[Federal Register Volume 68, Number 40 (Friday, February 28, 2003)]
[Notices]
[Pages 9660-9666]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-4257]


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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: [email protected].

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:
    [sbull] Crop production (NAICS 111)
    [sbull] Animal production (NAICS 112)
    [sbull] Food manufacturing (NAICS 311)
    [sbull] 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.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-2003-0006. 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 [email protected], 
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:
    [sbull] 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.
    [sbull] 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.
    [sbull] 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:
    [sbull] 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).
    [sbull] 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.
    [sbull] 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
------------------------------------------------------------------------
 
------------------------------------------------------------------------
Bacterial gene mutation           Salmonella          Negative
                                   typhimurium
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Mammalian gene mutation in vitro  CHO/HGPRT           Negative
------------------------------------------------------------------------
Mammalian chromosome aberrations  CHO                 Positive
 in vitro
------------------------------------------------------------------------
Mammalian chromosome aberrations  Mouse micronucleus  Negative
 in vitro
------------------------------------------------------------------------
Unscheduled DNA synthesis in      Primary rat         Negative
 vitro                             hepatocytes
------------------------------------------------------------------------
Unscheduled DNA synthesis in      Primary rat         Negative
 vitro                             hepatocytes and
                                   Spermatocytes
------------------------------------------------------------------------


[[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