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Pyriproxyfen - Pesticide Petition Filing for Food Commodities 3/98

[Notices]
[Page 14926-14936]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr27mr98-78]

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ENVIRONMENTAL PROTECTION AGENCY

[PF-799; FRL-5579-6]

Notice of Filing of Pesticide Petitions

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 the docket control number PF-799, must
be received on or before April 27, 1998.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch, Information Resources and Services Division
(7506C), Office of Pesticides Programs, Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments
to: Rm. 1132, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
    Comments and data may also be submitted electronically by following
the instructions under "SUPPLEMENTARY INFORMATION." No confidential
business information should be submitted through e-mail.

    Information submitted as a comment concerning this document may be
claimed confidential by marking any part or all of that information as
"Confidential Business Information" (CBI). CBI should not be
submitted through e-mail. Information marked as CBI will not be
disclosed except in accordance with procedures set forth in 40 CFR part
2. A copy of the comment that does not contain CBI must be submitted
for inclusion in the public record. Information not marked confidential
may be disclosed publicly by EPA without prior notice. All written
comments will be available for public inspection in Rm. 1132 at the
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.

FOR FURTHER INFORMATION CONTACT: The product reviewer listed in the
table below:

------------------------------------------------------------------------
                                   Office location/
        Product Manager            telephone number          Address
------------------------------------------------------------------------
Ann Sibold....................  Rm. 212, CM #2, 703-    1921 Jefferson
                                 305-6502, e-            Davis Hwy,
                                 mail:sibold.ann@epama   Arlington, VA
                                 il.epa.gov.
Joseph M. Tavano..............  Rm. 214, CM #2, 703-    Do.
                                 305-6411, e-mail:
                                 tavano.joseph@epamail
                                 .epa.gov.
------------------------------------------------------------------------

SUPPLEMENTARY INFORMATION: 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.
    The official record for this notice of filing, as well as the
public version, has been established for this notice of filing under
docket control number [PF-799] (including comments and data submitted
electronically as described below). A public version of this record,
including printed, paper versions of electronic comments, which does
not include any information claimed as CBI, is available for inspection
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal
holidays. The official record is located at the address in
"ADDRESSES" at the beginning of this document.
    Electronic comments can be sent directly to EPA at:
    opp-docket@epamail.epa.gov

    Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption. Comment and data
will also be accepted on disks in

[[Page 14927]]

Wordperfect 5.1 file format or ASCII file format. All comments and data
in electronic form must be identified by the docket number (insert
docket number) and appropriate petition number. Electronic comments on
notice may be filed online at many Federal Depository Libraries.

List of Subjects

    Environmental protection, Agricultural commodities, Food additives,
Feed additives, Pesticides and pests, Reporting and recordkeeping
requirements.

    Dated: March 19, 1998

Peter Caulkins,

Acting 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. EPA is publishing the petition summaries verbatim
without editing them in any way. 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.

3. Valent U.S.A. Corporation

PP 7F4882

    EPA has received a pesticide petition (PP 7F4882) from Valent
U.S.A. Corporation, 1333 N. California Blvd., Walnut Creek, CA 94596.
proposing pursuant to section 408(d) of the Federal Food, Drug and
Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR part 180 by
establishing a tolerance for residues pyriproxyfen, 2-[ 1-methyl-2-(4-
phenoxyphenoxy)ethoxy]pyridine in or on the raw agricultural commodity
Pome Fruits(Crop Group 11, including apples and pears) at 0.2 (ppm),
Walnuts at 0.02 ppm, and Apple Pomace,wet at 0.8 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 nature of the residues in cotton, apples,
and animals is adequately understood. Metabolism of 14C-pyriproxyfen
labelled in the phenoxyphenyl ring and in the pyridyl ring was studied
in cotton, apples, lactating goats, and laying hens (and rats). The
nature of the residue is defined by the metabolism studies primarily as
pyriproxyfen. The major metabolic pathways in plants is hydroxylation
and cleavage of the ether linkage, followed by further metabolism into
more polar products by oxidation or conjugation reactions, however, the
bulk of the radiochemical residues was parent. Comparing metabolites
from cotton, apple, 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.
    Ruminant and poultry metabolism studies demonstrated that transfer
of administered 14C residues to tissues was low. Total 14C residues in
goat milk, muscle and tissues accounted for less than 2% of the
administered dose, and were less than 1 ppm in all cases. In poultry,
total 14C 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 for the raw agricultural commodities,
their respective processing fractions, and animal tissues. The methods
have been independently validated in cottonseed and apples (and
oranges) and the extraction methodology has been validated using aged
radiochemical residue samples from metabolism studies. EPA has(personal
communication) successfully validated the analytical method for
analysis of cottonseed raw agricultural commodity. The limit of
detection of pyriproxyfen in the methods is 0.01 ppm which will allow
monitoring of food with residues at or above the levels set for the
proposed tolerance.
    3. Magnitude of residues--i. Apples. A total of fifteen trials were
conducted in 1994, 1995, and 1996 to determine the magnitude of the
residue in apples and apple processing commodities from regions
representing approximately 97% of the commercial U.S. apple acreage.
The mean residue of pyriproxyfen found in these samples was 0.091 ppm
with a standard deviation (<greek-d>, n-1 degrees of freedom) of 0.035
ppm and a maximum residue of 0.18 ppm. Apples from two sites were
processed into juice and wet pomace. The results from the processing
samples show that pyriproxyfen was substantially retained with the wet
pomace fraction, resulting in a 5 x concentration in this fraction. The
average processing concentration factor for pyriproxyfen from fruit
into apple pomace, wet, was 4.89 x. No residues of pyriproxyfen above
the 0.01 LOD was detected in the juice fractions.
    ii. Pears. A total of eight trials were conducted in 1994, 1995,
and 1996 to determine the magnitude of the residue of pyriproxyfen in
pears from regions representing approximately 95% of the commercial
U.S. pear acreage. The mean residue of pyriproxyfen found in these
samples was 0.039 ppm with a standard deviation (<greek-d>, n-1 degrees
of freedom) of 0.016 ppm and a maximum residue of 0.07 ppm.
    iii. Walnuts. A total of 4 trials were conducted in 1996 to
determine the magnitude of the residue of pyriproxyfen in walnut
nutmeats all in region x where 98% of the commercial walnut acreage is
located. No residues of pyriproxyfen above the 0.01 ppm limit of
detection were found in any walnut nutmeat collected for this study.
    4. Secondary residues. Since low residues were detected in animal
feed items (cotton gin byproducts, apple pomace, wet) and animal
metabolism studies do not show potential for significant residue
transfer, detectable secondary residues in animal tissues, milk, and
eggs are not expected. Therefore, tolerances are not needed for these
commodities.

B. Toxicological Profile

    1. Acute toxicity. The acute toxicity of technical grade
pyriproxyfen is low by all routes, 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.

[[Page 14933]]

    2. Genotoxicty. 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 toxicant. In the rat teratology study, maternal toxicity
was observed at doses of 300 mg/kg/day and greater, the NOEL for
prenatal developmental toxicity was 100 mg/kg/day. A rabbit teratology
study resulted in a maternal NOEL of 100 mg/kg/day, with no
developmental effects observed in the rabbit fetuses.
    In the study conducted with rats, technical pyriproxyfen was
administered by gavage at levels of 0, 100, 300, and 1,000 mg/kg/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/day and greater. The maternal NOEL
was 100 mg/kg/day. A transient increase in skeletal variations was
observed in rat fetuses exposed to 300 mg/kg/day and greater. These
effects were not present in animals examined at the end of the
postnatal period, therefore, the NOEL for prenatal developmental
toxicity was 100 mg/kg/day. An increased incidence of visceral and
skeletal variations was observed postnatally at 1,000 mg/kg/day. The
NOEL for postnatal developmental toxicity was 300 mg/kg/day. In the
study conducted with rabbits, technical pyriproxyfen was administered
by gavage at levels of 0, 100, 300, and 1,000 mg/kg/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/day or higher. The maternal NOEL was 100 mg/kg/day. No
developmental effects were observed in the rabbit fetuses. The NOEL for
developmental toxicity in rabbits was 1,000 mg/kg/day.
    Pyriproxyfen is not a reproductive toxicant. 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/day in males, 498 mg/kg/
day in females during the pre-mating period). The systemic NOEL was
1,000 ppm (87 mg/kg/day in males, 96 mg/kg/day in females). No effects
on reproduction were produced even at 5,000 ppm, the highest dose
tested.
    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 NOELs from these studies were 400 ppm (23.5 mg/kg/
day for males, 27.7 mg/kg/day for females) in rats, 1,000 ppm (149.4
mg/kg/day for males, 196.5 mg/kg/day for females) in mice, and 100 mg/
kg/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 NOEL 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/day, the highest dose tested. In a 21-day dermal study conducted
with KNACK Insect Growth Regulator the test material produced a NOEL of
1,000 mg/kg/day (highest dose tested) for systemic effects, and a NOEL
for skin irritation of 100 mg/kg/day.
    5. Chronic toxicity. Pyriproxyfen technical has been tested in
chronic studies with dogs, rats and mice.
    Pyriproxyfen technical was administered to dogs in capsules at
doses of 0, 30, 100, 300 and 1,000 mg/kg/day for 1-year. Dogs exposed
to dose levels of 300 mg/kg/day or higher showed overt clinical signs
of toxicity, elevated levels of blood enzymes and liver damage. The
NOEL in this study was 100 mg/kg/day.
    Pyriproxyfen technical was administered to mice at doses of 0, 120,
600 and 3,000 ppm in diet for 78-weeks. The NOEL for systemic effects
in this study was 600 ppm (84 mg/kg/day in males, 109.5 mg/kg/day in
females), and a LOEL of 3,000 ppm (420 mg/kg/day in males, 547 mg/kg/
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 NOEL for
systemic effects in this study was 600 ppm (27.31 mg/kg/day in males,
35.1 mg/kg/day in females). A LOEL of 3,000 ppm (138 mg/kg/day in
males, 182.7 mg/kg/day in females) was established based on a
depression in body weight gain in females.
    EPA has established a RfD for pyriproxyfen of 0.35 mg/kg/day, based
on the rat 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 show
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/
oncogenicitystudy or in a 78-week study on mice.
    Pyriproxyfen's oncogenicity classification is "E" (no evidence of
carcinogenicity for humans).
    6. Animal metabolism. The mammalian metabolism of pyriproxyfen is
understood. 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 (phenoxyphenyl and pyridyl label), and
after a single oral dose of 2 mg/kg (phenoxyphenyl label only)
following 14 daily oral doses at 2 mg/kg of unlabelled material.
    Both the phenoxyphenyl-label and pyridyl-label studies exhibited
very similar results. 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. 7-days after dosing,
tissue residues were generally low, accounting for no more than 0.3% of
the dosed 14**C. 14**C concentrations in fat were the
highest in tissues analyzed. Recovery in tissues over time indicates
that the potential for bioaccumulation is minimal. There are no
significant sex or dose-related differences in excretion or metabolism.
    7. Endocrine disruption. Pyriproxyfen is specifically designed to
be an insect growth regulator and is known to produce juvenile hormone-
mediated effects in arthropods. However, this mechanism-of-action in
target insects has no relevance to the 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. The results of these studies show no

[[Page 14934]]

evidence of any endocrine-mediated effects and no pathology of the
endocrine organs. Consequently, it is concluded that Sumilarv does not
possess estrogenic or endocrine disrupting properties applicable to
mammals.

C. Aggregate Exposure

    1. Dietary exposure. A chronic dietary exposure and risk assessment
based on anticipated residues from samples from field residue studies
was performed in cotton, apple, pear, and walnut and assumed that 100%
of the crops were treated. The exposure analysis also reflected the
contribution of meat and milk residues, without regard to
detectability, based on commodities used for feed containing residues
at anticipated residue levels.
    Using mean anticipated residue values and 100% of the crop treated,
exposure to the U.S. population - 48 States - all seasons is calculated
to be only 0.000049 mg/kg body-wt/day. The most exposed sub-population,
non-nursing infants (<1-year), is calculated to be 0.000273 mg/kg bwt./
day. These calculated exposures represent, respectively, 0.014, and
0.078 percent occupancy of the RfD of 0.35 mg/kg body-wt/day. Chronic
dietary risk from exposure to pyriproxyfen residues on the proposed
crops may be characterized as negligible.
    2. Drinking water. Since pyriproxyfen is to be applied outdoors to
growing agricultural crops, the potential exists for the parent or its
metabolites to reach ground or surface water that may be used for
drinking water.
    3. Ground water. Pyriproxyfen is extremely insoluble in water
(0.367 mg/L at 25 deg., with high octanol/water partitioning constant
(Log P O/W = 5.37 at 25 deg., and relatively short soil half-life
(aerobic soil metabolism T \1/2\ = 6 to 9 days). Given the low use
rates, the immobility of the parent and the instability of the soil
metabolites in soil, it is very unlikely that pyriproxyfen or its
metabolites could leach to and contaminate potable groundwater.
    4. Surface water. In connection with the potential for dietary
exposure from surface potable water, a simulation of expected exposure
concentration (EEC) values in aquatic systems has been performed using
the Pesticide Root Zone Model (PRZM-3) and the Exposure Analysis
Modeling System, version 2.97 (EXAMSII). The simulation was designed to
approximate as closely as possible the conditions associated with the
high rate proposed use on tree crops. The results of the
modelingdemonstrate that the maximum upper tenth percentile
concentrations modeled in water adjacent to treated fields are
instantaneous, 0.36 ppb; 96-hour, 0.23 ppb; and 21-day, 0.14 ppb.
    To obtain a very conservative estimate of a possible dietary
exposure from drinking water, it could be assumed that all water
consumed contains pyriproxyfen at the maximum upper tenth percentile
concentrations modeled in aquatic systems adjacent to treated orchards.
The 21-day concentration, 0.14 ppb (0.00014 mg/kg), is used because
drinking water is considered to be a chronic exposure, and there are no
identified acute or short term endpoints of concern. Using standard
assumptions of body weight and water consumption (adult 70 kg, 2 kg
water per day; child 10 kg, 1 kg water), the highest possible exposure
would be 4.0 x 10-6 and 1.4 x 10-5 mg/kg bwt./day for the adult and
child, respectively. This very small, but probably exaggerated,
exposure would occupy 0.00114 (adult) and 0.004 (child) percent of the
chronic reference dose of 0.35 mg/kg body-wt/day.
    5. Non-dietary exposure. Pyriproxyfen has numerous registered
products for household use primarily of indoor, non-food applications
by consumers. The consumer uses of pyriproxyfen typically do not
involve chronic exposure. Instead, consumers are exposed intermittently
to a particular product (e.g., pet care pump spray) containing
pyriproxyfen. Since the pharmacokinetics of pyriproxyfen indicate a
relatively short elimination half-life, cumulative toxicological
effects resulting from bioaccumulation are not plausible following
these short-term, intermittent exposures. Further, pyriproxyfen is very
short-lived in the environment and this indoor domestic use of
pyriproxyfen may provide only relatively short-term reservoirs.
    The most relevant exposure for non-dietary exposure assessment is
short-term to intermediate average daily exposure estimates. The non-
dietary exposure assessment for pyriproxyfen conservatively focuses on
upper-bound estimates of potential applicator (adult) and post-
application (adult and child - less than 1-year old) exposures on the
day of application. Subsequent days present no applicator exposure, and
a decreasing contribution to short-term total exposure.
    The assessment presented herein estimates exposures for selected
consumer uses that are considered representative, plausible, and
reasonable worst case exposure scenarios. The scenarios selected
include:
    (i) Potential exposures associated with adult application (dermal
and inhalation exposures) and post-application (adult and child
inhalation exposures) of pyriproxyfen-containing pet care products; and
    (ii) Potential adult application exposures (dermal and inhalation),
and adult (inhalation) and child exposures (inhalation, dermal,
incidental oral ingestion associated with hand-to-mouth behavior) post-
application exposures associated with consumer use of a carpet spray
product.
    Using a combination of representative information from the PHED
data base for applicators (adult), and surrogate data from a study of
exposure to indoor broadcast applications (post-application adult and
child) a series of adsorbed dose estimates were calculated for adult
applicators, and post-application exposures to adults and children by
dermal, inhalation, and (hand-to-mouth) oral routes. The methodology,
assumptions, and estimates are presented in detail in the full FQPA
exposure analysis, the table below presents the results.

Summary of Estimated Human Application and Post-Application Exposures Associated
With Use of Pet Spray and Carpet Spray Products Containing Pyriproxyfen
as the Active Ingredient
--------------------------------------------------------------------------------------------------------------
                                                                     Daily Dose (mg/kg bw/day)
Product           Population     Timing of Exposure ----------------------------------------------------------
                                                      Inhalation\1\   Dermal\2\     Oral\1\        Total
--------------------------------------------------------------------------------------------------------------
Pet Spray..... Adults..........  Application........  4.3 x 10**-6        0.085     **3NA          0.085
                                 Post-Application...  1.8 x 10**-5           NA      NA          1.8 x 10**-5
                                 TOTAL..............  2.2 x 10**-5        0.085      NA            0.085
               Children........  Post-Application...  3.7 x 10**-5           NA      NA          3.7 x 10**-5
Carpet Spray.. Adults..........  Application........  1.3 x 10**-6   5.1 x 10**-4    NA          5.1 x 10**-4
                                 Post-Application...  5.4 x 10**-6           NA      NA          5.4 x 10**-6

[[Page 14935]]

                                 TOTAL..............  6.7 x 10**-6   5.1 x 10**-4    NA          5.2 x 10**-4
               Crawling Infant.  Post-Application...  1.5 x 10**-5   1.3 x 10**-3  2.1 x 10**-4  1.5 x 10**-3
--------------------------------------------------------------------------------------------------------------
\1\ 100 % adsorption.
\2\ Conservatively assumes a dermal absorption factor of 50%.
\3\ Exposure pathway not applicable.

    It is important to emphasize that the exposures summarized in the
table are based on conservative assumptions and surrogate data.
Further, the exposures are calculated for the day of application.
Subsequent daily exposures would be less as pyriproxyfen is adsorbed
into substrate, or dissipates and becomes unavailable by other
mechanisms. Exposures to applicators on non-application days would be
zero.
    Further, the Agency has not identified acute or short term toxicity
endpoints of concern. Endpoints that could be considered for short term
and intermediate exposures include a developmental toxicity no observed
effect level (NOEL) of 100 mg/kg/day (rat and rabbit), a rat 21-day
dermal systemic NOEL of 1,000 mg/kg/day (technical grade and end-use
products), a 4-week rat inhalation toxicity NOEL of 482 mg/m3, and a
90-day rat oral toxicity NOEL of 23.5 mg/kg/day. There are no dermal
absorption data for pyriproxyfen. The 1-day exposure calculated for the
applicator of the pet spray (0.085 mg/kg/day) is 57-times larger than
the next highest calculated exposure which is the total exposure to a
crawling infant on the day of application of the carpet spray (1.5 x
10-3 mg/kg/day). Furthermore, the return frequency is much different.
Label instructions allow treatment of the dog every 14-days during the
flea season, while the carpet can be treated only each 120-days. The 1-
day exposure can be compared to the smallest short term endpoint, that
from the 90-day rat oral toxicity NOEL of 23.5 mg/kg/day, and a Margin
of Exposure (MOE) can be calculated. This compares an acute exposure to
a sub-chronic endpoint.
    MOE = Toxicity Endpoint (mg/kg/day) / Daily Short Term
Exposure (mg/kg/day)
    MOEPet Spray Applicator, One day = 276
    Probably more realistic, a short term daily exposure to the adult

applicator can be calculated and compared to the same endpoint.
    Daily Exposure (mg/kg/day) = Applicator Exposure (mg/kg/day)
/ Frequency (days)
    MOEPet Spray Applicator = 3900
    Based on the available toxicity data and the conservative exposure
assumptions, and because infants and children are not applicators in
the household, the smallest acute and short term MOE value for children
is based on post-application exposures. The day of application exposure
to a crawling infant is the sum of inhalation, dermal adsorption, and
oral (hand to mouth) exposures. Subsequent daily exposures are not
quantified, but because of dissipation of the active ingredient in the
home environment but must be smaller than on the day of application.
    MOECarpet Spray, Crawling Infant = 15,700
    There is usually no cause for concern if margins of exposure exceed
100. All other margins of exposure that can be calculated from the non-
occupational, non-dietary exposures summarized in the table above are
considerably larger than that for the pet spray applicator and (post
carpet spray application) crawling infant.
     Summary of Aggregate Non-Occupational Exposures. Aggregate
exposure is defined as the sum all non-occupational exposures to the
general U.S. population and relevant sub-populations to the single
active ingredient, pyriproxyfen. These exposures can be classified as
acute, short term, and chronic.
    Acute and Short Term Non-Occupational Potential acute and short
term non-occupational exposures to pyriproxyfen are associated with
household uses -- applicator, bystander, and post-application
exposures. For preliminary risk analysis, these exposures, oftentimes
calculated using conservative assumptions and surrogate data, are
compared to appropriate acute and short term toxicity endpoints to
yield margins of exposure (MOE). In general, if exposure estimates are
conservative and the resulting MOE values are greater than 100, the
Agency is not concerned. In contrast, if conservative MOE values are
less than 100, then more refined exposure estimates and/or exposure
mitigation are required.
    The Agency has not identified acute or short term toxicity
endpoints of concern for pyriproxyfen. Valent has identified the 90-day
rat oral toxicity with a NOEL of 23.5 mg/kg/day as the short term study
with the lowest exposure endpoint. Comparing this endpoint with the
short term non-occupational exposures calculated for the household uses
of pyriproxyfen gives MOE values all much larger than 100. These acute
and short term exposures are small enough to be of little significance.

C. Chronic Exposures

    Potential chronic exposures to pyriproxyfen are considered to be
derived from dietary exposures to primary and secondary residues in
food, and to potential residues in drinking water. To calculate the
total potential chronic exposure from food and drinking water, the
calculated exposures from both media can be summed. To assess risk
these totals can then be compared to the chronic RfD.

 Summation of the Calculated Potential Chronic Exposure to Pyriproxyfen in Food
 and Drinking Water and Percent Occupancy of the RfD for Two U.S. Populations
----------------------------------------------------------------------------------
                                                 General
 Medium(mg/kg body-wt/day)         Population(adult)      Non-NursingInfant ( 1)
----------------------------------------------------------------------------------
Food...............................   0.000049                 0.000273
Drinking Water.....................   0.000004                 0.000014

[[Page 14936]]

Total..............................   0.000053                 0.000287
%RfD(0.35 mg/kg body-wt/day).......      0.015                    0.082
----------------------------------------------------------------------------------

    If the occupancy of the RfD is less than 100%, the Agency usually
has little cause for concern. From the table above, it can be seen that
the total potential chronic exposure to pyriproxyfen is truly
insignificant, and should not be cause for concern.

D. Cumulative Effects

    Valent has considered the potential for cumulative exposure to
substances with a common mechanism of toxicity to pyriproxyfen.
However, a cumulative exposure assessment is not appropriate at this
time because there is no available information to indicate that the
effects of pyriproxyfen would be cumulative with those of any other
chemical compound. Therefore, Valent is considering only the potential
risk of pyriproxyfen in its aggregate exposure assessment.

E. Safety Determination

    1. U.S. population. Based on a complete and reliable toxicity
database, EPA has established an RfD value of 0.35 mg/kg bwt./day using
the NOEL from the chronic rat feeding study and a 100-fold uncertainty
factor. The aggregate chronic exposure to pyriproxyfen will utilize
less than 0.1% of the RfD for the U.S. population. Because estimated
exposures are far below 100 percent of the RfD, Valent concludes that
there is a reasonable certainty that no harm will result from aggregate
exposure to pyriproxyfen residues.
    2. Infants and children. Using the same conservative exposure
assumptions as for the general population, the percent of the RfD
utilized by aggregate chronic exposure to residues of pyriproxyfen is
0.082% for non-nursing infants, the most highly exposed population
subgroup. Valent concludes that there is a reasonable certainty that no
harm will result to infants and children from aggregate exposure to
residues of pyriproxyfen.

F. International Tolerances

     There are presently no Codex maximum residue levels established
for residues of pyriproxyfen on any crop.

[FR Doc. 98-8065 Filed 3-26-98; 8:45 am]
BILLING CODE 6560-50-F