EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER EPA Registration Division contact: Mark Suarez , (703) 305 - 0120 INSTRUCTION S: 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. Simpl y replace the instructions that appear in green , i.e., “[ insert company name ],” with the information specific to your action. TEMPLATE: Bayer CropScience [Insert petition number] EPA has received a pesticide petition ( [insert petition number] ) from Bayer CropScience , 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. (Options (pick one) by establishin g a tolerance for residues of S pirotetramat (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 - one), calculated as spirotetramat equivalents, ] in or on the raw agricultural commodities [ asparagus, spear s (stems) ] at [ 0. 10 ] ppm . EPA has determined that the petition contains data or informat ion 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

M-526170-01-12 livestock is adequately understood. The plant residues of concern for tolerance enforcement are the combined residues of spirotetram at (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 - dimethylpheny l) - 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 - azaspi ro[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 t he 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 includi ng the following:

- Asparagus : A total of eight field trials were conducted in Mexico and Peru . 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; Categ ory III) and inhalative toxicity (LC 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 d oes exhibit skin sensitizing potential. 2. Genotoxic i ty. Tr eatment - 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 a ssays. 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 toxici ty (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 to xicity was not 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.3 In ad dition 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 F 1 - 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 - findi ng study, in which decreased sperm motility and progression and increased abnormal sperm cells in the epididymides were observed in F 1 males at ≥6000 ppm (320 mg/kg bw/day). Development of the sexual organs of offspring (balano preputial separation, vagina l 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 spirotetra mat 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 at the highest dose tested (616 mg/kg bw/day) . Increases in abnormal sper matozoa 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 do se 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. No significant effects were observed in the mouse up to th e limit dose. 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 ex creted 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 f requency did not have any significant effects on the rates of absorption and excretion.4 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 d etection 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 predom inant 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 glucuron ic 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 metaboli tes 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 (LD 50 > 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 spirotetr amat. 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, ther e were no data to suggest the effect was mediated through some form of 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 ef fect 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 intraspecies5 variation (1 0X). 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 0.0 5 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 varia tion (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. popul ation and selected population subgroups to residues of spirotetramat. These analyses included the existing use s of spirotetramat on taro leaves, watercress, pomegranate, banana, bulb vegetables (3 - 07), low growing berry (13 - 07H), bushberry (13 - 07B), globe artichoke, fruiting vegetables (8 - 10), pome fruit (11 - 10), citrus fruit (10 - 10), pineapple, coffee, and corn import tolerance. The following analysis was based on the most recent EPA dietary assessment on March 26, 2013 (D398858) with additional proposed uses of spirotetramat on asparagus import tolerance. Potential exposure from drinking water is also included in these assessments. Potential concentrations of spirotetramat residues in drinking water were determined by EPA using SCI - GROW and Tier 1 Rice Model v1.0 . These conservative surface water estimates were added to the potential exposure from food. Dietary exposure was determine d using DEEM - FCID Ver. 3.16 . Consumption data used in this program were taken from NHANES WWEIA 2003 to 2008 . i. Food . Food exposure estimates were calculated using DEEM - FCID Ver. 3.16 software, with NHANES WWEIA 2003 to 2008 consumption data. The a cute assessment assumed that 100% of crops with registered and pending uses of spirotetramat are treated, default processin g factors were used, and that all treated crops contain residues at tolerance level. The refined chronic assessment assumed that 100% of crops with registered and pending uses of spirotetramat are treated, empirical processing factors were used, and that some treated crops contain residues at the average residue levels found in crop field trials while the remaining treated crops were at tolerance - level residues . In addition, tolerance level residues for livestock commodities were also included in the anal yses to account for the potential transfer of plant residues to livestock tissues. The addition of asparagus residues at tolerance - levels had negligible effects on the previous risk assessment. Tier 1 a cute exposure (95th percentile) for food only utiliz es 5 % of the aPAD for the US Population and 14 % for Children 1 - 2 yrs., the most highly exposed subpopulation. Refined c hronic exposure for food only utilizes 19 % of the cPAD for the US Population and 53 % of the cPAD for Children 1 - 2 yrs., the most highly exposed subpopulation . ii. Drinking water. The Tier 1 Estimated Drinking Water Concentration s (EDWCs) associated with spirotetramat use on all crops were calculated using SCI - GROW v.2.3 (ground water) and Tier 1 Rice Model v.1.0 (surface water) . The hi ghest potential drinking water exposure from registered and pending uses of spirotetramat was from surface water scenario. For acute and chronic exposure, the6 EDWC of 395 μ g/L was used in the assessment s . EDWCs were incorporated into exposure assessments using DEEM - FCID v. 3.16. The addition of asparagus residues at tolerance - levels had negligible effects on the previous risk assessment. A cute aggregate dietary exposure (food and water) was 7 % aPAD for the overall U.S. population. For the most highly ex posed population subgroup, children 1 - 2 yrs., acute aggregate exposure (food and water) was 16 % of the aPAD. C hronic aggregate dietary exposure (food and water) was 36 % cPAD for the overall U.S. population. For the most highly exposed population subgrou p, children 1 - 2 yrs., chronic aggregate exposure (food and water) was 76 % of the cPAD . 2. Non - dietary exposure . There is a potential for exposure from non - dietary turf and ornamental uses previously submitted [ 12ESP703 SC Insecticide (Reg No. 432 - 1530) and 14ACP703 SC Insecticide/Miticide ( pending registration) ] . 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 application s 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. HED conducted a human health risk assessment for the turfgrass use (D413575, 10/16/14). 14ACP703 SC Insecticide/Miticide ( pendin g registration ) is intended for professional application citrus trees grown in residential areas. There is a potential for short - term post - application dermal exposure for adults and children 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. D. Cumulative Effect s Spirotetramat is a ketoenol tetramic acid insecticide. At this time, the EPA has not made a determination that spirot etramat 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 conclu ded 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 36% of the cPAD. These values include potential exposure from both food and drinking wat er. 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 the7 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. Thes e 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 stu dy 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 desig ned 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 ani mals 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 dat a 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. Therefor e, 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 accounts for 16 % of the aPAD at the 95 th percentile and 76 % of the cPAD for the most sensitive population subgroup . Aggregate dietary and residential exposures were not performed because there are no registered or proposed residential non - food uses of sp irotetramat, 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 Peru has established a national MRL for spirotetramat residues in/ on asparagus at 0.1 ppm . Therefore we proposed to establish the US tolerance at 0.1 ppm to harmonize and minimize any potential trade irritant.