 

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

EPA Registration Division contact: [insert name and telephone number
with area code]

 

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TEMPLATE:

[Bayer CropScience]

[Insert petition number]

	EPA has received a pesticide petition ([insert petition number]) from
[Bayer CropScience] [P. O. Box 12014, 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
[Spirodiclofen;
3-(2,4-dichlorophenyl)-2-oxo-1-oxaspiro[4,5]dec-3-en-4-yl ester
2,2-dimethylbutanoate] in or on the raw agricultural commodity [avocado
plus the tropical fruit subgroup which can be surrogated with avocado
data i.e. black sapote, canistel, mamey sapote, mango, papaya,
sapodilla, and star apple] at [1.3 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

	1. Plant metabolism. [The metabolism of spirodiclofen in plants is
adequately understood. Studies have been conducted to delineate the
metabolism of radiolabeled spirodiclofen in various crops, all showing
similar results. The residue of concern is spirodiclofen.]

	2. Analytical method. [Adequate analytical methodology using LC/MS/MS
detection is available for enforcement purposes.]

	3. Magnitude of residues. [Magnitude of the residue data was conducted
on avocado in accordance with OPPTS Guideline 860.1500. The data
supports establishing the requested tolerance.]

B. Toxicological Profile

	1. Acute toxicity.  [Oral and dermal LD50 values were >2000 mg/kg bw. 
Inhalation LC50 values were >5030 mg/m3 air.  Spirodiclofen was not
irritating to rabbit skin or eyes but did cause skin sensitization in
the Magnusson/Kligman maximization test in guinea pigs.  Acute toxicity
studies for spirodiclofen support an overall toxicity Category III.]

	2. Genotoxicty. [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.]

	3. Reproductive and developmental toxicity. [An oral developmental
toxicity study in rat did not reveal any evidence of teratogenic
potential.  The maternal and developmental NOELs were 1000
mg/kg bw/day.  An oral developmental toxicity study in rabbits
demonstrated a maternal NOEL 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 5.2 mg/kg bw/day, did not reveal evidence of a primary
reproductive toxicity potential.  The reproductive NOAEL was 26.2 mg/kg
bw/day based on various clinical and histopathological findings at
higher dose levels.]  A LOAEL of 6.5 mg/kg-day was established in a
developmental neurotoxicity study, based on a decreased retention in the
memory phase of the water maze in PND 60 females.  

	4. Subchronic toxicity. [A subchronic toxicity feeding study with rats
over 90 days demonstrated a NOAEL of 32.1 and 8.1 mg/kg bw/day for males
and females, respectively, based on effects on the lipid metabolism
(decrease of triglycerides and cholesterol), liver effects (increase in
transaminases) and adrenal effects (vacuolation) at the higher dose
levels.  A subchronic feeding study in mice over 13 weeks revealed no
clinical toxicological signs.  A NOAEL of 30.1 mg/kg bw/day for females
was observed (a clear NOAEL was not established for males).  A 14-week
feeding study in dogs demonstrated a NOAEL of 7.7 mg/kg bw/day.]

	5. Chronic toxicity. [A 24-month combined chronic
feeding/carcinogenicity study in rats demonstrated a NOAEL of 14.7 mg/kg
bw/day.  An oncogenicity study in the mouse revealed a NOAEL of 4.1
mg/kg bw/day.  Uterine and testicular oncogenicity was noted in the rat
and hepatic neoplasia was observed in the mouse.  A one-year feeding
study with dog demonstrated a NOAEL of 1.38 mg/kg bw day based on
adrenal effects (vacuolization) as well as changes in circulating
cholesterol and prostate weight at higher dose levels.]

	6. Animal metabolism. [Metabolism and pharmacokinetic studies in the
rat demonstrate that spirodiclofen residues are rapidly absorbed,
metabolized and eliminated.  The primary metabolite is the enol, which
is formed by cleavage of the alkyl ester group, but numerous other
metabolites are also formed.]

	7. Metabolite toxicology. [In crop matrices, spirodiclofen is the only
residue of concern.  The residues of concern in livestock tissues are
spirodiclofen and its enol metabolite.  Since the enol is inherently
present after administration, toxicology data for this metabolite is
completely supported by data obtained for spirodiclofen.]

	8. Endocrine disruption. [The mammalian mode of action for
spirodiclofen includes that classified as inhibitory to steroid
biosynthesis, resulting in an indirect and endogenously-mediated
toxicological response.  Effects do not have an impact on fertility,
reproduction, developmental or neuropathological parameters.  Additional
mechanistic studies with the chemical indicated that there is no direct
effect on the endocrine system as there is no interaction with hormone
receptors.]

C. Aggregate Exposure

	1. Dietary exposure. [Spirodiclofen has a low acute toxicity via the
oral, dermal or inhalation route.  An endpoint of concern attributable
to a single dose was not identified in the hazard database; therefore an
acute reference dose was not established.  Chronic dietary analysis was
conducted to estimate exposure to potential spirodiclofen residues for
the proposed use on avocado and all registered and pending uses. 
DEEM-FCID™ software (Version 2.14) utilizing the 94-96-98 CSFII
consumption database was used to estimate exposure.  Average anticipated
residues, processing factors (where available) and average percent crop
treated values were used in the chronic assessment. The chronic
reference dose of 0.0065 mg/kg-day was based on a chronic LOAEL of 6.5
mg/kg-day from the rat developmental neurotoxicity study and the
application of an uncertainty factor of 1000.  The chronic cancer
assessment was based on a Q* of 0.0149 (mg/kg-day)-1. ]   

	i. Food. [Chronic dietary exposure estimates from residues of
spirodiclofen for the U.S. population was 0.5% of the cPAD. The
population with the highest exposure was children 1-2 years with 1.7% of
the cPAD utilized.  The chronic cancer dietary exposure estimate for the
general population was 5.3 x 10-7.]

	ii. Drinking Water. [To assess chronic risk, drinking water estimates
were incorporated directly into the dietary analysis (DEEM-FCID residue
file).  The chronic estimated environmental concentration (EEC) for
drinking water was based on the PRZM/EXAMS model.  The chronic
(non-cancer) exposure for spirodiclofen (total residue including its
three metabolites: spirodiclofen-enol, spirodiclofen-ketohydroxy, and
spirodiclofen-dihydroxy) in surface water was estimated to be 0.8 ppb
in surface water.  The EEC for chronic (cancer) exposure in surface
water was estimated to be 0.5 ppb.]

	2. Non-dietary exposure. [There are no indoor residential, indoor
commercial or outdoor residential uses for spirodiclofen.]

D. Cumulative Effects

	[Spirodiclofen represents a new class of chemistry, ketoenoles.  There
are no data available to indicate that toxic effects produced by
spirodiclofen are a result of a common mechanism and should be cumulated
with those of any other compound.  EPA has not made a common mechanism
of toxicity finding as to spirodiclofen and any other substances and
spirodiclofen does not appear to product a toxic metabolite produced by
other substances.  Bayer CropScience will submit information, if
necessary, for EPA to consider concerning potential cumulative effects
of spirodiclofen 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

	1. U.S. population. [Based on the exposure assessments described above
and on the completeness and reliability of the toxicity data, it can be
concluded that total aggregate exposure to spirodiclofen from all label
uses as well as the proposed avocado and corresponding tropical subgroup
use will utilize less than 2 percent of the PAD (Population Adjusted
Dose) for chronic dietary exposures to the U.S. Population and all
population subgroups.  EPA generally has no concerns for exposures below
100 percent of the PAD, because it represents the level at or below
which daily aggregate exposure over a lifetime will not pose appreciable
risks to human health.  Cancer aggregate risk was calculated for the
U.S. population only.  The cancer risk estimate with drinking water
included was 6.6 x 10 -7.  Since EPA considers a cancer risk to be
greater than negligible when it exceeds the range of 1-3 in a million,
the estimated cancer risk for spirodiclofen is not likely to exceed the
Agency’s level of concern.  Thus, it can be concluded that there is a
reasonable certainty that no harm will result to the U.S. population
from aggregate exposure to spirodiclofen residues.]

	2. Infants and children. [The Agency has concluded that there is no
evidence of increased susceptibility following the in utero and/or
prenatal/postnatal exposure in the developmental toxicity studies in
rabbits and 2-generation reproduction studies in rats.  A 10X safety
factor was retained for the use of a LOAEL of 6.5 mg/kg-day from a DNT
study in calculating the reference dose for chronic risk.  The most
highly exposed population subgroup was children 1-2 years with a total
aggregate (food and water) exposure to spirodiclofen from all the
registered uses and the proposed avocado and corresponding tropical
fruit subgroup use was 2% of the cPAD for chronic dietary exposures. 
EPA generally has no concerns for exposures below 100 percent of the,
because the PAD, because it represents the level at or below which daily
aggregate exposure over a lifetime will not pose appreciable risks to
human health.

F. International Tolerances

<	[Codex maximum residue levels (MRLs) are not yet established for
spirodiclofen.]  >

