[Federal Register Volume 68, Number 19 (Wednesday, January 29, 2003)]
[Notices]
[Pages 4475-4481]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-2020]


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ENVIRONMENTAL PROTECTION AGENCY

[OPP-2003-0001; FRL-7287-6]


Lactofen; Notice of Filing Pesticide Petitions to Establish 
Tolerances for Certain Pesticide Chemicals in or on Food

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

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SUMMARY: This notice announces the initial filing of pesticide 
petitions proposing the establishment of regulations for residues of 
certain pesticide chemicals in or on various food commodities.

DATES: Comments, identified by docket ID number OPP-2003-0001, must be 
received on or before February 28, 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: Joanne I. Miller, Registration 
Division (7505C), Office of Pesticide Programs, Environmental 
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460-
0001; telephone number: (703) 305-6224; 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 categories and 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 the table could also be 
affected. The North American Industrial Classification System (NAICS) 
codes have been provided to assist you and others in determining 
whether or not this action might apply to certain entities. If you have 
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 identification (ID) number OPP-2003-0001. 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 EPA's 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

[[Page 4476]]

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 in 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-2003-0001. 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-2003-0001. 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-2003-0001.
    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-2003-0001. 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.

[[Page 4477]]

    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 pesticide petitions as follows proposing the 
establishment and/or amendment of regulations for residues of certain 
pesticide chemicals in or on various food commodities under section 408 
of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a. 
EPA has determined that these petitions contain data or information 
regarding the elements set forth in FFDCA section 408d)2); however, EPA 
has not fully evaluated the sufficiency of the submitted data at this 
time or whether the data support granting of the petitions. Additional 
data may be needed before EPA rules on the petitions.

List of Subjects

    Environmental protection, Agricultural commodities, Feed additives, 
Food additives, Pesticides and pests, Reporting and recordkeeping 
requirements.

    Dated: January 17, 2003.
 Debra Edwards,
Acting Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

    The petitioner's summaries of the pesticide petitions are printed 
below as required by FFDCA section 408(d)(3). The summaries of the 
petitions were prepared by the petitioner and represent the views of 
the petitioner. The petitions summaries announce the availability of a 
description of the analytical methods available to EPA for the 
detection and measurement of the pesticide chemicals residues or an 
explanation of why no such method is needed.

Valent U.S.A. Corporation

PP 8F3591 and PP 9F3798

    EPA has received pesticide petitions (8F3591 and 9F3798) from 
Valent U.S.A. Corporation, 1333 North California Boulevard, Suite 600, 
Walnut Creek, California 94596-8025 proposing, pursuant to section 
408(d) of the FFDCA, 21 U.S.C. 346a(d), to amend 40 CFR 180.432 by 
establishing tolerances for residues of the herbicide lactofen, 1-
(carboethoxy)ethyl 5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-
nitrobenzoate, in or on the raw agricultural commodities (RACs) 
cottonseed at 0.01 part per million (ppm), cotton gin byproducts at 
0.02 ppm, and peanut nutmeats at 0.01 ppm. EPA has determined that the 
petitions contain 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 petitions. Additional data may be needed before 
EPA rules on the petitions.

A. Residue Chemistry

    1. Plant metabolism. The nature of the residue in plants is 
adequately understood based on plant metabolism studies on cotton, 
peanut, soybean, and tomato. The Health Effects Division (HED) 
Metabolism Assessment Review Committee (MARC) met on April 4, 2000, 
considered all of the metabolism studies submitted to date and 
concluded that only the parent compound needs to be regulated for plant 
commodities, provided that pre-harvest intervals exceed 45 days.
    2. Analytical method. Adequate analytical methodology is available 
for detecting and measuring levels of lactofen in or on RACs with a 
limit of detection (LOD) that allows monitoring of food with residues 
at or above the level of the proposed tolerances. The method, RM-28D, 
has been successfully radio validated in conjunction with a tomato 
metabolism study and has undergone a successful independent laboratory 
validation trial. This method was also successfully validated by EPA's 
Analytical Chemistry Laboratory using peanut nutmeats and cottonseed. 
In general, the analytical method has a LOD of 0.005 ppm and limit of 
quantitation (LOQ) of 0.01 ppm in crops.
    3. Magnitude of residues. Adequate lactofen residue data are 
available for cotton and peanuts. An adequate number of field trials 
distributed throughout cotton and peanut growing areas of the United 
States have been conducted on these crops to determine lactofen 
residues resulting from the application of lactofen at the maximum 
labeled or proposed use rate.
    i. Cotton. Residues of lactofen were each <0.01 ppm, in/on 
cottonseed (n=14) harvested 59-127 days following a single 
postemergence soil-directed application of lactofen at 0.4 lb active 
ingredient per acre (lb active ingredient/acre) (2x the single 
application rate) and in/on cottonseed (n=10) harvested 23-108 days 
following the last of two postemergence directed applications at 0.4 lb 
active ingredient/acre application (2x the maximum seasonal rate). With 
one exception, residues of lactofen were also each <0.01 ppm, in/on 
cotton gin byproducts (gin trash) (n=11) derived from cotton harvested 
69-108 days following two applications at 0.2 lb active ingredient/
acre. One gin trash sample bore residues of lactofen at 0.03 ppm, but 
confirmatory analyses of this sample detected lactofen at <0.01-0.02 
ppm, and residues of lactofen were <0.01 ppm, in the duplicate treated 
sample from the same trial.
    In a single processing study, residues of lactofen were <0.01 ppm, 
in/on cottonseed harvested 76 days following the last of two directed 
applications of lactofen at 0.6 lb active ingredient/acre application 
(1.2 lb active ingredient/acre/season, 3x rate). Residues of lactofen 
were <0.01 ppm in samples of meal, hulls, oil, (crude and refined) and 
soapstock.
    All these data support proposed tolerance for lactofen in/on 
cottonseed at 0.01 ppm, and in/on cotton, gin byproducts at 0.02 ppm. 
No separate tolerances are needed for cotton processed commodities.
    ii. Peanuts. In 8 field trials, residues of lactofen were each 
<0.01 ppm, in/on 16 samples of peanut nutmeats and hulls harvested 65-
71 days following the last of 2 broadcast applications of lactofen 
totaling 0.45 lb active ingredient/acre (1x the maximum proposed rate). 
Residues of lactofen were also <0.01 ppm, in/on peanut nutmeats and 
hulls from 2 trials conducted at 2x and 5x the maximum seasonal rate.
    In a processing study, residues of lactofen were <0.01 ppm in meal, 
oil, crude and refined, and soapstock processed from nutmeats treated 
at 3x and 5x the maximum proposed use rates.
    All these data support proposed tolerance for lactofen in/on peanut 
nutmeats at 0.01 ppm. No separate tolerances are needed for peanut 
processed commodities.

B. Toxicological Profile

    1. Acute toxicity. Lactofen has very low acute toxicity. The acute 
oral LD50 is 5.96 gram/kilogram/body weight (g/kg/bwt) 
toxicity category IV, the acute dermal LD50 is >2.0 g/kg/bwt 
toxicity category III and the acute inhalation LD50 is >6.3 
milligrams/liter (mg/L) toxicity category IV. Lactofen is not a

[[Page 4478]]

skin sensitizer but is a very slight dermal irritant.
    2. Genotoxicity. Lactofen has very little mutagenic or genotoxic 
activity. While a positive mutagenic response was reported in one trial 
of a Salmonella typhimurium/mammalian microsome mutagenicity assay, 
this response was not repeated in the second assay conducted. In 
addition, lactofen did not appear to induce chromosomal aberrations, 
unscheduled deoxyribonucleic acid (DNA) synthesis or inhibit DNA 
repair.
    3. Reproductive and developmental toxicity. Reproduction and 
teratology studies indicate that adverse effects, including 
embryotoxicity, occur only at doses that are also maternally toxic. 
Since lactofen causes effects only at levels which also produce 
systemic toxicity, the compound is not a reproductive hazard.
    In a 2-generation reproduction study in rats, decreased pup weight 
and decreased absolute and relative weights of the spleen were first 
reported at approximately 26.2 milligrams/kilogram/day (mg/kg/day) 
(based on dose administered to the parental group). The same dose level 
elicited mortality and decreased male fertility in the parental groups. 
The no observed adversed effect level (NOAEL) for both systemic and 
reproductive toxicity in this study was 2.6 mg/kg/day.
    In the developmental toxicity study in rats, effects were observed 
at the 150 mg/kg/day dose level consisting of decreases in fetal weight 
as well as skeletal abnormalities. This dose level also elicited signs 
of toxicity in the parental group. The NOAEL for this study was 50 mg/
kg/day. Based on this NOAEL and an uncertainty factor (UF) of 100, the 
acute reference dose (RfD) for lactofen has been set at 0.50 mg/kg/day.
    Two developmental toxicity studies were conducted in rabbits. In 
the first study, pregnant rabbits were administered oral doses of 0, 5, 
15, or 50 mg/kg bwt/day lactofen technical on days 6-18 of gestation. 
Maternal toxicity (clinical signs and reduced weight gain) and 
developmental effects (increased embryonic death, decreased litter size 
and increased post-implantation loss) were reported at 15 and 50 mg/kg. 
The Agency concluded that the data were insufficient to establish a 
clear NOAEL. In the second rabbit developmental toxicity study, 
pregnant rabbits were exposed to 0, 1, 4, or 20 mg/kg bwt/day oral 
doses on days 6-18 of gestation. Maternal toxicity (reduced food 
consumption) was observed at 20 mg/kg bwt/day, but no developmental 
effects were observed at any dose. Therefore, the maternal NOAEL was 4 
mg/kg bwt/day and the developmental NOAEL was greater than 20 mg/kg 
bwt/day.
    4. Subchronic toxicity--i. Rats 4-week. Male and female rats were 
fed diets containing lactofen technical at concentrations of 0, 200, 
1,000, 5,000, and 10,000 ppm, for 4 weeks. A slight increase in spleen 
weight was the basis for a lowest observed adversed effect level 
(LOAEL) of 200 ppm, lowest dose tested (LDT). At doses of 1,000 ppm, or 
higher, the following findings were reported: clinical signs of 
toxicity; decreased red blood cell (RBC), hemoglobin, hematocrit, and 
increased white blood cell (WBC); increased relative liver and spleen 
weights; and necrosis and pigmentation of hepatocytes. At 10,000 ppm, 
severe toxic signs were observed by day 7 and all animals were dead or 
killed in extremis by day 11. Hypocellularity of the spleen, thymus, 
and bone marrow was also observed in animals exposed to 10,000 ppm.
    ii. Rats 3-month. Lactofen technical was fed to male and female 
rats at dietary concentrations of 0, 40, 200, and 1,000 ppm, for 13 
weeks. Histopathological changes in the liver and significant changes 
in clinical chemistry associated with the liver were observed in rats 
exposed to 1,000 ppm, dosage. Decreased RBC, hemoglobin and hematocrit 
values were also observed at 1,000 ppm. The NOAEL in this study was 200 
ppm, 14.1 mg/kg/day.
    iii. Dogs 4-week. In a range finding study lactofen technical was 
fed in the diet of dogs at 0, 1,000, 3,000, and 10,000 ppm, for 4 
weeks. Toxic effects noted in dogs fed 10,000 ppm, included decreased 
RBC count and hemocrit, and increased blood urea nitrogen (BUN) and 
serum glutamic-pyruvic transaminase (SGPT). Food palatability problems 
led to greatly decreased feed consumption at higher dosages. The NOAEL 
appeared to be 1,000 ppm.
    iv. Mice 3-month. Groups of male and female mice were fed diets 
containing lactofen technical at concentrations of 0, 40, 200, 1,000, 
5,000, and 10,000 for 13 weeks. At week 5, the dosage of the 40 ppm, 
groups was increased to 2,000 ppm. Treatment related mortality occurred 
at dosages above 1,000 ppm. The LOAEL was 200 ppm, 28.6 mg/kg/day based 
on:
    [sbull] Increased WBC; decreased hematocrit, hemoglobin and RBC.
    [sbull] Increased alkaline phosphatase, serum glutamic-oxloacetic 
transaminase (SGOT), SGPT, cholesterol and total serum protein levels.
    [sbull] Increased weights or enlargement of the spleen, liver, 
adrenals, heart, and kidney; histopathological changes of the liver, 
kidney, thymus, spleen, ovaries, and testes.
    In general, effects were slight in the 200 ppm groups, and moderate 
to severe in the 1,000 ppm groups.
    v. Peroxisome proliferation. Butler et al (1988) studied the 
effects of lactofen on peroxisome proliferation in mice exposed for 7 
weeks to dietary concentrations of 2, 10, 50, and 250 ppm. Liver-weight 
to body-weight ratio, liver catalase, liver acyl-CoA oxidase, liver 
cell cytoplasmic eosinophilia, nuclear, and cellular size, and 
peroxisomal staining were increased by the tumorigenic dose of 
lactofen, i.e. 250 ppm. Lower doses of lactofen had little to no effect 
on these parameters. This study indicates that lactofen induces 
peroxisome proliferation and further, that 50 ppm, 7 mg/kg/day, a dose 
which is not tumorigenic, would be considered a threshold dose in mice 
for peroxisome proliferation produced by lactofen. A subchronic study 
conducted in chimpanzees (Couch and Erickson 1986), indicated no effect 
on clinical chemistry or histological endpoints that would suggest 
liver toxicity or peroxisome proliferation at doses up to 75 mg/kg bwt/
day administered for 93 days. Therefore, Valent believes that 75 mg/kg 
bwt/day is a clear NOAEL for peroxisome proliferation observed in a 
species closely related to man. On January 17, 2001, the Mechanism of 
Toxicity Assessment Review Committee (MTARC) reviewed the merits of the 
toxicological data supporting peroxisome proliferation as the proposed 
mode of action for lactofen. Based on the weight-of-evidence from 
guideline, as well as mechanistic studies, the MTARC concluded that 
there are sufficient data to classify lactofen as a non-genotoxic 
hepatocarcinogen in rodents with peroxisome proliferation being a 
plausible mode of action.
    5. Chronic toxicity. Lactofen causes adverse health effects when 
administered to animals for extended periods of time. These effects 
include proliferative changes in the liver, spleen, and kidney; 
hematological changes; and blood biochemistry changes.
    i. Mouse 18-month. In a dietary 18-month oncogenicity study in mice 
at dosages of 10, 50, and 250 ppm, lactofen technical, an increase in 
liver adenomas and carcinomas, cataracts, and liver pigmentation was 
observed at 250 ppm, a dose that clearly exceeded the maximum tolerance 
dose (MTD). The lowest dose, 10 ppm, 1.4 mg/kg/day, was the LOAEL based 
on increased liver weight and hepatocytomegaly.

[[Page 4479]]

    ii. Rat 24-month. In a 2-year chronic feeding/oncogenicity study of 
lactofen technical in rats at dosages of 0, 500, 1,000 ppm; and 2,000 
ppm, in the diet, an increase in liver neoplastic nodules and foci of 
cellular alteration was observed in both sexes at 2,000 ppm. The NOAEL 
for systemic toxicity is 500 ppm, 2 mg/kg/day based on kidney and liver 
pigmentation.
    iii. Dog 12-month. In a 1-year study in dogs exposed to 40, 200, 
and 1,000 ppm; week 1-17 or 3,000 ppm; week 18-52 lactofen technical in 
their diet, the NOAEL was determined to be 200 ppm, (0.79 mg/kg/day) 
based on renal dysfunction and decreased RBC, hemoglobin hematocrit and 
cholesterol observed at 1,000/3,000 ppm. Based on this NOAEL and an 
uncertainty factor (UF) of 100, the chronic RfD for lactofen has been 
set at 0.008 mg/kg/day.
    iv. Carcinogenicity. As a member of the diphenyl ether chemical 
family, lactofen is structurally related to four other chemicals that 
are oncogenic in rodents:
    [sbull] Sodium acifluorfen (acifluorfen is a lactofen metabolite), 
nitrofen, oxyfluorfen, and fomesafen.
    [sbull] Sodium acifluorfen produces hepatocellular adenomas and 
carcinomas in mice but is negative in rats.
    [sbull] Nitrofen produces hepatocellular carcinomas in mice and 
pancreatic carcinomas in rats.
    [sbull] Oxyfluorfen produces marginally positive liver tumors in 
mice but is negative in rats.
    [sbull] Fomesafen produces hepatocellular adenomas and carcinomas 
in mice.
    The Cancer Peer Review Committee (CPRC) evaluated the relevant data 
on the carcinogenic potential of lactofen in 1987 and classified 
lactofen as a B2 carcinogen Probable Human Carcinogen and assigned a 
Cancer Potency Factor (Q1*) of 1.7 x 10-1 mg/kg/
day-1, based on a interspecies scaling factor of 0.67. This 
Q1* has since been reduced to 1.19 x 10-1 mg/kg/
day-1 based on recent EPA guidance indicating that 0.75 is a 
more appropriate interspecies scaling factor. The B2 classification is 
based on an increase in the combined incidence of liver adenomas and 
carcinomas in mice and increases in liver neoplastic nodules and foci 
of cellular alteration (possible precursor of tumors) in rats. In 1996, 
and 1999, EPA proposed new cancer risk assessment guidelines which 
state that nonmutagenic carcinogens known to cause cancer via a 
threshold mechanism, such as peroxisome proliferation, could be 
assessed using a nonlinear margin of exposure (MOE) approach rather 
than the Q1 * method. EPA has recently determined that 
lactofen acts via a peroxisome proliferation mechanism and is currently 
reevaluating its approach to the quantification of the cancer risk for 
lactofen.
    6. Animal metabolism. In a rat metabolism study, lactofen was shown 
to metabolize to acifluorfen, 5-[2-chloro-4-(trifluoromethyl)phenoxy]-
2-nitrobenzoate, which was eliminated via both urine and feces. While 
lactofen was the primary compound found in the feces, acifluorfen 
accounted for >90% of the radioactivity in the urine. Negligible 
amounts of the administered radioactivity were found in any tissue with 
less than 0.8% of the administered radioactivity being found in the 
liver one of the main target organs.
    7. Metabolite toxicology. Acifluorfen is also a hydrolytic 
metabolite of lactofen. The sodium salt of this benzoic acid is the 
registered herbicide, sodium acifluorfen. This product has a complete 
data base supporting registration with a RfD of 0.013 mg/kg/day and a 
Q1* of 5.30 x 10-2 mg/kg/day-1. 
Because lactofen and its metabolites are not retained in the body, the 
potential for acute toxicity from in situ formed metabolites is low. 
The potential for chronic toxicity of lactofen metabolites has been 
adequately addressed by an extensive battery of lactofen chronic 
toxicity testing.
    8. Endocrine disruption. No special studies to investigate the 
potential for estrogenic or other endocrine effects of lactofen have 
been performed. However, a large and detailed toxicology data base 
exists for the compound including studies acceptable to the Agency in 
all required categories. These studies include evaluations of 
reproduction and reproductive toxicity and detailed pathology and 
histology of endocrine organs following repeated or long-term exposure. 
These studies are considered capable of revealing endocrine effects and 
no such effects were observed.

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 lactofen. For 
the following risk assessments, the NOAEL from the chronic oral 
toxicity study in dogs, 0.79 mg/kg/day, was selected as the chronic 
oral toxicity endpoint. Based on this NOAEL, and an UF of 100, the 
chronic RfD and the chronic population adjusted dose (cPAD) for 
lactofen has been set at 0.008 mg/kg/day. The NOAEL from the rat 
developmental study, 50 mg/kg/day, was selected as the acute oral 
toxicity endpoint. Based on this NOAEL and an UF of 100, the acute RfD 
for lactofen has been set at 0.50 mg/kg/day. An acute adjusted dose 
(aPAD) of 0.17 mg/kg/day was calculated using this endpoint and an 
additional Food Quality Protection Act (FQPA) safety factor of 3. This 
aPAD will only be used to assess acute exposures to the females 13 to 
50 year old population subgroup since it is derived from a 
developmental toxicity endpoint. No other acute endpoints were 
identified to assess acute exposures to other populations.
    i. Food. Dietary risk was considered for the currently registered 
uses of lactofen on soybeans, snap beans, and cotton and for the 
pending use on peanuts. Dietary risk assessments were done using the 
Dietary Exposure Evaluation Model (DEEM\TM\), which incorporates 
consumption data generated in U. S. Department of Agriculture (USDA) 
Continuing Surveys of Food Intakes by Individuals (CSFII), 1989-1992. 
For chronic dietary risk assessments, the 3-day average of consumption 
for each subpopulation is combined with residues in commodities to 
determine average exposure in mg/kg/day. For refined acute dietary risk 
assessments, the entire distribution of consumption events for 
individuals is multiplied by a distribution of residues to obtain a 
distribution of exposures in mg/kg/day. This is a probabilistic 
analysis, referred to as ``Monte Carlo,'' and the risk is reported at 
the 99.\9th\ percentile of exposure. Food monitoring data are not 
available from Food and Drug Administration (FDA) or USDA for residues 
of lactofen. Therefore, only field trial data were used. A value of 
one-half the LOQ, 0.005 ppm, was used to represent the residues in all 
treated commodities. Percent crop treated (PCT) were incorporated for 
soybeans and snap beans, as reliable usage information was available 
for these commodities. The estimated risk from food is presented in the 
following table:

[[Page 4480]]



                                            Table 1.--Dietary Exposure and Risk to Lactofen from Food Sources
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                              Acute Endpoint                         Chronic Endpoint                        Cancer Endpoint2
           Population            -----------------------------------------------------------------------------------------------------------------------
                                  Exposure mg/kg/day         %aPAD        Exposure mg/kg/day         %aPAD        Exposure mg/kg/day         Risk
--------------------------------------------------------------------------------------------------------------------------------------------------------
U.S. population                   NA1                 NA                  1 x 10-\6\          <0.1                1 x 10-\6\          8 x 10-\8\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Females 13 to 50                  2 x 10-\6\          <0.1                <1 x 10-\6\         <0.1                NA                  NA
--------------------------------------------------------------------------------------------------------------------------------------------------------
Children 1 to 6                   NA1                 NA                  2 x 10-\6\          <0.1                NA                  NA
--------------------------------------------------------------------------------------------------------------------------------------------------------
1Acute endpoint applies only to females of childbearing age.
2Cancer risk is generally reported for the U.S. population.

    ii. Drinking water. Environmental fate properties indicate that 
lactofen is not very persistent or mobile. Hydrolysis half-lives are 
10.7, 4.6, and <1.0 days at pH 5, 7, and 9 at 40[deg] C, respectively. 
This temperature most likely exceeds temperatures that lactofen would 
be expected to be exposed to under normal conditions, thus the 
hydrolysis rates are probably slower. Aerobic soil metabolism half-
lives range from 1 to 3 days. Lactofen has a low probability to 
contaminate drinking water because it has a short half-life (3 days or 
less) and high binding potential( Koc>1,000). Limited data 
suggest that lactofen conversion to acifluorfen in water is 
approximately 52%. The HED MARC has concluded that the residues of 
concern in drinking water are acifluorfen and amino acifluorfen. 
Insufficient information is available to estimate the amino acifluorfen 
concentration in water, but it is likely to be less than that of 
acifluorfen. Laboratory studies have shown that acifluorfen reaches its 
maximum concentration of 53.3% of applied lactofen at 7 days following 
application and it is most likely to form under the soil surface. Thus, 
the formed acifluorfen is not subject to drift, erosion, or runoff 
forces that contribute to surface water contamination. Surface water, 
however, could be contaminated with acifluorfen from lactofen 
applications via spray drift. The registrant also has conducted two 
prospective ground water studies which showed that neither lactofen nor 
acifluorfen from lactofen applications contaminate ground water. 
Therefore, in the following discussion, the potential exposure to 
lactofen from drinking water will address only potential surface water 
contamination with lactofen and acifluorfen.
    The Tier II estimated environmental concentration (EEC) assessment 
in surface water uses a single site, or multiple single sites, which 
represents a high-end exposure scenario from pesticide use on a 
particular crop or non-crop use site. The EEC's for lactofen were 
generated for the standard Mississippi cotton scenario. The Agency has 
implemented the concept of index reservoirs (IR) and the PCT area to 
better estimate potential residue level in drinking water sources. The 
scenarios used with EPA pesticide root zone model (PRZM) and exposure 
analysis modeling systems (EXAMS) to estimate lactofen in the 
``standard pond'' were rerun with the IR for the cotton and soybean 
scenarios. The Agency has estimated that the PCT area for the 
Mississippi cotton scenario is 0.20 (20%).
    The Office of Pesticide Programs (OPP) has calculated drinking 
water levels of comparison (DWLOCs) for acute and chronic exposure to 
lactofen and acifluorfen from applications of lactofen in surface 
water. To calculate the DWLOC for acute exposure, the acute dietary 
food exposure from the DEEMTM analysis was subtracted from 
the aPAD. To calculate the DWLOC for chronic (non-cancer) exposure, the 
chronic dietary food exposure from the DEEMTM analysis was 
subtracted from the cPAD to obtain the acceptable chronic non-cancer 
exposure to lactofen and acifluorfen in drinking water. A DWLOC cancer 
was calculated in a similar manner, assuming a negligible risk of 1 x 
10-\6\. Assumptions used in calculating the DWLOCs include 
70 kg bwt for the U.S. population, 60 kg bwt for adult females, 10 kg 
bwt for children, 2 liters of water consumption per day for adults, and 
1 liter consumption for children.

                                           Table 2.--Dietary Exposure and Risk to Lactofen from Drinking Water
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                              Acute Endpoint                         Chronic Endpoint                        Cancer Endpoint2
           Population            -----------------------------------------------------------------------------------------------------------------------
                                   Exposure [mu]g/L      DWLOC [mu]g/L     Exposure [mu]g/L      DWLOC [mu]g/L     Exposure [mu]g/L      DWLOC [mu]g/L
--------------------------------------------------------------------------------------------------------------------------------------------------------
U.S. population                   NA1                 NA                  0.022               280                 0.012               0.3
--------------------------------------------------------------------------------------------------------------------------------------------------------
Females 13 to 50                  0.62                5,100               0.022               240                 -                   -
--------------------------------------------------------------------------------------------------------------------------------------------------------
Children 1 to 6                   NA1                 NA                  0.022               80                  -                   -
--------------------------------------------------------------------------------------------------------------------------------------------------------
1 Acute endpoint applies only to females of childbearing age.
2 Cancer risk is generally reported for the U.S. population.


                                         Table 3.--Dietary Exposure and Risk to Acifluorfen1 from Drinking Water
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                              Acute Endpoint                         Chronic Endpoint                        Cancer Endpoint3
           Population            -----------------------------------------------------------------------------------------------------------------------
                                   Exposure [mu]g/L      DWLOC [mu]g/L     Exposure [mu]g/L      DWLOC [mu]g/L     Exposure [mu]g/L      DWLOC [mu]g/L
--------------------------------------------------------------------------------------------------------------------------------------------------------
U.S. population                   NA2                 NA                  0.99                140                 0.34                0.7
--------------------------------------------------------------------------------------------------------------------------------------------------------
Females 13 to 50                  4.9                 600                 0.99                120                 -                   -
--------------------------------------------------------------------------------------------------------------------------------------------------------

[[Page 4481]]

 
Children 1 to 6                   NA2                 NA                  0.99                40                  -                   -
--------------------------------------------------------------------------------------------------------------------------------------------------------
1 Acifluorfen derived from applications of lactofen.
2 Acute endpoint applies only to females of childbearing age.
3 Cancer risk is generally reported for the U.S. population.

    HED has a concern if the DWLOC for any scenario is below the 
estimated environmental concentration from the models. All of the 
DWLOCs shown in the tables above exceed the estimated EECs.
    2. Non-dietary exposure. Lactofen is proposed only for agricultural 
uses and no home owner or turf uses. Thus, no non-dietary risk 
assessment is needed.

D. Cumulative Effects

    Section 408(b)(2)(D)(v) requires that the Agency must consider 
``available information'' concerning the cumulative effects of a 
particular pesticide's residues and ``other substances that have a 
common mechanism of toxicity.'' Available information in this context 
include not only toxicity, chemistry, and exposure data, but also 
scientific policies and methodologies for understanding common 
mechanisms of toxicity and conducting cumulative risk assessments. For 
most pesticides, although the Agency has some information in its files 
that may turn out to be helpful in eventually determining whether a 
pesticide shares a common mechanism of toxicity with any other 
substances, EPA does not at this time have the methodologies to resolve 
the complex scientific issues concerning common mechanism of toxicity 
in a meaningful way.
    There are other pesticidal compounds that are structurally related 
to lactofen and have similar effects on animals. In consideration of 
potential cumulative effects of lactofen 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 lactofen would be cumulative with those of other chemical 
compounds. Thus, only the potential risks of lactofen have been 
considered in this assessment of aggregate exposure and effects.
    Valent will submit information for EPA to consider concerning 
potential cumulative effects of lactofen consistent with the schedule 
established by EPA in the Federal Register of August 4, 1997 (62 FR 
42020) (FRL-5734-6), and other subsequent EPA publications pursuant to 
FQPA.

E. Safety Determination

    1. U.S. population. Water is not expected to be a significant 
source of exposure for lactofen, as it degrades quickly in the 
environment to numerous degradates, including acifluorfen. EECs for 
lactofen and acifluorfen are well below the DWLOC for chronic, acute, 
and cancer risk. Therefore, the only significant source of human 
exposure to lactofen is in food. Residues of lactofen are generally 
non-detectable at a LOQ of 0.005 ppm, in all food forms. The exposure 
is <0.1% of the acute and chronic PAD for all population subgroups. 
Exposure is generally not of concern if it is less than 100% of the 
PAD. The estimated cancer risk for the U.S. population is 8 x 
10-\8\, which is more than an order of magnitude less than 
the risk that is generally considered negligible 1 x 10-\6\.
    2. Infants and children. As stated above, dietary exposure 
assessments, including drinking water, utilize less than 0.1% of the 
acute and chronic PADs for all population subgroups, including infants 
and children. Reproduction and developmental effects have been found in 
toxicology studies for lactofen but only at levels that were also 
maternally toxic. This indicates that developing animals are not more 
sensitive than adults. FQPA requires an additional safety factor of up 
to 10 for chemicals which present special risks to infants or children. 
Lactofen does not meet the criterion for application of an additional 
safety factor for infants and children. The FQPA Safety Factor 
Committee met on March 13, 2000 to evaluate the hazard and exposure 
data for lactofen and recommended that FQPA, safety factor for 
protection of infants and children should be reduced to 3x for 
lactofen. This safety factor was reduced to 3x by The FQPA, Safety 
Factor Committee because available data provide no indication of 
quantitative or qualitative increased susceptibility from in utero and/
or postnatal exposure to lactofen in rats. Information on the 
reproduction and developmental effects caused by the other diphenyl 
ether herbicides is not available to Valent. Additional time is needed 
for the Agency to evaluate the need for an additional safety factor 
related to these other chemicals. However, even if an additional safety 
factor were deemed necessary, the dietary exposures are still expected 
to be well below the established reference doses.

F. International tolerances.

    There are no Codex maximum residue limits established for lactofen 
on cotton or peanut commodities, so there is no conflict between this 
proposed action and international residue limits.
[FR Doc. 03-2020 Filed 1-28-03; 8:45 a m]
BILLING CODE 6560-50-S