Document ID: EPA-HQ-OPP-2009-0677-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-10-07T04:00Z

COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE

EPA Registration Division contact: Tony Kish, 703-308-9443

I. Arysta LifeScience North America, LLC

9F7567

Summary of Petitions

	EPA has received a pesticide petition (9F7567) from (15401 Weston
Parkway, Suite 150, Cary, North Carolina 27513) 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 Fluoxastrobin,
(1E)-[2-[[6-(2-chlorophenoxy)-5-fluoro-4-pyrimydinyl]oxy]phenyl](5,6-dih
ydro-1,4,2-dioxazin-3-yl)methanone O-methyloxime, and its Z isomer,
(1Z)-[2-[[6-(2-chlorophenoxy)-5-fluoro-4-pyrimydinyl]oxy]phenyl](5,6-dih
ydro-1,4,2-dioxazin-3-yl)methanone O-methyloxime] in or on the raw
agricultural commodities [wheat grain at 0.09 ppm; wheat bran at 0.2
ppm; wheat forage at 7 ppm; wheat hay at 17 ppm; wheat straw at 11 ppm;
aspirated grain fractions at 15 ppm; sweet corn (kernels plus cob with
husks removed) at 0.02 ppm; sweet corn forage at 13 ppm; sweet corn
stover at 10 ppm; and meat byproducts (cattle, goat, horse sheep) at 0.2
ppm.  EPA has determined that the petition contains data or information
regarding the elements set forth in section 408(d)(2) of the FFDCA;
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

. The metabolism of fluoxastrobin in plants is adequately understood.
Studies have been conducted to delineate the metabolism of radiolabeled
fluoxastrobin in peanut, tomato, spring wheat, and various
representative rotational crops, all showing similar results. The
residue of concern is parent fluoxastrobin (sum of E and Z isomers).

. Adequate analytical methodology using HPLC/MS/MS detection is
available for enforcement purposes.

. Magnitude of residue and processing trials were conducted on wheat and
sweet corn.  Therefore, the data support the proposed tolerances.

B. Toxicological Profile

.  Oral and dermal LD50 values were >2000 mg/kg bw.  Inhalation LC50
values were >4998 mg/m3 air.  Fluoxastrobin technical was not irritating
to rabbit skin, was moderately irritating to eyes in rabbits and was
non-sensitizing dermally in the Magnusson/Kligman maximization test in
guinea pigs.  Acute toxicity studies for fluoxastrobin technical support
an overall toxicity Category III.

.  Several genotoxicity tests were conducted to test for point-mutagenic
activity, chromosome aberration in vitro and in vivo, and for DNA
repair.  All tests conducted were negative, indicating no evidence of
mutagenic or genotoxic potential.

.  An oral developmental toxicity study in rat did not reveal any
evidence of teratogenic potential.  The maternal NOAEL was 300 mg/kg and
the developmental NOAEL was 1000 mg/kg bw/day.  An oral developmental
toxicity study in rabbits demonstrated a maternal NOAEL of 25 mg/kg
bw/day, a developmental NOAEL of 100 mg/kg bw/day and did not reveal any
teratogenic potential.  A two-generation study in rats, with a parental
toxicity NOAEL of 73.7 mg/kg bw/day for males and 86.7 mg/kg bw/day for
females, did not reveal evidence of a primary reproductive toxicity
potential.  The reproductive NOAEL was 763.6 mg/kg bw/day for males and
806.5 mg/kg bw/day in females.

A subchronic toxicity feeding study with rats over 90 days demonstrated
a NOAEL of 7.3 and 18.3 mg/kg bw/day for males and females,
respectively, based on reduced body weights and alterations in several
urinary tract related clinical chemistry parameters, at the higher dose
levels.  In a subchronic feeding study in mice over 14 weeks a NOAEL was
not established based on decreased alanine aminotransferase (ALAT) and
increased absolute and relative liver weights at the low dose level
(21.7 and 35.3 mg/kg bw/day for males and females, respectively).  A
14-week feeding study in dogs demonstrated a NOAEL of 3.0 mg/kg bw/day
based on decreased body weights and food consumption, and liver effects
(enzyme induction, increased liver weights and cytoplasmic change) and
thyroid effects (decreased T3).

.  A 24-month chronic/oncogenicity feeding study in rats demonstrated a
NOAEL of 53.0 and 35.2 mg/kg bw/day for males and females, respectively.
 An oncogenicity study in the mouse revealed a NOAEL of 18.5 and 29.5
mg/kg bw/day for males and females, respectively based on liver effects.
 There was no indication in the rat or mouse for an oncogenic effect of
fluoxastrobin.  A one-year feeding study with dogs demonstrated a NOAEL
of 1.7 and 1.5 mg/kg bw/day for males and females, respectively based on
decreased body weights and slight  liver effects (increased alkaline
phosphatase (Aph) and liver weights).

. Metabolism and pharmacokinetic studies in the rats, lactating goats
and laying hens demonstrate that fluoxastrobin residues are rapidly
absorbed, metabolized and eliminated.  There was no evidence of
accumulation of residues in any tissues or organs.  The metabolic
pattern was always complex and numerous metabolites were identified. 
The main metabolic reactions, however, are very comparable for all
tested animal species and most metabolites were present at low levels. 
As per the meat and milk tolerances established in 40 CFR 180.609, the
tolerance expression includes fluoxastrobin (sum of E and Z isomers) and
its phenoxy-hydroxypyrimidine metabolite.

. The residues of concern are fluoxastrobin and its
phenoxy-hydroxypyrimidine metabolite.  This metabolite was investigated
for acute oral toxicity and point mutagenic activity in a bacterial
reverse mutation assay.  The phenoxy-hydroxypyrimidine metabolite did
not show mutagenic activity in the reverse mutation assay and the oral
LD50 was >300<500 mg/kg body weight.

.  There is no evidence to suggest that fluoxastrobin has any primary
endocrine disruptive potential.  Reproductive and developmental findings
provided no evidence of an enhanced sensitivity of the young.

C. Aggregate Exposure

. 

.  A chronic dietary analysis was conducted to estimate exposure to
potential fluoxastrobin residues in/on wheat and sweet corn in addition
to all currently proposed and registered crops.  Acute analyses were not
conducted since, as per EPA’s 1/24/05 human health risk assessment,
there was no indication of an adverse effect attributable to a single
dose and therefore an acute reference dose (aRfD) was not established.
Tier I analysis was conducted for the chronic scenario using the
DEEM-FCID( (Exponent, Inc.) software.  Chronic dietary exposure
estimates from potential residues of fluoxastrobin for the US Population
was 17.8% of the chronic RfD.  The sub-population with the highest
exposure was Children 1-2 with 40.7% of the chronic RfD used. Tier I
assessments use tolerance residue values and 100% crop treated.  These
can be considered very conservative estimates of exposure.

. EPA has previously demonstrated (as per EPA’s 1/24/05 human health
risk assessment) that the use on turf is associated with the highest
potential impacts to surface water using PRZM/EXAMS, with the average
concentration in surface water of 28 ppb.  Groundwater concentrations
have been estimated to be <1 ppb.  Since the application rate on turf (4
applications at 0.55 lb ai/A) is higher than the rates on wheat (2
applications at 0.12 lb ai/A) and sweet corn (4 applications at 0.12 lb
ai/A), there is no need to evaluate potential drinking water impacts for
the proposed use on wheat and sweet corn. Therefore, the worst-case
assumption is 28 ppb fluoxastrobin in drinking water.

. [Residential Post-application Exposures: The proposed use on wheat and
sweet corn will not result in residential post-application exposures;
therefore residential post-application exposures are associated only
with adults and children who may contact treated turf. In EPA’s 2005
assessment, MOEs for residential post-application exposures were found
to be greater than 100 for all scenarios.

Aggregate Exposures: Short-term and intermediate-term aggregate
exposures were calculated.  Dietary exposures include the addition of
the wheat and sweet corn uses to all proposed and registered crops and
impacts to drinking water.  Short-term aggregate calculations include
only oral exposures because there is no short-term dermal endpoint.  The
intermediate-term aggregate calculations include both dermal and oral
exposures.  Aggregate MOEs are greater than 100 for adults and children
for both short- and intermediate-term exposure durations.

Aggregate exposures are not calculated for the long-term (i.e., chronic)
because only dietary exposures factor into the long-term scenario. 
Therefore, the chronic dietary exposures are the same as the long-term
exposures.

D. Cumulative Effects

Fluoxastrobin is a novel strobilurin analog.  Arysta LifeScience North
America, LLC will submit information, if necessary, for EPA to consider
concerning potential cumulative effects of fluoxastrobin consistent with
the schedule established by EPA at 62 Federal Register 42020 (Aug. 4,
1997) and other EPA publications pursuant to the Food Quality Protection
Act.

E. Safety Determination

. Using the conservative assumptions described above, based on the
completeness and reliability of the toxicity data, it is concluded that
dietary exposure (food and water) from the proposed and registered uses
of fluoxastrobin will utilize at most 17.8% of the reference dose for
the US Population, and is likely to be much less as more realistic data
and models are developed.  EPA generally has no concern for exposures
below 100% of the RfD because the RfD represents the level at or below
which daily dietary (food plus water) exposure over a lifetime will not
pose appreciable risks to human health.  In addition, aggregate (food
and water dietary plus residential) MOEs are greater than 100 for adults
for both short- and intermediate-term exposure durations. Finally, all
handler exposure scenarios also have MOE greater than 100. Therefore,
there is a reasonable certainty that no harm will occur to the US
Population from aggregate exposure to fluoxastrobin.

. Consideration of the toxicology database as described above leads to
no additional concerns for infants and children.  Therefore the FQPA
safety factor can be established at 1X.  Using the conservative exposure
assumptions described in the exposure section above, the margins of
exposure that will result for short- and intermediate-term aggregate
exposure (food plus water plus residential) to residues of fluoxastrobin
are greater than 100 for children. This value is based on a worst-case
aggregate exposure calculation of a child 1-6 who has a background
dietary exposure to potential residues and plays on a maximally treated
lawn.  Therefore, there is a reasonable certainty that no harm will
occur to infants and children from aggregate exposure to residues of
fluoxastrobin.

F. International Tolerances

	Codex maximum residue levels (MRLs) are not yet established for
fluoxastrobin.

 PAGE  1 

{<HD2>}

{<HD1>}

{<P>}

{<HD2>}

{<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>}

{<HD2>}

{<P>}

{<E T=’03'>}

{</E>}

{<P>}

{<E T=’03'>}

{</E>}

{<P>}

{<E T=’03'>}

{</E>}

{<P>}

{<E T=’03'>}

{</E>}

{<HD2>}

{<P>}

{<HD2>}

{<P>}

{<E T=’03'>}

{</E>}

{<P>}

{<E T=’03'>}

{</E>}

{<HD2>}

{<P>}