Notice of Filing Pesticide Petitions to Establish Tolerance 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: January 10, 2000 (Volume 65, Number 6)]
[Notices]
[Page 1370-1381]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr10ja00-39]

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ENVIRONMENTAL PROTECTION AGENCY

[PF-902; FRL-6394-6]

Notice of Filing Pesticide Petitions to Establish Tolerance 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-901, must be
received on or before February 9, 2000.

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-901 in the subject line on the first page of your
response.

FOR FURTHER INFORMATION CONTACT: The product manager listed in the
table below:

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Office location/telephone
Product Manager number/e-mail address Address Petition number(s)
----------------------------------------------------------------------------------------------------------------
James A. Tompkins (PM 25).......... Rm. 239, CM #2, 703-305- 1921 Jefferson Davis PP 8F4973, 9F5096,
5697, Hwy. Arlington, VA 9F6007, and 0F6071
e-mail:
tompkins.james@epamail.epa
.gov..

Joe Travano (PM 10)................ Rm. 214, CM #2, 703-305- Do. PP 9F6033 and 9F6062
6411,
e-mail:
travano.joe@epamail.epa.go
v..
----------------------------------------------------------------------------------------------------------------

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 potentially
affected entities
------------------------------------------------------------------------
Industry 111 Crop production

112 Animal production

311 Food manufacturing
32532 Pesticide
manufacturing
------------------------------------------------------------------------

[[Page 1371]]

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 action under docket control number PF-901. 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-901 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, 401 M St., SW., 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-901. 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 pesticide petitions as follows proposing the
establishment and/or amendment of regulations for residues of certain
pesticide chemicals 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 these petitions contain 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 supports 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: December 3, 1999.

Peter Caulkins, Acting

Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

The petitioner summaries of the pesticide petitions are printed
below as required by section 408(d)(3) of the FFDCA. The summaries of
the petitions were prepared by the petitioners and represent the views
of the petitioners. EPA is publishing the petitions summaries verbatim
without editing them in any way. The petition summary

[[Page 1372]]

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. Monsanto Company

PP 8F4973, 9F5096, 9F6007, and 0F6071

EPA has received pesticide petitions (8F4973, 9F5096, 9F6007, and
0F6071) from Monsanto Company, 600 13th Street NW., Suite 660,
Washington, DC 20005 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 glyphosate (N-(phosphonomethyl)glycine) in or
on the raw agricultural commodities (RACs) corn, field, forage at 3.0
parts per million (ppm); (8F4973); alfalfa, hay at 400 ppm and alfalfa,
forage at 175 ppm (9F5906); and stover and straw of cereal grains group
at 100 ppm (9F6007). Monsanto proposes deletion of currently
established tolerances on alfalfa at 200 ppm, alfalfa, fresh 0.2 ppm
(9F5906); corn, field, stover at 100 ppm; sorghum, grain, stover at 40
ppm, and wheat straw at 85 ppm (9F6007). The proposed deletions are
either no longer needed or are superceded by the proposed crop group
tolerance.
Under PP 0F6071, Monsanto proposes that 40 CFR 180.364(a) header be
amended to read as follows:

General. Tolerances are established for residues of glyphosate
(N-(phosphonomethyl)glycine) per se resulting from the application
of the isopropylamine salt of glyphosate, the ethanolamine salt of
glyphosate, and the ammonium salt of glyphosate in or on the
following RAC.

Monsanto also proposes that 40 CFR 180.364(a) be amended so that
the headers for paragraphs (a)(2) and (a)(3) are deleted and the
commodity tolerances listed in paragraphs (a)(2) and (a)(3) are
reorganized into section (a) in alphabetical order under the header
amended above.
Monsanto proposes that 40 CFR 180.364(d) be amended to read as
follows:

Indirect or inadvertent residues. Tolerances are established for
residues of glyphosate (N-(phosphonomethyl)glycine) per se resulting
from the use of irrigation water containing residues of 0.5 ppm
following applications on around aquatic sites at 0.1 ppm on the
crop groupings citrus, cucurbits, forage grasses, forage legumes,
fruiting vegetables, grain crops, leafy vegetables, nuts, pome
fruits, root crop vegetables, seed and pod vegetables, stone fruits,
and the individual commodities cottonseed, hops, and avocados. Where
tolerances are established at higher levels from other uses of
glyphosate in or on the subject crops, the higher tolerance should
also apply to residues from the aquatic uses cited in this
paragraph.

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
petitions. Additional data may be needed before EPA rules on these
petitions.

A. Residue Chemistry

1. Plant metabolism. The qualitative nature of the residue in
plants is adequately understood. Studies with a variety of plants
including corn, cotton, soybeans, and wheat indicate that the uptake of
glyphosate or its metabolite, aminomethylphosphonic acid (AMPA), from
soil is limited. The material which is taken up is readily
translocated. Foliarly applied glyphosate is absorbed and translocated
throughout the trees or vines to the fruit of apples, coffee, dwarf
citrus (calamondin), pears, and grapes. Metabolism via N-methylation
yields N-methylated glycines and phosphonic acids. For the most part,
the ratio of glyphosate to AMPA is 9 to 1 but can approach 1 to 1 in a
few cases (e.g., soybeans and carrots). Much of the residue data for
crops reflect a detectable residue of parent (0.05 - 0.15 ppm) along
with residues below the level of detection (< 0.05 ppm) of AMPA. Only
glyphosate parent is regulated in plant and animal commodities since
the metabolite AMPA is not of toxicological concern.
2. Analytical method. Adequate enforcement methods are available
for analysis of residues of glyphosate in or on plant commodities.
These methods include gas liquid chromatography (GLC) (Method I in
Pesticides Analytical Manual (PAM) II; the limit of detection is 0.05
ppm) and high performance liquid chromatography (HPLC) with
fluorometric detection. The HPLC procedure has undergone successful
Agency validation and was recommended for inclusion in PAM II. A gas
chromatography/mass spectrometry (GC/MS) method for glyphosate in crops
has also been validated by EPA's Analytical Chemistry Laboratory (ACL).
The proposed revision in the tolerance regulation does not change the
residue to be analyzed, which remains as glyphosate per se.
Adequate analytical methods are available for residue data
collection and enforcement of proposed tolerances of glyphosate in or
on alfalfa, hay; alfalfa, forage; corn, field, forage; and the stover
and straw of cereal grains group.
3. Magnitude of residues. Adequate data concerning glyphosate
residues on RAC have previously been submitted to the Agency.
Accordingly, the available residue data for glyphosate support the
proposed revision of the tolerance expression for glyphosate. As noted
above, the proposed revision will permit glyphosate residues from the
application of glyphosate in the form of its ethanolamine salt. In
addition, any secondary residues occurring in liver, or kidney of
cattle, goats, horses, and sheep, and liver and kidney of poultry will
be covered by existing tolerances.
The submitted residue data adequately support the proposed
tolerance on corn, field, forage at 3.0 ppm. The available crop residue
data support the establishment of tolerances on alfalfa, hay at 400 ppm
and alfalfa, forage at 175 ppm. The available data also support
deletion of the current entries for alfalfa at 200 ppm and alfalfa,
fresh at 0.2 ppm. The available crop field trial data support the
establishment of tolerances in stover and straw of cereal grains group
at 100 ppm. This tolerance is based on data from the three indicator
crops corn, field, stover, wheat straw, and sorghum, stover that have
previously been reviewed. Any secondary residues occurring in liver and
kidney of cattle, goats, hogs, horses, and sheep, and liver and kidney
of poultry will be covered by existing tolerances and the available
data indicate that residues of glyphosate are not anticipated to occur
in any other livestock commodities as a result of this action.

B. Toxicological Profile

EPA has previously evaluated the available toxicity data and
considered its validity, completeness, and reliability as well as the
relationship of the results of the studies to human risk. EPA has also
considered available information concerning the variability of the
sensitivities of major identifiable subgroups of consumers, including
infants and children. The nature of the toxic effects caused by
glyphosate are summarized below:
1. Acute toxicity. Several acute toxicology studies placing
technical-grade glyphosate in Toxicity Category III and Toxicity
Category IV. Technical glyphosate is not a dermal sensitizer.
2. A 21-day dermal toxicity study rabbits were exposed to
glyphosate at levels of 0, 10, 1,000, or 5,000 milligrams/kilograms/day
(mg/kg/day). The systemic no observed adverse effect level (NOAEL) was
1,000 mg/kg/day

[[Page 1373]]

and the lowest observed adverse effect level (LOAEL) was 5,000 mg/kg/
day based on decreased food consumption in males. Although serum
lactate dehydrogenase was decreased in both sexes at the high dose,
this finding was not considered to be toxicologically significant.
3. Genotoxicity. Mutagenicity data included chromosomal aberration
in vitro (no aberrations in Chinese hamster ovary (CHO) cells were
caused with and without S9 activation); DNA repair in rat hepatocyte;
in vivo bone marrow cytogenetic test in rats; rec-assay with B.
subtilis; reverse mutation test with S. typhimurium; Ames test with S.
typhimurium; and dominant-lethal mutagenicity test in mice. These
genotoxicity studies are all negative.
4. Reproductive and developmental toxicity. Developmental toxicity
studies were conducted with glyphosate in the rat and rabbit. In the
rat study, test animals were given oral doses of 0, 300, 1,000, and
3,500 mg/kg/day with a developmental (fetal) NOAEL of 1,000 mg/kg/day
based on an increase in number of litters and fetuses with delayed
maturation of sternebrae and reduced body weight at 3,500 mg/kg/day,
and a maternal NOAEL of 1,000 mg/kg/day based on clinical signs of
toxicity and mortality at 3,500 mg/kg/day highest dose tested (HDT).
In the rabbit study, test animals were orally given doses of 0, 75,
175 and, 350 mg/kg/day of glyphosate. The maternal NOAEL is 175 mg/kg/
day based on clinical signs of toxicity and mortality and the fetal
NOAEL is 350 mg/kg/day HDT based on no developmental toxicity at any
dose tested.
Two studies evaluating the reproductive effects of glyphosate were
conducted in the rat. In a 3-generation study, rats were fed dosage
levels of 0, 3, 10, and 30 mg/kg/day of glyphosate. The NOAEL for
systemic and reproductive/developmental parameters is 30 mg/kg/day
based on no-adverse effects noted at any dose level.
In a 2-generation reproduction study, rats were fed dosage levels
of 0,100, 500, and 1,500 mg/kg/day of glyphosate. The NOAEL for
systemic and developmental parameters is 500 mg/kg/day based on body
weight effects, clinical signs of toxicity in adult males and decreased
pup body weights and a reproductive NOAEL of 1,500 mg/kg/day HDT.
5. Subchronic toxicity. Subchronic (90-day) feeding studies were
conducted with the rat, mouse, and dog. In the rat study, the test
animals were fed dosage levels of 0, 1,000, 5,000, and 20,000 ppm of
glyphosate. The NOAEL is 20,000 ppm based on no-effects at the HDT. In
the mouse study, the test animals were fed dosage levels of 0, 5,000,
10,000, and 50,000 ppm of glyphosate. The NOAEL is 10,000 ppm based on
body weight effects at the HDT.
In the dog study, the test animals were given glyphosate, via
capsule, at doses of 0, 200, 600, and 2,000 mg/kg/day. The NOAEL is
2,000 mg/kg/day based on no-effects at the HDT.
6. Chronic toxicity. In a 12-month oral study, dogs were given
glyphosate, via capsule, at doses of 0, 20, 100, and 500 mg/kg/day. The
NOAEL is 500 mg/kg/day based on no-adverse effects at any dose level.
In a 26-month chronic feeding/oncogenicity study, rats were fed
glyphosate at dosage levels of 0, 3, 10, and 31 mg/kg/day (males) and
0, 3, 11, and 34 mg/kg/day (females). The NOAEL is 31 mg/kg/day (males)
and 34 mg/kg/day (females) based on no carcinogenic or other adverse
effects at any dose level. Because a maximum tolerated dose (MTD) was
not reached, this study was classified as supplemental for
carcinogenicity.
In a 24-month chronic feeding/oncogenicity study, rats were fed
glyphosate at dosage levels of 0, 89, 362, and 940 mg/kg/day (males)
and 0, 113, 457, and 1,183 mg/kg/day (females). The systemic NOAEL is
362 mg/kg/day based on body weight effects in the female and eye
effects in males. There was no carcinogenic response at any dose level.
In a mouse oncogenicity study, mice were fed glyphosate at dosage
levels of 0, 150, 750, and 4,500 mg/kg/day with a NOAEL of 750 mg/kg/
day based on body weight effects and microscopic liver changes at the
HDT. There was no carcinogenic effect at the HDT of 4,500 mg/kg/day.
Glyphosate is classified as a Group E (evidence of non-carcinogenicity
for humans). This classification is based on the following findings:
i. There were no treatment related tumor findings in three state-
of-the-art long-term bioassays.
ii. Glyphosate was tested up to the limit dose in the rat and up to
levels higher than the limit dose in mice.
iii. There is no evidence of genotoxicity for glyphosate.
7. Animal metabolism. The qualitative nature of the residue in
animals is adequately understood. Studies with lactating goats and
laying hens fed a mixture of glyphosate and AMPA indicate that the
primary route of elimination was by excretion (urine and feces). These
results are consistent with metabolism studies in rats, rabbits, and
cows. The terminal residues in eggs, milk, and animal tissues are
glyphosate and its metabolite AMPA; there was no evidence of further
metabolism. The terminal residue to be regulated in livestock is
glyphosate per se.
8. Metabolite toxicology. Only glyphosate parent is to be regulated
in plant and animal commodities since the metabolite AMPA is not of
toxicological concern in food.
9. Endocrine disruption. The toxicity studies required by EPA for
the registration of pesticides measure numerous endpoints with
sufficient sensitivity to detect potential endocrine-modulating
activity. No effects have been identified in subchronic, chronic, or
developmental toxicity studies to indicate any endocrine-modulating
activity by glyphosate. In addition, negative results were obtained
when glyphosate was tested in a dominant-lethal mutation assay. While
this assay was designed as a genetic toxicity test, agents that can
affect male reproduction function will also cause effects in this
assay. More importantly, the multi-generation reproduction study in
rodents is a complex study design which measures a broad range of
endpoints in the reproductive system and in developing offspring that
are sensitive to alterations by chemical agents. Glyphosate has been
tested in two separate multi-generation studies and each time the
results demonstrated that glyphosate is not a reproductive toxin.

C. Aggregate Exposure

1. Dietary exposure. Tolerances have been established (40 CFR
180.364) for the residues of (n-(phosphonomethyl)glycine resulting from
the application of the isopropylamine salt of glyphosate and/or the
monoammonium salt of glyphosate, in or on a variety of plant and animal
RACs including kidney of cattle, goats, hogs, horses, and sheep at 4.0
ppm; liver of cattle, goats, hogs, horses, and sheep at 0.5 ppm; and
liver and kidney of poultry at 0.5 ppm based on animal feeding studies
and worst-case livestock diets. The RAC corn, field, forage is not
consumed by humans. Thus, the only possible exposure from this
increased tolerance would be secondary residues in animal commodities
which may occur from this use through the feeding of corn forage to
livestock.
The petition proposes to expand this residue definition to include
application of the ethanolamine salt of glyphosate. Risk assessments
were conducted by EPA to assess dietary exposures from glyphosate as
follows:
i. Food--Acute exposure and risk. Acute dietary risk assessments
are

[[Page 1374]]

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. An acute dietary risk assessment was not
performed because no endpoints attributable to single dose were
identified in the oral studies including rat and rabbit developmental
studies. There are no data requirements for acute and subchronic
neurotoxicity studies and no evidence of neurotoxicity in any of the
toxicity studies at very high doses. The Agency has concluded with
reasonable certainty that glyphosate dose not elicit an acute
toxicological response, and that an acute dietary risk assessment is
not needed.
ii. Chronic exposure and risk. The chronic dietary exposure
analysis was conduced using the reference dose (RfD) of 2.0 mg/kg/day
based on the maternal NOAEL of 175 mg/kg/day from a developmental study
and an uncertainty factor of 100 (applicable to all population groups)
the Dietary Exposure Evaluation Model (DEEM) analysis assumed tolerance
levels residues and 100% of the crop treated. These assumptions
resulted in the following theoretical maximum residue contributions
(TMRC) and percentage RfDs for certain population subgroups. The TMRC
for the U.S. population (48 contiguous States) was 0.029960 or 1.5% of
the RfD, 0.026051 or 1.3% of the RfD for nursing infants (less than on
1 year old), 0.065430 or 3.3% of the RfD for non-nursing infants less
than 1 year old; 0.064388 or 3.2% of the RfD for children (1-6 years
old); 0.043017 or 2.2% of the RfD for children (7-12 years old);
0.030928 or 1.5% of the RfD for females (13+/nursing); 0.030241 or 1.5%
of the RfD for non-Hispanic whites; and 0.030206 or 1.5% of the RfD for
non-Hispanic blacks. These exposure levels will be unaffected by the
proposed amendment to the tolerance regulation.
iii. Chronic risk-carcinogenic. Glyphosate has been classified as a
Group E chemical evidence of carcinogenicity in two acceptable animal
species.
iv. Drinking water. Generic Expected Environmental Concentration
(GENEEC) and Screening Concentration and Ground Water (SCI-GROW) models
were run by EPA to produce maximum estimates of glyphosate
concentrations in surface and ground water, respectively. The drinking
water exposure for glyphosate from the ground water screening model,
SCI-GROW, yields a peak and chronic Estimated Environmental
Concentration (EEC) of 0.0011 parts per billion (ppb) in ground water.
The GENEEC values represent upper-bound estimates of the concentrations
that might be found in surface water due to glyphosate use. Thus, the
GENEEC model predicts that glyphosate surface water concentrations
range from a peak of 1.64 ppb to a 56-day average of 0.19 ppb. The
model estimates are compared directly to drinking water level of
comparison (DWLOC) (chronic). The DWLOC (chronic) is the theoretical
concentration of glyphosate in drinking water so that the aggregate
chronic exposure (food + water + residential) will occupy no more than
100% of the RfD. This assessment does not take into account expected
reductions in any glyphosate concentrations in water arising from water
treatment of surface water prior to releasing it for drinking purposes.
The Agency's default body weights and consumption values used to
calculate DWLOCs are as follows: 70 kg/2L (adult male), 60 kg/2L (adult
female), and 10 kg/1L (child).
v. Acute exposure and risk. An acute dietary endpoint and dose was
not identified in the toxicology data base. Adequate rat and rabbit
developmental studies did not provide a dose or endpoint that could be
used for acute dietary risk purposes. Additionally, there were no data
requirements for acute or subchronic rat neurotoxicity studies since
there was no evidence of neurotoxicity in any of the toxicology studies
at very high doses.
vi. Chronic exposure and risk. The DWLOC (chronic, non-cancer) risk
is calculated by multiplying the allowed chronic water exposure (mg/kg/
day) x body weight (kg) divided by the consumption (L) x 103
g/mg. The DWLOCs are 69,000 g/L for the U.S.
population in 48 contiguous States, males (13+), non-Hispanic whites,
and non-Hispanic blacks; and 19,000 for non-nursing infants (less than
1 year old) and children (1-6 years). Although the GENEEC and SCI-GROW
models are known to produce worst-case estimates, the resulting average
concentrations of glyphosate in the surface and ground water are more
than 10,000-fold less than the DWLOC (chronic). Therefore, taking into
account present uses and uses proposed in this action, Monsanto
concludes with reasonable certainty that no harm will result from
chronic aggregate exposure to glyphosate.
2. Non-dietary exposure. Glyphosate is currently registered for use
on the following residential non-food sites: Around ornamentals, shade
trees, shrubs, walk, driveways, flower beds, and home lawns. Based on
the registered uses of glyphosate, the potential for residential
exposures exists. However, based on the low acute toxicity and lack of
other toxicological concerns, glyphosate does not meet the Agency's
criteria for residential data requirements and a residential exposure
assessment is not required since there are no toxicological endpoints
selected for either dermal or inhalation exposure. Exposures from
residential uses are not expected to pose undue risks or harm to public
health.
i. Acute exposure and risk. There are no acute toxicological
concerns for glyphosate. Glyphosate has been the subject of numerous
incident reports, primarily for eye and skin irritation injuries, in
California. Some glyphosate end-use products are in Toxicity Categories
I and II for eye and dermal irritation. The Reregistration Eligibility
Decision Document for Glyphosate (September 1993) indicated that the
Agency is not adding additional personal protective equipment (PPE)
requirements to labels of end-use products, but that it continues to
recommend the PPE and precautionary statements required for end-use
products in Toxicity Categories I and II.
ii. Chronic exposure and risk. Although there are registered
residential uses for glyphosate, glyphosate does not meet the Agency's
criteria for residential data requirements, due to the lack of
toxicological concerns. Incidental acute and/or chronic dietary
exposures from residential uses of glyphosate are not expected to pose
undue risks to the general population, including infants and children.
iii. Short- and intermediate-term exposure and risk. EPA identified
no toxicological concerns for short- intermediate- and long-term dermal
or inhalation routes of exposures for glyphosate. The Agency has
concluded that exposures from residential uses of glyphosate are not
expected to pose undue risks.

D. Cumulative Effects

Section 408(b)(2)(D)(v) requires that, when considering whether to
establish, modify, or revoke a tolerance, the Agency consider
``available information''concerning the cumulative effects of a
particular pesticide's residues and ``other substances that have a
common mechanism of toxicity.''
EPA does not have, at this time, available data to determine
whether glyphosate 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,
glyphosate does not produce a toxic metabolite that is also produced by
other substances. For the purposes of

[[Page 1375]]

this tolerance action, therefore, EPA should assume that glyphosate
does not have a common mechanism of toxicity with other substances. For
information regarding EPA's efforts to determine which chemicals have a
common mechanism of toxicity and to evaluate the cumulative effects of
such chemicals, see the final rule for Bifenthrin Pesticide Tolerances
November 26, 1997, (62 FR 62961) (FRL-5754-7).

E. Safety Determination

1. U.S. population--i. Acute risk. There was no acute dietary
endpoint identified, therefore, there are no acute toxicological
concerns for glyphosate.
ii. Chronic risk. Using the TMRC exposure assumptions described in
this unit, EPA has concluded that aggregate exposure to glyphosate from
food will utilize 1.5% of the RfD for the U.S. population. The major
identifiable subgroup with the highest aggregate exposure is non-
nursing infants (less than 1 year) and children (1-6 years old) as
discussed below. EPA generally has no concern for exposures below 100%
of the RfD because the RfD 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 glyphosate
in drinking water and from non-dietary, non-occupational exposure, the
aggregate exposure will not exceed 100% of the RfD. EPA has previously
concluded that there is a reasonable certainty that no harm will result
from aggregate exposure to glyphosate residues at this level. The
safety determination is unaffected by the proposed change in the
tolerance regulation.
iii. Short- and intermediate-term risk. Short-and intermediate-term
dermal and inhalation risk is not a concern due to the lack of
significant toxicological effects observed with glyphosate under these
exposure scenarios. 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.
iv. Aggregate cancer risk for U.S. population. Glyphosate has been
classified as a Group E chemical, with no evidence of carcinogenicity
for humans in two acceptable animal studies.
v. Determination of safety. Based on these risk assessments,
Monsanto concludes that there is a reasonable certainty that no harm
will result from aggregate exposure to glyphosate residues.
2. Infants and children. In general, when assessing the potential
for additional sensitivity of infants and children to residues of
glyphosate, EPA considers 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 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/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.
i. Prenatal and postnatal sensitivity. The oral prenatal and
prenatal data demonstrated no indication of increased sensitivity of
rats or rabbits to in utero and postnatal exposure to glyphosate.
ii. Conclusion. There is a complete toxicity data base for
glyphosate and exposure data are complete or are estimated based on
data that reasonably accounts for potential exposures. Based on these
data, there is no indication that the developing fetus or neonate is
more sensitive than adult animals. No developmental neurotoxicity
studies have been required at this time. A developmental neurotoxicity
data requirement is an upper tier study and is required only if effects
observed in the acute and 90-day neurotoxicity studies indicate
concerns for frank neuropathy or alterations seen in fetal nervous
system in the developmental or reproductive toxicology studies. The
Agency has concluded that reliable data support the use of the standard
100-fold uncertainty factor for glyphosate, and that a tenfold (10x)
uncertainty factor is not needed to protect the safety of infants and
children.
iii. Acute risk. There are no acute toxicological endpoints for
glyphosate. The Agency has concluded that establishment of the proposed
tolerances would not pose an unacceptable aggregate risk.
3. Chronic risk. Using the exposure assumptions described in this
unit, EPA has concluded that aggregate exposure to glyphosate from food
utilizing present tolerances will utilize 3.0% of the RfD for infants
and children. EPA generally has no concern for exposures below 100% of
the RfD because the RfD represents the level at or below which daily
aggregate dietary exposure over a lifetime will not pose appreciable
risks to human health. These dietary exposure levels are unaffected by
the proposed tolerances on alfalfa, hay and alfalfa, forage, because
these commodities are only consumed by livestock, and the existing
tolerances in liver and kidney fractions of cattle, goats, horses,
sheep, and poultry are considered sufficient to account for any
additional dietary burden these animals may encounter. Although there
is a low likelihood potential exposure to glyphosate in drinking water
and from non-dietary, non-occupational exposure, EPA has previously
concluded that the aggregate exposure is not expected to exceed 100% of
the RfD. The safety determination is unaffected by the proposed change
in the tolerance regulation.
4. Short- or intermediate-term risk. Short-term and intermediate-
term dermal and inhalation risk is not a concern due to the lack of
significant toxicological effects observed with glyphosate under these
exposure scenarios.
5. Determination of safety. Based on these risk assessments, EPA
has previously concluded that there is a reasonable certainty that no
harm will result to infants and children from aggregate exposure to
glyphosate residues at these levels.

F. International Tolerances

No Codex Maximum Residue Levels (MRLs) exist for alfalfa, hay,
alfalfa, forage; or corn, field, forage. A MRL exists for straw and
fodder (dry) of cereal grains (Code as 0091) at 100 ppm. Therefore, the
proposed tolerance for stover and straw of cereal grains group at 100
ppm will harmonize to United States regulations with those in place
internationally. Codex MRLs have been established in or on many RACs.
These petitions propose no additional numerical changes; therefore, the

[[Page 1376]]

agreement between United States tolerances and Codex MRLs are not
affected by other proposals in this action.

2. Rohm and Haas Company

9F6033

EPA has received a pesticide petition (9F6033) from Rohm and Haas
Company, 100 Independence Mall West, Philadelphia, PA 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
methoxyfenozide benzoic acid, 3-methoxy-2-methyl-,2-(3,5-
dimethylbenzoyl)-2-(1,1- dimethylethyl) hydrazide in or on the RACs
grapes, raisins, and fruiting vegetables (except cucurbits) at 1.0,
1.5, and 2.0 ppm respectively. 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 metabolism of methoxyfenozide in plants
(grapes, apples, cotton, and rice) is adequately understood for the
purposes of these tolerances. The metabolism of methoxyfenozide in all
crops was similar and involves cleavage of the methoxyl side chain to
the free phenol, RH-117236 or oxidation of the alkyl substituents of
the aromatic rings primarily at the benzylic positions. In all crops,
parent compound comprised the majority of the total dosage. None of the
metabolites were in excess of 10% of the total dosage.
2. Analytical method. A high performance liquid chromatographic
(HPLC) analytical method using ultraviolet (UV) or mass selective (MS)
detection has been validated for grapes, raisins, grape juice, wine,
peppers, tomatoes, and tomato processed fractions (juice, puree,
paste). The method involves extraction by blending with solvents,
purification of the extracts by liquid-liquid partitions and final
purification of the residues using basic alumina column chromatography
and solid phase extraction. The LOQ is 0.02 ppm for all matrices.
3. Magnitude of residues--i. Grapes. Residue studies showed a range
of residues in grapes from 0.20-0.86 ppm, and support a tolerance of
1.0 ppm in grapes and 1.5 ppm in raisins. Residues did not concentrate
in red and white wine or in clarified and unclarified juice.
ii. Fruiting vegetables. Residue studies showed a range of residues
in peppers from 0.032-1.03 ppm and in tomatoes (cherry and non-cherry)
from 0.05-1.86, supporting a tolerance of 2.0 ppm for the crop group.
No concentration of residues was seen in the tomato processed fractions
juice, puree or paste.

B. Toxicological Profile

1. Acute toxicity. Methoxyfenozide has low acute toxicity.
Methoxyfenozide was practically non-toxic by ingestion of a single oral
dose in rats and mice (LD50 > 5,000 mg/kg) and was
practically non-toxic by dermal application (LD50 > 5,000
mg/kg). Methoxyfenozide was not significantly toxic to rats after a 4-
hour inhalation exposure with an LC50 value of > 4.3
milligrams per liter (mg/L) (highest attainable concentration), is not
considered to be a primary eye irritant or a skin, irritant, and is not
a dermal sensitizer. An acute neurotoxicity study in rats did not
produce any neurotoxic or neuropathologic effects with a NOAEL > 2,000
mg/kg.
2. Genotoxicty. Methoxyfenozide tested negative (non-mutagenic,
non-genotoxic) in a battery of in vitro and in vivo assays, which
included an Ames assay with and without metabolic activation, a CHO/
HGPRT assay, an in vitro chromosome aberration assay in CHO cells with
and without a metabolic activation, an in vivo micronucleus assay in
mouse bone marrow cells.
3. Reproductive and developmental toxicity--i. NOAELs for
developmental and maternal toxicity to methoxyfenozide were established
at 1,000 mg/kg/day HDT in both the rat and rabbit. No signs of
developmental toxicity were exhibited.
ii. In a 2-generation reproduction study in the rat, the
reproductive/developmental toxicity NOAELs of 1,552 mg/kg/day was 100-
fold higher than the parental (systemic) toxicity NOAEL of 200 ppm
(15.5 mg/kg/day).
4. Subchronic toxicity--i. The NOAEL in a 90-day rat feeding study
was 1,000 ppm (69.3 mg/kg/day for males, 72.4 mg/kg/day for females).
The LOAEL was 5,000 ppm (353 mg/kg/day for males, 379 mg/kg/day for
females). Increased liver weight and liver histopathology were observed
at the LOAEL of 5,000 ppm. Methoxyfenozide did not produce neurotoxic
or neuropathologic effects when administered in the diets of rats for 3
months at concentrations up to and including the limit dose of 20,000
ppm (NOAEL = 1,318 mg/kg/day for males, 1,577 mg/kg/day for females).
ii. In a 90-day feeding study with mice, the NOAEL was 2,500 ppm
(428 and 589 mg/kg/day for males and females, respectively). The LOAEL
was 7,000 ppm (1,149 and 1,742 mg/kg/day for males and females,
respectively). Decreases in body weight gain were noted in both sexes
of mice at the LOAEL of 7,000 ppm.
iii. A 90-day dog feeding study gave a NOAEL of 3,000 ppm, the HDT
(198 and 209 mg/kg/day for males and females, respectively). Extension
of treatment of the low dose animals for 6 weeks at 15,000 ppm (422 and
460 mg/kg/day for males and females, respectively) produced no signs of
systemic toxicity.
Methoxyfenozide did not produce toxicity in the rat when
administered dermally for 4 weeks at doses up to and including the
limit dose of 1,000 mg/kg/day. These findings correlate with the low
dermal penetration observed with ¹⁴C-methoxyfenozide,
formulated as the wettable powder (i.e., after 24 hours 1-3% of the
administered dose was systemically absorbed).
5. Chronic toxicity--i. The NOAEL in a 1 year feeding study in dogs
was 300 ppm (9.8 and 12.6 mg/kg/day for male and females,
respectively). The LOAEL was 3,000 ppm (106 and 111 mg/kg/day for male
and females, respectively) based on minimal hematological effects.
ii. An 18-month mouse carcinogenicity study showed no signs of
carcinogenicity at dosage levels up to and including 7,000 ppm (1,020
and 1,354 mg/kg/day for male and females, respectively), the HDT.
iii. In a combined rat chronic/oncogenicity study, the NOAEL for
chronic toxicity was 200 ppm (10.2 and 11.9 mg/kg/day for males and
females, respectively) and the LOAEL was 8,000 ppm (411 and 491 mg/kg/
day for males and females, respectively). No carcinogenicity was
observed at the dosage levels up to 20,000 ppm (1,045 and 1,248 mg/kg/
day for males and females, respectively).
6. Animal metabolism. In toxicokinetic and metabolism studies in
the rat, methoxyfenozide was rapidly absorbed following oral exposure
with peak plasma levels occurring within 0.5 hours of administration.
Methoxyfenozide does not bioaccumulate in that the compound is rapidly
and almost completely eliminated within 24 hours. Methoxyfenozide was
extensively metabolized in rats. Including parent compound, 32
metabolites, of which 26 were identified, were isolated from the rat
urine and feces. The primary pathway of methoxyfenozide metabolism
involves demethylation of the A-ring methoxyl moiety to form the
corresponding A-ring phenol, RH-

[[Page 1377]]

117,236, which is readily conjugated with glucuronic acid to RH-1518.
Hydroxylation on the B-ring methyl moieties is also an important
metabolic pathway.
7. Metabolite toxicology. Common metabolic pathways for
methoxyfenozide have been identified in both plants (grape, apple,
rice, and cotton) and animals (rat, goat, hen). Extensive degradation
and elimination of polar metabolites occurs in animals such that
residues are unlikely to accumulate in humans or animals exposed to
these residues through the diet. The rapid metabolism and excretion of
methoxyfenozide in part accounts for the compound's overall low
toxicity profile in animals.2 The main metabolite of methoxyfenozide in
plants and animals, the A-ring phenol, RH-117,236, produced no toxicity
in mice (LD50 > 5,000 mg/kg) and was negative when tested in
the Ames mutagenic assay. Other metabolites of methoxyfenozide (e.g.,
glucuronides) would be expected to produce minimal to no toxicity given
structure activity considerations.
8. Endocrine disruption. Based on structure-activity information as
well as the lack of developmental and reproductive toxicity,
methoxyfenozide is unlikely to exhibit estrogenic activity. No
indicators of estrogenic or other endocrine effects were observed in
mammalian chronic studies or in mammalian and avian reproduction
studies. Methoxyfenozide is within a class of chemistry
(diacylhydrazines) that is not known to bind to mammalian steroid
receptors. Overall, the weight of evidence provides no indication that
methoxyfenozide has endocrine activity in vertebrates.

C. Aggregate Exposure

1. Dietary exposure. Tolerances are proposed for the residues of
methoxyfenozide in or grapes, raisins, and fruiting vegetables. Risk
assessments were conducted by Rohm and Haas to assess dietary exposures
and risks from methoxyfenozide as follows:
i. Food--a. Acute exposure and risk. No acute endpoint of concern
was identified for methoxyfenozide and no acute risk assessment is
required.
b. Chronic exposure and risk. For chronic dietary risk assessment,
the proposed tolerance values and anticipated (average) residues are
used and the assumption that 100% of all grapes and fruiting vegetables
(in addition to cotton, and pome fruit) will contain residues of
methoxyfenozide at the tolerance or anticipated residue levels. The RfD
used for the chronic dietary analysis is 0.1 mg/kg/day based on the
NOAEL of 9.8-10.0 mg/kg/day from the rat and dogs chronic studies.
Potential chronic exposures were estimated using NOVIGEN'S (DEEM
Version 6.74) which uses USDA food consumption data from the 1994-1996
survey. With the proposed tolerances and anticipated residue levels for
methoxyfenozide, the percentage of the RfD utilized is as follows:

----------------------------------------------------------------------------------------------------------------
Groups Tolerance Levels, Total %RfD Anticipated Residues, Total %RfD
----------------------------------------------------------------------------------------------------------------
U.S. Population - 48 contiguous States.. 6.8 0.6
Hispanics............................... 7.5 0.6
Non-Hispanic/non-white/non-black........ 6.9 0.7
Nursing Infants > 1 year old............ 5.2 0.8
Non-Nursing Infants > 1 year old........ 14.7 2.0
Children 1-6 years old.................. 20.2 1.9
Children 7-12 years old................. 9.3 0.8
----------------------------------------------------------------------------------------------------------------

The chronic dietary risks from these uses do not exceed EPA's level
of concern.
ii. Drinking water. Submitted environmental fate studies suggest
that methoxyfenozide is moderately persistent and mobile, and could
potentially leach to ground water and runoff to surface water under
certain environmental conditions. However, in terrestrial field
dissipation and orchard dissipation studies, residues of
methoxyfenozide showed minimal mobility and remained associated with
the upper layers of soil. Foliar interception (up to 70% of the total
dosage applied) by target crops reduces the ground level residues of
methoxyfenozide.
Acute and chronic exposures to methoxyfenozide in drinking water
were estimated using the GEENEC V1.2 and SCI-GROW models, as directed
in OPP's Interim Approach for Addressing Drinking Water Exposure.
GEENEC is a highly conservative model used to estimate residue
concentrations in surface water. SCI-GROW is an equally conservative
model used to estimate residue concentrations in shallow, highly
vulnerable ground water (i.e., sites with sandy soils and depth to
ground water of 10 to 20 feet). As indicated in EPA's drinking water
exposure guidance, a very small percentage of people in the United
States would derive their drinking water from such sources. GEENEC (56-
day average) and SCI-GROW water exposure values for methoxyfenozide
utilize 1% or less of the RfD for adults and children.
There is no established Maximum Concentration Level (MCL) for
residues of methoxyfenozide in drinking water. No drinking water health
advisory levels have been established for methoxyfenozide. There is no
entry for methoxyfenozide in the ``Pesticides in Groundwater Database''
(EPA 734-12-92-001, September 1992).
iii. Chronic exposure and risk. There are insufficient water-
related exposure data to complete a comprehensive drinking water
assessment for methoxyfenozide at this time. However, in order to
mitigate the potential for methoxyfenozide to leach into ground water
or runoff to surface water, precautionary language has been
incorporated into the proposed product label. Also, to the best of our
knowledge, previous experience at EPA with more persistent and mobile
pesticides for which there were available data to perform quantitative
risk assessments demonstrated that drinking water exposure was
typically a small percentage of the total dietary exposure. This
observation holds even for pesticides detected in wells and drinking
water at levels nearing or exceeding established MCLs. Considering the
precautionary language on the label and our knowledge of previous
experience with persistent chemicals, no risk from residues of
methoxyfenozide in drinking water is anticipated.
2. Non-dietary exposure. Methoxyfenozide is not currently
registered for any indoor or outdoor residential uses; therefore, no
non-

[[Page 1378]]

dietary residential exposure is anticipated.

D. Cumulative Effects

The methodologies to resolve the complex scientific issues
concerning common mechanism of toxicity in a meaningful way are not
available at this time. EPA has begun a pilot process to study this
issue further through the examination of particular classes of
pesticides. The Agency hopes that the results of this pilot process
will increase the Agency's scientific understanding of this question
such that EPA will be able to develop and apply scientific principles
for better determining which chemicals have a common mechanism of
toxicity and evaluating the cumulative effects of such chemicals. The
Agency anticipates, however, that even as its understanding of the
science of common mechanisms increases, decision on specific classes of
chemicals will be heavily dependent on chemical-specific data, much of
which may not be presently available.
Although at present the Agency does not know how to apply the
information in its files concerning common mechanism issues to most
risk assessments, there are pesticides for which the common mechanism
issues can be resolved. These pesticides include pesticides that are
toxicologically dissimilar to existing chemical substances (in which
case the Agency can conclude that it is unlikely that a pesticide
shares a common mechanism of activity with other substances) and
pesticides that produce a common toxic metabolite (in which case common
mechanism of activity will be assumed).
At this time, no data are available to determine whether
methoxyfenozide benzoic acid, 3-methoxy-2-methyl-, 2-(3,5-
dimethylbenzoyl)-2-(1,1-dimethylethyl)hydrazide has a common mechanism
of toxicity with other substances. Thus, it is not appropriate 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 benzoic acid, 3-
methoxy-2-methyl-,2-(3,5-dimethylbenzoyl)-2-(1,1-dimethylethyl)
hydrazide does not produce a toxic metabolite produced by other
substances. For the purposes of this tolerance action, therefore,
methoxyfenozide benzoic acid, 3-methoxy-2-methyl-,2-(3,5-
dimethylbenzoyl)-2-(1,1-dimethylethyl) hydrazide is assumed not to have
a common mechanism of toxicity with other substances.

E. Safety Determination

1. U.S. population--i. Acute exposure and risk. Since no acute
endpoint of concern has been identified for methoxyfenozide, no acute
risk assessment is required.
ii. Chronic exposure and risk. Using the conservative exposure
assumptions described above and taking into account the completeness
and reliability of the toxicity data, the percentage of the RfD that
will be utilized by dietary (food only) exposure to residues of
methoxyfenozide from the proposed tolerances is 6.8% (tolerance levels)
and 0.6% (anticipated residues) for the U.S. population. Aggregate
exposure (food and water) are not expected to exceed 100%. EPA
generally has no concern for exposures below 100% of the RfD because
the RfD represents the level at or below which daily aggregate dietary
exposure over a lifetime will not pose appreciable risks to human
health. Rohm and Haas concludes that there is a reasonable certainty
that no harm will result from aggregate exposure to methoxyfenozide
residues to the U.S. population.
2. Infants and children--i. Children. The potential for additional
sensitivity of infants and children to residues of methoxyfenozide are
assessed using data from developmental toxicity studies in the rat and
rabbit and 2-generation reproduction studies 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.
ii. Developmental toxicity studies--a. Rats. In a developmental
toxicity study in rats, the maternal (systemic) NOAEL was 1,000 mg/kg/
day HDT. The developmental (pup) NOAEL was > 1,000 mg/kg/day HDT
b. Rabbits. In a developmental toxicity study in rats, the maternal
(systemic) NOAEL was 1,000 mg/kg/day HDT. The developmental (pup) NOAEL
was > 1,000 mg/kg/day HDT.
iii. Reproductive toxicity study--Rats. In a multi-generation
reproductive toxicity study in rats, the parental (systemic) NOAEL was
15.5 mg/kg/day, based on liver effects at the LOAEL of 153 mg/kg/day.
The reproductive (pup) NOAEL was 1,552 mg/kg/day HDT. No adverse
reproductive effects were observed.
iv. Prenatal and postnatal sensitivity--a. Prenatal sensitivity.
The developmental NOAELs of > 1,000 mg/kg/day HDT from the
developmental toxicity studies in rats and rabbits demonstrate that
there is no developmental (prenatal) toxicity present for
methoxyfenozide. Additionally, these developmental NOAELs are greater
than 100-fold higher than the NOAEL of 9.8-10.0 mg/kg/day from the rat
and dogs chronic studies which are the basis of the RfD.
b. Postnatal sensitivity. In the reproductive toxicity study in
rats, the reproductive NOAEL (1,552 mg/kg/day) is about 100-fold higher
than the parental NOAEL (15.5 mg/kg/day). These developmental and
reproductive studies indicate that methoxyfenozide does not have
additional prenatal and postnatal sensitivity for infants and children
in comparison to other exposed groups.
v. Acute exposure and risk. No acute endpoint was identified for
methoxyfenozide, and therefore, no acute risk assessment is required.
vi. Chronic exposure and risk. For chronic dietary risk assessment,
tolerances and anticipated residue values are used and the assumption
that 100% of all grapes and fruiting vegetables (in addition to cotton
and pome fruit) will contain residues at the tolerance or anticipated
residue levels. The percentage RfD utilized from the proposed
tolerances and anticipated residues is calculated using the DEEM
(Version 6.74, licensed by Novigen Sciences Inc.) which uses USDA food
consumption data from the 1994-1996 survey.
With the proposed tolerances and anticipated residues for
methoxyfenozide, the percentage of the RfD that will be utilized by
dietary (food only) exposure to residues of methoxyfenozide is 20.2%
(tolerance levels ) and 1.9% (anticipated residues) for children 1-6
years old. Aggregate exposure (food and water) are not expected to
exceed 100%. Rohm and Haas concludes that there is a reasonable
certainty that no harm will result from aggregate exposure to
methoxyfenozide residues to non-nursing infants.

F. International Tolerances

There are currently no CODEX, Canadian or Mexican MRLs established
for methoxyfenozide in grapes, raisins, or fruiting vegetables, so no
harmonization issues are required for this action.

3. Rohm and Haas Company

9F6062

EPA has received a pesticide petition (9F6062) from Rohm and Haas

[[Page 1379]]

Company, 100 Independence Mall West, Philadelphia, PA, 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
methoxyfenozide benzoic acid, 3-methoxy-2-methyl-, 2-(3,5-
dimethylbenzoyl)-2-(1,1-dimethylethyl) hydrazide in or on the RACs,
leafy green vegetables, leaf petioles, head and stem brassica, and
leafy brassica greens at 25.0, 10.0, 6.5, and 20.0 ppm respectively.
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

B. Toxicological Profile

1. Acute toxicity. Methoxyfenozide has low acute toxicity.
Methoxyfenozide was practically non-toxic by ingestion of a single oral
dose in rats and mice (LD50 > 5,000 mg/kg) and was
practically non-toxic by dermal application (LD50 > 5,000
mg/kg). Methoxyfenozide was not significantly toxic to rats after a 4-
hour inhalation exposure with an LC50 value of > 4.3 mg/L
(highest attainable concentration), is not considered to be a primary
eye irritant or a skin irritant, and is not a dermal sensitizer. An
acute neurotoxicity study in rats did not produce any neurotoxic or
neuropathologic effects with a NOAEL > 2,000 mg/kg.
2. Genotoxicty. Methoxyfenozide tested negative (non-mutagenic,
non-genotoxic) in a battery of in vitro and in vivo assays, which
included an Ames assay with and without metabolic activation, a CHO/
HGPRT assay, an in vitro chromosome aberration assay in CHO cells with
and without a metabolic activation, an in vivo micronucleus assay in
mouse bone marrow cells.
3. Reproductive and developmental toxicity--i. NOAELs for
developmental and maternal toxicity to methoxyfenozide were established
at 1,000 mg/kg/day HDT in both the rat and rabbit. No signs of
developmental toxicity were exhibited.
ii. In a 2-generation reproduction study in the rat, the
reproductive/developmental toxicity NOAEL of 1,552 mg/kg/day was 100-
fold higher than the parental (systemic) toxicity NOAEL of 200 ppm
(15.5 mg/kg/day).
4. Subchronic toxicity--i. The NOAEL in a 90-day rat feeding study
was 1,000 ppm (69.3 mg/kg/day for males, 72.4 mg/kg/day for females).
The LOAEL was 5,000 ppm (353 mg/kg/day for males, 379 mg/kg/day for
females). Increased liver weight and liver histopathology were observed
at the LOAEL of 5,000 ppm. Methoxyfenozide did not produce neurotoxic
or neuropathologic effects when administered in the diets of rats for 3
months at concentrations up to and including the limit dose of 20,000
ppm (NOAEL = 1,318 mg/kg/day for males, 1,577 mg/kg/day for females).
ii. In a 90-day feeding study with mice, the NOAEL was 2,500 ppm
(428 and 589 mg/kg/day for males and females, respectively). The LOAEL
was 7,000 ppm (1,149 and 1,742 mg/kg/day for males and females,
respectively). Decreases in body weight gain were noted in both sexes
of mice at the LOAEL of 7,000 ppm.
iii. A 90-day dog feeding study gave a NOAEL of 3,000 ppm, the HDT
(198 and 209 mg/kg/day for males and females, respectively). Extension
of treatment of the low dose animals for 6 weeks at 15,000 ppm (422 and
460 mg/kg/day for males and females, respectively) produced no signs of
systemic toxicity.
Methoxyfenozide did not produce toxicity in the rat when
administered dermally for 4 weeks at doses up to and including the
limit dose of 1,000 mg/kg/day. These findings correlate with the low
dermal penetration observed with ¹⁴C-methoxyfenozide,
formulated as the wettable powder (i.e., after 24 hours 1-3% of the
administered dose was systemically absorbed).
5. Chronic toxicity--i. The NOAEL in a 1 year feeding study in dogs
was 300 ppm (9.8 and 12.6 mg/kg/day for male and females,
respectively). The LOAEL was 3,000 ppm (106 and 111 mg/kg/day for male
and females, respectively) based on minimal hematological effects.
ii. An 18-month mouse carcinogenicity study showed no signs of
carcinogenicity at dosage levels up to and including 7,000 ppm (1,020
and 1,354 mg/kg/day for male and females, respectively), the HDT.
iii. In a combined rat chronic/oncogenicity study, the NOAEL for
chronic toxicity was 200 ppm (10.2 and 11.9 mg/kg/day for males and
females, respectively) and the LOAEL was 8,000 ppm (411 and 491 mg/kg/
day for males and females, respectively). No carcinogenicity was
observed at the dosage levels up to 20,000 ppm (1,045 and 1,248 mg/kg/
day for males and females, respectively).
6. Animal metabolism. In toxicokinetic and metabolism studies in
the rat, methoxyfenozide was rapidly absorbed following oral exposure
with peak plasma levels occurring within 0.5 hour of administration.
Methoxyfenozide does not bioaccumulate in that the compound is rapidly
and almost completely eliminated within 24 hours. Methoxyfenozide was
extensively metabolized in rats. Including parent compound, 32
metabolites, of which 26 were identified, were isolated from the rat
urine and feces. The primary pathway of methoxyfenozide metabolism
involves demethylation of the A-ring methoxyl moiety to form the
corresponding A-ring phenol, RH-117,236, which is readily conjugated
with glucuronic acid to RH-1518. Hydroxylation on the B-ring methyl
moieties is also an important metabolic pathway.
7. Metabolite toxicology. Common metabolic pathways for
methoxyfenozide have been identified in both plants (grape, apple,
rice, and cotton) and animals (rat, goat, hen). Extensive degradation
and elimination of polar metabolites occurs in animals such that
residues are unlikely to accumulate in humans or animals exposed to
these residues through the diet. The rapid metabolism and excretion of
methoxyfenozide in part accounts for the compound's overall low
toxicity profile in animals. The main metabolite of methoxyfenozide in
plants and animals, the A-ring phenol, RH-117,236, produced no toxicity
in mice (LD50 > 5,000 mg/kg) and was

[[Page 1380]]

negative when tested in the Ames mutagenic assay. Other metabolites of
methoxyfenozide (e.g., glucuronides) would be expected to produce
minimal to no toxicity given structure activity considerations.
8. Endocrine disruption. Based on structure-activity information as
well as the lack of developmental and reproductive toxicity,
methoxyfenozide is unlikely to exhibit estrogenic activity. No
indicators of estrogenic or other endocrine effects were observed in
mammalian chronic studies or in mammalian and avian reproduction
studies. Methoxyfenozide is within a class of chemistry
(diacylhydrazines) that is not known to bind to mammalian steroid
receptors. Overall, the weight of evidence provides no indication that
methoxyfenozide has endocrine activity in vertebrates.

C. Aggregate Exposure

1. Dietary exposure. Tolerances are proposed for the residues of
methoxyfenozide in or grapes, raisins, and fruiting vegetables. Risk
assessments were conducted by Rohm and Haas to assess dietary exposures
and risks from methoxyfenozide as follows:
i. Food--a. Acute exposure and risk. No acute endpoint of concern
was identified for methoxyfenozide and no acute risk assessment is
required.
b. Chronic exposure and risk. For chronic dietary risk assessment,
the proposed tolerance values and anticipated (average) residues are
used and the assumption that 100% of all leafy and cole crop vegetable
crops (in addition to cotton, pome fruit, grapes, and fruiting
vegetables) will contain residues of methoxyfenozide at the tolerance
levels. The RfD used for the chronic dietary analysis is 0.1 mg/kg/day
based on the NOAEL of 9.8-10.0 mg/kg/day from the rat and dogs chronic
studies. Potential chronic exposures were estimated using NOVIGEN'S
(DEEM Version 6.74) which uses USDA food consumption data from the
1994-1996 survey. With the proposed tolerances for methoxyfenozide, the
percentage of the RfD utilized is as follows:

------------------------------------------------------------------------
Population Subgroup Tolerance Levels, Total %RfD
------------------------------------------------------------------------
U.S. Population - 48 contiguous 16.4
States.............................
Non-Hispanic/non-white/non-black.... 22.4
Nursing Infants < 1 year old........ 5.4
Non-Nursing Infants < 1 year old.... 23.1
Children 1-6 years old.............. 29.9
Children 7-12 years old............. 18.1
Females 13+ (nursing)............... 16.7
------------------------------------------------------------------------

D. Cumulative Effects

[[Page 1381]]

chemical-specific data, much of which may not be presently available.
Although at present the Agency does not know how to apply the
information in its files concerning common mechanism issues to most
risk assessments, there are pesticides for which the common mechanism
issues can be resolved. These pesticides include pesticides that are
toxicologically dissimilar to existing chemical substances (in which
case the Agency can conclude that it is unlikely that a pesticide
shares a common mechanism of activity with other substances) and
pesticides that produce a common toxic metabolite (in which case common
mechanism of activity will be assumed).
At this time, no data are available to determine whether
methoxyfenozide benzoic acid, 3-methoxy-2-methyl-, 2-(3,5-
dimethylbenzoyl)-2-(1,1-dimethylethyl) hydrazide has a common mechanism
of toxicity with other substances. Thus, it is not appropriate 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 benzoic acid, 3-
methoxy-2-methyl-,2-(3,5-dimethylbenzoyl)-2-(1,1-dimethylethyl)
hydrazide does not produce a toxic metabolite produced by other
substances. For the purposes of this tolerance action, therefore,
methoxyfenozide benzoic acid, 3-methoxy-2-methyl-,2-(3,5-
dimethylbenzoyl)-2-(1,1-dimethylethyl) hydrazide is assumed not to have
a common mechanism of toxicity with other substances.

E. Safety Determination

1. U.S. population--i. Acute exposure and risk. Since no acute
endpoint of concern has been identified for methoxyfenozide, no acute
risk assessment is required.
ii. Chronic exposure and risk. Using the conservative exposure
assumptions described above and taking into account the completeness
and reliability of the toxicity data, the percentage of the RfD that
will be utilized by dietary (food only) exposure to residues of
methoxyfenozide from the proposed tolerances is 16.4% for the U.S.
population. Aggregate exposure (food and water) are not expected to
exceed 100%. EPA generally has no concern for exposures below 100% of
the RfD because the RfD represents the level at or below which daily
aggregate dietary exposure over a lifetime will not pose appreciable
risks to human health. Rohm and Haas concludes that there is a
reasonable certainty that no harm will result from aggregate exposure
to methoxyfenozide residues to the U.S. population.
2. Infants and children--i. In general. The potential for
additional sensitivity of infants and children to residues of
methoxyfenozide are assessed using data from developmental toxicity
studies in the rat and rabbit and 2-generation reproduction studies 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.
ii. Developmental toxicity studies--a. Rats. In a developmental
toxicity study in rats, the maternal (systemic) NOAEL was 1,000 mg/kg/
day HDT. The developmental (pup) NOAEL was > 1,000 mg/kg/day HDT.
b. Rabbits. In a developmental toxicity study in rats, the maternal
(systemic) NOAEL was 1,000 mg/kg/day HDT. The developmental (pup) NOAEL
was > 1,000 mg/kg/day.
iii. Reproductive toxicity study rats. In a multigeneration
reproductive toxicity study in rats, the parental (systemic) NOAEL was
15.5 mg/kg/day, based on liver effects at the LOAEL of 153 mg/kg/day.
The reproductive (pup) NOAEL was 1,552 mg/kg/day HDT. No adverse
reproductive effects were observed.
iv. Prenatal and postnatal sensitivity--a. Prenatal sensitivity.
The developmental NOAELs of > 1,000 mg/kg/day HDT from the
developmental toxicity studies in rats and rabbits demonstrate that
there is no developmental (prenatal) toxicity present for
methoxyfenozide. Additionally, these developmental NOAELs are greater
than 100-fold higher than the NOAEL of 9.8-10.0 mg/kg/day from the rat
and dogs chronic studies which are the basis of the RfD.
b. Postnatal sensitivity. In the reproductive toxicity study in
rats, the reproductive NOAEL (1,552 mg/kg/day) is about 100-fold higher
than the parental NOAEL (15.5 mg/kg/day). These developmental and
reproductive studies indicate that methoxyfenozide does not have
additional prenatal and postnatal sensitivity for infants and children
in comparison to other exposed groups.
3. Acute exposure and risk. No acute endpoint was identified for
methoxyfenozide, and therefore, no acute risk assessment is required.
4. Chronic exposure and risk. For chronic dietary risk assessment,
tolerances and anticipated residue values are used and the assumption
that 100% of all leafy and cole crop vegetables (in addition to cotton,
pome fruit, grapes, and fruiting vegetables) will contain residues at
the tolerance levels. The percentage RfD utilized from the proposed
tolerances is calculated using the DEEM (Version 6.74, licensed by
Novigen Sciences Inc.) which uses USDA food consumption data from the
1994-1996 survey.
With the proposed tolerances for methoxyfenozide, the percentage of
the RfD that will be utilized by dietary (food only) exposure to
residues of methoxyfenozide is 29.9% for children 1-6 years old.
Aggregate exposure (food and water) are not expected to exceed 100%.
Rohm and Haas concludes that there is a reasonable certainty that no
harm will result from aggregate exposure to methoxyfenozide residues to
non-nursing infants.

F. International Tolerances

There are currently no CODEX, Canadian or Mexican maximum residue
levels (MRLs) established for methoxyfenozide in leafy or cole crop
vegetables so no harmonization issues are required for this action.
[FR Doc. 00-492 Filed 1-7-00; 8:45 am]
BILLING CODE 6560-50-F

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

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