[Federal Register Volume 63, Number 128 (Monday, July 6, 1998)]
[Rules and Regulations]
[Pages 36366-36373]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-17729]
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ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 180
[OPP-300666; FRL-5794-6]
RIN 2070-AB78
Pyriproxyfen (2-[1-methyl-2-(4-phenoxyphenoxy)ethoxy]pyridine;
Pesticide Tolerance
AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.
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SUMMARY: This regulation establishes a tolerance for combined residues
of pyriproxfen in or on cotton seed and cotton gin byproducts. Valent
U.S.A. Corporation requested this tolerance under the Federal Food,
Drug, and Cosmetic Act (FFDCA), as amended by the Food Quality
Protection Act of 1996 (Pub. L. 104-170).
DATES: This regulation is effective July 6, 1998. Objections and
requests for hearings must be received by EPA on or before September 4,
1998.
ADDRESSES: Written objections and hearing requests, identified by the
docket control number, [OPP-300666], must be submitted to: Hearing
Clerk (1900), Environmental Protection Agency, Rm. M3708, 401 M St.,
SW., Washington, DC 20460. Fees accompanying objections and hearing
requests shall be labeled ``Tolerance Petition Fees'' and forwarded to:
EPA Headquarters Accounting Operations Branch, OPP (Tolerance Fees),
P.O. Box 360277M, Pittsburgh, PA 15251. A copy of any objections and
hearing requests filed with the Hearing Clerk identified by the docket
control number, [OPP-300666], must also be submitted to: Public
Information and Records Integrity Branch, Information Resources and
Services Division (7502C), Office of Pesticide Programs, Environmental
Protection Agency, 401 M St., SW., Washington, DC 20460. In person,
bring a copy of objections and hearing requests to Rm. 119, CM #2, 1921
Jefferson Davis Hwy., Arlington, VA.
A copy of objections and hearing requests filed with the Hearing
Clerk may also be submitted electronically by sending electronic mail
(e-mail) to: [email protected]. Copies of objections and
hearing requests must be submitted as an ASCII file avoiding the use of
special characters and any form of encryption. Copies of objections and
hearing requests will also be accepted on disks in WordPerfect 5.1/6.1
file format or ASCII file format. All copies of objections and hearing
requests in electronic form must be identified by the docket control
number [OPP-300666]. No Confidential Business Information (CBI) should
be submitted through e-mail. Electronic copies of objections and
hearing requests on this rule may be filed online at many Federal
Depository Libraries.
FOR FURTHER INFORMATION CONTACT: By mail: Joseph Tavano, 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: Crystal Mall #2, 1921
Jefferson Davis Hwy., Arlington, VA, (703) 305-6411, e-mail:
[email protected].
SUPPLEMENTARY INFORMATION: In the Federal Register of March 6, 1998 (63
FR 11240) (FRL-5777-5), EPA, issued a notice pursuant to section 408 of
the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(e)
announcing the filing of a pesticide petition (PP 6F4737) for tolerance
by Valent U.S.A. Corporation, 1333 N. California Blvd., Walnut Creek,
CA 94596. This notice included a summary of the petition prepared by
Valent U.S.A. Corporation, the registrant. There were no comments
received in response to the notice of filing.
The petition requested that 40 CFR 180.534 be amended by
establishing tolerances for combined residues of the insecticide,
pyriproxfen, in or on cotton seed and cotton gin byproducts at 0.05 and
2.0 parts per million (ppm) respectively.
I. Risk Assessment and Statutory Findings
New section 408(b)(2)(A)(i) of the FFDCA allows EPA to establish a
tolerance (the legal limit for a pesticide chemical residue in or on a
food) only if EPA determines that the tolerance is ``safe.'' Section
408(b)(2)(A)(ii) defines ``safe'' to mean that ``there is a reasonable
certainty that no harm will result from aggregate exposure to the
pesticide chemical residue, including all anticipated dietary exposures
and all other exposures for which there is reliable information.'' This
includes exposure through drinking water and in residential settings,
but does not include occupational exposure. Section 408(b)(2)(C)
requires EPA to give special consideration to exposure of infants and
children to the pesticide chemical residue in establishing a tolerance
and to ``ensure that there is a reasonable certainty that no harm will
result to infants and children from aggregate exposure to the pesticide
chemical residue. . . .''
[[Page 36367]]
EPA performs a number of analyses to determine the risks from
aggregate exposure to pesticide residues. First, EPA determines the
toxicity of pesticides based primarily on toxicological studies using
laboratory animals. These studies address many adverse health effects,
including (but not limited to) reproductive effects, developmental
toxicity, toxicity to the nervous system, and carcinogenicity. Second,
EPA examines exposure to the pesticide through the diet (e.g., food and
drinking water) and through exposures that occur as a result of
pesticide use in residential settings.
A. Toxicity
1. Threshold and non-threshold effects. For many animal studies, a
dose response relationship can be determined, which provides a dose
that causes adverse effects (threshold effects) and doses causing no
observed effects (the ``no-observed effect level'' or ``NOEL'').
Once a study has been evaluated and the observed effects have been
determined to be threshold effects, EPA generally divides the NOEL from
the study with the lowest NOEL by an uncertainty factor (usually 100 or
more) to determine the Reference Dose (RfD). The RfD is a level at or
below which daily aggregate exposure over a lifetime will not pose
appreciable risks to human health. An uncertainty factor (sometimes
called a ``safety factor'') of 100 is commonly used since it is assumed
that people may be up to 10 times more sensitive to pesticides than the
test animals, and that one person or subgroup of the population (such
as infants and children) could be up to 10 times more sensitive to a
pesticide than another. In addition, EPA assesses the potential risks
to infants and children based on the weight of the evidence of the
toxicology studies and determines whether an additional uncertainty
factor is warranted. Thus, an aggregate daily exposure to a pesticide
residue at or below the RfD (expressed as 100% or less of the RfD) is
generally considered acceptable by EPA. EPA generally uses the RfD to
evaluate the chronic risks posed by pesticide exposure. For shorter
term risks, EPA calculates a margin of exposure (MOE) by dividing the
estimated human exposure into the NOEL from the appropriate animal
study. Commonly, EPA finds MOEs lower than 100 to be unacceptable. This
100-fold MOE is based on the same rationale as the 100-fold uncertainty
factor.
Lifetime feeding studies in two species of laboratory animals are
conducted to screen pesticides for cancer effects. When evidence of
increased cancer is noted in these studies, the Agency conducts a
weight of the evidence review of all relevant toxicological data
including short-term and mutagenicity studies and structure activity
relationship. Once a pesticide has been classified as a potential human
carcinogen, different types of risk assessments (e.g., linear low dose
extrapolations or MOE calculation based on the appropriate NOEL) will
be carried out based on the nature of the carcinogenic response and the
Agency's knowledge of its mode of action.
2. Differences in toxic effect due to exposure duration. The
toxicological effects of a pesticide can vary with different exposure
durations. EPA considers the entire toxicity data base, and based on
the effects seen for different durations and routes of exposure,
determines which risk assessments should be done to assure that the
public is adequately protected from any pesticide exposure scenario.
Both short and long durations of exposure are always considered.
Typically, risk assessments include ``acute,'' ``short-term,''
``intermediate term,'' and ``chronic'' risks. These assessments are
defined by the Agency as follows.
Acute risk, by the Agency's definition, results from 1-day
consumption of food and water, and reflects toxicity which could be
expressed following a single oral exposure to the pesticide residues.
High end exposure to food and water residues are typically assumed.
Short-term risk results from exposure to the pesticide for a period
of 1-7 days, and therefore overlaps with the acute risk assessment.
Historically, this risk assessment was intended to address primarily
dermal and inhalation exposure which could result, for example, from
residential pesticide applications. However, since enaction of FQPA,
this assessment has been expanded to include both dietary and non-
dietary sources of exposure, and will typically consider exposure from
food, water, and residential uses when reliable data are available. In
this assessment, risks from average food and water exposure, and high-
end residential exposure, are aggregated. High-end exposures from all
three sources are not typically added because of the very low
probability of this occurring in most cases, and because the other
conservative assumptions built into the assessment assure adequate
protection of public health. However, for cases in which high-end
exposure can reasonably be expected from multiple sources (e.g.
frequent and widespread homeowner use in a specific geographical area),
multiple high-end risks will be aggregated and presented as part of the
comprehensive risk assessment/characterization. Since the toxicological
endpoint considered in this assessment reflects exposure over a period
of at least 7 days, an additional degree of conservatism is built into
the assessment; i.e., the risk assessment nominally covers 1-7 days
exposure, and the toxicological endpoint/NOEL is selected to be
adequate for at least 7 days of exposure. (Toxicity results at lower
levels when the dosing duration is increased.)
Intermediate-term risk results from exposure for 7 days to several
months. This assessment is handled in a manner similar to the short-
term risk assessment.
Chronic risk assessment describes risk which could result from
several months to a lifetime of exposure. For this assessment, risks
are aggregated considering average exposure from all sources for
representative population subgroups including infants and children.
B. Aggregate Exposure
In examining aggregate exposure, FFDCA section 408 requires that
EPA take into account available and reliable information concerning
exposure from the pesticide residue in the food in question, residues
in other foods for which there are tolerances, residues in groundwater
or surface water that is consumed as drinking water, and other non-
occupational exposures through pesticide use in gardens, lawns, or
buildings (residential and other indoor uses). Dietary exposure to
residues of a pesticide in a food commodity are estimated by
multiplying the average daily consumption of the food forms of that
commodity by the tolerance level or the anticipated pesticide residue
level. The Theoretical Maximum Residue Contribution (TMRC) is an
estimate of the level of residues consumed daily if each food item
contained pesticide residues equal to the tolerance. In evaluating food
exposures, EPA takes into account varying consumption patterns of major
identifiable subgroups of consumers, including infants and children.
The TMRC is a ``worst case'' estimate since it is based on the
assumptions that food contains pesticide residues at the tolerance
level and that 100% of the crop is treated by pesticides that have
established tolerances. If the TMRC exceeds the RfD or poses a lifetime
cancer risk that is greater than approximately one in a million, EPA
attempts to derive a more accurate exposure estimate for the pesticide
by evaluating additional types
[[Page 36368]]
of information (anticipated residue data and/or percent of crop treated
data) which show, generally, that pesticide residues in most foods when
they are eaten are well below established tolerances.
Percent of crop treated estimates are derived from federal and
private market survey data. Typically, a range of estimates are
supplied and the upper end of this range is assumed for the exposure
assessment. By using this upper end estimate of percent of crop
treated, the Agency is reasonably certain that exposure is not
understated for any significant subpopulation group. Further, regional
consumption information is taken into account through EPA's computer-
based model for evaluating the exposure of significant subpopulations
including several regional groups, to pesticide residues. For this
pesticide, the most highly exposed population subgroup was not
regionally based.
II. Aggregate Risk Assessment and Determination of Safety
Consistent with section 408(b)(2)(D), EPA has reviewed the
available scientific data and other relevant information in support of
this action, EPA has sufficient data to assess the hazards of
pyriproxyfen (2-[1-methyl-2-(4-phenoxyphenoxy)ethoxy]pyridine and to
make a determination on aggregate exposure, consistent with section
408(b)(2), tolerances for combined residues of pyriproxfen on cotton
seed and cotton gin byproducts at 0.05 and 2.0 ppm respectively EPA's
assessment of the dietary exposures and risks associated with
establishing the tolerance follows.
A. Toxicological Profile
EPA has evaluated the available toxicity data and considered its
validity, completeness, and reliability as well as the relationship of
the results of the studies to human risk. EPA has also considered
available information concerning the variability of the sensitivities
of major identifiable subgroups of consumers, including infants and
children. The nature of the toxic effects caused by pyriproxyfen (2-[1-
methyl-2-(4-phenoxyphenoxy)ethoxy]pyridine are discussed below.
1. Acute toxicity-- Acute toxicity studies with technical
pyriproxyfen. Oral LD50 in the rat is >5,000 milligram/
kilogram (mg/kg) for males and females - Toxicity Category IV; dermal
LD50 in the rabbit at >2,000 mg/kg - Toxicity Category IV;
inhalation LC50 in the rat is >1.3 mg/L (highest dose
attainable) - Toxicity Category III; primary eye irritation in the
rabbit (mild irritatant) - Toxicity Category III; primary dermal
irritation in the rabbit (not an irritant: non-irritating to the skin
under conditions of test))- Toxicity Category IV. Pyriproxyfen is not a
sensitizer.
2. Subchronic toxicity-- i. Rats. In the subchronic feeding study
in rats, the no-observed effect level (NOEL) was 27.68 mg/kg/day. The
lowest oberved effect level (LOEL) was 141.28 mg/kg/day, based upon
higher mean total cholesteral and phospholipids, decreased mean RBCs,
hematocrit and hemoglobin counts and increased relative liver weight.
ii. Dogs. In the subchronic feeding study in dogs, the NOEL was 100
mg/kg/day and the LOEL was 300 mg/kg/day. The effects were based on
increased absolute and relative liver weight in males and
hepatocellular hypertrophy in females. These findings were also
observed at 1,000 mg/kg/day and may represent adaptive changes at both
300 mg/kg/day and the limit dose of 1,000 mg/kg/day.
iii. Dermal study - Rats. In a 21-day dermal study in rats, the
NOEL for systemic effects was >1,000 mg/kg/day (limit dose). The LOEL
for systemic effects was not established in this study. No dermal or
systemic toxicity was observed at any dose tested.
3. Chronic toxicity/carcinogenicity-- i. Dogs. In a one-year
chronic feeding study in dogs, the NOEL was 100 mg/kg/day. The LOEL was
300 mg/kg/day based on decreased weight gain, increased absolute and
relative liver weight, mild anemia, increased cholesterol and
triglycerides.
ii. Mice. The oncogenicity study in mice the NOEL and LOEL for
systemic toxicity in males are 600 ppm and 3,000 ppm, respectively,
based on an renal lesions in males. The technical grade test material
was given to male and female CD-1 mice in diet for 18 months at 0, 120,
600, or 3,000 ppm. No statistically significant increase in tumor
incidence relative to controls were observed in either sex at any does
up to 3,000 ppm (highest dose tested).
iii. Rats. In the chronic feeding/oncogenicity study in rats, the
NOEL (systemic) was 35.1 mg/kg/day and the LOEL (systemic) was 182.7
mg/kg/day. The technical grade test material was administered to male
and female Sprague-Dawley rats in diet for 24 months at 0, 120, 600, or
3,000 ppm. A decrease of 16.9% in bogy weight gain in females at 3,000
ppm (182.7 mg/kg/day) was basis for the systemic LOEL.
4. Developmental toxicity-- i. Rabbits. In the developmental study
in rabbits, the maternal NOEL/LOEL for maternal toxicity were 100 and
300 mg/kg/day based on premature delivery/abortions, soft stools,
emaciation, decreased activity and bradypnea. The developmental NOEL
was determined to be 300 mg/kg/day and developmental LOEL was
determined to be undetermined; no dose related anomalies occurred in
the 4 remaining litters studied at 1,000 mg/kg/day.
ii. Rats. In the developmental study in rats, a maternal NOEL/LOEL
were determined to be 100 mg/kg/day and 300 mg/kg/day, respectively.
These findings were based on increased incidences in mortality and
clinical signs at 1,000 mg/kg/day with decreases in food consumption,
body weight, and body weight gain together with increases in water
consumption at 300 and 1,000 mg/kg/day. The developmental NOEL/LOEL
were 100 mg/kg/day and 300 mg/kg/day based on the increase of skeletal
variations at 300 mg/kg/day and above.
5. Reproductive toxicity. In a two-generation reproduction study in
rats, the systemic NOEL was 1,000 ppm (87 mg/kg/day). The LOEL for
sytemic toxicity was 5,000 ppm (453 mg/kg/day). Effects were based on
decreased body weight, weight gain and food consumption in both sexes
and both generations, and increased liver weights in both sexes
associated with liver and kidney histopathology in males. The
reproductive NOEL was 5,000 ppm. A reproductive LOEL was not
established.
6. Mutagenicity. Studies on gene mutation and other genotoxic
effects: In a Gene Mutation Assay (Ames Test)/Reverse Mutation, finding
were determined as negative for induction of gene mutation measured as
the reversion to histine protrophy of 5 S.typhimurium strains and
E.Coli WP2 uvra at doses from 10 to 5,000 g/plate with &
without S-9 activation. The highest dose was insoluble. A Gene Mutation
assay in Mammalian Cells was found to be negative f or mutagencity in
CHO (Chinese hamster ovary) V79 cells with and without metabolic
activation up to cytotoxic doses (300 g/mL). In a Structural
Chromosomal Aberration Assay in vivo, findings proved nonclastogenic in
CHO cells both with and without S-9 activation up to cytotoxic doses
(300 g/mL). In Other Genotoxicity Assays, an increase in
unscheduled DNA synthesis was not induced both with and without
activation in HeLa cells exposed up to insoluble doses ranging to 6.4
g/mL (without activation) and 51.2 g/mL (with
activation).
7. Metabolism. The results of the metabolism studies are as
follows:
Acceptable: Rats were orally dosed with 14C-labeled
pyriproxyfen at 2 or
[[Page 36369]]
1,000 mg/kg and at repeated oral doses (14 daily doses) of unlabeled
pyriproxyfen at 2 mg/kg followed by administration of a single oral
dose of labeled pyriproxyfen at 2 mg/kg. Most radioactivity was
excreted in the feces (81-92%) and urine (5-12%) over a 7 day
collection period. Expired air was not detected. Tissue radioactivity
levels were very low (less than 0.3%) except for fat. Examination of
urine, feces, liver, kidney, bile and blood metabolites yielded
numerous (>20) identified metabolites when compared to synthetic
standards. The major biotransformation reactions of pyriproxyfen
include: (i) Oxidation of the 4' - position of the terminal phenyl
group; (ii) oxidation at the 5' - position of pyridine; and (iii)
cleavage of the ether linkage and conjugation of the resultant phenols
with sulfuric acid.
8. Neurotoxicity. Neurotoxicity has not been observed in any of the
acute, subchronic, chronic, developmental or reproductive studies
performed with pyriproxyfen.
B. Toxicological Endpoints
1. Acute toxicity. An acute dietary dose and endpoint was not
identified in the database. The Agency concludes that there is a
reasonable certainty of no harm from acute dietary exposure.
2. Short - and intermediate - term toxicity. Doses and endpoints
were not identified for short and intermediate-term dermal and
inhalation exposure. The Agency concludes that there are reasonable
certainties of no harm from these exposures.
3. Chronic toxicity. EPA has established the RfD for pyriproxyfen
(2-[1-methyl-2-(4-phenoxyphenoxy)ethoxy]pyridine at 0.35 mg/kg/day.
This RfD is based on a NOEL of 35.1 mg/kg/day and an uncertainty factor
(UF) of 100. The NOEL was established from the combined chronic
feeding/oncogenicity study in rats where the LOEL was 3,000 ppm, based
on a 16.9% decrease in body weight gain in females when compared to
controls.
4. Carcinogenicity. Pyriproxyfen is classified as Category E: not
carcinogenic in two acceptable animal studies.
C. Exposures and Risks
1. From food and feed uses. In today's action tolerances will be
established (40 CFR 180.534) for the combined residues of pyriproxfen,
in or on the raw agricultural commodities: cotton seed and cotton gin
byproducts at 0.05 and 2.0 ppm respectively. Risk assessments were
conducted by EPA to assess dietary exposures and risks from
pyriproxyfen (2-[1-methyl-2-(4-phenoxyphenoxy)ethoxy]pyridine as
follows:
i. Acute exposure and risk. Acute dietary risk assessments are
performed for a food-use pesticide if a toxicological study has
indicated the possibility of an effect of concern occurring as a result
of a one day or single exposure. No acute dietary endpoint and dose was
identified in the toxicology data base for pyriproxyfen, therefore the
Agency concludes that there is a reasonable certainty of no harm from
acute dietary exposure.
ii. Chronic exposure and risk. The chronic dietary exposure
analysis from food sources was conducted using the RfD of 0.35 mg/kg/
day. The RfD is based on the NOEL of 35.1 mg/kg/day in male and female
rats from the Chronic Feeding/Oncogenicity study in rats, and an
uncertainty factor of 100 applicable to all population subgroups.
In conducting this chronic dietary risk assessment, EPA has made
very conservative assumptions: 100% of cottonseed having pyriproxyfen
tolerances will contain pyriproxyfen residues and those residues will
be at the level of the established tolerance. This results in an
overestimate of human dietary exposure. Thus, in making a safety
determination for this tolerance, EPA is taking into account this
conservative exposure assessment.
The existing pyriproxyfen tolerances (published, pending, and
including the necessary Section 18 tolerances) result in a Theoretical
Maximum Residue Contribution (TMRC) that is equivalent to the following
percentages of the RfD: U.S. population (48 states) 0.00029%; Nursing
infants (< 1 year old) 0.00003%; Non-nursing infants (< 1 year old)
0.00009%; Children (1-6 years old) 0.00053%; Children (7-12 years old)
0.00045%; Non-Hispanic Whites 0.00030%; Males (13-19 years old)
0.00032%.
The subgroups listed above are: (1) the U.S. population (48
states); (2) those for infants and children; and (3) the other
subgroups for which the percentage of the RfD occupied is greater than
that occupied by the subgroup U.S. population (48 states).
2. From drinking water-- i. Acute exposure and risk. As previously
stated, no acute dietary endpoint was identified for assessment of
acute dietary risk. Thus the risk from acute exposure is considered to
be negligible.
ii. Chronic exposure and risk. No monitoring data is available to
perform a quantitative drinking water risk assessment for pyriproxyfen
at this time. Thus, the GENEEC model and the SCI-GROW model were run to
produce estimates of pyriproxyfen concentrations in surface and ground
water respectively. The primary use of these models is to provide a
coarse screen for sorting out pesticides for which OPP has a high
degree of confidence that the true levels of the pesticide in drinking
water will be less than the human health drinking water levels of
concern (DWLOCs). A human health DWLOC is the concentration of a
pesticide in drinking water which would result in unacceptable
aggregate risk, after having already factored in all food exposures and
other non-occupational exposures for which OPP has reliable data.
For chronic (non-cancer) exposure to pyriproxyfen in surface and
ground water, the drinking water levels of concern are 12,250 g/L for
males (13 yrs+), 10,500 g/L for females (13 yrs+) and 3,500 g/L for
children (1-6 yrs). To calculate the DWLOC for chronic (non-cancer)
exposure relative to a chronic toxicity endpoint, the chronic dietary
food exposure (from DRES) was subtracted from the RfD to obtain the
acceptable chronic (non-cancer) exposure to pyriproxyfen in drinking
water. DWLOCs were then calculated using default body weights and
drinking consumption figures.
Estimated average concentrations of pyriproxyfen in surface and
ground water are 0.011 ppb (after adjustment for the highly
conservative nature of the GENEEC model and 0.006 ppb, respectively).
The estimated average concentrations of pyriproxyfen in surface and
ground water are less than OPP's level of concern for pyriproxyfen in
drinking water as a contribution to chronic aggregate exposure.
Therefore, taking into account present uses and uses proposed in this
action, OPP concludes with reasonable certainty that residues of
pyriproxyfen in drinking water (when considered along with other
sources of exposure for which OPP has reliable data) would not result
in unacceptable levels of aggregate human health risk at this time.
3. From non-dietary exposure. Pyriproxyfen is the active ingredient
in many registered residential (indoor, non-food) products for flea and
tick control. Formulations include foggers, aerosol sprays,
emulsifiable concentrates, and impregnated materials (pet collars).
Pyriproxyfen (2-[1-methyl-2-(4-phenoxyphenoxy)ethoxy]pyridine is
currently registered for use on the following residential non-food
sites: indoor premise, pet bedding, dogs and cats.
i. Acute exposure and risk. An acute dietary dose and endpoint was
not
[[Page 36370]]
identified. Thus the risk from acute aggregate exposure is considered
to be negligible.
ii. Chronic exposure and risk. Long-term exposure to pyriproxyfen
in residential use products is not expected. Therefore there is no
chronic risk. Consumer use of these products typically results in
short-term, intermittent exposures.
iii. Short- and intermediate-term exposure and risk. The Agency
concludes that there is reasonable certainty of no harm from short term
and intermediate-term dermal and inhalation occupational and
residential exposure due to the lack of significant toxicological
effects observed.
4. Cumulative exposure to substances with common mechanism of
toxicity. Section 408(b)(2)(D)(v) requires that, when considering
whether to establish, modify, or revoke a tolerance, the Agency
consider ``available information'' concerning the cumulative effects of
a particular pesticide's residues and ``other substances that have a
common mechanism of toxicity.'' The Agency believes that ``available
information'' in this context might 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. EPA has
begun a pilot process to study this issue further through the
examination of particular classes of pesticides. The Agency hopes that
the results of this pilot process will increase the Agency's scientific
understanding of this question such that EPA will be able to develop
and apply scientific principles for better determining which chemicals
have a common mechanism of toxicity and evaluating the cumulative
effects of such chemicals. The Agency anticipates, however, that even
as its understanding of the science of common mechanisms increases,
decisions on specific classes of chemicals will be heavily dependent on
chemical specific data, much of which may not be presently available.
Although at present the Agency does not know how to apply the
information in its files concerning common mechanism issues to most
risk assessments, there are pesticides as to which the common mechanism
issues can be resolved. These pesticides include pesticides that are
toxicologically dissimilar to existing chemical substances (in which
case the Agency can conclude that it is unlikely that a pesticide
shares a common mechanism of activity with other substances) and
pesticides that produce a common toxic metabolite (in which case common
mechanism of activity will be assumed).
EPA does not have, at this time, available data to determine
whether pyriproxyfen (2-[1-methyl-2-(4-phenoxyphenoxy)ethoxy]pyridine
has a common mechanism of toxicity with other substances or how to
include this pesticide in a cumulative risk assessment. Unlike other
pesticides for which EPA has followed a cumulative risk approach based
on a common mechanism of toxicity, pyriproxyfen (2-[1-methyl-2-(4-
phenoxyphenoxy)ethoxy]pyridine does not appear to produce a toxic
metabolite produced by other substances. For the purposes of this
tolerance action, therefore, EPA has not assumed that pyriproxyfen (2-
[1-methyl-2-(4-phenoxyphenoxy)ethoxy]pyridine has a common mechanism of
toxicity with other substances.
D. Aggregate Risks and Determination of Safety for U.S. Population
1. Acute risk. An acute dietary dose and endpoint was not
identified. Thus the risk from acute aggregate exposure is considered
to be negligible.
2. Chronic risk. Using the TMRC exposure assumptions described
above, EPA has concluded that aggregate exposure to pyriproxyfen (2-[1-
methyl-2-(4-phenoxyphenoxy)ethoxy]pyridine from food will utilize
0.0003% of the RfD for the U.S. population. The major identifiable
subgroup with the highest aggregate exposure is children (1-6 years
old). See discussion below. 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. There are currently no chronic
residential scenarios. The estimated average concentrations of
pyriproxyfen in surface and ground water are less than OPP's level of
concern for pyriproxyfen in drinking water as a contribution to chronic
aggregate exposure. Therefore, EPA concludes with reasonable certainty
that residues of pyriproxyfen (2-[1-methyl-2-(4-
phenoxyphenoxy)ethoxy]pyridine in drinking water do not contribute
significantly to the aggregate chronic human health risk at the present
time when considering the present uses and uses proposed by this
action.
E. Aggregate Cancer Risk for U.S. Population
Pyriproxyfen is classified as Category E: not carcinogenic in two
acceptable animal studies.
F. Aggregate Risks and Determination of Safety for Infants and Children
1. Safety factor for infants and children-- i. In general . In
assessing the potential for additional sensitivity of infants and
children to residues of pyriproxyfen (2-[1-methyl-2-(4-
phenoxyphenoxy)ethoxy]pyridine, EPA considered data from developmental
toxicity studies in the rat and rabbit and a two-generation
reproduction study in the rat. The developmental toxicity studies are
designed to evaluate adverse effects on the developing organism
resulting from maternal pesticide exposure gestation. Reproduction
studies provide information relating to effects from exposure to the
pesticide on the reproductive capability of mating animals and data on
systemic toxicity.
FFDCA section 408 provides that EPA shall apply an additional
tenfold margin of safety for infants and children in the case of
threshold effects to account for pre-and post-natal toxicity and the
completeness of the database unless EPA determines that a different
margin of safety will be safe for infants and children. Margins of
safety are incorporated into EPA risk assessments either directly
through use of a MOE analysis or through using uncertainty (safety)
factors in calculating a dose level that poses no appreciable risk to
humans. EPA believes that reliable data support using the standard
uncertainty factor (usually 100 for combined inter- and intra-species
variability)) and not the additional tenfold MOE/uncertainty factor
when EPA has a complete data base under existing guidelines and when
the severity of the effect in infants or children or the potency or
unusual toxic properties of a compound do not raise concerns regarding
the adequacy of the standard MOE/safety factor.
ii. Developmental toxicity studies. In the rat developmental study,
the developmental NOEL was 100 mg/kg/day and the maternal NOEL was 100
mg/kg/day. Therefore, there was no prenatal developmental toxicity in
the presence of maternal toxicity. Similarly in rabbits, the prenatal
developmental NOEL was 300 mg/kg/day and the maternal NOEL was 300 mg/
kg/day. Therefore, prenatally exposed fetuses were not more sensitive
to the effects of pyriproxyfen than maternal animals.
[[Page 36371]]
iii. Reproductive toxicity study. In the rat reproduction study,
the parental NOEL of 1,000 ppm was identical to the pup NOEL of 1,000
ppm and decreased body weight was seen in both pup and parental
animals. This finding demonstrates that there are no extra
sensitivities with respect to pre- and post-natal toxicity between
adult and infant animals.
iv. Pre- and post-natal sensitivity. The oral perinatal and
prenatal data demonstrated no indication of increased sensitivity of
rats or rabbits to in utero and postnatal exposure to pyriproxyfen.
v. Conclusion. The 10x factor for infants and children (as required
by FQPA) was removed, since there was no special sensitivity for
infants and children and the data base is complete. For chronic dietary
risk assessment, a UF of 100 is adequate for protection from exposure
to pyriproxyfen.
2. Acute risk. An acute dietary dose and endpoint was not
identified. Thus the risk from acute aggregate exposure is considered
to be negligible.
3. Chronic risk. Using the conservative exposure assumptions
described above, EPA has concluded that aggregate exposure to
pyriproxyfen (2-[1-methyl-2-(4-phenoxyphenoxy)ethoxy]pyridine from food
will utilize 0.00053% of the RfD for infants and children. 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. There are currently no chronic residential scenarios. The
estimated average concentrations of pyriproxyfen in surface and ground
water are less than OPP's level of concern for pyriproxyfen in drinking
water as a contribution to chronic aggregate exposure. Therefore, OPP
concludes with reasonable certainty that residues of pyriproxyfen (2-
[1-methyl-2-(4-phenoxyphenoxy)ethoxy]pyridine in drinking water do not
contribute significantly to the aggregate chronic human health risk at
the present time when considering the present uses and uses proposed by
this action. EPA concludes that there is a reasonable certainty that no
harm will result to infants and children from aggregate exposure to
pyriproxyfen (2-[1-methyl-2-(4-phenoxyphenoxy)ethoxy]pyridine residues.
4. Short- or intermediate-term risk. 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.
III. Other Considerations
A. Metabolism In Plants and Animals
EPA considers the nature of the residue in cotton to be adequately
understood. Metabolism of pyriproxyfen in cotton proceeds through
hydroxylation and cleavage of the phenoxy ether linkage, with
additional metabolism by oxidation and conjugation reactions. Much of
the metabolized pyriproxyfen is reincorporated into natural products.
The HED Metabolism Committee previously issued a tentative conclusion
(15-JUL-1996) that the residue of concern in plants is pyriproxyfen per
se. A meeting of the Chemistry Science Advisory Council (25-FEB-1998)
confirmed this conclusion for cotton and determined that future food
uses involving pyriproxyfen should be reviewed by the HED Metabolism
Committee. Metabolism of phenyl-14C pyriproxyfen in poultry
proceeds through hydroxylation of the phenoxyphenyl ring, sulfation of
the 4'-OH phenoxyphenyl moiety, hydroxylation of the pyridyl ring, and
cleavage of the ether linkage. Metabolism of pyridyl-14C
pyriproxyfen in poultry proceeds through hydroxylation of the
phenoxyphenyl ring, sulfation of the 4'-OH phenoxyphenyl moiety,
hydroxylation of the pyridyl ring, cleavage of the ether linkage and
oxidation of the side chain. EPA concludes that the nature of the
residue in poultry is adequately understood, and that tolerances are
not needed.
Metabolism of phenyl-14C pyriproxyfen in goats proceeds
through hydroxylation of the phenoxyphenyl and pyridyl rings, sulfation
of the 4'-OH phenoxyphenyl moiety, and cleavage of the ether linkage.
Metabolism of pyridyl-14C pyriproxyfen in goats proceeds
through hydroxylation of the phenoxyphenyl and pyridyl rings, sulfation
of the 4'-OH phenoxyphenyl moiety, cleavage of the ether linkage and
oxidation of the side chain. EPA concludes that the nature of the
residue in ruminants is adequately understood for this present use and
that tolerances are not required.
B. Analytical Enforcement Methodology
Residue analytical method RM-33P-2 has undergone validation in EPA
laboratories and is suitable to gather residue data and to enforce
tolerances.
The multiresidue method will serve as a confirmatory method for
residues of pyriproxyfen.
C. Magnitude of Residues
Based on the radioactive metabolic studies and the calculated
dietary burden, EPA concludes that the proposed uses on cotton fall
under 40 CFR 180.6(a)(3) since there is no reasonable expectation of
finite residues in meat, milk, poultry, and eggs and thus tolerances
are not required at this time. If additional uses are sought that could
result in greater livestock dietary exposure from feedstuffs, the need
for milk, meat, poultry and eggs tolerances will be reassessed.
D. International Residue Limits
There are no CODEX, Canadian, or Mexican tolerances for
pyriproxyfen residues on cottonseed or cotton gin byproducts.
Therefore, international harmonization is not an issue at this time.
Pyriproxyfen is scheduled as a new compound for JMPR review (both
toxicology and residue chemistry) in 1999.
E. Rotational Crop Restrictions
An acceptable confined accumulation in rotational crops study with
Ph-14C and Py-14C pyriproxyfen was submitted .
The study showed no significant uptake (<0.01 ppm) of radioactive
residues (pyriproxyfen) by lettuce, radish, or wheat. The majority of
the 14C was found in the unextractable material in the post
extraction solids. These findings indicated that the 14C has
been reincorporated in other, non-pyriproxyfen related compounds.
Therefore a plant back interval is not necessary for cotton treated
with pyriproxyfen.
IV. Conclusion
Therefore, tolerances are established for combined residues of
pyriproxfen in cotton seed and cotton gin byproducts at 0.05 and 2.0
ppm respectively.
V. Objections and Hearing Requests
The new FFDCA section 408(g) provides essentially the same process
for persons to ``object'' to a tolerance regulation issued by EPA under
new section 408(e) and (l)(6) as was provided in the old section 408
and in section 409. However, the period for filing objections is 60
days, rather than 30 days. EPA currently has procedural regulations
which govern the submission of objections and hearing requests. These
regulations will require some modification to reflect the new law.
However, until those modifications can be made, EPA will continue to
use those procedural regulations with appropriate adjustments to
reflect the new law.
[[Page 36372]]
Any person may, by September 4, 1998, file written objections to
any aspect of this regulation and may also request a hearing on those
objections. Objections and hearing requests must be filed with the
Hearing Clerk, at the address given above (40 CFR 178.20). A copy of
the objections and/or hearing requests filed with the Hearing Clerk
should be submitted to the OPP docket for this rulemaking. The
objections submitted must specify the provisions of the regulation
deemed objectionable and the grounds for the objections (40 CFR
178.25). Each objection must be accompanied by the fee prescribed by 40
CFR 180.33(i). If a hearing is requested, the objections must include a
statement of the factual issues on which a hearing is requested, the
requestor's contentions on such issues, and a summary of any evidence
relied upon by the requestor (40 CFR 178.27). A request for a hearing
will be granted if the Administrator determines that the material
submitted shows the following: There is genuine and substantial issue
of fact; there is a reasonable possibility that available evidence
identified by the requestor would, if established, resolve one or more
of such issues in favor of the requestor, taking into account
uncontested claims or facts to the contrary; and resolution of the
factual issues in the manner sought by the requestor would be adequate
to justify the action requested (40 CFR 178.32). Information submitted
in connection with an objection or hearing request may be claimed
confidential by marking any part or all of that information as CBI.
Information so marked will not be disclosed except in accordance with
procedures set forth in 40 CFR part 2. A copy of the information 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.
VI. Public Record and Electronic Submissions
EPA has established a record for this rulemaking under docket
control number [OPP-300666] (including any comments and data submitted
electronically). 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 public
record is located in Room 119 of the Public Information and Records
Integrity Branch, Information Resources and Services Division (7502C),
Office of Pesticide Programs, Environmental Protection Agency, Crystal
Mall #2, 1921 Jefferson Davis Hwy., Arlington, VA.
Electronic comments may be sent directly to EPA at:
[email protected].
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption.
The official record for this rulemaking, as well as the public
version, as described above will be kept in paper form. Accordingly,
EPA will transfer any copies of objections and hearing requests
received electronically into printed, paper form as they are received
and will place the paper copies in the official rulemaking record which
will also include all comments submitted directly in writing. The
official rulemaking record is the paper record maintained at the
Virginia address in ``ADDRESSES'' at the beginning of this document.
VII. Regulatory Assessment Requirements
This final rule establishes tolerances under FFDCA section 408(d)
in response to a petition submitted to the Agency. The Office of
Management and Budget (OMB) has exempted these types of actions from
review under Executive Order 12866, entitled Regulatory Planning and
Review (58 FR 51735, October 4, 1993). This final rule does not contain
any information collections subject to OMB approval under the Paperwork
Reduction Act (PRA), 44 U.S.C. 3501 et seq., or impose any enforceable
duty or contain any unfunded mandate as described under Title II of the
Unfunded Mandates Reform Act of 1995 (UMRA) (Pub. L. 104-4). Nor does
it require any prior consultation as specified by Executive Order
12875, entitled Enhancing the Intergovernmental Partnership (58 FR
58093, October 28, 1993), or special considerations as required by
Executive Order 12898, entitled Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations (59 FR 7629, February 16, 1994), or require OMB review in
accordance with Executive Order 13045, entitled Protection of Children
from Environmental Health Risks and Safety Risks (62 FR 19885, April
23, 1997).
In addition, since these tolerances and exemptions that are
established on the basis of a petition under FFDCA section 408(d), such
as the tolerances in this final rule, do not require the issuance of a
proposed rule, the requirements of the Regulatory Flexibility Act (RFA)
(5 U.S.C. 601 et seq.) do not apply. Nevertheless, the Agency has
previously assessed whether establishing tolerances, exemptions from
tolerances, raising tolerance levels or expanding exemptions might
adversely impact small entities and concluded, as a generic matter,
that there is no adverse economic impact. The factual basis for the
Agency's generic certification for tolerance actions published on May
4, 1981 (46 FR 24950) and was provided to the Chief Counsel for
Advocacy of the Small Business Administration.
VIII. Submission to Congress and the Comptroller General
The Congressional Review Act, 5 U.S.C. 801 et seq., as added by the
Small Business Regulatory Enforcement Fairness Act of 1996, generally
provides that before a rule may take effect, the agency promulgating
the rule must submit a rule report, which includes a copy of the rule,
to each House of the Congress and to the Comptroller General of the
United States. EPA will submit a report containing this rule and other
required information to the U.S. Senate, the U.S. House of
Representatives, and the Comptroller General of the United States prior
to publication of the rule in the Federal Register. This rule is not a
``major rule'' as defined by 5 U.S.C. 804(2).
List of Subjects in 40 CFR Part 180
Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Reporting and
recordkeeping requirements.
Dated: June 18, 1998.
Stephen L. Johnson,
Acting Director, Office of Pesticide Programs.
Therefore, 40 CFR chapter I is amended as follows:
PART 180-- [AMENDED]
1. The authority citation for part 180 continues to read as
follows:
Authority: 21 U.S.C. 346a and 371.
2. Section 180.534 is added to subpart C to read as follows:
Sec. 180.534 Pyriproxyfen; tolerances for residues.
(a) General. Tolerances are established for combined residues of
the insecticide pyriproxyfen in or on the following agricultural
commodities:
------------------------------------------------------------------------
Commodity Parts per million
------------------------------------------------------------------------
Cotton gin byproducts..................... 2.0
[[Page 36373]]
Cottonseed................................ 0.05
------------------------------------------------------------------------
(b) Section 18 emergency exemptions. [Reserved]
(c) Tolerances with regional registrations. [Reserved]
(d) Indirect or inadvertent residues. [Reserved]
[FR Doc. 98-17729 Filed 7-2-98; 8:45 am]
BILLING CODE 6560-50-F