Tebufenozide - Pesticide Petition Filing for Grapes 3/98
[Federal Register: March 6, 1998 (Volume 63, Number 44)]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
ENVIRONMENTAL PROTECTION AGENCY
Notice of Filing of Pesticide Petitions
AGENCY: Environmental Protection Agency (EPA).
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 agricultural commodities.
DATES: Comments, identified by the docket control number PF-798, must
be received on or before April 6, 1998.
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, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically to: opp-
firstname.lastname@example.org. 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, Product
Manager (PM) 10, Registration Division, (7505C), Office of Pesticide
Programs, Environmental Protection Agency, 401 M St., SW., Washington,
DC 20460. Office location, telephone number, and e-mail address: Rm.
214, CM#2, 1921 Jefferson Davis Hwy., Arlington, VA. 22202, (703) 305-
6411; e-mail: email@example.com.
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
agricultural 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 grantinig of the 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-798 (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:
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 PF-798 and appropriate petition
number. Electronic comments on this notice may be filed online at many
Federal Depository Libraries.
Authority: 21 U.S.C. 346a.
List of Subjects
Environmental protection, Agricultural commodities, Food additives,
Feed additives, Pesticides and pests, Reporting and recordkeeping
Dated: March 2, 1998.
Acting 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 petitioners. 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.
2. Rohm and Haas Company
EPA has received a pesticide petition (PP 6E4679) from Rohm and
Haas Company, 100 Independence Mall West, Philadelphia, PA 19106.
proposing pursuant to section 408(d) of the Federal Food, Drug and
Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR part 180 by
establishing a 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 wine grapes at 0.5 ppm. EPA has
determined that the petition contains data or information regarding the
elements set forth in section 408(d)(2) of the FFDCA; however, EPA has
not fully evaluated the sufficiency of the submitted data at this time
or whether the data supports granting of the petition. Additional data
may be needed before EPA rules on the petition.
A. Residue Chemistry
1. Plant metabolism. The metabolism of tebufenozide in plants
(grapes, apples, rice and sugar beets) is adequately understood for the
purposes of these tolerances. 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. The metabolism of tebufenozide in goats and
hens proceeds along the same metabolic pathway as observed in plants.
No accumulation of residues in tissues, milk or eggs occurred. Because
wine grape processed fractions are not fed to livestock, there is no
reasonable expectation that measurable residues of tebufenozide will
occur in meat, milk, eggs, or poultry.
2. Analytical method. A high performance liquid chromatographic
(HPLC) analytical method using ultraviolet (UV) detection has been
validated for grapes and wine. For these matrices, 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 is 0.01 ppm for grapes and 0.005 ppm for wine.
B. Toxicological Profile
1. Acute toxicity. Tebufenozide has low acute toxicity.
Tebufenozide Technical was practically non-toxic by ingestion of a
single oral dose in rats and mice (LD50 > 5,000 mg/kg) and
was practically non-toxic by dermal application (LD50 >
5,000 mg/kg). Tebufenozide Technical was not significantly toxic to
rats after a 4-hour inhalation exposure with an LC50 value
of 4.5 mg/L (highest attainable concentration), is not considered to be
a primary eye irritant or a skin irritant and is not a dermal
sensitizer. An acute neurotoxicity study in rats did not produce any
neurotoxic or neuropathologic effects.
2. Genotoxicity. Tebufenozide technical was negative (non-
mutagenic) in an Ames assay with and without hepatic enzyme activation
and in a reverse mutation assay with E. coli. Tebufenozide technical
was negative in a hypoxanthine guanine phophoribosyl transferase
(HGPRT) gene mutation assay using Chinese hamster ovary (CHO) cells in
culture when tested with and without hepatic enzyme activation. In
isolated rat hepatocytes, tebufenozide technical did not induce
unscheduled DNA synthesis (UDS) or repair when tested up to the maximum
soluble concentration in culture medium. Tebufenozide did not produce
chromosome effects in vivo using rat bone marrow cells or in vitro
using Chinese hamster ovary cells (CHO). On the basis of the results
from this battery of tests, it is concluded that tebufenozide is not
mutagenic or genotoxic.
3. Reproductive and developmental toxicity. NOELs for developmental
and maternal toxicity to tebufenozide were established at 1,000 mg/kg/
day (HDT) in both the rat and rabbit. No signs of developmental
toxicity were exhibited.
In a 2-generation reproduction study in the rat, the reproductive/
developmental toxicity NOEL of 12.1 mg/kg/day was 14-fold higher than
the parental (systemic) toxicity NOEL 10 ppm 0.85 mg/kg/day. Equivocal
reproductive effects were observed only at the 2,000 ppm dose.
In a second rat reproduction study, the equivocal reproductive
effects were not observed at 2,000 ppm (the NOEL equal to 149-195 mg/
kg/day) and the NOEL for systemic toxicity was determined to be 25 ppm
4. Subchronic toxicity. The NOEL in a 90-day rat feeding study was
200 ppm (13 mg/kg/day for males, 16 mg/kg/day for females). The LOEL
was 2,000 ppm (133 mg/kg/day for males, 155 mg/kg/day for females).
Decreased body weights in males and females was observed at the LOEL of
2,000 ppm. As part of this study, the potential for tebufenozide to
produce subchronic neurotoxicity was investigated. Tebufenozide did not
produce neurotoxic or neuropathologic effects when administered in the
diets of rats for 3 months at concentrations up to and including the
limit dose of 20,000 ppm (NOEL = 1,330 mg/kg/day for males, 1,650 mg/
kg/day for females).
In a 90-day feeding study with mice, the NOEL was 20 ppm (3.4 and
4.0 mg/kg/day for males and females, respectively). The LOEL was 200 ppm
(35.3 and 44.7 mg/kg/day for males and females, respectively).
Decreases in body weight gain were noted in male mice at the LOEL of
A 90-day dog feeding study gave a NOEL of 50 ppm (2.1 mg/kg/day for
males and females). The LOEL was 500 ppm (20.1 and 21.4 mg/kg/day for
males and females, respectively). At the LOEL, females exhibited a
decrease in rate of weight gain and males presented an increased
A 10-week study was conducted in the dog to examine the
reversibility of the effects on hematological parameters that were
observed in other dietary studies with the dog. Tebufenozide was
administered for 6-weeks in the diet to 4 male dogs at concentrations
of either 0 or 1,500 ppm. After the 6 weeks, the dogs receiving treated
feed were switched to the control diet for 4- weeks. Hematological
parameters were measured in both groups prior to treatment, at the end
of the 6-week treatment, after 2-weeks of recovery on the control diet
and after 4-weeks of recovery on the control diet. All hematological
parameters in the treated/recovery group were returned to control
levels indicating that the effects of tebufenozide on the hemopoietic
system are reversible in the dog.
In a 28-day dermal toxicity study in the rat, the NOEL was 1,000
mg/kg/day, the highest dose tested. Tebufenozide did not produce
toxicity in the rat when administered dermally for 4-weeks at doses up
to and including the limit dose of 1,000 mg/kg/day.
5. Chronic toxicity. A 1-year feeding study in dogs resulted in
decreased red blood cells, hematocrit, and hemoglobin and increased
Heinz bodies, reticulocytes, and platelets at the LOEL of 8.7 mg/kg/
day. The NOEL in this study was 1.8 mg/kg/day.
An 18-month mouse carcinogenicity study showed no signs of
carcinogenicity at dosage levels up to and including 1,000 ppm, the
highest dose tested.
In a combined rat chronic/oncogenicity study, the NOEL for chronic
toxicity was 100 ppm (4.8 and 6.1 mg/kg/day for males and females,
respectively) and the LOEL was 1,000 ppm (48 and 61 mg/kg/day for males
and females, respectively). No carcinogenicity was observed at the
dosage levels up to 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
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. Acute risk. No appropriate acute dietary
endpoint was identified by the Agency. This risk assessment is not
ii. Chronic risk. For chronic dietary risk assessment, the
tolerance values are used and the assumption that all of these crops
which are consumed in the U.S. will contain residues at the tolerance
level. The TMRC using existing and future potential tolerances for
tebufenozide on food crops is obtained by multiplying the tolerance
level residues (existing and proposed) by the consumption data which
estimates the amount of those food products consumed by various
population subgroups and assuming that 100% of the food crops grown in
the U.S. are treated with tebufenozide. The TMRC from current and
future tolerances is calculated 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.
With the current and proposed uses of tebufenozide, the TMRC
estimate represents 20.1% of the RfD for the U.S. population as a
whole. The subgroup with the greatest chronic exposure is non-nursing
infants (less than 1-year old), for which the TMRC estimate represents
52.0% of the RfD. Using anticipate residue levels for these crops
utilizes 3.38% of the RfD for the U.S. population and 12.0% for non-
nursing infants. The chronic dietary risks from these uses do not
exceed EPA's level of concern.
2. Food. Tolerances for residues of tebufenozide are currently
expressed as benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2(4-
ethylbenzoyl) hydrazide. Tolerances currently exist for residues on
apples at 1.0 ppm (import tolerance) and on walnuts at 0.1 ppm (see 40
CFR 180.482). In addition to this action, a request to establish a
tolerance in or on wine grapes, other petitions are pending for the
following tolerances: pome fruit, livestock commodities, pecans,
cotton, the crop subgroups leafy greens, leaf petioles, head and stem
Brassica and leafy Brassica greens, and kiwifruit (import tolerance).
3. Drinking water. An additional potential source of dietary
exposure to residues of pesticides are residues in drinking water.
Review of environmental fate data by the Environmental Fate and Effects
Division concludes that tebufenozide is moderately persistent to
persistent and mobile, and could potentially leach to groundwater and
runoff to surface water under certain environmental conditions.
However, in terrestrial field dissipation studies, residues of
tebufenozide and its soil metabolites showed no downward mobility and
remained associated with the upper layers of soil. Foliar interception
(up to 60% of the total dosage applied) by target crops reduces the
ground level residues of tebufenozide. There is no established maximum-
concentration-level (MCL) for residues of tebufenozide in drinking
water. No drinking water health advisory levels have been established
There are no available data to perform a quantitative drinking
water risk assessment for tebufenozide at this time. However, in order
to mitigate the potential for tebufenozide to leach into groundwater or
runoff to surface water, precautionary language has been incorporated
into the product label. Also, to the best of our knowledge, previous
experience with more persistent and mobile pesticides for which there
have been available data to
perform quantitative risk assessments have demonstrated that drinking
water exposure is typically a small percentage of the total exposure
when compared to the total dietary exposure. This observation holds
even for pesticides detected in wells and drinking water at levels
nearing or exceeding established MCLs. Considering the precautionary
language on the label and based on our knowledge of previous experience
with persistent chemicals, significant exposure from residues of
tebufenozide in drinking water is not anticipated.
4. Non-dietary exposure. Tebufenozide is not registered for either
indoor or outdoor residential use. Non-occupational exposure to the
general population is therefore not expected and not considered in
aggregate exposure estimates.
D. Cumulative Effects
The potential for cumulative effects of tebufenozide with other
substances that have a common mechanism of toxicity was considered.
Tebufenozide belongs to the class of insecticide chemicals known as
diacylhydrazines. The only other diacylhydrazine currently registered
for non-food crop uses is halofenozide. Tebufenozide and halofenozide
both produce a mild, reversible anemia following subchronic/chronic
exposure at high doses; however, halofenozide also exhibits other
patterns of toxicity (liver toxicity following subchronic exposure and
developmental/systemic toxicity following acute exposure) which
tebufenozide does not. Given the different spectrum of toxicity
produced by tebufenozide, there is no reliable data at the molecular/
mechanistic level which would indicate that toxic effects produced by
tebufenozide would be cumulative with those of halofenozide (or any
other chemical compound).
In addition to the observed differences in mammalian toxicity,
tebufenozide also exhibits unique toxicity against target insect pests.
Tebufenozide is an agonist of 20-hydroxyecdysone, the insect molting
hormone, and interferes with the normal molting process in target
lepidopteran species by interacting with ecdysone receptors from those
species. Unlike other ecdysone agonists such as halofenozide,
tebufenozide does not produces symptoms which may be indicative of
systemic toxicity in beetle larvae (Coleopteran species). Tebufenozide
has a different spectrum of activity than other ecdysone agonists. In
contrast to the other agonists such as halofenozide which act mainly on
coleopteran insects, tebufenozide is highly specific for lepidopteran
Based on the overall pattern of toxicity produced by tebufenozide
in mammalian and insect systems, the compound's toxicity appears to be
distinct from that of other chemicals, including organochlorines,
organophosphates, carbamates, pyrethroids, benzoylureas, and other
diacylhydrazines. Thus, there is no evidence to date to suggest that
cumulative effects of tebufenozide and other chemicals should be
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, the dietary exposure to tebufenozide
from the current and future tolerances will utilize 20.1% of the RfD
for the U.S. population and 52.0% for non-nursing infants under 1-year
old. Using anticipate residue levels for these crops utilizes 3.38% of
the RfD for the U.S. population and 12.0% for non-nursing infants. EPA
generally has no concern for exposures below 100% of the RfD because
the RfD represents the level at or below which daily aggregate dietary
exposure over a lifetime will not pose appreciable risks to human
health. Rohm and Haas concludes that there is a reasonable certainty
that no harm will result from aggregate exposure to tebufenozide
residues to the U.S. population and non-nursing infants.
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 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 NOEL 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 NOEL of 12.1 mg/kg/day was 14-fold
higher than the parental (systemic) toxicity NOEL (0.85 mg/kg/day). The
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 NOEL equal to 149-195 mg/kg/day) and the NOEL 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
grapes and proposed an MRL (Step 3) of 0.5 mg/kg.
[FR Doc. 98-5985 Filed 3-5-98; 8:45 am]
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