 

<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# 0E7820>

<	EPA has received a pesticide petition, PP# 0E7820, from Interregional
Research Project Number 4 (IR-4), 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 establishing tolerances 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 commodities sugar
apple, cherimoya, atemoya, custard apple, ilama, soursop, biriba, guava,
feijoa, jaboticaba, wax jambu, starfruit, passionfruit, persimmon and
acerola at 0.45 parts per million (ppm) and lychee, longan, Spanish
lime, rambutan and pulasan at 3.5 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

guava, sugar apple and lychee in accordance with OPPTS Guideline
860.1500. The data supports establishing the requested tolerances.>

<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. Spirodiclofen did not show any evidence
of neurotoxicity in an acute neurotoxicity study in rats.

<	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. The results of a second DNT study demonstrated no changes in
developmental/ functional parameters in offspring at the highest dose
tested.

<	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 and a NOAEL of 15 mg/kg bw was established for
males). A 14-week feeding study in dogs demonstrated a NOAEL of 7.7
mg/kg bw/day for males and <8.4 mg/kg bw/day for females based on
adrenal gland effects in 2 out of 4 animals. Spirodiclofen did not show
any evidence of neurotoxicity in a subchronic neurotoxicity study in
rats. A 28 day immunotoxicity investigation in rats in combination with
other guideline studies provide evidence that spirodiclofen does not
adversely affect the immune system.>

<	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 sugar apple,
cherimoya, atemoya, custard apple, ilama, soursop, briba, guava, fejoa,
jaboticaba, wax jambu, starfruit, passionfruit,  acerola, persimmon,
lychee, longan, Spanish lime, rambutan and pulasan 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 0.014 mg/kg bw/day is based on the one
year dog study NOAEL of 1.38 mg/kg bw/day and an applied uncertainty
factor of 100X (10x for interspecies extrapolation and 10x for
intraspecies variations). Spirodiclofen has been classified by EPA as
“likely to be carcinogenic to humans” by the oral route.  The unit
risk, Q1*(mg/kg/day)-1 for spirodiclofen is 1.49 x 10-2 based on male
rat testes Leydig cell adenoma.  Chronic and cancer aggregate risk
estimates include exposure from drinking water and from food sources. >

<	i. Food. Chronic dietary exposure estimates from residues of
spirodiclofen

for the U.S. population is 0.3% of the cPAD. The population with the
highest

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

cancer dietary exposure estimate for the general population is 5.88 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.
Combined chronic dietary exposure estimates from residues of
spirodiclofen in food and drinking water for the U.S. population is 0.4%
of the cPAD. The populations with the highest potential; exposures are
infants and children 1-2 years with 1.1% of the cPAD utilized. The
chronic cancer dietary exposure estimate for the general population is
8.96 x 10-7. >

<	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 residues in food and drinking water
resulting from all label and pending uses as well as the proposed
tropical fruit uses will utilize 0.4 percent of the cPAD for chronic
dietary exposures to the U.S. Population. 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 is 8.96 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. The results from developmental, reproduction and 2 DNT studies
do not indicate a significant concern for increased susceptibility, and
therefore the FQPA safety factor has not been retained in calculating
the reference dose for chronic risk. The most highly exposed population
subgroups are infants and children 1-2 years with a total aggregate
(food and water) exposure to spirodiclofen from all the registered and
pending uses and the proposed tropical fruit uses 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>

<	At the July 2010 Codex meeting, the Committee decided to advance the
proposed draft MRLs for adoption at Step 5/8 as follows:

Commodity	MRL (mg/kg)

Dried grapes (= currants, sultanas, raisins)	0.3

Tree nuts	0.05

Tomato	0.5

Strawberry	2

Stone fruits	2

Pome fruits	0.8

Papaya	0.03*

Meat (from mammals other than marine mammals)	0.01*

Milks	0.004*

Hops, Dry	40

Gherkins	0.07

Edible offal (mammalian)	0.05*

Currants (red, black, white)	1

Cucumber	0.07

Citrus fruits	0.4

Coffee beans	0.03*

Apple pomace, Dry	4

Almond hulls	15

Peppers, sweet (including pimento, pimiento)	0.2

Grapes	0.2

>

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