[Federal Register Volume 63, Number 160 (Wednesday, August 19, 1998)]
[Notices]
[Pages 44439-44456]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-21747]
-----------------------------------------------------------------------
ENVIRONMENTAL PROTECTION AGENCY
[PF-821; FRL-6019-6]
Rohm and Haas Company; Pesticide Tolerance Petition Filing
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
-----------------------------------------------------------------------
SUMMARY: This notice announces the filing of pesticide petitions
proposing the establishment of a tolerance for residues of a certain
pesticide chemical in or on various raw agricultural commodities.
DATES: Comments, identified by the docket control number [PF-821], must
be received on or before September 18, 1998.
ADDRESSES: By mail, submit written comments to Information and Records
Integrity Branch, Public Information and Services Division (7502C),
Office of Pesticide 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 by following
the instructions under ``SUPPLEMENTARY INFORMATION.'' No confidential
business information should be submitted through e-mail.
Information submitted as a comments 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 number, and e-mail address: Rm. 214, CM #2, 1921
Jefferson Davis Highway, Arlington, VA 22202. (703) 305-6411;
[email protected].
SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as
follows from Rohm and Haas Company, 100 Independence Mall West,
Philadelphia, PA. 19106-2399, proposing pursuant to section 408(d) of
the Federal Food, Drug and Cosmetic Act, 21 U.S.C. 346a(d), to amend 40
CFR 180.472 by establishing a tolerance for residues of tebufenozide
[benzoic acid, 3,5-dimethyl-, 1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl)
hydrazide in or on various raw agricultural commodities. EPA has
determined that these petitions contain 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.
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-821 (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:
[email protected]
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-821) 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, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Reporting and
recordkeeping requirements.
Dated: August 6, 1998.
Arnold E. Lane,
Acting Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
Petitioner summaries of the pesticide petitions are printed below
as required by section 408(d)(3) of the FFDCA. The summaries of the
petitions were prepared by the petitioner and represent the views of
the petitioner. EPA is publishing the petition summaries verbatim
without editing them in any way. The petition summary announces the
availability of a description of the analytical methods available to
EPA for the detection and measurement of the pesticide chemical
residues or an explanation of why no such method is needed.
1. PP 7F4815
EPA has received a pesticide petition (PP 7F4815) from Rohm and
Haas Company, 100 Independence Mall West, Philadelphia, PA 19106-2399,
proposing pursuant to section 408(d) of the Federal Food, Drug and
Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR Part 180 by
establishing a 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 the crop group pome fruit at 1.0
parts per million (ppm) and in or on apple pomace at 3.0 ppm; fat of
cattle, goats, sheep and hogs at 0.25 ppm; liver of cattle, goats,
sheep and hogs at 0.075 ppm; meat and meatby-products of cattle, goats,
sheep and hogs at 0.05 ppm and milk at 0.05 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
[[Page 44440]]
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. High performance liquid chromatographic
(HPLC) analytical methods using ultraviolet (UV) or mass selective
detection have been validated for pome fruit, processed apple fractions
and animal commodities (meat, organ meats, fat and milk). 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 limits of quantitation is 0.02 ppm for pome fruit
and processed commodities, meat, meat organs and fat and 0.01 ppm for
milk.
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-hr 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. Genotoxicty. 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 concluded that tebufenozide is not mutagenic
or genotoxic.
3. Reproductive and developmental toxicity. --i. No Observable
Effect Levels (NOELs) for developmental and maternal toxicity to
tebufenozide were established at 1,000 mg/kg/day (Highest Dose Tested)
in both the rat and rabbit. No signs of developmental toxicity were
exhibited.
ii. In a 2-generation reproduction study in the rat, the
reproductive/developmental toxicity 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.
iii. 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
(1.9-2.3 mg/kg/day).
4. Subchronic toxicity. --i. 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
Lowest Observable Effect Level (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 = 1330 mg/kg/day for males, 1,650 mg/kg/day for females).
ii. 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
200 ppm.
iii. 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 reticulocyte.
iv. 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 6th week, 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.
v. 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.--i. 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 lowest-observed-
effect-level (LOEL) of 8.7 mg/kg/day. The NOEL in this study was 1.8
mg/kg/day.
ii. 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.
iii. 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
diet.
8. Endocrine disruption. The toxicology profile of tebufenozide
shows no evidence of physiological effects characteristic of the
disruption of the
[[Page 44441]]
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. The Reference Dose (RfD) represents the level
at or below which daily aggregate dietary exposure over a lifetime will
not pose appreciable risks to human health. The RfD is determined by
using the toxicological endpoint or the NOEL for the most sensitive
mammalian toxicology study. To assure the adequacy of the RfD, the
Agency uses an uncertainty factor, usually 100 to account for both
interspecies extrapolation and intraspecies variability represented by
the toxicological data. The RfD Committee of the USEPA Health Effects
Division established the RfD for tebufenozide at 0.018 milligrams (mg)/
kilogram (kg)/day based on the 1 year feeding study in dogs. An
uncertainty factor of 100 was applied to the NOEL of 1.8 mg/kg/day.
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
tolerances for the crop group pome fruit and for livestock commodities,
other petitions are pending for the following tolerances: pecans, wine
grapes (import tolerance), cotton, the crop subgroups leafy greens,
leaf petioles, head and stem Brassica and leafy Brassica greens, and
kiwifruit (import tolerance).
i. Acute risk. No appropriate acute dietary endpoint was identified
by the Agency. This risk assessment is not required.
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 theoretical maximum residue contribution (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 Theoretical Maximum Residue Contribution (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.
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
for tebufenozide.
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
insects.
Based on the overall pattern of toxicity produced by tebufenozide
in mammalian and insect systems, the compound's toxicity appears to be
[[Page 44442]]
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
considered.
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 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 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
pome fruit and proposed an MRL (Step 3) of 1.0 mg/kg.
2. PP 7F4819
EPA has received a pesticide petition (PP 7F4819) from Rohm and
Haas Company, 100 Independence Mall West, Philadelphia, PA. 19106-2399,
proposing pursuant to section 408(d) of the Federal Food, Drug and
Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR Part 180 by
establishing a 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 cottonseed and cotton gin trash at
1.5 and 30 parts per million (ppm) repectively. 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 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. The
metabolic pathway in rotation crops follows the same scheme as in other
soil, plant and animal studies although a greater proportion of
conjugated metabolites rather than parent were identified in these
crops.
2. Analytical method. High performance liquid chromatographic
(HPLC) analytical methods using ultraviolet (UV) or mass selective
detection have been validated for cottonseed, gin trash and cottonseed
processed fractions. 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 limits of quantitation are
0.01 ppm for cottonseed, meal and hulls and 0.025 ppm for refined oil
and gin trash.
3. Magnitude of residues. A total of 15 cotton residue trials were
conducted in the U.S. in geographically diverse regions. Four
applications of CONFIRM were made at 0.25 lb. a.i./A. Cotton was
harvested 13 to 14 days after the last application. Tebufenozide
residues in cottonseed ranged from 0.0405 to 1.43 ppm. The average
residue from all GAP trials is 0.448. Residues of tebufenozide in gin
trash ranged from 1.23 to 30.1 ppm. Residues did not concentrate in
cottonseed processed fractions (hulls, meal or refined oil).
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 milligram/
[[Page 44443]]
kilogram (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-hr 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. Genotoxicty. 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. --i. No Observable
Effect Levels (NOELs) for developmental and maternal toxicity to
tebufenozide were established at 1,000 milligrams/kilogram/day (mg/kg/
day) highest dose tested (HDT) in both the rat and rabbit. No signs of
developmental toxicity were exhibited.
ii. In a 2-generation reproduction study in the rat, the
reproductive/developmental toxicity 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.
iii. 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
(1.9-2.3 mg/kg/day).
4. Subchronic toxicity. --i. 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
lowest-observed-effect-level (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).
ii. 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
200 ppm.
iii. 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 reticulocyte.
iv. 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 6th week, 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.
v. In a 28-day dermal toxicity study in the rat, the NOEL was 1,000
mg/kg/day (HDT). 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. --i. 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.
ii. 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.
iii. 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). Extensive degradation and
elimination of polar metabolites occurs in animals such that residues
are unlikely to accumulate in humans or animals exposed to these
residues through the diet.
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. Tolerances have been established (40 CFR
180.482) for the residues of tebufenozide, in or on walnuts at 0.1 ppm.
A permanent tolerance at 1.0 ppm has also previously been established
for imported apples. Risk assessments were conducted by Rohm and Haas
to assess dietary exposures and risks from tebufenozide as follows:
2. Food. -- i. Acute exposure and risk. No acute endpoint was
identified for tebufenozide and no acute risk assessment is required.
ii. Chronic exposure and risk. For chronic dietary risk assessment,
only permanent (walnuts and imported apples) and the proposed
(cottonseed,
[[Page 44444]]
gin trash) tolerance values are used and the assumption that 100% of
all walnuts, imported apples and cottonseed meal and oil which are
consumed in the U.S. will contain residues of tebufenozide at the
tolerance levels. The Reference Dose (RfD) used for the chronic dietary
analysis is 0.018 mg/kg/day. Potential chronic exposures were estimated
using NOVIGEN'S Dietary Exposure Evaluation Model (DDEM Version 5.03b)
which uses USDA food consumption data from the 1989-1992 survey. With
the current and proposed tolerances for tebufenozide, the percentage of
the RfD utilized is 6.95% for the U.S. population as a whole and 46.2%
for non-nursing infants less than 1 year old. The chronic dietary risks
from these uses do not exceed EPA's level of concern.
3. Drinking water. Submitted environmental fate studies suggest
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 for tebufenozide. There is
no entry for tebufenozide in the ``Pesticides in Groundwater Database''
(EPA 734-12-92-001, September 1992).
Chronic exposure and risk. There are insufficient water-related
exposure data to complete a comprehensive drinking water 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 currently registered
for any indoor or outdoor residential uses; therefore, no non-dietary
residential exposure is anticipated.
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
insects.
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
considered.
E. Safety Determination
1. U.S. population. --i. Acute exposure and risk. Since no acute
endpoint was identified for tebufenozide, no acute risk assessment is
required.
ii. Chronic exposure and risk. Using the conservative exposure
assumptions described above and taking into account the completeness
and reliability of the toxicity data, the percentage of the RfD that
will be utilized by dietary (food only) exposure to residues of
tebufenozide from current (walnuts and imported apples) and proposed
(cottonseed, gin trash) tolerances is 6.95% for the U.S. population.
Aggregate exposure (food and water) are not expected to exceed 100%.
EPA generally has no concern for exposures below 100% of the RfD
because the RfD represents the level at or below which daily aggregate
dietary exposure over a lifetime will not pose appreciable risks to
human health. Rohm and Haas concludes that there is a reasonable
certainty that no harm will result from aggregate exposure to
tebufenozide residues to the U.S. population.
2. Infants and children. --i. Safety factor for infants and
children...In general. 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 maternal pesticide exposure
during gestation. Reproduction studies provide information relating to
effects from exposure to the pesticide on the reproductive capability
of mating animals and data on systemic toxicity.
ii. Developmental toxicity studies -- a. Rats. In a developmental
toxicity study in rats, the maternal (systemic) NOEL was 250 mg/kg/day.
The LOEL was 1,000 mg/kg/day based on decrease body weight and food
consumption. The developmental (pup) NOEL as > 1,000 mg/kg/day (HDT).
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 Rats. In a multigeneration
reproductive toxicity study in rats, the parental (systemic) NOEL was
0.85 mg/kg/day. Spleenic pigmentation changes and extramedullary
hematopoiesis occurred at the LOEL of 12.1 mg/kg/day. In addition to
these effects, decreased body weight gain and food consumption
[[Page 44445]]
occurred at 171.1 mg/kg/day. The reproductive (pup) NOEL was 12.1 mg/
kg/day. The reproductive LOEL of 171.1 mg/kg/day was based on a slight
increase in the number of pregnant females that did not deliver or had
difficulty and had to be sacrificed. Additionally at the LOEL, in F1
dams, the length of gestation increased and implantation sites
decreased significantly. In a 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).
iv. Pre- and post-natal sensitivity -- a. Pre-natal sensitivity.
The developmental NOELs of >1,000 mg/kg/day (HDT) from the
developmental toxicity studies in rats and rabbits demonstrate that
there is no developmental (prenatal) toxicity present for tebufenozide.
Additionally, these developmental NOELs are greater than 500-fold
higher than the NOEL of 1.8 mg/kg/day from the 1-year feeding study in
dogs which was the basis of the RfD.
b. Post-natal sensitivity. In the reproductive toxicity study in
rats, the reproductive NOEL (12.1 mg/kg/day from the first study; 149-
195 mg/kg/day from the second study) is between 14-fold higher than the
parental NOEL (0.85 mg/kg/day) in the first study and 83-fold higher
than the parental NOEL (1.8-2.3 mg/kg/day) in the second study. These
data indicate that post-natal toxicity in the reproductive studies
occurs only in the presence of significant parental toxicity. These
developmental and reproductive studies indicate that tebufenozide does
not have additional post-natal sensitivity for infants and children in
comparison to other exposed groups. 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.
v. Acute exposure and risk. Since no acute endpoint was identified
for tebufenozide, no acute risk assessment is required.
vi. Chronic exposure and risk. For chronic dietary risk assessment,
tolerance values are used and the assumption that all walnuts, imported
apples and cottonseed meal and oil which are consumed in the U.S. will
contain residues at the tolerance levels. The Theoretical Maximum
Residue Contribution (TMRC) from current and proposed food 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 (walnuts
and imported apples) and proposed (cottonseed, gin trash) tolerances
for tebufenozide, the percentage of the RfD that will be utilized by
dietary (food only) exposure to residues of tebufenozide is 46.2% for
non-nursing infants less than 1 year old. Aggregate exposure (food and
water) are not expected to exceed 100%. Rohm and Haas concludes that
there is a reasonable certainty that no harm will result from aggregate
exposure to tebufenozide residues to non-nursing infants.
F. International Tolerances
There are currently no CODEX or Canadian maximum residue levels
(MRLs) established for tebufenozide in cottonseed or gin trash. A
Mexican MRL of 0.5 ppm for cottonseed has been established.
3. PP 7F4824
EPA has received a pesticide petition (PP 7F4824) from Rohm and
Haas Company, 100 Independence mall West, Philadelphia, PA 19106-2399,
proposing pursuant to section 408(d) of the Federal Food, Drug and
Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR Part 180 by
establishing a 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 leafy greens, leaf petioles, head
and stem Brassica, and leafy Brassica greens at 6.0, 2.0, 2.0, and 10
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 and Animal 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.
2. Analytical method. A high performance liquid chromatographic
(HPLC) analytical method using ultraviolet (UV) detection has been
validated for leafy and cole crop vegetables. 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 for all representative crops
of these crop subgroups except for celery which is 0.05 ppm.
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-hr 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. Genotoxicty. 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. -- i. No Observable
Effect
[[Page 44446]]
Levels (NOELs) for developmental and maternal toxicity to tebufenozide
were established at 1,000 mg/kg/day (Highest Dose Tested) in both the
rat and rabbit. No signs of developmental toxicity were exhibited.
ii. In a 2-generation reproduction study in the rat, the
reproductive/developmental toxicity 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 wereobserved only at the 2,000 ppm
dose.
iii. 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
(1.9-2.3 mg/kg/day).
4. Subchronic toxicity. --i. 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
lowest-observed-effect-level (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).
ii. 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
200 ppm.
iii. 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 reticulocyte.
iv. 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 6th week, 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.
v. 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. --i. 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 Lowest Observed
Effect Level (LOEL) of 8.7 mg/kg/day. The NOEL in this study was 1.8
mg/kg/day.
ii. 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.
iii. 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
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. Use of an agricultural pesticide may result,
directly or indirectly in pesticide residues in food. These residues
are determined by chemical analysis. Data from field studies are
evaluated to determine the appropriate level of residue that would not
be exceeded if the pesticide were used according to the label use
directions.
In examining aggregate exposure, FQPA directs EPA to consider
available information concerning exposures from the pesticide residue
in food and all other non-occupational exposures. The primary non-food
sources of exposure the Agency looks at include drinking water (whether
from groundwater or surface water), and exposure through pesticide use
in gardens, lawns or buildings (residential and other indoor uses). In
evaluating food exposures, EPA takes into account varying consumption
patterns of major identifiable subgroups of consumers, including
infants and children.
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
tolerances for the crop subgroups leafy greens, leaf petioles, head and
stem Brassica and leafy Brassica greens, other petitions are pending
for the following tolerances: pome fruit, livestock commodities,
pecans, wine grapes (import tolerance), cotton, and kiwifruit (import
tolerance).
i. Acute risk. No appropriate acute dietary endpoint was identified
by the Agency. This risk assessment is not required.
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
[[Page 44447]]
tolerance level. The theoretical maximum residue contribution (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 Theoretical Maximum Residue Contribution (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 Reference Dose (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.
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
for tebufenozide.
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
insects.
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
considered.
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 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 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
[[Page 44448]]
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.
4. PP 7E4829
EPA has received a pesticide petition (PP 7E4829) from Rohm and
Haas Company, 100 Independence Mall West, Philadelphia, PA 19106-2399,
proposing pursuant to section 408(d) of the Federal Food, Drug and
Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR Part 180 by
establishing a 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 kiwifruit at 0.5 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
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.
2. Analytical method. A validated high performance liquid
chromatographic (HPLC) analytical method using ultraviolet (UV) or mass
selective detection is employed for measuring residues of tebufenozide
in kiwifruit. 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 0.02 ppm.
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-hr 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. Genotoxicty. 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. --i. No Observable
Effect Levels (NOELs) for developmental and maternal toxicity to
tebufenozide were established at 1,000 mg/kg/day (Highest Dose Tested)
in both the rat and rabbit. No signs of developmental toxicity were
exhibited.
ii. In a 2-generation reproduction study in the rat, the
reproductive/developmental toxicity 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.
iii. 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
(1.9-2.3 mg/kg/day).
4. Subchronic toxicity. --i. 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
lowest-observed-effect-level (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).
ii. 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
200 ppm.
iii. A 90-day dog feeding study gave a NOEL of 50 ppm (2.1 mg/kg/
day for males and females). TheLOEL was 500 ppm (20.1 and 21.4 mg/kg/
day for males and females, respectively). At the
[[Page 44449]]
LOEL,females exhibited a decrease in rate of weight gain and males
presented an increased reticulocyte.
iv. 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 6th week, 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.
v. 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. Chronic Feeding Toxicity and Carcinogenicity:
i. 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 Lowest Observed Effect Level (LOEL)
of 8.7 mg/kg/day. The NOEL in this study was 1.8 mg/kg/day.
ii. 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.
iii. 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
diet.
8. Endocrine disruption. Estrogenic Effects. 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. Use of an agricultural pesticide may result,
directly or indirectly in pesticide residues in food. These residues
are determined by chemical analysis. Data from field studies are
evaluated to determine the appropriate level of residue that would not
be exceeded if the pesticide were used according to the label use
directions.
In examining aggregate exposure, FQPA directs EPA to consider
available information concerning exposures from the pesticide residue
in food and all other non-occupational exposures. The primary non-food
sources of exposure the Agency looks at include drinking water (whether
from groundwater or surface water), and exposure through pesticide use
in gardens, lawns or buildings (residential and other indoor uses). In
evaluating food exposures, EPA takes into account varying consumption
patterns of major identifiable subgroups of consumers, including
infants and children.
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 kiwifruit, other petitions are pending for the
following tolerances: pome fruit, livestock commodities, pecans, wine
grapes (import tolerance), cotton, and the crop subgroups leafy greens,
leaf petioles, head and stem Brassica and leafy Brassica greens.
i. Acute risk. No appropriate acute dietary endpoint was identified
by the Agency. This risk assessment is not required.
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 theoretical maximum residue contribution (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 Theoretical Maximum Residue Contribution (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 Reference Dose (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.
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
[[Page 44450]]
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 for tebufenozide.
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
insects.
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
considered.
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 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 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.
[[Page 44451]]
5. PP 7F4863
EPA has received a pesticide petition (PP 7F4863) from Rohm and
Haas Company, 100 Independence Mall West, Philadelphia, PA. 19106-2399,
proposing pursuant to section 408(d) of the Federal Food, Drug and
Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR Part 180 by
establishing a 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 sugarcane molasses at
0.3 and 1.0 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
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.
2. Analytical method. A validated high performance liquid
chromatographic (HPLC) analytical method using ultraviolet (UV)
detection is employed for measuring residues of tebufenozide in
sugarcane, molasses and refined sugar. 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 for sugarcane, refined sugar and molasses is 0.01 ppm.
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-hr 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. Genotoxicty. 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. --i. No Observable
Effect Levels (NOELs) for developmental and maternal toxicity to
tebufenozide were established at 1,000 mg/kg/day (Highest Dose Tested)
in both the rat and rabbit. No signs of developmental toxicity were
exhibited.
ii. In a 2-generation reproduction study in the rat, the
reproductive/developmental toxicity 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.
iii. 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
(1.9-2.3 mg/kg/day).
4. Subchronic toxicity. --i. 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
lowest-observed-effect-level (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).
ii. 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
200 ppm.
iii. 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 reticulocyte.
iv. 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 6th week, 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.
v. 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. --i. 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 Lowest Observed
Effect Level (LOEL) of 8.7 mg/kg/day. The NOEL in this study was 1.8
mg/kg/day.
ii. 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.
iii. In a combined rat chronic/oncogenicity study, the NOEL for
chronic toxicity was 100 ppm (4.8 and
[[Page 44452]]
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
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. Use of an agricultural pesticide may result,
directly or indirectly in pesticide residues in food. These residues
are determined by chemical analysis. Data from field studies are
evaluated to determine the appropriate level of residue that would not
be exceeded if the pesticide were used according to the label use
directions.
In examining aggregate exposure, FQPA directs EPA to consider
available information concerning exposures from the pesticide residue
in food and all other non-occupational exposures. The primary non-food
sources of exposure the Agency looks at include drinking water (whether
from groundwater or surface water), and exposure through pesticide use
in gardens, lawns or buildings (residential and other indoor uses). In
evaluating food exposures, EPA takes into account varying consumption
patterns of major identifiable subgroups of consumers, including
infants and children. In examining aggregate exposure, FQPA directs EPA
to consider available information concerning exposures from the
pesticide residue in food and all other non-occupational exposures. The
primary non-food sources of exposure the Agency looks at include
drinking water (whether from groundwater or surface water), and
exposure through pesticide use in gardens, lawns or buildings
(residential and other indoor uses). In evaluating food exposures, EPA
takes into account varying consumption patterns of major identifiable
subgroups of consumers, including infants and children.
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
tolerance in or on sugarcane and sugarcane molasses, other petitions
are pending for the following tolerances: pome fruit, livestock
commodities, pecans, wine grapes (import tolerance), cotton, and the
crop subgroups leafy greens, leaf petioles, head and stem Brassica and
leafy Brassica greens and kiwifruit.
i. Acute risk. No appropriate acute dietary endpoint was identified
by the Agency. This risk assessment is not required.
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 theoretical maximum residue contribution (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 Theoretical Maximum Residue Contribution (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 28.9% of the Reference Dose (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 57.0% of the RfD. Using anticipate residue levels
for these crops utilizes 5.37% of the RfD for the U.S. population and
13.0% for non-nursing infants. The chronic dietary risks from these
uses do not exceed EPA's level of concern.
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
for tebufenozide. 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
[[Page 44453]]
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
insects.
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
considered.
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 28.9% of the RfD
for the U.S. population and 57.0% for non-nursing infants under 1 year
old. Using anticipate residue levels for these crops utilizes 5.37% of
the RfD for the U.S. population and 13.0% 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 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 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.
6. PP 7F4869
EPA has received PP 7F4869 from Rohm and Haas Company, 100
Independence Mall West, Philadelphia, PA. 19106-2399, proposing
pursuant to section 408(d) of the Federal Food, Drug and Cosmetic Act,
21 U.S.C. 346a(d), to amend 40 CFR Part 180 by establishing a 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 fruiting vegetables (except cucurbits) at 0.8
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
purposes of these tolerances. The metabolism of tebufenozide in all
crops was similar and involves oxidation of the alkyl
[[Page 44454]]
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.
2. Analytical method. A validated high performance liquid
chromatographic (HPLC) analytical method using ultraviolet (UV)
detection is employed for measuring residues of tebufenozide in
tomatoes, peppers and tomato processed fractions. 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 for all matrices is 0.02 ppm.
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-hr 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. Genotoxicty. 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. --i. No Observable
Effect Levels (NOELs) for developmental and maternal toxicity to
tebufenozide were established at 1,000 mg/kg/day (Highest Dose Tested)
in both the rat and rabbit. No signs of developmental toxicity were
exhibited.
ii. In a 2-generation reproduction study in the rat, the
reproductive/developmental toxicity 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.
iii. 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
(1.9-2.3 mg/kg/day).
4. Subchronic toxicity. --i. 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
lowest-observable-effect-level (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).
ii. 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
200 ppm.
iii. 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 reticulocyte.
iv. 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 6th week, 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.
v. 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. --i. 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 Lowest Observed
Effect Level (LOEL) of 8.7 mg/kg/day. The NOEL in this study was 1.8
mg/kg/day.
ii. 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.
iii. 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
[[Page 44455]]
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. Use of an agricultural pesticide may result,
directly or indirectly in pesticide residues in food. These residues
are determined by chemical analysis. Data from field studies are
evaluated to determine the appropriate level of residue that would not
be exceeded if the pesticide were used according to the label use
directions.
In examining aggregate exposure, FQPA directs EPA to consider
available information concerning exposures from the pesticide residue
in food and all other non-occupational exposures. The primary non-food
sources of exposure the Agency looks at include drinking water (whether
from groundwater or surface water), and exposure through pesticide use
in gardens, lawns or buildings (residential and other indoor uses). In
evaluating food exposures, EPA takes into account varying consumption
patterns of major identifiable subgroups of consumers, including
infants and children.
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 the crop group fruiting vegetables (except
cucurbits), other petitions are pending for the following tolerances:
pome fruit, livestock commodities, pecans, wine grapes (import
tolerance), cotton, and the crop subgroups leafy greens, leaf petioles,
head and stem Brassica and leafy Brassica greens, kiwifruit (import
tolerance) and sugarcane.
i. Acute risk. No appropriate acute dietary endpoint was identified
by the Agency. This risk assessment is not required.
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 theoretical maximum residue contribution (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 Theoretical Maximum Residue Contribution (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 28.9% of the Reference Dose (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 57.0% of the RfD. Using anticipate residue levels
for these crops utilizes 5.37% of the RfD for the U.S. population and
13.0% for non-nursing infants. The chronic dietary risks from these
uses do not exceed EPA's level of concern.
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
for tebufenozide.
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
[[Page 44456]]
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 insects.
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
considered.
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 28.9% of the RfD
for the U.S. population and 57.0% for non-nursing infants under 1 year
old. Using anticipate residue levels for these crops utilizes 5.37% of
the RfD for the U.S. population and 13.0% 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 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 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.
[FR Doc. 98-21747 Filed 8-18-98; 8:45 am]
BILLING CODE 6560-50-F