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Pyriproxyfen - Pesticide Petition Filing for Agricultural Commodities 3/98

[Notices]
[Page 11240-11252]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr06mr98-78]

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ENVIRONMENTAL PROTECTION AGENCY

[PF-798; FRL-5777-5]

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 agricultural commodities.

DATES: Comments, identified by the docket control number PF-798, must
be received on or before April 6, 1998.

ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch, Information Resources and Services Divison
(7502C), Office of Pesticides Programs, Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments
to: Rm. 119, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
    Comments and data may also be submitted electronically to: opp-
docket@epamail.epa.gov. 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. 119 at the
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.

FOR FURTHER INFORMATION CONTACT: By mail: Joseph Tavano, Product
Manager (PM) 10, Registration Division, (7505C), Office of Pesticide
Programs, Environmental Protection Agency, 401 M St., SW., Washington,
DC 20460. Office location, telephone number, and e-mail address: Rm.
214, CM#2, 1921 Jefferson Davis Hwy., Arlington, VA. 22202, (703) 305-
6411; e-mail: tavano.joe@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 raw
agricultural 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 grantinig of the petition. Additional data may be needed
before EPA rules on the petition.
    The official record for this notice, as well as the public version,
has been established for this notice of filing under docket control
number PF-798 (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,

[[Page 11241]]

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 Wordperfect 5.1/6.1 file format or
ASCII file format. All comments and data in electronic form must be
identified by the docket control number PF-798 and appropriate petition
number. Electronic comments on this notice may be filed online at many
Federal Depository Libraries.
    Authority: 21 U.S.C. 346a.

List of Subjects

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

    Dated: March 2, 1998.

Peter Caulkins,

Acting Director, Registration Division, Office of Pesticide Programs.

Summaries of Petitions

    Below summaries of the pesticide petitions are printed. The
summaries of the petitions were prepared by 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.

3. Valent U.S.A. Corporation

PP 6F4737

    EPA has received a pesticide petition (PP 6F4737) 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 of pyriproxyfen, 2-[ 1-methyl-2-
(4-phenoxyphenoxy) ethoxy) ethoxy] pyridine in or on the raw
agricultural commodity cottonseed at 0.05 ppm and cotton gin byproducts
at 2.0 ppm. EPA has determined that the petition contains data or
information regarding

[[Page 11247]]

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--Nature of the residues in food, feed and
secondary residues. The residue of concern is best defined as the
parent, pyriproxyfen.
    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 residue 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-- Pyriproxyfen and metabolites. Practical
analytical methods for detecting and measuring levels of pyriproxyfen
(and relevant metabolites) have been developed and validated in cotton
raw agricultural commodities, respective processing fractions, animal
tissues, and environmental samples. The methods have been independently
validated in cottonseed, apples, soil, and oranges and the extraction
methodology has been validated using aged radiochemical residue samples
from metabolism studies. EPA has successfully validated the analytical
method for analysis of cottonseed raw agricultural commodity (personal
communication). 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 proposed for the tolerances.
    3. Magnitude of residues-- i. Cotton. Data from fifteen field
trials in cotton conducted in 1994 and 1995, showed that mean
pyriproxyfen residues from duplicate samples were <0.01 - 0.04 ppm in
cottonseed, and 0.35 - 2.3 ppm in gin trash, following two or three
treatments totaling 80 grams active ingredient per acre at 14 day
intervals with a 28 day pre-harvest interval. The seasonal use rate
tested in the residue trials was approximately 2.6 times the maximum
seasonal use rate presently proposed for cotton in the pending
KNACK® Insect Growth Regulator label. No concentration of
residues was observed from processing cottonseed treated with an 12.8 x
application rate into hulls, meal, crude oil or refined oil.
    ii. Secondary residues. Since low residues were detected in cotton
derived animal feed items and since 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.
    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 mg/kg bw/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 body
weight/day (bw/day) and greater. The maternal NOEL was 100 mg/kg bw/
day. A transient increase in skeletal variations was observed in rat
fetuses from females exposed to 300 mg/kg bw/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 bw/day. An increased incidence of visceral and
skeletal variations was observed postnatally at 1,000 mg/kg bw/day. The
NOEL for postnatal developmental toxicity was 300 mg/kg bw/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 bw/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 bw/day or higher.
The maternal NOEL was 100 mg/kg bw/day. No developmental effects were
observed in the rabbit fetuses. The NOEL for developmental toxicity in
rabbits was 1,000 mg/kg bw/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 body weights, liver and
kidney histopathology, and increased liver weight) was produced at the
5,000 ppm dose (453 mg/kg bw/day in males, 498 mg/kg bw/day in females
during the pre-mating period). The systemic NOEL was 1,000 ppm (87 mg/
kg bw/day in males, 96 mg/kg bw/day in females). No effects on
reproduction were produced at 5,000 ppm, the 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 NOELs from these studies were 400 ppm (23.5 mg/kg
bw/day for males, 27.7 mg/kg bw/day for females) in rats, 1,000 ppm
(149.4 mg/kg bw/day for males, 196.5

[[Page 11248]]

mg/kg bw/day for females) in mice, and 100 mg/kg bw/day in dogs.
    In a four week inhalation study of pyriproxyfen technical in rats,
decreased body weight and increased water consumption were observed at
1,000 mg/m**3. The NOEL in this study was 482 mg/m**3.
    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
bw/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 bw/day (HDT) for systemic effects, and a NOEL for
skin irritation of 100 mg/kg bw/day.
    5. Chronic toxicity. Pyriproxyfen technical has been tested in
chronic studies with dogs, rats and mice. EPA has established a RfD for
pyriproxyfen of 0.35 mg/kg bw/day, based on the NOEL in female rats
from the two year chronic/oncogenicity study. Effects cited by EPA in
the Reference Dose 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 two-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 bw/day for one year. Dogs
exposed to dose levels of 300 mg/kg bw/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 bw/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 bw/day in males, 109.5 mg/kg bw/day
in females), and a LOEL of 3,000 ppm (420 mg/kg bw/day in males, 547
mg/kg bw/day in females) was established based on an increase in kidney
lesions.
    In a two-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 bw/day
in males, 35.1 mg/kg bw/day in females). A LOEL of 3,000 ppm (138 mg/kg
bw/day in males, 182.7 mg/kg bw/day in females) was established based
on a depression in body weight gain in females.
    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 bw (phenoxyphenyl and
pyridyl label), and after a single oral dose of 2 mg/kg bw
(phenoxyphenyl label only) following 14 daily oral doses at 2 mg/kg bw
of unlabelled 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 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. Seven days after dosing,
tissue residues were low, 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 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≥-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 bw. The two pyridines,
2-OH-pyridine and 2,5-diOH-pyridine, gave acute oral LD50
values of 124 (male) and 166 (female) mg/kg bw, and 1,105 (male) and
1,000 (female) mg/kg bw, 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 arthropods has no relevance to mammalian endocrine
systems. 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 Sumilarv does not possess estrogenic
or endocrine disrupting properties applicable to mammals.

C. Aggregate Exposure

    1. Dietary exposure. EPA has established a RfD for pyriproxyfen of
0.35 mg/kg bw/day, based on the rat 2 year chronic/oncogenicity study
and a safety factor of 100. The chronic dietary risk can be evaluated
using this endpoint. 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 bw/day as the
short term study with the lowest exposure endpoint. This figure will be
used for all acute and short term risk analyses.
    2. Food. Chronic and acute dietary exposure analyses have been
performed for pyriproxyfen using (proposed) tolerance level and
anticipated residues and 100% of the crop treated. Included in the
analyses are cottonseed, cotton gin trash and secondary residues in
meat, milk, and eggs. These exposure/risk analyses have been submitted
to the Agency along with a detailed description of the methodology and
assumptions used.
    i. Chronic. Long term dietary exposure was calculated for the U.S.
population and 26 population subgroups. The results from several

[[Page 11249]]

representative subgroups are listed below. The highest exposed sub-
population, Children (1 - 6 Years) with tolerance level exposure,
showed an occupancy of the RfD of 0.03%. In all other cases, chronic
dietary exposure was below 0.03 % of the RfD.

       Potential Chronic Dietary Exposure to Pyriproxyfen Residues
------------------------------------------------------------------------
                                           Exposure (mg/kg bw/day)
        Population Subgroup        -------------------------------------
                                        Tolerances        Anticipated
------------------------------------------------------------------------
U.S.population - 48 States - All
 seasons..........................           0.000026           0.000016
U.S. population - Autumn season...           0.000027           0.000017
Midwest Region....................           0.000030           0.000018
All infants.......................           0.000049           0.000030
Non-nursing infants (<1 year old).           0.000065           0.000040
Children (1 - 6 years)............           0.000095           0.000058
Females (13+/pregnant/not nursing)           0.000025           0.000015
------------------------------------------------------------------------

    ii. Acute. A tier 2 acute dietary exposure analysis assuming 100%
of crop treated was performed for the U.S. population and six subgroups
-- All Infants, Non-Nursing Infants (<1 Year), Children 1-6, Children
7-12, Females 13-50, and males 20+. The calculated exposures are all
very low, ranging from 0.000002 to 0.000018 mg/kg bw/day, for the
higher exposed proportions, 95th and 99.9th
percentiles, of the subgroups. It should be noted that the population
sizes are small at the lower probability exposures (e.g. 99th and
 99.9th percentiles) oftentimes leading to
unrealistically high calculated exposures. In all cases, MOEs to
pyriproxyfen residues exceed one-million.
    3. Drinking water. Since pyriproxyfen is to be applied outdoors to
growing cotton crops, the potential exists for the parent or its
metabolites to reach ground or surface water that may be used for
drinking water.
    i. Ground water. Pyriproxyfen is extremely insoluble in water
(0.367 mg/L at 25 deg.C), with high octanol/water partitioning
coefficient (Log P o/w = 5.37 at 25 deg.C), 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.
    ii. Surface water. In connection with the potential for dietary
exposure from surface potable water, a simulation of expected
environmental concentration (EEC) values in aquatic systems has been
performed using the Pesticide Root Zone Model (PRZM-2.3) and the
Exposure Analysis Modeling System, version 2.95 (EXAMSII). The
simulation was designed to approximate as closely as possible the
conditions associated with two aerial applications totaling 0.084 lb.
a.i. per acre to cotton with a 28-day interval. This use pattern
exceeds the presently proposed use pattern by approximately 1.2 x. The
results of the modeling estimate that the maximum upper tenth
percentile concentrations modeled in water adjacent to treated fields
are instantaneous, 0.23 ppb; 96-hour, 0.14 ppb; and 21 day, 0.08 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 (static, stagnant farm ponds)
adjacent to treated cotton fields. Standard, conservative exposure
assumptions of body weight and water consumption (adult 70 kg, 2 kg
water per day; child 10 kg, 1 kg water) will be used.
    iii Chronic. The 21 day concentration, 0.08 ppb (0.00008 mg/kg), is
used to represent chronic exposure. The highest possible exposure would
be 2.3 x 10**-6 and 8 x 10**-6 mg/kg bw/day for an
adult and child, respectively. This very small, but probably
exaggerated, exposure would occupy 0.00065 (adult) and 0.0023 (child)
percent of the chronic RfD of 0.35 mg/kg bw/day.
    iv. Acute. The modeled instantaneous concentration of 0.23 ppb
(0.00023 mg/kg), can be used to represent potential acute exposure to
pyriproxyfen in surface source drinking water. A corresponding
calculation shows that the maximum acute exposure would be 6.6 x
10**-6 and 2.3 x 10**-5 mg/kg bw/day for the adult
and child, respectively. When compared to the short term endpoint of
23.5 mg/kg bw/day, MOEs for both adults and children exceed one
million.
    4. Non-dietary exposure. Pyriproxyfen is the active ingredient in
numerous registered products for household use -- primarily for 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 pyriproxyfen has a relatively
short elimination half-life, cumulative toxicological effects resulting
from bioaccumulation are not plausible following short-term,
intermittent exposures. Further, pyriproxyfen is short-lived in the
environment and this indoor domestic use of pyriproxyfen provides only
relatively short-term reservoirs.
    This non-dietary exposure assessment for pyriproxyfen
conservatively focuses on upper-bound estimates of potential applicator
(adult) and post-application (adult and child - less than one 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 estimates exposures for selected consumer uses
that are 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 applicator exposures (dermal and inhalation),
and post-application adult (inhalation) and child (inhalation, dermal,
incidental oral ingestion associated with hand-to-mouth behavior)
exposures associated with consumer use of an aerosol carpet spray
product.
    The risk analyses use a combination of representative models.
Information from the pesticide handlers exposure data base (PHED) was
used to estimate exposures to applicators (adult). Surrogate data from
a study of exposure to indoor broadcast applications were used to
calculate a series of absorbed dose estimates for adult applicators,
and

[[Page 11250]]

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
                                 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. Application exposures on non-application days would be
zero.
    Further, the Agency has not identified acute or short term toxicity
endpoints of concern for oral inhalation or dermal exposure. Endpoints
that could be considered for short term and intermediate exposures
include developmental toxicity NOEL values of 100 mg/kg bw/day (rat and
rabbit), rat 21-day dermal systemic NOEL values of 1,000 mg/kg bw/day
(technical grade and end-use product), a four week rat inhalation
toxicity NOEL of 482 mg/m**3, and, the endpoint chosen by
Valent to be used in these analyses, the 90-day rat oral toxicity NOEL
of 23.5 mg/kg bw/day. There are no dermal absorption data for
pyriproxyfen.
    The largest 1 day exposure is calculated for the applicator of the
pet spray (0.085 mg/kg bw/day). This value 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 bw/day). Furthermore, the return frequency is
much different. Label instructions allow treatment of the pet every 14-
days during the flea season, while the carpet can be treated only each
120 days. The 1 day exposure is compared to the smallest short term
endpoint choosen by Valent, the 90-day rat oral toxicity NOEL of 23.5
mg/kg bw/day, and a MOE can be calculated. This compares an acute, one
day, dermal exposure to a sub-chronic 90-day dietary endpoint.
    MOE = Toxicity Endpoint (mg/kg bw/day) / Daily Short Term
Exposure (mg/kg bw/day)
    MOE(Pet 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 bw/day) = Applicator Exposure (mg/kg bw/day)
/ Frequency (days)
    MOE(Pet Spray Applicator) = 3,900
    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 subsequent exposure must be less than exposure on the
day of application.
    MOE(Carpet Spray, Crawling Infant) = 15,700
    There is usually no cause for concern if MOEs exceed 100. All other
MOEs 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.
    5. Summary of acute and chronic 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.
    i. Acute and short term non-occupational exposures. Potential acute
and short term non-occupational exposures to pyriproxyfen are
associated with food, water, and household uses -- applicator 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 MOE. Valent has identified the 90-day rat oral
toxicity with a NOEL of 23.5 mg/kg bw/day as the short term study with
the lowest exposure endpoint. In general, if exposure estimates are
conservative and the resulting MOE values are greater than 100, the
Agency has no cause for concern.
    It is possible to sum calculated acute exposures from various
sources as shown in the table below. However, summation is exceedingly
conservative because the approach assumes that two or more low
probability events occurr symultaneously. For example, it is highly
unlikely that an individual consuming the 99.9th percentile
dietary exposure (one-in-a-thousand), also treats a large dog for
fleas, and consumes all drinking water from a pond surrounded by
treated cotton fields in a single day. Even so, the short term non-
occupational exposures shown below that sum exposures from food,
drinking water and household uses of pyriproxyfen gives MOE values all
much larger than 100. These calculated acute and short term exposures
are very conservative, and are small enough to be of little
significance.

[[Page 11251]]

  Aggregate Acute Exposure to Pyriproxyfen for Two Representative U.S.
                               Populations
              (summation of low probability maximum values)
------------------------------------------------------------------------
                                           Exposure (mg/kg bw/day)
                                   -------------------------------------
          Exposure Medium                                 Non-Nursing
                                     U.S. Population   Infant (less than
                                      (all seasons)         1 year)

------------------------------------------------------------------------
Non-dietary.......................              0.085             0.0015
Food..............................           0.000012           0.000012
Drinking water....................          0.0000066           0.000023
Sum of acute exposures............          0.0850186           0.001535
Margin of exposure................                276             15,300
------------------------------------------------------------------------

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

      Aggregate Chronic Exposure to Pyriproxyfen for Two Representative U.S. Populations
-----------------------------------------------------------------------------------------------------

                                                              Exposure (mg/kg bw/day)
                                             --------------------------------------------------------
                    Exposure Medium                                 Non-Nursing
                                               U.S. Population   Infant (less than   Children (1 - 6
                                                (all seasons)         1 year)             Years)
-----------------------------------------------------------------------------------------------------
Food........................................           0.000026           0.000065           0.000095
Drinking water..............................          0.0000023           0.000008           0.000008
Sum of chronic exposures....................          0.0000283           0.000073           0.000103
Occupancy of RfD (percent)..................             0.0081              0.021              0.029
-----------------------------------------------------------------------------------------------------

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 appear to be
structurally, closely related to pyriproxyfen and may 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 at 62 FR 42020 (Aug. 4, 1997) (FRL-5734-6)
and other EPA publications pursuant to the Food Quality Protection Act.

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 bw/day using
the NOEL from the chronic rat feeding study and a 100-fold uncertainty
factor.
    i. Chronic. The aggregate chronic exposure to pyriproxyfen will
utilize much less than 0.1% of the RfD for the U.S. population. Because
estimated exposures are far below 100% of the RfD, Valent concludes
that there is a reasonable certainty that no harm will result from
chronic aggregate exposure to pyriproxyfen residues.
    ii. Acute. Assessment of aggregate acute exposure to food and non-
food uses of pyriproxyfen to the U.S. population and numerous sub-
populations has demonstrated that exposures are small. MOE values using
very conservative assumptions and a conservative toxicity endpoint are
all greater than 100 and it can be concluded that there is reasonable
certainty of no harm from acute exposures to pyriproxyfen.
    2. Infants and children-- i. Chronic. 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 0.021% for Non-Nursing Infants, and 0.029% for Children (1 - 6
Years), the most highly exposed child population subgroup. Because
estimated exposures to infants and children are far below 100% of the
RfD, Valent concludes that there is a reasonable certainty that no harm
will result from chronic aggregate exposure to pyriproxyfen residues.
    ii. Acute. Assessment of aggregate acute exposure to food and non-
food uses of pyriproxyfen to infants and children has demonstrated that
exposures allow calculation of acceptable MOE values. Using very
conservative assumptions and a

[[Page 11252]]

conservative toxicity endpoint are all MOE values are greater than 100.
Therefore, it can be concluded that there is reasonable certainty of no
harm to infants and children from potential acute exposures to
pyriproxyfen.
    3. Additional safety factor to provide additional protection to
infants and children. Pyriproxyfen is supported by a complete, reviewed
and reliable toxicology database. 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 unique pathology or other effects to fetal or
developing young experimentsl animals. In all these studies there is no
indication that young or developing animals are any more sensitive to
toxicity from pyriproxyfen or its metabolites than adult animals. The
developmental toxicity studies and reproduction study all demonstrated
that any toxicity attributable to pyriproxyfen was observed in adults
at lower levels than in fetuses or in developing young animals. There
is no indication that a higher safety factor, other than 100, is needed
for additional protection for infants and children.

F. International Tolerances

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

[FR Doc. 98-5985 Filed 3-5-98; 8:45 am]
BILLING CODE 6560-50-F