[Federal Register Volume 64, Number 249 (Wednesday, December 29, 1999)]
[Proposed Rules]
[Pages 72972-72985]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-33831]
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ENVIRONMENTAL PROTECTION AGENCY
40 CFR PARTS 160, 792, and 806
RIN 2020-AA26
[ECDIC-1998-02; FRL-5782-7]
Consolidation of Good Laboratory Practice Standards
AGENCY: Environmental Protection Agency (EPA).
ACTION: Proposed rule.
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SUMMARY: EPA is proposing to consolidate its Good Laboratory Practice
Standards (GLPS), which currently exist in two separate regulations at
40 CFR part 160 and 40 CFR part 792. The proposed consolidated GLPS
rule would be applicable to programs under the Federal Insecticide,
Fungicide, and Rodenticide Act (FIFRA) and the Toxic Substances Control
Act (TSCA) to which the current rules apply. In addition to the
proposed consolidation, EPA is also proposing amendments to the GLPS
that streamline and ease
[[Page 72973]]
compliance while still maintaining the rule's data integrity assurance
purpose. The consolidation will reduce the volume of regulations
administered by EPA without adversely affecting current data integrity
requirements. GLPS are intended to ensure the integrity of data
gathered from studies in a wide variety of disciplines such as
toxicology, ecological effects, chemical fate, residue chemistry, and
product performance testing. Under FIFRA, compliance with regulations
on GLPS applies to all studies required to be submitted in support of
pesticide registrations, reregistrations, and experimental use permits.
Under TSCA, GLPS are required for testing conducted pursuant to consent
agreements/orders and test rules issued under sections 4 and 5 of that
Act. Failure to comply with applicable GLPS is an actionable violation
which may result in civil or criminal penalties, and can render data
from non-compliant studies unacceptable for consideration by EPA.
DATES: Comments, identified by the docket control number EC-1998-02,
must be received by March 29, 2000.
ADDRESSES: By mail, submit comments to: Enforcement and Compliance
Docket and Information Center (2201A), Office of Enforcement and
Compliance Assurance, Environmental Protection Agency, 401 M St., SW.,
Washington, DC 20460. In person, bring comments to: Enforcement and
Compliance Docket and Information Center, Office of Enforcement and
Compliance Assurance, Rm. 4033, Ariel Rios Bldg., 1200 Pennsylvania
Ave., Washington, DC. The telephone number for the Enforcement and
Compliance Docket and Information Center is (202) 564-2614.
Information submitted and any comment(s) concerning this proposed
rule may be claimed confidential by marking any or all of that
information as ``Confidential Business Information'' (CBI). Information
so marked will not be disclosed except in accordance with procedures
set forth in 40 CFR part 2. A copy of the comment(s) that does not
contain CBI must be submitted for inclusion in the public record.
Information not marked confidential may be disclosed publicly by EPA
without prior notice to the submitter. Information on the proposed rule
and any written comments received will be available for public
inspection in Room 4033 at the Ariel Rios Bldg. address given above,
from 8 a.m. to 4 p.m., Monday through Friday, excluding legal holidays.
Comments and data may also be submitted electronically by sending
electronic mail (e-mail) to Donna W[email protected]. Comments
and data will also be accepted on disks in WordPerfect in 5.1/6.1 or
ASCII file format. All comments and data in electronic form must be
identified by the docket control number EC-1998-02. No CBI should be
submitted through e-mail. Electronic comments on this proposed rule,
but not the record, may be viewed or new comments filed online at many
Federal Depository Libraries.
FOR FURTHER INFORMATION CONTACT: David Stangel, Agriculture and
Ecosystems Division, Office of Compliance (2225A), U. S. Environmental
Protection Agency, 401 M St., SW., Washington, DC 20460, Telephone:
(202) 564-4162, e-mail: [email protected].
SUPPLEMENTARY INFORMATION:
I. Introduction
EPA proposes to amend the FIFRA GLPS (40 CFR part 160) and the TSCA
GLPS (40 CFR part 792) to consolidate these regulations into one rule.
In addition, EPA proposes to provide clarifications of certain
requirements and amend other requirements of the rule to reflect the
experience gained in administering the GLPS.
A. Legal Authority
These GLPS are promulgated under the authority of sections 3, 4, 5,
6, 8, 18, 24(c), and 25(a) of FIFRA, 7 U.S.C. 136 et seq., as amended,
sections 408, 4091, and 701 of the Federal Food, Drug, and
Cosmetic Act (FFDCA), 21 U.S.C. 301 et seq., the Reorganization Plan
No. 3 of 1970, and sections 4(b)(1) and 5 of TSCA, 15 U.S.C. 2603 et
seq.
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1Prior to August 3, 1996 (the effective date of the Food Quality
Protection Act of 1996), data were submitted to the Agency pursuant
to section 409. References in this rule to section 409 remain with
respect to such data.
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B. Background
EPA published FIFRA and TSCA GLPS in the Federal Register on
November 29, 1983 (48 FR 53946 and 48 FR 53922), which were codified as
40 CFR parts 160 and 792 respectively, and were amended on August 17,
1989 (54 FR 34052 and 54 FR 34034). These TSCA and FIFRA regulations
were initially promulgated to address assuring the validity of data in
the wake of investigations by EPA and the Food and Drug Administration
(FDA) during the mid-1970's which revealed that some studies submitted
to the Agencies had not been conducted in accordance with acceptable
laboratory practices. Some studies had been conducted so poorly that
the resulting data could not be relied upon in EPA's regulatory
decision-making process. In some cases, results were selectively
reported, underreported, or fraudulently reported. In addition, it was
discovered that some testing facilities displayed poor animal care
procedures and inadequate recordkeeping techniques. The GLPS specify
minimum practices and procedures in order to ensure the quality and
integrity of data submitted to EPA in support of a research or
marketing permit for a pesticide product, or the quality and integrity
of data submitted in accordance with a TSCA section 4 or 5 requirement.
When EPA published its initial FIFRA and TSCA GLPS in the Federal
Register of November 29, 1983, EPA sought to harmonize the requirements
and language with those regulations promulgated by the FDA in the
Federal Register of December 22, 1978 (43 FR 60013), and codified as 21
CFR part 58. Differences between the two Agencies' current GLPS
regulations existed only to the extent necessary to reflect the
Agencies' different statutory responsibilities under TSCA, FIFRA, and
FFDCA. Similar to the FDA GLPS regulations, the FIFRA and TSCA GLPS
delineate standards for studies required to be submitted to EPA for its
regulatory decision-making.
Compliance with EPA's FIFRA and TSCA GLPS has been monitored
through a program of laboratory inspections and data audits coordinated
between EPA and FDA. Under an Interagency Agreement originated in 1978
between FDA and EPA, FDA carries out GLPS inspections at laboratories
which conduct health effects testing. EPA primarily performs GLPS
inspections for environmental laboratories and conducts data audits for
health effects and environmental studies. Because of the cooperative
nature of FDA's and EPA's GLPS programs, it is important that the GLPS
remain substantially consistent not only between programs within each
Agency but also between Agencies.
FDA revised its GLPS regulations on September 4, 1987 (52 FR
33768), to simplify the regulations and reduce the regulatory burden on
testing facilities without compromising study integrity. EPA published
amendments to its FIFRA and TSCA GLPS in the Federal Register of August
17, 1989 (54 FR 34052 and 54 FR 34043 respectively). During that
rulemaking, EPA expanded the applicability of its FIFRA GLPS to cover
all data required to be submitted under FIFRA.
On March 4, 1995, the President directed all Federal agencies to
conduct
[[Page 72974]]
a comprehensive review of the regulations these agencies administer and
reduce or eliminate unnecessary or duplicative regulations. In
response, EPA conducted a review of its regulations to determine
candidates for such reductions. During this process, EPA identified the
FIFRA and TSCA GLPS as providing an opportunity for such reductions.
The goal of consistency of GLPS resulted in the same regulatory
language being duplicated throughout these two rules. This proposed
rulemaking reflects EPA's belief that it is not necessary to duplicate
the same language in two separate regulations.
Since the 1989 rulemaking, EPA has received many requests for
clarifications with respect to compliance requirements, especially
regarding FIFRA studies that came under GLPS coverage in 1989. EPA's
responses to those requests facilitated compliance with the FIFRA GLPS
rule and have been made available to the regulated community in a
Question and Answer document which may be obtained from the address
listed above in the ``FOR FURTHER INFORMATION CONTACT'' section.
EPA has been in communication with representatives of the regulated
community who indicated that it would improve the quality of and
compliance with the GLPS if previous clarifications were incorporated.
As a result of these initial consultations, EPA believes that it makes
sense to incorporate these clarifications and consider other
suggestions for improving these regulations, and is proposing several
modifications to the GLPS requirements as part of this rulemaking.
II. Summary of Proposed Changes
A. Consolidation
Currently, EPA has GLPS at 40 CFR part 160 and part 792. These
rules are identical in general format, each consisting of the following
subparts: A--General Provisions; B--Organization and Personnel; C--
Facilities; D--Equipment; E--Testing Facilities Operation; F--Test,
Control, and Reference Substances; G--Protocol for and Conduct of a
Study; H and I--[Reserved]; and J--Records and Reports.
Most of the sections under these subparts are identical between the
two rules. In such cases, EPA proposes to continue the current language
except where amended as provided in Unit II.B. of this preamble. Some
sections include rule differences for the two regulatory areas--TSCA
and FIFRA. In such cases, it is necessary to provide separate, distinct
sections, or subsections applicable to those programs.
Therefore, the proposed 40 CFR part 806 will continue the common
language currently found in both 40 CFR parts 160 and 792. Current
differences between the TSCA and FIFRA rules will be treated in one of
two ways: (1) Differences which are programmatic and necessary will be
continued in the form of separate regulatory provisions under the
consolidated GLPS; and (2) differences that are determined to be
inadvertent, e.g., typographic errors, minor grammatical differences,
etc., will be eliminated.
1. Program differences. The two subparts in which there are
significant differences between the two rules are Subpart A (General
Provisions) and Subpart J (Records and Reports). All other subparts are
virtually identical.
a. Subpart A--General Provisions--i. Sec. 806.1--Scope. Section
806.1(a) proposes to include the relevant statutory authorities under
FIFRA and FFDCA (currently applicable to pesticides studies), and the
authorities under TSCA (currently applicable to substances regulated
under TSCA). In Sec. 806.1(a)(2), the Agency states that the GLPS apply
to any study which any person conducts, initiates, or supports by a
certain date. If a study is initiated prior to that date but conducted
after that date, the GLPS would apply to the study. Only if the study
is completed prior to the effective date of the rule would it not be
subject to the amended GLPS.
ii. Sec. 806.3--Definitions. Section 806.3 includes definitions
which are specific to program areas and are currently listed separately
in the two rules.
iii. Sec. 806.12--Statement of Compliance or Noncompliance. Section
806.12 proposes specific and separate applicability under the current
program areas (toxics and pesticides) which provide for compliance
statements.
b. Subpart J--Records and Reports. -- Sec. 806.195--Retention of
Records. Section 806.195 proposes separate record retention
requirements for documentation records, raw data, and specimens
pertaining to FIFRA and TSCA studies.
B. Clarifying Amendments
In addition to consolidating the regulations, the Agency is
proposing to amend the current regulatory language in 40 CFR parts 160
and 792 to clarify certain requirements and simplify others. These
amendments are being proposed in response to feedback received from the
regulated community as well as comments received in response to
publication of the Agency's intent to consolidate the FIFRA and TSCA
GLPS.
1. Subpart A--General Provisions. The proposal would amend the
current definitions of the terms ``carrier'' and ``test systems'' by
adding the word ``air'' to each definition to clarify that air is
considered both a carrier and a test system in certain circumstances.
This change will alleviate confusion on this point.
EPA proposes to amend the current definition of the term ``quality
assurance unit'' by deleting the phrase ``the study director'' and
adding the phrase ``individual(s) directly involved in the conduct of
the study, including the study director.'' This change is being
proposed because it is equally improper for persons other than the
study director who are working directly on the study to perform quality
assurance of the study.
EPA proposes to amend the current definition of the term
``vehicle'' by adding examples of substances which are considered
vehicles.
EPA proposes to amend the current Secs. 160.10 and 792.10 by adding
the phrase ``prior to initiation of the study,'' to the end of the
sentence as well as requiring the notification to be made in writing.
This change clarifies a number of questions that have been raised in
the past and is in keeping with normal practices. Section 806.10
reflects the change.
EPA proposes to amend the current Secs. 160.17(a)(2) and
792.17(a)(2) by changing the reference to FFDCA section 406, which was
a typographical error, to section 408, the proper reference. EPA
proposes to amend the term ``consent agreement'' to ``consent
agreement/order'' and the reference to ``section 4 of TSCA'' to
``section 4 or 5 of TSCA'' throughout the proposed rule to reflect that
GLPS are required in both test rules and consent agreements/orders, and
that testing can be required under both sections 4 and 5 of TSCA.
Section 806.17(a)(2) reflects these changes.
EPA proposes to amend the current Secs. 160.33(f) and 792.33(f) to
read: ``. . .during or at the close or termination of the study.'', to
address those instances where a study is terminated prior to completion
of the study. Section 806.33(f) reflects the change.
2. Subpart B--Organization and Personnel. EPA proposes to amend the
current Secs. 160.35(b)(1) and 792.35(b)(1) to include the following
language ``. . .indexed to permit expedient retrieval, which identifies
the. . .'' to allow the study director to employ an indexing system
which may not reference the test substance but would still allow the
[[Page 72975]]
facility to quickly extract the information. Section 806.35(b)(1)
reflects this change. EPA proposes to amend the current
Secs. 160.35(b)(2) and 792.35(b)(2) to read: ``. . .all protocols until
study completion pertaining. . . .'' Protocols are required to be
archived at the completion of a study and requiring the maintenance of
another copy of the protocol would be duplicative. Section 806.35(b)(2)
reflects this change.
3. Subpart C--Facilities. Questions have been raised in the past
about the applicability of the language in the current Secs. 160.43(a)
and 792.43(a); specifically whether co-exposure of test species to the
test substance (e.g., inhalation studies) is allowable given the
requirement for proper separation of species or test systems. Co-
exposure of test species in inhalation studies is allowable unless the
study protocol specifically prohibits the practice. Section 806.43(a)
reflects this change.
4. Subpart D--Equipment. The Agency proposes to amend the current
Secs. 160.63 and 792.63 by adding paragraph (d) to address the
integrity of data stored and manipulated by computers, data processors,
and automated laboratory procedures to make it clear that these types
of equipment are subject to the same provisions as other laboratory
equipment. Section 806.63 reflects this change.
5. Subpart E--Testing Facilities Operation. The Agency is proposing
to amend the current Secs. 160.83 and 792.83 to allow the testing
facility to develop a documentation performance standard as an
alternative to an expiration date for the contents of transfer bottles
and wash bottles. The testing facility has the option of labeling
transfer and wash bottles or developing another well documented system
to ensure that these solutions have not deteriorated or exceeded their
expiration date. Section 806.63 reflects this change. EPA specifically
requests comment on a documentation performance standard that would
provide the same assurances that the solutions have not deteriorated or
exceeded their expiration date. Other alternatives being considered
include the development of a list of substances that do not require
expiration dates, e.g., distilled water.
6. Subpart F--Test, Control, and Reference Substances. The Agency
proposes to amend the current Secs. 160.105(b) and 792.105(b) to allow
concurrent determination of solubility as well as stability of the
test, control, or reference substance. The rule presently allows only
concurrent determination of the stability of the test, control, or
reference substance. Section 806.105(b) reflects this change.
EPA proposes to amend the current Secs. 160.105(c) and 792.105(c)
to allow the study director the options of discarding containers which
contained the test substance, with proper recordkeeping of the
disposition of the containers, or retaining the containers until the
termination of the study. The proposal to relax the requirement for
retention of test substance containers is being made to address the
burden of retaining containers in field studies where large amounts of
the test substance are used. The approach proposed is prescriptive in
nature and gives the testing facility and study director EPA's position
on what the Agency considers adequate documentation. EPA is requesting
comments on whether such a prescriptive approach is necessary or should
be relaxed to state that the study director may authorize container
disposal and simply note in the raw data that this has been done.
In addition, the Agency is proposing to amend the current
Secs. 160.105(c) and 792.105(c) by deleting the term ``where
appropriate'' from the first sentence to now read ``. . .expiration
date, if any, and storage conditions necessary to maintain the
identity, . . .'' because information on storage conditions is always
appropriate. Section 806.105(c) reflects these changes.
The Agency proposes to amend the current Secs. 160.113(a)(2) and
792.113(a)(2) by the addition of the following language ``. .
.reference substance in the mixture; or if the solubility of the
substance is difficult to determine, appropriate homogeneity data, by
the testing facility. . .'' to address those situations in which the
test, control, or reference substance is insoluble and may create
emulsions that are very difficult to analyze. Section 806.113(a)(2)
reflects this change. EPA proposes to amend the current
Secs. 160.113(b) and 792.113(b) to exempt tank mixes and solutions
prepared for immediate administration (within 12 hours) in mammalian
acute toxicology studies, metabolism studies, or mutagenicity studies
from requirements for concentration determinations (but not from
uniformity determinations) under Secs. 160.113(a)(1) and 792.113(a)(1)
and solubility determinations under Secs. 160.113(a)(2) and
792.113(a)(2). This addition is being proposed in response to comments
that these mixes must be made and used quickly, and it is not possible
to perform solubility testing before the experimental start date.
Section 806.113(b) reflects this change.
7. Subpart G--Protocol for and Conduct of a Study. EPA proposes to
amend the current Secs. 160.120(a)(2) and 792.120(a)(2) to exempt
metabolism studies from the requirement to identify the test, control,
or reference substance when their identities are to be determined
during the study. In metabolism studies, the identity of the metabolite
or metabolites may not be known at the time that the protocol is
written. EPA proposes that the protocol need not identify reference
substances for metabolites when they cannot be identified before the
beginning of the study. This proposal does not affect the requirement
to identify metabolism study test, reference, or control substances at
the beginning of the study, unless the purpose of the study is to
identify them. Section 806.120(a)(2) reflects this change.
EPA proposes to amend the current Secs. 160.120(c) and 792.120(c)
to allow discontinued studies or studies otherwise terminated before
completion to be finalized by writing a protocol amendment with the
reasons for the termination, in lieu of preparing a final report. All
documentation for the terminated study must be retained in accordance
with Sec. 806.195. Sponsors are still obligated to meet section 6(a)(2)
of FIFRA and section 8(e) of TSCA requirements for submission of
adverse effects data including, but not limited to, those generated by
terminated studies. Section 806.120(c) reflects this change.
8. Subpart J--Records and Reports. EPA proposes to amend the
current Secs. 160.185(a)(1) and 792.185(a)(1) by deleting the words
``terminated or discontinued,'' because Sec. 806.120(c) was added to
address terminated or discontinued studies. Section 806.185(a)(1)
reflects this change.
EPA proposes to amend the current Secs. 160.185(a)(7) and
792.185(a)(7) by deleting the phrase ``or other test organisms,''
because the required information is relevant chiefly to animal systems.
Section 806.185(a)(7) reflects this change.
Finally, EPA proposes to amend the current Sec. 792.195 by
replacing the existing record retention requirements for studies
submitted under sections 4 and 5 of TSCA with a single requirement to
retain records for a period of 5 years following the date on which the
final report of the study is submitted to the Agency. The change will
simplify record retention requirements for persons required to retain
records by providing a single standard for record retention. Section
806.195 reflects this change.
III. Public Docket
A record has been established for this rulemaking under docket
number EC-
[[Page 72976]]
1998-02. This record is available for public inspection from 8 a.m. to
4 p.m., Monday through Friday, excluding legal holidays. The public
record is located in Rm. 4033, Office of Enforcement and Compliance
Assurance, Environmental Protection Agency, Ariel Rios Bldg., 1200
Pennsylvania Ave., Washington, DC. Written requests should be mailed
to: Enforcement and Compliance Docket and Information Center (2201A),
Environmental Protection Agency, 401 M St., SW., Washington, DC 20460.
IV. Statutory Review
In accordance with FIFRA section 25(a), this proposal was submitted
to the FIFRA Scientific Advisory Panel, the Secretary of Agriculture,
and appropriate Congressional Committees. No comments were received.
V. Regulatory Assessment Requirements
A. Executive Order 12866
Pursuant to Executive Order 12866 (58 FR 51735, October 4, 1993),
it has been determined that this proposed action is not a ``significant
regulatory action'' and is therefore not subject to the Office of
Management and Budget (OMB) review. The Agency believes that the
amendments associated with this action constitute regulatory relief,
and therefore will not impose any additional costs or burdens. The
analysis related to the costs and burdens of the original requirements
were discussed in conjunction with their promulgation in 1989. Because
this action consolidates the requirements contained in the original
GLPS, no new costs or burdens are imposed. Instead, the Agency believes
that the consolidation of the GLPS may actually increase efficiencies
for those companies that are required to use both TSCA and FIFRA GLPS,
because these companies will now only have one version of GLPS to use.
Additionally, many of the changes in the rule allow the laboratories to
use more efficient means of achieving the requirements of the GLPS. The
Agency solicits comments on the impacts of this consolidation on the
regulated community.
B. 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. The Agency believes that this
action will not adversely impact low-income and minority communities.
These regulations consolidate existing regulations and have not been
the subject of any environmental justice concerns in the past.
C. Executive Order 13084
Under Executive Order 13084, entitled Consultation and Coordination
with Indian Tribal Governments (63 FR 27655, May 19, 1998), EPA may not
issue a regulation that is not required by statute, that significantly
or uniquely affects the communities of Indian tribal governments, and
that imposes substantial direct compliance costs on those communities,
unless the Federal government provides the funds necessary to pay the
direct compliance costs incurred by the tribal governments. If EPA
complies by consulting, Executive Order 13084 requires EPA to provide
OMB, in a separately identified section of the preamble to the rule, a
description of the extent of EPA's prior consultation with
representatives of affected Tribal governments, a summary of the nature
of their concerns, and a statement supporting the need to issue the
regulation. In addition, Executive Order 13084 requires EPA to develop
an effective process permitting elected and other representatives of
Indian tribal governments ``to provide meaningful and timely input in
the development of regulatory policies on matters that significantly or
uniquely affect their communities.''
Today's proposed rule does not significantly or uniquely affect the
communities of Indian tribal governments. The proposed rule does not
involve or impose any requirements that affect Indian Tribes.
Accordingly, the requirements of section 3(b) of Executive Order 13084
do not apply to this document.
D. Unfunded Mandates Reform Act and Executive Order 12875
This proposed action does not contain any new requirements or
impose any additional burden because it proposes to consolidate
requirements together which currently exist in two separate
rulemakings. As such, this proposed action is expected to result in
savings and burden relief rather than in an expenditure by any State,
local, or Tribal governments, or by anyone in the private sector, and
will not result in any unfunded Federal mandates as defined by Title II
of the Unfunded Mandates Reform Act of 1995 (Public Law 104-4).
In addition, since this action does not contain any Federal
mandates on States, localities, or Tribes, it is not subject to the
requirements of Executive Order 12875, entitled Enhancing the
Intergovernmental Partnership (58 FR 58093, October 28, 1993).
E. Regulatory Flexibility Act
Pursuant to section 605(b) of the Regulatory Flexibility Act (5
U.S.C. 601 et seq.), the Agency hereby certifies that this regulatory
action does not have any significant adverse economic impacts on a
substantial number of small entities. This proposed rule does not
impose any new requirements that would impose any adverse impacts on
small entities. In consolidating the existing requirements, EPA is
allowing those companies that are currently conducting various testing
for use either pursuant to FIFRA or TSCA, to adhere to and follow a
single GLP standard. Given the efficiencies provided, the Agency has
determined that this proposal will not result in adverse impacts. As
such, no impact analysis is required.
Information related to this determination has been included in the
docket for this rulemaking, and, in accordance with Small Business
Administration (SBA) policy, will be provided to the Chief Counsel for
Advocacy of the SBA upon request. Any comments regarding the economic
impacts that this regulatory action may impose on small entities should
be submitted to the Agency at the address listed under Unit III. of
this preamble.
F. Paperwork Reduction Act
This proposed action does not contain any new information
collection requirements. The GLPS do not directly impose any
information collection requirements, but they describe standards
regarding testing conducted for other information collections currently
approved by the Office of Management and Budget (OMB) under the
provisions of the Paperwork Reduction Act, 44 U.S.C. 3501 et seq.:
Maximum Residue Limit (MRL) Petitions on Food/Feed Crops and New
Inert Ingredients (EPA ICR No. 597.06, OMB Control No. 2070-0024)
Notice of Pesticide Registration by States to Meet a Special Local
Need (SLN) under FIFRA Section 24(c) (EPA ICR No. 595.06, OMB Control
No. 2070-0055)
Application for New or Amended Registration (EPA ICR No. 277.10,
OMB Control No. 2070-0060)
Application for Experimental Use Permit (EUP) to Ship a Pesticide
for Experimental Purposes Only (EPA ICR
[[Page 72977]]
No. 276.08, OMB Control No. 2070-0040)
Data Call-In for Special Review Chemicals (EPA ICR No. 922.05, OMB
Control No. 2070-0057)
Application and Summary Report for an Emergency Exemption for
Pesticides (EPA ICR No. 596.05, OMB Control No. 2070-0032)
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.
G. Request for Comment on Potential Voluntary Consensus Standards to
Consider for Future Regulatory Actions
This proposal does not involve a regulatory action that would
require the Agency to consider voluntary consensus standards pursuant
to section 12(d) of the National Technology Transfer and Advancement
Act of 1995 (NTTAA), Public Law 104-113, section 12(d) (15 U.S.C. 272
note). Section 12(d) 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 Congress, through OMB, explanations 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, these guidelines represent an Agency effort
to harmonize the test guidelines between the Office of Pesticide
Programs (OPP) and the Office of Pollution Prevention and Toxics
(OPPT), as well as harmonizing the OPP and OPPT test guidelines with
those of the Organization for Economic Cooperation and Development. The
process for developing and amending these test guidelines includes the
extensive involvement of the scientific community, including peer
review by the FIFRA SAP and other expert scientific panels, and
providing extensive public comment.
In the future, these test guidelines could be incorporated into
regulatory actions taken by EPA pursuant to TSCA section 4. Although
the NTTAA requirements do not specifically apply to the issuance of
these particular test guidelines today, EPA invites your comment on
whether or not there are any voluntary consensus standards that should
be considered during the development of any future action under TSCA.
Future actions under TSCA section 4 would go through notice and comment
rulemaking or be negotiated as voluntary testing enforcement
agreements/consent orders/decrees, allowing for additional public
comment on this issue. Nevertheless, the Agency is interested in
whether or not there are any voluntary consensus standards that EPA
should considered in lieu of these test guidelines when the Agency
develops any future regulatory action that incorporates these test
guidelines. Any comments provided will assist the Agency in complying
with the NTTAA by facilitating the Agency's identification of voluntary
consensus standards that should be considered during the development of
a proposed regulatory action that incorporates any standards included
in these test guidelines. Please submit your comments to the person
identified in the FOR FURTHER INFORMATION CONTACT section.
H. Executive Order 13045
Executive Order 13045 entitled Protection of Children from
Environmental Health Risks and Safety Risks (62 FR 19885, April 23,
1997) applies to any rule that: (1) is determined to be ``economically
significant'' as defined under Executive Order 12866, and (2) concerns
an environmental health or safety risk that EPA has reason to believe
may have a disproportionate effect on children. If the regulatory
action meets both criteria, the Agency must evaluate the environmental
health or safety effects of the planned rule on children, and explain
why the planned regulation is preferable to other potentially effective
and reasonably feasible alternatives considered by the Agency.
EPA interprets Executive Order 13045 as applying only to those
regulatory actions that are based on health or safety risks, such that
the analysis required under section 5-501 of the Order has the
potential to influence the regulation. This proposed rule is not
subject to Executive Order 13045 because it does not establish an
environmental standard intended to mitigate health or safety risks.
I. Executive Order 13132
On August 4, 1999, President Clinton issued a new executive order
on federalism, Executive Order 13132 (64 FR 43255, August 10, 1999),
which will take effect on November 2, 1999. In the interim, the current
Executive Order 12612 (52 FR 41685, October 30, 1987), on federalism
still applies. This proposed rule will not have a substantial direct
effect on States, on the relationship between the national government
and the States, or on the distribution of power and responsibilities
among the various levels of government, as specified in Executive Order
12612.
List of Subjects
40 CFR Part 160
Environmental protection, Laboratories, Pesticides and pests,
Reporting and recordkeeping requirements.
40 CFR Part 792
Environmental protection, Hazardous substances, Laboratories,
Reporting and recordkeeping requirements.
40 CFR Part 806
Environmental protection, Data requirements, Good laboratory
practice, Hazardous materials, Pesticides and pests, Reporting and
recordkeeping requirements, Testing.
Dated: October 28, 1999.
Carol M. Browner,
Administrator.
Therefore, it is proposed that 40 CFR chapter I be amended as
follows:
PART 160 [Removed]
1. By removing part 160.
PART 792 [Removed]
2. By removing part 792.
3. By adding subchapter S consisting of part 806 to read as
follows:
[[Page 72978]]
SUBCHAPTER S--STANDARDS, TEST METHODS, AND GUIDELINES
PART 806--GOOD LABORATORY PRACTICE STANDARDS
Subpart A--General Provisions
Sec.
806.1 Scope.
806.3 Definitions.
806.10 Applicability to studies performed under grants and
contracts.
806.12 Statement of compliance or non-compliance.
806.15 Inspection of a testing facility.
806.17 Effects of non-compliance.
Subpart B--Organization and Personnel
806.29 Personnel.
806.31 Testing facility management.
806.33 Study director.
806.35 Quality assurance unit.
Subpart C--Facilities
806.41 General.
806.43 Test system care facilities.
806.45 Test system supply facilities.
806.47 Facilities for handling test, control, and reference
substances.
806.49 Laboratory operation areas.
806.51 Specimen and data storage facilities.
Subpart D--Equipment
806.61 Equipment design.
806.63 Maintenance and calibration of equipment.
Subpart E--Testing Facilities Operation
806.81 Standard operating procedures.
806.83 Reagents and solutions.
806.90 Animal and other test system care.
Subpart F--Test, Control, and Reference Substances
806.105 Test, control, and reference substance characterization.
806.107 Test, control, and reference substance handling.
806.113 Mixtures of substances with carriers.
Subpart G--Protocol for and Conduct of a Study
806.120 Protocol.
806.130 Conduct of a study.
806.135 Physical and chemical characterization studies.
Subparts H and I--[RESERVED]
Subparts J--Records and Reports
806.185 Reporting of study results.
806.190 Storage and retrieval of records and data.
806.195 Retention of records.
Authority: 7 U.S.C. 136a, 136c, 136d, 136f, 136j, 136t, 136v,
136w; 15 U.S.C. 2603; 21 U.S.C. 346a, 348, 371, Reorganization Plan
No. 3 of 1970.
Subpart A--General Provisions
Sec. 806.1 Scope.
(a)(1) This part prescribes good laboratory practices for
conducting studies that support or are intended to support applications
for research or marketing permits for pesticide products regulated by
the EPA. This part is intended to assure the quality and integrity of
data submitted pursuant to sections 3, 4, 5, 8, 18, and 24(c) of the
Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), as amended
(7 U.S.C. 136a, 136c, 136f, 136q, and 136v(c)) and sections 408 and 409
of the Federal Food, Drug, and Cosmetic Act (FFDCA), as amended (21
U.S.C. 346a, 348).
(2) This part applies to any study described by paragraph (a)(1) of
this section which any person conducts, initiates, or supports on or
after [Insert date 60 days after date of publication in the Federal
Register of the final rule].
(b)(1) This part also prescribes good laboratory practices for
conducting studies relating to health effects, environmental effects,
and chemical fate testing pursuant to the Toxic Substances Control Act
(TSCA) (Public Law 94-469, 90 Stat. 2006, 15 U.S.C. 2603 et seq.). This
part is intended to assure the quality and integrity of data submitted
pursuant to test rules and testing consent agreements/orders issued
under section 4 and section 5 of TSCA.
(2) This part applies to any study described by paragraph (b)(1) of
this section which any person conducts, initiates, or supports on or
after [Insert date 60 days after date of publication in the Federal
Register of the final rule].
(3) It is EPA's policy that all data developed for submission
under section 5 of TSCA be in accordance with provisions of this part.
If data are not developed in accordance with the provisions of this
part, EPA will consider such data insufficient to evaluate the health
and environmental effects of the chemical substances unless the
submitter provides additional information demonstrating that the data
are reliable and adequate.
Sec. 806.3 Definitions.
As used in this part, the following terms shall have the meanings
specified:
Application for research or marketing permit includes:
(1) An application for registration, amended registration, or
reregistration of a pesticide product under FIFRA sections 3, 4, or
24(c).
(2) An application for an experimental use permit under FIFRA
section 5.
(3) An application for an exemption under FIFRA section 18.
(4) A petition or other request for establishment or modification
of a tolerance, for an exemption for the need for a tolerance, or for
other clearance under FFDCA section 408.
(5) A petition or other request for establishment or modification
of a food additive regulation or other clearance by EPA under FFDCA
section 409.
(6) A submission of data in response to a notice issued by EPA
under FIFRA section 3(c)(2)(B).
(7) Any other application, petition, or submission sent to EPA
intended to persuade EPA to grant, modify, or leave unmodified a
registration or other approval required as a condition of sale or
distribution of a pesticide.
Batch means a specific quantity or lot of a test, control, or
reference substance that has been characterized according to
Sec. 806.105(a).
Carrier means any material, including but not limited to feed,
water, soil, air, or nutrient media, with which the test substance is
combined for administration to a test system.
Control substance means any chemical substance or mixture, or any
other material other than a test substance, feed, or water, that is
administered to the test system in the course of a study for the
purpose of establishing a basis for comparison with the test substance
for known chemical or biological measurements.
EPA means the U.S. Environmental Protection Agency.
Experimental start date means the first date the test substance is
applied to the test system.
Experimental termination date means the last date on which data are
collected directly from the study.
FDA means the U.S. Food and Drug Administration.
FFDCA means the Federal Food, Drug, and Cosmetic Act, as amended
(21 U.S.C. 321 et seq).
FIFRA means the Federal Insecticide, Fungicide, and Rodenticide Act
as amended (7 U.S.C. 136 et seq).
Person includes an individual, partnership, corporation,
association, scientific or academic establishment, government agency,
or organizational unit thereof, and any other legal entity.
Quality assurance unit means any person or organizational element
(except individual(s) directly involved in the conduct of the study,
including the study director), designated by testing facility
management to perform the duties relating to quality assurance of the
studies.
Raw data means any laboratory worksheets, records, memoranda,
notes, or exact copies thereof, that are the result of original
observations and activities of a study and are necessary for the
reconstruction and evaluation of the report of that study. In the event
that exact transcripts of raw data have been prepared (e.g., tapes
which have been transcribed verbatim, dated, and verified accurate by
signature), the exact
[[Page 72979]]
copy or exact transcript may be substituted for the original source as
raw data. Raw data may include photographs, microfilm or microfiche
copies, computer printouts, any original data captured electronically
or by some other medium, dictated observations, and recorded data from
automated instruments.
Reference substance means any chemical substance or mixture, or
analytical standard, or material other than a test substance, feed, or
water, that is administered to or used in analyzing the test system in
the course of a study for the purposes of establishing a basis for
comparison with the test substance for known chemical or biological
measurements.
Specimens means any material or sample derived from a test system
for examination or analysis.
Sponsor means:
(1) A person who initiates and supports, by provision of financial
or other resources, a study;
(2) A person who submits a study to the EPA: in support of an
application for a research or marketing permit; or in response to a
TSCA section 4 test rule and/or a person who submits a study under a
TSCA section 4 testing consent agreement/order or a TSCA section 5
consent order to the extent the agreement, rule or order references
this part; or
(3) A testing facility, if it both initiates and actually conducts
the study.
Study means any experiment at one or more test sites, in which a
test substance is studied in a test system under laboratory conditions
or in the environment to determine or help predict its effects,
metabolism, product performance (pesticide efficacy studies only as
required by 40 CFR 158.640) environmental and chemical fate,
persistence, or residue, or other characteristics in humans, other
living organisms, or media. The term ``study'' does not include basic
exploratory studies carried out to determine whether a test substance
or a test method has any potential utility.
Study completion date means the date the final report is signed by
the study director.
Study director means the individual responsible for the overall
conduct of a study.
Study initiation date means the date the protocol is signed by the
study director.
Test substance means a substance or mixture administered or added
to a test system in a study, which substance or mixture:
(1) Is the subject of an application for a research or marketing
permit supported by the study, or is the contemplated subject of such
an application; or
(2) Is an ingredient, impurity, degradation product, metabolite, or
radioactive isotope of a substance described by paragraph (1) of this
definition, or some other substance related to a substance described by
that paragraph, which is used in the study to assist in characterizing
the toxicity, metabolism, or other characteristics of a substance
described by that paragraph; or
(3) Is used to develop data to meet the requirements of a TSCA
section 4 test rule and/or is developed under a TSCA section 4 testing
consent agreement/order or TSCA section 5 consent order to the extent
the agreement, rule, or order references this part.
Test system means any animal, plant, microorganism, chemical or
physical matrix, including but not limited to soil, water or air, or
subparts thereof, to which the test, control, or reference substance is
administered or added for study. ``Test system'' also includes
appropriate groups or components of the system not treated with the
test, control, or reference substance.
Testing facility means a person who actually conducts a study,
i.e., actually uses the test substance in a test system. Testing
facility encompasses only those operational units that are being or
have been used to conduct studies.
TSCA means the Toxic Substances Control Act (15 U.S.C., 2601 et
seq.)
Vehicle means any agent which facilitates the mixture, dispersion,
or solubilization of a test substance with a carrier (e.g., water,
mineral oil, animal feed).
Sec. 806.10 Applicability to studies performed under grant and
contracts.
When a sponsor or other person utilizes the services of a
consulting laboratory, contractor, or grantee to perform all or a part
of a study to which this part applies, that sponsor or person shall
notify the consulting laboratory, contractor, or grantee, in writing,
that the service is, or is part of, a study that must be conducted in
compliance with the provisions of this part, prior to initiation of the
study.
Sec. 806.12 Statement of compliance or non-compliance.
Any person who submits to EPA either an application for a research
or marketing permit and who, in connection with the application,
submits data from a study to which this part applies, or a test
required by a test rule or testing consent agreement/order issued under
section 4 or 5 of TSCA, shall include in the application or submission
a true and correct statement, signed by the applicant, the sponsor, and
the study director, of one of the following types:
(a) A statement that the study was conducted in accordance with
this part.
(b) A statement describing in detail all differences between the
practices used in the study and those required by this part.
(c) A statement that the person was not a sponsor of the study,
did not conduct the study, and does not know whether the study was
conducted in accordance with this part.
Sec. 806.15 Inspection of a testing facility.
(a) Testing facility management shall permit an authorized
employee or duly designated representative of EPA or FDA, at reasonable
times and in a reasonable manner, to inspect the facility and to
inspect (and in the case of records also to copy) all records and
specimens required to be maintained regarding studies to which this
part applies. The records inspection and copying requirements shall not
apply to quality assurance unit records of findings and problems, or to
actions recommended and taken, except that EPA may seek production of
these records in litigation or formal adjudicatory hearings.
(b) EPA will not consider reliable for purposes of supporting an
application for a research or marketing permit, or showing that a
chemical substance or mixture does not present a risk of injury to
health or the environment, any data developed by a testing facility or
sponsor that refuses to permit inspection in accordance with this part.
The determination that a study will not be considered in support of an
application for a research or marketing permit or reliable for other
purposes does not, however, relieve the applicant for such a permit or
the sponsor of a required test of any obligation under any applicable
statute or regulation to submit the results of the study to EPA.
(c) Because a testing facility is a place where chemicals are
stored or held, it is subject to inspection under section 11 of TSCA.
Sec. 806.17 Effects of non-compliance.
(a)(1) EPA may refuse to consider reliable for purposes of
supporting an application for a research or marketing permit any data
from a study which was not conducted in accordance with this part.
(2) Submission of a statement required by Sec. 806.12 which is
false may form the basis for cancellation, suspension, or modification
of the
[[Page 72980]]
research or marketing permit, or denial or disapproval of an
application for such a permit, under FIFRA section 3, 4, 5, 6, 18, or
24 or FFDCA section 408 or 409, or for criminal prosecution under 18
U.S.C. 2 or 1001 or FIFRA section 14, or for imposition of civil
penalties under FIFRA section 14.
(b)(1) The sponsor or any other person who is conducting or has
conducted a test to fulfill the requirements of a test rule or testing
consent agreement/order issued under section 4 or 5 of TSCA will be in
violation of section 15 of TSCA if:
(i) The test is not being or was not conducted in accordance with
any requirement of this part;
(ii) Data or information submitted to EPA under this part include
information or data that are false or misleading, contain significant
omissions, or otherwise do not fulfill the requirements of this part;
or
(iii) Entry in accordance with Sec. 806.15 for the purpose of
auditing test data or inspecting test facilities is denied. Persons who
violate the provisions of this part may be subject to civil or criminal
penalties under section 16 of TSCA, legal action in United States
District Court under section 17 of TSCA, or criminal prosecution under
18 U.S.C. 2 or 1001.
(2) EPA, at its discretion, may not consider reliable for purposes
of showing that a chemical substance or mixture does not present a risk
of injury to health or the environment any study which was not
conducted in accordance with this part. EPA, at its discretion, may
rely upon such studies for purposes of showing adverse effects. The
determination that a study will not be considered reliable does not,
however, relieve the sponsor of a required test of the obligation under
any applicable statute or regulation to submit the results of the study
to EPA.
(3) If data submitted to fulfill a requirement of a test rule or
testing consent agreement/order issued under section 4 or 5 of TSCA are
not developed in accordance with this part, EPA may determine that the
sponsor has not fulfilled its obligations under section 4 or 5 of TSCA
and may require the sponsor to develop data in accordance with the
requirements of this part in order to satisfy such obligations.
Subpart B--Organization and Personnel
Sec. 806.29 Personnel.
(a) Each individual engaged in the conduct of or responsible for
the supervision of a study shall have the appropriate education,
training, and experience, or a combination thereof, to enable that
individual to perform the assigned functions.
(b) Each testing facility shall maintain a current summary of
training and experience and job description for each individual engaged
in or supervising the conduct of a study.
(c) There shall be a sufficient number of personnel for the timely
and proper conduct of the study according to the protocol.
(d) Personnel shall take necessary personal sanitation and health
precautions designed to avoid contamination of test systems and test,
control, and reference substances.
(e) Personnel engaged in a study shall wear clothing appropriate
for the duties they perform. Such clothing shall be changed as often as
necessary to prevent microbiological, radiological, or chemical
contamination of test systems and test, control, and reference
substances.
(f) Any individual found at any time to have an illness that may
adversely affect the quality and integrity of the study shall be
excluded from direct contact with test systems, test, control, and
reference substances, and any other operation or function that may
adversely affect the study until the health or medical condition is
corrected. All personnel shall be instructed to report to their
immediate supervisors any health or medical conditions that may
reasonably be considered to have an adverse effect on a study.
Sec. 806.31 Testing facility management.
For each study, testing facility management shall:
(a) Designate a study director as described in Sec. 806.33 before
the study is initiated.
(b) Replace the study director promptly if it becomes necessary to
do so during the conduct of a study.
(c) Assure that there is a quality assurance unit as described in
Sec. 806.35.
(d) Assure that test, control, and reference substances or mixtures
have been appropriately tested for identity, strength, purity,
stability, and uniformity, as applicable.
(e) Assure that personnel, resources, facilities, equipment,
materials and methodologies are available as scheduled.
(f) Assure that personnel clearly understand the functions they are
to perform.
(g) Assure that any deviations from these regulations reported by
the quality assurance unit are communicated to the study director and
corrective actions are taken and documented.
Sec. 806.33 Study director.
For each study, a scientist or other professional of appropriate
education, training, and experience, or combination thereof, shall be
identified as the study director. The study director has overall
responsibility for the technical conduct of the study, as well as for
the interpretation, analysis, documentation, and reporting of results,
and represents the single point of study control. The study director
shall assure that:
(a) The protocol, including any change, is approved as provided by
Sec. 806.120 and is followed.
(b) All experimental data, including observations of unanticipated
responses of the test system are accurately recorded and verified.
(c) Unforeseen circumstances that may affect the quality and
integrity of the study are noted when they occur, and corrective action
is taken and documented.
(d) Test systems are as specified in the protocol.
(e) All applicable GLPS regulations are followed.
(f) All raw data, documentation, protocols, specimens, and final
reports are transferred to the archives during or at the close or
termination of the study.
Sec. 806.35 Quality assurance unit.
(a) A testing facility shall have a quality assurance unit which
shall be responsible for monitoring each study to assure management
that the facilities, equipment, personnel, methods, practices, records,
and controls are in conformance with the regulations in this part. For
any given study, the quality assurance unit shall be entirely separate
from and independent of the personnel engaged in the direction and
conduct of that study. The quality assurance unit shall conduct
inspections and maintain records appropriate to the study.
(b) The quality assurance unit shall:
(l) Maintain a copy of a master schedule sheet of all studies
conducted at the testing facility indexed to permit expedient
retrieval, which identifies the test substance, the test system, nature
of study, date study was initiated, current status of each study, date
of completion or termination if study is not ongoing, identity of the
sponsor, and name of the study director.
(2) Maintain copies of all protocols until study completion
pertaining to all studies for which the unit is responsible.
(3) Inspect each study at intervals adequate to ensure the
integrity of the study and maintain written and properly signed records
of each periodic inspection showing the date of the
[[Page 72981]]
inspection, the study inspected, the phase or segment of the study
inspected, the person performing the inspection, findings and problems,
action recommended and taken to resolve existing problems, and any
scheduled date for reinspection. Any problems which are likely to
affect study integrity found during the course of an inspection shall
be brought to the attention of the study director and management
immediately.
(4) Periodically submit to management and the study director
written status reports on each study, noting any problems and the
corrective actions taken.
(5) Determine that no deviations from approved protocols or
standard operating procedures were made without proper authorization
and documentation.
(6) Review the final study report to assure that such report
accurately describes the methods and standard operating procedures, and
that the reported results accurately reflect the raw data of the study.
(7) Prepare and sign a statement to be included with the final
study report which shall specify the dates inspections were made and
findings reported to management and to the study director.
(c) The responsibilities and procedures applicable to the quality
assurance unit, the records maintained by the quality assurance unit,
and the method of indexing such records shall be in writing and shall
be maintained. These items including inspection dates, the study
inspected, the phase or segment of the study inspected, and the name of
the individual performing the inspection shall be made available for
inspection to authorized employees or duly designated representatives
of EPA or FDA.
(d) An authorized employee or a duly designated representative of
EPA or FDA shall have access to the written procedures established for
the inspection and may request testing facility management to certify
that inspections are being implemented, performed, documented, and
followed-up in accordance with this paragraph.
Subpart C--Facilities
Sec. 806.41 General.
Each testing facility shall be of suitable size and construction to
facilitate the proper conduct of studies. Testing facilities which are
not located within an indoor controlled environment shall be of
suitable location to facilitate the proper conduct of studies. Testing
facilities shall be designed so that there is a degree of separation
that will prevent any function or activity from having an adverse
effect on the study.
Sec. 806.43 Test system care facilities.
(a) A testing facility shall have a sufficient number of animal
rooms or other test system areas, as needed, to ensure: proper
separation of species or test systems, isolation of individual
projects, quarantine or isolation of animals or other test systems, and
routine or specialized housing of animals or other test systems.
(1) In tests with plants or aquatic animals, proper separation of
species can be accomplished within a room or area by housing them
separately in different chambers or aquaria. Separation of species is
unnecessary where the protocol specifies the simultaneous exposure of
two or more species in the same chamber, aquarium, or housing unit.
(2) Aquatic toxicity tests for individual projects shall be
isolated to the extent necessary to prevent cross-contamination of
different chemicals used in different tests.
(b) A testing facility shall have a number of animal rooms or other
test system areas separate from those described in paragraph (a) of
this section to ensure isolation of studies being done with test
systems or test, control, and reference substances known to be
biohazardous, including volatile substances, aerosols, radioactive
materials, and infectious agents.
(c) Separate areas shall be provided, as appropriate, for the
diagnosis, treatment, and control of laboratory test system diseases.
These areas shall provide effective isolation for the housing of test
systems either known or suspected of being diseased, or of being
carriers of disease, from other test systems.
(d) Facilities shall have proper provisions for collection and
disposal of contaminated water, soil, or other spent materials. When
animals are housed, facilities shall exist for the collection and
disposal of all animal waste and refuse or for safe sanitary storage of
waste before removal from the testing facility. Disposal facilities
shall be so provided and operated as to minimize vermin infestation,
odors, disease hazards, and environmental contamination.
(e) Facilities shall have provisions to regulate environmental
conditions (e.g., temperature, humidity, photoperiod) as specified in
the protocol.
(f) For marine test organisms, an adequate supply of clean sea
water or artificial sea water (prepared from deionized or distilled
water and sea salt mixture) shall be available. The ranges of
composition shall be as specified in the protocol.
(g) For freshwater organisms, an adequate supply of clean water of
the appropriate hardness, pH, and temperature, and which is free of
contaminants capable of interfering with the study, shall be available
as specified in the protocol.
(h) For plants, an adequate supply of soil of the appropriate
composition, as specified in the protocol, shall be available as
needed.
Sec. 806.45 Test system supply facilities.
(a) There shall be storage areas, as needed, for feed, nutrients,
soils, bedding, supplies, and equipment. Storage areas for feed
nutrients, soils, and bedding shall be separated from areas where the
test systems are located and shall be protected against infestation or
contamination. Perishable supplies shall be preserved by appropriate
means.
(b) When appropriate, plant supply facilities shall be provided. As
specified in the protocol, these include:
(1) Facilities for holding, culturing, and maintaining algae and
aquatic plants.
(2) Facilities for plant growth, including, but not limited to,
greenhouses, growth chambers, light banks, and fields.
(c) When appropriate, facilities for aquatic animal tests shall be
provided. These include, but are not limited to, aquaria, holding
tanks, ponds, and ancillary equipment, as specified in the protocol.
Sec. 806.47 Facilities for handling test, control, and reference
substances.
(a) As necessary to prevent contamination or mixups, there shall be
separate areas for:
(1) Receipt and storage of the test, control, and reference
substances.
(2) Mixing of the test, control, and reference substances with a
carrier, e.g., feed.
(3) Storage of the test, control, and reference substance mixtures.
(b) Storage areas for test, control, and/or reference substance and
for test, control, and/or reference mixtures shall be separate from
areas housing the test systems and shall be adequate to preserve the
identity, strength, purity, and stability of the substances and
mixtures.
Sec. 806.49 Laboratory operation areas.
Separate laboratory space and other space shall be provided, as
needed, for the performance of the routine and
[[Page 72982]]
specialized procedures required by studies.
Sec. 806.51 Specimen and data storage facilities.
Space shall be provided for archives, limited to access by
authorized personnel only, for the storage and retrieval of all raw
data and specimens from completed or terminated studies.
Subpart D--Equipment
Sec. 806.61 Equipment design.
Equipment used in the generation, measurement, or assessment of
data and equipment used for facility environmental control shall be of
appropriate design and adequate capacity to function according to the
protocol and shall be suitably located for operation, inspection,
cleaning, and maintenance.
Sec. 806.63 Maintenance and calibration of equipment.
(a) Equipment shall be adequately inspected, cleaned, and
maintained. Equipment used for the generation, measurement, or
assessment of data shall be adequately tested, calibrated, and/or
standardized.
(b) The written standard operating procedures required under
Sec. 806.81(b)(11) shall set forth in sufficient detail the methods,
materials, and schedules to be used in the routine inspection,
cleaning, maintenance, testing, calibration, and/or standardization of
equipment, and shall specify, when appropriate, remedial action to be
taken in the event of failure or malfunction of equipment. The written
standard operating procedures shall designate the person(s) responsible
for the performance of each operation.
(c) Written records shall be maintained of all inspection,
maintenance, testing, calibrating, and/or standardizing operations.
These records, containing the date of the operations, shall describe
whether the maintenance operations were routine and followed the
written standard operating procedures. Written records shall be kept of
nonroutine repairs performed on equipment as a result of failure and
malfunction. Such records shall document the nature of the defect, how
and when the defect was discovered, and any remedial action taken in
response to the defect.
(d) The integrity of data from computers, data processors, and
automated laboratory procedures involved in the collection, generation,
or measurement of data shall be ensured through appropriate validation
processes, maintenance procedures, disaster recovery, and security
measures.
Subpart E--Testing Facilities Operation
Sec. 806.81 Standard operating procedures.
(a) A testing facility shall have standard operating procedures in
writing setting forth study methods that management is satisfied are
adequate to ensure the quality and integrity of the data generated in
the course of a study. All deviations in a study from standard
operating procedures shall be authorized by the study director and
shall be documented in the raw data. Significant changes in established
standard operating procedures shall be properly authorized in writing
by management.
(b) Standard operating procedures shall be established for, but not
limited to, the following:
(1) Test system area preparation.
(2) Test system care.
(3) Receipt, identification, storage, handling, mixing, and method
of sampling of the test, control, and reference substances.
(4) Test system observations.
(5) Laboratory or other tests.
(6) Handling of test systems found moribund or dead during study.
(7) Necropsy of test systems or postmortem examination of test
systems.
(8) Collection and identification of specimens.
(9) Histopathology.
(10) Data handling, storage, and retrieval.
(11) Maintenance and calibration of equipment.
(12) Transfer, proper placement, and identification of test
systems.
(c) Each laboratory or other study area shall have immediately
available manuals and standard operating procedures relative to the
laboratory or field procedures being performed. Published literature
may be used as a supplement to standard operating procedures.
(d) A historical file of standard operating procedures, and all
revisions thereof, including the dates of such revisions, shall be
maintained.
Sec. 806.83 Reagents and solutions.
All reagents and solutions in the laboratory areas shall be labeled
to indicate identity, titer or concentration, storage requirements, and
expiration date. Deteriorated or outdated reagents and solutions shall
not be used. As an alternative to labeling wash bottles and transfer
bottles with the expiration date, the testing facility may develop a
well-documented performance standard to ensure that the reagents or
solutions have not deteriorated or are outdated.
Sec. 806.90 Animal and other test system care.
(a) There shall be standard operating procedures for the housing,
feeding, handling, and care of animals and other test systems.
(b) All newly received test systems from outside sources shall be
isolated and their health status or appropriateness for the study shall
be evaluated. This evaluation shall be in accordance with acceptable
veterinary medical practice or scientific methods.
(c) At the initiation of a study, test systems shall be free of any
disease or condition that might interfere with the purpose or conduct
of the study. If during the course of the study, the test systems
contract such a disease or condition, the diseased test systems should
be isolated, if necessary. These test systems may be treated for
disease or signs of disease provided that such treatment does not
interfere with the study. The diagnosis, authorization of treatment,
description of treatment, and each date of treatment shall be
documented and shall be retained.
(d) Warm-blooded animals, adult reptiles, and adult terrestrial
amphibians used in laboratory procedures that require manipulations and
observations over an extended period of time or in studies that require
these test systems to be removed from and returned to their test
system-housing units for any reason (e.g., cage cleaning, treatment,
etc.), shall receive appropriate identification (e.g., tattoo, color
code, ear tag, ear punch, etc.). All information needed to specifically
identify each test system within the test system-housing unit shall
appear on the outside of that unit. Suckling mammals and juvenile birds
are excluded from the requirement of individual identification unless
otherwise specified in the protocol.
(e) Except as specified in paragraph (e)(1) of this section, test
systems of different species shall be housed in separate rooms when
necessary. Test systems of the same species, but used in different
studies, should not ordinarily be housed in the same room when
inadvertent exposure to test, control, or reference substances or test
system mixup could affect the outcome of either study. If such mixed
housing is necessary, adequate differentiation by space and
identification shall be made.
(1) Plants, invertebrate animals, aquatic vertebrate animals, and
organisms that may be used in multispecies tests need not be housed in
[[Page 72983]]
separate rooms, provided that they are adequately segregated to avoid
mixup and cross contamination.
(2) [Reserved]
(f) Cages, racks, pens, enclosures, aquaria, holding tanks, ponds,
growth chambers, and other holding, rearing and breeding areas, and
accessory equipment, shall be cleaned and sanitized at appropriate
intervals.
(g) Feed, soil, and water used for the test systems shall be
analyzed periodically to ensure that contaminants known to be capable
of interfering with the study and reasonably expected to be present in
such feed, soil, or water are not present at levels above those
specified in the protocol. Documentation of such analyses shall be
maintained as raw data.
(h) Bedding used in animal cages or pens shall not interfere with
the purpose or conduct of the study and shall be changed as often as
necessary to keep the animals dry and clean.
(i) If any pest control or cleaning materials are used, the use
shall be documented. Cleaning and pest control materials that interfere
with the study shall not be used.
(j) All plant and animal test systems shall be acclimatized to the
environmental conditions of the test, prior to their use in a study.
Subpart F--Test, Control, and Reference Substances
Sec. 806.105 Test, control, and reference substance characterization.
(a) The identity, strength, purity, and composition, or other
characteristics which will appropriately define the test, control, or
reference substance shall be determined for each batch and shall be
documented before its use in a study. Methods of synthesis,
fabrication, or derivation of the test, control, or reference substance
shall be documented by the sponsor or the testing facility, and the
location of such documentation shall be specified.
(b) When relevant to the conduct of the study, the solubility of
each test, control, or reference substance shall be determined by the
testing facility or the sponsor before the experimental start date or
concurrently according to written standard operating procedures, which
provide for periodic analysis of each batch. The stability of the test,
control, or reference substance shall be determined before the
experimental start date or concurrently according to written standard
operating procedures, which provide for periodic analysis of each
batch.
(c) Each storage container for a test, control, or reference
substance shall be labeled by name, Chemical Abstracts Service (CAS)
registry number or code number, batch number, expiration date, if any,
and storage conditions necessary to maintain the identity, strength,
purity, and composition of the test, control, or reference substance.
Storage containers shall be assigned to a particular test substance for
the duration of the study. With the study director's written approval,
test substance storage containers need not be retained after use,
provided that full documentation of the disposition of the containers
is maintained as raw data for the study. This documentation shall
include:
(1)(i) Information of shipments pertaining to each container
leaving the storage site (examples of such records are shipping request
records, bills of lading, carrier bills, and monthly inventories of
warehouse activity).
(ii) Test substance receipt records at each testing facility.
(iii) Complete use logs of material taken from containers.
(iv) A record of the final destination of the container, including
the place and date of disposal or reclaiming, and any appropriate
receipts.
(2) An inventory record of empty containers before disposal,
including sufficient information to uniquely identify containers,
maintained in an up-to-date manner recording all arrivals of empty
containers and their disposal. This record shall be maintained as raw
data for this study.
(3) Locations of facilities; where test substance is stored; where
empty containers are stored prior to disposal; where records of use,
shipment, and disposal of containers are maintained; and where the test
substance is used in studies (i.e., testing facility).
(d) For studies of more than 4 weeks from the experimental start to
completion dates, reserve samples from each batch of test, control, and
reference substances shall be retained for the period of time provided
by Sec. 806.195.
(e) The stability of test, control, and reference substances under
storage conditions at the test site shall be known for all studies.
Sec. 806.107 Test, control, and reference substance handling.
Procedures shall be established for a system for the handling of
the test, control, and reference substances to ensure that:
(a) There is proper storage.
(b) Distribution is made in a manner designed to preclude the
possibility of contamination, deterioration, or damage.
(c) Proper identification is maintained throughout the distribution
process.
(d) The receipt and distribution of each batch is documented. Such
documentation shall include the date and quantity of each batch
distributed or returned.
Sec. 806.113 Mixtures of substances with carriers.
(a) For each test, control, or reference substance that is mixed
with a carrier, tests by appropriate analytical methods shall be
conducted:
(1) To determine the uniformity of the mixture and to determine,
periodically, the concentration of the test, control, or reference
substance in the mixture.
(2) When relevant to the conduct of the study, to determine the
solubility of each test, control, or reference substance in the
mixture; or if the solubility of the substance is difficult to
determine, appropriate homogeneity data, by the testing facility or the
sponsor before the experimental start date.
(3) To determine the stability of the test, control, or reference
substance in the mixture before the experimental start date or
concomitantly according to written standard operating procedures, which
provide for periodic analysis of each batch.
(b) Tank mixes prepared for application to soil or plants by
typical agricultural practices within a 12-hour period between
preparation and application, and solutions prepared for immediate
administration in mammalian acute toxicology studies, metabolism
studies, or mutagenicity studies, are exempt from requirements for
concentration determinations (but not from uniformity determinations)
under paragraph (a)(1) of this section and are exempt from requirements
for solubility determinations under paragraph (a)(2) of this section.
(c) Where any of the components of the test, control, or reference
substance carrier mixture has an expiration date, that date shall be
clearly shown on the container. If more than one component has an
expiration date, the earliest date shall be shown.
(d) If a vehicle is used to facilitate the mixing of a test
substance with a carrier, assurance shall be provided that the vehicle
does not interfere with the integrity of the test.
Subpart G--Protocol for and Conduct of a Study
Sec. 806.120 Protocol.
(a) Each study shall have an approved written protocol that clearly
indicates the objectives and all methods for the conduct of the study.
The protocol shall contain but shall not necessarily be limited to the
following information:
[[Page 72984]]
(1) A descriptive title and statement of the purpose of the study.
(2) Identification of the test, control, and reference substance by
name, Chemical Abstracts Service (CAS) registry number or code number.
When a reference substance for a metabolite cannot be identified prior
to the beginning of a study (only in the case of metabolism studies),
it is not necessary to identify the substance in the protocol. However,
a statement must be included that the identity of the reference
substance will be determined during the course of the study and
maintained as raw data.
(3) The name and address of the sponsor and the name and address of
the testing facility at which the study is being conducted.
(4) The proposed experimental start and termination dates.
(5) Justification for selection of the test system.
(6) Where applicable, the number, body weight range, sex, source of
supply, species, strain, substrain, and age of the test system.
(7) The procedure for identification of the test system.
(8) A description of the experimental design, including methods for
the control of bias.
(9) Where applicable, a description and/or identification of the
diet used in the study as well as solvents, emulsifiers and/or other
materials used to solubilize or suspend the test, control, or reference
substances before mixing with the carrier. The description shall
include specifications for acceptable levels of contaminants that are
reasonably expected to be present in the dietary materials and are
known to be capable of interfering with the purpose or conduct of the
study if present at levels greater than established by the
specifications.
(10) The route of administration and the reason for its choice.
(11) Each dosage level, expressed in milligrams per kilogram of
body or test system weight or other appropriate units, of the test,
control, or reference substance to be administered and the method and
frequency of administration.
(12) The type and frequency of tests, analyses, and measurements to
be made.
(13) The records to be maintained.
(14) The date of approval of the protocol by the sponsor and the
dated signature of the study director.
(15) A statement of the statistical method to be used.
(b) All changes in or revisions of an approved protocol and the
reasons therefore shall be documented, signed by the study director,
dated, and maintained with the protocol.
(c) Discontinued studies or studies otherwise terminated before
completion shall be finalized by writing a protocol amendment providing
the reason(s) for termination. All documentation for terminated studies
including the protocol, protocol amendment(s), and raw data, if
collected, shall be retained as provided at Sec. 806.195.
Sec. 806.130 Conduct of a study.
(a) The study shall be conducted in accordance with the protocol.
(b) The test systems shall be monitored in conformity with the
protocol.
(c) Specimens shall be identified by test system, study, nature,
and date of collection. This information shall be located on the
specimen container or shall accompany the specimen in a manner that
precludes error in the recording and storage of data.
(d) In animal studies where histopathology is required, records of
gross findings for a specimen from postmortem observations shall be
available to a pathologist when examining that specimen
histopathologically.
(e) All data generated during the conduct of a study, except those
that are generated by automated data collection systems, shall be
recorded directly, promptly, and legibly in ink. All data entries shall
be dated on the day of entry and signed or initialed by the person
entering the data. Any change in entries shall be made so as not to
obscure the original entry, shall indicate the reason for such change,
and shall be dated and signed or identified at the time of the change.
In automated data collection systems, the individual responsible for
direct data input shall be identified at the time of data input. Any
change in automated data entries shall be made so as not to obscure the
original entry, shall indicate the reason for change, shall be dated,
and the responsible individual shall be identified.
Sec. 806.135 Physical and chemical characterization studies.
(a) All provisions of the GLPS shall apply to physical and chemical
characterization studies designed to determine stability, solubility,
octanol water partition coefficient, volatility, and persistence (such
as biodegradation, photodegradation, and chemical degradation studies)
of test, control, or reference substances.
(b) The following GLPS shall not apply to studies, other than those
designated in paragraph (a) of this section, designed to determine
physical and chemical characteristics of a test, control, or reference
substance: Secs. 806.31(c), (d), and (g), 806.35(b) and (c), 806.43,
806.45, 806.47, 806.49, 806.81(b)(1), (2), (6) through (9), and (12),
806.90, 806.105(a) through (d), 806.113, 806.120(a)(5) through (12),
and (15), 806.185(a)(5) through (8), (10), (12), and (14), and
806.195(c) and (d).
Subparts H and I--[Reserved]
Subpart J--Records and Reports
Sec. 806.185 Reporting of study results.
(a) With the exception of discontinued or otherwise terminated
studies, as provided at Sec. 806.120(c), a final report shall be
prepared for each study and shall include, but not necessarily be
limited to, the following:
(1) Name and address of the facility performing the study and the
dates on which the study was initiated and was completed.
(2) Objectives and procedures stated in the approved protocol,
including any changes in the original protocol.
(3) Statistical methods employed for analyzing the data.
(4) The test, control, and reference substances identified by name,
Chemical Abstracts Service (CAS) registry number or code number,
strength, purity, and composition, or other appropriate
characteristics.
(5) Stability and, when relevant to the conduct of the study,
solubility of the test, control, and reference substances under the
conditions of administration.
(6) A description of the methods used.
(7) A description of the test system used. Where applicable, the
final report shall include the number of animals used, sex, body weight
range, source of supply, species, strain and substrain, age, and
procedure used for identification. For other test organisms (plants,
bacteria), similarly detailed descriptions of the test system are
required.
(8) A description of the dosage, dosage regimen, route of
administration, and duration.
(9) A description of all circumstances that may have affected the
quality or integrity of the data.
(10) The name of the study director, the names of other scientists
or professionals, and the names of all supervisory personnel, involved
in the study.
(11) A description of the transformations, calculations, or
operations performed on the data, a summary and analysis of the data,
and a statement of the conclusions drawn from the analysis.
[[Page 72985]]
(12) The signed and dated reports of each of the individual
scientists or other professionals involved in the study, including each
person who, at the request or direction of the testing facility or
sponsor, conducted an analysis or evaluation of data or specimens from
the study after data generation was completed.
(13) The locations where all specimens, raw data, and the final
report are to be stored.
(14) The statement prepared and signed by the quality assurance
unit as described in Sec. 806.35(b)(7).
(b) The final report shall be signed and dated by the study
director.
(c) Corrections or additions to a final report shall be in the form
of an amendment by the study director. The amendment shall clearly
identify that part of the final report that is being added to or
corrected and the reasons for the correction or addition, and shall be
signed and dated by the person responsible. Modification of a final
report to comply with the submission requirements of EPA does not
constitute a correction, addition, or amendment to a final report.
(d) A copy of the final report and of any amendment to it shall be
maintained by the sponsor and the test facility.
Sec. 806.190 Storage and retrieval of records and data.
(a) All raw data, documentation, records, protocols, specimens, and
final reports generated as a result of a study shall be retained.
Specimens obtained from mutagenicity tests, specimens of soil, water,
and plants, and wet specimens of blood, urine, feces, and biological
fluids, do not need to be retained after quality assurance
verification. Correspondence and other documents relating to
interpretation and evaluation of data, other than those documents
contained in the final report, also shall be retained.
(b) There shall be archives for orderly storage and expedient
retrieval of all raw data, documentation, protocols, specimens, and
interim and final reports. Conditions of storage shall minimize
deterioration of the documents or specimens in accordance with the
requirements for the time period of their retention and the nature of
the documents of specimens. A testing facility may contract with
commercial archives to provide a repository for all material to be
retained. Raw data and specimens may be retained elsewhere provided
that the archives have specific reference to those other locations.
(c) An individual shall be identified as responsible for the
archives.
(d) Only authorized personnel shall enter the archives.
(e) Material retained or referred to in the archives shall be
indexed to permit expedient retrieval.
Sec. 806.195 Retention of records.
(a) Record retention requirements set forth in this section do not
supersede the record retention requirements of any other regulations in
this subchapter.
(b) Except as provided in paragraph (c) of this section,
documentation records, raw data, and specimens pertaining to a study
and required to be retained by this part shall be retained in the
archive(s) for:
(1) In the case of applicability under Sec. 806.1(a), whichever of
the following periods is longest:
(i) In the case of any study used to support an application for a
research or marketing permit approved by EPA, the period during which
the sponsor or any successor(s) hold(s) any research or marketing
permit to which the study is pertinent.
(ii) A period of at least 5 years following the date on which the
results of the study are submitted to EPA in support of an application
for a research or marketing permit.
(iii) In other situations (e.g., where the study does not result in
the submission of the study in support of an application for a research
or marketing permit), a period of at least 2 years following the date
on which the study is completed, terminated, or discontinued.
(2) In the case of applicability under Sec. 806.1(b):
(i) In the case of a study required to be conducted under TSCA
section 4 or section 5, except for those items listed in paragraph (c)
of this section, all documentation, records, raw data, and specimens
pertaining to that study and required to be retained by this part shall
be retained in the archive(s) for a period of at least 5 years
following the date on which the final report of that required study is
submitted to EPA.
(ii) [Reserved]
(c) Wet specimens, samples of test, control, or reference
substances, and specially prepared material which are relatively
fragile and differ markedly in stability and quality during storage,
shall be retained only as long as the quality of the preparation
affords evaluation. Specimens obtained from mutagenicity tests,
specimens of soil, water, and plants, and wet specimens of blood,
urine, feces, and biological fluids, do not need to be retained after
quality assurance verification. In no case shall retention be required
for longer periods than those set forth in paragraph (b) of this
section.
(d) The master schedule sheet, copies of protocols, and records of
quality assurance inspections, as required by Sec. 806.35(c) shall be
maintained by the quality assurance unit as an easily accessible system
of records for the period of time specified in paragraph (b) of this
section.
(e) Summaries of training and experience and job descriptions
required to be maintained by Sec. 806.29(b) may be retained along with
all other testing facility employment records for the length of time
specified in paragraph (b) of this section.
(f) Records and reports of the maintenance and calibration and
inspection of equipment, as required by Sec. 806.63(b) and (c), shall
be retained for the length of time specified in paragraph (b) of this
section.
(g) If a facility conducting testing or an archive contracting
facility goes out of business, all raw data, documentation, and other
material specified in this section shall be transferred to the archives
of the sponsor of the study. EPA shall be notified in writing of such a
transfer.
(h) Specimens, samples, or other non-documentary materials need not
be retained after EPA has notified in writing the sponsor or testing
facility holding the materials that retention is no longer required by
EPA. Such notification normally will be furnished upon request after
EPA or FDA has completed an audit of the particular study to which the
materials relate and EPA has concluded that the study was conducted in
accordance with this part.
(i) Records required by this part may be retained either as
original records or as true copies such as photocopies, microfilm,
microfiche, or other accurate reproductions of the original records.
[FR Doc. 99-33831 Filed 12-28-99; 8:45 am]
BILLING CODE 6560-50-F