Document ID: EPA-HQ-OPP-2011-0343-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2011-07-20T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITION 

EPA Registration Division contact: Sidney Jackson (703) 305-7610 

Interregional Research Project Number 4

PP# 1E7842 

     	EPA has received a pesticide petition (PP) 1E7842) from Interregional Research Project #4 (IR-4), IR-4 Project Headquarters, Rutgers, The State University of New Jersey, 500 College Road East, Suite 201 W, Princeton, NJ 08540 proposing, 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 tolerances for residues of methoxyfenozide, including its metabolites and degradates, in or on the raw agricultural commodities Fruit, citrus, group 10-10 at 1.9 parts per million (ppm); Lemon, oil at 45 ppm; Citrus, oil (except lemon) at 100 ppm; Vegetable, root, except sugar beet, subgroup 1B at 0.8 ppm; Beet, sugar at 0.5 ppm.  The petition also proposes to remove the established tolerances for Vegetable, root, subgroup 1A and citrus oil at 100 ppm from table in paragraph (a) as well as Fruit, citrus, group 10 from the table in paragraph (c) upon the approval of the proposed tolerances listed above, and additionally, the petition proposes to revise the tolerance expressions in 40 CFR part 180.544 to read as follows:
     
(a)(1) Tolerances are established for residues of the insecticide methoxyfenozide, 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 methoxyfenozide [benzoic acid, 3-methoxy-2-methyl-, 2-(3,5-dimethylbenzoyl)-2-(1,1-dimethylethyl) hydrazide].

(a)(2) Tolerances are established for residues of the insecticide methoxyfenozide, 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 methoxyfenozide  [benzoic acid, 3-methoxy-2-methyl-, 2-(3,5-dimethylbenzoyl)-2-(1,1-dimethylethyl) hydrazide] and its glucuronide metabolite (β-D-Glucopyranuronic acid, 3-[[2-(1,1-dimethylethyl)-2-(3,5-dimethylbenzoyl)-
hydrazino]carbonyl]-2-methylphenyl-), calculated as the stoichiometric equivalent of methoxyfenozide.

b) Section 18 emergency exemptions. Time-limited tolerances specified in the following table are established for residues of the insecticide methoxyfenozide, including its metabolites and degradates, in or on the specified agricultural commodities, resulting from use of the pesticide pursuant to FFIFRA section 18 emergency exemptions.  Compliance with the tolerance levels specified below is to be determined by measuring only methoxyfenozide [benzoic acid, 3-methoxy-2-methyl-, 2-(3,5-dimethylbenzoyl)-2-(1,1-dimethylethyl) hydrazide].  The tolerances expire and will be revoked on the date specified in the table.

d) Indirect or inadvertent residues. (1) Tolerances are established for the indirect or inadvertent residues of the insecticide methoxyfenozide, including its metabolites and degradates, in or on the raw agricultural commodities in the table below, when present therein as a result of the application of methoxyfenozide to growing crops as listed in paragraph (a) of this section.  Compliance with the tolerance levels specified below is to be determined by measuring only methoxyfenozide [benzoic acid, 3-methoxy-2-methyl-, 2-(3,5-dimethylbenzoyl)-2-(1,1-dimethylethyl) hydrazide].

(2)  Tolerances are established for the indirect or inadvertent residues of the insecticide methoxyfenozide, including its metabolites and degradates, in or on the raw agricultural commodities in the table below, when present therein as a result of the application of methoxyfenozide to growing crops as listed in paragraph (a) of this section.  Compliance with the tolerance levels specified below is to be determined by measuring only the sum of methoxyfenozide [benzoic acid, 3-methoxy-2-methyl-, 2-(3,5-dimethylbenzoyl)-2-(1,1-dimethylethyl) hydrazide] and the following metabolites (all calculated as the stoichiometric equivalent of methoxyfenozide): free phenol of methoxyfenozide [3,5-dimethylbenzoic acid N-tert-butyl- N′-(3-hydroxy-2-methylbenzoyl) hydrazide], the glucose conjugate of the phenol [3,5-dimethyl benzoic acid N-tert-butyl- N'-[3 (β-D-glucopyranosyloxy)-2-methylbenzoyl]-hydrazide] and the malonylglycosyl conjugate of the phenol [3,5-dimethyl benzoic acid N-tert-butyl- N'-[3 (β-D-6-malonyl-glucopyranosyl-1-oxy)-2-methylbenzoyl]-hydrazide].

      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 supports granting of the petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

	1. Plant metabolism. Per the most recent 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.  For primary crops and drinking water, the tolerance expression is methoxyfenozide per se.

	2. Analytical method. Per the most recent EPA analytical summary for methoxyfenozide (D. Rate, US EPA, DP358341, June 10, 2009), adequate enforcement methods are available for determination of methoxyfenozide residues in plant commodities.  Analytical methodology for the magnitude of residue studies in citrus was based on a procedure 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".  The limit of detection (LOD) and the limit of quantitation (LOQ) values in citrus were calculated as 0.0072 ppm and 0.022 ppm, respectively.  Analytical methodology for the magnitude of residue studies in root crops used a procedure based on the Rohm and Haas Technical Report No. 34-98-87, "Tolerance enforcement method for Parent RH-2485 in Pome Fruit" with minor modifications.  The LOD and LOQ values were calculated as 0.0028 ppm and 0.0084 ppm, respectively.

	3. Magnitude of residues. For carrots, IR-4 recently completed trials in carrot (IR-4 PR No. 09884, May 28, 2010) to support reduction of the PHI on root crops in subgroup 1B from 14 days to 1 day.  Residues of methoxyfenozide were determined following 4 foliar applications of Intrepid 2F insecticide in 8 field locations in the EPA Regions 3, 5, 6, and 10 during the 2007 and 2008 growing season.  Methoxyfenozide was applied at a target rate of 0.25 lb ai/A, for a total of approximately 1.0 lb ai/A.  Applications were made 14 (2) days apart and samples collected 1 day after the final application.  A decline trial also included samples at 0, 1, 3, 6, 7, and 10 days after the last application.  The methoxyfenozide residues in carrot roots ranged from a maximum of 0.130 ppm to a minimum of 0.0266 ppm with a 0.1245 HAFT (Highest Average Field Trial) value at the PHI of 1 day and some decline was noted over the 10 days within the decline trial.  

For radish, IR-4 recently completed trials (IR-4 PR No. 09895, June 14, 2010) to support reduction of the PHI on root crops in subgroup 1B from 14 days to 1 day.  Radish trials are limited to fewer applications based on the short growing season.  Residues of methoxyfenozide were determined following 2 foliar applications of Intrepid 2F insecticide across 4 Regions.  Methoxyfenozide was applied at a target rate of 0.25 lb ai/A, for a total of approximately 0.5 lb ai/A.  Applications were made 14 to 15 days apart and samples collected 1 day after the final application.  A decline trial also included samples at 0, 1, 3, 5, 7, and 9 days after the last application.  The methoxyfenozide residues in radish roots ranged from a maximum of 0.601 ppm to a minimum of 0.0442 ppm with a 0.453 ppm HAFT value at the PHI of 1 day and there was no significant decline over 9 days.

For citrus, IR-4 recently completed additional trials in orange, grapefruit and lemon (IR-4 PR No. A9367, August 25, 2010) to expand the currently approved regional use to a national registration for use of methoxyfenozide in citrus with a 1 day PHI.  Residues of methoxyfenozide were determined following four foliar applications of Intrepid 2F insecticide in 14 field locations in California, Florida and Texas during the 2008 growing season.  Methoxyfenozide was applied at a target rate of 0.25 lb ai/A, for a total of approximately 1.0 lb ai/A.  Applications were made 12 to 15 days apart and marketable citrus fruit was collected 1 day after the final application.  This new data is in addition to the 7 citrus trials (6 harvest trials and one processing trial) conducted from Regions 6 and 10 during 2005 and 2006 (IR-4 ID 09367, MRID 47556401, August 1, 2008; Federal Register of September 2, 2009 74 FRL-8433-8).

Based on the combined set of methoxyfenozide residues in citrus ranged from a maximum of 1.72 ppm to a minimum of 0.112 ppm with a 1.67 ppm HAFT value at the PHI of 1 day and there was no significant decline over the 14 days.  Residues ranges by sample type were: 0.191 to 0.1.72 ppm in oranges, from 0.112 to 0.312 ppm in grapefruit, and from 0.140 to 0.933 ppm in lemons).

The requested tolerances are adequately supported.

B. Toxicological Profile  The toxicological profile for methoxyfenozide which supports this petition to revise tolerances is assessed in the 2009 Human Health review (Rate, EPA-HQ-OPP-2009-0012-0004, D357983, July 22, 2009), and the endpoints for risk assessment are reiterated in EPA's most recent dietary assessment (EPA, Hanson, DP361376, July 7, 2009).  EPA has concluded "The toxicological database is adequate for the purpose of risk assessment and tolerance setting."

	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 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-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), methoxyfenozide "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 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 (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.

	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, [14]C-methoxyfenozide was rapidly absorbed, distributed, metabolized and 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 most recent 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 concern 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 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 methoxy 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 methoxyfenozide 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 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 parent methoxyfenozide in the residue of concern for certain commodities: ruminant liver and kidney, eggs, poultry live and poultry meat byproducts.

	8. Endocrine disruption. The available mammalian toxicity and toxicokinetic studies on methoxyfenozide, including 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 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 2009 EPA dietary assessment (EPA, Hanson, DP361376, July 7, 2009).  The Dietary Exposure Evaluation Model(TM) (DEEM-FCID, ver. 2.16, Exponent, Inc., Washington, DC-20036) software was employed.  DEEM contains food consumption data as reported by respondents in the USDA Continuing Surveys of Food Intake by Individuals (CSFII) conducted in 1994-1996 and 1998 and food translation to RACs, as indicated by EPA/USDA FCID recipe set as of August, 2002.

	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 as revised proposed tolerances.  The current dietary assessment is an unrefined Tier I assessment using tolerance values and 100% crop-treated assumption to estimate dietary exposure to methoxyfenozide.  DEEM (ver 7.81) default processing factors for all food commodities, with the exception of a methoxyfenozide-specific processing factor for orange juice (0.2X).  The proposed citrus, and root crop uses do not alter the livestock burden calculations; assessment of livestock tolerances is not required.

	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 for potential drinking water exposures have 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 mg/kg/day.  The Tier-I DEEM exposure for food and water with revised proposed tolerances resulted in an estimated exposure of 0.023895 mg/kg/day for the US general population which is 23.9% of the chronic RfD.  For the most highly exposed population subgroup, children 1 to 2 years old, the estimated exposure is 0.056857 mg/kg/day at 56.9% 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 recently approved for methoxyfenozide in 2009.  Residential uses are limited to commercial applications on ornamentals for use in areas such as parks, recreation areas and residential property.  Because there is no homeowner use, the potential exposure is limited to a post-application scenario.  To account for this additional use in the aggregate assessment, an estimate of the potential exposure according to the residential SOPs was conducted.  Per the ornamental use label for Intrepid 2F Insecticide, the maximum label rate is 0.25 lb/A.  Per the 2009 Human Health review (Rate, EPA-HQ-OPP-2009-0012-0004, D357983, July 22, 2009), methoxyfenozide has not shown significant toxicity by dermal and/or inhalation routes; endpoints were deemed unnecessary for dermal or inhalation exposure.  Therefore, only the combined oral exposure for toddlers was estimated.  Without a dermal endpoint, there is no assessment necessary for adult post-application exposure from ornamental uses.  For toddlers, the combined potential oral exposure from hand to mouth, soil ingestion and object to mouth as 0.003747 mg/kg/day.  Potential exposure was conservatively assessed against the chronic dietary NOAEL of 10.2 mg/kg/day which was determined in the 2-year chronic rat study.  The resulting MOE value of 2669 for the combined oral routes in toddlers is well above the 100 value threshold of concern for the EPA.

For children, the potential post-application short term exposure from the ornamental use pattern were combined with chronic dietary (food and water) exposure for determination of aggregate short-term exposure.  The combined exposures were conservatively assessed against the chronic dietary endpoint with an assumed level of concern for incidental oral exposure of 100, for an aggregate risk assessment.  The table below is a summary of the short-term aggregate exposures and risk estimates.  Because the aggregate MOE values are 170 or greater, short-term aggregate exposure to methoxyfenozide is not of concern.  Based on EPA's conclusion that no dermal or inhalation endpoints were necessary, no aggregate risk assessment was conducted for adult.

 Short-Term Aggregate Risk Calculations for Children
                                   Population
                                     NOAEL
                                  (mg/kg/day)
                                     Target
                                      MOE
                        Chronic Food and Water Exposure
                                  (mg/kg/day)
                           Residential Oral Exposure
                                  (mg/kg/day)
                               Aggregate Exposure
                                  (mg/kg/day)
                                 Aggregate MOE 
                         (food, water, and residential)
                              Children 1-2 yrs old
                                     10.2)
                                     Target
                                      MOE
                                    0.056857
                                    0.003747
                                    0.060604
                                      170
                              Children 3-5 yrs old
                                        
                                        
                                    0.044916
                                    0.003747
                                    0.048663
                                      210
                             Children 6-12 yrs old
                                        
                                        
                                    0.028025
                                    0.003747
                                    0.031772
                                      320

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 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 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 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. population. Using the DEEM exposure assumptions described above, the dietary and water exposure to methoxyfenozide from the current and proposed new tolerances will utilize 23.9% 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 certainty that no harm will result to US-general population from exposure to methoxyfenozide residues.

	2. Infants and children. Per the 2009 Human Health review (Rate, EPA-HQ-OPP-2009-0012-0004, D357983, July 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 methoxyfenozide with the current and proposed new tolerances, the highest exposed subpopulation is children 1-2 years at 56.9% 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 aggregate dietary exposure over a lifetime will not pose appreciable risks to human health.  When the food, water and residential exposures are aggregated for children, the resulting MOEs are 170 or greater, which are well above the LOC of 100. Therefore, there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to methoxyfenozide exposure to methoxyfenozide residues.

F. International Tolerances

      Several governing bodies have established Maximum Residue Levels (MRLs) for methoxyfenozide in a variety of crops.  The germane international MRLs for root crops and citrus fruits are found in the following table based on a MRLs compiled by searches in Homologa (http://www.homologa.com/), the EU SANCO website (http://ec.europa.eu/sanco_pesticides/public/index.cfm) and the Australian MRL website (http://www.foodstandards.gov.au/foodstandards/foodstandardscode/standard142maximumre4244.cfm) .  Homologa is a third party database; IR-4 makes no claim regarding the verification of these values relative to the individual national authoritative sources.  The proposed change from 10 ppm to 1.9 ppm for citrus is congruent with other international tolerances.
      
Country
Crop
Amount
Unit
                                   Australia
CITRUS FRUITS
                                       1
                                      PPM
                                   Australia
CITRUS: PULP-DRY
                                      10
                                      PPM
                                     CODEX
Citrus 
                                      0.7
                                      PPM
                                 EU Harmonized
Citrus fruit
                                       1
                                      PPM
                                 EU Harmonized
Root and tuber vegetables
                                     0.02
                                      PPM