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Proposed Policy; Plant-Pesticides Subject to the Federal Insecticide, Fungicide, and Rodenticide Act and the Federal Food, Drug, and Cosmetic Act
Note: EPA no longer updates this information, but it may be useful as a reference or resource.
[Federal Register: November 23, 1994]
ENVIRONMENTAL PROTECTION AGENCY
[OPP-300370; FRL-4755-2]
RIN 2070-AC02
Proposed Policy; Plant-Pesticides Subject to the Federal
Insecticide, Fungicide, and Rodenticide Act and the Federal Food, Drug,
and Cosmetic Act
AGENCY: Environmental Protection Agency (EPA).
ACTION: Statement of policy.
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SUMMARY: This notice describes how EPA proposes to address pesticidal
substances produced by plants under the Federal Insecticide, Fungicide,
and Rodenticide Act (FIFRA) and the Federal Food, Drug, and Cosmetic
Act (FFDCA). Substances that plants produce to protect themselves
against pests and disease are pesticides under the definition of FIFRA
section 2, (i.e., if they are ``. . .intended for preventing,
destroying, repelling, or mitigating any pest. . .'') regardless of
whether the pesticidal capabilities evolved in the plants or were
introduced by breeding or through the techniques of modern
biotechnology. These substances, along with the genetic material
necessary to produce them, are designated ``plant-pesticides.'' This
policy statement: (1) Clarifies the regulatory status under FIFRA and
FFDCA of plants and plant-pesticides; (2) stipulates that EPA's
regulatory attention will focus on plant-pesticides rather than on
plants per se; (3) describes the criteria EPA is proposing to use in
determining which plant-pesticides will be subject to regulation and
which will be exempt; and (4) describes EPA's proposed procedures and
information needs for the regulation of testing and commercial sale and
distribution of plant-pesticides.
DATES: Comments identified by the docket control number [OPP-300370]
must be received on or before January 23, 1995.
ADDRESSES: Submit written comments by mail to: Program Resources
Section, Public Response and Program Resources Branch, Field Operations
Division (7506C), Environmental Protection Agency, 401 M St., SW.,
Washington, DC 20460. In person, bring comments to Rm. 1132, Crystal
Mall #2, 1921 Jefferson Davis Highway, Arlington, VA 22202.
Information submitted as a comment concerning this document may be
claimed confidential by marking any part or all of that information as
``Confidential Business Information'' (CBI). Information so marked will
not be disclosed except in accordance with procedures set forth in 40
CFR part 2. A copy of the comment that does not contain CBI must be
submitted for inclusion in the public record. Information not marked
confidential may be disclosed publicly by EPA without prior notice. All
written comments will be available for public inspection in Rm. 1132 at
the Virginia address given above from 8 a.m. to 4 p.m., Monday through
Friday, excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: By mail: Bernice Slutsky, Science and
Policy Staff, Office of Prevention, Pesticides and Toxic Substances
(7101), Environmental Protection Agency, 401 M St., SW., Washington, DC
20460. Office location and telephone number: Rm. E-627, 401 M St., SW.,
Washington, DC, (202-260-6900).
SUPPLEMENTARY INFORMATION:
I. Introduction and History of the Policy
A. Introduction
EPA has received numerous inquiries concerning the regulation of
plants that have been modified to produce pesticidal substances,
particularly since modern biotechnology has provided the means of
introducing novel pesticidal substances into plants. These inquiries
have come from industry, public interest groups, and other government
agencies. The principal focus of these inquiries has been requests for
clarification of the regulatory status, under FIFRA (7 U.S.C. 136 et
seq.) and FFDCA (21 U.S.C. 321 et seq.), of plants and the pesticidal
substances that they produce. -
Most plant varieties have the ability to resist pests and disease.
The mechanisms of resistance can be varied, including structural
characteristics of the plant, the production of general metabolites
that have toxic properties, or the production of specific toxic
substances in response to pest attack. A plant can be completely immune
to a pest or can be partially resistant.
Plant varieties with a greater ability to withstand pests have
traditionally been bred from progenitor plants that have high levels of
resistance to the target pest. It is now also possible to introduce
into plants mechanisms of pest and disease resistance that are not
found in the plant kingdom. For example, plants can be modified to
express toxins from invertebrates and microorganisms. These toxins can
confer plant resistance to insect attack and disease. Such pesticidal
substances can be diverse and can potentially originate from any
taxonomic kingdom.
There are a number of types of substances produced in plants that
enable plants to resist pest attack and disease. These substances
include both those pesticidal substances that would be considered
normally a component of a plant and those that would be considered new
to a plant. Examples of plant-pesticides that would be considered
normally a component of a plant are phytoalexins (plant-produced
substances that act against phytopathogenic microorganisms). An example
of a plant-pesticide that would not be considered normally a component
of a plant is the insecticidal delta endotoxin that is produced in the
bacterium, Bacillus thuringiensis.
This policy statement clarifies the regulatory status, under FIFRA
and FFDCA, of plants that act as biological control agents (and thus
can be considered pesticides) and the plant-pesticides produced by
plants. In doing so, it clarifies that plants continue to be exempt,
and it defines the categories of plant-pesticides that would be
regulated by EPA under FIFRA and FFDCA. This document outlines EPA's
proposed procedures to assess plant-pesticides at different stages of
testing and at sale or distribution. It also describes the information
that EPA would need to evaluate those plant-pesticides that the Agency
is proposing would be subject to EPA regulation under FIFRA and FFDCA.
This policy statement is based upon the Agency's current knowledge
of new plant varieties under development in agricultural research,
particularly those developed through the new techniques of
biotechnology. Accordingly, while this policy statement would apply to
all plant-pesticides produced in plants (including bryophytes such as
mosses, seedless vascular plants such as ferns, gymnosperms such as
conifers, and angiosperms such as most major crop plants), it
concentrates primarily on proteinaceous plant-pesticides produced in
new varieties of terrestrial crops.
In developing its policy on plant-pesticides under FIFRA and FFDCA,
the Agency considered how the two statutes authorize EPA to regulate
pesticides and pesticide residues, the differences in statutory
criteria imposed by each statute, and how the statutes complement each
other. Under the approach articulated in this policy statement, the
Agency believes that most plant-pesticides would not require regulation
under FIFRA. However, the Agency believes some type of oversight is
appropriate for plant-pesticides that are new to the plant and have a
toxic mechanism of action (see Unit IV.B. of this document). Similarly
under FFDCA, the Agency believes that most plant-pesticides should be
exempt from the requirement of a tolerance. However, the Agency
believes that EPA review should take place for certain plant-pesticides
that are used in food/feed (see Unit IV.C. of this document).
This statement of policy is one of several documents published in
today's Federal Register that address EPA's regulation of plant-
pesticides. The other documents are: (1) a proposed regulatory
amendment that would describe categories of plant-pesticides that are
subject to or exempt from regulation under FIFRA and clarifies the
status of plants that produce plant-pesticides (``Plant-pesticides
Subject to the Federal Insecticide, Fungicide, and Rodenticide Act;
Proposed Policy''); (2) a proposed exemption from the requirement of a
tolerance under FFDCA for categories of plant-pesticides that do not
result in significantly different dietary exposures (``Plant-
pesticides; Proposed Exemption from the Requirement of a Tolerance
Under the Federal Food, Drug, and Cosmetic Act''); (3) a proposed
exemption from the requirement of a tolerance under FFDCA for viral
coat proteins (``Plant-pesticides; Proposed Exemption from the
Requirement of a Tolerance Under the Federal Food, Drug, and Cosmetic
Act for Viral Coat Proteins Produced in Plants''); and (4) a proposed
exemption from the requirement of a tolerance under FFDCA for nucleic
acids, including deoxyribonucleic and ribonucleic acids (``Plant-
pesticides; Proposed Exemption from the Requirement of a Tolerance
Under the Federal Food, Drug, and Cosmetic Act for Nucleic Acids
Produced in Plants'').
B. History
Since 1987, EPA has sponsored, or co-sponsored with other Federal
agencies, three conferences that discussed whether transgenic plants
(plant varieties developed through new biotechnology methodologies)
producing pesticidal substances pose potential risks and the nature of
those risks. In addition, EPA has requested advice on how best to
address plant-pesticides from two scientific advisory committees at
three meetings. On December 18, 1992, a Subpanel of the FIFRA
Scientific Advisory Panel (SAP) was convened to review a draft proposed
policy statement and to answer a series of scientific questions
concerned primarily with EPA's proposed approach for plant-pesticides
under FIFRA. On July 13, 1993, a Subcommittee of the EPA Biotechnology
Science Advisory Committee (BSAC) was convened to address a series of
scientific questions concerned primarily with EPA's proposed approach
for plant-pesticides under FFDCA. On January 21, 1994, a joint SAP/BSAC
Subpanel was convened to address a series of scientific questions
concerned with the scope of regulation under FIFRA and FFDCA and
guidance for data needs for the evaluation of plant-pesticides. For
more detailed discussion of the reports from the three advisory
committee meetings, refer to Unit VIII. of this document.
II. Summary of Proposed Policy Under FIFRA and FFDCA
A. Introduction
On June 2, 1982, EPA promulgated a final regulation under FIFRA
section 25(b) that exempted all biological control agents, except for
certain microorganisms, from the requirements of FIFRA (47 FR 23928;
see 40 CFR 152.20). EPA defines the term ``biological control agent''
as ``any living organism applied to or introduced into the environment
that is intended to function as a pesticide against another organism
declared to be a pest by the Administrator'' (40 CFR 152.3). The
exemption of biological control agents was promulgated because EPA
found that the risks posed by biological control agents other than
microorganisms were adequately addressed by other Federal agencies such
as the U.S. Department of Agriculture's (USDA) Animal and Plant Health
Inspection Service (APHIS) and the U.S. Department of the Interior.
Although plants used as biological control agents were not specifically
addressed in the June 2, 1982, Federal Register notice, they have been
excluded from regulation under FIFRA through this exemption. EPA
continues to believe that plants used as biological control agents are
adequately regulated by other Federal agencies. However, EPA believes
that the status of pesticidal substances produced in plants (i.e.,
plant-pesticides) requires regulatory clarification.
Although plants used as biological control agents were excluded
from FIFRA regulation under 40 CFR 152.20, substances that are
extracted from plants and used as pesticides are not similarly
excluded. For example, chrysanthemums produce pyrethrum, a substance
that has insecticidal activity. The chrysanthemum plants that produce
pyrethrum have been exempted from regulation when used as biological
control agents (i.e., living chrysanthemums), but pyrethrum itself, as
the pesticide substance, has not been exempted when extracted from
chrysanthemums and applied to other plants as an insecticide.
This distinction is reasonable in light of the potential for
increased and unique exposures due to large-scale application of
extracted pyrethrum to plants that do not naturally produce it. The use
of extracted pyrethrum as an insecticide can involve exposure to the
pesticide over large acreages, whereas the exposure associated with
pyrethrum in living chrysanthemum plants would not be expected to reach
such proportions. In addition, application of pyrethrum beyond the
environment in which it is normally produced (i.e., beyond the living
chrysanthemum plant) could result in new or unique exposures of
nontarget organisms, including humans.
Although it has been EPA's policy under FIFRA to regulate
pesticidal substances extracted from plants, EPA has not, thus far,
clearly stated its policies for regulation of pesticidal substances
that are produced in living plants but not extracted from the plants
(plant-pesticides). This policy statement, and the companion document
published elsewhere in today's issue of the Federal Register entitled
``Plant-pesticides Subject to the Federal Insecticide, Fungicide, and
Rodenticide Act; Proposed Rule,'' is designed to provide such
clarification for pesticidal substances that have evolved in plants,
for pesticidal substances introduced into plants by breeding, and for
pesticidal substances introduced into plants through biotechnology.
Similarly under FFDCA, EPA has regulated substances that are
extracted from plants and used as pesticides on food or feed. For
example, a tolerance has been set for pyrethrum that is extracted from
plants and applied to food or feed. However, the Agency has not clearly
explained how pesticidal substances produced in plants (plant-
pesticides) would be regulated under FFDCA. For example, if a food
plant could be modified, for pesticidal purposes, to produce pyrethrum,
EPA has not, thus far, explained how this pyrethrum would be regulated
under FFDCA.
It is the intent of this policy statement to give guidance as to
the types of plant-pesticides that would be evaluated by the Agency
under FFDCA. The considerations used to determine whether EPA review
would be required will be set forth in this policy statement and the
companion Federal Register documents (``Plant-pesticides; Proposed
Exemption from the Requirement of a Tolerance Under the Federal Food,
Drug, and Cosmetic Act''; ``Plant-pesticides; Proposed Exemption from
the Requirement of a Tolerance Under the Federal Food, Drug, and
Cosmetic Act for Viral Coat Proteins Produced in Plants''; ``Plant-
pesticides; Proposed Exemption from the Requirement of a Tolerance
Under the Federal Food, Drug, and Cosmetic Act for Nucleic Acids
Produced in Plants'').
B. Proposed Regulatory Scheme
In order to establish an effective regulatory scheme appropriate to
plant-pesticides, EPA proposes to take the following actions under
FIFRA and FFDCA. The Agency makes clear that the substances plants
produce to protect themselves against pests and disease are pesticides
under the FIFRA section 2 definition of ``pesticide,'' i.e., if they
are ``. . .intended for preventing, destroying, repelling or mitigating
any pest.'' Pesticidal substances that are produced in the living plant
along with the genetic material necessary for the production of those
substances are designated by EPA as plant-pesticides (Unit IV.B. of
this document). The definition of pesticide under FIFRA section 2 also
includes ``plant regulators.'' The Agency provides criteria for
determining when a substance produced in a living plant but not
extracted from the plant is a plant regulator (Unit IV.D. of this
document), and the rationales EPA employed in developing these
criteria.
EPA indicates that it proposes to focus its regulatory attention on
the plant-pesticide and not on the plant per se. The Agency defines the
categories of plant-pesticides that it proposes to regulate under FIFRA
and FFDCA. In general, the Agency would regulate, under FIFRA, those
plant-pesticides that have the greatest potential for new environmental
exposures and adverse effects to nontarget organisms. To do this, EPA
proposes to exempt from FIFRA requirements, certain classes of plant-
pesticides based upon the source from which the plant-pesticide is
derived and the mechanism of action of the pesticidal substance. Also
contained in the proposed FIFRA exemption are coat proteins from plant
viruses. Plant-pesticides that do not fall within these exemptions
would be subject to FIFRA regulation. In a proposal published elsewhere
in todays issue of the Federal Register a new part in 40 CFR, part 174,
would establish the scope of regulation for plant-pesticides under
FIFRA (``Plant-pesticides Subject to the Federal Insecticide,
Fungicide, and Rodenticide Act; Proposed Rule'').
Under FFDCA, the Agency would regulate those plant-pesticides that
have the greatest potential for new dietary exposures. To establish the
FFDCA scope of coverage, EPA proposes three exemptions from the
requirements of a tolerance for three categories of plant-pesticides:
(1) Certain plant-pesticides commonly found in food; (2) coat proteins
from plant viruses; and (3) nucleic acids (see documents published
elsewhere in todays issue of the Federal Register entitled, ``Plant-
pesticides; Proposed Exemption from the Requirement of a Tolerance
Under the Federal Food, Drug, and Cosmetic Act''; ``Plant-pesticides;
Proposed Exemption from the Requirement of a Tolerance Under the
Federal Food, Drug, and Cosmetic Act for Viral Coat Proteins Produced
in Plants''; and ``Plant-pesticides; Proposed Exemption from the
Requirement of a Tolerance Under the Federal Food, Drug, and Cosmetic
Act for Nucleic Acids Produced in Plants''). Plant-pesticides that do
not fall within these exemptions would be subject to the FFDCA
tolerance requirements.
Recognizing the unique characteristics of plant-pesticides, the
Agency is proposing to establish a new part 174, in 40 CFR under FIFRA
for plant-pesticides (``Plant-pesticides Subject to the Federal
Insecticide, Fungicide, and Rodenticide Act; Proposed Rule''). In the
future EPA will propose, under part 174, procedural requirements for
plant pesticides.
In this proposed policy statement, EPA provides information on how
manufacturers, importers, and distributors of plant-pesticides subject
to FIFRA and FFDCA requirements should interact with the Agency. This
guidance contains (1) Information on when and how manufacturers should
first consult with the Agency; (2) a set of ``points to consider'' to
assist manufacturers in developing data for review; (3) descriptions of
proposed Agency procedures for Experimental Use Permits (EUPs) and
registration; and (4) descriptions of EPA's interaction with other
agencies.
III. Statutory and Regulatory Background
This policy was developed under the authority of FIFRA, as amended
(7 U.S.C. 136 et seq.) and FFDCA (21 U.S.C. 321 et seq.). Under FIFRA,
a pesticide may not be sold or distributed in the United States unless
it is registered, or has been exempted from regulation. Under FFDCA,
EPA has the authority to set tolerances or establish an exemption from
the requirement of a tolerance for pesticide residues in or on raw
agricultural commodities and to establish food additive regulations for
pesticide residues in or on processed foods.
A. FIFRA
FIFRA section 2(u) defines ``pesticide'' as: ``(1) any substance or
mixture of substances intended for preventing, destroying, repelling,
or mitigating any pest, and (2) any substance or mixture of substances
intended for use as a plant regulator, defoliator, or desiccant. . .
.''
FIFRA section 3 provides that no person may distribute or sell in
the United States any pesticide that is not registered under the Act.
Before a product may be registered as a pesticide under FIFRA, it must
be shown that when used in accordance with widespread and commonly
recognized practice, it will not generally cause ``unreasonable adverse
effects on the environment.'' FIFRA section 2(bb) defines the term
``unreasonable adverse effects on the environment'' as any unreasonable
risk to ``man or the environment, taking into account the economic,
social, and environmental costs and benefits of the use of any
pesticide.'' Thus, FIFRA involves a balancing of the risks presented by
the use of the pesticide against the benefits associated with the use
of that pesticide.
In addition to the requirement for a registration, FIFRA authorizes
EPA to issue EUPs under section 5 and to otherwise regulate the use of
unregistered pesticides under FIFRA section 3(a). Section 5 of FIFRA
and 40 CFR part 172 provide for issuance by the Agency of Experimental
Use Permits (EUP's) for the testing of new, unregistered pesticides or
registered pesticides being tested for new uses in which the purpose is
only to determine its value for pesticide purposes or to determine its
toxicity or other properties. Such permits are generally issued for
large-scale testing of pesticides on more than 10 cumulative acres of
land or 1 surface acre of water. Contained within the scope of the
regulation, however, is the presumption that small-scale testing, i.e.,
on not more than 10 cumulative acres of land or 1 surface acre of
water, does not require an EUP provided that the crops are destroyed or
an appropriate tolerance is in place (40 CFR 172.3(a)). This
presumption, however, is caveated not to preclude experimental testing
on larger areas in certain circumstances where the purpose of the large
acreage test is only to determine the substance's value for pesticidal
purposes or to determine its toxicity or other properties, and no
benefit from pest control is expected (40 CFR 172.3(b)). In the Federal
Register of January 22, 1993 (58 FR 5878), EPA issued a proposed
amendment to 40 CFR part 172. The proposed amendment would, among other
things, modify section 172.3 to clarify that the determination of
whether an EUP is required is based on risk/benefit considerations. The
amendment would provide that tests conducted on not more than 10 acres
of land and 1 surface acre of water are presumed not to involve
unreasonable risks, and therefore, do not require an EUP.
FIFRA also authorizes EPA to require data to be submitted to
evaluate whether an EUP or registration will be granted. Moreover,
under FIFRA, EPA can impose labeling restrictions and FIFRA requires
that the pesticide be used in accordance with such labeling
restrictions. Under FIFRA section 25(b), EPA may exempt, by regulation,
any pesticide determined to be: (1) Adequately regulated by another
Federal agency, or (2) of a character which is unnecessary to be
subject to the Act in order to carry out the purposes of the Act.
B. FFDCA
The Reorganization Plan of 1970 that created EPA reallocated the
authority under FFDCA to regulate pesticide residues in foods and
animal feeds to EPA. Pursuant to section 402 of FFDCA, foods that are
raw agricultural commodities are deemed to be adulterated if they
contain a pesticide chemical which is unsafe within the meaning of
section 408(c) of FFDCA. Under FFDCA section 408, any poisonous or
deleterious pesticide chemical added to a raw agricultural commodity,
that is not ``generally recognized as safe'' (GRAS), is deemed to be
unsafe unless a tolerance, or an exemption from the requirement of a
tolerance, for such pesticide chemical is established and the pesticide
chemical residue is within the tolerance limits. Section 408 of FFDCA
applies to all ``pesticide chemicals'' which are defined in section
201(q) of FFDCA as:
any substance which, alone, in chemical combination or in
formulation with one or more other substance, is ``a pesticide''
within the meaning of [FIFRA] . . .and which is used in the
production, storage, or transportation of raw agricultural
commodities.
Thus, pesticide chemicals subject to regulation under FFDCA are defined
by reference to the definition of pesticide under FIFRA.
Section 408 of FFDCA authorizes EPA to set tolerances for pesticide
chemical residues on raw agricultural commodities to the extent
necessary to protect the public health. In establishing a tolerance,
EPA must give appropriate consideration to the following factors: (1)
The necessity for the production of an adequate, wholesome, and
economical food supply; (2) the other ways in which the consumer may be
affected by the same pesticide chemical or by other related substances
that are poisonous or deleterious; and (3) the opinion submitted with a
certification of usefulness under the Act (FFDCA section 408(b)). Thus,
as with FIFRA, the regulatory decisions EPA makes under FFDCA section
408 involve a risk/benefit balance. Unlike FIFRA, however, FFDCA only
addresses dietary risks to humans and other animals.
Under FFDCA section 408(c), EPA can exempt, by regulation, any
pesticide chemical from the necessity of a tolerance when such
tolerance is not necessary to protect the public health. In the absence
of such an exemption, any pesticide chemical used on raw agricultural
commodities is deemed unsafe unless EPA establishes a tolerance for the
pesticide chemical residue, and the pesticide chemical residue is
within the tolerance limits, or the pesticide chemical is GRAS.
Under FFDCA section 402, food is deemed to be adulterated if it
contains any food additive not authorized by a food additive regulation
under section 409. Because of the ``flowthrough'' provision in section
402(a)(2), EPA has interpreted section 409 as applying to pesticide
residues in processed food which result from use of the pesticide in or
on raw food if the concentration of the pesticide in the processed food
is greater than the level set under section 408 for the raw food
tolerance. If EPA grants an exemption from the requirement of a
tolerance under section 408 for the raw food, residues in the resulting
processed food are also exempt even if they are higher than in the raw
food. Section 409 also applies to pesticide residues in processed food
resulting from direct application of the pesticide to processed food.
However, since the plant-pesticides that EPA is addressing would all be
present in the plant which would be a raw agricultural commodity, this
aspect of section 409 would not come into play. In issuing a food
additive regulation under section 409, EPA must determine that the
proposed use of the food additive, under the conditions of use
specified in the regulation, will be safe. In EPA's view, the
determination of whether use of a pesticidal food additive is safe
should take into account the net effects of use of the additive on the
food supply. These net effects include the benefit of an adequate,
wholesome, and economical food supply that may result from a
pesticide's use as well as any harm to the food supply that may result
from the pesticide's use.
A section 409 food additive regulation is not required for any
substance that is GRAS. A GRAS finding must be based either on a record
of safe use in food prior to 1958 (when Congress modified FFDCA) or
evidence of safety and widespread agreement in the appropriate
scientific community (FFDCA section 201(s)).
IV. Rationale and Regulatory Status of Plant-pesticides
A. Introduction
As are all pesticides, all plant-pesticides are potentially subject
to EPA's regulatory authority under FIFRA. Since FFDCA defines
pesticides in terms of the definition in FIFRA section 2, EPA also has
the authority to regulate residues of plant-pesticides under FFDCA
sections 408 and 409 (Unit III.). Both FIFRA and FFDCA give EPA the
authority to exempt pesticides from regulation through notice and
comment rulemaking.
EPA has attempted to identify, for regulatory oversight, those
types of plant-pesticides that appear to have greater potential for
environmental and/or human health risks. Through FIFRA section 25(b),
EPA proposes to exempt certain categories of plant-pesticides that do
not warrant oversight. Those plant-pesticides, or categories of plant-
pesticides, not exempted would form the scope of EPA's regulatory
scrutiny under FIFRA.
FIFRA section 25(b) allows the Agency to exempt a pesticide if it
is of a character unnecessary to be subject to the Act in order to
carry out the purposes of the Act. For plant-pesticides, the Agency
proposes to amend 40 CFR part 152 and to create a new part 174 that
would exempt, from regulation under FIFRA, certain categories of plant-
pesticides that pose low probability of risk and will not cause
unreasonable adverse effects on the environment (See the proposal
published elsewhere in todays issue of the Federal Register entitled
``Plant-pesticides Subject to the Federal Insecticide, Fungicide, and
Rodenticide Act; Proposed Rule'').
Under FFDCA section 408(c), EPA can establish an exemption from the
requirement of a tolerance for a pesticide chemical if the Agency
determines that a tolerance is not necessary to protect the public
health. The Agency is proposing to exempt, on that basis, certain
categories of plant-pesticides from the requirement from a tolerance
(described in documents published elsewhere in todays issue of the
Federal Register entitled, ``Plant-pesticides; Proposed Exemption from
the Requirement of a Tolerance Under the Federal Food, Drug, and
Cosmetic Act''; ``Plant-pesticides; Proposed Exemption from the
Requirement of a Tolerance Under the Federal Food, Drug, and Cosmetic
Act for Viral Coat Proteins Produced in Plants''; ``Plant-pesticides;
Proposed Exemption from the Requirement of a Tolerance Under the
Federal Food, Drug, and Cosmetic Act for Nucleic Acids Produced in
Plants''). Those plant-pesticides not exempt would be subject to EPA
review under the FFDCA authorities.
The following unit of this statement describes the environmental
and human health considerations that the Agency weighed in determining
which plant-pesticides to propose for exemption from regulation under
FIFRA and FFDCA. Those plant-pesticides that would not be exempt would
be subject to regulation.
B. FIFRA
1. Summary of proposed regulatory status for plant-pesticides. The
following unit summarizes the proposed regulatory status of plant-
pesticides under FIFRA. Because of the unique nature of plant-
pesticides, the Agency is proposing regulatory definitions that would
apply to plant-pesticides only. In addition, the Agency is proposing to
exempt certain classes of plant-pesticides from regulation under FIFRA
because the Agency believes that they pose low probability of risk and
will not cause unreasonable adverse affects (see the proposal published
elsewhere in todays issue of the Federal Register entitled, ``Plant-
pesticides Subject to the Federal Insecticide, Fungicide, and
Rodenticide Act; Proposed Rule'').
a. Definition of plant-pesticide. EPA is proposing to define
``plant-pesticide'' under FIFRA as:
A pesticidal substance that is produced in a living plant and
the genetic material necessary for the production of the substance,
where the substance is intended for use in the living plant.
EPA is including the genetic material necessary to produce the
substance in the proposed definition of plant-pesticide for a number of
reasons. First, it is the genetic material that is introduced into the
plant with the intent that it will ultimately result in a pesticidal
effect. Additionally, EPA's regulation of pesticides is based on an
evaluation of the potential for unreasonable adverse effects to humans
and the environment associated with the use of the pesticidal
substance, in this case, the pesticidal substance produced in the
plant. Regulation also includes risk management considerations. A focus
on the genetic material would permit the Agency to address the
potential for the spread of the pesticidal substance in the environment
through the spread of the genetic material necessary for the production
of the substance. Moreover, the amount of pesticidal substance likely
to be produced by the plant is also an important consideration that the
Agency may, in some circumstances, be able to address through the
inclusion of genetic material in the definition of plant-pesticide. In
addition, including the genetic material in the definition of plant-
pesticide would permit the Agency to address plant-pesticides during
stages of the plant's life cycle or in plant parts where the pesticidal
substance itself is not produced or is produced in very small amounts
(e.g., in pollen or seed). In these cases, it is technically easier to
verify the presence of the genetic material than the pesticidal
substance.
b. Active and inert ingredients. The regulation of pesticides under
FIFRA entails the identification of ``active ingredients'' and ``inert
ingredients.'' Under FIFRA section 2, the term active ingredient means
``. . .an ingredient which will prevent, destroy, repel, or mitigate
any pest. . . [or acts as a plant regulator, defoliant or desiccant].''
The term inert ingredient means ``. . .an ingredient which is not
active.'' EPA recognizes that plant-pesticides have certain
characteristics that are different from those of more traditional
chemical pesticides. EPA believes that the overall characteristics of
plant-pesticides require specifically tailored active and inert
ingredient definitions.
In light of this consideration, EPA proposes to use the following
definitions for active and inert ingredients for plant-pesticides.
``Active ingredient,'' when referring to plant-pesticides only,
means a pesticidal substance that is produced in a living plant and the
genetic material necessary for the production of the substance, where
the substance is intended for use in the living plant.
``Inert ingredient,'' when referring to plant-pesticides only,
means any substance, such as a selectable marker, other than the active
ingredient, and the genetic material necessary for the production of
the substance, that is intentionally introduced into a living plant
along with the active ingredient, where the substance is used to
confirm or ensure the presence of the active ingredient.
Note that the plant-pesticide active ingredient is the plant-
pesticide and therefore the proposed definition of active ingredient
for plant-pesticides is the same as the definition of plant-pesticide.
The plant-pesticide product includes both the active and inert
ingredients.
The definition of plant-pesticide and the active and inert
ingredient definitions would include all of the genetic material
``necessary for the production'' of the pesticidal and inert substance.
The following genetic regions are considered ``necessary for the
production'' of the plant-pesticide, active and inert substances: (1)
The genetic material that encodes for a pesticidal substance or leads
to the production of a pesticidal substance and (2) regulatory regions
such as promoters, enhancers, and terminators.
The genetic material can either directly encode for the pesticidal
substance or may encode for enzymes that lead to the production of a
pesticidal substance (e.g., phenylalanine ammonia-lyase (PAL) catalyzes
the first reaction in the synthesis of such phytoalexins as
pterocarpans in Leguminosae and furanocoumarins in Solanaceae and
Umbelliferae; Ref. 6). It might also include genetic regions encoding
for RNA that acts as the pesticidal substance or leads to the
production of the pesticidal substance (e.g., antisense mRNA). The
active and inert ingredients would also include any regulatory regions,
such as promoters, that control the expression of the genetic material
encoding for the pesticidal or inert substance or leading to the
production of the pesticidal or inert substance and are introduced into
the plant along with that gene.
The genetic material ``necessary for the production'' of the plant-
pesticide, active and inert substances does not include genetic regions
that are not involved in DNA expression (i.e., noncoding, nonexpressed
sequences such as linkers, adapters, homopolymers and sequences of
restriction enzyme recognition sites). However, the Agency would
require information concerning these sequences if it determines that
such information is necessary for the evaluation of the active or inert
ingredient.
There may be genetic material encoding other functions (e.g.,
genetic material intended to alter the amount of carbohydrate in the
plant) that are introduced into the plant along with the active and
inert ingredients. These functions would be subject to Food and Drug
Administration (FDA) authorities.
c. Exemptions under FIFRA. EPA has attempted to identify those
types of plant-pesticides that have greater potential for environmental
and/or human health risks and to focus its regulatory scrutiny on these
plant-pesticides. To exempt from regulation those plant-pesticides
having less potential for risk, EPA is proposing to employ its
exemption authority under FIFRA section 25(b). FIFRA section 25(b)(2)
allows the Agency to exempt a pesticide from FIFRA regulation if it is
of a character unnecessary to be subject to the Act in order to carry
out the purposes of the Act. Through FIFRA section 25(b)(2), EPA
proposes to exempt, from FIFRA regulation, certain categories of plant-
pesticides that EPA believes pose low probability of risk and are not
likely to cause unreasonable adverse effects even in the absence of any
regulatory oversight under FIFRA and, thus, are of a character
unnecessary to be subject to the Act. Those plant-pesticides not
exempted would form the scope of EPA's regulatory scrutiny under FIFRA.
EPA finds that the plant-pesticides it is proposing to exempt have
a low probability of risk and have potential benefits associated with
them (e.g., economic benefit to farmers and reducing the need for
chemical pesticides) that outweigh any potential risks associated with
them, and that the low probability of risk does not justify the cost of
regulation. For a detailed description and analysis of the proposed
exemptions under FIFRA, see the proposal published elsewhere in todays
issue of the Federal Register entitled ``Plant-pesticides Subject to
the Federal Insecticide Fungicide and Rodenticide Act; Proposed Rule.''
(i) Exemption of plant-pesticides derived from closely related
plants. The Agency is proposing to concentrate its regulatory efforts
under FIFRA on those plant-pesticides that are new to the plant and,
thus, have the greatest potential for exposing nontarget organisms to a
new pesticidal substance. The Agency is proposing to exempt from FIFRA
regulation those plant-pesticides that are normally a component of (not
new to) the plant. The approach EPA is proposing to use to capture the
concept of ``normally a component'' is based on the concept of sexual
compatibility. The standard of sexual compatibility is embodied in the
following language from the proposed regulatory text:
[Plant-pesticides are exempt from FIFRA requirements if:]
. . .The genetic material that encodes for a pesticidal
substance or leads to the production of a pesticidal substance is
derived from plants that are sexually compatible with the recipient
plant and has never been derived from a source that is not sexually
compatible with the recipient plant;. . .
Key definitions associated with this language are:
``Bridging crosses'' between plants means the utilization of an
intermediate plant in a cross to produce a viable zygote between the
intermediate plant and a first plant, in order to cross the plant
resulting from that zygote with a third plant that would not otherwise
be able to produce viable zygotes from the fusion of its gametes with
those of the first plant. The result of the bridging cross is the
mixing of genetic material of the first and third plant through the
formation of an intermediate zygote.
``Genetic material that encodes for a pesticidal substance or leads
to the production of a pesticidal substance'' does not include
regulatory regions or noncoding, nonexpressed nucleotide sequences.
``Regulatory region'' means genetic material that controls the
expression of the genetic material that encodes for a pesticidal
substance or leads to the production of a pesticidal substance.
Examples of regulatory regions include promoters, enhancers, and
terminators.
``Sexually compatible,'' when referring to plants, means capable of
forming a viable zygote through the fusion of two gametes, including
the use of bridging crosses or wide crosses between plants.
``Source'' means the donor of the genetic material that encodes for
a pesticidal substance or leads to the production of a pesticidal
substance.
``Wide crosses'' between plants means to facilitate the formation
of viable zygotes through the use of surgical alteration of the plant
pistil, bud pollination, mentor pollen, immunosuppressants, in vitro
fertilization, pre- and post- pollination hormone treatments,
manipulation of chromosome numbers, embryo culture, or ovary and ovule
cultures or any other technique that the Administrator determines meets
this definition.
EPA is also proposing for discussion two alternative options for
describing this category of plant-pesticides in plants (see Unit
IV.B.2. of this document and the proposal published elsewhere in
today's issue of the Federal Register entitled ``Plant-pesticides
Subject to the Federal Insecticide, Fungicide, and Rodenticide Act;
Proposed Rule'').
(ii) Exemption of plant-pesticides that act primarily by affecting
the plant. One of EPA's primary goals in regulating pesticides is to
control the potential for adverse effects of pesticides on nontarget
organisms. An important component in the evaluation of this potential
is the way in which the pesticidal substance acts on the target pest
since it would also likely affect nontarget organisms through the same
mechanism. Based on this rationale, the Agency is proposing to exempt
from FIFRA regulation plant-pesticides that are not directly toxic to
the target pest. This proposed exemption is embodied in the following
language from the proposed regulatory text:
[Plant-pesticides are exempt from FIFRA requirements if:]
. . .The pesticidal substance acts primarily by affecting the
plant so that the target pest is inhibited from attaching to the
plant, penetrating the plant, or invading the plant's tissue in at
least one of the following ways:
(1) The pesticidal substance acts as a structural barrier to
attachment of the pest to a host plant, a structural barrier to
penetration of the pest into a host plant, or a structural barrier
to spread of the pest in a host plant, for example, through the
production of wax or lignin, or length of trichomes (plant hairs);
or
(2) The pesticidal substance acts in the host plant to
inactivate or resist toxins or other disease-causing substances
produced by the target pest; or
(3) The pesticidal substance acts by creating a deficiency of a
plant nutrient or chemical component essential for pest growth on/in
the host plant.
(iii) Exemption of coat proteins from plant viruses. Coat proteins
are those substances that viruses produce to encapsulate and protect
their genetic material. When the genetic material encoding the coat
protein from a plant virus is introduced into a plant's genome, the
plant is able to resist infections by the virus (termed viral coat
protein mediated resistance or vcp-mediated resistance). The Agency
proposes to exempt the genetic material encoding the coat protein and
the coat protein itself when these are introduced into a plant to
effectuate vcp-mediated resistance. This proposed exemption is embodied
in the following regulatory text:
[Plant-pesticides are exempt from FIFRA requirements if:] . . .The
pesticidal substance is a coat protein from a plant virus. . .
EPA is also proposing for discussion an alternative, more
restrictive exemption for coat proteins from plant viruses used in
viral coat protein mediated resistance (see Unit IV.B.2. of this
document and the proposal published elsewhere in todays issue of the
Federal Register entitled ``Plant-pesticides Subject to the Federal
Insecticide, Fungicide, and Rodenticide Act; Proposed Rule'').
2. Rationale for Proposed Exemptions under FIFRA. As with
traditional pesticides, the underlying considerations in analyzing
risks posed by plant-pesticides are the potential for exposure to the
pesticidal substance and hazards of the pesticidal substance to humans
and other nontarget organisms. For plant pesticides, exposure and
hazard will be determined by the chemical and toxicological properties
of the pesticidal substance and the biological characteristics of the
plant that is producing the substance.
The properties of the plant-pesticide, including the mechanism by
which it affects the target pest, will determine the potential for
hazards to nontarget organisms. The type of organism exposed to the
plant-pesticide will be determined by the characteristic of the plants
that produce the substance and the environment where the plants are
grown; e.g., whether the production of the substance is limited to
particular plant parts, the organisms that normally associate with the
plant, and the acreage and location planted. An important consideration
not seen with traditional pesticides is the potential for spread of the
plant's genetic material. Because plants can reproduce sexually and/or
asexually, unintentional exposure to the plant-pesticide could occur in
both the agro- or natural ecosystems, particularly if wild relatives
acquire the ability to produce the plant-pesticide through successful
hybridization.
Such hazard and exposure considerations form the bases of the three
exemptions that the Agency is proposing for plant-pesticides under
FIFRA (see the proposal published elsewhere in todays issue of the
Federal Register entitled ``Plant-pesticides Subject to the Federal
Insecticide, Fungicide, and Rodenticide Act; Proposed Rule'' for more
detailed analyses of these exemptions).
The benefits associated with use of some categories of plant-
pesticides include the economic benefit to farmers for use of plant-
pesticides in circumstances where traditional pesticides may not be as
effective (e.g., for some systemic plant pests) or may be more
expensive, thus increasing crop yield and/or reducing farmers' costs.
An additional benefit is the environmental benefit associated with
potential reduced use of pesticides that may be less environmentally
benign than these plant-pesticides.
a. Exemption of plant-pesticides derived from closely related
plants. A primary consideration in evaluating plant-pesticides is the
potential for new exposures of nontarget organisms to the pesticide. If
a plant normally produces a pesticidal substance, organisms that
normally come in contact with the plant have likely been exposed to
that substance in the past, perhaps over long periods of time. No new
exposures would be expected to occur.
In contrast, if a plant-pesticide is new to a plant, the organisms
that come in contact with the plant may never have been exposed to the
substance. For instance, certain spiders produce a toxin that is
targeted for their insect prey. Plants are not known to produce this
toxin in nature nor in cultivation. If this toxin were to enter the
gene pool of specific plants, organisms that had never previously been
exposed to the toxin could now be exposed. Prior to the introduction of
the toxin into these plants, only the insect prey of the spider would
potentially be exposed to the toxin. If plants could now express the
toxin, a different or larger group of organisms could be exposed to it,
possibly resulting in adverse effects to these organisms. For instance,
insects or animals that feed on the plant could be exposed to the
toxin. If the toxin is found in pollen, pollinators could also be
exposed.
EPA proposes to concentrate its regulatory efforts under FIFRA on
those plant-pesticides that are new to the plant and thus have the
greatest potential for exposing nontarget organisms to a new pesticidal
substance. The Agency would consider plant-pesticides produced in
sexually compatible plants to be least likely to result in these new
exposures (see the proposal published elsewhere in todays issue of the
Federal Register entitled ``Plant-pesticides Subject to the Federal
Insecticide, Fungicide, and Rodenticide Act; Proposed Rule''). Sexually
compatible plants are more apt to share common traits than are
unrelated plants. It is a common expectation that similarity is
associated with the degree of relatedness. Natural hybridization and
selection have produced groups of plants which have a common gene pool.
Generations of artificial hybridization practiced to produce improved
crops for cultivation have tended to increase the extent of relatedness
among elements of a broader segment of agricultural plants. Since
traits can be passed through a plant population by sexual
recombination, it is reasonable to predict that, in a sexually
compatible population, new exposures of organisms that associate with
plants in the population to the pesticidal substance is unlikely.
The practice of saving seed from desirable plants has been going on
for thousands of years and controlled crosses to produce plant hybrids
have been documented since the eighteenth century. Since the
rediscovery of Mendel's work on the inheritance of traits, there is a
base of experience of 50 to 100 years of breeding for most major crops.
During that time, it has been common agricultural practice to cross
sexually compatible wild relatives with crop plants to develop crop
varieties with better pest resistance. Techniques such as genetic
mapping reveal the presence of genetic loci in cultivated plants that
previously were considered to be present only in the wild species.
Sexually compatible crop varieties are also crossed with each other to
achieve better pest resistance in their progeny. Because of these
common practices, the potential for significantly different
environmental exposures is likely to be low.
EPA proposes to extend the concept of sexual compatibility to
include wide crosses because wide crosses are commonly used to expand
the gene pool for varietal improvement. EPA believes that the fact that
a wide cross produces a viable zygote indicates a fairly high degree of
relatedness between the parental plants. However, for regulatory
purposes it is somewhat difficult to define what constitutes a wide
cross in a definitive way since techniques may change over time. EPA is
thus proposing to define, for the purposes of this rulemaking, wide
crosses based on existing techniques with the provision that new
techniques can be added if they meet the definition.
A second approach that EPA is considering for defining when a
plant-pesticide is new to the plant is a standard based on taxonomy.
Under this approach, the standard would rely on the taxonomic grouping
of genus; plant-pesticides moved between plants in the same genus would
be exempt. The assumption under this approach is that the genus
grouping correlates with a relatively high degree of relatedness among
plants even though not all plants in a genus are sexually compatible.
A third approach EPA is considering combines the above two
standards of taxonomy and sexual compatibility. The standard under this
option would rely primarily on the taxonomic grouping of genus as a
measure of relatedness. Recognizing that some plants that are sexually
compatible are classified in different genera and assuming that sexual
compatibility is correlated with a high degree of relatedness, EPA also
includes a provision extending the exemption to include plant-
pesticides moved between sexually compatible plants even if the plants
are classified in different taxonomic genera.
For all of the approaches presented in this unit, the Agency has
evaluated whether changes in the levels of plant-pesticides that plants
normally produce would warrant regulation under FIFRA. (Ref. 1 and
Federal Register document entitled ``Plant-pesticides Subject to the
Federal Insecticide Fungicide and Rodenticide Act; Proposed Rule'' for
a more thorough analysis of this issue.) The Agency's analysis
indicates that changes in the levels of such plant-pesticides expressed
by a plant could result in increased or decreased exposures of
nontarget organisms to a plant-pesticide. However, EPA believes, for
the reasons outlined below, that the potential for unreasonable adverse
effects from these exposures is low and these types of plant-pesticides
do not warrant regulation under FIFRA.
In deciding whether and how to regulate such plant-pesticides, EPA
first considered whether an increase in the levels of such plant-
pesticides is likely to exceed the ranges normally found within and
between plant varieties (both cultivated and uncultivated). EPA
believes that increases in the levels of such plant-pesticides are not
likely to result in overall significantly different exposures of
nontarget organisms to the pesticide. The level of production of
pesticidal substances normally produced by plants varies among related
plants because of differences in genetic makeup and environmental
conditions. EPA also considered the extent to which any substance can
be increased in cultivated plants without unwanted effects on other,
desirable characteristics of the plant (e.g., yield or palatability of
fruit). In general, breeders balance all of these characteristics in
developing marketable plant varieties. Considerations of
characteristics such as yield could serve to mitigate against exceeding
certain ranges of pesticide levels. EPA anticipates that the majority
of plants with modified levels of plant-pesticides will fall within
existing ranges of pesticide levels and does not anticipate that
increasing the level of a plant-pesticide that is normally a component
of a plant would lead to significantly different spectrum of exposure
to the plant-pesticide.
b. Exemption of plant-pesticides that act primarily by affecting
the plant. As discussed previously, an important component in
evaluating the potential for adverse affects on nontarget organisms is
the way in which the pesticidal substance acts on the target pest. A
pesticidal substance that acts directly on the target pest through a
toxic mechanism of action might also exert a similar effect on other
organisms. For example, a substance that acts by inhibiting DNA
synthesis of the pest could inhibit DNA synthesis in other nontarget
organisms.Toxic mechanisms of action include, but are not limited to,
those that affect: (i) membrane permeability, (ii) cell division, (iii)
gene expression, (iv) DNA replication, or (v) other metabolic functions
(Ref. 4).
Pesticidal substances can also act through mechanisms that are less
likely to be directly toxic. Although it is possible for these
substances to adversely affect nontarget organisms, the Agency believes
that, in most cases, they pose significantly lower levels of
environmental risk than plant-pesticides with a generalized toxic
mechanism of action. For example, if a plant is modified so that it can
counter specific disease-producing compounds by inactivating them, it
is less likely that organisms that interact with the plant in other,
more beneficial ways will be affected. Similarly, a plant may produce
defense structures such as layers of cork cells in response to
microbial infections. These structures form a barrier to further
penetration by the pests and may block the spread of any toxins. Those
organisms that do not stimulate this response are not likely to be
adversely affected.
Plant-pesticides that are less directly toxic generally act
primarily by affecting the plant so that the pest is inhibited from
attaching to the plant, penetrating the plant's surface, or invading
the plant's tissue. The Agency believes that it would be appropriate to
exempt from regulation, under FIFRA, plant-pesticides that act through
mechanisms such as these. (See the proposal published elsewhere in
todays issue of the Federal Register entitled ``Plant-pesticides
Subject to the Federal Insecticide, Fungicide, and Rodenticide Act;
Proposed Rule'' for a more detailed discussion of this exemption.) EPA
believes that by focusing its regulatory attention on plant-pesticides
that act through toxic mechanisms, it will be able to focus on those
plant-pesticides presenting higher levels of risk potential.
c. Exemption of coat proteins from plant viruses. The Agency is
proposing to exempt the genetic material encoding the viral coat
protein and the coat protein itself when these are introduced into a
plant to effectuate viral coat protein mediated resistance. A more
detailed discussion of the Agency's assessment of the risks and
benefits of viral coat proteins can be found in the Federal Register
document entitled, ``Plant-pesticides Subject to the Federal
Insecticide, Fungicide, and Rodenticide Act; Proposed Rule.'' Major
points of the analysis are summarized here.
The Agency's proposal is made in light of a number of
considerations which, when taken together, bring EPA to the conclusion
that coat proteins from plant viruses generally pose a low probability
of risk and would not pose unreasonable adverse effects even in the
absence of any regulation under FIFRA. These considerations include the
low potential for adverse affects to nontarget organisms and the
potential benefits of utilizing vcp-mediated resistance.
Environmental benefits associated with the use of viral coat
proteins include the reduction of the use of chemical pesticides for
viruses that are spread by vectors (usually insects). Chemical
pesticides are used for those crop plants where the most effective
method of protection against viral attack is by controlling the vector.
These pesticides may not be environmentally benign. The expression of
viral coat proteins by plants for protection from viral infection would
likely reduce the amount of chemical pesticide used to control the
vectors.
In addition to environmental benefits associated with the use of
viral coat proteins, an effective method for controlling virus
infection will have economic benefits. Plant viruses create economic
losses for a vast variety of crops by reducing yields and negatively
affecting the quality of the crop. Yield losses and quality effects for
a specific crop may vary depending on the host plant and strains of the
virus present, the incidence and activity of vectors, timing of the
infection, health and nutritional state of the plant, and weather (Ref.
8).
Presently, growers may need to use several control methods during a
crop season in an attempt to prevent viral infection and dissemination,
primarily by planting virus free material (for mechanically transmitted
viruses) and by controlling plant virus vectors, such as insect
populations (for vector transmitted viruses). Insecticides,
nematicides, and fungicides are all used for vector control with
varying success, depending upon the virus/vector relationship and
vector efficiency. Plants developed through conventional breeding
techniques offer some degree of virus resistance. Such resistance may
not be uniform or the virus may develop new strains. However, breeding
for resistance has not been successful for the majority of field crops
and, in particular, vegetable crops that are severely affected by
viruses (Ref. 8).
In enabling plants to resist viral attack, viral coat proteins act
in a very specific fashion, apparently adversely affecting only viruses
by blocking or limiting their ability to infect, replicate, and/or
translocate within the plant. This specificity minimizes the potential
for viral coat proteins produced in plants to adversely affect nonviral
organisms. In addition, plants in nature and in the agro-ecosystem
frequently exhibit viral infections; nontarget organisms, including
humans, have been and continue to be exposed to the viral coat proteins
with no observed adverse effects.
The possibility that environmental risk might be associated with
the use of vcp-mediated resistance was discussed at the December 18,
1992, FIFRA SAP Subpanel meeting. EPA agrees with the conclusions of
the SAP Subpanel and in developing its proposal has utilized the advice
of the Subpanel to supplement EPA's own evaluation of the scientific
literature (Ref. 2). The considerations discussed at this meeting
included: (1) The potential for new viruses to be formed through
transcapsidation (also called heterologous encapsidation) and
recombination; (2) the potential for synergistic infections; (3) the
potential for seed transmission; and (4) the potential for the
development of selective advantage in wild relatives through successful
hybridization with the plant producing the viral coat protein. (See
Unit VIII. of this document for a more detailed discussion of the SAP
report and the proposal published elsewhere in todays issue of the
Federal Register entitled ``Plant-pesticides Subject to the Federal
Insecticide, Fungicide, and Rodenticide Act; Proposed Rule'' for
discussion of the Agency's preferred proposed exemption and the
alternative approach to viral coat proteins).
With regard to selective advantage, the Subpanel report noted that
while the series of events that must occur for the wild plant to
acquire a selective advantage from vcp-mediated resistance coat
proteins is rather improbable, such a series of events is not
impossible. An alternative option presented by the Agency offers a more
limited exemption of vcp-mediated resistance coat proteins to address
the possibility that plants acquiring the vcp-mediated resistance genes
might also acquire a selective advantage. With regard to the
alternative option, the Agency has defined a set of criteria that would
be used to identify those viral coat protein/plant combinations that
have the greatest potential for outcrossing to wild, free living
relatives and thus have the possibility endowing these wild relatives
with a competitive advantage. Viral coat proteins that potentially
could be outcrossed to wild relatives would be subject to regulation
while those viral coat protein/plant combinations with a lesser or no
probability of outcrossing would be exempt from regulation. The
language covering this alternative is as follows.
Coat proteins from plant viruses [would be exempt] if the
genetic material necessary to produce a coat protein is introduced
into a plant's genome and the plant has at least one of the
following characteristics:
(1) The plant has no wild relatives in the United States with
which it can successfully exchange genetic material, i.e., corn,
tomato, potato, soybean, or any other plant species that EPA has
determined has no sexually compatible wild relatives in the United
States.
(2) It has been demonstrated to EPA that the plant is incapable
of successful genetic exchange with any existing wild relatives
(e.g., through male sterility, self-pollination).
(3) If the plant can successfully exchange genetic material with
wild relatives, it has been empirically demonstrated to EPA that
existing wild relatives are resistant or tolerant to the virus from
which the coat protein is derived or that no selective pressure is
exerted by the virus in natural populations.
For the purposes of this option, ``introduced into the plant's
genome'' would mean movement of nucleotide sequences into the genetic
material in a plant cell's nucleus, mitochondria, chloroplasts and any
other plastids. ``Successful genetic exchange'' would mean capable of
forming zygotes viable in the laboratory and/or field through the
fusion of two gametes.
C. FFDCA
1. Summary of regulatory status. As indicated previously, the
Agency has available, under FFDCA section 408(c), the authority to
exempt plant-pesticides from the requirement of a tolerance if such
tolerance is not necessary to protect the public health (Unit III). The
Agency is proposing that such a finding is appropriate for three
classes of plant-pesticides: (1) Categories of pesticidal substances
produced in plants that do not result in new dietary exposures based
upon the source from which the pesticidal substance is derived; (2)
nucleic acids produced in plants as part of a plant-pesticide; and (3)
coat proteins from plant viruses when they are produced in plants. (For
more detail on these proposed exemptions refer to the following Federal
Register documents: ``Plant-pesticides; Proposed Exemption from the
Requirement of a Tolerance Under the Federal Food, Drug, and Cosmetic
Act''; ``Plant-pesticides; Proposed Exemption from the Requirement of a
Tolerance Under the Federal Food, Drug, and Cosmetic Act for Viral Coat
Proteins Produced in Plants''; ``Plant-pesticides; Proposed Exemption
from the Requirement of a Tolerance Under the Federal Food, Drug, and
Cosmetic Act for Nucleic Acids Produced in Plants'').
a. Exemption from the requirement of a tolerance for categories of
plant-pesticides that would not result in new dietary exposures. Under
this exemption, the Agency is proposing to exempt from the requirement
of a tolerance two categories of plant-pesticides: (1) Plant-pesticides
produced in food plants and derived from closely related food or non-
food plants and (2) plant-pesticides produced in food plants and
derived from food plants that are not closely related to the recipient
food plant and would not result in significantly different dietary
exposures when produced in the recipient food plant. The proposed
exemption is as follows:
(a) Residues of pesticidal substances produced in living plants
as plant-pesticides are exempt from the requirement of a tolerance
if the genetic material that encodes for a pesticidal substance or
leads to the production of a pesticidal substance is derived from
plants that are sexually compatible with the recipient plant and has
never been derived from a source that is not sexually compatible
with the recipient plant;
(b) Residues of pesticidal substances produced in living plants
as plant-pesticides are exempt from the requirement of a tolerance
when the genetic material that encodes for a pesticidal substance or
leads to the production of a pesticidal substance is derived from
plants that are not sexually compatible with the recipient plants
if:
(1) The genetic material that encodes for a pesticidal substance
or leads to the production of a pesticidal substance is derived from
food plants; and
(2) The pesticidal substances would not result in significantly
different dietary exposures.
For the purposes of this exemption, the following definitions
apply:
``Bridging crosses'' between plants means the utilization of an
intermediate plant in a cross to produce a viable zygote between the
intermediate plant and a first plant, in order to cross the plant
resulting from that zygote with a third plant that would not otherwise
be able to produce viable zygotes from the fusion of its gametes with
those of the first plant. The result of the bridging cross is the
mixing of genetic material of the first and third plant through the
formation of an intermediate zygote.
``Food plant'' means a plant which, either in part or in toto is
used as food by humans.
``Genetic material that encodes for a pesticidal substance or leads
to the production of a pesticidal substance'' does not include
regulatory regions or noncoding, nonexpressed nucleotide sequences.
``Living plant'' means a plant that is alive, including periods of
dormancy, and all viable plant parts/organs involved in the plant's
life cycle.
``Major crops for human dietary consumption'' means wheat, corn,
soybeans, potatoes, oranges, tomatoes, grapes, apples, peanuts, rice,
beans, and any other crops that the Agency has determined is a major
crop for human dietary consumption.
``Noncoding, nonexpressed nucleotide sequences'' means the
nucleotide sequences are not transcribed and are not involved in gene
expression. Examples of noncoding, nonexpressed nucleotide sequences
include linkers, adapters, homopolymers, and sequences of restriction
enzyme recognition sites.
``Recipient plant'' means the plant into which the plant-pesticide
is introduced and in which the plant-pesticide is produced.
``Regulatory region'' means genetic material that controls the
expression of the genetic material that encodes for a pesticidal
substance or leads to the production of a pesticidal substance.
Examples of regulatory regions include promoters, enhancers, and
terminators.
``Result in significantly different dietary exposure'' means:
(1) The pesticidal substance is produced in inedible portions of
the source food plant, but, in the recipient plant, the pesticidal
substance is present in the plant's edible portions.
(2) The pesticidal substance is produced in the immature, but not
in the mature, edible portions of the source food plant, but, in the
recipient plant, the pesticidal substance is present in the mature,
edible portions.
(3) The pesticidal substance is from a source food plant normally
cooked or processed prior to consumption and is produced in a recipient
plant that is not normally cooked or processed prior to consumption.
(4) The pesticidal substance is derived from a source food plant
that is not a major crop for human dietary consumption and is
introduced into a recipient plant that is a major crop for human
dietary consumption.
``Sexually compatible,'' when referring to plants, means capable of
forming a viable zygote through the fusion of two gametes, including
the use of bridging crosses or wide crosses between plants.
``Source food plant'' means the donor of the genetic material that
encodes for a pesticidal substance or leads to the production of a
pesticidal substance.
``Wide crosses,'' between plants, means to facilitate the formation
of viable zygotes through the use of surgical alteration of the plant
pistil, bud pollination, mentor pollen, immunosuppressants, in vitro
fertilization, pre- and post-pollination hormone treatments,
manipulation of chromosome numbers, embryo culture, or ovary and ovule
cultures, or any other technique that the Administrator determines
meets this definition.
The Agency is also proposing an alternative approach that uses a
standard that relies primarily on the taxonomic grouping of genus as a
measure of relatedness between plants (for more discussion of this
alternative approach, see Unit IV.C.2. of this document and the
proposal published elsewhere in todays issue of the Federal Register
entitled ``Plant-pesticides; Proposed Exemption from the Requirement of
a Tolerance Under the Federal Food, Drug, and Cosmetic Act.''
b. Exemption from the requirement of a tolerance for nucleic acids
produced in plants as part of a plant-pesticide. This proposed
exemption would exempt nucleic acids (i.e., deoxyribonucleic acid (DNA)
and ribonucleic acid (RNA)) from the requirement for a food tolerance
when produced in plants as part of a plant-pesticide active or inert
ingredient (refer to Unit IV.B.1. of this document for a discussion of
the definition of plant-pesticide active and inert ingredients). The
proposed exemption is as follows:
Residues of nucleic acids produced in living plants as part of a
plant-pesticide active or inert ingredient, including both
deoxyribonucleic and ribonucleic acids, are exempt from the
requirement of a tolerance.
For the purposes of this exemption, ``nucleic acids'' means
ribosides or deoxyribosides of adenine, thymine, guanine, cytosine, and
uracil and the polymers of these ribosides and deoxyribosides and does
not apply to nucleic acid analogues.
c. Exemption from the requirement of a tolerance for viral coat
proteins produced in plants. EPA proposes to exempt from the
requirement of a tolerance coat proteins from plant viruses when they
are produced by plants to enable the plants to resist viral infection.
The proposed exemption is as follows:
Residues of coat proteins from plant viruses, or segments of the
coat proteins, produced in living plants as plant-pesticides are
exempt from the requirement of a tolerance.
2. Rationale for exemptions under FFDCA. There are circumstances
where EPA believes that plant-pesticides should be reviewed by EPA
either to set a tolerance or issue an exemption from the requirement of
a tolerance. In general, EPA believes that plant-pesticides resulting
in significantly different dietary exposures than those that already
occur should be subject to EPA review under FFDCA tolerance procedures.
a. Exemption from the requirement of a tolerance for categories of
plant-pesticides that would not result in new dietary exposures. Many
substances having pesticidal activity occur naturally in the edible
parts of plants (i.e., they are inherent to the plant) and have long
been accepted as part of the human diet. The safety of foods containing
these substances is demonstrated by extensive consumption and
experience. For many foods, the inherent toxicants they may contain,
including pesticidal substances, are known (Ref. 5). Also, the
established practices that plant breeders employ in selecting and
developing new plant varieties, such as chemical analyses, taste-
testing and visual analyses, have historically proven to be reliable
for ensuring food safety. That there are few examples of new plant
varieties causing food safety concerns, despite the large numbers of
new varieties introduced into commerce each year, is a reflection of
the effectiveness of this process. Moreover, consumer experience with
the handling and preparation of food from these plants contributes to
the safety of food from these plants.
(i) Plant-pesticides from closely related plants. This proposed
exemption is based upon the premise that new dietary exposures would
not likely arise for plant-pesticides produced in food plants if the
genetic material leading to the production of the plant-pesticide is
derived from closely related plants. In establishing this exemption,
EPA is proposing to use a standard that is similar to the standard
proposed for an exemption for plant-pesticides under FIFRA (see Unit
IV.B. of this document). That standard would be sexual compatibility.
Under both statutes, this standard would be used as a measure of
relatedness between plants. However, under FFDCA, the standard of
sexual compatibility must be examined specifically within the context
of the food supply and dietary consumption. The Agency believes, based
on the experience with sexually compatible plants (see Unit IV.B. of
this document), that most plant varieties developed by plant breeders
using genetic material from plants that meet the sexually compatible
standard produce food that is safe for human consumption and/or that
appropriate processing procedures are widely known and routinely used
by consumers in preparation of food from such sources.
As under FIFRA, EPA proposes to extend the concept of sexual
compatibility to include wide crosses because wide crosses are commonly
used to expand the gene pool for varietal improvement and, as discussed
earlier, EPA believes that the fact that wide crosses can produce a
viable zygote indicates a fairly high degree of relatedness between
parental plants.
The Agency is considering, for this exemption, a second option
based primarily on the taxonomic standard of genus rather than on
sexual compatibility. Under this approach, a plant-pesticide would be
exempt if it were derived from a plant within the same genus as the
recipient plant. The Agency recognizes that some plants that are
closely related (as evidenced by sexual compatibility) are not
classified in the same genus. Under this alternative option, the Agency
would extend the exemption to plant-pesticides derived from plants in
these populations, as well as to intrageneric plant-pesticides.
Therefore, if a plant-pesticide is derived from a plant outside of the
same genus, sexual compatibility between the two plants would need to
be demonstrated. The language defining this option would be as follows.
[Residues of pesticidal substances produced in living plants as
plant-pesticides are exempt from the requirement of a tolerance if:]
The genetic material that encodes for a pesticidal substance or
leads to the production of a pesticidal substance:
(1) Is derived from plants that are within the same genus as the
recipient plant [regardless of sexual compatibility] or, is derived
from plants that are sexually compatible with the recipient plant;
and
(2) Has never been derived from a source outside the same genus
that is not sexually compatible with the recipient plant.
For a more detailed analysis of EPA's preferred approach and Option
2, refer to the Federal Register document published elsewhere in
today's issue of the Federal Register entitled, ``Plant-pesticides;
Proposed Exemption from the Requirement of a Tolerance under the
Federal Food, Drug, and Cosmetic Act.''
(ii) Plant-pesticides derived from food plants that are not closely
related with the recipient plant. There are circumstances where
experience with exposure can be inferred for plant-pesticides
introduced into food plants from other food plants that are not closely
related to the recipient plant. For plant-pesticides derived from a
food plant that is not sexually compatible with the recipient food
plant, there is experience with exposure because both plants have
contributed to the food supply. Thus, the Agency is proposing to exempt
from the requirement of a tolerance plant-pesticides derived from food
plants that are not closely related to the recipient plant, if there
would not be significantly different dietary exposures when the plant-
pesticide is produced in the recipient food plant.
The Agency has defined a set of criteria to determine whether
significantly different dietary exposures from the these plant-
pesticides will occur. For example, if a pesticidal substance is
normally only produced in inedible portions or immature fruit of the
food plant, the Agency would require a tolerance review if the modified
food plant were to produce that substance in its mature fruit or edible
portions. For example, tomatine is a toxicant produced in much higher
amounts in immature tomato fruit (that is normally eaten) than it is in
the fruit. If the genetic material leading to the production of
tomatine were introduced into a plant for pesticidal purposes such that
the tomatine were produced in the mature fruit as it is in the immature
fruit, the Agency would need to conduct a tolerance review to determine
whether a tolerance is necessary to protect the public health.
Similarly, if a pesticidal substance is produced in a food that is
almost always cooked or processed prior to consumption, the Agency
would want to conduct a tolerance review if another food plant that is
not cooked or processed prior to consumption is modified to produce the
substance. For example, some beans are rich in lectins, glycoproteins
that are natural toxicants. Soaking and cooking the beans destroys the
lectins. If the genetic material encoding lectins were transferred, for
pesticidal purposes, from beans to a plant which is not normally cooked
(e.g., lettuce), the Agency would need to conduct a tolerance review. A
significantly different dietary exposure could also result if a widely
consumed food staple such as corn is modified to produce a pesticidal
substance from a food crop with minor consumption such as eggplant.
EPA is also considering adding another criterion to the exemption
from the requirement of a tolerance for categories of plant-pesticides
that would not result in new dietary exposures (Unit IV.C.1.a. of this
document). This criterion would address the potential for allergenicity
of plant-pesticides in food. Under this criterion, if a plant-pesticide
is derived from a commonly allergenic food, the plant-pesticide would
not be exempt from tolerance requirements and the Agency would conduct
a tolerance review on a case-by-case basis to determine whether to
establish an exemption from the requirement of a tolerance, establish a
tolerance, or deny a tolerance. Some examples of foods that commonly
cause an allergenic response are milk, eggs, fish, crustacea, molluscs,
tree nuts, wheat, and legumes (particularly peanuts and soybeans).
b. Nucleic acids in plants. The Agency is also proposing to exempt
from the requirement of a tolerance nucleic acids produced in plants as
part of plant-pesticide active or inert ingredients. Nucleic acids
(deoxyribonucleic and ribonucleic acid) are present in the cells of
every living organism, including plants, microorganisms, and animals.
Because nucleic acids are ubiquitous in the food supply and lack any
toxicity when they are consumed in food, EPA believes that a tolerance
for nucleic acids is not necessary to protect the public health (see
the proposal published elsewhere in todays issue of the Federal
Register entitled ``Plant-pesticides; Proposed Exemption from the
Requirement of a Tolerance Under the Federal Food, Drug, and Cosmetic
Act for Nucleic Acids Produced in Plants'' for a more detailed
discussion).
c. Coat proteins from plant viruses. The Agency's proposal for
exempting coat proteins from plant viruses is based on virus-infected
plants having always been a part of the human and domestic animal food
supply without detectable adverse human health effects. There is no
evidence of any plant virus being able to replicate in mammals or other
vertebrates. In addition, the exemption will only apply when the
portion of the viral genome coding for the whole coat protein or a sub-
component of the coat protein will be expressed in the plant. This
portion of the viral genome by itself is incapable of forming
infectious particles. Since whole, intact plant viruses are not known
to cause untoward human health effects, it is reasonable to assume that
a subunit of these viruses will not be harmful (see the proposal
published elsewhere in todays issue of the Federal Register entitled
``Plant-pesticides; Proposed Exemption from the Requirement of a
Tolerance Under the Federal Food, Drug, and Cosmetic Act for Viral Coat
Proteins Produced in Plants'' for a more detailed discussion).
D. Plant-pesticides and Plant Regulators
As discussed in Unit III. of this document, FIFRA section 2(u)
defines ``pesticide'' as: ``. . .(2) any substance or mixture of
substances intended for use as a plant regulator, defoliator, or
desiccant. . . .'' FIFRA section 2 also defines ``plant regulator'' as
``. . .any substance or mixture of substances intended, through
physiological action, for accelerating or retarding the rate of growth
or rate of maturation, or for otherwise altering the behavior of the
plants or the produce thereof. . . .'' With regard to substances
applied to plants, this definition has been interpreted to include, for
example, plant hormones (e.g., auxin, gibberellin, cytokinin and
ethylene). In the area of plant-pesticides, the issue arises as to
which substances produced by a plant should be considered plant
regulators, as a result of a change in the physiology of the plant, and
therefore, pesticides, subject to regulation.
At the time that the term ``plant regulator'' was added to the
definition of pesticide, in 1959, Congress addressed substances applied
to plants but did not address how the definition applied to substances
produced in plants. EPA believes this is because the technology to
develop plant varieties expressing substances using genetic information
derived from diverse sources (e.g., outside the plant kingdom) was not
in existence, and thus, Congress did not provide direct guidance on the
implications of the definition of plant regulator for substances
produced in plants.
EPA, therefore, believes that it has the discretion to develop a
reasonable approach to defining what constitutes a plant regulator for
substances produced in plants. In developing this interpretation, EPA
looked at previous Congressional action relating to ``plant
regulators,'' plant science, the traditional roles of EPA and FDA in
this area, and the extent to which risk concerns would go unaddressed
if EPA did not include certain plant substances in the definition of
``plant regulator.''
While Congress has not spoken on the full extent of the definition
of ``plant regulator,'' it has given some guidance on what it does not
consider to be plant regulators through exclusions to the definition in
FIFRA itself. For example, Congress specifically excluded ``substances
to the extent that they are intended as plant nutrients, trace
elements, nutritional chemicals, plant inoculants, and soil
amendments.'' Arguably, Congress recognized that no purpose would be
served by requiring substances such as plant nutrients to be regulated
as ``pesticides.''
In 1972, Congress added the vitamin-hormone horticultural product
exclusion to the definition of plant regulator. This exclusion provides
that ``the term plant regulator shall not be required to include any of
such of those nutrient mixtures or soil amendments as are commonly
known as vitamin-hormone horticultural products, intended for
improvement, maintenance, survival, health, and propagation of plants,
and as are not for pest destruction and are non-toxic, nonpoisonous in
the undiluted packaged concentration'' (FIFRA section 2(v) emphasis
added). This exclusion can be used as a reasonable starting point for
EPA's identification of the types of substances that fall within its
jurisdiction.
Another factor that the Agency considered in developing its
approach to ``plant regulators'' was harmonization with the traditional
split between EPA and FDA jurisdiction under FFDCA. The reorganization
plan of 1970 generally placed the FFDCA responsibility for setting
tolerances for pesticide residues in food under EPA's jurisdiction and
the responsibility for regulating all other substances in food under
FDA's jurisdiction. FDA traditionally regulates, for example,
substances in food that are used for improved food processing or
improved nutritional content. The issue here, therefore, is not whether
or under what statutory authority a substance will be regulated.
Rather, the issue is who will regulate. If a substance is defined by
FIFRA as a pesticide, it is subject to EPA's regulatory authority. If
the substance is not a pesticide under FIFRA, FDA has regulatory
responsibility. EPA believes it is reasonable to develop a plant
regulator interpretation for plant-pesticides that provides for FDA to
regulate the types of substances that it has experience and expertise
in regulating and that avoids regulation by EPA as ``pesticides,''
substances that relate to nutrition and food quality. Accordingly, EPA
is proposing the following interpretation of ``plant regulator'' for
the purpose of determining which substances produced by a plant as a
result of changes in the plant's physiology should be considered to be
``pesticides,'' subject to EPA's regulatory jurisdiction. EPA believes
that this interpretation is consistent with Congress' intent of
including a category of substances they termed ``plant regulators,'' or
at least certain types of growth regulators, within the definition of
pesticide.
A substance that is produced in a plant as a result of a change in
the plant's physiology would be considered a plant regulator if:
It is intended to accelerate or retard the rate of growth or rate
of maturation, or alter the behavior of the plants and meets one of the
following criteria:
(1) Is a plant hormone.
(2) Acts to prevent, destroy, repel, or mitigate a pest.
(3) Is toxic in concentrations found in the plant (undiluted
package).
Plant hormones that are produced in plants as the result of an
intentional change in the plants' physiology would be considered plant
regulators. As plant regulators, they would also be considered a plant-
pesticide and under EPA's authority. However, EPA believes that some of
these substances would be candidates for exemption from regulation
under FIFRA under the exemption of plant-pesticides derived from
closely related plants (see Unit IV.B.1.c.i. of this document and the
proposal published elsewhere in today's issue of the Federal Register
entitled ``Plant-pesticides Subject to the Federal Insecticide,
Fungicide, and Rodenticide Act; Proposed Rule''). EPA is also
considering extending the exemption of plant-pesticides that act
primarily by affecting the plant to include substances such as plant
hormones (see Unit IV.B.1.c.i. of this preamble and the proposal
published elsewhere in today's issue of the Federal Register entitled
``Plant-pesticides Subject to the Federal Insecticide, Fungicide, and
Rodenticide Act; Proposed Rule'').
A few examples of substances expressed in plants that would not be
considered plant regulators and therefore not under EPA's authority
are: (1) Substances intended to alter the nutritional composition of
the plant; (2) substances intended to enhance the plant's resistance to
chemical herbicides; and (3) substances intended to alter the flavor or
the texture of the food.
V. Regulatory Process Under FIFRA and FFDCA
This section outlines the process EPA proposes to follow for plant-
pesticides subject to FIFRA and/or FFDCA requirements. It describes the
options that EPA is evaluating for its approach to the regulation of
testing of plant-pesticides and includes current proposed Agency's
thinking for sale or distribution of a plant-pesticide. In the future,
EPA will propose regulations concerning the procedures for plant-
pesticides under FIFRA (e.g., EUPs and labeling).
In the period before procedures that are specific for plant-
pesticides are finalized, existing regulations (e.g., 40 CFR parts 156,
158, and 172) will be used as the basis for plant-pesticide regulatory
procedures. However, the Agency is aware that many of these existing
procedures may not be appropriate for plant-pesticides, and encourages
producers to contact EPA on a case-by-case basis.
Producers of plant-pesticides should be aware that having no
obligations under one of the statutes (FIFRA or FFDCA) does not
necessarily mean that there are no obligations under the other statute.
Producers should therefore evaluate the requirements of both statutes
before reaching a determination on their responsibilities.
Producers should also be aware that if certain plant-pesticides
present unreasonable risk and there are limited or no risk mitigation
options available to the Agency for certain plant-pesticides submitted
for registration, the Agency would not be able to register the plant-
pesticides. Potential registrants are again encouraged to consult with
EPA for guidance early in the product development cycle.
A. Testing of Plant-pesticides
The following unit outlines EPA's preferred approach to when a
producer would contact EPA under FIFRA and FFDCA during testing of a
plant-pesticide. The procedures are laid out in terms of whether the
crop would be used as food and/or feed since this question is among the
first considerations in determining when to contact EPA.
1. Food and/or feed use. This unit gives guidance as to when a
producer would have obligations under FFDCA and FIFRA if a plant-
pesticide is tested in a crop/plant used for food and/or feed or if any
adjacent food/feed plants would produce the plant-pesticide.
a. FFDCA requirements. The FFDCA requirements for a plant-pesticide
would be based on the following considerations.
(i) Existing exemption from the requirement of a tolerance. If
there is an existing exemption from the requirement of a tolerance for
the plant-pesticide in the crop/plant to be tested (e.g., if EPA's
proposed tolerance exemptions published elsewhere in todays issue of
the Federal Register), there would be no further obligations under
FFDCA.
(ii) Containment. A tolerance review would not be required for the
test if the crops/plants containing the plant-pesticide are tested in a
way that ensures adequate containment within the test site of the
genetic material necessary for the production of the pesticidal
substance. ``Adequate containment'' in this context would include
ensuring any adjacent crops, to be used as food, do not express the
plant-pesticide as a result of successful pollination by the plant used
to test the plant-pesticide.
(iii) Crop destruct. A tolerance review would not be required for
the test if all crops within the test site are destroyed or used for
experimental purposes only.
(iv) Petition for temporary tolerance or exemption. If there is no
existing exemption from the requirement of a tolerance for the plant-
pesticide, if containment is not adequate or the crop is not destroyed,
a petition for a temporary tolerance, a full tolerance, or an exemption
from the requirement of a tolerance must be submitted to the Agency, as
described at 40 CFR 180.7 and 180.31. Such a crop cannot be sold or
distributed for use as food or feed unless a tolerance or exemption
from the requirement of a tolerance has been obtained for the plant-
pesticide in that crop and the plant-pesticide residues fall within the
tolerance limits.
b. FIFRA requirements. Prior to registration, if a plant- pesticide
is produced in a crop/plant that is to be used as food or feed
(condition (iv) above) at any field test acreage, producers would apply
for an Experimental Use Permit (EUP) for that plant-pesticide under
FIFRA.
2. Nonfood and nonfeed use. This unit describes when a producer
would have obligations under FFDCA and FIFRA if the plant-pesticide is
used in a crop or plant that will not be used for food and/or feed.
a. FFDCA requirements. If a plant-pesticide is produced in a crop/
plant that will not be used as food and/or feed, there would be no
requirements under FFDCA as long as the genetic material is adequately
contained to avoid successful transfer and expression of the plant-
pesticide in adjacent crops. (Refer to Unit V.A.1.a.(ii) and (iii).
above for conditions of containment and crop destruction under which
there are no FFDCA requirements.)
b. FIFRA requirements. If a plant-pesticide is produced in a crop/
plant that will not be used as food and/or feed, an Experimental Use
Permit would be required under the following conditions.
(i) Not subject to the Plant Pest Act. If a plant-pesticide is
produced in a plant that is not subject to the authority of the Plant
Pest Act, an EUP would be required at first field introduction. This
EUP requirement would extend to plant-pesticides in plants that are not
within the statutory jurisdiction of the Plant Pest Act, including
those for which APHIS has made a determination of nonregulated article
status (58 FR 17044).
(ii) Acreage requirements for plant-pesticides in plants subject to
the Plant Pest Act. For plant-pesticides produced in plants that are
(1) subject to the authority of the Plant Pest Act and (2) not used as
food or feed, an EUP would be required when one of the following two
conditions is met.
(A) Acreage limit for individual field test. An EUP generally would
be required if an individual field test for a plant-pesticide in a
particular crop will be on greater than 10 acres of land. Once a
requirement for an EUP has been triggered, if there are other field
test site locations, for that plant-pesticide, of less than 10 acres
that would also be planted in the same year, they would be included in
the EUP. If a field test site of greater than 10 acres is planted for a
crop that is producing more than one plant-pesticide, all field test
sites for each of the plant-pesticides would be included in the EUP if
these field tests would occur in the same year.
(B) Upper cumulative acreage limit for field tests. Notwithstanding
(A) above, an EUP would be required if the cumulative acreage of all
field tests for the plant-pesticide in a particular crop exceeds 50
acres of land regardless of the acreage of individual field sites.
(iii) Other conditions for EUPs. The Agency could grant multi-year
EUPs for plant-pesticides under certain conditions. For example, a
multi-year EUP could be appropriate if the acreage of the field sites
will increase yearly but the field test design and containment measures
for the field sites remain the same such that there is not an increased
risk for nontarget effects or outcrossing. In addition, producers
should be aware that the data requirements for an EUP may not be
different from the data requirements for a registration of the plant-
pesticide (see Unit VI. of this document).
B. Sale or Distribution
1. FFDCA. If a plant-pesticide is produced in a crop to be sold or
distributed as food and/or feed and is not already exempt from the
requirement of a tolerance, the Agency must establish a tolerance or
exemption from the requirement of a tolerance before sale or
distribution.
2. FIFRA. Before sale or distribution of a plant-pesticide, a
producer would have to obtain a registration for the plant-pesticide
product, unless it is otherwise exempt, as described in this document
(Unit VI.B. of this document). The plant-pesticide product consists of
the active ingredients and inert ingredients, as defined in Unit IV.B.
of this document, EPA anticipates that the plant-pesticide product
would be registered for use in a particular plant or crop (e.g., field
corn). While the Agency anticipates that most registrations of plant-
pesticides would be for use in a particular plant or crop, there may be
instances where a registration of a plant-pesticide could be limited to
a particular variety or be restricted in some other way if risk
considerations warrant such a restriction.
In terms of shipping, EPA does not intend to change the status of
the exemption under section 12(b)(5) of FIFRA which allows the shipping
of a pesticidal substance under the conditions of section 12(b)(5)
without being subject to penalty for failure to have a registration or
EUP.
C. Agency Considerations Underlying Regulatory Procedures and
Alternative Approaches for Testing of Plant-pesticides
1. Agency considerations underlying FFDCA regulatory procedures.
Under FFDCA at the field testing stage, the Agency will generally treat
plant-pesticides as it treats other pesticides in terms of when EPA
regulatory oversight begins. Thus, producers will be subject to FFDCA
requirements when the crop plant containing the plant-pesticide is to
be used as food or feed. EPA recognizes that many of its requirements
for addressing feed under FFDCA arise because some pesticidal
substances may be metabolized or stored by domesticated animals in ways
that expose humans to these pesticides and/or their residues through
consumption of meat or other animal products (e.g., milk and eggs). EPA
also recognizes that the possibility that consumers might be exposed to
proteinaceous plant-pesticides through such animal products is
extremely low. Proteinaceous plant-pesticides are likely to be composed
of the same constituents as animal protein or other animal cellular
components, and, thus, would readily enter the metabolic cycles of the
animal cell. For proteins, it is not anticipated that recalcitrant
residues will be generated or accumulated in animals used as sources of
meat. However, EPA cannot predict that all plant-pesticides will behave
as proteinaceous plant-pesticides. Thus, EPA will require plant-
pesticides to be subject to FFDCA when the plants producing the plant-
pesticide are used as feed. Data requirements associated with the
tolerance review will, however, be imposed recognizing the
characteristics of proteinaceous plant-pesticides.
2. Agency considerations underlying FIFRA regulatory procedures.
The following unit describes EPA's rationale for its preferred trigger
for EUP's and describes alternative approaches to the EUP trigger EPA
is considering. The preferred approach and the alternative approaches
address testing of plant-pesticides that are subject to the Plant Pest
Act and are not used as food and/or feed (conditions described in Unit
V.A.2.b.ii. of this document).
EPA believes some type of oversight of plant-pesticides at the
field testing stage is appropriate. Plant-pesticides are, by
definition, part of a living organism. Thus, plant-pesticides present
unique mechanisms by which they can be produced and spread in the
environment. Because of the different risk considerations and risk
mitigation measures associated with plant-pesticides than with
traditional chemical pesticides, EPA is examining whether the 10
cumulative acre presumption in 40 CFR 172.3 is appropriate with regard
to plant-pesticides.
Potential risks associated with tests of plant-pesticides will
depend upon a number of variables, including the size of the test plot,
the biology of the plant and the properties of the pesticidal
substance. At smaller acreages, tests of plant-pesticides can usually
be designed with containment that is adequate to minimize the spread of
the plants' genetic material beyond the test site, thereby limiting the
spread of the active ingredient from the field test site. Successful
containment of the genetic material would result in minimal exposure of
humans and other nontarget organisms to the active ingredient beyond
the test site.
During the development of plant-pesticides, depending upon the
biology of the plant tested and the location of the field test sites,
there will be a point at which it will be impractical to try to contain
the spread of the genetic material. In terms of risk, the Agency
believes its oversight of plant-pesticides under FIFRA should begin at
the point when containment is impractical and the potential for
significant exposure to nontarget organisms begins to increase.
As tests of plant-pesticides progress to larger acreages, the
potential hazards to nontarget organisms will generally be increased
because of the potential for significant exposure to nontarget
organisms on the test site. In addition, lack of adequate containment
may mean the spread of the active ingredient and subsequent possible
environmental exposure beyond the test site. Moreover, if the active
ingredient is spread to neighboring crops used for food and/or feed,
human dietary exposure could occur.
Under any of the options put forth by EPA for EUP thresholds for
plant-pesticides, EPA would retain the authority to rebut the
presumption that an EUP is not required for certain small-scale
testing. Such a rebuttal would be based on risk/benefit considerations.
Thus, EPA may, on a case-by-case basis require EUP's for testing
conducted with plant-pesticides at acreages smaller than those
described in the options. EPA does not anticipate requiring EUP's at
acreages below the threshold triggering EUP requirements (regardless of
which option is chosen) very often, and when EPA determines that such
an EUP is warranted, EPA will provide notice to the producer of the
plant-pesticide being tested.
In addition to risks in terms of hazard and exposure, EPA
considered the following in developing its options for the threshold
for EUPs for plant-pesticides: (1) Differences in the traits of plant-
pesticides (e.g., the delivery system of the pesticide in that plant-
pesticides are produced and used in a living plant) in comparison to
more traditional chemical pesticides (e.g., they are applied to a
plant); (2) varietal development procedures used in the plant breeding
industry and the impact this has on the design of field testing; (3)
USDA's activities under the Plant Pest Act for transgenic plants (some
of which will be engineered to express plant-pesticides); (4) clarity
to the regulated and other communities; (5) EPA's traditional approach
to oversight of field testing in terms of establishing acreage cutoffs
so as to provide regulatory consistency; and (6) costs to potential
registrants and efficient utilization of Agency resources.
a. EPA's preferred approach: single-site acreage threshold. Under
its preferred approach, the Agency would use the concept that larger
acreage for individual field sites leads, in general, to greater
exposures and greater potential for escape from biological containment.
Therefore, the Agency would link the concept of greater exposure to an
acreage cutoff (i.e., 10 acres for a single field test site, 50
cumulative acres; see Unit V.A.2.b.ii of this document). EPA recognizes
that the acreage cutoff in its preferred approach may be more closely
correlated with the potential for larger exposures for some crops than
for others. However, it believes that the advantage of clarity and
predictability associated with the acreage cutoff would outweigh this
disadvantage. In addition, EPA would put an upper limit on the number
of cumulative acres that could be planted without an EUP because
multiple sites of larger acreages would lead to an increased potential
for exposure to nontarget organisms on the cumulative acreage.
b. Alternative approaches for testing of plant-pesticides. EPA is
also considering four alternative approaches to triggers for Agency
oversight for testing of plant-pesticides, under FIFRA section 5, for
plant-pesticides that are subject to the Plant Pest Act and are not
used as food/feed.
(i) Containment as trigger for EUP. EPA seriously considered, and
may yet choose to use as its trigger for EUP requirements, the concept
of containment. Essentially, once a plant can no longer be effectively
isolated biologically, EPA's EUP requirements would be triggered. To be
isolated biologically means that the genetic material of the plants on
the test site does not have a significant potential for successfully
spreading to neighboring plants (including neighboring crop plants)
through sexual recombination. The concept of biological isolation is
basic to USDA's approach and use of such a standard by both agencies
could permit a smooth transfer of oversight for plant-pesticides from
USDA to EPA. The disadvantage of using this approach for EPA and for
potential registrants, is that what constitutes ``appropriate
containment'' varies from crop to crop and test to test. EPA is
concerned that the lack of a clear line as a standard may result in
numerous consultations between EPA and potential registrants over what
constitutes appropriate containment. In addition, other groups, such as
the public and public interest groups, may not be able to readily
determine whether a potential registrant is in compliance with EPA
requirements. Finally, there are exposure issues (i.e., larger
potential for exposure on individual field sites at larger acreages)
that are not addressed by this alternative.
(ii) USDA/APHIS determination of nonregulated status as trigger for
EUP. A second alternative approach EPA is considering is based on
USDA's determination of nonregulated article status (58 FR 17044).
Under this alternative, producers would apply to EPA for an EUP (or
registration) at the time that they apply to APHIS for a determination
of nonregulated article status. Although this approach could
potentially minimize duplicative efforts by the two agencies, it lacks
regulatory clarity and consistency as to when a producer would have to
comply with EPA requirements. This approach may result in producers
being uncertain as to when they should contact EPA. The result of this
lack of regulatory clarity could be producers applying to EPA too late
in their product development cycle.
(iii) Cumulative acreage in a single state as trigger for EUP. The
third alternative would be based on an acreage trigger, as is EPA's
preferred approach. Under this approach, an EUP would be required when
the cumulative acreage in any one state exceeds 10 acres. This
alternative would allow producers to test a plant-pesticide in a number
of different locales yet limit exposure to the plant-pesticide in any
one locale. However, this approach also lacks regulatory clarity as to
when producers must contact EPA if a number of different states are
involved. Other groups, such as the public and public interest groups
may not be able to readily determine whether a producer is in
compliance with EPA requirements. In addition, fairly large total
acreages of testing might occur since up to 10 acres could be tested in
each of 50 states. The potential for exposure to nontarget organisms
and outcrossing to wild relatives could be greater with this
alternative than for the preferred or other alternative approaches.
(iv) Cumulative acreage as trigger for EUP. A fourth alternative
EPA is considering is to utilize for plant-pesticides the acreage
presumption in the current EUP regulations; i.e., an EUP is presumed
not to be required at less than 10 cumulative acres of land. The
advantage this alternative presents is consistency in EPA's EUP
regulations for all pesticides. The disadvantages to this approach are
that it may not correlate well with current plant breeding procedures
(varietal testing) that can require a number of field sites of smaller
acreages and it may result in more duplicative efforts by EPA and USDA.
It should be noted that EPA has not addressed in this document how
it will approach aquatic testing of plant-pesticides. Producers
anticipating research and commercialization activities with aquatic
plants are encouraged to contact the Agency.
D. Labeling Requirements under FIFRA
Labeling is required for pesticides that are regulated by EPA under
FIFRA. Labeling includes both written material accompanying the
pesticide and labels on or attached to the pesticide, its container, or
wrapper. Labeling thus may have different forms. A pesticide which does
not meet labeling requirements is considered to be misbranded and
enforcement action can be taken.
The Agency recognizes that certain types of labeling which are
appropriate for chemical pesticides will not be practical for plant-
pesticides. For example, it would be impractical to require labels to
be physically attached to the plant-pesticide itself (i.e., the
pesticidal substance and the genetic material necessary for the
production of the substance) at any point in the regulatory process
(i.e., EUPs or registration). Therefore, the Agency is considering the
types of labeling that would be appropriate for plant-pesticides during
testing and at the time of registration.
Labeling can include both prescriptive and informational
components. The Agency is considering utilizing both these types of
labeling for plant-pesticides. For example, plant-pesticides that are
regulated by EPA but are not yet registered (e.g., are under an EUP)
may have prescriptive labeling that would set forth the appropriate
conditions for field testing, such as geographic location, field test
design, and other limitations. The Agency believes that this type of
labeling would be appropriate at this point in the regulatory process
because the Agency would not have yet made a determination that the
plant-pesticide generally will not result in ``unreasonable adverse
effects'' without the restrictions specified on the label. Thus, the
prescriptive labeling would be necessary to assure there would not be
unreasonable adverse effects during the test of the plant-pesticide.
Plant-pesticides that are registered would also have prescriptive
labeling that would accompany the plant-pesticide throughout the
process of developing and producing the commercial plant variety that
contains the plant-pesticide. Such prescriptive labeling would, for
example, specify the EPA registration number, the ingredient statement,
and the plants/crops in which the plant-pesticide may be produced. It
is unlikely, however, to include many of the limitations, discussed
above, likely to be used for unregistered plant-pesticides because
these types of limitations would not be practical for registered plant-
pesticides. For example, limitations such as conditions for planting,
field design, or certain geographical restrictions may not be practical
given the nature of the use and distribution patterns of the plants
that produce the plant-pesticide (e.g., farmers saving seed for
replanting, the potential for spread of the plants' genetic material).
In some cases it will be appropriate for the Agency to assume that, at
sale or distribution, the plant-pesticide will be introduced into all
plants/crops (and their varieties) that are included in the plant-
pesticide registration (e.g., all corn varieties). The appropriateness
of this assumption will be considered, on a case-by-case basis, by EPA
in its assessment of whether a plant-pesticide produced in a particular
crop/plant presents ``no unreasonable adverse effects.''
The prescriptive label for a registered plant-pesticide may include
a provision requiring informational labeling on plants/seeds containing
the plant-pesticide to give information or notice to farmers and
growers of the plant-pesticide. For example, informational labeling of
this type could be attached to bags of seeds and could inform farmers
of the type of pesticide that the plants will produce and against which
pest it is active. EPA believes that such informational labeling will
help to prevent unnecessary application of additional pesticides to the
plants. The prescriptive label may require that the informational
labeling accompanying plants or seeds bear other necessary statements.
For example, the informational label could be required to have a
statement that informs farmers and growers that they should report any
adverse effects to the registrant through an address or telephone
number provided on the label.
E. Import/Export of Plant-pesticides
Unregistered, exported plant-pesticides that are not exempt from
FIFRA regulation will be subject to the Final Export Policy Statement;
Rule (40 CFR parts 168 and 169, 58 FR 9062). However, the Agency
recognizes that some of the labeling requirements for exports may not
be applicable to plant-pesticides (e.g., net weight of the plant-
pesticide may be difficult to determine in some cases). EPA is also
considering whether to require an informational label on exported
seeds/plants containing a registered plant-pesticide that contains: (1)
Information about the type of plant-pesticide produced by the plants
and the target pest, and (2) a statement that EPA's determination for
registration of the plant-pesticide is based solely on consideration of
risks in the United States and that this determination does not extend
to use in other countries.
If an imported plant-pesticide will be used for pesticidal purposes
(e.g., if the seeds are sold to be planted and the resulting plants are
intended to produce the plant-pesticide), the producer must apply for a
registration of the plant-pesticide under FIFRA. As with labeling for
exports, certain provisions in the ``Notice of Arrival of Pesticides
and Devices'' (EPA form 3540-1) may not be applicable to plant-
pesticides. If a producer plans to import seeds/plants that contain a
plant-pesticide, a tolerance or exemption from the requirement of a
tolerance must be obtained if the plants/seeds will be used for food
and/or feed. The Agency encourages producers to contact EPA with
questions concerning procedures for both import and export of plant-
pesticides.
VI. Information Needs Under FIFRA and FFDCA
A. Introduction
This unit describes the types of information EPA would need, in
general, to evaluate a plant-pesticide during product development and
before the pesticide could be registered for sale or distribution. The
types of information the Agency would need for its evaluation of a
plant-pesticide will depend upon a number of variables, including the
biology of the plant and the properties of the pesticidal substance.
The specifics of EPA's evaluation of testing of a plant-pesticide
(e.g., evaluation of containment) will also depend, to a certain
extent, on which of the options for EUP triggers apply in a final
policy statement (i.e., the time during product development that a
producer is required to contact the Agency varies depending on the
option selected (see Unit V. of this document).
This unit is designed to give general guidance while maintaining an
appropriate flexibility to data needs for individual cases. It covers
the areas of product analysis, environmental fate, ecological effects,
and human health effects. Producers are encouraged to consult with the
Agency on the types of information relevant to EPA's evaluation of
their particular product.
Although plant-pesticides present new considerations for risk
assessment, the framework that is used to evaluate risks for chemical
and biological pesticides can be used as a model if the unique aspects
of the plant-pesticides are taken into account. The major
characteristic of plant-pesticides that is different from traditional
pesticides is that the plant itself produces the pesticidal substance
rather than the pesticide being applied to the plant.
Thus, the exposure pattern may be very different for plant-
pesticides than for traditional pesticides, both because of how the
pesticide is produced and the biology of plants. This different
exposure pattern has implications for the evaluation of field tests
(e.g., the analysis of containment of the test) and for exposures
resulting from sale or distribution. In turn, the unique exposure
potential may involve different non-target or endangered species than
for a traditional pesticide. However, the potential for causing adverse
health effects may be more circumscribed than for traditional
pesticides because, in many cases, the only significant route of human
exposure may be oral.
B. General Considerations for Product Development and Sale or
Distribution
1. Product development. As a plant-pesticide product is developed,
it is usually necessary to test, in the field, plants producing the
pesticide. At this point, EPA may not have extensive information on
ecological and human health effects for these products. Unreasonable
adverse effects associated with field tests can be minimized by
conducting these tests under conditions appropriate to ensure
containment. Adequate containment would ensure that exposure of humans
and nontarget organisms to the active ingredient beyond the field test
site is minimal. Thus, for field testing during product development the
Agency would need information to determine whether containment is
sufficient. If containment is not sufficient, information to determine
the potential effects of the uncontained testing would be needed.
Any human dietary exposure will require a tolerance, or exemption
from requirement for a tolerance, regardless of the stage of product
development or the size of the field tests. Even if the crop is
destroyed, a tolerance, or exemption from requirement for a tolerance,
may be necessary if there is genetic outcrossing to other crops that
would be used as food or feed (See Unit V. of this document).
Information addressing health effects thus may be necessary to allow a
tolerance assessment.
2. Sale or distribution. In order to assess the potential exposure
when a plant-pesticide is sold or distributed, EPA will consider
whether all varieties of a crop in which the plant-pesticide is
registered (see Unit V.B. of this document) will be able to express the
pesticidal substance. Potential exposure could also result if the
plant-pesticide is expressed by plant relatives to which the genetic
material encoding the plant-pesticide could be transferred. This
analysis of exposure is a component in the possible identification of
the types of nontarget organisms that associate with particular types
of crops/plants and therefore may be exposed to the pesticidal
substance. This type of analysis would be considered depending on the
plant-pesticide/plant combination. In addition, sale or distribution
will often involve human dietary exposure and may thus require
information to address those risks and to support a tolerance or
tolerance exemption.
C. Product Analysis
Product analysis/characterization data and information are critical
for assessing potential risks to humans and the environment. Product
characterization embraces five basic areas: (1) Identification of the
donor organisms and the nucleotide sequences that are inserted into the
recipient plant; (2) identification and description of the vector or
delivery system used to move the nucleotide sequences into the
recipient plant; (3) identification of the recipient organism,
including information on the insertion of the nucleotide sequences
(e.g., stability of insertion); (4) chemical characterization of the
plant pesticide products; and (5) data and information on the levels of
the pesticidal substances in the recipient plant, including any tissue
specificity of expression.
D. Environmental Fate Analysis
1. Environmental fate risk issues. An accurate assessment of the
fate, transport, and persistence of the pesticidal gene product
(pesticidal substance) in the environment is essential to the entire
risk assessment process. This information will determine if there is
adequate containment during product development and will support the
ecological non-target species and the health effects risk assessments
for sale or distribution of the products. The following environmental
fate risk issues are associated with field tests and sale or
distribution of a plant-pesticide:
(1) Increasing the ability of the modified plant to survive outside
of cultivation through the introduction of a specific trait.
(2) Gene capture and expression of the introduced trait by a wild
or weedy relative.
(3) Potential for a trait conferring a selective advantage to a
plant in a natural plant community with the result of increasing the
``weediness'' of that species.
(4) Environmental fate of the pesticidal substance. The dosage to
soils after plant senescence and incorporation into the soil, rate of
degradation or dissipation and transport in the environment. Also
whether or not the pesticidal substance is either exuded or volatilized
from the plant during the growing season, resulting in a continuous
application to the environment.
The environmental fate of plant-pesticides introduced into the
environment is composed of two facets: the movement of the gene
encoding for the pesticidal substance (biological fate) and the fate of
the pesticidal substance itself (chemical fate). Some of the
information about the biology of the plant producing the plant-
pesticide may be available in the published literature and this
information should be used to address the biological fate risk issues.
There are several points of information that a producer should consider
when developing a plant-pesticide for sale or distribution in
agriculture. These points of information are presented in the Units
VI.D.2. through VI.D.4. of this document. The points are arranged in a
tiered framework that allows for resolution of the risk issue as early
as possible in the review process.
2. Biological fate analysis. The first consideration in the
biological fate analysis is whether or not the plant producing the
plant-pesticide can exist under other than cultivated conditions. This
consideration results from risk issue (1) in Unit V.D.1. above.
The next consideration is whether or not the plant producing the
plant-pesticide has weedy or wild relatives and whether the relatives
are distributed in or near the areas where the plant will be grown.
This consideration results from risk issue (2) in Unit VI.D.1. above.
If the plant producing the plant-pesticide does have weedy or wild
relatives of concern, the next consideration is whether, based on its
life cycle, pollinator requirements, and genetic limitations, it can
take part in a successful outcrossing event.
If the plant producing the plant-pesticide has the ability to
outcross, the next considerations are its outcrossing rate and pollen
longevity under laboratory conditions. If it is determined that either
or both of these factors are high, outcrossing rates should be
determined under field conditions. This consideration addresses risk
issue (2) in Unit VI.D.1. above.
If significant outcrossing is achieved under field conditions a
determination of whether the plant-pesticide confers a selective
advantage to the relative would be made. This consideration addresses
risk issue (3) in Unit VI.D.1. above.
3. Exposure to the pesticidal substance produced by the plant. If
there is a toxicological concern for the plant pesticidal substance, an
assessment of expression levels in all or some parts of the plant may
be required. This consideration addresses risk issue (4) in Unit
VI.D.1. above.
4. Chemical fate analysis. Determining the persistence and movement
of the pesticidal substance in the environment would be required if
there is a toxicological concern for that pesticidal substance. Points
that should be considered are the pesticidal substance's persistence
and mobility in all environmental media (soil, water, and air). If the
substance is persistent and another crop is grown in rotation with the
transformed crop, a crop rotation study would be required. Similarly,
if the pesticidal substance is stable in the environment and is
expected to reach aquatic environments, a fish accumulation study would
be required. This consideration addresses risk issue (4) in Unit
VI.D.1. above.
E. Ecological Effects
Sale or distribution of a plant-pesticide may ultimately lead to
the plant-pesticide being expressed in the entire agricultural crop of
the plant that is producing the plant-pesticide and in any other crops
and/or relatives with which the plant can cross-breed. A careful
analysis of all potential nontarget species (including threatened or
endangered species) that may be susceptible to the pesticidal substance
may thus be needed. Some plant/plant-pesticide combinations may not be
acceptable for registration if use could be expected to result in
unreasonable environmental effects if traditional risk mitigation
restrictions are not appropriate for the plant-pesticide. In these
cases, genetic limitations on the expression of the pesticidal
substance in plants, or on the potential for gene transfer to other
plants, may result in sufficient risk reduction to allow registration.
Also, if the presence of the plant-pesticide is limited to the actual
plant material, the number and kinds of species exposed may also be
limited.
EPA has, for traditional pesticides, relied on single species
testing to evaluate potential effects on nontarget species, and this
approach will continue to be of value. However, the standard test
species and the standard acute exposure protocols used for chemical
pesticides may not be sufficient to evaluate plant-pesticides due to
their unique exposure scenario, e.g., the presence of the pesticidal
substance as part of the plant and the potential for gene flow to other
plants.
In addition, the substance to be tested (whole plants, extracts of
plants, pure pesticidal-substance, etc.) may have to be determined on a
case-by-case basis, but the substance should be tested in an
ecologically relevant manner. Unlike traditional chemical pesticides
where direct contact is the predominant form of exposure, exposure to
plant-pesticides will primarily be from ingestion of, or contact with,
plant tissues that contain plant-pesticides.
Traditional test protocols rely on a maximum-hazard dose to ensure
that potential adverse effects are detected. However, it may be
difficult to obtain a maximum-hazard dose using plant-pesticide
materials if there are low expression levels of the pesticidal
substance in the plant. Therefore, in some cases, chronic exposure
testing may be more appropriate.
The following points may be of particular value in performing an
ecological risk assessment:
(1) An analysis of which non-target species feed on, or contact,
plant parts that will contain the pesticidal substance will be
particularly helpful in identifying the species to be tested.
Consideration should be given to which species are most representative
of those likely exposed to the plant-pesticide.
(2) If the pollen of a plant contains the pesticidal substance, the
pesticide substance may be airborne beyond the immediate field
location. The effect on aquatic invertebrates may need to be
determined. Plant pollen enters the aquatic environment quite readily
through wind movement. In addition, honeybees, and particularly
honeybee larvae, are likely to be exposed to pollen. Honeybee larvae
may be susceptible to these plant-pesticides, especially those intended
to control insect larvae, even if the adult honeybees are resistant.
(3) If the pesticidal substance is expressed in the seed or fruit,
a different range of non-target organisms will be exposed than if the
pesticidal substance is produced in the pollen. In this instance,
possible effects on birds and mammals should be considered.
(4) The duration of testing is a factor. If the pesticidal
substance is expressed by the plant throughout the entire plant life-
cycle, some nontarget species may be exposed to a chronic dose of the
substance as compared to traditional pesticide usage which often
results in an acute dose. Chronic exposure in terms of the duration of
expression of the plant-pesticide by the plant could be measured in
terms relative to the life cycles of nontarget organisms likely to be
exposed.
(5) If, after harvest at the end of the growing season, the plant
tissue containing the plant-pesticide is tilled into the soil or left
in the field to decompose, soil organisms (i.e., Colembola and other
soil arthropods, nematodes, mollusks, and annelids) may receive a low
level chronic exposure, depending on the stability of the pesticidal
substance. This may affect decomposition processes which occur
naturally in the soil.
(6) Threatened or endangered species may be at risk from widespread
or uncontained use of the plant-pesticide. Since the pesticidal
substance may have the potential to be expressed in the entire crop and
related plants, it may be difficult to limit the exposure of threatened
or endangered species. There is particular cause for concern if there
are any threatened or endangered species related to the target species
that feed on the plants or if there are any threatened or endangered
species related to species susceptible to the pesticidal substance.
Information on the feeding habits and preferred food sources of any
potentially affected threatened or endangered species will be needed to
address this issue.
(7) Secondary feeding effects may increase the possibility of non-
target exposure, e.g., the possibility that species feeding on the
plant would accumulate enough pesticide to affect predatory species
feeding on them.
(8) The possibility of transfer of a disease- or insect- resistant
trait to wild or weedy relatives or the presence of the trait in the
crop, itself, may create a weed or may increase the competitiveness of
a known weed. There may be cause for concern if related, naturally-
occurring, pest-resistant plants are weeds, particularly if this
particular pest-resistant trait is found in the most aggressive
varieties of the weeds. If the pesticidal trait results in
significantly greater pest-resistance, analysis of the competitiveness
with naturally occurring weeds may be a practical way to address this
issue.
F. Human Health Affects
Plant-pesticides are likely to present a limited exposure of the
pesticidal substance to humans. In most cases, the predominant, if not
the only, exposure route of concern will be dietary. Significant
respiratory and dermal exposures would be unlikely. A full assessment
to be made from a specific, limited, data set (as compared to
traditional pesticides) can thus be made. Information on the presence
of the pesticidal substance in edible portions of the crop will help
determine the degree of human dietary exposure. In cases where the
plant-pesticide containing crop is used as animal feed, domestic animal
safety information may be necessary.
The types and numbers of mammalian toxicology studies needed for
human health effects risk assessment will depend on whether the plant
pesticide is a protein; and, if not, whether the plant pesticide is
analogous to a traditional chemical pesticide or a biochemical
pesticide.
For plant-pesticides that are proteins, an acute oral toxicity
study in the rodent may be sufficient to address health issues and/or
questions. Although not yet validated, an in vitro digestibility assay
may answer questions about allergenicity or about the potential for
toxicity of proteins including those with a deliberately altered amino
acid sequence.
Naturally occurring non-proteinaceous plant pesticides with a non-
toxic mode of action against the target pest could be addressed in a
manner analogous to biochemical pesticides (although the Agency is
proposing to exempt this category of plant-pesticide under FIFRA, they
would not necessarily be exempt under FFDCA). Non-proteinaceous plant-
pesticides with a toxic mode of action could be addressed as for
traditional chemical pesticides. The focus on data requirements for
non-proteinaceous plant-pesticides will also primarily be on the oral
route of exposure.
G. Development of Resistance to Plant-pesticides
EPA recognizes that there is a potential for the development of
resistance to plant-pesticides. At present, the issue has been raised
particularly in the case of the Bacillus thuringiensis insecticidal
delta-endotoxin. Field resistance to the delta-endotoxin has been
documented for foliar applications of the microbial pesticide, Bacillus
thuringiensis (Ref. 7). It is postulated that resistance to the delta-
endotoxin could develop when it is produced by plants. The development
of insect resistance to the delta-endotoxin could lead to a loss in the
effectiveness of this valuable pesticide. EPA is committed to the
development of pesticides that are viable alternatives to more toxic
and persistent chemical pesticides. The Agency is considering how it
can best encourage the development of agricultural practices that will
minimize the development of resistance to plant-pesticides. Toward this
end, the Agency has begun to analyze the regulatory and nonregulatory
tools it could use to address resistance to all pesticides, including
plant-pesticides.
VII. Interactions With Other Agencies
EPA is the Federal agency primarily responsible for the regulation
of pesticides. However, in fulfilling this mission EPA works closely
with the U.S. Department of Agriculture (USDA) which has
responsibilities under the Plant Pest Act and the Plant Quarantine Act
and the U.S. Food and Drug Administration (FDA) which has
responsibilities under FFDCA.
A. USDA
USDA has authority to prevent the introduction and dissemination of
plant pests under the Plant Pest Act and the Plant Quarantine Act. An
introduction at any acreage of a plant that is under the jurisdiction
of the Plant Pest Act requires either that a permit be obtained from
USDA's Animal and Plant Health Inspection Service (USDA/APHIS) or for
certain plants that a notification be submitted to USDA/APHIS, unless
it has been exempted from those requirements.
EPA and USDA/APHIS have consulted and exchanged information on
plants and plant-pesticides and intend to continue to do so in the
coordination of their regulatory activities. The two agencies also have
and intend to continue to consult closely on scientific issues related
to the safety considerations associated with the environmental impact
of field tests of plant-pesticides.
B. FDA
Pursuant to FFDCA and the reorganization that created EPA,
pesticides as defined by FIFRA are subject to EPA's regulatory
authority under FFDCA. However, FDA's authority under FFDCA extends to
any nonpesticidal substance that may be introduced into a new plant
variety and that is expected to become a component of food.
FDA and EPA have and intend to continue to consult closely on any
jurisdictional questions, as well as on scientific matters where
consultation will be helpful in resolving safety questions. Both
agencies agree that EPA will address under its regulatory jurisdiction
the food safety issues associated with the plant-pesticide, including
marker genes used to confirm the presence of the DNA necessary for the
production of the pesticidal substance. Any food safety questions
beyond those associated with the plant-pesticide, such as those
involving changes to food quality or raised by unexpected or unintended
compositional changes, are under FDA's jurisdiction (Ref. 3).
Similarly, food safety issues associated with alterations in levels of
a substance with pesticidal properties, or the appearance of a
substance with pesticidal properties, that occur as an unintended
consequence of modifications to a non-pesticidal trait would also fall
under FDA's authority..
VIII. External Review
In developing its approach to regulating plant-pesticides, EPA has
requested the advice of two scientific advisory committees in three
meetings. On December 19, 1992, pursuant to section 25 of FIFRA, a
Subpanel of the FIFRA SAP was convened to review a draft policy
statement on plant-pesticides and respond to a series of scientific
questions posed by the Agency primarily on EPA's approach under FIFRA.
On July 13, 1993, a Subcommittee of the EPA Biotechnology Science
Advisory Committee (BSAC) was convened to address a series of
scientific questions primarily on EPA's approach under FFDCA. On
January 21, 1994, a joint meeting of the SAP/BSAC Subpanel on plant-
pesticides was held. The issues raised at these meetings are discussed
below, together with the Agency's response. (Full reports from these
meetings are available in the public docket.)
A. Substances New to the Plant
Questions on how best to describe ``substances that are new to the
plant'' were posed at all three science advisory meetings. At its
December 1992 meeting, the FIFRA Subpanel was asked whether the
taxonomic demarcation of ``genus'' was appropriate, or whether some
other demarcation would be more appropriate. The Subpanel expressed
concern over an exemption based on a taxonomic definition and suggested
the Agency evaluate a series of considerations involving the potential
for quantitative and qualitative differences in exposure to a plant-
pesticide.
The SAP Subpanel suggested that the Agency would ``need to create a
workable balance between effective regulatory oversight and
encouragement of the development of plant-produced pesticides.''
At its July 13, 1993 meeting, the BSAC Subcommittee addressed a
related issue with regard to the regulation of plant-pesticides under
the FFDCA and human dietary exposures to plant pesticides.
Included in questions to the Subcommittee were queries on the
availability of information on current levels of exposure in the diet
to plant-pesticides in raw agricultural commodities and on which plant-
pesticides might be of concern should their levels be significantly
increased.
The BSAC Subcommittee in their report stated that no formal,
complete data base for such information exists. Rather most of this
knowledge is part of breeders' experience, with breeders depending
primarily on familiarity with food crops (e.g., knowledge of which crop
plants have the ability to produce which toxicants) to ensure consumers
are not exposed to deleterious levels of such substances. In general,
little information exists on the range of levels of plant-pesticides in
plants, including ranges within the most studied grouping, food plants.
The mechanisms through which plants display resistance to pests,
moreover, have not been worked out very well. Based on experience,
however, the BSAC Subcommittee suggested EPA consider a scheme based on
sexual compatibility to identify those groupings wherein plant-
pesticides might present new and novel dietary exposures and those that
would not.
The use of sexual compatibility and/or taxonomy as a standard for
the potential for significantly different environmental exposures was
discussed at the January 21, 1994, joint SAP/BSAC Subpanel meeting. The
joint Subpanel members were supplied with the reports of the previous
meetings and drafts of proposals analyzing the strengths and weaknesses
of approaches based on sexual compatibility and/or taxonomy. In
response to the question of whether plants in a sexually compatible
population are likely to share substances or traits, the joint Subpanel
agreed that sexually compatible plants are more likely to have a common
constitution than unrelated plants and thus are less likely to lead to
novel exposures.
The report of the January 21, 1994, joint SAP/BSAC Subpanel
meeting, indicates that the joint Subpanel agrees that both the concept
of sexual compatibility and the concept of taxonomy should restrict the
occurrence of significantly different exposures and finds that Option 3
is a reasonable approach for agricultural plants. However, the Subpanel
questioned whether under the taxonomic criterion of Option 3 (and
Option 2) a low probability of novel exposures can be extended to wild
or semi-wild plants. For these types of plants, the genus standard may
result in the exemption from regulation of plant-pesticides that may
present novel exposures.
The Agency also included a question, at the January 21, 1994, joint
BSAC/SAP meeting, concerning an approach using a criterion based on the
process used to modify the plant, e.g., recombinant DNA methodologies.
As described in the report of the joint BSAC/SAP Subpanel meeting, if
the Agency were to use this approach, it would first exempt plant-
pesticides developed through techniques other than those of modern
biotechnology from its regulatory scope. For those plant-pesticides
that are not exempted because they were developed through techniques of
modern biotechnology, the exemptions proposed by the Agency would apply
(see Units IV.B. and IV.C. of this document).
The joint Subpanel supported the inclusion of a criterion based on
methodologies such as rDNA as a rational approach to making the first
cut as to which plant-pesticides would be regulated. However, the joint
Subpanel cautioned that further exemptions such as those proposed by
EPA should be used in conjunction with the criterion based on
methodology. In addition, the joint Subpanel recommended that the
Agency define methodologies in a way that clearly delineates to the
scientific community and the public what is and is not included in the
regulatory scope, based on current state-of-the-science.
EPA Response: The Agency has chosen to propose to use under both
statutes, an approach based on sexual compatibility. First, this
approach would exempt under both FIFRA and FFDCA, plant-pesticides
having a high probability of being derived from plants having high
numbers of genes in common. Under such circumstances, the likelihood of
new or novel exposures both to the environment and in terms of human
consumption is low.
Second, use of the standard of sexual compatibility will allow EPA
to use its authorities under FIFRA and FFDCA in concert to regulate
plant-pesticides, and thus to utilize, to the extent possible in light
of the different statutory standards, similar approaches to oversight
under each of the two statutes.
Third, the Agency believes that its proposed approach would be
consistent with the SAP Subpanel's concern that EPA ``. . .create a
workable balance between effective regulatory oversight and
encouragement of the development of plant-produced pesticides.'' Under
the preferred approach, novel exposures are not likely to occur with
plant-pesticides exchanged between plants that are sexually compatible
(See also Unit V. of this document for additional discussion).
With regard to the advice of the January 21, 1994, joint SAP/BSAC
Subpanel concerning the use of a process-based criterion in the scope,
if the Agency were to use this approach, plant-pesticides developed
through techniques other than those involving in vitro manipulation of
genetic material would be exempt. In order to meet the recommendations
of the joint Subpanel, the Agency would define this category of plant-
pesticides in the following way: The genetic material that encodes for
the pesticidal substance or leads to the production of the pesticidal
substance is extracted from an organism and introduced into the genome
of the recipient plant or is synthesized in vitro and introduced into
the genome of the recipient plant. The exemptions proposed by the
Agency in Unit IV. of this document would be used in concert with this
criterion. The Agency believes this approach would meet the
recommendations of the SAP/BSAC joint Subpanel. The Agency is
soliciting comment on this approach (see the proposal published
elsewhere in today's issue of the Federal Register entitled ``Plant-
pesticides Subject to the Federal Insecticide, Fungicide, and
Rodenticide Act; Proposed Rule'').
B. Plant-pesticides That Act Primarily by Affecting the Plant
The SAP Subpanel at its December 1992 meeting considered whether
EPA's language clearly and sufficiently identified plant resistance
mechanisms that do not involve substances whose mode of action produces
a direct toxic effect on the pest. The SAP Subpanel stated that for the
most part the language EPA was proposing was clear and appropriately
identified plant resistance mechanisms whose mode of action was not
directly toxic. The Subpanel noted, however, that the issue of
resistance to toxins produced by the pests was not addressed by that
language. The Subpanel recommended insertion of the following statement
into EPA's proposed language: ``Acts in the host plant to produce
target(s) of the toxin that are resistant to the toxin's deleterious
action.''
EPA Response: EPA accepted this recommendation and modified the
language of its approach to incorporate the issue of resistance to
toxins.
C. Viral Coat Proteins
1. FIFRA. The December 18, 1992, SAP Subpanel meeting and the
January 21, 1994, joint SAP/BSAC Subpanel meeting addressed the use of
viral coat protein genes to modify plants to protect the plant from
damage from viral infection. In the discussion at the December 18,
1992, SAP Subpanel meeting, several risk considerations were identified
and the probability of occurrence of each addressed in the SAP Subpanel
report. The SAP Subpanel report stated that the probability of
occurrence of the risks examined is very low (see Unit IV.B.1.c.iii. of
this document and the proposal published elsewhere in todays issue of
the Federal Register entitled, ``Plant-pesticides Subject to the
Federal Insecticide, Fungicide, and Rodenticide Act; Proposed Rule,''
for a more complete discussion). The January 21, 1994, joint SAP/BSAC
Subpanel meeting discussed the alternative option for the exemption of
viral coat proteins from FIFRA regulation. The joint Subpanel
reiterated the statement of the December 18, 1992, SAP Subpanel report
that the potential risks associated with the use of vcp-mediated
resistance coat proteins are low. The SAP/BSAC joint Subpanel, at the
January 21, 1994 meeting, did not support the inclusion of the
alternative partial exemption option. Unit IV.B.1.c. of this document
describes how the SAP and joint SAP/BSAC discussion of vcp-mediated
resistance viral coat proteins supplements and influences EPA's
analysis.
EPA Response: EPA agrees that the probability of risks from the
introduction of viral coat protein genes into plant genomes is low, and
as its preferred option proposes to exempt these plant-pesticides from
FIFRA oversight. Because of public comments received at the December
18, 1992, SAP Subpanel meeting and the January 21, 1994, joint SAP/BSAC
meeting, however, concerning viral coat proteins and selective
advantage to wild relatives of managed plants, EPA is offering for
comment in this document the alternative approach to viral coat
proteins to allow the fullest discussion possible.
2. FFDCA. The December 18, 1992, SAP Subpanel also addressed the
question of whether viral coat proteins might present a dietary risk.
It stated that ``[s]ince viruses are ubiquitous in the agricultural
environment at levels higher than will be present in transgenic plants,
and there has been a long history of `contamination' of the food supply
by virus coat protein, there is scientific rational for exempting
transgenic plants expressing virus coat protein from the require of a
tolerance.''
EPA Response: EPA agrees with this position and is proposing an
exemption from the requirement of a tolerance for viral coat proteins.
D. Nucleic Acids
The BSAC Subcommittee on July 13, 1993, confirmed that nucleic
acids (DNA and RNA), are present in the cells of every living organism,
including plants, microorganisms and animals, used for food, and do not
raise safety concerns as a component of food.
EPA Response: EPA agrees with the BSAC Subcommittee and is
proposing to exempt nucleic acids (DNA and RNA) as a class from the
requirement of a tolerance under FFDCA.
E. Pest Resistance
The SAP Subpanel on December 18, 1992, addressed the issue of
development of pest resistance to a pesticidal substance produced by
plants. The Subpanel stated that ``[d]elaying the evolution of
resistance is clearly important if we are to realize the full potential
of effective and safe crop protection that could be obtained by
application of biotechnology.'' The SAP Subpanel urged EPA to actively
assess the problem of pesticide resistance, especially when the
pesticide is part of the progression toward use of ``safer
pesticides.''
EPA Response: EPA agrees that the issue of the development of
resistance is an important one and is examining what it might do to
address this issue under its regulatory authorities.
F. Allergenicity
The December 18, 1992, SAP Subpanel, in its discussion of EPA's
approach for oversight of plant-pesticides under FFDCA, raised the
question of the potential allergenicity of certain food components.
EPA Response: EPA is aware that there are food components that can
induce food allergies and that the issue of allergenicity in novel
foods is important. EPA hosted, along with FDA and USDA/APHIS, a
scientific conference on food allergens on April 18-19, 1994. The
agencies are now reviewing the discussions that were held at the
conference.
G. In Vitro Digestibility Assay
EPA asked the July 13, 1993, BSAC Subcommittee to consider the
scientific merits and limitations of an in vitro digestibility assay to
predict toxicity from dietary exposure to proteinaceous transgenic
plant pesticides. This in vitro digestibility assay would use features
of the test, 701- Disintegration for Plain Coated Tablets or Enteric-
coated Tablets, of the US Pharmacopeia.
The Subcommittee responded to the following specific questions on
the in vitro digestibility assay. What are the appropriate assay
endpoints (i.e., free amino acids, peptides) to conclude that a protein
is digested to harmless components? What are the best methods to
quantify digestibility? With plant associated proteinaceous pesticides,
what is the most relevant test material? How predictive is the in vitro
assay for addressing the variations in luminal adsorption that occur
with maturation, (i.e., infant versus adult versus geriatric uptake)?
What is the significance of digestive disorders like hypochlorhydria
and enzyme deficiencies with respect to the in vitro digestibility
assay and interpretation of assay results? To what extent can the amino
acid sequence of known toxic proteins and known sequences of non-toxic
proteins be used to predict toxicity or lack of toxicity in other
proteins? Would fragments of non-toxic proteins also be expected to be
non-toxic?
In response, the Subcommittee indicated that it could not endorse
use of an in vitro digestibility assay as the sole test for determining
toxicity. An in vitro digestibility assay might provide useful
information if employed in conjunction with other tests.
The Subcommittee suggested that if an in vitro digestibility test
assay is to be used as part of a more comprehensive toxicological
evaluation, the test should utilize a range of gastric and intestinal
phases in order to address variations in luminal absorption that occur
with maturation.
In response to the question concerning the appropriate test
material, the Subcommittee suggested the test be conducted with
purified plant-pesticide. Purified plant-pesticide may be tested in the
presence or absence of standardized mixtures, (e.g., protein/agar). The
standardized mixture would approximate the condition of a plant-
pesticide ingested in food.
With regard to the question concerning how to best quantify
digestibility, the Subcommittee suggested a Western blot could be used
to determine the degree of digestion of the plant-pesticide.
In response to the question on what constitutes the appropriate
test material and assay endpoint and the question of whether fragments
of non-toxic proteins could be expected to be non-toxic, the
Subcommittee noted that partially digested proteins and peptides may be
toxic even if the parent protein is not. They suggested it may
therefore be difficult to declare anything short of complete digestion
to amino acids as non-toxic.
The Subcommittee suggested the Agency consider exploring other
methods of addressing the issue of toxicity from dietary exposure,
including: in vitro cell and culture systems to address questions of
digestibility, translocation/transport across the lumen, and binding to
cells of the GI tract; feeding studies involving whole animal systems,
specifically those involving ``failure to thrive'' assays; cell binding
assays to test for the presence of receptors for toxins; an in vivo
assay using brine shrimp. The Subcommittee cautioned, however, that the
brine shrimp or other nonmammalian test systems need to be evaluated
carefully to ensure that the data can be extrapolated to mammalian
species and to determine that the test responds appropriately to
proteinaceous plant-pesticides. The Subcommittee indicated that EPA may
have to rely on a case-by-case approach to assessing toxicity for the
near future.
EPA Response: EPA is exploring the suggestions of the BSAC
Subcommittee as it develops its data requirements for plant pesticides.
H. Points to Consider for Data Needs
EPA asked the January 21, 1994, joint SAP/BSAC Subpanel to consider
the ``points to consider'' EPA had developed for plant-pesticides in
terms of product analysis, ecological effects, environmental fate, and
human health effects.
1. Product analysis. In terms of product analysis, the joint
Subpanel endorsed the Agency position that the evaluation of the risks
posed by plant-pesticides demands that methods be available for product
analysis and characterization of plant-pesticides in terms of: (1)
Identification of the donor organisms and gene sequences that are
inserted into the recipient plant; (2) identification and description
of the vector or gene delivery systems; (3) identification of the
recipient organisms, including information on the insertion of the gene
sequences; (4) chemical characterization of the plant-pesticide
products; and (5) quantification of the plant-pesticides in recipient
plants.
The joint Subpanel suggested some additional information may be
useful: (1) Are the gene sequences stable in the recipient organism or
are they prone to deletion or mutation?; (2) The chemical
characterization of the plant-pesticides should be equally rigorous
whether the products are proteinaceous or nonproteinaceous; (3) Methods
for quantification of plant-pesticides are essential for assessing
exposure to target and nontarget organisms, for assessing human
exposure, for determining environmental fate, transport, and
persistence, and for determining the distribution (i.e., in edible and
nonedible portions) of plant-pesticides within plants.
2. Ecological effects. In terms of ecological effects, the joint
Subpanel stated that EPA in its proposed policy statement addresses the
major issues of concern in assessing the ecological risks associated
with the testing and commercialization of plant-pesticide products.
They suggested, however, that there are several points that could be
expanded to better address potential ecological risks. These are:
(1) Substances to be tested: While a case-by-case determination is
appropriate, it is important that the substance be tested in an
ecologically relevant form under an ecologically relevant protocol.
Unlike conventional pesticides for which direct contact with the
pesticide is a primary means of exposure, exposure to plant-pesticides
will be primarily through ingestion of, or contact with, pesticide-
containing plant tissues. Experience with bioassays of plant defensive
chemicals has shown the plant milieu, and the method of exposure, may
dramatically modify (enhance or ameliorate) the resultant effects of
the chemical. Consequently, test substances and test protocols that
lack ecological relevance may provide results that are inappropriate as
a basis for regulatory decisions. The joint Subpanel recommended that
EPA develop a series of guidelines for identifying ecologically
relevant test substances and develop ecologically relevant test
protocols.
(2) The joint Subpanel noted that EPA identifies expression of the
plant-pesticide by the plant throughout the entire plant life-cycle as
a consideration in determining the potential for chronic exposure on
nontarget species to the plant-pesticide. Because plant life-cycles can
vary in duration, and because exposure of nontarget species to a plant-
pesticide for periods of shorter duration than a plant's life-cycle
could have potentially significant ecological effects, expression of
the pesticidal substance throughout the plant's life cycle seems to be
a criterion that is not necessarily relevant in an ecological context.
Although recognizing that it would lack the regulatory consistency of
the plant life-cycle criterion, the joint Subpanel concluded that a
criterion based on expression of the plant- pesticide for ``prolonged
periods'' would seem to have greater ecological relevance. The joint
Subpanel also stated that the meaning of ``prolonged period'' would
have to be determined on a case-by-case basis and would depend on the
types of nontarget organisms that are likely to be affected. The joint
Subpanel recommended that EPA develop guidelines that define the
potential for chronic exposure in terms of the duration of expression
of the pesticide substance by a plant, relative to the life cycles of
nontarget organisms likely to be exposed.
(3) The joint Subpanel also commented on triggers for requiring
EUPs for plant-pesticides during the testing stage, noting that the
potential for nontarget exposure through gene capture by wild relatives
will increase as the number of test sites increases, in areas where
wild relatives may occur. Accordingly, the joint Subpanel recommended
that EPA give careful consideration to addressing this potential for
increased ecological risk in those situations in which there is
potential for gene capture by wild plants when establishing an EUP
trigger.
3. Human health effects. In terms of human health effects, the
joint Subpanel noted that nontarget populations at potential risk from
exposure to plant-pesticides may include humans and data requirements
should take into account the diverse nontarget subpopulations that
could be potentially exposed or at risk. Examples of specific
subpopulations at potential risk may include individuals who are high
consumers (e.g., vegetarians; children with high intake to body weight
ratios; over eaters), individuals with compromised digestive systems
(e.g., elderly individuals; persons receiving treatment for digestive
disorders or diseases).
4. EPA response. EPA agrees with the joint Subpanel's suggestions
and has considered them in the points to consider and will consider
them as the Agency develops its data requirements for plant-pesticides.
IX. Request for Comment
A. Scope of Coverage for the Regulatory Scheme for Plant-Pesticides
under FIFRA and FFDCA
1. FIFRA exemptions: Requests for comment on the proposed
exemptions under FIFRA and the options for these exemptions can be
found in the Federal Register document entitled: ``Plant-pesticide
Subject to the Federal Insecticide, Fungicide, and Rodenticide Act;
Proposed Rule.'' All comments relating to the proposed exemptions under
FIFRA should be submitted in the context of this proposed regulation
and should be identified by the docket control number OPP-300369.
2. FFDCA exemptions: Requests for comment on EPA's proposed
exemption from the requirement of a tolerance for categories of plant-
pesticides that will not result in significantly different dietary
exposure can be found in the Federal Register document entitled,
``Plant-pesticides; Proposed Exemption from the Requirement of a
Tolerance Under the Federal Food, Drug, and Cosmetic Act'' and should
be identified by the docket control number OPP-300368. All comments
relating to this proposed exemption from the requirement of a tolerance
should be submitted in the context of that proposed regulation.
Similarly, all comments relating to the other two proposed exemptions
from the requirement of a tolerance should be submitted in the context
of these proposed regulations and should be submitted under the docket
control numbers OPP-300367 and OPP-300371 (see the proposals published
elsewhere in todays issue of the Federal Register entitled ``Plant-
pesticides; Proposed Exemption from the Requirement of a Tolerance for
Viral Coat Proteins in Plants'' and ``Plant-pesticides; Proposed
Exemption from the Requirement of a Tolerance For Nucleic Acids
Produced in Plants.''
B. EUP Triggers for Field Testing
EPA has described in this Federal Register document one preferred
approach and four alternative approaches for identifying when producers
would be required to obtain an EUP. Commenters are advised that the
Agency may choose to implement any of these five approaches or some
combination thereof. EPA recognizes that each of these five approaches
has advantages and disadvantages. EPA is soliciting comment on these
approaches. Commenters in stating a preference for an approach are
asked to describe the factors weighing most heavily in forming their
preference.
X. Economic Analysis
The regulatory impact analysis (RIA) evaluates the costs and
benefits of amending the Code of Federal Regulations to allow for the
regulation or exemption of specific types of plant-pesticides under
FIFRA (40 CFR 152.20 and 40 CFR part 174). This report is intended to
meet the requirements for a RIA as established by Executive Order No.
12866, the Regulatory Flexibility Act, and section 25 of FIFRA.
The RIA presents the alternative regulatory options and the costs
that were considered by the Agency under FIFRA, including two options
that were considered by the Agency but not included in the proposed
rule. Four possible approaches to the regulation of plant-pesticides
under FIFRA were evaluated in the RIA that allowed for varying degrees
of regulatory coverage. RIA Option 1 is the most limited alternative in
regulatory scope. RIA Option 2 represents EPA's proposed, and
preferred, regulatory scope and is broader in coverage than RIA Option
1. In addition to those plant-pesticides regulated under RIA Option 2,
RIA Option 3's scope would include viral coat proteins used as plant-
pesticides. Finally, under RIA Option 4, all plant-pesticides,
including those that result from traditional plant breeding, would be
subject to the requirements of FIFRA. The costs for RIA Option 2 (the
Agency's preferred option) are substantially lower than RIA Option 4.
Refer to the proposal published elsewhere in todays issue of the
Federal Register entitled ``Plant-Pesticides Subject to the Federal
Insecticide, Fungicide, and Rodenticide Act; Proposed Rule'' for a
summary of the RIA. The entire text of the RIA can be found in the
public docket for this proposed rule (OPP-300370).
XI. References
(1) EPA issue paper. FIFRA: Benefit and environmental risk
considerations for inherent plant-pesticides.
(2) EPA issue paper. Issues associated with the regulation of viral
coat proteins under FIFRA and FFDCA.
(3) Food and Drug Administration. 1992. Foods derived from new
plant varieties. (57 FR 22984).
(4) Klaasen, C.D., M.O. Amdur, and J.D. Doull. 1986. Casarett and
Doull's Toxicology: The Basic Science of Poisons. Third Edition.
Macmillan Publishing Company, New York.
(5) International Food Biotechnology Council, 1990. Biotechnologies
and food: Assuring the safety of foods produced by genetic
modification. In: Regulatory Toxicology and Pharmacology. Vol. 12.
Academic Press, New York.
(6) Lamb, C.J., J.A. Ryals, E.R. Ward, and R.A. Dixon. 1992.
Emerging strategies for enhancing crop resistance to microbial
pathogens. Bio/Technology. 10:1436-1445.
(7) Tabashnick, B.E., M.L. Cushing, N. Finson and M.W. Johnson.
1990. Field development of resistance to Bacillus thuringiensis in
diamondback moth (Lepidoptera: Plutellidae). Journal of Economic
Entomology. 83:1671-1676.
(8) Tolin, S.A. 1991. Persistence, establishment, and mitigation of
phytopathogenic viruses. In: Risk Assessment in Genetic Engineering.
Edited by M.A. Levin and H.S. Strauss. McGraw-Hill, Inc., New York. pp
114-139.
XII. Regulatory Assessment Requirements
A. Executive Order 12866
Under Executive Order 12866 (58 FR 51735, October 4, 1993), the
Agency must determine whether the regulatory action is ``significant''
and therefore subject to review by the Office of Management and Budget
(OMB) and the requirements of the Executive Order. Under section 3(f),
the order defines a ``significant regulatory action'' as an action that
is likely to result in a rule (1) Having an annual effect on the
economy of $100 million or more, or adversely and materially affecting
a sector of the economy, productivity, competition, jobs, the
environment, public health or safety, or State, local, or tribal
governments or communities (also referred to as ``economically
significant''); (2) creating serious inconsistency or otherwise
interfering with an action taken or planned by another agency; (3)
materially altering the budgetary impacts of entitlement, grants, user
fees, or loan programs or the rights and obligations of recipients
thereof; or (4) raising novel legal or policy issues arising out of
legal mandates, the President's priorities, or the principles set forth
in this Executive Order. Pursuant to the terms of this Executive Order,
it has been determined that this proposed policy statement is a
``significant regulatory action'' because it raises novel policy issues
arising out of FIFRA legal mandates. As such, this action has been
submitted to OMB for review, and any comments or changes made in
response to OMB suggestions or recommendations, will be documented in
the public record.
B. Regulatory Flexibility Act
This proposed policy statement was reviewed under the provisions of
section 3(a) Regulatory Flexibility Act (RFA) [5 U.S.C. 605(b)]. The
RFA requires that agencies take special note of the impact of proposed
regulations on small entities. Analysis requirements under the RFA can
and should be combined with the analysis required under Executive Order
12866.
The regulatory flexibility analysis of this proposed policy for
plant-pesticides on small entities is demonstrated within the
structuring of the four regulatory options proposed. These options were
considered after extensive evaluations of the benefit/risk tradeoffs
between option cost and risk reduction provided. The Agency has
structured the resulting options from a narrow regulatory scope (RIA
Option 1) to a broad regulatory scope (RIA Option 4) and as such, has
conducted an ``inherent'' sensitivity analysis for small firms likely
to be affected by this regulation. The Agency has determined that the
tradeoffs between the benefits and risks of the proposed regulations
are optimized under RIA Option 2, EPA's proposed scope.
C. Paperwork Reduction Act
The information collection requirements in this proposed policy
statement have been submitted for approval to the Office of Management
and Budget (OMB) under the Paperwork Reduction Act, 44 U.S.C. 3501 et
seq. An Information Collection Request document has been prepared by
EPA (ICR No. 1693.01) and a copy may be obtained from Sandy Farmer,
Information Policy Branch, (Mail Code 2136), Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460, or by calling (202) 260-
2740.
This collection of information has an estimated reporting burden
averaging 1,143 hours per response and an estimated annual
recordkeeping burden averaging 74 hours per respondent. These estimates
include time for reviewing instructions, searching existing data
sources, gathering and maintaining the data needed, and completing and
reviewing the collection of information.
Send comments regarding the burden estimate or any other aspect of
this collection of information, including suggestions for reducing this
burden to Chief, Information Policy Branch, (Mail Code 2136),
Environmental Protection Agency, 401 M St., SW., Washington, DC 20460;
and to the Office of Information and Regulatory Affairs, Office of
Management and Budget, Washington, DC 20503, marked ``Attention: Desk
Officer for EPA.'' The final rule will respond to any OMB or public
comments on the information collection requirements contained in this
proposed policy statement.
List of Subjects
Environmental protection, Biotechnology, Labeling, Plant-
pesticides, Plants.
Dated: November 15, 1994.
Carol M. Browner,
Administrator.
[FR Doc. 94-28821 Filed 11-22-94; 8:45 am]
BILLING CODE 6560-50-F