[Federal Register Volume 65, Number 61 (Wednesday, March 29, 2000)]
[Notices]
[Pages 16608-16614]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-7231]
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ENVIRONMENTAL PROTECTION AGENCY
PF-919; FRL-6493-8
Notice of Filing Pesticide Petitions To Establish a Tolerance for
Certain Pesticide Chemicals in or on Food
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: This notice announces the initial filing of pesticide
petitions proposing the establishment of regulations for residues of
certain pesticide chemicals in or on various food commodities.
DATES: Comments, identified by docket control number PF-919, must be
received on or before April 28, 2000.
ADDRESSES: Comments may be submitted by mail, electronically, or in
person. Please follow the detailed instructions for each method as
provided in Unit I.C. of the SUPPLEMENTARY INFORMATION. To ensure
proper receipt by EPA, it is imperative that you identify docket
control number PF-919 in the subject line on the first page of your
response.
FOR FURTHER INFORMATION CONTACT: The product manager listed in the
table below:
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Office location/
Product Manager telephone number/e-mail Address Petition number(s)
address
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Mary Waller (PM 21).................. Rm. 249, CM #2, 703-308- 1921 Jefferson Davis PP 9F3727
9354, e-mail:waller. Hwy, Arlington, VA
[email protected]
Joe Travano (PM 10).................. Rm. 214, CM #2, 703-305- Do. PP 0F6069
6411, e-mail:
[email protected].
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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 production
112 Animal production
311 Food manufacturing
32532 Pesticide
manufacturing
------------------------------------------------------------------------
This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in the table could also be
affected. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether or not this action might apply to certain entities. If you have
questions regarding the applicability of this action to a particular
entity, consult the person listed under FOR FURTHER INFORMATION
CONTACT.
B. How Can I Get Additional Information, Including Copies of this
Document and Other Related Documents?
1. Electronically. You may obtain electronic copies of this
document, and certain other related documents that might be available
electronically, from the EPA Internet Home Page at http://www.epa.gov/.
To access this document, on the Home Page select ``Laws and
Regulations'' and then look up the entry for this document under the
``Federal Register--Environmental Documents.'' You can also go directly
to the Federal Register listings at http://www.epa.gov/fedrgstr/.
2. In person. The Agency has established an official record for
this action under docket control number PF-919. The official record
consists of the documents specifically referenced in this action, any
public comments received during an applicable comment period, and other
information related to this action, including any information claimed
as confidential business information (CBI). This official record
includes the documents that are physically located in the docket, as
well as the documents that are referenced in those documents. The
public version of the official record does not include any information
claimed as CBI. The public version of the official record, which
includes printed, paper versions of any electronic comments submitted
during an applicable comment period, is available for inspection in the
Public Information and Records Integrity Branch (PIRIB), Rm. 119,
Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA, from 8:30
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The
PIRIB telephone number is (703) 305-5805.
C. How and to Whom Do I Submit Comments?
You may submit comments through the mail, in person, or
electronically. To ensure proper receipt by EPA, it is
[[Page 16609]]
imperative that you identify docket control number PF-919 in the
subject line on the first page of your response.
1. By mail. Submit your comments to: Public Information and Records
Integrity Branch (PIRIB), Information Resources and Services Division
(7502C), Office of Pesticide Programs (OPP), Environmental Protection
Agency, Ariel Rios Bldg., 1200 Pennsylvania Ave., NW., Washington, DC
20460.
2. In person or by courier. Deliver your comments to: Public
Information and Records Integrity Branch (PIRIB), Information Resources
and Services Division (7502C), Office of Pesticide Programs (OPP),
Environmental Protection Agency, Rm. 119, Crystal Mall #2, 1921
Jefferson Davis Highway, Arlington, VA. The PIRIB is open from 8:30
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The
PIRIB telephone number is (703) 305-5805.
3. Electronically. You may submit your comments electronically by
e-mail to: ``[email protected],'' or you can submit a computer disk as
described above. Do not submit any information electronically that you
consider to be CBI. Avoid the use of special characters and any form of
encryption. Electronic submissions will be accepted in Wordperfect 6.1/
8.0 or ASCII file format. All comments in electronic form must be
identified by docket control number PF-919. Electronic comments may
also be filed online at many Federal Depository Libraries.
D. How Should I Handle CBI That I Want to Submit to the Agency?
Do not submit any information electronically that you consider to
be CBI. You may claim information that you submit to EPA in response to
this document as CBI by marking any part or all of that information as
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 version of the
official record. Information not marked confidential will be included
in the public version of the official record without prior notice. If
you have any questions about CBI or the procedures for claiming CBI,
please consult the person identified 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
control number assigned to this action in the subject line on the first
page of your response. You may also provide the name, date, and Federal
Register citation.
II. What Action is the Agency Taking?
EPA has received pesticide petitions as follows proposing the
establishment and/or amendment of regulations for residues of certain
pesticide chemicals in or on various food commodities under section 408
of the Federal Food, Drug, and Comestic Act (FFDCA), 21 U.S.C. 346a.
EPA has determined that these petitions contain 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 supports 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: March 16, 2000.
James Jones,
Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
Petitioner summaries of the pesticide petitions are printed below
as required by section 408(d)(3) of the FFDCA. The summaries of the
petitions were prepared by the petitioners and represent the views of
the petitioners. 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.
1. McLaughlin Gormley King Company
0F6069
EPA has received a pesticide petition (0F6069) from McLaughlin
Gormley King Company, 8810 Tenth Avenue North, Minneapolis, MN 55427-
4372 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 a tolerance for residues of pyriproxyfen in or on food
products in food handling establishments at 0.1 parts per million
(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 supports granting of
the petition. Additional data may be needed before EPA rules on the
petition.
A. Residue Chemistry
1. Plant metabolism. Radiocarbon plant and animal metabolism
studies have been conducted with pyriproxyfen. These studies
demonstrate that the nature of the residues in these matrices is
primarily pyriproxyfen.
2. Analytical method. An analytical method is available to detect
residues of pyriproxyfen in or on food commodities. Pyriproxyfen can be
extracted from samples and analyzed by high performance liquid
chromotography (HPLC), or nitrogen phosphorous/gas liquid
chromotography (NP-GLC). The HPLC method has been validated by an
independent laboratory.
3. Magnitude of residues. Studies were conducted to determine
levels of residues resulting from the application of Nylar to
representative food commodities in simulated feed and/or food
processing and simulated warehouse situations. The representative foods
were potatoes, loaves of bread, flour, lettuce, meat, candy, butter,
banana cream pies, navy beans, Spanish peanuts, dried prunes, and
granulated sugar. No significant residues were found in covered
samples; however, residues were detectable in uncovered samples and
samples with permeable wrapping.
B. Toxicological Profile
1. Acute toxicity. The acute toxicity of technical grade
pyriproxyfen is low by all routes. The compound is classified as
Category III for acute dermal and
[[Page 16610]]
inhalation toxicity, and Category IV for acute oral toxicity, and skin/
eye irritation. Pyriproxyfen is not a skin sensitizing agent.
2. Genotoxicity. Pyriproxyfen does not present a genetic hazard.
Pyriproxyfen was negative in the following tests for mutagenicity: Ames
assay with and without S9, in vitro unscheduled DNA synthesis (UDS) in
HeLa S3 cells, in vitro gene mutation in V79 Chinese hamster cells
(CHO), and in vitro chromosomal aberration with and without S9 in CHO
cells.
3. Reproductive and developmental toxicity. Pyriproxyfen is not a
developmental or reproductive toxicant. Developmental toxicity studies
have been performed in rats and rabbits, and multi-generational effects
on reproduction were tested in rats. These studies have been reviewed
and found to be acceptable to the Agency.
In the developmental toxicity study conducted with rats, technical
pyriproxyfen was administered by gavage at levels of 0, 100, 300, and
1,000 milligrams/kilograms bodyweight/day (mg/kg bwt/day) during
gestation days 7-17. Maternal toxicity (mortality, decreased body
weight gain and food consumption, and clinical signs of toxicity) was
observed at doses of 300 mg/kg bwt/day and greater. The maternal no
observed adverse effect level (NOAEL) was 100 mg/kg bwt/day. A
transient increase in skeletal variations was observed in rat fetuses
from females exposed to 300 mg/kg bwt/day and greater. These effects
were not present in animals examined at the end of the postnatal
period, therefore, the NOAEL for prenatal developmental toxicity was
100 mg/kg bwt/day. An increased incidence of visceral and skeletal
variations was observed postnatally at 1,000 mg/kg bwt/day. The NOAEL
for postnatal developmental toxicity was 300 mg/kg bwt/day.
In the developmental toxicity study conducted with rabbits,
technical pyriproxyfen was administered by gavage at levels of 0, 100,
300, and 1,000 mg/kg bwt/day during gestation days 6-18. Maternal
toxicity (clinical signs of toxicity including one death, decreased
body weight gain and food consumption, and abortions or premature
deliveries) was observed at oral doses of 300 mg/kg bwt/day or higher.
The maternal NOAEL was 100 mg/kg bwt/day. No developmental effects were
observed in the rabbit fetuses. The NOAEL for developmental toxicity in
rabbits was > 1,000 mg/kg bwt/day.
In the rat reproduction study, pyriproxyfen was administered in the
diet at levels of 0, 200, 1,000, and 5,000 ppm through 2 generations of
rats. Adult systemic toxicity (reduced body weights, liver and kidney
histopathology, and increased liver weight) was produced at the 5,000
ppm dose (453 mg/kg bwt/day in males, 498 mg/kg bwt/day in females)
during the pre-mating period. The systemic NOAEL was 1,000 ppm (87 mg/
kg bwt/day in males, 96 mg/kg bwt/day in females). No effects on
reproduction were produced at 5,000 ppm, the highest dose tested (HDT).
4. Subchronic toxicity. Subchronic oral toxicity studies conducted
with pyriproxyfen technical in the rat, mouse and dog indicate a low
level of toxicity. Effects observed at high dose levels consisted
primarily of decreased body weight gain; increased liver weights;
histopathological changes in the liver and kidney; decreased red blood
cell counts, hemoglobin and hematocrit; altered blood chemistry
parameters; and, at 5,000 and 10,000 ppm in mice, a decrease in
survival rates. The NOAELs from these studies were 400 ppm (23.5 mg/kg
bwt/day for males, 27.7 mg/kg bw/day for females) in rats, 1,000 ppm
(149.4 mg/kg bwt/day for males, 196.5 mg/kg bwt/day for females) in
mice, and 100 mg/kg bwt/day in dogs.
In a 4-week inhalation study of pyriproxyfen technical in rats,
decreased body weight and increased water consumption were observed at
1,000 mg/m3. The NOAEL in this study was 482 mg/
m3.
A 21-day dermal toxicity study in rats with pyriproxyfen technical
did not produce any signs of dermal or systemic toxicity at 1,000 mg/kg
bwt/day, the HDT.
5. Chronic toxicity. Pyriproxyfen technical has been tested in
chronic studies with dogs, rats and mice. EPA has established a
reference dose (RfD) for pyriproxyfen of 0.35 mg/kg bwt/day, based on
the NOAEL in female rats from the 2-year chronic/oncogenicity study.
Effects cited by EPA in the RfD tracking report include negative trend
in mean red blood cell volume, increased hepatocyte cytoplasm and
cytoplasm nucleus ratios, and decreased sinusoidal spaces.
Pyriproxyfen is not a carcinogen. Studies with pyriproxyfen have
shown that repeated high dose exposures produced changes in the liver,
kidney, and red blood cells, 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. The
oncogenicity classification of pyriproxyfen is ``E'' (no evidence of
carcinogenicity for humans).
Pyriproxyfen technical was administered to dogs in capsules at
doses of 0, 30, 100, 300, and 1,000 mg/kg bwt/day for 1-year. Dogs
exposed to dose levels of 300 mg/kg bwt/day or higher showed overt
clinical signs of toxicity, elevated levels of blood enzymes and liver
damage. The NOAEL in this study was 100 mg/kg bwt/day.
Pyriproxyfen technical was administered to mice at doses of 0, 120,
600, and 3,000 ppm in diet for 78 weeks. The NOAEL for systemic effects
in this study was 600 ppm (84 mg/kg bwt/day in males, 109.5 mg/kg bwt/
day in females), and a lowest observed adverse effect level (LOAEL) of
3,000 ppm (420 mg/kg bwt/day in males, 547 mg/kg bwt/day in females)
was established based on an increase in kidney lesions.
In a 2-year study in rats, pyriproxyfen technical was administered
in the diet at levels of 0, 120, 600, and 3,000 ppm. The NOAEL for
systemic effects in this study was 600 ppm (27.31 mg/kg bwt/day in
males, 35.1 mg/kg bwt/day in females). A LOAEL of 3,000 ppm (138 mg/kg
bwt/day in males, 182.7 mg/kg bwt/day in females) was established based
on a depression in body weight gain in females.
6. Animal metabolism. The absorption, tissue distribution,
metabolism and excretion of 14C-labeled pyriproxyfen were
studied in rats after single oral doses of 2 or 1,000 mg/kg bwt
(phenoxyphenyl and pyridyl label), and after a single oral dose of 2
mg/kg bwt (phenoxyphenyl label only) following 14 daily oral doses at 2
mg/kg bwt of unlabeled material. For all dose groups, most (88-96%) of
the administered radiolabel was excreted in the urine and feces within
2 days after radiolabeled test material dosing, and 92-98% of the
administered dose was excreted within 7 days. Seven days after dosing,
tissue residues were generally low, accounting for no more than 0.3% of
the dosed 14C. Radiocarbon concentrations in fat were higher
than in other tissues analyzed. Recovery in tissues over time indicates
that the potential for bioaccumulation is minimal. There were no
significant sex or dose-related differences in excretion or metabolism.
7. Metabolite toxicology. Metabolism studies of pyriproxyfen in
rats, goats, and hens, as well as the fish bioaccumulation study
demonstrate that the parent is very rapidly metabolized and eliminated.
In the rat, most (88-96%) of the administered radiolabel was excreted
in the urine and feces within 2 days of dosing, and 92-98% of the
administered dose was excreted within 7 days. Tissue residues were low
7 days
[[Page 16611]]
after dosing, accounting for no more than 0.3% of the dosed
14C. 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 MTD and consequent chronic
exposure to the internally formed metabolites.
Seven metabolites of pyriproxyfen, 4'-OH-pyriproxyfen, 5''-OH-
pyriproxyfen, desphenyl-pyriproxyfen, POPA, PYPAC, 2-OH-pyridine and
2,5-diOH-pyridine, have been tested for mutagenicity (Ames) and acute
oral toxicity to mice. All seven metabolites were tested in the Ames
assay with and without S9 at doses up to 5,000 micrograms per plate or
up to the growth inhibitory dose. The metabolites did not induce any
significant increases in revertant colonies in any of the test strains.
Positive control chemicals showed marked increases in revertant
colonies. The acute toxicity to mice of 4'-OH-pyriproxyfen, 5''-OH-
pyriproxyfen, desphenyl-pyriproxyfen, POPA, and PYPAC did not appear to
markedly differ from pyriproxyfen, with all metabolites having acute
oral LD50 values greater than 2,000 mg/kg bwt. The two
pyridines, 2-OH-pyridine and 2,5-diOH-pyridine, gave acute oral
LD50 values of 124 (male) and 166 (female) mg/kg bwt, and
1,105 (male) and 1,000 (female) mg/kg/bwt, respectively.
8. Endocrine disruption. Pyriproxyfen is specifically designed to
be an insect growth regulator and is known to produce juvenoid effects
on arthropod development. However, this mechanism-of-action in target
insects and some other arthropods has no relevance to any mammalian
endocrine system. While specific tests, uniquely designed to evaluate
the potential effects of pyriproxyfen on mammalian endocrine systems
have not been conducted, the toxicology of pyriproxyfen has been
extensively evaluated in acute, sub-chronic, chronic, developmental,
and reproductive toxicology studies including detailed histopathology
of numerous tissues. The results of these studies show no evidence of
any endocrine-mediated effects, and no pathology of the endocrine
organs. Consequently, it is concluded that pyriproxyfen does not
possess estrogenic or endocrine disrupting properties applicable to
mammals.
C. Aggregate Exposure
1. Dietary exposure--i. Food. An evaluation of chronic dietary
exposure to potential pyriproxyfen residues in all foods that may be
exposed to pyriproxyfen through agricultural and food handling
establishment treatments, including exposure from drinking water, was
estimated for the overall U.S. population and 26 sub-populations,
including infants and children.
Chronic dietary exposure was estimated using the chronic module of
the DEEMTM software. Residue data used in the analysis
included current and pending tolerances for agricultural crops, results
from warehouse simulation studies, and processing data. The data base
providing levels of food consumption was the USDA Continuing Surveys of
Food Intake by Individuals conducted from 1994 through 1996. MGK
provided estimated marketshare information.
Chronic dietary exposure was estimated to be 0.000550 mg/kg bwt/
day, or 0.2% of the RfD. Exposure for the most highly exposed
population subgroup, non-nursing infants, was calculated to be 0.002438
mg/kg bwt/day, or 0.7% of the RfD.
ii. Drinking water. The generic expected environmental
concentration (GENEEC) modeling was used to estimate potential
pyriproxyfen residues in surface water and/or ground water. The chronic
drinking water estimated concentration value of 0.053 parts per billion
(ppb) for pyriproxyfen was compared to the drinking water levels of
concern (DWLOC) calculated for pyriproxyfen for adult males, adult
females, and toddlers, that were 12,545 ppb, 10,489 ppb, and 5,229 ppb,
respectively. There is reasonable certainty that no harm will result
from aggregate exposure to potential pyriproxyfen residues.
2. Non-dietary exposure. Many products for indoor, non-food
applications such as pet care products and carpet treatments containing
pyriproxyfen as an active ingredient are registered with EPA.
Typically, the directions for use of these products describe
intermittent application, with no resulting chronic exposures. Since
neither acute oral, dermal, or inhalation toxicity endpoints, nor doses
and endpoints for short- and intermediate-term dermal or inhalation
exposures have been identified for pyriproxyfen, the Agency has
concluded that there is reasonable certainty of no harm from non-
dietary exposures to pyriproxyfen.
D. Cumulative Effects
There are no other compounds that are structurally related to
pyriproxyfen and have similar effects on animals. No other data are
available that indicate that any toxicological effects produced by
pyriproxyfen would be cumulative with those of any other compound, so
only the potential risks of pyriproxyfen have been considered in the
risk assessment.
E. Safety Determination
1. U.S. population. Based on the estimated aggregate exposures to
residues of pyriproxyfen from food and drinking water, and the reliable
toxicology data base, the chronic exposure to pyriproxyfen for the
overall U.S. population is 0.000550 mg/kg bwt/day, representing only
0.2% of the RfD. EPA has no concerns about exposure which are less than
100% of the RfD as the RfD represents the level at or below which daily
aggregate dietary exposure over a lifetime will not pose appreciable
risks to human health. It is therefore, safe to conclude that there is
reasonable certainty that no harm to the overall U.S. population will
result from chronic exposure to pyriproxyfen residues.
2. Infants and children. EPA has the right to apply an additional
margin of safety, up to ten-fold, for the protection of infants and
children due to their additional sensitivities, unless EPA can
determine that a different margin of safety will adequately protect
them. Rat and rabbit developmental toxicity studies and the 2-
generation reproductive toxicity study in rats demonstrated that no
special prenatal or postnatal toxicity concerns apply for exposure to
pyriproxyfen. Therefore, an additional uncertainty factor does not need
to be added for the safety determination of pyriproxyfen.
Based on the estimated aggregate exposures to residues of
pyriproxyfen from food and drinking water, and the reliable toxicology
data base, the chronic exposure to pyriproxyfen for infants and
children ranged from 0.000739 mg/kg bwt/day for children 7-12 years
old, representing 0.2% of the RfD, to 0.002438 mg/kg bwt/day for non-
nursing infants 1-year old, representing 0.7% if the RfD. It is safe
to conclude that there is reasonable certainty that no harm to any
subgroup of children will result from chronic exposure to pyriproxyfen
residues.
F. International Tolerances
No Codex MRLs presently exist for pyriproxyfen, although they may
be established in the future.
2. Uniroyal Chemical Company, Inc.
9F3727
EPA has received a pesticide petition (9F3727) from Uniroyal
Chemical Company Inc., 74 Amity Rd, Bethany, CT proposing, pursuant to
section 408(d) of the FFDCA, 21 U.S.C. 346a(d), to amend 40 CFR part
180 by
[[Page 16612]]
establishing a tolerance for residues of carboxin (5,6-dihydro-2-
methyl-1,4-oxathiin-3-carboxanilide) and its sulfoxide metabolite (5,6-
dihydro-3-carboxanilide-2-methyl-1,4-oxathiin-4-oxide) in or on the RAC
onions (dry bulb) at 0.2 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
supports granting of the petition. Additional data may be needed before
EPA rules on the petition.
A. Residue Chemistry
1. Plant metabolism. The metabolism of carboxin in plants is
adequately understood. The major metabolites in all commodities of
wheat were carboxin sulfoxide and sulfone. Metabolites in cotton seeds
were at too low a level to be identified. The metabolism of carboxin in
soybeans is characterized by the oxidation of sulfur (present as
sulfoxides and sulfones), cleavage of the oxathiin ring, and
conjugation with glucose.
2. Analytical method. The analytical method employed for analysis
of residues of carboxin in the onions from the trials described below
used a caustic reducing medium to hydrolyze extracted residues of
carboxin and its sulfoxide metabolite to liberate aniline, which is
distilled and concentrated. The aniline is analyzed with a gas
chromatograph equipped with a microcoulometric nitrogen detector. The
limit of detection by this method is 0.1 ppm. The current method for
the analysis of residues of carboxin in animal tissues, milk and eggs
employs alkaline hydrolysis with the liberated aniline derivatized with
heptafluorobutyric anhydride. Analysis is by gas chromatography of the
derivatized aniline, with mass selective detection (GC/MSD). Thus the
sensivity of the method limit of quantitation (LOQ) in all tissue was
0.02 ppm, and the precision of the method as indicated by the
coefficient of variation (COV) was 1.9%.
3. Magnitude of residues. Uniroyal Chemical Company has submitted
data to determine residues of carboxin in mature onions grown from
seed, which was treated prior to planting with PRO-GRO. Nine trials
were conducted in the following States; Michigan (3), Oregon (2),
Washington (1), New York (2), Illinois (1), and one trial was conducted
in Ontario, Canada. At each trial site onion seed, which had been
treated with 2.5 lbs. PRO-GRO containing 0.75 lbs. active ingredient
per 100 lbs. seed (1x the label rate), was planted and onions were
grown to maturity. Mature onions, depending upon variety, were
harvested from 118 days to 197 days after treatment. Residues of
carboxin, and its sulfoxide metabolite, both quantitated as carboxin,
were as follows. Seventeen of 18 onion samples grown from seed treated
at the 1x rate had residues of total carboxin less than the limit of
detection of 0.1 ppm. One sample had a total carboxin residue value of
0.1 ppm. One onion sample grown from seed which had been treated with
PRO-GRO at 2x the label rate had no carboxin residues above the 0.1 ppm
limit of detection. The submitted field trial data indicate that
residues of carboxin will not exceed the proposed tolerance of 0.2 ppm
in mature onions grown from seed which had been treated with PRO-GRO at
the label rate.
B. Toxicological Profile
1. Acute toxicity. Acute toxicity studies on carboxin demonstrate
that the oral and dermal LD50 values for the technical
material are 2.86 and > 4.0 g/kg, respectively. The 4-hour inhalation
LC50 in rats is 4.7 milligrams/Liter (mg/L). Irritation
tests in rabbits showed carboxin to be a mild eye irritant and non-
irritating to the skin. Carboxin did not cause skin sensitization in
studies with guinea pigs.
2. Genotoxicity. Bacterial/mammalian microsomal mutagenicity assays
were performed and carboxin was found not to be mutagenic. Two
chromosomal aberration assays were conducted, in CHO cells and in mouse
bone marrow in vivo, and were also negative. A study was performed in
rat hepatocytes and demonstated the induction of UDS.
3. Reproductive and developmental toxicity. In a developmental
toxicity study in rats conducted in 1989, carboxin was administered by
oral gavage to pregnant, Sprague Dawley rats at dosage levels of 10,
90, and 175 mg/kg/day. Decreased maternal body weight gain was seen at
dose levels of 90 and 175 mg/kg/day. The report states that there was a
slightly reduced mean fetal body weight in the high dose group compared
to controls (3.3 g vs. 3.5 g). However, a recent evaluation of 59
studies of the historical control data in the final report shows that
between 10/83 and 4/87, the range for fetal weight was 3.1 g to 5.1 g.
Therefore, a mean fetal weight of 3.3 g in the 175 mg/kg/day group is
within the historical control range. Maternal toxicity was also noted
at this dosage level. Therefore, the NOAEL for developmental toxicity
is greater than 175 mg/kg/day and the NOAEL for maternal toxicity,
based on decreased body weight gain, is 10 mg/kg/day.
In a developmental toxicity study in rabbits, carboxin was
administered by oral gavage to pregnant White rabbits at dosage levels
of 75, 375, and 750 mg/kg/day. There were no treatment related effects
at any dose level with the exception of three abortions in the high
dose group and one abortion in the mid dose group. An evaluation of
historical control data from 28 studies conducted at that time shows
abortion rates of 3/17, and 5/16 in two studies, as well as a number of
studies in which there were one or two abortions each. Therefore,
considering that there was no maternal toxicity at dose levels of 375
or 750 mg/kg/day of carboxin, it would have to be concluded that the 1/
16 and 3/16 abortions seen in the mid and high dose groups were
spontaneous. The NOAEL for maternal and developmental toxicity was
considered to be greater than 750 mg/kg/day.
In a dietary 2-generation rat reproduction study, carboxin was fed
to male and female Sprague Dawley rats at dietary concentrations of 20,
200, and 400 ppm in males, and 20, 300 and 600 ppm in females. At the
high dose level there was a decrease in body weight gain in parental
males and females and a reduction in pup growth during lactation. No
effects on reproduction were observed. The NOAEL for systemic, adult
toxicity was 200 ppm (10 mg/kg/day). The NOAEL for offspring growth was
300 ppm (15 mg/kg/day) and the NOAEL for reproductive effects was
greater than 400 ppm (20 mg/kg/day).
4. Subchronic toxicity. A 13-week rat feeding study was conducted
at dietary concentrations of 200, 800, and 2,000 ppm. A reduction in
body weight gain was seen in males at 800, and 2,000 ppm, and in
females at 2,000 ppm. A reduction in blood levels of glucose, protein
and/or globulin was seen in males at 800, and/or 2,000 ppm, and an
increase in urea nitrogen was seen in females at 2,000 ppm. Nephritis
was seen in males and females given 800 and 2,000 ppm and in males
given 200 ppm. The NOAEL for subchronic toxicity in rats was 200 ppm
(10 mg/kg/day) in females and less than 200 ppm in males.
5. Chronic toxicity. Carboxin was fed to Beagle dogs for 1-year at
dietary concentrations of 40, 500 and 7,500 ppm. There was a reduction
in body weight gain in female dogs at dose levels of 500 and 7,500 ppm.
At a dose level of 7,500 ppm, there was a decreased hematocrit in males
and an increase in serum alkaline phosphatase
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in males and females. The NOAEL for chronic toxicity was 1 mg/kg/day.
Carboxin was fed to Sprague Dawley rats for 2 years at dietary
concentrations of 20, 200, and 400 ppm in males, and 20, 300, and 600
ppm in females in a study completed in 1991. Survival was reduced in
high dose males and body weight gain was significantly reduced in high
dose males and females. Chronic nephritis was seen in mid and high dose
rats, and this effect was more severe in males. There was no treatment
related increase in tumor incidence in rats. The NOAEL for chronic
toxicity was 1 mg/kg/day.
Carboxin was fed to B6C3F1 mice for 18 months at dietary
concentrations of 50, 2,500, and 5,000 ppm. At dosage levels of 2,500,
and 5,000 ppm there was in increased incidence of liver hypertrophy.
There was no treatment related increase in tumor incidence.
6. Animal metabolism. In the rat metabolism study, the percentage
of dose did not exceed 0.21% in any tissue and the total percentage of
dose in all tissues was 0.26-0.40%. The majority of the dose was
excreted in the urine (about 80% within 72 hours). The predominant
metabolite was p-hydroxy carboxin sulfoxide and the other major
metabolite was 4-acetamidophenol. Unchanged carboxin was not detected
in the excreta.
7. Metabolite toxicology. Although no toxicology studies have been
conducted on carboxin metabolites per se, none of these would be
expected to have significant toxicity. The residue of concern is the
parent compound only.
8. Endocrine disruption. No specific studies have been conducted to
evaluate potential estrogenic or endocrine effects; however, the
standard battery of required studies has not demonstrated any evidence
which is suggestive of hormonal effects. Evaluation of the rat
multigenerational study demonstrated no effect on the time to mating or
on the mating and fertility indices. Chronic and subchronic toxicity
studies in rats and dogs did not demonstrate any evidence of toxicity
to the male or female reproductive tract or to any endocrine organ
associated with endocrine disruption.
C. Aggregate Exposure
1. Dietary exposure. The potential dietary exposure from food was
assessed using the conservative assumptions that all residues would be
at tolerance levels (existing tolerances and the proposed onion
tolerance) and that all the commodities would contain residues (100%
crop treated). Since onions are not a livestock feed item, the existing
tolerances for animal commodities would be adequate.
i. Food. The dietary exposure estimate was determined using the
tolerance assessment system (TAS) exposure 1 software (1977
food consumption data). The chronic RfD used in the analysis was 0.01
mg/kg/day, based on the NOAEL of 1 mg/kg/day in the rat and dog chronic
studies and a 100-fold safety factor. The calculated exposure
contribution from carboxin use on onions to the general population was
0.000021 mg/kg/day, 0.21% of the RfD. Infant exposure was 0.000008 mg/
kg/day, 0.1% of the RfD. For the population subgroup children 1-6, the
exposure contribution from carboxin was 0.000036 mg/kg/day, 0.36% of
the RfD. Total estimated dietary exposure to the general population
from the combined existing carboxin uses and the proposed use on onions
was determined as 0.001037 mg/kg/day (10.4% of the RfD). For infants
and children, the exposure was 0.002444 mg/kg/day (24.4% of the RfD)
and 0.002245 mg/kg/day (22.4% of the RfD), respectively.
ii. Drinking water. There are no established MCLs for residues of
carboxin in drinking water. Health advisory (HA) levels for carboxin in
drinking water for adults are 4 and 0.7 mg/L (longer term and life time
HA levels respectively) and 1 day, 10 day, and longer term HA levels
are all 1 mg/L for children. Seed treatment uses do not typically
require a drinking water assessment. Use of carboxin as a seed
treatment (at an application rate of one half ounce active ingredient
per acre) is not expected to impact ground water or surface waters or
result in significant human exposure. The estimated acute and chronic
DWLOC were compared to estimated maximum acute and chronic
concentrations of carboxin in surface and ground water from the
proposed onion use, as calculated using GENEEC and screning
concentration in ground water (SCI-GRO) models. These maximum estimates
were well below the DWLOC values by 2-6 orders of magnitude, indicating
carboxin would not pose a drinking water concern.
2. Non-dietary exposure. Carboxin is registered only for commercial
agricultural use, and not for homeowner use. Therefore, non-
occupational exposure to the general population from carboxin is
unlikely, and is not considered in the aggregate exposure assessments.
D. Cumulative Effects
The potential for cumulative effects of carboxin and other
substances that have a common mechanism was considered. The mammalian
toxicity of carboxin is well defined, with the kidney being identified
as target organ. However, since the biochemical mechanism of toxicity
of this compound is not known, it cannot be determined if toxic effects
produced by carboxin would be cumulative with any other chemical
compound. Thus, only the potential risk of carboxin is considered in
the aggregate exposure assessment.
E. Safety Determination
1. U.S. population. Exposure to carboxin would occur primarily from
the dietary route. Maximum theoretical levels of carboxin in drinking
water were well below drinking water levels of concern for adults and
children. Non-occupational exposure to the general population is not
expected. Because calculation of the dietary exposure used tolerance
levels for all crops and animal commodities and assumed 100% of the
crop was treated, the exposure values are considered to be
overestimates. Consideration of anticipated residues and actual percent
crop treated would likely result in a significantly lower dietary
exposure.
Chronic dietary exposure to the general U.S. population from
existing uses and the proposed onion use of carboxin was 10.4% of the
RfD. For infants and children, the exposure was 24.4% and 22.4% of the
RfD, respectively. Therefore, there is a reasonable certainty that no
harm will result from dietary exposure to carboxin residues.
2. Infants and children. The potential for carboxin to induce toxic
effects in children at a greater sensitivity than the general
population has been assessed by the rat and rabbit developmental and 2-
generation reproduction studies. There was no evidence of
embryotoxicity or teratogenicity, and no effects on reproductive
parameters as a result of carboxin exposure. The lowest NOAEL for any
developmental effect in these studies (15 mg/kg/day reduced pup growth
during lactation in the rat reproduction study) is considerably greater
than the NOAEL for systemic toxicity in rats (1 mg/kg/day for nephritis
in the rat chronic feeding study) which demonstrates that there is no
prenatal or postnatal sensitivity to carboxin. Therefore, it is
inappropriate to assume that infants and children are more sensitive
than the general population to the effects from exposure to carboxin
residues.
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F. International Tolerances
A MRL has not been established for carboxin by the Codex
Alimentarius Commission.
[FR Doc. 00-7231 Filed 3-28-00; 8:45 am]
BILLING CODE 6560-50-F