Document ID: EPA-HQ-OPP-2006-0965-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-02-16T05:00Z

COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE  (7/1/2006)

EPA Registration Division contact: [Tobi Colvin-Snyder. 703-305-7801.

 

INSTRUCTIONS:  Please utilize this outline in preparing tolerance
petition documents.  In cases where the outline element does not apply
please insert “NA-Remove” and maintain the outline.  The comment
notes that appear on the left margin represent hidden typesetting codes
designed to expedite the processing of the Federal Register document. 
Please do not remove or alter these comment notes or change the margins,
font, or format in your document. Simply replace the instructions that
appear in italics and brackets, i.e., “[insert company name],” with
the information specific to your action.]

TEMPLATE:

[Bayer CropScience]

[0F6095]

	EPA has received a pesticide petition ([0F6095]) from [Bayer
CropScience], [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.by
establishing a tolerance for residues of [the herbicide flufenacet
(N-(4-fluorophenyl) -N-(1-methylethyl) -2- [ [5-(trifluoromethyl)
-1,3,4-thiadiazol-2-yl] oxy] acetamide and its metabolites containing
the 4-fluoro-N-methylethyl benzenamine moiety in or on the raw
agricultural commodities: corn, sweet, forage at 0.4 ppm; corn, sweet,
kernel plus cob with husks removed at 0.05 ppm; corn, sweet, stover at
0.4 ppm; wheat, forage at 10.0 ppm; wheat, grain at 1.0 ppm; wheat, hay
at 2.0 ppm; wheat, straw at 0.5 ppm; seed-grass, forage at 7.0 ppm;
seed-grass, forage, regrowth at 0.1 ppm; seed-grass, hay, regrowth at
0.5 ppm.  ADVANCE \d 4  ADVANCE \d 4 

Bayer previously requested in petition 0F6095 that the section 18
tolerances listed below in 40 CFR 180.527 (b) for combined residues of
the herbicide flufenacet, N-(4-fluorophenyl)-N-(1-methylethyl)-2-[[5-
(trifluoromethyl)-1,3,4-thiadiazol-2-yl]oxy]acetamide and it's
metabolites containing 4-fluoro-N-methylethyl benzenamine moiety] be
made permanent and moved to 40 CFR 180.527 (a), cattle, fat at 0.05 ppm;
cattle, kidney at 0.5 ppm; cattle, meat at 0.05 ppm; cattle, meat
byproducts at 0.1 ppm; goat, fat at 0.05 ppm; goat, kidney at 0.5 ppm;
goat, meat at 0.05 ppm; goat, meat byproducts at 0.1 ppm; hog, fat at
0.05 ppm; hog, kidney at 0.5 ppm; hog, meat at 0.05 ppm; hog, meat,
byproducts at 0.1 ppm; horse, fat at 0.05 ppm; horse, kidney at 0.5 ppm;
horse, meat at 0.05 ppm; horse, meat byproducts at 0.1 ppm; sheep, fat
at 0.05 ppm; sheep, kidney at 0.5 ppm; sheep, meat at 0.05 ppm; sheep,
meat byproducts at 0.1 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         

                              

. ADVANCE \d 4 [The nature of the residue in field corn, soybean,
rotational crops and livestock is adequately understood. The residues of
concern for the tolerance expression are flufenacet parent and its
metabolites containing the 4-fluoro-N-methylethyl benzenamine moiety.
Based on the results of animal metabolism studies, it is unlikely that
secondary residues would occur in animal commodities from the use of
flufenacet on sweet corn, perennial grasses grown for seed or wheat.]

. [An adequate analytical method, gas chromatography/mass spectrometry
with selected ion monitoring, is available for enforcement purposes.

. [ ADVANCE \d 4 Field residue trials were conducted across the major
production regions of corn (including sweet corn), wheat and perennial
grasses grown for seed in the United States. In all cases, the treatment
regime was selected to represent the use patterns that are most likely
to result in the highest residue and used a 60% dry flowable formulation
of the active ingredient. For corn (field and sweet) the test plots
received a single application of the product at a rate of 0.9 lbs. of
active ingredient per acre and was applied at preplant soil
incorporated, preemergence broadcast and early postemergence application
timings.  For corn collected at the early milk stage (and sweet corn),
the highest average field trial residues in corn raw agricultural
commodities were 0.36 ppm in forage, 0.16 ppm in fodder, and less than
0.05 ppm in grain (K+CWHR). For wheat, a single post-emergence foliar
application of flufenacet was made to wheat at 0.36 lb ai/A/season.
Applications were made in the fall or 2 weeks after the beginning of
spring growth using broadcast ground equipment. The highest average
field trial residues in wheat raw agricultural commodities were
8.12 ppm in/on wheat forage, 0.95 ppm in/on hay, 0.35 ppm in/on grain
and 0.30 ppm in/or on straw. A comparison of the residues in the raw
agricultural commodity with processed fractions obtained from a wheat
processing study indicate that residues of flufenacet concentrate in
bran and germ only by factors of 2.1x and 1.3x, respectively, but are
reduced in flour (0.4x), shorts (0.9x), and middlings (0.8x).  The
maximum theoretical concentration factor for wheat is 8x (860.1520,
Table 1). For perennial grasses grown for seed, a single post-emergence
foliar application of flufenacet was made to grass grown for seed at
0.45 lb ai/A/season. Applications were made to immature grass at the end
of winter dormancy using broadcast ground equipment. The highest average
field trial residues in grass forage was 6.08 ppm, grass straw was 0.2
ppm, grass forage from regrowth was 0.08 ppm and was 0.20 ppm for hay
from grass regrowth.]

B. Toxicological Profile

. [Technical grade flufenacet has a low to moderate order of toxicity in
rats by the oral route of exposure. The acute oral LD50 was 1,617
milligrams/kilogram (mg/kg) for males and 589 mg/kg for females. ii. A
dermal toxicity study on technical grade flufenacet revealed low acute
toxicity to rats. The dermal LD50 for both sexes was >2,000 mg/kg, the
highest dose tested. iii. An acute inhalation study on technical grade
flufenacet showed low toxicity in rats with a 4-hour liquid aerosol LC50
for males and females of >3,740 mg/m3 air, the highest concentration
tested. iv. An eye irritation study on technical grade flufenacet in
rabbits showed minimal irritation to the [[Page 13706]] conjunctiva
completely reversible within 7 days. v. A dermal irritation study on
technical grade flufenacet in rabbits did not produce any irritation.
vi. Skin sensitization studies on technical grade flufenacet in guinea
pigs have produced equivocal results. A skin sensitization potential was
exhibited under the conditions of a maximization test, whereby, there
was no skin sensitization potential when tested by the Buehler Topical
Closed Patch Technique.]

. [Flufenacet was negative for mutagenic/genotoxic effects in a gene
mutation/in vitro assay in bacteria, a gene mutation/ in vitro assay in
Chinese hamster lung fibroblasts cells, a cytogenetics/in vitro assay in
Chinese hamster ovary cells, a cytogenetics/in vivo mouse micronucleus
assay, and an in vitro unscheduled DNA synthesis assay in primary rat
hepatocytes.]

. [A two-generation rat reproduction study with a parental systemic no
observed adverse effect level (NOAEL) of 20 ppm (1.4 mg/kg/day in males
and 1.5 mg/kg/day in females) and a reproductive NOAEL of 20 ppm (1.3
mg/kg/day) and a parental systemic lowest observed adverse effect level
(LOAEL) of 100 ppm (7.4 mg/kg/day in males and 8.2 mg/kg/day in females)
based on increased liver weight in F1 females and hepatocytomegaly in F1
males and a reproductive LOAEL of 100 ppm (6.9 mg/kg/day) based on
increased pup death in early lactation (including cannibalism) for F1
litters and the same effects in both F1 and F2 pups at the high dose
level of 500 ppm (37.2 mg/kg/ day in F1 males and 41.5 mg/kg/day in F1
females, respectively).  A rat developmental study with a maternal NOAEL
of 25 mg/kg/day and with a maternal LOAEL of 125 mg/kg/day based on
decreased body weight gain initially and a developmental NOEL of 25
mg/kg/day and a developmental LOAEL of 125 mg/kg/day based on decreased
fetal body weight, delayed development (mainly delays in ossification in
the skull, vertebrae, sternebrae, and appendages), and an increase in
the incidence of extra ribs. A rabbit developmental study with a
maternal NOAEL of 5 mg/kg/ day and a maternal LOAEL of 25 mg/kg/day
based on histopathological finds in the liver and a developmental NOAEL
of 25 mg/kg/day and a developmental LOAEL of 125 mg/kg/day based on
increased skeletal variations.]

 [An 84-day rat feeding study with a NOAEL less than 100 ppm (6.0
mg/kg/day) for males and a NOAEL of 100 ppm (7.2 mg/kg/day) for females
and with a LOAEL of 100 ppm (6.8 mg/kg/day) for males based on
suppression of thyroxine (T4) level and a LOAEL of 400 ppm (28.8
mg/kg/day) for females based on hematology and clinical chemistry
findings.  A 13-week mouse feeding study with a NOAEL of 100 ppm (18.2
mg/ kg/day for males and 24.5 mg/kg/day for females) and a LOAEL of 400
ppm (64.2 mg/kg/day for males and 91.3 mg/kg/day for females) based on
histopathology of the liver, spleen and thyroid. A 13-week dog dietary
study with a NOAEL of 50 ppm (1.70 mg/ kg/day for males and 1.67
mg/kg/day for females) and a LOAEL of 200 ppm (6.90 mg/kg/day for males
and 7.20 mg/kg/day for females) based on evidence that the
bio-transformation capacity of the liver has been exceeded, (as
indicated by an increase in LDH, liver weight, ALK and hepatomegaly),
globulin and spleen pigment in females, decreased T4 and ALT values in
both sexes, decreased albumin in males, and decreased serum glucose in
females.  A 21-day rabbit dermal study with the dermal irritation NOAEL
of 1,000 mg/kg/day for males and females and a systemic NOAEL of 20 mg/
kg/day for males and 150 mg/kg/day for females and a systemic LOAEL of
150 mg/kg/day for males and 1,000 mg/kg/day for females based on
clinical chemistry data (decreased T4 and FT4 levels in both sexes) and
centrilobular hepatocytomegaly in females.]

. [A 1-year dog chronic feeding study with a NOAEL was 40 ppm (1.29
mg/kg/day in males and 1.14 mg/kg/day in females) and a LOAEL of 800 ppm
(27.75 mg/kg/day in males and 26.82 mg/ kg/day in females) based on
increased alkaline phosphatase, kidney, and liver weight in both sexes,
increased cholesterol in males, decreased T2, T4 and ALT values in both
sexes, and increased incidences of microscopic lesions in the brain,
eye, kidney, spinal cord, sciatic nerve and liver. A rat chronic
feeding/carcinogenicity study with a NOAEL less than 25 ppm (1.2
mg/kg/day in males and 1.5 mg/kg/day in females) and a LOAEL of 25 ppm
(1.2 mg/kg/day in males and 1.5 mg/kg/day in females) based on
methemoglobinemia and multi-organ effects in blood, kidney, spleen,
heart, and uterus. Under experimental conditions the treatment did not
alter the spontaneous tumor profile.  In a mouse carcinogenicity study
the NOAEL was less than 50 ppm (7.4 mg/kg/day) for males and the NOAEL
was 50 ppm (9.4 mg/kg/day) for females and the LOAEL was 50 ppm (7.4
mg/kg/day) for males and the LOAEL was 200 ppm (38.4 mg/kg/day) for
females based on cataract incidence and severity. There was no evidence
of carcinogenicity for flufenacet in this study.]

. [A rat metabolism study showed thatradio- labeled flufenacet was
rapidly absorbed and metabolized by both sexes. Urine was the major
route of excretion at all dose levels and smaller amounts were excreted
via the feces.]

. [A 55-day dog study with subcutaneous administration of thiadone
(flufenacet metabolite) supports the hypothesis that limitations in
glutathione interdependent pathways and antioxidant stress result in
metabolic lesions in the brain and heart following flufenacet exposure.]

. [EPA is required to develop a screening program to determine whether
certain substances (including all pesticides and inerts) may have an
effect in humans that is similar to an effect produced by a naturally
occurring estrogen, or such other effect. The Agency is currently
working with interested stakeholders, including other government
agencies, public interest groups, industry and research scientists in
developing a screening and testing program and a priority setting scheme
to implement this program. EPA may require further testing of this
active ingredient and end use products for endocrine disrupter effects.
Based on the toxicological findings for flufenacet relating to endocrine
disruption effects, flufenacet may be considered as a candidate for
evaluation as an endocrine disrupter when the exact criteria are
established.] 

	9. Other studies. [An acute rat neurotoxicity study with a NOAEL less
than 75 mg/kg/day and a LOAEL of 75 mg/kg/day based on decreased motor
activity in males. A rat subchronic neurotoxicity study with a NOAEL of
120 ppm (7.3 mg/kg/day in males and 8.4 mg/kg/day in females) and a
LOAEL of 600 (38.1 mg/kg/day in males and 42.6 mg/kg/day in females)
based on microscopic lesions in the cerebellum/medulla and spinal cords.
A rat developmental neurotoxicity dietary study established an overall
NOAEL for both dams and offspring of 17.5 ppm. A LOAEL of 80.8 ppm was
established based on body weight and feed consumption declines common to
both dams and offspring as well as developmental delays which were noted
in the offspring (eye opening, preputial separation). No evidence of
specific neurobehavioral effects in the offspring were observed at
dietary concentrations of up to 404 ppm.] 

C. Aggregate Exposure

. [A tolerance currently exists for the combined residues of flufenacet
(N-(4-fluorophenyl)-N-(1-methylethyl)-2-[[5-
(trifluoromethyl)-1,3,4-thiadiazol-2-yl]oxy]acetamide and its
metabolites containing the 4-fluoro-N-methylethyl benzenamine moiety in
or on corn, field, forage; corn, field, grain; corn, field, stover; and
soybean, seed; and for indirect or inadvertent residues for flufenacet
and its metabolites in or on alfalfa, forage; alfalfa, hay; alfalfa,
seed; clover, forage; clover, hay; grain, cereal, group 15, except rice;
grain, cereal, forage, fodder and straw, group 16, except rice; and
grass, forage, fodder, and hay, group 17. Section 18 emergency
exemptions for use on wheat have been approved in several states. Bayer
CropScience is requesting that the current time limited tolerances for
meat and meat by-products also be made permanent. There are no
residential uses for flufenacet; therefore aggregate exposure would
consist of any potential exposure to flufenacet residues in the
registered and proposed crops and in drinking water.]

t corn, popcorn and grasses grown for seed are included in this
assessment. The analyses were conducted using Exponent, Inc.’s
DEEM-FCID™ software. Consumption data used in this program were taken
from USDA’s CSFII, 1994-1996 and 1998. Acute dietary risk is expressed
as a percentage of the acute Population Adjusted Dose (aPAD) of 0.0017
mg/kg bw/day based on a LOAEL of 1.7 mg/kg bw/day from a developmental
neurotoxicity study in rats with an uncertainty factor of 1000 [10X
uncertainty factor (UF) for interspecies extrapolation, 10X UF for
intraspecies variation; and 10X UF due to the lack of a
No-Observed-Adverse-Effect-Level]. The estimated acute exposure at the
99.9th percentile for the U. S. population was 12.2% of the aPAD.
Children 1-2 years were the most highly exposed subpopulation at 22.4%
of the aPAD. Beef was the main contributor to the acute exposure for all
population groups. Chronic dietary risk is expressed as a percentage of
the chronic Population Adjusted Dose (cPAD) of 0.0017 mg/kg bw/day based
on a LOAEL of 1.7 mg/kg bw/day from a developmental neurotoxicity study
in rats with an uncertainty factor of 1000 [10X uncertainty factor for
interspecies extrapolation, 10X UF for intraspecies variation; and 10X
UF due to the lack of a No-Observed-Adverse-Effect-Level]. The estimated
chronic exposure for the U.S. population was 0.8% of the cPAD. Two
subpopulations, Children 1-2 year and Children 3-5 years, were the most
highly exposed groups at 1.6% of the cPAD. Commodities contributing to
the over-all dietary exposure for all the population groups were beef
(~80%) and cereal grains (~15%).]

. [In EPA’s HED Human Health Risk Assessment, Environmental Fate and
Ecological Effects Division (EFED) provided the Estimated Environmental
Concentration (EEC) for flufenacet and for thiadone, its primary
degradate of concern in water. The drinking water assessment was driven
by the peak concentration in surface water. The surface water estimates
were calculated using the PRZM and EXAMS simulation models. For surface
water, the acute (peak) value of 9.6 ppb, as well as the long-term
average of 1.3 ppb, were based on application of flufenacet to corn. The
simulation also showed that thiadone would not exceed three percent of
the amount of the parent compound at the time of year when the parent
compound concentrations are highest. Therefore, the parent plus
degradate acute concentration value was estimated not to exceed 9.9 ppb.
The groundwater EEC concentration of 0.21 ppb was estimated using the
SCIGROW program. Both the surface and groundwater values represent
upper-bound conservative estimates for concentrations that might be
found in surface water and ground water due to the use of flufenacet.
The peak and annual average concentrations calculated by the model are
well below the calculated Drinking Water level of Comparison (DWLOC) and
demonstrate that the dietary exposure to flufenacet residue with these
registered and pending uses is below the Agency’s level of concern.]

. [There are no non-food uses of flufenacet currently registered under
the Federal Insecticide, Fungicide and Rodenticide Act, as amended. No
non-dietary exposures are expected for the general population.]

D. Cumulative Effects

Flufenacet is structurally a thiadiazole. Bayer CropScience is not aware
of any other pesticides with this structure. For flufenacet, EPA has not
yet conducted a detailed review of common mechanisms to determine
whether it is appropriate, or how to include this chemical in a
cumulative risk assessment. After EPA develops a methodology to address
common mechanism of toxicity issues to risk assessments, the Agency will
develop a process (either as part of the periodic review of pesticides
or otherwise) to reexamine these tolerance decisions. Unlike other
pesticides for which EPA has followed a cumulative risk approach based
on a common mechanism of toxicity, flufenacet does not appear to produce
a toxic metabolite produced by other substances.

E. Safety Determination

. [Using the conservative exposure assumptions described above and based
on the completeness of the toxicity data, it can be concluded that
aggregate exposure to residues of flufenacet present a reasonable
certainty of no harm.  Exposure from residues in crops utilize 12.2% of
the aPAD and 0.8% of the cPAD.  EPA generally has no concerns for
exposures below 100% of the Population Adjusted Doses.  Drinking water
levels of concern are well above the estimated drinking water
concentrations as calculated by conservative models.  An aggregate
assessment for all uses for flufenacet demonstrated that there is a
reasonable certainty that no harm will result to the US Population from
uses of flufenacet.]

. [EPA has considered data from developmental toxicity studies in the
rat and rabbit and a 2-generation reproduction study in the rat. These
studies are discussed under Section B (Toxicology Profile) above.  The
developmental toxicity data demonstrated no increased sensitivity of
rats or rabbits to in utero exposure to flufenacet. In addition, the
multi-generation reproductive toxicity study did not identify any
increased sensitivity of rats to in utero or post-natal exposure.
Parental NOAELs were lower or equivalent to developmental or offspring
NOAELs. The developmental toxicity studies are designed to evaluate
adverse effects on the developing organism resulting from maternal
pesticide exposure during gestation. Reproduction studies provide
information relating to effects from exposure to the pesticide on the
reproductive capability of mating animals and data on systemic toxicity.

FFDCA section 408 provides that EPA shall apply an additional tenfold
margin of safety for infants and children in the case of threshold
effects to account for pre-and post-natal toxicity and the completeness
of the data base unless EPA determines that a different margin of safety
will be safe for infants and children. EPA has determined that the
toxicological database is complete for FQPA purposes and that there are
no residual uncertainties for pre-/post-natal toxicity for flufenacet. 
Based on the available toxicity data the EPA has recommended that the
Special FQPA Safety Factor be reduced to 1x.  

Based on the exposure assessments described above and on the
completeness and reliability of the toxicity data, it can be concluded
that the dietary exposure from all label and pending uses of flufenacet
consumes 22.4% of the aPAD at the 99.9th percentile and 1.6% of the cPAD
for the most sensitive population subgroups, children 1-2 years and
children 3-5 years.  Thus, it can be concluded that there is a
reasonable certainty that no harm will result from aggregate exposure to
flufenacet residues.]

	

F. International Tolerances

	[[No CODEX Maximum Residue Levels (MRLs) have been established for
residues of flufenacet on any crops.]

{<HD2>}

{<P>}

	{<P>}

{<E T=’03'>}

{</E>}

{<P>}

{<E T=’03'>}

{</E>}

{<P>}

{<E T=’03'>}

{</E>}

{<HD2>}

	{<P>}

{<E T=’03'>}

{</E>}

	{<P>}

{<E T=’03'>}

{</E>}

	{<P>}

{<E T=’03'>}

{</E>}

	{<P>}

{<E T=’03'>}

{</E>}

	{<P>}

{<E T=’03'>}

{</E>}

	{<P>}

{<E T=’03'>}

{</E>}

	{<P>}

{<E T=’03'>}

{</E>}

	{<P>}

{<E T=’03'>}

{</E>}

{<E T=’03'>}

{</E>}

{<P>}

{<E T=’03'>}

{</E>}

{<P>}

B*

B*

!

"

,

-

A

B

L

"

-

@

B

C

L

M

N

v

~

…

˜

š

Ô

Q

W

‡

‰

¡

옍)

옍)

옍)

옍)

{<E T=’03'>}

{</E>}

	{<P>}

{<E T=’03'>}

{</E>}

{<HD2>}

{<E T=’03'>}

{</E>}

{<P>}

{<E T=’03'>}

{</E>}