Page 1 of 65 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES

MEMORANDUM

Date: 14-MAY-2008

SUBJECT: Spirotetramat . Human-Health Risk Assessment for Proposed Uses on Citrus (Crop Group 10); Cucurbit Vegetables (Cr op Group 9); Fruiting Vegetables (Crop Group 8); Grape (Crop Subgroup 13F); Hops; Leafy Brassica Vegetables (Crop Group 5); Leafy Non- Brassica Vegetables (Crop Group 4); Pome Fruit (Crop Group 11); Potato and Other Tuberous and Corm Vegetables (Crop Subgroup 1C); Stone Fruit (Crop Group 12); Tree Nuts (Crop Group 14); Onions; Strawberries; Livestock Commod ities; and Greenhouses/Nurseries.

PC Code: 392201 DP#: 333437 and 345276 Decision No.: 371317 Registration No.: 264-xxx Petition No.: 6F7199 Regulatory Action: Section 3 Registration Risk Assessment Type: Single Chemical Aggregate Case No.: None

T XR No.: None CAS No.: 382608-10-8 MRID No.: 46904479-99, 46904501-27, 46904529-32, 46904536-39, 46904541-44, 46904546-58, 46904560-63, 46904565, 46904569, 46904594-95, 46904597, 46904599, 46904601-02, 46904604, 47070901, 47151101-05, 47180401-02, 47281301-07, 47291201, 47143501-02, 47208001 40 CFR: None

Ver.Apr.08

FROM: Jennifer R. Tyler, Risk Assessor

George F. Kramer, Ph.D., Chemist Kelly Lowe, Environmental Scientist Robert Mitkus, Ph.D., Toxicologist Registration Action Branch 1 (RAB1) Health Effects Division (HED; 7509P)

THROUGH: Dana M. Vogel, Branch Chief RAB1/HED (7509P)

TO: Rita Kumar/Meredith Laws, PM Team 01 Registration Division (RD; 7505P)

The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides. The RD of OPP has requested that HE D evaluate hazard and exposure data and conduct dietar y, occupational, residential and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from proposed tolerances for thePage 2 of 65 new active ingredient (ai) spirotetrama t (cis-3-(2,5-dimethlyphenyl)-8-methoxy-2-oxo-1- azaspiro[4.5]dec-3-en-4-yl-ethyl carbonate]) on seve ral agricultural and livestock commodities.

Spirotetramat is being evaluated as a part of a trilateral review with Canada and Austria. The U.S. provided the primary review of the availa ble toxicology studies, a nd Canada provided the primary review of the residue chemistry data. A ll of the residues of concern for tolerances and maximum-residue limits (MRLs) have been harm onized among the participating countries. All toxicology endpoints have been harmonized, with the exception of the acute reference dose (aRfd), which has been harmonized with Canada.

A summary of the findings and an assessment of human-health risk resulting from the proposed tolerances for spirotetramat are provided in this document. The risk assessment was provided by Jennifer Tyler (RAB1); the residue chemistry data review and dietary exposure assessment by George Kramer (RAB1); the hazard characteriza tion and endpoint selection by Robert Mitkus (RAB1); the occupational exposure assessment by Kelly Lowe (RAB1); and the drinking water exposure assessment by José Meléndez of the Envi ronmental Fate and Effects Division (EFED).

Recommendations for Tolerances: Pending submission of revised Sections B and F and the submission of reference standards for the sp irotetramat metabolites, there are no residue chemistry, toxicology, or occupational exposure issues that would preclude granting an unconditional registration for the requested uses of spirotetramat on the requested crops.

The proposed uses and the submitted data support the following permanent tolerances for 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-azaspi ro[4.5]dec-3-en-2-one), BYI 08330-ketohydroxy (cis-3-(2,5-dimethylphenyl)-3-hydroxy-8-me thoxy-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-m ono-hydroxy (cis-3-(2,5-dimethylphenyl)-4- hydroxy-8-methoxy-1-azaspiro[4.5]decan-2-one), calcula ted as spirotetramat equivalents, in/on the following commodities:

Fruit, citrus, group 10 0.60 ppm Vegetable, fruiting, group 8 2.5 ppm Citrus, oil 6.0 ppm Vegetable, cucurbit, group 9 0.30 ppm Vegetable, leafy, except Brassica, group 4 9.0 ppm Brassica , head and stem, subgroup 5A 2.5 ppm Fruit, pome, group 11 0.70 ppm Brassica , leafy greens, subgroup 5B 8.0 ppm Fruit, stone, group 12 4.5 ppm Vegetable, tuberous and corm, subgroup 1C 0.60 ppm Small fruit vine climbing subgroup, except fuzzy kiwifru it, subgroup 13-07F 1.3 ppm Potato, flakes 1.6 ppm

Grape, raisin 3.0 ppm Nut, tree, group 14 0.25 ppm Strawberry 0.40 ppm Almond, hulls 9.0 ppm Onion, bulb, subgroup 3A-07 0.30 ppm Hop, dried cones 10 ppm

The proposed uses and the submitted data support the following tolerances for the combined residues of spirotetramat (c is-3-(2,5-dimethlyphenyl)-8-methoxy- 2-oxo-1-azaspiro[4.5]dec-3-en4-yl-ethyl carbonate]) and its metabolit e BYI 08330-enol (cis-3-(2,5-dimethylphenyl)-4- hydroxy-8-methoxy-1-azaspiro[4.5]dec-3-en-2-one), ca lculated as spirotetramat equivalents, in/on the following livestock commodities:Page 3 of 65 Milk 0.01 ppm Sheep, meat 0.02 ppm Cattle, meat 0.02 ppm Sheep, fat 0.02 ppm Cattle, fat 0.02 ppm Sheep, meat byproducts 0.02 ppm Cattle, meat byproducts 0.02 ppm Horse, meat 0.02 ppm Goat, meat 0.02 ppm Horse, fat 0.02 ppm Goat, fat 0.02 ppm Horse, meat byproducts 0.02 ppm Goat, meat byproducts 0.02 ppm

Data Needs/Deficiencies

 The petitioner is requested to submit a re vised Section B specifying the following

o A 30-day plantback interval (PBI) for all non-labeled crops.

o A 24-hour restricted entry interval (REI).

 Analytical standards for the metabolites of sp irotetramat are currently not available in the National Pesticide Standards Repository [S ource: personal comm unication with D. Wright Jr. of the Analytical Chemistry Laboratory/Biological and Economics Analysis Division (ACL/BEAD), 11/2/2007]. Analytical reference standards (both technical-grade and isotopically labele d) of BYI 08330-enol, BYI 08330-ketohydroxy, BYI 08330-monohydroxy, and BYI 08330-enol-Glc should be su pplied, and supplies replenished as requested by the Repository.

 The petitioner is requested to submit a revi sed Section F specifying the following:

o The tolerance expression for plant comm odities should be revised to include the combined residues of spirotetramat and its metabolites BYI 08330-enol, BYI 08330-ketohydroxy, BYI08330-enol-Glc, and BYI 08330-mono-hydroxy, expressed as spirotetramat equivalents.

o Revised tolerance levels and commodity definitions summarized in Appendix C.Page 4 of 65 Table of Contents 1.0 Executive Summary ......................................................................................................... ... 5 2.0 Ingredient Profile ........................................................................................................ ...... 11 2.1 Summary of Proposed Uses .................................................................................. 12 2.2 Structure and Nomenclature ................................................................................. 13 2.3 Physical and Chemical Properties ......................................................................... 15 3.0 Hazard Characterization/Assessment ................................................................................ 15 3.1 Hazard and Dose-Response Characterization ....................................................... 15 3.2 FQPA Considerations ........................................................................................... 18 3.3 Hazard Identification and Toxicity Endpoint Selection ........................................ 19 3.4 Endocrine Disruption ............................................................................................ 22 4.0 Public Health and Pesticide Epidemiology Data .............................................................. 22 5.0 Dietary Exposure/Risk Characterization ........................................................................... 22 5.1 Pesticide Metabolism and Environmental Degradation ........................................ 23 5.2 Dietary Exposure and Risk ................................................................................... 29 6.0 Residential (Non-Occupational) E xposure/Risk Characterization ................................... 31 6.1 Spray Drift ............................................................................................................ 31 7.0 Aggregate Risk Assessments and Risk Characterization .................................................. 32 7.1 Acute Aggregate Risk ........................................................................................... 32 7.2 Chronic Aggregate Risk ........................................................................................ 32 8.0 Cumulative Risk Characterization/Assessment ................................................................ 32 9.0 Occupational Exposure/Risk Pathway .............................................................................. 33 9.1 Short- and Intermediate -Term Handler Risk ........................................................ 33 9.2 Short-Term Post-application Risk......................................................................... 34 10.0 Data Needs and Label Recommendations ........................................................................ 36 10.1 Toxicology ............................................................................................................ 36 10.2 Residue Chemistry ................................................................................................ 36 Appendix A. Toxicology Assessment ............................................................................ 37 A.2. Toxicity Profiles .................................................................................................... 38 A.3. Executive Summaries............................................................................................ 45 Appendix B. Metabolism Assessment ............................................................................ 59 Appendix C. Tolerance Summary Table for Spirotetramat ........................................... 65Page 5 of 65 1.0 Executive Summary

Bayer CropSciences has submitted a petition for the use of the new insecticide spirotetramat for use on citrus, cucurbit vegetables, fr uiting vegetables, grapes, hops, leafy Brassica vegetables, leafy non- Brassica vegetables, pome fruit, tuberous and co rm vegetables, stone fruit, tree nuts, and greenhouse/nurseries. Spirotetramat is a te tramic acid derivative (k etoenole), and is active against sucking insects in vegeta bles, citrus, pome fruit, stone fruit, grapes, cotton and other plants. It is systemic (xylem and phloem mobile) and can cont rol hidden pests and protect new shoots.

There are currently no food/feed uses or toleran ces for spirotetramat in the U.S. In addition, there are currently no registered or proposed residential uses for spirotetramat. Spirotetramat is being evaluated as part of a trilateral joint revi ew with Canada and Austria. Spirotetramat will be formulated as MoventoTM [EPA Reg. No. 264- xxx; a 2 pound (lb) ai/g allon (gal) suspensionconcentrate (SC) formulation], UltorTM (EPA Reg. No. 264-xxx; a 1.25 lb ai/gal SC formulation); BYI 8330 OD [EPA Reg. No. 264-xxx ; a 1.25 lb ai/gal oil-dispersion (OD) formulation]; and Spirotetramat 240 SC Greenhous e and Nursery Insectic ide/Miticide (EPA Reg. No. 264.xxx; a 2 lb ai/gal SC formulation).

Hazard Assessment : The acute, short-term, and long-term toxicity of spirotetramat is well understood. Spirotetramat technical demonstrated moderate to low acute toxicity (Toxicity Category III or IV) via the oral, dermal, and inhalation routes. Sp irotetramat is non-irritating to the skin (Toxicity Category IV), although it is an irritant to the eyes (Toxicity Category II) and exhibits a skin-sensitization potential in animal s and humans. The thyroid and thymus glands were target organs in oral subchronic toxicity studies in the dog; whereas, the testesepididymides were the target organs following subchronic oral treatment of rats. Long-term toxicity studies reflected the short-term toxicol ogical profile of spirotetramat with the thymus and thyroid as target or gans following one-year oral exposure of dogs. Chronic exposure of rats to spirotetramat also reflected the subchronic patter n of testicular toxicity. No evidence of tumor formation was found following long-term studies of rodents, and spirotetra mat was also negative for mutagenicity and clastoge nicity in several standard in vivo and in vitro assays.

The reproductive and developmenta l toxicity potential of spirotetramat was tested in rats and rabbits. In addition to testicular histopat hology observed following subchronic and chronic exposure of rats to spirotetramat, male reprodu ctive toxicity was recorded in the 2-generation reproductive toxicity study. However, developmen t of the sexual organs of offspring (balanopreputial separation, vaginal opening) was unaffect ed. In an investig ative study designed to explore the time of onset of testicular toxicity in rats, decreased epididymal sperm counts were noted after 10 days of exposure. Therefore, re peated dosing with spirotetramat is necessary to produce male reproductive toxicity in rats. Simi lar effects were observed after repeated dosing with the enol metabolite of spirotetramat. Developmental toxicity was not observed with spirotetramat in the absence of maternal toxicity in either the rat or rabbit.

Dose Response Assessment and Food Qua lity Protection Act (FQPA) Decision : After review by HED’s Risk Assessment Review Committee (R ARC) and Toxicology Science Advisory Committee (ToxSAC), the spirotetramat risk as sessment team recommends that the 10X FQPA safety factor (SF) be reduced to 1X since there is a complete toxicity database for spirotetramatPage 6 of 65 and exposure data are complete or are estima ted based on data that reasonably account for potential exposures. The recommen dation is based on the following:

 There was no evidence of increased susceptibi lity of offspring following pre- or postnatal exposure in any study. In the rat devel opmental toxicity study, toxicity to offspring was observed at the same dose as maternal toxi city, which was also the limit dose. In the developmental toxicity study in the rabbit, only maternal toxi city was observed. In both reproductive toxicity studies, toxicity to offspring (decreased body weight) was observed at the same dose as parental toxicity. Therefore, no eviden ce of increased susceptibility of offspring was found across four relevant toxicity studies wi th spirotetramat.

 Spirotetramat does not operate by way of a neurotoxic mechanism of action in target pests.

 Spirotetramat is not considered a neurotoxic chemical in mammals. Clinical signs of toxicity and decreased motor ac tivity were observed in adult rats following a single dose of spirotetramat in the acute neurotoxicity study in the rat; howeve r, these effects only attained statistical significance at high doses and were not observed at the limit dose in the acute oral toxicity study in the rat.

 There is no concern for neurotoxicity with sp irotetramat in the developing animal based on the fact that brain dilation in the one -year dog study is most likely a congenital anomaly (see section 3.1.2) that was not obser ved in any other study in the database, and the fact that the stru cturally related Bayer compounds spirodiclofen and spiromesifen are not neurotoxic in adults or young.

 The dietary food exposure assessment utilizes tolerance-level re sidues and 100% crop treated (CT) information for all proposed co mmodities. By using this screening-level assessment, the acute and chronic expos ures/risks will not be underestimated.

 The dietary drinking water assessment (Tier 1 estimates) utilizes values generated by model and associated modeling parameters wh ich are designed to provide conservative, health-protective, high-end estimates of water concentrations.

 There are no registered or proposed uses of spirotetramat which would result in residential exposure.

Risk assessments were conducted for the followi ng specific exposure scenarios listed below. The acute and chronic reference doses (aRfD and cRfD) were calcula ted by dividing the noobserved-adverse-effect-level ( NOAEL) by 100 (10X for interspecies extrapolation and 10X for intraspecies variation). Since the FQPA SF has been reduced to 1X, the acute and chronic population-adjusted doses (aPAD and cPAD) are e qual to the aRfD and cRfD, respectively. A 100% oral-equivalent inhalation-ab sorption factor is assumed. The level of concern (LOC) for occupational dermal and inhalation exposures are for margins of exposure (MOEs) <100.Page 7 of 65 Exposure Scenario Point of Departure RfD, PAD, LOC for Risk Assessment Study/Effect

Acute dietary NOAEL = 100 mg/kg/day aRfD = aPAD = 1.0 mg/kg/day Acute neurotoxicity in rats (gavage)/C linical signs (M&F) and decreased motor activity (M) seen at the lowest-observed-adverse-effect-level (LOAEL) of 200 mg/kg/day.
Chronic dietary NOAEL = 5 mg/kg/day cRfD = cPAD = 0.05mg/kg/day Chronic toxicity study in dogs (dietary)/ Thymus involution seen at LOAEL of 20 mg/kg/day (M).

Short- andIntermediateterm dermal NOAEL = 10 mg/kg/day LOC for MOE < 100 (occupational) Prenatal developmental study in rabbits/ Late abortion ( ≥ GD 22), clinical signs, impaired food and water consumption and body weight loss seen at maternal LOAEL of 40 mg/kg/day.
Short- andIntermediateterm inhalation NOAEL = 10 mg/kg/day LOC for MOE < 100 (occupational) Prenatal developmental study in rabbits/ Late abortion ( ≥ GD 22), clinical signs, impaired food and water consumption and body weight loss seen at maternal LOAEL of 40 mg/kg/day.

Residue Chemistry and Drinking Water Assessments: The residue chemis try and drinking water databases are adequate to assess poten tial human exposure to spirotetramat.

The residues of concern in plants (primary cr ops) for tolerance expression and risk assessment purposes are spirotetramat and its me tabolites BYI 08330-enol, BYI 08330-ketohydroxy, BYI08330-enol-Glc, and BYI 08330-mono-hydroxy. Th e residues of concern for rotational crops are spirotetramat and BYI 08330-ke tohydroxy and free and conjugated BYI 08330- desmethyl-ketohydroxy, BYI 08330-desmet hyl-di-hydroxy and BYI 08330-ketohydroxyalcohol. Based on the currently proposed uses , the residues of con cern for the tolerance expression for livestock commodities are spirot etramat and its metabolite BYI 08330-enol and the residues of concern for the risk assessment for livestock commodities are spirotetramat and its metabolites BYI 08330-enol and BYI 08330-enol-GA. If future proposed uses result in significant exposure of livest ock to the plant metabolit es BYI 08330-ketohydroxy, BYI08330- enol-Glc, and BYI 08330-mono-hydroxy, then these metabolites may need to be included as additional residues of concern for livestock comm odities. For drinking water, the residues of concern for risk assessment purposes are spirotetramat, BYI 08330-enol, and BYI 08330- ketohydroxy.

Adequate crop field trial data have been submitted for citrus, cucurbit vegetables, fruiting vegetables, grapes, hops, leafy Brassica vegetables, leafy non- Brassica vegetables, pome fruit, tuberous and corm vegetables, stone fruit, and tree nuts and the European residue for strawberries and onions data are adequate. Fo r all commodities, the data reflect the maximum rates and minimum preharvest intervals (PHI s) requested and have sufficient geographic representation to support tolerances for the proposed uses (See Appendix C). All crop field trial studies are supported by adequate st orage stability data. Adequate processing data indicate that tolerances should be established for citrus oil, raisins, potato flakes, and almond hulls. Based on the available livestock feeding study, tolerances on several livestock commodities should be established (see Appendix C). HED has de termined that high-performance liquid chromatography with tandem mass spectrome try (HPLC-MS/MS) Methods 00857 and 00966 are suitable enforcement methods for plant and li vestock commodities, respectively, since the methods passed a successful petition method validation (PMV) by Agency chemists at ACL/BEAD (E-mail, C. Stafford to D. Voge l; 2/19/08). The existing confined and field rotational crop data are adequate to suppor t the proposed rotationa l crop restrictions.Page 8 of 65 As spirotetremat is a new ai, drinking water mon itoring data are not availa ble. The effects of water treatment on the pesticide and degradates is uncertain. Spirotetramat and its metabolites, BYI 08330-enol, BYI 08330-ketohydroxy and BYI 08330- MA-amide, were highly mobile to moderately mobile, and low levels of binding ar e expected. It appear s that spirotetramat metabolites BYI 08330-enol and BYI 08330-ketohydroxy are of high concern because the parent and BYI 08330 degrade relatively fast in most e nvironments. EFED provided Tier 1 estimated drinking water concentrations (EDWCs) for surface and ground water which were generated using the FQPA Index Reservoir Screening T ool (FIRST) and Screen ing Concentration in Ground Water (SCI-GROW) models, respectively.

Dietary (Food and Drinking Wa ter) Exposure Estimates: Acute and chronic dietary exposure analyses were conducted using the Dietary Expo sure Evaluation Model-Food Commodity Intake Database (DEEM-FCID  ; ver. 2.03) program which incorpor ates consumption data from the United States Department of Agriculture’s (U SDA’s) Continuing Surveys of Food Intakes by Individuals (CSFII), 1994-1996/1998. For acute and chronic dietary risk estimates, HED’s level of concern is for estimates that ex ceed 100% aPAD or cPAD, respectively.

The acute analysis assumed 100% CT and toleran ce-level residues for all foods. Empirical and DEEM TM (ver. 7.81) default processing factors we re used for processed commodities. A conservative chronic dietary assessment assuming average field-trial residues, empirical and DEEM TM (ver. 7.81) default processing factors, and 100% CT was also conducted. Drinking water was incorporated directly in the di etary assessment using the acute or chronic concentrations for surface water generated by th e FIRST model. The acute dietary exposure estimates (95 th percentile) are not of concern to HED (<100% of the aPAD) for the general U.S. population (4.2% of the aPAD) and all other pop ulation subgroups. Th e most highly exposed population subgroup is children 1-2 y ears old at 10% of the aPAD. The chronic dietary exposure estimates are not of concern to HED (<100% of the cPAD) for the general U.S. population (28% of the cPAD) and all populati on subgroups. The most highly exposed population subgroup is children 1-2 years old at 77% of the cPAD.

Aggregate Exposure Scenarios and Risk Conclusions : For the proposed uses, human-health aggregate risk assessments have been conducte d for the following exposur e scenarios: acute aggregate exposure (food + dri nking water), and chronic aggreg ate exposure (food + drinking water). Short- and intermediate-term aggregat e risk assessments were not performed because there are no registered or proposed residential uses for spirotetramat. A cancer aggregate risk assessment was not performed because spirotetramat is classified as “Not Likely to be Carcinogenic to Humans.” All potential exposure pa thways were assessed in the aggregate risk
assessment. All aggregate exposure and risk estimate s are not of concern to HED for the scenarios listed above.

Occupational Exposure Estimates : Based on the proposed use patt erns, HED believes short-term (1-30 days) dermal and inhalation exposures are expected for commercial and private applicators. However, the s hort- and intermediate-term toxi cological endpoints are the same; therefore, the estimates of risk for short-term duration exposur es are protective of those for intermediate-term duration exposures. The mo st highly exposed occupational workers are expected to be mixer/loaders of liquids for aerial applications, applicators using airblast equipment, and mixer/loader/applicators of liq uid concentrates using high-pressure handwand equipment. No chemical-specific data are availa ble with which to assess potential exposure toPage 9 of 65 pesticide handlers; therefore, estimates of expos ure are based on data available in the Pesticide Handler Exposure Database Version 1.1 (P HED Surrogate Exposure Guide, 8/98). Exposure/risks for short-term dermal and inha lation handler mixer/loader exposures were presented at baseline (workers wearing a single layer of workclothing consisting of a longsleeved shirt, long pants, shoes pl us socks and no protective gloves). Provided workers wear protective gloves as recommended on the label, all occupational handle r MOEs are >100; and, therefore, are not of concern to HED ( i.e. , MOE>100).

Short- and intermediate-term (1-30 days and 1- 6 months, respectively) dermal exposures are expected for post-application ag ricultural activities. Post-a pplication inhala tion exposure is expected to be negligible due to the low vapor pressure of spirot etramat. There are no chemicalspecific data with which to estimate post-app lication exposure of agri cultural workers to dislodgeable residues of spirot etramat. Therefore, post-application worker exposure was estimated using Agency default assumptions for dislodgeable residues, wh ich lists scouting and irrigating as the activities with the highest ( i.e. , most conservative) transfer coefficients (TCs) related to the proposed uses. All MOEs are >100 ; therefore, post-application dermal exposure to agricultural workers is not of concern to HED ( i.e. , MOE >100).

Based on the acute Toxicity Category classifica tion for spirotetramat, the interim Worker Protection Standard (WPS) REI of 24 hours is ad equate to protect agri cultural workers from post-application exposures. The proposed end-use product labels list an REI of 12 hours. The labels should be revised to include a 24-hour REI.

Environmental Justice Considerations : Potential areas of environm ental justice concerns, to the extent possible, were considered in this human -health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to A ddress Environmental Justice in Minority Populations and Low-Income Populations," ( http://homer.ornl.gov/nuclearsafety/n sea/oepa/guidance/justice/eo12898.pdf ).

As a part of every pesticide risk assessment , OPP considers a large variety of consumer subgroups according to well-esta blished procedures. In line with OPP policy, HED estimates risks to population subgroups fr om pesticide exposures that ar e based on patterns of that subgroup’s food and water consumption, and activ ities in and around the home that involve pesticide use in a residential se tting. Extensive data on food consumption patterns are compiled by the USDA under CSFII and are used in pesticide risk assessments for all registered food uses of a pesticide. These data ar e analyzed and categor ized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non-diet ary exposures based on home use of pesticide products and associated ri sks for adult applicators and for toddlers, youths, and adults entering or playing on treated ar eas post-application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditi onal dietary patterns among specific subgroups.

Review of Human Research : This risk assessment relies in pa rt on data from PHED studies in which adult human subjects were intentionally ex posed to a pesticide or other chemical. These studies have been determined to require a review of their ethical conduct, and have received thatPage 10 of 65 review.

Recommendations for Tolerances : Pending submission of revise d Sections B and F and the submission of reference standards for the sp irotetramat metabolites, there are no residue chemistry, toxicology, or occupational exposure issues that would preclude granting an unconditional registration for the requested uses of spirotetramat on the requested crops.

The proposed uses and the submitted data support the following permanent tolerances for 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-azaspi ro[4.5]dec-3-en-2-one), BYI 08330-ketohydroxy (cis-3-(2,5-dimethylphenyl)-3-hydroxy-8-me thoxy-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-m ono-hydroxy (cis-3-(2,5-dimethylphenyl)-4- hydroxy-8-methoxy-1-azaspiro[4.5]decan-2-one), calcula ted as spirotetramat equivalents, in/on the following commodities:

Fruit, citrus, group 10 0.60 ppm Vegetable, fruiting, group 8 2.5 ppm Citrus, oil 6.0 ppm Vegetable, cucurbit, group 9 0.30 ppm Vegetable, leafy, except Brassica, group 4 9.0 ppm Brassica , head and stem, subgroup 5A 2.5 ppm Fruit, pome, group 11 0.70 ppm Brassica , leafy greens, subgroup 5B 8.0 ppm Fruit, stone, group 12 4.5 ppm Vegetable, tuberous and corm, subgroup 1C 0.60 ppm Small fruit vine climbing subgroup, except fuzzy kiwifru it, subgroup 13-07F 1.3 ppm Potato, flakes 1.6 ppm

Grape, raisin 3.0 ppm Nut, tree, group 14 0.25 ppm Strawberry 0.40 ppm Almond, hulls 9.0 ppm Onion, bulb, subgroup 3A-07 0.30 ppm Hop, dried cones 10 ppm

The proposed uses and the submitted data support the following tolerances for the combined residues of spirotetramat (c is-3-(2,5-dimethlyphenyl)-8-methoxy- 2-oxo-1-azaspiro[4.5]dec-3-en4-yl-ethyl carbonate]) and its metabolit e BYI 08330-enol (cis-3-(2,5-dimethylphenyl)-4- hydroxy-8-methoxy-1-azaspiro[4.5]dec-3-en-2-one), ca lculated as spirotetramat equivalents, in/on the following livestock commodities:

Milk 0.01 ppm Sheep, meat 0.02 ppm Cattle, meat 0.02 ppm Sheep, fat 0.02 ppm Cattle, fat 0.02 ppm Sheep, meat byproducts 0.02 ppm Cattle, meat byproducts 0.02 ppm Horse, meat 0.02 ppm Goat, meat 0.02 ppm Horse, fat 0.02 ppm Goat, fat 0.02 ppm Horse, meat byproducts 0.02 ppm Goat, meat byproducts 0.02 ppm

Data Needs/Deficiencies

 The petitioner is requested to submit a re vised Section B specifying the following

o A 30-day PBI for all non-labeled crops.

o A 24-hour REI.

 Analytical standards for the metabolites of sp irotetramat are currently not available in the National Pesticide Standards Repository [S ource: personal comm unication with D. Wright Jr. of ACL/BEAD, 11/2/2007]. Analy tical reference standa rds (both technicalgrade and isotopically labeled) of BYI 08330-enol, BYI 08330-ketohydroxy, BYI 08330-Page 11 of 65 mono-hydroxy, and BYI 08330-enol-Glc should be supplied, and supplies replenished as requested by the Repository.

 The petitioner is requested to submit a revi sed Section F specifying the following:

o The tolerance expression for plant comm odities should be revised to include the combined residues of spirotetramat and its metabolites BYI 08330-enol, BYI 08330-ketohydroxy, BYI08330-enol-Glc, and BYI 08330-mono-hydroxy, expressed as spirotetramat equivalents.

o Revised tolerance levels and commodity definitions summarized in Appendix C.

2.0 Ingredient Profile

Spirotetramat is a tetramic acid derivative (k etoenole) developed by Ba yer CropScience AG. This foliar insecticide is active against sucking in sects in vegetables, citrus, pome fruit, stone fruit, grapes, cotton and other pl ants. It is systemic (xylem and phloem mobile) and can control hidden pests and pr otect new shoots.

As spirotetramat is a new ai, there are no to lerances currently established under 40 CFR. Spirotetramat is being evaluated as part of a trilateral joint re view with Canada and Austria.

The petitioner has submitted draft labels dated 10/5/07 for the 2 lb ai/gal SC formulation (MoventoTM; EPA Reg. No. 264-xxx), the 1.25 lb ai/g al SC formulation (UltorTM; EPA Reg. No. 264-xxx), the 1.25 lb ai/gal OD formulation (BYI 8330 OD; EPA Reg. No. 264-xxx); and the 2 lb ai/gal SC formulation (Spirotetramat 240 SC Greenhouse and Nursery Insecticide/Miticide; EPA Reg. No. 264.xxx). A summary of the proposed us e patterns on citrus, cucurbit vegetables, fruiting vegetables, grapes, hops, leafy Brassica vegetables, leafy non- Brassica vegetables, pome fruit, tuberous and corm vegetables, stone fruit, tree nuts, and greenhouse/nur series is detailed in Table 2.1.Page 12 of 65 2.1 Summary of Proposed Uses

Table 2.1. Summary of Direct ions for Use of Spirotetramat.

Trade Names Application Timing, Type, and Equipment Applic. Rate (lb ai/A) Maximum Number Applications per Season Maximum Seasonal Application Rate (lb ai/A) PHI (days) Use Directions and Limitations

CITRUS (Crop Group 10)

BYI 8330 OD

Movento TM

Ultor TM Ground & aerial 0.12-0.16 2 0.32 1 Minimum RTI: 21 days Minimum spray volume: 15 gallons per acre (GPA) ground, 10 GPA aerial GRAPE and SMALL FRUIT VINE CLIMBING (except kiwifruit) BYI 8330 OD

Movento TM

Ultor TM Ground & aerial 0.08-0.12 2 0.20 7 Minimum RTI: 30 days Minimum spray volume: 15 GPA ground, 10 GPA aerial POME FRUIT (Crop Group 11) BYI 8330 OD

Movento TM

Ultor TM Ground & aerial 0.10-0.14 4 0.40 7 Minimum RTI: 14 days Minimum spray volume: 15 GPA ground, 10 GPA aerial STONE FRUIT (Crop Group 12) BYI 8330 OD

Movento TM

Ultor TM Ground & aerial 0.10-0.14 2 0.24 7 Minimum RTI: 14 days Minimum spray volume: 15 GPA ground, 10 GPA aerial TREE NUTS (Crop Group 14) BYI 8330 OD

Movento TM

Ultor TM Ground & aerial 0.10-0.14 3 0.34 7 Minimum RTI: 14 days Minimum spray volume: 15 GPA ground, 10 GPA aerial HOPS BYI 8330 OD

Movento TM

Ultor TM Ground & aerial 0.08-0.10 2 0.20 7 Minimum RTI: 14 days Minimum spray volume: 10 GPA ground, 10 GPA aerial CUCURBIT VEGETABLES (Crop Group 9) BYI 8330 OD

Movento TM

Ultor TM Ground, chemigation,

& aerial 0.05-0.08 3 0.16 1 Minimum RTI: 7 days Minimum spray volume: 15 GPA ground, 5 GPA aerial FRUITING VEGETABLES (Crop Group 8) + OKRA BYI 8330 OD

Movento TM

Ultor TM Ground, chemigation,

& aerial 0.05-0.08 3 0.16 1 Minimum RTI: 7 days Minimum spray volume: 15 GPA ground, 5 GPA aerial LEAFY VEGETABLES - NON- BRASSICA (Crop Group 4) BYI 8330 OD

Movento TM

Ultor TM Ground, chemigation,

& aerial 0.05-0.08 3 0.16 3 Minimum RTI: 7 days Minimum spray volume: 15 GPA ground, 5 GPA aerial BRASSICA (COLE) LEAFY VEGETABLES (Crop Group 5) BYI 8330 OD

Movento TM Ultor TMTM Ground, chemigation,

& aerial 0.05-0.08 3 0.16 1 Minimum RTI: 7 days Minimum spray volume: 15 GPA ground, 5 GPA aerial POTATO and OTHER TUBEROUS AND CORM VEGETABLES (Crop Group 1C) BYI 8330 OD

Movento TM

Ultor TM Ground, chemigation,

& aerial 0.06-0.08 2 0.16 7 Minimum RTI: 7 days Minimum spray volume: 15 GPA ground, 5 GPA aerial GREENHOUSES, NURSERIES, INTERIOR PLANTSCAPES Spirotetramat

240 SC Greenhouse and Nursery Insecticide/

Miticide Chemigation, Groundboom, Airblast, High

Pressure Handwand 0.16 - 0.39 N/A Minimum RTI: 14 days REI: 24 hours.

Additional Restrictions for all Crops: MOVENTOTM and UltorTM must be tank-mixed with a spray adjuvant/additive. BYI 8330 OD may be tank-mixed with a spray adjuvant/additive. Use in enclosed structures, such as gree nhouses or planthouses, is not permitted unless specified otherwise by state-specific supplemental labeling. Rotational PBIs: Immediate plant-back: All cropsPage 13 of 65 HED Conclusions : The submitted use directions for MoventoTM, UltorTM, BYI 8330 OD, and Spirotetramat 240 SC Greenhouse and Nursery Ins ecticide/Miticide are adequate to allow evaluation of the residue data relative to the proposed use. The specified rotational PBIs allow immediate plantback of all crops. However, th e rotational crop data s upport a rotational crop restriction of 30 days for all non-labeled crops. The labels should thus be amended to specify the 30-day PBI.

2.2 Structure and Nomenclature

Table 2.2. Test Compound Nomenclature.

Compound Chemical Structure

Common name Spirotetramat Company experimental name BYI 08330 IUPAC name cis -4-(ethoxycarbonyloxy)-8-methoxy-3-(2,5-xylyl)-1-azaspiro[4.5]dec-3-en-2-one

CAS name cis -3-(2,5-dimethylphenyl)-8-methoxy-2-oxo -1-azaspiro[4.5]dec-3-en-4-yl ethyl carbonate CAS # 382608-10-8 End-use product/EP MoventoTM, UltorTM, BYI 8330 OD

Compound: BYI08330-enol Chemical Structure

Common name BYI08330-enol Company experimental name BYI08330-enol IUPAC name None provided CAS name cis -3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy-1-azaspiro[4.5]dec-3-en-2-one CAS # None provided

Compound: BYI08830- ketohydroxy Chemical Structure

Common name BYI08830-ketohydroxy Company experimental name BYI08830-ketohydroxy IUPAC name None provided CAS name cis -3-(2,5-dimethylphenyl)-3-hydroxy-8-methoxy-1-azaspiro[4.5]decane-2,4-dione CAS # None provided Compound: BYI08330-enol-Glc Chemical StructurePage 14 of 65 Common name BYI08330-enol-Glc Company experimental name BYI08330-enol-Glc IUPAC name None provided

CAS name cis -3-(2,5-dimethylphenyl)-8-methoxy-2-oxo -1-azaspiro[4.5]dec-3-en-4-yl beta-Dglucopyranoside CAS # None provided

Compound: BYI 08330-monohydroxy Chemical Structure

Common name BYI 08330-mono-hydroxy Company experimental name BYI 08330-mono-hydroxy IUPAC name None provided CAS name cis -3-(2,5-dimethylphenyl)-4-hydroxy-8-methoxy-1-azaspiro[4.5]decan-2-one CAS # None provided

Compound: BYI 08330-enolGA Chemical Structure

Common name BYI 08330-enol-GA Company experimental name BYI 08330-enol-GA IUPAC name None provided

CAS name cis -3-(2,5-dimethylphenyl)-4-( β -D-glucopyranosyloxy)-8-methoxy-1-azaspiro[4.5]dec-3- en-2-one CAS # None providedPage 15 of 65 2.3 Physical and Chemical Properties

Table 2.3 Physicochemical Properties of the Technical Grade Spirotetramat. Parameter Valu e Reference Melting Point (°C) 142 Bayer CropScience AG Report M-063268-01-1 pH 6.3 Bayer CropScience AG Report M-269907-01-1 Density D 4 20 = 1.22 Bayer CropScience AG Report M-270041-01-1 Solubility in water at 20oC pH 4 - 33.5 mg/L pH 7 - 29.9 mg/L pH9 - 19.1 mg/L Bayer CropScience AG Report M-103256-01-1
Solubility in organic solvent at 20oC Solvent g/L n-hexane 0.055 Dichloromethane >600 Dimethyl Sulfoxide 200-300 Toluene 60 Acetone 100–120 Ethyl acetate 67 Ethanol 44 Bayer CropScience AG Report M-122802-01-1

Partition Coefficient n-octanol/water (log K ow ) pH 4 - 2.51 pH 7 - 2.51 pH 9 - 2.50 Bayer CropScience AG Report M-103244-01-1

Vapor pressure (Pa) Extrapolated Values: 5.6 x 10 -9 (20oC) 1.5 x 10 -8 (25oC) 1.5 x 10 -6 (50oC) Bayer CropScience AG Report M-066171-01-1

UV/Visible Absorption Spectra Peak Maxima Molar Absorptivity (nm) (1000 cm 2 / mol) 211 22.0 x 10 3
276 0.8 x 10 3 Bayer CropScience AG M-182543-02-1

3.0 Hazard Characterization/Assessment

3.1 Hazard and Dose-Response Characterization

3.1.1 Database Summary

Data from the following studies were used to evaluate the hazard pot ential of spirotetramat:

 Acute: One acute neurotoxicity study (rat), in ad dition to standard acu te toxicity battery.

 Subchronic: Six oral (mouse, rat, dog) and on e dermal (rat) toxicity studies.

 Long-term: Two oral toxicity (dog, rat) and two oral carcinogen icity (rat, mouse) studies.

 Reproduction/developmental: Two developmental (rat, rabbit), one single-generation (rat), and one two-generation reproduction (rat) studies.

 Other: Eight genotoxicity screens ( in vivo / in vitro ), two disposition studies (rat), and

one in vivo dermal penetration study (rat).

The submitted acute, subchronic, and chronic studies were sufficient to evaluate human hazard potential, and data qualit y is acceptable.Page 16 of 65 3.1.2 Mammalian Toxicology

Spirotetramat is an insecticidal compound and belongs to the chemical class of cyclic ketoenols. In insects, spirotetramat is an inhibitor of acetyl-CoA carboxylase, which is a key enzyme in fatty acid biosynthesis in eukaryotes and prokary otes. The insecticidal mode of action of spirotetramat correlates with i nhibition of lipogenesis in treated insects, resulting in decreased lipid contents (notably trigly cerides and free fatty acids), i nhibition of the ability of younger insects to develop through the va rious growth stages, and ultimate ly culminating in a diminished capacity of the insects to reproduce as adults. Changes in plasma lipid parameters such as plasma triglycerides and plasma cholesterol were not observed in any animal study in the toxicology database for spirotetramat.

Absorption, Distribution, Me tabolism, and Excretion : Absorption of spirotetramat by the rat was 89-98% 48 hrs after single low (2 mg/kg bw) and higher (100 mg/kg bw) doses, as well as repeated low doses (2 mg/kg bw). Systemic exposure, as estimated by AUC 0- ∞ , was slightly higher for males than females. Less than 0.2% of the administered dose was detected in the body 48 hrs after sacrifice, and the hi ghest equivalent concentrations were detected in the liver and kidney, a fact that is consistent with the detoxification/excretor y functions of these organs. Spirotetramat was completely metabolized by the rat, since no parent compound was detected in the excreta. The main metabolic reaction was cleavage of the ester group which resulted in formation of the major metabolite BYI 08330-enol (53-87% of administered dose). All other identified metabolites could be derived from enol . Male rats exhibited much higher rates of demethylation of BYI 08330-enol to BYI 08330-desmethyl-enol ( 25-37%) when compared to female rats (5-10 %). Spirotet ramat was excreted quickly with 88-95% of the administered dose eliminated via urine and 2-11% via feces within 48 hrs of exposure.

Absorption and excretion in anim als treated one time with 1000 mg/ kg bw was less than that at the lower doses, with 27% of dose excreted in urine after 24 hours and 18% in feces. Plasma radioactivity was slightly higher than that for liver and kidne y, thereby suggesting saturation of cellular transport mechanisms at this high dose. Tissue radioactivity decr eased from 1 h to 24 h post dose. The metabolism profile was qualitative ly similar to that of the low dose studies.Similar to the low-dose studies, BYI 08330-enol was the most prominent metabolite in the highdose study. Physiologically based pharmacokinetic (PBPK) simulations with the enol metabolite suggest that repeated daily doses ≥ 300 mg/kg bw spirotetramat l eads to non-linear elimination kinetics, possibly due to sa turation of uptake processes in the liver and kidney.

Acute toxicity : Spirotetramat technical demonstrated moderate to low acute toxicity (Toxicity Category III or IV) via the oral, dermal, and inhalation routes. Sp irotetramat is non-irritating to the skin (Toxicity Category IV), although it is an irritant to the eyes (Toxicity Category II) and exhibits a skin-sensitization potential under the conditions of the guinea pig maximization test and the local lymph node assay, but not the Buehle r patch test. The sensitization potential of spirotetramat was supported by two cases of Type IV hypersensitivity that were reported in spirotetramat manufactur ing plant personnel.

Subchronic toxicity : A summary of the prechronic and chronic toxicity and genotoxicity databases for spirotetramat is found in Appendi x A.2. The thyroid and thymus glands were target organs in oral subchroni c toxicity studies in the dog. S ubchronic (90-day) exposure of dogs to spirotetramat was character ized by statistically significant d eclines in circulating thyroidPage 17 of 65 hormones (T4) at ≥ 1200 ppm (32 mg/kg bw/day); decreased T3 was observed at the highest dose tested only (2500 ppm; 72 mg kg bw/day). Howe ver, correlative changes in thyroid weight, thyroid histopathology, or thyroid-stimulating hormone (TSH) were not observed in either sex.

In rats, the testes were the target organ follo wing subchronic oral trea tment at a high dose. Abnormal spermatozoa and hypospermia in the ep ididymis, decreased testicular weight, and testicular degeneration and vac uolation were observed in males after 90 days of exposure at 10,000 ppm (616 mg/kg bw/day). Thes e effects proved to be revers ible in most animals after cessation of treatment. It is not eworthy that the thyroid and thym us were unaffected in rats at any dose, while testicular hist opathology was unobserved in dogs. No adverse effects of any kind were observed in mice following oral exposure . Subchronic exposure of rats by the dermal route yielded no evidence of systemic toxicity.

Long-term toxicity : The thymus and thyroid were also target organs following one-year oral exposure of dogs to spirotetramat. Thymus involution and brain dila tion with dose-related severity were observed in one male each at 600 ppm (20 mg/kg bw/day) and 1800 ppm (55 mg/kg bw/day). Brain dilation has been observe d by veterinary patholog ists in up to 5% of Beagle dog colonies and is considered a c ongenital anomaly by Bayer CropScience. Brain dilation was not observed in any other study in the dog or in any other species tested with spirotetramat. For these reasons, and since br ain dilation was also obs erved sporadically in several other Bayer dog studies with other chemicals of varying dur ations (from f our weeks up to one year), this observation was considered to be an equivocal effect and not likely treatmentrelated. Declines in circulati ng thyroid hormone (T4) were observed in males and females at ≥ 600 ppm (20 mg/kg bw/day). Reduction in folli cle size, a possible i ndication of a reduced amount of colloid in the organ, and decreased T3 levels were observed in 1800-ppm males (55 mg/kg bw/day) only. Correlative changes in thyroi d weight or TSH were not observed in either sex. No morphological changes in the test es were observed in dogs at any dose.

In rats, abnormal sperm or sperma tid degeneration in the testes and germ cell exfoliated debris in the epididymis were observed in male rats at the high dose only (7500 ppm; 414 or 373 mg/kg bw/day) following 12 (not statistic ally significant) or 24 months of oral exposure. Other target organs in rats following exposure for 2 years were the kidney (both sexes) at mid and high doses and the liver (females) at the highest dose only. These results are consistent with the excretory and/or detoxification roles of the kidney and liver . Similar kidney toxicity was also observed at higher doses (419.3 or 484.7 mg/kg bw/day) in parental animals of th e F1 generation in the 2- generation reproductive toxicity st udy in rats. No adverse findi ngs were observed in mice up to the limit dose following long-term treatment with spirotetramat.

Carcinogenicity and Genotoxicity : Treatment-related increases in tumor incidence were not observed in either sex in rats or mice. Spir otetramat was also negative for mutagenicity and clastogenicity in several standard in vivo and in vitro assays.

Developmental Toxicity : Developmental toxicity in the absence of maternal toxicity was not observed in either the rat or rabbit. In the rat, decreased body wei ght and food consumption were observed in dams at the limit dose in a developmental toxicity study. Developmental toxicity (reduced fetal weight a nd 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, developmen tal toxicity was notPage 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-depe ndent increase in abortion and other clinical signs of systemic t oxicity in affected animals.

Reproductive Toxicity : In addition to testicular hist opathology observed following subchronic and chronic exposure of male rats to spirotetramat, evidence of male reproductive toxicity was provided in the 2-generation repr oductive 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 obser ved in one of these males. Similar results were obtained in the 1-generati on reproductive toxicity range-fi nding study, in which decreased sperm motility and progression and increased abnor mal sperm cells in the epididymides were observed in F1 males at ≥ 6000 ppm (320 mg/kg bw/day). Devel opment of the sexual organs of offspring (balano-preputial sepa ration, vaginal opening) was unaff ected 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, therefor e, is necessary to produce male reproductive toxicity in rats. In a second investigative study, ma le 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-e pididymides of treated animals. Therefore, male reproductive toxicity in rats is likely due to the enol metabolite of spirotetramat.

3.2 FQPA Considerations

After review by HED’s Hazard Science Policy Council (HASPOC), the spirotetramat risk assessment team recommends that the FQPA SF be reduced to 1X for the following reasons:

 There was no evidence of increased susceptibi lity of offspring following pre- or postnatal exposure in any study. In the rat devel opmental toxicity study, toxicity to offspring was observed at the same dose as maternal toxi city, which was also the limit dose. In the developmental toxicity study in the rabbit, only maternal toxi city was observed. In both reproductive toxicity studies, toxicity to offspring (decreased body weight) was observed at the same dose as parental toxicity. Therefore, no eviden ce of increased susceptibility of offspring was found across four relevant toxicity studies wi th spirotetramat.

 Spirotetramat does not operate by way of a neurotoxic mechanism of action in target pests.

 Spirotetramat is not considered a neurotoxic chemical in mammals. Clinical signs of toxicity and decreased motor ac tivity were observed in adult rats following a single dose of spirotetramat in the acute neurotoxicity study in the rat; howeve r, these effects only attained statistical significance at high doses and were not observed at the limit dose in the acute oral toxicity study in the rat.

 There is no concern for neurotoxicity with sp irotetramat in the developing animal based on the fact that brain dilation in the one -year dog study is most likely a congenital anomaly (see section 3.1.2) that was not obser ved in any other study in the database, and the fact that the stru cturally related Bayer compounds spirodiclofen and spiromesifen are not neurotoxic in adults or young.Page 19 of 65  There are no residual uncerta inties with respect to e xposure data. The dietary food exposure assessment utilizes recommended tolerance-level residues and 100% CT information for all proposed commodities. By using this screening-level assessment, the acute and chronic exposures/ris ks will not be underestimated.

 The dietary drinking water assessment (Tier 1 estimates) utilizes values generated by model and associated modeling parameters wh ich are designed to provide conservative, health-protective, high-end estimates of water concentrations.

 There are no registered or proposed uses of spirotetramat which would result in residential exposure.

3.3 Hazard Identification and Toxicity Endpoint Selection

3.3.1 Acute Reference Dose (aRfD)

The aRfD for the general populat ion, including females 13-49 years of age, was established based on the NOAEL (100 mg/kg/day) from the acute neurotoxicity study in rats. The LOAEL of 200 mg/kg/day is based on clinic al signs of toxicity in males and females and decreased motor activity in males. This study and endpoint are th e most appropriate sing le-dose effects for the general population, including women of childbeari ng age. For reasons outlined in Section 3.2, the 10X FQPA SF has been reduced to 1x.

3.3.2 Chronic Reference Dose (cRfD )

The cRfD was established based on the NOAEL (5 mg /kg/day) from the 1-y ear toxicity study in the dog. The LOAEL of 20 mg/kg/day is based on thymus involution in males. The NOAEL of 5 mg/kg is the lowest in the database. In a ddition, the study duration is appropriate for the duration of exposure. For reas ons outlined in Section 3.2, the 10X FQPA SF has been reduced to 1x.

3.3.3 Incidental Oral Exposure ( Short- and Intermediate-Term)

No residential uses are proposed for the current acti on. Therefore, an endpoi nt for incidental oral exposure was not chosen.

3.3.4 Dermal Absorption

An in vivo dermal penetration study was performed in the rat using the OD150 formulation. Dermal absorption was estimated to be 10%, ba sed on the directly absorbed dose and compound remaining at the dose site (including stratum corneum) 168 hrs following a 10-hr exposure. Compound retained in the stratum corneum wa s included in this calculation, because radioactivity in the feces increased over the 168-hr time period, which suggested that compound measured in the stratum corneum immediately afte r the 10-hr exposure continued to be absorbed.

3.3.5 Dermal Exposure (Short- and Intermediate-Term)

There are no registered or propos ed residential uses for spirotet ramat. The oral developmental toxicity study in the rabbit was considered the most relevant st udy for short- and intermediateterm dermal occupational exposure scenarios, beca use it is protective of potential exposure toPage 20 of 65 pregnant workers. Dose-dependent systemic toxicity (including body we ight loss, decreased food consumption, clinical signs of toxicity, abortion) was observed in one dam at the LOAEL of 40 mg/kg bw/day (NOAEL = 10 mg/kg bw/day). The route of exposure of th is study is not ideal for these dermal exposure scenarios; however, th e NOAEL in this study is protective of potential systemic toxicity in pregnant workers.

3.3.6 Dermal Exposure (Long-Term)

There are no registered or proposed residential uses for spirotetra mat. The 1-year toxicity study in the dog was chosen for the long-term dermal occupational exposure scenario. The LOAEL of 20 mg/kg/day is based on thymus involution in males. The NOAEL of 5 mg/kg is the lowest in the database. Although the route of exposure is not ideal, the study duration is ideal for the duration of exposure.

3.3.7 Inhalation Exposure (Short- and Intermediate-Term)

There are no registered or propos ed residential uses for spirotet ramat. The effects of concern that are relevant to the selection of the short- and intermediate-term occupational inhalation doses are dose-dependent systemic toxicity (including body weight loss, decreased food consumption, clinical signs of toxicity, abortion) observed in one dam at 40 mg/kg bw/day (NOAEL = 10 mg/kg bw/day). The route of expo sure of this study is not ideal for these inhalation exposure scenarios; however, the NOA EL in this study is protective of potential toxicity to pregnant workers.

3.3.8 Inhalation Exposure (Long-Term)

There are no registered or proposed residential uses for spirotetra mat. The 1-year toxicity study in the dog was chosen for the long-term inhalatio n occupational exposure scenario. The LOAEL of 20 mg/kg/day is based on thymus involution in males. The NOAEL of 5 mg/kg is the lowest in the database. Although the route of exposure is not ideal, the study dur ation is ideal for the duration of exposure.

3.3.9 Level of Concern for Margin of Exposure

There are no registered or proposed residential uses for spirotetra mat. A summary of the levels of concern for occupatio nal (worker) exposure is listed in Table 3.3.9.

Table 3.3.9. Summary of Levels of Concern for Occupational (Worker) Exposure Risk Assessment.
Route Short-Term (1-30 Days) Intermediate- Term (1-6 Months) Long-Term (>6 Months)

Dermal 100 100 100

Inhalation 100 100 100

3.3.10 Recommendation for Aggregat e Exposure Risk Assessments

For oral exposure, dietary and drinking water exposures were combined. For occupational exposure dermal and inhalation exposures were combined since the toxi cological effects of concern are the same and iden tified from the same study.Page 21 of 65 3.3.11 Classification of Carcinogenic Potential

Spirotetramat was determined to be non-mutageni c in bacteria and mammalian cells, as well as non-clastogenic in in vivo mammalian assays. No evidence of carcinogenicity was observed in carcinogenicity studies in the rat and mouse. Based on thes e results, RAB1 toxicologists classified spirotetramat as “Not Like ly to be Carcinogenic to Humans.”

3.3.12 Summary of Toxicological Doses and En dpoints for Spirotetramat for Use in Human-Health Risk Assessments

Summaries of the toxicological doses and endpoi nts for spirotetramat for use in dietary/nonoccupational risk assessments and occupational risk assessment are listed below in Tables 3.3.12a and 3.3.12b, respectively.

Table 3.3.12a. Summary of Toxicological Doses and Endpoint s for Spirotetramat for Use in Dietary Human Health Risk Assessments.
Exposure Scenario Point of Departure Uncertainty/FQPA Safety Factors RfD, PAD, LOC for Risk Assessment Study and Relevant Toxicological Effects Acute Dietary (General Population, including Infants and Children) NOAEL = 100 mg/kg/day UF A = 10X UF H = 10X UF FQPA = 1X aRfD = aPAD = 1.0 mg/kg/day Acute neurotoxicity (rat; gavage) LOAEL = 200 mg/kg based on clinical signs (M&F) and decreased motor activity (M). Chronic Dietary (All populations) NOAEL = 5 mg/kg/day UF A = 10X UF H = 10X UF F Q PA = 1X cRfD = cPAD = 0.05 mg/kg/day 1 Chronic toxicity (dog; dietary) LOAEL = 20 mg/kg/day (M) based on thymus involution. Cancer (oral, dermal, inhalation) Classification: “Not Likely to be Carcinoge nic to Humans” based on lack of evidence of carcinogenicity in two oral ro dent carcinogenicity studies. Abbreviations: UF = uncertainty factor, UF A = extrapolation from animal to human (interspecies), UF H = potential variation in sensitivity among members of the human population (intraspecies), UF FQPA = FQPA Safety Factor, NOAEL = no-observe d adverse-effect level, LOAEL = lowestobserved adverse-effect level, RfD = reference dose (a = acute, c = chronic), PAD = population-adjusted dose, MOE = margin of e xposure, LOC = level of concern.

1 The cRfD has been harmonized across American (USEPA), Canadian (PMRA), and Austrian (AGES) regulatory agencies. However, it i s noted that USEPA considered a NOAEL=6 mg/kg/day in males and a NOAEL= 19 mg/kg/day in females to more accurately reflect the toxicolog ical data. The difference between 5 mg/kg/day (N OAEL in females for PMRA and AGES) and 6 mg/kg/day was considered negligible for ri sk
assessment.

Table 3.3.12b. Summary of Toxicological Doses and Endpoint s for Spirotetramat for Use in Occupational Human Health Risk Assessments. Exposure Scenario Point of Departure Uncertainty Factors Level of Concern for Risk Assessment Study and Toxicological Effects Dermal Short- andIntermediateTerm (1-30 days and 1-6 months) NOAEL = 10 mg/kg/day

Dermal absorption factor = 10% UF A = 10X UF H = 10X Occupational LOC for MOE <100 Prenatal developmental toxicity (rabbit) Maternal LOAEL = 40 mg/kg/day based on late abortion ( ≥ GD 22), clinical signs, impaired food and water consumption and body weight loss. Dermal Long-Term (>6 months) NOAEL = 5 mg/kg/day

Dermal absorption factor = 10% UF A = 10X UF H = 10X Occupational LOC for MOE <100 Chronic toxicity (dog; dietary) LOAEL = 20 mg/kg/day (M) based on thymus involution.

Inhalation Short- andIntermediateTerm (1-30 days and 1-6 NOAEL = 10 mg/kg/day

100% inhalation UF A = 10X UF H = 10X Occupational LOC for MOE <100 Prenatal developmental toxicity (rabbit) Maternal LOAEL = 40 mg/kg/day based on late abortion ( ≥ GD 22), clinical signs, impaired foodPage 22 of 65 Table 3.3.12b. Summary of Toxicological Doses and Endpoint s for Spirotetramat for Use in Occupational Human Health Risk Assessments. Exposure Scenario Point of Departure Uncertainty Factors Level of Concern for Risk Assessment Study and Toxicological Effects months) assumed and wa ter consumption and body weight loss. Inhalation Long-Term (>6 months) NOAEL = 5 mg/kg/day

100% inhalation assumed UF A = 10X UF H = 10X Occupational LOC for MOE <100 Chronic toxicity (dog; dietary) LOAEL = 20 mg/kg/day (M) based on thymus involution.

Cancer (oral, dermal, inhalation) Classification: Not likely to be carcinogenic to humans based on lack of evidence of carcinogenicity in two oral rodent carcinogenicity studies.

Abbreviations: UF = uncertainty factor, UF A = extrapolation from animal to human (interspecies), UF H = potential variation in sensitivity among members of the human population (intraspecies), UF FQPA = FQPA Safety Factor, NOAEL = no-observe d adverse-effect level, LOAEL = lowestobserved adverse-effect level, RfD = reference dose (a = acute, c = chronic), LOC = level of concern.

3.4 Endocrine Disruption

EPA is required under the FFDCA, as amended by FQPA, to develop a screening program to determine whether certain substances (including a ll pesticide active and ot her ingredients) “may have an effect in humans that is similar to an effect produced by a natu rally occurring estrogen, or other such endocrine effects as the Administrator may designate.” Following recommendations of its Endocrine Disruptor and Testing Advisory Committee (EDSTAC), EPA determined that there was a scientific basis fo r including, as part of the program, the androgen and thyroid hormone systems, in addition to th e estrogen hormone system. EPA also adopted EDSTAC’s recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an eff ect in humans, FFDCA authority to require the wildlife evaluations. As the sc ience develops and resources a llow, screening of additional hormone systems may be added to the Endoc rine Disruptor Screen ing Program (EDSP).

When additional appropriate scre ening and/or testing protocol s being considered under the Agency’s EDSP have been developed, spirotetra mat may be subjected to further screening and/or testing to better characterize effects related to endocrine disruption.

4.0 Public Health and Pesticide Epidemiology Data

Literature searches performed by the registra nt did not yield any epidemiology data for spirotetramat. Two cases of Type IV hypersen sitivity (facial) were reported and confirmed by patch testing in spirotetramat manu facturing plant personnel in 2004.

5.0 Dietary Exposure/Risk Characterization

The residue chemistry data submitted in support of the proposed uses were summarized in the HED memorandum by G. Kramer (DP# 339694). The drinking water assessment was provided by EFED in a memo dated 01/22/08 (J. Meléndez; DP# 345275). The acute and chronic dietary exposure assessments were completed in a HED memorandum by G. Kramer (DP# 339710).Page 23 of 65 5.1 Pesticide Metabolism and Environmental Degradation

5.1.1 Metabolism in Primary Crops

The submitted metabolism data for apple, lettuce, cotton and potato are adequate to elucidate the nature of the residue in plants. Major metabolic reaction involved the hydrolytic cleavage of the carbonate ester parent bo nd of the parent compound to form BYI 08330-enol. Further reduction of the double bond in the tetramic acid moiety of BYI 08330-enol occurred to form the BYI 08330-mono-hydroxy metabolite. Hydroxylation in th e tetramic acid moiety resulted in BYI 08330-ketohydroxy. Demethylation of the methoxy group of the cyclohexyl ring resulted via a proposed intermediate (BYI 08330-desmethyl-e nol) in BYI 08330-desmethyl-ketohydroxy (after the corresponding hydroxylation). Oxidati on of the methoxy group resulted in BYI 08330- ketohydroxy-formiate. Partly, metabolites bearing a hydroxy group we re conjugated with glucose.

5.1.2 Metabolism in Rotational Crops

It appears that two major metabo lic routes in rotational crops st art with the soil metabolites BYI 08330-ketohydroxy and BYI 08330-enol. The first metabolic route proceeds by demethylation of the cyclohexyl ring or hydroxylation of one methyl group of the xylol ring. Another metabolic route starts with the addition of wa ter to the tetramic aci d ring of BYI 08330-enol resulting in the formation of BYI 08330-di- hydroxy, followed by the demethylation of the metabolite. Additionally, hydroxylation of one methyl group of the xylol ring of BYI 08330- enol followed by demethylation of the cycl ohexyl ring results in BYI 08330-desmethyl-enolalcohol, which was detected in all matrices. Mo st of the metabolites were rapidly conjugated. Glucosides and/or glucosyl malonic acid conjugates were detected for BYI 08330-enol, BYI 08330-desmethyl-di-hydroxy, BYI 08330-desmet hyl-ketohydroxy and BYI 08330-ketohydroxyalcohol. The percentage of conjugates increased from the 30-day to the 260-day rotation.

5.1.3 Metabolism in Livestock

The submitted goat and poultry metabolism data are ad equate to satisfy data requirements. The biodegradation of spirotetramat in livestock ca n be characterized as cleavage of the carbonate ester group to the primary metabolite BYI 08330- enol followed by conjugation of the enol hydroxy group with glucuronic acid to BYI 08330-e nol-GA. Oxidation of the azaspirodecenyl moiety to BYI 08330-ketohydroxy and demet hylation of the methoxy group to BYI 08330- desmethyl-enol were minor metabolic reactions in ruminants as well as reduction of the azaspirodecenyl moiety to BYI 08330-monohydroxy.

5.1.4 Analytical Methodology

The petitioner has submitted several HPLC-MS/ MS residue analytical methods for the determination of residues of the parent and its metabolites in/on plant and livestock commodities. Analytical method 00857 was devel oped for the determination of residues of spirotetramat, the metabolites BYI 08330-enol, BYI 08330-ket ohydroxy, BYI 08330-mono-hydroxy and BYI 08330-enol-Glc in plant matrices by HPLC -MS/MS. The analytical method 00966 was developed for the determination of residues of spirotetramat and the metabolites BYI 08330-enol and BYI 08330-enol-GA in livestock matrices by HPLC-MS/MS. These methods were used asPage 24 of 65 the data-collection methods in the analysis of samples for residues of concern from the various studies associated with the curr ent petition. Each method has b een adequately validated by the petitioner as well as by inde pendent laboratories. Met hods 00857 and 00966 were also adequately radiovalidated using weathered samples obtained from metabolism studies.

HED has determined that Methods 00857 and 00966 are suitable enforcement methods for plant and livestock commodities, respectively, since the methods passed a successful PMV by Agency chemists at ACL/BEAD (E-mail, C. Stafford to D. Vogel; 2/19/08).

Spirotetramat and five metabolites BYI 08330-enol, BYI 08330-ketohydroxy, BYI 08330-monohydroxy, BYI 08330-enol-Glc, and BYI 08330-enol- GA were screened through multiresidue methods described in the U.S. Food and Drug Administration (FDA) Pesticide Analytical Manual, Vol. I (PAM I). The multiresidue methods (MRMs) are not suitable for the analysis of spirotetramat or its metabolites. The multiresid ue methods testing data will be forwarded to FDA for further evaluation and inclusi on of results in PAM Vol. I.

5.1.5 Environmental Degradation

The hydrolysis of spirotetramat is pH and temperat ure dependent. The rate of reaction increased with increasing pH. At 25°C, the experimental half-lives for the chemical were 32.5, 8.6 and 0.32 days at pHs of 4, 7 and 9, respectively. In addition, hydrolysis rates increased with increasing temperature. The ma jor hydrolysate is BYI 08330-enol, wh ich appeared to be stable to hydrolysis. Spirotetramat photolyzes with hydrolysis-corrected DT50’s of 3.0 and 0.22 days, in sterile buffer (pH 5) solution and natural water (pH 7.9), respectively. These half-lives correspond to 14.4 and 0.74 days, respectively, under environmental conditions (summer light in Phoenix, AZ). In sterilized natural water the major products observed were BYI 08330-enol (81.9% at 1 day), methoxycyclohexanone (17.5% at 8 days) and me thoxy-cyclohexylamino carboxylic acid (11.3 % at 10 days). In sterile buffer solution (p H 5), four major photoproducts (at up to 42.9%) are the resu lt of rearrangement of the parent. Definite conclusions on the rate of soil photodegradation could not be derived fr om the available study. However, useful information on the identity of the degradates in the study may be obtained from it. The following degradates were identified only in th e irradiated samples: methoxycyclohexanone and dimethyl-benzoic acid.

Spirotetramat degraded quickly, with DT50’s of <1 day in four aerobic soils. Furthermore, spirotetramat-enol also degraded relatively quick ly, with calculated DT50’s of <1 day, in four aerobic soils. DT50’s for BYI 08330-ketohydroxy (at a maximum of 24.0% of the applied, range of DT50’s 1.5-16.7 days) and spirotetrama t-amide (maximum 5.2% of the applied, range of DT50’s 0.03-5.4 days) were derived from the study conducted on BYI 08330-enol. Carbon dioxide formation was 9.7-19.4% by 50 days in the study conducted with spirotetramat and 10.9- 34.9 by 60 days in the study conducted with BYI 08330- enol. Volatiles were insignificant while non-extractable residues were important (bot h cases). In an outdoor metabolism study spirotetramat degraded with calculated DT50’s of 1.2 and 2.9 days. BYI 08330-enol was a maximum of 7.8%. The degradates spirotetrama t-glyoxylic amide and dimethyl-benzoic acid were observed besides the aerobic soil metabolite s observed in the laboratory. The latter two compounds were also observed in the marginal ly supplemental soil photodegradation studies.Page 25 of 65 In aquatic environment, under aerobic aquatic cond itions, spirotetramat degraded with calculated half-lives (DT50’s) of 0.7 and 0.9 days in the to tal system. Spirotetramat was initially mostly associated with the aqueous phase. The metabolite BYI 08330-enol reached a maximum at 14 days at 99.0%, and decreased to less than the limit of quantitation (<LOQ) to 21.0% at 120 days. The degradate BYI 08330-ketohydroxy was a maximu m of 50.8% at study termination. It appeared to be relatively stable in the aer obic aquatic system. Non-extractable residues increased throughout the study to a maximum of 33.9% at 120 days. Mineralization was a maximum of 13.5-24.0% at 120 days.

In the anaerobic soil metabolism study, the metabo lites observed were consistent with the ones for the aerobic soil metabolism studies for sp irotetramat and BYI 08330-enol. Under anaerobic soil conditions, spirotetramat di ssipated quickly with a calculated half-life of <<1 day. The major degradates were BYI 08330-enol, which increased throughout the study (maximum 54.6% at 180 days) and BYI 08330-ketohydroxy (maximum 19.3% at 1 day). Mineralization was very low. Non-extractable residues were a maximum of 17.5% at 0.6 days. In an anaerobic aquatic metabolism system, spirotetramat completely degraded to BYI 08330-enol, which was found to be stable thereafter. The half-life for (DT50) the transformation of spir otetramat was calculated to be 2.8 days in the total anaerobic system.

5.1.6 Comparative Metabolic Profile

Spirotetramat was completely metabolized by the rat; no parent compound was detected in the excreta. Identified metabolites accounted for 87-95% of the administered dose. Only very minor metabolites (<0.7% of the dose) were not identif ied. The main metabolic reaction was cleavage of the ester group which resulted in the form ation of the primary and most predominant metabolite BYI 08330-enol (53-87% of the administer ed dose). All other identified metabolites could be derived from the enol intermediate. The second prominent metabolic transformation was oxidative demethylation of the 8-met hoxy group to BYI 08330-desmethyl-enol (5-37% of the administered dose). Oxidation of the azaspiro moiety to BYI 08330-ketohydroxy and BYI 08330-desmethyl-ketohydroxy were detected as minor pathways. Other minor metabolic transformations were conjugation of the enol with glucuronic acid to BYI 08330-enol-GA and oxidation of the aromatic methyl group of the enol metabolit e to BYI 08330-enol-alcohol. A sex-related difference was observed in metabolism with male rats showin g much higher rates of demethylation to BYI 08330-desmethyl-e nol compared to female rats.

The metabolism of spirotetramat in plants and liv estock appears to be similar to its metabolism in rats. The primary metabolic pathway in animal s (rats, goats and hens) and plants involves the hydrolytic cleavage of the carbona te ester parent bond of the parent compound to form BYI 08330-enol. All other identified metabolites ar e derived from the enol intermediate. Hydroxylation in the tetramic acid moiety of BYI 08330-enol resulted in BYI 08330- ketohydroxy (animals and plants ) and oxidative demethylation of the 8-methoxy group to BYI 08330-desmethyl-enol (animals and plants). Furt her reduction of the double bond in the teramic acid moiety of BYI 08330-enol occurred to form the BYI 08330-mono-hydroxy metabolite (ruminants and plants). Conjugation of BYI 083 30-enol was also a significant pathway in both plants and animals. Minor pathways include hyd roxylation of one methyl group of the xylol ring of BYI 08330-enol followed by demethylation of the cyclohexyl ring resulting in BYI 08330- desmethyl-enol-alcohol (rotational crops), oxi dation of the methoxy group of BYI 08330- ketohydroxy resulted in BYI 08330- ketohydroxy-formiate (plants), co njugation with glucose ofPage 26 of 65 various metabolites beari ng a hydroxy group (plants).

5.1.7 Toxicity Profile of Major Metabolites and Degradates

Limited information is available on the toxicity of the major spirotetramat metabolites (BYI 08330-enol, BYI 08330-ketohydroxy, BYI08330-enol -Glc/GA, and BYI 08330-mono-hydroxy). However, based on the structural similarity of the parent and these metabolites, and in the absence of toxicological evidence to the contrary, they are assumed to be of comparable toxicity to the parent.

5.1.8 Pesticide Metabolites and Degradates of Concern

Table 5.1.8. Summary of Metabolites and Degradates to be included in Risk Assessment and Tolerance Expression.

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression
Plants Primary Crop Spirotetramat, BYI 08330-enol, BYI 08330- ketohydroxy, BYI08330-enol-Glc, and BYI 08330- mono-hydroxy Spirotetramat, BYI 08330-enol, BYI08330-ketohydroxy, BYI08330-enolGlc, and BYI 08330-mono-hydroxy

Rotational Crop Not Applicable 1 Not Applicable 1

Livestock (Ruminant and Poultry) Spirotetramat, BYI 08330-enol, and BYI 08330-enolGA 2 Spirotetramat and BYI 08330-enol 2

Drinking Water Spirotetramat, BYI 08330-enol, and BYI 08330- ketohydroxy Not Applicable

1 The following potential residues of co ncern were identified in the confined rotational crop study: Spirotetramat, BYI 08330- ketohydroxy and free and conjugated BYI 08330-desmethyl-ke tohydroxy, BYI 08330-desmethyl-di-hydroxy and BYI 08330- ketohydroxy-alcohol. None of these residues were found in the limited rotational crop field tria ls at a 30-day PBI. Provided a 30-day PBI is specified on the spirotetramat labels, residues in rotational crops are not currently of concern for the risk assessment or for tolerance setting.
2 If future proposed uses result in significant exposure of livestock to the plant metabolites BYI 08330-ketohydroxy, BYI08330- enol-Glc, and BYI 08330-mono-hydroxy, then these metabolites may need to be included as additional residues of concern for livestock commodities.

Plants (Primary Crops): The risk assessment team determin ed that the residues of concern for both tolerance and risk assessment purposes ar e spirotetramat and its metabolites BYI 08330- enol, BYI 08330-ketohydroxy, BYI08330-enol-G lc, and BYI 08330-mono-hydroxy. This decision was based on the following:

 BYI 08330-enol was a major metabolite in appl e leaves; lettuce; cotton gin trash & seed, and in rat tissues and excreta. Based on th e structural similarity to the parent, BYI 08330-enol is assumed to be of comp arable toxicity to the parent.

 BYI 08330-ketohydroxy was a major metabolite in cotton gin trash a nd lint; and potato tops. Also, in the cauliflower field tria ls, BYI 08330-ketohydroxy (0.32 ppm) accounted for >80% of the total spirotetramat residue in some samples. Based on the structural similarity to the parent, BY I 08330-ketohydroxy is assumed to be of comparable toxicity to the parent.

 BYI08330-enol-Glc was a major metabolite in lettuce. Also, in the hop field trials, BYI08330-enol-Glc (0.79 ppm) accounted for ~20% of the total spirotetramat residue in some samples. Based on the structural si milarity to the parent, BYI08330-enol-Glc is assumed to be of comparable toxicity to the parent.Page 27 of 65  BYI 08330-mono-hydroxy was a major metabolite in apple fruit. Also, in the plum field trials, BYI 08330-mono-hydroxy (0.18 ppm) accounted for >50% of the total spirotetramat residue in some samples. Base d on the structural similarity to the parent, BYI 08330-mono-hydroxy is assumed to be of comparable toxicity to the parent.

 The data collection method, Method 00857 is a HPLC-MS/MS method for residues of spirotetramat, BYI 08330-enol, BYI 08330- ketohydroxy, BYI08330-enol-Glc, and BYI 08330-mono-hydroxy in crop matrices. The anal ytes are all determined in a single chromatographic analysis. All samples in the cr op residue trials were analyzed with this method.

Plants (Rotational Crops): The risk assessment team determin ed that the residues of concern are spirotetramat and its metabolites BYI 08330-ketohydroxy and free and conjugated BYI 08330-desmethyl-ketohydroxy, BYI 08330-desmet hyl-di-hydroxy and BYI 08330-ketohydroxyalcohol. This decision was based on the following:

 BYI 08330-ketohydroxy was a major metabolite in wheat forage, chard, and turnip roots. Based on the structural similarity to the parent, BYI 08330-ketohydroxy is assumed to be of comparable toxicity to the parent.

 BYI 08330-desmethyl-ketohydroxy (conjugated) was a major metabolite in wheat forage, hay, and straw; and chard. Based on the stru ctural similarity to the parent, BYI 08330- desmethyl-ketohydroxy is assumed to be of comparable toxicity to the parent.

 BYI 08330-desmethyl-di-hydroxy (conjugated) was a major metabolite in wheat straw, forage, and hay. Based on the structural si milarity to the parent, BYI 08330-desmethyldi-hydroxy is assumed to be of comp arable toxicity to the parent.

 BYI 08330-ketohydroxy-alcohol (conjugated) was a major metabolite in wheat straw, hay, and grain; chard, and turnip leaves. Based on the structural similarity to the parent, BYI 08330-ketohydroxy-alcohol is a ssumed to be of comparable toxicity to the parent.

 The data collection method, Method 00929 is a HPLC-MS/MS method for residues of spirotetramat, BYI 08330-ketohydroxy and free and conjugated BYI 08330-desmethylketohydroxy, BYI 08330-desmethyl-di-hydroxy and BYI 08330-ketohydroxy-alcohol in crop matrices. The analytes are all determined in a single chromatogr aphic analysis. All samples in the limited field rotational crop resi due trials were analy zed with this method.

Livestock: The risk assessment team determined that, based on the currently proposed uses, the residues of concern for the tolerance expression for livestock commodities are spirotetramat and its metabolite BYI 08330-enol and th e residues of concern for the risk assessment for livestock commodities are spirotetramat and its meta bolites BYI 08330-enol and BYI 08330-enol-GA. This decision was based on the following:

 BYI 08330-enol was a major metabolite in all ruminant commodities and in rat tissues and excreta. Based on the structural simila rity to the parent, BYI 08330-enol is assumed to be of comparable toxicity to the parent.

 BYI 08330-enol-GA was a major metabolite in ruminant fat, liver, kidney, milk; and poultry liver. Based on the structural sim ilarity to the parent, BYI 08330-enol-GA is assumed to be of comparable toxicity to th e parent. However, as the low dietary burden associated with the currently proposed uses is expected to resu lt in non-quantifiable residues and BYI 08330-enol can serve as a marker for potential misuse, BYI 08330- enol-GA does not need to be incl uded in the tolerance expression.Page 28 of 65  If future proposed uses result in significant exposure of lives tock to the plant metabolites BYI 08330-ketohydroxy, BYI08330-enol-Glc, and BYI 08330-mono-hydroxy, then these metabolites may need to be included as additional residues of concern for livestock commodities.

Drinking Water: The risk assessment team determined that the residues of concern in drinking water for risk assessment purposes are spirotetramat, BYI 08330-enol, and BYI 08330- ketohydroxy. BYI 08330-enol and BYI 08330-ketohydr oxy were the major metabolites in the aerobic soil outdoor metabolism studies. BYI 08330-MA-amide was excluded as a residue of concern since it was never found at a level of >10% of the total residue.

5.1.9 Drinking Water Residue Profile

All the following appear to be important routes of degradation/transfor mation for spirotetramat: hydrolysis in basic media, photolysis in steril e natural water and biode gradation in aerobic and anaerobic environments (DT50s range <1-2.8 days). Hydrolysis in neutral and acidic environments and photolysis in sterile buffered solution (half-lives 8.6-32.5 days) appear to be routes of transformation of rela tively low importance for spirotetramat. Spirotetramat degrades to BYI 08330-enol (product of cleavage of the este r link), which also degrades relatively rapidly in aerobic environments and under photolytic conditions, and subsequently forms numerous degradates most of which have th e basic backbone struct ure of spirotetramat. It appears that the metabolites BYI 08330-enol and BYI 08330-ketohydroxy ar e of high concern in soils, sediments and water. The parent spirotetra mat appears to be labile in most environments (particularly in aerobic media). Total residues (spirotetr amat + BYI 08330-enol + BYI 08330-ketohydroxy) have a potential to contaminate surface waters fo r a period of weeks to months post-treatment, and a potential to move subsurface and contaminat e groundwater. There is also the chance that spirotetramat would be deposited off-target by spray drift (the chemical may be applied by ground and aerial methods or via airblast). In ad dition, given the relatively high solubility of BYI 08330-enol and BYI 08330-ketohydroxy and their relatively low level of binding, these particular transformation products could be released via plant wa sh-off to soils in large rain events, especially if they occur shortly after applicati on. It appears that th e residues could reach adjacent bodies of water in runoff events both via dissolution or bound to the soils (high levels of bound residue were observed in most laborato ry studies).

Since this is a new chemical, there are no mon itoring data available. The effects of water treatment on the pesticide and de gradates is uncertain. Spirot etramat and its metabolites, BYI 08330-enol, BYI 08330-ketohydroxy and BYI 08330- MA-amide, were highly mobile to moderately mobile, and low levels of binding ar e expected. It appear s that spirotetramat metabolites BYI 08330-ketohydroxy and BYI 08330-MA -amide are of higher concern because the parent degrades relatively fast in most environments.

EFED provided Tier 1 ground and surface wate r EDWCs for spirotetramat and its major transformation products spirotetramat-enol and spirotetramat-ketohydroxy. The ground and surface water EDWCs were generated using SC I-GROW and FIRST, respectively. The ground water EDWCs are based on the use of spirotetra mat on pome fruit (0.4 lb ai/A/year); and the surface water EDWCs are based on the use of spirotetramat on Christmas trees (0.32 lb ai/A/year). The total surface water EDWCs (s pirotetramat and transformation products of concern) are 0.212 ppb (acute) and 1.37x10 -3 ppb (chronic). The acute and chronic groundwaterPage 29 of 65 EDWC is 3.96x10 -4 ppb. Table 5.1.9 lists the summary of estimated ground and surface water EDWCs for spirotetramat.

Table 5.1.9. Summary of Surface Water and Groundwater EDWCs fo r Spirotetramat.
Drinking Water Source (Model) Type of Risk EDWC (ppb)
Spirotetramat Spirotetramatenol Spirotetramatketohydroxy Maximum Total Residues 3
Ground-water (SCI-GROW) 1 Acute and Chronic 2.25x10 -5 1.64x10 -5 3.57x10 -4 3.96x10 -4

Surface Water (FIRST) 2 Acute 0.208 8.0x10 -5 3.60x10 -3 0.212

Chronic 1.1x10 -3 1.7x10 -5 2.50x10 -4 1.37x10 -3

1 From the SCI-GROW model. Input parameters are based on application to pome fruit at a rate of 0.4 lb ai/A/year.
2 From the Tier 1 FIRST model. Input parameters are based on application to Christmas trees at a rate of 0.32 lb ai/A/year.
3 Total residues = spirotetramat + spirotetramat-enol + spirotetramat-ketohydroxy.

5.1.10 Food Residue Profile

The submitted magnitude of the residue data fo r the raw agricultural commodities (RACs) of citrus, cucurbit vegetables, fruiti ng vegetables, grapes, hops, leafy Brassica vegetables, leafy

non- Brassica vegetables, pome fruit, tuberous and corm vegetables, stone fruit, and tree nuts and the European residue for strawberries and onions data are adequate. There are adequate storage stability data to validate the st orage conditions and intervals of samples collected from the field trials.

Acceptable apple, orange, grape, plum, potato, and tomato processing studies are available. The processing studies show that fo llowing processing of RAC sample s bearing quantifiable residues, total residues of spirotetramat and its metabo lites concentrated in apple wet pomace (1.9X), citrus oil (13.5X), raisins (2.6X), prunes ( 2.2X), potato flakes (3.5X), potato chips (1.2X), tomato paste (7.4X) and tomato purée (3.5X).

An adequate dairy cow feeding study has been submitted; this study is acceptable for determining tolerance levels for livestock co mmodities. Based on the submitted data, HED has concluded that the tolerances, expressed as sp irotetramat and its metabolite BYI 08330-enol, are required for some livestock commodities. As none of the proposed target crops are considered as a commodity for poultry feed, data depicting residues in laying hens are not required.

The Agency’s Guidance for Setting Pesticide Tolerances Based on Field Trial Data was utilized for determining appropriate toleranc e levels listed in Appendix C.

5.1.11 International Residue Limits

There are no Codex, Canadian, or Mexican MRLs established for residues of spirotetramat and its metabolites in crop or livestock commodities. Harmonization is not an issue at this time.

5.2 Dietary Exposure and Risk

Spirotetramat acute and chronic dietary expos ure assessments were conducted using DEEMFCID  , Version 2.03), which incorporates consum ption data from USDA’s CSFII, 1994-1996 and 1998. The 1994-96, 98 data are based on the reported consumption of more than 20,000Page 30 of 65 individuals over two non- consecutive survey days. Foods “as consumed” ( e.g ., apple pie) are linked to EPA-defined food commodities ( e.g ., apples, peeled fruit - cooke d; fresh or N/S; baked; or wheat flour - cooked; fresh or N/S, baked) using publicly avai lable recipe translation files developed jointly by USDA/ARS and EPA. Consum ption data are averaged for the entire U.S. population and within population subgroups for chr onic exposure assessment, but are retained as individual consumption events for acute exposur e assessment. Based on analysis of the 1994-96, 98 CSFII consumption data, which took into acc ount dietary patterns and survey respondents, HED concluded that it is most appropriate to report risk fo r the following population subgroups: the general U.S. population, all infants (<1 year old), children 1-2, childr en 3-5, children 6-12, youth 13-19, adults 20-49, females 13-49, and adults 50+ years old.

For chronic exposure and risk assessment, an esti mate of the residue level in each food or foodform ( e.g ., orange or orange juice) on the food co mmodity residue list is multiplied by the average daily consumption estimate for that food/ food form. The resultin g residue consumption estimate for each food/food-form is summed with the residue consumption estimates for all other food/food-forms on the commodity resi due list to arrive at the tota l average estimated exposure. Exposure is expressed in mg/kg body weight/day and as a percent of the cPAD. This procedure is performed for each population subgroup.

For acute exposure assessments, individual one-d ay food consumption data are used on an individual-by-individual basis. The reported consumption amounts of each food item can be multiplied by a residue point estimate and summed to obtain a total daily pesticide exposure for a deterministic exposure assessment, or “matched” in multiple random pairings with residue values and then summed in a probabilistic assessment. The resulting distribution of exposures is expressed as a percentage of the aPAD on both a user ( i.e. , those who reported eating relevant commodities/food forms) and a per-capita ( i.e. , those who reported eating the relevant commodities as well as those who did not) basi s. In accordance with HED policy, per capita exposure and risk are reported for all tiers of an alysis. However, for Tiers 1 and 2, significant differences in user vs. per capita exposure a nd risk are identified and noted in the risk
assessment.

HED’s level of concern is when the exposure is greater than 100% of the PAD. That is, estimated exposures above this le vel are of concern, while estimate d exposures at or below this level are not of concern. The DEEM-FCIDTM analys is estimates the dietary exposure of the U.S. population and 26 population subgroups. The results reported in Table 5.2 are for the U.S. population, all infants (<1 year old), childre n 1-2, children 3-5, children 6-12, youth 13-19, females 13-49, males 20-49, and adults 50+ years.

5.2.1 Acute Dietary Exposure/Risk

The acute analysis assumed 100% CT and toleran ce-level residues for all foods. Empirical and DEEM TM (ver. 7.81) default processing factors were used for processed commodities. Drinking water was incorporated directly in the dietary assessment using the acute concentration for surface water generated by the FIRST model. The re sults of this assessment indicate that the acute dietary exposure estimates (95 th percentile) are not of co ncern to HED (<100% of the aPAD) for the general U.S. population (4.2% of the aPAD) and all othe r populations subgroups. The most highly exposed population subgroup is ch ildren 1-2 years old at 10% of the aPAD.Page 31 of 65 5.2.2 Chronic Dietary Exposure/Risk

A conservative chronic dietary assessment assumi ng average field-trial residues, empirical and DEEM TM (ver. 7.81) default processing factors, and 100% CT was also conducted. Drinking water was incorporated directly into the dietar y assessment using the chronic concentration for surface water generated by the FIRST model. The results of the assessmen t conclude that the chronic dietary exposure estimates are below HED’ s level of concern (<1 00% of the cPAD) for the general U.S. population (28% of the cPAD) and all population subgroups. The most highly exposed population subgroup is children 1-2 years old at 77% of the cPAD.

Table 5.2. Summary of Dietary (Food and Drinking Water) Exposure Risk for Spirotetramat.

Population Subgroup Acute Dietary (95 th Percentile) Chronic Dietary

Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/day) % cPAD

General U.S. Population 0.042364 4.2 0.013768 28

All Infants (<1 year old) 0.081433 8.1 0.019464 39

Children 1-2 years old 0.102892 10 0.038373 77

Children 3-5 years old 0.080506 8.1 0.029638 59

Children 6-12 years old 0.050723 5.1 0.018032 36

Youth 13-19 years old 0.035371 3.5 0.011795 24

Adults 20-49 years old 0.033504 3.4 0.011145 22

Adults 50+ years old 0.033253 3.3 0.011139 22

Females 13-49 years old 0.033564 3.4 0.011180 22 *The values for the highest exposed population fo r each type of risk assessment are bolded.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

As there are currently no register ed or proposed residential uses for spirotetremat, a residential exposure assessment was not conducted.

6.1 Spray Drift

Spray drift is always a potential source of expos ure to residents nearby to spraying operations. This is particularly the case with aerial appl ication, but, to a lesser ex tent, could also be a potential source of exposure from the ground ap plication method employed for spirotetramat. The Agency has been working with the Spray Dr ift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and ot her parties to develop the best spray drift management practices. On a chem ical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide regi strants, and is developing a policy on how to appropriately apply the data and the AgDRIFT ® computer model to its risk assessments forPage 32 of 65 pesticides applied by air, orch ard airblast and ground hydraulic me thods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drift with specific products with significant ri sks associated with drift.

7.0 Aggregate Risk Assessment s and Risk Characterization

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks from three major sources: food, drinking water, a nd residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard ( e.g ., a NOAEL or PAD), or the risks them selves can be aggregated. When aggregating exposures and risks from various sources, HED consider s both the route and duration of exposure.

For spirotetramat, aggregate exposure risk assessments were performed for the following scenarios: acute aggregate exposure (food and drinking water), and chro nic aggregate exposure (food and drinking water). Short- and intermediate-term assessments , which are used to evaluate aggregate dietary and residential exposures, were not performed because there are no registered or proposed residential non-food uses. Spirotetramat is classi fied as “Not Likely to be Carcinogenic to Humans;” therefore, cancer aggr egate risk assessments were not performed.

7.1 Acute Aggregate Risk

The acute aggregate risk assessment takes in to account exposure estimates from dietary consumption of spirotetremat (food and drinking water). The acute dietary exposure estimates are not of concern to HED (<100% aPAD) at the 95 th exposure percentile for the general U.S. population and all other population subgroups (see Table 5.2). The dietary exposure assessment was a screening-level assessment, utilizing tole rance-level residues and 100% CT information for all proposed agricultural uses and a Tier 1 acute surface water EDWCs generated by FIRST. Therefore, the acute aggregate risk associated wi th the proposed uses of spirotetramat is not of concern to HED for the general U.S. population or any population subgroups.

7.2 Chronic Aggregate Risk

The chronic aggregate risk assessment takes into account average exposure estimates from dietary consumption of spirotetramat (food and drinking water). The ch ronic dietary exposure estimates are not of concern to HED (<100% cPAD) for the general U.S. population and all population subgroups (see Table 5.2). The diet ary exposure assessment was a conservative assessment, utilizing average field-trial resi dues and 100% CT information for all proposed agricultural uses and a Tier 1 chronic surface wa ter EDWCs generated by FIRST. Therefore, the chronic aggregate risk associated with the proposed uses of spirotetramat is not of concern to HED for the general U.S. populat ion or any population subgroups.

8.0 Cumulative Risk Characterization/Assessment

Unlike other pesticides for which EPA has fo llowed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to spirotetramat and any other substances and sp irotetramat does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore,Page 33 of 65 EPA has not assumed that spirotetramat has a common mechanism of toxicity with other substances. For information regarding EPA’s ef forts to determine which chemicals have a common mechanism of toxicity and to evaluate th e cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and proc edures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pestic ides/cumulative/.

9.0 Occupational Exposure/Risk Pathway

An occupational exposure assessment was provi ded in a HED memorandum dated 3/13/08 (K. Lowe; DP# 338101). Based on the proposed use patterns, occupational handler and postapplication exposure to sp irotetramat is expected.

9.1 Short- and Intermediate-Term Handler Risk

The proposed use patterns indica te that the most highly-expose d occupational pe sticide handlers are likely to be mixer/loaders of liquids for aerial applications, applicators using airblast equipment, and mixers/loaders/applicators of liquid concentrates using a high-pressure handwand.

As no chemical-specific data were available with which to assess potential exposure of spirotetramat to pesticide handl ers, the estimates of exposure to pesticide handlers are based upon surrogate study data available in the PHED Surrogate Exposure Guide (August 1998). For pesticide handlers, it is HED st andard practice to present estimates of dermal exposure for “baseline;” that is, for workers wearing a singl e layer of work clothing consisting of a longsleeved shirt, long pants, shoes plus socks and no protective gloves, as well as for “baseline” and the use of protective gloves or other personal pr otective equipment (PPE) as might be necessary. The proposed product labels direct applicators and other handlers to wear a long-sleeved shirt, long pants, socks, shoes, chemical-re sistant gloves and protective eyewear.

HED believes most exposure durations will be shor t-term (1-30 days). However, HED’s Science Advisory Council for Exposure (Ex poSAC) maintains it is possible fo r commercial applicators to be exposed to intermediate-term exposure durations (1-6 months). In addition, the short- andintermediate-term toxicological endpoints are the same; therefore, the estimates of risk for shortterm duration exposures are prot ective of those for intermediate-term duration exposures. Longterm exposures are not expected; therefore, a long-term assessment was not conducted.

Table 9.1 presents the exposure/ risks for short and intermediate-term dermal and inhalation exposures at baseline and with gloves. A MO E of 100 is adequate to protect occupational pesticide handlers. HED has determined that risks are not of concern ( i.e. , MOEs >100), provided workers wear protective gl oves as recommended on the label

.Page 34 of 65 Table 9.1. Occupational Handler Dermal and Inhalation Exposures and Risks. Dermal and Inhalation Unit Exposures (mg/lb ai) Application rate (lb ai/A) a Area Treated Daily (A) b Short- and Intermediate-term Doses (mg/kg/day) c Short- and Intermediate-term MOEs d Combined Short- and Intermediate-term MOEs i

Mixer/Loader – Aerial Application
Dermal Baseline e : 2.9 (HC) h

Single layer w/gloves g : 0.023 (HC)

Inhalation Baseline f : 0.0012 (HC) 0.16 350 Dermal Baseline: 0.27

Single layer w/gloves: 0.0021 Dermal Baseline: 37

Single layer w/gloves: 4700 Baseline: 37

Single layer w/gloves: 3100 Inhalation Baseline: 0.0011 Inhalation Baseline: 8,900

Applicator –Airblast Application Dermal Baseline: 0.36 (HC)

Single layer w/gloves g : 0.24

Inhalation Baseline: 0.0045 (HC) 0.16 40 Dermal Baseline: 0.0038

Single layer w/gloves: 0.0026 Dermal Baseline: 2,600

Single layer w/gloves: 3900 Baseline: 2,300

Single layer w/gloves: 3,200 Inhalation Baseline: 0.00048 Inhalation Baseline: 21,000

Mixer/Loader – High Pressure Handwand

Dermal Baseline: No Data

Single layer w/gloves g : 2.5 (LC)

Inhalation Baseline: 0.12 (LC) 0.00125 lb ai/gallon 1000 gallons Dermal Single layer w/gloves: 0.0052 Dermal Single layer w/gloves: 1,900 Single layer w/gloves: 1300 Inhalation Baseline: 0.0025 Inhalation Baseline: 4,000

a Application rates are the maximum recommended rates provided on the spirotetramat product labels. b Area treated per day and amount handled va lues are HED estimates based on ExpoSAC Po licy #9 “Standard Values for Daily Acres Treated in Agriculture,” industr y sources, and HED estimates. c Dose (mg/kg/day) = Unit exposure(mg/lb ai) x App Rate (l b ai/acre or lb ai/gallon) x Area Treated/Amount Handled (acres/day or gallons/day) x %Absorption (10% dermal and 100% inhalation assumed) / Body weight (60 kg). d MOE = NOAEL/Dose; where the short- and intermedia te-term dermal and inhalation NOAEL = 10 mg/kg/day . e Baseline Dermal: Long-sleeve sh irt, long pants, and no gloves. f Baseline Inhalation: no respirator. g Single layer w/gloves: Single layer baseline attire plus chemical-resistant gloves. h Data Confidence for PHED unit exposures: LC = Low Conf idence, MC = Medium Confidence, HC = High Confidence. i. Combined MOE = NOAEL / (dermal + inhalation daily dose).

9.2 Short-Term Post-application Risk

HED expects that post-application exposure will o ccur since spirotetramat is applied as a foliar spray. Since no post-application data were subm itted in support of th is registration action, exposures during post-application activities we re estimated using dermal TCs from HED’s ExpoSAC Policy Number 3.1 “Agricultural Tr ansfer Coefficients” (August, 2000).

The activities with the highest ( i.e. , most conservative) TCs relate d to the proposed uses were tying (cane turning), turning (can e turning), and girdling grapes (with an applic ation rate of 0.125 lb ai/A and a high TC of 10,000 cm 2 /hr); and hand-harvesting, skating, topping andPage 35 of 65 training Christmas trees (with an application rate of 0.16 lb ai/A and a high TC of 8,000 cm 2 /hr). In addition, the following assumptions were used in the calculations:

Assumptions:

• Exposure Duration = 8 hours per day

• Body Weight = 60 kg

• Dermal Absorption = 10%

• Fraction of ai retained on foliage = assumed to be 20% on day zero (= % dislodgeable foliar residue, DFR, after initial treatment). This fractio n is assumed to further dissipate at the rate of 10% per day on following days. These are default values established by ExpoSAC.

Daily dermal exposures were calculated on each post-applic ation day after application using the following equation:

DE (t) (mg/day) = (TR (t) (μg/cm 2 ) x TC (cm 2 /hr) x Hr/Day)/1000 (μg/mg)

Where:

DE(t) = Daily exposure or amount deposited on the surface of the skin at time (t) attributable for activity in a previously treated area, also referred to as potential dose (mg ai/day); TR(t) = Transferable residues that can be dislodgeable foliar residue at time “t” (μg/cm 2 ); TC = Transfer Coefficient (cm 2 /hour); and Hr/day = Exposure duration meant to represent a typical workday (8 hours).

Note that the (TR (t) ) input may represent levels on the day of applica tion in the case of short-term risk calculations. Once daily exposures are calculated, the calculation of da ily absorbed dose and the resulting MOEs use the same algorithms that are described above for the handler exposu res. These calculations are completed for each day or appropriate block of ti me after application.

HED has determined that risks are not of concern ( i.e. , MOEs >100) on the day of treatment ( i.e.
, Day 0) for all post-application e xposure activities. Table 9.2 pres ents a summary of occupational short-and intermediate-term post-application ri sks associated with the proposed uses of spirotetramat.

Table 9.2. Summary of Occupational Post-application Risks for Spirotetramat.

Crop Grouping Application rate (lb ai/A) TC (μg/cm 2 ) Day after Treatment Short- and Intermediate-term MOE at Day 0 (Level of Concern = 100)

Vine / trellis 0.125 10,000 (Tying (Cane turning); Turning (Cane turning); Girdling) 0 (12 hours) 270

Tree, "fruit",

evergreen 0.16 8,000 (Hand-harvest; Staking; Topping; Training) 260

Spirotetramat is classified as Toxicity Categor y III for acute oral and acute dermal; Toxicity Category II for primary eye irritation; and as Toxicity Category IV for acute inhalation and primary dermal irritation. It is a positive dermal sensitizer. Therefore, while an assessment of systemic toxicity from post-application exposur e would indicate acceptable MOEs on the day of treatment, the acute toxicity ca tegories for this chemical requi re a 24-hour REI under the WPS. HED recommends that all spirotetramat labels have a 24-hour REI. The proposed end-use labels specify a 12-hour REI. The labels sh ould be revised to include a 24-hour REI.Page 36 of 65 10.0 Data Needs and Label Recommendations

10.1 Toxicology

 None.

10.2 Residue Chemistry

860.1200 Directions for Use

 The labels should be amended to specify a 30-day PBI for all non-labeled crops.

860.1650 Submittal of Analytical Reference Standards

 Analytical standards for the metabolites of sp irotetramat are currently not available in the National Pesticide Standards Repository [S ource: personal comm unication with D. Wright Jr. of ACL/BEAD, 11/2/2007]. Analy tical reference standa rds (both technicalgrade and isotopically labeled) of BYI 08330-enol, BYI 08330-ketohydroxy, BYI 08330- mono-hydroxy, and BYI 08330-enol-Glc should be supplied, and supplies replenished as requested by the Repository.

860.1550 Proposed Tolerances

 The petitioner is requested to submit a revi sed Section F specifying the following:

o The tolerance expression for plant comm odities should be revised to include the combined residues of spirotetramat and its metabolites BYI 08330-enol, BYI 08330-ketohydroxy, BYI08330-enol-Glc, and BYI 08330-mono-hydroxy, expressed as spirotetramat equivalents.

o Revised tolerance levels and commodity definitions presented in Appendix C.

10.3 Occupational Exposure

 Based on the acute toxicity ca tegories for this chemical, 24- hour REI is needed under the Worker Protection Standard. As the proposed end-use labels specify a 12-hour REI, the labels should be revised to include a 24-hour REI.Page 37 of 65 Appendix A. Toxicology Assessment

A.1. Toxicology Data Requirements

The requirements (40 CFR 158.340) for the use of spirotetramat on food at the time of data submission are listed in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Test Technical
Required Satisfied
870.1100 Acute Oral Toxicity ....................................................... 870.1200 Acute Dermal Toxicity .................................................. 870.1300 Acute In halation Toxicity .............................................. 870.2400 Primar y Eye Irr itation

.................................................... 870.2500 Primar y Dermal Irr itation

.............................................. 870.2600 Derm al Sensiti zation...................................................... yes yes yes yes yes yes yes yes yes yes yes yes

870.3100 Oral Su bchronic (rodent) ............................................... 870.3150 Oral Su bchronic (nonr odent) ......................................... 870.3200 21-Day Dermal .............................................................. 870.3250 90-Day Dermal .............................................................. 870.3465 90-D ay Inhala tion .......................................................... yes yes yes

no

no yes yes yes

-

- 870.3700a Developmental Toxicity (rodent) ................................... 870.3700b Developmental Toxicity (nonrodent)............................. 870.3800 Reproduc tion ................................................................. yes yes yes yes yes yes
870.4100a Chronic T oxicity (rodent) .............................................. 870.4100b Chronic Toxi city (nonrodent) ........................................ 870.4200a Oncoge nicity (ra t) .......................................................... 870.4200b Oncogenicity (mouse) .................................................... 870.4300 Chroni c/Oncogeni city .................................................... yes yes yes yes

no yes yes yes yes

- 870.5100 Mutagenicity—G ene Mutation - bacterial ..................... 870.5300 Mutagenicity—Gene Mutation - mammalian ................ 870.5xxx Mutagenicity—Struc tural Chromosomal Aberrations ... 870.5xxx Mutagenicity—O ther Genotoxic Effects ....................... yes yes yes yes yes yes yes
yes 870.6100a Acute Delaye d Neurotox. (hen) ..................................... 870.6100b 90-Day Neurotoxicity (hen) ........................................... 870.6200a Acute Neurotox. Screening Battery (rat) ....................... 870.6200b 90-Day Neuro. Screening Batte ry (rat) .......................... 870.6300 Develop. Neuro .............................................................. no

no

yes

no

no -

-

yes

-

- 870.7485 Gene ral Metabo lism ...................................................... 870.7600 Derm al Penetr ation ........................................................ yes yes yes yesPage 38 of 65 A.2. Toxicity Profiles

Table A.2.1 Acute Toxicity Prof ile – Spirotetramat Technical

Guideline No. Study Type MRID(s) Results Toxicity Category
870.1100 Acute oral (rat) 46904527 LD 50 >2000 mg/kg (F) III

870.1200 Acute dermal (rat) 46904529 LD 50 >2000 mg/kg (M&F) III

870.1300 Acute inhalation (rat) 46904530 LC 50 >4.183 mg/L (M&F) IV

870.2400 Primary eye irritation (rabbit) 46904531 Corneal opacity and iritis (grade 1); cleared by day 8 II

870.2500 Primary dermal irritation (rabbit) 46904532 Negative IV
870.2600 Dermal sensitization (mouse) 46904565 Positive (LLNA) N/APage 39 of 65 Table A.2.2 Subchronic and Chronic Toxicity and Genotoxicity Profile – Spirotetramat Technical

Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.3100 28-Day oral toxicity (mouse) 46904536 (2001) Acceptable/non-guideline
0, 500 or 5000 ppm (equivalent to 0, 136.5 or 1415 mg/kg bw/day [M]) NOAEL = 5000 ppm (1415 mg/kg/day [M]). LOAEL not observed.

870.3100 90-Day oral toxicity (mouse) 46904539 (2005) Acceptable/guideline
0, 70, 350, 1700, or 7000 ppm (equivalent to 0/0, 12.8/16, 59.6/72.4, 300/389 or 1305/1515 mg/kg bw/day [M/F]) NOAEL = 7000 ppm (1305/1515 mg/kg/day [M/F]). LOAEL not observed.

870.3100 28-Day oral toxicity (rat) 46904537 (1998) Acceptable/non-guideline
0, 500 or 5000 ppm (equivalent to 0, 47.3 or 501.8 mg/kg bw/day [F]) NOAEL = 5000 ppm (501.8 mg/kg/day [F]). LOAEL not observed.

870.3100 90-Day oral toxicity (rat) 46904538 (2005) Acceptable/guideline
0, 150, 600, 2500, or 10000 ppm (equivalent to 0/0, 9/11, 26/46, 148/188 or 616/752 mg/kg bw/day [M/F]) NOAEL = 2500 ppm (148/188 mg/kg/day [M/F]). LOAEL = 10000 ppm (616/752 mg/kg/day [M/F]), based on decreased body weight, abnormal spermatozoa and hypospermia in the epididymis, decreased testicular weight, and testicular degeneration and vacuolation in males; and alveolar macrophages in both sexes.

870.3150 28-Day oral toxicity (dog) 46904572 (2004)
Acceptable/non-guideline
0, 100, 400, 1600, or 6400 ppm (equivalent to 0/0, 3/3, 13/12, 42/70, or 104/127 mg/kg/day [M/F]) NOAEL = 1600 ppm (42/70 mg/kg/day [M/F]). LOAEL = 6400 ppm (104/127 mg/kg/day [M/F]) based on decreased thymus size and weight as well as decreased body weight and food consumption, which resulted in emaciation.

870.3150 90-Day oral toxicity (dog) 46904541 (2005) Acceptable/guideline
0, 150, 300, 1200, or 4000/2500 ppm (equivalent to 0/0, 5/6, 9/10, 33/32, or 81/72 mg/kg bw/day) NOAEL = 1200 (32 mg/kg/day)[F] & 2500 ppm (81 mg/kg/day)[M]. LOAEL = 2500 ppm (72 mg/kg/day)[F] based on decreased body-weight gain and food consumption, depressed RBC parameters (red blood cell count, hemoglobin level and hematocrit), and thymus atrophy.Page 40 of 65 870.3200 28-Day dermal toxicity (rat) 46904542 (2006)
Acceptable/guideline
0, 100, 300, or 1000 mg/kg bw/day (limit dose) NOAEL = 1000 mg/kg/day. LOAEL not established.

870.3700a Prenatal developmental (rat) 46904543 (2004)
Acceptable/guideline
0, 20, 140, or 1000 mg/kg bw/day Maternal NOAEL = 140 mg/kg/day. LOAEL = 1000 mg/kg/day based on impaired food consumption, transient body weight loss, impaired body-weight gain, and reduced final body weight. Developmental NOAEL = 140 mg/kg/day. LOAEL = 1000 mg/kg/day based on reduced fetal weight and increased incidences of malformations and skeletal variations.

870.3700b Prenatal developmental (rabbit) 46904544 (2004)
Acceptable/guideline
0, 10, 40 or 160 mg/kg bw/day Maternal NOAEL = 10 mg/kg/day. LOAEL = 40 mg/kg/day based on late abortion ( ≥ GD 22), clinical signs, impaired food and water consumption and body weight loss. Developmental NOAEL = 160 mg/kg/day. LOAEL not observed.

870.3800 1-gen. reproduction and fertility effects (rat) – range finding 46904571 (2006)
Acceptable/non-guideline
0, 200, 500, 6000 or 10000 ppm (equivalent to 0/0, 10.5/12.8, 27.8/31.4, 320.1/384.1, or 537.9/645.7 mg/kg bw/day [M/F]) Parental/Systemic NOAEL = 500 ppm (27.8 and 31.4 mg/kg bw/day [M/F]). LOAEL =6,000 ppm (320.1 and 384.1 mg/kg bw/day [M/F]) based on decreased body-weight gain (P females) and terminal body weight (F 1 males). Reproductive NOAEL = 500 ppm (27.8 mg/kg bw/day [M]) and 10,000 ppm (645.7 mg/kg/day) [F]. LOAEL = 6,000 ppm (320.1 mg/kg bw/day [M]) based on decreased sperm motility and progression and increased abnormal sperm cells in the F 1 males. Offspring NOAEL = 500 ppm (27.8 and 31.4 mg/kg bw/day [M/F]). LOAEL = 6,000 ppm (320.1 and 384.1 mg/kg bw/day [M/F]) based on decreased body weight and body-weight gain during lactation in F 1 pups.Page 41 of 65 870.3800 2-gen. reproduction and fertility effects (rat) 46904546 (2006)
Acceptable/guideline
0, 250, 1,000 or 6,000 ppm (equivalent to 0/0, 17.2/20, 70.7/82.5 or 419.3/484.7 mg/kg bw/day [M/F]) Parental/Systemic NOAEL = 1000 ppm (70.7/82.5 mg/kg/day [M/F]). LOAEL = 6000 ppm (419.3/484.7 mg/kg/day [M/F]) based on decreases in body weight (F 1 males and females), weight gain (P males, F 1 males and females), and food consumption during lactation (P- and F 1 -generation females); and kidney histopathology and decreased kidney weights (F 1 males and females). Reproductive NOAEL = 1000 ppm (70.7 mg/kg/day)[M] & 6000 ppm (484.7 mg/kg/day)[F]. LOAEL = 6000 ppm (419.3 mg/kg/day)[M] based on abnormal sperm cells and decreased reproductive performance in the F 1 males. Offspring NOAEL = 1000 ppm (70.7/82.5 mg/kg/day [M/F]). LOAEL = 6000 ppm (419.3/484.7 mg/kg/day [M/F]) based on decreased body weight and body-weight gain during lactation in both F 1 and F 2 generations.

870.4100 Chronic toxicity (1 year; dog) 46904548 (2006)
Acceptable/guideline
0, 200, 600 or 1800 ppm (equivalent to 0/0, 6/5, 20/19, or 55/48 mg/kg/day [M/F]) NOAEL = 200 ppm (6 mg/kg/day)[M] & 1800 ppm (48 mg/kg/day)[F]. LOAEL = 600 ppm (20 mg/kg/day)[M] based on thymus involution [M] and not observed [F]..

870.4100 Chronic toxicity (1 year; rat) 46904547 (2005)
Acceptable/guideline
0, 250, 3500, or 7500/12000 ppm (M/F) (equivalent to 0/0, 13.2/18, 189/255, or 414/890 mg/kg bw/day [M/F]) NOAEL = 250 ppm (13.2 mg/kg/day)[M] & 3500 ppm (255 mg/kg/day)[F]. LOAEL = 3500 ppm (189 mg/kg/day)[M] based on dose-dependent increase in alveolar macrophages; & 12000 ppm (890 mg/kg/day)[F] based on decreased body weight and body-weight gain, alveolar macrophages, discoloration of the lung, and yellow/brown staining of the perigenital area and tail.

870.4200 Carcinogenicity (rat) 46904549 (2006)
Acceptable/guideline
0, 250, 3500, or 7500/12000 ppm (M/F) (equivalent to 0/0, 12.5/16.8, 169/229, or 373/823 mg/kg bw/day [M/F]) NOAEL = 250 ppm (12.5/16.8 mg/kg/day [M/F]). LOAEL = 3500 ppm (169/229 mg/kg/day [M/F]) based on decreased kidney weight and renal tubular dilation.

No evidence of carcinogenicity.

870.4200 Carcinogenicity (mouse) 46904550 (2006)
Acceptable/guideline 0, 70, 1700 or 7000/6000 ppm (M/F) (equivalent to 0/0, 10.9/13.7, 263/331, or 1022/1319 mg/kg/day [M/F]) NOAEL = 7000/6000 ppm (1022/1319 mg/kg/day [M/F]). LOAEL not observed.

No evidence of carcinogenicity.Page 42 of 65 870.5100 Bacterial Gene Mutation 46904551 (2006)
Acceptable/guideline
0, 16, 50, 158, 500, 1581 or 5000 μg/plate +/- S9 activation Negative.

870.5100 Bacterial Gene Mutation 46904552 (2002)
Acceptable/guideline
0, 16, 50, 158, 500, 1581 or 5000 μg/plate +/- S9 activation Negative.

870.5300 Mammalian Gene Mutation 46904553 (2002)
Acceptable/guideline
0, 2.5, 5, 10, 20, 30, 40, 50, 60, 70, or 80  g/mL (- S9)
0, 20, 40, 60, 80, 92, 100, 108, 116, 120, 124, 132, or 140  g/mL (+S9) Negative.

870.5375 In vitro mammalian chromosome aberration 46904554 (2002)
Acceptable/guideline
0, 10, 12, 24, 30, 48, or 50 μg/mL (-S9)
0, 20, 40 or 80 μg/mL (+S9) Weakly clastogenic at cy totoxic concentrations only.

870.5375 In vitro mammalian chromosome aberration 46904555 (2003)
Unacceptable/guideline
0, 30, 50, 70, 90 or 110 μg/mL (-S9)
0, 40, 60, 80, 100 or 120 μg/mL (+S9) N/A

870.5395 In vivo erythrocyte micronucleus assay (mouse) 46904556 (2002)
Acceptable/guideline
0, 125, 250, or 500 mg/kg bw Negative.

870.5385 In vivo bone

marrow chromosomal aberration assay (mouse) 46904558 (2003)
Acceptable/guideline
0, 125, 250 or 500 mg/kg bw Negative.

870.5550 In vivo / in vitro UDS assay (rat hepatocytes) 46904557 (2003)
Acceptable/guideline
0, 1000, or 2000 mg/kg bw Negative.Page 43 of 65 870.6200a Acute neurotoxicity screening battery 46904560 (2005)
Acceptable/guideline
0, 50, 100, 200, 500 or 2000 mg/kg bw NOAEL = 100 mg/kg/day. LOAEL = 200 mg/kg/day based on clinical signs (males and females) and decreased motor activity (males).

870.7485 Metabolism and pharmacokinetics (rat) 46904504 (2006)
Acceptable/guideline
2 or 100 mg/kg bw (single)
2 mg/kg bw (repeat) Absorption: 89-98% after 48 hrs (no significant differences among low dose, high dose, and repeated dose tests).

Distribution: AUC 0- ∞ (measure of systemic exposure) slightly higher for males than females; <0.2% of administered dose detected in body 48 hrs after sacrifice; highest equivalent concentrations detected in liver and kidney.
Metabolism: parent compound undetected in urine and feces of all tests; main metabolic reaction was cleavage of the ester group which resulted in formation of the primary metabolite BYI 08330-enol (53-87% of administered dose); all other identified metabolites could be derived from enol; male rats exhibited much higher rates of demethylation of BYI 08330- enol to BYI 08330-desmethyl-enol (25-37%) vs. females rats (5-10 %).

Excretion: 88-95% of administered dose eliminated via urine and 2-11% via feces within 48 hrs.

870.7485 Metabolism and pharmacokinetics (rat) 46904561 (2006)
Acceptable/guideline
2 or 1000 mg/kg bw (single) At 1000 mg/kg bw: Absorption and excretion less than low dose, with 27% of dose excreted in urine after 24 hours (18% in feces); plasma radioactivity slightly higher than in liver and kidney; these results are consistent with saturation of cellular transport mechanisms. Tissue radioactivity decreased from 1 h to 24 h post dose. Metabolism profile qualitatively similar to that of the low dose; BYI 08330-enol was most prominent metabolite; similar to low dose group, BYI 08330-desmethyl-enol levels greater in urine than in plasma and organs.

870.7600 In vivo dermal penetration (rat) 46904563 (2006)
Acceptable/guideline
100, 15, or 5 μg ai/cm 2 (OD150 formulation) Dermal absorption = 10%.

Special study Male reproductive toxicity 46904569 (2005)
Acceptable/non-guideline
1000 mg/kg bw/day (3, 10, 21 or 41 days) Primary testicular effect s on or after day 10 were degeneration of round and elongating spermatids (stage 7-8 and 9-14, respectively), decreased sperm count, and increased numbers of aberrant/abnormal spermatozoa in the epididymis.Page 44 of 65 Table A.2.3 USEPA Toxicity Profile – Metabolites

Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

Exploratory study 10-day gavage (enol metabolite) 46904601 (2006)
Acceptable/non-guideline
800 mg/kg bw/day Decreased BWG; histopathology not evaluated.

Special study 21-day gavage (enol metabolite) 47070901 (2006)
Acceptable/non-guideline
800 mg/kg bw/day Clinical signs of toxicity, decreased BWG, Testicular/spermatotoxicity.

870.5100 Bacterial Gene Mutation
(ketohydroxy metabolite) 46904594 (2005)
Acceptable/guideline
0, 16, 50, 158, 500, 1581 or 5000 μg/plate +/- S9 activation Negative.

870.7485 Metabolism and Pharmacokinetics (rat)
(ketohydroxy metabolite) 46904595 (2006)
Acceptable/guideline
2 mg/kg bw (single) Absorption: ≥ 55% after 48 hrs.
Distribution: highest concentrations detected in GI, liver, and kidney; <0.2% of administered dose detected in body 48 hrs post dose.
Metabolism: parent compound undetected in urine and trace amounts in feces; main metabolic reaction was oxidative demethylation of cyclohexyl-O-methyl group to form desmethyl-ketohydroxy metabolite (15% of administered dose); all other identifiedmetabolites could be derived from desmethylketohydroxy metabolite.

Excretion: 54% of administered dose eliminated via urine an d 44% via feces within 48 hrs.
870.5100 Bacterial Gene Mutation
(desmethylketohydroxy metabolite) 46904597 (2006)
Acceptable/guideline
0, 16, 50, 158, 500, 1581 or 5000 μg/plate +/- S9 activation Negative.

870.5100 Bacterial Gene Mutation
(dihydroxy metabolite) 46904599 (2005)
Acceptable/guideline
0, 16, 50, 158, 500, 1581 or 5000 μg/plate +/- S9 activation Negative.Page 45 of 65 Table A.2.3 USEPA Toxicity Profile – Metabolites

Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.7485 Metabolism and Pharmacokinetics (rat)
(enol glucoside metabolite) 46904602 (2006)
Acceptable/non-guideline
0.1 mg/kg bw (single; 1 rat) Absorption: 54% after 48 hrs.
Distribution: plasma concentrations peaked 4 hrs post dose; 1% of administered dose detected in body 48 hrs post dose.
Metabolism: parent compound detected in feces (21%); main metabolite was enol (64% of administered dose).

Excretion: 53% of administered dose eliminated via urine an d 44% via feces within 48 hrs.
870.5100 Bacterial Gene Mutation
(monohydroxy metabolite) 46904604 (2005)
Acceptable/guideline
0, 16, 50, 158, 500, 1581 or 5000 μg/plate +/- S9 activation Negative.

A.3. Executive Summaries

A.3.1 Subchronic Toxicity

870.3100 90-Day Oral Toxicity – Rat

In a 14-week oral toxicity study (MRID 46904538) spirotetramat (batch NLL 6425-9, 93.1 to 96.5%) was administered to 10 Wistar Hanover strain rats/sex/dose in the diet at dose levels of 0, 150, 600, 2500 or 10000 ppm (equivalent to 0, 9, 26, 148 and 616 mg/kg bw/day in males and 0, 11, 46, 188 and 752 mg/kg/day in females, respectively) . A satellite group of 10 rats/sex for the control and high dose groups was also included for a four-week recovery period. Special assessments of hepatic enzymes (N-demethylas e, O-demethylase, UDP glucuronyltransferase and hepatic cytochrome P450) were included.

All animals survived the dosing and recovery periods, and there were no clinical signs or changes in hematology, clinical chemistry or urinal ysis parameters attribut ed to treatment. The hepatic enzyme profile was unc hanged. Week 14 body weights in males were 3%, 5%, 2% and 8.4% lower than controls and net body-weight ga in for the dosing period was decreased by 4.4%, 12%, 1% and 17.6% (p < 0.05) for the 150, 600, 2500 and 10000 ppm dose groups, respectively. Only the high dose group was considered aff ected. Female high dose body weight was only 3.5% (not statistically significant) less than the control, while net body-weight gain was 13% less than the control indicating a po ssible effect. Other treatment-re lated effects in the high dose were decreased kidney (11%) and testicular (6.5 %) weights in males. Kidney weight for high dose males was similar to controls after recove ry. Kidney weight in females was decreased by 6% (NSS) at termination and equivalent to th e control group after recovery. No treatmentrelated histopathological changes in the kidney we re reported. Histopathological findings in the epididymis (abnormal spermatozoa: 9 animals; hypospermia: 5 animals) and testis (tubularPage 46 of 65 degeneration and vacuolization: 5 animals each) were observed in high dose males. Following recovery, the control and high dos e group testis weights were esse ntially equal. The lungs of both sexes had increased inciden ces of alveolar macrophages. Partial recovery of body weight, epididymal and testicular weights, and lungs conditions was evident after four weeks.

The LOAEL is 10000 ppm (616/752 mg/kg/day [M /F]), based on decreased body weight, abnormal spermatozoa and hypospermia in th e epididymis, decreased testicular weight, and testicular degeneration and vacuolation in males; and alveolar macrophages in both sexes. The NOAEL is 2500 ppm (148/188 mg/kg/day [M/F]).

This 90-day oral toxic ity study in the rat is Acceptable/Guideline and satisfies the guideline requirement for a 90-day oral toxicity study (OPPTS 870.3100; OE CD 408) in the rat.

870.3100 90-Day Oral Toxicity - Mouse

In a 90-day feeding study (MRID 46904539), groups of 15 CD-1 mice/sex were dosed with 0, 70, 350, 1700 or 7000 ppm of spirotetramat (B YI08330, purity 96.5 to 93.1%, batch no.: NLL 6425-9) for approximately 14 weeks. Th ese doses correspond to 12.8, 59.6, 300 and 1305 mg/kg/day in males and 0, 16, 72.4, 389 and 1515 mg/kg/day in females, respectively. Assessments for clinical signs, mortality, body weight and food consumption, hematology, limited clinical chemistry, urinalysis, organ weig ht and gross and histopathology (on the control and high dose) were made.

There were no adverse reactions to treatment of any kind noted. The LOAEL was not established. The NOAEL was 700 0 ppm (1305/1515 mg/kg/day [M/F]).

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a 90-day feeding study in mi ce [OPPTS 870.3100; OECD 408].

870.3150 90-Day Oral Toxicity - Dog

In a subchronic oral toxicity study (M RID 46904541), BYI 08330 (97.6-97.8%, Batch No. 08045/0014) was initially administered to 4 beagle dogs/s ex/group at dietary levels of 0, 150, 300, 1200 and 4000 ppm. During the first two weeks of the study, males and females in the 4000 ppm dietary groups lost body weight; therefore, the dietary level of test material was reduced fr om 4000 to 2500 ppm beginning on test day 15 and was maintain ed at that level for the rema ining duration of the 90-day study. Consequently, the equivalent dosages (excluding 4000 ppm during the first 2 weeks) were 0, 5, 9, 33 and 81 mg/kg/day, respectively, in males and 0, 6, 10, 32 and 72 mg/kg/day, respectively, in females.

There were no significant com pound-related effects based on the assessment of mortality, clinical chemistry, urine, eyes and organ weights.

Compound-related decreases in th e circulating levels of T 4 at 1200 and 2500 ppm and T 3 at 2500 ppm were observed in both sexes. These change s were not considered to xicologically significant since there were no related cha nges in thyroid weight or hi stopathology, and no compensatory increases in TSH were seen.

Compound-related inhibition of body-weight ga in and food consumption, depressed RBCPage 47 of 65 parameters (red blood cell count, hemoglobin le vel and hematocrit) and reduced thymus size were observed at 2500 ppm in females; th ese were considered adverse effects.

The LOAEL for BYI 08330 in this study for fema le dogs is 2500 ppm (72 mg/kg/day) based on decreased body-weight gain and food consumption, depressed RBC parameters (red blood cell count, hemoglobin level and hemato crit) and thymus atrophy; a LOAEL was not established for males. The NOAELs for ma les and females are 2500 ppm (81 mg/kg/day) and 1200 ppm (32 mg/kg/day), respectively.

This 90-day oral toxi city study in dogs is Acceptable/Guideline and satisfies the guideline requirement [OPPTS 870.3150, OECD 409] for a 90- day oral toxicity st udy in a non-rodent species.

870.3200 21/28-Day Dermal Toxicity – Rat

In a 28-day dermal toxicity study, BYI 08330 (MRID 46904542), batch no. 08045/0014, purity: 97.6 % to 98.5%, was administered to groups of 10 male and 10 female Wistar Hanover rats of the strain Crl:WI[G1x/BRL/Han]IGS BR at dos e levels of 0, 100, 300, and 1,000 mg/kg (limit dose) by dermal application. The doses were ad ministered for a minimum of six hours/day for five consecutive days/week for four weeks. An alytical determinations of stability and homogeneity were not performed because the test substance was applied undiluted and only moistened with water immediately before applic ation. One mortality of a female at 100 mg/kg occurred on Day 22 during blood collection due to isoflurane anesthesia and was not treatmentrelated. There were no treatment-related e ffects on body weight, organ weight, or body weight:organ weight ratios. Stat istically significant differences (p ≤ 0.05) observed in treated groups in hematology (increased white blood cel l count, activated partial prothromboblastin time, prothrombin time, differential cell counts) and clinical chemis try (decreased creatine kinase, lactate dehydrogenase, aspartate aminotra nsferase) measurements were not considered toxicologically or biologically significant since they did not ha ve a clear dose-response pattern, were within historical contro l ranges, and/or no histological correlations were found. Only tissues from the control and high dose groups we re examined microscopically, and no treatmentrelated findings were reported.

A systemic LOAEL for male and female rats was not established. The NOAEL for male and female rats is 1000 mg/kg/day.

A dermal LOAEL for male and female rats was not established. The NOAEL for male and female rats is 1000 mg/kg/day.

This 28-day dermal toxicity study in the rat is Acceptable/Guideline and satisfies the guideline requirement for a 28-day dermal toxicity study (OPPTS 870.3200).

A.3.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study – Rat

In a developmental toxicity study (MRI D 46904543), BYI 08330 (99.0% ai, batch # NLL 6425- 14-a), suspended in 0.5% aqueous carboxymethylcellu lose, was administered to 25 mated femalePage 48 of 65 Wistar (Hsd Cpb:WU) rats/dose by oral gava ge at dose levels of 0, 20, 140, or 1000 mg/kg bw/day from days 6 through 19 of gestation (G D 6-19). The fetuses were delivered by cesarean section on day 20 of gestation. The total numbers of fetuses examined (number of litters) was 247 (20), 301 (24), 253 (23), and 270 (22) for the 0, 20, 140, and 1000 mg/kg bw/day groups, respectively. All live fe tuses were weighed, sexed, and exam ined for external abnormalities. Every other fetus within a litter wa s prepared for either skeletal or visceral evaluation. The doses were selected based on the results of a pilot deve lopmental toxicity study in rats in which doses of 0, 50, 200, 800 and 1000 mg/kg bw/day were tested.

Maternal mortality, appearance and behavior were not aff ected by treatment with BYI 08330. Treatment-related effects at 1000 mg/kg bw/day included impaired food consumption, transient marginal body weight loss, impaired body-weight gain, reduced final body weight and reduced carcass weight. Light colored feces were obs erved in the 1000 mg/kg bw/day dose group, although this finding may be related to the high amount of white test substance given. Body weight gain during treatment a nd final body weight were slightly impaired at the 140 mg/kg bw/day dose level; however, corrected body-weight gain remained unaffected. Because of this and since the finding was not rep licated in a supplementary study, a treatment related effect on body weight was not concluded. Necropsy revealed no treatment-related findings at a dose level up to and including 1000 mg/kg bw/day.

The oral maternal toxicity LOAEL for BY I 08330 in rats is 1000 mg/kg bw/day, based on impaired food consumption, transient body weight loss, impaired body-weight gain, and reduced final body weight. The maternal NOAEL is 140 mg/kg bw/day.

A marginal reduction of placental weight together w ith a more distinct reduction of fetal weight (86% of control) was observed in the 1000 mg/ kg bw/day dose group. Treatment related effects were not evident for mean post-implantation loss, litter size, fetal sex di stribution and placental appearance at a dose level up to a nd including 1000 mg/kg bw/day.

External, visceral and skeletal evaluation of fetuses revealed a slightly increased number of fetuses and litters with genera lly common unspecific malformations at the maternally toxic 1000 mg/kg bw/day dose level, including single cases of cleft palate, co-a rctation of aortic arch, atrial septal defect of the heart, microphthalmia, supernumerary lumb ar vertebra and 4 cases of dysplastic forelimb bones and 3 cases of malformed sacral vertebral arches with pelvic shift. A potential of BYI 08330 to induce a specific type of malformation was not deduced from these findings. Overall incidence and type of malf ormations at the 20 and 140 mg/kg bw/day dose level did not indicate a treatment related effect. Fetal external deviations were not observed in this study and incidence and type of visceral deviations of fetu ses revealed no treatment-related effects at a dose level up to and including 1000 mg/kg bw/day. Skeletal evaluation of fetuses revealed retarded ossification of skull bones, fo re- and hindlimbs, sternum and vertebral column at the 1000 mg/kg bw/day dose leve l in the osseous and cartilaginous parts. Increased incidence of skeletal variations (wavy ribs, 14 th ribs, and combined osseous a nd cartilaginous findings) also was observed. Furthermore, retard ed ossification of single localis ations and increased incidence of wavy ribs were noted in the 140 mg/kg bw/d ay dose group and at the 20 mg/kg bw/day dose level without clear dose relation.

Based on the results of a supplementary study with BYI 08330 (MRID 46904545) which revealed no evidence for a treatment-related incr ease of wavy ribs at a dose level up to andPage 49 of 65 including 140 mg/kg bw/day and no evidence for e ffects on degree of ossifi cation at a dose level up to and including 140 mg/kg bw/day, treatment re lationship was excluded in the present study for retarded ossification and for incidence of wa vy ribs at a dose level up to and including 140 mg/kg bw/day.

The oral developmental toxicity LOAEL for BYI 08330 in rats is 1000 mg/kg bw/day (limit dose), based on reduced fetal weight, increase d incidence of malformations, and increased incidence of skeletal deviations (incomplete ossification of sk ull bones, fore- and hindlimbs, sternum and vertebral column; wavy ribs, 14 th ribs, and combined osseous and cartilaginous findings). The developmen tal toxicity NOAEL is 140 mg/kg bw/day.

The developmental toxicity st udy in the rat is classified Acceptable/Guideline and does satisfy the guideline requirement for a developmenta l toxicity study (OPPTS 870.3700; OECD 414) in the rat.

870.3700b Prenatal Developmenta l Toxicity Study - Rabbit

In a developmental toxicity study (MRID 46904544), BYI 08330 (98.9% ai, batch # 08045/0004), suspended in 0.5% aqueous carboxymet hylcellulose, was admi nistered to groups of 22, 22, 24 or 30 mated female Himalayan rabbits (CHBB.HM) by oral gavage at dose levels of 0, 10, 40 or 160 mg/kg bw/day, respectively, fr om days 6 through 28 of gestation (GD6-28). The fetuses were delivered by cesar ean section on day 29 of gestati on; the dams were killed and subjected to necropsy. The total numbers of fetu ses (litters) examined was 170 (22), 152 (22), 172 (21) and 132 (19) for the 0, 10, 40 and 160 mg/kg bw/day groups, respectively. All live fetuses were weighted, sexed, and examined for ex ternal, visceral and skel etal abnormalities. The doses were selected based on the results of a pi lot developmental toxicity study in rabbits in which doses of 0, 5, 25, 100, 160, 250 or 500 mg/ kg bw/day were tested (MRID 46904570).

One female of the 160 mg/kg bw/day group was f ound dead and 5 females were sacrificed in moribund condition with severely reduced food cons umption, severe body weight loss, cold ears, alopecia, reduced amount of feces, diarrhea or soft and light colored feces, reddish excretion, decreased water intake and decr eased/discolored urination. Fema les at necropsy revealed fluid and/or gaseous contents in caecum, discolored liver and mottled gall bladder. Late abortion ( ≥ GD 22) was observed, most likely as a consequen ce of maternal toxicity, in two other females of the 160 mg/kg bw/day group and in one fe male of the 40 mg/kg bw/day group showing clinical signs, impaired food consumption and body weight loss before abortion. The remaining females of the 160 mg/kg bw/day dose group exhibi ted cold ears, alopecia and soft, mucoid and light colored feces.

The gestation rate was decrease d by one abortion in the 40 mg/ kg bw/day dose group for which a treatment related effect cannot be excluded and two abortions in the 160 mg/kg group most likely as a consequence of severe maternal toxi city. There were no treatment-related effects in the remaining females on postimplantation loss, nu mber of fetuses, or placental weight and appearance; fetal weight and feta l sex distribution were unaffected by treatment at dose levels up to and including 160 mg/kg bw/day. Teratogeni c effects of BYI 08330 were excluded at a dose level up to and including 160 mg/kg bw/day. Malf ormations were different in type, scattered within the different dose groups and reveal ed no dose dependency. Malformations of cartilaginous parts of ribs, cardi ac ventricular septal defects a nd malpositioned forelimbs werePage 50 of 65 not dose related and single malformations which appeared only once in the 160 mg/kg bw/day dose group (domed head together with encepha lomeningocele, cleft pa late, microphthalmia) were different in type and comparable with hi storical control data. There was an increased incidence of fetuses with distin ct liver lobulation in the 160 mg/ kg bw/day group (8 fetuses in 2 litters). No other treatment related effects on feta l external and visceral deviations were observed at dose levels up to and including 160 mg/kg bw/d ay. Fetal skeletal eval uation did not reveal treatment related effects at a dose level up to and including 160 mg/kg bw/day. Findings on the progeny (abortions at the 40 mg /kg bw/day and 160 mg/kg bw/day dose level; possibly distinct fetal liver lobulation at the 160 mg /kg bw/day dose level) occurred only at dose levels with signs of distinct to severe maternal toxicity.

The oral maternal toxicity LOAEL for BYI 08330 in rabbits is 40 mg/kg bw/day, based on late abortion, clinical signs, impaired food and water consumption and body weight loss in one animal. The maternal NOAEL is 10 mg/kg bw/day.

The oral developmental toxicity LOAEL for BY I 08330 in rabbits was not established. The developmental NOAEL is 160 mg/kg bw/day.

The developmental toxicity st udy in the rabbit is classified Acceptable/Guideline and does satisfy the guideline requirement for a deve lopmental toxicity st udy (OPPTS 870.3700b; OECD 414) in the rabbit.

A.3.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects – Rat

In the present two-generation study (MRID 46904546), groups of 30 male and 30 female Wistar Hanover rats (strain: Crl:WI(Glx/BRL/Han)IG S BR) were exposed to BYI 08330 (batch no. 08045/0014, purity: 97.4 – 98.5%) at dietary concen trations of 0, 250, 1,000 or 6,000 ppm. The dietary concentrations were equal to prema ting doses of 0, 17.2, 70.7 and 419.3 mg/kg bw/day in P-generation males; 0, 20.0, 82.5 and 484.7 mg/kg bw/day in P-generation females; 0, 19.3, 79.5 and 486.7 mg/kg bw/day in F 1 -generation males; and 0, 21.7, 90.3 and 539.5 mg/kg bw/day in F 1 -generation females, respectively. P-generation rats were approxi mately 8-9 weeks of age at the time of study initiation, corresponding to body weights of 240.9 - 307.7 g. They were pretreated for ten weeks, duri ng the subsequent mating period a nd until the last litters were produced (males) or until lactation day 21 (females). F 1 offspring were nursed up to an age of three weeks. Some of them were selected for further treatment and for breeding an F 2 generation at 5-9 weeks of age.

No treatment-related mortalities or clinical signs of toxicity were observed in parental animals of either generation. A decline in body-weight ga in (Wk 1-10) was noted in P-generation males (13.2%) of the 6,000 ppm group. In the F 1 -generation, the males of the 6,000 ppm group exhibited statistically significan t declines in body weight (mean of 6.4%) from premating days 14-70 and declines in overall body-weight gain (8%). In F 1 -generation females of the 6,000 ppm group, statistically significant decl ines in body weight (6%, week 10 of premating) and declines in overall body-weight gain (11%) were observe d at the end of the premating phase. The premating effects on F 1 females in the 6,000 ppm group continue d into gestation and lactation as a decline in body-weight gain (8%) accompanied by statistically significan tly lower body weightPage 51 of 65 means (7%) from day 0-20 of gestation and sta tistically significant body weight declines (6-8%) throughout lactation. Food consum ption during premating was not affected by treatment in either sex of either generation. P-generation fe males of the 6,000 ppm group showed statistically significant declines in food c onsumption throughout lactation on both a g/kg/day (11.5 %) and g/animal/day (13.4 %) basis. In the F 1 -generation, females of the 6,000 ppm group exhibited significantly declined food cons umption (lactation days 7-21) on both a g/kg/day (8.6 %) and g/animal/day (13.9 %) basis. This effect could not be attributed to less food consumed by the pups since it occurred prior to the time when the pups would start eating the treated diet.

Gross necropsy was unremarkable for both gene rations. No treatment-related microscopic changes were observed in P-generation rats. In F 1 -generation male and female rats of the 6,000 ppm group, a minimal to moderate multifocal tubula r dilatation was observed in the outer portion of the medulla, containing occasional proteinaceo us material. In general, both kidneys were affected with the incidences (s everity) of 23/30 (1.7) in males and 15/30 (1.5) in females; this finding was not seen in animals from the contro l or other treated groups. Decreased absolute (11%) and relative (5%) kidney weights in ma les and females at 6000 ppm were considered toxicologically significant in th e presence of renal histopathology.

The parental systemic LOAEL for BYI 08330 in ma le and female Wistar rats is 6000 ppm (419.3 and 484.7 mg/kg bw/day in males and females, respectively) based on decreases in body weight (F 1 males and females), weight gain (P males, F 1 males and females), and food consumption during lactation (P- and F 1 -generation females), a nd kidney histopathology and decreased kidney weights (F 1 males and females). The parental systemic NOAEL is 1000 ppm (70.7 and 82.5 mg/kg bw/day in males and females, respectively).

Evaluation of female reproductive performance revealed no effects on any parameter measured in either parental generation at 6,000 ppm and be low. The litter parameters determined at birth were not affected in either generation. Histopathology of the reproductive tract of females of either generation showed no treatment-related findings. Ovarian follic le counts of 6,000 ppm F 1 - generation females showed no difference from c ontrols. Female reproductive function (estrus cycle staging) was not affected in the P- or F 1 -generation at any di etary level tested.

In P-generation males, reproductive function (s perm analysis: sperm count, motility, progression, and morphology as well as gross examination, weight and histopath ology of reproductive organs) was not affected by treatment. In F 1 -generation males, sperm motility, epididymal and testicular sperm count were also not affected at 6,000 ppm. Howe ver, abnormal sperm cells were noted at 6,000 ppm, with a high degree of variati on as 9/30 males exhibited a minimal effect (1 to 4 abnormal sperm was noted out of 200 cells vi ewed). One of these males presented with 82% total abnormal sperm with 77% of these sperm presenting as amorphous heads and had decreased reproductive performance. At histopa thology, this same male showed abnormal sperm in the epididymis. Reproductive f unction was not affected in F 1 -generation males at 1,000 and 250 ppm.

The reproductive toxicity LOAEL for BYI 08330 in male Wistar rats is 6000 ppm (419.3 mg/kg bw/day) based on abnormal sperm cells and decreased reproductive performance in the F 1 males. The reproductive toxicity NOAEL is 1000 ppm in males (70.7 mg/kg bw/day). The reproductive toxicity LOAEL was not observed in females; the reproductive toxicity NOAEL in females was 6000 ppm (484.7 mg/kg bw/day).Page 52 of 65 There were no treatment-related effects on the vi ability parameters (viability index, lactation index), and no clinical signs and no malformations were observed in F 1 and F 2 pups. Offspring toxicity was limited to de creased body weights in F 1 and F 2 litters. Pup weights at birth were not affected (F 1 and F 2 ). On lactation day 21, the F 1 pup body weights for both sexes in the 6,000 ppm group was significantly lower than control (8.2%) with fema les also significantly lower on day 14 (6%). The pup body-weight gains for th e 6,000-ppm group was statistically decreased (9.1%) during days 4-21 of lactati on. On lactation days 14 and 21, the F 2 pup body weights for both sexes in the 6,000-ppm group were signifi cantly less than cont rol (7.5% and 10.3%, respectively). The pup body-weight gains for th e 6,000-ppm group were stat istically decreased (12.0%) during days 4-21 of lactation.

Gross necropsy, organ weights (brain, thymus , spleen, uterus) and histopathology of the reproductive organ system revealed no direct co mpound-related findings at any dietary levels tested. Statistically significant decreases in brai n, spleen, and thymus weights were considered secondary to the lower mean body weights of th e 6,000 ppm dose groups. Maturation of external sexual organs (balano-preputial separation, vaginal opening) was not affected in F 1 weanlings.

The offspring toxicity LOAEL for BYI 08330 in male and female Wistar rats is 6000 ppm (419.3 and 484.7 mg/kg bw/day in males and females, respectively) based on decreased body weight and body-weight gain during lactation in both F 1 and F 2 generations. The offspring NOAEL is 1000 ppm (70.7 and 82.5 mg/kg/ bw/day in males and females, respectively).

This study is Acceptable/Guideline and satisfies the guideline re quirement for a two-generation reproductive toxicity study (O PPTS 870.3800); OECD 416 in rats.

A.3.4 Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity – Rat

In a chronic toxicity study (MRID 46904547) , spirotetramat (97.5- 98.5% purity, batch no. 0845/0014) was administered to 25 Wi star Hanover strain rats/sex/dos e in the diet at dose levels of 0, 250 and 3500 ppm for both sexes and 7,500 ppm for males and 12,000 ppm for females (equivalent to 0, 13.2, 189, or 414 mg/kg bw/day for males and 0, 18, 255, or 890 mg/kg bw/day for females) for 12 months. In the last month of the study, 10 rats/sex/dose were evaluated in an FOB assessment that included evaluation of motor activity and responses to sensory stimuli.

Consistent with the subchronic study (MRID 46904538) the lung demonstrated treatment-related presence of alveolar macrophages in mid (6/25, se verity 1) and high (11/ 25, severity 1.2) dose males and high dose females (21/25, severity 1.3) relative to 1/25 control males and 5/25 control females (severity 1 for both sexes) . Clinical signs were limited to yellow/brown staining of the perigenital area and tail in females in the hi gh dose group. Body weight and body-weight gain were decreased by 7% and 14%, re spectively in high dose females at termination. Other findings include slightly elevated (8%) relative kidney we ight in females and relative liver weight in males (9%) and females (15%); however neith er the kidney nor the liver had related histopathological changes. The lung showed some discoloration in high-dose females. Although not statistically si gnificant, histopathology of the testis (abnormal spermatozoa) and epididymis (germ cell debris) was observed in high-dose males. These findings were consideredPage 53 of 65 toxicologically significant, si nce histopathology of both of th ese organs was also observed following 24 months of treatment. There were no obvious treatment-relate d effects in the FOB
assessments.

The LOAEL is 3500 ppm (189 mg/kg/ day) in males, based on alveolar macrophages; and 12000 ppm (890 mg/kg/day) in females based on decreased body weight and body-weight gain, alveolar macrophages, discoloration of the lung, and yellow/brown staining of the perigenital area and tail. The NOAEL is 250 ppm (13.2 mg/kg/day) in males and 3500 ppm (255 mg/kg/day) in females.

This chronic study in the rat is Acceptable/Guideline and satisfies the guideline requirement for a chronic oral toxicity study (O PPTS 870.4100, OECD 452) in the rat.

870.4100b Chronic Toxicity – Dog

In a chronic oral toxicity study (MRI D 46904548), BYI 08330 (97.6-98.5%, Batch No. 08045/0014) was administered to 4 beagle dogs/sex/group at di etary levels of 0, 200, 60 0 and 1800 ppm (equivalent to 0, 6, 20 or 55 mg/kg/day, respectively in male s and 0, 5, 19 or 48 mg/kg/day, respectively, in females). There were no significant compound-relate d effects based on the assessment of mortality, urine, eyes or organ weights. Compound-rela ted decreases in the ci rculating levels of T 4 at 600 and 1800 ppm in both sexes and T 3 at 1800 ppm in males were observed. Changes at ≤ 600 ppm were not considered toxicologically signifi cant since there were no correlativ e changes in thyroid weight or histopathology, no compensatory increases in TSH, a nd there were no clinical signs of toxicity or changes in body weight at these doses that might result from d ecreased thyroid output. The only histopathological change in thyroid was a reduction in follicle size at 1800 ppm in males, a possible indication of a reduced amount of colloid in the orga n. Notable gross observations were reduced thymus size in 1 male each at 600 and 1800 ppm. Histopathology of the thymus (thymus involution) was observed with dose-related severity in 1 male each at 600 and 1800 ppm.

The LOAEL for BYI 08330 in this study for male dogs is 600 ppm (20 mg/kg/day) based on thymus involution and was not observed in females. The NOAELs for males and females are 200 ppm (6 mg/kg/day) and 1800 ppm (48 mg/kg/day), respectively.

This one-year oral toxicity in dogs is Acceptable/Guideline and satisfies the guideline requirement [OPPTS 870.4100b, OECD 452] for a one-year oral toxi city study in a non-rodent species.

A.3.5 Carcinogenicity

870.4200a Carcinogenicity Study – rat

In a carcinogenicity study (MRID 46904549 ), spirotetramat (BYI 08330, batch no.: 08045/0014, purity: 97.4 – 98.5 %) was administered to 55 Wistar Hanover rats (strain: Crl:WI[Glx/BRL/Han] IGS BR)/sex/dose in the di et at dose levels of 0, 250, or 3500 ppm for both males and females and 7500 ppm for males and 12,000 ppm for females (equivalent to 0, 12.5, 169 or 373 mg/kg bw/day for males and 0, 1 6.8, 229 or 823 mg/kg bw/day for females) for two years.Page 54 of 65 Survival was not affected by treatment since there were 40, 34, 44 and 35 males and 39, 39, 37 and 42 females that survived to termination at each increasing dose level. Clinical signs were limited to yellow and/or brown perigenital stai ning in the mid (females) and high dose groups (both sexes) and body scaling in high dose animals. Terminal body weight was statistically significantly (p< 0.05) decrea sed in high dose males (10.2%) and females (14.2%). Correspondingly lower inte rim body-weight gains -- e.g. , at week 13 where gains were 10% lower for males and 17% lower for females -- were also noted at the high dose. The kidney demonstrated statistically significant lower abso lute weights in the low (9.7%), mid (10.2%) and high (14.6%) dose males and in mid (10.8%) and hi gh (13.7%) dose females. Tubular dilation of the kidneys of mid (8/54 males and 16/55 fema les) and high (19/54 males and 42/55 females) dose animals was also observed. Because ther e was no corresponding pat hology, the decrease in absolute kidney weight at the low dose was not c onsidered toxicologically significant. In males, the high dose caused spermatid degeneration in th e testes (9/55 vs. 0/55 in other groups) and germ cell exfoliated debris in the epididymis (31/55 vs. ≤ 10/55 in the other groups). Relative liver weight was increased in the high dose females (11.8%), a nd high dose (32/55, severity 1.7) females had an increased incidence (NSS) of bilia ry hyperplasia/fibrosis relative to the control group (18/55, severity 1.9).

Increased incidences of alveolar macrophages we re observed in males at the low and mid doses only. Females did not demonstrate a pattern of increased alveolar macrophages. High dose males demonstrated an increased incidence a nd severity of inters titial pneumonia, while increased incidences and/or se verity of interstitia l pneumonia were observed in all treated females. It is unclear how treatment with sp irotetramat and interstitial pneumonia are linked, if at all. Relative lung weight was increased in females in the high dose group. High-dose females also had more incidents of discol ored zones in their lungs. It is noted that the subchronic (MRID 46904538) and chronic (MRID 46904547) studies in th e rat demonstrated the presence of alveolar macrophages following treatment with spirotetramat.

The systemic LOAEL is 3500 ppm (169/229 mg/kg/day [M/F]), based on decreased kidney weight and renal tubular dilation. The NO AEL is 250 ppm (12.5/16.8 mg/kg/day [M/F]).

There were no treatment-related increases in tumo r incidence. Dosing was considered adequate based on pathological findings in the kidney (tubular d ilation) and decreases in absolute kidney weight at the mid and high doses. At the highest dose tested, there were also indications of testicular (males) and liver histopathologies (females).

This carcinogenicity study in the rat is Acceptable/Guideline and satisfies the guideline requirement for a carcinogenicity study [OPPTS 870.4200; OECD 451] in rats.

870.4200b Carcinogenicity (feeding) - Mouse

In a carcinogenicity study (MRID 46904550), spirotetramat (BYI08330, 97.4 to 98.3% purity, batch 90945/0014) was administered to 55 CD-1 mice/sex via their diets for a period of 18 months at dose levels of 0, 70, 1,700 or 7000 (for males) or 6000 (for females) ppm. These doses correspond to 0, 10.9, 263 or 1022 mg/kg/day for males and 0, 13.7, 331 or 1319 mg/kg/day for females.Page 55 of 65 There were no adverse reactions to treatment of any kind. There were 43, 42, 41 and 44 males and 36, 35, 41, and 37 females that survived to term inal sacrifice in the control, low, mid and high dose groups, respectively. The LOAEL was not established. The NOAEL was 7000/6000 ppm (1022/1319 mg/kg/day [M/F]).

At the doses tested, there were no treatment related increases in tumor incidence. Dosing was considered adequate since the limit dose of 1000 mg/kg/day was achieved.

This carcinogenicity study in mice is Acceptable/Guideline and satisfies the guideline requirement for a carcinogenicity st udy [OPPTS 870.4200; OECD 451] in mice.

A.3.6 Neurotoxicity

870.6200 Acute Neurotoxicity Screening Battery

In an acute neurotoxicity study (MRID 46904560), groups of nonfasted Wistar Hanover (Crl:WI[Glx/BRL/Han]IGS BR) rats (12/sex/dose), at least 9 weeks old, we re given a single oral gavage dose of BYI 08330 (spirotetramat) t echnical (97.8-98.5%, mix batch 08045/0014) in 0.5% methylcellulose/0.4% Tween 80 in deioni zed water at nominal doses of 0, 200, 500 or 2000 mg/kg bw and observed for 14 days. Since tr eatment-related effects were observed at 200 mg/kg, a follow-up study with 12 animals/sex/dose was conducted at nominal doses of 0, 50, 100 and 500 mg/kg. In the initial study, neurobeha vioral assessment (functional observational battery and motor activity testing) was perfor med on all animals/sex/ group pre-dosing and on days 0 (day of treatment), 7 and 14. Body we ight was measured weekly throughout the study. At study termination, 6 animals/sex/gr oup were euthanized and perfused in situ for neuropathological examination; brai n weight was recorded from these animals. Of the perfused animals, 6 animals/sex from the control a nd high dose groups were subjected to histo– pathological evaluation of brai n and peripheral nervous system tissues. In the follow-up study, the following parameters were measured: clin ical observations, body weight, FOB testing (pretreatment and day 0) and motor activity (pre -treatment and day 0); no necropsies were conducted.

In the initial study, treatment-related observations involved urine stain in males and females at 200 mg/kg and above and perianal stain in ma les at 500 mg/kg and above. Total motor and locomotor activity in the initial study were significantly reduced at 2,000 mg/kg in males (48 % and 64 %, respectively) and females (40% a nd 65%, respectively) on day 0. At 500 mg/kg, motor activity was reduced (32%) and locomoto r activity was significantly reduced (44 %) in males only on day 0. Locomotor activity was slig htly reduced (29 %) in males of the low dose group (200 mg/kg). In addition, interval motor ac tivity on day 0 was significantly reduced in males at several intervals at 500 and 2,000 mg/kg; interval locomotor activity was decreased in males at 200 mg/kg. A similar trend was evident in females, but the difference from control was not statistically significant. In the follow-up study, total motor and locomotor activity was slightly reduced (21 % and 30 %, respectively) on day 0 in male s dosed at 500 mg/kg, but not in lower levels (50 and 100 mg/kg) or in females at any dose. Interval motor and locomotor activity was reduced at several interval s in both sexes at 500 mg/kg on day 0.Page 56 of 65 The LOAEL for acute neurotoxicity of spir otetramat technical in rats was 200 mg/kg based on clinical signs (urine stain; males and females) and decreased motor activity (males). The NOA EL was 100 mg/kg.

This neurotoxicity st udy is classified as Acceptable/Guideline and satisfies the guideline requirement for an acute neurotoxicity study in rats (870.6200a; OECD 424).

A.3.7 Special

870.7485 Metabolism – Rat

I. In a metabolism and pharmacokinetic study (MRID 46904504), four groups of 4 male and 4 female Wistar rats were administered a single gavage dose of [azaspirodecenyl-3- 14 C]BYI 08330 (Lot/Batch Nos. BECH 0826, 0834, 0843, 0906, 0948, ra diochemical purity >99%) in aqueous Tragacanth ® and nonlabelled azaspirodecenyl-BYI 08330 (Lot/Batch No. 08045/0003, chemical purity >99%) at target doses of 2 or 100 mg/kg body weight. Two groups of 4 male or female rats were also pre-treated for 14 days with 2 mg/kg non-radiolabelled BYI 08330 followed by a single radiolabelled dose of 2 mg/ kg. The animals of all groups were sacrificed 2 days after dosing. The total radioactivity which included the test item and metabolites was determined in plasma samples, the excreta (urine and feces) as well as in organs and tissues. The metabolism was investigated by radio-HPLC, normal phase TLC and spectroscopic methods in selected urine samples and feces extracts.

Radioactivity inventory showed total recovery of 91.4% to 99.8% of the administered dose. [Azaspirodecenyl-3- 14 C]BYI 08330 was rapidly absorbed from th e gastrointestinal tract of male and female rats in all test groups. The absorption rate in all tests was between 89 and 98% of the total recovered radioactivity, based upon rec overy from the urine and carcass (without the gastrointestinal tract). No significant differe nces in the absorption rate were observed among any of the dose groups. The absorpti on rate in the single low dose te st was 95% for male rats and 96% for female rats.

The maximum of plasma concentration was reac hed for all dose groups within 0.09 to 2.03 hours after administration (values calculated by pharmacokinetic m odelling). The radioactivity concentrations in plasma declined steadily by se veral orders of magnitude within 48 hours for all dose groups. Radioactivity in tissu es and organs at the 48-hou r termination were very low (<0.2% and below the limit of detec tion for some organs/tissues).

Urinary excretion was very rapid and was the major excretion rout e. Faecal excretion accounted for 2-11% of the dose in male and female rats. The excretion behaviour was similar for all dose
groups.

BYI 08330 was completely metabolized by the ra t; no parent compound was detected in the excreta. Identified metabolites accounted for 87-95% of the administered dose. Only very minor metabolites (<0.7% of the dose) were not identif ied. The main metabolic reaction was cleavage of the ester group which resulted in the form ation of the primary and most predominant metabolite BYI 08330-enol (53-87% of the administ ered dose). All other identified metabolites could be derived from the enol intermediate . The second prominent metabolic transformation was oxidative demethylation of the 8-met hoxy group to BYI 08330-desmethyl-enol (5-37% ofPage 57 of 65 the administered dose). Oxidation of the azaspiro moiety to BYI 08330-ketohydroxy and BYI 08330-desmethyl-ketohydroxy were detected as minor pathways. Other minor metabolic transformations were conjugation of the enol with glucuronic acid to BYI 08330-enol-GA and oxidation of the aromatic methyl group of the enol metabolit e to BYI 08330-enol-alcohol. A sex-related difference was observed in metabolism with male rats showin g much higher rates of demethylation to BYI 08330-desmethyl-e nol compared to female rats.

This study in the rat is considered Acceptable/Guideline and meets the guideline requirement for a metabolism and pharmacokinetics study (870.7485) in rats.

II. In a metabolism study (MRID 46904561), three groups of 4 male Wistar rats were administered by oral gavage a single dose of [azaspirodecenyl-3- 14 C]BYI 08330 (Lot/batch No. BECH 1943, radiochemical purity >98%) and non-radiolabelled BYI 08330 (Lot/Batch No. 08045/0003, chemical purity >98%) in aqueous Tragacan th® at a target dose level of 2 mg/kg body weight. Three additional groups received a dose of 1000 mg/kg body weight. One group of animals from each test group was sacrificed at 1 h, 8 h, and 24 h after dosage, respectively. The total radioactivity (parent compound and metabolites) was determined in the urine and feces over the test period. Radioactivity in plasma, tes tis, liver and kidney were determined following terminal sacrifice.

Recovery of administered radioactivity was excellent; 100.3-121.8% (tests 1–3) and 94.8-98.9 % (tests 4–6). Metabolites were iden tified and characterized in urin e, plasma, testis, liver, and kidney. Metabolites accounted for more than 89% of the total recovered radioactivity for all samples.

For the 2 mg/kg dose, the administered radioact ivity was rapidly absorbed, widely distributed and rapidly excreted. Excretion wa s primarily via the urine and ne arly complete at 24 hours post dose. Absorption and excretion rate and amount were less for the 1000 mg/kg dose with only 27 % of the dose excreted in the ur ine after 24 hours. Radioactivity in plasma and organs declined rapidly after dosing resulting in low plasma residues at 24 hours post dose. For all time points, the residues in liver and kidney were distinctively higher than in pl asma while residues in testis, carcass and skin were distinctively lower than in plasma. The ratio of the two main metabolites, BYI 08330-enol and BYI 08330-desmethyl-enol, in urine was about 2:1. Due to its greater polarity, BYI 08330-desmethyl-enol wa s found at higher percentages in urine than in plasma and organs. The highest percentages of BYI 08330-desmet hyl-enol were detected in liver, where the compound is formed by metabolic transformation of BYI 08330-enol. BYI 08330-enol levels in the plasma, kidney and testis were comparab le but significantly lower than in liver.

For the 1000 mg/kg dose, excretion rate was di stinctively less than for the low-dose while plasma radioactivity was slightly higher than in liver and kidney. This is consistent with saturation of cellular transport mechanisms. Decline of tissue radioactivity was minimal from 1 h to 8 h post dose and increased only slightly to 24 hours. The residues in testis, carcass and skin were lower than in plasma. The metabolism profile was qualitatively similar to that of the low dose; however, BYI 08330-desmethyl-e nol occurred at lower levels at the high dose and is likely a reflection of the decreased ab sorption at the high dose. Si milar to the low dose group, BYI 08330-desmethyl-enol levels were greater in urine than in plasma and organs. The highest percentage of BYI 08330-desmethyl-enol was detect ed in liver and kidney. The percentage in plasma, kidney and testis was lower.Page 58 of 65 For all dose regimens, the most prominent metabo lic reaction was the cleavage of the ester bond of the side chain yielding the BYI 08330-enol. The demethylation of the cyclohexyl-O-methyl group to the respective alcohol (BYI 08330-desmethyl-enol) was a further important metabolic reaction as well as the hydroxyla tion in the azaspiro ring of BYI 08330-enol resulting in BYI 08330-ketohydroxy, which was mainly detected in liver and kidney. Other metabolic reactions ( e.g. , conjugation of the BYI 08330-e nol with glucuronic acid, oxida tion of one of the methyl groups of the phenyl ring forming the BYI 08330-enol-alcohol, and demethylation of BYI 08330-ketohydroxy to BYI 08330-desmethyl-ketohydr oxy) were of minor importance.

Results of this study indicate that saturation of active transport mechanisms occurs at a dose of 1000 mg/kg but not 2 mg/kg. This results in de creased excretion via urine and feces and a potential for accumulation of BYI 08330 related residues in the body following repeated high doses.

This study in rats does meet current O PPTS 870.7485 Guidelines for a metabolism and pharmacokinetics study. This st udy in the rat is considered Acceptable/Guideline and meets the guideline requirement for a metabolism a nd pharmacokinetics study (870.7485) in rats.

870.7600 Dermal Absorption - Rat

In an in vivo dermal absorption study (MRID No.46904563), ma le Wistar rats were administered nominal doses of 100, 15, or 5 μg ai/cm 2 of [ 14 C]-BY1 08330 (synthesis ref. No. KML 2978-2; >99% radiopurity) to approximately 12 cm 2 of body surface and monitored up to 168 hr postdosing. Mean dermal absorption values (excluding skin), for the groups fo r which the skin site was washed and the animals sacrificed after 10 hours exposure (n=4), were 1.73%, 1.92%, and 1.43%, respectively, for the high, medium, and low dose levels. Ten hours is considered most applicable to the typical worker exposure time. When the animals were skin washed after 10 hrs exposure and sacrificed at 168 hrs, the mean de rmal absorption values (excluding skin) were 7.69%, 2.99%, and 3.99% for the high, medium, and low dose (n=4) exposure groups, respectively. Mean radioactivity (percent of the applied dose) rema ining at the dose site (treated skin and stratum corneum) after 10 hours exposure was 15.89%, 8.43%, and 10.60% for the high, medium, and low dose rats. The respectiv e values decreased to 2.87%, 1.72%, and 1.82% at the 168 hr sacrifice following a 10 hour exposure, indicating that the ac tivity remaining at the application site decrease d with time. Because the amount of radioactivity at the dose site (including stratum corneum) decreased during this time period and the amount of radioactivity in excreta increased, the small amount of the active ingredient ( 2.87% 1.72%, and 1.82%, respectively, for the high, medium, and low dose groups) retained at the skin site after 168 hours was considered part of the absorbed dose. Ther efore, mean dermal absorption values (including skin) for the animals sacrificed 168 hrs af ter a 10-hr exposure were 10.57%, 4.71%, and 5.81% for the high, medium, and low dose (n=4) exposure groups, respectively.

This study in the rat is acceptable/guideline and satisfies the guideline requirement for an in vivo dermal penetration study.Page 59 of 65 Appendix B. Metabolism Assessment

Table B.2. Tabular Summary of Metabolites and Degradates

Chemical Name (other names in

parenthesis) Matrix Percent TRR (PPM) 1

Structure Matrices - Major Residue (>10%TRR) Matrices - Minor Residue (<10%TRR) Spirotetramat ( cis -3-(2,5- dimethylphenyl)-8- methoxy-2-oxo-1- azaspiro[4.5]dec-3- en-4-yl ethyl carbonate) Plants Apple Fruit & Leaves; Lettuce; Cotton Gin Trash & Lint; Potato Tops Cotton Seed

Rotational Crops - -
Ruminant - - Poultry - -

Rat - -
Water - -
BYI08330-enol ( cis -3-(2,5- dimethylphenyl)-4-hydroxy-8-methoxy1-azaspiro[4.5]dec3-en-2-one) Plants Apple Leaves; Lettuce; Cotton Gin Trash & Seed Apple Fruit, Cotton Lint, Potato Tops Rotational Crops Wheat Grain Ruminant Muscle, Fat, Liver, Kidney, Milk Poultry Muscle, Eggs, Fat, Liver Rat Liver, Kidney, Excreta, Plasma Water Aerobic Soil,
Aerobic Outdoor
BYI08830- ketohydroxy ( cis -3-(2,5- dimethylphenyl)-3-hydroxy-8-methoxy1-azaspiro[4.5]decane2,4-dione) Plants Cotton Gin Trash& Lint; Potato Tops Apple Fruit & Leaves, Lettuce, Cotton Seed Rotational Crops Wheat Forage; Chard; Turnip Roots Wheat Straw, Hay; Turnip Leaves Ruminant Muscle, Liver, Kidney, Milk Poultry - - Rat Kidney, Liver Excreta, Plasma Water Aerobic Soil,
Aerobic Outdoor
BYI08330-enolGlc ( cis -3-(2,5- dimethylphenyl)-8- methoxy-2-oxo-1- azaspiro[4.5]dec-3-en-4-yl beta-Dglucopyranoside) Plants Lettuce Apple Fruit, Potato Tops Rotational Crops Wheat Hay, Straw
Ruminant - - Poultry - -

Rat - -
Water - -Page 60 of 65 Table B.2. Tabular Summary of Metabolites and Degradates

Chemical Name (other names in

parenthesis) Matrix Percent TRR (PPM) 1

Structure Matrices - Major Residue (>10%TRR) Matrices - Minor Residue (<10%TRR)
BYI 08330- mono-hydroxy ( cis-3-(2,5- dimethylphenyl)-4-hydroxy-8-methoxy1-azaspiro[4.5]decan2-one ) Plants Apple Fruit - Rotational Crops - - Ruminant Liver, Milk Poultry - -

Rat - -
Water - -

BYI 08330- enol-GA ( cis -3-( cis -3-(2,5- dimethylphenyl)-4- ( β -Dglucopyranosyloxy)- 8-methoxy-1- azaspiro[4.5]dec-3- en-2-one) Plants - - Rotational Crops Ruminant Fat, Liver, Kidney, Milk Poultry Liver, Muscle, Eggs Rat Liver, Kidney, Excreta
Water - -
BYI 08330-desmethylketohydroxy ( cis3-(2,5- dimethylphenyl)-3,8- dihydroxy-1- azaspiro[4.5]decane -2,4-dione ) Plants Apple Fruit, Cotton Gin Trash Rotational Crops Wheat Forage, Straw, Hay; Chard, Turnip Leaves, Roots
Ruminant - - Poultry - - Rat Liver, Kidney, Excreta
Water - -
BYI 08330-dihydroxy ( cis- 3- (2,5- dimethylphenyl)- 3,4-dihydroxy-8- methoxy-1-azaspiro[4.5]decan2-one) Plants - Apple Fruit Rotational Crops Wheat Straw, Chard Wheat Forage, Hay, Grain; Turnip Leaves, Roots
Ruminant - - Poultry - -

Rat - -
Water - -
BYI 08330-desmethylketohydroxyglucoside (isomers), in leaves also +BYI 08330-ketohydroxyformiatePlants - Apple Fruit & Leaves; Cotton Gin Trash & Lint

+ Rotational Crops Wheat Forage, Hay, Straw; Chard Wheat Grain; Turnip Leaves
Ruminant - - Poultry - -

Rat - -Page 61 of 65 Table B.2. Tabular Summary of Metabolites and Degradates

Chemical Name (other names in

parenthesis) Matrix Percent TRR (PPM) 1

Structure Matrices - Major Residue (>10%TRR) Matrices - Minor Residue (<10%TRR) glycoside Water - -

BYI 08330- desmethyl-enol
Or
BYI 08330-4- hydroxy-enol ( cis-3-(2,5- dimethylphenyl)-4,8- dihydroxy-1- azaspiro[4.5]dec-3- en-2-one ) Plants - Potato Tops Rotational Crops - - Ruminant Goat Muscle, Liver, Kidney, Milk; Poultry - - Rat Excreta Liver, Kidney, Plasma
Water Aerobic Soil
BYI 08330-desmethyl-enolGlc (Glucoside of 3-(2,5- dimethylphenyl)- 4,8-dihydroxy-1- azaspiro[4.5]dec-3- en-2-one) Plants Cotton Gin Trash & Seed; Potato Tops Rotational Crops - -
Ruminant - - Poultry - -

Rat - -
Water - -
BYI 08330-MAamide (1-{[(2,5- dimethylphenyl)(hyd roxy)acetyl]amino}- 4- methoxycyclohexan ecarboxylicacid) Plants - Cotton Gin Trash
Cotton Lint Rotational Crops - -
Ruminant - - Poultry - -

Rat - - Water Aerobic Soil,
Aerobic Outdoor
BYI 08330- mandelic acid amide (2-(2,5- dimethylphenyl)-2- hydroxyacetamide) Plants Cotton Lint Cotton Gin Trash
Cotton Seed Rotational Crops - -
Ruminant - - Poultry - -

Rat - -
Water - -
BYI 08330- mandelic acid ((2,5- dimethylphenyl)(hyd roxy) Plants - Cotton Lint Rotational Crops - -
Ruminant - - Poultry - -Page 62 of 65 Table B.2. Tabular Summary of Metabolites and Degradates

Chemical Name (other names in

parenthesis) Matrix Percent TRR (PPM) 1

Structure Matrices - Major Residue (>10%TRR) Matrices - Minor Residue (<10%TRR)
acetic acid) Rat - -
Water - -
BYI 08330- hydroxymorphol inedion (3-(2,5- dimethylphenyl)-3-hydroxy-9-methoxy4-oxa1- azaspiro[5.5]undeca ne-2,5- dione) Plants Cotton Gin Trash Rotational Crops - -
Ruminant - - Poultry - -

Rat - -
Water - -

BYI 08330- olefine (2-(2,5- dimethylphenyl)-2- hydroxy-N-(4- methoxycyclohex-1- en-1-yl)acetamide

or 2-(2,5- dimethylphenyl)-2- hydroxy-N-(4- methoxycyclohexyli dene) acetamide) Plants - Cotton Gin Trash
Cotton Lint Rotational Crops - -
Ruminant - - Poultry - -

Rat - -
Water - -

BYI 08330-ketohydroxyalcohol ( cis -3- hydroxy-3-[5- (hydroxymethyl)-2- methylphenyl]-8- methoxy-1-azaspiro[4.5]decane2,4-dione) Plants - - Rotational Crops Wheat Straw, Hay, Grain; Chard, Turnip Leaves
Ruminant - - Poultry - -

Rat - -
Water - -
BYI 08330-ketohydroxyalcoholglycoside (glycoside of cis-3- hydroxy-3-[5- (hydroxymethyl)-2- methylphenyl]-8- methoxy-1-azaspiro[4.5]decane2,4-dione) Plants - - Rotational Crops Wheat Forage, Straw, Hay, Grain; Turnip Leaves
Ruminant - - Poultry - -

Rat - -
Water - -
BYI 08330- enol-alcohol ( cis4-hydroxy-3-[5- (hydroxymethyl)-2- methylphenyl]-8- methoxy-1- azaspiro[4.5]dec-3- en-2-one) Plants - Potato Tops Rotational Crops - -
Ruminant - - Poultry - - Rat Liver, Kidney, ExcretaPage 63 of 65 Table B.2. Tabular Summary of Metabolites and Degradates

Chemical Name (other names in

parenthesis) Matrix Percent TRR (PPM) 1

Structure Matrices - Major Residue (>10%TRR) Matrices - Minor Residue (<10%TRR)

Water - -
BYI 08330-desmethyl-dihydroxy-Glc (glucoside of (5s,8s)-3-(2,5- dimethylphenyl)- 3,4,8-trihydroxy-1-azaspiro[4.5]decan2-one) Plants - - Rotational Crops Wheat Straw, Forage, Hay Wheat Grain; Chard, Turnip Leaves
Ruminant - - Poultry - -

Rat - -
Water - -
BYI 08330-desmethyl-dihydroxy ((5s,8s)-3-(2,5- dimethylphenyl)- 3,4,8-trihydroxy-1-azaspiro[4.5]decan2-one) Plants - - Rotational Crops Wheat Straw, Hay, Grain, Turnip Leaves
Ruminant - - Poultry - -

Rat - -
Water - -
BYI 08330-desmethyldihydroxy-GlcMA (glucosylmalonic acid conjugate of (5s,8s)- 3-(2,5- dimethylphenyl)- 3,4,8-trihydroxy-1-azaspiro[4.5]decan2-one) Plants - - Rotational Crops Wheat Hay Wheat Straw, Grain; Chard, Turnip Leaves, Roots
Ruminant - - Poultry - -

Rat - -
Water - -
BYI 08330- desmethyl-enol - alcohol ((5s,8s)- 4,8-dihydroxy-3-[5- (hydroxymethyl)-2- methylphenyl]-1- azaspiro[4.5]dec-3- en-2-one) Plants - - Rotational Crops Wheat Forage, Straw, Hay, Grain; Chard, Turnip Leaves, Roots
Ruminant - - Poultry - -

Rat - -
Water - -
BYI 08330-desmethylketohydroxyGlc-MA (isomer 1 & isomer 2) (glucosyl-malonic acid conjugate of Plants - - Rotational Crops Wheat Forage, Hay, Straw Wheat Grain; Turnip Leaves
Ruminant - - Poultry - -

Rat - -Page 64 of 65 Table B.2. Tabular Summary of Metabolites and Degradates

Chemical Name (other names in

parenthesis) Matrix Percent TRR (PPM) 1

Structure Matrices - Major Residue (>10%TRR) Matrices - Minor Residue (<10%TRR) (5s,8s)-3-(2,5- dimethylphenyl)- 3,8-dihydroxy-1-azaspiro[4.5]decane2,4-dione) Water - -

Apple, 46904480; 0.982 lb ai/A; 2.5X rate; first application at growth stage 69 BBCH and the second application at growth stage 71; 63 days (fruit & leaves). Lettuce, 46695529; 0.15 lb ai/A; 0.9X rate; two applications at a 14-day RTI; 7 days. Cotton, 46904479; 0.23 lb ai/A; first application at growth stage 15 BBCH and the second application at growth stage 85; 39 days (gin trash, lint and undelinted seed). Potato, 46904484; 0.275 lb ai/A; 1.7X rate; three applications at a 21-day RTI; 14 days. Cow (PH label); 46695532; 8.01 ppm; 6.8X MTDB; 7 days; 23 hour PSI Hen (PH label); 46695534; 11.33 ppm; 470X MTDB; 14 days; 24 hour PSI Rotational Crops; 46695612; Swiss chard, turnips, and spring wheat; 1.2X, applied to bare soil;90-day PBI Rat Metabolism; 46904504, 46904561; 2, 100, 1000 mg/kg oral dose; Wistar, 2-day depuration.Page 65 of 65 Appendix C. Tolerance Summary Table for Spirotetramat

Commodity Proposed Tolerance

(ppm) Recommended Tolerance

(ppm) Correct Commodity Definition

Citrus, crop group 10 0.5 0.60 Fruit, citrus, group 10 Citrus, oil 4 6.0 Leafy vegetables, crop group 4 5 9.0 Vegetable, leafy, except Brassica, group 4 Pome fruit, crop group 11 0.5 0.70 Fruit, pome, group 11 Apple pomace, wet 0.6
- Stone fruit, crop group 12 2 4.5 Fruit, stone, group 12 Grape, wine and table grape, Crop Group 13F 1 1.3 Small fruit vine climbing subgroup, except fuzzy kiwifruit, subgroup 13- 07F Grapes, raisins 2.5 3.0 Grape, raisin Strawberry 0.5 0.40 Bulb vegetables, onion, crop group 3A 0.3 0.30 Onion, bulb, subgroup 3A-07 Fruiting vegetables, crop group 8 1 2.5 Vegetable, fruiting, group 8 Tomato, dried 2.5 - Cucurbits, crop group 9 0.2 0.30 Vegetable, cucurbit, group 9
Brassica , head and stem, crop group 5A 1 2.5 Brassica , head and stem, subgroup 5A Leafy Brassica , crop group 5B 16 8.0 Brassica , leafy greens, subgroup 5B Potato, crop group 1C 1 0.60 Vegetable, tuberous and corm, subgroup 1C Potato, flakes 2.5 1.6 Tree Nuts, Crop Group 14 0.5 0.25 Nut, tree, group 14 Almond, hulls 9 9.0 Hop (dried cones) 10 10 Hop, dried cones
- - 0.01 Milk Cattle, meat 0.01 0.02 Cattle, fat 0.01 0.02 Cattle, liver 0.01 - Cattle, meat byproduc ts, except liver 0.02 0.02 Cattle, meat byproducts Goat, meat 0.01 0.02 Goat, fat 0.01 0.02 Goat, liver 0.01 Goat, meat byproducts, except liver 0.02 0.02 Goat, meat byproducts Hog, meat 0.01 - Hog, fat 0.01 - Hog, liver 0.01 - Hog, meat byproducts, except liver 0.02 - Sheep, meat 0.01 0.02 Sheep, fat 0.01 0.02 Sheep, liver 0.01 - Sheep, meat byproducts, except liver 0.02 0.02 Sheep, meat byproducts Horse, meat 0.01 0.02 Horse, fat 0.01 0.02 Horse, liver 0.01 - Horse, meat byproducts, ex cept liver 0.02 0.02 Horse, meat byproducts