Document ID: EPA-HQ-OPP-2009-0018-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-04-08T04:00Z

Notice of Filing of Pesticide Petition #8E7492; Prepared by Valent
U.S.A. Corporation on Behalf of IR-4

<Petition #8E7492;Interregional Research Project Number 4>

<EPA Registration Division contact: Susan Stanton, 703-305-5218>

<	EPA has received a pesticide petition (PP8E7492) from the
Interregional Research Project Number 4, 500 College Road East, Suite
201W, Princeton, NJ 08540, proposing, pursuant to section 408(d) of the
Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to
amend 40 CFR part 180, by establishing a tolerance for residues of
Pyriproxyfen in or on the raw agricultural commodity Vegetable, leaves
of root and tuber, group 2 at 2.0 parts per million (ppm); Vegetable,
leafy, except brassica, group 4 at 3.0 ppm; Vegetable, foliage of
legume, group 7 at 2.0 ppm; Artichoke, globe at 2.0 ppm; Asparagus at
2.0 ppm; Watercress at 2.0 ppm; and Small fruit vine climbing subgroup,
except grape 13-07E at 0.35 parts per million (ppm).  EPA has determined
that the petition contains data or information regarding the elements
set forth in section 408 (d)(2) of  FDDCA; 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 14C-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 radiochemical 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 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 in/on all appropriate agricultural commodities,
respective processing fractions, milk, animal tissues, and environmental
samples. The extraction methodology has been validated using aged
radiochemical residue samples from metabolism studies. The methods have
been validated in cottonseed, apples, soil, and oranges at independent
laboratories. EPA has successfully validated the analytical methods for
analysis of cottonseed, 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.  Residue data has been submitted which
adequately support the requested tolerances.>

<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. 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 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
1000 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 bw/day
and greater. The maternal NOAEL 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
NOAEL for prenatal developmental toxicity was 100 mg/kg bw/day. An
increased incidence of visceral and skeletal variations was observed
postnatally at 1000 mg/kg bw/day. The NOAEL 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
1000 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 NOAEL
was 100 mg/kg bw/day. No developmental effects were observed in the
rabbit fetuses. The NOAEL for developmental toxicity in rabbits was 1000
mg/kg bw/day.

In the rat reproduction study, pyriproxyfen was administered in the diet
at levels of 0, 200, 1000, and 5000 ppm through two generations of rats.
 Adult systemic toxicity (reduced body weights, liver and kidney
histopathology, and increased liver weight) was produced at the 5000 ppm
dose (453 mg/kg bw/day in males, 498 mg/kg bw/day in females) during the
pre-mating period. The systemic NOAEL was 1000 ppm (87 mg/kg bw/day in
males, 96 mg/kg bw/day in females). No effects on reproduction were
produced at 5000 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 NOAELs from these studies were 400 ppm (23.5 mg/kg bw/day for
males, 27.7 mg/kg bw/day for  females) in rats, 1000 ppm (149.4 mg/kg
bw/day for males, 196.5 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
1000 mg/m3. The NOAEL in this study was 482 mg/m3.	

A 21-day dermal toxicity study in rats with pyriproxyfen technical did
not produce any signs of dermal or systemic toxicity at 1000 mg/kg
bw/day, the highest dose tested.  In a 21-day dermal study conducted
with KNACK7 Insect Growth Regulator the test material produced a NOAEL
of 1000 mg/kg bw/day (highest dose tested) for systemic effects, and a
NOAEL 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
reference dose (RfD) for pyriproxyfen of 0.35 mg/kg bw/day, based on the
NOAEL 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 1000 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 NOAEL
in this study was 100 mg/kg bw/day.

Pyriproxyfen technical was administered to mice at doses of 0, 120, 600
and 3000 ppm in diet for 78 weeks. The NOAEL 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 LOAEL of 3000 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 3000 ppm. The NOAEL 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 LOAEL of 3000 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 absorption, tissue distribution, metabolism
and excretion of 14C-labeled pyriproxyfen were studied in rats after
single oral doses of 2 or 1000 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 two days after
radiolabeled test material dosing, and 92-98% of the administered dose
was excreted within seven 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 two days of dosing, and 92-98% of the administered dose
was excreted within seven days. Tissue residues were low seven days
after dosing, accounting for no more than 0.3% of the dosed 14C. Because
parent and metabolites are not retained in the body, the potential for
acute toxicity from in situ formed metabolites is low. The potential for
chronic toxicity is adequately tested by chronic exposure to the parent
at the MTD and consequent chronic exposure to the internally formed
metabolites. 

Seven metabolites of pyriproxyfen, 4'-OH-pyriproxyfen,
5''-OH-pyriproxyfen, desphenyl-pyriproxyfen, POPA, PYPAC, 2-OH-pyridine
and 2,5-diOH-pyridine, have been tested for mutagenicity (Ames) and
acute oral toxicity to mice. All seven metabolites were tested in the 
Ames assay with and without S9 at doses up to 5000 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 2000 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 1105 (male) and 1000 (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 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 per cent of the crop treated. The analyses included residue data for
all existing uses, pending uses, and proposed new uses. The results from
several representative subgroups are listed below. Chronic exposure to
the overall U.S. population is estimated to be 0.0008 mg/kg body-wt/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 body-wt/day, or 0.26% of the RfD. Generally speaking,
the Agency has no cause for concern if total residue contribution for
established and proposed tolerances is less than 100 percent of the RfD.

Calculated Chronic Dietary Exposures to the Total U.S. Population

and Selected Sub-Populations to Pyriproxyfen Residues in Food

Population Subgroup	

Exposure

(mg/kg bw/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 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
groundwater. To quantify potential exposure from drinking water, surface
water concentrations for pyriproxyfen were estimated using GENEEC. The
peak predicted concentration in drinking water was 0.86 ppb. Using
standard assumptions about body weight 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 percent 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 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 body weight for a 1 B
6 year old child of 10 kg, the active ingredient dissipates uniformly
through 365 days (the label instruct to change collar once a year), 1%
of the active ingredient 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 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 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 at 62 Federal Register 42020 (Aug. 4, 1997) and other
subsequent EPA publications pursuant to the Food Quality Protection Act.

>

<E. Safety Determination>

	1. U.S. population.  

i. Chronic Dietary Exposure and Risk - 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 bw/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 bw/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 bw/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 percent 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 - 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 - 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 pre- and post-natal toxicity
for pyriproxyfen is complete with respect to current data requirements.
There are no special pre- or post-natal 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 Risk - 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 bw/day for Nursing
Infants, up to 0.00091 mg/kg bw/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 bw/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 - 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 - 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

The following are the only existing Codex MRLs for pyriproxyfen.>

 

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