EPA REGI STRATION DIVISION COMPANY NOTICE OF FILING FOR PESTI CI DE

PETI TI ONS PUBLISHED IN THE FEDERAL REGI STER Interregional Research Project #4 Pesticide Petition, PP# 4E8298 EPA h as received a pesticide petition, PP# 4E8298, from Interregional R esearch Project Number 4 (IR - 4) , Rutgers, The State University of New Jersey , 500 College Road East, Suite 201 W, Princeton, NJ 08540 request ing, 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 methoxy fenozide, including its metabolites and degradates . Compliance with the tolerance levels is to be determined b y measuring only

the active ingredient: methoxy fenozide 3 - methoxy- 2 - methylbenzoic acid 2 - (3,5 - dimethylbenzoyl) - 2 - (1,1 - dimethylethyl) hydrazide . The petition requests to establish the following tolerances in or on the raw agricultural commodity under paragraph (a): Chive, fresh leaves at 30 p arts per million (p pm ); fruit, stone, group 1 2 - 12 except plum, prune, fresh at 3.0 ppm ; and nut, tree, group 14 - 12 at 0.1 ppm. Additionally , the petition seeks to amend o nion, green , subgroup 3 - 07B at 5.0 ppm to o nio n, green, subgroup 3 - 07B, except chive at 5.0 ppm; and Herb subgroup 19A, except chi ve at 400 ppm to Herb subgroup 19A , except chive, fresh leaves at 400 ppm . It is also proposed that the tolerance s under paragraph (a) be removed upon the approval of the proposed tolerances listed above : Fruit, stone, group 12, except plum, prune, fresh at 3.0 ppm ; p istachio at 0.10 ppm ; and nut, tree, group 14 at 0.1 ppm . Finally, it is proposed that the tolerance under paragraph (d) of chive at 4.5 ppm be removed upon approval of the proposed tolerances listed above . EPA has determined that the petit ion 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 supports granting of the petition. Additional dat a may be needed before EPA rules on the petition. A. Residue Chemistry 1. Plant metabolism. Per the EPA anal yt ical summary for methox yf

enozide (D. Rate, US EPA, DP358341, June 10, 2009), the nature of the residue of methoxyfenozide in plants has been st

udied in several plants (apple, cotton, grape and rice) and is adequatel y understood. 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 tole rance enforcement in primary crops and animal commodities. Analy tical methodology

for the magnitude of residue studies was based on Dow AgroSciences2

method GRM 02.25 “Determination of Residues of Methoxy fenozide in High Moisture Crops by L iquid Chromatogr aph y with Tandem Mass Spectrometry Detection“. 3. Magnitude of residues. The proposed tolerance for chives, fresh leaves at 30ppm is supported by

magnitude of residue studies in chives (fresh leaves). The amendment adding dried chives to complete Herb subgroup 19A , except chive, fresh leaves, is supported b y m agnitude of residue studies in chives (dried leaves) . Thus, the established tolerance of 400ppm for Herb subgroup 19A , except chive, fresh leaves is adequatel y supported . Interregional Regional R esearch Project No. 4 (IR - 4) recentl y completed trials in chives with 1 day

PHI ( IR - 4 PR No. 07240 , December 20 , 2013 ). Residues of methoxyfenozide were determined following 4 foliar applications of Intrepid 2F at 2 field locations in California and 1 fie ld location in Maryland during the 2012 growing season. Methox yf enozide was applied at a target rate of 0. 25 lb ai/A, for a total of approximately 1.0 lb ai/A. A surfactant was included in each tank mix. M arketable chives and chives for drying were coll ected 1 day after the final application. Methox yfenozide observed residues in fresh leaves ranged from 5.7 - 13 ppm with a HAFT of 12.5 . For the dried leaves , methoxy fenozide observed residues ranged from 12 - 118 ppm with a HAFT of 115 ppm. The LOD and LOQ values were calculated as 0. 00160 ppm and 0. 00480 ppm, respectivel y for fresh chives and 0.0146 ppm and 0.0438ppm, respectivel y for dried chives . IR - 4 requests revisions to the following crop groups/subgroups based upon established tolerances: stone f

ruit group 12 - 12 except plum, prune, fresh ; tree nut group 14 - 12. B. Toxicological Profile The toxicological profile for methox yfenozide 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 2012 Human Health review (Collantes, US EPA, D388978, May

23, 2012) and the 2013 Human Health Assessment Scoping Document in Support of Registration Review (Swartz, US EPA, D 408668) , and the endpoints for risk assessment are re iterated in EPA’s most recent dietary assessment (EPA, Holman, D389738, 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 methox yf enozide 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 (Rate, 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 developmenta l toxicity studying rats and the developmental toxicity

study in rabbits. Since no acute toxicological endpoints were established, no acute assessment is required .3 2. Genotoxicty. Per the 2009 Human Health review (Rate, EPA - HQ - OPP - 2009 - 0012 - 0004, D35798 3, July 22, 2009), methoxy fenozide 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, 20 09), methox yfenozide “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 stud y in rats. 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 (FQ PA 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 toxicologicall y significant effects were mild anemia and mild effect s on the liver, thy roid gland, and adrenal gland. In subchronic and chronic oral studies in dogs, the predominant toxic effect was anemia, which was often accompanied b y signs of a compensatory

response . In 2012 (Colantes, US EPA, D388978, M ay 2012), new inhalation endpoints for Short - Term (1 - 30 day s) 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 - O PP 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 th yroid and possible adrenal toxicity observed at the LOAEL of 411 mg/kg/d ay

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 anal yt ical summary for methoxy fenozide (D. Rate, US EPA, DP358341, June 10, 2009), the qualitative nature of methox yf enozide residues in livestock are adequatel y understood based on ruminant and poultry metabolism studies. The residue of con cern is parent in milk and ruminant tissues (except meat by products), poultry

meat and fat. The residues of concern in meat b yproducts and eggs are methox yf enozide and the RH - 141,518 metabolite . 7. Metabolite toxicology . Per the 2009 Human Health review (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 methox y4

group and oxidative hydroxylation of the B - ring methyl groups followed by conjugation with glucuronic acid. No significant sex - related or dose - dependent differences in metabolic disposition were noted. The methox yfenozide glucuronide conjugates are considered to be less toxic than the parent compound because glucuronide conjugation is well known to be a commonly occurring detoxification mechanism in mammalian species since it results in the formation of more polar, more water - soluble metabolites which are readil y and easily excreted from the bod y (in this case, in the bile and urine). F urther, 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 b y inclusion of RH - 141,518 along with the parent methoxyfenozide in the residue of concern for certain commodities: ruminant liver and kidney , eggs, poultry

live r and poultry

meat b yproducts . 8. Endocrine disruption . The available mammalian toxicity and toxicokinetic studies on methoxyfenozide, includi ng a 2 - generation reproduction study , developmental toxicity studies in two species, and repeat dose toxicity studies ranging from 28 day s to 2 ye ar studies in three species (rat, mouse, and dog), do not demonstrate that methoxyfenozide possesses endocrine 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 2013 EPA dietary assessment (EPA, Holman , D412460 , July 16, 2013 ). The Dietary Exposure Eva luation ModelTM (DEEM - FCID, ver. 3.14 ) software was employ ed. 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 methox yfenozide. These anal ys es cover all registered crops, as well the proposed tolerance s for chives , and also includ es pineapple which is currentl y under review . Additionally , the analy ses include tolerances for peas, blackey ed, seed and pea, southern, seed at 4.0ppm (these were omitted from the DEEM file in D412460, perhaps as an oversight when crop group 6C was revis ed (D412460, Table 1). The current dietary 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 th e exception of a methox yf enozide - 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 analy sis and risk assessment for methoxyf enozide. The previous EPA estimates of 43.4 ppb were conservatively increased b y EFED based on new model assumptions in 2013 ( Milians, US EPA, D407566, April 23, 2013 ). F or potential drinking water exposures , the new value of 251 ppb ha s been directl y in corporated in the DEEM - FCID into the food categories “water,5

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 mg/kg/day . The Tier - I DEEM exposure for food and water with revised proposed tolerances resulted in an estimated exposure of 0.031627 mg/kg/day for the US general population which is 31.6% of the chronic RfD. For the most highly exposed popul ation subgroup, children 1 to 2 y ears old, the estimated exposure is 0.085929 mg/kg /day at 85.9% of cPAD. These results are conservative (health protective) risk estimates. Refinements such as use of percent crop - treated information and/or anticipated r esidue 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 preclude homeowner use on ornamentals. Thus in accordance with FQPA, EPA conducted an aggregate assessment to include residential handler exposure for adults in the most recent review (Collantes, US EPA, D407285, Augus t 6, 2013) . The dietary exposure of the general adult US population was aggregated with exposure estimates from residential use of a backpack spray er treatment of ornamentals. The calculated exposure resulted in an aggregate MOE of 5 30 , which is signific antl y higher than the stated LOC of 100 for methoxyfenozide, and thus is not of concern. The current assessment resulted in slightly higher estimates of adult dietary exposure but no change in the MOE for adults which remained at 530 ; the risk estimate is not of concern for adults . It is also noted that for children, the EPA concluded that: “there are no residential uses of methox yfenozide that would result in significant postapplication exposure to children, based on ornamental use only . Therefore the a ggregate 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 “available infor mation” 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 mechanism 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 prod uce a toxic metabolite produced b y other substances. For the purposes of this tolerance action, therefore, it is assumed that methox yfenozide does not have a common mechanism of toxicity with other substances . E. Safety Determination 1. U.S. population . Using the DEEM 3. 16 exposure assumptions described above,6

the dietary

and water exposure to methoxy fenozide from the current and proposed new tolerances will utilize 31.6 % of the chronic RfD for the US population. EPA generally has no concern for exposures below 100% of the chronic RfD. It is concluded that there is a reasonable certaint y that no harm will result to US - general population from dietary exposure to methoxyfenozide residues . When the food, water and residential exposures are aggregated for a dults , the resulting MOEs are 530 , which are well above the LOC of 100 ; values above the LOC are t ypicall y 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, July 22, 2009 0, EPA has previousl y determined that an additional safet y 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 methoxyfenozide with the current and proposed new tolerances, the highest exposed subpopulation is children 1 - 2 y ears at 85.9 % of the cPAD. EPA generall y has no concern for exposures below 100% of the cPAD because the cPAD represents the level at or below which dail y aggregate di etary exposure over a lifetime will not pose appreciable risks to human health. 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 L evels (MRLs) for methoxyfenozide in a variety of crops. The related international MRL s are found in the following table based on a review of MRL s compiled by searches in the USDA MRL database ( http://www.mrldatabase.com/results.cfm ), Homologa ( http://www.homologa.com/ ), the EU SANCO website ( http://ec.europa.eu/sanco_pesticides/public/index.cfm ), Japan MRLlisting ( http://www.m5.ws001.squarestart.ne.jp/foundation/agrdtl.php?a_inq=75700 ) and the Australian MRLwebsite ( http://www.comlaw.gov.au/Details/F2014C00164/Download ). Homologa is a third party database; Dow AgroSciences makes no claim regarding the veri fication of these values relative to the individual national authoritative sources. Commodity

a Existing MRL a (ppm) Regulatory

Authority Chives 4 EU SANCO Herbs T20 Australia ‘Other herbs’ 30 Japan ‘Other spices’ 30 Japan a as listed on regulatory authority websites b A “T” denotes that the MRLor ERL, residue definition or use is temporary to enable further experimental work to be carried out in Australia or overseas, and will be reconsidered at some future date.7