[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]


-----------------------------------------------------------------------

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.

-----------------------------------------------------------------------

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:

----------------------------------------------------------------------------------------------------------------
                                           Office location/
           Product Manager             telephone number/e-mail          Address             Petition number(s)
                                               address
----------------------------------------------------------------------------------------------------------------
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].
----------------------------------------------------------------------------------------------------------------


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

[[Page 16613]]

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.

[[Page 16614]]

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