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Flufenpyr-ethyl (Valent). June 25, 2003. Pesticide tolerance petition. Federal Register.
http://www.epa.gov/fedrgstr/EPA-PEST/2003/June/Day-25/p16033.htm
[Federal Register: June 25, 2003 (Volume 68, Number 122)]
[Notices]
[Page 37813-37820]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr25jn03-47]
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ENVIRONMENTAL PROTECTION AGENCY
[OPP-2003-0166; FRL-7307-8]
Flufenpyr-ethyl; Notice of Filing a Pesticide Petition to
Establish a Tolerance for a Certain Pesticide Chemical in or on Food
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: This notice announces the initial filing of a pesticide
petition proposing the establishment of regulations for residues of a
certain pesticide chemical in or on various food commodities.
DATES: Comments, identified by docket ID number OPP-2003-0166, must be
received on or before July 25, 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@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.
Potential affected entities may include, but are not limited to:
¥ Crop production (NAICS)
¥ 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
[[Page 37814]]
entities not listed in this unit could also be affected. The North
American Industrial Classification System (NAICS) codes have been
provided to assist you and others in determining whether this action
might apply to certain entities. If you have any questions regarding
the applicability of this action to a particular entity, consult the
person listed under FOR FURTHER INFORMATION CONTACT.
B. How Can I Get Copies of this Document and Other Related Information?
1. Docket. EPA has established an official public docket for this
action under docket identification (ID) number OPP-2003-0166. The
official public docket consists of the documents specifically
referenced in this action, any public comments received, and other
information related to this action. Although a part of the official
docket, the public docket does not include Confidential Business
Information (CBI) or other information whose disclosure is restricted
by statute. The official public docket is the collection of materials
that is available for public viewing at the Public Information and
Records Integrity Branch (PIRIB), Rm. 119, Crystal Mall #2,
1921 Jefferson Davis Hwy., Arlington, VA. This docket facility is open
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal
holidays. The docket telephone number is (703) 305-5805.
2. Electronic access. You may access this Federal Register document
electronically through the EPA Internet under the ``Federal Register''
listings at http://www.epa.gov/fedrgstr/.
An electronic version of the public docket is available through
EPA's electronic public docket and comment system, EPA Dockets. You may
use EPA Dockets at http://www.epa.gov/edocket/ to submit or view public
comments, access the index listing of the contents of the official
public docket, and to access those documents in the public docket that
are available electronically. Although not all docket materials may be
available electronically, you may still access any of the publicly
available docket materials through the docket facility identified in
Unit I.B.1. Once in the system, select ``search,'' then key in the
appropriate docket ID number.
Certain types of information will not be placed in the EPA Dockets.
Information claimed as CBI and other information whose disclosure is
restricted by statute, which is not included in the official public
docket, will not be available for public viewing in EPA's electronic
public docket. EPA's policy is that copyrighted material will not be
placed in EPA's electronic public docket but will be available only in
printed, paper form in the official public docket. To the extent
feasible, publicly available docket materials will be made available in
EPA's electronic public docket. When a document is selected from the
index list in EPA Dockets, the system will identify whether the
document is available for viewing in EPA's electronic public docket.
Although not all docket materials may be available electronically, you
may still access any of the publicly available docket materials through
the docket facility identified in Unit I.B. EPA intends to work towards
providing electronic access to all of the publicly available docket
materials through EPA's electronic public docket.
For public commenters, it is important to note that EPA's policy is
that public comments, whether submitted electronically or 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-2003-0166. 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-2003-0166. 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
[[Page 37815]]
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-2003-0166.
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-2003-0166. Such deliveries are only accepted during the
docket's normal hours of operation as identified in Unit I.B.1.
D. How Should I Submit CBI to the Agency?
Do not submit information that you consider to be CBI
electronically through EPA's electronic public docket or by e-mail. You
may claim information that you submit to EPA as CBI by marking any part
or all of that information as CBI (if you submit CBI on disk or CD ROM,
mark the outside of the disk or CD ROM as CBI and then identify
electronically within the disk or CD ROM the specific information that
is CBI). Information so marked will not be disclosed except in
accordance with procedures set forth in 40 CFR part 2.
In addition to one complete version of the comment that includes
any information claimed as CBI, a copy of the comment that does not
contain the information claimed as CBI must be submitted for inclusion
in the public docket and EPA's electronic public docket. If you submit
the copy that does not contain CBI on disk or CD ROM, mark the outside
of the disk or CD ROM clearly that it does not contain CBI. Information
not marked as CBI will be included in the public docket and EPA's
electronic public docket without prior notice. If you have any
questions about CBI or the procedures for claiming CBI, please consult
the person listed under FOR FURTHER INFORMATION CONTACT.
E. What Should I Consider as I Prepare My Comments for EPA?
You may find the following suggestions helpful for preparing your
comments:
1. Explain your views as clearly as possible.
2. Describe any assumptions that you used.
3. Provide copies of any technical information and/or data you used
that support your views.
4. If you estimate potential burden or costs, explain how you
arrived at the estimate that you provide.
5. Provide specific examples to illustrate your concerns.
6. Make sure to submit your comments by the deadline in this
notice.
7. To ensure proper receipt by EPA, be sure to identify the docket
ID number assigned to this action in the subject line on the first page
of your response. You may also provide the name, date, and Federal
Register citation.
II. What Action is the Agency Taking?
EPA has received a pesticide petition as follows proposing the
establishment and/or amendment of regulations for residues of a certain
pesticide chemical in or on various food commodities under section 408
of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a.
EPA has determined that this petition contains data or information
regarding the elements set forth in FFDCA section 408(d)(2); however,
EPA has not fully evaluated the sufficiency of the submitted data at
this time or whether the data support granting of the petition.
Additional data may be needed before EPA rules on the petition.
List of Subjects
Environmental protection, Agricultural commodities, Feed additives,
Food additives, Pesticides and pests, Reporting and recordkeeping
requirements.
Dated: June 16, 2003.
Debra Edwards,
Director, Registration Division, Office of Pesticide Programs.
Summary of Petition
The petitioner summary of the pesticide petition is printed below
as required by FFDCA section 408(d)(3). The summary of the petition was
prepared by the petitioner and represents the view of the petitioner.
The petition summary announces the availability of a description of the
analytical methods available to EPA for the detection and measurement
of the pesticide chemical residues or an explanation of why no such
method is needed.
Valent U.S.A. Corporation
PP 0F6164
EPA has received a request from Valent U.S.A. Corporation at 1333
North California Boulevard, Suite 600, Walnut Creek, California 94596-
8025 pursuant to section 408(d) of FFDCA, 21 U.S.C. 346a(d), to amend
40 CFR part 180 to establish tolerances for residues of the herbicide
chemical flufenpyr-ethyl, ethyl [2-chloro-4-fluoro-5-(5-methyl-6-oxo-4-
trifluoromethyl-1,6-dihydropyridazin-1-yl)phenoxy]acetate, in or on the
raw agricultural commodities corn, field, grain; soybean, seed; and
sugarcane, cane at 0.01 parts per million (ppm) and for the combined
residues of the herbicide chemical flufenpyr-ethyl, and its metabolite,
S-3153-acid-4-OH, [2-chloro-4-hydroxy-5-(5-methyl-6-oxo-4-
trifluoromethyl-1,6-dihydropyridazin-1-yl)phenoxy]acetic acid, free and
conjugated, in or on the raw agricultural commodities corn, field,
forage and corn, field, stover at 0.05 ppm. EPA has determined that the
request contains data or information consistent with 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 request.
A. Residue Chemistry
Plant and animal metabolism studies with 14C-flufenpyr-
ethyl have demonstrated that the residue of concern is adequately
understood for the purposes of these tolerances. Practical, validated
residue methodology is available to analyze all appropriate matrices
for flufenpyr-ethyl residues with an LOQ (limit of quantitation) of
0.01 ppm, and for S-3153-acid-4-OH metabolite with an LOQ of 0.02 ppm,
adequate to enforce all proposed tolerances. The potential for residues
of flufenpyr-ethyl has been evaluated in field corn grain, forage, and
stover; soybeans; sugarcane; feed items; in appropriate processed
products; and animals. These studies are adequate to support
appropriate tolerances and dietary risk analyses.
1. Plant metabolism. Metabolism of flufenpyr-ethyl radiolabeled
with 14C in the phenyl and in the pyridazinyl rings has been
studied in corn and soybean plants and in lactating goats, laying hens,
and rats. The major metabolic pathway in plants is hydrolysis of the
ethyl ester, followed by further metabolism into more polar products by
formation of phenolic glyclones. At the proposed pre-harvest intervals
total radiocarbon residue in grain samples was very low and adequately
represented by parent. However, in plant material and forage samples, a
conjugated carboxylic acid phenolic metabolite was present, the
aglycone of which, S-3153-acid-4-OH, was not detected as an animal
metabolite. This metabolite was not detected in any raw
[[Page 37816]]
agricultural commodity (RAC) grain sample or in sugarcane. The residue
of concern in grain and sugarcane is best defined as the parent,
flufenpyr-ethyl. However, consistent with plant metabolism studies,
finite residues of S-3153-acid-4-OH were detected in field corn forage
and stover, and tolerances are proposed.
2. Ruminant and poultry metabolism. Metabolism studies in goats and
hens demonstrated that transfer of administered 14C-
flufenpyr-ethyl residues to tissues was low. Total 14C-
residues in goat milk, muscle and tissues accounted for less than 1% of
the administered dose. Total radiocarbon residues (parent equivalent)
were less than 0.01 ppm in all cases except for approximately 0.15 ppm
in kidney and 0.04 ppm in liver. Residues were identified in excreta
and all appropriate tissues. In milk (0.002 to 0.008 ppm), kidney, and
liver approximately 70 to 90 percent of the residues was identified as
the ester hydrolysis product, S-3153-acid. In poultry, total
14C residues (parent equivalent) in eggs, muscle and tissues
accounted for about 0.1% of the administered dose, and were less than
0.01 ppm in all cases except for approximately 0.02 ppm in liver. More
than half of the liver residue was S-3153-acid.
3. Analytical method. Practical analytical method for detecting and
measuring levels of flufenpyr-ethyl and validated in/on all appropriate
agricultural commodities and respective processing fractions.
Methodology that converts the S-3153-acid-4-O-glucoside to the
corresponding aglycone, S-3153-acid-4-OH, was developed and validated
with an LOQ of 0.02 ppm. The extraction methodologies have been
validated using plant samples containing aged radiochemical residue
samples from 14C-metabolism studies. The methods have been
validated in soybean seed, corn grain, and corn stover at an
independent laboratory. The LOQ for flufenpyr-ethyl is 0.01 ppm and the
LOQ for S-3153-acid-4-OH is 0.02 ppm which will allow monitoring of
food with residues at the levels proposed for the tolerances. Both
flufenpyr-ethyl and S-3153-acid-4-OH have been evaluated using the FDA
multiresidue method protocol.
4. Magnitude of residues-- i. Soybean seed. Twenty-two field trials
in soybeans were conducted in 1997 and 1998 in 15 states representing
approximately 99% of the soybean acreage in the U.S. (EPA Regions II,
IV, and V). Analysis of duplicate samples from these trials showed that
at the proposed maximum application rate (24.5 grams active ingredient
(a.i.)/acre), or at 5 times the proposed maximum application rate,
there were no measurable residues of flufenpyr-ethyl in soybean seed
(<0.005 ppm). The analytical LOQ was 0.01 ppm. A processing study in
soybean seed treated at the 5-fold application rate demonstrated that
flufenpyr-ethyl was undetectable in all processed commodities. All
these data support a proposed tolerance of 0.01 ppm for flufenpyr-ethyl
in/on soybean seed. No additional tolerances are necessary for
processed commodities.
ii. Sugarcane cane. Nine field trials in sugarcane were conducted
in 1998 in 4 states representing approximately 100% of the sugarcane
acreage in the U.S. (EPA Regions II, IV and V). Analysis of duplicate
samples from these trials showed that at the proposed seasonal maximum
application rate (24.5 grams a.i./acre), or at five times the proposed
maximum application rate, there were no measurable residues of
flufenpyr-ethyl in sugarcane cane (<0.005 ppm). The analytical LOQ was
0.01 ppm. Because sugarcane is the vegetative portion of the plant, it
is possible that residues of the carboxylic acid phenol metabolite (S-
3153-acid-4-OH) might be present. With an LOQ of 0.02 ppm, there was no
detected metabolite in any sugarcane sample. Samples of processed
commodities from the sugarcane processing studies treated at 5-fold
were not analyzed because of the absence of finite residues in any of
the cane RAC samples. All these data support a proposed tolerance of
0.01 ppm for flufenpyr-ethyl in/on sugarcane cane. No additional
tolerances are necessary for processed commodities.
5. Field corn. Twenty-four field trials in field corn were
conducted in 1997 (10) and 1998 (14) in 16 states representing
approximately 97% of the field corn acreage in the U.S. (EPA Regions I,
II, V, VI, VII, VIII, and X). Field plots were treated at the V10 crop
stage. Forage was sampled 32 to 65 days after treatment at late R4 to
early R5 crop stage. Grain and stover were sampled at dry maturity 58
to 115 days after application.
i. Field corn grain. Analysis of duplicate samples of grain from
these trials showed that at the proposed maximum application rate (24.5
grams a.i./acre), at half the proposed maximum application rate (12
grams a.i./acre), or from two field plots treated at five times the
proposed maximum application rate (121 grams a.i./acre) there were no
measurable residues of flufenpyr-ethyl (<0.005ppm). The analytical LOQ
was 0.01 ppm. A processing study in field corn grain treated at the
five times the normal application rate demonstrated that flufenpyr-
ethyl was undetectable in all processed commodities. All these data
support a proposed tolerance of 0.01 ppm for flufenpyr-ethyl in/on
field corn grain. No additional tolerances are necessary for processed
commodities.
ii. Field corn forage and stover. Analysis of duplicate samples of
forage and stover from these trials showed that at the proposed maximum
application rate (24.5 grams a.i./acre), and at half the proposed
maximum application rate (12 grams a.i./acre) there were no measurable
residues of flufenpyr-ethyl (<0.005 ppm). In forage and stover from
plots treated at 5 times the proposed application rate (121 grams a.i./
acre) finite residue of flufenpyr-ethyl were detected (0.015 to 0.008
ppm). Forage and stover samples were also analyzed for S-3153-acid-4-
OH. Finite residues of the metabolite were detected in 28 of 52 forage
samples, and 11 of 54 stover samples from plots treated at 24.5 grams
a.i./acre. Maximum residue values in the two feed commodities were 0.03
ppm. Forage and stover samples from the two plots treated at the 5-fold
rate showed maximum residue values of 0.05 ppm. All these data support
proposed tolerances of 0.01 ppm for flufenpyr-ethyl and 0.04 ppm S-
3153-acid-4-OH in/on field corn forage and stover.
6. Secondary residues. Using proposed tolerances, or for field corn
forage and stover the sum of the tolerances for parent and metabolite,
to calculate the maximum feed exposure to fed animals, and using the
very low potential for residue transfer demonstrated in the lactating
goat and laying hen metabolism studies, detectable secondary residues
in animal tissues, milk, and eggs are not expected. Therefore,
tolerances are not proposed for these commodities.
7. Rotational crops. The results of a confined rotational crops
accumulation study with 14C-flufenpyr-ethyl indicate that no
rotational crop planting restrictions or rotational crop tolerances are
required.
B. Toxicological Profile
A full battery of toxicology testing including studies of acute,
chronic, oncogenicity, developmental, mutagenicity, and reproductive
effects is available for flufenpyr-ethyl. The acute toxicity of
flufenpyr-ethyl is low by all routes. Subchronic and chronic toxicity
studies exhibit no observable adverse effect level (NOAEL) values from
a low of 40 milligrams/kilogram/day (mg/kg/day) (male mouse 18-month
oncogenicity) to greater than 1,000 mg/kg/day. Flufenpyr-ethyl is not
oncogenic
[[Page 37817]]
or mutagenic, and it is not a reproductive or developmental toxicant
when tested in standard toxicity studies. Animal metabolism and
excretion is rapid; there appear to be no special toxicity concerns for
a unique plant metabolite; and there is no evidence for endocrine
effects. The kidney and liver appear to be the target organs of
flufenpyr-ethyl. EPA has not had the opportunity to review the toxicity
studies on flufenpyr-ethyl and has not established toxic endpoints. For
chronic oral exposure, Valent has chosen the NOAEL from the second rat
reproduction study of 100 ppm (5 mg/kg/day nominal) as the toxic
endpoint. There is no study with flufenpyr-ethyl that showed toxicity
that could be associated with a single, or acute, oral exposure.
Therefore no acute endpoint could be identified, and no acute oral risk
analyses are performed.
1. Acute toxicity. The acute toxicity of technical grade flufenpyr-
ethyl is low by all routes. Flufenpyr-ethyl produces minimal toxicity
following acute oral, dermal or inhalation exposures. The technical
material is essentially non-irritating to the eye, is not irritating to
the skin and does not cause dermal sensitization in guinea pigs.
Flufenpyr-ethyl technical will be classified as Toxicity Class IV.
2. Genotoxicity. Flufenpyr-ethyl does not present a genetic hazard.
Flufenpyr-ethyl technical was negative in the following tests for
mutagenicity: Ames assay with and without S9, in vitro mammalian cell
gene mutation assay using L5178Y/TK+/- mouse lymphoma cells,
and the in vivo mouse bone marrow micronucleus test.
3. Reproductive and developmental toxicity. Developmental toxicity
studies have been performed in rats and rabbits, and multigenerational
effects on reproduction were tested in rats.
i. Rats. In the developmental toxicity study conducted with rats,
technical flufenpyr-ethyl was administered by gavage at levels of 0,
100, 300, and 1,000 mg/kg/day during gestation days 6 through 19. There
were no adverse maternal or fetal effects observed. The NOAEL for both
maternal and developmental toxicity was found to be 1,000 mg/kg/day,
the highest dose tested.
ii. Rabbits. Flufenpyr-ethyl technical was tested in a
developmental toxicity study in rabbits at doses of 0, 100, 300 and
1,000 mg/kg/day during gestation days 6 through 28. Maternal mortality
occurred at the two highest doses tested but the deaths at 300 ppm were
not considered to be the result of systemic toxicity. In surviving
animals and their fetuses, there were no adverse effects. Based on
these results, the maternal toxicity NOAEL was 300 mg/kg/day and the
developmental toxicity NOAEL was 1,000 mg/kg/day.
A second developmental toxicity study was conducted to confirm the
maternal NOAEL at dose levels of 0, 100, 200, 300 or 1,000 mg/kg/day
during gestation. Again, maternal mortality occurred, but at all dose
levels. Detailed examination of these animals showed in the majority of
cases the cause of death to be test material aspiration into the lungs.
The cause of death for several animals at the high dose could not be
determined. Their deaths were therefore attributed to systemic
toxicity. There were no other adverse effects in the surviving dams or
fetuses. The NOAEL for this study (and overall for both rabbit
developmental toxicity studies) were found to be 300 mg/kg/day
(maternal) and 1,000 mg/kg/day (developmental).
iii. Reproduction. In the rat reproduction study, flufenpyr-ethyl
technical was administered in the diet at levels of 0, 200, 2,000, and
20,000 ppm for 2-generations. Parental toxicity was observed at all
dose levels, although the effects at the low dose were minimal.
Parental toxicity was exhibited by dose-related microscopic changes in
the kidney in high dose F0 animals, in all treated
F1 males, and in high dose F1 females. There were
also 2 high dose F1 males that died possibly as a result of
treatment. Midzonal cytoplasmic vacuolation of the hepatocytes was also
observed in the liver of all groups of treated animals in both
generations. Based on the results of this study, the NOAEL for parental
toxicity was considered to be less than 200 ppm. The NOAEL for
reproductive and neonatal toxicity was considered to be 20,000 ppm.
A second 1-generation reproduction study was performed to establish
a clear NOAEL for adult kidney lesions using the dose levels of 20, 50
and 100 ppm. The results of the study indicate that the NOAEL for
histological changes in the kidneys of F1 male rats was 100
ppm. No other treatment related findings were noted at any dose level
indicating 100 ppm as the NOAEL for treatment and reproductive effects
evaluated in the study.
A mechanistic study was also conducted to investigate the
reproducibility and reversibility of the kidney lesions observed in the
initial 2-generation reproduction study. In the first study, the
effects observed at 200 ppm in the F1 males, basophilic
tubules and interstitial inflamation, were minimal but slightly
increased in incidence and severity and a slight increase in
interstitial fibrosis of the cortex was also observed. In this
mechanistic study, using dose levels of 0 and 2,000 ppm, the NOAEL for
histological changes in the kidneys of F0 and F1
male rats and reproductive effects was 2,000 ppm. The histological
changes seen in the kidneys in the original study was not reproducible.
4. Subchronic toxicity. Subchronic oral toxicity studies conducted
with flufenpyr-ethyl in the rat, mouse and dog indicate a low level of
toxicity.
i. Rats. Pure (99.4%) flufenpyr-ethyl was tested in rats at dose
levels of 0, 600, 2,000, 6,000, and 20,000 ppm in the diet for 13
weeks. Effects observed included urinary incontinence, increased food
and water consumption, slight hematological and blood biochemistry
changes, decreased spleen weights, an increase in the incidence and
severity of basophilic tubules of the kidneys and slight to mild
diffusely distributed vacuolation in the liver. Based on these results,
the NOAEL was 2,000 ppm (134.2 mg/kg/day) for the males and 20,000 ppm
(1,509.6 mg/kg/day) for the females.
In an additional study, flufenpyr-ethyl technical was tested in
rats at dose levels of 0, 1,000, 10,000, and 20,000 ppm in the diet for
13 weeks. Effects observed included urinary incontinence, increased
food and water consumption, and mild urinalysis, hematological and
blood biochemistry changes. Thymus weights were slightly increased.
Diffusely distributed hepatic vacuolation was seen in the high dose
males. Based on these findings, the NOAEL was 10,000 ppm (595.2 mg/kg/
day) in the males and 20,000 ppm (1,377.5 mg/kg/day) in the females.
ii. Mice. In a 4-week study, CD-1 mice were fed pure flufenpyr-
ethyl at dose levels of 0, 300, 1,000, 3,000, and 7,000 ppm. Effects
were slight anemia, changes in blood biochemistry, increased liver and
thymus weights, and enlarged liver. Centrilobular hepatocellular
hypertrophy and vacuolation and increases in the severity and incidence
of hepatic focal and single cell necrosis were observed. Based on these
findings, the NOAEL was 300 ppm (44.9 mg/kg/day) for males and 1,000
(210.5 mg/kg/day) for females. In a 13-week study, flufenpyr-ethyl
technical was administered to mice at dose levels of 0, 300, 1,000,
3,000, and 7,000 ppm. Slight anemia and blood biochemistry changes were
noted. Liver weights were increased and ovary weights were decreased.
Histopathological findings included: Hepatocellular fatty vacuolation.
The NOAEL for this study in both sexes was
[[Page 37818]]
1,000 ppm (128.4 mg/kg/day for males and 155.7 mg/kg/day for females).
iii. Dogs. Flufenpyr-ethyl technical was administered for 13 weeks
via capsule to Beagle dogs at levels of 0, 100, 300 or 1,000 mg/kg/day.
The effects were very minimal. Only small nonsignificant decreases in
body weight and slightly elevated alkaline phosphatase values were
noted. In the absence of other effects, the NOAEL in both sexes was
determined to be 1,000 mg/kg/day.
iv. Dermal. A 21-day dermal toxicity study in rats with flufenpyr-
ethyl technical did not produce any signs of dermal or systemic
toxicity at 1,000 mg/kg/day, the highest dose tested.
5. Chronic toxicity. Flufenpyr-ethyl technical has been tested in
chronic studies with dogs, rats and mice.
i. Rats. In a 104-week combined chronic/oncogenicity study in rats,
flufenpyr-ethyl technical was administered at dose levels of 0, 100,
1,000, 10,000, or 20,000 ppm in the diet for 24 months. Urinary
incontinence, increased food and water consumption, changes in
urinalysis, hematological and blood biochemistry changes were observed
but the effects were not toxicologically significant. No neoplastic
lesions were observed. The NOAEL was found to be 20,000 ppm (777.5 mg/
kg/day for males and 1024 mg/kg/day for females).
ii. Mice. In a 78-week oncogenicity study with mice, flufenpyr-
ethyl technical was administered at dose levels of 0, 350, 3,500, and
7,000 ppm. Male animals exhibited slight anemia. Females had increased
liver and kidney weights (week 53 only). Slight to moderate
hepatocellular fatty vacuolation and necrosis were observed. There were
no increases in incidence of pre-neoplastic or neoplastic lesions.
Based on these results, the NOAEL was 350 ppm for both sexes (39.9 mg/
kg/day for males and 43.7 mg/kg/day for females).
iii. Dogs. In a 52-week chronic study, flufenpyr-ethyl technical
was administered by capsule to Beagle dogs at dose levels of 0, 50,
200, and 1,000 mg/kg/day. There were very few observations related to
treatment. Slightly elevated alkaline phosphatase values were again
observed, but they were not accompanied with any other findings and
were thus considered not to be an adverse effect. The NOAEL was
determined to be 1,000 mg/kg/day, the highest dose tested.
iv. Carcinogenicity. Flufenpyr-ethyl is not a carcinogen. Studies
with flufenpyr-ethyl technical have shown that repeated high dose
exposures produced minimal signs of toxicity, including slight
hematologic, liver and kidney effects, but did not produce cancer in
test animals. No oncogenic response was observed in a rat 2-year
chronic feeding/oncogenicity study or in a 78-week study on mice.
Valent anticipates that the oncogenicity classification of flufenpyr-
ethyl will be ``E'' (no evidence of carcinogenicity for humans).
6. Animal metabolism. Following oral administration of
14C-phenyl-labeled flufenpyr-ethyl to rats at 50 mg/kg, the
majority of the radiocarbon is eliminated from the body within 2 days.
Approximately half is excreted in the urine and the balance is excreted
in the feces. Tissue residues are very low 7 days after administration
(<0.09% of the administered dose). The major metabolite was identified
as [2-chloro-4-fluoro-5-(5-methyl-6-oxo-4-trfluoro-methyl-1,6-
dihydropyridazin-1-yl)phenoxy]acetic acid (S-3153-acid) which accounted
for 93.2% of the dose. Two other minor metabolites each accounted for
less than 5% of the administered radiocarbon. Flufenpyr-ethyl was
detected only in feces (0.5%). The major reaction was cleavage of the
ester linkage; minor reactions were hydroxylation of the 5-methyl of
pyridazine ring and cleavage of the ether linkage between the phenyl
group and the carboxymethyl group.
7. Metabolite toxicity. Metabolism studies of flufenpyr-ethyl in
rats, goats and hens, as well as the fish bioaccumulation study
demonstrate that the parent is very rapidly metabolized and eliminated.
Because parent and metabolites are not retained in the body, the
potential for acute toxicity from in situ formed metabolites is low.
The potential for chronic toxicity is adequately tested by chronic
exposure to the parent at the maximum tolerated dose (MTD) and
consequent chronic exposure to the internally formed metabolites. One
plant metabolite, S-3153-acid-4-OH was not detected as an animal
metabolite. This compound was tested for acute oral toxicity in rats,
and for mutagenicity Ames testing with and without mixed function
oxidation (S9 mix). The metabolite caused no mortality in rats at 5,000
mg/kg the highest dose tested, and was not mutagenic at up to 5,000
micrograms per plate.
8. Potential endocrine effects. No special studies to investigate
the potential for estrogenic or other endocrine effects of flufenpyr-
ethyl have been performed. However, as summarized above, a large and
detailed toxicology data base exists for the compound including studies
in all required categories. These studies include acute, sub-chronic,
chronic, developmental, and reproductive toxicology studies including
detailed histology and histopathology of numerous tissues, including
endocrine organs, following repeated or long-term exposures. These
studies are considered capable of revealing endocrine effects. The
results of all of these studies show no evidence of any endocrine-
mediated effects and no pathology of the endocrine organs.
Consequently, it is concluded that flufenpyr-ethyl does not possess
estrogenic or endocrine disrupting properties.
C. Aggregate Exposure
1. Dietary exposure. A full battery of toxicology testing including
studies of acute, chronic, oncogenicity, developmental, mutagenicity,
and reproductive effects is available for flufenpyr-ethyl. EPA has not
had the opportunity to review the toxicity studies on flufenpyr-ethyl
and has not established toxic endpoints of concern for use in risk
analyses. For chronic oral exposure, Valent has chosen the NOAEL from
the second rat reproduction study of 100 ppm (5 mg/kg/day nominal) as
the toxic endpoint. There is no study with flufenpyr-ethyl that showed
toxicity that could be associated with a single, or acute, oral
exposure. Therefore no acute endpoint could be identified, and no acute
oral risk analyses are performed. The chronic RfD using the standard
100-fold uncertainty factor is 0.05 mg/kg/day, and because there is no
evidence of enhances susceptibility of infants and children, the FQPA
extra 10-fold uncertainty factor is removed. Thus, the Population
Adjusted Dose for chronic oral exposure (cPAD) used in these risk
assessments is 0.05 mg/kg/day.
i. Food--a. Acute dietary exposure. There is no acute oral toxic
endpoint identified, and so no acute exposure and risk analysis was
performed.
b. Chronic dietary exposures to flufenpyr-ethyl residues were
calculated for the U.S. population and 25 population subgroups. This
Tier I analysis includes residue contribution from the field corn,
soybean and sugarcane uses and assumes tolerance-level residues and
100% of the crops treated. The results from several representative
subgroups are listed below. For all population subgroups, chronic
dietary exposure was below 0.2% of the cPAD. Generally, the Agency has
no cause for concern if total chronic exposure to residues contributed
by published and proposed tolerances is less than 100% of the cPAD.
[[Page 37819]]
Tier I--Calculated Chronic Dietary Exposures to the Total U.S.
Population and Selected Sub-Populations to Flufenpyr-Ethyl Residues in
Food (cPAD = 0.05 mg/kg/day)
------------------------------------------------------------------------
Exposure (mg/kg/
Population Subgroup day) Percent of cPAD
------------------------------------------------------------------------
Total U.S. population 0.000025 0.05
-------------------------------------------------------
Males (13 - 19 years) 0.000032 0.06
-------------------------------------------------------
Females (13 + (nursing)) 0.000019 0.04
-------------------------------------------------------
Females (13 + (pregnant/not 0.000021 0.04
nursing))
-------------------------------------------------------
Children (7 - 12 years) 0.000043 0.09
-------------------------------------------------------
Children (1 - 6 years) 0.000056 0.11
-------------------------------------------------------
All infants (< 1 year) 0.000067 0.13
-------------------------------------------------------
Non-nursing infants 0.000082 0.16
-------------------------------------------------------
Nursing infants 0.000017 0.03
------------------------------------------------------------------------
ii. Drinking water. Since flufenpyr-ethyl is applied outdoors to
growing agricultural crops and can be applied by aircraft, the
potential exists for the parent or its metabolites to reach ground
water or surface water that may be used for drinking water. Because of
the physical and environmental fate properties of flufenpyr-ethyl, it
is unlikely that flufenpyr-ethyl or its metabolites can leach to
potable ground water. To quantify potential exposure from drinking
water, surface water concentrations for flufenpyr-ethyl were estimated
using Generic Expected Enviornmental Concentration (GENEEC 1.2.). The
56-day average GENEEC concentration was 0.027 ppb. Using standard
assumptions about body weight and water consumption, the maximum
chronic exposure from this drinking water would be 0.000000763 and
0.00000267 mg/kg/day for adults and children, respectively; 0.0053
percent of the cPAD of 0.05 mg/kg/day for children. The contribution of
drinking water to chronic dietary exposures is much smaller than that
from food, and adds negligible risk.
2. Non-dietary exposure. Flufenpyr-ethyl is proposed only for
agricultural uses and no homeowner, turf, or industrial 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 flufenpyr-ethyl and may have similar effects on animals. In
consideration of potential cumulative effects of flufenpyr-ethyl 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 flufenpyr-ethyl would be
cumulative with those of other chemical compounds. Thus, only the
potential risks of flufenpyr-ethyl have been considered in this
assessment of aggregate exposure and effects.
Valent will submit information for EPA to consider concerning
potential cumulative effects of flufenpyr-ethyl 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 the Food Quality Protection Act of 1996 (FQPA).
E. Safety Determination
The FQPA introduced a new standard of safety, a reasonable
certainty of no harm. To make this determination, at this time the
Agency should consider only the incremental risk of flufenpyr-ethyl in
its exposure assessment. Since the potential chronic and acute
exposures to flufenpyr-ethyl are small (<100% of cPAD and aPAD) the
provisions of the FQPA will not be violated.
1. U.S. population--i. Acute risk. There is no acute oral toxic
endpoint available, so no risk analysis was performed.
ii. Chronic risk. Using the dietary exposure assessment procedures
described above for flufenpyr-ethyl, calculated chronic dietary
exposure resulting from residue exposure from proposed uses of
flufenpyr-ethyl is minimal. The estimated chronic dietary exposure from
food for the overall U.S. population and many non-child/infant
subgroups is 0.064 to 0.042% of the cPAD. Addition of the small but
worse case potential exposure from drinking water (calculated above)
increases exposure by only 0.000000763 mg/kg/day (0.0053% of cPAD) and
the maximum occupancy of the cPAD from 0.064% to 0.066%. Generally, the
Agency has no cause for concern if total residue contribution is less
than 100% of the cPAD. It can be concluded that there is a reasonable
certainty that no harm will result to the overall U.S. population and
many non-child/infant subgroups from aggregate, chronic exposure to
flufenpyr-ethyl residues.
2. Safety factor for infants and children. In assessing the
potential for additional sensitivity of infants and children to
residues of flufenpyr-ethyl, FFDCA section 408 provides that EPA shall
apply an additional margin of safety, up to 10-fold, for added
protection for infants and children in the case of threshold effects
unless EPA determines that a different margin of safety will be safe
for infants and children.
[[Page 37820]]
In assessing the potential for additional sensitivity of infants
and children to residues of flufenpyr-ethyl, EPA considers the
completeness of the human health effects data, particularly those
studies that evaluate toxicity to reproduction and to fetal and
developing young experimental animals. These studies include
developmental toxicity studies in the rat and rabbit and a 2-generation
reproduction study in the rat. The developmental toxicity studies are
designed to evaluate adverse effects on the developing organism
resulting from maternal pesticide exposure during gestation.
Reproduction studies provide information relating to prenatal and
postnatal effects from exposure to the pesticide, information on the
reproductive capability of both male and female mating animals and data
on systemic toxicity.
3. Developmental toxicity. Flufenpyr-ethyl is not a developmental
toxicant in either rats or rabbits. In the developmental toxicity study
conducted with rats, the NOAEL for both maternal and developmental
toxicity was found to be 1,000 mg/kg/day, the highest dose tested.
Flufenpyr technical was tested in two developmental toxicity
studies in rabbits because of unexpected maternal mortality. In the
first study maternal mortality occurred at the two highest doses
tested. In surviving animals and their fetuses, there were no adverse
effects. Based on these results, the maternal toxicity NOAEL was 100
mg/kg/day and the developmental toxicity NOAEL was 1,000 mg/kg/day. In
the second study maternal mortality again occurred, but at all dose
levels. Detailed examination of most these animals showed the cause of
death to be test material aspiration into the lungs. There were no
other adverse effects in the surviving dams or fetuses. The NOAEL for
this study and the overall NOAEL for rabbits was found to be 300 mg/kg/
day (maternal) and 1,000 mg/kg/day (developmental).
4. Reproduction. In the rat reproduction study, flufenpyr-ethyl
technical was administered for 2-generations. Parental toxicity (kidney
and liver effects) was observed at all dose levels, although the
effects at the low dose were minimal. There were no effects at any dose
on any reproductive parameter. Based on the results of this study, the
NOAEL for parental toxicity was considered to be less than 200 ppm. The
NOAEL for reproductive and neonatal toxicity was considered to be
20,000 ppm.
A second 1-generation reproduction study was performed to establish
a clear NOAEL for adult kidney lesions using the dose levels of 20, 50
and 100 ppm. The results of the study indicate that the NOAEL for
histological changes in the kidneys for F1 male rats was 100
ppm. No other treatment-related findings were noted at any dose level
indicating 100 ppm as the NOAEL for treatment and reproductive effects
evaluated in the study.
A mechanistic study was also conducted to investigate the
reproducibility and reversibility of the kidney lesions observed in the
initial 2-generation reproduction study. In the first study, the
effects observed at 200 ppm in the F1 males, basophilic
tubules and interstitial inflamation, were minimal but slightly
increased in incidence and severity and a slight increase in
interstitial fibrosis of the cortex was also observed. In this
mechanistic study, using dose levels of 0 and 2,000 ppm, the NOAEL for
histological changes in the kidneys of F0 and F1
male rats and reproductive effects was 2,000 ppm. The histological
changes seen in the kidneys in the original study was not reproducible.
The toxicological data base for evaluating prenatal and postnatal
toxicity for flufenpyr-ethyl is complete with respect to current data
requirements. Valent concludes that there is no evidence that fetal, or
developing young experimental animals are any more susceptible to the
effects of flufenpyr-ethyl than adult animals. Therefore there is no
need for an extra FQPA uncertainly factor to be further protective of
infants and children.
5. Acute exposure and risk. There is no acute oral toxic endpoint
available, so no risk analysis was performed.
6. Chronic exposure and risk. Using the conservative exposure
assumptions described above, the percentage of the cPAD that will be
utilized by dietary (food only) exposure to residues of flufenpyr-ethyl
ranges from 0.16% for non-nursing infants, to 0.03% for nursing
infants. Adding the worse case potential incremental exposure to
infants and children from flufenpyr-ethyl in drinking water (0.00000267
mg/kg/day) increases the aggregate, chronic dietary exposure by 0.0053%
The addition of the exposure attributable to drinking water increases
the occupancy of the cPAD for Non-Nursing Infants from 0.164 to 0.169
percent. EPA generally has no concern for exposures below 100% of the
cPAD because the cPAD represents the level at or below which daily
aggregate dietary exposure over a lifetime will not pose appreciable
risks to human health. It can be concluded that there is a reasonable
certainty that no harm will result to infants and children from
aggregate, chronic exposure to flufenpyr-ethyl residues.
7. Safety determination summary. Aggregate chronic dietary exposure
to various sub-populations of children and adults demonstrate
acceptable risk. Chronic dietary exposures to flufenpyr-ethyl occupy
considerably less than 100% of the cPAD. Acute dietary risk to children
from flufenpyr-ethyl should not be of concern. Further, flufenpyr-ethyl
has only agricultural uses and no other uses, such as indoor pest
control, homeowner or turf, that could lead to unique, enhanced
exposures to vulnerable sub-groups of the population. It can be
concluded that there is a reasonable certainty that no harm will result
to the U.S. population or to any sub-group of the U.S. population,
including infants and children, from aggregate chronic exposures to
flufenpyr-ethyl residues resulting from proposed uses. There is no
evidence that acute oral exposures to flufenpyr ethyl causes
appreciable toxicity, and no exposure and risk analyses are
appropriate.
F. International Tolerances
There are no existing U.S. tolerances or Codex Maximum Residue
Limits for flufenpyr-ethyl.
[FR Doc. 03-16033 Filed 6-24-03; 8:45 am]
BILLING CODE 6560-50-S