 

EPA REGISTRATION DIVISION - COMPANY NOTICE OF FILING FOR PESTICIDE
PETITION

Docket ID Number: EPA-HQ-OPP-2016-0255

EPA Registration Division Contact: Sidney Jackson (703-305-7610)

Pesticide Petition Number: 6E8467  

EPA has received a pesticide petition (6E8467) from Interregional
Research Project Number 4 (IR-4), IR-4 Project Headquarters, 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 180.641 by establishing a tolerance for residues of  the
insecticide 

spirotetramat
(cis-3-(2,5-dimethlyphenyl)-8-methoxy-2-oxo-1-azaspiro[4.5]dec-3-en-4-yl
-ethyl carbonate) and its metabolites
cis-3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy-1-azaspiro[4.5]dec-3-en-2
-one,
cis-3-(2,5-dimethylphenyl)-3-hydroxy-8-methoxy-1-azaspiro[4.5]decane-2,4
-dione,
cis-3-(2,5-dimethylphenyl)-8-methoxy-2-oxo-1-azaspiro[4.5]dec-3-en-4-yl
beta-D-glucopyranoside, and
cis-3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy-1-azaspiro[4.5]decan-2-on
e, calculated as the stoichiometric equivalent of spirotetramat, in or
on the raw agricultural commodities carrot, roots at 0.15 parts per
million (ppm); nut, tree, group 14-12 at 0.25 ppm; and fruit, stone,
group 12-12 at 4.5 ppm.  Upon establishment of the aforementioned
tolerances, the petitioner proposes to be deleted the following existing
tolerances in order to eliminate redundancies: fruit, stone, group 12 at
4.5 ppm; nut, tree, group 14 at 0.25 ppm; and pistachio at 0.25 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 support 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
(cis-3-(2,5-dimethlyphenyl)-8-methoxy-2-oxo-1-azaspiro[4.5]dec-3-en-4-yl
-ethyl carbonate) and its metabolites
cis-3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy-1-azaspiro[4.5]dec-3-en-2
-one,
cis-3-(2,5-dimethylphenyl)-3-hydroxy-8-methoxy-1-azaspiro[4.5]decane-2,4
-dione,
cis-3-(2,5-dimethylphenyl)-8-methoxy-2-oxo-1-azaspiro[4.5]dec-3-en-4-yl
beta-D-glucopyranoside, and
cis-3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy-1-azaspiro[4.5]decan-2-on
e, calculated as the stoichiometric equivalent of spirotetramat.

	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. A total of 8 residue field trials were
conducted to support the tolerances requested above including carrots.  

B. Toxicological Profile

	1. Acute toxicity.  Spirotetramat has a low acute oral (lethal dose
(LD)50 > 2,000 milligrams (mg)/kilogram (kg) body weight (bw); Category
III), dermal (LD50: > 2,000 mg/kg bw; Category III) and inhalation
toxicity (lethal concentration (LC)50: > 4.183 mg/liter (L) air;
Category IV) in male and female rats.  Although the technical material
is slightly irritating to the eye (Category II), spirotetramat is not a
skin irritant (Category IV), but did exhibit a skin sensitizing
potential under the conditions of the guinea pig maximization test.

	2. Genotoxicity. 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. In both the rabbit
developmental toxicity study and rat two-generation reproductive study,
changes in developmental endpoints were observed at equivalent or higher
doses than those resulting in maternal toxicity.  No treatment-related
developmental effects were seen in the rabbit, while maternal animals
exhibited clinical signs and an increase in sacrifice of moribund
animals at the highest dose tested (HDT) of 160 mg/kg/day.  In the
two-generation reproduction study in rats, effects were observed only at
the HDT of 419.3/484.7 mg/kg/day (m/f, premating P-generation).  The
incidence of abnormal sperm cells increased to a minimal degree and
decreased reproductive performance was observed in F1 males, but overall
fertility was unaffected since fertility was compromised in only 1 male.
 The effects on sperm cells confirm similar findings seen in the
one-generation reproduction study at the same dose level.  The
reproductive changes, as well as kidney effects (i.e. decreased absolute
and relative weights with minimal to moderate multifocal tubular
dilatation) and decreased pup body weight (F1 and F2 during lactation)
were accompanied by decreased parental body weight (F1; males throughout
premating, females during premating and lactation) and food consumption
(P and F1 females).  Evidence of qualitative susceptibility was observed
in the rat developmental study, where reduced fetal weight (-14%
compared to control) and increased incidences of malformations and
skeletal variations were observed in the presence of maternal toxicity
(i.e. significantly reduced final body weight and body weight gain (BWG)
during the overall treatment period and gestation, decreased corrected
BWG and significantly decreased food consumption through most of
gestation).  The developmental changes, however, were within historical
control values for fetal incidence, occurred only at the limit dose.  

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/day
spirotetramat 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.  Based on these
findings, male reproductive toxicity observed in rats is likely due to
the enol metabolite of spirotetramat and not the parent compound.

	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 were seen in the mouse up to the limit dose. 
Non-adverse decreases in circulating thyroid hormones were identified
exclusively in the dog without any other corresponding thyroid-related
changes.

arget organs in the rat.  An increased incidence of alveolar macrophages
was observed (≥189/890 mg/kg/day, m/f) and a complex of changes in the
lung described as interstitial pneumonia occurred after chronic exposure
at the HDT in both sexes.  Decreased kidney weights correlated with an
increased incidence of tubular dilatation in the carcinogenicity study
in both sexes (≥169/229 mg/kg/day, m/f).

	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 plasma concentration was reached for all dose groups within
0.09 to 2.03 hours after administration; radioactivity concentrations in
plasma then 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.

Spirotetramat 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 were observed 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 lack of dose-related thyroid changes
in the 90-day and 1-year dog studies, the changes in circulating thyroid
hormones in the dog were determined to be non-adverse.  No thyroid
effects 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 changes were mediated through
spirotetramat-induced hormonal interference.

C. Aggregate Exposure

	1. Dietary exposure. The toxicology database for spirotetramat is
complete for the purposes of this risk assessment and the
characterization of potential pre- and postnatal risks to infants and
children.  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 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.

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 for all existing registered uses.
 These analyses also included additional proposed uses of spirotetramat
on sugar beets and carrots, and import tolerance on asparagus and
strawberries.  Potential exposure from drinking water is also included
in these assessments.  Potential concentrations of spirotetramat
residues in drinking water were determined by EPA using the Tier I
Screening Concentration in Ground Water (SCI-GROW) model and Tier 1 Rice
model v1.0.  These conservative surface water estimates were added to
the potential exposure from food.  Dietary exposure was determined using
Dietary Exposure Evaluation Model using the Food Commodity Intake
Database (DEEM-FCID) Ver. 4.02.  Consumption data used in this program
were taken from the U.S. Department of Agriculture’s National Health
and Nutrition Examination Survey, What We Eat in America,
(NHANES/WWEIA), 2005 to 2010.

	i. Food. Food exposure estimates were calculated using DEEM-FCID Ver.
4.02 software, with NHANES WWEIA 2005 to 2010 consumption data.  Acute
assessments assumed that 100% of crops with registered and pending uses
of spirotetramat are treated, and that all treated crops contain
residues at tolerance level.  In addition, tolerance level residues for
livestock commodities were also included in the analyses to account for
the potential transfer of plant residues to livestock tissues.  The
refined chronic assessments assumed 100% of crops are treated with
average field trial residues for some commodities and tolerance-level
residues for the remaining residues.  For acute assessment the default
processing factors were used, while for chronic assessment
experimentally determined processing factors were incorporated, where
available.  Tier 1 acute exposure (95th percentile) for food only
utilizes 5% of the aPAD for the US Population and 14% for Children 1-2
yrs., the most highly exposed subpopulation.  Refined chronic exposure
for food only utilizes 19% of the cPAD for the US Population and 57% of
the cPAD for Children 1-2 yrs., the most highly exposed subpopulation.

	ii. Drinking water. The Tier 1 Estimated Drinking Water Concentration
(EDWCs) associated with spirotetramat use on all crops was calculated
using SCI-GROW v.2.3 (ground water) and Tier 1 Rice Model v.1.0 (surface
water).  The highest potential drinking water exposure from registered
and pending uses of spirotetramat was from surface water scenario.  For
acute and chronic exposure, the EDWC of 395 µg/L was used in the
assessments.  EDWCs were incorporated into exposure assessments using
DEEM-FCID v.4.02.  Acute aggregate dietary exposure (food and water) was
7% aPAD for the overall U.S. population.  For the most highly exposed
population subgroup, children 1 -2 yrs., acute aggregate exposure (food
and water) was 16% of the aPAD.  Chronic aggregate dietary exposure
(food and water) was 35% cPAD for the overall U.S. population.  For the
most highly exposed population subgroup, children 1 -2 yrs., chronic
aggregate exposure (food and water) was 90% of the cPAD.

	2. Non-dietary exposure. There is a potential for non-dietary exposure
from registered uses on turf (sod farms and golf courses) and citrus
grown in residential areas [12ESP703 SC Insecticide (Reg No. 432-1530)
and 14ACP703 SC Insecticide/Miticide (Reg No. 264-1050)].  12ESP703 SC
Insecticide is intended for professional use by lawn care operators for
application to golf course turf and sod farms.  Typical application
equipment consists of handgun applications by LCOs and to golf course
greens and tees, and boom applications to fairways and sod farms.  There
is a potential for short-term post-application dermal exposure for
golfers (adults, 11<16 yrs, and 6<11 yrs), however, a reevaluation of
the toxicological database was conducted by EPA and yielded no dermal
hazard.  Therefore, a quantification of dermal risk is not necessary. 
EPA conducted a human health risk assessment for the turfgrass use.  

14ACP703 SC Insecticide/Miticide is intended for application citrus
trees grown in residential areas.  There is potential for short-term
residential handler and post-application exposures from the ornamental
use. The residential handler exposure and risk estimates indicate that
the short-term inhalation margin of exposures (MOE)s are not of concern
(MOE≥100).  While residential post-application exposure may
potentially occur for adults and children 6<11 yrs.), there is no dermal
Point of Departure (POD) identified for spirotetramat, therefore, a
quantitative assessment was not conducted.  EPA conducted a human health
risk assessment for the citrus grown in residential areas use.  

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 7% of the aPAD and 35% 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.  

Short-term aggregate assessment for adults combines dietary (food +
drinking water) exposures with inhalation exposures due to potential
handler exposure from residential use on citrus trees.  The aggregate
MOE for adults was 2,000, which is above the level of concern (100). 
Therefore, the aggregate assessment for all proposed uses for
spirotetramat demonstrates that there is a reasonable certainty that no
harm will result to the U.S. 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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ss 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 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
accounts for 16% of the aPAD at the 95th percentile and 90% of the cPAD
for the most sensitive population subgroup.  

F. International Tolerances

	International and Codex tolerances or Maximum Residue Limits (MRLs) for
spirotetramat are established for many crops in various countries. At
this time, no Codex MRL has been established for spirotetramat residues
in/on carrot.  MRLs of 0.10 ppm and 0.30 ppm have been established by
the EU and S. Korea, respectively.

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