[Federal Register Volume 64, Number 125 (Wednesday, June 30, 1999)]
[Rules and Regulations]
[Pages 35072-35080]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-16526]
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ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 799
[OPPTS-42193A; FRL-6067-4]
RIN 2070-AB94
Toxic Substances Control Act Test Guidelines
AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.
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[[Page 35073]]
SUMMARY: With this rule, EPA is amending 7 of the 11 existing health
effects guidelines. These guidelines are a part of the series of test
guidelines which consist of standardized test procedures for test rules
promulgated under section 4 of the Toxic Substances Control Act (TSCA),
that are published in part 799 of Title 40 of the Code of Federal
Regulations (CFR). These TSCA test guidelines are based on the
harmonized test guidelines in the unified library for test guidelines
issued by the Office of Prevention, Pesticides and Toxic Substances
(OPPTS) for use in testing chemical substances to develop data for
submission to EPA under TSCA, the Federal Food, Drug and Cosmetic Act
(FFDCA), and the Federal Insecticide, Fungicide, and Rodenticide Act
(FIFRA). The process for developing and amending the harmonized test
guidelines includes broad public participation and extensive
involvement of the scientific community. The TSCA test guidelines do
not in themselves impose any obligations on anyone until they are
incorporated in a test rule promulgated under section 4 of TSCA.
DATES: This rule is effective on June 30, 1999.
FOR FURTHER INFORMATION CONTACT: For general information contact:
Christine Augustyniak, Associate Director, Environmental Assistance
Division (7408), Office of Pollution Prevention and Toxics,
Environmental Protection Agency, 401 M St., SW., Washington, DC 20460;
telephone numbers: (202) 554-1404 and TDD: (202) 554-0551; e-mail
address: TSCA-Hotline@epa.gov.
For technical information contact: Roger Nelson, Chemical Control
Division, Office of Prevention, Pesticides and Toxic Substances,
Environmental Protection Agency, 401 M St., SW., Washington, DC 20460;
telephone number: (202) 260-8163; e-mail address: nelson.roger@epa.gov.
SUPPLEMENTARY INFORMATION:
I. General Information
A. Does This Action Apply to Me?
You may be particularly interested in this action if you
manufacture (defined by statute to include import) or process a
chemical substance that could become the subject of a proposed test
rule under TSCA section 4. This action does not, however, impose any
obligations on anyone until the test guidelines are incorporated in a
future test rule that would be proposed under TSCA section 4.
Therefore, entities potentially affected by this action may include,
but are not limited to:
----------------------------------------------------------------------------------------------------------------
Examples of potentially
Type of entity SIC NAICS affected entities
----------------------------------------------------------------------------------------------------------------
Chemical manufacturers or importers 28, 2911 325, 32411 Persons who manufacture
(defined by statute to
include import) one or more
of the subject chemical
substances.
Chemical processors 28, 2911 325, 32411 Persons who process one or
more of the subject chemical
substances.
----------------------------------------------------------------------------------------------------------------
This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. The Standard Industrial Classification (SIC) codes and the
North American Industrial Classification System (NAICS) codes have been
provided to assist you and others in determining whether or not this
action might apply to certain entities. If you have any questions
regarding the applicability of this action to a particular entity,
consult the technical person listed in the ``FOR FURTHER INFORMATION
CONTACT'' section.
B. How Can I Get Additional Information, Including Copies of This
Document and Other Related Documents?
1. Electronically. You may obtain electronic copies of this
document from and certain other available documents from the EPA
Internet Home Page at http://www.epa.gov/. On the Home Page, select
``Laws and Regulations'' and then look up the entry for this document
under ``Federal Register--Environmental Documents.'' You can also go
directly to the Federal Register listings at http://www.epa.gov/
fedrgstr/EPA-TOX/1999/.
2. In person. The Agency has established an official record for
this action under docket control number OPPTS-42193. The official
record consists of the documents specifically referenced in this
action, any public comments received during an applicable comment
period, and other information related to this action, including any
information claimed as confidential business information (CBI). This
official record includes the documents that are physically located in
the docket, as well as the documents that are referenced in those
documents. The public version of the official record does not include
any information claimed as CBI. The public version of the official
record, which includes printed, paper versions of any electronic
comments submitted during an applicable comment period, is available
for inspection in the TSCA Nonconfidential Information Center,
Environmental Protection Agency, North East Rm. NE-B607, Waterside
Mall, 401 M St., SW., Washington, DC. The Center is open from 12 noon
to 4 p.m., Monday through Friday, excluding legal holidays. The
telephone number for the Center is (202) 260-7099.
3. By phone. If you need additional information about this action,
you may also contact the person identify in the ``FOR FURTHER
INFORMATION CONTACT'' section.
II. Background
A. What are Test Guidelines?
Test guidelines are a standardized set of test procedures or
protocols organized by health effect or other testing endpoint. These
guidelines present generally formulated procedures for laboratory
testing of an effect or characteristic deemed important for the
evaluation of health and environmental hazards of a chemical. These
guidelines are designed to, when followed, produce data which are
accurate, reliable, and reproducible. Such data are necessary for the
regulatory programs under TSCA.
B. What are TSCA Test Guidelines?
TSCA test guidelines are guidelines which were established to meet
the regulatory needs of TSCA, particularly the needs of the TSCA
section 4 testing program. The TSCA section 4 testing program is a
regulatory program which is based on the promulgation of rules
requiring certain persons identified in the rule, usually manufacturers
and processors of the chemical to conduct testing of the chemical
specified in the rule. Section 4(b)(1)(B) of TSCA specifically requires
that test rules promulgated under the section 4 include ``standards for
the development of test data for such substance or mixture * * *.''
These ``standards for the development of test data'' specify how the
study is to be conducted, what data will be collected, and how the data
will be analyzed. Each test rule must specify such ``test standards''
which contain specifications for testing. Section 4(b)(1)
[[Page 35074]]
of TSCA describes the elements which must be described in these test
standards.
The Agency has found that most of these elements can be
standardized into the common set of protocols which EPA defines as
``test guidelines.'' These guidelines are organized by testing
endpoint. The test rule itself can add or subtract to the requirements
of the test guidelines in order to meet the unique testing
circumstances for the particular chemical substance.
C. How are TSCA Test Guidelines Used?
The Agency uses this system of standardized guidelines, organized
by testing endpoint and codified in a subpart in 40 CFR part 799 for
use in cross-referencing in a TSCA section 4 action. When a section 4
test rule is promulgated, the test rule cross-references the
appropriate TSCA test guideline for the bulk of the testing
requirements. In this context, the public is given notice of, and an
opportunity to comment on, these guidelines as they are applied in
chemical-specific test rules. This approach eliminates the need to
repeat the same test specifications for each substance-specific test
rule since most of the specifications for testing do not change across
substances. The test specifications in a guideline can be varied, when
necessary, to the specific requirements of a test rule by amendatory
language in the test rule itself.
D. Where Did the TSCA Test Guidelines Come From?
The TSCA test guidelines series were first promulgated in 1985 (50
FR 39252, September 27, 1985) and were established in 40 CFR parts 795,
796, 797, and 798. The Agency has over time amended and improved these
guidelines (52 FR 19072, May 20, 1987) and in some cases revoked those
guidelines which had not been cross-referenced in any test rules (60 FR
31917, June 19, 1995) (FRL-4955-2).
In 1991, EPA began an effort to blend the testing guidance and
requirements that existed in the Office of Pollution Prevention and
Toxics (OPPT) (and appeared in 40 CFR parts 795 through 798), the
Office of Pesticides Programs (OPP) guidelines which appeared in
publications of the National Technical Information Service (NTIS), and
the guidelines published by the Organization for Economic Cooperation
and Development (OECD). The product of this effort would be one set of
guidelines which would be thus blended or ``harmonized.'' These
harmonized guidelines would then be made available to the EPA, other
government agencies, and the public through EPA's Internet web site and
would be accessible by anyone with a personal computer and the ability
to connect to the Internet. The EPA Internet web site would be the site
and publication source for the ``OPPTS Harmonized Guidelines'' at
http://www.epa.gov/epahome/research.htm/.
E. How Were These OPPTS Harmonized Test Guidelines Developed?
The OPPTS harmonized test guidelines were first drafted by EPA
scientists for specific testing endpoints. These drafts were reviewed
by other EPA experts and, in some instances, presented at domestic and
international colloquia in order to solicit the views of recognized
experts and the regulated community. These draft harmonized guidelines
were made available on EPA's Internet web site as public drafts and
public comment was solicited and received. After review of the public
drafts and comments, EPA published the final OPPTS harmonized
guidelines on EPA's Internet web site and announced their availability
to the public in a Federal Register notice (63 FR 41845, August 5,
1998)(FRL-5740-1).
F. What is Done to Make TSCA Test Guidelines From the OPPTS Harmonized
Test Guidelines?
Harmonization has resulted in significantly improved guidelines.
However, creating a single set of guidelines which can be used by both
OPP, in its administration of the FIFRA and the Federal Food, Drug and
Cosmetic Act (FFDCA), and the Office of Pollution Prevention and
Toxics, which administers TSCA presented certain challenges. Under
FIFRA, test guidelines are used in an interactive process between the
Agency and registrants seeking registration of pesticides or food
residue tolerances. Flexibility to tailor required testing to
individual circumstances is critical, and the Agency has considerable
discretion to determine whether submitted test results are adequate to
support the requested action. Under this scheme, registrants have an
intrinsic motivation to conduct well-grounded testing. Thus, pesticide
testing protocols tend to have few absolute requirements specifying the
details of the conduct of the testing.
Under section 4 of TSCA, on the other hand, the Agency is required
to impose prescriptive test requirements using notice and comment
rulemaking. Rules promulgated under section 4 of TSCA must specify
classes of affected parties and specify the standards to be followed by
these parties in conducting the required testing. In contrast to FIFRA,
the Agency does not interact with companies on an individual basis in
designing the testing requirements.
TSCA section 4 rulemakings typically take years to complete.
Without initiating another rulemaking process, the Agency has the
ability to require further testing only if the tests were not conducted
in accordance with the procedures specified in the test rule. In
addition, the Agency has an alternative process of negotiating TSCA
testing requirements via enforceable consent agreements (ECAs), but
these agreements require the consent of all the parties involved. Under
TSCA section 4 enforceable test standards, much in the conduct of these
test protocols is left to the judgment of those professionals
conducting the testing. EPA believes that certain provisions must be
mandatory whenever the guidelines are cross-referenced in specific test
rules.
Therefore, the Agency has used the OPPTS harmonized test
guidelines developed using the public notice and comment process to
create the TSCA-specific test guidelines which are the subject of this
rule. TSCA section 4 test rules now cross-reference only the 40 CFR
part 799 guidelines rather than the older, non-harmonized guidelines
established in 40 CFR parts 795 through 798 mostly in 1985. The only
significant difference between the TSCA test guidelines and the OPPTS
harmonized test guidelines is that certain discretionary procedures in
the OPPTS harmonized test guidelines are made mandatory (i.e., the
guideline states that they ``must'' be carried out) in order to ensure
the enforcibility of the test standard.
III. What Changes Is EPA Making to the TSCA Guidelines in 40 CFR
Part 799?
EPA is making changes to seven of the existing 40 CFR part 799
guidelines in order that they more accurately reflect the equivalent
OPPTS harmonized guideline as finalized in August 1998. The TSCA
guidelines which were promulgated in August 1997 were based on early
versions of the final OPPTS harmonized guidelines. Seven of the 11 TSCA
guidelines promulgated in 1997 have differences in text with the OPPTS
guidelines finalized in August 1998. This Federal Register document
corrects those differences.
The changes that EPA is making to the existing 40 CFR part 799
guidelines are summarized in the following Table 1 and discussed
guideline by guideline in detail below:
[[Page 35075]]
Table 1
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Number of changes made to guideline in this
Existing TSCA 40 CFR part 799 guideline and cite rule
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TSCA acute inhalation toxicity with histopathology (799.9135).... 0
TSCA subchronic inhalation toxicity (799.9346)................... 8
TSCA prenatal developmental toxicity (799.9370).................. 0
TSCA reproduction and fertility effects (799.9380)............... 2
TSCA carcinogenicity (799.9420).................................. 14
TSCA bacterial reverse mutation test (799.9510).................. 3
TSCA in vitro mammalian cell gene mutation test (799.9530)....... 0
TSCA mammalian bone marrow chromosomal aberration test (799.9538) 1
TSCA mammalian erythrocyte micronucleus test (799.9539).......... 2
TSCA neurotoxicity screening battery (799.9620).................. 1
TSCA immunotoxicity (799.9780)................................... 0
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The description of the changes with the detailed discussion of the
changes being made to the existing 40 CFR part 799 TSCA guidelines are
contained in the following lettered sections.
A. Section 799.9135 TSCA Acute Inhalation Toxicity with Histopathology
EPA is making no changes to this section.
B. Section 799.9346 TSCA Subchronic Inhalation Toxicity
1. EPA is revising the title of the TSCA guideline from ``TSCA
Subchronic Inhalation Toxicity'' in Sec. 799.9346 with ``TSCA 90-Day
Inhalation Toxicity.'' This change tracks the change made in the title
of the final OPPTS harmonized guideline.
2. EPA is revising paragraph (d) to track changes in the final
OPPTS harmonized guideline. This revision better explains when a full
study (using three test concentrations) might not be necessary.
3. EPA is revising the provision of paragraph (e)(1)(ii)(B) to
track the OPPTS harmonized guideline emphasis that only testing on
rodents (as opposed to all mammalian species) would be permitted.
Provisions referencing non-rodents in the OPPTS guideline have been
removed.
4. EPA is revising paragraph (e)(1)(iv)(A) be deleting provisions
which imply the permissibility of using non-rodents as test animals.
This language tracks the language in the final OPPTS harmonized
guideline.
5. EPA is revising paragraphs (e)(1)(v)(E) and (e)(1)(v)(F) to
track the language in the final OPPTS harmonized guideline. This
language reorganizes these paragraphs and emphasizes the permissibility
of using an unlimited supply of drinking water in the diets of the test
animals.
6. EPA is revising the language in paragraph (e)(12) with new
language which modifies the hematology and clinical chemistry
parameters to track the modifications made in the final OPPTS
harmonized guideline.
7. EPA is revising paragraph (e)(15)(i)(D) to delete the
requirement for full histopathology of livers and kidneys of all
animals. This change tracks the changes in the final OPPTS harmonized
guideline.
8. EPA is adding additional requirements for test system
information collection. New paragraphs (f)(3)(ii)(D)and (f)(3)(ii)(E)
are added to include data on identification of the animal diet and the
acclimation period. This tracks new language in the final OPPTS
harmonized guideline.
C. Section 799.9370 TSCA Prenatal Developmental Toxicity
EPA made no changes to this section.
D. Section 799.9380 TSCA Reproduction and Fertility Effects
EPA is amending the existing TSCA Reproduction and Fertility
Effects guideline by making several changes and clarifications to bring
the text into agreement with the final OPPTS harmonized guideline
870.3800, Reproduction and Fertility Effects guideline (August 1998).
Specific changes to the TSCA guideline are:
1. Paragraphs (e)(4)(i)(D) and (f)(3)(vi) were revised to
incorporate the decisions made by the Agency in finalizing the OPPTS
harmonized guideline to revise the definition of ``abnormal'' estrous
cyclicity. There, the guideline wording which described assessment of
cyclicity data in terms of normality was revised to indicate that the
evaluation of the pattern of cycling to better reflect current
scientific opinion.
2. Paragraph (e)(9) was revised to remove the triggers specified
in the June 1996 draft guideline because EPA determined that these
triggers would not be useful in identifying chemicals that require
further examination. Instead, an assessment of F1 females for every
study was specified (P females need not be assessed). Since EPA
believes that there is more than one valid method of selecting the
ovarian sections that will be evaluated and that the June 1996 draft
guideline was excessively prescriptive in its description of
methodology, specific instructions were removed in order to allow the
performing laboratory to determine the most appropriate methodological
criteria to attain biologically and statistically valid results.
Supporting references were provided in Sec. 799.9380 (g) of the TSCA
guideline.
E. Section 799.9420 TSCA Carcinogenicity
EPA is amending the existing TSCA Carcinogenicity guideline by
making several changes and clarifications to bring the text into
agreement with the final OPPTS harmonized guideline 870.4200,
Carcinogenicity guideline (August 1998). Specific changes to the TSCA
guideline are:
1. EPA is further specifying its recommended procedures for test
substance preparation. Paragraphs (d)(5)(ii)(C) and (d)(5)(ii)(D) are
revised with modified language which is designed for consistency with
other guidelines.
2. Paragraph (d)(5)(iii)(G) is revised to track technical changes
made to the OPPTS harmonized guideline.
3. EPA is tracking changes made to the OPPTS harmonized guideline
by adding provisions in paragraph (d)(7)(iv) recommending that water
consumption be measured at the same intervals as the test substance if
the test substance is administered in the drinking water.
4. EPA is tracking changes in the final OPPTS harmonized guideline
by revising the provisions in paragraph (d)(9)(ii) for trimming and
weighing organs during the gross necropsy phase
[[Page 35076]]
of the testing conducted under the TSCA guideline.
5. The requirement in paragraph (d)(9)(iii)(A)(13) for full
histopathology and preservation of the bile duct (for rats when the rat
is the test animal) is deleted in order to track changes made in the
final OPPTS harmonized guideline.
6. The requirement in paragraph (d)(9)(iii)(D)(5) for full
histopathology and preservation of the nose of the test animal has been
deleted to track changes in the final OPPTS harmonized guideline.
7. The requirement in paragraph (d)(9)(iii)(E)(6) for full
histopathology and preservation of the thymus of the test animal has
been deleted to track changes in the final OPPTS harmonized guideline.
8. The requirement for the histopathology and the preservation of
the female mammary gland was redesignated as new paragraph
(d)(9)(iii)(F)(8). This addition tracks the change made in the final
OPPTS harmonized guideline.
9. Requirements in paragraphs (d)(9)(iii)(G)(1),
(d)(9)(iii)(G)(2), (d)(9)(iii)(G)(4), and (d)(9)(iii)(G)(6) for the
histopathology and preservation of the lacrymal gland, skeletal muscle,
the sternum, and femur were deleted in accordance with changes made in
the final OPPTS harmonized guideline.
10. The requirement in paragraph (d)(10)(i)(D) for the full
histopathology of lungs, liver and kidneys of all test animals was
deleted in accordance with changes made in the final OPPTS harmonized
guidelines.
11. Paragraph (d)(10)(ii) was revised to indicate the correct
citation to the provisions specifying the methodology for examination
of animals exposed to lower dose levels. This citation was incorrect in
the original promulgation.
12. Paragraph (d)(10)(iv) was revised to remove the allowable
maximum thickness provision for trimming tissues designated for
microscopic examination. This change tracks changes made in the final
OPPTS harmonized guideline.
13. New paragraphs (e)(3)(i)(B)(4) and (e)(3)(i)(B)(5) were added
to specify that data on the identification of the animal diet and the
animal acclimation period should be included in the test system data
collection requirement. This addition tracks language added to the
final OPPTS harmonized guideline.
14. A new paragraph (e)(4)(ii)(J) was added to specify that
achieved dose (mg/kg/day) data (as a time-weighted average) would be
recorded as part of the individual animal data recordation requirement
if the test substance is administered in the diet or drinking water. A
similar provision was added in the final OPPTS harmonized guideline.
F. Section 799.9510 TSCA Bacterial Reverse Mutation Test
1. Paragraph (e)(2)(i)(A)(3) was revised to delete language which
indicated a preference for a particular approach to detect cross-
linking mutagens. This revision tracks changes made in the final OPPTS
harmonized guideline.
2. Paragraph (e)(2)(ii)(A) was revised to make grammatical
corrections erroneously omitted in the original promulgation.
3. The language of paragraph (f)(3) was revised to be consistent
with the test report requirement paragraph of the other TSCA
guidelines.
G. Section 799.9530 TSCA In Vitro Mammalian Cell Gene Mutation Test
EPA is making no changes to this section.
H. Section 799.9538 TSCA Mammalian Bone Marrow Chromosomal Aberration
Test
EPA is adding mandatory requirements in paragraph (e)(2)(ii)(B)(3)
for the treatment of negative controls.
I. Section 799.9539 TSCA Mammalian Erythrocyte Micronucleus Test
The EPA is correcting some errors in the original promulgation.
1. Paragraphs (e)(2)(ii)(A) and (e)(3)(iii) were revised to be
consistent with the comparable paragraphs in Sec. 799.9538.
2. Paragraph (f)(2)(ii) was revised to identify the specific
citation for the criteria to assess mutagencity instead of merely
referring to ``the above criteria.''
3. The language of paragraph (f)(3) was revised to be consistent
with the test report requirement paragraph of the other TSCA
guidelines.
J. Section 799.9620 TSCA Neurotoxicity Screening Battery
The only change EPA is making to the TSCA neurotoxicity screening
battery is the elimination of any need to use permanently injurious
chemicals for behavioral measurements. Paragraph (e)(3)(ii) is thus
revised by adding the same provisions which were added to the OPPTS
final harmonized guideline.
K. Section 799.9780 TSCA Immunotoxicity
EPA is making no changes to this section.
IV. Why Is This Action Being Issued as a Final Rule?
EPA is publishing this action as a final rule without prior notice
and an opportunity to comment because the Agency believes that
providing notice and an opportunity to comment is unnecessary and would
be contrary to the public interest. As explained above, this final rule
does not impose any obligations on anyone until the test guidelines are
incorporated in a test rule promulgated under TSCA section 4. Before
any such test rule is promulgated, EPA will provide notice and an
opportunity to comment on the incorporation of a particular test
guideline into a specific test rule. In addition, the process for
developing and amending the harmonized test guidelines includes broad
public participation and extensive involvement of the scientific
community. EPA therefore finds that there is ``good cause'' under
section 553(b)(3)(B) of the Administrative Procedure Act (APA) (5
U.S.C. 553(b)(3)(B)) to make this amendment without prior notice and
comment. Thus, this rule may be promulgated without prior opportunity
for public notice and comment, pursuant to the Administrative Procedure
Act, 5 U.S.C. 553(b)(3)(B), and may be made effective immediately,
without a 30-day delay, pursuant to 5 U.S.C. 553(d)(3).
V. How Do the Regulatory Assessment Requirements Apply to This
Action?
This final rule does not impose any requirements. It only amends
test guidelines in the TSCA series of test guidelines that are
published in the CFR and which would be considered for potential
incorporation in a future test rule that would be proposed under TSCA
section 4. As such, this action does not require review by the Office
of Management and Budget (OMB) under Executive Order 12866, entitled
Regulatory Planning and Review (58 FR 51735, October 4, 1993), the
Paperwork Reduction Act (PRA), 44 U.S.C. 3501 et seq., or Executive
Order 13045, entitled Protection of Children from Environmental Health
Risks and Safety Risks (62 FR 19885, April 23, 1997). This action does
not impose any enforceable duty, contain any unfunded mandate, or
impose any significant or unique impact on small governments as
described in the Unfunded Mandates Reform Act of 1995 (UMRA) (Pub. L.
104-4). Nor does it require prior consultation with State, local, and
tribal government officials as specified by Executive Order 12875,
entitled Enhancing the Intergovernmental
[[Page 35077]]
Partnership (58 FR 58093, October 28, 1993) and Executive Order 13084,
entitled Consultation and Coordination with Indian Tribal Governments
(63 FR 27655, May 19,1998), or special consideration of environmental
justice related issues under Executive Order 12898, entitled Federal
Actions to Address Environmental Justice in Minority Populations and
Low-Income Populations (59 FR 7629, February 16, 1994). In addition,
since this action is not subject to notice and comment requirements
under the APA as discussed in Unit IV. of this preamble, or in any
other statute, it is not subject to the regulatory flexibility
provisions of the Regulatory Flexibility Act (RFA) (5 U.S.C. 601 et
seq.).
VI. Are There Any Applicable Voluntary Consensus Standards?
No. Section 12(d) of the National Technology Transfer and
Advancement Act of 1995 (NTTAA), Pub. L. 104-113, section 12(d) (15
U.S.C. 272 note), directs EPA to use voluntary consensus standards in
its regulatory activities unless to do so would be inconsistent with
applicable law or otherwise impractical. Voluntary consensus standards
are technical standards (e.g., materials specifications, test methods,
sampling procedures, business practices, etc.) that are developed or
adopted by voluntary consensus standards bodies. The NTTAA requires EPA
to provide an explanation to Congress, through OMB, when the Agency
decides not to use available and applicable voluntary consensus
standards when the NTTAA directs the Agency to do so.
As indicated earlier, this final rule does not impose any
obligations on anyone until the test guidelines are incorporated in a
test rule promulgated under TSCA section 4. Before any such test rule
is promulgated, EPA will provide notice and an opportunity to comment
on the incorporation of a particular test guideline into that specific
test rule, including the availability of applicable voluntary consent
standards.
In addition, although the NTTAA requirements do not specifically
apply to the issuance of the harmonized test guidelines, EPA has sought
comments on the availability of applicable voluntary consensus
standards that should be considered during the development of future
rules under TSCA. This allows the Agency to consider such standards
during the development of the harmonized test guidelines, upon which
the TSCA test guidelines are based.
VII. Will EPA Submit This Action to Congress and the Comptroller
General?
Yes. The Congressional Review Act, 5 U.S.C. 801 et seq., as added
by the Small Business Regulatory Enforcement Fairness Act of 1996,
generally provides that before a rule may take effect, the agency
promulgating the rule must submit a rule report, which includes a copy
of the rule, to each House of the Congress and to the Comptroller
General of the United States. Section 808 allows the issuing agency to
make a good cause finding that notice and public procedure is
impracticable, unnecessary or contrary to the public interest. This
determination must be supported by a brief statement. 5 U.S.C. 808(2).
EPA has made such a good cause finding for this final rule, and
established an effective date of June 30, 1999. Pursuant to 5 U.S.C.
808(2), this determination is supported by the brief statement in Unit
IV. of this preamble. EPA will submit a report containing this final
rule and other required information to the U.S. Senate, the U.S. House
of Representatives, and the Comptroller General of the United States
prior to publication of the rule in the Federal Register. This is not a
``major rule'' as defined by 5 U.S.C. 804(2).
List of Subjects in 40 CFR Part 799
Environmental protection, Chemicals, Hazardous substances, Health,
Reporting and recordkeeping requirements.
Dated: June 21, 1999.
Susan H. Wayland,
Acting Assistant Administrator for Prevention, Pesticides and Toxic
Substances.
Therefore, 40 CFR part 799 is amended as follows:
PART 799--[AMENDED]
1. The authority citation for part 799 continues to read as
follows:
Authority: 15 U.S.C. 2603, 2611, 2625.
2. Section 799.9346 is amended by revising the section heading, by
revising paragraphs (d), (e)(1)(ii)(B), (e)(1)(iv)(A), (e)(1)(v)(E),
(e)(1)(v)(F), (e)(12), and (e)(15)(i)(D), and adding paragraphs
(f)(3)(ii)(D) and (f)(3)(ii)(E) to read as follows:
Sec. 799.9346 TSCA 90-Day Inhalation Toxicity.
* * * * *
(d) Limit test. If exposure at a concentration of 1 mg/L (expected
human exposure may indicate the need for a higher concentration), or
where this is not possible due to physical or chemical properties of
the test substance, the maximum attainable concentration produces no
observable toxic effects, then a full study using three concentrations
might not be necessary.
(e) * * *
(1) * * *
(ii) * * *
(B) Dosing of rodents should generally begin no later than 8 weeks
of age.
* * * * *
(iv) Numbers. (A) At least 20 animals (10 females and 10 males)
should be used for each test group.
* * * * *
(v) * * *
(E) Control and test animals should be fed from the same batch and
lot. The feed should be analyzed to assure adequacy of nutritional
requirements of the species tested and for impurities that might
influence the outcome of the rest. For feeding, conventional laboratory
diets may be used with an unlimited supply of drinking water.
(F) The study should not be initiated until animals have been
allowed a period of acclimatization/quarantine to environmental
conditions, nor should animals from outside sources be placed on test
without an adequate period of quarantine. An acclimatization period of
at least 5 days is recommended.
* * * * *
(12) Clinical pathology. Hematology and clinical chemistry
examinations shall be made on all animals, including controls, of each
sex in each group. The hematology and clinical chemistry parameters
should be examined at terminal sacrifice at the end of the study.
Overnight fasting of the animals prior to blood sampling is
recommended. Overall, there is a need for a flexible approach in the
measures examined, depending on the observed or expected effects from a
chemical, and in the frequency of measures, depending on the duration
of potential chemical exposures.
(i) Hematology. The recommended parameters are red blood cell
count, hemoglobin concentration, hematocrit, mean corpuscular volume,
mean corpuscular hemoglobin, and mean corpuscular hemoglobin
concentration, white blood cell count, differential leukocyte count,
platelet count, and a measure of clotting potential, such as
prothrombin time or activated partial thromboplastin time.
(ii) Clinical chemistry. (A) Parameters which are considered
appropriate to all studies are electrolyte balance, carbohydrate
metabolism, and liver and kidney function. The selection of specific
tests will be influenced by observations on the mode of action of the
substance and signs of clinical toxicity.
[[Page 35078]]
(B) The recommended clinical chemistry determinations are
potassium, sodium, glucose, total cholesterol, urea nitrogen,
creatinine, total protein and albumin. More than 2 hepatic enzymes,
(such as alanine aminotransferase, aspartate aminotransferase, alkaline
phosphatase, sorbitol dehydrogenase, or gamma glutamyl transpeptidase)
should also be measured. Measurements of addtional enzymes (of hepatic
or other origin) and bile acids, may also be useful.
(C) If a test chemical has an effect on the hematopoietic system,
reticulocyte counts and bone marrow cytology may be indicated.
(D) Other determinations that should be carried out if the test
chemical is known or suspected of affecting related measures include
calcium, phosphorus, fasting triglycerides, hormones, methemoglobin,
and cholinesterases.
(iii) Optionally, the following urinalysis determinations could be
performed during the last week of the study using timed urine volume
collection: appearance, volume, osmolality or specific gravity, pH,
protein, glucose, and blood/blood cells.
* * * * *
(15) * * *
(i) * * *
(D) Lungs of all animals. Special attention to examination of the
respiratory tract should be made for evidence of infection as this
provides a convenient assessment of the state of health of the animals
* * * * *
(f) * * *
(3) * * *
(ii) * * *
(D) Identification of animal diet.
(E) Acclimation period.
* * * * *
3. Section 799.9380 is amended by revising paragraphs (e)(4)(i)(D),
(e)(9) and (f)(3)(vi) to read as follows:
Sec. 799.9380 TSCA reproduction and fertility effects.
* * * * *
(e) * * *
(4) * * *
(i) * * *
(D) Estrous cycle length and pattern should be evaluated by vaginal
smears for all P and F1 females during a minimum of 3 weeks prior to
mating and throughout cohabitation; care should be taken to prevent the
induction of pseudopregnancy
* * * * *
(9) Histopathology--(i) Parental animals. Full histopathology of
the organs listed in paragraph (e)(8)(i) of this section shall be
performed for ten randomly chosen high dose and control P and F1
animals per sex, for those animals that were selected for mating.
Organs demonstrating treatment-related changes shall also be examined
for the remainder of the high-dose and control animals and for all
parental animals in the low- and mid-dose groups. Additionally,
reproductive organs of the low- and mid-dose animals suspected of
reduced fertility, e.g., those that failed to mate, conceive, sire, or
deliver healthy offspring, or for which estrous cyclicity or sperm
number, motility, or morphology were affected, shall be subjected to
histopathological evaluation. Besides gross lesions such as atrophy or
tumors, testicular histopathological examination should be conducted in
order to to identify treatment-related effects such as retained
spermatids, missing germ cell layers or types, multinucleated giant
cells, or sloughing of spermatogenic cells into the lumen. Examination
of the intact epididymis should include the caput, corpus, and cauda,
which can be accomplished by evaluation of a longitudinal section, and
should be conducted in order to identify such lesions as sperm
granulomas, leukocytic infiltration (inflammation), aberrant cell types
within the lumen, or the absence of clear cells in the cauda epididymal
epithelium. The postlactational ovary should contain primordial and
growing follicles as well as the large corpora lutea of lactation.
Histopathological examination should detect qualitative depletion of
the primordial follicle population. A quantitative evaluation of
primordial follicles should be conducted for all F1 females; the number
of animals, ovarian section selection, and section sample size should
be statistically appropriate for the evaluation procedure used.
Examination should include enumeration of the number of primordial
follicles, which can be combined with small growing follicles (see
paragraphs (g)(1) and (g)(2) of this section), for comparison of
treated and control ovaries.
(ii) Weanling. For F1 and F2 weanlings, histopathological
examination of treatment-related abnormalities noted in macroscopic
examination should be considered, if such evaluation were deemed
appropriate and would contribute to the interpretation of the study
data.
(f) * * *
(3) * * *
(vi) Number of P and F1 females cycling pattern and mean estrous
cycle length.
* * * * *
4. Section 799.9420 is amended as follows:
a. By revising paragraphs (d)(5)(ii)(C), (d)(5)(ii)(D),
(d)(5)(iii)(G), (d)(7)(iv), (d)(9)(ii), (d)(9)(iii)(D)(5), (d)(10)(ii),
and (d)(10)(iv).
b. By adding paragraphs (d)(9)(iii)(F)(8), (e)(3)(i)(B)(4),
(e)(3)(i)(B)(5), and (e)(4)(ii)(J).
c. By removing paragraphs (d)(9)(iii)(A)(13), (d)(9)(iii)(E)(6),
(d)(9)(iii)(G)(1), (d)(9)(iii)(G)(2), (d)(9)(iii)(G)(4), and
(d)(9)(iii)(G)(6) and redesignating paragraph (d)(9)(iii)(G)(3) as
paragraph (d)(9)(iii)(G)(1) and paragraph (d)(9)(iii)(G)(5) as
paragraph (d)(9)(iii)(G)(2), and removing paragraph (d)(10)(i)(D).
Sec. 799.9420 TSCA carcinogenicity.
* * * * *
(d) * * *
(5) * * *
(ii) * * *
(C) Preparation of test substance. Liquid test substances are
generally used undiluted, except as indicated in paragraph (e)(4)(vi)
of this section. Solids should be pulverized when possible. The
substance should be moistened sufficiently with water or, when
necessary, with a suitable vehicle to ensure good contact with the
skin. When a vehicle is used, the influence of the vehicle on toxicity
of, and penetration of the skin by, the test substance should be taken
into account. The volume of application should be kept constant, e.g.
less than 100 uL for the mouse and less than 300 uL for the rat.
Different concentrations of test solution should be prepared for
different dose levels.
(D) The test substance shall be applied uniformly over a shaved
area which is approximately 10 percent of the total body surface area.
In order to dose approximately 10 percent of the body surface, the area
starting at the scapulae (shoulders) to the wing of the ileum (hipbone)
and half way down the flank on each side of the animal should be
shaved. With highly toxic substances, the surface area covered may be
less, but as much of the area as possible should be covered with as
thin and uniform a film as practical.
(iii) * * *
(G) The actual concentration of the test substance shall be
measured in the breathing zone. During the exposure period, the actual
concentrations of the test substance should be held as constant as
practicable, monitored continuously or intermittently depending on the
method of analysis. Chamber concentrations may be measured using
gravimetric or analytical methods as appropriate. If
[[Page 35079]]
trial run measurements are reasonably consistent (plus or minus 10
percent for liquid aerosol, gas, or vapor; plus or minus 20 percent for
dry aerosol), the two measurements should be sufficient. If
measurements are not consistent, then three to four measurements should
be taken.
* * * * *
(7) * * *
(iv) Measurements of feed consumption should be determined weekly
during the first 13 weeks of the study and at approximately monthly
intervals thereafter unless health status or body weight changes
dictate otherwise. Measurement of water consumption should be
determined at the same intervals if the test substance is administered
in the drinking water.
* * * * *
(9) * * *
(ii) At least the liver, kidneys, adrenals, testes, epididymides,
ovaries, uterus, spleen, brain, and heart should be weighed wet as soon
as possible after dissection to avoid drying. The lungs should be
weighed if the test substance is administered by the inhalation route.
The organs should be weighed from interim sacrifice animals as well as
from at least 10 animals per sex per group at terminal sacrifice.
(iii) * * *
(D) * * *
(5) Nose.
* * * * *
(F) * * *
(8) Female mammary gland.
* * * * *
(10) * * *
(ii) If the results show substantial alteration of the animal's
normal life span, the induction of effects that might affect a
neoplastic response, or other effects that might compromise the
significance of the data, the next lower dose levels shall be examined
as described in paragraph (d)(10)(i) of this section.
* * * * *
(iv) Tissues and organs designated for microscopic examination
should be fixed in 10 percent buffered formalin or a recognized
suitable fixative as soon as necropsy is performed and no less than 48
hours prior to trimming.
* * * * *
(e) * * *
(3) * * *
(i) * * *
(B) * * *
(4) Identification of animal diet.
(5) Acclimation period.
* * * * *
(4) * * *
(ii) * * *
(J) Achieved dose (mg/kg/day) as a time-weighted average if the
test substance is administered in the diet or drinking water.
5. Section 799.9510 is amended by revising paragraphs
(e)(2)(i)(A)(3) introductory text, (e)(2)(ii)(A), and (f)(3)
introductory text to read as follows:
Sec. 799.9510 TSCA bacterial reverse mutation test.
* * * * *
(e) * * *
(2) * * *
(i) * * *
(A) * * *
(3) At least five strains of bacteria should be used. These should
include four strains of S. typhimurium (TA1535; TA1537 or TA97a or
TA97; TA98; and TA100) that have been shown to be reliable and
reproducibly responsive between laboratories. These four S. typhimurium
strains have GC base pairs at the primary reversion site and it is
known that they may not detect certain oxidizing mutagens, cross-
linking agents, and hydrazines. Such substances may be detected by E.
coli WP2 strains or S. typhimurium TA102 (see reference in paragraph
(g)(19) of this section) which have an AT base pair at the primary
reversion site. Therefore the recommended combination of strains is:
* * * * *
(ii) * * *
(A) Solvent/vehicle. The solvent/vehicle should not be suspected of
chemical reaction with the test substance and shall be compatible with
the survival of the bacteria and the S9 activity (for further
information see the reference in paragraph (g)(22) of this section). If
other than well-known solvent/vehicles are used, their inclusion should
be supported by data indicating their compatibility. It is recommended
that wherever possible, the use of an aqueous solvent/vehicle be
considered first. When testing water-unstable substances, the organic
solvents used be free of water.
* * * * *
(f) * * *
(3) Test report. The test report shall include the following
information:
* * * * *
6. Section 799.9538 is amended by revising paragraph
(e)(2)(ii)(B)(3) to read as follows:
Sec. 799.9538 TSCA mammalian bone marrow chromosomal aberration test.
* * * * *
(e) * * *
(2) * * *
(ii) * * *
(B) * * *
(3) Negative controls, treated with solvent or vehicle alone, and
otherwise treated in the same way as the treatment groups, shall be
included for every sampling time, unless acceptable inter-animal
variability and frequencies of cells with chromosome aberrations are
available from historical control data. If single sampling is applied
for negative controls, the most appropriate time is the first sampling
time. In the absence of historical or published control data
demonstrating that no deleterious or mutagenic effects are induced by
the chosen solvent/vehicle, untreated animals should be used.
* * * * *
7. Section 799.9539 is amended by revising paragraphs
(e)(2)(ii)(A), (e)(3)(iii), (f)(2)(ii), and (f)(3) introductory text to
read as follows:
Sec. 799.9539 TSCA mammalian erythrocyte micronucleus test.
* * * * *
(e) * * *
(2) * * *
(ii) * * *
(A) Solvent/vehicle. The solvent/vehicle shall not produce toxic
effects at the dose levels used, and shall not be suspected of chemical
reaction with the test substance. If other than well-known solvents/
vehicles are used, their inclusion should be supported with reference
data indicating their compatibility. It is recommended that wherever
possible, the use of an aqueous solvent/vehicle should be considered
first.
* * * * *
(3) * * *
(iii) Dose levels. If a range finding study is performed because
there are no suitable data available, it shall be performed in the same
laboratory, using the same species, strain, sex, and treatment regimen
to be used in the main study (guidance on dose setting is provided in
the reference in paragraph (g)(9) of this section). If there is
toxicity, three dose levels shall be used for the first sampling time.
These dose levels shall cover a range from the maximum to little or no
toxicity. At the later sampling time only the highest dose needs to be
used. The highest dose is defined as the dose producing signs of
toxicity such that higher dose levels, based on the same dosing
regimen, would be expected to produce lethality. Substances with
specific biological activities at low non-toxic doses (such as hormones
and mitogens) may be exceptions to the dose-setting criteria and should
be evaluated on a case-by-case basis. The highest dose may also be
defined as a dose that produces some indication of toxicity in the bone
marrow (e.g. a reduction in the proportion of immature erythrocytes
[[Page 35080]]
among total erythrocytes in the bone marrow or peripheral blood).
* * * * *
(f) * * *
(2) * * *
(ii) A test substance for which the results do not meet the
criteria in paragraph (f)(2)(i) of this section is considered non-
mutagenic in this test.
* * * * *
(3) Test report. The test report shall include the following
information:
* * * * *
8. Section 799.9620 is amended by revising paragraph (e)(3)(ii) to
read as follows:
Sec. 799.9620 TSCA neurotoxicity screening battery.
* * * * *
(e) * * *
(3) * * *
(ii) Positive control data from the laboratory performing the
testing shall provide evidence of the ability of the observational
methods used to detect major neurotoxic endpoints including limb
weakness or paralysis, tremor, and autonomic signs. Positive control
data are also required to demonstrate the sensitivity and reliability
of the activity-measuring device and testing procedures. These data
should demonstrate the ability to detect chemically induced increases
and decreases in activity. Positive control groups exhibiting central
nervous system pathology and peripheral nervous system pathology are
also required. Separate groups for peripheral and central
neuropathology are acceptable (e.g. acrylamide and trimethyl tin).
Permanently injurious substances need not be used for the behavioral
tests. Historical data may be used if the essential aspects of the
experimental procedure remain the same. Periodic updating of positive
control data is recommended. New positive control data should also be
collected when personnel or some other critical element in the testing
laboratory has changed.
* * * * *
[FR Doc. 99-16526 Filed 6-29-99; 8:45 am]
BILLING CODE 6560-50-F
