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**EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER**  **EPA Registration**  **Division contact: [insert name and telephone number with area**  **code] INSTRUCTIONS:**  **Please utilize this outline in preparing the pesticide petition. In**  **cases where the outline element does not apply, please insert “NA -** **Remove” and maintain the outline. Please do not change the margins, font, or format in your**  **pesticide petition. Simply replace the instr uctions that appear in**  **green , i.e., “**  **[ insert**  **company name ]**  **,” with the information specific to your action. TEMPLATE:**  [ **Dow AgroSciences, LLC** ] [Insert petition number] EPA has received a pesticide petition ( [insert petition number] ) from [ **Dow AgroScienc**  **es, LLC** ] , [ **9330 Zionsville Rd., Indianapolis, IN 46268** ] requesting, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a tolerance for residues of [ **methoxyfenozid e, including its metabolites and**  **degradates . Compliance**  **with the tolerance levels is to be determined by measuring only the active ingredient: methoxyfenozide**  **[3 -**  **methoxy -**  **2 -**  **methylbenzoic acid 2 -**  **(3,5 -**  **dimethylbenzoyl) -**  **2 -**  **(1,1 -**  **dimethylethyl) hydrazide]** ] in or on the raw agricultural commodity [ **under paragraph (a) as Pineapple**  ] at [ 0. **7** ] parts per million (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 no t fully evaluated the sufficiency

of the submitted data at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition. A. Residue Chemistry 1. Plant metabolism. **[Per the EPA analytical summary for methoxyfenozide**  **(D. Rate, US EPA, DP358341, June 10, 2009), the nature of the residue of methoxyfenozide in plants has been studied in several plants (apple, cotton, grape**  **and rice) and is adequately understood.**2 2. Analytical method. [ **Per a recent 2012 decision on tolerances (M. Collantes,**  **US EPA, D388978, May 23, 2012), EPA stated adequate single methods are available**  **for tolerance enforcement in primary crops and animal commodities. Analytical**  **methodology for the magnitude of residue stud ies was based on Dow AgroSciences**  **method GRM 02.25 “Determination of Residues of Methoxyfenozide in High Moisture Crops by Liquid Chromatography with Tandem Mass Spectrometry**  **Detection“.** ] 3. Magnitude of residues. [ **The proposed tolerance**  **in pineapple is**  **supported by magnitude of residue studies in**  **pineapple . Thus,**  **t he requested tolerance**  **is adequately supported**  **. Dow AgroSciences**  **recently completed trials in pineapples**  **with 3 and 10**  **day PHI s**  **( Dow AgroSciences Study**  **No. 1**  **1 0**  **317 ,**  **March 14**  **, 2012 ). Residues o**  **f methoxyfenozide**  **were determined following 4**  **foliar applications of GF**  **- 837**  **at 4 field locations in C**  **osta Rica and 4 field locations in Hawaii during the 201**  **1 growing**  **season. Methoxyfenozide was applied at a target rate of 0.**  **107 lb ai/A, for a total of**  **ap proximately**  **0. 428**  **lb ai/A. A surfactant was included in each tank mix.**  **M arketable**  **ma ture fruit**  **was collected**  **3 and 10 day**  **s after the final application**  **. For**  **the 3 -**  **day PHI, m ethoxyfenozide**  **observed residues in**  **pin e**  **apple ranged from**  **0.0808 -**  **0.365 ppm**  **with a HAFT of 0.346**  **in the Hawaii trials and 0.0276**  **- 0.0824 ppm**  **with a HAFT of 0.0626**  **in the Costa Rica trials .**  **Fo r the 10**  **- day PHI, m**  **ethoxyfenozide observed**  **residues in pineapple**  **ranged from 0.109**  **- 0.374**  **ppm with a HAFT of 0.355**  **ppm in the Hawaii trials and 0.01**  **89 -**  **0.0277 ppm with a HAFT of 0.0266 ppm in the Costa Rica trials**  **. The LOD and LOQ values were calculated as 0.003 ppm and**  **0.00 1**  **ppm, respectively for pineapple**  **. ]**  B. Toxicological Profile **[ The toxicological profile for methoxyfenozide which**  **supports this petition to revise tolerances**  **was reviewed in**  **2009 ( Rate, EPA** **- HQ**  **** **OPP -**  **2009 -**  **0012 -**  **0004, D357983, July 22, 2009 ) and again in the**  **the 20 12**  **Human Health review (**  **Collantes, US EPA, D388978, May 23, 2012 ), and the endpoints for**  **risk assessment are reiterated in E PA’s most recent dietary assessment (EPA,**  **Holman , D**  **389738 ,**  **March 2, 2012 ). EPA has concluded “The toxicity database is**  **considered complete for the purposes of characterizing the hazard associated with methoxyfenozide and for conducting a human health risk**  **assessment.” EPA has not**  **established an acute reference dose for methoxyfenozide and the chronic RfD is equivalent to the chronic PAD = 0.1 mg/kg/day, because the FQPA SF has been**  **reduced to 1X .**  **]** 1. Acute toxicity. [ **Per the 2009 Human Health review (R ate, EPA** **- HQ**  **- OPP**  **** **2009 -**  **0012 -**  **0004, D357983, July 22, 2009) , no significant acute hazards were attributable to a single exposure in the available toxicology studies on**  **methoxyfenozide including the acute neurotoxicity study in rats, the developmental toxicity**  **studying rats and the developmental toxicity study in rabbits. Since no acute toxicological endpoints were established, no acute assessment is required**  .] 2. Genotoxicty. [ **Per the 2009 Human Health review (Rate, EPA -** **HQ -**  **OPP -** 3

**2009 -**  **0012 -**  **0004, D357983, July 22, 2009), methoxyfenozide demonstrated a “lack of**  **genotoxicity in an acceptable battery of mutagenicity studies.” ]**  3. Reproductive and developmental toxicity. [ **Per the 2009 Human Health review (Rate, EPA** **- HQ**  **- OPP**  **- 2009**  **- 0012**  **- 0004, D357983, July 22, 2009),**  **m ethoxyfenozide “is not a developmental or reproductive toxicant”. The toxicology**  **data base available for methoxyfenozide included acceptable developmental toxicity studies in both rats and rabbits as well as a 2**  **- generation reproductive toxicity study**  **in r ats. The data provided no indication of increased sensitivity of rats or rabbits to**  **in utero and/or postnatal exposure to methoxyfenozide. EPA determined that an additional safety factor was not needed for the protection of infants and children**  **(FQPA SF = 1x).**  **]** 4. Subchronic toxicity. [ **Per the 2009 Human Health review (Rate, EPA -**  **HQ**   ** OPP** **- 2009**  **- 0012**  **- 0004, D357983, July 22, 2009), in subchronic and chronic oral**  **studies in rats, the most toxicologically significant effects were mild anemia and mild effects on**  **the liver, thyroid gland, and adrenal gland. In subchronic and chronic oral studies in dogs, the predominant toxic effect was anemia, which was**  **often accompanied by signs of a compensatory response .**  **In 2012 (Colantes, US EPA, D388978,**  **M ay 2012),**  **new inha lation endpoints for Short** **- Term (1**  **- 30 days)**  **and Intermediate Term (1 -**  **6 months) were established with a NOAEL of 16.8 mg/kg/day for use in residential and occupational assessments** 

. ] 5. Chronic toxicity. [ **Per the 2009 Human Health review (Rate, EPA -** **HQ -**  **OPP**   ** 2009** **- 0012**  **- 0004, D357983, July 22, 2009), the chronic population**  **- adjusted dose**  **(cPAD) is 0.1 mg/kg/day based on hematological changes, liver toxicity, histopathological changes in thyroid and possible adrenal toxicity observed at the**  **LOAEL of 411 mg/kg/day**  **in a chronic toxicity study in rats** .] 6. Animal metabolism. [ **Per the 2009 Human Health review (Rate, EPA -**  **HQ**   ** OPP** **- 2009**  **- 0012**  **- 0004, D357983, July 22, 2009), in a metabolism study in rats, 14C**  **** **methoxyfenozide was rapidly absorbed, distributed, metabolized an d almost**  **completely excreted within 48 hours. The major route of excretion was feces (86 -**  **97%) with lesser amounts in the urine (5 -**  **13%). Metabolism of methoxyfenozide in other animals (poultry and ruminants) appears to be similar to its metabolism in**  **rats. Per the EPA analytical summary for methoxyfenozide (D. Rate, US EPA,**  **DP358341, June 10, 2009), the qualitative nature of methoxyfenozide residues in livestock are adequately understood based on ruminant and poultry metabolism**  **studies. The residue of con cern is parent in milk and ruminant tissues (except meat**  **byproducts), poultry meat and fat. The residues of concern in meat byproducts and eggs are methoxyfenozide and the RH**  **- 141,518 metabolite**  **.** ] 7. Metabolite toxicology

. [ **Per the 2009 Human Health revi ew (Rate, EPA** **- HQ**  **** **OPP -**  **2009 -**  **0012 -**  **0004, D357983, July 22, 2009), in a metabolism study in rats, methoxyfenozide is metabolized principally by O**  **- demethylation of the A** **- ring**  **methoxy group and oxidative hydroxylation of the B -**  **ring methyl groups followed by conju**  **gation with glucuronic acid. No significant sex -**  **related or dose -**  **dependent**4

**differences in metabolic disposition were noted. The methoxyfenozide glucuronide conjugates are considered to be less toxic than the parent compound because**  **glucuronide conjugation i s well known to be a commonly occurring detoxification**  **mechanism in mammalian species since it results in the formation of more polar, mo**  **re water -**  **soluble metabolites which are readily and easily excreted from the body (in this case, in the bile and urine).**  **Further, based on similarities of chemical structure, the non**  **- conjugated metabolites would be expected to be no more toxic**  **than the parent compound. Furthermore, HED has covered potential metabolite exposure by inclusion of RH**  **- 141,518 along with the paren**  **t methoxyfenozide in the residue of concern for certain commodities: ruminant liver and kidney, eggs,**  **poultry live r**  **and poultry meat byproducts** .] 8. Endocrine disruption

. [ **The available mammalian toxicity and toxicokinetic studies on methoxyfenozide, inc** **luding a 2 -**  **generation reproduction study, developmental toxicity studies in two species, and repeat dose toxicity studies**  **ranging from 28 days to 2 year studies in three species (rat, mouse, and dog), do not demonstrate that methoxyfenozide possesses endoc**  **rine disrupting properties that are relevant to humans**  .] C. Aggregate Exposure 1. Dietary exposure. [ **The starting point for this assessment was the DEEM file**  **from the 2012 EP** **A dietary assessment (EPA, Holman**  **, D389738**  **, March**  **2 , 20**  **12 ).**  **The Dietary Exposu re Evaluation ModelTM (DEEM** **- FCID, ver.**  **3.14 ) software was**  **employed. DEEM contains food consumption data based on NHANES 2**  **- day food**  **Consumption data for 2003 to 2008 and food translation to RACs, as indicated by**  **EPA/USDA FCID recipe set as of February 2012** 

. ] i. Food. [ **A chronic assessment was conducted to evaluate potential chronic dietary exposure of the U.S. population subgroups to residues of methoxyfenozide.**  **These analyses cover all registered crops, as well the**  **proposed tolerance. The current dietar** **y assessment is an unrefined Tier I assessment using tolerance values and 100% crop**  **- treated assumption to estimate dietary exposure to methoxyfenozide**  **and default processing factors for all food commodities, with the exception of a**  **methoxyfenozide -**  **specific processing factor for orange juice (0.2X).**  ] ii. Drinking water

. [ **There are no water -**  **related exposure data from monitoring to complete a quantitative drinking water exposure analysis and risk**  **assessment for methoxyfenozide. The previous EPA estimates of**  **33.1 ppb were**  **conservatively increased by EFED based on new model assumptions in 2012 (Gebken, US EPA, D388876, May 23, 2012). F**  **or potential drinking water exposures**  **, the new value of 43.4 ppb**  **ha s**  **been directly incorporated in the DEEM****** **FCID into the food categories “water, direct, all sources” and “water, indirect, all**  **sources.” Per the 2009 Human Health review (Rate, EPA** **- HQ**  **- OPP**  **- 2009**  **- 0012**  **- 0004, D357983,**  **July 22, 2009), the established chronic endpoints are cRfD = cPAD = 0.10**5

**mg/kg/day. The Tier -** **I DEEM e xposure for food and water with revised proposed**  **tolerances resulted in an estimated exposure of 0.0**  **23719 mg/kg/day for the US**  **general population which is 23.7**  **% of the chronic RfD. For the most highly exposed population subgroup, children 1 to 2 years old**  **, the estimated exposure is 0.0**  **63427 mg/kg/day at**  **6 3.4**  **% of cPAD. These results are conservative (health protective) risk estimates. Refinements such as use of percent crop**  **- treated information and/or**  **anticipated residue values would yield lower estimates of chronic dietary exposure.]**  2. Non

- dietary exposure

. [ **A new use in ornamentals was approved for methoxyfenozide in 2009.**  **Per the 2012 review ( Collantes, US EPA, D388978, May**  **23, 2012),**  **EPA made the conservative interpretation that the label did not pr eclude**  **homeowner use on ornamentals .**  **Thus in accordance with FQPA, EPA conducted an aggregate assessment to include residential handler exposure for adults. The**  **dietary exposure of the general adult US population was aggregated with exposure estimates fro**  **m residential use of a backpack sprayer treatment of ornamentals**  **. The**  **calculated exposure resulted in an aggregate MOE of 670**  **, which is significantly higher than the stated LOC of 100 for methoxyfenozide, and thus is not of concern**  **. The**  **current assessmen t resulted in slightly lower estimates of adult dietary exposure**  **(due to changes in the DEEM -**  **FCID dietary intake model) . Thus the small change**  **in the dietary contribution result ed**  **in a slight increase**  **in the**  **MOE for adults from**  **670 to 700; the risk estima**  **te is not of concern for adults**  **. It is also noted that for**  **children, the EPA concluded that: “**  **there are no residential uses of methoxyfenozide that would result in significant postapplication exposure to children, based on**  **ornamental use only. Therefore the aggregate exposure and risk for children is**  **equivalent to those from food and water .”**  **]** D. Cumulative Effects [ **Section 408(b)(2)(D)(v) requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency considers “availabl**  **e information” concerning the cumulative effects of a particular pesticide’s residues and “other**  **substances that have a common mechanism of toxicity.” EPA does not have, at this time, available data to determine whether methoxyfenozide has a common**  **mechan ism of toxicity with other substances or how to include this pesticide in a**  **cumulative risk assessment. Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity,**  **methoxyfenozide does not appear to produce a toxic metabolite produced by other**  **substances. For the purposes of this tolerance action, therefore, it is assumed that methoxyfenozide does not have a common mechanism of toxicity with other**  **substances .**  **]** E. Safety Determination 1. U.S. po pulation. [ **Using the DEEM 3.14 exposure assumptions described above, the dietary and water exposure to methoxyfenozide from the current and**  **proposed new tolerances will utilize 23.7**  **% of the chronic RfD for the US**6

**population. EPA generally has no concern f or exposures below 100% of the chronic**  **RfD. It is concluded that there is a reasonable certainty that no harm will result to US**  **- general population from**  **dietary exposure to methoxyfenozide residues**  **. When the food, water and residential exposures are aggrega** **ted for adults**  **, the resulting MOEs are**  **70 0**  **, which are well above the LOC of 100 ; values above the LOC are**  **typically not of a concern for the Agency .]**  2. Infants and children

. [ **Per the 2009 Human Health review (Rate, EPA -**  **HQ**   ** OPP** **- 2009**  **- 0012**  **- 0004, D357983, Ju**  **ly 22, 20090, EPA has previously determined that an additional safety factor was not needed for the protection of infants and children**  **(FQPA SF = 1x). Using the DEEM exposure assumptions described above for the dietary and water exposure to methoxyfenozid**  **e with the current and proposed new tolerances, the highest exposed subpopulation is children 1**  **- 2 years at**  **63.4 % of the**  **cPAD. EPA generally has no concern for exposures below 100% of the cPAD because the cPAD represents the level at or below which daily a**  **ggregate dietary exposure over a lifetime will not pose appreciable risks to human healt** **h. The residential uses are not anticipated to result in exposure to children, so the**  **aggregate exposure is equivalent to the dietary exposure, and therefore is not of concern.**  ] F. International Tolerances [ **Several governing bodies have established Maximum Residue Levels (MRLs) for methoxyfenozide in a variety of crops. The related international MRLs**  **are found in the following table based on a review of MRLs compile d by searches in**  **the USDA MRL database ( http://www.m** **rldatabase.com /results.cfm** **), Homologa (**  **http://www.hom ologa.com** **/ ), the EU SANCO website**  **( http://ec.europa.eu/sanco_pesticides/public/index.cfm** **), Japan MRL listing (**  **http://www.m 5.ws001.squarestart.ne.jp/foundation/agr**  **dtl.php?a_inq=75700 ) and the**  **Australian MRL website ( http://www.comlaw.gov.au/Series/F2008B00619**  **) . Homologa is a third party database;**  **Dow AgroSciences makes no claim regarding the verification**  **o f these values relative to the**  **individual national authoritative sources** 

. **Listed tolerance on pineapples, seem to have been driven by positive lists which are set at**  **the method LOQ level. Commodity**  **Existing MRLa (ppm)**  **Regulatory**

**Authority Pineapple**  **0. 02**  **EU SANCO Other Fruits**  **0.1 Japan**  **Pineapple 0.02**  **Chile** ]