[Federal Register Volume 69, Number 245 (Wednesday, December 22, 2004)]
[Notices]
[Pages 76724-76729]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 04-27769]


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

ENVIRONMENTAL PROTECTION AGENCY

[OPP-2004-0403; FRL-7689-6]


Pyriproxyfen: 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.

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

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 identification (ID) number OPP-
2004-0403, must be received on or before January 21, 2005.

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: Joseph Tavano, Registration Division 
(7505C), Office of Pesticide Programs, Environmental Protection Agency, 
1200 Pennsylvania Ave., NW., Washington, DC 20460-0001; telephone 
number: (703) 305-6411; e-mail address: <a href="/cdn-cgi/l/email-protection#65110413040b0a4b0f0a1600150d250015044b020a13"><span class="__cf_email__" data-cfemail="fa8e9b8c9b9495d49095899f8a92ba9f8a9bd49d958c">[email protected]</span></a>.

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this Action Apply to Me?

    You may be potentially affected by this action if you an 
agricultural producer, food manufacturer, or pesticide manufacturer. 
Potentially affected entities may include, but are not limited to:
    <bullet> Crop production (NAICS 111)
    <bullet> Animal production (NAICS 112)
    <bullet> Food manufacturing (NAICS 311)
    <bullet> Pesticide manufacturing (NAICS 32532)
    This listing is not intended to be exhaustive, but rather provides 
a guide for readers regarding entities likely to be affected by this 
action. Other types of 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 ID number OPP-2004-0403. 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 <greek-i>2, 1801 S. Bell St., Arlington, VA. This docket 
facility is open from 8:30 a.m. to 4 p.m., Monday through Friday, 
excluding legal holidays. The docket telephone number is (703) 305-
5805.
    2. Electronic access. You may access this Federal Register document 
electronically through the EPA Internet under the ``Federal Register'' 
listings at http://www.epa.gov/fedrgstr/.
    An electronic version of the public docket is available through 
EPA's electronic public docket and comment system, EPA Dockets. You may 
use EPA Dockets at http://www.epa.gov/edocket/ to submit or view public 
comments, access the index listing of the contents of the official 
public docket, and to access those documents in the public docket that 
are available electronically. Although not all docket materials may be 
available electronically, you may still access any of the publicly 
available docket materials through the docket facility identified in 
Unit I.B.1. Once in the system, select ``search,'' then key in the 
appropriate docket ID number.
    Certain types of information will not be placed in the EPA Dockets. 
Information claimed as CBI and other information whose disclosure is 
restricted by statute, which is not included in the official public 
docket, will not be available for public viewing in EPA's electronic 
public docket. EPA's policy is that copyrighted material will not be 
placed in EPA's electronic public docket but will be available only in 
printed, paper form in the official public docket. To the extent 
feasible, publicly available docket materials will be made available in 
EPA's electronic public docket. When a document is selected from the 
index list in EPA Dockets, the system will identify whether the 
document is available for viewing in EPA's electronic public docket. 
Although not all docket materials may be available electronically, you 
may still access any of the publicly available docket materials through 
the docket facility identified in Unit I.B. EPA intends to work towards 
providing electronic access to all of the publicly available docket 
materials through EPA's electronic public docket.
    For public commenters, it is important to note that EPA's policy is 
that public comments, whether submitted electronically or in paper, 
will be made available for public viewing in EPA's electronic public 
docket as EPA receives them and without change, unless the comment 
contains copyrighted material, CBI, or other information whose 
disclosure is restricted by statute. When EPA identifies a comment 
containing copyrighted material, EPA will provide a reference to that 
material in the version of the comment that is placed in EPA's 
electronic public docket. The entire printed comment, including the 
copyrighted material, will be available in the public docket.
    Public comments submitted on computer disks that are mailed or 
delivered to the docket will be transferred to EPA's electronic public 
docket. Public comments that are mailed or delivered to the docket will 
be scanned and placed in EPA's electronic public docket. Where 
practical, physical objects will be photographed, and the photograph 
will be placed in EPA's electronic public docket along with a brief 
description written by the docket staff.

C. How and to Whom Do I Submit Comments?

    You may submit comments electronically, by mail, or through hand 
delivery/courier. To ensure proper receipt by EPA, identify the 
appropriate docket ID number in the subject line on the first page of 
your comment. Please ensure that your comments are submitted within the 
specified comment period. Comments received after the close of the 
comment period will be marked ``late.'' EPA is not required to consider 
these late comments. If you wish to submit CBI or information that

[[Page 76725]]

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-2004-0403. 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 <a href="/cdn-cgi/l/email-protection#6c031c1c4108030f0709182c091c0d420b031a"><span class="__cf_email__" data-cfemail="bed1cece93dad1ddd5dbcafedbcedf90d9d1c8">[email protected]</span></a>, 
Attention: Docket ID number OPP-2004-0403. 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-2004-0403.
    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 
<greek-i>2, 1801 S. Bell St., Arlington, VA, Attention: Docket ID 
number OPP-2004-0403. Such deliveries are only accepted during the 
docket's normal hours of operation as identified in Unit I.B.1.

D. How Should I Submit CBI to the Agency?

    Do not submit information that you consider to be CBI 
electronically through EPA's electronic public docket or by e-mail. You 
may claim information that you submit to EPA as CBI by marking any part 
or all of that information as CBI (if you submit CBI on disk or CD ROM, 
mark the outside of the disk or CD ROM as CBI and then identify 
electronically within the disk or CD ROM the specific information that 
is CBI). Information so marked will not be disclosed except in 
accordance with procedures set forth in 40 CFR part 2.
    In addition to one complete version of the comment that includes 
any information claimed as CBI, a copy of the comment that does not 
contain the information claimed as CBI must be submitted for inclusion 
in the public docket and EPA's electronic public docket. If you submit 
the copy that does not contain CBI on disk or CD ROM, mark the outside 
of the disk or CD ROM clearly that it does not contain CBI. Information 
not marked as CBI will be included in the public docket and EPA's 
electronic public docket without prior notice. If you have any 
questions about CBI or the procedures for claiming CBI, please consult 
the person listed under FOR FURTHER INFORMATION CONTACT.

E. What Should I Consider as I Prepare My Comments for EPA?

    You may find the following suggestions helpful for preparing your 
comments:
    1. Explain your views as clearly as possible.
    2. Describe any assumptions that you used.
    3. Provide copies of any technical information and/or data you used 
that support your views.
    4. If you estimate potential burden or costs, explain how you 
arrived at the estimate that you provide.
    5. Provide specific examples to illustrate your concerns.
    6. Make sure to submit your comments by the deadline in this 
notice.
    7. To ensure proper receipt by EPA, be sure to identify the docket 
ID number as signed 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: December 9, 2004.
Lois Rossi,
Director, Registration Division, Office of Pesticide Programs.

Summary of Petition

    The petitioner summary of the pesticide petition is printed below 
as required by FFDCA section 408(d)(3). The summary of the petition was 
prepared by the petitioner and represents the view of the petitioner. 
The petition summary announces the availability of a description of the 
analytical methods available to EPA for the detection and measurement 
of the pesticide chemical residues or an explanation of why no such 
method is needed.

Valent U.S.A. Corporation

PP 4F6847

    EPA has received a pesticide petition 4F6847 from Valent U.S.A. 
Corporation, 1600 Riviera Ave., Suite 200, Walnut

[[Page 76726]]

Creek, California 94596-8025 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 tolerances for residues of 
pyriproxyfen, 2-[1-methyl-2-(4-phenoxyphenoxy)ethoxy]pyridine (CA), in 
or on the raw agricultural commodities (RAC) grass forage and hay (crop 
group 17). 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. Metabolism of <SUP>14</SUP>C-pyriproxyfen 
labeled in the phenoxyphenyl ring and in the pyridyl ring has been 
studied in cotton, apples, tomatoes, lactating goats, and laying hens 
(and rats). The major metabolic pathways in plants is aryl 
hydroxylation and cleavage of the ether linkage, followed by further 
metabolism into more polar products by further oxidation and/or 
conjugation reactions. However, the bulk of the radio-chemical residue 
on RAC samples remained as parent. Comparing metabolites detected and 
quantified from cotton, apple, tomato, goat and hen (and rat) shows 
that there are no significant metabolites in plants which are not also 
present in the excreta or tissues of animals. Therefore, the residue of 
concern is best defined as the parent, pyriproxyfen.
    Ruminant and poultry metabolism studies demonstrated that transfer 
of administered <SUP>14</SUP>C-residues to tissues was low. Total 
<SUP>14</SUP>C-residues in goat milk, muscle and tissues accounted for 
less than 2% of the administered dose, and were less than 1 part per 
million (ppm) in all cases. In poultry, total <SUP>14</SUP>C-residues 
in eggs, muscle and tissues accounted for about 2.7% of the 
administered dose, and were less than 1 ppm in all cases except for 
gizzard.
    2. Analytical method. Practical analytical methods for detecting 
and measuring levels of pyriproxyfen (and relevant metabolites) have 
been developed and validated in/on all appropriate agricultural 
commodities, respective processing fractions, milk, animal tissues, and 
environmental samples. The extraction methodology has been validated 
using aged radio-chemical residue samples from metabolism studies. The 
methods have been validated in cotton seed, apples, soil, and oranges 
at independent laboratories. EPA has successfully validated the 
analytical methods for analysis of cotton seed, pome fruit, nutmeats, 
almond hulls, and fruiting vegetables. The limit of detection of 
pyriproxyfen in the methods is 0.01 ppm which will allow monitoring of 
food with residues at the levels proposed for the tolerances.
    3. Magnitude of residues--i. Grass, forage, fodder, and hay. Twelve 
field trials in grass were conducted in 2002 and 2003. The analytical 
data show that the average measured residue in/on grass forage samples 
was 0.05 ppm (n = 24, [sigma]n-1 = 0.10 ppm) pyriproxyfen. Similarly, 
the analytical data show that the average measured residue in/on grass 
hay samples was 0.10 ppm (n = 24, [sigma]n-1 = 0.19 ppm). These data 
support a proposed tolerance for pyriproxyfen in/on grass forage of 0.5 
ppm and grass hay of 1.0 ppm.
    ii. Secondary residues. The proposed new use on grass represents an 
additional feed commodity. Using established and proposed tolerances to 
calculate the maximum feed exposure to feed animals, and using the very 
low potential for residue transfer demonstrated in the milk cow feeding 
residue study, detectable secondary residues in animal tissues, milk, 
and eggs are not expected. Therefore, no tolerances are required for 
these commodities.
    iii. Rotational crops. The results of a confined rotational crops 
accumulation study indicate that no rotational crop planting 
restrictions or rotational crop tolerances are required.

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 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 in HeLa 
S3 cells, in vitro gene mutation in V79 Chinese hamster cells, and in 
vitro chromosomal aberration with and without S9 in Chinese hamster 
ovary 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 multigenerational 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/kilogram/bodyweight day (mg/kg/bwt day) during 
gestation days 7-17. Maternal toxicity (mortality, decreased bwt 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 bwt 
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 two generations 
of rats. Adult systemic toxicity (reduced bwts, 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 higest 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 bwt gain; increased liver weights; 
histopathological changes in the liver and kidney; decreased red blood 
cell counts, hemoglobin and hematocrit;

[[Page 76727]]

altered blood chemistry parameters; and, at 5,000 and 10,000 ppm in 
mice, adecrease in survival rates. The NOAELs from these studies were 
400 ppm (23.5 mg/kg/bwt day for males, 27.7 mg/kg/bwt 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 four week 
inhalation study of pyriproxyfen technical in rats, decreased bwt and 
increased water consumption were observed at 1,000 mg/m<SUP>3</SUP>. 
The NOAEL in this study was 482 mg/m<SUP>3</SUP>.
    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. In a 21-day dermal study conducted with 
KNACK[reg]. Insect Growth Regulator, the test material produced a NOAEL 
of 1,000 mg/kg/bwt day HDT for systemic effects, and a NOAEL for skin 
irritation of 100 mg/kg/bwt day.
    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 cancerin test animals. 
No oncogenic response was observed in a rat 2-year chronic feeding/
oncogenicity study or in a seventy-eight 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 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 lowest observed adverse effect 
level (LOAEL) of 3,000 ppm (138 mg/kg/bwt day inmales, 182.7 mg/kg/bwt 
day in females) was established based on a depression in bwt gain in 
females.
    6. Animal metabolism. The absorption, tissue distribution, 
metabolism and excretion of <SUP>14</SUP>C-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 unlabelled material. For all dose groups, most (88-96%) of 
the administered radio-label was excreted in the urine and feces within 
2-days after radio- labeled 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 <SUP>14</SUP>C. Radio-carbon concentrations in fat were the 
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 after dosing, accounting for no more than 0.3% of the dosed 
<SUP>14</SUP>C. Because parent and metabolites are not retained in the 
body, the potentil for acute toxicity from in situ formed metabolites 
is low. The potential for chronic toxicity is adequately tested by 
chronic exposure to the parent at the maximum tolerance dose and 
consequent chronic exposure to the internally formed metabolites.
    Seven metabolites of pyriproxyfen, 4'-OH-pyriproxyfen, 5'3'-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 micro-grams 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, 5'3'-OH-
pyriproxyfen, desphenyl-pyriproxyfen, POPA, and PYPAC did not appear to 
markedly differ from pyriproxyfen, with all metabolites having acute 
oral LD<INF>50</INF> values greater than 2,000 mg/kg/bwt. The two 
pyridines, 2-OH-pyridine and 2,5-diOH-pyridine, gave acute oral 
LD<INF>50</INF> 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 other some 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. An evaluation of chronic dietary exposure to 
including both food and drinking water has been performed for the U.S. 
population and various sub-populations including infants and children. 
No acute dietary endpoint and dose was identified in the toxicology 
data base for pyriproxyfen, therefore, the Agency has concluded that 
there is a reasonable certainty of no harm from acute dietary exposure.
    i. Food. Chronic dietary exposure to pyriproxyfen residues was 
calculated for the U.S.population and 16 population subgroups assuming 
tolerance level residues, processing factors from residue studies, and 
100 percent of the crop treated (PCT). The analyses included residue 
data for all existing uses, pending uses, and proposed new uses. The 
results from

[[Page 76728]]

several representative subgroups are listed below. Chronic exposure to 
the overall U.S. population is estimated to be 0.0008 mg/kg/bwt day, 
representing 0.24% of the RfD. For the most highly exposed sub-
population, children 1 to 2 years of age, exposure is calculated to be 
0.0009 mg/kg/bwt day, or 0.26% of the RfD in the following Table 1. 
Generally speaking, the Agency has no cause for concern if total 
residue contribution for established and proposed tolerances is less 
than 100% of the RfD.

        Table 1.--Calculated Chronic Dietary Exposures to the Total U.S. Population and Selected Sub-Populations to Pyriproxyfen Residues in Food
--------------------------------------------------------------------------------------------------------------------------------------------------------
         Population Subgroup                          Exposure (mg/kg/bwt day)                                       Percent of RfD
--------------------------------------------------------------------------------------------------------------------------------------------------------
Total U.S. population                                                                  0.00083                                                      0.24
--------------------------------------------------------------------------------------------------------------------------------------------------------
Children (1-2 years)                                                                   0.00091                                                      0.26
--------------------------------------------------------------------------------------------------------------------------------------------------------
Non-nursing infants(<1 year old)                                                       0.00049                                                      0.14
--------------------------------------------------------------------------------------------------------------------------------------------------------
All infants (<1 year old)                                                              0.00051                                                      0.15
--------------------------------------------------------------------------------------------------------------------------------------------------------
Children (6-12 years)                                                                  0.00044                                                      0.13
--------------------------------------------------------------------------------------------------------------------------------------------------------
Females (13-49 years)                                                                  0.00042                                                      0.12
--------------------------------------------------------------------------------------------------------------------------------------------------------
Nursing Infants (<1 year old)                                                          0.00023                                                      0.07
--------------------------------------------------------------------------------------------------------------------------------------------------------

    ii. Drinking water. Since pyriproxyfen is applied outdoors to 
growing agricultural crops, the potential exists for pyriproxyfen or 
its metabolites to reach ground surface or surface water that may be 
used for drinking water. Because of the physical properties of 
pyriproxyfen, it is unlikely that pyriproxyfen or its metabolites can 
leach to potable ground water. To quantify potential exposure from 
drinking water, surface water concentrations for pyriproxyfen were 
estimated using generic expected environmental concentration (GENEEC). 
The peak predicted concentration in drinking water was 0.86 part per 
billion (ppb). Using standard assumptions about bwt and water 
consumption, the chronic exposure to pyriproxyfen from this drinking 
water would be 0.00009 mg/kg/day for infants, the most sensitive 
subpopulation. This represents 0.025% of the RfD (0.35 mg/kg/day) for 
infants. Based on this worse case analysis, the contribution of water 
to the dietary risk is negligible.
    2. Non-dietary exposure. Pyriproxyfen is currently registered for 
use on residential non-food sites. Pyriproxyfen is the active 
ingredient (a.i.) in numerous registered products for flea and tick 
control. Formulations include foggers, aerosol sprays, emulsifiable 
concentrates, and impregnated materials (pet collars). With the 
exception of the pet collar uses, consumer use of pyriproxyfen 
typically results in acute and short-term intermittent exposures. No 
acute dermal, or inhalation dose or endpoint was identified in the 
toxicity data for pyriproxyfen. Similarly, doses and endpoints were not 
identified for short and intermediate term dermal or inhalation 
exposure to pyriproxyfen. The Agency has concluded that there are 
reasonable certainties of no harm from acute, short term, and 
intermediate term dermal and inhalation occupational and residential 
exposures due to the lack of significant toxicological effects 
observed.
    Chronic residential post-application exposure and risk assessments 
were conducted to estimate the potential risks from pet collar uses. 
The risk assessment was conducted using the following assumptions: 
Application rate of 0.58 mg/a.i. day (product label), average bwt for a 
1-6 year old child of 10 kg, the a.i. dissipates uniformly through 365 
days (the label instruct to change collar once a year), 1% of the a.i. 
is available for dermal and inhalation exposure per day (assumption 
from Draft EPA Standard Operating Procedures (SOPs) for Residential 
Exposure Assessments, December 18, 1997). The assessment also assumes 
an absorption rate of 100%. This is a conservative assumption since the 
dermal absorption was estimated to be 10%. The estimated chronic term 
margin of exposure (MOE) was 61,000 for children, and 430,000 for 
adults. The risk estimates indicate that potential risks from pet 
collar uses do not exceed the Agency's level of concern.

D. Cumulative Effects

    Section 408(b)(2)(D)(v) requires that the Agency must consider 
``available information'' concerning the cumulative effects of a 
particular pesticide's residues and ``other substances that have a 
common mechanism of toxicity.'' Available information in this context 
include not only toxicity, chemistry, and exposure data, but also 
scientific policies and methodologies for understanding common 
mechanisms of toxicity and conducting cumulative risk assessments. For 
most pesticides, although the Agency has some information in its files 
that may turn out to be helpful in eventually determining whether a 
pesticide shares a common mechanism of toxicity with any other 
substances, EPA does not at this time have the methodologies to resolve 
the complex scientific issues concerning common mechanism of toxicity 
in a meaningful way.
    There are no other pesticidal compounds that are structurally 
related

[[Page 76729]]

to pyriproxyfen and have similar effects on animals. In consideration 
of potential cumulative effects of pyriproxyfen and other substances 
that may have a common mechanism of toxicity, there are currently no 
available data or other reliable information indicating that any toxic 
effects produced by pyriproxyfen would be cumulative with those of 
other chemical compounds. Thus, only the potential risks of 
pyriproxyfen have been considered in this assessment of aggregate 
exposure and effects.
    Valent will submit information for EPA to consider concerning 
potential cumulative effects of pyriproxyfen consistent with the 
schedule established by EPA Federal Register of August 4, 1997 (62 FR 
42020) (FRL-5734-6) and other subsequent EPA publications pursuant to 
the Food Quality Protection Act(FQPA).

E. Safety Determination

    1. U.S. population--i. Chronic dietary exposure and risk s adult 
sub-populations. The results of the chronic dietary exposure assessment 
described above demonstrate that estimates of chronic dietary exposure 
for all existing, pending and proposed uses of pyriproxyfen are well 
below the chronic RfD of 0.35 mg/kg/bwt day. The estimated chronic 
dietary exposure from food for the overall U.S. population and many 
non-child/infant subgroups is from 0.00014 to 0.00042 mg/kg/bwt day, 
0.04 to 0.12% of the RfD. Addition of the small but worse case 
potential chronic exposure from drinking water (calculated above) 
increases exposure by only 0.00002 mg/kg/bwt day and does not change 
the maximum occupancy of the RfD significantly. Generally, the Agency 
has no cause for concern if total residue contribution is less than 
100% of the RfD. It can be concluded that there is a reasonable 
certainty that no harm will result to the overall U.S. population or 
any non-child/infant subgroups from aggregate, chronic dietary exposure 
to pyriproxyfen residues.
    ii. Acute dietary exposure and risk s adult sub-populations. No 
acute dietary endpoint and dose were identified in the toxicology data 
base for pyriproxyfen; therefore, it can be concluded that there is a 
reasonable certainty that no harm will result to the overall U.S. 
Population or any non-child/infant subgroups from aggregate, acute 
dietary exposure to pyriproxyfen residues.
    iii. Non-dietary exposure and aggregate risk s adult sub-
populations. Acute, short term,and intermediate term dermal and 
inhalation risk assessments for residential exposure are not required 
due to the lack of significant toxicological effects observed. The 
results of a chronic residential post-application exposure and risk 
assessment for pet collar uses demonstrate that potential risks from 
pet collar uses do not exceed the Agency's level of concern. The 
estimated chronic term MOE for adults was 430,000.
    2. Infants and children--i. Safety factor for infants and children. 
In assessing the potential for additional sensitivity of infants and 
children to residues of pyriproxyfen, FFDCA section 408 provides that 
EPA shall apply an additional margin of safety, up to ten-fold, for 
added protection for infants and children in the case of threshold 
effects unless EPA determines that a different margin of safety will be 
safe for infants and children.
    The toxicological data base for evaluating prenatal and postnatal 
toxicity for pyriproxyfen is complete with respect to current data 
requirements. There are no special prenatal or postnatal toxicity 
concerns for infants and children, based on the results of the rat and 
rabbit developmental toxicity studies or the 2-generation reproductive 
toxicity study in rats. Valent concludes that reliable data support use 
of the standard 100-fold uncertainty factor and that an additional 
uncertainty factor is not needed for pyriproxyfen to be further 
protective of infants and children.
    ii. Chronic dietary exposure and risks infants and children. Using 
the conservative exposure assumptions described above, the percentage 
of the RfD that will be utilized by chronic dietary (food only) 
exposure to residues of pyriproxyfen ranges from 0.00023 mg/kg/bwt day 
for nursing infants, up to 0.00091 mg/kg/bwt day for children (1 to 2 
years of age), 0.07 to 0.26% of the RfD, respectively. Adding the worse 
case potential incremental exposure to infants and children from 
pyriproxyfen in drinking water (0.00009 mg/kg/bwt day) does not 
materially increase the aggregate, chronic dietary exposure and only 
increases the occupancy of the RfD by 0.009% to 0.010% for children (1 
to 2 years of age). EPA generally has no concern for exposures below 
100% of the RfD because the RfD represents the level at or below which 
daily aggregate dietary exposure over a lifetime will not pose 
appreciable risks to human health. It can be concluded that there is a 
reasonable certainty that no harm will result to infants and children 
from aggregate, chronic dietary exposure to pyriproxyfen residues.
    iii. Acute dietary exposure and risk s infants and children.No 
acute dietary endpoint and dose were identified in the toxicology data 
base for pyriproxyfen; therefore, it can be concluded that there is a 
reasonable certainty that no harm will result to infants and children 
from aggregate, acute dietary exposure to pyriproxyfen residues.
    iv. Non-dietary exposure and aggregate risk s infants and children. 
Acute, short term, and intermediate term dermal and inhalation risk 
assessments for residential exposure are not required due to the lack 
of significant toxicological effects observed. The results of a chronic 
residential post-application exposure and risk assessment for pet 
collar uses demonstrate that potential risks from pet collar uses do 
not exceed the Agency's level of concern. The estimated chronic term 
MOE for children was 61,000.

F. International Tolerances

    There are no presently existing Codex MRLs for pyriproxyfen.
[FR Doc. 04-27769 Filed 12-21-04; 8:45 am]
BILLING CODE 6560-50-S


</pre><script data-cfasync="false" src="/cdn-cgi/scripts/5c5dd728/cloudflare-static/email-decode.min.js"></script></body>
</html>