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http://www.epa.gov/fedrgstr/EPA-PEST/2002/November/Day-20/p29330.htm
[Federal Register: November 20, 2002 (Volume 67, Number 224)]
[Notices]
[Page 70073-70079]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr20no02-67]
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ENVIRONMENTAL PROTECTION AGENCY
[OPP-2002-0126; FRL-7184-7]
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-2002-0126, must be
received on or before December 20, 2002.
ADDRESSESS: 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. To ensure proper
receipt by EPA, it is imperative that you identify docket ID number
OPP-2002-0126 in the subject line on the first page of your response.
FOR FURTHER INFORMATION CONTACT: By mail: Joanne I. Miller,
Registration Division, Office of Pesticide Programs, (7505C)
Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,
Washington, DC 20460; 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 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:
------------------------------------------------------------------------
Examples of
Categories NAICS codes potentially
affected entities
------------------------------------------------------------------------
Industry 111 Crop
productionmption
112 Animal production
311 Food manufacturing
32532 Pesticide
manufacturing
------------------------------------------------------------------------
[[Page 70074]]
This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in this unit could also be
affected. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether this action might apply to certain entities. To determine
whether you or your business may be affected by this action, you should
examine the applicability provisions in OPP-2002-0126. 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-2002-0126. 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. 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
feasable, 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.1. 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 indentifying 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-2002-0126. 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-2002-0126. In contrast to EPA's
electronic public docket, EPA's email 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
[[Page 70075]]
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-2002-0126.
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-2002-0126. 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 ckearly 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. Offer alternative ways to improve the notice or collection
activity.
7. Make sure to submit your comments by the deadline in this
document.
8. 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 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, Pesticides and pests.
Dated: October 27, 2002.
Debra Edwards,
Acting Director, Registration Division, Office of Pesticide Programs.
Summary of Petition
The petitioner summary of the pesticide petition is printed below
as required by section 408(d)(3) of the FFDCA. The summary of the
petition was prepared by Nichino America Incorporated, and represents
the view of Nichino America Incorporated. 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.
Nichino America Incorporated
PP 1F6428
EPA has received a pesticide petition (1F6428) from Nichino America
Incorporated, 4550 New Linden Hill Road, Suite 501, Wilmington, DE
19808 proposing, pursuant to section 408(d) of the FFDCA, 21 U.S.C.
346a(d), to amend 40 CFR part 180, by establishing a tolerances for
combined residues of pyraflufen-ethyl (ethyl 2-chloro-5-(4-chloro-5-
difluoromethoxy-1-methylpyrazol-3-yl)-4-fluorophenoxyacetate) and its
acid metabolite, E-1, (2-chloro-5-(4-chloro-5-difluoromethoxy-1-
methylpyrazol-3-yl)-4-fluorophenoxyacetic acid) expressed as the ester
equivalent in or on the raw agricultural commodities (RACs) derived
from cotton; undelinted seed at 0.05 parts per million (ppm); and gin
byproducts at 1.5 ppm; in or on the RAC potato at 0.02 ppm; in or on
the RACs corn grain, corn stover, corn forage, soybean seed, soybean
forage, and soybean hay at 0.01 ppm; wheat forage, wheat hay, wheat
straw, and wheat grain at 0.01 ppm. EPA has determined that the
petition contains data or information regarding the elements set forth
in section 408(d)(2) of the FFDCA; however, EPA has not fully evaluated
the sufficiency of the submitted data at this time or whether the data
support granting of the petition. Additional data may be needed before
EPA rules on the petition.
A. Residue Chemistry
1. Plant metabolism. The qualitative nature of the residues of
pyraflufen-ethyl (ET-751) in cotton, potatoes, corn, soybeans, and
wheat is adequately understood. The metabolism of pyraflufen-ethyl has
been studied in cotton, wheat, and potato. Metabolism in the plant
involves ester hydrolysis, de-methylation on the pyrazole ring and
further degradation of the phenoyxyacetate moiety to bound polar
metabolites. The nature of the residue is adequately understood and the
residues of concern are the parent, pyraflufen-ethyl, and the acid
metabolite, E-1, only.
2. Analytical method. The enforcement analytical method utilizes
gas chromatography/mass spectrophotometry with selected ion monitoring
for detecting and measuring levels of pyraflufen-ethyl and the acid
metabolite with a general limit of quantification (LOQ) of 0.02 ppm
(combined E-1 and parent). This method allows detection of residues at
or above the proposed tolerances. The method has undergone independent
laboratory validation as required by PR Notices 88-5 and 96-1.
3. Magnitude of residues in crops--i. Potato. No apparent residues
of pyraflufen-ethyl were observed in potato at or above 0.02 ppm (the
LOQ
[[Page 70076]]
for the analytical method). The field studies, conducted at 3x the
highest intended label use rate, in 16 trials in 11 states, clearly
support the proposed tolerances of 0.02 ppm (combined E-1 and parent).
No detectable residues of parent or the acid metabolite were observed
in any processed potato fraction at 5x the maximum proposed application
rate and proposed pre-harvest interval (PHI) in a field study, with the
LOQ of 0.02 ppm (combined E-1 and parent). The tolerance that is being
proposed for the use of pyraflufen-ethyl plus the acid metabolite on
potato is 0.02 ppm.
ii. Cotton. Twelve field residue trials were conducted in seven
different states. Applications in the trials were 3x the proposed label
directions for use and at the proposed PHI of 7 days. Analysis of the
treated samples showed that the residues of pyraflufen-ethyl (ethyl 2-
chloro-5-(4-chloro-5-difluoromethoxy-1-methylpyrazol-3-yl)-4-
fluorophenoxyacetate) plus its acid metabolite, E-1, (2-chloro-5-(4-
chloro-5-difluoromethoxy-1-methylpyrazol-3-yl)-4-fluorophenoxyacetic
acid) expressed as the ester equivalent at the exaggerated rate, were
below the proposed tolerance of 0.05 ppm in cotton seed at the proposed
labeled PHI in all samples. No residues were seen in the processed
fractions of meal, hull, and oil, when one trial was run in a typical
cotton growing area. The application rate for this processing study was
15x the maximum proposed application rate and at the proposed PHI. This
indicates that there is no concentration of pyraflufen-ethyl (ethyl 2-
chloro-5-(4-chloro-5-difluoromethoxy-1-methylpyrazol-3-yl)-4-
fluorophenoxyacetate) plus its acid metabolite, E-1, (2-chloro-5-(4-
chloro-5-difluoromethoxy-1-methylpyrazol-3-yl)-4-fluorophenoxyacetic
acid), expressed as the ester equivalent in any of the processed
fractions. Low residues seen in the undelinted cottonseed were
consistent with the magnitude of residue trials. Combined residues of
pyraflufen-ethyl (ethyl 2-chloro-5-(4-chloro-5-difluoromethoxy-1-
methylpyrazol-3-yl)-4-fluorophenoxyacetate) plus its acid metabolite,
E-1 (2-chloro-5-(4-chloro-5-difluoromethoxy-1-methylpyrazol-3-yl)-4-
fluorophenoxyacetic acid) in cotton gin byproducts from applications at
3x the proposed application rate ranged from 0.125 ppm to 1.314 ppm,
and averaged 0.035 ppm from applications made at 1x the proposed
application rate. The proposed tolerance of 0.05 ppm for pyraflufen-
ethyl (ethyl 2-chloro-5-(4-chloro-5-difluoromethoxy-1-methylpyrazol-3-
yl)-fluorophenoxyacetate) plus its acid metabolite, E-1, (2-chloro-5-
(4-chloro-5-difluoromethoxy-1-methylpyrazol-3-yl)-4-fluorophenoxyacetic
acid) in cotton seed and 1.5 ppm in cotton gin byproducts are supported
by the field residue data.
iii. Corn. Three exaggerated rate residue trials were conducted in
three different states on different soil types. Applications in the
trials were 5x to 10x the proposed label directions for use as a pre-
plant burndown herbicide. Analysis of the treated samples showed zero
residues of pyraflufen-ethyl (ethyl 2-chloro-5-(4-chloro-5-
difluoromethoxy-1-methylpyrazol-3-yl)-4-fluorophenoxyacetate) plus its
acid metabolite, E-1, (2-chloro-5-(4-chloro-5-difluoromethoxy-1-
methylpyrazol-3-yl)-4-fluorophenoxyacetic acid) expressed as the ester
equivalent at the exaggerated rate. The LOQ for the parent and the
metabolite was 0.005 ppm in each case. Since no residues were observed
at exaggerated rates in RACs, no processing studies were conducted.
iv. Soybean. Three exaggerated rate residue trials were conducted
in three different states on different soil types. Applications in the
trials were 5x to 10x the proposed label directions for use as a pre-
plant burndown herbicide. Analysis of the treated samples showed zero
residues of pyraflufen-ethyl (ethyl 2-chloro-5-(4-chloro-5-
difluoromethoxy-1-methylpyrazol-3-yl)-4-fluorophenoxyacetate) plus its
acid metabolite, E-1, (2-chloro-5-(4-chloro-5-difluoromethoxy-1-
methylpyrazol-3-yl)-4-fluorophenoxyacetic acid) expressed as the ester
equivalent at the exaggerated rate. The LOQ for the parent and the
metabolite was 0.005 ppm in each case. Since no residues were observed
at exaggerated rates in RACs, no processing studies were conducted.
v. Wheat. Three exaggerated rate residue trials were conducted in
three different states on different soil types. Applications in the
trials were 5x to 10x the proposed label directions for use as a pre-
plant burndown herbicide. Analysis of the treated samples showed zero
residues of pyraflufen-ethyl (ethyl 2-chloro-5-(4-chloro-5-
difluoromethoxy-1-methylpyrazol-3-yl)-4-fluorophenoxyacetate) plus its
acid metabolite, E-1, (2-chloro-5-(4-chloro-5-difluoromethoxy-1-
methylpyrazol-3-yl)-4-fluorophenoxyacetic acid) expressed as the ester
equivalent at the exaggerated rate. The LOQ for the parent and the
metabolite was 0.005 ppm in each case. Since no residues were observed
at exaggerated rates in RACs, no processing studies were conducted.
4. Magnitude of the residue in animals.--i. Ruminants. The maximum
dietary burden in beef and dairy cows results from a diet comprised of
undelinted cottonseed, cotton meal, cotton hulls, cotton gin
byproducts, potato culls, potato waste, and from grain (seed), forage,
hay, stover (fodder), silage, meal, hulls, straw, aspirated grain
fractions, and milled byproducts of corn, soybeans, and wheat for a
total dietary burden that is significantly lower than levels that would
require the proposal of tolerances in ruminants. This conclusion is
based on exaggerated rate animal metabolism studies carried out on
pyraflufen-ethyl and its significant metabolites. Therefore, an
exemption from tolerances in milk, meat, and meat by-products under 40
CFR 180.6(a)(3) and (b) is proposed as it is not possible to establish
with certainty whether finite residues will be incurred, but there is
no reasonable expectation of finite residues.
ii. Poultry. The maximum poultry dietary burden results from a diet
comprised of cotton meal, corn grain, corn milled byproducts, soybean
seed, soybean meal, soybean hulls, wheat grain, and wheat milled
byproducts for a total dietary burden that is significantly lower than
the levels that would require the proposal of tolerances in poultry.
This conclusion is based on the exaggerated rate metabolism studies
carried out on pyraflufen-ethyl and its acid metabolite. Therefore, an
exemption from tolerances in poultry meat, meat byproducts, fat, and
eggs under 40 CFR 180.6(a)(3) and (b) is proposed as it is not possible
to establish with certainty whether finite residues will be incurred,
but there is no reasonable expectation of finite residues.
B. Toxicological Profile
1. Acute toxicity. Pyraflufen-ethyl technical is considered to be
nontoxic (toxicity category IV) to the rat by the oral route of
exposure. In an acute oral toxicity study conducted in rats, the oral
LD50 value for technical pyraflufen-ethyl was determined to
be >5,000 milligrams/kilograms body weight (mg/kg bwt). The results
from the acute dermal toxicity study in rabbits indicate that
pyraflufen-ethyl is slightly toxic (toxicity category III) to rabbits
by the dermal route of exposure. The dermal LD50 value of
technical pyraflufen-ethyl was determined to be >2,000 mg/kg for both
male and female rabbits. Pyraflufen-ethyl technical is considered to be
nontoxic (toxicity category IV) to the rat by the respiratory route of
exposure. Inhalation exposure of rats to pyraflufen-ethyl technical
resulted in an
[[Page 70077]]
LC50 >5.53 milligrams/Liter (mg/L) (analytical) for both
males and females. Pyraflufen-ethyl technical was shown to be non-
irritating to rabbit skin (toxicity category IV). Pyraflufen-ethyl
technical was shown to be slightly irritating to rabbit eyes (toxicity
category III). Application of technical material to the rabbit eye
resulted in iris and conjunctival irritation from 1 to 24 hours, which
was clear by 72 hours. Based on the results of a dermal sensitization
study, pyraflufen-ethyl technical is not considered a sensitizer in
guinea pigs.
2. Genotoxicity. Pyraflufen-ethyl technical was not mutagenic in
any of the following genotoxicity studies. Point mutations in bacteria
in an Ames study with Salmonella typhimurium, and Escherichia coli;
negative in chromosome aberrations in vitro human lymphocytes, and in
the mouse micronucleus; negative for DNA repair in in vitro and in vivo
rat liver hepatocyte assays and Bacillus subtillis. For mammalian gene
mutation, in one in vitro mouse lymphoma mutation assay, no evidence of
mutagenicity was seen in the absence of metabolic activation. With S9
activation at levels up to 200 [igrave]g/Liter, equivocal results were
seen. The study report provided no criteria for positive or negative
responses. When this in vitro study was repeated, no positive or
equivocal results in the presence of activation with S9 at levels of S9
up to 350 [igrave]g/Liter were seen. These levels of activation were
greater than those tested in the earlier study and both small and large
colonies were counted. The overall weight of evidence indicates that
pyraflufen-ethyl is not genotoxic.
3. Reproductive and developmental toxicity. The developmental
toxicity study in rats conducted with pyraflufen-ethyl technical showed
no evidence of teratogenic effects in fetuses and no evidence of
developmental toxicity. Thus, pyraflufen-ethyl is neither a
developmental toxicant nor a teratogen in the rat. Pyraflufen-ethyl was
administered by gavage during gestation and showed no adverse effects
on dams or fetuses at dose levels of 0, 100, 300, up to and including a
limit dose of 1,000 mg/kg/day. The maternal and developmental toxicity
no observe adverse effects (NOAELs) were both >1,000 mg/kg/day. Results
from a developmental toxicity study in rabbits conducted with
pyrafluflen-ethyl technical also indicated no evidence of
teratogenicity or developmental toxicity. Thus, pyraflufen-ethyl
technical is neither a developmental toxicant nor a teratogen in the
rabbit. Rabbits fed pyraflufen-ethyl at 0, 20, 60, or 150 mg/kg/day,
resulted in severe maternal toxicity, including lethality, from
gastrointestinal irritation at doses of 60 and 150 mg/kg/day. The
maternal NOAEL was 20 mg/kg/day. The NOAEL for the offspring was 60 mg/
kg/day, based on increased post-implantation loss observed at 150 mg/
kg/day. Neither the rat nor the rabbit developmental study showed
evidence of unique fetal susceptibility to pyraflufen-ethyl.
In a multigeneration rat reproduction study conducted at dietary
concentrations of 0, 100, 1,000 and 10,000 ppm, pyraflufen-ethyl had no
effect on reproductive parameters, including mating indices, fertility
index, gestation index, duration of gestation, numbers of implantation
sites, numbers and morphology of epididymal sperm, and estrous cycle at
any dose level. Reproductive performance was not affected by
pyraflufen-ethyl at the highest dose level of 10,000 ppm (male 721 to
844 mg/kg/day and female 813 to 901 mg/kg/day). The pup NOAEL was 1,000
ppm, based on decreased body weight in the F1 and F2 male and female
pups on day 17 at the 10,000 ppm dose level. Results from the
reproduction study and the developmental toxicity studies conducted
with pyraflufen-ethyl technical show no increased sensitivity to
developing offspring as compared to parental animals, because the
NOAELs for growth and development of offspring were equal to or greater
than the NOAELs for parental or maternal toxicity.
4. Subchronic toxicity. A short-term (28-day) dermal study in
rabbits was conducted with pyraflufen-ethyl technical. Pyraflufen-ethyl
was administered dermally to rats for 28 days at dose levels of 0, 300,
and 1000 mg/kg day. Slight, transient erythema was observed during week
3 in 3 treated males. This finding was not dose-related, was not
considered to be adverse, and the relationship to the test material
administration was unclear. The NOAEL was considered to be 1,000 mg/kg/
day. A 90-day rat feeding study was conducted at dose levels of 0, 200,
1,000, 5,000, or 15,000 ppm pyraflufen-ethyl. The NOAEL in this study
was considered to be 1,000 ppm (85.6 mg/kg/day for males and 95.4 mg/
kg/day for females), based on slightly increased phosphorous
concentrations in females and hepatocytic hypertrophy in males at 5,000
ppm. In addition, the highest dose of 15,000 ppm resulted in erythocyte
toxicity, mitochondrial changes in the hepatocytes and the presence of
Kupffer cells. Also, at the high dose level increased kidney weights in
males and increased absolute and relative spleen weights in both sexes
were observed.
In a 90-day oral toxicity study in dogs, pyraflufen-ethyl was
administered via capsule at dose levels of 0, 40, 200, and 1,000 mg/kg/
day. No treatment-related findings were observed and the NOAEL was
determined to be >1,000 mg/kg/day. At the limit dose, no effects in
body weight or organ weights, clinical chemistry, hematology,
histopathology, and gross pathology were observed. To determine whether
the test material was absorbed or not, plasma was collected 1-hour
after administration of pyraflufen-ethyl during week 13. The detection
of 2 major degradation products, E-1 and E-9, confirmed the adsorption
and gastrointestinal and systemic exposure to pyraflufen-ethyl.
5. Chronic toxicity. A 1-year chronic dog study was conducted in
Beagle dogs, with pyraflufen-ethyl administered orally by gelatin
capsule at doses of 0, 40, 200, and 1,000 mg/kg/day. There were no
mortalities and no clinical signs of toxicity. No treatment-related
effects were noted on body weights, food consumption, hematology and
clinical chemistry parameters, urinalysis, ophthmoscopy, and organ
weights. No macrosopic or microscopic lesions were noted. The NOAEL was
>1,000 mg/kg/day.
In a 2-year chronic toxicity/oncogenicity study, pyraflufen-ethyl
was administered to CD rats at dietary levels of 0, 80, 400, 2,000, or
10,000 ppm (equivalent to 0, 3.4, 17.2, 86.7, and 468.1 mg/kg/day for
males and 0, 4.4, 21.8, 111.5, and 578.5 mg/kg/day for females).
Mortality was unaffected by treatment. Body weight gain was
statistically significantly depressed for those rats fed 10,000 ppm at
1-year compared to the control. Treatment-related histopathology was
seen in the kidney, liver, and bile duct at 10, 000 ppm. At 2,000 and
10,000 ppm, vacuoles within the mitochondria of centriacinar and
periacinar hepatocytes were seen. Effects on urine volume, urine
specific gravity, and kidney weights were seen at 2,000 ppm in males.
The NOAEL was 17.2 mg/kg/day for males and 21.8 mg/kg/day for females.
No evidence of carcinogenicity was observed.
In a 78-week carcinogenicity study, mice were fed pyraflufen-ethyl
in the diet at levels of 0, 200, 1,000, or 5,000 ppm (equivalent to 0,
21, 110, 547 mg/kg/day for males and 0. 20, 98, 524 mg/kg/day for
females). An maximum tolerance dose (MTD) was reached at 1,000 ppm,
based on increased liver weight and liver histopathological changes
(including necrosis) seen at this
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feeding level. In the highest dose group, effects of pyraflufen-ethyl
on hematological parameters were observed. The incidence of
hepatocellular adenoma was increased in animals receiving 5,000 ppm,
compared to controls. This benign tumor was likely induced by the
adaptive response to the hepatocellular degeneration and not as a
result of any genotoxic potential of pyraflufen-ethyl. In addition the
response was observed only at a dose level that was in excess of an
MTD.
6. Animal metabolism. The qualitative nature of the residues of
pyraflufen-ethyl and its acid metabolite, E-1, in animals is adequately
understood. Pyraflufen-ethyl is rapidly absorbed, metabolized, and
excreted to feces and urine, with greater than 90% of the administered
dose excreted within 24 hours in rats. Based on metabolism studies with
goats, hens, and rats, there is no reasonable expectation that
measurable pyraflufen-ethyl-related residues will occur in meat, milk,
poultry, or eggs from the proposed use.
7. Metabolite toxicology. No toxicologically significant
metabolites were detected in plant or animal metabolism studies for
cotton or potatoes.
8. Endocrine disruption. Chronic, lifespan, and multigenerational
bioassays in mammals and acute and subchronic studies on aquatic
organisms and wildlife did not reveal any endocrine effects for
pyraflufen-ethyl. Any endocrine related effects would have been
detected in this comprehensive series of required tests. The
probability of any such effect due to agricultural uses of pyraflufen-
ethyl is negligible.
C. Aggregate Exposure
1. Dietary exposure. The potential dietary exposure to pyraflufen-
ethyl has been calculated from the proposed tolerances for use on
cotton, and potato. While tolerances at the LOQ are proposed for corn,
soybean, and wheat, it is concluded that there is no potential for
residues in these crops and thus no dietary exposure. These very
conservative chronic dietary exposure estimates used the tolerance
value for all the raw agricultural commodities. In addition these
estimates assume that 100% of the cotton and potato crops contain
pyraflufen-ethyl residues.
i. Food. The chronic population adjusted dose (cPAD) for the
general population, based on residues at the tolerance levels and 100%
of potato and cotton crops treated is expected to be approximately
0.000020 mg/kg bwt/day or <0.1% of the reference dose (RFD) ( 0.172 mg/
kg/day). Of the standard subgroups analyzed by the dietary exposure
evaluation model (DEEM), the subgroup with the highest exposures are
children ages 1 to 6 years, with a cPAD of 0.000041 mg/kg/day or less
than 0.1% of the RfD mg/kg/day. With children ages 7 to 12 with
exposures of 0.000027 mg/kg/day, the exposure is less than 0.1% of the
RfD.
ii. Drinking water. As a screening level assessment for aggregate
exposure, EPA evaluates drinking water level of comparison (DWLOC),
which is the maximum concentration of a chemical in drinking water that
would be acceptable in terms of total aggregate exposure to that
chemical. Based on the chronic RFD of 0.172 mg/kg/day, based on the
NOAEL of 17.2 mg/kg/day observed in the chronic rat feeding study and
an uncertainty factor (UF) of 100, and EPA's default factors for body
weight and drinking water consumption, the DWLOCs have been calculated
to assess the potential dietary exposure from residues of pyraflufen-
ethyl and the acid metabolite, E-1, in water. For the adult population,
the chronic DWLOC was 35,086 parts per billion (ppb) for the U.S.
population, and for children 10,172 ppb.
Chronic drinking water exposure analyses were calculated using EPA
screening models, screening concentration in ground water (SCI-GROW)
for ground water and generic expected environmental concentration
(GENEEC) for surface water). The calculated peak GENEEC value for the
acid metabolite, E-1, the major degradation of pyraflufen-ethyl which
is formed within an hour of addition to a water solution or to soil, is
0.3321 ppb and the SCI-GROW value is 0.00024 ppb. These values are very
conservative estimates compared to the values derived from the parent.
Nonetheless, for the U.S. adult population, the estimated exposures of
the E-1 acid metabolite in surface water and ground water are
approximately 0.00094% and 0.0000007%, respectively, of the DWLOC. For
children, the estimated exposures of the acid metabolite in surface
water and ground water are approximately 0.0033% and 0.000002%,
respectively of the DWLOC. Therefore, the exposures to drinking water
from the acid metabolite are negligible. Based on the dietary and
drinking water assessments, aggregate exposure to residues of
pyraflufen-ethyl and the acid metabolite in food and water can be
considered to be negligible.
2. Non-dietary exposure. It is being proposed that pyraflufen-ethyl
be registered in the following non-food sites: airports, commercial
plants, fence lines, farmyards, and farm buildings; storage and lumber
yards; barrier strips and firebreaks; equipment areas, nurseries and
ornamental plantings; established ornamental turf; railroad, roadside,
and utility rights-of-ways; dry ditches and ditch banks; fuel tank
farms and pumping stations; other similar non-crop areas. Exposure to
pyraflufen-ethyl for the mixer/loader/groundboom/ aerial applicator was
calculated using the Pesticides Handlers Exposure Database (PHED).
These PHED assessments were based on a 70 kg operator treating 80 acres
per day using ground boom equipment on both cotton and potato fields;
an operator treating 1,200 acres per day using aerial equipment on
cotton fields; and an operator treating 350 acres per day using aerial
equipment on potato fields (EPA, 1999) at a maximum use rate of 0.009
pounds active ingredient per acre for potato and 0.0045 pounds active
ingredient per acre for cotton. All workers were assumed to be wearing
long pants and long-sleeved shirts. Mixer-loaders were assumed to be
wearing gloves, while aerial and ground applicators and flaggers were
not assumed to be wearing gloves. Margins of exposure (MOE) for acute
and short-term exposure were calculated utilizing a dermal and
inhalation NOAEL of 20 mg/kg/day, based on maternal toxicity seen in
the rabbit teratology study at 60 mg/kg/day, and assuming 100% dermal
absorption. MOEs for intermediate-term exposure were calculated
utilizing a dermal endpoint of 250 mg/kg/day, the systemic NOAEL from
the 28-day dermal toxicity study in the rat with the 2.5% EC
formulation. This was the highest dose level in the study and no
systemic effects were seen at this dose level. For the acute inhalation
endpoint we used 86 mg/kg/day, based on a NOAEL of 1,000 ppm or 85.6
mg/kg/day in males in the 90-day oral feeding study in the rat. The
combined MOE (inhalation plus dermal) for pyraflufen-ethyl was greater
than 4,900 for acute and short-term exposure, while the intermediate-
term total MOEs were all greater than 56,000. The results indicate that
large margins of safety exist for the proposed uses of pyraflufen-
ethyl.
D. Cumulative Effects
Pyraflufen-ethyl belongs to the protox inhibitor class of
compounds, and chemically is a 3-phenylpyrazole. The herbicidal
activity of protox inhibitors is due to the inhibition of
protoporphyrinogen IX oxidase. All relevant toxicological data has been
provided to EPA. Chemicals with a similar mode of action, i.e., the
protox inhibitors, have different chemical
[[Page 70079]]
structures compared to pyraflufen-ethyl. Although other protox
inhibitors have a similar herbicidal mode of action, there is no
information available to suggest that these compounds exhibit a similar
toxicity profile in the mammalian system. We are aware of no
information to indicate or suggest that pyraflufen-ethyl has any toxic
effects on mammals that would be cumulative with those of any other
chemical. Since pyraflufen-ethyl is relatively non-toxic, cumulative
effects of residues and other compounds are not anticipated. Therefore,
for the purposes of this Food Quality Protection Act (FQPA) document,
there should be no consideration of cumulative risk that would require
assessment.
E. Safety Determination
1. U.S. population. Based on the chronic toxicity data, the RfD for
pyraflufen-ethyl is considered to be 0.172 mg/kg/day. This value is
based on the NOAEL of 17.2 mg/kg/day observed in the chronic rat
feeding study and a safety (uncertainty) factor of 100, the worse case
estimate of chronic dietary exposure of pyraflufen-ethyl from cotton,
potatoes, corn, or soybean will utilize less than 0.1% of the RfD for
the general U.S. population. EPA generally has no concern for exposures
below 100% of the RfD because the RfD represents the level at or below
which daily aggregate dietary exposure over a lifetime will not pose
appreciable risks to human health. The complete and reliable toxicity
data and the conservative chronic exposure assumptions support the
conclusion that there is a reasonable certainty of no harm from dietary
(food) exposure to pyraflufen-ethyl and the acid metabolite residues.
Moreover, as exposure to residues of pyraflufen-ethyl and the acid
metabolite via water is negligible, there is a reasonable certainty of
no harm from aggregate exposure to pyraflufen-ethyl and the acid
metabolite residues.
2. Infants and children. The conservative estimates, as described
above, indicate that chronic dietary exposure of pyraflufen-ethyl and
the acid metabolite from cotton and potato will utilize less than 0.1%
of the RfD for non-nursing infants, less than 0.1% of the RfD for
children ages 1 to 6; and less than 0.1% of the RfD for all populations
examined. No developmental, reproductive, or fetotoxic effects were
noted at the highest doses of pyraflufen-ethyl tested in guideline
reproductive or developmental toxicity studies. Based on the current
toxicological data requirements, the data base relative to prenatal and
postnatal effects for children is complete, valid and reliable. Results
from the teratology studies and the 2-generation reproduction study
support NOAELs for fetal/developmental effects or reproductive/
offspring effects, respectively, equivalent to the highest
concentrations tested. As such, there is no increased sensitivity of
infants and children to residues of pyraflufen-ethyl. Therefore, an
additional safety (uncertainty) factor is not warranted, and the RfD of
0.172 mg/kg/day, which utilizes a 100-fold safety factor, is
appropriate to assure a reasonable certainty of no harm to infants and
children.
F. International Tolerances
There is no Codex maximum residue level established for residues of
pyraflufen-ethyl and the acid metabolite on any crops.
[FR Doc. 02-29330 Filed 11-19-02; 8:45 am]
BILLING CODE 6560-50-S