[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:banks.melody@epa Arlington, VA
mail.epa.gov.
Joseph M. Tavano.............. Rm. 214, CM #2, 703- Do.
305-6411, e-mail:
tavano.joseph@epamail
.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:
[email protected]
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption. Comment and data
will also be accepted on disks in Wordperfect 5.1 file format or ASCII
file format. All comments and data in electronic form must be
identified by the docket 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 F1 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 F1 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 LD50 in the rat is > 5 grams for males and females -
Toxicity Category IV; dermal LD50 in the rat is = 5,000
milligram/kilogram (mg/kg) for males, and females - Toxicity Category
III; inhalation LD50 in the rat is > 4.5 mg/l - Toxicity
Category III; primary eye irritation study in the rabbit is a non-
irritant; primary skin irritation in the rabbit > 5 mg - Toxicity
Category IV. tebufenozide is not a sensitizer.
2. Genotoxicty. Several mutagenicity tests which were all negative.
These include an Ames assay with and without metabolic activation, an
in vivo cytogenetic assay in rat bone marrow cells, and in vitro
chromosome aberration assay in CHO cells, a CHO/HGPRT assay, a reverse
mutation assay with E. Coli, and an unscheduled DNA synthesis assay
(UDS) in rat hepatocytes.
3. Reproductive and developmental toxicity. In a prenatal
developmental toxicity study in Sprague-Dawley rats 25/group
tebufenozide was administered on gestation days 6-15 by gavage in
aqueous methyl cellulose at dose levels of 50, 250, or 1,000 mg/kg/day
and a dose volume of 10 ml/kg. There was no evidence of maternal or
developmental toxicity; the maternal and developmental toxicity no-
observed adverse effect level (NOAEL was 1,000 mg/kg/day.
In a prenatal developmental toxicity study conducted in New Zealand
white rabbits 20/group tebufenozide was administered in 5 ml/kg of
aqueous methyl cellulose at gavage doses of 50, 250, or 1,000 mg/kg/day
on gestation days 7-19. No evidence of maternal or developmental
toxicity was observed; the maternal and developmental toxicity NOAEL
was 1,000 mg/kg/day.
In a 1993 2-generation reproduction study in Sprague-Dawley rats
tebufenozide was administered at dietary concentrations of 0, 10, 150,
or 1,000 ppm (0, 0.8, 11.5, or 154.8 mg/kg/day for males, and 0, 0.9,
12.8, or 171.1 mg/kg/day for females). The parental systemic NOAEL was
10 ppm (0.8/0.9 mg/kg/day for males and females, respectively) and the
lowest-observed 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