 

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

<EPA Registration Division contact: Laura E. Nollen, (703) 305-7390>

<<Interregional Research Project Number 4 (IR-4) >

>

<Petition Number PP #9E7632>

<	EPA has received a pesticide petition, PP #9E7632, from Interregional
Research Project Number 4 (IR-4), Rutgers, The State University of NJ,
500 College Road East, Suite 201 W Princeton, NJ 08540 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 180.608> by revising
the tolerance expression under (a)(1) and (a)(2) to read: 

(a)(1).  Tolerances are established for residues of the insecticide
spirodiclofen, including its metabolites and degradates. Compliance with
the tolerance levels specified is to be determined by measuring only
spirodiclofen (3-(2,4-dichlorophenyl)-2-oxo-1-oxaspiro[4,5]dec-3-en-4-yl
2,2-dimethylbutanoate).

180.608 (2).  Tolerances are established for residues of the insecticide
spirodiclofen, including its metabolites and degradates. Compliance with
the tolerance levels specified is to be determined by measuring only the
sum of spirodiclofen
(3-(2,4-dichlorophenyl)-2-oxo-1-oxaspiro[4,5]dec-3-en-4-yl
2,2-dimethylbutanoate) and its metabolite
3-(2,4-dichlorophenyl)-4-hydroxy-1-oxaspiro[4.5]dec-3-en-2-one,
calculated as the stoichiometric equivalent of spirodiclofen.  

Additionally, this petition proposes to amend 40 CFR part 180.608 by
establishing a tolerance for residues of spirodiclofen
(3-(2,4-dichlorophenyl)-2-oxo-1-oxaspiro[4,5]dec-3-en-4-yl
2,2-dimethylbutanoate) in or on the raw agricultural commodity Bushberry
subgroup 13-07B at 4.0 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>

<	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

blueberry 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

es. 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 0.3% of the cPAD. The population with the
highest

exposure was children 1-2 years with 0.9% of the cPAD utilized. The
chronic

cancer dietary exposure estimate for the general population was 5.81 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 water exposure
assessment was done using the latest EPA modeling tool PE5 and the
latest modeling scenarios.  In the assessment, regional percent crop
areas were used.  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 0.98 ppb in surface water. The EEC for chronic
(cancer) exposure in surface water was estimated to be 0.67 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, ketoenols. 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

blueberry and the corresponding bushberry subgroup use will utilize 0.4
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 cPAD, 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 7.92 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

û

ü

Ñ

Ò

&

E

à

ᜀB use being 1.1% of the cPAD for chronic dietary exposures. EPA
generally has no concerns for exposures below 100 percent of the cPAD,
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.>

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