**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** E PA 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 - eth ylcarbonate]) and its metabolites BYI 08330 - enol (cis - 3 - (2,5 - dimethylphenyl) - 4 - hydrox y - 8 - methoxy- 1 - azaspiro[4.5]dec - 3 - en - 2 - one), BYI 08330 - ketohydroxy

(cis - 3 - (2,5 - dimethylphen yl ) - 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 - gluco py ranoside), and BYI 08330 - mono - hydroxy (cis 3 - (2,5 - dimethylphenyl) - 4 - hydroxy - 8 - methoxy- 1 - azaspiro[4.5]decan - 2 - one), 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 coffe e, roast beans at 0.32 ppm . Upon approval of the aforementioned tol erances, 40 CFR part 180.641 should be amended to remove the f

ollowing established tolerances as they will be superseded b y inclusion in updated crop groups or subgroups : Onion, bulb, subgroup 3A - 07 at 0.30 ppm; fruit, citrus, group 10 at 0.60 ppm; fruit, pome, group 11 at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 ev aluated 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 adequatel y understood. The plant residues of concern for tolerance enforcement are the combined residues of spirotetramat (cis - 3 - (2,5 - dimethly phenyl) - 8 -2

methoxy- 2 - oxo - 1 - azaspiro[4.5]dec - 3 - en - 4 - yl - eth yl carbonate]) and its metabolites BYI 08330 - enol (cis - 3 - (2,5 - dimethylphen yl ) - 4 - hydroxy - 8 - methoxy- 1 - azaspiro[4.5]dec - 3 - en 2 - one), BYI 08330 - ketohydroxy (cis - 3 - (2,5 - dimethylphen yl ) - 3 - hydrox y- 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 - ylbeta - D - glucop yranoside), and BYI 08330 - mono - hydrox y (cis - 3 - (2,5 - dimethylphen yl ) - 4 - hydroxy - 8 - methoxy- 1 - azaspiro[4.5]decan 2 - one), calculated as spirotetramat equivalents . 2. Analytical method. S pirotetramat 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 analy

tes as internal standards. The limit of quantification (LOQ) for each analy te 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 1 1 field trials were conducted in the US A and Canada . Cranb erry : 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 US A.

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

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

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

- Onion, Dry Bulb: A total of 1 2 field trials were conducted in the US A 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 US A. B. Toxicological Profile 1. Acute toxicity. Spirotetramat has a low acute oral (LD 50 > 2,000 mg/kg bw; Category III), dermal (LD 50 : > 2,000 mg/kg bw; Category III) and inhalative toxicity (L C 50 : > 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 v ivo and in vitro a ssay s. 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 the3

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 i n abortion and other clinical signs of s ys temic 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 ran ge - finding study , in which decreased sperm motility and progression and increased abnormal sperm cells in the epididy mides 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 epididym al sperm counts were observ ed after 10 day s 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 b y gavage with the enol metabolite of sp irotetramat for 21 day s at a dose of 800 mg/kg bw/day . Spermatotoxicity , abnormal sperm, and Sertoli cell vacuolation were observed in the testes - epididy mides of treated animals. Therefore, male reproductive toxicity in rats is likely

due to the enol metab olite of spirotetramat. 4. Subchronic toxicity. Inthe rat, spirotetramat - induced testicular changes were characterized b y increases in tubular degeneration and decreased testicle weight. Increases in abnormal spermatozoa and hy pospermia were also ident ified in the rat epididy mis. Unlike the rat no effects of an y kind emerged in the mouse, which was tested up to the limit dose. Nonadverse declines in circulating th yroid hormones were identified exclusively in the dog; however, no other th yroid - related changes were noted following subchronic exposure. 5. Chronic toxicity. Inthe dog prolonged exposure to spirotetramat was characterized by nonadverse declines in circulating thyr oid hormones. Below the highest dose tested, no changes in thy roid weight, thy

roid pathology , compensating increases in thy rotropin (TSH), or clinical observations (e.g., neurological signs) suggestive of thy roid compromise and/or hy pothy roidism were detected in either sex. In contrast to the dog, the rat showed no signs of thy roid involvement; slight increases in liver weight and alveolar macrophage accumulation in the lung, characterized the one - ye ar chronic response in the rat. 6. Animal metabolism. The pharmacokinetic behavior of spirotetramat is characterized by

a r apid 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. T he predominant route of excretion was by urine, accounting for 88%4

to 95% of the admini stered dose. L ess than 0.2 % of the dose was detected in the body and the gastro - intestinal tract at 48 hours after the dose. D ose rate and frequency did not have an y significant effects on the rates of absorption and excretion. The maximum of plasma co ncentration was reached for all dose groups within 0.09 to 2.03 hours after administration. From the maximum, the radioactivity c oncentrations in plasma declined steadil y by s everal orders of magnitude within 48 hours for all dose groups. Concentrations of radioactivity d etected in tissues and organs at the time of sacrifice 48 hours post dose administration were very l ow and below the limit of detection for some organs/tissues. BYI08330 was completely m etabolized by

the rat and no parent compound was dete cted in the excreta. T he major metabolic reaction was cleavage of the ester group leading to the formation of the primary and most predominant metabolite BY I08330 - enol (53

– 87 % of the dose administered). A ll other identified metabolites could be derive d from the enol intermediate. The second prominent metabolic transformation was demethylation of the 8 - methoxy

group to BYI08330 - desmeth yl - enol (5

– 37 % of the dose administered). Oxidation of the py

rroline moiety to BYI08330 - ketohydroxy and BYI08330 - des methyl ketohydroxy

w ere detected as minor pathway s. O ther very m inor 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 - ketoh ydrox y, BYI 08330 - desmethyl - ketohydrox y, BYI 08330 - desmeth yl - di - hydroxy , and BYI 08330 - mono hydrox y. 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 th yroid - and testicular - related changes emerged in the dog and rat, respectively , following exposure to spirotetramat. During both the 90 - day

and 1 - ye ar 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 thy roid profile that emerged in both the 90 - day and 1 - year dog studies, the changes in circulating thy

roid hormones in the dog were judged to be nonadverse. No thy roid 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 berries5

(Crop Group 13B and 13 H ), 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 Baye r CropScience using the Provisional Cranberry Model . These conservative surface water estimates were added to the potential exposure from food. Die tary exposure was determine d using the CARES Version 3.0 software which uses the food consumption data from the 1994 - 1996, 1998 USDA Continuing Survey s 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 (NOAE L) of 100 mg/kg body weight/day

from an acute oral neurotoxicity screening study with technical grade spirotetramat in rats, applying an uncertai nty 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 chron ic reference dose (cRfD) of 0. 05 mg/kg body weight/day . This cRfD is based on a no observed adve rse 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 Drin king W ater. 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 re sidues was used for non - blended and partiall y 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 determ ined 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 highl y exposed population subgroup was infants with an acute exposure at the 99.9 th percentile of 5 % of the acute RfD/acute PAD. For the over all U.S. Population the acute exposure at the 99.9 th percentile wa s 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 99.9 th percentile of about 9 % of the chronic RfD/chronic PAD. For the overall U.S.6

Population the chronic exposure at the 99.9 th 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 tol erance 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. Us ing 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 cro ps 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 generall y has no concerns for exposures below 100% of the Population Adjusted Doses. Therefore, the aggregate as sessment 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 spiro tetramat 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 increa sed sensitivity

of rats or rabbits to in utero exposure to spirotetramat. In addition, the multi - generation reproductive toxicity study did not identify

an y increased sensitivity of rats to in utero or post - natal exposure. Non - maternal toxicity was identif

ied 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. Rep roduction studies provide information relating to effects from exposure to the pesticide on the reproductive capability of mating animals and data on s ys temic toxicity . FFDCA section 408 provides that EPA shall apply an additional tenfold margin of safety7

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 dat abase 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 5 % o f the aRfD/aPAD at the 99.9 th percentile and less than 9 % o f the cRfD/cPAD for the most sensitive p opulation subgroup . Thus, it can be concluded that there is a reasonable certainty that no harm will result from aggregate expo sure to spirotetramat residues. F. International Tolerances There are currently

no CODEX tolerances for spirotetramat.