 

<COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE  (1/1/2006)>

<EPA Registration Division contact: [Janet Whitehurst, 703 305-6129]>

 

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<[Bayer CropScience]>

<[6F7123]>

<	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.>

<(Options (pick one)>

<	1. by establishing a tolerance for residues of>

<	2. to establish an exemption from the requirement of a tolerance for>

<	[the fungicide trifloxystrobin and the free form of its acid
metabolite

(CGA–32113)] in or on the raw agricultural commodity [fruit, citrus,
group 10] at [0.4] parts per million (ppm); [citrus, oil] at [36] ppm;
and [citrus, dry pulp] at [1.0] 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.>

<A. Residue Chemistry>

<	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.]>

<	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.]>

αE)-α-(methoxyimino)-2-[[[(E)-[1-[3-(trifluoromethyl)
phenyl]ethylidene]amino]oxy] methyl]benzeneacetate] residue in citrus
fruit with a target rate of 0.125 lb ai/A following 7-day pre-harvest
interval. Thirteen trials were conducted on oranges (eleven harvest and
two decline), five trials were conducted on lemons (four harvest and one
decline) and six trials were conducted on grapefruit (five harvest and
one decline). Each trial had two treated plots and one control plot. One
treated plot received concentrated spray applications while the other
received diluted spray applications.

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 0.305 ppm. The maximum total trifloxystrobin
residue in oranges, lemons and grapefruit were all within a factor of 5
of each other and, therefore, within the EPA guidelines for the
establishment of a group tolerance for Crop Group 10 (Citrus Fruit).]>

<B. Toxicological Profile>

<	1. Acute toxicity.  [  SEQ CHAPTER \h \r 1 Studies conducted with the
technical material of trifloxystrobin:

rat acute oral toxicity study with a LD50 >5000 mg/kg

mouse acute oral toxicity study with a LD50 >5000 mg/kg

rabbit acute dermal toxicity study with  a LD50 >2000 mg/kg

rat acute dermal toxicity study with  a LD50 >2000 mg/kg

rat acute inhalation toxicity study with a LC50 >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.]>

<	2. Genotoxicty. [  SEQ CHAPTER \h \r 1 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.]>

<	3. Reproductive and developmental toxicity. [  SEQ CHAPTER \h \r 1
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.

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.

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.]>

<	4. Subchronic toxicity. [  SEQ CHAPTER \h \r 1 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.]>

<	5. Chronic toxicity. [  SEQ CHAPTER \h \r 1 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.]>

<	6. Animal metabolism. [  SEQ CHAPTER \h \r 1 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.]>

<	7. Metabolite toxicology. [  SEQ CHAPTER \h \r 1 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 (LD50 >2000 mg/kg). In conclusion, the metabolism and
toxicity profiles support the use of an analytical enforcement method 
that accounts for parent trifloxystrobin.]>

<	8. Endocrine disruption. [  SEQ CHAPTER \h \r 1 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.]>

<C. Aggregate Exposure>

<	1. Dietary exposure. [  SEQ CHAPTER \h \r 1 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, and star apple;
plus this proposal to reduce the PHI on citrus.  

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 oxicity study and an uncertainty factor or 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 and 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.]>

<	i. Food. [  SEQ CHAPTER \h \r 1 For food, a Tier 1 acute and a Tier 2
chronic dietary exposure assessments were performed. Acute exposure,
expressed at the 95th 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 25.1%
cPAD for the most sensitive population, children 1-2 years old.]>

<	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).]>

<	2. Non-dietary exposure. [  SEQ CHAPTER \h \r 1 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.]>

<D. Cumulative Effects>

<	[  SEQ CHAPTER \h \r 1 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.]>

<E. Safety Determination>

<	1. U.S. population. [  SEQ CHAPTER \h \r 1 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.]>

<	2. Infants and children. [  SEQ CHAPTER \h \r 1 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.]>

<F. International Tolerances>

<	[No Codex MRLs have been established for trifloxystrobin on citrus.
MRLs have been established for citrus in the following countries:
Argentina, Belgium, Brazil, European Union, Spain, Germany, Netherlands,
Japan, and South Africa.]>

