Document ID: EPA-HQ-OPP-2012-0107-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-04-04T04:00Z

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

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

<Interregional Research Project Number 4 (IR-4)

Petition # 1E7958>

<>

	EPA has received a pesticide petition, PP#1E7958 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 180.641 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 taro, leaves at 9 parts per million (ppm);
watercress at 1.5 ppm; pomegranate at 0.5 ppm; banana at 4 ppm;
vegetable, bulb, group 3-07 at 0.6 ppm; berry, low growing, except
strawberry, subgroup 13-07H at 0.3 ppm; bushberry subgroup 13-07B at 3
ppm; artichoke, globe at 2 ppm; vegetable, fruiting, group 8-10 at 2.5
ppm; fruit, pome, group 11-10 at 0.7 ppm; fruit, citrus, group 10-10 at
0.6 ppm; pineapple at 0.3 ppm; pineapple, process residue at 0.36 ppm;
coffee, green beans at 0.2 ppm; and coffee, roast beans at 0.32 ppm.

Upon approval of the aforementioned tolerances, 40 CFR part 180.641
should be amended to remove the following established tolerances as they
will be superseded by inclusion in updated crop groups or subgroups:
Onion, bulb, subgroup 3A-07 at 0.30 ppm; fruit, citrus, group 10 at 0.60
ppm; fruit, pome, group 11 at 0.70 ppm; okra at 2.5 ppm; and vegetable,
fruiting, group 8 at 2.5 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: 

Blueberry: A total of 11 field trials were conducted in the USA and
Canada. Cranberry: A total of 6 field trials were conducted in the USA
and Canada. 

Watercress: A total of 3 field trials were conducted in the USA.

Coffee: A total of 5 field trials were conducted in the USA.

Banana: A total of 5 field trials were conducted in the USA.

Pomegranate: A total of 4 field trials were conducted in the USA. 

Globe Artichoke: A total of 5 field trials were conducted in the USA and
Canada. 

Onion, Dry Bulb: A total of 12 field trials were conducted in the USA
and Canada.

Green Onion: A total of 11 field trials were conducted in Canada.

Pineapple: A total of 5 field trials were conducted in the USA.

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.

ge-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 bulb vegetables
(Crop Group 3), bushberries and low growing berries (Crop Group 13B and
13H), artichoke, banana, coffee, pineapple, pomegranate, and watercress.
Potential exposure from drinking water is also included in these
assessments.  Potential concentrations of spirotetramat residues in
drinking water were determined by Bayer CropScience using the
Provisional Cranberry Model.  These conservative surface water estimates
were added to the potential exposure from food.  Dietary exposure was
determined using the CARES Version 3.0 software which uses the food
consumption data from the 1994-1996, 1998 USDA Continuing Surveys of
Food Intake by Individuals.

	

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 0.05 mg/kg body weight/day.  This cRfD is based
on a no observed adverse effect level (NOAEL) of 5 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 assessment, the entire distribution of field trial residues was
used for non-blended and partially blended food commodities and for
blended commodities the average value was used.  For the chronic
assessment, the average residue value was used.  Anticipated secondary
residues in livestock tissues were determined based the Maximum
Reasonably Balanced Diets (MRBD) approach.  The MRBD is constructed from
spirotetramat treated feedstuffs and then adjusting to feed ratio
derived from cattle feed study.  

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
5% of the acute RfD/acute PAD.  For the overall U.S. Population the
acute exposure at the 99.9th percentile was about 2% 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 CARES 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 infants with a chronic exposure at the 99.9th percentile of
about 9% of the chronic RfD/chronic PAD. For the overall U.S. Population
the chronic exposure at the 99.9th percentile was less than 4% 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 CARES 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 2% of the aPAD and less than 4% 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. 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.

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.  

 

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pleteness and reliability of the toxicity data, it can be concluded that
the dietary exposure from all proposed uses of spirotetramat consumes
less than 5% of the aRfD/aPAD at the 99.9th percentile and less than 9%
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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