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-DGlucopyranuronic 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-Dglucopyranosyloxy)-2-methylbenzoyl]-hydrazide] and the malonylglycosyl conjugate of 

the phenol [3,5-dimethyl benzoic acid N-tert-butyl- N'-[3 (β-D-6-malonylglucopyranosyl-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 (IR4 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-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.

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 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-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 

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 ModelTM (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 postapplication 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-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 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/standard142maximu

mre4244.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