Consolidation of Good Laboratory Practice Standards

ENVIRONMENTAL PROTECTION AGENCY

40 CFR PARTS 160, 792, and 806

RIN 2020-AA26

[ECDIC-1998-02; FRL-5782-7]

Consolidation of Good Laboratory Practice Standards

AGENCY: Environmental Protection Agency (EPA).

ACTION: Proposed rule.

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

SUMMARY: EPA is proposing to consolidate its Good Laboratory Practice

Standards (GLPS), which currently exist in two separate regulations at

40 CFR part 160 and 40 CFR part 792. The proposed consolidated GLPS

rule would be applicable to programs under the Federal Insecticide,

Fungicide, and Rodenticide Act (FIFRA) and the Toxic Substances Control

Act (TSCA) to which the current rules apply. In addition to the

proposed consolidation, EPA is also proposing amendments to the GLPS

that streamline and ease

[[Page 72973]]

compliance while still maintaining the rule's data integrity assurance

purpose. The consolidation will reduce the volume of regulations

administered by EPA without adversely affecting current data integrity

requirements. GLPS are intended to ensure the integrity of data

gathered from studies in a wide variety of disciplines such as

toxicology, ecological effects, chemical fate, residue chemistry, and

product performance testing. Under FIFRA, compliance with regulations

on GLPS applies to all studies required to be submitted in support of

pesticide registrations, reregistrations, and experimental use permits.

Under TSCA, GLPS are required for testing conducted pursuant to consent

agreements/orders and test rules issued under sections 4 and 5 of that

Act. Failure to comply with applicable GLPS is an actionable violation

which may result in civil or criminal penalties, and can render data

from non-compliant studies unacceptable for consideration by EPA.

DATES: Comments, identified by the docket control number EC-1998-02,

must be received by March 29, 2000.

ADDRESSES: By mail, submit comments to: Enforcement and Compliance

Docket and Information Center (2201A), Office of Enforcement and

Compliance Assurance, Environmental Protection Agency, 401 M St., SW.,

Washington, DC 20460. In person, bring comments to: Enforcement and

Compliance Docket and Information Center, Office of Enforcement and

Compliance Assurance, Rm. 4033, Ariel Rios Bldg., 1200 Pennsylvania

Ave., Washington, DC. The telephone number for the Enforcement and

Compliance Docket and Information Center is (202) 564-2614.

Information submitted and any comment(s) concerning this proposed

rule may be claimed confidential by marking any or all of that

information as ``Confidential Business Information'' (CBI). Information

so marked will not be disclosed except in accordance with procedures

set forth in 40 CFR part 2. A copy of the comment(s) that does not

contain CBI must be submitted for inclusion in the public record.

Information not marked confidential may be disclosed publicly by EPA

without prior notice to the submitter. Information on the proposed rule

and any written comments received will be available for public

inspection in Room 4033 at the Ariel Rios Bldg. address given above,

from 8 a.m. to 4 p.m., Monday through Friday, excluding legal holidays.

Comments and data may also be submitted electronically by sending

electronic mail (e-mail) to Donna W[email protected]. Comments

and data will also be accepted on disks in WordPerfect in 5.1/6.1 or

ASCII file format. All comments and data in electronic form must be

identified by the docket control number EC-1998-02. No CBI should be

submitted through e-mail. Electronic comments on this proposed rule,

but not the record, may be viewed or new comments filed online at many

Federal Depository Libraries.

FOR FURTHER INFORMATION CONTACT: David Stangel, Agriculture and

Ecosystems Division, Office of Compliance (2225A), U. S. Environmental

Protection Agency, 401 M St., SW., Washington, DC 20460, Telephone:

(202) 564-4162, e-mail: [email protected].

SUPPLEMENTARY INFORMATION:

I. Introduction

EPA proposes to amend the FIFRA GLPS (40 CFR part 160) and the TSCA

GLPS (40 CFR part 792) to consolidate these regulations into one rule.

In addition, EPA proposes to provide clarifications of certain

requirements and amend other requirements of the rule to reflect the

experience gained in administering the GLPS.

A. Legal Authority

These GLPS are promulgated under the authority of sections 3, 4, 5,

6, 8, 18, 24(c), and 25(a) of FIFRA, 7 U.S.C. 136 et seq., as amended,

sections 408, 4091, and 701 of the Federal Food, Drug, and

Cosmetic Act (FFDCA), 21 U.S.C. 301 et seq., the Reorganization Plan

No. 3 of 1970, and sections 4(b)(1) and 5 of TSCA, 15 U.S.C. 2603 et

seq.

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

1Prior to August 3, 1996 (the effective date of the Food Quality

Protection Act of 1996), data were submitted to the Agency pursuant

to section 409. References in this rule to section 409 remain with

respect to such data.

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

B. Background

EPA published FIFRA and TSCA GLPS in the Federal Register on

November 29, 1983 (48 FR 53946 and 48 FR 53922), which were codified as

40 CFR parts 160 and 792 respectively, and were amended on August 17,

1989 (54 FR 34052 and 54 FR 34034). These TSCA and FIFRA regulations

were initially promulgated to address assuring the validity of data in

the wake of investigations by EPA and the Food and Drug Administration

(FDA) during the mid-1970's which revealed that some studies submitted

to the Agencies had not been conducted in accordance with acceptable

laboratory practices. Some studies had been conducted so poorly that

the resulting data could not be relied upon in EPA's regulatory

decision-making process. In some cases, results were selectively

reported, underreported, or fraudulently reported. In addition, it was

discovered that some testing facilities displayed poor animal care

procedures and inadequate recordkeeping techniques. The GLPS specify

minimum practices and procedures in order to ensure the quality and

integrity of data submitted to EPA in support of a research or

marketing permit for a pesticide product, or the quality and integrity

of data submitted in accordance with a TSCA section 4 or 5 requirement.

When EPA published its initial FIFRA and TSCA GLPS in the Federal

Register of November 29, 1983, EPA sought to harmonize the requirements

and language with those regulations promulgated by the FDA in the

Federal Register of December 22, 1978 (43 FR 60013), and codified as 21

CFR part 58. Differences between the two Agencies' current GLPS

regulations existed only to the extent necessary to reflect the

Agencies' different statutory responsibilities under TSCA, FIFRA, and

FFDCA. Similar to the FDA GLPS regulations, the FIFRA and TSCA GLPS

delineate standards for studies required to be submitted to EPA for its

regulatory decision-making.

Compliance with EPA's FIFRA and TSCA GLPS has been monitored

through a program of laboratory inspections and data audits coordinated

between EPA and FDA. Under an Interagency Agreement originated in 1978

between FDA and EPA, FDA carries out GLPS inspections at laboratories

which conduct health effects testing. EPA primarily performs GLPS

inspections for environmental laboratories and conducts data audits for

health effects and environmental studies. Because of the cooperative

nature of FDA's and EPA's GLPS programs, it is important that the GLPS

remain substantially consistent not only between programs within each

Agency but also between Agencies.

FDA revised its GLPS regulations on September 4, 1987 (52 FR

33768), to simplify the regulations and reduce the regulatory burden on

testing facilities without compromising study integrity. EPA published

amendments to its FIFRA and TSCA GLPS in the Federal Register of August

17, 1989 (54 FR 34052 and 54 FR 34043 respectively). During that

rulemaking, EPA expanded the applicability of its FIFRA GLPS to cover

all data required to be submitted under FIFRA.

On March 4, 1995, the President directed all Federal agencies to

conduct

[[Page 72974]]

a comprehensive review of the regulations these agencies administer and

reduce or eliminate unnecessary or duplicative regulations. In

response, EPA conducted a review of its regulations to determine

candidates for such reductions. During this process, EPA identified the

FIFRA and TSCA GLPS as providing an opportunity for such reductions.

The goal of consistency of GLPS resulted in the same regulatory

language being duplicated throughout these two rules. This proposed

rulemaking reflects EPA's belief that it is not necessary to duplicate

the same language in two separate regulations.

Since the 1989 rulemaking, EPA has received many requests for

clarifications with respect to compliance requirements, especially

regarding FIFRA studies that came under GLPS coverage in 1989. EPA's

responses to those requests facilitated compliance with the FIFRA GLPS

rule and have been made available to the regulated community in a

Question and Answer document which may be obtained from the address

listed above in the ``FOR FURTHER INFORMATION CONTACT'' section.

EPA has been in communication with representatives of the regulated

community who indicated that it would improve the quality of and

compliance with the GLPS if previous clarifications were incorporated.

As a result of these initial consultations, EPA believes that it makes

sense to incorporate these clarifications and consider other

suggestions for improving these regulations, and is proposing several

modifications to the GLPS requirements as part of this rulemaking.

II. Summary of Proposed Changes

A. Consolidation

Currently, EPA has GLPS at 40 CFR part 160 and part 792. These

rules are identical in general format, each consisting of the following

subparts: A--General Provisions; B--Organization and Personnel; C--

Facilities; D--Equipment; E--Testing Facilities Operation; F--Test,

Control, and Reference Substances; G--Protocol for and Conduct of a

Study; H and I--[Reserved]; and J--Records and Reports.

Most of the sections under these subparts are identical between the

two rules. In such cases, EPA proposes to continue the current language

except where amended as provided in Unit II.B. of this preamble. Some

sections include rule differences for the two regulatory areas--TSCA

and FIFRA. In such cases, it is necessary to provide separate, distinct

sections, or subsections applicable to those programs.

Therefore, the proposed 40 CFR part 806 will continue the common

language currently found in both 40 CFR parts 160 and 792. Current

differences between the TSCA and FIFRA rules will be treated in one of

two ways: (1) Differences which are programmatic and necessary will be

continued in the form of separate regulatory provisions under the

consolidated GLPS; and (2) differences that are determined to be

inadvertent, e.g., typographic errors, minor grammatical differences,

etc., will be eliminated.

1. Program differences. The two subparts in which there are

significant differences between the two rules are Subpart A (General

Provisions) and Subpart J (Records and Reports). All other subparts are

virtually identical.

a. Subpart A--General Provisions--i. Sec. 806.1--Scope. Section

806.1(a) proposes to include the relevant statutory authorities under

FIFRA and FFDCA (currently applicable to pesticides studies), and the

authorities under TSCA (currently applicable to substances regulated

under TSCA). In Sec. 806.1(a)(2), the Agency states that the GLPS apply

to any study which any person conducts, initiates, or supports by a

certain date. If a study is initiated prior to that date but conducted

after that date, the GLPS would apply to the study. Only if the study

is completed prior to the effective date of the rule would it not be

subject to the amended GLPS.

ii. Sec. 806.3--Definitions. Section 806.3 includes definitions

which are specific to program areas and are currently listed separately

in the two rules.

iii. Sec. 806.12--Statement of Compliance or Noncompliance. Section

806.12 proposes specific and separate applicability under the current

program areas (toxics and pesticides) which provide for compliance

statements.

b. Subpart J--Records and Reports. -- Sec. 806.195--Retention of

Records. Section 806.195 proposes separate record retention

requirements for documentation records, raw data, and specimens

pertaining to FIFRA and TSCA studies.

B. Clarifying Amendments

In addition to consolidating the regulations, the Agency is

proposing to amend the current regulatory language in 40 CFR parts 160

and 792 to clarify certain requirements and simplify others. These

amendments are being proposed in response to feedback received from the

regulated community as well as comments received in response to

publication of the Agency's intent to consolidate the FIFRA and TSCA

GLPS.

1. Subpart A--General Provisions. The proposal would amend the

current definitions of the terms ``carrier'' and ``test systems'' by

adding the word ``air'' to each definition to clarify that air is

considered both a carrier and a test system in certain circumstances.

This change will alleviate confusion on this point.

EPA proposes to amend the current definition of the term ``quality

assurance unit'' by deleting the phrase ``the study director'' and

adding the phrase ``individual(s) directly involved in the conduct of

the study, including the study director.'' This change is being

proposed because it is equally improper for persons other than the

study director who are working directly on the study to perform quality

assurance of the study.

EPA proposes to amend the current definition of the term

``vehicle'' by adding examples of substances which are considered

vehicles.

EPA proposes to amend the current Secs. 160.10 and 792.10 by adding

the phrase ``prior to initiation of the study,'' to the end of the

sentence as well as requiring the notification to be made in writing.

This change clarifies a number of questions that have been raised in

the past and is in keeping with normal practices. Section 806.10

reflects the change.

EPA proposes to amend the current Secs. 160.17(a)(2) and

792.17(a)(2) by changing the reference to FFDCA section 406, which was

a typographical error, to section 408, the proper reference. EPA

proposes to amend the term ``consent agreement'' to ``consent

agreement/order'' and the reference to ``section 4 of TSCA'' to

``section 4 or 5 of TSCA'' throughout the proposed rule to reflect that

GLPS are required in both test rules and consent agreements/orders, and

that testing can be required under both sections 4 and 5 of TSCA.

Section 806.17(a)(2) reflects these changes.

EPA proposes to amend the current Secs. 160.33(f) and 792.33(f) to

read: ``. . .during or at the close or termination of the study.'', to

address those instances where a study is terminated prior to completion

of the study. Section 806.33(f) reflects the change.

2. Subpart B--Organization and Personnel. EPA proposes to amend the

current Secs. 160.35(b)(1) and 792.35(b)(1) to include the following

language ``. . .indexed to permit expedient retrieval, which identifies

the. . .'' to allow the study director to employ an indexing system

which may not reference the test substance but would still allow the

[[Page 72975]]

facility to quickly extract the information. Section 806.35(b)(1)

reflects this change. EPA proposes to amend the current

Secs. 160.35(b)(2) and 792.35(b)(2) to read: ``. . .all protocols until

study completion pertaining. . . .'' Protocols are required to be

archived at the completion of a study and requiring the maintenance of

another copy of the protocol would be duplicative. Section 806.35(b)(2)

reflects this change.

3. Subpart C--Facilities. Questions have been raised in the past

about the applicability of the language in the current Secs. 160.43(a)

and 792.43(a); specifically whether co-exposure of test species to the

test substance (e.g., inhalation studies) is allowable given the

requirement for proper separation of species or test systems. Co-

exposure of test species in inhalation studies is allowable unless the

study protocol specifically prohibits the practice. Section 806.43(a)

reflects this change.

4. Subpart D--Equipment. The Agency proposes to amend the current

Secs. 160.63 and 792.63 by adding paragraph (d) to address the

integrity of data stored and manipulated by computers, data processors,

and automated laboratory procedures to make it clear that these types

of equipment are subject to the same provisions as other laboratory

equipment. Section 806.63 reflects this change.

5. Subpart E--Testing Facilities Operation. The Agency is proposing

to amend the current Secs. 160.83 and 792.83 to allow the testing

facility to develop a documentation performance standard as an

alternative to an expiration date for the contents of transfer bottles

and wash bottles. The testing facility has the option of labeling

transfer and wash bottles or developing another well documented system

to ensure that these solutions have not deteriorated or exceeded their

expiration date. Section 806.63 reflects this change. EPA specifically

requests comment on a documentation performance standard that would

provide the same assurances that the solutions have not deteriorated or

exceeded their expiration date. Other alternatives being considered

include the development of a list of substances that do not require

expiration dates, e.g., distilled water.

6. Subpart F--Test, Control, and Reference Substances. The Agency

proposes to amend the current Secs. 160.105(b) and 792.105(b) to allow

concurrent determination of solubility as well as stability of the

test, control, or reference substance. The rule presently allows only

concurrent determination of the stability of the test, control, or

reference substance. Section 806.105(b) reflects this change.

EPA proposes to amend the current Secs. 160.105(c) and 792.105(c)

to allow the study director the options of discarding containers which

contained the test substance, with proper recordkeeping of the

disposition of the containers, or retaining the containers until the

termination of the study. The proposal to relax the requirement for

retention of test substance containers is being made to address the

burden of retaining containers in field studies where large amounts of

the test substance are used. The approach proposed is prescriptive in

nature and gives the testing facility and study director EPA's position

on what the Agency considers adequate documentation. EPA is requesting

comments on whether such a prescriptive approach is necessary or should

be relaxed to state that the study director may authorize container

disposal and simply note in the raw data that this has been done.

In addition, the Agency is proposing to amend the current

Secs. 160.105(c) and 792.105(c) by deleting the term ``where

appropriate'' from the first sentence to now read ``. . .expiration

date, if any, and storage conditions necessary to maintain the

identity, . . .'' because information on storage conditions is always

appropriate. Section 806.105(c) reflects these changes.

The Agency proposes to amend the current Secs. 160.113(a)(2) and

792.113(a)(2) by the addition of the following language ``. .

.reference substance in the mixture; or if the solubility of the

substance is difficult to determine, appropriate homogeneity data, by

the testing facility. . .'' to address those situations in which the

test, control, or reference substance is insoluble and may create

emulsions that are very difficult to analyze. Section 806.113(a)(2)

reflects this change. EPA proposes to amend the current

Secs. 160.113(b) and 792.113(b) to exempt tank mixes and solutions

prepared for immediate administration (within 12 hours) in mammalian

acute toxicology studies, metabolism studies, or mutagenicity studies

from requirements for concentration determinations (but not from

uniformity determinations) under Secs. 160.113(a)(1) and 792.113(a)(1)

and solubility determinations under Secs. 160.113(a)(2) and

792.113(a)(2). This addition is being proposed in response to comments

that these mixes must be made and used quickly, and it is not possible

to perform solubility testing before the experimental start date.

Section 806.113(b) reflects this change.

7. Subpart G--Protocol for and Conduct of a Study. EPA proposes to

amend the current Secs. 160.120(a)(2) and 792.120(a)(2) to exempt

metabolism studies from the requirement to identify the test, control,

or reference substance when their identities are to be determined

during the study. In metabolism studies, the identity of the metabolite

or metabolites may not be known at the time that the protocol is

written. EPA proposes that the protocol need not identify reference

substances for metabolites when they cannot be identified before the

beginning of the study. This proposal does not affect the requirement

to identify metabolism study test, reference, or control substances at

the beginning of the study, unless the purpose of the study is to

identify them. Section 806.120(a)(2) reflects this change.

EPA proposes to amend the current Secs. 160.120(c) and 792.120(c)

to allow discontinued studies or studies otherwise terminated before

completion to be finalized by writing a protocol amendment with the

reasons for the termination, in lieu of preparing a final report. All

documentation for the terminated study must be retained in accordance

with Sec. 806.195. Sponsors are still obligated to meet section 6(a)(2)

of FIFRA and section 8(e) of TSCA requirements for submission of

adverse effects data including, but not limited to, those generated by

terminated studies. Section 806.120(c) reflects this change.

8. Subpart J--Records and Reports. EPA proposes to amend the

current Secs. 160.185(a)(1) and 792.185(a)(1) by deleting the words

``terminated or discontinued,'' because Sec. 806.120(c) was added to

address terminated or discontinued studies. Section 806.185(a)(1)

reflects this change.

EPA proposes to amend the current Secs. 160.185(a)(7) and

792.185(a)(7) by deleting the phrase ``or other test organisms,''

because the required information is relevant chiefly to animal systems.

Section 806.185(a)(7) reflects this change.

Finally, EPA proposes to amend the current Sec. 792.195 by

replacing the existing record retention requirements for studies

submitted under sections 4 and 5 of TSCA with a single requirement to

retain records for a period of 5 years following the date on which the

final report of the study is submitted to the Agency. The change will

simplify record retention requirements for persons required to retain

records by providing a single standard for record retention. Section

806.195 reflects this change.

III. Public Docket

A record has been established for this rulemaking under docket

number EC-

[[Page 72976]]

1998-02. This record is available for public inspection from 8 a.m. to

4 p.m., Monday through Friday, excluding legal holidays. The public

record is located in Rm. 4033, Office of Enforcement and Compliance

Assurance, Environmental Protection Agency, Ariel Rios Bldg., 1200

Pennsylvania Ave., Washington, DC. Written requests should be mailed

to: Enforcement and Compliance Docket and Information Center (2201A),

Environmental Protection Agency, 401 M St., SW., Washington, DC 20460.

IV. Statutory Review

In accordance with FIFRA section 25(a), this proposal was submitted

to the FIFRA Scientific Advisory Panel, the Secretary of Agriculture,

and appropriate Congressional Committees. No comments were received.

V. Regulatory Assessment Requirements

A. Executive Order 12866

Pursuant to Executive Order 12866 (58 FR 51735, October 4, 1993),

it has been determined that this proposed action is not a ``significant

regulatory action'' and is therefore not subject to the Office of

Management and Budget (OMB) review. The Agency believes that the

amendments associated with this action constitute regulatory relief,

and therefore will not impose any additional costs or burdens. The

analysis related to the costs and burdens of the original requirements

were discussed in conjunction with their promulgation in 1989. Because

this action consolidates the requirements contained in the original

GLPS, no new costs or burdens are imposed. Instead, the Agency believes

that the consolidation of the GLPS may actually increase efficiencies

for those companies that are required to use both TSCA and FIFRA GLPS,

because these companies will now only have one version of GLPS to use.

Additionally, many of the changes in the rule allow the laboratories to

use more efficient means of achieving the requirements of the GLPS. The

Agency solicits comments on the impacts of this consolidation on the

regulated community.

B. Executive Order 12898

Pursuant to Executive Order 12898 (59 FR 7629, February 16, 1994),

entitled Federal Actions to Address - Environmental Justice in Minority

Populations and Low-Income Populations, the Agency has considered

environmental justice related issues with regard to the potential

impacts of this action on the environmental and health conditions in

low-income and minority communities. The Agency believes that this

action will not adversely impact low-income and minority communities.

These regulations consolidate existing regulations and have not been

the subject of any environmental justice concerns in the past.

C. Executive Order 13084

Under Executive Order 13084, entitled Consultation and Coordination

with Indian Tribal Governments (63 FR 27655, May 19, 1998), EPA may not

issue a regulation that is not required by statute, that significantly

or uniquely affects the communities of Indian tribal governments, and

that imposes substantial direct compliance costs on those communities,

unless the Federal government provides the funds necessary to pay the

direct compliance costs incurred by the tribal governments. If EPA

complies by consulting, Executive Order 13084 requires EPA to provide

OMB, in a separately identified section of the preamble to the rule, a

description of the extent of EPA's prior consultation with

representatives of affected Tribal governments, a summary of the nature

of their concerns, and a statement supporting the need to issue the

regulation. In addition, Executive Order 13084 requires EPA to develop

an effective process permitting elected and other representatives of

Indian tribal governments ``to provide meaningful and timely input in

the development of regulatory policies on matters that significantly or

uniquely affect their communities.''

Today's proposed rule does not significantly or uniquely affect the

communities of Indian tribal governments. The proposed rule does not

involve or impose any requirements that affect Indian Tribes.

Accordingly, the requirements of section 3(b) of Executive Order 13084

do not apply to this document.

D. Unfunded Mandates Reform Act and Executive Order 12875

This proposed action does not contain any new requirements or

impose any additional burden because it proposes to consolidate

requirements together which currently exist in two separate

rulemakings. As such, this proposed action is expected to result in

savings and burden relief rather than in an expenditure by any State,

local, or Tribal governments, or by anyone in the private sector, and

will not result in any unfunded Federal mandates as defined by Title II

of the Unfunded Mandates Reform Act of 1995 (Public Law 104-4).

In addition, since this action does not contain any Federal

mandates on States, localities, or Tribes, it is not subject to the

requirements of Executive Order 12875, entitled Enhancing the

Intergovernmental Partnership (58 FR 58093, October 28, 1993).

E. Regulatory Flexibility Act

Pursuant to section 605(b) of the Regulatory Flexibility Act (5

U.S.C. 601 et seq.), the Agency hereby certifies that this regulatory

action does not have any significant adverse economic impacts on a

substantial number of small entities. This proposed rule does not

impose any new requirements that would impose any adverse impacts on

small entities. In consolidating the existing requirements, EPA is

allowing those companies that are currently conducting various testing

for use either pursuant to FIFRA or TSCA, to adhere to and follow a

single GLP standard. Given the efficiencies provided, the Agency has

determined that this proposal will not result in adverse impacts. As

such, no impact analysis is required.

Information related to this determination has been included in the

docket for this rulemaking, and, in accordance with Small Business

Administration (SBA) policy, will be provided to the Chief Counsel for

Advocacy of the SBA upon request. Any comments regarding the economic

impacts that this regulatory action may impose on small entities should

be submitted to the Agency at the address listed under Unit III. of

this preamble.

F. Paperwork Reduction Act

This proposed action does not contain any new information

collection requirements. The GLPS do not directly impose any

information collection requirements, but they describe standards

regarding testing conducted for other information collections currently

approved by the Office of Management and Budget (OMB) under the

provisions of the Paperwork Reduction Act, 44 U.S.C. 3501 et seq.:

Maximum Residue Limit (MRL) Petitions on Food/Feed Crops and New

Inert Ingredients (EPA ICR No. 597.06, OMB Control No. 2070-0024)

Notice of Pesticide Registration by States to Meet a Special Local

Need (SLN) under FIFRA Section 24(c) (EPA ICR No. 595.06, OMB Control

No. 2070-0055)

Application for New or Amended Registration (EPA ICR No. 277.10,

OMB Control No. 2070-0060)

Application for Experimental Use Permit (EUP) to Ship a Pesticide

for Experimental Purposes Only (EPA ICR

[[Page 72977]]

No. 276.08, OMB Control No. 2070-0040)

Data Call-In for Special Review Chemicals (EPA ICR No. 922.05, OMB

Control No. 2070-0057)

Application and Summary Report for an Emergency Exemption for

Pesticides (EPA ICR No. 596.05, OMB Control No. 2070-0032)

Burden means the total time, effort, or financial resources

expended by persons to generate, maintain, retain, or disclose or

provide information to or for a Federal agency. This includes the time

needed to review instructions; develop, acquire, install, and utilize

technology and systems for the purposes of collecting, validating, and

verifying information, processing and maintaining information, and

disclosing and providing information; adjust the existing ways to

comply with any previously applicable instructions and requirements;

train personnel to be able to respond to a collection of information;

search data sources; complete and review the collection of information;

and transmit or otherwise disclose the information.

An Agency may not conduct or sponsor, and a person is not required

to respond to a collection of information unless it displays a

currently valid OMB control number. The OMB control numbers for EPA's

regulations are listed in 40 CFR part 9 and 48 CFR chapter 15.

G. Request for Comment on Potential Voluntary Consensus Standards to

Consider for Future Regulatory Actions

This proposal does not involve a regulatory action that would

require the Agency to consider voluntary consensus standards pursuant

to section 12(d) of the National Technology Transfer and Advancement

Act of 1995 (NTTAA), Public Law 104-113, section 12(d) (15 U.S.C. 272

note). Section 12(d) directs EPA to use voluntary consensus standards

in its regulatory activities unless to do so would be inconsistent with

applicable law or otherwise impractical. Voluntary consensus standards

are technical standards (e.g., materials specifications, test methods,

sampling procedures, business practices, etc.) that are developed or

adopted by voluntary consensus standards bodies. The NTTAA requires EPA

to provide Congress, through OMB, explanations when the Agency decides

not to use available and applicable voluntary consensus standards when

the NTTAA directs the Agency to do so.

As indicated earlier, these guidelines represent an Agency effort

to harmonize the test guidelines between the Office of Pesticide

Programs (OPP) and the Office of Pollution Prevention and Toxics

(OPPT), as well as harmonizing the OPP and OPPT test guidelines with

those of the Organization for Economic Cooperation and Development. The

process for developing and amending these test guidelines includes the

extensive involvement of the scientific community, including peer

review by the FIFRA SAP and other expert scientific panels, and

providing extensive public comment.

In the future, these test guidelines could be incorporated into

regulatory actions taken by EPA pursuant to TSCA section 4. Although

the NTTAA requirements do not specifically apply to the issuance of

these particular test guidelines today, EPA invites your comment on

whether or not there are any voluntary consensus standards that should

be considered during the development of any future action under TSCA.

Future actions under TSCA section 4 would go through notice and comment

rulemaking or be negotiated as voluntary testing enforcement

agreements/consent orders/decrees, allowing for additional public

comment on this issue. Nevertheless, the Agency is interested in

whether or not there are any voluntary consensus standards that EPA

should considered in lieu of these test guidelines when the Agency

develops any future regulatory action that incorporates these test

guidelines. Any comments provided will assist the Agency in complying

with the NTTAA by facilitating the Agency's identification of voluntary

consensus standards that should be considered during the development of

a proposed regulatory action that incorporates any standards included

in these test guidelines. Please submit your comments to the person

identified in the FOR FURTHER INFORMATION CONTACT section.

H. Executive Order 13045

Executive Order 13045 entitled Protection of Children from

Environmental Health Risks and Safety Risks (62 FR 19885, April 23,

1997) applies to any rule that: (1) is determined to be ``economically

significant'' as defined under Executive Order 12866, and (2) concerns

an environmental health or safety risk that EPA has reason to believe

may have a disproportionate effect on children. If the regulatory

action meets both criteria, the Agency must evaluate the environmental

health or safety effects of the planned rule on children, and explain

why the planned regulation is preferable to other potentially effective

and reasonably feasible alternatives considered by the Agency.

EPA interprets Executive Order 13045 as applying only to those

regulatory actions that are based on health or safety risks, such that

the analysis required under section 5-501 of the Order has the

potential to influence the regulation. This proposed rule is not

subject to Executive Order 13045 because it does not establish an

environmental standard intended to mitigate health or safety risks.

I. Executive Order 13132

On August 4, 1999, President Clinton issued a new executive order

on federalism, Executive Order 13132 (64 FR 43255, August 10, 1999),

which will take effect on November 2, 1999. In the interim, the current

Executive Order 12612 (52 FR 41685, October 30, 1987), on federalism

still applies. This proposed rule will not have a substantial direct

effect on States, on the relationship between the national government

and the States, or on the distribution of power and responsibilities

among the various levels of government, as specified in Executive Order

12612.

List of Subjects

40 CFR Part 160

Environmental protection, Laboratories, Pesticides and pests,

Reporting and recordkeeping requirements.

40 CFR Part 792

Environmental protection, Hazardous substances, Laboratories,

Reporting and recordkeeping requirements.

40 CFR Part 806

Environmental protection, Data requirements, Good laboratory

practice, Hazardous materials, Pesticides and pests, Reporting and

recordkeeping requirements, Testing.

Dated: October 28, 1999.

Carol M. Browner,

Administrator.

Therefore, it is proposed that 40 CFR chapter I be amended as

follows:

PART 160 [Removed]

1. By removing part 160.

PART 792 [Removed]

2. By removing part 792.

3. By adding subchapter S consisting of part 806 to read as

follows:

[[Page 72978]]

SUBCHAPTER S--STANDARDS, TEST METHODS, AND GUIDELINES

PART 806--GOOD LABORATORY PRACTICE STANDARDS

Subpart A--General Provisions

Sec.

806.1 Scope.

806.3 Definitions.

806.10 Applicability to studies performed under grants and

contracts.

806.12 Statement of compliance or non-compliance.

806.15 Inspection of a testing facility.

806.17 Effects of non-compliance.

Subpart B--Organization and Personnel

806.29 Personnel.

806.31 Testing facility management.

806.33 Study director.

806.35 Quality assurance unit.

Subpart C--Facilities

806.41 General.

806.43 Test system care facilities.

806.45 Test system supply facilities.

806.47 Facilities for handling test, control, and reference

substances.

806.49 Laboratory operation areas.

806.51 Specimen and data storage facilities.

Subpart D--Equipment

806.61 Equipment design.

806.63 Maintenance and calibration of equipment.

Subpart E--Testing Facilities Operation

806.81 Standard operating procedures.

806.83 Reagents and solutions.

806.90 Animal and other test system care.

Subpart F--Test, Control, and Reference Substances

806.105 Test, control, and reference substance characterization.

806.107 Test, control, and reference substance handling.

806.113 Mixtures of substances with carriers.

Subpart G--Protocol for and Conduct of a Study

806.120 Protocol.

806.130 Conduct of a study.

806.135 Physical and chemical characterization studies.

Subparts H and I--[RESERVED]

Subparts J--Records and Reports

806.185 Reporting of study results.

806.190 Storage and retrieval of records and data.

806.195 Retention of records.

Authority: 7 U.S.C. 136a, 136c, 136d, 136f, 136j, 136t, 136v,

136w; 15 U.S.C. 2603; 21 U.S.C. 346a, 348, 371, Reorganization Plan

No. 3 of 1970.

Subpart A--General Provisions

Sec. 806.1 Scope.

(a)(1) This part prescribes good laboratory practices for

conducting studies that support or are intended to support applications

for research or marketing permits for pesticide products regulated by

the EPA. This part is intended to assure the quality and integrity of

data submitted pursuant to sections 3, 4, 5, 8, 18, and 24(c) of the

Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), as amended

(7 U.S.C. 136a, 136c, 136f, 136q, and 136v(c)) and sections 408 and 409

of the Federal Food, Drug, and Cosmetic Act (FFDCA), as amended (21

U.S.C. 346a, 348).

(2) This part applies to any study described by paragraph (a)(1) of

this section which any person conducts, initiates, or supports on or

after [Insert date 60 days after date of publication in the Federal

Register of the final rule].

(b)(1) This part also prescribes good laboratory practices for

conducting studies relating to health effects, environmental effects,

and chemical fate testing pursuant to the Toxic Substances Control Act

(TSCA) (Public Law 94-469, 90 Stat. 2006, 15 U.S.C. 2603 et seq.). This

part is intended to assure the quality and integrity of data submitted

pursuant to test rules and testing consent agreements/orders issued

under section 4 and section 5 of TSCA.

(2) This part applies to any study described by paragraph (b)(1) of

this section which any person conducts, initiates, or supports on or

after [Insert date 60 days after date of publication in the Federal

Register of the final rule].

(3) It is EPA's policy that all data developed for submission

under section 5 of TSCA be in accordance with provisions of this part.

If data are not developed in accordance with the provisions of this

part, EPA will consider such data insufficient to evaluate the health

and environmental effects of the chemical substances unless the

submitter provides additional information demonstrating that the data

are reliable and adequate.

Sec. 806.3 Definitions.

As used in this part, the following terms shall have the meanings

specified:

Application for research or marketing permit includes:

(1) An application for registration, amended registration, or

reregistration of a pesticide product under FIFRA sections 3, 4, or

24(c).

(2) An application for an experimental use permit under FIFRA

section 5.

(3) An application for an exemption under FIFRA section 18.

(4) A petition or other request for establishment or modification

of a tolerance, for an exemption for the need for a tolerance, or for

other clearance under FFDCA section 408.

(5) A petition or other request for establishment or modification

of a food additive regulation or other clearance by EPA under FFDCA

section 409.

(6) A submission of data in response to a notice issued by EPA

under FIFRA section 3(c)(2)(B).

(7) Any other application, petition, or submission sent to EPA

intended to persuade EPA to grant, modify, or leave unmodified a

registration or other approval required as a condition of sale or

distribution of a pesticide.

Batch means a specific quantity or lot of a test, control, or

reference substance that has been characterized according to

Sec. 806.105(a).

Carrier means any material, including but not limited to feed,

water, soil, air, or nutrient media, with which the test substance is

combined for administration to a test system.

Control substance means any chemical substance or mixture, or any

other material other than a test substance, feed, or water, that is

administered to the test system in the course of a study for the

purpose of establishing a basis for comparison with the test substance

for known chemical or biological measurements.

EPA means the U.S. Environmental Protection Agency.

Experimental start date means the first date the test substance is

applied to the test system.

Experimental termination date means the last date on which data are

collected directly from the study.

FDA means the U.S. Food and Drug Administration.

FFDCA means the Federal Food, Drug, and Cosmetic Act, as amended

(21 U.S.C. 321 et seq).

FIFRA means the Federal Insecticide, Fungicide, and Rodenticide Act

as amended (7 U.S.C. 136 et seq).

Person includes an individual, partnership, corporation,

association, scientific or academic establishment, government agency,

or organizational unit thereof, and any other legal entity.

Quality assurance unit means any person or organizational element

(except individual(s) directly involved in the conduct of the study,

including the study director), designated by testing facility

management to perform the duties relating to quality assurance of the

studies.

Raw data means any laboratory worksheets, records, memoranda,

notes, or exact copies thereof, that are the result of original

observations and activities of a study and are necessary for the

reconstruction and evaluation of the report of that study. In the event

that exact transcripts of raw data have been prepared (e.g., tapes

which have been transcribed verbatim, dated, and verified accurate by

signature), the exact

[[Page 72979]]

copy or exact transcript may be substituted for the original source as

raw data. Raw data may include photographs, microfilm or microfiche

copies, computer printouts, any original data captured electronically

or by some other medium, dictated observations, and recorded data from

automated instruments.

Reference substance means any chemical substance or mixture, or

analytical standard, or material other than a test substance, feed, or

water, that is administered to or used in analyzing the test system in

the course of a study for the purposes of establishing a basis for

comparison with the test substance for known chemical or biological

measurements.

Specimens means any material or sample derived from a test system

for examination or analysis.

Sponsor means:

(1) A person who initiates and supports, by provision of financial

or other resources, a study;

(2) A person who submits a study to the EPA: in support of an

application for a research or marketing permit; or in response to a

TSCA section 4 test rule and/or a person who submits a study under a

TSCA section 4 testing consent agreement/order or a TSCA section 5

consent order to the extent the agreement, rule or order references

this part; or

(3) A testing facility, if it both initiates and actually conducts

the study.

Study means any experiment at one or more test sites, in which a

test substance is studied in a test system under laboratory conditions

or in the environment to determine or help predict its effects,

metabolism, product performance (pesticide efficacy studies only as

required by 40 CFR 158.640) environmental and chemical fate,

persistence, or residue, or other characteristics in humans, other

living organisms, or media. The term ``study'' does not include basic

exploratory studies carried out to determine whether a test substance

or a test method has any potential utility.

Study completion date means the date the final report is signed by

the study director.

Study director means the individual responsible for the overall

conduct of a study.

Study initiation date means the date the protocol is signed by the

study director.

Test substance means a substance or mixture administered or added

to a test system in a study, which substance or mixture:

(1) Is the subject of an application for a research or marketing

permit supported by the study, or is the contemplated subject of such

an application; or

(2) Is an ingredient, impurity, degradation product, metabolite, or

radioactive isotope of a substance described by paragraph (1) of this

definition, or some other substance related to a substance described by

that paragraph, which is used in the study to assist in characterizing

the toxicity, metabolism, or other characteristics of a substance

described by that paragraph; or

(3) Is used to develop data to meet the requirements of a TSCA

section 4 test rule and/or is developed under a TSCA section 4 testing

consent agreement/order or TSCA section 5 consent order to the extent

the agreement, rule, or order references this part.

Test system means any animal, plant, microorganism, chemical or

physical matrix, including but not limited to soil, water or air, or

subparts thereof, to which the test, control, or reference substance is

administered or added for study. ``Test system'' also includes

appropriate groups or components of the system not treated with the

test, control, or reference substance.

Testing facility means a person who actually conducts a study,

i.e., actually uses the test substance in a test system. Testing

facility encompasses only those operational units that are being or

have been used to conduct studies.

TSCA means the Toxic Substances Control Act (15 U.S.C., 2601 et

seq.)

Vehicle means any agent which facilitates the mixture, dispersion,

or solubilization of a test substance with a carrier (e.g., water,

mineral oil, animal feed).

Sec. 806.10 Applicability to studies performed under grant and

contracts.

When a sponsor or other person utilizes the services of a

consulting laboratory, contractor, or grantee to perform all or a part

of a study to which this part applies, that sponsor or person shall

notify the consulting laboratory, contractor, or grantee, in writing,

that the service is, or is part of, a study that must be conducted in

compliance with the provisions of this part, prior to initiation of the

study.

Sec. 806.12 Statement of compliance or non-compliance.

Any person who submits to EPA either an application for a research

or marketing permit and who, in connection with the application,

submits data from a study to which this part applies, or a test

required by a test rule or testing consent agreement/order issued under

section 4 or 5 of TSCA, shall include in the application or submission

a true and correct statement, signed by the applicant, the sponsor, and

the study director, of one of the following types:

(a) A statement that the study was conducted in accordance with

this part.

(b) A statement describing in detail all differences between the

practices used in the study and those required by this part.

(c) A statement that the person was not a sponsor of the study,

did not conduct the study, and does not know whether the study was

conducted in accordance with this part.

Sec. 806.15 Inspection of a testing facility.

(a) Testing facility management shall permit an authorized

employee or duly designated representative of EPA or FDA, at reasonable

times and in a reasonable manner, to inspect the facility and to

inspect (and in the case of records also to copy) all records and

specimens required to be maintained regarding studies to which this

part applies. The records inspection and copying requirements shall not

apply to quality assurance unit records of findings and problems, or to

actions recommended and taken, except that EPA may seek production of

these records in litigation or formal adjudicatory hearings.

(b) EPA will not consider reliable for purposes of supporting an

application for a research or marketing permit, or showing that a

chemical substance or mixture does not present a risk of injury to

health or the environment, any data developed by a testing facility or

sponsor that refuses to permit inspection in accordance with this part.

The determination that a study will not be considered in support of an

application for a research or marketing permit or reliable for other

purposes does not, however, relieve the applicant for such a permit or

the sponsor of a required test of any obligation under any applicable

statute or regulation to submit the results of the study to EPA.

(c) Because a testing facility is a place where chemicals are

stored or held, it is subject to inspection under section 11 of TSCA.

Sec. 806.17 Effects of non-compliance.

(a)(1) EPA may refuse to consider reliable for purposes of

supporting an application for a research or marketing permit any data

from a study which was not conducted in accordance with this part.

(2) Submission of a statement required by Sec. 806.12 which is

false may form the basis for cancellation, suspension, or modification

of the

[[Page 72980]]

research or marketing permit, or denial or disapproval of an

application for such a permit, under FIFRA section 3, 4, 5, 6, 18, or

24 or FFDCA section 408 or 409, or for criminal prosecution under 18

U.S.C. 2 or 1001 or FIFRA section 14, or for imposition of civil

penalties under FIFRA section 14.

(b)(1) The sponsor or any other person who is conducting or has

conducted a test to fulfill the requirements of a test rule or testing

consent agreement/order issued under section 4 or 5 of TSCA will be in

violation of section 15 of TSCA if:

(i) The test is not being or was not conducted in accordance with

any requirement of this part;

(ii) Data or information submitted to EPA under this part include

information or data that are false or misleading, contain significant

omissions, or otherwise do not fulfill the requirements of this part;

or

(iii) Entry in accordance with Sec. 806.15 for the purpose of

auditing test data or inspecting test facilities is denied. Persons who

violate the provisions of this part may be subject to civil or criminal

penalties under section 16 of TSCA, legal action in United States

District Court under section 17 of TSCA, or criminal prosecution under

18 U.S.C. 2 or 1001.

(2) EPA, at its discretion, may not consider reliable for purposes

of showing that a chemical substance or mixture does not present a risk

of injury to health or the environment any study which was not

conducted in accordance with this part. EPA, at its discretion, may

rely upon such studies for purposes of showing adverse effects. The

determination that a study will not be considered reliable does not,

however, relieve the sponsor of a required test of the obligation under

any applicable statute or regulation to submit the results of the study

to EPA.

(3) If data submitted to fulfill a requirement of a test rule or

testing consent agreement/order issued under section 4 or 5 of TSCA are

not developed in accordance with this part, EPA may determine that the

sponsor has not fulfilled its obligations under section 4 or 5 of TSCA

and may require the sponsor to develop data in accordance with the

requirements of this part in order to satisfy such obligations.

Subpart B--Organization and Personnel

Sec. 806.29 Personnel.

(a) Each individual engaged in the conduct of or responsible for

the supervision of a study shall have the appropriate education,

training, and experience, or a combination thereof, to enable that

individual to perform the assigned functions.

(b) Each testing facility shall maintain a current summary of

training and experience and job description for each individual engaged

in or supervising the conduct of a study.

(c) There shall be a sufficient number of personnel for the timely

and proper conduct of the study according to the protocol.

(d) Personnel shall take necessary personal sanitation and health

precautions designed to avoid contamination of test systems and test,

control, and reference substances.

(e) Personnel engaged in a study shall wear clothing appropriate

for the duties they perform. Such clothing shall be changed as often as

necessary to prevent microbiological, radiological, or chemical

contamination of test systems and test, control, and reference

substances.

(f) Any individual found at any time to have an illness that may

adversely affect the quality and integrity of the study shall be

excluded from direct contact with test systems, test, control, and

reference substances, and any other operation or function that may

adversely affect the study until the health or medical condition is

corrected. All personnel shall be instructed to report to their

immediate supervisors any health or medical conditions that may

reasonably be considered to have an adverse effect on a study.

Sec. 806.31 Testing facility management.

For each study, testing facility management shall:

(a) Designate a study director as described in Sec. 806.33 before

the study is initiated.

(b) Replace the study director promptly if it becomes necessary to

do so during the conduct of a study.

(c) Assure that there is a quality assurance unit as described in

Sec. 806.35.

(d) Assure that test, control, and reference substances or mixtures

have been appropriately tested for identity, strength, purity,

stability, and uniformity, as applicable.

(e) Assure that personnel, resources, facilities, equipment,

materials and methodologies are available as scheduled.

(f) Assure that personnel clearly understand the functions they are

to perform.

(g) Assure that any deviations from these regulations reported by

the quality assurance unit are communicated to the study director and

corrective actions are taken and documented.

Sec. 806.33 Study director.

For each study, a scientist or other professional of appropriate

education, training, and experience, or combination thereof, shall be

identified as the study director. The study director has overall

responsibility for the technical conduct of the study, as well as for

the interpretation, analysis, documentation, and reporting of results,

and represents the single point of study control. The study director

shall assure that:

(a) The protocol, including any change, is approved as provided by

Sec. 806.120 and is followed.

(b) All experimental data, including observations of unanticipated

responses of the test system are accurately recorded and verified.

(c) Unforeseen circumstances that may affect the quality and

integrity of the study are noted when they occur, and corrective action

is taken and documented.

(d) Test systems are as specified in the protocol.

(e) All applicable GLPS regulations are followed.

(f) All raw data, documentation, protocols, specimens, and final

reports are transferred to the archives during or at the close or

termination of the study.

Sec. 806.35 Quality assurance unit.

(a) A testing facility shall have a quality assurance unit which

shall be responsible for monitoring each study to assure management

that the facilities, equipment, personnel, methods, practices, records,

and controls are in conformance with the regulations in this part. For

any given study, the quality assurance unit shall be entirely separate

from and independent of the personnel engaged in the direction and

conduct of that study. The quality assurance unit shall conduct

inspections and maintain records appropriate to the study.

(b) The quality assurance unit shall:

(l) Maintain a copy of a master schedule sheet of all studies

conducted at the testing facility indexed to permit expedient

retrieval, which identifies the test substance, the test system, nature

of study, date study was initiated, current status of each study, date

of completion or termination if study is not ongoing, identity of the

sponsor, and name of the study director.

(2) Maintain copies of all protocols until study completion

pertaining to all studies for which the unit is responsible.

(3) Inspect each study at intervals adequate to ensure the

integrity of the study and maintain written and properly signed records

of each periodic inspection showing the date of the

[[Page 72981]]

inspection, the study inspected, the phase or segment of the study

inspected, the person performing the inspection, findings and problems,

action recommended and taken to resolve existing problems, and any

scheduled date for reinspection. Any problems which are likely to

affect study integrity found during the course of an inspection shall

be brought to the attention of the study director and management

immediately.

(4) Periodically submit to management and the study director

written status reports on each study, noting any problems and the

corrective actions taken.

(5) Determine that no deviations from approved protocols or

standard operating procedures were made without proper authorization

and documentation.

(6) Review the final study report to assure that such report

accurately describes the methods and standard operating procedures, and

that the reported results accurately reflect the raw data of the study.

(7) Prepare and sign a statement to be included with the final

study report which shall specify the dates inspections were made and

findings reported to management and to the study director.

(c) The responsibilities and procedures applicable to the quality

assurance unit, the records maintained by the quality assurance unit,

and the method of indexing such records shall be in writing and shall

be maintained. These items including inspection dates, the study

inspected, the phase or segment of the study inspected, and the name of

the individual performing the inspection shall be made available for

inspection to authorized employees or duly designated representatives

of EPA or FDA.

(d) An authorized employee or a duly designated representative of

EPA or FDA shall have access to the written procedures established for

the inspection and may request testing facility management to certify

that inspections are being implemented, performed, documented, and

followed-up in accordance with this paragraph.

Subpart C--Facilities

Sec. 806.41 General.

Each testing facility shall be of suitable size and construction to

facilitate the proper conduct of studies. Testing facilities which are

not located within an indoor controlled environment shall be of

suitable location to facilitate the proper conduct of studies. Testing

facilities shall be designed so that there is a degree of separation

that will prevent any function or activity from having an adverse

effect on the study.

Sec. 806.43 Test system care facilities.

(a) A testing facility shall have a sufficient number of animal

rooms or other test system areas, as needed, to ensure: proper

separation of species or test systems, isolation of individual

projects, quarantine or isolation of animals or other test systems, and

routine or specialized housing of animals or other test systems.

(1) In tests with plants or aquatic animals, proper separation of

species can be accomplished within a room or area by housing them

separately in different chambers or aquaria. Separation of species is

unnecessary where the protocol specifies the simultaneous exposure of

two or more species in the same chamber, aquarium, or housing unit.

(2) Aquatic toxicity tests for individual projects shall be

isolated to the extent necessary to prevent cross-contamination of

different chemicals used in different tests.

(b) A testing facility shall have a number of animal rooms or other

test system areas separate from those described in paragraph (a) of

this section to ensure isolation of studies being done with test

systems or test, control, and reference substances known to be

biohazardous, including volatile substances, aerosols, radioactive

materials, and infectious agents.

(c) Separate areas shall be provided, as appropriate, for the

diagnosis, treatment, and control of laboratory test system diseases.

These areas shall provide effective isolation for the housing of test

systems either known or suspected of being diseased, or of being

carriers of disease, from other test systems.

(d) Facilities shall have proper provisions for collection and

disposal of contaminated water, soil, or other spent materials. When

animals are housed, facilities shall exist for the collection and

disposal of all animal waste and refuse or for safe sanitary storage of

waste before removal from the testing facility. Disposal facilities

shall be so provided and operated as to minimize vermin infestation,

odors, disease hazards, and environmental contamination.

(e) Facilities shall have provisions to regulate environmental

conditions (e.g., temperature, humidity, photoperiod) as specified in

the protocol.

(f) For marine test organisms, an adequate supply of clean sea

water or artificial sea water (prepared from deionized or distilled

water and sea salt mixture) shall be available. The ranges of

composition shall be as specified in the protocol.

(g) For freshwater organisms, an adequate supply of clean water of

the appropriate hardness, pH, and temperature, and which is free of

contaminants capable of interfering with the study, shall be available

as specified in the protocol.

(h) For plants, an adequate supply of soil of the appropriate

composition, as specified in the protocol, shall be available as

needed.

Sec. 806.45 Test system supply facilities.

(a) There shall be storage areas, as needed, for feed, nutrients,

soils, bedding, supplies, and equipment. Storage areas for feed

nutrients, soils, and bedding shall be separated from areas where the

test systems are located and shall be protected against infestation or

contamination. Perishable supplies shall be preserved by appropriate

means.

(b) When appropriate, plant supply facilities shall be provided. As

specified in the protocol, these include:

(1) Facilities for holding, culturing, and maintaining algae and

aquatic plants.

(2) Facilities for plant growth, including, but not limited to,

greenhouses, growth chambers, light banks, and fields.

(c) When appropriate, facilities for aquatic animal tests shall be

provided. These include, but are not limited to, aquaria, holding

tanks, ponds, and ancillary equipment, as specified in the protocol.

Sec. 806.47 Facilities for handling test, control, and reference

substances.

(a) As necessary to prevent contamination or mixups, there shall be

separate areas for:

(1) Receipt and storage of the test, control, and reference

substances.

(2) Mixing of the test, control, and reference substances with a

carrier, e.g., feed.

(3) Storage of the test, control, and reference substance mixtures.

(b) Storage areas for test, control, and/or reference substance and

for test, control, and/or reference mixtures shall be separate from

areas housing the test systems and shall be adequate to preserve the

identity, strength, purity, and stability of the substances and

mixtures.

Sec. 806.49 Laboratory operation areas.

Separate laboratory space and other space shall be provided, as

needed, for the performance of the routine and

[[Page 72982]]

specialized procedures required by studies.

Sec. 806.51 Specimen and data storage facilities.

Space shall be provided for archives, limited to access by

authorized personnel only, for the storage and retrieval of all raw

data and specimens from completed or terminated studies.

Subpart D--Equipment

Sec. 806.61 Equipment design.

Equipment used in the generation, measurement, or assessment of

data and equipment used for facility environmental control shall be of

appropriate design and adequate capacity to function according to the

protocol and shall be suitably located for operation, inspection,

cleaning, and maintenance.

Sec. 806.63 Maintenance and calibration of equipment.

(a) Equipment shall be adequately inspected, cleaned, and

maintained. Equipment used for the generation, measurement, or

assessment of data shall be adequately tested, calibrated, and/or

standardized.

(b) The written standard operating procedures required under

Sec. 806.81(b)(11) shall set forth in sufficient detail the methods,

materials, and schedules to be used in the routine inspection,

cleaning, maintenance, testing, calibration, and/or standardization of

equipment, and shall specify, when appropriate, remedial action to be

taken in the event of failure or malfunction of equipment. The written

standard operating procedures shall designate the person(s) responsible

for the performance of each operation.

(c) Written records shall be maintained of all inspection,

maintenance, testing, calibrating, and/or standardizing operations.

These records, containing the date of the operations, shall describe

whether the maintenance operations were routine and followed the

written standard operating procedures. Written records shall be kept of

nonroutine repairs performed on equipment as a result of failure and

malfunction. Such records shall document the nature of the defect, how

and when the defect was discovered, and any remedial action taken in

response to the defect.

(d) The integrity of data from computers, data processors, and

automated laboratory procedures involved in the collection, generation,

or measurement of data shall be ensured through appropriate validation

processes, maintenance procedures, disaster recovery, and security

measures.

Subpart E--Testing Facilities Operation

Sec. 806.81 Standard operating procedures.

(a) A testing facility shall have standard operating procedures in

writing setting forth study methods that management is satisfied are

adequate to ensure the quality and integrity of the data generated in

the course of a study. All deviations in a study from standard

operating procedures shall be authorized by the study director and

shall be documented in the raw data. Significant changes in established

standard operating procedures shall be properly authorized in writing

by management.

(b) Standard operating procedures shall be established for, but not

limited to, the following:

(1) Test system area preparation.

(2) Test system care.

(3) Receipt, identification, storage, handling, mixing, and method

of sampling of the test, control, and reference substances.

(4) Test system observations.

(5) Laboratory or other tests.

(6) Handling of test systems found moribund or dead during study.

(7) Necropsy of test systems or postmortem examination of test

systems.

(8) Collection and identification of specimens.

(9) Histopathology.

(10) Data handling, storage, and retrieval.

(11) Maintenance and calibration of equipment.

(12) Transfer, proper placement, and identification of test

systems.

(c) Each laboratory or other study area shall have immediately

available manuals and standard operating procedures relative to the

laboratory or field procedures being performed. Published literature

may be used as a supplement to standard operating procedures.

(d) A historical file of standard operating procedures, and all

revisions thereof, including the dates of such revisions, shall be

maintained.

Sec. 806.83 Reagents and solutions.

All reagents and solutions in the laboratory areas shall be labeled

to indicate identity, titer or concentration, storage requirements, and

expiration date. Deteriorated or outdated reagents and solutions shall

not be used. As an alternative to labeling wash bottles and transfer

bottles with the expiration date, the testing facility may develop a

well-documented performance standard to ensure that the reagents or

solutions have not deteriorated or are outdated.

Sec. 806.90 Animal and other test system care.

(a) There shall be standard operating procedures for the housing,

feeding, handling, and care of animals and other test systems.

(b) All newly received test systems from outside sources shall be

isolated and their health status or appropriateness for the study shall

be evaluated. This evaluation shall be in accordance with acceptable

veterinary medical practice or scientific methods.

(c) At the initiation of a study, test systems shall be free of any

disease or condition that might interfere with the purpose or conduct

of the study. If during the course of the study, the test systems

contract such a disease or condition, the diseased test systems should

be isolated, if necessary. These test systems may be treated for

disease or signs of disease provided that such treatment does not

interfere with the study. The diagnosis, authorization of treatment,

description of treatment, and each date of treatment shall be

documented and shall be retained.

(d) Warm-blooded animals, adult reptiles, and adult terrestrial

amphibians used in laboratory procedures that require manipulations and

observations over an extended period of time or in studies that require

these test systems to be removed from and returned to their test

system-housing units for any reason (e.g., cage cleaning, treatment,

etc.), shall receive appropriate identification (e.g., tattoo, color

code, ear tag, ear punch, etc.). All information needed to specifically

identify each test system within the test system-housing unit shall

appear on the outside of that unit. Suckling mammals and juvenile birds

are excluded from the requirement of individual identification unless

otherwise specified in the protocol.

(e) Except as specified in paragraph (e)(1) of this section, test

systems of different species shall be housed in separate rooms when

necessary. Test systems of the same species, but used in different

studies, should not ordinarily be housed in the same room when

inadvertent exposure to test, control, or reference substances or test

system mixup could affect the outcome of either study. If such mixed

housing is necessary, adequate differentiation by space and

identification shall be made.

(1) Plants, invertebrate animals, aquatic vertebrate animals, and

organisms that may be used in multispecies tests need not be housed in

[[Page 72983]]

separate rooms, provided that they are adequately segregated to avoid

mixup and cross contamination.

(2) [Reserved]

(f) Cages, racks, pens, enclosures, aquaria, holding tanks, ponds,

growth chambers, and other holding, rearing and breeding areas, and

accessory equipment, shall be cleaned and sanitized at appropriate

intervals.

(g) Feed, soil, and water used for the test systems shall be

analyzed periodically to ensure that contaminants known to be capable

of interfering with the study and reasonably expected to be present in

such feed, soil, or water are not present at levels above those

specified in the protocol. Documentation of such analyses shall be

maintained as raw data.

(h) Bedding used in animal cages or pens shall not interfere with

the purpose or conduct of the study and shall be changed as often as

necessary to keep the animals dry and clean.

(i) If any pest control or cleaning materials are used, the use

shall be documented. Cleaning and pest control materials that interfere

with the study shall not be used.

(j) All plant and animal test systems shall be acclimatized to the

environmental conditions of the test, prior to their use in a study.

Subpart F--Test, Control, and Reference Substances

Sec. 806.105 Test, control, and reference substance characterization.

(a) The identity, strength, purity, and composition, or other

characteristics which will appropriately define the test, control, or

reference substance shall be determined for each batch and shall be

documented before its use in a study. Methods of synthesis,

fabrication, or derivation of the test, control, or reference substance

shall be documented by the sponsor or the testing facility, and the

location of such documentation shall be specified.

(b) When relevant to the conduct of the study, the solubility of

each test, control, or reference substance shall be determined by the

testing facility or the sponsor before the experimental start date or

concurrently according to written standard operating procedures, which

provide for periodic analysis of each batch. The stability of the test,

control, or reference substance shall be determined before the

experimental start date or concurrently according to written standard

operating procedures, which provide for periodic analysis of each

batch.

(c) Each storage container for a test, control, or reference

substance shall be labeled by name, Chemical Abstracts Service (CAS)

registry number or code number, batch number, expiration date, if any,

and storage conditions necessary to maintain the identity, strength,

purity, and composition of the test, control, or reference substance.

Storage containers shall be assigned to a particular test substance for

the duration of the study. With the study director's written approval,

test substance storage containers need not be retained after use,

provided that full documentation of the disposition of the containers

is maintained as raw data for the study. This documentation shall

include:

(1)(i) Information of shipments pertaining to each container

leaving the storage site (examples of such records are shipping request

records, bills of lading, carrier bills, and monthly inventories of

warehouse activity).

(ii) Test substance receipt records at each testing facility.

(iii) Complete use logs of material taken from containers.

(iv) A record of the final destination of the container, including

the place and date of disposal or reclaiming, and any appropriate

receipts.

(2) An inventory record of empty containers before disposal,

including sufficient information to uniquely identify containers,

maintained in an up-to-date manner recording all arrivals of empty

containers and their disposal. This record shall be maintained as raw

data for this study.

(3) Locations of facilities; where test substance is stored; where

empty containers are stored prior to disposal; where records of use,

shipment, and disposal of containers are maintained; and where the test

substance is used in studies (i.e., testing facility).

(d) For studies of more than 4 weeks from the experimental start to

completion dates, reserve samples from each batch of test, control, and

reference substances shall be retained for the period of time provided

by Sec. 806.195.

(e) The stability of test, control, and reference substances under

storage conditions at the test site shall be known for all studies.

Sec. 806.107 Test, control, and reference substance handling.

Procedures shall be established for a system for the handling of

the test, control, and reference substances to ensure that:

(a) There is proper storage.

(b) Distribution is made in a manner designed to preclude the

possibility of contamination, deterioration, or damage.

(c) Proper identification is maintained throughout the distribution

process.

(d) The receipt and distribution of each batch is documented. Such

documentation shall include the date and quantity of each batch

distributed or returned.

Sec. 806.113 Mixtures of substances with carriers.

(a) For each test, control, or reference substance that is mixed

with a carrier, tests by appropriate analytical methods shall be

conducted:

(1) To determine the uniformity of the mixture and to determine,

periodically, the concentration of the test, control, or reference

substance in the mixture.

(2) When relevant to the conduct of the study, to determine the

solubility of each test, control, or reference substance in the

mixture; or if the solubility of the substance is difficult to

determine, appropriate homogeneity data, by the testing facility or the

sponsor before the experimental start date.

(3) To determine the stability of the test, control, or reference

substance in the mixture before the experimental start date or

concomitantly according to written standard operating procedures, which

provide for periodic analysis of each batch.

(b) Tank mixes prepared for application to soil or plants by

typical agricultural practices within a 12-hour period between

preparation and application, and solutions prepared for immediate

administration in mammalian acute toxicology studies, metabolism

studies, or mutagenicity studies, are exempt from requirements for

concentration determinations (but not from uniformity determinations)

under paragraph (a)(1) of this section and are exempt from requirements

for solubility determinations under paragraph (a)(2) of this section.

(c) Where any of the components of the test, control, or reference

substance carrier mixture has an expiration date, that date shall be

clearly shown on the container. If more than one component has an

expiration date, the earliest date shall be shown.

(d) If a vehicle is used to facilitate the mixing of a test

substance with a carrier, assurance shall be provided that the vehicle

does not interfere with the integrity of the test.

Subpart G--Protocol for and Conduct of a Study

Sec. 806.120 Protocol.

(a) Each study shall have an approved written protocol that clearly

indicates the objectives and all methods for the conduct of the study.

The protocol shall contain but shall not necessarily be limited to the

following information:

[[Page 72984]]

(1) A descriptive title and statement of the purpose of the study.

(2) Identification of the test, control, and reference substance by

name, Chemical Abstracts Service (CAS) registry number or code number.

When a reference substance for a metabolite cannot be identified prior

to the beginning of a study (only in the case of metabolism studies),

it is not necessary to identify the substance in the protocol. However,

a statement must be included that the identity of the reference

substance will be determined during the course of the study and

maintained as raw data.

(3) The name and address of the sponsor and the name and address of

the testing facility at which the study is being conducted.

(4) The proposed experimental start and termination dates.

(5) Justification for selection of the test system.

(6) Where applicable, the number, body weight range, sex, source of

supply, species, strain, substrain, and age of the test system.

(7) The procedure for identification of the test system.

(8) A description of the experimental design, including methods for

the control of bias.

(9) Where applicable, a description and/or identification of the

diet used in the study as well as solvents, emulsifiers and/or other

materials used to solubilize or suspend the test, control, or reference

substances before mixing with the carrier. The description shall

include specifications for acceptable levels of contaminants that are

reasonably expected to be present in the dietary materials and are

known to be capable of interfering with the purpose or conduct of the

study if present at levels greater than established by the

specifications.

(10) The route of administration and the reason for its choice.

(11) Each dosage level, expressed in milligrams per kilogram of

body or test system weight or other appropriate units, of the test,

control, or reference substance to be administered and the method and

frequency of administration.

(12) The type and frequency of tests, analyses, and measurements to

be made.

(13) The records to be maintained.

(14) The date of approval of the protocol by the sponsor and the

dated signature of the study director.

(15) A statement of the statistical method to be used.

(b) All changes in or revisions of an approved protocol and the

reasons therefore shall be documented, signed by the study director,

dated, and maintained with the protocol.

(c) Discontinued studies or studies otherwise terminated before

completion shall be finalized by writing a protocol amendment providing

the reason(s) for termination. All documentation for terminated studies

including the protocol, protocol amendment(s), and raw data, if

collected, shall be retained as provided at Sec. 806.195.

Sec. 806.130 Conduct of a study.

(a) The study shall be conducted in accordance with the protocol.

(b) The test systems shall be monitored in conformity with the

protocol.

(c) Specimens shall be identified by test system, study, nature,

and date of collection. This information shall be located on the

specimen container or shall accompany the specimen in a manner that

precludes error in the recording and storage of data.

(d) In animal studies where histopathology is required, records of

gross findings for a specimen from postmortem observations shall be

available to a pathologist when examining that specimen

histopathologically.

(e) All data generated during the conduct of a study, except those

that are generated by automated data collection systems, shall be

recorded directly, promptly, and legibly in ink. All data entries shall

be dated on the day of entry and signed or initialed by the person

entering the data. Any change in entries shall be made so as not to

obscure the original entry, shall indicate the reason for such change,

and shall be dated and signed or identified at the time of the change.

In automated data collection systems, the individual responsible for

direct data input shall be identified at the time of data input. Any

change in automated data entries shall be made so as not to obscure the

original entry, shall indicate the reason for change, shall be dated,

and the responsible individual shall be identified.

Sec. 806.135 Physical and chemical characterization studies.

(a) All provisions of the GLPS shall apply to physical and chemical

characterization studies designed to determine stability, solubility,

octanol water partition coefficient, volatility, and persistence (such

as biodegradation, photodegradation, and chemical degradation studies)

of test, control, or reference substances.

(b) The following GLPS shall not apply to studies, other than those

designated in paragraph (a) of this section, designed to determine

physical and chemical characteristics of a test, control, or reference

substance: Secs. 806.31(c), (d), and (g), 806.35(b) and (c), 806.43,

806.45, 806.47, 806.49, 806.81(b)(1), (2), (6) through (9), and (12),

806.90, 806.105(a) through (d), 806.113, 806.120(a)(5) through (12),

and (15), 806.185(a)(5) through (8), (10), (12), and (14), and

806.195(c) and (d).

Subparts H and I--[Reserved]

Subpart J--Records and Reports

Sec. 806.185 Reporting of study results.

(a) With the exception of discontinued or otherwise terminated

studies, as provided at Sec. 806.120(c), a final report shall be

prepared for each study and shall include, but not necessarily be

limited to, the following:

(1) Name and address of the facility performing the study and the

dates on which the study was initiated and was completed.

(2) Objectives and procedures stated in the approved protocol,

including any changes in the original protocol.

(3) Statistical methods employed for analyzing the data.

(4) The test, control, and reference substances identified by name,

Chemical Abstracts Service (CAS) registry number or code number,

strength, purity, and composition, or other appropriate

characteristics.

(5) Stability and, when relevant to the conduct of the study,

solubility of the test, control, and reference substances under the

conditions of administration.

(6) A description of the methods used.

(7) A description of the test system used. Where applicable, the

final report shall include the number of animals used, sex, body weight

range, source of supply, species, strain and substrain, age, and

procedure used for identification. For other test organisms (plants,

bacteria), similarly detailed descriptions of the test system are

required.

(8) A description of the dosage, dosage regimen, route of

administration, and duration.

(9) A description of all circumstances that may have affected the

quality or integrity of the data.

(10) The name of the study director, the names of other scientists

or professionals, and the names of all supervisory personnel, involved

in the study.

(11) A description of the transformations, calculations, or

operations performed on the data, a summary and analysis of the data,

and a statement of the conclusions drawn from the analysis.

[[Page 72985]]

(12) The signed and dated reports of each of the individual

scientists or other professionals involved in the study, including each

person who, at the request or direction of the testing facility or

sponsor, conducted an analysis or evaluation of data or specimens from

the study after data generation was completed.

(13) The locations where all specimens, raw data, and the final

report are to be stored.

(14) The statement prepared and signed by the quality assurance

unit as described in Sec. 806.35(b)(7).

(b) The final report shall be signed and dated by the study

director.

(c) Corrections or additions to a final report shall be in the form

of an amendment by the study director. The amendment shall clearly

identify that part of the final report that is being added to or

corrected and the reasons for the correction or addition, and shall be

signed and dated by the person responsible. Modification of a final

report to comply with the submission requirements of EPA does not

constitute a correction, addition, or amendment to a final report.

(d) A copy of the final report and of any amendment to it shall be

maintained by the sponsor and the test facility.

Sec. 806.190 Storage and retrieval of records and data.

(a) All raw data, documentation, records, protocols, specimens, and

final reports generated as a result of a study shall be retained.

Specimens obtained from mutagenicity tests, specimens of soil, water,

and plants, and wet specimens of blood, urine, feces, and biological

fluids, do not need to be retained after quality assurance

verification. Correspondence and other documents relating to

interpretation and evaluation of data, other than those documents

contained in the final report, also shall be retained.

(b) There shall be archives for orderly storage and expedient

retrieval of all raw data, documentation, protocols, specimens, and

interim and final reports. Conditions of storage shall minimize

deterioration of the documents or specimens in accordance with the

requirements for the time period of their retention and the nature of

the documents of specimens. A testing facility may contract with

commercial archives to provide a repository for all material to be

retained. Raw data and specimens may be retained elsewhere provided

that the archives have specific reference to those other locations.

(c) An individual shall be identified as responsible for the

archives.

(d) Only authorized personnel shall enter the archives.

(e) Material retained or referred to in the archives shall be

indexed to permit expedient retrieval.

Sec. 806.195 Retention of records.

(a) Record retention requirements set forth in this section do not

supersede the record retention requirements of any other regulations in

this subchapter.

(b) Except as provided in paragraph (c) of this section,

documentation records, raw data, and specimens pertaining to a study

and required to be retained by this part shall be retained in the

archive(s) for:

(1) In the case of applicability under Sec. 806.1(a), whichever of

the following periods is longest:

(i) In the case of any study used to support an application for a

research or marketing permit approved by EPA, the period during which

the sponsor or any successor(s) hold(s) any research or marketing

permit to which the study is pertinent.

(ii) A period of at least 5 years following the date on which the

results of the study are submitted to EPA in support of an application

for a research or marketing permit.

(iii) In other situations (e.g., where the study does not result in

the submission of the study in support of an application for a research

or marketing permit), a period of at least 2 years following the date

on which the study is completed, terminated, or discontinued.

(2) In the case of applicability under Sec. 806.1(b):

(i) In the case of a study required to be conducted under TSCA

section 4 or section 5, except for those items listed in paragraph (c)

of this section, all documentation, records, raw data, and specimens

pertaining to that study and required to be retained by this part shall

be retained in the archive(s) for a period of at least 5 years

following the date on which the final report of that required study is

submitted to EPA.

(ii) [Reserved]

(c) Wet specimens, samples of test, control, or reference

substances, and specially prepared material which are relatively

fragile and differ markedly in stability and quality during storage,

shall be retained only as long as the quality of the preparation

affords evaluation. Specimens obtained from mutagenicity tests,

specimens of soil, water, and plants, and wet specimens of blood,

urine, feces, and biological fluids, do not need to be retained after

quality assurance verification. In no case shall retention be required

for longer periods than those set forth in paragraph (b) of this

section.

(d) The master schedule sheet, copies of protocols, and records of

quality assurance inspections, as required by Sec. 806.35(c) shall be

maintained by the quality assurance unit as an easily accessible system

of records for the period of time specified in paragraph (b) of this

section.

(e) Summaries of training and experience and job descriptions

required to be maintained by Sec. 806.29(b) may be retained along with

all other testing facility employment records for the length of time

specified in paragraph (b) of this section.

(f) Records and reports of the maintenance and calibration and

inspection of equipment, as required by Sec. 806.63(b) and (c), shall

be retained for the length of time specified in paragraph (b) of this

section.

(g) If a facility conducting testing or an archive contracting

facility goes out of business, all raw data, documentation, and other

material specified in this section shall be transferred to the archives

of the sponsor of the study. EPA shall be notified in writing of such a

transfer.

(h) Specimens, samples, or other non-documentary materials need not

be retained after EPA has notified in writing the sponsor or testing

facility holding the materials that retention is no longer required by

EPA. Such notification normally will be furnished upon request after

EPA or FDA has completed an audit of the particular study to which the

materials relate and EPA has concluded that the study was conducted in

accordance with this part.

(i) Records required by this part may be retained either as

original records or as true copies such as photocopies, microfilm,

microfiche, or other accurate reproductions of the original records.

[FR Doc. 99-33831 Filed 12-28-99; 8:45 am]

BILLING CODE 6560-50-F