[Federal Register Volume 64, Number 127 (Friday, July 2, 1999)]
[Notices]
[Pages 35999-36008]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-16768]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-878; FRL-6085-6]


Notice of Filing; Pesticide Petition

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

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SUMMARY: This notice announces the initial filing of pesticide 
petitions proposing the establishment of regulations for residues of 
certain pesticide chemicals in or on various food commodities.

DATES: Comments, identified by the docket control number PF-878, must 
be received on or before August 2, 1999.

ADDRESSES: By mail submit written comments to: Information and Records 
Integrity Branch, Public Information and Services Division (7502C), 
Office of Pesticides Programs, Environmental Protection Agency, 401 M 
St., SW., Washington, DC 20460. In person bring comments to: Rm. 1132, 
CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
    Comments and data may also be submitted electronically by following 
the instructions under ``SUPPLEMENTARY INFORMATION (CBI).'' No 
confidential business information (CBI) should be submitted through e-
mail.
    Information submitted as a comment concerning this document may be 
claimed confidential by marking any part or all of that information as 
CBI. CBI should not be submitted through e-mail. Information marked as 
CBI will not be disclosed except in accordance with procedures set 
forth in 40 CFR part 2. A copy of the comment that does not contain CBI 
must be submitted for inclusion in the public record. Information not 
marked confidential may be disclosed publicly by EPA without prior 
notice. All written comments will be available for public inspection in 
Rm. 1132 at the address given above, from 8:30 a.m. to 4 p.m., Monday 
through Friday, excluding legal holidays.

FOR FURTHER INFORMATION CONTACT: Joseph Tavano, Registration Support 
Branch, 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, Crystal 
Mall #2, 1921 Jefferson Davis Highway, Arlington, VA 22202, (703) 305-
6411; e-mail: [email protected].
SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as 
follows proposing the establishment and/or

[[Page 36000]]

amendment of regulations for residues of certain pesticide chemicals in 
or on various food commodities under section 408 of the Federal Food, 
Drug, and Comestic Act (FFDCA), 21 U.S.C. 346a. EPA has determined that 
this petition contains data or information regarding the elements set 
forth in section 408(d)(2); however, EPA has not fully evaluated the 
sufficiency of the submitted data at this time or whether the data 
supports granting of the petition. Additional data may be needed before 
EPA rules on the petition.
    The official record for this notice of filing, as well as the 
public version, has been established for this notice of filing under 
docket control number [PF-878] (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 file format or ASCII 
file format. All comments and data in electronic form must be 
identified by the docket control number (PF-878) and appropriate 
petition number. Electronic comments on this proposed rule may be filed 
online at many Federal Depository Libraries.

List of Subjects

    Environmental protection, Agricultural commodities, Feed additives, 
Food additives, Pesticides and pests, Reporting and recordkeeping 
requirements.

    Dated: June 23, 1999.

James Jones,

Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

    Petitioner summaries of the pesticide petitions are printed below 
as required by section 408(d)(3) of the FFDCA. The summaries of the 
petitions were prepared by the petitioners and represent the views of 
the petitioners. EPA is publishing the petition summaries verbatim 
without editing them in any way. The petition summary announces the 
availability of a description of the analytical methods available to 
EPA for the detection and measurement of the pesticide chemical 
residues or an explanation of why no such method is needed.

1. Rohm and Haas Company

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 tolerances for indirect or inadvertent residues of 
tebufenozide (benzoic acid, 3,5-dimethyl-1-(1,1- dimethylethyl)-2-(4-
ethylbenzoyl)hydrazide) and its metabolite RH-111,788 in or on the raw 
agricultural commodity (RAC) foliage of legume vegetables at 0.1 parts 
per million (ppm) and forage, fodder hay, and straw of cereal grains at 
0.5 ppm. EPA has determined that the petition contains data or 
information regarding the elements set forth in section 408(d)(2) of 
the FFDCA; however, EPA has not fully evaluated the sufficiency of the 
submitted data at this time or whether the data supports granting of 
the petition. Additional data may be needed before EPA rules on the 
petition.

A. Residue Chemistry

    1. Plant metabolism. The metabolism of tebufenozide in plants 
(grapes, apples, rice, and sugar beets) is adequately understood for 
the purpose of this tolerance. 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. Tebufenozide, the metabolite, benzoic acid, 
3,5-dimethyl-1-(1,1-dimethylethyl)-2-[4-(1-hydroxyethyl) benzoyl, and 
sugar conjugates of the metabolite were detected in a confined rotation 
crop study.
    2. Analytical method. Validated high performance liquid 
chromatographic (HPLC) analytical methods using ultraviolet (UV) or 
mass selective (MS) detection are employed for measuring residues of 
tebufenozide and its metabolite in grains, forage, fodder, stover, hay, 
and straw. 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 (LOQ) of the method for all 
matrices is 0.02 ppm for tebufenozide and its metabolite.
    3. Magnitude of residues. Field rotation crop residue trials were 
conducted and residues of tebufenozide and its metabolite were 
measured. Results of analyses showed that residues of tebufenozide and 
its metabolite will not exceed 0.1 ppm in forage of legumes and 0.5 ppm 
in forage, hay, or straw of cereal grains.

B. Toxicological Profile

    1. Acute toxicity--Acute toxicity studies with technical grade. 
Oral LD50 in the rat is > 5 grams for males and females (Ms/
Fs) - Toxicity Category IV; dermal LD50 in the rat is = 
5,000 milligrams/kilograms (mg/kg) for Ms/Fs - Toxicity Category III; 
inhalation LD50 in the rat is > 4.5 milligrams/per liter 
(mg/L) Toxicity Category III; primary eye irritation study in the 
rabbit is a non-irritant; primary skin irritation in the rabbit > 5 mg 
- Toxicity Category IV. Tebufenozide is not a sensitizer.
    2. Genotoxicty. Several mutagenicity tests were all negative. These 
include an Ames assay with and without metabolic activation, an in vivo 
cytogenetic assay in rat bone marrow cells, and in vitro chromosome 
aberration assay in CHO cells, a CHO/HGPRT assay, a reverse mutation 
assay with E. Coli, and an unscheduled DNA synthesis assay (UDS) in rat 
hepatocytes.
    3. Reproductive and developmental toxicity--i. In a prenatal 
developmental toxicity study in Sprague-Dawley rats 25/group 
tebufenozide was administered on gestation days 6-15 by gavage in 
aqueous methyl cellulose at dose levels of 50, 250, or 1,000 mg/kg/day 
and a dose volume of 10 milliliters/kilograms (ml/kg). There was no 
evidence of maternal or developmental toxicity; the maternal and 
developmental toxicity NOAEL was 1,000 mg/kg/day.
    ii. In a prenatal developmental toxicity study conducted in New 
Zealand white rabbits 20/group, tebufenozide was administered in 5 ml/
kg of aqueous methyl cellulose at gavage doses of 50, 250, or 1,000 mg/
kg/day on gestation days 7-19. No evidence of maternal or developmental 
toxicity was observed; the maternal and developmental toxicity no-
observed adverse effect level (NOAEL) was 1,000 mg/kg/day.

[[Page 36001]]

    iii. In a 1993 2-generation reproduction study in Sprague-Dawley 
rats, tebufenozide was administered at dietary concentrations of 0, 10, 
150, or 1,000 ppm (0, 0.8, 11.5, or 154.8 mg/kg/day for males and 0, 
0.9, 12.8, or 171.1 mg/kg/day for females). The parental systemic NOAEL 
was 10 ppm (0.8/0.9 mg/kg/day for Ms/Fs, respectively) and the lowest-
observed adverse effect level (LOAEL) was 150 ppm (11.5/12.8 mg/kg/day 
for Ms/Fs, respectively) based on decreased body weight (bwt) gain, and 
food consumption in males, and increased incidence and/or severity of 
splenic pigmentation. In addition, there was an increased incidence and 
severity of extramedullary hematopoiesis at 2,000 ppm. The reproductive 
NOAEL was 150 ppm. (11.5/12.8 mg/kg/day for Ms/Fs, respectively) and 
the LOAEL was 2,000 ppm (154.8/171.1 mg/kg/day for Ms/Fs, respectively) 
based on an increase in the number of pregnant females with increased 
gestation duration and dystocia. Effects in the offspring consisted of 
decreased number of pups per litter on postnatal days 0 and/or 4 at 
2,000 ppm (154.8/171.1 mg/kg/day for Ms/Fs, respectively) with a NOAEL 
of 150 ppm (11.5/12.8 mg/kg/day for Ms/Fs, respectively).
    iv. In a 1995 2-generation reproduction study in rats, tebufenozide 
was administered at dietary concentrations of 0, 25, 200, or 2,000 ppm 
(0, 1.6, 12.6, or 126.0 mg/kg/day for males and 0, 1.8, 14.6, or 143.2 
mg/kg/day for females). For parental systemic toxicity, the NOAEL was 
25 ppm (1.6/1.8 mg/kg/day in Ms/Fs, respectively), and the was 200 ppm 
(12.6/14.6 mg/kg/day in Ms/Fs), based on histopathological findings 
(congestion and extramedullary hematopoiesis) in the spleen. 
Additionally, at 2,000 ppm (126.0/143.2 mg/kg/day in Ms/Fs), treatment-
related findings included reduced parental bwt gain and increased 
incidence of hemosiderin-laden cells in the spleen. Columnar changes in 
the vaginal squamous epithelium and reduced uterine and ovarian weights 
were also observed at 2,000 ppm, but the toxicological significance was 
unknown. For offspring, the systemic NOAEL was 200 ppm. (12.6/14.6 mg/
kg/day in Ms/Fs), and the LOAEL was 2,000 ppm (126.0/143.2 mg/kg/day in 
Ms/Fs) based on decreased bwt on postnatal days 14 and 21.
    4. Subchronic toxicity. In a 21-day dermal toxicity study, Crl: CD 
rats (6/sex/dose) received repeated dermal administration of either the 
technical 96.1% product RH-75,992 at 1,000 mg/kg/day limit dose (LTD) 
or the formulation 23.1% a.i. product RH-755,992 2F at 0, 62.5, 250, or 
1,000 mg/kg/day, 6 hours/day, 5 days/week for 21 days. Under conditions 
of this study, RH-75,992 Technical or RH-75,992 2F demonstrated no 
systemic toxicity or dermal irritation at the highest dose tested (HDT) 
1,000 mg/kg/ during the 21 day study. Based on these results, the NOAEL 
for systemic toxicity and dermal irritation in both sexes is 1,000 mg/
kg/day HDT. A LOAEL for systemic toxicity and dermal irritation was not 
established.
    5. Chronic toxicity--i. In a 1-year dog feeding study with a LOAEL 
of 250 ppm, 9 mg/kg/day for Ms/Fs dogs based on decreases in red blood 
cells (RBC), HCT, and HGB, increases in Heinz bodies, methemoglobin, 
MCV, MCH, reticulocytes, platelets, plasma total bilirubin, spleen 
weight, and spleen/bwt ratio, and liver/bwt ratio. Hematopoiesis and 
sinusoidal engorgement occurred in the spleen, and hyperplasia occurred 
in the marrow of the femur and sternum. The liver showed an increased 
pigment in the Kupffer cells. The NOAEL for systemic toxicity in both 
sexes is 50 ppm (1.9 mg/kg/day).
    ii. An 18-month mouse carcinogenicity study with no carcinogenicity 
observed at dosage levels up to and including 1,000 ppm.
    iii. A 2-year rat carcinogenicity with no carcinogenicity observed 
at dosage levels up to and including 2,000 ppm (97 mg/kg/day and 125 
mg/kg/day for Ms/Fs, respectively).
    6. Animal metabolism. The pharmacokinetics and metabolism of 
tebufenozide were studied in female Sprague-Dawley rats (3-6/sex/group) 
receiving a single oral dose of 3 or 250 mg/kg of RH-5992 
14C labeled in one of three positions (A-ring, B-ring or N-
butylcarbon). The extent of absorption was not established. The 
majority of the radiolabeled material was eliminated or excreted in the 
feces within 48 hours within 48 hours; small amounts (1 to 7% of the 
administered dose) were excreted in the urine and only traces were 
excreted in expired air or remained in the tissues. There was no 
tendency for bioaccumulation. Absorption and excretion were rapid. A 
total of 11 metabolites, in addition to the parent compound, were 
identified in the feces; the parent compound accounted for 96 to 99% of 
the administered radioactivity in the high dose group and 35 to 43% in 
the low dose group. No parent compound was found in the urine; urinary 
metabolites were not characterized. The identity of several fecal 
metabolites was confirmed by mass spectral analysis and other fecal 
metabolites were tentatively identified by cochromatography with 
synthetic standards. A pathway of metabolism was proposed based on 
these data. Metabolism proceeded primarily by oxidation of the three 
benzyl carbons, two methyl groups on the B-ring and an ethyl group on 
the A-ring to alcohols, aldehydes or acids. The type of metabolite 
produced varies depending on the position oxidized and extent of 
oxidation. The butyl group on the quaternary nitrogen also can be 
cleaved (minor), but there was no fragmentation of the molecule between 
the benzyl rings.
    No qualitative differences in metabolism were observed between 
sexes, when high or low dose groups were compared or when different 
labeled versions of the molecule were compared.
    7. Metabolite toxicology. The absorption and metabolism of 
tebufenozide were studied in a group of M/F bile-duct cannulated rats. 
Over a 72-hour period, biliary excretion accounted for 30% M to 34% F 
of the administered dose while urinary excretion accounted for about 5% 
of the administered dose and the carcass accounted for < 0.5% of the 
administered dose for both Ms/Fs. Thus systemic absorption (percent of 
dose recovered in the bile, urine and carcass) was 35% M to 39% F. The 
majority of the radioactivity in the bile (20% M to 24% F of the 
administered dose) was excreted within the first 6 hours post-dosing 
indicating rapid absorption. Furthermore, urinary excretion of the 
metabolites was essentially complete within 24 hours post-dosing. A 
large amount 67% F to 70% M of the administered dose was unabsorbed and 
excreted in the feces by 72 hours. Total recovery of radioactivity was 
105% of the administered dose.
    A total of 13 metabolites were identified in the bile; the parent 
compound was not identified, i.e. unabsorbed compound, nor were the 
primary oxidation products seen in the feces in the pharmacokinetics 
study. The proposed metabolic pathway proceeded primarily by oxidation 
of the benzylic carbons to alcohols, aldehydes, or acids. Bile 
contained most of the other highly oxidized products found in the 
feces. The most significant individual bile metabolites accounted for 
5% to 18% of the total radioactivity (F and/or M). Bile also contained 
the previously undetected (in the pharmacokinetics study) ``A'' ring 
ketone and the ``B'' ring diol. The other major components were 
characterized as high molecular weight conjugates. No individual bile 
metabolite for > 5% of the total administered dose. Total bile

[[Page 36002]]

radioactivity accounted for about 17% of the total administered dose.
    No major qualitative differences in biliary metabolites were 
observed between sexes. The metabolic profile in the bile was similar 
to the metabolic profile in the feces and urine.

C. Aggregate Exposure

    1. Dietary exposure--From food and feed uses. Tolerances have been 
established (40 CFR 180.482) for the residues of tebufenozide, in or on 
walnuts at 0.1 ppm, apples at 1.0 ppm, pecans at 0.01 ppm and wine 
grapes at 0.5 ppm. Numerous section 18 tolerances have been established 
at levels ranging from 0.3 ppm in sugar beet roots to 5.0 ppm in turnip 
tops. Other tolerance petitions are pending at EPA with proposed 
tolerances ranging from 0.5 ppm in or on kiwifruit to 10 ppm in leafy 
and cole crop vegetables. The current petition requests establishment 
of tolerances due to indirect or inadvertent residues of tebufenozide 
and its metabolite in or on foliage of legume vegetables and forage, 
straw, and hay of cereal grains. Risk assessments were conducted by 
Rohm and Haas to assess dietary exposures and risks from tebufenozide, 
benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl) 
hydrazide and are presented in the following discussion.
    2. Food--i. Acute exposure and risk. Acute dietary risk assessments 
are performed for a food-use pesticide if a toxicological study has 
indicated the possibility of an effect of concern occurring as a result 
of a 1-day or single exposure. Toxicity observed in oral toxicity 
studies were not attributable to a single dose (exposure). No neuro- or 
systemic toxicity was observed in rats given a single oral 
administration of tebufenozide at 0, 500, 1,000 or 2,000 mg/kg. No 
maternal or developmental toxicity was observed following oral 
administration of tebufenozide at 1,000 mg/kg/day LTD during gestation 
to pregnant rats or rabbits. This risk is considered to be negligible.
    ii. Chronic exposure and risk. The RfD used for the chronic dietary 
analysis is 0.018 mg/kg/day. In conducting this chronic dietary (food) 
exposure assessment, Rohm and Haas used tolerance level residues for 
pecans, walnuts, wine, and sherry, imported apples and all other 
commodities with established or pending tebufenozide tolerances; and 
percent crop-treated (%CT) information on some of these crops. Further 
refinement using anticipated residue values and additional %CT 
information would result in a lower estimate of chronic dietary 
exposure. The Novigen DEEM system was used for this chronic dietary 
exposure analysis. The subgroups listed below are the U.S. population 
(48 contiguous States); those for infants and children; and the other 
subgroups (adult) for which the percentage of the RfD occupied is 
greater than that occupied by the subgroup U.S. population (48 
contiguous States). The results are summarized below:

------------------------------------------------------------------------
               Groups                          RfD (Percentage)
------------------------------------------------------------------------
U.S. Population.....................                                10.0
All Infants (<1 year)...............                                12.2
Nursing Infants (<1 year old).......                                 5.7
Non-Nursing Infants (<1 year old)...                                15.0
Children (1-6 years old)............                                22.5
Children (7-12 years old)...........                                14.1
Females (13 + years old, nursing)...                                10.1
U.S. Population (autumn season).....                                10.3
U.S. Population (winter season).....                                10.1
Non-Hispanic Blacks.................                                10.4
Non-Hispanic Other than Black or                                    11.0
 White..............................
Northeast Region....................                                10.3
Southern Region.....................                                10.1
Western Region......................                                10.5
Pacific Region......................                                10.7
------------------------------------------------------------------------

    3. Drinking water--i.  Acute exposure and risk. Because no acute 
dietary endpoint was determined, Rohm and Haas concludes that there is 
a reasonable certainty of no harm from acute exposure from drinking 
water.
    ii. Chronic exposure and risk. Submitted environmental fate studies 
suggest that tebufenozide is moderately persistent to persistent and 
mobile. Under certain conditions, tebufenozide appears to have the 
potential to contaminate ground and surface water through runoff and 
leaching; subsequently potentially contaminating drinking water. There 
are no established Maximum Contaminant Levels (MCL) for residues of 
tebufenozide in drinking water and no Health Advisories (HA) have been 
issued for tebufenozide; therefore, these could not be used as 
comparative values for risk assessment. Therefore, potential residue 
levels for drinking water exposure were calculated previously by EPA 
using GENEEC (surface water) and SCIGROW (ground water) for human 
health risk assessment. Because of the wide range of half-life values 
(66-729 days) reported for the aerobic soil metabolism input parameter 
a range of potential exposure values were calculated. In each case, the 
worst case upper bound exposure limits were then compared appropriate 
chronic drinking water level of concern (DWLOC). In each case, the 
calculated exposures based on model data were below the DWLOC.
    4. Non-dietary exposure. Tebufenozide is not currently registered 
for use on any residential non-food sites. Therefore there is no 
chronic, short- or intermediate-term exposure scenario.

D. Cumulative Effects

    Section 408(b)(2)(D)(v) requires that, when considering whether to 
establish, modify, or revoke a tolerance, the Agency consider 
``available information'' concerning the cumulative effects of a 
particular pesticide's residues and ``other substances that have a 
common mechanism of toxicity.'' The Agency believes that ``available 
information'' in this context might include not only toxicity, 
chemistry, and exposure data, but also scientific policies and 
methodologies for understanding common mechanisms of toxicity and 
conducting cumulative risk assessments. For most pesticides, although 
the Agency has some information in its files that may turn out to be 
helpful in eventually determining whether a pesticide shares a common 
mechanism of toxicity with any other

[[Page 36003]]

substances, EPA does not at this time have the methodologies to resolve 
the complex scientific issues concerning common mechanism of toxicity 
in a meaningful way. EPA has begun a pilot process to study this issue 
further through the examination of particular classes of pesticides. 
The Agency hopes that the results of this pilot process will increase 
the Agency's scientific understanding of this question such that EPA 
will be able to develop and apply scientific principles for better 
determining which chemicals have a common mechanism of toxicity and 
evaluating the cumulative effects of such chemicals. The Agency 
anticipates, however, that even as its understanding of the science of 
common mechanisms increases, decisions on specific classes of chemicals 
will be heavily dependent on chemical-specific data, much of which may 
not be presently available.
    Although at present the Agency does not know how to apply the 
information in its files concerning common mechanism issues to most 
risk assessments, there are pesticides as to which the common mechanism 
issues can be resolved. These pesticides include pesticides that are 
toxicologically dissimilar to existing chemical substances (in which 
case the Agency can conclude that it is unlikely that a pesticide 
shares a common mechanism of activity with other substances) and 
pesticides that produce a common toxic metabolite (in which case common 
mechanism of activity will be assumed).
    EPA does not have, at this time, available data to determine 
whether tebufenozide, benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-
2-(4-ethylbenzoyl) hydrazide has a common mechanism of toxicity with 
other substances or how to include this pesticide in a cumulative risk 
assessment. Unlike other pesticides for which EPA has followed a 
cumulative risk approach based on a common mechanism of toxicity, 
tebufenozide, benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-
ethylbenzoyl) hydrazide does not appear to produce a toxic metabolite 
produced by other substances. For the purposes of this tolerance 
action, therefore, Rohm and Haas has not assumed that tebufenozide, 
benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl) 
hydrazide has a common mechanism of toxicity with other substances.

E. Safety Determination

    1. U.S. population--i  Acute risk. Since no acute toxicological 
endpoints were established, no acute aggregate risk exists.
    ii. Chronic risk. Using the conservative exposure assumptions 
described above, and taking into account the completeness and 
reliability of the toxicity data, Rohm and Haas has concluded that 
dietary (food only) exposure to tebufenozide will utilize 10.0% of the 
RfD for the U.S. population. Submitted environmental fate studies 
suggest that tebufenozide is moderately persistent to persistent and 
mobile; thus, tebufenozide could potentially leach to ground water and 
runoff to surface water under certain environmental conditions. The 
modeling data for tebufenozide indicate levels less than OPP's drinking 
water level of concern (DWLOC). EPA generally has no concern for 
exposures below 100% of the RfD because the RfD represents the level at 
or below which daily aggregate dietary exposure over a lifetime will 
not pose appreciable risks to human health. There are no registered 
residential uses of tebufenozide. Since there is no potential for 
exposure to tebufenozide from residential uses, Rohm and Haas does not 
expect the aggregate exposure to exceed 100% of the RfD.
    iii. Short- and intermediate-term risk. Short- and intermediate-
term aggregate exposure takes into account chronic dietary food and 
water (considered to be a background exposure level) plus indoor and 
outdoor residential exposure. Since there are currently no registered 
indoor or outdoor residential non-dietary uses of tebufenozide and no 
short- or intermediate-term toxic endpoints, short- or intermediate-
term aggregate risk does not exist.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of tebufenozide, 
benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl) 
hydrazide, EPA previously considered data from developmental toxicity 
studies in the rat and rabbit and a 2-generation reproduction study in 
the rat. The developmental toxicity studies are designed to evaluate 
adverse effects on the developing organism resulting from maternal 
pesticide exposure gestation. Reproduction studies provide information 
relating to effects from exposure to the pesticide on the reproductive 
capability of mating animals and data on systemic toxicity.
    FFDCA section 408 provides that EPA shall apply an additional 
tenfold margin of safety for infants and children in the case of 
threshold effects to account for pre-and postnatal toxicity and the 
completeness of the data base unless EPA determines that a different 
margin of safety will be safe for infants and children. Margins of 
safety are incorporated into EPA risk assessments either directly 
through use of a MOE analysis or through using uncertainty (safety) 
factors in calculating a dose level that poses no appreciable risk to 
humans. EPA believes that reliable data support using the standard 
uncertainty factor (usually 100 for combined inter- and intra-species 
variability) and not the additional tenfold MOE/uncertainty factor when 
EPA has a complete data base under existing guidelines and when the 
severity of the effect in infants or children or the potency or unusual 
toxic properties of a compound do not raise concerns regarding the 
adequacy of the standard MOE/safety factor.
    3. Developmental toxicity studies--i. Rats. In a developmental 
toxicity study in rats, the maternal (systemic) NOAEL was 250 mg/kg/
day. The LOAEL was 1,000 mg/kg/day, based on decreased bwt and food 
consumption. The developmental (pup) NOAEL was 1,000 mg/kg/day (HGT)
    ii. Rabbits. In a developmental toxicity study in rabbits, the 
maternal and developmental NOAELs were 1,000 mg/kg/day highest dose 
tested (HDT).
    iii. Reproductive toxicity study. In a 1993 2-generation 
reproduction study in Sprague-Dawley rats, tebufenozide was 
administered at dietary concentrations of 0, 10, 150, or 1,000 ppm (0, 
0.8, 11.5, or 154.8 mg/kg/day for Ms and 0, 0.9, 12.8, or 171.1 mg/kg/
day for Fs).The parental systemic NOAEL was 10 ppm (0.8/0.9 mg/kg/day 
for Ms/Fs, respectively) and the LOAEL was 150 ppm (11.5/12.8 mg/kg/day 
for Ms/Fs, respectively) based on decreased bwt gain, and food 
consumption in males, and increased incidence and/or severity of 
splenic pigmentation. In addition, there was an increased incidence and 
severity of extramedullary hematopoiesis at 2,000 ppm. The reproductive 
NOAEL was 150 ppm (11.5/12.8 mg/kg/day for Ms/Fs, respectively) and the 
LOAEL was 2,000 ppm (154.8/171.1 mg/kg/day for Ms/Fs, respectively) 
based on an increase in the number of pregnant females with increased 
gestation duration and dystocia. Effects in the offspring consisted of 
decreased number of pups per litter on postnatal days 0 and/or 4 at 
2,000 ppm (154.8/171.1 mg/kg/day for Ms/Fs, respectively) with a NOAEL 
of 150 ppm (11.5/12.8 mg/kg/day for Ms/Fs, respectively).
    In a 1995 2-generation reproduction study in rats, tebufenozide was 
administered at dietary concentrations of 0, 25, 200, or 2,000 ppm (0, 
1.6, 12.6, or 126.0 mg/kg/day for males and 0, 1.8, 14.6, or 143.2 mg/
kg/day for females). For parental systemic toxicity, the

[[Page 36004]]

NOAEL was 25 ppm (1.6/1.8 mg/kg/day in Ms/Fs, respectively), and the 
LOAEL was 200 ppm (12.6/14.6 mg/kg/day in males and females), based on 
histopathological findings (congestion and extramedullary 
hematopoiesis) in the spleen. Additionally, at 2,000 ppm (126.0/143.2 
mg/kg/day in Ms/Fs), treatment-related findings included reduced 
parental body weight gain and increased incidence of hemosiderin-laden 
cells in the spleen. Columnar changes in the vaginal squamous 
epithelium and reduced uterine and ovarian weights were also observed 
at 2,000 ppm, but the toxicological significance was unknown. For 
offspring, the systemic NOAEL was 200 ppm (12.6/14.6 mg/kg/day in Ms/
Fs), and the LOAEL was 2,000 ppm (126.0/143.2 mg/kg/day in M/F) based 
on decreased bwt on postnatal days 14 and 21.
    iv. Pre- and postnatal sensitivity. The toxicology data base for 
tebufenozide is complete and includes acceptable developmental toxicity 
studies in both rats and rabbits as well as a 2-generation reproductive 
toxicity studies in rats. EPA determined that the data provided no 
indication of increased sensitivity of rats or rabbits to in utero and/
or postnatal exposure to tebufenozide. No maternal or developmental 
findings were observed in the prenatal developmental toxicity studies 
at doses up to 1,000 mg/kg/day in rats and rabbits. In the 2-generation 
reproduction studies in rats, effects occurred at the same or lower 
treatment levels in the adults as in the offspring.
    4.  Acute risk. Since no acute toxicological endpoints were 
established, no acute aggregate risk exists.
    5. Chronic risk. Using the conservative exposure assumptions 
described above, Rohm and Haas has concluded that aggregate exposure to 
tebufenozide, benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-
ethylbenzoyl) hydrazide from food will utilize from 10.0% of the RfD 
for the U.S. population to 22.5% of the RfD for children 1-6 years old. 
The potential for exposure to tebufenozide in drinking water does not 
exceed EPA's level of concern. There are currently no tebufenozide 
residential or non-dietary exposure scenarios. EPA generally has no 
concern for exposures below 100% of the RfD because the RfD represents 
the level at or below which daily aggregate dietary exposure over a 
lifetime will not pose appreciable risks to human health. Rohm and Haas 
does not expect the aggregate exposure to exceed 100% of the RfD. Rohm 
and Haas concludes that there is a reasonable certainty that no harm 
will result to infants and children from aggregate exposure to 
tebufenozide, benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-
ethylbenzoyl) hydrazide residues.
    6. Short- or intermediate-term risk. Since no short- and 
intermediate-term toxicological endpoints were established by EPA, no 
acute aggregate risk exists.

F. International Tolerances

    There are currently no CODEX, Canadian or Mexican maximum residue 
levels (MRLs) established for tebufenozide in rotation crops so no 
harmonization issues are required for this action.

2. Rohm and Haas Company

 9F5077

    EPA has received a pesticide petition (9F5077) 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 (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by 
establishing a tolerance for residues of tebufenozide (benzoic acid, 
3,5-dimethyul-,1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl)hydrazide) in or 
on the RAC crop grouping, tree nuts, at 0.1 ppm and in or almond hulls 
at 25 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 
purpose of this tolerance. The metabolism of tebufenozide in all crops 
was similar and involves oxidation of the alkyl substituents of the 
aromatic rings primarily at the benzylic positions. The extent of 
metabolism and degree of oxidation are a function of time from 
application to harvest. In all crops, parent compound comprised the 
majority of the total dosage. None of the metabolites were in excess of 
10% of the total dosage.
    2. Analytical method. Validated high performance liquid 
chromatographic (HPLC) analytical methods using ultraviolet (UV) or 
mass selective (MS) detection are employed for measuring residues of 
tebufenozide and its metabolite in nut meat and almond hulls. 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 (LOQ) of the method for all matrices is 0.01 ppm for 
tebufenozide.
    3. Magnitude of residues. Field residue trials were conducted in 
the representative nut crops pecans and almonds and residues of 
tebufenozide were measured in nut meat and almond hulls. Results of 
analyses showed that residues of tebufenozide will not exceed 0.1 ppm 
in nut meat and 25 ppm in almond hulls.

B. Toxicological Profile

    1. Acute toxicity. Acute toxicity studies with technical grade. 
Oral LD50 in the rat is > 5 grams for Ms/Fs - Toxicity 
Category IV; dermal LD50 in the rat is = 5,000 mg/kg for Ms/
Fs - Toxicity Category III; inhalation LD50 in the rat is > 
4.5 mg/l - Toxicity Category III; primary eye irritation study in the 
rabbit is a non-irritant; primary skin irritation in the rabbit > 5 mg 
- Toxicity Category IV. Tebufenozide is not a sensitizer.
    2. Genotoxicty. Several mutagenicity tests were all negative. These 
include an Ames assay with and without metabolic activation, an in vivo 
cytogenetic assay in rat bone marrow cells, and in vitro chromosome 
aberration assay in CHO cells, a CHO/HGPRT assay, a reverse mutation 
assay with E. Coli, and an unscheduled DNA synthesis assay (UDS) in rat 
hepatocytes.
    3. Reproductive and developmental toxicity--i. In a prenatal 
developmental toxicity study in Sprague-Dawley rats (25/group), 
tebufenozide was administered on gestation days 6-15 by gavage in 
aqueous methyl cellulose at dose levels of 50, 250, or 1,000 mg/kg/day 
and a dose volume of 10 ml/kg. There was no evidence of maternal or 
developmental toxicity; the maternal and developmental toxicity NOAEL 
was 1,000 mg/kg/day.
    ii. In a prenatal developmental toxicity study conducted in New 
Zealand white rabbits 20/group, tebufenozide was administered in 5 ml/
kg of aqueous methyl cellulose at gavage doses of 50, 250, or 1,000 mg/
kg/day on gestation days 7-19. No evidence of maternal or developmental 
toxicity was observed; the maternal and developmental toxicity NOAEL 
was 1,000 mg/kg/day.
    iii. In a 1993 2-generation reproduction study in Sprague-Dawley 
rats, tebufenozide was administered at dietary concentrations of 0, 10, 
150, or 1,000 ppm (0, 0.8, 11.5, or 154.8 mg/kg/

[[Page 36005]]

day for males and 0, 0.9, 12.8, or 171.1 mg/kg/day for females). The 
parental systemic NOAEL was 10 ppm (0.8/0.9 mg/kg/day for M/F, 
respectively) and the LOAEL was 150 ppm (11.5/12.8 mg/kg/day for Ms/Fs, 
respectively) based on decreased bwt gain, and food consumption in 
males, and increased incidence and/or severity of splenic pigmentation. 
In addition, there was an increased incidence and severity of 
extramedullary hematopoiesis at 2,000 ppm. The reproductive NOAEL was 
150 ppm. (11.5/12.8 mg/kg/day for M/F, respectively) and the LOAEL was 
2,000 ppm (154.8/171.1 mg/kg/day for M/F, respectively) based on an 
increase in the number of pregnant females with increased gestation 
duration and dystocia. Effects in the offspring consisted of decreased 
number of pups per litter on postnatal days 0 and/or 4 at 2,000 ppm 
(154.8/171.1 mg/kg/day for Ms/Fs, respectively) with a NOAEL of 150 ppm 
(11.5/12.8 mg/kg/day for Ms/Fs, respectively).
    iv. In a 1995 2-generation reproduction study in rats, tebufenozide 
was administered at dietary concentrations of 0, 25, 200, or 2,000 ppm 
(0, 1.6, 12.6, or 126.0 mg/kg/day for males and 0, 1.8, 14.6, or 143.2 
mg/kg/day for females). For parental systemic toxicity, the NOAEL was 
25 ppm (1.6/1.8 mg/kg/day in Ms/Fs, respectively), and the LOAEL was 
200 ppm (12.6/14.6 mg/kg/day in Ms/Fs), based on histopathological 
findings (congestion and extramedullary hematopoiesis) in the spleen. 
Additionally, at 2,000 ppm (126.0/143.2 mg/kg/day in Ms/Fs), treatment-
related findings included reduced parental bwt gain and increased 
incidence of hemosiderin-laden cells in the spleen. Columnar changes in 
the vaginal squamous epithelium and reduced uterine and ovarian weights 
were also observed at 2,000 ppm, but the toxicological significance was 
unknown. For offspring, the systemic NOAEL was 200 ppm (12.6/14.6 mg/
kg/day in Ms/Fs), and the LOAEL was 2,000 ppm (126.0/143.2 mg/kg/day in 
Ms/Fs) based on decreased bwt on postnatal days 14 and 21.
    4. Subchronic toxicity. In a 21-day dermal toxicity study, Crl: CD 
rats (6/sex/dose) received repeated dermal administration of either the 
technical 96.1% product RH-75,992 at 1,000 mg/kg/day limit dose (LTD) 
or the formulation 23.1% a.i. product RH-755,992 2F at 0, 62.5, 250, or 
1,000 mg/kg/day, 6 hours/day, 5 days/week for 21-days. Under conditions 
of this study, RH-75,992 Technical or RH-75,992 2F demonstrated no 
systemic toxicity or dermal irritation at the highest dose tested (HDT) 
1,000 mg/kg during the 21-day study. Based on these results, the NOAEL 
for systemic toxicity and dermal irritation in both sexes is 1,000 mg/
kg/day HDT. A LOAEL for systemic toxicity and dermal irritation was not 
established.
    5. Chronic toxicity--i. In a 1 year dog feeding study with a LOAEL 
of 250 ppm, 9 mg/kg/day for Ms/Fs dogs based on decreases in RBC, HCT, 
and HGB, increases in Heinz bodies, methemoglobin, MCV, MCH, 
reticulocytes, platelets, plasma total bilirubin, spleen weight, and 
spleen/bwt ratio, and liver/bwt ratio. Hematopoiesis and sinusoidal 
engorgement occurred in the spleen, and hyperplasia occurred in the 
marrow of the femur and sternum. The liver showed an increased pigment 
in the Kupffer cells. The NOAEL for systemic toxicity in both sexes is 
50 ppm (1.9 mg/kg/day).
    ii. An 18-month mouse carcinogenicity study with no carcinogenicity 
observed at dosage levels up to and including 1,000 ppm.
    iii. A 2-year rat carcinogenicity with no carcinogenicity observed 
at dosage levels up to and including 2,000 ppm (97 mg/kg/day and 125 
mg/kg/day for Ms/Fs, respectively).
    6. Animal metabolism. The pharmacokinetics and metabolism of 
tebufenozide were studied in female Sprague-Dawley rats (3-6/sex/group) 
receiving a single oral dose of 3 or 250 mg/kg of RH-5992 14C labeled 
in one of three positions (A-ring, B-ring or N-butylcarbon). The extent 
of absorption was not established. The majority of the radiolabeled 
material was eliminated or excreted in the feces within 48 hours; small 
amounts (1 to 7% of the administered dose) were excreted in the urine 
and only traces were excreted in expired air or remained in the 
tissues. There was no tendency for bioaccumulation. Absorption and 
excretion were rapid. A total of 11 metabolites, in addition to the 
parent compound, were identified in the feces; the parent compound 
accounted for 96 to 99% of the administered radioactivity in the high 
dose group and 35 to 43% in the low dose group. No parent compound was 
found in the urine; urinary metabolites were not characterized. The 
identity of several fecal metabolites was confirmed by mass spectral 
analysis and other fecal metabolites were tentatively identified by 
cochromatography with synthetic standards. A pathway of metabolism was 
proposed based on these data. Metabolism proceeded primarily by 
oxidation of the three benzyl carbons, two methyl groups on the B-ring 
and an ethyl group on the A-ring to alcohols, aldehydes or acids. The 
type of metabolite produced varies depending on the position oxidized 
and extent of oxidation. The butyl group on the quaternary nitrogen 
also can be cleaved (minor), but there was no fragmentation of the 
molecule between the benzyl rings.
    No qualitative differences in metabolism were observed between 
sexes, when high or low dose groups were compared or when different 
labeled versions of the molecule were compared.
    7. Metabolite toxicology. The absorption and metabolism of 
tebufenozide were studied in a group of Ms/Fs bile-duct cannulated 
rats. Over a 72-hour period, biliary excretion accounted for 30% Ms to 
34% Fs of the administered dose while urinary excretion accounted for 
about 5% of the administered dose and the carcass accounted for < 0.5% 
of the administered dose for both Ms/Fs. Thus systemic absorption 
(percent of dose recovered in the bile, urine and carcass) was 35% Ms 
to 39% Fs. The majority of the radioactivity in the bile (20% Ms to 24% 
Fs of the administered dose) was excreted within the first 6 hours 
post-dosing indicating rapid absorption. Furthermore, urinary excretion 
of the metabolites was essentially complete within 24 hours post-
dosing. A large amount (67% Fs to 70% Ms) of the administered dose was 
unabsorbed and excreted in the feces by 72 hours. Total recovery of 
radioactivity was 105% of the administered dose.
    A total of 13 metabolites were identified in the bile; the parent 
compound was not identified, i.e. unabsorbed compound, nor were the 
primary oxidation products seen in the feces in the pharmacokinetics 
study. The proposed metabolic pathway proceeded primarily by oxidation 
of the benzylic carbons to alcohols, aldehydes or acids. Bile contained 
most of the other highly oxidized products found in the feces. The most 
significant individual bile metabolites accounted for 5% to 18% of the 
total radioactivity (Fs and/or Ms). Bile also contained the previously 
undetected (in the pharmacokinetics study) ``A'' ring ketone and the 
``B'' ring diol. The other major components were characterized as high 
molecular weight conjugates. No individual bile metabolite accounted 
for > 5% of the total administered dose. Total bile radioactivity 
accounted for about 17% of the total administered dose. No major 
qualitative differences in biliary metabolites were observed between 
sexes. The metabolic profile in the bile was similar to the metabolic 
profile in the feces and urine.

[[Page 36006]]

C. Aggregate Exposure

    1. Dietary exposure--From food and feed uses. Tolerances have been 
established (40 CFR 180.482) for the residues of tebufenozide, in or on 
walnuts at 0.1 ppm, apples at 1.0 ppm, pecans at 0.01 ppm and wine 
grapes at 0.5 ppm. Numerous section 18 tolerances have been established 
at levels ranging from 0.3 ppm in sugar beet roots to 5.0 ppm in turnip 
tops. Other tolerance petitions are pending at EPA with proposed 
tolerances ranging from 0.5 ppm in or on kiwifruit to 10 ppm in leafy 
and cole crop vegetables. The current petition requests establishment 
of tolerances in or on tree nuts and almond hulls. Risk assessments 
were conducted by Rohm and Haas to assess dietary exposures and risks 
from tebufenozide, benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2-
(4-ethylbenzoyl) hydrazide as follows.
    2. Food--i. Acute exposure and risk. Acute dietary risk assessments 
are performed for a food-use pesticide if a toxicological study has 
indicated the possibility of an effect of concern occurring as a result 
of a 1 day or single exposure. Toxicity observed in oral toxicity 
studies were not attributable to a single dose (exposure). No neuro- or 
systemic toxicity was observed in rats given a single oral 
administration of tebufenozide at 0, 500, 1,000 or 2,000 mg/kg. No 
maternal or developmental toxicity was observed following oral 
administration of tebufenozide at 1,000 mg/kg/day (LTD) during 
gestation to pregnant rats or rabbits. This risk is considered to be 
negligible.
    ii. Chronic exposure and risk. The reference dose (RfD) used for 
the chronic dietary analysis is 0.018 mg/kg/day. In conducting this 
chronic dietary (food) exposure assessment, Rohm and Haas used 
tolerance level residues for nut crops, wine, and sherry, imported 
apples and all other commodities with established or pending 
tebufenozide tolerances; and percent crop-treated (%CT) information for 
some of these crops. Further refinement using anticipated residue 
values and additional %CT information would result in a lower estimate 
of chronic dietary exposure. The Novigen DEEM system was used for this 
chronic dietary exposure analysis. The subgroups listed below are (i) 
the U.S. population (48 contiguous States); (ii) those for infants and 
children; and (iii) the other subgroups (adult) for which the 
percentage of the RfD occupied is greater than that occupied by the 
subgroup U.S. population (48 contiguous States). The results are 
summarized below:

------------------------------------------------------------------------
                  Groups                          RfD (percentage)
------------------------------------------------------------------------
U.S. Population...........................                          10.0
All Infants (< 1 year)....................                          12.2
Nursing Infants (< 1 year old)............                           5.7
Non-Nursing Infants (< 1 year old)........                          15.0
Children (1-6 years old)..................                          22.5
Children (7-12 years old).................                          14.1
Females (13 + years old, nursing).........                          10.1
U.S. Population (autumn season)...........                          10.3
U.S. Population (winter season)...........                          10.1
Non-Hispanic Blacks.......................                          10.4
Non-Hispanic Other than Black or White....                          11.0
Northeast Region..........................                          10.3
Southern Region...........................                          10.1
Western Region............................                          10.5
Pacific Region............................                          10.7
------------------------------------------------------------------------

    3. Drinking water--i. Acute exposure and risk. Because no acute 
dietary endpoint was determined, Rohm and Haas concludes that there is 
a reasonable certainty of no harm from acute exposure from drinking 
water.
    ii. Chronic exposure and risk. Submitted environmental fate studies 
suggest that tebufenozide is moderately persistent to persistent and 
mobile. Under certain conditions tebufenozide appears to have the 
potential to contaminate ground and surface water through runoff and 
leaching; subsequently potentially contaminating drinking water. There 
are no established Maximum Contaminant Levels (MCL) for residues of 
tebufenozide in drinking water and no Health Advisories (HA) have been 
issued for tebufenozide therefore these could not be used as 
comparative values for risk assessment. Therefore, potential residue 
levels for drinking water exposure were calculated previously by EPA 
using GENEEC (surface water) and SCIGROW (ground water) for human 
health risk assessment. Because of the wide range of half-life values 
(66-729 days) reported for the aerobic soil metabolism input parameter 
a range of potential exposure values were calculated. In each case the 
worst case upper bound exposure limits were then compared to 
appropriate chronic drinking water level of concern (DWLOC). In each 
case the calculated exposures based on model data were below the DWLOC.
    4. Non-dietary exposure. From non-dietary exposure. Tebufenozide is 
not currently registered for use on any residential non-food sites. 
Therefore there is no chronic, short- or intermediate-term exposure 
scenario.

D. Cumulative Effects

    Cumulative exposure to substances with common mechanism of 
toxicity. Section 408(b)(2)(D)(v) requires that, when considering 
whether to establish, modify, or revoke a tolerance, the Agency 
consider ``available information'' concerning the cumulative effects of 
a particular pesticide's residues and ``other substances that have a 
common mechanism of toxicity.'' The Agency believes that ``available 
information'' in this context might include not only toxicity, 
chemistry, and exposure data, but also scientific policies and 
methodologies for understanding common mechanisms of toxicity and 
conducting cumulative risk assessments. For most pesticides, although 
the Agency has some information in its files that may turn out to be 
helpful in eventually determining whether a pesticide shares a common 
mechanism of toxicity with any other substances, EPA does not at this 
time have the methodologies to resolve the complex scientific issues 
concerning common mechanism of toxicity in a meaningful way. EPA has 
begun a pilot process to study this issue further through the 
examination of particular classes of pesticides. The Agency hopes that 
the results of this pilot process will

[[Page 36007]]

increase the Agency's scientific understanding of this question such 
that EPA will be able to develop and apply scientific principles for 
better determining which chemicals have a common mechanism of toxicity 
and evaluating the cumulative effects of such chemicals. The Agency 
anticipates, however, that even as its understanding of the science of 
common mechanisms increases, decisions on specific classes of chemicals 
will be heavily dependent on chemical-specific data, much of which may 
not be presently available.
    Although at present the Agency does not know how to apply the 
information in its files concerning common mechanism issues to most 
risk assessments, there are pesticides as to which the common mechanism 
issues can be resolved. These pesticides include pesticides that are 
toxicologically dissimilar to existing chemical substances (in which 
case the Agency can conclude that it is unlikely that a pesticide 
shares a common mechanism of activity with other substances) and 
pesticides that produce a common toxic metabolite (in which case common 
mechanism of activity will be assumed).
    EPA does not have, at this time, available data to determine 
whether tebufenozide, benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-
2-(4-ethylbenzoyl) hydrazide has a common mechanism of toxicity with 
other substances or how to include this pesticide in a cumulative risk 
assessment. Unlike other pesticides for which EPA has followed a 
cumulative risk approach based on a common mechanism of toxicity, 
tebufenozide, benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-
ethylbenzoyl) hydrazide does not appear to produce a toxic metabolite 
produced by other substances. For the purposes of this tolerance 
action, therefore, Rohm and Haas has not assumed that tebufenozide, 
benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl) 
hydrazide has a common mechanism of toxicity with other substances.

E. Safety Determination

    1. U.S. population--i. Acute risk. Since no acute toxicological 
endpoints were established, no acute aggregate risk exists.
    ii. Chronic risk. Using the conservative exposure assumptions 
described above, and taking into account the completeness and 
reliability of the toxicity data, Rohm and Haas has concluded that 
dietary (food only) exposure to tebufenozide will utilize 10.0% of the 
RfD for the U.S. population. Submitted environmental fate studies 
suggest that tebufenozide is moderately persistent to persistent and 
mobile; thus, tebufenozide could potentially leach to ground water and 
runoff to surface water under certain environmental conditions. The 
modeling data for tebufenozide indicate levels less than OPP's DWLOC. 
EPA generally has no concern for exposures below 100% of the RfD 
because the RfD represents the level at or below which daily aggregate 
dietary exposure over a lifetime will not pose appreciable risks to 
human health. There are no registered residential uses of tebufenozide. 
Since there is no potential for exposure to tebufenozide from 
residential uses, Rohm and Haas does not expect the aggregate exposure 
to exceed 100% of the RfD.
    iii.  Short- and intermediate-term risk. Short- and intermediate-
term aggregate exposure takes into account chronic dietary food and 
water (considered to be a background exposure level) plus indoor and 
outdoor residential exposure. Since there are currently no registered 
indoor or outdoor residential non-dietary uses of tebufenozide and no 
short- or intermediate-term toxic endpoints, short- or intermediate-
term aggregate risk does not exist.
    2. Infants and children. In assessing the potential for additional 
sensitivity of infants and children to residues of tebufenozide, 
benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl) 
hydrazide, EPA previously considered data from developmental toxicity 
studies in the rat and rabbit and a 2-generation reproduction study in 
the rat. The developmental toxicity studies are designed to evaluate 
adverse effects on the developing organism resulting from maternal 
pesticide exposure gestation. Reproduction studies provide information 
relating to effects from exposure to the pesticide on the reproductive 
capability of mating animals and data on systemic toxicity. FFDCA 
section 408 provides that EPA shall apply an additional tenfold margin 
of safety for infants and children in the case of threshold effects to 
account for pre-and postnatal toxicity and the completeness of the data 
base unless EPA determines that a different margin of safety will be 
safe for infants and children. Margins of safety are incorporated into 
EPA risk assessments either directly through use of a margin of 
exposure (MOE) analysis or through using uncertainty (safety) factors 
in calculating a dose level that poses no appreciable risk to humans. 
EPA believes that reliable data support using the standard uncertainty 
factor (usually 100 for combined inter- and intra-species variability) 
and not the additional tenfold MOE/uncertainty factor when EPA has a 
complete data base under existing guidelines and when the severity of 
the effect in infants or children or the potency or unusual toxic 
properties of a compound do not raise concerns regarding the adequacy 
of the standard MOE safety factor.
    3. Developmental toxicity studies--i. Rats. In a developmental 
toxicity study in rats, the maternal (systemic) NOAEL was 250 mg/kg/
day. The LOAEL was 1,000 mg/kg/day, based on decreased bwt and food 
consumption. The developmental (pup) NOAEL was 1,000 mg/kg/day (HGT).
    ii. Rabbits. In a developmental toxicity study in rabbits, the 
maternal and developmental NOAELs were 1,000 mg/kg/day (HDT).
    iii. Reproductive toxicity study. In a 1993 2-generation 
reproduction study in Sprague-Dawley rats, tebufenozide was 
administered at dietary concentrations of 0, 10, 150, or 1,000 ppm (0, 
0.8, 11.5, or 154.8 mg/kg/day for males and 0, 0.9, 12.8, or 171.1 mg/
kg/day for females. The parental systemic NOAEL was 10 ppm (0.8/0.9 mg/
kg/day for Ms/Fs, respectively) and the LOAEL was 150 ppm (11.5/12.8 
mg/kg/day for Ms/Fs, respectively) based on decreased bwt, bwt gain, 
and food consumption in males, and increased incidence and/or severity 
of splenic pigmentation. In addition, there was an increased incidence 
and severity of extramedullary hematopoiesis at 2,000 ppm. The 
reproductive NOAEL was 150 ppm. (11.5/12.8 mg/kg/day for Ms/Fs, 
respectively) and the LOAEL was 2,000 ppm (154.8/171.1 mg/kg/day for 
Ms/Fs, respectively) based on an increase in the number of pregnant 
females with increased gestation duration and dystocia. Effects in the 
offspring consisted of decreased number of pups per litter on postnatal 
days 0 and/or 4 at 2,000 ppm (154.8/171.1 mg/kg/day for Ms/Fs, 
respectively) with a NOAEL of 150 ppm (11.5/12.8 mg/kg/day for males 
and females, respectively)
    In a 1995 2-generation reproduction study in rats, tebufenozide was 
administered at dietary concentrations of 0, 25, 200, or 2,000 ppm (0, 
1.6, 12.6, or 126.0 mg/kg/day for males and 0, 1.8, 14.6, or 143.2 mg/
kg/day for females). For parental systemic toxicity, the NOAEL was 25 
ppm (1.6/1.8 mg/kg/day in Ms/Fs, respectively), and the LOAEL was 200 
ppm (12.6/14.6 mg/kg/day in Ms/Fs), based on histopathological findings 
(congestion and extramedullary hematopoiesis) in the spleen. 
Additionally, at 2,000 ppm (126.0/143.2 mg/kg/day in Ms/Fs), treatment-
related findings included reduced parental bwt

[[Page 36008]]

gain and increased incidence of hemosiderin-laden cells in the spleen. 
Columnar changes in the vaginal squamous epithelium and reduced uterine 
and ovarian weights were also observed at 2,000 ppm, but the 
toxicological significance was unknown. For offspring, the systemic 
NOAEL was 200 ppm. (12.6/14.6 mg/kg/day in Ms/Fs), and the LOAEL was 
2,000 ppm (126.0/143.2 mg/kg/day in Ms/Fs) based on decreased bwt on 
postnatal days 14 and 21.
    iv. Pre- and postnatal sensitivity. The toxicology data base for 
tebufenozide is complete and includes acceptable developmental toxicity 
studies in both rats and rabbits as well as a 2-generation reproductive 
toxicity studies in rats.
    EPA determined that the data provided no indication of increased 
sensitivity of rats or rabbits to in utero and/or postnatal exposure to 
tebufenozide. No maternal or developmental findings were observed in 
the prenatal developmental toxicity studies at doses up to 1,000 mg/kg/
day in rats and rabbits. In the 2-generation reproduction studies in 
rats, effects occurred at the same or lower treatment levels in the 
adults as in the offspring.
    v. Acute risk. Since no acute toxicological endpoints were 
established, no acute aggregate risk exists.
    vi. Chronic risk. Using the conservative exposure assumptions 
described above, Rohm and Haas has concluded that aggregate exposure to 
tebufenozide, benzoic acid, 3,5-dimethyl-1-(1,1-dimethylethyl)-2-(4-
ethylbenzoyl) hydrazide from food will utilize from 10.0% of the 
reference dose RfD for the U.S. population to 22.5% of the RfD for 
children 1-6 years old. The potential for exposure to tebufenozide in 
drinking water does not exceed EPA's level of concern. There are 
currently no tebufenozide residential or non-dietary exposure 
scenarios. EPA generally has no concern for exposures below 100% of the 
RfD because the RfD represents the level at or below which daily 
aggregate dietary exposure over a lifetime will not pose appreciable 
risks to human health. Rohm and Haas does not expect the aggregate 
exposure to exceed 100% of the RfD. Rohm and Haas concludes that there 
is a reasonable certainty that no harm will result to infants and 
children from aggregate exposure to tebufenozide, benzoic acid, 3,5-
dimethyl-1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl) hydrazide residues.
    vii. Short- or intermediate-term risk. Since no short- and 
intermediate-term toxicological endpoints were established by EPA, no 
acute aggregate risk exists.

F. International Tolerances

    There are currently no CODEX, Canadian or Mexican maximum residue 
levels (MRLs) established for tebufenozide in nut crops so no 
harmonization issues are required for this action.
[FR Doc. 99-16768 Filed 7-1-99; 8:45 am]
BILLING CODE 6560-50-F