EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE 

PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

Interregional Research Project #4

Pesticide Petition, PP# 4E8298

EPA has received a pesticide petition, PP# 4E8298, from Interregional Research 

Project Number 4 (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) 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 methoxyfenozide, 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. The petition requests to 

establish the following tolerances in or on the raw agricultural commodity under 

paragraph (a): Chive, fresh leaves at 30 parts per million (ppm); fruit, stone, group 12-12 

except plum, prune, fresh at 3.0 ppm; and nut, tree, group 14-12 at 0.1 ppm. 

Additionally, the petition seeks to amend onion, green, subgroup 3-07B at 5.0 ppm to 

onion, green, subgroup 3-07B, except chive at 5.0 ppm; and Herb subgroup 19A, except 

chive at 400 ppm to Herb subgroup 19A, except chive, fresh leaves at 400 ppm. 

It is also proposed that the tolerances 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; pistachio 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 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 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. 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 studies was based on Dow AgroSciences 
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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 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 by magnitude of residue studies in chives (dried leaves). Thus, the 

established tolerance of 400ppm for Herb subgroup 19A, except chive, fresh leaves is

adequately supported. 

Interregional Regional Research Project No. 4 (IR-4) recently 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 field location in Maryland during the 2012 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. A surfactant was included in each tank mix. Marketable chives and chives 

for drying were collected 1 day after the final application. Methoxyfenozide observed 

residues in fresh leaves ranged from 5.7 - 13 ppm with a HAFT of 12.5. For the dried 

leaves, methoxyfenozide 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, 

respectively for fresh chives and 0.0146 ppm and 0.0438ppm, respectively for dried 

chives.

IR-4 requests revisions to the following crop groups/subgroups based upon established 

tolerances: stone fruit group 12-12 except plum, prune, fresh; tree nut group 14-12.

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 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 reiterated 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 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 (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.
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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-OPP2009-0012-0004, 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, May 2012), new 

inhalation 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-OPP2009-0012-0004, 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-OPP2009-0012-0004, D357983, July 22, 2009), in a metabolism study in rats, 14Cmethoxyfenozide 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 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-HQOPP-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 
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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 liver 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 2013 EPA dietary assessment (EPA, Holman, D412460, July 16, 2013). The 

Dietary Exposure 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 tolerances for chives, and also 

includes pineapple which is currently under review. Additionally, the analyses include 

tolerances for peas, blackeyed, 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 revised (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 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 43.4 ppb were conservatively

increased by EFED based on new model assumptions in 2013 (Milians, US EPA, 

D407566, April 23, 2013). For potential drinking water exposures, the new value of 251

ppb has been directly incorporated in the DEEM-FCID into the food categories “water, 
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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 population subgroup, children 1 

to 2 years 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 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 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, August 6, 2013). The dietary exposure of the 

general adult US population was aggregated with exposure estimates from residential use 

of a backpack sprayer treatment of ornamentals. The calculated exposure resulted in an 

aggregate MOE of 530, which is significantly 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 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 “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 3.16 exposure assumptions described above, 
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the dietary and water exposure to methoxyfenozide 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 certainty 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 adults, the resulting MOEs are 530, 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-OPP2009-0012-0004, 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 85.9% 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. 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 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 MRL listing 

(http://www.m5.ws001.squarestart.ne.jp/foundation/agrdtl.php?a_inq=75700) and the 

Australian MRL website (http://www.comlaw.gov.au/Details/F2014C00164/Download ). 

Homologa is a third party database; Dow AgroSciences makes no claim regarding the 

verification of these values relative to the individual national authoritative sources. 

CommodityaExisting MRLa

(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 MRL or 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.
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