Document ID: EPA-HQ-OPP-2014-0379-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2014-10-24T04:00Z

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

EPA Registration Division contact: Erin Malone, 703-347-0253

TEMPLATE:

Cheminova, Inc.

P# 4G8247

	EPA has received a pesticide petition (P#4G8247) from Cheminova, Inc.,
1600 Wilson Blvd., Suite 700, Arlington, VA 22209-2510 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
temporary tolerance for residues of Flutriafol in or on the raw
agricultural commodity corn, sweet, kernel plus cob with husks removed
at 0.01 parts per million (ppm); corn, sweet, forage at 5 parts per
million (ppm); corn, sweet, stover at 15 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

Plant metabolism. 

The nature of the residue in plants is adequately understood. The major
residue in apples, oilseed rape, sugar beet and cereals treated with
flutriafol is the parent compound.

Analytical method. 

Adequate enforcement analytical methods for determining flutriafol in/on
appropriate raw agricultural commodities and processed commodities are
available for the established and proposed tolerances.

Magnitude of residues. 

Crop Field Trials

There are no available residue data for sweet corn.  The proposed
maximum use rate for flutriafol on sweet corn is the same as the
currently registered use rate on field corn and popcorn. Consequently,
Cheminova believes that the field corn data are applicable to this
petition and support the proposed temporary tolerance for sweet corn at
the same level.  For example, the existing tolerance for corn, field,
grain is 0.01 ppm (which corresponds to the LOQ). 

Field trial data have been generated for flutriafol and three triazole
metabolites on field corn.  Twenty trials were conducted in major field
corn growing regions during the 2009 growing season.  Two decline trials
were conducted, and data on field corn processed commodities were
provided from one site. 

The LOQ and LOD for flutriafol in corn matrices were 0.01 ppm and 0.003
ppm, respectively.  Results from the decline trials show that flutriafol
residues were <LOQ (<0.01 ppm) in all grain samples collected at each of
the five sampling intervals, up to 21 days after the last application
(DALA).

Field corn commodity and processed samples were also analyzed for the
three metabolites, 1,2,4-triazole (T), triazole alanine (TA), and
triazole acetic acid (TAA).  The LOQ for each metabolite was 0.01 ppm. 
No residues of metabolites T and TAA >LOQ were found in treated grain,
whereas TA residues ranged from <LOQ to 0.112 ppm.  

For dietary exposure assessment, EPA has concluded that the residues of
concern in field corn and popcorn consist of flutriafol (free and
conjugated) and defluorinated flutriafol.  Total residues of concern are
estimated by multiplying the measured parent flutriafol residue by a
factor of 2.2X.  

B. Toxicological Profile

	1. Acute toxicity.  

The acute oral LD50 is 1140 mg/kg bw and 1480 mg/kg bw in male and
female rats, respectively. The acute dermal LD50 of flutriafol is >2000
mg/kg bw in rats. The acute inhalation LC50 in rats is >5.20 mg/L.
Flutriafol displayed mild eye irritation in rabbits. It is not a skin
irritant to rabbits. Flutriafol is not a skin sensitizer.

	2. Genotoxicty. 

Flutriafol was evaluated for possible mutagenic/genotoxic effects in in
vitro and in vivo test systems. In these studies flutriafol was not
mutagenic in either bacterial or mammalian cells at concentrations that
were not highly cytotoxic in the presence and absence of metabolic
activation in vitro. No clastogenic potential in in vitro and in vivo
cytogenetic studies was demonstrated, and no induction of forward
mutations was observable in vitro. Furthermore, flutriafol did not
induce unscheduled DNA synthesis in vivo, and no clastogenicity was
observable in germ cells of mice. Overall, the data indicate that
flutriafol has no genotoxic/mutagenic potential in vitro and in vivo.

In three genotoxicity studies flutriafol was not mutagenic in either
bacterial or mammalian cells at concentrations that were not highly
cytotoxic in the presence and absence of metabolic activation in vitro.
No clastogenic potential in the in vitro chromosome aberration study was
demonstrated. These results are consistent with the conclusions of the
originally submitted genotoxicity studies.

	3. Reproductive and developmental toxicity. 

A two-generation reproductive toxicity study in rats was conducted with
flutriafol at doses of 0, 60, 240 or 1000 ppm in the diet. The parental
NOAEL was 240 ppm (calculated by EPA to be 20.6 mg/kg bw/day in males
and 21.9 mg/kg bw/day in females) based on reduced body weight gain and
food consumption, and effects on the liver (increased liver weights,
centrilobular hypertrophy and fatty changes). The NOAEL for
developmental and reproductive toxicity was 240 ppm (20.6 mg/kg bw/day
for males and 21.9 mg/kg bw/day for females) based on reduced litter
sizes and effects on the liver (fatty change/vacuolation).

In a second two-generation reproduction study, flutriafol was
administered to groups of rats at concentrations of 0, 30, 80, 150 and
300 ppm in the diet. In the P and F1 parental generations, dietary
exposure to flutriafol resulted in centrilobular hepatocellular
hypertrophy at 300 ppm. These findings correlated with increased liver
to body weight ratios in P parental animals, which are indicative of an
adaptive change to metabolic activation by a xenobiotic and not a toxic
response due to the administration of flutriafol. At 150 ppm, 80 ppm and
30 ppm, no test item-related effects were noted.

There were no treatment-related differences in reproductive parameters
between treated animals and controls. There were no treatment-related
differences in litter parameters between treated groups and controls.
Based on these results, 300 ppm (15.6 mg/kg bw/day for males and 20.7
mg/kg bw/day for females) is the NOAEL for parental toxicity and is the
NOEL for effects on reproductive function. The NOEL for parental
toxicity is 150 ppm. The results of this new study confirm the earlier
study that flutriafol is not a reproductive toxicant to rats.

In the rat developmental toxicity study, flutriafol was orally
administered at doses of 0, 2, 5, 10 or 75 mg/kg bw/day. The maternal
toxicity NOAEL was 10 mg/kg bw/day based on reduced body weight gain and
food consumption. The developmental toxicity NOAEL was 10 mg/kg bw/day
based on increased late resorptions and specific
malformations/variations, including hyoid arch absent, interrupted,
and/or misshapen.

In the rabbit developmental study, flutriafol was administered at doses
of 0, 2.5, 7.5 or 15 mg/kg bw/day. The NOAEL for maternal toxicity was
7.5 mg/kg bw/day based on reduced body weight gain and food consumption.
The NOAEL for developmental toxicity was 7.5 mg/kg bw/day based on an
increase in post-implantation losses and a reduction in the number of
viable fetuses.

Flutriafol is neither a reproductive nor developmental toxicant in the
absence of paternal/maternal toxicity.

Subchronic toxicity. 

The short-term toxicity of flutriafol was investigated in several
subchronic studies including a 90-day feeding study in rats and a 90-day
study in dogs. A 28-day dermal toxicity study in rats was also
performed.

The 90-day rat feeding study was conducted with dietary concentrations
of 0, 20, 200 or 2000 ppm. The NOAEL of 200 ppm (14 mg/kg bw/day for
males and 22 mg/kg bw/day for females) was based on decreased body
weight gain and food consumption and liver toxicity (increased absolute
and relative liver weights, increased endoplasmic reticulum
proliferation in the male rats and increased APDM activity).

In the 90-day study in dogs, flutriafol was administered at
concentrations of 0, 1, 5 or 15 mg/kg bw/day via capsule. The NOAEL was
5 mg/kg bw/day based on reduced body weight gain in females, changes in
hematology and clinical chemistry parameters in both sexes, and effects
in the livers of males and females and in the spleens of the males at
the 15 mg/kg bw/day.

In the 28-day dermal toxicity study in rats, there was no evidence of
systemic toxicity and the NOAEL was >1000 mg/kg bw/day.

Chronic toxicity. 

A one-year oral study in the dog was conducted at concentrations of 0,
1, 5 or 20 mg/kg bw/day. The NOAEL was 5 mg/kg bw/day based on adverse
liver findings (increased liver weights, increased lipid content of
hepatocytes, and increased alkaline phosphatase, albumin and
triglycerides), increased adrenal cortical vacuolation of the zona
fasciculate, and increased hemosiderin deposition in the spleen and
liver of both sexes; decreased body weight gain, and increased adrenal
weights in females.

In a two-year chronic toxicity and oncogenicity study, flutriafol was
administered in the diet to rats at doses of 0, 20, 200 or 2000 ppm. The
NOAEL was 200 ppm (calculated by EPA to be 10.0 mg/kg bw/day in males
and 12.2 mg/kg bw/day in females) based on reduced body weight, body
weight gain, and food consumption in both sexes and adverse liver
effects (increased liver weights, fatty change, bile duct
proliferation/cholangiolarfibrosis, hemosiderin accumulation in Kupffer
cells and centrilobular hypertrophy) and clinical chemistry findings.
There was no evidence of carcinogenicity in this study.

In a two-year oncogenicity study, flutriafol was administered in the
diet to mice at doses of 0, 10, 50 or 200 ppm. The NOAEL was 50 ppm
(calculated by EPA to be 5.9 mg/kg bw/day in males and 7.4 mg/kg bw/day
in females) based on reduced body weight and body weight gain in males
and females, increased liver weight, and hepatocellular hypertrophy and
centrilobular fatty change in the liver. There was no evidence of
carcinogenicity in this study.

Neurotoxicity. 

In an acute neurotoxicity study, rats were administered flutriafol by
gavage at doses of 0, 125, 250 or 750 mg/kg bw. EPA concluded that the
systemic NOAEL was 250 mg/kg bw based on decreased body weight gain and
food consumption and clinical signs of toxicity indicative of a moribund
condition. The neurotoxicity NOAEL was >750 mg/kg bw.

In a subchronic neurotoxicity study, flutriafol was administered in the
diet to rats at doses of 0, 500, 1500 or 3000 ppm. The systemic NOAEL
was 1500 ppm (84.3 mg/kg bw/day in males and 97.6 mg/kg bw/day in
females) based on decreased body weight gain and decreased absolute and
relative food consumption. The neurotoxicity NOAEL was >3000 ppm (>172.1
mg/kg bw/day in males and >185.0 mg/kg bw/day in females).

	7. Immunotoxicity. 

In an immunotoxicity study, flutriafol was administered to 10
Crl:CD1(ICR) female mice/group in the diet at dose levels of 0, 50, 250,
500 and 1000 ppm (equivalent to 0, 9.8, 46.8, 94.0 and 208.0 mg/kg
bw/day, respectively) for 28 consecutive days. Immunotoxicity was
evaluated by assessment of the spleen IgM antibody response to the
T-dependent antigen, sheep red blood cells (sRBCs). The NOAEL for
general toxicity in female CD-1 mice was 50 ppm (9.8 mg/kg bw/day) based
on increased absolute and relative liver weights and hematology effects
(decreased mean corpuscular volume). There were no significant effects
on absolute and relative spleen weights, spleen cell number and spleen
IgM antibody response to the T cell-dependent antigen, sheep
erythrocytes at any dose level. Therefore, the immunotoxic NOEL is 1000
ppm (208 mg/kg bw/day), the highest dose tested.

	8. Animal Metabolism. 

Based on a series of studies, flutriafol is extensively metabolized in
the rat and the metabolic processes are well understood. 

	

Flutriafol was quantitatively absorbed after oral administration to rats
and the extent of absorption was in the range of 90% to 99% of the
administered dose. Flutriafol is rapidly distributed, metabolized and
eliminated in rats for all dosing regimens after oral administration.
After single oral administration 78% and 91% of the dose given was
excreted in urine and bile/feces within 72 hours and 47% to 79% of the
dose was eliminated with bile. Only 0.8% to 10.4% of the dose given was
directly excreted with feces. After repeated oral administration,
excretion in urine and feces 24 hours after the first and last dose was
comparable. The major route of excretion was urinary accounting for
approximately 50% to 61% of the daily dose excreted within 24 hours
after dosing, while fecal excretion accounted for approximately 30% to
40%. Residues in carcass 168 hours after the last of 14 daily doses of
flutriafol were found to be less than 3% of administered doses.
Flutriafol is distributed systemically resulting in highest tissue
levels in whole blood, kidneys, liver, and muscle within the range of
0.7% to 1.46 % of daily dose.

The metabolites identified indicated that the 2-fluorophenyl ring of
flutriafol was the main site for biotransformation. The initial
metabolic step probably involved epoxidation followed by either
rearrangement to form the dihydrodiol isomers of flutriafol or to form
hydroxy or dihydroxy metabolites. The hydroxyl groups on these primary
metabolites may then be either conjugated with glucuronic acid or
methylated. A second, minor route, for the metabolism of flutriafol was
via the removal of the triazole ring to form 1-(2
fluorophenyl)-1-(4-fluorophenyl)-ethandiol, which is then conjugated
with glucuronic acid.

The results demonstrated that absorption, distribution, metabolism, and
excretion of flutriafol was comparable in both sexes and also similar
after single low, single high, or repeated low-dose scenario. The data
indicate that flutriafol and/or its metabolites do not bioaccumulate.

9. Metabolite Toxicology

Data regarding the potential toxicity of the three metabolites common to
triazoles have been developed and submitted by the US Triazole Task
Force. The Task Force has entered into a data access agreement with
Cheminova A/S by which it has authorized Cheminova to rely on all of the
studies, data and information that the Task Force has submitted to EPA.
This includes the comprehensive risk assessment of these three
metabolites. Cheminova hereby incorporates and relies on the Task Force
studies, data and information in support of its pesticide action. This
includes relying on the T-D metabolite risk assessment submitted to the
EPA by the Task Force.

10. Endocrine Disruption

All guideline studies conducted to characterize the toxicological
profile showed no endocrine-related toxicity or tumorigenicity.

C. Aggregate Exposure

Dietary exposure. 

Temporary tolerances are proposed for residues of flutriafol on corn,
sweet, K+CWHR; corn, sweet, forage; and corn, sweet, stover.  These
temporary tolerances, which reflect direct foliar application, will
replace the existing tolerances for sweet corn commodities as a
rotational crop.  

For the purposes of assessing the potential dietary (food and drinking
water) exposure, an exposure assessment including sweet corn commodities
in addition to all of the registered and pending crops was conducted
using the Dietary Exposure Evaluation Model-Food Consumption Intake
Database (DEEM-FCID) software, consumption data derived from the
2003-2008 National Health and Nutrition Examination Survey (NHANES),
assuming tolerance-level residues and 100% crop treated.  Estimated
potential concentrations in drinking water were incorporated directly
into the dietary exposure assessments to provide total aggregate dietary
exposure estimates.

For the purpose of dietary exposure assessment, it is assumed that the
residues of concern for all commodities are parent flutriafol and the
three triazole metabolites designated as T, TA and TAA.  Adjustment
factors to account for potential residues of conjugated or defluorinated
flutriafol metabolites are included as appropriate in risk assessment
calculations for corn, cotton, peanut, wheat and triticale commodities.

	

Non-dietary exposure. 

Flutriafol is currently not registered for use on any residential
non-food site.  Therefore, residential exposure to flutriafol residues
will be through dietary exposure only.

D. Cumulative Effects

Flutriafol is a member of the triazole class of fungicides.  Other
members of this class are registered for use in the United States. 
Although flutriafol and other triazoles may have similar fungicidal
modes of action, there are no available data to determine whether
flutriafol has a common mechanism of mammalian toxicity with other
triazoles or information on how to include this pesticide in a
cumulative risk assessment.  Therefore, for the purposes of this
tolerance petition no assumption has been made with regard to cumulative
exposure with other compounds having a common mode of action.

E. Safety Determination

U.S. population. 

Using the conservative exposure assumptions described above and based on
the completeness of the toxicity data, it can be concluded that total
food and drinking water exposure to flutriafol from all registered,
pending and proposed crop uses will be 1.08% of the aPAD and 19.4% of
the cPAD for the overall US population.  For females 13-49 years old,
the population-specific aPAD is 0.075 mg/kg bw and estimated acute
dietary exposures accounted for 29.03% of the aPAD.  EPA generally has
no concern for exposures below 100% of the PAD because the PAD
represents the level at or below which daily aggregate exposures will
not pose appreciable risks to human health.  Thus, it can be concluded
that there is a reasonable certainty that no harm will result from
aggregate exposure to residues arising from the proposed tolerances that
are the subject of this petition and all approved and pending uses of
flutriafol.

Infants and children. 

t can be concluded that total food and drinking water exposure to
flutriafol from all proposed crop uses will be ≤2.58% of the aPAD and
≤62.4% of the cPAD for infants and children.

In assessing the potential for additional sensitivity of infants and
children to residues of flutriafol, the data from developmental toxicity
studies in both the rat and rabbit and a reproduction study in rats have
been considered.

The developmental toxicity studies evaluate potential adverse effects on
the developing animal resulting from pesticide exposure to the mother
during prenatal development.  The reproduction study evaluates effects
from exposure to the pesticide on the reproductive capability of mating
animals through two generations, as well as any observed systemic
toxicity.

EPA has concluded that there is no increased quantitative sensitivity to
infants and children based on the developmental and reproductive studies
conducted with flutriafol.  Therefore, infants and children are
adequately protected and an additional uncertainty factor for infants
and children is not warranted.

F. International Tolerances

Codex Maximum Residue Levels (MRLs) were established in 2012 for
residues of flutriafol for the following commodities: banana (0.3 ppm);
coffee beans (0.15 ppm); peanut (0.15 ppm); peanut fodder (20 ppm);
peppers, sweet (including pimento or pimiento) (1 ppm); peppers chili,
dried (10 ppm); pome fruits (0.3 ppm); soya bean (dry) (0.4 ppm); wheat
(0.15 ppm); wheat bran, unprocessed (0.3 ppm); and wheat straw and
fodder, dry (8 ppm). Codex MRLs are under review for grapes (0.8 ppm)
and dried grapes (2 ppm). There are no established tolerances for
flutriafol on any crops in Canada and Mexico.

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