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Rule2023-11477

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

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Published

May 31, 2023

Effective

July 31, 2023

Issuing agencies

Environmental Protection Agency

Abstract

The Environmental Protection Agency (EPA) is exempting a class of plant-incorporated protectants (PIPs) that have been created using genetic engineering from certain registration requirements under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), and from the requirements to establish a tolerance or tolerance exemption for residues of these substances on food or feed under the Federal Food, Drug, and Cosmetic Act (FFDCA). Specifically, EPA is finalizing its exemptions as described in its October 2020 proposal for PIPs now termed "PIPs created through genetic engineering from a sexually compatible plant" and "loss-of-function PIPs," finalizing the process through which the Agency determines their eligibility for exemption, and finalizing the associated recordkeeping requirements. This set of exemptions reflects the biotechnological advances made since 2001, when EPA first exempted PIPs derived through conventional breeding and excluded from the exemptions those PIPs that are created through biotechnology. EPA anticipates that today's exemptions will benefit the public by ensuring that human health and the environment are adequately protected, while also reducing the regulatory burden for the regulated community. These exemptions may also result in increased research and development activities, commercialization of new pest control options for farmers, particularly in minor crops, and increase the diversity of options for pest and disease management, which could provide environmental benefits.

Full Text

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<title>Federal Register, Volume 88 Issue 104 (Wednesday, May 31, 2023)</title>
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[Federal Register Volume 88, Number 104 (Wednesday, May 31, 2023)]
[Rules and Regulations]
[Pages 34756-34779]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2023-11477]

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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 174

[EPA-HQ-OPP-2019-0508; FRL-7261-04-OCSPP]
RIN 2070-AK54

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

AGENCY: Environmental Protection Agency (EPA).

ACTION: Final rule.

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SUMMARY: The Environmental Protection Agency (EPA) is exempting a class
of plant-incorporated protectants (PIPs) that have been created using
genetic engineering from certain registration requirements under the
Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), and from
the requirements to establish a tolerance or tolerance exemption for
residues of these substances on food or feed under the Federal Food,
Drug, and Cosmetic Act (FFDCA). Specifically, EPA is finalizing its
exemptions as described in its October 2020 proposal for PIPs now
termed ``PIPs created through genetic engineering from a sexually
compatible plant'' and ``loss-of-function PIPs,'' finalizing the
process through which the Agency determines their eligibility for
exemption, and finalizing the associated recordkeeping requirements.
This set of exemptions reflects the biotechnological advances made
since 2001, when EPA first exempted PIPs derived through conventional
breeding and excluded from the exemptions those PIPs that are created
through biotechnology. EPA

[[Page 34757]]

anticipates that today's exemptions will benefit the public by ensuring
that human health and the environment are adequately protected, while
also reducing the regulatory burden for the regulated community. These
exemptions may also result in increased research and development
activities, commercialization of new pest control options for farmers,
particularly in minor crops, and increase the diversity of options for
pest and disease management, which could provide environmental
benefits.

DATES: This final rule is effective on July 31, 2023.

ADDRESSES: The docket for this action, identified under docket
identification (ID) number EPA-HQ-OPP-2019-0508, is available at
<a href="https://www.regulations.gov">https://www.regulations.gov</a>. Additional instructions on visiting the
docket, along with more information about dockets generally, is
available at <a href="https://www.epa.gov/dockets">https://www.epa.gov/dockets</a>. For the latest status
information on EPA/DC services and docket access, visit <a href="https://www.epa.gov/dockets">https://www.epa.gov/dockets</a>.

FOR FURTHER INFORMATION CONTACT: Amanda Pierce, Biopesticides and
Pollution Prevention Division (7511P), Office of Pesticide Programs,
Environmental Protection Agency, 1200 Pennsylvania Ave. NW, Washington,
DC 20460-0001; main telephone number: (202) 948-3693; email address:
<a href="/cdn-cgi/l/email-protection#723022223634203c1d061b111701321702135c151d04"><span class="__cf_email__" data-cfemail="a6e4f6f6e2e0f4e8c9d2cfc5c3d5e6c3d6c788c1c9d0">[email&#160;protected]</span></a>.

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 action 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 document applies to them.
Potentially affected entities may include:
<bullet> 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.
<bullet> Crop Production (NAICS code 111), e.g., seed companies.
<bullet> Colleges, universities, and professional schools (NAICS
code 611310), e.g., establishments of higher learning which are engaged
in development and marketing of PIPs.
<bullet> 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?

This rule establishes exemptions under the Federal Insecticide,
Fungicide, and Rodenticide Act (FIFRA), 7 U.S.C. 136 et seq. and
codified at 40 CFR 174.26 and 174.27 and for the residues of such PIPs
under the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a
and codified at 40 CFR 174.541 for certain PIPs that are created in
plants using biotechnology. In this final rule, the term ``exemption''
is applied to actions under both of these statutes. (EPA notes that
this action only exempts qualifying PIPs from regulation under FIFRA
and the need to establish a tolerance for residues of qualifying PIPs
under section 408(e) of the FFDCA; other statutory or regulatory
requirements may still apply, e.g., State, Tribal, or local
requirements). This rule provides criteria and definitions that
identify the two groups of PIPs that are exempted through this action,
called ``PIPs created through genetic engineering from a sexually
compatible plant'' and ``loss-of-function PIPs,'' and codifies the
process through which the Agency determines their eligibility for
exemption. The rule also codifies the recordkeeping requirements for
exempted PIPs, and the preamble, along with the accompanying Response
to Comments document (Ref. 1), addresses the public comments that the
Agency received on the proposed rule (85 FR 64308; October 9, 2020;
FRL-10014-10) (Ref. 2) during the public comment period. EPA's
responses to those comments are summarized in Unit IV. and in the
Response to Comments document (Ref. 1) that is available in docket for
this action.

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

This action is being taken 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. Section 408 of the FFDCA is focused on
human risk. To make a safety finding under FFDCA to support a tolerance
or exemption for pesticide residues on food, EPA considers, among other
things: the toxicity of the pesticide and its metabolites and
degradates, aggregate exposure to the pesticide in foods and from other
sources of exposure, and any special risks posed to infants and
children. The potential for pesticide exposure through food from food-
producing animals that consume feed is part of the human health risk
assessment used in EPA's FFDCA determinations. Risk to non-target
organisms and risk associated with occupational exposure is evaluated
under FIFRA. A more detailed discussion of EPA's statutory authority is
available in Units III.A., III.B., and III.C. of the proposed rule (85
FR 64313-64314, October 9, 2020) (Ref. 2).

D. Why is EPA taking this action?

Recent advances in genetic engineering offer not only precise means
by which genes coding for pesticidal substances can be inserted into a
plant genome but also allow for modifications of genes that already
exist within a plant. Due to the sophistication of these technologies,
PIPs can now be created through genetic engineering that are virtually
indistinguishable from those created through conventional breeding.
These advances also allowed EPA to develop specific exemption criteria
to circumscribe PIPs created through genetic engineering that pose no
greater risk than the PIPs created through conventional breeding that
have been exempt since 2001.
This rule is an effort to implement the policy goals articulated by
multiple administrations to improve, clarify, and streamline
regulations of biotechnology, beginning with the White House Office of
Science and Technology Policy in a policy statement in 1986 on the
``Coordinated Framework for the Regulation of Biotechnology'' (51 FR
23302; June 26, 1986), the update to the Coordinated Framework in 2017
(Ref. 3), Executive Order 13874 (84 FR 27899, June 11, 2019) on
``Modernizing the

[[Page 34758]]

Regulatory Framework for Agricultural Biotechnology Products,'' and
more recently, Executive Order 14801 (87 FR 56849, September 12, 2022)
on ``Advancing Biotechnology and Biomanufacturing Innovation for a
Sustainable, Safe, and Secure American Bioeconomy.''

E. What are the estimated incremental impacts?

EPA has evaluated the potential incremental impacts of the proposed
exemptions in the document entitled ``Cost Analysis For the Final Rule
Exempting Certain Plant-Incorporated Protectants (PIPs) from
Registration'' (Ref. 4), which is available in the docket and is
briefly summarized here.
1. Benefits
This rule reduces the regulatory hurdle (primarily cost) of getting
certain PIPs to market. Accordingly, this rule is likely to 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 producing products designed for minor crops may not
support markets large enough to warrant fixed registration costs. These
entities may feel the most regulatory relief as a result of this rule.
Crop varieties modified for greater pest and disease resistance
could increase the diversity of options for pest and disease
management, which in turn, could provide environmental benefits and
lower exposure for workers who apply pesticides. Growers may also
benefit because they will have more tools available to combat pest
pressures.
The rule is estimated to reduce overall registration costs (fees
plus information and data requirement costs) to developers of ``PIPs
created through genetic engineering from a sexually compatible plant''
and ``loss-of-function PIPs.'' On a per-product basis, the cost savings
are estimated to range from $472,000-$886,000 using a 3% discount rate
on future maintenance fees. A range of cost savings is provided because
``loss-of-function PIPs'' have fewer data requirements than ``PIPs
created through genetic engineering from a sexually compatible plant''
and are not required to submit a request for EPA confirmation (thereby
avoiding an M009 PRIA fee). Therefore, the savings to developers for
``loss-of-function PIPs'' is higher.
On an annual basis, the Agency estimates that anywhere from one to
ten PIPs may be eligible for exemption. This upper and lower bound
estimate is provided because, while the number of PIPs eligible for
exemption is unknown, EPA has determined that it is likely to be
greater than one. This is an increase from the estimate provided in the
cost analysis for the proposed rule, which only included savings from
one PIP. Accordingly, EPA estimates the annual savings of this rule to
range from $472,000-$8,856,000 using a 3% discount rate on future
maintenance fees (the lower bound represents one PIP per year and the
upper bound represents ten PIPs per year will be eligible for
exemption).
Of the entities likely to develop the types of PIPs this rule
exempts, EPA currently estimates that approximately 80% are small
entities. These cost savings would be realized as EPA approval of new
active ingredients are sought. These exemptions are likely to remove a
potential barrier to market entry for small entities because the
monetary investment via Pesticide Registration Improvement Act (PRIA)
fees and information and data requirement costs are substantially
reduced from what would have been required under the registration
process (in the absence of this rulemaking).
2. Costs
The costs of the rule includes costs imposed on developers and
differences to societal welfare as a result of the rulemaking. The cost
imposed on developers of PIPs include the costs to:
<bullet> Meet the requirements of the eligibility determination
process per 40 CFR 174, subpart E;
<bullet> Maintain records related to the requirements of the
eligibility determination for five years starting from the effective
date of the exemption per 40 CFR 174.73; and
<bullet> Report any information regarding adverse effects on human
health and the environment alleged to be caused by the PIP be reported
to EPA per 40 CFR 174.71.
These costs are outlined in the cost analysis for the final rule.
In consideration of the benefits and costs of the rule, the net effect
is a cost savings to regulated entities. This is because the
requirements to meet the eligibility determination process are less
than what is required under registration. In the baseline, or no rule
scenario, developers must maintain records related to registration; in
the rule scenario, developers must similarly maintain records related
to the exemption and exemption eligibility determination process--the
net effect therefore of this requirement on developers is zero. In both
the baseline, or no rule scenario, and in the rule scenario, developers
are subject to the adverse effects reporting requirement--the net
effect therefore of this requirement on developers is also zero.
The costs of the rule also include differences to societal welfare
as a result of the rulemaking, which in this case would be any
increased risk to human health or the environment from the change in
regulatory oversight from the rule. There are little to no costs such
as these anticipated by the rule because the criteria for qualification
were chosen to minimize any such risks. EPA has concluded that adverse
effects due to aggregate exposure to residues of pesticidal substances
from ``PIPs created through genetic engineering from a sexually
compatible plant'' through the dietary, non-food oral, dermal and
inhalation routes are highly unlikely.

II. Summary of the Proposed Rule

In a proposed rule issued in October 2020 (Ref. 2), EPA proposed
to:
1. Exempt ``plant-incorporated protectants based on sexually
compatible plants created through biotechnology'' (40 CFR 174.26) from
the requirement of a tolerance under FFDCA and from certain
registration requirements under FIFRA, except for the following
requirements: a proposed requirement of recordkeeping (40 CFR 174.73),
a proposed eligibility determination process (40 CFR 174, subpart E),
and the existing adverse effects reporting requirement for exempt
plant-incorporated protectants (40 CFR 174.71);
2. Clarify the general qualifications for exemption for plant-
incorporated protectants at 40 CFR 174.21;
3. Clarify how the proposed exemption relates to the existing
exemption for plant-incorporated protectants derived from sexually
compatible plants at 40 CFR 174.25; and
4. Allow the existing inert ingredient exemption at 40 CFR 174.705
to include biotechnology.
Unit VI. of the proposed rule explained the proposed exemption for
``PIPs based on sexually compatible plants created through
biotechnology,'' detailed the rationale underlying that proposal, and
described associated definitions that were proposed for codification or
amendment (85 FR 64308) (Ref. 2), and also described the two primary
considerations that EPA believed together would 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 the expression profile).
Also described were the details of the proposed eligibility
determination process, and a proposed recordkeeping requirement for

[[Page 34759]]

exempted PIPs listed under 40 CFR 174.21(d).
In addition, EPA proposed edits to 40 CFR 174.21 to clarify the
applicability of this framework to other PIP exemptions and EPA
proposed 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.'' EPA also proposed to allow the
existing inert ingredient exemption at 40 CFR 174.705 to include inert
ingredients created using biotechnology so long as they still meet the
existing criteria.

III. Summary of the Final Rule

In this action, EPA is finalizing the following:
1. An exemption for a category of ``PIPs created through genetic
engineering from a sexually compatible plant;''
2. An exemption for a category of ``loss-of-function PIPs;''
3. An exemption eligibility determination process for certain
exempted PIPs, including exemption specific information required for
submission to support the exemption;
4. Recordkeeping requirements for certain exempted PIPs;
5. Clarifications for the general qualifications for exemption at
40 CFR 174.21;
6. Clarifications on the relationship between the existing
exemptions for PIPs from sexually compatible plants and the newly
issued exemption for ``PIPs created through genetic engineering from a
sexually compatible plant;'' and
7. Allow the existing inert ingredient exemption at 40 CFR 174.705
to include genetic engineering.

A. Exemption for ``PIPs Created Through Genetic Engineering From a
Sexually Compatible Plant''

This rule exempts from all FIFRA requirements, except for the
adverse effects reporting requirements at 40 CFR 174.71, the
recordkeeping requirements at 40 CFR 174.73 (as specified in 40 CFR
174.21(d)), and the eligibility determination process outlined in
subpart E, ``PIPs created through genetic engineering from a sexually
compatible plant.'' In the proposed rule, PIPs described under 40 CFR
174.26 were termed ``PIPs based on sexually compatible plants created
through biotechnology.'' In this final rule, EPA has updated the name
of the PIPs described under 40 CFR 174.26 to be ``PIPs created through
genetic engineering from a sexually compatible plant'' based on public
comment, as discussed in Unit IV.A.3.
1. Associated Definitions
The language describing the exemption appears in 40 CFR 174.26.
Pertinent definitions associated with the exemption are found in 40 CFR
174.3 and include:
``Gene'' and other grammatical variants such as ``genic,'' means a
unit of heritable genetic material that is comprised of the genetic
material necessary for the production of a substance.
The definition for ``gene'' was revised from the proposal to remove
the word ``functional'' before the phrase ``unit of heritable genetic
material that is comprised of the genetic material necessary for the
production of a substance.'' EPA made this change because loss-of-
function traits are created by targeting a gene underlying an unwanted
trait by reducing or removing the gene's function. While the gene may
no longer be functional, structurally it is still a gene. Although this
is commonly understood in the scientific community, removing the word
``functional'' from the definition may reduce confusion over the
relationship between the definition of ``gene'' and ``loss-of-function
PIPs.'' Therefore, for the reasons outlined, EPA removed the word
``functional'' from the definition of ``gene.'' As discussed in Unit
V.A. of the proposal, the two genic regions relevant to the exemptions
under 40 CFR 174.26 are the coding and regulatory regions. These
regions are delineated through use of the phrase ``genetic material
necessary for the production,'' which as defined under 40 CFR 174.3
means both ``genetic material that encodes a substance or leads to the
production of a substance; and regulatory regions. It does not include
noncoding nonexpressed nucleotide sequences.'' ``Noncoding,
nonexpressed nucleotide sequences'' is also defined under 40 CFR 174.3
and includes examples such as linkers, adapters, homopolymers, and
sequences of restriction enzyme recognition sites (further discussed in
the context of these exemptions in Unit IV.B.1.).
``Genetic engineering'' means the modification of the genome of an
organism using recombinant, synthesized, or amplified nucleic acids or
other techniques excluded from the definition of conventional breeding.
``Genome'' is a defined term in 40 CFR 174.3 which means ``the sum of
the heritable genetic material in the plant, including genetic material
in the nucleus and organelles.'' EPA believes the use of the defined
word ``genome'' in the ``genetic engineering'' definition would capture
genetic engineering edits resulting in modifications to the proteome or
transcriptome that are stably heritable.
As discussed in Unit IV.A.2., EPA received a comment suggesting a
definition for ``biotechnology.'' However, for consistency across the
Coordinated Framework, the Agency chose to instead define ``genetic
engineering.'' EPA used the two phrases synonymously in its proposed
rule and therefore does not consider the change from ``biotechnology''
to ``genetic engineering'' to be substantive. For additional discussion
on maintaining consistency across the Coordinated Framework for
exemptions of products derived from genetic engineering, see Unit
III.H.: ``Alignment of the proposed rule with USDA's amendment to 7 CFR
340'' of the Response to Comments document in the docket associated
with this rulemaking.
``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 source plants that are sexually compatible with the recipient
plant. It does not include genes introduced through genetic engineering
from a source organism that is not sexually compatible with the source
plant.
The definition for ``native gene'' was revised from the proposal
based on public comment (Unit IV.A.1.). In the proposal, rather than
specifically excluding genes introduced through recombinant DNA or
similar techniques from a non-sexually compatible source organism, EPA
used the term ``never derived.'' EPA received comment suggesting that a
greater focus on excluding transgenes (i.e., genes introduced from non-
sexually compatible organisms) may aid in clarity and in turn reduce
uncertainty around genes originating through natural horizontal gene
transfer. EPA agreed with the suggestion and revised the definition to
state EPA's intent more explicitly as outlined in the proposed rule
(i.e., to exclude substances that conventional plant breeders do not
have experience with, such as a bacterial endotoxin not historically
found in a food plant). Screening practices and analyses performed as
part of the standard conventional breeding process serve to eliminate
plants that raise safety, quality or performance concerns. By limiting
exempt substances to those

[[Page 34760]]

in which conventional plant breeders have experience, EPA can have
confidence that these conventional plant breeding practices would still
be protective for substances of exempt PIPs.
In addition, EPA revised the definition in 40 CFR 174.3 for
``Sexually compatible.'' In the proposed definition EPA stated that ``a
viable zygote can be formed.'' This phrase was minorly revised to state
``plants must be capable of forming a viable zygote'' for clarity.
2. Exemption Criteria
PIPs that are created through genetic engineering but that could
have otherwise been created through conventional breeding are exempt
(40 CFR 174.26). The exemption criteria and associated definitions
circumscribe PIPs that are created through genetic engineering using
knowledge of nucleotide sequences in sexually compatible source plants
to re-create a native allele or other functional nucleotide sequence
identical to that which is found in a source plant. This would enable
the use of genetic engineering of clonally-propogated cultivars of
crops such as potato, grape, tree fruits, etc., to recreate pesticidal
alleles found in sexually compatible cultivars or crop wild relatives.
The exemption specifies criteria regarding the types of modifications
that are allowed to be made to ensure that the exempt PIPs are
characteristic in identity and in expression profile to those found in
conventionally bred plants, and are therefore substances with which
conventional plant breeders and conventional plant breeding screening
methods have experience.
The scope of ``PIPs created through genetic engineering from a
sexually compatible plant'' is delineated in 40 CFR 174.26(a). The
regulatory text identifies two overarching categories that specify what
will qualify as an exempt PIP pesticidal substance: (1) The insertion
of new genetic material and (2) The modification of existing genetic
material.
The provision at 40 CFR 174.26(a)(1) allows for insertions of new
genetic material into the recipient plant so long as the genetic
material is a native gene that is found in the sexually compatible
plant population of that plant. This category requires that the entire
pesticidal substance (e.g., amino acid sequence for proteinaceous PIPs)
that is created from the native gene be identical to that produced in
the source plant. 40 CFR 174.26(a)(1) was revised from the proposed
text to include a criterion related to inserted regulatory regions. 40
CFR 174.26(a)(1) now requires that any regulatory regions inserted as
part of the native gene be identical to the regulatory regions of the
native gene identified in the source plant. This change was made in
response to comments EPA received stating that the proposed criterion
related to expression profile (proposed 40 CFR 174.26(b)) was unclear
(Units IV.C.2. and IV.E.4.b.). In response to these comments, EPA
instead now provides specific criteria at codified 174.26(a)(1) related
to the types of modifications that may impact expression. EPA is aware
that intronic regions of genes may exhibit regulatory functions, but
EPA does not expect that all introns necessarily need to be inserted as
part of a native gene. Therefore, when describing the criterion related
to identical sequences in the regulatory regions, EPA used the phrase
``regulatory regions inserted as part of the native gene,'' to specify
that the criterion only applies to those regulatory regions that are
ultimately inserted as part of the native gene (i.e., it is not
required that all regulatory regions be inserted, but those that are
inserted must meet the criterion).
The final text in 40 CFR 174.26(a)(1) was revised from what was in
the proposed text to remove the clause ``into a non-genic location'' in
the phrase ``A native gene is engineered into a non-genic location of
the recipient plant genome [. . .].'' In the proposal, EPA stated that
this phrase was intended to preclude the insertion of the native gene
into an existing gene to prevent the production of a novel substance
(e.g., a partial or modified substance) by the existing gene. However,
upon further evaluation of this clause, prompted by public comment
(Response to Comments document Unit III.A.3.), EPA determined that this
restriction is not necessary as any novel substance that would be
produced as a result of a fusion with the inserted PIP gene (i.e.,
through the creation of a novel open reading frame), would not meet the
exemption under 40 CFR 174.26.
The provision at 40 CFR 174.26(a)(2) describes permissible
modifications to the existing genetic material in the recipient plant.
40 CFR 174.26(a)(2) allows for modifications of the existing native
gene to match corresponding polymorphic sequence(s) in a native allele
of that gene using a single source plant as a template. Polymorphisms
are variants of a gene sequence that are shared between native alleles.
These genetic variations may be composed of single nucleotides (i.e.,
Single nucleotide polymorphisms (SNPs)) or larger DNA segments and they
are found at the same locus within the genetic sequence of two or more
native alleles. In some cases, enhanced pesticidal properties of a gene
product can be attributed to one or more of these genetic variations
within a native gene (Refs. 5, 6). The final rule (see 40 CFR
174.26(a)(2)) allows developers to utilize their knowledge of specific
polymorphisms in regulatory and coding regions of native alleles to
make changes to the native gene in their recipient plant. The phrase
``using a single source plant as a template'' in the provision limits
the number of source plants for the polymorphic sequences to one. For
example, it is not permissible to modify the polymorphic sequence of a
native gene (in the recipient plant) to match a polymorphic sequence
found in the native allele of a source plant and also modify a second
polymorphic sequence in the native gene to match a sequence found in
the native allele of a different source plant. This requirement is
because EPA believes that increasing the amount of plants used as
source plants for a single PIP may also lead to an increase in the
likelihood that the substance is altered to something that plant
breeders may not have experience. The second part of the phrase ``as a
template'' indicates that the polymorphism that is engineered into the
recipient plant must be identical in sequence to that which is found in
the native allele of the source plant.
The final rule (see 40 CFR 174.26(a)(2)) differs from what was
proposed at 40 CFR 174.26(a)(2)(ii) in that EPA previously proposed to
require that modifications resulting in a native allele produce a
pesticidal substance identical to that produced in the source plant.
The exemption category at 40 CFR 174.26(a)(2) is promulgated in
response to comments received indicating that the proposed exemption
categories were too narrow in that they do not capture the full extent
of genetic variation that can occur in plants (Unit IV.C.1.). While the
final text in 40 CFR 174.26(a)(2) does not require the entire substance
to be identical to a substance found in the sexually compatible
population of the recipient plant, it does require the individual
polymorphism(s) to have been identified. By requiring the polymorphic
sequences to be identical, this new exemption category allows the
Agency to capture more of the possible genetic variation that can occur
in plants, while staying within the bounds of what could have been
achieved through conventional breeding and what was proposed.
EPA acknowledges that the genetic variation that is observed in
plants has the potential to be greater than what is captured at 40 CFR
174.26(a). Therefore, the Agency intends to revisit the

[[Page 34761]]

question of capturing a broader range of genetic variation under 40 CFR
174.26 in the future; a new rulemaking process that would be initiated
by the Agency if, for example, new scientific information becomes
available or if prompted by an interested party through an Agency
inquiry, e.g., based on a specific PIP product. Importantly, any new
categories of exempt PIPs that would be added to 40 CFR 174.26 through
this process in the future: (1) Would be required to fall within the
previously defined scope of exempt PIPs, i.e., those that can be
created through conventional breeding; (2) Would be subject to
recordkeeping requirements and documentation for exemption (Unit
III.D.); and (3) Would at least initially be subject to the EPA
confirmation process (Unit III.C.3.). By adhering to these
requirements, EPA can ensure that any future categories of PIPs created
through genetic engineering from sexually compatible plants will remain
within the scientific scope that was presented in the proposal, and
that underlies the current exemptions at 40 CFR 174.26, and that these
categories would remain subject to the procedural guard rails set in
place by the eligibility determination process.
The proposed regulatory text included additional categories that
are not being finalized under 40 CFR 174.26. To increase clarity, the
category encompassing ``loss-of-function PIPs'' that was proposed at 40
CFR 174.26(a)(2)(iv) has been removed and a new, stand alone exemption
for ``loss-of-function PIPs'' at 40 CFR 174.27 was created in its place
(Unit III.B.). Proposed 40 CFR 174.26(a)(2)(i) allowed for regulatory
region modifications so long as the pesticidal substance remained
unchanged, but relied on proposed 174.26(b) to specify the bounds of
the expression profile. However, EPA received public comment stating
that the criterion related to expression profile at proposed 40 CFR
174.26(b) was unclear (Units IV.C.2. and IV.E.4.b.). In response to
these comments, 40 CFR 174.26(a)(2) now includes a criterion related to
inserted regulatory region modifications (i.e., must match
corresponding polymorphic sequences in a native allele), therefore
making proposed 40 CFR 174.26(a)(2)(i) redundant. Because proposed 40
CFR 174.26(a)(2)(i) was removed, proposed 40 CFR 174.26(a)(2)(iii) was
also removed as it was dependent on proposed 40 CFR 174.26(a)(2)(i).
Proposed 40 CFR 174.26(a)(2)(ii) is effectively a subset of what is
possible under codified 40 CFR 174.26(a)(2), and is therefore not
finalized. Finally, proposed 40 CFR 174.26(b) previously specified
expression profile bounds, but due to public comment, EPA now includes
specific criteria related to allowable modifications that could impact
expression in the subsections of 40 CFR 174.26(a), thereby making
proposed 40 CFR 174.26(b) unnecessary.
EPA does not believe that the removal of the proposed categories
from the final regulatory text at 40 CFR 174.26 reduces the scope of
PIPs exempted through this rulemaking since proposed 40 CFR
174.26(a)(2)(iv) is now being finalized as 40 CFR 174.27, proposed 40
CFR 174.26(a)(2)(ii) represents a subset of what can be accomplished
under codified 40 CFR 174.26(a)(2), and since proposed 40 CFR
174.26(a)(2)(i) and proposed 40 CFR 174.26(a)(2)(iii) were deemed
redundant.
The final text of 40 CFR 174.26(b) states that the requirements in
40 CFR 174.21(d) (i.e., the recordkeeping requirements and the
eligibility determination procedures) must be met in order for the
exemption to apply. This is minorly revised from the proposed
regulatory text which stated that the ``exemption does not apply until
the requirements in subpart E of this part have been met;'' however,
the recordkeeping requirements are located in subpart D, and therefore
citing to 40 CFR 174.21(d) is a more streamlined citation.
In addition to exempting the active ingredient of PIPs created
through genetic engineering from sexually compatible plants from the
requirements of FIFRA, EPA is also finalizing the exemption for
residues of these substances from the requirement of a tolerance under
the FFDCA at 40 CFR 174.541. The exemption criteria are identical to
those at 40 CFR 174.26 except that in order to be exempted from the
requirements of a tolerance, residues of the pesticidal substance must
also not be present at levels that are injurious or deleterious to
human health (40 CFR 174.541(b)). The ``injurious or deleterious''
language is included in this rule to align with the same criteria found
in 40 CFR 174.508 for residues of PIPs in sexually compatible plants.
(<a href="https://www.govinfo.gov/content/pkg/FR-2001-07-19/pdf/01-17983.pdf">https://www.govinfo.gov/content/pkg/FR-2001-07-19/pdf/01-17983.pdf</a>).
This language was adopted in the 2001 rule in response to comments
about the potential for naturally occurring compounds to be present in
foods at hazardous levels and to be more consistent with FDA policy and
the standard applied to evaluate adulterated food: ``food shall be
deemed to be adulterated . . . if it bears or contains any poisonous or
deleterious substance which may render it injurious to health. . . .''
21 U.S.C. 342(a)(1). The purpose of this language was to allow
expeditious removal of the offending food from the market if injurious
or deleterious levels of a substance were present in food. All of the
criteria in 174.541 must be met: the conditions in paragraph (a) limit
the identity of the substance, the condition in paragraph (b) set
limits on the level of expression in the plant, and the conditions in
paragraph (c) ensure the application of the exemption is properly
documented. Regarding the condition in paragraph (b), one example of
how this might work is if a source plant were to produce a pesticidal
substance at levels that are injurious or deleterious to human health,
that PIP would not qualify for exemption if the level of expression in
the recipient plant matched the injurious or deleterious levels seen in
the source plant. It is also important to note that EPA considers
multiple native gene insertions of the same gene to be one PIP (further
discussed in Unit IV.B.2.), so the criterion related to safe expression
levels in food plants (40 CFR 174.541(b)) would apply to the overall
expression level from all inserted gene copies. Developers modifying or
inserting genes that produce substances with sequence homology to known
mammalian toxins, toxicants, or allergens should ensure that the levels
of pesticidal substances are within the ranges of levels generally seen
in plant varieties currently on the market and known to produce food
safe for consumption (i.e., ensure that their levels are not injurious
or deleterious to human health). Such substances expressed above these
levels would likely trigger additional review during the EPA
confirmation and may not fit the exemption criteria.
Additionally, 40 CFR 174.541(c) has been edited to more
specifically cite to 40 CFR 174.90, rather than the entire subpart E.
This citation is different from that found at 40 CFR 174.26(b) due to a
difference in statutes. Specifically, 40 CFR 174.26(b) cites to 40 CFR
174.21(d), which describes the general qualifications for exemption
under FIFRA, whereas 40 CFR 174.541 is an exemption from the
requirement of a tolerance under FFDCA and therefore would not cite to
exemption qualifications under FIFRA. Because the regulatory text at 40
CFR 174.26 for the active ingredient of ``PIPs created through genetic
engineering from a sexually compatible plant'' and the corresponding
tolerance exemption for residues of these active ingredients at 40 CFR
174.541 are identical (except for

[[Page 34762]]

the two clauses discussed in this paragraph) all other changes to the
regulatory text that were discussed for 40 CFR 174.26 in this Unit were
also applied to 40 CFR 174.541.

B. Exemption of ``Loss-of-Function PIPs''

This rule exempts ``loss-of-function PIPs'' from all FIFRA
requirements, except for the adverse effects reporting requirements at
40 CFR 174.71, the recordkeeping requirements at 174.73 (as specified
in 40 CFR 174.21(d)), and the eligibility determination process
outlined in subpart E. The exempt PIPs represent a subcategory of PIPs
described in the proposed rule (Ref. 2). In this final rule, EPA is
creating a separate exemption for ``loss-of-function PIPs,'' which
allows the Agency to create criteria specific to these types of PIPs
and an accompanying definition for increased clarity. EPA made this
change in response to comments that indicated the need for greater
clarity and the broadening of the exemption text related to ``loss-of-
function PIPs'' regarding the identicality of the substance (Unit
IV.D.2.). As discussed in Unit IV.D.1., the modified genetic material
of a ``loss-of-function PIP'' constitutes both the pesticidal substance
and the active ingredient. The language describing the exemption
appears in 40 CFR 174.27.
1. Associated Definitions
Because EPA is creating a separate exemption for ``loss-of-function
PIPs,'' EPA is also codifying a definition associated with the
exemption in 40 CFR 174.3:
``Loss-of-function plant-incorporated protectant'' means a plant-
incorporated protectant in which the genetic material of a native gene
is modified to result in a pesticidal effect through the reduction or
elimination of the activity of that gene. For purposes of loss-of-
function plant-incorporated protectants, the active ingredient and
pesticidal substance are one and the same and are defined as the
genetic material that has been modified to create the pesticidal trait
(i.e., modification of the sequence of nucleic acids). Loss-of-function
plant-incorporated protectants do not include instances where the
reduction or elimination of the activity of the modified native gene
results in the intentional increase of activity of another pesticidal
gene.
The first sentence of this definition specifies that for a PIP to
be considered a ``loss-of-function PIP,'' a pesticidal effect must be
created through the genetic modification of a native gene, which then
leads to the reduction or elimination of the activity of that native
gene. The second sentence defines the regulated substance (see Unit
IV.D.1. for additional discussion). The third sentence explicitly
excludes the scenario in which a modification of a native gene not only
leads to the reduction in the expression of that native gene, but
additionally leads to an increase of activity of another, ``secondary''
gene, with that ``secondary'' gene then conferring the pesticidal
activity (e.g., the altered gene encodes for a repressor whose absence
does not itself lead to a pesticidal effect but rather the increased
expression of a second gene that encodes a pesticidal substance). This
definition is consistent with the description of ``loss-of-function
PIPs'' in Unit VII.E. of the proposed rule (Ref. 2).
2. Exemption Criteria
Both the definition at 40 CFR 174.3 and the exemption text at 40
CFR 174.27 focus on the loss-of-function trait that results from the
modification (i.e., the reduction or elimination of the activity of the
modified gene), and do not include requirements related to source
plants or limit the location within the gene to which modifications are
allowed to be made (i.e., regulatory region or coding region).
Specifically, 40 CFR 174.27 specifies two requirements, the first of
which at 40 CFR 174.27(a) is almost identical in language to the loss-
of-function definition and specifies that the genetic modification must
result in a ``loss-of-function PIP.'' The type of genetic modification
to a native gene that results in the loss of activity of that gene is
not relevant so long as a ``loss-of-function PIP'' is the result of
that modification. As with the exemptions at 40 CFR 174.26, the second
requirement at 40 CFR 174.27(b) specifies that the exemption for
``loss-of-function PIPs'' only goes into effect after the requirements
for the eligibility determination in 40 CFR 174.21(d) have been met.
In the proposed rule, ``loss-of-function PIPs'' were a subcategory
under 40 CFR 174.26 (specifically proposed 40 CFR 174.26(a)(2)(iv)),
and they were held to the same ``identical substance'' criterion as
other PIPs described in proposed 40 CFR 174.26. While the EPA does not
find that it can make an a priori safety determination under FIFRA and
FFDCA for non-identical pesticidal substances now exempted under 40 CFR
174.26 (Unit IV.C.1.), it finds that no such restriction is warranted
for ``loss-of-function PIPs'' under 40 CFR 174.27 (Unit IV.D.2.). This
conclusion is based on characteristics of ``loss-of-function PIPs,''
the common occurrence of pesticidal traits resulting from the loss-of-
function of endogenous genes in conventional breeding, and the
biological processes that all proteins undergo within plants (Unit
IV.D.2.).
The absence of function is a hallmark of ``loss-of-function PIPs,''
e.g., loss of the activity of a native gene that would otherwise
facilitate the susceptibility of that plant to a pathogen. Importantly,
the criteria and definition state that for a ``loss-of-function PIP,''
the native gene modification results in a pesticidal effect from the
reduction or elimination of the activity of that gene. This indicates a
direct cause-and-effect relationship between the reduction in the
expression of a specific native gene and a pesticidal effect. This
direct cause-and-effect relationship also means that not all
modifications that lead to a loss-of-function of a gene and that result
in a pesticidal effect are considered ``loss-of-function PIPs.'' For
example, this scenario may occur if a modification of a native gene not
only leads to the reduction in the expression of that native gene, but
also to an increase of the activity of another, ``secondary'' gene,
with that ``secondary'' gene then conferring the pesticidal activity
(e.g., the altered gene encodes for a repressor protein whose absence
does not itself lead to a pesticidal trait but rather the increased
expression of a second gene that encodes a pesticidal substance).
Because in this instance there is no direct cause-and-effect
relationship between the reduction of the expression of the modified
native gene and the pesticidal effect, that gene modification and
resulting ``secondary'' activity would not be considered a ``loss-of-
function PIP'' under 40 CFR 174.27. Further, in the scenario described,
that gene modification and resulting ``secondary'' activity would only
be exempt under the new regulations if it meets the criteria outlined
in 40 CFR 174.26 and from FFDCA if the residues meet the requirements
under 40 CFR 174.541. For ``loss-of-function PIPs,'' EPA clearly
indicates the requirement for this direct cause-and-effect relationship
of native gene modification and the pesticidal effect in the second
sentence of the ``loss-of-function PIP'' definition.

C. Eligibility Determination Process

The Agency is finalizing subpart E, which includes provisions
describing the eligibility determination process and documentation
required for an exemption of certain PIPs. Specifically, in order for a
PIP listed under 40 CFR 174.21(d) to be eligible for exemption, an
exemption eligibility determination must be completed prior to engaging
in

[[Page 34763]]

FIFRA-regulated activities. EPA agrees with commenters arguing that
requiring an eligibility determination will provide additional clarity
to developers of PIP products under certain circumstances and increase
transparency and public trust in products containing these PIPs (Unit
IV.E.1.). The primary difference between the proposal and the final
rule is the restriction of the self-determination option to only
certain PIPs exempted by this rulemaking. In the proposal, all exempted
PIPs had the option of self-determination. However, in the final rule,
only developers of ``loss-of-function PIPs'' (40 CFR 174.27) currently
have the option to self-determine whether the exemption criteria are
met. To that end, modifications were made to proposed 40 CFR 174.90, 40
CFR 174.91, and 40 CFR 174.93 (Units III.C.1., C.2., and C.3.). In
addition, the titles of these three subsections were minorly revised
from the proposal for clarity.
Given the straightforward criteria describing ``loss-of-function
PIPs'' (i.e., a focus on function rather than source plant or
underlying sequence), EPA believes it is appropriate for ``loss-of-
function PIPs'' to be eligible for the self-determination option as it
is unlikely for a developer to accidentally misdetermine exemption
eligibility of these PIPs. Additionally, the mode of action of ``loss-
of-function PIPs'' (i.e., reduction or elimination of an endogenous
gene) is fundamentally different from ``PIPs created through genetic
engineering from a sexually compatible plant'' (e.g., intentional
production of a pesticidal protein), and as such, further lends itself
to the availability of a self-determination option. Although ``PIPs
created through genetic engineering from a sexually compatible plant''
are not currently eligible for the self-determination option, EPA
intends to reconsider this in future rulemakings.
A separate determination of eligibility of exemption for purposes
of the FFDCA exemption for a PIP proposed for use in food or feed is
required only if that determination has not already been submitted
under FIFRA. This is because the exemption eligibility determination
process described in 40 CFR 174.21 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.
A scenario in which a developer will need an exemption eligibility
determination specifically for the purposes of FFDCA, but not FIFRA,
would be when residues of a PIP are 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). Additional discussion on the types of activities that
warrant an eligibility determination can be found in Unit IV.E.5.
1. Determining Eligibility
Regarding the process of an exemption eligibility determination
under 40 CFR 174.90, this provision states at 40 CFR 174.90(a) that,
depending on the applicable exemption, developers have two, non-
mutually exclusive options to notify EPA that their PIP meets the
exemption criteria: (1) Seek EPA confirmation that a PIP meets the
exemption criteria, and (2) Submit a self-determination letter that a
PIP meets the exemption criteria. For PIPs subject to the eligibility
determination process, an EPA confirmation is mandatory unless the PIP
is listed at 40 CFR 174.90(a)(2) as eligible for the self-determination
option. For PIPs eligible for the self-determination option, an EPA
confirmation can be sought instead of, in conjunction with, or
subsequent to the submission of the self-determination letter.
As stated in Unit III.C., only ``loss-of-function PIPs'' under 40
CFR 174.27 are currently eligible for the self-determination option and
no ``PIPs created through genetic engineering from a sexually
compatible plant'' under 40 CFR 174.26 are currently listed under 40
CFR 174.90(a)(2). Therefore all ``PIPs created through genetic
engineering from a sexually compatible plant'' are required to undergo
an EPA confirmation process. However, EPA intends to reconsider this in
future rulemakings, and as such, EPA has codified text at 40 CFR
174.90(a)(2)(ii) to accommodate this possibility.
The provision explains at 40 CFR 174.90(b) that submissions for a
request for EPA confirmation or a letter of self-determination must be
made electronically, which means that they may not be made by mailing
the information in physical form to the Agency (e.g., sending hard
copies or data storage devices such as DVD). Specifically, electronic
submissions are required to be made through EPA's electronic submission
portal which receives legally acceptable data in a secure manner (see
Unit IV.E.6. for additional discussion). That system is used, amongst
other things, for submission of pesticide registration applications,
and will now additionally accommodate the eligibility determination
processes associated with the PIPs identified in this rule. The
electronic submission process will accommodate submissions when the
final rule is effective, specifically, 60 days after the date of
publication in the Federal Register. This electronic submission process
differs from the proposal, which included instructions on how to submit
a self-determination or confirmation request via physical mail.
Guidance for electronic submission can be found in Pesticide
Registration Notice 2011-3 (Ref. 7) or any subsequent revision or
replacement. The provision at 40 CFR 174.90(c) also explains the
procedures that must be followed to claim information submitted as
confidential.
For PIPs that are eligible for both the self-determination and EPA
confirmation options, the provision at 40 CFR 174.90(d) 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 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. 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.
The provision also includes text at 40 CFR 174.90(e) stating that
EPA reserves the right to assess or revisit at any time after EPA
issues a confirmation of eligibility or the letter of self-
determination is submitted, whether a PIP meets, or has met, the
criteria for exemption. If EPA finds or has reason to believe that, at
any time before or during this review of eligibility for exemption, the
product is non-compliant with FIFRA or presents an adverse risk to
human health, the environment, or program integrity, the Agency can
take immediate steps--including enforcement--to address that non-
compliance or to protect against those adverse risks. This is revised
from the proposed text to make explicitly clear

[[Page 34764]]

that although EPA will generally notify the submitter in writing of
EPA's intention to initiate a review of eligibility for exemption, EPA
may take such action without first informing the submitter of an
eligibility review if the situation warrants.
As exempt PIPs are still subject to 40 CFR 174.71, upon learning of
any adverse effects (i.e., that a person or nontarget organism
allegedly suffered an adverse effect due to exposure to a PIP), 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;
FRL-6057-7) (Ref. 8), 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). Additional discussion regarding EPA enforcement
can be found in Unit III.D.7. of the Response to Comments document
found in the docket associated with this rulemaking.
The provision outlines instances at 40 CFR 174.90(f) in which an
exemption determination for a PIP can be extended to other PIPs. A
determination that a PIP meets the exemption criteria would be required
for each modified gene and plant species combination (e.g., PIP ``A''
in corn and PIP ``A'' in tomato would each require their own
determination). 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. In order to extend the exemption for a PIP,
the developer would need to comply with the provisions outlined in 40
CFR 174.21(d) for the first modification in that plant species and that
exemption can then be extended in one of two ways. If the exempted PIP
is moved through conventional breeding, the exemption is extended to
the subsequent PIP. To extend the exemption of the PIP to subsequent
genetic engineering events, the PIP must meet exemption-specific
criteria outlined by EPA. The paragraph in this text was edited from
the proposed rule to explicitly state that movement of exempt PIPs
through conventional breeding also results in the extension of
exemption status of that PIP and to clarify that the subparagraphs 40
CFR 174.90(f)(1) and 40 CFR 174.90(f)(2) are specific to genetic
engineering.
For a ``PIP created through genetic engineering from a sexually
compatible plant,'' the exemption extends to subsequent engineering of
that PIP by the submitter into other varieties of that same plant
species as long as the subsequent PIP produces the identical substance
as in the exempt PIP and no new modifications were made to the
regulatory regions. For example, if a developer first 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. For a ``loss-of-function PIP,'' an exemption
extends to subsequent engineering of that PIP by the submitter into
other varieties of that same plant species as long as the submitter is
targeting the same native gene to create the ``loss-of-function PIP.''
This text is modified from the proposal based on a comment arguing that
the criteria should focus on the trait phenotype and function (Unit
IV.E.2.). As described in Unit IV.D.2., ``loss-of-function PIPs'' now
have their own exemption category with a focus on function rather than
substance identity, and as such, the extension of the exemption for
``loss-of-function PIPs'' is now described in 40 CFR 174.90(f)(2) with
a similar focus.
Finally, EPA has added a new paragraph (g) to 40 CFR 174.90, which
explains that a duplicative eligibility submission is not required for
purposes of 40 CFR 174.541(c), if it is already being submitted for
purposes of 40 CFR 174.21(d). This provision was not in the proposal,
but was added for clarification based on public comment (Unit IV.E.5.).
Related to these comments, EPA is confirming that the Agency is
requiring a separate eligibility determination to be made through EPA's
electronic submission portal for residues of those PIPs under 40 CFR
174.541 that are imported into the United States and that are used for
food or feed if the developer has not already obtained an exemption
under 40 CFR 174.541. This submission includes an acknowledgement that
the developer is only submitting an exemption eligibility determination
for the purposes of FFDCA but not FIFRA, and therefore it is not
permissible for the PIP to be sold or distributed for pesticidal use
(e.g., PIP-containing seed or plant sold for planting) in the United
States. As discussed in the preamble of the proposed rule, a separate
submission of the eligibility determination 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.
2. Process for a ``Letter of Self-Determination'' for a PIP To Qualify
for an Exemption
This rule finalizes a new provision in subpart E, 40 CFR 174.91,
entitled ``Submitting a letter of self-determination'' The provision
describes the requirements and process of notifying EPA that the
developer has determined (or ``self-determined'') that a PIP qualifies
for exemption.
The provision at 40 CFR 174.91 explains that a developer must
submit the letter of self-determination prior to engaging in activities
that would be subject to FIFRA for the proposed PIP (e.g., distribution
and sale of the PIP at issue). As specified in 40 CFR 174.90(b), self-
determination letters must be submitted electronically. If a developer
does not have an EPA company number, they will be required to obtain
one in order to be able to submit a self-determination letter. Self-
determination letters will not be submitted under FIFRA section 33 and
will not be subject to application fees under the Pesticide
Registration Improvement Extension Act of 2022 (PRIA 5). The exemption
does not apply until EPA confirms receipt of the self-determination,
but since the submission of the self-determination letter will be made
electronically, the receipt confirmation by the Agency occurs
automatically upon submission and is considered equivalent to written
confirmation of receipt.
The provision at 40 CFR 174.91(b) includes information on the
required contents of the self-determination letter. This includes a
statement certifying the developer's determination of exemption
eligibility, the identity of the recipient plant, a unique gene
identifier for the native gene, the trait type (e.g., insect
resistance), and information on the applicable exemption. The gene
identifier is for the native gene (not necessarily the exact sequence
of the PIP) and must be from databases curated by the National Center
for Biotechnology Information (NCBI), which is part of the National
Library of Medicine of the National Institutes of Health (NLM) at the
National Institutes of Health (NIH). These databases are available free
of charge to scientists globally and will ensure availability of the
gene information to EPA and a means to standardize that information.
Based on public comment (Unit IV.E.3.), this provision was clarified to
explicitly request the identity of the recipient plant, an identifier
for the native gene,

[[Page 34765]]

and the trait type, rather than the name of the PIP, which may or may
not have included such information. Additionally, rather than listing
PIP categories eligible for self-determination under 40 CFR
174.91(b)(2) as had been proposed, the provision now cites to the list
under 40 CFR 174.90(a)(2). Lastly, EPA streamlined the regulatory text
by merging 40 CFR 174.91(b)(4) with 40 CFR 174.91(b)(3) and removing
the text of the certification statement from the provisions. The
statement is captured in the electronic submission portal and thus
listing it in the regulatory text was deemed redundant.
EPA notes that the developer is responsible at all times for
ensuring the self-determination is accurate and if at any time EPA
determines that a self-determination was fraudulently or incorrectly
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 will notify FDA of this new information, and the Agencies
can take action to protect the environment and public health,
respectively. This includes the possibility of enforcement under FIFRA
or FFDCA.
3. Process To Obtain an EPA Confirmation That a PIP Qualifies for
Exemption
This rule establishes a new provision in subpart E entitled
``Requesting EPA confirmation'' (40 CFR 174.93), which describes the
process through which a developer may seek confirmation from EPA as to
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 created through
genetic engineering from a sexually compatible plant'' is described in
40 CFR 174.95 and discussed in Unit III.C.4.a.
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 will 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. As discussed in Unit III.C.1., 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.
Requests for EPA confirmation are to be submitted using the
submission category (M009) and associated fee structure for a Non-FIFRA
Regulated Determination under FIFRA section 33 (PRIA). 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. Documentation for an Exemption
a. PIPs Created Through Genetic Engineering From Sexually Compatible
Plants
The rule finalizes the documentation needed for an exemption for
``PIPs created through genetic engineering from a sexually compatible
plant.'' There are four main information elements associated with the
required documentation, which capture the: (1) Biology of the plant;
(2) Description of how the trait was engineered into the plant; (3)
Molecular characterization of the PIP; and (4) Information on the
history of safe use for those PIPs that are either known mammalian
toxins or toxicants or that are from a source plant that is a wild
relative of the recipient plant. Collectively, this information allows
EPA to ensure that a PIP meets the exemption criteria at 40 CFR 174.26
and 40 CFR 174.541.
The first element (40 CFR 174.95(a)) requires information on the
biology of the plant and has two components: (1) 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 (2) Information to support that the
recipient plant and the source plant are sexually compatible. The
regulatory text regarding sexual compatibility was minorly revised from
proposed ``if the plant-incorporated protectant was derived from
another plant species'' to ``if the plant-incorporated protectant was
derived from a plant species other than the recipient plant species''
to more directly articulate that this information is only needed if the
source and recipient plant are taxonomically classified as belonging to
different plant species. As stated in the preamble of the proposed rule
(Unit VI.C.4.), to meet this requirement a developer may provide a
peer-reviewed literature rationale (e.g., breeding guides, journal
articles) instead of generating empirical data to demonstrate that the
two plant species are sexually compatible. Therefore, for clarity based
on public comment (Unit IV.E.4.a.), the regulatory text regarding
sexual compatibility was further modified to replace ``demonstrate''
with ``information to support.''
The second element (40 CFR 174.95(b)) captures information on the
pesticidal trait and how it was engineered into the plant. EPA
anticipates that this element can be addressed through a narrative
description of the intended pesticidal function of the PIP and
information on the techniques used to make the genetic modification in
the recipient plant (e.g., the molecular tools used, transformation
method). The text was revised from the proposal to also require
information on the steps that were taken to ensure that no engineering
components (i.e., PIP inert ingredients) are expected to remain in the
final plant product. Engineering components include, but are not
limited to, those associated with the genetic engineering of the plant
itself (e.g., Cas protein) and selectable markers that, in the early
steps of PIP development, aid in the selection of plant transformants
that contain the desired traits (e.g., herbicide resistant markers).
Unless the engineering components themselves meet the requirements at
40 CFR 174.705, they would not be exempt inert ingredients. Thus, by
requiring this information, EPA will be able to ensure that no
unapproved inert ingredients are expected to remain in the final plant
product. Similarly, based on public comment (Unit IV.A.2.), EPA has
also included a requirement that the developer describe the measures
taken to maximize the likelihood that the modification to the recipient
plant is limited to the intended modification, including ensuring off-
target mutations were minimized (e.g., through the use of in silico
techniques in guide RNA development). This could be information on the
specificity of the endonuclease in the recipient plant species and the
use of predictive in silico tools that can identify other potential
target sites. As discussed in the preamble of the proposed rule (Unit
V.A.), by using the definition of a ``gene'' the Agency restricts any
genetic modifications made through biotechnology that would fall under
the exemption to modifications to the gene itself. Thus, by requiring
this information, EPA can determine that this is true.
The third element (40 CFR 174.95(c)) requires information on the
molecular identity of the PIP. Specifically, EPA is requiring the
sequence of the PIP in the recipient plant and its comparator. This was
revised per public comment to clarify the required sequence
information, which is based on the

[[Page 34766]]

relevant comparator and the type of pesticidal substance (Unit
IV.E.4.a.). For example, for native gene insertions the comparator is
the sequence of the PIP in the source plant, whereas for native genes
that are modified to match corresponding polymorphic site(s), the
relevant comparators are the sequence of the PIP in the source plant,
the modified recipient plant, and the original native gene in the
unmodified recipient plant. What determines the type of sequence
information that must be provided is the molecular composition of the
pesticidal substance. Nucleic acid sequences must be provided for both
native gene insertions and for genes modified to match a corresponding
polymorphic site. In addition, if the pesticidal substance is
proteinaceous, an amino acid sequence must also be provided. In
addition to basic sequence information, if a native allele has been
modified according to 40 CFR 174.26(a)(2), then documentation is also
required that identifies the modified polymorphic sites within the
relevant sequences.
To provide more clarity in response to several comments that were
received on the proposal (Unit IV.E.4.b.), EPA has removed the
requirement to provide information on the expression profile for those
PIPs where the regulatory region has been modified. In the final rule,
EPA was able to remove the requirement to provide information on the
expression profile because the Agency now includes at 40 CFR 174.26(a)
specific criteria related to allowable modifications that could impact
expression, thereby restricting expression to what is found in the
sexually compatible plant population.
The fourth element (40 CFR 174.95(d)) captures the requirement from
proposed 40 CFR 174.95(b) for pesticidal substances that are known
allergens or mammalian toxins/toxicants. For these substances, a
description of how conventional breeding practices are being used to
ensure they do not exceed human dietary safety levels in the recipient
food plant must be provided. EPA revised this from the proposed text to
specify ``human dietary safety levels'' rather than ``safe levels'' for
clarity. EPA also added a clarifying parenthetical, ``ensure residues
of pesticidal substance are not present in food at levels that are
injurious or deleterious and are within the ranges of levels generally
seen in plant varieties currently on the market and/or known to produce
food safe for consumption,'' to further define what is meant by ``human
dietary safety levels.'' EPA is aware that the conventional breeding
process is generally comprised of three stages: trait mapping, trait
introgression, and field testing (Ref. 9). Through genetic engineering,
the second stage, trait introgression, can occur more quickly and more
precisely (i.e., insert only the trait of interest without linkage drag
of undesirable traits). However, trait mapping (requires knowledge of
plant genetics and biology, likely includes an understanding of any
naturally occuring plant toxins) and field testing (evaluates traits
related to agronomic parameters, consumer preferences, allergens/
toxins/nutrition) are expected to still occur under their normal
timeframes. The second component of this section is specific to those
PIPs that are from a source plant that is a wild relative, i.e., a non-
domesticated relative. 40 CFR 174.95(d)(2) is new and was added as a
result of comments that the Agency received on the proposed rule (Unit
IV.E.4.a.). For PIPs from wild relatives, a rationale as to why they do
not pose a hazard to humans or the environment must be submitted.
Several examples of the type of information that can be used to address
this requirement are provided in the regulatory text itself.
Information described under elements one through four will inform
whether the PIP meets criteria (a) and (b) of the FIFRA exemption and
criteria (a) and (b) of the FFDCA exemption for the requirement of a
tolerance for residues of PIPs.
b. Loss-of-Function PIPs
This rule also finalizes the documentation needed for an exemption
for ``loss-of-function PIPs.'' As discussed in Unit III.B., ``loss-of-
function PIPs'' have now been removed as a subcategory from 40 CFR
174.26 and an exemption specific to ``loss-of-function PIPs'' has been
created at 40 CFR 174.27. Consequently, establishment of documentation
requirements for this PIP category were necessary (40 CFR 174.96). As
the ``loss-of-function PIPs'' exemption is focused on phenotype rather
than specific underlying nucleic acid sequences, the documentation
associated with the exemption is similarly focused on the trait. To
this end, the identity of the modified plant (i.e., genus and species)
and a description of the pesticidal trait is required (40 CFR
174.96(a)). Along with the description of the pesticidal trait, a
description of how the trait was engineered is also required (40 CFR
174.96(b)). This includes a description of the steps that were taken to
ensure that no engineering components (e.g., Cas proteins) are expected
to remain in the plant and measures taken to maximize the likelihood
that the modification to the recipient plant is limited to the intended
modification, including ensuring off-target mutations were minimized
(e.g., through the use of in silico techniques in guide RNA
development). This information allows the EPA to ensure the criteria
for exemption are met (e.g., no non-exempt inert ingredients remain in
the final plant).

D. Recordkeeping Requirements for PIPs Exempt by This Rulemaking

At 40 CFR 174.73, subpart D, EPA is codifying a requirement under
FIFRA section 3(a) that any person who is required to submit
documentation for the eligibility determination of a PIP under 40 CFR
174.21(d), must maintain documentation of either the request for EPA
confirmation or the letter of self-determination (or both, if
applicable) along with all supporting documentation for the specific
exemption as specified in subpart E. These documents must be maintained
for five years starting with the effective date of the exemption. This
text is minorly revised from the proposed text for clarity.

E. Clarification of General Qualifications for Exemption

This rule finalizes edits to the ``General Qualifications for
Exemptions'' provisions at 40 CFR 174.21 to clarify the applicability
of this framework to other PIP exemptions. For paragraph (a), this
revision simply clarifies that this paragraph is specific to the active
ingredient of the PIP, rather than the PIP as a whole. This is because
the definition of a PIP under 40 CFR 174.3 also includes ``any inert
ingredient,'' and inert ingredients are not exempt under subpart B but
rather subpart X. In the proposed rule, EPA used the phrase
``pesticidal substance'' in its proposed revisions to 40 CFR 174.21(a),
while in the final rule, the Agency uses the phrase ``active
ingredient.'' The active ingredient definition at 40 CFR 174.3 includes
both the genetic material and any pesticidal substance produced (e.g.,
a protein). Exemption criteria related to both the genetic material and
the pesticidal substance are specified in exemptions under subpart B.
As such, the titles for the exemptions in subpart B are similarly
codified to specify ``active ingredient.''
Paragraph (b) is revised to refer to subpart W, rather than the
specific sections and is also revised to specify that the tolerance
exemptions apply to the residues of the active ingredient, rather than
the PIP as a whole for the same rationale as outlined for the edit

[[Page 34767]]

to 40 CFR 174.21(a). It should be noted that although paragraph (b)
specifies active ingredient, there are separate tolerance exemptions
specific to both the residues of the pesticidal substance (e.g., 40 CFR
174.541) and the genetic material (i.e., 40 CFR 174.507) under subpart
W.
Paragraph (c) is revised to refer to subpart X, rather than the
specific section of 40 CFR 174.705.
EPA is also finalizing a new paragraph (d) in section 40 CFR 174.21
to accommodate the exemption eligibility determination process (Unit
III.C.) and the recordkeeping requirements (Unit III.D.). This
paragraph specifies that for PIPs listed in the subsequent
subparagraphs, the exemption is contingent upon compliance with
recordkeeping requirements and the eligibility determination process.
The addition of paragraph (d) does not impact the exemption under
section 40 CFR 174.25 for PIPs from sexually compatible plants through
conventional breeding as this exemption is not identified in paragraph
(d). EPA made two revisions to 40 CFR 174.21(d) since proposal of the
rule. First, the Agency added a clarification that 40 CFR 174.73 is
implemented ``per sections 8 and 9 of FIFRA (U.S.C. 136f and 136g).''
Those sections of FIFRA specify EPA's inspection authority and impose
recordkeeping requirements and they still apply to the PIPs exempted
under this rule. Secondly, ``[Reserved]'' was moved to 40 CFR
174.21(d)(3) and replaced in its proposed position at 40 CFR
174.21(d)(2) with ``Loss-of-function plant-incorporated protectants,''
to accommodate the newly created exemption for these types of PIPs at
40 CFR 174.27.

F. Clarification of the Exemption for Sexually Compatible PIPs

The rule finalizes clarifications of the relationship between the
newly exempted ``PIPs created through genetic engineering from a
sexually compatible plant'' and ``loss-of-function PIPs'' with the
previous FIFRA and FFDCA exemptions related to conventionally bred
plants (i.e., 40 CFR 174.25 and 40 CFR 174.508). EPA inserted ``created
through conventional breeding'' at the end of each section title, and
inserted an additional criterion into 40 CFR 174.25 and 40 CFR 174.508,
stating that the genetic material is transferred only through
conventional breeding. The exemptions at 40 CFR 174.25 and 40 CFR
174.508 have always meant ``only through conventional breeding,'' but
this clarification is necessary given the amended definition for
``sexually compatible.''

G. Inert Ingredient Exemption Includes Genetic Engineering

While EPA revised 40 CFR 174.25 and 40 CFR 174.508 to include a
criterion specifying that the genetic material is transferred from the
source plant to the recipient plant only through conventional breeding,
a parallel revision was not proposed or finalized at 40 CFR 174.705.
The amended definition for ``sexually compatible'' states that
``plants must be capable of forming a viable zygote through the union
of two gametes through conventional breeding'' (emphasis added), which
differs from the definition promulgated in 2001 that specified that ``a
viable zygote is formed only through the union of two gametes through
conventional breeding'' (emphasis added). The amendment of the
``sexually compatible'' definition therefore removes the criterion that
the gamete formation may only occur through conventional breeding,
which would otherwise preclude the use of genetic engineering to create
PIPs that are exempt even if those PIPs are moved between sexually
compatible plants. Because EPA is not adding an additional conventional
breeding criterion to 40 CFR 174.705, like it is for 40 CFR 174.25 and
40 CFR 174.508, the inert ingredient exemption at 40 CFR 174.705 is no
longer bound by conventional breeding and therefore allows for the
exemption of inert ingredients that are initiated through
biotechnology, so long as they still meet the existing criteria of that
section.

IV. Discussion of Public Comments and the Agency's Responses

EPA received a total of 8,120 comments on the proposed rule. Of
those, 28 were unique and one of those unique comments was supported by
8,093 co-signers. Comments were received from private citizens,
industry, academia, professional and trade associations, State
regulatory associations, and public interest groups. Of the 28 unique
comments, twenty-three were generally supportive of an exemption for
PIPs created through biotechnology, while three comments, one of which
included the mass mailer, were opposed. An additional two respondents
commented on specific aspects of the rule while remaining silent as to
their overall position on its promulgation.
In this unit, EPA provides a summary of the major issues raised by
commenters and EPA's responses, as well as summaries of public comments
that prompted changes to the proposed requirements for the final rule.
All public comments and EPA's responses, including those that do not
raise significant issues or substantially change the proposed
requirements, are included in Response to Comments document (Ref. 1).

A. Definitions and Titles

1. Relationship Between ``Conventional Breeding'' and the Terms
``Native'' and ``Never Derived''
In the proposed rule, EPA sought comment on whether the intent
behind the use of the terms ``native'' and ``never derived'' is clear
or whether alternative phrasing should be used instead. Most of the
commenters that responded to this request stated that EPA's intent was
clear but had suggestions on edits to the definitions of ``native
gene'' and ``native allele.'' A concern raised by several of the
commenters was that alleles that emerged from the use of common
conventional breeding techniques, such as induced mutagenesis, may be
unintentionally excluded from the definition of ``native allele.''
Thus, some commenters suggested explicitly including the use of induced
mutagenesis, embryo rescue, and other conventional breeding techniques
in the 40 CFR 174.3 definitions for ``native allele,'' ``native gene,''
``sexually compatible,'' or ``conventional breeding.'' Another
commenter provided an alternative and suggested to focus on the
exclusion of transgenes from the native gene definition more
explicitly. EPA agreed with the suggestion to focus on the exclusion of
transgenes and revised the definition accordingly (Unit III.A.1.). As
stated in the proposal, the Agency does not mean to imply that using
the term ``native'' would exclude genes originated through conventional
breeding techniques like mutagenesis. Native genes comprising the gene
pool of sexually compatible plant populations have been developed
through the processes of mutation, selection, and genetic exchange.
Mutations in any part of a gene can occur naturally or may be induced
including through chemical mutagenesis used by plant breeders to create
new varieties. 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.'' Additionally,
as the requirement does not specify an allele frequency that must be
met to qualify as a native allele, identifying one individual with a
particular allele is sufficient to claim an allele as a ``native
allele.'' EPA also notes that there is no time component of the
requirement, and so use of a

[[Page 34768]]

native allele identified in a plant from the 1950s, for example, is
permissible so long as that plant species is a species known to be
sexually compatible with the recipient plant.
Regarding requests to explicitly list conventional breeding
techniques like mutagenesis in one of the definitions, EPA does not
find this to be necessary, and listing specific conventional breeding
techniques may only serve to further cause confusion. EPA finds that
the techniques listed in the conventional breeding definition (e.g.,
bridging crosses and wide crosses) focus on the merging of genetic
material from different organisms. Therefore, specific conventional
breeding techniques, such as induced mutagenesis, are not explicitly
included in the ``conventional breeding'' definition because they are
not relevant techniques to the merging of genetic material between
organisms.
2. Definition of ``Genetic Engineering''
Two commenters requested that the term ``biotechnology'' be
defined. As the regulations have a definition for ``conventional
breeding'' under 40 CFR 174.3, which forms the basis for the exemption
under 40 CFR 174.25, EPA agrees that it would be prudent to similarly
provide a definition to inform the exemption under 40 CFR 174.26. Given
that USDA's recent revisions to 7 CFR 340 use the phrase ``genetic
engineering,'' EPA chose to define ``genetic engineering'' rather than
``biotechnology,'' to provide consistency across the Coordinated
Framework (Ref. 3). EPA thusly updated the term used in the exemption
title to be ``genetic engineering.'' EPA used ``genetic engineering''
and ``biotechnology'' synonymously in its proposed rule as evidenced by
Unit VI.A.3.g. titled ``Are there any considerations associated with
newer biotechnology techniques?,'' where EPA discussed genetic
engineering techniques like clustered regularly interspaced short
palindromic repeats (CRISPR), zinc-finger nucleases, transcription
activator-like effector nucleases, and oligonucleotide-directed
mutagenesis.
EPA also received comments requesting the Agency limit the
definition of ``genetic engineering'' and therefore the exemptions at
40 CFR 174.26 and 40 CFR 174.27 to high precision techniques such as
CRISPR. The Agency has chosen to adopt a broader definition of
``genetic engineering,'' which is more consistent with the dictionary
definition of the term. Although the exemptions at 40 CFR 174.26 and 40
CFR 174.27 are not restricted to specific genetic engineering
techniques, the exemption criteria in the provisions themselves
inherently limit the types of techniques which are likely to be used.
For example, it is unlikely for a developer to be able to make the
modifications described in 40 CFR 174.26(a)(2)(i) or 40 CFR
174.26(a)(2)(ii) using techniques other than high precision
technologies.
Commenters also pointed out that such high precision techniques can
be used to limit potential off-target effects from genetic engineering.
EPA agrees with the commenters that existing gene editing technologies
can be used in a manner to limit off-target effects (e.g., through the
use of in silico analyses in guide RNA development), and EPA notes that
it is expected that the majority of developers already use these types
of techniques (Ref. 10). Rather than explicitly limiting the exemption
to specific gene modifying techniques, such as CRISPR, the Agency has
added an item in the documentation required for developers in 40 CFR
174.95 to describe the measures taken to maximize the likelihood that
the modification to the recipient plant is limited to the intended
modification (Unit III.C.4.a.). As noted, it is anticipated that
developers are already utilizing basic measures to reduce off-target
effects, and as such, EPA does not anticipate that this requirement for
a description would be unduly burdensome.
3. Title of the Exemption, Name of Exempted PIPs
EPA received comments related to various aspects of the name EPA
chose for PIPs proposed for exemption under 40 CFR 174.26. One
commenter requested that EPA move the clause ``created through
biotechnology'' to directly follow ``PIP.'' The concern was that the
original phrasing of ``PIPs based on sexually compatible plants created
through biotechnology'' may suggest that the plant has been modified to
be sexually compatible, rather than the intended requirement that the
resulting PIP be based on a PIP from a sexually compatible plant. EPA
agreed with this comment and reordered the clauses as suggested for
clarity.

B. Clarification on Allowable Modifications

1. Noncoding, Nonexpressed
EPA received several comments requesting clarification as to
whether the presence of ``noncoding, nonexpressed nucleotide
sequences'' would affect the exemption status of a PIP at 40 CFR
174.26(a). Commenters argued that because noncoding, nonexpressed
sequences are currently excluded from the definition of ``genetic
material necessary for the production'' at 40 CFR 174.3, their presence
in the recipient plant should not affect the exemption status of a PIP
that otherwise meets the exemption criteria.
``Noncoding, nonexpressed nucleotide sequences'' are defined at 40
CFR 174.3, in part as ``nucleotide sequences that are not transcribed
and are not involved in gene expression.'' One such example are the
left and right border sequences that flank the genetic material that is
inserted into the plant genome when using Agrobacterium-mediated
transformation. These sequences facilitate the integration of the
genetic cargo into the plant genome and will remain in the recipient
plant together with the genetic material that the developer wishes to
express to create the pesticidal trait. Other examples of ``noncoding,
nonexpressed nucleotide sequences'' are linker sequences and
restriction enzyme recognition sites.
As discussed in the preamble of the proposed rule, ``EPA expects
that any ingredients intentionally added during the development of
``PIPs created through genetic engineering from a sexually compatible
plant'' 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 proposed under the new
40 CFR 174.26 and would not qualify for the new exemptions.'' Like the
inert ingredients cited in this quote, noncoding, nonexpressed
sequences are intentionally added during the development of the PIP to
facilitate the integration of the genetic cargo. Thus, EPA finds that
if these sequences are not removed from the final product, i.e., the
recipient plant, they similarly do not meet the criteria for exemption
under 40 CFR 174.26 and 40 CFR 174.27. In this way, the PIPs exempted
under this rulemaking remain indistinguishable from those created
through conventional breeding.
2. Editing or Insertion of Multiple PIPs in a Single Event
EPA received requests to clarify whether modifications to multiple
genes within a single recipient plant would qualify for the exemptions
at 40 CFR 174.26. The exemptions at 40 CFR 174.26 and 40 CFR 174.27 do
not limit the number of PIPs that can be created in a single recipient
plant. Therefore,

[[Page 34769]]

changes to multiple genes in a single recipient plant are allowed, so
long as each resulting PIP individually meets the exemption criteria.
In these instances, the M009 PRIA fee for an EPA determination applies
to each individual PIP, meaning that if one plant contains multiple
unique PIPs, the M009 PRIA fee would apply multiple times (e.g., the
M009 PRIA fee is applied three times for the creation of three unique
PIPs in a single recipient plant). The exception is a scenario in which
the same gene is modified or inserted multiple times across the genome.
For example, it may be necessary to modify several homologous genes of
a native gene in a recipient plant to create a single PIP (i.e., to
create a loss-of-function PIP where the trait requires all homologous
genes to be modified). Conversely, a developer may wish to insert
multiple copies of the same native gene. In the instance of modifying/
inserting the same gene multiple times across the genome, the M009 fee
is only applied once, as the application contains only one PIP.

C. PIPs Created Through Genetic Engineering From a Sexually Compatible
Plant

1. Identical Substance Criterion
EPA received several comments on the ``identical substance''
criteria stating, amongst other things, that modifications that result
in non-identical substances may not result in a change in risk profile
and that the requirement for the production of an identical substance
is not consistent with the requirements for PIPs from sexually
compatible plants that are moved through conventional breeding. In
response, EPA has edited the exemption category related to
modifications in an existing native gene at 40 CFR 174.26(a)(2) to
incorporate the use of polymorphic regions (Unit III.A.2.).
The exemption category at 40 CFR 174.26(a)(2) does not require the
production of an identical substance, while still staying within the
scope of what could be achieved through conventional breeding and thus
within the scope of the proposed rulemaking. The exemption criterion at
40 CFR 174.26(a)(2) now allows for modifications of the existing native
gene using a single source plant as a template to match corresponding
polymorphic sequence(s) in a native allele of that gene. Polymorphisms
are variants of a gene sequence that are shared between native alleles.
These genetic variations may be composed of single nucleotides (i.e.,
SNPs) or larger DNA segments and they are found at the same locus
within the genetic sequence of two or more native alleles (Ref. 11). In
some cases, enhanced pesticidal properties of a gene product can be
attributed to one or more of these genetic variations within a native
gene. 40 CFR 174.26(a)(2) allows developers to utilize their knowledge
of specific polymorphisms in native alleles to make changes to the
native gene in their recipient plant. While this category does not
require the entire substance to be identical to a substance found in
the sexually compatible population of the recipient plant, it does
require the individual polymorphism(s) to have been identified. It is
also important to note that this category requires the use of a single
source plant as a template, meaning it is not allowed to combine
polymorphisms from multiple native alleles in a single PIP. By
requiring the polymorphic sequences to be identical and the use of a
single source plant as a template, this separate exemption category
allows the Agency to capture more of the possible genetic variation
that can occur in plants, while staying within the bounds of what could
have been achieved through conventional breeding.
2. Expression Profile Criterion
EPA proposed at 40 CFR 174.26(b) a criterion that was intended to
ensure that the expression profile of exempted PIPs falls within that
which is found in the sexually compatible population. Limiting
expression profiles of exempted PIPs in this way is a key limitation to
prevent novel environmental and dietary exposures. However, commenters
expressed concern over the feasibility to generate the information
required to demonstrate eligibility for exemption and had several
questions on how these requirements could be met (Unit IV.E.4.b.).
Additionally, the Agency received requests to clarify whether the
criteria that the pesticidal substance may not be expressed at higher
levels, in different tissues, or at different developmental stages,
would apply simultaneously or independently. Commenters also requested
clarification on the identity of the appropriate comparator for the
expression profile criteria at 40 CFR 174.26(b). These comments
prompted the Agency to reevaluate the text proposed at 40 CFR
174.26(b).
Given the number of comments received surrounding the expression
criteria, and that limiting expression profiles of exempted PIPs is a
key limitation to prevent novel environmental and dietary exposures,
EPA is not codifying proposed 40 CFR 174.26(b) and is instead
finalizing specific criteria at codified 40 CFR 174.26(a) related to
the types of permissible modifications that may impact expression. EPA
now requires that regulatory regions inserted as part of a native gene
per codified 40 CFR 174.26(a)(1), be identical to those found in the
native gene in the source plant. The exemption category at 40 CFR
174.26(a)(2) specifies that modifications to an existing native gene,
which includes regulatory and coding regions, must match corresponding
polymorphic sequence(s) in a native allele. By requiring that inserted
regulatory regions match those found in the native gene in the source
plant and that modified regulatory regions match polymorphic sequences
found in a native allele, EPA can ensure that the expression profile of
PIPs exempted under 40 CFR 174.26 will stay within the bounds of what
could be obtained through conventional breeding. Furthermore, this
criterion coupled with the information on the history of safe use (40
CFR 174.95(d)) allows EPA to ensure that the expression profile of PIPs
exempt from the requirement of a tolerance under 40 CFR 174.541 meet
the requirement that expression be at levels that are not injurious or
deleterious to human health.

D. Loss-of-Function PIPs

1. How are Loss-of-Function Traits Regulated Under FIFRA?
EPA received a number of comments questioning whether loss-of-
function traits conferring pesticidal effects are considered pesticides
under FIFRA. As stated in the preamble of the proposed rule (Ref. 2),
EPA considers the modification of existing native genes in a plant that
elicit a loss-of-function trait conferring a pesticidal effect, i.e.,
``loss-of-function PIPs,'' to be a pesticide. In the case of ``loss-of-
function PIPs,'' the genetic material of the plant has been altered to
reduce or eliminate the activity of a gene that would otherwise
facilitate the susceptibility of that plant to a pathogen; therefore,
the reduction or elimination of that activity has a mitigating or
pesticidal effect.
FIFRA defines a ``pesticide,'' in relevant part, as ``any substance
or mixture of substances intended for preventing, destroying,
repelling, or mitigating any pest.'' FIFRA section 2(u), 7 U.S.C.
136(u). For ``loss-of-function PIPs'' (now exempted under 40 CFR
174.27), the modified genetic material, e.g., the modified gene or the
genetic material surrounding an excised gene, is the pesticidal
substance, since that material operates in the plant to mitigate the
pest. Further, the modified

[[Page 34770]]

genetic material has been modified with the intent to mitigate the
pest. Therefore, any plant containing the loss of function trait sold
or distributed with pesticidal claims would meet the statutory
definition of a pesticide.
Under EPA's regulations, a substance is considered to be intended
for a pesticidal purpose if, among other things, the person who
distributes or sells the substance as a pesticide product claims,
states, or implies that the substance can or should be used as a
pesticide; the substance has no significant commercially valuable use
other than use for pesticidal purpose; or a person sells or distributes
a product with actual or constructive knowledge that the product will
be used, or is intended to be used, for a pesticidal purpose. See 40
CFR 152.15. Therefore, products carrying a pesticidal claim, such as
stating that the plant variety resists disease, indicate clear
pesticidal intent. Further, even if such claims were not made, if the
seller or distributor knew that the loss of function trait was
contained in the plant, the substance would still be considered to be
intended for a pesticidal purpose. Likewise, even for loss-of-function
PIPs that result in the complete elimination of activity from the
modified genetic material, the intentional modification of the plant's
genetic material to result in a pesticidal effect indicates that the
developer has actual or constructive knowledge that the substance will
be used, or is intended to be used, for a pesticidal purpose and that
there is not a significant commercially valuable use other than for a
pesticidal purpose. The result is that ``loss-of-function PIPs'' are
subject to regulation under FIFRA. This Final Rule exempts ``loss-of-
function PIPs'' that meet the criteria under 40 CFR 174.27 from certain
regulation under FIFRA. Without this exemption, sale and distribution
of plants containing those modifications would require registration
under FIFRA.
Furthermore, PIPs from sexually compatible plants have been exempt
under 40 CFR 174.25 for over 20 years. Had a developer sought
confirmation that their conventionally bred, disease-resistant plant
was exempt, EPA would have exempted such a product under 40 CFR 174.25
on the basis that it is a PIP trait that has been created via
conventional breeding. (See e.g., 66 FR 37772; July 19, 2001 (FRL-6057-
7)). This determination would be made without making a distinction of
mode of action (e.g., gene loss-of-function or production of a
protein). Disease-resistant traits are often caused by the loss-of-
function of a gene, and the 2001 preamble focused on the presence of a
pesticidal trait (i.e., disease resistance) and claims of resistance in
its determinations that such a trait would be considered a pesticide
and a PIP, indicating that EPA did not make a distinction as to whether
the disease-resistant trait was conferred via a gene loss-of-function
or via production of a proteinaceous substance. Therefore, it is
consistent to consider loss-of-function traits to be both pesticides
and PIPs.
2. Criteria for the Exemption Specific to ``Loss-of-Function PIPs''
EPA received several comments from industry, trade, and academia on
the criterion of substance identity, requesting that the exemptions
should be broadened to include non-identical pesticidal substances. By
creating a separate exemption for ``loss-of-function PIPs'' with
specific criteria and an accompanying definition, EPA finds that
``loss-of-function PIPs'' as described by 40 CFR 174.27 do not require
the ``identical substance'' criterion, as do PIPs exempt under 40 CFR
174.26, due to fundamental differences in the pesticidal activity of
``loss-of-function PIPs'' compared to PIPs exempt under 40 CFR 174.26.
``Loss-of-function PIPs'' are characterized by a modification that
leads to the reduction or elimination of the activity of that gene,
which then results in a pesticidal trait (e.g., the inactivation of a
gene coding for a plant receptor confers disease resistance). Mutations
that lead to a loss of gene function occur naturally and are prevalent
within many organisms, including plants. For example, one study of
1,071 genomes of the model plant Arabidopsis thaliana showed a total of
60,819 loss-of-function variants within 12,907 genes, out of a genome-
wide total of approximately 25,500 genes (Refs. 12, 13). In addition to
their natural occurrence as a result of various biotic and abiotic
factors, plant breeders have intentionally induced these types of
mutations during the conventional breeding process. One example is the
treatment of seeds by chemical mutagens, which is a technique used by
breeders to create new plant varieties (Refs. 14, 15).
The traits that may result from the loss of function of a gene are
diverse, ranging from altered grain size, increased drought tolerance,
and resistance to plant diseases (Refs. 16-20). Disease resistance in
plants from the loss of function of S-genes (susceptibility genes) have
been identified in natural plant populations, and researchers have used
knowledge about naturally occurring gene variants to create pest
resistance in various plant species using genetic engineering (Refs.
18, 19). For example, genetically engineered deletions in parts of the
regulatory region of the SWEET14 gene in rice created a plant line that
is resistant to the Xanthomonas oryzae pv. oryzae (Xoo) pathogen, and
genetically engineered loss-of-function of eIF4E achieved potyvirus
resistance in cucumber (Refs. 21, 22).
As previously stated, EPA does not require an ``identical
substance'' criterion for ``loss-of-function PIPs,'' and this is
because mutations in any part of a gene have the potential to result in
the loss of its function. Examples include deletions within the
regulatory region that lead to the reduced expression (and thus reduced
abundance) of an unmodified protein, or a single nucleotide change in
the coding region, which can result in the creation of a premature stop
codon, leading to the production of a shorter version of the protein
originally encoded by that gene. Other changes to the coding region may
also lead to mis-splicing of the pre-mRNA, which can subsequently
result in the degradation of the pre-mRNA (no protein produced) or the
production of a non-functional protein (Refs. 23, 24). If a non-
functional protein is produced, a normal part of routine biological
processes is for the cell to recognize it as such and target it for
degradation into its amino acid constituents. This turnover of protein
occurs independent of how the non-functional protein was created, be it
the result from a permanent genetic change (either through natural or
induced mutation) or errors created when cells transcribe and/or
translate the genetic code (Refs. 25-28). The ability of the cell to
recognize and break down non-functional proteins is a routine cell
function, and it enables the organism to be economical with its
resources by reusing the amino acids for those proteins that do serve a
purpose.
Based on the prevalence of loss-of-function mutations in plants and
the biological considerations of protein homeostasis, EPA finds that it
does not need the same requirements on characteristics as it does for
``PIPs created through genetic engineering from a sexually compatible
plant.'' Therefore, ``loss-of-function PIPs,'' as exempted under 40 CFR
174.27, are still supported by the risk assessment as presented in the
proposed rule.
As the ``loss-of-function PIP'' exemption is focused on function,
there is no nucleic acid sequence requirement in the exemption criteria
under 40 CFR 174.27 or in the exemption documentation under 40 CFR
174.96. Commenters have stated a concern that

[[Page 34771]]

minor crops may face a disadvantage due to fewer genomic resources
being available for their specific crop species. For example, one
commenter stated that knowledge of genes in major crops or model
organisms can inform the development of minor crops due to conserved
gene function from a shared common ancestor, even when those plants are
no longer sexually compatible. EPA believes that the codified exemption
for ``loss-of-function PIPs'' with its focus on function will allow for
use of this knowledge and provide a benefit for developers, including
those of minor crops.

E. Eligibility Determination Process

1. Options To Determine Exemption Eligibility
In the proposal, all exempted ``PIPs created through genetic
engineering from a sexually compatible plant'' had the option of self-
determination. However, in the final rule, only developers of ``loss-
of-function PIPs'' (40 CFR 174.27) have the option to self-determine
whether the exemption criteria are met.
The Agency finds the approach to require an EPA confirmation for
``PIPs created through genetic engineering from sexually compatible
plants'' justified. Commenters felt that a mandatory EPA confirmation
process would prevent an incorrect exemption determination. EPA agrees
with commenters arguing that doing so will provide additional clarity
to developers of ``PIPs created through genetic engineering from
sexually compatible plants'' and increase transparency and public trust
in products containing these PIPs.
Other commenters were supportive of the flexibility that a
mandatory self-determination process with a voluntary EPA confirmation
process would provide. EPA acknowledges the value of this flexibility
and has determined that developers of ``loss-of-function PIPs'' will
have the option to either self-determine or request EPA confirmation of
exemption eligibility. Given the straightforward nature of the criteria
describing ``loss-of-function PIPs'' (i.e., a focus on function rather
than source plant or underlying sequence), EPA believes it appropriate
for ``loss-of-function PIPs'' to be eligible for the self-determination
option as it is unlikely for a developer to accidentally mis-determine
these PIPs. Furthermore, the mode of action of ``loss-of-function
PIPs'' (i.e., reduction or elimination of an endogenous gene) is
fundamentally different from ``PIPs created through genetic engineering
from a sexually compatible plant'' (e.g., intentional production of a
pesticidal protein), and as such, further lends itself to the
availability of a self-determination option.
2. Extension of Exemption Status
Commenters were largely supportive of the option to transfer the
exemption status of a particular PIP to other plant varieties.
Regarding this option, one commenter felt that the criterion in the
proposal at 40 CFR 174.90(e)(1)(ii) that required that the same
phenotype be created through non-homologous end joining repair
modifications was too narrow. EPA agreed with this comment and, given
the creation of a separate exemption for ``loss-of-function PIPs''
focused on function, was able to revise the exemption extension
criteria for ``loss-of-function PIPs'' to be similarly focused on
function (Unit III.C.1.).
3. Contents of a Self-Determination Letter
In the proposal, EPA proposed to require submitters of self-
determination letters to identify the PIP (at proposed 40 CFR
174.91(b)(2) and 40 CFR 174.91(b)(3)). Two commenters stated that EPA
should require additional information on the PIP with the submission of
a self-determination letter. Specifically, it was requested that EPA
require information on the plant species, a description of the
pesticidal trait, and a short summary of how the pesticidal trait was
introduced into the plant variety. It was also requested that EPA
require developers to submit information that would be required for an
EPA confirmation. EPA agrees that information on the recipient plant
species and a unique gene identifier should be included in the self-
determination letter and has updated the text at 40 CFR 174.91 to
reflect this (Unit III.C.2.). Because the identity of the PIP may or
may not include the name of the modified gene or plant species (e.g.,
the identity of the PIP could also be a trade name), the Agency has
clarified that a gene identifier and the identity of the recipient
plant must also be included in the submission of a self-determination
letter.
Regarding the other suggestions, such as a description of the
pesticidal trait, a short summary of how the trait was introduced, and
other information otherwise provided to the Agency as part of the EPA
confirmation process, the Agency does not find this information
necessary to be submitted with the self-determination letter. This is
because the self-determination process does not involve an EPA review
or confirmation. However, the information provided during an EPA
confirmation is the same information required to be maintained by the
recordkeeping requirements under 40 CFR 174.73, which equally applies
to those submitting a self-determination of exemption. As part of the
recordkeeping requirements, the information suggested by the commenters
must already be made available to EPA upon request. Although the Agency
is not requiring a summary description of the pesticidal trait and how
it was introduced in the self-determination letter, the Agency agrees
that identifying the trait type (e.g., insect resistance or disease
resistance) would provide useful information for the public and for
State level agencies and edited 40 CFR 174.91(b)(2) to reflect this.
Thus, the language at 40 CFR 174.91(b)(2) now requires information on
plant species, gene identifier, and trait type.
4. Documentation for an Exemption for ``PIPs Created Through Genetic
Engineering From a Sexually Compatible Plant''
a. Scope of the Required Documentation
EPA received comments on the scope of the documentation that is
required to be produced to support an exemption for ``PIPs created
through genetic engineering from a sexually compatible plant.'' One
commenter requested that, in addition to discussing the categories of
information needed to assess applicability of the exemption to a PIP,
EPA furthermore establish expectations in the regulatory text on what
information the Agency deems sufficient to satisfy each of the
exemption criteria. In line with this, one commenter suggested to
revise 40 CFR 174.95(a)(2) to replace ``information to demonstrate the
recipient plant and the source plant are sexually compatible'' with
``information to support that the recipient plant and the source plant
are sexually compatible.'' The Agency agrees with this suggestion as a
developer may, for example, provide a peer-reviewed literature
rationale instead of generating empirical data to demonstrate that two
plants are sexually compatible. The Agency revised the regulatory text
in the final rule accordingly (Unit III.C.4.a.).
The same commenter also suggested two revisions to 40 CFR
174.95(c)(1). First, the commenter suggested that the documentation
requirements should limit sequence comparison to nucleic acids, rather
than require both the nucleic acid and the amino acid sequence for
proteinaceous PIPs and to limit the nucleic acid sequence comparison to
the location of the

[[Page 34772]]

intended modification(s) rather than the entire PIP. Second, the
commenter requested that if an amino acid sequence was required, EPA
further clarify the language on the sequence requirements to state
``nucleotide sequence and deduced amino acid sequence.'' EPA has
revised the text at 40 CFR 174.95(c)(1) for increased clarity as to the
required sequence information based on the relevant comparator, i.e.,
the specific comparator at 40 CFR 174.95(c) is now listed based on the
corresponding exemption category at 40 CFR 174.26. The Agency maintains
that the entire nucleic acid sequence must be provided for all PIPs
exempted under 174.26(a), as both exemptions at 40 CFR 174.26(a) allow
for modifications in the regulatory regions. Thus, providing EPA with
the nucleic acid sequence of the entire gene will allow the
determination if the modifications meet the exemption requirements
(Unit III.C.4.a.). The Agency maintains that the full-length amino acid
sequence must additionally be provided for proteinaceous PIPs but
agrees with the commenter that the deduced amino acid sequence would be
sufficient to inform the identity of that PIP in these instances.
Commenters requested that EPA exclude wild relatives as potential
source plants and/or impose geographic restrictions on source plants,
noting that non-target organisms living within the range of the wild
donor plants would have adapted to exposures from these wild plants and
that non-target organisms from outside this range may therefore be
negatively impacted by a PIP from the wild plant due to lack of
previous exposure. Additionally, it was noted that allowing sexually
compatible wild relatives as source plants may result in toxins from
these plants being missed as part of the plant breeder screening.
EPA understands that wild relatives provide an important source of
genetic variation for developers and therefore has chosen not to
exclude them from use as sexually compatible source plants for exempt
PIPs. However, to address the concern raised by the commenters, EPA has
added a requirement at 40 CFR 174.95(d)(2) that if the source plant is
a wild relative of the recipient plant, the developer must describe why
the PIP is not anticipated to pose a hazard to humans or the
environment. EPA provides a list in the regulatory text at 40 CFR
174.95(d)(2) of the types of information that can be used to describe
why a PIP is not anticipated to pose a hazard to humans or the
environment.
b. Feasibility To Meet the PIP Expression Criteria and Develop Adequate
Documentation
EPA received several comments on the proposed rule regarding the
PIP expression criteria at 40 CFR 174.26(b) and the associated
documentation requirements at 40 CFR 174.95(c)(2). Several commenters
raised concerns that meeting the documentation requirements would be
impractical and cost prohibitive given the large variation in plant
gene expression between tissues and growth stages, especially when
considering gene expression in different environmental conditions. One
commenter submitted that data to meet the expression limitation
exemption criteria should only be required if the intent of the
modification is to increase levels of the expressed pesticidal
substance. This approach is consistent with the Agency's analysis of
gene expression articulated in the proposal. Specifically, EPA found
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. EPA finds that this is especially true for regulatory
regions and polymorphic sequences that are present in regulatory
regions that are moved between native alleles. In other words, there is
the expectation that the expression pattern of a PIP would be within
that what is found within the sexually compatible population, so long
as it is under the control of the regulatory elements found within a
native allele.
Consistent with this assessment and taking into consideration the
comments received on the impracticality and potential financial burden
of determining the expression levels to comply with proposed 40 CFR
174.95(c)(2), the Agency removed the exemption criterion at proposed 40
CFR 174.26(a)(2)(i) that would have allowed modifications to regulatory
regions for the purpose of altering the expression level of a
pesticidal substance. Instead, EPA is now requiring at 40 CFR
174.26(a)(1) that any regulatory region that is inserted as part of a
native gene must be identical in nucleotide sequence to the regulatory
region of the native gene as it is identified in the source plant.
Similarly, 40 CFR 174.26(a)(2) allows regulatory region changes only
based on polymorphic sequence(s) identified in a native allele of the
modified gene. In making these revisions to 40 CFR 174.26, EPA is able
to remove the requirements for expression profile confirmation at
proposed 40 CFR 174.95(c)(2), as the expectation is that the expression
profiles of PIPs that meet these exemption criteria at 40 CFR 174.26(a)
will not be outside of that what is found within the sexually
compatible population of the recipient plant.
5. Activities That Require Submission of an Eligibility Determination
Two commenters requested clarification on which activities may
require a separate notification of self-determination for a PIP under
40 CFR 174.541. Specifically, commenters requested clarification in
those instances in which a plant containing the PIP is imported to the
United States for the distribution in commerce for consumption or
planting in the absence of a tolerance or tolerance exemption granted
under FFDCA.
EPA is confirming that the Agency is requiring a separate
eligibility determination under 40 CFR 174.541 for residues of those
PIPs that are imported into the United States and that are used for
food or feed if the developer has not already obtained an exemption
under 40 CFR 174.21. As discussed in the preamble of the proposed rule,
a separate submission of the eligibility determination 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. To clarify, EPA has
added a new paragraph (g) to 40 CFR 174.90, which explains that a
duplicative eligibility submission is not required for purposes of 40
CFR 174.541(c), if it is already being submitted for purposes of 40 CFR
174.21(d). The proposal discussed one such scenario where this might be
the case (e.g., Unit VI.C.1. of the proposed rule). Briefly, a
developer will need an exemption eligibility determination for the
purposes of FFDCA but not FIFRA 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. In that case, the PIP
residues in the imported food would need a tolerance or tolerance
exemption to allow for distribution in interstate commerce in the
United States under the FFDCA, but would not need a FIFRA exemption
since it is not intended to be sold or distributed for pesticidal
purposes in the United States.
Other commenters inquired whether testing of PIPs at or under 10
acres of land would require an Experimental Use Permit (EUP) under
FIFRA section 5 and

[[Page 34773]]

therefore whether an eligibility determination for certain PIPs would
be required at these acreages. 40 CFR 172.3 applies to PIPs. As
described in 40 CFR 172.3, tests on 10 acres or less are presumed to
not require an EUP so long as any food or feed crops involved in, or
affected by, such tests (including, but not limited to, crops
subsequently grown on such land which may reasonably be expected to
contain residues of the tested pesticides) are destroyed or consumed
only by experimental animals unless an appropriate tolerance or
exemption from a tolerance has been established under FFDCA for
residues of the pesticide. Further, pursuant to 40 CFR 172.3(e), EPA
may, on a case-by-case basis, require that testing be carried out under
an EUP even if such testing involves 10 acres or less. For a PIP
subject to this rulemaking that would be used in testing taking place
on 10 acres or less to be able to take advantage of the presumption in
40 CFR 172.3, that PIP would need to either demonstrate that the
appropriate tolerance or exemption has been established or follow the
requirements of crop destruction. Pursuant to subpart E of 40 CFR 174
as codified in this rule, for PIPs exempted under 40 CFR 174.26,
demonstrating that the tolerance exemption at section 40 CFR 174.541
applied would require an EPA confirmation, and for PIPs exempted under
40 CFR 174.27, it would require the submission of a self-determination.
For a PIP for which a tolerance exemption has not been established, in
addition to requirements of crop destruction for field testing at or
under 10 acres, EPA previously published and still relies on guidance
(Ref. 29) detailing containment measures to restrict the flow of
genetic material, including seeds, from field tests to minimize the
potential for PIP residues that do not have a tolerance exemption to
enter the food supply. These additional considerations are crucial to
prevent PIPs lacking a tolerance exemption from entering the food
supply and the consequences of adulteration under FFDCA. EPA notes that
it is expecting to provide an update to the information and/or process
provided in PRN 2007-2 (Ref. 29) regarding measures needed for
containing small-scale testing of PIPs in light of changes in
regulatory oversight due to USDA's recently revised 7 CFR part 340
regulations.
6. Submitting Confidential Business Information (CBI)
Several commenters noted that information included in a request for
EPA confirmation may be classified as CBI and requested assurance and
clarification for how EPA would protect intellectual property and other
proprietary information. As EPA is using its existing electronic
reporting site for receiving submissions, this information will be
transmitted to EPA in a secure manner. As stated in 40 CFR 174.90(c),
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 of subpart A. 40 CFR 174.9 instructs a
submitter on how to claim data or other information as CBI. Information
likely to be claimed as CBI may be part of the documentation for an
exemption (e.g., sequence information on the pesticidal substance).
Developers also have the option to claim information submitted as part
of the self-determination as CBI (e.g., gene ID, plant species).
However, it is important to note that every individual piece of
information claimed as CBI must be supported by its own substantiation.
For this reason, and for reasons of public transparency, as it has for
all PIPs, EPA continues to encourage PIP developers to limit their
claims to CBI to only the most pertinent pieces of information.

F. Endangered Species Assessment

EPA received public comment regarding whether the proposed
exemption may affect endangered species. EPA determined that this
action invokes obligations under the Endangered Species Act because
this is a discretionary action that exempts certain pesticidal
substances from some requirements under FIFRA, such that the exemptions
could cause potential exposures in the environment. Therefore, EPA
conducted an Endangered Species Assessment for ``PIPs created through
genetic engineering from a sexually compatible plant'' and for ``loss-
of-function PIPs.''
In the proposed rule, after careful consideration of potential
interactions that the PIPs proposed for exemption may have with
nontarget organisms (see Unit VI.A.3. of the proposed rule), EPA
preliminarily determined that use of the PIPs proposed for exemption is
not likely to cause unreasonable adverse effects on the environment and
humans in the absence of regulatory oversight (although ``regulatory
oversight'' still exists in the form of the adverse effects reporting
requirement in existing 40 CFR 174.71) resulting in a reasonable
expectation that no discernible effects to nontarget organisms will
occur. As no discernible effects to nontarget organisms are reasonably
expected to occur due to the use of these PIPs, which necessarily
includes any threatened or endangered species (listed species), EPA
therefore reaches a ''No Effect'' determination for listed species and
their critical habitats.
Herein, EPA provides brief summaries of key considerations used in
the Agency's determination that the PIP exemptions proposed in the 2020
preamble and finalized in this rule are reasonably expected to result
in no discernable effects to nontarget organisms, including listed
species. In the proposed rule, EPA considered several factors in
determining whether PIPs 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 (Unit VI.A.3.h. of the proposed rule). In
its assessment, the Agency relied on the large body of knowledge that
currently exists on sexually compatible plants and genetic diversity.
Briefly, with regard to the potential ecological effects, the Agency
found that there is: ``(1) Low potential for novel exposures; (2) Low
potential for levels of ``PIPs created through genetic engineering from
a sexually compatible plant'' to exceed levels found in sexually
compatible plants; and (3) Low potential for ``PIPs created through
genetic engineering from a sexually compatible plant'' to move from
cultivated plants to wild or weedy relatives through gene flow and
increase weediness.'' (Unit VI.A.3. of the proposed rule). EPA also
evaluated considerations specific to newer biotechnology techniques
related to the PIPs proposed for exemption and found that their use in
creating these PIPs would pose negligible risk to the environment.
Lastly, the Agency found that the likelihood is negligible that the
transfer of a PIP via biotechnology from a nonagricultural (wild)
relative to an agricultural one would pose a greater risk than if it
were transferred through conventional breeding.
In summary, PIPs that are exempted under 40 CFR 174.26 represent a
subset of substances already present in related plants and are
equivalent both in identity and in expression profile (how much, where,
and when the substances are expressed in plants). As ``loss-of-function
PIPs'' exempted under 40 CFR 174.27 were originally proposed as a
subcategory of PIPs exempted under 40 CFR 174.26, they too fall within
the scope of the Agency's analysis in the proposed rule preamble.
Pesticidal traits resulting from the loss-of-function of an endogenous
gene are common occurrences in wild plants and in conventional breeding
(Refs. 18, 19) and EPA finds that there is no potential for

[[Page 34774]]

novel exposures or hazards for ``loss-of-function PIPs,'' as this group
of PIPs is characterized by a modification that leads to the reduction
or elimination of the activity of a gene that had already been present
in the recipient plant. As the PIPs exempted under this rule are
considered to be equivalent to those already found in nature and used
in conventional breeding, there is a reasonable expectation that no
discernible effects to listed species will occur from their use. As no
discernible effects are reasonably expected to occur to listed species
due to the use of these PIPs, EPA therefore reaches a ''No Effect''
determination for listed species and their critical habitats.

VII. 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 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. Response to Comments to the Proposed Rule to Exempt Certain
Plant-Incorporated Protectants (PIPs) Derived from Newer
Technologies. Available at <a href="https://www.regulations.gov">https://www.regulations.gov</a> under Docket
ID No. EPA-HQ-OPP-2019-0508.
2. USEPA. 2020. Pesticides; Exemptions of Certain Plant-Incorporated
Protectants (PIPs) Derived from Newer Technologies. 85 FR 64308,
October 9, 2020 (FRL-10014-10). Available at <a href="https://www.regulations.gov">https://www.regulations.gov</a> under Docket ID No. EPA-HQ-OPP-2019-0508.
3. 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: <a href="https://www.epa.gov/regulation-biotechnology-under-tsca-and-fifra/update-coordinated-framework-regulation-biotechnology">https://www.epa.gov/regulation-biotechnology-under-tsca-and-fifra/update-coordinated-framework-regulation-biotechnology</a>.
4. USEPA. 2022. Cost Analysis For the Final Rule Exempting Certain
Plant-Incorporated Protectants (PIPs) from Registration. Available
at <a href="https://www.regulations.gov">https://www.regulations.gov</a> under Docket ID No. EPA-HQ-OPP-2019-
0508.
5. Mhoswa L., O'Neill M.M., Mphahlele M.M., Oates C.N., Payn K.G.,
Slippers B., Myburg A.A., and Naidoo S. A Genome-Wide Association
Study for Resistance to the Insect Pest Leptocybe invasa in
Eucalyptus grandis Reveals Genomic Regions and Positional Candidate
Defense Genes. Plant and Cell Physiology. 2020. 61(7), pp.1285-96.
6. Jamie, Gabriel A., and Joana I. Meier. The persistence of
polymorphisms across species radiations. Trends in Ecology &
Evolution. 2020. 35(9), pp.795-808.
7. Pesticide Registration (PR) Notice 2011-3. Standard Format for
Data Submitted Under the Federal Insecticide, Fungicide, and
Rodenticide Act (FIFRA) and Certain Provisions of the Federal Food,
Drug, and Cosmetic Act (FFDCA), November 2011. Available online at
<a href="https://www.epa.gov/sites/default/files/2014-04/documents/pr2011-3.pdf">https://www.epa.gov/sites/default/files/2014-04/documents/pr2011-3.pdf</a>.
8. USEPA Federal Register. 2001. Regulation Under the Federal
Insecticide, Fungicide, and Rodenticide Act for Plant-Incorporated
Protectants (Formerly Plant-Pesticides). 66 FR 37772, July 19, 2001
(FRL-6057-7). Available online at <a href="https://archive.epa.gov/pesticides/biopesticides/web/pdf/pip_rule.pdf">https://archive.epa.gov/pesticides/biopesticides/web/pdf/pip_rule.pdf</a>.
9. Kaiser, N., Douches, D., Dhingra, A., Glenn, K.C., Herzig, P.R.,
Stowe, E.C., and Swarup, S. The role of conventional plant breeding
in ensuring safe levels of naturally occuring toxins in food crops.
Trends in Food Science & Technology. 2020. 100, pp.51-66.
10. Graham, N., Patil, G.B., Bubeck, D.M., Dobert, R.C., Glenn,
K.C., Gutsche, A.T., Kumar, S., Lindbo, J.A., Maas, L., May, G.D.
and Vega-Sanchez, M.E. Plant genome editing and the relevance of
off-target changes. Plant Physiology. 2020. 183(4), pp.1453-1471.
11. Hartl, D.L., A primer of population genetics. 3rd ed. 2000,
Sunderland, MA: Sinauer Associates, Inc.
12. Xu, Y.C., Niu, X.M., Li, X.X., He, W., Chen, J.F., Zou, Y.P.,
Wu, Q., Zhang, Y.E., Busch, W. and Guo, Y.L., 2019. Adaptation and
phenotypic diversification in Arabidopsis through loss-of-function
mutations in protein-coding genes. The Plant Cell, 31(5), pp.1012-
1025.
13. Kaul, S., Koo, H.L., Jenkins, J., Rizzo, M., Rooney, T., Tallon,
L.J., Feldblyum, T., Nierman, W., Benito, M.I., Lin, X. and Town,
C.D., 2000. Analysis of the genome sequence of the flowering plant
Arabidopsis thaliana. Nature, 408(6814), pp.796-815.
14. Oladosu, Y., Rafii, M.Y., Abdullah, N., Hussin, G., Ramli, A.,
Rahim, H.A., Miah, G. and Usman, M., 2016. Principle and application
of plant mutagenesis in crop improvement: a review. Biotechnology &
Biotechnological Equipment, 30(1), pp.1-16.
15. Jankowicz-Cieslak, J., Mba, C. and Till, B.J., 2017. Mutagenesis
for crop breeding and functional genomics. In Biotechnologies for
plant mutation breeding (pp.3-18). Springer, Cham.
16. Duan, P., Xu, J., Zeng, D., Zhang, B., Geng, M., Zhang, G.,
Huang, K., Huang, L., Xu, R., Ge, S. and Qian, Q., 2017. Natural
variation in the promoter of GSE5 contributes to grain size
diversity in rice. Molecular plant, 10(5), pp.685-694.
17. Monroe, J.G., Powell, T., Price, N., Mullen, J.L., Howard, A.,
Evans, K., Lovell, J.T. and McKay, J.K., 2018. Drought adaptation in
Arabidopsis thaliana by extensive genetic loss-of-function. Elife,
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18. Bai, Y., Pavan, S., Zheng, Z., Zappel, N.F., Reinst[auml]dler,
A., Lotti, C., De Giovanni, C., Ricciardi, L., Lindhout, P., Visser,
R. and Theres, K., 2008. Naturally occurring broad-spectrum powdery
mildew resistance in a Central American tomato accession is caused
by loss of Mlo function. Molecular Plant-Microbe Interactions,
21(1), pp.30-39.
19. Acevedo[hyphen]Garcia, J., Kusch, S. and Panstruga, R., 2014.
Magical mystery tour: MLO proteins in plant immunity and beyond. New
Phytologist, 204(2), pp.273-281.
20. Van de Wiel, C.C.M., Schaart, J.G., Lotz, L.A.P. and Smulders,
M.J.M. New traits in crops produced by genome editing techniques
based on deletions. Plant biotechnology reports. 2017. 11(1), pp.1-
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21. Li, T., Liu, B., Spalding, M.H., Weeks, D.P. and Yang, B., 2012.
High-efficiency TALEN-based gene editing produces disease-resistant
rice. Nature biotechnology, 30(5), pp.390-392.
22. Chandrasekaran, J., Brumin, M., Wolf, D., Leibman, D., Klap, C.,
Pearlsman, M., Sherman, A., Arazi, T. and Gal[hyphen]On, A., 2016.
Development of broad virus resistance in non[hyphen]transgenic
cucumber using CRISPR/Cas9 technology. Molecular plant pathology,
17(7), pp.1140-1153.
23. Reddy A.S.N., Marquez Y., Kalyna M., and Barta A. Complexity of
the alternative splicing landscape in plants. The Plant Cell. 2013.
25(10), pp.3657-83.
24. Roy SW, Irimia M. Intron mis-splicing: no alternative?. Genome
biology. 2008. 9(2), pp.1-3.
25. Merchante, C., Stepanova A. N., and Alonso J. M. Translation
regulation in plants: an interesting past, an exciting present and a
promising future. The Plant Journal. 2017. 90, pp. 628-653.
26. Gordon A.J., Satory D., Halliday J.A., and Herman C. Lost in
transcription: transient errors in information transfer. Current
opinion in microbiology. 2015. 24, pp.80-7.
27. Li L., Nelson C.J., Tr[ouml]sch J., Castleden I., and Huang S.,
Millar A.H. Protein degradation rate in Arabidopsis thaliana leaf
growth and development. The Plant Cell. 2017. 29(2), pp.207-28.
28. Toyama B.H. and Hetzer M.W. Protein homeostasis: live long,
won't prosper. Nature reviews Molecular cell biology. 2013. 14(1),
pp.55-61.
29. Pesticide Registration (PR) Notice 2007-2: Guidance on Small-
Scale Field Testing and Low-level Presence in Food of Plant-
incorporated Protectants (PIPs), April 30, 2007. Available online at
<a href="https://www.epa.gov/pesticide-registration/prn-2007-2-guidance-small-scale-field-testing-and-low-level-presence-food">https://www.epa.gov/pesticide-registration/prn-2007-2-guidance-small-scale-field-testing-and-low-level-presence-food</a>.
30. USEPA. Supporting Statement for the Information Collection
Request (ICR) entitled: Exemptions of Certain Plant-Incorporated
Protectants (PIPs) Derived from Newer Technologies Rulemaking (Final
Rule; RIN 2070-AK54). EPA ICR No.: 2619.02; OMB Control No. 2070-
0214. (May 2023).

[[Page 34775]]

VIII. FIFRA Review Requirements

Pursuant to FIFRA section 25(a), EPA submitted the draft final rule
to the United States Department of Agriculture (USDA) for review, with
a copy sent to the appropriate Congressional Committees as required
under FIFRA section 25(a). The Agency did not receive any comments from
USDA.
In accordance with FIFRA section 25(d), the EPA asked the FIFRA
Scientific Advisory Panel (SAP) to waive review of the draft final
rule, as was done for the draft proposed rule. The FIFRA SAP waived its
scientific review of the draft final rule on October 12, 2022, because
the rule does not raise scientific or science policy issues that
warrant a scientific review by the SAP.

IX. Statutory and Executive Order Reviews

Additional information about these statutes and Executive Orders
can be found at <a href="https://www.epa.gov/laws-regulations/laws-and-executive-orders">https://www.epa.gov/laws-regulations/laws-and-executive-orders</a>.

A. Executive Orders 12866: Regulatory Planning and Review and 14094:
Modernizing Regulatory Review

This action is a significant regulatory action that was submitted
to the Office of Management and Budget (OMB) for review under Executive
Order 12866 (58 FR 51735, October 4, 1993), as amended by Executive
Order 14094 (88 FR 21879, April 11, 2023). Any changes made in response
to OMB recommendations during that review have been documented in the
docket. EPA prepared an analysis of the potential costs and benefits
associated with this action (Ref. 4) which is summarized in more detail
in Unit I.E., and included in the docket.

B. Paperwork Reduction Act (PRA)

The information collection activities in this 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. 2619.02 (Ref. 30), and identified by OMB Control
No. 2070-0214. You can find a copy of the ICR in the docket for this
rule, and it is briefly summarized here. The information collection
requirements are not enforceable until OMB approves them.
The information collection activities in this rule are associated
with the exemption eligibility process (i.e., self-determination,
request for EPA confirmation, and associated recordkeeping) established
in this rule as an alternative to the existing pesticide registration
and tolerance activities that are currently approved by OMB under OMB
Control No. 2070-0060 (EPA ICR No. 0277.23), OMB Control No. 2070-0142
(EPA ICR No. 1693.10), OMB Control No. 2070-0028 (EPA ICR No. 0143.13,
and OMB Control No. 2070-0024 (EPA ICR No. 0597.13). Once this ICR is
approved, EPA intends to amend the ICR approved by OMB under OMB
Control No. 2070-0060 (EPA ICR No. 0277.23) to incorporate the
information collection activities and burden attributable to this rule.
Respondents/affected entities: See Unit I.A.
Respondent's obligation to respond: Required to obtain the
exemption (40 CFR part 174).
Frequency of response: On occasion.
Total estimated number of respondents: 10.
Total estimated number of responses: 10 (per year), which reflects
an estimate of 1 response per respondent each year. The ICR accounts
for the most conservative burden estimate, which the Agency projects
will be up to 10 submissions per year.
Total estimated burden: 850 hours (per year), which reflects an
approximate burden of 85 hours per submission. Burden is defined at 5
CFR 1320.3(b).
Total estimated cost: $125,800 (per year), includes $0 annualized
capital or operation and 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. When OMB approves
this ICR, the Agency will announce that approval in the Federal
Register and publish a technical amendment to 40 CFR part 9 to display
the OMB control number for the approved information collection
activities contained in this final rule.

C. Regulatory Flexibility Act (RFA)

I certify that this action will not have a significant economic
impact on a substantial number of small entities under the RFA, 5
U.S.C. 601 et seq. In making this determination, EPA concludes that the
impact of concern for this rule is any significant adverse economic
impact on small entities and that the Agency is certifying that this
rule will not have a significant economic impact on a substantial
number of small entities because the rule relieves regulatory burden on
the small entities subject to the rule. The rule is expected to reduce
costs to developers of ``PIPs created through genetic engineering from
a sexually compatible plant'' and ``loss-of-function PIPs,'' and the
cost savings per product are approximately $472,000-$886,000. The cost
savings per product will be realized when the developer submits a
letter of self-determination or requests EPA confirmation, as
applicable. The exemption for ``PIPs created through genetic
engineering from a sexually compatible plant'' and ``loss-of-function
PIPs'' reduces the costs associated with meeting regulatory
requirements for these types of PIPs and therefore removes a potential
barrier to market entry for small entities. Of the entities likely to
develop PIPs that meet the exemptions outlined in this rulemaking, EPA
currently estimates that approximately 80% are small entities.
I have therefore concluded that this action will relieve regulatory
burden for all directly regulated small entities. The basis for this
determination is presented in the small entity analysis prepared as
part of the cost analysis for this rulemaking (Ref. 4), which is
summarized in Unit I.E., and a copy is available in the docket.

D. Unfunded Mandates Reform Act (UMRA)

This action does not contain an unfunded mandate of $100 million or
more as described in UMRA, 2 U.S.C. 1531-1538, and does not
significantly or uniquely affect small governments. This 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.
Accordingly, EPA has determined that the requirements of sections 202,
203, or 205 do not apply to this action.

E. Executive Order 13132: Federalism

This action does not have federalism implications as specified in
Executive Order 13132 (64 FR 43255, August 10, 1999), because 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 action.

F. 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), because it will
not have substantial direct effects on Tribal governments, on the
relationship

[[Page 34776]]

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 action.

G. 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 to those regulatory actions that concern environmental
health or safety risks that the 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
concern an environmental health risk or safety risk.

H. 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 and has not otherwise been designated as a significant
energy action by the Administrator of the Office of Information and
Regulatory Affairs.

I. National Technology Transfer Advancement Act (NTTAA)

This action does not involve technical standards that would require
Agency consideration under NTTAA section 12(d), 15 U.S.C. 272.

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

Executive Order 12898 (59 FR 7629, February 16, 1994) directs
Federal agencies, to the greatest extent practicable and permitted by
law, to make environmental justice part of their mission by identifying
and addressing, as appropriate, disproportionately high and adverse
human health or environmental effects of their programs, policies, and
activities on minority populations (people of color and/or indigenous
peoples) and low-income populations.
EPA believes that this type of action does not concern human health
or environmental conditions and therefore cannot be evaluated with
respect to potentially disproportionate and adverse effects on people
of color, low-income populations and/or indigenous peoples. Although
this action does not concern human health or environmental conditions,
EPA considered potential environmental justice concerns during the
development of the proposed rule, sought comments specifically on this
point with regard to the proposed exemptions, and finds that this
action will not result in disproportionately high and adverse human
health, environmental, climate-related, or other cumulative impacts on
disadvantaged communities.

K. Congressional Review Act (CRA)

This action is subject to the CRA, 5 U.S.C. 801 et seq., and EPA
will submit a rule report to each House of the Congress and to the
Comptroller General of the United States. This action is not a ``major
rule'' as defined by 5 U.S.C. 804(2).

L. Executive Orders 13874: Modernizing the Regulatory Framework for
Agricultural Biotechnology Products and 14801: Advancing Biotechnology
and Biomanufacturing Innovation for a Sustainable, Safe, and Secure
American Bioeconomy

This action is intended to further implement section 4(b) of
Executive Order 13874 (84 FR 27899, June 11, 2019), and section 8 of
Executive Order 14801 (87 FR 56849, September 12, 2022). This final
rule may promote future innovation and competitiveness by efficiently
exempting through regulation qualifying ``PIPs created through genetic
engineering from a sexually compatible plant'' and ``loss-of-function
PIPs'' 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.

Michael S. Regan,
Administrator.

Therefore, for the reasons stated in the preamble, 40 CFR part 174
is amended as follows:

PART 174--PROCEDURES AND REQUIREMENTS FOR PLANT-INCORPORATED
PROTECTANTS

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 definitions for
``Gene'', ``Genetic engineering'', ``Loss-of-function plant-
incorporated protectant'', ``Native allele'', and ``Native gene'' and
revising the definition of ``Sexually compatible'' to read as follows:

Sec. 174.3 Definitions.

* * * * *
Gene, and other grammatical variants such as ``genic,'' means a
unit of heritable genetic material that is comprised of the genetic
material necessary for the production of a substance.
Genetic engineering means the modification of the genome of an
organism using recombinant, synthesized, or amplified nucleic acids or
other techniques excluded from the definition of conventional breeding.
* * * * *
Loss-of-function plant-incorporated protectant means a plant-
incorporated protectant in which the genetic material of a native gene
is modified to result in a pesticidal effect through the reduction or
elimination of the activity of that gene. For purposes of loss-of-
function plant-incorporated protectants, the active ingredient and
pesticidal substance are one and the same and are defined as the
genetic material that has been modified to create the pesticidal trait
(i.e., modification of the sequence of nucleic acids). Loss-of-function
plant-incorporated protectants do not include instances where the
reduction or elimination of the activity of the modified native gene
results in the intentional increase of activity of another pesticidal
gene.
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 source plants that are sexually compatible with the recipient plant.
It does not include genes introduced through genetic engineering from a
source organism that is not sexually compatible with the source plant.
* * * * *
Sexually compatible, when referring to plants, means plants must be
capable of forming a viable zygote 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,

[[Page 34777]]

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 active ingredient of 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 active
ingredient 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 recordkeeping requirements specified in Sec. 174.73 per
sections 8 and 9 of FIFRA, 7 U.S.C. 136f and 136g, and only after
compliance with the relevant eligibility determination procedures
specified in Sec. 174.90:
(1) Plant-incorporated protectant created through genetic
engineering from a sexually compatible plant.
(2) Loss-of-function plant-incorporated protectant.

0
4. Amend Sec. 174.25 by revising the section heading and the
introductory text and adding paragraph (c) to read as follows:

Sec. 174.25 Active ingredient of a plant-incorporated protectant from
a sexually compatible plant created through conventional breeding.

The active ingredient 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 subpart B to read as follows:

Sec. 174.26 Active ingredient of a plant-incorporated protectant
created through genetic engineering from a sexually compatible plant.

The active ingredient is exempt if the conditions in paragraphs (a)
and (b) of this section are met.
(a) The active ingredient is characteristic of the population of
plants sexually compatible with the recipient plant and is created
through genetic engineering from either an insertion of a native gene
into the recipient plant as specified in paragraph (a)(1) of this
section or a modification of an existing native gene in the recipient
plant as specified in paragraph (a)(2) of this section.
(1) Insertion. A native gene is inserted into the genome of the
recipient plant and produces a pesticidal substance identical in
sequence to the pesticidal substance identified in the source plant.
The regulatory regions inserted as part of the native gene must be
identical in nucleic acid sequence to those regulatory regions of the
native gene identified in the source plant.
(2) Modification. The existing native gene is modified to match
corresponding polymorphic sequence(s) in a native allele of that gene
using a single source plant as a template.
(b) This exemption does not apply until the requirements in Sec.
174.21(d) have been met.

0
6. Add Sec. 174.27 to subpart B to read as follows:

Sec. 174.27 Active ingredient of a loss-of-function plant-
incorporated protectant.

The active ingredient is exempt if the following conditions are
met:
(a) The genetic material of a native gene is modified using genetic
engineering to result in a pesticidal effect through the reduction or
elimination of the activity of that gene; and
(b) This exemption does not apply until the requirements in Sec.
174.21(d) have been met.

0
7. Add Sec. 174.73 to subpart D 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 is required to submit
documentation for the determination of eligibility for a plant-
incorporated protectant listed under Sec. 174.21(d) must do both of
the following:
(a) Maintain documentation of either the request for EPA
confirmation or the letter of self-determination (or both, if
applicable) along with all supporting documentation for the specific
exemption listed in subpart E of this part.
(b) Make the documentation outlined in paragraph (a) of this
section available to EPA upon request.

0
8. Add subpart E to read as follows:
Subpart E--Exemption Eligibility Determination Process and Requirements
Sec.
174.90 Determining eligibility.
174.91 Submitting a letter of self-determination.
174.93 Requesting EPA confirmation.
174.95 Documentation for an exemption for a plant-incorporated
protectant created through genetic engineering from a sexually
compatible plant.
174.96 Documentation for an exemption for a loss-of-function plant-
incorporated protectant.

Subpart E--Exemption Eligibility Determination Process and
Requirements

Sec. 174.90 Determining eligibility.

(a) Options for determining eligibility. As required in Sec. Sec.
174.21(d) and 174.541(c), the developer must notify EPA to be eligible
for exemption. Available notification options differ by plant-
incorporated protectant. The developer must do at least one of the
following:
(1) EPA confirmation. Unless permitted in paragraph (a)(2) of this
section, a developer must submit a request for EPA confirmation of
eligibility in accordance with Sec. 174.93. Any developer may submit a
request for EPA confirmation of eligibility in accordance with Sec.
174.93.
(2) Self-determination. A developer may submit a letter of self-
determination in accordance with Sec. 174.91 if the plant-incorporated
protectant qualifies for exemption as one of the following:
(i) A loss-of-function plant-incorporated protectant eligible for
exemption under Sec. 174.27.
(ii) [Reserved]
(b) Where to submit a request for EPA confirmation or letter of
self-determination. A request for EPA confirmation of eligibility or a
letter of self-determination must be submitted electronically.
(c) Claims of confidentiality. Any claims of confidentiality for
information submitted in the request for EPA confirmation or a letter
of self-determination must be made in accordance with the procedures
outlined in Sec. 174.9.
(d) Overlapping determinations of eligibility. If a plant-
incorporated protectant is eligible for a self-determination option, 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.

[[Page 34778]]

(e) Revisiting eligibility determination. If, at any time after EPA
issues a confirmation of eligibility or the letter of self-
determination is submitted, EPA becomes aware of information indicating
that a 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 generally notify
the submitter in writing of EPA's intention to initiate a review of
eligibility for exemption and may request additional information from
the submitter in order to evaluate that eligibility for exemption. Upon
conclusion of its review, EPA will notify the submitter in writing of
its determination as to 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. At any time, if EPA finds or has reason to believe
that a plant-incorporated protectant's non-compliance with FIFRA
requires immediate action, EPA may take such action, including
enforcement, without first informing the submitter of an eligibility
review.
(f) Extension of exemption. An exemption can be extended in one of
two ways. First, if the exempted plant-incorporated protectant is moved
through conventional breeding to other plants, the exemption is
extended to the subsequent plant-incorporated protectant. Second, to
extend the exemption of the plant-incorporated protectant to subsequent
genetic engineering events in other plants, the following exemption-
specific criteria apply:
(1) Plant-incorporated protectant created through genetic
engineering from a sexually compatible plant. An exemption extends to a
plant-incorporated protectant when that plant-incorporated protectant
is genetically engineered by the submitter into another variety of that
same plant species, the substance produced is identical to the
substance produced in the original recipient plant, and no new
modifications were made to the regulatory regions.
(2) Loss of function plant-incorporated protectant. An exemption
extends to a plant-incorporated protectant when that plant-incorporated
protectant is genetically engineered by the submitter into another
variety of that same plant species and the same native gene is targeted
to create the loss-of-function PIP.
(g) No duplication necessary. A developer is not required to submit
duplicative requests for eligibility determination or self-
determination under both Sec. Sec. 174.541(c) and 174.21(d), if it has
already been submitted for purposes of determining eligibility under
Sec. 174.21(d).

Sec. 174.91 Submitting a letter of self-determination.

To self-determine eligibility for the exemption of a plant-
incorporated protectant listed under Sec. 174.90(a)(2), a developer
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 any activity that would be subject to FIFRA absent an
exemption.
(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 telephone number and email address), company name, or other
affiliation.
(2) Identify the plant-incorporated protectant by providing: the
identity of the recipient plant (genus and species), a unique
identifier for the native gene from the National Center for
Biotechnology Information (NCBI) at the National Library of Medicine of
the National Institutes of Health (NLM) at the National Institutes of
Health (NIH) (i.e., Entrez GeneID), the trait type (e.g., insect
resistance), and cite the paragraph under Sec. 174.90(a)(2) that
indicates that the plant-incorporated protectant is eligible for self-
determination.
(3) Complete and submit the certification statement provided in the
electronic submission portal. The statement must be dated and signed by
the certifying official identified in the certification statement.
(c) EPA response. EPA will provide electronic confirmation of
receipt immediately. Electronic confirmation of receipt shall be
equivalent to written confirmation of receipt.
(d) Effective date of exemption. The exemption does not apply until
EPA confirms receipt of the letter of self-determination.

Sec. 174.93 Requesting EPA confirmation.

To request EPA confirmation of eligibility for exemption of a
plant-incorporated protectant listed under Sec. 174.21(d), a developer
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 any activity that would be subject to FIFRA absent an
exemption.
(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, as specified in exemption-
specific sections of this subpart (e.g., Sec. 174.95).
(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 of 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 created through genetic engineering from a sexually
compatible plant.

A developer requesting EPA confirmation of exemption eligibility
for a plant-incorporated protectant created through genetic engineering
from a sexually compatible plant pursuant to Sec. 174.93 must submit
the information in the following paragraphs to EPA. The following
documentation must be maintained by a developer of a plant-incorporated
protectant created through genetic engineering from a sexually
compatible plant per Sec. 174.73:
(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 a plant
species other than the recipient plant species, provide the identity of
the source plant including genus and species and information to support
the determination that the recipient plant and the source plant are
sexually compatible (e.g., through peer-reviewed literature rationale).
(b) Description of the pesticidal trait and how the trait was
engineered into

[[Page 34779]]

the plant. Include a description of the measures that were taken to
ensure that no engineering components (e.g., Cas proteins) are present
in the final plant product and the measures taken to maximize the
likelihood that the modification to the recipient plant is limited to
the intended modification.
(c) Molecular characterization of the plant-incorporated
protectant. A nucleic acid sequence comparison of the plant-
incorporated protectant between the recipient plant and the
comparator(s). A deduced amino acid sequence comparison is additionally
required when the pesticidal substance is proteinaceous. The relevant
comparator(s) for the sequence comparison(s) are determined by the type
of modification:
(1) For Sec. 174.26(a)(1), sequences in the source plant and in
the recipient plant.
(2) For Sec. 174.26(a)(2), sequences in the recipient plant before
the modification, after the modification, and the sequence in the
source plant. The polymorphic site(s) must be indicated.
(d) Information on the history of safe use of the plant-
incorporated protectant. (1) If the pesticidal substance is a known
allergen or mammalian toxin/toxicant (e.g., solanine), describe how
conventional breeding practices are being used to ensure that it does
not exceed human dietary safety levels in the recipient food plant
(i.e., ensure residues of pesticidal substance are not present in food
at levels that are injurious or deleterious and are within the ranges
of levels generally seen in plant varieties currently on the market
and/or known to produce food safe for consumption).
(2) If the source plant is a wild relative of the recipient plant,
describe why the plant-incorporated protectant is not anticipated to
pose a hazard to humans or the environment (e.g., Are levels of the
pesticidal substance produced in the recipient plant within the ranges
of levels generally seen in plant varieties currently on the market
and/or known to produce food safe for consumption? Is the pesticidal
mode of action non-toxic? Does the plant-incorporated protectant lack
sequence similarity to known mammalian toxins, toxicants, or allergens?
Is the plant-incorporated protectant a commonly screened substance and
therefore familiar to plant breeders?).

Sec. 174.96 Documentation for an exemption for a loss-of-function
plant-incorporated protectant.

A developer requesting EPA confirmation of exemption eligibility
for a loss-of-function plant-incorporated protectant pursuant to Sec.
174.93 must submit the information in the following paragraphs to EPA
along with the developer's request for exemption confirmation. The
following documentation must be maintained by a developer of a loss-of-
function plant-incorporated protectant per Sec. 174.73:
(a) Biology of the plant: The identity of the recipient plant,
including genus and species.
(b) Description of the pesticidal trait that results from the loss-
of-function and how the trait was engineered into the plant. Include a
description of the steps that were taken to ensure that no engineering
components (e.g., Cas proteins) remain in the plant and the measures
taken to maximize the likelihood that the modification to the recipient
plant is limited to the intended modification.

0
9. Amend Sec. 174.508 by:
0
a. Revising the section heading and introductory text;
0
b. Redesignating paragraph (c) as paragraph (d); and
0
c. Adding a new paragraph (c).
These revisions and addition read as follows:

Sec. 174.508 Pesticidal substance of 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 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.
* * * * *

0
10. Add Sec. 174.541 to read as follows:

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

Residues of a pesticidal substance are exempt from the requirements
of a tolerance if the conditions in paragraphs (a) through (c) of this
section are met.
(a) The pesticidal substance is characteristic of the population of
plants sexually compatible with the recipient food plant and is created
through genetic engineering from either an insertion of a native gene
into the recipient food plant as specified in paragraph (a)(1) of this
section or a modification of an existing native gene in the recipient
food plant as specified in paragraph (a)(2) of this section.
(1) Insertion. A native gene is inserted into the genome of the
recipient food plant and produces a pesticidal substance identical in
sequence to the pesticidal substance identified in the source plant.
The regulatory regions inserted as part of the native gene must be
identical in nucleic acid sequence to those regulatory regions of the
native gene identified in the source plant.
(2) Modification. The existing native gene is modified to match
corresponding polymorphic sequence(s) in a native allele of that gene
using a single source plant as a template.
(b) The residues of the pesticidal substance are not present in
food from the plant at levels that are injurious or deleterious to
human health.
(c) This exemption does not apply until the requirements in Sec.
174.90 have been met.

[FR Doc. 2023-11477 Filed 5-30-23; 8:45 am]
BILLING CODE 6560-50-P

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