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Etoxazole (Valent). August 13, 2003. Pesticide tolerance petition. Federal Register.
http://www.epa.gov/fedrgstr/EPA-PEST/2003/August/Day-13/p20642.htm
[Federal Register: August 13, 2003 (Volume 68, Number 156)]
[Notices]
[Page 48377-48383]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr13au03-81]
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ENVIRONMENTAL PROTECTION AGENCY
[OPP-2003-0271; FRL-7322-6]
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 ID number OPP-2003-0271, must be
received on or before September 12, 2003.
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: Daniel Kenny, Registration Division
(7505C), Office of Pesticide Programs, Environmental Protection Agency,
1200 Pennsylvania Ave., NW., Washington, DC 20460-0001; telephone
number: (703) 305-7546; e-mail address: kenny.dan@epa.gov.
SUPPLEMENTARY INFORMATION:
I. General Information
A. Does this Action Apply to Me?
You may be potentially affected by this action if you are 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-2003-0271. 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
[[Page 48378]]
collection of materials that is available for public viewing at the
Public Information and Records Integrity Branch (PIRIB), Rm. 119,
Crystal Mall #2, 1921 Jefferson Davis Hwy., 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 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-2003-0271. 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-2003-0271. 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-2003-0271.
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, 1921 Jefferson Davis Hwy., Arlington, VA, Attention: Docket
ID number OPP-2003-0271. 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
[[Page 48379]]
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. 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: August 6, 2003.
Debra Edwards,
Director, Registration Division, Office of Pesticide Programs.
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 2F6420
EPA has received a pesticide petition (2F6420) from Valent U.S.A.
Corporation, 1333 North California Blvd., Suite 600, Walnut Creek, CA
94596 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 etoxazole in or on the raw
agricultural commodity pome fruit (Crop Group 11) at 0.2 parts per
million (ppm), apple wet pomace at 1.0 ppm, strawberry at 0.5 ppm,
cottonseed at 0.05 ppm, cotton, gin byproducts (gin trash) at 1.0 ppm,
and oranges at 0.10 ppm (to support the importation of mandarin oranges
into the U.S.). As residues in processed commodities fed to animals may
be transferred to milk and edible tissue of ruminants, tolerances are
also proposed for animal fat at 0.03 ppm and milk fat at 0.04 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. Metabolism of 14C-etoxazole labeled in the t-
butylphenyl, difluorophenyl, or oxazole rings has been studied in
apples, cotton, oranges, and eggplants. Etoxazole was rapidly and
extensively metabolized to many metabolites in all plants. Even with
exaggerated treatment, individual metabolites and parent were only
found at very low concentrations. Comparisons of metabolites detected
and quantified from plants and animals show that there are no
significant aglycones in plants which are not also present in the
excreta or tissues of animals. The residue of concern is best defined
as the parent etoxazole.
2. Analytical method. 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 mandarin oranges and
cottonseed and 0.2 ppm in cotton gin trash, which will allow monitoring
of food with residues at the levels proposed for the tolerances.
Methods have also been developed and validated for determining
etoxazole in animal samples. The LOQ of etoxazole in these methods is
0.02 ppm in milk fat and beef fat.
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: apples and pears (representing pome
fruits), strawberries, and cotton. Residue trials have also been
conducted for etoxazole in Europe to support the importation of
mandarin oranges into the U.S. The results of these studies can be
summarized as follows:
¥ For pome fruit, the maximum etoxazole residues from two
applications at 0.135 lbs. active ingredient/acre/treatment, are 0.07
ppm for apples and 0.11 for pears harvested 28 days after application.
¥ The results of an apple processing study indicate that
etoxazole residues do not concentrate in apple juice, but do
concentrate in wet apple pomace with an average concentration factor of
5.7x.
¥ The maximum etoxazole residue in strawberries harvested one
day following the last of two treatments at
[[Page 48380]]
0.135 lbs. active ingredient/acre/treatment is 0.32 ppm.
¥ The maximum expected etoxazole residues in cottonseed and
cotton gin trash from two applications at 0.045 lbs. active ingredient/
acre/treatment applied 28 days before harvest are 0.02 ppm and 0.60
ppm, respectively. Cotton gin trash was also analyzed for metabolite R-
3 but was detected in samples from only one of seven test sites at a
level only slightly above the 0.10 ppm limit of detection (LOD) (mean
residue was 0.13 ppm). Therefore, no tolerance is being proposed for
metabolite R-3 in cotton gin trash.
¥ The results of a cotton processing study indicate that
etoxazole does not concentrate in hulls, meal, or oil.
¥ Following a single application to mandarin oranges of 0.05
lbs. active ingredient/acre, the maximum etoxazole residues in whole
fruit harvested 14 days after application is 0.05 ppm.
¥ No processing of mandarins was required because only fresh
or canned mandarins will be imported for direct consumption. Separate
analysis of mandarin peel and pulp from residue field trials
demonstrated that etoxazole residues are confined to the peel. Canned
mandarins that contain only mandarin pulp would therefore not be
expected to contain detectable residues of etoxazole.
These field trial data are adequate to support proposed tolerances
of 0.2 ppm for pome fruit; 1.0 ppm for wet apple pomace; 0.5 ppm for
strawberries; 0.05 ppm for cottonseed; 1.0 ppm in cotton gin trash; and
0.1 ppm in oranges.
Apple pomace and all cotton commodities are significant feed items
for beef and dairy cattle and results of a goat metabolism study
suggest the possibility that etoxazole residues in feed may transfer to
edible tissues and milk. Therefore, a cow feeding study was conducted
with etoxazole to determine the level of secondary residues and the
need for corresponding tolerances. Etoxazole was detected in fat and
cream only and Valent is therefore proposing tolerances of 0.03 ppm in
the fat of animals and 0.04 ppm in milk fat. Cotton meal is the only
commodity under consideration that is used as a poultry feed item and
the results of the cotton processing study indicate that etoxazole
residues in this commodity are very low. 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. The
toxicology reports for etoxazole have not yet been reviewed by EPA and
thus, the Agency has not yet established toxic endpoints of concern,
specifically chronic and acute oral toxicity endpoints for the
compound. For the purpose of dietary risk analysis, Valent proposes
0.04 mg/kg bwt/day as the chronic Population Adjusted Dose (cPAD) and
an acute Population Adjusted Dose (aPAD) of 2 mg/kg bwt/day. The cPAD
is based on a chronic endpoint of 4 mg/kg bw/day NOEL 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 NOEL 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.
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. Genotoxicty. 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.
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
[[Page 48381]]
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
highest dose tested.
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 highest dose tested.
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 two-
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 two years at dietary concentrations of 4, 16,
and 64 mg/kg/day. A trend toward decreased 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 two years at dietary concentrations of 50,
5,000, and 10,000 ppm. In this study, decreased mortality, bodyweight
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 two 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 of 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 no observed effect level 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
seven 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
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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 six 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 Escherichia 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. EPA has not had
the opportunity to review all of the toxicity studies on etoxazole and
has not established toxic endpoints. Thus, 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 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 DEEMTM,
proposed tolerances, and assuming 100% crop treated. Results of the
acute analysis demonstrate that estimated exposure is 0.5% or less of
the estimated aPAD (at the 95th percentile) for all
population groups examined. Acute dietary exposure for the overall U.S.
population was estimated to be 0.002572 mg/kg bwt/day at the
95th percentile of exposure (0.13% of the aPAD). Chronic
dietary exposure was estimated for the overall U.S. population and 25
population sub groups. Daily exposure for the overall U.S. population
was estimated to be 0.000574 mg/kg bwt/day, representing 1.4% of the
estimated cPAD. Daily exposure for the most highly exposed population
subgroup, children 1-6 years of age, was estimated to be 0.002293 mg/kg
bwt/day, or 5.7% 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 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
groundwater. 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 and groundwater residues. Estimated surface water residues were
much higher than estimated groundwater 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 to1380 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, Valent concludes 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
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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 Federal Register 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 0.06 to 0.13 % 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, Valent concludes
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 0.7% to 1.9% 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, Valent concludes 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 0.16 to 0.50 % 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, Valent concludes that there is
a reasonable certainty that 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 2.1 to 5.7% 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, Valent concludes 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 sub-populations 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. Valent concludes 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 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 to allow the following uses of 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. 03-20642 Filed 8-12-03; 8:45 am]
BILLING CODE 6560-50-S