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Tebufenozide - Pesticide Petition Filing for Pome Fruits 2/99

[Federal Register: February 17, 1999 (Volume 64, Number 31)]
[Notices]
[Page 7883-7890]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr17fe99-95]

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ENVIRONMENTAL PROTECTION AGENCY
[PF-860; FRL-6060-1]
Rohm and Haas Company; Notice of Filing of Pesticide Petitions
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-860, must
be received on or before March 19, 1999.

ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch, Information Resources and Services Divison
(7502C), Office of Pesticides Programs, Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments
to: Rm. 119, Crystal Mall 2 (CM #2), 1921 Jefferson Davis Highway,
Arlington, VA.
    Comments and data may also be submitted electronically to: opp-
docket@epamail.epa.gov. Following the instructions under
"SUPPLEMENTARY INFORMATION." No confidential business information
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
"Confidential Business Information" (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. 119 at the
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.

FOR FURTHER INFORMATION CONTACT: By mail: Joseph Tavano, Registration
Division (7505C), Office of Pesticide Programs, Environmental
Protection Agency, 401 M St., SW., Washington, DC 20460. Office
location/telephone and e-mail address: Rm. 214, 1921 Jefferson Davis
Hwy, Arlington, VA, Crystal Mall 2 (CM #2), 703-305-6411, e-mail:
tavano.joseph@epamail.epa.gov.

SUPPLEMENTARY INFORMATION: 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 raw 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

[[Page 7884]]

petition. Additional data may be needed before EPA rules on the
petition.
    The official record for this notice, as well as the public version,
has been established for this notice of filing under docket control
number PF-860 (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@epamail.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 5.1/6.1 file format or
ASCII file format. All comments and data in electronic form must be
identified by the docket control number (insert docket number) and
appropriate petition number. Electronic comments on this notice may be
filed online at many Federal Depository Libraries.

List of Subjects

    Environmental protection, Agricultural commodities, Food additives,

Feed additives, Pesticides and pests, Reporting and recordkeeping
requirements.

    Dated: February 4, 1999.

James Jones,
Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

    Below summaries of the pesticide petitions are printed. The
summaries of the petitions were prepared by the petitioner. 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.

Rohm and Haas Company

1. 7F4815

    EPA has received a revised pesticide petition (7F4815) from Rohm
and Haas Company, 100 Independence Mall West, Philadelphia, PA
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-dimethyl-, 1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl) hydrazide] in
or on the raw agricultural commodity crop grouping, pome fruit at 1.25
parts per million (ppm). EPA has determined that the petition contains
data or information regarding the elements set forth in section
408(d)(2) of the FFDCA; however, EPA has not fully evaluated the
sufficiency of the submitted data at this time or whether the data
supports granting of the petition. Additional data may be needed before
EPA rules on the petition.

A. Residue Chemistry

    1. 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. A validated high performance liquid
chromatographic (HPLC) analytical method using ultraviolet (UV)
detection is employed for measuring residues of tebufenozide in pome
fruit. The method involves extraction by blending with solvents,
purification of the extracts by liquid-liquid partitions and final
purification of the residues using solid phase extraction column
chromatography. The limit of quantitation of the method in pome fruit
is 0.02 ppm.
    3. Magnitude of residues. Magnitude of the residue studies were
conducted in apples and pears using the maximum application rate of
0.308 pounds active ingredient per acre applied 6 times during the
growing season. Fruit were collected 14 days after the last application
and were analyzed for residues of tebufenozide. The average residue in
apples from 12 trials was 0.52 ppm and the average residue detected in
pears from 6 trials was 0.27 ppm. A tolerance of 1.25 ppm is proposed
for residues of tebufenozide in or on pome fruit.

B. Toxicological Profile

    1. Acute toxicity. Acute toxicity studies with technical grade:
Oral LD50 in the rat is > 5 grams for males and females -
Toxicity Category IV; dermal LD50 in the rat is = 5,000
milligram/kilogram (mg/kg) for males and females - Toxicity Category
III; inhalation 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 which were all negative.
These include an Ames assay with and without metabolic activation, an
in vivo cytogenetic assay in rat bone marrow cells, and in vitro
chromosome aberration assay in Chinese hampster ovary (CHO) cells, a
CHO/Hypoxanthine guanine phophoribosyl transferase (HGPRT) assay, a
reverse mutation assay with E. Coli, and an unscheduled DNA synthesis
(UDS) assay in rat hepatocytes.
    3. Reproductive and developmental toxicity. In a prenatal
developmental toxicity study in Sprague-Dawley rats 25/group
Tebufenozide was administered on gestation days 6-15 by gavage in
aqueous methyl cellulose at dose levels of 50, 250, or 1,000 mg/kg/day
and a dose volume of 10 ml/kg. There was no evidence of maternal or
developmental toxicity; the maternal and developmental toxicity no
observed adverse effect level (NOAEL) was 1,000 mg/kg/day.
    In a prenatal developmental toxicity study conducted in New Zealand
white rabbits 20/group Tebufenozide was administered in 5 ml/kg of
aqueous methyl cellulose at gavage doses of 50, 250, or 1,000 mg/kg/day
on gestation days 7-19. No evidence of maternal or developmental
toxicity was observed; the maternal and developmental toxicity NOAEL
was 1,000 mg/kg/day.
    In a 1993 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 males and females, respectively) and the
lowest observed effect level (LOEL) was 150 ppm (11.5/12.8 mg/kg/day
for males and females, respectively) based on decreased body weight,
body weight gain, and food consumption in males, and increased
incidence and/or severity of splenic pigmentation. In addition, there
was an increased incidence and severity of extramedullary hematopoiesis
at 2,000 ppm. The reproductive NOAEL was 150 ppm. (11.5/12.8 mg/kg/day
for males and females, respectively) and the LOEL

[[Page 7885]]

was 2,000 ppm (154.8/171.1 mg/kg/day for males and females,
respectively) based on an increase in the number of pregnant females
with increased gestation duration and dystocia. Effects in the
offspring consisted of decreased number of pups per litter on postnatal
days 0 and/or 4 at 2,000 ppm (154.8/171.1 mg/kg/day for males and
females, respectively) with a NOAEL of 150 ppm (11.5/12.8 mg/kg/day for
males and females, respectively).
    In a 1995 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 males and females, respectively), and the
LOEL 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 M/F), treatment-related findings included reduced parental
body weight gain and increased incidence of hemosiderin-laden cells in
the spleen. Columnar changes in the vaginal squamous epithelium and
reduced uterine and ovarian weights were also observed at 2,000 ppm,
but the toxicological significance was unknown. For offspring, the
systemic NOAEL was 200 ppm. (12.6/14.6 mg/kg/day in males and females),
and the LOEL was 2,000 ppm (126.0/143.2 mg/kg/day in M/F) based on
decreased body weight on postnatal days 14 and 21.
    4. Subchronic toxicity. 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.
    5. Chronic toxicity. A 1-year dog feeding study with a LOEL of 250
ppm, 9 mg/kg/day for male and female dogs based on decreases in RBC,
HCT, and HGB, increases in Heinz bodies, methemoglobin, MCV, MCH,
reticulocytes, platelets, plasma total bilirubin, spleen weight, and
spleen/body weight ratio, and liver/body weight ratio. Hematopoiesis
and sinusoidal engorgement occurred in the spleen, and hyperplasia
occurred in the marrow of the femur and sternum. The liver showed an
increased pigment in the Kupffer cells. The NOAEL for systemic toxicity
in both sexes is 50 ppm (1.9 mg/kg/day).
    An 18-month mouse carcinogenicity study with no carcinogenicity
observed at dosage levels up to and including 1,000 ppm.
    A 2-year rat carcinogenicity with no carcinogenicity observed at
dosage levels up to and including 2,000 ppm (97 mg/kg/day and 125 mg/
kg/day for males and females, respectively).
    6. Animal metabolism. The adsorption, distribution, excretion and
metabolism of tebufenozide in rats was investigated. Tebufenozide is
partially absorbed, is rapidly excreted and does not accumulate in
tissues. Although tebufenozide is mainly excreted unchanged, a number
of polar metabolites were identified. These metabolites are products of
oxidation of the benzylic ethyl or methyl side chains of the molecule.
These metabolites were detected in plant and other animal (rat, goat,
hen) metabolism studies.
    7. Metabolite toxicology. Common metabolic pathways for
tebufenozide have been identified in both plants (grape, apple, rice
and sugar beet) and animals (rat, goat, hen). The metabolic pathway
common to both plants and animals involves oxidation of the alkyl
substituents (ethyl and methyl groups) of the aromatic rings primarily
at the benzylic positions. Extensive degradation and elimination of
polar metabolites occurs in animals such that residue are unlikely to
accumulate in humans or animals exposed to these residues through the
diet.
    8. Endocrine disruption. The toxicology profile of tebufenozide
shows no evidence of physiological effects characteristic of the
disruption of the hormone estrogen. Based on structure-activity
information, tebufenozide is unlikely to exhibit estrogenic activity.
Tebufenozide was not active in a direct in vitro estrogen binding
assay. No indicators of estrogenic or other endocrine effects were
observed in mammalian chronic studies or in mammalian and avian
reproduction studies. Ecdysone has no known effects in vertebrates.
Overall, the weight of evidence provides no indication that
tebufenozide has endocrine activity in vertebrates.

C. Aggregate Exposure

    1. Dietary exposure -- i. Food. 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 0.3 ppm in or on sugarcane to 10 ppm in cole crop
vegetables. 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:
    ii. Acute exposure and risk. Acute dietary risk assessments are
performed for a food-use pesticide if a toxicological study has
indicated the possibility of an effect of concern occurring as a result
of a one day or single exposure. 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 (Limit-Dose) during
gestation to pregnant rats or rabbits. This risk is considered to be
negligible.
    2. Chronic exposure and risk  -- i. The reference dose (RfD) used
for the chronic dietary analysis is 0.018 mg/kg/day. In conducting this
exposure assessment, Rohm and Haas has made very conservative
assumptions 100% of pecans, walnuts, wine and sherry, pome fruit and
all other commodities having tebufenozide tolerances or pending
tolerances will contain tebufenozide residues, and those residues would
be at the level of the tolerance which result in an overestimate of
human dietary exposure. Thus, in making a safety determination for this
tolerance, Rohm and Haas is taking into account this conservative
exposure assessment. The existing tebufenozide tolerances published,
pending, and including the necessary section 18 tolerance(s) resulted
in a Theoretical Maximum Residue Contribution (TMRC) that is equivalent
to the following percentages of the RfD:
     U.S. Population (35.6% of RfD);
     All Infants (<1 year) (63.8%);
     Nursing Infants (<1 year old) (41.0% of RfD);
     Non-Nursing Infants (<1 year old) (73.3% of RfD);
     Children (1-6 years old) (81.8% of RfD);
     Children (7-12 years old) (50.0% of RfD);
     Females (13 + years old, nursing) (40.0% of RfD);
     Non-Hispanic Whites (35.8%);
     Non-Hispanic Other than Black or White (40.8% of RfD);
     Northeast Region (38.2% of RfD);
     Western Region (37.6%);

[[Page 7886]]

     Pacific Region (37.6%).
     The subgroups listed above are subgroups for which the percentage
of the RfD occupied is greater than that occupied by the subgroup U.S.
population (48 States).
    ii. Drinking water -- 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.
    iii. 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 using
Generic expected environmental concentration (GENEEC (surface water))
and screening concentration in ground water (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.
    2. 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 hassome 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 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. 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 35.6% 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.
    Since, tebufenozide has been classified as a Group E, "no evidence
of carcinogenicity for humans," this risk does not exist.
    2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of tebufenozide, data
from developmental toxicity studies in the rat and rabbit and two 2-
generation reproduction studies in the rat are considered. The
developmental toxicity studies are designed to evaluate adverse effects
on the developing organism resulting from pesticide exposure during
prenatal development to one or both parents. Reproduction studies
provide information relating to effects from exposure to the pesticide
on the reproductive capability of mating animals and data on systemic
toxicity. Developmental toxicity was not observed in developmental
studies using rats and rabbits. The NOAEL for developmental effects in
both rats and rabbits was 1,000 mg/kg/day, which is the limit dose for
testing in developmental studies.
    In the 2-generation reproductive toxicity study in the rat, the
reproductive/ developmental toxicity NOAEL of 12.1 mg/kg/day was 14-
fold higher than the parental (systemic) toxicity NOAEL (0.85 mg/kg/
day). The reproductive (pup) LOEL of 171.1 mg/

[[Page 7887]]

kg/day was based on a slight increase in both generations in the number
of pregnant females that either did not deliver or had difficulty and
had to be sacrificed. In addition, the length of gestation increased
and implantation sites decreased significantly in F1 dams.
These effects were not replicated at the same dose in a second 2-
generation rat reproduction study. In this second study, reproductive
effects were not observed at 2,000 ppm (the NOAEL equal to 149-195 mg/
kg/day) and the NOAEL for systemic toxicity was determined to be 25 ppm
(1.9-2.3 mg/kg/day).
    Because these reproductive effects occurred in the presence of
parental (systemic) toxicity and were not replicated at the same doses
in a second study, these data do not indicate an increased pre-natal or
post-natal sensitivity to children and infants (that infants and
children might be more sensitive than adults) to tebufenozide exposure.
FFDCA section 408 provides that EPA shall apply an additional safety
factor for infants and children in the case of threshold effects to
account for pre-and post-natal toxicity and the completeness of the
data base unless EPA concludes that a different margin of safety is
appropriate. Based on current toxicological data discussed above, an
additional uncertainty factor is not warranted and the RfD at 0.018 mg/
kg/day is appropriate for assessing aggregate risk to infants and
children. Rohm and Haas concludes that there is a reasonable certainty
that no harm will occur to infants and children from aggregate exposure
to residues of tebufenozide.

F. International Tolerances

    There are no approved CODEX maximum residue levels (MRLs)
established for residues of tebufenozide. At the 1996 Joint Meeting for
Pesticide Residues, the FAO expert panel considered residue data for
pome fruit and proposed an MRL of 1.0 mg/kg. An MRL of 1.0 mg/kg was
established for apples in Canada.

2. 7F4863

    EPA has received a revised pesticide petition (7F4863) from Rohm
and Haas Company, 100 Independence Mall West, Philadelphia, PA
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-dimethyl-,1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl) hydrazide] in or
on the raw agricultural commodity sugarcane and molasses at 1.0 and 6.0
parts per million (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 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. A high performance liquid chromatographic
(HPLC) analytical method using ultraviolet (UV) detection has been
validated for sugarcane, molasses and refined sugar. For all matrices,
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 of the method is 0.01 ppm.
    3. Magnitude of residues. Magnitude of the residue and processing
studies were conducted in sugarcane using the maximum proposed label
rate. Samples were collected 14 days after the last application and
were analyzed for residues of tebufenozide. The residue data support a
tolerance of 1.0 ppm for sugarcane and 6.0 ppm for molasses. Residues
were not found in refined sugar and no tolerance is needed for this
commodity.

B. Toxicological Profile

    1. Acute toxicity. Acute toxicity studies with technical grade:
Oral LD50 in the rat is > 5 grams for males and females -
Toxicity Category IV; dermal LD50 in the rat is = 5,000
milligram/kilogram (mg/kg) for males and females - Toxicity Category
III; inhalation 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 which were all negative.
These include an Ames assay with and without metabolic activation, an
in vivo cytogenetic assay in rat bone marrow cells, and in vitro
chromosome aberration assay in CHO cells, a CHO/HGPRT assay, a reverse
mutation assay with E. Coli, and an unscheduled DNA synthesis assay
(UDS) in rat hepatocytes.
    3. Reproductive and developmental toxicity. In a prenatal
developmental toxicity study in Sprague-Dawley rats 25/group
Tebufenozide was administered on gestation days 6-15 by gavage in
aqueous methyl cellulose at dose levels of 50, 250, or 1,000 mg/kg/day
and a dose volume of 10 ml/kg. There was no evidence of maternal or
developmental toxicity; the maternal and developmental toxicity no
observed adverse effect level (NOAEL) was 1,000 mg/kg/day.
    In a prenatal developmental toxicity study conducted in New Zealand
white rabbits 20/group Tebufenozide was administered in 5 ml/kg of
aqueous methyl cellulose at gavage doses of 50, 250, or 1,000 mg/kg/day
on gestation days 7-19. No evidence of maternal or developmental
toxicity was observed; the maternal and developmental toxicity NOAEL
was 1,000 mg/kg/day.
    In a 1993 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 males and females, respectively) and the
lowest observed effect level (LOEL) was 150 ppm (11.5/12.8 mg/kg/day
for males and females, respectively) based on decreased body weight,
body weight gain, and food consumption in males, and increased
incidence and/or severity of splenic pigmentation. In addition, there
was an increased incidence and severity of extramedullary hematopoiesis
at 2,000 ppm. The reproductive NOAEL was 150 ppm. (11.5/12.8 mg/kg/day
for males and females, respectively) and the LOEL was 2,000 ppm (154.8/
171.1 mg/kg/day for males and females, respectively) based on an
increase in the number of pregnant females with increased gestation
duration and dystocia. Effects in the offspring consisted of decreased
number of pups per litter on postnatal days 0 and/or 4 at 2,000 ppm
(154.8/171.1 mg/kg/day for males and females, respectively) with a
NOAEL of 150 ppm (11.5/12.8 mg/kg/day for males and females,
respectively).

[[Page 7888]]

    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 males and females, respectively), and the
LOEL 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 M/F), treatment-related findings included reduced parental
body weight gain and increased incidence of hemosiderin-laden cells in
the spleen. Columnar changes in the vaginal squamous epithelium and
reduced uterine and ovarian weights were also observed at 2,000 ppm,
but the toxicological significance was unknown. For offspring, the
systemic NOAEL was 200 ppm. (12.6/14.6 mg/kg/day in males and females),
and the LOEL was 2,000 ppm (126.0/143.2 mg/kg/day in M/F) based on
decreased body weight on postnatal days 14 and 21.
    4. Subchronic toxicity. 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.
    5. Chronic toxicity. A 1-year dog feeding study with a LOEL of 250
ppm, 9 mg/kg/day for male and female dogs based on decreases in RBC,
HCT, and HGB, increases in Heinz bodies, methemoglobin, MCV, MCH,
reticulocytes, platelets, plasma total bilirubin, spleen weight, and
spleen/body weight ratio, and liver/body weight ratio. Hematopoiesis
and sinusoidal engorgement occurred in the spleen, and hyperplasia
occurred in the marrow of the femur and sternum. The liver showed an
increased pigment in the Kupffer cells. The NOAEL for systemic toxicity
in both sexes is 50 ppm (1.9 mg/kg/day).
    An 18-month mouse carcinogenicity study with no carcinogenicity
observed at dosage levels up to and including 1,000 ppm.
    A 2-year rat carcinogenicity with no carcinogenicity observed at
dosage levels up to and including 2,000 ppm (97 mg/kg/day and 125 mg/
kg/day for males and females, respectively).
    6. Animal metabolism. The adsorption, distribution, excretion and
metabolism of tebufenozide in rats was investigated. Tebufenozide is
partially absorbed, is rapidly excreted and does not accumulate in
tissues. Although tebufenozide is mainly excreted unchanged, a number
of polar metabolites were identified. These metabolites are products of
oxidation of the benzylic ethyl or methyl side chains of the molecule.
These metabolites were detected in plant and other animal (rat, goat,
hen) metabolism studies.
    7. Metabolite toxicology. Common metabolic pathways for
tebufenozide have been identified in both plants (grape, apple, rice
and sugar beet) and animals (rat, goat, hen). The metabolic pathway
common to both plants and animals involves oxidation of the alkyl
substituents (ethyl and methyl groups) of the aromatic rings primarily
at the benzylic positions. Extensive degradation and elimination of
polar metabolites occurs in animals such that residue are unlikely to
accumulate in humans or animals exposed to these residues through the
diet.
    8. Endocrine disruption. The toxicology profile of tebufenozide
shows no evidence of physiological effects characteristic of the
disruption of the hormone estrogen. Based on structure-activity
information, tebufenozide is unlikely to exhibit estrogenic activity.
Tebufenozide was not active in a direct in vitro estrogen binding
assay. No indicators of estrogenic or other endocrine effects were
observed in mammalian chronic studies or in mammalian and avian
reproduction studies. Ecdysone has no known effects in vertebrates.
Overall, the weight of evidence provides no indication that
tebufenozide has endocrine activity in vertebrates.

C. Aggregate Exposure

    1. Dietary exposure --i. Food. 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 also been established. Other
tolerance petitions are pending at EPA with proposed tolerances. Risk
assessments were conducted by Rohm and Haas to assess dietary exposures
and risks from tebufenozide, benzoic acid, 3,5-dimethyl-1-(1,1-
dimethylethyl)-2-(4-ethylbenzoyl) hydrazide as follows:
    a. Acute exposure and risk. Acute dietary risk assessments are
performed for a food-use pesticide if a toxicological study has
indicated the possibility of an effect of concern occurring as a result
of a one day or single exposure. 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 (Limit-Dose) during
gestation to pregnant rats or rabbits. This risk is considered to be
negligible.
    b. Chronic exposure and risk. The RfD used for the chronic dietary
analysis is 0.018 mg/kg/day. In conducting this exposure assessment,
Rohm and Haas has made very conservative assumptions 100% of pecans,
walnuts, wine and sherry, pome fruit and all other commodities having
tebufenozide tolerances or pending tolerances will contain tebufenozide
residues, and those residues would be at the level of the tolerance
which result in an overestimate of human dietary exposure. Thus, in
making a safety determination for this tolerance, Rohm and Haas is
taking into account this conservative exposure assessment. Using the
Dietary Exposure Evaluation Model (Version 5.03b, licensed by Novigen
Sciences Inc.) which uses USDA food consumption data from the 1989-1992
survey and the appropriate concentration or reduction factors, the
existing tebufenozide tolerances published, pending, and including the
necessary section 18 tolerance(s) resulted in a Theoretical Maximum
Residue Contribution (TMRC) that is equivalent to the following
percentages of the RfD:
    U.S. Population (35.8% of RfD);
    Northeast Region (37.5% of RfD);
    Western Region (39.8%);
    Pacific Region (40.9%)All Infants (<1 year) (36.3%);
    Nursing Infants (<1 year old) (16.8% of RfD);
    Non-Nursing Infants (<1 year old) (44.5% of RfD);
    Children (1-6 years old) (61.9% of RfD);
    Children (7-12 years old) (45.6% of RfD);
    Females (13 + years old, nursing) (30.6% of RfD);
    Non-Hispanic Whites (36.0%);
    Non-Hispanic Other than Black or White (43.1% of RfD).
    The subgroups listed above are subgroups for which the percentage
of the RfD occupied is greater than that occupied by the subgroup U.S.
population (48 States).
    ii. Drinking water. Acute exposure and risk. Because no acute
dietary endpoint was determined, Rohm and

[[Page 7889]]

Haas concludes that there is a reasonable certainty of no harm from
acute exposure from drinking water.
    iii. 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 using
Generic expected environmental concentration (GENEEC (surface water))
and screening concentration in ground water (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.
    2. 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 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. 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 35.8% 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.
    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.
    Since, tebufenozide has been classified as a Group E, "no evidence
of carcinogenicity for humans," this risk does not exist.
    2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of tebufenozide, data
from developmental toxicity studies in the rat and rabbit and two 2-
generation reproduction studies in the rat are considered. The
developmental toxicity studies are designed to evaluate adverse effects
on the developing organism resulting from pesticide exposure during
prenatal development to one or both parents. Reproduction studies
provide information relating to effects from exposure to the pesticide
on the reproductive capability of mating animals and data on systemic
toxicity. Developmental toxicity was not observed in developmental
studies using rats and rabbits. The NOAEL for developmental effects in
both rats and rabbits was 1,000 mg/kg/day, which is the limit dose for
testing in developmental studies.
     In the 2-generation reproductive toxicity study in the rat, the
reproductive/ developmental toxicity NOAEL of 12.1 mg/kg/day was 14-
fold higher than the parental (systemic) toxicity NOAEL (0.85 mg/kg/
day). The

[[Page 7890]]

reproductive (pup) LOEL of 171.1 mg/kg/day was based on a slight
increase in both generations in the number of pregnant females that
either did not deliver or had difficulty and had to be sacrificed. In
addition, the length of gestation increased and implantation sites
decreased significantly in F1 dams. These effects were not
replicated at the same dose in a second 2-generation rat reproduction
study. In this second study, reproductive effects were not observed at
2,000 ppm (the NOAEL equal to 149-195 mg/kg/day) and the NOAEL for
systemic toxicity was determined to be 25 ppm (1.9-2.3 mg/kg/day).
    Because these reproductive effects occurred in the presence of
parental (systemic) toxicity and were not replicated at the same doses
in a second study, these data do not indicate an increased pre-natal or
post-natal sensitivity to children and infants (that infants and
children might be more sensitive than adults) to tebufenozide exposure.
FFDCA section 408 provides that EPA shall apply an additional safety
factor for infants and children in the case of threshold effects to
account for pre-and post-natal toxicity and the completeness of the
data base unless EPA concludes that a different margin of safety is
appropriate. Based on current toxicological data discussed above, an
additional uncertainty factor is not warranted and the RfD at 0.018 mg/
kg/day is appropriate for assessing aggregate risk to infants and
children. Rohm and Haas concludes that there is a reasonable certainty
that no harm will occur to infants and children from aggregate exposure
to residues of tebufenozide.

F. International Tolerances

    There are no approved CODEX maximum residue levels (MRLs)
established for residues oftebufenozide.

[FR Doc. 99-3662 Filed 2-16-99; 8:45 am]
BILLING CODE 6560-50-F