[Federal Register Volume 85, Number 197 (Friday, October 9, 2020)]
[Proposed Rules]
[Pages 64308-64344]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-19669]



[[Page 64307]]

Vol. 85

Friday,

No. 197

October 9, 2020

Part IV





Environmental Protection Agency





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





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  

[[Page 64308]]


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

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.

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

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: (703) 305-7090; email address: 
[email protected].

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

[[Page 64309]]

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

[[Page 64310]]

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

[[Page 64311]]

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

[[Page 64312]]

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

[[Page 64313]]

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

[[Page 64314]]

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.

[[Page 64315]]

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

[[Page 64316]]

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

[[Page 64317]]

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.

[[Page 64318]]

(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

[[Page 64319]]

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

[[Page 64320]]

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

[[Page 64321]]

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.

[[Page 64322]]

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.

[[Page 64323]]

    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

[[Page 64324]]

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 
sexually compatible plant created through biotechnology. The proposed 
exemption may encourage more research and development in this area of 
biotechnology and better enable firms of all sizes to engage in the 
development of these types of PIPs.
    Entities that support major crops or larger markets can more easily 
absorb fixed registration costs. As a portion of the total costs of 
researching and developing a new active ingredient, registration costs 
often represent a small proportion of the overall costs of bringing a 
product to market. However, an outlay of fixed registration costs can 
be significant for a firm that supports minor crops. Removal of 
registration costs for these entities can be significant, so smaller 
entities may feel the most regulatory relief as a result of this rule.
    Crop varieties modified for greater pest and disease resistance 
could also reduce the use of externally applied pesticides, which in 
turn could reduce

[[Page 64325]]

farm expenditures and provide environmental benefits. Finally, the 
proposed exemption would also reduce the burden on the Agency to review 
applications for registration.
    Exempting PIPs based on sexually compatible plants created through 
biotechnology from registration while also promulgating an exemption 
from the requirement of an FFDCA tolerance for residues of such PIPs in 
or on food or feed has an estimated incremental cost savings (the 
primary benefit of the rule) of about $444,000-$459,000 per product. 
This savings represents the difference between the new costs of the 
process to submit a letter of self-determination and the old estimated 
costs that developers would have had to incur to meet Agency data 
requirements and to register the PIP. The annual number of PIPs based 
on sexually compatible plants created through biotechnology cannot be 
forecasted, so the Agency based annual and annualized cost savings 
estimates on an assumption that there would be one PIP that fit the 
exemption category per year for the next ten years. This estimate is 
meant to inform the public of the cost savings and their magnitude over 
time. The estimate avoids Agency conjecture about how many products 
would be registered in the absence of this exemption over time. The 
number of future PIPs based on sexually compatible plants created 
through biotechnology being developed will depend on the market for 
these products.
a. Growers
    Growers will have more tools to combat pest pressure because the 
proposed exemption might accelerate the development of new plant 
varieties containing exempt PIPs based on sexually compatible plants 
created through biotechnology that target those pests. Faster marketing 
of PIPs based on sexually compatible plants created through 
biotechnology will allow the market to respond faster to changes in 
disease pressure and the emergence of resistance to existing 
pesticides, which can be important to growers. EPA anticipates that the 
proposed exemption for PIPs based on sexually compatible plants created 
through biotechnology will particularly encourage the development of 
PIPs based on sexually compatible plants created through biotechnology 
in minor crops. The limited acreage on which minor crops are cultivated 
makes it more difficult to recoup investment in research and 
development into new varieties, especially if regulatory costs are 
high.
b. The Agency
    Finally, the proposed exemption would also reduce the burden on the 
Agency to review applications for registration. By proposing to exempt 
those PIPs based on sexually compatible plants created through 
biotechnology due to low probability of risk and lack of unreasonable 
adverse effects in the absence of oversight, EPA will concentrate its 
regulatory efforts on other PIPs that may pose potential risks. Whereas 
the introduction of transgenes into a plant could result in the 
exposure of humans and the environment to a new substance or a 
previously known substance in a new way, the modifications associated 
with qualifying PIPs based on sexually compatible plants created 
through biotechnology are unlikely to result in novel exposures. Thus, 
concentrating regulatory efforts on PIPs with a higher potential of 
novel exposures is a more efficient use of EPA's resources.

B. What is the proposal to exempt residues of PIPs based on sexually 
compatible plants created through biotechnology from the requirement of 
a tolerance?

    Pursuant to its authority under FFDCA section 408(e), 21 U.S.C. 
346a(e), EPA is proposing to exempt from the requirement of a tolerance 
residues of pesticidal substances from PIPs based on sexually 
compatible plants created through biotechnology that meet the 
conditions proposed for this exemption. The Agency believes that when 
the proposed conditions are met, there is a reasonable certainty that 
no harm will result from aggregate exposure to residues of these 
pesticidal substances from PIPs based on sexually compatible plants 
created through biotechnology, including all anticipated dietary 
exposures and all other exposures for which there is reliable 
information. The Agency believes the exemption criteria will ensure 
that the exempt PIPs would not result in exposures that are 
significantly different from what humans are currently exposed to in 
the food supply; therefore, the exemption would be safe in light of the 
history of safe exposures.
    This proposed exemption is intended to address the second condition 
for exemption from FIFRA regulation under 40 CFR 174.21(b): The 
requirement for a tolerance exemption for the residues of PIPs intended 
to be produced and used in a plant used as food or feed. 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. That process is proposed at 40 
CFR 174.90, and details of the process for and contents of an exemption 
eligibility determination submission are found in Unit VI.C. That unit 
also describes the circumstances in which submission of a separate 
determination for purposes of the FFDCA exemption for a PIP proposed 
for use in food or feed is required.
    Given that the proposed exemption could potentially cover thousands 
of substances, a small fraction of which are known toxicants (for 
discussion see Unit VI.B.3.), the Agency is proposing to use certain 
guardrails to account for the rare instances in which residues of a 
pesticidal substance may reach levels in food or feed that are unsafe. 
First, EPA proposes a criterion for exemption under FFDCA that limits 
the presence of residues of the pesticidal substance in the recipient 
plant. Specifically, residues of a pesticidal substance in plants used 
for food are allowed to be present only in the same plant tissues and 
developmental stages where such residues are found in a sexually 
compatible plant. Additionally, the levels of that pesticidal substance 
cannot exceed levels found in a sexually compatible plant, with the 
added limitation that those levels may not be injurious or deleterious 
to human health. In other words, if levels that are injurious or 
deleterious to human health are observed, the PIP and its residues 
would not be covered by the proposed exemption from the requirement of 
a tolerance. This approach is consistent with the existing exemption 
criteria for residues of a pesticidal substance from a sexually 
compatible plant, which also limit the levels of residues of exempt 
PIPs present in the food from that plant to those that are not 
injurious or deleterious to human health (40 CFR 174.508(c)). Second, 
under the proposed exemption for PIPs based on sexually compatible 
plants created through biotechnology, a developer may wish to request 
an exemption for residues of a pesticidal substance whose levels are 
commonly screened for in conventional breeding to ensure the safety of 
the food. In these instances, the developer of such a PIP would be 
required, as part of the exemption eligibility determination process 
proposed at 40 CFR 174.90, to describe how conventional breeding 
practices have been and will be performed on the recipient food plant 
to ensure that the levels of the pesticidal substance are not injurious 
or deleterious to human health. This is to

[[Page 64326]]

affirm that PIPs based on sexually compatible plants created through 
biotechnology will be held to the same safety standards by the plant 
breeders as PIPs in plants created through conventional breeding. This 
requirement can be fulfilled by a developer with a confirmation that 
the product has been screened for acceptable levels of the pesticidal 
substance (e.g., generally accepted safe content for solanine in 
potatoes is 20-25 mg/100 g of fresh potato). Breeders have decades of 
experience developing new plant varieties and are familiar with the 
toxins that may be produced by certain plants used for food and feed, 
e.g., by chemically analyzing the components of plants. Because PIPs 
based on sexually compatible plants created through biotechnology are 
equivalent to those substances found within plants that are sexually 
compatible with the recipient plant, these substances are not expected 
to be novel to breeders and the existing screening methods are 
similarly expected to remain effective. Third, as described further in 
Unit VI.C.1., residues of a PIP used in food or feed, which would 
include residues of a PIP based on a sexually compatible plant created 
through biotechnology, remain subject to the adverse effects reporting 
under 40 CFR 174.71 even after the residues have been exempted from the 
requirements of FFDCA. Therefore, upon learning of any adverse effects, 
which includes injurious or deleterious levels of the pesticidal 
substance in food or feed, EPA has the authority to reconsider whether 
the PIP and the residues of the PIP continue to meet the criteria for 
exemption. Further, as described in the preamble of the July 19, 2001 
Federal Register notice implementing 40 CFR 174.71 (66 FR 37772; July 
19, 2001), reports involving food or feed (i.e., those subject to 
enforcement under FFDCA) would be made to EPA, but EPA will share such 
reports with FDA. EPA and FDA will individually determine whether any 
action is necessary to protect the public health, and if so, what 
constitutes appropriate action based on their respective statutes 
(EPA--FIFRA, FDA--FFDCA). Therefore, 40 CFR 174.71 is a means of 
ensuring that EPA and FDA can address any potential hazard identified 
subsequent to self-determination or EPA confirmation that a PIP meets 
the requirements for exemption.
1. Proposed Criteria and Associated Definitions
    Unit VI.A.2. outlines the scope of the FIFRA exemption proposal for 
PIPs based on sexually compatible plants created through biotechnology. 
The criteria and associated definitions discussed in that unit are 
equally relevant to the proposed FFDCA exemption for residues of these 
PIPs for food and feed use. For example, the proposed definitions of 
``native allele,'' and ``native gene'' are discussed in greater detail 
in Unit VI.A.2. Also discussed in Unit VI.A.2. are the following 
phrases: ``(1) The pesticidal substance is found in plants that are 
sexually compatible with the recipient plant; and (2) Limitations on 
expression profile.'' The proposed definition of ``gene'' is discussed 
in Unit V.A. Thus, the following considerations under the proposed 
FFDCA exemption refer to the concepts discussed in other parts of the 
exemption proposal when appropriate.
    EPA is proposing criteria and supporting definitions that describe 
residues from PIPs based on sexually compatible plants created through 
biotechnology that the Agency expects to meet the FFDCA safety standard 
for establishing exemptions. This proposed exemption covers the 
residues of the pesticidal substance of those qualifying PIPs and would 
eliminate the need to establish a maximum permissible level in or on 
food and feed for these residues.
    EPA's basis for its proposal is that the criteria of the exemption 
circumscribe a group of PIPs that will not result in novel exposures, 
dietary or otherwise. This analysis is based on the large body of 
knowledge about the history of safe use from foods containing these 
substances that have been consumed by humans for long periods of time. 
Because PIPs based on sexually compatible plants created through 
biotechnology are equivalent to those that could have been created 
through conventional breeding, plant breeders will retain their ability 
to ensure that the substances will be at safe levels for humans in the 
resulting food plant. EPA concludes that the potential is low that 
qualifying PIPs based on sexually compatible plants created through 
biotechnology introduce novel exposures (Unit VI.A.3.b.).
a. Large Body of Knowledge
    EPA relied on the large body of scientific literature that 
describes constituents of food from plants in sexually compatible 
populations (Ref. 37). EPA used scientific literature on the effect on 
humans of consumption of whole foods from plants generated from 
epidemiological studies (Ref. 24, 25, 27, 29, 31, 69, 70, 71, 72, 73) 
and animal model testing of the effects of either whole foods, or 
constituents from food, contained in these crops (Ref. 26, 28, 30, 74, 
75, 76, 77) to draw conclusions on the potential risks to humans 
through the dietary (including drinking water) and residential (or non-
occupational) route of exposure to these substances. EPA also 
considered scientific knowledge from a number of disciplines including 
genetics, plant physiology, phytopathology, toxicology, ecology, 
biochemistry, evolutionary biology, genomics, and plant breeding. 
Information from the field of plant physiology was considered regarding 
plant metabolism to evaluate the production of substances that may have 
pesticidal effects and conditions that may limit the plant's production 
of such substances, see Unit VI.B.1.c. and Unit VI.A.3.c. (Ref. 33). 
EPA considered information from the fields of biochemistry and 
toxicology, for example, to identify which substances in food from 
plants might pose a dietary risk (Ref. 37, 39, 78). The Agency also 
used experimental data derived from the science of phytopathology that 
characterize the pest resistance mechanisms in plants to understand the 
types of traits through which PIPs may confer resistance or tolerance 
to pests (Ref. 3, 79). The sciences of ecology and evolutionary biology 
were considered for information on genetic diversity, mutation, and 
reproductive isolation mechanisms in populations to understand the 
types of genetic changes that are likely to occur when plants 
interbreed in nature (Ref. 34). Plant breeding and genetics provided 
considerations to help describe the mechanisms of incompatibility and 
interbreeding, which aided EPA in determining when plants are likely to 
interbreed in nature. As discussed in greater detail in Unit VI.A.3.g., 
information from genomics and molecular biology were considered to 
understand the ability of newer biotechnology techniques, such as those 
using genome editing techniques, to create traits equivalent to those 
found in conventionally bred plants (Ref. 35, 36).
    Recommendations from several FIFRA SAP reports were considered in 
the development of the proposed exemption criteria for PIPs based on 
sexually compatible plants created through biotechnology, and to 
circumscribe the types of genetic modifications in the recipient plant 
that are unlikely to result in novel exposure to humans, dietary or 
otherwise (Unit II.C.3., Table 1).
b. Low Potential for Novel Exposure
    All plants, including those commonly consumed as food, naturally 
contain pesticidal substances that confer pest

[[Page 64327]]

resistance. Humans have for approximately 10,000 years selected and 
bred certain plants for food, feed, and fiber, that have these 
pesticidal characteristics. Humans are therefore familiar with and have 
been exposed to many plant-produced pesticidal substances and their 
residues, such as those that could be developed for use as PIPs based 
on sexually compatible plants created through biotechnology, in their 
diet and otherwise for millennia. Given that PIPs based on sexually 
compatible plants created through biotechnology are intended to 
represent a subset of substances present in plants that breeders are 
familiar with and that in many instances have been safely consumed by 
humans, EPA does not expect that these substances, or residues of these 
substances, would result in novel dietary exposures.
    Several considerations for assessing the potential for novel risks 
for PIPs based on sexually compatible plants created through 
biotechnology are discussed in Unit II.C.3. in the context of the 
proposed FIFRA exemption. The concepts presented in that unit are 
equally relevant to the FFDCA safety assessment of residues of PIPs 
based on sexually compatible plants created through biotechnology that 
are used for food or feed.
    Pesticidal traits have evolved in plant populations over time 
through the processes of mutation, selection, and genetic exchange with 
sexually compatible species (Ref. 47, 48). The ability to produce 
viable offspring is only possible in nature for organisms that are 
genetically similar and possess many traits in common. Traits, and the 
genetic material encoding them, can be passed through a sexually 
compatible plant population by breeding. The mixing of genetic material 
that occurs through breeding results in the members of a sexually 
compatible population having similar traits and similar genetic 
material. Due to the mixing of traits by mating, similar exposure 
scenarios are expected for food plants that are 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 reports 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 (Unit II.C.3., Table 1).
    For agricultural plants, those defined as 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 followed established practices to ensure safety when moving genes 
into agricultural varieties from nonagricultural relatives, 
particularly from inedible 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 followed (Ref. 13, 14, 15, 16). 
Therefore, the likelihood that the inclusion of nonagricultural 
varieties as potential source plants would lead to unsafe dietary 
exposures from residues of PIPs based on sexually compatible plants 
created through biotechnology is low.
    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 novel changes 
resulting in the differential expression of 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 a sexually compatible plant. Modifications that lead to differential 
expression of a substance are not expected to result in levels that 
exceed the boundaries of the natural variation found in sexually 
compatible plants due to physiological constraints that are related to 
energy expenditure (further discussed in Unit VI.B.1.c. and Unit 
VI.A.1.c.). The potential for novel dietary exposures to occur with the 
differential expression of existing genes, or the movement of native 
genes and native alleles among sexually compatible plants, is therefore 
low, because no substance novel to plants that are sexually compatible 
with the recipient plant will be produced, nor will the substance be 
found in tissues or developmental stages at levels, in which it is not 
currently found.
c. Low Potential for Levels of PIPs Based on Sexually Compatible Plants 
Created Through Biotechnology To Exceed Those Found in Sexually 
Compatible Plants
    EPA has evaluated whether there are likely to be quantitative 
changes in expression levels of PIPs based on sexually compatible 
plants created through biotechnology that may pose dietary risks. As 
discussed later in this unit, EPA has determined that the probability 
is low because the highest levels of pesticidal substances likely to be 
expressed by qualifying PIPs based on sexually compatible plants 
created through biotechnology is not likely to be significantly 
different from those that humans are currently exposed to in the food 
supply. To codify this principle into EPA's regulatory text, EPA is 
proposing an exemption criterion in which the level of expression of 
PIPs based on sexually compatible plants created through biotechnology 
is bound by the upper limit of expression of the pesticidal substance 
observed in sexually compatible plants. By limiting the level of 
expression that qualifies for an exemption in this way, EPA can ensure 
that the exposures fall within the normal historical range of exposures 
with which plant breeders have experience limiting to ensure safe 
exposures when introduced into food plants.
    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.'' A summary of that analysis is presented in 
Unit VI.A.3.c. The factors that influence the determination of low 
probability of risk under FIFRA that are discussed in that unit are 
equally relevant to the FFDCA safety assessment of residues of those 
same PIPs in food or feed. Relevant considerations summarized in that 
unit include: (1) The level of production of substances normally varies 
among sexually compatible plants because of differences in potential to 
express a substance and environmental conditions; (2) Physiological and 
practical considerations limit the expression levels of PIPs based on 
sexually compatible plants created through biotechnology; (3) Humans 
have been and are currently exposed to the range of levels of 
substances that might be used as PIPs based on sexually compatible 
plants created through biotechnology.
    Moreover, in varietal development, plant breeders assess the new 
cultivar for food safety, based in part on knowledge of and familiarity 
with the characteristics of agricultural plants in the relevant 
sexually compatible populations (Ref. 6, 37). Because PIPs based on 
sexually compatible plants created through biotechnology represent a 
subset of substances already present in related plants, the procedures 
routinely used in agriculture and food processing would continue to be 
efficacious in identifying these substances, and levels

[[Page 64328]]

of these substances, in new food plant varieties.
    Although hundreds of new plant varieties enter the market each year 
within the past 70 years, conventional plant breeding has recorded very 
few instances of plant varieties causing food safety problems (Ref. 37, 
80). EPA believes this same demonstrated record of safety can be 
applied to the pesticidal substances produced by these plants. 
Therefore, the Agency considers it highly unlikely that residues of a 
PIP based on a sexually compatible plant created through biotechnology 
would occur in or on food or feed at levels that are hazardous. To 
account for the rare instances in which a substance may reach levels 
that are unsafe, EPA is proposing as a criterion for exemption that 
residues of the pesticidal substance are only present in tissues and 
developmental stages identified in a plant that is sexually compatible 
with the recipient food plant, and do not exceed levels found within 
that plant, as long as those levels are not injurious or deleterious to 
human health. If levels that are injurious or deleterious to human 
health are observed, the PIP and its residues would not be covered by 
the proposed exemption from the requirement of a tolerance. In failing 
to meet the FFDCA requirements for exemption, the PIP would similarly 
fail to meet the exemption requirements under FIFRA.
    In conclusion, EPA considered the potential variability of 
expression levels of PIPs based on sexually compatible plants created 
through biotechnology and whether such variations would be hazardous if 
they were to be present in the food or feed supply. EPA concluded that 
although variations in the production of plant substances will occur in 
response to environmental conditions, there are physiological and 
practical considerations that limit the expression level, and thus the 
abundance of a particular substance in plants that are sexually 
compatible. By limiting the expression of PIPs based on sexually 
compatible plants created through biotechnology to not exceed levels 
that are found in sexually compatible plants, EPA believes that 
breeders will be able to ensure that exposures fall within the normal 
historical range of exposures that have proved to be safe through 
conventional breeding.
2. Dietary Risk Evaluation
    For chemical pesticides, EPA's dietary risk evaluation relies on 
data generated by testing in laboratories using representative animal 
models to estimate acute, subchronic, or chronic hazard endpoints, 
e.g., acute toxicity, carcinogenicity, and developmental toxicity. 
Conclusions from animal models are used to assess dose-response and 
describe such endpoints for potential human hazards. Other information, 
including residue data and information generated by use of mathematical 
models, are used to develop human exposure estimates. These exposure 
and hazard components are combined to quantify the potential risk 
associated with the pesticide's use and to determine the appropriate 
maximum residue levels of the chemical in or on food or feed, i.e., to 
set the numerical tolerance. Uncertainty factors are often used in the 
risk assessment to account for extrapolation from animal models to 
human toxicity. If the substance is found to be safe, the Agency may 
issue a tolerance or, as proposed here for qualifying PIPs based on 
sexually compatible plants created through biotechnology, an exemption 
from the requirement of a tolerance for the pesticide chemical 
residues. EPA described the information base typically used to assess 
the potential risks and safety of PIPs at a public symposium held in 
September 2016. The materials developed for this symposium are 
available on http://www.regulations.gov in Docket ID No. EPA-HQ-OPP-
2016-0427 and on EPA's website at https://www.epa.gov/pesticides/public-symposium-regulation-plant-incorporated-protectants-rebroadcast-live-webcast.
    In some cases, the use of animal model testing may not be required 
to support a safety finding for a pesticide chemical residue. For 
example, for PIPs that are already part of the food supply but moved 
through the use of biotechnology between two distantly related food 
plant species (i.e., those that are not sexually compatible and could 
not have been moved through conventional breeding), EPA has used 
various forms of information aside from animal testing to assess the 
safety of PIP residues. These included the open scientific literature 
to understand the characteristics of the PIP itself as well as the 
biology of the source plant from which the PIP is derived and the 
recipient plant in which the PIP will be produced and used. Similarly, 
in performing the assessment for the proposed tolerance exemption for 
PIPs based on sexually compatible plants created through biotechnology, 
the Agency is assessing the substances present in these plants in the 
context of the history of human consumption of the whole food, and 
animal model testing of the effects of either whole foods, or 
constituents from food, contained in these crops (Unit VI.B.1.a.). 
EPA's conclusion that qualifying PIPs based on sexually compatible 
plants created through biotechnology would be safe for human 
consumption is based on this information. EPA considered that 
appropriate processing procedures are widely known and are routinely 
used by consumers and companies involved in food production and 
processing in the preparation of food containing residues that are the 
subject of this proposed exemption, including those foods that require 
specific processing and/or preparation steps in order to be safely 
consumed B.3.). Importantly, the efficacy of the food preparation 
techniques, as well as dietary avoidance strategies, are expected to 
apply equally to food containing residues of PIPs based on sexually 
compatible plants created through biotechnology, since residues of 
those pesticidal substances are a subset of substances already present 
in related food plants. Similarly, the plant breeding practices that 
are routinely employed in selecting and developing new plant varieties, 
such as chemical analysis and visual analysis, are not expected to be 
affected by this proposed exemption. As a result, the residues are not 
expected to pose any risk that differs from what people already are 
exposed to in the food supply.
    EPA considered health risks to the general population, including 
infants and children. Residues of pesticidal substances in or on food 
or feed from PIPs based on sexually compatible plants created through 
biotechnology that meet the proposed criteria for exemption would not 
be new to the food supply, as they are a subset of substances already 
present in related plants. Accordingly, this proposal should not change 
anything about the way that children, and to some extent infants, are 
exposed to substances already found in food that are identical to 
residues of PIPs based on sexually compatible plants created through 
biotechnology. EPA's risk assessment also included subgroups as part of 
the general population, i.e., reflecting differences in diet due to the 
influence of culture, and allowed for consumption pattern differences 
of such subgroups.
a. Dietary Consumption Patterns
    EPA considered the available information on the varying dietary 
consumption patterns of consumers and major identifiable consumer 
subgroups as it pertains to residues of pesticidal substances from PIPs 
based on sexually compatible plants created through biotechnology. The 
consumption of food

[[Page 64329]]

from plants is part of a balanced and varied diet (Ref. 81). For 
purposes of this proposed exemption, EPA considered a normal diet to be 
balanced and varied and to include food from a variety of sources. It 
does not include plants or plant parts consumed in times of 
deprivation, for religious reasons, in substance abuse, or by accident. 
Humans have been consuming food containing pesticidal substances 
produced by sexually compatible plants for long periods of time. It is 
not anticipated that this proposed exemption from the requirement of a 
tolerance, should it be finalized, will affect current consumption 
patterns of food from crop plants by consumers or major identifiable 
consumer subgroups, and thus no differences in exposure patterns are 
anticipated.
b. Validity, Completeness, and Reliability of Available Data
    EPA considered the validity, completeness, and reliability of the 
available information on human consumption of food containing 
substances that would be identical to the expected residues of 
pesticidal substances from PIPs based on sexually compatible plants 
created through biotechnology, including the extensive history of 
humans safely consuming foods from plants containing these substances, 
epidemiological studies of human dietary assessments and animal model 
testing, as well as information from the disciplines of genetics, 
molecular biology, plant physiology, phytopathology, toxicology, 
ecology, biochemistry, evolutionary biology, genomics, and plant 
breeding (Unit VI.B.1.a.). EPA concluded that this information was 
valid, complete, and reliable, and adequately addressed the issues of 
hazard and exposure with regard to residues of pesticidal substances 
from PIPs based on sexually compatible plants created through 
biotechnology in or on food or feed.
3. Toxicological Profile
    EPA considered whether toxic effects could be associated with any 
pesticidal substances that developers might wish to use as PIPs based 
on sexually compatible plants created through biotechnology and that 
might be residues in or on food or feed (Ref. 6). The examination led 
EPA to conclude that, since the vast majority of substances in plants 
that are used for food are not toxic, any of these nontoxic substances, 
should they be used as PIPs based on sexually compatible plants created 
through biotechnology, would not present any toxic effects.
    Plants produce hundreds of thousands of substances of which only 
about 200 have been identified as potential toxins in food plants, and 
only 10% of those substances (about 0.01% of all substances) may pose a 
dietary risk when consumed as part of a normal diet (Ref. 37, 82, 83). 
One example is the glycoalkaloid solanine, which is commonly 
biosynthesized in potatoes and to some extent eggplant and peppers 
(Ref. 6). Solanine poisoning is very rare. However, in large doses it 
can cause effects such as gastrointestinal tract irritation and 
drowsiness. Solanine imparts a bitter taste to the tuber, and at high 
concentrations can even leave a persistent irritation and burning 
sensation on the tongue, both of which may to some extent deter 
consumption. Potatoes are bred and monitored in the United States to 
ensure that they produce only low levels of solanine.
    There are several factors that could have contributed to the 
relatively low number of toxins in food plants. In crop development, 
low toxicant abundance has been a desired trait to increase usability 
of a particular plant as a source of nutrition and to enhance its 
palatability (Ref. 4, 37). Further, the risk of toxins that may be 
present in a particular food crop appears to be well known, and methods 
of processing exist to reduce the potential for toxic effects (Ref. 
37). For example, as part of the development and characterization of 
new plant varieties, plant breeders use methods such as gas and/or 
liquid chromatography coupled with mass spectrometry to identify and 
quantify toxins in food plants and use this information to identify and 
remove new varieties from the development pipeline that contain 
potentially harmful levels of these substances. Over the past 50 years, 
the sensitivity of some metabolic profiling techniques has increased 
over 100,000-fold, enabling the detection of exceedingly small amounts 
of these substances (Ref. 37). As a result, the majority of toxicants 
in food plants are already known and plant varieties can be screened 
for their presence and removed from the market if necessary. In this 
context it is relevant to note that no newly released plant variety 
exhibited any previously unknown food or feed hazard (Ref. 37, 80).
    Because PIPs based on sexually compatible plants created through 
biotechnology are a subset of those PIPs found in related plants, these 
substances are not novel to plant breeders. Therefore, the efficacy of 
the existing monitoring, processing, and preparation methodologies that 
have been and are being used to produce food safe for consumption is 
expected to be equally effective at screening foods that would contain 
PIPs based on sexually compatible plants created through biotechnology. 
For the reasons described in Unit VI.B.1.b., EPA expects that PIPs 
based on sexually compatible plants created through biotechnology do 
not pose novel exposures (dietary or otherwise) compared to pesticidal 
substances present in sexually compatible plants. Furthermore, EPA 
expects that the levels of PIPs based on sexually compatible plants 
created through biotechnology have a low potential to exceed levels 
found in sexually compatible plants (Unit VI.B.1.c.) and codifies these 
levels in the proposed exemption criteria.
4. Cumulative Effects From Substances With a Common Mechanism of 
Toxicity
    FFDCA section 408(b)(2)(D)(v) requires that, when considering 
whether to establish, modify, or revoke a tolerance, the Agency 
consider ``available information'' concerning the cumulative effects of 
a particular pesticide's residues and ``other substances that have a 
common mechanism of toxicity.'' This factor is also relevant when 
considering whether to establish an exemption from the requirement of a 
tolerance (21 U.S.C. 346a(c)(2)(B)).
    As discussed in Unit VI.B.3., EPA recognizes that there are 
toxicants of plant origin that may be part of the human diet, which 
could theoretically be used as PIPs based on sexually compatible plants 
created through biotechnology and which may cause adverse effects. EPA 
has considered available information on the cumulative effects of such 
residues and other substances that have a common mechanism of toxicity 
and that may be developed as PIPs based on sexually compatible plants 
created through biotechnology. EPA also considered whether the 
cumulative expression (i.e., expression of the PIP across all plants) 
would result in an adverse effect. Because the PIP based on a sexually 
compatible plant created through biotechnology could have otherwise 
been created through conventional breeding, and by extension would not 
be novel to plant breeders, EPA does not consider 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.
    For the reasons discussed in Units VI.B.1.a. through c., any 
potential cumulative effects from PIPs based on sexually compatible 
plants created through biotechnology are not expected

[[Page 64330]]

to be quantitatively different from those present in the current food 
supply and the presence of these substances and their residues has 
historically been safe.
5. Aggregate Exposures of Consumers Including Non-Occupational 
Exposures
    EPA considered the available information on the aggregate exposure 
of consumers to the residues of PIPs based on sexually compatible 
plants created through biotechnology. EPA examines exposure through the 
dietary route (including drinking water), and exposure in the 
residential non-occupational setting in greater detail in the following 
units (Unit VI.B.5.a. through e.).
a. Dietary Exposures From Food
    Dietary exposure is the most likely route of exposure to PIPs based 
on sexually compatible plants created through biotechnology as these 
pesticidal substances are contained within plants consumed as food. As 
described in this preamble at Unit VI.B.1.a., a large knowledge base 
and experience exists for the residues that are subject of this 
proposed exemption, including information on human dietary exposure. 
Information from all of these sources can be used in evaluating the 
safety of residues of PIPs based on sexually compatible plants created 
through biotechnology, as food from a plant engineered to contain such 
a PIP is comparable to the situation presented by the natural whole 
food from that plant prior to introducing the genetic modification: No 
substances new to the sexually compatible plant population would be 
introduced, and the introduced substances would be consumed as part of 
the whole food.
    The exemption criteria prohibit the introduction of substances that 
are novel to the sexually compatible plant population and, as discussed 
earlier, nothing about the PIP would alter the existing mechanisms for 
breeding, processing or preparing the food. Thus, the Agency expects 
any exempt PIPs would be consumed as part of the whole food in the same 
manner as existing foods currently in the food supply and that plants 
containing residues of these PIPs would be subject to the same 
procedures plant breeders rely on to ensure the safety of food. There 
is no evidence in the many studies performed on the relationship of 
diet to health that food containing substances from sexually compatible 
plants, when properly processed and prepared, has resulted in adverse 
health effects (Unit VI.B.1.a. through c.). The Agency believes this 
assumption is supported by the record of safety of the food products 
from plants in sexually compatible populations. Although hundreds of 
new varieties come on the market each year (Ref. 84), breeding of 
plants in sexually compatible populations has recorded very few 
instances of exposures to substances that are not safe in food. 
Further, no previously unknown food hazard has been observed in new 
plant varieties developed through plant breeding (Ref. 37, 80).
    The primary exposure consideration associated with the pesticidal 
chemical residues that are the subject of this proposed exemption is 
whether substances that might be harmful at higher concentrations (or 
in different tissues or stages) are likely to be present in food from 
sexually compatible plants at such concentrations. EPA considered the 
probability of variations in levels of PIPs based on sexually 
compatible plants created through biotechnology, and whether such 
variations would be hazardous if these PIPs were to be present in the 
food supply (Unit VI.B.1.c.). EPA concluded that, based on biological 
and agronomic considerations, any variations in the levels of PIPs 
based on sexually compatible plants created through biotechnology is 
not expected to exceed the levels of these substances currently present 
in the food supply, which has been determined to be safe. This 
principle is also codified in EPA's proposed regulatory text in which 
the level of expression of a PIP based on a sexually compatible plant 
created through biotechnology is bound by the upper limit of expression 
of the pesticidal substance observed in sexually compatible plants and 
that it can only be present at levels that are not injurious or 
deleterious to human health.
    A second exposure consideration is whether this proposed exemption 
will affect the ability of individuals with food sensitivities to 
manage these sensitivities. Individuals with food sensitivities, 
including food allergies, generally avoid foods from plants that they 
are sensitive to. This proposed exemption, if finalized, would not 
affect the efficacy of this strategy of avoidance because the proposed 
exemption will not affect the ability of individuals to recognize and 
avoid foods they are sensitive to. For example, the ability of persons 
who have the Mediterranean form of the inherited Glucose-6-phosphate 
dehydrogenase (G6PD) deficiency to manage their disease by not 
consuming fava beans or foods made with fava beans will not be 
affected. The substances in fava beans that can cause hemolytic anemias 
in such persons would be exempt only if they are used in fava bean 
plants and plant varieties that interbreed with fava beans; a 
population of plants in which such substances normally occur (Ref. 85).
    In conclusion, qualifying PIPs based on sexually compatible plants 
created through biotechnology represent a subset of substances already 
present in related plants. Therefore, should residues of these 
substances be present in or on food derived from plants, EPA does not 
expect them to have any meaningful impact on the already existing 
dietary exposure profile for these residues and thus risk from dietary 
exposure to such residues in or on food would be low. Moreover, as an 
additional measure of safety for residues of qualifying PIPs, the 
pesticidal substance can only be present at levels that are not 
injurious or deleterious to human health.
b. Residential, Non-Occupational Exposure
    Residues of qualifying PIPs based on sexually compatible plants 
created through biotechnology may be present in plants grown 
residentially for consumption. Consequently, EPA examined the potential 
for non-occupational exposures to these substances in the sections for 
dermal and inhalation exposure in sections of Unit V.B.5.d. and e.
c. Dietary Exposure From Drinking Water
    Dietary exposure through drinking water is considered unlikely. The 
substances in plants or parts of plants, including residues of PIPs 
based on sexually compatible plants created through biotechnology, are 
produced and used inside the living plant itself. As such, the residues 
are part of the tissue of the plant. When the plant dies or a part is 
removed from the living plant, microorganisms colonizing the tissue 
immediately begin to degrade it, using the components of the tissue, 
including any residues that are the subject of this proposed exemption, 
as building blocks for making their own cellular components or for 
fueling their own metabolisms. The residues that EPA is proposing to 
exempt in this action are subject to the same processes of 
biodegradation and decay that all biotic materials undergo. This 
turnover of biotic materials in nature through a process of 
biodegradation is expected to occur in rapid fashion and is likely to 
preclude these residues from persisting in the environment long enough 
to reach the drinking water supply (Ref. 40). There is no indication 
that plant biotic materials, including the residues

[[Page 64331]]

that are the subject of this proposed exemption, are resistant to 
biodegradation. Even if residues were to reach surface waters, through 
pollen dispersal or parts of the plants (leaves, fruits etc.) falling 
directly into bodies of water, they are still subject to microbial 
degradation and are unlikely to present anything other than a 
negligible exposure in drinking water drawn either from surface water 
or ground water sources. Importantly, PIPs based on sexually compatible 
plants created through biotechnology represent a subset of substances 
already present in related plants. Therefore, should these residues be 
present in drinking water, they are not expected to meaningfully alter 
the already existing pattern of exposure to these residues and thus EPA 
expects risk to be negligible.
d. Dermal Exposure
    Although a potential for dermal exposure may exist, EPA expects 
such exposure to be negligible because PIPs based on sexually 
compatible plants created through biotechnology are present in the 
plant tissue (Ref. 60). In some cases, residues of PIPs based on 
sexually compatible plants created through biotechnology may be present 
in sap or other exudates from the plant and thus may present some 
limited opportunity for dermal exposure to persons coming physically 
into contact with the plant or raw agricultural food from the plant, 
e.g., during food preparation (see also Unit VI.A.3.e.). Although 
contact dermatitis can occur from such exposure (Ref. 60, 86), these 
reactions are generally mild, of a self-limiting nature, or self-
diagnosed and treated. For those substances that possess to some degree 
properties that might allow some penetration of the skin, the potential 
amount passing through the outer epidermal layer of the skin 
(epidermis) is likely to be low (Ref. 60).
    Furthermore, 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 allergic sensitization (Ref. 60, 61, 86, 
87). Importantly, those substances that do possess properties that 
allow some penetration of the skin represent a subset of substances 
already present in related plants and would therefore not be expected 
to alter the already existing exposures to plant proteins or other 
plant substances through handling of the plant containing these 
substances. Therefore, EPA does not expect novel hazards or exposures 
from residues of the substances involved and thus these PIPs are 
expected to represent a low potential of quantitatively different 
dermal exposures; therefore, risks from dermal exposures are expected 
to be low.
e. Inhalation Exposure
    Although a potential for inhalation exposure may exist, EPA expects 
such exposure also to be negligible because PIPs based on sexually 
compatible plants created through biotechnology are contained within 
plant cells, which essentially eliminates this exposure route, or 
reduces this exposure route to negligible levels (Ref. 60). However, 
residues of PIPs based on sexually compatible plants created through 
biotechnology may in some cases be present in pollen and other 
agricultural dust and some individuals, e.g., those living or working 
in close enough proximity to farms, nurseries or other plant-growing 
areas, may be exposed to wind-blown pollen, or through visiting such 
areas may be exposed, through inhalation, to the pollen. The most 
likely 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.
    On a per person basis, the potential amounts of pollen involved in 
these exposures are likely to be low and residues of the pesticidal 
substance will not in every case be present in the pollen. Importantly, 
pollen characteristics (e.g., wind versus insect dispersal, amount 
produced) are often maintained within plant families and, therefore, 
residues of PIPs based on sexually compatible plants created through 
biotechnology, which are found among sexually compatible plants, should 
not alter already established characteristics of any particular plant 
species. This proposed exemption will not change current exposures, nor 
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). Thus, EPA concludes that risk from 
inhalation exposure to residues of PIPs based on sexually compatible 
plants created through biotechnology is low.
6. Other Considerations
    Other considerations for EPA's safety finding under the FFDCA 
include the sensitivities of population subgroups, endocrine effects, 
and special consideration for risks to infants and children.
a. Sensitivities of Subgroups
    EPA considered available information on the sensitivities of 
subgroups as it pertains to residues of qualifying PIPs based on 
sexually compatible plants created through biotechnology. In performing 
its assessment, the Agency considered that the diet includes all of the 
food items that are customarily eaten by human populations or 
population subgroups. As discussed in this preamble, this proposed 
exemption will not affect the current pattern of exposure to residues 
that are the subject of this proposed exemption because the substances 
at issue are equivalent to substances present in sexually compatible 
plants and are limited in their level of expression to those observed 
in sexually compatible plants. Relatedly, the expression pattern of 
these substances (timing and location of the expression) are limited to 
those found in sexually compatible plants through the proposed 
criteria. Individuals recognize and are familiar with the plant-derived 
food they consume, (e.g., based on prior experience of consumption) and 
would avoid consuming foods containing substances they know they are 
sensitive to (Ref. 37, 88, 89). Because the exposure pattern to these 
foods will not be affected by this proposed exemption, the efficacy of 
the current strategy whereby sensitive individuals or subgroups of 
sensitive individuals recognize and avoid certain foods would not 
similarly not be affected (Ref. 88, 89). Thus, the Agency does not 
expect any subgroup to be adversely affected by the proposed exemption.
b. Estrogenic or Other Endocrine Effects
    Certain food plants, e.g., soybeans, contain estrogen mimics, 
termed phytoestrogens. Such phytoestrogens are currently being consumed 
by humans in food derived from plants and are part of the extensive 
history of safe human consumption of food from plants. Although the 
Agency considers use of these phytoestrogens as PIPs to be unlikely, 
EPA cannot rule out the possibility that such phytoestrogens could be 
developed as PIPs based on sexually compatible plants created through 
biotechnology. Based on available information concerning levels of 
phytoestrogens that must be consumed before effects can be seen (Ref. 
90), the natural limitations of gene expression (Unit VI.A.3.c.), and 
the limitations the Agency is proposing on the levels and expression 
pattern of these substances at 40 CFR 174.541(b), EPA expects that this 
exemption, as proposed, will not result in levels of phytoestrogens in 
foods that would be quantitatively different from those currently being 
safely consumed.

[[Page 64332]]

c. Infants and Children
    FFDCA section 408(b)(2)(C) provides that EPA shall assess the risk 
of pesticide residues based on available information about infants' and 
childrens' consumption patterns, special susceptibility to pesticide 
chemical residues, and the cumulative effects. EPA's evaluation of 
these factors is presented in the following units (Unit VI.B.6.c.i. 
through iii.).
    In addition, this section of the FFDCA requires that, in the 
context of threshold effects, EPA apply an additional tenfold margin of 
safety to take into account potential pre- and postnatal toxicity and 
completeness of the toxicity and exposure databases with respect to 
infants and children. This safety factor is most relevant when the 
Agency conducts a quantitative risk assessment upon identifying 
threshold effects of concern and employs various uncertainty factors, 
including this safety factor, to ensure an appropriate margin of safety 
in its risk analysis. For residues of PIPs based on sexually compatible 
plants created through biotechnology, EPA has concluded that 
consumption of food containing residues of PIPs based on sexually 
compatible plants created through biotechnology is safe for infants and 
children, and that a margin of safety need not be proposed for these 
residues in food. EPA based its assessment of exposure and toxicity 
upon the information base described in this preamble in Unit VI.B.1.
i. Dietary Consumption Patterns
    EPA considered available information on the dietary consumption 
pattern of infants and children as it pertains to residues of PIPs 
based on sexually compatible plants created through biotechnology. The 
range of foods consumed by infants and children is in general more 
limited than the range of foods consumed by adults. Most newborns rely 
on milk products for nutrition, although some infants are fed with soy-
based products. Soy-based products may contain residues that are the 
subject of this proposed exemption. Infants begin as early as 4 months 
of age to consume specific types of solid foods, including foods from 
plants that may contain residues that are the subject of this proposed 
exemption. Later on, apart from processing to facilitate swallowing, 
the diets of toddlers begin to be based on foods consumed by the 
general adult population albeit in different proportions. As infants 
and children mature, more and more of the foods consumed by adults 
become part of their diets and the relative proportions of the 
different types of food consumed change to more closely resemble an 
adult diet.
    Foods that may contain residues that are the subject of this 
proposed exemption are part of a normal diet. They have been consumed 
by infants and children over long periods of time. The likelihood that 
exposure as part of a normal diet to these substances could lead to 
harm to infants and children is low. As the diets of humans change from 
infancy through childhood and into adulthood, there is some possibility 
that the amount of foods that contain residues that are the subject of 
this proposed exemption being consumed may change, with those consuming 
the greatest amounts of plant-based foods being the most exposed to 
substances that may be subject of this proposed exemption. There is no 
evidence, however, that such changes are likely to result in 
disproportionately high consumption of these residues in comparison to 
the general population. Thus, there is no evidence that any exposures 
would be different from those currently in existence. The evidence 
suggests that consumption of foods containing residues from PIPs based 
on sexually compatible plants created through biotechnology, including 
changes in exposure (i.e., relative proportions of the different types 
of food consumed from infancy through childhood and into adulthood) is 
highly unlikely to lead to any harm (Units VI.B.1. through 5.).
ii. Special Susceptibility
    EPA considered available information on the potential for special 
susceptibility of infants and children, including prenatal and 
postnatal toxicity, to residues of qualifying PIPs based on sexually 
compatible plants created through biotechnology. The substances that 
are the subject of this proposed exemption occur in the normal diet, 
and there is no evidence that exposure to such residues, as components 
of food, present a different level of dietary risk for infants and 
children.
iii. Cumulative Effects of Residues With Other Substances With a Common 
Mechanism of Toxicity
    EPA examined the available information on the cumulative effect of 
residues of PIPs based on sexually compatible plants created through 
biotechnology, as well as other substances in food that may have a 
common mechanism of toxicity with these residues, and considered 
effects on infants and children (Unit VI.B.4.). Food from sexually 
compatible crop plants is being safely consumed by humans, including 
infants and children, either directly or indirectly in products such as 
meat and milk that are derived from animals that consume forage and 
other crops, e.g., corn and other grains. Considering the history of 
safe consumption and the information base described in Unit VI.B.4., 
EPA has not found that substances in food from plants share common 
mechanisms of toxicity with other substances.
d. Safety Conclusion
    Based on the information discussed in this preamble and in the 
associated record, EPA preliminarily concludes that when the proposed 
conditions are met, there is reasonable certainty that no harm will 
result from aggregate exposure to residues of PIPs based on sexually 
compatible plants created through biotechnology, including all 
anticipated dietary exposures to humans for which there is reliable 
information. This preliminary finding is based on the Agency's 
determination that the proposed exemption criteria would only exempt 
PIPs that share relevant characteristics with PIPs already found in 
sexually compatible plants, thereby ensuring that residues of these 
PIPs do not pose different risks to humans. Specifically, the proposed 
exemption only applies to substances already found in plants that are 
sexually compatible with the recipient food plant, that are present in 
tissues and developmental stages identified in those plants, and whose 
expression does not exceed levels that are found within those plants. 
Moreover, as an additional measure of safety, the exemption 
specifically excludes those residues of PIPs from the exemption that 
are present in the recipient food plant at levels that are injurious or 
deleterious to human health. The safety determination for PIPs based on 
sexually compatible plants created through biotechnology is based on a 
large body of knowledge about the history of safe use from foods 
containing residues of PIPs that are present in plants and EPA's 
assessment of scientific literature that describes constituents of food 
from plants in sexually compatible populations. To develop the proposed 
exemption criteria for PIPs based on sexually compatible plants created 
through biotechnology, and to circumscribe the types of genetic 
modifications in the recipient plant that are unlikely to result in 
novel exposure to humans, dietary or otherwise, EPA relied on 
recommendations from several FIFRA SAP reports and considered 
information from the public literature to understand the ability of 
newer biotechnology techniques to create traits

[[Page 64333]]

equivalent to those found in sexually compatible plants.
e. Analytical Enforcement Methodology
    Before issuing an exemption from the requirement of a tolerance, 
the FFDCA requires an analytical method for detecting and measuring the 
levels of the pesticide chemical residue at issue in food, unless the 
Administrator determines that there is no need for such a method and 
explains the reasons for that determination in the rulemaking 
establishing the exemption (21 U.S.C. 346a(c)(3)). In the case of a 
reversal of an exemption decision, established analytical methods could 
be critical to enable detection of the affected crop, e.g., should a 
recall of foods be necessary. To meet the proposed exemption criteria 
at 40 CFR 174.21(d), a developer is likely to already be in possession 
of the analytical methods that can be used for the detection of either 
the genetic material or the gene product associated with the PIP. For 
example, to provide the nucleic acid sequence information of the PIP as 
part of the exemption eligibility process, developers may use several 
oligonucleotide primers for gene sequencing. These primers can 
similarly be used for the specific detection of the PIP in the food 
plant using standard PCR methods. Conversely, in those instances in 
which primers are not already available, the information provided on 
the nucleic acid sequence of the PIP is expected to be sufficient to 
promptly design oligonucleotide primers de novo. Therefore, EPA does 
not find it necessary to require submission of analytical methods for 
the detection in plants of PIPs based on sexually compatible plants 
created through biotechnology.

C. What are the proposed exemption eligibility determination procedures 
and requirements of 40 CFR part 174, subpart E?

    EPA proposes to use currently reserved Subpart E of 40 CFR part 174 
for a proposed exemption eligibility determination process related to 
the proposed exemptions. Within that subpart, EPA proposes adding four 
sections: One to describe the process for determining eligibility for 
an exemption, one to describe the general submission process for a 
self-determination letter, one to describe the general submission 
process for EPA confirmation, and one to describe the information 
requirements specific to PIPs based on sexually compatible plants 
created through biotechnology. These additions are necessary because 
EPA is proposing to make the exemption of PIPs based on sexually 
compatible plants created through biotechnology contingent upon 
notifying EPA prior to a PIP being brought to market through a self-
determination letter and/or by seeking EPA confirmation that a PIP 
meets the exemption criteria (options described in Unit VI.C.1.).
    The proposed exemption eligibility determination process will allow 
the Agency to maintain a record of the PIPs that meet the criteria for 
exemption. This record will aid in inspections conducted by the Agency 
to ensure compliance and to confirm that PIPs in the food supply do 
indeed meet the standard of safety as defined by the exemption 
criteria. Also, if it were determined based on new information that a 
PIP was not eligible for exemption, such a record would help inform EPA 
and the FDA of the most appropriate steps to protect public health 
(including enforcement). As described in Unit VI.A.4., with the 
proposed exemption eligibility determination process, exempting PIPs 
based on sexually compatible plants created through biotechnology has 
an estimated incremental cost saving of about $444,000-$459,000 per 
product, compared to traditional registration, due to reductions in 
PRIA fees and data generation.
1. Proposed Section for Determining the Eligibility of a PIP To Qualify 
for Exemption
    The Agency is proposing a new provision in Subpart E, 40 CFR 
174.90, entitled ``Determining eligibility for exemption.'' This 
provision states that developers have two, non-mutually exclusive 
options to notify EPA that their PIP meets the exemption criteria: (1) 
Submit a self-determination letter that a PIP meets the exemption 
criteria, and (2) seek EPA confirmation that a PIP meets the exemption 
criteria. EPA confirmation can be sought instead of, in conjunction 
with, or subsequent to the submission of the self-determination letter. 
EPA believes that such a confirmation holds multiple potential 
benefits, including reduced barriers to international trade, increased 
public confidence in product safety, and affirmation for the developer 
that it has correctly determined that the PIP meets the criteria for 
exemption.
    The provision further explains the relationship between the EPA 
confirmation processes and a letter of self-determination. 
Specifically, if a developer chooses to request EPA confirmation in 
accordance with 40 CFR 174.93 in conjunction with or subsequent to 
submitting a self-determination letter in accordance with 40 CFR 
174.91, the exemption is effective from the time at which the company 
receives confirmation of submission of the self-determination letter. 
The exemption remains effective if EPA affirms the developer's 
determination that the PIP meets the exemption criteria and the self-
determination is superseded by EPA's written confirmation in response 
to the confirmation request. However, if at any time after submission 
of the self-determination, EPA determines that the PIP was not eligible 
for exemption under this proposed rule, the exemption will not have 
applied, and EPA may take enforcement against that product to ensure 
compliance with FIFRA. Similarly, FDA may take enforcement action if an 
incorrect self-determination was made by a developer of a PIP in a 
plant used for food or feed. As indicated in Unit VI.C.2., the 
developer is responsible for ensuring the accuracy of its self-
determination.
    Alternatively, in instances in which no prior self-determination 
has been provided to the Agency in accordance with 40 CFR 174.91 and 
the developer submits a request for confirmation to the Agency, the 
exemption applies only once EPA provides written notice to the 
developer confirming that the PIP meets the criteria for exemption. EPA 
reserves the right to assess or revisit at any time whether a PIP 
meets, or has met, the criteria for exemption regardless of whether the 
developer requests EPA confirmation. In particular, as exempt PIPs are 
still subject to 40 CFR 174.71, upon learning of any adverse effects 
(e.g., injurious or deleterious levels in food), EPA has the authority 
to evaluate whether the PIP still meets the criteria for exemption. As 
described in the preamble of the July 19, 2001 Federal Register notice 
implementing 40 CFR 174.71 (66 FR 37772; July 19, 2001), reports 
involving food or feed (i.e., those subject to enforcement under FFDCA) 
would be made to EPA, but EPA will share such reports with FDA. EPA and 
FDA will individually determine whether any action, including the 
possibility of enforcement, is necessary to protect the public health 
or the environment, and if so, what constitutes appropriate action 
based on their respective statutes (EPA--FIFRA, FDA--FFDCA). Therefore, 
40 CFR 174.71 is a means of ensuring that EPA and FDA can address any 
potential hazard identified subsequent to self-determination or EPA 
confirmation that a PIP meets the requirements for exemption.
    The provision also outlines instances in which an exemption 
determination

[[Page 64334]]

can be extended to subsequent variations of the PIP. For a PIP based on 
a sexually compatible plant created through biotechnology, EPA is 
proposing that a determination that the PIP meets the exemption 
criteria would be required for each modified gene and plant species 
combination, made either by the developer through a self-determination 
letter or by EPA through a confirmation request. However, EPA is aware 
that a plant species can comprise multiple varieties and does not 
intend for the PIP in each variety to require its own submission if a 
developer creates the same modification in different varieties. In this 
case, that developer would need to notify EPA only for the first 
modification in that species. The specific circumstances when an 
exemption determination is not required when modifying additional 
varieties of a plant species differ slightly depending on whether the 
developer is creating the same substance with the modification (e.g., 
native allele) or whether the developer is creating the same phenotype 
via a novel mutation. If the developer is creating the same substance 
with the modification (e.g., native allele) in other varieties, then 
subsequent notifications are not required so long as no additional 
modifications were made to the regulatory region. If the developer is 
creating the same phenotype by modifying the regulatory region via a 
novel mutation in other varieties, then subsequent notifications are 
not required. For example, if a developer modifies an existing gene in 
a tomato variety to create a native allele, this would require a 
determination; however, if the developer subsequently creates the same 
native allele in another tomato variety, the developer would not be 
required to submit a second determination request for the additional 
variety. Similarly, if a developer creates a differentially expressed 
gene, subsequent modifications in other varieties would not require a 
determination if the developer targets the same nucleic acid sequence 
(e.g., uses a guide RNA to target the same location in a gene in a 
CRISPR/Cas system) to create a mutation via double stranded DNA break 
repaired by non-homologous end joining. Finally, separate submission of 
a self-determination or request for EPA confirmation for purposes of 
the FFDCA exemption for a PIP proposed for use in food or feed is 
required only if it has not already been submitted under FIFRA. This is 
because the exemption eligibility determination process already 
requires the applicant to certify that the PIP meets the general 
qualifications for exemption, which includes exemption under the FFDCA 
for PIPs used in food or feed. We envision at least one scenario in 
which a developer may need to submit a self-determination or request 
for EPA confirmation for the purposes of FFDCA but not FIFRA. That 
scenario arises when residues of a PIP will be in or on food imported 
into the United States, but the PIP is not intended to be sold or 
distributed for pesticidal use (e.g., PIP containing seed or plant sold 
for planting) in the United States (and thus is not subject to FIFRA 
regulation).
2. Proposed Process for a Letter of Self-Determination for a PIP To 
Qualify for Exemption
    The Agency is proposing a new provision in Subpart E, 40 CFR 
174.91, entitled ``Submitting a letter of self-determination for 
exemption.'' The proposed provision describes the requirements and 
process of notifying EPA that the developer has determined (or ``self-
determined'') that a PIP qualifies for exemption.
    Self-determination letters may be submitted electronically 
(guidance for electronic submission can be found in Pesticide 
Registration Notice 2011-3 or any subsequent revision or replacement) 
or by paper submission. Proposed 40 CFR 174.91 includes information on 
how to format the letter and the required contents of the letter, 
including a statement certifying the developer's determination of 
exemption eligibility. If a developer does not have an EPA company 
number they will be required to obtain a company number prior to 
submission of a self-determination letter. EPA intends that self-
determination letters will not be submitted under FIFRA section 33 
(Pesticide Registration Improvement Extension Act of 2018 (PRIA)) and 
will not be subject to application fees.
    In addition, this provision explains that a developer must submit 
its letter of self-determination prior to engaging in activities 
subject to FIFRA for the proposed PIP (e.g., distribution and sale of 
the PIP at issue), and the exemption does not apply until EPA confirms 
receipt of the self-determination. EPA notes that the developer is 
responsible at all times for ensuring its self-determination is 
accurate and if at any time EPA determines that a self-determination 
was wrongly made, or is no longer accurate due to the availability of 
new information that was not available at the time the self-
determination was made, EPA and the FDA can take action to protect 
public health or the environment. This includes the possibility of 
enforcement under FIFRA or FFDCA. For electronically submitted letters, 
this receipt confirmation occurs automatically upon submission and is 
considered equivalent to written confirmation of receipt. EPA will 
provide written confirmation of receipt within 30 days of receiving a 
self-determination letter via mail. EPA will notify FDA when it 
receives a letter of self-determination.
3. Proposed EPA Confirmation Submission Process for a PIP To Qualify 
for Exemption
    The Agency is proposing a new provision in Subpart E, 40 CFR 
174.93, entitled ``Obtaining EPA confirmation of eligibility for the 
exemption.'' This provision describes the process through which a 
developer may seek confirmation from EPA whether a PIP meets the 
criteria for exemption codified in 40 CFR 174.21. A developer must 
submit information as outlined in 40 CFR 174.91 along with specific 
supporting documentation. For example, the information required to 
support the request for a PIP based on a sexually compatible plant 
created through biotechnology is described in proposed 40 CFR 174.95 
and discussed in Unit VI.C.3. The provision also specifies that any 
claims of confidentiality for information submitted in the request for 
EPA confirmation must be made in accordance with the procedures 
outlined in 40 CFR 174.9.
    In addition, the provision at 40 CFR 174.93 explains that upon 
receipt of the request, EPA will review the submission and determine 
whether the PIP meets all necessary criteria to be exempt under 40 CFR 
174.21. The Agency proposes to notify the submitter in writing of its 
determination. The exemption goes into effect only once the developer 
receives EPA's confirmation in writing, unless a self-determination 
letter was previously submitted. Once a decision has been made that a 
PIP meets the criteria for exemption, this decision applies to all 
requirements under FIFRA, except for the adverse effects reporting 
under 40 CFR 174.71. As described in Unit VI.C.1., exempt PIPs are 
still subject to 40 CFR 174.71 and EPA reserves the right to reassess 
whether a PIP meets the criteria for exemption should the Agency learn 
of relevant information subsequent to confirming its eligibility to be 
exempt under 40 CFR 174.21. EPA intends for requests for EPA 
confirmation to be submitted using the current submission category 
(M009) and associated fee structure for a Non-FIFRA Regulated 
Determination under FIFRA section 33 (PRIA). Currently, under the Non-
FIFRA Regulated Determination

[[Page 64335]]

category, the statutory time for EPA to review and make a determination 
is 120 days. The logistics of the submission for a request and EPA 
review times may change in the future if PRIA changes or a different 
structure for submissions is adopted.
4. Proposed Documentation for an Exemption for PIPs Based on Sexually 
Compatible Plants Created Through Biotechnology
    The Agency is proposing a new provision in Subpart E, 40 CFR 
174.95, entitled ``Documentation for an exemption for a plant-
incorporated protectant based on a sexually compatible plant created 
through biotechnology.'' This proposed provision describes the specific 
information that must be documented for any PIPs based on sexually 
compatible plants created through biotechnology for which a developer 
is claiming an exemption. This provision serves two purposes. First, 
the provision describes the information that must be submitted to EPA, 
pursuant to 40 CFR 174.93, for confirmation that a PIP meets the 
exemption criteria. Second, the provision describes the information 
that any developer must maintain for 5 years pursuant to the 
recordkeeping requirements set forth in 40 CFR 174.73.
    For PIPs based on sexually compatible plants created through 
biotechnology, the Agency is proposing that the information documented 
for recordkeeping and submitted during a request for EPA confirmation 
contain three main information elements: (1) Information on the biology 
of the plant; (2) a description of the pesticidal trait and how it was 
engineered; and (3) information on the molecular characterization of 
the PIP. The proposed information elements are necessary to ensure that 
the PIP based on a sexually compatible plant created through 
biotechnology meets the FIFRA and FFDCA proposed exemption criteria. 
Specifically, information that EPA proposes will be needed for each 
element is as follows.
    The first proposed element, information on the biology of the 
plant, will include: The identity of the recipient plant, including 
genus and species; and if the PIP was derived from another plant 
species, the identity of the source plant, including genus and species, 
and information to demonstrate the recipient plant and the source plant 
are sexually compatible. EPA anticipates that information fulfilling 
the first element will typically be a narrative description to show 
that the PIP is found in plants that are sexually compatible with the 
recipient plant.
    The proposed second element, description of the pesticidal trait 
and how it was engineered into the plant, will include a narrative 
description of the intended pesticidal function resulting from the 
modification of the plant and the technique used to make the 
modification (e.g., was the Cas enzyme stably integrated during 
development and if so was it segregated out of the final product). This 
information ensures that no unapproved ingredients remain in the final 
product. In products where the recipient plant is a food plant in which 
the levels of the pesticidal substance are commonly screened for in 
conventional breeding to ensure safe levels, the second element 
requires that the developer describe how conventional breeding 
practices have been and will be performed on the product proposed for 
exemption. This criterion can be fulfilled with a confirmation that the 
developer has screened its product for acceptable levels of the 
pesticidal substance (e.g., generally accepted safe content for 
solanine is 20-25 mg/100g of fresh potato weight). This criterion 
ensures that levels of the pesticidal substance are not present in the 
recipient food plant, as the plant is grown and harvested under normal 
conditions of use, at levels that are injurious or deleterious to human 
health as stated in the FFDCA proposed exemption criteria.
    The proposed third element, molecular characterization of the PIP, 
includes two components. First, EPA is proposing to require the 
nucleotide sequence and the amino acid sequence of the PIP in the 
recipient plant, including a sequence comparison between the recipient 
plant and the relevant comparator (i.e., the source plant if a source 
plant was used or the unmodified plant if no source plant was used). 
For a plant-incorporated protectant where the regulatory region has not 
been modified, the sequence information will confirm that this is true. 
For PIPs where the regulatory region of an existing or inserted native 
gene has been modified, the second component is EPA's proposal to 
require confirmation that the expression profile (i.e., tissues, 
developmental stages, and levels of expression) of the PIP is not 
outside that observed in plants that are sexually compatible with the 
recipient plant. In this circumstance, the developer must show that the 
highest level of expression of the PIP obtained under normal 
environmental conditions across the lifespan of the plant does not 
exceed the upper limit observed in a plant that is sexually compatible 
with the recipient plant. EPA envisions that a developer can meet this 
requirement through either rationale or data confirmation: A developer 
can document a rationale regarding the expected phenotype given the 
type of modification made (e.g., is the modification meant to optimize 
an allele and therefore may result in a slight increase in expression 
but no change in expression pattern or has something more significant 
been done that could lead to altered expression patterns), or the 
developer can provide expression data examining the tissue/life stage 
in which expression is expected to be highest to corroborate its 
expectation. The extent of expression data required is expected to be 
directly correlated to the likelihood that the modification could lead 
to a novel expression profile. Information described under elements one 
through three will inform whether the PIP meets criteria (a) and (b) of 
proposed FIFRA exemption and criteria (a) and (b) of proposed exemption 
from the requirement of a tolerance.

D. What are the proposed recordkeeping requirements?

    EPA proposes to add a new provision in Subpart D, 40 CFR 174.73, 
entitled ``General recordkeeping requirements for exemptions.'' This 
section describes the documentation and recordkeeping that must be done 
for exempted PIPs listed under 40 CFR 174.21(d). Specifically, in order 
for a PIP listed under 40 CFR 174.21(d) to be eligible for exemption, a 
developer must submit to EPA either a self-determination letter or a 
request for EPA confirmation that the PIP is eligible for exemption 
prior to engaging in FIFRA regulated activities. Accordingly, proposed 
40 CFR 174.73 mandates that the developer maintain documentation of 
such a submission along with supporting information. Supporting 
information would include the information listed in the exemption 
specific section of subpart E. This documentation would need to be 
maintained for five years starting from the effective date of the 
exemption. Finally, proposed 40 CFR 174.73 states that this information 
must be made available to EPA upon request. This request may occur as 
part of routine enforcement activities (e.g., auditing, inspections) 
conducted by EPA to ensure compliance with EPA regulations or 
subsequent to EPA receiving an adverse effects report.

E. What is the proposed clarification to general qualifications for 
exemptions?

    In 2001, EPA developed ``General Qualifications for Exemptions'' at 
40 CFR 174.21, which describes criteria that are required for any PIP 
to be

[[Page 64336]]

exempt from the requirements of FIFRA, with the exception of the 
adverse effects reporting requirement at 40 CFR 174.71. These criteria 
were developed at the same time as the FIFRA and FFDCA exemptions for 
PIPs derived through conventional breeding and thus were drafted with 
reference to those specific sections. The Agency is proposing edits to 
40 CFR 174.21 to clarify the applicability of this framework to other 
PIP exemptions, including the language in the proposal.
    For paragraph (a), this revision simply clarifies that this 
paragraph is specific to the pesticidal substance of the PIP. This 
update is necessary to avoid confusion over the current dual use of the 
word ``plant-incorporated protectant'' in 40 CFR 174.21 to refer to 
both the pesticidal substance and the PIP as a whole, per the 
definition in 40 CFR 174.3. For paragraph (b), the current reference to 
sections 40 CFR 174.507 through 174.508 only allows for a PIP to be 
exempt if the residues of the PIP are nucleic acids or come from a 
sexually compatible plant. This restriction was established when the 
only exempt PIPs were from sexually compatible plants. EPA is proposing 
to revise paragraph (b) to refer to subpart W, rather than the specific 
sections. For paragraph (c), the current reference to 40 CFR 174.705 
only allows for a PIP to be exempt if the inert ingredients are from 
sexually compatible plants. Again, this restriction was established 
when the only exempt PIPs were from sexually compatible plants. 
Although EPA is not proposing an inert ingredient exemption specific to 
this proposal, EPA believes it is important to add flexibility to the 
regulatory text to allow PIPs to be exempt based on other inert 
ingredient exemptions that EPA may establish in subpart X in the 
future. Thus, EPA is proposing to revise paragraph (c) to refer to 
subpart X, rather than the specific section of 40 CFR 174.705. Finally, 
EPA proposes to add a new paragraph (d) to section 40 CFR 174.21 to 
account for the proposed exemption eligibility determination process 
(Unit VI.C.) and proposed recordkeeping requirements (Unit VI.D.). This 
paragraph specifies that for PIPs listed in the subsequent subparagraph 
(i.e., subparagraph (d)(i)), compliance with recordkeeping and 
providing an exemption eligibility determination to EPA is a 
requirement of the exemption. The addition of paragraph (d) does not 
impact the current exemption under section 40 CFR 174.25 for PIPs from 
sexually compatible plants, because PIPs from sexually compatible 
plants (or the proposed amended title, PIPs from sexually compatible 
plants through conventional breeding) are not identified in paragraph 
(d).

F. What is the clarification of exemptions for sexually compatible 
PIPs?

    In 2001, EPA exempted one category of PIPs from all FIFRA 
requirements, with the exception of the adverse effects reporting 
requirement at 40 CFR 174.71. PIPs derived through conventional 
breeding from plants sexually compatible with the recipient plant were 
exempted from FIFRA, and a companion FFDCA exemption from the section 
408 requirement of a tolerance for residues of this category of PIPs 
was also issued. Conventional breeding is defined at 40 CFR 174.3 as 
``the creation of progeny through either: the union of gametes, i.e., 
syngamy, brought together through processes such as pollination, 
including bridging crosses between plants and wide crosses, or 
vegetative reproduction. It does not include use of any of the 
following technologies: Recombinant DNA; other techniques wherein the 
genetic material is extracted from an organism and introduced into the 
genome of the recipient plant through, for example, micro-injection, 
macro-injection, micro-encapsulation; or cell fusion.''
    The Agency is proposing to clarify the relationship between the 
proposal on PIPs based on sexually compatible plants created through 
biotechnology and the exemptions currently at 40 CFR 174.25, ``Plant-
incorporated protectant from sexually compatible plant,'' and 40 CFR 
174.508 ``Pesticidal substance from sexually compatible plant; 
exemption from the requirement of a tolerance.'' To this end, EPA would 
insert ``created through conventional breeding'' immediately after the 
subject of the exemption (e.g., ``pesticidal substance'') in each 
section title, and insert an additional criterion into 40 CFR 174.25 
and 174.508 as follows:
    ``(c) The genetic material is transferred from the source plant to 
the recipient plant only through conventional breeding.''
    This clarification would explicitly state in the title and criteria 
at 40 CFR 174.25 and 174.508 the condition underlying the rationale for 
exemption offered in the preamble of the July 19, 2001 Federal Register 
notice implementing these paragraphs (66 FR 37772; July 19, 2001). 
Although 40 CFR 174.25 has always meant ``only through conventional 
breeding,'' this is a necessary clarification now given that the 
proposed amended definition for ``sexually compatible'' states that ``a 
viable zygote can be formed through the union of two gametes through 
conventional breeding,'' which would modify the existing definition 
that states that ``a viable progeny is formed only through the union of 
two gametes through conventional breeding.'' The clarification would 
also explicitly indicate how proposed sections 40 CFR 174.26 and 
174.541 on PIPs based on sexually compatible plants created through 
biotechnology relate to the existing exemptions for PIPs created 
through conventional breeding from sexually compatible plants at 40 CFR 
174.25 and 174.508. The Agency is not proposing similar modifications 
at 40 CFR 174.705, and instead proposes to expand the scope of that 
exemption to include both conventional breeding and biotechnology, as 
described in Unit VI.G.

G. What is the proposed expansion of the inert ingredient exemption at 
40 CFR 174.705 to include intermediary substances initiated through 
biotechnology?

    1. Description of the expansion. EPA is proposing to expand the 
scope of the existing inert ingredient exemption at 40 CFR 174.705 to 
include inert ingredients that are intermediary substances initiated 
through biotechnology so long as they still meet the existing criteria. 
In the 2001 preamble promulgating 40 CFR 174, EPA stated ``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.'' Although the 
biochemical pathway may be initiated by a modification created through 
biotechnology, EPA believes the plant-produced intermediaries leading 
to the ultimate production of the pesticidal substance meet the 
scientific rationale of the existing inert ingredient exemption at 40 
CFR 174.705. This is because EPA's proposed exemption at 40 CFR 174.26 
provides developer flexibility by allowing changes to the nucleic acid 
sequence of the PIP as long as those modifications still result in the 
same pesticidal substances exempt under 40 CFR 174.25, thereby 
maintaining the integrity of such biochemical pathways described in the 
2001 preamble. Therefore, although the technique used to initiate such 
a biochemical pathway may be different, the intermediary substances 
themselves remain the same.

[[Page 64337]]

    2. Risk analysis. EPA believes the risk analysis at Unit VI.A.3. 
supporting the proposal for exemption from FIFRA requirements and the 
risk analysis at Unit VI.B. supporting the FFDCA section 408 proposal 
for exemption from the requirement of a tolerance also supports the 
exemption from FIFRA and the FFDCA for inerts that meet the criteria 
under the proposed expansion of 40 CFR 174.705, because these 
substances would be endogenous to plants in sexually compatible 
populations and thus would not present novel exposures should inert 
ingredient intermediaries be initiated through a modification using 
biotechnology.

VII. Request for Comment

    EPA is seeking public comment on all aspects of this proposed rule, 
including comments on the specific points discussed in this unit and 
the specific points raised in Units V. and VI. of this proposal.

A. What inert ingredients could be present in PIPs based on sexually 
compatible plants created through biotechnology?

    An ``inert ingredient'' is defined in 40 CFR 174.3 to mean ``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.'' As 
stated in Unit VI.G., the Agency is expanding the current inert 
ingredient exemption at 40 CFR 174.705 to be inclusive of both 
conventional breeding and biotechnology in order to account for 
potential intermediary substances as described in the 2001 quote that 
would ultimately lead to the production of the pesticidal substance.
    However, outside of these intermediary substances, the Agency does 
not anticipate other types of inert ingredients (e.g., herbicide 
tolerance) in PIPs based on sexually compatible plants created through 
biotechnology. Previous biotechnology approaches that relied on DNA 
constructs were constructed with the genetic material encoding for both 
the active and the inert ingredient. These DNA constructs ensured that 
the inert ingredient could be used to confirm the plants or cells that 
successfully integrated the genetic material encoding for the active 
ingredient. However, to create PIPs based on sexually compatible plants 
created through biotechnology, modifications coding for non-pesticidal 
traits in transgenic PIPs (e.g., herbicide resistance) would instead be 
incorporated into the recipient plant genome independent of the active 
ingredient. Because these events occur 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) and that could function as an inert ingredient would 
either be transiently transformed or would be removed (e.g., through 
segregation of the trait) during the breeding process and that if these 
ingredients have not been removed from the final product the product 
would not meet the criteria at proposed under the new 40 CFR 174.26 and 
would not qualify for the new exemptions.
    The Agency therefore 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. If the Agency 
receives comments that indicate inert ingredients other than the 
intermediary substances described in the 2001 quote may be present in 
the final plant product and/or that developer flexibility in the 
nucleic acid sequence of inert ingredients would be beneficial, the 
Agency will consider finalizing the proposed rule with exemptions under 
FIFRA and FFDCA for inert ingredients derived through biotechnology 
from sexually compatible plants. These exemptions would be based on the 
proposed exemptions 40 CFR 174.26 and 174.541 in that the use of 
biotechnology is permitted and only inert ingredients composed of 
genetic material that is derived from sexually compatible plants would 
be exempt. The Agency is not currently considering an exemption for 
potential inert ingredients that are derived from sources that are not 
sexually compatible with the recipient plant (e.g., Cas proteins).

B. What process should EPA use to provide notice that a PIP no longer 
meets the criteria for exemption if new information is provided?

    EPA is proposing to exempt PIPs based on sexually compatible plants 
created through biotechnology from regulation under FIFRA, except for 
the adverse reporting effects at 40 CFR 174.71. In the event EPA learns 
of information that affects a previous determination that a PIP based 
on a sexually compatible plant created through biotechnology meets the 
criteria, EPA will reconsider the new information and provide a new 
determination in writing whether the PIP continues to meet the criteria 
for exemption. EPA requests comment on whether the process outlined is 
detailed enough.

C. Should EPA consider other approaches for its confirmation process?

    EPA is proposing that the exemption of PIPs based on sexually 
compatible plants created through biotechnology include a process 
through which developers of PIPs based on sexually compatible plants 
created through biotechnology submit either a self-determination letter 
or request confirmation that their PIP meets the criteria for 
exemption. EPA seeks comment on whether the Agency should consider 
different approaches for its proposed exemption eligibility 
determination process. For example, one alternative process could be to 
require mandatory EPA confirmation so that all developers must submit 
information to EPA for EPA confirmation that their PIP meets the 
exemption criteria prior to engaging in activities subject to FIFRA. 
EPA requests comment on whether or how such a mandatory approach could 
be workably implemented, and whether such an approach would be useful 
or justified.

[[Page 64338]]

    This alternative process would follow the same submission 
procedures that are outlined in proposed 40 CFR 174.93, and the 
information required to determine the eligibility of exemption would 
remain the same as outlined in proposed 40 CFR 174.95. Another 
alternative could be a voluntary confirmation process for all PIP 
products exempted under the proposed rule similar to that in USDA's 
final rule titled ``Movement of Certain Genetically Engineered 
Organisms.'' (85 FR 29790; May 18, 2020). Only those developers who 
seek EPA's confirmation would be required to submit to the Agency 
information and data sufficient to establish that their PIPs are 
eligible under the proposed exemptions. Developers who do not seek EPA 
confirmation would not be required to submit any documentation to EPA 
(and thus this alternative would be different from EPA's proposed 
process through which developers submit either a self-determination 
letter or request confirmation that their PIP meets the criteria for 
exemption). EPA requests comment on whether or how such a voluntary 
approach could be workably implemented (e.g., should the recordkeeping 
requirements at proposed 40 CFR 174.73 be required for developers who 
do not submit for EPA confirmation) and whether such an approach would 
be useful or justified?

D. Is EPA's intent behind the use of the terms ``native'' and ``never 
derived'' clear?

    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 
not qualify for the proposed exemption if the gene was introduced into 
the genome of the source plant through transgenic technology, as those 
genes may not be representative of the shared genetic information 
between sexually compatible plants. For example, bacterial endotoxin 
genes (e.g., from the source Bacillus thuringiensis) are a commonly 
engineered pesticidal trait, but EPA does not intend for these genes to 
be considered part of the sexually compatible gene pool nor does EPA 
intend for these genes to qualify for the proposed exemption. However, 
EPA is also aware that horizontal gene transfer from Agrobacterium to 
plants can occur and that in some cases, like the domesticated sweet 
potato, it may result in a variant so commonly found that it could be 
considered part of the gene pool. It is the Agency's intent to exclude 
substances that plant breeders do not have experience with (e.g., a 
bacterial endotoxin not found in a food plant) from the proposed 
exemption. Given the explanation of the intent behind the terms 
``native'' and ``never derived,'' EPA seeks comment on whether the 
intent behind the use of the terms is clear. The Agency also seeks 
comment on whether alternative phrasing rather than ``native'' would be 
more appropriate. Similarly, the Agency seeks comment on whether a 
definition for ``native gene'' or ``native allele'' is necessary, or if 
the criteria included in these definitions should instead be 
incorporated into the exemption text.

E. Should EPA issue a clarifying exemption for loss-of-function traits 
that result in pesticidal effects?

    As described in Unit II.A., the Agency considers the modification 
of existing genes in a plant to elicit a loss-of-function trait in 
order to confer a pesticidal effect to be a pesticide. EPA recognizes 
that this scenario is different from transgenic PIPs that traditionally 
produce a pesticidal substance, e.g., PIPs that produce a protein or 
other substance that kill a pest. In many instances, for loss-of-
function traits, the genetic material of the recipient plant has been 
altered to reduce the production of a substance that would otherwise 
facilitate the susceptibility of that plant to a pathogen; therefore, 
the reduction or elimination of that substance has a mitigating or 
pesticidal effect. For PIPs created through conventional breeding, EPA 
considers these loss-of-function traits to be included in the existing 
exemption at 40 CFR 174.25. It is also EPA's intention that loss-of-
function traits created through biotechnology are included under the 
proposed exemption at 40 CFR 174.26 so long as the exemption criteria 
are met (e.g., only substances produced that are found in sexually 
compatible plants).
    In situations where the existing plant genes are acting as the 
pesticidal substance, EPA recognizes that it can be confusing under the 
current regulatory definitions in 40 CFR 174.3 to interpret the 
pesticidal substance and the genetic material necessary for the 
production of the pesticidal substance as applying to the same thing. 
Given that it is potentially confusing to refer to both of these as a 
``pesticidal substance'' interchangeably, EPA requests comment as to 
whether a clarifying exemption specific to ``loss-of-function PIPs,'' 
where the genetic material is the pesticidal substance, would aid in 
reducing ambiguity over the use of the term ``pesticidal substance'' in 
the regulatory text. EPA proposes to accomplish this by separating 
exempt PIPs into two categories, those where the gene product is the 
pesticidal substance and those where the genetic material itself is the 
pesticidal substance. Similar to the existing exemption at 40 CFR 
174.25 and the proposed exemption at 40 CFR 174.26, the clarifying 
exemption specific to loss-of-function PIPs would be written to limit 
permissible modifications to those that do not result in the production 
of a modified substance. In other words, only the reduced expression of 
an unmodified protein or the elimination of the unmodified protein 
would be permissible. This is to ensure (1) limitation of substances to 
only those with which plant breeders have experience, (2) the 
applicability of EPA's risk assessment for the exemption at 40 CFR 
174.25 and the risk assessment for the proposed exemption at 40 CFR 
174.26 to the proposed ``loss-of-function PIPs'' exemption, and (3) 
that if the reduced substance is in fact a pesticidal substance (or its 
reduction leads to an increase of another substance that is pesticidal) 
it is covered by either the existing tolerance exemption at 40 CFR 
174.508 or the proposed tolerance exemption at 40 CFR 174.541. It is 
also important to note that when the loss of function of a gene 
intentionally results in the increase in production of another gene 
which ultimately produces a pesticidal substance, this PIP would fall 
under either the existing exemption at 40 CFR 174.25 or the proposed 
exemption at 40 CFR 174.26. If EPA were to issue an exemption for loss-
of-function PIPs, EPA would no longer include the category at proposed 
40 CFR 174.26(a)(2)(iv). In addition, EPA also requests comment on how 
a separate exemption or exemptions (if any) specific to loss-of-
function PIPs might be implemented. Should such a separate exemption(s) 
be technique-specific (e.g., should it be specific to loss-of-function 
PIPs created through conventional breeding?) or should there be one 
exemption that covers loss of function PIPs regardless of the technique 
used in their creation?

VIII. References

    The following is a listing of the documents that are specifically 
referenced in this document. The docket includes these documents and 
other information considered by EPA, including documents that are 
referenced

[[Page 64339]]

within the documents that are included in the docket, even if the 
referenced document is not physically located in the docket. For 
assistance in locating these other documents, please consult the person 
listed under FOR FURTHER INFORMATION CONTACT.

1. USEPA, Federal Register. 2018. Withdrawal of Proposed Rules; 
Discontinuing Several Rulemaking Efforts Listed in the Semiannual 
Regulatory Agenda; May 7, 2018. 83 FR 20004. Available online at 
https://www.federalregister.gov/documents/2018/05/07/2018-09206/withdrawal-of-proposed-rules-discontinuing-several-rulemaking-efforts-listed-in-the-semiannual (last accessed December 11, 2019).
2. USEPA, Cost Analysis of the Proposed Rule Exempting Certain 
Plant-Incorporated Protectants (PIPs) from Registration. 2019, EPA: 
Washington, DC.
3. Andersen, E.J., et al., Disease Resistance Mechanisms in Plants. 
Genes, 2018. 9(7).
4. National Academies of Science Engineering and Medicine, 
Genetically Engineered Crops: Experiences and Prospects. 2016, 
Washington, DC: National Academies Press.
5. USEPA, USFDA, and USDA. Modernizing the Regulatory System for 
Biotechnology Products: Final Version of the 2017 Update to the 
Coordinated Framework for the Regulation of Biotechnology. 2017; 
Available from: https://www.epa.gov/regulation-biotechnology-under-tsca-and-fifra/update-coordinated-framework-regulation-biotechnology.
6. USEPA, Natural Toxicants in Food From Plants. 2019. EPA-HQ-OPP-
2019-0508.
7. FIFRA Scientific Advisory Panel (SAP) and Biotechnology Science 
Advisory Committee (BSAC) Joint Meeting, Final Report of the Joint 
FIFRA Scientific Advisory Panel and Biotechnology Science Advisory 
Committee Meeting for January 21, 1994. 1994.
8. FIFRA Scientific Advisory Panel (SAP) Subpanel on Plant 
Pesticides, Final FIFRA Scientific Advisory Panel Subpanel Report on 
the December 18, 1992 Meeting. 1993.
9. The Biotechnology Science Advisory Committee (BSAC) Subcommittee 
on Plant Pesticides, Report: BSAC Subcommittee on Plant Pesticides, 
July 13, 1993 Meeting. 1993.
10. National Research Council, Genetically Modified Pest Protected 
Plants: Science and Regulation. 2000, Washington, DC: National 
Academy Press.
11. National Research Council and Institute of Medicine, Safety of 
Genetically Engineered Foods: Approaches to Assessing Unintended 
Health Effects. 2004, Washington, DC: National Academies Press.
12. National Academies of Science Engineering and Medicine, 
Preparing for Future Products of Biotechnology. 2017, Washington, 
DC: National Academies Press.
13. Hajjar, R. and T. Hodgkin, The use of wild relatives in crop 
improvement: A survey of developments over the last 20 years. 
Euphytica, 2007. 156(1-2): p. 1-13.
14. Harlan, J.R., Genetic Resources in Wild Relatives of Crops. Crop 
Science, 1976. 16(3): p. 329-333.
15. Tanksley, S.D., et al., Advanced backcross QTL analysis in a 
cross between an elite processing line of tomato and its wild 
relative L-pimpinellifolium. Theoretical and Applied Genetics, 1996. 
92(2): p. 213-224.
16. Xiao, J.H., et al., Genes from wild rice improve yield. Nature, 
1996. 384(6606): p. 223-224.
17. Ghorbani, M., E.A. Jonckheere, and P. Bogdan, Gene Expression Is 
Not Random: Scaling, Long-Range Cross-Dependence, and Fractacl 
Characteristics of Gene Regulatory Networks. Frontiers in 
Phsyiology, 2018. 22.
18. Hamner, K.C. and R.Q. Parks, Effect of light intensity on 
ascorbic acid content of turnip greens. Journal of the American 
Society of Agronomy, 1944. 36: p. 269-273.
19. Orr, H.A., Dobzhansky, Bateson, and the genetics of speciation. 
Genetics, 1996. 144(4): p. 1331-1335.
20. Ouyang, Y.D. and Q.F. Zhang, The molecular and evolutionary 
basis of reproductive isolation in plants. Journal of Genetics and 
Genomics, 2018. 45(11): p. 613-620.
21. Servedio, M.R., The role of linkage disequilibrium in the 
evolution of premating isolation. Heredity, 2009. 102(1): p. 51-56.
22. Glenn, K.C., et al., Bringing New Plant Varieties to Market: 
Plant Breeding and Selection Practices Advance Beneficial 
Characteristics while Minimizing Unintended Changes. Crop Science, 
2017. 57(6): p. 2906-2921.
23. USEPA, FIFRA: Benefit and environmental risk considerations for 
inherent plant-pesticides. 1994.
24. Aune, D., et al., Fruit and vegetable intake and the risk of 
cardiovascular disease, total cancer and all-cause mortality-a 
systematic review and dose-response meta-analysis of prospective 
studies. International Journal of Epidemiology, 2017. 46(3): p. 
1029-1056.
25. Brondani, J.E., et al., Fruit and vegetable intake and bones: A 
systematic review and meta-analysis. Plos One, 2019. 14(5).
26. dos Santos Bueno, P.C., et al., Effects of Green Wheat (Triticum 
turgidum) and Common Wheat (Triticum aestivum) on the Metabolic 
Profile of Wistar Rats. Journal of Medicinal Food, 2019.
27. Oyebode, O., et al., Fruit and vegetable consumption and all-
cause, cancer and CVD mortality: analysis of Health Survey for 
England data. Journal of Epidemiology and Community Health, 2014. 
68(9): p. 856-862.
28. Ravn-Haren, G., et al., Apple pomace improves gut health in 
Fisher rats independent of seed content. Food & Function, 2018. 
9(5): p. 2931-2941.
29. Schwingshackl, L., et al., Fruit and Vegetable Consumption and 
Changes in Anthropometric Variables in Adult Populations: A 
Systematic Review and Meta-Analysis of Prospective Cohort Studies. 
Plos One, 2015. 10(10).
30. Thangthaeng, N., et al., Tart cherry supplementation improves 
working memory, hippocampal inflammation, and autophagy in aged 
rats. Age, 2016. 38(5-6): p. 393-404.
31. Wang, X., et al., Fruit and vegetable consumption and mortality 
from all causes, cardiovascular disease, and cancer: systematic 
review and dose-response meta-analysis of prospective cohort 
studies. British Medical Journal, 2014. 349.
32. Wang, P.Y., et al., Higher intake of fruits, vegetables or their 
fiber reduces the risk of type 2 diabetes: A meta-analysis. Journal 
of Diabetes Investigation, 2016. 7(1): p. 56-69.
33. Berger, S., A.K. Sinha, and T. Roitsch, Plant physiology meets 
phytopathology: plant primary metabolism and plant-pathogen 
interactions. Journal of Experimental Botany, 2007. 58(15-16): p. 
4019-4026.
34. Hartl, D.L., A primer of population genetics. 3rd ed. 2000, 
Sunderland, MA: Sinauer Associates, Inc.
35. Harlan, J.R. and J.M.J. de Wet, Toward a rational classification 
of cultivated plants. Taxon, 1971. 20(4): p. 509-517.
36. Chen, C., Z.G. E, and H.X. Lin, Evolution and Molecular Control 
of Hybrid Incompatibility in Plants. Frontiers in Plant Science, 
2016. 7.
37. International Food Biotechnology Council, Biotechnologies and 
Food; Assuring the safety of foods produced by genetic modification. 
Regulatory Toxicology and Pharmacology. Academic Press. New York 
(NY), 1990. 12.
38. Henry J. Thompson, et al., Effect of increased vegetable and 
fruit consumption on markers of oxidative cellular damage. 
Carcinogenesis, 1999. 20(12): p. 2261-2266.
39. Agrios, G., Plant Pathology. Third Edition. Academic Press, New 
York (NY).
40. Atlas, R.a.R.B., Microbial Ecology. 1987: Benjamin/Cummings 
Publishing Company, Inc. Menlo Park, California.
41. Varshney, R.K., A. Graner, and M.A. Sorrells, Genomics-assisted 
breeding for crop improvement. TRENDS in Plant Science, 2005. 
10(12): p. 1360-1385.
42. Kadama, S., et al., Genomic-assisted phylogenetic analysis and 
marker development fornext generation soybean cyst nematode 
resistance breeding. Plant Science, 2016. 242: p. 342-350.
43. Crossa, J., et al., Genomic Selectionin Plant Breeding: Methods, 
Models, and Perspectives. TRENDS in Plant Science, 2017. 22(11): p. 
961-975.
44. Shirasawa, K., et al., The genome sequence of sweet cherry 
(Prunus avium) for use in genomics-assisted breeding. DNA Research, 
2017. 24(5): p. 499-508.
45. Rimbert, H., et al., High throughput SNP discovery and 
genotyping in hexaploid wheat. PloS one, 2018. 13(1): p. e0186329.

[[Page 64340]]

46. Chen, K.L., et al., CRISPR/Cas Genome Editing and Precision 
Plant Breeding in Agriculture, in Annual Review of Plant Biology, 
Vol 70, S.S. Merchant, Editor. 2019. p. 667-697.
47. Dempewolf, H., et al., Past and Future Use of Wild Relatives in 
Crop Breeding. Crop Science, 2017. 57(3): p. 1070-1082.
48. Mammadov, J., et al., Wild Relatives of Maize, Rice, Cotton, and 
Soybean: Treasure Troves for Tolerance to Biotic and Abiotic 
Stresses. Frontiers in Plant Science, 2018. 9.
49. Karban, R. and A.A. Agrawal, Herbivore offense. Annual Review of 
Ecology and Systematics, 2002. 33: p. 641-664.
50. Wozniak, C. and J.L. Kough, Safety of Pesticidal Proteins in 
Food, in Toxicology and Regulatory Process, S. Green, Editor. 2006, 
Marcel Decker, Inc.: NY.
51. Gressel, J., ed. Crop ferality and volunteerism. 2005, CRC 
Press: Boca Raton, FL.
52. den Nijs, H.C.M., D. Bartsch, and J. Sweet, eds. Introgression 
from genetically modified plants into wild relatives. 2004, CABI 
Publishing: Oxfordshire, UK.
53. Abbott, R., et al., Hybridization and speciation. Journal of 
Evolutionary Biology, 2013. 26(2): p. 229-246.
54. Rieseberg, L.H. and S.E. Carney, Plant hybridization. New 
Phytologist, 1998. 140(4): p. 599-624.
55. Pfennig, K.S., A.L. Kelly, and A.A. Pierce, Hybridization as a 
facilitator of species range expansion. Proceedings of the Royal 
Society B-Biological Sciences, 2016. 283(1839).
56. USEPA, Risk considerations for outcrossing and hybridization. 
1992, Issue paper.
57. Baack, E., et al., The origins of reproductive isolation in 
plants. New Phytologist, 2015. 207(4): p. 968-984.
58. Gonzalez, J.D.S., et al., Ecogeography of teosinte. Plos One, 
2018. 13(2).
59. Heslop-Harrison, J.S. and T. Schwarzacher, Domestication, 
genomics and the future for banana. Annals of Botany, 2007. 100(5): 
p. 1073-1084.
60. USEPA, Dermal and inhalation exposure to plant substances. 2000, 
Issue paper.
61. Lozano-Ojalvo, D., C. Berin, and L. Tordesillas, Immune Basis of 
Allergic Reactions to Food. Journal of Investigational Allergology 
and Clinical Immunology, 2019. 29(1): p. 1-14.
62. Hahn, F. and V. Nekrasov, CRISPR/Cas precision: do we need to 
worry about off-targeting in plants? Plant Cell Reports, 2019. 
38(4): p. 437-441.
63. Tabei, Y., Risk and safety considerations 2: genetic variations 
and potential risks-traditional breeding and genome editing. 
Transgenic Research, 2019. 28: p. 119-124.
64. Young, J., et al., CRISPR-Cas9 Editing in Maize: Systematic 
Evaluation of Off-target Activity and Its Relevance in Crop 
Improvement. Scientific Reports, 2019. 9.
65. Tang, X., et al., A large-scale whole-genome sequencing analysis 
reveals highly specific genome editing by both Cas9 and Cpf1 
(Cas12a) nucleases in rice. Genome Biology, 2018. 19.
66. Leitch, A.R. and I.J. Leitch, Perspective--Genomic plasticity 
and the diversity of polyploid plants. Science, 2008. 320(5875): p. 
481-483.
67. Henikoff, S., Rapid changes in plant genomes. Plant Cell, 2005. 
17(11): p. 2852-2855.
68. Wendel, J.F., et al., Evolution of plant genome architecture. 
Genome Biology, 2016. 17.
69. Joshipura, K.J., et al., Fruit and vegetable intake in relation 
to risk of ischemic stroke. Journal of the American Medical 
Association, 1999. 282(3).
70. Michaud, D.S., et al., Fruit and Vegetable Intake and Incidence 
of Bladder Cancer in a Male Prospective Cohort. Journal of the 
National Cancer Institute, 1999. 91(7).
71. Segasothy, M. and P.A. Phillips, Vegetarian diet: panacea for 
modern lifestyle diseases? QJM: An International Journal of 
Medicine, 1999. 92(9): p. 531-544.
72. Ogimoto, I., A. Shibata, and K. Fukuda, World Cancer Research 
Fund/American Institute of Cancer Research 1997 Recommendations: 
applicability to digestive tract cancer in Japan. Cancer Causes and 
Control, 2000. 11(1): p. 9-23.
73. Bazzano, L.A., et al., Fruit and vegetable intake and risk of 
cardiovascular disease in US adults: the first National Health and 
Nutrition Examination Survey Epidemiologic Follow-up Study. American 
Journal of Clinical Nutrition, 2002. 76: p. 93-99.
74. Joseph, J.A., et al., Reversals of age-related declines in 
neuronal signal transduction, cognitive, and motor behavioral 
deficits with blueberry, spinach, or strawberry dietary 
supplementation. Journal of Neuroscience, 1999. 18(18): p. 8114-
8121.
75. Galli, R.L., et al., Fruit polyphenolics and brain aging: 
nutritional interventions targeting age-related neuronal and 
behavioral deficits. Annals of the New York Academy of Sciences, 
2006. 959(1).
76. M[uuml]hlbauer, R.C., A. Lozano, and A. Reinli, Onion and a 
Mixture of Vegetables, Salads, and Herbs Affect Bone Resorption in 
the Rat by a Mechanism Independent of Their Base Excess. Journal of 
Bone and Mineral Research, 2002. 17(7): p. 1230-6.
77. Goyarzu, P., et al., Blueberry supplemented diet: effects on 
object recognition memory and nuclear factor-kappa B levels in aged 
rats. Nutritional Neuroscience, 2004. 7(2): p. 75-83.
78. Raven, P.H., R.F. Evert, and S.E. Eichhorn, Biology of Plants. 
Fifth Edition. 1992: Worth Publishers.
79. Das, A., N. Sharma, and M. Prasad, CRISPR/Cas9: A Novel Weapon 
in the Arsenal to Combat Plant Diseases. Frontiers in Plant Science, 
2019. 9.
80. Weber, N., et al., Editor's choice: Crop genome plasticity and 
its relevance to food and feed safety of genetically engineered 
breeding stacks. Plant Physiology, 2012. 160(4): p. 1842-53.
81. USEPA, Benefits of fruits and vegetables. 2000. Issue Paper.
82. Dolan, L.C., R.A. Matulka, and G.A. Burdock, Naturally Occurring 
Food Toxins. Toxins, 2010. 2: p. 2289-2332.
83. Speijers, G., et al., Evaluation of Agronomic Practices for 
Mitigation of Natural Toxins. 2010.
84. Fernandez-Cornejo, J., The seed industry in US agriculture: An 
exploration of data and information on crop seed markets, 
regulation, industry structure, and research and development. 2004, 
U.S. Department of Agriculture Economic Research Service.
85. Cooper, R.A. and H.F. Bunn, Hemolytic Anemies, in Harrison's 
Principles of Internal Medicine, K.J. Isselbacher, et al., Editors. 
1980, McGraw-Hill Company.
86. Lovell, C.R., Plants and the skin. Vol. First edition. 1993: 
Oxford, Blackwell Scientific Publications.
87. Guy, R.H. and J. Hadgraft, Principles of skin permeability 
relevant to chemical exposure, in Dermal and Ocular Toxicology: 
Fundamentals and Methods, D.W. Hobson, Editor. 1991, CRC Press: Boca 
Raton, Florida.
88. Yunginger, J.W., Food Antigens. In: Food Allergy: Adverse 
Reactions to Foods and Food Additives. 1991.
89. O'Mahony, S. and A. Ferguson, Gluten-Sensitive Enteropathy 
(Celiac Disease), in Food Allergy: Adverse Reactions to Foods and 
Food Additives, D.D. Metcalfe, H.A. Sampson, and R.A. Simon, 
Editors. 1991, Blackwell Scientific Publications: Cambridge, 
Massachusetts.
90. Organisation for Economic Cooperation and Development (OECD), 
OECD Guideline 440: Uterotrophic Bioassay in Rodents. 2007.

IX. Statutory and Executive Order Reviews

    Additional information about these statutes and Executive orders 
can be found at https://www.epa.gov/laws-regulations/laws-and-executive-orders.

A. Executive Order 12866: Regulatory Planning and Review and Executive 
Order 13563: Improving Regulation and Regulatory Review

    This action is a significant regulatory action that was submitted 
to the Office of Management and Budget (OMB) for review under Executive 
Orders 12866 (58 FR 51735, October 4, 1993) and 13563 (76 FR 3821, 
January 21, 2011). Any changes made in response to OMB recommendations 
have been documented in the docket for this action as required by 
section 6(a)(3)(E) of Executive Order 12866.

B. Executive Order 13771: Reducing Regulations and Controlling 
Regulatory Costs

    This action is expected to be an Executive Order 13771 deregulatory 
action. Details on the estimated cost savings of this proposed rule can 
be found in EPA's cost analysis (Ref. 2).

[[Page 64341]]

C. Paperwork Reduction Act (PRA)

    The information collection activities in this proposed rule have 
been submitted for approval to OMB under the PRA, 44 U.S.C. 3501 et 
seq. The Information Collection Request (ICR) document that EPA 
prepared is assigned EPA ICR No. 2619.01. You can find a copy of the 
ICR in the docket for this rule, and it is briefly summarized here.
    The information collection activities in this proposed rule are 
associated with the proposed exemption eligibility process (i.e., self-
determination or request for EPA-confirmation, and associated 
recordkeeping) that would be made available as an alternative to the 
existing pesticide registration and tolerance activities that are 
already approved by OMB under OMB Control No. 2070-0060 (EPA ICR No. 
0277). As such, the ICR accompanying this proposed rule is intended to 
amend that existing ICR at the final rule stage, incorporating the 
information collection activities for the exemption and related 
estimated burden.
    Respondents affected entities: See Unit I.A.
    Respondent's obligation to respond: Mandatory to obtain the 
exemption (40 CFR part 174, as proposed).
    Estimated number of respondents: 1.
    Frequency of response: Once.
    Total estimated burden: 14 hours (per EPA determination). Burden is 
defined at 5 CFR 1320.3(b).
    Total estimated cost: $1,487 (per EPA determination), includes $0 
annualized capital or operation & maintenance costs.
    An agency may not conduct or sponsor, and a person is not required 
to respond to, a collection of information unless it displays a 
currently valid OMB control number. The OMB control numbers for EPA's 
regulations in 40 CFR are listed in 40 CFR part 9.
    Submit your comments on the Agency's need for this information, the 
accuracy of the provided burden estimates, and any suggested methods 
for minimizing respondent burden to EPA using the docket identified at 
the beginning of this rule. You may also send your ICR-related comments 
to OMB's Office of Information and Regulatory Affairs via email to 
[email protected], Attention: Desk Officer for the EPA. Since 
OMB is required to make a decision concerning the ICR between 30 and 60 
days after receipt, OMB must receive comments no later than November 9, 
2020. EPA will respond to any ICR-related comments received on the 
proposed ICR amendment when issuing the final rule.

D. Regulatory Flexibility Act (RFA)

    Pursuant to the RFA section 605(b), 5 U.S.C. 601 et seq., I hereby 
certify that this action will not have a significant economic impact on 
a substantial number of small entities. In making this determination, 
EPA believes that the impact of concern is any adverse economic impact, 
and that an agency may certify that a rule will not have a significant 
economic impact on a substantial number of small entities if the rule 
relieves regulatory burden, has no net burden, or otherwise has a 
positive economic effect on the small entities subject to the rule. The 
factual basis for this determination is presented in the small entity 
impact analysis prepared as part of the cost analysis for this proposed 
rule (Ref. 2), which is summarized in Units I.E. and VI.A.4., and a 
copy is available in the docket for this rulemaking. The following is a 
brief summary of the factual basis for this certification.
    The effect of the rule is to reduce costs to developers of PIPs 
based on sexually compatible plant created through biotechnology, and 
the cost savings per product are approximately $444,000-$459,000. The 
cost savings per product would be realized when a letter of self-
determination is sent. The proposed exemption for PIPs based on 
sexually compatible plants created through biotechnology reduces the 
cost associated with meeting regulatory requirements and so removes a 
potential barrier to market entry for small entities. Of the entities 
likely to develop PIPs based on sexually compatible plants created 
through biotechnology, EPA currently estimates that approximately 80% 
are small entities. We have therefore concluded that this action will 
relieve regulatory burden for all directly regulated small entities.
    Any comments regarding the potential impacts on small entities from 
this action should be submitted to the Agency in the manner specified 
under ADDRESSES.

E. Unfunded Mandates Reform Act (UMRA)

    This action does not contain an unfunded mandate as described in 
UMRA, 2 U.S.C. 1531-1538, and does not significantly or uniquely affect 
small governments. The action is not expected to impose an enforceable 
duty on any state, local or tribal governments, and the requirements 
imposed on the private sector are not expected to result in annual 
expenditures of $100 million or more for the private sector. 
Accordingly, EPA has determined that the requirements of UMRA sections 
202, 203, 204, or 205 do not apply to this action.

F. Executive Order 13132: Federalism

    This action does not have federalism implications as specified in 
Executive Order 13132 (64 FR 43255, August 10, 1999). It will not have 
substantial direct effects on the states, on the relationship between 
the national government and the states, or on the distribution of power 
and responsibilities among the various levels of government. Thus, 
Executive Order 13132 does not apply to this proposed rule.

G. Executive Order 13175: Consultation and Coordination With Indian 
Tribal Governments

    This action does not have tribal implications as specified in 
Executive Order 13175 (65 FR 67249, November 9, 2000). It will not have 
substantial direct effects on tribal governments, on the relationship 
between the Federal government and the Indian tribes, or on the 
distribution of power and responsibilities between the Federal 
government and Indian tribes. Thus, Executive Order 13175 does not 
apply to this proposed rule.

H. Executive Order 13045: Protection of Children From Environmental 
Health Risks and Safety Risks

    EPA interprets Executive Order 13045 (62 FR 19885, April 23, 1997) 
as applying only to those regulatory actions that concern environmental 
health or safety risks that EPA has reason to believe may 
disproportionately affect children, per the definition of ``covered 
regulatory action'' in section 2-202 of the Executive Order. This 
action is not subject to Executive Order 13045 because it does not 
establish an environmental standard intended to mitigate a health or 
safety risk.

I. Executive Order 13211: Actions Concerning Regulations That 
Significantly Affect Energy Supply, Distribution, or Use

    This action is not a ``significant energy action'' as defined in 
Executive Order 13211 (66 FR 28355, May 22, 2001) because it is not 
likely to have a significant adverse effect on the supply, 
distribution, or use of energy.

J. National Technology Transfer Advancement Act (NITAA)

    NTTAA section 12(d), 15 U.S.C. 272 note, does not apply to this 
proposed action because it would not impose any technical standards 
requiring Agency consideration of voluntary consensus standards. This 
regulation proposes the

[[Page 64342]]

types of information to be submitted in a self-determination letter or 
EPA confirmation request concerning the exemption of PIPs based on 
sexually compatible plants created through biotechnology, but does not 
propose to require specific methods or standards to generate that 
information.

K. Executive Order 12898: Federal Actions To Address Environmental 
Justice in Minority Populations and Low-Income Populations

    EPA believes that this action is not subject to Executive Order 
12898 (59 FR 7629, February 16, 1994) because it does not establish an 
environmental health or safety standard.

L. FIFRA Review Requirements

    In accordance with FIFRA section 25(a), EPA submitted the draft 
proposed rule to the Secretary of the United States Department of 
Agriculture (USDA) and the FIFRA Scientific Advisory Panel (SAP) for 
review. A draft of the proposed rule was also submitted to the 
appropriate Congressional Committees.

M. Executive Order 13874: Modernizing the Regulatory Framework for 
Agricultural Biotechnology Products

    This action is intended to further implement section 4(b) of 
Executive Order 13874 (84 FR 27899, June 11, 2019). If this proposal is 
made final, the final rule may promote future innovation and 
competitiveness by efficiently exempting through regulation qualifying 
PIPs based on sexually compatible plants created through biotechnology 
that meet the FIFRA and FFDCA standards for exemption.

List of Subjects in 40 CFR Part 174

    Environmental protection, Administrative practice and procedure, 
Agricultural commodities, Pesticides and pests, Plant-incorporated 
protectants, Reporting and recordkeeping requirements.

Andrew Wheeler,
Administrator.

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

PART 174--[AMENDED]

0
1. The authority citation for part 174 continues to read as follows:

    Authority: 7 U.S.C. 136-136y; 21 U.S.C. 321(q), 346a and 371.

0
 2. Amend Sec.  174.3 by adding in alphabetical order the following 
definitions to read as follows:


Sec.  174.3  Definitions

* * * * *
    Gene, and other grammatical variants such as ``genic,'' means a 
functional unit of heritable genetic material that is comprised of the 
genetic material necessary for the production of a substance.
* * * * *
    Native allele means a variant of a native gene that is identified 
in the genetic diversity of plants sexually compatible with the 
recipient plant.
    Native gene means a gene that is identified in the recipient plant 
or plants sexually compatible with the recipient plant; and has never 
been derived from a source that is not sexually compatible with the 
source plant.
* * * * *
    Sexually compatible, when referring to plants, means a viable 
zygote can be formed through the union of two gametes through 
conventional breeding.
* * * * *
0
 3. Revise Sec.  174.21 to read as follows:


Sec.  174.21  General qualifications for exemptions.

    A plant-incorporated protectant is exempt from the requirements of 
FIFRA, other than the requirements of Sec.  174.71, if it meets the 
exemption criteria in paragraphs (a) through (d) of this section. 
Plant-incorporated protectants that are not exempt from the 
requirements of FIFRA under this subpart are subject to all the 
requirements of FIFRA.
    (a) The pesticidal substance from the plant-incorporated protectant 
meets the exemption criteria listed in at least one of the sections in 
Sec. Sec.  174.25 through 174.50.
    (b) When the plant-incorporated protectant is intended to be 
produced and used in a crop used as food, the residues of the 
pesticidal substance of the plant-incorporated protectant are either 
exempted from the requirement of a tolerance under FFDCA (21 U.S.C. 321 
et seq.) as listed in subpart W of this part, or no tolerance would 
otherwise be required.
    (c) Any inert ingredient that is part of the plant-incorporated 
protectant is listed as an approved inert ingredient in subpart X of 
this part.
    (d) For plant-incorporated protectants listed in the subparagraphs 
below, the exemption applies only if the developer is compliant with 
the general record keeping requirements specified in Sec.  174.73 and 
only after compliance with the relevant eligibility determination 
procedures specified in Sec.  174.90:
    (1) Plant-incorporated protectant based on a sexually compatible 
plant created through biotechnology.
    (2) [Reserved]
0
 4. Amend Sec.  174.25 by:
0
 a. Revising the section heading;
0
 b. Revising the introductory paragraph; and
0
c. Adding paragraph (c).
    The revisions read as follows:


Sec.  174.25  Pesticidal substance from a plant-incorporated protectant 
from a sexually compatible plant created through conventional breeding.

    The pesticidal substance from a plant-incorporated protectant from 
a sexually compatible plant created through conventional breeding is 
exempt if all of the following conditions are met:
* * * * *
    (c) The genetic material is transferred from the source plant to 
the recipient plant only through conventional breeding.
0
 5. Add Sec.  174.26 to read as follows:


Sec.  174.26  Pesticidal substance from a plant-incorporated protectant 
based on a sexually compatible plant created through biotechnology.

    The pesticidal substance from a plant-incorporated protectant based 
on a sexually compatible plant created through biotechnology is exempt 
if all of the following conditions are met:
    (a) The pesticidal substance is created through biotechnology from 
either an insertion of new genetic material as discussed in paragraph 
(a)(1) of this section or a modification of existing genetic material 
as discussed in paragraph (a)(2) of this section.
    (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.
    (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; or
    (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; or
    (iii) The existing genetic material is modified pursuant to both 
(i) and (ii).
    (iv) 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.
    (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.

[[Page 64343]]

    (c) This exemption does not apply until the requirements in subpart 
E of this part have been met.
0
 6. Add Sec.  174.73 to read as follows:


Sec.  174.73  General recordkeeping requirements for exemptions.

    For 5 years, starting with the effective date of a plant-
incorporated protectant exemption, any person who produces an exempt 
plant-incorporated protectant listed under Sec.  174.21(d) must do both 
of the following:
    (a) Maintain documentation of either the letter of self-
determination or the request for EPA confirmation along with all 
supporting documentation for the specific exemption listed in subpart 
E.
    (b) Make the documentation of exemption eligibility available to 
EPA upon request.
0
 7. Amend subpart E to read as follows:

Subpart E--Exemption Eligibility Determination Process and 
Requirements


Sec.  174.90  Determining Eligibility for Exemption

    (a) Options for determining eligibility. For a plant-incorporated 
protectant listed under Sec.  174.21(d), the developer must do at least 
one of the following actions to be eligible for the exemption in Sec.  
174.21:
    (1) Self-determination. A developer may submit a letter of self-
determination in accordance with Sec.  174.91.
    (2) Request for EPA confirmation of eligibility. A developer may 
submit a request for EPA confirmation of eligibility in accordance with 
Sec.  174.93.
    (b) Where to submit a letter of self-determination or request for 
EPA confirmation. A letter of self-determination or a request for EPA 
confirmation of eligibility must be submitted to the Office of 
Pesticide Programs' Document Processing Desk at the appropriate address 
as set forth in Sec.  150.17(a) or (b) of this chapter, with the 
relevant ``Attention'' line: ``Attention: Plant-Incorporated Protectant 
Exemption Self-Determination'' or ``Attention: Plant-Incorporated 
Protectant Request for Confirmation of Exemption Eligibility.'' 
[placeholder for future instructions covering electronic submissions].
    (c) Overlapping determinations of eligibility. A developer may 
elect to submit a letter of self-determination as well as a request for 
EPA confirmation of eligibility concurrently or at a later time. If the 
developer so elects, the letter of self-determination will remain in 
effect while EPA evaluates the request for confirmation of eligibility.
    (d) Revisiting eligibility determination. If, at any time after the 
letter of self-determination is submitted or EPA issues a confirmation 
of eligibility, EPA becomes aware of information indicating that the 
exempt plant-incorporated protectant no longer meets the criteria for 
exemption (e.g., adverse effects reports submitted under Sec.  174.71) 
or that the self-determination was incorrect, EPA will notify the 
original submitter in writing of EPA's intention to initiate a review 
of eligibility for exemption and may request additional information 
from the developer in order to evaluate that eligibility for exemption. 
Upon conclusion of its review, EPA will notify the developer in writing 
of its determination whether the plant-incorporated protectant meets 
the exemption criteria and any actions that will be required should the 
plant-incorporated protectant be found to not meet the exemption 
criteria. Under those circumstances, the plant-incorporated protectant 
may be considered to be noncompliant with FIFRA and subject to possible 
enforcement by EPA.
    (e) Extension of exemption to subsequent variations of the plant-
incorporated protectant.
    (1) Plant-incorporated protectant based on a sexually compatible 
plant created through biotechnology. A letter of self-determination or 
EPA's confirmation that the plant-incorporated protectant based on a 
sexually compatible plant created through biotechnology meets the 
criteria for exemption applies to subsequent engineering of that plant-
incorporated protectant by the submitter into other varieties of that 
same plant species as long as the submitter is doing one of the 
following:
    (i) Producing the identical substance as in the exempt plant-
incorporated protectant, so long as no modifications were made to the 
regulatory regions.
    (ii) Creating the same phenotype as in the exempt plant-
incorporated protectant by targeting the same nucleic acid sequence in 
the regulatory region to result in a mutation via double-strand DNA 
break repaired by non-homologous end joining.
    (iii) For subsequent engineering events that do not meet either 
criterion (e)(1)(i) or (1)(ii), a letter of self-determination or 
request for EPA determination must be submitted.
    (2) [Reserved]


Sec.  174.91  Submitting a letter of self-determination for exemption.

    A developer who elects to self-determine eligibility for the 
exemption of a plant-incorporated protectant listed under Sec.  
174.21(d) must comply with all of the following requirements.
    (a) When to submit a letter of self-determination. A letter of 
self-determination for an exemption must be submitted to EPA prior to 
engaging in activities subject to FIFRA.
    (b) Contents of a letter of self-determination. The letter of self-
determination must:
    (1) Provide the name and contact information for the submitter 
(including phone and email address), company name, or other 
affiliation.
    (2) Identify the plant-incorporated protectant and the following 
exemption-specific information for the exemption for which eligibility 
is self-determined:
    (i) Plant-incorporated protectant based on a sexually compatible 
plant created through biotechnology. Cite the paragraph under 
Sec. Sec.  174.26 or 174.541 that is applicable to the PIP (i.e., 
(a)(1), (a)(2)(i), (a)(2)(ii), (a)(2)(iii), or (a)(2)(iv)).
    (ii) [Reserved]
    (3) Include the following statement of certification, filling in 
the information described in italics:

    ``I, [name of submitter], on behalf of [name of company] am 
submitting this Plant-Incorporated Protectant Exemption Self-
Determination consistent with the provisions of 40 CFR part 174. I 
hereby confirm that the plant-incorporated protectant known as [name 
of the plant-incorporated protectant] is eligible under 40 CFR 
174.21 to be exempt from the requirements of FIFRA, other than the 
requirements of 40 CFR 174.71 and 174.73. I understand that it is a 
violation of 18 U.S.C. 1001 to willfully make any false statement to 
EPA. I further understand that if this self-determination is not 
consistent with the provisions of 40 CFR part 174, this plant-
incorporated protectant product may not be exempt from the 
requirements of FIFRA, and [name of company] may be subject to 
enforcement actions and penalties under FIFRA sections 12, 13, and 
14, 7 U.S.C. 136j, 136k, and 136l. Moreover, I also understand that 
if this self-determination is not consistent with 40 CFR part 174, 
the residues of this plant-incorporated protectant may not be exempt 
from the requirement of a tolerance under the FFDCA, and [name of 
company], as well as foods containing such residues, may be subject 
to enforcement actions and penalties under Chapter III of the FFDCA, 
21 U.S.C. 331 et seq.''

    (4) The statement must be dated and signed by an authorized 
representative of the developer of the plant-incorporated protectant.
    (c) EPA response. For electronic submissions, EPA will provide 
electronic confirmation of receipt immediately. Electronic confirmation 
shall be equivalent to written confirmation. For submissions by mail, 
written confirmation of receipt within 30 business days of receipt of a 
letter of self-determination.

[[Page 64344]]

    (d) Effective date of exemption. The exemption does not apply until 
EPA confirms receipt of the letter of self-determination.


Sec.  174.93  Obtaining EPA confirmation of eligibility for the 
exemption.

    A developer who elects to request EPA confirmation of eligibility 
for exemption of a plant-incorporated protectant listed under Sec.  
174.21(d) must comply with all of the following requirements.
    (a) When to submit a request for EPA confirmation. Unless the 
developer has received confirmation of receipt of a letter of self-
determination, the request for EPA confirmation must be submitted prior 
to engaging in activities subject to FIFRA.
    (b) Contents of a request for EPA confirmation of exemption 
eligibility. The request must contain information as specified in Sec.  
174.91(b) and supporting documentation demonstrating that the plant-
incorporated protectant meets the criteria for the exemption, as 
specified in exemption-specific sections of this subpart. Any claims of 
confidentiality for information submitted in the request for EPA 
confirmation must be made in accordance with the procedures outlined in 
Sec.  174.9 of subpart A.
    (c) EPA review and response. Upon receipt of a request, EPA will 
review and evaluate the information provided to determine whether the 
plant-incorporated protectant meets the exemption criteria in Sec.  
174.21. EPA may require additional information to assess whether a 
plant-incorporated protectant meets the criteria for exemption. EPA 
will notify the submitter in writing of its determination. If EPA 
determines that the plant-incorporated protectant does not meet the 
criteria for exemption, EPA will notify the submitter in writing of any 
actions that will be required.
    (d) Effective date for the EPA confirmed exemption. If the plant-
incorporated protectant is not already exempt pursuant to the self-
determination process under Sec.  174.91, this exemption applies once 
EPA notifies the submitter in writing, confirming that the plant-
incorporated protectant meets the criteria for exemption.


Sec.  174.95  Documentation for an exemption for a plant-incorporated 
protectant based on a sexually compatible plant created through 
biotechnology.

    A developer requesting EPA confirmation of exemption eligibility 
for a plant-incorporated protectant from a sexually compatible plant 
created through biotechnology pursuant to Sec.  174.93 must submit the 
information in the following paragraphs to EPA along with its request 
for exemption confirmation. Any developer required to maintain records 
under Sec.  174.73 must maintain the following documentation.
    (a) Biology of the plant.
    (1) The identity of the recipient plant, including genus and 
species.
    (2) If the plant-incorporated protectant was derived from another 
plant species, provide the identity of the source plant including genus 
and species and information to demonstrate the recipient plant and the 
source plant are sexually compatible.
    (b) Description of the pesticidal trait and how the trait was 
engineered into the plant. If the pesticidal substance is a known 
mammalian toxin or toxicant (e.g., solanine) describe how conventional 
breeding practices are being used to ensure it does not exceed safe 
levels in the recipient food plant.
    (c) Molecular characterization of the plant-incorporated 
protectant.
    (1) The nucleotide sequence and the amino acid sequence of the 
plant-incorporated protectant in the recipient plant, including a 
sequence comparison between the recipient plant and the relevant 
comparator (i.e., the source plant if a source plant was used or the 
unmodified plant if no source plant was used).
    (2) For a plant-incorporated protectant where the regulatory region 
of an existing or inserted native gene has been modified, confirmation 
that the expression level does not exceed that found in a sexually 
compatible plant and the plant-incorporated protectant is not expressed 
in tissues or developmental stages outside of that observed in a plant 
that is sexually compatible with the recipient plant.
0
 8. Amend Sec.  174.508 by:
0
a. Revising the section heading,
0
b. Revising the introductory paragraph,
0
 c. Designating paragraph (c) as paragraph (d), and
0
d. Adding a new paragraph (c).
    These revisions read as follows:


Sec.  174.508  Pesticidal substance from a plant-incorporated 
protectant from a sexually compatible plant created through 
conventional breeding; exemption from the requirement of a tolerance.

    Residues of a pesticidal substance from a plant-incorporated 
protectant from a sexually compatible plant created through 
conventional breeding are exempt from the requirement of a tolerance if 
all the following conditions are met:
* * * * *
    (c) The genetic material is transferred from the source plant to 
the recipient plant only through conventional breeding.
    (d) The residues of the pesticidal substance are not present in 
food from the plant at levels that are injurious or deleterious to 
human health.
0
 9. Add Sec.  174.541 to read as follows:


Sec.  174.541  Pesticidal substance from a plant-incorporated 
protectant based on a sexually compatible plant created through 
biotechnology; exemption from the requirement of a tolerance.

    Residues of a pesticidal substance from a plant-incorporated 
protectant based on a sexually compatible plant created through 
biotechnology are exempt if all of the following conditions are met:
    (a) The pesticidal substance is created through biotechnology from 
either an insertion of new genetic material as discussed in paragraph 
(1) or a modification of existing genetic material as discussed in 
paragraph (2).
    (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.
    (2)(i) The existing native gene in the recipient food plant is 
modified to alter the amount of pesticidal substance produced without 
altering the identity of the pesticidal substance produced; or
    (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; or
    (iii) The existing genetic material is modified pursuant to both 
(i) and (ii).
    (iv) 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.
    (b) The residues of the pesticidal substance are present only in 
tissues and developmental stages identified in a plant that is sexually 
compatible with the recipient food plant, and do not exceed levels 
found within that plant, as long as those levels are not injurious or 
deleterious to human health.
    (c) This exemption does not apply until the requirements in subpart 
E of this part have been met.

[FR Doc. 2020-19669 Filed 10-8-20; 8:45 am]
 BILLING CODE 6560-50-P