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**EPA REGISTRATION DIVISION -**  **COMPANY NOTICE OF FILING OF PESTICIDE PETITION**  **EPA Registration Division contact: Sidney Jackson (703) 305 -**  **7610 Interregional Research Project Number 4**  **Pesticide Petition Number:**  **3 E8**  **203** EPA has received a pesticide petition ( 3E8203 ) from Interregional Research Project Number 4 (IR - 4) Headquarters , IR - 4, Rutgers, The State University of New Jersey , 500 College Road East, Suite 201 W, Princeton, NJ 08540 requesting, pursuant to section 408(d) o f the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing or revising the tolerance s for residues of the insecticide spinetoram, including its metabolites and degradates. Compliance with the tolerance levels is to be determined b y measuring **XDE -**  **175 -**  **J** : 1 - H - as - indaceno[3,2 - d]oxacyclododecin - 7,15 - dione, 2 - [(6 - deox y- 3 - O - ethyl - 2,4 - di - O - methyl - a - L mannopy ranos yl )ox y] - 13 - [[(2R,5S,6R) - 5 - (dimethylamino)tetrahydro - 6 - methyl - 2H py ran - 2 - yl ]oxy] - 9 - eth yl - 2,3,3a,4,5,5a ,5b,6,9,10,11,12,13,14,16a,16b - hexadecahydro 14 - methyl - ,(2R,3aR,5aR,5bS,9S,13S,14R,16aS,16bR); **XDE -**  **175 -**  **L** : 1H - as - indaceno[3,2 - d]oxacyclododecin - 7,15 - dione, 2 - [(6 - deox y- 3 - O - ethyl - 2,4 - di - O - methyl - a - L mannopy ranos yl )ox y] - 13 - [[(2R,5S,6R) - 5 - (dimethylamino)tetrahydro - 6 - methyl - 2H py ran - 2 - yl ]oxy] - 9 - eth yl - 2,3,3a,5a,5b,6,9,10,11,12,13,14,16a,16b - tetradecahydro - 4,14 - dimethyl - , (2S,3aR,5aS,5bS,9S,13S,14R,16aS,16bS); **ND**   ** J** :(2R,3aR,5aR,5bS,9S,13S,14R,16aS,16bR) - 9 - ethyl - 14 - methyl - 13 - [[(2S,5S,6R) - 6 - methyl - 5 - (meth yl amino)tetrah ydro - 2H - py ran - 2 - yl ]ox y] - 7,15 - dioxo 2,3,3a,4,5,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b - octadecah ydro - 1H - as - indaceno[3,2 - d]oxacyclododecin - 2 - yl6 - deox y- 3 - O - eth yl - 2,4 - di - O - methyl - alpha - L - mannopy ranoside; and **NF -**  **J** : (2R,3S,6S) - 6 - ([(2R,3aR,5aR,5bS,9S,13S,14R,16a S,16bR) - 2 - [(6 - deox y- 3 - O ethyl - 2,4 - di - O - methyl - alpha - L - mannop yr anos yl ) oxy] - 9 - eth yl - 14 - methyl - 7,15 - dioxo 2,3,3a,4,5,5a,5b,6,7,9,10,11,12,13,14,15,16a,16b - octadecah ydro - 1H - as - indaceno[3,2 - d]oxacyclododecin - 13 - yl ]ox y) - 2 - methyltetrahydro - 2H - py ran - 3 - yl (meth yl )f

ormamide in or on the raw agricultural commodity coffee, green bean at 0.2 parts per million (ppm) , coffee, instant at 0.4 ppm , coffee, roasted bean at 0.4 ppm , cottonseed subgroup 20C at 0.04 ppm , caneberry

subgroup 13.07A at 0.7 ppm , bushberry subgroup 1 3 - 07B, except lingonberry at 0.25 ppm , f ruit, small, vine climbing, except fuzzy kiwifruit subgroup 13 - 07F at 0.5 ppm , berry , low growing, subgroup 13 - 07G, except blueberry , lowbush, and cranberry at 1.0 ppm , fruit, pome group 11 - 10 at 0.2 ppm , vegetable, fruiting, group 8 - 10 at 0.4 ppm , fruit, citrus, group 10 - 10 at 0.3 ppm , fruit, stone, group 12 - 12 at 0.2 ppm , onion, bulb, subgroup 3 - 07A at 0.1 ppm , onion, green, subgroup 3 - 07B at 2.0 ppm , nuts, tree, group 14 - 12 at 0.1 ppm . EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully

evaluated the sufficiency of the submitted data at this time or whether the data support granting of the petition. Additional data may be needed before EPA rules2

on the petition. It is also noted that the Agency has concluded that spinetoram should be considered toxicologically identical to another pesticide, spinosad. This conclusion is based on the following: (1) Spinetoram and spinosad are large molecules with nearl y identical structures; and (2) the toxicological profiles for each are similar (generalized sy stemic toxicity) with similar doses and endpoints chosen for human - health risk assessment. Spinosad and spinetoram sho uld be considered toxicologicall y identical in the same manner that metabolites are generall y considered toxicologicall y identical t o the parent. A. Residue Chemistry 1. Plant metabolism. The nature of the residue in plants (turnip, apple and lettuce) h as been determined using radiolabeled spinetoram and is adequatel y understood , per the EPA document entitled, ``Spinetoram: Residue Chemistry Summary

Concerning the Application of Spinetoram to Numerous Crop'' dated August 9, 2007 (DP#325387). Three metab olic pathways are believed responsible for the breakdown of spinetoram in plants. The first involves changes to the N - demethyl moiety on the forosamine sugar to give the N - demeth yland N - form ylmetabolites; it is believed photoly sis play s a key role in th is pathway . The second pathway involves cleavage of the macrolide ring s ys tem at one or more positions and results in a complex residue mixture of numerous components. The third involves changes to the XDE - 175 - J only and produces 3 - O - deethyl and C9 - pseud oagl ycone (in apples) or the C17 - pseudoagl ycone (in turnip tops). It is presumed the XDE - 175 - L underwent degradation b y the third pathway also, but too quickly

to allow detection of any m etabolites. Based on the plant metabolism studies and the product ratio of 3:1 for XDE - 175 - J and XDE - 175 - L, HED has established the residue of concern in plants for the purposes of tolerances enforcement and risk as spinetoram (XDE - 175 - J and XDE - 175 - L) plus the two metabolites: N - demethyl - XDE - 175 - J (also known as ND - J) and N - formyl - XDE - 175 - J (also called NF - J). 2. Analytical method. Per the Federal Register of October 10, 2007 ( 72 FR 57492 ) (FRL - 8149 - 9) supported by DP # 325387, August 9, 2008, EPA has determined adequate anal ytical methods are available for enforcement purposes for spinetoram in plant and animal matrices. For more details on the anal ytical methods and for specific GRMs, see the 2011 spinosad and spinetoram scoping document (EPA, D P# 446932, August 9, 2011). EPA conservatively concluded that for water, residues should be estimated using the total spinetoram residue method (EPA, DP# 331741, September 20, 2007). 3. Magnitude of residues. IR - 4 supports translation of the proposed to lerances for spinosad in coffee, green bean, coffee, instant, and coffee, roasted bean to spinetoram. Per the Federal Register of April 15, 1998 (63 FR 18329)(FRL - 5785 - 7), EPA previously concluded that the translation of spinosad residue data to spinetoram for crops was acceptable due to the similar chemical structures, similar residue levels for similar application rates, and the similar or lower application rates of spinetoram relative to spinosad . Translation of spinosad processing factors to spinetoram has also been deemed acceptable (EPA, DP# 325387, April 28, 2009) . Based on this, and the similar proposed3

use patterns of spinosad and spinetoram in coffee (with maximal use rates being lower for spinetoram than for spinosad) , the IR - 4 spinosad MOR trials in coffee

— summarized in a separate Notice of Filing

— support spinetoram tolerances of 0.2 ppm for coffee, green bean and 0.4 ppm for coffee, instant and coffee, roasted bean . IR - 4 requests revisions to the following crop groups/subgroups based upon esta blished tolerances: onion, bulb subgroup 3 - 07A; onion, green subgroup 3 - 07B; 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 ; small fruit vine, climbing subgroup, except fuzzy kiwifruit 13 - 07F; low growing berry subgroup 13 - 07G, except blueberry , lowbush, and cranberry ; tree nut group 14 - 12; and cottonseed subgroup 20C. B. Toxicological Profile . The toxicity database for spinet oram relies on studies for spinetoram as well as studies for a similar spinosyn insecticide, spinosad. EPA concluded that spinetoram is toxicologically identical to the pesticide spinosad “in the same manner that metabolites are generall y considered toxic ologicall y identical to the parent”. EPA picked the lowest of the spinosad and spinetoram endpoints for each exposure scenario. A summary of the toxicological endpoints for spinosad and spinetoram used for human risk assessment can be found at http://www.regulations.gov in docket EPA - HQ - OPP - 2007 - 0310. Relevant information is summarized in the subsections below. Per ``Spinetoram: Human Health Risk Assessment for Numerous Proposed Application Scenarios'' dated September 20, 2007 (DP#331741), EPA determined the toxicological profile and endpoints for spinetoram are adequate for risk assessment evaluations and determination of FQPA. Under the new 40 CFR Part 158 data requirements for spinosad/spinetoram, there are no missing studies at this time. There was no evidence of increased pre - and post - natal susceptibility based on prenatal developmental toxicity

studies (rat and rabbit) and 2 - generation reproductive toxicity studies (rat) with either spinosad or spinetoram . In addition, there was no evidence of neurotoxicity

in the toxicity

database that included acute and subchronic neurotoxicity studies with spinosad and an acute neurotoxicity study with spinetoram. An immunotoxicity

study has been conducted with Spinosad and EPA’s initial review indicate the level of concern for immunotoxicity is low ( EPA, DP# 446932, August 9, 2011 ). 1. Acute toxicity. No appropriate endpoint attributable to a single dose was identified; the EPA has not established an acute reference dose ( RfD ) for spinetoram. 2. Genotoxicty. All mutagenicity studies conducted on spinetoram were negative. 3. Reproductive and developmental toxicity. EPA has concluded there is no evidence of increased susceptibility of rat and rabbit fetuses to in ut ero exposure to spinetoram. In the developmental toxicity study in rats, no developmental effects were observed at dose levels that induced maternal toxicity . In the developmental study in rabbits, no developmental toxicity was seen at dose levels that i nduced maternal toxicity . In the 2 - generation reproduction study , no offspring toxicity occurred. Parental/sy stemic toxicity was observed at a lower dose than the dose at which offspring showed no effects.4

EPA has determined that “reliable data show that it would be safe for infants and children to reduce the 10x FQPA safety factor to 1x.” 4. Subchronic toxicity. Both Short - term endpoints (inhalation and incidental oral) were established for spinetoram based on the Oral no - observed adverse effect level (NOAEL ) of 4.9 mg/kg/day from the subchronic feeding study in dogs with spinosad and a Level of Concern ( LOC ) for the Margin of Exposure ( MOE ) of 100. 5. Chronic toxicity. EPA used the lowest NOAEL of 0.249 mg/kg/day from the chronic toxicity

study in d ogs for spinetoram and a 100X UF to establish a chronic reference dose ( cRfD ) of 0.0249 mg/kg/day . Spinetoram is considered ``Not likely to be Carcinogenic to Humans'' based on its similarity to spinosad. 6. Animal metabolism. From single and multiple dose ADME studies in rats, it was estimated that the fraction of an orall y administered dose absorbed is 70% or greater for both isomers of spinetoram. Fecal excretion was the major route of elimination, while urine was a minor route (10% or less of the ab sorbed dose). At 168 hours post - dosing, the radioactivity did not exceed 1% of the administered dose in any of the anal yz ed tissues. The majority

of the radioactivity

recovered for urine and fecal extracts was present as parent plus several metabolites including the glutathione and hydroxylated conjugates. Livestock metabolism studies conducted in the goat and hen were confirmatory

that excreta account for the majority of the recovered administered dose; this especially

true in the hen (91 to 93%). In the hen, the highest residues were observed in the fat followed b y skin fat, liver, eggs and muscle. 7. Metabolite toxicology . Per the Federal Register of March 19, 2008 (Vol 73, No 54; FRL - 8344 - 1), the results of the plant and animal metabolism studies and toxicity testing have been assessed. Metabolite toxicity has been addressed by

establishment of the total residue for tolerance purposes as the parent materials XDE - 175 - J and XDE - 175 - L plus the two metabolites: ND - J and NF - J. Per the EPA Hunan Health Risk Assessment for Spinetoram of Sept 20, 2007 (DP#331741), it was concluded that the demethylated, deeth yl ated and h ydrox yl ated forms of the parent are “highl y unlikel y” to be more toxic than the parent. 8. Endocrine disruption . The EPA’s EDSP (Endocri ne Disruptor Screening Program) is still under development. For now, the EPA has concluded that “the NOAELs derived from the reproduction/fertility study , are well defined and together with the 100X UF, will provide adequate protection for potential endoc rine effects.” C. Aggregate Exposure 1. Dietary exposure. i. Acute exposure. No quantitative acute dietary exposure assessment has been required for spinosad. ii. Chronic exposure. Spinosad and spinetoram are deemed toxicologicall y equivalent b y EPA. Based on the similarity of the insecticides and the anticipated markets for each, it is unlikely

that spinosad and spinetoram will be applied to the same crop. Hence, EPA aggregated exposure b y either assuming that all commodities contain spinosad (becaus e5

side - by- side spinosad and spinetoram residue data indicated that spinetoram residues were less than or equal to spinosad residues) or summing the percentage of a crop that would be treated with spinosad and the percentage that would be treated with spine toram. i. Food. The chronic dietary exposure assessment (EPA, DP#380915, August 18, 2010) was recreated in Dietary Exposure Evaluation Model - Food Consumption Intake Database (DEEM - FCID) (version 3.14) as a starting point **.** The new proposed tolerance values for coffee commodities were included in this dietary assessment. The EPA anal ys is assumed 100% crop treated for many commodities, tolerance - level residues, and default processing factors, but with several exceptions: average field trial residues were applied for the cucurbit vegetables (group 9), citrus (group 10), pome fruit (group 11), cereal grain (group 15), herbs (group 19a), spices except black pepper (group 19b), banana and plantain, strawberry , and grape; average United States Department of Agriculture ( USDA ) Pesticide Data Program (PDP) detected residues were applied for cherry and peach, with the peach residues applied to fennel as well; experimental processing factors were applied for corn meal, corn oil, corn flour, corn starch, wheat flour , wheat germ, apple juice, raisin, and orange juice, with the orange juice processing factor applied to all citrus juice. Ruminant and hog residues were estimated based on reasonabl y balanced dietary burdens and extrapolation from a dermal pour - on study ( a cancelled use) to the registered premise application for estimation of residues resulting from dermal absorption. Poultry residues were also estimated based on reasonably balanced dietary

burdens and the premise application. ii. Drinking water. Drinki ng water estimates were previously determined based on EPA screening models and concentrations were directly entered into the dietary exposure model. For spinosad, estimated environmental concentrations (EECs) for chronic exposures are conservatively calculated based on a total residue approach to be 10.5 ppb for surface water using the First Index Reservoir Screening Tool (FIRST) and 1.1 ppb for ground water using the Screening Concentration in Ground Water (SCI - GROW) model (EPA, DP#331271, July

28, 2006). Thus, for the joint chronic dietary risk assessment, EPA has used the water concentration value of 10.5 ppb to assess the contribution to drinking water. This value was supported b y a 2010 drinking water assessment in support of a seed treatment use for spinosad (EPA, DP#377550, November 15, 2010). 2. Non - dietary exposure . EPA has determined there is potential for residential handler and post - application exposures to spinosad/spinetoram. Because spinosad and spinetoram control similar pests, EPA concluded these products will not be used in combination with each other and combining the residential exposures is unnecessary . The most recent residential exposure assessment was performed in 2011 (EPA, DP# 446932, August 9, 2011), however in 2012, new “Stan dard Operating Procedures (SOPs) for Residential Pesticide Exposure Assessment” were released by EPA. Residential exposure assessments have been updated to reflect the new SOPs . Short - term residential inhalation risks were estimated for adult residential handlers, as well as short - term post application incidental oral risks for toddlers, based on applications to home lawns, home gardens and ornamentals. Additionally , short - term and intermediate - term post application incidental oral risks for toddlers wer e estimated based on a cat/kitten spot - on6

application. D. Cumulative Effects EPA has not made a common mechanism of toxicity finding as to spinosad and any other substances and spinosad does not appear to produce a toxic metabolite produced b y other sub stances. EPA’s H ealth E ffects D ivision (HED), Hazard Assessment and Policy

Committee noted that toxicologically equivalent does not imply a cumulative assessment which involves the concepts of mechanism of toxicity and potency . For the purposes of tolerance action, it is not assumed that spinosad has a common mechanism of toxicity with other substances. E. Safety Determination The proposed actions of this petition have been added via DEEM to EPA’s most recent dietary assessment for spinetoram/spinosad (E PA, DP#380915, August 18, 2010) and the residential assessment has been updated to reflect current EPA practices. The additional exposure from the proposed coffee use is estimated to be 0 to 0.02% of the cPAD. Short - term, intermediate - term, and chronic a ggregate exposure estimates all resulted in MOEs that were above the establishe d LOC of 100 . Dow AgroSciences concludes with reasonable certainty that no harm will result to the general population or infants and children from the aggregate exposure to spinetoram residues from these uses. 1. U.S. population. The resulting dietary (food and drinking water) exposure estimates are not of concern to E PA ; exposure for the general population is estimated as <11% of the cPAD. When the dietary exposure is summed with the estimated residential inhalation exposure, the resulting short - term aggregate MOE value was approximately 1800. 2. Infants and children . EPA has determined that reliable data allow a reduction of the FQPA safety factor to 1X for infants and chi ldren **.** The resulting dietary exposure for the most exposed subpopulation (children 1 to 2 years) is estimated as <28% of the cPAD . Short - term post - application risks were estimated for toddlers, based on application to home lawns, home gardens, ornamental s, and pets and risks were not of concern given that resulting MOEs were > 500 . The resulting short - term aggregate MOE values were >300 and are, therefore, not of concern to E PA . Intermediate - term post application risks were estimated for toddlers, based on application to pets and risks were not of concern given resulting MOEs were ≥ 700. The resulting intermediate - term aggregate MOE values were >200 and are, therefore, not of concern to E PA . F. International Tolerances International MRL s are in place f or spin etoram on coffee beans in the EU and Australi a . The USDA MRLdatabase, the third party database Homologa, the EU SANCO website, the Australian MRLwebsite, and the Japan MRLwebsite were queried for MRL s germane to this petition. These MRL s are li sted to the best of our knowledge; no claim is made regarding the verification of these values relative to the national authorities.7 **Spinetoram Comm**  **odity Existing MRL**  **a (ppm)**  **Regulatory Authority** Coffee beans 0.1* EU Coffee beans 0.01* Australia athe * and T notations are direct translations from the country website listings.