Document ID: EPA-HQ-OPP-2015-0179-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-04-22T04:00Z

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

EPA Registration Division contact: [Hope Johnson, 703-305-5410]

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:

[Cheminova, Inc.]

[Insert petition number]

	EPA has received a pesticide petition ([insert petition number]) 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 tolerance for residues of

	[Flutriafol] in or on the raw agricultural commodity [hops, dried
cones] at [20] 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.  Appropriate residue field trials have been
conducted to support the use of flutriafol on hops as proposed in this
petition.  All raw agricultural commodities in all fied trials were
analyzed for flutriafol and three triazole metabolites –
1,2,4-triazole (T), triazole alanine (TA), and triazole acetic acide
(TAA).  The flutriafol residues reported in these field trials support
the proposed tolerances.

B. Toxicological Profile

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.

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.

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).

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.

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.

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.

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

C. Aggregate Exposure

Dietary exposure.  A tolerance is proposed for residues of flutriafol on
hops, dried cones.  For the purposes of assessing the potential dietary
(food and drinking water) exposure, an exposure assessment including
hops, dried cones 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
in treated commodities and calculated anticipated residues in livestock
commodities.  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.

Acute Dietary Exposure.  The acute population adjusted dose (aPAD) for
females 13-49 years old is 0.075 mg/kg bw (NOAEL of 7.5 mg/kg/day from
the rabbit developmental toxicity study with a 100-fold uncertainty
factor).  The aPAD for other subpopulations is 2.5 mg/kg bw (NOAEL of
250 mg/kg from the acute neurotoxicity screening battery with a 100-fold
uncertainty factor).  These endpoints were used to characterize the risk
associated with acute dietary exposures.  Cheminova has conducted an
acute dietary exposure Tier 1 analysis with DEEM-FCID using the proposed
temporary tolerances that are the subject of this petition in addition
to all previously registered and pending tolerances.  Additional
assumptions included 100% crop treated and default processing factors,
where appropriate.  To account for total residues of concern for risk
assessment purposes in animal diets (i.e., free and conjugated
flutriafol and defluorinated flutriafol), residues in grain sorghum,
corn (field, pop and sweet), cotton, peanut, and wheat commodities were
multiplied by a factor of 2.2.  Maximum reasonable dietary burdens for
livestock were calculated using median or highest average field trial
(HAFT) residues in feed commodities, as appropriate.  Anticipated
residues in livestock commodities were calculated based on the resulting
maximum total residue dietary burdens.  For purposes of risk assessment,
secondary residues of flutriafol in meat and milk were estimated using
tissue:feed ratios from the feeding studies, and then factors derived
from the goat metabolism study were used to account for all of the
residues of concern in livestock tissues.  Potential residues in water
were included using the peak concentration in ground water modeled with
PRZM-GW (version 1.07, dated May 14, 2014) of 152 ppb based on the
pending use pattern on cotton (one at-plant in-furrow application at
0.26 lb ai/A and two foliar applications at 0.114 lb ai/A).  The acute
dietary assessment was conducted for the overall US population and
select subpopulations (i.e., all infants <1 year old, children aged 1-2
years old, children aged 3-5 years old, children aged 6-12 years old,
youths aged 13-19 years old, adults aged 20-49 years old, adults 50+
years old, and females aged 13-49 years old).  The results of this Tier
1 acute analysis indicate that the most highly exposed population is
children 1-2 years old, with an estimated acute exposure of 0.061006
mg/kg bw at the 95th percentile, which corresponds to 2.44% of the aPAD
of 2.5 mg/kg bw.  For the overall US population, the acute exposure at
the 95th percentile is 0.026195 mg/kg bw, which corresponds to 1.05% of
the aPAD.  For females 13-49 years old, the acute exposure at the 95th
percentile is 0.021614 mg/kg bw, which corresponds to 28.82% of the
population-specific aPAD of 0.075 mg/kg bw.

Chronic Dietary Exposure.  The chronic population adjusted dose (cPAD)
of 0.05 mg/kg bw/day (NOAEL of 5 mg/kg/d from the one-year feeding study
in the dog with a 100-fold uncertainty factor) was used to characterize
risk associated with chronic dietary exposures.  Cheminova has conducted
a dietary exposure Tier 1 analysis with DEEM-FCID using the proposed
temporary tolerances that are the subject of this petition in addition
to the previously registered and pending tolerances.  Additional
assumptions included 100% crop treated and default processing factors,
where appropriate.  To account for total residues of concern for risk
assessment purposes in animal diets (i.e., free and conjugated
flutriafol and defluorinated flutriafol), tolerances for grain sorghum,
corn (field, pop and sweet), cotton, peanut, and wheat commodities were
multiplied by a factor of 2.2.  Maximum reasonable dietary burdens for
livestock were calculated using median or HAFT residues in feed
commodities, as appropriate.  Anticipated residues in livestock
commodities were calculated based on the resulting maximum total residue
dietary burdens.  For purposes of risk assessment, secondary residues of
flutriafol in meat and milk were estimated using tissue:feed ratios from
the feeding studies, and then factors derived from the goat metabolism
study were used to account for all of the residues of concern in
livestock tissues.  In addition, potential residues in water were
included using the post-breakthrough average concentration in ground
water modeled with PRZM-GW (version 1.07, dated May 14, 2014) of 137 ppb
based on the pending use pattern on cotton (one at plant in-furrow
application at 0.26 lb ai/A and two foliar applications at 0.114 lb
ai/A).  The chronic dietary assessment was conducted for the overall US
population and select subpopulations (i.e., all infants <1 year old,
children aged 1-2 years old, children aged 3-5 years old, children aged
6-12 years old, youths aged 13-19 years old, adults aged 20-49 years
old, adults 50+ years old, and females aged 13-49 years old).  The
results of this Tier 1 chronic analysis indicate that the most highly
exposed population is children aged 1-2 years old, with an estimated
chronic exposure of 0.028747 mg/kg bw/day, which corresponds to 57.5% of
the cPAD.  For the overall US population, the chronic exposure is
calculated to be 0.009533 mg/kg bw/day, which corresponds to 19.1% of
the cPAD.

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 1.05% of the aPAD
and 19.1% 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 28.82% 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.  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 proposed crop uses will be <2.44% of the aPAD and
<57.5% 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) are established for residues of
flutriafol for the following commodities:  banana (0.3 ppm); coffee
beans (0.15 ppm); grapes (0.8 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); raisin (2 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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