Document ID: EPA-HQ-OPP-2012-0912-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2013-01-16T05:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: Laura Nollen, (703) 305-7390,  
HYPERLINK "mailto:nollen.laura@epa.gov"  nollen.laura@epa.gov  

Interregional Research Project Number 4 (IR-4)

Petition Number (PP#) 2E8118

	EPA has received a pesticide petition, PP# 2E8118 from Interregional
Research Project Number 4 (IR-4), 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 180.544 by establishing a tolerance for residues of
methoxyfenozide, (3-methoxy-2-methylbenzoic acid
2-(3,5-dimethylbenzoyl)-2-(1,1-dimethylethyl) hydrazide) including its
metabolites and degradates in or on the raw agricultural commodities
under paragraph (a) in or on herb subgroup 19A, except chive at 400
parts per million (ppm); date at 7 ppm; caneberry subgroup 13-07A at 6
ppm; sorghum, grain, forage at 9 ppm; sorghum, grain, stover at 15 ppm;
sorghum, grain, grain at 4 ppm; sorghum, sweet, forage at 9 ppm;
sorghum, sweet, stover at 15 ppm; sorghum, sweet, grain at 4 ppm;
sorghum, sweet, stalk at 9 ppm; grain, aspirated grain fractions at 80
ppm; pea and bean, dried shelled, except soybean, subgroup 6C, except
pea, blackeyed, seed and pea, southern, seed at 0.5 ppm;  fruit, small,
vine climbing, except fuzzy kiwifruit, subgroup 13-07F at 1 ppm; berry,
low growing, except cranberry, subgroup 13-07G at 1.5 ppm; fruit, pome,
group 11-10 at 1.5 ppm; vegetable, fruiting, group 8-10 at 2 ppm; sugar
apple at 0.6 ppm; cherimoya at 0.6 ppm; atemoya at 0.6 ppm; custard
apple at 0.6 ppm; ilama at 0.6 ppm; soursop at 0.6 ppm; and biriba at
0.6 ppm. Additionally, the petition requested to amend 40 CFR 180.544,
under paragraph (2)(d) by establishing a tolerance for indirect or
inadvertent residues of methoxyfenozide in or on rapeseed subgroup 20A
at 1.0 ppm and sunflower subgroup 20B at 1.0 ppm. 

Upon approval of the tolerances in paragraph (a), the petition also
requests to amend the tolerance in paragraph (2)(d) from herb and spice,
group 19, except coriander, leaves at 4.5 ppm to spice subgroup 19B at
4.5 ppm. It is also proposed that the tolerance for residues of
methoxyfenozide in or on pea, dry, seed at 2.5 ppm; bean, dry, seed at
0.24 ppm; coriander, leaves at 30 ppm; grape at 1.0 ppm; strawberry at
1.5 ppm; fruit, pome, group 11 at 1.5 ppm; vegetable, fruiting, group 8
at 2.0 ppm; and okra at 2.0 ppm be removed upon the 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 tolerances in Crop Subgroup 19A
(except chives), dates, Crop Subgroup 13-07A, and sorghum commodities
are all supported by  magnitude of residue studies in basil, dates,
caneberry, sorghum and  processed sorghum. The proposed tolerances in
Crop subgroup 13-07F (except fuzzy kiwifruit), Crop subgroup 13-07G,
Crop Group 11-10  and Crop group 8-10 are all supported by existing
tolerances on representative commodities for that crop or subgroup
(Grape, Strawberry, Crop Group 11 and Crop Group 8, respectively)
without the need for additional data.  The proposed tolerances for
inadvertent or indirect tolerances in oilseeds are supported by an EPA
2009 review of existing data (D. Rate, US EPA, D357983, July 22, 2009)
and a 2012 EPA recommendation (W. Drew, US EPA, D396397, May 1, 2012)
for reinstatement without the need for additional data.  In addition, a
request is made for international harmonization of tolerances for Pea
and bean, dried shelled, except soybean, subgroup 6C, except pea,
blackeyed, seed and pea, southern, seed.  Thus, the requested tolerances
are all adequately supported.

For Herb subgroup 19A, except chives, IR-4 recently completed trials in
fresh and dried basil with a 1 day PHI (IR-4 PR No. 07525, May 23,
2012).  Residues of methoxyfenozide were determined following 4 foliar
applications of Intrepid( 2F insecticide in at 5 field locations in
Florida, North Carolina, New Mexico, Wisconsin and British Columbia
during the 2009 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 9-11 days apart and marketable basil leaves and
stems were collected 1 day after the final application for analysis of
both fresh and dried samples.  The methoxyfenozide residues in fresh
basil ranged from a maximum of 47.2 ppm to a minimum of 9.26 ppm with a
43.4 ppm HAFT (Highest Average Field Trial) value at the PHI of 1 day. 
In dried basil observed residues ranged from a maximum of 194 ppm to a
minimum of 56.3 ppm with HAFT value of 188 ppm.  Some decline was noted
over the 12 days within the decline trial. The limit of detection (LOD)
and the limit of quantitation (LOQ) values were calculated as 0.0031 ppm
and 0.0092 ppm, respectively for fresh basil, and 0.016 ppm and 0.049
ppm, respectively for dried basil.

For Date, IR-4 recently completed trials in dates with a 7 day PHI (IR-4
PR No. 10154, April 23, 2012).  Residues of methoxyfenozide were
determined following 3 foliar applications of Intrepid( 2F insecticide
at 4 field locations in California during the 2010 growing season. 
Methoxyfenozide was applied at a target rate of 0.31 lb ai/A, for a
total of approximately 0.93 lb ai/A.  Applications were made 9-11 days
apart and marketable mature fruit was collected 7 days after the final
application.  Methoxyfenozide observed residues in date ranged from a
maximum of 3.3 ppm to a minimum of 1.5 ppm with a 3.1 ppm HAFT value at
the PHI of 7 day.  The LOD and LOQ values were calculated as 0.0013 ppm
and 0.0038 ppm, respectively for dates.

For Caneberry subgroup 13-07A, IR-4 recently completed trials in
blackberry and raspberry with a 3 day PHI (IR-4 PR No. 10470, February
6, 2012).  Residues of methoxyfenozide were determined following 3
foliar applications of Intrepid( 2F insecticide at 6 field locations in
Michigan, North Carolina, California and Oregon during the 2010 growing
season.  Methoxyfenozide was applied at a target rate of 0.25 lb ai/A,
for a total of approximately 0.75 lb ai/A.  Applications were made 6-8
days apart and marketable mature fruit was collected 3 days after the
final application.  Methoxyfenozide observed residues in blackberry
ranged from a maximum of 2.5 ppm to a minimum of 0.62 ppm with a 2.5ppm
HAFT value at the PHI of 3 day.  In raspberry observed residues ranged
from a maximum of 2.3 ppm to a minimum of 1.6 ppm with HAFT value of 2.2
ppm.  The LOD and LOQ values were calculated as 0.0040 ppm and 0.012
ppm, respectively for caneberry.

For Sorghum, IR-4 recently completed trials with a 3 day PHI for forage
and a 21 day PHI for stover and grain (IR-4 PR No. 07241, March 23,
2012).  Residues of methoxyfenozide were determined following 4 foliar
applications of Intrepid( 2F insecticide at 12 field locations in
Arkansas, North Carolina, North Dakota, Nebraska, New Mexico, South
Dakota, and Texas during the 2010 growing season.  Methoxyfenozide was
applied at a target rate of 0.12 lb ai/A, for a total of approximately
0.48 lb ai/A.  Applications were made 9-14 days apart and forage was
collected 2-3 days after the final application, and grain and stover
were collected 11-23 days after the final application.  Methoxyfenozide
observed residues in forage ranged from a maximum of 5.6 ppm to a
minimum of 0.7 ppm with a 5.0 ppm HAFT value at the PHI of 3 day.  In
stover observed residues ranged from a maximum of 9.7 ppm to a minimum
of 0.29 ppm with HAFT value of 2.8 ppm.   In grain observed residues
ranged from a maximum of 2.6 ppm to a minimum of 0.15 ppm with HAFT
value of 2.25 ppm.   Aspirated grain fractions (AGF) processed from bulk
grain samples had a residue of 17 ppm whereas the unprocessed grain from
the same trial had a residue of 0.48 ppm.  The syrup sample processed
from sweet sorghum stalks had the same residue (1.1 ppm) as the
unprocessed stalks.  The LOD and LOQ values were calculated as 0.0071
ppm and 0.0213 ppm, 0.0012 and 0.0037 ppm, 0.0026 and 0.0079 ppm, 0.0006
and 0.0019 ppm, 0.0003 and 0.0008 ppm, respectively for sorghum forage,
grain, stover, aspirated grain and syrup.

Tolerance requests for fruiting vegetable group 8-10, pome fruit group
11-10, subgroup 13-07F and subgroup 13-07G are crop group/subgroup
revisions based upon established tolerances.  Tolerances for sugar
apple, cherimoya, atemoya, custard apple, ilama, soursop, and biriba are
based upon the existing avocado tolerances and registration.

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 the 2012 Human Health review (Collantes, US EPA, D388978, May 23,
2012), 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

).  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 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 and default
processing factors for all food commodities, with the exception of a
methoxyfenozide-specific processing factor for orange juice (0.2X). 
Although the proposed sorghum uses alter the MRBD livestock burden
calculations very slightly, existing tolerances for meat and milk are
sufficient to cover the very small change and no increase in tolerance
for animal commodities is needed.

	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 have recently been conservatively increased by EFED based on
new model assumptions in 2012 (Gebken, US EPA, D388876, May 23, 2012). 
For potential drinking water exposures the new value of 43.4 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
0.024775 mg/kg/day for the US general population which is 24.8% of the
chronic RfD.  For the most highly exposed population subgroup, children
1 to 2 years old, the estimated exposure is 0.06666 mg/kg/day at 66.7%
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.  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.  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 670, which is
significantly higher than the stated LOC of 100 for methoxyfenozide, and
thus is not of concern.  The proposed tolerances in this petition do not
make significant contributions to the dietary consumption patterns. 
Thus the small change in the dietary contribution did not result in a
change in MOE for adults; it remains 670 and hence 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 3.14 exposure assumptions described
above, the dietary and water exposure to methoxyfenozide from the
current and proposed new tolerances will utilize 24.8% 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 670, 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 66.7% 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.

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/Series/F2008B00619"
http://www.comlaw.gov.au/Series/F2008B00619 ) .  Homologa is a third
party database; IR-4 makes no claim regarding the verification of these
values relative to the individual national authoritative sources.  

Commodity	Existing MRLa

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Cane fruit, Dates, Herbs	0.02*	EU SANCO

Sorghum	0.05*	EU SANCO

Rape seed (Bird rapeseed, turnip rape)	0.05*	EU SANCO

Sunflower seed	0.05*	EU SANCO

Herbs	T20	Australia

Cherimoya (Custard apple, sugar apple (sweetsop), Ilama and other medium
sized Annonaceae)	0.6	EU SANCO

Soursop (guanabana)	0.02*	EU SANCO

Custard apple	0.3	Australia

aThe * and T notations are direct translations from the country website
listings.

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