### U N ITED STATE S ENVIRONMENTAL PROTECTION AGENCY WA S HIN G TON , D .C. 2 0 4 6 0

OFF I CE O F CHEMICAL SAFETY AND POLLUTI O N PRE V E N TION 

### ME MORAND U M 

### Date: S ubj e ct:

F r o m : Throu g h : To : I O-March-2015 S pi n o s ad and Sp i netoram - H u m an Hea l t h Risk Assessment to Support the Sect i on 3 Registration Reque st for Application to Coffee; L abe l Amendments for P l um/Prune and 

## Brassica (Co l e) Leafy Vegetab l es Crop Group 5; and Updates to Several Crop Group / Subgroup Commodity Definitions. P C Codes: I 10008 and I I 0003 DP B a r co d es: 0415812, 0415814 , 0420288 , 04 20289, 0420291 D ec i s i o n Nos.: 483225, 483254, 490184 , R eg i s tr a ti o n Nos.: 62719-541 , 62719-545 , and 62719-621 490185,490186 P e t i ti on Nos.: 3E8203 and 3E8204 R eg u l atory A ct i o n s: Section 3 Regi strat ion s; Lab el Amendments Ri s k Assess m e n t T y p e: au!?.regate Case N o s.: 7448 and 7421 TX R No.: not aoolicable CAS Nos.: 187166-40-1, 187166-15-0 , and 1319 29 -60- 7 M RJD Nos.: not aool i cable 40 C F'R : 1 80.495 and 180.635 

### To m Bloem ,

# Chen**~~""'::.** . Monique M. Perron ,

# Sc.D.,fix~1co giJk-

# ~**~** Jennifer R. Ty ler , Chemist 

# K -- W-- Risk Assessment Branch 

### 1 BI ,

## ealt~fe:_.ts2~is**~~ED,** 7509P ) Thruston Morton, Acting Bra n ch Chief

# .IL//~ George F. Kramer , Ph.D. , Senior

## Chem**~5'7 ::!:~**  RABl/HED (7509P) Barbara Madden/S i d n ey Jackso n , RM 5 ; R ic h a r d Gebken/Olga Oddiott (RM l 1) 

### R eg istration Di v i sio n ( RD; 7505P) The HED of the Offic e of Pesticide P rograms (OPP) is charged with est i mat i ng the risk to human health from exposure to pesticid es. T h e RD of OP P h a s requested that HED eva lu ate haza r d and ex po s ure data and conduct dietary , occupational, residential, and aggregate exposure assessments, as need ed, to estimate the r i sk to human hea l th that w i ll res ul t from t h e proposed use of sp i nosad and spinetoram. A summary of the findings and an assessment of human health risk resulting from the proposed/registered u ses of spinosad and spine t oram a r e p r ovi d ed in thi s document. The r i sk assessment , residu e chemistry. and dietary exposure assessment were provided by Tom Bloem (RAB 1) , the hazard characterization by Mon j q u e P e r ron (RA B 1) , the occupational/reside n tial exposure ( ORE) assessment by Jenni fer T y l er (RAB 1 ), and the d r inkin g water assessment by Larry Liu of the E nvironmental Fate and Effects Div i s i on (EFED) . Page I o f 45

### Spinosad a nd Sp in e toram 

### H u m an H ea lth Ri s k Assessment 041581 2 

### Tab l e of Co nt e nt s 1 .0 EXECUTIVE SUMMARY ... ..... .......................... ..... ... ...... ............... ..... .. ................. .... ....................................................... . .... 3 2.0 R ECOM M EN DATION S ......................................................... . ................................. . ...... .. ....... ..... . ................. . ..... . .................. 6 2.1 Data Deficiencie s/ Data ccds ............................................................................................. ... ........................................... .. 6 2.2 Tolerance Considerations ........................................................................ . .......... . .................... . .... .... ...... .. ........................... 6 2.2. I Enforcement Analytical Method ....... . ....................................................................................... .. ...... . ......... ... ............ 6 2.2.2 Recommended To l e r

ances .... ....... .... ....................... . . ....................................................... . ...... . . .... . ............................ 7 2.2.3 Re visions to Petitioned - For To lerance s ......................... ... ....... ... ................................................................................ 9 2.2. 4 Int erna ti o nal Harmonization ............................... . ............... . .......... ..... ................................................................ . ...... 9 2.3 Label R ecomme nd ations ...................................................................................... .. ....... ... ....... . .......................... . .............. I 0 2.3.1 Recommendation s from Residue Reviews ........... . ........................... ... ..................................... ... ............................. I 0 2.3.2 R ecommenda ti ons from Occupational Assessment.. ......................... ... ................. ..... ..... . . ....................................... 1 0 2.3.3 Recommendation s from Re s idential As ses sment ........................................... ...... ......................... .... ....................... 1 0 3.0 I TRODUCTION .... .. ........ .. ................................................................................................................................................... I I 3. 1 C hemical Id ent it y .......................................... . ........................... .. .................... .. ...... ..... ..................................................... 11 3.2 Physical / C hemical Propenic s .. .................. . .................................................................... ... ....... ..... .... .. ....... ... . ................... 1 2 3.3 P es ticide Use Panem / Directions ................ . ........ .. ............................. .. .............................................................................. 12 3.4 Anticipated Exposure Pathways ........................................................ . ............................................................................... 1 4 3.5 Cons ideration of Environmental Justice ............................................................................... ... .................................. .... .... 14 -l .O 1 IAZARD C l IARA C T ERIZAT IO N AND DOSE-RESPONSE ASSESSMENT ................................................................... 1 5 4. 1 Toxico l ogy S tudie s Available for Ana l ysis ........................................... . ....................... . ............. .... .................................. 1 5 4.2 Absorption. Distribution. Metabolism. and Excretion (ADME) ............................................... . ......... . ........ .. ............... . .... I S 4.3 Toxicological Ellects ....................... . ........................ . ............................. .... ....................................................................... 16 4.4 Safety Factor for In fants and Chi l dren (FQPA SF) ........................................................................................................... 1 7 4.4.1 Comple tenes s of the Toxicology Database .............................................................................................................. 17 4.4 .2 Evidence ofNcurotoxicity .................................... . ...... .. .......... .................................. .............................................. 17 4.4.3 Evidence of Sensitivity / Susceptibility in the Developing or Young Animal. ........................................................... 1 7 4 .4.4 Re s idual U n cer t ai nt y in th e Exposure Databa se ...... . .......................................................... . ................... . ........... .... .. 17 4.5 Toxicity Endpoint and Point of Dcpanure Selections ..................................................................................................... .. . 1 7 4 .5. 1 Dose -R esponse Assessme n t .. ...................................... .. ..... ..... ..... ............................................ .. .............................. 18 -l.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment ......................... . ......... ... ....... . ............ 1 9 4 .5.3 Cancer C las si fication and Risk Assessment Recommendation ..................................................................... ....... .... 1 9 4.5.4 Summary of Points of Departure and T oxici t y Endpoints Used in Human Ri sk Assessment .................................. 1 9 5.0 D I ETARY EX PO SU R E AND R I SK ASSESSMENT ...... ....... .... . .......... . .................. ...... ........................ ..... ..... .. ..... ... ........... 21 5.1 Residues of Concern Summary and Rational e ................................................................................................................... 2 1 5.2 Food Re s idu e Proli l c ............. . ......... . ................. . ..... .... ........... . . . ....... .. . . ............... ... ............................................. ... ........... 22 5.3 Water Residue Prolile ............. . ................................................................... .. ............................................................... . ..... 22 5.4 Dietary Ri s k Assessment ..................................................................... .... .................... . ....... ... ........................... .... ............ 23 5.4.1 Summa r y of Dietary Exposure/ Ri sk Estima t es .............. . ......................................................................................... 23 5.4.2 Percent CT Used in Dietary Assessment.. ............................................................................................................... . 23 6.0 RESIDENTIAL ( ON-OCCUPATIONAL) EX P OSURE/ RI SK .. .. ........ .. ........................... . .................................................. 24 6. 1 R es idential By s tander Po s t-Application Inhalation Ex po s ure ............................................. .. ............................................ 26 6.2 Spray Drift ..................................................................................... .. .................................................................................. 26 7.0 AGGREGATE EXPOSU R E/R I SK C H ARACTER I ZATION ............. . ............................................................ . ..................... 27 8.0 CUMULAT IV E RISK CllARACTER IZ AT I O / ASSESSME T .......................................................................................... 27 9.0 OCCUPAT I ONAL EXPOSURE / RI S K C l IARJ\ CTE RI ZAT I ON ................................................ .. ........................................ 28 9.1 Occupational I l andlcr Exposure/Risk Assessment ............................................................................................. .. ..... ..... ... 28 9.2 Occupationa l Post-Application Exposure / Ri s k Assessme nt ................................ .. ........ ... ........ . .................. .. .................... 29 APPEND I X A. TOXICOLOGY ASSESSMENT ................................................. . ....................................................................... 30 APPE DIX B . CHEM ICAL NAMES AND STRUCTURES ....................................................................................................... 40 APPEND I X C. P HY S I OC I IE MI CAL PR O P E RTI ES ................................................................................................................... 44 APPEND I X D: REGI STERED RES I DENTIAL USES FOR S PINOSAD / SPINETORAM ........... . ... .... ...... ........... ..................... 45



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### Spinosad and Spinetoram Human Health Risk Assessment D 415812

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### 1.0 EXECUTIVE SUMMARY Background: Spinosad, which consists of spinosyn A and spinosyn D (A:D of 85:15), is a fermentation product of Saccharopolyspora spinosa . Spinetoram, which consists of XDE - 175 - J and XDE - 175 - L (J:L of 3:1), is derived from the synthetic modification of Saccharopolyspora spinosa fermentation products. Spinosad and spinetoram are structurally similar with both regis tered for application to numerous crops for control of foliage - feeding pests including lepidoptera larvae (worms or caterpillars), Colorado potato beetles, dipterous leafminers, thrips, and/or certain psyllids. The insecticidal mode of action for both spi nosad and spinetoram involves disruption of the nicotinic acetylcholine receptors. The Interregional Research Project No. 4 (IR - 4) requested Section 3 Registrations and permanent tolerances for foliar application of spinosad and spinetoram to coffee (se e Table 2.2.2.1 for proposed tolerances) . IR - 4 is also requesting l abel amendments for plum/p rune and Brassica (cole) l eafy v egetables c rop g roup 5 and updating existing spinosad and spinetoram crop group/subgroup commodity definitions to the following: b ulb vegetable crop group 3 - 07; fruiting vegetable crop group 8 - 10; citrus fruit crop group 10 - 10; pome fruit crop group 11 - 10; stone fruit crop group 12 - 12; caneberry crop subgroup 13 - 07A; bushberry crop subgroup 13 - 07B (except lingonberry); s mall fruit v ine climbing, except fuzzy kiwifruit, crop s ubgroup 13 - 07F; low growing berry crop subgroup 13 - 07G (except cranberry and lowbush blueberry), tree nut crop group 14 - 12; and cottonseed crop subgroup 20C . Hazard Assessment: Spinosad and spinetoram are con sidered toxicologically identical for the purposes of human health risk assessment based on their nearly identical chemical structures and similar toxicological profiles. The primary toxic effect observed from exposure to spinosad or spinetoram was histop athological changes in multiple organs (specific target organs were not identified). Vacuolization of cells and/or macrophages was the most common histopathological finding noted across both toxicological databases with the dog being the most sensitive sp ecies. In addition to the numerous organs observed with histopathological changes, anemia was noted in several studies. There was no evidence of increased quantitative or qualitative susceptibility from spinosad or spinetoram exposure. In developmenta l studies, no maternal or developmental effects were seen in rats or rabbits. In the rat reproduction toxicity studies, offspring toxicity (decreased litter size, survival, and body weights with spinosad; increased incidence of late resorptions and post i mplantation loss with spinetoram) was seen in the presence of parental toxicity (increased organ weights, mortality, and histopathological findings) at approximately the same dose for both chemicals. Dystocia and/or other parturition abnormalities were ob served with both chemicals in the reproduction toxicity studies. There was no evidence of neurotoxicity, immunotoxicity, or carcinogenicity from spinosad or spinetoram exposure. Food Quality Protection Act (FQPA) Safety Factor (SF) Decision: The RAB1 r isk assessment team recommends that the FQPA SF be reduced to 1X for all exposure scenarios based on the following considerations: (1) the toxicology database for spinosad/spinetoram is adequate for FQPA SF consideration; (2) there is no evidence of neuro toxicity from spinosad/spinetoram exposure; (3) there is no evidence of increased pre - or post - natal susceptibility; and (4) the exposure databases are sufficient and unlikely to underestimate exposure.

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### Dose Response Assessment: Tables 4.5.4.1 and 4.5.4.2 provide summaries of the toxicological doses and endpoints used for assessment of dietary and occupational /residential exposure, respectively. Assessment of acute dietary and dermal (all durations) exposure are considered unnecessary as no endpoint of co ncern attributable to a single dose was observed and no hazard was identified following dermal exposure. The chronic toxicity study (dog; NOAEL = 2.49 mg/kg/day) was selected for assessment of chronic dietary exposure. The subchronic oral toxicity study (dog; NOAEL = 4.9 mg/kg/day) was selected for assessment of incidental oral (short - and intermediate term) exposure and inhalation (short - and intermediate - term) exposure in both the residential and occupational settings. For all exposure scenarios, a 100 x uncertainty factor (UF) was applied (10x interspecies extrapolation; 10x for intraspecies variation; 1x FQPA SF (when applicable)). Residue Chemistry and Drinking Water Assessments: Adequate residue chemistry data have been submitted to support the establishment of the proposed tolerances . In addition, adequate data are available for the generation of modeled estimated drinking water concentrations (EDWCs). Dietary Risk Estimates (Food + Drinking Water ): A chronic dietary risk assessment was conducted using the Dietary Exposure Evaluation Model - Food Consumption Intake Database (DEEM - FCID, ve r. 3.16) which incorporates food consumption data from the United States Department of Ag riculture (USDA) National Health and Nutrition Examination Survey, What We Eat in America (NHANES/WWEIA; 2003 - 2008). Acute and cancer analyses were not conducted as toxicological effects attributable to a single dose were not identified and spinetoram and spinosad are classified as not likely to be carcinogens (cancer risk assessment is not required). The chronic analysis assumed 100% crop treated , average field - trial residues or tolerance - level residues for crop commodities , average residues fr o m the liv estock feeding studies, spinosad residue estimates for fish/shellfish (residues of spinetoram in fish/shellfish are expected to be insignificant) , experimental processing factors when available , and modeled drinking water estimates . The resulting chronic exposure estimates do not exceed HED's level of concern ( LOC; ≤ 64 % chronic population - adjusted dose (cPAD); children 1 - 2 years old were the most highly exposed subpopulation). Residential (Non - Occupational) Exposure and Risk Assessment: The proposed uses will not result in residential exposure. However, residential handler (s hort - term inhalation exposures ) and post application (short - term incidental oral ) exposures are expected as a result of the following registered uses (based on toxic ological considerations, assessment of dermal exposure is unnecessary) : (1) homeowner application of spinosad to gardens, turfgrass, and ornamentals ; (2) homeowner application of spinetoram to lawns, gardens, and ornamentals ; and (3) spot - on application o f spinetoram to cat s and kitten s . Residential exposure resulting from these existing uses were reassessed to conform with the most recent policies and guidance with all handler and post - application exposure estimates resulting in margins of exposure (MOEs ) which are not of concern to HED ( LOC for MOEs < 100; calculated MOEs were ≥ 720). Aggregate - Risk Estimates: In accordance with the FQPA, HED aggregate s dietary (food and water) and residential exposure to pesticide s. B ased on the anticipated exposure scenarios , and since acute and cancer risk assessments are not required, only short - term (residential, food, and water) and chronic (food and water) aggregate exposure assessments were conducted. The resulting aggregate exposure estimates do not exceed HED’s LOC (short - term MOEs ≥ 220 ; chronic exposure estimates ≤64% cPAD ) . HED notes that the short - term aggregate risk assessment is protective of intermediate - term exposure as the short - / intermediate - term PODs are identical.

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### Occupational Exposure a nd Risk Assessment: Occupational exposure assessments were only conducted for the proposed coffee use as the application scenarios for the proposed updates to the crop group/subgroup commodity definitions are identical to those currently registered ( label amendment requests also do no warrant a new occupational exposure assessment ) . For the scenarios where baseline data are available, all inhalation risks for occupational handlers are not of concern to HED (i.e., MOE> the LOC of 100) with baseline protect ion (i.e., long - sleeve shirt, long pants, shoes, and socks) . Only engineering control data (i.e., enclosed cockpits) are available for aerial application scenarios. All inhalation risks for occupational aerial applicators are above the LOC (100) with bas eline clothing and enclosed cockpits . A quantitative occupational post - application inhalation exposure assessment was not performed as it is expected that handler inhalation exposure estimates, which included the airblast scenario, are protective of post - application inhalation exposure scenarios. Since no hazard was identified via the dermal route of exposure, dermal exposure assessments were not performed . Reentry Interval (REI): Spinosad and spinetoram are classified as Toxicity Category III or IV based upon data for acute dermal toxicity, acute inhalation toxicity, primary skin irritation, and primary eye irritation. Typically, the REI specified on the proposed label is based on the acute toxicity of the active ingredient. Under 40 CFR 156.208 (c ) (2) (iii), active ingredients classified as Acute III or IV for acute dermal, eye irritation, and primary skin irrigation are assigned a 12 - hour REI. However, it is noted that the proposed product label has a 4 - h ou r REI listed. REIs may be further redu ced from 12 hours if certain criteria are met for both the technical material and the different end - use products in accordance with the Pesticide Registration (PR) Notice 95 - 3 ( Reduction of Worker Protection Standard (WPS) Interim REIs for Certain Low Risk Pesticides ; http://www.epa.gov/PR_Notices/pr95 - 3.html ) . Based only on the acute toxicity categories, spinosad and spinetoram are possible candidates for a 4 - h ou r REI ; however, RD should ensure tha t the additional criteria listed in PR Notice 95 - 3 a re met for both a ctive ingredients and the end - use product s . Environmental Justice Considerations: Potential areas of environmental justice concerns, to the extent possible, were considered in this h uma n health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and Low - Income Populations.” Review of Human Research : This risk assessment relies in part on data from stu dies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from the Pesticide Handlers Exposure Database (PHED) 1.1, the Agricultural Handler Exposure Task Force (AHETF) database, and the Agricultural Reentry Task Force (ARTF) database are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the following Agency websites: http://www.epa.gov/p esticides/science/handler - exposure - data.html and http://www.epa.gov/pesticides/science/post - app - exposure - data.html .

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### 2.0 Recommendations Spinosad: Provided revised Sections B and F are submitted, HED concludes that the toxicological, residue chemistry , and occupational/residential exposure (ORE) database s support the proposed label amendments, an unconditional coffee registration, and establishment of the permanent tolerances detailed in Table 2.2.2.1. In addition, per the request of RD , HED determined that the current asparagus tolerance of 0.2 ppm is incorrect and should be 0.02 ppm as previously recommended by HED (D277485, G. Herndon, 6 - Aug - 200 1) . Spinetoram: Provided a revised Section F is submitted, HED concludes that the toxicological, residue chemistry , and ORE database s support the proposed label amendments, an unconditional coffee registration, and establishment of the permanent toleran ces detailed in Table 2.2.2.1. 2.1 Data Deficiencies/Data Needs Toxicology : None Residue Chemistry : Revised Section s B (see Section 2.3 .1 ) and F (see Section 2.2.2). ORE : Revised Section B (see Section 2.3 .2 ) . 2.2 Tolerance Considerations 2.2.1 Enforcement Analytical Method Spinosad: Method RES 94025 (GRM 94.02) is a high - performance liquid chromatography method with ultraviolet detection (HPLC/UV) method which was originally submitted for the determination of spinosyn A and D in/on cottonseed and related commodities (LOQ = 0.01 ppm for spinosyn A and D). The method was successfully subjected to an independent laboratory validation (ILV) as well as an EPA laboratory validation and has been forwarded to the Food and Drug Administration (FDA) for tolerance enforcement ( D228791, G. Herndon, 13 - Aug - 1996). The following additional methods have also been determined to be adequate for tolerance enforcemen t purposes and were forwarded to the FDA (LOQ = 0.01 ppm for all; D242940, G. Herndon, 18 - Feb - 1998; D237752, G. Herndon, 2 - Mar - 1998; D232203, G. Herndon, 2 - Mar 1998; D243795, G. Herndon, 2 - Mar - 1998): GRM 95.17 (leafy vegetables; HPLC/UV); GRM 96.09 (citru s; HPLC/UV); GRM 96.14 (tree nuts; HPLC/UV); GRM 95.04 (fruiting vegetables; HPLC/UV); GRM 94.02.S1 (cotton gin byproducts; HPLC/UV); and GRM 96.16 (multiple commodities; immunoassay method). Since the coffee magnitude of the residue data submitted in support of the current petition were generated using an immunoassay method very similar to the current enforcement method GRM 96.16 and since the study included adequate validation data, HED concludes that method GRM 96.16 is suitable for enforcement of th e spinosad coffee tolerances recommended herein. The remaining recommended tolerances reflect an update to the current crop group /subgroup commodity definitions and, therefore, the current enforcement methods are sufficient.

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### Spinetora m: Method GRM 05.04 is a HPLC /mass spectrometry ( MS ) /MS method which has been determined to be adequate for enforcement of the currently - established spinetoram plant tolerances and was forwarded to FDA (D325387, T. Bloem, 12 - Sep - 2007; D343662, T. Bloem, 12 - Sep - 2007). Since method GRM 05.04 has been validated on a wide - variety of crops (46695013.der), HED concludes that it is sufficient to enforce the coffee tolerances recommended as part of the current petition. The remaining recommended tolerances reflect an update to the current crop group /subgroup commodity definitions and, therefore, the current enforcement method is also sufficient. 2.2.2 Recommended Tolerances Table 2.2.2.1 is a summary of the petitioner - proposed and HED - recommended tolerances for spinosad (combined residues of spinosyns A and D) and spinetoram (combined residues of XDE 175 - J, XDE - 175 - L, ND - J, and NF - J ) . A revised Section F is requested for both spinosad and spinetoram which specifies the residue definitions indicated below and the commodity definitions/values indicated in Table 2.2.2.1. With the establishment of the tolerances listed in Table 2.2.2.1, the following spinosad and spinetoram tolerances should be deleted: cotton, undelinted seed; cranberry; grape; juneberry, lingonberry; okra; onion, green; pistachio; salal; strawberry; vegetable, bulb, group 3, except green onion; vegetable, fruiting, group 8; fruit, citrus, group 10; fruit pome, group 11; fruit stone, gr oup 12; caneberry, subgroup 13A; bushberry, subgroup 13B; and nut, tree, group 14. Spinosad (40 CFR 180.495(a)): Tolerances are established for residues of the insecticide spinosad, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only the sum of sp inosyn A (Factor A: CAS # 131929 - 60 - 7; (2 R ,3a S ,5a R ,5b S ,9 S ,13 S ,14 R ,16a S ,16b R ) - 2 - [(6 - deoxy - 2,3,4 - tri - O

- methyl - α - L - manno - pyranosyl)oxy] - 13 - [[5 - (dimethylamino) - tetrahydro - 6 - methyl - 2 H - pyran - 2 - yl]oxy] - 9 - ethyl - 2,3,3a,5a,5b,6,9,10,11,12,13,14,16a,16b - tetrade cahydro - 14 - methyl - 1 H - as i ndaceno[3,2 - d]oxacyclododecin - 7,15 - dione; and spinosyn D (Factor D; CAS # 131929 - 63 - 0; (2 S ,3a R ,5a S ,5b S ,9 S ,13 S ,14 R ,16a S ,16b S ) - 2 - [(6 - deoxy - 2,3,4 - tri - O - methyl - α - L - manno pyranosyl)oxy] - 13 - [[5 - (dimethyl - amino) - tetrahydro - 6 - methyl - 2 H - pyran - 2 - yl]oxy] - 9 - ethyl 2,3,3a,5a,5b,6,9,10,11,12,13,14,16a,16b - tetradecahydro - 4,14 - methyl - 1 H - as - i ndaceno[3,2 - d]oxacyclododecin - 7,15 - dione , calculated as the stoichiometric equivalent of spinosad . Spinetoram (40 CFR 180.635(a)): Tolerances are establis hed for residues of the insecticide s pinetoram , including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only the sum of XDE - 175 - J (1 - H - as - indaceno[3,2 - d]oxacyclododecin - 7,15 - dione, 2 - [(6 - deoxy - 3 - O - ethyl - 2,4 - di O - methyl - α - L - mannopyranosyl)oxy] - 13 - [[(2 R ,5 S ,6 R ) - 5 - (dimethylamino)tetrahydro - 6 - methyl - 2 Hpyran - 2 - yl] oxy] - 9 - ethyl - 2,3,3a,4,5,5a,5b,6,9,10,11,12,13,14,16a,16b - hexadecahydro - 14 - methyl - , ( 2 R ,3a R ,5a R ,5b S ,9 S , 13 S ,14 R ,16a S ,16b R ); XDE - 175 - L : 1 H - as - indaceno[3,2 - d]oxacyclododecin 7,15 - dione, 2 - [(6 - deoxy - 3 - O - ethyl - 2,4 - di - O - methyl - α - L - mannopyranosyl)oxy] - 13 - [[(2 R ,5 S ,6 R ) - 5 - (dimethylamino)tetrahydro - 6 - methyl - 2 H - pyran - 2 - yl]oxy] - 9 - ethyl - 2,3,3a,5a,5b,6,9,10,11, 12,13,14,16a,16b - tetradecahydro - 4,14 - dimethyl - , (2 S ,3a R ,5a S ,5b S ,9 S , 13 S ,14 R ,16a S ,16b S ); ND - J ((2 R ,3a R ,5a R ,5b S ,9 S , 13 S ,14 R ,16a S ,16b R ) - 9 - ethyl - 14 - methyl - 13 - [[(2 S ,5 S ,6R) - 6 - methyl - 5 - (methylamino)tetrahydro - 2 H - pyr an - 2 - yl]oxy] - 7,15 - dioxo - 2,3,3a,4,5,5a,5b,6,7,9,

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### 10,11,12,13,14,15,16a,16b - octadecahydro - 1 H - as - indaceno[3,2 - d]oxacyclododecin - 2 - yl - 6 - deoxy - 3 - O - ethyl - 2,4 - di - O - methyl - α - L - mannopyranoside); and NF - J ((2 R ,3 S ,6 S ) - 6 - ([(2 R ,3a R ,5a R ,5b S ,9 S , 13 S ,14 R ,16a S ,16b R ) - 2 - [(6 - deoxy - 3 - O - ethyl - 2,4 - di - O - methyl - α - L - mannopyranosyl)oxy] - 9 - ethyl - 14 - methyl - 7,15 - dioxo - 2,3,3a,4,5,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b - octadecahydro - 1 H - as indaceno[3,2 - d]oxacyclododecin - 13 - yl]oxy) - 2 - methyltetrahydro - 2 H - pyran - 3 - yl(methyl)formamide) , calculated as the stoichiometric equivalent of s pinetoram . Table 2.2.2.1: Tolerance Summary.

Commodity Proposed Tolerance (ppm) 1 HED Recommended Tolerance (ppm) Comments Spin osad (40 CFR 180.495(a)) Coffee, green bean 0.2 0.04 Based on the available field trial data and the Organization for Economic Co - operation and Development (OECD) tolerance - calculation procedure, a tolerance of 0.04 is appropriate for coffee (green bean); tolerances in/on instant coffee and roasted bean are unnecessary. Coffee, instant 0.4 -- Coffee, roasted bean 0.4 -- Onion, bulb, subgroup 3 - 07A 0.10 0.10 Based on the available data, the proposed update s to the crop group/subgroup commodity definitions are acceptable. Some of the tolerance values were updated to conform with current practices concerning significant figures and/or for purposes of harmonization. The commodity definitions for subgroups 13 - 07B and 13 - 07G should be as follows: Bushberry, subg roup 13 - 07B 1 and Berry, low growing, subgroup 13 - 07G, except cranberry. 2 Onion, green, subgroup 3 - 07B 2.0 4.0 Vegetable, fruiting, group 8 - 10 0.4 0.40 Fruit, citrus, group 10 - 10 0.3 0.30 Fruit, pome, group 11 - 10 0.20 0.20 Fruit, stone, group 12 - 12 0.20 0.20 Caneberry subgroup 13 - 07A 0.7 1.0 Nut, tree, group 14 - 12 0.10 0.10 Cottonseed subgroup 20C 0.02 0.02 Bushberry, subgroup 13 - 07B, except lingonberry 0.25 0.40 Fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13 - 07F 0.50 0.50 Grape, raisin -- 1.0 Berry, low growing, subgroup 13 - 07G, except blueberry, lowbush and cranberry 1.0 0.90 Spin etoram (40 CFR 180.635(a)) Coffee, green bean 0.2 0.04 Based on the available field trial data and the OECD tolerance - calculation procedure, a tolerance of 0.04 is appropriate for coffee (green bean); tolerances in/on instant coffee and roasted bean are unnecessary. Coffee, instant 0.4 -- Coffee, roasted bean 0.4 --

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Commodity Proposed Tolerance (ppm) 1 HED Recommended Tolerance (ppm) Comments Onion, bulb, subgroup 3 - 07A 0.10 0.10 Based on the available data, the proposed update s to the crop group/subgroup commodity definitions are acceptable. Some of the tolerance values were updated to conform with current practices concerning significant figures and/or for purposes of harmonizat ion. The commodity definitions for subgroups 13 - 07B and 13 - 07G should be as follows: Bushberry, subgroup 13 - 07B 1 and Berry, low growing, subgroup 13 - 07G, except cranberry. 2 Onion, green, subgroup 3 - 07B 2.0 2.0 Vegetable, fruiting, group 8 - 10 0.4 0.40 Fruit, citrus, group 10 - 10 0.3 0.30 Fruit, pome, group 11 - 10 0.20 0.20 Fruit, stone, group 12 - 12 0.20 0.30 Caneberry subgroup 13 - 07A 0.7 0.80 Fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13 - 07F 0.50 0.50 Nut, tree, group 14 - 12 0.10 0.10 Cottonseed subgroup 20C 0.04 0.04 Bushberry, subgroup 13 - 07B, except lingonberry 0.25 0.50 Berry, low growing, subgroup 13 - 07G, except blueberry, lowbush and cranberry 1.0 0.90 1 Lingonberry is a member of the 13 - 07B and 13 - 07G subgroups (also a member of the 13 - 07H subgroup but this is not relevant here). The lingonberry tolerance will default to the highest of these and, therefore, excluding lingonberry is unnecessary. 2 Si nce lowbush blueberry is not a member of the 13 - 07G subgroup, exclusion is unnecessary . Based on the magnitude of the residue data, a separate cranberry tolerance is required (D277485, G. Herndon, 6 - Aug - 2001) . 

### 2.2.3 Revisions to Petitioned - For Toleran ces Based on the available coffee field trial and processing data and the OECD tolerance calculation procedure, HED concludes that the coffee (green bean) tolerances listed in Table 2.2.2.1 are correct and tolerances in/on coffee processed commodities are unnecessary. The remaining revisions pertain to alterations to the tolerance value for purposes of harmonization (see Section 2.2.4) or revisions to the commodity definitions and/or tolerance values so as to conform with current practices. 2.2.4 International Harmonization There are currently Canadian and Codex maximum residue limits ( MRLs ) in/on several of the relevant crops or crop groups/subgroups (Mexican MRLs are not established in/on any of the relevant commodities). As detailed in D416068 (T. Bloem, 10 - Mar - 2015 ), the HED - recommended tolerances were harmonized with the Canadian and/or Codex MRLs when possible .

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### 2.3 Label Recommendations 2.3.1 Recommendations from Residue Reviews Spinosad: Provided a revised Entrust® SC ( soluble concentrate; EPA Reg. No. 62719 - 621) label is submitted which indicates that the maximum seasonal application rates consider foliar, soil, and /or seed treatment applications, HED concludes that the proposed application scenarios are supported by th e available data. 2.3.2 Recommendations from Occupational Assessment Spinosad and Spinetoram (note to RD) : Spinosad and spinetoram are classified as Toxicity Category III or IV based upon data for acute dermal toxicity, acute inhalation toxicity, pri mary skin irritation, and primary eye irritation. Typically, the REI specified on the proposed label is based on the acute toxicity of the active ingredient. Under 40 CFR 156.208 (c) (2) (iii), active ingredients classified as Acute III or IV for acute d ermal, eye irritation, and primary skin irrigation are assigned a 12 - hour REI. However, it is noted that the proposed product label has a 4 - h our REI listed. REIs may be further reduced from 12 hours if certain criteria are met for both the technical mate rial and the different end - use products in accordance with the PR Notice 95 - 3 ( Reduction of W PS Interim REIs for Certain Low Risk Pesticides ; http://www.epa.gov/PR_Notices/pr95 - 3.html ). Based only on the acute toxicity categories, spinosad and spinetoram are possible candidates for a 4 - h our REI; however, RD should ensure that the additional criteria listed in PR Notice 95 - 3 a re met for both active ingredients and the end - use product s . 2.3.3 Recommendations from Residential Assessment None.

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### 3.0 Introduction 3.1 Chemical Identity Spinosad, which consists of spinosyn A and spinosyn D (A:D of 85:15), is a fermentation product of Saccharopolyspora spinosad . Spinetoram, which consists of XDE - 175 - J and XDE 175 - L (J:L of 3:1), is derived from the synthetic modification of Saccharopolyspora spinosa fermentation products. The chemical structure and nomenclature for spinosad and spinetoram are presented in Tabl e 3.1.1 and 3.1.2 respectively. Table 3.1.1: Spinosad Nomenclature

Chemical Structure

Common name Spinosad Company experimental name XDE - 105 IUPAC name Spinosyn A: (2 R ,3a S ,5a R ,5b S ,9 S ,13 S ,14 R ,16a S ,16b R ) - 2 - (6 - deoxy - 2,3,4 - tri - O - methyl - α - L mannopyranosyloxy) - 13 - (4 - dimethylamino - 2,3,4,6 - tetradeoxy - β - D - erythropyranosyloxy) - 9 - ethyl 2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b - hexadecahydro - 14 - methyl - 1 H - 8 - oxacyclododeca[ b ] as indacene - 7,15 - dione Spinosyn D: (2 S ,3a

R ,5a S ,5b S ,9 S ,13 S ,14 R ,16a S ,16b R ) - 2 - (6 - deoxy - 2,3,4 - tri - O - methyl - α - L mannopyranosyloxy) - 13 - (4 - dimethylamino - 2,3,4,6 - tetradeoxy - β - D - erythropyranosyloxy) - 9 - ethyl 2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b - hexadecahydro - 4,14 - dimethyl - 1 H - 8 - oxacyclododeca[ b ] as - indacene - 7,15 - dione CAS name Spinosyn A: 2 - [(6 - deoxy - 2,3,4 - tri - O - methyl - α - L - manno - pyranosyl)oxy] - 13 - [[5 - (dimethylamino) - tetrahydro - 6 - methyl - 2 H

- pyran - 2 - yl]oxy] - 9 - ethyl - 2,3,3a,5a,5b,6,9,10,11,12,13,14,16a,16b tetradecahydro - 14 - methyl - 1 H - as - Indaceno[3,2 - d]oxacyclododecin - 7,15 - d ione Spinosyn D: 2 - [(6 - deoxy - 2,3,4 - tri - O - methyl - α - L - manno - pyranosyl)oxy] - 13 - [[5 - (dimethylamino) - tetrahydro - 6 - methyl - 2 H

- pyran - 2 - yl]oxy] - 9 - ethyl - 2,3,3a,5a,5b,6,9,10,11,12,13,14,16a,16b tetradecahydro - 4,14 - methyl - 1 H - as - Indaceno[3,2 - d]oxacyclododecin - 7,15 - dione CAS # Spinosyn A: 131929 - 60 - 7; Spinosyn D: 131929 - 63 - 0 Table 3.1.2: Spinetoram Nomenclature.

Compound Chemical Structure

XDE - 175 - J XDE - 175 - L

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Page 12 of 45 Table 3.1.2: Spinetoram Nomenclature. Common name Spinetoram (mixture of XDE - 175 - J and XDE - 175 - L) Company experimental name XDE - 175 - J : TSN104472; 3’ - O - ethyl 5,6 - dihydro spinosyn J; 175 - J XDE - 175 - L : TSN104480; 3’ - O - ethyl spinosyn L; 175 - L

IUPAC name XDE - 175 - J : (2 R ,3a R ,5a R ,5b S ,9 S ,13 S ,14 R ,16a S ,16b R ) - 13 - {[(2 R ,5 S ,6 R ) - 5 - (dimethylamino) - 6 - methyltetrahydro - 2 H

- pyran - 2 - yl]oxy} - 9 - ethyl - 14 - methyl - 7,15 - dioxo 2,3,3a,4,5,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b - octadecahydro - 1 H - as - indaceno[3,2 - d ]oxacyclododecin - 2 - yl 6 - deoxy - 3 - O - ethyl - 2,4 - di - O - methyl - alpha - L - mannopyranoside XDE - 175 - L: (2 S ,3a

R ,5a S ,5b S ,9 S ,13 S ,14 R ,16a S ,16 b S ) - 13 - {[(2 R ,5 S ,6 R ) - 5 - (dimethylamino) - 6 - methyltetrahydro - 2 H

- pyran - 2 - yl]oxy} - 9 - ethyl - 4,14 - dimethyl - 7,15 - dioxo 2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b - hexadecahydro - 1 H - as - indaceno[3,2 - d ]oxacyclododecin - 2 - yl 6 - deoxy - 3 - O - ethyl - 2,4 - di - O - methyl - alpha - L - mannopyranoside

CAS name XDE - 175 - J: 1 H - as - indaceno[3,2 - d ]oxacyclododecin - 7,15 - dione, 2 - [(6 - deoxy - 3 - O - ethyl - 2,4 - di - O methyl - a - L - mannopyranosyl)oxy] - 13 - [[(2 R ,5 S ,6 R ) - 5 - (dimethylamino)tetrahydro - 6 - methyl 2 Hpyran - 2 - yl]oxy] - 9 - ethyl - 2,3,3a,4,5,5a,5b,6,9,10,11,12,13,14,16a,16b - hexadecahydro 14 - methyl - (2 R ,3a R ,5a R ,5b S ,9 S ,13 S ,14 R ,16a S ,16b R ) XDE - 175 - L: 1 H

- as - indaceno[3,2 - d ]oxacyclododecin - 7,15 - dione,2 - [(6 - deoxy - 3 - O - ethyl - 2,4 - di - O methyl - a - L - mannopyranosyl)oxy] - 13 - [[(2 R ,5 S ,6 R ) - 5 - (dimethylamino)tetrahydro - 6 - methyl - 2 Hpyran - 2 - yl]oxy] - 9 - ethyl - 2,3,3a,5a,5b,6,9,10,11,12,13,14,16a,16b - tetradecahydro - 4,14 - dimethyl - (2 S ,3a R ,5a S ,5b S ,9 S ,13 S ,14 R ,16a S ,16b S ) CAS # XDE - 175 - J: 187166 - 40 - 1; XDE - 175 - L: 187166 - 15 - 0 

### 3.2 Physical/Chemical Properties The physical/chemical properties for spinosad and spinetoram are presented in Appendix C. Spinosad is moderately soluble in water, has a high Log K ow 

### , and is nonvolatile. S pinetoram is weakly soluble in w ater, has a high L og K ow 

### , and is nonvolatile . 3.3 Pesticide Use Pattern/Directions IR - 4 requested Section 3 Registrations for application of spinosad and spinetoram to coffee; label amendments which reduce the PHI for plums/prunes from 7 days to 1 day and permit applications directed to the base of Brassica (Cole) l eafy v egetables g roup 5 crops (only foliar application is currently registered) ; and updates to the crop group/subgroup tolerance commodity definitions for the following: b ulb vegetable crop group 3 - 07; f ruiting v egetable crop g roup 8 - 10; c itrus f ruit crop g roup 10 - 10; p ome f

r uit crop g roup 11 - 10; s tone f ruit crop g roup 12 - 12; c aneberry crop s ubgroup 13 - 07A; b ushberry crop s ubgroup 13 - 07B (except lingonberry); s mall f ruit v ine c limbing, e xcept f uzzy k iwifruit , crop s ubgroup 13 - 07F; low growing b erry crop s ubgroup 13 - 07G (except cranberry and lowbush blueberry), t ree n ut c rop g roup 14 - 12; and c ottonseed crop s ubgroup 20C . Table 3.3.1 is a summary of the end - use products and target pests and Table 3.3.2 is a summary of the proposed application scenarios. Since the application scenarios for the crop group/subgroup commodity updates are identical to that currently registered, they are not included in Tables 3.3.1 and 3.3.2. The proposed labels also specify the following: (1) adjuvants may be added to the spray sol ution; (2) excluding the spinetoram labels concerning application to citrus grown in Florida, the labels specify a minimum spray volume for ground and aerial application of 5 gallons per acre (GPA) and 3 GPA (10 GPA for tree, vine, grove, and orchard crops ), respectively; the minimum spray volume for ground application of spinetoram to citrus grown in Florida is 2 GPA; (3) applications to crops grown in a greenhouse are permitted on the spinosad label but are prohibited on the spinetoram labels; (4) the spi nosad label does not specify any rotational crop restrictions while the spinetoram

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### labels indicates that labeled crops may be rotated immediately to a treated field and nonlabeled crops may be rotated 30 days after application; and (5) REI = 4 hours. HED request revised labels as described in Section 2.3. Table 3 .3.1: Summary of End - Use Products. Trade Name Conc. Formulation Label Date Target Crops Target Pests Spinosad Entrust® SC (EPA Reg. No. 62719 - 621) 2 lb

ai/gallon soluble

concentrate not

specified coffee; Brassica (Cole) leafy vegetables group 5 ; bulb

vegetable group 3 - 07; fruiting vegetable group 8 - 10; citrus fruit group 10 - 10; pome fruit group 11 - 10; stone fruit group 12 - 12; caneberry subgroup 13 - 07A; bushberry subgroup 13 - 07B (except lingonberry); s mall fruit vine climbing, except fuzzy kiwifruit s ubgroup 13 - 07F; low growing berry subgroup 13 - 07G (except cranberry and lowbush blueberry), tree nut crop group 14 - 12; and cottonseed subgroup 20C Foliage feeding pests including lepidoptera larvae (worms or caterpillars), Colorado potato beetles, leafminers, and thrips. Spinetoram Delegate® WG (EPA Reg. No. 62719 - 541) 25% water dispersible granule not

specified coffee; Brassica (Cole) leafy vegetables group 5 ; bulb

vegetable group 3 - 07; fruiting vegetable group 8 - 10; citrus fruit group 10 - 10; pome fruit group 11 - 10; stone fruit group 12 - 12; caneberry subgroup 13 - 07A; bushberry subgroup 13 - 07B (except lingonberry); s mall fruit vine climbing, except fuzzy kiwifruit s ubgroup 13 - 07F; low grow ing berry subgroup 13 - 07G (except cranberry and lowbush blueberry), tree nut crop group 14 - 12; and cottonseed subgroup 20C Foliage feeding pests including lepidoptera larvae (worms or caterpillars), Colorado potato beetles, dipterous leafminers, thrips, an d certain psyllids. Radiant® SC (EPA Reg. No. 62719 - 545) 1 lb

ai/gallon soluble

concentrate not

specified Table 3.3.2: Summary of Proposed Application Scenarios . App. Timing ; Type ; and Equip. Formulation Single App. Rate ( lb ai/acre ) Max. # A pp s . Max. A pp. Rate ( lb ai/acre ) PHI

(days) Use Directions and Limitations c offee foliar broadcast spray Spinetoram -

Radiant® Delegate® 0.03 - 0.08 6 0.30 7 - RTI = 5 days

- Do not make more than two consecutive applications. Spinosad - Entrust® 0.06 - 0.16 6 0.45 7 - RTI = 5 days

- Do not make more than three consecutive applications. plum/prune 1 foliar broadcast spray Spinetoram -

Radiant® Delegate® 0.05 - 0.11 4 0.44 1 - RTI = 3 - 7 days

- Do not make more than three consecutive applications. Spinosad - Entrust® 0.06 - 0.12 -- 0.45 1 - RTI = 7 days

- Do not make more than two consecutive applications. Brassica (Cole) leafy vegetables group 5 crops 2 foliar broadcast spray Spinetoram -

Radiant® 0.04 - 0.08 6 0.27 1 - RTI = 4 days; includes instructions for application to the base of the crop Spinosad - Entrust® 0.02 - 0.16 6 0.45 1 - RTI = 4 days; includes instructions for application to the base of the crop 1 The proposed application scenario is identical to that currently registered except for a reduction in the PHI from 7 days to 1 day. 2 The proposed application scenario is identical to that currently registered except for the addition of instructions con cerning application to the base of the crop (currently only foliar application is registered).

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### 3.4 Anticipated Exposure Pathways Spinosad and spinetoram are registered for application to numerous food/feed crops; spinosad is also registered for appl ication as a mosquito larvicide and for application to livestock premises. As a result of these uses, dietary (food and water) exposure to spinosad and spinetoram is possible including exposure to spinosad residues in fish/shellfish as a result of the mos quito larvicide use ; based on the registered uses, spinetoram residues in fish/shellfish are unlikely . Residential exposure to spinosad and spinetoram is also possible as a result of the registered turf, ornamental, garden, and/or pet spot - on uses. 3.5 Consideration of Environmental Justice Potential areas of environmental 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 Address Environmen tal Justice in Minority Populations and Low - Income Populations,” ( http://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf ). As a part of every pesticide risk ass essment, OPP consider s a large variety of consumer subgroups according to well - established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and wat er consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the NHANES/WWEIA (2003 - 2008) and are used in pesticide risk assessments f or all registered food uses of a pesticide. These data are analyzed and categorized 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 subgr oups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non - dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults enter ing or playing on tre ated areas postapplication 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 traditional dietary patterns among specific subgroups.

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### 4.0 Hazard Characterization and Dose - Response Assessment Spinosad and spinetoram are nearly identical structurally. Spinosad consists of spinosyn A and D, wh ile spinetoram consists of factors J and L (see Section 3.1 ). The pesticidal mode action for both chemicals is the disruption of nicotinic/gamma amino butyric acid (GABA) - gated chloride channels. 4.1 Toxicology Studies Available for Analysis The HED Hazard Assessment and Policy Committee (HASPOC) concluded that spinosad and spinetoram should be considered toxicologically identical for the purposes of human health risk assessment based on their nearly identical chemical structures and similar toxicolog ical profiles ( D340521, P. Shah , 18 - J un - 2007). As a result, the toxicological databases for spinosad and spinetoram are considered together for evaluation. The HASPOC also noted that this is not a cumulative assessment. Spinosad and spinetoram should be considered toxicologically identical in the same manner that metabolites are generally considered toxicologically identical to a parent compound. The toxicological database for spinosad/spinetoram is adequate for hazard characterization, toxicity endpoin t selection, and FQPA SF evaluation. An immunotoxicity study with spinosad (MRID 48329601) has been submitted since the last risk assessment and the results incorporated into the current assessment. HED previously requested a subchronic inhalation study to characterize the effects of spinosad/spinetoram via the inhalation route; however, the registrant submitted a waiver request as well as a 14 - day inhalation study with spinosad (MRID 49425601) showing no effects up to the highest dose tested (9.5 mg/m 3 

### ). Although this study did not dose high enough to elicit adverse effects, it did demonstrate that exposure via the inhalation route was not more sensitive than the or al route. As a result, the HASPOC concluded using a weight of - evidence approach that the subchronic inhalation study is not required at this time (U. Habiba, 15 - OCT - 2014, TXR #0057052). 4.2 Absorption, Distribution, Metabolism, and Excretion (ADME) Spinosad: There were no major differences between the bioavailability, routes of excretion, or metabolism of radiolabeled spinosyn A and spinosyn D in rats following oral administration. Approximately 80% (spinosyn A) and approximately 66% (spinosyn D) of the administered dose was absorbed with the remaining dose eliminated as unchanged parent i n the feces. The major elimination route was fecal excretion for both spinosyn A (82 - 87% of the administered dose) and spinosyn D (84 - 92% of the administered dose). Excretion via the urine ranged from 7 - 10% and 3 - 5% of the administered dose for spinosyn A and spinosyn D, respectively. In bile - cannulated rats with spinosyn D, 28 - 40% of the administered dose was found in the bile. Blood levels after single and multiple doses of spinosyn A (10 mg/kg) were highest 1 hour after dosing in both sexes. Half

- li ves (t max 

### ) at this dose were 6 and 12 hours after dosing in males and females, respectively. The tissues and carcass contained very low levels of radioactivity 168 hours post dosing (<3% of the administered dose). The primary fecal, urinary , and biliary metabolites were identified as the glutathione conjugates of the parent and N - and O - demethylated forms of the parent.

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### Spinetoram: There were no major differences between the bioavailability, routes of excretion, or metabolism of radiolabeled Factor J an d Factor L in rats following oral administration. Absorption was ≥70% for both Factor J and Factor L with measurements in the plasma as soon as 15 minutes after administration. After 168 hours, 88 - 97% and 90 - 95% of the administered dose was recovered for Factor J and Factor L, respectively. The majority was recovered in excreta within 24 hours of dosing. The major route of elimination was fecal excretion (77 - 92% and 79 - 87% of the administered dose for Factor J and Factor L, respectively) with unchanged parent in the feces accounting for 7 - 26% of the eliminated radioactivity. Excretion via the urine ranged from 3 - 10% and 2 - 4% of the administered dose for Factor J and Factor L, respectively. Animals given an intravenous dose of Factor J eliminated a larg er proportion of radioactivity in the urine and elimination of radioactivity in the feces was prolonged compared to orally - dosed animals; however the total amount excreted in the feces was similar regardless of route of administration indicating that a lar ge portion of orally - administered chemical would be eliminated in the feces via biliary excretion. For Factor J, 0.2 - 3% of the administered dose was found in the carcass 168 hours post - dosing with ≤0.4% measured in all other tissues. For Factor L, 1 - 6% a nd 0.4 - 6% of the administered dose was found in the carcass and skin, respectively, 168 hours post - dosing with ≤0.6% measured in all other tissues. The primary metabolites were identified as the glutathione and cysteine conjugates of the parent and N - and O - demethylated forms of the parent. Dermal Absorption : There are no dermal absorption studies available for spinosad /spinetoram; however, no hazard was identified for dermal exposure to spinosad or spinetoram (see Section 4.5.1) . As a result, a dermal absorption factor is not needed because a quantitative dermal assessment was not performed. 4.3 Toxicological Effects The primary toxic effect observed from exposure to spinosad or spinetoram was histopathological changes in multiple organs (specific t arget organs were not identified). Vacuolization of cells and/or macrophages was the most common histopathological finding noted across both toxicological databases with the dog being the most sensitive species. In addition to the numerous organs observe d with histopathological changes, anemia was noted in several studies. There was no evidence of increased quantitative or qualitative susceptibility from spinosad or spinetoram exposure. In developmental studies, no maternal or developmental effects we re seen in rats or rabbits. In the rat reproduction toxicity studies, offspring toxicity was seen in the presence of parental toxicity at approximately the same dose for both chemicals (75 - 100 mg/kg/day). Parental toxicity was evidenced by increased orga n weights, mortality, and histopathological findings in several organs. Offspring effects included decreased litter size, survival, and body weights with spinosad while an increased incidence of late resorptions and post - implantation loss was seen with sp inetoram. Dystocia and/or other parturition abnormalities were observed with both chemicals. Spinosad and spinetoram are classified as having low acute toxicity via the oral, dermal, and inhalation routes of exposure (Toxicity Category III or IV). Neith er chemical is an eye or dermal irritant. Spinetoram was found to be a dermal sensitizer. In acute and subchronic neurotoxicity studies, there was no evidence of neurotoxicity from exposure to spinosad or spinetoram. In an

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### immunotoxicity study with spin osad, systemic effects (decreased body weights, increased liver weights, and abnormal hematology results) were seen at the highest dose tested (141 mg/kg/day); however , there was no evidence of immunotoxicity. Spinosad and spinetoram are classified as “no t likely to be carcinogenic to humans” based on lack of evidence of carcinogenicity in mice and rats and negative findings in mutagenicity assays (see Section 4.5.3). 4.4 Safety Factor for Infants and Children (FQPA SF) The RAB1 risk assessment team recommends that the FQPA SF be reduced to 1X for all exposure scenarios based on the following considerations outlined in more detail in the sections below: (1) the toxicology database for spinosad/spinetoram is adequate for FQPA SF consideration; (2) the re is no evidence of neurotoxicity from spinosad/spinetoram exposure; (3) there is no evidence of increased pre - or post - natal susceptibility; and (4) the exposure databases are sufficient and unlikely to underestimate exposure. 4.4.1 Completeness of the Toxicology Database The existing toxicological database is adequate for characterizing spinosad/spinetoram toxicity and quantification of hazard for dietary and occupational exposures. Developmental toxicity studies in rats and rabbits and two - generatio n reproduction toxicity studies in rats are available to assess potential fetal/offspring sensitivity. Acute and subchronic neurotoxicity studies in rats are available to assess potential neurotoxicity due to spinosad/spinetoram exposure. 4.4.2 Evidence of Neurotoxicity There is no evidence of neurotoxicity from spinosad/spinetoram exposure. 4.4.3 E vidence of Sensitivity/Susceptibility in the Developing or Young Animal There is no evidence of quantitative or qualitative susceptibility to offspring in the developmental studies with rats and rabbits or the rat reproduction toxicity studies (see Section 4.3). 4.4.4 Residual Uncertainty in the Exposure Database The dietary exposure assessment is considered conservative as it assumed 100% crop treat ed and residue estimates based on field trial data. The residential exposure assessment is also considered conservative as it incorporated default assumptions from the 2012 Residential SOPs . 4.5 Toxicity Endpoint and Point of Departure Selections As noted previously, the HASPOC concluded that spinosad and spinetoram should be considered toxicologically equivalent for the purposes of human health risk assessment (P. Shah; 18 - JUN 2007; D340521); therefore, studies from both toxicological databases we re considered for

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### endpoint selection. No changes have been made to toxicity endpoints and points of departure since the last risk assessment for spinosad/spinetoram (T. Bloem; 12 - OCT - 2010; DP#376415) except one endpoint was selected to assess short - and i ntermediate - term durations for incidental oral exposure scenarios and one endpoint was selected to assess short - and intermediate - term durations for inhalation exposure scenarios. 4.5.1 Dose - Response Assessment Acute Dietary Endpoint (all populations) : There were no effects observed attributable to a single dose. Therefore, an endpoint was not selected for this exposure scenario. Chronic Dietary Endpoint (all populations) : Chronic dietary exposures were assessed using the spinetoram chronic oral toxi city study in dogs. The LOAEL of 5.36 mg/kg/day is based on arteritis and necrosis of the arterial walls of the epididymides in males and of the thymus, thyroid, larynx, and urinary bladder in females. The study and endpoint are appropriate for the route and duration of exposure. It is protective of adverse effects seen in rats, mice, and dogs after chronic repeated exposures to spinosad or spinetoram. The cPAD of 0.0249 is based on the NOAEL of 2.49 mg/kg/day from the chronic oral toxicity study in dog s and a 100 - fold uncertainty factor (10X for interspecies extrapolation, 10X for intraspecies extrapolation, and 1X for FQPA SF). Incidental Oral Exposure (short - and intermediate - term) : The spinosad subchronic oral toxicity study in dogs was chosen for evaluating incidental oral exposures with a NOAEL of 4.9 mg/kg/day. The LOAEL of 9.73 mg/kg/day is based on microscopic changes in multiple organs, clinical signs, decreases in body weight and food consumption, biochemical evidence of anemia, and liver da mage. This endpoint is protective of adverse effects seen in rats, mice, and dogs after subchronic repeated exposures to spinosad or spinetoram. The LOC for incidental oral exposures is 100 (10X for interspecies extrapolation, 10X for intraspecies extrap olation, and 1X for FQPA SF). Dermal Endpoints (all durations) : A dermal endpoint was not selected. Since there is no concern for enhanced sensitivity/susceptibility to offspring from spinosad/spinetoram exposure, the effects of concern in adults and of fspring are adequately assessed in the dermal toxicity studies with spinosad and spinetoram where no adverse dermal or systemic effects were observed up to the limit dose (1000 mg/kg/day). Inhalation Endpoints (short - and intermediate - term) : The spinosad subchronic oral toxicity study in dogs was chosen for evaluating inhalation exposures with a NOAEL of 4.9 mg/kg/day. The LOAEL of 9.73 mg/kg/day is based on microscopic changes in multiple organs, clinical signs, decreases in body weight and food consump tion, biochemical evidence of anemia, and liver damage. This endpoint is protective of adverse effects seen in rats, mice, and dogs after subchronic repeated exposures to spinosad or spinetoram. The LOC for inhalation exposures is 100 (10X for interspeci es extrapolation, 10X for intraspecies extrapolation, and 1X for FQPA SF when applicable). Inhalation exposure is assumed to be equivalent to oral exposures.

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### 4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment When there are pote ntial occupational and residential exposures to a pesticide, the risk assessment must address exposures from three major routes (oral, dermal, and inhalation) and determine whether the individual exposures can be combined if they have the same toxicologica l effects. For short - and intermediate - exposures, incidental oral and inhalation exposures can be combined for spinosad/spinetoram since the same endpoint was chosen for both routes. No dermal endpoint was selected. 4.5.3 Cancer Classification and Risk Assessment Recommendation A cancer risk assessment is not required. The Agency classified spinosad as “not likely to be carcinogenic to humans” by all routes of exposure based upon lack of evidence of carcinogenicity in rats and mice. Based on the stru ctural similarity of spinosad and spinetoram and similarities of the toxicological databases for these chemicals, spinetoram is classified as “not likely to be carcinogenic to humans” based on the spinosad carcinogenicity studies. Carcinogenicity studies with spinetoram have been submitted. No evidence of carcinogenicity was observed in rats. The carcinogenicity study in mice is currently under review and preliminary review yields no evidence of carcinogenicity. Mutagenicity studies conducted with spine toram were also negative. 4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment Table 4.5.4.1 : Summary of Toxicological Doses and Endpoints for Spinosad/Spinetoram for Use in Dietary and Non Occupational Human Health Risk Assessments . Exposure/ Scenario Point of Departure Uncertainty/FQPA

Safety Factors RfD, PAD, LOC for

Risk Assessment Study and Toxicological Effects Acute Dietary (All Populations) A dose and endpoint of concern attributable to a single dose was not observed. Chronic Dietary (All Populations) NOAEL =

2.49 mg/kg/day UF A = 10X

UF H = 10X FQPA = 1X cRfD = 0.0249

mg/kg/day cPAD = 0.0249 mg/kg/day Chronic Toxicity

– Dog (Spinetoram)

LOAEL = 5.36/5.83 mg/kg/day (males/females) based on arteritis and necrosis of the arterial walls of the epididymides in males and of the thymus, thyroid, larynx, and urinary bladder in females Incidental Oral Short - Term (1 - 30 days) and Intermediate - Term (1 - 6 months) NOAEL =

4.9 mg/kg/day UF A = 10X

UF H = 10X FQPA = 1X Residential LOC for

MOE < 100 Subchronic Oral Toxicity

– Dog (Spinosad)

LOAEL = 9.73 mg/kg/day based on microscopic changes in multiple organs, clinical signs of toxicity, decreases in body weights and food consumption, and biochemical evidence of anemia and liver damage Dermal (All durations) No hazard was identified for dermal exposure; therefore a quantitative dermal assessme nt is not

needed.

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Page 20 of 45 Table 4.5.4.1 : Summary of Toxicological Doses and Endpoints for Spinosad/Spinetoram for Use in Dietary and Non Occupational Human Health Risk Assessments . Exposure/ Scenario Point of Departure Uncertainty/FQPA

Safety Factors RfD, PAD, LOC for

Risk Assessment Study and Toxicological Effects Inhalation Short - Term (1 - 30 days) and Intermediate - Term (1 - 6 months) NOAEL =

4.9 mg/kg/day Inhalation assumed equivalent to oral UF A = 10X

UF H = 10X FQPA = 1X Residential LOC for

MOE < 100 Subchronic Oral Toxicity

– Dog (Spinosad)

LOAEL = 9.73 mg/kg/day based on microscopic changes in multiple organs, clinical signs of toxicity, decreases in body weights and food consumption, and biochemical evidence of anemia and liver damage Cancer (oral, dermal, inhalation) Classified as “ not li kely to be carcinogenic to humans” Point of Departure (POD) = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. 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 L = use of a LOAEL to extrapolate a NOAEL. FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. Tab le 4.5.4.2 : Summary of Toxicological Doses and Endpoints for Spinosad/Spinetoram 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 (All durations) No hazard was identified for dermal exposure; therefore a quantitative dermal assessment is not

needed. Inhalation Short - Term (1 - 30 days) and Intermediate - Term (1 - 6 months) NOAEL =

4.9 mg/kg/day Inhalation assumed equivalent to oral UF A = 10X

UF H = 10X Occupational LOC

for MOE < 100 Subchronic Oral Toxicity

– Dog (Spinosad)

LOAEL = 9.73 mg/kg/day based on microscopic changes in multiple organs, clinical signs of toxicity, decreases in body weights and food consumption, and biochemical evidence of anemia and liver damage Cancer (oral, dermal, inhalation) Classified as “ not likely to be carcinogenic to humans” Point of Departure (POD) = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adver se effect level. LOAEL = lowest observed adverse effect level. UF = uncertaint y factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. MOE = margin of exposure. LOC = level of con cern.

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### 5.0 Dietary Exposure and Risk Assessment residue chemistry summary: D416068, T. Bloem, 10 - Mar - 2015 dietary exposure memorandum: D423657, T. Bloem, 10 - Mar - 2015 5.1 Residues of Concern Summary and Rationale Tables 5.1.1 and 5.1.2 are summaries of the residues of concern for dietary risk assessment and the tolerance expression for spinosad and spinetoram, respectively. The following paragraphs are brief summaries of the available metabolism data. Spinosad: The metabolic pathway in crops (primary and rotational), livestock, fish, and rat were similar and involved demethylation of the forosamine ring, demethylation of the rhamnose ring, and/or hydroxylation of the macrolide . In primary crops, spinosad was fur ther degraded to multiple low molecular weight compounds which are subsequently incorporated into natural plant constituents. Spinetoram: The metabolic pathway in crops, livestock, and rats were qualitatively similar. The metabolic pathway in primary cr ops involved demethylation of the forosamine ring, changes to the rhamnose ring producing the 3 - O - deethyl, and/or cleavage of the rhamnose ring. Parent and the metabolites were ultimately subjected to opening of the macrolide ring system at several positi ons resulting in numerous components with this pathway predominating in the residue profile. The confined rotation crop study resulted in a similar metabolic profile as primary crops (soil application at 0.45 lb ai/acre). No significant metabolism of spi netoram was observed in ruminants , as the unchanged parent molecule was the primary residue component identified in milk and tissue samples. Ruminant liver and muscle contained one unidentified metabolite (XDE - 175 - J labeled study - <10% TRR; XDE - 175 - L labeled study - <27% TRR) and minor amounts of ND - J and ND - L. In hen, parent was the major residue in egg and all tissues except liver where parent and the demethylated and/or deethylated metabolites predominated. In the rat, the major route of metabolis m was found to be glutathione conjugation with the parent compound, as well as glutathione conjugation with N - demethylated, O - deethylated, and hydroxylated forms of parent. Table 5.1.1: Residues for Tolerance Expression and Risk Assessment for Spinosad. Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants 1 spinosyn A and D spinosyn A and D Hog and Ruminants 1 oral and dermal - spinosyn A and D oral and dermal - spinosyn A and D Poultry 1 ,2 oral - spinosyn A and D ; dermal (excluding liver) - spinosyn A

and D ; dermal (liver) - spinosyns A, B, D, J, N - demethyl D, and N - demethyl J oral and dermal spinosyn A and D Rotational Crops 1 spinosyn A and D spinosyn A and D Drinking Water 3 total spinosad -- Fish/Shellfish 4 adjustment of the TRRs in the edible tissues from the spinosyn A

bioconcentration study (19 ppb data) for the EFED water concentration resulting from the mosquito larvicide use spinosyn A and D 1 D243816 , G. Herndon, 0 3 - Mar - 1998 ; D264984 , W. Donovan, 14 - Jun - 2002 . 2 D374794 , T. Bloem, 25 - Mar - 2010 . 3 D316077 , T. Bloem et al. , 0 2 - Aug - 2006 . 4 HED notes that these conclusions are appropriate for this mosquito larvicide petition only and will be reevaluated if the petitioner alters the aquati c application scenario (D316077, T. Bloem et al , 0 2 - Aug - 2006) .

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Page 22 of 45 Table 5.1.2: Residues for Tolerance Expression and Risk Assessment . Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants XDE - 175 - J, XDE - 175 - L, N D - J , and N F - J XDE - 175 - J, XDE - 175 - L, N D - J , and N F - J Rotational Crops Not determined. Based on the available data and provided the application rate is ≤0.45 lb ai/acre, the following

rotational crop restrictions are appro priate : labeled crops may be rotated immediately to a treated field and nonlabeled crops may be rotated 30 days after application. Ruminants 1 XDE - 175 - J , XDE - 175 - L , N D - J , and NF - J XDE - 175 - J, XDE - 175 - L, ND - J, and NF - J Hen 1 XDE - 175 - J , XDE - 175 - L, ND - J, NF - J, 3' - O - deethyl - 175 - J,

3' - O - deethyl - 175 - L , and O - demethyl - 175 - L 2 XDE - 175 - J, XDE - 175 - L, ND - J, and NF - J 1 ND - J and NF - J were included as residues of concern in livestock due to their presence in/on feed commodities. 2 O - demethyl - 175 - L is either 2’ - O - demethyl - 175 - L or 4’ - O - demethyl - 175 - L or a mixture of both. 

### 5.2 Food Residue Profile Magnitude of the Residue Primary Crops: In support of the proposed application to coffee (spinosad and spinetoram), PHI reduction for plum/prune (spinosad and spinetoram), and the addition of instructions permitting application directed to the base crop group 5 crops (spinosad and spinetoram), t he petitioner submitted adequate coffee (included processing data), plum (included processing data), and broccoli/cabbage field trial data. The remaining propos als pertain to updates to the crop group/subgroup tolerance commodity definitions ; s ince the pr oposed application scenario s for crops a re identical to that previously reviewed, no residue data were submitted and none are required. HED concludes that the available magnitude of the residue data are adequate and support the HED recommended tolerance l isted in Table 2.2.2.1 (a revised Section F is requested) . It is noted that the currently established spinosad and spinetoram stone fruit ( i.e. , plum) and crop group 5 tolerances are adequate to cover the proposed label amendments. Magnitude of the Residue – Rotational Crops : Based on the results of a spinosad confined rotational crop study and the proposed application rates, HED concludes that no rotational crop re strictions or tolerances are required for the currently - proposed cro ps ( D243816, G. Herndon, 0 3 - Mar - 1998 ) . Field rotational crop data have not been submitted and are not required. Based on the results of a spinetoram confined rotational crop study and the proposed application rates, HED concludes that the proposed 30 - d ay plant - back interval ( PBI ) for all nonlabeled crops is appropriate ( 46695021.der.doc; 47396301.der.doc ). Magnitude of the Residue – Livestock: Since coffee, plum, and crop group 5 do not include any significant ruminant/hog/poultry feed commodities a nd since the proposed application scenario for the remaining crops is identical to that previously assessed, HED concludes that a discussion concerning the magnitude of the residue in meat, milk, poultry, and eggs is unnecessary. 5.3 Water Residue Profile Drinking water residues were incorporated directly into the chronic dietary analyses ( “water, direct, all sources” and “water, indirect, all sources”) and were provided by EFED using the following models (D415816, L. Liu, 19 - Feb - 2015; D 325409 , L. Liu, 14 - May - 200 7) : Surface Water Concentration Calculator (SWCC) and S creening C oncentration i n G ro und W ater (SCIGROW ). Table 5.3.1 is a summ ary of the modeled water concentrations. Based on these estimates, the chronic analysis assumed a water residue estimate of 21.7 ppb. The models and their description are available at the EPA internet site: http://www.epa.gov/ oppefed1/models/water/ .

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### EFED provided Pesticide Root Zone Model

– Groundwater (PRZM - GW) EDWCs for spinosad and spinetoram using only the pro po sed application scenarios. The resulting EDWCs were significantly lower than the surface water EDWCs generated using the same application scenario and the SWCC model. Based on this, HED conc ludes that generation of PRZM - GW EDWCs using the spinosad/spinetoram turf application scenario is unnecessary. Table 5.3.1 : E DWCs for Spinosad/Spinetoram ( ppb) . Surface/Ground (Model) Acute Chronic Long - term average spinosad (turf application scenario; 4 x 0.4 lb ai/acre; RTI = 7 days) 1 s urface (SWCC) 25.0 21.7 14.2 ground (SCIGROW) 1.1 1.1 1.1 spinetoram (turf and fire ant mound application; 1 x 0.454 lb ai/acre) 1 surface (SWCC) 8.6 5.9 3.8 ground (SCIGROW) 0.072 0.072 0.072 1 D415816, L. Liu, 19 - Feb - 2015; D 325409 , L. Liu, 14 - May - 2007 

### 5.4 Dietary Risk Assessment 5.4.1 Summary of Dietary Exposure/Risk Estimates A chronic dietary risk assessment was conducted using DEEM - FCID ( ve r. 3.16) which incorporates food consumption d ata from the USDA NHANES/WWEIA ( 2003 - 2008). Acute and cancer analyses were not conducted as toxicological effects attributable to a single dose were not identified and spinetoram and spinosad are classified as not likely to be carcinogens (cancer risk ass essment is not required). The chronic analysis assumed 100% crop treated , average field - trial residues or tolerance level residues for crop commodities , average residues fr o m the livestock feeding studies, spinosad residue estimates for fish/shellfish (residues of spinetoram in fish/shellfish are expected to be insignificant) , experimental processing factors when available , and modeled drinking water estimates . The resulting chronic exposure estimates do not exceed HED's level of concern (≤ 64 % cPAD; ch ildren 1 - 2 years old were the most highly exposed subpopulation). Table 5.4.1.1 is a summary of the dietary exposure and risk estimates. Table 14 : Summary of Chronic Dietary (food and water) Exposure and Risk for Spinosad/Spinetoram. Population Subgroup cPAD (mg/kg/day) Chronic Exposure (mg/kg/day) %cPAD g eneral U.S. Population 0.0249 0.005029 20 a ll Infants (<1 year old) 0.007054 28 c hildren 1 - 2 years old 0.0 15861 64 c hildren 3 - 5 years old 0.010909 44 c hildren 6 - 12 years old 0.006734 27 y outh 13 - 19 years old 0.003924 16 a dults 20 - 49 years old 0.004353 18 a dults 50+ years old 0.003889 16 f emales 13 - 49 years old 0.003967 16 

### 5.4.2 Percent CT Used in Dietary Assessment The dietary analysis assumed 100% CT for all commodities.

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### 6.0 Residential (Non - Occupational) Exposure/Risk D417200, J. Tyler, 10 - Mar - 2015 

### The proposed uses will not result in residential exposure . H owever, residential handler (s hort term inhalation e xposures ) and post - application (short - term incidental oral ) exposures are expected as a result of the following registered uses and were reassessed to conform with current policies and guidance ( see Appendix D for application scenarios; based on toxicologi cal considerations, a dermal assessment is unnecessary) : (1) homeowner application of spinosad to gardens, turfgrass, ornamentals and fire ant mounds ; (2) homeowner application of spinetoram to lawns, gardens, and ornamentals ; a nd (3) spot - on application of spinetoram to cat s and kitten s . The handler and post application risk estimates are summarized in Table 6.0.1 and 6.0.2, respectively , and are not of concern for all scenarios (LOC for MOEs < 100; calculated MOEs were ≥ 720 ) . Table 6 .0 . 3 are the residential risk estimates that are recommended for use in the aggregate assessment for spinosad and spinetoram and reflect the highest do s es for each applicable lifestages for all exposure scenarios resulting f r o m the uses which yield residentia l exposure . A ggregating exposure resulting from the turf and pet uses was not conducted as the products control different pest s and, therefore, making application on the same day unlikely. In a ddit i on, c urrent HED policy requires assessment for residential post - application exposures of short - (1 to 30 days), intermediate - (1 to 6 months), and long - term (greater than 6 months) exposures from spot - on products due to the preventative nature of these products and the potential for extended usage in more temperate parts of the country. However, for s pinetoram, there is no progression of toxicity with time; therefore, the short - term assessment is protective of intermediate - and long - term exposure. In support of the turf uses, a n adequate spinosad turf transferable residue ( TTR ) study has been submitted and was incorporated into the current assessment ( D256668, S. Weiss, 28 - S ep - 1999 ). In addition, an adequate spinetoram study measuring dislodgeable residues fr om petting after topical administration to cats was submitted and was incorporated in this assessment (D395611, L. Venkateshwara, 20 - A pr - 2012). Spinosad and spinetoram dislodgeable - foliar residue (DFR) stud ies are unnecessary a t th is time as there is n o hazard via the dermal route of exposure . Table 6.0.1: Residential Handler Inhalation Exposures and Risk Estimates for Spinosad and Spinetoram.

Exposure Scenario Application Rate 1 Area

Treated Daily 2 Inhalation Unit

Exposure 2 (mg/lb ai) Inhalation Dose

(mg/kg/day) 3 Short - term

Inhalation MOE 4 Spinosad Mixing/Loading/Applying Dust Formulations to Home Gardens and Ornamentals via Shaker Can, Hand Crank Duster, and Electric/power Duster 0.00001 lb ai/1000 feet 2 1200 feet 2 Baseline 5 : 18 Baseline: 0.0000027 Baseline:

1,800,000 Mixing/Loading/Applying Dust Formulations to Home Gardens and Ornamentals via Plunger Duster and Bulb Duster Baseline: 1.7 Baseline: 0.00000026 Baseline:

19,000,000 Mixing/Loading/Applying Liquid Formulations to Lawns/Turf via Hose - end Sprayer 0.41 lb ai/ acre 0.5 acre 6 Baseline:

0.022 Baseline:

0.000056 Baseline:

87,000 Mixing/Loading/Applying Liquid Formulations to Lawns/Turf via Manually - pressurized Handwand Baseline: 0.018 Baseline:

0.000046 Baseline:

110,000 Mixing/Loading/Applying Liquid Formulations to Lawns/Turf via Backpack Sprayer Baseline: 0.14 Baseline: 0.00036 Baseline:

14,000

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Page 25 of 45 Table 6.0.1: Residential Handler Inhalation Exposures and Risk Estimates for Spinosad and Spinetoram.

Exposure Scenario Application Rate 1 Area

Treated Daily 2 Inhalation Unit

Exposure 2 (mg/lb ai) Inhalation Dose

(mg/kg/day) 3 Short - term

Inhalation MOE 4 Spinosad Mixing/Loading/Applying SC Formulations to Fire Ant Mounds via Shaker Can 0.0013 lb ai/mound 5 mounds Baseline:

0.022 Baseline:

0.0000018 Baseline:

2,700,000 Spinetoram Mixing/Loading/Applying DF Formulations Turf, Home Gardens and Ornamentals via Manually - pressurized Handwands and Backpacks 0.0005 lb ai/gal 5 gallons Baseline: 1.1 Baseline: 0.000034 Baseline:

140,000 Mixing/Loading/Applying DF Formulations Turf, Home Gardens and Ornamentals via Sprinkler Can 5 gallons Baseline: 0.0014 Baseline:

0.000000044 Baseline:

110,000,000 Mixing/Loading/Applying DF Formulations to Lawns/Turf via Hose - end Sprayer 0.061 lb ai/ acre 0.5 acre Baseline: 0.022 Baseline: 0.0000084 Baseline:

580,000 1 Application rate = maximum application rate from current labels ( see Appendix D ). 2 Area treated and Unit Exposure value s based on 2012 Residential SOPs. 3 Dose (mg/kg/day) = Unit exposure (mg/lb ai) x App Rate (lb ai/acre or lb ai/gallon) x Area Treated or Amount Handled (acres/day or gallons/days) x %Absorption (100% inhalation) / Body weig ht (80 kg). 4 MOE = NOAEL (mg/kg/day) / Dose (mg/kg/day); where the short - term NOAEL = 4.9 mg/kg/day. 5 Baseline Inhalation: no respirator. 6 0.5 A is a typical assumption for broadcast applications per the 2012 Residential SOPs, and is considered con servative for manually - pressurized handwands and backpacks which are typically used for spot treatments. Table 6.0 .2 : Residential Post - application Non - cancer Exposure and Risk Estimates for Spinosad / Spinetoram. Lifestage Post - application Exposure Scenario Application Rate 1 TTR (ug/cm 2 ) 2 Dose (mg/kg/day) 3 MOEs 4 Use Site Route of Exposure Child (1 to <2 years) Turf/Home

Gardens/ Ornamental Liquid Formulations Hand - to - mouth 0.41 lb ai/ acre 0.05 0.0069 720

Object - to - mouth 0.00021 24,000 Soil Ingestion 0.00014 350,000 Cat Spot - on Hand - to - Mouth 231 mg ai/app. N/A 0.0039 1,200 1 Based on registered labels (See Table 4.2). 2 TTR based on submitted chemical - specific study (MRID 44828401; D256668). Predicted value from CA site used as conservative assumption. 3 Dose (mg/kg/day) equations provided in 2012 Residential SOPs. F AR for cat spot - on dose calculations taken from che mical specific study (MRID 48595401; D395611). 4 MOE = POD (mg/kg/day) ÷ Dose (mg/kg/day). Table 6.0 . 3 : Recommendations for the Residential Exposures for the Spinosad / Spinetoram Aggregate Assessment. Lifestage Exposure Scenario Dose (mg/kg/day) 1 MOE 2 Inhalation Oral Inhalation Oral Adults Mixing/Loading/Applying Liquid Formulations to

Turf via Backpack Sprayer 0.00036 -- 14,000 -- Child (1 to <2 years) Hand - to - Mouth Exposure from Liquid Formulation

on Turf/Home Gardens/Ornamentals -- 0.0069 -- 720 1 Dose = the highest dose for each applicable lifestages of all residential scenarios assessed. 2 MOE = the MOEs associated with the highest residential doses.

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### 6. 1 Residential Bystander Post - Application Inhalation Exposure Volatilization of pesticides may be a source of post - application inhalation exposure to individuals nearby pesticide applications. The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Roden ticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA - HQ - OPP - 2014 - 0219). During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route - specif

ic inhalation toxicological studies) or further analysis is required for spinetoram and spinosad. 6.2 Spray Drift Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed for spinosad and spinetoram . The agency has been working with the Spray Drift Task Fo rce (a task force composed of various registrants which was developed as a result of a Data Call - In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the agency’s Spray Drift website for more information ; http://www.epa.gov/opp00001/factsheets/spraydrift.htm ). The agency has also developed a policy on how to appropriately consi der spray drift as a potential source of exposure in risk assessments for pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide w ill be considered concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs) - Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift. T his document outlines the quantification of indirect non - occupational exposure to drift.

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### 7.0 Aggregate Exposure/Risk Characterization In accordance with the FQPA, HED consider s and aggregate s pesticide exposures and risks from three major sources: food, drinking water, and 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 PA D), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. Based on the anticipated residential exposure scenarios and since acute and cancer risk ass essments are not required, only short - term (residential, food, and water) and chronic (food and water) aggregate exposure assessments were conducted. Since the aggregate chronic assessment is made up of only dietary sources (food and water) , the dietary e xposure estimates provided in Section 5.4.4 represents chronic aggregate exposure ; all chronic exposures were less than HED’s LOC (≤64% cPAD) . For calculation of aggregate short - term exposure a nd as indicated in Section 6.0 , residential exposure to adult s (handler) and children (post - application ) resulting from the application of spinosad to turf/ornamentals/home garden yield the highest residential exposure and were therefore used in calculation of aggregate short - term exposure. Table 7 .0.1 is a summar y of the short - term aggregate exposures and risk estimates. Since the aggregate MOEs are ≥ 220 (LOC for MOEs <100) , short - term aggregate exposure to spinosad and spinetoram do not exceed HED's LOC. HED notes that although only a short - term aggregate risk assessment was conducted, the short - term assessment is protective of intermediate - term exposure as the short - /intermediate - term PODs are identical. Table 6.0.1 : Short - Term Aggregate Risk Calculations. Population NOAEL

(mg/kg/day) Target

MOE Chronic Food Water Exposure (mg/kg/day) Incidental Oral

Exposur e (mg/kg/day) 1 Handler Inhalation

Exposure (mg/kg/day) 1 Aggregate MOE

(food, water, and residential) 2 General U.S. Population 4.9 100 0.005029 -- 0.000 36 910 Children 1 - 2 years old 0.015861 0.0 069 -- 2 2 0 Adults 20 - 49 years old 0.004353 -- 0.000 36 10 00 1 See Section 6.0 and Table 6 .0.1. 2 A ggregate MOE = NOAEL ÷ ( c hronic dietary e xposure + r esidential e xposure) . 

### 8.0 Cumulative Risk Characterization/Assessment Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to spinosad/spinetoram a nd any other substances and spinosad/spinetoram d o not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that spinosad/spinetoram h a ve a common mechanism of toxicity with other substances. For information regarding EP A’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and p rocedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides /cumulative .

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### 9.0 Occupational Exposure/Risk Characterization D417200, J. Tyler, 10 - Mar - 2015 

### Occupational exposures were assessed for the proposed use on coffee . For the updates to the crop group/subgroups commodity definitions , n o amendments to the use patterns ( i.e., maximum use rates, RTIs , PHIs , REIs, PPE, use of adjuvants, etc.) have been proposed. Therefore, an occup ational assessment for these uses was not performed , and are considered covered by previous assessments . In addition, the label amendment requests do no warrant a new occupational exposure assessment. 9.1 Occupational Handler Exposure/Risk Assessment Based on the anticipated use patterns and current labeling, types of equipment , and techniques that can potentially be used, short - and intermediate - term occupational handler exposure for the following scenarios are expected: (1) mixer/loader: op en mixing/loading DF (dry flowable) /WDG and SC formulations for aerial and airblast application s ; (2) a pplicator: a pplying sprays using aerial and airblast equipment; (3) fl agger: fl agging to s upport a erial applications; and (4) mixer/loader/applicator : ope n mixing/loading/applying DF (dry flowable), WDG , and SC formulations for applications via mechanically - pre s surized handgun. It is noted that no hazard was identified for dermal exposure (all durations); therefore a dermal assessment is unnecessary. For the scenarios where baseline data are available, all inhalation risks for occupational handlers are not of concern to HED (i.e., MOE> the LOC of 100 ) with baseline protection (i.e., long - sleeve shirt, long pants, shoes, and socks) . Only engineering contro l data (i.e., enclosed cockpits) are available for aerial application scenarios. All inhalation risks for occupational aerial applicators are above the LOC (100) with baseline clothing and enclosed cockpits . Table 9 .1.1: Occupational Handler Non - Cancer Exposure and Risk Estimates for Spinosad and Spinetoram . Exposure Scenario Crop or Target Inhalation Unit Exp (μg/lb ai) 1 Max . App . Rate (lb ai/ acre ) 2 Area Treated or

Amount Handled Daily 3 Inhalation Mitigation Level Dose (mg/kg/day) 4 MOE 5 Mixer/Loader DF/WDG

– Aerial application Coffee Baseline: 8.96 0.08 350 acres 0.00314 1,600 DF/WDG

– Airblast application 0.08 40 acres 0.000359 14,000 SC

– Aerial application Baseline: 0.219 0.16 350 acres 0.000154 32,000 SC

– Airblast application 0.16 40 acres 0.0000175 280,000 Applicator Aerial applications Coffee Eng. control : 0.0049 0.16 350 acres 0.00000343 1,400,00 Airblast applications Baseline: 4.71 0.16 40 acres 0.000376 13,000 Flagger Flagger Coffee Baseline: 0.35 0.16 350 acres 0.000245 20,000 Mixer/Loader/Applicator DF/WDG

– Mechanically pressurized handgun Coffee Baseline: 3.9 0.016 1000 gal 0.00078 6,300 SC

– Mechanically - pressurized handgun 0.032 0.00156 3,100 1 Unit Exposures are taken from “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table,” Feb. 2015 . 2 Based on proposed Entrust ® SC (EPA Reg No. 62719 - 621), Delegate ® WG (EPA Reg No. 62719 - 541) and Radiant ® SC (EPA Reg No. 62719 - 545) la bels. 3 Units Treated are taken from “Standard Values for Daily Acres Treated in Agriculture”; ExpoSAC SOP No. 9.1, 25 - Sep - 2001. 4 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or g al) × Area Treated or Amount Handled ( acres or gal/day) ÷ BW (80 kg). 5 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). Inhalation NOAEL = 4.9 mg/kg/day.

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### 9.2 Occupational Pos t - Application Exposure/ Risk Assessment HED uses the term post - application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re entry exposure). Such exposures may occur when workers enter previously tre ated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. Post - application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or ta rget that was treated, the type of pesticide application, and the chemical’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post - application exposure. A quan titative occupational post - application inhalation exposure assessment was not performed . However, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post - application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post - application inhalation exposure scenarios. Furthermore, inhalatio n exposure during dusty mechanical activities such as shaking and mechanical harvesting is another potential source of post application inhalation exposure. However, the airblast applicator scenario is believed to represent a reasonable worst - case surroga te estimate of post - application inhalation exposur e during these dusty mechanical harvesting activities. The non - cancer inhalation risk estimate for commercial airblast application is not of concern (i.e., MOE > 100) . It is noted that no hazard was identified for dermal exposure (all durations); therefore a dermal assessment is unnecessary. Spinosad and spinetoram are classified as Toxicity Category III or IV based upon data for acute dermal toxicity, acute inhalatio n toxicity, primary skin irritation, and primary eye irritation. Typically, the REI specified on the proposed label is based on the acute toxicity of the active ingredient. Under 40 CFR 156.208 (c) (2) (iii), active ingredients classified as Acute III or IV for acute dermal, eye irritation, and primary skin irrigation are assigned a 12 - hour REI. However, it is noted that the proposed product label has a 4 - h ou r REI listed. REIs may be further reduced from 12 hours if certain criteria are met for both the technical material and the different end - use products in accordance with the Pesticide Registration (PR) Notice 95 - 3 ( Reduction of Worker Protection Standard (WPS) Interim R EIs for Certain Low Risk Pesticides ; http://www.epa.gov/PR_Notices/pr95 - 3.html ) . Based only on the acute toxicity categories, spinosad and spinetoram are possible candidates for a 4 - h our REI; howev er, RD should ensure that the additional criteria listed in PR Notice 95 - 3 a re met for both active ingredients and the end - use product s . RDI: RAB1 ( 04 - Mar - 201 5 ) Appendix A. Toxicology Assessment Appendix B. Chemical Names and Structures Appendix C. P hysiochemical Properties Appendix D: Registered Residential Uses for Spinosad/Spinetoram

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### Appendix A. Toxicology Assessment A.1. Toxicology Data Requirements Study requirements for spinosad/spinetoram are presented below. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used. Study Technical Required Satisfied 870.1100 Acute Oral Toxicity 870.1200 Acute Dermal Toxicity 870.1300 Acute Inhalation Toxicity 870.2400 Acute Eye Irritation 870.2500 Acute Dermal Irritation 870.2600 Skin Sensitization yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 90 - Day Oral Toxicity (rodent) 870.3150 90 - Day Oral Toxicity (nonrodent) 870.3200 21/28 - Day Dermal Toxicity 870.3250 90 - Day Dermal Toxicity 870.3465 90 - Day Inhalation Toxicity yes yes yes no no 1 yes

yes yes

--

-- 870.3700a Prenatal Developmental Toxicity (rodent) 870.3700b Prenatal Developmental Toxicity (nonrodent) 870.3800 Reproduction and Fertility Effects yes yes yes yes

yes yes 870.4100a Chronic Toxicity (rodent) 870.4100b Chronic Toxicity (nonrodent) 870.4200a Carcinogenicity (rat) 870.4200b Carcinogenicity (mouse) 870.4300 Combined Chronic Toxicity/Carcinogenicity yes yes yes yes yes yes 2

yes yes 2 yes yes 870.5100 Mutagenicity

— Bacterial Reverse Mutation Test 870.5300 Mutagenicity

— Mammalian Cell Gene Mutation Test 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations 870.5xxx Mutagenicity

— Other Genotoxic Effects yes yes yes yes yes

yes yes yes 870.6200a Acute Neurotoxicity Screening Battery (rat) 870.6200b 90 - Day Neurotoxicity Screening Battery (rat) 870.6300 Developmental Neurotoxicity yes yes no yes

yes

-- 870.7485 Metabolism and Pharmacokinetics 870.7600 Dermal Penetration 870.7800 Immunotoxicity yes no yes yes

-- yes 1 HED HASPOC concluded that the subchronic inhalation study was not required at this time (U. Habiba, 15 - OCT 2014, TXR #0057052). 2 The combined chronic toxicity/carcinog enicity study satisfies the requirement of the study.

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### A.2 Toxicity Profiles Table A.2.1 : Acute Toxicity - Spinosad Guideline No. Study Type MRID Results Toxicity Category 870.1100 Acute Oral - Rat 43770701; 43414515 LD50 = >2000 mg/kg III 870.1200 Acute Dermal - Rabbit 43414516 LD50 = >2000 mg/kg III 870.1300 Acute Inhalation - Rat 43414517 LC50 = >5.18 m/L IV 870.2400 Acute Eye Irritation 43414518 not an eye irritant IV 870.2500 Acute Dermal Irritation 43414519 not a skin irritant IV 870.2600 Dermal Sensitization 43414520 not a skin sensitizer N/A Table A.2.2: Subchronic, Chronic, and Other Toxicity Studies - Spinosad Guideline No./Study Type MRID No. (year)/

Classification/Doses Results 870.3100 90 - Day oral toxicity rodents - Mouse 43566602 (1992)

Acceptable/guideline 0, 0.005, 0.015, 0.045, or 0.12% 0, 7.5, 22.5, 67.5, or 180 mg/kg/day NOAEL = 7.5 mg/kg/day in males and females. LOAEL = 22.5 mg/kg/day in males and females; based on cytoplasmic vacuolation of lymphoid organs, liver, kidney , stomach, female reproductive tract, and epididymis. Other tissues less severely affected are heart, lung, pancreas, adrenal cortex, bone marrow, tongue, and pituitary gland. 870.3100 90 - Day oral toxicity rodents - Rat 43566601 (1992)

Acceptable/guideline 0, 0.05, 0.1, 0.2, or 0.4% 0/0, 33.9/38.8, 68.5/78.1, 133.5/151.6, or 273.1/308.2 mg/kg/day; M/F NOAEL = 33.9 mg/kg/day in males; 38.8 mg/kg/day in females. LOAEL = 68.5 mg/kg/day in males; 78.1 mg/kg/day in females based on adrenal co rtical vacuolation in males, lymph node histiocytosis in both sexes. 870.3100 90 - Day oral toxicity rodents - Rat 43557502 (1994)

Acceptable/guideline 0, 0.003, 0.006, 0.012, or 0.06% 0/0, 2.2/2.6, 4.3/5.2, 8.6/10.4, or 42.7/52.1 mg/kg/day; M/F NOAEL = 42.7 mg/kg/day in males; 52.1 mg/kg/day in females (HDT). LOAEL= Not observed in males and females. 870.3150 90 - Day oral toxicity nonrodents - Dog 43444102 (1994)

Acceptable/guideline 0, 150, 300, or 1350/900 (males) 900 (females) ppm 0/0, 4.89/5.38, 9.73/10.47, or 33.4/29.9 mg/kg/day; M/F NOAEL = 4.89 mg/kg/day in males; 5.38 mg/kg/day in females. LOAEL = 9.73 mg/kg/day in males; 10.47 mg/kg/day in females based on microscopic changes in a variety of tissues, clinical signs of toxicity, decreases in m ean body weights and food consumption, and biochemical evidence of anemia and possible liver damage. 870.3200 Repeated Dose Dermal Toxicity - Rabbit (21 days) 43557503 (1984)

Acceptable/guideline 0, 100, 500, or 1000 mg/kg/day NOAEL = 1000 mg/kg/day in males and females (HDT). LOAEL = Not observed. 870.3465 Subchronic Inhalation Study 49425601 (1999)

Acceptable/non - guideline 0, 0.0003, 0.0014, or 0.0095 mg/L NOAEL = 0.0095 mg/L LOAEL = not established 870.3700a Prenatal developmental in rodents - Rat 43557505 (1993)

43770702 (1992; range finding) Acceptable/guideline 0, 10, 50, or 200 mg/kg/day Maternal : NOAEL = 200 mg/kg/day (HDT). LOAEL = Not observed. Developmental : NOAEL = 200 mg/kg/day (HDT). LOAEL = Not observed.

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Classification/Doses Results 870.3700b Prenatal developmental in nonrodents - Rabbit 43414521 (1994)

43770703 (1992; range finding) Acceptable/guideline 0, 2.5, 10.0, or 50.0 mg/kg/day Maternal : NOAEL = 50 mg/kg/day (HDT). LOAEL = Not observed. Developmental : NOAEL = 50 mg/kg/day (HDT). LOAEL = Not obs erved.

870.3800 Reproduction and fertility effects - Rat 43701506 (1994)

Acceptable/guideline 0, 0.005, 0.02, or 0.2% 0, 3, 10, or 100 mg/kg/day Parental/Systemic NOAEL = 10 mg/kg/day. LOAEL = 100 mg/kg/day based on increases in heart, kidney, liver, spleen, and thyroid weights (both sexes), corroborative histopathology in the spleen and thyroid (both sexes), heart and kidney (males only), and histopathologic lesions in the lungs and mes enteric lymph nodes (both sexes), stomach (females only), and prostate. Reproductive NOAEL = 10 mg/kg/day. LOAEL = 100 mg/kg/day based on increased incidence of dystocia and/or vaginal bleeding after parturition with associated increases in mortality in the dams. Offspring NOAEL = 10 mg/kg/day. LOAEL = 100 mg/kg/day based on decreases in litter size, survival and body weights. 870.4100a Chronic toxicity

– Rat See 870.4300 See 870.4300

870.4100b Chronic toxicity - Dog 43701504 (1995)

Acceptable/guideline 0, 50/60, 100/120, or 300/360 ppm 0/, 1.44/1.33, 2.68/2.72, or 8.46/8.22 mg/kg/day; M/F NOAEL = 2.68 mg/kg/day in males, 2.72 mg/kg/day in females. LOAEL = 8.46 mg/kg/day in males; 8.22 mg/kg/day in females based on increases in serum alanine aminotransferase, aspartate aminotransferase, and triglycerides levels, and the presence of tissue abnormalities, including vacuolated cell aggregations, arteritis, and glandular cell vacuolation (parathyroid). 870.4200a Carcinogenicity - Rat See 870.4300 See 870.4300

870.4200b Carcinogenicity - Mouse 43701505 (1995)

Acceptable/guideline 0, 0.0025, 0.008, or 0.036% 0, 25, 80, or 360 ppm M/F: 0/0, 3.4/4.2, 11.4/13.8, or 50.9/67.0 mg/kg/day A nd 44123601 (1996) Acceptable/guideline 0, 0.0008, or 0.024% M/F: 0/0, 1.1/1.3, or 32.7/41.5 mg/kg/day NOAEL = 11.4 mg/kg/day in males, 13.8 mg/kg/day in females. LOAEL = 50.9 mg/kg/day in males; 67.0 mg/kg/day in females based on decreased weight gains, increased mortality, the hematologic effects, and the gross finding of increased thickening of the gastric mucosa in females and the histologic changes in the stomach of males. No evidence of carcinogenicity.

870.4300 Chronic/ Carcinogenicity - Rat 43701507, 43710503 (1995)

0, 0.005, 0.02, 0.05, or 0.1% 0/0, 2.4/3.0, 9.5/12.0, 24.1/30.3, or 49.4/62.8 mg/kg/day; M/F NOAEL = 9.5 mg/kg/day in males, 12.0 mg/kg/day in females. LOAEL = 24.1 mg/kg/day in males; 30.3 mg/kg/day in females based on vacuolation of the epithelial follicular cells of the thyroid in both sexes. No evidence of carcinogenicity.

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Classification/Doses Results

870.5265 Reverse Mutation Assay 43414522 (1992)

Unacceptable/guideline In the Ames Test, the mutation rates observed after treatment of Salmonella typhimurium strains (TA1535, TA1537, TA98, and TA100) and one strain of Escherichia coli (WP2/uvrA) with XDE105 increased in a dose - related manner when compared to the vehicle control. The colonies were shown in a replica plate assay to be predominately auxotrophs an d not revertants. No growth of auxotrophs is expected in the Ames assay, but their presence in this assay suggests that XDE - 105 supported their growth. The investigators noted that trace amounts of histidine and other amino acids were present in the test substance, which is a fermentation product. Therefore, an Ames assay with XDE - 105 may not be appropriate, and this assay is considered to be unacceptable. 870.5300 Mouse lymphoma cell/mammalian activation gene forward mutation assay 43414523 (1992)

Acceptable/guideline 0, 1, 5, 10, 15, 20, or 35 μg/ml 15 through 50 μg/ml with metabolic activation. In a forward mutation assay using mouse lymphoma cells, spinosad did not induce forward mutations in mouse lymphoma L5178Y Tk+/ - cells at concentrations of 0, 1, 5, 10, 15, 20, or 35 μg/ml without metabolic activation or at concentrations of 15 through 50 μg/ml with metabolic activation. 870.5375 In Vitro mammalian cytogenetic assay 43414524 (1992)

Acceptable/guideline 20, 26, or 35 μg/ml 100, 250, or 500 μg/ml with metabolic activation. In a chromosomal aberrations assay, spinosad did not increase the number of CHO cells with chromosome aberrations at concentrations of 20, 26, or 35 μg/ml without metabolic activation or at concentrations of 100, 250 or 500 μg/ml with metabolic activation. 870.5385 Micronucleus Assay 43414525 (1992)

Acceptable/guideline 0, 500, 1000, or 2000 mg/kg/day In a mouse micronucleus test, spinosad did not increase the frequency of micronuclei in replicate assays with bone marrow ce lls from ICR mice treated with doses of 0, 500, 1000, or 2000 mg/kg/day for two consecutive days. 870.5550 Unscheduled DNA Synthesis 43414526 (1992)

Acceptable/guideline 0.01 to 5 μg/ml 10 to 1000 μg/ml In the unscheduled DNA synthesis assay using primary rat hepatocytes, spinosad did not induce unscheduled DNA synthesis (UDS) in adult rat hepatocytes in vitro at concentrations of 0.01 to 5 μg/ml. Concentrations from 10 to 1000 μg/ml of XDE - 105 were cyto toxic. 870.6200a Acute Neurotoxicity - Rat 43557501 (1994)

Acceptable/nonguideline 0, 200, 630, or 2000 mg/kg NOAEL = 2000 mg/kg in males and females (HDT). LOAEL = Not established in both sexes. 870.6200b Repeat Dose Neurotoxicity - Rat 43557504 (1993)

Acceptable/nonguideline 0, 0.003, 0.006, 0.012 or 0.06% 0/0, 2.2/2.6, 4.3/5.2, 8.6/10.4, or 42.7/52.1 mg/kg/day; M/F NOAEL = 42.7 mg/kg/day in males; 52.1 mg/kg /day in females (HDT). LOAEL = Not established in both sexes. 870.6200b Repeat Dose Neurotoxicity - Rat 43701507, 43701503 (1995)

Acceptable/guideline 0 or 0.1% 0/0 or 46.0/57.0 mg/kg/day, M/F NOAEL = 46.0 mg/kg/day in males; 57.0 mg/kg/day in females (HDT). LOAEL = Not established in both sexes.

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Classification/Doses Results

870.7485 Metabolism and pharmacokinetics - Rat 43701508 (1995)

Acceptable/guideline 10 or 100 mg/kg (single oral dose) 10 mg/kg (repeated dose 14 days) Elimination via feces was major route of excretion (82 - 87% at 168 hours post - dose), and ~7 - 10% was excreted in the urine. Approximately 70 - 80% was absorbed with ~20% of the dose eliminated unabsorbed in feces. Blood levels after single and multiple low doses were highest at 1 hour. Half - lives were 6 hours (males) and 12 hours (females). Blood levels after high dose were highest at 6 (males) and 2 hours (females). At low dose, kidney, liver and fat had the highest levels. At high dose, adrenals (females only), kidney, lymph nodes, fat, and thyroids had the highest levels. Total radioactivity remaining in tissues and carcass of low and high dose a nimals was <0.6% and <3%, respectively. At high dose, radioactivity observed in fat was 3X higher in females than males. Primary metabolites excreted were glutathione conjugates of the parent and O - and N - demethylated of parent. Absorption, disposition, a nd elimination demonstrated no differences due to dose or repeated dosing.

870.7485 Metabolism and pharmacokinetics - Rat 43701509 (1995)

Acceptable/guideline 100 mg/kg (single dose) Elimination via the feces was the major route of excretion (84 to 92% of the dose at 168 hours after dosing), and 3 - 5% of the dose was excreted in the urine. Greater than 68% of the administered radioactivity was recovered in the feces within the first 24 hours following dosing. The excretion kinetics was biphasic with the α and ß excretion halftimes (t 1⁄2 ) of approximately 6 and 30 hours, respectively. The primary metabolites excreted were identified as the glutathione conjugates of the parent and O - demethylated XDE - 105 (spinosyn D). Metabolites in the tissues were characterized as the N and O - demethyla ted forms of spinosyn D. The absorption, disposition, and elimination of 14 C - XDE - 105 (Factor D) demonstrated no appreciable differences based on, dose or repeated dosing.

870.7485 Metabolism and pharmacokinetics - Rat 43701510 (1995)

Acceptable/guideline 100 mg/kg (single dose, bile cannulated) Feces contained 23 to 55% of the dose (an average of 34%), and the bile had an average of approximately 36% (range of 28 to 40%) of the administered radioactivity. Approximately 21% of the dose was found in the ti ssues and carcass (range of 12 to 26%). The urine and CO 2 accounted for 3.3 and <0.1% of the dose. The bile excretion rate results suggested an uptake phase for the first 4 hr after dosing which preceded a biphasic decrease in the biliary excretion rate. The maximum rate of bile excretion was ~644 μg equivalents per hour at 2 - 4 hr; then the rate decreased to ~123 μg equivalents per hour at the 12 - 24 hr interval. The results of the study suggested that metabolites in the bile included the glutathione con jugates of the unchanged form, as well as

– and O - demethylated forms of XDE - 105 (Factor D). 870.7800 Immunotoxicity 48329601 (2010)

Acceptable/guideline 0, 8.65, 40.6, or 141 mg/kg/day Systemic NOAEL = 40.6 mg/kg/day Systemic LOAEL = 141 mg/kg/day based o n decrease body weights, increased liver weights, and abnormal hematology results. Immunotoxicity NOAEL = 141 mg/kg/day Immunotoxicity LOAEL = not established

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Page 35 of 45 Table A.2.3: Acute Toxicity Profile - Spinetoram Guideline No. Study Type MRID Results Toxicity Category 870.1100 Acute oral 46695031 LD 50 (F) >5000 mg/kg IV 870.1200 Acute dermal 46695034 LD 50 ≥5000 mg/kg IV 870.1300 Acute inhalation 46695037 LC 50 >5.50 mg/L IV 870.2400 Acute eye irritation 46695040 slight eye irritant IV 870.2500 Acute dermal irritation 46695043 not a dermal irritant IV 870.2600 Dermal sensitization 46695046 positive -- Table A.2.4: Subchronic, Chronic, and Other Toxicity Studies - Spinetoram Guideline No. Study Type MRID No. (year)/ Classification/dose Results

870.3100 90 - Day oral toxicity Rat 46695104 (2005) Acceptable/guideline 0, 120, 500, 1000, or 2000 ppm M: 0, 7.9, 32.4, 65.8, and 128 mg/kg/d F: 0, 9.5, 39.6, 79.3, 159, and 311 mg/kg/d NOAEL (F) = 120 ppm (9.5 mg/kg/day). LOAEL (F) = 500 ppm (39.6 mg/kg/day) based on an increased incidence of very slight to slight kidney tubular vacuolization, very slight vacuolization of the follicular epithelial cells of the thyroid, and increased incidence of histiocytic aggregates of macrophages in the bone marrow, spleen and mesenteric lymph node. NOAEL (M) = 500 ppm (32.4 mg/kg/day). LOAEL (M) = 1000 ppm (65.8 mg/kg/day) based on an increased incidence of histiocytic aggregates of macrophages in lymph nodes, spleen, thymus, and ileum and jejunum (Peyer’s patches), and follicular epithelial cell vacuolization of the thyroid with colloid depletion . 870.3100 90 - Day oral toxicity Mouse 46695105 (2005) Acceptable/guideline 0, 50, 150, or 450 ppm M: 0, 7.5, 22.8, and 70.5 mg/kg/d F: 0, 10.2, 29.6, and 89.9 mg/kg/d 11 mg/kg/d NOAEL = 22.8/29.6 mg/kg/day (M/F). LOAEL = 70.5/89.9 mg/kg/day (M/F).

870.3150 90 - Day oral toxicity Dog 46568501 (2005) Acceptable/guideline 0, 150, 300 or 900 ppm M: 0, 5.73, 9.82, and 27.1 mg/kg/d F: 0, 4.97, 10.2, and 31.0 mg/kg/d NOAEL (M) = 150 ppm [(4.97/5.73 (females/males)] mg/kg/day). LOAEL (M) = 300 ppm [ 9.8/ 10.2 (males/females) mg/kg bw/day in males/females, respectively], based on decreased body - weight gain (males), generalized vacuolizat ion of macrophages within lymphoid tissue, arteritis and/or perivascular inflammation in numerous organs with necrosis of the bone marrow leading to regenerative anemia, and a decrease in thymus weights (males) with slight atrophy of the thymic cortex (mal es) . 870.3200 21/28 - Day dermal toxicity Rat 46695106 (2005) Acceptable/ guideline 0, 100, 500, and 1000 mg/kg/d NOAEL = 1000 mg/kg/day. LOAEL = not established. 870.3700a Prenatal developmental in Rat 46695108 (2005) Acceptable/ guideline 0, 30, 100, and 300 mg/kg/d from GD 6 - 20 Maternal NOAEL = 300 mg/kg/day. Maternal LOAEL = not established Developmental NOAEL = 300 mg/kg/day. Developmental LOAEL = not established. 870.3700b Prenatal developmental in 46695107 (2005) Acceptable/ guideline Maternal NOAEL = 60 mg/kg/day. Maternal LOAEL = not established

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Page 36 of 45 Table A.2.4: Subchronic, Chronic, and Other Toxicity Studies - Spinetoram Guideline No. Study Type MRID No. (year)/ Classification/dose Results Rabbit 0, 2.5, 10, and 60 mg/kg/d from GD 7 - 27 Developmental NOAEL = 60 mg/kg/day. Developmental LOAEL = not established.

870.3800 Reproduction and fertility effects Rat 46887501 (2006) Acceptable/ guideline 0, 3, 10, or 75 mg/kg/d Parental/Systemic NOAEL = 10.46 mg/kg/day (M) and 9.87 mg/kg/day (F). LOAEL = 78.97 mg/kg/day (M) and 74.87 mg/kg/day (F) based on thyroid histopathology (cytoplasmic vacuolation of follicular epithelial cells) in F 0 and F 1 animals of both sexes and decreased serum T 4 and/or increased serum TSH in F 0 females and F 1 animals of both sexes. Reproductive NOAEL (F) = 9.87 mg/kg/day LOAEL = 74.87 mg/kg/day based on dystocia/other parturition abnormalities and late resorptions/ retained fetuses and increased postimplantation loss in F 0 and F 1 dams. Reproductive NOAEL (M)  78.87 mg/kg/day LOAEL (M) was not identified. Offspring NOAEL  78.97 mg/kg/day (M) and 74.87 mg/kg/day (F). LOAEL was not identified. 870.4100a Chronic toxic ity - Rat See 870.4300 See 870.4300 870.4100b Chronic toxicity - Dog 47011901 (2006) Acceptable/ guideline 0, 50, 100, or 200 ppm M: 0, 1.57, 2.96, and 5.36 mg/kg/d F: 0, 1.31, 2.49, and 5.83 mg/kg/d NOAEL = 100 ppm (2.49 mg/kg/day in females/2.96 mg/kg/day in males). LOAEL = 200 ppm (5.36 mg/kg/day in males/5.83 mg/kg/day in females) based on arteritis and necrosis of the arterial walls of the epididymides in males, and the thymus, thyroid, larynx and urinary bladder in females. 870.4200a Carcinogenicity - Rat See 870.4300 See 870.4300 870.4200b Carcinogenicity - Mouse 47143801 (2007) 0, 25, 80, 150, or 300 ppm M: 0, 3, 10, 18.8 or 37.5 mg/kg/day F: 0, 4, 12.8, 23.9, or 46.6 mg/kg/day Currently under review. Preliminary results show no ev idence of carcinogenicity.

870.4300 Chronic/carcinogenicity Rat 47212901 & 47212902 (2007) 0, 50, 250, or 750 ppm M. 0, 2.12, 10.8, 21.6, & 32.9 mg/kg/day F: 0, 2.63, 13.2, 26.6, & 40 mg/kg/day NOAEL = 250 ppm (10.8 mg/kg/day in males/ 13.2 mg/kg/day in females). LOAEL = 500 ppm (21.6 mg/kg/day in males/26.6 mg/kg/day in females). Based on increased incidences of thyroid follicular cell vacuolation and of aggregates of marcrophages/ histiocytes inpeyer’s patches in the ileum and mediastinals lymph nodes and an increased severity of aggregates of marcrophages/histiocytes in mesenteric lymph nodes. 870.5100 In vitro Bacterial Gene Mutation (Salmonella typhimurium/ E. coli) / mammalian activation gene mutation assay 466951109 (2005) Acceptable/ guideline 0, 33, 100, 333, 1000, 2500, or 5000  g/plate (+/ - S9 - activation) in the E. coli strain ; or 0, 1, 3.33, 10, 33.3, 100, 333, and 1000  g/plate ( - S9) and 0, There was no evide nce of induced mutant colonies over background. (Negative)

### Spinosad and Spinetoram Human Health Risk Assessment D 415812

Page 37 of 45 Table A.2.4: Subchronic, Chronic, and Other Toxicity Studies - Spinetoram Guideline No. Study Type MRID No. (year)/ Classification/dose Results 3.33, 10, 33.3, 100, 333, 1000, and 5000  g/plate (+S9) in the Salmonella strains 870.5300 In Vitro Gene Mutation assay in Chinese Hamster Ovary cells 46695110 (2005) Acceptable/ guideline 0, 10, 20, 30, 40, 50, 60, 70, 80, 100, 120, 140, 160, 180, 200, 260, and 320  g/mL ( - S9), 0, 10, 20, 40, 80, 160, 200, 240, 280, and 320  g/mL (+S9) There was no evidence of induced mutant colonies over background in the presence or absence of S9 - activation. (Negative) 870.5375 In vitro Mammalian Cytogenetics (Chromosomal Aberration Assay in Rat Lymphocytes) 46695111 (2005) Acceptable/guideline 0, 2.5, 5, 10, 20, 30, 40, 50, or 100 μg/mL ( - S9), 0, 5, 10, 20, 30, 40, 50, 60, 80, or 100 μg/mL (+S9). There were no significant increases in the frequency of aberrant cells (excluding gaps) noted in the presence or absence of S9 at any exposure period. (Negative) 870.5395 In Vivo Mammalian Cytogenetics - Erythrocyte Micronucleus Assay in Mice 46695112 (2005) Acceptable/guideline 0, 500, 100 0, or 2000 mg/kg No statistically significant increases in the micronucleated polychromatic erythrocytes (MPCE) frequency or % of polychromatic erythrocytes (PCE) were observed in any treatment group when compared to controls. (Negative) 870.6200 Acute Neurotoxicity screening battery 46995113 (2005) Acceptable/guideline 0, 200, 630, and 2000 mg/kg NOAEL = 2000 mg/kg. LOAEL was not observed.

870.7485 Metabolism and pharmacokinetics Rat 46695114 (2005) Acceptable/ guideline single p.o. dose 10 or 100 mg/kg 14 daily doses 10 mg/kg single i.v. dose 10 mg/kg The absorbed dose ≥70%. After 168 h, total recoveries were 88.1 - 97.1% of the administered doses, with no differences observed between dose levels, single or multiple doses, or route of exposure. Th e majority of the radioactivity was recovered in the feces (77.4 - 89.6% of the administered dose), while urine (3.3 - 9.6%) was a minor route of elimination. The majority of the radioactivity in the feces was recovered during the first 24 h, while the majorit y of radioactivity recovered in the urine was recovered during the first 12 h. Animals given an i.v. dose of the test compound eliminated a larger proportion of radioactivity in the urine and elimination of radioactivity in the feces was prolonged compare d to orally - dosed animals. However the total amount of radioactivity excreted in the feces was similar regardless of route of administration. The carcass contained the highest levels of radioactivity (0.2 - 1.3% administered dose); no other tissue exceeded 0.4% of the administered dose. The highest concentrations of radioactivity were generally detected in fat, kidneys, liver, and lymph nodes, and in the ovaries in females. There was no evidence of bioaccumulation. The majority of radioactivity recovered from urine and fecal extract samples was present as parent and a total of seven metabolites, the

### Spinosad and Spinetoram Human Health Risk Assessment D 415812

Page 38 of 45 Table A.2.4: Subchronic, Chronic, and Other Toxicity Studies - Spinetoram Guideline No. Study Type MRID No. (year)/ Classification/dose Results largest proportion of which were found in the fecal extracts. Metabolic profiles were qualitatively similar for all of the experimental groups. The major rou te of metabolism was found to be glutathione conjugation with the parent compound, as well as glutathione conjugation with N - demethylated, O - demethylated, and hydroxylated forms of the parent compound. Parent and identified compounds accounted for 70.9 - 83 .4% of the administered dose, while unidentified metabolites accounted for 9.6 - 17.1% of the administered dose. The total administered dose accounted for in the excreta was 86.4 - 94.7%. Parent compound accounted for 7.0 - 22.2% (40.0% in the 100 mg/kg males) of the total radioactivity eliminated, and was found almost exclusively in the fecal extracts.

870.7485 Metabolism and pharmacokinetics Rat 46695115 (2005) Acceptable/ guideline single p.o. dose 10 or 100 mg/kg 14 daily doses 10 mg/kg single i.v. dose 10 mg/kg Radioactivity was detected in the plasma at 15 minutes post - dosing indicating rapid absorption. It was considered likely that the fraction of the orally administered dose absorbed was 70% or greater in both the low and high oral dose groups. Af ter 168 h, total recoveries ranged from 90.4 - 94.9% of the administered doses, with no differences observed between dose levels, single or multiple doses, or route of exposure. The majority of the radioactivity was recovered in the feces (78.5 - 86.7% of the administered dose), while urine (2.3 - 3.8%) was a minor route of elimination. The majority of the radioactivity in the feces was recovered during the first 24 h, while the majority of radioactivity recovered in the urine was recovered during the first 12 h. Generally, tissues, carcass, and cage wash accounted for <8%, except for the i.v. - dosed females (13%). At 168 h, the carcass (1.3 - 5.8% of the administered dose) and skin (0.4 - 5.9%) contained the highest mean levels of radioactivity; no other tissue (e xcluding the gastrointestinal tract) exceeded 0.6% of the administered dose. In general, the highest concentrations of radioactivity were detected in fat, lymph nodes, skin, and adrenals in the males, and in the fat, ovaries, lymph nodes, uterus, skin, an d adrenals in females. Radioactivity was detected at low levels in other tissues. There was no evidence of bioaccumulation. The test compound was extensively metabolized regardless of the route of administration. The majority of radioactivity in urine and fecal extract samples was present as parent and a total of nine metabolites. Metabolic profiles were qualitatively similar across dose levels and route of exposure, and no major differences were noted between sexes. The major route of metabolism was found to be glutathione conjugation with the parent compound, as well as glutathione conjugation with N - demethylated and O -

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Page 39 of 45 Table A.2.4: Subchronic, Chronic, and Other Toxicity Studies - Spinetoram Guideline No. Study Type MRID No. (year)/ Classification/dose Results demethylated forms of the parent compound. In excreta, parent and identified compounds accounted for 70.7 - 85.8% of the administered dose, while unidentified metabolites accounted for 0.8 - 16.1% of the administered dose. The total administered dose accounted for in the excreta was 82.0 - 89.1%. Parent compound accounted for 6.5 - 26.1% of the total radioactivity eliminated, and was found a lmost exclusively in the fecal extracts.

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### Appendix B. Chemical Names and Structures Spinosad Common name Chemical structure

spinosyn A (parent) R 1 = N(CH 3 ) 2 , R 2 = H, R 3 = CH 3 , R 4 = CH 3 , R 5 = CH 3 spinosyn B ( N

- demethyl spinosyn A) spinosyn A demethylated in the forosamine ring R 1 = NH(CH 3 ), R 2 = H, R 3 = CH 3 , R 4 = CH 3 , R 5 = CH 3 spinosyn H ( O - demethyl spinosyn A) spinosyn A demethylated in the rhamose ring R 1 = N(CH 3 ) 2 , R 2 = H, R 3 = H, R 4 = CH 3 , R 5 = CH 3 spinosyn J ( O - demethyl spinosyn A) spinosyn A demethylated in the rhamose ring R 1 = N(CH 3 ) 2 , R 2 = H, R 3 = CH 3 , R 4 = H, R 5 = CH 3 spinosyn K ( O - demethyl spinosyn A) spinosyn A demethylated in the rhamose ring R 1 = N(CH 3 ) 2 , R 2 = H, R 3 = CH 3 , R 4 = CH 3 , R 5 = H N - demethyl spinosyn J spinosyn J demethylated in the forosamine ring R 1 = NH(CH 3 ), R 2 = H, R 3 = CH 3 , R 4 = H, R 5 = CH 3 N - formyl spinosyn B spinosyn A where one N - methyl group on the forosamine group has been removed and the other converted to CHO R 1 = N( CH 3 )(CHO), R 2 = CH 3 , R 3 = CH 3 , R 4 = CH 3 , R 5 = CH 3 spinosyn D (parent) R 1 = N(CH 3 ) 2 , R 2 = CH 3 , R 3 = CH 3 , R 4 = CH 3 , R 5 = CH 3 N - demethyl spinosyn D spinosyn D demethylated in the forosamine ring R 1 = NH(CH 3 ), R 2 = CH 3 , R 3 = CH 3 , R 4 = CH 3 , R 5 = CH 3 spinosyn L ( O - demethyl spinosyn D) spinosyn D demethylated in the rhamose ring R 1 = N(CH 3 ) 2 , R 2 = CH 3 , R 3 = CH 3 , R 4 = H, R 5 = CH 3 spinosyn O ( O - demethyl spinosyn D) spinosyn D demethylated in the rhamose ring R 1 = N(CH 3 ) 2 , R 2 = CH 3 , R 3 = CH 3 , R 4 = CH 3 , R 5 = H spinosyn Q ( O - demethyl spinosyn D) spinosyn D demethylated in the rhamose ring R 1 = N(CH 3 ) 2 , R 2 = CH 3 , R 3 = H, R 4 = CH 3 , R 5 = CH 3 N - demethyl spinosyn L spinosyn L demethylated in the forosamine ring R 1 = NH(CH 3 ), R 2 = CH 3 , R 3 = CH 3 , R 4 = H, R 5 = CH 3

### Spinosad and Spinetoram Human Health Risk Assessment D 415812

Page 41 of 45 Spinetoram Common name/code Chemical name Chemical structure

XDE - 175 - J (2R,3aR,5aR,5bS,9S,13S,14R,16aS,16bR) - 13 -

{[(2R,5S,6R) - 5 - (dimethylamino) - 6 - methyltetrahydro - 2H - pyran - 2 - yl]oxy} - 9 - ethyl - 14 - methyl - 7,15 - dioxo 2,3,3a,4,5,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b octadecahydro - 1H - as - indaceno[3,2 - d]oxacyclododecin - 2 - yl 6 - deoxy - 3 - O - ethyl - 2,4 - di - O methyl - alpha - L - mannopyranoside

XDE - 175 - L (2S,3aR,5aS,5bS,9S,13S,14R,16aS,16bS) - 13 -

{[(2R,5S,6R) - 5 - (dimethylamino) - 6 - methyltetrahydro - 2H - pyran - 2 - yl]oxy} - 9 - ethyl - 4,14 - dimethyl - 7,15 - dioxo 2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b hexadecahydro - 1H - as - indaceno[3,2 - d]oxacyclododecin - 2 - yl 6 - deoxy - 3 - O - ethyl - 2,4 - di - O methyl - alpha - L - mannopyranoside

N - demethyl - 175 - J ND - J (2R,3aR,5aR,5bS,9S,13S,14R,16aS,16bR) - 9 - ethyl 14 - methyl - 13 - {[(2S,5S,6R) - 6 - methyl - 5 - (methylamino)tetrahydro - 2H - pyran - 2 - yl]oxy} - 7,15 - dioxo - 2,3,3a,4,5,5a,5b,6,7,9, 10,11,12,13,14,15,16a,16b - octadecahydro - 1H - as indaceno[3,2 - d]oxacyclododecin - 2 - yl 6 - deoxy - 3 - O e thyl - 2,4 - di - O - methyl - alpha - L - mannopyranoside

N - demethyl - 175 - L ND - L (2S,3aR,5aS,5bS,9S,13S,14R,16aS,16bS) - 9 - ethyl 4,14 - dimethyl - 13 - {[(2S,5S,6R) - 6 - methyl - 5 - (methylamino)tetrahydro - 2H - pyran - 2 - yl]oxy} - 7,15 - dioxo 2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16bhexadec ahydro - 1H - as - indaceno[3,2 - d]oxacyclododecin - 2 - yl 6 - deoxy - 3 - O - eth yl - 2,4 - di - O - methyl - alpha - L mannopyranoside

N - formyl - 175 - J NF - J (2R,3S,6S) - 6 -

({(2R,3aR,5aR,5bS,9S,13S,14R,16aS,16bR) - 2 - [(6 - deoxy - 3 - O - ethyl - 2,4 - di - O - methyl - alpha - L mannopyranosyl) oxy] - 9 - ethyl - 14 - methyl - 7,15 - dioxo 2,3,3a,4,5,5a,5 b,6,7,9,10,11,12,13,14,15,16a,16b octadecahydro - 1H - as - indaceno[3,2 - d]oxacyclododecin - 13 - yl}oxy) - 2 - methyltetrahydro 2H - pyran - 3 - yl(methyl)formamide N - formyl - 175 - L NF - L (2R,3S,6S) - 6 -

({(2S,3aR,5aS,5bS,9S,13S,14R,16aS,16bS) - 2 - [(6 - deoxy - 3 - O - ethyl - 2,4 - di - O - methyl - alpha - L mannopyranosyl)oxy] - 9 - ethyl - 4,14 - dimethyl - 7,15 - dioxo - 2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b hexadecahydro - 1H - asindaceno[3,2 - d]oxacyclododecin - 13 - yl}oxy ) - 2 - methyltetrahydro 2H - pyran - 3 - yl(methyl)formamide

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Page 42 of 45 Spinetoram Common name/code Chemical name Chemical structure

3’ - O - deethyl - 175 - J (2R,3aR,5aR,5bS,9S,13S,14R,16aS,16bR) - 13 -

{[(2S,5S,6R) - 5 - (dimethylamino) - 6 - methyltetrahydro - 2H - pyran - 2 - yl]oxy} - 9 - ethyl - 14 - methyl - 7,15 - dioxo 2,3,3a,4,5,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b octadecahydro - 1H - as - indaceno[3,2 - d]oxacyclododecin - 2 - yl 6 - deoxy - 2,4 - di - O - methyl alpha - L - mannopyranoside

3’ - O - deethyl - 175 - L (2S,3aR,5aS,5bS,9S,13S,14R,16aS,16bS) - 13 -

{[(2S,5S,6R) - 5 - (dimethylamino) - 6 - methyltetrahydro - 2H - pyran - 2 - yl]oxy} - 9 - ethyl - 4,14 - dimethyl - 7,15 - dioxo 2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16bhexadec ahydro - 1H - as - indaceno[3,2 - d] oxacyclododecin - 2 - yl 6 - deoxy - 2,4 - di - O - methyl - alpha - L - mannopyranoside

2’ - O - demethyl - 175 - J (2R,3aR,5aR,5bS,9S,13S,14R,16aS,16bR) - 13 -

{[(2S,5S,6R) - 5 - (dimethylamino) - 6 - methyltetrahydro - 2H - pyran - 2 - yl]oxy} - 9 - ethyl - 14 - methyl - 7,15 - dioxo 2,3,3a,4,5,5a,5b,6,7,9,10,11,12,1 3,14,15,16a,16b octadecahydro - 1H - as - indaceno[3,2 - d] oxacyclododecin - 2 - yl 6 - deoxy - 3 - O - ethyl - 4 - O methyl - alpha - L - mannopyranoside

2’ - O - demethyl - 175 - L (2S,3aR,5aS,5bS,9S,13S,14R,16aS,16bS) -

13{[(2S,5S,6R) - 5 - (dimethylamino) - 6 - methyltet rahydro - 2H - pyran - 2 - yl]oxy} - 9 - ethyl 4,14 - dimethyl - 7,15 - dioxo 2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b hexadecahydro - 1H - as - indaceno[3,2 - d]oxacyclododecin - 2 - yl 6 - deoxy - 3 - O - ethyl - 4 - O methyl - alpha - L - mannopyranoside Aglycone - 175 - J (2R,3aR,5aR,5bS,9S,13S,14R,16aS,16bR) - 9 - ethyl 2,13 - dihydroxy - 14 - methyl 2,3,3a,4,5,5a,5b,6,9,10,11,12,13,14,16a,16b hexadecahydro - 1H - as - indaceno[3,2 - d]oxacyclododecine - 7,15 - dione

Aglycone - 175 - L (2S,3aR,5aS,5bS,9S,13S,14R,16aS,16bS) - 9 - ethyl 2,13 - dihydroxy - 4,14 - dimethyl 2,3,3a,5a,5b,6,9,10,11,12,13,14,16a,16b tetradecahydro - 1H - as - indaceno[3,2 - d]oxacyclododecine - 7,15 - dione

### Spinosad and Spinetoram Human Health Risk Assessment D 415812

Page 43 of 45 Spinetoram Common name/code Chemical name Chemical structure

C9 - pseudoaglycone 175 - J (2R,3aR,5aR,5bS,9S,13S,14R,16aS,16bR) - 13 -

{[(2S,5S,6R) - 5 - (dimethylamino) - 6 - methyltetrahydro - 2H - pyran - 2 - yl]oxy} - 9 - ethyl - 2 - hydroxy - 14 - methyl 2,3,3a,4,5,5a,5b,6,9,10,11,12,13,14,16a,16b hexadecahydro - 1H - as - indaceno[3,2 - d]oxacyclododecine - 7,15 - dione

C9 - pseud oaglycone 175 - L (2S,3aR,5aS,5bS,9S,13S,14R,16aS,16bS) - 13 -

{[(2S,5S,6R) - 5 - (dimethylamino) - 6 - methyltetrahydro - 2H - pyran - 2 - yl]oxy} - 9 - ethyl - 2 - hydroxy - 4,14 - dimethyl 2,3,3a,5a,5b,6,9,10,11,12,13,14,16a,16b tetradecahydro - 1H - as - indaceno[3,2 - d]oxacyclododecine - 7,15 - dione C9 - ketopseudoaglycone 175 - J (3aR,5aR,5bS,9S,13S,14R,16aS,16bR) - 13 -

{[(2S,5S,6R) - 5 - (dimethylamino) - 6 - methyltetrahydro - 2H - pyran - 2 - yl]oxy} - 9 - ethyl - 14 - methyl - 3a,4,5,5a,5b,6,9,10,11,12,13,14,16a,16b tetradecahydro - 1H - as - indaceno[3,2 - d]oxacyclododecine - 2,7,15(3H) - trione

C9 - ketopseudoaglycone 175 - L (3aR,5aS,5bS,9S,13S,14R,16aS,16bS) - 13 -

{[(2S,5S,6R) - 5 - (dimethylamino) - 6 - methyltetrahydro - 2H - pyran - 2 - yl]oxy} - 9 - ethyl - 4,14 - dimethyl - 3a,5a,5b,6,9,10,11,12,13,14,16a,16b dodecahydro - 1H - as - indaceno[3,2 - d]oxacyclododecine - 2,7,15(3H) - tr ione

C17 - ketopseudoaglycone 175 - J (2R,3aR,5aR,5bS,9S,13S,14R,16aS,16bR) - 9 - ethyl 13 - hydroxy - 14 - methyl - 7,15 - dioxo 2,3,3a,4,5,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b octadecahydro - 1H - asindaceno[3,2 - d]oxacyclododecin - 2 - yl 6 - deoxy - 3 - O - ethyl - 2,4 - di - O methyl - alp ha - Lmannopyranoside

C17 - ketopseudoaglycone 175 - L (2S,3aR,5aS,5bS,9S,13S,14R,16aS,16bS) - 9 - ethyl 13 - hydroxy - 4,14 - dimethyl - 7,15 - dioxo 2,3,3a,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b hexadecahydro - 1H - asindaceno[3,2 - d]oxacyclododecin - 2 - yl 6 - deoxy - 3 - O - ethyl - 2,4 - di - O methyl - alpha - Lmannopyranoside

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### Appendix C. Physiochemical Properties Table C.1: Spinosad Physicochemical Properties. Melting range Spinosyn A: 84 - 99.5°C; Spinosy n D: 161.5 - 170°C pH (10% slurry of spinosad in water) 7.74 Density 0.512 g/ml ( 20 °C ) Water solubility (ppm; distilled water) Spinosyn A: 89.4 ppm; Spinosyn D: 0.495 ppm Vapor pressure (kPa; 25°C) Spinosyn A: 3.0 x 10 - 11 ; Spinosyn D: 2.0 x 10 - 11 Dissociation constant (pK a ) not available Octanol/water partition coefficient Log (K OW ) Spinosyn A : 2.8 (pH 5), 4.0 (pH 7), and 5.2 (pH 9) Spinosyn D : 3.2 (pH 5), 4.5 (pH 7), and 5.2 (pH 9) UV/visible absorption spectrum not available Table C.2: Spinetoram Physicochemical Properties . Melting points XDE - 175 - J: 143.4°C; XDE - 175 - L: 70.8°C pH 6.46 (1 % w/w aqueous solution) Density 1.1485 g/ml (20 °C) Water solubility (purified water; pm; 20°C) XDE - 175 - J: 10.0 ppm; XDE - 175 - L 31.9 ppm Vapor pressure (Pa; 25 °C) XDE - 175 - J: 5.3 x10 - 5 ; XDE - 175 - L: 2.1 x10 - 5 Dissociation constant (pKa) XDE - 175 - J: pKa = 7.86; XDE - 175 - L : pKa = 7.59 Octanol/water partition coefficient Log K ow (20°C) XDE - 175 - J: 2.44 (pH 5), 4.09 (pH 7), 4.22 (pH 9) XDE - 175 - L: 2.94 (pH 5), 4.49 (pH 7), 4.82 (pH 9) UV/visible absorption spectrum XDE - 175 - J: 245nm (  max ; 12200  , L/(mol*cm) extinction coefficient ) XDE - 175 - L: 24 3 nm (  max; 1 11 00  , L/(mol*cm) extinction coefficient )

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### Appendix D: Registered Residential Uses for Spinosad/Spinetoram S pinosad is currently registered for residential uses including homeowner applications to gardens, turfgrass, and ornamentals. Spinetoram currently is registered for homeowner applications to gardens, lawns/ornamentals, and turfgrass, as well as for pet use as a spo t - on formulation for cats and kittens that weigh more than 4 pounds. A summary of residential uses is listed in Table D.1 . Table D.1 . Summary of Representative Residential Use Patterns, Formulations, and Application Rates for Spinosad and Spinetoram.

Product Formulation Application Equipment Use Sites Max. App. Rates Spinosad Spinosad ® Dust under the brand name Captain Jack’s Deadbug Brew ® Dust (EPA Reg. No. 4 - UT0) Dust Dust applicator, crank garden duster or bulb duster Home Gardens 1 0.00001 lb ai/1000 ft 2 Ornamentals 2 Conserve SC Turf and Ornamental (EPA Reg. No. 62719 - 291) Soluble Concentrate Broadcast Spray Turf and Ornamentals 0.41 lbs ai/acre Conserve Fire Ant Bait (EPA Reg. No. 62719 - 304) Granular Broadcast or Mound Treatment Control Fire Ants 0.0003 lbs ai/acre Fruit fly bait (EPA Reg. No. NAF - 550) Granular Broadcast Non - crop vegetation 0.0003lb ai/acre Spinosad 0.5% SC (EPA Reg. No. 62719 - 314) Soluble Concentrate Broadcast spray Home Gardens 0.086 lb ai/acre Spinosad 0.5% SC (EPA Reg. No. 62719 - 314) Soluble Concentrate Mound Treatment Control Fire Ants 0.0013 lb ai/mound

Spinoteram AssurityTM (EPA Reg. No. 72642 - 9) Spot - on Spot - on applicator Cats and Kittens (8 weeks or older) 0.019 fl oz or 0.55

ml: 231 mg ai/treatment GF - 1640 WG - NC (EPA Reg. No. 62719 - 540) GF - 1587 SC - NC (EPA Reg. No. 62719 - 544) Dry Flowable Soluble concentrate Handheld sprayers Home Lawns, Gardens and Ornamentals 0.0005 lb ai/gal

(0.061 lb ai/acre) 1 Crops include apple and other pome fruits, asparagus, bushberries and caneberries, citrus trees, cole crops (brassica vegetables), cucurbits, fruiting vegetables, grape, leafy and dried herbs, leafy vegetables, stone fruits, strawberry, succul ent beans and peas, sweet corn and popcorn, tree nuts, t ree fruits, tuberous and corm vegetables. 2 Includes outdoor ornamentals (herbaceous and woody plants).