Tebufenozide - Pesticide Petition Filing 1/99
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ENVIRONMENTAL PROTECTION AGENCY
Notice of Filing of Pesticide Petitions
AGENCY: Environmental Protection Agency (EPA).
SUMMARY: This notice announces the initial filing of pesticide
petitions proposing the establishment of regulations for residues of
certain pesticide chemicals in or on various food commodities.
DATES: Comments, identified by the docket control number PF-856, must
be received on or before March 11, 1999.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch, Information Resources and Services Division
(7502C), Office of Pesticides Programs, Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments
to: Rm. 119, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically to: opp-
email@example.com. Follow the instructions under "SUPPLEMENTARY
INFORMATION." No confidential business information should be submitted
Information submitted as a comment concerning this document may be
claimed confidential by marking any part or all of that information as
"Confidential Business Information" (CBI). CBI should not be
submitted through e-mail. Information marked as CBI will not be
disclosed except in accordance with procedures set forth in 40 CFR part
2. A copy of the comment that does not contain CBI must be submitted
for inclusion in the public record. Information not marked confidential
may be disclosed publicly by EPA without prior notice. All written
comments will be available for public inspection in Rm. 1132 at the
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: The product manager listed in the
Product Manager telephone number Address
Joanne I. Miller (PM 23)...... Rm. 237, CM #2, 703- 1921 Jefferson
305-6224, e- Davis Hwy,
mail:miller.joanne@ep Arlington, VA
Sidney Jackson (PM 23)........ Rm. 233, CM #2, 703- Do.
SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as
follows proposing the establishment and/or amendment of regulations for
residues of certain pesticide chemicals in or on various food
commodities under section 408 of the Federal Food, Drug, and Comestic
Act (FFDCA), 21 U.S.C. 346a. EPA has determined that these petitions
contain data or information regarding the elements set forth in section
408(d)(2); however, EPA has not fully evaluated the sufficiency of the
submitted data at this time or whether the data supports granting of
the petition. Additional data may be needed before EPA rules on the
The official record for this notice of filing, as well as the
public version, has been established for this notice of filing under
docket control number [PF-856] (including comments and data submitted
electronically as described below). A public version of this record,
including printed, paper versions of electronic comments, which does
not include any information claimed as CBI, is available for inspection
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal
holidays. The official record is located at the address in
"ADDRESSES" at the beginning of this document.
Electronic comments can be sent directly to EPA at:
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption. Comments and data
will also be accepted on disks in Wordperfect 5.1 file format or ASCII
file format. All comments and data in electronic form must be
identified by the docket number (insert docket number) and appropriate
petition number. Electronic comments on notice may be filed online at
many Federal Depository Libraries.
List of Subjects
Environmental protection, Agricultural commodities, Food additives,
Feed additives, Pesticides and pests, Reporting and recordkeeping
Dated: January 29, 1999.
Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
Petitioner summaries of the pesticide petitions are printed below
as required by section 408(d)(3) of the FFDCA. The summaries of the
petitions were prepared by the petitioners and represent the views of
the petitioners. EPA is publishing the petition summaries verbatim
without editing them in any way. The petition summary announces the
availability of a description of the analytical methods available to
EPA for the detection and measurement of the pesticide chemical
residues or an explanation of why no such method is needed.
2. IR4 Project
PP 8E4983, 8E5019, 8E5020,8E5021, and 8E5024
EPA has received pesticide petitions (PP 8E4983, 8E5018, 8E5019,
8E5020, 8E5021, and 8E5024) from the Interregional Research Project
Number 4 (IR-4), 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 tolerances for residues of the insecticide,
tebufenozide (benzoic acid, 3,5-dimethyl-, 1-(1,1-dimethylethyl)-2-(4-
ethylbenzoyl)hydrazide) in or on the raw agricultural commodities.
1. PP 8E4983 proposed the establishment of a tolerance for
blueberries at 2.0 parts per million (ppm), and PP 8E5018 proposed a
tolerance for caneberries at 1.0 ppm. Subsequently, IR-4 amended these
tolerance proposals to include a single tolerance at 3.0 ppm for
berries (Crop Group 13) that will include both blueberries, and
caneberries under PP 8E4983.
2. PP 8E5024 proposes the establishment of tolerances for canola
seed at 1.75 ppm, and canola oil at 3.75 ppm.
3. PP 8E5019 proposes the establishment of a tolerance for
cranberries at 1.0 ppm.
4. PP 8E5021 proposes the establishment of a tolerance for mint at
5, PP 8E5020 proposes the establishment of tolerances for turnips
tops at 9.0 ppm, and turnip roots at 0.25 ppm.
EPA has determined that the 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 support granting of the
petitions. Additional data may be needed before EPA rules on the
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.
2. Analytical method. High performance liquid chromatographic
(HPLC) analytical methods using ultraviolet(UV) detection have been
validated for blueberries, raspberries, canola seed and oil,
cranberries, mint foliage and oil, and turnip roots and tops. 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 (LOQ) is 0.005 ppm for blueberries, 0.01 ppm for canola
seed and meal, mint foliage, raspberries, and turnip roots and tops,
0.02 ppm for mint oil, 0.03 ppm for canola soapstock and oil, and 0.05
ppm for cranberries.
3. Magnitude of residues. Field residue trials were conducted with
a 70 wettable power (WP) formulation in geographically representative
regions of the U.S. A total of 8 field residue trials were conducted in
blueberries. The average blueberry residue value from all trials was
A total of 7 field residue trials were conducted in canola. The
average canola seed residue value from all trials was 0.84 ppm. Two
processing studies were conducted. Average residues in meal, soapstock
and oil were 0.11 ppm, 0.83 ppm, and 1.75 ppm, respectively. Residues
did not concentrate in soapstock (Concentration Factor (CF) is less
than 1), and a tolerance in soapstock is not needed. For oil, the
average CF is 2.26, and the proposed tolerance is 3.75 ppm (2.26 times
A total of 6 field residue trials were conducted in cranberries.
The average cranberry residue value from all trials was 0.30 ppm.
A total of 5 field residue trials were conducted in mint. The
average mint foliage residue value from all trials was 7.11 ppm. Mint
oil was prepared from foliage from two residue trials. The average oil
residue was 0.23 ppm. Since residues do not concentrate in oil, a
tolerance is not needed.
A total of 5 field residue trials were conducted in raspberries.
The average raspberry residue value from all trials was 0.62 ppm.
A total of 6 field residue trials were conducted in turnips. The
average residue value from all trials was 0.10 ppm for roots, and 2.27
ppm for tops.
B. Toxicological Profile
1. Acute toxicity. Results of a battery of toxicological studies
show 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/kilograms (mg/kg)) and was
practically non-toxic by dermal application LD50 > 5,000 mg/
kg. Tebufenozide Technical was not significantly toxic to rats after a
4 hour inhalation exposure with an LC50 value of 4.5
mg/L (highest attainable concentration), is not considered
to be a primary eye irritant or a skin irritant, and is not a dermal
sensitizer. An acute neurotoxicity study in rats did not produce any
neurotoxic or neuropathologic effects.
2. 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. See discussion of
studies under section E.2. Infant and Children.
4. Subchronic toxicity-- i. The no-observed adverse effect level
(NOAEL) 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 adverse effect
level (LOAEL) was 2,000 ppm (133 mg/kg/day for males, 155 mg/kg/day for
females). Decreased body weight in males, and females was observed at
the LOAEL 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 (NOAEL = 1,330 mg/kg/day for
males, and 1,650 mg/kg/day for females).
ii. In a 90 day feeding study with mice, the NOAEL was 20 ppm (3.4
and 4.0 mg/kg/day for males and females, respectively). The LOAEL 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 LOAEL of
iii. A 90 day dog feeding study gave a NOAEL of 50 ppm (2.1 mg/kg/
day for males and females). The LOAEL was 500 ppm (20.1 and 21.4 mg/kg/
day for males and females, respectively). At the LOAEL, females
exhibited a decrease in rate of weight gain and males presented an
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 6 weeks, the dogs receiving treated
feed were switched to the control diet for 4 weeks. Hematological
parameters were measured in both groups prior to treatment, at the end
of the 6 weeks 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 NOAEL was
1,000 mg/kg/day highest dose tested (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/
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 LOAEL of 8.7 mg/kg/
day. The NOAEL 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
iii. In a combined rat chronic/oncogenicity study, the NOAEL for
chronic toxicity was 100 ppm (4.8 and 6.1 mg/kg/day for males and
females, respectively), and the LOAEL 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,
and 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, and hen). The metabolic
pathway common to both plants and animals involves oxidation of the
alkyl substituents (ethyl and methyl groups) of thearomatic rings
primarily at the benzylic positions. 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.
C. Aggregate Exposure
1. Dietary exposure--i. Food. Tolerances have been established (40
CFR 180.482) for the residues of tebufenozide, in or on a variety of
raw agricultural commodities. A permanent tolerance has been
established for the residues of tebufenozide in/on walnuts at 0.1 ppm,
and pecans at 0.05 ppm. Permanent tolerances at 0.5 ppm and 1.0 ppm
have been established for imported wine grapes, and apples,
respectively. Other proposed tolerances are pending. Risk assessments
were conducted by Rohm and Haas to assess dietary exposures and risks
from tebufenozide as follows:
ii. Acute exposure and risk. No acute endpoint was identified for
tebufenozide and no acute risk assessment is required.
iii. Chronic exposure and risk. For chronic dietary risk
assessment, it is assumed that 100% of all crops which are consumed
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. The existing and
proposed tebufenozide tolerances result in a theoretical maximum
residue contribution (TMRC) that is equivalent to 34.5% of the RfD for
the U.S. population, 61.4% of the RfD for infants, 70.4% of the RfD for
non-nursing infants (> 1 year old), and 79.8% of the RfD for chlidren 1
to 6 years old. The chronic dietary risks from these uses do not exceed
EPA's level of concern.
iv. 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).
v. 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.
Considering the precautionary language on the label and based on the
Registrant's knowledge of environmental occurrence of the chemicals,
significant exposure from residues of tebufenozide in drinking water is
2. 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, Rohm Haus concludes that 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).
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, according to Rohm Haus, 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
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 existing, pending and proposed tolerances is 34.5%
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-children-- i. 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
ii. Developmental toxicity studies-- a. Rats. In a developmental
toxicity study in rats, the maternal (systemic) NOAEL was 250 mg/kg/
day. The LOAEL was 1,000 mg/kg/day based on decrease body weight and
food consumption. The developmental (pup) NOAEL as > 1,000 mg/kg/day
b. Rabbits. In a developmental toxicity study in rabbits, the
maternal and developmental NOAELs were > 1,000 mg/kg/day HDT.
iii. Reproductive toxicity study rats. In a multigeneration
reproductive toxicity study in rats, the parental (systemic) NOAEL was
0.85 mg/kg/day. Spleenic pigmentation changes and extramedullary
hematopoiesis occurred at the LOAEL of 12.1 mg/kg/day. In addition to
these effects, decreased body weight gain and food consumption occurred
at 171.1 mg/kg/day. The reproductive (pup) NOAEL was 12.1 mg/kg/day.
The reproductive LOAEL 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 LOAEL, 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 NOAEL equal to 149-195 mg/kg/day) and
the NOAEL for systemic toxicity was determined to be 25 ppm (1.9-2.3
iv. Pre- and post-natal sensitivity-- a. Pre-natal sensitivity. The
developmental NOAELs 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 NOAELs are greater than 500-fold
higher than the NOAEL 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 NOAEL (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 NOAEL (0.85 mg/kg/day) in the first study and 83-fold higher
than the parental NOAEL (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-natalor post-natal sensitivity to children
and infants (that infants and children might be more sensitive than
adults) to tebufenozide exposure.
c. Acute exposure and risk. Since no acute endpoint was identified
for tebufenozide, no acute risk assessment is required.
d. Chronic exposure and risk. With the existing, pending and
proposed tolerances for tebufenozide, the percentage of the RfD that
will be utilized by dietary (food only) exposure to residues of
tebufenozide range from 39.9% for nursing infants less than 1 year old
to 79.8.% for children 1 to 6 years 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, Canadian or Mexican maximum residue
levels (MRLs) established for tebufenozide in blueberries, caneberries,
canola, cranberries, mint or turnips so no harmonization issues are
required for this action.
[FR Doc. 99-3146 Filed 2-8-99; 8:45 am]
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