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 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.

	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.  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-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 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-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 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 Model™ (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, 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, 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-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 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 ( HYPERLINK
"http://www.mrldatabase.com/results.cfm"
http://www.mrldatabase.com/results.cfm ), Homologa ( HYPERLINK
"http://www.homologa.com/" http://www.homologa.com/ ), the EU SANCO
website ( HYPERLINK
"http://ec.europa.eu/sanco_pesticides/public/index.cfm"
http://ec.europa.eu/sanco_pesticides/public/index.cfm ), Japan MRL
listing ( HYPERLINK
"http://www.m5.ws001.squarestart.ne.jp/foundation/agrdtl.php?a_inq=75700
"
http://www.m5.ws001.squarestart.ne.jp/foundation/agrdtl.php?a_inq=75700
) and the Australian MRL website ( HYPERLINK
"http://www.comlaw.gov.au/Details/F2014C00164/Download%20"
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.  

Commoditya	Existing 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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