[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: <a href="/cdn-cgi/l/email-protection#660916164b0209050d0312260316070b070f0a4803160748010910"><span class="__cf_email__" data-cfemail="1b746b6b367f7478707e6f5b7e6b7a767a7277357e6b7a357c746d">[email protected]</span></a>. 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: 
<a href="/cdn-cgi/l/email-protection#11657067707f7e3f7b7e62746179517461707c70787d3f7461703f767e67"><span class="__cf_email__" data-cfemail="94e0f5e2f5fafbbafefbe7f1e4fcd4f1e4f5f9f5fdf8baf1e4f5baf3fbe2">[email protected]</span></a>.

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 LD<INF>50</INF> in the rat is >5,000 milligram/
kilogram (mg/kg) for males and females - Toxicity Category IV; dermal 
LD<INF>50</INF> in the rabbit at >2,000 mg/kg - Toxicity Category IV; 
inhalation LC<INF>50</INF> 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 <greek-m>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 <greek-m>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 <greek-m>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 
<greek-m>g/mL (without activation) and 51.2 <greek-m>g/mL (with 
activation).
    7. Metabolism. The results of the metabolism studies are as 
follows:
    Acceptable: Rats were orally dosed with <SUP>14</SUP>C-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-<SUP>14</SUP>C 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-<SUP>14</SUP>C 
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-<SUP>14</SUP>C 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-<SUP>14</SUP>C 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-<SUP>14</SUP>C and Py-<SUP>14</SUP>C 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 <SUP>14</SUP>C was found in the unextractable material in the post 
extraction solids. These findings indicated that the <SUP>14</SUP>C 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:
    <a href="/cdn-cgi/l/email-protection#7d120d0d5019121e1618093d180d1c101c141153180d1c531a120b"><span class="__cf_email__" data-cfemail="acc3dcdc81c8c3cfc7c9d8ecc9dccdc1cdc5c082c9dccd82cbc3da">[email protected]</span></a>.


    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


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