Cymoxanil; Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food

Note: EPA no longer updates this information, but it may be useful as a reference or resource.

[Federal Register: February 28, 2003 (Volume 68, Number 40)]
[Notices]
[Page 9660-9666]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr28fe03-90]

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ENVIRONMENTAL PROTECTION AGENCY
[OPP-2003-0006; FRL-7288-9]

Cymoxanil; 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-2003-0006, must be
received on or before March 31, 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: Mary L. Waller, Registration Division
(7505C), Office of Pesticide Programs, Environmental Protection Agency,
1200 Pennsylvania Ave., NW., Washington, DC 20460-0001; telephone
number: (703) 308-9354; e-mail address: waller.mary@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. To determine
whether you or your business may be affected by this action, you should
carefully examine the applicability provisions in OPP-2003-0006. If you
have any questions regarding the applicability of

[[Page 9661]]

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-2003-0006. 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, 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.regulations.gov/ 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-2003-0006. 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-2003-0006. 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,

[[Page 9662]]

DC 20460-0001, Attention: Docket ID number OPP-2003-0006.
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-2003-0006. 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. 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: February 10, 2003.
Debra Edwards,
Acting Director, Registration Division, Office of Pesticide Programs.

Summary of Petition

The petitioner summary of the pesticide petition is printed below
as required by FFDCA section 408(d)(3). The summary of the petition was
prepared by E. I. du Pont de Nemours and Company 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.

E. I. du Pont de Nemours and Company

PP 0F6072

EPA has received a pesticide petition (0F6072) from E. I. du Pont
de Nemours and Company, DuPont Agricultural Products, Barley Mill
Plaza, Wilmington, DE 19880-0038 proposing, pursuant to section 408(d)
of the FFDCA, 21 U.S.C. 346a(d), to amend 40 CFR 180.503 by
establishing tolerances for residues of the fungicide, cymoxanil; 2-
cyano-N-(ethylamino)carbonyl l-2-(methoxyimino)acetamide in or on the
raw agricultural commodities cucurbit vegetables at 0.05 parts per
million (ppm), fruiting vegetables at 0.2 ppm, and head lettuce at 4.0
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 plant metabolism of cymoxanil is
adequately understood in three diverse crops: potatoes, tomatoes, and
lettuce. The results of these plant metabolism studies indicate that
cymoxanil degrades extensively to primarily the amino acid glycine,
with subsequent re-incorporation into other naturally-occurring
products, such as glucose.
2. Analytical method. An analytical enforcement method is available
for determining these plant residues by high performance level
chromotography (HPLC) with ultraviolet (UV) detection. The limit of
quantitation allows monitoring of crops with cymoxanil residues at or
above the levels proposed in these tolerances.
3. Magnitude of residues--i. Cucurbit vegetables. The magnitude and
decline of residues of cymoxanil was determined on cucumber, cantaloupe
and summer squash, the representative commodities for the cucurbit
vegetable crop group as follows:
? Cucumber. DPX-KP481 50DF, containing 25% cymoxanil and 25%
famoxadone, was applied as a water dispersible granule to six test
sites in Florida, Georgia, Minnesota, Ohio, Virginia, and Texas. DPX-
KP481 50DF was applied as seven broadcast applications at the maximum
rate of 0.1875 lb cymoxanil acre for a maximum seasonal use rate of
1.31 lb cymoxanil/acre. Applications were made approximately 5 days
apart. The target pre-harvest interval (PHI) was 3 days. Residues of
cymoxanil were less than 0.05 ppm.
? Cantaloupe. DPX-KP481 50DF, containing 25% cymoxanil and
25% famoxadone, was applied as a water dispersible granule to six test
sites in Florida, Georgia, Minnesota, Ohio, Virginia, and Texas. DPX-
KP481 50DF was applied as seven broadcast applications at the maximum
rate of 0.1875 lb cymoxanil/acre for a maximum seasonal use rate of
1.31 lb cymoxanil/acre. Applications were made approximately 5 days
apart. The target PHI was 3 days. Residues of cymoxanil were less than
0.05 ppm.
? Summer squash. DPX-KP481 50DF, containing 25% cymoxanil and

[[Page 9663]]

25% famoxadone, was applied as a water dispersible granule to five test
sites in Florida, Pennsylvania, Minnesota, North Carolina and
California. DPX-KP481 50DF was applied as seven broadcast applications
at the maximum rate of 0.1875 lb cymoxanil/acre for a maximum seasonal
use rate of 1.31 lb cymoxanil/acre. Applications were made
approximately 5 days apart. The target PHI was 3 days. Residues of
cymoxanil were less than 0.05 ppm.
ii. Fruiting vegetables. The magnitude and decline of residues of
cymoxanil was determined on tomato and pepper, the representative
commodities for the fruiting vegetable crop group as follows:
? Pepper. Bell and non-bell DPX-KP481 50DF, containing 25%
cymoxanil and 25% famoxadone, was applied as a water dispersible
granule to nine test sites in Georgia, Florida, Ohio, Texas, Arizona,
California, and New Mexico. DPX-KP481 50DF was applied as nine
broadcast applications at a maximum seasonal use rate of 1.12 lb
cymoxanil/acre. Applications were made approximately 5 days apart. The
target PHI was 3 days. Residues of cymoxanil at the target PHI of 3
days ranged from less than 0.05-0.12 ppm in peppers (bell and non-
bell).
? Tomato. DPX-KP481 50DF, containing 25% cymoxanil and 25%
famoxadone was applied as a water dispersible granule to 12 test sites
in Florida, Maryland, Pennsylvania, California and Indiana. DPX-KP481
50DF was applied as nine broadcast applications at a maximum seasonal
use rate of 1.12 lb cymoxanil/acre. Applications were made
approximately 5 days apart. The target PHI was 3 days. Residues of
cymoxanil at the target PHI of 3 days were less than 0.05 ppm in
tomatoes.
? Tomato, process fractions. DPX-KP481 50DF, containing 25%
cymoxanil and 25% famoxadone, was applied as a water dispersible
granule to one site in California to determine the magnitude of residue
in tomato and the extent to which the residue concentrated in tomato
processed fractions. DPX-KP481 50DF was applied in nine broadcast
applications at 1X and 5X the proposed maximum rate of 1.12 lb
cymoxanil/acre. Applications were made approximately 5 days apart. The
target PHI was 3 days. When applied at 5X the maximum use rate residues
did not concentrate in tomato washed, unwashed, paste or puree.
iii. Head lettuce. DPX-KP481 50DF, containing 25% cymoxanil and 25%
famoxadone, was applied as a water dispersible granule to eight test
sites in Arizona, California, Florida, New York, and New Mexico. DPX-
KP481 50DF was applied as seven broadcast applications at the maximum
rate of 0.1875 lb cymoxanil/acre for a maximum seasonal use rate of
1.31 lb cymoxanil/acre. Applications were made approximately 5 days
apart. The target PHI was 3 days. Residues of cymoxanil in head lettuce
ranged from less than 0.05-2.8 ppm (wrapper leaves attached) and less
than 0.05-1.1 ppm (wrapper leaves removed).

B. Toxicological Profile

1. Acute toxicity. A battery of acute toxicity tests on technical
cymoxanil places it in the following Toxicity Categories:

Table 1.--Acute Toxicity Results On Technical Cymoxanil
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Oral LD₅₀ Rat 960 mg/kg Category III
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Dermal LD₅₀ Rabbit >2,000 mg/kg Category III
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Inhalation LC₅₀ Rat > 5.06 mg/L Category IV
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Eye irritation Rabbit Slight irritant Category IV
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Dermal irritation Rabbit Not an irritant Category IV
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Dermal sensitization................. Guinea pig Not a sensitizer
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An acute neurotoxicity study was not required with cymoxanil and
no acute neurotoxicity has been observed in short-term or subchronic
studies.
2. Genotoxicty. Cymoxanil was tested in a battery of assays to
evaluate genotoxicity and chromosome aberrations with the following
results. Based on the weight-of-evidence, cymoxanil is not considered
to be genotoxic or clastogenic.

Table 2.--Genotoxicity and Chromosome Aberrations Assay Results
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Bacterial gene mutation Salmonella Negative
typhimurium
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Mammalian gene mutation in vitro CHO/HGPRT Negative
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Mammalian chromosome aberrations CHO Positive
in vitro
------------------------------------------------------------------------
Mammalian chromosome aberrations Mouse micronucleus Negative
in vitro
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Unscheduled DNA synthesis in Primary rat Negative
vitro hepatocytes
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Unscheduled DNA synthesis in Primary rat Negative
vitro hepatocytes and
Spermatocytes
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[[Page 9664]]

3. Reproductive and developmental toxicity. The results of a series
of studies indicated that there were no reproductive, developmental, or
teratogenic hazards associated with cymoxanil.
In a 2-generation cymoxanil rat reproduction study, the no
observed effect level (NOEL) for both parents and offspring was
approximately 7 milligrams/kilogram/day (mg/kg/day), based on decreased
body weight, weight gain and food consumption in adults and decreased
pup weight in offspring at 32 mg/kg/day. There were no reproductive or
fertility effects. Since offspring effects occurred only in the
presence of maternal toxicity, it is considered a secondary effect to
the health effects on the dam.
With cymoxanil, developmental studies conducted in rats
demonstrated a NOEL of 10 mg/kg/day and a lowest observed effect level
(LOEL) of 25 mg/kg/day for both adult and developmental effects.
Maternal effects in rats included decreased weight, weight gain, and
food consumption. Developmental effects were increases in fetal
variations, which were the result of generalized delays in
ossification, and overall malformations, although malformations
detected were not dose-related. In rabbits, several developmental
toxicity studies were conducted with cymoxanil. Based on the weight-of-
evidence of all three studies, EPA considered there was no unique
sensitivity of perinatal animals to the effects of cymoxanil, nor any
anomalies of the fetal nervous system at maternally toxic doses up to
and including 32 mg/kg/day (Cymoxanil Agency Risk Assessment, February
18, 1998).
4. Subchronic toxicity. Subchronic (90-day) feeding studies were
conducted with rats, mice, and dogs. In addition, the following
subchronic feeding studies were conducted: A 90-day in rats to evaluate
neurotoxicity and 28-day feeding studies in rats and mice to evaluate
immunotoxicity. A 28-day dermal study was conducted in rats.
In a subchronic toxicity/neurotoxicity study in rats with
cymoxanil, the NOEL of 47.6 mg/kg/day in males was based on decreased
body weights and minimal to mild testicular and epididymal effects at
higher concentrations. In females, the NOEL of 59.9 mg/kg/day was based
on effects on body weight, weight gain, and food efficiency at higher
levels.
The subchronic NOEL for male mice administered cymoxanil was 8.25
mg/kg/day based on body weight and weight gain effects at 82.4 mg/kg/
day and above. The NOEL for females was 121 mg/kg/day based on
increases in spleen and liver weights at 433 mg/kg/day and above.
For cymoxanil, dogs were the most sensitive species in subchronic
studies. Reduced body weight gain and/or food consumption was observed
at 3 mg/kg/day or greater in females and 5 mg/kg/day and above in
males. Both sexes had red blood cells (RBC) changes decreased RBC
counts, hemaglobin (Hb), and/or hematocrit (Hct) and increased
incidence of ketonuria at the intermediate and high concentration, and
changes in serum chemistry (decreases in various electrolytes and
proteins) at the high dose. Males had testicular and epididymal effects
at the highest concentration, 11 mg/kg/day (raised from 5 mg/kg/day at
week 3); this was considered to be retardation of development due to
markedly reduced body weight in this group. The NOEL for males was 3
mg/kg/day. There was no NOEL in female dogs in the 90-day study.
Although, a NOEL was not established in the dog subchronic study, 3 mg/
kg/day was found to be a NOEL in a subsequent chronic study in dogs.
Subchronic 28-day studies were conducted in rats and mice to
evaluate the immunotoxicity potential of cymoxanil. Cymoxanil was not
immunotoxic up to and including the highest dose tested which was 1,600
ppm in rats (108 and 117 mg/kg/day in males and females, respectively),
1,200 ppm (218 mg/kg/day) in male mice, and 2,400 ppm (552 mg/kg/day)
in female mice.
Cymoxanil was applied to the skin of rats 6-hours/day for 28 days
at doses of 0, 50, 500, and 1,000 mg/kg/day. There were no effects at
any dose tested. The 28-day dermal NOEL was 1,000 mg/kg/day, the
highest dose tested.
5. Chronic toxicity. Chronic studies with cymoxanil were conducted
on rats, mice, and dogs to determine oncogenic potential and/or chronic
toxicity of the compound. Effects generally similar to those observed
in the 90-day studies were seen in the chronic studies. Cymoxanil was
not oncogenic.
The chronic NOEL for cymoxanil in male rats was 4.08 mg/kg/day
based on decreased body weight, weight gain, food efficiency, and non-
neoplastic lesions in several organs including lung inflammation,
spermatid degeneration, and retinal atrophy at 30.3 mg/kg/day or
higher. In addition, male rats in the two highest groups displayed
increased aggressiveness and hyperreactivity consistent with the
compromised general health status (i.e. systemic toxicity) of those
groups. In females, the NOEL of 5.36 mg/kg/day was based on decreased
body weight, weight gain, food efficiency, and non-neoplastic lesions
in several organs including lungs, liver, intestines, mesenteric lymph
nodes, sciatic nerve, and retina at 38.4 mg/kg/day or higher. Retinal
atrophy and sciatic lesions are common spontaneous lesions associated
with aging. These effects observed in cymoxanil test animals were
considered aging-related effects. Spermatid degeneration occurs
spontaneously in rats. While the incidence was increased in cymoxanil-
treated rats, most were mild or minimal and none were more than
moderate. Thus, the effects are considered a mild exacerbation of a
spontaneously occurring lesion.
In mice, the chronic NOELs for cymoxanil were 4.19 and 5.83 mg/kg/
day for males and females, respectively, based on changes in organ
weights, gastrointestinal effects in females and liver, testes and
epididymal effects in males at the LOEL. Similar to the rat, the
testicular effects were considered an exacerbation of a spontaneous
lesion, that occurred in one-quarter of the control mice. The LOELs
were 42.0 and 58.1 mg/kg/day for males and females, respectively.
The chronic cymoxanil NOEL for male dogs was 3.0 mg/kg/day based
on a temporary decrease in body weight and food consumption, and lower
RBC count, hemoglobin, and hematocrit at 5.7 mg/kg/day. In female dogs
the only finding was a transient effect on body weight, food
consumption, and food efficiency at the highest dose tested, 3.1 mg/kg/
day, only during the first week of the study. EPA considered the NOEL
in females to be 3.1 mg/kg (Cymoxanil Agency Risk Assessment, February
18, 1998).
6. Animal metabolism. When administered by gavage to rats,
cymoxanil was readily absorbed and eliminated. Absorption reached
maximum concentrations in whole blood within 4 hours post-dosing. A
rapid and almost complete elimination was observed in the urine and
feces. The majority of radioactivity was recovered within 96 hours,
mainly in urine but also in feces. Radioactivity in the tissues and
carcass was less than 1%. In the urine and feces, the majority of the
radioactivity was free and/or conjugated glycine. 2-Cyano-2-
methoxyimino-acetic acid was also found in low levels in the urine and
trace levels in the feces. Intact cymoxanil was less than 1% in feces
and not detected in the urine. The metabolite profile in urine and
feces was similar between sexes, among dose groups, and between dosing
regimens (single vs. multiple).

[[Page 9665]]

7. Metabolite toxicology. There are no metabolites of toxicological
significance to mammals.
8. Endocrine disruption. Chronic, lifespan, and multi-generational
bioassays in mammals and acute and subchronic studies on aquatic
organisms and wildlife did not reveal endocrine effects. Any endocrine-
related effects would have been detected in this definitive array of
required tests. The probability of any such effect due to agricultural
uses of cymoxanil is negligible.

C. Aggregate Exposure

1. Dietary exposure. Cymoxanil is a fungicide currently registered
in the United States for use on potatoes. In addition, tolerances have
been for cymoxanil on imported tomatoes and grapes. This tolerance
petition proposes the following new uses in the United States: Cucurbit
vegetables, fruiting vegetables and head lettuce. There are no
residential uses.
i. Food--a. Chronic dietary exposure assessment. The chronic RfD of
0.041 mg/kg/day is based on a NOEL of 4.08 mg/kg/day from the 1 year
rat feeding study and an uncertainty factor of 100. The acute NOEL of
4.0 mg/kg/day is based upon maternal clinical signs and weight effects
at higher levels in a rat developmental study.
Chronic dietary cymoxanil exposure risks resulting from the
proposed use of DPX-KP481 50DF on cucurbits, fruiting vegetables, head
lettuce, potatoes and imported grapes were estimated using the Dietary
Exposure Evaluation Model (DEEM, Novigen Sciences, Inc., 1999 Version
6.74). The analysis conservatively assumed that 30% of the crops on the
proposed label would be treated with DPX-KP481 50DF and used field
trial residue data. The chronic dietary risk estimate for cymoxanil
shows that an adequate margin of safety exists for all population
subgroups and that no effects would result from dietary exposure to
cymoxanil.
The following table presents the analysis which indicate large
margins of safety for each population subgroup and very low probability
of effects resulting from chronic exposure to cymoxanil in DPX-KP481
50DF. No sensitive subpopulations were identified. For the general
populations and all subpopulations 0.2% or less of the chronic RfD
used.

Table 3.--Results of Chronic Dietary Analysis with Cymoxanil
----------------------------------------------------------------------------------------------------------------
Maximum Dietary Exposure (mg/
Population Group kg/day) % RfD
----------------------------------------------------------------------------------------------------------------
U.S. population 0.000063 0.2
----------------------------------------------------------------------------------------------------------------
Non-nursing infants (<1 yr.) 0.000016 <0.1
----------------------------------------------------------------------------------------------------------------
Children (1-6 yr.) 0.000074 0.2
----------------------------------------------------------------------------------------------------------------
Children (7-12 yr.) 0.000068 0.2
----------------------------------------------------------------------------------------------------------------
Females (13+) 0.000074 0.2
----------------------------------------------------------------------------------------------------------------

b. Acute dietary exposure. Results of the Tier 3 acute dietary
exposure analysis show that an adequate margin of safety exists for all
population subgroups and that no acute effects would result from
dietary exposure to cymoxanil. The analysis conservatively assumed that
30% of the crops on the proposed label would be treated with DPX-KP481
50DF and used field trial residue data.
The results of the acute dietary exposure analysis for cymoxanil
are given in the table below. The percentages of acute reference dose
(aRFD) for cymoxanil were calculated based on an acute NOEL of 4 mg/kg/
day from the rabbit developmental study based on maternal clinical
signs and weight effects at the higher levels and an uncertainty factor
of 100. The results of the acute dietary exposure analysis for
cymoxanil indicate that the predicted exposures, expressed as a
percentage of the aRFD are well below 100%, showing cymoxanil clearly
meets the Food Quality Protection Act (FQPA) standard of reasonable
certainty of no harm and presents much lower acute dietary risk than
many of its competitors. At the 99.9th percentile, the
percentage of the aRFD was 4.47% for the general population and 5.72%
for the most sensitive subpopulation, nursing females.

Table 4.--Results of Acute Dietary Analysis with Cymoxanil
--------------------------------------------------------------------------------------------------------------------------------------------------------
99th Percentile of Exposure 99th Percentile of Exposure
--------------------------------------------------------------------------------------
Population Group Exposure (mg/kg/
Exposure (mg/kg/day) %aRfD day) %aRfD
--------------------------------------------------------------------------------------------------------------------------------------------------------
U.S. population 0.000475 1.19 0.001789 4.47
--------------------------------------------------------------------------------------------------------------------------------------------------------
Non-nursing infants (<1 yr.) 0.000184 0.46 0.000599 1.50
--------------------------------------------------------------------------------------------------------------------------------------------------------
Children (1-6 yr.) 0.000576 1.44 0.002096 5.24
--------------------------------------------------------------------------------------------------------------------------------------------------------
Children (7-12 yr.) 0.000485 1.21 0.001936 4.84
--------------------------------------------------------------------------------------------------------------------------------------------------------
Females (13+ nursing) 0.000635 1.59 0.002287 5.72
--------------------------------------------------------------------------------------------------------------------------------------------------------

ii. Drinking water. Surface water exposure was estimated using the
Generic Expected Environmental Concentration (GENEEC) model. Ground
water exposure was estimated using SCI-GROW. These are screening level

[[Page 9666]]

models used for determining upper bound concentrations of pesticides in
surface water and ground water.
The acute drinking water levels of concern (DWLOCs) are 1.3 parts
per million (ppm) for the U.S. population, and 0.38 ppm for the most
exposed population subgroup, children (1-6 years). The estimated
maximum concentration of cymoxanil in surface water (8.15 ppb) derived
from GENEEC is much lower than the acute DWLOC. Therefore, one can
conclude with reasonable certainty that residues of cymoxanil in
drinking water will not contribute significantly to the aggregate acute
human health risk.
The chronic DWLOCs are 1.4 ppm for the U.S. population and 0.4 ppm
for the most sensitive subgroup, children (1-6 years). The DWLOCs are
substantially higher than the GENEEC 56-day estimated environmental
concentration of 0.37 ppb for cymoxanil in surface water. Therefore,
one can conclude with reasonable certainty that residues of cymoxanil
in drinking water do not contribute significantly to the aggregate
chronic human health risk.
2. Non-dietary exposure. Cymoxanil products are not labeled for
residential non-food uses, thereby eliminating the potential for
residential exposure. Non-occupational, non-dietary exposure for
cymoxanil has not been estimated because the proposed products are
limited to commercial crop production. Therefore, the potential for
non-occupational exposure is insignificant.

D. Cumulative Effects

EPA's consideration of a common mechanism of toxicity is not
necessary at this time because there is no indication that toxic
effects of cymoxanil should be cumulative with those of any other
chemical compounds or with each other. Cymoxanil is a unique
cyanoacetamide and is chemically unrelated to any other commercial
plant disease control agent. Its biochemical mode of action on fungi
appears to be unique; it is theorized to act through inhibition of
multiple cellular processes, but a definitive mechanism has not been
completely elucidated. Similarly, the mechanism of action underlying
observed toxicological effects in mammals is not fully characterized
and there is no reliable information to suggest that cymoxanil has a
mechanism of toxicity in common with any other compound.
Given the distinct chemical and toxicological profile of
cymoxanil, its low acute toxicity, absence of genotoxic, oncogenic,
developmental, or reproductive effects, and low exposure potential, the
expression of cumulative human health effects with any other natural or
synthetic pesticide is not anticipated.

E. Safety Determination

1. U.S. population. Dietary and occupational exposure will be the
major routes of exposure to the U.S. population for cymoxanil, and
ample margins of safety have been demonstrated for both.
For cymoxanil, assuming 30% crop treated and residues estimated
based on field trial results, the chronic dietary exposure for the
overall U.S. population is estimated to be 0.000063 mg/kg/day, using
0.2 percent of the RfD. For acute dietary exposure, the estimated
exposure is 0.000475 and 0.001789 at the 99th and
99.9th percentiles, which will utilize 1.19 and 4.47%,
respectively, of the RfD for the overall U.S. population. The ground
application margin of exposure (MOE) was 7,814 for mixers/loaders and
1,430 for applicators. The aerial application MOE was 3,907 for mixers/
loaders and 38,763 for applicators. The MOE for flaggers was 10,916.
Based on the completeness and reliability of the toxicity data and the
conservative exposure assessments, there is reasonable certainty that
no harm will result from the aggregate exposure of residues of
cymoxanil including all anticipated dietary exposure and all other non-
occupational exposures.
2. Infants and children. Chronic dietary exposure of cymoxanil for
the most highly exposed children's subpopulations are: 0.000074 mg/kg/
day for children 1-6 years and 0.000068 mg/kg/day for children 7-12
years, representing 0.2% of the chronic reference dose (cRfD) for each
subpopulation. Exposure for all infant subpopulations was negligible.
For acute dietary exposure of cymoxanil, the %RfD for children 1-6
years is 1.44 at the 99th percentile and 5.24 at the
99.9th percentile. For non-nursing infants (>1 yr.), the
%RfD is 0.46 at the 99th percentile and 1.50 at the
99.9th percentile. There are no residential uses of
cymoxanil; it is extremely unlikely that drinking water will be
contaminated. Based on the completeness and reliability of the toxicity
data base, the lack of toxicological endpoints of special concern, the
lack of any indication that children are more sensitive than adults to
cymoxanil, and the conservative exposure assessment, there is a
reasonable certainty that no harm will result to infants and children
from the aggregate exposure of residues of cymoxanil, including all
anticipated dietary exposure and all other non-occupational exposures.
Accordingly, there is no need to apply an additional safety factor for
infants and children.

F. International Tolerances

To date, no international tolerances exist for cymoxanil.
[FR Doc. 03-4257 Filed 2-27-03; 8:45 am]
BILLING CODE 6560-50-S

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Cymoxanil; Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food

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