**[\<]{.mark}COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE
(1/1/2006)**[\>]{.mark}

**[\<]{.mark}EPA Registration Division contact: \[Janet Whitehurst, 703
305-6129\][\>]{.mark}**

**[\<]{.mark}*INSTRUCTIONS:* Please utilize this outline in preparing
tolerance petition documents. In cases where the outline element does
not apply please insert "NA-Remove" and maintain the outline. The
comment notes that appear on the left margin represent hidden
typesetting codes designed to expedite the processing of the Federal
Register document. Please do not remove or alter these comment notes or
change the margins, font, or format in your document. Simply replace the
instructions that appear in italics and brackets, i.e., "****\[*insert
company name*\]," with the information specific to your
action.\][\>]{.mark}**

**[\<]{.mark}*TEMPLATE:*[\>]{.mark}**

**[\<]{.mark}\[Bayer CropScience\][\>]{.mark}**

**[\<]{.mark}\[7F7171\][\>]{.mark}**

**[\<]{.mark}** EPA has received a pesticide petition **(****\[insert
petition number\])** from **\[Bayer CropScience\], \[P.O. Box 12014, 2
T.W. Alexander Drive, Research Triangle Park, NC 27709\]** 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.**[\>]{.mark}**

**[\<]{.mark}(Options (pick one)[\>]{.mark}**

> [\<]{.mark} 1. by establishing a tolerance for residues of[\>]{.mark}

**[\<]{.mark}**

**[\<]{.mark} \[the fungicide trifloxystrobin and the free form of its
acid metabolite**

**(CGA--32113)\]** in or on the raw agricultural commodity
**\[**strawberry**\]** at **\[1.1\]** parts per million (ppm). EPA has
determined that the petition contains data or information regarding the
elements set forth in section 408 (d)(2) of the FDDCA; 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.**[\>]{.mark}**

[\<]{.mark}*A. Residue Chemistry*[\>]{.mark}

**[\<]{.mark}** 1. *Plant metabolism* **\[The metabolism of
trifloxystrobin in plants (cucumbers, apples, wheat, sugar beets and
peanuts) is well understood. Identified metabolic pathways are
substantially similar in plants and animals (goat, rat and hen). EPA has
determined that trifloxystrobin parent and its metabolite CGA-321113 are
the residue of concern for tolerance setting purposes.\][\>]{.mark}**

**[\<]{.mark}** 2. *Analytical method.* **\[A practical analytical
methodology for detecting and measuring levels of trifloxystrobin in or
on raw agricultural commodities has been submitted. The limit of
detection (LOD) for each analyte of this method is 0.08 ng injected, and
the limit of quantitation (LOQ) is 0.02 ppm. The method is based on crop
specific cleanup procedures and determination by gas chromatography with
nitrogen-phosphorus detection.\][\>]{.mark}**

**[\<]{.mark}** 3. *Magnitude of residues.* **\[A total of eight field
trials were conducted to measure the magnitude of the total
trifloxystrobin \[Methyl
(α*E*)-α-(methoxyimino)-2-\[\[\[(*E*)-\[1-\[3-(trifluoromethyl)
phenyl\]ethylidene\]amino\]oxy\] methyl\] benzeneacetate\] residue in
strawberry with a target rate of 0.1 lb ai/A following 0-day pre-harvest
interval. In one of the trails samples were collected at PHIs of 3-, 5-,
7-, and 10-days.**

**The residues of trifloxystrobin and trifloxystrobin acid were
quantitated by liquid chromatography/mass spectrometry-mass spectrometry
(LC/MS-MS) with an electrospray interface, operated in the positive ion
mode, using deuterated internal standards. The limit of quantitation
(LOQ) was 0.01 ppm. The highest average field trial (HAFT) total
trifloxystrobin residue was 0.562 ppm. Total trifloxystrobin residue was
found to decrease with time and upon washing and cooking.\][\>]{.mark}**

**[\<]{.mark}***B. Toxicological Profile***[\>]{.mark}**

**[\<]{.mark}** 1. *Acute toxicity.* **\[**Number range
CHAPTER**[Studies conducted with the technical material of
trifloxystrobin]{.underline}:**

**rat acute oral toxicity study with a LD~50~ \>5000 mg/kg**

**mouse acute oral toxicity study with a LD~50~ \>5000 mg/kg**

**rabbit acute dermal toxicity study with a LD~50~ \>2000 mg/kg**

**rat acute dermal toxicity study with a LD~50~ \>2000 mg/kg**

**rat acute inhalation toxicity study with a LC~50~ \>4.65 mg/L**

**rabbit eye irritation study showing slight irritation (Category III)**

**rabbit dermal irritation study showing slight irritation (Category
IV)**

**Guinea pig dermal sensitization study with the Buehler's method
showing negative findings**

**Guinea pig dermal sensitization study with the Maximization method
showing some positive findings.\][\>]{.mark}**

**[\<]{.mark}** 2. *Genotoxicty.* **\[**Number range CHAPTER**No
genotoxic activity is expected of trifloxystrobin under *in-vivo* or
physiological conditions. The compound has been tested for its potential
to induce gene mutation and chromosomal changes in five different test
systems. The only positive finding was seen in the *in vitro* test
system (Chinese hamster V79 cells) as a slight increase in mutant
frequency at a very narrow range (250 - 278 g/ml) of cytotoxic and
precipitating concentrations (compound solubility in water was reported
to be 0.61 g/ml; precipitate was visually noted in culture medium at
150 g/ml). The chemical was found to be non-mutagenic in the *in vivo*
system or all other *in vitro* systems. Consequently, the limited gene
mutation activity in the V79 cell line is considered a nonspecific
effect under non-physiological *in vitro* conditions and not indicative
of a real mutagenic hazard.\][\>]{.mark}**

**[\<]{.mark}** 3. *Reproductive and developmental toxicity.*
**\[**Number range CHAPTER**FFDCA section 408 provides that EPA may
apply an additional safety factor for infants and children in the case
of threshold effects to account for pre- and post-natal toxicity and the
completeness of the database. Based on the current toxicological data
requirements, the database on trifloxystrobin relative to pre- and
post-natal effects for children is complete.**

**In assessing the potential for additional sensitivity of infants and
children to residues of trifloxystrobin, data were considered from
teratogenicity studies in the rat and the rabbit and a 2-generation
reproduction studies in the rat. The teratogenicity studies are designed
to evaluate adverse effects on the developing embryo as a result of
chemical exposure during the period of organogenesis. Reproduction
studies provide information on effects from chemical exposure on the
reproductive capability of mating animals and systemic and developmental
toxicity from in-utero exposure.**

**In the rat teratology study, reductions in body weight gain and food
consumption were observed in the dam at 100 mg/kg. No teratogenic
effects or any other effects were seen on pregnancy or fetal parameters
except for the increased incidence of enlarged thymus, which is a type
of variation, at 1000 mg/kg. The developmental NOEL was 100 mg/kg.**

**In the rabbit teratology study, body weight loss and dramatically
reduced food consumption were observed in the dam at 250 mg/kg. No
teratogenic effects or any other effects were seen on pregnancy or fetal
parameters except for the increase in skeletal anomaly of fused
sternebrae-3 and -4 at the top dose level of 500 mg/kg. This finding is
regarded as a marginal effect on skeletal development that could have
resulted from the 40-65% lower food intake during treatment at this dose
level. The developmental NOEL was 250 mg/kg.**

**In the 2-generation rat reproduction study, body weight gain and food
consumption were decreased at 750 ppm, especially in females during
lactation. Consequently, the reduced pup weight gain during lactation
(750 ppm) and the slight delay in eye opening (1500 ppm) are judged to
be a secondary effect of maternal toxicity. No other fetal effects or
any reproductive changes were noted. The low developmental NOEL, 50 ppm
(5 mg/kg), seen in this study was probably due to the lack of
intermediate dose levels between 50 and 750 ppm. Based on an evaluation
of the dose-response relationship for pup weight at 750 ppm and 1500
ppm, the NOEL should have been nearly ten-fold higher if such a dose was
available.**

**Based on all these teratology and reproduction studies, the lowest
NOEL for developmental toxicity is 5 mg/kg while the lowest NOEL in the
subchronic and chronic studies is 2.5 mg/kg/day (from the rat chronic
study). Therefore, no additional sensitivity for infants and children to
trifloxystrobin is suggested by the data base.\][\>]{.mark}**

**[\<]{.mark}** 4. *Subchronic toxicity.* **\[**Number range CHAPTER**In
subchronic studies, several mortality related changes were reported for
the top dose in dogs (500 mg/kg) and rats (800 mg/kg). At these dose
levels, excessive toxicity has resulted in body weight loss and
mortality with the associated and nonspecific changes in several organs
(such as atrophy in the thymus, pancreas, bone marrow, lymph node, and
spleen) which are not considered specific target organs for the test
compound. In the dog, specific effects were limited to hepatocellular
hypertrophy at 150 mg/kg and hyperplasia of the epithelium of the gall
bladder at 500 mg/kg. Target organ effects in the rat were noted as
hepatocellular hypertrophy (200 mg/kg) and the related liver weight
increase (50 mg/kg). In the mouse, target organ effects included single
cell necrosis (300 mg/kg) and hypertrophy (1050 mg/kg) in the liver and
extramedullary hematopoiesis (300 mg/kg) and hemosiderosis in the
spleen (1050 mg/kg).**

**In general, definitive target organ toxicity, mostly in the liver, was
seen at high feeding levels of over 100 mg/kg for an extended treatment
period. At LOEL, no serious toxicity was observed other than mostly
non-specific effects including a reduction in body weight and food
consumption or liver hypertrophy.\][\>]{.mark}**

**[\<]{.mark}** 5. *Chronic toxicity.* **\[**Number range CHAPTER**The
liver appears to be the major primary target organ based on the chronic
studies conducted in mice, rats, and dogs. It was identified as a target
organ in both the mouse and the dog studies with trifloxystrobin.
However, no liver effect was seen in the chronic rat study which
produced the lowest NOEL of 2.5 mg/kg based on reduced body weight gain
and food consumption seen at higher dose levels.**

**The compound did not cause any treatment-related increase in general
tumor incidence, any elevated incidence of rare tumors, or shortened
time to the development of palpable or rapidly lethal tumors in the
18-month mouse and the 24-month rat studies. Dosages in both studies
were sufficient for identifying a cancer risk. In the absence of
carcinogenicity, a Reference Dose approach is appropriate for
quantitation of human risks.\][\>]{.mark}**

**[\<]{.mark}** 6. *Animal metabolism.* **\[**Number range
CHAPTER**Trifloxystrobin is moderately absorbed from the
gastrointestinal tract of rats and is rapidly distributed. Subsequent to
a single oral dose, the half life of elimination is about 2 days and
excretion is primarily via bile. Trifloxystrobin is extensively
metabolized by the rat into about 35 metabolites, but the primary
actions are on the methyl ester (hydrolysis into an acid), the
methoxyimino group (O-demethylation), and the methyl side chain
(oxidation to a primary alcohol). Metabolism is dose dependent as it was
almost complete at low doses but only about 60% complete at high
doses.**

**In the goat, elimination of orally administered trifloxystrobin is
primarily via the feces. The major residues were the parent compound and
the acid metabolite (CGA-321113) plus its conjugates. In the hen,
trifloxystrobin is found as the major compound in tissues and in the
excreta, but hydroxylation of the trifluormethyl-phenyl moiety and other
transformations, including methyl ester hydrolysis and demethylation of
the methoxyimino group, are also seen. In conclusion, the major pathways
of metabolism in the rat, goat, and hen are the same.\][\>]{.mark}**

**[\<]{.mark}** 7. *Metabolite toxicology*. **\[**Number range
CHAPTER**Metabolism of trifloxystrobin has been well characterized in
plants, soil, and animals. In plants and soil, photolytically induced
isomerization results in a few minor metabolites not seen in the rat;
however, most of the applied materials remained as parent compound as
shown in the apple and cucumber studies. All quantitatively major plant
and/or soil metabolites were also seen in the rat. The toxicity of the
major acid metabolite, CGA-321113 (formed by hydrolysis of the methyl
ester), has been evaluated in cultured rat hepatocytes and found to be
20-times less cytotoxic than the parent compound. Additional toxicity
studies were conducted for several minor metabolites seen uniquely in
plants and/or soil. The studies indicate that these metabolites,
including CGA-357261, CGA-373466, and NOA-414412, are not mutagenic to
bacteria and are of low acute toxicity (LD~50~ \>2000 mg/kg). In
conclusion, the metabolism and toxicity profiles support the use of an
analytical enforcement method that accounts for parent
trifloxystrobin.\][\>]{.mark}**

**[\<]{.mark}** 8. *Endocrine disruption*. **\[**Number range
CHAPTER**Trifloxystrobin does not belong to a class of chemicals known
for having adverse effects on the endocrine system. Developmental
toxicity studies in rats and rabbits and reproduction study in rats gave
no indication that trifloxystrobin might have any effects on endocrine
function related to development and reproduction. The subchronic and
chronic studies also showed no evidence of a long-term effect related to
the endocrine system.\][\>]{.mark}**

**[\<]{.mark}***C. Aggregate Exposure***[\>]{.mark}**

**[\<]{.mark}** 1. *Dietary exposure.* **\[**Number range
CHAPTER**Assessments, using the DEEM FCID Version 2.0, 1994-1996,98
CSFII software, were conducted to evaluate potential risks due to
chronic and acute dietary (food and water) exposure of the U.S.
population and selected population subgroups to residues of
trifloxystrobin. These analyses cover all registered crops; the pending
uses on asparagus, radish, the tropical crops papaya, black sapote,
canistel, mamey sapote, mango, sapodilla, star apple, citrus (reduce
PHI); plus this proposal to establish tolerances on strawberries.**

**The EPA has established an acute Population Adjusted Dose (aPAD) of
2.5 mg/kg/day for acute dietary risk assessments based on a NOAEL of 250
mg/kg bwt/day from a rabbit developmental toxicity study and an
uncertainty factor of 100. For chronic dietary analyses, the EPA
established a chronic Population Adjusted Dose (cPAD) of 0.038 based on
a NOAEL of 3.8 from a rat reproductive toxicity study and an uncertainty
factor of 100.**

**Results from the acute and chronic dietary exposure analyses described
below demonstrate a reasonable certainty that no harm to the overall
U.S. population or any population subgroup will result from the use of
trifloxystrobin on currently registered uses plus pending
uses.\]**[\>]{.mark}

[\<]{.mark} i. *Food.* **\[**Number range CHAPTER**For food, a Tier 1
acute and a Tier 2 chronic dietary exposure assessments were performed.
Acute exposure, expressed at the 95^th^ percentile of exposure, was
0.66% of the aPAD for females 13-49 years old (only population subgroup
of concern). The chronic exposure was 10.3% cPAD for the total US
population and 31.1% cPAD for the most sensitive population, all infants
(\< 1 yr).\]**[\>]{.mark}

[\<]{.mark} ii. *Drinking Food.* **\[Acute and chronic exposure
estimates from water are included in the exposure values given above for
food. These exposure estimates for water are based on EPA's surface
water estimated environmental concentrations (EECs) of trifloxystrobin
and CGA-321113 for acute exposure at 92 parts per billion (ppb) and for
chronic exposures at 140 ppb. These values are listed in the *Federal
Register* (71 FR 55313).\]**[\>]{.mark}

[\<]{.mark} 2. *Non-dietary exposure*. **\[**Number range CHAPTER**As
published in the *Federal Register* (71 FR 55313), the EPA considered
chronic, short term and intermediate term risk from residential uses of
trifloxystrobin. The EPA determined that the risk did not exceed the
Agency's level of concern.\]**[\>]{.mark}

[\<]{.mark}*D. Cumulative Effects*[\>]{.mark}

[\<]{.mark} **\[**Number range CHAPTER**EPA has determined, as published
in the *Federal Register* (71 FR 55313), that unlike other pesticides
for which EPA has followed a cumulative risk approach based on a common
mechanism of toxicity, trifloxystrobin does not appear to produce a
toxic metabolite produced by other substances. Therefore EPA has not
assumed that trifloxystrobin has a common mechanism of toxicity with
other substances.\]**[\>]{.mark}

[\<]{.mark}*E. Safety Determination*[\>]{.mark}

[\<]{.mark} 1. *U.S. population.* **\[**Number range CHAPTER**Based on
the information supplied under Aggregate Exposure describe above, there
is reasonable certainty that exposure from trifloxystrobin will not
result in harm to the adult U.S. population.\]**[\>]{.mark}

[\<]{.mark} 2. *Infants and children*. **\[**Number range CHAPTER**Based
on the information supplied under Aggregate Exposure describe above,
there is reasonable certainty that exposure from trifloxystrobin will
not result in harm to infants and children.\][\>]{.mark}**

**[\<]{.mark}***F. International Tolerances***[\>]{.mark}**

**[\<]{.mark} \[A Codex MRL has been established for trifloxystrobin on
strawberry at 0.2 ppm. MRLs have been established for strawberry in the
following countries: Australia, European Union, France, Germany Japan,
Spain and Switzerland.\][\>]{.mark}**