic nerve.  An initial
combined chronic/oncogencity study was initiated in the male and female
rats.  However, a high mortality rate in the high dose males led to
early termination of the male portion of this study.  The female portion
of the study continued through scheduled completion while a new combined
chronic/carcinogenicity study of tembotrione in the male rat by dietary
administration was initiated at lower dose levels.  The resulting
chronic toxicity NOAEL from these two was 0.04 based on eye effects,
decreased body weights, kidney effects and chronic nephropathy and
atrophy of the sciatic nerve.  A chronic toxicity NOAEL in mice was not
determined but the LOAEL was 4 mg/kg based on hematological, liver, gall
bladder and kidney effects.  There was a slight increase in neoplastic
lesions; i.e., squamous cell carcinoma of the cornea at higher dose
levels when compared to controls. This change was considered to be a
result of the keratitis of the eye.  Based on this, the HED CARC has
classified tembotrione as “Suggestive Evidence of Carcinogenic
Potential” and determined that quantification of carcinogenic
potential is not required. The RfD is assumed to be protective of any
potential cancer effects.

	6. Animal metabolism. Metabolism studies conducted in the rat show the
majority of residue was excreted within 48 hours.  A sex difference in
relation to the route of excretion was observed with the females
eliminating higher levels in the urine and the males eliminating higher
levels in the feces. The accumulation of radioactivity in tissues was
not apparent.  The major metabolic process in plants and mammals is
similar but metabolism is less complete in mammals with more limited
hydroxylation and ring cleavage compared to plants. In plants and
mammals monohydroxylation of the cyclohexane dione ring was the major,
initial metabolic process. Further hydroxylation to the dihydroxy
occurred in both but to a lesser extent in mammals than plants. Also the
dihdroxy metabolites formed were positional isomers with the
4,6-dihydroxy being formed in plants and the 4,5-dihydroxy being formed
in mammals. Cleavage of the cyclohexane dione ring to form the benzoic
acid metabolite, AE 046148 (M6) also occurred to a greater extent in
plants than animals. The benzyl alcohol plant metabolite, AE 1392936
(M2) which is closely related to AE 046148 (M6) was not detected in
mammals.

	7. Metabolite toxicology.  Toxicological evaluations of the three major
metabolites of tembotrione were conducted.  None of the metabolites
tested were mutagenic and all indicated lower toxicity than the parent
tembotrione.  AE 1417268 was tested as it was the major metabolite in
animal fodder and a different positional isomer from the related
compound found in mammals.  AE 046148 was tested as it was the major
metabolite found in grain and was only detected at a low level in
mammals.  Some toxicological testing was conducted on AE 1392936
confirming that it has properties similar to the more prevalent, related
molecule AE 046148, which can be considered not of toxicological
concern.

	8. Endocrine disruption.  The toxicology database for tembotrione is
current and complete.  Studies in this database include evaluation of
the potential effects on reproduction and development and an evaluation
of the pathology of the endocrine organs following short- or long-term
exposure.

C. Aggregate Exposure

The proposed reduction in tolerances for sweet corn has no impact on the
existing exposure and risk assessments for tembotrione.  A summary of
the Agency’s dietary and aggregate assessments for tembotrione was
published in the federal register on September 28, 2007.

D. Cumulative Effects

The proposed reduction in tolerances for sweet corn has no impact on
the existing exposure and risk assessments for tembotrione.  A summary
of the Agency’s cumulative assessment for tembotrione was published in
the federal register on September 28, 2007.

E. Safety Determination

The proposed reduction in tolerances for sweet corn has no impact on the
existing exposure and risk assessments for tembotrione.  A summary of
the Agency’s safety determination for tembotrione was published in the
federal register on September 28, 2007.

F. International Tolerances

[Codex MRLs are not yet established for tembotrione.]

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