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 P r o ject He a dquarters, Rut g ers, The State Uni v ers i ty o f N J , 500 C ol l e g e Ro a d E a st, Su i te 201 W, Pr i nce t o n, N J 08540 proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346 a(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 ca rbonate) 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 - one, calculated as the stoichiometric equivalent of spirotetramat, in or on the raw agricultural commodities ca rrot, roots at 0.15 parts per million (ppm) ; nu t, tree, group 14 - 12 at 0.25 ppm; and f ruit, 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 : f ruit, stone, g roup 12 at 4.5 ppm ; n ut, 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 p lants 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 - dime thylphenyl) - 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 - di methylphenyl) - 4 - hydroxy - 8 - methoxy - 1 - azaspiro[4.5]decan - 2 - one, calculated as the stoichiometric equivalent of spirotetramat . 2. Analytical method. S pirotetramat residues are quantified in raw agricultural2

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 r esidu e field trials were conducted to support the tolerances requested above including c arrots . 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 ) ; Cate gory III), dermal (LD 50 : > 2,000 mg/kg bw; Category III) and inhalati on 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 u nder the conditions of the guinea pig maximization test. 2. Genotoxic i ty. 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 a ssays. 3. Reproductive and developmental toxicity. In both the rabbit developmental toxicity study and rat two - generation reprodu ctive 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 F 1 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 (F 1 and F 2 during lactation) were accompanied by decreased parental body weight (F 1 ; males throughout premating, females during premating and lactation) and food consumption (P and F 1 females). Evidence of qualitative susceptibility was observed in the ra t 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, o ccurred only at the limit dose.3

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 gavag e. 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. Spermatotox icity, 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 r at 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. 5. Chronic toxicity. In the dog, prolonged exposure to spirotetramat was characterized by non - adverse decreases in circulating thyroid hormones. Below the highest dose tested, no changes in thyroid weight, thyroid pathology, compensating increases in thyrotr opin (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. Similar male reproductive findings as those seen after subchronic exposure were observed after chronic exposure. Abnormal spermatozoa, hypospermia, and germ cell exfoliated debris in the epididymis, decreased testicular weight, and testicular degeneration and vacuolation were seen in male s only at the HDT (616 mg/kg/day, 90 days; 373 mg/kg/day, 24 months) and were largely reversible after cessation of treatment. The lung and kidney were also t 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 ki dney 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 a bsorption 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 tiss ues 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.4

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 intermedia te. 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 de tected 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 toxicolo gy . 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 th yroid - 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. Ultimat ely, 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 s pirotetramat 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 f or 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 extrapolatio n (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.5

Assessments were conducted to evaluate potential risks due to acute and chronic diet ary 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 Wate r (SCI - GROW) model and T ier 1 Rice m odel v1.0 . These conservative surface water estimates were added to the potential exposure from food. Dietary exposure was determine d using Dietary Exposure Evaluation Model using the Food Commodity Intake Database ( DE EM - FCID ) Ver. 4.02 . Consumption data used in this program were taken fro m the U.S. Department of Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA), 200 5 to 20 10 . i. Food. Food exposure estimates were calculated using DEEM - FCID Ver. 4.02 software, with NHANES WWEIA 200 5 to 20 10 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 tole rance 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 treate d 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 calculate d 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 o f 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 subgr oup, 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 areas6

[12ESP703 SC Insecti cide (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 LCO s 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. E PA conducted a human health risk assessment for the turfgrass use. 14ACP703 SC Insecticide/Miticide is inten ded 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 inh alation 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 q uantitative assessment was not conducted. E PA 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 det ermination 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 othe r 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 bot h 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 increased7

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 pesticid e 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 completene 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 spirotetram at. Therefore, the FQPA Safety Factor can be reduced to 1 X. 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 spirotetra mat accounts for 16 % o f the aPAD at the 95 th percentile and 90 % o f the cPAD for the most sensitive population subgroup . F. International Tolerances International and C odex tolerances or Maximum Residue Limits (MRLs) for spirotetramat are established f or 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.