99-4023. Notice of Filing of Pesticide Petitions

[Federal Register Volume 64, Number 32 (Thursday, February 18, 1999)]
[Notices]
[Pages 8090-8102]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-4023]


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ENVIRONMENTAL PROTECTION AGENCY

[PF-859; FRL-6059-9]


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-859, must 
be received on or before March 22, 1999.

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

FOR FURTHER INFORMATION CONTACT: The product manager listed in the 
table below:

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                                   Office location/
        Product Manager            telephone number          Address
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Melody A. Banks (PM 03).......  Rm. 205, CM #2, 703-    1921 Jefferson
                                 305-5413, e-            Davis Hwy,
                                 mail:[email protected]   Arlington, VA
                                 mail.epa.gov.
Joseph M. Tavano..............  Rm. 214, CM #2, 703-    Do.
                                 305-6411, e-mail:
                                 [email protected]
                                 .epa.gov.
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[[Page 8091]]

SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as 
follows proposing the establishment and/or amendment of regulations for 
residues of certain pesticide chemicals in or on various food 
commodities under section 408 of the Federal Food, Drug, and Comestic 
Act (FFDCA), 21 U.S.C. 346a. EPA has determined that these petitions 
contain data or information regarding the elements set forth in section 
408(d)(2); however, EPA has not fully evaluated the sufficiency of the 
submitted data at this time or whether the data supports granting of 
the petition. Additional data may be needed before EPA rules on the 
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-859] (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:
    [e-mail]


    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 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 10, 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. Nihon Nohyaku Co., Ltd.

PP 5E4435

    EPA has received a pesticide petition (PP 5E4435) from Nihon 
Nohyaku Co., Ltd., 2-5, Nihonbashi 1-Chome, Chuo-ku, Tokyo 103, Japan, 
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 an import tolerance for residues of fenpyroximate tert-
butyl (E)--(1,3-dimethyl-5-phenoxypyrazol-4-ylmethyleneamino 
oxy)-p-toluate, CASRN 134098-61-6 in or on grapes and hops (green and 
dried). The proposed analytical method involves gas chromatography 
using nitrogen-sensitive detection against authentic standards for the 
parent and its two main metabolites. 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 completed a partial 
review of the sufficiency of the submitted data at this time. Nihon 
Nohyaku Co., Ltd. has submitted supplemental information to EPA which 
EPA believes it needs to review and evaluate before EPA rules on the 
petition.

A. Residue Chemistry

    1. Plant metabolism. Radiolabel metabolism studies, using 
14C labeled fenpyroximate, were conducted with grapes, 
apples, and citrus. Radiolabeling was at two positions (in separate 
study series), in the pyrazole ring of the molecule and in the benzyl 
ring of the molecule. The studies established that: Fenpyroximate 
applied to growing grape vines leads to parent and metabolites being 
found mostly on leaves with less than 10% of the total residue being 
found in the grapes and generally less than 1% of the total residues 
being found in grape juice. In grapes, the predominant metabolites were 
the Z-isomer of the parent, terephthalic acid, terephthaldehydic acid, 
and species resulting from cleavage of the tert-butyl group and of the 
imino linkage. Fenpyroximate applied to apple trees leads to parent and 
metabolites being found mostly on leaves with less than 10% of the 
total residue being found in the grapes and generally less than 1% of 
the total residues being found in apple juice. In grapes, the 
predominant metabolites were the Z-isomer of the parent, terephthalic 
acid, terephthaldehydic acid, and species resulting from cleavage of 
the tert-butyl group and of the imino linkage. Application of 
fenpyroximate to citrus gave similar results. Comparison of the plant 
metabolites to metabolites in mammalian metabolism studies did not 
reveal novel metabolites in plants which were not seen in mammals. 
Nihon Nohyaku believes the results of these plant metabolism studies 
establish that: (i) fenpyroximate metabolism is similar among the 
different plant species studies; (ii) metabolism in hops will be 
similar to that in grapes, apples, and citrus; (iii ) the dietary 
safety of the various plant metabolites of fenpyroximate is well 
addressed by the animal toxicology data on fenpyroximate since there do 
not appear to be novel plant metabolites not seen in mammalian 
metabolism; and, (iv) the tolerance expression for fenpyroximate TTR 
can be given as:
    TTR = (parent + Z-isomer) x 3
where the factor of 3 accounts for the highest levels of TTR (including 
non-extractable residues) seen in the plant metabolism studies in 
relation to the combined parent + Z-isomer residues.
    2. Analytical method. An adequate analytical method for detecting 
fenpyroximate parent and Z-isomer residues in plants is available. The 
method has been validated by several laboratories, is a standard 
European multi-residue method (DFG-S19: Manual of Pesticide Residue 
Analysis DFG, Deutsche Forschungsgemeinschaft Pesticides Committee), 
and EPA will independently validate this method as part of EPA's 
continued review of this petition. Analytical method for detecting 
fenpyroximate parent and Z-isomer residues in plants is available. In 
brief, plant material is extracted with acetone/water, maintaining an 
acetone/water ratio of 2:1 v/v (taking into account, also, the natural 
water content of the plant material). The extract is saturated with 
sodium chloride and then diluted with dichloromethane, resulting in the 
separation of excess water. The evaporative residue of the organic 
phase is cleaned up by gel permeation chromatography on Bio Beads S-x3 
polystyrene gel (or equivalent) using a mixture of cyclohexane and 
ethyl acetate (1+1) as eluant and an automated gel permeation 
chromatograph. The residue containing fraction is concentrated and 
after supplemental clean-up on a small silica

[[Page 8092]]

gel column is analyzed by gas chromatography using a widebore capillary 
column and a nitrogen sensitive detector. Limits of detection are: 
(LOD) (i) 0.02 milligram/kilogram (mg/kg) for grapes, cider, and wine; 
and, (ii) 0.05 mg/kg for green hops; and, (iii) 1 mg/kg in dried hops. 
Limits of quantitation (LOQ) are: (i) 0.05 mg/kg for grapes, cider, and 
wine; and, (ii) 0.1 mg/kg for green hops; and, (iii) 2 mg/kg in dried 
hops.
    3. Magnitude of residues. Four field trials were conducted for 
hops, in each of which residues in dried and green hops were 
determined. These trials were all conducted in Germany since it is the 
predominant growing area for hops and registration in that country is 
imminent. Czechoslovakia is the only other significant exporter of hops 
to the United States but fenpyroximate registration in Czechoslovakia 
is not imminent nor has Nihon Nohyaku filed for same at this time. Hops 
growing areas are, in any case, quite restricted in regard to their 
micro-climates. Therefore, essentially identical environmental 
conditions of degree-days, rainfall, and hours of daylight are to be 
found from one hops growing region to another. As such, Nihon Nohyaku 
believes that magnitude of the residue data from Germany would 
adequately represent residues on Czech hops should registration in 
Czechoslovakia someday be sought.
    Twenty-six field trials were conducted in wine grapes, with eleven 
different grape varietals. These trials were conducted in Germany, 
Italy, and France since these are major wine producing countries and 
are major exporters of wines to the United States. No trials data from 
Spain, another major wine exporter to the United States, or Portugal, a 
minor exporter, were submitted. Nihon Nohyaku believes that micro-
climate conditions in the south of France, and in Italy, which have 
mediterranean climates, are adequately representative of growing 
condition in Spanish, and Portuguese vineyards. As below noted: (i) 
quantifiable residues of fenpyroximate were found in only one juice 
sample from treated grapes and this was just at the LOQ = 0.02 ppm; 
(ii) residues in all other juice and in all wine samples were less than 
the LOQ;, and (iii) there is, therefore, no reasonable basis to expect 
that quantifiable residues would occur in wines from any country.
    In the hops trials, residues in green hops ranged from 1.1 ppm at 7 
days post-application and ranged from 0.8 ppm to 3.2 ppm at 21 days 
post-application (i.e., at harvest). In dried hops residue levels 
ranged from 2.1 ppm to 6.4 ppm at 21 days post-application (i.e., at 
harvest with immediate on site drying).
    In the grapes trials, residues in grapes ranged from > 0.02 ppm 
(i.e., non-detect) to 0.41 ppm at 7 days post-application and ranged 
from > 0.02 ppm (i.e., non-detect) to 0.23 ppm at 36 days post-
application (i.e., at harvest). The highest residue level found in 
grapes was 0.57 ppm in a 14 day post-application sample in one trial. 
In these trials, a 5-fold range of application rates was used. The 
label rate recommendation on grapes is 60 - 120 g AI/hectare. The 
application rates used in these grape trials was from a low of 60 g AI/
hectare to a high of 360 g AI/hectare. At from 28 to 36 days post-
application mean residues in grapes were > 0.02 ppm at the lowest 
application rate and were 0.15 - 0.23 ppm at the highest application 
rates. Residue levels were determined in juice and wines from grapes 
treated at from 120 to 360 g AI/hectare. In one juice sample residues 
were just at the (LOQ = 0.02ppm). Resudues in all other juice and in 
all wine samples were less than the LOQ.

B. Toxicological Profile

    1. Acute toxicity. Technical fenpyroximate (99+% active ingredient) 
is moderately toxic by the oral route, with a rat acute oral 
LD50 of 480 mg/kg (95% CI: 298 <> 662) in males, 245 mg/kg 
(95% CI: 167 <> 323) in females, and 350 mg/kg (95% CI: 272 <> 428) for 
males and females combined (MRID 43560501). These LD50 
values place fenpyroximate into EPA's acute oral toxicity Category II 
(signal word: WARNING). Data on acute dermal toxicity, acute inhalation 
toxicity, eye irritation, skin irritation, and dermal sensitization 
were not submitted since these are not relevant to the dietary safety 
ecaluation required in support of an import tolerance.
    2. Chronic and subchronic toxicity. The following studies were 
submitted by Nihon Nohyaku: subchronic toxicity in rats (MRID 
43429501), chronic toxicity rats (MRID 43560502), subchronic toxicity 
in dogs (MRID 43429502), and chronic toxicity in dogs (MRID 434329503).
    i. Rat subchronic toxicity. Fenpyroximate (technical grade) was 
administered to ten rats/sex/dose in the diet at dose levels of 0, 20, 
100 or 500 ppm (average 1.47, 7.43, or 36.9 mg/kg/day; 0 ppm =control) 
for 13 weeks. No treatment related effects were observed in the 20 ppm 
groups. Both sexes in the 100 ppm and 500 ppm groups had impaired 
growth performance, reduced food intake, and decreased body weights and 
body weight gains. The decrease in body weight gain was dose related. 
Males in the 100 ppm group had lower white cell counts. In males from 
the 500 ppm group, hematocrit, hemoglobin, and red cell counts were 
higher and white cell counts were lower than in controls. In females 
from the 500 ppm group, hematocrit, hemoglobin, red cell counts, and 
platelet counts were higher than in controls. Total plasma proteins 
were reduced in the 500 ppm males and in the 100 and 500 ppm females. 
Females in the 500 ppm group had lower plasma acetyl- and butyryl-
cholinesterase activity and elevated alkaline phosphatase. Males in the 
500 ppm group had lower urine volume and pH values. Various treatment 
related gross pathology changes were noted in the 500 ppm group for 
both sexes. Micropathology changes noted in the 100 ppm and 500 ppm 
groups were limited to minimal hepatocytic hypertrophy seen in both 
sexes. EPA has already reviewed this study and concluded that: (i) the 
study is acceptable; and, (ii) the no-observed adverse effect level 
(NOAEL), and lowest-observed adverse effect levels (LOAEL) in this 
study were 20 ppm (1.3 mg/kg/day) and 100 ppm (6.57 mg/kg/day) 
respectively based on reduced body weight gain in both sexes.
    ii. Rat chronic toxicity. A combined oncogenicity/chronic toxicity 
study (Guideline 83-5) was conducted. For the chronic toxicity phase of 
this study, fenpyroximate (technical grade) was administered to 30 
rats/sex/dose in the diet at dose levels of 0, 10, 25, 75, or 150 ppm 
(male average: 0.40, 0.97, 3.1, or 6.2 mg/kg/day; Female average: 0.48, 
1.2, 3.8, or 7.6 mg/kg/day; 0 ppm = control) for 104 weeks. Chronic 
toxicity was observed in males and females receiving 75 or 150 ppm. 
This consisted of depressed growth rate and food efficiency. No 
treatment related effect on general condition, hematology, clinical 
chemistries, urinalysis, ophthalmology examinations, gross pathology, 
or micro pathology were observed. EPA has already reviewed this study 
and concluded that: (i) the study is acceptable; and, (ii) the NOAEL, 
and LOAEL in this were 25 ppm (0.97 mg/kg/day in males, and 1.2 mg/kg/
day in females), and 75 ppm (3.1 mg/kg/day in males and 3.8 mg/kg/day 
in females) respectively based on reduced body weight gain in both 
sexes.
    iii. Dog subchronic toxicity. Fenpyroximate (technical grade) was 
administered to four beagle dogs/sex/dose by capsule at dose levels of 
2, 10, or 50 mg/kg/day plus a vehicle control group for 13 weeks. Two 
50 mg/kg/day females were sacrificed in extremis

[[Page 8093]]

during weeks 4 or 5 after a period of appetite loss and body weight 
loss. Both sexes at all treatment levels exhibited slight bradycardia 
and a dose-dependent increase in diarrhea. Emaciation and torpor were 
observed in the 2 mg/kg/day females and in both sexes at 50 mg/kg/day. 
Emesis was observed in both sexes at 10 and 50 mg/kg/day. Reduced body 
weight gain and body weight was observed in all female treatment groups 
and in the 50 mg/kg/day. These effects on weight and weight gain were 
significant only at the mid and high doses for females. Decreased blood 
glucose and white cell counts were observed in the 10 and 50 mg/kg/day 
males. Prothrombin times and blood urea levels were increased in the 50 
mg/kg/day females. Increased relative adrenal gland and liver weights 
were observed in the 50 mg/kg/day males, and females. The 50 mg/kg/day 
females exhibited depleted glycogen in their hepatocytes and a fine 
vacuolation of the cellular cytoplasm in the renal medullary rays. EPA 
has already reviewed this study and concluded that: (i) the study is 
acceptable; and,(ii) a NOAEL was not established and the LOAEL in this 
study was 2 mg/kg/day based on slight bradycardia and an increased 
incidence of diarrhea in both sexes and, in females only, reduced body 
weight gain, reduced body weight, reduced food consumption, emaciation, 
and torpor.
    iv. Dog chronic toxicity. Fenpyroximate (technical grade) was 
administered to four beagle dogs/sex/dose by capsule at dose levels of 
0.5, 1.5, 5.0, or 15 mg/kg/day plus a vehicle control group for 52 
weeks. Dogs of both sexes in all treatment groups had 26% - 45% lower 
blood cholesterol concentrations compared to controls. No accompanying 
changes in liver function or pathology were noted. There was a more 
frequent occurrence of diarrhea in males of the 5 and 15 mg/kg/day 
groups. Males in the 15 mg/kg/day dose group had reduced body weight, 
consumed less food, and exhibited bradycardia during the first 24 hours 
after dosing. Aside from lowered cholesterol levels, the only effect 
noted in females was an increased incidence of diarrhea in the 5 and 15 
mg/kg/day groups. No treatment related changes in ophthalmology, 
hematology, urinalysis, organ weights, electrocardiogram, clinic 
chemistry (aside from lower cholesterol), and in gross or micro 
pathology were observed. Relative prostate weights were elevated in all 
male treatment groups relative to contols. EPA has already reviewed 
this study and concluded that: (i) the study is acceptable; and, (ii) 
the NOAEL, and LOAEL in this study were 5 mg/kg/day, and 15 mg/kg/day, 
respectively, for both males, and females based on diarrehea, 
bradycardia decreased cholesterol, body weight and food consumption in 
males and on vomiting, diarrhea, excessive salivation, and decreased 
cholesterol in females. EPA has inquired as to the mechanism of the 
prostate weight effect and Nihon Nohyaku has recently sumitted 
historical control data and other information which demonstrate that in 
this study the control group has an unusually low mean relative 
prostate weight and that no fenpyroximate related effect on relative 
prostate weight in fact occurred in this study.
    3. Oncogenicity. The following studies were submitted by Nihon 
Nohyaku: oncogenicity in rats (MRID 43560502), and oncogenicity in mice 
(MRID 43560503).
    i. Rat oncogenicity. A combined oncogenicity/chronic toxicity study 
(Guideline 83-5) was conducted. For the oncogenicity phase of this 
study, fenpyroximate (technical grade) was administered to 50 rats/sex/
dose in the diet at dose levels of 0, 10, 25, 75, or 150 ppm (Male 
average: 0.40, 0.97, 3.0, or 6.2 mg/kg/day; Female average: 0.49, 1.2, 
3.8, or 8.0 mg/kg/day; 0 ppm = control) for 104 weeks. Chronic toxicity 
was observed in males, and females receiving 75 or 150 ppm. This 
consisted of depressed growth rate and food efficiency. No treatment 
related effect on general condition, hematology, clinical chemistries, 
urinalysis, ophthalmology examinations, gross pathology, or micro 
pathology were observed. There were no treatment related increases in 
tumor incidence when compared to controls. EPA has already reviewed 
this study and concluded that: (i) the study is acceptable; and, (ii) 
fenpyroximate was not oncogenic in the rat in this study.
    ii. Mouse oncogenicity. Fenpyroximate (technical grade) was 
administered to 50 mice/sex/dose in the diet at dose levels of 0, 25, 
100, 400, or 800 ppm (Male average: 2.4, 9.5, 38, or 70 mg/kg/day; 
Female average: 2.5, 10, 42, or 73 mg/kg/day; 0 = control) for 104 
weeks. mption were dose related in magnitude and were significant 
throughout the study at 400 or 800 ppm and were significant during 
weeks 8 - 12 at 100 ppm. No other treatment related effects of 
biological significance were observed. There were no treatment related 
increases in tumor incidence when compared to controls. EPA has already 
reviewed this study and concluded that: (i) the study is acceptable; 
(ii) fenpyroximate was not oncogenic in mice in this study; and, (iii) 
the NOAEL, and the LOAEL in this study were 25 ppm (2.4 mg/kg/day in 
males, and 2.5 mg/kg/day in females) and 100 ppm (9.5 mg/kg/day in 
males, and 10 mg/kg in females) respectively based on decreased body 
weight and food comsumption.
    4. Developmental effects. The following studies were submitted by 
Nihon Nohyaku: developmental toxicity in rats (MRID 43429505), and 
developmental toxicity in rabbits (MRID 43429504).
    i. Rat developmental toxicity. Fenpyroximate was administered to 22 
CD Sprague Dawley female rats per dose group, via gavage dosing, at 
levels of 0, 1.0, 5.0, or 25 mg/kg/day from days 6 - 15 of gestation. 
Maternal body weight and food consumption were significantly depressed 
at 25 mg/kg/day on days 6 - 11 of gestation. There were no treatment 
related effects on mortality, clinical signs, cesarean parameters, or 
fetal observations at necropsy at any dose level. Potential 
developmental effects were characterized as an increase in the litter 
incidence of additional thoracic ribs which was most marked in the 25 
mg/kg/day group. EPA has already reviewed this study and concluded 
that: (i) the study is acceptable; (ii) the maternal NOAEL, and LOAEL 
are 5.0 mg/kg/day and, 25 mg/kg/day respectively based on the maternal 
toxicity data; and, (iii) the NOAEL, and LOAEL for developmental 
toxicity in this study were 5.0 mg/kg/day, and 25 mg/kg/day 
respectively based on the increased fetal incidence of thoracic ribs. 
EPA has requested more detailed historical control data to assess 
whether the increased incidence of thoracic ribs is indeed treatment 
related and Nihon Nohyaku has recently submitted these data for review.
    ii. Rabbit developmental toxicity. Fenpyroximate was administered 
to 15 New Zealand white female rabbits per dose group, via gavage 
dosing, at levels of 0, 1.0, 2.5, or 5.0 mg/kg/day from days 6 - 19 of 
gestation. In its initial review of this study, EPA concluded that 
there were no treatment related effects on maternal body weight, 
mortality, clinical signs, cesarean parameters, or fetal observations 
at necropsy at any dose level. Potential developmental effects were 
characterized as an increase in retinal folding in the 5 mg/kg/day 
group. EPA has already reviewed this study and concluded in its initial 
review that: (i) the study is supplemental because overt maternal 
toxicity had not been demonstrated; (ii) the maternal NOAEL, and LOAEL 
are both > 5.0 mg/kg/day the highest dose tested (HDT); and, (iii) the 
NOAEL, and LOAEL for

[[Page 8094]]

developmental toxicity in this study were both > 5.0 mg/kg/day the HDT. 
EPA has requested more detailed historical control data on retinal 
folding in the performing laboratory, a combined analysis of unilateral 
and bilateral retinal folding in this study, and a justification for 
dose selection in this study (in the form of the range finding data and 
other re-analysis which may be developed). Nihon Nohyaku has recently 
submitted the requested historical control and range finding data, a 
combined analysis of unilateral and bilateral retinal folding, and a 
correlation analysis of weight losses and decreases in fecal output 
intreated dams for review. Nihon Nohyaku's evaluation of these 
additional data indicates that bilateral folding was not a treatment 
effect, falling into the range of historical controls, and that 
significant body weight decreases occurred in the 5 mg/kg/day group 
dams during a period critical to fetal organ development, this decrease 
exhibited a dose trend in magnitude of the effect, with no effect at 1 
mg/kg/day, and that this effect on body weight correlated with a drop 
in fecal output but not in feed consumption. Nihon Nohyaku believes 
that the NOAEL for maternal toxicity should be 2.5 mg/kg/day; the LOAEL 
for maternal toxicity should be 5 mg/kg/day; the NOAEL for 
developmental effects should be 5 mg/kg/day HDT; and that maternal 
toxicity has been demonstrated and the dose selection in this study was 
reasonable.
    5. Reproductive effects. A 2-generation reproductive effects study 
with fenpyroximate was performed in the rat (MRID 43429506). In this 
study the technical form of fenpyroximate was used. There were three 
dose groups (10, 30, and 100 ppm) and a control group. There were 24 
males, and 24 females per group in the F0 generation and 24 per sex per 
group were selected to form the F1 breeding generation. The 
age of the parent animals at the commencement of the study was 
approximately 6 weeks and the weight range was 168-217 g for males and 
128-167 g for females. The F0 generation was treated 
continuously by the dietary route throughout the study and until 
termination after the breeding phase. After 14 weeks of treatment, F0 
animals were paired to produce F1 litters. The F1 generation 
was treated from weaning until termination after the breeding phase. 
Both sexes received 14 weeks treatment before pairing to produce the 
F2 litters. For each breedingcycle, a 7 day mating period 
was used. Females not mated within the mating period were then mated 
for an additional 7 day period with a different male, of a proven 
mating ability, from the same treatment group. The study was continued 
through weaning of the F2 generation. During general, daily 
observations the condition of F0 and F1 males, 
and females was similar to that of the controls throughout the study. 
The general condition of the F2 males and females up through 
weaning was similar among all group. The litter size, sex ratio, the 
offspring viability indices before and after culling and the rate of 
development (pinna unfolding, hair growth, tooth eruption and eye 
opening) were not adversely affected by treatment in the F1 
and F2 generations. Macro- and micro-pathology examinations 
at sacrifice revealed no treatment related changes were in the 
F0 animals, the F1 animals, the F2 
offspring that were culled on day 4 post-partum, nor in the 
F2 offspring at termination after weaning. Signs of toxicity 
which were observed in the high dose group included:
    i. Males (Fo). Body weight was statistically, slightly lower, in 
the high dose group (100 ppm) compared to controls. Food consumption 
was reduced for the majority of the period before pairing.
    ii. Females (Fo). Prior to pairing, at commencement of gestation, 
during gestation, and on day 1 post-partum the weight gain of females 
at the high dose was significantly lower than that of controls (P= < .05).="" iii.="" offspring.="" body="" weight="" of="" male="" offspring="" at="" the="" high="" dose="" was="" significantly="" reduced="" at="" commencement="" of="" the="">1 generation 
and subsequent weight gain to termination was reduced compared with the 
concurrent control group (P= <.001). food="" consumption="" in="" the="" period="" before="" pairing="" was="" marginally="" reduced.="" the="" testes="" weight="" relative="" to="" body="" weight="" of="">1 males showed a significant increase at the 
high dose. In females, weight gain was slightly reduced with the result 
that absolute body weight was significantly reduced at the commencement 
of gestation (p =< 0.05),="" was="" further="" reduced="" during="" gestation,="" but="" recovered="" during="" lactation.="" epa="" has="" already="" reviewed="" this="" study="" and="" concluded="" that:="" (a)="" the="" study="" is="" acceptable;="" (b)="" there="" were="" no="" adverse="" effects="" on="" reproductive="" performance;="" and,="" (c)="" the="" noael,="" and="" loael="" for="" reproductive="" and="" systemic="" toxicity="" in="" this="" study="" were="" 30="" ppm="" (2.44="" mg/="" kg/day)="" and,="" 100="" ppm="" (8.60="" mg/kg/day)="" respectively="" based="" on="" reduced="" pup="" weights="" after="" birth.="" 6.="" genotoxicity.="" fenpyroximate="" was="" tested="" for="" genotoxic="" effects="" in="" several="" standard="" test="" systems="" with="" the="" following="" results:="" ----------------------------------------------------------------------------------------------------------------="" test="" endpoint="" result="" ----------------------------------------------------------------------------------------------------------------="" ames="" test="" (s.="" typhimurium)..............="" mutagenicity="" negative="" chinese="" hamster="" v79="" forward="" mutation....="" mutagenicity="" negative="" cultured="" human="" lymphocytes..............="" chromosome="" damage="" negative="" mouse="" micronucleus="" test.................="" chromosome="" damage="" negative="" dna="" repair="" test="" (reca-assay)............="" non-specific="" gene="" damage="" negative="" unscheduled="" dna="" synthesis...............="" non-specific="" gene="" damage="" negative="" ----------------------------------------------------------------------------------------------------------------="" on="" the="" basis="" of="" the="" above="" genotoxicity="" test="" battery="" results,="" nihon="" nohyaku="" co.,="" ltd.="" concludes="" that="" fenpyroximate="" is="" not="" mutagenic,="" clastogenic,="" or="" otherwise="" genotoxic.="" 7.="" general="" metabolism.="" in="" support="" of="" the="" import="" tolerance="" for="" fenpyroximate,="" severalmammalian="" metabolism="" studies="" were="" submitted="" by="" nihon="" nohyaku="" co.,="" ltd..="" these="" studies="" are:="" 1.="" mrid="" 43560504.="" metabolism="" and="" disposition="" of="" benzyl-="">14C NNI-850 in Rats HLA 6283-101
    2. MRID 43560505. Metabolism and Disposition of Pyrazole-
14C NNI-850 in Rats HLA 6283-102
    3. MRID 43429513. Pharmacokinetics of a Benzyl-14C NNI-
850 in Rats (High and Low Doses) HLA 6283-103 and Pharmacokinetics of a 
Pyrazole-14C NNI-850 in Rats (High and Low Doses) HLA 6283-
103 (note: reports for two studies submitted as one combined volume 
under a single MRID)
    These studies are summarized, here, in aggregate so as to provide a 
more comprehensive picture of the mammalian metabolism of 
fenpyroximate.
    The test article was purified fenpyroximate (99+% purity) with 
14C radio-labeled fenpyroximate. Labeling was in either the 
pyrazole or the benzyl rings of the compound so as to assure

[[Page 8095]]

detection of metabolites resulting from cleavage of the imine linkage 
between these two ring systems. Young, healthy Sprague Dawley rats were 
used. Five animals were assigned per sex/time point group for 
pharmacokinetic studies and for time course determinations of urinary 
and fecal metabolites. Three animals per sex/time point were assigned 
for tissue distribution as a function of time studies. Both low and a 
high doses were tested (2 mg/kg, and 400 mg/kg). Test article 
administration was by the oral route for all dose groups. The sample 
collection schedules (blood, urine, and feces) for pharmacokinetics 
(absorption and elimination) were at 1, 3, 6, 9, 12, 18, 24, 48, 72, 
96, 120, 144, and 168 hours post-dose. For metabolism and distribution, 
sample collection was as follows: urine and feces at the same time 
points as for pharmacokinetics; and, tissues taken at 24, 96, and 120 
hours. Expired air was not collected since preliminary study showed 
negligible excretion of the label by this route. The results of these 
studies were as follows:
    i. Pharmacokinetics--a. Pyrazole labeled. The half-life of 
elimination from blood for the low dose group was 8.9 hours (M & F) and 
the time to peak blood levels was 11.0 (M) - 11.4 hours (F). Mean 
maximum concentrations were 0.152 g equivalents/g (M) and 
0.176 g eq./g (F). AUCs for males and females were 3.49 and 
3.82 g-hr/ml respectively. By 72 hours the level of label in 
blood declines to below detectable levels.
    The half-life of elimination from blood for the high dose group was 
48.7 hours (M), and 45.3 hours (F). The time to peak blood levels was 
90 (F) -101 hours (M). Mean maximum concentrations were 4.67 g 
eq./g (M), and 4.69 g eq./g (F). AUCs for males and females 
were 377, and 411 g-hr/ml respectively. By 216 hours the level 
of label in blood declines to below detectable levels.
    b. Benzyl labeled. The half-life of elimination from blood for the 
low dose group was 6.1 hours (M), and 7.9 hours (F). Time to peak blood 
levels was 7.2 (F) - 7.8 hours (M). Mean maximum concentrations were 
0.097 g eq./g (M), and 0.181 g eq./g (F). AUCs for 
males and females were 1.80, and 3.01 g-hr/ml respectively. By 
48 hours the level of label in blood declines to below detectable 
levels.
    The half-life of elimination from blood for the high dose group was 
47.0 hours (M), and 35.4 hours (F). The time to peak blood levels was 
28.2 (M) -86.4 hours (F). Mean maximum concentrations were 5.10 
g eq./g (M), and 8.88 g eq./g (F). AUCs for males and 
females were 425, and 728 g-hr/ml respectively. After 168 
hours the level of label in blood declines to below detectable levels.
    ii. Metabolism--a. Pyrazole labeled. Fenpyroximate was not 
metabolized to volatiles to any significant degree. The majority of 
label is excreted in the feces (69.7% - 84.8% for males, and females). 
Urinary excretion accounts for from 10.8% - 17.8% of the label. Thus, 
feces and urine are the major routes of excretion for fenpyroximate. 
Tissue did not accumulate fenpyroximate or its metabolites to any great 
extent. The greatest levels of label were in liver, kidneys, heart, and 
urinary bladder. These tissues had much higher levels of label than did 
fat. In blood, nearly all of the label is in the plasma.
    b. Benzyl labeled. Fenpyroximate was not metabolized to volatiles 
to any significant degree. The majority of label is excreted in the 
feces (77.9% - 91.6% for males, and females). Urinary excretion 
accounts for from 9.47% - 13.8% of the label. Thus, feces and urine are 
the major routes of excretion for fenpyroximate. Tissue did not 
accumulate fenpyroximate or its metabolites to any great extent. The 
greatest levels of label were in liver, kidneys, adrenals, and fat (to 
a lesser degree). In blood, nearly all of the label is in the plasma.
    c. Overall. The major urinary metabolites of fenpyroximate were 
1,3-dimetyl-5-phenoxypyrazole-4-carboxylic acid, 4-cyano-1-methyl-5-
phenoxypyrazole-3-carboxylic acid, and terephthalic acid. In feces, 
there was a large amount of fenpyroximate itself with major fecal 
metabolites being (E)--(1,3-dimethyl-5-phenoxypyrazol-4-
ylmethyleneamino-oxy)-p-toluic acid, (Z)--(1,3-dimethyl-5-
phenoxypyrazol-4-ylmethyleneamino-oxy)-p-toluic acid, and (E)-2-4-(1,3-
dimethyl-5-phenoxypyrazol-4-ylmethyleneamino-oxymethyl)benzoyloxy-2-
methypropionic acid. The mammalian metabolism of fenpyroximate appears 
to proceed by oxidation of the tert-butyl and pyrazole-3-methyl groups, 
by p-hydroxylation of the phenoxy moiety, by N-demethylation, by 
hydrolysis of the ester and methyleneamino bonds, by conjugation, and 
by E/Z isomerization.
    8. Oral reference dose (RfD). In 1997, an oral RfD of 0.01 mg/kg/
day for fenpyroximate was recommended by EPA. This is based on the 2 
year rat feeding study in which the NOAEL for males, and females was 
0.97 mg/kg/day, and 1.21 mg/kg/day (respectively), and application of a 
100-fold uncertainty factor (UF).

C. Aggregate Exposure

    1. Dietary exposure--Food. Nihon Nohyaku Co., Ltd. has submitted 
residue data and information on consumption of end-use processed foods 
from grapes, and hops (wine, and beer) which allow for estimation of 
the percent RfD utilization at the upper 99th percentile of consumption 
for beer or wine. These estimates are as follows:
    i.  Wine. According to data publicly available from the Department 
of Commerce and USDA, imports of wine to the United States, are in the 
range of 52.8 - 58.1 million gallons (from Italy, France, Spain, 
Germany, and Portugal combined) in comparison to an annual wine 
consumption in the United States of 721 million gallons per year. Thus, 
imported wines account for only 8% of wine consumption. USDA food and 
beverage consumption data establish that at the upper 99th percentile, 
male wine drinkers consume 0.89 L wine per day and females wine 
drinkers consume 0.45 L wine per day. Data submitted by Nihon Nohyaku 
establish that fenpyroximate residues in wines made from treated grapes 
are less than 20 parts per billion (ppb), and that TTR in grapes is at 
most 3-fold the measured fenpyroximate level (i.e., TTR will be less 
than 60 ppb in wines). Therefore, assuming that 100% of the grapes 
going into such imported wines are fenpyroximate treated (a deliberate 
over-estimate), the RfD percent utilization at the upper 99th 
percentile for wine consumption is 0.61% for males, and 0.36% for 
females. Nihon Nohyaku Co.,Ltd. has noted that wine drinkers at the 
upper 99th percentile will be less likely to consume imported wine than 
will wine drinkers at the median consumption levels. At median 
consumption levels (approximately 5-fold lower than the upper 99th 
percentile consumption) the percent RfD utilization is 0.12% for male 
wine drinkers, and 0.072% for female wine drinkers.
    ii. Beer. Data available from the Hop Growers of America, Inc. 
indicate: (a) that United States hops production ranges, annually, from 
75 million to 79 million pounds, of which between 43-million and 51 
million pounds are exported annually; and, (b) that United States 
imports of hops from Germany are a maximum of 7.9-milion lbs/year, and 
from Czechoslovakia are a maximum of 2.0 million lbs/year (the combined 
maxima equal 9.9 million lbs/year). Therefore, domestic hops utilized 
in the United States are a minimum of 24 million lbs/year against a 
maximum of 9.9 million lbs/year of imported hops and an annual hop use 
of 34 million lbs/

[[Page 8096]]

year. This means that at most 29% of beer which is domestically brewed 
will contain imported hops. The exposure contribution of imported beer 
can be similarly estimated from BATF and USDA data which are publicly 
available. Annual production of domestic beer is 190-198 million 
barrels (31 gallons each = 6.13 billion gallons) with a total value of 
13.6 - 14.3 billion. Of this, exports account for approximately 0.08 
billion, meaning that nearly all domestic beer is consumed in the 
United States. Annual consumption of beer in the United States is 8.56 
billion gallons, of which as above-noted, 6.13 billion gallons are 
produced domestically. Thus, comparing the domestic production to the 
annual consumption gives an estimate for imported beer as 28% of annual 
beer consumption. Imported beer in the United States derives primarily 
from the Netherlands, Canada, and Mexico with lesser contributions from 
other countries (USDA data). For purposes of exposure assessment, a 
prudent ``worst case'' assumption is that European derived beer is 33% 
of total imported beer, the balance being from Canada, Mexico, and 
other sources. Thus, European derived imported beer can be estimated to 
account for not more than 9.2% of beer consumed in the United States. 
Combining consumption of domestic beer utilizing imported hops (maximum 
of 29% of beer consumed), and the consumption of European derived 
imported beer (maximum of 9.2% of beer consumed) provides that not more 
than 38% of beer consumed has any potential to contain fenpyroximate 
residues as a result of approval of this petition. Hopping rates in 
beer production are less than 0.001 parts by weight in brew water (Hop 
Growers of America data) which means that fenpyroximate residues in 
hops will be diluted by at least 0.001 fold in finished beer. At the 
tolerance of 10 ppm in dried hops (which are what is used in brewing) 
and using the TTR fenpyroximate ratio of 3x, TTR in dried hops would be 
30 ppm and would be not more than 30 ppb in finished beer. USDA food 
and beverage consumption data establish that at the upper 99th 
percentile, male beer and ale drinkers consume 2.76 L beer or ale per 
day, and females beer and ale drinkers consume 1.44 L beer or ale per 
day. Therefore, applying the factor of 38% for the maximum percent of 
beer which could contain fenpyroximate residues, the RfD percent 
utilization at the upper 99th percentile for beer consumption is 4.5% 
for males, and 2.7% for females. Nihon Nohyaku Co., Ltd. has noted: (a) 
that beer and ale drinkers at the upper 99th percentile will be less 
likely to consume imported beer and ale than will beer and ale drinkers 
at the median consumption levels; and, (b) that ales are not hopped. At 
median consumption levels (approximately 5 fold lower than the upper 
99th percentile consumption) the percent RfD utilization is 0.90% for 
male beer and ale drinkers, and 0.54% for female beer and ale drinkers
    iii. Drinking water. This is an import tolerance petition and there 
are no uses of fenpyroximate in the United States. Accordingly, there 
is no potential for drinking water exposure associated with the 
approval of this petition.
    2. Non-dietary exposure. Fenpyroximate is not registered in the 
United States and is only an agricultural use miticide. Therefore, 
there are non-dietary exposure which could result from approval of this 
petition. Were fenpyroximate to be registered in the United States 
there would still be no potential for non-dietary, non-occupational 
exposures.

D. Cumulative Effects

    There is no reliable information to indicate that fenpyroximate has 
a common mechanism of toxicity with any other chemical compound.

E. Endocrine Effects

    There is no reliable information to indicate that fenpyroximate has 
a potential to produce endocrine effects.

F. Safety Determination

    1. U.S. population. Since the proposed import tolerances for 
fenpyroximate in or on grapes and hops are, under worst case 
conditions, anticipated to lead to only negligible adult dietary 
exposures to fenpyroximate TTR (i.e., not greater than 0.61% of the RfD 
for adult wine drinkers at the upper 99th percentile of consumption, 
and not greater than 4.5% of the RfD for adult beer and ale drinkers at 
the upper 99th percentile of consumption, with ``negligible'' defined 
at 40 CFR 180.1(l) as ``ordinarily'' not greater than 5% of the RfD) 
Nihon Nohyaku Co., Ltd. concludes that there is a reasonable certainty 
that no harm to the general adult population will result from dietary 
exposure to residues which could occur as a result of approval of this 
petition.
    2. Infants and children. The proposed import tolerance does not 
affect foods or beverages legally consumed by children and infants. 
Therefore, Nihon Nohyaku Co., Ltd. concludes that there is a reasonable 
certainty that no harm to infants and children will result from dietary 
exposure to residues which could occur as a result of approval of this 
petition.
    3. Sensitive individuals. The toxicology data base for 
fenpyroximate demonstrates a consistency in effects, NOAELs, and LOAELs 
among rats, mice, and dogs. This suggests that inter-species 
differences in metabolism and sensitivity to fenpyroximate are not 
large which, in turn, suggests that metabolic and sensitivity 
differences among human subpopulations exposed to fenpyroximate will be 
small. Also, worst case exposure to residues is at negligible levels 
and the margins of exposure for wine drinkers are at least 16,000 for 
wine drinkers, and at least 2,200 for beer and ale drinkers, which 
suggests that differences in sensitivity to fenpyroximate among human 
subpopulations, including persons who were ill, would have to be quite 
large in order to lead to exposures of concern in sensitive 
individuals. Therefore, Nihon Nohyaku Co., Ltd. concludes that there is 
a reasonable certainty that no harm to sensitive persons will result 
from dietary exposure to residues which could occur as a result of 
approval of this petition.

G. International Tolerances

    There are no Codex maximum residue levels (MRLs) established for 
residues of fenpyroximate resulting from the application of 
fenpyroximate to grapes or hops. Proposals for a German MRL of 10 ppm 
on green hops and, 0.5 ppm on grapes and for Italian and Spanish MRLs 
of 0.3 ppm on grapes are being reviewed by the respective countries. 
Since these are lower than the proposed import tolerances, there is 
very little likelihood that residues in violation of the import 
tolerances could occur.
    There are no Codex MRLs established for residues of fenpyroximate 
resulting from the application of fenpyroximate to grapes or hops. 
Proposals for a German MRL of 10 ppm on green hops, and 0.5 ppm on 
grapes and for Italian and Spanish MRLs of 0.3 ppm on grapes are being 
reviewed by the respective countries. Since these are lower than the 
proposed import tolerances, there is very little likelihood that 
residues in violation of the import tolerances could occur.

2. Rohm and Haas Company

PP 7F4824

    EPA has received a revised pesticide petition (7F4824) 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

[[Page 8097]]

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 subgroup leafy greens, 
crop subgroup leaf petioles, crop subgroup head and stem Brassica and 
crop subgroup leafy Brassica greens at 10.0, 2.0, 5.0, and 10.0 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) or mass spectrometry 
(MS) detection has been validated for leafy and cole crop vegetables. 
For all matrices, the methods involve extraction by blending with 
solvents, purification of the extracts by liquid-liquid partitions and 
final purification of the residues using solid phase extraction column 
chromatography. The limit of quantitation (LOQ) of the method is 0.01 
part per million (ppm) for all representative crops of these crop 
subgroups except for celery which is 0.05 ppm.
    3. Magnitude of residues. Magnitude of the residue studies were 
conducted in celery, and mustard greens using the maximum proposed 
label rate. Samples were collected 7 days after the last application 
and were analyzed for residues of tebufenozide. The residue data 
support a tolerance of 5.0 ppm for the crop subgroup leaf petioles 
(4A), and 10.0 ppm for the crop subgroup Leafy Brassica Green 
Vegetables (5B).

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 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 adverse effect level (LOAEL) 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 LOAEL 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 
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 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 LOAEL 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 LOAEL 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

[[Page 8098]]

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 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 (Limit-Dose) during 
gestation to pregnant rats or rabbits. This risk is considered to be 
negligible.
    iii. 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 over estimate 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).="" iv.="" 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.="" v.="" 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="" 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.="" 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="" [[page="" 8099]]="" 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="" reproductive="" (pup)="" loael="" 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="" of="" tebufenozide.="" (melody="" banks)="" [[page="" 8100]]="" 3.="" rohm="" and="" haas="" company="" pp="" 7f4869="" epa="" has="" received="" a="" revised="" pesticide="" petition="" (7f4869)="" 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,="" fruiting="" vegetables="" except="" cucurbits="" at="" 1.0="" 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="" peppers,="" tomatoes,="" and="" tomato="" process="" fractions.="" the="" method="" involves="" extraction="" by="" blending="" with="" solvents,="" purification="" of="" the="" extracts="" by="" liquid-liquid="" partitions="" and="" final="" purification="" of="" the="" residues="" using="" solid="" phase="" extraction="" column="" chromatography.="" the="" limit="" of="" quantitation="" (loq)="" of="" the="" method="" for="" all="" matrices="" is="" 0.02="" ppm.="" 3.="" magnitude="" of="" residues.="" field="" residue="" trials="" in="" tomatoes,="" and="" peppers="" were="" conducted="" in="" geographically="" representative="" regions="" of="" the="" u.s.="" the="" highest="" field="" residue="" value="" for="" a="" single="" replicate="" sample="" was="" 0.76="" parts="" per="" million="" (ppm).="" results="" of="" analysis="" of="" tomato="" paste="" and="" puree="" samples="" from="" a="" processing="" study="" with="" treated="" tomatoes="" showed="" no="" concentration="" of="" residues.="" b.="" toxicological="" profile="" 1.="" acute="" toxicity.="" acute="" toxicity="" studies="" with="" technical="" grade:="" oral="">50 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 adverse level (LOAEL) 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 LOAEL 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 
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 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 LOAEL 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 LOAEL 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

[[Page 8101]]

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, 
and hen) metabolism studies.
    7. Metabolite toxicology. Common metabolic pathways for 
tebufenozide have been identified in both plants (grape, apple, rice, 
and sugar beet), and animals (rat, goat, and hen). The metabolic 
pathway common to both plants and animals involves oxidation of the 
alkyl substituents (ethyl and methyl groups) of 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 noindication that tebufenozide 
has endocrine activity in vertebrates.

C. Aggregate Exposure

    1. Dietary exposure. The dietary exposure is discussed below.
    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 
fromtebufenozide, 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 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 limit-dose (LTD) 
during gestation to pregnant rats or rabbits. This risk is considered 
to be negligible.
    iii. Chronic exposure and risk. The refrence 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 that 100% of pecans, walnuts, wine and sherry, imported 
apples 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 over 
estimate of human dietary exposure. 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 (34.5% of RfD);
    All Infants (> 1 year) (61.4%);
    Nursing Infants (> 1 year old) (39.9% of RfD);
    Non-Nursing Infants (> 1 year old) (70.4% of RfD);
    Children (1-6 years old) (79.8% of RfD);
    Children (7-12 years old) (48.5% of RfD);
    Females (13 + years old, nursing) (39.5% of RfD);
    Non-Hispanic Whites (34.8%);
    Non-Hispanic Other than Black or White (40.2% of RfD);
    Northeast Region (37.4% of RfD);
    Western Region (36.8%);
    Pacific Region (36.8%).
    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).
    iv. 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.
    v. 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.
    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,

[[Page 8102]]

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 34.5% 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.
    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 LTD 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) LOAEL 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 currently no CODEX, Canadian or Mexican maximum residue 
levels (MRLs) established for tebufenozide in fruiting vegetables so no 
harmonization issues are required for this action.
[FR Doc. 99-4023 Filed 2-17-99; 8:45 am]
BILLING CODE 6560-50-F