 

<EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  (7/1/2007) >

<EPA Registration Division contact: [insert name and telephone number
with area code] >

 

<INSTRUCTIONS:  Please utilize this outline in preparing the pesticide
petition.  In cases where the outline element does not apply, please
insert “NA-Remove” and maintain the outline. Please do not change
the margins, font, or format in your pesticide petition. Simply replace
the instructions that appear in green, i.e., “[insert company
name],” with the information specific to your action. >

<TEMPLATE: >

<Bayer CropScience >

< [Insert petition number] >

<	EPA has received a pesticide petition ([insert petition number]) from
Bayer CropScience, 2 T.W. Alexander Drive, P.O. Box 12014, 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 tolerances and/or changing existing tolerances for
residues of>

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

<	trifloxystrobin (benzeneacetic acid,
(E,E)-α-(methoxyimino)-2-[[[[1-[3- (trifluoromethyl)
phenyl]ethylidene]amino]oxy]methyl]-methyl ester) and the free form of
its acid metabolite CGA–321113
((E,E)-methoxyimino-[2-[1-(3-trifluoromethyl-phenyl)-ethylideneaminooxym
ethyl]-phenyl]acetic acid) in or on the raw agricultural commodity
[alfalfa, forage] at 0.01 parts per million (ppm) and  [alfalfa, hay] at
0.01 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  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.   SEQ CHAPTER \h \r 1 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.   SEQ CHAPTER \h \r 1 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.  A newer analytical method is available
employing identical solvent mixtures and solvent to matrix ratio (as the
first method), deuterated internal standards, and liquid
chromatography/mass spectrometry-mass spectrometry (LC/MS-MS) with an
electrospray interface, operated in the positive ion mode.  The limits
of detection (LOD) for trifloxystrobin range from 0.002 ppm to 0.01 ppm,
depending on the crops, and the limit of quantitation is 0.01 ppm. >

<	3. Magnitude of residues.  

Alfalfa seed, treated with [benzeneacetic-phenyl-UL-14C] trifloxystrobin
at rates of

0.0039 lb. ai/100 lb. seed and 0.0125 lb. ai/100 lb. seed (0.83X the
target maximum rate of 0.015 lb. ai/100 lb. seed), was planted, and
alfalfa was grown to maturity.

The alfalfa raw agricultural commodity (RAC) of forage was collected
from three cuttings at BBCH 61 to 65 (10% flowering to 50% flowering).
Additionally, alfalfa hay samples were collected, following drying, from
the second and third cuttings.

All RAC samples were homogenized and radioassayed. The limit of
quantitation (LOQ) for detection of total radioactive residue from all
RACs was 0.0028 ppm. The total radioactive residue (TRR) in both alfalfa
forage and hay from seed treated at both application rates was
comparable to that of control samples at all three cuttings (net residue
<0.0028 ppm).  

<B. Toxicological Profile>

<	1. Acute toxicity.  There is a full battery of acute toxicity studies
for trifloxystrobin. Trifloxystrobin is of mild acute toxicity by oral,
dermal, or inhalation routes of exposure (Cat. IV), however it is a
strong dermal sensitizer. Trifloxystrobin is a mild ocular (Cat III) and
dermal irritant (Cat IV). >

<	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 In a
developmental study in rats, reductions in body weight gain and food
consumption were observed in the dams at (100 mg/kg/day. No teratogenic
effects or any other effects were seen on pregnancy or fetal parameters
except for the increased incidence of enlarged thymus at
1000 mg/kg/day. The developmental NOEL was 1000 mg/kg/day.

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 (3.8 mg/kg) seen in this
study was probably due to the lack of intermediate dose levels between
50 and 750 ppm. The reproductive NOAEL was 1500 ppm (=110.6 mg/kg/day).
>

<	4. Subchronic toxicity.   SEQ CHAPTER \h \r 1 In a subchronic study in
rats a NOAEL of 500 ppm (30.6-32.8 mg/kg/day) was found based on
decreased body weights (males), hypertrophy of hepatocytes (males), and
pancreatic atrophy observed at the LOAEL of 2000 ppm (127-133
mg/kg/day).

In mice, a NOAEL was determined at 500 ppm (76.9-110 mg/kg/day) based on
increased liver weights and necrosis of hepatocytes observed at the
LOAEL of 2000 ppm (315-425 mg/kg/day).

A subchronic feeding study in dogs resulted in a NOAEL of 30 mg/kg/day.
Increased liver weight and hepatocyte hypertrophy in males were observed
at the LOAEL of 150 mg/kg/day. 

In a 28–day dermal toxicity study in rats the NOAEL was found at 100
mg/kg/day. Increased liver and kidney weight were observed at the LOAEL
of 1,000 mg/kg/day. >

<	5. Chronic toxicity. A chronic feeding study in dogs established a
no-observed adverse effect level (NOAEL) of 5 mg/kg/day. The lowest
effect level (LOAEL) for this study was found at 50 mg/kg/day, based on
clinical signs, increased liver weight and hepatocellular hypertrophy. 

In a carcinogenicity study in mice liver effects were observed at doses
of and above the LOAEL of 1000 ppm (131.1 mg/kg/day). The NOAEL was
determined to be 300 ppm (39.4 mg/kg/day).

A chronic toxicity/carcinogenicity study in rats established a NOAEL of
250 ppm (9.81–11.37 mg/kg/day). Decreased mean body weight and
decreased mean body weight gain (compared to control) were observed at
the LOAEL of 750 ppm (29.7–34.5 mg/kg/day).

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.  An ad hoc subcommittee of
the Cancer Assessment Review Committee on May 27, 1999 determined that
trifloxystrobin should be classified as a "Not Likely Human Carcinogen,"
based on the lack of evidence for carcinogenicity in rats and mice.  >

<	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 elimination
half life 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 material 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 exposure of
the U.S. population and selected population subgroups to residues of
trifloxystrobin.  These analyses cover all registered and pending uses
including the proposed use as a seed treatment in alfalfa.  

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 bw/day from a rabbit developmental toxicity study and an
uncertainty factor or 100. The FQPA SF was reduced to 1x based on
toxicological considerations by the FQPA Safety Factor Committee (HED
Doc. No. 013545, B. Tarplee, 01/JUL/1999), the conservative residue
assumptions used in the dietary and residential exposure risk
assessments, and the completeness of the residue chemistry and
environmental fate databases (DP Num: 3 17330, B. O'Keefe,1 6/AUG/2006).
 For chronic dietary analyses, the EPA established a chronic Population
Adjusted Dose (cPAD) of 0.038 mg/kg/day based on a NOAEL of 3.8 mg/kg
bw/day from the rat reproduction 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 the proposed changes
to corn and sweet corn tolerances. >

<	i. Food.    SEQ CHAPTER \h \r 1 For food, a Tier 1 acute and chronic
dietary exposure assessments were performed. Acute exposure, expressed
at the 95th percentile of exposure, was 1.5 % of the aPAD for Females
13-49 years old (only population subgroup of concern).  The chronic
exposure was 36.2 % cPAD for the Total US Population and 69.6 % cPAD for
the most sensitive population, Children 1-2 years old. >

<	ii. Drinking water. 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 and for chronic exposures at 140 ppb. These values
are listed in the Federal Register (71 FR 55313). >

<	2. Non-dietary exposure. There is no potential for dermal or
incidental oral exposure during or post application of trifloxystrobin
when applied as a seed dressing to alfalfa.   As such, non-dietary
exposure from these new tolerances are covered by previous non-dietary
risk assessments performed by EPA.   SEQ CHAPTER \h \r 1 As published in
the Federal Register (FR Vol 68, no. 175, 10-Sep-03, FR Vol 73, no. 1,
02-Jan-08), 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>

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under Aggregate Exposure, there is reasonable certainty that exposure
from trifloxystrobin will result in no harm to the adult U.S.
population. >

<	2. Infants and children. Based on the information supplied above under
Aggregate Exposure, there is reasonable certainty that exposure from
trifloxystrobin will result in no harm to the infants and children. >

<F. International Tolerances>

<	International tolerances and CODEX tolerances for trifloxystrobin are
established for many crops in various countries. No tolerances exist yet
in Canada or Mexico for the new proposed uses. >

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