Microbial Products of Biotechnology; Proposed Regulation Under the Toxic Substances Control Act; Proposed Rule ENVIRONMENTAL PROTECTION AGENCY
Federal RegisterSep 1, 1994
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SUMMARY: EPA is proposing this regulation under section 5 of the Toxic
Substances Control Act (TSCA), 15 U.S.C 2604, to screen microorganisms
before they are introduced into commerce. Under an interpretation EPA
issued in 1986 (51 FR 23302, June 26, 1986), ``new'' microorganisms are
those formed by deliberate combinations of genetic material from
organisms in different genera. This proposed rule is designed to
prevent unreasonable risk to human health and the environment without
imposing unnecessary regulatory burdens on the biotechnology industry.
This proposed regulation describes notification procedures and
microorganisms that would be exempt from notification.
DATES: Written comments on this proposed rule should be received by
October 31, 1994.
EPA may hold an informal hearing in Washington, DC, if EPA receives
written requests to hold a public hearing. For further information on
the hearing, see Unit IV.I. of this preamble. Written requests to make
an oral presentation should be submitted to the Environmental
Assistance Division by October 3, 1994 at the address below. Persons
are advised to call the Environmental Assistance Division after October
11, 1994 to ascertain if a hearing is to be held, and the date, time,
and location.
ADDRESSES: Comments on issues concerning this proposed rule should bear
the docket control number OPPTS-00049C, and should be submitted to the
following address: Document Processing Center (7407), Office of
Pollution Prevention and Toxics, Environmental Protection Agency, Rm.
L-100, 401 M St., SW., Washington, DC 20460.
FOR FURTHER INFORMATION CONTACT: For general information including
copies of this document and related materials: Susan Hazen, Director,
Environmental Assistance Division (7408), Office of Pollution
Prevention and Toxics, Environmental Protection Agency, Rm. EB-44, 401
M St., SW., Washington, DC 20460, In the USA: (202-554-1404), TDD:
(202-554-0551). For technical information regarding this document: Paul
Campanella, Office of Pollution Prevention Toxics (7405), Environmental
Protection Agency, Rm. E-611, 401 M St., SW., Washington, DC 20460, In
the USA: (202-260-3725).
SUPPLEMENTARY INFORMATION: The preamble accompanying this proposed rule
is divided into the following Units:
I. Introduction
A. Purpose of This Proposed Rule
B. Role of This Propose Rule in the Federal Coordinated
Framework for Regulation of Biotechnology
C. Statutory Framework
II. Structure of This Proposed Rule
A. Determining Whether Reporting is Required
B. General Administrative Procedures
C. Reporting General Commercial Use of TSCA Microorganisms
D. Reporting R&D Activities for TSCA Microorganisms
III. Rationale for Proposed Reporting Mechanisms
A. Research for Commercial Purposes
B. Exemption for Research in Contained Structures
C. Section 5(h)(4) Exemptions
IV. Other Issues
A. Microorganisms Covered By This Rulemaking
B. Listing Microorganisms on the Inventory
C. SNUR Process
D. Confidential Business Information
E. User Fees
F. Section 8(e) Reporting Requirements
G. Export Notification and State Preemption
H. Regulatory Text Overview
I. Rulemaking Process and Public Hearings
V. Economic Impact and Regulatory Flexibility Analysis
A. Regulatory Impact Analysis
B. Request for Comment on Economic Issues
VI. Rulemaking Record and Electronic Availability of Documents
VII. Public Record
VIII. References
IX. Regulatory Assessment Requirements
A. Executive Order 12866
B. Regulatory Flexibility Act
C. Paperwork Reduction Act
I. Introduction
A. Purpose of This Proposed Rule
This document proposes procedures for EPA to screen new
microorganisms. EPA's goals in proposing these rules are to take into
account scientific uncertainties surrounding the behavior of these
microorganisms and avoid unreasonable risks to health and the
environment which may be associated with their use, to avoid imposing
unwarranted costs and restrictions on a promising industry, and to
establish a flexible review program that can adjust as the technology
evolves and matures.
EPA will screen new microorganisms before they are manufactured for
general commercial use, or in some circumstances used for commercial
research and development (R&D) purposes, until sufficient familiarity
is gained with their behavior. As EPA acquires familiarity with new
microorganisms through reviews or other avenues, EPA expects certain of
these organisms to become eligible for reduced reporting or to be
eliminated from screening altogether.
EPA recognizes the enormous potential of biotechnology to fight
disease, pollution, and hunger, and to replace some chemicals that are
harmful to the environment. The realization of these benefits depends
upon public confidence in the safety of biotechnology. Public
perception will strongly affect the conduct of field tests and the
acceptance of commercial applications of biotechnology (Ref. 1). At the
same time, EPA recognizes the importance of retaining the competitive
advantage the United States presently maintains in the development and
application of biotechnology. Recognizing that regulations can affect
competitiveness and public acceptance either negatively or positively
(Ref. 2), EPA is proposing rules that it believes balance the needs of
the public without adversely affecting the capacity for innovation.
B. Role of This Proposed Rule in the Federal Coordinated Framework For
Regulation of Biotechnology
This proposed rule implements EPA's program for oversight of
microorganisms in accordance with the Federal ``Coordinated Framework
for Regulation of Biotechnology; Announcement of Policy and Notice for
Public Comment'' which was published by the Office of Science and
Technology Policy (OSTP) on June 26, 1986 (51 FR 23302, 23313). EPA's
policies regarding use of its statutes to regulate biotechnology
products are published in the ``Statement of Policy: Microbial Products
Subject to the Federal Insecticide, Fungicide, and Rodenticide Act and
Toxic Substances Control Act'' (``1986 Policy Statement'') which was
published as part of the Coordinated Framework. EPA is currently
operating its biotechnology program under the 1986 Policy Statement.
Prior to the 1986 Policy Statement, EPA issued a ``Proposed Policy
Regarding Certain Microbial Products'' on December 31, 1984 (49 FR
50880) (``1984 Proposed Policy Statement''). Subsequent to the 1986
Policy Statement, EPA issued a notice, entitled ``Biotechnology;
Request for Comment on Regulatory Approach'' on February 15, 1989 (54
FR 7027), in order to solicit comments on the direction of EPA's
program under TSCA. Comments on the 1984 and 1986 documents and the
February 15, 1989 Federal Register notice are addressed, as
appropriate, in this preamble.
On September 7, 1990, EPA convened a subcommittee of its
Biotechnology Science Advisory Committee (Subcommittee on
Implementation of Scope) to comment on topics associated with this
proposed rule. EPA again convened a subcommittee, the Subcommittee on
the Proposed Biotechnology Rule under TSCA, which met on July 22, 1991.
Advice from both of these subcommittees has been incorporated as
appropriate in this preamble, and summaries of subcommittee
deliberations have been placed in the docket for this rulemaking. This
proposed rule announced today is intended to describe implementation of
EPA's program for regulation of microorganisms under TSCA.
C. Statutory Framework
This Unit describes the TSCA provisions used for this rulemaking.
1. Jurisdiction. TSCA authorizes EPA to regulate any chemical
substance, except for certain substances covered by other Federal
agencies. The Act defines chemical substance broadly enough to cover
microorganisms. Specifically, section 3(2) of TSCA defines chemical
substance, in part, as any organic substance of a particular molecular
identity including any combination of such substances resulting in
whole or in part from a chemical reaction or occurring in nature.
a. Organisms are chemical substances. The TSCA definition of
chemical substance describes any deoxyribonucleic acid (DNA) or
ribonucleic acid (RNA) molecule, however created, that is a component
of an organism's genetic material. Similarly, a microorganism is a
chemical substance, because it is a combination of substances of
particular identities that occur in nature or occur, in whole or in
part, as a result of a chemical reaction (Ref. 3). EPA has consistently
applied this definition to life forms and in the 1984 Proposed Policy
Statement (49 FR 50886-87) clarified that this interpretation applies
to microorganisms. While the statutory term ``chemical substance'' has
been interpreted to include microorganisms, EPA acknowledges that
microorganisms are not generally referred to as chemicals. Therefore,
throughout this preamble, the term ``traditional chemicals'' will be
used to refer to chemical substances other than microorganisms.
The fact that microorganisms can be considered chemical substances
under TSCA only establishes EPA authority over them. Implementation of
that authority requires further action, either to interpret specific
terms or to issue rules. Discussion of the types of microorganisms
covered in this proposal can be found in Unit IV.A. of this preamble.
b. Plants and animals are not subject to this proposed rule. Plants
and animals could also be chemical substances under TSCA. Nevertheless,
as a matter of policy, EPA has limited this rulemaking to
microorganisms, e.g., microalgae of the plant kingdom. Transgenic
plants and animals are not subject to requirements under this proposed
rule, either as whole organisms or when their cells or parts of cells
are cultured in vitro. However, microorganisms into which plant or
animal gene segments are intentionally incorporated would be considered
microorganisms potentially subject to TSCA. Traditional chemicals
extracted from a plant or animal also may be subject to TSCA, as are
other chemical substances. EPA is reserving authority under TSCA to
screen transgenic plants and animals in the future as needed.
c. Microorganisms excluded by statute. The definition of ``chemical
substance'' in TSCA excludes pesticides, tobacco and tobacco products,
food, food additives, drugs (including human drugs, animal drugs, and
animal biologics), cosmetics, and substances that are used as medical
devices. These substances are regulated under other statutes by the EPA
Office of Pesticide Programs, the United States Department of
Agriculture (USDA), or the Food and Drug Administration (FDA).
Certain microorganisms that are subject to TSCA but are also known
plant pests are regulated jointly by EPA under TSCA and the USDA under
the Federal Plant Pest Act. In cases where microorganisms are not known
to be plant pests, the microorganisms used for TSCA purposes would be
regulated solely by EPA. However, USDA would become involved if an EPA
review determined that the microorganism had plant pest qualities.
d. Microorganisms used as intermediates. Microorganisms may be used
as intermediates to produce substances that are in turn used as
products subject to TSCA or other statutes. Under the Federal Food,
Drug, and Cosmetics Act (FFDCA), intermediates used to make products
subject to FFDCA are considered to be components of foods, food
additives, drugs, cosmetics and medical devices, as the case may be.
Therefore, those microorganism intermediates are excluded from
regulation under TSCA. All other intermediates, including pesticide
intermediates, are subject to TSCA jurisdiction. Traditional chemicals
not excluded from TSCA and produced by microorganism intermediates are
subject to TSCA section 5. These chemicals produced by microorganisms
are subject to the same requirements and procedures as chemicals
produced by other means. EPA discussed its approach to microorganism
intermediates and their products in its 1984 Proposed Policy Statement
(49 FR 50887, 50890; December 31, 1984).
2. Application of TSCA section 5. TSCA gives EPA comprehensive
authority to regulate chemical substances and mixtures of chemical
substances under four major provisions. Section 4 authorizes the
issuance of rules requiring testing of chemicals. Section 6 authorizes
the Agency to issue substantive regulations to protect against
chemicals that present an unreasonable risk. Section 7 authorizes
protection against imminent hazards. EPA has based its biotechnology
rulemaking efforts on section 5, the other major TSCA provision.
Section 5 establishes a 90-day process for EPA to screen certain
chemical substances before they are produced. Within the 90 days
following receipt of notification, EPA has to decide whether to drop
the substance from further consideration or to impose controls.
Section 5(a) allows EPA to require submission of a notification for
two types of microorganisms, those that are considered ``new'' chemical
substances and those that will be made for a ``significant new use.''
In both cases, notification is not triggered by a determination that a
risk is present. Risk is fully considered during or after the screening
process. Those substances defined as ``new chemical substances'' are
automatically subject to notice requirements. Chemical substances which
are made for a significant new use are subject to notification when EPA
issues a rule for the particular substance.
While the statute TSCA does not distinguish between the form or
content of the notifications for new substances or new uses, EPA's
current regulatory program, which is largely applicable to traditional
chemicals, does. The notification for a new chemical substance is
called a premanufacture notice (PMN). The notification for a
significant new use is called a significant new use notice (SNUN). For
the biotechnology program, however, EPA is proposing to refer to either
type of notification as a Microbial Commercial Activity Notice or MCAN.
Notices under section 5(a) are submitted by manufacturers of new
chemical substances, and by persons who manufacture or process chemical
substances for a significant new use. TSCA section 3(7) defines
``manufacture'' to mean import into the United States, production or
manufacture. Thus, the word manufacture as used in this preamble refers
to importation and any type of production, as well as to those
activities that may commonly be considered manufacture. TSCA section
3(10) defines ``process'' as preparation of a substance, after its
manufacture, for distribution in commerce.
a. Distinction between ``commercial purposes'' and ``general
commercial use.'' TSCA section 5(i) limits section 5 screening to
activities ``for commercial purposes.'' The term ``commercial
purposes'' applies to all activities that derive actual or potential
commercial benefit for persons associated with those activities. This
includes R&D designed to result in a commercial product, whether or not
a product is actually developed. A discussion of various options for
EPA to decide what constitutes commercial purposes under this rule
appears at Unit III.A.
These rules propose different review procedures for microorganisms
used for commercial R&D and for microorganisms that are no longer in
R&D and are intended for commercial distribution. In order to
distinguish between commercial R&D and other types of commercial
activity, EPA is describing use for commercial purposes beyond R&D as
``general commercial use.''
b. Definition of ``new.'' The term, ``new chemical substance,'' is
defined at TSCA section 3(9) as a substance not on the TSCA Inventory
of Chemical Substances (``Inventory'') manufactured in the United
States. Compilation and publication of the Inventory is a requirement
imposed on EPA by TSCA section 8(b). When EPA completes review of a new
substance, the substance is placed on the Inventory upon EPA's receipt
of a Notice of Commencement which indicates that production has begun.
At this point, the substance is no longer new, and subsequent producers
do not have to submit PMNs.
EPA has a longstanding policy of not explicitly listing on the
Inventory unprocessed naturally occurring substances. Instead, these
substances are considered to be implicitly included on the Inventory
(see 40 CFR 710.4(b)). Thus, they are not ``new'' and do not require
PMNs.
In defining what constitutes an unprocessed naturally occurring
substance, EPA has distinguished between substances isolated from
nature using more or less mechanical means and those isolated from
nature using more sophisticated forms of human intervention, such as
chemical reactions. The latter substances remove from a natural product
something that, by itself, does not exist in nature. One example is
that natural latex extracted from trees is a naturally occurring
substance, but the rubber formed after chemical coagulants are added is
not (42 FR 64589, December 23, 1977).
EPA is retaining for this rulemaking its interpretation of ``new''
microorganisms as discussed in the 1986 Policy Statement. Under that
interpretation, microorganisms resulting from deliberate, intergeneric
combinations of genetic material constitute ``new'' microorganisms
subject to PMN requirements. For the purposes of the Policy Statement,
the Agency defined intergeneric microorganisms as those formed by
deliberate combinations of genetic material from source organisms in
different genera. EPA may decide to reconsider its interpretation of
``new'' microorganism at a later time and in aseparate rulemaking. EPA
requests comment on whether it should explore alternative
interpretations of ``new'' microorganism.
In the 1986 Policy Statement, EPA excluded from the definition of a
``new'' microorganism, those microorganisms that have resulted from the
addition of intergeneric material that is well-characterized and
contains only non-coding regulatory regions such as operators,
promoters, origins of replication, terminators, and ribosome-binding
regions. EPA is also proposing to retain this exclusion as part of its
interpretation of ``new'' microorganism.
In the course of implementing the 1986 Policy Statement, the Agency
recognized that it had to develop additional guidance concerning the
definition of a new microorganism. It became apparent that a policy was
needed to address certain genetic elements which can be transferred
between microorganisms of different genera. These are termed mobile
genetic elements (MGEs) and include plasmids and transposons. EPA
developed additional guidance concerning whether microorganisms
modified using vectors that contained MGEs or parts of MGEs were
considered new. The Agency indicated that the major consideration is
the source of the original isolation of the MGE. EPA stated that
microorganisms would be considered ``new'' and thus subject to PMN
requirements, if the MGE was originally isolated from a microorganism
in a genus different from the recipient genus. Microorganisms would be
considered intrageneric, and hence not subject to PMN requirements, if
the MGE was originally isolated from a microorganism in the same genus
as the recipient.
The Agency has adopted this interpretation for reasons of
regulatory clarity and uncertainty about the possibility of the
resulting microorganism exhibiting new traits. For example, some MGEs
may contain genetic material that normally is not expressed in one
microorganism but, when inserted into another microorganism, may be
expressed and result in a new trait. Since the Agency plans to continue
to use the 1986 Policy Statement interpretation of ``new'' to be
intergeneric microorganisms, the Agency will continue to use this MGE
guidance to clarify what microorganisms would be subject to TSCA
section 5 reporting. EPA specifically requests comments on whether the
MGE interpretation provides appropriate assistance for determining
whether a microorganism is intergeneric or whether additional
modifications which would be useful in clarifying which intergeneric
microorganisms should be reported under TSCA section 5.
c. Significant new use. EPA determines a use is a significant new
use by issuing a rule. The rule is called a significant new use rule or
SNUR. Section 5(a)(2) sets forth some of the relevant considerations
for issuing a SNUR. The considerations generally include changes in the
type or form of exposure to a substance. Although EPA is not proposing
any specific SNURs in this rulemaking, EPA is proposing to set up
processes for issuing SNURs for microorganisms if needed in the future.
See Unit IV.C. of this preamble for a discussion of the proposed SNUR
processes.
d. Section 5 regulatory mechanisms. If the 90-day period provided
for review of a PMN or SNUN expires and EPA has taken no action,
production of the substance may begin. However, within the review
period, EPA may prevent or limit production of the substance under
section 5(e) or 5(f). Under section 5(e) EPA may issue an order
prohibiting or limiting production of a substance, if the Agency
determines that information is insufficient and the substance may
present unreasonable risk or its use may result in substantial
exposure. If the notification submitter objects, the section 5(e) order
does not take effect and EPA may go to court to obtain an injunction to
accomplish the same goals as the section 5(e) order.
Alternatively, if EPA finds that a substance presents or will
present an unreasonable risk, the Agency may, under section 5(f), go to
court for an order restricting or prohibiting production or issue an
administrative order or immediately effective rule to accomplish that
result.
If EPA decides subsequent to Inventory listing that further
oversight is needed, the Agency may use other provisions of TSCA. These
could include SNURs or other rules that would require testing (TSCA
section 4), information submission (TSCA section 8) or substantive
restrictions (TSCA section 6).
e. Exemptions from the section 5 notification process. Section 5(h)
provides for certain exemptions from screening. Three are relevant to
biotechnology. Section 5(h)(1) allows manufacturers or processors of
substances only for test marketing to apply to EPA for an exemption
from full notification. Unit II.C.3. of this preamble discusses the
test marketing exemption (TME) for microorganisms.
Section 5(h)(3) provides that the screening mechanisms do not apply
to substances manufactured or processed only in ``small quantities''
for R&D, provided that persons engaged in R&D activities for a
manufacturer are notified of any risks to health associated with the
substance. Section 5(h)(3) authorizes EPA to define by rule what
constitutes small quantities and to prescribe the form and manner of
risk notification. EPA is proposing a small quantities definition that
is limited to contained structure R&D uses of microorganisms. There
would be no small quantities exemption for microorganisms introduced
into the environment during commercial R&D, thus use of such
microorganisms must be reviewed. This modification is described at Unit
II.D. of this preamble. The rationale for this modification is
discussed at Unit III.B. of this preamble.
Section 5(h)(4) allows EPA to exempt new substances from all or
part of section 5 screening requirements, if the Agency determines, by
rule, that such substances will not present an unreasonable risk. EPA
is proposing to use section 5(h)(4) to exempt certain categories of
microorganisms from screening as new microorganisms. Additionally, EPA
is proposing under section 5(h)(4) to allow R&D introductions of
microorganisms into the environment on the condition that EPA has
approved them through expedited review of information submitted in a
TSCA Experimental Release Application, or TERA. The TERA process is
described in Unit II.D. of this preamble. EPA is also proposing other
section 5(h)(4) exemptions for specific microorganisms and classes of
microorganisms as described in Unit II.C. of this preamble. The
rationale for all exemptions proposed under section 5(h)(4) appears in
Unit III.C. of this preamble.
3. Substantial risk notification. Section 8(e) requires reporting
by manufacturers, processors and distributors who come across
information that their chemical substance could cause a ``substantial
risk.'' Section 8(e) is a self-implementing provision of TSCA. Thus, if
a manufacturer, processor or distributor of a microorganism finds
applicable information, that information must be submitted to EPA. Unit
IV.F. of this preamble discusses section 8(e) in further detail.
4. Applicability of TSCA section 26. Section 26(c) authorizes EPA
to take any action under TSCA for a category of chemical substances.
EPA proposes to use this authority extensively in this rule. The
reasons for grouping microorganisms into categories, which include new
microorganisms used for R&D and certain new microorganisms manufactured
for general commercial use, are explained in applicable sections.
II. Structure of the Proposed Rule
This portion of the preamble discusses the major provisions of
these rules. The rationale supporting these provisions follows in Unit
III. Unit II.A. describes how to determine whether reporting is
required. Unit II.B. describes general administrative procedures that
would be applicable to all notices submitted. To facilitate
understanding of this proposed rule, requirements for microorganisms
manufactured for general commercial use are discussed separately from
those for microorganisms used for commercial R&D. Unit II.C. describes
procedures applicable to microorganisms which are manufactured for
general commercial use. Unit II.D. contains a similar description of
procedures applicable to microorganisms used for R&D.
While these regulations are modelled after and incorporate many of
the procedures in the existing TSCA section 5 screening program for
traditional chemical substances which EPA has operated for the past
decade, modifications have been made, as appropriate, to address the
specific characteristics of microorganisms. In this respect, this
proposed rule incorporates well-established procedures which EPA has
adopted in previous rulemakings. The procedures are currently contained
in the Code of Federal Regulations (``CFR'') at parts 720
(premanufacture notification) and 721 (significant new use notification
requirements). EPA has decided, however, to establish a new part in the
CFR which applies specifically to microorganisms. EPA believes that
placing regulations affecting microorganisms screened under TSCA
section 5 in one place, part 725, will be more convenient and
efficient.
EPA has only made changes to the procedures in parts 720 and 721 to
the extent required by unique characteristics of microorganisms. EPA is
therefore not soliciting comment on the procedures in proposed part 725
that are incorporated from parts 720 and 721.
EPA will only consider comments to the extent they address the new
procedures and requirements in proposed part 725.
In addition to a preferred approach for certain issues, this
preamble often contains a discussion of alternatives. EPA solicits
public comment on the preferred approaches and the alternatives
discussed in this document. Depending on public comment received on the
various proposals, any of these alternatives may be adopted in the
final rules.
A. Determining Whether Reporting Is Required
Manufacturers or processors would follow the process laid out below
to determine whether their microorganism is subject to reporting and,
if it is, how it would be treated under this proposed rulemaking. They
must first determine whether their microbial products are subject to
TSCA. Subpart A of part 725 contains the regulations applicable to this
determination. Many microorganisms are not subject to the requirements
of this proposed rule, because they are statutorily outside the
jurisdiction of TSCA. Statutory jurisdiction is discussed in Unit I.C.
of this preamble.
1. Determining whether a microorganism is new or subject to a SNUR.
After manufacturers of microorganisms determine that their products are
subject to TSCA, they must determine whether the microorganisms are
new. Section 725.3 defines a new microorganism as one that is not
included on the Inventory. Microorganisms may be either implicitly or
explicitly included on the Inventory.
a. Implicit inclusion. In its 1986 Policy Statement, EPA stated
that intergeneric microorganisms were the only microorganisms that
would not be implicitly included on the Inventory. As discussed in Unit
I.C. of this preamble, EPA will continue to use the 1986 Policy
Statement interpretation for this rulemaking.
b. Explicit listing. A microorganism is not new, if it is
explicitly listed or implicitly included on the Inventory.
Microorganisms are placed on the Inventory if they have been previously
manufactured in the United States for general commercial use. EPA
explicitly lists microorganisms that it has previously reviewed, after
it is informed that production has begun through receipt of a Notice of
Commencement of Manufacture (NOC) (see Sec. 725.190). If a
microorganism is not considered to be implicitly included on the
Inventory, the public Inventory needs to be consulted to determine
whether the microorganism is explicitly listed. Microorganisms may also
be explicitly listed but treated as confidential and not placed on the
public Inventory.
c. SNUR listing. After persons determine that their microorganisms
are included on the Inventory, they must then check to see if the
microorganisms are subject to a SNUR. Where appropriate, microorganisms
subject to SNURs will be identified, both on the Inventory and in
Subpart M of part 725. The SNUR process is discussed in Unit IV.C. of
this preamble.
2. Consulting EPA when microorganism identity or use is
confidential or uncertain. Specific situations arise under these rules
when persons would need to consult listings of microorganisms to
determine whether a particular microorganism, or use of a
microorganism, is subject to reporting. These listings include the
Inventory; Subpart M of part 725, which lists significant new use
rules; and Sec. 725.239, which lists certain microorganisms exempt from
R&D reporting under part 725. The listings are explained in the text of
the regulation.
There would be two specific circumstances under which it may not be
possible to determine whether a particular microorganism is listed.
First, the actual identity or use may be claimed confidential by a
person who originally manufactured or processed the microorganism. In
this case, a so-called generic name or use would appear on the public
Inventory, and the actual identity or use would be on a confidential
listing not available to the public. Unit IV.D. on Confidential
Business Information (CBI) explains the generic name and use. The
second circumstance would be that a non-confidential identity of a
microorganism may not be precise enough for a person to determine
whether it describes a particular microorganism that could be subject
to reporting. This circumstance may arise because of the imprecision of
scientific nomenclature in biology, particularly in microbiology, or
because similarities in modified genetic material may raise questions
of equivalency (see Unit IV.B.).
To assist persons in determining their reporting obligations, EPA
has established a procedure whereby a person may file a submission
establishing a bona fide intent to manufacture or process a
microorganism and request that the Agency determine whether that
microorganism is on the applicable listing. EPA's goal is to respond in
30 days to the request, informing the requestor whether there is an
obligation to report under these regulations (see Sec. 725.15). This
procedure allows EPA to ensure appropriate reporting while maintaining
the confidentiality of legitimate trade secrets. This is a well-
established procedure in the Agency's current regulations on TSCA
section 5 reporting (see Secs. 720.25 and 721.11). This preamble will
note when this process, known as a ``bona fide,'' applies.
B. General Administrative Procedures
After submitters determine that they have a microorganism subject
to TSCA section 5, they must determine what type of submission will
satisfy their reporting obligations. The first decision is whether the
microorganism will be used for R&D or general commercial use. The
specifics of the submission and review processes for general commercial
use and for R&D are covered in Units II.C. and II.D. of this preamble,
respectively. However, some administrative procedures apply generally
to all microorganism submissions. Therefore, general administrative
procedures are discussed in this Unit.
Subpart B of part 725 contains administrative procedures generally
applicable to all submissions. Most of these are rather mechanical,
such as general recordkeeping requirements, procedures for determining
whether submissions are complete and properly filed, how to determine
when the Agency will begin the review period designated for a
particular submission, and under what circumstances the Agency or the
submitter may suspend, extend, or terminate a review. The more
important administrative procedures are discussed in this Unit.
1. Prenotice consultation. EPA recommends that potential submitters
begin discussions with EPA staff early in the submission planning
process to identify any special data requests and preliminary concerns
that may be associated with the microorganism. This may save
significant time later in the review process. Any meetings and relevant
written communications may be claimed confidential. Persons who are
unsure as to whether their microorganisms are subject to any of the
requirements of part 725 should consult with EPA before preparing any
submission.
With reference to R&D, EPA recognizes that research proceeds
through various stages. Potential submitters may find it advantageous
to begin discussions with EPA as early as the grant proposal stage,
even though they would not be required to file a submission under part
725 until the latter stages of their research program. Early
consultation with the Agency could assist submitters in the planning
stages of their research program in addition to providing a smoother
submission and review process.
2. Submission process. The general requirements pertaining to the
submission process are found at Secs. 725.25 through 725.36.
a. Preparing submissions. The data to be included in submissions
for microorganisms would be different from those for traditional
chemicals, because microorganisms may pose different risks than those
posed by traditional chemicals. To assist persons preparing submissions
under this proposed rule, EPA has developed a special guidance document
entitled ``Points to Consider in the Preparation and Submission of TSCA
Notifications for Microorganisms.'' At this time, a special form has
not been developed for microorganism submissions. Therefore, persons
preparing microorganism submissions should follow the format outlined
in the guidance document. This document is available from the
Environmental Assistance Division (see the address listed under the FOR
FURTHER INFORMATION CONTACT Unit).
The regulatory text describes the type of information that is
relevant for each specific type of submission. Submitters should submit
all reasonably ascertainable information which they believe will assist
EPA in evaluating the microorganisms, including information not
specifically listed that submitters believe will be useful for EPA's
risk assessment. When information listed in the regulatory text is not
submitted, a brief explanation of why such information is not available
or not applicable should be included. Prenotice consultation may assist
in identifying specific information appropriate for a submission.
b. Incomplete submissions. After an initial evaluation, EPA may
determine that a submission is incomplete and that the review period
cannot begin (see Sec. 725.33 of the regulatory text). If EPA finds the
submission incomplete, EPA will notify the submitter within 30 days of
receipt of the submission and will provide the submitter with an
opportunity to provide additional information. If the submitter
promptly provides additional information sufficient to evaluate the
effects of the microorganism, the evaluation will not be delayed beyond
time for a reasonable consideration of the new information. Otherwise,
EPA may declare the submission incomplete and the review period will
not begin until EPA receives the necessary information.
3. Review process. The requirements pertaining generally to the
review process are found at proposed Secs. 725.40 through 725.60.
a. Public involvement. EPA is aware that there is considerable
public interest in the review of submissions involving new
microorganisms and is committed to keeping the process as open as
possible. Following receipt of a submission, EPA is required by TSCA to
issue a notice in the Federal Register describing the submission (see
Sec. 725.40 of the regulatory text). The Federal Register notice would
include nonconfidential information on such items as the identity of
the microorganism, the type of use, occupational exposure, production
volume, a summary of test data included in the submission, and the
submitter's identity. If microorganism identity and use are claimed
confidential, EPA includes generic descriptions of this information in
the Federal Register notice. Unit IV.D. of this preamble discusses
confidentiality and generic descriptions. EPA would maintain a
nonconfidential copy of the submission in the TSCA Nonconfidential
Information Center for public inspection. The public will have an
opportunity to comment on submissions received by EPA. The length of
the comment period may be affected by the need to hold a meeting of
experts to address a particular submission, or to consider novel
scientific issues raised by the submission.
b. State coordination. EPA has developed comprehensive procedures
to coordinate reviews of submissions and to share scientific
information to the fullest extent with appropriate State and local
authorities. For example, under EPA's current procedures for review of
field tests under the 1986 Policy Statement, within the first week of
receipt of a submission, an EPA review coordinator contacts by
telephone the appropriate regulatory agencies in the State(s) where the
test will be conducted to inform them of the submission. If requested,
a nonconfidential copy of the submission is mailed to the State. If a
site visit is to be conducted, EPA staff contacts State and EPA
regional personnel early in the review period to begin coordination of
the site visit. Nonconfidential reports, assessments, and public
comments added to the Public Docket are routinely made available to
State personnel upon request. In addition, State personnel receive a
copy of EPA's draft risk assessment, and comments and concerns raised
by the State(s) are given careful attention in the risk assessment. At
the conclusion of the review period, State personnel receive a copy of
any document which addresses the conditions under which the field test
can be performed.
EPA is also requiring that persons who are preparing submissions
for R&D activities provide evidence of having notified appropriate
State authorities (see Sec. 725.255 of the regulatory text). Submission
of copies of any correspondence with State authorities concerning the
proposed field trial, for example, would satisfy this requirement. EPA
also strongly encourages such submitters to inform communities located
near potential test sites of their plans to introduce microorganisms
into the environment.
c. Use of experts. In performing assessments, EPA intends to
supplement its staff expertise as necessary by using experts from other
government agencies, academia, and other independent sources. EPA
assessments may be reviewed by a subcommittee, composed of scientists
with relevant expertise, of EPA's Biotechnology Science Advisory
Committee (BSAC) at a public meeting. Certain portions of the meetings
may be closed to discuss confidential business information (CBI). EPA
will consider all BSAC Subcommittee recommendations in its final
decisions. Procedures have been developed to ensure that experts
contributing to EPA's biotechnology reviews will not have conflicts of
interest.
d. Changes to the review process. The review period starts on the
date EPA determines the submission is complete and runs for a period of
time specified for each submission type. A submitter may voluntarily
withdraw a submission at any time, or suspend the review period for a
specified period of time. Suspension of the review period may be
beneficial when questions that arise during the notice review period
require additional time to address. For good cause, EPA may extend the
review period up to a total of the length of time specified for each
type of submission.
4. Recordkeeping and compliance. The requirements for
recordkeeping, compliance, and inspections are found at Secs. 725.65,
725.70, and 725.75, respectively. In addition to recordkeeping
requirements generally applicable to all submissions, EPA is proposing
recordkeeping requirements specific to each submission type. For
certain exemptions from full reporting under section 5, the
recordkeeping requirements are a key part of compliance with the
exemption. Compliance and inspection requirements are the same as those
for traditional chemicals.
5. Petitions to exempt new microorganisms. Provisions for
applications to request exemptions for new microorganisms from the
requirements of all or part of part 725 are found at Sec. 725.67.
C. Reporting General Commercial Use of TSCA Microorganisms
This Unit discusses who is subject to microbial commercial activity
notice (MCAN) reporting, the MCAN submission and review process, and
exemptions from MCAN reporting for general commercial use.
1. Determining whether MCAN reporting is required. Subpart D of
part 725 would require, with some exceptions, submission of a MCAN by
persons who intend to manufacture or import new microorganisms, and by
persons who intend to manufacture, import, or process microorganisms
for a significant new use. A MCAN must be submitted 90 days before
manufacture, import, or processing of the microorganism for commercial
purposes. Because EPA has a separate, less burdensome, screening
process for R&D involving microorganisms (see Unit II.D. of this
preamble), the Agency expects that, in general, the MCAN will be
submitted only for microorganisms for general commercial use.
2. MCAN submission and review process--a. MCAN submission process.
The purpose of EPA's review of MCANs would be similar to EPA's purpose
in reviewing PMNs and SNUNs submitted for traditional chemical
substances. The purpose of a MCAN would be to provide EPA with
information necessary to identify and list a microorganism on the TSCA
Inventory (if the microorganism is new) and to determine whether the
microorganism would pose an unreasonable risk to human health or the
environment. EPA must conduct a review that considers all the
reasonably ascertainable information on potential human health and
environmental effects of a microorganism. The information to be
included in the MCAN is listed in Secs. 725.155 and 725.160 of subpart
D. Submitters must develop a MCAN that describes the characteristics
and construction of the new microorganism as well as describing
conditions of manufacture and use. In addition, submitters must
reference any published literature on the microorganism and its
parental strains and submit available data from laboratory, greenhouse
studies, and/or R&D field tests using the microorganism.
b. MCAN review process. All reviews of microorganisms will follow
established administrative steps that are the same for all chemical
substances subject to 90-day review. For good cause, EPA may extend the
initial review period by an additional 90 days, for a total of 180
days. During this time the microorganism cannot be manufactured or
processed for commercial purposes.
c. Regulatory decision. EPA may reach one of three decisions during
the review period based on a balancing of the risks and benefits
presented by the microorganism: There is sufficient information to
determine that the risks will not be unreasonable; there is sufficient
information to determine that the risks are unreasonable; or there is
insufficient information to make a reasoned evaluation of risk, and the
substance may present an unreasonable risk or there may be significant
or substantial human or environmental exposure to it.
Unless EPA notifies the submitter to the contrary, the submitter
may begin to manufacture and use the microorganism at the end of the
90-day period. However, if the information available is insufficient to
reasonably evaluate the risk and the substance may present an
unreasonable risk, EPA may issue an order under TSCA section 5(e) to
limit or prohibit the manufacture, processing, distribution in
commerce, use, or disposal of the microorganism. In the past, EPA has
found it useful to negotiate with submitters to develop consent orders,
sparing both the submitter and EPA the legal proceedings that may be
involved in a unilaterally issued order. Under a consent order, the
submitter generally agrees to develop additional information or to
accept certain restrictions in return for permission to proceed with
its plans to manufacture or import the substance.
In the situation where EPA decides that risks will be unreasonable,
it may use TSCA section 5(f) to require measures to reduce risks to an
acceptable level as a condition of manufacture and use. Alternatively,
EPA may prohibit manufacture or use, if there are no measures available
or practicable to sufficiently reduce the risk.
3. Exemptions from MCAN reporting. Persons intending to manufacture
new microorganisms for general commercial use may not have to submit a
MCAN prior to commencing manufacture, if the microorganisms they intend
to use qualify for exemptions from MCAN reporting. This unit discusses
one exemption developed for traditional chemicals that will not be
applied to microorganisms and two exemptions that are applicable to
microorganisms.
a. Low volume exemption. EPA has previously promulgated rules
providing for an exemption from the notification requirements of
section 5 of TSCA for new chemical substances produced for general
commercial use in volumes less than 1,000 kilograms per year (see 40
CFR 723.50). This exemption requires applicants to submit a notice to
EPA 21 days before manufacture begins to provide the Agency an
opportunity to review the chemical. EPA believes that this exemption is
inappropriate for microorganisms, which have the ability to reproduce,
disseminate, and transfer genetic material. EPA is therefore proposing
to amend Sec. 723.50 to state that the exemption provisions of that
section do not apply to microorganisms.
b. Test marketing exemption. Test marketing activities usually
involve limited sale or distribution of a substance within a
predetermined period of time to determine its competitive value when
its market is uncertain. EPA is required by TSCA section 5(h)(6) to
grant or deny the test marketing exemption (TME) no later than 45 days
after receipt of an application. Subpart F of part 725 proposes the
requirements for obtaining a TME. These requirements are adopted
verbatim from Sec. 720.38, the Agency regulations that currently apply
to all chemicals substances.
In general, EPA suggests that manufacturers who intend to test
market new microorganisms file a MCAN rather than a request for a TME.
However, there may be situations in which this exemption may be
appropriate, such as for microorganisms which were previously reviewed
by EPA at the R&D stage. EPA encourages anyone who is considering
requesting a TME for a new microorganism to begin prenotice
consultation as early as possible, so that EPA can determine if it
would have sufficient information to determine that the test marketing
activities would not present an unreasonable risk.
c. Tiered exemption for general commercial use. Under TSCA section
5(h)(4), EPA is proposing to exempt from MCAN requirements certain new
microorganisms manufactured for general commercial use which it has
determined will not present an unreasonable risk. Subpart G of part 725
contains the conditions for this exemption, which consists of two
tiers, each based on certain criteria discussed below. The rationale
for this exemption appears in Unit III.C.7. of this preamble.
Microorganisms produced under this exemption would not be listed on the
Inventory.
(i) Tier I. Manufacturers meeting Tier I requirements will be
completely exempt from review by EPA. They would submit a one-time
certification statement to EPA 30 days prior to the first use of a
microorganism eligible for a Tier I exemption. The conditions for this
exemption are listed at Sec. 725.424. The statement must include
information identifying the manufacturer or importer, the location of
the facility involved, and a statement certifying that the manufacturer
complies with all the criteria required for the Tier I exemption.
Information in the statement may be claimed confidential. A
certification would be required for the first use of an eligible
recipient microorganism at a specific facility. Subsequent uses of the
same recipient microorganism at the same facility would not require
additional certification, so long as the manufacturer complied with the
other Tier I exemption conditions.
(ii) Tier II. Manufacturers meeting the requirements at proposed
Sec. 725.428 may submit an exemption request to EPA 45 days prior to
use of the microorganisms, if they believe that containment conditions
other than those listed at proposed Sec. 725.422 would still allow the
requirements of the exemption to be met (see Sec. 725.455 of the
regulatory text). Information included in such a submission may be
claimed confidential. Submitters must certify in the request that they
have complied with the requirements. EPA would approve or deny an
exemption request within 45 days and could impose restrictions to
ensure that the microorganisms would not present an unreasonable risk
(see Sec. 725.470 of the regulatory text).
(iii) Criteria for the exemption. Three conditions are placed on
the Tier I and Tier II exemptions. The recipient microorganisms must be
listed at proposed Sec. 725.420, the introduced genetic material must
meet certain requirements, and performance-based criteria for
containment and inactivation of the new microorganisms are to be used.
(A) Recipient microorganisms. EPA is proposing that new
microorganisms certified to be developed using a recipient species or
strain listed at proposed Sec. 725.420 would qualify for the tiered
exemption.
(B) Introduced genetic material. The introduced genetic material
used to modify the recipient microorganisms must be well characterized,
limited in size to the genetic material required to perform the
intended function, and poorly mobilizable (see Sec. 725.421 of the
regulatory text). Further explanation of these terms appears in Unit
III.C.7. of this preamble. In addition, genetic material which encodes
for all or part of the toxins listed in proposed Sec. 725.421(d) may
not be used to modify any recipient microorganism.
(C) Containment and inactivation. EPA is also proposing
performance-based criteria for limiting exposures. These criteria would
have to be used for the Tier I exemption, because EPA would not review
these activities prior to production. For the Tier II exemption,
because the containment and inactivation controls would be reviewed in
the exemption request, the criteria would serve as guidance for
submitters. Proposed Sec. 725.422 lists the criteria for containment
and inactivation at a facility.
(iv) Exemption applications. Using the provisions in proposed
Sec. 725.67, individuals may submit an application under section
5(h)(4) requesting that a recipient microorganism be added to the
exempt list. Submitters may request an exemption with different
conditions. EPA would evaluate the request using appropriate procedures
under section 5(h)(4).
D. Reporting R&D Activities for TSCA Microorganisms
This Unit discusses EPA's proposal for which microorganisms are
subject to R&D reporting and recordkeeping, exemptions from R&D
reporting, and the TSCA experimental release application (TERA)
submission and review process.
1. Overview of considerations for determining whether a researcher
has TSCA section 5 obligations for R&D activities. Persons planning to
conduct R&D activities involving new microorganisms subject to TSCA may
be subject to these rules. While any researcher may submit a complete
MCAN as required for general commercial use, EPA is proposing a number
of exemptions from MCAN reporting that reduce researchers' reporting
obligations under TSCA section 5. All R&D activities are eligible for
reporting using the TERA process which is discussed below. However, EPA
expects that the TERA will be used primarily for environmental
experiments. Laboratory and other research in contained structures
would more likely comply with certain recordkeeping requirements
provided under TSCA section 5(h)(3) in the rule. Finally, certain
research may be exempt from TSCA section 5, because EPA has determined
review is unnecessary altogether or it is appropriate to defer in
whole, or in part, to another Federal agency.
The series of considerations to be used to determine TSCA section 5
obligations for R&D activities is displayed in chart form in Figure 1
below. The following paragraphs summarize the steps on Figure 1.
The first three steps list the issues that must be addressed for
determining if any substance is subject to TSCA section 5 reporting,
whether for general commercial use or for R&D activities. The
subsequent steps are employed to determine R&D obligations. Determining
whether an R&D activity is subject to TSCA jurisdiction and whether the
microorganism is intended for commercial purposes are discussed below
in Units II.D.2.a. and 2.b., respectively. Determining whether a
microorganism is ``new'' for the purposes of TSCA section 5 is
discussed in Unit I.C. of this preamble.
If researchers have determined that their R&D activities are
subject to TSCA jurisdiction, are intended for commercial purposes, and
involve new microorganisms, their R&D activities will be subject to
some obligations under TSCA section 5. Researchers would then proceed
through the remainder of the questions to determine their reporting
status. They would first determine whether their R&D activities are
eligible for the contained structures exemption. This determination is
discussed below in Unit II.D.2.c.
The next question deals with other agencies. An R&D activity that
is eligible for the contained structures exemption may also be subject
to the authority of another Federal agency. Overlapping jurisdiction
for R&D conducted in contained structures is discussed below in Unit
II.D.2.d.
If the R&D activity does not qualify for the contained structures
exemption, TERA reporting would next need to be considered. However,
EPA is also proposing in this rulemaking a category of specific
microorganisms that are exempt from TERA reporting. Thus, researchers
who are not eligible for the contained structures exemption and/or for
deferral to another agency may qualify for a specific TERA exemption.
The determination of whether the research qualifies for a TERA
exemption is discussed below in Unit II.D.2.e.
Figure 1 shows the four distinct types of TSCA section 5
obligations existing for R&D activities. The reporting requirements for
each of these obligations are discussed below in Units II.D.3. and 4.
The corresponding paragraphs are noted on the following Figure 1.
TP01SE94.000
2. Specifics for determining eligibility for R&D exemptions. The
five points which researchers must consider in order to determine their
TSCA section 5 obligations for R&D are discussed in this paragraph.
a. Determination that the R&D activity is subject to TSCA
jurisdiction. Statutory jurisdiction is discussed in Unit I.C. of this
preamble. As noted in that Unit, uses of some microorganisms are
specifically excluded from TSCA section 5, because they are subject to
other statutes. Uses that are not specifically excluded are subject to
TSCA. When developing the initial TSCA Inventory, EPA indicated that
undifferentiated uses of chemical substances would be subject to TSCA
(42 FR 64585, December 23, 1977). In the 1986 Policy Statement, EPA
stated that unless the uses were explicitly excluded by TSCA, ``all
microorganisms produced for environmental, industrial, or consumer uses
are potentially regulable under TSCA'' (51 FR 23324, June 26, 1986).
Thus, EPA would consider that R&D activities involving new
microorganisms where researchers are unsure of the final use would be
subject to TSCA section 5. This would include microorganisms in early
stages of research, where the researchers have not determined a
specific commercial application of the microorganism. As noted in Unit
II.B. of this preamble, researchers who are uncertain of the status of
their microorganism, for any reason, should consult EPA regarding their
TSCA section 5 obligations.
b. Determination that the R&D activity is intended for commercial
purposes. TSCA section 5 covers only uses of new microorganisms for
commercial purposes. EPA discusses its interpretation of commercial R&D
in Unit III.A. of this preamble. The Agency is proposing three
alternative interpretations of commercial purposes. Depending on public
reaction to the alternative interpretations discussed in this proposal,
the interpretation of commercial R&D could differ from one R&D activity
to another in a final rule, if public comment supports different
interpretations for different types of R&D activities.
c. Determination that the R&D activity is eligible for the
contained structures exemption. This exemption would most likely apply
to research performed in contained structures such as pilot
fermentation plants, greenhouses, laboratories, and certain bioreactors
used for waste treatment. The term ``structure'' is defined in proposed
Sec. 725.3. Research involving intentional testing of microorganisms in
the environment would not be eligible for this exemption. Requirements
for the exemption are in section 3 of this Unit. The rationale for this
exemption is discussed in Unit III.B. of this preamble.
d. Determination that oversight of the R&D activity is also subject
to the authority of another Federal agency. Some R&D activities may be
subject to the authority of another Federal agency in addition to EPA.
Where there is overlapping jurisdiction for R&D activities that are
eligible for the contained structures exemption, EPA proposes to defer
to the other Federal agency which has authority for oversight over such
activities. This would apply to researchers who are receiving funding
from the other Federal agency, which requires that researchers comply
with the ``NIH Guidelines for Research Involving Recombinant DNA
Molecules'' (``NIH Guidelines'') in order to receive funding.
Researchers who are voluntarily complying with the NIH Guidelines but
are not actually receiving funding from a Federal agency would not be
eligible for the deferral.
e. Determination that specific microorganisms are exempt from TERA
reporting. EPA is proposing exemptions from TERA reporting for certain
new microorganisms derived from the microorganisms Bradyrhizobium
japonicum and Rhizobium meliloti. R&D involving these microorganisms
performed in accordance with specified conditions would be exempt from
review. Additional microorganisms may be exempted by rule under section
5(h)(4), as EPA gains familiarity with them. Unit III.C.5. of this
preamble discusses the rationale for this exemption.
3. Requirements necessary for eligibility for exemptions from TERA
reporting. Once researchers have determined which exemptions their R&D
activities are eligible for, they must determine their specific TSCA
section 5 obligations. Proposed Secs. 725.232 through 725.239 specify
the requirements for each of the exemptions from TERA reporting.
a. The contained structures exemption--(i) R&D subject to another
Federal agency. R&D activities which are eligible for the contained
structures exemption (see Sec. 725.234(a) and (c) of the regulatory
text) but are also subject to the oversight of another Federal agency
will be exempt from the requirements of TSCA section 5. If researchers
comply with the other agency's requirements, there will be no EPA-
specific requirements (see Sec. 725.232 of the regulatory text).
(ii) R&D not subject to another Federal agency. This document
proposes that R&D eligible for the contained structures exemption but
not subject to another Federal agency must be conducted in accordance
with proposed Secs. 725.234 (containment and recordkeeping) and 725.235
(employee notification). Although researchers that comply with these
provisions are not required to report to EPA under TSCA section 5, the
recordkeeping and employee notification requirements would apply and
would be enforceable by EPA.
There are two types of standards in Secs. 725.234 and 725.235. The
employee notification standards of Sec. 725.235 are taken directly from
current regulations in Secs. 720.36 and 721.47, and are the same as
those for traditional chemical substances. Section 725.234 contains
general research standards but adds some provisions that apply
specifically to microorganisms. However, these additional provisions
are minor changes to EPA's current requirements for the research
exemption, and these provisions should be standard practices for
research activities involving microorganisms.
Specifically, the small quantities exemption for traditional
chemical substances requires research to be conducted by, or directly
under the supervision of, a technically qualified individual (TQI).
This is a requirement under EPA's current regulations at Secs. 720.36
and 721.47. Section 725.234 applies the same requirement to
microorganisms eligible for the contained structures exemption.
Section 725.234 states that the TQI must select appropriate
measures to control release of the research microorganism, write a
brief description of the reasons for choosing the measures and ensure
maintenance of records to document routine use of the selected
controls. In addition, the choice of control measures must be certified
by an authorized official of the institution at which the research is
conducted. Finally, EPA may request that the records be sent to EPA for
review. Subsequent to such review, EPA may in some circumstances offer
recommendations to modify control or documentation measures. In what
EPA anticipates would be rare occurrences, EPA might order the
researcher to modify controls or documentation measures. Failure to
comply with such an order would result in loss of eligibility for the
exemption for the specific R&D activity.
For those researchers who are voluntarily complying with, but are
not subject to, the NIH Guidelines, the requirements of the contained
structures exemption could be met by having the principal investigators
serve as the TQIs (see Sec. 725.234(b) of the regulatory text) and keep
records indicating that they abide by the NIH Guidelines.
b. Exemption from TERA reporting for specific microorganisms. In
order to be exempt from both TERA reporting and MCAN reporting, persons
using the exemptions for microorganisms listed in Sec. 725.239 must
comply with the general requirements for the exemption listed in
Sec. 725.238 as well as any specific requirements listed in
Sec. 725.239. Similar to its proposal for the tiered exemption for
general commercial use discussed in Unit II.C., EPA is proposing to
place restrictions on the recipient microorganisms, the introduced
genetic material, and the conditions of use (see Sec. 725.239 of the
regulatory text).
4. TERA submission and review process. EPA is proposing to
establish the TERA, which is an abbreviated notification process for
environmental testing of new microorganisms.
a. TERA submission process. Sections 725.255 and 725.260 detail
specific information that should be submitted with a TERA. The basic
microorganism identity information is the same as that for the MCAN.
Other information requested specifically addresses the proposed R&D
activity and therefore is not as extensive as the MCAN information.
b. TERA review process. EPA's goal is to review TERAs in 60 days
(see Sec. 725.270 of the regulatory text). For good cause, EPA could
extend the initial TERA review period by an additional 60 days, for a
total of 120 days (see Sec. 725.56 of the regulatory text). Due to the
small number of experiments that have been conducted and the
uncertainty concerning field tests that involve new microorganisms, EPA
expects that initial TERA reviews may take closer to 120 days. During
the prenotice consultation, EPA would estimate for the submitter
whether the review is likely to require closer to 120 days or 60 days.
Generally, EPA believes that approval of TERAs in 60 days or less
would be possible for field tests that are similar to previously
reviewed field tests (for example, use of the same or similar
microorganisms, modifications to a previous test, or change in
geographic conditions). When novel circumstances are presented in a
TERA, however, EPA may need to extend the review period in order to
complete its review. Specific examples of extension for good cause
would include the need for a subcommittee meeting of the Biotechnology
Science Advisory Committee to supplement Agency expertise or the need
to coordinate review with other Federal agencies. When EPA coordinates
the review of a microorganism with another Federal agency, the review
period would automatically be extended to the length of the other
agency's review, to allow the two agencies to coordinate reviews and
decisionmaking. TERA submitters may not proceed with their field trials
until EPA has provided written approval of the TERA submission. As soon
as EPA completes its review, however, researchers will be able to start
their test immediately upon notification from EPA.
c. Regulatory decision. EPA will approve a TERA if it determines
that the experiment(s) will not present an unreasonable risk to human
health or the environment. If the submission is approved, EPA may
negotiate with the submitter a TERA Agreement, which would be legally
binding on all parties and would set out any conditions governing the
conduct of the specific field trial (see Sec. 725.270 of the regulatory
text). The TERA Agreement could include provisions for maintaining
restrictions on the use of the test site after the completion of the
test. This may require the submitter to make appropriate arrangements
with the owner of the test site, in cases where the submitter does not
own the test site. If EPA concludes that the proposed R&D activity may
present an unreasonable risk of injury to human health or the
environment, EPA will deny the TERA and will provide reasons for the
denial in writing. Section 725.288 provides for revocation or
modification of TERA approvals following the receipt of additional
information.
5. Options for oversight of R&D activities--a. Range of options
possible. EPA's intent in offering a variety of alternatives for
oversight of R&D activities was to provide a flexible process which
tailored oversight to the level of risk. In developing TSCA section 5
obligations for R&D activities using new microorganisms, EPA looked at
a range of options. These fall on a continuum ranging from an option
which would exempt all R&D activities under a small quantities
exemption similar to the exemption for traditional chemicals to an
option which would require TERA reporting for all R&D activities,
including those conducted in laboratories and other contained
structures.
As discussed in Unit III.B. of this preamble, because
microorganisms can multiply and spread beyond the site of introduction,
EPA must redefine the small quantities definition applied to
traditional chemicals. EPA developed the TERA process, because it
believes that review of environmental uses of microorganisms should
begin during the R&D stage. At the same time, EPA does not believe that
all microorganisms used in all R&D activities should be subject to TERA
reporting. Neither of the extreme options seemed appropriate to EPA for
coverage of R&D, because they would not be tailored to potential risk.
Thus, EPA chose an intermediate approach.
In keeping with the goals of the Coordinated Framework, EPA has
included in its proposed option opportunities to address overlapping
jurisdiction with other Federal agencies. EPA has attempted to balance
the Coordinated Framework's goal to reduce duplicative oversight with
TSCA section 5's goal to screen for potential unreasonable risks. As
discussed in Unit III.B. of this preamble, in developing its
requirements for the contained structures exemption, EPA selected an
approach which recognized the diversity of microorganisms which would
be used in research and therefore left to the researcher the choice of
appropriate containment and inactivation controls. Additionally, in
order to keep the TERA process flexible, EPA has developed a provision
allowing microorganisms tested in the environment to be exempted from
TERA reporting as the Agency gains more familiarity with them.
EPA requests comments on its proposed option for R&D activities for
TSCA microorganisms. In particular, EPA would like to know whether
commenters feel that the flexibility provided by the various exemptions
available under the proposed option counterbalances the complexity of
the approach. The public may suggest other options along the continuum,
providing those options also meet the intent of TSCA and adequately
protect public health and the environment from unreasonable risks. In
addition to the proposed option, when EPA prepares its final rule, it
will consider the variety of options along the continuum discussed
above, as well as options suggested by the public.
b. Specific alternative for low risk field tests. EPA realizes that
there are a variety of possible options along the continuum discussed
above. Although EPA has decided that case-by-case review is important
for many microorganisms intentionally tested in the environment, EPA
recognizes that there will be low risk field tests that would not
require TERA review. For this reason, some have suggested an
alternative exemption for certain R&D releases. This alternative, which
is similar to the R&D contained structures exemption in that it would
be dependent on determinations made by a TQI, would apply to certain
low risk field tests and would be included with the exemptions which
are part of the proposal for coverage of R&D activities under TSCA
section 5. Like the proposed exemption for R&D in contained structures,
this alternative would contain requirements for documentation and
recordkeeping by a TQI and certification by an authorized company
official. It would also provide for EPA to inspect records and order
changes, if necessary.
Under this alternative, a company planning a small-scale field test
which meets the eligibility requirements for the exemption would have
the option of submitting a TERA for review by EPA or submitting a
notice with the determination that the field test qualified for the
exemption. The alternative includes a number of requirements which are
intended to minimize the likelihood of inconsistent determinations.
The TQI would be expected to make the determination that the new
microorganism was eligible for the exemption, based on the following:
(1) The test site must be 10 acres or less of land, (2) the parent
microorganism(s) must have a history of safe use, and (3) the
introduced genetic material must be limited in size, well-
characterized, free of certain nucleotide sequences, and poorly
mobilizable. Further explanation of the terms in (3) appears in Unit
III.C.7. of this preamble.
In determining that the parent microorganism has a history of safe
use, EPA would expect researchers to be able to classify taxonomically
the microorganism and to evaluate its relationship with closely related
microorganisms which may have a potential for adverse effects on human
health or the environment. Information on the potential for the
microorganism to cause adverse effects on human health and the
environment should be evaluated.
EPA recognizes that a determination that a microorganism has a
history of safe use involves a balancing of various factors. This
determination should be premised on the researcher's prediction of the
behavior of the microorganism based on experience with its use. The
more information the researcher has on the behavior of the
microorganism (for example, the ability to establish, compete, and
survive in the environment), the better the researcher can estimate the
safety of the field test. In conducting their risk assessment,
researchers should consider the scale, since the tests must be
conducted on 10 acres or less of land.
An additional requirement for this alternative exemption would be
that an official having authority to represent the organization (e.g.,
the Chief Executive Officer, the General Counsel) certifies that the
determination has been made by a TQI and is considered to be the
official position of the organization. The official would also be
required to state that the organization accepts full liability for all
potentially harmful consequences of the field test. To show that
relevant considerations had been evaluated, a TQI would be required to
prepare a written analysis to be kept in the company's records. These
records would be kept for 5 years from the date of the field test, with
EPA retaining the right to review the records upon request. In lieu of
a TQI, the analysis could be performed by a third party review group
with relevant scientific expertise (i.e., ecological expertise) as
exemplified by the Institutional Biosafety Committees (IBCs) described
in the NIH Guidelines.
Following the TQI's determination, the researcher would be required
to submit a short notice to EPA, providing the organization name and
address, a summary of the new microorganism and the proposed field
test, the name of the TQI, and the official certification, including
the liability statement. EPA would have 45 days to determine whether to
require submission of a TERA before the researcher could conduct the
planned field test.
EPA requests comments on this alternative approach for low risk
field tests. In particular, EPA would like to know whether there are
other criteria which would be appropriate for defining a category of
low risk small-scale field tests and what additional guidance would be
needed for researchers to utilize such an approach. The rationale for
this alternative exemption is discussed in Unit III.C. of this
preamble.
III. Rationale for Proposed Reporting Mechanisms
A. Research for Commercial Purposes
1. Introduction. TSCA section 5(i), while it limits all section 5
screening to activities for commercial purposes, has had little
practical effect on research using traditional chemicals, because of
the research exemption. However, because this proposed rule would place
more requirements on research with microorganisms than on research with
traditional chemicals, EPA believes it should provide its current view
on the applicability of the commercial purposes limitation to this
proposed rule.
As a preliminary matter, there is no difficulty in determining when
any chemical substance, including a microorganism, is being
manufactured or processed for a commercial purpose after the R&D stage.
It is clear when a PMN is required or when a MCAN would be required at
general commercial use.
Research on traditional chemicals is not generally affected by the
commercial purposes limitation, because EPA's current regulatory
definition of small quantities for R&D using traditional chemicals (any
amounts reasonably necessary for research) at Sec. 720.3 effectively
exempts research with these chemicals from section 5 screening.
However, as noted in Unit III.B. of this preamble, these rules propose
a small quantities definition for microorganisms; and this definition,
because it would recognize the ability of microorganisms to reproduce,
would differ from the definition for traditional chemicals. A
researcher utilizing microorganisms, therefore, may need to consider
what constitutes a commercial purpose.
Research involving microorganisms used in contained structures
would be considered ``small quantities solely for research and
development'' as defined at Sec. 725.3 of the regulatory text. Although
EPA expects the requirements for this contained structures exemption
simply to reflect common practices, a researcher may have to evaluate
whether research conducted in contained structures is commercial. The
contained structures exemption would not apply to field testing of
microorganisms because of the ability of living microorganisms to
reproduce and spread in the environment (see Unit III.B. of this
preamble). As a result researchers will, in all cases, need to decide
which environmental testing is commercial.
EPA wishes to emphasize that any coverage of research under this
proposed rule should not duplicate appropriate oversight by other
Federal authorities. As explained in Unit III.C.3. of this preamble,
contained research appropriately overseen by other Federal agencies
would be exempt from EPA oversight, because EPA believes such research
does not present an unreasonable risk. As a practical matter,
therefore, while testing conducted at institutions that do not normally
consider themselves commercial (academic and non-profit institutions)
could theoretically be commercial under interpretations discussed in
this Unit, EPA anticipates that other parts of these rules will exempt
much of the research from EPA oversight.
2. Public comments. During development of regulations on
biotechnology, EPA has received numerous public comments that differ
substantially on oversight of research. Of particular concern has been
the appropriateness of EPA review based on the status of an activity as
commercial rather than on its potential risk.
Comments argue that there is no reason to suspect any difference in
risk between commercial or noncommercial research. Thus, if a
university and a business release the same microorganism in similar
settings, both should be subject to oversight.
On the other hand, comments suggest there may be risk differences.
Some argue that a commercial enterprise is more likely to be careful
than a noncommercial institution due to concern for liability. Others
argue that academic researchers are more likely to be concerned with,
and aware of, the need to consider health and environmental safety
issues and that commercial entities may be willing to take shortcuts in
the interest of reducing costs.
Other comments complain that increased government regulations may
have a deleterious effect on academic research, because it may be more
difficult for pure research institutions to comply. Burdens that are
relatively minor for a business could be major for a university or an
individual researcher.
Comments have also indicated that a number of practical
difficulties increase the burden on research institutions. For example,
increasingly complex and intermingled financial arrangements in the
biotechnology field have emerged as universities seek funding from
businesses. These arrangements may result in universities conducting
product development for money or equipment donations from business.
Undue burdens to academic researchers can result from requirements that
research which is funded by a commercial entity be distinguished from
that funded by a noncommercial entity, particularly when a university
may pool its funds from various sources.
Finally, even though an academic research institution may engage in
product development for a business, the institution may not be engaging
in a commercial activity for its own benefit. For example, a university
may use income from a commercial entity to improve its teaching and its
ability to increase knowledge. Industry could be an important source of
income for upgrading equipment used for teaching.
The remainder of this Unit discusses EPA's view of the law and
policy and responds to these public comments.
3. EPA's view of the law as it applies to commercial activities at
noncommercial institutions. EPA wishes to make it clear that the
interpretations discussed in this Unit are consistent with
interpretations in current regulations. That is, a commercial activity
is one undertaken with the purpose of obtaining an immediate or
eventual commercial advantage. This is the common thread in
Sec. 720.3(r) which defines ``manufacture or import for commercial
purposes'' and Sec. 721.3 which defines ``process for commercial
purposes.'' Similarly, Sec. 720.30(i) provides that ``non-commercial
research and development'' consists of activities conducted by
academic, government, or independent not-for-profit organizations
``unless the activity is for eventual commercial purposes.''
All research conducted directly by a commercial entity is clearly
for commercial purposes, as was decided in The Dow Chemical Company v.
EPA, 605 F.2d 673 (3d Cir. 1979). Consequently, if a business directly
funds a research activity for product development, the activity is for
commercial purposes, regardless of the location. A business may not
avoid review by simply funding research at an academic institution.
In section 5, Congress distinguished between commercial and
noncommercial activities and, thus, expected them to be treated
differently. Although the statute has no definitive explanation as to
what this distinction means, it does not appear to have been risk-
based. EPA believes that Congress did not provide a definitive
explanation and therefore left to the Agency's discretion the balancing
of competing interests. TSCA section 2(b) states that it is the policy
of the United States that TSCA authority should be exercised so as not
to ``impede unduly or create unnecessary economic barriers to
technological innovation,'' while fulfilling the primary purpose of
assuring that innovation does not present unreasonable risks.
If EPA considers that section 5 provides a screening mechanism, as
opposed to a direct regulatory mechanism, EPA has an indication why the
commercial purposes limitation applies. Under other TSCA provisions,
EPA may regulate without regard to a commercial purposes limitation.
For example, the commercial purposes limitation does not apply to EPA's
authority under TSCA section 6 to prohibit or limit manufacture,
processing, or distribution in commerce of chemical substances if the
Agency finds that the particular activities present an unreasonable
risk.
By providing a commercial purposes limitation for EPA to cover
early phases of product development, Congress recognized the need for
EPA to balance the competing interests of fostering innovation and
protecting human health and the environment from unreasonable risk. In
balancing these interests, EPA could construe the commercial purposes
limitation to exclude relatively few activities during screening to
cover a broad range of risk possibilities. Therefore, the broadest
meaning of commercial purposes would miss hardly any research.
4. Alternative interpretations affecting which activities at
noncommercial institutions will be considered commercial. Any of the
three alternative interpretations of commercial purposes set forth
below, as well as any other interpretation that is suggested by public
comment and meets the intent of TSCA and adequately protects public
health and the environment from unreasonable risks, may be adopted by
the Agency in its final rule. Regardless of the alternative chosen, EPA
would encourage researchers to voluntarily consult with EPA to find out
if EPA considers their research to be commercial.
a. Indicia of commercial purposes. The usual way to interpret a
statutory term of art like ``commercial purposes'' would be to look for
indicia of commercial intent. This is what EPA does in its TSCA section
5 program for traditional chemicals. The Agency has not provided any
detailed public discussion of what these indicia may be for traditional
chemicals, but because the Agency will be reviewing R&D activities in
its biotechnology program, a discussion of these indicia for the
biotechnology program is appropriate.
While EPA may develop a general discussion, no exhaustive list of
commercial indicia can be developed a priori. If EPA adopts this
approach, the commercial indicia would apply to R&D in laboratories and
other contained structures, as well as to intentional testing in the
environment. Some environmental testing of new microorganisms would not
be screened, because it would not be for commercial purposes.
EPA acknowledges that noncommercial institutions may find it
difficult to trace funding for particular activities or to decide
whether an activity is commercial or not. However, EPA supports this
alternative, under the theory that the burdens of reporting to EPA are
costs of doing business for any organization that wants the benefits of
commercial financing. In addition, EPA believes that reporting at the
research stage under this proposed rule does not impose an unnecessary
burden on innovation and that the indicia described below would be
consistent with the intent of TSCA. There are two general categories of
commercial indicia for activities at nonprofit institutions; one
involves industry involvement, either directly or indirectly; the other
does not.
(i) Direct industry involvement. As noted above, any direct
industry involvement in an activity at a noncommercial institution is
for commercial purposes. Examples of direct commercial funding include
situations in which a commercial entity contracts directly with a
university, or gives a conditional grant where the commercial entity
holds patent rights, or establishes a joint venture where the
commercial entity holds patent or licensing rights.
(ii) Indirect industry involvement. Indirect benefits to the
commercial entity are not as clear. For example, a commercial entity
may give a gift to a research institution with no limits on the use of
the funds or research results. However, since the funds originated from
a commercial source, a commercial purpose may nonetheless exist. Other
indirect relationships between commercial and noncommercial entities
need to be considered. For example, a commercial entity may guarantee a
university bank loan for research, a faculty member associated with
biotechnology research may have a financial interest in a biotechnology
company, research may be conducted at a science park jointly owned by a
university and commercial enterprises.
(iii) No industry involvement. If there is no industry involvement,
EPA needs to look at the intent of the individual researcher or
institution. Entrepreneurial faculty members may obtain financial
rewards from their own inventions. Some may take out personal patents
or derive personal income. The university may benefit from the patents
or may sell products or services commercially, for example, to farmers.
Because products may be sold to consumers, EPA is inclined to consider
these activities commercial. However, if profits are used to support
research or improve teaching facilities, EPA may recognize a case for
considering the activity not to be commercial.
EPA could also consider activities supported by Federal or State
government to be commercial. Many of these government activities are
designed to foster economic benefits for particular groups, such as
farmers. Also, the government may support university centers for
technology transfer to industry. The issue may be philosophical,
regarding whether government economic activities benefit individuals or
the general welfare. EPA believes there are legitimate arguments for
either view.
Finally, EPA may consider all activities at a nonprofit institution
to be commercial if any activity is. Thus, if a company finances one
activity at the university, all of the university's research may be
considered commercial. If a university has an equity interest in a
biotechnology company or a faculty member is associated with a firm,
all the university's research activities may be considered commercial.
This interpretation is supported by the fact that commercial activities
free resources for noncommercial activities.
If EPA interprets all these situations strictly, for practical
purposes, almost all research could be commercial. EPA notes for
comment, however, not-for-profit institutions that obtain self-
generated funds through charitable or religious donations and
government grants for pure research to identify health or environmental
hazards. These situations may not be commercial under any
circumstances.
Regardless of the alternative chosen for environmental research,
EPA would base its interpretation of commercial purposes for research
qualifying for the contained structures exemption on the broad set of
indicia discussed under this first alternative, in light of its belief
that EPA requirements for contained commercial R&D are similar to
requirements placed on academic researchers by the NIH Guidelines. See
Unit III.B. of this preamble. Therefore, the second and third
alternatives would apply only to research which does not qualify for
the contained structures exemption.
b. All environmental research is commercial. Because of the ability
of microorganisms to reproduce, disseminate and spread and the features
of intentional testing in the environment, EPA believes it should
propose another interpretation to address such testing. Under this
interpretation, all intentional testing outside of contained structures
would be commercial. This interpretation would avoid the most
significant problem identified by comments, which is that there is no
real difference in risk between research conducted by industry and by
noncommercial entities.
As discussed more fully in Unit III.B. of this preamble,
microorganisms function differently than other chemical substances.
Because R&D involving the introduction of new microorganisms into the
environment involves greater uncertainty than R&D involving use of
microorganisms under contained conditions, EPA believes that a
different position is warranted for intentional testing of
microorganisms in the environment.
Because the TERA burden is structured to be minimal, EPA believes
reporting will not seriously restrict academic R&D. In fact, this
interpretation of commercial purposes in some respects could lessen the
burden on universities, because they will not have to separate their
industry funding from other funding that they may not consider
commercial.
While considering all environmental releases to be commercial may
seem contrary to the usual view, the actual status of funding for the
biotechnology industry supports this interpretation. Research
relationships in biotechnology are pervasive and take many forms.
According to an Office of Technology Assessment (OTA) report,
in recent years, the rapid proliferation of collaborations in
biological research, involving partnerships between universities,
industry and government, has greatly extended the frequency, scope
and visibility of such activities. Attempts to commercialize
biological techniques have occurred at an accelerated rate when
compared to other fields, involving a greater range of commercial
application than discoveries in most other disciplines. (Ref. 4,
page 13).
Even the United States government is involved, under the Technology
Transfer Act, in the commercialization of biotechnology, having
developed a technology transfer policy between universities and
industry with the goal of developing commercially useful products.
Nonprofit foundations also participate in activities for commercial
purposes, often to finance other nonprofit activities.
c. Rebuttable presumption of commercial activity. The same
arguments for the option that all environmental releases are commercial
support the rebuttable presumption option. The rebuttable presumption
is also supported by the need to distinguish commercial and
noncommercial activities under TSCA. The above discussion of commercial
indicia indicates the types of evidence that a researcher may present
to rebut the presumption. However, EPA believes that this option would
be burdensome to researchers, because it would require them to maintain
evidence concerning sources of funding for each environmental
experiment. EPA also believes that this approach would be less
protective of public health and the environment, because it does not
adequately address uncertainty about the behavior of new microorganisms
in the environment.
d. Voluntary consultation. EPA recognizes that regardless of the
interpretation of commercial purposes adopted for the final rule, it
will be difficult to apply any one interpretation in all cases. For
this reason, EPA would encourage persons who believe that they are
engaging in non-commercial R&D to voluntarily consult the Agency before
initiating testing of microorganisms that would be considered new if
used for commercial purposes.
B. Exemption for Research in Contained Structures
This Unit explains EPA's reasons for exempting from section 5
screening R&D activities performed under conditions that would minimize
the number of microorganisms emitted, or where appropriate prevent
emission of microorganisms from structures such as pilot fermentation
facilities, greenhouses, and laboratories. The R&D reporting process is
discussed in Unit II.D. of this preamble.
1. Background. The statutory authority for this exemption is TSCA
section 5(h)(3). Section 5(h)(3) exempts from section 5 screening
chemical substances manufactured or processed in small quantities
solely for R&D, and directs EPA to define small quantities by rule.
Accordingly, proposed Sec. 725.3 provides that R&D activities involving
microorganisms would qualify for the section 5(h)(3) exemption when
these activities are conducted under conditions designed to meet
appropriate standards of containment and when employees are notified of
risks. Some R&D activities which are eligible for the contained
structures exemption may also be subject to the jurisdiction of another
Federal agency. In these cases, EPA proposes to defer to the authority
of the other Agency. The rationale for this proposed deferral is
discussed in Unit III.C.3. of this preamble.
2. Difficulties in ensuring that microorganisms used for R&D will
not increase beyond small quantities. EPA's current regulations for
traditional chemicals at Sec. 720.3(cc) define ``small quantities
solely for R&D'' as those quantities that are ``not greater than
reasonably necessary for ... [R&D] purposes.'' This definition of small
quantities for R&D has been appropriate for traditional chemical
substances, because these chemicals do not have the ability to increase
their own volume or amount. To the extent a finite amount of a
traditional chemical released during an experiment may leave a test
site, it will only be diluted in the environment.
Living microorganisms are not, however, subject to these same
limitations. Microorganisms may reproduce and increase beyond the
number initially introduced, may establish in the environment (i.e.,
develop a self-sustaining population), and may spread beyond the test
site. Thus, what begins as a small, localized population of
microorganisms may become a large, widespread population. Even if
certain microorganisms do not exhibit the ability to reproduce,
increase in number, establish, and spread beyond the test site, they
may be capable of passing some of their traits to other microorganisms
in the environment. These other microorganisms may, in turn, multiply,
establish, spread and subsequently pass the acquired trait to other
microorganisms. This could result in widespread propagation of the
trait, and exposure of a number of different environments to novel
traits.
These abilities of living microorganisms render the general
definition of small quantities that applies well to traditional
chemicals invalid for microorganisms. If the definition developed for
traditional chemicals was applied to living microorganisms, EPA would
not review microorganisms until they were produced for general
commercial use. New microorganisms could be released, with no EPA
review, during R&D testing in the environment, perhaps numerous times,
and could become established and spread. This would defeat the purpose
of TSCA, which is designed to permit EPA to review chemical substances
before they become widely disseminated.
Consequently, a determination of what constitutes small quantities
for microorganisms requires that more factors be taken into
consideration than are considered for traditional chemicals. These
factors revolve around the probability that a microorganism will
establish itself in the environment. Establishment is a key
consideration, because unless a microorganism establishes, any effects
it might have would probably be spatially and temporally limited.
Several factors influence whether a microorganism will be able to
establish itself. These include the numbers of microorganisms involved,
the frequency with which they are applied to the area, the method of
application, the characteristics of the microorganism, the
physiological condition of the microorganism at the time of
application, and the characteristics and condition of the receiving
environment.
Case histories of both disease epidemics and invasions of higher
organisms suggest that the number of organisms present in the inoculum
directly influences whether the introduction yields a self-sustaining
population (Ref. 5). Experience with microorganisms used in biocontrol
(i.e., purposeful use of microorganisms as antagonists to reduce the
disease-producing ability of plant pathogens) has shown that success in
some instances can be enhanced if a large number of the biocontrol
microorganism is introduced (Ref. 6).
It can be inferred from this information that the number of
organisms, both with regard to the density of the inoculum and the
geographic range over which it is introduced (Refs. 7 and 8), is
related to probability of establishment. Several hypotheses on why this
may be so can be offered. In some cases, mortality in the introduced
population can be overcome if the inoculum contains a large number of
individuals. In other situations, a large inoculum population may
provide sufficient genetic variation that individuals that can tolerate
or prosper in the environment of introduction will be within the
inoculum (Refs. 9 and 10). A biocontrol strategy that relies on the
inoculum containing large numbers of microorganisms is thought to be
successful because the introduced microorganisms may by sheer numbers
have an advantage in reaching and filling available suitable
microhabitats, availability of suitable habitat being a limiting factor
for any population of organisms.
The frequency with which organisms are released to an environment
also affects whether an organism can establish. Frequent releases
increase the likelihood that the microorganism will find sites
favorable for establishment by increasing the total number of
microorganisms placed in the environment and by increasing the
probability that a microorganism will be introduced during a time
favorable for establishment. This latter probability is related to
factors such as the variations in temperature, moisture, light, and
biota observed with seasonality. In other words, conditions favorable
for establishment may exist at some period of time and not at others,
and frequent application increases the probability that some
individuals will be at the right place at the right time.
3. Regulatory conditions to prevent microorganisms used for R&D
from increasing beyond small quantities. EPA's proposed standards at
Secs. 725.234 (containment and recordkeeping) and 725.235 (employee
notification) are designed to reduce the probability of establishment
by reducing the number and frequency of viable microorganisms emitted
from a facility. The reduced probability of establishment increases the
probability that a microorganism will remain a small quantity.
EPA is proposing performance-based standards for this exemption.
EPA's approach relies on the experience and judgement of the TQI, and
EPA will not generally substitute its own judgement for that of the
TQI. The approach recognizes that many different kinds of
microorganisms displaying a wide range of characteristics could
potentially be used in research, and that for certain microorganisms,
emission of only a few viable individuals could cause an effect, while
emission of large quantities of viable microorganisms of another type
would not. It also recognizes that the type of controls (e.g.,
procedural, mechanical, and/or engineering) appropriate for one
microorganism might have limited relevance to other microorganisms. EPA
expects that the TQI will be cognizant of these factors when selecting
containment and inactivation controls appropriate to the
microorganism(s) being utilized.
EPA does not believe the documentation requirements proposed for
this exemption will be overly burdensome. EPA believes that for most
cases, laboratory notebooks normally kept in the course of research
will contain most of the information required by this proposal. Control
measures selected could be indicated by reference to existing standards
(e.g., one of the containment levels described in the NIH Guidelines).
The TQI would simply record the reasons for choosing particular
measures. With regard to the requirement that records document use of
the selected controls, EPA is relying on the TQI to prepare and retain
the appropriate degree of documentation. The amount of documentation
would be correlated with the characteristics of the research
microorganism and standard practices employed to address risk. Thus,
documentation could range from general documentation of routine
standard operating procedures, to specific notations in laboratory
notebooks, to daily log entries for microorganisms that present the
greatest risk concerns. If the NIH Guidelines are used as guidance, the
TQI's notebook should indicate the level of containment recommended by
the Guidelines and that this guidance was selected and used. EPA
believes that persons following the NIH Guidelines would keep adequate
records as part of normal procedures for informing their Institutional
Biosafety Committee of the contained research.
With respect to the certification requirement, many if not most
research institutions have Institutional Biosafety Committees (IBCs) as
required by the NIH Guidelines, or committees fulfilling a similar
role. These committees are charged with assessing the containment
selected by the investigator. EPA recognizes the value of this NIH
system and would like to make its requirements consistent to the extent
possible with such existing systems. The Agency also encourages the
active use of such committees.
The provision which indicates that EPA may request these records be
sent to EPA for review (see Sec. 725.234(d)(3) of the regulatory text)
is a restatement of the authority EPA has under TSCA section 11 to
request and review information. It is also similar to provisions used
by EPA in other exemptions. In the three exemptions from PMN reporting
under part 723 that currently exist for traditional chemicals, one of
the conditions for eligibility for the exemptions gives EPA access to
the records demonstrating eligibility for the exemptions. EPA can
require a company to produce the records upon EPA's written request.
EPA does not plan to routinely review such records, although it may
choose periodically to select some records for review. Should the
institution or researcher receive a request for records review, the
status of the research as exempt would not a priori be affected.
Technical staff with experience reviewing TERA and MCAN submissions
would examine the records. This provision allows EPA and the researcher
to discuss what constitutes appropriate control measures and
appropriate implementation and use. Under this provision, EPA may, upon
review of the records, offer recommendations concerning what it
considers appropriate control measures for the specific microorganisms
used in the research. These recommendations would be non-binding. If
EPA determines, however, that the control measures selected and used
are so inadequate as to present an unreasonable risk, EPA can issue an
order directed at modifying the control measures it finds problematic.
Refusal to comply with an order would result in loss of eligibility for
the exemption for the research in question. The researcher would then
be subject to the notification requirements of TSCA section 5.
EPA's criteria at proposed Secs. 725.234 and 725.235 are designed
to reduce the probability of establishment by reducing the number of
viable microorganisms emitted from a facility. However, EPA's proposed
approach also takes into consideration factors such as the
physiological condition of the microorganisms and how this might affect
the ability of microorganisms to establish in the environment.
Microorganisms used in laboratory research are more likely to be
debilitated with regard to their ability to compete in the environment
against wild type relatives. Thus, they may be less likely to prevail
in the struggle in nature for limited resources. In general, incidental
releases of microorganisms from research facilities are less likely to
occur under conditions which favor the establishment of the
microorganism. Incidentally released microorganisms may be
physiologically debilitated by aerosolization or other process
procedures, and may be less likely to find an environment that favors
their survival and persistence than those microorganisms that are
specifically tested in an environment where they are intended to
survive, at least long enough to perform a specific function.
EPA recognizes that parts of the rationale offered for exempting
research conducted under the conditions set forth in proposed
Sec. 725.234 can be applied to some small-scale field tests involving
microorganisms. The rationale cannot, however, be applied to small
scale field tests as a class. Microorganisms intentionally tested in
the environment are more likely to be acclimated to the environment
into which they are introduced, be physiologically fit enough to be
competitive in that environment for a significant period of time, and
be placed in an area suitable for growth and persistence. Because of
the lessons learned with biocontrol microorganisms, researchers will
purposefully apply large enough numbers to ensure that the
microorganism persists long enough and competes well enough to perform
the function the researcher intends to study. In general, the
probability that these types of microorganisms, used under these
conditions, will establish is thus higher than the probability
associated with incidental emissions from facilities employing EPA's
proposed criteria.
4. Alternative reasons for the research exemption. An alternative
rationale would hold that the small quantities exemption in section
5(h)(3) does not apply to microorganisms as a class, because some
microorganisms, whether they are released through intentional testing
or incidental emission, can establish even though the initial inoculum
is very small. For some microorganisms, a single microorganism may be a
sufficient inoculum for establishment to occur. Thus, for
microorganisms as a class, there can be no concept of ``small
quantities'' similar to that envisioned for other chemicals.
EPA would find, however, that research conducted under the criteria
specified in Secs. 725.234 and 725.235 could be exempted under TSCA
section 5(h)(4). EPA's authority under TSCA Sec. 5(h)(4) is discussed
in Unit III.C. of this preamble. In situations where the EPA criteria
at Secs. 725.234 and 725.235 are followed, EPA believes that the
resulting reduction in the number of microorganisms emitted from R&D
facilities will reduce the probability that a microorganism will
establish in the environment. This reduced probability of establishment
leads directly to a reduction in risk. If a microorganism does not
establish, its ability to present risk is far less likely to be
expressed. If the microorganism is not able to establish, any adverse
effects that might be associated with that microorganism will probably
be spatially and temporally limited.
EPA recognizes that some research activities may present special
considerations; e.g., when the research utilizes microorganisms that
can successfully establish from a very small inoculum. In such cases,
incidental emission from the facility may have to be much more
stringently controlled to reduce risk. EPA believes that its
requirement that a technically qualified individual (TQI) select and
validate procedures appropriate to the microorganism addresses this
concern. That person should select, validate, and follow procedures
that would ensure that insufficient numbers of viable microorganisms
are emitted from the facility for establishment to occur.
EPA believes that any potential risk presented by incidental
releases from research facilities that might occur, even when its
criteria for reducing the number of microorganisms emitted from the
facility are followed, is outweighed by the benefits to society of
biotechnology research. EPA can use its limited resources, which
otherwise would be used to review these low risk research activities
for microorganisms, for reviewing higher risk activities and
microorganisms. Industry, by having this exemption, can develop and
test microorganisms in the early stages of the product development
process (e.g., laboratory) without having to be reviewed by EPA. This
would reduce the time and cost for industry in developing new products.
More time and resources could be allotted for actual R&D and less time
and resources allotted to EPA notifications. This should assist the
development of this industry and the emergence of new, useful products,
and thus not present an unreasonable risk of injury to human health and
the environment.
5. Alternative methods of reducing the number of microorganisms
emitted. EPA believes its proposed approach to reducing the number of
microorganisms emitted from research facilities is preferable to more
prescriptive approaches which have been suggested. The suggested
approaches include setting a specific numerical standard for the number
of microorganisms that might be incidentally released to the
environment from a research facility, prescribing a single standard
based on one of the containment levels described in the NIH Guidelines,
or an approach wherein several increasingly stringent levels of
containment are described and specific microorganisms are matched to
specific levels. These three approaches would be complex and unwieldy
to implement. Because of their prescriptive nature, such approaches
would result in EPA regulating the containment standards rather than
exempting the research. This would unnecessarily restrict research
contrary to the intent of TSCA. Each change to a prescriptive standard
would have to be incorporated into the standards through rule
amendments or variance procedures. Establishing prescriptive standards
could restrict advances in technology for controlling microorganisms
and stifle individual initiative at the research level.
C. Section 5(h)(4) Exemptions
1. Introduction--a. Statutory background. Section 5(h)(4) of TSCA
provides that EPA may exempt by rule the manufacture of any new
chemical substance from all or part of the requirements of section 5,
if it is determined that activities involving the substance will not
present an unreasonable risk of injury to health or the environment. A
section 5(h)(4) rule must be promulgated under the procedures set forth
in TSCA sections 6(c)(2) and (3), which generally require preparation
of a rulemaking record and an administrative hearing. EPA is proposing
to use section 5(h)(4) to support various exemptions from the
notification requirements of the rule.
The term ``unreasonable risk'' is not defined in TSCA. Section 6(c)
of TSCA lists considerations for determining whether a chemical
substance presents an unreasonable risk for purposes of promulgating
regulations under TSCA section 6. These considerations include the
effects of the substance on human health and on the environment and the
magnitude of exposure to the substance, the benefits of the substance
for various uses, the availability of substitutes for such uses, and
the reasonably ascertainable economic consequences of the potential
regulatory action, considering effects on the national economy, small
business, technological innovation, the environment, and public health.
EPA believes it is reasonable to consider these factors in determining
whether a risk is unreasonable under section 5(h)(4).
TSCA offers no further direct guidance on what constitutes
unreasonable risk. In particular, TSCA does not discuss how each of the
section 6(c) considerations are to be weighed in relation to each
other. The legislative history, therefore, needs to be considered. The
House Report (H.R. Rep. 94-1341, 94th Cong., 2d Sess. at 13-15, 32)
provides the most useful pertinent explanation. First, the standard
under TSCA is ``unreasonable'' risk, not a decision to eliminate all
risk (House Report at 15). For an activity that is of some value to
society, some level of risk may be acceptable. With respect to section
5(h)(4), granting an exemption does not require a showing that there
will be no risk, only that there will be no unreasonable risk.
The House Report states that the unreasonable risk standard cannot
be defined in precise terms but, instead, requires exercise of judgment
by the decisionmaker. The House Report describes the finding of
unreasonable risk as involving a balancing of the probability that harm
will occur, and the magnitude and severity (potential consequences) of
that harm, against the effects (social and economic) of proposed action
on society.
According to the House Report, these evaluations of harm often must
be based on considerations of ``scientific theories, projections of
trends from currently available data, modeling using reasonable
assumptions, and extrapolations from limited data'' (House Report at
32). The unreasonable risk standard recognizes that, as a practical
matter, all the scientific evidence is uncertain to some degree and
that EPA can consider such factors as the strength of the evidence on
toxicity, the nature of the effects that may occur (e.g., death vs.
reversible effects), and the likely numbers of individuals exposed and
the levels of exposure.
The House Report points out that the unreasonable risk standard is
flexible enough to allow EPA to calibrate the stringency of a
regulatory measure to the levels of risks and benefits. Thus, a testing
rule, because it does not deprive the public of the benefits of a
chemical, requires a lesser showing of harm compared to a rule which
may remove a substance from the market or impose other restrictions on
its availability. Similarly, a stronger showing would be required to
ban an activity than to impose lesser restrictions on use or a
requirement, such as labelling, that does not restrict directly.
The greater the probability and the more severe the potential harm
presented by an activity EPA may allow, the less likely a no
unreasonable risk finding can be made. Similarly, the greater the
benefit of the activity, the greater the risk to be tolerated.
Determinations of whether an exemption should be partial or full will
depend on the probability and severity of the harm and the benefits to
be derived from the activity. Less restrictions should apply if there
are substantial benefits from the activity and the probability of harm
appears to be lower or the consequences are of low concern.
b. Summary of section 5(h)(4) exemptions. EPA is proposing to use
its authority under TSCA section 5(h)(4) to establish six separate
types of exemptions. These are partial exemptions that involve limited
reporting and/or recordkeeping for new microorganisms that meet the
eligibility requirements of the specific exemptions. Five of these
exemptions specifically relate to R&D activities. The sixth case is a
tiered exemption for general commercial use.
Because each exemption involves a different set of issues, each
exemption requires a different weighing of risks and product benefits.
The remainder of this unit sets out the no unreasonable risk findings
for each of the exemptions. For each exemption, a review of the
relevant scientific risk considerations is followed by a discussion of
the social and economic benefits resulting from microbiological
products. The extent to which both risks and benefits are considered is
dependent on the breadth of the exemption.
2. Alternative finding of no unreasonable risk for microorganisms
used for R&D in contained structures. The reasoning for this
alternative finding relies on the factors discussed in Unit III.B. of
this preamble for research that meets the criteria at proposed
Secs. 725.234 and 725.235 for R&D conducted in contained structures.
See Unit III.B. of this preamble for a full discussion of the rationale
for exempting research in contained structures.
3. Deferral to other Federal authorities for oversight of R&D. Unit
II.D. of this preamble describes a proposed exemption from this
regulation for research controlled by other federal authorities. This
section provides EPA's reasons for establishing this exemption. The
exemption is based on the general policy that TSCA should not apply to
research adequately overseen by other federal authorities.
TSCA jurisdiction is discussed in Unit I.C. of this preamble.
Generally microorganisms controlled by other Federal agency
authorities, other than those microorganisms regulated under FIFRA or
FDA authorities, are also subject to TSCA. Agencies, such as the Animal
and Plant Health Inspection Service (APHIS) of the U.S. Department of
Agriculture (USDA), have regulatory authority that overlaps TSCA
authority for microorganisms. Research subject to TSCA may also be
funded by Federal agencies, such as the Department of Defense (DOD),
the Department of Energy (DOE), the National Institutes of Health
(NIH), the National Science Foundation (NSF), USDA's APHIS or its
Office of Science and Education (S&E), or EPA's own Office of Research
and Development (EPA/ORD).
On November 23, 1976, all Federal agencies represented on the
Federal Interagency Committee endorsed the NIH Guidelines. Departments
which support or conduct laboratory rDNA research agreed to abide by
the Guidelines in June 1983 (48 FR 24577). Because of the 1983
agreement, as a condition for Federal funding of rDNA laboratory
research, institutions must ensure that all rDNA research conducted at
or sponsored by the institution, regardless of the source of the
funding, complies with the Guidelines.
a. Finding of no unreasonable risk for R&D in contained structures
subject to the authority of other Federal agencies. This proposed rule
would provide an exemption for research in contained structures
(principally laboratories) covered by the NIH Guidelines. EPA considers
the NIH Guidelines to provide the primary standard for laboratory
research. EPA's rules are designed to provide complementary oversight
of those activities not covered by NIH. As a result, EPA is proposing a
complete exemption under TSCA section 5(h)(4) for research on new
microorganisms in contained structures, if the researcher is required
to comply with the NIH Guidelines. This may be achieved through direct
regulatory authority or through requiring recipients of Federal funds
to comply with the NIH Guidelines. Without this exemption, the
recordkeeping and employee notification requirements of proposed
Secs. 725.234 and 725.235 would apply to this research. EPA's summary
analysis of the NIH Guidelines may be found in the docket which
supports this rulemaking.
EPA proposes under TSCA section 5(h)(4) to exempt from the
requirements described in proposed Secs. 725.234 and 725.235 the
manufacturers, producers and importers of new microorganisms for R&D in
contained structures, if the research is regulated or funded by a
Federal agency which has agreed to abide by the NIH Guidelines.
The pertinent parts of EPA's regulations applying to R&D in
contained structures are Sec. 725.234(b) and (d). They require a
technically qualified individual (TQI) to maintain documentation that
describes the selection of containment and inactivation procedures and
ensures the procedures are followed. The TQI's selections must be
approved and certified by an authorized official of the institution
conducting the experiment (Sec. 725.234(d)(2)). EPA may request the
records, review containment/inactivation controls and may order changes
in containment/inactivation procedures (Sec. 725.234(d)(3) and (d)(4)).
These provisions are designed to complement the NIH Guidelines and
extend their benefits, without imposing an overly rigid regulatory
regime. EPA's regulation is in the same spirit as the NIH Guidelines in
that it is also based on the fact that all conceivable experiments
cannot be foreseen and that it is the responsibility of the
experimenting institution to devise appropriate containment. Like NIH,
EPA emphasizes the importance of the motivation and good judgment of
the investigators.
Because the NIH Guidelines are very well entrenched in the research
community, EPA expects that the procedures chosen by the TQI will very
closely follow the Guidelines. In addition, any EPA review of records
will rely heavily on the Guidelines. Thus, by establishing the
provisions of proposed Sec. 725.234(d), EPA would effectively apply
Guideline principles to those institutions, primarily commercial
facilities, that are not required to abide by them. This would
complement the NIH request for voluntary compliance.
Further, the NIH Guidelines apply directly only to those
microorganisms, and categories of microorganisms, that have been listed
in the Guidelines and, in particular, Guideline Appendices A through F.
Other microorganisms would require specific review by NIH. EPA
regulations extend the benefits of the NIH Guidelines by effectively
applying their principles to microorganisms other than those
specifically mentioned in the Guidelines.
At the same time, by not incorporating the Guidelines directly into
regulations, EPA would avoid overly rigid adherence to Guidelines that
are, themselves, meant to be flexible. EPA, however, retains sufficient
control to protect against risk by the review procedures in proposed
Sec. 725.234(d)(3) and (d)(4).
Requiring researchers to adhere to the proposed requirements of
Secs. 725.234 and 725.235 as well as to the requirements of these other
federal authorities would be a duplication of oversight and enforcement
that would unnecessarily restrict potentially beneficial research
without any incremental reduction in potential risk. Thus, there would
be no increase in risk from removing the TSCA section 5 restrictions
placed on contained structure R&D. Further, costs will be reduced,
because there would be no costs incurred in complying with TSCA. R&D
would be encouraged without an attendant increase in risk. Therefore,
the risks of exempting this research from the TSCA section 5 contained
structure R&D restrictions are far outweighed by the costs saved.
Accordingly, EPA finds there will be no unreasonable risk from this
exemption.
b. Federal agency R&D subject to TERA reporting. EPA has also
considered how it might use its TSCA section 5(h)(4) exemption
authority to minimize duplicative reviews of environmental release
tests that are also subject to other Federal agencies. EPA has
determined that a different exemption process should apply to
experiments in the environment than to contained experiments. While the
NIH Guidelines are recognized as a standard for contained R&D, the same
situation does not pertain to R&D activities involving releases to the
environment. Accordingly, EPA is planning to propose the procedures
outlined below for exemptions from the TERA process for deliberate
release experiments reviewed by other Federal agencies.
With agencies that have clear regulatory authority, EPA would
propose to exempt from TSCA section 5 requirements intentional
environmental testing of new microorganisms and to defer to the other
Federal agency's review, when EPA determines that the other Federal
agency's review addresses criteria equivalent to those which would be
evaluated under TSCA section 5. When EPA develops such an exemption
involving deferral to another Federal agency, it will propose the
exemption using notice and comment rulemaking. EPA is currently working
with USDA-APHIS to develop an exemption for R&D field tests reviewed by
APHIS under the Federal Plant Pest Act and the Plant Quarantine Act and
implementing regulations at 7 CFR part 340 and hopes to include such an
exemption when the rule is promulgated.
4. Finding of no unreasonable risk for TERA approval of new
microorganisms--a. Background. EPA recognizes that many small-scale
tests will not present unreasonable risks and that requirements
restricting R&D could stifle innovation contrary to the intent of TSCA.
Therefore, under section 5(h)(4) EPA is proposing to conditionally
exempt from MCAN notification R&D involving certain new microorganisms.
The exemption is conditional, since researchers must submit a TERA.
EPA's current experience with reviewing PMNs for microorganisms
used for R&D in the environment under the 1986 Policy Statement has
indicated that EPA could more efficiently review these activities.
While the current process provides an adequate mechanism, R&D
activities present a very different risk assessment situation than
general commercial use. Differences in exposure, the ability to apply
procedures for controlling routes of exposure or dissemination and the
procedures for controlling potential risks, and the need for
flexibility in R&D comprise different risk assessment scenarios than
found in general commercial use. As a result, in light of these
different scenarios, a more straightforward and flexible approach to
reviewing experiments for new microorganisms is indicated. The TERA
provisions of this proposed rule will provide such an approach.
A TERA provides for submission of information commensurate with the
nature of the R&D process, because the review is focused on a specific
R&D activity. Therefore, not as much information is required compared
to a MCAN. For example, persons who submit a TERA would not have to
include information on all commercial manufacture, processing,
transport, use, and disposal activities that may involve the new
microorganism as is the case for a MCAN.
The more flexible deadlines and procedures for the TERA would avoid
unnecessary delays or restrictions on experiments. TSCA imposes a 90-
day waiting period for section 5(a)(1) screening; and persons who
submit MCANs must wait at least 90 days before an activity can begin,
even if EPA should determine no unreasonable risk is posed by the
activity before the 90-day review period expires. A similar waiting
period may not be appropriate for experiments when more rapid decisions
can be made. If TERA review shows that an experiment poses little or no
risk, EPA could notify the submitter to proceed at any time during the
review period prior to expiration of the review clock.
b. No unreasonable risk determination. EPA has decided that case-
by-case review is required to determine the potential risk presented by
a microorganism which may establish in the environment during the
course of a field trial. The review would allow EPA to determine if it
would be necessary to set limitations to minimize the probability of
establishment and dissemination in the environment. Microorganisms
intentionally tested in the environment are more likely to be
acclimated to the environment into which they are introduced, be
physiologically fit enough to be competitive in that environment for a
significant period of time, and be placed in an area suitable for
growth and persistence. Researchers generally apply large numbers of
microorganisms to ensure that they persist long enough and compete well
enough to perform the function the researcher intends to study. This
fact increases the probability that microorganisms used under these
conditions could establish and possibly pose a risk or result in
significant exposure. Therefore EPA has concluded that R&D which
involves intentional testing of microorganisms in the environment
should be subject to some review.
EPA has balanced a number of considerations to determine that
experiments reviewed under a TERA will not present an unreasonable risk
to health or the environment and should be exempt from MCAN
requirements. First, TERA review should result in no greater risks than
those that might occur as a result of the MCAN process, because the no
unreasonable risk criteria for approval are the same for either
process. Second, TERA review may even reduce risks in some instances by
allowing EPA to focus resources on activities that may pose the
greatest potential for risk. Third, TERA review will reduce reporting
costs by eliminating Agency need for information and procedures that
are unnecessary for R&D. Fourth, when compared to the MCAN process,
TERAs should encourage technological innovation and have a beneficial
effect on small businesses engaged in R&D utilizing new microorganisms.
5. Finding of no unreasonable risk for microorganisms proposed for
exemption from TERA reporting. EPA recognizes that some field
experiments with new microorganisms do not need to be reviewed at all.
EPA therefore intends to exempt from review some R&D experiments with
certain new microorganisms. EPA will, however, still review any general
commercial uses of these new microorganisms through the MCAN process.
The no unreasonable risk finding for exemption from TERA reporting is
based on the interaction of three principal criteria addressing the
recipient species, the introduced genetic material, and procedures for
limiting exposure during experimental use. The three criteria must be
considered in concert, because any potential concerns raised in one set
of criteria may be balanced or compensated by other criteria. These
criteria are discussed in more detail in Unit III.C.7. of this
preamble.
EPA requests comment on whether this approach should be used to
exempt from TERA screening certain new microorganisms. EPA is proposing
certain intergeneric strains of Bradyrhizobium japonicum and Rhizobium
meliloti as candidates for exemption from TERA review, based on reviews
of voluntary PMNs submitted under the 1986 Policy Statement and field
test data generated in these field trials. Persons possessing
information which they believe would support an exemption from TERA
reporting for other new microorganisms may use the procedures in
proposed Sec. 725.67 to apply for such an exemption.
EPA proposes to list Bradyrhizobium japonicum and Rhizobium
meliloti as acceptable recipient species. Both are well-characterized
taxonomically and have been used in the environment for over 80 years
to improve nitrogen fixation in specific agricultural crops. There is
extensive information on these two species documenting the lack of
adverse effects in the environment, and no reports exist that they are
pathogenic to humans or animals. In addition, EPA has reviewed field
test data from several experiments which have demonstrated that the
intergeneric strains are similar to the unmodified parental strains in
colonization, survival, nodulation and effects on plant growth. The
public dockets pertaining to the reviews of B. japonicum (six strains:
P88-1275 through 1278, and P89-340 and 341) and R. meliloti (18
strains: P87-568 through 570, P88-1115 through 1122, P89-280, P90-339,
and P92-399 through 403), along with the field test data, are
incorporated into the docket for this rulemaking. These strains were
modified in antibiotic resistance traits, and some were modified for
nitrogen fixation traits as well. In the course of these reviews, EPA
evaluated general and specific information in the open scientific
literature concerning these species, and BSAC subcommittees were
convened to discuss general issues associated with the proposed R&D
experiments with these strains.
Modification of traits, the second criterion, limits the source of
the introduced genetic material to the genera of Rhizobium and
Bradyrhizobium but allows the introduction of antibiotic resistance
traits from any source organism. In addition, the introduced genetic
material must be poorly mobilizable. The introduction of genetic
material for traits other than antibiotic resistance is limited to
Bradyrhizobium and Rhizobium species, because EPA is most familiar with
these two genera.
Based on the results of the field tests with these strains, EPA
proposes to exempt the use of well-characterized, limited in size, and
poorly mobilizable antibiotic resistance markers in Bradyrhizobium
japonicum and Rhizobium meliloti. EPA believes that there would be no
significant risk resulting from small-scale field tests with the
resulting microorganisms containing antibiotic resistance, because
broad antibiotic resistance already exists in naturally occurring
microorganisms of these two species (as demonstrated in the data
submitted for PMNs P88-1115 (rhizobia) and P88-1275 (bradyrhizobia). In
addition, higher levels of antibiotic resistance can be easily induced
in these microorganisms by mutation or selection. EPA requests comment
on the appropriateness of exempting antibiotic resistance traits.
EPA is proposing that these exemptions would only apply to test
sites of 10 acres or less. This test area limit for Bradyrhizobium
japonicum and Rhizobium meliloti is based on the field data reviewed by
EPA which show that such releases have remained small-scale, with the
modified strains exhibiting survival and persistence similar to their
unmodified parental strains. The TQI must select appropriate methods to
limit dissemination of these modified rhizobial species in order to
maintain the small-scale nature of the field tests. Also, this proposal
is based on the lack of adverse effects observed in humans and animals
resulting from use of these naturally occurring rhizobial species.
EPA is proposing to exempt intergeneric strains of these two
rhizobia species, in order to facilitate research using these
microorganisms and to encourage development of products that could
increase crop productivity while decreasing dependance on chemical
fertilizers. These experiments could generate important information
that will increase understanding of the environmental fate of
intergeneric microorganisms. Information from these field tests would
advance the understanding of microbial ecology, which could facilitate
review of commercial products. The possible risks due to exempting
these two rhizobia species from review at small-scale will be balanced
by the innovation and development of safer, environmentally sound
products to promote crop production.
6. Finding of no unreasonable risk for specific alternative
exemption for low risk field tests. Unit II.D. of this preamble
describes an alternative exemption from TERA reporting for certain R&D
field tests. While EPA acknowledges that parts of the rationale offered
in Unit III.B. of this preamble for exempting research conducted under
the proposed contained structures exemption could be applied to some
small-scale field tests involving microorganisms, EPA does not believe
that the rationale can be applied to small-scale field tests as a
class. Therefore, it was suggested that EPA define a class of small-
scale field tests which would be expected to pose low risks and be
exempt from TERA reporting. The no unreasonable risk finding for this
alternative exemption from TERA reporting is based on the interaction
of three primary criteria which consider the safety of the parent
microorganism, the role of the traits that have been modified, and the
scale of the field tests. If the parent microorganism is shown to have
a history of safe use, introduced genetic material meeting the
specified criteria would be unlikely to significantly increase the
potential for adverse effects. EPA would expect that TQIs would use the
criteria discussed in III.C.7. of this preamble for the recipient
microorganism and the introduced genetic material as guidance in
determining that their new microorganisms would be eligible for this
exemption. As in the contained structures exemption for R&D, EPA is
relying on the experience and judgement of the TQI to select
appropriate methods to limit dissemination of the new microorganisms in
order to maintain the small-scale nature of the field tests. Reliance
on the judgement of the TQI is discussed further in Unit III.B. of this
preamble. EPA believes that the criteria it has specified circumscribe
a category of field tests which can be considered low risk. In
addition, should EPA receive a notice for a planned field test which
did not appear to be low risk, EPA could require the submission of a
TERA in order to review more completely the proposal.
EPA believes that the field tests potentially eligible for this
alternative exemption could generate important information which will
generally advance the understanding of microbial ecology and
specifically facilitate EPA's review of intergeneric microorganisms.
The low risks posed by the field tests will be balanced by benefits in
the form of reduction in reporting burden for researchers and the
encouragement of innovation in the development of environmentally sound
products. EPA would like to receive public comment on whether the
benefits of this exemption outweigh the potential risks posed by small-
scale field tests eligible for the exemption.
Although field tests which meet the proposed criteria would be
considered to pose low risks, additional concerns could be raised for
unlimited uses of the same microorganisms at the general commercial use
stage. Once development of these microorganisms moves beyond R&D to
general commercial use, they would be subject to the MCAN reporting
requirements discussed in Unit II.C. of this preamble.
7. Finding of no unreasonable risk for new microorganisms eligible
for tiered commercial use exemption. EPA recognizes that some
microorganisms present a low risk when used under specific conditions
at general commercial use. Therefore, EPA is proposing expedited
processes for certain microorganisms at the general commercial use
stage. The requirements and processes for the Tier I and Tier II
exemptions are discussed in Unit II.C. of this preamble. The criteria
for Tier I and Tier II exemptions address: (1) The recipient
microorganism; (2) the introduced genetic material; and (3) performance
based standards for minimizing the numbers of microorganisms emitted
from the manufacturing facility.
To evaluate the potential for unreasonable risk to human health or
the environment in developing these exemptions, EPA focused primarily
on the characteristics of the recipient microorganisms. If the
recipient is shown to have little or no potential for adverse effects,
introduced genetic material meeting the specified criteria would not
likely significantly increase potential for adverse effects. As further
assurance that risks would be low, EPA is also specifying procedures
for minimizing numbers of organisms emitted from the facility. When
balanced against resource savings for society and expected product
benefits, these exemptions will not present unreasonable risks.
a. The recipient microorganism. Six criteria were used to determine
eligibility of recipient microorganisms for the tiered exemption.
First, it should be possible to clearly identify and classify the
microorganism. Available genotypic and phenotypic information should
allow the microorganism to be assigned without confusion to an existing
taxon which is easily recognized. Second, information should be
available to evaluate the relationship of the microorganism to any
other closely related microorganisms which have a potential for adverse
effects on human health or the environment. Third, there should be a
history of safe commercial use for the microorganism. Fourth, the
commercial uses should indicate that the microorganism products might
be subject to TSCA jurisdiction. Fifth, studies are available which
indicate the potential for the microorganism to cause adverse effects
on human health and the environment. Sixth, studies are available which
indicate the survival characteristics of the microorganism in the
environment. EPA requests comment on whether these are the appropriate
criteria to consider to determine the eligibility of recipient
microorganisms for the tiered exemption. After each microorganism was
reviewed using the six evaluation criteria, a decision was made to
place the microorganism on the list in proposed Sec. 725.420. Summaries
of the individual risk assessments, are discussed below. The full risk
assessments for the recipient microorganisms are in the docket for this
proposed rulemaking.
(i) Acetobacter aceti is an obligate aerobic bacterium naturally
found in the restrictive niche of fermenting fruit, where it can
tolerate and utilize ethanol as a nutrient. This species has no
recorded pathogenicity on plants, humans, or animals and has a history
of safe industrial use. A. aceti is well-defined taxonomically and
clearly distinguished from other Acetobacter species known to cause the
browning of processed fruit. While it can be expected to survive in the
environment, A. aceti is unlikely to cause any significant
environmental effects.
(ii) Aspergillus niger is an asexual fungus commonly found
degrading organic matter in nature. This organism has a history of safe
use for the production of citric acid and several enzymes. It has been
shown to be an opportunistic human pathogen and to damage several
species of plants. While production of certain mycotoxins has been
associated with strains of A. niger, companies have been using
naturally occurring strains of A. niger to produce a variety of
products for many years without reports of toxic effects of workers.
The limited in size constraints as well as the restriction on
vertebrate toxins imposed on introduced genetic material by the
criteria for the tiered exemption should reduce the likelihood of
increased production or exposure to malformins A and C, the two most
potent mycotoxins potentially produced by A. niger strains. In general,
the restrictions placed on the introduced DNA and containment mean that
the recombinant A. niger strains eligible for the tiered exemption
should pose no greater risks than naturally occurring strains of A.
niger.
(iii) Aspergillus oryzae is an asexual fungus found in nature and
used for hundreds of years in the production of soy sauce, miso and
sake without recorded incidents. This fungus has no reported adverse
effects on either plants or animals. It has been suggested that genetic
engineering of A. oryzae might inadvertently produce an aflatoxigenic
strain. Naturally occurring strains of A. oryzae are not known to
produce aflatoxins; however, some scientists believe that A. oryzae is
a domesticated version of A. flavus and may possess dormant genes for
aflatoxin production. It is likely that companies have already been
using genetically modified strains of A. oryzae, but these strains have
not yet met the PMN reporting requirements, that is, they are not
intergeneric. The limitations placed by the tiered exemption on the
introduced genetic material, in particular the well-characterized and
limited in size restrictions, should reduce the likelihood that any
sequences relating to aflatoxin production could be introduced. The
containment requirements would limit exposure to any mycotoxins
produced. In addition, A. oryzae does not colonize humans. In general,
the restrictions placed on the introduced genetic material and
containment mean that the recombinant A. oryzae strains eligible for
the tiered exemption should pose no greater risks than naturally
occurring strains of A. oryzae.
(iv) Bacillus licheniformis is an aerobic sporeforming bacterium
that is well defined taxonomically. It can be readily isolated from the
environment, where it persists primarily as endospores. Many strains
have been tested and shown to have no adverse effects on humans,
animals or plants. B. licheniformis has been reported as an
opportunistic pathogen in livestock; however, it has never been
diagnosed as a causal agent. B. licheniformis has a history of safe use
in large-scale fermentation production of specialty chemicals and
substances such as citric acid and detergent enzymes. Although the
majority of experience with industrial fermentations employing B.
licheniformis is with asporogenic strains, all strains of this
microorganism are being recommended for the tiered exemption.
(v) Bacillus subtilis is an aerobic sporeforming bacterium which is
not completely defined at either the genus or species level. This
species is commonly found in nature, particularly in terrestrial
environments. Many strains have been tested and shown to have no
adverse effects on humans, animals or plants. Reports of B. subtilis
acting as an opportunistic pathogen are few in number and have not been
well substantiated. B. subtilis has a history of safe use in large-
scale fermentation production of specialty chemicals and enzymes and
even as a source of single cell protein for human consumption in Asia.
Although the majority of experience with industrial fermentations
employing B. subtilis is with asporogenic strains, all strains of this
microorganism are being recommended for the tiered exemption.
(vi) Clostridium acetobutylicum is an obligate anaerobic endospore-
forming bacterium which has been isolated from soils, sediments, well
water, and from animal and human feces. Various strains of C.
acetobutylicum have a history of safe use industrially or in research
for the production of butanol and acetone from various feedstocks.
While C. acetobutylicum may survive in the environment, it is not
likely to cause any significant environmental effects. Although the
current taxonomic classification of Clostridium species is not well-
defined, C. acetobutylicum can be distinguished from closely related
species which are known to be human pathogens. In general, the
restrictions placed on the introduced genetic material and containment
mean that the recombinant C. acetobutylicum strains eligible for the
tiered exemption should pose not greater risks that the naturally
occurring strains of C. acetobutylicum which have been used in industry
without reports of adverse effects to workers or the environment.
(vii) Escherichia coli K-12 is a strain which is well defined
taxonomically, although the genus Escherichia as a whole is not. E.
coli K-12 strains can be readily distinguished from those close
relatives that are pathogens. E. coli K-12 is a debilitated bacterium
which does not normally colonize the human intestine. It has also been
shown to survive poorly in the environment, has a history of safe
commercial use, and is not known to have adverse effects on humans,
microorganisms, or plants. Although some K-12 substrains produce low
levels of toxins, toxin expression by these substrains is mitigated by
E. coli K-12's poor survival in the environment and its inability to
colonize normal human or animal hosts.
(viii) Penicillium roqueforti is an asexual fungus which decomposes
organic materials in nature. Most strains of P. roqueforti, including
those used in cheese production, have been shown capable of producing a
variety of mycotoxins. P. roqueforti's long history of use in the
production of blue cheese has shown no adverse effects. P. roqueforti
is generally considered to be a benign organism, but it does raise
concerns because of its ability to produce mycotoxins under certain
conditions. Despite these concerns, the organism has a history of use
without noted reports of adverse effects to workers or the environment.
In general, the restrictions placed on the introduced genetic material
and containment mean that the recombinant P. roqueforti strains
eligible for the tiered exemption should pose no greater risk than
naturally occurring strains of P. roqueforti.
(ix) Saccharomyces cerevisiae is a yeast that occurs commonly in
the environment. Although it is not well defined taxonomically and
survives well in the environment, it has a history of safe use in the
commercial production of many products (e.g., beer). Further, it is not
known to cause pathological effects on humans, plants, or animals. S.
cerevisiae has no known effects on microorganisms, other than possible
effects on strains of its own species.
(x) Saccharomyces uvarum is a yeast capable of fermenting a variety
of sugars into ethanol. S. uvarum has a long history of safe use in
production of alcoholic beverages and industrial ethanol. Although it
is expected to survive in the environment, it is not expected to cause
any adverse environmental effects. While S. uvarum has been used
industrially for years, specific strains have not been distinguished.
b. The introduced genetic material. In order to qualify for either
Tier I or Tier II exemption, any introduced genetic material must be
limited in size, well-characterized, free of certain nucleotide
sequences, and poorly mobilizable.
(i) Limited in size. Introduced genetic material must be limited in
size to those segments required to perform the intended function, as
described at proposed Sec. 725.421(a). This criterion reduces
uncertainty by excluding the introduction into a recipient of
extraneous and potentially uncharacterized genetic material. The
requirement that the regulatory sequences permit the expression solely
of the structural gene(s) of interest reduces risk by preventing
expression of genes downstream of the inserted genetic material. The
limitation on the vector sequences that are components of the
introduced genetic material prevents the introduction of novel traits
beyond those associated with the gene(s) of interest. The overall
result of the limited in size criterion is improved ability to predict
the behavior of the resulting microorganism. EPA requests comment on
the usefulness of this criterion in reducing uncertainty about the
behavior of the new microorganism and any difficulties researchers may
have in isolating the genetic material required to perform the intended
functions.
(ii) Well-characterized. The requirement at proposed
Sec. 725.421(b) that the introduced genetic material be well-
characterized also contributes to improved ability to predict the
behavior of the resulting microorganism. Well characterized includes
knowledge of the function of the introduced sequences and the
phenotypic expression associated with the introduced genetic material.
Genetic material which has been examined at the restriction map or
sequence level, but for which a function or phenotypic trait has not
yet been ascribed, is not considered well-characterized.
Well-characterized would include knowing whether multiple reading
frames exist within the operon. This relates to whether more than one
biological product might be encoded by a single sequence, and addresses
the possibility that a modified microorganism could display unpredicted
behavior should such multiple reading frames exist and their action not
be anticipated.
(iii) Free of certain sequences. In addition to improving the
ability to predict the behavior of the modified microorganism, the
well-characterized requirement ensures that segments encoding for
either part or the whole of the toxins listed at proposed
Sec. 725.421(d) would not inadvertently be introduced into the
recipient microorganism (Refs. 11 and 12).
The toxins listed at proposed Sec. 725.421(d) are polypeptides of
relatively high potency. Other types of toxins (e.g., modified amino
acids, heterocyclic compounds, complex polysaccharides, glycoproteins,
and peptides) are not listed for two reasons. First, their toxicity
falls within the range of moderate to low. Second, these types of
toxins generally arise from the activity of a number of genes in
several metabolic pathways (multigenic).
In order for a microorganism to produce toxins of multigenic
origin, a large number of different sequences would have to be
introduced and appropriately expressed. It is unlikely that all of the
genetic material necessary for metabolizing multigenic toxins would be
inadvertently introduced into a recipient microorganism when
requirements that the genetic material be limited in size and well-
characterized are followed. Should any of the necessary sequences not
be introduced, or not be expressed appropriately by the recipient, a
toxin of multigenic origin would not be produced. EPA, thus, sees no
reason why a manufacturer who wishes to modify a microorganism listed
in proposed Sec. 725.420 with a single or a few sequences involved in
metabolism of a multigenic toxin should not be allowed to do so.
Introduction of a single or a few such sequences into a candidate
microorganism should not result in production of a multigenic toxin and
thus would not present significant risk.
Similarly, other properties that might present risk concerns result
from the interactive expression of a large number of genes. For
example, pathogenic behavior is the result of a large number of genes
being appropriately expressed. Because of the complex nature of
behaviors such as pathogenicity, the probability is low that an insert
consisting of well-characterized, limited in size genetic material
could transform the microorganisms listed at proposed Sec. 725.420 into
microorganisms which display pathogenic behavior. For this reason, with
the exception of certain toxins which are listed because of their
potency, EPA is not listing at proposed Sec. 725.421(d) sequences that
are one of a series of sequences needed in combination in order for a
microorganism to display a complex behavior such as pathogenicity. If
commenters believe they can identify sequences which present risk
concerns which should be addressed and listed at proposed
Sec. 725.421(d), EPA requests they inform the Agency of these
sequences.
(iv) Poorly mobilizable. The requirement, at proposed
Sec. 725.421(c), that the introduced genetic material be poorly
mobilizable reduces potential for transfer of introduced genetic
sequences to other microorganisms in the environment. Such transfers
would occur through the interaction of the introduced microorganism
with indigenous microorganisms through conjugation, transduction, or
transformation. Through such transfers, the introduced genetic material
could be transferred to and propagated within different populations of
microorganisms, including microorganisms which may never previously
have been exposed to this genetic material. It is not possible to
predict how the behavior of these potential recipient microorganisms
will be affected after uptake and expression of the genetic material.
Since EPA is not limiting the type of organism that can serve as
the source for the introduced genetic material, some limitation is
placed on the ability of the introduced genetic material to be
transferred. This limitation mitigates risk by significantly reducing
the probability that the introduced genetic material would be
transferred to and expressed by other microorganisms.
The transfer frequency of 10-8 was selected as defining
``poorly mobilizable'' for four reasons. First, it represents the lower
end of the range of transfer frequencies observed in nature. Transfer
of plasmids, for example, commonly occurs through conjugation between
bacteria at rates ranging from no detectable transfer (typically less
than 10-8 transfer events per donor) to 10-2 transfer events
per donor in soil, water and sewage (Ref. 13). A similar range of
transfer frequencies has been associated with transduction of
chromosomal and plasmid DNA in soil and aquatic microcosms (Refs. 14,
15, and 16). Also, a limited number of studies on natural
transformation have documented a range of transformation events from
0.3 x 10-8 to 1 x 10-8 transformants per recipient (Ref. 17).
Second, studies of certain genetic traits (e.g., amino acid auxotrophy,
resistance to antibiotics) suggest the spontaneous rate of mutation to
be within the range of 10-5 to 10-8 per cell generation
(Refs. 18 and 19). A frequency of 10-8 appears to represent,
therefore, a baseline frequency at which change occurs in genetic
material. Third, this frequency sets the technical limit for
measurability. Below the rate of spontaneous mutation, it becomes
difficult to distinguish gene transfer from mutation. Fourth, the
10-8 criterion should not be difficult to meet, and, in fact, is a
standard employed in the NIH Guidelines.
The 10-8 frequency is attainable given current techniques.
Plasmids with transfer rates of 10-8 exist or are easily
constructed. In bacteria this low rate is readily engineered through
the inactivation of the transfer functions of mobile genetic elements,
or the inactivation/removal of pilus formation functions of plasmids
(Ref. 20). Some of the plasmids most commonly employed as vectors in
genetic engineering (e.g., pBR325 and pBR322) have mobilization/
transfer frequencies of 10-8 or less. The plasmid pBR322 has been
used as a vector to construct several microorganisms reviewed by EPA
under the 1986 Policy Statement.
The criteria set for ``poorly mobilizable'' for transduction and
transformation should not prevent most microorganisms from meeting the
exemption criteria, since the majority of transfer frequencies reported
for transduction and natural transformation are less than 10-8.
Higher frequencies are likely only if the introduced genetic material
has been altered or selected to enhance frequency.
Fungal gene transfer has also been considered in development of the
poorly mobilizable criterion. Although mobile genetic elements such as
transposons, plasmids, and double stranded RNA exist in fungi and
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