Document ID: EPA-HQ-OPP-2013-0504-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2013-10-25T04:00Z

<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 >

< PP# 3F8180 >

<	EPA has received a pesticide petition (PP#3F8180) 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 180.555 >

<	by establishing tolerances and/or changing existing tolerances for
residues of>

<	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 [pea,
dry, seed] at 0.06 parts per million (ppm); [pea, field, hay] at 15
parts per million (ppm); [pea, field, vines] at 4.0 parts per million
(ppm); [chickpea, seed] at 0.06 parts per million (ppm); and [lentil,
seed] at 0.06 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 LODs for
trifloxystrobin range from 0.002 ppm to 0.01 ppm, depending on the
crops, and the LOQ of each analyte is 0.01 ppm. >

<	3. Magnitude of residues.  

Nine field-residue trials (eight harvest, one decline) were established
across Canada (three trials in Crop Growing Region 7, five in Crop
Growing Region 14) and the US (1 in Crop Growing Regions 7) where dry
peas are commonly grown. The treated plot received two foliar spray
applications of FOX 325 SC at 0.88 L FOX 325 SC/ha/application (286 g
ai/ha/application) for a total target seasonal rate of 572 g ai/ha. FOX
325 SC active ingredient is comprised of 150 g trifloxystrobin/L and 175
g prothioconazole/L. The corresponding target rate for trifloxystrobin
was 132 g trifloxystrobin/ha/application for a total seasonal rate of
264 g trifloxystrobin/ha.  The residue data from this study with dry
peas is intended to support proposed tolerances for dry peas, chickpeas
and lentils.

Dry pea vines (forage) and hay were collected at PHIs of 6 to 8 days in
the eight harvest trials and at 0, 3, 7, and 13 days in the single
decline trial. Dry pea seed was collected at PHIs of 29 to 31 days in
the harvest trials and at 20, 25, 31, 34, and 40 days in the decline
trial. Vines, hay, and seed samples were collected from the control
plots at the same time the 7 day vine and pea and the 30-day seed
samples were collected from the treated plots.  All samples were placed
in frozen storage within 8¼ hours after collection.  The samples were
analyzed for residue of total trifloxystrobin (sum of trifloxystrobin
and trifloxystrobin acid). The residue of total trifloxystrobin was
quantitated by high-pressure liquid chromatography/triple stage
quadrupole mass spectrometry (LC/MS/MS) using stable-labeled internal
standards. The limit of quantitation (LOQ) for total trifloxystrobin
residue was 0.02 ppm for dry pea vines, hay, and seed. 

Total trifloxystrobin residue in dry pea seed ranged from <0.020 ppm to
a maximum of 0.033 ppm for individual samples collected at the desired
PHI of 30 days. The HAFT residue found in/on dry pea seed was 0.032 ppm.

Total trifloxystrobin residue in dry pea hay ranged from 2.1 ppm to a
maximum of 8.4 ppm for individual samples collected at the desired PHI
of 7 days. The HAFT residue found in/on dry pea hay was 7.1 ppm. 

Total trifloxystrobin residue in dry pea vines ranged from 0.58 ppm to a
maximum of 2.3 ppm for individual samples collected at the desired PHI
of 7 days. The HAFT residue found in/on dry pea vines was 2.0 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.

	In the rabbit developmental study, body weight loss and reduced food
consumption were observed in the dams at 50 mg/kg/day, resulting in a
maternal NOEL of 50 mg/kg/day. 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/day. 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/day.

	In the 2-generation rat reproduction study, body weight gain and food
consumption were decreased at 750 ppm (55.3 mg/kg/day), especially in
females during lactation. Consequently, the reduced pup weight gain
during lactation (750 ppm) and the slight delay in eye opening (1500
ppm; 110.6 mg/kg/day) were 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/day) 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 1000 mg/kg/day. >

<	5. Chronic toxicity. A chronic feeding study in dogs established a
NOAEL of 5 mg/kg/day. The 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
at 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  Dietary risk assessments,
using the DEEM-FCID software Version 3.14 with USDA’s National Health
and Nutrition Examination Survey (NHANES) from 2003 to 2008 nationwide
continuing surveys of food intake by individuals, 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 uses on dry peas, chickpeas and lentils.

A Tier 1 dietary assessment was evaluated based on established
tolerances for all registered uses and 100% crop treated.  For the
proposed use on dry peas, chickpeas and lentils, the proposed tolerance
of 0.06 ppm was used in this assessment.  Chickpeas and dry peas can be
used as alternative feedstuff serving as a source of roughage and
protein.  The proposed uses are not feed to feedlot beef.  Addition of
the proposed uses on feed items will have minimal effect on total burden
for dairy cattle.  The current risk assessments are based on established
livestock tolerances (milk = 0.02 ppm) which are more conservative than
residues estimated from Maximum Reasonably Balanced Diets (MRBD).  

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 and proposed uses on dry
peas, chickpeas and lentils.

<	i. Food.    SEQ CHAPTER \h \r 1 For food, a Tier 1 acute and chronic
dietary exposure assessments were performed. Acute exposure for food
only, expressed at the 95th percentile of exposure, was 1.3% of the aPAD
for Females 13-49 years old (only population subgroup of concern).  The
chronic exposure for food only was 27% cPAD for the Total US Population
and 59% 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 48 ppb and 47 ppb
respectively as given in EPA’s Human Health Risk Assessment for a
Section 3 Petition Proposing Increased Tolerances for Residues in/on
Field, Sweet, and Pop Corn (February 25, 2010, DP Barcode 369104). >

<	2. Non-dietary exposure. There is no potential for dermal or
incidental oral exposure during or post application of trifloxystrobin
when applied to dry peas, chickpeas and lentils.   As such, non-dietary
exposure from this new tolerance is 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>

<	  SEQ CHAPTER \h \r 1 EPA has determined, as published in the Federal
Register (FR Vol 73, no. 1, 02-Jan-08)), 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  Acute and chronic dietary
risk estimates associated with exposure to trifloxystrobin in food and
water are expected to be well below the Agency's level of concern.  The
Tier I acute exposure analysis performed for all currently registered
and proposed food uses show that exposure to trifloxystrobin utilizes 2%
of the aPAD for Females 13-49 years old (only population subgroup of
concern).  The Tier I chronic exposure analysis performed for all
currently registered and proposed food uses show that exposure to
trifloxystrobin utilizes 30% of the cPAD for the U.S. population and 62%
of the cPAD for children 

1-2 years old, the subpopulation at greatest exposure.  This analysis
was conducted assuming 100% crop treated and tolerance level residue
values for all crops.  The contribution of trifloxystrobin residues in
drinking water to acute and chronic aggregate exposure was minimal. 
Therefore, Bayer CropScience concludes that even when considering the
potential incremental risk resulting from the proposed use on dry peas,
chickpeas and lentils, there is a reasonable certainty that no harm will
result from aggregate exposure to trifloxystrobin residues. >

ú

û

B*

B*

B*

B*

¸

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

hÎ

B*

# h

h

B*

h

B*

# h

B*

B*

B*

B*

B*

B*

B*

B*

hÎ

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

hÎ

B*

B*

B*

B*

B*

B*

B*

B*

옍)

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

B*

ᜀn drinking water and from non-dietary, non-occupational exposure, the
aggregate exposure to trifloxystrobin is expected to be well below the
level of concern. Bayer CropScience concludes that there is a reasonable
certainty that no harm will result to infants and children from
aggregate exposure to trifloxystrobin residues. >

<F. International Tolerances>

<	International and CODEX tolerances (MRLs) for trifloxystrobin are
established for many crops in various countries. At this time, there are
no international tolerances established for trifloxystrobin on dry pea,
chickpea, or lentil. 

 PAGE   

 PAGE   2