Document ID: EPA-HQ-OPP-2009-0012-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-04-08T04:00Z

COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE  (9/27/2007)

EPA Registration Division contact: [Barbara Madden, (703) 305-6463]

 

INSTRUCTIONS:  Please utilize this outline in preparing tolerance
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TEMPLATE:

[Dow AgroSciences LLC]

[Petition]

	EPA has received a pesticide petition ([Petition]) from [Dow
AgroSciences LLC], [9330 Zionsville Road –Indianapolis, Indiana 46268]
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.

(Options (pick one)

	1. by establishing a tolerance for residues of

	2. to establish an exemption from the requirement of a tolerance for

[methoxyfenozide and its metabolites RH-117,236 free phenol of
methoxyfenozide; 3,5-dimethylbenzoic acid N-tert-butyl-N'-(3-hydroxy-
2-methylbenzoyl) hydrazide, RH-151,055 glucose conjugate of RH-117,236;
3,5-dimethylbenzoic acid N-tert-butyl-N-[3(
-[beta]-D-glucopyranosyloxy)-2-methylbenzoyl]-hydrazide) and RH-152,072
the malonylglycosyl conjugate of RH-117,236] in or on the raw
agricultural commodities Fruit, citrus, group 10 at 2.0 parts per
million (ppm) and Citrus oil at [70] ppm for tolerances with regional
registrations; and [Pea and bean, dried shelled, except soybean,
subgroup 6C] at [0.35] ppm; [Pomegranate] at [0.6] ppm; [Corn, pop,
grain] at [0.05] ppm; [Corn, pop, stover] at [125] ppm, [Corn, pop,
forage] at [30] ppm. Additionally, the petition requests that the
existing tolerance for dry bean seed at 0.24 ppm be deleted since it is
a member of the proposed subgroup 6C. EPA has determined that the
petition contains data or information regarding the elements set forth
in section 408 (d)(2) of the FFDCA; 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. [The qualitative nature of methoxyfenozide
residues in plants and animals is adequately understood.  Residues in
plants, meat and fat are defined in terms of parent compound only. 
Residues in eggs, liver and meat by-products (mbyp) are defined in terms
of combined residues of parent and its glucuronide metabolite, expressed
as parent.  More details were previously published in the Federal
Register of July 5, 2000 (65 FR 41355) (FRL-6497-5).]

	2. Analytical method. [Adequate enforcement methods are available for
determination of methoxyfenozide residues in plant commodities, as
derived from Dow AgroSciences GRM 02.25, “Determination of Residues of
Methoxyfenozide in High Moisture Crops by Liquid Chromatography with
Tandem Mass Spectrometry Detection” which has been validated.  

This method is based on enforcement method TR 34-00-28 developed by Rohm
and Haas which has been extensively validated (recovery data;
confirmatory data; ILV data; radiovalidation data; paper review by
ACB/BEAD).  It was judged to be adequate to enforce tolerances for
indirect or inadvertent residues of methoxyfenozide and relevant
metabolites in/on high and low moisture rotational crops.]

	3. Magnitude of residues. [Adequate crops residue trials were conducted
and residues of methoxyfenozide and its metabolites measured.  The
requested tolerances are adequately supported.]

B. Toxicological Profile  [The toxicological profile and endpoints for
methoxyfenozide which supports this petition can be found at   HYPERLINK
"http://www.regulations.gov"  http://www.regulations.gov  in docket ID
number EPA-HQ-OPP-2007-0495]

	1. Acute toxicity.  [EPA has established that no appropriate endpoint
was identified in the oral toxicity studies, including the acute
neurotoxicity study in rats and the developmental toxicity studies in
rats and rabbits.  Therefore, there is no concern for acute dietary
risk.]

	2. Genotoxicty. [In a battery of four mutagenicity studies (with and
without metabolic activation, as appropriate for the specific study),
technical grade methoxyfenozide was negative for genotoxicity in all
studies.]

	3. Reproductive and developmental toxicity. [the NOAEL for reproductive
toxicity is greater than 20,000 ppm (1,551.9–2,036.5 mg/kg day).  The
LOAEL for reproductive toxicity was not identified.]

	4. Subchronic toxicity. [In a subchronic oral neurotoxicity study in
rats, there were no observable signs of a neurotoxic effect at the
highest concentration in males or females.]

	5. Chronic toxicity. [The cRfD used in the chronic risk assessment was
0.10 mg/kg/day as established by EPA, as determined by the 2-Year
combined chronic feeding/carcinogenicity study in rats.]

	6. Animal metabolism. [In a metabolism study in rats,
14C-methoxyfenozide was rapidly absorbed, distributed, metabolized and
almost completely excreted within 48 hours in rats.  Metabolism of
methoxyfenozide in other animals (poultry and ruminants) appears to be
similar to its metabolism in rats.] 

	7. Metabolite toxicology. [The methoxyfenozide glucuronide conjugates
are considered to be less toxic than the parent compound.  Further,
based on similarities of chemical structure, the nonconjugated
metabolites would be expected to be no more toxic than the parent
compound.] 

 

	8. Endocrine disruption. [Since the definition and regulatory
significance of the term “endocrine disruptor chemical” has not yet
been established by the Agency, it is not clear whether methoxyfenozide,
should be considered to be an “endocrine disruptor” chemical.] 

C. Aggregate Exposure

	1. Dietary exposure. [Assessments were conducted to evaluate potential
risks             due to chronic and acute dietary exposure of the U.S.
population subgroups to residues of methoxyfenozide.  These analyses
cover all registered crops, as well as, uses pending with the Agency,
active and proposed section 18 uses, proposed IR-4 minor uses and the
proposed time-limited tolerances for rotational crops.  There are no
registered residential nonfood uses of methoxyfenozide.]

	i. Food. [a. Acute risk.  No appropriate toxicological endpoint
attributable to a single exposure was identified 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, the acute aggregate risk is expected to be
negligible.

b. Chronic assessments were conducted to evaluate potential risks due to
chronic dietary exposure of the U.S. population and sensitive population
subgroups to residues of methoxyfenozide.  The tier-1 assessment used
the Dietary Exposure Evaluation Model™ (DEEM-FCID, ver. 2.14,
Exponent, Inc., Washington, DC-20036) software for conducting the
chronic dietary (food) risk analysis. DEEM is a dietary exposure
analysis system that is used to estimate exposure to a pesticide
chemical in foods comprising the diets of the U.S. population, including
population subgroups.  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.

Based on the high levels used in the initial establishment of the
tolerances for crops commonly used as feed for livestock, the addition
of any increased exposure from citrus, as an animal feedstock component
would not require an increase in meat and milk tolerances.  

This tier-I assessment considers residues at tolerance levels for all
current and proposed uses; it also includes the worse-case adjustment
factors historically used in DEEM, when no refinements for processing
factors are available. 

The chronic tox-endpoint is the cRfD = 0.1 mg/kg-bw/day, published in
the docket ID number EPA-HQ-OPP-2007-0495.  The published FQPA Safety
Factor (SF) = 1x for methoxyfenozide and therefore the cPAD = 0.1
mg/kg/day.  The tier-I exposure for food was found to occupy up to 26.8%
of the chronic population adjusted dose (PAD) for US-general population
and 68.4% of PAD for the most highly exposed population subgroup,
children 1 to 2 years old.  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.

All population subgroups have shown potential tier-I (worst-case)
exposure below the Agencies level of concern (100% cPAD).]

	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.  Screening level exposure
levels to surface drinking water were estimated from EPA’s water
models Pesticide Root Zone Model (PRZM) coupled to EXAMS, using EFED’s
standard index reservoir which incorporates flow into and out of a
reservoir to calculate estimated the expected environmental
concentrations (EECs) for surface water.  The screening concentration in
ground water was estimated by using the model Screening Concentrations
in Ground Water (SCI-GROW), an empirical model based upon actual
monitoring data collected for a number of pesticides that serve as
benchmarks.  These models take into account the use patterns and the
environmental profile of a pesticide, but do not include consideration
of the impact that processing raw water for distribution as drinking
water would likely have on the removal of pesticides from the source
water.  The primary use of these models is to provide a coarse screen
for assessing whether a pesticide is likely to be present in drinking
water at concentrations which would exceed human health levels of
concern.

The EECs for chronic exposure are expected to be 33.1 ppb for surface
water and <7.43 ppb for ground water.  For chronic dietary risk
assessment, the water concentration value of 33.1 ppb was used to asses
the contribution to drinking water.  The modeled estimate of drinking
water concentration was directly entered into the dietary exposure
model.

a.  Acute exposure and risk.  Because no acute dietary endpoint was
established, Dow AgroSciences concludes that there is a reasonable
certainty of no harm from acute exposure from drinking water.

b.  Chronic exposure and risk.  Tier I screening-level exposure
assessments can be conducted using the simulation models PRZM/EXAMS and
SCI-GROW to generate EECs for surface and ground water, respectively. 
The modeling was conducted based on the environmental profile and the
maximum seasonal application rate proposed across current and proposed
labels.  The concentration used for chronic exposure from drinking-water
was estimated from the higher value of the two models, thus the output
from the screening model PRZM/EXAMS as an annual average concentration
EEC = 33.1 parts per billion (ppb) was used.

Using the assumptions described above and an cRfD of 0.10 mg/kg/day, the
chronic/long-term food + drinking water exposure was estimated to be
27.5% cPAD for the US population and 69.4% cPAD for children aged 1 to 2
years old, the sub-population with the highest estimated exposure.  

Dow AgroSciences thus concludes with reasonable certainty that residues
of methoxyfenozide in drinking water will not contribute significantly
to the aggregate chronic human health risk and that the chronic
aggregate exposure from methoxyfenozide residues in food and drinking
water will not exceed the Agency’s level of concern (100% of the
chronic PAD) for chronic dietary aggregate exposure by any population
subgroup.  EPA generally has no concern for exposures below 100% of the
chronic PAD, because it is a level at or below which daily aggregate
dietary exposure over a lifetime will not pose appreciable risks to the
health and safety of any population subgroup.  This risk assessment is
conservative in nature based on the assumptions used, and resultant in a
profile of methoxyfenozide that is very protective of human health.] 

	2. Non-dietary exposure. [Methoxyfenozide is not currently registered
for use on any residential non-food sites.  Therefore, there is no
non-dietary acute, chronic, short-or intermediate-term exposure.]

D. Cumulative Effects

[Section 408(b)(2)(D)(v) requires that, when considering whether to
establish, modify, or revoke a tolerance, the Agency consider
“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 in
this unit, Dow AgroSciences has concluded that the aggregate exposure to
methoxyfenozide from the current and proposed new tolerances will
utilize 26.8% of the chronic PAD for the U.S. population.  If potable
water is aggregated into the tier-I dietary exposure, at the maximum
residue level estimated by EPA’s PRZM/EXAMS model, (0.0331 ppm), the
aggregate exposure to the US-population is slightly increased to 27.5%
of the PAD.  EPA generally has no concern for exposures below 100% of
the chronic PAD because the chronic PAD represents the level at or below
which daily aggregate dietary exposure over a lifetime will not pose
appreciable risks to human health.  Despite the potential for exposure
to methoxyfenozide in drinking water, the aggregate exposure is not
expected to exceed 100% of the chronic PAD.  Dow AgroSciences concludes
that there is a reasonable certainty that no harm will result to
U.S.-general population from aggregate exposure to methoxyfenozide
residues.]

	2. Infants and children. [In assessing the potential for additional
sensitivity of infants and children to residues of methoxyfenozide, EPA
considered data from developmental toxicity studies in the rat and
rabbit and a 2-generation reproduction study in the rat.  The
developmental toxicity studies are designed to evaluate adverse effects
on the developing organism resulting from maternal pesticide exposure
during gestation.  Reproduction studies provide information relating to
effects from exposure to the pesticide on the reproductive capability of
mating animals and data on systemic toxicity.  

FFDCA section 408 provides that EPA shall apply an additional ten-fold
safety factor for infants and children in the case of threshold effects
to account for prenatal and postnatal toxicity and the completeness of
the database unless EPA determines that a different margin of safety
will be safe for infants and children.  Margins of safety are
incorporated into EPA risk assessments either directly through use of a
margin of exposure (MOE) analysis, or through using uncertainty (safety)
factors in calculating a dose level that poses no appreciable risk to
humans.  EPA believes that reliable data support using the standard
uncertainty factor (UF = 100 for combined interspecies and intraspecies
variability) and no additional safety factor is required for the
calculation of MOE for any of the population sub-groups. 

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.  A complete toxicity
data base is available for methoxyfenozide and the exposure data are
complete or are estimated based on data/assumptions that reasonably
accounts for potential exposures.  Based on the completeness of the data
base and the lack of prenatal and postnatal toxicity, EPA determined
that an additional safety factor was not needed for the protection of
infants and children (FQPA SF = 1x).

Since no acute toxicological endpoints were established, the acute
aggregate risk is considered to be negligible.  Using the exposure
assumptions described above, Dow AgroSciences has concluded that chronic
dietary exposure to methoxyfenozide from the existing and proposed new
tolerances will utilize 68.4% of the cPAD for children 1-2 years.  If
exposure from drinking water is aggregated to the tier-I dietary
exposure, at the maximum residue level estimated by EPA’s PRZM/EXAMS
model, (0.0331 ppm), the aggregate exposure to children 1-6 is slightly
increased from 56.8 to 57.7 % PAD, and the highest exposed subpopulation
is children 1-2 years where the aggregate exposure is slightly increased
from 68.4 to 69.4 % 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.  Despite the potential for
exposure to methoxyfenozide in drinking water, Dow AgroSciences does not
expect the aggregate exposure to exceed 100% of the cPAD.  Short and
intermediate term risks are judged to be negligible due to the lack of
significant toxicological effects observed.  Based on these risk
assessments, Dow AgroSciences concludes that 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

[There are several countries that have established tolerances/MRLs for
methoxyfenozide.  The most extensive list has been published by Codex
(25 food commodities).  Among others countries, Canada, Australia,
Brazil, United Kingdom, and several other European countries have MRLs
established for residues of methoxyfenozide.  By comparing them, it is
concluded that the MRLs established by different agencies are not
harmonized and are rather incompatible.  The differences may be
attributable to the use of diverse good agricultural practices (GAPs)
for efficacious pest control, different guidelines for conducting field
crop residue studies, and different calculation methods used to propose
tolerances.  Based on the current non-harmonized MRL situation, it is
not reasonable to conclude that the U.S. tolerance levels can be
harmonized with MRLs from other countries, and therefore the condition
of MRL incompatibility amongst differing countries, relative to
methoxyfenozide, will persist.]