[Federal Register: April 13, 2005 (Volume 70, Number 70)]
[Notices]
[Page 19446-19452]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr13ap05-103]
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ENVIRONMENTAL PROTECTION AGENCY
[OPP-2005-0047; FRL-7699-9]
Etoxazole; Notice of Filing a Pesticide Petition to Establish a
Tolerance for a Certain Pesticide Chemical in or on Food
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: This notice announces the initial filing of a pesticide
petition proposing the establishment of regulations for residues of a
certain pesticide chemical in or on various food commodities.
DATES: Comments, identified by docket identification (ID) number OPP-
2005-0047, must be received on or before May 13, 2005.
ADDRESSES: Comments may be submitted electronically, by mail, or
through hand delivery/courier. Follow the detailed instructions as
provided in Unit I. of the SUPPLEMENTARY INFORMATION.
FOR FURTHER INFORMATION CONTACT: Kable Bo Davis, Registration Division
(7505C), Office of Pesticide Programs, Environmental Protection Agency,
1200 Pennsylvania Ave., NW., Washington, DC 20460-0001; telephone
number: (703) 306-0415; e-mail address: davis.kable@epa.gov.
SUPPLEMENTARY INFORMATION:
I. General Information
A. Does this Action Apply to Me?
You may be potentially affected by this action if you an
agricultural producer, food manufacturer, or pesticide manufacturer.
Potentially affected entities may include, but are not limited to:
Crop production (NAICS 111)
Animal production (NAICS 112)
Food manufacturing (NAICS 311)
Pesticide manufacturing (NAICS 32532)
This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in this unit could also be
affected. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether this action might apply to certain entities. If you have any
questions regarding the applicability of this action to a particular
entity, consult the person listed under FOR FURTHER INFORMATION
CONTACT.
B. How Can I Get Copies of this Document and Other Related Information?
1. Docket. EPA has established an official public docket for this
action under docket ID number OPP-2005-0047. The official public docket
consists of the documents specifically referenced in this action, any
public comments received, and other information related to this action.
Although, a part of the official docket, the public docket does not
include Confidential Business Information (CBI) or other information
whose disclosure is restricted by statute. The official public docket
is the collection of materials that is available for public viewing at
the Public Information and Records Integrity Branch (PIRIB), Rm. 119,
Crystal Mall 2, 1801 S. Bell St., Arlington, VA. This docket
facility is open from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays. The docket telephone number is (703) 305-
5805.
2. Electronic access. You may access this Federal Register document
electronically through the EPA Internet under the ``Federal Register''
listings at http://www.epa.gov/fedrgstr/.
An electronic version of the public docket is available through
EPA's electronic public docket and comment system, EPA Dockets. You may
use EPA Dockets at http://www.epa.gov/edocket/ to submit or view public
comments, access the index listing of the contents of the official
public docket, and to access those documents in the public docket that
are available electronically. Although, not all docket materials may be
available electronically, you may still access any of the publicly
available docket materials through the docket facility identified in
Unit I.B.1. Once in the system, select ``search,'' then key in the
appropriate docket ID number.
Certain types of information will not be placed in the EPA
Dockets. Information claimed as CBI and other information whose
disclosure is restricted by statute, which is not included in the
official public docket, will not be available for public viewing in
EPA's electronic public docket. EPA's policy is that copyrighted
material will not be placed in EPA's electronic public docket but will
be available only in printed, paper form in the official public docket.
To the extent feasible, publicly available docket materials will be
made available in EPA's electronic public docket. When a document is
selected from the index list in EPA Dockets, the system will identify
whether the document is available for viewing in EPA's electronic
public docket. Although, not all docket materials may
[[Page 19447]]
be available electronically, you may still access any of the publicly
available docket materials through the docket facility identified in
Unit I.B. EPA intends to work towards providing electronic access to
all of the publicly available docket materials through EPA's electronic
public docket.
For public commenters, it is important to note that EPA's policy
is that public comments, whether submitted electronically or on paper,
will be made available for public viewing in EPA's electronic public
docket as EPA receives them and without change, unless the comment
contains copyrighted material, CBI, or other information whose
disclosure is restricted by statute. When EPA identifies a comment
containing copyrighted material, EPA will provide a reference to that
material in the version of the comment that is placed in EPA's
electronic public docket. The entire printed comment, including the
copyrighted material, will be available in the public docket.
Public comments submitted on computer disks that are mailed or
delivered to the docket will be transferred to EPA's electronic public
docket. Public comments that are mailed or delivered to the docket will
be scanned and placed in EPA's electronic public docket. Where
practical, physical objects will be photographed, and the photograph
will be placed in EPA's electronic public docket along with a brief
description written by the docket staff.
C. How and to Whom Do I Submit Comments?
You may submit comments electronically, by mail, or through hand
delivery/courier. To ensure proper receipt by EPA, identify the
appropriate docket ID number in the subject line on the first page of
your comment. Please ensure that your comments are submitted within the
specified comment period. Comments received after the close of the
comment period will be marked ``late.'' EPA is not required to consider
these late comments. If you wish to submit CBI or information that is
otherwise protected by statute, please follow the instructions in Unit
I.D. Do not use EPA Dockets or e-mail to submit CBI or information
protected by statute.
1. Electronically. If you submit an electronic comment as
prescribed in this unit, EPA recommends that you include your name,
mailing address, and an e-mail address or other contact information in
the body of your comment. Also, include this contact information on the
outside of any disk or CD ROM you submit, and in any cover letter
accompanying the disk or CD ROM. This ensures that you can be
identified as the submitter of the comment and allows EPA to contact
you in case EPA cannot read your comment due to technical difficulties
or needs further information on the substance of your comment. EPA's
policy is that EPA will not edit your comment, and any identifying or
contact information provided in the body of a comment will be included
as part of the comment that is placed in the official public docket,
and made available in EPA's electronic public docket. If EPA cannot
read your comment due to technical difficulties and cannot contact you
for clarification, EPA may not be able to consider your comment.
i. EPA Dockets. Your use of EPA's electronic public docket to
submit comments to EPA electronically is EPA's preferred method for
receiving comments. Go directly to EPA Dockets at http://www.epa.gov/edocket/
, and follow the online instructions for submitting comments.
Once in the system, select ``search,'' and then key in docket ID number
OPP-2005-0047. The system is an ``anonymous access'' system, which
means EPA will not know your identity, e-mail address, or other contact
information unless you provide it in the body of your comment.
ii. E-mail. Comments may be sent by e-mail to opp-docket@epa.gov,
Attention: Docket ID number OPP-2005-0047. In contrast to EPA's
electronic public docket, EPA's e-mail system is not an ``anonymous
access'' system. If you send an e-mail comment directly to the docket
without going through EPA's electronic public docket, EPA's e-mail
system automatically captures your e-mail address. E-mail addresses
that are automatically captured by EPA's e-mail system are included as
part of the comment that is placed in the official public docket, and
made available in EPA's electronic public docket.
iii. Disk or CD ROM. You may submit comments on a disk or CD ROM
that you mail to the mailing address identified in Unit I.C.2. These
electronic submissions will be accepted in WordPerfect or ASCII file
format. Avoid the use of special characters and any form of encryption.
2. By mail. Send your comments to: Public Information and Records
Integrity Branch (PIRIB) (7502C), Office of Pesticide Programs (OPP),
Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,
Washington, DC 20460-0001, Attention: Docket ID number OPP-2005-0047.
3. By hand delivery or courier. Deliver your comments to: Public
Information and Records Integrity Branch (PIRIB), Office of Pesticide
Programs (OPP), Environmental Protection Agency, Rm. 119, Crystal Mall
2, 1801 S. Bell St., Arlington, VA, Attention: Docket ID
number OPP-2005-0047. Such deliveries are only accepted during the
docket's normal hours of operation as identified in Unit I.B.1.
D. How Should I Submit CBI to the Agency?
Do not submit information that you consider to be CBI
electronically through EPA's electronic public docket or by e-mail. You
may claim information that you submit to EPA as CBI by marking any part
or all of that information as CBI (if you submit CBI on disk or CD ROM,
mark the outside of the disk or CD ROM as CBI and then identify
electronically within the disk or CD ROM the specific information that
is CBI). Information so marked will not be disclosed except in
accordance with procedures set forth in 40 CFR part 2.
In addition to one complete version of the comment that includes
any information claimed as CBI, a copy of the comment that does not
contain the information claimed as CBI must be submitted for inclusion
in the public docket and EPA's electronic public docket. If you submit
the copy that does not contain CBI on disk or CD ROM, mark the outside
of the disk or CD ROM clearly that it does not contain CBI. Information
not marked as CBI will be included in the public docket and EPA's
electronic public docket without prior notice. If you have any
questions about CBI or the procedures for claiming CBI, please consult
the person listed under FOR FURTHER INFORMATION CONTACT.
E. What Should I Consider as I Prepare My Comments for EPA?
You may find the following suggestions helpful for preparing your
comments:
1. Explain your views as clearly as possible.
2. Describe any assumptions that you used.
3. Provide copies of any technical information and/or data you used
that support your views.
4. If you estimate potential burden or costs, explain how you
arrived at the estimate that you provide.
5. Provide specific examples to illustrate your concerns.
6. Make sure to submit your comments by the deadline in this
notice.
7. To ensure proper receipt by EPA, be sure to identify the docket
ID number assigned to this action in the subject line on the first page
of your response.
[[Page 19448]]
You may also provide the name, date, and Federal Register citation.
II. What Action is the Agency Taking?
EPA has received a pesticide petition as follows proposing the
establishment and/or amendment of regulations for residues of a certain
pesticide chemical in or on various food commodities under section 408
of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a.
EPA has determined that this petition contains data or information
regarding the elements set forth in FFDCA section 408(d)(2); however,
EPA has not fully evaluated the sufficiency of the submitted data at
this time or whether the data support granting of the petition.
Additional data may be needed before EPA rules on the petition.
List of Subjects
Environmental protection, Agricultural commodities, Feed
additives, Food additives, Pesticides and pests, Reporting and
recordkeeping requirements.
Dated: April 1, 2005.
Lois Rossi,
Director, Registration Division, Office of PesticidePrograms.
Summary of Petition
The petitioner's summary of the pesticide petition is printed
below as required by FFDCA section 408(d)(3). The summary of the
petition was prepared by Valent U.S.A. Corporation and represents the
view of the petitioner. The petition summary announces the availability
of a description of the analytical methods available to EPA for the
detection and measurement of the pesticide chemical residues or an
explanation of why no such method is needed.
Valent U.S.A. Corporation
PP 3F6739
EPA has received a pesticide petition PP 3F6739 from Valent U.S.A.
Corporation, 1333 North California Boulevard, Suite 600, Walnut Creek,
CA 94596-8025 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 the chemical
etoxazole, 2-(2,6-difluorophenyl)-4-[4-(1,1-dimethylethyl)-2-
ethoxyphenyl]-4,5-dihydrooxazole, in or on the raw agricultural
commodities nut, tree (Crop Group 14), including pistachios at 0.01
parts per million (ppm), almond, hulls at 2.0 ppm, grapes at 0.5 ppm,
and raisins at 1.5 ppm. EPA has determined that the petition contains
data or information regarding the elements set forth in section
408(d)(2) of the FFDCA; however, EPA has not fully evaluated the
sufficiency of the submitted data at this time or whether the data
support granting of the petition. Additional data may be needed before
EPA rules on the petition.
A. Residue Chemistry
1. Plant metabolism. The metabolism of etoxazole is adequately
understood for the purpose of the proposed tolerances.
2. Analytical methods. Practical analytical methods for detecting
and measuring levels of etoxazole have been developed and validated in/
on all appropriate agricultural commodities and respective processing
fractions. The extraction methodology has been validated using aged
radiochemical residue samples from 14C-metabolism studies.
The enforcement methods have been validated in cottonseed, cotton gin
trash, and in fresh mandarin oranges at independent laboratories. The
LOQ of etoxazole in these methods is 0.01 ppm in grapes and nutmeats
and 0.05 ppm in almond, hulls, which will allow monitoring of food with
residues at the levels proposed for the tolerances.
3. Magnitude of residues. An extensive crop residue program has
been conducted for etoxazole in all major growing regions of the United
States for the following crops: Almond and pecans (representing nut,
tree, Crop Group 14), and grapes. The results of these studies can be
summarized as follows:
For almonds, the maximum etoxazole residues from two
applications at 0.135 pounds active ingredient/acre/treatment, was
0.005 ppm for nutmeats and 1.79 ppm for hulls harvested 28-days after
application. Almond hulls were also analyzed for R-3, a metabolite of
etoxazole. The maximum residue of R-3 was as 0.12 ppm.
For pecans, no etoxazole residues were observed in
nutmeats (LOD = 0.005 ppm) treated twice at 0.135 pounds active
ingredient/acre/treatment and harvested 28-days after application.
The maximum etoxazole residue in grapes harvested 28-days
following the last of two treatments at 0.135 pounds active ingredient/
acre/treatment was 0.33 ppm.
The results of a grape processing study indicate that
etoxazole residues concentrate in both grape juice and raisins. The
concentration factor for grape juice was determined in this study to be
5.3X, which exceeds the theoretical concentration factor of 1.2X. Using
this theoretical concentration factor to estimate the tolerance for
juice, a tolerance of 0.32 ppm was calculated. Since this tolerance is
less than the tolerance proposed for grapes, grape juice tolerances are
not required. The concentration factor for raisins was determined in
this study to be 3.5X. The theoretical concentration factor for raisins
is, however, 4.7x. To be consistent with the grape juice calculations,
this theoretical concentration factor was used to determine the
proposed tolerance for raisins.
These field trial data are adequate to support proposed tolerances
of 0.01 ppm for nut, tree (Crop Group 14); pistachios at 0.01 ppm; 2.0
ppm for almond, hull; 0.5 ppm for grapes; and 1.5 ppm for raisins.
Almond, hull is the only commodity under consideration that is a
significant feed item for beef and dairy cattle. Tolerances of 0.03 ppm
in the fat of animals and 0.04 ppm in milk fat, previously proposed and
pending at the Agency, are adequate to support the use on almonds.
None of the commodities under consideration are used as poultry
feed items. Additionally, the results of a hen metabolism study
demonstrated very low potential for residues in feed to transfer to
poultry tissues or eggs. Therefore, no hen residue feeding study was
performed and tolerances are not proposed for secondary residues in
poultry commodities.
B. Toxicological Profile
A full battery of toxicology testing, including studies of acute,
chronic, oncogenicity, developmental, mutagenicity, and reproductive
effects has been completed for etoxazole. The acute toxicity of
etoxazole is low by all routes. Etoxazole is not a developmental or
reproductive toxicant, and is not mutagenic or oncogenic. For the
purpose of dietary risk analysis, Valent proposes 0.04 milligrams/
kilogram body weight/day (mg/kg bwt/day) as the chronic Population
Adjusted Dose (cPAD) and 2 mg/kg bwt/day as the acute Population
Adjusted Dose (aPAD). The cPAD is based on a chronic endpoint of 4 mg/
kg bwt/day no observed adverse effect level (NOAEL) for males from the
rat chronic/oncogenicity feeding study and an uncertainty factor of
100. The aPAD is based on the 200 mg/kg bwt/day NOAEL from the rabbit
developmental toxicity study and an uncertainty factor of 100. Valent
is unable to identify toxicity endpoints of concern for acute, short-
term or chronic human exposures by any route other than oral.
[[Page 19449]]
1. Acute toxicity. The acute toxicity of technical grade etoxazole
is low by all routes. The battery of acute toxicity studies place
etoxazole in Toxicity Category III. The oral LD50 in the rat
was greater than 5 grams/kilogram (g/kg), the dermal LD50
was greater than 2.0 g/kg, and the inhalation LC50 in the
rat was greater than 1.09 milligrams/liter (mg/L). Etoxazole technical
was not an irritant to eyes or skin and was not a skin sensitizer.
2. Genotoxicity. Etoxazole was evaluated and found to be negative
in an Ames reverse mutation assay, a chromosome aberration assay, a
micronucleus assay, and an unscheduled DNA synthesis (UDS) assay.
Etoxazole produced a positive result in the mouse lymphoma gene
mutation assay but only in the presence of metabolic activation.
Etoxazole does not present a genetic hazard.
3. Reproductive and developmental toxicity--i. Rat developmental
study. Etoxazole did not produce developmental toxicity in rats.
Etoxazole technical was administered by oral gavage to pregnant rats at
dosage levels of 40, 200, and 1,000 mg/kg/day on days 6 through 15 of
gestation. There were no mortalities or treatment-related adverse
effects in any dose group. Food consumption was slightly decreased in
dams during the dosing period for the 1,000 mg/kg/day group. On
cesarean section evaluation there was no differences in number of
corpora lutea, number of live and dead fetuses, percent resorption,
placental weight, fetal weight or sex ratio in the dams and no
treatment-related external, visceral or skeletal malformations noted in
any of the fetuses. It was concluded that, the maternal no observed
adverse effect Level (NOAEL) was 200 mg/kg/day, based on decreased food
consumption at 1,000 mg/kg/day. The developmental NOAEL was 1,000 mg/
kg/day, the highest dose tested (HDT).
ii. Rabbit developmental study. Etoxazole did not produce
developmental toxicity in rabbits. Etoxazole technical was administered
by oral gavage to pregnant rabbits at dosage levels of 40, 200, and
1,000 mg/kg/day on days 6 through 18 of gestation. No treatment-related
adverse effects were found on maternal rabbits in the 40 and 200 mg/kg/
day groups. One high dose rabbit died but it is unclear whether this
death was attributed to treatment. Decreased body weight, body weight
gain, food consumption and enlarged liver were noted at 1,000 mg/kg/
day. Cesarean section findings showed that there was no differences in
number of corpora lutea, number of live and dead fetuses, percent
resorptions, placental weight, fetal weight and sex ratio in the dams
and showed no treatment-related malformations (external, visceral,
skeletal) in any of the fetuses. A statistically significant increased
incidence of 27 presacral vertebrae with 13th ribs was
observed in fetuses at 1,000 mg/kg/day compared with controls. This
finding was within historical control range for fetal incidence but
above the historical control range for litter incidence. No dose
response was evident and the variation is considered to be equivocally
treatment related. The NOAEL for maternal and developmental toxicity
was 200 mg/kg/day based on decreased body weight and body weight gain,
decreased food consumption, and liver enlargement at 1,000 mg/kg/day.
The NOAEL for developmental toxicity was 200 mg/kg/day based on
statistically significant increased incidence of 27 presacral vertebrae
with 13th ribs in fetuses at 1,000 mg/kg/day.
iii. Rat reproduction study. Etoxazole showed no effects on
reproduction in a two-generation rat study. Etoxazole technical was fed
to two generations of male and female Sprague Dawley rats at dietary
concentrations of 80, 400, and 2,000 ppm. No treatment-related adverse
effects were observed in the 80 and 400 ppm groups for any parameter.
In the 2,000 ppm group, relative liver weights were increased in the F0
and F1 parental males. No adverse reproductive effects were noted at
any dose level in the incidence of normal estrous cycle, mating index,
fertility and gestation indices, the number of implantation sites, and
duration of gestation in F0 and F1 parental animals. For the offspring,
it was noted that at 2,000 ppm, the viability index on lactation Day 4
was significantly lower in the F1 pups and body weights were lowered in
pups during the latter half of the lactation period. For the F0 and F1
pups of the 80 and 400 ppm groups, there were no treatment-related
adverse effects observed for any parameter, i.e. mean number of pups
delivered, sex ratio, viability indices on lactation days 0, 4 and 21,
clinical signs, body weights and gross pathological findings. The
parental NOAEL was 400 ppm (17.0 mg/kg/day) based on the effects on
relative liver weight in males at 2,000 ppm. The pup NOAEL was 400 ppm
(37.9 mg/kg/day) based on decreased viability on lactation Day 4 and
decreased body weight at 2,000 ppm in the F1 pups. The reproductive
NOAEL was 2,000 ppm (86.4 mg/kg/day), the (HDT).
4. Subchronic toxicity. Subchronic toxicity studies conducted with
etoxazole technical in the rat (oral and dermal), mouse and dog
indicate a low level of toxicity. Effects observed at high dose levels
consisted primarily of anemia and histological changes in the adrenal
gland, liver and kidneys.
i. Rat feeding study. A 90-day subchronic toxicity study was
conducted in rats, with dietary intake levels of 100, 300, 1,000 and
3,000 ppm etoxazole technical. The NOAEL was 100 ppm for males and 300
ppm for females based on increased incidence of hepatocellular swelling
at 1,000 ppm and 3,000 ppm.
ii. Mouse feeding study. A 90-day subchronic toxicity study was
conducted in mice, with dietary intake levels of 100, 400, 1,600, and
6,400 ppm etoxazole technical. The NOAEL was 400 ppm for males and
1,600 ppm for females based on increased alkaline phosphatase activity,
increased liver weights, and increased incidence of hepatocellular
swelling at 6,400 ppm (both sexes) and at 1,600 ppm in males and
enlarged livers in females at 6,400 ppm.
iii. Dog feeding study. Etoxazole technical was fed to male and
female Beagle dogs for 13 weeks at dietary concentrations of 200,
2,000, and 10,000 ppm. The NOAEL was 200 ppm (5.3 mg/kg/day) based on
clinical signs, clinical pathology changes, liver weight effects and
histopathological changes at 2,000 and 10,000 ppm.
iv. Repeated dose dermal study. A 28-day dermal toxicity study was
conducted in rats at dose levels of 30, 100, and 1,000 mg/kg. There
were no treatment related changes in any of the parameters monitored.
The NOAEL was 1,000 mg/kg, the (HDT).
5. Chronic toxicity. Etoxazole technical has been tested in chronic
studies with dogs, rats and mice. Valent proposes a chronic oral
endpoint of 4 mg/kg bwt/day, based on the NOAEL for male rats in a 2-
year chronic toxicity oncogenicity feeding study.
i. Dog chronic feeding study. Etoxazole technical was fed to male
and female beagle dogs for one year at dietary concentrations of 200,
1,000, and 5,000 ppm. The NOAEL was 200 ppm (4.6 mg/kg/day for males
and 4.79 mg/kg/day for females) based on increased absolute and
relative liver weights with corresponding histopathological changes in
the liver at 1,000 and 5,000 ppm.
ii. Rat chronic feeding/oncogenicity study. Etoxazole was not
oncogenic in rats in either of two chronic feeding studies conducted.
In the first study, etoxazole technical was fed to male and female
Sprague Dawley rats for 2-years at dietary concentrations of 4, 16, and
64 mg/kg/day. A trend toward decreased
[[Page 19450]]
body weight gain for males at 64 mg/kg/day in the latter half of the
study was observed. Hemotology and clinical chemistry changes,
increased liver weights and hepatic enlargement at 16 mg/kg/day or
above were observed. Testicular masses, centrilobular hepatocellular
swelling and testicular interstitial (Leydig) cell tumors occurred at
or above 16 mg/kg/day. The interstitial (Leydig) cell tumors were
believed to be incidental. The NOAEL was 4 mg/kg/day for males and 16
mg/kg/day for females. Because an MTD level was not achieved in this
study, a second study was conducted in which etoxazole technical was
fed to male and female Sprague Dawley rats for 2-years at dietary
concentrations of 50, 5,000, and 10,000 ppm. In this study, decreased
mortality, body weight and food consumption/ efficiency (females) at
10,000 ppm was observed. Hematological, clinical, and histopathological
changes of the incisors, and increased liver weights occurred in both
sexes at 5,000 and 10,000 ppm. Centrilobular hepatocellular hypertrophy
was observed in both sexes at 10,000 ppm. The interstitial (Leydig)
cell tumors observed in the first study, were not observed in the
repeat study. The NOAEL in the repeat study was 50 ppm (1.8 mg/kg/day).
iii. Mouse oncogenicity study. Etoxazole was not oncogenic in
either of 2 mouse oncogenicity studies conducted. In the first study,
etoxazole technical was fed to male and female CD-1 mice for 18-months
at dietary concentrations of 15, 60, and 240 mg/kg/day. Increased liver
weights occurred in females at the highest dose tested. Histopathology
parameters were altered for males at 240 mg/kg/day. No neoplastic
lesions were observed at any dose level. The NOAEL was 60 mg/kg/day.
Since the toxicity in this study was minimal and did not meet the
definition of MTD, a second study was conducted at dose levels of 2,250
and 4,500 ppm etoxazole. There were no effects in any group on clinical
observations, mortality, body weight, food consumption or hematology.
Females showed a significant elevation in relative liver weight after
52-weeks of treatment at 4,500 ppm. In histopathology, a significantly
higher incidence of centrilobular hepatocellular fatty change was
observed in males in the 4,500 ppm group necropsied after 78-weeks of
treatment. There were no treatment-related changes in either sex in the
2,250 ppm dose group. No increase in neoplastic lesions were observed
in any treated group of either sex. Therefore, it was concluded that,
the NOAEL is 2,250 ppm (242 mg/kg/day for the males and 243 mg/kg/day
for the females).
6. Animal metabolism. The absorption, tissue distribution,
metabolism and excretion of etoxazole were studied in rats after single
oral doses of 5 or 500 mg/kg, and after 14 daily oral doses at 5 mg/kg.
Etoxazole, labeled in both the t-butylphenyl ring and the oxazole ring
were used in this study. For both single dose groups, most (94-97%) of
the administered radiolabel was excreted in the urine and feces within
7-days after dosing. Most of this excretion occurred in the first 48
hours after dosing. Maximum plasma concentrations occurred 2-4 hours
after dosing, with half-lives ranging from 53-89 hours at the low dose
and 7-44 hours at the high dose. Plasma levels were significantly lower
in females. Concentrations of radioactivity were significantly higher
in the tissues of male rats compared to females. The highest
concentrations occurred at 3 hours after dosing and were greatest in
the gastrointestinal tract and tissues such as liver and kidneys, which
are responsible for metabolism and excretion. By 168 hours, the
concentration in most tissues was below the concentration in the
corresponding plasma, with only the liver and fat having significant
levels of radioactivity. After multiple doses, peak concentrations of
radioactivity in tissues occurred 2 hours after dosing and then
declined. The distribution of radioactivity showed a similar profile to
those found after single oral doses but were significantly higher,
indicating some accumulation. Etoxazole was extensively metabolized by
rats. The main metabolic reactions in rats were postulated to be
hydroxylation of the 4,5-hydrooxazole ring followed by cleavage of the
molecule and hydroxylation of the t-butyl side chain.
7. Metabolite toxicology. In an oral toxicity limit test in rats,
the oral LD50 of metabolite R-3 was estimated to be greater
than 5 g/kg for both male and female rats. No treatment related body
weight changes and no treatment related macroscopic abnormalities were
observed in this study. In another test, the oral toxicity of
metabolite R-7 (as the HCl salt) was assessed. The oral LD50
of this metabolite was also estimated to be greater than 5 g/kg for
both male and female rats. No treatment related macroscopic
abnormalities were observed in this test, although, some clinical signs
were observed within 6-minutes of dosing. Mutagenicity screens were
performed with metabolite R-3 and metabolite R-7 (as the HCl salt).
Neither metabolite was mutagenic when tested with multiple strains of
two bacterial cultures (salmonella typhimurium and e coli).
8. Endocrine disruption. No special studies to investigate the
potential for estrogenic or other endocrine effects of etoxazole have
been performed. However, as summarized above, a large and detailed
toxicology data base exists for the compound including studies in all
required categories. These studies include acute, sub-chronic, chronic,
developmental, and reproductive toxicology studies including detailed
histology and histopathology of numerous tissues, including endocrine
organs, following repeated or long term exposures. These studies are
considered capable of revealing endocrine effects. The results of all
of these studies show no evidence of any endocrine-mediated effects and
no pathology of the endocrine organs. Consequently, it is concluded
that etoxazole does not possess estrogenic or endocrine disrupting
properties.
C. Aggregate Exposure
1. Dietary exposure. A full battery of toxicology testing including
studies of acute, chronic, oncogenicity, developmental, mutagenicity,
and reproductive effects is available for etoxazole. In these risk
assessments, Valent proposes as the chronic oral toxic endpoint the
NOAEL for males from the rat chronic/oncogenicity feeding study, 4 mg/
kg/day. To assess the chronic risk to the U.S. population from exposure
to etoxazole, the daily chronic exposures were compared against an
estimated chronic population adjusted dose (cPAD) of 0.04 mg/kg bwt/
day. This endpoint is derived from the NOAEL from the 2-year chronic
rat study by applying an uncertainty factor of 100 to account for
intraspecies and interspecies variations. There is no evidence that any
additional safety factors are needed to further protect vulnerable
subpopulations. The proposed acute oral toxic endpoint is the NOAEL
from the rabbit oral developmental toxicity study, 200 mg/kg/day. To
assess the acute risk to the U.S. population from exposure to
etoxazole, acute exposures were compared against an estimated acute
population adjusted dose (aPAD) of 2 mg/kg bwt/day. This endpoint is
derived from the NOAEL from the rabbit oral developmental toxicity
study by applying an uncertainty factor of 100 to account for
intraspecies and interspecies variations. Based on dietary, drinking
water, and non-occupational exposure assessments, there is reasonable
certainty of no harm
[[Page 19451]]
to the U.S. population, any population subgroup, or infants and
children from short-term or chronic exposure to etoxazole.
i. Food. Dietary exposure was estimated using the Cumulative and
Aggregate Risk Evaluation System (CARES). Acute dietary exposure was
estimated for the overall U.S. population and 16 population subgroups
using proposed tolerances and conservative estimates of the percentages
of crop treated. The results demonstrate that estimated exposure is
less than 1% of the estimated aPAD (at the 99.9th
percentile) for all population groups examined. Acute dietary exposure
for the overall U.S. population was estimated to be 0.006 mg/kg bwt/day
at the 99.9th percentile of exposure (0.29% of the aPAD).
Chronic dietary exposure was estimated for the overall U.S. population
and 16 population subgroups. Annual exposure for the overall U.S.
population was estimated to be 0.00014 mg/kg bwt/day, representing
0.36% of the estimated cPAD. Annual exposure for the most highly
exposed population subgroup, children 1-2 years of age, was estimated
to be 0.00065 mg/kg bwt/day, or 1.62% of the estimated cPAD.
ii. Drinking water. Since etoxazole is applied outdoors to growing
agricultural crops, the potential exists for the parent or its
metabolites to reach ground water or surface water that may be used for
drinking water. But, because of the physical properties of etoxazole,
it is unlikely that etoxazole or its metabolites can leach to potable
ground water. Although, relatively stable to hydrolysis, etoxazole
undergoes fairly rapid photolysis, degrades fairly readily in soil and
is immobile in all soil types examined. To quantify potential exposure
from drinking water, FIRST and SCI-GROW models were used to estimate
surface water and ground water residues. Estimated surface water
residues were much higher than estimated ground water residues and
therefore, the surface residues were used as the Drinking Water
Environmental Concentration (DWEC). The peak (acute) concentration
predicted in the simulated pond water was estimated to be 2.47 ppb and
the annual average (chronic) concentration predicted in the simulated
pond water was estimated to be 1.93 ppb. To assess the contribution to
the dietary risk from exposure to drinking water containing residues of
etoxazole, these DWEC's are compared to drinking water levels of
comparison (DWLOC's), the maximum drinking water concentration allowed
before combined water, dietary, and other exposures will exceed the
population adjusted doses. If the DWLOC is greater than the DWEC, then
overall exposure will not exceed the population adjusted doses and
combined exposure from water and food is considered to be acceptable.
Acute DWLOC's for etoxazole range from 19,900 to 69,910 ppb and chronic
DWLOC's range from 377 to 1,380 ppb for all U.S. population subgroups
examined. Since these DWLOC's exceed the modeled acute and chronic DWEC
surface water residues by a wide margin, it can be concluded that,
exposure to potential residues in drinking water is negligible and that
aggregate (food and water) exposure to etoxazole residues will be
acceptable.
2. Non-dietary exposure. Etoxazole is proposed only for
agricultural uses and no homeowner or turf uses. Thus, no non-dietary
risk assessment is needed.
D. Cumulative Effects
Section 408(b)(2)(D)(v) requires that the Agency must consider
``available information'' concerning the cumulative effects of a
particular pesticide's residues and ``other substances'' that have a
common mechanism of toxicity. Available information in this context
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.
In consideration of potential cumulative effects of etoxazole and
other substances that may have a common mechanism of toxicity, there
are currently no available data or other reliable information
indicating that any toxic effects produced by etoxazole would be
cumulative with those of other chemical compounds. Thus, only the
potential risks of etoxazole have been considered in this assessment of
aggregate exposure and effects.
Valent will submit information for EPA to consider concerning
potential cumulative effects of etoxazole consistent with the schedule
established by EPA at (62 FR 42020) (Aug. 4, 1997) and other subsequent
EPA publications pursuant to the Food Quality Protection Act.
E. Safety Determination
1. U.S. population--i. Acute risk. The potential acute exposure
from food to the U.S. population and various non-child/infant
population subgroups are estimated to be 0.15 to 0.30% of the proposed
aPAD. Exposure to potential acute residues in drinking water is
expected to be negligible, as acute DWLOC's are substantially higher
than modeled acute DWEC's. Based on this assessment, it can be
concluded that, there is a reasonable certainty that no harm to the
U.S. population or any population subgroup will result from acute
exposure to etoxazole.
ii. Chronic risk. The potential chronic exposure from food to the
U.S. population and various non-child/infant population subgroups are
estimated to be 0.24 to 1.59% of the proposed cPAD. Chronic exposure to
potential residues in drinking water is also expected to be negligible,
as chronic DWLOC's are substantially higher than modeled chronic
DWEC's. Based on this assessment, it can be concluded that there is a
reasonable certainty that no harm to the U.S. population or any
population subgroup will result from chronic exposure to etoxazole.
2. Infants and children--i. Safety factor for infants and children.
In assessing the potential for additional sensitivity of infants and
children to residues of etoxazole, FFDCA section 408 provides that EPA
shall apply an additional margin of safety, up to ten-fold, for added
protection for infants and children in the case of threshold effects
unless EPA determines that a different margin of safety will be safe
for infants and children. The toxicological data base for evaluating
prenatal and postnatal toxicity for etoxazole is complete with respect
to current data requirements. There are no special prenatal or
postnatal toxicity concerns for infants and children, based on the
results of the rat and rabbit developmental toxicity studies or the 2-
generation reproductive toxicity study in rats. Valent has concluded,
that reliable data support use of the standard 100-fold uncertainty
factor and that an additional uncertainty factor is not needed for
etoxazole to be further protective of infants and children.
ii. Acute risk. The potential acute exposure from food to infants
and children are estimated to be 0.28 to 0.97% of the proposed aPAD.
Exposure to potential acute residues in drinking water is expected to
be negligible, as acute DWLOC's are substantially higher than modeled
acute DWEC's. Based on this assessment, it can be concluded that, there
is a reasonable certainty that
[[Page 19452]]
no harm to infants and children will result from acute exposure to
etoxazole.
iii. Chronic risk. The potential chronic exposure from food to
infants and children are estimated to be 0.64 to 1.62% of the proposed
cPAD. Chronic exposure to potential residues in drinking water is
expected to be negligible, as chronic DWLOC's are substantially higher
than modeled DWEC's. Based on this assessment, it can be concluded
that, there is a reasonable certainty that no harm to infants and
children will result from chronic exposure to etoxazole.
3. Safety determination summary. Aggregate acute or chronic dietary
exposure to various subpopulations of children and adults demonstrate
acceptable risk. Acute and chronic dietary exposures to etoxazole
occupy considerably less than 100% of the appropriate PAD. EPA
generally has no concern for exposures below 100% of the acute and
chronic PAD's because these represent levels at or below which daily
aggregate dietary exposure over a lifetime will not pose appreciable
risks to human health. Chronic and acute dietary risk to children from
etoxazole should not be of concern. Further, etoxazole has only
agricultural uses and no other uses, such as indoor pest control,
homeowner or turf, that could lead to unique, enhanced exposures to
vulnerable sub-groups of the population. It can be concluded that,
there is a reasonable certainty that no harm will result to the U.S.
population or to any sub-group of the U.S. population, including
infants and children, from aggregate chronic or aggregate acute
exposures to etoxazole residues resulting from the proposed uses.
F. International Tolerances
Etoxazole has not been evaluated by the JMPR and there are no
codex maximum residue limits (MRL) for etoxazole. MRL values have been
established for etoxazole in the following countries: Turkey, Israel,
South Africa, Japan, France, Taiwan, and Korea. The use pattern and
MRL's are similar to those proposed for the U.S.
[FR Doc. 05-7223 Filed 4-12-05; 8:45 am]
BILLING CODE 6560-50-S