Notice of Filing Pesticide Petitions to Establish Tolerances for Certain Pesticide Chemicals in or on Food

Note: EPA no longer updates this information, but it may be useful as a reference or resource.

[Federal Register: March 19, 2001 (Volume 66, Number 53)]
[Notices]
[Page 15443-15459]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr19mr01-67]

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ENVIRONMENTAL PROTECTION AGENCY

[PF-997; FRL-6766-7]

Notice of Filing Pesticide Petitions to Establish Tolerances for
Certain Pesticide Chemicals in or on Food

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

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SUMMARY: This notice announces the initial filing of pesticide
petitions proposing the establishment of regulations for residues of
certain pesticide chemicals in or on various food commodities.

DATES: Comments, identified by docket control number PF-000, must be
received on or before April 18, 2001.

ADDRESSES: Comments may be submitted by mail, electronically, or in
person. Please follow the detailed instructions for each method as
provided in Unit I.C. of the SUPPLEMENTARY INFORMATION. To ensure
proper receipt by EPA, it is imperative that you identify docket
control number PF-000 in the subject line on the first page of your
response.

FOR FURTHER INFORMATION CONTACT: By mail: Joseph Tavano, Registration
Support Branch, Registration Division (7505C), Office of Pesticide
Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,
Washington, DC 20460; telephone number: (703) 305-6411; e-mail address:
tavano.joseph@epa.gov.

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this Action Apply to Me?

You may be affected by this action if you are an agricultural
producer, food manufacturer or pesticide manufacturer. Potentially
affected categories and entities may include, but are not limited to:

------------------------------------------------------------------------
Examples of
Categories NAICS codes potentially
affected entities
------------------------------------------------------------------------
Industry 111 Crop production
112 Animal production
311 Food manufacturing
32532 Pesticide
manufacturing
------------------------------------------------------------------------

This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in the table could also be
affected. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether or not this action might apply to certain entities. If you have
questions regarding the applicability of this action to a particular
entity, consult the person listed under FOR FURTHER INFORMATION
CONTACT.

B. How Can I Get Additional Information, Including Copies of this
Document and Other Related Documents?

1. Electronically. You may obtain electronic copies of this
document, and certain other related documents that might be available
electronically, from the EPA Internet Home Page at http://www.epa.gov/.
To access this document, on the Home Page select ``Laws and
Regulations'' and then look up the entry for this document under the
``Federal Register--Environmental Documents.'' You can also go directly
to the Federal Register listings at http://www.epa.gov/fedrgstr/.
2. In person. The Agency has established an official record for
this

[[Page 15444]]

action under docket control number PF-000. The official record consists
of the documents specifically referenced in this action, any public
comments received during an applicable comment period, and other
information related to this action, including any information claimed
as confidential business information (CBI). This official record
includes the documents that are physically located in the docket, as
well as the documents that are referenced in those documents. The
public version of the official record does not include any information
claimed as CBI. The public version of the official record, which
includes printed, paper versions of any electronic comments submitted
during an applicable comment period, is available for inspection in the
Public Information and Records Integrity Branch (PIRIB), Rm. 119,
Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA, from 8:30
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The
PIRIB telephone number is (703) 305-5805.

C. How and to Whom Do I Submit Comments?

You may submit comments through the mail, in person, or
electronically. To ensure proper receipt by EPA, it is imperative that
you identify docket control number PF-000 in the subject line on the
first page of your response.
1. By mail. Submit your comments to: Public Information and Records
Integrity Branch (PIRIB), Information Resources and Services Division
(7502C), Office of Pesticide Programs (OPP), Environmental Protection
Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460.
2. In person or by courier. Deliver your comments to: Public
Information and Records Integrity Branch (PIRIB), Information Resources
and Services Division (7502C), Office of Pesticide Programs (OPP),
Environmental Protection Agency, Rm. 119, Crystal Mall #2, 1921
Jefferson Davis Highway, Arlington, VA. The PIRIB is open from 8:30
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The
PIRIB telephone number is (703) 305-5805.
3. Electronically. You may submit your comments electronically by
e-mail to: opp-docket@epa.gov, or you can submit a computer disk as
described above. Do not submit any information electronically that you
consider to be CBI. Avoid the use of special characters and any form of
encryption. Electronic submissions will be accepted in Wordperfect 6.1/
8.0 or ASCII file format. All comments in electronic form must be
identified by docket control number PF-000. Electronic comments may
also be filed online at many Federal Depository Libraries.

D. How Should I Handle CBI That I Want to Submit to the Agency?

Do not submit any information electronically that you consider to
be CBI. You may claim information that you submit to EPA in response to
this document as CBI by marking any part or all of that information as
CBI. Information so marked will not be disclosed except in accordance
with procedures set forth in 40 CFR part 2. In addition to one complete
version of the comment that includes any information claimed as CBI, a
copy of the comment that does not contain the information claimed as
CBI must be submitted for inclusion in the public version of the
official record. Information not marked confidential will be included
in the public version of the official record without prior notice. If
you have any questions about CBI or the procedures for claiming CBI,
please consult the person identified under FOR FURTHER INFORMATION
CONTACT.

E. What Should I Consider as I Prepare My Comments for EPA?

You may find the following suggestions helpful for preparing your
comments:
1. Explain your views as clearly as possible.
2. Describe any assumptions that you used.
3. Provide copies of any technical information and/or data you used
that support your views.
4. If you estimate potential burden or costs, explain how you
arrived at the estimate that you provide.
5. Provide specific examples to illustrate your concerns.
6. Make sure to submit your comments by the deadline in this
notice.
7. To ensure proper receipt by EPA, be sure to identify the docket
control number assigned to this action in the subject line on the first
page of your response. You may also provide the name, date, and Federal
Register citation.

II. What Action is the Agency Taking?

EPA has received a pesticide petition as follows proposing the
establishment and/or amendment of regulations for residues of a certain
pesticide chemical in or on various food commodities under section 408
of the Federal Food, Drug, and Comestic Act (FFDCA), 21 U.S.C. 346a.
EPA has determined that this petition contains data or information
regarding the elements set forth in section 408(d)(2); however, EPA has
not fully evaluated the sufficiency of the submitted data at this time
or whether the data support granting of the petition. Additional data
may be needed before EPA rules on the petition.

List of Subjects

Environmental protection, Agricultural commodities, Feed additives,
Food additives, Pesticides and pests, Reporting and recordkeeping
requirements.

Dated: February 26, 2001.
James Jones,
Director, Registration Division, Office of Pesticide Programs.

Summary of Petitions

Petitioner summaries of the pesticide petitions are printed below
as required by section 408(d)(3) of the Federal Food, Drug, and
Cosmetic Act (FFDCA). The summaries of the petitions were prepared by
the petitioner and represent the view of the petitioner. EPA is
publishing the petition summaries verbatim without editing them in any
way. The petition summary announces the availability of a description
of the analytical methods available to EPA for the detection and
measurement of the pesticide chemical residues or an explanation of why
no such method is needed.

1. Rohm and Haas Company

PP 0F6176

EPA has received a pesticide petition (0F6176) from Rohm and Haas
Company, 100 Independence Mall West, Philadelphia, PA 19106-02399
proposing, pursuant to section 408(d) of the FFDCA, 21 U.S.C. 346a(d),
to amend 40 CFR part 180 by establishing a tolerance for residues of
tebufenozide benzoic acid, 3,5-dimethyl-,1-(1,1-dimethylethyl)-2-(4-4-
ethylbenzoyl) hydrazide in or on the raw agricultural commodity citrus
crop group (Crop Group 10) at 0.8 parts per million (ppm) and in or on
citrus oil at 15 parts per million (ppm). 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. Nature of the residue--Plants. The qualitative nature of the
residue in plants is adequately understood based

[[Page 15445]]

upon acceptable apple, sugar beet, and rice metabolism studies. The
Agency has concluded that the residue of regulatory concern is
tebufenozide per se.
2. Nature of the residue--Animal. The results of the ruminant and
poultry metabolism studies have been reviewed by the Agency and the
determination was made that the tebufenozide residues of regulatory
concern in animals are the parent tebufenozide and the four metabolites
designated: RH-2703 [benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-
2-((4-carboxymethyl)benzoyl)hydrazide], RH-9886 [benzoic acid, 3-
hydroxymethyl,5-methyl-1-(1,1-dimethylethyl)-2-(4-
ethylbenzoyl)hydrazide], the stearic acid conjugate of RH-9886, and RH-
0282 [benzoic acid, 3-hydroxymethyl-5-methyl-1-(1,1-dimethylethyl)-2-
(4-(1-hydroxyethyl) benzoyl)hydrazide].
3. Analytical method-- i. Plant tissues. Rohm and Haas method TR
34-96-184, with minor modifications, was used to determine tebufenozide
residue levels in/on lemons, grapefruit and oranges. This method was
independently validated. The method involves extraction by blending
with solvents, purification of the extracts by liquid-liquid partitions
and final purification of the residues using solid phase extraction
column chromatography. The limit of quantitation (LOQ) of the method
for all matrices is 0.02 ppm for tebufenozide and the limit of
detection (LOD) is 0.006 ppm.
ii. Animal tissues. A submitted high performance liquid
chromotography (HPLC/UV) Method, Rohm and Haas Method TR 34-96-109, has
been determined to be adequate for collecting data on residues of
tebufenozide in animal tissues. The validated LOQ for tebufenozide in
animal tissue is 0.02 ppm. The LOQ for each of the metabolites studied
are as follows: RH-2703 in liver, 0.02 ppm; RH-9886 and RH-0282 in
meat, 0.02 ppm; RH-9526 in fat, 0.02 ppm. The LODs for the analytes are
0.006 ppm in tissues.
iii. Multi-residue methods. Rohm and Haas has previously submitted
data involving multi-residue method testing.
a. Magnitude of residues. Field residue trials were conducted in
the representative citrus fruit crops lemons, grapefruit and oranges
and residues of tebufenozide were measured in whole fruit, peel and
fresh pulp. The highest average field trial residue observed was in
oranges at 047 ppm. Results of analyses showed that residues of
tebufenozide will not exceed 0.8 ppm in whole fruit. Residues were
found to be mainly associated in the peel and not in the fresh pulp.
b. Processed food/feed. Grapefruit and orange processing studies
were conducted. Residues of tebufenozide did not concentrate in dry
pulp or juice. Residues of tebufenozide concentrated in citrus oil. The
average concentration factor for citrus oil was determined to be 26.
The Highest Average Field Trial residue was in oranges at 0.47 ppm.
Residues of tebufenozide in citrus oil should not exceed 15 ppm
(rounded up from 0.47 ppm X 26).

B. Toxicological Profile

1. Acute toxicity. Acute toxicity studies with technical grade:
Oral LD50 in the rat is > 5 grams for males and females -
Toxicity Category IV; dermal LD50 in the rat is = 5,000
milligram/kilogram (mg/kg) for males and females - Toxicity Category
III; inhalation LD50 in the rat is > 4.5 mg/l - Toxicity
Category III; primary eye irritation study in the rabbit is a non-
irritant; primary skin irritation in the rabbit > 5 mg - Toxicity
Category IV. Tebufenozide is not a sensitizer.
In a 21-day dermal toxicity study, Crl: CD rats (6/sex/dose)
received repeated dermal administration of either the technical 96.1%
product RH-75,992 at 1,000 mg/kg/day Limit-Dose or the formulation
23.1% a.i. product RH-755,992 2F at 0, 62.5, 250, or 1,000 mg/kg/day, 6
hours/day, 5 days/week for 21 days. Under conditions of this study, RH-
75,992 Technical or RH-75,992 2F demonstrated no systemic toxicity or
dermal irritation at the highest dose tested 1,000 mg/kg/ during the
21-day study. Based on these results, the NOAEL for systemic toxicity
and dermal irritation in both sexes is 1,000 mg/kg/day highest dose
tested (HDT). A lowest-observable-effect level (LOAEL) for systemic
toxicity and dermal irritation was not established.
2. Genotoxicity. Several mutagenicity tests which were all
negative. These include an Ames assay with and without metabolic
activation, an in vivo cytogenetic assay in rat bone marrow cells, and
in vitro chromosome aberration assay in CHO cells, a CHO/HGPRT assay, a
reverse mutation assay with E. Coli, and an unscheduled DNA synthesis
assay (UDS) in rat hepatocytes.
3. Reproductive and developmental toxicity. In a prenatal
developmental toxicity study in Sprague-Dawley rats 25/group
Tebufenozide was administered on gestation days 6-15 by gavage in
aqueous methyl cellulose at dose levels of 50, 250, or 1,000 mg/kg/day
and a dose volume of 10 ml/kg. There was no evidence of maternal or
developmental toxicity; the maternal and developmental toxicity NOAEL
was 1,000 mg/kg/day.
In a prenatal developmental toxicity study conducted in New Zealand
white rabbits 20/group Tebufenozide was administered in 5 ml/kg of
aqueous methyl cellulose at gavage doses of 50, 250, or 1,000 mg/kg/day
on gestation days 7-19. No evidence of maternal or developmental
toxicity was observed; the maternal and developmental toxicity NOAEL
was 1,000 mg/kg/day.
In a 1993 two-generation reproduction study in Sprague-Dawley rats
tebufenozide was administered at dietary concentrations of 0, 10, 150,
or 1,000 ppm (0, 0.8, 11.5, or 154.8 mg/kg/day for males and 0, 0.9,
12.8, or 171.1 mg/kg/day for females). The parental systemic NOAEL was
10 ppm (0.8/0.9 mg/kg/day for males and females, respectively) and the
LOAEL was 150 ppm (11.5/12.8 mg/kg/day for males and females,
respectively) based on decreased body weight, body weight gain, and
food consumption in males, and increased incidence and/or severity of
splenic pigmentation. In addition, there was an increased incidence and
severity of extra-medullary hematopoiesis at 2,000 ppm. The
reproductive NOAEL was 150 ppm. (11.5/12.8 mg/kg/day for males and
females, respectively) and the LOAEL was 2,000 ppm (154.8/171.1 mg/kg/
day for males and females, respectively) based on an increase in the
number of pregnant females with increased gestation duration and
dystocia. Effects in the offspring consisted of decreased number of
pups per litter on postnatal days 0 and/or 4 at 2,000 ppm (154.8/171.1
mg/kg/day for males and females, respectively) with a NOAEL of 150 ppm
(11.5/12.8 mg/kg/day for males and females, respectively).
In a 1995 two-generation reproduction study in rats tebufenozide
was administered at dietary concentrations of 0, 25, 200, or 2,000 ppm
(0, 1.6, 12.6, or 126.0 mg/kg/day for males and 0, 1.8, 14.6, or 143.2
mg/kg/day for females). For parental systemic toxicity, the NOAEL was
25 ppm (1.6/1.8 mg/kg/day in males and females, respectively), and the
LOAEL was 200 ppm (12.6/14.6 mg/kg/day in males and females), based on
histopathological findings (congestion and extra-medullary
hematopoiesis) in the spleen. Additionally, at 2,000 ppm (126.0/143.2
mg/kg/day in M/F), treatment-related findings included reduced parental
body weight gain and increased incidence of hemosiderin-laden cells in
the spleen. Columnar changes in the vaginal squamous epithelium and
reduced uterine and ovarian weights were also observed at

[[Page 15446]]

2,000 ppm, but the toxicological significance was unknown. For
offspring, the systemic NOAEL was 200 ppm. (12.6/14.6 mg/kg/day in
males and females), and the LOAEL was 2,000 ppm (126.0/143.2 mg/kg/day
in M/F) based on decreased body weight on postnatal days 14 and 21.
4. Subchronic toxicity. A 1-year dog feeding study with a (LOAEL)
of 250 ppm, 9 mg/kg/day for male and female dogs based on decreases in
RBC, HCT, and HGB, increases in Heinz bodies, methemoglobin, MCV, MCH,
reticulocytes, platelets, plasma total bilirubin, spleen weight, and
spleen/body weight ratio, and liver/body weight ratio. Hematopoiesis
and sinusoidal engorgement occurred in the spleen, and hyperplasia
occurred in the marrow of the femur and sternum. The liver showed an
increased pigment in the Kupffer cells. The no-observed effect level
(NOAEL) for systemic toxicity in both sexes is 50 ppm (1.9 mg/kg/day).
5. Chronic toxicity. An 18-month mouse carcinogenicity study with
no carcinogenicity observed at dosage levels up to and including 1,000
ppm.
A 2-year rat carcinogenicity with no carcinogenicity observed at
dosage levels up to and including 2,000 ppm (97 mg/kg/day and 125 mg/
kg/day for males and females, respectively).
6. Animal metabolism. The pharmacokinetics and metabolism of
tebufenozide were studied in female Sprague-Dawley rats (3-6/sex/group)
receiving a single oral dose of 3 or 250 mg/kg of RH-5992
¹⁴C labeled in one of three positions (A-ring, B-ring or N-
butyl carbon). The extent of absorption was not established. The
majority of the radio labeled material was eliminated or excreted in
the feces within 48 hours within 48 hours; small amounts (1 to 7% of
the administered dose) were excreted in the urine and only traces were
excreted in expired air or remained in the tissues. There was no
tendency for bioaccumulation. Absorption and excretion were rapid. A
total of 11 metabolites, in addition to the parent compound, were
identified in the feces; the parent compound accounted for 96 to 99% of
the administered radioactivity in the high dose group and 35 to 43% in
the low dose group. No parent compound was found in the urine; urinary
metabolites were not characterized. The identity of several fecal
metabolites was confirmed by mass spectral analysis and other fecal
metabolites were tentatively identified by cochromatography with
synthetic standards. A pathway of metabolism was proposed based on
these data. Metabolism proceeded primarily by oxidation of the three
benzyl carbons, two methyl groups on the B-ring and an ethyl group on
the A-ring to alcohols, aldehydes or acids. The type of metabolite
produced varies depending on the position oxidized and extent of
oxidation. The butyl group on the quaternary nitrogen also can be
cleaved (minor), but there was no fragmentation of the molecule between
the benzyl rings. No qualitative differences in metabolism were
observed between sexes, when high or low dose groups were compared or
when different labeled versions of the molecule were compared.
The absorption and metabolism of tebufenozide were studied in a
group of male and female bile-duct cannulated rats. Over a 72 hour
period, biliary excretion accounted for 30%[M] to 34%[F] of the
administered dose while urinary excretion accounted for about 5% of the
administered dose and the carcass accounted for <0.5% of the
administered dose for both males and females. Thus systemic absorption
(percent of dose recovered in the bile, urine and carcass) was 35%[M]
to 39%[F]. The majority of the radioactivity in the bile (20%[M] to
24%[F] of the administered dose) was excreted within the first 6 hours
post-dosing indicating rapid absorption. Furthermore, urinary excretion
of the metabolites was essentially complete within 24 hours post-
dosing. A large amount [67%[F] to 70%[M)] of the administered dose was
unabsorbed and excreted in the feces by 72 hours. Total recovery of
radioactivity was 105% of the administered dose.
7. Metabolite toxicology. A total of 13 metabolites were identified
in the bile; the parent compound was not identified, i.e. unabsorbed
compound, nor were the primary oxidation products seen in the feces in
the pharmacokinetics study. The proposed metabolic pathway proceeded
primarily by oxidation of the benzylic carbons to alcohols, aldehydes
or acids. Bile contained most of the other highly oxidized products
found in the feces. The most significant individual bile metabolites
accounted for 5% to 18% of the total radioactivity (F and/or M). Bile
also contained the previously undetected (in the pharmacokinetics
study) ``A'' Ring ketone and the ``B'' Ring diol. The other major
components were characterized as high molecular weight conjugates. No
individual bile metabolite accounted for 5% of the total administered
dose. Total bile radioactivity accounted for about 17% of the total
administered dose.
No major qualitative differences in biliary metabolites were
observed between sexes. The metabolic profile in the bile was similar
to the metabolic profile in the feces and urine.
8. Short- and intermediate-term toxicity. No dermal or systemic
toxicity was seen in rats receiving 15 repeated dermal applications of
the technical (97.2%) product at 1,000 mg/kg/day (Limit- Dose) as well
as a formulated (23% a.i) product at 0, 62.5, 250, or 1,000 mg/kg/day
over a 21-day period. In spite of the hematological effects seen in the
dog study, similar effects were not seen in the rats receiving the
compound via the dermal route indicating poor dermal absorption. Also,
no developmental endpoints of concern were evident due to the lack of
developmental toxicity in either rat or rabbit studies. This risk is
considered to be negligible.

C. Aggregate Exposure

1. Dietary exposure--i. Food-- From food and feed uses. Tolerances
have been established (40 CFR 180.482) for the residues of
tebufenozide, in or on a variety of raw agricultural commodities. The
current petition requests establishment of tolerances in or on the crop
group Citrus Fruit at 0.8 ppm and in citrus oil at 15 ppm. Risk
assessments were conducted by Rohm and Haas to assess dietary exposures
and risks from tebufenozide, benzoic acid, 3,5-dimethyl-1-(1,1-
dimethylethyl)-2-(4-ethylbenzoyl) hydrazide as follows:
a. Acute exposure and risk. Acute dietary risk assessments are
performed for a food-use pesticide if a toxicological study has
indicated the possibility of an effect of concern occurring as a result
of a one day or single exposure. Neither neurotoxicity nor systemic
toxicity was observed in rats given a single oral administration of
tebufenozide at 0, 500, 1,000 or 2,000 mg/kg. No maternal or
developmental toxicity was observed following oral administration of
tebufenozide at 1,000 mg/kg/day (Limit-Dose) during gestation to
pregnant rabbits. This risk is considered to be negligible.
b. Chronic exposure and risk. The RfD used for the chronic dietary
analysis is 0.018 mg/kg/day. In conducting the DEEM (Dietary Exposure
Evaluation Model) analysis for chronic exposure to and risk from
tebufenozide residues in food, Rohm and Haas used tolerance level
residues for all crops and other commodities with established or
pending tebufenozide tolerances; and percent crop-treated (PCT)
information for some of these crops. The following tolerances were
used: Citrus fruit at 0.8 ppm, citrus oil at 15 ppm, tree nut crop
group at 0.1 ppm, pome fruit at 1.5 ppm, cotton at 1.5 ppm, leafy and
cole crop groups ranging from 2.0 to 10.0 ppm,

[[Page 15447]]

turnip tops at 9.0 ppm, turnip roots at 0.25 ppm, canola seed at 1.75
ppm, canola oil at 3.75 ppm, mint at 10.0 ppm, fruiting vegetables at
1.0 ppm, sugarcane at 1.0 ppm, molasses at 0.6 ppm, cranberries at 1.0
ppm, berry crops at 3.0 ppm, imported kiwifruit at 1.0 ppm and imported
wine grapes at 0.5 ppm, and the livestock commodities milk, meat and
meat by-products ranging from 0.05 to 0.25 ppm. The % CT information
utilized is found in Table 1 below:

Table 1.--Maximum Percent Crop Treated Values for Various Crops Utilized
in Chronic Dietary Exposure Analyses
------------------------------------------------------------------------
Crop Maximum PCT (Percent)
------------------------------------------------------------------------
Cranberries 100
Kiwifruit 100
Canola 100
Mint 100
Grapes 100
Citrus 100
Meat, Meat By-Products, Milk 100
Sugarcane 82
Turnips 75
Pecans 40
Walnuts 30
Berry Crops 25
Cotton 19
Cole Crop Vegetables 18
Almonds 16
Leafy Vegetables 14
Pome Fruit 10
Fruiting Vegetables 10
------------------------------------------------------------------------

The Novigen DEEM system (version 7.075) was used for this chronic
dietary exposure analysis. The analysis evaluates individual food
consumption as reported by respondents in the USDA Continuing Surveys
of Food Intake by Individuals conducted in 1989 through 1992. Summaries
of the exposures and their representations as percentages of the cPAD
for the general population and subgroups of interest are presented in
Table 2 below. The subgroups listed below are (1) the U.S. Population
(48 states); (2) those for infants and children; and (3) the other
subgroups (adult) for which the percentage of the RfD occupied is
greater than that occupied by the subgroup U.S. Population (48 states).
cPAD% is defined as Exposure X 100% divided by the cPAD. The results
are summarized below in Table 2:

Table 2.--Chronic Exposure Analysis by the DEEM System for Tebufenozide
------------------------------------------------------------------------
Exposure (mg/kg/
Population day ) cPAD (Percent)
------------------------------------------------------------------------
U.S. Population 0.0038 21.1
All Infants (< 1 year ) 0.0041 23.0
Nursing Infants (< 1 year) 0.0023 12.9
Non-Nursing Infants (< 1 year) 0.0049 27.3
Children (1-6 years old) 0.0092 51.0
Children (7-12 years old) 0.0057 31.8
Females (13+ years, nursing) 0.0043 23.9
U.S. Population Autumn 0.0038 21.4
U.S. Population Winter 0.0039 21.9
Hispanics 0.0042 23.1
Non-Hispanic Blacks 0.0043 23.6
Non-Hispanic Other than Black or 0.0049 27.5
White
Northeast Region 0.0042 23.1
Western Region 0.0042 23.5
Pacific Region 0.0043 24.1
------------------------------------------------------------------------

This chronic dietary (food only) risk assessment should be viewed
as conservative. Further refinement using anticipated residue values
and additional PCT information would result in a lower estimate of
chronic dietary exposure from food.
ii. Drinking water-- a. Acute exposure and risk. Because no acute
dietary endpoint was determined, Rohm and Haas concludes that there is
a reasonable certainty of no harm from acute exposure from drinking
water.
b. Chronic exposure and risk. The Agency calculated the Tier I
Estimated Environmental Concentrations (EECs) for tebufenozide using
generic expected environmental concentration (GENEEC) (surface water)
and screening concentration in ground water (SCI- GROW) (ground water)
models for use in the human health risk assessment. For chronic
exposure, the worst case EECs for surface water and ground water were
16.5 parts per billion (ppb) and 1.04 ppb, respectively. These values
represent upper-bound estimates of the concentrations that might be
found in surface and ground water. These modeling data were compared to
the chronic drinking water levels of comparison (DWLOC) for
tebufenozide in ground and surface water.
For purposes of chronic risk assessment, the estimated maximum
concentration for tebufenozide in surface and ground waters (16.5 ppb)
was compared to the back-calculated human health DWLOCs for the chronic
(non-cancer) endpoint. These DWLOCs for various population categories
are summarized below in Table 3:

Table 3.--Drinking Water Levels of Comparison for Chronic Exposure to Tebufenozide\1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
EEC\7\ calc. max.
Population Category\2\ Chronic RfD (mg/kg/ Food exposure (mg/kg/ exposure Max. water DWLOC (µg/ (µg/L) (in
day) day) (mg/kg/day)\3\ L)\4,5,6\ percent)
--------------------------------------------------------------------------------------------------------------------------------------------------------
U.S. Population (48 contiguous 0.018 0.0038 0.0142 497 16.5
states)
Females (13+ years) 0.018 0.0043 0.0137 411 16.5
Children (1-6 years) 0.018 0.0092 0.0088 88 16.5
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Values are expressed to 2 significant figures.
\2\ Within each of these categories, the subgroup with the highest food exposure was selected.
\3\ Maximum water exposure (chronic) (mg/kg/day) = Chronic PAD (mg/kg/day).
\4\ DWLOC (µg/L) = Max. water exposure (mg/kg/day) x body wt (kg) divided by 10-\3\ mg/µg) x water consumed daily (L/day).
\5\ HED Default body weights are: General U.S. population, 70 kg; females (13+ years old), 60 kg; other adult populations, 70 kg; and, all infants/
children, 10 kg.
\6\ HED Default daily drinking rates are 2 L/day for adults and 1 L/day for children.
\7\ EEC: Estimated Environmental Concentration. (Chronic 56-day value).

[[Page 15448]]

2. Non-dietary exposure. There is a potential for occupational
exposure to tebufenozide during mixing, loading, and application
activities. However, the Agency did not identify dermal or inhalation
endpoints for tebufenozide and determined that risks from these routes
of exposure are negligible.

D. Cumulative Effects

Cumulative exposure to substances with a common mechanism of
toxicity. 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 tebufenozide 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, tebufenozide does not appear to produce a toxic metabolite
produced by other substances. For the purposes of this tolerance
petition, Rohm and Haas has not assumed that tebufenozide has a common
mechanism of toxicity with other substances.

E. Safety Determination

1. U.S. population-- aggregate risks and determination of safety
for U.S. population--i. Acute risk. The Agency did not identify an
acute dietary toxicological endpoint, therefore, the risk from this
route of exposure is negligible.
ii. Chronic risk. Using the exposure assumptions described above,
and taking into account the completeness and reliability of the
toxicity data, Rohm and Haas has concluded that dietary (food only)
exposure to tebufenozide will utilize 21% of the cPAD for the U.S.
population, and 51% of the cPAD for the most highly exposed population
subgroup (children 1-6 years old). EPA generally has no concern for
exposures below 100% of the cPAD. Submitted environmental fate studies
suggest that tebufenozide is moderately persistent to persistent and
mobile; thus, tebufenozide could potentially leach to ground water and
runoff to surface water under certain environmental conditions. The
modeling data for tebufenozide indicate levels less than the Agency's
DWLOCs. There are no chronic non- occupational/residential exposures
expected for tebufenozide. Therefore, the Rohm and Haas concludes that
there is a reasonable certainty that no harm will result to adults,
infants and children from chronic aggregate exposure to tebufenozide
residues.
iii. Short- and intermediate-term risk. There are potential non-
occupational/residential short-term post application exposures
(incidental non-dietary ingestion) to toddlers from the use of
tebufenozide on ornamentals. However, since the Agency did not identify
acute dietary endpoint, the short-term post application exposure risk
assessment is expected to be negligible. Intermediate-term incidental
non-dietary exposures are not expected.
iv. Determination of safety. Based on these risk assessments, Rohm
and Haas concludes that there is a reasonable certainty that no harm
will result from aggregate exposure to tebufenozide residues.
2. Infants and children--aggregate risk and determination of safety
for infants and children-- i. Safety factor for infants and children.
In assessing the potential for additional sensitivity of infants and
children to residues of tebufenozide, EPA considered data from
developmental toxicity studies in the rat and rabbit and a two-
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 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
tenfold margin of safety for infants and children in the case of
threshold effects to account for pre- and post-natal 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 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 (usually 100 for combined inter- and intra-species
variability) and not the additional tenfold MOE/uncertainty factor when
EPA has a complete data base under existing guidelines and when the
severity of the effect in infants or children or the potency or unusual
toxic properties of a compound do not raise concerns regarding the
adequacy of the standard MOE/safety factor.
ii. Conclusion. There is a complete toxicity data base for
tebufenozide and exposure data are complete or are estimated based on
data that reasonably accounts for potential exposures. For the reasons
summarized above, Rohm and Haas concludes that an additional safety
factor is not needed to protect the safety of infants and children.
iii. Acute risk. Since no acute toxicological endpoints were
established, it is unlikely that acute aggregate risk exists.
iv. Chronic risk. Using the exposure assumptions described above,
and taking into account the completeness and reliability of the
toxicity data, the Agency has concluded that dietary (food only)
exposure to tebufenozide will utilize 21% of the cPAD for the U.S.
population, and 51% of the cPAD for the most highly exposed population
subgroup (children 1-6 years old). EPA generally has no concern for
exposures below 100% of the cPAD. Despite the potential for exposure to
tebufenozide in drinking water and from non-dietary, non- occupational
exposure, Rohm and Haas does not expect the aggregate exposure to
exceed 100% of the RfD.
v. Short- or intermediate-term risk. Short- and intermediate-term
risks are judged to be negligible due to the lack of significant
toxicological effects observed.
vi. Determination of safety. Based on these risk assessments, Rohm
and Haas concludes that there is a reasonable certainty that no harm
will result to infants and children from aggregate exposure to
tebufenozide residues.

F. International Tolerances

Codex MRLs have been established for residues of tebufenozide in/on
pome fruit (1.0 ppm), husked rice (0.1 ppm) and walnuts (0.05 ppm).
Tebufenozide is registered in Canada, and a tolerance for residues in/
on apples is established at 1.0 ppm. EPA has set the pome fruit
tolerance at 1.5 ppm based on U.S. field residue trials.

2. Rohm and Haas Company

PP 0F6201

EPA has received a pesticide petition (0F6201) from Rohm and Haas
Company, 100 Independence Mall West, Philadelphia, PA, 19106-2399
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 time-limited tolerances for indirect or inadvertent
residues of methoxyfenozide [benzoic acid, 3-methoxy-2-methyl-, 2-(3,5-
dimethylbenzoyl)-2-(1,1-dimethylethyl) hydrazide] and its metabolites
RH-117,236 (free phenol of methoxyfenozide; 3,5-dimethylbenzoic

[[Page 15449]]

acid N-tert-butyl-N'-(3-hydroxy- 2-methylbenzoyl) hydrazide), RH-
151,055 (the glucose conjugate of RH-117,236; 3,5-dimethylbenzoic acid
N-tert- butyl-N-[3( -D-glucopyranosyloxy)-2-methylbenzoyl]-hydrazide)
and RH-152,072 (the malonylglycosyl conjugate of RH-117,236) in or on
the raw agricultural commodities root and tuber vegetables at 0.05
parts per million (ppm); leaves of root and tuber vegetables at 0.1
ppm; bulb vegetables at 0.1 ppm; leafy vegetables (except Brassica) at
0.2 ppm; Brassica vegetables at 0.2 ppm; legume vegetables at 0.05 ppm;
foliage of legume vegetables at 8 ppm; forage, fodder, hay and straw of
cereal grains at 7 ppm; grass forage, fodder and hay at 7 ppm; forage,
fodder, straw and hay of non-grass animal feeds at 8 ppm; and herbs and
spices at 8 ppm. 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 is adequately understood based upon acceptable
cotton, apple and grape metabolism studies. EPA has determined that the
residue of concern for dietary exposure and tolerance setting purposes
in primary crops and water is the parent compound, methoxyfenozide. The
qualitative nature of methoxyfenozide residues in rotation crop plants
is adequately understood based upon ¹⁴C confined rotation
crop studies. The residue of concern for dietary exposure and tolerance
setting purposes in rotation crops is the parent compound,
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 (the glucose conjugate of RH-
117,236; 3,5-dimethylbenzoic acid N-tert-butyl-N-[3(-D-
glucopyranosyloxy)-2- methylbenzoyl]-hydrazide) and RH-152,072 (the
malonylglycosyl conjugate of RH-117,236).
The qualitative nature of the residue in animals is adequately
understood based on acceptable studies conducted on goats and laying
hens. EPA has determined that the residue of concern in milk and
ruminant tissues (other than liver and kidney) is the parent compound,
methoxyfenozide. The residue of concern in ruminant liver and kidney is
the parent compound, methoxyfenozide, and its glucuronide metabolite
designated as RH-141,518 (also referred to as RH-1518).
2. Analytical method. An HPLC/UV Method TR 34-00-41 for the
enforcement of tolerances in rotation crops has been developed.
Confirmatory method validation, radiovalidation, and independent method
validation data have been submitted for this method. The validated
limit of quantitation (LOQ) of the analytical method was 0.02 ppm in
all matrices for methoxyfenozide and RH-117,236 and 0.05 ppm for RH-
151,055.
3. Magnitude of residues. Magnitude of the residue in rotation
crops. Two geographically representative field trials were submitted to
support the proposed time-limited tolerances on rotation crops.
Turnips, onions, mustard greens, tomatoes, cucumbers, soybeans and
wheat were planted back 7 days after the last application to growing
lettuce crops of methoxyfenozide 80WP formulation according to the
maximum proposed use patterns. The rotated crops were harvested at
maturity. Residues of methoxyfenozide in turnip roots, turnip tops,
onions, mustard greens, tomatoes and cucumbers ranged from no-
detectable residues to 0.07 ppm.
The results of the field trials indicate that residues of
methoxyfenozide will not exceed the proposed tolerances of 0.05 ppm in
root and tuber vegetables, 0.1 ppm in the leaves of root and tuber
vegetables, 0.1 ppm in bulb vegetables, 0.2 ppm in leafy and cole crop
vegetables. No residues were found in fruiting vegetables or cucurbit
vegetables. Residues of methoxyfenozide and its metabolites RH-117236,
RH-151055 and RH-152072 in soybean seeds did not exceed 0.033 ppm and
no residues were detected in wheat grain. Residues of methoxyfenozide
and its metabolites concentrated in the dry matrices soybean hay and
wheat straw at 7.1 ppm and 6.4 ppm, respectively. The results of the
field trials indicate that residues of methoxyfenozide and its
metabolites will not exceed the proposed tolerances of 7 ppm in forage,
fodder and straw of cereal grains and grass forage, fodder and hay.
Residues of methoxyfenozide and its metabolites will not exceed the
proposed tolerances of 8 ppm in foliage of legume vegetables, forage,
fodder, straw and hay of non-animal feeds, or in herbs and spices.
Additional rotation crop trials are in progress to support these time-
limited tolerances.
Residues in meat, milk, poultry, and eggs. The maximum theoretical
dietary burden of methoxyfenozide for dairy or beef cattle associated
with this petition is estimated to be less than 20 ppm. The established
tolerances of 0.02 ppm in the milk and meat of cattle, goats, hogs,
horses, and sheep, 0.1 ppm in the fat of cattle, goats, hogs, horses,
and sheep, 0.1 ppm in liver and 0.02 ppm in meat byproduct (except
liver) of cattle, goat, hogs, horses, and sheep were established based
on a dairy cow feeding level of 45 ppm. These tolerances are adequate
for the proposed rotation crop tolerances.
The maximum theoretical dietary burden of methoxyfenozide for
poultry animals associated with this petition (from cotton meal and
soybean seed) would contribute a maximum theoretical dietary burden for
methoxyfenozide at 0.41 ppm. A poultry metabolism study was conducted
at feeding levels of 58 ppm, 60 ppm, and 68 ppm which are equivalent to
145x, 150x, and 170x, respectively, the maximum theoretical dietary
burden for poultry. Assuming a linear relationship between dose and
residues, the expected residues in eggs and poultry tissues would be
below the LOD for methods used to measure residues in poultry products.
Rohm and Haas concludes that there is no reasonable expectation of
finite residues in eggs and poultry tissues and that a poultry feeding
study is not required at this time.

B. Toxicological Profile

1. Acute toxicity. Acute toxicity studies with technical grade:
Oral LD50 in the rat is 5,000 milligrams/kilograms (mg/kg)
for males and females- Toxicity Category IV; Oral LD50 in
the mouse is 5,000 mg/kg for males and females-Toxicity Category IV;
Dermal LD50 in the rat is > 2,000 mg/kg-Toxicity Category
III; Inhalation LC50 in the rat is > 4.3 milligram/liter
(mg/L)-Toxicity Category IV; Primary Eye Irritation in the rabbit-very
mild irritant-Toxicity Category IV; Primary skin irritation in the
rabbit-not a skin irritant-Toxicity Category IV. Methoxyfenozide is not
a skin sensitizer.
In an acute neurotoxicity study in rats, statistically significant
decreased hind limb grip strength was observed in male rats at 3 hours
(approximate time of peak effect) following a single oral dose of 2,000
mg/kg (limit dose) of methoxyfenozide. Decreased hindlimb grip strength
was also observed in the male rats at 7 and 14 days, but was not
statistically significant. No other systemic or neurotoxic effects were
observed in the male rats or in the female rats at any time in this
study. Since this marginal effect occurred only in one sex, was
statistically significant at only one time, was observed only at the
high dose (limit dose) and no other

[[Page 15450]]

signs of toxicity were observed in the rats in this study, this
possible effect is not considered to be biologically significant. In
addition, neither decreased hindlimb grip strength nor any other signs
of neurotoxicity were observed in any of the animals at any time in a
90-day subchronic neurotoxicity study in rats.
2. Genotoxicity. 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 four studies. The four studies satisfy the new revised
mutagenicity guideline requirements for a new chemical (published in
1991). An additional mutagenicity study, performed on RH-117,236
(Metabolite M-B), a metabolite of methoxyfenozide, was also negative
for genotoxicity.
3. Reproductive and developmental toxicity. In a developmental
toxicity study in rats, no signs of maternal toxicity in dams or of
developmental toxicity in fetuses were observed at the limit dose of
1,000 mg/kg/day. The No Observed Adverse Effect Level (NOAEL) in this
study for both maternal toxicity and developmental toxicity was 1,000
mg/kg/day. The Lowest Observed Adverse Effect Level (LOAEL) > 1,000 mg/
kg/day. Similarly, in a developmental toxicity study in rabbits, no
signs of maternal toxicity or of developmental toxicity were observed
at the limit dose of 1,000 mg/kg/day. The NOAEL in this study for both
maternal toxicity and developmental toxicity was 1,000 mg/kg/day. The
LOAEL was > 1,000 mg/kg/day.
In neither the developmental toxicity study in rats nor in the
developmental toxicity study in rabbits was there any evidence for
increased susceptibility of fetuses to in utero exposure to
methoxyfenozide. In these studies, methoxyfenozide was determined not
to be a developmental toxicant.
In a 2-generation (1 litter/generation) reproduction study in
rats, treatment-related parental toxicity was observed only at 20,000
ppm, the highest dose tested (HDT). At this dose, increased liver
weights were observed in males and females of both generations and
midzonal to periportal hepatocellular hypertrophy was observed in the
livers of all males and females of both generations. The LOAEL for
parental toxicity was 20,000 ppm (1,552/1,821 mg/kg/day for males/
females,respectively) and the NOAEL was 2,000 ppm (153/181 mg/kg/day
for males/females, respectively). There were no treatment-related
effects on reproductive parameters for adult (parent) animals. The
NOAEL for reproductive toxicity was 20,000 ppm. Since no treatment-
related effects were observed in the pups, the NOAEL for neonatal
toxicity was also, 20,000 ppm. The NOAEL for parental toxicity in this
reproduction study is higher than the NOAEL for the 2-year combined
chronic feeding/carcinogenicity study in rats because many of the toxic
effects observed in the 2-year study at the LOAEL (hematological
changes, liver toxicity, histopathological changes in the thyroid gland
and increased adrenal weights) were not examined in the reproduction
study.
4. Subchronic toxicity. In a 2-week range-finding dietary study in
rats, treatment-related effects were observed at > 5,000 ppm in the
liver (increased liver weights and hepatocellular hypertrophy in males
and females), in the thyroid gland (hypertrophy/hyperplasia of
follicular cells in males and females), and in the adrenal gland
(increased adrenal weights and/or hypertrophy of the zona fasciculata
in females). Hypertrophy/hyperplasia of thyroid follicular cells was
also observed in males and females at 1,000 ppm, the lowest observed
adverse effect level (LOAEL) in this study. The no observed adverse
effect level (NOAEL) was 250 ppm. Treatment-related hematological
changes were not observed in the rats in this study.
In a 3-month feeding study in rats, the predominant treatment-
related effects were increased liver weights in males and females and
periportal hepatocellular hypertrophy in all males and females at
20,000 ppm highest dose tested (HDT) and at 5,000 ppm. In addition, at
20,000 ppm, a slightly decreased (7-8%) RBC count and slightly
decreased (7-8%) hemoglobin concentration, compared to control rats,
were observed in the females. The LOAEL in this study was 5,000 ppm
(353/379 mg/kg/day in males/females, respectively). The NOAEL was 1,000
ppm (69/72 mg/kg/day in males/females, respectively). Although observed
in the 2-week dietary study and in the 2-year chronic feeding/
carcinogenicity study in rats, treatment-related effects in the thyroid
and adrenal glands were not observed in the rats in this 3-month study.
There is no available biological explanation for this difference in
findings in the studies.
In a 2-week range-finding study in dogs, treatment-related
hematological changes were observed in both males and females at 3,500
ppm, 7,000 ppm, 15,000 ppm, and 30,000 ppm (HDT). These changes
included decreased RBC counts, decreased hemoglobin concentrations,
decreased hematocrits, decreased MCHC, increased MCV, increased MCH,
increased Heinz bodies, methemoglobinemia, changes in RBC morphology
such as Howell-Jolly bodies and polychromasia, increased reticulocyte
counts, increased nucleated RBC and increased platelet counts. At the
same dose levels (> 3,500 ppm), increased spleen weights and/or
enlarged spleens were also observed. At 7,000 ppm, plasma total
bilirubin was increased. The LOAEL in this study was 3,500 ppm (90-184
mg/kg/day in males and females). The NOAEL was 300 ppm (11-16 mg/kg/day
in males and females).
In a 3-month feeding study in dogs, no treatment-related effects
other than a suggestion of decreased body weight gains in males and
females were observed in either males or females at the HDT viz. 5,000
ppm (198/209 mg/kg/day in males/females, respectively). Although
hematological effects were noted in dogs in the 2-week range-finding
study > 3,500 ppm (90-184 mg/kg/day) and in the 1-year chronic feeding
study at > 3,000 ppm (106/111 mg/kg/day), hematological changes were
not observed in this 3-month study at 5,000 ppm (198/209 mg/kg/day).
There is no available biological explanation for this difference in
findings in the studies.
As part of the 3-month study in dogs, some male and female dogs
were given 15 ppm (0.6 mg/kg/day) of methoxyfenozide in the diet for 15
weeks followed by an increase in the dietary dose to 15,000 ppm (422/
460 mg/kg/day in males/females, respectively) for an additional 6
weeks. After about 2 weeks and 6 weeks at 15,000 ppm, hematological
examinations were conducted. No hematological changes in these dogs
were observed. Apparently, pretreatment of the dogs at 15 ppm for 15
weeks prevented the occurrence of hematological changes which would
have been expected to occur based on results in the 2-week and 1-year
feeding studies. One possible explanation is that the liver microsomal
enzyme system may have been stimulated so much during pretreatment at
15 ppm that the metabolic (detoxification) rate of methoxyfenozide was
increased to the point where blood levels of methoxyfenozide may have
remained below critical effect levels at 15,000 ppm. Another possible
explanation is that compensatory mechanisms for replacing damaged RBC
in pretreated dogs may have been so efficient that hematological
changes were not observed in these dogs even at 15,000 ppm. Other
explanations for this finding are also possible.
5. Chronic toxicity. In a 2-year combined chronic feeding/

[[Page 15451]]

carcinogenicity study in rats, the following treatment-related effects
were observed at 20,000 ppm (highest dose tested): decreased survival
in males, decreased body weight and food efficiency in females during
the last year of the study, hematological changes (decreased RBC
counts, hemoglobin concentrations, and/or hematocrits;
methemoglobinemia; and increased platelet counts) in males and females,
increased liver weights and periportal hepatocellular hypertrophy in
males and females, thyroid follicular cell hypertrophy in males,
altered thyroid colloid in males and females, and increased adrenal
weights in males and females. At 8,000 ppm, the following treatment-
related effects were observed: hematological changes (decreased RBC
counts, hemoglobin concentrations, and/or hematocrits in males and
females), liver toxicity (increased liver weights in males and
periportal hepatocellular hypertrophy in males and females),
histopathological changes in the thyroid (increased follicular cell
hypertrophy in males and altered colloid in males) and possible adrenal
toxicity (increased adrenal weights in males and females). The LOAEL in
this study was 8,000 ppm (411/491 mg/kg/day in males/females,
respectively), based on the effects described above. The NOAEL was 200
ppm (10.2/11.9 mg/kg/day in males/females, respectively). This NOAEL
was used to establish the reference dose (RfD) for methoxyfenozide.
Utilizing an uncertainty factor of 100 to account for both interspecies
extrapolation (10x) and intraspecies variability (10x), the chronic RfD
for methoxyfenozide was calculated to be 0.10 mg/kg/day. No evidence of
carcinogenicity was observed in this study. Dosing was considered
adequate because of the decreased survival in males and the decreased
body weights and food efficiency in females at 20,000 ppm. In addition,
the HDT for both males and females, 20,000 ppm (1,045/1,248 mg/kg/day
in males/females, respectively), is higher than the limit dose of 1,000
mg/kg/day.
In a 1-year chronic feeding study in dogs, the predominant toxic
effects were anemia and signs of an associated compensatory response.
At 30,000 ppm, the HDT, the following treatment-related effects were
observed in both males and females: decreased RBC counts, decreased
hemoglobin concentrations, decreased hematocrits, methemoglobinemia,
nucleated RBC, increased platelets, increased serum total bilirubin,
bilirubinurea, increased hemosiderin in macrophages in liver and
spleen, and increased hyperplasia in bone marrow of rib and sternum.
Increased liver weights in males and females and increased thyroid
weights in males were also observed at 30,000 ppm. Signs of anemia were
also noted at 3,000 ppm and included decreased RBC counts, decreased
hemoglobin concentrations, decreased hematocrits, methemoglobinemia,
increased platelets, and increased serum total bilirubin and
bilirubinurea. The LOAEL in this study was 3,000 ppm (106/111 mg/kg/day
in males/females, respectively). The NOAEL was 300 ppm (9.8/12.6 mg/kg/
day in males/females, respectively).
6. Animal metabolism. 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%). An enterohepatic circulation was observed. The test material
was 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. Seven
metabolites and the parent accounted for 74-90% of the administered
dose in all groups. The 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. In a
dermal absorption study in rats using an 80% wettable powder
formulation as the test material, the cumulative dermal absorption of
test material after a 10- or 24-hour dermal exposure was determined to
be 2%. In a 28-day dermal toxicity study in rats, no treatment-related
systemic or skin effects were observed at the limit dose of 1,000 mg/
kg/day (HDT). Regarding effects on endocrine organs, methoxyfenozide
affected the thyroid gland and adrenal gland in the 2-week and 2-year
feeding studies in rats. In the thyroid gland, hypertrophy/hyperplasia
of follicular cells and altered colloid were observed in males and
females at or near the LOAEL in both of these studies. In the adrenal
gland, increased adrenal weights and hypertrophy of the zona
fasciculata were also observed in males and females at or near the
LOAEL. In addition, in the 1-year chronic feeding study in dogs,
increased thyroid weight in males was observed, but only at the very
high dose of 30,000 ppm. 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, on the basis of these effects on the thyroid gland and
adrenal gland, should be considered to be an ``endocrine disruptor
chemical.'' Other than the morphological changes described above, there
were no signs of thyroid or adrenal dysfunction in these or in any
other studies on methoxyfenozide.
7. Endocrine disruption. Regarding effects on endocrine organs,
methoxyfenozide affected the thyroid gland and adrenal gland in the 2-
week and 2-year feeding studies in rats. In the thyroid gland,
hypertrophy/hyperplasia of follicular cells and altered colloid were
observed in males and females at or near the LOAEL in both of these
studies. In the adrenal gland, increased adrenal weights and
hypertrophy of the zona fasciculata were also observed in males and
females at or near the LOAEL. In addition, in the 1-year chronic
feeding study in dogs, increased thyroid weight in males was observed,
but only at the very high dose of 30,000 ppm. 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, on the basis of these effects on the thyroid gland and
adrenal gland, should be considered to be an ``endocrine disruptor
chemical.'' Other than the morphological changes described above, there
were no signs of thyroid or adrenal dysfunction in these or in any
other studies on methoxyfenozide.

C. Aggregate Exposure

[[Page 15452]]

respectively. Other petitions pending request tolerances for grapes at
1.0 ppm, raisins at 1.5 ppm, fruiting vegetables at 2.0 ppm, Leafy
Vegetables (4A) at 25 ppm, Leaf Petioles (4B) at 10.0 ppm, Head and
Stem Brassica (5A) at 6.5 ppm and Leafy Brassica Greens (5B) at 20.0
ppm. The current petition requests establishment of tolerances due to
indirect or inadvertent residues of methoxyfenozide [benzoic acid, 3-
methoxy-2-methyl-, 2-(3,5-dimethylbenzoyl)-2-(1,1-dimethylethyl)
hydrazide] in or on root and tuber vegetables at 0.05 parts per million
(ppm); leaves of root and tuber vegetables at 0.1 ppm; bulb vegetables
at 0.1 ppm; leafy vegetables (except Brassica) at 0.2 ppm; Brassica
vegetables at 0.2 ppm; and for indirect or inadvertent combined
residues of 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 (the glucose conjugate
of RH-117,236; 3,5-dimethylbenzoic acid N-tert-butyl-N-[3( -D-
glucopyranosyloxy)-2-methylbenzoyl]-hydrazide) and RH-152,072 (the
malonylglycosyl conjugate of RH-117,236) in or on legume vegetables at
0.05 ppm; foliage of legume vegetables at 8 ppm; forage, fodder, hay
and straw of cereal grains at 7 ppm; grass forage, fodder and hay at 7
ppm; forage, fodder, straw and hay of non-grass animal feeds at 8 ppm;
and herbs and spices at 8 ppm.
Risk assessments were conducted by Rohm and Haas to assess dietary
exposures and risks from methoxyfenozide as follows:
a. Acute exposure and risk. Acute dietary risk assessments are
performed for a food-use pesticide if a toxicological study has
indicated the possibility of an effect of concern occurring as a result
of a 1-day or single exposure. 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 study in rats and the
developmental toxicity study in rabbits. This risk is considered to be
negligible.
b. Chronic exposure and risk. Rohm and Haas used the Dietary
Exposure Evaluation Model (DEEM ) software for conducting a 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 conducted in 1989-1992. Rohm and Haas assumed 100% of crops
would be treated and contain methoxyfenozide residues at the tolerance
level. The following tolerance levels were used in the analysis:

------------------------------------------------------------------------
Tolerance Level (parts per
Commodity million) (ppm)
------------------------------------------------------------------------
Cotton, undelinted seed 2.0
Pome fruits 1.5 ppm
Grapes 1.0 ppm
Raisins 1.5 ppm
Leafy Vegetables (4A) 25 ppm
Leaf Petioles (4B) 10.0 ppm
Head and Stem Brassica (5A) 6.5 ppm
Leafy Brassica Greens (5B) 20.0 ppm
Fruiting vegetables 2.0 ppm
Root and tuber vegetables 0.05 ppm
Leaves of root and tuber vegetables 0.1 ppm
Bulb vegetables 0.1 ppm
Leafy vegetables (except Brassica) 0.2 ppm
Brassica vegetables 0.2ppm
Legume vegetables 0.05 ppm
Herbs and spices 8 ppm
Milk 0.02 ppm
Meat* 0.02 ppm
Meat byproducts* (except liver) 0.02 ppm
Fat* 0.1 ppm
Liver 0.1 ppm
------------------------------------------------------------------------
* of cattle, goats, hogs, horses and sheep.

Processing factors were also applied to grape juice (1.2x), grape
juice concentrate (3.6x), apple juice/cider (1.3x), apple juice
concentrate (3.9x), dried apples (8x), dried beef (1.92x), dried pears
(6.25x), tomato juice (1.5x), tomato puree (3.3x), tomato paste (5.4x),
tomato catsup (2.5x), dried tomatoes (14.3x), dehydrated onions (9x),
white dry potatoes (6.5x), and dried veal (1.92x). The processing
factors are default values from DEEM.
As shown in the following table, the resulting dietary food
exposures occupy up to 28.3% of the Chronic PAD for the most highly
exposed population subgroup, children 1-6 years old. These results
should be viewed as conservative (health protective) risk estimates.
Refinements such as use of percent crop-treated information and/or
anticipated residue values would yield even lower estimates of chronic
dietary exposure.

Summary: Chronic Dietary Exposure Analysis by DEEM (Tier 1)
------------------------------------------------------------------------
Exposure (mg/kg/ Percent of Chronic
Population Subgroup\1\ day) PAD\2\
------------------------------------------------------------------------
U.S. Population - 48 States 0.0149............ 14.9
All infants (<1 year) 0.0144 14.4
Nursing Infants<1 year old 0.0084 8.4
Non-Nursing Infants < 1 year old 0.0169 6.9
Children 1-6 years old 0.0283 28.3
Children 7-12 years old 0.0193 19.3
Females 13 + (nursing) 0.0172 17.2
U.S. population (autumn season) 0.0150 15.0
U.S. population (winter season) 0.0151 15.1
U.S. population (spring season) 0.0152 15.2
Northeast region 0.0161 16.1
Western region 0.0161 16.1
Non-Hispanic whites 0.0150 15.0
Non-Hispanic/non-white/non-black 0.0171 17.1
Pacific region 0.0162 16.2
------------------------------------------------------------------------
\1\The subgroups listed are: (1) The U.S. population (total); (2) Those
for infants and children; (3) The other subgroup(s), if any, for which
the percentage of the Chronic PAD occupied is greater than that
occupied by the subgroup U.S.population (total); and, (4) The most
highly exposed of the females subgroups (in this case, females, (13+
years, nursing).
\2\Percent chronic PAD = (Exposure divided by Chronic PAD) x 100%.

ii. Drinking water-- From drinking water. The are no water-related
exposure data from monitoring to complete a quantitative drinking water
exposure analysis and risk assessment for methoxyfenozide. GENEEC and/
or PRZM/EXAMS (both produce estimates of pesticide concentration in a
farm pond) are used to generate EECs for surface water and SCI-GROW (an
empirical model based upon actual monitoring data collected for a
number of pesticides that serve as benchmarks) predicts EECs in ground
water. 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 at this stage 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.

[[Page 15453]]

A drinking water level of comparison (DWLOC) is the concentration
of a pesticide in drinking water that would be acceptable as a
theoretical upper limit in light of total aggregate exposure to that
pesticide from food, water, and residential uses. HED uses DWLOCs
internally in the risk assessment process as a surrogate measure of
potential exposure associated with pesticide exposure through drinking
water. In the absence of monitoring data for a pesticide, the DWLOC is
used as a point of comparison against the conservative EECs provided by
computer modeling (SCI-GROW, GENEEC, PRZM/EXAMS).
a. Acute exposure and risk. Because no acute dietary endpoint was
determined, Rohm and Haas concludes that there is a reasonable
certainty of no harm from acute exposure from drinking water.
b. Chronic exposure and risk. Tier II screening-level assessments
can be conducted using the simulation models SCI-GROW and PRZM/EXAMS to
generate EECs for ground and surface water, respectively. The modeling
was conducted based on the environmental profile and the maximum
seasonal application rate proposed for methoxyfenozide (1.0 lb ai/acre/
season). PRZM/EXAMS was used to generate the surface water EECs,
because it can factor the persistent nature of the chemical into the
estimates.
The EECs for assessing chronic aggregate dietary risk used by HED
are 6 parts per billion (ppb) (in ground water, based on SCI-GROW) and
98.5 ppb (in surface water, based on the PRZM/EXAMS, long-term mean).
The back-calculated DWLOCs for assessing chronic aggregate dietary risk
range from 720 ppb for the most highly exposed population subgroup
(children 1-6 years old) to 2,979 ppb for the U.S. population (48
contiguous States--all seasons).
The SCI-GROW and PRZM/EXAMS chronic EECs are less than the Agency's
level of comparison (the DWLOC value for each population subgroup) for
methoxyfenozide residues in drinking water as a contribution to chronic
aggregate exposure. Rohm and Haas 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 cPAD) for chronic dietary aggregate exposure by any
population subgroup. EPA generally has no concern for exposures below
100% of the cPAD, 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 considered high confidence, conservative, and very
protective of human health.

Drinking Water Levels of Comparison for Chronic Exposure to Methoxyfenozide
--------------------------------------------------------------------------------------------------------------------------------------------------------
Max. Water GENEEC 56-Day
Population Subgroup Chronic PAD (mg/kg/ Food Exposure (m/ Exposure (mg/kg/ SCI-GROW ( Average ( DWLOC (µ/
d) kg/d) d)\1\ µg/L) µg/L) L)%
--------------------------------------------------------------------------------------------------------------------------------------------------------
U.S. Population -48 States 0.10 0.0149 0.0851 6 98.5 2,979
Females 13+ (nursing) 0.10 0.0171 0.0829 6 98.5 2,487
Non-Nursing>1 year old 0.10 0.0169 0.083 6 98.5 830
Children 1-6 years old 0.10 0.0283 0.0720 6 98.5 720
Children 7-12 years old 0.10 0.0193 0.0807 6 98.5 807
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\Maximum Water Exposure (mg/kg/d) = Chronic PAD (mg/kg/day) - Chronic Food Exposure DWLOC (µ/L) = [Maximum water Exposure (mg/kg/d) x body
weight (kg)] divided by [1/1000 mg/µ x water consumed daily (L/day)].

2. Non-dietary exposure. From 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

Cumulative exposure to substances with a common mechanism of
toxicity. 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.''
PA 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 -- i. Acute risk. Since no acute toxicological
endpoints were established, Rohm and Haas considers acute aggregate
risk to be negligible.
ii. Chronic risk. Using the DEEM exposure assumptions described in
this unit, Rohm and Haas has concluded that aggregate exposure to
methoxyfenozide from food will utilize 14.9% of the cPAD for the U.S.
population. The major identifiable subgroup with the highest aggregate
exposure is children 1-6 years old at 28.3% of the cPAD and is
discussed below. 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, the aggregate exposure is not
expected to exceed 100% of the cPAD. Rohm and Haas concludes that there
is a reasonable certainty that no harm will result from aggregate
exposure to methoxyfenozide residues.
iii. Short- and intermediate-term risk. Short- and intermediate-
term aggregate exposure takes into account chronic dietary food and
water (considered to be a background exposure level) plus indoor and
outdoor residential exposure.
Since there are currently no registered indoor or outdoor
residential non-dietary uses of methoxyfenozide and no short or
intermediate term toxic endpoints, Rohm and Haas considers short or
intermediate term aggregate risks to be negligible.
iv. Aggregate cancer risk for U.S. population. Methoxyfenozide is
classified as a ``not likely'' human carcinogen. Therefore this risk
does is negligible.

[[Page 15454]]

v. Determination of safety. Based on these risk assessments, Rohm
and Haas concludes that there is a reasonable certainty that no harm
will result from aggregate exposure to methoxyfenozide residues.
2. Safety factor for infants and children-- i. In general. 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 margin of safety for infants and children in the case of threshold
effects to account for prenatal and postnatal toxicity and the
completeness of the data base 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 (usually 100 for combined
interspecies and intraspecies variability) and not the additional
tenfold MOE/UF when EPA has a complete data base under existing
guidelines and when the severity of the effect in infants or children
or the potency or unusual toxic properties of a compound do not raise
concerns regarding the adequacy of the standard MOE/safety factor.
ii. Prenatal and postnatal sensitivity. The toxicology data base
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.
iii. Conclusion. There is a complete toxicity data base for
methoxyfenozide and exposure data are complete or are estimated based
on data 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.
iv. Acute risk. Since no acute toxicological endpoints were
established, acute aggregate risk is considered to be negligible.
v. Chronic risk. Using the exposure assumptions described in this
unit, Rohm and Haas has concluded that aggregate exposure to
methoxyfenozide from food will utilize 28.3% of the cPAD for infants
and children. 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, Rohm and Haas does not expect the
aggregate exposure to exceed 100% of the cPAD.
vi. Short- or intermediate-term risk. Short and intermediate term
risks are judged to be negligible due to the lack of significant
toxicological effects observed.
vii. Determination of safety. Based on these risk assessments, Rohm
and Haas concludes that there is a reasonable certainty that no harm
will result to infants and children from aggregate exposure to
methoxyfenozide residues.

F. International Tolerances

There are no established or proposed Codex, Canadian or Mexican
limits for residues of methoxyfenozide in/on plant or animal
commodities. Therefore, no compatibility issues exist with regard to
the proposed U.S. tolerances discussed in this petition review.

3. Rohm and Haas Company

PP OF6213

EPA has received a pesticide petition (0F6213) from Rohm and Haas
Company, 100 Independence Mall West, Philadelphia, PA, 19106-2399
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 [benzoic acid,
3-methoxy-2-methyl-, 2-(3,5-dimethylbenzoyl)-2-(1,1- dimethylethyl)
hydrazide] in or on the raw agricultural commodities field corn grain
at 0.05 parts per million (ppm), sweet corn (K +CWHR) at 0.05 ppm,
field corn forage at 15 ppm, field corn stover (fodder) at 105 ppm,
corn oil at 0.2 ppm, aspirated grain factions at 1.0 ppm, corn silage
at 5.0 ppm, sweet corn forage at 30 ppm, and sweet corn stover (fodder)
at 60 ppm. In addition, this petition requests an increase in the
established tolerance for residues of methoxyfenozide to 0.1 ppm in
milk and an increase in the established tolerances for residues of
methoxyfenozide and its glucuronide metabolite to 0.5 ppm in fat, to
0.4 ppm in liver and to 0.1 ppm in meat by products (except liver) of
cattle, goats, horses, hogs and sheep. 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 and was
previously published in the Federal Register of July 5, 2000 (65 FR
41355)(FRL-6496-5). The qualitative nature of methoxyfenozide residues
in rotation crop plants is adequately understood based upon
¹⁴C confined rotation crop studies. The residue of concern
for dietary exposure and tolerance setting purposes in rotation crops
is the parent compound, 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 (the glucose
conjugate of RH-117,236; 3,5-dimethylbenzoic acid N-tert-butyl-N-[3( -
D-glucopyranosyloxy)-2-methylbenzoyl]-hydrazide) and RH-152,072 (the
malonylglycosyl conjugate of RH-117,236).
2. Analytical method. An high performance liquid chromatography
using ultra violet Method TR 34-00-38 for the enforcement of tolerances
in field and sweet corn matrices has been developed. Confirmatory
method validation, radiovalidation, and independent method validation
data have been submitted for this method. The validated limit of
quantitation (LOQ) of the analytical method was 0.02 ppm in all
matrices for methoxyfenozide.
3. Magnitude of residues-- i. Magnitude of the residue.
Geographically representative field trials with methoxyfenozide 80WP
and 2F formulations were conducted to support the proposed tolerances
on field and sweet corn. The results of the field trials indicate that
residues of methoxyfenozide will not exceed the proposed tolerances of
0.05 ppm in field grain and sweet corn (K+CWHR), 15 ppm in field corn
forage, 105 ppm in

[[Page 15455]]

field corn stover (fodder), 1.0 ppm in aspirated grain factions, 5.0
ppm in corn silage, 30 ppm in sweet corn forage and 60 ppm in sweet
corn stover (fodder). A processing study was conducted and showed that
residues concentrated in oil and a tolerance of 0.2 ppm is proposed.
ii. Residues in meat, milk, poultry, and eggs. The maximum
theoretical dietary burden of methoxyfenozide for dairy or beef cattle
associated with this petition and previous petition is estimated to be
less than 75 ppm. Based on a feeding study with methoxyfenozide at 150
ppm, tolerances should be increased to 0.1 ppm in milk, to 0.5 ppm in
fat, to 0.4 ppm in liver and to 0.1 ppm in meat by-products (except
liver). The maximum theoretical dietary burden of methoxyfenozide for
poultry animals associated with this petition (from cotton meal, corn
meal and grain) was calculated to be 0.03 ppm.
A poultry feeding study was conducted at levels of 2 ppm, 6 ppm,
and 20 ppm which are equivalent to 67x, 200x, and 1,500x, respectively,
the maximum theoretical dietary burden for poultry. No detectable
residues of methoxyfenozide were found in any of the muscle, fat or
liver samples from any dose level. In eggs, no quantifiable residues
(i.e., greater than the limit of quantitation of 0.01 ppm) of either
methoxyfenozide or its glucuronide metabolite were found in any of the
samples. Average residues of RH-1518 in liver from hens dosed at 6 ppm
were 0.016 ppm while those in the liver of hens dosed at 20 ppm were
0.031 ppm. After a 7-day depuration period, no detectable residues of
RH-1518 were found in the liver of hens dosed at 20 ppm. Assuming a
linear relationship between dose and residues, the expected residues in
eggs and poultry tissues would be below the LOD of 0.01 ppm for methods
used to measure residues in poultry products. Rohm and Haas concludes
that there is no reasonable expectation of finding finite residues in
eggs and poultry tissues.

B. Toxicological Profile

1. Acute toxicity. Acute toxicity studies with technical grade:
Oral LD50 in the rat is > 5,000 milligrams/kilograms (mg/kg)
for males and females- Toxicity Category IV; Oral LD50 in
the mouse is > 5,000 mg/kg for males and females-Toxicity Category IV;
Dermal LD50 in the rat is > 2,000 mg/kg-Toxicity Category
III; Inhalation LD50 in the rat is > 4.3 milligram/liter
(mg/L)-Toxicity Category IV; Primary Eye Irritation in the rabbit -very
mild irritant-Toxicity Category IV; Primary skin irritation in the
rabbit-not a skin irritant-Toxicity Category IV. Methoxyfenozide is not
a skin sensitizer.
In an acute neurotoxicity study in rats, statistically significant
decreased hind limb grip strength was observed in male rats at 3 hours
(approximate time of peak effect) following a single oral dose of 2,000
mg/kg (limit dose) of methoxyfenozide. Decreased hindlimb grip strength
was also observed in the male rats at 7 and 14 days, but was not
statistically significant. No other systemic or neurotoxic effects were
observed in the male rats or in the female rats at any time in this
study. Since this marginal effect occurred only in one sex, was
statistically significant at only one time, was observed only at the
high dose (limit dose) and no other signs of toxicity were observed in
the rats in this study, this possible effect is not considered to be
biologically significant. In addition, neither decreased hindlimb grip
strength nor any other signs of neurotoxicity were observed in any of
the animals at any time in a 90-day subchronic neurotoxicity study in
rats.
2. Genotoxicity. 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 four studies. The four studies satisfy the new revised
mutagenicity guideline requirements for a new chemical (published in
1991). An additional mutagenicity study, performed on RH-117,236
(Metabolite M-B), a metabolite of methoxyfenozide, was also negative
for genotoxicity.
3. Reproductive and developmental toxicity. In a developmental
toxicity study in rats, no signs of maternal toxicity in dams or of
developmental toxicity in fetuses were observed at the limit dose of
1,000 mg/kg/day. The No Observed Adverse Effect Level (NOAEL) in this
study for both maternal toxicity and developmental toxicity was 1,000
mg/kg/day. The Lowest Observed Adverse Effect Level (LOAEL) 1,000 mg/
kg/day. Similarly, in a developmental toxicity study in rabbits, no
signs of maternal toxicity or of developmental toxicity were observed
at the limit dose of 1,000 mg/kg/day. The NOAEL in this study for both
maternal toxicity and developmental toxicity was 1,000 mg/kg/day. The
LOAEL was > 1,000 mg/kg/day.
In neither the developmental toxicity study in rats nor in the
developmental toxicity study in rabbits was there any evidence for
increased susceptibility of fetuses to in utero exposure to
methoxyfenozide. In these studies, methoxyfenozide was determined not
to be a developmental toxicant.
In a 2-generation (1 litter/generation) reproduction study in rats,
treatment-related parental toxicity was observed only at 20,000 ppm,
the HDT. At this dose, increased liver weights were observed in males
and females of both generations and midzonal to periportal
hepatocellular hypertrophy was observed in the livers of all males and
females of both generations. The LOAEL for parental toxicity was 20,000
ppm (1,552/1,821 mg/kg/day for males/females, respectively) and the
NOAEL was 2,000 ppm (153/181 mg/kg/day for males/females,
respectively). There were no treatment-related effects on reproductive
parameters for adult (parent) animals. The NOAEL for reproductive
toxicity was 20,000 ppm. Since no treatment-related effects were
observed in the pups, the NOAEL for neonatal toxicity was also, 20,000
ppm. The NOAEL for parental toxicity in this reproduction study is
higher than the NOAEL for the 2-year combined chronic feeding/
carcinogenicity study in rats because many of the toxic effects
observed in the 2-year study at the LOAEL (hematological changes, liver
toxicity, histopathological changes in the thyroid gland and increased
adrenal weights) were not examined in the reproduction study.
4. Subchronic toxicity. In a developmental toxicity study in rats,
no signs of maternal toxicity in dams or of developmental toxicity in
fetuses were observed at the limit dose of 1,000 mg/kg/day. The NOAEL
in this study for both maternal toxicity and developmental toxicity was
1,000 mg/kg/day. The LOAEL > 1,000 mg/kg/day. Similarly, in a
developmental toxicity study in rabbits, no signs of maternal toxicity
or of developmental toxicity were observed at the limit dose of 1,000
mg/kg/day. The NOAEL in this study for both maternal toxicity and
developmental toxicity was 1,000 mg/kg/day. The LOAEL was > 1,000 mg/
kg/day.
In neither the developmental toxicity study in rats nor in the
developmental toxicity study in rabbits was there any evidence for
increased susceptibility of fetuses to in utero exposure to
methoxyfenozide. In these studies, methoxyfenozide was determined not
to be a developmental toxicant.
In a 2-generation (1 litter/generation) reproduction study in rats,
treatment-related parental toxicity was observed only at 20,000 ppm,
the HDT. At this dose, increased liver weights were observed in males
and females of both generations and midzonal to periportal
hepatocellular hypertrophy was observed in the livers of all males and
females of both generations. The LOAEL

[[Page 15456]]

for parental toxicity was 20,000 ppm (1,552/1,821 mg/kg/day for males/
females, respectively) and the NOAEL was 2,000 ppm (153/181 mg/kg/day
for males/females, respectively). There were no treatment-related
effects on reproductive parameters for adult (parent) animals. The
NOAEL for reproductive toxicity was 20,000 ppm. Since no treatment-
related effects were observed in the pups, the NOAEL for neonatal
toxicity was also, 20,000 ppm. The NOAEL for parental toxicity in this
reproduction study is higher than the NOAEL for the 2-year combined
chronic feeding/carcinogenicity study in rats because many of the toxic
effects observed in the 2-year study at the LOAEL (hematological
changes, liver toxicity, histopathological changes in the thyroid gland
and increased adrenal weights) were not examined in the reproduction
study.
5. Chronic toxicity. In a 2-year combined chronic feeding/
carcinogenicity study in rats, the following treatment-related effects
were observed at 20,000 ppm (highest dose tested): decreased survival
in males, decreased body weight and food efficiency in females during
the last year of the study, hematological changes (decreased RBC
counts, hemoglobin concentrations, and/or hematocrits;
methemoglobinemia; and increased platelet counts) in males and females,
increased liver weights and periportal hepatocellular hypertrophy in
males and females, thyroid follicular cell hypertrophy in males,
altered thyroid colloid in males and females, and increased adrenal
weights in males and females. At 8,000 ppm, the following treatment-
related effects were observed: hematological changes (decreased RBC
counts, hemoglobin concentrations, and/or hematocrits in males and
females), liver toxicity (increased liver weights in males and
periportal hepatocellular hypertrophy in males and females),
histopathological changes in the thyroid (increased follicular cell
hypertrophy in males and altered colloid in males) and possible adrenal
toxicity (increased adrenal weights in males and females). The LOAEL in
this study was 8,000 ppm (411/491 mg/kg/day in males/females,
respectively), based on the effects described above. The NOAEL was 200
ppm (10.2/11.9 mg/kg/day in males/females, respectively). This NOAEL
was used to establish the reference dose (RfD) for methoxyfenozide.
Utilizing an uncertainty factor of 100 to account for both interspecies
extrapolation (10x) and intraspecies variability (10x), the chronic RfD
for methoxyfenozide was calculated to be 0.10 mg/kg/day. No evidence of
carcinogenicity was observed in this study. Dosing was considered
adequate because of the decreased survival in males and the decreased
body weights and food efficiency in females at 20,000 ppm. In addition,
the HDT for both males and females, 20,000 ppm (1,045/1,248 mg/kg/day
in males/females, respectively), is higher than the limit dose of 1,000
mg/kg/day.
In a 1-year chronic feeding study in dogs, the predominant toxic
effects were anemia and signs of an associated compensatory response.
At 30,000 ppm, the HDT, the following treatment-related effects were
observed in both males and females: decreased RBC counts, decreased
hemoglobin concentrations, decreased hematocrits, methemoglobinemia,
nucleated RBC, increased platelets, increased serum total bilirubin,
bilirubinurea, increased hemosiderin in macrophages in liver and
spleen, and increased hyperplasia in bone marrow of rib and sternum.
Increased liver weights in males and females and increased thyroid
weights in males were also observed at 30,000 ppm. Signs of anemia were
also noted at 3,000 ppm and included decreased RBC counts, decreased
hemoglobin concentrations, decreased hematocrits, methemoglobinemia,
increased platelets, and increased serum total bilirubin and
bilirubinurea. The LOAEL in this study was 3,000 ppm (106/111 mg/kg/day
in males/females, respectively). The NOAEL was 300 ppm (9.8/12.6 mg/kg/
day in males/females, respectively).
6. Animal metabolism. 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%).
An enterohepatic circulation was observed. The test material was
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. Seven
metabolites and the parent accounted for 74-90% of the administered
dose in all groups. The 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. In a
dermal absorption study in rats using an 80% wettable powder
formulation as the test material, the cumulative dermal absorption of
test material after a 10- or 24-hour dermal exposure was determined to
be 2%. In a 28-day dermal toxicity study in rats, no treatment-related
systemic or skin effects were observed at the limit dose of 1,000 mg/
kg/day (HDT). Regarding effects on endocrine organs, methoxyfenozide
affected the thyroid gland and adrenal gland in the 2-week and 2-year
feeding studies in rats. In the thyroid gland, hypertrophy/hyperplasia
of follicular cells and altered colloid were observed in males and
females at or near the LOAEL in both of these studies. In the adrenal
gland, increased adrenal weights and hypertrophy of the zona
fasciculata were also observed in males and females at or near the
LOAEL. In addition, in the 1-year chronic feeding study in dogs,
increased thyroid weight in males was observed, but only at the very
high dose of 30,000 ppm. 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, on the basis of these effects on the thyroid gland and
adrenal gland, should be considered to be an ``endocrine disruptor
chemical.'' Other than the morphological changes described above, there
were no signs of thyroid or adrenal dysfunction in these or in any
other studies on methoxyfenozide.
7. Endocrine disruption. Regarding effects on endocrine organs,
methoxyfenozide affected the thyroid gland and adrenal gland in the 2-
week and 2-year feeding studies in rats. In the thyroid gland,
hypertrophy/hyperplasia of follicular cells and altered colloid were
observed in males and females at or near the LOAEL in both of these
studies. In the adrenal gland, increased adrenal weights and
hypertrophy of the zona fasciculata were also observed in males and
females at or near the LOAEL. In addition, in the 1-year chronic
feeding study in dogs, increased thyroid weight in males was observed,
but only at the very high dose of 30,000 ppm. 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, on the basis of these effects on the thyroid

[[Page 15457]]

gland and adrenal gland, should be considered to be an ``endocrine
disruptor chemical.'' Other than the morphological changes described
above, there were no signs of thyroid or adrenal dysfunction in these
or in any other studies on methoxyfenozide.

C. Aggregate Exposure

1. Dietary exposure-- i. Food.-- From food and feed uses.
Tolerances have been established (40 CFR 180.544) for residues of
methoxyfenozide on cotton, undelinted seed; cotton gin byproducts; pome
fruit; apple pomace, wet; milk; meat and fat of cattle, goats, hogs,
horses and sheep and for the combined residues of methoxyfenozide and
its glucuronide metabolite in liver and meat byproducts (except liver)
of cattle, goats, hogs, horses and sheep. The established tolerances
are listed in the table below. Other petitions pending request
tolerances for grapes, raisins, fruiting vegetables, Leafy Vegetables
(4A), Leaf Petioles (4B), Head and Stem Brassica (5A) and Leafy
Brassica Greens (5B), and tolerances due to indirect or inadvertent
residues of methoxyfenozide [benzoic acid, 3-methoxy-2-methyl-, 2-(3,5-
dimethylbenzoyl)-2-(1,1-dimethylethyl) hydrazide] in or on root and
tuber vegetables; leaves of root and tuber vegetables; bulb vegetables;
leafy vegetables (except Brassica); Brassica vegetables; and for
indirect or inadvertent combined residues of 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 (the glucose conjugate of RH-117,236; 3,5-
dimethylbenzoic acid N-tert-butyl-N-[3( -D-glucopyranosyloxy)-2-
methylbenzoyl]-hydrazide) and RH-152,072 (the malonylglycosyl conjugate
of RH-117,236) in or on legume vegetables; foliage of legume
vegetables; forage, fodder, hay and straw of cereal grains; grass
forage, fodder and hay; forage, fodder, straw and hay of non-grass
animal feeds; and herbs and spices. The proposed tolerances are listed
in the table below. The current petition requests establishment of
tolerances in field corn grain at 0.05 ppm, sweet corn (K+CWHR) at 0.05
ppm, field corn forage at 15 ppm, field corn stover (fodder) at 105
ppm, corn oil at 0.2 ppm, aspirated grain factions at 1.0 ppm, corn
silage at 5.0 ppm, sweet corn forage at 30 ppm, and sweet corn stover
(fodder) at 60 ppm. In addition, this petition requests an increase in
the established tolerance for residues of methoxyfenozide to 0.1 ppm in
milk and an increase in the established tolerances for residues of
methoxyfenozide and its glucuronide metabolite to 0.5 ppm in fat, to
0.4 ppm in liver and to 0.1 ppm in meat by products (except liver) of
cattle, goats, horses, hogs and sheep.
Risk assessments were conducted by Rohm and Haas to assess dietary
exposures and risks from methoxyfenozide as follows:
a. Acute exposure and risk. Acute dietary risk assessments are
performed for a food-use pesticide if a toxicological study has
indicated the possibility of an effect of concern occurring as a result
of a 1-day or single exposure. 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 study in rats and the
developmental toxicity study in rabbits. Since no acute toxicological
endpoints were established, Rohm and Haas considers acute aggregate
risk to be negligible.
b. Chronic exposure and risk. Rohm and Haas used the Dietary
Exposure Evaluation Model (DEEM ) software for conducting a 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 conducted in 1994-1996. Rohm and Haas assumed 100 percent
of crops would be treated and contain methoxyfenozide residues at the
tolerance level. The following table shows the tolerance levels which
were used in the analysis:

------------------------------------------------------------------------
Tolerance Level (parts per)
Commodity million (ppm)
------------------------------------------------------------------------
Cotton, undelinted seed 2.0
Pome fruit 1.5
Grapes 1.0
Raisins 1.5
Leafy Vegetables (4A) 25
Leaf Petioles (4B) 10.0
Head and Stem Brassica (5A) 6.5
Leafy Brassica Greens (5B) 20.0
Fruiting vegetables 2.0
Root and tuber vegetables 0.05
Leaves of root and tuber vegetables 0.1
Bulb vegetables 0.1
Legume vegetables 0.05
Herbs and spices 8
Corn, field, grain 0.05
Corn, field, forage 15
Corn, field, stover (fodder) 105
Corn, oil 0.2
Corn, aspirated grain fractions 1.0
Corn, silage 5.0
Corn, sweet (K+CWHR) 0.05
Corn, sweet, forage 30
Corn, sweet, stover (fodder) 60
Milk 0.1
Meat\1\ 0.02
Meat byproducts\1\ (except liver) 0.1
Fat\1\ 0.5
Liver 0.4
------------------------------------------------------------------------
\1\of cattle, goats, hogs, horses and sheep.

Processing factors were also applied to grape juice (1.2x), grape
juice concentrate (3.6x), apple juice/cider (1.3x), apple juice
concentrate (3.9x), dried apples (8x), dried pears (6.25x), tomato
juice (1.5x), tomato puree (3.3x), tomato paste (5.4x), tomato catsup
(2.5x), dried tomatoes (14.3x), dehydrated onions (9x), white dry
potatoes (6.5x), sprouted soybean seeds (0.33x), corn grain sugar (high
fructose corn syrup; 1.5x), dried beef (1.92x), and dried veal (1.92x).
The processing factors are default values from DEEM.
As shown in the following table the resulting dietary food
exposures occupy up to 34.5% of the Chronic PAD for the most highly
exposed population subgroup, children 1-6 years old. These results
should be viewed as conservative (health protective) risk estimates.
Refinements such as use of percent crop-treated information and/or
anticipated residue values would yield even lower estimates of chronic
dietary exposure.

Summary: Chronic Dietary Exposure Analysis by DEEM (Tier 1)
------------------------------------------------------------------------
Exposure (mg/kg/
Population Subgroup day) % of Chronic PAD*
------------------------------------------------------------------------
U.S. Population -- 48 States 0.0176 17.6
All infants (< 1 year) 0.226 22.6
Nursing Infants < 1 year old 0.00678 6.8
Non-Nursing Infants < 1 year old 0.0273 27.3
Children 1-6 years old 0.0345 34.5

[[Page 15458]]

Children 7-12 years old 0.0200 20.0
Females 13+ (nursing) 0.0177 17.7
U.S. population (autumn season) 0.0181 18.1
U.S. population (winter season) 0.0178 17.8
U.S. population (spring season) 0.0178 17.8
Northeast region 0.0193 19.3
Western region 0.0195 19.5
Hispanics 0.0177 17.7
Non-Hispanic/non-white/non-black 0.0237 23.7
------------------------------------------------------------------------
*Percent chronic PAD = (Exposure divided by Chronic PAD) x 100%

The subgroups listed are: (1) The U.S. population (total); (2)
those for infants and children; (3) the other subgroup(s), if any, for
which the percentage of the Chronic PAD occupied is greater than that
occupied by the subgroup U.S. population (total); and, (4) the most
highly exposed of the females subgroups (in this case, females, (13+
years, nursing).
ii. Drinking water-- From drinking water. The are no water-related
exposure data from monitoring to complete a quantitative drinking water
exposure analysis and risk assessment for methoxyfenozide. GENEEC and/
or PRZM/EXAMS (both produce estimates of pesticide concentration in a
farm pond) are used to generate EECs for surface water and SCI-GROW (an
empirical model based upon actual monitoring data collected for a
number of pesticides that serve as benchmarks) predicts EECs in ground
water. 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 at this stage 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.
A drinking water level of comparison (DWLOC) is the concentration
of a pesticide in drinking water that would be acceptable as a
theoretical upper limit in light of total aggregate exposure to that
pesticide from food, water, and residential uses. HED uses DWLOCs
internally in the risk assessment process as a surrogate measure of
potential exposure associated with pesticide exposure through drinking
water. In the absence of monitoring data for a pesticide, the DWLOC is
used as a point of comparison against the conservative EECs provided by
computer modeling (SCI-GROW, GENEEC, PRZM/EXAMS).
a. Acute exposure and risk. Because no acute dietary endpoint was
determined, Rohm and Haas concludes that there is a reasonable
certainty of no harm from acute exposure from drinking water.
b. Chronic exposure and risk. Tier II screening-level assessments
can be conducted using the simulation models SCI-GROW and PRZM/EXAMS to
generate EECs for ground and surface water, respectively. The modeling
was conducted based on the environmental profile and the maximum
seasonal application rate proposed for methoxyfenozide (1.0 lb ai/acre/
season). PRZM/EXAMS was used to generate the surface water EECs,
because it can factor the persistent nature of the chemical into the
estimates.
The EECs for assessing chronic aggregate dietary risk used by HED
are 6 parts per billion (ppb) (in ground water, based on SCI-GROW) and
98.5 ppb (in surface water, based on the PRZM/EXAMS, long-term mean).
The back-calculated DWLOCs for assessing chronic aggregate dietary risk
range from 655 ppb for the most highly exposed population subgroup
(children 1-6 years old) to 2,884 ppb for the U.S. population (48
contiguous States--all seasons).
The SCI-GROW and PRZM/EXAMS chronic EECs are less than the Agency's
level of comparison (the DWLOC value for each population subgroup) for
methoxyfenozide residues in drinking water as a contribution to chronic
aggregate exposure. Rohm and Haas 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 cPAD) for chronic dietary aggregate exposure by any
population subgroup. EPA generally has no concern for exposures below
100% of the cPAD, 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 considered high confidence, conservative, and very
protective of human health. The following table shows the drinking
water level of comparison for chronic exposure to methoxyfenozine:

Drinking Water Levels of Comparison for Chronic Exposure to Methoxyfenozide
--------------------------------------------------------------------------------------------------------------------------------------------------------
GENEEC 56-Day
Population Subgroup Chronic PAD (mg/kg/ Food Exposure (m/ Max. Water SCI-GROW ( Average ( DWLOC (µg/
d) kg/d) Exposure (mg/kg/d) µg/L) µg/L) L) %
--------------------------------------------------------------------------------------------------------------------------------------------------------
U.S. Population - 48 States 0.10 0.0176 0.0824 6 98.5 2,884
Females 13+ (nursing) 0.10 .0177 0.0823 6 98.5 2,469
Non-Nursing Infants < 1 year old 0.10 0.0273 0.0727 6 98.5 727
Children 1-6 years old 0.10 0.0345 0.0655 6 98.5 655
Children 7-12 years old 0.10 0.0200 0.080 6 98.5 800
--------------------------------------------------------------------------------------------------------------------------------------------------------
Maximum Water Exposure (mg/kg/d) = Chronic PAD (mg/kg/day) - Chronic Food Exposure DWLOC (µg/L) = [Maximum water Exposure (mg/kg/d) x body
weight (kg)] divided by [1/1,000 mg/µg x water consumed daily (L/day)]. Body weights (kg) for adults is 70, for females 13+ is 60 kg and for
all children is 10 kg. Drinking water consumption is 2 liters per day for adults and 1 liter per day for children.

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

Cumulative exposure to substances with a common mechanism of
toxicity. Section 408(b)(2)(D)(v) requires that,

[[Page 15459]]

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, Rohm and Haas has concluded that aggregate exposure to
methoxyfenozide from food will utilize 17.6% of the cPAD for the U.S.
population. The major identifiable subgroup with the highest aggregate
exposure is children 1-6 years old at 34.5% of the cPAD and is
discussed below. 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, the aggregate exposure is not
expected to exceed 100% of the cPAD. Rohm and Haas concludes that there
is a reasonable certainty that no harm will result from aggregate
exposure to methoxyfenozide residues.
2. Safety factor for infants and children--i. In general. In
assessing the potential for additional sensitivity of infant 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
tenfold margin of safety for infants and children in the case of
threshold effects to account for prenatal and postnatal toxicity and
the completeness of the data base 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 (usually 100 for combined
interspecies and intraspecies variability) and not the additional
tenfold MOE/UF when EPA has a complete data base under existing
guidelines and when the severity of the effect in infants or children
or the potency or unusual toxic properties of a compound do not raise
concerns regarding the adequacy of the standard MOE/safety factor.
ii. Prenatal and postnatal sensitivity. The toxicology data base
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.
iii. Conclusion. There is a complete toxicity data base for
methoxyfenozide and exposure data are complete or are estimated based
on data 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.
iv. Acute risk. Since no acute toxicological endpoints were
established, acute aggregate risk is considered to be negligible.
v. Chronic risk. Using the exposure assumptions described in this
unit, Rohm and Haas has concluded that aggregate exposure to
methoxyfenozide from food will utilize 34.5% of the cPAD for infants
and children. 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, Rohm and Haas does not expect the
aggregate exposure to exceed 100% of the cPAD.
vi. Short- or intermediate-term risk. Short and intermediate term
risks are judged to be negligible due to the lack of significant
toxicological effects observed.
vii. Determination of safety. Based on these risk assessments, Rohm
and Haas concludes that there is a reasonable certainty that no harm
will result to infants and children from aggregate exposure to
methoxyfenozide residues.

F. International Tolerances

[FR Doc. 01-6721 Filed 3-16-01; 8:45 am]
BILLING CODE 6560-50-S

Notice of Filing Pesticide Petitions to Establish Tolerances for Certain Pesticide Chemicals in or on Food

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