[Federal Register Volume 61, Number 124 (Wednesday, June 26, 1996)]
[Proposed Rules]
[Pages 33178-33200]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-16203]
[[Page 33177]]
_______________________________________________________________________
Part II
Environmental Protection Agency
_______________________________________________________________________
40 CFR Part 799
Proposed Test Rule for Hazardous Air Pollutants; Proposed Rule
Federal Register / Vol. 61, No. 124 / Wednesday, June 26, 1996 /
Proposed Rules
[[Page 33178]]
ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 799
[OPPTS-42187; FRL-4869-1]
RIN 2070-AC76
Proposed Test Rule for Hazardous Air Pollutants
AGENCY: Environmental Protection Agency (EPA).
ACTION: Proposed rule.
-----------------------------------------------------------------------
SUMMARY: EPA is proposing a test rule under section 4(a) of the Toxic
Substances Control Act (TSCA) to require manufacturers and processors
of 21 hazardous air pollutants (HAPs) (biphenyl, carbonyl sulfide,
chlorine, chlorobenzene, chloroprene, cresols [3 isomers],
diethanolamine, ethylbenzene, ethylene dichloride, ethylene glycol,
hydrochloric acid, hydrogen fluoride, maleic anhydride, methyl isobutyl
ketone, methyl methacrylate, naphthalene, phenol, phthalic anhydride,
1,2,4-trichlorobenzene, 1,1,2-trichloroethane, and vinylidene chloride)
to test these substances for certain health effects. EPA is also
soliciting proposals for enforceable consent agreements (ECAs)
regarding the performance of pharmacokinetics studies which would
permit extrapolation from oral data to predict risk from inhalation
exposure. EPA is also withdrawing the oncogenicity testing proposed for
vinylidene chloride on August 12, 1986 (51 FR 28840).
DATES: Written comments on this proposed HAPs test rule must be
received by EPA on or before December 23, 1996. Proposals for
pharmacokinetics studies must be received by EPA on or before October
24, 1996. EPA will hold a public meeting in Washington, DC prior to the
close of the comment period. If any person requests an additional
public meeting by November 25, 1996, EPA will hold a second public
meeting in Washington, DC.
ADDRESSES: Submit three copies of written comments on this proposed
HAPs test rule, identified by document control number (OPPTS-42187A;
FRL-4869-1) and three copies of proposals for pharmacokinetics studies,
identified by document control number (OPPTS-42187B; FRL-4869-1) to:
U.S. Environmental Protection Agency, Office of Pollution Prevention
and Toxics (OPPT), Document Control Office (7407), Rm. G-099, 401 M
St., SW., Washington, DC, 20460.
A public version of the rulemaking record supporting this action,
excluding confidential business information (CBI), is available for
inspection at the TSCA Nonconfidential Information Center, Rm. NE-B607,
401 M St., SW., Washington, DC 20460, from 12 noon to 4 p.m., Monday
through Friday, except on legal holidays.
All comments which contain information claimed as CBI must be
clearly marked as such. Three additional sanitized copies of any
comments containing information claimed as CBI must also be submitted.
Nonconfidential versions of comments on this proposed rule will be
placed in the rulemaking record and will be available for public
inspection at the TSCA Nonconfidential Information Center. Unit IX of
this preamble contains additional information on submitting comments
containing information claimed as CBI.
Comments and data may also be submitted in electronic form by
sending electronic mail (e-mail) to: [email protected]. Such
comments and data must be submitted in an ASCII file avoiding the use
of special characters and any form of encryption. Comments and data
will also be accepted on disks in WordPerfect in 5.1 file format or
ASCII file format. All comments and data in electronic form must be
identified by (OPPTS-42187A) (FRL-4869-1). No information claimed as
CBI should be submitted through e-mail. Comments in electronic form may
be filed online at many federal depository libraries. Additional
information on electronic submissions can be found under Unit X of this
preamble.
FOR FURTHER INFORMATION CONTACT: Susan B. Hazen, Director,
Environmental Assistance Division (7408), Office of Pollution
Prevention and Toxics, U.S. Environmental Protection Agency, Room E-
543B, 401 M St., SW., Washington, DC 20460; telephone: (202) 554-1404;
TDD: (202) 554-0551; e-mail: TSCA-H[email protected]. For specific
information regarding this action or related activities, contact Gary
E. Timm, Chemical Control Division, OPPT; telephone: (202) 260-1859; e-
mail: [email protected].
SUPPLEMENTARY INFORMATION:
Regulated persons. Potentially regulated persons are manufacturers
(including importers) and processors of the chemical substances
included in this proposed test rule. Processors, small-quantity
manufacturers, and manufacturers of small quantities of these
substances solely for research and development purposes, while legally
subject to the rule, would be required to comply with the rule only if
directed to do so in a subsequent notice.
------------------------------------------------------------------------
Examples of regulated
Category persons
------------------------------------------------------------------------
Manufacturers Persons who manufacture or
import 500 kg (1,100 lbs)
or more of a subject
chemical per year.
Persons who produce a
subject chemical as a
byproduct.
Processors Persons who process one or
more subject chemicals.
Small-quantity manufacturers Persons who manufacture or
import less than 500
kg(1,100 lbs) per year of a
subject chemical.
Manufacturers of small quantities of these Persons who manufacture
substances solely for research and quantities of these
development purposes substances no greater than
those necessary for
purposes of scientific
experimentation or analysis
for research and
development purposes.
------------------------------------------------------------------------
This table is not intended to be exhaustive, but, rather, provides
a guide for readers regarding entities likely to be regulated by this
action. This table lists the types of persons of which EPA is now aware
that potentially could be regulated by this action. To determine
whether you would be subject to this rule, you should examine Unit
IV.F. of the preamble entitled ``Persons Required to Test'' and consult
40 CFR 790.42.
I. Statutory Authority
This notice proposes a test rule under section 4 of the Toxic
Substances Control Act (TSCA), 15 U.S.C. 2603 et seq., that would
require certain health effects testing for 21 chemical substances
listed as hazardous air pollutants (HAPs) in section 112 of the Clean
Air Act (CAA), 42 U.S.C. 7412.
Section 2(b)(1) of TSCA, 15 U.S.C. 2601(b)(1), states that it is
the policy of the United States that ``adequate data should be
developed with respect to the effect of chemical substances and
mixtures on health and the environment and that the development of such
data should be the responsibility of those who manufacture and those
who process such chemical substances and mixtures[.]'' To implement
this policy, section 4(a) of TSCA authorizes EPA to require by rule
that manufacturers and processors of chemical substances conduct
testing if the Administrator finds that:
[[Page 33179]]
(1)(A)(i) the manufacture, distribution in commerce, processing,
use, or disposal of a chemical substance or mixture, or that any
combination of such activities, may present an unreasonable risk of
injury to health or the environment, [or]
(1)(B)(i) a chemical substance or mixture is or will be produced
in substantial quantities, and (I) it enters or may reasonably be
anticipated to enter the environment in substantial quantities or
(II) there is or may be significant or substantial human exposure to
such substance or mixture, [and]
(1)(A)(ii) and (1)(B)(ii) there are insufficient data and
experience upon which the effects of the manufacture, distribution
in commerce, processing, use, or disposal of such substance or
mixture or of any combination of such activities on health or the
environment can reasonably be determined or predicted, and
(1)(A)(iii) and (1)(B)(iii) testing of such substance or mixture
with respect to such effects is necessary to develop such data[.]
Thus once the Administrator has made a finding under TSCA section
4(a)(1)(A)(i) that a chemical substance may present an unreasonable
risk of injury to health or the environment or a finding under section
4(a)(1)(B)(i) that a chemical substance is or will be produced in
substantial quantities and either it may enter the environment in
substantial quantities or there may be significant substantial human
exposure to the chemical substance, EPA may require any type of health
effects or environmental testing necessary to address unanswered
questions about the effects of the chemical substance. EPA need not
limit the scope of testing required to the factual basis for the
section 4(a)(1)(A)(i) or (B)(i) findings as long as EPA finds that data
relevant to a determination of whether a substance does or does not
present an unreasonable risk of injury to health or the environment are
insufficient and that testing is necessary to develop such data. This
concept is explained in more detail in EPA's statement of policy for
making findings under TSCA section 4(a)(1)(B) (frequently described as
the ``B policy'') in the Federal Register of May 14, 1993 (58 FR
28736). Unit V of this preamble also describes the B policy. Moreover,
EPA need not limit the scope of the requirement only to testing needed
to support regulatory action under TSCA. For further discussion of
findings under TSCA section 4, see Unit V of this preamble and the
document entitled ``TSCA Section 4 Findings for 21 Hazardous Air
Pollutants'' in the record for this rulemaking.
In this proposed rule, EPA intends to use its TSCA section 4
authority to obtain data necessary to implement section 112 of the CAA,
which provides a detailed strategy for the assessment and management of
HAPs. EPA has used this broad TSCA section 4 authority in the past to
support regulatory programs requiring health and environmental effects
testing data. See, e.g., final test rule for the Office of Solid Waste
chemicals (53 FR 22300, June 15, 1988); final test rule for the Office
of Water Chemicals (58 FR 59667, November 10, 1993). Additional users
of information collected under this test rule would include other
federal agencies (e.g. the Agency for Toxic Substances and Disease
Registry (ATSDR), the National Institute for Occupational Safety and
Health (NIOSH), the Occupational Safety and Health Administration
(OSHA), the Consumer Product Safety Commission (CPSC), other program
areas within EPA (such as the hazardous waste program under the
Resource Conservation and Recovery Act (RCRA), the Toxics Release
Inventory (TRI), the Integrated Risk Information System database
(IRIS), and the Office of Pesticide Programs (OPP)), and state and
local environmental authorities.
Supporting statutory authority for this proposed rule is provided
by section 112(b)(4) of the CAA, 42 U.S.C. 7412(b)(4), which
specifically authorizes EPA to use any authority available to EPA to
obtain the information needed to make determinations regarding the
addition or deletion of substances to the statutory list of HAPs in CAA
section 112(b)(1), 42 U.S.C. 7412(b)(1). If the data collected under
this proposed test rule show that a chemical substance is not a concern
to human health, this information would be helpful in making decisions
concerning delisting the substance from the Clean Air Act HAPs list.
This toxicity testing program is also intended to fulfill in part
EPA's statutory obligation under section 103(d) of the CAA, 42 U.S.C.
7403(d), to conduct a research program on the health effects of HAPs.
This preamble, along with the supporting material in the record,
provides information that would be used in the research program under
CAA section 103(d) for the HAPs proposed for testing in this rule.
II. Uses for Data
EPA will primarily use the data proposed to be collected under this
rule to implement several provisions of section 112 of the CAA,
including the determination of residual risk (see below), the
estimation of the risks associated with accidental releases of
chemicals, and determinations whether or not substances should be
removed from the CAA section 112(b)(1) list of hazardous air pollutants
(delisting). The acute toxicity test data and developmental toxicity
test data will be useful in judging risks from accidental release. The
term ``accidential release'' is used broadly in this proposal to
include any short-term, relatively high-level chemical exposure lasting
from several minutes to several hours. Such a release may result from
various causes, including spills, transportation accidents, process-
upset conditions, or short bursts during charging of reaction vessels.
All data are relevant to delisting decisions and all non-acute data
will be used by EPA in meeting its statutory obligation under CAA
section 112(f), 42 U.S.C. 7412(f), to assess the risk remaining (i.e.
residual risk) after the imposition of technology-based emission
standards (maximum achievable control technology or MACT standards)
required by CAA section 112(d), 42 U.S.C. 7412(d). Section 112(e) of
the CAA, 42 U.S.C. 7412(e), directs EPA to promulgate these standards
between 1992 and 2000.
Section 112(f)(1) of the CAA requires EPA to submit, by November
1996, a report to Congress that will describe the methods for assessing
the risk remaining after the application of technology-based standards
under section 112(d) of the CAA. These methods will be used to assess
any residual risk for persons exposed to MACT-regulated emissions. The
assessment will include an analysis of both cancer and noncancer
endpoints. Data generated by the proposed test rule would be used in
the analysis to determine the nature and magnitude of any residual
risk.
Within eight years after the promulgation of technology-based
standards, EPA may need to set additional standards (``post-MACT
standards'') to protect public health with an ample margin of safety.
Section 112(f)(2) of the CAA specifies that if MACT standards have not
reduced lifetime cancer risk to the individual most exposed to known or
suspected carcinogenic emissions from a source to a level of less than
1 in a million (1 x 10-6), health-based emission standards must be
promulgated in order to protect public health with an ample margin of
safety. EPA, therefore, would use data obtained under this proposed
rule to determine whether health-based post-MACT standards are needed
and, if they are needed, to assist in establishing the appropriate
level of these standards.
For noncancer health effects, EPA applies an appropriate
mathematical model to toxicity data in order to determine the benchmark
dose level. The benchmark dose or concentration (BMD/C) is defined as
the statistical
[[Page 33180]]
lower confidence limit on the dose estimated to produce a predetermined
level of change in response (the benchmark response--BMR) relative to
controls. If the data are not amenable to modeling, a no-observed-
adverse-effect level (NOAEL) or a lowest-observed-adverse-effect level
(LOAEL) may be obtained from an evaluation of the toxicity database.
``Uncertainty factors'' are then applied to these levels to account for
uncertainties in deriving a dose-response estimate for human exposure
(reference concentration (RfC)) from experimental data. An RfC is
defined as ``an estimate (with uncertainty perhaps spanning an order of
magnitude) of a continuous inhalation exposure to the human population
(including sensitive subgroups) that is likely to be without
appreciable risk of deleterious noncancer health effects during the
lifetime'' (Ref. 1).
Uncertainties due to the extrapolation of effects data between
species and for individual susceptibility within a species are
accounted for by uncertainty factors. Because RfCs are intended to
characterize risk for lifetime exposures, an uncertainty factor may be
applied if the effects data are extrapolated from a subchronic study.
An additional uncertainty factor is applied if a LOAEL is used to
derive the RfC rather than a NOAEL. To provide an accurate
characterization of lifetime risk, the database for a chemical should
be comprehensive and, in principle, should address all potential
endpoints at critical life stages. Therefore, an uncertainty factor
also may be applied if data for appropriate endpoints are not
available. Thus while each uncertainty factor may range up to 10, the
composite factor used to derive an RfC for a chemical with a limited
database may be on the order of up to 3,000 for inhalation studies and
up to 10,000 for oral studies. Five uncertainty factors are never
applied at the same time (i.e. no composite uncertainty factor can be
greater than 10,000) because such derivations are considered too
inaccurate to be used.
Large composite uncertainty factors result in lower RfCs (higher
risk estimates) than do smaller composite uncertainty factors. If the
RfC is low, EPA may be required to promulgate more stringent emission
standards. Industrial plants subject to these standards would, in turn,
be required to meet such standards, perhaps necessitating the
installation of more costly emission controls. Better and more complete
health effects data, on the other hand, may permit EPA to use smaller
composite uncertainty factors, resulting in higher RfCs and, as a
consequence, less stringent emission standards. Thus the economic cost
of using poor-quality health effects data to make residual risk
determinations under CAA section 112(f) could be considerable.
In addition, secondary--though as important--uses of the data to be
collected under this proposed rule would be:
(1) Helping to better inform communities and citizens of toxic
chemical hazards in their own localities. Understanding health effects
associated with these chemicals is integral to furthering the public's
involvement in environmental decisionmaking, especially at the state
and local level. To be an effective participant in this process, the
public needs information on both the inherent toxicity (i.e., hazard)
of a chemical and the potential sources of exposure to the chemical.
This rule will provide valuable information on health effects related
to the affected chemicals, and under TSCA, such health and safety data
are available to the public. Taken together with such publicly
available information sources such as the Toxics Release Inventory
(TRI), which provides site-specific information on chemical releases
into the environment, the health effects data generated under this rule
will allow all segments of the public to better assess the risks
associated with the releases of these chemicals. Taken as part of a
comprehensive right-to-know program, these data will provide the basis
for individuals, communities, governments, producers, and users to
assess the nature and relative severity of toxicity among different
chemicals, as well as to assess site-specific, individual chemical
risk.
(2) Assisting other agencies (e.g., ATSDR, NIOSH, OSHA, CPSC) in
assessing chemical risks and in taking appropriate action within their
programs. For example, OSHA has expressed a need for the data that will
be acquired under the proposed rule. Fifteen of the 21 HAPS are
candidates for OSHA's Permissible Exposure Limit (PEL) update and an
additional 3 have no corresponding PEL. OSHA does not have authority to
require testing, and must rely on toxicology data collected by other
agencies for their risk assessments (Ref. 2). Establishing an ongoing
mechanism for updating its PELs continues to be a high priority for
OSHA. Five of the HAPs are on ATSDR's list of hazardous substances
found at National Priorities List sites and are the subject of
toxicological profiles. CPSC noted that 11 of the 21 substances are
found in or are emitted by consumer products (Ref. 3).
(3) Assisting EPA in evaluating delisting petitions received under
the CAA and the Emergency Planning and Community Right-to-Know Act
(EPCRA), 42 U.S.C. 1101 et seq., in making better clean-up decisions
under the Comprehensive Environmental Response, Compensation, and
Liability Act (CERCLA), 42 U.S.C. 9601 et seq., in assessing inert
ingredients in pesticide products, in setting more appropriate
standards for hazardous wastes under RCRA, and by providing support for
chemical risk assessment activities under TSCA.
(4) Assisting state and local permitting authorities in setting
standards within their programs.
(5) Supporting assessments of ``burst'' exposures (high-level
releases of short duration), such as in the accidental release
prevention program under section 112(r) of the CAA, 42 U.S.C. 7412(r),
due to the inclusion of an acute testing protocol.
Many HAPs are of broad programmatic interest, and are included in
the Agency's Integrated Risk Assessment System (IRIS) database. Thus, a
secondary benefit of this rule is that the health effects data
generated by the rule may result in improvement to the data and
increased confidence in the RfCs contained in IRIS. Improvements to the
IRIS data can result in considerable benefits to the public since IRIS
is publicly available and is used by a wide variety of governmental and
non-governmental entities to assess the safety of chemicals.
In some cases where EPA has had access to better data, the Agency
has been able to revise standards to make them less stringent, thus
mandating less economically costly levels of control. For example, EPA
has revised the maximum contaminant levels (MCL) of barium (from 1 mg/L
to 2 mg/L) and selenium (from 0.01 mg/L to 0.05 mg/L) in drinking water
and withdrew the MCL for silver (0.05 mg/L) based on new data (Ref. 4).
Data have also been used to remove chemical substances from lists
of regulatory significance. Acrylic acid was removed from a list of
``high-risk'' pollutants developed under section 112(i)(5) of the CAA,
42 U.S.C. 7412(i)(5), for the early reductions program. The high-risk
listing for this chemical was based on its predicted environmental
exposure being at least 10 times larger than its RfC. Designation of
acrylic acid as ``high risk'' had the effect of limiting the use of
offsetting reduction of other pollutants in meeting early reduction
goals. Recent data,
[[Page 33181]]
including those related to reproductive effects, developmental
toxicity, and bioavailability, resulted in a decrease in the
uncertainty factor for database deficiency by a factor of three and an
increase in the RfC by the same amount (i.e. from 0.0003 mg/m3 to
0.001 mg/m3). Consequently, acrylic acid no longer met the
criteria for the high-risk list.
Serious deficiencies exist in the current toxicity database for the
189 HAPs listed in the CAA, in that no toxicity data exist for many
HAPs regarding various endpoints of concern. This problem is expected
to be especially serious because post-MACT residual risks will arise
primarily from exposures to emissions that contain different
combinations of HAPs in varying concentrations. In view of the large
number of HAPs of concern and the much larger number of combinations of
those HAPs found in the mixtures of emissions subject to residual risk
evaluation, the toxicity database should provide consistent
characterization of individual HAPs. Therefore, EPA is proposing to
obtain an even, across-the-board database for the HAPs listed in this
proposed rule.
In its report regarding the risk assessment of HAPs, the National
Academy of Sciences (NAS) states that ``[a]vailability of requisite
data varies widely among the 189 [HAPs] chemicals'' (Ref. 5). According
to this report, ``the toxicity data are incomplete on almost all 189
chemicals'' (Ref. 5). For example, the level of carcinogenic risk for
approximately 40% of the 189 HAPs cannot be classified under EPA's
current cancer risk classification system (Ref. 6). Moreover, while
quantitative estimates exist for 70% of the HAPs that have been
classified for cancer risk, about 70% of these estimates are based only
on oral data and thus may not reliably characterize the potential risk
encountered through inhalation exposure.
In evaluating 124 of the 189 HAPs for noncancer risk, EPA found
that the databases for about 62% of the 124 HAPs were not adequate for
deriving an RfC (Ref. 7). Even for those HAPs that have an RfC, the
level of uncertainty associated with such figures is often high. EPA
would use data from the testing proposed in this rule to identify the
critical health risks posed by many individual HAPs and to characterize
the adverse impact posed by exposure to mixtures of HAPs. EPA
anticipates that the test data produced in response to this rule would
provide the consistent database that the National Academy says is
lacking at this time.
III. Testing Approach and Selection of Chemical Substances for This
Proposed Rule
A. Testing Approach Chosen by EPA
With respect to EPA's responsibilities for meeting the requirements
under section 112 of the CAA, the central question is: How broad and
deep a data set should EPA require on each HAP?
Regarding specific endpoints and routes of exposure, CAA section
112(b)(2), 42 U.S.C. 7412(b)(2), indicates that Congress intended that
adverse effects from any endpoint by any route of exposure be taken
into account in listing substances as HAPs. According to this
subsection, substances added to the Clean Air Act HAPs list shall
include:
* * * pollutants which present, or may present, through
inhalation or other routes of exposure, a threat of adverse human
health effects (including, but not limited to, substances which are
known to be, or may reasonably be anticipated to be, carcinogenic,
mutagenic, teratogenic, neurotoxic, which cause reproductive
dysfunction, or which are acutely or chronically toxic) * * * .
Thus the CAA indicates that Congress was very concerned about the
wide variety of health risks attributable to HAPs and intended that
data necessary for characterizing both cancer and noncancer health
risks from exposure to HAPs be developed.
Faced with a broad range of options and little specific guidance
from Congress, EPA decided that some provision should be made for
evaluating the health effects endpoints listed in the CAA, including
respiratory tract toxicity, systemic effects, reproductive toxicity,
developmental toxicity, genotoxicity, neurotoxicity, and
carcinogenicity. EPA's objective was to select endpoints representing
serious health effects that could occur as a result of exposure to
HAPs. Each endpoint represents a health effect of concern arising from
one or more of the following exposures--local concentrations (e.g.,
hotspots and plumes), area-wide sources, or accidental releases of
HAPs.
EPA believes that it is critical to evaluate the respiratory tract
thoroughly in addition to examining extra-respiratory effects (i.e.,
systemic toxicity) because inhalation is an important exposure route of
concern. Carcinogenicity testing is significant because cancer is a
serious health effect that may be caused by long-term, low-level
exposure to toxic substances. Developmental toxicity addresses the
potential of chemical substances to interfere adversely with human
development (i.e., to cause death, structural abnormalities, growth
alterations, and/or functional deficits in the immature organism that
may be more sensitive than the adult to many chemical substances).
Reproductive testing is designed to assess the effects of an
environmental agent on male and female fertility and general
reproductive function to humans exposed prenatally as well as
postnatally. There is general consensus among toxicologists regarding
the assessment of cancer and reproductive and developmental effects,
and further explanation can be found in EPA's risk assessment
guidelines (Guidelines for Carcinogen Risk Assessment (51 FR 33992,
September 24, 1986); Guidelines for Developmental Toxicity Risk
Assessment (56 FR 63798, December 5, 1991); Guidelines for Reproductive
Toxicity Risk Assessment (Pub. No. EPA/600/AP-94/001, February 1994).
Finally, certain aspects of the neurotoxicity and immunotoxicity
testing required in this proposed rule warrant more explanation, which
is provided below. EPA recently published a proposed revision of the
1986 Guidelines for Carcinogen Risk Assessment (see ``Proposed
Guidelines for Carcinogen Risk Assessment'' at 61 FR 17960, April 23,
1996 (FRL-5460-3)).
Neurotoxicity resulting from chemical exposure can affect an
organism in many ways, causing, for example, functional and structural
deficits as well as behavioral effects. To assess neurotoxicity, EPA is
proposing a screening-level battery, consisting of the functional
observational battery and motoractivity and neuropathology tests. At
this time, EPA is not proposing to require additional, more specialized
testing for cognitive functions such as learning, memory, and
performance.
The interest in the potential toxic effects of chemicals on the
immune system arises from the critical role that the immune system
plays in maintaining health. EPA considers the field of immunotoxicity
a promising, scientifically sound, and important area in public health
protection. From time to time, the Agency has considered information on
the effects of chemicals on the immune system in risk assessments. For
example, in its draft report reassessing the effects of dioxin
compounds on human health (Ref. 8), EPA considered the effects of
dioxin on the immune system to serve as an important health endpoint
that provides useful information in developing a hypothesis about
toxicity. In the draft reassessment report, however, EPA arrived at the
preliminary conclusion that ``the impact of dioxin and related
compounds on the immune system and
[[Page 33182]]
implications for characterizing risks are largely unknown at this
time.''
This rule calls for an immunotoxicity screening test which can be
performed as a satellite test to either a 90-day subchronic test or a
reproductive effects test. This immunotoxicity screen will help
identify chemicals as potential immunotoxicants. EPA is not proposing
more comprehensive immunotoxicity testing at present because the
application of immunotoxicity data in risk assessment has not yet
sufficiently matured. As EPA's science policy develops and the Agency's
use of immunotoxicity data in risk assessment increases, EPA will
reconsider this position. Meanwhile, EPA seeks comments on its proposed
approach of using a minimal screen and its preliminary conclusion that
it is premature at this time to include more comprehensive
immunotoxicity testing in this proposed HAPs test rule.
In developing this proposed rule, EPA considered the following
range of options to select the information needed to characterize
health effects of concern to implement section 112 of the CAA.
Option 1. One-species 90-day inhalation subchronic plus follow-up
for known or suspect toxicities. Under this option, a 90-day inhalation
subchronic test would be required, as well as testing for endpoints
that have already been identified as existing or potential concerns,
including cancer, by previous test results of the HAP at issue or
structurally similar agents. A one-species 90-day inhalation test is
considered the minimum information for the development of an RfC. The
inhalation RfC takes into account toxic effects both for the
respiratory tract (portal-of-entry effects) and peripheral to the
respiratory system (extra-respiratory effects). Well-defined and well-
conducted inhalation subchronic toxicity studies--that provide for
histopathologic evaluation of organ toxicities, including the
respiratory tract--are considered to be reliable predictors of certain
kinds of chronic toxicity. But such studies do not, or do not
adequately, account for neurological, developmental and reproductive
toxicities. An RfC based solely on a 90-day subchronic test is, thus,
usually given a low confidence rating because some potentially
important toxic endpoints are not characterized.
In addition, EPA believes that for 90-day inhalation subchronic
testing to constitute a minimally credible option, such a test should
at least be augmented by testing for adverse health effects that are
suggested or indicated, but not adequately characterized, by existing
information such as short-term test data, mechanistic information or
structure-activity relationships (SAR). Even with this modification,
however, Option 1 still provides no test data on those health endpoints
of concern for which no current information exists. If such testing
were included, these effects might become critical in evaluating dose-
response relationships or in demonstrating that a standard uncertainty
factor is inadequate or inappropriate.
EPA thus believes that Option 1 is insufficient to meet EPA's
mandate under section 112 of the CAA because the endpoints listed in
section 112(b)(2) of the CAA, in particular, reproductive,
developmental, and neurological toxicities, would be considered for
testing only if data already exist that indicate or suggest the
potential for these adverse effects. Moreover, this option also does
not adequately address health risks associated with acute or accidental
releases.
EPA did not select Option 1 for the reasons stated above. EPA
believes that the TSCA section 4 program adopted for testing HAPs must
go further toward ensuring that no serious health threat exists from
both long- and short-term exposure for endpoints of potential concern
for which there are no existing data.
Option 2. Option 1 plus inhalation screening for untested toxicity
endpoints. The second option considered by EPA would require the
incorporation of screening level testing for certain untested
toxicities into Option 1. Like Option 1, Option 2 would include testing
for endpoints (including cancer) that have already been identified as
existing or potential concerns. At a minimum Option 2 would consist
of--a 90-day subchronic inhalation study, a screening test for
reproductive effects (i.e., a one-generation reproductive effects
study), a subchronic inhalation neurotoxicity screening battery
(consisting of the functional observation battery and motor activity
and neuropathology tests), an E. coli reverse mutation assay, gene
mutation in somatic cells in culture detection, an in vivo cytogenetics
test (chromosomal analysis or micronucleus assay), and an
immunotoxicity screening test. Any toxicity suggested but not
characterized by existing studies in the toxicological literature would
still be followed up on through more rigorous protocols.
Although Option 2 would conserve resources while allowing for the
testing of a broader range of endpoints, including cancer, it has
serious shortcomings. First, a one-generation reproductive test does
not adequately address reproductive and developmental risk. Two-
generation tests (in which animals have been exposed prenatally as well
as postnatally, including the prepubertal period) are generally needed
to evaluate the effects on reproduction from most exposures to chemical
substances (Ref. 9). Two-generation tests permit the evaluation of
delayed or latent manifestations of some toxicities, detection of
effects absent in the first generation, and the expression and
detection of some effects that may have a heritable basis. Because the
standard two-generation reproductive test would not detect internal
malformations, however, developmental toxicity testing is also needed
for an adequate assessment of developmental risk. The Agency's policy
is to require developmental testing in two species to adequately
characterize the risk because of species-specific differences.
EPA did not select Option 2 because this level of testing would not
provide an adequate evaluation of developmental or reproductive
toxicity. Additional follow-up testing would be required to confirm
suggestive results obtained in screening studies and provide data
adequate for risk assessment under this option. Such testing would
require an additional rulemaking cycle, costing further resources and
incurring so much delay that data would not be available to meet the
deadlines for setting risk-based standards. Moreover, this option does
not adequately address health risks, such as respiratory tract effects
and neurotoxicity, associated with acute or accidental releases.
Option 3. Option 1 plus less than chronic testing for noncancer
endpoints of concern. In addition to the 90-day inhalation subchronic
testing specified in Option 1, this option would add inhalation testing
to assess reproductive effects (i.e., two-generation reproductive test)
and developmental effects (developmental toxicity tests in two
mammalian species). Option 3 includes an acute toxicity testing
guideline for histopathology of the respiratory tract, kidney, and
liver and a bronchoalveolar lavage after four hours of exposure. EPA
believes that it is necessary to characterize the acute effects
associated with accidental releases of HAPs. In addition, a respiratory
sensory irritation assay is included. Acute and subchronic inhalation
neurotoxicity screening batteries consisting of the functional
observation battery, and motor activity and neuropathology tests would
also be conducted. As in Option 2, first-tier tests would be required
for mutagenicity
[[Page 33183]]
(i.e., an E. coli reverse mutation assay, gene mutation in somatic
cells in culture detection, an in vivo cytogenetics test (chromosomal
analysis or micronucleus assay)), as well as immunotoxicity.
Option 3 would follow Options 1 and 2 in requiring a cancer
bioassay where concern for cancer is indicated by short-term data,
general toxicity data, mechanistic information or structure-activity
relationships (SAR). Where no cancer bioassay data exist, testing two
species in both sexes would be required. If cancer bioassay data exist
but are found to be too uncertain for inhalation dose-response
assessment, a modified test, such as testing of the opposite sex in two
species, may be required (Ref. 10).
The Option 3 level of testing would enable EPA to better
characterize risk associated with both acute and longer-term exposures
by providing data to identify and evaluate all the health effects
listed under section 112 of the CAA and by providing data for dose-
response evaluation within the general time frame for risk-based
standards under CAA section 112(f). Accordingly, EPA has selected the
Option 3 level as its preferred option for testing under this proposed
rule.
Option 4. Option 3 plus chronic testing. Under this option, in the
absence of existing adequate data, EPA would require chronic inhalation
bioassays (for both cancer and noncancer effects) in two different
mammalian species for each chemical substance. The balance of the test
program would be the same as under Option 3 (developmental studies in
two mammalian species, a two-generation reproductive study, acute and
subchronic neurotoxicity screening batteries, first-tier mutagenicity
tests, an immunotoxicity screening test, and acute testing). In
general, cancer bioassay data in two species, a two-generation
reproductive test, and a developmental study in two species are
required to establish a high-confidence RfC. Because the RfC is
intended to serve as a lifetime estimate, lifetime exposure studies to
evaluate potential health endpoints at various critical life stages
should be considered.
To a greater degree than under other options, the broad and deep
database that would be produced by this comprehensive testing scheme
could help defuse complaints that EPA frequently regulates industrial
activities without sufficient data regarding either the need for an
appropriate level of regulation or what such a level should be. EPA has
decided, however, that the disadvantages of choosing this option
outweigh its considerable benefits. The extensive chronic testing
required under Option 4 would impose a significant cost on industry. In
addition, as compared to Option 3, the strain that choosing this option
would place on certain resources--such as inhalation testing facilities
and supplies of laboratory animals--would significantly diminish the
cost-effectiveness of compiling the data. For these reasons, EPA did
not select this option. EPA is soliciting comments on the testing
approach to the HAPs that it has selected in this proposal.
It should be noted that, regardless of the test option chosen, if
adequate toxicity data on a HAP is produced by testing using a route of
exposure other than inhalation, route-to-route extrapolation may be
possible (see Unit IV.D. of this preamble).
B. National Academy of Sciences Approach
In section 112(o) of the CAA, 42 U.S.C. 7412(o), Congress directed
EPA to arrange for the NAS to review EPA's risk assessment methodology
relevant to HAPs subject to section 112. EPA has considered the
recommendations of the NAS regarding the assessment of risks associated
with HAPs. The NAS recommended that EPA ``* * * compile for each of the
189 chemicals an inventory of the existing and relevant chemical,
toxicologic, clinical, and epidemiologic literature'' (Ref. 5). It also
recommended that EPA ``screen the 189 chemicals for priorities for the
assessment of health risks, identify the data gaps, and develop
incentives to expedite generation of the needed data by other public
agencies (such as the National Toxicology Program, the Agency for Toxic
Substances and Disease Registry, and state agencies) and by other
organizations (industry, academia, etc.)'' (Ref. 5). As discussed in
Unit III.C. of this preamble, EPA agrees and has taken this approach.
To identify testing needs and help prioritize HAPs testing, Syracuse
Research Corporation, an EPA contractor, has identified and summarized
the existing health and exposure literature on the HAPs, and has
identified testing programs currently in progress (Refs. 11, 12).
The NAS report also discussed how a gradual, highly iterative
testing approach to the generation of health effects data on HAPs might
work. The report recommended that HAPs could be prioritized on the
basis of their acute toxicity and chemical structure, and testing might
proceed stepwise, on a case-by-case basis, from acute toxicity to
studies of the uptake, distribution, retention, and excretion of the
substance, to subchronic toxicity, and ultimately, if needed, to
endpoint testing in animals. Depending on the animal toxicity data
produced by this iterative testing scheme, according to the NAS, EPA
might decide that further studies of human toxicity or mechanisms of
toxicity are warranted.
Although EPA agrees with the need to prioritize testing, it has
taken a different approach to prioritization that is based on
consideration of exposure potential and the rulemaking schedule of
section 112 of the CAA. The amount and type of existing data vary
greatly among the chemical substances that Congress designated as HAPs.
In practice, therefore, no single uniform iterative approach based on
toxicity factors alone would apply to all chemical substances. For
example, one HAP might have only acute and short-term test data, while
longer-term studies might exist for another HAP. Nevertheless, both the
NAS and EPA approaches recognize that existing data must be considered
if EPA is to avoid requiring duplicative testing that previously
produced adequate data.
An iterative testing approach based on toxicity factors alone would
be time consuming and require multiple rulemakings. This process would
take too long to collect useful data for making decisions needed to
meet upcoming statutory deadlines established in the CAA. Furthermore,
multiple iterative rulemakings to develop needed test data would be
prohibitively costly to EPA and would not recognize limitations on EPA
resources. For Option 3, EPA's preferred testing level, follow-up
testing would rarely be required beyond that level proposed in this
rule. Such testing, if necessary, would be required in a separate
rulemaking.
To make the multichemical decisions required under section 112 of
the CAA regarding, for example, residual risk and delisting HAPs, EPA
believes that it needs a consistent, even database covering HAPs across
the same broad set of endpoints. EPA believes that Option 3 will permit
timely gathering of a consistent database on HAPs more efficiently and
at less cost to industry and EPA than is possible with other
approaches.
C. Review of Data and Selection of HAPs
In choosing candidates for this proposed test rule, EPA considered,
consistent with TSCA section 4 requirements, the potential for a
chemical substance to present an unreasonable risk of injury to health
or the environment, the production
[[Page 33184]]
volume of the substance, the amount of emissions produced by the
chemical substance entering or reasonably anticipated to enter the
environment or become a source of exposure for humans, the sufficiency
of the existing database, and the need for further testing to develop
needed data. Consequently, as indicated in Unit IV of this preamble,
and explained in a separate document in the record entitled ``TSCA
Section 4 Findings for 21 Hazardous Air Pollutants'', each candidate
listed for testing in this proposed rule is:
(1) Considered to have the potential of presenting an unreasonable
risk of injury to health or the environment (except in the case of
ethylene glycol, for which no A finding was made--see the table in Unit
V of this preamble);
(2) Produced in quantities exceeding 1,000,000 pounds per year;
(3) Emitted (i.e., released into the atmosphere) in the amount of
50 tons (100,000 pounds) per year or more according to the 1993 Toxics
Release Inventory (TRI);
(4) Considered to have health effects data needs not addressed in
other testing and research programs;
(5) Considered to have health effects data that are insufficient
under TSCA section 4 for determining effects of the HAP on health; and
(6) Considered to need further testing to develop the needed data.
The determination that data are insufficient to ascertain the
effects of the HAPs on human health is based on several factors. First,
EPA determined the effects of concern (toxicological endpoints) and the
depth and quality of data which the Agency needs in order to make
residual risk determinations. This decision and the range of options
EPA considered are discussed in Unit III.A. of this preamble. Having
made the decision that standard endpoint tests are appropriate, EPA
reviewed existing studies and, for the purposes of this rule, compared
such studies against the testing methodology used in the 1985 version
of the EPA test guidelines for these endpoints. The 1985 test
guidelines were the first test guidelines issued by EPA for its TSCA
chemical testing program and represent widely accepted, peer-reviewed
methods for characterizing chemical toxicity.
The reasons why existing studies were judged to be inadequate are
explained in a separate document in the record entitled ``TSCA Section
4 Findings for 21 Hazardous Air Pollutants'', and summarized in the
table in Unit V of this preamble. The reasons are varied but include
the following examples--not studying the appropriate endpoint; too few
dose levels; inappropriately high- or low-dose levels; and too few
animals to have statistical confidence in the results. Nevertheless, in
some cases, EPA toxicologists determined that data were adequate when
the weight of evidence from several flawed studies, which, when
considered individually were determined to be inadequate, gave an
adequate characterization of the toxicity of the substance. Thus expert
judgment must always play a role in determinations of data adequacy.
Indeed, the determination of adequacy is so intimately connected to the
unique characteristics of study design for each toxicological endpoint
that EPA is unable to articulate a universal test of data adequacy that
might be applied consistently in all situations. EPA is soliciting
comments on its approach to determining data adequacy for the HAPs.
To select HAPs for testing, EPA initially reviewed the production
data and TRI data for all 189 HAPs. EPA realizes that TRI data
represent estimates of environmental emissions of the TRI-listed
chemicals and do not account for all chemical substances in the United
States. Nevertheless, TRI figures offer the most complete, readily
available emissions data, and EPA has determined that this database is
sufficient for the purpose of helping EPA select high-emission HAPs for
consideration as potential test candidates. While publicly available
sources of production data are cited in the analysis supporting this
rule, data from these sources were checked against the TSCA chemical
inventory update production data, most of which are claimed as CBI.
After reviewing TRI data for all HAPs, EPA decided to select a
number of HAPs for initial consideration by focusing its attention on
HAPs with TRI emissions of 50 tons or more per year. The 66 HAPs in
this group constituted a reasonably sized group for further review. The
selection of 50 tons per year or more as a cutoff is appropriate
because this number captures high-emission HAPs and because section 112
(a)(1) of the CAA, 42 U.S.C. 7412(a)(1), defines ``major source'' as
emitting ``* * * 10 tons per year or more of any hazardous air
pollutant or 25 tons per year or more of any combination of hazardous
air pollutants * * *.''
A survey of testing conducted by EPA under TSCA section 4, the
Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), and other
testing programs supplemented a preliminary review of health findings
from secondary source documents and the IRIS database. This initial
survey revealed that certain HAPs having high emissions (50 tons or
more) already have a large inhalation toxicology database or are
subject to testing or research in existing programs. Therefore, EPA
decided not to pursue additional testing under this rule for benzene,
butadiene, carbon disulfide, chromium, cyanide, ethylene oxide,
formaldehyde, lead, methanol, methyl tertiary butyl ether, methylene
chloride, tetrachloroethylene, toluene, trichloroethylene, vinyl
chloride, and vinyl acetate. Additional testing under TSCA for these
chemicals may be considered at some time in the future.
EPA decided that the remaining group of 50 HAPs could be handled
most efficiently by promulgating more than one rule. Consequently, 21
high-emission HAPs were scrutinized further and were selected as
candidates for this proposed rule, and the remaining 29 HAPs were
deferred for consideration in subsequent HAPs test rulemaking efforts.
In the second HAPs test rule, EPA plans to focus on persistent HAPs
that may bioaccumulate. EPA may, therefore, require ecological and
environmental testing for these HAPs. EPA also may require testing in
the second rule to collect data needed to implement the ``Great
Waters'' program of section 112(m) of the CAA, 42 U.S.C. 7412(m).
During the selection process for this proposed rule, EPA's
contractor undertook a comprehensive search of the toxicological,
health, and exposure literature for the 21 HAPs proposed for testing in
the current rule (Refs. 11, 12). EPA's contractor performed the
literature search in a stepwise manner to save both time and expense.
The first step was to review secondary source health effects documents.
EPA's contractor identified documents published by EPA, the
International Agency for Research on Cancer (IARC), and ATSDR and
extracted relevant data. EPA performed online Environmental Mutagen
Information Center (EMIC) searches for genetic toxicity information
(Ref. 13). In addition, an article entitled ``Genetic Activity Profiles
of 110 Hazardous Air Pollutants Listed Under Title III of the Clean Air
Act'' (Ref. 14) and the International Commission for Protection against
Environmental Mutagens and Carcinogens (ICPEMC) have provided useful
summary information.
EPA realizes that using secondary sources of information is not
ideal. For example, it is possible that a secondary source document
could miss an important study or that the document could fail to
properly interpret a study. Consequently, whenever essential
[[Page 33185]]
information appeared to be missing from the review documents or was not
explained clearly, EPA's contractor consulted original articles.
Through its contractor, EPA next checked several sources for
relevant published and unpublished studies. It obtained unpublished but
publicly available studies submitted to EPA under TSCA, searched the
Toxic Substances Control Act Test Submissions (TSCATS) database by CAS
Registry number, and reviewed the National Toxicology Program (NTP)
Results Report (generated from NTP's CHEMTRACK database) to locate
completed but unpublished NTP studies. With the contractor's
assistance, EPA next undertook an update search of the open literature
to locate any as yet unidentified studies published either shortly
before or after the review documents appeared. For this purpose, EPA's
contractor searched the National Library of Medicine (NLM) TOXLINE
database for studies published during a period of time beginning three
years prior to the date of the review document initially used to obtain
toxicity information and ending on the date of the search.
In addition, EPA's contractor consulted with representatives of
NIOSH, OSHA, the Food and Drug Administration (FDA), the National
Institute of Environmental Health Sciences (NIEHS), and various
chemical companies. The purpose of these inquiries was to determine if
these organizations had any information on completed or ongoing studies
that might not be found in any readily available database. Through its
contractor, EPA also contacted the Chemical Industry Institute of
Toxicology (CIIT), as well as trade associations and allied
organizations to determine whether these organizations were sponsoring
or knew of any relevant studies currently in progress. Finally, EPA's
contractor closely reviewed data sheets compiled by EPA's IRIS RfD/RfC
Working Group to ascertain if the group had identified any additional,
otherwise unlocated information.
Varied levels of scrutiny were applied to different types of
toxicity testing information throughout the literature search. Because
the primary focus of the review of acute, subchronic, and chronic
systemic toxicity literature was inhalation exposure, only inhalation
studies were reviewed for these endpoints. Although oral studies can
provide important information on target organ toxicity and should be
considered in the design of any testing protocol, these studies usually
provide limited information on the effects of a compound on the
respiratory tract. In addition, the systemic dose remote to the
respiratory tract for many compounds is affected by modulation of
uptake at the portal of entry into the body. This modulation is not
only from first-pass effects but from other influences of anatomy and
physiology (Ref. 15). Because EPA's literature search did not encompass
oral acute and subchronic toxicity studies, the preliminary findings of
risk that EPA is making below, under TSCA section 4(a)(1)(A), are not
based on such studies. Thus, oral acute and subchronic studies may
provide additional evidence of potential toxicity.
The contractor reviewed studies of carcinogenicity, neurotoxicity,
and reproductive and developmental toxicity, regardless of the route of
administration.
EPA took a different approach to identify HAP candidates for
immunotoxicity testing. EPA relied on an EPA document ``Hazardous Air
Pollutants: Profiles of Non-Cancer Toxicity from Inhalation Exposures''
(Ref. 16), containing a database that was developed from EPA and ATSDR
documents and data files, and from the Hazardous Substances Data Bank
(HSDB) of NLM. The contractor searched recent literature (i.e., 1989 to
present) for immunotoxicity data on the 21 HAPs in both MEDLINE and
TOXLINE. For chemicals with ATSDR Toxicological Profiles, the profile
was used to identify immunotoxicity data. Much of the identified
immunotoxicity literature used rather insensitive indicators of impact
(e.g., organ weight changes, histopathology, leukocyte counts, and
total serum protein determinations), that were judged to constitute an
inadequate evaluation of suppression of immune system responsiveness
(Ref. 17). Thus, an immunotoxicity screening test is being proposed in
this rule for many of these HAPs.
Although EPA has made intense and thorough attempts to identify all
relevant studies, EPA recognizes the limitations inherent in relying on
secondary sources and realizes that its literature search may have
failed to locate studies recently undertaken or completed. Therefore,
EPA solicits comments bringing to its attention any valid studies not
identified in its search efforts.
D. Previous TSCA Testing Actions Affecting These Chemical Substances
Eight of the substances included in this proposed rule have been
the subject of previous testing under TSCA section 4. Testing by the
inhalation route was not generally required, however, and acute
effects--including respiratory tract effects--were not generally a
target endpoint. This subunit will briefly summarize previous testing
decisions and explain the relationship between those activities and
this proposed rule.
1,1'-Biphenyl was recommended by the Interagency Testing Committee
(ITC) in its 10th report for environmental effects and chemical fate
testing (47 FR 22585, May 25, 1982). Focusing only on environmental
testing, EPA found that 1,1'-biphenyl may present an unreasonable risk
to the environment and issued a test rule requiring environmental
effects and chemical fate testing of the chemical on September 12, 1985
(50 FR 37182). This proposed rule complements the earlier action by
requiring health effects testing of 1,1'-biphenyl, namely, acute
toxicity, respiratory sensory irritation, subchronic toxicity,
developmental toxicity, reproductive toxicity, neurotoxicity and
immunotoxicity.
Chlorobenzene was recommended to EPA for health and environmental
effects testing in the first report of the ITC (42 FR 55026, October
12, 1977). Subsequently, EPA found that the chemical may present an
unreasonable risk to human health (an A finding) and issued a rule
requiring reproductive effects testing (51 FR 24657, July 8, 1986).
Although the preamble of the proposed rule described specific
neurotoxicity concerns, EPA stated that neurotoxicity testing
requirements were not being proposed because it had not issued
neurotoxicity test guidelines at that time. Instead EPA explained its
then-current views on neurotoxicity testing in the preamble and
solicited public comment on those views (45 FR 48524, July 18, 1980).
Because a neurotoxicity screening battery guideline (OPPTS 870.6200)
has since been proposed, this rule proposes the testing of
chlorobenzene for neurotoxicity, acute toxicity, respiratory sensory
irritation, subchronic toxicity, and immunotoxicity.
Cresols are members of a chemical category consisting of three
isomers: ortho-, para-, and meta-cresol. Based on both A and B
findings, a test rule proposed on July 11, 1983 (48 FR 31812) would
have required testing of cresols for subchronic toxicity, mutagenicity,
carcinogenicity, developmental toxicity, reproductive effects,
neurotoxicity, and skin sensitization. The final rule, published on
April 28, 1986 (51 FR 15771), which specified testing for all three
isomers and provided a rationale for this decision, required testing
for mutagenicity, developmental toxicity, and reproductive effects.
Data received
[[Page 33186]]
under this test rule satisfy the HAPs data needs for these endpoints.
Based on the results from this first tier of tests, a conditionally
required cancer bioassay was not triggered. In addition, oral
subchronic toxicity studies and subchronic neurotoxicity studies were
conducted by EPA's Office of Solid Waste. In accordance with the need
for data on respiratory tract effects, today's rule proposes acute and
subchronic inhalation toxicity, respiratory sensory irritation, acute
neurotoxicity, and immunotoxicity tests for all three cresol isomers
(see Unit IV.B. of this preamble). For the purposes of this proposal,
the three cresol isomers are counted as a single chemical.
Methyl isobutyl ketone was the subject of a negotiated testing
agreement between EPA and industry for mutagenicity, developmental
toxicity, and subchronic testing (47 FR 58025, December 29, 1982, and
48 FR 44905, September 30, 1983). Data received under the negotiated
testing agreement satisfy the HAPs data needs for these endpoints.
Methyl isobutyl ketone is also being tested for neurotoxicity under a
TSCA enforceable consent agreement (ECA) with industry (announced at 60
FR 4514, January 23, 1995 (FRL-4924-8)). This rule proposes testing for
reproductive toxicity, acute toxicity, respiratory sensory irritation,
and immunotoxicity to complement ongoing testing and existing data.
Phenol is the subject of a test rule proposed on the basis of A and
B findings on November 22, 1993 (58 FR 61654). That rule proposed
subchronic toxicity, neurotoxicity, and reproductive and developmental
toxicity testing and a study of phenol's pharmacokinetics. EPA has
received a proposal for an ECA for this chemical substance that would
cover the testing proposed in the 1993 rule. The rule proposed herein
would add acute inhalation toxicity, respiratory sensory irritation,
and immunotoxicity to the testing program for phenol. Under the
procedures set forth at 40 CFR 790.22, members of the CMA Phenol Panel
and EPA have negotiated an ECA which provides for the testing proposed
in November 1993 as well as additional testing, including
immunotoxicity. Such testing would meet the HAPs-related data needs for
phenol. If the ECA is successfully concluded, EPA will drop the testing
requirement for phenol from the final HAPs rule.
1,2,4-Trichlorobenzene has been tested for carcinogenicity under a
test rule (51 FR 24657, July 8, 1986) based on an A finding. Data
received under this test rule satisfy the HAPs data needs for this
endpoint. Although the preamble of the proposed rule described specific
neurotoxicity concerns, EPA stated that neurotoxicity testing
requirements were not being proposed because it had not issued
neurotoxicity test guidelines at that time (45 FR 48545, July 18,
1980). Because a neurotoxity screening battery guideline (OPPTS
870.6200) has since been proposed, this rule proposes the testing of
1,2,4-trichlorobenzene for acute toxicity, respiratory sensory
irritation, neurotoxicity, immunotoxicity, and developmental toxicity.
Oncogenicity testing for vinylidene chloride was called for in a
proposed test rule based on an A finding on August 12, 1986 (51 FR
28840). The rule proposed that distribution, metabolism, and excretion
studies and an inhalation oncogenicity study be conducted in mice on
behalf of EPA's Office of Air Quality Planning and Standards (OAQPS).
EPA has not finalized the vinylidene chloride proposal and is hereby
withdrawing it. EPA is not pursuing these studies because the Agency
has concluded that, at this time, an oncogenicity bioassay would do
little to add to EPA's understanding of the oncogenic potential of the
substance. Today's rule proposes testing for acute toxicity,
respiratory sensory irritation, and neurotoxicity.
IV. Proposed Testing
A. Testing and Reporting Requirements
EPA is proposing specific testing and reporting requirements for
each of the 21 HAPs as specified in table 1 in Sec. 799.5053(a)(5) of
this proposed rule. EPA is proposing for the first time in a TSCA
section 4 rule to require an immunotoxicity screen and an acute
inhalation toxicity test that focuses on respiratory damage and
sublethal systemic toxicity. These and other test guidelines are
discussed below in Unit IV.C. of this preamble.
EPA is proposing to require a modified inhalation carcinogenicity
bioassay using only the male rat and female mouse when existing oral
carcinogenicity data and supporting information for a chemical
substance are deemed too uncertain to determine its carcinogenicity via
inhalation (Ref. 10). The reduced protocol is less expensive than a
traditional bioassay. However, test sponsors would also have the
alternative of performing pharmacokinetics studies and using route-to-
route extrapolation from existing adequate oral toxicity data under
enforceable consent agreements (EDAs) in lieu of this and other test
requirements if the Agency decides to use this approach (see Units
IV.D. and IV.E. of this preamble).
A total of 21 months would be given for the submission of final
reports for acute toxicity testing because the acute inhalation
toxicity with histopathology guideline proposes to make certain
histopathology studies contingent upon the results of the 90-day
subchronic studies. The time for the submission of immunotoxicity
studies would vary as a function of the test with which they can be
combined (e.g., subchronic and reproductive effects).
B. Test Substance
EPA is proposing that a substance of at least 97% purity be used as
the test substance. EPA recognizes that exposure to HAPs will occur as
exposure to complex mixtures and that ideally one would like data on
the mixtures themselves. However, it is not practical to test mixtures
due to the huge number of possible combinations. EPA will thus evaluate
the toxicity of HAP mixtures using data on the relatively pure
components in order to avoid the possible confounding effects of
impurities that might be found in technical grade substances. These
impurities, if substantial contributors to air pollution, should also
be captured as separate entries on the CAA list of HAPs. EPA believes
that a purity of 97% is available or readily achievable for all
substances covered by this rule.
For cresols, the subject of the test rule is a mixture (CAS No.
1319-77-3) of three isomers: ortho- (CAS No. 95-48-7), para- (CAS No.
106-44-5) and meta- (CAS No. 108-39-4). The mixture and individual
isomers are contained in the CAA section 112(b)(1) list of hazardous
air pollutants. Most human exposure is to the mixture. However, because
the mixture is of variable composition, EPA believes that it would be
very burdensome to test every possible variation of the mixture, which
would have different proportions of isomers. Therefore EPA is proposing
to follow the approach taken in the final test rule for cresols (51 FR
15771, 15776, April 28, 1986) and test each isomer (see Unit III.D. of
this preamble).
Another critical factor in study design for HAP testing is the low
vapor pressure of several of these substances (diethanolamine, 1,1'-
biphenyl, phthalic anhydride). This raises two questions. To which
forms of the chemical are humans exposed--vapor, aerosol or particle?
How does one design a valid toxicity study that can be used to assess
human risk to such exposures? Given the reported TRI releases to the
atmosphere for these substances, EPA has assumed that exposures are to
[[Page 33187]]
aerosols or particulates from the condensation of high temperature
stack gases. EPA is proposing that diethanolamine, 1,1'-biphenyl and
phthalic anhydride be tested via aerosol exposure. EPA invites
manufacturers and processors to submit information about the forms of
these substances that are encountered in ambient exposures and the
forms that should be tested, and encourages the development of
pharmacokinetics data that would permit testing by the less expensive
oral route for HAPs with low vapor pressure.
C. Test Guidelines
The 11 guidelines being proposed for use in testing HAPs under this
rule are included in the recently harmonized health effects test
guidelines proposed by EPA's Office of Prevention, Pesticides, and
Toxic Substances (OPPTS). When final, these harmonized guidelines will
incorporate an updated version of the test guidelines previously
developed for use under TSCA and FIFRA into a single set. A notice of
availability and request for comments on the proposed guidelines was
published in the Federal Register of June 20, 1996 (61 FR 31522).
The 11 guidelines proposed for use in testing HAPs are included in
the public version of the record for this rulemaking at the address
specified in the ``ADDRESSES'' section of this document. The complete
set of proposed guidelines is available electronically from the EPA
Public Access Gopher (gopher.epa.gov) under the heading:
``Environmental Test Methods and Guidelines''; by internet e-mail:
[email protected]; by mail: Public Docket and Freedom of
Information Section, Field Operations Division (7506C), Office of
Pesticide Programs, U.S. Environmental Protection Agency, Washington,
DC 20460; or in person or for courier pick-up: Room 1132, CM #2, 1921
Jefferson Davis Highway, Arlington, VA; telephone: (703) 305-5805.
The 11 guidelines proposed to be used for testing HAPs are as
follows:
(1) Acute Inhalation Toxicity with Histopathology, OPPTS 870.1350,
EPA Pub. No. 712-C-96-291, June 1996;
(2) Subchronic Inhalation Toxicity, OPPTS 870.3465, EPA Pub. No.
712-C-96-204, June 1996;
(3) Inhalation Developmental Toxicity Study, OPPTS 870-3600, EPA
Pub. No. 712-C-96-206, June 1996;
(4) Reproduction and Fertility Effects, OPPTS 870.3800, EPA Pub.
No. 712-C-96-208, February 1996;
(5) Carcinogenicity, OPPTS 870.4200, EPA Pub. No. 712-C-96-211,
June 1996;
(6) Escherichia coli WP2 and WP2 uvrA Reverse Mutation Assays,
OPPTS 870.5100, EPA Pub. No. 712-C-96-247, June 1996;
(7) Detection of Gene Mutations in Somatic Cells in Culture, OPPTS
870.5300, EPA Pub. No. 712-C-96-221, June 1996;
(8) In Vivo Mammalian Cytogenetics Tests: Bone Marrow Chromosomal
Analysis, OPPTS 870.5385, EPA Pub. No. 712-C-96-225, June 1996;
(9) In Vivo Mammalian Cytogenetics Tests: Erythrocyte Micronucleus
Assay, OPPTS 870.5395, EPA Pub. No. 712-C-96-226, June 1996;
(10) Neurotoxicity Screening Battery, OPPTS 870.6200, EPA Pub. No.
712-C-96-238, June 1996; and
(11) Immunotoxicity, OPPTS 870.7800, EPA Pub. No. 712-C-96-351,
June 1996.
To be considered in this rulemaking, comments on the 11 proposed
test guidelines that are specific to HAPs testing must be submitted to
the OPPT Document Control Office. The comments must be submitted in the
manner specified in the ``DATES'' and ``ADDRESSES'' sections at the
beginning of this document. Comments on the 11 proposed guidelines,
which are not specific to the HAPs test rule must be submitted to the
Office of Pesticide Programs by August 19, 1996, at the address
identified in the Federal Register of June 20, 1996 (61 FR 31522).
The process of developing OPPTS harmonized guidelines described
above is proceeding at the same time as the development of the HAPs
test rule. The OPPTS harmonization process may result in the revision
of the guidelines prior to the end of the ocmment period for this
proposed rule. If so, EPA will announce the availability of those of
the 11 guidelines used in the HAPs rule that have been revised in order
to allow for public comment on the applicability of the revised
guidelines to the HAPs rule. If any of these 11 guidelines has not been
revised by the end of the comment period for this proposed rule, EPA
may issue the corresponding HAPs-specific guideline independent of the
OPPTS harmonization process.
EPA is proposing to modify the subchronic inhalation toxicity test
guideline (OPPTS 870.3465) for the purposes of this rulemaking to
include enhanced histopathology of the respiratory tract and an assay
for cell damage via lung lavage. EPA is requesting comment on adding
these parameters to the subchronic test guideline for testing HAPs.
As part of this rulemaking, EPA proposes to use the acute
inhalation toxicity with histopathology test guideline (OPPTS
870.1350). As indicated in Unit III.A. of this preamble, the study of
sublethal effects, especially effects on the respiratory system,
associated with accidental release and acute exposures is necessary for
the HAPs. The standard acute inhalation toxicity test guideline (OPPTS
870.1300) focuses on gross lesions, body weight changes, and effects on
mortality. The acute inhalation toxicity with histopathology test
guideline assesses two endpoints: (1) histopathology of the respiratory
tract, kidney, liver, and other target organs; and (2) cell damage via
lung lavage. The guideline takes a stepwise approach to the evaluation
of acute toxicity and initially requires a 4-hour exposure at three
concentration levels. If the 4-hour study shows positive results in
histopathology or the bronchoalveolar lavage, a 1-hour study and an 8-
hour study would be required to define better the time and
concentration dependence of acute exposures. Histopathology is being
proposed for the respiratory tract, liver, and kidney. Other target
organs identified by either gross pathology in the 4-hour acute study
or by histopathology in the 90-day study would also have to be examined
by histopathology in the 4-hour acute study. If these results are
positive in the 4-hour study, histopathology in the 1-hour and 8-hour
studies would be required. The 4-hour acute testing may be combined
with acute neurotoxicity testing.
A respiratory sensory irritation test using American Standard Test
Method (ASTM) E 981-84 is also being proposed to provide a quantitative
estimate of the sensory irritant potential of an inhaled chemical.
Irritation is detected by a characteristic change in the breathing
pattern of mice, which results in a reduction in the breathing rate
during exposure to a test atmosphere.
For all testing proposed in this rule, test sponsors would have to
conduct testing and generate data in accordance with the specified test
guideline. Data developed under the final rule must be reported in
accordance with TSCA Good Laboratory Practice (GLP) Standards, 40 CFR
part 792.
EPA is considering three alternative procedures for handling these
test guidelines in the context of the final HAPs test rule. The first
alternative is for the final HAPs rule to incorporate the guidelines by
reference. Under this alternative, the text of the guideline would not
appear in the Code of Federal Regulations. Instead the rule would
include a reference to the guideline which would be available on the
internet and elsewhere, as noted above.
[[Page 33188]]
A copy of the applicable guideline would also be maintained in the
public version of the rulemaking record.
The second alternative would be for the final HAPs rule to refer to
the guideline, the text of which would be available on the internet and
elsewhere, as the pre-approved protocol. However, test sponsors may use
other protocols after such protocols have been approved by EPA
(``previously approved equivalents''). If EPA decides on this course of
action, the Agency may issue a supplemental notice proposing specific
implementation procedures if they are significantly different from the
following procedures. A test sponsor would be required to submit to EPA
for review and approval each test protocol that such sponsor believes
is equivalent to the corresponding OPPTS test guideline. A submission
would have to demonstrate equivalency, include a description of the
differences between the sponsor's protocol and the corresponding OPPTS
guideline, and indicate the rationale for changing the guideline. The
deadline for these submissions would be 90 days after the effective
date of the final HAPs rule. In the case of a study where the design
depends upon the results of an earlier test (such as carcinogenicity
where the dose level is contingent upon the results of a subchronic
study), the deadline is 90 days following the date of submission of the
final report for that study.
The third alternative is for the final HAPs rule to reference the
guidelines currently in part 798 of title 40 of the Code of Federal
Regulations and modify these guidelines to make them as nearly
identical as possible to the harmonized OPPTS guidelines. The
modifications that the Agency currently believes would be appropriate
are set forth in a separate document in the record entitled
``Modifications to Health Effects Test Guidelines Currently in 40 CFR
Part 798 for Use in the HAPs Test Rule''. EPA is soliciting comment on
these three alternative procedures.
D. Route-to-Route Extrapolation
EPA would consider route-to-route extrapolation of toxicity data
from routes other than inhalation when it is scientifically defensible
to empirically derive the inhalation risk. Derivation of the inhalation
risk is generally only reasonable when portal-of-entry effects (toxic
effects on the respiratory tract from inhalation exposure) and/or
first-pass effects can be ruled out or adequately characterized.
``First-pass'' effects refer to the metabolism that can take place
in portal-of-entry tissue, prior to a chemical's entry into the
systemic circulation. For example, after oral administration, many
chemicals are delivered to the liver via the portal vein from the
gastrointestinal (GI) tract before they enter into the systemic
circulation. The respiratory tract can also exhibit a first-pass effect
after inhalation due to its various cell types and metabolic enzyme
systems. The first-pass action can alter the disposition of the parent
and metabolites, thereby modulating the dose to remote or systemic
target tissues in a route-dependent fashion. Therefore, unless this
first-pass effect and dosimetry are adequately understood and taken
into account, substantial error can be introduced in route-to-route
extrapolation.
In the absence of data to determine dosimetry via inhalation,
quantitative route-to-route extrapolation is subject to substantial
error when a chemical is thought to be susceptible to first-pass
effects (e.g., metabolized) or when a potential for portal-of-entry
effects is indicated (e.g., skin irritation after dermal
administration). There are situations where oral data should not be
used for route extrapolation to inhalation. For example, chemicals with
a short active half-life that were administered by gavage may result in
high short-term blood concentrations and consequently much greater
effects than the much lower constant blood levels that occur with
inhalation exposure. Conversely, if a chemical requires metabolic
activation via a rate-limited reaction, bolus dosing via gavage may
underestimate the dose. Consideration of factors such as these is
important in judging whether the oral study of interest qualifies for
route extrapolation.
Regardless of the toxic endpoint considered, EPA's ability to
perform quantitative route-to-route extrapolation is critically
dependent on the amount and type of data available. The minimum
information generally needed includes both the nature of the toxic
effect and a description of the relationship between exposure and the
toxic effect. The actual impact of exposure by different routes can
best be estimated by taking account of factors that influence
absorption at the portal of entry, such as:
(1) Physicochemical characteristics of the chemical (e.g.,
disassociation state, molecular weight, partition coefficient,
reactivity, solubility);
(2) Exposure factors (e.g., concentration, duration, regimen); and
(3) Physiologic parameters (e.g., barrier capacity as related to
variability in species, blood flow, cell types and morphology,
metabolism, pH, specialized absorption sites, storage in cells) and
those parameters that influence dose that are remote to the portal of
entry including metabolism, clearance, tissue binding, tissue blood
flows, tissue:blood partition coefficients, and tissue volumes.
Oral toxicity data are the most commonly available data as
alternatives to inhalation data. Oral data are problematic for route-
to-route extrapolation in the following instances:
(1) When groups of chemicals are expected to have different
toxicities by the two routes, for example, metals, irritants, and
sensitizers.
(2) When a first-pass effect by the liver is expected.
(3) When a respiratory tract effect is established but nodosimetry
comparison can be clearly established between the two routes.
(4) When the respiratory tract was not adequately studied in the
oral studies.
(5) When short-term inhalation studies, dermal irritation, or in
vitro studies indicate potential portal-of-entry effects at the
respiratory tract, but the studies themselves are not adequate for risk
assessment.
Dose-response data from other routes of exposure, such as
intravenous, intraperitoneal, subcutaneous, dermal, and intramuscular
routes also may be available. Intravenous data can provide reliable
information on blood levels, but such information should be
supplemented by knowledge of the quantitative relationship between
exposure concentration and blood levels in order to be useful. The
other routes usually are less useful in route-to-route extrapolation
because the pharmacokinetics are, in general, poorly characterized.
Methods for route-to-route extrapolation vary in accuracy and,
therefore, in inherent uncertainty. The simplest approach is to use
default absorption values for each exposure route dependent on the
chemical class in question. Such values have only been developed for a
few classes of organic chemicals. Because this approach entails
increased uncertainty compared with those that use pharmacokinetics
(PK) data and physiologically based pharmacokinetics (PBPK) modeling,
use of default absorption values is generally considered highly
uncertain for quantitative dose-response assessment.
EPA's optimal but most complex and data intensive method for
performing route-to-route extrapolation involves the development of a
PBPK model that describes the disposition (deposition, absorption,
distribution, metabolism, and elimination) of the chemical for the
routes of interest (Ref. 15). Such models
[[Page 33189]]
account for fundamental physiological and biochemical parameters and
processes such as blood flows, ventilatory parameters, metabolic
capacities, and renal clearance tailored by the physicochemical (e.g.,
blood:air and tissue:blood partitions) and biochemical properties
(e.g., binding, depletion of cofactors) of the chemical in question.
PBPK models should be used in conjunction with toxicity and mechanistic
studies in order to relate the effective dose associated with an
adverse effect for the test species and conditions to other scenarios.
Although the development of a full PBPK model can involve greater
effort than other methods using pharmacokinetics data, the application
of pharmacokinetics modeling to determine health risk provides a
considerable improvement in the reliability of an extrapolation across
routes. The use of an existing model structure, essentially a template,
can greatly reduce the effort required for model development of
analogous chemicals.
More limited pharmacokinetics data such as measurement of
bioavailability and disposition of an internal dose marker (e.g., blood
cholinesterase activity, enzyme elevation, and amount of chemical bound
to protein) may be used for route-to-route extrapolation in conjunction
with a consideration of the uncertainties involved in each case. As
above, if the portal of entry is affected by the agent, then more
elaborate data may be required.
EPA realizes that the use of pharmacokinetics data for route-to-
route extrapolation, as well as for the broader purpose of generally
identifying the mechanisms by which exposure to a specific agent causes
particular health effects, is a fast-developing and often controversial
area of science at this time. However, under certain circumstances, as
explained above, route-to-route extrapolation based on valid
pharmacokinetics data can offer a useful and less expensive alternative
to testing or retesting by another route of exposure.
E. Opportunity To Submit Proposals for Enforceable Consent Agreements
for Pharmacokinetics Studies
Basic pharmacokinetics parameters provide information on a
substance's absorption, distribution, biotransformation, and excretion
which can aid in understanding the potential for accumulation of the
substance in various tissues or organs and the mechanism of toxicity.
Basic PK parameters can be determined through use of the OPPTS
harmonized test guideline for pharmacokinetics studies (870.7485). EPA
considered but rejected the option of requiring the use of this
guideline in this proposed rule because the Agency is interested in a
more sophisticated level of study that could potentially support PBPK
modeling.
EPA believes that enforceable consent agreements (ECAs) and testing
consent orders offer an opportunity to obtain this more in-depth
understanding of the pharmacokinetics of HAPs. The Agency, therefore,
is inviting manufacturers to submit proposals for pharmokinetics
studies for HAPs to be used in the ECA process. Each study proposal
should include the name of the chemical(s), a detailed description of
the proposed pharmacokinetics study, and discussion of the application
of the pharmacokinetics data in performing route-to-route
extrapolations. Study proposals should reflect an understanding of the
scientific reasoning presented in Unit IV.D. of this preamble, the
existing database on the chemical and testing required under this
proposed test rule. EPA expects to use a previously published decision
tree (Ref. 15) as an element in the evaluation of these proposals. As
noted in Unit IV.D., these data may be used for route-to-route
extrapolation with a level of uncertainty in inverse proportion to
their level of complexity and sophistication.
Each study proposal should be labeled: ``Proposal for
Pharmacokinetics Study of (name of chemical),'' identified by document
control number (OPPTS-42187B, FRL-4869-1), and sent to: U.S.
Environmental Protection Agency, Office of Pollution Prevention and
Toxics, Document Control Office (7407), Room G-099, 401 M St., SW.,
Washington, DC 20460. Proposals for pharmacokinetics studies must be
received by EPA no later than October 24, 1996. Enforceable consent
agreements must be negotiated and signed no later than 12 months after
the date of proposal of this rule in order to permit timely development
of the final HAPs rule.
EPA will review the submissions and will select promising
candidates for negotiation under the procedures in 40 CFR 790.22. If
the Agency decides to proceed with the ECA process, it will publish a
notice in the Federal Register soliciting persons interested in
participating in or monitoring negotiations for the development of ECAs
for PK studies to notify the Agency in writing.
EPA noted in Unit IV.D. that the development and use of a PBPK
model represents the optimal approach to route-to-route extrapolation.
The development of such models is often a complex and uncertain task
that in most cases lies beyond the expectations of performance that
could be embodied in an ECA. However, EPA would like to encourage
extension of the data generated under the ECAs described above to the
development of PBPK models. EPA envisions that PBPK models could be
developed through voluntary cooperative arrangements and is interested
in a dialogue with industry and others on ways to encourage and support
PBPK model development.
F. Persons Required To Test
Based on the findings in Unit V of this preamble, EPA is proposing
that persons who manufacture (including import) or process, or who
intend to manufacture or process 1,1'-biphenyl, carbonyl sulfide,
chlorine, chlorobenzene, chloroprene, cresols (all three isomers),
diethanolamine, ethylbenzene, ethylene dichloride, ethylene glycol,
hydrochloric acid, hydrogen fluoride, maleic anhydride, methyl isobutyl
ketone, methyl methacrylate, naphthalene, phenol, phthalic anhydride,
1,2,4-trichlorobenzene, 1,1,2-trichloroethane, and vinylidene chloride,
other than as an impurity, at any time from the effective date of the
final test rule to the end of the reimbursement period, be subject to
the testing requirements in this rule. Manufacturers would be required
to submit letters of intent to conduct testing or exemption
applications (40 CFR 790.45). However, under 40 CFR 790.42, processors,
small-quantity manufacturers, and manufacturers of small quantities of
these substances solely for research and development purposes would not
be required to submit letters of intent or exemption applications
unless directed to do so in a subsequent notice as described in 40 CFR
790.48(b).
EPA is proposing to exempt those manufacturers and processors that
produce the chemical substances listed above only as an impurity, as
defined in 40 CFR 790.3, because it would be difficult and
prohibitively expensive for EPA, manufacturers, and processors to
identify with complete assurance all chemical substances that contain
the 21 substances solely as an impurity. In addition, EPA would find it
difficult to apply both the exemption and reimbursement processes to
those who manufacture and/or process these chemical substances solely
as an impurity. EPA's reimbursement regulations, issued pursuant to
TSCA section 4(c), 15 U.S.C. 2603(c), state that those persons who
manufacture or process chemical substances as impurities are not
subject to test
[[Page 33190]]
requirements unless a particular test rule specifically states
otherwise (40 CFR 791.48(b)). EPA finds no basis to propose such a
requirement in this rule.
Persons who manufacture these substances as byproducts, as defined
in 40 CFR 791.3(c), would be subject to the testing requirements set
forth in this proposed rule. The total amount of imports and domestic
production of these chemical substances, including the amount produced
as a byproduct, would be used in determining reimbursement shares under
the TSCA section 4 data reimbursement regulations in 40 CFR part 791.
In a previous multichemical test rule (undertaken for EPA's Office of
Solid Waste) for which EPA had likewise proposed that byproducts be
subject to the rule, an industry commenter objected to this inclusion
based on historical grounds. The commenter said, ``The historical roots
of section 4 in the Eckart Subcommittee work on TSCA were the sharing
of the costs of test generation in direct proportion to the economic
benefits which producers derived from the chemicals.'' In response to
this comment, EPA explained that,
EPA does not agree that the intention of Congress to have
producers share the cost of testing should be interpreted to exclude
producers of byproducts from TSCA section 4 testing requirements.
While economic benefit is not derived directly from the production
of the subject chemical, the production and disposal of the
byproduct are a result of a production process by which the company
does derive economic benefit (an indirect benefit). (53 FR 22300,
22305, June 15, 1988)
Carbonyl sulfide would be the first chemical substance subject to a
TSCA section 4 test rule that is produced almost exclusively as a
byproduct. Although some carbonyl sulfide is reported to be used in
chemical synthesis, its large production and release, as reported in
the TRI, is due to its creation as a byproduct which is unwanted.
Consistent with EPA's position on byproducts testing, as explained
above, all persons reporting the release of carbonyl sulfide in the TRI
would be considered to be manufacturers of carbonyl sulfide and would
be subject to the provisions of this proposed rule.
V. Findings
As explained in Unit I of this preamble, EPA is proposing findings
under TSCA sections 4(a)(1)(A) and 4(a)(1)(B) for the 21 HAPs subject
to this rule. The findings are summarized in the table below. The
detailed discussion of the findings for each chemical substance
included in this rule is contained in a separate document entitled
``TSCA Section 4 Findings for 21 Hazardous Air Pollutants'' that is
available in the rulemaking record. Requirements for sections
4(a)(1)(A) and 4(a)(1)(B) findings appear in Unit I of this preamble.
In articulating its policy for making findings under TSCA section
4(a)(1)(B) (frequently described as the ``B policy'', see Unit I of
this preamble), EPA has defined ``substantial production'' as aggregate
annual production of 1 million pounds or more and ``substantial
release'' as an annual release, from all sources, into the environment
of 1 million pounds or 10% of production, whichever is lower (58 FR
28736, 28746, May 14, 1993). These definitions apply to the terms
``substantial production'' and ``substantial release'' as used in this
preamble. (As explained in Unit III.C. of this preamble, all the
chemical substances proposed for testing in this proposed rule are
emitted into the atmosphere in the amount of 50 tons per year or more
according to the TRI.) EPA also defined ``substantial human exposure''
as an annual exposure of 100,000 members of the general population,
10,000 consumers, or 1,000 workers. Id.
TSCA Section 4(a) Statutory Findings
----------------------------------------------------------------------------------------------------------------
4(a)(1)(A)(ii)/(iii)
Chemical substance 4(a)(1)(A)(i) Finding 4(a)(1)(B)(i) Findinga and 4(a)(1)(B)(ii)/
is based on: is based on: (iii) Finding are for:
----------------------------------------------------------------------------------------------------------------
1,1'-Biphenyl--------------------------Reproductive toxicity----Substantial production:--Acute toxicity\6\,\9\--
(CAS No. 92-52-4) Respiratory toxicity 53.5 million lbs Subchronic
Substantial human toxicity\5\,\9\
exposure: 20,351 Developmental
workers toxicity\2\
Consumer exposure Reproductive
toxicity\1\
Neurotoxicity\7\
Immunotoxicity\7\
Respiratory sensory
irritation\7\
----------------------------------------------------------------------------------------------------------------
Carbonyl Sulfide Oncogenicity Substantial production: Acute toxicity\6\
(CAS No. 463-58-1) Neurotoxicity production is at least Subchronic toxicity\7\
as much as Developmental
environmental release toxicity\7\
(produced as a Reproductive
byproduct) toxicity\5\,\6\
Substantial Neurotoxicity\6\,\7\
environmental release: Oncogenicity\7\
16.7 million lbs Immunotoxicity\7\
Genetic toxicity\7\
Respiratory sensory
irritation\7\
----------------------------------------------------------------------------------------------------------------
Chlorine Respiratory toxicity Substantial production: Acute toxicity\5\,\8\
(CAS No. 7782-50-5) 22.3 billion lbs
Substantial human
exposure: 170,000
workers
Consumer exposure
Substantial
environmental release:
78,498 million lbs
----------------------------------------------------------------------------------------------------------------
[[Page 33191]]
Chlorobenzene Respiratory toxicity Substantial production: Acute toxicity\6\
(CAS No. 108-90-7) Developmental toxicity 210 million lbs Subchronic
Reproductive toxicity Substantial human toxicity\3\,\4\,\6\,\8
Liver toxicity exposure: 17,056 \
Kidney toxicity workers Neurotoxicity\7\
Neurotoxicity General population Immunotoxicity\6\,\7\
Substantial
environmental release:
2.58 million lbs
----------------------------------------------------------------------------------------------------------------
Chloroprene Respiratory toxicity Substantial production: Acute toxicity\3\,\6\
(CAS No. 126-99-8) Reproductive toxicity 321 million lbs Reproductive
Liver toxicity Substantial human toxicity\7\,\8\
Neurotoxicity exposure: 17,749 Neurotoxicity\6\,\8\
Hematotoxicity workers Immunotoxicity\7\
Developmental toxicity General population Respiratory sensory
Substantial irritation\7\
environmental release:
1.7 million lbs
----------------------------------------------------------------------------------------------------------------
Cresols
(CAS No. 1319-77-3)
mixture of 3 isomers:
ortho-isomer
(CAS No. 95-48-7)
para-isomer
(CAS No. 106-445)
Respiratory toxicity Substantial production: Acute toxicity\8\
meta-isomer Developmental toxicity 84.3 million lbs Subchronic
(CAS No. 108-39-4) Neurotoxicity Substantial human toxicity\5\,\8\
exposure: 132,742 Acute
workers neurotoxicity\5\,\6\
Consumer exposure Immunotoxicity\6\,\7\
General population Respiratory sensory
Substantial irritation\7\
environmental release:
1.5 million lbs
----------------------------------------------------------------------------------------------------------------
Diethanolamine Reproductive toxicity Substantial production: Acute toxicity\8\
(CAS No. 111-42-2) Neurotoxicity 198 million lbs Subchronic toxicity\5\
Substantial human Developmental
exposure: 573,025 toxicity\6\
workers Reproductive
Consumer exposure toxicity\7\
Neurotoxicity\5\,\6\,\7
\
Immunotoxicity\7\
Respiratory sensory
irritation\7\
----------------------------------------------------------------------------------------------------------------
Ethylbenzene Developmental toxicity Substantial production: Acute toxicity\6\
(CAS No. 100-41-4) Kidney toxicity 11.4 billion lbs Developmental
Neurotoxicity Substantial human toxicity\2\
exposure: 80,726 Reproductive
workers toxicity\7\
Consumer exposure Neurotoxicity\6\,\7\
General population Immunotoxicity\6\,\7\
Substantial Respiratory sensory
environmental release: irritation\7\
8.8 million lbs
----------------------------------------------------------------------------------------------------------------
Ethylene dichloride Oncogenicity Substantial production: Acute
(CAS No. 107-06-2) General systemic 14.3 billion lbs toxicity\1\,\4\,\5\,\6
toxicity General population \
Substantial human Subchronic
exposure: 77,111 toxicity\4\,\5\,\8\
workers Developmental
Consumer exposure toxicity\2\
Substantial Reproductive
environmental release: toxicity\9\
4 million lbs Neurotoxicity\6\,\7\
Respiratory sensory
irritation\7\
----------------------------------------------------------------------------------------------------------------
Ethylene glycol Substantial production: Acute toxicity\7\
(CAS No. 107-21-1) 7.2 billion lbs Subchronic
Substantial human toxicity\4\,\6\
exposure: 1,133,792 Neurotoxicity\7\
workers Immunotoxicity\5\
Consumer exposure Respiratory sensory
Substantial irritation\7\
environmental release:
17.5 million lbs
----------------------------------------------------------------------------------------------------------------
Hydrochloric acid Respiratory toxicity Substantial production: Acute toxicity\5\,\6\
(CAS No. 7647-01-0) 5.75 billion lbs
Substantial human
exposure: 1,131,879
workers
Consumer exposure
Substantial
environmental release:
287.7 million lbs
----------------------------------------------------------------------------------------------------------------
[[Page 33192]]
Hydrogen fluoride Respiratory toxicity Substantial production: Acute
(CAS No. 7664-39-3) Liver toxicity 322 million lbs toxicity\3\,\5\,\6\,\8
Eye irritation Substantial human \
exposure: 182,589 Subchronic
workers toxicity\8\,\10\
Substantial Developmental
environmental release: toxicity\7\
9.2 million lbs Reproductive
toxicity\7\
Neurotoxicity\7\
Immunotoxicity\7\
Respiratory sensory
irritation\7\
----------------------------------------------------------------------------------------------------------------
Maleic anhydride Respiratory toxicity Substantial production: Acute toxicity\7\
(CAS No. 108-31-6) Eye irritation 382 million lbs Developmental
Substantial human toxicity\2\
exposure: 37,897 Neurotoxicity\7\
workers Oncogenicity\5\,\6\
Immunotoxicity\7\
Respiratory sensory
irritation\7\
----------------------------------------------------------------------------------------------------------------
Methyl isobutyl ketone Developmental toxicity Substantial production: Acute toxicity\5\,\6\
(CAS No. 108-10-1) Neurotoxicity 175 million lbs Reproductive
Substantial human toxicity\7\
exposure: 467,763 Immunotoxicity\7\
workers Respiratory sensory
Consumer exposure irritation
General population
Substantial
environmental release:
27.7 million lbs
----------------------------------------------------------------------------------------------------------------
Methyl methacrylate Respiratory toxicity Substantial production: Acute
(CAS No. 80-62-6) Liver toxicity 1,200 million lbs toxicity\1\,\3\,\4\,\6
Kidney toxicity Substantial human \
Neurotoxicity exposure: 120,788 Developmental
workers toxicity\2\
Consumer exposure Reproductive
Substantial toxicity\7\
environmental release: Neurotoxicity\3\,\4\,\6
2.8 million lbs \,\8\
Immunotoxicity\6\,\7\
Respiratory sensory
irritation\7\
----------------------------------------------------------------------------------------------------------------
Naphthalene Respiratory toxicity Substantial production: Acute toxicity\5\,\6\
(CAS No. 91-20-3) Neurotoxicity 235 million lbs Reproductive
Substantial human toxicity\5\,\6\,\7\
exposure: 23,092 Immunotoxicity\6\,\7\
workers Respiratory sensory
Consumer exposure irritation\7\
General population
Substantial
environmental release:
2.8 million lbs
----------------------------------------------------------------------------------------------------------------
Phenolb Respiratory toxicity Substantial production: Acute
(CAS No. 108-95-2) 3.9 billion lbs toxicity\4\,\5\,\8\
Substantial human Immunotoxicity\4\,\5\,\
exposure: 192,739 6\
workers Respiratory sensory
Consumer exposure irritation
General population
Substantial
environmental release:
10 million lbs
----------------------------------------------------------------------------------------------------------------
Phthalic anhydride Respiratory Substantial production: Acute toxicity\6\,\7\
(CAS No. 85-44-9) sensitization 874 million lbs Subchronic toxicity\7\
Substantial human Developmental
exposure: 62,644 toxicity\5\,\8\
workers Reproductive
toxicity\7\
Neurotoxicity\7\
Oncogenicity\5\
Immunotoxicity\7\
Respiratory sensory
irritation\7\
----------------------------------------------------------------------------------------------------------------
1,2,4-Trichlorobenzene Oncogenicity Substantial production: Acute
(CAS No. 120-82-1) Developmental toxicity CBI toxicity\1\,\3\,\6\
Substantial human Developmental
exposure: 4,032 toxicity\1\,\5\,\6\
workers Neurotoxicity\6\
General population Immunotoxicity\7\
Respiratory sensory
irritation\7\
----------------------------------------------------------------------------------------------------------------
[[Page 33193]]
1,1,2-Trichloroethane Oncogenicity Substantial production: Acute toxicity\7\
(CAS No. 79-00-5) Liver toxicity estimated - 210 Subchronic toxicity\7\
Kidney toxicity million lbs Developmental
Neurotoxicity Substantial human toxicity\5\,\6\
exposure: 1,036 Reproductive
workers toxicity\7\
General population Neurotoxicity\6\,\7\
Oncogenicity\5\
In vivo cytogenicity\7\
Immunotoxicity\6\
Respiratory sensory
irritation\7\
----------------------------------------------------------------------------------------------------------------
Vinylidene chloride Oncogenicity Substantial production: Acute toxicity\5\,\6\
(CAS No. 75-35-4) Respiratory toxicity 230 million lbs Neurotoxicity\7\
Developmental toxicity Substantial human Respiratory sensory
Liver toxicity exposure: 2,675 irritation\7\
Kidney toxicity workers
Consumer exposure
----------------------------------------------------------------------------------------------------------------
\1\ Too few animals were tested.
\2\ Only one species was adequately tested.
\3\ Only one sex was tested.
\4\ Too few exposure levels were tested.
\5\ Inadequate exposure duration, schedule, or route.
\6\ Only limited endpoints were assessed.
\7\ No study addressing the specific endpoint was found.
\8\ Insufficient reporting of data to make the study useful.
\9\ No no-observed-adverse-effect level (NOAEL) was identified.
\10\ No lowest-observed-adverse-effect level (LOAEL) was identified.
Notes to table:
a ``B'' findings are based on Ref. (10). It should be noted that
all HAPs meet the 50 tons of emissions per year selection criteria
discussed in Unit III.C. of this preamble.
b Findings made in 58 FR 61654, 61659-60, November 22, 1993.
VI. Economic Analysis of the Proposed Rule
EPA has prepared and placed in the record for this proposed rule an
economic analysis that evaluates the potential for significant economic
impacts as a result of the testing proposed in this notice. The total
cost of this proposed rule is estimated to range up to $41.4 million.
The total cost of testing for each chemical substance has been
annualized and compared with annual revenues (defined as the product of
sales price and total supply) as an indication of potential economic
impact. Annualized test costs, calculated over 15 years using a 7%
discount rate, represent the equivalent constant costs that would have
to be recouped each year of the payback period to finance the testing
expenditure in the first year. Annualized test costs are then divided
by the total supply of the chemical substance to derive the annualized
unit test costs. The percent price impact is calculated by dividing the
annualized unit test costs by the sales price and multiplying by 100.
The upper-bound estimated total costs of testing (including both
laboratory costs and administrative costs), annualized tests costs, and
price impact for the chemicals in this proposed rule are as follows:
--------------------------------------------------------------------------------------------------------------------------------------------------------
Chemical Substances Total test cost ($) Annualized test cost ($) Price impact (%)
--------------------------------------------------------------------------------------------------------------------------------------------------------
1,1'-Biphenyl 2,213,900 243,074 0.64
Carbonyl sulfide 5,509,163 609,876 NA
Chlorine 85,400 9,376 0.0003
Chlorobenzene 972,900 106,819 0.098
Chloroprene 1,603,488 176,054 0.076
Cresols (all 3 isomers) 2,139,600 234,917 0.39
Diethanolamine 2,327,838 255,584 0.23
Ethylbenzene 1,732,050 190,170 0.013
Ethylene dichloride 2,007,325 220,393 0.0071
Ethylene glycol 986,638 108,327 0.0097
Hydrochloric acid 85,400 9,376 0.0040
Hydrogen fluoride 2,135,888 234,509 0.094
Maleic anhydride 4,148,588 454,834 0.25
Methyl isobutyl ketone 1,228,913 134,928 0.16
Methyl methacrylate 1,732,050 190,170 0.023
Naphthalene 1,242,650 136,436 0.16
Phenol 85,400 9,376 0.0010
[[Page 33194]]
Phthalic anhydride 5,650,338 620,377 0.21
1,2,4-Trichlorobenzene 963,163 105,750 CBI
1,1,2-Trichloroethane 3,837,900 421,381 0.41
Vinylidene chloride 708,700 77,811 0.12
--------------------------------------------------------------------------------------------------------------------------------------------------------
Note: The table shows the maximum costs and impacts estimated by
EPA. The full range of estimates is given in the economic analysis
document placed in the record for this proposed rule.
EPA believes, on the basis of these calculations, that the proposed
testing of the HAPs presents a low potential for adverse economic
impact. Because these chemical substances have relatively large
production volumes, with the exception of carbonyl sulfide (to which
this methodology does not apply) the annualized costs of testing,
expressed as a percentage of annual revenue, are very small--ranging
from 0.0003% to 0.64%. Costs of testing are therefore found to be
insignificant relative to revenues for these chemical substances.
VII. Availability of Test Facilities and Personnel
Although earlier studies indicated that test facilities and
personnel were available to perform the testing specified in this
proposed rule (Ref. 18), the impact of this rule combined with other
testing requirements may exceed capacity for inhalation testing
facilities in the short term. While EPA believes that over the longer
term, additional inhalation facilities will become available, any
short-term effects can be dealt with by adjusting study due dates in
response to comments on this rule or in response to a request for
modification of reporting deadlines.
VIII. Public Meeting
EPA will hold a public meeting in Washington, DC prior to the close
of the comment period. Announcemment of this meeting will be published
in the Federal Register. If requested, EPA will hold an additional
public meeting in Washington, DC.
IX. Comments Containing Confidential Business Information
All comments will be placed in the public version of the rulemaking
record unless they are clearly labeled as containing information
claimed as CBI when they are submitted. CBI claims will be deemed to
have been waived if they are not made at the time of submission of the
document containing the information claimed as CBI, and such document
may be made public with no further notice to the submitter. While a
part of the rulemaking record, comments claimed as CBI will be treated
in accordance with 40 CFR part 2. A sanitized version of all comments
containing information claimed as CBI must be submitted to EPA for
inclusion in the public version of the rulemaking record.
It is the responsibility of the submitter to comply with 40 CFR
part 2 so that all materials claimed as CBI may be properly protected.
This includes, but is not limited to, clearly indicating on the face of
the revelant section of the comment (as well as on any revelant
associated correspondence) that information claimed as CBI is included
and marking ``CONFIDENTIAL,'' ``TSCA CBI,'' or similar designation on
the face of each section of any document or attachment in the comment
that contains information claimed as CBI. Should putatively private
information be put into the public file because of the submitter's
failure to clearly claim and designate its confidential claim on the
face of the comment, EPA will presume any such information that has
been in the public file for more than 30 days to be in the public
domain.
X. Rulemaking Record
EPA has established a record for this rulemaking (docket number
OPPTS-42187) (including comments and data submitted electronically).
This record contains the basic information considered by EPA in
developing this proposal and appropriate Federal Register notices. EPA
will supplement this record as necessary.
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 12 noon to 4 p.m., Monday
through Friday, except legal holidays. The public record is located in
the TSCA Nonconfidential Information Center, Rm. NE-B607, 401 M St.,
SW., Washington, DC 20460.
Comments in electronic form may be submitted directly to EPA at:
[email protected]
Comments in electronic form must be submitted in 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, will be kept in paper form. Accordingly, EPA will transfer all
comments 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 record includes the following information.
A. Supporting Documentation
(1) Federal Register notices/EPA documents pertaining to this
proposed rule consisting of:
(a) ``TSCA Interagency Testing Committee; Initial Report to the
Administrator, Environmental Protection Agency'' (42 FR 55026, October
12, 1977).
(b) ``Chloromethane and Chlorinated Benzenes Proposed Test Rule;
Amendment to Proposed Health Effects Standards'' (45 FR 48524, July 18,
1980).
(c) ``Dichloromethane, Nitrobenzene and 1,1,1-Trichloroethane;
Proposed Test Rule'' (46 FR 30300, June 5, 1981).
(d) ``Tenth Report of the Interagency Testing Committee to the
Administrator; Receipt of Report and Request for Comments Regarding
Priority List of Chemicals'' (47 FR 22585, May 12, 1982).
(e) ``Methyl Isobutyl Ketone and Methyl Ethyl Ketone; Response to
the Interagency Testing Committee'' (47 FR 58025, December 29, 1982).
(f) ``Toxic Substances Control Act; Data Reimbursement'' (48 FR
31786, July 11, 1983).
(g) ``Cresols; Proposed Test Rule'' (48 FR 31813, July 11, 1983).
(h) ``Methyl Isobutyl Ketone and Methyl Ethyl Ketone Decision to
Adopt Negotiated Testing Program'' (48 FR 44905, September 30, 1983).
(i) ``Toxic Substances; Biphenyl; Test Rule'' (50 FR 37182,
September 12, 1985).
(j) ``Cresols; Testing Requirements'' (51 FR 15771, April 28,
1986).
(k) ``Chlorinated Benzenes; Final Test Rule'' (51 FR 24657, July 8,
1986).
(l) ``Toxic Substances, 1,1,-Dichloroethylene; Proposed Test Rule''
(51 FR 28840, August 12, 1986).
(m) ``Guidelines for Carcinogen Risk Assessment'' (51 FR 33992
(September 24, 1986).
[[Page 33195]]
(n) ``Office of Solid Waste Chemicals; Final Test Rule'' (53 FR
22300, June 15, 1988).
(o) ``Toxic Substances Control Act (TSCA); Good Laboratory Practice
Standards'' (54 FR 34034, August 17, 1989).
(p) ``Metabolism and Pharmacokinetics Test Guideline'' (56 FR
32537, July 17, 1991).
(q) ``Guidelines for Developmental Toxicity Risk Assessment'' (56
FR 63798, December 5, 1991).
(r) ``TSCA section 4(a)(1)(B) Final Statement of Policy; Criteria
for Evaluating Substantial Production, Substantial Release, and
Substantial or Significant Human Exposure'' (58 FR 28736, May 14,
1993).
(s) ``Office of Water Chemicals; Final Test Rule'' (58 FR 59667,
November 10, 1993).
(t) ``Acetophenone, Phenol, N,N-Dimethylaniline, Ethyl Acetate, and
2,6-Dimethylphenol; Proposes Test Rule, Notice of Opportunity to
Initiate Negotiations for TSCA Section 4 Testing Consent Agreements''
(58 FR 61654, November 22, 1993).
(u) ``Testing Consent Orders for Acetone, n-Amyl Acetate, n-Butyl
Acetate, Ethyl Acetate, Isobutyl Alcohol, Methyl Isobutyl Ketone, and
Tetrahyrofuran'' (60 FR 4514, January 23, 1995).
(v) ``Executive Order 12866 of September 30, 1993; Regulatory
Planning and Review'' (58 FR 51735, October 4, 1993).
(w) ``Executive Order 12898 of February 11, 1994; Federal Actions
to Address Environmental Justice in Minority Populations and Low-Income
Populations'' (59 FR 7629, February 16, 1994).
(x) ``Guidelines for Reproductive Toxicity Risk Assessment'' (Pub.
No. EPA/600/AP-94/001, February 1994).
(2) OPPTS test guidelines used in this proposed rule:
(a) Acute Inhalation Toxicity with Histopathology, OPPTS 870.1350,
EPA Pub. No. 712-C-96-291, June 1996;
(b) Subchronic Inhalation Toxicity, OPPTS 870.3465, EPA Pub. No.
712-C-96-204, June 1996;
(c) Inhalation Developmental Toxicity Study, OPPTS 870-3600, EPA
Pub. No. 712-C-96-206, June 1996;
(d) Reproduction and Fertility Effects, OPPTS 870.3800, EPA Pub.
No. 712-C-96-208, February 1996;
(e) Carcinogenicity, OPPTS 870.4200, EPA Pub. No. 712-C-96-211,
June 1996;
(f) Escherichia coli WP2 and WP2 uvrA Reverse Mutation Assays,
OPPTS 870.5100, EPA Pub. No. 712-C-96-247, June 1996;
(g) Detection of Gene Mutations in Somatic Cells in Culture, OPPTS
870.5300, EPA Pub. No. 712-C-96-221, June 1996;
(h) In Vivo Mammalian Cytogenetics Tests: Bone Marrow Chromosomal
Analysis, OPPTS 870.5385, EPA Pub. No. 712-C-96-225, June 1996;
(i) In Vivo Mammalian Cytogenetics Tests: Erythrocyte Micronucleus
Assay, OPPTS 870.5395, EPA Pub. No. 712-C-96-226, June 1996;
(j) Neurotoxicity Screening Battery, OPPTS 870.6200, EPA Pub. No.
712-C-96-238, June 1996; and
(k) Immunotoxicity, OPPTS 870.7800, EPA Pub. No. 712-C-96-351, June
1996.
(3) Technical Support Documents consisting of:
(a) TSCA Section 4 Findings for 21 Hazardous Air Pollutants.
(b) Exposure Profiles for HAPs--Group 1.
(c) Summary Tables on the Health Effects Data for Hazardous Air
Pollutants (HAPs)--Group 1.
(d) Economic Analysis of the Impact of the Test Rule.
(4) Communications consisting of:
(a) Written letters and memoranda.
(b) Contact reports of telephone conversations.
(c) Meeting summaries.
B. References
(1) U.S. Environmental Protection Agency. ``Methods for derivation
of inhalation reference concentrations and application of inhalation
dosimetry.'' p. xxviii. Prepared by the Office of Health and
Environmental Assessment, Washington, DC. EPA/600/8-90/066F (1994).
(2) Letter from John F. Martonik, OSHA, to Susan B. Hazen, EPA, May
31, 1995.
(3) Letter from Val Schaeffer, CPSC, to Joe Carra, EPA, June 2,
1995.
(4) Orme-Zavaleta, J. ``OMB Question-Reply.'' Memorandum to Vicki
Dellarco. May 9, 1996.
(5) NAS. National Academy of Sciences, Washington DC, ``Science and
Judgment in Risk Assessment'' pp. 154, 157, 265 (1994).
(6) Siegel-Scott, C. ``Slope factors for hazardous air
pollutants.'' Memorandum to Vicki Dellarco. September 7, 1994.
(7) Shoaf, C.R. ``Clean Air Act chemicals with adequate databases
for development of RfC's.'' Memorandum to Vicki Dellarco. September 20,
1994.
(8) U.S. Environmental Protection Agency. Health assessment
document for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related
compounds, Vol. III of III, pp. 9-48 to 9-50. Prepared by the Office of
Health and Environmental Assessment, Washington, DC. EPA/600/PB-92/001C
(1994).
(9) Francis, E.Z., and Kimmel, G.A. ``Proceedings of the workshop
on one versus two-generation reproductive effects studies.'' Journal of
the American College of Toxicology. 7:911-925 (1988).
(10) Lai, D.Y., Baetcke, K.P., Vu, V.T., Cotruvo, J.A., and Eustis,
S.L. ``Evaluation of reduced protocols for carcinogenicity testing of
chemicals: Report of a joint EPA/NIEHS workshop.'' Regulatory
Toxicology and Pharmacology. 19:183-201 (1994).
(11) Syracuse Research Corporation. ``Summary tables on the health
effects data for hazardous air pollutants (HARs)-Group 1.'' Syracuse,
New York. (1995a).
(12) Syracuse Research Corporation. ``Exposure profiles for HAPs-
Group 1.'' Syracuse, New York. (1995b).
(13) Valcovic, L.R. Memorandum: ``Genetic toxicity evaluation of
HAPs'' to Vicki Dellarco, July 14, 1994.
(14) Waters, M.D., Stack, H.F., and Jackson, M.A. 1990. ``Genetic
Activity Profiles of 110 Hazardous Air Pollutants Listed Under Title
III of the Clean Air Act, as amended.'' U. S. Environmental Protection
Agency. Internal Report. October 30, (1990).
(15) Gerrity, T.R., and Henry, C.J. ed. Principles of Route-to-
Route Extrapolation for Risk Assessment. pp 1-12. Elsevier Science
Publishing Co., Inc. New York, N.Y. (1990).
(16) U.S. Environmental Protection Agency. ``Hazardous Air
Pollutants: Profiles of Non-Cancer Toxicity from Inhalation
Exposures.'' Washington, DC. EPA/600/R-93/142. September 1993.
(17) Luster, M.I., Portier, C., Pait, D.G., White, K.L., Genings,
C., Munson, A.E., and Rosenthal, G.J. ``Risk assessment in
immunotoxicology. I. Sensitivity and predictability of immune tests.''
Fundamental and Applied Toxicology. 18:200-210 (1992).
(18) U.S. Environmental Protection Agency. ``EPA census of the
toxicological testing industry final report.'' (1990).
XI. Regulatory Assessment Requirements
A. Executive Order 12866
Pursuant to Executive Order 12866 (58 FR 51735, October 4, 1993),
it has been determined by OMB that this is a ``significant regulatory
action.'' OMB was concerned that the amount of inhalation testing
required by this rule may exceed the capacity of the testing industry,
at least in the short run. This action was submitted to OMB for review,
and any comments or changes made during that review have been
documented in the public record.
In addition, EPA has prepared an economic analysis of the impact of
this
[[Page 33196]]
action, which is contained in a document entitled ``Test Rule Support
for 21 Hazardous Air Pollutants.'' This document is available as a part
of the public record at the address listed in Unit X of this preamble
and is briefly summarized in Unit VI of this preamble.
B. Regulatory Flexibility Act
Under the Regulatory Flexibility Act (5 U.S.C. 601 et seq.), EPA
has determined that this test rule, if promulgated, would not have a
significant impact on small businesses. EPA has identified the entities
that currently manufacture or import the chemical substances required
to be tested under this proposed rule and examined the practices that
industry uses in carrying out chemical testing in response to EPA test
rules. EPA believes that: (1) small businesses would not be expected to
perform testing themselves, or to participate in the organization of
the testing effort, because health effects testing of chemical
substances is generally carried out by consortia of the large
manufacturers or importers of the chemical substances; (2) small
businesses would experience only very minor costs, if any, in securing
exemption from testing requirements because exemption request
requirements, described at 40 CFR 790.82, are minimal--particularly
when, as in this proposed rule, EPA is not requiring exemption
applicants to submit equivalence data (see Unit IV.F of this
preamble)--and EPA does not charge a fee for filing such requests; and
(3) small businesses are unlikely to be affected by reimbursement
requirements because under the reimbursement rules (at 40 CFR 791.40
through 791.52), manufacturers or importers with a significant share of
production or importation are the entities that must share testing
costs under the reimbursement rules, and small businesses generally do
not manufacture or import a significant portion of high-volume chemical
substances.
C. Paperwork Reduction Act
OMB has approved the information collection requirements contained
in this proposed rule under the provisions of the Paperwork Reduction
Act, 44 U.S.C. 3501 et seq., and has assigned OMB control number 2070-
0033.
The public reporting burden for this collection of information is
estimated to average approximately the following number of hours per
response for the chemicals listed below, including time for reviewing
instructions, searching existing data sources, gathering and
maintaining the data needed, and completing and reviewing the
collection of information.
------------------------------------------------------------------------
Total
Chemical substance burden
------------------------------------------------------------------------
1,1'-Biphenyl 20,620
Carbonyl sulfide 47,644
Chlorine 693
Chlorobenzene 7,707
Chloroprene 13,039
Cresols (all 3 isomers) 6,048
Diethanolamine 21,826
Ethylbenzene 14,400
Ethylene dichloride 16,707
Ethylene glycol 7,816
Hydrochloric acid 693
Hydrogen fluoride 18,068
Maleic anhydride 35,849
Methyl isobutyl ketone 10,471
Methyl methacrylate 14,400
Naphthalene 10,580
Phenol 693
Phthalic anhydride 51,032
1,2,4-Trichlorobenzene 8,091
1,1,2-Trichloroethane 33,133
Vinylidene chloride 5,439
------------------------------------------------------------------------
The total public reporting burden is estimated to be 357,045 hours
for all responses. The overall average per chemical is 15,524 hours.
Burden means the total time, effort, or financial resources
expended by persons to generate, maintain, retain, or disclose or
provide information to or for a Federal agency. This includes the time
needed to review instructions; develop, acquire, install, and utilize
technology and systems for the purposes of collecting, validating, and
verifying information, processing and maintaining information, and
disclosing and providing information; adjust the existing ways to
comply with any previously applicable instructions and requirements;
train personnel to be able to respond to a collection of information;
search data sources; complete and review the collection of information;
and transmit or otherwise disclose the information.
An Agency may not conduct or sponsor, and a person is not required
to respond to a collection of information unless it displays a
currently valid OMB control number. The OMB control numbers for EPA's
regulations are listed in 40 CFR part 9 and 48 CFR chapter 15.
Comments are requested on the Agency's need for this information,
the accuracy of the provided burden estimates, and any suggested
methods for minimizing respondent burden, including through the use of
automated collection techniques. Send comments on the ICR to Sandy
Farmer, OPPE Regulatory Information Division; U.S. Environmental
Protection Agency (2136), 401 M St., SW., Washington, DC 20460, (202)
260-2740, or electronically by sending an e-mail message to:
[email protected]. Send a copy of these comments to the
Office of Information and Regulatory Affairs, Office of Management and
Budget, 725 17th St., NW., Washington, DC 20503, marked ``Attention:
Desk Officer for EPA.'' Please remember to include the ICR number in
any correspondence. The final rule will respond to any comments on the
information collection requirements contained in this proposal.
D. Unfunded Mandates Reform Act and Executive Order 12875
Pursuant to Title II of the Unfunded Mandates Reform Act of 1995
(UMRA) (Pub. L. 104-4), EPA has determined that this action does not
contain a Federal mandate that may result in expenditures of $100
million or more for State, local, and tribal governments, in the
aggregate, or the private sector in any one year. (The analysis of the
costs associated with this action is referenced in Unit XI.A. of this
preamble.) Therefore, this action is not subject to the requirements of
sections 202 and 205 of the UMRA.
E. Executive Order 12898
Pursuant to Executive Order 12898 (59 FR 7629, February 16, 1994),
entitled ``Federal Actions to Address Environmental Justice in Minority
Populations and Low-Income Populations,'' the Agency has considered
environmental justice-related issues with regard to the potential
impacts of this action on the environmental and health conditions in
low-income and minority communities. Because many sources of HAP
emissions are located near populations of lower socioeconomic status
and with a higher proportion of minorities, the improved health
database that will be generated by this action will help to protect
these individuals and communities.
List of Subjects in 40 CFR Part 799
Environmental protection, Chemicals, Hazardous substances, and
Reporting and recordkeeping requirements.
Dated: June 20, 1996.
Lynn R. Goldman,
Assistant Administrator for Prevention, Pesticides and Toxic
Substances.
Therefore, it is proposed that 40 CFR, chapter I, subchapter R, be
amended as follows:
[[Page 33197]]
PART 799--[AMENDED]
3. The authority citation for part 799 would continue to read as
follows:
Authority: 15 U.S.C. 2603, 2611, 2625.
4. By adding Sec. 799.5053 to Subpart D of part 799 to read as
follows:
Sec. 799.5053 Chemical testing requirements for hazardous air
pollutants.
(a) General testing provisions--(1) Identification of test
substances. Table 1 in paragraph (a)(5) of this section identifies
those chemical substances that shall be tested in accordance with this
section. The purity of each test substance shall be 97 percent or
greater unless otherwise specified.
(2) Persons required to submit study plans, conduct tests, and
submit data. All persons who manufacture (including those who import
the substance or manufacture it as a byproduct) or intend to
manufacture one or more of the substances listed in table 1 after the
effective date listed in table 1 until the end of the reimbursement
period shall submit letters of intent to conduct testing, submit study
plans, conduct tests and submit data, or submit exemption applications,
as specified in this section, subpart A of this part and parts 790 and
792 of this chapter. Persons who manufacture or process these
substances only as an impurity are not subject to these requirements.
As explained in part 790 of this chapter, processors, small-quantity
manufacturers, and manufacturers of small quantities of these
substances solely for research and development purposes would become
subject to these requirements only after notification in the Federal
Register that no manufacturer had notified EPA of its intent to conduct
testing.
(3) Applicability of test guidelines. The guidelines and other test
methods cited in table 1 in paragraph (a)(5) of this section are
referenced here as they exist on the effective date listed in table 1
for that specific test. Testing shall be conducted in accordance with
the designated Series 870--Health Effects Test Guidelines and other
test methods. This incorporation by reference was approved by the
Director of the Federal Register in accordance with 5 U.S.C. 552(a) and
1 CFR part 51. Copies may be obtained from the Public Docket and
Freedom of Information Section, Field Operations Division (7506C),
Office of Pesticide Programs, Environmental Protection Agency, 401 M
St., SW., Washington, DC 20360. Copies may be inspected at the above
address or at the Office of the Federal Register, 800 North Capitol
Street, NW., suite 700, Washington, DC.
(4) Interim reporting requirements. All testing requirements in
this section are subject to the submission of interim progress reports
every 6 months beginning 6 months after the effective date for any
specific test listed in table 1 in paragraph (a)(5) of this section.
The date for the submission of final reports is specified as the number
of months after the effective date for the specific test listed in
table 1.
(5) Testing and reporting requirements. The substances identified
by CAS Registry number and chemical name in the following table 1 shall
be tested in accordance with the designated OPPTS Harmonized Guideline
testing requirements and any additional requirements and limitations
specified in the ``Specific requirements under this section'' column of
table 1. The numbers and letters in this column refer to the specific
requirements set forth in paragraph (b) of this section. Final reports
shall be submitted by the deadlines indicated as the number of months
after the effective date shown in table 1.
Table 1
----------------------------------------------------------------------------------------------------------------
Specific
Chemical substance/ OPPTS harmonized requirements Final Effective
CAS No. required testing guidelines under this report date
section
----------------------------------------------------------------------------------------------------------------
75-35-4-------------------------Vinylidene---------- ----------------- ----------------- ---------- --------
chloride:
Acute 870.1350 (b)(2) 21 mo
Neurotoxicity 870.6200 (b)(1)(ii)(A), 21 mo
(b)(1)(iii)(A),
(b)(1)(iii)(B)
----------------------------------------------------------------------------------------------------------------
79-00-5 1,1,2-
Trichloroethane:
Acute 870.1350 (b)(2) 21 mo
Subchronic 870.3465 (b)(3) 18 mo
Developmental 870.3600 12 mo
Reproductive 870.3800 (b)(1)(ii)(A), 29 mo
(b)(5)
Neurotoxicity 870.6200 (b)(1)(ii)(A), 21 mo
(b)(1)(iii)(A),
(b)(1)(iii)(B)
Carcinogenicity 870.4200 (b)(1)(i)(D), 60 mo
(b)(1)(ii)(A)
In vivo 870.5385 or (b)(1)(ii)(A) 14 mo
cytogenetics 870.5395
Immunotoxicity 870.7800 (b)(1)(ii)(A) 18 mo
----------------------------------------------------------------------------------------------------------------
80-62-6 Methyl
methacrylate:
Acute 870.1350 (b)(2) 21 mo
Developmental 870.3600 (b)(1)(i)(A) 12 mo
Reproductive 870.3800 (b)(1)(ii)(A), 29 mo
(b)(5)
Neurotoxicity 870.6200 (b)(1)(ii)(A), 21 mo
(b)(1)(iii)(A),
(b)(1)(iii)(B)
Immunotoxicity 870.7800 (b)(1)(ii)(A) 21 mo
----------------------------------------------------------------------------------------------------------------
85-44-9 Phthalic
anhydride:
Acute 870.1350 (b)(2) 21 mo
Subchronic 870.3465 (b)(1)(ii)(B), 18 mo
(b)(3)
Developmental 870.3600 (b)(1)(ii)(B) 12 mo
Reproductive 870.3800 (b)(1)(ii)(B), 29 mo
(b)(5)
Neurotoxicity 870.6200 (b)(1)(ii)(B), 21 mo
(b)(1)(iii)(A),
(b)(1)(iii)(B)
Carcinogenicity 870.4200 (b)(1)(ii)(B) 60 mo
[[Page 33198]]
Immunotoxicity 870.7800 (b)(1)(ii)(B) 18 mo
----------------------------------------------------------------------------------------------------------------
91-20-3 Naphthalene:
Acute 870.1350 (b)(2) 21 mo
Reproductive 870.3800 (b)(1)(ii)(A), 29 mo
(b)(5)
Immunotoxicity 870.7800 (b)(1)(ii)(A) 21 mo
----------------------------------------------------------------------------------------------------------------
92-52-4 1,1'-Biphenyl:
Acute 870.1350 (b)(2) 21 mo
Subchronic 870.3465 (b)(1)(ii)(B), 18 mo
(b)(3)
Developmental 870.3600 (b)(1)(i)(A), 12 mo
(b)(1)(ii)(B)
Reproductive 870.3800 (b)(1)(ii)(B), 29 mo
(b)(5)
Neurotoxicity 870.6200 (b)(1)(ii)(B), 21 mo
(b)(1)(iii)(A),
(b)(1)(iii)(B)
Immunotoxicity 870.7800 (b)(1)(ii)(B) 18 mo
----------------------------------------------------------------------------------------------------------------
95-48-7, Cresols:
106-44-5, and
108-39-4
Acute 870.1350 (b)(2) 21 mo
Subchronic 870.3465 (b)(3) 18 mo
Neurotoxicity 870.6200 (b)(1)(ii)(A), 21 mo
(b)(1)(iii)(A)
Immunotoxicity 870.7800 (b)(1)(ii)(A) 18 mo
----------------------------------------------------------------------------------------------------------------
100-41-4 Ethylbenzene:
Acute 870.1350 (b)(2) 21 mo
Developmental 870.3600 (b)(1)(i)(A) 12 mo
Reproductive 870.3800 (b)(1)(ii)(A), 29 mo
(b)(5)
Neurotoxicity 870.6200 (b)(1)(ii)(A), 21 mo
(b)(1)(iii)(A),
(b)(1)(iii)(B)
Immunotoxicity 870.7800 (b)(1)(ii)(A) 21 mo
----------------------------------------------------------------------------------------------------------------
107-06-2 Ethylene
dichloride:
Acute 870.1350 (b)(2) 21 mo
Subchronic 870.3465 (b)(3) 18 mo
Developmental 870.3600 (b)(1)(i)(C) 12 mo
Reproductive 870.3800 (b)(1)(ii)(A), 29 mo
(b)(5)
Neurotoxicity 870.6200 (b)(1)(ii)(A), 21 mo
(b)(1)(iii)(A),
(b)(1)(iii)(B)
----------------------------------------------------------------------------------------------------------------
107-21-1 Ethylene glycol:
Acute 870.1350 (b)(2) 21 mo
Subchronic 870.3465 (b)(3) 18 mo
Neurotoxicity 870.6200 (b)(1)(ii)(A), 21 mo
(b)(1)(iii)(A),
(b)(1)(iii)(B)
Immunotoxicity 870.7800 (b)(1)(ii)(A) 18 mo
----------------------------------------------------------------------------------------------------------------
108-10-1 Methyl isobutyl
ketone:
Acute 870.1350 (b)(2) 21 mo
Reproductive 870.3800 (b)(1)(ii)(A), 29 mo
(b)(5)
Immunotoxicity 870.7800 (b)(1)(ii)(A) 29 mo
----------------------------------------------------------------------------------------------------------------
108-31-6 Maleic anhydride:
Acute 870.1350 (b)(2) 21 mo
Developmental 870.3600 (b)(1)(i)(A) 12 mo
Neurotoxicity 870.6200 (b)(1)(ii)(A), 21 mo
(b)(1)(iii)(A),
(b)(1)(iii)(B)
Carcinogenicity 870.4200 (b)(1)(ii)(A) 60 mo
Immunotoxicity 870.7800 (b)(1)(ii)(A) 21 mo
----------------------------------------------------------------------------------------------------------------
108-90-7 Chlorobenzene:
Acute 870.1350 21 mo
Subchronic 870.3465 (b)(3) 18 mo
Neurotoxicity 870.6200 (b)(1)(ii)(A), 21 mo
(b)(1)(iii)(A),
(b)(1)(iii)(B)
Immunotoxicity 870.7800 (b)(1)(ii)(A) 18 mo
----------------------------------------------------------------------------------------------------------------
[[Page 33199]]
108-95-2 Phenol:
Acute 870.1350 (b)(2) 21 mo
Immunotoxicity 870.7800 (b)(1)(ii)(A) 12 mo
----------------------------------------------------------------------------------------------------------------
111-42-2 Diethanolamine:
Acute 870.1350 (b)(2) 21 mo
Subchronic 870.3465 (b)(1)(ii)(B), 18 mo
(b)(3)
Developmental 870.3600 (b)(1)(ii)(B) 12 mo
Reproductive 870.3800 (b)(1)(ii)(B), 29 mo
(b)(5)
Neurotoxicity 870.6200 (b)(1)(ii)(B), 21 mo
(b)(1)(iii)(A),
(b)(1)(iii)(B)
Immunotoxicity 870.7800 (b)(1)(ii)(B) 18 mo
----------------------------------------------------------------------------------------------------------------
120-82-1 1,2,4-
Trichlorobenzene:
Acute 870.1350 (b)(2) 21 mo
Developmental 870.3600 12 mo
Neurotoxicity 870.6200 (b)(1)(ii)(A), 21 mo
(b)(1)(iii)(A),
(b)(1)(iii)(B)
Immunotoxicity 870.7800 (b)(1)(ii)(A) 21 mo
----------------------------------------------------------------------------------------------------------------
126-99-8 Chloroprene:
Acute 870.1350 (b)(2) 21 mo
Reproductive 870.3800 (b)(1)(ii)(A), 29 mo
(b)(5)
Neurotoxicity 870.6200 (b)(1)(ii)(A), 21 mo
(b)(1)(iii)(A),
(b)(1)(iii)(B)
Immunotoxicity 870.7800 (b)(1)(ii)(A) 21 mo
----------------------------------------------------------------------------------------------------------------
463-58-1 Carbonyl sulfide:
Acute 870.1350 (b)(2) 21 mo
Subchronic 870.3465 (b)(3) 18 mo
Developmental 870.3600 12 mo
Reproductive 870.3800 (b)(1)(ii)(A), 29 mo
(b)(5)
Neurotoxicity 870.6200 (b)(1)(ii)(A), 21 mo
(b)(1)(iii)(A),
(b)(1)(iii)(B)
Carcinogenicity 870.4200 (b)(1)(ii)(A) 60 mo
E.coli reverse 870.5100 6 mo
mutation
Gene mutation 870.5300 6 mo
In vivo 870.5385 or (b)(1)(ii)(A) 14 mo
cytogenetics 870.5395
Immunotoxicity 870.7800 (b)(1)(ii)(A) 18 mo
----------------------------------------------------------------------------------------------------------------
7647-01-0 Hydrochloric acid:
Acute 870.1350 (b)(2) 21 mo
----------------------------------------------------------------------------------------------------------------
7664-39-3 Hydrogen fluoride:
Acute 870.1350 (b)(2) 21 mo
Subchronic 870.3465 (b)(3) 18 mo
Developmental 870.3600 12 mo
Reproductive 870.3800 (b)(1)(ii)(A), 29 mo
(b)(5)
Neurotoxicity 870.6200 (b)(1)(ii)(A), 21 mo
(b)(1)(iii)(A),
(b)(1)(iii)(B)
Immunotoxicity 870.7800 (b)(1)(ii)(A) 18 mo
----------------------------------------------------------------------------------------------------------------
7782-50-5 Chlorine:
Acute 870.1350 (b)(2) 21 mo
----------------------------------------------------------------------------------------------------------------
(b) Test-specific requirements--(1) General. In addition to the
testing requirements specified in table 1 in paragraph (a)(5) of this
section and applicable test guideline-specific modifications listed
therein, the following additional requirements and limitations also
apply when specified for a particular chemical substance in table 1
under ``Specific requirements under this section''.
(i) Test species. The test animal shall be:
(A) A mammalian species other than the rat.
(B) A mammalian species other than the mouse.
(C) A mammalian species other than the rabbit.
(D) The male rat and the female mouse.
(ii) Route of exposure. Animals shall be exposed:
(A) Via vapor-phase inhalation.
(B) Via inhalation of aerosol.
(C) Orally in the diet.
(iii) Duration and frequency of exposure. (A) Animals shall be
exposed for a 4-hour period in an acute study.
[[Page 33200]]
(B) Animals shall be exposed for 6 hours per day, 5 days per week
for a 90-day period in a subchronic study.
(2) Acute test modifications. In addition to the acute testing
requirements specified in table 1 in paragraph (a)(5) of this section,
the following additional requirements and limitations also apply when
specified for a particular chemical substance in table 1 under
``Specific requirements under this section''.
(i) The appraisal of pulmonary irritation shall be evaluated during
exposure to the substance by the use of the mouse respiratory sensory
irritation assay method as outlined in ASTM E 981-84 (see paragraph
(b)(2)(iii)(C) of this section). This method assesses the breathing
patterns of test animals. This incorporation by reference was approved
by the Director of the Federal Register in accordance with 5 U.S.C.
552(a) and 1 CFR part 51. This material is incorporated as it exists on
the date of approval and notice of any change in this material will be
published in the Federal Register. Copies of the incorporated materials
may be obtained from the TSCA Nonconfidential Information Center, Rm.
NE-B607, 401 M St., SW., Washington, DC, 20460 or from the American
Society for Testing and Materials (ASTM), 1916 Race Street,
Philadelphia, PA 10103. Copies may be inspected at the above address or
at the Office of the Federal Register, 800 North Capitol Street, NW.,
suite 700, Washington, DC. For information on this test guideline, the
references in paragraph (b)(2)(iii) should be consulted.
(ii) Results of respiratory sensory irritation assay. (A) Data
shall be included in the final report and tabulated to show:
(1) The magnitude of change in respiratory rate with exposure
concentration and with time for each animal.
(2) A response concentration, which indicates the concentration at
which the respiration rate is decreased by 50% (RD50), will be
calculated, along with the 95% confidence limits.
(B) Time-effect curves shall be included in the final report to
evaluate the onset and shape of the response.
(iii) References.
(A) Alarie, Y., and Luo, J.E. ``Sensory Irritation by Airborne
Chemicals: A basis to establish acceptable levels of exposure.''
Toxicology of the Nasal Passages. Hemisphere Publishing Corporation:
New York pp. 91-100 (1986).
(B) Alarie, Y., and Stokinger, H.E. ``Sensory Irritation by
Airborne Chemicals.'' CRC Critical Reviews in Toxicology. pp. 299-363
(1973).
(C) ASTM. ``Standard Test Method for Estimating Sensory Irritancy
of Airborne Chemicals.'' In: 1984 Annual Book of ASTM Standards. Water
and Environmental Technology. Section 11. Volume 11.04 Designation E
981-84 pp. 572-584 (1984).
(3) Subchronic test modifications. In addition to the subchronic
testing requirements specified in table 1 in paragraph (a)(5) of this
section, the following additional requirements and limitations also
apply when specified for a particular chemical substance in table 1
under ``Specific requirements under this section''.
(i) Respiratory tract pathology. (A) Care shall be taken that the
method used to kill the animal does not result in damage to the tissues
of the upper or lower respiratory tract. The heart-lung, including the
trachea, shall be removed in bloc.
(B) Representative sections of the lungs shall be examined
histologically. This shall include trachea, major conducting airways,
alveolar region, terminal and respiratory bronchioles, alveolar ducts
and sacs, and interstitial tissues.
(C) The nasopharyngeal tissue shall be examined for histopathologic
lesions. This shall include sections through the nasal cavity, and
examination of the squamous, transitional, respiratory, and olfactory
epithelia.
(D) The larynx mucosa shall be examined for histopathologic
changes. Sections of the larynx to be examined include the epithelium
covering the base of the epiglottis, the ventral pouch, and the medial
surfaces of the vocal processes of the arytenoid cartilages.
(ii) Bronchoalveolar lavage. (A) The lungs shall be lavaged in situ
or after sacrifice. If the study will not be compromised, one lobe of
the lungs may be used for lung lavage while the other is fixed for
histologic evaluation. The lungs shall be lavaged using physiological
saline after cannulation of the trachea. The lavages shall consist of
two washes each of which consists of approximately 80 percent (e.g., 5
ml in rats and 1 ml in mice) of total lung volume. Additional washes
merely tend to reduce the concentrations of the material collected. The
lung lavage fluid shall be stored on ice at approximately 5 deg.C
until assayed.
(B) The following parameters shall be determined in the lavage
fluid as indicators of cellular damage in the lungs: total protein,
cell count and percent leukocytes. In addition, a phagocytosis assay
using the procedure of Burleson (Burleson et al., 1987; Gilmour and
Selgrade, 1993) shall be performed to determine macrophage activity.
The following references may be consulted:
(1) Burleson, G.R. et al. ``Poly (I): poly (C)-enhanced alveolar
peritoneal macrophage phagocytosis: Quantification by a new method
utilizing fluorescent beads.'' Proceedings of the Society for
Experimental Biology and Medicine. 184:468-476 (1987).
(2) Gilmour, G.I., and Selgrade, M.K. ``A Comparison of the
Pulmonary Defenses against Streptococcal Infection in Rats and Mice
Following O3 Exposure: Differences in Disease Susceptibility and
Neutrophil Recruitment.'' Toxicology and Applied Pharmacology. 123:211-
218 (1993).
(4) [Reserved]
(5) Reproductive toxicity and fertility study test modifications.
In addition to the reproductive toxicity and fertility testing
requirements specified in table 1 in paragraph (a)(5) of this section,
the following additional requirements and limitations also apply when
specified for a particular chemical substance in table 1 under
``Specific requirements under this section''.
(i) Administration of the test substance. The test substance shall
be administered by inhalation. The requirements of OPPTS
870.3800(e)(2)(iii) do not apply.
(ii) [Reserved]
[FR Doc. 96-16203 Filed 6-25-96; 8:45 am]
BILLING CODE 6560-50-F