[Federal Register Volume 64, Number 31 (Wednesday, February 17, 1999)]
[Notices]
[Pages 7883-7890]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-3662]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-860; FRL-6060-1]


Rohm and Haas Company; Notice of Filing of Pesticide Petitions

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-860, must 
be received on or before March 19, 1999.

ADDRESSES: By mail submit written comments to: Public Information and 
Records Integrity Branch, Information Resources and Services Divison 
(7502C), Office of Pesticides Programs, Environmental Protection 
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments 
to: Rm. 119, Crystal Mall 2 (CM #2), 1921 Jefferson Davis Highway, 
Arlington, VA.
    Comments and data may also be submitted electronically to: opp-
[email protected]. Following the instructions under 
``SUPPLEMENTARY INFORMATION.'' No confidential business information 
should be submitted through e-mail.
    Information submitted as a comment concerning this document may be 
claimed confidential by marking any part or all of that information as 
``Confidential Business Information'' (CBI). CBI should not be 
submitted through e-mail. Information marked as CBI will not be 
disclosed except in accordance with procedures set forth in 40 CFR part 
2. A copy of the comment that does not contain CBI must be submitted 
for inclusion in the public record. Information not marked confidential 
may be disclosed publicly by EPA without prior notice. All written 
comments will be available for public inspection in Rm. 119 at the 
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday, 
excluding legal holidays.

FOR FURTHER INFORMATION CONTACT: By mail: Joseph Tavano, Registration 
Division (7505C), Office of Pesticide Programs, Environmental 
Protection Agency, 401 M St., SW., Washington, DC 20460. Office 
location/telephone and e-mail address: Rm. 214, 1921 Jefferson Davis 
Hwy, Arlington, VA, Crystal Mall 2 (CM #2), 703-305-6411, e-mail: 
[email protected].

SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as 
follows proposing the establishment and/or amendment of regulations for 
residues of certain pesticide chemicals in or on various raw food 
commodities under section 408 of the Federal Food, Drug, and Comestic 
Act (FFDCA), 21 U.S.C. 346a. EPA has determined that these petitions 
contain data or information regarding the elements set forth in section 
408(d)(2); however, EPA has not fully evaluated the sufficiency of the 
submitted data at this time or whether the data supports grantinig of 
the

[[Page 7884]]

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-860 (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 (insert docket number) and 
appropriate petition number. Electronic comments on this notice may be 
filed online at many Federal Depository Libraries.

List of Subjects

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

    Dated: February 4, 1999.

James Jones,
Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

    Below summaries of the pesticide petitions are printed. The 
summaries of the petitions were prepared by the petitioner. 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.

Rohm and Haas Company

1. 7F4815

    EPA has received a revised pesticide petition (7F4815) from Rohm 
and Haas Company, 100 Independence Mall West, Philadelphia, PA 
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-dimethyl-, 1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl) hydrazide] in 
or on the raw agricultural commodity crop grouping, pome fruit at 1.25 
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 
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. A validated high performance liquid 
chromatographic (HPLC) analytical method using ultraviolet (UV) 
detection is employed for measuring residues of tebufenozide in pome 
fruit. 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 in pome fruit 
is 0.02 ppm.
    3. Magnitude of residues. Magnitude of the residue studies were 
conducted in apples and pears using the maximum application rate of 
0.308 pounds active ingredient per acre applied 6 times during the 
growing season. Fruit were collected 14 days after the last application 
and were analyzed for residues of tebufenozide. The average residue in 
apples from 12 trials was 0.52 ppm and the average residue detected in 
pears from 6 trials was 0.27 ppm. A tolerance of 1.25 ppm is proposed 
for residues of tebufenozide in or on pome fruit.

B. Toxicological Profile

    1. Acute toxicity. Acute toxicity studies with technical grade: 
Oral LD50 in the rat is > 5 grams for males and females - 
Toxicity Category IV; dermal LD50 in the rat is = 5,000 
milligram/kilogram (mg/kg) for males and females - 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 which 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 Chinese hampster ovary (CHO) cells, a 
CHO/Hypoxanthine guanine phophoribosyl transferase (HGPRT) assay, a 
reverse mutation assay with E. Coli, and an unscheduled DNA synthesis 
(UDS) assay in rat hepatocytes.
    3. Reproductive and developmental toxicity. 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 no 
observed adverse effect level (NOAEL) was 1,000 mg/kg/day.
    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.
    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 males and females, respectively) and the 
lowest observed effect level (LOEL) was 150 ppm (11.5/12.8 mg/kg/day 
for males and females, respectively) based on decreased body weight, 
body weight 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 males and females, respectively) and the LOEL

[[Page 7885]]

was 2,000 ppm (154.8/171.1 mg/kg/day for males and females, 
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 males and 
females, 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 males and females, respectively), and the 
LOEL 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 M/F), 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 males and females), 
and the LOEL was 2,000 ppm (126.0/143.2 mg/kg/day in M/F) based on 
decreased body weight on postnatal days 14 and 21.
    4. Subchronic toxicity. 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.
    5. Chronic toxicity. A 1-year dog feeding study with a LOEL of 250 
ppm, 9 mg/kg/day for male and female 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/body weight ratio, and liver/body weight 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).
    An 18-month mouse carcinogenicity study with no carcinogenicity 
observed at dosage levels up to and including 1,000 ppm.
    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 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 -- i. Food. 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 0.3 ppm in or on sugarcane to 10 ppm in cole crop 
vegetables. 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:
    ii. 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 one 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 (Limit-Dose) during 
gestation to pregnant rats or rabbits. This risk is considered to be 
negligible.
    2. Chronic exposure and risk  -- i. The reference dose (RfD) used 
for the chronic dietary analysis is 0.018 mg/kg/day. In conducting this 
exposure assessment, Rohm and Haas has made very conservative 
assumptions 100% of pecans, walnuts, wine and sherry, pome fruit and 
all other commodities having tebufenozide tolerances or pending 
tolerances will contain tebufenozide residues, and those residues would 
be at the level of the tolerance which result in an overestimate of 
human dietary exposure. Thus, in making a safety determination for this 
tolerance, Rohm and Haas is taking into account this conservative 
exposure assessment. The existing tebufenozide tolerances published, 
pending, and including the necessary section 18 tolerance(s) resulted 
in a Theoretical Maximum Residue Contribution (TMRC) that is equivalent 
to the following percentages of the RfD:
     U.S. Population (35.6% of RfD);
     All Infants (<1 year) (63.8%);
     Nursing Infants (<1 year old) (41.0% of RfD);
     Non-Nursing Infants (<1 year old) (73.3% of RfD);
     Children (1-6 years old) (81.8% of RfD);
     Children (7-12 years old) (50.0% of RfD);
     Females (13 + years old, nursing) (40.0% of RfD);
     Non-Hispanic Whites (35.8%);
     Non-Hispanic Other than Black or White (40.8% of RfD);
     Northeast Region (38.2% of RfD);
     Western Region (37.6%);

[[Page 7886]]

     Pacific Region (37.6%).
     The subgroups listed above are subgroups for which the percentage 
of the RfD occupied is greater than that occupied by the subgroup U.S. 
population (48 States).
    ii. Drinking water -- 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.
    iii. 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 using 
Generic expected environmental concentration (GENEEC (surface water)) 
and screening concentration in ground water (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.
    2. 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 hassome 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 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. 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 35.6% 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.
    Since, tebufenozide has been classified as a Group E, ``no evidence 
of carcinogenicity for humans,'' this risk does not exist.
    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 NOAEL 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 NOAEL of 12.1 mg/kg/day was 14-
fold higher than the parental (systemic) toxicity NOAEL (0.85 mg/kg/
day). The reproductive (pup) LOEL of 171.1 mg/

[[Page 7887]]

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 NOAEL equal to 149-195 mg/
kg/day) and the NOAEL 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 of 1.0 mg/kg. An MRL of 1.0 mg/kg was 
established for apples in Canada.

2. 7F4863

    EPA has received a revised pesticide petition (7F4863) from Rohm 
and Haas Company, 100 Independence Mall West, Philadelphia, PA 
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-dimethyl-,1-(1,1-dimethylethyl)-2-(4-ethylbenzoyl) hydrazide] in or 
on the raw agricultural commodity sugarcane and molasses at 1.0 and 6.0 
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 
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. A high performance liquid chromatographic 
(HPLC) analytical method using ultraviolet (UV) detection has been 
validated for sugarcane, molasses and refined sugar. 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.
    3. Magnitude of residues. Magnitude of the residue and processing 
studies were conducted in sugarcane using the maximum proposed label 
rate. Samples were collected 14 days after the last application and 
were analyzed for residues of tebufenozide. The residue data support a 
tolerance of 1.0 ppm for sugarcane and 6.0 ppm for molasses. Residues 
were not found in refined sugar and no tolerance is needed for this 
commodity.

B. Toxicological Profile

    1. Acute toxicity. Acute toxicity studies with technical grade: 
Oral LD50 in the rat is > 5 grams for males and females - 
Toxicity Category IV; dermal LD50 in the rat is = 5,000 
milligram/kilogram (mg/kg) for males and females - 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 which 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. 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 no 
observed adverse effect level (NOAEL) was 1,000 mg/kg/day.
    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.
    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 males and females, respectively) and the 
lowest observed effect level (LOEL) was 150 ppm (11.5/12.8 mg/kg/day 
for males and females, respectively) based on decreased body weight, 
body weight 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 males and females, respectively) and the LOEL was 2,000 ppm (154.8/
171.1 mg/kg/day for males and females, 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 males and females, respectively) with a 
NOAEL of 150 ppm (11.5/12.8 mg/kg/day for males and females, 
respectively).

[[Page 7888]]

    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 males and females, respectively), and the 
LOEL 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 M/F), 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 males and females), 
and the LOEL was 2,000 ppm (126.0/143.2 mg/kg/day in M/F) based on 
decreased body weight on postnatal days 14 and 21.
    4. Subchronic toxicity. 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.
    5. Chronic toxicity. A 1-year dog feeding study with a LOEL of 250 
ppm, 9 mg/kg/day for male and female 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/body weight ratio, and liver/body weight 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).
    An 18-month mouse carcinogenicity study with no carcinogenicity 
observed at dosage levels up to and including 1,000 ppm.
    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 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 --i. Food. 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 also been established. Other 
tolerance petitions are pending at EPA with proposed tolerances. 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:
    a. 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 one 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 (Limit-Dose) during 
gestation to pregnant rats or rabbits. This risk is considered to be 
negligible.
    b. Chronic exposure and risk. The RfD used for the chronic dietary 
analysis is 0.018 mg/kg/day. In conducting this exposure assessment, 
Rohm and Haas has made very conservative assumptions 100% of pecans, 
walnuts, wine and sherry, pome fruit and all other commodities having 
tebufenozide tolerances or pending tolerances will contain tebufenozide 
residues, and those residues would be at the level of the tolerance 
which result in an overestimate of human dietary exposure. Thus, in 
making a safety determination for this tolerance, Rohm and Haas is 
taking into account this conservative exposure assessment. 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 and the appropriate concentration or reduction factors, the 
existing tebufenozide tolerances published, pending, and including the 
necessary section 18 tolerance(s) resulted in a Theoretical Maximum 
Residue Contribution (TMRC) that is equivalent to the following 
percentages of the RfD:
     U.S. Population (35.8% of RfD);
    Northeast Region (37.5% of RfD);
    Western Region (39.8%);
    Pacific Region (40.9%)All Infants (<1 year) (36.3%);
    Nursing Infants (<1 year old) (16.8% of RfD);
    Non-Nursing Infants (<1 year old) (44.5% of RfD);
    Children (1-6 years old) (61.9% of RfD);
     Children (7-12 years old) (45.6% of RfD);
    Females (13 + years old, nursing) (30.6% of RfD);
    Non-Hispanic Whites (36.0%);
    Non-Hispanic Other than Black or White (43.1% of RfD).
    The subgroups listed above are subgroups for which the percentage 
of the RfD occupied is greater than that occupied by the subgroup U.S. 
population (48 States).
    ii. Drinking water. Acute exposure and risk. Because no acute 
dietary endpoint was determined, Rohm and

[[Page 7889]]

Haas concludes that there is a reasonable certainty of no harm from 
acute exposure from drinking water.
    iii. 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 using 
Generic expected environmental concentration (GENEEC (surface water)) 
and screening concentration in ground water (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.
    2. 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 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. 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 35.8% 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.
    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.
    Since, tebufenozide has been classified as a Group E, ``no evidence 
of carcinogenicity for humans,'' this risk does not exist.
    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 NOAEL 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 NOAEL of 12.1 mg/kg/day was 14-
fold higher than the parental (systemic) toxicity NOAEL (0.85 mg/kg/
day). The

[[Page 7890]]

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 NOAEL equal to 149-195 mg/kg/day) and the NOAEL 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 oftebufenozide.

[FR Doc. 99-3662 Filed 2-16-99; 8:45 am]
BILLING CODE 6560-50-F