[Federal Register Volume 85, Number 197 (Friday, October 9, 2020)]
[Proposed Rules]
[Pages 64308-64344]
[FR Doc No: 2020-19669]

Vol. 85

Friday,

No. 197

October 9, 2020

Part IV

Environmental Protection Agency

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40 CFR Part 174

Pesticides; Exemptions of Certain Plant-Incorporated Protectants (PIPs)
Derived From Newer Technologies; Proposed Rule

Federal Register / Vol. 85, No. 197 / Friday, October 9, 2020 /
Proposed Rules

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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 174

[EPA-HQ-OPP-2019-0508; FRL-10014-10]
RIN 2070-AK54

Pesticides; Exemptions of Certain Plant-Incorporated Protectants
(PIPs) Derived From Newer Technologies

AGENCY: Environmental Protection Agency (EPA).

ACTION: Proposed rule.

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SUMMARY: The Environmental Protection Agency (EPA) is proposing
regulations that would allow for an exemption under the Federal
Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal
Food, Drug, and Cosmetic Act (FFDCA) for certain PIPs that are created
in plants using biotechnology, as long as their pesticidal substances
are found in plants that are sexually compatible with the recipient
plant and meet the proposed exemption criteria, ensuring their safety.
The current exemption for PIPs is limited to PIPs moved through
conventional breeding. EPA's proposed rule would allow certain PIPs
created through biotechnology to also be exempt under existing
regulations, in cases where those PIPs pose no greater risk than PIPs
that meet EPA safety requirements, and could have otherwise been
created through conventional breeding. The proposed rule also includes
a process through which developers of PIPs based on sexually compatible
plants created through biotechnology submit either a self-determination
letter or request for EPA confirmation that their PIP meets the
criteria for exemption. For increased flexibility in bringing PIPs to
market, a developer can also submit both. EPA anticipates several
benefits that may result from exempting these PIPs. These include lower
costs from reduced regulatory burden, increased research, development,
and commercialization of pest control options for farmers, particularly
in minor crops, and reduced use of conventional pesticides which could
provide environmental benefits.

DATES: Comments must be received on or before December 8, 2020.

ADDRESSES: Submit your comments, identified by docket identification
(ID) number EPA-HQ-OPP-2019-0508, through the Federal eRulemaking
Portal at http://www.regulations.gov. Follow the online instructions
for submitting comments. Do not submit electronically any information
you consider to be Confidential Business Information (CBI) or other
information whose disclosure is restricted by statute.
    Due to the public health concerns related to COVID-19, the EPA
Docket Center (EPA/DC) and Reading Room is closed to visitors with
limited exceptions. The staff continues to provide remote customer
service via email, phone, and webform. For the latest status
information on EPA/DC services and docket access, visit https://www.epa.gov/dockets.

FOR FURTHER INFORMATION CONTACT: Anne Overstreet, Biopesticides and
Pollution Prevention Division (7511P), Office of Pesticide Programs,
Environmental Protection Agency, 1200 Pennsylvania Ave. NW, Washington,
DC 20460-0001; main telephone number:<PHONE_NUMBER>; email address:
<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION:

I. Executive Summary

A. Does this action apply to me?

    You may be potentially affected by this action if you are a
developer or registrant of a PIP. This proposal also may affect any
person or company who might petition the Agency for a tolerance or an
exemption from the requirement of a tolerance for any residue of a PIP.
The following list of North American Industrial Classification System
(NAICS) codes is not intended to be exhaustive, but rather provides a
guide to help readers determine whether this action may apply to them:
     Pesticide and Other Agricultural Chemical Manufacturing
(NAICS code 325320), e.g., pesticide manufacturers or formulators of
pesticide products, importers or any person or company who seeks to
register a pesticide or to obtain a tolerance for a pesticide.
     Crop Production (NAICS code 111), e.g., seed companies.
     Colleges, universities, and professional schools (NAICS
code 611310), e.g., establishments of higher learning which are engaged
in development and marketing of PIPs.
     Research and Development in the Physical, Engineering, and
Life Sciences (except Nanobiotechnology) (NAICS code 541714), e.g.,
biotechnology research and development laboratories or services.
    If you have any questions regarding the applicability of this
action to a particular entity after reading the regulatory text,
consult the technical person listed under FOR FURTHER INFORMATION
CONTACT.

B. What action is the Agency taking?

    EPA is proposing to exempt qualifying ``PIPs based on sexually
compatible plants created through biotechnology'' from the requirements
of FIFRA (except for the adverse effects reporting requirement at 40
CFR 174.71 and a proposed recordkeeping requirement at 40 CFR 174.73),
and the residues of those PIPs from section 408 of FFDCA. PIPs are
defined at 40 CFR 174.3 as ``a pesticidal substance that is intended to
be produced and used in a living plant, or in the produce thereof, and
the genetic material necessary for the production of such a pesticidal
substance. [The PIP] also includes any inert ingredient contained in
the plant or the produce thereof.'' EPA's proposal identifies a class
of PIPs, i.e., ``PIPs based on sexually compatible plants created
through biotechnology,'' as those PIPs that are created through
biotechnology and in which the pesticidal substance is found in plants
that are sexually compatible with the recipient plant (i.e., the
engineered plant) and that meet specific safety criteria. Although the
amended definition proposed for ``sexually compatible'' specifically
refers to a viable zygote formed through the union of two gametes, for
this proposal EPA includes in its exemption also PIPs engineered in
plants that are propagated vegetatively (e.g., potatoes and bananas).
This approach aligns with the Agency's longstanding approach for
exempting PIPs in vegetatively propagated plants created through
conventional breeding and is consistent with the existing exemption of
PIPs from sexually compatible plants created through conventional
breeding. The proposed regulatory text for the exemptions from FIFRA
and the FFDCA identifies a number of factors intended to ensure that
the resulting PIP only produces a pesticidal substance found in plants
that are sexually compatible with the recipient plant and thereby
ensuring that these substances do not pose different risks to humans
and the environment compared to those present in conventionally bred
plants. While EPA believes the possibility of adverse effects from the
PIPs proposed for exemption to be highly unlikely, it is important to
note that the adverse effects reporting requirement under 40 CFR 174.71
would also apply to those PIPs proposed for exemption, as it does for
currently exempt PIPs from sexually compatible plants. This requirement
allows EPA to reconsider whether a PIP continues to meet the criteria
for exemption upon learning of any adverse effects (e.g., injurious or
deleterious

levels in food plants). As described in the preamble of the July 19,
2001 Federal Register notice implementing 40 CFR 174.71 (66 FR 37772;
July 19, 2001), the reports on human health or the environment alleged
to have been caused by the PIP would be made to EPA, but EPA will share
such reports with the Food and Drug Administration (FDA), and as such,
40 CFR 174.71 is a means of ensuring that EPA and FDA can address any
potential hazard. The proposed rule also includes a process through
which developers are required to submit either a letter of self-
determination or a request for EPA confirmation that a PIP based on a
sexually compatible plant created through biotechnology meets the
criteria for exemption.

C. What is the Agency's authority for taking this action?

    This action is being proposed under the authority of FIFRA section
25 (7 U.S.C. 136w) and FFDCA section 408(e) (21 U.S.C. 346a(e)). FIFRA
section 25(a)(1) authorizes EPA to issue regulations to carry out the
provisions of FIFRA in accordance with certain procedures prescribed in
that section. In addition, FIFRA section 25(b) allows EPA to promulgate
regulations to exempt from the requirements of FIFRA any pesticide
which the Administrator determines is ``of a character which is
unnecessary to be subject to [FIFRA] in order to carry out the purposes
of [FIFRA].''
    FFDCA section 408(e) authorizes EPA to initiate actions to
establish tolerances or exemptions for pesticide chemical residues that
meet the safety standard. See also the discussion in Unit IV.

D. Why is EPA taking this action?

    Many plants, including those used for food, naturally produce
substances that have pesticidal properties. Humans have relied on the
presence of these substances for millennia to improve resistance in new
agricultural and non-agricultural plant varieties by moving these
traits between sexually compatible plants through conventional
breeding. Because these substances may be at unsafe levels in
undomesticated plants, rendering such plants inedible, breeders have
developed established procedures to ensure that the substances are kept
to safe levels when introduced into plant varieties intended for human
consumption. For the purposes of FIFRA, when these substances are
introduced intentionally into a plant for a pesticidal purpose, the
resulting product is considered a pesticide, and more specifically, a
PIP.
    In 2001, EPA published exemptions for PIPs moved through
conventional breeding at 40 CFR 174.25, ``plant-incorporated protectant
from sexually compatible plant,'' and at 40 CFR 174.508, ``pesticidal
substance from sexually compatible plant; exemption from the
requirement of a tolerance.'' For these exemptions, EPA defined
sexually compatible plants as those for which ``a viable zygote is
formed only through the union of two gametes through conventional
breeding.'' This includes those plants which can exchange genetic
information unrestrictedly with each other through natural processes,
such as pollination, and also those that are unable to exchange genetic
information freely, but that are closely related enough that techniques
employed in conventional breeding can facilitate their interbreeding.
It specifically excludes plants developed through biotechnology. At
that time, EPA did not exempt PIPs that are created through
biotechnology and that are found in sexually compatible plants, but
rather issued a supplemental proposal to exempt these PIPs because
additional criteria needed to be developed. EPA ultimately withdrew
that proposal in 2018 and indicated that, if the Agency were to pursue
exemption of PIPs developed through biotechnology in the future, a new
proposed rule would be issued (Ref. 1), as it became evident that
exemption criteria should be developed given advances in biotechnology
tools (see Unit II.C.2.).
    Recent advances in biotechnology offer precise means by which genes
coding for pesticidal substances can be inserted into a plant genome
and allow for engineering of those genes that already exist within a
plant. Due to these technical characteristics, PIPs can now be created
that are virtually indistinguishable from those created through
conventional breeding. EPA was therefore able to develop specific
exemption criteria that reflect the precise nature of new technologies.
The proposed criteria are intended to identify a group of PIPs that
would be exempt from both the requirements of FIFRA, with the exception
of the adverse effects reporting requirement (codified at 40 CFR
174.71) and the recordkeeping requirement (proposed at 40 CFR 174.73),
and that would also qualify for a tolerance exemption under the FFDCA.
These PIPs are created through the use of biotechnology and, given the
proposed regulatory criteria, pose no greater risk than the sexually
compatible PIPs that are already exempt. EPA refers to this group as
``PIPs based on sexually compatible plants created through
biotechnology.'' The Agency's findings, including an assessment of the
environmental and human health risks for this proposal, are presented
in Unit VI.
    EPA's proposal limits the type of plants, and thus the gene pool,
that can act as a source of these exempt PIPs to those that are
sexually compatible with the recipient plant. EPA is also proposing to
amend the definition of ``sexually compatible'' to state that ``a
viable zygote can be formed through the union of two gametes through
conventional breeding.'' EPA believes that this proposed definition is
more biologically correct, because it refers to the ability of two
gametes to form a viable zygote. This amendment would also allow for
use of the phrase ``sexually compatible'' in the proposed exemptions.
As a housekeeping task, EPA proposes to amend the existing PIPs from
sexually compatible plants exemption at 40 CFR 174.25, along with its
accompanying exemptions at 40 CFR 174.508 and 174.705, to clarify that
those apply only to PIPs created through conventional breeding, thus
differentiating them from those PIPs proposed for exemption that are
created through biotechnology. These changes are necessary due to the
amended definition of ``sexually compatible'' but will not change
implementation of the existing exemption for PIPs from conventional
breeding. EPA's proposed exemptions are developed to be consistent with
the current exemption at 40 CFR 174.25 for PIPs developed through
conventional breeding techniques, and are expected to alleviate
regulatory burden for developers that may wish to utilize biotechnology
in creating pesticide products that are equivalent to those already
exempt under FIFRA and the FFDCA.
    On June 11, 2019, Executive Order 13874 (84 FR 27899, June 11,
2019) on ``Modernizing the Regulatory Framework for Agricultural
Biotechnology Products'' was issued. The exemption proposed by EPA in
this document is intended to further implement section 4(b) of that
Executive Order, which directs the U. S. Department of Agriculture
(USDA), EPA, and FDA (``to the extent consistent with law and the
principles set forth in section 3'' of the order) to ``use existing
statutory authority, as appropriate, to exempt low-risk products of
agricultural biotechnology from undue regulation.'' Among other things,
section 3 of Executive Order 13874 provides that regulatory decisions
should be science-based and evidence-based, taking economic factors
into account as

appropriate and consistent with applicable law; that regulatory reviews
should be conducted in a timely and efficient manner; and that
biotechnology regulations should be transparent, predictable, and
consistent. As part of the effort to implement Executive Order 13874,
the USDA recently revised its regulations at 7 CFR part 340 through a
rulemaking entitled ``Movement of Certain Genetically Engineered
Organisms.'' (85 FR 29790, May 18, 2020). In that rule, USDA amended
its regulations regarding the movement (importation, interstate
movement, and environmental release) of certain genetically engineered
organisms in response to advances in genetic engineering and USDA's
understanding of the plant pest risk posed by genetically engineered
organisms, thereby reducing the regulatory burden for developers of
organisms that are unlikely to pose plant pest risks. Both EPA and USDA
use the term ``conventional breeding'' in their respective rulemakings.
However, it should be noted that each Agency uses the term in the
context of its own regulations and that the term may have slightly
different meanings depending on context.
    The process for exemption under both the EPA proposal and USDA's
rule includes the option for developers to self-determine whether their
product meets the criteria for exemption. EPA is proposing to require
the developer notify EPA of that self-determination with a letter or,
in the alternative, to request EPA confirmation that a particular PIP
qualifies for exemption (developers may also submit both a self-
determination letter and a confirmation request). Because developers of
exempted PIPs will still be subject to FIFRA's adverse effects
reporting requirement and the recordkeeping requirement that is part of
EPA's proposed rule, EPA believes it is appropriate to require
submission of a self-determination letter or a confirmation request in
order to enable EPA to monitor compliance with EPA's regulations and to
take action to avoid adverse health impacts, if necessary.

E. What are the estimated incremental impacts of this action?

    EPA has evaluated the potential incremental impacts of the proposed
exemptions in the document entitled ``Cost Analysis of the Proposed
Rule Exempting Certain Plant-Incorporated Protectants (PIPs) from
Registration'' (Ref. 2), which is available in the docket, discussed in
greater detail in Unit VI.A., and is briefly summarized here.
1. Benefits of the Proposed Exemptions
    The rule is estimated to reduce overall registration costs to
developers of PIPs based on sexually compatible plants created through
biotechnology, and the cost savings per product are approximately
$444,000-$459,000. Of the entities likely to develop PIPs based on
sexually compatible plants created through biotechnology, EPA currently
estimates that approximately 80% are small entities. These cost savings
would be realized as EPA approval of new active ingredients are sought.
The proposed exemption of PIPs based on sexually compatible plants
created through biotechnology is likely to remove a potential barrier
to market entry for small entities.
2. Costs of the Proposed Exemptions
    In the proposed rule, for a PIP to be exempt, a developer would be
required to notify EPA through a self-determination letter or through a
request for EPA confirmation that the PIP meets the exemption criteria.
The proposed rule would also require that a developer maintain
documents supporting its determination. Developer costs pertaining to
the required exemption eligibility determination process and
recordkeeping are estimated in the Agency cost analysis for the
proposed rule. These costs are representative of developer labor and
laboratory costs that would be required to generate the necessary
information and data.
    The developer cost of the exemption eligibility determination
process is expected to be less than what would otherwise be required of
a developer to obtain a registration. The cost analysis developed by
the Agency is an overall cost reduction for developers of these types
of PIPs. Adverse effects due to aggregate exposure to residues of
pesticidal substances from PIPs based on sexually compatible plants
created through biotechnology through the dietary, non-food oral,
dermal and inhalation routes are highly unlikely, as the exemption
eligibility determination process requires that the developer certify
that the PIP meets the exemption criteria.

F. What should I consider as I prepare my comments for EPA?

1. Submitting CBI
    Do not submit this information to EPA through regulations.gov or
email. Clearly mark the part or all of the information that you claim
to be CBI. For CBI information in a disk or CD-ROM that you mail to
EPA, mark the outside of the disk or CD-ROM as CBI and then identify
electronically within the disk or CD-ROM the specific information that
is claimed as CBI. In addition to one complete version of the comment
that includes information claimed as CBI, a copy of the comment that
does not contain the information claimed as CBI must be submitted for
inclusion in the public docket. Information so marked will not be
disclosed except in accordance with procedures set forth in 40 CFR part
2.
2. Tips for Preparing Your Comments
    When preparing and submitting your comments, see the commenting
tips at http://www.epa.gov/dockets/comments.html.

II. Background

A. What are Plant-Incorporated Protectants (PIPs)?

    Through natural evolutionary processes, plants develop mechanisms
to resist pests. The mechanisms of resistance can be varied, including,
for example, the production of metabolites that have toxic properties,
biochemical cascades resulting in localized necrosis of plant tissue,
or the production of substances in response to pest attack (Ref. 3).
Humans have for approximately 10,000 years selected and bred certain
plants for food, feed, and fiber, and a frequently selected
characteristic has been the ability to resist pests (Ref. 4). When
humans intend to use substances involved in these mechanisms in plants
for ``preventing, destroying, repelling, or mitigating any pest,'' the
substances fall into the FIFRA definition of pesticide, regardless of
whether the pesticidal capability evolved in the plant, or was
introduced by conventional breeding or through the techniques of
biotechnology.
    A PIP is defined as ``pesticidal substance that is intended to be
produced and used in a living plant, or in the produce thereof, and the
genetic material necessary for the production of such a pesticidal
substance. It also includes any inert ingredient contained in the plant
or produce thereof'' (40 CFR 174.3). For example, scientists can take
the gene encoding for a pesticidal protein from a wild relative of corn
and introduce the gene into another corn plant's genetic material. The
plant then manufactures the pesticidal protein that kills the pest when
the pest feeds on the plant. The genetic material necessary for the
production of such a pesticidal substance also meets the FIFRA
statutory definition of a pesticide, because such genetic material is
introduced into the plant with the intent of ultimately producing a
pesticidal effect. For transgenic PIPs, the

relationship between the genetic material, the pesticidal substance,
and the pesticidal effect has typically been linear (i.e., the genetic
material inserted into the plant directly produces the pesticidal
substance that confers the pesticidal effect). However, PIPs found in
conventionally bred plants and their wild relatives can introduce
additional biological complexity. For example, as described in the 2001
preamble (66 FR 37772; July 19, 2001), a PIP can encompass genetic
material encoding an enzyme that ultimately leads to the production of
the pesticidal substance (e.g., solanine). PIPs can also include traits
intended for a pesticidal purpose that result from the loss-of-function
of an existing plant gene where, for example, the inactivation of a
gene coding for a plant receptor protein confers disease resistance. It
is important to clarify that EPA regulates the modified genetic
material that confers the loss-of-function trait as the pesticidal
substance which is consistent with both the 1994 proposed rule preamble
(59 FR 60496; November 23, 1994) and the 2001 final rule preamble (66
FR 37772; July 19, 2001) promulgating 40 CFR 174. EPA is requesting
comment on whether a clarifying exemption specific to loss-of-function
traits would be helpful (Unit VII.E.), although EPA considers these
traits to be included under the current exemption at 40 CFR 174.25 and
the proposed exemption at 40 CFR 174.26. For the sake of clarity,
although the genetic material meets the statutory definition of a
pesticidal substance under FIFRA, in this preamble EPA uses
``pesticidal substance'' to mean a protein or other substance produced
from genetic material that has pesticidal properties as per the
definition at 40 CFR 174.3.
    Although the PIP is regulated by EPA, the plant containing a PIP is
not regulated by EPA. Additionally, many types of traits can be
engineered into plants, but only those intended for a pesticidal
purpose are PIPs. EPA does not regulate non-pesticidal traits under
FIFRA or the FFDCA, or any other federal statutes. For example, EPA
does not regulate traits introduced into a plant using biotechnology
that enhance vitamin C content for nutritional purposes. Food from such
a plant variety would be regulated by FDA.

B. How are PIPs regulated?

1. By EPA
    Because PIPs are pesticides, they are regulated under FIFRA and, to
the extent necessary, FFDCA section 408. Under FIFRA, unless there is
an applicable exemption, EPA is required to register PIPs so they may
lawfully be sold and distributed. EPA evaluates each PIP application to
determine whether its proposed use would cause unreasonable adverse
effects on the environment. To avoid potential unreasonable adverse
effects, the Agency may impose (and has imposed) terms and conditions
on registration of PIPs (e.g., conditions to slow insect resistance).
Additionally, EPA has the authority to take enforcement action with
respect to any violations of activities subject to FIFRA. Under the
FFDCA, EPA has established exemptions from the requirement of a
tolerance for residues of PIPs in food. EPA evaluates each PIP to
determine whether exposure to the residue of that PIP in or on food/
feed is safe (i.e., there is a reasonable certainty that no harm will
result from aggregate exposure to the pesticide, which includes all
anticipated dietary exposures and all other exposures for which there
is reliable information).
2. By Other Federal Agencies
    EPA is part of an interagency effort to improve, clarify, and
streamline the regulation of biotechnology, including the regulation of
plants developed using biotechnology that includes oversight by the
USDA, FDA, and EPA. This approach was articulated by the White House
Office of Science and Technology Policy in a policy statement in 1986
(51 FR 23302; June 26, 1986) and updated most recently in 2017 (Ref.
5). This document is known as the Coordinated Framework for the
Regulation of Biotechnology. EPA is the federal agency primarily
responsible for the regulation of pesticides. In fulfilling this
mission, EPA works closely with the USDA, which has responsibilities
under the Plant Protection Act, and the FDA, which has responsibilities
under the FFDCA, including the enforcement of tolerances set by EPA
under the FFDCA. EPA, USDA, and FDA consult and exchange information
when such consultation is helpful in resolving safety questions. In
addition to the Coordinated Framework, Executive Order 13874 requires
EPA, FDA, and USDA to further coordinate their activities with regard
to agricultural biotechnology. The PIPs that EPA is proposing to exempt
are also exempted from regulation by USDA under 7 part 340 as revised
by USDA's recently issued final rule titled ``Movement of Certain
Genetically Engineered Organisms.'' (85 FR 29790, 29791-92, May 18,
2020).

C. What actions did EPA take to prepare for this proposed rule?

1. Updated Issue Paper
    For this proposal, EPA updated an issue paper entitled ``Natural
Toxicants in Food from Plants'' (Ref. 6). This issue paper summarizes
and reviews the literature on the most common toxicants found in crop
plants and discusses the regulatory status and current testing methods
for each of those toxicants. Information from this issue paper was used
in the Agency's safety analysis for residues of PIPs based on sexually
compatible plants created through biotechnology in or on food or feed.
This document is available in the docket for this rulemaking.
2. Withdrawal of Previous Rule Proposal
    In May 2018, the Agency withdrew a proposed rule entitled: ``Plant-
Incorporated Protectants (PIPs); Exemption for Those Derived Through
Genetic Engineering From Sexually Compatible Plants'' (Ref. 1). The
proposed rule was withdrawn because the Agency determined that to
exempt PIPs derived through genetic engineering from sexually
compatible plants, more scientifically current criteria needed to be
developed to reflect advances in genetics and molecular biology since
the 2001 proposal. Consequently, EPA indicated that to pursue a future
exemption, the Agency would issue a new proposed rule based on the
types of products possible to create with newest technology rather than
issue a final rule based on previous proposals (Ref. 1). As discussed
in Unit VI., in developing this proposal for PIPs based on sexually
compatible plants created through biotechnology, the Agency developed
criteria that are scientifically more current and that more accurately
describe the PIPs that would be exempted. Additionally, because the
previous rule was withdrawn, the Agency will not consider comments made
on the previous proposal. Therefore, if you believe a comment made
regarding previous proposals is relevant to this proposal, you must
resubmit the comment for this proposal.
3. Scientific Advisory Committees
    The FIFRA Scientific Advisory Panel (SAP) is a body of experts that
provide independent scientific advice to EPA on issues related to
pesticides, such as the impact to human health or the environment.
FIFRA requires that EPA submit any proposed and final rule promulgated
under FIFRA section 25(a) to the SAP for comment on the impact of the
rule on human health and the

environment. For this proposed rule, EPA requested that the FIFRA SAP
waive review of the proposal. In developing the scientific rationales
in this proposal, EPA relied on previously provided advice from the
FIFRA SAPs and analyses by the National Research Council of the
National Academy of Science, Engineering and Medicine (Table 1).

    Table 1--Advice Sources for Key Concepts To Exempt PIPs Based on
        Sexually Compatible Plants Created Through Biotechnology
------------------------------------------------------------------------
                              Relevance to current
           Concept                  proposal           Relevant report
------------------------------------------------------------------------
Exemption of PIPs based on    Establishes the       FIFRA SAP 1992,
 sexually compatible plants    overall scope of      1993, 1994; NRC
 created through               the exemption. PIP    2000. (Ref. 7, 8,
 biotechnology.                would be developed    9, 10).
                               by engineering a
                               plant's genetic
                               material to result
                               in a PIP that could
                               otherwise be found
                               in the gene pool of
                               the plant itself,
                               e.g., in other
                               varieties of the
                               crop plant or in a
                               sexually compatible
                               relative. This
                               scope should result
                               in no novel dietary
                               or environmental
                               exposures.
Criteria limiting the types   Establishes how much  FIFRA SAP 2004,
 of possible modifications     a gene could be       https://
 introduced into a PIP in      modified (e.g.,       archive.epa.gov/
 the plant.                    through               scipoly/sap/
                               truncations,          meetings/web/html/
                               deletions, or point   101304_mtg.html.
                               mutations) while     FIFRA SAP 2005,
                               still retaining       https://
                               scientific support    archive.epa.gov/
                               for the idea that     scipoly/sap/
                               humans have           meetings/web/html/
                               consumed the          120605_mtg.html.
                               products of such
                               genes for
                               generations and
                               that products of
                               such modifications
                               present no new
                               dietary exposures.
Introduction of a gene        Establishes criteria  FIFRA SAP 1992,
 isolated from a plant in      to ensure that any    1993, 1994; NRC
 the same gene pool as the     introduced gene is    2000. (Ref. 7, 8,
 recipient plant.              part of the genetic   9, 10).
                               diversity found in
                               plants that are
                               sexually compatible
                               with the recipient
                               plant.
Ensuring expression profile   Establishes criteria  FIFRA SAP 1993,
 falls within the gene pool    to ensure that any    1994; NRC 2000.
 of the plant and plants       substance expressed   (Ref. 7, 9, 10).
 that are sexually             from the modified
 compatible with the plant.    genetic material is
                               not expressed at
                               higher levels, in
                               different tissues,
                               or at different
                               developmental
                               stages than seen in
                               plants that are
                               sexually compatible
                               with the recipient
                               plant.
Precision associated with     Establishes criteria  NRC 2004; NASEM
 newly developed techniques    to ensure that only   2016, 2017. (Ref.
 of genetic engineering,       precise               4, 11, 12).
 e.g., allowing genes          modifications are
 present in the plant to be    introduced into the
 edited.                       modified plant--
                               e.g., modifications
                               of regulatory
                               regions, allelic
                               substitutions,
                               introduction only
                               of genes that falls
                               within the genetic
                               diversity found in
                               plants that are
                               sexually compatible
                               with the recipient
                               plant.
Exemption eligibility         Establishes           NRC 2004; NASEM
 determination process.        streamlined           2017. (Ref. 11,
                               procedures for        12).
                               developers to
                               notify EPA of a PIP
                               that qualifies for
                               exemption.
------------------------------------------------------------------------

    Two scientific advisory committees, the FIFRA SAP and the
Biotechnology Science Advisory Committee (BSAC), a sister committee of
equal stature later merged into the FIFRA SAP, offered advice that
forms the foundation of EPA's current approach to PIPs. The Agency's
2001 final rule exempting PIPs from sexually compatible plants created
through conventional breeding (40 CFR 174.25) and proposed exemptions
(under both FIFRA and the FFDCA) for PIPs from sexually compatible
plants derived through genetic engineering (see Unit II.C.2.) are based
on advice from the FIFRA SAP.
    The proposed exemptions in this document, are similarly based on
advice provided by the FIFRA SAP, as the 1992, 1993, and 1994 FIFRA SAP
reviews did not distinguish between PIPs moved among sexually
compatible plants through conventional breeding and those moved through
genetic engineering. Taking that advice into account, along with
additional advice from NASEM reports in 2000, 2004, 2016, and 2017,
this proposal describes the criteria that PIPs based on sexually
compatible plants created through biotechnology, must meet to qualify
for the proposed exemption. In response to the Agency's 1994 proposal
to exempt PIPs from sexually compatible plants derived through genetic
engineering, NASEM pointed out in its report in 2000 that the Agency's
proposed language would exempt genetic material moved among plants in
sexually compatible populations through the use of biotechnology
without taking into consideration whether the moved genetic material
would be expressed in the same pattern and at the same levels as occurs
naturally in the plant (Ref. 10 at p. 129). This directly led to the
Agency incorporating a criterion addressing expression levels and
pattern in the proposed exemption requirements set out in this
document. In addition to the advice from the 1992, 1993, and 1994 FIFRA
SAPs, EPA received additional advice from expert groups on scientific
topics relevant to the current PIP proposed rule including, but not
limited to, the 2004 and 2005 FIFRA SAPs that discussed how much a gene
could be modified (e.g., through truncations, deletions, or point
mutations) while still retaining scientific support for the conclusion
that humans have consumed the products of such genes for generations
and that products of such modifications present no new dietary
exposures; and several reports from NASEM in 2004, 2016, and 2017 that
describe the precision of modifications that can be

achieved using new technologies for genetic engineering (Ref. 4, 11,
12).
    The proposal in this document also describes an exemption
eligibility determination process in which a developer must notify the
Agency through either a self-determination letter or a request for EPA
confirmation that the PIP meets the exemption criteria. For additional
flexibility, EPA also proposes to allow a developer to submit both a
self-determination letter and request for EPA confirmation, should they
so choose. This proposed set of options takes into account advice from
two reports by NASEM (Ref. 10, 12).
4. Stakeholder Engagement
    EPA has participated in domestic and international events relevant
to the proposed exemptions, all of which provided opportunities to
engage with the regulated and research communities, the public, and
other U.S. government agencies. Recent conferences and workshops
include: Genome Editing--Putting Together the Pieces 2018; 2018 OECD
Conference on Environmental Health and Safety of Applications of Gene
Editing; Responsible CRISPR: Genome Engineering Conference 2019; North
Carolina State University/ASTA Plant Breeding Workshop 2019; Plant
Genomics & Gene Editing Congress: USA 2019; and the 2019 Global
Regulatory Workshop on Plant and Animal Biotechnology Innovation. These
meetings supported EPA's horizon-scanning efforts for novel PIP
products and presented engagement opportunities with the scientific and
regulated community. These meetings also provided opportunities to
develop practical knowledge of techniques and technology used in plant
breeding and genetic engineering, which supported development of
exemption criteria and rationale for assessing risks of PIPs created
using biotechnology. Topics of discussion included plant breeding,
technical aspects of biotechnology, and considerations regarding
regulation and risk assessment of products.

III. Statutory Authorities and Regulatory Framework

    EPA is authorized to regulate pesticides under two federal
statutes. FIFRA regulates the sale, distribution, and use of pesticide
products through a licensing (registration) scheme. FFDCA, among other
things, regulates the safety of pesticide chemical residues in or on
food and feed. EPA is proposing these exemptions under FIFRA section
25(b)(2) and FFDCA section 408.

A. What authority does EPA have under FIFRA section 25(b)(2)?

    This section of FIFRA allows EPA to exempt, by regulation, any
pesticide from some or all of the requirements of FIFRA, if the
pesticide is of a character that is unnecessary to be subject to all
the requirements of FIFRA in order to carry out the purposes of that
Act (7 U.S.C. 136w(b)(2)). EPA interprets FIFRA section 25(b)(2) to
authorize EPA to exempt a pesticide or category of pesticides that EPA
determines (1) poses a low probability of risk to the environment and
(2) is not likely to cause unreasonable adverse effects to the
environment even in the absence of regulatory oversight under FIFRA.
    In evaluating whether use of the pesticide poses a low probability
of risk to the environment, EPA considers the extent of the potential
risks caused by use of the pesticide to the environment, including
humans, animals, plants, water, air, and land. Potential risks to
humans include dietary risks (which are assessed under the safety
standard of the FFDCA section 408) and non-dietary risks, such as those
resulting from occupational or residential exposure to the pesticide.
EPA will not exempt pesticides under FIFRA section 25(b)(2) that fail
to meet the required low probability of risk.
    In evaluating whether the use of a pesticide is likely to cause
unreasonable adverse effects on the environment even in the absence of
regulatory oversight under FIFRA, EPA balances potential risks to human
health and the environment from use of the pesticide against the
potential benefits associated with its use. In balancing risks and
benefits, EPA considers the economic, social, and environmental costs
and benefits of the use of the pesticide.

B. What authority does EPA have under FFDCA section 408?

    Under the FFDCA, food or feed containing pesticide residues may be
considered adulterated (and subject to seizure if introduced, delivered
for introduction, or received in interstate commerce) unless there is a
tolerance or an exemption from the requirement of a tolerance in place
covering those residues (21 U.S.C. 342(a)(1)(B)). EPA is authorized to
establish tolerances (the maximum level) for residues in or on food or
establish exemptions from the requirement of a tolerance, if it
determines that the tolerance or exemption would be safe (21 U.S.C.
346a(b)(2), (c)(2)). Section 408 of the FFDCA defines ``safe'' to mean
that ``there is a reasonable certainty that no harm will result from
aggregate exposure to the pesticide chemical residue, including all
anticipated dietary exposures and all other exposures for which there
is reliable information'' (21 U.S.C. 346a(c)(2)(A)(ii)). This includes
exposure through drinking water, and residential and other indoor uses,
but does not include occupational exposure. In addition, FFDCA section
408 requires EPA to give special consideration to exposure of infants
and children to the pesticide chemical residue in establishing an
exemption and to ``ensure that there is a reasonable certainty that no
harm will result to infants and children from aggregate exposure to the
pesticide chemical residue'' (21 U.S.C. 346a(b)(2)(C)(ii)(I)) and
(c)(2)(B)). FFDCA section 408(b)(2)(D) specifies other general factors
EPA must consider in establishing an exemption (21 U.S.C.
346a(b)(2)(D)). In establishing a tolerance or an exemption from the
requirement of a tolerance, the FFDCA does not authorize EPA to
consider potential benefits associated with use of the pesticide
chemical. Although EPA establishes tolerances or exemptions from the
requirement of a tolerance under the FFDCA, FDA enforces these
tolerances.

C. What is the relationship of FIFRA exemptions to the FFDCA section
408 standard?

    EPA uses the FFDCA section 408 safety standard, as described in
Unit III.B., in evaluating whether a pesticide used in or on food and
feed meets the standard for exemption under FIFRA with respect to human
dietary risk. A pesticide in or on food and feed presents a low
probability of human dietary risk if it meets the FFDCA section 408
standard for an exemption from the requirement of a tolerance.
    Additionally, a determination that a pesticide chemical meets the
safety standard of FFDCA section 408(c) may also be relevant to whether
a pesticide qualifies for a FIFRA section 25(b)(2) exemption with
respect to human health risks arising from other routes of exposure. In
determining whether a pesticide chemical residue is safe, EPA must
consider ``available information regarding the aggregate exposure
levels of consumers . . . to the pesticide chemical residue and to
other related substances, including dietary exposure under the
tolerance and all other tolerances in effect for the pesticide chemical
residue, and exposures from other non-occupational sources'' (21 U.S.C.
346a(b)(2)(D)(vi)).
    FIFRA, however, does not provide for exemption of a pesticide in or
on food

based solely upon consistency with the FFDCA section 408 exemption
standard. At a minimum, EPA also must evaluate risks to the environment
and risks arising from occupational exposure to humans and determine
that such risks meet both exemption criteria (i.e., posing a low
probability of risk to the environment and being not likely to cause
unreasonable adverse effects to the environment even in the absence of
regulatory oversight under FIFRA).

IV. Proposed Regulatory Framework for Exempting PIPs Based on Sexually
Compatible Plants Created Through Biotechnology

    In 2001, EPA created a regulatory structure at 40 CFR 174.21, for
exempting PIPs from the requirements of FIFRA, other than the adverse
effects reporting requirement at 40 CFR 174.71. First, the active
ingredient of the PIP must meet codified criteria addressing FIFRA
requirements listed in 40 CFR part 174, subpart B; these provisions
primarily deal with the pesticidal substance of the PIP and the genetic
material necessary for production of that substance (40 CFR 174.21(a)).
Second, when the PIP is intended to be produced and used in a food or
feed crop, an exemption from the requirement of tolerance must be in
place for residues of the PIP (40 CFR 174.21(b)). Third, any inert
ingredient that is part of the PIP must be exempt under 40 CFR 174.705
(174.21(c)).
    EPA is proposing to create an exemption from FIFRA requirements for
certain PIPs based on sexually compatible plants created through
biotechnology. These PIPs are created through biotechnology and their
pesticidal substance is found in plants that are sexually compatible
with the recipient plant. To satisfy the requirement of 40 CFR
174.21(a), EPA proposes to create a new section under subpart B for 40
CFR 174.26 containing criteria that an active ingredient of a PIP based
on a sexually compatible plant created through biotechnology must meet
to qualify for the new exemption.
    To meet the condition of 40 CFR 174.21(b), EPA is proposing to
exempt from the requirement of a tolerance under the FFDCA residues of
PIPs based on sexually compatible plants created through biotechnology
that are present in or on food or feed. This exemption and the safety
criteria that the residues must meet to qualify for the exemption will
be codified in 40 CFR part 174, subpart W with other PIP-related FFDCA
exemptions.
    Per 40 CFR 174.3, an inert ingredient is defined as ``any
substance, such as a selectable marker, other than the active
ingredient, where the substance is used to confirm or ensure the
presence of the active ingredient, and includes the genetic material
necessary for the production of the substance, provided that genetic
material is intentionally introduced into a living plant in addition to
the active ingredient.'' Additionally, in 2001 EPA stated that ``with
regard to the enzymes, precursors, or intermediates in biosynthetic
pathways necessary for anabolizing the pesticidal substance, EPA at
this time considers them to be part of the plant-incorporated
protectant because the substance is intended to ``ensure the presence
of the active ingredient''--i.e., it is an inert ingredient.'' EPA is
therefore proposing to expand the scope of the existing inert
ingredient exemption at 40 CFR 174.705 to include inert ingredients
initiated through a modification made using biotechnology, as EPA
believes the intermediary substances described in the 2001 quote would
be included in this.
    Other than these intermediary substances, the Agency does not
expect other, more traditional inert ingredients (e.g., a gene coding
for herbicide tolerance) in PIPs based on sexually compatible plants
created through biotechnology. This is because older methods of
biotechnology that have typically been used to create PIPs use a
bacterial plasmid vector to incorporate a DNA construct into the genome
of the plant. The DNA construct is an artificially constructed segment
of nucleic acid consisting of regulatory elements, the gene coding for
the active ingredient, and sometimes a gene coding for an inert
ingredient. Because the gene coding for the active ingredient and the
gene coding for the inert ingredient are located on the same DNA
construct and will therefore be incorporated into the plant genome
together, the inert ingredient is able to confirm or ensure the
presence of the active ingredient. However, newer biotechnology
techniques, such as CRISPR, that are precise enough to create PIPs
proposed for this exemption do not use DNA constructs in this way.
Instead, these newer techniques allow developers to perform targeted
edits to existing genes, and do not require the incorporation of inert
ingredients in the same way as historically seen in transgenic PIPs.
Modifications coding for substances similar to inert ingredients seen
in transgenic PIPs (e.g., herbicide resistance) would instead be
incorporated into the recipient plant genome independent of the active
ingredient. Because newer techniques allow for these events to be
introduced independently, the modification cannot confirm or ensure the
presence of the active ingredient. The modification therefore would not
meet the definition of an inert ingredient under 40 CFR 174.3 because
it is an independent, non-pesticidal trait not regulated under FIFRA.
EPA expects that any ingredients intentionally added during the
development of PIPs based on sexually compatible plants created through
biotechnology that are specific to the production of the active
ingredient (e.g., guide RNA, DNA nuclease) would either be transiently
transformed or would be removed (e.g., through segregation of the
trait) during the breeding process. If these traits have not been
removed from the final product the product would not meet the criteria
proposed under the new 40 CFR 174.26 and would not qualify for the new
exemptions. The Agency requests comment on whether there are any inert
ingredients other than the intermediary substances described in the
2001 quote that will remain in the final plant products containing PIPs
based on sexually compatible plants created through biotechnology. If
inert ingredients other than the intermediary substances described in
the 2001 quote are identified in the responses to the previous request,
the Agency also requests comment as to whether the inert ingredients in
PIPs based on sexually compatible plants created through biotechnology
require the proposal of an exemption that would be specific to those
created through biotechnology and would allow developer flexibility in
the nucleic acid sequence (see Unit VII.A.). EPA is also proposing to
add a recordkeeping requirement and exemption eligibility determination
process to 40 CFR 174.21 applicable to PIPs based on sexually
compatible plants created through biotechnology that would require a
developer to notify EPA that the PIP meets the criteria for exemption
from the requirements of FIFRA under the conditions of 40 CFR 174.21
and to maintain supporting documentation of its determination. The
exemption eligibility determination can be submitted in two, non-
mutually exclusive ways: a self-determination letter or a request to
EPA for confirmation of the self-determination.

V. Proposed Revisions to the General Provisions (Subpart A)

    Provisions that apply to PIPs are codified in 40 CFR part 174,
subpart A. EPA is proposing several changes to these general
provisions.

A. What are the proposed new definitions?

    Definitions that apply to PIPs are codified in 40 CFR part 174,
subpart A, and EPA is proposing to add new definitions for ``gene,''
``native allele,'' and ``native gene.'' Only one term, ``gene,'' is
discussed in this unit. The other proposed definitions are discussed in
detail in Unit VI.
    EPA is proposing to define ``gene'' as meaning a ``functional unit
of heritable genetic material that is comprised of the genetic material
necessary for the production of a substance.'' All living organisms
encode the substances they need to perform their normal metabolic
functions in discrete units in their genome, called genes. This
includes the pesticidal substances plants produce to defend against
pests. Genes are further comprised of several functionally distinct
regions within that unit that work in concert to produce the substance
that is encoded by the gene's nucleic acid sequence. The two regions
relevant to the criteria proposed to circumscribe PIPs based on
sexually compatible plants created through biotechnology are the
regulatory and coding regions. Together, they determine the function of
a given gene within the plant. The sequence within the regulatory
region of a gene determines the amount of substance that is produced
and the spatiotemporal pattern of expression within the plant tissues.
The coding region, which is the sequence that is ultimately
transcribed, determines the identity of the substance that is produced
from the gene (e.g., the amino acid sequence of a protein). Because the
regulatory and coding regions of a given gene are inherited together as
a single unit, they have evolved together over evolutionary time. In
proposing the definition of a gene, the Agency clearly identifies and
delineates the physical unit of the genetic material within the plant
genome that encodes the substance and leads to the production of the
pesticidal substance and, in doing so, restricts any genetic
modifications made through biotechnology that would fall under the
proposed exemption to the coding and regulatory regions. Defining the
term ``gene'' was not necessary in the context of PIPs before this
proposed exemption because previous methods employed to create PIPs,
such as particle gun transformation, relied on the integration of a
genetic construct, which included other genetic sequences in addition
to a gene.

B. What is the proposed amendment to the existing definition for
``sexually compatible?''

    The term ``sexually compatible'' is currently defined at 40 CFR
174.3 as ``when referring to plants, means a viable zygote is formed
only through the union of two gametes through conventional breeding.''
EPA is proposing to amend the existing definition for ``sexually
compatible'' to instead state ``when referring to plants, means a
viable zygote can be formed through the union of two gametes through
conventional breeding.'' EPA believes this amended definition is more
in line with the biological definition of sexually compatible, in that
being sexually compatible is widely accepted to mean that two organisms
are capable of forming viable progeny. The amended definition also
allows the Agency to use the term ``sexually compatible'' in the
biological sense in the proposed exemption. The proposed clarification
to the sexually compatible definition necessitates changes to the
existing PIP from sexually compatible plant exemption at 40 CFR 174.25,
along with its accompanying exemptions at 40 CFR 174.508 and 174.705;
however, these changes do not result in modifications to the existing
exemption for PIPs moved through conventional breeding. EPA discusses
this proposed clarification in detail in Unit VI.F.

VI. Proposed Exemptions and Exemption Eligibility Determination Process
(Subparts B, D, E, and W)

    EPA is proposing to create an exemption from FIFRA requirements for
certain PIPs based on sexually compatible plants created through
biotechnology (described in Unit VI.A.) and to create a companion
exemption from the FFDCA section 408 requirement of a tolerance for
residues of certain PIPs based on sexually compatible plants created
through biotechnology in or on food or feed (described in Unit VI.B.).
EPA is also proposing to add a new subpart (subpart E) to 40 CFR part
174 that would codify the procedures and requirements for the new
exemption eligibility determination process (described in Unit VI.C.).
EPA is proposing a new section in subpart D, 40 CFR part 174.73, that
would codify recordkeeping requirements for exemptions (described in
Unit VI.D.). To accommodate the exemption eligibility determination
process and recordkeeping requirements, EPA is making some clarifying
edits to 40 CFR 174.21 as described in Unit VI.E. Finally, EPA is also
clarifying the relationship between the proposed exemptions for PIPs
based on sexually compatible plants created through biotechnology and
the exemptions currently at 40 CFR 174.25, 174.508, and 174.705 by
modifying 174.25, 174.508, and 174.705 as described in Unit VI.F.

A. What is the proposed FIFRA exemption for the active ingredients of
PIPs based on sexually compatible plants created through biotechnology?

1. What the Proposed Exemption Covers
    EPA currently exempts PIPs from sexually compatible plants as
described in 40 CFR 174.25. Because EPA had previously defined sexually
compatible plants as including only those plants that create viable
progeny through conventional breeding, the current exemption excludes
PIPs created through biotechnology, even if they are equivalent to PIPs
that could have been developed through conventional breeding.
Technological advances surrounding genome editing (e.g., meganucleases,
zinc-finger nucleases, transcription activator-like effector nucleases,
and CRISPR-Cas nuclease system) allow for targeted, rapid, and precise
changes directly to chromosomes of living cells (Ref. 12). These
technologies allow for such precise editing of the genome, that the
resulting genes can be indistinguishable from those found in a plant
created through conventional breeding. Given the recent advances in
technology, EPA was able to develop specific criteria proposed in a new
section for 40 CFR 174.26 to exempt certain PIPs developed through the
use of biotechnology that pose no greater risk than the currently
exempt sexually compatible PIPs. The definition of sexually compatible
is also proposed to be amended to refer to the ability of two gametes
to form a viable zygote and thus be more biologically correct in
stating that ``a viable zygote can be formed through the union of two
gametes through conventional breeding.'' This amendment allows for use
of the phrase ``sexually compatible'' in the proposed exemption.
    The proposed criteria and supporting proposed definitions of
``native gene'' and ``native allele'' circumscribe the PIPs based on
sexually compatible plants created through biotechnology that would
qualify for the new exemption. The proposed criteria and the proposed
definitions limit the types of PIPs that would be exempt to those that
are found in plants that are sexually compatible with the recipient
plant and meet specific safety criteria, thereby resulting in
negligible risk of novel exposures. It is important to note that

although the amended definition proposed for ``sexually compatible''
specifically refers to a viable zygote formed through the union of two
gametes, for this proposal EPA includes in its exemption also PIPs
engineered in plants that are propagated vegetatively (e.g., potatoes
and bananas). This approach aligns with the Agency's longstanding
approach for exempting PIPs in vegetatively propagated plants created
through conventional breeding and is consistent with the existing
exemption of PIPs from sexually compatible plants created through
conventional breeding.
    The definition of ``native genes'' limits the substances eligible
for exemption to those found in plants that are sexually compatible
with the recipient plant. As genes code for and produce substances,
restricting the genes to only those found in plants that are sexually
compatible with the recipient plant will limit the PIPs eligible for
the new exemption to those found in plants that are sexually compatible
with the recipient plant. The term ``native'' is used in the scientific
literature in the context of cisgenes (e.g., a native promoter is a
promoter endogenous to that gene). However, the Agency seeks comment on
use of the term ``native'' in the names of ``native gene'' and ``native
allele'' and associated definitions as the Agency does not mean to
imply with the use of the term ``native'' that genes which originated
through conventional breeding techniques like mutagenesis would somehow
be excluded from the proposed exemption. It is the Agency's intention
that alleles found in sexually compatible plants that may have been
created through conventional breeding would be included in the
definition of ``native allele'' and ``native gene.''
    Native genes comprising the gene pool of sexually compatible plant
populations have been developed through the processes of mutation,
selection, and genetic exchange. The proposed exemption captures
ongoing diversification within gene pools by including within the
proposed criteria a definition for native alleles. The definition of
``native allele'' is similarly limited to only those variants of native
genes that are found in plants that are sexually compatible with the
recipient plant.
    EPA also proposes to capture additional ongoing diversification
within existing native genes through the concept of differentially
expressed genes. These are changes to a native gene that result in
alterations in the amount of substance that is produced from that gene.
An additional restriction on differentially expressed genes requires
that the original pesticidal substance is preserved, which again limits
eligible pesticidal substances to only those that are found in plants
that are sexually compatible with the recipient plant. Native genes,
native alleles, and differentially expressed genes represent the
genetic diversity of sexually compatible plants; thus, these criteria
limit exempt pesticidal substances of PIPs based on sexually compatible
plants created through biotechnology to only those substances that are
found in plants that are sexually compatible with the recipient plant.
    For agricultural plants, those defined as being sexually compatible
would include existing plant cultivars, landraces (i.e., a locally
isolated variety of a domesticated plant species adapted to the natural
and cultural environment in which it lives), and breeding lines, as
well as plant relatives that can breed with crops but are not currently
used as agricultural plants. Including nonagricultural relatives in the
sexually compatible pool is appropriate, as some traits found in
nonagricultural wild relatives of cultivated plants, although not
expressed in existing agricultural cultivars, have been accessible in
plant breeding by conventional breeding techniques. For example,
nonagricultural plant relatives may express defense mechanisms (i.e.,
pesticidal substances) that have been lost during domestication of crop
plants and thus have not been entirely utilized in agricultural
varieties.
    Plant breeders have for many years been following established
practices to ensure safety when moving genes into agricultural
varieties from nonagricultural relatives, particularly from wild
relatives, with no indication that substances resulting from these
genes present higher levels of risk than those from genes moved only
amongst agricultural varieties as long as those established practices
are diligently followed (Ref. 13, 14, 15, 16). The ability to produce
viable offspring is only possible in nature for organisms that possess
many traits (and the genetic material encoding them) in common.
Therefore, many of the traits present in agricultural plants and their
wild relatives are likely to be similar in nature; the fact that the
specific substance from the nonagricultural relative may not be found
in the agricultural variety today does not mean that breeders do not
have the experience and tools to ensure that it will be present in safe
levels if transferred to the agricultural variety. Therefore, the
likelihood is negligible that the transfer of such a substance via
biotechnology from a nonagricultural relative to an agricultural one
would pose a greater risk than if it were transferred through
conventional breeding. The same logic defining the sexually compatible
gene pool for agricultural crop plants also applies to other plants
such as ornamental, turf, and semi-managed plants (e.g., trees).
    EPA's proposed criteria and associated definitions are based on the
ability of closely related plants to hybridize and share genetic
information. Because the substances produced by native genes and native
alleles are present in sexually compatible plants, breeders have
experience in ensuring that the substances will be at safe levels. This
is also true for differentially expressed genes (i.e., genes with
modified regulatory regions) because the proposed exemption criteria
require that (a) the substance produced from the genetic material be
not different than what was being produced prior to the modification,
(b) the expression profile of the pesticidal protein does not exceed
the limits seen in the sexually compatible plant population of the
recipient plant. Although the proposed criteria allow for the use of
biotechnology, the associated definitions are written to intentionally
exclude ``transgenes,'' which can be generally defined as derived from
a source organism unable to share genetic material with the recipient
plant through breeding. EPA does not consider transgenes to be native
to the gene pool or a part of the genetic diversity of the recipient
plant. Transgenic traits have been the focus of current PIP
registration activities since 1995 (e.g., those derived from the
bacterium Bacillus thuringiensis), and the registered PIPs generally
present novel exposure scenario considerations for the transgenic
trait.
2. Proposed Criteria and Associated Definitions
    The Agency is proposing to define ``native gene'' to mean ``a gene
that is identified in the recipient plant or plants that are sexually
compatible with the recipient plant; and has never been derived from a
source that is not sexually compatible with the source plant.'' The
phrase ``has never been derived from a source that is not sexually
compatible with the source plant'' is meant to clarify that a PIP would
qualify for the proposed exemption only if the native gene is present
in the source plant as a result of conventional breeding. For example,
if a bacterial endotoxin (e.g., from the source Bacillus thuringiensis)
was engineered into plant ``A'' (the source

plant), this bacterial endotoxin-based PIP would not qualify as a
native gene to be used in plant ``B'' (the recipient plant) under the
proposed exemption, even if plant ``B'' is sexually compatible with
plant ``A''. This is because while plant ``B'' and ``A'' can
interbreed, the bacterium Bacillus thuringiensis (the source) and plant
``A'' (the source plant) are not sexually compatible. This proposed
limitation on the source of the PIP therefore prevents a developer from
claiming that a gene that encodes for a PIP is a ``native gene'' under
the proposed definition when it is not, i.e., when the gene has been
derived from a source that is not sexually compatible with the source
plant. Given this explanation of the intent behind the phrase ``never
derived,'' EPA seeks comment on whether the use of the phrase in the
proposed definition of ``native gene'' is clear.
    ``Native allele'' means ``a variant of a native gene that is
identified in the genetic diversity of plants that are sexually
compatible with the recipient plant.'' This definition is meant to
clarify that the native allele must be a variant found in plants that
are sexually compatible with the recipient plant, thereby limiting the
potential pesticidal substances to those found in that population. By
stating that the native allele is a variant of a native gene, the
restriction that the genetic material cannot be derived from a source
that is not sexually compatible with the source plant also applies to
native alleles.
    Equally important are two considerations, discussed in detail in
the following sections, that are captured by the proposed criteria for
40 CFR 174.26 and that EPA believes together constitute the basis for
meeting the FIFRA section 25(b)(2) standard for exemption: the
pesticidal substance is found in plants that are sexually compatible
with the recipient plant; and limitations on expression profile.
a. The Pesticidal Substance Is Found in Plants That Are Sexually
Compatible With the Recipient Plant
    The proposed provisions for 40 CFR 174.26(a) delineate the scope of
the new exemption for PIPs based on sexually compatible plants created
through biotechnology to only include those substances that are found
in sexually compatible plants and substances with which plant breeders
have experience. The regulatory text identifies two major categories
that specify what will qualify as an exempt PIP pesticidal substance:
(i) The insertion of new genetic material; and (ii) The modification of
existing genetic material. Modifications of existing genetic material
are further broken down into: Modifications resulting in the
differential expression of a gene, modifications resulting in a native
allele, and modifications resulting in the differential expression of a
native allele. The restrictions on the intended insertion or
modification, as discussed in this section, ensure that no substance
novel to plants that are sexually compatible with the recipient plant
is produced.
    By limiting the types of modifications permissible to those
resulting in a pesticidal substance found in plants that are sexually
compatible with the recipient plant (including substances already in
the recipient plant), EPA can ensure that no substance novel to plants
that are sexually compatible with the recipient plant is produced. This
allows the Agency to ensure that PIPs based on sexually compatible
plants created through biotechnology can meet the FIFRA section
25(b)(2) exemption standard because the modification would present a
low risk of unreasonable adverse effects to humans and the environment
due to the history of ensuring safe exposure through conventional
breeding to the exempt substance. Criteria specific to the permissible
modifications are described as follows.
i. The Insertion of New Genetic Material
    For the insertion of new genetic material, 40 CFR 174.26(a)(1)
proposes to limit insertions to native genes. EPA finds it important to
include a native gene insertion option in its proposed exemption of
PIPs based on sexually compatible plants created through biotechnology,
because there may be gene variability among sexually compatible plants.
For example, plant genomes can be highly variable with the presence or
absence of entire genes across different crop lines. If native gene
insertion was excluded from the proposed exemption, EPA would be
excluding a class of modifications that can be found in sexually
compatible plant populations. For native gene insertion, the phrase
proposed for 40 CFR 174.26(a)(1), ``A native gene is engineered into a
non-genic location of the recipient plant genome, resulting in a
pesticidal substance identical to the pesticidal substance identified
in the source plant,'' contains two criteria. First, the phrase
``engineered into a non-genic location'' is intended to preclude the
insertion of the native gene into an existing gene. This is because the
insertion of the native gene in the coding region of an existing gene
within the recipient plant may then lead to production of a novel
substance (e.g., a partial or modified substance) by the existing gene.
    Second, the phrase ``resulting in a pesticidal substance identical
to the pesticidal substance identified in the source plant'' ensures
that the substance produced by the inserted native gene does not result
in a substance with which breeders have no experience in preventing
unsafe exposures. The requirement for an identical substance to be
produced, rather than requiring the native gene to be composed of an
identical nucleic acid sequence, allows for some flexibility in the
nucleic acid sequence of the genetic material inserted into the
recipient plant. It is important to allow for this flexibility because
many nucleotide variations found within the coding region of the
genetic material necessary for the production of a proteinaceous
substance are silent, in that they do not result in changes to the
amino acid sequence of the encoded protein. Thus, for proteinaceous
substances, it is therefore permissible to insert a native gene that is
composed of a nucleic acid sequence that is not identical to that found
in the source plant so long as the pesticidal substance for which the
nucleic acid sequence codes is identical to that identified in the
source plant. However, no such flexibility in the modification of the
nucleic acid sequence of the coding region is granted for non-
proteinaceous substances, i.e., in cases when the genetic material
codes for the production of a type of RNA that is not subsequently
translated into a protein (e.g., miRNA), as every nucleic acid in the
coding region is reflected in the final sequence of the non-
proteinaceous substance. For both proteinaceous and non-proteinaceous
substances, flexibility is permissible in the nucleotide sequence of
the regulatory regions. This allows for modifications to the expression
level of the PIP resulting from the native gene insertion, so long as
it meets expression profile criterion 174.26(b) as discussed in Unit
VI.A.2.b.
ii. The Modification of Existing Genetic Material
    Proposed provisions for 40 CFR 174.26(a)(2) describe permissible
modifications of existing genetic material and is further delineated
into four possible categories: Modifications resulting in the
differential expression of a gene, modifications resulting in a native
allele, modifications resulting in the differential expression of a
native allele, and modifications resulting in the loss-of-function of
an existing gene.

(A) Modifications Resulting in the Differential Expression of a Gene
    For the first category, the phrase proposed for 40 CFR
174.26(a)(2)(i), ``the existing native gene in the recipient plant is
modified to alter the amount of pesticidal substance produced without
altering the identity of the pesticidal substance produced,'' limits
the permissible modification in three ways. First, the modification
must be made within the existing native gene in the recipient plant.
The types of genes that can be modified only include those that have
never been derived from sources that are not sexually compatible with
the recipient plant; e.g., it is not permissible to adjust the
expression level of a Bt gene. Second, the permissible modification is
limited to changes that result in changes to the amount of pesticidal
substance. While the abundance of a substance in a plant is not solely
determined by its level of expression (i.e., the amount of messenger
RNA produced), it is reasonable to assume that they generally
correlate, e.g., reducing the expression of a gene is expected to also
reduce the abundance of the substance that is encoded by that gene
(Ref. 17).
    Third, the phrase ``without altering the identity of the pesticidal
substance produced'' prevents modifications to the coding region of the
gene that result in a partial or modified pesticidal substance. By
requiring that the identity of the pesticidal substance be preserved,
EPA can ensure that the identity of the substance produced by that gene
remains the same as it was before the modification. In other words, a
novel substance cannot be produced as a result of the modification; the
only modification permitted is a change in the expression level of the
substance produced by a gene. This position is consistent with the
advice of the FIFRA SAP in the October 2004 meeting on ``Issues
Associated with Deployment of a Type of Plant-Incorporated Protectant
(PIP), Specifically Those Based on Plant Viral Coat Proteins (PVCP-
PIPs),'' which stated that in the context of maintaining a ``safe
history'' assumption, ``only changes that affect an expressed protein
are of concern and that changes to regulatory and untranslated regions
are not relevant.'' (FIFRA SAP meeting held October 13-15, 2004, page
44 of minutes, Unit VI.A.3.a., Table 1). The statement that ``changes
to regulatory and untranslated regions are not relevant,'' indicates
that modifications to those genetic regions do not result in a novel
substance and therefore are not modifications of concern. Additional
criteria surrounding permitted expression profiles are discussed in
Unit VI.A.2.b.
(B) Modifications Resulting in a Native Allele
    For the second category, the phrase in proposed 40 CFR
174.26(a)(2)(ii) ``the genetic material that encodes the substance of
the existing native gene is modified to result in a pesticidal
substance that is identical to the pesticidal substance encoded by a
native allele of that gene,'' limits the types of modifications that
could qualify for exemption. Like the restriction on differentially
expressed genes, modifications to the recipient plant genome resulting
in a native allele must be made within the existing native gene in the
recipient plant. This criterion is intended to limit modifications
solely to a single gene and would therefore exclude from exemption
modifications that would affect more than one gene, e.g., those
affecting chromosomal structure.
    Although EPA recognizes that large-scale changes like
translocations may be considered genetic variants, changes that affect
the structure of chromosomes can affect many genes along the chromosome
and are likely to disrupt or change the substances made by those genes.
Insufficient information is available to allow the Agency to a priori
conclude which structural changes would result in novel exposures, and
therefore which changes may or may not result in unreasonable adverse
effects. Thus, at this time, the Agency is unable to make a generic
risk assessment on the consequences of chromosomal structural
modifications and is not proposing an exemption that would allow for
changes such as chromosomal inversions, translocations, or
rearrangements. This does not preclude the Agency from registering
these types of products or proposing an exemption at a later time
should information become available that supports a determination of
low risk.
    The second half of the phrase, ``to result in a pesticidal
substance that is identical to the pesticidal substance encoded by a
native allele of that gene,'' is another key limitation applied to
native alleles and is based on the same concepts underlying the no
novel exposure argument articulated for native genes in Unit
VI.A.2.a.i. Briefly, requiring that the pesticidal substance produced
in the recipient plant be identical to the substance encoded by the
native allele ensures that there will be no novel situations for plant
breeders, and therefore no novel exposures. This requirement also
allows for more flexibility in the modifications made to the recipient
plant, in a way that restricting the nucleic acid sequence would not.
Again, no such flexibility in the modification of the nucleic acid
sequence of the coding region is granted for non-proteinaceous
substances, i.e., in cases when the genetic material codes for the
production of a type of RNA that is not subsequently translated into a
protein (e.g., miRNA), as every nucleic acid in the coding region is
reflected in the final sequence of the non-proteinaceous substance.
(C) Modifications Resulting in the Differential Expression of a Native
Allele
    For the third category, proposed 40 CFR 174.26(a)(2)(iii) states,
``the existing genetic material is modified pursuant to both (i) and
(ii).'' This phrase is intended to indicate that it is also acceptable
to create a differentially expressed native allele so long as the
criteria under proposed 40 CFR 174.26(a)(2)(i) and 174.26(a)(2)(ii) are
met.
(D) Modifications Resulting in the Loss of Function of a Gene
    For the fourth category, the phrase proposed for 40 CFR
174.26(a)(2)(vi), states ``The existing native gene in the recipient
plant is modified to lose function through the reduction or elimination
of the substance encoded by that gene.'' EPA believes a separate
exemption category to allow for instances in which the pesticidal trait
in the plant is created via the loss-of-function of an existing gene
helps clarify that the rule is intended to cover these types of
modifications. To that end, EPA specifically uses the term
``substance'' rather than ``pesticidal substance'' for this exemption
category when referring to the native gene product (e.g., protein). For
example, a gene coding for a receptor protein may be modified to result
in the loss-of-function of that protein to confer disease resistance.
By specifying that the substance must maintain the same identity, EPA
therefore prevents the production of modified proteins not previously
identified in the gene pool while still allowing for modifications in
the coding region that ultimately prevent the production of a protein
(e.g., premature termination codon). Additionally, modifications in the
regulatory region of a gene would be allowed under the proposed
exemption as these do not result in changes to the identity of the
substance produced by the genetic material. EPA requests comment on
whether an exemption category specific to loss-of-function

traits (rather than including them in proposed 174.26) would be clearer
(see Unit VII.E.).
b. Limitations on Expression Profile
    The proposed criterion at 40 CFR 174.26(b), ``the pesticidal
substance is not expressed at higher levels, in different tissues, or
at different developmental stages than identified in a plant that is
sexually compatible with the recipient plant,'' is a key limitation to
prevent novel dietary and environmental exposures. The limitation on
levels is important because endogenous plant compounds that result in
plant resistance to pests can be toxic to mammals or other non-target
organisms (Ref. 11). Limiting the expression profile of pesticidal
substances to that found in a plant capable of being sexually
compatible with the recipient plant ensures that the assumptions used
to justify the proposed exemption (specifically, a long history of
breeder experience with such substances and situations) support the
statutory findings required to exempt PIPs based on sexually compatible
plants created through biotechnology. For example, breeders will be
able to ensure that modifications that lead to an increase in the
expression of a substance are limited to levels accepted in
conventional breeding because of their experience with the levels
observed in plants that are sexually compatible with the recipient
plant. The level of expression of pesticidal substances is expected to
vary among sexually compatible plants depending on environmental
conditions and due to intrinsic variations in their potential to
express a substance (Ref. 17). Variation exists even among plants of
the same variety due to different weather and soil condition (Ref. 18).
As such, limiting changes in the expression of a pesticidal substance
not to exceed levels found within a sexually compatible plant supports
meeting the FIFRA section 25(b)(2) exemption standard because such
changes do not result in exposure levels not otherwise encountered
through conventional breeding.
    The proposed phrase also ensures that modifications allowed under
the proposed exemption do not result in changes in the expression
pattern of pesticidal substances. Specifically, this criterion ensures
that pesticidal substances are only expressed in the same plant tissues
and at the same developmental stages as what is found in a sexually
compatible plant. For example, an insect toxin typically produced in
the leaves of a plant would not meet the proposed exemption criterion
if the plant is modified to produce the toxin in the nectar or pollen,
as this may result in novel exposure of pollinators to the toxin. To
ensure that the exempt PIPs are low risk and meet the FIFRA section
25(b)(2) exemption standard, EPA finds it necessary that pesticidal
substances would not exceed expression levels or be expressed in
different tissues or at different developmental stages from the
exposure encountered among sexually compatible plants.
3. Risk Analysis
    EPA considered several factors in determining whether PIPs based on
sexually compatible plants created through biotechnology that meet the
criteria under proposed 40 CFR 174.26 could be exempted from FIFRA
requirements in order to meet the 40 CFR 174.21(a) requirement. That
consideration relied upon the large body of knowledge that currently
exists on sexually compatible plants and genetic diversity. The factors
include: ``(1) Low potential for novel exposures; (2) Low potential for
levels of PIPs based on sexually compatible plants created through
biotechnology to exceed levels found in sexually compatible plants; (3)
Low potential for PIPs based on sexually compatible plants created
through biotechnology to move from cultivated plants to wild or weedy
relatives through gene flow and increase weediness; (4) Low potential
for occupational and non-occupational risks to humans; and (5) Low
potential for resistance selection pressure posed by PIPs based on
sexually compatible plants created through biotechnology to exceed that
found in sexually compatible plants.'' EPA also evaluated
considerations specific to newer biotechnology techniques related to
PIPs based on sexually compatible plants created through biotechnology.
    In addition to the analyses discussed in this unit for exemption
under FIFRA, EPA also performed similar analyses for the proposed
tolerance exemption under FFDCA discussed in Unit VI.B. EPA refers
readers to the detailed discussions in that unit for information
specific to the dietary safety of PIPs based on sexually compatible
plants created through biotechnology.
a. Large Body of Knowledge
    In the issue paper entitled ``FIFRA: Benefit and Environmental Risk
Considerations for Inherent Plant-Pesticides'' (Ref. 23), EPA describes
a large part of the information base on nontarget plants, insects,
birds, mammals and other herbivores that the Agency relied on for its
evaluation of the potential effects of PIPs based on sexually
compatible plants created through biotechnology on the environment. In
addition, to understand the history of exposure of non-target organisms
to substances found in nature that are equivalent to PIPs based on
sexually compatible plants created through biotechnology, EPA used the
large body of literature on the effect on humans of consumption of food
from sexually compatible plants generated from epidemiological studies,
nutritional assessments, animal model testing and biochemical studies
(Ref. 24, 25, 26, 27, 28, 29, 30, 31, 32) to draw conclusions on the
potential risk for animal non-targets, including birds and fish, which
might consume food containing the PIPs proposed for exemption. Testing
in animal models can supply information that is extrapolated to make
conclusions on the effect of a substance on humans; similarly,
information and conclusions drawn in the dietary risk assessment on the
effects on humans can be extrapolated to predict effects on non-human
mammals and other animals in an assessment of environmental risk. In
addition, there is a long history of humans using foods containing PIPs
as food for domesticated and other animals, including birds and fish.
EPA relied on this history of exposure and the large literature
generated by a century of systematic studies of the constituents of
food (Ref. 23) to assess PIPs based on sexually compatible plants
created through biotechnology.
    EPA also considered scientific knowledge from a number of
disciplines, including plant genetics, plant physiology,
phytopathology, biochemistry, ecology, evolutionary biology, genomics,
and plant breeding. From the disciplines of plant physiology and
biochemistry, EPA considered, for example, information on plant
metabolism, the production of substances that may have a pesticidal
effect, and conditions that may limit the production of such substances
(Ref. 33). The Agency also used information from the science of
phytopathology to characterize the pest resistance mechanisms in plants
in order to understand the types of traits PIPs based on sexually
compatible plants created through biotechnology may confer to recipient
plants (Ref. 3). The sciences of ecology and evolutionary biology were
considered for information on genetic diversity, mutation, and
reproductive isolation mechanisms in populations (Ref. 34) to
understand the types of genetic changes that are likely to occur when
plants interbreed. Plant breeding and genetics were considered to

describe the mechanisms of incompatibility and interbreeding (Ref. 35,
36), which aided EPA in determining when plants are likely to
interbreed. Information from genomics and molecular biology were
considered to understand the ability of newer biotechnology techniques
to create traits equivalent to those found in conventionally bred
plants (Ref. 23, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46).
    Finally, recommendations from several FIFRA SAPs and NASEM reports
were considered in the development of the proposed exemption criteria
for PIPs based on sexually compatible plants created through
biotechnology, and when describing the types of genetic modifications
in the recipient plant that are unlikely to result in novel exposure to
humans and the environment (see Table 1 in Unit II.C.3.).
b. Low Potential for Novel Exposure
    Given that PIPs based on sexually compatible plants created through
biotechnology are intended to represent a subset of substances present
in plants that plant breeders have experience with, EPA does not expect
novel exposures from the substances involved.
    Pesticidal traits, and the genetic material encoding them, have
evolved and been developed in plant populations through the processes
of mutation, selection, and genetic exchange among sexually compatible
species (Ref. 47, 48). The ability to produce viable offspring is only
possible for organisms that are genetically similar and possess many
traits in common. Traits, and the genetic material encoding them, can
be passed through a plant population by breeding. The mixing of genetic
material that occurs through breeding results in sexually compatible
plants having similar genetic material and similar traits. Due to the
mixing of traits by mating, similar exposure scenarios are expected for
plants that are capable of being sexually compatible, in other words,
substances in sexually compatible plants are expected to be similar and
therefore, only substances that plant breeders are already familiar
with are expected to be present in sexually compatible plants. This
conclusion is consistent with the 1992, 1993, and 1994 FIFRA SAP
meetings that indicated that sexually compatible plants are more likely
to have a common constitution than unrelated plants and thus movement
of genetic material between sexually compatible plants is less likely
to lead to novel exposures (Ref. 7, 8, 23).
    For agricultural plants, those defined as capable of being sexually
compatible would also include existing plant cultivars, landraces, and
breeding lines, as well as plant relatives that interbreed with crops
but that are not currently used as agricultural plants. Plant breeders
have for many years been moving genes into agricultural varieties from
nonagricultural relatives with no indication that substances resulting
from these genes present higher levels of risk than those from genes
moved only amongst agricultural varieties (Ref. 13, 14, 15, 16).
Therefore, the likelihood that the inclusion of nonagricultural
varieties as potential source plants would pose an increased potential
for novel environmental exposures from PIPs based on sexually
compatible plants created through biotechnology is low.
    If a population of sexually compatible plants normally possesses a
pesticidal substance, organisms that encounter plants in that
population have likely been exposed to the pesticidal substance in the
past, perhaps over multiple generations. These past exposures,
particularly if they occur over long periods of time, may lead to a
degree of adaptation, or tolerance in the population of organisms
exposed to the pesticidal substance (Ref. 49). Relatedly, the proposed
exemption would not affect exposure patterns because the proposed
criteria require that the pesticidal substance have an expression
profile found in sexually compatible plants (e.g., the pesticidal
substance is expressed in the same developmental stages or tissues).
Any avoidance strategies of nontarget organisms (e.g., avoid eating
certain parts of the plant) would still be protective in the case of
PIPs based on sexually compatible plants created through biotechnology.
Thus, the potential is low that PIPs based on sexually compatible
plants created through biotechnology would pose novel exposures for
organisms that typically encounter related plants.
    Genetic diversity is created over time and EPA proposes to capture
some of the ongoing diversification not identified in existing native
genes or native alleles through the inclusion of changes resulting in
the alteration of the amount of substance produced by existing genes,
so long as no novel substance is produced and the substance is not
produced in different tissues or at different developmental stages than
those found in sexually compatible plants. Modifications that lead to
differential expression levels of a substance are not expected to
result in levels that exceed the boundaries of the variation found in
sexually compatible plants due to physiological constraints that are
related to energy expenditure (further discussed in Unit VI.A.3.c.).
Therefore, the potential for novel exposures to occur with the
differential expression of existing genes, or the movement of native
genes and native alleles among sexually compatible plants, is low,
because no substance novel to plants capable of being sexually
compatible with the recipient plant will be produced, nor will the
substance be found at higher levels, in tissues, or at developmental
stages in which it is not currently found.
c. Low Potential for Levels of PIPs Based on Sexually Compatible Plants
Created Through Biotechnology To Exceed Levels Found in Sexually
Compatible Plants
    EPA has evaluated whether there are likely to be quantitative
changes in levels of PIPs based on sexually compatible plants created
through biotechnology expressed by the recipient plant, such that
adverse effects to the environment or to humans might occur (see Unit
VI.B. for an analysis on human dietary risk). EPA has determined that
the potential of such an event is low because the highest levels of
pesticidal substances likely to be expressed with PIPs based on
sexually compatible plants created through biotechnology are not likely
to result in significantly different environmental exposure levels.
    An analysis discussing the likely range of expression of PIPs in
sexually compatible plants was presented in an EPA issue paper,
entitled: ``FIFRA: Benefit and Environmental Risk Considerations for
Inherent Plant-Pesticides'' (Ref. 23). A summary of the analysis and
how it applies to the proposed exemption is presented here. EPA first
considered whether any increase in the levels of substances, including
PIPs, that plants normally produce is likely to exceed the ranges
normally found within and between plant varieties and uncultivated
plants. The level of production of such substances normally varies
among sexually compatible plants because of differences in potential to
express a substance and environmental conditions. Indeed, variation is
seen even among plants in the same variety because of differences such
as weather and soil condition. For example, one report has shown an
8.3-fold variation in the amount of ascorbic acid in turnip greens
depending on the degree of exposure to light (Ref. 18). EPA's proposal
would exempt PIPs based on sexually compatible plants created through
biotechnology that are not

expressed above the range of variation on the basis that such exposures
would not be considered novel. EPA considers that nontarget organisms,
such as birds and insect pollinators, that associate with such sexually
compatible plant populations have been and are currently being exposed
to the upper levels of substances that might be used as PIPs based on
sexually compatible plants created through biotechnology.
    EPA considered the extent to which any substance can be increased
in highly managed plants without unwanted effects on other, desirable
characteristics of the plant such as yield or palatability of fruit. In
general, breeders balance all of these characteristics in developing
marketable plant varieties. Greatly increased levels of any substance,
including PIPs based on sexually compatible plants created through
biotechnology, generally would only be accomplished at the expense of
the expression of other, agriculturally desirable traits due to
physiological constraints related to energy expenditure in the plant
(Ref. 23). A plant, like any other living organism, has a finite energy
budget, and can only harvest so much energy from the environment to
allocate to all of its activities; therefore, a significant increase in
the production of one substance, like a PIP, would reduce the energy
that could be put towards the production of other substances critical
to the plant's metabolism. Thus, there are practical considerations
that limit the upper expression levels of a PIP based on a sexually
compatible plant created through biotechnology to that found in a plant
that is sexually compatible with the recipient plant. To codify this
principle into regulatory text, EPA is proposing criteria in which the
level of expression of the PIP based on a sexually compatible plant
created through biotechnology is bound by the upper limit of expression
of the pesticidal substance observed in a sexually compatible plant. By
limiting the expression of PIPs based on sexually compatible plants
created through biotechnology in this way, EPA can ensure that the
exposures fall within the normal historical range of exposures with
which plant breeders have experience limiting. EPA also considered
whether the total expression (i.e., expression of the PIP across all
plants capable of producing that PIP) would result in an adverse effect
different than that possible through conventional breeding. Because the
PIP based on a sexually compatible plant created through biotechnology
could have otherwise been created through conventional breeding, EPA
does not expect that the cumulative expression of a PIP based on a
sexually compatible plant created through biotechnology would pose a
higher risk than what is currently possible through conventional
breeding.
    The potential for exposure to PIPs is typically lower than for
other types of pesticides because PIPs are produced within the living
plant and used in situ in the plant. Other pesticides, such as
conventional chemicals, must be applied to the plant, or near the
plant. Because a PIP is produced and used within the plant,
physiological constraints limit the amount of pesticidal substance
produced by the plant. Moreover, the routes by which other organisms
may be exposed to the PIP are typically more limited, e.g., dietary
exposure is likely to be the predominant route of exposure; there is a
potential for dermal or inhalation exposure, although that likelihood
is more limited (see Unit VI.A.3.e. for additional discussion of dermal
and inhalation exposure in humans). In addition, PIPs are part of the
metabolic cycles of plants, meaning they are biotic and subject to the
processes of biodegradation and decay. Furthermore, PIPs are
biodegradable to their constituent elements through catabolism by
living organisms. Because they are readily degraded, PIPs do not
bioconcentrate in the tissues of living organisms (Ref. 50) or persist
in the environment. Given these characteristics, the potential for new
exposures to occur, beyond direct physical exposures to the plant or
plant parts, is limited for PIPs generally, including PIPs based on
sexually compatible plants created through biotechnology.
    EPA also considered whether variations of expression levels of PIPs
based on sexually compatible plants created through biotechnology
contained in semi-managed systems (e.g., trees) presented any novel
issues for exposure to nontarget organisms (Ref. 23). Semi-managed
systems received specific consideration because their semi-managed
state can result in exposure to a larger variety of nontarget organisms
compared to highly managed row crop systems. For the reasons stated in
the preceding paragraphs in this unit, EPA anticipates that for such
plants, levels of expression of PIPs based on sexually compatible
plants created through biotechnology will continue to fall within the
upper limit of expression currently observed for such substances in
sexually compatible plants. Therefore, it is anticipated that the
levels of PIPs based on sexually compatible plants created through
biotechnology in semi-managed plants would not exceed the levels
observed in sexually compatible free-living relatives (Ref. 23).
    Finally, while not necessary to support the Agency's low
probability of risk determination under FIFRA, EPA did nonetheless
consider the role of the plant breeding process in maintaining levels
of substances in plants. Plants containing PIPs based on sexually
compatible plants created through biotechnology will, as would plants
in other development programs, pass through a post-development
screening and selection process. During this process, plants with
undesired or unexpected traits are identified and eliminated from
further development. The development of new plant varieties, whether
through conventional breeding or through biotechnology, begins with the
production of a large number of plants containing the trait of
interest. Plants are cultivated over several propagation cycles in
order to identify those plants that inherit the intended phenotype
across multiple generations while maintaining desirable agronomic
characteristics such as uniform growth characteristics, fertility, and
yield (Ref. 22). The screening and selection practices result in the
selection of plants intended for commercialization that display
desirable behavior, including desired levels of expression of various
traits. Historically, these practices have proven to be reliable for
ensuring safety and plants containing PIPs based on sexually compatible
plants created through biotechnology are expected to also pass through
these same screening and selection processes.
    In conclusion, in its assessment, EPA considered the potential of
variations in expression levels of PIPs based on sexually compatible
plants created through biotechnology and whether those variations would
present risk. EPA concluded that although variations in PIP expression
levels will occur in response to environmental conditions in plants
that interbreed, these variances are within exposure levels already
encountered. The purpose of EPA's second criterion limiting expression
levels to no higher than presently found in plants that are sexually
compatible ensures that any exempt PIPs based on sexually compatible
plants created through biotechnology would not pose a higher risk than
what is currently found through conventionally bred plants. Given the
history of safe exposure to those substances, this criterion helps to
ensure that exempt PIPs pose a low probability of risk from
quantitatively different exposures.

d. Low Potential for PIPs Based on Sexually Compatible Plants Created
Through Biotechnology To Move From Cultivated Plants to Wild or Weedy
Relatives Through Gene Flow and Increase Weediness
    Because PIPs based on sexually compatible plants created through
biotechnology are produced and used in the living plant, EPA considered
the possibility that the PIP may be transferred by hybridization from
the crop plant to a cultivated, wild or weedy relative. A large volume
of information is available in the public literature on this
possibility and the likelihood of hybridization (Ref. 36, 51, 52, 53,
54, 55). EPA's issue paper entitled ``Risk Considerations for
Outcrossing and Hybridization'' addresses these considerations for PIPs
in plants in sexually compatible populations (Ref. 56). As the genes
used to create the PIPs proposed for exemption produce the same
substances as found in sexually compatible plant populations, EPA
relied on this analysis to address this aspect of the assessment.
    One of the considerations evaluated for this proposed exemption was
whether a PIP based on a sexually compatible plant created through
biotechnology could be transmitted to wild relatives through gene flow
of genetic material. A second and more important consideration is
whether such an outcrossing event could, in turn, increase weediness of
the wild relative. For the following reasons, EPA concluded that the
potential is low for weediness to increase in wild relatives through
the flow of genetic material coding for a PIP based on a sexually
compatible plant created through biotechnology.
    There are several factors governing whether gene flow occurs, and
thus governing the potential for hybridization between crops and their
wild relatives (Ref. 53, 54, 57). First, genetic barriers can prevent
hybrids from forming, render them sterile, or reduce the fertility of
hybrids, and thus restrict their contribution to subsequent
generations. The strength of genetic barriers is correlated to the
degree of evolutionary relatedness between the crop and wild relatives,
with the barriers being stronger the more distantly related the plants.
Second, geographic space is an effective barrier to hybridization. For
instance, wild relatives with which corn can hybridize are restricted
to Mexico and Central America. There is no potential of hybridization
between domesticated corn and its wild relatives in other regions of
the globe (Ref. 58). Third, temporal barriers such as time of flowering
also affects hybridization, as hybridization cannot occur when there is
no overlap in the time of flowering of cultivated and wild forms (Ref.
54, 57). For some species (e.g., peanut), the flowers do not ordinarily
open, and self-pollination may be very near 100 percent; thus,
hybridization between cultivated and wild forms is unlikely even if the
cultivated and wild forms are synchronized in flowering and close
enough geographically for pollen to move between them. Fourth, the
ploidy level may differ between a crop and its relatives with many
cultivated plants having higher ploidy than their wild relatives.
Differences in ploidy levels can significantly reduce the likelihood
that the cultivated plant and wild relative will form fertile hybrids
(Ref. 54). Finally, some varieties of certain crop species, such as
banana, are sterile, and thus are incapable of hybridizing not only
with members of other species, but also with members of their own
species (Ref. 59). For some crops in the United States, the probability
of hybridization and gene transfer with the wild relative is zero,
while for other crops, despite the variety of potential barriers to and
selection against hybridization, gene transfer is possible. However,
even in instances where hybridization is possible, wild relatives
generally tend to possess higher levels of resistance to pests and
disease than do the cultivated members of those populations (Ref. 23).
Wild relatives also tend to express a greater range of levels of
inherent plant defense compounds than do cultivated plants, including
the production of higher levels of substances that could potentially be
used as PIPs (Ref. 23).
    If an agricultural or semi-managed plant containing a PIP based on
a sexually compatible plant created through biotechnology hybridizes
with a wild relative, it is unlikely that the levels of expression of
the transferred PIP in the wild relative will be substantially
increased. For reasons described in Unit VI.A.3.c., EPA anticipates
that for agricultural, semi-managed, and feral plants, levels of
substance expressed by the PIP based on a sexually compatible plant
created through biotechnology will not exceed levels currently observed
for the substance in sexually compatible plants (Ref. 23, 51). Thus,
because the levels of expression of a PIP based on a sexually
compatible plant created through biotechnology will not exceed levels
currently observed in plant populations pursuant to proposed criteria,
the potential for an increase in weediness in wild relatives is low
should the wild relative acquire the exempted PIP trait.
e. Low Potential for Occupational and Non-Occupational Risk to Humans
    In general, PIPs are likely to present a limited exposure to
humans. In most cases, the predominant, if not the only, exposure route
will be dietary. Significant respiratory and dermal exposures are
unlikely in non-occupational settings because most plant substances,
including PIPs based on sexually compatible plants created through
biotechnology, are expressed at relatively low levels and are found
inside the cell, and therefore any human health risks in non-
occupational settings are expected to be negligible. Although a
potential for non-dietary exposure (e.g., dermal and inhalation) in
occupational settings may exist due to the processing of plants
resulting in increased exposure to intracellular substances like PIPs,
EPA expects exposure to be low due to the relatively low levels of such
substances in plants (Ref. 60). Given that PIPs based on sexually
compatible plants created through biotechnology represent a subset of
substances present in sexually compatible plants that breeders have
experience with and must be expressed at or below existing levels, in
the same tissues, and at the same developmental stages, EPA does not
expect novel exposures from the substances involved, as the sexually
compatible plant sources have a history of being safe sources of
genetic diversity for use in cultivated plants. Because these PIPs are
indistinguishable from those found in a sexually compatible plant,
which in many cases is a close relative or even the same plant species,
existing allergen avoidance strategies for certain plants would still
be protective.
    Regarding dermal exposure, expressed substances of PIPs based on
sexually compatible plants created through biotechnology may in some
cases be present in sap or other exudates from the plant or the produce
and thus may present some limited opportunity for dermal exposure to
persons physically contacting the plant or raw agricultural food from
the plant. Farmers and food handlers (e.g., individuals harvesting
produce by hand, preparing food for sale, or stocking produce bins in
grocery stores) or floral workers are those most likely to experience
dermal contact with the substances on an occupational basis. However,
because most plant substances, including PIPs, are expressed at
relatively low levels and are found inside the cell, the level of
exposure is still expected to be low.

    Most of the substances that could be the subject of this proposed
exemption are unlikely to pass through the skin to affect other organ
systems or elicit allergenic sensitization (Ref. 60, reviewed in 61).
The most common skin reaction to plant products is likely irritant
contact dermatitis. These dermal reactions are generally mild, of a
self-limiting nature or self-diagnosed, and self-treated (Ref. 60).
Skin penetration of the substances comprising a PIP is dependent on
several characteristics, including the substances molecular structure
and hydrophobicity, accompanying mechanical irritation (e.g., thorns),
the duration and site of contact, and the lipid content of the skin.
For most PIPs, human skin, which is composed of two layers, the
epidermis and the dermis, is a natural barrier. The outer epidermal
layer of the skin consists of dead cells in tight junctions (keratin)
that provide a shield against elements in the outside world. The rapid
shedding and replacement of the keratin layer serves as a further
protective feature of the skin, as any damaged cells are quickly shed
and replaced. For those PIPs based on sexually compatible plants
created through biotechnology that might possess some properties that
allow limited penetration of the skin, the potential amount passing
through the outer epidermal layer of the skin (epidermis) is likely to
be negligible (Ref. 60). Some irritant contact dermatitises are
initiated by mechanical means which allow for limited penetration of
the skin. For example, the small needle-like hairs of some plants
(e.g., stinging nettle) penetrate the skin to deliver small doses of
irritant toxins (e.g., histamine). However, plants with these
characteristics are rare in cultivation, further limiting exposure
(Ref. 60).
    Importantly, PIPs based on sexually compatible plants created
through biotechnology represent a subset of substances already present
in related plants. PIPs based on sexually compatible plants created
through biotechnology would therefore not be expected to alter
predicted exposures of workers to plant proteins or other plant
substances. Thus, dermal exposure to residues of PIPs based on sexually
compatible plants created through biotechnology would not be predicted
to alter exposure patterns in occupational settings.
    Regarding inhalation exposure, PIPs based on sexually compatible
plants created through biotechnology may in some cases be present in
pollen, and some individuals (e.g., those working on farms in nurseries
or other plant-growing areas) may be exposed through inhalation to
wind-blown pollen. When present in pollen, the pesticidal substance is
likely to be integrated into the tissue of the pollen grain. The
likeliest impact of pollen exposure is rhinitis, or inflammation of the
mucous membranes lining the nose, resulting in symptoms like nasal
congestion, sneezing, itching, post-nasal drainage, and runny nose.
This proposed exemption will not change current exposures or affect
strategies for dealing with reactions to PIPs based on sexually
compatible plants created through biotechnology that may be aero-
allergens or irritants (Ref. 60). Pollen grains are solid, insoluble
particles of sufficiently large diameter that they are filtered out in
the nasopharynx or in the upper respiratory tract (Ref. 60), from which
they are generally swallowed into the gastrointestinal tract. The
gastrointestinal surface forms a barrier between the body and the
lumenal environment and is often described as having two components:
``(1) The intrinsic barrier is composed of the epithelial cells lining
the alimentary canal and the tight junctions that tie them together,
and (2) The extrinsic barrier consists of secretions and other
influences that are not physically part of the epithelium, but which
affect the epithelial cells and maintain their barrier function.''
Regarding the intrinsic barriers, the alimentary canal is lined by
sheets of epithelial cells that form the defining structure of the
mucosa and establish the basic gastrointestinal barrier. Regarding the
extrinsic barriers, the gastrointestinal epithelium is coated with
mucus, which is synthesized by cells that form part of the epithelium.
Mucus contributes to barrier function in several ways by slowing the
diffusion of molecules. Additionally, molecules in food, including
edible plant tissue, are too large to be absorbed by the
gastrointestinal tract and are broken down into smaller molecules to be
absorbed and utilized by the body. Plant materials such as pollen are
also subjected to the processes in the digestive tract that reduce
larger molecules to smaller constituents that can be absorbed by the
membranes of the small intestine. Importantly, pollen characteristics
(e.g., wind vs. insect dispersal, amount produced) are often maintained
within plant families, as is necessary for successful breeding to
occur. Therefore, PIPs based on sexually compatible plants created
through biotechnology should not alter already established
characteristics of any particular species. In cases of occupational
rhinitis, these PIPs would not be expected to significantly alter
already established patterns of exposure to occupational dusts.
f. Low Potential for Resistance Selection Pressure Posed by PIPs Based
on Sexually Compatible Plants Created Through Biotechnology To Exceed
That Found in Sexually Compatible Plants
    A component of EPA's oversight historically for PIPs created
through biotechnology has been the requirement for registrants to
implement an insect resistance management plan. Transgenic Bacillus
thuringiensis (Bt) PIPs are likely at greater risk for insects
developing resistance than many conventional pesticides targeting the
same insects because Bt PIPs are expressed throughout all plant tissues
for the entire lifespan of the plant compared to conventional
pesticides, which typically have shorter periods of efficacy and are
applied when pests are likely to cause yield loss. To address
resistance management due to increased exposure, the Agency has
required detailed information for Bt PIPs (e.g., dose expression
levels, cross-resistance potential, modeling scenarios) alongside terms
of registration (e.g., resistance monitoring programs, remedial action
plans, compliance assurance, and grower education activities).
    As mentioned in the previous paragraph, the risk of resistance to
Bt PIPs primarily stems from increased exposure to the PIP from
expression across plant tissues and across the plant lifespan, which
are achieved due to transgenic regulatory elements used in the creation
of the PIP. However, in the case of PIPs based on sexually compatible
plants created through biotechnology, the potential to develop
resistance is lower than that of Bt PIPs due to the limitation on
expression profile (e.g., same tissues and developmental stages) to be
within what is found in sexually compatible plants. EPA does not
anticipate an increased resistance risk posed by PIPs based on sexually
compatible plants created through biotechnology compared to those
developed by conventional breeding. The proposed rule does not require
specific resistance management plans from developers of PIPs based on
sexually compatible plants created through biotechnology that qualify
for the new exemption.
g. Are there any considerations associated with newer biotechnology
techniques?
    Newer biotechnology techniques using present-day genome editing
techniques (e.g., CRISPR, zinc-finger

nucleases, transcription activator-like effector nucleases,
oligonucleotide-directed mutagenesis) can present some additional
considerations beyond those discussed previously, and these were taken
into consideration in developing the proposal to exempt PIPs based on
sexually compatible plants created through biotechnology from FIFRA
requirements in order to meet the requirement at 40 CFR 174.21(a).
Present-day genome editing techniques allow for precise modifications
to the plant genome such that the PIP in question meets the proposed
criteria. These new technologies can aid in plant breeding and result
in varieties indistinguishable from those developed through
conventional breeding (Ref. 12).
    Although genome editing technologies allow for more precise editing
or insertion compared to older technologies, there is still a
possibility of unintended modifications, also called ``off-target''
mutations. With genome editing technologies, off-target mutations may
occur when the genome editing machinery cuts DNA at sites that share
sequence similarity with the actual target sequence. However, off-
target mutations may occur as a result of any form of plant breeding,
including conventional breeding, and an off-target mutation is not
necessarily significant in a specific PIP/plant combination with regard
to food, feed and/or environmental risk. In plants, off-target
mutations can largely be removed by backcrossing, if necessary,
regardless of the method by which they were introduced (Ref. 62). It is
very likely that the off-target mutation and the desired trait are
inherited separately, which allows for developers to select plants that
have the desired trait, but that do not have the off-target mutation.
    A recent comparison of single-base pair substitution mutations
resulting from plant breeding technologies found that the number of
mutations detected after genome editing was not significantly different
from what was found after routine tissue culture (Ref. 63). This
analysis supports the conclusion that off-target mutations from genome
editing are not inherently different or riskier than off-target
mutations occurring through other forms of plant breeding. In addition,
recent studies in rice and maize found that compared to the inherent
variation found in the plant, mutations resulting from genome edited
off-target mutations were negligible and far fewer (Ref. 64, 65).
    The majority of unintended changes at the genomic level, whether
due to off-target mutations from plant breeding technologies or through
natural mutations, do not result in significantly deleterious effects
to the plant at the phenotypic level (Ref. 4). This is primarily due to
the highly plastic nature of plant genomes (Ref. 66, 67, 68). The small
percentage of unintended changes that do result in significant
deleterious effects are far more likely to produce an effect
deleterious to the plant itself (e.g., stunted growth) than a novel
exposure to humans or the environment (Ref. 34). Although EPA only
regulates the PIP, FDA regulates the remainder of the plant for food
safety (see Unit II.B.). In the context of the genetic material
encoding the PIP, off-target mutations in the coding region resulting
in protein-level changes would not be eligible for exemption based on
the proposed criteria requiring that the substance be the same as
identified in a source plant. Off-target mutations in the regulatory
region would not be considered a significant risk due to the same
rationale allowing for modifications to regulatory regions as described
in Unit VI.A.2.a. EPA therefore considers off-target mutations
resulting from genome editing technologies to present a negligible risk
to the environment in the context of PIPs based on sexually compatible
plants created through biotechnology.
h. FIFRA Section 25(b)(2): Preliminary Statutory Finding
    EPA preliminarily concludes that PIPs based on sexually compatible
plants created through biotechnology as described for proposed 40 CFR
174.26, warrant exemption under FIFRA section 25(b) because these
substances are of a character that is unnecessary to be subject to all
the requirements of FIFRA to carry out the purposes of the Act.
Specifically, EPA has preliminarily concluded that PIPs based on
sexually compatible plants created through biotechnology that meet the
exemption criteria pose a low probability of risks to humans and the
environment.
    As discussed in Unit VI.A.3., EPA has preliminarily concluded that
PIPs based on sexually compatible plants created through biotechnology
that meet the exemption criteria pose a low probability of non-dietary
risk to humans and the environment. As explained in this preamble in
Unit VI.B., EPA has also determined that there is a reasonable
certainty that no harm will result from aggregate exposure to the
residues of such products, including all anticipated dietary residues
and all other exposures for which there is reliable information. As
such, EPA has preliminarily determined that use of PIPs based on
sexually compatible plants created through biotechnology is not likely
to cause unreasonable adverse effects on the environment and humans in
the absence of regulatory oversight other than the adverse effects
reporting requirement in existing 40 CFR 174.71. Based on the low
probability of the potential risks coupled with the proposed exemption
eligibility determination process, EPA anticipates minimal societal
benefits would be gained by imposing the full degree of oversight
associated with FIFRA registration (see Unit VI.A.4. for additional
information on benefits). Finally, the adverse effects reporting
requirement at existing 40 CFR 174.71 provides a mechanism that could
alert the Agency to information regarding adverse effects associated
with a PIP based on a sexually compatible plant created through
biotechnology. Based on the information available, the benefits of
exempting PIPs based on sexually compatible plants created through
biotechnology from FIFRA outweigh the potential risk associated with
these PIPs (risk that is low).
4. Benefits
    This unit summarizes the benefits that are described in greater
detail in the cost analysis (Ref. 2). This cost analysis quantifies
registration or Pesticide Registration Improvement Extension Act of
2018 (PRIA) related fees as required by FIFRA. These fees represent
savings to developers if the proposed exemption becomes final.
    The direct benefit of the proposed rule is the reduced regulatory
burden associated with developing and marketing a PIP based on a