Proposed Policy; Plant-Pesticides Subject to the Federal Insecticide, Fungicide, and Rodenticide Act and the Federal Food, Drug, and Cosmetic Act

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 int

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