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U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF INFORMATION RESOURCES MANAGEMENT
RESEARCH TRIANGLE PARK, NORTH CAROLINA 27711
DRAFT
AUTOMATED LABORATORY STANDARDS:
EVALUATION OF GOOD LABORATORY
PRACTICES
FOR EPA PROGRAMS
CONTRACT 68-W9-0037, DELIVERY ORDER 035
JUNE 1990

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Automated Laboratory Standards:
Evaluation of Good Laboratory Practices
for EPA Programs
DRAFT
Prepared for.
Office of Information Resources Management
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina 27711
June 6,1990
Prepared by:
Booz* Allen & Hamilton Inc.
4330 East-West Highway
Bethesda, Maryland 20814
(301) 951-2200
Contract No. 68-W9-0037
Computer Sciences Corporation
79 T.W. Alexander Drive
Research Triangle Park, North Carolina 27709
(919) 541-9287
Contract No. 68-01-7365

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Table of Contents
Executive Summary	iii
Background	1
Findings	7
Scope and Definitions	7
Applicability to Automated Systems	8
Specific Requirements for Automated Systems	18
Conclusions	23
Glossary
References
Appendix A: Good Laboratory Practices for TSCA and FIFRA

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Executive Summary
The U.S. Environmental Protection Agency (EPA) has initiated a program to
ensure the integrity of computer-resident data in laboratories performing analyses
in support of EPA programs. The possession of sound technical data provides a
fundamental resource for EPA's mission to protect the public health and
environment.
This report describes the findings of a review of existing Good Laboratory
Practices (GLPs) first promulgated by the U.S. Food and Drug Administration and
subsequently by EPA, as well as the impact of those standards on automated
laboratory practices. EPA's GLPs are regulations that describe acceptable laboratory
management practices to ensure the quality and integrity of health, environmental,
and chemical data submitted to the Agency through requirements of the Toxic
Substances Control Act (TSCA) and the Federal Insecticide, Fungicide, and
Rodenticide Act (FIFRA). Other EPA programs can adopt and have adopted these
requirements by administrative decision.
The GLPs set forth procedures to govern general laboratory practices and
include specific requirements for ensuring the integrity of data collected. When an
automated system is used to collect or process data, all GLP requirements that apply
to manual laboratory operations also apply to automated laboratory operations.
These include documentation of personnel qualifications and establishment of a
separate quality assurance group. The GLPs include additional requirements for
facilities, maintenance of equipment, description of testing facility operations
(including availability of written standard operating procedures), and specifications
for storage and retrieval of records.
This report discusses the application of GLP requirements to automated
laboratory operations. A future report will provide guidance for the
implementation of these requirements.
Compliance with GLPs in an automated laboratory can be achieved through
practices that include the following:
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•	Identifying a person responsible for the operation of the automated
data collection system
•	Establishing an independent quality assurance unit to oversee
automated data operations
•	Developing standard operating procedures (SOPs) for automated data
processes to be followed by all users
•	Developing a policy regarding computer-resident data as "raw data,"
subject to program-specific retention requirements.
Standards developed to protect computer-resident data integrity must comply with
the GLP regulation. These standards include the following:
•	A security program that restricts both system access and functionality
(e.g., data input, data changes, data processing) to authorized personnel
•	A documentation program (audit trail) that catalogs all original and
altered data, identifies those individuals responsible for data changes,
and records the date and reasons for any data changes
•	A validation program to ensure data integrity, especially during data
entry or transmission, when data are most vulnerable to errors.
The GLP requirements provide a clear directive to protect the integrity of
computer-resident data. This report clarifies the GLP requirements itemized above
regarding automated operations in laboratories and provides a management
framework for either implementing these requirements or strengthening them, as
needed.
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Background
The U.S. Environmental Protection Agency (EPA) has initiated a program to
ensure the integrity of computer-resident data in laboratories performing analyses
in support of EPA programs by developing standards for automated laboratory
processes. The possession of sound technical data provides a fundamental resource
for EPA's mission to protect the public health and environment, implemented
through several environmental programs. The activities of these environmental
programs are diverse, and include basic research at EPA's environmental research
centers, environmental sample analyses at EPA's regional laboratories and
contractors' laboratories, and product registration relying on analytical data
submitted by the private sector.
EPA recognizes that the implementation of an automated laboratory
standards program will require each laboratory to allocate resources of dollars and
time for the program's execution. Although this program may be considered too
expensive by some, laboratory managers must consider that in developing and
using a proper standards program, they will achieve a net savings as information
processes do not have to be repeated and expensive mistakes can be avoided.
Within EPA, the Office of Information Resources Management (OIRM) has
assumed the objective of establishing an automated laboratory standards program.
The need for this program is evidenced by several factors. Exhibit 1 illustrates these
factors, which include the rising use of computerized operations by laboratories, the
lack of uniform standards developed or accepted by EPA, evidence of problems
associated with computer-resident data, and the evolving needs of EPA auditors and
inspectors for guidance in evaluating automated laboratory operations.
Laboratories collecting data for EPA's programs have taken advantage of
increasing technology to streamline the analytical processes. Initially, automated
instrumentation entered the laboratories to increase productivity and enhance the
accuracy of reported results. Then, computers maintaining data bases of results were
used for data management and tracking. These computer systems were integrated
into more sophisticated laboratory information management systems (LIMS).
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EXHIBIT 1
Need for EPA's Automated Laboratory Standards Program
|	STANDARDS PROGRAM
MFl
ro
t
~ Rising Use of Computer Operations by Laboratories
~ Lack of Standards Accepted by EPA
~ Problems with Computer-Resident Data
~ Need of EPA Auditors for Guidance in Evaluating
Automation in Laboratory Operations

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Methods for data reporting include electronic mail, electronic bulletin boards, and
direct links between central processing units. Each of these advances necessitates
thorough quality control procedures for data generation, storage, and retrieval to
ensure the integrity of computer-resident data.
Currently, EPA has no Agency-wide principles that laboratories collecting and
evaluating computer-resident data must follow. The requirements that must be
considered in developing automated laboratory standards come from a variety of
sources, as Exhibit 2 illustrates, including the requirements of the Computer
Security Act of 1987 (P.L. 100-235, January 8, 1988) and various EPA program-specific
data collection requirements under Superfund, the Resource Conservation and
Recovery Act, the Clean Water Act, and the Safe Drinking Water Act, among others.
Additionally, OIRM has developed electronic transmission standards and is
developing a strategy for electronic record keeping that will impact on all Agency
activities. The development of uniform principles for automated data in EPA
laboratories, regardless of program, will take into account the common elements of
all these data collection activities, and provide a minimum standard that each
laboratory should achieve.
There is increasing evidence of problems associated with the collection and
use of computer-resident laboratory data supporting various EPA programs. To
illustrate, as of November 1989, EPA's Office of the Inspector General was
investigating between 10 and 12 laboratories in Superfund's Contract Laboratory
Program (CLP) for a variety of allegations, including "time traveling" and
instrument calibration violations. In "time traveling," sample testing dates are
manipulated, by either adjusting the internal clock of the instrumentation
performing the analyses or manipulating the resultant computer-resident data.
(Hazardous waste samples must be assayed within a prescribed time period or the
results may be compromised.) Additionally, calibration standard results have
allegedly been electronically manipulated and other calibration results substituted
when the actual results did not meet the range specifications of the CLP procedure
being followed. If proven, these allegations may be treated as felonies.
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EXHIBIT 2
Considerations in Developing Automated Laboratory Standards
IE5I©yOIEilffiiOIMT
Computer Security
Act of 1987
Others
Statutory
Requirements for
Environmental
Programs:
National Archives
and Records
Administration's
Electronic Records
Management
Regulations
Superfund
Resource
Conservation
and Recovery Act
Clean Water Act
Safe Drinking
Water Act
Others
EPA IRM Policy:
EPA System Design
and Development
Guidance
EPA's Operations and
Maintenance Manual
EPA Information
Security Manual
EPA's Data Standards
for Electronic
Transmission of
Laboratory
Measurement Results
Findings of EPA's
Electronic Reporting
Standards Work
Group
EPA's
Good Laboratory
Practice
Regulations

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Because the introduction of automation is relatively new and still evolving,
no definitive guidelines for EPA auditors and inspectors have been developed.
Inspectors must be alert to the steps in those procedures used by laboratories
generating and using computer-resident data where the greatest risk exist. These
critical process points indicate the magnitude of control that should be placed on
each portion of the process. If adequate controls are not present, the remainder of
the process cannot correct a deviation, and the entire process will provide no
reliable conclusions. Automation introduces many new variables into a system,
each with its own set of critical process points. Inspectors must verify that laboratory
management has recognized the various risks and has instituted an appropriate risk
management program.
As part of the EPA's program to ensure the integrity of computer-resident
data, EPA's Good Laboratory Practice regulations (GLPs) were reviewed to determine
their applicability to automated laboratories. This document describes the findings
of that review and is one of a series of background assessments prepared for the
Agency's program to develop standards for automated laboratories. These draft
reports in the series present a review of automated data standards and practices in
financial systems (OIRM, 1989a), a review of currently available automated
technology (OIRM, 1989b), and the results of a survey and on-site visits conducted to
determine procedures and practices used in automated laboratories (OIRM, 1989c).
The GLP regulations were promulgated by the U.S. Food and Drug
Administration (FDA) in 1979 as a result of the discovery of fraud and
misrepresentation in the food additive and pharmaceutical testing industry. EPA
issued almost identical regulations in 1983 to cover required health and safety
(animal toxicity) testing of agricultural and industrial chemicals under the Federal
Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Toxic Substances
Control Act (TSCA), respectively. The GLPs were promulgated in response to
problems encountered with the reliability of submitted studies. Some of the studies
were so poorly conducted that "the resulting data could not be relied upon in EPA's
regulatory decision-making process" [EPA (TSCA GLPs), 1983; p. 53923]. The EPA
regulations were extensively amended in 1989 and now cover essentially all testing
required to be submitted to EPA under either Act [EPA (FIFRA GLPs), 1989a; EPA
(TSCA GLPs), 1989b].
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It is important to remember that these regulations were issued to ensure good
management practices in the conduct of health and safety testing in laboratory
animals and at a time when most data were collected and analyzed manually. Both
FDA and EPA recognized that automated data collection would become more
common, and accordingly, included in the amended GLP regulations language
specific to automated data collection to make certain that industry clearly recognized
that collection of data by any means would be controlled by one set of standards.
The GLPs were issued to ensure that reliable data were generated and
available for Agency decision-making processes of two specific programs. However,
the possession of sound data is an equally important consideration for Agency
decision makers in all programs that protect the public health and environment.
EPA programs outside industrial chemicals or pesticides have already adopted the
GLP regulations for certain applications. For example, the Office of Solid Waste
included the GLPs in contract terms for reproductive toxicology studies supporting
information-collection activities of the Characterization and Assessment Division,
beginning in 1985. The studies involved nickel in drinking water, and were
conducted under several prime contracts. Because of the fundamental reason for
the GLP's existence (i.e., the provision of adequate management controls to permit
the conduct and reporting of good science), it is anticipated that the regulations will
become more widely used.
The TSCA and FIFRA GLPs are both found in title 40 of the Code of Federal
Regulations. They follow a similar format and, with few exceptions, have the same
wording. The citations made in this report are generally identical in each of these
publications and are, therefore, given a single reference. The section references are
given as 792.xx in the TSCA GLPs. Parallel regulations would be found in the
FIFRA GLPs as 160.xx. For example, rules governing personnel are found under
792.29 and 160.29 in the TSCA and FIFRA GLPs, respectively. The references are
provided in this report only in the TSCA format for convenience. In those cases
where the TSCA and FIFRA regulations differ, the specific citation is provided. For
reference, EPA's GLPs are included in Appendix A.
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Findings
SCOPE AND DEFINITIONS
The scope of the TSCA [Sections 4(a) and 5] GLPs is as follows:
This part [regulation] prescribes good laboratory practices for conducting
studies relating to health effects, environmental effects, and chemical fate
testing. [792.1(a)]
The FIFRA GLPs apply to all data submitted for "studies that support or are intended
to support applications for research or marketing permits for pesticide products by
the EPA" [160.1(a)]. FIFRA GLP standards also include efficacy testing of
antimicrobials or vertebrate control agents that claim to control threats to human
health, as currently required to be submitted by 40 CFR 158.640, which lists the
product performance data requirements for all regulated pesticide products (160.3).
Both GLPs further define this scope by the following definitions:
•	"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,
environmental and chemical fate, persistence, or other characteristics
in human organisms, other living organisms, or media." (792.3)
•	"Test substance means a substance or mixture administered or added to
a test system in a study." (792.3)
•	"Test system means any animal, plant, microorganism, chemical or
physical matrix, including, but not limited to, soil or water, or
components thereof, to which a test, control, or reference substance is
administered or added for study." (792.3)
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The remainder of the Findings section will describe how the GLP regulations
are applicable to automated systems and will highlight some specific requirements
and considerations in the implementation of GLPs to automated systems.
APPLICABILITY TO AUTOMATED SYSTEMS
The GLPs requirements apply equally to manual and automated data systems.
These regulations dictate several criteria, including requiring that systems be
designed to identify users entering and/or modifying data, providing for
documentation (audit trail) of data transactions, and protecting the quality and
integrity of data generated using either manual or automated laboratory operations
to capture and process data. The GLP regulations describe several components of an
operating environment that can contribute to meeting the requirements of the
GLPs. These include personnel (including quality assurance), facilities, equipment
and maintenance, testing facility operations (including standard operating
procedures), and storage and retrieval of data. Minimum standards must be met in
each of these five areas and apply to laboratory operations, whether the operations
are manual or automated. The remainder of the discussion in this section presents
the GLP requirements in order of their presentation in the regulations themselves.
Subpart A of the GLPs lists general provisions, such as the scope and
definitions for the regulations, and will not be discussed in further detail in this
report.
Subpart B - Organization and Personnel
Personnel
GLPs require the following for all technical personnel:
• "Each individual engaged in the conduct of or responsible for the
supervision of a study shall have education, training, and experience,
or combination thereof, to enable that individual to perform the
assigned functions." [792.29(a)]
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•	"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." [792.29(b)]
•	"There shall be sufficient number of personnel for timely and proper
conduct of the study according to the protocol." [792.29(c)]
If the laboratory uses an automated system in the conduct of a study, these concepts
extend to staff involved in the design or operation of that automated system. If
there are no staff members with formal training in systems, the laboratory should be
prepared to support the qualifications of staff members designated as systems
personnel as adequate to perform system functions,
Quality Assurance
The GLPs require the following:
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 of this part. For any given study, the
quality assurance unit shall be entirely separate from and independent of
personnel engaged in the direction and conduct of the study. [792.35(a)]
This concept requires that the activities of the laboratory's quality assurance unit
(QAU) include oversight for the manual as well as automated laboratory equipment
and procedures. This does not require that the QAU staff become expert in
computer operations, but rather that they have sufficient competence to inspect and
audit the system procedures and practices to evaluate their compliance to GLPs. The
QAU might seek expert assistance from an independent source to assist the QAU in
carrying out its responsibilities.
The GLPs further require that the QAU shall:
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•	"Inspect each study at intervals adequate to ensure the integrity of the
study and maintain written and properly signed records of each
periodic inspection ..[792.35(b)(3)]
•	"Determine that no deviations from approved protocols or standard
operating procedures were made without proper authorization and
documentation." [792.35(b)(5)]
In automated laboratories, the QAU's GLP responsibilities must include periodic
inspections of the automated laboratory operations and proper documentation of
these inspections. The QAU will also have oversight responsibilities to ensure that
no deviations are made from the written procedures for design and use of the
automated system without prior written authorization. This would also extend to
the written operative instruction (software) for the automated systems.
Subpart C - Facilities
The GLPs require the following:
•	"Facilities shall have provisions to regulate environmental
conditions ..." [792.43(e)]
•	"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 studies." (792.51)
These statements indicate that automated laboratory equipment shall be placed in a
facility that will provide for protection of the experimental or testing equipment,
including automated laboratory equipment. Vendors' specifications for
temperature and humidity must be followed in designing the location of automated
equipment. Additionally, sufficient storage capacity of the automated equipment or
of the facility itself shall be planned to provide retention of all data, including
computer-resident data.
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Subpart D - Equipment
The GLPs require the following:
•	"Equipment used in the generation, measurement, or assessment of
data .. . shall be of appropriate design and adequate capacity to function
according to protocol and shall be suitably located for operation,
inspection, cleaning, and maintenance." (792.61)
•	"... Equipment used for the generation, measurement, or assessment
of data shall be adequately tested, calibrated, and/or standardized."
[792.63(a)]
•	"The written standard operating procedures . . . shall set forth in
sufficient detail the methods, materials, and schedules to be used for
routine inspection, cleaning, maintenance, testing, calibration, and/or
standardization of equipment. . ." [792.63(b)]
•	"Written records shall be maintained of all inspection, maintenance,
testing, calibrating, and/or standardizing operations ..." [792.63(c)]
These concepts extend to the computer system hardware because it is a piece of
laboratory equipment. The system must be of adequate capacity to perform its
functions. Procedures for performing maintenance must be established, and records
must be kept to document this maintenance.
Subpart E - Testing Facilities Operation
Standard Operating Procedures
Most laboratories conducting analytical testing are familiar with writing
standard operating procedures (SOPs) for scientific operations to provide a reference
to ensure consistency. GLPs require that a facility shall have the following:
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•	"... [Standard operating procedures in writing, setting forth study
methods that management is satisfied are adequate to insure the
quality and integrity of the data generated in the course of a study
[792.81(a)]
•	Established SOPs for "[d]ata handling, storage, and retrieval"
[792.81(b)(10)]
•	Established SOPs for "[m]aintenance and calibration of equipment"
[792.81 (b)(ll)]
•	"A historical file of standard operating procedures, and all revisions
thereof, including the dates of such revisions . . [792.81(d)]
The concept of having written SOPs available extends to include tasks aided
or conducted by computer systems or to data handled by the computer. Computer
software is considered a set of operating instructions for the automated system and
is subject, therefore, to GLP requirements. SOPs must include written instructions
for computer systems to ensure uniform programming standards, control
procedures, and to describe specific operational procedures. At a minimum, written
SOPs must be available in the following areas:
•	Specifications for and use of laboratory hardware and software.
•	How to use software that is an integral part of a laboratory operation.
For example, when an automated system is used to log-in samples or to
capture, process, track, or report data, the laboratory SOPs must include
written instructions for operation of the automated system.
•	How software applications are to be developed. This would include
coding standards, documentation requirements, requirements for
validation, and acceptance testing.
•	How software change is to be controlled. This includes specific
mechanisms to request, authorize, implement, and approve a change
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to the software and to determine the version of software used to
generate any given data set.
How back-up will be implemented. This includes procedures for
backing up the system to protect against data loss during system failure,
system start-up and recovery, maintenance, and record keeping.
How often software validation is to be accomplished and what data sets
will be used for validation.
How new/revised software is tested against existing algorithms, data,
and data recovery prior to acceptance.
Physical security of hardware and software as well as security
procedures for access to computer-resident data.
Subpart J - Records and Reports
Raw Data
GLP regulations define raw data in the following way:
. . . [A]ny 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 that study. . . "Raw
data" may include photographs, microfilm or microfiche copies, computer
printouts, magnetic media, . . . and recorded data from automated
instruments. (792.3)
Raw data can be further interpreted as those data, necessary for the evaluation and
reconstruction of a study, that cannot be easily derived or recalculated from other
available information. Data that are captured through automated data acquisition
or direct keyboard entry are raw data.
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The GLPs define how raw data are to be handled, stored, and retrieved. In
order to determine the applicability of these requirements to computer-resident
data, it must be determined what constitutes raw data in an automated laboratory
system. In a solely manual operation, the laboratory notebook contained the first
written observations of study findings. With the introduction of automation,
simultaneous recording of data is possible in the form of strip charts, computer-
resident data bases, printouts or reports, on-line storage, off-line storage, etc. If a
report (appropriately signed and dated) is to be considered raw data, it should be the
first printed report. Subsequent printouts are not raw data.
Within the confines of the general requirements for raw data (e.g., the first
record of an observation), each laboratory must develop a policy that will designate
what constitutes raw data in its operation. The definition should be clearly
delineated and specified in the laboratory's SOPs. In many instances, "raw data" is
defined by example.
Additional attempts have been made to define raw data (Taylor, 1984, or
Mattes, 1987). The definitions given below were presented by those authors for
discussion and interpretation and are presented here to provide guidance to
laboratories attempting to define raw data for their individual operations.
•	If data are recorded to a written record and then entered into the
system, the written record is considered raw data.
•	When data are input directly (from instrumentation or manually) to a
computer data base, the data base is considered raw data.
•	If data are generated by equipment that produces a report with
• integrated or calculated values, the report is considered raw data.
•	If data are generated by equipment and integrated or calculated values
are input directly into a computer data base, the data base is considered
raw data.
•	If data are entered directly into a computer, and the computer rejects
the input as incomplete or erroneous, and the operator corrects the
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input data and then applies it to a data base, the data base is considered
raw data. Any further changes to the data base must be documented
according to GLPs.
For example, an automated system may use input data to perform complicated
statistical analyses. It would not be necessary to store the results of such
manipulations as raw data as they could easily be recalculated by the system. It is
imperative, however, that the system maintain records of the algorithms used to
calculate given data sets in order for such recalculations to be possible. Further, as
algorithms are changed over time (e.g., with new software versions), a record must
be maintained to indicate which software version was used to calculate each data set.
The interpretation of "raw data" in automated systems has led to the
development of examples or definitions that are subject to question. To illustrate,
both Taylor (1984) and Mattes (1987) provide the following as one example:
Where the observations are recorded by a chart recorder and integrated or
calculated values are produced on a printout, either the chart or the printout
can be raw data, but not both. The decision as to which becomes raw data is
left to the laboratory management and should be documented before any
inspection. (Mattes, 1987, p. 336)
However, since the printout produced in this example contains calculated values, it
should not be considered raw data. We disagree with Taylor and Mattes by asserting
that in this example, only the chart containing original observations shall be
considered "raw data," because reintegration can be accomplished from the
information contained on the chart directly.
Storage and Retrieval of Records and Data
The GLPs require the following:
• "All raw data, documentation, records, protocols, and final reports
generated as a result of a study shall be retained.. . " [792.190(a)]
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•	"... Conditions of storage shall minimize deterioration of the
documents ..[792.190(b)]
•	"An individual shall be identified as responsible for the archives."
[792.190(c)]
•	"Only authorized personnel shall enter the archives." [792.190(d)]
•	"Material retained or referred to in the archives shall be indexed to
permit expedient retrieval." [792.190(e)]
These concepts extend to all computer-resident raw data. The data from
automated laboratory systems must be archived in accordance with these
requirements:
•	The environment of the archives should be such as to minimize
deterioration of magnetic media. [It is recommended that the National
Archives and Records Administration (NARA) regulations on
electronic records management, recently published at 36 CFR Part 1234,
be followed in establishing environmental conditions for maintenance
of electronic media (NARA, 1990).]
•	The facility must develop SOPs on how often the media should be
backed up.
•	An individual must be designated (in writing) as responsible for the
archives.
•	Only authorized personnel may enter the archives.
•	Archived computer records must be indexed so that they can be
efficiently retrieved.
•	An inventory system must be developed to permit tracking and
recovery of materials removed from the archives.
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In practice, the maintenance of the archives of paper records and specimens is often
a responsibility of the QAU. This is not a requirement, but may also be practical for
the archiving of computer-generated information.
Retention of Records
The GLPs require that all:
. . . [Documentation [,] records [and] raw data . . . shall be retained in the
archive(s) for specified periods [792.195(b)(1)].
The periods for retention of records differ under TSCA and FIFRA by program and
by record type and will not be provided here. The requirements for retention of
records include any raw data and would, therefore, extend to computer-resident raw
data.
The GLPs also require retention of the following records:
•	"... [R]ecords of quality assurance inspections" [792.195(d)] (but not the
inspection reports themselves)
•	"Summaries of training and experience and job descriptions"
[792.195(e)]
•	"Records and reports of the maintenance and calibration and
inspection of equipment" [792.195(f)].
The concepts apply to those records that pertain to automated laboratory systems.
The records to be retained would therefore include the schedule of quality assurance
inspections of the automated system(s), personnel records of the individuals who
designed or used the automated system(s), and maintenance records for the
automated equipment.
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SPECIFIC REQUIREMENTS FOR AUTOMATED SYSTEMS
The GLPs were promulgated as a risk-management tool. Proper adherence to
GLPs will minimize risk associated with collecting, analyzing, and reporting data. In
automated data management systems, there are at least two steps or processes with
high levels of risk that require commensurate attention. These are data entry and
data editing. The GLPs address specific procedures that should be followed to
minimize risk at these two critical points.
Data Entry
The GLP requirements for collecting data are as follows:
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. [792.130(e)]
Compliance with this requirement is most frequently implemented by using
laboratory notebooks and consists of the following:
•	Laboratory notebooks used are bound and have sequentially numbered
pages, thereby delineating the historical development of data.
•	Initial entries are made in permanent ink and must be signed and
dated.
•	Corrections are made so as not to obliterate the original entry. Changes
are initialed and dated, and a reason is given for each change.
This method of implementation ensures the integrity of data because the initial
entry is documented in a permanent record whose ownership is clearly defined and
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historical records are maintained for data changes. Additionally, the fact that
changes were made is clearly evident.
The GLPs specifically define how data integrity is to be protected in an
automated system. The following GLP requirements have the most critical impact
on design and implementation of an automated laboratory system:
In automated data collection systems, the individual responsible for direct
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. [792.130(e)]
These requirements for automated data collection system parallel those for data
collected manually.
Compliance with GLPs is required for automated data collection systems.
Because data integrity in an automated system is most vulnerable during entry,
criteria must be established for data validation. This may be accomplished by
validating all input data or by a statistically based sampling system for less than 100
percent data verification. Compliance can be documented by maintaining historical
records of data changes (using an audit trail) and by implementing system security
procedures to establish ownership of the data.
Data Validation
The integrity of data is vulnerable in laboratory configurations where data
elements are transfered to the automated system from another source. Data
integrity is particularly vulnerable when collected information is typed into an
automated laboratory system during data entry. Input data should, therefore, be
validated. This can be facilitated through the use of the following procedures:
• Verifying that data are entered in the correct format (e.g., alphabetic or
numeric).
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•	Verifying the data against predetermined acceptable ranges (e.g., pH
values must be between 0 and 14).
•	Verifying that data against values in previously entered tables of
information (e.g., samples must originate from certain locations or
from certain client accounts).
•	Re-keying data by a second individual.
•	Reviewing entered data by an individual not responsible for its entry.
Additionally, validation of data transmission from instrument to data
management system should be conducted. The specifics of this type of validation
depend heavily on the instrumentation itself and on the types of data being
transfered (e.g., analog to digital). Essentially, a useful validation technique is
periodic stress testing of the system.
Audit Trails
The GLPs require that an automated data collection system document the
entry and/or modification of data. This ensures that during an audit the "paper
trail" or history of results can be reviewed in detail. The GLPs require the following
conditions:
•	The individual responsible for direct data input must be documented.
•	Any data changes must be made so as not to obscure the original data
entered.
•	The date of, reason for, and individual responsible for the data change
must be documented.
The audit trail means that data in the system must be identified by the time
and date of entry, the identity of the individual(s) entering the data, the time and
date of any data change(s), the original and changed data, the reason for any data
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change(s), and the identity of the individual(s) making the data changes(s). A
program should be operating to identify what data have been changed so that
changes can be reviewed, verified, or audited.
By itself, journaling, or maintenance of a transaction log, may not be a
sufficient audit trail. In general, automated journaling allows the system to be
reconstructed back to a specific time. The time and date of, and often the individual
responsible for, the data change are recorded. Reasons for change are not typically
recorded. Additionally, journaling of information often overwrites, thereby
obscuring, previous records. Thus, not all components of a GLP audit trail have
been satisfied. A properly programmed and unalterable transaction log may provide
an adequate audit trail if the altered data are identified in some manner and
referenced to the transaction log.
Ideally, the audit trail should be an integral part of the subject data. If an
auditor must consult two or more locations to reconstruct the trail, it would be too
easy to overlook information or for information to be lost. The audit trail should be
an electronic equivalent of the annotated notebook that keeps all required
information (i.e., original data, an indication that specific data elements were
altered, revised data, who altered the data, when, and why) in a single place.
Security
In a manual environment, the use of the laboratory notebook ensures that
only authorized individuals enter and/or modify data. The notebook can be
reviewed and approved by appropriate staff before data are reported and can be
audited readily for accuracy.
An automated system should have similar attributes to protect data integrity.
To maintain documentation of individuals that enter and/or modify data, the
system must be designed to restrict data entry and editing access only to authorized
users. This typically can be implemented as follows:
• Identify individual users through individualized log-ons followed by
restricted passwords. These are typically input through a keyboard, but
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other methods that uniquely identify individual users are acceptable
(e.g., voice or fingerprints).
•	Institute password security measures: change passwords periodically or
force their expiration, establish strict policies against exchanging
passwords among personnel, remove passwords when employees
terminate.
•	Remove "guest" passwords that hardware/software installers use to
gain entry into programs for maintenance and other operations as soon
as the need for that entry has passed.
•	Secure functional access: restrict users to only those functions (e.g.,
input, review, accept, output) for which they are authorized and restrict
users to "read-only" or "read-and-write" privileges as authorized.
•	Limit remote access to computer-resident data by modem/telephone
lines.
Because the GLPs provide managers with an assurance of the validity of data
and of a proper audit trail, the general principles of the GLPs can readily be applied
to any laboratory arena where an assurance of high-quality data is needed. It should
be noted, however, that no security measure is perfect. Security can always be
breached.
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Conclusions
EPA's GLP regulations apply to laboratories collecting, analyzing,
maintaining, and reporting data under the Agency's environmental programs
regardless of the process used, be it manual or automated. GLPs have been
promulgated with specific requirements for ensuring the integrity of data, regardless
of source. Despite the existence of these requirements, outside the pesticide and
industrial chemical registration programs, few laboratories submitting data to EPA
have incorporated GLPs into their automated laboratory operations (OIRM, 1989c).
The Agency is developing standards specifically for automated laboratory systems.
These standards will be sensitive to current technology and incorporate current EPA
policies on automation and information management as well as GLP requirements
that pertain to automated laboratory systems. These GLP requirements include the
following:
•	The laboratory shall ensure the adequacy of staff who design and use
the automated laboratory system.
•	The laboratory shall maintain documentation of training, experience,
and job descriptions for staff who design and use the automated
laboratory system.
•	The QAU shall maintain oversight responsibility for the automated
laboratory system equipment and procedures. This shall include
periodic, documented inspections.
•	The QAU shall ensure that no significant deviations are made without
prior written authorization from procedures for design and operation
of the automated laboratory system. This shall include the written
operation instructions (software) for the system.
•	Automated equipment must be located in a facility such that the
operating environment is maintained within vendor specifications.
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The laboratory shall ensure that the automated laboratory system is of
adequate capacity to perform its functions. Procedures for performing
maintenance must be established and records must be maintained to
document the maintenance.
The laboratory's written SOPs shall extend to include descriptions of
those tasks aided or conducted by the automated laboratory system.
SOPs shall include written instructions for computer systems in the
following areas:
How software applications are to be developed. This would
include coding standards, documentation requirements,
requirements for validation, and acceptance testing.
How software change is to be controlled. This includes specific
mechanisms to request, authorize, implement, and approve a
change to the software and to determine the version of software
used to generate any given data set.
How often software validation is to be accomplished and what
data sets will be used for validation.
How new/revised software is tested against existing algorithms,
data, and data recovery prior to acceptance.
The laboratory shall define what constitutes computer-resident raw
data in its operation and shall clearly delineate and specify this
definition in the laboratory's SOPs.
Data entry must be carefully documented.
Individuals responsible for data entry shall be identified.
The date and time of data entry shall be recorded.
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•	Data editing must be controlled.
All changes made to data shall be made so as not to obscure the
original data.
Individuals responsible for data changes shall be identified.
The date, time, and reason for change shall be recorded.
The edited data shall be clearly recognizable as having been
modified.
•	All computer-resident raw data from automated laboratory systems
must be properly archived: the archives should be designed to
minimize deterioration of magnetic media, an individual shall be
designated (in writing) as responsible for the archives, only authorized
personnel shall enter the archives, and archived computer records
shall be indexed to expedite their retrieval.
•	Retained records for automated laboratory systems shall include the
following: schedules of QAU inspections, personnel records for staff
who designed and used the system, and maintenance records for the
automated system equipment.
The standards for automated laboratories will be supplemented by an
implementation plan, which will help each laboratory select the best method to
achieve compliance with each aspect of the GLPs. The implementation plan will
describe different approaches, with differing levels of risk minimization and cost,
that will will assist laboratory management in realizing the full potential of data
gathering for decision-making processes.
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Automated Laboratory Standards Program
GLOSSARY
Application controls - one of the two sets or types of controls recognized by
the auditing discipline. They are specific for each application and include
items such as data entry verification procedures (for instance, re-keying all
input); data base recovery and roll back procedures that permit the data base
administrator to recreate any desired state of the data base; audit trails that not
only assist the data base administrator in recreating any desired state of the
data base, but also provide documentary evidence of a chain of custody for
data; and use of automated reconciliation transactions that verify the final
data base results against the results as reconstructed through the audit trail.
Application software - a program developed, adapted, or tailored to the
specific user requirements for the purpose of data collection, data
manipulation, data output, or data archiving [Drug Information Association].
Audit trail - records of transactions that collectively provide documentary
evidence of processing, used to trace from original transactions forward to
related records and reports or backwards from records and reports to source
transactions. This series of records documents the origination and flow of
transactions processed through a system [Datapro], Also, a chronological
record of system activities that is sufficient to enable the reconstruction,
reviewing, and examination of the sequence of environments and activities
surrounding or leading to an operation, a procedure, or an event in a
transaction from its inception to final results [NCSC-TG-004].
Auditing - (1) the process of establishing that prescribed procedures and
protocols have been followed; (2) a technique applied during or at the end of a
process to assess the acceptability of the product. [Drug Information
Association]; (3) a function used by management to assess the adequacy of
control [Perry]. That is, auditing is the set of processes that evaluate how well
controls ensure data integrity. As a financial example, auditing would
include those activities that review whether deposits have been attributed to
the proper accounts; for example, providing an individual with a hard-copy
record of the transaction at the time of deposit and sending the individual a
monthly statement that lists all transactions.
Automated laboratory data processing - calculation, manipulation, and
reporting of analytical results using computer-resident data, in either a LIMS
or a personal computer.
Availability - see "data availability."
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Automated Laboratory Standards Program
Back-up - provisions made for the recovery of data files or software, for restart
of processing, or for use of alternative computer equipment after a system
failure or disaster [Drug Information Association].
Change control - ongoing evaluation of system operations and changes
during the production use of a system, to determine when and if repetition of
a validation process or a specific portion of it is necessary. This includes both
the ongoing, documented evaluation, plus any validation testing necessary to
maintain a product in a validated state [Drug Information Association].
Checksum - an error-checking method used in data communications in
which groups of digits are summed, usually without regard for overflow, and
that sum checked against a previously computed sum to verify that no data
digits have been changed [Drug Information Association].
Cipher - a method of transforming a text in order to conceal its meaning.
Confidentiality - see "data confidentiality."
Control - "that which prevents, detects, corrects, or reduces a risk" [Perry], and
thus reasonably ensures that data are complete, accurate, and reliable. For
instance, any system that verifies the sample number against sample
identifier information would be a control against inadvertently assigning
results to the wrong sample.
Computer system - a group of hardware components assembled to perform in
conjunction with a set of software programs that are collectively designed to
perform a specific function or group of functions [Drug Information
Association].
Data - a representation of facts, concepts, or instructions in a formalized
manner suitable for communication, interpretation, or processing by human
or automatic means [ISO, as reported by Drug Information Association],
Data availability - the state when data are in the place needed by the user, at
the time the user needs them, and in the form needed by the user [NCSC-TG-
004-88]' the state where information or services that must be accessible on a
timely basis to meet mission requirements or to avoid other types of losses
[OMB]. Data stored electronically require a system to be available in order to
have access to the data. Data availability can be impacted by several factors,
including system "down time," data encryption, password protection, and
system function access restriction.
Data Base Management System (DBMS) - software that allows one or many
persons to create a data base, modify data in the data base, or use data in the
data base (e.g., reports).
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Automated Laboratory Standards Program
Data base - a collection of data having a structured format.
Data confidentiality - the ability to protect the privacy of data; protecting data
from unauthorized disclosure [OMB].
Data element (field) - contains a value with a fixed size and data type (see
below). A list of data elements defines a data base.
Data integrity - ensuring the prevention of information corruption [modified
from EPA Information Security Manual]; ensuring the prevention of
unauthorized modification [modified from OMB]; ensuring that data are
complete, consistent, and without errors.
Data record - consists of a list of values possessing fixed sizes and data types
for each data element in a particular data base.
Data types - alphanumeric (letters, digits, and special characters), numeric
(digits only), boolean (true or false), and specialized data types such as date.
Electronic data integrity - data integrity protected by a computer system;
automated data integrity refers to the goal of complete and incorruptible
computer-resident data.
Encryption - the translation of one character string into another by means of a
cipher, translation table, or algorithm, in order to render the information
contained therein meaningless to anyone who does not possess the decoding
mechanism [Datapro].
Error - accidental mistake caused by human action or computer failure.
Fraud - deliberate human action to cause an inaccuracy.
General controls - one of the two sets or types of controls recognized by the
auditing discipline. These operate across all applications. These would
include developing and staffing a quality assurance program that works
independently of other staff; developing and enforcing documentation
standards; developing standards for data transfer and manipulation, such as
prohibiting the same individual from both performing and approving
sample testing; training individuals to perform data transfers; and developing
hardware controls, such as writing different backup cycles to different disk
packs and developing and enforcing labelling conventions for all cabling.
Integrity - see "data integrity."
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Automated Laboratory Standards Program
Journaling - recording all significant access or file activity events in their
entirety. Using a journal plus earlier copies of a file, it would be possible to
reconstruct the file at any point and identify the ways it has changed over a
specified period of time [Datapro].
Laboratory Information Management System (LIMS) - automation of
laboratory processes under a single unified system. Data collection, data
analysis, and data reporting are a few examples of laboratory processes that
can be automated.
Password - a unique word or string of characters used to authenticate an
identity. A program, computer operator,or user may be required to submit a
password to meet security requirements before gaining access to data. The
password is confidential, as opposed to the user identification [Datapro].
Quality assurance - (1) a process for building quality into a system; (2) the
process of ensuring that the automated data system meets the user
requirements for the system and maintains data integrity; (3) a planned and
systematic pattern of all actions necessary to provide adequate confidence that
the item or product conforms to established technical requirements
[ANSI/IEEE Std 730-1981, as reported by Drug Information Association].
Raw data - . 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 that
study. . . "Raw data" may include photographs, microfilm or microfiche
copies, computer printouts, magnetic media, . . . and recorded data from
automated instruments." [40 CFR 792.3] Raw data are the first or primary
recordings of observations or results. Transcribed data (e.g., manually keyed
computer-resident data taken from data sheets or notebooks) are not raw data.
Risk - "the probable result of the occurrence of an adverse event..." [Perry].
An "adverse event" could be either accidental (error) or deliberate (fraud).
An example of an adverse event would be the inaccurate assignment of an
accessionary number to a test sample. Risk, then, would be the likelihood
that the results of an analysis would be attributed to the wrong sample.
Risk analysis - a means of measuring and assessing the relative
vulnerabilities and threats to a collection of sensitive data and the people,
systems, and installations involved in storing and processing those data. Its
purpose is to determine how security measures can be effectively applied to
minimize potential loss. Risk analyses may vary from an informal,
quantitative review of a microcomputer installation to a formal, fully
quantified review of a major computer center [EPA IRM Policy Manual],
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Automated Laboratory Standards Program
Security - the protection of computer hardware and software from accidental
or malicious access, use, modification, destruction, or disclosure. Security
also pertains to personnel, data, communications, and the physical protection
of computer installations [Drug Information Association].
System - (1) a collection of people, machines, and methods organized to
accomplish a set of specific functions; (2) an integrated whole that is
composed of diverse, interacting, specialized structures and subfunctions; (3) a
group of subsystems united by some interaction or interdependence,
performing many duties but functioning as a single unit [ANSI N45.2.10,
1973, as reported by Drug Information Association].
System Development Life Cycle (SDLC) - a series of distinct phases through
which development projects progress. An approach to computer system
development that begins with an evaluation of the user needs and
identification of the user requirements and continues through system design,
module design, programming and testing, system integration and testing,
validation, and operation and maintenance, ending only when use of the
system is discontinued [modified from Drug Information Association].
Transaction log - also Keystroke, capture, report, and replay - the technique of
recording and storing keystrokes as entered by the user for subsequent replay
to enable the original sequence to be reproduced exactly [Drug Information
Association].
Valid - having legal strength or force, executed with proper formalities,
incapable of being rightfully overthrown or set aside [Black's Law Dictionary].
Validity - legal sufficiency, in contradistinction to mere regularity (being
steady or uniform in course, practice, or occurrence) [Black's Law Dictionary],
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References
Black, Henry C. (1968), Black's Law Dictionary, Revised Fourth Edition (West
Publishing Co., St. Paul, Minnesota).
Datapro Research (1989), Datapro Reports on Information Security (McGraw-Hill,
Inc., Delran, NJ).
Drug Information Association (1988), Computerized Data Systems for Nonclinical
Safety Assessment: Current Concepts and Quality Assurance (Drug Information
Association, Maple Glen, PA).
National Bureau of Standards (1976), Glossary for Computer Systems Security (U.S.
Department of Commerce, FIPS PUB 39).
National Computer Security Center (1988), Glossary of Computer Security (U.S.
Department of Defense, NCSC-TG-004-88, Version 1).
OIRM (1989a), Automated Laboratory Standards: Evaluation of the Use of
Automated Financial System Procedures (U.S. E.P.A., Office of Information
Resources Management, Research Triangle Park, NC, 1989).
OIRM (1989b), Automated Laboratory Standards: Survey of Current Automated
Technology (U.S. E.P.A., Office of Information Resources Management, Research
Triangle Park, NC, 1989).
OIRM (1989c), Automated Laboratory Standards: Current Automated Laboratory
Data Management Practices (U.S. E.P.A., Office of Information Resources
Management, Research Triangle Park, NC, 1989).
Mattes, D.C. (1987), "LIMS and Good Laboratory Practice," Chapter 24 in R.D.
McDowall, ed., Laboratory Information Management Systems (Sigma Press,
Wilmslow, U.K).

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National Archives and Records Administration (1990), Federal Register. Electronic
Records Management; Final Rule. 36 CFR Part 1234. Vol. 55, No. 89, May 8, 1990,
19216-21.
Perry, William E. (1983), Ensuring Data Base Integrity (John Wiley and Sons, New
York).
Taylor, D.W. (1984), "Inspection of Computer-Supported Toxicology Data Submitted
to the FDA," Drug Information Journal, 18, pp. 189-194.
U.S. Environmental Protection Agency (1983), Federal Register. Toxic Substance
Control Act (TSCA); Good Laboratory Practice Standards; Final Rule. 40 CFR
Part 792. Vol. 48, No. 230, November 23, 1983, 53922-44.
U.S. Environmental Protection Agency (1989a), Federal Register. Federal Insecticide,
Fungicide, and Rodenticide Act (FIFRA); Good Laboratory Practice Standards; Final
Rule. 40 CFR Part 160. Vol. 54, No. 158, August 17, 1989, 34052-74.
U.S. Environmental Protection Agency (1989b), Federal Register. Toxic Substance
Control Act (TSCA); Good Laboratory Practice Standards; Final Rule. 40 CFR
Part 792. Vol. 54, No. 158, August 17,1989, 34034-50.

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Appendix A
Good Laboratory Practices
forTSCA and FIFRA

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Thursday
August 17, 1989.
Part III
Environmental
Protection Agency
40 CFR Part 792
Toxic Substances Control Act (TSCA);
Good Laboratory Practice Standards;
Final Rule

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3*034 ffcdaal gqgbttar J V± 51 No. 15fl j Painday. AugMt 17.1969 / Rules and ttagolations
ENVIROfflHKNT AL PROTECTION
AGENCY
40 CFR Part 782
[OPTS-46016A; FRL-3518-31
RIN 2070-AB65
Toxic Substance* Control Act (TSCA);
Good Laboratory Practice Standards
aoency: Environmental Protection
Agency (EPA).
ACTION: Final rule.
summary: EPA is issuing this final rule
to amend the TSCA Good Laboratory
Practice (GLP) standards to incorporate
many of the changes made by the Food
and Drug Administration (FDAJ to its
GLP regulations and to expand the
scope of the TSCA GLP standards to
apply to testing conducted in the field
under TSCA. EPA is amending these
regulations to ensure the quality and
integrity of data generated from such
studies.
EFFECTIVE DATE: September 18.1989
FOa FURTHER INFORMATION CONTACT:
Michael M. Stahl, Director.
Environmental Assistance Division (TS-
799). Office of Toxic Substances. Rm.
EB-44, 401 M St.. SW„ Washington. DC
20460. (202) 554-1404. TDD: 1202) 554-
0551
SUPPLEMENTARY INFORMATION:
Following is an index to the remainder
of this preamble:
1. introduction
A.	Legal Authority.
B.	Background.
C.	Consistency With FDA GLP Regulations.
D.	Publication of the Complete Rule.
I!. Summary of Comments and Responses
A.	Genera] Provisions: Definitions
B.	Organization and Personcel.
C.	Facilities.
D.	Equipment.
E.	Testing Facilities Operation
F.	Te9L Control, and Reference Substances
C. Protocol For and Condurt of a Study.
H. Records and Reports.
111. Regulatory Requirements
A.	Executive Order 12291.
B.	Regulatory Flexibility Act
I. Introduction
EPA is amending the TSCA Good
Laboratory Practice standards (40 CFR
part 792) to incorporate many of the
changes made by FDA to its GLP
regulations and to expand the scope of
TSCA GLP standards.
Public reporting for this collection of
information is estimated to be negligible,
including time for reviewing
instructions, searching existing data
sources, gathering and maintaining the
data needed, and completing and
reviewing the collection of information.
Send casta en ts regarding the bvden
estimate or lay other aspect of Ab
collection of information, including
suggestions for reducing this buiden. to
Chief. Information Policy Branch. PM-
223. U.S. Environmental Protection
Agency. 401 M St. SW., Washington. DC
20503.
A. Legal Authority
On November 29, 1983 (48 FR 53922),
EPA promulgated the GLP standards
under the authority of TSCA section 4
(90 Stat. 2006.15 U.S.C. 2603). Section
4(a) of TSCA authorizes the EPA
Administrator to require, by rule, that
manufacturers (including importers) end
processors cf identified chemical
substances and mixtures (chemicals)
test such chemicals if certain finding?
are made. Section 4(b)(1) of TSCA
specifies that each test rule shall include
standards for the development of teat
data. These standards are defined in
section 3(12) of TSCA to mean a
prescription of—
(A)	the—
|i) health end environmental effects, tad
(li) information relating to the toxicity,
persistence, and other characteristic* which
affect healdi aod the environment for which
test data for a chemical substance or mixture
are to be developed and any analysis t) at is
to be performed on such data, and
(B)	to the extent necessary to assure thai
data respecting such effects and
characteristics are reliable and adequate—
(i) the manner in which such data are to be
developed.
(II) the specification of any test pistocal or
methodology to be employed in the
development ol such data, and
(iii) such other requirements as ate
neceitiry to provide such assurance.
In summary, the specific authority to
issue the GLP standards is provided by
section 4(b)(1) of TSCA. which is further
explained by the definitions in sections
3(12)(B)(i) and 3(12)(B)(iii).
In addition. EPA also requires
sponsors to utilize these GLP standards
when conducting testing under TSCA
section 4 testing consent agreements
end \\nll include provisions to adhere to
these GLP standards in those
agreements (see 40 CFR 790.00(a)(7))
Also. It is EPA's policy that all data
developed as a result of rules or orders
under section 5 of TSCA should be in
accordance with the GLP standacds. If
data developed under section 5 of TSCA
are not generated in accordance with
the GLP standards. EPA may elect to
consider such data insufficient to
evaluate the health effects,
environmental effects, and fateoftbe
chemicai(s).
8. Background
EPA. originally published TSCA GLP
standards in the Federal Register of
November 29,1983 (48 FR 53922). which
were codified as 40 CFR part 792. At the
same time. EPA published GLP
standards applicable to testing under
the Federal Insecticide. Fungicide, and
Rodenticide Act (FIFRA, 48 FR 53963.40
CFR part 160). These regulations were
promulgated in response to
investigations by EPA and FDA during
the mid-1970s 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. For instance,
some studies had been submitted which
did not adhere to specified protocols,
were conducted by underqualified
personnel and supervisors, or were not
adequately monitored by study
sponsors. 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 record-keeping
techniques. The TSCA CLP standards
specify minimum practices and
procedures which must be followed in
order to ensure the quality and integrity
of data submitted in accordance with
TSCA section 4 requirements. The 1983
TSCA GLP standards also established a
policy that persons should comply with
the GLP standards when submitting data
in response to rules and orders issued
under section 5 of TSCA. and when
submitting data to EPA voluntarily.
When EPA published its final TSCA
and FIFRA GLP standards in the Federal
Register of November 29.1983. the
Agency sought to harmonize the
requirements and language with those
regulations promulgated by the FDA in
the Federal Register of December 22,
1078 (43 FR 60013). and codified as 21
CFR part 58. Differences between the
two Agencies' current GLP regulations
exist only to the extent necessary to
reflect the Agencies' different statutory
responsibilities under TSCA. FIFRA.
and the Federal Food. Drug and
Cosmetic Act (FFDCA). Similar to the
PDA GLP regulations, the FIFRA and
TSCA GLP regulations delineate
standards for studies designed to
determine the health effects of a test
substance: however, the TSCA GLP
standards also contain provisions
to environmental testing (i.e.,
ecological effects and chemical fate).

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Federal Register / Vol 54, No. 158 / Thursday. August 17. 1889 / Rules and Regulations 34035
Compliance with EPA's CLP
regulations has been monitored through
a program of laboratory inspections and
study audits coordinated between EPA
and FDA. Under an Interagency
Agreement originated in 1878, FDA
carries out GLP inspections at
laboratories which conduct health
effects testing. EPA primarily performs
CLP inspections for environmental
laboratories and conducts data audits
for health effects and environmental
studies.
After a thorough review of its GLP
regulations and compliance program,
FDA concluded that some of the
provisions of the GLPs needed to be
clarified, amended, or deleted in order
to reduce the regulatory burden on
testing facilities. Accordingly, FDA
revised its GLP regulations in the
Federal Register of September 4,1987
(52 FR 33768). These GLP standards are
intended to simplify the regulations
without compromising study integrity.
EPA agrees with FDA that many
provisions of the GLP regulations can be
streamlined without compromising the
goals of the CLP standards. Therefore.
EPA is amending the TSCA GLP
standards to incorporate many of the
changes made by FDA to its GLP
regulations. In addition. EPA is
expanding the scope of the TSCA CLP
standards to cover testing wherever it is
conducted (e.g., field testing). Elsewhere
in this Federal Register. EPA is finalizing
similar changes to the FIFRA GLP
standards.
C. Consistency With FDA CLP
Regulations
It is EPA's policy to minimize the
regulatory bunien on the public which
might arise from conflicting
requirements which could be
promulgated under different regulatory
authorities. In keeping with this policy,
the final 1S83 TSCA GLP standards, 40
CFR part 792, followed the format and,
with few exceptions, the wording of
FDA's final CLP regulations. 21 CFR part
58. Differences between the EPA and
FDA GLP regulations were based upon
varying needs and responsibilities under
each Agency's regulatory statutes. This
revision to the TSCA GLP standards
follows this same policy by conforming
to many of the changes FDA made to its
GLP regulations, published In the
Federal Register of September 4,1987
(52 FR 33768). EPA has varied from
FDA's revised GLP regulations only
when necessary due to EPA's statutory
responsibilities. The most significant
differences between the EPA changes
and the revised FDA GLP regulations
are the scope of the testing and test
systems affected.
As In the 1983 TSCA GLP standards,
the revisions to the TSCA GLP
standards vary from the FDA GLP
regulations in that the TSCA CLP
standards Incorporate provisions for
environmental testing (EPA is extending
the FIFRA GLP standards to extend to
environmental studies as well).
Environmental studies include
ecological effects and chemical fate
studies. Ecological effects studies are
those performed for development of
information on non-human toxicity and
potential ecological impact of chemicals
and their degradation products.
Chemical fate studies are studies
performed to characterize physical,
chemical, and persistence properties of
a substance in order to evaluate the
transport and transformation of the
substance in the environment.
To ensure the quality and integrity of
all data generated from environmental
studies, the current TSCA GLP
standards contain requirements within
40 CFR part 792. subpart L applicable to
testing plants, microbial organisms,
aquatic organisms, amphibians, reptiles,
and birds, where appropriate.
These requirements include
provisions for care, care facilities, and
supply facilities for the various test
systems used in environmental testing.
As a means of simplifying the
regulations. EPA is changing the
requirements currently found within
subpart L by merging them into subparts
A through J of the TSCA GLP standards
(40 CFR part 792, subparts A through J).
Accordingly. S 792.43 Animal care
facilities. 1 792.45 Animal supply
facilities, and J 792.90 Animal care,
incorporate the provisions relating to the
care of test systems, test system care
facilities, and test system supply
facilities from ( 792.228 in subpart L of
the 1983 GLP standards. The expanded
sections are retitled in the revision as
follows: { 792.43 Test system care
facilities, ( 792.45 Test system supply
facilities, and J 792.90 Animal and other
test system care. Further, in most
instances, EPA is replacing the term
"animal." used in the 1983 EPA and 1978
FDA GLP regulations, with the broader
term "test system." Specifically, this
change occurs in fi 8 792.43, 792.45,
792.81, 792.90, and 792.120. These
changes are further discussed in Unit ~
of this preamble.
EPA'a TSCA GLP standards also vary
from FDA's in their coverage of testing
conducted in the field. To ensure the
quality and integrity of data submitted
to the Agency, EPA believes that GLP
standards must apply whenever data
collection occurs. Because many of the
test data required by EPA are developed
in the field, or more accurately In
outdoor laboratories (ground water
studies, air monitoring studies,
degradation in soil. etc.). EPA is
amending the GLP standards to include
field testing within the scope of these
regulations.
The remaining differences between
the EPA and FDA GLP regulations are
described in the preamble to this final
rule and the preamble to the TSCA GLP
standards, published in the Federal
Register of November 29.1983 (48 FR
53922). EPA has coordinated this final
rule with FDA and has considered
public comments received on the
December 28,1987 proposal (52 FR
48933).
D. Publication of the Complete Rule
The entire TSCA GLP rule is
published in this notice to simplify
interpretation and facilitate the use of
this notice by the regulated community.
The following lists the sections of 40
CFR part 792 that were changed from
the 1983 rule:
Section
changed
Changes
792.1	
(a) and (c). revised.
792.3	
"Batch," "Control substance."

"Study." and "Test syswm." re-

vised: "Test substance or mofture."

removed; "Camer." "Experimental

start date." "Experimental termma-

tion date." "Reference substance."

"Study completion date." "Study

initiation date." Test substance."

and "Vehicle," added.
732.12	_....
Introductory text revised.
792.17..	
(a) and (c). revised.
792.29	
(
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I Paieed E«M«r/VflU No- 138 / Ifcitnday. August IT. MBC / Safes
Jettons
regulBtB^trSPA. 1 iraa anodaiim. 4
from taatfagorcDOMitinglabentDnaa.
and 1 from another y etmnect agsmcj.
The mejoiity of ibeconuMBtB wpponed
the proposed changes. although
numerous suggestions were Bade for
additional revisions to parts of die CLP
reflations not .subject to ihw
rulemakiag or modifioBtiong to the
proposed duuges. Comments that
raised important policy questions,
suggested nodificatioo to the essence of
the proposed regulation. or required an
Individual response, are discussed
below. Coalmen ts addressing changes to
the GLP standards that v.'a re not
proposed are not the subject of this
rulemaking. However, all comments
made have been placed in the public
record.
A General Prorisions: Definitions
1. Batch. The definition of "batch" is
expanded to include reference
substances. This was an omission in the
proposed rule that if corrected in the
final rule to maintain consistency wilb
the use of the term in 9 782.105(a).
Z Carrier—i- Comment: The word
"systems" should replace the word
"organisms" in the definition of
"carrier," to be consistent with the term
"test system."
Response: SPA concurs with the
suggestion, la order to be consistent
with the definition of "test systems," the
word is changed accordingly
ii Comment EPA should revise the
list in parentheses that follows the word
"material" in the definition of "carrier"
to make it all inclusive
Response: EPA h&s decided to add the
phrase "including but not limited
to ' * to indicate that the list
provides examples and is not meant to
be all inclusive.
3. Control substance—Comment: EPA
should delete the phrase "for no-effect
levels" in the definition of control
substance- The definition as written is
too narrow and excludes analytical
chemistry (&g.. chemical fate, residue
chemistry) operations where the term
"control" has a meaning distinctly
different from biological effects.
Response: Since the purpose of the
analytical control is to eventually
establish that none of the materials
administered to the test system interfere
with ideabficeUoa of the test substance
and its degrBdate^s) and metabolite[s),
EPA agrees than the terminology is tco
limiting and is replacing the phrase "for
no-effect levels" with the phrase "for
known chemical or biological
measurements"The definition now
reads: "Control substance means any
chemical tubstmce or nixtare. or any
oth er material «tber than a test
wbrtMftfalcrNhr,teii
administered ta lbs its! jysfena in ft*
course of a study far the porposa at
establishing a basis fat oasspansoc with
the test substance for known cheoicaJ
or biological measurements."
4.	Experimental start and termination
dates—Comae/it These dates would be
difficult to predict, especially far field
studies, because they would be subject
to natural or man-made conditions that
cannot be controlled or aafcapeied.
Since the dates would be sobject to
change, many protocol amendments
would be required creating an undue
administrative burden.
Response: The experimental start and
termination dates specified in the
protocol are merely proposed dates.
Therefore ii the actual experimental
start or termination data Is different
from the proposed data* no protocol
amendment would be required
5.	Reference substance—Coauoent If
EPA intended the term "reference
substance" to include analytical and
calibration standards, then several other
sections of the proposed rule which
mention "reference substance," would
also require the same types of records to
be kept for analytical standards. This
would constitute an excessive burden
on management which would require
maintaining various records that do not
add any value to the study.
Response: The definition of reference
substance is Intended to Include
analytical reference standards.
Therefore. EPA believes this change
eliminates any ambiguity In the
definition. EPA has modified the
definition of "reference substance." as
follows: "Reference subBtance means
any chemical substance or mixture,
analytical reference 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 ot a study for purposes of
establishing a basis for comparison with
the test substance for known chemical
or biological measurements.M
EPA disagrees that inclusion of
analytical reference standards in this
part constitutes an excessive
documentation burden or adds no value
to the study. Documentation which
supports defining of analytical reference
standards under this pan should not
require excess paperwork since common
laboratory practices already require
assurance of the validity of standards to
make certain that tb« tMasureoeats are
accurate.
6.	Study—I. Comment Tta proposed
definition of study would imply tbet
each determination such as stability,
solubility, octanol water partition
coefficient, volatility, penristenoe. and
other data point Alwtulnsttosw would
be stadtea wfch ooaconiUat
re^elPseentB snob «s-protoooh end
quality assurance salt ^QAU)
inspections.
Respotrse:TPA faitends that QAU
inspections aa listed in f 792-35 be
conducted at interval* adequate to
ensure the integrity of the study for each
determination such as stability,
solubility, octanol water partition
coefficient, volatility, persistence, end
other data point determinations.
However, if done as part of a larger
study, then these determinations are
covered under the larger study's
protocol or standard operating
procedure (SOP). If they are submitted
to EPA as a study unto itself, then they
require their own protocols].
ii.	Comment¦ An experiment such as
product chemlBtry which doeB not
Involve a test system cannot be
considered a "stud/* and therefore
should not be covered by CLP
standards.
Response: Studies designed to
determine the physical or chemical
characteristics of a test aubstaacesre
included within the scope of these^
regulations. Therefore, EPA intends to
include product chemistry experiments
in the definition of "stuily." This change
is consistent with the definition of the
tenn "study" as it now appears, and as
it appears in tbe FIFRA GLP standards
at 40 CFR pert 160. In the case of
product chemistiy experiments, the test
substance itself may be the test system.
iii.	Comment The addition of the term
"or in the environment" to the definition
of "study" indicates that the change
extends the proposed regulations to field
studies. While it is necessary to ess ore
the validity of all data collected, the
variety and special requirements of field
researdi have not been addressed in tbe
new rules.
Response: These regulations ere
intended to apply to all studies required
to be submitted under TSCA. including
those conducted in the field. CPA
recognizes that field studies vary and
have special requirement*, but believes
that tbe development of protocols and
SOPs by tbe testing facility provides
adequate flexibility in this respect.
iv.	Comment "Prospectively" should
not be deleted from the definition of
"study .*' If the essence of CLP standards
requires a carefully planned study and
the proposed nde is very strict ebout
documentation that must be oompleted
prior to the experfanental start date, how
can the GLP standards also apply to
studies that were generated without a
protocol or ndvanoe planning, such as
epidemiology?

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Federal Regjjiai / Vol 54. No. 158 / Thnrsday. August 17, 188? / Rules and Regulation* 34837
Response: EPA disagrees with the
comment. The term prospectively is
deleted because EPA wishes all studies,
including epidemiological studies where
past exposure to a study population is
determined or estimated retrospectively,
to be performed under CLP standards.
EPA recognizes that in such studies data
used may not have been generated in
conformance with FTFRA GLP
standards. However, it is EPA's position
that the study itself can be conducted
and submitted to EPA in accordance
with the CLP standards. Retrospective
aspects of such studies that are not
performed according to CLP standards,
for example, test system treatment,
should be identified tn the compliance
statement submitted with the study
report.
In addition, the types of studies
potentially not covered by these
regulations were expanded in the
definition to include experiments
involving test methods.
7.	Test system—Comment What
constitutes the "test system" in tests of
product chemistry studies?
Response: The definition of "test
system" includes the statement that it is
"* * * any * * * chemical or physical
matrix ' * V" Including subparts thereof
that are treated with the test control, or
reference substance and also
appropriate components of the system
that are not treated. Therefore, in the
case of product chemistry, the test
system may be the test substance itself.
EPA is including the term "reference."
which was inadvertently omitted from
the definition as it appeared in the
proposed rule, in order to remain
consistent. In addition. EPA is replacing
"e g." in the parenthetical by adding
"including but rot limited to" in order to
clarify that it is not EPA's intent for the
list to be ell encompassing.
8.	Vehia'e—Comment: The definition
cf "vehicle" serves to clarify the CLP
standards, but there has been no
confusion based on the current
standards and this changed contrary to
EPA's stated objective of being
consistent with FDA'a GLP regulation*.
Response: EPA believes thai
clarification is needed. The EPA GLP
standards cover a larger number of
types of studies end the need for
clarification of the meaning of
potentially ambiguous terms is greater.
B. Organization and Personnel
1. Testing Facility Management—
Comment; The "master schedule"
should not be considered "raw data" a9
was indicated in the preamble (52 FR
48936) to the proposed rule.
Response: EPA deleted the
requirement that the replacement of a
study director must be documented as
"raw data" in order to conform to the
revised FDA GLP regulations. This Is
because replacement of the study
director must be reflected on the master
schedule sheet, which is a study record
that must be retained.
Li addition, the term "reference,"
which was inadvertently omitted in the
proposed rule, has been added to this
section.
2. Quality Assurance Unit—L
Comment: A QAU that is entirely
separate from and independent of the
personnel engaged in the conduct of the
study creates an unjustified financial
b-jrden on some facilities. In some cases
it would be impossible to establish a
completely independent QAU with
qualified personnel.
Response: As stated in the proposed
rule (52 FR 4S933), EPA does not require
the QAU to be a fixed, permanently
staffed unit whose only functions are to
monitor the quality of a study. EPA is
only concerned that there be a distinct
separation of duties between those
personnel involved with the conduct or
direction of a study and those personnel
performing quality assurance on the
same study. Therefore, { 792.35(a)
prohibits personnel from performing
quality assurance activities on their own
study. The rules allow a study director
for a particular study to serve as a part
cf the QAU or as the QAU for a
different study. FDA noted (52 FR 33771)
that il was aware that many small
laboratories could not afford the
operation of a permanently staffed
QAU. EPA would like to point out that
in those situations where there are
different individuals performing the
quality assurance functions for different
studies, each individual is required to
maintain that portion of the master
schedule sheet which relates to the
study being monitored. For this reason,
EPA egrets with FDA's conclusion that
the separation of functione on a study-
by-study ha Bis. as permitted in the
existing and revised regulations, would
provide effective quality assurance. In
view of the potential gain to
management, to sponsors, and loEPA.
through the added assurance of well-
ccmducted studies, the increased coBts
are thereby justified. EPA believes that
its intent is more clearly indicated by
the changes now being made.
ii. Comment Laboratory management
should have the discretion to determine
who enters the data into the master
schedule, bb long bb the required
information is Listed.
Response: EPA believes that
management reiatns such discretion
since it is involved in determining the
composition of the QAU and it provides
an adequate number of such personnel
(U 7S2.31 (c) and (e)). The QAU is
distinguished by training that ensures
that QAU functions are properly
conducted. As stated above, study
personnel may belong to the QAU, as
long as they are not performing the QAU
functions associated with studies in
which they are involved.
iil. Comment The requirement for
Inspection of each study under
5 792.35(b)(3), regardless of duration. Is
excessive for the quality assurance
needed to address study integrity,
especially where studies are performed
by highly standardized procedures. The
repetitive inspection of these types of
studies would consume large amounts of
time for both the study personnel and
QAU staff. Auditing each study is not
necessary 1o ensure the work is
conducted in compliance with the
regulations. Random sampling
procedures should be allowed in
selecting studies and phases of studies
to inspect to decrease the work load and
resource requirements of the QAU.
Response: EPA does not believe that a
random inspection program wouldlie an
appropriate method of evaluating si-
study. Generally, random sampling
provides an adequate means of quality
control where analysis involves
repetition or identical procedures.
However, any assumption that the
conduct of one phase of one study
would be representative of another
would be invalidated by the differences
among study personnel and the
operations they conduct. Furthermore,
this requirement docs not apply to all
routine studies. Section 792.35(b) is
among the exclusions for chemical and
physical characterization studies as
listed in $ 792.135(b).
In conformance with the revised FDA
GLP regulations (52 FR 33780), EPA
modified the requirements of
! 792.35(b)(3) to provide for inspection
of a study on a schedule adequate to
ensure the integrity of the study. The
changeB to this section will allow the
QAU the necessary latitude to adjust its
monitoring activities to meet the
individual problems of each study.
However, each study, no matter how
short, must be inspected at least once
whil* in progress. EPA expects that by
allowing the QAU flexibility in
designing a reasonable inspection
schedule, the goal of ensuring the
quality of the study can be best
achieved.
iv. Comment EPA indicates in the
preamble to the proposed rule
(5 792.35(e), 52 FR 48936) that all QAU
records will now be routinely available
to inspector*. Existing GLP standards

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$4036 Federal Register f Vol. 54, No. 158 / Thursday. AuguBt 17, 1969 / Rulea and Regulations
treat certain QAU records as
confidential and explicitly slate that the
only QAU records to be re viewed by
EPA auditors would be the master
schedule (e.g., the inspection dates,
study Inspected, the phase or segment of
the study inspected, and the name of the
individual performing the inspection). If
QAU records for findings end corrective
action are available on an auditor's
request QAUb would lose their
effectiveness.
Response: EPA shares the concerns of
the commenters that access to all pans
of a QAU inspection would weaken the
inspection system, end recognizes the
need to maintain a degree of
confidentiality. Therefore, records of
findings and problems, as well as
records of corrective action
recommended and taken, are exempt
from routine EPA inspections, except
under special circumstances as
indicated in { 792.15. However. EPA
maintains that all other reports and
records must be easily accessible and
made available to EPA and FDA
inspectors when requested as indicated
in S 792.35(c).
C. Facilities
1, General—Comment OutdooT
testing facilities should not be under
GLP standards since: (a} Outdoor test
facilities will be conducting studies
according to approved protocols; (b)
ensuring suitability ie highly subjective
based on the diverse number of possible
locations; (c) there is a concomitant lack
of clear standards far determining
suitability of locations.
Despite best efforts, the choice could
always be subject to criticism and even
criminal liability based on a good faith
compliance statement indicating GLP
standards had been followed. Most
outdoor testing is done to mimic normal
environmental conditions which are
specific for the test substance and use
being proposed. Therefore, the
determination of whether the size,
construction ot location of a facility is
suitable for a study is a technical issue,
and is not within the scope of the GLP
regulation and would be considered in
the experimental design of the protocol.
Response: In cases where an EPA-
approved protocol establishes lest
locations, that protocol would satisfy
GLP requirements EPA cor Bid era any
site to be the testing facility wherever
testing is undertaken to generate data
required to be submitted to EPA. The
conditions required by the protocol are
not necessarily conducive to artificial
manipulation in the field, or to other
outdoor testing facilities. Therefore,
ensuring the suitability of the location of
these types of testing facilities Is both a
valid and necessary part of protocols
approved by EPA.
2.	Test system care facilities 1
Comment: Instead of expanding the
original document to fit all test systems,
the old rules Bhould be left as is. and a
statement added to cover non-animal
lest systems.
Response: EPA disagrees with the
comment and believeB that specific
changes of the old rule are necessary to
avoid ambiguity concerning the meaning
of non-animal test systems.
li. Comment• Section 792.43(a)(2) and
(b). (e). (f), (g). and (h) should be deleted
because EPA has already stated that
these CLP requirements will be
applicable to all types of testing. It is not
necessary lo add the four new
paragraphs detailing specific
requirements of en virorou e» tel
conditions Tor aquatic organisms and
plants.
Response: EPA believes that some test
systems, e.g.. aquatic, are unique to the
extent that they require special
treatment in the rules.
iii. Comment The change in
} 792.43(c) is appropriate but the current
wording does not require separate
disease handling facilities in every case.
The proposed change has merit In
clarifying the options avaitable lo
laboratories and the change promotes
harmony between EPA and TOA GLP
regulations.
Response: EPA agrees with the
comment. In { 792.43(c). EPA is deleting
the requirement that separate areas be
provided in alL cases for the diagnosis,
treatment and control of test system
diseases. Instead, a change ia made so
that separate areas are provided "as
appropriate." This change is consistent
with the September 4,1987 revised FDA
GLP regulations and the revised FTFRA
GLP regulations.
EPA has made this change to allow
laboratories the option of disposing of
diseased test systems without also
bearing the expense of maintaining
separate areaB in testing facilities for
diagnosis, treatment, and control of
disease. Additionally. EPA recognizes
that the diagnosis and treatment
requirements of § 792.43(c) may not be
appropriate when dealing with such test
systems as soil, plants, or
microorganisms. However If the
decision ia made not to dispose of (he
test system, then test system care
facilities, as specified in { 782.43(c).
must be provided.
3.	Test system supply facilities, i.
Comment- The addition of the two new
paragraphs outlining plant and aquatic
facilities to ( 792.45(b) Is unnecessary.
These considerations are addressed in
f 792.41 with the requirement that
testing facilities be of suitable
construction "to facilitate proper
conduct or studies."
Response: EPA maintains that testing
facilities as mentioned in ] 792.41 and
test system supply facilities as
mentioned in 1792.45. are nol the same
end must be addressed separately.
li. Comment EPA should delete
S 792.45(b) introductory text, (b)(1).
(b)(2), and (c) because this information
was adequately covered in { 792.45(a)
and in { 792.43, and the facilities they
refer to will be addressed in study
protocol.
Response: EPA maintains that 5 782.43
(test ayslem care] is different from
t 792.45 (test system supply) and must
therefore be treated separately.
4. Facilities for handling test control,
end reference substances—Comment-
Would il be necessary to provide
separate sink facilities or separate
rooms for mixing of the test, control, and
reference substances or for adding
water lo tank sprayers?
Response: Separate areas are required
for receipt, mixing and storage attest,
control, and reference substantias and
their mixtures as necessary to prevent
contamination ot mixups. The Ba'me sink
could be uBed for ail work involving
mixing provided that the procedures
(standard operating procedures] used
are adequate to prevent contamination
and mixups. Separate areas for receipt
and storage, mixing and storage of test.
control, and reference substances as
required in i 792.47(a) (1], (2) and (3)
does not mandate the use ol separate
rooms. The aress could be in the aajne
room provided there is adequale space
end equipment to provide that
contamination and mixup do not occur.
This determination should be made on a
case-by-case basis.
D. Equipment
Maintenance and calibration of
equipment—Comment It Is better to
designate in { 792.63(b) that repair and
maintenance will be performed by
"qualified personnel," than to require
that a peraoa be designated in the
written SOP. The requirement lor
written SOPs In J 792.63(b) causes
problems since at many laboratories the
equipment used in conducting a study is
shared by & number ol individuals and
the care and maintenance of the
equipment is also shared. In the event of
equipment failure, a number of
laboratory personnel may be capable of
effecting repair or correcting a problem,
or in more serious equipment failures, a
service representative of the
manufacturer may be called. It is
therefore difficult end very inefficient to

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Federal Regbtat / Vol. 54. No. 158 / Thurtday. August 17. 1989 / Rules and Regulations 34039
designate specific people to perform
each specific maintenance and repair
operation.
Response: The definition of "person"
as it appears in § 792.3(h) is not limited
to an individual scientist or technician,
but includes an organizational suburit.
Consequently, the SOP that designates
the "person responsible" will be
designating a aubunit of the testing
facility, which could be one or several
individuals. This view is consistent with
FDA's (52 PR 33774) Interpretation and
definition of "person." Where duties ere
delegated in the SOPs all contingencies
may be addressed, including the
contracting of service personnel.
£". Testing FociLtiea Operation
1. Standard operating procedures—i.
Comment: Some of the examples of
required SOPs provided in § 792.81 fb)
are not applicable to ail test systems or
study types. For example, "test room
preparation" would not be appropriate
when conducting field studies, and
"necropsy of test system or postmortem
examination of test systems." would rot
apply to studies using a chemical or
physical matrix as the test system
(sterile water, soil, agricultural fields).
Furthermore. S 792.81(c) states that.
"Each laboratory or other study are8
shall have immediately available
manuals and SOPs relative to the
laboratory or field procedures being
performed."
Response: EPA agrees that the term
"room" in 8 792.81(b)(1) is inappropriate
to many studies and is changing the
word to "area" to clarify that field
studies are included. EPA believes that
S 792.81(b) should apply in all cases
since the purpose of SOPs is to insure
the quality and integrity of the data
generated in the course of a study as
stated in 9 792.81(a). However,
procedures that are not performed, such
as necropsy in the case of field studies,
do not require SOPs.
li. Comment- Published literature (e.g.,
ASTM methods) should be .acceptable in
S 792-81 (c) as an appropriate part of an
SOP and not )ust as a supplement to a
written SOP. The written SOP could
incorporate the published literature into
it by reference, without having to
rewrite the entire procedure.
Response: EPA agrees that it would
not be appropriate to rewrite published
literature, hence the allowance for SOPs
to um them as supplements. The SOPs
are still needed to establish the
relationship of the method todata
collection procedures and needs in the
laboratory. While the resulting SOP
would still have to be written it would in
effect be abbreviated in that all of the
methodology referenced would not need
to be rewritten.
2. Animal and other test system
care—i. Comment: The evaluation of
certain test systems according to
"acceptable * * * scientific practice
creates some difficulty, particularly for
plants, microorganisms, soil, and water,
since such practices are not defined.
"Acceptable" should be deleted
regarding scientific practice and the
requirement be only that a scientific
basis be used in determining
appropriateness for testing. In this way,
testing facilities would not need to
justify or prove their basis to be
"acceptable" in Ill-defined arees or
those in flux.
Response: EPA agrees that the term
"acceptable scientific practice" may not
be definable when method
developments are in flux. The tern
"acceptable" is retained, but the term
"scientific practice" Is changed to
"scientific methods." This change
preserves the EPA's Intent that rigorous
scientific methodology be used without
implying that rigid practices be adhered
to where they may not appropriately
exist.
ii. Comment: Section 792.90(c) should
be deleted since the effect of corrective
treatment cannot be accounted for In
test results.
Response: EPA believes that while the
effects of corrective actions taken to
isolate and treat disease or signs of
disease may complicate interpretation of
test results, bo might the effects of the
disease itself. This requirement for field
studies is not inconsistent with Its
inclusion for laboratory, i.e. toxicology,
studies.
Lii. Comment Markings which identify
animals individually, rather than the
group as required by i 792.90(d). are
needed in many studies with warm
blooded vertebrates in pens, or tn the
field. For example, precocial young of
avian speriea should be marked
individually.
Response: Specific criteria for
marking of individuals to meet study
requirements should be addressed
separately in the protocol of the study.
The requirement in I 792.90(d)
addresses the need that teat systems be
adequately identified to prevent
confounding with other test systems.
Identification of precocial birds, for
example, may be outlined In the study
protocol.
iv. Comment- The proposed
multispecies housing under
§ 792.90(e)(1) is redundant to proposed
S 792.43(a)(1) and is inconsistent with
EPA's desire to streamline CLP
standards.
Response: EPA disagrees with the
conclusion that these provisions are
redundant. While § 792.43(a)(1) states
that the facilities shall be sufficient to
allow proper separation of species.
§ 792.90(e)(1) refers specifically to test
system care within the facilities.
v. Comment: The requirement in
5 792.90(j) for acclimatization of plants
and animals should be deleted, since it
is r.ot defined and promotes confusion.
Animal toxicology tests would be
subject to isolation and separately to
acclimatization. Organisms in
environmental Btudies will have been
Isolated with their health status being
evaluated per J 792.90(b) and
acclimatization wodd have already
keen performed as part of the process.
This part should be amended to indicate
mat test organisms should be
acclimatized to all experimental
conditions except the test substance.
Response: EPA believes that the term
acclimatization has common meaning
that is clear in the coctext of its usage in
the rule. Acclimatization implies
accustoming to experimental, i.e.
environmental, conditions other tlgpi the
actual introduction of the effect (e.g. test
substance) to be measured in the
experiment. If acclimatization is
achieved during the process of isolation
then it should be so stated in the
protocol and does not require additional
technical effort.
In addition, the term "organisms" in
S 7D2.90U) has been changed to
"systems." This change is consistent
with the intended expansion of CLP
standards and was an inadvertent
omission in the proposed rule.
F. Test Control, and Reference
Substances
1. Test control, and reference
substance characterization— I.
Comment The term "purity" should be
expanded to include radiochemical
purity since further definition is needed
to encompass metabolism/
environmental fate studies conducted
with radioactive materials.
Response: Radiochemical purity is
covered under "other characteristics
which appropriately define the test,
control or reference substance." It la not
neceasary to specifically list thia
characteristic.
ii. Comment- What level of analysis
constitutes "appropriate"
characterization? la quality control
batch analysis sufficient? Is it necessary
to fully characterize technical materials
to 0.1 percent?
Response: The details of what
"appropriately" defines the test
substance is a guideline or protocol

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34040 Fwfatri Register / Vol 54, No. 158 / Thursday. Angus! 17, 196G / Rules and .Regulations
Issue that cannot be specified in a
generic document such as GLP
standards. The appropriate level of
characterization h largely dependent on
the nature and purpose of the study.
ill. Comment The characterization
requirement is inappropriate since it
conflicts with management
responsibilities, is costly and adds
unnecessary delays to the development
process. It removes a necessary option
of planning by objectives that
responsible business management must
retain. Delays and rescheduling, which
may result If inadequate work is
permitted by management are real
consequences that must be accepted by
management and management must
decide whether or not to risk beginning
an experiment prior to doing
characterization atudieB. Since the
ultimate validity of a study will require
that such data be obtained before the
study is completed and as long as the
sponsor can demonstrate that a study
was conducted with authentic material.
It is irrelevant when the characterization
is completed. This proposal is not in
concert with FDA GLPs. Many times
prospective products fail to reach the
marketplace due to unuBual or
insurmountable problems. Therefore,
eliminating the need for characterization
of product will reduce the costs of theBe
products that fall out of the
developmental process.
Response: Characterization is
necesBary to ensure integrity of Btudies.
It is also necessary for EPA to have
characterization data available for
inspectional purposes during ongoing
studies, and thus to have this
information complete at the beginning of
the study. Without characterization, it is
not possible to know whether test,
control, or reference substances from
different batches that are used in a
single study are in fact identical.
Adequate testing for characterization
normally occurs during the synthesis or
production of teat, control, and reference
substances, and thus should already be
available before the test begins.
Consequently, having characterization
data available should not Ispose an
additional burden in most cases.
EPA does agree, however, that
stability testing should be allowed to be
performed concurrently with the study,
to prevent unreasonable delays. The
sponsor will bear the burden of a
repeated test in tht- case that concurrent
stability testing suggests that the study
is not valid. For that reason. EPA is
revising ! 792.106(b) to allow for
concomitant determination of stability.
iv. Comment The last sentence of
S 792.105(a), relating to methods and
fabrication should be deleted since
these may coataln oonfidenti&l business
Information (CBI).
Response: This Is not a new
requirement and has not posed any
problems. Inspectors an cleared to
handle CBI material: any sensitive
information can be declared CBI and
treated as such.
v.	Comment Many of the tests coming
under the scope of the proposed GLP
standards are in themselves stability
studies. The proposal places indushy in
the quandary of conducting stability
studies prior to a stability study.
Response: The performance tests dted
cannot be considered to be stability
tests under the CLP standards. In the
context described above, the persistence
of the substance in the environment is a
separately measured parameter.
However, when performing such tests, it
is still important to know the stability of
the substance to ensure that the
measured effect was due to the effect of
the test system.
vi.	Comment Would it be acceptable
to EPA if the stability knowledge is
based on the extrapolation of the results
of a ehort-tenn stability study under
extreme conditions carried out before
the experimental starting date?
Response: Such an accelerated study
would not demonstrate stability under
test conditions, and could not be part of
the concurrent stability testing in
conjunction with a larger study. It would
be a separate study with its own
protocol.
vii.	Comment' The proposed rule does
not address whether quality control
activities fall under the GLP standards.
Response: Not all quality control
activities are GLP issues. Quality control
work that is Integral to the laboratory
performing the study would be under
GLP standards, but not that performed
during manufacturing. Studies, as
defined in this part are subject to GLP
standards only when required to be
submitted to fulfill data requirements.
viii.	Comment- The part related to
"storage container assignment for the
duration of a study" in i 782.105(c)
would be unrealistic for field studies,
especially where storage containers may
be large tanks, or delivery systems
which are possibly not even owned by
the sponsor or testing facility.
Response: The delivery systems and
tanks that are part of delivery systems
are not "storage containers." Test
control and reference substances will
however, be stored before use In some
container that is unique to that
substance during the test This may be
the container that the substance comes
in or that is assigned to it by the testing
facility.
ix.	Comment: Liquids from large
containers are often placed into smaller
containers for use during the study.
Consolidation of the test substance Into
smaller containers as the supply Is
depleted should be allowed. These
containers need not be retained after
they are empty, since their retention
does not enhance the quality or Integrity
of the data collected.
Response: EPA disagrees with the
suggestion. The retention of containers
Is necessary to ensure the integrity of
the study. This includes empty
containers, which must be kept to verify
the disposition of the test control and
reference substance. Disposal of
containers adversely affects
accountability. This provision of the rule
is not changed from the 1663 rule, but
was commented on by the public
because it may affect types of studies,
such 88 field studies, that will now fall
under the provisions of the rule as a
result of these amendments.
x.	Comment How are "studies of
more than 4 weeks duration" specified
in s 792.105(d) defined? They should be
defined as studies having an "in-life
phase" of more than 4 weeks.
Response. The term "4 weeks
duration" is meant to apply to the
experimental start and experimental
termination dates. The suggestion of
using the term "in-Ufe phase" is not
accepted since this introduces new
terminology that is not adequately
defined. The term "4 weeks
experimental duration" replaces "4
weeks duration" in S 792.105(d) to
clarify that the study initiation and
study completion dates are not Implied.
xl. Comment Knowledge of stability
makes sense for long-term, but not
short-term studies because If stability is
suspect then doses are made up each
day and given or sprayed immediately.
Adequate knowledge of stability may
exist from chemical information about
the test substance.
Response: If a substance is known to
be stable for a few days, then its
stability is known in terms of the test
requirements. If the stability is not
known then It must be determined, even
for short studies. Storage stability needs
to be known even il the material is used
"immediately". If enough information is
known about the material to support Its
stability from other testing then its
stability is known and the requirement
is met However, theoretical stability is
not considered to be adequate. The
method used to compensate for poor
stability, such as daily mixing or
immediate application, is a technical
issue that cannot be specifically
prescribed In GLP standards.

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Fadeql Register / VoL S4. No. 156 / Thursday, August 17, 1989 / Rules and Regulations 34041
2.	Test, control, and reference
substance handling—Comment; U the
test, control, or reference substance is
Inherently unstable, tTmay not be
possible to "preclude
deterioration * * Therefore, the
regulation should alloft for periodic
evaluation of the purity of the test
substance during a study to assure Its
integrity and replace it when shown to
be warranted.
Response: The intent la to prevent
deterioration due to handling. Periodic
testing is allowed under | 792.105(b) as
changed in the final rule.
3.	Mixtures of substances with
carriers—i. Comment Does { 792.113
require determination of uniformity,
stability, and solubility during field
residue studies? If so. does it require
analyses for each tank preparation? This
requirement would impose a large
burden on testing facilities performing
these types of studies.
Response: The purpose of this section
is to assure that the methodology used
to prepare the mixture is valid. Once the
methodology has been proven for a
particular mixture, it need not be
reconfirmed each time that mixture is
prepared For field trials, there will
likely already be data submitted to EPA
that support the uniformity, stability and
solubility of a substance in the carrier
when prepared by appropriate
methodology, i.e. according to the
proposed use or label. In such cases It
should not be necessary to test each
batch that is prepared for Held
application. However, field trials do
remain subject to the requirements of
this section. Where available data are
Inadequate to support uniformity,
stability, and solubility in a particular
case, then it is necessary for the data to
be generated under this section. Also,
there may be protocol stipulations
applicable to a particular study that
require tank mixture analyses in
addition to any provisions of this
section.
ii.	Comment¦ The range of
environmental condiben&encountered
in field trials are great and would
require extensive evaluations of
stability and solubility under numerous
environmental conditions. This amount
of data could not be evaluated prior to
study initiation.
Response: Section 792.113(a)(2) states
that the determination(s) shall be* *
under the environmental conditions
specified in the protocol and as required
by the conditions of the test" All
possible environmental conditions do
not have to be anticipated and tested
unless required in the prolocol.
iii.	Comment Short-term toxicity and
field residue studies should be exempted
from this section since supplementary
analyses are performed for other studies
with the same test subatance. The
analytical cost could equal or exceed
the cost of the remainder of the short-
term study.
Response: The GLP standards do not
require characterization for each study.
The characterization is required for each
test, control and reference substance.
The same substance may need to be
characterized only once, even if used on
multiple studies.
iv.	Comment The requirement for
stability and solubility should allow
flexibility tor the sponsor to make the
determination either before, during, or
after the study. When to determine the
stability is a business decision based on
knowledge of the risk of having to
repeat a study, if the stability data
negatively impacts the integrity of the
study.
Response: EPA understands lhat
requiring stability testing to be
completed prior to a study may
Introduce unreasonable delays. In
harmony with the modification of
S 792.105(b) to allow concurrent stability
testing of test control, and reference
substances. { 792.113(a)(2) is changed to
allow stability testing of mixtures to be
performed concomitantly with the study.
This allows flexibility and is consistent
with FDA's GLP regulations.
v.	Comment In the very early stage of
a compound's development there is a
need for basic acute toxicity tests.
However, there are no analytical
methods and calibrated reference
standards available to test the stability
of the test substance in the carrier
according to GLP standards. An
estimate of the stability of the
compound in an inert carrier like starch,
oil, or polyethylene glycol is possible
and should be sufficient as a
preliminary approach. The stability test
will be carried out as early as the
analytical methods are available.
Response: If a carrier is used, the
mixture with the carrier must go through
the same test, i.e. stability, solubility,
etc. Instability of the mixture in a
specific carrier Is important since it may
affect the apparent effects of the test
substance.
vi.	Comment• The assurances called
for in { 792.113(c) are not well defined.
How would the addition of the vehicle
used to facilitate mixing of the test
substance with the carrier to the control
system affect this requirement? If the
vehicle is identically mixed in control, is
there a need to show noninterference?
Response: Any vehicle used to
facilitate mixing must be shown not to
Interfere with the study. This includes a
vehicle control to determine Interaction
effect
C. Protocol for and Conduct af a Study
1. Protocol—Genera}—1. Comment
Section 792.120(b) (5), (7), (10), and (11)
should not apply to product chemistry
experiments.
Response: The term "(est system" fs
redefined to include any physical
matrix, which may thus be applicable to
product chemistry studies. However,
note that a study designed solely for the
determination of certain chemical or
physical characteristics of a test
substance are exempted from
s 792J 20(a) (5). (7), (10). and (11) as
described in | 792.135.
In additioa the word "or* prior to
"frequency" should be "and". This was
a typographical error noticed by one
commenter and has been corrected in
the final rule.
ii.	Comment Guidance is needed in
the final preamble lor presenting
addresses, as required by
{ 792.120(a)(3), of field and
environmental locations used fe' conduct
tests.
Response: The address of the testing
facility is the address of the "person"
(i.e. organizational unit or subunit) who
actually conducts the study. Even if this
organizational unit includes parts
situated in different locations it may still
be considered to have one address. The
address should be a permanent address
and would probably be synonymous
with the address of the study director
and/or testing facility's management.
iii.	Comment "Address of sponsor"
should be removed from this part to
maintain consistency with FDA GLP
regulations.
Response: EPA maintains that the
address of the sponsor is essential lo its
Inspectional process, which differs From
that of FDA.
iv.	Comment The requirement in
S 792.120(a)(4) to state the proposed
experimental start and termination
dates poses problems for field studies
where these dates cannot be predicted
with certainty. Would thia result in
protocol deviations whenever these
dates are not exactly met?
Response: The requirement to
document the proposed experimental
start and termination date in the
protocol does not suggest that a protocol
deviation occurs when the dale is not
met The term "proposed" signifies that
this date ia estimated. However, gross
deviation from the proposed date may
be a violation of the protocol, if there
are date-critical aspects of the study
that are Identified as such.

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a lie JwW Be^aNg J VoL 5<. N» lfift / Hwirtifij, ftqgusl 17. tgB9 } Rriaa>,aBd J^gnlattocs
». CanuiKiiL Section T92.120faflS) is
inappropriate because: (a) Justification
shouid be required only w^cn rooce Uw_r.
one test Byslem can be used in a study;
(b) where standard test systems are
used. 'justificetMA should not be
required', W ^uMif»c«k>n skouW only be
required for those that deviate from, or
fall outside the test standards; (d) ibis
requirement does not promote harmony
between the H>A and FDA CLPs
Response: EevrrcounentaJ studies ore
mare dereae thea heaitb effect* testing
and are sabpeci to details relevant to
test system design thai are more
chemically dependeat tbar is the case is
health effects studies. Furthermore.
$ 792.120(a)(5) is not seen to impose a
burden in tie cases described in this
comment, in the case vrbere only one
test system can be used, that is a
justification that should be stated. If a
standard test system is used because it
is the referenced system io EPA or
Organization Tor Economic Cooperation
and Development (OECDJ guidelines,
then citing the use of such guidelines is
sufficient justification. Thus, detailed
discussions are required only in the
relatively few cases where ibe 6tudv
design requires deviation ot special
choices to be made in selection of the
test system.
vi.	Comment: EPA should add "ranpe"
to § 792.120(a)(6) so it reads
"" " * body vreight range." since
without specifying rsnje. (he protocol
requirement could be misinterpreted to
mean that all individual body wights of
the test ¦system shotiki be tnofoded. This
would not be possible since exact
weights of test systems would not be
known wfcea the protocol is prepared.
Response: EPA 
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Federal Register / Vol. 54. No. 156 / Thursday, August 17. 1989 / Rules and Regulations 34043
reduce the responsibilities of the QAU,
i.e.. master schedule requirements, etc..
but do not eliminate thentn^
xi. Comment: The QAU should be
responsible for looking at the functional
components of the laboratory (e.g., all
melting points, alt GC/MS analyses,
etc.) rather than focusing on a particular
study, such as with toxicology studies.
Response: EPA agrees and is
modifying the inspectional requirements
of the QAU under { 792.35. This change
specifies that the QAU conduct
inspections and maintain records that
are appropriate to particular studies.
This gives latitude to the QAU with
respect to how the information is
gathered; i.e.. as part of the standard
review procedures of the laboratory, or
as needed for the teat. This change
should reduce burden in cases where it
is appropriate to maintain central
records regarding functional
components that affect several studies
rather than requiring such records to be
maintained separately.
H. Records and Reports
1. Storage and retrieval of records and
data—i. Comment:The phrase "beyond
quality assurance" in { 792.190(a) needs
clarification since it could be
ambiguously interpreted. Does tt mean
the date of the final approved report?
Does it mean beyond initial evaluation
of the specimens, since that was the
statement used in the corresponding
preamble section?
Response: EPA intends that the
specimens be retained until QAU
assures that their discarding does not
negatively impact the integrity of the
study. The wording is being changed to
"after quality assurance verification" to
clarify this intent.
ii.	Comment- Tissues and animal feeds
collected from non-toxicology studies
should also be discarded after quality
assurance verification. If EPA does not
intend for animal tissues to be retained
from residue studies thetv^arumal" not
appearing after "plants" fSin oversight.
Response: EPA did noHnclude the
term "animal" in the list since it would
potentially include tissues and feeds
from toxicology studies which must be
kept under the GLP standards. The
suggested wording would not provide
sufficient breadth to cover non-residue
samples. Therefore EPA will require that
all animal tissue samples, even from
non-toxicology studies, be included in
this section.
iii.	Comment- Retention time for MC-
labelled specimens needs to be
addressed since a facilities license limit
could be exceeded for storing
radioactive material.
Response: The problem of licensing
requirements is a facility responsibility
under GLP standards. EPA does not
agree that special consideration be
given to sample storage based on this
reasoning.
2. Retention of records—1. Comment-
The appropriate endpoint for specimen
retention in fi 762.195 should be baaed
on the integrity of the specimens and
use by the study director, or other
technical personnel not based on when
QAU personnel may perform a review.
Response: Quality assurance
evaluation is needed to assure that the
integrity of the data is not compromised
by the decision not to retain specimens.
For consistency, EPA is changing the
wording of j 792.195(c) to concur with
the wording of } 792.190(a).
ii. Comment: EPA should explicitly
state in j 792.195(i) that when exact
copies are substituted for original source
as raw data, then the original may be
discarded. In the pest EPA inspectors
have required retention of original data
sources even if exact copies existed.
The burden imposed by some EPA
auditors, that each copy must be signed
and dated, is unrealistic. Verification of
"batches" of reproduction copies is just
as meaningful and would eliminate most
of the unnecessary burden on personnel
and time resources.
Response: Specific wording advising
the discarding of raw data after copying
is not necessary or useful. "True copies"
will be acceptable as raw data by EPA
inspectors under S 792.190. Signing and
dating each copy may be impractical
and an acceptable alternative method
may be devised and incorporated into
standard operating procedures to ensure
the integrity of the copies. Laboratories
are cautioned that discarding originals
places additional burden on verification
of the authenticity of the copies.
III. Regulatory Requirements
A. Executive Order 12291
Under Executive Order 12291, EPA is
required to judge whether a rule is a
"major" one and Is therefore subject to
the requirement of a Regulatory Impact
Analysis. EPA has determined that
these amendments of the TSCA Good
Laboratory Practice standards do not
constitute a major rule because they do
not meet any of the criteria set forth and
defined in section 1(b) of the Order.
This rule was submitted to the Office
of Management and Budget (OMB] for
review as required by Executive Order
12291. Any comments from OMB to EPA
end any EPA response to those
comments are available for public
inspection at Information Policy Branch,
PM-223, U S. Environmental Protection
Agency, 401 M St.. SW., Washington. DC
20460; and at the Office of Management
end Budget, Washington. DC 20503. with
OMB requests marked "Attention: Desk
Officer for EPA."
B. Regulatory Flexibility Act
Under the Regulatory Flexibility Act, 5
U.S.C. 601, et seq., EPA is certifying that
these amendments to the Good
Laboratory Practice standards will not
have a significant impact on small
businesses. Further, the revisions to the
TSCA GLP standards which reflect the
FDA GLP revisions primarily provide
relief from the original GLP standards
(ICF1987). Therefore, these amendments
to the TSCA GLP standards are not
expected to have a significant economic
impact on a substantial number of small
businesses since little or no economic
impact is expected from the changes
overall.
List of Subjects in 40 CFR Pari 792
Chemicals. Environmental protection.
Good laboratory practices. Hazardous
materials. Laboratories. RecordkSiping
and reporting requirements.
Dated: July 27. 1989.
William K. Reilly.
Administrator.
Therefore. 40 CFR part 792 is revised
to read as follows:
PART 792—GOOD LABORATORY
PRACTICE STANDARDS
Subpart A—General Provisions
Sec.
792.1 Scope.
792.3 Definitions.
792.10 Applicability to studies performed
under grants and contracts.
792.12 Statement of compliance or non-
compliance.
792.15 Inspection of a testing facility.
792.17 Effects of non-compliance.
Subpart B—Organization and Personnel
792.29 Personnel.
792.31 Testing facility management.
792.33 Study director.
792.35 Quality assurance unit.
Subpart C—Facilities
792.41 General.
792.43 Test system care facilities.
792.45 Test system supply facilities.
792.47 Facilities for handling test, control.
and reference substances.
792.49 Laboratory operation areas.
792.51 Specimen and data storage facilities.
Subpart D—Equipmeot
792.81 Equipment design.
792.63 Maintenance and calibration of
equipment.
Subpart E—'Testing Facilities Operation
792.81 Standard operating procedures.

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34044 Federal Register J Vol 54, Jjp. 15a J Tharaday, August 17, tfl89 / Arias
See
7MLB l«9BtlM<«luH8M.
7itas Aaiiaal sad oOnrMtjvism cars.
8dbp«Hf fH GoofcoL id Ksfwencs
Mbataaoaa
792.105 Test. control, and reference
substance <4ar#cl«riMt©S.
792.107 Test, control, and reference
•wbatsncs hasdhng.
79ZT13 MUfuBsdfstjbunanes wlOi
carriers.
Subpart G—for and Coodect of A
Study
791.120 ftOtOCOl
792.130 Condaetof astudy.
79Z.US fhyrical and ciwrmcal
cfaaractHi 11 Hi ¦! Hasina.
Subpart! H and 1—{Reserved!]
Subpart J—Baoaeds and Reports
792.165 Hapartint of afudy results.
792.180 Siotagsaad retrieval of Moonis and
data.
792.195 Retention of records.
Authority: IS U.S.C. 2003.
Subpart A—General Provieions
$ 7t2.t •eope.
(n) Thw port prescribes good
laboratory practices for conducting
studies relating to health effect*,
environmental effects, and chemical fate
testing. This part is intended to ensure
the quality and integrity of data
submitted pursuant to testing consent
agreements and test rules issued under
section 4 of the Tonic Substances
Control Act (TSCA) (Pub. L. 64-460. 90
Stat. 2006,15 U.S.C. 2603 et seq.).
(b)	This part applies to any study
described by paragraph (a) of this
section which any person conducts,
initiates, or supports on or after
September 1& HISS.
(c)	it is EPA's policy thai ail data
developed wider section 5 of TSCA be
in accordance with provisions of tfaiB
part. If data aie not developed in
accordanoe «rtth the provisions of this
part EPA will con airier such data
insufficient to evaluate the health and
environmental effects of the chemical
substances unless the suhmltle:
provides additional iafonBegSB
demonstrating that the data-are reliable
end adequate.
{792.3 MWMm.
As used in this part the foHew'mg
terms shall here the meanings specified:
Batch means a specific quantity or lot
of a test control or reference substance
that has been characterized according to
§ 792.105(a).
Carrier means any material including
but not	to. feed, water, soil, and
nutrient media, with which the test
substance is	for
administration to a test system.
Control aabstancemo&as sny
chemical substance or mixture, or soy
other material other lhan a test
substance, feed, or water, that Is
admiulsteced to the test system In the
course of a study for the purpose of
establishing a basis for comparison with
the test substance far chemical or
biological measurements.
EPA means the U.S. Environmental
Protection Agency.
Experimental start date means the
first dale 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 end Drug
Administration.
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 organisational element except
the study director, designated by testing
facility management to perform the
duties relating to qaaiity assurance of
tbe studies.
flaw 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 ere 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 oopy or exact transcript may be
substituted for the original source as
raw data. Haw data" may include
photographs, microfilm or microfiche
copies, oomputer print oats, magnetic
media, including dictated observations,
and recorded data from automated
instruments.
Reference substance means any
chemical substance or mixture, or
analytical standard or material oiher
than a test substance, feed, or water,
that is administered to or used in
analyzing the lest system in the course
of a study for the purposes of
establishing a basis for comparison with
the teat substance for known chemical
or biological measurements.
Specimen means any material derived
from a test system for i""»inan«i or
analysts.
Sponsor means:
(1)	A person who initiates and
supports, by provision of finnnrial or
other resources, a study;
(2)	A person who submits a study to
the EPA in response to a TSCA section
4(a) test rule and/or a person who
suhmks a-ekufy uadac a JESCA aedioa 4
testing w""w| ^gteemeot or a TSCA
section 5 rule or order to the extent die
agreement, nde et arder references this
part or
(3) A testing farikty, if it both initiates
and actually conduct* the study.
Study means any experiment at one or
mare test sites, In which a test
substance is	in a test system
nnHpr laboratory conditions or in
environment to determine or help
predict its effects, metabolism,
environmental rJipmimil fate,
persistence, or other characteristics in
humans, other living oiganisms. 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 "»""«¦ the individual
responsible for the overall conduct of a
study.
Study initiation date means the date
the protocol is wgoed by the study '
director.
Test substance means a substance or
mixture administered or added to a test
system in ¦ study, which substance or
mixture is ttsed to develop data to meet
the requirements of a TSCA eection 4(a)
test rule and/or is developed under a
TSCA section 4 testing consent
agreement or section 5 rule or order to
the extent the agreement rale or order
references this part
Test system means any animal, plant,
microorganism, rtwirnt or physical
matrix, mchiding bat not limited to. eoil
or water, or component* thereof to
which the test control, or reference
substanoe ie administered or added for
study. 'Test system" also includes
appropriate groups or components of the
system Dot treated with the test oontroL
or reference aubstaace.
Teetmg facility mams a person who
actually conducts a study, Le. actually
uses the teat substance in a test system.
"Testing facility" eaoaanpesses only
those operational wmMt that an being er
have been ased to coadaot studies.
TSCA moans the Toxic Substances
Control Act (ISU.&C. 2801 et seq.)
Vehicle any agent which
facilitates the aixtws. diapers too. or
solubilization of a teal subistaxoe with a
earner.
8782.10 AppticaMfty to studies
parlor mad under grants and contracts.
When a sponsor or other person
utilizes the aerwees of a consulting
laboratory, contractor or gsaalee to

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Fadwad aagirtac / Vol 5*. No. 15» / Tktutdayi August 17. 1989 / Rtdes and Regulation* NMI
perform all or a part of a study to which
this part applies, it shall notify the
consulting laboratory, contractor or
grantee that the service is. dr-ia^part of.
a study that must be conducted io
compliance with the provisions of this
part.
t 792.12 Statement of compliance or noo-
compllaftoe.
Any person who submits to EPA a test
required by a testing consent agreement
or a test rule issued under section 4 of
TSCA shall include in the submission a
true and correct statement signed by
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:
or
(b)	A statement describing in detail all
differences between the practices used
in the study and those required by this
part: or
(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.
§792.15 Inspection of ¦ testing facWty.
(a) A testing facility 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 die 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 the EPA may seek
production of these records in litigation
or formal adjudicatory hearings
(b| EPA will 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 data developed by a
testing facility or sponsor t&at refuses to
permit inspection in accordance with
this part The determinatiojCthst a study
will not be considered reliable"does not.
however, relieve the sponsor of a
required test of any obligation under
any spplicable statute or regulation to
submit the results of the study to EPA.
(c) Since a testing facility is a place
where chemicals are stored or held, it is
subject to inspection under section 11 of
TSCA.
§792.17 ENacts of noa-compllanca.
(a) The sponsor or any other person
who is con ducting or has conduciad a
test to fulfill the requirements of a
testing ooosent ayosiacnt or a test rule
issued under section 4 of TSCA will be
in violation of section lfi of TSCA if:
(1)	The test is not being or was not
conducted in accordance with any
requirement of this part
(2)	Data or information submitted to
EPA under this part (including the
statement required by 8 792.12) include
information or data that are falsa or
misleading, contain significant
omissions, or otherwise do not fulfill the
requirements of this part; or
(3)	Entry in accordance with | 792.15
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.
(b)	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.
(c)	If data submitted to fulfill a
requirement of a testing consent
agreement or a test rule issued under
section 4 of TSCA are not developed In
accordance with this part. EPA may
determine that the sponsor has not
fulfilled its obligations under section 4
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 0—Organization and
Personnel
5 7V2J9 Personnel
(a)	Each individual engaged in the
conduct of or responsible for the
supervision of a study shall have
education, training, and experience, or
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 sheU be s sufficient number
of personnel for tbe 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 control and
reference substances and test systems.
(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
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 advene affect
on a study.
§ 792J1 Tasting facility management
For each study, testing facdity
management shall:
(a)	Designate a study director as
described in { 792.33 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 { 792.35.
(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.
$729.33 Study director.
For each study, a scientist or other
professional of appropriate education,
training, and experience, or combination
thereof, shall be identified as tbe study
director. The study director has overall
responsibility for the technical conduct
of the study, as weii as for the
interpretation, analysis, documentation.

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34048 Federal Register / Vol. 54. No. 158 / Thursday, August 17. 1989 / Rules and Regulations
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
S 792.120 and is followed.
(b)	All experimental (Jala. 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 good laboratory
practice regulations are followed.
(f)	All raw data, documentation,
protocols, specimens, and final reports
are transferred to the archives during or
at the close of the study.
9 782.35 Quality mouranc* 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:
(1)	Maintain a copy of a master
schedule sheet of all studies conducted
at the testing facility indexed by test
substance and containing the test
system, nature of study, date study was
initiated, current status of each study,
identity of the sponsor, and name of the
study director.
(2)	Maintain copies of all protocols
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
inspection, the study inspected, the
phase or segment of the study inspected,
the person performing the inspection,
findings end problems, action
recommended and taken to resolve
existing problems, and any scheduled
date for re-inspection. 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 Anal 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
{792.41 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.
{ 792.43 Test system car* fsdim**.
(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.

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FnriawA Begrtw. /-Vol S4( N«. 158 / Thursday, August 17. 1969 ,/ Rulgg and RggulaUoni 34M7.
(h) For pJants. aa adequatesupply of
soil of the appropriate composition, as
specified in the protocol, shall be
available as needed
§ 792.45 Tut system Supply fsclltos.
(a) There shall be storage areeft as
needed, for feed, nutrients, soils,
bedding. supplf««. end equipment.
Storage areas (or feed, nutrients, soils,
and bedding shall be separated from
areas where the test systems are located
and shall be protected against
infestetion or contamination. Perishable
supplies shall be preserved by
appropriate means.
(bl When appropriate, plant supply
facilities shall be provided. These
include:
(IJ Facilities, as specified in the
protocol, for holding, cultunng, and
maintaining alaae ard aquatic plants
{2) Facilities, es specified in the
protocol, for plant growth, including bu!
not li.T.ited to. greenhouses. growth
chambers, light banks, and fields.
1c] When appropriate, facilities for
aquatic animal tests shall be provided.
These include but are not limited lo
aquaria, holding tanl
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34048 Fbderal Register / Vol. 54, No. 158 / Thursday, August 17, 1989 / Rules and Regulations
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 Bhall be retained.
(d)	Warm-blooded animafcrfldult
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 ByBtem
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
multispedes tests need not be housed in
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 shell be cleaned^nd
sanitized at appropriate in&vals.
(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 insuch 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 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
9792.105 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 such location of
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. The stability of the test, control or
reference substance shall be determined
before the experimental start date or
concomitantly 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 number (CAS) or code number,
batch number, expiration date, if any,
and, where appropriate, 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.
(d)	For studies of more than 4 weeks
experimental duration, reserve samples
from each batch of test, control, and
reference substances shall be retained
for the period of time provided by
8 792.195.
(e)	The stability of test control, and
reference substances under storage
conditions at the test site shall be
known for all studies.
S 792.107 Test control, and reference
•ubstance 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-
Id) The receipt and distribution of
each batch is documented. Such
documentation shall include the date
and quantity of each batch distributed
or returned.
{792.113 Mixtures of substances with
ctrvt9Tt>
(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 experiment to determine the
solubility of each test control, or
reference substance in the mixture by
the testing facility or the sponsor before
the experimental start date.
(3)	To determine the stability ofrlfe
test control or reference substanc»4n
the mixture before the experiment^
start date or concomitantly according to
written standard operating procedures,
which provide for periodic analysis of
each batch.
(b)	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.
(c)	If a vehicle is used to facilitate the
mixing of a test substance witl\ a carrier,
assurance shall be provided that the
vehicle does not interfere with the
integrity of the test
Subpart O—Protocol for and Conduct
of a Study
(792.120 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:
(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)
number or code number.
(3)	The name and address of the
sponsor and the name and address of
the testing facility at which the study is
being conducted.

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Fbderal Register / Vol 54. No. 158 / Thursday, August 17, 1989 / Rules and Regulations 34049
(4)	The proposed experimental start
and termination dates.
(5)	Justification for selectidttB? the
test system.
(6)	Where applicable, the aumber.
body weight sex. source of SOpply,
species, strain, substrain, and age of the
test system.
(7)	The procedure for identification of
the test system.
(S) 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 proposed
statistical method.
(b) All changes in or revisions of an
approved protocol and the reasons
therefor shall be documented, signed by
the study director, dated, and
maintained with the protocol.
9 792.130 Conduct of a study„
(a)	The study shall be conducted In
accordance with the protocol.
(b)	The test systems shaft 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 daCa
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.
5 792.135 Physical and cttamicai
characterization studias.
(a)	All provisions of the CLPs 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).
(b)	The following CLP standards shall
not apply to studies designed to
determine physical and chemical
characteristics of a test control, or
reference substance:
} 792.31 (c). (d). and (g)
} 792.35 (b) and (c)
} 792.43
i 792.45
{ 792.47
i 792.49
( 792.61(b) (1). (2). (6) through (9). and (12)
J 792.90
i 792.105 (a) through (d)
I 792.113
I 792.120(a) (5) through (12). and (15)
i 792.135(8) (5) through (8). (10). (12). and (14)
t 792.195 (c) end (d)
Subparts H and I—[Reaarvtd]
Subpart J—Racords and Raporta
! 792.165 Reporting of study raautts.
(a) 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, terminated, or discontinued.
(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) number or code
number, strength, purity, and
composition, or other appropriate
characteristics.
(5)	Stability, and when relevant to the
conduct of the study, the solubility of
the test control, and reference
substances under the conditions of
administration.
(0) 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 or
other test organisms used, sex, body
weight range, source of supply, species,
strain and substrain, age. and procedure
used for identification.
(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 dlrecfc^
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.
(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 S 792.35(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.

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S4Q5& Fadetal Relator / VoL 84. Ho. 1S8 / Tbtraday. August 17, lflflfl f Bates and ?»ylat.ja»
id) A copy of the final report and el
any amendment to ft shall be
TnairUined by the sponsoT and tire l«1
Facility.
$7M.1K 8tor»g«[«utortio(r*cwtfs
•net data.
(a J All raw data, docowenration,
records, protocols, specimen, aad final
reports generated at • resol t cf a Mod?
shall be retained. Speciment obtained
from mutagenicity tews, specimens of
soil, wsi*r, and jptap;*, sm) wej
specimens of blood, urine, feces. end
bioVoSic«1 tbiids, do net need to be
retained after qtafiiy atgutaotx
verification. Corr&&potvneiKe and oYhsr
document* relating to interpretation and
evaluation of data, ether Vnsn those
document! contained m the fmai report,
also thaU be retained.
[b| There shall be archive* (or orderly
storage and expedient retrieval of afl
rat* data, document a lion, protocols,
specimens, and interim and ficvat
reports. Oaoiiaans  Specimens, samples, or o&.^r r.oti-
doenmemary materials need TiOite
retained cfteTEPA has notified®
writrnp the sponsor or testing facility
holding the material that retenrion is nc
Id riser reeruIrvJ by EPA. Soch
rctifrcaaon normalh' ml!! be fnrri^hed
upon reqtrejf after EPA or FDA has
completed an amfrt of the perticoter
study icr which the mareriaJs re/ate and
EPA has concluded that the study uss
conducted in accordance with this part.
(j) Becordt reqnJred by Oris part may
be wt^iredetliieT ssorrgiwl rero'ds or
as true copies such a* photocopies,
microfilm, nricroTtche, or other accvuate
reproductions of the original records.
|FR Doc. «S~1908fi Filed 8-lfi-OT; 845 !it|
KUMCOHtsiMMl

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Thursday
August 17, 1989
Part IV
Environmental
Protection Agency
40 CFR Part 160
Federal Insecticide, Fungicide and
Rodenticide Act (FIFRA); Good
Laboratory Practice Standards; Final Rule

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34052 Federal Register / Vol. 54, No. 158 / Thursday. August 17. 1989 / Rules and Regulations
ENVIRONMENTAL PROTECTION
AGENCY
40 CFR Part 160
[OPP-300165A; r&L-351fl-J|
RIN 2070-ABC 8
Federal Insecticide. Fungicide anc
Rodentlcide Act (FIFRA); Good
Laboratory Practice Standards
AGENCY: Environmental Protection
Agency (EPA).
ACTION: Final rule.
summary: EPA is issuing this final rule
that expands the regulations to require
compliance wi'.h Good Laboratory
Practice (GLP) standards for testing
conducted in the field and for such
disciplines of testing as ecological
effects, chemical fate, residue chemistry,
and, as required to be submitted by 40
CFR 15B.640, product performance
(efficacy testing). EPA is amending these
regulations to ensure the quality and
integrity of all data submitted to EPA in
conjunction with pesticide product
registration, or other marketing and
research permits. EPA is also amending
the FIFRA GLP standards to incorporate
many of the changes made by the Food
and Drug Administration (FDA) to its
GLP regulations (52 FR 33768. September
4,1987; 21 CFR Fart 58).
DATE: Effective: This rule becomes
effective on October 16.1909.
Compliance: All studies conducted,
initiated, or supported after the effective
date of this rule shall be subject to these
regulations.
FOR FURTHER INFORMATION CONTACT:
Stephen Howie. Office of Compliance
Monitoring (EN-342). Rm. E-707B, 401 M
St.. SVV.. Washington. DC 20460.
Telephone: (202) 382-7825.
SUPPLEMENTARY INFORMATION:
Following is an index to the remainder
of this preamble:
I.	Introduction
A.	Legal Authorily.
B.	Background.
C.	Consistency With FDJt&fcP Regulations.
D.	Publication of the Complete Rule.
II.	Summary of Comments and Responses
A.	General Provisions
B.	Organization and Personnel.
C.	Facilities.
D.	Equipment.
EL Testing Facilities Operation.
F. Test and Control Substances.
C. Protocol For and Conduct of A Study
H. Records and Reports.
III.	Regulatory Requirements
A.	Executive Older 12291.
B.	Regulatory Flexibility Act.
C.	Paperwork Reduction Act.
L iDtroductMa
EPA is amending the FIFRA GLP
standards (40 CFR Part 160) to
incorporate many of the changes made
by the Food and Drug Administration to
its GLP regulations.
A.	Legal Authority
These standards 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 406,
409, and 701 of the Federal Food. Drag
and Cosmetic Act (FFDCA1, 21 U.S.C.
3C1 et seq.. and the Reorganization Plan
No. 3 of 1970.
B.	Background
EPA originally published FIFRA CLP
standards in the Federal Register of
November 29.1983 (48 FR S3946J, which
were codified as 40 CFR part 160. At the
same time. EPA published GLP
standards applicable to testing required
under the Toxic Substances Control Act
(TSCA, 48 FR 53922, 40 CFR part 792).
These regulations were promulgated in
response to investigations by EPA and
FDA during the mid-1970s 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. For
instance, some studies had been
submitted which did not adhere to
specified protocols, were conducted by
underqualified personnel and
supervisors, or were not adequately
monitored by study sponsors. In some
cases results were selectively reported
underreported. or fraudulently reported.
In addition, tt was discovered that some
testing facilities displayed poor animal
care procedures and inad. cosie record-
keeping techniques. The FLF3A GLP
standards specify minimum practices
and procedures which must be followed
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.
When EPA published its final FIFRA
and TSCA GLP standards 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 pert 58.
Differences between the two Agencies'
current GLP regulations exist onFy to the
extent necessary to reflect the Agencies'
different statutory responsibilities nnder
TSCA. FIFRA. and the Federal Food.
Drug and Cosmetic Act (FFDCA).
Similar to the FDA GLP regulations, the
FIFRA and TSCA GLP standards
delineate standards for studies designed
to determine the health effects of a test
substance: however, the TSCA GLP
standards also contain provisions
related to environmental testing (i.e..
ecological effects and chemical fate).
Compliance with EPA's FIFRA and
TSCA GLP standards has been
monitored through a program of
laboratory inspections and study eudits
coordinated between EPA and FDA.
Under an Interagency Agreement
originated in 1978. FDA carries out CLP
inspections at laboratories which
conduct health effects testing. EPA
primarily performs GLP inspections for
environmental laboratories and
conducts data audits for health effects
and environmental studies.
After a thorough review of its CLP
regulations and compliance procrc:-,i.
FDA concluded that some of the
provisions of the GLP regulations
needed to be clarified, amended, or
deleted to reduce the regulatory burden
on testing facilities. According!*. FDA
revised its GLP regulations in tier
Federal Register of September i f967
(52 FR 33768). These GLP revisiorvs are
Intended to simplify the regulations
without compromising study integrity
EPA agrees with FDA that many
provisions cf the GLP regulations car. be
streamlined without compromising the
goals of the GLP standards Therefore.
EPA is amending the FIFRA GLP
standards to incorporate many of thr>
changes made by FDA to its revised
CLP regulations. In addition. EPA is
expanding the scope of the FIFRA GLP
standards to include the environment
testing provisions currently found in the
TSCA GLP standards. EPA's revision to
the FIFRA GLP standards aiso extends
their scope to inciude product
performance data (efficacy testing! as
currently required to be submitted by 40
CFR 158.640. In summary, the FIFRA
GLP standards will allow EPA to ensure
the quality and integrity of all data
submitted in support of pesticide
product research or marketing permits.
Elsewhere in this Federal Register. EPA
is making similar changes to the TSCA
GLP standards.
C Consistency With FDA CLP
Regulations
It is EPA's policy to minimize the
regulatory burden on the public which
might arise from conflicting
rajnirenents promulgated under
different regulatory authorities. In
keeping with this policy, the final FIFRA
19B3 CLP standards. 40 CFR part 160.
followed the format and. with few

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Fad—ai Ragaiw / Vol. 54. No. 158 / Thursday, Aaguat 17. 1988 / Bales and Bagubtiaas MBH
exceptions, the wording of FDA'a Finai
CLP regulations. 21 CFR part 58.
Differences between the EPA and FDA
CLP regulations were based urno-
varying needs and reepoasibi&S^s under
each Agency's regulatory statutes. This
revision to the FIFRA CLP at^sh&tla
Follows this same policy by conforming
10	many of the changes FDA made to its
CLP regulations, published in the
Federal Register of September 4.1987
\52 FR 33768). EPA has varied from
FDA's revised GLP regulations only
when necessary due to EPA's statutory
responsibilities. The most significant
differences between the EPA and the
FDA revised GLP regulations are the
scope of the testing and test systems
affected.
More specifically. EPA is requiring
compliance with the FIFRA GLP
standards for all studies submitted to
FJA which are intended to support
pesticide product research or marketing
permits. Under the 1983 FIFRA GLP
regulations EPA only required GLP
compliance under FiFRA for health
effects lesting. However, unlike FDA.
testing required by EPA in support of
research or marketing permits may
include ecological effects,
environmental and chemical fate, and
efficacy (as stipulated by 40 CFR 158.640
Product performance data
requirements), as well as health effects
testing. Therefore, in an effort to attain
consistency in the qualify and the
integrity of all data submitted to the
Agency. EPA has determined that it is
necessary to expand the scope of the
FIFRA CLP standards to require that all
types of testing which are used to obtain
data in support of research or marketing
permits be conducted in accordance
with the amended GLP standards that
are required to be submitted under 40
CFR 158 640.
EPA's amended FIFRA GLP standards
also vary from FDA's in their coverage
of testing conducted in the field. To
ensure the quality and integrity of ail
data submitted in support otaeaearch or
marketing permits. EPA bel&BS'that
CLP standards mux apply vf£*Kever
data collection occurs. Bec«w?-macy of
the test data required by EPA under
FIFRA are developed in the field, or
more accurately in outdoor laboratories
11	e., ground water studies, air
monitoring studies, degradation in soil,
etc.). EPA is including field testing
within the scope of the standards.
EPA's FIFRA GLP standards aiso
differ from FDA's in the scope of the
requirements provided lor test system
care facilities* test system supply
facilities, aod test system care. Because
testing required by FDA is focused on
health testing, in which aninais are the
central test system, it is appropriate for
FDA's GLP regulations to focus on
requirements For appropriate animal
care facilities (21 CFR 5M3). adequate
animal supply facilities (21 CFR 58.45).
and proper animal care (21 CFR 58.00).
However, the broad range of testing
required by EPA may involve plants,
sods. and microorganisms, as well as
animals, for the primary test systems. To
ensure the quality and integrity of all
data submitted to EPA 1160.43 Animal
care facilities. S 160,45 Animal supply
facilities, and 1 100.90 Animal care are
being expanded to cover facilities,
handling, and care of all test systems.
Accordingly. EPA Is retitliAg these
sections as follows: 1180.43 Test system
care facilities. { 160.45 Test system
supply facilities, and J 160.00 Animal
and other test system care. Further, in
most instances. EPA is replacing the
term "animal." which is currently used
in the FIFRA GLP standards, with the
broader term "test system." Specifically,
this change occurs in $$ 180.43.160.45.
180.81.160 90 and 180.120. These
changes are further discussed in Unit II.
of this preamble.
The remaining differences between
the EPA and FDA GLP regulations are
described in the preamble to this final
rule and the preamble to the FIFRA GLP
standards, published in the Federal
Register of November 29,1983 (48 FR
53946). EPA has coordinated this final
rule with FDA and has considered
public comments on the December 28.
1987 EPA proposal (52 FR 48920).
D Publication of the Complete Rule
The entire FIFRA GLP rule (40 CFR
part 100) is published in this notice to
simplify interpretation and facilitate the
use of this notice by the regulated
community. The following lists the
sections of 40 CFR part 180 that were
changed from the 1983 rule:
Sections
affected
Changes
-4-
160.3
'.60.29
160.31
160.35
160.41
>60.43
160.45
160.47
160 48
160.53
SacBons
affected
Change*
160.61
Rawed.
160.S3
(t>). revised.
1E0.B1
tw ID. (2). P). (5). (8). IT), and (123 snd

(cl. reused.
160.00
Revised.
Subosft f
1IWlt
t60.105
Ran—a.
160 107
Hearing and Introductory lead. rvmaO.
160.113
Revised.
160 120
(a). r*"i—d
160 130
(di and (•). nMd
160 135
Added.
160.185
nei*«f start OsM."
"Experimental MrmmsDon dais,"
"Ha
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34054 Federal Register / Vol. M. No. 158 / Thursday; August 17. 1989 / Rules and Regulations
to all existing and prospective product
performance studies required under 40
CFR 158.940.
2. Definitions—a. Batd&Mle
definition of "batch" is-expanded to
include reference substances. This was
an omission in the propoAd-ruIe that is
corrected in the final rule to maintain
consistency with the use of the term in
{ 160.105(a).
b.	Carrier— i. Comment• The word
"systems" should replace the word
"organisms" in the definition of
"carrier," to be consistent with the term
"test system."
Response: EPA concurs with the
suggestion. To be consistent with the
definition of "test systems." the word is
changed accordingly.
ii. Comment¦ EPA should revise the
list in parentheses that follows the word
"material" in the definition of "carrier"
to make it all inclusive.
Response: EPA has decided to add the
phrase "including but not limited to
' * to indicate that the list provides
examples and is not meant to be all
inclusive.
c.	Control substance—i. Comment-
Since "material" conveys a broader
description than "substance" and is
already used in definitions for "carrier."
"control substance." and "reference
substance," "chemical substance"
should be changed to "chemical
material" in the definition of "control
substance."
Response: EPA does not believe that a
change in terminology is needed to
broaden the definition since the term
"material" is already included in the
present definition. The term "substance"
must also be retained to maintain
consistency with TSCA and the TSCA
CLP standards.
ii. Comment EPA should delete the
phrase "for no-effect levels" in the
definition of control substance. The
definition as written is too narrow and
excludes analytical chemistry (e.g..
chemical fate, residue chemistry]
operations where the term "control" has
a meaning distinctly differesl from
biological effects.
Response: Since the pilose of the
analytical control is to es&Sish
eventually that none of the materials
administered to the test system interfere
with identification of the test substance
and itB degradate(s) and metabolite(s).
EPA agrees that the terminology is too
limiting and is replacing the phrase "for
no-effect levels" with the phrase "for
known chemical or biological
measurements." The definition now
reads: "Control substance means any
chemical substance or mixture, or any
other materia) 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."
d.	Experimental start and termination
dates—Comment- These dates would be
difficult to predict, especially for field
studies, because they would be subject
to natural or man-made conditions that
cannot be controlled or anticipated.
Since the dates would be subject to
change, many protocol amendments
would be required, thereby creating an
undue administrative burden.
Response: The experimental start and
termination dates specified in the
protocol are merely proposed dates.
Therefore if the actual experimental
start or termination date is different
from the proposed dates no protocol
amendment shall be required.
e.	Reference substance—Comment: If
EPA intended the term "reference
substance" to include analytical and
calibration standards, then several other
sections of the proposed rule which
mention "reference substance," would
also require the same types of records to
be kept for analytical standards. This
would constitute an excessive burden
on management which would require
maintaining various records that do not
add any value to the study.
Response: The definition of reference
substance is intended to include
analytical reference standards.
Therefore. EPA has modified the
definition of "reference substance." as
follows: "Reference Bubstance means
any chemical substance or mixture,
analytical reference 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 purposes of
establishing a basis for comparison with
the test substance for known chemical
or biological measurements." EPA
believes this change eliminates any
ambiguity in the definition.
EPA disagrees that inclusion of
analytical reference standards in this
part constitutes an excessive
documentation burden or adds no value
to the study. Documentation which
supports defining analytical reference
standards should not require excess
paperwork since common laboratory
practices already require assurance of
the validity of standards In order to
make certain that the measurements are
accurate.
f.	Study—i. Comment: "Basic
exploratory studies" are excluded from
CLP standards, but the results of such
studies may be required to meet CLP
standards, if included in support of
research or marketing permits.
Response: EPA does not wish to
discourage basic exploratory testing and
does not explicitly require CLP
standards for such tests even if the data
are later submitted to EPA. However, if
the data are to be used in sole support of
a marketing permit such non-CLP
studies may not be accepted. CLP
standards are required when data is
developed in the context of a study that
is required to be submitted to EPA in
support of a research or marketing
permit. Where CLP standards were not
followed in the case of a study
performed with the original intent of
exploratory testing, a GLP compliance
statement should be included in the
study report to indicate this.
ii.	Comment- It is not clear what
constitutes separate studies and what
studies could be included under a single
protocol. Specifically, is a test system
located in several different geographical
locations a single study or would each
location by means of its particular
requirements need to be a separate
study?
Response: The protocol defines fvhal
the study entails. Therefore, if ttle(est
system for a specific study is located in
different geographical locations, the
protocol will describe the study as being
located at the different sites. EPA is
adding the phrase "at one or more test
sites" to the definition of "study" to
clarify the intent that more than one
field site may be included in one 9tudy.
iii.	Comment- The proposed definition
of study would imply that each
determination such as stability,
solubility, octanol water partition
coefficient, volatility, persistence, and
other data point determinations would
be separate studies with concomitant
requirements such as protocols and
quality assurance unit (QAU)
inspections.
Response: EPA intends that QAU
inspections as listed in { 160.35 be
conducted at intervals adequate to
ensure the integrity of the study for each
determination such as stability,
solubility, octanol water partition
coefficient, volatility, persistence, and
other data point determinations.
However, if done as part of a larger
study, then these determinations are
covered under the larger study's
protocol or standard operating
procedure (SOP). If they are submitted
to EPA as studies unto themselves, then
they do require their own protocols.
iv.	Comment: An experiment such as
product chemistry which does not
involve a test system cannot be
considered a "study" and therefore
would not be covered by CLP standards.

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Ptdml-gtjbf /- Vol 54. Wo. 1S0 / Thursday, Angust 17. 1989 f Rales and Regulation* 34S5S
Response: Studies designed to
determine the physical or chemical
characteristic* of a test substance are
included within the scope of these
regulations. Therefore. EPA intends to
include product chemistry experiments
in the definition of "study." litis change
is consistent with the definition of the
term "study" as it now appears, and as
it appears in the TSCA GLP &taacUrd» at
40 CFR Part 792. In the case of product
chemistry experiments. the test
substance itself may be the test system.
v.	Comment: The addition of the term
"or in the environment" to the definition
of "study" indicates that the change
extends the proposed regulations to field
s:udies. While it is necessary to ensure
the validity of all data collected, the
>.driety and special requirements of field
research have not been addressed in the
r.ew rules.
Response: These regulations are
intended to apply to all studies required
:o be submitted under FIFRA. including
those conducted in the field. EPA
rccogiuzes that field studies vary and
have special requirements, but believes
that the development of protocols and
SOPs by the testing facility provides
adequate flexibility in this respect.
vi.	Comment VVby are metabolism,
product performance, environmental
ond chemical fate, persistence and
residue listed in the definition of
'study", but not toxicology data or da'.;i
io assess hazards and product
chemistry.
Response: The list is not meant to be
i;rni:ra in any way. Data to assess
toxicology, hazards and product
chemiitiy are included under "effects"
and "other characteristics" under the
new definition of "study".
vii.	Comment: "Prospectively" should
not be deleted from the definition of
study. If the essence of GLPs requires a
carefully planned study end the
proposed rule is very strict about
documentation that must be completed
prior to the experimental starl date, how
can the CLP standards also apply to
studies that were generated without a
protocol or advance planning, such as
ppidemiology.
Response: EPA disagrees with the
comment. The term prospectively is
deleted because EPA wishes all studies,
including epidemiological studies where
past exposure to a study population is
determined or estimated retrospectively,
to be performed under GLP standards.
EPA recognizes that in such studies data
used may not have been generated in
conformance with FIFRA GLP
standards. However, it is EPA's position
that the epidemiological study itself can
be conducted and Mbrntttad to EPA in
accordance with the GLP standards.
Retrospective aspects of such studies
that are not performed according to GLP
standards, for example, test system
treatment, should be identified in the
compliance statement submitted with
the study report.
In addition, the types of studies
potentially not covered by these
regulations were expanded in the
definition of "study" to include
experiments involving test methods.
g. Study initiation and completion
date—Comment¦ EPA should delete the
definition of "study initiation date" and
"study oompletion date." since these
terms were not defined in the 1983 GLP
standards. The dates will be included in
the protocol and final report and do not
need further emphasis.
Response: EPA believes that it is
necessary to define the terms to
differentiate them from "experimental
start and termination" dates. These
terms indicate the dates on which
specific milestones occur during a study.
The definition i6 necessary to clarify
EPA's requirements, and lo ensure
consistency with FDA's GLP regulations
(52 FR 33780).
The phrase "close of the study" as
used in { 160.33(f). and the phrase
"study is completed" as used in
§ 160.195(b)(3) both refer to the "study
completion date." Therefore, as of the
study completion date: (1) Under
§ 160.33(f). the study director must
ensure that all raw data, documentation,
protocols, specimens, and final reports
are transferred to the archives: (2) after
this date under 5 160.185(c), corrections
or additions to the final report must be
in the form of an amendment by the
study director under the procedures
specified in that section: and (3) in the
applicable situations described in
§ 160.195(b)(3). records must be
maintained for a period of at least 2
years following the study completion
date.
Furthermore, the phrase "study is
initiated" as used in { 100.31(a). and the
phrase "study was initiated" as used In
5 100.35(b)(1) would refer to the "study
initiation date " Therefore, as of the
study initiation date: (1) Under
S 160.31(a). the testing facility
management would designate a study
director (2) under 1160.35(b)(1). the
study would be entered on the master
schedule sheet by the QAU: and (3)
under { 160.120(b). after this date all
changes or revisions in the protocol
would be documented, signed by the
study director, and dated. EPA also
expects that as of the study initiation
date, ander { 160.31(e). the testing
facility management would have
ensured that pereonnel. resources,
facilities, equipment, material, and
methodologies are available as
scheduled.
h.	Test system—Comment: What
constitutes the "test system" in tests of
pre-emergent herbicides, soil pesticides,
and product chemistry studies?
Response: The definition of "test
system" includes the statement that it is
	any * * * chemical or physical
matrix		 including subparts thereof
that are treated with the test, control, or
reference substance and also
appropriate components of the system
that are noQjgated. Therefore, test
systems ma^Hirfude the soils that
pesticides ase^pplied to. and in the case
of product dSemistry, the test system
may be the test substance itself.
EPA is including the term "reference."
which was inadvertently omitted from
the definition as it appeared in the
proposed rule. In addition. EPA is
replacing "e.g." in the parenthetical with
"including but not limited to" in order to
clarify that it is not our intent for the list
to be all encompassing.
i.	Vehicle—Comment The definition
of "vehicle" serves to clarify the GLP
standards, but there has been no
confusion based on the current
standards and this change is contrary to
EPA's stated objective of being
consistent with FDA's GLP regulations.
Response: EPA believes that
clarification is needed. The EPA GLP
standards cover a larger number of
types of studies and the need for
clarification of the meaning of
potentially ambiguous terms is greater.
B. Organization and Personnel
1.	Testing Facility Management—
Comment- The specific requirement to
document the replacement of the study
director as raw data Ehould be retained.
The "master schedule" should not be
considered "raw data" as was indicated
in the preamble (52 FR 4B923) to the
proposed rule.
Response: EPA deleted the
requirement that the replacement of a
study director must be documented as
"raw data" to conform to the revised
FDA GLP regulations. This is because
replacement of the study director must
be reflected on the master schedule
sheet, which is a study record that must
be retained.
In addition, the term "reference."
which was inadvertently omitted in the
proposed rulejwi been added to
S 160.31(d).
2.	Study Direstor—Comment:
Archiving tte^hrdy records within a
"reasonable-period" after the study
completion dote, instead of iH the dose
of the study as required by 1180.33(f),

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34056 Federal Register / Vol. 54. No. 158 / Thursday, Augupt 17. 1988 / Rules and Regulations
would not impact on the integrity of the
records.
Response: EPA believes that the
requirement that all raw^sft.
documentation, protocol, specimens,
and final reports be transferred to the
archives at a definitive tSftr; i.e. the
study completion date, is necessary.
This assures an intact audit trail for the
study.
3. Quality assurance unit—i.
Comment A QAU that is entirely
separate from and independent of the
personnel engaged in the conduct of the
study creates an unjustified financial
burden on some facilities. In some cases
it would be impossible to establish a
completely independent QAU with
qualified personnel.
Response: As stated in the proposed
rule (52 FR 48920). EPA does not require
the QAU to be a fixed, permanently
staffed unit whose only functions are to
monitor the quality of a study. EPA is
only concerned that there be a distinct
separation of duties between those
personnel involved with the conduct or
direction of a study and those personnel
performing quality assurance on the
same study. Therefore, g 160.35(a)
prohibits personnel from performing
quality assurance activities on their own
study. The regulations allow a study
director for a particular study to serve
as a part of the QAU or as the QAU for
a different study. FDA noted (52 FR
33771) that it was aware that many
small laboratories could not afford the
operation of a permanently staffed
QAU. EPA would like to point out that
in those situations where there are
different individuals performing the
quality assurance functions for different
studies, each individual is required to
maintain that portion of the master
schedule sheet which relates to the
study being monitored. For this reason,
EPA agrees with FDA's conclusion that
the separation of functions on a study-
by-study basis. as permitted in the
existing and revised regulations, would
provide effective quality assurance. In
view of the potential gaiiQQ~,
management to sponsor^ed to EPA.
through the added assuraacs of well-
conducted studies, the increased costs
are thereby justified. EPA believes that
its intent is more clearly Indicated by
the changes now being msde.
li. Comment- EPA should delete the
requirement to index the master
schedule by lest substance, and the
QAU should only be required to index
the master schedule to facilitate
retrieval of the information monitored.
Response: EPA acknowledges that a
test facility may have several studies in
progress on each test substance that is
listed on the master schedule sheet.
However. EPA concludes that deleting
the requirement to index by test
substance would be inappropriate, since
the master schedule Bheet is the
mechanism through which the QAU can
assure management that the facilities
are satisfactory and there are adequate
numbers of competent personnel
available to perform the scheduled
tasks. Furthermore, i 160.31(e) requires
that management assure that study
materials (e.g.. test substances) are
available as planned. Therefore,
elimination of this requirement would
hinder a major function of the master
schedule sheet and hamper the conduct
of a critical management role.
iii.	Comment: Laboratory management
should have the discretion to determine
who enters the data into the master
schedule, as long as the required
information is listed.
Response: EPA believes that
management retains such discretion
since it is involved in determining the
composition of the QAU and it provides
an adequate number of such personnel
(Sfi 160.31(c) and (e)). The QAU is
distinguished by training that ensures
that QAU functions are properly
conducted. As stated above, study
personnel may belong to the QAU as
long as they are not performing the QAU
functions associated with Bludies they
are involved in.
iv.	Comment Do all studies conducted
by an analytical laboratory have to be
listed on a master schedule, or just those
studies that will be. or likely be,
submitted to EPA?
Response: The CLP standards
specifically exempt many product
chemistry studies as described in
I 160.135. The master schedule need
only list those analytical chemistry
studies that will be or will likely be
submitted to EPA.
v.	Comment The requirement for
inspection of each study under
1 160.35(b)(3) regardless of duration is
excessive for the quality assurance
needed to address study integrity,
especially where studies are performed
by highly standardized procedures. The
repetitive inspection of these typeB of
studies would consume large amounts of
time for both the study personnel and
QAU staff. Auditing each study is not
necessary to ensure the work is
conducted in compliance with the
regulations. Random sampling
procedures should be allowed in
selecting studies and phases of studies
to inspect to decrease the work load and
resource requirements of the QAU.
Response: EPA does not believe that a
random inspection program would be an
appropriate method of evaluating a
Btudy. Generally, random sampling
provides an adequate means of quality
control where analysis involves
repetition or identical procedures.
However, any assumption that the
conduct of one phase of one study
would be representative of another
would be invalidated by the differences
among study personnel and the
operations they conduct. Furthermore,
this requirement is not intended for all
routine studies. Section 160.35(b) is
among the exclusions for chemical and
physical characterization studies as
listed in fi 160.135(b).
In conformance with the revised FDA
GLP regulations (52 FR 33780], EPA
modified the requirements of
1 160.35(b)(3) to provide for Inspections
of a study on a schedule adequate to
ensure the integrity of the study. The
changes to this section will allow the
QAU the necessary latitude to adjust its
monitoring activities to meet the
individual needs of each study.
However, each study, no matter how
short, must be inspected at least once
while in progress. EPA expectsjhpt by
allowing the QAU flexibility iru« J.
designing a reasonable inspection-
schedule, the goal of ensuring tlje"
quality of the study can be best'
achieved.
vl. Comment- EPA indicates in the
preamble to the proposed rule
[5 160.35(e). (52 FR 48923)) that all QAU
records will now be routinely available
to inspectors. Existing GLP standards
treat certain QAU records as
confidential, and explicitly state that the
only QAU records to be reviewed by
EPA auditors would be the master
schedule (e.g.. the inspection dates,
study inspected, the phase or segment of
the study inspected and the name of the
individual performing the inspection). If
QAU records for findings and corrective
action are available on an auditor's
request, QAUs would lose their
effectiveness.
Response: EPA shares the concerns of
the commenters that access to bII parts
of a QAU inspection would weaken the
inspection system, and recognizes the
need to maintain a degree of
confidentiality. Therefore, records of
findings and problems, as well as
records of corrective action
recommended and taken, are exempt
from routine EPA inspections, except
under special circumstances as
indicated in S 160.15. However. EPA
maintains that all other reports and
records must be easily accessible and
made available to EPA and FDA
inspectors when requested as indioated
in } 160.35(c).

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Federal Register / Vol. 54, No. 158 / Thursday, August 17. 1989 / Rules and Regulations 34057
C. Facilities
1.	General—i. Comment: Outdoor
testing facilities should not be under
GLP standards since: (a) Outdoor test
facilities will be conducting studies
according to approved protocols; (b)
ensuring suitability is highly subjective
based on the diverse number of possible
locations: (c) there is a concomitant lack
of clear standards for determining
suitability of locations. Procedures must
be specified by EPA regarding the
determination of suitability for
locations, testing facilities, etc.
Despite best efforts, the choice could
always be subject to criticism and even
criminal liability based on a good faith
Compliance Statement indicating CLP
standards had been followed. Most
outdoor testing is done to mimic normal
agricultural conditions which are
specific for the test substance and use
being proposed. Therefore, the
determination of whether the size,
construction or location of a facility is
suitable for a study is a technical issue,
and is not within the scope of the CLP
regulation and would be considered in
the experimental design of the protocol.
Response: In cases where an EPA-
approved protocol establishes test
locations, that protocol would satisfy
GLP requirements. EPA considers any
site to be the testing facility wherever
testing is undertaken to generate data
required to be submitted to EPA. The
conditions required by the protocol are
not necessarily conducive to artificial
manipulajon in the field, or to other
outdoor tfcting facilities. Therefore,
ensuring-the suitability of the location of
these tyf>*§ of testing facilities is both a
valid and necessary part of protocols
approved by EPA.
ii. Comment: The design of the
individual scientist could be dictated by
§ 160.41 since a "testing facility"
(definition from § 160.3) means "a
person who actually conducts a study
	The term "test site" should be
defined to refer to the actual location of
a given "study system." Testing
facility" could then be used as currently
defined and refer to an individual
(mobile development scientist or
scientist working from a testing farm
facility).
Response: The definition of "person"
in this Part refers to the legal entity
responsible for testing, including
organizational units. Consequently, it
does not specifically indicate an
individual scientist.
2.	Test system care facilities—i.
Comment- Instead of expanding the
original document to fit all test systems,
the old rules should be left as is. and a
statement added to cover non-animal
test systems.
Response: EPA disagrees with the
comment and believes that specific
changes of the old rule are necessary to
avoid ambiguity concerning the meaning
of non-animal test systems.
ii.	Comment- Section 160.43(a)(2) and
(b), (e). (f), (g), and (h) should be deleted
because EPA has already stated that
these GLP requirements will be
applicable to all types of testing. It is not
necessary to add the four new
paragraphs detailing specific
requirements of environmental
conditions for aquatic organisms and
plants.
Response: EPA believes that some test
systems, e.g. aquatic, are unique, and for
the sake of clarity, they require special
treatment in the regulations.
iii.	Comment: Field studies should be
exempted because isolation is not
possible in these types of studies.
Response: EPA disagrees and believes
that inclusion of field studies poses no
unusual burden, since the separation is
only required to be "as needed" to
ensure "proper separation." If the
procedures used are justifiable based on
experimental design and documented,
then this requirement is met. "Proper
separation" in a field study may mean
simply that only one crop is planted in
the same subplot.
iv.	Comment The change in
§ 160.43(c) is appropriate but the current
wording does not require separate
disease handling facilities in every case.
The proposed change has merit in
clarifying the options available to
laboratories and the change promotes
harmony between EPA and FDA GLP
regulations.
Response: EPA agrees with the
comment. In 8 160.43(c), EPA is deleting
the requirement that separate areas be
provided in all cases for the diagnosis,
treatment and control of test system
diseases. Instead a change is made so
that separate areas are provided "as
appropriate." This change is consistent
with the September 4.1987, revised FDA
CLP regulations and the revised TSCA
GLP regulations.
EPA has made this change to allow
laboratories the option of disposing of
diseased test systems without also
bearing the expense of maintaining
separate areas in testing facilities for
diagnosis, treatment and control of
disease. Additionally. EPA recognizes
that the diagnosis and treatment
requirements of 1 160.43(c) may not be
appropriate when dealing with such test
systems as soil, plants, or
microorganisms. However, if the
decision is made not to dispose of the
test system, test system care facilities.
as specified in (160.43(c), must be
provided.
3.	Test system supply facilities—i.
Comment The first sentence in
9 160.45(a) should be changed so that
plants and plant materials are covered
in this section.
Response: EPA believes that since
plants and plant materials are covered
in S 160.45(b), including them in
fi 160.45(a) is unnecessary.
iL Comment Change S 160.45(b) by
deleting it or expanding it to include
tests not confined to the indoor
laboratory or greenhouse.
Response: EEjfcflgrees with the
comment and ponding the wording
of S 160.45 tojB^tesize that this section
is not intendeds be confining.
Therefore, i 160.45(a) is changed to read
"* * * areas where the test systems are
located * * V and { 160.45(b) is
changed to read	(included but
not limited to fields,
greenhouses. * * •)."
iii.	Comment- The addition of the two
new paragraphs outlining plant and
aquatic facilities to 8 160.45(b) is
unnecessary. These considerations are
addressed in { 160.41 with the
requirement that testing facilities be of
suitable construction "to facilitate
proper conduct of studies."
Response: EPA maintains that testing
facilities as mentioned in 8 160.41 and
test system supply facilities as
mentioned in 9 160.45, are not the same
and must be addressed separately.
iv.	Comment- EPA should delete
9 160.45(b) introductory text, (b)(1),
(b)(2), and (c) because this information
was adequately covered in 1 160.45(a)
and in ( 160.43. and the facilities they
refer to will be addressed in study
protocol.
Response: EPA maintains that 9 160.43
(test system care) is different from
9 160.45 (test system supply facilities)
and must therefore be treated
separately.
4.	Facilities for handling test control
and reference substances—i. Comment:
These requirements would severely
restrict the ability of efficacy
investigators to test their product since
9 160.47 would require separation of
facilities for test animals and testing
material. The real issue for efficacy
testing is test substance accountability,
which should be a vital part of the
efficacy testing protocol, and
appropriate records maintained to verify
test substance accountability.
Response: notes that similar
concerns were l^ed by commenters
regarding the lSBTrule. The wording "as
necessary" wM^icluded then to allow
latitude in facility design and operation.

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Federal Ragirter / Vol. M. No. 158 / Tlwday. August 17,-1889 / Bdes ami Regulations
EPA egreet thai other nnnm, Le
protocul SOPs. and appropriate records,
must bp adequate to demonstrate the
integrity of teat, controUmd reference
sub jtenew during frandfcgi
li. Comment: WoiiJiMtb« necessary to
provide separate siTik kaiiliw or
separate rooms far mtatrgOf the test,
control. and reference substances or for
adding water to tank sprayers?
Response: Separate areas ore required
for receipt mixing and storage of test,
control and reference auinstances and
their mixture* as necessary to prevent
contamination or mixups. The Bane sink
could be Died for all work involving
mixing provided that the procedures
(SOPs) used are adequate to prevent
contamination and mixups. Separate
areas ior receipt and storage end for
mixing and storage of test, control, and
reference subslarioes as required ir
5 180.47(a)Ll|. [2]. and (3| does not
mandate ike use of separate rooms. The
areas could be in the seme room
provided there is adequate space ar.d
equipment to provide that
contamination and miwip do not occur.
This delenntnakon should be mace on b
case-bjf-ci» bas.is.
D. Eqixprrert
Main ienc ice end rawaten a;
equipment—i. Conmeet: Tbe entire
section. { U3a.63{t) requires
unnecessary documentation and/or is
vague about what is required, especially
for field portions of residue studies.
Equipment used in these studies may
only be used on an occasional basis,
and routine Inspection should only be
"bfefore U4e " Requiring calibration and
maintenance logs for alt equipment
involved in generating a residue sample
would be prohibitive, would often be
forgotten or overlooked snd would then
be a canse for not meeting audits.
Response: The requirement states that
equipment ah»U be "adequately
inspected, cleaned and maintained" and
"adequately teBied. calibrated and/or
standardized " This requirement is not
changed from the old rele. The
laboratory has letitudeisadtfining 'n 'ts
SOPs what is "adequaofwless given
specific jftridante trth«rfS*t U.e. In test
rules or testing ymdrfiiweTrHawever,
EPA recommends that cafrbrs tioc and
maintenance records be available for all
equipment oted in field stud'es. This
includes equipment used only rarely and
rental equipment.
ti. Comment It is better to designate
in J l60.B3(b) thaf repair and
maintenance will be performed by
"quaWJed personnel," than to require
that • person be designated in the
written SOP. The requirement for
written SOPs in § 160.6Mb) causes
proHenw since at many Wboratorie* the
equipment used in conducting a study is
shared by a number of individuals and
the care and maintenance of the
equipment Lb also shared. Irr the evert of
equipment failure, a number of
laboratory personnel mar be capable or
repairing or correcting a probfem, or La
more serious equipment faifares. a
service representative of the
manufacturer may be called. It is
therefore difficult and very inefficient 'o
designate specific people to perform
each specific maintenance and repair
opera lion.
Response: The definition cf "persor:"
as it appears in $ 160.3(h) is not limited
to an individual scientist or technician,
but ir "fades an organizational subunil.
Consequently, thi SOP that designates
the "person responsible" wilt be
designating a saSruiil af we testing
Tacih-y, which cculd be one or several
individuals. This view tscooEisteril with
FDA's (52 FR 2377-9) interpretation e"d
definition of "person." Where duties are
delegated in the SDrs, all contingencies
may be addressed, including the
contracting of service personnel.
iii.CcHnmert Certain pieces o!
equipment, such as traders land
preparation and land measuring devices
all 3i.lc be exenptfromtbec^Liraboii
requirement, as should standard
commercially available laboratory ware,
such as graduated cylinders, beakers,
flasks, etc. Only equipment directly
related to application of the test
substance, such as sprayers or granular
applicators should be listed as requiring
calibration. Therefore, {150.83(c) is not
appropriate for field studies.
Response:EPA believes that
calibration should be required for the
application phase of Held studies.
However, the method of calibration, and
hence the exact equipment to be
calibrated, are not specified in GLP
standards, as long as the methods and
records ensure the quality and integrity
of the Btudy. Some equipment, audi as
graduated cylinders and volumetric
flasks are pre-calibiated and do not
need to be recalibrated. Equipment
directly related to the application of the
test substance may require calibration,
but application rates may Include other
parameters. The methods used to
measure aft parameters inherent in the
determination of application rates
would have io be adequately calibrated
in order to ensure the quatlty and
integrity of the study,
£. Testing Facilities Operation
1. Standard operating procedures—i-
Comment' There are few standardized
lests available to researchers related to
novel microbial pesticides. An
experimental use permit is required for
the evaluation of certain microbials at
an earlier stage of re starch than ts
required for chemical evaluations.
Therefore, it would be very cumbersome
to require written SOPs for microbial
pesticides, since the methodology may
be in a slate of flux. It may only be
possible to develop SOP# following the
completion of a study. If methods of
application and assessment need to ue
modified forescb microbial developed,
it would be best to affirm that methods
development could be performed tn
accordance with accepted scientific
standards without having SOPs as
described in £ 160.81. EPA is encouraeed
to take a flexible. case-by-car.e
approach to establishing appropriate
CLP v.andards for a given set o;
experiments concerning developiner,: oi
ir.itr
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Federal-'Ra^wtar / Vol. 54. No. 158 / Thursday. August 17. 1989 / Rules and Regulations 34050
make decisions if necessary to deviate
from the SOPs; (d) in field studies,
deviations from SOPs will occur before
the researcher is able to coiaulfcwith the
study director (e) decisions^tftut
deviations from SOPs thetare made by
field personnel would be bawd on
standard agricultural practrces.
Response: EPA disagrees with the
suggestion that some deviations do not
require authorization by the study
director. It is necessary for the study
director to authorize deviations from
SOPs to ensure that these deviations do
not have an adverse impact on the
study. SOPs should be written with
sufficient flexibility to accommodate
field studies by anticipating conditions
under which appropriate actions must
be taken without the need for
authorization by the study director.
Standard agricultural practices can be
referenced in SOPs as long as this does
not lead to ambiguity concerning the
appropriate action to be taken in a given
situation. If SOPs state the constraints
on action and a decision is made within
these limits, there is no deviation. This
is in concert with FDA's CLP regulations
(52 FR 33774) which require that the
study director make certain that
specified procedures are followed and
that all modifications to the procedures
in the approved study plan are
documented and approved.
iii.	Comment: Some of the examples of
required SOPs provided in {160.81(b)
are not applicable to all test systems or
study types. For example, "test room
preparation" would not be appropriate
when conducting field residue studies,
and "necropsy of test system or post-
mortem examination of test systems."
would not apply to studies using a
chemical or physical matrix as the test
system (sterile water, soil, agricultural
fields). Furthermore. $ 160.81(c) states
that, "Each laboratory or other study
area shall have immediately available
manuals and SOPs relative to the
laboratory or field procedures being
performed."
Response: EPA agrees tha*ihe term
"room" in { 160.81(b)(1) Is impropriate
to many studies and is	the
word to "area" in ordeMo tRaify that
field studies are includecfrEPA believes
that } 160.81(b) should apply in all cases
since the purpose of SOPs is to insure
the quality and integrity of the data
generated in the course of a study as
stated in $ 160.81(a). However,
procedures that are not necessary to be
performed, such as necropsy In the case
of Held studies, do not require SOPs.
iv.	Comment: The term "test systems"
should not replace "animals" in
$ 160.81(b) (6) and (7). Although this
requirement Is useful for preventing or
slowing autolysis for toxicology studies,
for other studies, such as metabolism,
addressing the handling of moribund or
dead test systems is not appropriate. In
these types of studies, if a test system
were moribund or dead, the testing
guidelines require the part of the study
that was impacted to be repeated, and
this requirement is only applicable to
animals.
Response: EPA disagrees with the
comment. This rule applies to plants as
well as animals.
v. Comment: Published literature (e.g.,
ASTM methods) should be acceptable in
S 160.81(c) as an appropriate part of an
SOP and not juBt as a supplement to a
written SOP. The written SOP could
incorporate the published literature by
reference, without having to rewrite the
entire procedure.
Response: EPA agrees that it would
not be appropriate to rewrite published
literature, hence the allowance for SOPs
to use it as supplements. The SOPs are
still needed to establish the relationship
of the method to data collection
procedures and needs in the laboratory.
While the resulting SOP would still have
to be written, it would in effect be
abbreviated in that all of the
methodology referenced would not need
to be rewritten.
2. Animal and other test system
care—i. Comment- Section 160.90(a)
should be deleted since the subject is
covered in $ 160.81(b).
Response: EPA recognizes that
§ 160.81(b) requires testing facilities to
establish SOPs for animal or other test
system care. Section 160.90(a), however,
expressly specifies that SOPs shall also
cover test system housing, feeding and
handling. This section is consistent with
FDA's CLP regulations and is not an
additional requirement.
ii.	Comment• Section 160.90(b) should
be simplified to provide that test
systems be evaluated prior to use but
not necessarily isolated. For some
studies, such as plant metabolism,
isolating the plants or soil is not
appropriate.
Response: EPA disagrees. Isolation is
necessary to insure that a test system is
free from disease or other conditions
that may impact the study. Further, the
inclusion of this Is consistent with
FDA's GLP regulations.
iii.	Comment- The evaluation of
certain test systems according to
"acceptable " * * scientific practice"
creates some difficulty, particularly for
plants, microorganisms, soil and water,
since such practices are not defined.
"Acceptable" should be deleted
regarding scientific practice and the
requirement be only that a scientific
basis be used in determining
appropriateness for testing. In this way.
testing facilities would not need to
justify or prove their basis to be
"acceptable" in ill-defined areas or
those in flux.
Response: EPA agrees that the term
"acceptable scientific practice" mav not
be definable when method
developments are in flux. The term
"acceptable" Is retained, but the term
"scientific practice" is changed to
"scientific methods." This change
preserves EPA's intent that rigorous
scientific methodology be uBed without
implying that rigid practices be adhered
to where they may not appropriately
exist.
iv.	Comment- The requirement under
S 160.90(c) that the test area be diBease-
free prior to study initiation is
inappropriate for field studies since it
would be impossible to declare areas
totally disease free under field
conditions. Also, one of the objectives of
performing studies in the field is to
conduct the studies under representative
environmental conditions which
includes encountered disease and jnsect
pressures, making this part in direct4
conflict with the study objective. -
Response: The requirement is fotlhe
test system to be "free of disease o»
condition that interfere with the purpose
or conduct of the study." The current
wording therefore provides sufficient
latitude for field studies. Furthermore,
EPA does not intend compliance with
this provision to require deviation from
accepted agricultural practices. If
disease and insect pressures are
considered to be an integral part of a
study, they clearly do not interfere with
the purpose and conduct of that study.
The test system would therefore not
need to be free of them.
v.	Comment Section 160.90(c) should
be deleted since the effect of corrective
treatment cannot be accounted for in
test results.
Response: EPA believes that while the
effects of corrective actions taken to
isolate and treat disease or signs of
disease may complicate interpretation of
test results, so might the effects of the
disease itself. This requirement for field
studies is not inconsistent with its
inclusion for laboratory, i.e.. toxicology,
studies.
vi.	Comment: Markings which identify
animals individually, rather than the
group as required by $ 160.90(d), are
needed in many studies with warm-
blooded vertebrates in pens, or in the
field. For example, precocial young of
avian species should be marked
individually.
Response: Specific criteria for
marking of individuals to meet study

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S4060 Federal R*galer / Vol. 54. No. 158 / Thursday, Auguat 17. 1989 / Rules and Regulations
requirements should be addressed
separately in the protocol of the study.
The requirement in § 100.90(d)
addresses the needjhaWest systems be
adequately identifititlCprevent
confounding withaiherjest systems.
Identification of rrawniiinl birds, fcr
exampie. may be oumiftd in the study
protocol.
vii.	Comment: The proposed
multispecies housing under
§ 160.90(e)(1) is redundant to proposed
§ 160.43(a)(1) and is inconsistent with
EPAs desire to streamline GLP
standards.
Response. EPA disagrees with the
conclusion that these sections are
redundant. While S 160.43(a)(1) states
that the facilities shall be sufficient to
allow proper separation of species.
S 160.90(e)(1) refers specifically to test
system care within the facilities.
viii.	Comment: Field studies should be
exempt from the periodic testing
requirement of § 160.90(g). A bioassay or
chemical analysis prior to study
initiation should suffice to show that
contaminants are not present at levels
capable of interfering with the study.
The need for prior analysis may even be
obviated by documentation of the
previous history of pesticide use in the
soil according to Standard Evaluation
Procedures to ensure that no interfering
contaminants are present.
Response: The regulations as written
do not require that periodic tests be
performed during a study unless there
are "contaminants known to be capable
of interfering with the study and
reasonably expected to be present at
levels above those specified in the
protocol." If there is no reasonable
expectation that a problem exists,
periodic testing is not needed. An
acceptable method to determine this,
such as evaluation of the history of
pesticide use. should be defined in the
protocol or SOPs.
ix.	Comment: The requirement in
S 160.9CHj) for acclimatization of plants
and animals should be deleted, since it
is not defined and promotes confusion.
Animal toxicologyJ£|}gpvouJd be
subject to isolauorr^pc&eparately to
acclimatization. Oz$«xu»ms in
environmental studitfWill have been
isolated with their health status being
evaluated per § 160.90(b) and
acclimatization would have already
been performed as part of the process.
Thia pari should be amended to indicate
that teat organisms be acclimatized to
all experimental conditions except the
test substance.
Response: EPA believes that the term
acclimatization has common meaning
that is clear in the context of its usage in
the regulation. Acclimatization implies
accustoming to experimental, i-e„
environmental, conditions other than the
actual introduction of the effect (e.g.,
test substance) to be measured in the
experiment. If acclimatization is
achieved during the process of isolation,
it should be so stated in the protocol and
does not require additional technical
effort.
In addition, the term "organisms" in
§ lt>0.90(|) has been changed to
"systems." This change is consistent
with the intended expansion of GLP
standards and was an inadvertent
omission in the proposed rule.
F. Test and Control Subslajtces
1. Test, control, and reference
substance characterization—i.
Comment- Requiring stability and
solubility before testing would result in
a costly burden to the efficacy testing
sponsor. The solubility testing portion of
this requirement would not cause
significant problems, but requiring
stability testing to be completed before
study initiation could result in
significant time and cost burdens.
Response: It is more costly to have to
repeat a study because of inadequate
solubility or stability in respect to
experimental needs. EPA agrees,
however, that requiring stability testing
to be completed before the study may
result in unnecessary delays end is
allowing concurrent stability testing.
Therefore, EPA has changed the
requirement to allow stability testing
concurrently with the study. Solubility,
where this is relevant to a study, must
still be known before the experimental
start date. Please note that the 1983 CLP
standards require determination of
characteristics which will appropriately
define the test or control article before
study initiation. Thus solubility
determination before a study, where it is
relevant to the study and hence an
appropriate characteristic, is not a new
requirement.
ii.	Comment: The term "purity" should
be expanded to include radiochemical
purity since further definition is needed
to encompass metabolism/
environmental fate studies conducted
with radioactive materials.
Response: Radiochemical purity is
covered under "other characteristics
which appropriately define the test,
control, or reference substance." It is not
necessary to specifically list this
characteristic.
iii.	Comment: What level of analysis
constitutes "appropriate"
characterization? lis quality control
batch analysis sufficient? is it necessary
to fully characterize technical materials
to 0.1 percent?
Response: Th>> details of what
"appropriately" defines the test
substance >9 a guideline or protocol
issue that cannot be specified in a
generic document such as GLP
standards. The appropriate level of
characterization is largely dependent on
the nature of the study (hat the
substance is to be used for.
iv.	Comment: What needs to be
characterized, the technice.' grade arnvc
ingredient or the end product?
Response: The test substance needs to
be characterized. If the test substance is
the end product the end product needs
to be characterized.
v.	Comment: The characterization
requirement is inappropriate since it
conflicts with management
responsibilities, is costly, end adds
unnecessary delays to the development
process. It removes a necessary option
of planning by objectives that
responsible business management must
retain. Delays and rescheduling, which
may result if inadequate work is
permitted by management, are real
consequences that must be;a$cepted by
management, and management must
decide whether or not to rin^begirruna
an experiment prior to doii^
characterization studies. Smte the
ultimate validity of a study will require
li.at sjch data be obtained before tne
study is completed and as Ions es the
sponsor can demonstrate that a study
was conducted with authentic material,
it is irrelevant when the charecterization
is completed. This proposal is not in
concert with FDA GLP regulations.
Many times prospective products fail to
reach the marketplace due to unusual or
insurmountable problems. Therefore,
eliminating the need for characterization
of product will reduce the costs of
products that fall out of developmental
process.
Response: Characterization is
necessary to ensure integrity of studies.
It is also necessary fcr EPA to have
characterization data available for
inspectional purposes during ongoing
studies, and thus to have this
information complete at the beginning of
the study. Without characterization, it is
not possible to know whether test,
control, or reference substances trout
different batches that are used in a
single study are in fact identical.
Adequate testing for characterization
normally occurs during the synthesis or
production of test, control, ami reference
substances, and thus should already be
available before the test begins.
Consequently, having characterization
data available should not impose so
additional burden in most cases.

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Federal Register / Vol. 54, No. 158 / Thursday, August 17, 1969 / Rules and Regulations 34fltt
EPA does agree, however, that
stability testing should be allowed to be
performed concurrently, to prevent
unreasonable delays. Thaoensor will
bear the burden of a repflSTed test in the
case that concurrent stcCffitv testing
suggests that the study is&aTvalid. For
that reason. EPA is revising § 160.105(b)
to allow for concomitant determination
of stability.
vi.	Comment: The last sentence of
§ 180105(a), relating to methods and
fabrication, should be deleted since
these may contain CBI.
Response: This is not a new
requirement and has not posed any
problems. Inspectors are cleared to
handle CBI material: any sensitive
information can be declared CBI and
treated as such.
vii.	Comment• Some EPA auditors are
interpreting this section to require that
the testing facility not only archive
certification records concerning the
purity or assay of an analytical standard
(reference substance), but to also
archive copies of the raw data and
records generated during the
certification process. The sponsor or
chemical supplier should only be
required to archive the raw data
supporting the certification of an
analytical standard. The testing facility
need only archive a copy of the
certification of the standard.
Response: EPA agrees with the
comment and is modifying S 160.105(a)
to allow for specification of the
availability of the documentation
supporting the characterization if it is
not available at the testing facility. The
phrase "and such documentation
availability shall be specified" is added
to the end of the first sentence in
8 160.105(a), following the word	
experiment."
viii.	Comment: Many of the tests
coming under the scope of the proposed
GLP standards are in themselves
stability studies. Soil dissipation tests
are stability determinations of
herbicides, as are tests qi-microbial
genetic markers for meaaUBg
persistence of recombirwSy derived
organisms. The propotal^faces industry
in the quandary of conducting stability
studies prior to a stability study.
Response: The performance tests cited
cannot be considered to be stability
tests under the GLP standards. In the
context described above, the persistence
of the substance in the environment is a
separately measured parameter.
However, when performing such tests, it
is still important to know the stability of
the substance to ensure that the
measured effect was due to the effect of
the test system.
ix.	Comment: Would it be acceptable
to EPA if the stability knowledge is
based on the extrapolation of the results
of a short-term stability study under
extreme conditions earned out before
the experimental starting date?
Response: Such an accelerated study
would not demonstrate stability under
test conditions, and could not be part of
the concurrent stability testing
performed in conjunction with a larger
study. It would be a separate study with
its own protocol.
x.	Comment: The proposed rule does
not address whether quality control
activities fall under the GLP standards.
Response: Not all quality control
activities are GLP issues. Quality control
work that is integral to the laboratory
performing the study would be under
GLP standards, but not that performed
during manufacturing. Studies as
defined in this part are subject to GLP
standards only when required to be
submitted to fulfill data requirements.
xi.	Comment: The part related to
"storage container assignment for the
duration of a study" in 3 160.105(c)
would be unrealistic for field studies,
especially where storage containers may
be large tanks, or delivery systems
"which are possibly not even owned by
the sponsor or testing facility.
Response: The delivery systems and
tanks that are part of delivery systems
are not "storage containers." Test,
control, and reference substance will,
however, be stored before use in some
container that is unique to that
substance during the test. This may be
the container that it comes in or that is
assigned to it by the testing facility.
xii.	Comment• Liquids from large
containers are often placed into smaller
containers for use during the study.
Consolidation of the test substance into
smaller containers as the supply is
depleted should be allowed. These
containers need not be retained after
they are empty, since their retention
does not enhance the quality or integrity
of the data collected.
Response: EPA disagrees with the
suggestion. The retention of containers
is necessary to ensure the integrity of
the study. This includes empty
containers, which must be kept to verify
the disposition of the test, control, and
reference substance. Disposal of
containers adversely affects
accountability. This provision of the rule
is not changed from the 1983 rale, but
was commented on by the public
because it may affect types of studies,
such as field studies, thBt will now fall
under the provisions of the rule as a
result of these amendments.
xiii.	Comment: How are "studies of
more than 4 weeks dotation" specified
in S 180.105(d) defined? TTiey should be
defined as studies having an "in-life
phase" of more than 4 weeks.
Response: The term "4 weeks
duration" is meant to apply to the
experimental start and experimental
termination dates. The suggestion of
using the term "in-life phase" is not
accepted since this introduces new
terminology that is not adequately
defined. The term "4 weeks
experimental duration" replace* "4
weeks duration" in 1 160.106(d) to
clarify that the study initiation and
study completion dates are sot Implied.
xiv.	Comment: Section 160.105 (b) and
(e) do not provide necessary discretion
to testing personnel to determine what
data are needed to characterize stability
for a substance, and how the
determination is made. The phrase
"under test conditions" needs additional
clarification, since a variety of
temperature, humidity, moisture, and
other test conditions may be
encountered across the United States.
Routine product chemistry testing for
emulsion stability, hydrolysis,
photostability, etc- should iatisfyithis
requirement.
Response: The terminology "taylcr
test conditions ' is ambiguous aHQ may
be misinterpreted, so EPA has decided
to delete "under test conditions" from
5 160.105(e) and replace it with "under
storage conditions at the test site." This
may be adequately addressed by routine
product chemistry testing as long as
storage of the substance at the test site
is in known, acceptable conditions.
xv.	Comment• Section 160.105(e)
should be deleted since it was
redundant with (160.113(a)(2).
Response: EPA disagrees that these
sections are redundant Section
160.105(e) refers to the test, control, and
reference substance, while 9 100.113
refers to mixtures.
xvi.	Comment: Knowledge of stability
makes sense for long-term, but not short
term studies because if stability is
suspect then doses ere made up each
day and given or sprayed immediately.
Adequate knowledge of stability may
exist from chemical information about
the test substance.
Response: If a substance is known to
be stable for a few days, then its
stability is known in terms of the test
requirements. If the stability is not
known, it must be determined, even ior
short-term studies. Storage stability
needs to be known even if the material
is used 'Immediately". If enough
information Is known about the material
to support its stability from other
testing, its stability is known and the
requirement is met. However.

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34062 Federal Register / Vol. 54, No. 158 / Thursday, August 17, 1089 / Rules and Regulations
theoretical stability is not considered to
be adequate. The method used to
compensate for poor stability, such as
daily mixing or immediate application,
is addressed in guidelines rather than in
GLP standards.
2.	Test, control, and reference
substance handling—Comment: If the
test, control, or reference substance is
inherently unstable, it may not be
possible to "preclude deterioration."
Therefore, the regulation should allow
for periodic evaluation of the purity of
the test substance during a Btudy to
assure its integrity and replace it when
shown to be warranted.
Response: The intent is to prevent
deterioration due to handling. Periodic
testing is allowed under { 160.105(b) as
changed in the final rule.
3.	Mixtures of substances with
carriers—i. Comment: Does { 160.113
require determination of uniformity,
stability, and solubility during field
residue studies? If so. does it require
analyses for each tank preparation? This
requirement would impose a large
burden on testing facilities performing
these types of studies.
Response: The purpose of this section
is to assure that the methodology used
to prepare the mixture is valid. Once the
methodology has been proven for a
particular mixture, it need not be
reconfirmed each time that mixture is
prepared. For field residue trials, there
will be data submitted to EPA that
support the uniformity, stability, and
solubility of a substance in the carrier
when prepared by appropriate
methodology, i.e. according to the
proposed use or label. In such cases it
may not be necessary to test each batch
that is prepared for field application.
However, field residue trials do remain
subject to the requirements of this
section. Where available data are
inadequate to support uniformity,
stability, #nd solubility in a particular
case, then it is necessary for the data to
be generated under this section. Also,
there may be protocol stipulations
applicable to a particular study that
require tank mixture analyses in
addition to any provisions of this
section.
ii. Comment: The range of
environmental conditions encountered
in field trials are great and would
require extensive evaluations of
stability and solubility under numerous
environmental conditions. This amount
of data could not be evaluated prior to
study initiation.
Response: Section 160.113(a)(2) states
that the determination(s) shall be	
under the environmental conditions
specified in the protocol and as required
by the conditions of the test." All
possible environmental conditions do
not have to be anticipated and tested
unless required in the protocol.
iii.	Comment- Short-term toxicity and
field residue studies should be exempted
from this section since supplementary
analyses are performed for other studies
with the same test substance. The
analytical cost could equal or exceed
the cost of the remainder of the short-
term study.
Response: The CLP standards do not
require characterization for each study.
The characterization is required for each
test, control, and reference substance.
The same substance may need to be
characterized only once, even if used on
multiple studies.
iv.	Comment: The requirement for
stability and solubility should allow
flexibility for the sponsor to make the
determination either before, during, or
after the study. When to determine the
stability is a business decision based on
knowledge of the risk of having to
repeat a study, if the stability data
negatively impacts the integrity of the
study.
Response: EPA understands that
requiring stability testing to be
completed prior to a study may
introduce unreasonable delays. In
harmony with the modification of
S 160.105(b) to allow concurrent stability
testing of test, control, and reference
substances, { 100.113(a)(2) is changed to
allow stability testing of mixtures to be
performed concomitantly with the study.
This allows the necessary flexibility and
is also consistent with FDA's GLP
regulations.
v.	Comment: In the very early stages
of a compound's development there is a
need for basic acute toxicity tests.
However, there are no analytical
methods and calibrated reference
standards available to test the stability
of the test substances in the carrier
according to GLP standards. An
estimate of the stability of the
compound in an inert carrier like starch,
oil. or polyethylene glycol is possible
and should be sufficient as a
preliminary approach. The stability test
will be carried out as early as the
analytical methods are available.
Response: If a carrier is used, the
mixture with the carrier must go through
the same test, i.e. stability, solubility,
etc. Instability of the mixture in a
specific carrier is important since it may
affect the apparent effects of the test
substance.
vi.	Comment- The assurances called
for in § 160113(c) are not well defined.
How would the addition of the vehicle
used to facilitate mixing of the test
substance with the carrier to the control
Bystem affect this requirement? If the
vehicle is identically mixed in control, is
there a need to show noninterference?
Response: Any vehicle used to
facilitate mixing must be shown not to
interfere with the study. This includes a
vehicle control to determine interaction
effect.
vii. Comment If a test substance is
applied to a soil, is the soil a carrier or
test system?
Response: This section does not
generally consider "soil" to be a carrier;
it is considered to be part of the test
system.
G. Protocol for and Conduct of a Study
1. Protocol—General—i. Comment:
The proposed regulations do not offer
sufficienf latitude for the generation of
protocols. The regulations state that a
protocol must exist prior to study
conduct, yet it would be almost
impossible to specify the exact analyses
that would be performed on biological
samples collected in the field until the
samples were collected.
Response: The protocol requirement is
not too restrictive to allow for situations
where the exact analysis performed may
not be known in advance. The type or
nature of analysis still needs to be
specified in the protocol. The protocol
should state what samples are intended
to be collected, how they are to be
collected, and how they are intended to
be analyzed. If there is a need for
latitude, (for instance it is not known
specifically how many samples will
result from a particular study) that
should be anticipated and stated in the
protocol.
ii.	Comment- Section 160.120(a)(5). (7).
(10). and (11) should not apply to
product chemistry experiments.
Response: The term "test system" is
redefined to include any physical
matrix, which may thus be applicable to
product chemistry studies. However,
note that a study designed solely for the
determination of certain chemical or
physical characteristics of a test
substance are exempted from
{ 160.120(a) (5). (7). (10). end (11) as
described in § 160.135.
In addition, the word "of prior to
"frequency" should be "and." This was
a typographical error noticed by one
commenter and has been corrected in
this final rule.
iii.	Comment: Guidance is needed in
the final preamble for presenting
addresses. 86 required by
§ 160.120(a)(3). of field and
environmental locations used to conduct
tests.
Response: The address of the testing
facility is the address of the "person"
(i.e. organizational unit or subunit) who

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Federal Ragbtn / Vol. 54. No. 158 / TTiuradfty. Anguat 17. 198S f. Rules and Regulations 340fd
actually conducts the stndy. Even if this
organizational unit includes parts
situated in different locations it may still
be considered to have one address. The
address should be a permanent address
and would probably be synonymous
with the address of the study director
and/or testing facility's management.
iv.	Comment: "Address of sponsor"
should be removed from this Part to
maintain consistency with FDA GLP
regulations.
Response: EPA maintains that the
address of the sponsor is essential to its
inspectionaJ process, which differs from
that of FDA.
v.	Comment• The requirement in
S 160.120(a)(4) to state proposed
experimental start and termination
dates poses problems for field studies
where these dates cannot be predicted
with certainty. Would this result In
protocol deviations whenever these
dates are not exactly met?
Response: The requirement to
document the proposed experimental
start and termination dates in the
protocol does not suggest that a protocol
deviation occurs when the date is not
met The term "proposed" signifies that
this date is estimated. However, gross
deviation from the proposed date may
be a violation of the protocol, if there
are date-critical aspects of the study
that are identified as such.
vi.	Comment: Section 160.120(a)(5) is
inappropriate because: (a) Justification
should be required only when more than
one test system can be used in a study
and not, for example, in residue
chemistry studies where residue levels
in specific target crops are the subject of
a study; (b) Justification should only be
required for those that deviate from, or
fall outside the normal EPA guidelines
and not where standard test systems
(Pesticide Assessment Guidelines and
Standard Evaluation Procedures) are
used; (c) The retention of this
requirement does not promote harmony
between the EPA and FDA GLP
regulations.
Response: Environmental studies are
more diverse than health effects testing
and are subject to details relevanf'to
test system design that are more
chemically dependent than is the case in
health effects studies. Furthermore, this
is not seen to impose a burden in the
cases described in this comment. In the
case where only one test system can be
used, that is the justification that should
be stated. The targeting of a specific
crop may be part of the jusiification and
so stated; it is still necessary to state
that the test system (e^. strain of crop,
soil, location) used is justified for the
purpose of the study. if a standard test
system is used because it is the
referenced system in EPA or
Organization for Economic Cooperation
and Development (OECD) guidelines,
citing the use of such guidelines is
sufficient justification. Thus, detailed
discussions are required only in the
relatively few cases where the study
design requires deviation or special
choices to be made in selection of the
test system.
vii.	Comment: EPA should add
"range" to {160.120(a)(8) so it reads
"* * * body weight range." since
without specifying range, the protocol
requirement could be misinterpreted to
mean that all individual body weights of
the test system should be included. This
would not be possible since exact
weights of test systems would not be
known when the protocol is prepared.
Response: EPA did not intend a
change here and retains the term "body
weight range" as used in the 1983 rule.
viii.	Comment• Section 160.120(a)(7)
should be deleted since the test system
will be identified and justification for its
selection will be In the protocol.
Response: Identification of the test
system is not covered in any of the other
parts of i 160.120. Identification is the
specific description of which individual
test system is used not a general
description of the kind of test system.
ix.	Comment The method for
controlling bias is usually in the SOP,
therefore inclusion of a reference in the
protocol to the SOP should suffice.
Response: EPA agrees that this is
allowed. The SOP may be referred to in
the protocol in such cases.
x.	Comment: The term "nutrients"
should be added to the list for the
description of the diet used in the study
to cover the use of fertilizer in plant
studies.
Response: EPA has incorporated this
suggestion into the final rule.
xi.	Comment Section 160.120(aHl0)
should be deleted, or amended with "if
appropriate" because: (a) The reason for
selecting the route of administration Is
the objective of the study; (b) route of
administration and reason for its choice
is not applicable to studies such as
aqueous hydrolysis and anaerobic
aquatic (c) EPA Pesticide Assessment
Guidelines require the use of certain
routes.
Response: Unlike FDA. EPA requires
many tests where a predefined route of
exposure is not available. Multiple
exposure routes may be possible for
many test substances. It is appropriate
to state that the route is mandated by
guidelines or by the purpose of the study
if either oflhese are the case.
xiL Comment Section 160.120(aKlO)
should be modified to read "* * * route
of administration and/or exposure * " '
to encompass other types of protocols.
Response: EPA disagrees with the
suggestion since the experimenter
controls administration but does not
have control of the route of exposure.
Administration routes cover the
potential of all exposure routes and
hence is a more general, all-inclusive
term in this case.
xiii.	Comment Section 160.120(a)
should be reworded so that it reads:
"The route or method of administration/
application and the reason for choice, if
appropriate."
Response: EPA disagrees with the
suggestion. The route of administration
is not the same concept as method of
application or administration. It would
not be appropriate to introduce
statements concerning methodology to
this section.
xiv.	Comment In the case where the
study director is part of a contract;
laboratory engaged for the study by the
sponsor, it should be clarified that such
signature as required under
S 160.120(a)(14) does not constitute
review and approval of those parts of
the protocol not related to the work
done by the contract lab. For example,
the study director for the chemical
analysis of pesticide residues in plants
may not be trained in the experimental
design of the sponsor's overall study,
although he or she may be qualified to
conduct the subpart of the study
contracted to the laboratory. Such a
dilemma may similarly arise in
S 160.120(a)(5). (7). (10). and (15).
Response: EPA believes that the study
director cannot, by definition, be an
individual who is not trained or
cognizant of the overall study. A study
is not subdivided into multiple studies
with multiple study directors. The
definitions of "study" and "study
director" preclude such a separation of
responsibility.
xv.	Comment "Where applicable"
should be added to } 160.120(a)(l5) since
statistical methods are not used in field
studies.
Response: Statistical methods are and
should be used in field studies.
However, where the use of statistics is
limited this can be so stated.
The phrase "to be used" should
modify the term "statistical method" as
in i 100.120(8)(10) of the 1983 rule. This
was a typographical error noted by one
commenter and has been corrected.
xvi.	Comment Section 10O.12O(e)(15)
is redundant since all of 1160.185(a)(3)
requires statistical methods employed
for analyzing the data.
Response: Section 160.185 describes
reporting requirements after the study.

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34064 Federal Register / Vol. 54. No. 156 / Thursday,. August 17, 1989 / Rules and Regulations
while { 160.120 describes protocol
requirements before the study.
2. Physical and chemical
characterization studies— i. Comment:
Section 160.135 is confusing sfRnreeds
to be read several times in coSer to
understand it. EPA should clffi|gtts
intent by specifying those stumes to be
conducted under GLP standards, and by
removing the double negatives currently
presented in i 160.135(a) and (b).
Response: EPA agrees with the
comment. The section is changed to
eliminate the double negative and
reworded for clarity while retaining the
intent of the proposed changes.
ii.	Comment¦ Should exemptions also
apply to "assembly line" biological
studies, such as the Ames test, acute
lethality, eye irritatioa etc?
Response: EPA does not intend to
expand exemptions to biological tests
previously covered by GLP standards,
even when repetitive in nature. Section
160.135 applies only to physical and
chemical characterization studies and is
intended to ease the burden on many
studies that will now come under GLP
standards.
iii.	Comment: The concept of what
constitutes a study is blurred by this
section. Partial deletion of protocol
requirements implies that a protocol is
still required for these "exempted
measurements."
Response: EPA intends that a protocol
still be required for the partially
exempted studies. Some, but not all. of
the full protocol requirements are
eliminated.
iv.	Comment: Areas for receipt and
storage of test substances have been
deleted in S 160.47(a)(1). but
corresponding SOPs are still required by
{ 160.81(b)(3).
Response: EPA maintains that SOPs
for test, control and reference substance
handling are still important, if not more
important, when facilities for their
handling are not specified.
v.	Comment¦ Stability is to be known
under conditions of the test under
( 160.105(e). but the requirement to
report that information is detaJ-in
S 160.165(a)(5)) and the requfisftnt to
determine stability is remotei&f
deleting { 160.105(b). r^~
Response: EPA agrees, but there is no
contradiction. The requirements for
determination and reporting of stability
are relaxed although stability still needs
to be known.
vL Comment- A protocol is required
even though certain specific elements
have been deleted (J 160.120(a)(5)
through (12) and (15)). but the
requirement for the quality assurance
unit to retain the protocol Is deleted
(S 160.195(d)).
Response: EPA agrees that this is true.
The QAU recordkeeping requirements
are relaxed although the protocol still
needs to be written.
vii.	Comment- A quality assurance
unit is required by fi 160.35(a), but by
deleting S 160.31(c) management will not
have to assure the existence of a QAU.
Response: EPA eliminated S 160.31(c)
because it requires management to
"assure that there is a quality assurance
unit as described in $ 160.35." This
would have contradicted the exclusion
of certain portions of {160.35 as
specified (i.e. { 160.35(b) and (c)). That
which is not excluded under S 160.35
must comply with fi 160.35(a).
viii.	Comment A study director is
required according to S S 160.12 and
160.33, but does not have to be shown in
the final report by the deletion of *
{160.185(a)(10).
Response: The study director is still
required to sign the compliance
statement submitted with the final
report as required in { 160.12 and is thus
required to be named in the final report.
A number of individuals are listed in
S 160.185(a)(10) in addition to the study
director. This section was exempted to
reduce reporting requirements.
ix.	Comment: Studies designed to
determine stability, octanol water
partition coefficient, volatility, and
environmental persistence
(biodegradation. photodegradation. or
chemical degradation studies) should
exclude J 160.43(a)(1) through (c) and (f)
through (h), 160.45,160.81(b)(1). 12), (6).
(7). and (9). and 160.90. Only the
physical and chemical properties that
are used to predict the environmental
fate of a test substance should be
developed in compliance with these
regulations. Those properties which are
not clearly used for this purpose should
be excluded.
Response: EPA does not agree that the
listed sections are irrelevant in their
entirety to the listed studies. Those
portions of the sections which are
plainly not applicable to these studies
(e.g. animal care facilities) do not place
any burden on these studies.
x.	Comment- The removal of physical
end chemical characterization from the
responsibilities of the QAU should not
be accepted because it presents a major
problem for the QAU personnel. The
QAU should be responsible for every
study within the laboratory with no
exception.
Response: EPA disagrees with the
conclusion that the QAU has no
responsibilities in physical and chemical
characterization studies. The exclusions
reduce the responsibilities of the QAU,
Le. master schedule requirements, etc-
but do not eliminate them.
xi.	Comment- The QAU should be
responsible for looking at the functional
components of the laboratory (e.g.. all
melting points, all GC/MS analyses,
etc.) rather than focusing on a particular
study, such as with toxicology studies.
Response: EPA agrees and is
modifying the inspectional requirements
of the QAU under 1 160.35. This change
specifies that the QAU conduct
inspections and maintain records that
are appropriate to particular studies.
This gives latitude to the QAU with
respect to how the information is
gathered: i.e.. as part of the standard
review procedures of the laboratory, or
as needed for the test. This change
should reduce the burden in cases
where it is appropriate to maintain
central records regarding functional
components that affect several studies
rather than requiring such records to be
maintained separately.
xii.	Comment- If physical and
chemical characteristics are to be
covered by GLP standards, they should
not be referred to as separate
"characterization studies." These tests
are listed in 40 CFR part 158 as phy&jc#l
and chemical characteristics and
properties and are submitted to EPATJ
studies by Guideline series numbersrnot
necessarily as individual
"characterization studies." Additionally.
In product chemistry many of the
characteristics listed in proposed
S 160.135(b) are part of Series 63 (I.e.
stability, solubility, etc.). which is
submitted as a single study. If these
characteristics are to be covered by GLP
standards, it should only be to the
extent of the data requirements in 40
CFR 156, because It is not the purpose of
the GLP standards to define studies for
registration.
Response: EPA disagrees with this
comment. GLP standards do not expand
data requirements. The regulations only
specify how the data are to be
generated.
xiii.	Comment- AH product chemistry
should be exempted from these
regulations, except for those studies
specifically noted in the preamble (i.e.
stability, solubility, octanol water
partition coefficient volatility and
persistence), which also affect the
environmental hazard assessment and/
or are required by other sections of the
guidelines.
Response:SPA maintains that all data
that are required to be submitted to EPA
be collected according to GLP
standards. While EPA believes that a
portion of the requirements of the
previous GLP standards can be reduced
for some studies, the standards are still

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Federal Register / Vol. 54. No. 158 / Thursday. August 17. 1989 / Rules and Regulations 34065
important to assure the quality and
integrity of the data generated.
xiv.	Comment: The seriesjO.JBl. 82.
and 63 requirements are inrtfclj process
and method development ^ki
experiments, and are develsed-over a
period of time with portior^TOtnetimes
contributed from laboratories in plant
locations, making it prohibitively
expensive and unrealistic to have these
portions under a GLP program.
Response: While there may be
additional cost, the need to have the
work performed under GLP standards
overrides this concern. EPA does not
agree that GLP requirements in this
section entail unrealistic requirements
on laboratories that perform these types
of experiments.
xv.	Comment¦ The data quality from
the series 60. 61. 62 and 63 studies would
not be compromised since the
companies that are generating these
data are usually doing so for their own
economic benefit as well as for
registration purposes.
Response: Data developed under
manufacturer's demands for quality
control information do not reflect the
same constraints upon data integrity as
required by EPA. During the
manufacturing process, cost and time
considerations may conflict with safety
assessment data quality needs.
xvi.	Comment¦ EPA should revise PR
Notice 86-5 to ensure that the definition
of study corresponds with the definition
in the GLP regulations.
Response: The GLP regulations
address the integrity of data generated
during a study. PR Notice 86-5
addresses the reporting of the data,
which is a separate concern.
xvii.	Comment: The term "studies" in
the title of { 160.135 should be replaced
with another term, such as
"experiments," to avoid the
misconception that these experiments
must be carried out as separate
"studies." As separate studies, they
would require separate protocols, study
directors, study reports. QAU audits,
etc.. when in fact these expertBents are
part of a larger study, whidFriready has
its own protocol covering 44be various
experiments to be performatTh may be
that this part should be deleted because
these tests do not fit the basic definition
of study and should not be Included, in
any way. under the scope of the GLP
standards.
Response: EPA disagrees that these
tests are not studies. The definition of
study includes the phrase "to determine
or help predict [the test substance's]
effect * ' * and fate." Therefore the
physical and chemical characterization
parameters are included EPA«gree«
that in some cases, the determinations
will have beeh performed as part of a
larger study (e.g. product chemistry) and
consequently will have been performed
under the protocol of the larger study. In
other cases, however, each of these
studies will require a separate protocol.
x'viii. Comment¦ Are GLP requirements
applicable when analyses are conducted
by an outBide laboratory, or are they
exempted from the various sections
outlined in 8 160.135(a)?
Response: The location where the
analyses are performed does not affect
the applicability of the GLP regulations.
xix.	Comment• Section 160.135(a) in
the proposed rule should be deleted
because the regulation is far too
complex to start applying parts of it to
one study, but not to another. It is a
major task to instruct personnel on the
requirements in the CLP standards: and
it would be an impossible task to
instruct them on multiple versions of
GLP standards.
Response: There should not be many
cases where the same workers will need
to be trained in both levels of GLP
interpretation. There are not "multiple
versions" of GLP standards, only a
relaxation of some requirements for
some studies. EPA does not consider
this to be imposing an additional
burden.
xx.	Comment• Under 8160.135(b). an
unusual situation can occur with quality
assurance because a QAU is required to
exist by retention of 8 160.35(a) and is
implied to have records of inspection by
retention of 8 160.35(d), but has no
duties by virtue of deleting 8 160.35 (b)
and (c). Both 8 160.35 (a) and (d) should
be added to the list of excluded
provisions.
Response: EPA agrees that there are
inconsistencies in eliminating { 160.35
(b) and (c) since there are no
inspectional responsibilities included in
S 160.35 (a) or (d). Consequently. EPA is
expanding { 160.35(a) to include
inspectional responsibilities.
xxi.	Comment: The repetitive
inspection of the types of studies
required in proposed 1160.135(b) would
consume large amounts of time for both
study personnel and the QAU staff
without contributing to the quality and
integrity of the data. The periodic
inspection of such operations would
provide the necessary assurance that
the data were of sufficient quality and
Integrity to meet all requirements tinder
GLP standards.
Response: EPA disagrees with the
comment and expects that each study be
inspected by the QAU at least once.
Where these types of tests are repetitive
or routine in nature it should be possible
for the QAU inspectional process to be
equally routine.
xxii. Comment¦ EPA should modify
proposed 8 160.135(b) to make it
perfectly clear that stability/solubility
experiments carried out as part of a
study are not excluded from the
exemption provided by 8 160.135(a).
When the sole purpose of a study is to
determine stability or solubility, GLP
standards should apply, but where
stability or solubility determinations are
being made prior to the initiation of the
actual experiment for which the study is
being conducted, there is no reason to
treat those determinations as a separate
study. The study protocol will cover the
need for. and method of. determining
stability and solubility in situations
where it is necessary to make those
determinations in order to ensure the
success of the study.
Response: EPA agrees that "sole
purpose" stability/ solubility studies are
under GLP standards, but disagrees that
these studies should be exempt when
they are part of another GLP study. If
they are a part of a larger study, they
are within its protocol, and hence under
CLP standards. If they are not withiA
that protocol, then they are "sole -
studies" under GLP standards in tb$r
own right
H. Records and Reports
1. Reporting of study results—i.
Comment: Section 160.165 delineates the
information to be included in the final
report. Since the Office of Pesticide
Programs (OPP) has already designed
Data Reporting Guidelines (DRGs) as
addenda to the Pesticide Assessment
Guidelines and these are being used by
applicants, this section appears to be
unnecessary. Furthermore, there are a
few issues where the GLP standards and
DRGs ere not compatible and illustrate
a possible conflict in EPA requirements:
(a) Section 160.165(a)(2)—(protocol)—
The reviewer at OPP needs to know the
study objectives, not necessarily what
the objectives were in the protocol and
what changes were made during the
course of the study; (b) Section
160.185(a)(8)—(methodology)—A
description of the methods used Is
required, but residue chemistry reports
require a separate report for
methodology, (c) Section 160.185(c)—
(report amendments)—Information
Services Branch has specific
requirements in PR Notice 86-5
regarding the submission of amended
reports. In cases such as these, which
document has the superseding
authority?
Response: DRGs are designed for
presentation of data to EPA after the
performance of the study, and GLP
standards are designed to ensure data

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SiOSS Federal Register / Vol 54, No. 158 / Thursday. August 17. 1389 { Rules and Regulations
integrity during the performance of the
study. GLP standards requite additional
information to be contained to the final
report that are not reauirjfr-fo the
DRGs. This should not qfultin any
issues of superseding aflffiatUy.
ii.	Comment: Section lS3&5(a](lZ)
should be modified to require reports
only when they are necessary to explain
results (hat are highly subject to
interpretation or critical to the final
evaluation of the study. Otherwise this
will result In an unusual reporting
burden with little benefit during Held
residue studies.
Response: EPA does not agree that the
requirement Is Impractical or
unnecessary. This reporting requirement
cannot be left entirely to the discretion
of the study director.
iii.	Comment At the EPA't second
data submitters' workshop on the
implementation of PR Notice 66-5 on
December 15.198ft EPA handed oot the
"Clarification of PR Notice 86-5
Requirements" pertaining to GLP
considerations. EPA states in this
clarification that reformatting final
study reports to comply with the
submission recjHiremerts of W Notice
86-5 does not constitute a formal
"correction or addition" to a final report
that would otherwise require the
signature of the study director under 40
cfr ieo.ias(c).
Bespcete: EPA agrees and is
incorporating the suggestion tn the final
rule so that modification to comply with
EPA submission requirements does not
constitute a correction, addition, or
amendneot. However. EPA advises that
the process of reformatting final study
reports does not alleviate the stody
director of accountability in signing the
final report or the compliance statement.
2. Storage and retrieval of records and
data—L Comment The phrase "beyond
quality asa&rance" in ( lOO.UOfa) needs
clarification since it could be
ambiguously interpreted Does it mean
the date of the final approved report or
does it mean beyond initial evaluation
of the specimen*, sincej^|twas the
statement used in the oQosponding
preamble section?
Reepcaee: EPA intefflttAat the
specimens be retained until the quality
assurance unit assures that their
discarding does not negatively impact
the integrity of the study. The wording is
being changed to "after quality
assurance verification" to clarify this.
ii. Comment Tissues and animal feeds
collected from non-toxicology studies
should also be discarded after quality
assurance verification. If EPA does not
intend tor animal tissues to be retained
from residue studies, "animal" not
appearing after "plants" is an oversight.
Response: EPA did not include the
term "animal" in the list since U would
potentially Include tissues and feeds
from toxicology studies which must be
kept. It is fell that the suggested wording
would not provide sufficient breadth to
cover non-residue samples. Therefore.
EPA will require that all animal tissue
samples, even from nan-toxicology
studies be included in this Part.
iii.	Comment Retention time for1 re-
labelled specimens needs to be
addressed since a facility's license limit
could be exceeded for storing
radioactive material
Response; The problem of
requirements is a facility responsibility
under GLP standards. EPA does not
agree that special consideration be
given to sample storage based on the
above reasoning.
iv.	Comment- This Part does not
clearly define who must archive raw
data or authenticated copies. If the test
facility's portion of the study is small
compared to the entire project, it does
not make sense to archive at the test
facility. The sponsor should be required
to archive all raw data in support of a
submission and provide that data to the
test facility in the event of an audit
Archiving at tha test facility will pat an
undue and unnecessary hardship on
small laboratory facilities. Another
problem to be considered is whether tha
test facility is required to archive the
final report submitted to EPA. U could
find itself archiving analytical data
generated by another facility.
Furthermore, in the event that the
sponsor may be involved in a lawsuit
concerning the study, the contingent
liability exposure for the test facility
should be clarified.
Response: The test facility may
contract with a commercial archiver
under i 160.195 fb) end (g). This implies
flexibility in the physical location of the
archives.
3. Retention of records—L Comment;
The appropriate end point for specimen
retention in {160.105 should be based
on the integrity of the specimens and
use by the study director, or other
technical penormel. not baaed oa when
QAU personnel may perform a review.
Response: Quality assurance
evaluation ia needed to assure that the
integrity of the data are not
compromised by the decision to discard
specimens. For consistency. EPA is
changing the wording of 4 IflfllQSfcl to
concur with the wording of f 160.190{a].
U. Com/nert EPA should explicitly
Btate In & 180.186(1] that when exact
copies are substituted for original source
as raw data, then the original may be
discarded. In the past, EPA inspectors
have required retention of original data
sources even if exact copies existed.
The burden Imposed by some ETA
auditors, that each copy must be signed
and dated. Is unrealistic. Verification of
"batches" of reproduction copies is just
as meaningful and would eliminate most
of the unnecessary burden on personnel
and time resources.
Response Specific wording advising
the discarding of raw data after copying
is not necessary or useful. "True copies"
will be acceptable as raw data by EPA
inspectors ualcr 1160.190. Signing and
dating each copy may be impractical
and an acceptable alternative method
may be devised and incorporated into
standard operating procedures to ensure
the integrity erf the copies. Laboratories
are cautioned that discarding originals
places an additional burden on
verification of the authenticity of the
copies.
HI. Regulatory Requirements
A.	Executive Order 12291
Under Executive Order 12291, EPA
must judge whether a rule is "major"
and therefore subject to the requfronent
of a Regulatory impart Analysts.tPA
has determined that the amenc^nts
are not a major rale because they do not
meet any of the criteria set fordTand
defined in section 1(b) of the Order.
Compliance costs were estimated using
data from a survey of laboratories
potentially affected by the revised GLP
standards and from data on pesticides
testing demand, and coets taken from a
1980 study of the pesticides testing
industry.
This rale was submitted to the Office
of Management and Budget (OMB} for
review as required by Executive Order
12291. Any comments from OMB to EPA
and any EPA response to those
comments are available for public
inspection at Information Poticy Branch.
PM-223, U.S. Environmental Protection
Agency. 401M St.. SW„ Washington. DC
20460; and at tha Office of Management
and Budget. Washington, DC 20503. wtth
OMB requests marked "Attention: Desk
Officer for fFA."
B.	Regulatory PiadbiHty Act
This rule has been reviewed under the
Regulatory Flexibility Act of 1980 (Pub.
L 9&-3G4; 94 Stat 11S5 [5 U.S.C. 601 el
seq )). and it has been determined that it
will not have significant economic
impact on a substantial niimher of small
businesses, small governments, or small
organization, It was found that the GLP
revisions will not increase the costs of
health	testing that nonhealth
effects testing costs will increase about
20 percent.

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Federal Register / Vol. 54. No. 158 / Thursday. August 17, 1989 / Rule* and Regulations 34067
C. Paperwork Reduction Act
The information collection — —
requirements in this role will
submitted for approval to OKjfemder
the Paperwork Reduction Act^ggrS.C.
3501 et seq. These requirements are not
effective until OMB approves them and
a technical amendment to that effect is
published in the Federal Register.
Public reporting for this collection of
information is estimated to average 15
hours per response, including time for
reviewing instructions, searching
existing data sources, gathering and
maintaining the data needed, and
completing and reviewing the collection
of information. Send comments
regarding the burden estimate or any
other aspect of this collection of
information, including suggestions for
reducing this burden, to Chief,
Information Policy Branch, PM-223, U.S.
Environmental Protection Agency, 401 M
St. SW. Washington. DC 20503.
List of Subjects In 40 CFR Part 160
Environmental protection. Good
laboratory practice. Hazardous
materials. Pesticides and pests.
Reporting and recordkeeping
requirements.
Dated: |uly 27.1389.
WUliara K. Re%,
Administrator.
Therefore, 40 CFR chapter I, part 160
is revised to read as follows:
PART 160—GOOD LABORATORY
PRACTICE STANDARDS
Subpart A—General Prevtsions
Sec.
160.1 Scope.
160.3 Definitions.
160.10 Applicability to studies performed
under grants and contracts.
160.12 Statement of compliance or non-
compliance.
16015 Inspection of a testing facility.
160.17 Effect* of non-compliance.
Subpart R—Organization and Biiginnrt
160-29	Personnel.
160.31	Testing facility tnmiimUPaC
160.33	Study director.	—
160.35	Quality assurance uniL
Subpart C—fsctttJes
180.41 General.
160.43 Test system care facilities.
160.45 Test system supply facilities.
160.47 Facilities for handling test, control,
and reference substances.
160.49 Laboratory operation areas.
16&51 Specimen and data storage facilities.
Subpart D Cqulpwnt
16041 . Equipment design.
160.63 Maintenance and calibration of
equipment.
Subpart E—Tasting Facttttta* Operation
160.61 Standard operating procedures.
16033 Reagents and solutions.
160.90 Animal and other test system care.
8ubpart F—Tast, Control, and Refaranco
8ubstanc*s
160.105 Test, control, and reference
substance characterization.
180.107 Test, control, and reference
substance handling.
160.113 Mixtures of substances with
carriers.
Subpart Q—Protocol for and Conduct of s
Study
160.120 Protocol.
160.130 Conduct of a study.
160.135 Physical and chemical
characterization studies.
Subparts H and I—{Reserved]
Subparts—Records and Reports
160.185 Reporting of study results.
160.190 Storage and retrieval of records and
data.
160.195 Retention of records.
Authority: 7 U.S.C. 136a, 136c, 138d. 136f.
1361.1361136v. 136w; 21 U.S.C. 346a, 348, 371.
Reorganization Plan No. 3 of 1970.
Subpart A—General Provisions
} 160.1 Scop*.
(a)	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, IB and 24(c) of the
Federal Insecticide. Fungicide, and
Rodenticide Act (FIFRA), as amended (7
U.S.C. 136a. 136c, 136f, 138q and 136v(c))
and sections 408 and 409 of the Federal
Food. Drug and Cosmetic Act (FFDCA)
(21 U.S.C. 346a, 348).
(b)	This part applies to any study
described by paragraph (a) of this
section which any person conducts,
initiates, or supports on or after October
16,1989.
{1MJ 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.
(8) 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
{100.105(a).
Carrier means any material, including
but not limited to feed, water, soil,
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 i
administered to the test system In the £
course of a study for the purpose of £
establishing a basis for comparison wfth
the test substance for known chemic&t
or biological measurements.
EPA means the U.S. Environmental
Protection Agency.
Experimental start date means the
first data 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 Rodentidde 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
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 transepts of raw data have been

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MMM Fwfarri Register / Vol 54. No. 156 / Thorsriay, August 17, 1968 / Rules and Regulations
prepared (e.£. tapes whk± have been
transcribed verbatim, dated, and
verified accurate by slgnaturekibe
exact copy o* exact tramaffiMov be
substituted for the oriainahaoarce as
raw data. "Raw data" mafAjiide
photograph#, microfilm or u&LuCche
copies, computer printouts, magnetic
media. Including dictated observations,
and recorded data from automated
instruments.
Reference nbstonce 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
derived from a test system for
examination or analysis
Sponsor means:
(1)	A person wbo Initiates and
supports, by provision of financial or
other resources, a study:
(2)	A penon wbo submits a study to
the EPA in support of an application for
a research or marketing permit: or
(3)	A twtbig facility, if it both initiates
and actually conducts the study.
Study means any experiment at one or
more test sftes. In which a test
substance is studied in a test system
under laboratory conditions or m the
environment to determine or help
predict its effects, metabolism, product
performance (efficacy studies only as
required by 40 CFR 158.840).
environmental and chemical fate,
persistence and residue, or other
characteristics in humans, other firing
organisms, or media. The term "study"
does not tnctode basic exploratory
studies carried out to determine whether
a test substance or a test method has
any potential utility.
Study completion date mean9 the date
the final report is signed by the study
director.
Study director meant theiggvidual
responsible lor the overall Mabel of a
study.
Study initiation date mf-Hfl* the date
the protocol is signed by the study
director.
Test mihHtaitce means a substance or
mixture xkrrmtstered or added to a test
system in a study, which substasce or
mixture:
(1)	Is the subject of an application for
a research os marketing permit
supported by the study, or is the
contemplated subject of socfc an
application or
(2)	b a* iagrafcem. iaapurity,
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.
Test system means any animal, plant,
microorganism, chemical or pbysical
matrix, including bat not limited to soil
or water, or subparts thereof, to which
the teat, 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.
Testinn 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.
Vehicle means any agent which
facilitates the mixture, dispersion, or
solubilization of a test substance with a
carrier.
} 160. tO AppHcaMTty to sfudto*
performed under grants 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, it shall notify the
consulting laboratory, contractor, or
grantee that the service is. or is part of.
a study that must be conducted in
compliance with the provisions of this
part.
I tSC.ll Mmw* of oompQanca or non-
Any person who submits to EPA 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 shall include
in the application 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;
or
(b)	A statement describing in detail aD
differences between the practices used
in the study and those required by this
part: or
(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
} 160.15 toapodtonaf ataatingfac<y.
(a) A testing facility shall permit an
authorized employee a duly designated
representative of EPA or FDA. a(
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
sludieB to which this part applies. The
records inspection and copying
requirements should 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 any
data developed by a testing facility or
sponsor that refuses to permit inspection
in accordance with thia part. The
determination that a study will not be
considered in support of an application
for a research or marketing permit does
not, however, relieve the applicant for
such a permit of any obligation under
any applicable statute or regulation to
submit the results of the study to EPA.
1160.17 Effects of noft-compHanoe.
(a)	EPA may refuse to consider
reliable for purposes of supporting aji
application for a research or marketing
permit any data from a study which was
not conducted in accordance with this
part.
(b)	Submission of a statement
required by ( 160.12 which is false may
form the basis for cancellation,
suspension, or modification of the
research or marketing permit, or denial
or disapproval of an application for sucb
a permit, under FIFRA section 3. 5.6.' 18.
or 24 or FFDCA section 406 or 409. or for
criminal prosecution under 18 U.SC. 2
or 1001 or FIFRA section 14. or for
imposition of civil penalties under
FIFRA section 14.
Subpart B—Organization and
P*rsoni>«<
gieo.a Psiaowitai
(a)	Each individual engaged in the
conduct of or responsible for the
supervision of a study shall have
education, training, and experience, or
combination thereof, to enable that
individual to perform the assigned
functions.
(b)	Each tasting facility shsU maintain
a current seminary of training and
experience and fob 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.

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Federal Regstar / Vol 54, No. 158 / Thursday, August 17, 1989 / Rules and Regulations 34089
(d)	Personnel shall take necessary
personal sanitation and health
precautions designed to avot(L
contamination of test, con&£fend
reference substances andi&stjvstems.
(e)	Personnel engaged tiD_study shall
wear clothing appropriate'Sulie 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 wiLn test systems, and test,
control, and reference substances, and
any other operation or function that may
adversely alTect the study until the
condition is corrected. AJI personnel
shall be instructed to report to their
immediate supervisors any health or
medical conditions that cay reasonably
be considered to have an adverse effect
on a study.
§160.31 Testing facility management
For each study, testing facility
management shall:
(a)	Designate a study director as
described in § 160.33 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 J 160.35.
(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 reportecLfe^he quality
assurance unit are committBied to the
study director and correcfiyfe -actions are
taken and documented.
$ 160.33 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 repotting 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
S 160.120 and is followed.
(b)	All experimental data, including
observations of unanticipated responses
of the test system are accurately
recorded and verified.
(c)	Unforseen 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 speciGed in
the protocol.
(e)	All applicable good laboratory
practice regulations are followed.
(f)	All raw data, documentation,
protocols, specimens, and final reports
are transferred to the archives during or
at the close of the study.
$ 160.35 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:
(1)	Maintain a copy of a master
schedule sheet of all studies conducted
at the testing facility indexed by test
substance, and containing the test
system, nature of study, date study was
Initiated, current status of each study,
identity of the sponsor, and name of the
study director.
(2)	Maintain copies of all protocols
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
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 anjr
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 iie
inspection shall be made availablejfor
inspection to authorized employee/or
duly designated representatives oTEPA
or FDA.
(d)	An authorized employee or a duly
designated representative of CPA 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—factttiM
$ 160.41 Ganerat
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 sny function or activity from
having an adverse effect on the study.
j 160.43 Test system care faculties.
(a) A testing facility shall beve a
sufficient number of animal rooms or
other test system areas, as needed, to
ensure: proper separation of species or
test systems, isolation of indiridaal
projects, quarantine or isolatioa of
animals or other test systems, and
routine or specialized housing of
animal* or ether test systems.

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34070 Federal Register / Vol. 54, No. 156 / Thursday, August 17, 1989 / Rules and Regulations
(1)	In tests with plants or aquatic
animals, proper separation of species
can be accomplished within a room or
area by housing them separate If in
different chambers or aqua?gf*
Separation of species is un®5essary
where the protocol specifiedjgg-
simultaneous exposure of two or more
species in the same chamber, aquanum.
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 organisnngn
adequate supply of clean seaatater or
artificial sea water (prepare fflam
deionized or distilled water alRfsea 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. 86
specified in the protocol, shall be
available as needed.
9160.45 Test system supply facflttles.
(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.
§ 160.47 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.
9 160.49 Laboratory operation areas.
Separate laboratory space and other
space shall be provided, as needed, for
the performance of the routine and
specialized procedures required by
studies.
9160.51 Specimen and data storage
faculties.
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 studies.
Subpart D—Equipment
9160.61 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 Bhall be suitably located
for operation, inspection, cleaning, and
maintenance.
9160.63 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
9 160.81(b)(ll) 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 .shell
specify, when appropriate, remedial
action to be taken in the event of failtre
or malfunction of equipment. The
written standard operating procedures
shall designate the person 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 dates 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.
Subpart E—Testing Facilities
Operation
9 160.61 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
insure 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

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Federal Register / Vol. 54, No. 156 / Thursday, August 17. 1989 / Rules and Regulations 34071
properly authorized in writing by
management.
(b)	Standard operating procedures
shall be established for, but gB&£mited
to. the following:	_
(1)	Test system area preparSTTon.
(2)	Test system care.
(3)	Receipt, identification, storage,
handling, mixing, and method of
sampling of the test, control, and
reference substances.
(4)	Teat system observations.
(5)	Laboratory or other testa.
(6)	Handling of lest 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
Held 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.
} 160.*3 RugMta and solutions.
All reagent* 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.
{160.00 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 tesftjstems
from outside sources shall bl^B&lated
and their health statu* 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 Jwch a disease or
condition, the diseased test systems
shcmM 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 tmits for any reason (e.g.. cage
cleaning, treatment, etc.), shall receive
appropriate identification (e.g.. tattoo,
color code, ear tag, ear punch, etc.). Ail
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 boused in
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 end 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 fn animal cages or
pens shall not interfere with the purpose
or conduct of the study and shaB be
changed as often as necessary to keep
the animals dry and clean.
(i) If any pest control 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
i 160.105 Test control, and reference
substanc* 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 shalljfce
determined by the testing facility or the
sponsor before the experimental start
date. The stability of the test, control* or
reference substance shall be determined
before the experimental start date or
concomitantly 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 number (CAS) or code number,
batch number, expiration date, if any.
and. where appropriate, 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
subftlance for the duration of the study.
(d)	For studies ot more than 4 weeks
experimental duration, reserve samples
from each batch of test. controL and
reference substances shall be retained
for the period of time provided by
{ 160.185.
(e)	The stability of test, control, and
reference substances under storage
conditions at the test site shall be
known for all studies.
{ 160.107 Test, control, and reference
•ubstance fcandRng.
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.

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84072 Federal Register / Vol. 84. No. 156 / Thursday, August 17, 1989 / Rules and Regulations
(b)	Distribution is made in a manner
designed to preclude the possibility of
contamination, deterioration, or damage.
(c)	Proper identification is rgftSained
throughout the distribution pgfce'ss.
(d)	The receipt and diatribi^jotrof
each batch is documented. SuS^T
documentation shall include (fie date
and quantity of each batch distributed
or returned.
{160.113 MbrturM of aubttancM wttti
cantor*.
(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 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)	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.
(c)	If a vehicle is used to facilitate the
mixing of a test subBtance 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
{160.120 Protocol
(a) Each study shall havean approved
written protocol that clearly te^cates
the objectives and all metho^ro- the
conduct of the study. The piflgcol shall
contain but shall not necesa^St be
limited to the following Information:
(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)
number or code number.
(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.
(0) Where applicable, a description
and/or identification of the diet used in
the Btudy 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 Bhall
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 proposed
statisUcal 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.
{160.130 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
teBt 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
hlstopathologically.
(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.
{160.135 Physical and ctwmlcal
ctwactwUaUon atudtes.
(a)	All provisions of the GLP
standards 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 GLP standards shall
not apply to studies, other than those
designated in paragraph (a) of this
section, designed to determine physical
and chemical characteristics of a teBt.
control, or reference substance:
{ 160.31 (c). (d). and (g)
1 160.35 (b) and (c)
i 160.43
1160.45
{ 160.47
(160.49
{ 160.81(b) (1). (2). (6) through (9). and (12)
{ 160.90
1 160.105 (a) through (d)
1160.113
1160.120(a) (5) through (12). and (15)
1 160.165(a) (5) through (6). (10). (12). and (14)
1160.195 (c) and (d)
Subparts H and I—(Reserved]
Subpart J Records and Reports
{160.166 Reporting of study rwutts.
(a) 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, terminated or discontinued.

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Fwfcral Register / Vol. M. No, 156 / Thuraday, August 17, 1989 / Rules and Regulations 34073
(2)	Objectives snd procedures stated
In the approved protocol, including any
changes in the original propcaj.
(3)	Statistical methods ag^foyed for
analyzing the data.
(4)	The test, control. an
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