PP Number:  6E7033	

Summary of Petition

EPA has received pesticide petitions (PP# 6E7033) from the Interregional
Research Project #4 (IR-4), Rutgers, The State University of New Jersey,
500 College Road East, Suite 201 W, Princeton, NJ 08540 proposing,
pursuant to section 408(d) of the FFDCA, 21 U.S.C. 346a(d), to amend 40
CFR part 180.510 by establishing tolerances for residues of
pyriproxyfen, 2-[1-methyl-2-(4-phenoxyphenoxy) ethoxy]pyridine, in or on
raw agricultural commodities as follows:  Grass, forage at 0.5 parts per
million (ppm); Grass, hay at 1.0 ppm; Vegetable, root and tuber, group 1
at 0.15 ppm; Vegetable, leaves of root and tuber, group 2 at 2.0 ppm;
Vegetable, bulb, group 3, except Onion, dry bulb at 0.70 ppm; Vegetable,
leafy, except brassica, group 4 at 2.0 ppm ;Vegetable, legume, group 6
at 0.2 ppm; Vegetable, foliage of legume, group 7 at 2.0 ppm; Caneberry,
subgroup 13A at 1.0 ppm; Grain, cereal, group 15 at 1.1 ppm; Grain,
cereal, forage, fodder and straw, group 16 at 1.1 ppm; Animal feed,
nongrass, group 18 at 0.7 ppm for forage, 2.0 for seed, and 1.1 for hay.
In addition, tolerances are proposed for the individual crops:
Artichoke, globe at 2.0 ppm; Asparagus at 2.0 ppm; Banana and plantain
at 0.2 ppm; Cacao bean at 0.02 ppm; Canola, seed at 0.20 ppm; Coffee at
0.02 ppm; Cranberry at 1.0 ppm; Date at 0.3 ppm; Kiwifruit at 0.1 ppm;
Pawpaw at 1.0 ppm; Peanut at 0.2 ppm; Pineapple at 0.3 ppm; Pomegranate
at 0.2 ppm; Safflower, seed at 0.2 ppm; Sesame, seed at 0.2 ppm;
Sugarcane at 1.1 ppm; Tea at 0.02 ppm and Watercress at 2.0 ppm.

EPA has determined that the petitions contain data or information
regarding the elements set forth in section 408(d)(2) of the Federal
Food Drug and Cosmetic Act (FFDCA); however, EPA has not fully evaluated
the sufficiency of the submitted data at this time or whether the data
supports granting of the petitions. Additional data may be needed before
EPA rules on the petitions.

A. Residue Chemistry

1. Plant and animal metabolism. Metabolism of 14C-pyriproxyfen labelled
in the phenoxyphenyl ring and in the pyridyl ring has been studied in
cotton, apples, tomatoes, lactating goats, 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 raw agricultural commodities
(RAC) samples remained as parent. Comparing metabolites detected and
quantified from cotton, apple, tomato, goat, hen and rat shows that
there are no significant aglycones in plants which are not also present
in the excreta or tissues of animals. 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 were generated with pyriproxyfen for tolerance setting and
dietary exposure estimates.  Adequate residue trials  were performed
with pyriproxyfen to support the uses described in this notice of
filing.

B. Toxicological Profile

 tc \l2 "B. Toxicological Profile 

An assessment of toxic effects caused by pyriproxyfen is discussed in
Unit III.A. and Unit III.B. of the Federal Register dated April 4, 2001,
(FRL-6772-4) (66 FR 17883).

    

1. Animal metabolism. The absorption, tissue distribution, metabolism
and excretion of 14C-labeled pyriproxyfen were studied in rats after
single oral doses of 2 or 1,000 milligrams/kilograms body weight (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 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.

    

2. Metabolite toxicology. Metabolism studies of pyriproxyfen in rats,
goats and hens, as well as the fish bioaccumulation study demonstrate
that the parent is very rapidly metabolized and eliminated. In the rat,
most (88-96%) of the administered radiolabel was excreted in the urine
and feces within 2 days of dosing, and 92-98% of the administered dose
was excreted within 7 days. Tissue residues were low 7 days after
dosing, accounting for no more than 0.3% of the dosed 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 maximum tolerated dose (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, via Ames
Assay, 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 revertible
colonies in any of the test strains. Positive control chemicals showed
marked increases in reverting 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 Lethal Dose (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.

3. Endocrine disruption. Pyriproxyfen is specifically designed to be an
insect growth regulator and is known to produce juvenoid effects on
arthropod development. However, this mechanism-of-action in target
insects and some other arthropods has no relevance to any mammalian
endocrine system. While specific tests, uniquely designed to evaluate
the potential effects of pyriproxyfen on mammalian endocrine systems
have not been conducted, the toxicology of pyriproxyfen has been
extensively evaluated in acute, sub-chronic, chronic, developmental, and
reproductive toxicology studies including detailed histopathology of
numerous tissues. The results of these studies show no evidence of any
endocrine-mediated effects and no pathology of the endocrine organs.
Consequently, it is concluded that pyriproxyfen does not possess
estrogenic or endocrine disrupting properties applicable to mammals.

C. Aggregate Exposure

 tc \l2 "C. Aggregate Exposure 

1. Dietary exposure. An evaluation of chronic dietary exposure 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, Valent Corporation concludes 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 assuming 100 % of
the crop will be treated with pyriproxyfen. 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 dietary exposure to the overall U.S. population is estimated to
be 0.0238 mg/kg bw/day, representing 6.8% of the Reference Dose (RfD).

For the most highly exposed sub-population, infants, 0 years of age,
dietary exposure is calculated to be 0.0245 mg/kg bw/day, or 7.0% 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% of the RfD.

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 ground water. To quantify potential
exposure from drinking water, surface water concentrations for
pyriproxyfen were estimated using GENEEC.  The residue levels in
drinking water are the peak chronic residue level as estimated by
GENEEC. Using standard assumptions about body weight and water
consumption, the chronic exposure to pyriproxyfen from this drinking
water would be 0.00009 mg/kg bw/day for adults and “0" year infants,
and represent 0.025% of the RfD (0.35 mg/kg/day). 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 active ingredient (ai)/day, average bw for a 1-6 year
old child of 10 kg, the a.i. dissipates uniformly through 365 days (the
label instructs to change the 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

 tc \l2 "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.

E. Safety Determination

 tc \l2 "E. Safety Determination 

U.S. population

i. Chronic dietary exposure and risk to 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 0.006 to 0.0245 mg/kg bw/day, 1.7 to 7.0% 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% 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 to 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 to 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 5700.

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 10-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-natal and post-natal
toxicity for pyriproxyfen is complete with respect to current data
requirements. There are no special prenatal or postnatal toxicity
concerns for infants and children, based on the results of the rat and
rabbit developmental toxicity studies or the 2-generation reproductive
toxicity study in rats. Valent concludes that reliable data support use
of the standard 100-fold uncertainty factor and that an additional
uncertainty factor is not needed for pyriproxyfen to be further
protective of infants and children.

ii. Chronic dietary exposure and risk to 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 0.013 mg/kg bw/day children 6-12
years old,  up to 0.0245 mg/kg bw/day for infants (0 years of age), 3.8
and 7.0% of the RfD, respectively. Adding the worse case potential
incremental exposure to infants from pyriproxyfen in drinking water (0.9
x 10-4 mg/kg bw/day) does not materially increase the aggregate, chronic
dietary exposure and only increases the occupancy of the RfD by 0.009%.
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. Valent concludes 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, Valent believes 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 1425.

F. International Tolerances

 tc \l2 "F. International Tolerances 

There are no presently existing Codex maximum residue levels (MRLs) for
pyriproxyfen.

