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Tebufenozide - Pesticide Petition 6/99

[Federal Register: July 2, 1999 (Volume 64, Number 127)]
[Notices]
[Page 35999-36008]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr02jy99-46]

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ENVIRONMENTAL PROTECTION AGENCY
[PF-878; FRL-6085-6]
Notice of Filing; Pesticide Petition
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 the docket control number PF-878, must
be received on or before August 2, 1999.

ADDRESSES: By mail submit written comments to: Information and Records
Integrity Branch, Public Information and Services Division (7502C),
Office of Pesticides Programs, Environmental Protection Agency, 401 M
St., SW., Washington, DC 20460. In person bring comments to: Rm. 1132,
CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
    Comments and data may also be submitted electronically by following
the instructions under "SUPPLEMENTARY INFORMATION (CBI)." No
confidential business information (CBI) should be submitted through e-
mail.
    Information submitted as a comment concerning this document may be
claimed confidential by marking any part or all of that information as
CBI. CBI should not be submitted through e-mail. Information marked as
CBI will not be disclosed except in accordance with procedures set
forth in 40 CFR part 2. A copy of the comment that does not contain CBI
must be submitted for inclusion in the public record. Information not
marked confidential may be disclosed publicly by EPA without prior
notice. All written comments will be available for public inspection in
Rm. 1132 at the address given above, from 8:30 a.m. to 4 p.m., Monday
through Friday, excluding legal holidays.

FOR FURTHER INFORMATION CONTACT: Joseph Tavano, Registration Support
Branch, Registration Division (7505C), Office of Pesticide Programs,
Environmental Protection Agency, 401 M St., SW., Washington, DC 20460.
Office location, telephone number, and e-mail address: Rm. 214, Crystal
Mall #2, 1921 Jefferson Davis Highway, Arlington, VA 22202, (703) 305-
6411; e-mail: tavano.joseph@epa.gov.
SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as
follows proposing the establishment and/or

[[Page 36000]]

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
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
supports granting of the petition. Additional data may be needed before
EPA rules on the petition.
    The official record for this notice of filing, as well as the
public version, has been established for this notice of filing under
docket control number [PF-878] (including comments and data submitted
electronically as described below). A public version of this record,
including printed, paper versions of electronic comments, which does
not include any information claimed as CBI, is available for inspection
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal
holidays. The official record is located at the address in
"ADDRESSES" at the beginning of this document.
    Electronic comments can be sent directly to EPA at:
    opp-docket@epa.gov

    Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption. Comment and data
will also be accepted on disks in Wordperfect 5.1 file format or ASCII
file format. All comments and data in electronic form must be
identified by the docket control number (PF-878) and appropriate
petition number. Electronic comments on this proposed rule may be filed
online at many Federal Depository Libraries.

List of Subjects

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

    Dated: June 23, 1999.

James Jones,

Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

    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 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 7F4824

    EPA has received a pesticide petition (PP 7F4824) 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, 21 U.S.C. 346a(d), to amend 40 CFR part 180 by
establishing a tolerances for indirect or inadvertent residues of
tebufenozide (benzoic acid, 3,5-dimethyl-1-(1,1- dimethylethyl)-2-(4-
ethylbenzoyl)hydrazide) and its metabolite RH-111,788 in or on the raw
agricultural commodity (RAC) foliage of legume vegetables at 0.1 parts
per million (ppm) and forage, fodder hay, and straw of cereal grains at
0.5 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 metabolism of tebufenozide in plants
(grapes, apples, rice, and sugar beets) is adequately understood for
the purpose of this tolerance. The metabolism of tebufenozide in all
crops was similar and involves oxidation of the alkyl substituents of
the aromatic rings primarily at the benzylic positions. The extent of
metabolism and degree of oxidation are a function of time from
application to harvest. 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. Tebufenozide, the metabolite, benzoic acid,
3,5-dimethyl-1-(1,1-dimethylethyl)-2-[4-(1-hydroxyethyl) benzoyl, and
sugar conjugates of the metabolite were detected in a confined rotation
crop study.
    2. Analytical method. Validated high performance liquid
chromatographic (HPLC) analytical methods using ultraviolet (UV) or
mass selective (MS) detection are employed for measuring residues of
tebufenozide and its metabolite in grains, forage, fodder, stover, hay,
and straw. The methods involve 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 its metabolite.
    3. Magnitude of residues. Field rotation crop residue trials were
conducted and residues of tebufenozide and its metabolite were
measured. Results of analyses showed that residues of tebufenozide and
its metabolite will not exceed 0.1 ppm in forage of legumes and 0.5 ppm
in forage, hay, or straw of cereal grains.

B. Toxicological Profile

    1. Acute toxicity--Acute toxicity studies with technical grade.
Oral LD50 in the rat is > 5 grams for males and females (Ms/
Fs) - Toxicity Category IV; dermal LD50 in the rat is =
5,000 milligrams/kilograms (mg/kg) for Ms/Fs - Toxicity Category III;
inhalation LC50 in the rat is > 4.5 milligrams/per liter
(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.
    2. Genotoxicty. Several mutagenicity tests 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--i. 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 milliliters/kilograms (ml/kg). There was no
evidence of maternal or developmental toxicity; the maternal and
developmental toxicity NOAEL was 1,000 mg/kg/day.
    ii. 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 no-
observed adverse effect level (NOAEL) was 1,000 mg/kg/day.

[[Page 36001]]

    iii. In a 1993 2-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 Ms/Fs, respectively) and the lowest-
observed adverse effect level (LOAEL) was 150 ppm (11.5/12.8 mg/kg/day
for Ms/Fs, respectively) based on decreased body weight (bwt) 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 extramedullary hematopoiesis at 2,000 ppm. The reproductive
NOAEL was 150 ppm. (11.5/12.8 mg/kg/day for Ms/Fs, respectively) and
the LOAEL was 2,000 ppm (154.8/171.1 mg/kg/day for Ms/Fs, 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 Ms/Fs, respectively) with a NOAEL
of 150 ppm (11.5/12.8 mg/kg/day for Ms/Fs, respectively).
    iv. In a 1995 2-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 Ms/Fs, respectively), and the was 200 ppm
(12.6/14.6 mg/kg/day in Ms/Fs), based on histopathological findings
(congestion and extramedullary hematopoiesis) in the spleen.
Additionally, at 2,000 ppm (126.0/143.2 mg/kg/day in Ms/Fs), treatment-
related findings included reduced parental bwt 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 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 Ms/Fs), and the LOAEL was 2,000 ppm (126.0/143.2 mg/kg/day in
Ms/Fs) based on decreased bwt on postnatal days 14 and 21.
    4. Subchronic toxicity. 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 (LTD)
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 (HDT)
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 HDT. A LOAEL for systemic toxicity and dermal irritation was not
established.
    5. Chronic toxicity--i. In a 1-year dog feeding study with a LOAEL
of 250 ppm, 9 mg/kg/day for Ms/Fs dogs based on decreases in red blood
cells (RBC), HCT, and HGB, increases in Heinz bodies, methemoglobin,
MCV, MCH, reticulocytes, platelets, plasma total bilirubin, spleen
weight, and spleen/bwt ratio, and liver/bwt 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 NOAEL for systemic toxicity in both
sexes is 50 ppm (1.9 mg/kg/day).
    ii. An 18-month mouse carcinogenicity study with no carcinogenicity
observed at dosage levels up to and including 1,000 ppm.
    iii. 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 Ms/Fs, 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-
butylcarbon). The extent of absorption was not established. The
majority of the radiolabeled 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.
    7. Metabolite toxicology. The absorption and metabolism of
tebufenozide were studied in a group of M/F 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 Ms/Fs. 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.
    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 for > 5% of the total administered dose. Total bile

[[Page 36002]]

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.

C. Aggregate Exposure

    1. Dietary exposure--From food and feed uses. Tolerances have been
established (40 CFR 180.482) for the residues of tebufenozide, in or on
walnuts at 0.1 ppm, apples at 1.0 ppm, pecans at 0.01 ppm and wine
grapes at 0.5 ppm. Numerous section 18 tolerances have been established
at levels ranging from 0.3 ppm in sugar beet roots to 5.0 ppm in turnip
tops. Other tolerance petitions are pending at EPA with proposed
tolerances ranging from 0.5 ppm in or on kiwifruit to 10 ppm in leafy
and cole crop vegetables. The current petition requests establishment
of tolerances due to indirect or inadvertent residues of tebufenozide
and its metabolite in or on foliage of legume vegetables and forage,
straw, and hay of cereal grains. 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 and are presented in the following discussion.
    2. Food--i. 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. Toxicity observed in oral toxicity
studies were not attributable to a single dose (exposure). No neuro- or
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 LTD during gestation
to pregnant rats or rabbits. This risk is considered to be negligible.
    ii. Chronic exposure and risk. The RfD used for the chronic dietary
analysis is 0.018 mg/kg/day. In conducting this chronic dietary (food)
exposure assessment, Rohm and Haas used tolerance level residues for
pecans, walnuts, wine, and sherry, imported apples and all other
commodities with established or pending tebufenozide tolerances; and
percent crop-treated (%CT) information on some of these crops. Further
refinement using anticipated residue values and additional %CT
information would result in a lower estimate of chronic dietary
exposure. The Novigen DEEM system was used for this chronic dietary
exposure analysis. The subgroups listed below are the U.S. population
(48 contiguous States); those for infants and children; and the other
subgroups (adult) for which the percentage of the RfD occupied is
greater than that occupied by the subgroup U.S. population (48
contiguous States). The results are summarized below:

------------------------------------------------------------------------
               Groups                          RfD (Percentage)
------------------------------------------------------------------------
U.S. Population.....................                                10.0
All Infants (<1 year)...............                                12.2
Nursing Infants (<1 year old).......                                 5.7
Non-Nursing Infants (<1 year old)...                                15.0
Children (1-6 years old)............                                22.5
Children (7-12 years old)...........                                14.1
Females (13 + years old, nursing)...                                10.1
U.S. Population (autumn season).....                                10.3
U.S. Population (winter season).....                                10.1
Non-Hispanic Blacks.................                                10.4
Non-Hispanic Other than Black or                                    11.0
 White..............................
Northeast Region....................                                10.3
Southern Region.....................                                10.1
Western Region......................                                10.5
Pacific Region......................                                10.7
------------------------------------------------------------------------

    3. Drinking water--i.  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.
    ii. Chronic exposure and risk. Submitted environmental fate studies
suggest that tebufenozide is moderately persistent to persistent and
mobile. Under certain conditions, tebufenozide appears to have the
potential to contaminate ground and surface water through runoff and
leaching; subsequently potentially contaminating drinking water. There
are no established Maximum Contaminant Levels (MCL) for residues of
tebufenozide in drinking water and no Health Advisories (HA) have been
issued for tebufenozide; therefore, these could not be used as
comparative values for risk assessment. Therefore, potential residue
levels for drinking water exposure were calculated previously by EPA
using GENEEC (surface water) and SCIGROW (ground water) for human
health risk assessment. Because of the wide range of half-life values
(66-729 days) reported for the aerobic soil metabolism input parameter
a range of potential exposure values were calculated. In each case, the
worst case upper bound exposure limits were then compared appropriate
chronic drinking water level of concern (DWLOC). In each case, the
calculated exposures based on model data were below the DWLOC.
    4. Non-dietary exposure. Tebufenozide is not currently registered
for use on any residential non-food sites. Therefore there is no
chronic, short- or intermediate-term exposure scenario.

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." The Agency believes that "available
information" in this context might include not only toxicity,
chemistry, and exposure data, but also scientific policies and
methodologies for understanding common mechanisms of toxicity and
conducting cumulative risk assessments. For most pesticides, although
the Agency has some information in its files that may turn out to be
helpful in eventually determining whether a pesticide shares a common
mechanism of toxicity with any other

[[Page 36003]]

substances, EPA does not at this time have the methodologies to resolve
the complex scientific issues concerning common mechanism of toxicity
in a meaningful way. 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, decisions 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 as to 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).
    EPA does not have, at this time, available data to determine
whether tebufenozide, benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-
2-(4-ethylbenzoyl) hydrazide 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, benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-
ethylbenzoyl) hydrazide does not appear to produce a toxic metabolite
produced by other substances. For the purposes of this tolerance
action, therefore, Rohm and Haas has not assumed that tebufenozide,
benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl)
hydrazide has 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, no acute aggregate risk exists.
    ii. Chronic risk. Using the conservative 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 10.0% of the
RfD for the U.S. population. 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 OPP's drinking
water level of concern (DWLOC). 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. There are no registered
residential uses of tebufenozide. Since there is no potential for
exposure to tebufenozide from residential uses, Rohm and Haas does not
expect the aggregate exposure to exceed 100% of the RfD.
    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 tebufenozide and no
short- or intermediate-term toxic endpoints, short- or intermediate-
term aggregate risk does not exist.
    2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of tebufenozide,
benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl)
hydrazide, EPA previously 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 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 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 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.
    3. Developmental toxicity studies--i. Rats. In a developmental
toxicity study in rats, the maternal (systemic) NOAEL was 250 mg/kg/
day. The LOAEL was 1,000 mg/kg/day, based on decreased bwt and food
consumption. The developmental (pup) NOAEL was 1,000 mg/kg/day (HGT)
    ii. Rabbits. In a developmental toxicity study in rabbits, the
maternal and developmental NOAELs were 1,000 mg/kg/day highest dose
tested (HDT).

    iii. Reproductive toxicity study. In a 1993 2-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 Ms and 0, 0.9, 12.8, or 171.1 mg/kg/
day for Fs).The parental systemic NOAEL was 10 ppm (0.8/0.9 mg/kg/day
for Ms/Fs, respectively) and the LOAEL was 150 ppm (11.5/12.8 mg/kg/day
for Ms/Fs, respectively) based on decreased bwt 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 extramedullary hematopoiesis at 2,000 ppm. The reproductive
NOAEL was 150 ppm (11.5/12.8 mg/kg/day for Ms/Fs, respectively) and the
LOAEL was 2,000 ppm (154.8/171.1 mg/kg/day for Ms/Fs, 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 Ms/Fs, respectively) with a NOAEL
of 150 ppm (11.5/12.8 mg/kg/day for Ms/Fs, respectively).
    In a 1995 2-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

[[Page 36004]]

NOAEL was 25 ppm (1.6/1.8 mg/kg/day in Ms/Fs, respectively), and the
LOAEL was 200 ppm (12.6/14.6 mg/kg/day in males and females), based on
histopathological findings (congestion and extramedullary
hematopoiesis) in the spleen. Additionally, at 2,000 ppm (126.0/143.2
mg/kg/day in Ms/Fs), 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 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 Ms/
Fs), and the LOAEL was 2,000 ppm (126.0/143.2 mg/kg/day in M/F) based
on decreased bwt on postnatal days 14 and 21.
    iv. Pre- and postnatal sensitivity. The toxicology data base for
tebufenozide is complete and includes acceptable developmental toxicity
studies in both rats and rabbits as well as a 2-generation reproductive
toxicity studies in rats. EPA determined that the data provided no
indication of increased sensitivity of rats or rabbits to in utero and/
or postnatal exposure to tebufenozide. No maternal or developmental
findings were observed in the prenatal developmental toxicity studies
at doses up to 1,000 mg/kg/day in rats and rabbits. In the 2-generation
reproduction studies in rats, effects occurred at the same or lower
treatment levels in the adults as in the offspring.
    4.  Acute risk. Since no acute toxicological endpoints were
established, no acute aggregate risk exists.
    5. Chronic risk. Using the conservative exposure assumptions
described above, Rohm and Haas has concluded that aggregate exposure to
tebufenozide, benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-
ethylbenzoyl) hydrazide from food will utilize from 10.0% of the RfD
for the U.S. population to 22.5% of the RfD for children 1-6 years old.
The potential for exposure to tebufenozide in drinking water does not
exceed EPA's level of concern. There are currently no tebufenozide
residential or non-dietary exposure scenarios. 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
does not expect the aggregate exposure to exceed 100% of the RfD. Rohm
and Haas concludes that there is a reasonable certainty that no harm
will result to infants and children from aggregate exposure to
tebufenozide, benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-
ethylbenzoyl) hydrazide residues.
    6. Short- or intermediate-term risk. Since no short- and
intermediate-term toxicological endpoints were established by EPA, no
acute aggregate risk exists.

F. International Tolerances

    There are currently no CODEX, Canadian or Mexican maximum residue
levels (MRLs) established for tebufenozide in rotation crops so no
harmonization issues are required for this action.

2. Rohm and Haas Company

 9F5077

    EPA has received a pesticide petition (9F5077) 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 a tolerance for residues of tebufenozide (benzoic acid,
3,5-dimethyul-,1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl)hydrazide) in or
on the RAC crop grouping, tree nuts, at 0.1 ppm and in or almond hulls
at 25 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 metabolism of tebufenozide in plants
(grapes, apples, rice and sugar beets) is adequately understood for the
purpose of this tolerance. The metabolism of tebufenozide in all crops
was similar and involves oxidation of the alkyl substituents of the
aromatic rings primarily at the benzylic positions. The extent of
metabolism and degree of oxidation are a function of time from
application to harvest. 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. Validated high performance liquid
chromatographic (HPLC) analytical methods using ultraviolet (UV) or
mass selective (MS) detection are employed for measuring residues of
tebufenozide and its metabolite in nut meat and almond hulls. The
methods involve 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 0.01 ppm for
tebufenozide.
    3. Magnitude of residues. Field residue trials were conducted in
the representative nut crops pecans and almonds and residues of
tebufenozide were measured in nut meat and almond hulls. Results of
analyses showed that residues of tebufenozide will not exceed 0.1 ppm
in nut meat and 25 ppm in almond hulls.

B. Toxicological Profile

    1. Acute toxicity. Acute toxicity studies with technical grade.
Oral LD50 in the rat is > 5 grams for Ms/Fs - Toxicity
Category IV; dermal LD50 in the rat is = 5,000 mg/kg for Ms/
Fs - Toxicity Category III; inhalation LC50 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.
    2. Genotoxicty. Several mutagenicity tests 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--i. 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.
    ii. 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.
    iii. In a 1993 2-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/

[[Page 36005]]

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 M/F,
respectively) and the LOAEL was 150 ppm (11.5/12.8 mg/kg/day for Ms/Fs,
respectively) based on decreased bwt 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
extramedullary hematopoiesis at 2,000 ppm. The reproductive NOAEL was
150 ppm. (11.5/12.8 mg/kg/day for M/F, respectively) and the LOAEL was
2,000 ppm (154.8/171.1 mg/kg/day for M/F, 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 Ms/Fs, respectively) with a NOAEL of 150 ppm
(11.5/12.8 mg/kg/day for Ms/Fs, respectively).
    iv. In a 1995 2-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 Ms/Fs, respectively), and the LOAEL was
200 ppm (12.6/14.6 mg/kg/day in Ms/Fs), based on histopathological
findings (congestion and extramedullary hematopoiesis) in the spleen.
Additionally, at 2,000 ppm (126.0/143.2 mg/kg/day in Ms/Fs), treatment-
related findings included reduced parental bwt 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 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 Ms/Fs), and the LOAEL was 2,000 ppm (126.0/143.2 mg/kg/day in
Ms/Fs) based on decreased bwt on postnatal days 14 and 21.
    4. Subchronic toxicity. 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 (LTD)
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 (HDT)
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 HDT. A LOAEL for systemic toxicity and dermal irritation was not
established.
    5. Chronic toxicity--i. In a 1 year dog feeding study with a LOAEL
of 250 ppm, 9 mg/kg/day for Ms/Fs 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/bwt ratio, and liver/bwt 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 NOAEL for systemic toxicity in both sexes is
50 ppm (1.9 mg/kg/day).
    ii. An 18-month mouse carcinogenicity study with no carcinogenicity
observed at dosage levels up to and including 1,000 ppm.
    iii. 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 Ms/Fs, 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-butylcarbon). The extent
of absorption was not established. The majority of the radiolabeled
material was eliminated or excreted in the feces 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.
    7. Metabolite toxicology. The absorption and metabolism of
tebufenozide were studied in a group of Ms/Fs bile-duct cannulated
rats. Over a 72-hour period, biliary excretion accounted for 30% Ms to
34% Fs 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 Ms/Fs. Thus systemic absorption
(percent of dose recovered in the bile, urine and carcass) was 35% Ms
to 39% Fs. The majority of the radioactivity in the bile (20% Ms to 24%
Fs 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% Fs to 70% Ms) of the administered dose was
unabsorbed and excreted in the feces by 72 hours. Total recovery of
radioactivity was 105% of the administered dose.
    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 (Fs and/or Ms). 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.

[[Page 36006]]

C. Aggregate Exposure

    1. Dietary exposure--From food and feed uses. Tolerances have been
established (40 CFR 180.482) for the residues of tebufenozide, in or on
walnuts at 0.1 ppm, apples at 1.0 ppm, pecans at 0.01 ppm and wine
grapes at 0.5 ppm. Numerous section 18 tolerances have been established
at levels ranging from 0.3 ppm in sugar beet roots to 5.0 ppm in turnip
tops. Other tolerance petitions are pending at EPA with proposed
tolerances ranging from 0.5 ppm in or on kiwifruit to 10 ppm in leafy
and cole crop vegetables. The current petition requests establishment
of tolerances in or on tree nuts and almond hulls. 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.
    2. Food--i. 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. Toxicity observed in oral toxicity
studies were not attributable to a single dose (exposure). No neuro- or
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 (LTD) during
gestation to pregnant rats or rabbits. This risk is considered to be
negligible.
    ii. Chronic exposure and risk. The reference dose (RfD) used for
the chronic dietary analysis is 0.018 mg/kg/day. In conducting this
chronic dietary (food) exposure assessment, Rohm and Haas used
tolerance level residues for nut crops, wine, and sherry, imported
apples and all other commodities with established or pending
tebufenozide tolerances; and percent crop-treated (%CT) information for
some of these crops. Further refinement using anticipated residue
values and additional %CT information would result in a lower estimate
of chronic dietary exposure. The Novigen DEEM system was used for this
chronic dietary exposure analysis. The subgroups listed below are (i)
the U.S. population (48 contiguous States); (ii) those for infants and
children; and (iii) the other subgroups (adult) for which the
percentage of the RfD occupied is greater than that occupied by the
subgroup U.S. population (48 contiguous States). The results are
summarized below:

------------------------------------------------------------------------
                  Groups                          RfD (percentage)
------------------------------------------------------------------------
U.S. Population...........................                          10.0
All Infants (< 1 year)....................                          12.2
Nursing Infants (< 1 year old)............                           5.7
Non-Nursing Infants (< 1 year old)........                          15.0
Children (1-6 years old)..................                          22.5
Children (7-12 years old).................                          14.1
Females (13 + years old, nursing).........                          10.1
U.S. Population (autumn season)...........                          10.3
U.S. Population (winter season)...........                          10.1
Non-Hispanic Blacks.......................                          10.4
Non-Hispanic Other than Black or White....                          11.0
Northeast Region..........................                          10.3
Southern Region...........................                          10.1
Western Region............................                          10.5
Pacific Region............................                          10.7
------------------------------------------------------------------------

    3. Drinking water--i. 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.
    ii. Chronic exposure and risk. Submitted environmental fate studies
suggest that tebufenozide is moderately persistent to persistent and
mobile. Under certain conditions tebufenozide appears to have the
potential to contaminate ground and surface water through runoff and
leaching; subsequently potentially contaminating drinking water. There
are no established Maximum Contaminant Levels (MCL) for residues of
tebufenozide in drinking water and no Health Advisories (HA) have been
issued for tebufenozide therefore these could not be used as
comparative values for risk assessment. Therefore, potential residue
levels for drinking water exposure were calculated previously by EPA
using GENEEC (surface water) and SCIGROW (ground water) for human
health risk assessment. Because of the wide range of half-life values
(66-729 days) reported for the aerobic soil metabolism input parameter
a range of potential exposure values were calculated. In each case the
worst case upper bound exposure limits were then compared to
appropriate chronic drinking water level of concern (DWLOC). In each
case the calculated exposures based on model data were below the DWLOC.
    4. Non-dietary exposure. From non-dietary exposure. Tebufenozide is
not currently registered for use on any residential non-food sites.
Therefore there is no chronic, short- or intermediate-term exposure
scenario.

D. Cumulative Effects

    Cumulative exposure to substances with 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." The Agency believes that "available
information" in this context might include not only toxicity,
chemistry, and exposure data, but also scientific policies and
methodologies for understanding common mechanisms of toxicity and
conducting cumulative risk assessments. For most pesticides, although
the Agency has some information in its files that may turn out to be
helpful in eventually determining whether a pesticide shares a common
mechanism of toxicity with any other substances, EPA does not at this
time have the methodologies to resolve the complex scientific issues
concerning common mechanism of toxicity in a meaningful way. 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

[[Page 36007]]

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, decisions 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 as to 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).
    EPA does not have, at this time, available data to determine
whether tebufenozide, benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-
2-(4-ethylbenzoyl) hydrazide 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, benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-
ethylbenzoyl) hydrazide does not appear to produce a toxic metabolite
produced by other substances. For the purposes of this tolerance
action, therefore, Rohm and Haas has not assumed that tebufenozide,
benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl)
hydrazide has 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, no acute aggregate risk exists.
    ii. Chronic risk. Using the conservative 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 10.0% of the
RfD for the U.S. population. 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 OPP's DWLOC.
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. There are no registered residential uses of tebufenozide.
Since there is no potential for exposure to tebufenozide from
residential uses, Rohm and Haas does not expect the aggregate exposure
to exceed 100% of the RfD.
    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 tebufenozide and no
short- or intermediate-term toxic endpoints, short- or intermediate-
term aggregate risk does not exist.
    2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of tebufenozide,
benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl)
hydrazide, EPA previously 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 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 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 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.
    3. Developmental toxicity studies--i. Rats. In a developmental
toxicity study in rats, the maternal (systemic) NOAEL was 250 mg/kg/
day. The LOAEL was 1,000 mg/kg/day, based on decreased bwt and food
consumption. The developmental (pup) NOAEL was 1,000 mg/kg/day (HGT).
    ii. Rabbits. In a developmental toxicity study in rabbits, the
maternal and developmental NOAELs were 1,000 mg/kg/day (HDT).
    iii. Reproductive toxicity study. In a 1993 2-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 Ms/Fs, respectively) and the LOAEL was 150 ppm (11.5/12.8
mg/kg/day for Ms/Fs, respectively) based on decreased bwt, bwt 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 extramedullary hematopoiesis at 2,000 ppm. The
reproductive NOAEL was 150 ppm. (11.5/12.8 mg/kg/day for Ms/Fs,
respectively) and the LOAEL was 2,000 ppm (154.8/171.1 mg/kg/day for
Ms/Fs, 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 Ms/Fs,
respectively) with a NOAEL of 150 ppm (11.5/12.8 mg/kg/day for males
and females, respectively)
    In a 1995 2-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 Ms/Fs, respectively), and the LOAEL was 200
ppm (12.6/14.6 mg/kg/day in Ms/Fs), based on histopathological findings
(congestion and extramedullary hematopoiesis) in the spleen.
Additionally, at 2,000 ppm (126.0/143.2 mg/kg/day in Ms/Fs), treatment-
related findings included reduced parental bwt

[[Page 36008]]

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 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 Ms/Fs), and the LOAEL was
2,000 ppm (126.0/143.2 mg/kg/day in Ms/Fs) based on decreased bwt on
postnatal days 14 and 21.
    iv. Pre- and postnatal sensitivity. The toxicology data base for
tebufenozide is complete and includes acceptable developmental toxicity
studies in both rats and rabbits as well as a 2-generation reproductive
toxicity studies in rats.
    EPA determined that the data provided no indication of increased
sensitivity of rats or rabbits to in utero and/or postnatal exposure to
tebufenozide. No maternal or developmental findings were observed in
the prenatal developmental toxicity studies at doses up to 1,000 mg/kg/
day in rats and rabbits. In the 2-generation reproduction studies in
rats, effects occurred at the same or lower treatment levels in the
adults as in the offspring.
    v. Acute risk. Since no acute toxicological endpoints were
established, no acute aggregate risk exists.
    vi. Chronic risk. Using the conservative exposure assumptions
described above, Rohm and Haas has concluded that aggregate exposure to
tebufenozide, benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-
ethylbenzoyl) hydrazide from food will utilize from 10.0% of the
reference dose RfD for the U.S. population to 22.5% of the RfD for
children 1-6 years old. The potential for exposure to tebufenozide in
drinking water does not exceed EPA's level of concern. There are
currently no tebufenozide residential or non-dietary exposure
scenarios. 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 does not expect the aggregate
exposure to exceed 100% of the RfD. Rohm and Haas concludes that there
is a reasonable certainty that no harm will result to infants and
children from aggregate exposure to tebufenozide, benzoic acid, 3,5-
dimethyl-1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl) hydrazide residues.
    vii. Short- or intermediate-term risk. Since no short- and
intermediate-term toxicological endpoints were established by EPA, no
acute aggregate risk exists.

F. International Tolerances

    There are currently no CODEX, Canadian or Mexican maximum residue
levels (MRLs) established for tebufenozide in nut crops so no
harmonization issues are required for this action.
[FR Doc. 99-16768 Filed 7-1-99; 8:45 am]
BILLING CODE 6560-50-F