Buprofezin (2-Tert-butylimino-3-isopropyl-5-phenyl-1,3,5- thiadiazinan-4-one); Time-Limited Pesticide Tolerances

[Federal Register: August 31, 2000 (Volume 65, Number 170)]
[Rules and Regulations]
[Page 52938-52947]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr31au00-10]

-----------------------------------------------------------------------

ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 180

[OPP-301040; FRL-6740-1]
RIN 2070-AB

Buprofezin (2-Tert-butylimino-3-isopropyl-5-phenyl-1,3,5-
thiadiazinan-4-one); Time-Limited Pesticide Tolerances

AGENCY: Environmental Protection Agency (EPA).

ACTION: Final rule.

-----------------------------------------------------------------------

SUMMARY: This regulation establishes time-limited tolerances for
residues of buprofezin in or on lettuce, head; lettuce, leaf; and
vegetables, cucurbits. Aventis CropScience requested these tolerances
under the Federal Food, Drug, and Cosmetic Act, as amended by the Food
Quality Protection Act of 1996. The tolerances will expire on December
31, 2004.

DATES: This regulation is effective August 31, 2000. Objections and
requests for hearings, identified by docket control number OPP-301040,
must be received by EPA on or before October 30, 2000.

ADDRESSES: Written objections and hearing requests may be submitted by
mail, in person, or by courier. Please follow the detailed instructions
for each method as provided in Unit VI. of the SUPPLEMENTARY
INFORMATION. To ensure proper receipt by EPA, your objections and
hearing requests must identify docket control number OPP-301040 in the
subject line on the first page of your response.

FOR FURTHER INFORMATION CONTACT: By mail: Richard J. Gebken,
Registration Division (7505C), Office of Pesticide Programs,
Environmental Protection Agency, Ariel Rios Bldg., 1200 Pennsylvania
Ave., NW., Washington, DC 20460; telephone number: (703) 305-6701; and
e-mail address: gebken.richard@epa.gov.

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this Action Apply to Me?

You may be affected by this action if you are an agricultural
producer, food manufacturer, or pesticide manufacturer. Potentially
affected categories and entities may include, but are not limited to:

------------------------------------------------------------------------
Examples of
Categories NAICS Potentially
Affected Entities
------------------------------------------------------------------------
Industry 111 Crop production
112 Animal production
311 Food manufacturing
32532 Pesticide
manufacturing
------------------------------------------------------------------------

[[Page 52939]]

This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in the table could also be
affected. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether or not this action might apply to certain entities. If you have
questions regarding the applicability of this action to a particular
entity, consult the person listed under FOR FURTHER INFORMATION
CONTACT.

B. How Can I Get Additional Information, Including Copies of this
Document and Other Related Documents?

1. Electronically.You may obtain electronic copies of this
document, and certain other related documents that might be available
electronically, from the EPA Internet Home Page at http://www.epa.gov/.
To access this document, on the Home Page select ``Laws and
Regulations,'' Regulations and Proposed Rules, and then look up the
entry for this document under the ``Federal Register--Environmental
Documents.'' You can also go directly to the Federal Register listings
at http://www.epa.gov/fedrgstr/.
2. In person. The Agency has established an official record for
this action under docket control number OPP-301040. The official record
consists of the documents specifically referenced in this action, and
other information related to this action, including any information
claimed as Confidential Business Information (CBI). This official
record includes the documents that are physically located in the
docket, as well as the documents that are referenced in those
documents. The public version of the official record does not include
any information claimed as CBI. The public version of the official
record, which includes printed, paper versions of any electronic
comments submitted during an applicable comment period is available for
inspection in the Public Information and Records Integrity Branch
(PIRIB), Rm. 119, Crystal Mall #2, 1921 Jefferson Davis Hwy.,
Arlington, VA, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays. The PIRIB telephone number is (703) 305-5805.

II. Background and Statutory Findings

In the Federal Register of August 26, 1998 (63 FR 45483) (FRL-5791-
1), EPA issued a notice pursuant to section 408 of the Federal Food,
Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a as amended by the Food
Quality Protection Act of 1996 (FQPA) (Public Law 104-170) announcing
the filing of a pesticide petition (PP) for tolerance by Aventis
CropScience (formerly AgrEvo USA Company, 2 T.W. Alexander Drive,
Research Triangle Park, N.C. 27709). This notice included a summary of
the petition prepared by Aventis CropScience, the registrant. There
were no comments received in response to the notice of filing.
The petition requested that 40 CFR 180.511 be amended by
establishing a tolerance for residues of the insecticide buprofezin, in
or on lettuce, head; lettuce, leaf; and vegetables, cucurbits at 5.0,
13.0, and 0.50 parts per million (ppm), respectively. The tolerances
will expire on December 31, 2004.
Buprofezin is an insecticide which will be sold under the trade
name of Applaud 70WP. Buprofezin is a new insect growth regulator used
for the control of several species of Homoptera spp., such as
planthoppers, mealybugs, leafhoppers, whiteflies and scales. It is
currently registered in 76 countries mainly for use on vegetables,
cotton, citrus, rice and ornamentals.
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. . . .''
EPA performs a number of analyses to determine the risks from
aggregate exposure to pesticide residues. For further discussion of the
regulatory requirements of section 408 and a complete description of
the risk assessment process, see the final rule on Bifenthrin Pesticide
Tolerances (62 FR 62961, November 26, 1997) (FRL-5754-7).

III. 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 and to
make a determination on aggregate exposure, consistent with section
408(b)(2), for a tolerance for residues of buprofezin on lettuce, head;
lettuce, leaf; and vegetables, cucurbits at 5.0, 13.0, and 0.50 parts
per million (ppm), respectively. EPA's assessment of 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 toxicological data base for buprofezin is adequate for
selecting toxicity endpoints according to the Agency guideline
requirements for a food-use chemical by 40 CFR part 158. However, an
additional developmental neurotoxicity study in rats is required to
address Agency concerns raised from the presence of thyroid effects
observed in rat and dog subchronic and/or chronic studies.
1. Acute toxicity. Buprofezin is classified by the Agency as
toxicity Category III for acute oral and toxicity category IV for acute
dermal toxicity, acute inhalation toxicity, eye irritation and dermal
irritation, and is not a dermal sensitizer. The nature of the toxic
effects caused by buprofezin are discussed in the following Table 1 as
well as the no observed adverse effect level (NOAEL) and the lowest
observed adverse effect level (LOAEL) from the toxicity studies
reviewed.

[[Page 52940]]

Table 1.--Acute Toxicity Data on Buprofezin Technical*
----------------------------------------------------------------------------------------------------------------
Guideline No. Study Type Results Toxicity Category
----------------------------------------------------------------------------------------------------------------
870.1100 Acute oral toxicity LD50 1,653 mg/kg males, III
LD50 2,015 mg/kg
females
----------------------------------------------------------------------------------------------------------------
870.1200 Acute dermal toxicity LD50 > 5,000 mg/kg IV
----------------------------------------------------------------------------------------------------------------
870.1300 Acute inhalation LC50 > 4.21 mg/L IV
toxicity (estimated)
----------------------------------------------------------------------------------------------------------------
870.2400 Acute eye irritation Mild IV
----------------------------------------------------------------------------------------------------------------
870.2500 Acute dermal irritation Slight IV
----------------------------------------------------------------------------------------------------------------
870.2600 Skin sensitization Negative NA
----------------------------------------------------------------------------------------------------------------
^*Buprofezin Technical (99% a.i.)

2. Subcronic, chronic, and other toxicity. For subchronic toxicity,
the primary effects of concern in the rat were increased microscopic
lesions in male and female liver and thyroid, increased liver weights
in males and females, and increased thyroid weight in males. Increased
focal necrosis with an inflammatory infiltrate in the liver was
observed in females following dermal subchronic exposure, as was
increased acanthosis and hyperkeratosis in skin.
In chronic studies in the rat, an increased incidence of follicular
cell hyperplasia and hypertrophy in the thyroid of males was reported.
Increased relative liver weights were reported in female dogs. In the
mouse, increased absolute liver weights in males and females, along
with an increased incidence of hepatocellular adenomas and
hepatocellular adenomas plus carcinomas in females were reported. The
Agency has evaluated the carcinogenic potential of buprofezin, based on
these liver tumors in female mice, and classified it as having
``Suggestive Evidence of Carcinogenicity, but not sufficient to assess
human carcinogenic potential.''
The developmental toxicity study in the rat produced reduced
ossification and reduced pup weight at maternally toxic doses (death,
decreased pregnancy rates, and increased resorption rates). No
developmental toxicity was observed in the rabbit at or below
maternally toxic dose levels.
The reproductive toxicity study showed decreased pup body weights
at dose levels where liver effects (increased relative and/or absolute
liver weights) and decreased body weight gains were observed in the
parental generations.
The data do not raise concern for susceptibility in offspring. The
developmental and reproductive studies showed toxicity in the offspring
only at dose levels that were toxic in the parent(s). The toxicity
observed in the offspring was not more severe, qualitatively, than the
toxicity observed in the parents.
The data do not indicate a basis for concern for neurotoxicity.
Possible neurotoxicity (hunched positions, lethargy) was observed in
the rat developmental toxicity study, at levels that caused death. In
the 90-day rat subchronic study, a 24% decrease in plasma
cholinesterase was reported in males and females at the high dose
level. However, this was not correlated with any pathological
observation or functional deficit. Neurotoxicity was not observed in
any of the chronic studies in the rat, mouse, or dog.
There is no concern for mutagenic activity in several studies such
as the Ames assay, forward mutation assay, mouse micronucleus assay, in
vitro human cytogenetic assay, and unscheduled DNA synthesis.
A rat metabolism study indicated that 95% of the administered
compound is recovered in the feces and urine within 72 hours, and that
45% is recovered as the parent compound, with the remainder as several
metabolites. The nature of the toxic effects caused by buprofezin are
discussed in the following Table 2 as well as the NOAEL and the LOAEL
from the toxicity studies reviewed.

Table 2.--Subchronic, Chronic, and Other Toxicity
------------------------------------------------------------------------
Guideline No. Study Type Results
------------------------------------------------------------------------
870.3100 90-Day oral NOAEL: 13.0 mg/kg/day
toxicity rodents (Males or M); 16.3
(rat) mg/kg/day (Females
or F)
LOAEL: 68.6 mg/kg/day
(M); 81.8 mg/kg/day
females based on
increased relative
thyroid weight
males, increased
liver weights M/F,
increased
microscopic lesions
in liver and thyroid
M/F
------------------------------------------------------------------------
870.3200 24-Day dermal Systemic NOAEL: 300
toxicity (rat) mg/kg/day
Dermal NOAEL: 300 mg/
kg/day
Systemic LOAEL: 1,000
mg/kg/day based on
increased focal
necrosis with an
inflammatory
infiltrate in liver
(F)
Dermal LOAEL: 1,000
mg/kg/day based on
increased acanthosis
and hyperkeratosis
in skin (F)
------------------------------------------------------------------------
870.3700a Developmental Maternal NOAEL 200 mg/
toxicity in kg/day
rodents (rat)
Developmental NOAEL
200 mg/kg/day
Maternal LOAEL 800 mg/
kg/day based on
mortality, decreased
pregnancy rates,
increased resorption
rates

[[Page 52941]]

Developmental LOAEL
800 mg/kg/day based
on reduced
ossification,
reduced pup weight,
fetal edema
------------------------------------------------------------------------
870.3700b Developmental Maternal NOAEL 50 mg/
toxicity in non- kg/day
rodents (rabbit)
Developmental NOAEL
250 mg/kg/day
Maternal LOAEL 250 mg/
kg/day based on
decreased food
consumption,
decreased body
weights.
Developmental LOAEL,
not established (>
250 mg/kg/day)
------------------------------------------------------------------------
870.3800 Reproduction and Parental NOAEL 7.89
fertility mg/kg/day
effects in rats
Reproductive/
Developmental NOAEL
7.89 mg/kg/day
Parental LOAEL 81.47
mg/kg/day based on
decreased body
weight gain and on
organ weight changes
Reproductive/
Developmental LOAEL
81.47 mg/kg/day
based on decreased
pup weight.
------------------------------------------------------------------------
870.4100 Chronic toxicity NOAEL 2 mg/kg/day
in dogs
LOAEL 20 mg/kg/day
based on increased
bile duct
hyperplasia M/F,
increased serum
alkaline phosphatase
activity M/F,
increased relative
and absolute liver
weights and
decreased liver
function in females
------------------------------------------------------------------------
870.4200 Carcinogenicity NOAEL 1.82/17.9 mg/kg/
study in mice day (M/F)
LOAEL 17.40/191.0 mg/
kg/day (M/F) based
on increased
absolute liver
weights in males and
females, increased
hepatocellular
adenomas in females,
increased
hepatocellular
adenomas +
carcinomas in
females
------------------------------------------------------------------------
870.4300 Chronic toxicity/ NOAEL 1.0 mg/kg/day
carcinogenicity
in rodents (rat)
LOAEL 8.7 mg/kg/day
based on increased
incidence of
follicular cell
hyperplasia and
hypertrophy in
thyroid in males
No evidence of
carcinogenicity
------------------------------------------------------------------------
870.5100 Mutagenicity: Not mutagenic, with
gene mutation or without
Salmonella activation tested up
to cytotoxic levels
------------------------------------------------------------------------
870.5300 Mutagenicity: Not mutagenic, with
gene mutation or without
mouse lymphoma activation tested up
to cytotoxic levels
------------------------------------------------------------------------
870.5300 Mutagenicity: in Negative for
vitro human chromosomal
cytogenetic aberrations tested
assay up to cytotoxic
levels
------------------------------------------------------------------------
870.5300 Mutagenicity: Negative for
mouse micronucleus
micronucleus induction in bone
assay marrow cells of
males and females
tested up to
cytotoxic levels
------------------------------------------------------------------------
870.5300 Mutagenicity: Negative for DNA
unscheduled DNA repair tested up to
synthesis cytotoxic levels
------------------------------------------------------------------------
870.7485 Metabolism 79.1% recovered from
feces, 12.9% from
urine within 72 hr.
45.4% recovered as
parent cpd, several
metabolites
identified
------------------------------------------------------------------------

B. Toxicological Endpoints

The dose at which no adverse effects are observed (the NOAEL) from
the toxicology study identified as appropriate for use in risk
assessment is used to estimate the toxicological level of concern
(LOC). However, the lowest dose at which adverse effects of concern are
identified (the LOAEL) is sometimes used for risk assessment if no
NOAEL was achieved in the toxicology study selected. An uncertainty
factor (UF) is applied to reflect uncertainties inherent in the
extrapolation from laboratory animal data to humans and in the
variations in sensitivity among members of the human population as well
as other unknowns. An UF of 100 is routinely used, 10X to account for
interspecies differences and 10X for intraspecies differences.
For dietary risk assessment (other than cancer), the Agency uses
the UF to calculate an acute or chronic reference dose (acute RfD or
chronic RfD) where the RfD is equal to the NOAEL divided by the
appropriate UF (RfD=NOAEL/UF). Where an additional safety factor is
retained due to concerns unique to the FQPA, this additional factor is
applied to the RfD by dividing the RfD by such additional factor. The
acute or chronic Population Adjusted Dose (aPAD or cPAD) is a
modification of the RfD to accommodate this type of FQPA Safety Factor.
For non-dietary risk assessments (other than cancer), the UF is
used to determine the LOC. For example, when 100 is the appropriate UF
(10X to account for interspecies differences and 10X for intraspecies
differences) the LOC is 100. To estimate risk, a ratio of the NOAEL to
exposures (margin of exposure (MOE)=NOAEL/exposure) is calculated and
compared to the LOC.
The linear default risk methodology (Q*) is the primary method
currently used by the Agency to quantify carcinogenic risk. The Q*
approach assumes that any amount of exposure will lead to some degree
of cancer risk.

[[Page 52942]]

A Q* is calculated and used to estimate risk which represents a
probability of occurrence of additional cancer cases (e.g., risk is
expressed as 1 x 10^-6 or one in a million). Under certain
specific circumstances, MOE calculations will be used for the
carcinogenic risk assessment. In this non-linear approach, a ``point of
departure'' is identified below which carcinogenic effects are not
expected. The point of departure is typically a NOAEL based on an
endpoint related to cancer effects though it may be a different value
derived from the dose response curve. To estimate risk, a ratio of the
point of departure to exposure (MOEcancer=point of
departure/exposures) is calculated. The doses and toxicological
endpoints selected and the LOC for margins of exposure for various
exposure scenarios are summaried in the following Table 3.

Table 3.--Toxicological Endpoint Summary for Use in Human Risk Assessment
----------------------------------------------------------------------------------------------------------------
Exposure Scenario Dose (mg/kg/day) Endpoint Study
----------------------------------------------------------------------------------------------------------------
Acute Dietary NOAEL = 200 UF = 100 LOAEL = 800 mg/kg/day Developmental toxicity
based on skeletal rabbit
effects in offspring
Acute RfD = 2.0 mg/kg NA
(females 13 - 50);
Acute RfD for general
population including
infants and children:
None, no endpoint
identified which was
attributable to a
single dose.
----------------------------------------------------------------------------------------------------------------
Chronic Dietary NOAEL = 1.0 UF = 100 LOAEL = 8.7 mg/kg/day 2-year chronic toxicity/
based on increased oncogenicity in rat
incidence of
follicular cell
hyperplasia and
hypertrophy in the
thyroid in males.
Chronic RfD = 0.01 mg/ NA
kg day
----------------------------------------------------------------------------------------------------------------
Short-term (dermal) NOAEL = 300 LOAEL = 1,000 mg/kg/day 24-Day dermal rat
based on an increase
of focal necrosis with
an inflammatory
infiltrate in liver in
females
----------------------------------------------------------------------------------------------------------------
Intermediate-term (dermal) NOAEL = 300 LOAEL = 1,000 mg/kg/day 24-Day dermal rat
based on an increase
of focal necrosis with
an inflammatory
infiltrate in liver in
females
----------------------------------------------------------------------------------------------------------------
Long-term (dermal) Oral NOAEL = 1.0* LOAEL = 8.7 mg/kg/day 2-Year chronic oral
based on increased toxicity/oncogenicity
incidence of in rat
follicular cell
hyperplasia and
hypertrophy in the
thyroid in males. 30%
dermal absorption
estimated.
----------------------------------------------------------------------------------------------------------------
Short-term (inhalation) Oral NOAEL = 200** LOAEL = 800 mg/kg/day Developmental toxicity
based on skeletal rat
effects in offspring
----------------------------------------------------------------------------------------------------------------
Intermediate-term (inhalation) Oral NOAEL = 13** LOAEL = 68.6 mg/kg/day 90-Day oral subchronic
abased on organ weight study in rat
changes and
microscopic findings
in liver and thyroid
(M and F) and kidney
(M)
----------------------------------------------------------------------------------------------------------------
Long-term (inhalation) Oral NOAEL = 1** LOAEL = 8.7 mg/kg/day 2-Year chronic oral
based on increased toxicity/oncogenicity
incidence of in rat
follicular cell
hyperplasia and
hypertrophy in the
thyroid in males.
----------------------------------------------------------------------------------------------------------------
^*Since an oral NOAEL was selected, 30% dermal absorption was used.
^**Since an oral NOAEL was selected, 100% inhalation absorption was used.

C. Exposure Assessment

1. Dietary exposure from food and feed uses. Time-limited
tolerances under section 18 emergency exemptions have been established
(40 CFR 180.511(b)) for the residues of buprofezin, in or on a variety
of raw agricultural commodities. The following time-limited tolerances
for residues of buprofezin are established in connection with use of
the pesticide under section 18 emergency exemptions: citrus fruit (2.0
ppm); citrus pulp dried (10 ppm); cotton seed (1.0 ppm); cotton gin
byproducts (20 ppm); cucurbits (0.5 ppm); tomatoes (0.7 ppm); tomato
paste (1.0 ppm); milk (0.03 ppm); and fat (0.02 ppm), meat (0.02 ppm),
and meat byproducts (0.5 ppm) of cattle, goats, hogs, horses, and
sheep. Risk assessments were conducted by EPA to assess dietary
exposures from buprofezin in food as follows:
i. Acute exposure. 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 1 day or
single exposure. The Dietary Exposure Evaluation Model
(DEEM^TM) analysis evaluated the individual food consumption
as reported by respondents in the U.S. Department of Agriculture (USDA)
1989-1992 nationwide Continuing Surveys of Food Intake by Individuals
(CSFII) and accumulated exposure to the chemical for each commodity.
The following assumptions were made for the acute exposure assessments:
The acute dietary exposure analysis assumed tolerance level residues
and 100% crop treated for all registered and proposed commodities (Tier
1). For females 13-50 years old, 4% of the aPAD is occupied by dietary
(food) exposure (no acute RfD established for the general population
including infants and children). Therefore acute exposure to
buprofezin, as a result of dietary exposure, is below the Agency's
level of concern. The anticipated residues were used for evaluation.
ii. Chronic exposure. In conducting this chronic dietary risk
assessment, the DEEM^TM analysis evaluated the individual
food consumption as reported by respondents in the USDA 1989-1992
nationwide CSFII and accumulated exposure to the chemical

[[Page 52943]]

for each commodity. The following assumptions were made for the chronic
exposure assessments: Since there are no chronic residential exposure
scenarios, the chronic aggregate risk assessment is concerned with food
and water only. The chronic dietary exposure analysis incorporated
anticipated residues calculated from field trial data and assumed 100%
crop treated for all commodities except tomatoes (44% and 0.6% crop
treated for the fresh market and for processing, respectively; Tier 2
analysis). Only 49% of the cPAD is occupied by dietary (food) exposure
The buprofezin estimated environmental concentrations in surface and
ground water are less than the Agency's DWLOC (for all population
subgroups). Chronic risk for buprofezin, as a result of dietary (food
and water) exposure, is below the Agency's level of concern. The Agency
concludes with reasonable certainty that residues of buprofezin in food
and drinking water do not contribute significantly to the acute or
chronic aggregate human health risk at the present time.
iii. Cancer. The Agency has evaluated the carcinogenicity
potential of buprofezin, based on these liver tumors in female mice.
Buprofezin was not carcinogenic to male and female rats. Administration
of buprofezin in the diet was associated with increased incidence of
liver tumors in female mice only because:
a. There was a significant increase by pair-wise comparison with
the controls for combined hepatocellular adenomas/carcinomas at 2,000
and 5,000 ppm (191.9 and 493 mg/kg/day, respectively) in females. The
increased incidence of combined tumors was driven by the incidence of
adenomas. There was a significant positive trend for combined tumors
and a dose-related increase in the incidence at the two top doses. The
increase in the combined incidence of liver tumors at 2,000 and 5,000
ppm was associated with non-neoplastic changes and the incidences were
slightly outside the historical control range. The increased incidence
of hepatocellular adenomas/carcinomas at 2,000 ppm in females was
considered by the Agency to be biologically significant.
b. In males, there was a significant increase by pair-wise
comparison with the controls for combined adenomas/carcinomas of the
lung at 20, 200 and 5,000 ppm (1.82, 17.4, or 481 mg/kg/day,
respectively). Although there was evidence of a positive trend with
increasing doses of buprofezin, the incidences in all dose groups were
within the range for the historical controls. The Agency, therefore,
concluded that the lung tumors in males were not treatment-related. The
dosing at 5,000 ppm was considered to be adequate and not excessive
based on increased liver weights in females, histopathological changes
in the liver, and decreased body weight gains at 5,000 ppm in both
sexes.
Although buprofezin was negative in in vitro and in vivo
genotoxicity assays, the findings from the published literature
indicate that it causes cell transformation and induces micronuclei in
vitro. However, in the absence of a positive response in an in vivo
micronucleus assay, the Agency concluded that buprofezin may have
aneugenic potential which is not expressed in vivo.
Consistent with the EPA Guidelines for Carcinogen Risk Assessment
(proposed July 1999), the Agency has classified buprofezin as having
``Suggestive Evidence of Carcinogenicity, but not sufficient to assess
human carcinogenic potential.'' The Agency concluded that no
quantification of cancer risk or assessment is appropriate, taking into
account all of the evidence bearing on carcinogenicity including that a
positive finding was limited to one sex of one species.
iv. Anticipated residues. Section 408(b)(2)(E) authorizes EPA to
use available data and information on the anticipated residue levels of
pesticide residues in food and the actual levels of pesticide chemicals
that have been measured in food. If EPA relies on such information, EPA
must require that data be provided 5 years after the tolerance is
established, modified, or left in effect, demonstrating that the levels
in food are not above the levels anticipated. Following the initial
data submission, EPA is authorized to require similar data on a time
frame it deems appropriate. As required by section 408(b)(2)(E), EPA
will issue a Data Call-In for information relating to anticipated
residues to be submitted no later than 5 years from the date of
issuance of this tolerance.
2. Dietary exposure from drinking water. The maximum and average
EECs for buprofezin in ground and surface water are less than the
Agency's DWLOC for buprofezin as a contribution to acute and chronic
aggregate exposure (for all population subgroups).
The Agency lacks sufficient monitoring exposure data to complete a
comprehensive dietary exposure analysis and risk assessment for
buprofezin in drinking water. Because the Agency does not have
comprehensive monitoring data, drinking water concentration estimates
are made by reliance on simulation or modeling taking into account data
on the physical characteristics of buprofezin.
The Agency uses the Generic Estimated Environmental Concentration
(GENEEC) or the Pesticide Root Zone/Exposure Analysis Modeling System
(PRZM/EXAMS) to estimate pesticide concentrations in surface water and
SCI-GROW, which predicts pesticide concentrations in ground water. In
general, EPA will use GENEEC (a tier 1 model) before using PRZM/EXAMS
(a tier 2 model) for a screening-level assessment for surface water.
The GENEEC model is a subset of the PRZM/EXAMS model that uses a
specific high-end runoff scenario for pesticides. GENEEC incorporates a
farm pond scenario, while PRZM/EXAMS incorporates an index reservoir
environment in place of the previous pond scenario. The PRZM/EXAMS
model includes a percent crop area factor as an adjustment to account
for the maximum percent crop coverage within a watershed or drainage
basin.
None of these models include consideration of the impact processing
(mixing, dilution, or treatment) of raw water for distribution as
drinking water would likely have on the removal of pesticides from the
source water. The primary use of these models by the Agency at this
stage is to provide a coarse screen for sorting out pesticides for
which it is highly unlikely that drinking water concentrations would
ever exceed human health levels of concern.
Since the models used are considered to be screening tools in the
risk assessment process, the Agency does not use EECs from these models
to quantify drinking water exposure and risk as a %RfD or PAD. Instead
drinking water levels of comparison (DWLOCs) are calculated and used as
a point of comparison against the model estimates of a pesticide's
concentration in water. DWLOCs are theoretical upper limits on a
pesticide's concentration in drinking water in light of total aggregate
exposure to a pesticide in food, and from residential uses. Since
DWLOCs address total aggregate exposure to buprofezin, they are further
discussed in the aggregate risk sections below.
Based on the GENEEC and SCI-GROW models the EECs of buprofezin in
surface water and ground water for acute exposures are estimated to be
11.48 ppb for surface water and 0.04 ppb for ground water. The EECs for
chronic exposures are estimated to be 1.80 ppb for surface water and
0.04 ppb for ground water.

[[Page 52944]]

3. From non-dietary exposure. The term ``residential exposure'' is
used in this document to refer to non-occupational, non-dietary
exposure (e.g., for lawn and garden pest control, indoor pest control,
termiticides, and flea and tick control on pets). Buprofezin is not
registered for use on any sites that would result in residential
exposure.
4. Cumulative exposure to substances with a 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.''
EPA does not have, at this time, available data to determine
whether buprofezin 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,
buprofezin 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 buprofezin has a common mechanism of toxicity
with other substances. For information regarding EPA's efforts to
determine which chemicals have a common mechanism of toxicity and to
evaluate the cumulative effects of such chemicals, see the final rule
for Bifenthrin Pesticide Tolerances (62 FR 62961, November 26, 1997).

D. Safety Factor for Infants and Children

1. Safety factor for infants and children--i. In general. 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 prenatal and postnatal toxicity and the completeness of the
data base on toxicity and exposure 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 margin of exposure (MOE) analysis or through
using uncertainty (safety) factors in calculating a dose level that
poses no appreciable risk to humans.
ii. Prenatal and postnatal sensitivity. The Agency concluded that
available toxicity data provide no indication of increased
susceptibility of rats or rabbits following in utero exposure or of
rats following prenatal/postnatal exposure to buprofezin. In the
prenatal developmental toxicity study in rats, developmental effects
were seen only in the presence of severe maternal toxicity including
deaths. No developmental toxicity was seen at the highest dose tested
in the prenatal developmental toxicity study in rabbits. And in the 2-
generation reproduction study in rats, effects in the offspring were
observed only at treatment levels which resulted in evidence of
parental toxicity.
iii. Conclusion. The toxicology data base for buprofezin is
complete for FQPA assessment. The developmental toxicity studies in
rats and rabbits and the 2-generation reproduction study in rats are
available and considered acceptable. Acute and subchronic neurotoxicity
studies are not required for buprofezin.
The Agency determined that an additional developmental
neurotoxicity study in rats is required based on the evidence of
thyroid toxicity following subchronic and chronic exposures to rats as
well as chronic exposures to dogs. In these studies, thyroid toxicity
was characterized as decreases in serum thyroxine levels and increased
thyroid weights in dogs and histopathological lesions in the subchronic
and chronic toxicity studies in rats. While the Agency recognized the
fact that thyroid toxicity was seen in the presence of hepatotoxicity,
there was concern that thyroid effects were seen in two species
following subchronic and chronic exposures. The Agency concluded that
the DNT study is needed to further evaluate the hormonal responses
associated with the developing fetal nervous system.
The Agency concluded that a safety factor is necessary for
buprofezin since there is an additional developmental neurotoxicity
characterization study needed in rats. This study is required due to
the evidence of thyroid effects observed following subchronic and
chronic exposures to rats and chronic exposure to dogs.
The safety factor was reduced to 3X because: There is no evidence
of increased susceptibility to young rats or rabbits following in utero
exposure or following prenatal and/or postnatal exposure to rats;
Adequate actual data, surrogate data, and/or modeling outputs are
available to satisfactorily assess dietary (food and water) exposure
assessment; and there are no registered residential uses at the present
time.
The FQPA safety factor for buprofezin is applicable to females 13-
50 and to infants and children due uncertainty resulting from an
additional confirmatory developmental neurotoxicity study in rats. This
additional study will characterize the potential for neurotoxic effects
on fetal development and may provide data that could be used in the
toxicology endpoint selection and further refine the dietary exposure
risk assessments for these population subgroups.

E. Aggregate Risks and Determination of Safety

To estimate total aggregate exposure to a pesticide from food,
drinking water, and residential uses, the Agency calculates DWLOCs
which are used as a point of comparison against the model estimates of
a pesticide's concentration in water (EECs). DWLOC values are not
regulatory standards for drinking water. DWLOCs are theoretical upper
limits on a pesticide's concentration in drinking water in light of
total aggregate exposure to a pesticide in food and residential uses.
In calculating a DWLOC, the Agency determines how much of the
acceptable exposure (i.e., the PAD) is available for exposure through
drinking water e.g., allowable chronic water exposure (mg/kg/day) =
cPAD - (average food + residential exposure). This allowable exposure
through drinking water is used to calculate a DWLOC.
A DWLOC will vary depending on the toxic endpoint, drinking water
consumption, and body weights. Default body weights and consumption
values as used by the USEPA Office of Water are used to calculate
DWLOCs: 2L/70 kg (adult male), 2L/60 kg (adult female), and 1L/10 kg
(child). Default body weights and drinking water consumption values
vary on an individual basis. This variation will be taken into account
in more refined screening-level and quantitative drinking water
exposure assessments. Different populations will have different DWLOCs.
Generally, a DWLOC is calculated for each type of risk assessment used:
acute, short-term, intermediate-term, chronic, and cancer.
When EECs for surface water and ground water are less than the
calculated DWLOCs, OPP concludes with reasonable certainty that
exposures to the pesticide 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. Because OPP considers the aggregate risk resulting from
multiple exposure pathways associated with a pesticide's uses, levels
of comparison in drinking water may vary as those uses change. If new
uses are added in the future, OPP will reassess the potential impacts
of residues of the pesticide in

[[Page 52945]]

drinking water as a part of the aggregate risk assessment process.
1. Acute risk. The acute dietary exposure analysis assumed
tolerance level residues and 100% crop treated for all registered and
proposed commodities (Tier 1). For females 13-50 years old, 4% of the
aPAD (.67 ppm/day) is occupied by dietary (food) exposure (no acute RfD
established for the general population including infants and children).
The acute exposure to buprofezin as a result of exposure from residues
in food is below the Agency's level of concern.
2. Chronic risk. Since there are no chronic residential exposure
scenarios, the chronic aggregate risk assessment is concerned with food
and water only. The chronic dietary exposure analysis incorporated
average residues calculated from field trial data and assumed 100% crop
treated for all commodities except tomatoes (44% and 0.6% crop treated
for the fresh market and for processing, respectively; Tier 2
analysis). Only 49% of the cPAD is occupied by dietary (food) exposure.
The buprofezin EECs in surface and ground water are less than the
Agency's DWLOC (for all population subgroups). Chronic risk for
buprofezin, as a result of dietary (food and water) exposure, is below
the Agency's level of concern. After calulating the DWLOCs and
comparing them to the EECs for surface and ground water, EPA does not
expect the aggregate exposure to exceed 100% of the cPAD, as shown in
the following Table 4.

Table 4.--Aggregate Risk Assessment for Chronic (Non-Cancer) Exposure to
Buprofezin
------------------------------------------------------------------------
Subgroups exposure (mg/kg/day) % cPAD¹
------------------------------------------------------------------------
U.S. population 0.000957 29
all seasons.....................
------------------------------------------------------------------------
All Infants 0.000452 14
(1 year)........................
------------------------------------------------------------------------
Children 0.001615 49
(1-6 years).....................
------------------------------------------------------------------------
Children 0.001305 40
(7-12 years)....................
------------------------------------------------------------------------
Females 0.000871 26
(13-50 years)...................
------------------------------------------------------------------------
Males 0.000858 26
(13-19 years)...................
------------------------------------------------------------------------
Males 0.000818 25
(20+ years).....................
------------------------------------------------------------------------
Seniors 0.000814 25
(55+)...........................
------------------------------------------------------------------------
¹cPAD = 0.0033 mg/kg/day

3. Short-term risk. Short-term aggregate exposure takes into
account residential exposure plus chronic exposure to food and water
(considered to be a background exposure level). Buprofezin is not
registered for use on any sites that would result in residential
exposure. Therefore, the aggregate risk is the sum of the risk from
food and water, which do not exceed the Agency's LOC.
4. Intermediate-term risk. Intermediate-term aggregate exposure
takes into account residential exposure plus chronic exposure to food
and water (considered to be a background exposure level). Buprofezin is
not registered for use on any sites that would result in residential
exposure. Therefore, the aggregate risk is the sum of the risk from
food and water, which do not exceed the Agency's LOC.
5. Aggregate cancer risk for U.S. population. Buprofezin has been
classified as ``Suggestive Evidence of Carcinogenicity, but not
sufficient to assess human carcinogenic potential'' based on liver
tumors in female mice, according to the Agency's Cancer Risk Assessment
Guidelines (proposed July 1999). The Agency concluded that no
quantification of cancer risk is required.
6. Determination of safety. Based on these risk assessments, EPA
concludes that there is a reasonable certainty that no harm will result
to the general population, and to infants and children from aggregate
exposure to buprofezin residues.

IV. Other Considerations

A. Analytical Enforcement Methodology

Adequate enforcement methodology (example - gas chromatography) is
available to enforce the tolerance expression. The method may be
requested from: Calvin Furlow, PIRIB, IRSD (7502C), Office of Pesticide
Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,
Washington, DC 20460; telephone number: (703) 305-5229; e-mail address:
furlow.calvin@epa.gov.

B. International Residue Limits

No maximum residue limits (MRLs) are established for buprofezin
in/on cucurbits or lettuce in Mexico or Canada. Codex has a buprofezin
MRL of 1 ppm in/on cucumbers. The field trial data do not support
harmonization.

C. Conditions

Conditions for continued registration are as follows: A
developmental neurotoxicity study in rats (OPPTS Guideline 870.6300)
guideline requirement (40 CFR part 158) for food/feed use, validation
of frozen storage intervals, petition method validation, an
interference study, a confirmatory method, and additional cantaloupe
and leaf lettuce field trials.

V. Conclusion

Therefore, the tolerance is established for residues of
buprofezin, 2-tert-butylimino-3-isopropyl-5-phenyl-1,3,5-thiadiazinan-
4-one, in or on lettuce, head; lettuce, leaf; and vegetables, cucurbits
at 5.0, 13.0, and 0.50 ppm, respectively.

VI. Objections and Hearing Requests

Under section 408(g) of the FFDCA, as amended by the FQPA, any
person may file an objection to any aspect of this regulation and may
also request a hearing on those objections. The EPA procedural
regulations which govern the submission of objections and requests for
hearings appear in 40 CFR part 178. Although the procedures in those
regulations require some modification to reflect the amendments made to
the FFDCA by the FQPA of 1996, EPA will continue to use those
procedures, with appropriate adjustments, until the necessary
modifications can be made. The new section 408(g) provides essentially
the same process for persons to ``object'' to a regulation for an
exemption from the requirement of a tolerance issued by EPA under new
section 408(d), as was provided in the old FFDCA sections 408 and 409.
However, the period for filing objections is now 60 days, rather than
30 days.

A. What Do I Need to Do to File an Objection or Request a Hearing?

You must file your objection or request a hearing on this
regulation in accordance with the instructions provided in this unit
and in 40 CFR part 178. To ensure proper receipt by EPA, you must
identify docket control number OPP-301040 in the subject line on the
first page of your submission. All requests must be in writing, and
must be mailed or delivered to the Hearing Clerk on or before October
30, 2000.
1. Filing the request. Your objection must specify the specific
provisions in the regulation that you object to, and the grounds for
the objections (40 CFR

[[Page 52946]]

178.25). If a hearing is requested, the objections must include a
statement of the factual issues(s) on which a hearing is requested, the
requestor's contentions on such issues, and a summary of any evidence
relied upon by the objector (40 CFR 178.27). 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.
Mail your written request to: Office of the Hearing Clerk (1900),
Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,
Washington, DC 20460. You may also deliver your request to the Office
of the Hearing Clerk in Rm. C400, Waterside Mall, 401 M St., SW.,
Washington, DC 20460. The Office of the Hearing Clerk is open from 8
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The
telephone number for the Office of the Hearing Clerk is (202) 260-4865.
2. Tolerance fee payment. If you file an objection or request a
hearing, you must also pay the fee prescribed by 40 CFR 180.33(i) or
request a waiver of that fee pursuant to 40 CFR 180.33(m). You must
mail the fee to: EPA Headquarters Accounting Operations Branch, Office
of Pesticide Programs, P.O. Box 360277M, Pittsburgh, PA 15251. Please
identify the fee submission by labeling it ``Tolerance Petition Fees.''
EPA is authorized to waive any fee requirement ``when in the
judgement of the Administrator such a waiver or refund is equitable and
not contrary to the purpose of this subsection.'' For additional
information regarding the waiver of these fees, you may contact James
Tompkins by phone at (703) 305-5697, by e-mail at tompkins.jim@epa.gov,
or by mailing a request for information to Mr. Tompkins at Registration
Division (7505C), Office of Pesticide Programs, Environmental
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460.
If you would like to request a waiver of the tolerance objection
fees, you must mail your request for such a waiver to: James Hollins,
Information Resources and Services Division (7502C), Office of
Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania
Ave., NW., Washington, DC 20460.
3. Copies for the Docket. In addition to filing an objection or
hearing request with the Hearing Clerk as described in Unit VI.A., you
should also send a copy of your request to the PIRIB for its inclusion
in the official record that is described in Unit I.B.2. Mail your
copies, identified by docket control number OPP-301040, to: Public
Information and Records Integrity Branch, Information Resources and
Services Division (7502C), Office of Pesticide Programs, Environmental
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460.
In person or by courier, bring a copy to the location of the PIRIB
described in Unit I.B.2. You may also send an electronic copy of your
request via e-mail to: opp-docket@epa.gov. Please use an ASCII file
format and avoid the use of special characters and any form of
encryption. Copies of electronic objections and hearing requests will
also be accepted on disks in WordPerfect 6.1/8.0 file format or ASCII
file format. Do not include any CBI in your electronic copy. You may
also submit an electronic copy of your request at many Federal
Depository Libraries.

B. When Will the Agency Grant a Request for a Hearing?

A request for a hearing will be granted if the Administrator
determines that the material submitted shows the following: There is a
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(s) in the manner sought
by the requestor would be adequate to justify the action requested (40
CFR 178.32).

VII. Regulatory Assessment Requirements

This final rule establishes a tolerance 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) (Public Law 104-4). Nor
does it require any prior consultation as specified by Executive Order
13084, entitled Consultation and Coordination with Indian Tribal
Governments (63 FR 27655, May 19, 1998); 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 or
any Agency action under Executive Order 13045, entitled Protection of
Children from Environmental Health Risks and Safety Risks (62 FR 19885,
April 23, 1997). This action does not involve any technical standards
that would require Agency consideration of voluntary consensus
standards pursuant to section 12(d) of the National Technology Transfer
and Advancement Act of 1995 (NTTAA), Public Law 104-113, section 12(d)
(15 U.S.C. 272 note). Since tolerances and exemptions that are
established on the basis of a petition under FFDCA section 408(d), such
as the tolerance 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. In addition, the Agency has
determined that this action will not have a substantial direct effect
on States, on the relationship between the national government and the
States, or on the distribution of power and responsibilities among the
various levels of government, as specified in Executive Order 13132,
entitled Federalism (64 FR 43255, August 10, 1999). Executive Order
13132 requires EPA to develop an accountable process to ensure ``
``meaningful and timely input by State and local officials in the
development of regulatory policies that have federalism implications.''
``Policies that have federalism implications'' is defined in the
Executive Order to include regulations that have ``substantial direct
effects on the States, on the relationship between the national
government and the States, or on the distribution of power and
responsibilities among the various levels of government.'' This final
rule directly regulates growers, food processors, food handlers and
food retailers, not States. This action does not alter the
relationships or distribution of power and responsibilities established
by Congress in the preemption provisions of FFDCA section 408(n)(4).

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

[[Page 52947]]

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 this final rule in
the Federal Register. This final 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: August 22, 2000.
Susan B. Hazen,
Deputy 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. 321(q), (346a) and 371.

2. Section 180.511 is amended by adding paragraph (a) to read as
follows:

Sec. 180.511 Buprofezin; tolerances for residues.

(a) General. Tolerances are established for residues of buprofezin
in or on the following food commodities:

------------------------------------------------------------------------
Expiration/Revocation
Commodity Parts per million Date
------------------------------------------------------------------------
Lettuce, head 5.0 12/31/04
Lettuce, leaf 13.0 12/31/04
Vegetables, cucurbits 0.50 12/31/04
------------------------------------------------------------------------

* * * * *

[FR Doc. 00-22371 Filed 8-30-00; 8:45 am]
BILLING CODE 6560-50-S

Buprofezin (2-Tert-butylimino-3-isopropyl-5-phenyl-1,3,5- thiadiazinan-4-one); Time-Limited Pesticide Tolerances

Local Navigation