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[Federal Register: January 29, 2003 (Volume 68, Number 19)]
[Notices]
[Page 4475-4481]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr29ja03-63]
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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:
miller.joanne@epamail.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 categories and 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 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 opp-docket@epa.gov,
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:
¥ Increased WBC; decreased hematocrit, hemoglobin and RBC.
¥ Increased alkaline phosphatase, serum glutamic-oxloacetic
transaminase (SGOT), SGPT, cholesterol and total serum protein levels.
¥ 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:
¥ Sodium acifluorfen (acifluorfen is a lactofen metabolite),
nitrofen, oxyfluorfen, and fomesafen.
¥ Sodium acifluorfen produces hepatocellular adenomas and
carcinomas in mice but is negative in rats.
¥ Nitrofen produces hepatocellular carcinomas in mice and
pancreatic carcinomas in rats.
¥ Oxyfluorfen produces marginally positive liver tumors in
mice but is negative in rats.
¥ 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