[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]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-821; FRL-6019-6]


Rohm and Haas Company; Pesticide Tolerance Petition Filing

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

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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