[Federal Register: May 26, 2004 (Volume 69, Number 102)]
[Notices]
[Page 29940-29945]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr26my04-58]
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ENVIRONMENTAL PROTECTION AGENCY
[OPP-2004-0119; FRL-7357-4]
Mepanipyrim, N-(4-methyl-6-prop-1-ynlypyrimidin-2-yl) aniline];
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-2004-0119, must be
received on or before June 25, 2004.
ADDRESSES: Comments may be submitted electronically, by mail, or
through hand delivery/courier. Follow the detailed instructions as
provided in Unit I. of the SUPPLEMENTARY INFORMATION.
FOR FURTHER INFORMATION CONTACT: Mary Waller, Registration Division
(7505C), Office of Pesticide Programs, Environmental Protection Agency,
1200 Pennsylvania Ave., NW., Washington, DC 20460-0001; telephone
number: (703) 308-9354; e-mail address: waller.mary@epa.gov.
SUPPLEMENTARY INFORMATION:
I. General Information
A. Does this Action Apply to Me?
You may be potentially affected by this action, if you are an
agricultural producer, food manufacturer, or pesticide manufacturer.
Potentially affected entities may include, but are not limited to:
Crop Production (NAICS code 111)
Animal Production (NAICS code 112)
Food Manufacturing (NAICS code 311)
Pesticide Manufacturing (NAICS code 32532)
This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in this unit could also be
affected. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether this action might apply to certain entities. 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-2004-0119. 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
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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.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 on paper,
will be made available for public viewing in EPA's electronic public
docket as EPA receives them and without change, unless the comment
contains copyrighted material, CBI, or other information whose
disclosure is restricted by statute. When EPA identifies a comment
containing copyrighted material, EPA will provide a reference to that
material in the version of the comment that is placed in EPA's
electronic public docket. The entire printed comment, including the
copyrighted material, will be available in the public docket.
Public comments submitted on computer disks that are mailed or
delivered to the docket will be transferred to EPA's electronic public
docket. Public comments that are mailed or delivered to the docket will
be scanned and placed in EPA's electronic public docket. Where
practical, physical objects will be photographed, and the photograph
will be placed in EPA's electronic public docket along with a brief
description written by the docket staff.
C. How and to Whom Do I Submit Comments?
You may submit comments electronically, by mail, or through hand
delivery/courier. To ensure proper receipt by EPA, identify the
appropriate docket ID number in the subject line on the first page of
your comment. Please ensure that your comments are submitted within the
specified comment period. Comments received after the close of the
comment period will be marked ``late.'' EPA is not required to consider
these late comments. If you wish to submit CBI or information that is
otherwise protected by statute, please follow the instructions in Unit
I.D. Do not use EPA Dockets or e-mail to submit CBI or information
protected by statute.
1. Electronically. If you submit an electronic comment as
prescribed in this unit, EPA recommends that you include your name,
mailing address, and an e-mail address or other contact information in
the body of your comment. Also, include this contact information on the
outside of any disk or CD ROM you submit, and in any cover letter
accompanying the disk or CD ROM. This ensures that you can be
identified as the submitter of the comment and allows EPA to contact
you in case EPA cannot read your comment due to technical difficulties
or needs further information on the substance of your comment. EPA's
policy is that EPA will not edit your comment, and any identifying or
contact information provided in the body of a comment will be included
as part of the comment that is placed in the official public docket,
and made available in EPA's electronic public docket. If EPA cannot
read your comment due to technical difficulties and cannot contact you
for clarification, EPA may not be able to consider your comment.
i. EPA Dockets. Your use of EPA's electronic public docket to
submit comments to EPA electronically is EPA's preferred method for
receiving comments. Go directly to EPA Dockets at http://www.epa.gov/edocket/
, and follow the online instructions for submitting comments.
Once in the system, select ``search,'' and then key in docket ID number
OPP-2004-0119. 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-2004-0119. In contrast to EPA's
electronic public docket, EPA's e-mail system is not an ``anonymous
access'' system. If you send an e-mail comment directly to the docket
without going through EPA's electronic public docket, EPA's e-mail
system automatically captures your e-mail address. E-mail addresses
that are automatically captured by EPA's e-mail system are included as
part of the comment that is placed in the official public docket, and
made available in EPA's electronic public docket.
iii. Disk or CD ROM. You may submit comments on a disk or CD ROM
that you mail to the mailing address identified in Unit I.C.2. These
electronic submissions will be accepted in WordPerfect or ASCII file
format. Avoid the use of special characters and any form of encryption.
2. By mail. Send your comments to: Public Information and Records
Integrity Branch (PIRIB) (7502C), Office of Pesticide Programs (OPP),
Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,
Washington, DC 20460-0001, Attention: Docket ID number OPP-2004-0119.
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-2004-0119. 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.
[[Page 29942]]
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: May 6, 2004.
Lois Rossi,
Director, Registration Division, Office of Pesticide Programs.
Summary of Petition
The petitioner's summary of the pesticide petition is printed
below as required by FFDCA section 408(d)(3). The summary of the
petition was prepared by K-I Chemical U.S.A., Inc. 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.
K-I Chemical U.S.A., Inc.
PP 8E5017
EPA has received a pesticide petition PP 8E5017 from K-I Chemical
U.S.A., Inc., 11 Martine Ave., 9th Floor, White Plains, NY,
10606 proposing, pursuant to section 408(d) of the Federal Food, Drug,
and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180,
by establishing import tolerances for residues of menpanipyrim N- (4-
methyl-6-prop-1-ynlypyrimidin-2-yl) aniline in or on the raw
agricultural commodities grape at 2.0 parts per million (ppm); grape,
raisin at 4.0 ppm; strawberry at 1.5 ppm; and tomato at 0.5 ppm. EPA
has determined that the petition contains data or information regarding
the elements set forth in section 408(d)(2) of 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 nature of the residues of mepanipyrim in
plants is adequately understood. Metabolism studies on apples, grapes,
and tomatoes have been conducted. The major residue is comprised of
unchanged parent compound with small amounts of the metabolite 1 (2-
anilino-6-methylpyrimidin-4-yl)-2-propanol and other metabolites.
Parent compound and 1(2-anilino-6-methylpyrimidin-4-yl)-2-propanol are
the only residues of concern.
2. Analytical method. An analytical method for measuring residues
of mepanipyrim and the metabolite 1(2-anilino-6-methylpyrimidin-4-yl)-
2-propanol has been submitted to EPA. The analytical method utilizes
gas chromatography with a thermionic nitrogen specific detector (NPD).
A confirmatory method utilizes an alternate chromatographic column. The
confirmatory method is also, quantitative. These methods can be used
for gathering residue data and for enforcement purposes.
3. Magnitude of residues. Residue field trials were conducted in
representative countries that will export the majority of the treated
commodities to the United States.
Grape residue field trials were conducted in Austria, France,
Germany, Italy, Portugal, and Spain. Combined residues of mepanipyrim
and its regulated metabolite were all less than the proposed 2.0 ppm
tolerance for grapes.
Strawberry residue field trials were conducted in Belgium, France
and Spain. Combined residues of mepanipyrim and its regulated
metabolite were all less than the proposed 1.5 ppm tolerance.
Tomato residue field trials were conducted in Italy and Spain.
Combined residues of mepanipyrim and its regulated metabolite were all
less than the proposed 0.5 ppm tolerance. Grape and tomato crops both
have processed commodities. Grape processed commodities are grape,
juice; grape, raisin; and grape, wine. Tomato processed commodities are
tomato paste and tomato puree. These processed commodities could be
imported into the United States. Grape and tomato processing studies
indicate that mepanipyrim residues concentrate in grape, raisin but do
not concentrate in other processed commodities of grape or in the
processed commodities of tomato. Tolerances are not required for grape,
juice derived from mepanipyrim treated grape or from tomato, paste and
tomato, puree derived from mepanipyrim treated tomato. A tolerance of
4.0 ppm is needed for the processed commodity grape, raisin.
No livestock feed items are associated with the crops for which
tolerances are proposed in this petition. Therefore, no livestock
residue tolerances are being proposed.
B. Toxicological Profile
1. Acute toxicity. Mepanipyrim has a very-low order of acute
toxicity demonstrated by an acute oral LD50 in rats (both
sexes) greater than 5,000 milligrams/kilogram/body weight (mg/kg/bwt).
2. Genotoxicity. A battery of in vitro and in vivo tests were
conducted to determine the genotoxic potential of mepanipyrim.
Mepanipyrim did not produce lethal DNA damage in three strains of E.
coli: WP2, WP67, and CM871. Mepanipyrim was active in the Ames reverse
gene mutation assay, with or without metabolic activation, employing
five strains of Salmonella typhimurium (TA 98, TA 100, TA 1538, TA
1535, and TA 1537) and one strain of E.coli (WP2). Mepanipyrim did not
produce unscheduled DNA synthesis in cultured human cells (HeLa S-3)
either in the presence or absence of S-9 metabolic activation. In vivo
chromosomal aberration assays (CD-1 mouse micronucleus and CD rat
clastogenicity) were both negative when compared to the positive
control, chlorambucil. In vitro chromosomal aberrations were assayed in
Chinese hamster ovary (CHO-K1) cells, with and without metabolic
activation S-9 mixture. Mepanipyrim did not show clastogenic activity
in the activated assay; however, a questionable increase in aberrant
cell frequency was produced in the non-activated assay. This increase
of aberrant cell frequency occurred only
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where the number of analyzable metaphases was significantly reduced.
Mepanipyrim was negative in an in vitro specific locus gene mutation
assay in cultured Chinese hamster (V79) cells as the hypoxanthine-
guanine-phosphoribosyl transferase locus. In summary, mepanipyrim was
not genotoxic and did not induce heritable effects in the assays
conducted.
3. Reproductive and developmental toxicity. A developmental
toxicity study was conducted in rabbits at doses of 0, 10, 30, and 90
mg/kg bwt/day. Doses of 30, and 90 mg/kg bwt/day produced marginal
reductions in body weight gain and an increased incidence of premature
delivery or abortion on days 28 and 29 of gestation. There was an
increased percentage of small and extra small anterior fontanelle, an
increased percentage of anomalous interparietal bones fissured or
reduced, and an increased percentage of incompletely ossified and
unossified centrales in all dosed groups. However, there was also an
increased incidence of enlarged medium anterior fontanelle and
posterior fontanelle in control fetuses. All indices were within the
range of historical controls reported for 15 studies. In view of the
percentage of variations that were evident across all groups, including
controls, these sporadic increased incidences are not considered to be
compound related. The developmental no adverse effects level (NOAEL) is
considered to be 90 mg/kg bwt/day; the NOAEL for the study is 10 mg/kg
bwt/day based on maternal toxicity at higher doses.
A developmental toxicity study was conducted in pregnant Charles
River CD rats at doses of 0, 30, 150, and 750 mg/kg bwt/day,
administered from day 6 though day 15 of gestation. There were no
adverse effects on body weight gain, fetal growth, or morphological
development at any dose. The only marginal non-dose related effects
were slight increases in unilateral hydronephrosis and hydroureter at
150 and 750 mg/kg. However, these are not considered compound-related
based upon the incidence in bilateral hydronephrosis and hydroureter
which were increased in controls relative to all treated groups. At 750
mg/kg bwt/day there was a non-significant increase in intramuscular
hemorrhage of the hind limb and subcutaneous hemorrhage of the lower
jaw. The effect observed in the hind limb, although, not statistically
significant, was outside the historical control range, whereas all
other effects were within the historical control range of 137 studies
reported. The developmental NOAEL is considered to be 750 mg/kg bwt.
The NOAEL for the study is 750 mg/kg bwt/day.
A range-finding reproduction study was conducted at 200; 1,000;
2,500; and 5,000 ppm using 6 male and 6 female Charles River rats and
evaluating the effects on a single litter per mating. Adult body weight
gain was decreased at doses of 1,000; 2,500; and 5,000 ppm in the diet.
No adverse effects on reproductive parameters were determined. A NOAEL
of 200 ppm was assessed for this study.
A 2-generation reproduction study was conducted in Charles River
CD rats using 28 males/females per dose. No reproductive effects were
evident at doses up to and including 2,000 ppm. Liver weights were
increased in parent and offspring, as well as histopathological changes
at 1,000 ppm (i.e., hepatocytic fatty vacuolation). Tubular germinal
epithelial degeneration was observed in F2A and
F2B males at 1,000 ppm, with interstitial cell hyperplasia
at 150 ppm. An overall NOAEL for the study was not demonstrated due to
adverse effects on the liver at 150 ppm.
In a second 2-generation reproduction study in Charles River CD
rats, 32 males/females were given 0, 50, or 150 ppm in the diet. The
fertility index was low in control and low-dose groups (i.e., 69%),
with 88% pregnant in the high dose group. All reproductive parameters
which were evaluated were unaffected at all dose levels. Liver weights
were increased in male and female F1 and F2
offspring at 150 ppm, as well as hepatocytic periacinar vacuolation in
males. A NOAEL for general toxicity is considered to be 50 ppm, with
150 ppm a NOAEL for reproductive parameters.
4. Subchronic dietary toxicity. Short-term exposure of rats and
dogs to mepanipyrim technical resulted in the following effects.
In a 13-week oral study with rats dosed at 0, 50, 100, 200, and
800 ppm, there were increased absolute and relative liver weights in
both sexes. Pathological examination revealed no specific lesions. In a
second 13-week dietary study in specific pathogen free rats dosed at 0;
1,600; and 4,000 ppm, decreased body weight gain was observed in both
sexes at 4,000 ppm. Hematological examinations conducted at 13 weeks
revealed decreased hematocrit (Hct), hemoglobin levels (Hgb), mean cell
volume (MCV), and mean cell hemoglobin (MCH) in both sexes which were
significantly less than controls at 4,000 ppm. Reticulocyte count,
however, was increased at 4,000 ppm. There were also, significant
increases in absolute and relative liver and kidney weights in both
sexes at 4,000 ppm. The livers of both sexes at the 4,000 ppm level had
a yellow pigment, showed fatty changes and granulation of the liver
cells. The NOAEL in the 13-week oral rat studies is 13.8 mg/kg bwt/day
in males and 15.3 mg/kg bwt/day in females (200 ppm).
In a 13-week oral study with mice dosed at 0; 100; 1,000; 3,000;
and 7,000 ppm pathological examination revealed no abnormal gross
findings in liver and kidney, although, absolute and relative liver and
kidney weights were significantly increased in both sexes at 3,000 ppm.
Histologic observations were limited to few organs and compound-related
effects were not demonstrated. The NOAEL in the mouse is 18.8 mg/kg
bwt/day in males and 22 mg/kg bwt/day for females.
In a 13-week oral study with beagle dogs dosed at 0, 15, 50, or
150 mg/kg bwt/day, body weight gain for high dose females was
significantly decreased (p< 0.001). Relative organ weight increases were
observed at the highest dose, as well as alanine amino-transferase
(ALT), which was increased in both sexes. Hematological examination
revealed no treatment related effects. A brown pigment positively
identified as lipofuscin by Schmorl's stain was seen in liver cells of
both sexes at the 15 mg/kg bwt/day dose. A NOAEL was not demonstrated
in this study. The study was repeated at 7.5 and 15 mg/kg bwt/day and
the NOAEL was determined to be 7.5 mg/kg bwt/day based on the formation
of lipofuscin in the liver.
5. Chronic toxicity--i. Chronic toxicity/oncogenicity in rat. Rats
were administered mepanipyrim in the diet for 104 weeks at doses of 0;
50; 150; 2,000; and 4,000 ppm. Males and females at 2,000 ppm had
significant decreases in body weight gain, Hct, Hgb, MCV, and MCH,
also, cholesterol, triglyceride, phospholipids, and non-esterified
fatty acid. Significant increase in relative and absolute liver,
kidney, and spleen weights were determined in males and females at
2,000 ppm. Yellowish enlarged livers occurred in males and females at
2,000 ppm, as well as fatty changes which were increased. There was an
increased incidence of transitional cell hyperplasia in kidneys of
males at 2,000 ppm. The incidence of hepatocellular adenoma was
significantly increased in females at the high dose. The NOAEL for the
study was 50 ppm (2.45 mg/kg bwt in males and 3.07 mg/kg bwt in
females).
ii. Chronic toxicity in the dog. Mepanipyrim was administered to
dogs for 52-weeks at doses of 0, 2.5, 7.5, and 50 mg/kg bwt/day. Body
weight gain was decreased in high-dose females.
[[Page 29944]]
Animals receiving 50 mg/kg bwt/day demonstrated significantly
increased relative liver weights in both sexes and hepatocellular
enlargement in females. Alkaline phosphatase (AP) and ALT were also
significantly increased in high-dose male and females. Hematologic
examination revealed a significant increase in neutrophils and
lymphocytes manifested as a ``left-shift'' in the M:E ratio of males
and females. Pigmentation in hepatocytes and Kupffer cells, identified
as lipofuscin, was increased in high-dose males and females. The NOAEL
for the study was 7.5 mg/kg bwt/day.
iii. Chronic toxicity/oncogenicity in the mouse. B6C3F1 mice were
administered mepanipyrim in the diet continuously for 2 years at dose
levels of 0; 70; 350, 3,500; and 7,000 ppm. Males and females showed
increased relative liver weights at 3,500 ppm. Male mice also had
decreased body weights at 7000 ppm. Hematocrit and hemoglobin were
decreased in males at 7,000 ppm. Several effects were observed in the
liver, including: Increased hepatic nodules (both sexes) at 3,500 ppm;
increased swelling of liver cells in males at 3,500 ppm and in females
at 7,000 ppm; and increased foci/hyperplasia in males and females at
3,500 ppm. Incidences of hepatocellular adenoma and carcinoma were
increased in both sexes at 3,500 ppm. A NOAEL was demonstrated for non-
neoplastic effects in both males and females at 350 ppm, equal to 56
mg/kg bwt/day in males and 68 mg/kg bwt/day in females.
Ancillary (non-good labotatory practice) studies were conducted to
explore the compound-related effects on the liver in rodents.
``Studies on fatty liver induced by mepanipyrim in rats.'' Young
adult Fischer 344 rats were dosed at 4,000 and 8,000 ppm for 3 weeks.
Various blood and liver examinations were conducted. The results
indicate that serum lipid concentrations decreased in conjunction with
the induction of fatty liver by mepanipyrim treatment.
``Study on the possible oxidative damage to DNA by mepanipyrim.''
Mepanipyrim was administered to rats and mice in a single-oral dose,
and in the diet for 3 and 6 weeks. Livers were removed at pre-
determined times after each compound administration regimen, and the
DNA extracted. Individual samples were assayed for 8-hydroxyquanine (8-
OHdG) by high performance liquid chromatography and enzyme-linked
immunosorbant assay. No significant increase in the 8-OHdG (an
indicator of oxidative DNA damage) was observed in rat livers or in the
3 and 6 week exposure periods in mice.
``Microsomal mixed function oxidase activity in liver of rats and
mice administered with mepanipyrim.'' Mepanipyrim was administered for
3 weeks to rats at dose levels of 150 and 4,000 ppm and to mice at 350
and 7,000 ppm. The study revealed that at the 4,000 and 7,000 ppm dose
levels the microsomal drug-metabolizing enzyme aminopyrine N-
demethylase increased slightly in the rat and mouse livers. Aniline
hydroxylase activity was unchanged in both species.
``Promoting activities of mepanipyrim liver carcinogenesis
initiated with dimethylnitrosamine in rats.'' Rats were fed a diet
containing 1,000 and 5,000 ppm mepanipyrim for 6 weeks after having
been injected with nitrosodiethylamine. Mepanipyrim has a weak
promoting effect evidenced by the induction of gamma-glutamyl
transpeptidase foci in the liver.
6. Animal metabolism. A rat metobolism study was conducted with 106
rats divided into 13 dose groups. No radioactivity was noted in expired
CO2 or other expired volatiles. The majority of
radioactivity was excreted in the feces. Urine was the other major
route of excretion. The same residues, parent and metabolites, were
found in both urine and feces. Most of the radioactivity had been
excreted by 24 hours after dosing. The majority of the radioactivity in
blood was acetonitrile extractable at 5-8 hours after dosing and
declined to zero at 120 hours. In bile duct cannulated rats, a
significant amount (50-70%) of the dose was excreted in bile. The
percentage of dose excreted in feces was reduced to 3-4% at 120 hours.
7. Metabolite toxicology. No toxicologically significant
metabolites were detected in plant and rat metabolism studies.
8. Endocrine disruption. No specific tests have been conducted with
mepanipyrim to determine whether mepanipyrim may have an effect in
humans that is similar to an effect produced by a naturally occurring
estrogen or other endocrine effects. There is no evidence at this time
that mepanipyrim causes endocrine effects, and no reason to suspect
that it does based upon the information available and mode of action of
this class of compounds.
C. Aggregate Exposure
1. Dietary exposure--i. Food The Theoretical Maximum Residue
Concentration (TMRC) of mepanipyrim in or on grape, strawberry, tomato,
and their processed commodities (grape, juice; grape, wine; grape,
raisin; tomato, paste; and tomato, puree) are as follows:
0.000936 mg/kg bodyweight/day for the general U.S. population;
0.000429 mg/kg bodyweight/day for non-nursing infants; 0.00178 mg/kg
body weight/day of children 1-6 years of age; and 0.00118 mg/kg
bodyweight/day of children 7-12 years of age.
The TMRC values are based on the assumption that all of the grape,
strawberry, and tomato and their processed commodities will bear
residues at the proposed tolerance levels for the raw agricultural
commodities. These chronic dietary exposure estimates are very
conservative because they assume that 100% of all grape, strawberry,
and tomato are imported. Imported grapes, strawberry, and tomato
actually comprise less than 10% of these commodities consumed in the
United States. The estimates also assume that all imported grape,
strawberry, and tomato and their processed products are treated with
mepanipyrim and that residue levels on all of the imported commodities
are at the proposed tolerance level.
Dietary exposure to residues of mepanipyrim will be from grape,
strawberry, tomato, and their processed products and also, from grape,
and wine. There are no livestock or poultry feed items associated with
these raw commodities. Thus, there will be no dietary exposure to
mepanipyrim residues in meat, milk, poultry, and eggs. There are no
other tolerances or exemptions from a tolerance for mepanipyrim in the
United States.
ii. Drinking water. There are neither tolerances nor registration
for the use of this chemical in the United States. Therefore, there
will be no exposure to mepanipyrim from residues in drinking water.
2. Non-dietary exposure. This petition is for a tolerance on
imported grape, strawberry, and tomato. There is no approved registered
use for mepanipyrim in the United States, and none is being sought.
Therefore, the potential for non-dietary exposure is not pertinent to
this petition.
D. Cumulative Effects
This chemical is in the anilinopyrimidine class. EPA consideration
of a common mechanism of toxicity is not appropriate at this time
because EPA has not made a determination that mepanipyrim and other
substances may have a common mechanism of toxicity that would have a
cumulative effect. K-I Chemical U.S.A., Inc., is considering only the
potential risk of mepanipyrim in its cumulative-exposure assessment.
Evidence from rodent studies indicate that mepanipyrim may be
oncogenic at
[[Page 29945]]
high doses in rodent livers. In the 2-year mouse study, at doses of
3,500 and 7,000 ppm, hepatocellular adenoma and hepatocellular
carcinoma of the liver of both sexes were statistically significantly
increased above those seen in the controls. A slight increase in
hepatocellular adenomas was observed in female rats dosed at 4,000 ppm
in the 2-year rat study. No increase was noted at lower doses or in the
male rats. Additionally, the tumors did not lead to a shortening of the
lifespan of affected animals and there was no decrease in the time-to-
tumor versus the concurrent control animals. In the chronic toxicity
portion of the rat study, there was also, the observation of hepatic
perilobular lipogenesis.
A complete battery of in vitro and in vivo mutagentcity studies
were performed to evaluate mepanipyrim's ability to induce gene
mutations, structural chromosomal aberrations, or other genotoxic
effects. Mepanipyrim showed no evidence of genotoxic activity in any of
the investigations performed.
While mepanipyrim is not genotoxic, mepanipyrim demonstrated an
ability to induce gamma glutamyl transferase (GGT) positive liver cell
foci and to induce the liver's metabolizing enzymes. Therefore,
mepanipyrim may be a non-genotoxic carcinogen suggested by its ability
to induce a proliferative effect in the liver which results in
increases in spontaneously occurring liver neoplasia in both mice and
rats. A threshold would exist in this case and no oncogenic response
would be anticipated below such a threshold level. In the current
studies, no hepatocellular tumors or liver toxicity were observed in
mice at 350 ppm (56.0 mg/kg/day mepanipyrim) and in rats at 50 ppm
(2.45 mg/kg/day mepanipyrim).
Based on the total information examined, mepanipyrim is considered
a Group C carcinogen not requiring quantitative risk assessment.
E. Safety Determination
1. U.S. population. The reference dose (RfD) represents the level
at or below which daily aggregate dietary exposure over a lifetime will
not pose appreciable risks to human health. For mepanipyrim, the RfD of
0.0245 mg/kg bwt/day is based on a NOAEL of 50 ppm or 2.45 mg/kg bwt/
day from the chronic toxicity/oncogenicity study. Considering the
extremely conservative estimates of exposure in comparison to the RfD
of 0.0245 mg/kg, the chronic dietary exposure of the U.S. population
will only utilize 3.8% of the RfD. This exposure is much less than 100%
of the RfD and K-I Chemical U.S.A., Inc., concludes that there is a
``reasonable certainty to no harm'' from aggregate exposure to
mepanipyrim residues.
2. Infants and children. The chronic dietary exposure estimates
will utilize approximately 1.8% of the RfD for non-nursing infants less
than 1-year of age, and approximately 7.3% of the RfD for children 1-6
years of age, and approximately 4.8% for children 7-12 years of age.
The conservative exposure estimates for the infant and children
populations are all well below the RfD for mepanipyrim.
F. International Tolerances
Registration of mepanipyrim is in progress in the European Union
(EU). A provisional registration has been granted in several countries
with temporary maximum residue levels (tMRL) set. These countries and
tMRLs are: Austria, strawberry and grape (2 mg/kg); Belgium, strawberry
(2); France, strawberry and grape (2), wine (0.2); Italy, strawberry
(2), grape (3), wine and tomato (1); Luxembourg, strawberry (2), grape
(3); Netherlands, strawberry (2); Portugal, strawberry and grape (2);
Spain, strawberry and grape (2), tomato (1); and United Kingdom,
strawberry (2).
Mepanipyrim is registered for crop uses in Switzerland, Japan, and
Israel.
[FR Doc. 04-11562 Filed 5-25-04; 8:45 am]
BILLING CODE 6560-50-S