 

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

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

 

<INSTRUCTIONS:  Please utilize this outline in preparing the pesticide
petition.  In cases where the outline element does not apply, please
insert “NA-Remove” and maintain the outline. Please do not change
the margins, font, or format in your pesticide petition. Simply replace
the instructions that appear in green, i.e., “[insert company
name],” with the information specific to your action.>

<TEMPLATE:>

<[Insert Company Name]>

<[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-dimethlyphenyl)-8-methoxy-2-oxo-1-azaspiro[4.5]dec-3-en-4-yl
-ethyl carbonate]) and its metabolites BYI 08330-enol
(cis-3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy-1-azaspiro[4.5]dec-3-en-
2-one), BYI 08330-ketohydroxy
(cis-3-(2,5-dimethylphenyl)-3-hydroxy-8-methoxy-1-azaspiro[4.5]decane-2,
4-dione), BYI08330-enol-Glc
(cis-3-(2,5-dimethylphenyl)-8-methoxy-2-oxo-1-azaspiro[4.5]dec-3-en-4-yl
beta-D-glucopyranoside), and BYI 08330-mono-hydroxy
(cis-3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy-1-azaspiro[4.5]decan-2-o
ne), calculated as spirotetramat equivalents,] in or on the raw
agricultural commodities [Vegetables, legume, group 06 (except soybean)]
at [4] parts per million (ppm); [Vegetables, foliage of legume, except
soybean, subgroup 07A] at [5] ppm; [cotton, undelinted seed] at [0.4]
ppm; [cotton, gin byproducts] at [7] ppm; [soybean] at [3] ppm;
[soybean, forage] at [9] ppm; [soybean, hay] at [16] ppm; [soybean,
aspirated grain fractions] at [10] ppm; [Acerola] at [1.5] ppm;
[Atemoya] at [1.5] ppm; [Avocado] at [1.5] ppm; [Birida] at [1.5] ppm;
[Black sapote] at [1.5] ppm; [Canistel] at [1.5] ppm; [Cherimoya] at
[1.5] ppm; [Custard Apple] at [1.5] ppm; [Feijoa] at [1.5] ppm;
[Jaboticaba] at [1.5] ppm; [Guava] at [1.5] ppm; [Ilama] at [1.5] ppm;
[Longan] at [1.5] ppm; [Mamey sapote] at [1.5] ppm; [Mango] at [1.5]
ppm; [Papaya] at [1.5] ppm; [Passionfruit] at [1.5] ppm; [Persimmon] at
[1.5] ppm; [Pulasan] at [1.5] ppm; [Rambutan] at [1.5] ppm; [Sapodilla]
at [1.5] ppm; [Soursop] at [1.5] ppm; [Spanish lime] at [1.5] ppm; [Star
apple] at [1.5] ppm; [Starfruit] at [1.5] ppm; [Sugar apple] at [1.5]
ppm; [Wax jambu] at [1.5] ppm; [White sapote] at [1.5] ppm; [Lychee] at
[12] ppm; [Okra] at [2.5] ppm; [pistachio] at [0.25] ppm and [plum,
prune, dried] at [4.5] 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
(cis-3-(2,5-dimethlyphenyl)-8-methoxy-2-oxo-1-azaspiro[4.5]dec-3-en-4-yl
-ethyl carbonate]) and its metabolites BYI 08330-enol
(cis-3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy-1-azaspiro[4.5]dec-3-en-
2-one), BYI 08330-ketohydroxy
(cis-3-(2,5-dimethylphenyl)-3-hydroxy-8-methoxy-1-azaspiro[4.5]decane-2,
4-dione), BYI08330-enol-Glc
(cis-3-(2,5-dimethylphenyl)-8-methoxy-2-oxo-1-azaspiro[4.5]dec-3-en-4-yl
beta-D-glucopyranoside), and BYI 08330-mono-hydroxy
(cis-3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy-1-azaspiro[4.5]decan-2-o
ne), calculated as spirotetramat equivalents. ]

	2. Analytical method. [Spirotetramat residues are quantified in raw
agricultural commodities by high pressure liquid chromatography/triple
stage quadrupole mass spectrometry (LC/MS/MS) using the stable
isotopically labeled analytes as internal standards. The limit of
quantification (LOQ) for each analyte was 0.01 ppm for all
commodities.]

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

Cotton: A total of 12 field trials were conducted. A cotton seed
processing study was also conducted.

Soybean: A total of 20 field trials were conducted. A soybean seed
processing study was also conducted.

Vegetables, legume, group 06 (except soybean): A total of twelve field
trials were conducted to evaluate the magnitude of spirotetramat
residues on succulent, shelled pea and bean (garden pea and lima bean),
and nine field trials to evaluate the magnitude of spirotetramat
residues on succulent, podded bean and pea (snap bean and snow pea). In
addition a total of fourteen trials were conducted to evaluate the
magnitude of spirotetramat residues in dried beans and peas. 

Vegetables, foliage of legume, except soybean, subgroup 07A: A total of
fourteen field trials were conducted as part of the dried bean and pea
trials above. 

Tropical Fruit: A total of fifteen GLP field trials (five avocado, two
guava, four lychee, and four papaya) were conducted. 

B. Toxicological Profile

	1. Acute toxicity.  [Spirotetramat 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,
spirotetramat 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. [Treatment-related increases in tumor incidence were
not observed in either sex in rats or mice. Spirotetramat was also
negative for mutagenicity and clastogenicity in several standard in vivo
and in vitro assays.]

]

	3. Reproductive and developmental toxicity. [Developmental toxicity in
the absence of maternal toxicity was not observed in either the rat or
rabbit. In the rat, decreased body weight and food consumption were
observed in dams at the limit dose in a developmental toxicity study.
Developmental toxicity (reduced fetal weight and increased incidences of
malformations and skeletal deviations) was also observed at the limit
dose. The NOAEL was established at the next lower dose (140 mg/kg
bw/day) in both dams and offspring. In the rabbit, developmental
toxicity was not Page 18 of 65 observed up to the highest dose tested
(160 mg/kg bw/day). However, maternal toxicity was observed at ≥40
mg/kg bw/day, including a dose-dependent increase in abortion and other
clinical signs of systemic toxicity in affected animals.

In addition to testicular histopathology observed following subchronic
and chronic exposure of male rats to spirotetramat, evidence of male
reproductive toxicity was provided in the 2-generation reproductive
toxicity study. Abnormal sperm cells were reported in F1-generation male
rats treated with 6000 ppm (419 mg/kg bw/day) spirotetramat in the diet,
and decreased reproductive performance was also observed in one of these
males. Similar results were obtained in the 1-generation reproductive
toxicity range-finding study, in which decreased sperm motility and
progression and increased abnormal sperm cells in the epididymides were
observed in F1 males at ≥6000 ppm (320 mg/kg bw/day). Development of
the sexual organs of offspring (balano-preputial separation, vaginal
opening) was unaffected in either study, and no treatment-related
effects were observed at lower doses.

In an investigative study designed to explore the time of onset of
testicular toxicity in rats, decreased epididymal sperm counts were
observed after 10 days or more of treatment with 1000 mg/kg bw/day by
gavage. Repeated dosing, therefore, is necessary to produce male
reproductive toxicity in rats. In a second investigative study, male
rats were treated by gavage with the enol metabolite of spirotetramat
for 21 days at a dose of 800 mg/kg bw/day. Spermatotoxicity, abnormal
sperm, and Sertoli cell vacuolation were observed in the
testes-epididymides of treated animals. Therefore, male reproductive
toxicity in rats is likely due to the enol metabolite of spirotetramat.]

	4. Subchronic toxicity. [In the rat, spirotetramat-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
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.

BYI08330 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 BYI08330-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 BYI08330-desmethyl-enol (5 –
37 % of the dose administered).  Oxidation of the pyrroline moiety to
BYI08330-ketohydroxy and BYI08330-desmethyl-ketohydroxy were detected as
minor pathways.  Other very minor metabolic transformations were
conjugation of the enol with glucuronic acid to BYI08330-enol-GA and
oxidation of the aromatic methyl group of the enol metabolite to
BYI08330-enol-alcohol.]>

	7. Metabolite toxicology. [Acute (oral rat) and genotoxicity (bacterial
reverse mutation) testing was conducted on four plant metabolites of
spirotetramat 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
spirotetramat.  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 spirotetramat-induced hormonal
interference]

C. Aggregate Exposure

	1. Dietary exposure. [Assessments were conducted to evaluate potential
risks due to acute and chronic dietary exposure of the U.S. population
and selected population subgroups to residues of spirotetramat. These
analyses included the proposed use of spirotetramat on cotton, soybean,
legume vegetables (CG6) and tropical fruit (unofficial crop group
containing Acerola, Atemoya, Avocado, Birida, Black sapote, Canistel,
Cherimoya, Custard Apple, Feijoa, Jaboticaba, Guava, Llama, Longan,
Mamey sapote, Mango, Papaya, Passionfruit, Persimmon, Pulasan, Rambutan,
Sapodilla, Soursop, Spanish lime, Star apple, Starfruit, Sugar apple,
Wax jambu and white sapote. Potential exposure from drinking water is
also included in these assessments.  Potential concentrations of
spirotetramat residues in drinking water were determined by EPA using
FIRST and SCI-GROW.  These conservative surface water estimates were
added to the potential exposure from food.  Dietary exposure was
determine using CARES. Consumption data used in this program were taken
from USDA’s CSFII, 1994-1996, 1998. The CARES 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 spirotetramat were based on a chronic
reference dose (cRfD) of 0.06 mg/kg body weight/day.  This cRfD is based
on a no observed adverse effect level (NOAEL) of 6 mg/kg body weight/day
from the chronic dog 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. 

The Tier 3 acute assessment determined acute dietary exposure to
spirotetramat residues (food and water) for the U.S. Population and
selected population subgroups. The most highly exposed population
subgroup was infants with an acute exposure at the 99.9th percentile of
less than 3% of the acute RfD/acute PAD. For the overall U.S. Population
the acute exposure at the 99.9th percentile was about 1% of the acute
RfD/acute PAD. These values include exposure from both food and water
since potential water exposure was added to the potential food exposure
in DEEM-FCID™ software.

The Tier 3 chronic assessment determined chronic dietary exposure to
spirotetramat residues (food and water) for the U.S. Population and
selected population subgroups. The most highly exposed population
subgroup was children (1-2) with a chronic exposure at the 99.9th
percentile of less than 4% of the chronic RfD/chronic PAD. For the
overall U.S. Population the chronic exposure at the 99.9th percentile
was about 1% of the chronic RfD/chronic PAD. These values include
exposure from food and water since potential water exposure was added to
the potential food exposure in the DEEM-FCID™ software.]

	ii. Drinking water. [Potential exposure to spirotetramat residues from
drinking water was included in the above assessment but contributed very
little to overall exposure. Therefore, exposure from both food and water
are included in the above values.]

	2. Non-dietary exposure. [There are currently no registered residential
uses of spirotetramat. Therefore, a non-dietary residential exposure
assessment was not required.]

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 about 1% of the aPAD and 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. The developmental
toxicity studies are designed to evaluate adverse effects on the
developing organism resulting from maternal pesticide exposure during
gestation. Reproduction studies provide information relating to effects
from exposure to the pesticide on the reproductive capability of mating
animals and data on systemic toxicity.

	



 

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FFDCA section 408 provides that EPA shall apply an additional tenfold
margin of safety for infants and children in the case of threshold
effects to account for pre-and post-natal toxicity and the completeness
of the data base unless EPA determines that a different margin of 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 1x.  

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 less than 3% of the aRfD/aPAD at the 99.9th percentile and less
than 4% of the cRfD/cPAD for the most sensitive population subgroup. 
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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