[Federal Register Volume 63, Number 121 (Wednesday, June 24, 1998)]
[Rules and Regulations]
[Pages 34310-34318]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-16822]
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ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 180
[OPP-300675; FRL 5796-9]
RIN 2070-AB78
Tebufenozide; Benzoic Acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2-
(4-ethylbenzoyl) hydrazide
AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.
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SUMMARY: This regulation establishes tolerances for residues of
tebufenozide in or on pecans and grapes, wine and a time-limited
tolerance for residues of tebufenozide in or on pears. The time-limited
tolerance for pears is being established to allow the use of
tebufenozide on pears under an Experimental Use Permit. Rohm and Haas
Company requested these tolerances under the Federal Food, Drug, and
Cosmetic Act (FFDCA), as amended by the Food Quality Protection Act of
1996 (Pub. L. 104-170).
DATES: This regulation is effective June 24, 1998. Objections and
requests for hearings must be received by EPA on or before August 24,
1998.
ADDRESSES: Written objections and hearing requests, identified by the
docket control number, [OPP-300675], must be submitted to: Hearing
Clerk (1900), Environmental Protection Agency, Rm. M3708, 401 M St.,
SW., Washington, DC 20460. Fees accompanying objections and hearing
requests shall be labeled ``Tolerance Petition Fees'' and forwarded to:
EPA Headquarters Accounting Operations Branch, OPP (Tolerance Fees),
P.O. Box 360277M, Pittsburgh, PA 15251. A copy of any objections and
hearing requests filed with the Hearing Clerk identified by the docket
control number, [OPP-300675], must also be submitted to: Public
Information and Records Integrity Branch, Information Resources and
Services Division (7502C), Office of Pesticide Programs, Environmental
Protection Agency, 401 M St., SW., Washington, DC 20460. In person,
bring a copy of objections and hearing requests to Rm. 119, CM #2, 1921
Jefferson Davis Hwy., Arlington, VA.
A copy of objections and hearing requests filed with the Hearing
Clerk may also be submitted electronically by sending electronic mail
(e-mail) to: [email protected]. Copies of objections and
hearing requests must be submitted as an ASCII file avoiding the use of
special characters and any form of encryption. Copies of objections and
hearing requests will also be accepted on disks in WordPerfect 5.1/6.1
file format or ASCII file format. All copies of objections and hearing
requests in electronic form must be identified by the docket control
number [OPP-300675]. No Confidential Business Information (CBI) should
be submitted through e-mail. Electronic copies of objections and
hearing requests on this
[[Page 34311]]
rule may be filed online at many Federal Depository Libraries.
FOR FURTHER INFORMATION CONTACT: By mail: Joseph M. Tavano,
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: Crystal Mall #2,
1921 Jefferson Davis Hwy., Arlington, VA, (703) 305-6411, e-mail:
[email protected].
SUPPLEMENTARY INFORMATION: In the Federal Register of January 28, 1998
(63 FR 4252) [FRL 5763-6]; March 6, 1998 (63 FR 11240) [FRL 5777-5] and
March 27, 1998 (63 FR 14926) [5577-6]. EPA, issued notices pursuant to
section 408 of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21
U.S.C. 346a(e) announcing the filing of pesticide petitions (PP) for
tolerance by Rohm and Haas Company, 100 Independence mall west,
Philadelphia, PA 19106-2399. These notices included a summary of the
petitions prepared by Rohm and Haas Company, the registrant. There were
no comments received in response to these notices of filing.
The petition requested that 40 CFR 180.482 be amended by
establishing a tolerance for residues of the insecticide, tebufenozide,
in or on pecans, grapes, wine and pears at 0.01, 0.5, and 1.0 part per
million (ppm) respectively.
I. Risk Assessment and Statutory Findings
New section 408(b)(2)(A)(i) of the FFDCA allows EPA to establish a
tolerance (the legal limit for a pesticide chemical residue in or on a
food) only if EPA determines that the tolerance is ``safe.'' Section
408(b)(2)(A)(ii) defines ``safe'' to mean that ``there is a reasonable
certainty that no harm will result from aggregate exposure to the
pesticide chemical residue, including all anticipated dietary exposures
and all other exposures for which there is reliable information.'' This
includes exposure through drinking water and in residential settings,
but does not include occupational exposure. Section 408(b)(2)(C)
requires EPA to give special consideration to exposure of infants and
children to the pesticide chemical residue in establishing a tolerance
and to ``ensure that there is a reasonable certainty that no harm will
result to infants and children from aggregate exposure to the pesticide
chemical residue. . . .''
EPA performs a number of analyses to determine the risks from
aggregate exposure to pesticide residues. First, EPA determines the
toxicity of pesticides based primarily on toxicological studies using
laboratory animals. These studies address many adverse health effects,
including (but not limited to) reproductive effects, developmental
toxicity, toxicity to the nervous system, and carcinogenicity. Second,
EPA examines exposure to the pesticide through the diet (e.g., food and
drinking water) and through exposures that occur as a result of
pesticide use in residential settings.
A. Toxicity
1. Threshold and non-threshold effects. For many animal studies, a
dose response relationship can be determined, which provides a dose
that causes adverse effects (threshold effects) and doses causing no
observed effects (the ``no-observed effect level'' or ``NOEL'').
Once a study has been evaluated and the observed effects have been
determined to be threshold effects, EPA generally divides the NOEL from
the study with the lowest NOEL by an uncertainty factor (usually 100 or
more) to determine the Reference Dose (RfD). The RfD is a level at or
below which daily aggregate exposure over a lifetime will not pose
appreciable risks to human health. An uncertainty factor (sometimes
called a ``safety factor'') of 100 is commonly used since it is assumed
that people may be up to 10 times more sensitive to pesticides than the
test animals, and that one person or subgroup of the population (such
as infants and children) could be up to 10 times more sensitive to a
pesticide than another. In addition, EPA assesses the potential risks
to infants and children based on the weight of the evidence of the
toxicology studies and determines whether an additional uncertainty
factor is warranted. Thus, an aggregate daily exposure to a pesticide
residue at or below the RfD (expressed as 100% or less of the RfD) is
generally considered acceptable by EPA. EPA generally uses the RfD to
evaluate the chronic risks posed by pesticide exposure. For shorter
term risks, EPA calculates a margin of exposure (MOE) by dividing the
estimated human exposure into the NOEL from the appropriate animal
study. Commonly, EPA finds MOEs lower than 100 to be unacceptable. This
100-fold MOE is based on the same rationale as the 100-fold uncertainty
factor.
Lifetime feeding studies in two species of laboratory animals are
conducted to screen pesticides for cancer effects. When evidence of
increased cancer is noted in these studies, the Agency conducts a
weight of the evidence review of all relevant toxicological data
including short-term and mutagenicity studies and structure activity
relationship. Once a pesticide has been classified as a potential human
carcinogen, different types of risk assessments (e.g., linear low dose
extrapolations or MOE calculation based on the appropriate NOEL) will
be carried out based on the nature of the carcinogenic response and the
Agency's knowledge of its mode of action.
2. Differences in toxic effect due to exposure duration. The
toxicological effects of a pesticide can vary with different exposure
durations. EPA considers the entire toxicity data base, and based on
the effects seen for different durations and routes of exposure,
determines which risk assessments should be done to assure that the
public is adequately protected from any pesticide exposure scenario.
Both short and long durations of exposure are always considered.
Typically, risk assessments include ``acute,'' ``short-term,''
``intermediate term,'' and ``chronic'' risks. These assessments are
defined by the Agency as follows.
Acute risk, by the Agency's definition, results from 1-day
consumption of food and water, and reflects toxicity which could be
expressed following a single oral exposure to the pesticide residues.
High end exposure to food and water residues are typically assumed.
Short-term risk results from exposure to the pesticide for a period
of 1-7 days, and therefore overlaps with the acute risk assessment.
Historically, this risk assessment was intended to address primarily
dermal and inhalation exposure which could result, for example, from
residential pesticide applications. However, since enaction of FQPA,
this assessment has been expanded to include both dietary and non-
dietary sources of exposure, and will typically consider exposure from
food, water, and residential uses when reliable data are available. In
this assessment, risks from average food and water exposure, and high-
end residential exposure, are aggregated. High-end exposures from all
three sources are not typically added because of the very low
probability of this occurring in most cases, and because the other
conservative assumptions built into the assessment assure adequate
protection of public health. However, for cases in which high-end
exposure can reasonably be expected from multiple sources (e.g.
frequent and widespread homeowner use in a specific geographical area),
multiple high-end risks will be aggregated and presented as part of the
comprehensive risk assessment/characterization. Since the toxicological
endpoint considered in
[[Page 34312]]
this assessment reflects exposure over a period of at least 7 days, an
additional degree of conservatism is built into the assessment; i.e.,
the risk assessment nominally covers 1-7 days exposure, and the
toxicological endpoint/NOEL is selected to be adequate for at least 7
days of exposure. (Toxicity results at lower levels when the dosing
duration is increased.)
Intermediate-term risk results from exposure for 7 days to several
months. This assessment is handled in a manner similar to the short-
term risk assessment.
Chronic risk assessment describes risk which could result from
several months to a lifetime of exposure. For this assessment, risks
are aggregated considering average exposure from all sources for
representative population subgroups including infants and children.
B. Aggregate Exposure
In examining aggregate exposure, FFDCA section 408 requires that
EPA take into account available and reliable information concerning
exposure from the pesticide residue in the food in question, residues
in other foods for which there are tolerances, residues in groundwater
or surface water that is consumed as drinking water, and other non-
occupational exposures through pesticide use in gardens, lawns, or
buildings (residential and other indoor uses). Dietary exposure to
residues of a pesticide in a food commodity are estimated by
multiplying the average daily consumption of the food forms of that
commodity by the tolerance level or the anticipated pesticide residue
level. The Theoretical Maximum Residue Contribution (TMRC) is an
estimate of the level of residues consumed daily if each food item
contained pesticide residues equal to the tolerance. In evaluating food
exposures, EPA takes into account varying consumption patterns of major
identifiable subgroups of consumers, including infants and children.
The TMRC is a ``worst case'' estimate since it is based on the
assumptions that food contains pesticide residues at the tolerance
level and that 100% of the crop is treated by pesticides that have
established tolerances. If the TMRC exceeds the RfD or poses a lifetime
cancer risk that is greater than approximately one in a million, EPA
attempts to derive a more accurate exposure estimate for the pesticide
by evaluating additional types of information (anticipated residue data
and/or percent of crop treated data) which show, generally, that
pesticide residues in most foods when they are eaten are well below
established tolerances.
Percent of crop treated estimates are derived from federal and
private market survey data. Typically, a range of estimates are
supplied and the upper end of this range is assumed for the exposure
assessment. By using this upper end estimate of percent of crop
treated, the Agency is reasonably certain that exposure is not
understated for any significant subpopulation group. Further, regional
consumption information is taken into account through EPA's computer-
based model for evaluating the exposure of significant subpopulations
including several regional groups, to pesticide residues. For this
pesticide, the most highly exposed population subgroup was not
regionally based.
II. Aggregate Risk Assessment and Determination of Safety
Consistent with section 408(b)(2)(D), EPA has reviewed the
available scientific data and other relevant information in support of
this action, EPA has sufficient data to assess the hazards of
tebufenozide, benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-
ethylbenzoyl) hydrazide and to make a determination on aggregate
exposure, consistent with section 408(b)(2), for tolerances for
residues of tebufenozide on pecans, grapes, wine and pears at 0.01,
0.5, and 1.0 ppm respectively. EPA's assessment of the dietary
exposures and risks associated with establishing the tolerance follows.
A. Toxicological Profile
EPA has evaluated the available toxicity data and considered its
validity, completeness, and reliability as well as the relationship of
the results of the studies to human risk. EPA has also considered
available information concerning the variability of the sensitivities
of major identifiable subgroups of consumers, including infants and
children. The nature of the toxic effects caused by tebufenozide,
benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl)
hydrazide are discussed below.
1. 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 > 5mg - Toxicity
Category IV. Tebufenozide is not a sentizer.
2. In a 21-day dermal toxicity study, Crl: CD rats (6/sex/dose)
received repeated dermal administration of either the technical 96.1%
product RH-75,992 at 1,000 mg/kg/day Limit-Dose or the formulation
23.1% a.i. product RH-755,992 2F at 0, 62.5, 250, or 1,000 mg/kg/day, 6
hours/day, 5 days/week for 21 days. Under conditions of this study, RH-
75,992 Technical or RH-75,992 2F demonstrated no systemic toxicity or
dermal irritation at the highest dose tested 1,000 mg/kg/ during the
21-day study. Based on these results, the NOEL for systemic toxicity
and dermal irritation in both sexes is 1,000 mg/kg/day highest dose
tested (HDT). A lowest-observable-effect level (LOEL) for systemic
toxicity and dermal irritation was not established.
3. 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 no-observed effect level (NOEL) for systemic
toxicity in both sexes is 50 ppm (1.9 mg/kg/day).
4. An 18-month mouse carcinogenicity study with no carcinogenicity
observed at dosage levels up to and including 1,000 ppm.
5. 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. 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 NOEL was 1,000 mg/kg/day.
7. 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 NOEL was
1,000 mg/kg/day.
[[Page 34313]]
8. In a 1993 two-generation reproduction study in Sprague-Dawley
rats tebufenozide was administered at dietary concentrations of 0, 10,
150, or 1,000 ppm (0, 0.8, 11.5, or 154.8 mg/kg/day for males and 0,
0.9, 12.8, or 171.1 mg/kg/day for females). The parental systemic NOEL
was 10 ppm (0.8/0.9 mg/kg/day for males and females, respectively) and
the 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
NOEL 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 NOEL of 150 ppm (11.5/12.8
mg/kg/day for males and females, respectively).
9. In a 1995 two-generation reproduction study in rats Tebufenozide
was administered at dietary concentrations of 0, 25, 200, or 2,000 ppm
(0, 1.6, 12.6, or 126.0 mg/kg/day for males and 0, 1.8, 14.6, or 143.2
mg/kg/day for females). For parental systemic toxicity, the NOEL 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 NOEL 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.
10. 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.
11. 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 bioacculmulation.
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
leaved (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.
12. The absorption and metabolism of tebufenozide were studied in a
group of male and female bile-duct cannulated rats. Over a 72 hour
period, biliary excretion accounted for 30%[M] to 34%[F] of the
administered dose while urinary excretion accounted for 5%
of the administered dose and the carcass accounted for < 0.5% of the
administered dose for both males and females. Thus systemic absorption
(percent of dose recovered in the bile, urine and carcass] was 35%[M]
to 39%[F]. The majority of the radioactivity in the bile (20% [M] to
24% [F]) of the administered dose] was excreted within the first 6
hours postdosing indicating rapid absorption. Furthermore, urinary
excretion of the metabolites was essentially complete within 24 hours
postdosing. 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 primary by oxidation of
the benzylic carbons to alcohols, aldehydes or acids. Bile contained
most of the other highly oxidized products found in the feces. The most
significant individual bile metabolites accounted for 5% to 18% of the
total radioactivity (F and/or M). Bile also contained the previously
undetected (in the pharmacokinetics study] ``A'' Ring ketone and the
``B'' Ring diol. The other major components were characterized as high
molecular weight conjugates. No individual bile metabolite accounted
for > 5% of the total administered dose. Total bile radioactivity
accounted for 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.
B. Toxicological Endpoints
1. Acute toxicity. 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. Thus the risk from acute exposure is
considered negligible.
2. Short - and intermediate - term toxicity. No dermal or systemic
toxicity was seen in rats receiving 15 repeated dermal applications of
the technical (97.2%) product at 1,000 mg/kg/day (Limit- Dose) as well
as a formulated (23% a.i) product at 0, 62.5, 250, or 1,000 mg/kg/day
over a 21-day period (MRID 42991507). The HIARC noted that in spite of
the hematological effects seen in the dog study, similar effects were
not seen in the rats receiving the
[[Page 34314]]
compound via the dermal route indicating poor dermal absorption. Also,
no developmental endpoints of concern were evident due to the lack of
developmental toxicity in either rat or rabbit studies. This risk is
considered to be negligable.
3. Chronic toxicity. EPA has established the RfD for tebufenozide,
benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl)
hydrazide at 0.018 mg/kg/day. This RfD is based on a NOEL of 1.8 mg/kg/
day and an uncertainty factor (UF) of 100. The NOEL was established
from the chronic toxicity study in dogs where the NOEL was 1.8 mg/kg/
day based on growth retardation, alterations in hematology parameters,
changes in organ weights, and histopathological lesions in the bone,
spleen and liver at 8.7 mg/kg/day. EPA determined that the 10 x factor
to protect children and infants as required by FQPA should be removed.
Therefore, the RfD remains the same at: 0.018 mg/kg/day. An UF of 100
is supported by the following factors.
(i) Developmental toxicity studies showed no increased sensitivity
in fetuses when compared to maternal animals following in utero
exposures in rats and rabbits.
(ii) Multi-generation reproduction toxicity studies in rats showed
no increased sensitivity in pups as compared to adults and offspring.
(iii) There are no data gaps.
4. Carcinogenicity. Tebufenozide has been classified as a Group E,
``no evidence of carcinogenicity for humans,'' chemical by EPA.
C. Exposures and Risks
1. 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 and apples at 1.0 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. Risk assessments were conducted by EPA to assess
dietary exposures and risks from tebufenozide, benzoic acid, 3,5-
dimethyl-1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl) hydrazide as follows:
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 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
negligable.
ii. Chronic exposure and risk. The RfD used for the chronic dietary
analysis is 0.018 mg/kg/day. In conducting this exposure assessment,
EPA has made very conservative assumptions 100% of pecans and wine and
sherry and and pears and all other commodities having tebufenozide
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, HED 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 (31% of RfD);
Nursing Infants (<1 year old) (41% of RfD); Non-Nursing Infants (<1
year old) (80% of Rfd); Children (1-6 years old) (60% of RfD); Children
(7-12 years old) (43% of Rfd); Females (13 + years old, nursing) (31%
of RfD); Males (13-19 years old) (28% of RfD); Non-Hispanic Blacks (34%
of RfD); Non Hispanic Others (42% of RfD) Western Region (35% of RfD).
The subgroups listed above are: (1) the U.S. population (48 States);
(2) those for infants and children; and, (3) the other subgroups for
which the percentage of the RfD occupied is greater than that occupied
by the subgroup U.S. population (48 States).
2. From drinking water-- i. Acute exposure and risk. Because no
acute dietary endpoint was determined, the Agency 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 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.
3. 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.
4. 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 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
[[Page 34315]]
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, EPA 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.
D. Aggregate Risks and Determination of Safety for U.S. Population
1. Acute risk. Since no acute toxicological endpoints were
established, no acute aggregate risk exists.
2. Chronic risk. Using the conservative exposure assumptions
described above, and taking into account the completeness and
reliability of the toxicity data, EPA has concluded that dietary (food
only) exposure to tebufenozide will utilize 31% 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, EPA does
not expect the aggregate exposure to exceed 100% of the RfD.
3. 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.
E. Aggregate Cancer Risk for U.S. Population
Since, tebufenozide has been classified as a Group E, ``no evidence
of carcinogenicity for humans,'' this risk does not exist.
F. Aggregate Risks and Determination of Safety for Infants and Children
1. Safety factor for infants and children-- i. In general. 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 considered data
from developmental toxicity studies in the rat and rabbit and a two-
generation reproduction study in the rat. The developmental toxicity
studies are designed to evaluate adverse effects on the developing
organism resulting from maternal pesticide exposure gestation.
Reproduction studies provide information relating to effects from
exposure to the pesticide on the reproductive capability of mating
animals and data on systemic toxicity.
FFDCA section 408 provides that EPA shall apply an additional
tenfold margin of safety for infants and children in the case of
threshold effects to account for pre-and post-natal toxicity and the
completeness of the database unless EPA determines that a different
margin of safety will be safe for infants and children. Margins of
safety are incorporated into EPA risk assessments either directly
through use of a MOE analysis or through using uncertainty (safety)
factors in calculating a dose level that poses no appreciable risk to
humans. EPA believes that reliable data support using the standard
uncertainty factor (usually 100 for combined inter- and intra-species
variability)) and not the additional tenfold MOE/uncertainty factor
when EPA has a complete data base under existing guidelines and when
the severity of the effect in infants or children or the potency or
unusual toxic properties of a compound do not raise concerns regarding
the adequacy of the standard MOE/safety factor.
ii. Developmental toxicity studies--a. Rats. In a developmental
toxicity study in rats, the maternal (systemic) NOEL was 250 mg/kg/day.
The LOEL was 1,000 mg/kg/day, based on decreased body weight and food
consumption. The developmental (pup) NOEL was 1,000 mg/kg/
day (HGT)
b. Rabbits. In a developmental toxicity study in rabbits, the
maternal and developmental NOELs were 1,000 mg/kg/day
(HDT).
iii. Reproductive toxicity study. In a 1993 two-generation
reproduction study in Sprague-Dawley rats, tebufenozide was
administered at dietary concentrations of 0, 10, 150, or 1,000 ppm (0,
0.8, 11.5, or 154.8 mg/kg/day for males and 0, 0.9, 12.8, or 171.1 mg/
kg/day for females). The parental systemic NOEL was 10 ppm (0.8/0.9 mg/
kg/day for males and females, respectively) and the 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 NOEL 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 NOEL of 150 ppm (11.5/12.8 mg/kg/day for
males and females, respectively)
In a 1995 two-generation reproduction study in rats, tebufenozide
was administered at dietary concentrations of 0, 25, 200, or 2,000 ppm
(0, 1.6, 12.6, or 126.0 mg/kg/day for males and 0, 1.8, 14.6, or 143.2
mg/kg/day for females). For parental systemic toxicity, the NOEL 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
[[Page 34316]]
epithelium and reduced uterine and ovarian weights were also observed
at 2,000 ppm, but the toxicological significance was unknown. For
offspring, the systemic NOEL 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.
iv. Pre- and post-natal sensitivity. The toxicology data base for
tebufenozide is complete and includes acceptable developmental toxicity
studies in both rats and rabbits as well as a two two-generation
reproductive toxicity studies in rats.
The 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 two two-generation
reproduction studies in rats, effects occurred at the same or lower
treatment levels in the adults as in the offspring.
2. Acute risk. Since no acute toxicological endpoints were
established, no acute aggregate risk exists.
3. Chronic risk. Using the conservative exposure assumptions
described above, EPA 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 31% of the RfD for
the U.S. population to 80% of the RfD for non-nursing infants less than
1 year 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. EPA does not expect the aggregate exposure to exceed 100% of
the RfD. EPA 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.
4. Short- or intermediate-term risk. Since no short- and
intermediate-term toxicological endpoints were established by EPA, no
acute aggregate risk exists.
III. Other Considerations
A. Metabolism In Plants and Animals
The nature of the residues of tebufenozide in/on plants is
adequately understood. The residue of concern for both regulatory
(tolerance expression) and risk assessment purposes is the parent
compound, tebufenozide per se.
There are no animal feed items associated with pecans. According to
information supplied by the petitioner, wine grapes and wine grape
processing commodities are not items of animal feed in Europe.
Therefore, a discussion of potential transfer of secondary residues to
animal commodities is not germane to these actions.
B. Analytical Enforcement Methodology
A HPLC/UV analytical method, Enforcement Residue Analytical Method
for RH-5992 in Pecans with HPLC-MS Confirmation is adequate for
enforcement purposes in pecans. A successful Agency validation for an
analytical method to detect residues of tebufenozide per se has been
conducted by ACL/BEAD.
The method used in the analysis of the total residue of concern in
the European field residue trials in wine, Method AL 013/92-0, was
developed by Rohm and Haas and independently validated. In the
validation of this method, at levels from 0.01 to 0.5 ppm in wine
recoveries ranged from 84 to 109%; in grapes at levels of 0.02 to 1.0
ppm recoveries ranged from 77 to 128%. The limit of quantitation was
given as 0.02 ppm for grapes and 0.01 ppm for wine. The method is
different from those validated for domestic commodities but was
determined to be adequate for data collection.
C. Magnitude of Residues
Adequate residue data were provided to support tolerances of 0.01
ppm for pecans and 0.5 ppm for grapes, wine and a time-limited
tolerance for pears.
There are no pecan or pear processed comodities of regulatory
concern. In those instances when treated grapes were vinified, residues
of tebufenozide in the aged wine were a third to a half of those in the
treated grapes. The maximum residue found in the wine treated at label
rates was 0.3 ppm; therefore, a tolerance for wine grapes would suffice
for the wine made from them.
Since there are no pecan or pear animal feed items and according to
information supplied by the petitioner, wine grapes and wine grape
processing commodities are not items of animal feed in Europe, no
secondary residues in animals are expected.
D. International Residue Limits
There are currently no CODEX, Canadian, or Mexican listings for
tebufenozide residues in or on pecans or pears, therefore there are no
harmonization issues for these crops.
Maximum residue levels (MRL) of 0.5 ppm have been established for
wine grapes in France, Italy, and Germany. The tolerance of 0.5 ppm in
or on wine grapes is in harmony with these MRLs.
E. Rotational Crop Restrictions
Since pecans, grapes, and pears are not rotated to other crops, a
discussion of tebufenozide accumulation in rotational crops is not
germane to this action.
IV. Conclusion
Therefore, the tolerance is established for residues of
tebufenozide in pecans, grapes, wine, and pears at 0.01, 0.5, and 1.0
ppm respectively.
V. Objections and Hearing Requests
The new FFDCA section 408(g) provides essentially the same process
for persons to ``object'' to a tolerance regulation issued by EPA under
new section 408(e) and (l)(6) as was provided in the old section 408
and in section 409. However, the period for filing objections is 60
days, rather than 30 days. EPA currently has procedural regulations
which govern the submission of objections and hearing requests. These
regulations will require some modification to reflect the new law.
However, until those modifications can be made, EPA will continue to
use those procedural regulations with appropriate adjustments to
reflect the new law.
Any person may, by August 24, 1998, file written objections to any
aspect of this regulation and may also request a hearing on those
objections. Objections and hearing requests must be filed with the
Hearing Clerk, at the address given above (40 CFR 178.20). A copy of
the objections and/or hearing requests filed with the Hearing Clerk
should be submitted to the OPP docket for this rulemaking. The
objections submitted must specify the provisions of the regulation
deemed objectionable and the grounds for the objections (40 CFR
178.25). Each objection must be accompanied by the fee prescribed by 40
CFR 180.33(i). If a hearing is requested, the objections must include a
statement of the factual issues on which a hearing is requested, the
requestor's contentions on such issues, and a summary of any evidence
relied upon by the requestor (40 CFR 178.27). A request for a hearing
will be granted if
[[Page 34317]]
the Administrator determines that the material submitted shows the
following:
There is genuine and substantial issue of fact; there is a
reasonable possibility that available evidence identified by the
requestor would, if established, resolve one or more of such issues in
favor of the requestor, taking into account uncontested claims or facts
to the contrary; and resolution of the factual issues in the manner
sought by the requestor would be adequate to justify the action
requested (40 CFR 178.32). Information submitted in connection with an
objection or hearing request may be claimed confidential by marking any
part or all of that information as Confidential Business Information
(CBI). Information so marked will not be disclosed except in accordance
with procedures set forth in 40 CFR part 2. A copy of the information
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.
VI. Public Record and Electronic Submissions
EPA has established a record for this rulemaking under docket
control number [OPP-300675] (including any comments and data submitted
electronically). 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 public
record is located in Room 119 of the Public Information and Records
Integrity Branch, Information Resources and Services Division (7502C),
Office of Pesticide Programs, Environmental Protection Agency, Crystal
Mall #2, 1921 Jefferson Davis Highway, Arlington, VA.
Electronic comments may be sent directly to EPA at: opp-
[email protected].
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption.
The official record for this rulemaking, as well as the public
version, as described above will be kept in paper form. Accordingly,
EPA will transfer any copies of objections and hearing requests
received electronically into printed, paper form as they are received
and will place the paper copies in the official rulemaking record which
will also include all comments submitted directly in writing. The
official rulemaking record is the paper record maintained at the
Virginia address in ``ADDRESSES'' at the beginning of this document.
VII. Regulatory Assessment Requirements
This final rule establishes tolerances under FFDCA section 408(d)
in response to a petitions submitted to the Agency. The Office of
Management and Budget (OMB) has exempted these types of actions from
review under Executive Order 12866, entitled Regulatory Planning and
Review (58 FR 51735, October 4, 1993). This final rule does not contain
any information collections subject to OMB approval under the Paperwork
Reduction Act (PRA), 44 U.S.C. 3501 et seq., or impose any enforceable
duty or contain any unfunded mandate as described under Title II of the
Unfunded Mandates Reform Act of 1995 (UMRA) (Pub. L. 104-4). Nor does
it require any prior consultation as specified by Executive Order
12875, entitled Enhancing the Intergovernmental Partnership (58 FR
58093, October 28, 1993), or special considerations as required by
Executive Order 12898, entitled Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations (59 FR 7629, February 16, 1994), or require OMB review in
accordance with Executive Order 13045, entitled Protection of Children
from Environmental Health Risks and Safety Risks (62 FR 19885, April
23, 1997).
In addition, since these tolerances and exemptions that are
established on the basis of petitions under FFDCA section 408(d), such
as the tolerances in this final rule, do not require the issuance of a
proposed rule, the requirements of the Regulatory Flexibility Act (RFA)
(5 U.S.C. 601 et seq.) do not apply. Nevertheless, the Agency has
previously assessed whether establishing tolerances, exemptions from
tolerances, raising tolerance levels or expanding exemptions might
adversely impact small entities and concluded, as a generic matter,
that there is no adverse economic impact. The factual basis for the
Agency's generic certification for tolerance actions published on May
4, 1981 (46 FR 24950) and was provided to the Chief Counsel for
Advocacy of the Small Business Administration.
VIII. Submission to Congress and the Comptroller General
The Congressional Review Act, 5 U.S.C. 801 et seq., as added by the
Small Business Regulatory Enforcement Fairness Act of 1996, generally
provides that before a rule may take effect, the agency promulgating
the rule must submit a rule report, which includes a copy of the rule,
to each House of the Congress and to the Comptroller General of the
United States. EPA will submit a report containing this rule and other
required information to the U.S. Senate, the U.S. House of
Representatives, and the Comptroller General of the United States prior
to publication of the rule in the Federal Register. This rule is not a
``major rule'' as defined by 5 U.S.C. 804(2).
List of Subjects in 40 CFR Part 180
Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Reporting and
recordkeeping requirements.
Dated:June 12, 1998.
James Jones,
Director, Registration Division, Office of Pesticide Programs.
Therefore, 40 CFR chapter I is amended as follows:
PART 180 -- [AMENDED]
1. The authority citation for part 180 continues to read as
follows:
Authority: 21 U.S.C. 346a and 371.
2. In Sec. 180.482, by alphabetically adding the following
commodities to the table in paragraph (b) to read as follows:
Sec. 180.482 Tebufenozide; tolerances for residues.
* * * * *
(b)* * *
------------------------------------------------------------------------
Expiration/
Commodity Parts per million Revocation Date
------------------------------------------------------------------------
* * * * * * *
Grapes, wine \1\................ 0.5 NA
Pears........................... 1.0 2001
Pecans.......................... 0.01 NA
[[Page 34318]]
* * * * * * *
------------------------------------------------------------------------
\1\ There are no U.S. registrations on grapes as of June 24, 1998.
[FR Doc. 98-16822 Filed 6-23-98; 8:45 am]
BILLING CODE 6560-50-F