Document ID: EPA-HQ-OPP-2007-0475-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-07-25T04:00Z

<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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<[Bayer CropScience LLC]>

<[Insert petition number] >

<	EPA has received a pesticide petition ([insert petition number]) from
[Bayer CropScience LLC], [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 ><<
[spirotetramat,
cis-3-(2,5-dimethylphenyl)-8-methoxy-2-oxo-1-azaspiro[4.5]dec-3-en-4-yl
ethyl carbonate and its metabolite
cis-3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy-
1-azaspiro[4.5]dec-3-en-2-one], calculated as spirotetramat equivalents,
in or on the raw agricultural commodities [vegetable, tuberous and corm,
subgroup 1C] at [1.0] parts per million (ppm); [potato, granules/flakes]
at [2.5] ppm; [onions, dry bulb, subgroup 3A] at [0.3] ppm; [vegetables,
leafy, except Brassica, group 4] at [5.0] ppm  [Brassica, head and stem,
subgroup 5A] at [3.0] ppm; [Brassica, leafy greens, subgroup 5B] at
[16.0] ppm; [vegetables, fruiting, group 8] at [1.0] ppm; [tomato, dried
pomace] at [2.5] ppm; [vegetable, cucurbit, group 9] at [0.2] ppm;
[fruit, citrus, group 10] at [0.5] ppm; [citrus, oil] at [4.0] ppm;
[fruit, pome, group 11] at [0.5] ppm; [fruit, stone, group 12] at [2.0]
ppm; [nut, tree, group 14] at [0.5] ppm; [almond, hulls] at [9.0] ppm;
[grape] at [1.0] ppm; [grape, raisin] at [2.5] ppm; [hop] at [10.0] ppm;
[strawberry] at [0.5] ppm; [cattle, goat, hog, sheep and horse, meat] at
[0.01] ppm; [cattle, goat, hog, sheep and horse, fat] at [0.01] ppm;
[cattle, goat, hog, sheep and horse, liver] at [0.01] ppm; [cattle,
goat, hog, sheep and horse, meat byproducts, except liver] at [0.02]
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 nature of the spirotetramat residues in
plants and livestock is adequately understood. The plant residues of
concern for tolerance enforcement are the combined residues of
spirotetramat and the metabolite
cis-3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy-
1-azaspiro[4.5]dec-3-en-2-one, calculated as spirotetramat equivalents.
The animal residue of concern for tolerance enforcement is
spirotetramat-enol only.]>

>

<	2. Analytical method. [The residues of spirotetramat and its
metabolites were quantified by high pressure liquid
chromatography/triple stage quadrupole mass spectrometry (LC/MS/MS)
using the stable isotopically labeled analytes as internal standards. 
The individual analyte residues were converted to spirotetramat molar
equivalents and summed to give total spirotetramat residues.  The limit
of quantification (LOQ) for each analyte was 0.01 ppm for all
commodities except citrus (0.05 ppm) and hops (0.1 ppm).]>

<	3. Magnitude of residues. [Residue trials were conducted to support
the tolerances requested above including the following: 

Tuberous and corm vegetable crop subgroup 1C: A total of 16-field trials
were conducted. A potato processing study was also conducted. 

Bulb vegetables crop group 3A: A total of 16 onion trials were conducted
to support the import tolerance for bulb onions including eight in
northern Europe and eight in southern Europe to support the import
tolerance (from the EU) for bulb vegetables to support the importation
of onions. 

Leafy vegetables (except brassica) crop group 4: Field trials were
conducted to evaluate residues of spirotetramat in/on head lettuce, leaf
lettuce, celery, and spinach.

Brassica head and stem crop subgroup 5A: A total of twelve field trials
were conducted in Crop Subgroup 5A, including three broccoli trials,
three cauliflower trials, and six cabbage trials.  A decline trial was
conducted with both broccoli and cabbage.

Brassica leafy greens crop subgroup 5B: Eight field trials were
conducted with mustard greens. A single decline trial was conducted with
mustard greens.

Fruiting vegetables crop group 8: Twelve trials were conducted on
tomatoes (including 1 decline trial), six trials were conducted on bell
pepper (including one decline trial) and three trials were conducted on
non-bell or chili pepper. A tomato processing study was also conducted.

Cucurbit vegetables crop group 9: Field trials were conducted at 17
locations (six each for cucumber and muskmelon and five for summer
squash).

Citrus crop group 10: A total of 23 field trials were conducted (twelve
orange, five lemon and six grapefruit) including a decline trial for
each crop. A citrus processing study was also conducted.

Pome fruit crop group 11: A total of 18 field trials, 12 on apples and 6
on pears were conducted. An apple processing study was also conducted.

Stone fruit crop group 12: A total of 21 trials were conducted including
six on cherry, nine on peach and six on plum. A plum processing study
was also conducted.

Tree Nuts crop group 14: A total of ten trials were conducted including
five on almonds and five on pecans.

Grapes: A total of 12 trials were conducted.  A grape processing study
was also conducted.

Hops: Three trials were conducted.

Strawberry: A total of 16 trials were conducted including four in
northern Europe, four in southern Europe and eight in the greenhouse, to
support the importation of strawberries. 

<B. Toxicological Profile>

<	1. Acute toxicity.  [Spirotetramat (BYI 08330) has a low acute oral
(LD50 > 2,000 mg/kg bw; Category III), dermal (LD50: > 2,000 mg/kg bw;
Category III) and inhalative toxicity (LC50: > 4.183 mg/L air; Category
IV) in male and female rats.  Though a Category II irritant to the eye,
BYI 08330 is not a skin irritant (Category IV) but did exhibit, under
the conditions of the guinea pig maximization test, a skin sensitizing
potential.]>

<	2. Genotoxicty. [With one exception, in vivo and in vitro mutagenicity
studies with Spirotetramat (BYI 08330) and its metabolites were
negative.  A weak positive finding was noted in a single in vitro
chromosome aberration test.  The test was repeated using a later, more
highly purified, batch of test material, containing significantly less
of the trans isomer of BYI 08330.  Negative findings in both the
follow-up study as well as three subsequent in vivo chromosome
aberration studies obviates a mutagenic/genetic toxicity concern for BYI
08330]>

<	3. Reproductive and developmental toxicity. [In both the reproductive
and prenatal developmental toxicity studies in rats and/or rabbits,
non-maternal toxicity was identified at equivalent or higher doses than
maternal toxicity in both species.  At the highest dose tested (HDT) of
10,000 ppm in the 1-generation pilot reproduction study, declines in
sperm motility, % progression, epididymal sperm count, and increases in
abnormal sperm were noted in the P males.  These high-dose effects on
male sperm presumably accounted for the lack of births at the 10,000-ppm
dose in the 1-generation study.  At 6,000 ppm in the 1-generation study,
sperm effects were limited to F1 interim males, including slight
declines in sperm motility, % progression, and increases in abnormal
sperm cells, most likely reflecting a higher dietary intake and
subsequent higher exposure to the test material.  In the 2-generation
study, there were no effects on sperm analysis (morphology, motility,
and sperm count) in the 6,000-ppm males of the P generation.  Marginal
increases in mean abnormal sperm cells were only noted in the 6,000-ppm
F1 males, which were mainly due to one outlying animal.]>

<	4. Subchronic toxicity. [In the rat, compound-induced testicular
changes were characterized by increases in tubular degeneration and
decreased testicle weight.  Increases in abnormal spermatozoa and
hypospermia were also identified in the rat epididymis.  Unlike the rat,
no effects of any kind emerged in the mouse, which was tested up to the
limit dose.  Nonadverse declines in circulating thyroid hormones were
identified exclusively in the dog; however, no other thyroid-related
changes were noted following subchronic exposure.]>

<	5. Chronic toxicity. [In the dog prolonged exposure to spirotetramat
(BYI 08330) was characterized by nonadverse declines in circulating
thyroid hormones.  Below the highest dose tested, no changes in thyroid
weight, thyroid pathology, compensating increases in thyrotropin (TSH),
or clinical observations (e.g., neurological signs) suggestive of
thyroid compromise and/or hypothyroidism were detected in either sex. 
In contrast to the dog, the rat showed no signs of thyroid involvement;
slight increases in liver weight and alveolar macrophage accumulation in
the lung, characterized the one-year chronic response in the rat.]>

<	6. Animal metabolism. [The pharmacokinetic behavior of spirotetramat
is characterized by a rapid and complete absorption and rapid
elimination from the plasma in rats. Following oral administration, 88%
to 98% of the administered dose was excreted within 24 hours.  The
predominant route of excretion was by urine, accounting for 88% to 95%
of the administered dose.  Less than 0.2 % of the dose was detected in
the body and the gastro-intestinal tract at 48 hours after the dose. 
Dose rate and frequency did not have any significant effects on the
rates of absorption and excretion.

The maximum of plasma concentration was reached for all dose groups
within 0.09 to 2.03 hours after administration. From the maximum, the
radioactivity concentrations in plasma declined steadily by several
orders of magnitude within 48 hours for all dose groups. Concentrations
of radioactivity detected in tissues and organs at the time of sacrifice
48-hours post dose administration were very low and below the limit of
detection for some organs/tissues.

BYI 8330 was completely metabolized by the rat and no parent compound
was detected in the excreta.  The major metabolic reaction was cleavage
of the ester group leading to the formation of the primary and most
predominant metabolite BYI 8330-enol (53 – 87 % of the dose
administered).  All other identified metabolites could be derived from
the enol intermediate. The second prominent metabolic transformation was
demethylation of the 8-methoxy group to BYI 8330-desmethyl-enol (5 –
37 % of the dose administered).  Oxidation of the pyrroline moiety to
BYI 8330-ketohydroxy and BYI 8330-desmethyl-ketohydroxy were detected as
minor pathways.  Other very minor metabolic transformations were
conjugation of the enol with glucuronic acid to BYI 8330-enol-GA and
oxidation of the aromatic methyl group of the enol metabolite to BYI
8330-enol-alcohol.]>

<	7. Metabolite toxicology. [Acute (oral rat) and genotoxicity
(bacterial reverse mutation) testing was conducted on four plant
metabolites of BYI 08330 not identified in the rat, or identified to a
minor degree:  BYI 08330-cis-ketohydroxy, BYI
08330-desmethyl-ketohydroxy, BYI 08330-desmethyl-di-hydroxy, and BYI
08330-mono-hydroxy.  With all four metabolites, the results were
equivalent to that observed with the parent compound (LD50 > 2000 mg/kg;
negative = no evidence of mutagenicity)]>

<	8. Endocrine disruption. [Evidence of thyroid- and testicular-related
changes emerged in the dog and rat, respectively, following exposure to
BYI 08330.  During both the 90-day and 1-year feeding studies, decreases
in circulating T3 and T4 were observed exclusively in the dog. 
Ultimately, based on the total response of the animals to the thyroid
profile that emerged in both the 90-day and 1-year dog studies, the
changes in circulating thyroid hormones in the dog were judged to be
nonadverse.  No thyroid effects of any form were observed in either the
rat or the mouse.  Though effects on sperm development in the testes of
the rat were identified, there were no data to suggest the effect was
mediated through some form of BYI 08330-induced hormonal interference]>

<C. Aggregate Exposure>

ere conducted using Exponent Inc.’s DEEM-FCID™ software. 
Consumption data used in this program were taken from USDA’s CSFII,
1994-1996, 1998. Exponent Inc.’s Dietary Exposure Evaluation Model
(DEEMTM), which is licensed to Bayer, was used to estimate the chronic
and acute dietary exposure. This software uses the food consumption data
from the 1994-1998 USDA Continuing Surveys of Food Intake by Individuals
(CSFII 1994-1998).

	

Acute exposure estimates for spirotetramat were based on an acute
reference dose (aRfD) of 1.0 mg/kg body weight/day.  This aRfD was based
on a no observed adverse effect level (NOAEL) of 100 mg/kg body
weight/day from an acute oral neurotoxicity screening study with
technical grade spirotetramat in rats, applying an uncertainty factor of
100 to account for interspecies extrapolation (10X) and intraspecies
variation (10X).  No additional FQPA safety factor was applied;
therefore, the aRfD and the acute population adjusted dose (aPAD) are
the same.  

Chronic exposure estimates for BYI08330 were based on a chronic
reference dose (cRfD) of 0.13 mg/kg body weight/day.  This cRfD is based
on a no observed adverse effect level (NOAEL) of 13.2 mg/kg body
weight/day from the chronic rat toxicity study for spirotetramat, 
applying an uncertainty factor of 100 to account for interspecies
extrapolation (10X) and intraspecies variation (10X).  No additional
FQPA safety factor was applied; therefore, the cRfD and the chronic
population adjusted dose (cPAD) are the same.]>

<	i. Food and Drinking Water. [Acute and chronic dietary assessments
were conducted based on residue data from GLP field trials and
processing studies. The assessments included both food and drinking
water. For the acute and chronic assessments the highest average field
trial residue value was used for “non-blended” and “partially
blended” commodities. The average crop field trial residue value was
used for “blended” commodities. Anticipated secondary residues in
livestock tissues were determined based on a “worst case” dietary
burden for livestock. 

™ software.

™ software. ]>

<	ii. Drinking water. [Potential exposure to spirotetramat residues from
drinking water was included in the residue files in the DEEM-FCID™
software. Therefore, exposure from both food and water are included in
the above values.]>

<	2. Non-dietary exposure. [There are currently no registered or
requested residential uses of spirotetramat. Therefore, a non-dietary
residential exposure assessment was not required at this time.]>

<D. Cumulative Effects>

<	[Spirotetramat is a ketoenol tetramic acid insecticide. At this time,
the EPA has not made a determination that spirotetramat and other
substances that may have a common mechanism of toxicity would have
cumulative effects. Therefore, for these tolerance petitions, it is
assumed that spirotetramat does not have a common mechanism of toxicity
with other substances and only the potential risks of spirotetramat in
its aggregate exposure are considered. ]>

<E. Safety Determination>

<	1. U.S. population. [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 spirotetramat
present a reasonable certainty of no harm.  Exposure from residues in
crops utilizes 3.3% of the aPAD and 0.3% of the cPAD.  These values
include potential exposure from both food and drinking water. EPA
generally has no concerns for exposures below 100% of the Population
Adjusted Doses.  Therefore, the aggregate assessment for all proposed
uses for spirotetramat demonstrates that there is a reasonable certainty
that no harm will result to the US Population from the use of
spirotetramat. ]>

<	2. Infants and children. [The developmental and reproductive toxicity
of spirotetramat was evaluated in 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 spirotetramat. In addition, the
multi-generation reproductive toxicity study did not identify any
increased sensitivity of rats to in utero or post-natal exposure.
Non-maternal toxicity was identified at equivalent or higher doses than
maternal toxicity in both the rat and the rabbit. Though effects on
sperm development in the testes of the rat were identified, there were
no data to suggest the effect was mediated through some form of BYI
08330-induced hormonal interference.

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safety will be safe for infants and children. The spirotetramat database
is complete for FQPA purposes and there are no residual uncertainties
for pre-/post-natal toxicity for spirotetramat.  Therefore, the Special
FQPA Safety Factor can be reduced to 1-fold.  

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 proposed uses of spirotetramat
consumes about 8% of the aRfD/aPAD at the 99.9th percentile and 0.7% of
the cRfD/cPAD for the most sensitive population subgroup, children 1-2
years.  Thus, it can be concluded that there is a reasonable certainty
that no harm will result from aggregate exposure to spirotetramat
residues.]

<F. International Tolerances>

<	[There are currently no CODEX tolerances for spirotetramat.]>

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