Pesticides; Exemptions of Certain Plant-Incorporated Protectants (PIPs) Derived From Newer Technologies, 64308-64344 [2020-19669]
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ENVIRONMENTAL PROTECTION
AGENCY
40 CFR Part 174
[EPA–HQ–OPP–2019–0508; FRL–10014–10]
RIN 2070–AK54
Pesticides; Exemptions of Certain
Plant-Incorporated Protectants (PIPs)
Derived From Newer Technologies
Environmental Protection
Agency (EPA).
ACTION: Proposed rule.
AGENCY:
FOR FURTHER INFORMATION CONTACT:
The Environmental Protection
Agency (EPA) is proposing regulations
that would allow for an exemption
under the Federal Insecticide,
Fungicide, and Rodenticide Act (FIFRA)
and the Federal Food, Drug, and
Cosmetic Act (FFDCA) for certain PIPs
that are created in plants using
biotechnology, as long as their
pesticidal substances are found in
plants that are sexually compatible with
the recipient plant and meet the
proposed exemption criteria, ensuring
their safety. The current exemption for
PIPs is limited to PIPs moved through
conventional breeding. EPA’s proposed
rule would allow certain PIPs created
through biotechnology to also be exempt
under existing regulations, in cases
where those PIPs pose no greater risk
than PIPs that meet EPA safety
requirements, and could have otherwise
been created through conventional
breeding. The proposed rule also
includes a process through which
developers of PIPs based on sexually
compatible plants created through
biotechnology submit either a selfdetermination letter or request for EPA
confirmation that their PIP meets the
criteria for exemption. For increased
flexibility in bringing PIPs to market, a
developer can also submit both. EPA
anticipates several benefits that may
result from exempting these PIPs. These
include lower costs from reduced
regulatory burden, increased research,
development, and commercialization of
pest control options for farmers,
particularly in minor crops, and
reduced use of conventional pesticides
which could provide environmental
benefits.
DATES: Comments must be received on
or before December 8, 2020.
ADDRESSES: Submit your comments,
identified by docket identification (ID)
number EPA–HQ–OPP–2019–0508,
through the Federal eRulemaking Portal
at https://www.regulations.gov. Follow
the online instructions for submitting
comments. Do not submit electronically
any information you consider to be
SUMMARY:
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Confidential Business Information (CBI)
or other information whose disclosure is
restricted by statute.
Due to the public health concerns
related to COVID–19, the EPA Docket
Center (EPA/DC) and Reading Room is
closed to visitors with limited
exceptions. The staff continues to
provide remote customer service via
email, phone, and webform. For the
latest status information on EPA/DC
services and docket access, visit https://
www.epa.gov/dockets.
Anne Overstreet, Biopesticides and
Pollution Prevention Division (7511P),
Office of Pesticide Programs,
Environmental Protection Agency, 1200
Pennsylvania Ave. NW, Washington, DC
20460–0001; main telephone number:
(703) 305–7090; email address:
BPPDFRNotices@epa.gov.
SUPPLEMENTARY INFORMATION:
I. Executive Summary
A. Does this action apply to me?
You may be potentially affected by
this action if you are a developer or
registrant of a PIP. This proposal also
may affect any person or company who
might petition the Agency for a
tolerance or an exemption from the
requirement of a tolerance for any
residue of a PIP. The following list of
North American Industrial
Classification System (NAICS) codes is
not intended to be exhaustive, but rather
provides a guide to help readers
determine whether this action may
apply to them:
• Pesticide and Other Agricultural
Chemical Manufacturing (NAICS code
325320), e.g., pesticide manufacturers or
formulators of pesticide products,
importers or any person or company
who seeks to register a pesticide or to
obtain a tolerance for a pesticide.
• Crop Production (NAICS code 111),
e.g., seed companies.
• Colleges, universities, and
professional schools (NAICS code
611310), e.g., establishments of higher
learning which are engaged in
development and marketing of PIPs.
• Research and Development in the
Physical, Engineering, and Life Sciences
(except Nanobiotechnology) (NAICS
code 541714), e.g., biotechnology
research and development laboratories
or services.
If you have any questions regarding
the applicability of this action to a
particular entity after reading the
regulatory text, consult the technical
person listed under FOR FURTHER
INFORMATION CONTACT.
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B. What action is the Agency taking?
EPA is proposing to exempt
qualifying ‘‘PIPs based on sexually
compatible plants created through
biotechnology’’ from the requirements
of FIFRA (except for the adverse effects
reporting requirement at 40 CFR 174.71
and a proposed recordkeeping
requirement at 40 CFR 174.73), and the
residues of those PIPs from section 408
of FFDCA. PIPs are defined at 40 CFR
174.3 as ‘‘a pesticidal substance that is
intended to be produced and used in a
living plant, or in the produce thereof,
and the genetic material necessary for
the production of such a pesticidal
substance. [The PIP] also includes any
inert ingredient contained in the plant
or the produce thereof.’’ EPA’s proposal
identifies a class of PIPs, i.e., ‘‘PIPs
based on sexually compatible plants
created through biotechnology,’’ as
those PIPs that are created through
biotechnology and in which the
pesticidal substance is found in plants
that are sexually compatible with the
recipient plant (i.e., the engineered
plant) and that meet specific safety
criteria. Although the amended
definition proposed for ‘‘sexually
compatible’’ specifically refers to a
viable zygote formed through the union
of two gametes, for this proposal EPA
includes in its exemption also PIPs
engineered in plants that are propagated
vegetatively (e.g., potatoes and bananas).
This approach aligns with the Agency’s
longstanding approach for exempting
PIPs in vegetatively propagated plants
created through conventional breeding
and is consistent with the existing
exemption of PIPs from sexually
compatible plants created through
conventional breeding. The proposed
regulatory text for the exemptions from
FIFRA and the FFDCA identifies a
number of factors intended to ensure
that the resulting PIP only produces a
pesticidal substance found in plants that
are sexually compatible with the
recipient plant and thereby ensuring
that these substances do not pose
different risks to humans and the
environment compared to those present
in conventionally bred plants. While
EPA believes the possibility of adverse
effects from the PIPs proposed for
exemption to be highly unlikely, it is
important to note that the adverse
effects reporting requirement under 40
CFR 174.71 would also apply to those
PIPs proposed for exemption, as it does
for currently exempt PIPs from sexually
compatible plants. This requirement
allows EPA to reconsider whether a PIP
continues to meet the criteria for
exemption upon learning of any adverse
effects (e.g., injurious or deleterious
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levels in food plants). As described in
the preamble of the July 19, 2001
Federal Register notice implementing
40 CFR 174.71 (66 FR 37772; July 19,
2001), the reports on human health or
the environment alleged to have been
caused by the PIP would be made to
EPA, but EPA will share such reports
with the Food and Drug Administration
(FDA), and as such, 40 CFR 174.71 is a
means of ensuring that EPA and FDA
can address any potential hazard. The
proposed rule also includes a process
through which developers are required
to submit either a letter of selfdetermination or a request for EPA
confirmation that a PIP based on a
sexually compatible plant created
through biotechnology meets the criteria
for exemption.
C. What is the Agency’s authority for
taking this action?
This action is being proposed under
the authority of FIFRA section 25 (7
U.S.C. 136w) and FFDCA section 408(e)
(21 U.S.C. 346a(e)). FIFRA section
25(a)(1) authorizes EPA to issue
regulations to carry out the provisions of
FIFRA in accordance with certain
procedures prescribed in that section. In
addition, FIFRA section 25(b) allows
EPA to promulgate regulations to
exempt from the requirements of FIFRA
any pesticide which the Administrator
determines is ‘‘of a character which is
unnecessary to be subject to [FIFRA] in
order to carry out the purposes of
[FIFRA].’’
FFDCA section 408(e) authorizes EPA
to initiate actions to establish tolerances
or exemptions for pesticide chemical
residues that meet the safety standard.
See also the discussion in Unit IV.
D. Why is EPA taking this action?
Many plants, including those used for
food, naturally produce substances that
have pesticidal properties. Humans
have relied on the presence of these
substances for millennia to improve
resistance in new agricultural and nonagricultural plant varieties by moving
these traits between sexually compatible
plants through conventional breeding.
Because these substances may be at
unsafe levels in undomesticated plants,
rendering such plants inedible, breeders
have developed established procedures
to ensure that the substances are kept to
safe levels when introduced into plant
varieties intended for human
consumption. For the purposes of
FIFRA, when these substances are
introduced intentionally into a plant for
a pesticidal purpose, the resulting
product is considered a pesticide, and
more specifically, a PIP.
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In 2001, EPA published exemptions
for PIPs moved through conventional
breeding at 40 CFR 174.25, ‘‘plantincorporated protectant from sexually
compatible plant,’’ and at 40 CFR
174.508, ‘‘pesticidal substance from
sexually compatible plant; exemption
from the requirement of a tolerance.’’
For these exemptions, EPA defined
sexually compatible plants as those for
which ‘‘a viable zygote is formed only
through the union of two gametes
through conventional breeding.’’ This
includes those plants which can
exchange genetic information
unrestrictedly with each other through
natural processes, such as pollination,
and also those that are unable to
exchange genetic information freely, but
that are closely related enough that
techniques employed in conventional
breeding can facilitate their
interbreeding. It specifically excludes
plants developed through
biotechnology. At that time, EPA did
not exempt PIPs that are created through
biotechnology and that are found in
sexually compatible plants, but rather
issued a supplemental proposal to
exempt these PIPs because additional
criteria needed to be developed. EPA
ultimately withdrew that proposal in
2018 and indicated that, if the Agency
were to pursue exemption of PIPs
developed through biotechnology in the
future, a new proposed rule would be
issued (Ref. 1), as it became evident that
exemption criteria should be developed
given advances in biotechnology tools
(see Unit II.C.2.).
Recent advances in biotechnology
offer precise means by which genes
coding for pesticidal substances can be
inserted into a plant genome and allow
for engineering of those genes that
already exist within a plant. Due to
these technical characteristics, PIPs can
now be created that are virtually
indistinguishable from those created
through conventional breeding. EPA
was therefore able to develop specific
exemption criteria that reflect the
precise nature of new technologies. The
proposed criteria are intended to
identify a group of PIPs that would be
exempt from both the requirements of
FIFRA, with the exception of the
adverse effects reporting requirement
(codified at 40 CFR 174.71) and the
recordkeeping requirement (proposed at
40 CFR 174.73), and that would also
qualify for a tolerance exemption under
the FFDCA. These PIPs are created
through the use of biotechnology and,
given the proposed regulatory criteria,
pose no greater risk than the sexually
compatible PIPs that are already
exempt. EPA refers to this group as
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‘‘PIPs based on sexually compatible
plants created through biotechnology.’’
The Agency’s findings, including an
assessment of the environmental and
human health risks for this proposal, are
presented in Unit VI.
EPA’s proposal limits the type of
plants, and thus the gene pool, that can
act as a source of these exempt PIPs to
those that are sexually compatible with
the recipient plant. EPA is also
proposing to amend the definition of
‘‘sexually compatible’’ to state that ‘‘a
viable zygote can be formed through the
union of two gametes through
conventional breeding.’’ EPA believes
that this proposed definition is more
biologically correct, because it refers to
the ability of two gametes to form a
viable zygote. This amendment would
also allow for use of the phrase
‘‘sexually compatible’’ in the proposed
exemptions. As a housekeeping task,
EPA proposes to amend the existing
PIPs from sexually compatible plants
exemption at 40 CFR 174.25, along with
its accompanying exemptions at 40 CFR
174.508 and 174.705, to clarify that
those apply only to PIPs created through
conventional breeding, thus
differentiating them from those PIPs
proposed for exemption that are created
through biotechnology. These changes
are necessary due to the amended
definition of ‘‘sexually compatible’’ but
will not change implementation of the
existing exemption for PIPs from
conventional breeding. EPA’s proposed
exemptions are developed to be
consistent with the current exemption at
40 CFR 174.25 for PIPs developed
through conventional breeding
techniques, and are expected to alleviate
regulatory burden for developers that
may wish to utilize biotechnology in
creating pesticide products that are
equivalent to those already exempt
under FIFRA and the FFDCA.
On June 11, 2019, Executive Order
13874 (84 FR 27899, June 11, 2019) on
‘‘Modernizing the Regulatory
Framework for Agricultural
Biotechnology Products’’ was issued.
The exemption proposed by EPA in this
document is intended to further
implement section 4(b) of that Executive
Order, which directs the U. S.
Department of Agriculture (USDA),
EPA, and FDA (‘‘to the extent consistent
with law and the principles set forth in
section 3’’ of the order) to ‘‘use existing
statutory authority, as appropriate, to
exempt low-risk products of agricultural
biotechnology from undue regulation.’’
Among other things, section 3 of
Executive Order 13874 provides that
regulatory decisions should be sciencebased and evidence-based, taking
economic factors into account as
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appropriate and consistent with
applicable law; that regulatory reviews
should be conducted in a timely and
efficient manner; and that biotechnology
regulations should be transparent,
predictable, and consistent. As part of
the effort to implement Executive Order
13874, the USDA recently revised its
regulations at 7 CFR part 340 through a
rulemaking entitled ‘‘Movement of
Certain Genetically Engineered
Organisms.’’ (85 FR 29790, May 18,
2020). In that rule, USDA amended its
regulations regarding the movement
(importation, interstate movement, and
environmental release) of certain
genetically engineered organisms in
response to advances in genetic
engineering and USDA’s understanding
of the plant pest risk posed by
genetically engineered organisms,
thereby reducing the regulatory burden
for developers of organisms that are
unlikely to pose plant pest risks. Both
EPA and USDA use the term
‘‘conventional breeding’’ in their
respective rulemakings. However, it
should be noted that each Agency uses
the term in the context of its own
regulations and that the term may have
slightly different meanings depending
on context.
The process for exemption under both
the EPA proposal and USDA’s rule
includes the option for developers to
self-determine whether their product
meets the criteria for exemption. EPA is
proposing to require the developer
notify EPA of that self-determination
with a letter or, in the alternative, to
request EPA confirmation that a
particular PIP qualifies for exemption
(developers may also submit both a selfdetermination letter and a confirmation
request). Because developers of
exempted PIPs will still be subject to
FIFRA’s adverse effects reporting
requirement and the recordkeeping
requirement that is part of EPA’s
proposed rule, EPA believes it is
appropriate to require submission of a
self-determination letter or a
confirmation request in order to enable
EPA to monitor compliance with EPA’s
regulations and to take action to avoid
adverse health impacts, if necessary.
E. What are the estimated incremental
impacts of this action?
EPA has evaluated the potential
incremental impacts of the proposed
exemptions in the document entitled
‘‘Cost Analysis of the Proposed Rule
Exempting Certain Plant-Incorporated
Protectants (PIPs) from Registration’’
(Ref. 2), which is available in the
docket, discussed in greater detail in
Unit VI.A., and is briefly summarized
here.
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1. Benefits of the Proposed Exemptions
The rule is estimated to reduce overall
registration costs to developers of PIPs
based on sexually compatible plants
created through biotechnology, and the
cost savings per product are
approximately $444,000–$459,000. Of
the entities likely to develop PIPs based
on sexually compatible plants created
through biotechnology, EPA currently
estimates that approximately 80% are
small entities. These cost savings would
be realized as EPA approval of new
active ingredients are sought. The
proposed exemption of PIPs based on
sexually compatible plants created
through biotechnology is likely to
remove a potential barrier to market
entry for small entities.
2. Costs of the Proposed Exemptions
In the proposed rule, for a PIP to be
exempt, a developer would be required
to notify EPA through a selfdetermination letter or through a request
for EPA confirmation that the PIP meets
the exemption criteria. The proposed
rule would also require that a developer
maintain documents supporting its
determination. Developer costs
pertaining to the required exemption
eligibility determination process and
recordkeeping are estimated in the
Agency cost analysis for the proposed
rule. These costs are representative of
developer labor and laboratory costs
that would be required to generate the
necessary information and data.
The developer cost of the exemption
eligibility determination process is
expected to be less than what would
otherwise be required of a developer to
obtain a registration. The cost analysis
developed by the Agency is an overall
cost reduction for developers of these
types of PIPs. Adverse effects due to
aggregate exposure to residues of
pesticidal substances from PIPs based
on sexually compatible plants created
through biotechnology through the
dietary, non-food oral, dermal and
inhalation routes are highly unlikely, as
the exemption eligibility determination
process requires that the developer
certify that the PIP meets the exemption
criteria.
F. What should I consider as I prepare
my comments for EPA?
1. Submitting CBI
Do not submit this information to EPA
through regulations.gov or email.
Clearly mark the part or all of the
information that you claim to be CBI.
For CBI information in a disk or CD–
ROM that you mail to EPA, mark the
outside of the disk or CD–ROM as CBI
and then identify electronically within
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the disk or CD–ROM the specific
information that is claimed as CBI. In
addition to one complete version of the
comment that includes information
claimed as CBI, a copy of the comment
that does not contain the information
claimed as CBI must be submitted for
inclusion in the public docket.
Information so marked will not be
disclosed except in accordance with
procedures set forth in 40 CFR part 2.
2. Tips for Preparing Your Comments
When preparing and submitting your
comments, see the commenting tips at
https://www.epa.gov/dockets/
comments.html.
II. Background
A. What are Plant-Incorporated
Protectants (PIPs)?
Through natural evolutionary
processes, plants develop mechanisms
to resist pests. The mechanisms of
resistance can be varied, including, for
example, the production of metabolites
that have toxic properties, biochemical
cascades resulting in localized necrosis
of plant tissue, or the production of
substances in response to pest attack
(Ref. 3). Humans have for approximately
10,000 years selected and bred certain
plants for food, feed, and fiber, and a
frequently selected characteristic has
been the ability to resist pests (Ref. 4).
When humans intend to use substances
involved in these mechanisms in plants
for ‘‘preventing, destroying, repelling, or
mitigating any pest,’’ the substances fall
into the FIFRA definition of pesticide,
regardless of whether the pesticidal
capability evolved in the plant, or was
introduced by conventional breeding or
through the techniques of
biotechnology.
A PIP is defined as ‘‘pesticidal
substance that is intended to be
produced and used in a living plant, or
in the produce thereof, and the genetic
material necessary for the production of
such a pesticidal substance. It also
includes any inert ingredient contained
in the plant or produce thereof’’ (40 CFR
174.3). For example, scientists can take
the gene encoding for a pesticidal
protein from a wild relative of corn and
introduce the gene into another corn
plant’s genetic material. The plant then
manufactures the pesticidal protein that
kills the pest when the pest feeds on the
plant. The genetic material necessary for
the production of such a pesticidal
substance also meets the FIFRA
statutory definition of a pesticide,
because such genetic material is
introduced into the plant with the intent
of ultimately producing a pesticidal
effect. For transgenic PIPs, the
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relationship between the genetic
material, the pesticidal substance, and
the pesticidal effect has typically been
linear (i.e., the genetic material inserted
into the plant directly produces the
pesticidal substance that confers the
pesticidal effect). However, PIPs found
in conventionally bred plants and their
wild relatives can introduce additional
biological complexity. For example, as
described in the 2001 preamble (66 FR
37772; July 19, 2001), a PIP can
encompass genetic material encoding an
enzyme that ultimately leads to the
production of the pesticidal substance
(e.g., solanine). PIPs can also include
traits intended for a pesticidal purpose
that result from the loss-of-function of
an existing plant gene where, for
example, the inactivation of a gene
coding for a plant receptor protein
confers disease resistance. It is
important to clarify that EPA regulates
the modified genetic material that
confers the loss-of-function trait as the
pesticidal substance which is consistent
with both the 1994 proposed rule
preamble (59 FR 60496; November 23,
1994) and the 2001 final rule preamble
(66 FR 37772; July 19, 2001)
promulgating 40 CFR 174. EPA is
requesting comment on whether a
clarifying exemption specific to loss-offunction traits would be helpful (Unit
VII.E.), although EPA considers these
traits to be included under the current
exemption at 40 CFR 174.25 and the
proposed exemption at 40 CFR 174.26.
For the sake of clarity, although the
genetic material meets the statutory
definition of a pesticidal substance
under FIFRA, in this preamble EPA uses
‘‘pesticidal substance’’ to mean a
protein or other substance produced
from genetic material that has pesticidal
properties as per the definition at 40
CFR 174.3.
Although the PIP is regulated by EPA,
the plant containing a PIP is not
regulated by EPA. Additionally, many
types of traits can be engineered into
plants, but only those intended for a
pesticidal purpose are PIPs. EPA does
not regulate non-pesticidal traits under
FIFRA or the FFDCA, or any other
federal statutes. For example, EPA does
not regulate traits introduced into a
plant using biotechnology that enhance
vitamin C content for nutritional
purposes. Food from such a plant
variety would be regulated by FDA.
B. How are PIPs regulated?
1. By EPA
Because PIPs are pesticides, they are
regulated under FIFRA and, to the
extent necessary, FFDCA section 408.
Under FIFRA, unless there is an
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applicable exemption, EPA is required
to register PIPs so they may lawfully be
sold and distributed. EPA evaluates
each PIP application to determine
whether its proposed use would cause
unreasonable adverse effects on the
environment. To avoid potential
unreasonable adverse effects, the
Agency may impose (and has imposed)
terms and conditions on registration of
PIPs (e.g., conditions to slow insect
resistance). Additionally, EPA has the
authority to take enforcement action
with respect to any violations of
activities subject to FIFRA. Under the
FFDCA, EPA has established
exemptions from the requirement of a
tolerance for residues of PIPs in food.
EPA evaluates each PIP to determine
whether exposure to the residue of that
PIP in or on food/feed is safe (i.e., there
is a reasonable certainty that no harm
will result from aggregate exposure to
the pesticide, which includes all
anticipated dietary exposures and all
other exposures for which there is
reliable information).
2. By Other Federal Agencies
EPA is part of an interagency effort to
improve, clarify, and streamline the
regulation of biotechnology, including
the regulation of plants developed using
biotechnology that includes oversight by
the USDA, FDA, and EPA. This
approach was articulated by the White
House Office of Science and Technology
Policy in a policy statement in 1986 (51
FR 23302; June 26, 1986) and updated
most recently in 2017 (Ref. 5). This
document is known as the Coordinated
Framework for the Regulation of
Biotechnology. EPA is the federal
agency primarily responsible for the
regulation of pesticides. In fulfilling this
mission, EPA works closely with the
USDA, which has responsibilities under
the Plant Protection Act, and the FDA,
which has responsibilities under the
FFDCA, including the enforcement of
tolerances set by EPA under the FFDCA.
EPA, USDA, and FDA consult and
exchange information when such
consultation is helpful in resolving
safety questions. In addition to the
Coordinated Framework, Executive
Order 13874 requires EPA, FDA, and
USDA to further coordinate their
activities with regard to agricultural
biotechnology. The PIPs that EPA is
proposing to exempt are also exempted
from regulation by USDA under 7 part
340 as revised by USDA’s recently
issued final rule titled ‘‘Movement of
Certain Genetically Engineered
Organisms.’’ (85 FR 29790, 29791–92,
May 18, 2020).
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C. What actions did EPA take to prepare
for this proposed rule?
1. Updated Issue Paper
For this proposal, EPA updated an
issue paper entitled ‘‘Natural Toxicants
in Food from Plants’’ (Ref. 6). This issue
paper summarizes and reviews the
literature on the most common toxicants
found in crop plants and discusses the
regulatory status and current testing
methods for each of those toxicants.
Information from this issue paper was
used in the Agency’s safety analysis for
residues of PIPs based on sexually
compatible plants created through
biotechnology in or on food or feed.
This document is available in the docket
for this rulemaking.
2. Withdrawal of Previous Rule Proposal
In May 2018, the Agency withdrew a
proposed rule entitled: ‘‘PlantIncorporated Protectants (PIPs);
Exemption for Those Derived Through
Genetic Engineering From Sexually
Compatible Plants’’ (Ref. 1). The
proposed rule was withdrawn because
the Agency determined that to exempt
PIPs derived through genetic
engineering from sexually compatible
plants, more scientifically current
criteria needed to be developed to
reflect advances in genetics and
molecular biology since the 2001
proposal. Consequently, EPA indicated
that to pursue a future exemption, the
Agency would issue a new proposed
rule based on the types of products
possible to create with newest
technology rather than issue a final rule
based on previous proposals (Ref. 1). As
discussed in Unit VI., in developing this
proposal for PIPs based on sexually
compatible plants created through
biotechnology, the Agency developed
criteria that are scientifically more
current and that more accurately
describe the PIPs that would be
exempted. Additionally, because the
previous rule was withdrawn, the
Agency will not consider comments
made on the previous proposal.
Therefore, if you believe a comment
made regarding previous proposals is
relevant to this proposal, you must
resubmit the comment for this proposal.
3. Scientific Advisory Committees
The FIFRA Scientific Advisory Panel
(SAP) is a body of experts that provide
independent scientific advice to EPA on
issues related to pesticides, such as the
impact to human health or the
environment. FIFRA requires that EPA
submit any proposed and final rule
promulgated under FIFRA section 25(a)
to the SAP for comment on the impact
of the rule on human health and the
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environment. For this proposed rule,
EPA requested that the FIFRA SAP
waive review of the proposal. In
developing the scientific rationales in
this proposal, EPA relied on previously
provided advice from the FIFRA SAPs
and analyses by the National Research
Council of the National Academy of
Science, Engineering and Medicine
(Table 1).
TABLE 1—ADVICE SOURCES FOR KEY CONCEPTS TO EXEMPT PIPS BASED ON SEXUALLY COMPATIBLE PLANTS CREATED
THROUGH BIOTECHNOLOGY
Concept
Relevance to current proposal
Relevant report
Exemption of PIPs based on sexually compatible plants created through biotechnology.
Establishes the overall scope of the exemption. PIP would be developed by engineering a plant’s genetic material to result in a
PIP that could otherwise be found in the
gene pool of the plant itself, e.g., in other
varieties of the crop plant or in a sexually
compatible relative. This scope should result in no novel dietary or environmental exposures.
Establishes how much a gene could be modified (e.g., through truncations, deletions, or
point mutations) while still retaining scientific support for the idea that humans
have consumed the products of such genes
for generations and that products of such
modifications present no new dietary exposures.
Establishes criteria to ensure that any introduced gene is part of the genetic diversity
found in plants that are sexually compatible
with the recipient plant.
Establishes criteria to ensure that any substance expressed from the modified genetic
material is not expressed at higher levels,
in different tissues, or at different developmental stages than seen in plants that are
sexually compatible with the recipient plant.
Establishes criteria to ensure that only precise
modifications are introduced into the modified plant—e.g., modifications of regulatory
regions, allelic substitutions, introduction
only of genes that falls within the genetic diversity found in plants that are sexually
compatible with the recipient plant.
Establishes streamlined procedures for developers to notify EPA of a PIP that qualifies
for exemption.
FIFRA SAP 1992, 1993, 1994; NRC 2000.
(Ref. 7, 8, 9, 10).
Criteria limiting the types of possible modifications introduced into a PIP in the plant.
Introduction of a gene isolated from a plant in
the same gene pool as the recipient plant.
Ensuring expression profile falls within the gene
pool of the plant and plants that are sexually
compatible with the plant.
Precision associated with newly developed
techniques of genetic engineering, e.g., allowing genes present in the plant to be edited.
Exemption eligibility determination process .......
Two scientific advisory committees,
the FIFRA SAP and the Biotechnology
Science Advisory Committee (BSAC), a
sister committee of equal stature later
merged into the FIFRA SAP, offered
advice that forms the foundation of
EPA’s current approach to PIPs. The
Agency’s 2001 final rule exempting PIPs
from sexually compatible plants created
through conventional breeding (40 CFR
174.25) and proposed exemptions
(under both FIFRA and the FFDCA) for
PIPs from sexually compatible plants
derived through genetic engineering (see
Unit II.C.2.) are based on advice from
the FIFRA SAP.
The proposed exemptions in this
document, are similarly based on advice
provided by the FIFRA SAP, as the
1992, 1993, and 1994 FIFRA SAP
reviews did not distinguish between
PIPs moved among sexually compatible
plants through conventional breeding
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and those moved through genetic
engineering. Taking that advice into
account, along with additional advice
from NASEM reports in 2000, 2004,
2016, and 2017, this proposal describes
the criteria that PIPs based on sexually
compatible plants created through
biotechnology, must meet to qualify for
the proposed exemption. In response to
the Agency’s 1994 proposal to exempt
PIPs from sexually compatible plants
derived through genetic engineering,
NASEM pointed out in its report in
2000 that the Agency’s proposed
language would exempt genetic material
moved among plants in sexually
compatible populations through the use
of biotechnology without taking into
consideration whether the moved
genetic material would be expressed in
the same pattern and at the same levels
as occurs naturally in the plant (Ref. 10
at p. 129). This directly led to the
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FIFRA SAP 2004, https://archive.epa.gov/
scipoly/sap/meetings/web/html/101304_
mtg.html.
FIFRA SAP 2005, https://archive.epa.gov/
scipoly/sap/meetings/web/html/120605_
mtg.html.
FIFRA SAP 1992, 1993, 1994; NRC 2000.
(Ref. 7, 8, 9, 10).
FIFRA SAP 1993, 1994; NRC 2000. (Ref. 7,
9, 10).
NRC 2004; NASEM 2016, 2017. (Ref. 4, 11,
12).
NRC 2004; NASEM 2017. (Ref. 11, 12).
Agency incorporating a criterion
addressing expression levels and pattern
in the proposed exemption
requirements set out in this document.
In addition to the advice from the 1992,
1993, and 1994 FIFRA SAPs, EPA
received additional advice from expert
groups on scientific topics relevant to
the current PIP proposed rule including,
but not limited to, the 2004 and 2005
FIFRA SAPs that discussed how much
a gene could be modified (e.g., through
truncations, deletions, or point
mutations) while still retaining
scientific support for the conclusion
that humans have consumed the
products of such genes for generations
and that products of such modifications
present no new dietary exposures; and
several reports from NASEM in 2004,
2016, and 2017 that describe the
precision of modifications that can be
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achieved using new technologies for
genetic engineering (Ref. 4, 11, 12).
The proposal in this document also
describes an exemption eligibility
determination process in which a
developer must notify the Agency
through either a self-determination
letter or a request for EPA confirmation
that the PIP meets the exemption
criteria. For additional flexibility, EPA
also proposes to allow a developer to
submit both a self-determination letter
and request for EPA confirmation,
should they so choose. This proposed
set of options takes into account advice
from two reports by NASEM (Ref. 10,
12).
4. Stakeholder Engagement
EPA has participated in domestic and
international events relevant to the
proposed exemptions, all of which
provided opportunities to engage with
the regulated and research communities,
the public, and other U.S. government
agencies. Recent conferences and
workshops include: Genome Editing—
Putting Together the Pieces 2018; 2018
OECD Conference on Environmental
Health and Safety of Applications of
Gene Editing; Responsible CRISPR:
Genome Engineering Conference 2019;
North Carolina State University/ASTA
Plant Breeding Workshop 2019; Plant
Genomics & Gene Editing Congress:
USA 2019; and the 2019 Global
Regulatory Workshop on Plant and
Animal Biotechnology Innovation.
These meetings supported EPA’s
horizon-scanning efforts for novel PIP
products and presented engagement
opportunities with the scientific and
regulated community. These meetings
also provided opportunities to develop
practical knowledge of techniques and
technology used in plant breeding and
genetic engineering, which supported
development of exemption criteria and
rationale for assessing risks of PIPs
created using biotechnology. Topics of
discussion included plant breeding,
technical aspects of biotechnology, and
considerations regarding regulation and
risk assessment of products.
III. Statutory Authorities and
Regulatory Framework
EPA is authorized to regulate
pesticides under two federal statutes.
FIFRA regulates the sale, distribution,
and use of pesticide products through a
licensing (registration) scheme. FFDCA,
among other things, regulates the safety
of pesticide chemical residues in or on
food and feed. EPA is proposing these
exemptions under FIFRA section
25(b)(2) and FFDCA section 408.
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A. What authority does EPA have under
FIFRA section 25(b)(2)?
This section of FIFRA allows EPA to
exempt, by regulation, any pesticide
from some or all of the requirements of
FIFRA, if the pesticide is of a character
that is unnecessary to be subject to all
the requirements of FIFRA in order to
carry out the purposes of that Act (7
U.S.C. 136w(b)(2)). EPA interprets
FIFRA section 25(b)(2) to authorize EPA
to exempt a pesticide or category of
pesticides that EPA determines (1) poses
a low probability of risk to the
environment and (2) is not likely to
cause unreasonable adverse effects to
the environment even in the absence of
regulatory oversight under FIFRA.
In evaluating whether use of the
pesticide poses a low probability of risk
to the environment, EPA considers the
extent of the potential risks caused by
use of the pesticide to the environment,
including humans, animals, plants,
water, air, and land. Potential risks to
humans include dietary risks (which are
assessed under the safety standard of
the FFDCA section 408) and non-dietary
risks, such as those resulting from
occupational or residential exposure to
the pesticide. EPA will not exempt
pesticides under FIFRA section 25(b)(2)
that fail to meet the required low
probability of risk.
In evaluating whether the use of a
pesticide is likely to cause unreasonable
adverse effects on the environment even
in the absence of regulatory oversight
under FIFRA, EPA balances potential
risks to human health and the
environment from use of the pesticide
against the potential benefits associated
with its use. In balancing risks and
benefits, EPA considers the economic,
social, and environmental costs and
benefits of the use of the pesticide.
B. What authority does EPA have under
FFDCA section 408?
Under the FFDCA, food or feed
containing pesticide residues may be
considered adulterated (and subject to
seizure if introduced, delivered for
introduction, or received in interstate
commerce) unless there is a tolerance or
an exemption from the requirement of a
tolerance in place covering those
residues (21 U.S.C. 342(a)(1)(B)). EPA is
authorized to establish tolerances (the
maximum level) for residues in or on
food or establish exemptions from the
requirement of a tolerance, if it
determines that the tolerance or
exemption would be safe (21 U.S.C.
346a(b)(2), (c)(2)). Section 408 of the
FFDCA defines ‘‘safe’’ to mean that
‘‘there is a reasonable certainty that no
harm will result from aggregate
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64313
exposure to the pesticide chemical
residue, including all anticipated
dietary exposures and all other
exposures for which there is reliable
information’’ (21 U.S.C.
346a(c)(2)(A)(ii)). This includes
exposure through drinking water, and
residential and other indoor uses, but
does not include occupational exposure.
In addition, FFDCA section 408 requires
EPA to give special consideration to
exposure of infants and children to the
pesticide chemical residue in
establishing an exemption and to
‘‘ensure that there is a reasonable
certainty that no harm will result to
infants and children from aggregate
exposure to the pesticide chemical
residue’’ (21 U.S.C. 346a(b)(2)(C)(ii)(I))
and (c)(2)(B)). FFDCA section
408(b)(2)(D) specifies other general
factors EPA must consider in
establishing an exemption (21 U.S.C.
346a(b)(2)(D)). In establishing a
tolerance or an exemption from the
requirement of a tolerance, the FFDCA
does not authorize EPA to consider
potential benefits associated with use of
the pesticide chemical. Although EPA
establishes tolerances or exemptions
from the requirement of a tolerance
under the FFDCA, FDA enforces these
tolerances.
C. What is the relationship of FIFRA
exemptions to the FFDCA section 408
standard?
EPA uses the FFDCA section 408
safety standard, as described in Unit
III.B., in evaluating whether a pesticide
used in or on food and feed meets the
standard for exemption under FIFRA
with respect to human dietary risk. A
pesticide in or on food and feed
presents a low probability of human
dietary risk if it meets the FFDCA
section 408 standard for an exemption
from the requirement of a tolerance.
Additionally, a determination that a
pesticide chemical meets the safety
standard of FFDCA section 408(c) may
also be relevant to whether a pesticide
qualifies for a FIFRA section 25(b)(2)
exemption with respect to human health
risks arising from other routes of
exposure. In determining whether a
pesticide chemical residue is safe, EPA
must consider ‘‘available information
regarding the aggregate exposure levels
of consumers . . . to the pesticide
chemical residue and to other related
substances, including dietary exposure
under the tolerance and all other
tolerances in effect for the pesticide
chemical residue, and exposures from
other non-occupational sources’’ (21
U.S.C. 346a(b)(2)(D)(vi)).
FIFRA, however, does not provide for
exemption of a pesticide in or on food
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based solely upon consistency with the
FFDCA section 408 exemption standard.
At a minimum, EPA also must evaluate
risks to the environment and risks
arising from occupational exposure to
humans and determine that such risks
meet both exemption criteria (i.e.,
posing a low probability of risk to the
environment and being not likely to
cause unreasonable adverse effects to
the environment even in the absence of
regulatory oversight under FIFRA).
IV. Proposed Regulatory Framework
for Exempting PIPs Based on Sexually
Compatible Plants Created Through
Biotechnology
In 2001, EPA created a regulatory
structure at 40 CFR 174.21, for
exempting PIPs from the requirements
of FIFRA, other than the adverse effects
reporting requirement at 40 CFR 174.71.
First, the active ingredient of the PIP
must meet codified criteria addressing
FIFRA requirements listed in 40 CFR
part 174, subpart B; these provisions
primarily deal with the pesticidal
substance of the PIP and the genetic
material necessary for production of that
substance (40 CFR 174.21(a)). Second,
when the PIP is intended to be
produced and used in a food or feed
crop, an exemption from the
requirement of tolerance must be in
place for residues of the PIP (40 CFR
174.21(b)). Third, any inert ingredient
that is part of the PIP must be exempt
under 40 CFR 174.705 (174.21(c)).
EPA is proposing to create an
exemption from FIFRA requirements for
certain PIPs based on sexually
compatible plants created through
biotechnology. These PIPs are created
through biotechnology and their
pesticidal substance is found in plants
that are sexually compatible with the
recipient plant. To satisfy the
requirement of 40 CFR 174.21(a), EPA
proposes to create a new section under
subpart B for 40 CFR 174.26 containing
criteria that an active ingredient of a PIP
based on a sexually compatible plant
created through biotechnology must
meet to qualify for the new exemption.
To meet the condition of 40 CFR
174.21(b), EPA is proposing to exempt
from the requirement of a tolerance
under the FFDCA residues of PIPs based
on sexually compatible plants created
through biotechnology that are present
in or on food or feed. This exemption
and the safety criteria that the residues
must meet to qualify for the exemption
will be codified in 40 CFR part 174,
subpart W with other PIP-related
FFDCA exemptions.
Per 40 CFR 174.3, an inert ingredient
is defined as ‘‘any substance, such as a
selectable marker, other than the active
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ingredient, where the substance is used
to confirm or ensure the presence of the
active ingredient, and includes the
genetic material necessary for the
production of the substance, provided
that genetic material is intentionally
introduced into a living plant in
addition to the active ingredient.’’
Additionally, in 2001 EPA stated that
‘‘with regard to the enzymes, precursors,
or intermediates in biosynthetic
pathways necessary for anabolizing the
pesticidal substance, EPA at this time
considers them to be part of the plantincorporated protectant because the
substance is intended to ‘‘ensure the
presence of the active ingredient’’—i.e.,
it is an inert ingredient.’’ EPA is
therefore proposing to expand the scope
of the existing inert ingredient
exemption at 40 CFR 174.705 to include
inert ingredients initiated through a
modification made using biotechnology,
as EPA believes the intermediary
substances described in the 2001 quote
would be included in this.
Other than these intermediary
substances, the Agency does not expect
other, more traditional inert ingredients
(e.g., a gene coding for herbicide
tolerance) in PIPs based on sexually
compatible plants created through
biotechnology. This is because older
methods of biotechnology that have
typically been used to create PIPs use a
bacterial plasmid vector to incorporate a
DNA construct into the genome of the
plant. The DNA construct is an
artificially constructed segment of
nucleic acid consisting of regulatory
elements, the gene coding for the active
ingredient, and sometimes a gene
coding for an inert ingredient. Because
the gene coding for the active ingredient
and the gene coding for the inert
ingredient are located on the same DNA
construct and will therefore be
incorporated into the plant genome
together, the inert ingredient is able to
confirm or ensure the presence of the
active ingredient. However, newer
biotechnology techniques, such as
CRISPR, that are precise enough to
create PIPs proposed for this exemption
do not use DNA constructs in this way.
Instead, these newer techniques allow
developers to perform targeted edits to
existing genes, and do not require the
incorporation of inert ingredients in the
same way as historically seen in
transgenic PIPs. Modifications coding
for substances similar to inert
ingredients seen in transgenic PIPs (e.g.,
herbicide resistance) would instead be
incorporated into the recipient plant
genome independent of the active
ingredient. Because newer techniques
allow for these events to be introduced
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independently, the modification cannot
confirm or ensure the presence of the
active ingredient. The modification
therefore would not meet the definition
of an inert ingredient under 40 CFR
174.3 because it is an independent, nonpesticidal trait not regulated under
FIFRA. EPA expects that any
ingredients intentionally added during
the development of PIPs based on
sexually compatible plants created
through biotechnology that are specific
to the production of the active
ingredient (e.g., guide RNA, DNA
nuclease) would either be transiently
transformed or would be removed (e.g.,
through segregation of the trait) during
the breeding process. If these traits have
not been removed from the final product
the product would not meet the criteria
proposed under the new 40 CFR 174.26
and would not qualify for the new
exemptions. The Agency requests
comment on whether there are any inert
ingredients other than the intermediary
substances described in the 2001 quote
that will remain in the final plant
products containing PIPs based on
sexually compatible plants created
through biotechnology. If inert
ingredients other than the intermediary
substances described in the 2001 quote
are identified in the responses to the
previous request, the Agency also
requests comment as to whether the
inert ingredients in PIPs based on
sexually compatible plants created
through biotechnology require the
proposal of an exemption that would be
specific to those created through
biotechnology and would allow
developer flexibility in the nucleic acid
sequence (see Unit VII.A.). EPA is also
proposing to add a recordkeeping
requirement and exemption eligibility
determination process to 40 CFR 174.21
applicable to PIPs based on sexually
compatible plants created through
biotechnology that would require a
developer to notify EPA that the PIP
meets the criteria for exemption from
the requirements of FIFRA under the
conditions of 40 CFR 174.21 and to
maintain supporting documentation of
its determination. The exemption
eligibility determination can be
submitted in two, non-mutually
exclusive ways: a self-determination
letter or a request to EPA for
confirmation of the self-determination.
V. Proposed Revisions to the General
Provisions (Subpart A)
Provisions that apply to PIPs are
codified in 40 CFR part 174, subpart A.
EPA is proposing several changes to
these general provisions.
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A. What are the proposed new
definitions?
Definitions that apply to PIPs are
codified in 40 CFR part 174, subpart A,
and EPA is proposing to add new
definitions for ‘‘gene,’’ ‘‘native allele,’’
and ‘‘native gene.’’ Only one term,
‘‘gene,’’ is discussed in this unit. The
other proposed definitions are discussed
in detail in Unit VI.
EPA is proposing to define ‘‘gene’’ as
meaning a ‘‘functional unit of heritable
genetic material that is comprised of the
genetic material necessary for the
production of a substance.’’ All living
organisms encode the substances they
need to perform their normal metabolic
functions in discrete units in their
genome, called genes. This includes the
pesticidal substances plants produce to
defend against pests. Genes are further
comprised of several functionally
distinct regions within that unit that
work in concert to produce the
substance that is encoded by the gene’s
nucleic acid sequence. The two regions
relevant to the criteria proposed to
circumscribe PIPs based on sexually
compatible plants created through
biotechnology are the regulatory and
coding regions. Together, they
determine the function of a given gene
within the plant. The sequence within
the regulatory region of a gene
determines the amount of substance that
is produced and the spatiotemporal
pattern of expression within the plant
tissues. The coding region, which is the
sequence that is ultimately transcribed,
determines the identity of the substance
that is produced from the gene (e.g., the
amino acid sequence of a protein).
Because the regulatory and coding
regions of a given gene are inherited
together as a single unit, they have
evolved together over evolutionary time.
In proposing the definition of a gene,
the Agency clearly identifies and
delineates the physical unit of the
genetic material within the plant
genome that encodes the substance and
leads to the production of the pesticidal
substance and, in doing so, restricts any
genetic modifications made through
biotechnology that would fall under the
proposed exemption to the coding and
regulatory regions. Defining the term
‘‘gene’’ was not necessary in the context
of PIPs before this proposed exemption
because previous methods employed to
create PIPs, such as particle gun
transformation, relied on the integration
of a genetic construct, which included
other genetic sequences in addition to a
gene.
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B. What is the proposed amendment to
the existing definition for ‘‘sexually
compatible?’’
The term ‘‘sexually compatible’’ is
currently defined at 40 CFR 174.3 as
‘‘when referring to plants, means a
viable zygote is formed only through the
union of two gametes through
conventional breeding.’’ EPA is
proposing to amend the existing
definition for ‘‘sexually compatible’’ to
instead state ‘‘when referring to plants,
means a viable zygote can be formed
through the union of two gametes
through conventional breeding.’’ EPA
believes this amended definition is
more in line with the biological
definition of sexually compatible, in
that being sexually compatible is widely
accepted to mean that two organisms are
capable of forming viable progeny. The
amended definition also allows the
Agency to use the term ‘‘sexually
compatible’’ in the biological sense in
the proposed exemption. The proposed
clarification to the sexually compatible
definition necessitates changes to the
existing PIP from sexually compatible
plant exemption at 40 CFR 174.25, along
with its accompanying exemptions at 40
CFR 174.508 and 174.705; however,
these changes do not result in
modifications to the existing exemption
for PIPs moved through conventional
breeding. EPA discusses this proposed
clarification in detail in Unit VI.F.
VI. Proposed Exemptions and
Exemption Eligibility Determination
Process (Subparts B, D, E, and W)
EPA is proposing to create an
exemption from FIFRA requirements for
certain PIPs based on sexually
compatible plants created through
biotechnology (described in Unit VI.A.)
and to create a companion exemption
from the FFDCA section 408
requirement of a tolerance for residues
of certain PIPs based on sexually
compatible plants created through
biotechnology in or on food or feed
(described in Unit VI.B.). EPA is also
proposing to add a new subpart (subpart
E) to 40 CFR part 174 that would codify
the procedures and requirements for the
new exemption eligibility determination
process (described in Unit VI.C.). EPA is
proposing a new section in subpart D,
40 CFR part 174.73, that would codify
recordkeeping requirements for
exemptions (described in Unit VI.D.). To
accommodate the exemption eligibility
determination process and
recordkeeping requirements, EPA is
making some clarifying edits to 40 CFR
174.21 as described in Unit VI.E.
Finally, EPA is also clarifying the
relationship between the proposed
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exemptions for PIPs based on sexually
compatible plants created through
biotechnology and the exemptions
currently at 40 CFR 174.25, 174.508,
and 174.705 by modifying 174.25,
174.508, and 174.705 as described in
Unit VI.F.
A. What is the proposed FIFRA
exemption for the active ingredients of
PIPs based on sexually compatible
plants created through biotechnology?
1. What the Proposed Exemption Covers
EPA currently exempts PIPs from
sexually compatible plants as described
in 40 CFR 174.25. Because EPA had
previously defined sexually compatible
plants as including only those plants
that create viable progeny through
conventional breeding, the current
exemption excludes PIPs created
through biotechnology, even if they are
equivalent to PIPs that could have been
developed through conventional
breeding. Technological advances
surrounding genome editing (e.g.,
meganucleases, zinc-finger nucleases,
transcription activator-like effector
nucleases, and CRISPR-Cas nuclease
system) allow for targeted, rapid, and
precise changes directly to
chromosomes of living cells (Ref. 12).
These technologies allow for such
precise editing of the genome, that the
resulting genes can be indistinguishable
from those found in a plant created
through conventional breeding. Given
the recent advances in technology, EPA
was able to develop specific criteria
proposed in a new section for 40 CFR
174.26 to exempt certain PIPs developed
through the use of biotechnology that
pose no greater risk than the currently
exempt sexually compatible PIPs. The
definition of sexually compatible is also
proposed to be amended to refer to the
ability of two gametes to form a viable
zygote and thus be more biologically
correct in stating that ‘‘a viable zygote
can be formed through the union of two
gametes through conventional
breeding.’’ This amendment allows for
use of the phrase ‘‘sexually compatible’’
in the proposed exemption.
The proposed criteria and supporting
proposed definitions of ‘‘native gene’’
and ‘‘native allele’’ circumscribe the
PIPs based on sexually compatible
plants created through biotechnology
that would qualify for the new
exemption. The proposed criteria and
the proposed definitions limit the types
of PIPs that would be exempt to those
that are found in plants that are sexually
compatible with the recipient plant and
meet specific safety criteria, thereby
resulting in negligible risk of novel
exposures. It is important to note that
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although the amended definition
proposed for ‘‘sexually compatible’’
specifically refers to a viable zygote
formed through the union of two
gametes, for this proposal EPA includes
in its exemption also PIPs engineered in
plants that are propagated vegetatively
(e.g., potatoes and bananas). This
approach aligns with the Agency’s
longstanding approach for exempting
PIPs in vegetatively propagated plants
created through conventional breeding
and is consistent with the existing
exemption of PIPs from sexually
compatible plants created through
conventional breeding.
The definition of ‘‘native genes’’
limits the substances eligible for
exemption to those found in plants that
are sexually compatible with the
recipient plant. As genes code for and
produce substances, restricting the
genes to only those found in plants that
are sexually compatible with the
recipient plant will limit the PIPs
eligible for the new exemption to those
found in plants that are sexually
compatible with the recipient plant. The
term ‘‘native’’ is used in the scientific
literature in the context of cisgenes (e.g.,
a native promoter is a promoter
endogenous to that gene). However, the
Agency seeks comment on use of the
term ‘‘native’’ in the names of ‘‘native
gene’’ and ‘‘native allele’’ and associated
definitions as the Agency does not mean
to imply with the use of the term
‘‘native’’ that genes which originated
through conventional breeding
techniques like mutagenesis would
somehow be excluded from the
proposed exemption. It is the Agency’s
intention that alleles found in sexually
compatible plants that may have been
created through conventional breeding
would be included in the definition of
‘‘native allele’’ and ‘‘native gene.’’
Native genes comprising the gene
pool of sexually compatible plant
populations have been developed
through the processes of mutation,
selection, and genetic exchange. The
proposed exemption captures ongoing
diversification within gene pools by
including within the proposed criteria a
definition for native alleles. The
definition of ‘‘native allele’’ is similarly
limited to only those variants of native
genes that are found in plants that are
sexually compatible with the recipient
plant.
EPA also proposes to capture
additional ongoing diversification
within existing native genes through the
concept of differentially expressed
genes. These are changes to a native
gene that result in alterations in the
amount of substance that is produced
from that gene. An additional restriction
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on differentially expressed genes
requires that the original pesticidal
substance is preserved, which again
limits eligible pesticidal substances to
only those that are found in plants that
are sexually compatible with the
recipient plant. Native genes, native
alleles, and differentially expressed
genes represent the genetic diversity of
sexually compatible plants; thus, these
criteria limit exempt pesticidal
substances of PIPs based on sexually
compatible plants created through
biotechnology to only those substances
that are found in plants that are sexually
compatible with the recipient plant.
For agricultural plants, those defined
as being sexually compatible would
include existing plant cultivars,
landraces (i.e., a locally isolated variety
of a domesticated plant species adapted
to the natural and cultural environment
in which it lives), and breeding lines, as
well as plant relatives that can breed
with crops but are not currently used as
agricultural plants. Including
nonagricultural relatives in the sexually
compatible pool is appropriate, as some
traits found in nonagricultural wild
relatives of cultivated plants, although
not expressed in existing agricultural
cultivars, have been accessible in plant
breeding by conventional breeding
techniques. For example,
nonagricultural plant relatives may
express defense mechanisms (i.e.,
pesticidal substances) that have been
lost during domestication of crop plants
and thus have not been entirely utilized
in agricultural varieties.
Plant breeders have for many years
been following established practices to
ensure safety when moving genes into
agricultural varieties from
nonagricultural relatives, particularly
from wild relatives, with no indication
that substances resulting from these
genes present higher levels of risk than
those from genes moved only amongst
agricultural varieties as long as those
established practices are diligently
followed (Ref. 13, 14, 15, 16). The
ability to produce viable offspring is
only possible in nature for organisms
that possess many traits (and the genetic
material encoding them) in common.
Therefore, many of the traits present in
agricultural plants and their wild
relatives are likely to be similar in
nature; the fact that the specific
substance from the nonagricultural
relative may not be found in the
agricultural variety today does not mean
that breeders do not have the experience
and tools to ensure that it will be
present in safe levels if transferred to
the agricultural variety. Therefore, the
likelihood is negligible that the transfer
of such a substance via biotechnology
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from a nonagricultural relative to an
agricultural one would pose a greater
risk than if it were transferred through
conventional breeding. The same logic
defining the sexually compatible gene
pool for agricultural crop plants also
applies to other plants such as
ornamental, turf, and semi-managed
plants (e.g., trees).
EPA’s proposed criteria and
associated definitions are based on the
ability of closely related plants to
hybridize and share genetic information.
Because the substances produced by
native genes and native alleles are
present in sexually compatible plants,
breeders have experience in ensuring
that the substances will be at safe levels.
This is also true for differentially
expressed genes (i.e., genes with
modified regulatory regions) because the
proposed exemption criteria require that
(a) the substance produced from the
genetic material be not different than
what was being produced prior to the
modification, (b) the expression profile
of the pesticidal protein does not exceed
the limits seen in the sexually
compatible plant population of the
recipient plant. Although the proposed
criteria allow for the use of
biotechnology, the associated
definitions are written to intentionally
exclude ‘‘transgenes,’’ which can be
generally defined as derived from a
source organism unable to share genetic
material with the recipient plant
through breeding. EPA does not
consider transgenes to be native to the
gene pool or a part of the genetic
diversity of the recipient plant.
Transgenic traits have been the focus of
current PIP registration activities since
1995 (e.g., those derived from the
bacterium Bacillus thuringiensis), and
the registered PIPs generally present
novel exposure scenario considerations
for the transgenic trait.
2. Proposed Criteria and Associated
Definitions
The Agency is proposing to define
‘‘native gene’’ to mean ‘‘a gene that is
identified in the recipient plant or
plants that are sexually compatible with
the recipient plant; and has never been
derived from a source that is not
sexually compatible with the source
plant.’’ The phrase ‘‘has never been
derived from a source that is not
sexually compatible with the source
plant’’ is meant to clarify that a PIP
would qualify for the proposed
exemption only if the native gene is
present in the source plant as a result of
conventional breeding. For example, if a
bacterial endotoxin (e.g., from the
source Bacillus thuringiensis) was
engineered into plant ‘‘A’’ (the source
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plant), this bacterial endotoxin-based
PIP would not qualify as a native gene
to be used in plant ‘‘B’’ (the recipient
plant) under the proposed exemption,
even if plant ‘‘B’’ is sexually compatible
with plant ‘‘A’’. This is because while
plant ‘‘B’’ and ‘‘A’’ can interbreed, the
bacterium Bacillus thuringiensis (the
source) and plant ‘‘A’’ (the source plant)
are not sexually compatible. This
proposed limitation on the source of the
PIP therefore prevents a developer from
claiming that a gene that encodes for a
PIP is a ‘‘native gene’’ under the
proposed definition when it is not, i.e.,
when the gene has been derived from a
source that is not sexually compatible
with the source plant. Given this
explanation of the intent behind the
phrase ‘‘never derived,’’ EPA seeks
comment on whether the use of the
phrase in the proposed definition of
‘‘native gene’’ is clear.
‘‘Native allele’’ means ‘‘a variant of a
native gene that is identified in the
genetic diversity of plants that are
sexually compatible with the recipient
plant.’’ This definition is meant to
clarify that the native allele must be a
variant found in plants that are sexually
compatible with the recipient plant,
thereby limiting the potential pesticidal
substances to those found in that
population. By stating that the native
allele is a variant of a native gene, the
restriction that the genetic material
cannot be derived from a source that is
not sexually compatible with the source
plant also applies to native alleles.
Equally important are two
considerations, discussed in detail in
the following sections, that are captured
by the proposed criteria for 40 CFR
174.26 and that EPA believes together
constitute the basis for meeting the
FIFRA section 25(b)(2) standard for
exemption: the pesticidal substance is
found in plants that are sexually
compatible with the recipient plant; and
limitations on expression profile.
a. The Pesticidal Substance Is Found in
Plants That Are Sexually Compatible
With the Recipient Plant
The proposed provisions for 40 CFR
174.26(a) delineate the scope of the new
exemption for PIPs based on sexually
compatible plants created through
biotechnology to only include those
substances that are found in sexually
compatible plants and substances with
which plant breeders have experience.
The regulatory text identifies two major
categories that specify what will qualify
as an exempt PIP pesticidal substance:
(i) The insertion of new genetic
material; and (ii) The modification of
existing genetic material. Modifications
of existing genetic material are further
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broken down into: Modifications
resulting in the differential expression
of a gene, modifications resulting in a
native allele, and modifications
resulting in the differential expression
of a native allele. The restrictions on the
intended insertion or modification, as
discussed in this section, ensure that no
substance novel to plants that are
sexually compatible with the recipient
plant is produced.
By limiting the types of modifications
permissible to those resulting in a
pesticidal substance found in plants that
are sexually compatible with the
recipient plant (including substances
already in the recipient plant), EPA can
ensure that no substance novel to plants
that are sexually compatible with the
recipient plant is produced. This allows
the Agency to ensure that PIPs based on
sexually compatible plants created
through biotechnology can meet the
FIFRA section 25(b)(2) exemption
standard because the modification
would present a low risk of
unreasonable adverse effects to humans
and the environment due to the history
of ensuring safe exposure through
conventional breeding to the exempt
substance. Criteria specific to the
permissible modifications are described
as follows.
i. The Insertion of New Genetic Material
For the insertion of new genetic
material, 40 CFR 174.26(a)(1) proposes
to limit insertions to native genes. EPA
finds it important to include a native
gene insertion option in its proposed
exemption of PIPs based on sexually
compatible plants created through
biotechnology, because there may be
gene variability among sexually
compatible plants. For example, plant
genomes can be highly variable with the
presence or absence of entire genes
across different crop lines. If native gene
insertion was excluded from the
proposed exemption, EPA would be
excluding a class of modifications that
can be found in sexually compatible
plant populations. For native gene
insertion, the phrase proposed for 40
CFR 174.26(a)(1), ‘‘A native gene is
engineered into a non-genic location of
the recipient plant genome, resulting in
a pesticidal substance identical to the
pesticidal substance identified in the
source plant,’’ contains two criteria.
First, the phrase ‘‘engineered into a nongenic location’’ is intended to preclude
the insertion of the native gene into an
existing gene. This is because the
insertion of the native gene in the
coding region of an existing gene within
the recipient plant may then lead to
production of a novel substance (e.g., a
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partial or modified substance) by the
existing gene.
Second, the phrase ‘‘resulting in a
pesticidal substance identical to the
pesticidal substance identified in the
source plant’’ ensures that the substance
produced by the inserted native gene
does not result in a substance with
which breeders have no experience in
preventing unsafe exposures. The
requirement for an identical substance
to be produced, rather than requiring
the native gene to be composed of an
identical nucleic acid sequence, allows
for some flexibility in the nucleic acid
sequence of the genetic material
inserted into the recipient plant. It is
important to allow for this flexibility
because many nucleotide variations
found within the coding region of the
genetic material necessary for the
production of a proteinaceous substance
are silent, in that they do not result in
changes to the amino acid sequence of
the encoded protein. Thus, for
proteinaceous substances, it is therefore
permissible to insert a native gene that
is composed of a nucleic acid sequence
that is not identical to that found in the
source plant so long as the pesticidal
substance for which the nucleic acid
sequence codes is identical to that
identified in the source plant. However,
no such flexibility in the modification of
the nucleic acid sequence of the coding
region is granted for non-proteinaceous
substances, i.e., in cases when the
genetic material codes for the
production of a type of RNA that is not
subsequently translated into a protein
(e.g., miRNA), as every nucleic acid in
the coding region is reflected in the final
sequence of the non-proteinaceous
substance. For both proteinaceous and
non-proteinaceous substances,
flexibility is permissible in the
nucleotide sequence of the regulatory
regions. This allows for modifications to
the expression level of the PIP resulting
from the native gene insertion, so long
as it meets expression profile criterion
174.26(b) as discussed in Unit VI.A.2.b.
ii. The Modification of Existing Genetic
Material
Proposed provisions for 40 CFR
174.26(a)(2) describe permissible
modifications of existing genetic
material and is further delineated into
four possible categories: Modifications
resulting in the differential expression
of a gene, modifications resulting in a
native allele, modifications resulting in
the differential expression of a native
allele, and modifications resulting in the
loss-of-function of an existing gene.
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(A) Modifications Resulting in the
Differential Expression of a Gene
For the first category, the phrase
proposed for 40 CFR 174.26(a)(2)(i),
‘‘the existing native gene in the
recipient plant is modified to alter the
amount of pesticidal substance
produced without altering the identity
of the pesticidal substance produced,’’
limits the permissible modification in
three ways. First, the modification must
be made within the existing native gene
in the recipient plant. The types of
genes that can be modified only include
those that have never been derived from
sources that are not sexually compatible
with the recipient plant; e.g., it is not
permissible to adjust the expression
level of a Bt gene. Second, the
permissible modification is limited to
changes that result in changes to the
amount of pesticidal substance. While
the abundance of a substance in a plant
is not solely determined by its level of
expression (i.e., the amount of
messenger RNA produced), it is
reasonable to assume that they generally
correlate, e.g., reducing the expression
of a gene is expected to also reduce the
abundance of the substance that is
encoded by that gene (Ref. 17).
Third, the phrase ‘‘without altering
the identity of the pesticidal substance
produced’’ prevents modifications to the
coding region of the gene that result in
a partial or modified pesticidal
substance. By requiring that the identity
of the pesticidal substance be preserved,
EPA can ensure that the identity of the
substance produced by that gene
remains the same as it was before the
modification. In other words, a novel
substance cannot be produced as a
result of the modification; the only
modification permitted is a change in
the expression level of the substance
produced by a gene. This position is
consistent with the advice of the FIFRA
SAP in the October 2004 meeting on
‘‘Issues Associated with Deployment of
a Type of Plant-Incorporated Protectant
(PIP), Specifically Those Based on Plant
Viral Coat Proteins (PVCP–PIPs),’’
which stated that in the context of
maintaining a ‘‘safe history’’
assumption, ‘‘only changes that affect an
expressed protein are of concern and
that changes to regulatory and
untranslated regions are not relevant.’’
(FIFRA SAP meeting held October 13–
15, 2004, page 44 of minutes, Unit
VI.A.3.a., Table 1). The statement that
‘‘changes to regulatory and untranslated
regions are not relevant,’’ indicates that
modifications to those genetic regions
do not result in a novel substance and
therefore are not modifications of
concern. Additional criteria
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surrounding permitted expression
profiles are discussed in Unit VI.A.2.b.
(B) Modifications Resulting in a Native
Allele
For the second category, the phrase in
proposed 40 CFR 174.26(a)(2)(ii) ‘‘the
genetic material that encodes the
substance of the existing native gene is
modified to result in a pesticidal
substance that is identical to the
pesticidal substance encoded by a
native allele of that gene,’’ limits the
types of modifications that could qualify
for exemption. Like the restriction on
differentially expressed genes,
modifications to the recipient plant
genome resulting in a native allele must
be made within the existing native gene
in the recipient plant. This criterion is
intended to limit modifications solely to
a single gene and would therefore
exclude from exemption modifications
that would affect more than one gene,
e.g., those affecting chromosomal
structure.
Although EPA recognizes that largescale changes like translocations may be
considered genetic variants, changes
that affect the structure of chromosomes
can affect many genes along the
chromosome and are likely to disrupt or
change the substances made by those
genes. Insufficient information is
available to allow the Agency to a priori
conclude which structural changes
would result in novel exposures, and
therefore which changes may or may not
result in unreasonable adverse effects.
Thus, at this time, the Agency is unable
to make a generic risk assessment on the
consequences of chromosomal
structural modifications and is not
proposing an exemption that would
allow for changes such as chromosomal
inversions, translocations, or
rearrangements. This does not preclude
the Agency from registering these types
of products or proposing an exemption
at a later time should information
become available that supports a
determination of low risk.
The second half of the phrase, ‘‘to
result in a pesticidal substance that is
identical to the pesticidal substance
encoded by a native allele of that gene,’’
is another key limitation applied to
native alleles and is based on the same
concepts underlying the no novel
exposure argument articulated for native
genes in Unit VI.A.2.a.i. Briefly,
requiring that the pesticidal substance
produced in the recipient plant be
identical to the substance encoded by
the native allele ensures that there will
be no novel situations for plant
breeders, and therefore no novel
exposures. This requirement also allows
for more flexibility in the modifications
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made to the recipient plant, in a way
that restricting the nucleic acid
sequence would not. Again, no such
flexibility in the modification of the
nucleic acid sequence of the coding
region is granted for non-proteinaceous
substances, i.e., in cases when the
genetic material codes for the
production of a type of RNA that is not
subsequently translated into a protein
(e.g., miRNA), as every nucleic acid in
the coding region is reflected in the final
sequence of the non-proteinaceous
substance.
(C) Modifications Resulting in the
Differential Expression of a Native
Allele
For the third category, proposed 40
CFR 174.26(a)(2)(iii) states, ‘‘the existing
genetic material is modified pursuant to
both (i) and (ii).’’ This phrase is
intended to indicate that it is also
acceptable to create a differentially
expressed native allele so long as the
criteria under proposed 40 CFR
174.26(a)(2)(i) and 174.26(a)(2)(ii) are
met.
(D) Modifications Resulting in the Loss
of Function of a Gene
For the fourth category, the phrase
proposed for 40 CFR 174.26(a)(2)(vi),
states ‘‘The existing native gene in the
recipient plant is modified to lose
function through the reduction or
elimination of the substance encoded by
that gene.’’ EPA believes a separate
exemption category to allow for
instances in which the pesticidal trait in
the plant is created via the loss-offunction of an existing gene helps
clarify that the rule is intended to cover
these types of modifications. To that
end, EPA specifically uses the term
‘‘substance’’ rather than ‘‘pesticidal
substance’’ for this exemption category
when referring to the native gene
product (e.g., protein). For example, a
gene coding for a receptor protein may
be modified to result in the loss-offunction of that protein to confer disease
resistance. By specifying that the
substance must maintain the same
identity, EPA therefore prevents the
production of modified proteins not
previously identified in the gene pool
while still allowing for modifications in
the coding region that ultimately
prevent the production of a protein (e.g.,
premature termination codon).
Additionally, modifications in the
regulatory region of a gene would be
allowed under the proposed exemption
as these do not result in changes to the
identity of the substance produced by
the genetic material. EPA requests
comment on whether an exemption
category specific to loss-of-function
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traits (rather than including them in
proposed 174.26) would be clearer (see
Unit VII.E.).
b. Limitations on Expression Profile
The proposed criterion at 40 CFR
174.26(b), ‘‘the pesticidal substance is
not expressed at higher levels, in
different tissues, or at different
developmental stages than identified in
a plant that is sexually compatible with
the recipient plant,’’ is a key limitation
to prevent novel dietary and
environmental exposures. The
limitation on levels is important
because endogenous plant compounds
that result in plant resistance to pests
can be toxic to mammals or other nontarget organisms (Ref. 11). Limiting the
expression profile of pesticidal
substances to that found in a plant
capable of being sexually compatible
with the recipient plant ensures that the
assumptions used to justify the
proposed exemption (specifically, a long
history of breeder experience with such
substances and situations) support the
statutory findings required to exempt
PIPs based on sexually compatible
plants created through biotechnology.
For example, breeders will be able to
ensure that modifications that lead to an
increase in the expression of a substance
are limited to levels accepted in
conventional breeding because of their
experience with the levels observed in
plants that are sexually compatible with
the recipient plant. The level of
expression of pesticidal substances is
expected to vary among sexually
compatible plants depending on
environmental conditions and due to
intrinsic variations in their potential to
express a substance (Ref. 17). Variation
exists even among plants of the same
variety due to different weather and soil
condition (Ref. 18). As such, limiting
changes in the expression of a pesticidal
substance not to exceed levels found
within a sexually compatible plant
supports meeting the FIFRA section
25(b)(2) exemption standard because
such changes do not result in exposure
levels not otherwise encountered
through conventional breeding.
The proposed phrase also ensures that
modifications allowed under the
proposed exemption do not result in
changes in the expression pattern of
pesticidal substances. Specifically, this
criterion ensures that pesticidal
substances are only expressed in the
same plant tissues and at the same
developmental stages as what is found
in a sexually compatible plant. For
example, an insect toxin typically
produced in the leaves of a plant would
not meet the proposed exemption
criterion if the plant is modified to
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produce the toxin in the nectar or
pollen, as this may result in novel
exposure of pollinators to the toxin. To
ensure that the exempt PIPs are low risk
and meet the FIFRA section 25(b)(2)
exemption standard, EPA finds it
necessary that pesticidal substances
would not exceed expression levels or
be expressed in different tissues or at
different developmental stages from the
exposure encountered among sexually
compatible plants.
3. Risk Analysis
EPA considered several factors in
determining whether PIPs based on
sexually compatible plants created
through biotechnology that meet the
criteria under proposed 40 CFR 174.26
could be exempted from FIFRA
requirements in order to meet the 40
CFR 174.21(a) requirement. That
consideration relied upon the large body
of knowledge that currently exists on
sexually compatible plants and genetic
diversity. The factors include: ‘‘(1) Low
potential for novel exposures; (2) Low
potential for levels of PIPs based on
sexually compatible plants created
through biotechnology to exceed levels
found in sexually compatible plants; (3)
Low potential for PIPs based on sexually
compatible plants created through
biotechnology to move from cultivated
plants to wild or weedy relatives
through gene flow and increase
weediness; (4) Low potential for
occupational and non-occupational
risks to humans; and (5) Low potential
for resistance selection pressure posed
by PIPs based on sexually compatible
plants created through biotechnology to
exceed that found in sexually
compatible plants.’’ EPA also evaluated
considerations specific to newer
biotechnology techniques related to PIPs
based on sexually compatible plants
created through biotechnology.
In addition to the analyses discussed
in this unit for exemption under FIFRA,
EPA also performed similar analyses for
the proposed tolerance exemption under
FFDCA discussed in Unit VI.B. EPA
refers readers to the detailed discussions
in that unit for information specific to
the dietary safety of PIPs based on
sexually compatible plants created
through biotechnology.
a. Large Body of Knowledge
In the issue paper entitled ‘‘FIFRA:
Benefit and Environmental Risk
Considerations for Inherent PlantPesticides’’ (Ref. 23), EPA describes a
large part of the information base on
nontarget plants, insects, birds,
mammals and other herbivores that the
Agency relied on for its evaluation of
the potential effects of PIPs based on
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sexually compatible plants created
through biotechnology on the
environment. In addition, to understand
the history of exposure of non-target
organisms to substances found in nature
that are equivalent to PIPs based on
sexually compatible plants created
through biotechnology, EPA used the
large body of literature on the effect on
humans of consumption of food from
sexually compatible plants generated
from epidemiological studies,
nutritional assessments, animal model
testing and biochemical studies (Ref. 24,
25, 26, 27, 28, 29, 30, 31, 32) to draw
conclusions on the potential risk for
animal non-targets, including birds and
fish, which might consume food
containing the PIPs proposed for
exemption. Testing in animal models
can supply information that is
extrapolated to make conclusions on the
effect of a substance on humans;
similarly, information and conclusions
drawn in the dietary risk assessment on
the effects on humans can be
extrapolated to predict effects on nonhuman mammals and other animals in
an assessment of environmental risk. In
addition, there is a long history of
humans using foods containing PIPs as
food for domesticated and other
animals, including birds and fish. EPA
relied on this history of exposure and
the large literature generated by a
century of systematic studies of the
constituents of food (Ref. 23) to assess
PIPs based on sexually compatible
plants created through biotechnology.
EPA also considered scientific
knowledge from a number of
disciplines, including plant genetics,
plant physiology, phytopathology,
biochemistry, ecology, evolutionary
biology, genomics, and plant breeding.
From the disciplines of plant physiology
and biochemistry, EPA considered, for
example, information on plant
metabolism, the production of
substances that may have a pesticidal
effect, and conditions that may limit the
production of such substances (Ref. 33).
The Agency also used information from
the science of phytopathology to
characterize the pest resistance
mechanisms in plants in order to
understand the types of traits PIPs based
on sexually compatible plants created
through biotechnology may confer to
recipient plants (Ref. 3). The sciences of
ecology and evolutionary biology were
considered for information on genetic
diversity, mutation, and reproductive
isolation mechanisms in populations
(Ref. 34) to understand the types of
genetic changes that are likely to occur
when plants interbreed. Plant breeding
and genetics were considered to
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describe the mechanisms of
incompatibility and interbreeding (Ref.
35, 36), which aided EPA in
determining when plants are likely to
interbreed. Information from genomics
and molecular biology were considered
to understand the ability of newer
biotechnology techniques to create traits
equivalent to those found in
conventionally bred plants (Ref. 23, 37,
38, 39, 40, 41, 42, 43, 44, 45, 46).
Finally, recommendations from
several FIFRA SAPs and NASEM
reports were considered in the
development of the proposed exemption
criteria for PIPs based on sexually
compatible plants created through
biotechnology, and when describing the
types of genetic modifications in the
recipient plant that are unlikely to result
in novel exposure to humans and the
environment (see Table 1 in Unit
II.C.3.).
b. Low Potential for Novel Exposure
Given that PIPs based on sexually
compatible plants created through
biotechnology are intended to represent
a subset of substances present in plants
that plant breeders have experience
with, EPA does not expect novel
exposures from the substances involved.
Pesticidal traits, and the genetic
material encoding them, have evolved
and been developed in plant
populations through the processes of
mutation, selection, and genetic
exchange among sexually compatible
species (Ref. 47, 48). The ability to
produce viable offspring is only possible
for organisms that are genetically
similar and possess many traits in
common. Traits, and the genetic
material encoding them, can be passed
through a plant population by breeding.
The mixing of genetic material that
occurs through breeding results in
sexually compatible plants having
similar genetic material and similar
traits. Due to the mixing of traits by
mating, similar exposure scenarios are
expected for plants that are capable of
being sexually compatible, in other
words, substances in sexually
compatible plants are expected to be
similar and therefore, only substances
that plant breeders are already familiar
with are expected to be present in
sexually compatible plants. This
conclusion is consistent with the 1992,
1993, and 1994 FIFRA SAP meetings
that indicated that sexually compatible
plants are more likely to have a common
constitution than unrelated plants and
thus movement of genetic material
between sexually compatible plants is
less likely to lead to novel exposures
(Ref. 7, 8, 23).
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For agricultural plants, those defined
as capable of being sexually compatible
would also include existing plant
cultivars, landraces, and breeding lines,
as well as plant relatives that interbreed
with crops but that are not currently
used as agricultural plants. Plant
breeders have for many years been
moving genes into agricultural varieties
from nonagricultural relatives with no
indication that substances resulting
from these genes present higher levels of
risk than those from genes moved only
amongst agricultural varieties (Ref. 13,
14, 15, 16). Therefore, the likelihood
that the inclusion of nonagricultural
varieties as potential source plants
would pose an increased potential for
novel environmental exposures from
PIPs based on sexually compatible
plants created through biotechnology is
low.
If a population of sexually compatible
plants normally possesses a pesticidal
substance, organisms that encounter
plants in that population have likely
been exposed to the pesticidal substance
in the past, perhaps over multiple
generations. These past exposures,
particularly if they occur over long
periods of time, may lead to a degree of
adaptation, or tolerance in the
population of organisms exposed to the
pesticidal substance (Ref. 49). Relatedly,
the proposed exemption would not
affect exposure patterns because the
proposed criteria require that the
pesticidal substance have an expression
profile found in sexually compatible
plants (e.g., the pesticidal substance is
expressed in the same developmental
stages or tissues). Any avoidance
strategies of nontarget organisms (e.g.,
avoid eating certain parts of the plant)
would still be protective in the case of
PIPs based on sexually compatible
plants created through biotechnology.
Thus, the potential is low that PIPs
based on sexually compatible plants
created through biotechnology would
pose novel exposures for organisms that
typically encounter related plants.
Genetic diversity is created over time
and EPA proposes to capture some of
the ongoing diversification not
identified in existing native genes or
native alleles through the inclusion of
changes resulting in the alteration of the
amount of substance produced by
existing genes, so long as no novel
substance is produced and the
substance is not produced in different
tissues or at different developmental
stages than those found in sexually
compatible plants. Modifications that
lead to differential expression levels of
a substance are not expected to result in
levels that exceed the boundaries of the
variation found in sexually compatible
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plants due to physiological constraints
that are related to energy expenditure
(further discussed in Unit VI.A.3.c.).
Therefore, the potential for novel
exposures to occur with the differential
expression of existing genes, or the
movement of native genes and native
alleles among sexually compatible
plants, is low, because no substance
novel to plants capable of being sexually
compatible with the recipient plant will
be produced, nor will the substance be
found at higher levels, in tissues, or at
developmental stages in which it is not
currently found.
c. Low Potential for Levels of PIPs Based
on Sexually Compatible Plants Created
Through Biotechnology To Exceed
Levels Found in Sexually Compatible
Plants
EPA has evaluated whether there are
likely to be quantitative changes in
levels of PIPs based on sexually
compatible plants created through
biotechnology expressed by the
recipient plant, such that adverse effects
to the environment or to humans might
occur (see Unit VI.B. for an analysis on
human dietary risk). EPA has
determined that the potential of such an
event is low because the highest levels
of pesticidal substances likely to be
expressed with PIPs based on sexually
compatible plants created through
biotechnology are not likely to result in
significantly different environmental
exposure levels.
An analysis discussing the likely
range of expression of PIPs in sexually
compatible plants was presented in an
EPA issue paper, entitled: ‘‘FIFRA:
Benefit and Environmental Risk
Considerations for Inherent PlantPesticides’’ (Ref. 23). A summary of the
analysis and how it applies to the
proposed exemption is presented here.
EPA first considered whether any
increase in the levels of substances,
including PIPs, that plants normally
produce is likely to exceed the ranges
normally found within and between
plant varieties and uncultivated plants.
The level of production of such
substances normally varies among
sexually compatible plants because of
differences in potential to express a
substance and environmental
conditions. Indeed, variation is seen
even among plants in the same variety
because of differences such as weather
and soil condition. For example, one
report has shown an 8.3-fold variation
in the amount of ascorbic acid in turnip
greens depending on the degree of
exposure to light (Ref. 18). EPA’s
proposal would exempt PIPs based on
sexually compatible plants created
through biotechnology that are not
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expressed above the range of variation
on the basis that such exposures would
not be considered novel. EPA considers
that nontarget organisms, such as birds
and insect pollinators, that associate
with such sexually compatible plant
populations have been and are currently
being exposed to the upper levels of
substances that might be used as PIPs
based on sexually compatible plants
created through biotechnology.
EPA considered the extent to which
any substance can be increased in
highly managed plants without
unwanted effects on other, desirable
characteristics of the plant such as yield
or palatability of fruit. In general,
breeders balance all of these
characteristics in developing marketable
plant varieties. Greatly increased levels
of any substance, including PIPs based
on sexually compatible plants created
through biotechnology, generally would
only be accomplished at the expense of
the expression of other, agriculturally
desirable traits due to physiological
constraints related to energy
expenditure in the plant (Ref. 23). A
plant, like any other living organism,
has a finite energy budget, and can only
harvest so much energy from the
environment to allocate to all of its
activities; therefore, a significant
increase in the production of one
substance, like a PIP, would reduce the
energy that could be put towards the
production of other substances critical
to the plant’s metabolism. Thus, there
are practical considerations that limit
the upper expression levels of a PIP
based on a sexually compatible plant
created through biotechnology to that
found in a plant that is sexually
compatible with the recipient plant. To
codify this principle into regulatory
text, EPA is proposing criteria in which
the level of expression of the PIP based
on a sexually compatible plant created
through biotechnology is bound by the
upper limit of expression of the
pesticidal substance observed in a
sexually compatible plant. By limiting
the expression of PIPs based on sexually
compatible plants created through
biotechnology in this way, EPA can
ensure that the exposures fall within the
normal historical range of exposures
with which plant breeders have
experience limiting. EPA also
considered whether the total expression
(i.e., expression of the PIP across all
plants capable of producing that PIP)
would result in an adverse effect
different than that possible through
conventional breeding. Because the PIP
based on a sexually compatible plant
created through biotechnology could
have otherwise been created through
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conventional breeding, EPA does not
expect that the cumulative expression of
a PIP based on a sexually compatible
plant created through biotechnology
would pose a higher risk than what is
currently possible through conventional
breeding.
The potential for exposure to PIPs is
typically lower than for other types of
pesticides because PIPs are produced
within the living plant and used in situ
in the plant. Other pesticides, such as
conventional chemicals, must be
applied to the plant, or near the plant.
Because a PIP is produced and used
within the plant, physiological
constraints limit the amount of
pesticidal substance produced by the
plant. Moreover, the routes by which
other organisms may be exposed to the
PIP are typically more limited, e.g.,
dietary exposure is likely to be the
predominant route of exposure; there is
a potential for dermal or inhalation
exposure, although that likelihood is
more limited (see Unit VI.A.3.e. for
additional discussion of dermal and
inhalation exposure in humans). In
addition, PIPs are part of the metabolic
cycles of plants, meaning they are biotic
and subject to the processes of
biodegradation and decay. Furthermore,
PIPs are biodegradable to their
constituent elements through catabolism
by living organisms. Because they are
readily degraded, PIPs do not
bioconcentrate in the tissues of living
organisms (Ref. 50) or persist in the
environment. Given these
characteristics, the potential for new
exposures to occur, beyond direct
physical exposures to the plant or plant
parts, is limited for PIPs generally,
including PIPs based on sexually
compatible plants created through
biotechnology.
EPA also considered whether
variations of expression levels of PIPs
based on sexually compatible plants
created through biotechnology
contained in semi-managed systems
(e.g., trees) presented any novel issues
for exposure to nontarget organisms
(Ref. 23). Semi-managed systems
received specific consideration because
their semi-managed state can result in
exposure to a larger variety of nontarget
organisms compared to highly managed
row crop systems. For the reasons stated
in the preceding paragraphs in this unit,
EPA anticipates that for such plants,
levels of expression of PIPs based on
sexually compatible plants created
through biotechnology will continue to
fall within the upper limit of expression
currently observed for such substances
in sexually compatible plants.
Therefore, it is anticipated that the
levels of PIPs based on sexually
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compatible plants created through
biotechnology in semi-managed plants
would not exceed the levels observed in
sexually compatible free-living relatives
(Ref. 23).
Finally, while not necessary to
support the Agency’s low probability of
risk determination under FIFRA, EPA
did nonetheless consider the role of the
plant breeding process in maintaining
levels of substances in plants. Plants
containing PIPs based on sexually
compatible plants created through
biotechnology will, as would plants in
other development programs, pass
through a post-development screening
and selection process. During this
process, plants with undesired or
unexpected traits are identified and
eliminated from further development.
The development of new plant varieties,
whether through conventional breeding
or through biotechnology, begins with
the production of a large number of
plants containing the trait of interest.
Plants are cultivated over several
propagation cycles in order to identify
those plants that inherit the intended
phenotype across multiple generations
while maintaining desirable agronomic
characteristics such as uniform growth
characteristics, fertility, and yield (Ref.
22). The screening and selection
practices result in the selection of plants
intended for commercialization that
display desirable behavior, including
desired levels of expression of various
traits. Historically, these practices have
proven to be reliable for ensuring safety
and plants containing PIPs based on
sexually compatible plants created
through biotechnology are expected to
also pass through these same screening
and selection processes.
In conclusion, in its assessment, EPA
considered the potential of variations in
expression levels of PIPs based on
sexually compatible plants created
through biotechnology and whether
those variations would present risk.
EPA concluded that although variations
in PIP expression levels will occur in
response to environmental conditions in
plants that interbreed, these variances
are within exposure levels already
encountered. The purpose of EPA’s
second criterion limiting expression
levels to no higher than presently found
in plants that are sexually compatible
ensures that any exempt PIPs based on
sexually compatible plants created
through biotechnology would not pose a
higher risk than what is currently found
through conventionally bred plants.
Given the history of safe exposure to
those substances, this criterion helps to
ensure that exempt PIPs pose a low
probability of risk from quantitatively
different exposures.
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d. Low Potential for PIPs Based on
Sexually Compatible Plants Created
Through Biotechnology To Move From
Cultivated Plants to Wild or Weedy
Relatives Through Gene Flow and
Increase Weediness
Because PIPs based on sexually
compatible plants created through
biotechnology are produced and used in
the living plant, EPA considered the
possibility that the PIP may be
transferred by hybridization from the
crop plant to a cultivated, wild or
weedy relative. A large volume of
information is available in the public
literature on this possibility and the
likelihood of hybridization (Ref. 36, 51,
52, 53, 54, 55). EPA’s issue paper
entitled ‘‘Risk Considerations for
Outcrossing and Hybridization’’
addresses these considerations for PIPs
in plants in sexually compatible
populations (Ref. 56). As the genes used
to create the PIPs proposed for
exemption produce the same substances
as found in sexually compatible plant
populations, EPA relied on this analysis
to address this aspect of the assessment.
One of the considerations evaluated
for this proposed exemption was
whether a PIP based on a sexually
compatible plant created through
biotechnology could be transmitted to
wild relatives through gene flow of
genetic material. A second and more
important consideration is whether such
an outcrossing event could, in turn,
increase weediness of the wild relative.
For the following reasons, EPA
concluded that the potential is low for
weediness to increase in wild relatives
through the flow of genetic material
coding for a PIP based on a sexually
compatible plant created through
biotechnology.
There are several factors governing
whether gene flow occurs, and thus
governing the potential for
hybridization between crops and their
wild relatives (Ref. 53, 54, 57). First,
genetic barriers can prevent hybrids
from forming, render them sterile, or
reduce the fertility of hybrids, and thus
restrict their contribution to subsequent
generations. The strength of genetic
barriers is correlated to the degree of
evolutionary relatedness between the
crop and wild relatives, with the
barriers being stronger the more
distantly related the plants. Second,
geographic space is an effective barrier
to hybridization. For instance, wild
relatives with which corn can hybridize
are restricted to Mexico and Central
America. There is no potential of
hybridization between domesticated
corn and its wild relatives in other
regions of the globe (Ref. 58). Third,
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temporal barriers such as time of
flowering also affects hybridization, as
hybridization cannot occur when there
is no overlap in the time of flowering of
cultivated and wild forms (Ref. 54, 57).
For some species (e.g., peanut), the
flowers do not ordinarily open, and selfpollination may be very near 100
percent; thus, hybridization between
cultivated and wild forms is unlikely
even if the cultivated and wild forms are
synchronized in flowering and close
enough geographically for pollen to
move between them. Fourth, the ploidy
level may differ between a crop and its
relatives with many cultivated plants
having higher ploidy than their wild
relatives. Differences in ploidy levels
can significantly reduce the likelihood
that the cultivated plant and wild
relative will form fertile hybrids (Ref.
54). Finally, some varieties of certain
crop species, such as banana, are sterile,
and thus are incapable of hybridizing
not only with members of other species,
but also with members of their own
species (Ref. 59). For some crops in the
United States, the probability of
hybridization and gene transfer with the
wild relative is zero, while for other
crops, despite the variety of potential
barriers to and selection against
hybridization, gene transfer is possible.
However, even in instances where
hybridization is possible, wild relatives
generally tend to possess higher levels
of resistance to pests and disease than
do the cultivated members of those
populations (Ref. 23). Wild relatives
also tend to express a greater range of
levels of inherent plant defense
compounds than do cultivated plants,
including the production of higher
levels of substances that could
potentially be used as PIPs (Ref. 23).
If an agricultural or semi-managed
plant containing a PIP based on a
sexually compatible plant created
through biotechnology hybridizes with a
wild relative, it is unlikely that the
levels of expression of the transferred
PIP in the wild relative will be
substantially increased. For reasons
described in Unit VI.A.3.c., EPA
anticipates that for agricultural, semimanaged, and feral plants, levels of
substance expressed by the PIP based on
a sexually compatible plant created
through biotechnology will not exceed
levels currently observed for the
substance in sexually compatible plants
(Ref. 23, 51). Thus, because the levels of
expression of a PIP based on a sexually
compatible plant created through
biotechnology will not exceed levels
currently observed in plant populations
pursuant to proposed criteria, the
potential for an increase in weediness in
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wild relatives is low should the wild
relative acquire the exempted PIP trait.
e. Low Potential for Occupational and
Non-Occupational Risk to Humans
In general, PIPs are likely to present
a limited exposure to humans. In most
cases, the predominant, if not the only,
exposure route will be dietary.
Significant respiratory and dermal
exposures are unlikely in nonoccupational settings because most
plant substances, including PIPs based
on sexually compatible plants created
through biotechnology, are expressed at
relatively low levels and are found
inside the cell, and therefore any human
health risks in non-occupational settings
are expected to be negligible. Although
a potential for non-dietary exposure
(e.g., dermal and inhalation) in
occupational settings may exist due to
the processing of plants resulting in
increased exposure to intracellular
substances like PIPs, EPA expects
exposure to be low due to the relatively
low levels of such substances in plants
(Ref. 60). Given that PIPs based on
sexually compatible plants created
through biotechnology represent a
subset of substances present in sexually
compatible plants that breeders have
experience with and must be expressed
at or below existing levels, in the same
tissues, and at the same developmental
stages, EPA does not expect novel
exposures from the substances involved,
as the sexually compatible plant sources
have a history of being safe sources of
genetic diversity for use in cultivated
plants. Because these PIPs are
indistinguishable from those found in a
sexually compatible plant, which in
many cases is a close relative or even
the same plant species, existing allergen
avoidance strategies for certain plants
would still be protective.
Regarding dermal exposure, expressed
substances of PIPs based on sexually
compatible plants created through
biotechnology may in some cases be
present in sap or other exudates from
the plant or the produce and thus may
present some limited opportunity for
dermal exposure to persons physically
contacting the plant or raw agricultural
food from the plant. Farmers and food
handlers (e.g., individuals harvesting
produce by hand, preparing food for
sale, or stocking produce bins in grocery
stores) or floral workers are those most
likely to experience dermal contact with
the substances on an occupational basis.
However, because most plant
substances, including PIPs, are
expressed at relatively low levels and
are found inside the cell, the level of
exposure is still expected to be low.
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Most of the substances that could be
the subject of this proposed exemption
are unlikely to pass through the skin to
affect other organ systems or elicit
allergenic sensitization (Ref. 60,
reviewed in 61). The most common skin
reaction to plant products is likely
irritant contact dermatitis. These dermal
reactions are generally mild, of a selflimiting nature or self-diagnosed, and
self-treated (Ref. 60). Skin penetration of
the substances comprising a PIP is
dependent on several characteristics,
including the substances molecular
structure and hydrophobicity,
accompanying mechanical irritation
(e.g., thorns), the duration and site of
contact, and the lipid content of the
skin. For most PIPs, human skin, which
is composed of two layers, the
epidermis and the dermis, is a natural
barrier. The outer epidermal layer of the
skin consists of dead cells in tight
junctions (keratin) that provide a shield
against elements in the outside world.
The rapid shedding and replacement of
the keratin layer serves as a further
protective feature of the skin, as any
damaged cells are quickly shed and
replaced. For those PIPs based on
sexually compatible plants created
through biotechnology that might
possess some properties that allow
limited penetration of the skin, the
potential amount passing through the
outer epidermal layer of the skin
(epidermis) is likely to be negligible
(Ref. 60). Some irritant contact
dermatitises are initiated by mechanical
means which allow for limited
penetration of the skin. For example, the
small needle-like hairs of some plants
(e.g., stinging nettle) penetrate the skin
to deliver small doses of irritant toxins
(e.g., histamine). However, plants with
these characteristics are rare in
cultivation, further limiting exposure
(Ref. 60).
Importantly, PIPs based on sexually
compatible plants created through
biotechnology represent a subset of
substances already present in related
plants. PIPs based on sexually
compatible plants created through
biotechnology would therefore not be
expected to alter predicted exposures of
workers to plant proteins or other plant
substances. Thus, dermal exposure to
residues of PIPs based on sexually
compatible plants created through
biotechnology would not be predicted to
alter exposure patterns in occupational
settings.
Regarding inhalation exposure, PIPs
based on sexually compatible plants
created through biotechnology may in
some cases be present in pollen, and
some individuals (e.g., those working on
farms in nurseries or other plant-
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growing areas) may be exposed through
inhalation to wind-blown pollen. When
present in pollen, the pesticidal
substance is likely to be integrated into
the tissue of the pollen grain. The
likeliest impact of pollen exposure is
rhinitis, or inflammation of the mucous
membranes lining the nose, resulting in
symptoms like nasal congestion,
sneezing, itching, post-nasal drainage,
and runny nose. This proposed
exemption will not change current
exposures or affect strategies for dealing
with reactions to PIPs based on sexually
compatible plants created through
biotechnology that may be aeroallergens or irritants (Ref. 60). Pollen
grains are solid, insoluble particles of
sufficiently large diameter that they are
filtered out in the nasopharynx or in the
upper respiratory tract (Ref. 60), from
which they are generally swallowed into
the gastrointestinal tract. The
gastrointestinal surface forms a barrier
between the body and the lumenal
environment and is often described as
having two components: ‘‘(1) The
intrinsic barrier is composed of the
epithelial cells lining the alimentary
canal and the tight junctions that tie
them together, and (2) The extrinsic
barrier consists of secretions and other
influences that are not physically part of
the epithelium, but which affect the
epithelial cells and maintain their
barrier function.’’ Regarding the
intrinsic barriers, the alimentary canal is
lined by sheets of epithelial cells that
form the defining structure of the
mucosa and establish the basic
gastrointestinal barrier. Regarding the
extrinsic barriers, the gastrointestinal
epithelium is coated with mucus, which
is synthesized by cells that form part of
the epithelium. Mucus contributes to
barrier function in several ways by
slowing the diffusion of molecules.
Additionally, molecules in food,
including edible plant tissue, are too
large to be absorbed by the
gastrointestinal tract and are broken
down into smaller molecules to be
absorbed and utilized by the body. Plant
materials such as pollen are also
subjected to the processes in the
digestive tract that reduce larger
molecules to smaller constituents that
can be absorbed by the membranes of
the small intestine. Importantly, pollen
characteristics (e.g., wind vs. insect
dispersal, amount produced) are often
maintained within plant families, as is
necessary for successful breeding to
occur. Therefore, PIPs based on sexually
compatible plants created through
biotechnology should not alter already
established characteristics of any
particular species. In cases of
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occupational rhinitis, these PIPs would
not be expected to significantly alter
already established patterns of exposure
to occupational dusts.
f. Low Potential for Resistance Selection
Pressure Posed by PIPs Based on
Sexually Compatible Plants Created
Through Biotechnology To Exceed That
Found in Sexually Compatible Plants
A component of EPA’s oversight
historically for PIPs created through
biotechnology has been the requirement
for registrants to implement an insect
resistance management plan. Transgenic
Bacillus thuringiensis (Bt) PIPs are
likely at greater risk for insects
developing resistance than many
conventional pesticides targeting the
same insects because Bt PIPs are
expressed throughout all plant tissues
for the entire lifespan of the plant
compared to conventional pesticides,
which typically have shorter periods of
efficacy and are applied when pests are
likely to cause yield loss. To address
resistance management due to increased
exposure, the Agency has required
detailed information for Bt PIPs (e.g.,
dose expression levels, cross-resistance
potential, modeling scenarios) alongside
terms of registration (e.g., resistance
monitoring programs, remedial action
plans, compliance assurance, and
grower education activities).
As mentioned in the previous
paragraph, the risk of resistance to Bt
PIPs primarily stems from increased
exposure to the PIP from expression
across plant tissues and across the plant
lifespan, which are achieved due to
transgenic regulatory elements used in
the creation of the PIP. However, in the
case of PIPs based on sexually
compatible plants created through
biotechnology, the potential to develop
resistance is lower than that of Bt PIPs
due to the limitation on expression
profile (e.g., same tissues and
developmental stages) to be within what
is found in sexually compatible plants.
EPA does not anticipate an increased
resistance risk posed by PIPs based on
sexually compatible plants created
through biotechnology compared to
those developed by conventional
breeding. The proposed rule does not
require specific resistance management
plans from developers of PIPs based on
sexually compatible plants created
through biotechnology that qualify for
the new exemption.
g. Are there any considerations
associated with newer biotechnology
techniques?
Newer biotechnology techniques
using present-day genome editing
techniques (e.g., CRISPR, zinc-finger
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nucleases, transcription activator-like
effector nucleases, oligonucleotidedirected mutagenesis) can present some
additional considerations beyond those
discussed previously, and these were
taken into consideration in developing
the proposal to exempt PIPs based on
sexually compatible plants created
through biotechnology from FIFRA
requirements in order to meet the
requirement at 40 CFR 174.21(a).
Present-day genome editing techniques
allow for precise modifications to the
plant genome such that the PIP in
question meets the proposed criteria.
These new technologies can aid in plant
breeding and result in varieties
indistinguishable from those developed
through conventional breeding (Ref. 12).
Although genome editing
technologies allow for more precise
editing or insertion compared to older
technologies, there is still a possibility
of unintended modifications, also called
‘‘off-target’’ mutations. With genome
editing technologies, off-target
mutations may occur when the genome
editing machinery cuts DNA at sites that
share sequence similarity with the
actual target sequence. However, offtarget mutations may occur as a result
of any form of plant breeding, including
conventional breeding, and an off-target
mutation is not necessarily significant
in a specific PIP/plant combination with
regard to food, feed and/or
environmental risk. In plants, off-target
mutations can largely be removed by
backcrossing, if necessary, regardless of
the method by which they were
introduced (Ref. 62). It is very likely that
the off-target mutation and the desired
trait are inherited separately, which
allows for developers to select plants
that have the desired trait, but that do
not have the off-target mutation.
A recent comparison of single-base
pair substitution mutations resulting
from plant breeding technologies found
that the number of mutations detected
after genome editing was not
significantly different from what was
found after routine tissue culture (Ref.
63). This analysis supports the
conclusion that off-target mutations
from genome editing are not inherently
different or riskier than off-target
mutations occurring through other
forms of plant breeding. In addition,
recent studies in rice and maize found
that compared to the inherent variation
found in the plant, mutations resulting
from genome edited off-target mutations
were negligible and far fewer (Ref. 64,
65).
The majority of unintended changes
at the genomic level, whether due to offtarget mutations from plant breeding
technologies or through natural
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mutations, do not result in significantly
deleterious effects to the plant at the
phenotypic level (Ref. 4). This is
primarily due to the highly plastic
nature of plant genomes (Ref. 66, 67,
68). The small percentage of unintended
changes that do result in significant
deleterious effects are far more likely to
produce an effect deleterious to the
plant itself (e.g., stunted growth) than a
novel exposure to humans or the
environment (Ref. 34). Although EPA
only regulates the PIP, FDA regulates
the remainder of the plant for food
safety (see Unit II.B.). In the context of
the genetic material encoding the PIP,
off-target mutations in the coding region
resulting in protein-level changes would
not be eligible for exemption based on
the proposed criteria requiring that the
substance be the same as identified in
a source plant. Off-target mutations in
the regulatory region would not be
considered a significant risk due to the
same rationale allowing for
modifications to regulatory regions as
described in Unit VI.A.2.a. EPA
therefore considers off-target mutations
resulting from genome editing
technologies to present a negligible risk
to the environment in the context of
PIPs based on sexually compatible
plants created through biotechnology.
h. FIFRA Section 25(b)(2): Preliminary
Statutory Finding
EPA preliminarily concludes that PIPs
based on sexually compatible plants
created through biotechnology as
described for proposed 40 CFR 174.26,
warrant exemption under FIFRA section
25(b) because these substances are of a
character that is unnecessary to be
subject to all the requirements of FIFRA
to carry out the purposes of the Act.
Specifically, EPA has preliminarily
concluded that PIPs based on sexually
compatible plants created through
biotechnology that meet the exemption
criteria pose a low probability of risks
to humans and the environment.
As discussed in Unit VI.A.3., EPA has
preliminarily concluded that PIPs based
on sexually compatible plants created
through biotechnology that meet the
exemption criteria pose a low
probability of non-dietary risk to
humans and the environment. As
explained in this preamble in Unit
VI.B., EPA has also determined that
there is a reasonable certainty that no
harm will result from aggregate
exposure to the residues of such
products, including all anticipated
dietary residues and all other exposures
for which there is reliable information.
As such, EPA has preliminarily
determined that use of PIPs based on
sexually compatible plants created
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through biotechnology is not likely to
cause unreasonable adverse effects on
the environment and humans in the
absence of regulatory oversight other
than the adverse effects reporting
requirement in existing 40 CFR 174.71.
Based on the low probability of the
potential risks coupled with the
proposed exemption eligibility
determination process, EPA anticipates
minimal societal benefits would be
gained by imposing the full degree of
oversight associated with FIFRA
registration (see Unit VI.A.4. for
additional information on benefits).
Finally, the adverse effects reporting
requirement at existing 40 CFR 174.71
provides a mechanism that could alert
the Agency to information regarding
adverse effects associated with a PIP
based on a sexually compatible plant
created through biotechnology. Based
on the information available, the
benefits of exempting PIPs based on
sexually compatible plants created
through biotechnology from FIFRA
outweigh the potential risk associated
with these PIPs (risk that is low).
4. Benefits
This unit summarizes the benefits that
are described in greater detail in the cost
analysis (Ref. 2). This cost analysis
quantifies registration or Pesticide
Registration Improvement Extension Act
of 2018 (PRIA) related fees as required
by FIFRA. These fees represent savings
to developers if the proposed exemption
becomes final.
The direct benefit of the proposed
rule is the reduced regulatory burden
associated with developing and
marketing a PIP based on a sexually
compatible plant created through
biotechnology. The proposed exemption
may encourage more research and
development in this area of
biotechnology and better enable firms of
all sizes to engage in the development
of these types of PIPs.
Entities that support major crops or
larger markets can more easily absorb
fixed registration costs. As a portion of
the total costs of researching and
developing a new active ingredient,
registration costs often represent a small
proportion of the overall costs of
bringing a product to market. However,
an outlay of fixed registration costs can
be significant for a firm that supports
minor crops. Removal of registration
costs for these entities can be
significant, so smaller entities may feel
the most regulatory relief as a result of
this rule.
Crop varieties modified for greater
pest and disease resistance could also
reduce the use of externally applied
pesticides, which in turn could reduce
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farm expenditures and provide
environmental benefits. Finally, the
proposed exemption would also reduce
the burden on the Agency to review
applications for registration.
Exempting PIPs based on sexually
compatible plants created through
biotechnology from registration while
also promulgating an exemption from
the requirement of an FFDCA tolerance
for residues of such PIPs in or on food
or feed has an estimated incremental
cost savings (the primary benefit of the
rule) of about $444,000–$459,000 per
product. This savings represents the
difference between the new costs of the
process to submit a letter of selfdetermination and the old estimated
costs that developers would have had to
incur to meet Agency data requirements
and to register the PIP. The annual
number of PIPs based on sexually
compatible plants created through
biotechnology cannot be forecasted, so
the Agency based annual and
annualized cost savings estimates on an
assumption that there would be one PIP
that fit the exemption category per year
for the next ten years. This estimate is
meant to inform the public of the cost
savings and their magnitude over time.
The estimate avoids Agency conjecture
about how many products would be
registered in the absence of this
exemption over time. The number of
future PIPs based on sexually
compatible plants created through
biotechnology being developed will
depend on the market for these
products.
a. Growers
Growers will have more tools to
combat pest pressure because the
proposed exemption might accelerate
the development of new plant varieties
containing exempt PIPs based on
sexually compatible plants created
through biotechnology that target those
pests. Faster marketing of PIPs based on
sexually compatible plants created
through biotechnology will allow the
market to respond faster to changes in
disease pressure and the emergence of
resistance to existing pesticides, which
can be important to growers. EPA
anticipates that the proposed exemption
for PIPs based on sexually compatible
plants created through biotechnology
will particularly encourage the
development of PIPs based on sexually
compatible plants created through
biotechnology in minor crops. The
limited acreage on which minor crops
are cultivated makes it more difficult to
recoup investment in research and
development into new varieties,
especially if regulatory costs are high.
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b. The Agency
Finally, the proposed exemption
would also reduce the burden on the
Agency to review applications for
registration. By proposing to exempt
those PIPs based on sexually compatible
plants created through biotechnology
due to low probability of risk and lack
of unreasonable adverse effects in the
absence of oversight, EPA will
concentrate its regulatory efforts on
other PIPs that may pose potential risks.
Whereas the introduction of transgenes
into a plant could result in the exposure
of humans and the environment to a
new substance or a previously known
substance in a new way, the
modifications associated with qualifying
PIPs based on sexually compatible
plants created through biotechnology
are unlikely to result in novel
exposures. Thus, concentrating
regulatory efforts on PIPs with a higher
potential of novel exposures is a more
efficient use of EPA’s resources.
B. What is the proposal to exempt
residues of PIPs based on sexually
compatible plants created through
biotechnology from the requirement of a
tolerance?
Pursuant to its authority under
FFDCA section 408(e), 21 U.S.C.
346a(e), EPA is proposing to exempt
from the requirement of a tolerance
residues of pesticidal substances from
PIPs based on sexually compatible
plants created through biotechnology
that meet the conditions proposed for
this exemption. The Agency believes
that when the proposed conditions are
met, there is a reasonable certainty that
no harm will result from aggregate
exposure to residues of these pesticidal
substances from PIPs based on sexually
compatible plants created through
biotechnology, including all anticipated
dietary exposures and all other
exposures for which there is reliable
information. The Agency believes the
exemption criteria will ensure that the
exempt PIPs would not result in
exposures that are significantly different
from what humans are currently
exposed to in the food supply; therefore,
the exemption would be safe in light of
the history of safe exposures.
This proposed exemption is intended
to address the second condition for
exemption from FIFRA regulation under
40 CFR 174.21(b): The requirement for
a tolerance exemption for the residues
of PIPs intended to be produced and
used in a plant used as food or feed. The
proposed rule also includes a process
through which developers of PIPs based
on sexually compatible plants created
through biotechnology submit either a
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self-determination letter or request for
EPA confirmation that their PIP meets
the criteria for exemption. That process
is proposed at 40 CFR 174.90, and
details of the process for and contents
of an exemption eligibility
determination submission are found in
Unit VI.C. That unit also describes the
circumstances in which submission of a
separate determination for purposes of
the FFDCA exemption for a PIP
proposed for use in food or feed is
required.
Given that the proposed exemption
could potentially cover thousands of
substances, a small fraction of which are
known toxicants (for discussion see
Unit VI.B.3.), the Agency is proposing to
use certain guardrails to account for the
rare instances in which residues of a
pesticidal substance may reach levels in
food or feed that are unsafe. First, EPA
proposes a criterion for exemption
under FFDCA that limits the presence of
residues of the pesticidal substance in
the recipient plant. Specifically,
residues of a pesticidal substance in
plants used for food are allowed to be
present only in the same plant tissues
and developmental stages where such
residues are found in a sexually
compatible plant. Additionally, the
levels of that pesticidal substance
cannot exceed levels found in a sexually
compatible plant, with the added
limitation that those levels may not be
injurious or deleterious to human
health. In other words, if levels that are
injurious or deleterious to human health
are observed, the PIP and its residues
would not be covered by the proposed
exemption from the requirement of a
tolerance. This approach is consistent
with the existing exemption criteria for
residues of a pesticidal substance from
a sexually compatible plant, which also
limit the levels of residues of exempt
PIPs present in the food from that plant
to those that are not injurious or
deleterious to human health (40 CFR
174.508(c)). Second, under the proposed
exemption for PIPs based on sexually
compatible plants created through
biotechnology, a developer may wish to
request an exemption for residues of a
pesticidal substance whose levels are
commonly screened for in conventional
breeding to ensure the safety of the food.
In these instances, the developer of such
a PIP would be required, as part of the
exemption eligibility determination
process proposed at 40 CFR 174.90, to
describe how conventional breeding
practices have been and will be
performed on the recipient food plant to
ensure that the levels of the pesticidal
substance are not injurious or
deleterious to human health. This is to
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affirm that PIPs based on sexually
compatible plants created through
biotechnology will be held to the same
safety standards by the plant breeders as
PIPs in plants created through
conventional breeding. This
requirement can be fulfilled by a
developer with a confirmation that the
product has been screened for
acceptable levels of the pesticidal
substance (e.g., generally accepted safe
content for solanine in potatoes is 20–
25 mg/100 g of fresh potato). Breeders
have decades of experience developing
new plant varieties and are familiar
with the toxins that may be produced by
certain plants used for food and feed,
e.g., by chemically analyzing the
components of plants. Because PIPs
based on sexually compatible plants
created through biotechnology are
equivalent to those substances found
within plants that are sexually
compatible with the recipient plant,
these substances are not expected to be
novel to breeders and the existing
screening methods are similarly
expected to remain effective. Third, as
described further in Unit VI.C.1.,
residues of a PIP used in food or feed,
which would include residues of a PIP
based on a sexually compatible plant
created through biotechnology, remain
subject to the adverse effects reporting
under 40 CFR 174.71 even after the
residues have been exempted from the
requirements of FFDCA. Therefore,
upon learning of any adverse effects,
which includes injurious or deleterious
levels of the pesticidal substance in food
or feed, EPA has the authority to
reconsider whether the PIP and the
residues of the PIP continue to meet the
criteria for exemption. Further, as
described in the preamble of the July 19,
2001 Federal Register notice
implementing 40 CFR 174.71 (66 FR
37772; July 19, 2001), reports involving
food or feed (i.e., those subject to
enforcement under FFDCA) would be
made to EPA, but EPA will share such
reports with FDA. EPA and FDA will
individually determine whether any
action is necessary to protect the public
health, and if so, what constitutes
appropriate action based on their
respective statutes (EPA—FIFRA,
FDA—FFDCA). Therefore, 40 CFR
174.71 is a means of ensuring that EPA
and FDA can address any potential
hazard identified subsequent to selfdetermination or EPA confirmation that
a PIP meets the requirements for
exemption.
1. Proposed Criteria and Associated
Definitions
Unit VI.A.2. outlines the scope of the
FIFRA exemption proposal for PIPs
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based on sexually compatible plants
created through biotechnology. The
criteria and associated definitions
discussed in that unit are equally
relevant to the proposed FFDCA
exemption for residues of these PIPs for
food and feed use. For example, the
proposed definitions of ‘‘native allele,’’
and ‘‘native gene’’ are discussed in
greater detail in Unit VI.A.2. Also
discussed in Unit VI.A.2. are the
following phrases: ‘‘(1) The pesticidal
substance is found in plants that are
sexually compatible with the recipient
plant; and (2) Limitations on expression
profile.’’ The proposed definition of
‘‘gene’’ is discussed in Unit V.A. Thus,
the following considerations under the
proposed FFDCA exemption refer to the
concepts discussed in other parts of the
exemption proposal when appropriate.
EPA is proposing criteria and
supporting definitions that describe
residues from PIPs based on sexually
compatible plants created through
biotechnology that the Agency expects
to meet the FFDCA safety standard for
establishing exemptions. This proposed
exemption covers the residues of the
pesticidal substance of those qualifying
PIPs and would eliminate the need to
establish a maximum permissible level
in or on food and feed for these
residues.
EPA’s basis for its proposal is that the
criteria of the exemption circumscribe a
group of PIPs that will not result in
novel exposures, dietary or otherwise.
This analysis is based on the large body
of knowledge about the history of safe
use from foods containing these
substances that have been consumed by
humans for long periods of time.
Because PIPs based on sexually
compatible plants created through
biotechnology are equivalent to those
that could have been created through
conventional breeding, plant breeders
will retain their ability to ensure that
the substances will be at safe levels for
humans in the resulting food plant. EPA
concludes that the potential is low that
qualifying PIPs based on sexually
compatible plants created through
biotechnology introduce novel
exposures (Unit VI.A.3.b.).
a. Large Body of Knowledge
EPA relied on the large body of
scientific literature that describes
constituents of food from plants in
sexually compatible populations (Ref.
37). EPA used scientific literature on the
effect on humans of consumption of
whole foods from plants generated from
epidemiological studies (Ref. 24, 25, 27,
29, 31, 69, 70, 71, 72, 73) and animal
model testing of the effects of either
whole foods, or constituents from food,
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contained in these crops (Ref. 26, 28, 30,
74, 75, 76, 77) to draw conclusions on
the potential risks to humans through
the dietary (including drinking water)
and residential (or non-occupational)
route of exposure to these substances.
EPA also considered scientific
knowledge from a number of disciplines
including genetics, plant physiology,
phytopathology, toxicology, ecology,
biochemistry, evolutionary biology,
genomics, and plant breeding.
Information from the field of plant
physiology was considered regarding
plant metabolism to evaluate the
production of substances that may have
pesticidal effects and conditions that
may limit the plant’s production of such
substances, see Unit VI.B.1.c. and Unit
VI.A.3.c. (Ref. 33). EPA considered
information from the fields of
biochemistry and toxicology, for
example, to identify which substances
in food from plants might pose a dietary
risk (Ref. 37, 39, 78). The Agency also
used experimental data derived from the
science of phytopathology that
characterize the pest resistance
mechanisms in plants to understand the
types of traits through which PIPs may
confer resistance or tolerance to pests
(Ref. 3, 79). The sciences of ecology and
evolutionary biology were considered
for information on genetic diversity,
mutation, and reproductive isolation
mechanisms in populations to
understand the types of genetic changes
that are likely to occur when plants
interbreed in nature (Ref. 34). Plant
breeding and genetics provided
considerations to help describe the
mechanisms of incompatibility and
interbreeding, which aided EPA in
determining when plants are likely to
interbreed in nature. As discussed in
greater detail in Unit VI.A.3.g.,
information from genomics and
molecular biology were considered to
understand the ability of newer
biotechnology techniques, such as those
using genome editing techniques, to
create traits equivalent to those found in
conventionally bred plants (Ref. 35, 36).
Recommendations from several
FIFRA SAP reports were considered in
the development of the proposed
exemption criteria for PIPs based on
sexually compatible plants created
through biotechnology, and to
circumscribe the types of genetic
modifications in the recipient plant that
are unlikely to result in novel exposure
to humans, dietary or otherwise (Unit
II.C.3., Table 1).
b. Low Potential for Novel Exposure
All plants, including those commonly
consumed as food, naturally contain
pesticidal substances that confer pest
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resistance. Humans have for
approximately 10,000 years selected and
bred certain plants for food, feed, and
fiber, that have these pesticidal
characteristics. Humans are therefore
familiar with and have been exposed to
many plant-produced pesticidal
substances and their residues, such as
those that could be developed for use as
PIPs based on sexually compatible
plants created through biotechnology, in
their diet and otherwise for millennia.
Given that PIPs based on sexually
compatible plants created through
biotechnology are intended to represent
a subset of substances present in plants
that breeders are familiar with and that
in many instances have been safely
consumed by humans, EPA does not
expect that these substances, or residues
of these substances, would result in
novel dietary exposures.
Several considerations for assessing
the potential for novel risks for PIPs
based on sexually compatible plants
created through biotechnology are
discussed in Unit II.C.3. in the context
of the proposed FIFRA exemption. The
concepts presented in that unit are
equally relevant to the FFDCA safety
assessment of residues of PIPs based on
sexually compatible plants created
through biotechnology that are used for
food or feed.
Pesticidal traits have evolved in plant
populations over time through the
processes of mutation, selection, and
genetic exchange with sexually
compatible species (Ref. 47, 48). The
ability to produce viable offspring is
only possible in nature for organisms
that are genetically similar and possess
many traits in common. Traits, and the
genetic material encoding them, can be
passed through a sexually compatible
plant population by breeding. The
mixing of genetic material that occurs
through breeding results in the members
of a sexually compatible population
having similar traits and similar genetic
material. Due to the mixing of traits by
mating, similar exposure scenarios are
expected for food plants that are
sexually compatible—in other words,
substances in sexually compatible
plants are expected to be similar and
therefore, only substances that plant
breeders are already familiar with are
expected to be present in sexually
compatible plants. This conclusion is
consistent with the 1992, 1993, and
1994 FIFRA SAP reports that indicated
that sexually compatible plants are more
likely to have a common constitution
than unrelated plants and thus
movement of genetic material between
sexually compatible plants is less likely
to lead to novel exposures (Unit II.C.3.,
Table 1).
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For agricultural plants, those defined
as sexually compatible would also
include existing plant cultivars,
landraces, and breeding lines, as well as
plant relatives that interbreed with
crops but that are not currently used as
agricultural plants. Plant breeders have
for many years followed established
practices to ensure safety when moving
genes into agricultural varieties from
nonagricultural relatives, particularly
from inedible relatives, with no
indication that substances resulting
from these genes present higher levels of
risk than those from genes moved only
amongst agricultural varieties as long as
those established practices are followed
(Ref. 13, 14, 15, 16). Therefore, the
likelihood that the inclusion of
nonagricultural varieties as potential
source plants would lead to unsafe
dietary exposures from residues of PIPs
based on sexually compatible plants
created through biotechnology is low.
Genetic diversity is created over time
and EPA proposes to capture some of
the ongoing diversification not
identified in existing native genes or
native alleles through the inclusion of
novel changes resulting in the
differential expression of existing genes,
so long as no novel substance is
produced and the substance is not
produced in different tissues or at
different developmental stages than
those found in a sexually compatible
plant. Modifications that lead to
differential expression of a substance
are not expected to result in levels that
exceed the boundaries of the natural
variation found in sexually compatible
plants due to physiological constraints
that are related to energy expenditure
(further discussed in Unit VI.B.1.c. and
Unit VI.A.1.c.). The potential for novel
dietary exposures to occur with the
differential expression of existing genes,
or the movement of native genes and
native alleles among sexually
compatible plants, is therefore low,
because no substance novel to plants
that are sexually compatible with the
recipient plant will be produced, nor
will the substance be found in tissues or
developmental stages at levels, in which
it is not currently found.
c. Low Potential for Levels of PIPs Based
on Sexually Compatible Plants Created
Through Biotechnology To Exceed
Those Found in Sexually Compatible
Plants
EPA has evaluated whether there are
likely to be quantitative changes in
expression levels of PIPs based on
sexually compatible plants created
through biotechnology that may pose
dietary risks. As discussed later in this
unit, EPA has determined that the
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probability is low because the highest
levels of pesticidal substances likely to
be expressed by qualifying PIPs based
on sexually compatible plants created
through biotechnology is not likely to be
significantly different from those that
humans are currently exposed to in the
food supply. To codify this principle
into EPA’s regulatory text, EPA is
proposing an exemption criterion in
which the level of expression of PIPs
based on sexually compatible plants
created through biotechnology is bound
by the upper limit of expression of the
pesticidal substance observed in
sexually compatible plants. By limiting
the level of expression that qualifies for
an exemption in this way, EPA can
ensure that the exposures fall within the
normal historical range of exposures
with which plant breeders have
experience limiting to ensure safe
exposures when introduced into food
plants.
An analysis discussing the likely
range of expression of PIPs in sexually
compatible plants was presented in an
EPA issue paper, entitled: ‘‘FIFRA:
Benefit and Environmental Risk
Considerations for Inherent PlantPesticides.’’ A summary of that analysis
is presented in Unit VI.A.3.c. The
factors that influence the determination
of low probability of risk under FIFRA
that are discussed in that unit are
equally relevant to the FFDCA safety
assessment of residues of those same
PIPs in food or feed. Relevant
considerations summarized in that unit
include: (1) The level of production of
substances normally varies among
sexually compatible plants because of
differences in potential to express a
substance and environmental
conditions; (2) Physiological and
practical considerations limit the
expression levels of PIPs based on
sexually compatible plants created
through biotechnology; (3) Humans
have been and are currently exposed to
the range of levels of substances that
might be used as PIPs based on sexually
compatible plants created through
biotechnology.
Moreover, in varietal development,
plant breeders assess the new cultivar
for food safety, based in part on
knowledge of and familiarity with the
characteristics of agricultural plants in
the relevant sexually compatible
populations (Ref. 6, 37). Because PIPs
based on sexually compatible plants
created through biotechnology represent
a subset of substances already present in
related plants, the procedures routinely
used in agriculture and food processing
would continue to be efficacious in
identifying these substances, and levels
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of these substances, in new food plant
varieties.
Although hundreds of new plant
varieties enter the market each year
within the past 70 years, conventional
plant breeding has recorded very few
instances of plant varieties causing food
safety problems (Ref. 37, 80). EPA
believes this same demonstrated record
of safety can be applied to the pesticidal
substances produced by these plants.
Therefore, the Agency considers it
highly unlikely that residues of a PIP
based on a sexually compatible plant
created through biotechnology would
occur in or on food or feed at levels that
are hazardous. To account for the rare
instances in which a substance may
reach levels that are unsafe, EPA is
proposing as a criterion for exemption
that residues of the pesticidal substance
are only present in tissues and
developmental stages identified in a
plant that is sexually compatible with
the recipient food plant, and do not
exceed levels found within that plant, as
long as those levels are not injurious or
deleterious to human health. If levels
that are injurious or deleterious to
human health are observed, the PIP and
its residues would not be covered by the
proposed exemption from the
requirement of a tolerance. In failing to
meet the FFDCA requirements for
exemption, the PIP would similarly fail
to meet the exemption requirements
under FIFRA.
In conclusion, EPA considered the
potential variability of expression levels
of PIPs based on sexually compatible
plants created through biotechnology
and whether such variations would be
hazardous if they were to be present in
the food or feed supply. EPA concluded
that although variations in the
production of plant substances will
occur in response to environmental
conditions, there are physiological and
practical considerations that limit the
expression level, and thus the
abundance of a particular substance in
plants that are sexually compatible. By
limiting the expression of PIPs based on
sexually compatible plants created
through biotechnology to not exceed
levels that are found in sexually
compatible plants, EPA believes that
breeders will be able to ensure that
exposures fall within the normal
historical range of exposures that have
proved to be safe through conventional
breeding.
2. Dietary Risk Evaluation
For chemical pesticides, EPA’s dietary
risk evaluation relies on data generated
by testing in laboratories using
representative animal models to
estimate acute, subchronic, or chronic
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hazard endpoints, e.g., acute toxicity,
carcinogenicity, and developmental
toxicity. Conclusions from animal
models are used to assess dose-response
and describe such endpoints for
potential human hazards. Other
information, including residue data and
information generated by use of
mathematical models, are used to
develop human exposure estimates.
These exposure and hazard components
are combined to quantify the potential
risk associated with the pesticide’s use
and to determine the appropriate
maximum residue levels of the chemical
in or on food or feed, i.e., to set the
numerical tolerance. Uncertainty factors
are often used in the risk assessment to
account for extrapolation from animal
models to human toxicity. If the
substance is found to be safe, the
Agency may issue a tolerance or, as
proposed here for qualifying PIPs based
on sexually compatible plants created
through biotechnology, an exemption
from the requirement of a tolerance for
the pesticide chemical residues. EPA
described the information base typically
used to assess the potential risks and
safety of PIPs at a public symposium
held in September 2016. The materials
developed for this symposium are
available on https://www.regulations.gov
in Docket ID No. EPA–HQ–OPP–2016–
0427 and on EPA’s website at https://
www.epa.gov/pesticides/publicsymposium-regulation-plantincorporated-protectants-rebroadcastlive-webcast.
In some cases, the use of animal
model testing may not be required to
support a safety finding for a pesticide
chemical residue. For example, for PIPs
that are already part of the food supply
but moved through the use of
biotechnology between two distantly
related food plant species (i.e., those
that are not sexually compatible and
could not have been moved through
conventional breeding), EPA has used
various forms of information aside from
animal testing to assess the safety of PIP
residues. These included the open
scientific literature to understand the
characteristics of the PIP itself as well
as the biology of the source plant from
which the PIP is derived and the
recipient plant in which the PIP will be
produced and used. Similarly, in
performing the assessment for the
proposed tolerance exemption for PIPs
based on sexually compatible plants
created through biotechnology, the
Agency is assessing the substances
present in these plants in the context of
the history of human consumption of
the whole food, and animal model
testing of the effects of either whole
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foods, or constituents from food,
contained in these crops (Unit VI.B.1.a.).
EPA’s conclusion that qualifying PIPs
based on sexually compatible plants
created through biotechnology would be
safe for human consumption is based on
this information. EPA considered that
appropriate processing procedures are
widely known and are routinely used by
consumers and companies involved in
food production and processing in the
preparation of food containing residues
that are the subject of this proposed
exemption, including those foods that
require specific processing and/or
preparation steps in order to be safely
consumed B.3.). Importantly, the
efficacy of the food preparation
techniques, as well as dietary avoidance
strategies, are expected to apply equally
to food containing residues of PIPs
based on sexually compatible plants
created through biotechnology, since
residues of those pesticidal substances
are a subset of substances already
present in related food plants. Similarly,
the plant breeding practices that are
routinely employed in selecting and
developing new plant varieties, such as
chemical analysis and visual analysis,
are not expected to be affected by this
proposed exemption. As a result, the
residues are not expected to pose any
risk that differs from what people
already are exposed to in the food
supply.
EPA considered health risks to the
general population, including infants
and children. Residues of pesticidal
substances in or on food or feed from
PIPs based on sexually compatible
plants created through biotechnology
that meet the proposed criteria for
exemption would not be new to the food
supply, as they are a subset of
substances already present in related
plants. Accordingly, this proposal
should not change anything about the
way that children, and to some extent
infants, are exposed to substances
already found in food that are identical
to residues of PIPs based on sexually
compatible plants created through
biotechnology. EPA’s risk assessment
also included subgroups as part of the
general population, i.e., reflecting
differences in diet due to the influence
of culture, and allowed for consumption
pattern differences of such subgroups.
a. Dietary Consumption Patterns
EPA considered the available
information on the varying dietary
consumption patterns of consumers and
major identifiable consumer subgroups
as it pertains to residues of pesticidal
substances from PIPs based on sexually
compatible plants created through
biotechnology. The consumption of food
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from plants is part of a balanced and
varied diet (Ref. 81). For purposes of
this proposed exemption, EPA
considered a normal diet to be balanced
and varied and to include food from a
variety of sources. It does not include
plants or plant parts consumed in times
of deprivation, for religious reasons, in
substance abuse, or by accident.
Humans have been consuming food
containing pesticidal substances
produced by sexually compatible plants
for long periods of time. It is not
anticipated that this proposed
exemption from the requirement of a
tolerance, should it be finalized, will
affect current consumption patterns of
food from crop plants by consumers or
major identifiable consumer subgroups,
and thus no differences in exposure
patterns are anticipated.
b. Validity, Completeness, and
Reliability of Available Data
EPA considered the validity,
completeness, and reliability of the
available information on human
consumption of food containing
substances that would be identical to
the expected residues of pesticidal
substances from PIPs based on sexually
compatible plants created through
biotechnology, including the extensive
history of humans safely consuming
foods from plants containing these
substances, epidemiological studies of
human dietary assessments and animal
model testing, as well as information
from the disciplines of genetics,
molecular biology, plant physiology,
phytopathology, toxicology, ecology,
biochemistry, evolutionary biology,
genomics, and plant breeding (Unit
VI.B.1.a.). EPA concluded that this
information was valid, complete, and
reliable, and adequately addressed the
issues of hazard and exposure with
regard to residues of pesticidal
substances from PIPs based on sexually
compatible plants created through
biotechnology in or on food or feed.
3. Toxicological Profile
EPA considered whether toxic effects
could be associated with any pesticidal
substances that developers might wish
to use as PIPs based on sexually
compatible plants created through
biotechnology and that might be
residues in or on food or feed (Ref. 6).
The examination led EPA to conclude
that, since the vast majority of
substances in plants that are used for
food are not toxic, any of these nontoxic
substances, should they be used as PIPs
based on sexually compatible plants
created through biotechnology, would
not present any toxic effects.
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Plants produce hundreds of
thousands of substances of which only
about 200 have been identified as
potential toxins in food plants, and only
10% of those substances (about 0.01%
of all substances) may pose a dietary
risk when consumed as part of a normal
diet (Ref. 37, 82, 83). One example is the
glycoalkaloid solanine, which is
commonly biosynthesized in potatoes
and to some extent eggplant and
peppers (Ref. 6). Solanine poisoning is
very rare. However, in large doses it can
cause effects such as gastrointestinal
tract irritation and drowsiness. Solanine
imparts a bitter taste to the tuber, and
at high concentrations can even leave a
persistent irritation and burning
sensation on the tongue, both of which
may to some extent deter consumption.
Potatoes are bred and monitored in the
United States to ensure that they
produce only low levels of solanine.
There are several factors that could
have contributed to the relatively low
number of toxins in food plants. In crop
development, low toxicant abundance
has been a desired trait to increase
usability of a particular plant as a source
of nutrition and to enhance its
palatability (Ref. 4, 37). Further, the risk
of toxins that may be present in a
particular food crop appears to be well
known, and methods of processing exist
to reduce the potential for toxic effects
(Ref. 37). For example, as part of the
development and characterization of
new plant varieties, plant breeders use
methods such as gas and/or liquid
chromatography coupled with mass
spectrometry to identify and quantify
toxins in food plants and use this
information to identify and remove new
varieties from the development pipeline
that contain potentially harmful levels
of these substances. Over the past 50
years, the sensitivity of some metabolic
profiling techniques has increased over
100,000-fold, enabling the detection of
exceedingly small amounts of these
substances (Ref. 37). As a result, the
majority of toxicants in food plants are
already known and plant varieties can
be screened for their presence and
removed from the market if necessary.
In this context it is relevant to note that
no newly released plant variety
exhibited any previously unknown food
or feed hazard (Ref. 37, 80).
Because PIPs based on sexually
compatible plants created through
biotechnology are a subset of those PIPs
found in related plants, these substances
are not novel to plant breeders.
Therefore, the efficacy of the existing
monitoring, processing, and preparation
methodologies that have been and are
being used to produce food safe for
consumption is expected to be equally
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effective at screening foods that would
contain PIPs based on sexually
compatible plants created through
biotechnology. For the reasons
described in Unit VI.B.1.b., EPA expects
that PIPs based on sexually compatible
plants created through biotechnology do
not pose novel exposures (dietary or
otherwise) compared to pesticidal
substances present in sexually
compatible plants. Furthermore, EPA
expects that the levels of PIPs based on
sexually compatible plants created
through biotechnology have a low
potential to exceed levels found in
sexually compatible plants (Unit
VI.B.1.c.) and codifies these levels in the
proposed exemption criteria.
4. Cumulative Effects From Substances
With a Common Mechanism of Toxicity
FFDCA section 408(b)(2)(D)(v)
requires that, when considering whether
to establish, modify, or revoke a
tolerance, the Agency consider
‘‘available information’’ concerning the
cumulative effects of a particular
pesticide’s residues and ‘‘other
substances that have a common
mechanism of toxicity.’’ This factor is
also relevant when considering whether
to establish an exemption from the
requirement of a tolerance (21 U.S.C.
346a(c)(2)(B)).
As discussed in Unit VI.B.3., EPA
recognizes that there are toxicants of
plant origin that may be part of the
human diet, which could theoretically
be used as PIPs based on sexually
compatible plants created through
biotechnology and which may cause
adverse effects. EPA has considered
available information on the cumulative
effects of such residues and other
substances that have a common
mechanism of toxicity and that may be
developed as PIPs based on sexually
compatible plants created through
biotechnology. EPA also considered
whether the cumulative expression (i.e.,
expression of the PIP across all plants)
would result in an adverse effect.
Because the PIP based on a sexually
compatible plant created through
biotechnology could have otherwise
been created through conventional
breeding, and by extension would not
be novel to plant breeders, EPA does not
consider that the cumulative expression
of a PIP based on a sexually compatible
plant created through biotechnology
would pose a higher risk than what is
currently possible through conventional
breeding.
For the reasons discussed in Units
VI.B.1.a. through c., any potential
cumulative effects from PIPs based on
sexually compatible plants created
through biotechnology are not expected
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to be quantitatively different from those
present in the current food supply and
the presence of these substances and
their residues has historically been safe.
5. Aggregate Exposures of Consumers
Including Non-Occupational Exposures
EPA considered the available
information on the aggregate exposure
of consumers to the residues of PIPs
based on sexually compatible plants
created through biotechnology. EPA
examines exposure through the dietary
route (including drinking water), and
exposure in the residential nonoccupational setting in greater detail in
the following units (Unit VI.B.5.a.
through e.).
a. Dietary Exposures From Food
Dietary exposure is the most likely
route of exposure to PIPs based on
sexually compatible plants created
through biotechnology as these
pesticidal substances are contained
within plants consumed as food. As
described in this preamble at Unit
VI.B.1.a., a large knowledge base and
experience exists for the residues that
are subject of this proposed exemption,
including information on human dietary
exposure. Information from all of these
sources can be used in evaluating the
safety of residues of PIPs based on
sexually compatible plants created
through biotechnology, as food from a
plant engineered to contain such a PIP
is comparable to the situation presented
by the natural whole food from that
plant prior to introducing the genetic
modification: No substances new to the
sexually compatible plant population
would be introduced, and the
introduced substances would be
consumed as part of the whole food.
The exemption criteria prohibit the
introduction of substances that are
novel to the sexually compatible plant
population and, as discussed earlier,
nothing about the PIP would alter the
existing mechanisms for breeding,
processing or preparing the food. Thus,
the Agency expects any exempt PIPs
would be consumed as part of the whole
food in the same manner as existing
foods currently in the food supply and
that plants containing residues of these
PIPs would be subject to the same
procedures plant breeders rely on to
ensure the safety of food. There is no
evidence in the many studies performed
on the relationship of diet to health that
food containing substances from
sexually compatible plants, when
properly processed and prepared, has
resulted in adverse health effects (Unit
VI.B.1.a. through c.). The Agency
believes this assumption is supported
by the record of safety of the food
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products from plants in sexually
compatible populations. Although
hundreds of new varieties come on the
market each year (Ref. 84), breeding of
plants in sexually compatible
populations has recorded very few
instances of exposures to substances
that are not safe in food. Further, no
previously unknown food hazard has
been observed in new plant varieties
developed through plant breeding (Ref.
37, 80).
The primary exposure consideration
associated with the pesticidal chemical
residues that are the subject of this
proposed exemption is whether
substances that might be harmful at
higher concentrations (or in different
tissues or stages) are likely to be present
in food from sexually compatible plants
at such concentrations. EPA considered
the probability of variations in levels of
PIPs based on sexually compatible
plants created through biotechnology,
and whether such variations would be
hazardous if these PIPs were to be
present in the food supply (Unit
VI.B.1.c.). EPA concluded that, based on
biological and agronomic
considerations, any variations in the
levels of PIPs based on sexually
compatible plants created through
biotechnology is not expected to exceed
the levels of these substances currently
present in the food supply, which has
been determined to be safe. This
principle is also codified in EPA’s
proposed regulatory text in which the
level of expression of a PIP based on a
sexually compatible plant created
through biotechnology is bound by the
upper limit of expression of the
pesticidal substance observed in
sexually compatible plants and that it
can only be present at levels that are not
injurious or deleterious to human
health.
A second exposure consideration is
whether this proposed exemption will
affect the ability of individuals with
food sensitivities to manage these
sensitivities. Individuals with food
sensitivities, including food allergies,
generally avoid foods from plants that
they are sensitive to. This proposed
exemption, if finalized, would not affect
the efficacy of this strategy of avoidance
because the proposed exemption will
not affect the ability of individuals to
recognize and avoid foods they are
sensitive to. For example, the ability of
persons who have the Mediterranean
form of the inherited Glucose-6phosphate dehydrogenase (G6PD)
deficiency to manage their disease by
not consuming fava beans or foods made
with fava beans will not be affected. The
substances in fava beans that can cause
hemolytic anemias in such persons
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would be exempt only if they are used
in fava bean plants and plant varieties
that interbreed with fava beans; a
population of plants in which such
substances normally occur (Ref. 85).
In conclusion, qualifying PIPs based
on sexually compatible plants created
through biotechnology represent a
subset of substances already present in
related plants. Therefore, should
residues of these substances be present
in or on food derived from plants, EPA
does not expect them to have any
meaningful impact on the already
existing dietary exposure profile for
these residues and thus risk from
dietary exposure to such residues in or
on food would be low. Moreover, as an
additional measure of safety for residues
of qualifying PIPs, the pesticidal
substance can only be present at levels
that are not injurious or deleterious to
human health.
b. Residential, Non-Occupational
Exposure
Residues of qualifying PIPs based on
sexually compatible plants created
through biotechnology may be present
in plants grown residentially for
consumption. Consequently, EPA
examined the potential for nonoccupational exposures to these
substances in the sections for dermal
and inhalation exposure in sections of
Unit V.B.5.d. and e.
c. Dietary Exposure From Drinking
Water
Dietary exposure through drinking
water is considered unlikely. The
substances in plants or parts of plants,
including residues of PIPs based on
sexually compatible plants created
through biotechnology, are produced
and used inside the living plant itself.
As such, the residues are part of the
tissue of the plant. When the plant dies
or a part is removed from the living
plant, microorganisms colonizing the
tissue immediately begin to degrade it,
using the components of the tissue,
including any residues that are the
subject of this proposed exemption, as
building blocks for making their own
cellular components or for fueling their
own metabolisms. The residues that
EPA is proposing to exempt in this
action are subject to the same processes
of biodegradation and decay that all
biotic materials undergo. This turnover
of biotic materials in nature through a
process of biodegradation is expected to
occur in rapid fashion and is likely to
preclude these residues from persisting
in the environment long enough to
reach the drinking water supply (Ref.
40). There is no indication that plant
biotic materials, including the residues
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that are the subject of this proposed
exemption, are resistant to
biodegradation. Even if residues were to
reach surface waters, through pollen
dispersal or parts of the plants (leaves,
fruits etc.) falling directly into bodies of
water, they are still subject to microbial
degradation and are unlikely to present
anything other than a negligible
exposure in drinking water drawn either
from surface water or ground water
sources. Importantly, PIPs based on
sexually compatible plants created
through biotechnology represent a
subset of substances already present in
related plants. Therefore, should these
residues be present in drinking water,
they are not expected to meaningfully
alter the already existing pattern of
exposure to these residues and thus EPA
expects risk to be negligible.
d. Dermal Exposure
Although a potential for dermal
exposure may exist, EPA expects such
exposure to be negligible because PIPs
based on sexually compatible plants
created through biotechnology are
present in the plant tissue (Ref. 60). In
some cases, residues of PIPs based on
sexually compatible plants created
through biotechnology may be present
in sap or other exudates from the plant
and thus may present some limited
opportunity for dermal exposure to
persons coming physically into contact
with the plant or raw agricultural food
from the plant, e.g., during food
preparation (see also Unit VI.A.3.e.).
Although contact dermatitis can occur
from such exposure (Ref. 60, 86), these
reactions are generally mild, of a selflimiting nature, or self-diagnosed and
treated. For those substances that
possess to some degree properties that
might allow some penetration of the
skin, the potential amount passing
through the outer epidermal layer of the
skin (epidermis) is likely to be low (Ref.
60).
Furthermore, most of the substances
that could be the subject of this
proposed exemption are unlikely to pass
through the skin to affect other organ
systems or elicit allergic sensitization
(Ref. 60, 61, 86, 87). Importantly, those
substances that do possess properties
that allow some penetration of the skin
represent a subset of substances already
present in related plants and would
therefore not be expected to alter the
already existing exposures to plant
proteins or other plant substances
through handling of the plant
containing these substances. Therefore,
EPA does not expect novel hazards or
exposures from residues of the
substances involved and thus these PIPs
are expected to represent a low potential
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of quantitatively different dermal
exposures; therefore, risks from dermal
exposures are expected to be low.
e. Inhalation Exposure
Although a potential for inhalation
exposure may exist, EPA expects such
exposure also to be negligible because
PIPs based on sexually compatible
plants created through biotechnology
are contained within plant cells, which
essentially eliminates this exposure
route, or reduces this exposure route to
negligible levels (Ref. 60). However,
residues of PIPs based on sexually
compatible plants created through
biotechnology may in some cases be
present in pollen and other agricultural
dust and some individuals, e.g., those
living or working in close enough
proximity to farms, nurseries or other
plant-growing areas, may be exposed to
wind-blown pollen, or through visiting
such areas may be exposed, through
inhalation, to the pollen. The most
likely impact of pollen exposure is
rhinitis, or inflammation of the mucous
membranes lining the nose, resulting in
symptoms like nasal congestion,
sneezing, itching, post-nasal drainage,
and runny nose.
On a per person basis, the potential
amounts of pollen involved in these
exposures are likely to be low and
residues of the pesticidal substance will
not in every case be present in the
pollen. Importantly, pollen
characteristics (e.g., wind versus insect
dispersal, amount produced) are often
maintained within plant families and,
therefore, residues of PIPs based on
sexually compatible plants created
through biotechnology, which are found
among sexually compatible plants,
should not alter already established
characteristics of any particular plant
species. This proposed exemption will
not change current exposures, nor affect
strategies for dealing with reactions to
PIPs based on sexually compatible
plants created through biotechnology
that may be aero-allergens or irritants
(Ref. 60). Thus, EPA concludes that risk
from inhalation exposure to residues of
PIPs based on sexually compatible
plants created through biotechnology is
low.
6. Other Considerations
Other considerations for EPA’s safety
finding under the FFDCA include the
sensitivities of population subgroups,
endocrine effects, and special
consideration for risks to infants and
children.
a. Sensitivities of Subgroups
EPA considered available information
on the sensitivities of subgroups as it
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pertains to residues of qualifying PIPs
based on sexually compatible plants
created through biotechnology. In
performing its assessment, the Agency
considered that the diet includes all of
the food items that are customarily
eaten by human populations or
population subgroups. As discussed in
this preamble, this proposed exemption
will not affect the current pattern of
exposure to residues that are the subject
of this proposed exemption because the
substances at issue are equivalent to
substances present in sexually
compatible plants and are limited in
their level of expression to those
observed in sexually compatible plants.
Relatedly, the expression pattern of
these substances (timing and location of
the expression) are limited to those
found in sexually compatible plants
through the proposed criteria.
Individuals recognize and are familiar
with the plant-derived food they
consume, (e.g., based on prior
experience of consumption) and would
avoid consuming foods containing
substances they know they are sensitive
to (Ref. 37, 88, 89). Because the
exposure pattern to these foods will not
be affected by this proposed exemption,
the efficacy of the current strategy
whereby sensitive individuals or
subgroups of sensitive individuals
recognize and avoid certain foods would
not similarly not be affected (Ref. 88,
89). Thus, the Agency does not expect
any subgroup to be adversely affected by
the proposed exemption.
b. Estrogenic or Other Endocrine Effects
Certain food plants, e.g., soybeans,
contain estrogen mimics, termed
phytoestrogens. Such phytoestrogens
are currently being consumed by
humans in food derived from plants and
are part of the extensive history of safe
human consumption of food from
plants. Although the Agency considers
use of these phytoestrogens as PIPs to be
unlikely, EPA cannot rule out the
possibility that such phytoestrogens
could be developed as PIPs based on
sexually compatible plants created
through biotechnology. Based on
available information concerning levels
of phytoestrogens that must be
consumed before effects can be seen
(Ref. 90), the natural limitations of gene
expression (Unit VI.A.3.c.), and the
limitations the Agency is proposing on
the levels and expression pattern of
these substances at 40 CFR 174.541(b),
EPA expects that this exemption, as
proposed, will not result in levels of
phytoestrogens in foods that would be
quantitatively different from those
currently being safely consumed.
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c. Infants and Children
FFDCA section 408(b)(2)(C) provides
that EPA shall assess the risk of
pesticide residues based on available
information about infants’ and
childrens’ consumption patterns,
special susceptibility to pesticide
chemical residues, and the cumulative
effects. EPA’s evaluation of these factors
is presented in the following units (Unit
VI.B.6.c.i. through iii.).
In addition, this section of the FFDCA
requires that, in the context of threshold
effects, EPA apply an additional tenfold
margin of safety to take into account
potential pre- and postnatal toxicity and
completeness of the toxicity and
exposure databases with respect to
infants and children. This safety factor
is most relevant when the Agency
conducts a quantitative risk assessment
upon identifying threshold effects of
concern and employs various
uncertainty factors, including this safety
factor, to ensure an appropriate margin
of safety in its risk analysis. For residues
of PIPs based on sexually compatible
plants created through biotechnology,
EPA has concluded that consumption of
food containing residues of PIPs based
on sexually compatible plants created
through biotechnology is safe for infants
and children, and that a margin of safety
need not be proposed for these residues
in food. EPA based its assessment of
exposure and toxicity upon the
information base described in this
preamble in Unit VI.B.1.
i. Dietary Consumption Patterns
EPA considered available information
on the dietary consumption pattern of
infants and children as it pertains to
residues of PIPs based on sexually
compatible plants created through
biotechnology. The range of foods
consumed by infants and children is in
general more limited than the range of
foods consumed by adults. Most
newborns rely on milk products for
nutrition, although some infants are fed
with soy-based products. Soy-based
products may contain residues that are
the subject of this proposed exemption.
Infants begin as early as 4 months of age
to consume specific types of solid foods,
including foods from plants that may
contain residues that are the subject of
this proposed exemption. Later on, apart
from processing to facilitate swallowing,
the diets of toddlers begin to be based
on foods consumed by the general adult
population albeit in different
proportions. As infants and children
mature, more and more of the foods
consumed by adults become part of
their diets and the relative proportions
of the different types of food consumed
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change to more closely resemble an
adult diet.
Foods that may contain residues that
are the subject of this proposed
exemption are part of a normal diet.
They have been consumed by infants
and children over long periods of time.
The likelihood that exposure as part of
a normal diet to these substances could
lead to harm to infants and children is
low. As the diets of humans change
from infancy through childhood and
into adulthood, there is some possibility
that the amount of foods that contain
residues that are the subject of this
proposed exemption being consumed
may change, with those consuming the
greatest amounts of plant-based foods
being the most exposed to substances
that may be subject of this proposed
exemption. There is no evidence,
however, that such changes are likely to
result in disproportionately high
consumption of these residues in
comparison to the general population.
Thus, there is no evidence that any
exposures would be different from those
currently in existence. The evidence
suggests that consumption of foods
containing residues from PIPs based on
sexually compatible plants created
through biotechnology, including
changes in exposure (i.e., relative
proportions of the different types of
food consumed from infancy through
childhood and into adulthood) is highly
unlikely to lead to any harm (Units
VI.B.1. through 5.).
ii. Special Susceptibility
EPA considered available information
on the potential for special
susceptibility of infants and children,
including prenatal and postnatal
toxicity, to residues of qualifying PIPs
based on sexually compatible plants
created through biotechnology. The
substances that are the subject of this
proposed exemption occur in the
normal diet, and there is no evidence
that exposure to such residues, as
components of food, present a different
level of dietary risk for infants and
children.
iii. Cumulative Effects of Residues With
Other Substances With a Common
Mechanism of Toxicity
EPA examined the available
information on the cumulative effect of
residues of PIPs based on sexually
compatible plants created through
biotechnology, as well as other
substances in food that may have a
common mechanism of toxicity with
these residues, and considered effects
on infants and children (Unit VI.B.4.).
Food from sexually compatible crop
plants is being safely consumed by
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humans, including infants and children,
either directly or indirectly in products
such as meat and milk that are derived
from animals that consume forage and
other crops, e.g., corn and other grains.
Considering the history of safe
consumption and the information base
described in Unit VI.B.4., EPA has not
found that substances in food from
plants share common mechanisms of
toxicity with other substances.
d. Safety Conclusion
Based on the information discussed in
this preamble and in the associated
record, EPA preliminarily concludes
that when the proposed conditions are
met, there is reasonable certainty that no
harm will result from aggregate
exposure to residues of PIPs based on
sexually compatible plants created
through biotechnology, including all
anticipated dietary exposures to humans
for which there is reliable information.
This preliminary finding is based on the
Agency’s determination that the
proposed exemption criteria would only
exempt PIPs that share relevant
characteristics with PIPs already found
in sexually compatible plants, thereby
ensuring that residues of these PIPs do
not pose different risks to humans.
Specifically, the proposed exemption
only applies to substances already
found in plants that are sexually
compatible with the recipient food
plant, that are present in tissues and
developmental stages identified in those
plants, and whose expression does not
exceed levels that are found within
those plants. Moreover, as an additional
measure of safety, the exemption
specifically excludes those residues of
PIPs from the exemption that are
present in the recipient food plant at
levels that are injurious or deleterious to
human health. The safety determination
for PIPs based on sexually compatible
plants created through biotechnology is
based on a large body of knowledge
about the history of safe use from foods
containing residues of PIPs that are
present in plants and EPA’s assessment
of scientific literature that describes
constituents of food from plants in
sexually compatible populations. To
develop the proposed exemption criteria
for PIPs based on sexually compatible
plants created through biotechnology,
and to circumscribe the types of genetic
modifications in the recipient plant that
are unlikely to result in novel exposure
to humans, dietary or otherwise, EPA
relied on recommendations from several
FIFRA SAP reports and considered
information from the public literature to
understand the ability of newer
biotechnology techniques to create traits
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equivalent to those found in sexually
compatible plants.
e. Analytical Enforcement Methodology
Before issuing an exemption from the
requirement of a tolerance, the FFDCA
requires an analytical method for
detecting and measuring the levels of
the pesticide chemical residue at issue
in food, unless the Administrator
determines that there is no need for
such a method and explains the reasons
for that determination in the rulemaking
establishing the exemption (21 U.S.C.
346a(c)(3)). In the case of a reversal of
an exemption decision, established
analytical methods could be critical to
enable detection of the affected crop,
e.g., should a recall of foods be
necessary. To meet the proposed
exemption criteria at 40 CFR 174.21(d),
a developer is likely to already be in
possession of the analytical methods
that can be used for the detection of
either the genetic material or the gene
product associated with the PIP. For
example, to provide the nucleic acid
sequence information of the PIP as part
of the exemption eligibility process,
developers may use several
oligonucleotide primers for gene
sequencing. These primers can similarly
be used for the specific detection of the
PIP in the food plant using standard
PCR methods. Conversely, in those
instances in which primers are not
already available, the information
provided on the nucleic acid sequence
of the PIP is expected to be sufficient to
promptly design oligonucleotide
primers de novo. Therefore, EPA does
not find it necessary to require
submission of analytical methods for the
detection in plants of PIPs based on
sexually compatible plants created
through biotechnology.
C. What are the proposed exemption
eligibility determination procedures and
requirements of 40 CFR part 174,
subpart E?
EPA proposes to use currently
reserved Subpart E of 40 CFR part 174
for a proposed exemption eligibility
determination process related to the
proposed exemptions. Within that
subpart, EPA proposes adding four
sections: One to describe the process for
determining eligibility for an
exemption, one to describe the general
submission process for a selfdetermination letter, one to describe the
general submission process for EPA
confirmation, and one to describe the
information requirements specific to
PIPs based on sexually compatible
plants created through biotechnology.
These additions are necessary because
EPA is proposing to make the
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exemption of PIPs based on sexually
compatible plants created through
biotechnology contingent upon
notifying EPA prior to a PIP being
brought to market through a selfdetermination letter and/or by seeking
EPA confirmation that a PIP meets the
exemption criteria (options described in
Unit VI.C.1.).
The proposed exemption eligibility
determination process will allow the
Agency to maintain a record of the PIPs
that meet the criteria for exemption.
This record will aid in inspections
conducted by the Agency to ensure
compliance and to confirm that PIPs in
the food supply do indeed meet the
standard of safety as defined by the
exemption criteria. Also, if it were
determined based on new information
that a PIP was not eligible for
exemption, such a record would help
inform EPA and the FDA of the most
appropriate steps to protect public
health (including enforcement). As
described in Unit VI.A.4., with the
proposed exemption eligibility
determination process, exempting PIPs
based on sexually compatible plants
created through biotechnology has an
estimated incremental cost saving of
about $444,000–$459,000 per product,
compared to traditional registration, due
to reductions in PRIA fees and data
generation.
1. Proposed Section for Determining the
Eligibility of a PIP To Qualify for
Exemption
The Agency is proposing a new
provision in Subpart E, 40 CFR 174.90,
entitled ‘‘Determining eligibility for
exemption.’’ This provision states that
developers have two, non-mutually
exclusive options to notify EPA that
their PIP meets the exemption criteria:
(1) Submit a self-determination letter
that a PIP meets the exemption criteria,
and (2) seek EPA confirmation that a PIP
meets the exemption criteria. EPA
confirmation can be sought instead of,
in conjunction with, or subsequent to
the submission of the self-determination
letter. EPA believes that such a
confirmation holds multiple potential
benefits, including reduced barriers to
international trade, increased public
confidence in product safety, and
affirmation for the developer that it has
correctly determined that the PIP meets
the criteria for exemption.
The provision further explains the
relationship between the EPA
confirmation processes and a letter of
self-determination. Specifically, if a
developer chooses to request EPA
confirmation in accordance with 40 CFR
174.93 in conjunction with or
subsequent to submitting a self-
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determination letter in accordance with
40 CFR 174.91, the exemption is
effective from the time at which the
company receives confirmation of
submission of the self-determination
letter. The exemption remains effective
if EPA affirms the developer’s
determination that the PIP meets the
exemption criteria and the selfdetermination is superseded by EPA’s
written confirmation in response to the
confirmation request. However, if at any
time after submission of the selfdetermination, EPA determines that the
PIP was not eligible for exemption
under this proposed rule, the exemption
will not have applied, and EPA may
take enforcement against that product to
ensure compliance with FIFRA.
Similarly, FDA may take enforcement
action if an incorrect self-determination
was made by a developer of a PIP in a
plant used for food or feed. As indicated
in Unit VI.C.2., the developer is
responsible for ensuring the accuracy of
its self-determination.
Alternatively, in instances in which
no prior self-determination has been
provided to the Agency in accordance
with 40 CFR 174.91 and the developer
submits a request for confirmation to the
Agency, the exemption applies only
once EPA provides written notice to the
developer confirming that the PIP meets
the criteria for exemption. EPA reserves
the right to assess or revisit at any time
whether a PIP meets, or has met, the
criteria for exemption regardless of
whether the developer requests EPA
confirmation. In particular, as exempt
PIPs are still subject to 40 CFR 174.71,
upon learning of any adverse effects
(e.g., injurious or deleterious levels in
food), EPA has the authority to evaluate
whether the PIP still meets the criteria
for exemption. As described in the
preamble of the July 19, 2001 Federal
Register notice implementing 40 CFR
174.71 (66 FR 37772; July 19, 2001),
reports involving food or feed (i.e., those
subject to enforcement under FFDCA)
would be made to EPA, but EPA will
share such reports with FDA. EPA and
FDA will individually determine
whether any action, including the
possibility of enforcement, is necessary
to protect the public health or the
environment, and if so, what constitutes
appropriate action based on their
respective statutes (EPA—FIFRA,
FDA—FFDCA). Therefore, 40 CFR
174.71 is a means of ensuring that EPA
and FDA can address any potential
hazard identified subsequent to selfdetermination or EPA confirmation that
a PIP meets the requirements for
exemption.
The provision also outlines instances
in which an exemption determination
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can be extended to subsequent
variations of the PIP. For a PIP based on
a sexually compatible plant created
through biotechnology, EPA is
proposing that a determination that the
PIP meets the exemption criteria would
be required for each modified gene and
plant species combination, made either
by the developer through a selfdetermination letter or by EPA through
a confirmation request. However, EPA is
aware that a plant species can comprise
multiple varieties and does not intend
for the PIP in each variety to require its
own submission if a developer creates
the same modification in different
varieties. In this case, that developer
would need to notify EPA only for the
first modification in that species. The
specific circumstances when an
exemption determination is not required
when modifying additional varieties of
a plant species differ slightly depending
on whether the developer is creating the
same substance with the modification
(e.g., native allele) or whether the
developer is creating the same
phenotype via a novel mutation. If the
developer is creating the same substance
with the modification (e.g., native allele)
in other varieties, then subsequent
notifications are not required so long as
no additional modifications were made
to the regulatory region. If the developer
is creating the same phenotype by
modifying the regulatory region via a
novel mutation in other varieties, then
subsequent notifications are not
required. For example, if a developer
modifies an existing gene in a tomato
variety to create a native allele, this
would require a determination;
however, if the developer subsequently
creates the same native allele in another
tomato variety, the developer would not
be required to submit a second
determination request for the additional
variety. Similarly, if a developer creates
a differentially expressed gene,
subsequent modifications in other
varieties would not require a
determination if the developer targets
the same nucleic acid sequence (e.g.,
uses a guide RNA to target the same
location in a gene in a CRISPR/Cas
system) to create a mutation via double
stranded DNA break repaired by nonhomologous end joining. Finally,
separate submission of a selfdetermination or request for EPA
confirmation for purposes of the FFDCA
exemption for a PIP proposed for use in
food or feed is required only if it has not
already been submitted under FIFRA.
This is because the exemption eligibility
determination process already requires
the applicant to certify that the PIP
meets the general qualifications for
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exemption, which includes exemption
under the FFDCA for PIPs used in food
or feed. We envision at least one
scenario in which a developer may need
to submit a self-determination or request
for EPA confirmation for the purposes of
FFDCA but not FIFRA. That scenario
arises when residues of a PIP will be in
or on food imported into the United
States, but the PIP is not intended to be
sold or distributed for pesticidal use
(e.g., PIP containing seed or plant sold
for planting) in the United States (and
thus is not subject to FIFRA regulation).
2. Proposed Process for a Letter of SelfDetermination for a PIP To Qualify for
Exemption
The Agency is proposing a new
provision in Subpart E, 40 CFR 174.91,
entitled ‘‘Submitting a letter of selfdetermination for exemption.’’ The
proposed provision describes the
requirements and process of notifying
EPA that the developer has determined
(or ‘‘self-determined’’) that a PIP
qualifies for exemption.
Self-determination letters may be
submitted electronically (guidance for
electronic submission can be found in
Pesticide Registration Notice 2011–3 or
any subsequent revision or replacement)
or by paper submission. Proposed 40
CFR 174.91 includes information on
how to format the letter and the
required contents of the letter, including
a statement certifying the developer’s
determination of exemption eligibility.
If a developer does not have an EPA
company number they will be required
to obtain a company number prior to
submission of a self-determination
letter. EPA intends that selfdetermination letters will not be
submitted under FIFRA section 33
(Pesticide Registration Improvement
Extension Act of 2018 (PRIA)) and will
not be subject to application fees.
In addition, this provision explains
that a developer must submit its letter
of self-determination prior to engaging
in activities subject to FIFRA for the
proposed PIP (e.g., distribution and sale
of the PIP at issue), and the exemption
does not apply until EPA confirms
receipt of the self-determination. EPA
notes that the developer is responsible
at all times for ensuring its selfdetermination is accurate and if at any
time EPA determines that a selfdetermination was wrongly made, or is
no longer accurate due to the
availability of new information that was
not available at the time the selfdetermination was made, EPA and the
FDA can take action to protect public
health or the environment. This
includes the possibility of enforcement
under FIFRA or FFDCA. For
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electronically submitted letters, this
receipt confirmation occurs
automatically upon submission and is
considered equivalent to written
confirmation of receipt. EPA will
provide written confirmation of receipt
within 30 days of receiving a selfdetermination letter via mail. EPA will
notify FDA when it receives a letter of
self-determination.
3. Proposed EPA Confirmation
Submission Process for a PIP To Qualify
for Exemption
The Agency is proposing a new
provision in Subpart E, 40 CFR 174.93,
entitled ‘‘Obtaining EPA confirmation of
eligibility for the exemption.’’ This
provision describes the process through
which a developer may seek
confirmation from EPA whether a PIP
meets the criteria for exemption
codified in 40 CFR 174.21. A developer
must submit information as outlined in
40 CFR 174.91 along with specific
supporting documentation. For
example, the information required to
support the request for a PIP based on
a sexually compatible plant created
through biotechnology is described in
proposed 40 CFR 174.95 and discussed
in Unit VI.C.3. The provision also
specifies that any claims of
confidentiality for information
submitted in the request for EPA
confirmation must be made in
accordance with the procedures
outlined in 40 CFR 174.9.
In addition, the provision at 40 CFR
174.93 explains that upon receipt of the
request, EPA will review the submission
and determine whether the PIP meets all
necessary criteria to be exempt under 40
CFR 174.21. The Agency proposes to
notify the submitter in writing of its
determination. The exemption goes into
effect only once the developer receives
EPA’s confirmation in writing, unless a
self-determination letter was previously
submitted. Once a decision has been
made that a PIP meets the criteria for
exemption, this decision applies to all
requirements under FIFRA, except for
the adverse effects reporting under 40
CFR 174.71. As described in Unit
VI.C.1., exempt PIPs are still subject to
40 CFR 174.71 and EPA reserves the
right to reassess whether a PIP meets the
criteria for exemption should the
Agency learn of relevant information
subsequent to confirming its eligibility
to be exempt under 40 CFR 174.21. EPA
intends for requests for EPA
confirmation to be submitted using the
current submission category (M009) and
associated fee structure for a Non-FIFRA
Regulated Determination under FIFRA
section 33 (PRIA). Currently, under the
Non-FIFRA Regulated Determination
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category, the statutory time for EPA to
review and make a determination is 120
days. The logistics of the submission for
a request and EPA review times may
change in the future if PRIA changes or
a different structure for submissions is
adopted.
4. Proposed Documentation for an
Exemption for PIPs Based on Sexually
Compatible Plants Created Through
Biotechnology
The Agency is proposing a new
provision in Subpart E, 40 CFR 174.95,
entitled ‘‘Documentation for an
exemption for a plant-incorporated
protectant based on a sexually
compatible plant created through
biotechnology.’’ This proposed
provision describes the specific
information that must be documented
for any PIPs based on sexually
compatible plants created through
biotechnology for which a developer is
claiming an exemption. This provision
serves two purposes. First, the provision
describes the information that must be
submitted to EPA, pursuant to 40 CFR
174.93, for confirmation that a PIP
meets the exemption criteria. Second,
the provision describes the information
that any developer must maintain for 5
years pursuant to the recordkeeping
requirements set forth in 40 CFR 174.73.
For PIPs based on sexually compatible
plants created through biotechnology,
the Agency is proposing that the
information documented for
recordkeeping and submitted during a
request for EPA confirmation contain
three main information elements: (1)
Information on the biology of the plant;
(2) a description of the pesticidal trait
and how it was engineered; and (3)
information on the molecular
characterization of the PIP. The
proposed information elements are
necessary to ensure that the PIP based
on a sexually compatible plant created
through biotechnology meets the FIFRA
and FFDCA proposed exemption
criteria. Specifically, information that
EPA proposes will be needed for each
element is as follows.
The first proposed element,
information on the biology of the plant,
will include: The identity of the
recipient plant, including genus and
species; and if the PIP was derived from
another plant species, the identity of the
source plant, including genus and
species, and information to demonstrate
the recipient plant and the source plant
are sexually compatible. EPA
anticipates that information fulfilling
the first element will typically be a
narrative description to show that the
PIP is found in plants that are sexually
compatible with the recipient plant.
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The proposed second element,
description of the pesticidal trait and
how it was engineered into the plant,
will include a narrative description of
the intended pesticidal function
resulting from the modification of the
plant and the technique used to make
the modification (e.g., was the Cas
enzyme stably integrated during
development and if so was it segregated
out of the final product). This
information ensures that no unapproved
ingredients remain in the final product.
In products where the recipient plant is
a food plant in which the levels of the
pesticidal substance are commonly
screened for in conventional breeding to
ensure safe levels, the second element
requires that the developer describe
how conventional breeding practices
have been and will be performed on the
product proposed for exemption. This
criterion can be fulfilled with a
confirmation that the developer has
screened its product for acceptable
levels of the pesticidal substance (e.g.,
generally accepted safe content for
solanine is 20–25 mg/100g of fresh
potato weight). This criterion ensures
that levels of the pesticidal substance
are not present in the recipient food
plant, as the plant is grown and
harvested under normal conditions of
use, at levels that are injurious or
deleterious to human health as stated in
the FFDCA proposed exemption criteria.
The proposed third element,
molecular characterization of the PIP,
includes two components. First, EPA is
proposing to require the nucleotide
sequence and the amino acid sequence
of the PIP in the recipient plant,
including a sequence comparison
between the recipient plant and the
relevant comparator (i.e., the source
plant if a source plant was used or the
unmodified plant if no source plant was
used). For a plant-incorporated
protectant where the regulatory region
has not been modified, the sequence
information will confirm that this is
true. For PIPs where the regulatory
region of an existing or inserted native
gene has been modified, the second
component is EPA’s proposal to require
confirmation that the expression profile
(i.e., tissues, developmental stages, and
levels of expression) of the PIP is not
outside that observed in plants that are
sexually compatible with the recipient
plant. In this circumstance, the
developer must show that the highest
level of expression of the PIP obtained
under normal environmental conditions
across the lifespan of the plant does not
exceed the upper limit observed in a
plant that is sexually compatible with
the recipient plant. EPA envisions that
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a developer can meet this requirement
through either rationale or data
confirmation: A developer can
document a rationale regarding the
expected phenotype given the type of
modification made (e.g., is the
modification meant to optimize an allele
and therefore may result in a slight
increase in expression but no change in
expression pattern or has something
more significant been done that could
lead to altered expression patterns), or
the developer can provide expression
data examining the tissue/life stage in
which expression is expected to be
highest to corroborate its expectation.
The extent of expression data required
is expected to be directly correlated to
the likelihood that the modification
could lead to a novel expression profile.
Information described under elements
one through three will inform whether
the PIP meets criteria (a) and (b) of
proposed FIFRA exemption and criteria
(a) and (b) of proposed exemption from
the requirement of a tolerance.
D. What are the proposed recordkeeping
requirements?
EPA proposes to add a new provision
in Subpart D, 40 CFR 174.73, entitled
‘‘General recordkeeping requirements
for exemptions.’’ This section describes
the documentation and recordkeeping
that must be done for exempted PIPs
listed under 40 CFR 174.21(d).
Specifically, in order for a PIP listed
under 40 CFR 174.21(d) to be eligible for
exemption, a developer must submit to
EPA either a self-determination letter or
a request for EPA confirmation that the
PIP is eligible for exemption prior to
engaging in FIFRA regulated activities.
Accordingly, proposed 40 CFR 174.73
mandates that the developer maintain
documentation of such a submission
along with supporting information.
Supporting information would include
the information listed in the exemption
specific section of subpart E. This
documentation would need to be
maintained for five years starting from
the effective date of the exemption.
Finally, proposed 40 CFR 174.73 states
that this information must be made
available to EPA upon request. This
request may occur as part of routine
enforcement activities (e.g., auditing,
inspections) conducted by EPA to
ensure compliance with EPA
regulations or subsequent to EPA
receiving an adverse effects report.
E. What is the proposed clarification to
general qualifications for exemptions?
In 2001, EPA developed ‘‘General
Qualifications for Exemptions’’ at 40
CFR 174.21, which describes criteria
that are required for any PIP to be
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exempt from the requirements of FIFRA,
with the exception of the adverse effects
reporting requirement at 40 CFR 174.71.
These criteria were developed at the
same time as the FIFRA and FFDCA
exemptions for PIPs derived through
conventional breeding and thus were
drafted with reference to those specific
sections. The Agency is proposing edits
to 40 CFR 174.21 to clarify the
applicability of this framework to other
PIP exemptions, including the language
in the proposal.
For paragraph (a), this revision simply
clarifies that this paragraph is specific to
the pesticidal substance of the PIP. This
update is necessary to avoid confusion
over the current dual use of the word
‘‘plant-incorporated protectant’’ in 40
CFR 174.21 to refer to both the
pesticidal substance and the PIP as a
whole, per the definition in 40 CFR
174.3. For paragraph (b), the current
reference to sections 40 CFR 174.507
through 174.508 only allows for a PIP to
be exempt if the residues of the PIP are
nucleic acids or come from a sexually
compatible plant. This restriction was
established when the only exempt PIPs
were from sexually compatible plants.
EPA is proposing to revise paragraph (b)
to refer to subpart W, rather than the
specific sections. For paragraph (c), the
current reference to 40 CFR 174.705
only allows for a PIP to be exempt if the
inert ingredients are from sexually
compatible plants. Again, this
restriction was established when the
only exempt PIPs were from sexually
compatible plants. Although EPA is not
proposing an inert ingredient exemption
specific to this proposal, EPA believes it
is important to add flexibility to the
regulatory text to allow PIPs to be
exempt based on other inert ingredient
exemptions that EPA may establish in
subpart X in the future. Thus, EPA is
proposing to revise paragraph (c) to refer
to subpart X, rather than the specific
section of 40 CFR 174.705. Finally, EPA
proposes to add a new paragraph (d) to
section 40 CFR 174.21 to account for the
proposed exemption eligibility
determination process (Unit VI.C.) and
proposed recordkeeping requirements
(Unit VI.D.). This paragraph specifies
that for PIPs listed in the subsequent
subparagraph (i.e., subparagraph (d)(i)),
compliance with recordkeeping and
providing an exemption eligibility
determination to EPA is a requirement
of the exemption. The addition of
paragraph (d) does not impact the
current exemption under section 40 CFR
174.25 for PIPs from sexually
compatible plants, because PIPs from
sexually compatible plants (or the
proposed amended title, PIPs from
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sexually compatible plants through
conventional breeding) are not
identified in paragraph (d).
F. What is the clarification of
exemptions for sexually compatible
PIPs?
In 2001, EPA exempted one category
of PIPs from all FIFRA requirements,
with the exception of the adverse effects
reporting requirement at 40 CFR 174.71.
PIPs derived through conventional
breeding from plants sexually
compatible with the recipient plant
were exempted from FIFRA, and a
companion FFDCA exemption from the
section 408 requirement of a tolerance
for residues of this category of PIPs was
also issued. Conventional breeding is
defined at 40 CFR 174.3 as ‘‘the creation
of progeny through either: the union of
gametes, i.e., syngamy, brought together
through processes such as pollination,
including bridging crosses between
plants and wide crosses, or vegetative
reproduction. It does not include use of
any of the following technologies:
Recombinant DNA; other techniques
wherein the genetic material is extracted
from an organism and introduced into
the genome of the recipient plant
through, for example, micro-injection,
macro-injection, micro-encapsulation;
or cell fusion.’’
The Agency is proposing to clarify the
relationship between the proposal on
PIPs based on sexually compatible
plants created through biotechnology
and the exemptions currently at 40 CFR
174.25, ‘‘Plant-incorporated protectant
from sexually compatible plant,’’ and 40
CFR 174.508 ‘‘Pesticidal substance from
sexually compatible plant; exemption
from the requirement of a tolerance.’’ To
this end, EPA would insert ‘‘created
through conventional breeding’’
immediately after the subject of the
exemption (e.g., ‘‘pesticidal substance’’)
in each section title, and insert an
additional criterion into 40 CFR 174.25
and 174.508 as follows:
‘‘(c) The genetic material is
transferred from the source plant to the
recipient plant only through
conventional breeding.’’
This clarification would explicitly
state in the title and criteria at 40 CFR
174.25 and 174.508 the condition
underlying the rationale for exemption
offered in the preamble of the July 19,
2001 Federal Register notice
implementing these paragraphs (66 FR
37772; July 19, 2001). Although 40 CFR
174.25 has always meant ‘‘only through
conventional breeding,’’ this is a
necessary clarification now given that
the proposed amended definition for
‘‘sexually compatible’’ states that ‘‘a
viable zygote can be formed through the
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union of two gametes through
conventional breeding,’’ which would
modify the existing definition that states
that ‘‘a viable progeny is formed only
through the union of two gametes
through conventional breeding.’’ The
clarification would also explicitly
indicate how proposed sections 40 CFR
174.26 and 174.541 on PIPs based on
sexually compatible plants created
through biotechnology relate to the
existing exemptions for PIPs created
through conventional breeding from
sexually compatible plants at 40 CFR
174.25 and 174.508. The Agency is not
proposing similar modifications at 40
CFR 174.705, and instead proposes to
expand the scope of that exemption to
include both conventional breeding and
biotechnology, as described in Unit
VI.G.
G. What is the proposed expansion of
the inert ingredient exemption at 40
CFR 174.705 to include intermediary
substances initiated through
biotechnology?
1. Description of the expansion. EPA
is proposing to expand the scope of the
existing inert ingredient exemption at
40 CFR 174.705 to include inert
ingredients that are intermediary
substances initiated through
biotechnology so long as they still meet
the existing criteria. In the 2001
preamble promulgating 40 CFR 174,
EPA stated ‘‘with regard to the enzymes,
precursors, or intermediates in
biosynthetic pathways necessary for
anabolizing the pesticidal substance,
EPA at this time considers them to be
part of the plant-incorporated protectant
because the substance is intended to
‘‘ensure the presence of the active
ingredient’’—i.e., it is an inert
ingredient.’’ Although the biochemical
pathway may be initiated by a
modification created through
biotechnology, EPA believes the plantproduced intermediaries leading to the
ultimate production of the pesticidal
substance meet the scientific rationale
of the existing inert ingredient
exemption at 40 CFR 174.705. This is
because EPA’s proposed exemption at
40 CFR 174.26 provides developer
flexibility by allowing changes to the
nucleic acid sequence of the PIP as long
as those modifications still result in the
same pesticidal substances exempt
under 40 CFR 174.25, thereby
maintaining the integrity of such
biochemical pathways described in the
2001 preamble. Therefore, although the
technique used to initiate such a
biochemical pathway may be different,
the intermediary substances themselves
remain the same.
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2. Risk analysis. EPA believes the risk
analysis at Unit VI.A.3. supporting the
proposal for exemption from FIFRA
requirements and the risk analysis at
Unit VI.B. supporting the FFDCA
section 408 proposal for exemption from
the requirement of a tolerance also
supports the exemption from FIFRA and
the FFDCA for inerts that meet the
criteria under the proposed expansion
of 40 CFR 174.705, because these
substances would be endogenous to
plants in sexually compatible
populations and thus would not present
novel exposures should inert ingredient
intermediaries be initiated through a
modification using biotechnology.
VII. Request for Comment
EPA is seeking public comment on all
aspects of this proposed rule, including
comments on the specific points
discussed in this unit and the specific
points raised in Units V. and VI. of this
proposal.
A. What inert ingredients could be
present in PIPs based on sexually
compatible plants created through
biotechnology?
An ‘‘inert ingredient’’ is defined in 40
CFR 174.3 to mean ‘‘any substance, such
as a selectable marker, other than the
active ingredient, where the substance is
used to confirm or ensure the presence
of the active ingredient, and includes
the genetic material necessary for the
production of the substance, provided
that genetic material is intentionally
introduced into a living plant in
addition to the active ingredient.’’
Additionally, in 2001 EPA stated that
‘‘with regard to the enzymes, precursors,
or intermediates in biosynthetic
pathways necessary for anabolizing the
pesticidal substance, EPA at this time
considers them to be part of the plantincorporated protectant because the
substance is intended to ‘‘ensure the
presence of the active ingredient’’—i.e.,
it is an inert ingredient.’’ As stated in
Unit VI.G., the Agency is expanding the
current inert ingredient exemption at 40
CFR 174.705 to be inclusive of both
conventional breeding and
biotechnology in order to account for
potential intermediary substances as
described in the 2001 quote that would
ultimately lead to the production of the
pesticidal substance.
However, outside of these
intermediary substances, the Agency
does not anticipate other types of inert
ingredients (e.g., herbicide tolerance) in
PIPs based on sexually compatible
plants created through biotechnology.
Previous biotechnology approaches that
relied on DNA constructs were
constructed with the genetic material
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encoding for both the active and the
inert ingredient. These DNA constructs
ensured that the inert ingredient could
be used to confirm the plants or cells
that successfully integrated the genetic
material encoding for the active
ingredient. However, to create PIPs
based on sexually compatible plants
created through biotechnology,
modifications coding for non-pesticidal
traits in transgenic PIPs (e.g., herbicide
resistance) would instead be
incorporated into the recipient plant
genome independent of the active
ingredient. Because these events occur
independently the modification cannot
confirm or ensure the presence of the
active ingredient. The modification
therefore would not meet the definition
of an inert ingredient under 40 CFR
174.3 because it is an independent, nonpesticidal trait not regulated under
FIFRA. EPA expects that any
ingredients intentionally added during
the development of PIPs based on
sexually compatible plants created
through biotechnology that are specific
to the production of the active
ingredient (e.g., guide RNA, DNA
nuclease) and that could function as an
inert ingredient would either be
transiently transformed or would be
removed (e.g., through segregation of the
trait) during the breeding process and
that if these ingredients have not been
removed from the final product the
product would not meet the criteria at
proposed under the new 40 CFR 174.26
and would not qualify for the new
exemptions.
The Agency therefore requests
comment on whether there are any inert
ingredients other than the intermediary
substances described in the 2001 quote
that will remain in the final plant
products containing PIPs based on
sexually compatible plants created
through biotechnology. If inert
ingredients other than the intermediary
substances described in the 2001 quote
are identified in the responses to the
previous request, the Agency also
requests comment as to whether the
inert ingredients in PIPs based on
sexually compatible plants created
through biotechnology require the
proposal of an exemption that would be
specific to those created through
biotechnology and would allow
developer flexibility in the nucleic acid
sequence. If the Agency receives
comments that indicate inert ingredients
other than the intermediary substances
described in the 2001 quote may be
present in the final plant product and/
or that developer flexibility in the
nucleic acid sequence of inert
ingredients would be beneficial, the
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Agency will consider finalizing the
proposed rule with exemptions under
FIFRA and FFDCA for inert ingredients
derived through biotechnology from
sexually compatible plants. These
exemptions would be based on the
proposed exemptions 40 CFR 174.26
and 174.541 in that the use of
biotechnology is permitted and only
inert ingredients composed of genetic
material that is derived from sexually
compatible plants would be exempt.
The Agency is not currently considering
an exemption for potential inert
ingredients that are derived from
sources that are not sexually compatible
with the recipient plant (e.g., Cas
proteins).
B. What process should EPA use to
provide notice that a PIP no longer
meets the criteria for exemption if new
information is provided?
EPA is proposing to exempt PIPs
based on sexually compatible plants
created through biotechnology from
regulation under FIFRA, except for the
adverse reporting effects at 40 CFR
174.71. In the event EPA learns of
information that affects a previous
determination that a PIP based on a
sexually compatible plant created
through biotechnology meets the
criteria, EPA will reconsider the new
information and provide a new
determination in writing whether the
PIP continues to meet the criteria for
exemption. EPA requests comment on
whether the process outlined is detailed
enough.
C. Should EPA consider other
approaches for its confirmation process?
EPA is proposing that the exemption
of PIPs based on sexually compatible
plants created through biotechnology
include a process through which
developers of PIPs based on sexually
compatible plants created through
biotechnology submit either a selfdetermination letter or request
confirmation that their PIP meets the
criteria for exemption. EPA seeks
comment on whether the Agency should
consider different approaches for its
proposed exemption eligibility
determination process. For example,
one alternative process could be to
require mandatory EPA confirmation so
that all developers must submit
information to EPA for EPA
confirmation that their PIP meets the
exemption criteria prior to engaging in
activities subject to FIFRA. EPA
requests comment on whether or how
such a mandatory approach could be
workably implemented, and whether
such an approach would be useful or
justified.
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This alternative process would follow
the same submission procedures that are
outlined in proposed 40 CFR 174.93,
and the information required to
determine the eligibility of exemption
would remain the same as outlined in
proposed 40 CFR 174.95. Another
alternative could be a voluntary
confirmation process for all PIP
products exempted under the proposed
rule similar to that in USDA’s final rule
titled ‘‘Movement of Certain Genetically
Engineered Organisms.’’ (85 FR 29790;
May 18, 2020). Only those developers
who seek EPA’s confirmation would be
required to submit to the Agency
information and data sufficient to
establish that their PIPs are eligible
under the proposed exemptions.
Developers who do not seek EPA
confirmation would not be required to
submit any documentation to EPA (and
thus this alternative would be different
from EPA’s proposed process through
which developers submit either a selfdetermination letter or request
confirmation that their PIP meets the
criteria for exemption). EPA requests
comment on whether or how such a
voluntary approach could be workably
implemented (e.g., should the
recordkeeping requirements at proposed
40 CFR 174.73 be required for
developers who do not submit for EPA
confirmation) and whether such an
approach would be useful or justified?
D. Is EPA’s intent behind the use of the
terms ‘‘native’’ and ‘‘never derived’’
clear?
The Agency is proposing to define
‘‘native gene’’ to mean ‘‘a gene that is
identified in the recipient plant or
plants that are sexually compatible with
the recipient plant; and has never been
derived from a source that is not
sexually compatible with the source
plant.’’ The phrase ‘‘has never been
derived from a source that is not
sexually compatible with the source
plant’’ is meant to clarify that a PIP
would not qualify for the proposed
exemption if the gene was introduced
into the genome of the source plant
through transgenic technology, as those
genes may not be representative of the
shared genetic information between
sexually compatible plants. For
example, bacterial endotoxin genes (e.g.,
from the source Bacillus thuringiensis)
are a commonly engineered pesticidal
trait, but EPA does not intend for these
genes to be considered part of the
sexually compatible gene pool nor does
EPA intend for these genes to qualify for
the proposed exemption. However, EPA
is also aware that horizontal gene
transfer from Agrobacterium to plants
can occur and that in some cases, like
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the domesticated sweet potato, it may
result in a variant so commonly found
that it could be considered part of the
gene pool. It is the Agency’s intent to
exclude substances that plant breeders
do not have experience with (e.g., a
bacterial endotoxin not found in a food
plant) from the proposed exemption.
Given the explanation of the intent
behind the terms ‘‘native’’ and ‘‘never
derived,’’ EPA seeks comment on
whether the intent behind the use of the
terms is clear. The Agency also seeks
comment on whether alternative
phrasing rather than ‘‘native’’ would be
more appropriate. Similarly, the Agency
seeks comment on whether a definition
for ‘‘native gene’’ or ‘‘native allele’’ is
necessary, or if the criteria included in
these definitions should instead be
incorporated into the exemption text.
E. Should EPA issue a clarifying
exemption for loss-of-function traits that
result in pesticidal effects?
As described in Unit II.A., the Agency
considers the modification of existing
genes in a plant to elicit a loss-offunction trait in order to confer a
pesticidal effect to be a pesticide. EPA
recognizes that this scenario is different
from transgenic PIPs that traditionally
produce a pesticidal substance, e.g.,
PIPs that produce a protein or other
substance that kill a pest. In many
instances, for loss-of-function traits, the
genetic material of the recipient plant
has been altered to reduce the
production of a substance that would
otherwise facilitate the susceptibility of
that plant to a pathogen; therefore, the
reduction or elimination of that
substance has a mitigating or pesticidal
effect. For PIPs created through
conventional breeding, EPA considers
these loss-of-function traits to be
included in the existing exemption at 40
CFR 174.25. It is also EPA’s intention
that loss-of-function traits created
through biotechnology are included
under the proposed exemption at 40
CFR 174.26 so long as the exemption
criteria are met (e.g., only substances
produced that are found in sexually
compatible plants).
In situations where the existing plant
genes are acting as the pesticidal
substance, EPA recognizes that it can be
confusing under the current regulatory
definitions in 40 CFR 174.3 to interpret
the pesticidal substance and the genetic
material necessary for the production of
the pesticidal substance as applying to
the same thing. Given that it is
potentially confusing to refer to both of
these as a ‘‘pesticidal substance’’
interchangeably, EPA requests comment
as to whether a clarifying exemption
specific to ‘‘loss-of-function PIPs,’’
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where the genetic material is the
pesticidal substance, would aid in
reducing ambiguity over the use of the
term ‘‘pesticidal substance’’ in the
regulatory text. EPA proposes to
accomplish this by separating exempt
PIPs into two categories, those where
the gene product is the pesticidal
substance and those where the genetic
material itself is the pesticidal
substance. Similar to the existing
exemption at 40 CFR 174.25 and the
proposed exemption at 40 CFR 174.26,
the clarifying exemption specific to lossof-function PIPs would be written to
limit permissible modifications to those
that do not result in the production of
a modified substance. In other words,
only the reduced expression of an
unmodified protein or the elimination
of the unmodified protein would be
permissible. This is to ensure (1)
limitation of substances to only those
with which plant breeders have
experience, (2) the applicability of
EPA’s risk assessment for the exemption
at 40 CFR 174.25 and the risk
assessment for the proposed exemption
at 40 CFR 174.26 to the proposed ‘‘lossof-function PIPs’’ exemption, and (3)
that if the reduced substance is in fact
a pesticidal substance (or its reduction
leads to an increase of another
substance that is pesticidal) it is covered
by either the existing tolerance
exemption at 40 CFR 174.508 or the
proposed tolerance exemption at 40 CFR
174.541. It is also important to note that
when the loss of function of a gene
intentionally results in the increase in
production of another gene which
ultimately produces a pesticidal
substance, this PIP would fall under
either the existing exemption at 40 CFR
174.25 or the proposed exemption at 40
CFR 174.26. If EPA were to issue an
exemption for loss-of-function PIPs,
EPA would no longer include the
category at proposed 40 CFR
174.26(a)(2)(iv). In addition, EPA also
requests comment on how a separate
exemption or exemptions (if any)
specific to loss-of-function PIPs might
be implemented. Should such a separate
exemption(s) be technique-specific (e.g.,
should it be specific to loss-of-function
PIPs created through conventional
breeding?) or should there be one
exemption that covers loss of function
PIPs regardless of the technique used in
their creation?
VIII. References
The following is a listing of the
documents that are specifically
referenced in this document. The docket
includes these documents and other
information considered by EPA,
including documents that are referenced
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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.
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89. O’Mahony, S. and A. Ferguson, GlutenSensitive Enteropathy (Celiac Disease),
in Food Allergy: Adverse Reactions to
Foods and Food Additives, D.D.
Metcalfe, H.A. Sampson, and R.A.
Simon, Editors. 1991, Blackwell
Scientific Publications: Cambridge,
Massachusetts.
90. Organisation for Economic Cooperation
and Development (OECD), OECD
Guideline 440: Uterotrophic Bioassay in
Rodents. 2007.
IX. Statutory and Executive Order
Reviews
Additional information about these
statutes and Executive orders can be
found at https://www.epa.gov/lawsregulations/laws-and-executive-orders.
A. Executive Order 12866: Regulatory
Planning and Review and Executive
Order 13563: Improving Regulation and
Regulatory Review
This action is a significant regulatory
action that was submitted to the Office
of Management and Budget (OMB) for
review under Executive Orders 12866
(58 FR 51735, October 4, 1993) and
13563 (76 FR 3821, January 21, 2011).
Any changes made in response to OMB
recommendations have been
documented in the docket for this action
as required by section 6(a)(3)(E) of
Executive Order 12866.
B. Executive Order 13771: Reducing
Regulations and Controlling Regulatory
Costs
This action is expected to be an
Executive Order 13771 deregulatory
action. Details on the estimated cost
savings of this proposed rule can be
found in EPA’s cost analysis (Ref. 2).
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C. Paperwork Reduction Act (PRA)
D. Regulatory Flexibility Act (RFA)
The information collection activities
in this proposed rule have been
submitted for approval to OMB under
the PRA, 44 U.S.C. 3501 et seq. The
Information Collection Request (ICR)
document that EPA prepared is assigned
EPA ICR No. 2619.01. You can find a
copy of the ICR in the docket for this
rule, and it is briefly summarized here.
The information collection activities
in this proposed rule are associated with
the proposed exemption eligibility
process (i.e., self-determination or
request for EPA-confirmation, and
associated recordkeeping) that would be
made available as an alternative to the
existing pesticide registration and
tolerance activities that are already
approved by OMB under OMB Control
No. 2070–0060 (EPA ICR No. 0277). As
such, the ICR accompanying this
proposed rule is intended to amend that
existing ICR at the final rule stage,
incorporating the information collection
activities for the exemption and related
estimated burden.
Respondents affected entities: See
Unit I.A.
Respondent’s obligation to respond:
Mandatory to obtain the exemption (40
CFR part 174, as proposed).
Estimated number of respondents: 1.
Frequency of response: Once.
Total estimated burden: 14 hours (per
EPA determination). Burden is defined
at 5 CFR 1320.3(b).
Total estimated cost: $1,487 (per EPA
determination), includes $0 annualized
capital or operation & maintenance
costs.
An agency may not conduct or
sponsor, and a person is not required to
respond to, a collection of information
unless it displays a currently valid OMB
control number. The OMB control
numbers for EPA’s regulations in 40
CFR are listed in 40 CFR part 9.
Submit your comments on the
Agency’s need for this information, the
accuracy of the provided burden
estimates, and any suggested methods
for minimizing respondent burden to
EPA using the docket identified at the
beginning of this rule. You may also
send your ICR-related comments to
OMB’s Office of Information and
Regulatory Affairs via email to OIRA_
submission@omb.eop.gov, Attention:
Desk Officer for the EPA. Since OMB is
required to make a decision concerning
the ICR between 30 and 60 days after
receipt, OMB must receive comments no
later than November 9, 2020. EPA will
respond to any ICR-related comments
received on the proposed ICR
amendment when issuing the final rule.
Pursuant to the RFA section 605(b), 5
U.S.C. 601 et seq., I hereby certify that
this action will not have a significant
economic impact on a substantial
number of small entities. In making this
determination, EPA believes that the
impact of concern is any adverse
economic impact, and that an agency
may certify that a rule will not have a
significant economic impact on a
substantial number of small entities if
the rule relieves regulatory burden, has
no net burden, or otherwise has a
positive economic effect on the small
entities subject to the rule. The factual
basis for this determination is presented
in the small entity impact analysis
prepared as part of the cost analysis for
this proposed rule (Ref. 2), which is
summarized in Units I.E. and VI.A.4.,
and a copy is available in the docket for
this rulemaking. The following is a brief
summary of the factual basis for this
certification.
The effect of the rule is to reduce
costs to developers of PIPs based on
sexually compatible plant created
through biotechnology, and the cost
savings per product are approximately
$444,000–$459,000. The cost savings
per product would be realized when a
letter of self-determination is sent. The
proposed exemption for PIPs based on
sexually compatible plants created
through biotechnology reduces the cost
associated with meeting regulatory
requirements and so removes a potential
barrier to market entry for small entities.
Of the entities likely to develop PIPs
based on sexually compatible plants
created through biotechnology, EPA
currently estimates that approximately
80% are small entities. We have
therefore concluded that this action will
relieve regulatory burden for all directly
regulated small entities.
Any comments regarding the potential
impacts on small entities from this
action should be submitted to the
Agency in the manner specified under
ADDRESSES.
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E. Unfunded Mandates Reform Act
(UMRA)
This action does not contain an
unfunded mandate as described in
UMRA, 2 U.S.C. 1531–1538, and does
not significantly or uniquely affect small
governments. The action is not expected
to impose an enforceable duty on any
state, local or tribal governments, and
the requirements imposed on the private
sector are not expected to result in
annual expenditures of $100 million or
more for the private sector. Accordingly,
EPA has determined that the
requirements of UMRA sections 202,
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203, 204, or 205 do not apply to this
action.
F. Executive Order 13132: Federalism
This action does not have federalism
implications as specified in Executive
Order 13132 (64 FR 43255, August 10,
1999). It will not have substantial direct
effects on the states, on the relationship
between the national government and
the states, or on the distribution of
power and responsibilities among the
various levels of government. Thus,
Executive Order 13132 does not apply
to this proposed rule.
G. Executive Order 13175: Consultation
and Coordination With Indian Tribal
Governments
This action does not have tribal
implications as specified in Executive
Order 13175 (65 FR 67249, November 9,
2000). It will not have substantial direct
effects on tribal governments, on the
relationship between the Federal
government and the Indian tribes, or on
the distribution of power and
responsibilities between the Federal
government and Indian tribes. Thus,
Executive Order 13175 does not apply
to this proposed rule.
H. Executive Order 13045: Protection of
Children From Environmental Health
Risks and Safety Risks
EPA interprets Executive Order 13045
(62 FR 19885, April 23, 1997) as
applying only to those regulatory
actions that concern environmental
health or safety risks that EPA has
reason to believe may
disproportionately affect children, per
the definition of ‘‘covered regulatory
action’’ in section 2–202 of the
Executive Order. This action is not
subject to Executive Order 13045
because it does not establish an
environmental standard intended to
mitigate a health or safety risk.
I. Executive Order 13211: Actions
Concerning Regulations That
Significantly Affect Energy Supply,
Distribution, or Use
This action is not a ‘‘significant
energy action’’ as defined in Executive
Order 13211 (66 FR 28355, May 22,
2001) because it is not likely to have a
significant adverse effect on the supply,
distribution, or use of energy.
J. National Technology Transfer
Advancement Act (NITAA)
NTTAA section 12(d), 15 U.S.C. 272
note, does not apply to this proposed
action because it would not impose any
technical standards requiring Agency
consideration of voluntary consensus
standards. This regulation proposes the
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types of information to be submitted in
a self-determination letter or EPA
confirmation request concerning the
exemption of PIPs based on sexually
compatible plants created through
biotechnology, but does not propose to
require specific methods or standards to
generate that information.
K. Executive Order 12898: Federal
Actions To Address Environmental
Justice in Minority Populations and
Low-Income Populations
EPA believes that this action is not
subject to Executive Order 12898 (59 FR
7629, February 16, 1994) because it does
not establish an environmental health or
safety standard.
L. FIFRA Review Requirements
In accordance with FIFRA section
25(a), EPA submitted the draft proposed
rule to the Secretary of the United States
Department of Agriculture (USDA) and
the FIFRA Scientific Advisory Panel
(SAP) for review. A draft of the
proposed rule was also submitted to the
appropriate Congressional Committees.
M. Executive Order 13874: Modernizing
the Regulatory Framework for
Agricultural Biotechnology Products
This action is intended to further
implement section 4(b) of Executive
Order 13874 (84 FR 27899, June 11,
2019). If this proposal is made final, the
final rule may promote future
innovation and competitiveness by
efficiently exempting through regulation
qualifying PIPs based on sexually
compatible plants created through
biotechnology that meet the FIFRA and
FFDCA standards for exemption.
List of Subjects in 40 CFR Part 174
Environmental protection,
Administrative practice and procedure,
Agricultural commodities, Pesticides
and pests, Plant-incorporated
protectants, Reporting and
recordkeeping requirements.
Andrew Wheeler,
Administrator.
Therefore, it is proposed that 40 CFR
chapter I be amended as follows:
PART 174—[AMENDED]
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.
2. Amend § 174.3 by adding in
alphabetical order the following
definitions to read as follows:
■
§ 174.3
*
*
Definitions
*
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*
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Gene, and other grammatical variants
such as ‘‘genic,’’ means a functional unit
of heritable genetic material that is
comprised of the genetic material
necessary for the production of a
substance.
*
*
*
*
*
Native allele means a variant of a
native gene that is identified in the
genetic diversity of plants sexually
compatible with the recipient plant.
Native gene means a gene that is
identified in the recipient plant or
plants sexually compatible with the
recipient plant; and has never been
derived from a source that is not
sexually compatible with the source
plant.
*
*
*
*
*
Sexually compatible, when referring
to plants, means a viable zygote can be
formed through the union of two
gametes through conventional breeding.
*
*
*
*
*
■ 3. Revise § 174.21 to read as follows:
§ 174.21 General qualifications for
exemptions.
A plant-incorporated protectant is
exempt from the requirements of FIFRA,
other than the requirements of § 174.71,
if it meets the exemption criteria in
paragraphs (a) through (d) of this
section. Plant-incorporated protectants
that are not exempt from the
requirements of FIFRA under this
subpart are subject to all the
requirements of FIFRA.
(a) The pesticidal substance from the
plant-incorporated protectant meets the
exemption criteria listed in at least one
of the sections in §§ 174.25 through
174.50.
(b) When the plant-incorporated
protectant is intended to be produced
and used in a crop used as food, the
residues of the pesticidal substance of
the plant-incorporated protectant are
either exempted from the requirement of
a tolerance under FFDCA (21 U.S.C. 321
et seq.) as listed in subpart W of this
part, or no tolerance would otherwise be
required.
(c) Any inert ingredient that is part of
the plant-incorporated protectant is
listed as an approved inert ingredient in
subpart X of this part.
(d) For plant-incorporated protectants
listed in the subparagraphs below, the
exemption applies only if the developer
is compliant with the general record
keeping requirements specified in
§ 174.73 and only after compliance with
the relevant eligibility determination
procedures specified in § 174.90:
(1) Plant-incorporated protectant
based on a sexually compatible plant
created through biotechnology.
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(2) [Reserved]
4. Amend § 174.25 by:
a. Revising the section heading;
b. Revising the introductory
paragraph; and
■ c. Adding paragraph (c).
The revisions read as follows:
■
■
■
§ 174.25 Pesticidal substance from a plantincorporated protectant from a sexually
compatible plant created through
conventional breeding.
The pesticidal substance from a plantincorporated protectant from a sexually
compatible plant created through
conventional breeding is exempt if all of
the following conditions are met:
*
*
*
*
*
(c) The genetic material is transferred
from the source plant to the recipient
plant only through conventional
breeding.
■ 5. Add § 174.26 to read as follows:
§ 174.26 Pesticidal substance from a plantincorporated protectant based on a sexually
compatible plant created through
biotechnology.
The pesticidal substance from a plantincorporated protectant based on a
sexually compatible plant created
through biotechnology is exempt if all of
the following conditions are met:
(a) The pesticidal substance is created
through biotechnology from either an
insertion of new genetic material as
discussed in paragraph (a)(1) of this
section or a modification of existing
genetic material as discussed in
paragraph (a)(2) of this section.
(1) A native gene is engineered into a
non-genic location of the recipient plant
genome, resulting in a pesticidal
substance identical to the pesticidal
substance identified in the source plant.
(2)(i) The existing native gene in the
recipient plant is modified to alter the
amount of pesticidal substance
produced without altering the identity
of the pesticidal substance produced; or
(ii) The genetic material that encodes
the substance of the existing native gene
is modified to result in a pesticidal
substance that is identical to the
pesticidal substance encoded by a
native allele of that gene; or
(iii) The existing genetic material is
modified pursuant to both (i) and (ii).
(iv) The existing native gene in the
recipient plant is modified to lose
function through the reduction or
elimination of the substance encoded by
that gene.
(b) The pesticidal substance is not
expressed at higher levels, in different
tissues, or at different developmental
stages than identified in a plant that is
sexually compatible with the recipient
plant.
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(c) This exemption does not apply
until the requirements in subpart E of
this part have been met.
■ 6. Add § 174.73 to read as follows:
§ 174.73 General recordkeeping
requirements for exemptions.
For 5 years, starting with the effective
date of a plant-incorporated protectant
exemption, any person who produces an
exempt plant-incorporated protectant
listed under § 174.21(d) must do both of
the following:
(a) Maintain documentation of either
the letter of self-determination or the
request for EPA confirmation along with
all supporting documentation for the
specific exemption listed in subpart E.
(b) Make the documentation of
exemption eligibility available to EPA
upon request.
■ 7. Amend subpart E to read as follows:
Subpart E—Exemption Eligibility
Determination Process and
Requirements
§ 174.90 Determining Eligibility for
Exemption
(a) Options for determining eligibility.
For a plant-incorporated protectant
listed under § 174.21(d), the developer
must do at least one of the following
actions to be eligible for the exemption
in § 174.21:
(1) Self-determination. A developer
may submit a letter of selfdetermination in accordance with
§ 174.91.
(2) Request for EPA confirmation of
eligibility. A developer may submit a
request for EPA confirmation of
eligibility in accordance with § 174.93.
(b) Where to submit a letter of selfdetermination or request for EPA
confirmation. A letter of selfdetermination or a request for EPA
confirmation of eligibility must be
submitted to the Office of Pesticide
Programs’ Document Processing Desk at
the appropriate address as set forth in
§ 150.17(a) or (b) of this chapter, with
the relevant ‘‘Attention’’ line:
‘‘Attention: Plant-Incorporated
Protectant Exemption SelfDetermination’’ or ‘‘Attention: PlantIncorporated Protectant Request for
Confirmation of Exemption Eligibility.’’
[placeholder for future instructions
covering electronic submissions].
(c) Overlapping determinations of
eligibility. A developer may elect to
submit a letter of self-determination as
well as a request for EPA confirmation
of eligibility concurrently or at a later
time. If the developer so elects, the letter
of self-determination will remain in
effect while EPA evaluates the request
for confirmation of eligibility.
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(d) Revisiting eligibility
determination. If, at any time after the
letter of self-determination is submitted
or EPA issues a confirmation of
eligibility, EPA becomes aware of
information indicating that the exempt
plant-incorporated protectant no longer
meets the criteria for exemption (e.g.,
adverse effects reports submitted under
§ 174.71) or that the self-determination
was incorrect, EPA will notify the
original submitter in writing of EPA’s
intention to initiate a review of
eligibility for exemption and may
request additional information from the
developer in order to evaluate that
eligibility for exemption. Upon
conclusion of its review, EPA will notify
the developer in writing of its
determination whether the plantincorporated protectant meets the
exemption criteria and any actions that
will be required should the plantincorporated protectant be found to not
meet the exemption criteria. Under
those circumstances, the plantincorporated protectant may be
considered to be noncompliant with
FIFRA and subject to possible
enforcement by EPA.
(e) Extension of exemption to
subsequent variations of the plantincorporated protectant.
(1) Plant-incorporated protectant
based on a sexually compatible plant
created through biotechnology. A letter
of self-determination or EPA’s
confirmation that the plant-incorporated
protectant based on a sexually
compatible plant created through
biotechnology meets the criteria for
exemption applies to subsequent
engineering of that plant-incorporated
protectant by the submitter into other
varieties of that same plant species as
long as the submitter is doing one of the
following:
(i) Producing the identical substance
as in the exempt plant-incorporated
protectant, so long as no modifications
were made to the regulatory regions.
(ii) Creating the same phenotype as in
the exempt plant-incorporated
protectant by targeting the same nucleic
acid sequence in the regulatory region to
result in a mutation via double-strand
DNA break repaired by non-homologous
end joining.
(iii) For subsequent engineering
events that do not meet either criterion
(e)(1)(i) or (1)(ii), a letter of selfdetermination or request for EPA
determination must be submitted.
(2) [Reserved]
§ 174.91 Submitting a letter of selfdetermination for exemption.
A developer who elects to selfdetermine eligibility for the exemption
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of a plant-incorporated protectant listed
under § 174.21(d) must comply with all
of the following requirements.
(a) When to submit a letter of selfdetermination. A letter of selfdetermination for an exemption must be
submitted to EPA prior to engaging in
activities subject to FIFRA.
(b) Contents of a letter of selfdetermination. The letter of selfdetermination must:
(1) Provide the name and contact
information for the submitter (including
phone and email address), company
name, or other affiliation.
(2) Identify the plant-incorporated
protectant and the following exemptionspecific information for the exemption
for which eligibility is self-determined:
(i) Plant-incorporated protectant
based on a sexually compatible plant
created through biotechnology. Cite the
paragraph under §§ 174.26 or 174.541
that is applicable to the PIP (i.e., (a)(1),
(a)(2)(i), (a)(2)(ii), (a)(2)(iii), or (a)(2)(iv)).
(ii) [Reserved]
(3) Include the following statement of
certification, filling in the information
described in italics:
‘‘I, [name of submitter], on behalf of [name
of company] am submitting this PlantIncorporated Protectant Exemption SelfDetermination consistent with the provisions
of 40 CFR part 174. I hereby confirm that the
plant-incorporated protectant known as
[name of the plant-incorporated protectant]
is eligible under 40 CFR 174.21 to be exempt
from the requirements of FIFRA, other than
the requirements of 40 CFR 174.71 and
174.73. I understand that it is a violation of
18 U.S.C. 1001 to willfully make any false
statement to EPA. I further understand that
if this self-determination is not consistent
with the provisions of 40 CFR part 174, this
plant-incorporated protectant product may
not be exempt from the requirements of
FIFRA, and [name of company] may be
subject to enforcement actions and penalties
under FIFRA sections 12, 13, and 14, 7 U.S.C.
136j, 136k, and 136l. Moreover, I also
understand that if this self-determination is
not consistent with 40 CFR part 174, the
residues of this plant-incorporated protectant
may not be exempt from the requirement of
a tolerance under the FFDCA, and [name of
company], as well as foods containing such
residues, may be subject to enforcement
actions and penalties under Chapter III of the
FFDCA, 21 U.S.C. 331 et seq.’’
(4) The statement must be dated and
signed by an authorized representative
of the developer of the plantincorporated protectant.
(c) EPA response. For electronic
submissions, EPA will provide
electronic confirmation of receipt
immediately. Electronic confirmation
shall be equivalent to written
confirmation. For submissions by mail,
written confirmation of receipt within
30 business days of receipt of a letter of
self-determination.
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(d) Effective date of exemption. The
exemption does not apply until EPA
confirms receipt of the letter of selfdetermination.
§ 174.93 Obtaining EPA confirmation of
eligibility for the exemption.
A developer who elects to request
EPA confirmation of eligibility for
exemption of a plant-incorporated
protectant listed under § 174.21(d) must
comply with all of the following
requirements.
(a) When to submit a request for EPA
confirmation. Unless the developer has
received confirmation of receipt of a
letter of self-determination, the request
for EPA confirmation must be submitted
prior to engaging in activities subject to
FIFRA.
(b) Contents of a request for EPA
confirmation of exemption eligibility.
The request must contain information as
specified in § 174.91(b) and supporting
documentation demonstrating that the
plant-incorporated protectant meets the
criteria for the exemption, as specified
in exemption-specific sections of this
subpart. Any claims of confidentiality
for information submitted in the request
for EPA confirmation must be made in
accordance with the procedures
outlined in § 174.9 of subpart A.
(c) EPA review and response. Upon
receipt of a request, EPA will review
and evaluate the information provided
to determine whether the plantincorporated protectant meets the
exemption criteria in § 174.21. EPA may
require additional information to assess
whether a plant-incorporated protectant
meets the criteria for exemption. EPA
will notify the submitter in writing of its
determination. If EPA determines that
the plant-incorporated protectant does
not meet the criteria for exemption, EPA
will notify the submitter in writing of
any actions that will be required.
(d) Effective date for the EPA
confirmed exemption. If the plantincorporated protectant is not already
exempt pursuant to the selfdetermination process under § 174.91,
this exemption applies once EPA
notifies the submitter in writing,
confirming that the plant-incorporated
protectant meets the criteria for
exemption.
§ 174.95 Documentation for an exemption
for a plant-incorporated protectant based
on a sexually compatible plant created
through biotechnology.
A developer requesting EPA
confirmation of exemption eligibility for
a plant-incorporated protectant from a
sexually compatible plant created
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through biotechnology pursuant to
§ 174.93 must submit the information in
the following paragraphs to EPA along
with its request for exemption
confirmation. Any developer required to
maintain records under § 174.73 must
maintain the following documentation.
(a) Biology of the plant.
(1) The identity of the recipient plant,
including genus and species.
(2) If the plant-incorporated
protectant was derived from another
plant species, provide the identity of the
source plant including genus and
species and information to demonstrate
the recipient plant and the source plant
are sexually compatible.
(b) Description of the pesticidal trait
and how the trait was engineered into
the plant. If the pesticidal substance is
a known mammalian toxin or toxicant
(e.g., solanine) describe how
conventional breeding practices are
being used to ensure it does not exceed
safe levels in the recipient food plant.
(c) Molecular characterization of the
plant-incorporated protectant.
(1) The nucleotide sequence and the
amino acid sequence of the plantincorporated protectant in the recipient
plant, including a sequence comparison
between the recipient plant and the
relevant comparator (i.e., the source
plant if a source plant was used or the
unmodified plant if no source plant was
used).
(2) For a plant-incorporated protectant
where the regulatory region of an
existing or inserted native gene has been
modified, confirmation that the
expression level does not exceed that
found in a sexually compatible plant
and the plant-incorporated protectant is
not expressed in tissues or
developmental stages outside of that
observed in a plant that is sexually
compatible with the recipient plant.
■ 8. Amend § 174.508 by:
■ a. Revising the section heading,
■ b. Revising the introductory
paragraph,
■ c. Designating paragraph (c) as
paragraph (d), and
■ d. Adding a new paragraph (c).
These revisions read as follows:
§ 174.508 Pesticidal substance from a
plant-incorporated protectant from a
sexually compatible plant created through
conventional breeding; exemption from the
requirement of a tolerance.
Residues of a pesticidal substance
from a plant-incorporated protectant
from a sexually compatible plant
created through conventional breeding
are exempt from the requirement of a
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tolerance if all the following conditions
are met:
*
*
*
*
*
(c) The genetic material is transferred
from the source plant to the recipient
plant only through conventional
breeding.
(d) The residues of the pesticidal
substance are not present in food from
the plant at levels that are injurious or
deleterious to human health.
■ 9. Add § 174.541 to read as follows:
§ 174.541 Pesticidal substance from a
plant–incorporated protectant based on a
sexually compatible plant created through
biotechnology; exemption from the
requirement of a tolerance.
Residues of a pesticidal substance
from a plant-incorporated protectant
based on a sexually compatible plant
created through biotechnology are
exempt if all of the following conditions
are met:
(a) The pesticidal substance is created
through biotechnology from either an
insertion of new genetic material as
discussed in paragraph (1) or a
modification of existing genetic material
as discussed in paragraph (2).
(1) A native gene is engineered into a
non-genic location of the recipient plant
genome, resulting in a pesticidal
substance identical to the pesticidal
substance identified in the source plant.
(2)(i) The existing native gene in the
recipient food plant is modified to alter
the amount of pesticidal substance
produced without altering the identity
of the pesticidal substance produced; or
(ii) The genetic material that encodes
the substance of the existing native gene
is modified to result in a pesticidal
substance that is identical to the
pesticidal substance encoded by a
native allele of that gene; or
(iii) The existing genetic material is
modified pursuant to both (i) and (ii).
(iv) The existing native gene in the
recipient plant is modified to lose
function through the reduction or
elimination of the substance encoded by
that gene.
(b) The residues of the pesticidal
substance are present only in tissues
and developmental stages identified in
a plant that is sexually compatible with
the recipient food plant, and do not
exceed levels found within that plant, as
long as those levels are not injurious or
deleterious to human health.
(c) This exemption does not apply
until the requirements in subpart E of
this part have been met.
[FR Doc. 2020–19669 Filed 10–8–20; 8:45 am]
BILLING CODE 6560–50–P
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[Federal Register Volume 85, Number 197 (Friday, October 9, 2020)]
[Proposed Rules]
[Pages 64308-64344]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-19669]
[[Page 64307]]
Vol. 85
Friday,
No. 197
October 9, 2020
Part IV
Environmental Protection Agency
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40 CFR Part 174
Pesticides; Exemptions of Certain Plant-Incorporated Protectants (PIPs)
Derived From Newer Technologies; Proposed Rule
Federal Register / Vol. 85, No. 197 / Friday, October 9, 2020 /
Proposed Rules
[[Page 64308]]
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ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 174
[EPA-HQ-OPP-2019-0508; FRL-10014-10]
RIN 2070-AK54
Pesticides; Exemptions of Certain Plant-Incorporated Protectants
(PIPs) Derived From Newer Technologies
AGENCY: Environmental Protection Agency (EPA).
ACTION: Proposed rule.
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SUMMARY: The Environmental Protection Agency (EPA) is proposing
regulations that would allow for an exemption under the Federal
Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal
Food, Drug, and Cosmetic Act (FFDCA) for certain PIPs that are created
in plants using biotechnology, as long as their pesticidal substances
are found in plants that are sexually compatible with the recipient
plant and meet the proposed exemption criteria, ensuring their safety.
The current exemption for PIPs is limited to PIPs moved through
conventional breeding. EPA's proposed rule would allow certain PIPs
created through biotechnology to also be exempt under existing
regulations, in cases where those PIPs pose no greater risk than PIPs
that meet EPA safety requirements, and could have otherwise been
created through conventional breeding. The proposed rule also includes
a process through which developers of PIPs based on sexually compatible
plants created through biotechnology submit either a self-determination
letter or request for EPA confirmation that their PIP meets the
criteria for exemption. For increased flexibility in bringing PIPs to
market, a developer can also submit both. EPA anticipates several
benefits that may result from exempting these PIPs. These include lower
costs from reduced regulatory burden, increased research, development,
and commercialization of pest control options for farmers, particularly
in minor crops, and reduced use of conventional pesticides which could
provide environmental benefits.
DATES: Comments must be received on or before December 8, 2020.
ADDRESSES: Submit your comments, identified by docket identification
(ID) number EPA-HQ-OPP-2019-0508, through the Federal eRulemaking
Portal at https://www.regulations.gov. Follow the online instructions
for submitting comments. Do not submit electronically any information
you consider to be Confidential Business Information (CBI) or other
information whose disclosure is restricted by statute.
Due to the public health concerns related to COVID-19, the EPA
Docket Center (EPA/DC) and Reading Room is closed to visitors with
limited exceptions. The staff continues to provide remote customer
service via email, phone, and webform. For the latest status
information on EPA/DC services and docket access, visit https://www.epa.gov/dockets.
FOR FURTHER INFORMATION CONTACT: Anne Overstreet, Biopesticides and
Pollution Prevention Division (7511P), Office of Pesticide Programs,
Environmental Protection Agency, 1200 Pennsylvania Ave. NW, Washington,
DC 20460-0001; main telephone number: (703) 305-7090; email address:
[email protected].
SUPPLEMENTARY INFORMATION:
I. Executive Summary
A. Does this action apply to me?
You may be potentially affected by this action if you are a
developer or registrant of a PIP. This proposal also may affect any
person or company who might petition the Agency for a tolerance or an
exemption from the requirement of a tolerance for any residue of a PIP.
The following list of North American Industrial Classification System
(NAICS) codes is not intended to be exhaustive, but rather provides a
guide to help readers determine whether this action may apply to them:
Pesticide and Other Agricultural Chemical Manufacturing
(NAICS code 325320), e.g., pesticide manufacturers or formulators of
pesticide products, importers or any person or company who seeks to
register a pesticide or to obtain a tolerance for a pesticide.
Crop Production (NAICS code 111), e.g., seed companies.
Colleges, universities, and professional schools (NAICS
code 611310), e.g., establishments of higher learning which are engaged
in development and marketing of PIPs.
Research and Development in the Physical, Engineering, and
Life Sciences (except Nanobiotechnology) (NAICS code 541714), e.g.,
biotechnology research and development laboratories or services.
If you have any questions regarding the applicability of this
action to a particular entity after reading the regulatory text,
consult the technical person listed under FOR FURTHER INFORMATION
CONTACT.
B. What action is the Agency taking?
EPA is proposing to exempt qualifying ``PIPs based on sexually
compatible plants created through biotechnology'' from the requirements
of FIFRA (except for the adverse effects reporting requirement at 40
CFR 174.71 and a proposed recordkeeping requirement at 40 CFR 174.73),
and the residues of those PIPs from section 408 of FFDCA. PIPs are
defined at 40 CFR 174.3 as ``a pesticidal substance that is intended to
be produced and used in a living plant, or in the produce thereof, and
the genetic material necessary for the production of such a pesticidal
substance. [The PIP] also includes any inert ingredient contained in
the plant or the produce thereof.'' EPA's proposal identifies a class
of PIPs, i.e., ``PIPs based on sexually compatible plants created
through biotechnology,'' as those PIPs that are created through
biotechnology and in which the pesticidal substance is found in plants
that are sexually compatible with the recipient plant (i.e., the
engineered plant) and that meet specific safety criteria. Although the
amended definition proposed for ``sexually compatible'' specifically
refers to a viable zygote formed through the union of two gametes, for
this proposal EPA includes in its exemption also PIPs engineered in
plants that are propagated vegetatively (e.g., potatoes and bananas).
This approach aligns with the Agency's longstanding approach for
exempting PIPs in vegetatively propagated plants created through
conventional breeding and is consistent with the existing exemption of
PIPs from sexually compatible plants created through conventional
breeding. The proposed regulatory text for the exemptions from FIFRA
and the FFDCA identifies a number of factors intended to ensure that
the resulting PIP only produces a pesticidal substance found in plants
that are sexually compatible with the recipient plant and thereby
ensuring that these substances do not pose different risks to humans
and the environment compared to those present in conventionally bred
plants. While EPA believes the possibility of adverse effects from the
PIPs proposed for exemption to be highly unlikely, it is important to
note that the adverse effects reporting requirement under 40 CFR 174.71
would also apply to those PIPs proposed for exemption, as it does for
currently exempt PIPs from sexually compatible plants. This requirement
allows EPA to reconsider whether a PIP continues to meet the criteria
for exemption upon learning of any adverse effects (e.g., injurious or
deleterious
[[Page 64309]]
levels in food plants). As described in the preamble of the July 19,
2001 Federal Register notice implementing 40 CFR 174.71 (66 FR 37772;
July 19, 2001), the reports on human health or the environment alleged
to have been caused by the PIP would be made to EPA, but EPA will share
such reports with the Food and Drug Administration (FDA), and as such,
40 CFR 174.71 is a means of ensuring that EPA and FDA can address any
potential hazard. The proposed rule also includes a process through
which developers are required to submit either a letter of self-
determination or a request for EPA confirmation that a PIP based on a
sexually compatible plant created through biotechnology meets the
criteria for exemption.
C. What is the Agency's authority for taking this action?
This action is being proposed under the authority of FIFRA section
25 (7 U.S.C. 136w) and FFDCA section 408(e) (21 U.S.C. 346a(e)). FIFRA
section 25(a)(1) authorizes EPA to issue regulations to carry out the
provisions of FIFRA in accordance with certain procedures prescribed in
that section. In addition, FIFRA section 25(b) allows EPA to promulgate
regulations to exempt from the requirements of FIFRA any pesticide
which the Administrator determines is ``of a character which is
unnecessary to be subject to [FIFRA] in order to carry out the purposes
of [FIFRA].''
FFDCA section 408(e) authorizes EPA to initiate actions to
establish tolerances or exemptions for pesticide chemical residues that
meet the safety standard. See also the discussion in Unit IV.
D. Why is EPA taking this action?
Many plants, including those used for food, naturally produce
substances that have pesticidal properties. Humans have relied on the
presence of these substances for millennia to improve resistance in new
agricultural and non-agricultural plant varieties by moving these
traits between sexually compatible plants through conventional
breeding. Because these substances may be at unsafe levels in
undomesticated plants, rendering such plants inedible, breeders have
developed established procedures to ensure that the substances are kept
to safe levels when introduced into plant varieties intended for human
consumption. For the purposes of FIFRA, when these substances are
introduced intentionally into a plant for a pesticidal purpose, the
resulting product is considered a pesticide, and more specifically, a
PIP.
In 2001, EPA published exemptions for PIPs moved through
conventional breeding at 40 CFR 174.25, ``plant-incorporated protectant
from sexually compatible plant,'' and at 40 CFR 174.508, ``pesticidal
substance from sexually compatible plant; exemption from the
requirement of a tolerance.'' For these exemptions, EPA defined
sexually compatible plants as those for which ``a viable zygote is
formed only through the union of two gametes through conventional
breeding.'' This includes those plants which can exchange genetic
information unrestrictedly with each other through natural processes,
such as pollination, and also those that are unable to exchange genetic
information freely, but that are closely related enough that techniques
employed in conventional breeding can facilitate their interbreeding.
It specifically excludes plants developed through biotechnology. At
that time, EPA did not exempt PIPs that are created through
biotechnology and that are found in sexually compatible plants, but
rather issued a supplemental proposal to exempt these PIPs because
additional criteria needed to be developed. EPA ultimately withdrew
that proposal in 2018 and indicated that, if the Agency were to pursue
exemption of PIPs developed through biotechnology in the future, a new
proposed rule would be issued (Ref. 1), as it became evident that
exemption criteria should be developed given advances in biotechnology
tools (see Unit II.C.2.).
Recent advances in biotechnology offer precise means by which genes
coding for pesticidal substances can be inserted into a plant genome
and allow for engineering of those genes that already exist within a
plant. Due to these technical characteristics, PIPs can now be created
that are virtually indistinguishable from those created through
conventional breeding. EPA was therefore able to develop specific
exemption criteria that reflect the precise nature of new technologies.
The proposed criteria are intended to identify a group of PIPs that
would be exempt from both the requirements of FIFRA, with the exception
of the adverse effects reporting requirement (codified at 40 CFR
174.71) and the recordkeeping requirement (proposed at 40 CFR 174.73),
and that would also qualify for a tolerance exemption under the FFDCA.
These PIPs are created through the use of biotechnology and, given the
proposed regulatory criteria, pose no greater risk than the sexually
compatible PIPs that are already exempt. EPA refers to this group as
``PIPs based on sexually compatible plants created through
biotechnology.'' The Agency's findings, including an assessment of the
environmental and human health risks for this proposal, are presented
in Unit VI.
EPA's proposal limits the type of plants, and thus the gene pool,
that can act as a source of these exempt PIPs to those that are
sexually compatible with the recipient plant. EPA is also proposing to
amend the definition of ``sexually compatible'' to state that ``a
viable zygote can be formed through the union of two gametes through
conventional breeding.'' EPA believes that this proposed definition is
more biologically correct, because it refers to the ability of two
gametes to form a viable zygote. This amendment would also allow for
use of the phrase ``sexually compatible'' in the proposed exemptions.
As a housekeeping task, EPA proposes to amend the existing PIPs from
sexually compatible plants exemption at 40 CFR 174.25, along with its
accompanying exemptions at 40 CFR 174.508 and 174.705, to clarify that
those apply only to PIPs created through conventional breeding, thus
differentiating them from those PIPs proposed for exemption that are
created through biotechnology. These changes are necessary due to the
amended definition of ``sexually compatible'' but will not change
implementation of the existing exemption for PIPs from conventional
breeding. EPA's proposed exemptions are developed to be consistent with
the current exemption at 40 CFR 174.25 for PIPs developed through
conventional breeding techniques, and are expected to alleviate
regulatory burden for developers that may wish to utilize biotechnology
in creating pesticide products that are equivalent to those already
exempt under FIFRA and the FFDCA.
On June 11, 2019, Executive Order 13874 (84 FR 27899, June 11,
2019) on ``Modernizing the Regulatory Framework for Agricultural
Biotechnology Products'' was issued. The exemption proposed by EPA in
this document is intended to further implement section 4(b) of that
Executive Order, which directs the U. S. Department of Agriculture
(USDA), EPA, and FDA (``to the extent consistent with law and the
principles set forth in section 3'' of the order) to ``use existing
statutory authority, as appropriate, to exempt low-risk products of
agricultural biotechnology from undue regulation.'' Among other things,
section 3 of Executive Order 13874 provides that regulatory decisions
should be science-based and evidence-based, taking economic factors
into account as
[[Page 64310]]
appropriate and consistent with applicable law; that regulatory reviews
should be conducted in a timely and efficient manner; and that
biotechnology regulations should be transparent, predictable, and
consistent. As part of the effort to implement Executive Order 13874,
the USDA recently revised its regulations at 7 CFR part 340 through a
rulemaking entitled ``Movement of Certain Genetically Engineered
Organisms.'' (85 FR 29790, May 18, 2020). In that rule, USDA amended
its regulations regarding the movement (importation, interstate
movement, and environmental release) of certain genetically engineered
organisms in response to advances in genetic engineering and USDA's
understanding of the plant pest risk posed by genetically engineered
organisms, thereby reducing the regulatory burden for developers of
organisms that are unlikely to pose plant pest risks. Both EPA and USDA
use the term ``conventional breeding'' in their respective rulemakings.
However, it should be noted that each Agency uses the term in the
context of its own regulations and that the term may have slightly
different meanings depending on context.
The process for exemption under both the EPA proposal and USDA's
rule includes the option for developers to self-determine whether their
product meets the criteria for exemption. EPA is proposing to require
the developer notify EPA of that self-determination with a letter or,
in the alternative, to request EPA confirmation that a particular PIP
qualifies for exemption (developers may also submit both a self-
determination letter and a confirmation request). Because developers of
exempted PIPs will still be subject to FIFRA's adverse effects
reporting requirement and the recordkeeping requirement that is part of
EPA's proposed rule, EPA believes it is appropriate to require
submission of a self-determination letter or a confirmation request in
order to enable EPA to monitor compliance with EPA's regulations and to
take action to avoid adverse health impacts, if necessary.
E. What are the estimated incremental impacts of this action?
EPA has evaluated the potential incremental impacts of the proposed
exemptions in the document entitled ``Cost Analysis of the Proposed
Rule Exempting Certain Plant-Incorporated Protectants (PIPs) from
Registration'' (Ref. 2), which is available in the docket, discussed in
greater detail in Unit VI.A., and is briefly summarized here.
1. Benefits of the Proposed Exemptions
The rule is estimated to reduce overall registration costs to
developers of PIPs based on sexually compatible plants created through
biotechnology, and the cost savings per product are approximately
$444,000-$459,000. Of the entities likely to develop PIPs based on
sexually compatible plants created through biotechnology, EPA currently
estimates that approximately 80% are small entities. These cost savings
would be realized as EPA approval of new active ingredients are sought.
The proposed exemption of PIPs based on sexually compatible plants
created through biotechnology is likely to remove a potential barrier
to market entry for small entities.
2. Costs of the Proposed Exemptions
In the proposed rule, for a PIP to be exempt, a developer would be
required to notify EPA through a self-determination letter or through a
request for EPA confirmation that the PIP meets the exemption criteria.
The proposed rule would also require that a developer maintain
documents supporting its determination. Developer costs pertaining to
the required exemption eligibility determination process and
recordkeeping are estimated in the Agency cost analysis for the
proposed rule. These costs are representative of developer labor and
laboratory costs that would be required to generate the necessary
information and data.
The developer cost of the exemption eligibility determination
process is expected to be less than what would otherwise be required of
a developer to obtain a registration. The cost analysis developed by
the Agency is an overall cost reduction for developers of these types
of PIPs. Adverse effects due to aggregate exposure to residues of
pesticidal substances from PIPs based on sexually compatible plants
created through biotechnology through the dietary, non-food oral,
dermal and inhalation routes are highly unlikely, as the exemption
eligibility determination process requires that the developer certify
that the PIP meets the exemption criteria.
F. What should I consider as I prepare my comments for EPA?
1. Submitting CBI
Do not submit this information to EPA through regulations.gov or
email. Clearly mark the part or all of the information that you claim
to be CBI. For CBI information in a disk or CD-ROM that you mail to
EPA, mark the outside of the disk or CD-ROM as CBI and then identify
electronically within the disk or CD-ROM the specific information that
is claimed as CBI. In addition to one complete version of the comment
that includes information claimed as CBI, a copy of the comment that
does not contain the information claimed as CBI must be submitted for
inclusion in the public docket. Information so marked will not be
disclosed except in accordance with procedures set forth in 40 CFR part
2.
2. Tips for Preparing Your Comments
When preparing and submitting your comments, see the commenting
tips at https://www.epa.gov/dockets/comments.html.
II. Background
A. What are Plant-Incorporated Protectants (PIPs)?
Through natural evolutionary processes, plants develop mechanisms
to resist pests. The mechanisms of resistance can be varied, including,
for example, the production of metabolites that have toxic properties,
biochemical cascades resulting in localized necrosis of plant tissue,
or the production of substances in response to pest attack (Ref. 3).
Humans have for approximately 10,000 years selected and bred certain
plants for food, feed, and fiber, and a frequently selected
characteristic has been the ability to resist pests (Ref. 4). When
humans intend to use substances involved in these mechanisms in plants
for ``preventing, destroying, repelling, or mitigating any pest,'' the
substances fall into the FIFRA definition of pesticide, regardless of
whether the pesticidal capability evolved in the plant, or was
introduced by conventional breeding or through the techniques of
biotechnology.
A PIP is defined as ``pesticidal substance that is intended to be
produced and used in a living plant, or in the produce thereof, and the
genetic material necessary for the production of such a pesticidal
substance. It also includes any inert ingredient contained in the plant
or produce thereof'' (40 CFR 174.3). For example, scientists can take
the gene encoding for a pesticidal protein from a wild relative of corn
and introduce the gene into another corn plant's genetic material. The
plant then manufactures the pesticidal protein that kills the pest when
the pest feeds on the plant. The genetic material necessary for the
production of such a pesticidal substance also meets the FIFRA
statutory definition of a pesticide, because such genetic material is
introduced into the plant with the intent of ultimately producing a
pesticidal effect. For transgenic PIPs, the
[[Page 64311]]
relationship between the genetic material, the pesticidal substance,
and the pesticidal effect has typically been linear (i.e., the genetic
material inserted into the plant directly produces the pesticidal
substance that confers the pesticidal effect). However, PIPs found in
conventionally bred plants and their wild relatives can introduce
additional biological complexity. For example, as described in the 2001
preamble (66 FR 37772; July 19, 2001), a PIP can encompass genetic
material encoding an enzyme that ultimately leads to the production of
the pesticidal substance (e.g., solanine). PIPs can also include traits
intended for a pesticidal purpose that result from the loss-of-function
of an existing plant gene where, for example, the inactivation of a
gene coding for a plant receptor protein confers disease resistance. It
is important to clarify that EPA regulates the modified genetic
material that confers the loss-of-function trait as the pesticidal
substance which is consistent with both the 1994 proposed rule preamble
(59 FR 60496; November 23, 1994) and the 2001 final rule preamble (66
FR 37772; July 19, 2001) promulgating 40 CFR 174. EPA is requesting
comment on whether a clarifying exemption specific to loss-of-function
traits would be helpful (Unit VII.E.), although EPA considers these
traits to be included under the current exemption at 40 CFR 174.25 and
the proposed exemption at 40 CFR 174.26. For the sake of clarity,
although the genetic material meets the statutory definition of a
pesticidal substance under FIFRA, in this preamble EPA uses
``pesticidal substance'' to mean a protein or other substance produced
from genetic material that has pesticidal properties as per the
definition at 40 CFR 174.3.
Although the PIP is regulated by EPA, the plant containing a PIP is
not regulated by EPA. Additionally, many types of traits can be
engineered into plants, but only those intended for a pesticidal
purpose are PIPs. EPA does not regulate non-pesticidal traits under
FIFRA or the FFDCA, or any other federal statutes. For example, EPA
does not regulate traits introduced into a plant using biotechnology
that enhance vitamin C content for nutritional purposes. Food from such
a plant variety would be regulated by FDA.
B. How are PIPs regulated?
1. By EPA
Because PIPs are pesticides, they are regulated under FIFRA and, to
the extent necessary, FFDCA section 408. Under FIFRA, unless there is
an applicable exemption, EPA is required to register PIPs so they may
lawfully be sold and distributed. EPA evaluates each PIP application to
determine whether its proposed use would cause unreasonable adverse
effects on the environment. To avoid potential unreasonable adverse
effects, the Agency may impose (and has imposed) terms and conditions
on registration of PIPs (e.g., conditions to slow insect resistance).
Additionally, EPA has the authority to take enforcement action with
respect to any violations of activities subject to FIFRA. Under the
FFDCA, EPA has established exemptions from the requirement of a
tolerance for residues of PIPs in food. EPA evaluates each PIP to
determine whether exposure to the residue of that PIP in or on food/
feed is safe (i.e., there is a reasonable certainty that no harm will
result from aggregate exposure to the pesticide, which includes all
anticipated dietary exposures and all other exposures for which there
is reliable information).
2. By Other Federal Agencies
EPA is part of an interagency effort to improve, clarify, and
streamline the regulation of biotechnology, including the regulation of
plants developed using biotechnology that includes oversight by the
USDA, FDA, and EPA. This approach was articulated by the White House
Office of Science and Technology Policy in a policy statement in 1986
(51 FR 23302; June 26, 1986) and updated most recently in 2017 (Ref.
5). This document is known as the Coordinated Framework for the
Regulation of Biotechnology. EPA is the federal agency primarily
responsible for the regulation of pesticides. In fulfilling this
mission, EPA works closely with the USDA, which has responsibilities
under the Plant Protection Act, and the FDA, which has responsibilities
under the FFDCA, including the enforcement of tolerances set by EPA
under the FFDCA. EPA, USDA, and FDA consult and exchange information
when such consultation is helpful in resolving safety questions. In
addition to the Coordinated Framework, Executive Order 13874 requires
EPA, FDA, and USDA to further coordinate their activities with regard
to agricultural biotechnology. The PIPs that EPA is proposing to exempt
are also exempted from regulation by USDA under 7 part 340 as revised
by USDA's recently issued final rule titled ``Movement of Certain
Genetically Engineered Organisms.'' (85 FR 29790, 29791-92, May 18,
2020).
C. What actions did EPA take to prepare for this proposed rule?
1. Updated Issue Paper
For this proposal, EPA updated an issue paper entitled ``Natural
Toxicants in Food from Plants'' (Ref. 6). This issue paper summarizes
and reviews the literature on the most common toxicants found in crop
plants and discusses the regulatory status and current testing methods
for each of those toxicants. Information from this issue paper was used
in the Agency's safety analysis for residues of PIPs based on sexually
compatible plants created through biotechnology in or on food or feed.
This document is available in the docket for this rulemaking.
2. Withdrawal of Previous Rule Proposal
In May 2018, the Agency withdrew a proposed rule entitled: ``Plant-
Incorporated Protectants (PIPs); Exemption for Those Derived Through
Genetic Engineering From Sexually Compatible Plants'' (Ref. 1). The
proposed rule was withdrawn because the Agency determined that to
exempt PIPs derived through genetic engineering from sexually
compatible plants, more scientifically current criteria needed to be
developed to reflect advances in genetics and molecular biology since
the 2001 proposal. Consequently, EPA indicated that to pursue a future
exemption, the Agency would issue a new proposed rule based on the
types of products possible to create with newest technology rather than
issue a final rule based on previous proposals (Ref. 1). As discussed
in Unit VI., in developing this proposal for PIPs based on sexually
compatible plants created through biotechnology, the Agency developed
criteria that are scientifically more current and that more accurately
describe the PIPs that would be exempted. Additionally, because the
previous rule was withdrawn, the Agency will not consider comments made
on the previous proposal. Therefore, if you believe a comment made
regarding previous proposals is relevant to this proposal, you must
resubmit the comment for this proposal.
3. Scientific Advisory Committees
The FIFRA Scientific Advisory Panel (SAP) is a body of experts that
provide independent scientific advice to EPA on issues related to
pesticides, such as the impact to human health or the environment.
FIFRA requires that EPA submit any proposed and final rule promulgated
under FIFRA section 25(a) to the SAP for comment on the impact of the
rule on human health and the
[[Page 64312]]
environment. For this proposed rule, EPA requested that the FIFRA SAP
waive review of the proposal. In developing the scientific rationales
in this proposal, EPA relied on previously provided advice from the
FIFRA SAPs and analyses by the National Research Council of the
National Academy of Science, Engineering and Medicine (Table 1).
Table 1--Advice Sources for Key Concepts To Exempt PIPs Based on
Sexually Compatible Plants Created Through Biotechnology
------------------------------------------------------------------------
Relevance to current
Concept proposal Relevant report
------------------------------------------------------------------------
Exemption of PIPs based on Establishes the FIFRA SAP 1992,
sexually compatible plants overall scope of 1993, 1994; NRC
created through the exemption. PIP 2000. (Ref. 7, 8,
biotechnology. would be developed 9, 10).
by engineering a
plant's genetic
material to result
in a PIP that could
otherwise be found
in the gene pool of
the plant itself,
e.g., in other
varieties of the
crop plant or in a
sexually compatible
relative. This
scope should result
in no novel dietary
or environmental
exposures.
Criteria limiting the types Establishes how much FIFRA SAP 2004,
of possible modifications a gene could be https://
introduced into a PIP in modified (e.g., archive.epa.gov/
the plant. through scipoly/sap/
truncations, meetings/web/html/
deletions, or point 101304_mtg.html.
mutations) while FIFRA SAP 2005,
still retaining https://
scientific support archive.epa.gov/
for the idea that scipoly/sap/
humans have meetings/web/html/
consumed the 120605_mtg.html.
products of such
genes for
generations and
that products of
such modifications
present no new
dietary exposures.
Introduction of a gene Establishes criteria FIFRA SAP 1992,
isolated from a plant in to ensure that any 1993, 1994; NRC
the same gene pool as the introduced gene is 2000. (Ref. 7, 8,
recipient plant. part of the genetic 9, 10).
diversity found in
plants that are
sexually compatible
with the recipient
plant.
Ensuring expression profile Establishes criteria FIFRA SAP 1993,
falls within the gene pool to ensure that any 1994; NRC 2000.
of the plant and plants substance expressed (Ref. 7, 9, 10).
that are sexually from the modified
compatible with the plant. genetic material is
not expressed at
higher levels, in
different tissues,
or at different
developmental
stages than seen in
plants that are
sexually compatible
with the recipient
plant.
Precision associated with Establishes criteria NRC 2004; NASEM
newly developed techniques to ensure that only 2016, 2017. (Ref.
of genetic engineering, precise 4, 11, 12).
e.g., allowing genes modifications are
present in the plant to be introduced into the
edited. modified plant--
e.g., modifications
of regulatory
regions, allelic
substitutions,
introduction only
of genes that falls
within the genetic
diversity found in
plants that are
sexually compatible
with the recipient
plant.
Exemption eligibility Establishes NRC 2004; NASEM
determination process. streamlined 2017. (Ref. 11,
procedures for 12).
developers to
notify EPA of a PIP
that qualifies for
exemption.
------------------------------------------------------------------------
Two scientific advisory committees, the FIFRA SAP and the
Biotechnology Science Advisory Committee (BSAC), a sister committee of
equal stature later merged into the FIFRA SAP, offered advice that
forms the foundation of EPA's current approach to PIPs. The Agency's
2001 final rule exempting PIPs from sexually compatible plants created
through conventional breeding (40 CFR 174.25) and proposed exemptions
(under both FIFRA and the FFDCA) for PIPs from sexually compatible
plants derived through genetic engineering (see Unit II.C.2.) are based
on advice from the FIFRA SAP.
The proposed exemptions in this document, are similarly based on
advice provided by the FIFRA SAP, as the 1992, 1993, and 1994 FIFRA SAP
reviews did not distinguish between PIPs moved among sexually
compatible plants through conventional breeding and those moved through
genetic engineering. Taking that advice into account, along with
additional advice from NASEM reports in 2000, 2004, 2016, and 2017,
this proposal describes the criteria that PIPs based on sexually
compatible plants created through biotechnology, must meet to qualify
for the proposed exemption. In response to the Agency's 1994 proposal
to exempt PIPs from sexually compatible plants derived through genetic
engineering, NASEM pointed out in its report in 2000 that the Agency's
proposed language would exempt genetic material moved among plants in
sexually compatible populations through the use of biotechnology
without taking into consideration whether the moved genetic material
would be expressed in the same pattern and at the same levels as occurs
naturally in the plant (Ref. 10 at p. 129). This directly led to the
Agency incorporating a criterion addressing expression levels and
pattern in the proposed exemption requirements set out in this
document. In addition to the advice from the 1992, 1993, and 1994 FIFRA
SAPs, EPA received additional advice from expert groups on scientific
topics relevant to the current PIP proposed rule including, but not
limited to, the 2004 and 2005 FIFRA SAPs that discussed how much a gene
could be modified (e.g., through truncations, deletions, or point
mutations) while still retaining scientific support for the conclusion
that humans have consumed the products of such genes for generations
and that products of such modifications present no new dietary
exposures; and several reports from NASEM in 2004, 2016, and 2017 that
describe the precision of modifications that can be
[[Page 64313]]
achieved using new technologies for genetic engineering (Ref. 4, 11,
12).
The proposal in this document also describes an exemption
eligibility determination process in which a developer must notify the
Agency through either a self-determination letter or a request for EPA
confirmation that the PIP meets the exemption criteria. For additional
flexibility, EPA also proposes to allow a developer to submit both a
self-determination letter and request for EPA confirmation, should they
so choose. This proposed set of options takes into account advice from
two reports by NASEM (Ref. 10, 12).
4. Stakeholder Engagement
EPA has participated in domestic and international events relevant
to the proposed exemptions, all of which provided opportunities to
engage with the regulated and research communities, the public, and
other U.S. government agencies. Recent conferences and workshops
include: Genome Editing--Putting Together the Pieces 2018; 2018 OECD
Conference on Environmental Health and Safety of Applications of Gene
Editing; Responsible CRISPR: Genome Engineering Conference 2019; North
Carolina State University/ASTA Plant Breeding Workshop 2019; Plant
Genomics & Gene Editing Congress: USA 2019; and the 2019 Global
Regulatory Workshop on Plant and Animal Biotechnology Innovation. These
meetings supported EPA's horizon-scanning efforts for novel PIP
products and presented engagement opportunities with the scientific and
regulated community. These meetings also provided opportunities to
develop practical knowledge of techniques and technology used in plant
breeding and genetic engineering, which supported development of
exemption criteria and rationale for assessing risks of PIPs created
using biotechnology. Topics of discussion included plant breeding,
technical aspects of biotechnology, and considerations regarding
regulation and risk assessment of products.
III. Statutory Authorities and Regulatory Framework
EPA is authorized to regulate pesticides under two federal
statutes. FIFRA regulates the sale, distribution, and use of pesticide
products through a licensing (registration) scheme. FFDCA, among other
things, regulates the safety of pesticide chemical residues in or on
food and feed. EPA is proposing these exemptions under FIFRA section
25(b)(2) and FFDCA section 408.
A. What authority does EPA have under FIFRA section 25(b)(2)?
This section of FIFRA allows EPA to exempt, by regulation, any
pesticide from some or all of the requirements of FIFRA, if the
pesticide is of a character that is unnecessary to be subject to all
the requirements of FIFRA in order to carry out the purposes of that
Act (7 U.S.C. 136w(b)(2)). EPA interprets FIFRA section 25(b)(2) to
authorize EPA to exempt a pesticide or category of pesticides that EPA
determines (1) poses a low probability of risk to the environment and
(2) is not likely to cause unreasonable adverse effects to the
environment even in the absence of regulatory oversight under FIFRA.
In evaluating whether use of the pesticide poses a low probability
of risk to the environment, EPA considers the extent of the potential
risks caused by use of the pesticide to the environment, including
humans, animals, plants, water, air, and land. Potential risks to
humans include dietary risks (which are assessed under the safety
standard of the FFDCA section 408) and non-dietary risks, such as those
resulting from occupational or residential exposure to the pesticide.
EPA will not exempt pesticides under FIFRA section 25(b)(2) that fail
to meet the required low probability of risk.
In evaluating whether the use of a pesticide is likely to cause
unreasonable adverse effects on the environment even in the absence of
regulatory oversight under FIFRA, EPA balances potential risks to human
health and the environment from use of the pesticide against the
potential benefits associated with its use. In balancing risks and
benefits, EPA considers the economic, social, and environmental costs
and benefits of the use of the pesticide.
B. What authority does EPA have under FFDCA section 408?
Under the FFDCA, food or feed containing pesticide residues may be
considered adulterated (and subject to seizure if introduced, delivered
for introduction, or received in interstate commerce) unless there is a
tolerance or an exemption from the requirement of a tolerance in place
covering those residues (21 U.S.C. 342(a)(1)(B)). EPA is authorized to
establish tolerances (the maximum level) for residues in or on food or
establish exemptions from the requirement of a tolerance, if it
determines that the tolerance or exemption would be safe (21 U.S.C.
346a(b)(2), (c)(2)). Section 408 of the FFDCA defines ``safe'' to mean
that ``there is a reasonable certainty that no harm will result from
aggregate exposure to the pesticide chemical residue, including all
anticipated dietary exposures and all other exposures for which there
is reliable information'' (21 U.S.C. 346a(c)(2)(A)(ii)). This includes
exposure through drinking water, and residential and other indoor uses,
but does not include occupational exposure. In addition, FFDCA section
408 requires EPA to give special consideration to exposure of infants
and children to the pesticide chemical residue in establishing an
exemption and to ``ensure that there is a reasonable certainty that no
harm will result to infants and children from aggregate exposure to the
pesticide chemical residue'' (21 U.S.C. 346a(b)(2)(C)(ii)(I)) and
(c)(2)(B)). FFDCA section 408(b)(2)(D) specifies other general factors
EPA must consider in establishing an exemption (21 U.S.C.
346a(b)(2)(D)). In establishing a tolerance or an exemption from the
requirement of a tolerance, the FFDCA does not authorize EPA to
consider potential benefits associated with use of the pesticide
chemical. Although EPA establishes tolerances or exemptions from the
requirement of a tolerance under the FFDCA, FDA enforces these
tolerances.
C. What is the relationship of FIFRA exemptions to the FFDCA section
408 standard?
EPA uses the FFDCA section 408 safety standard, as described in
Unit III.B., in evaluating whether a pesticide used in or on food and
feed meets the standard for exemption under FIFRA with respect to human
dietary risk. A pesticide in or on food and feed presents a low
probability of human dietary risk if it meets the FFDCA section 408
standard for an exemption from the requirement of a tolerance.
Additionally, a determination that a pesticide chemical meets the
safety standard of FFDCA section 408(c) may also be relevant to whether
a pesticide qualifies for a FIFRA section 25(b)(2) exemption with
respect to human health risks arising from other routes of exposure. In
determining whether a pesticide chemical residue is safe, EPA must
consider ``available information regarding the aggregate exposure
levels of consumers . . . to the pesticide chemical residue and to
other related substances, including dietary exposure under the
tolerance and all other tolerances in effect for the pesticide chemical
residue, and exposures from other non-occupational sources'' (21 U.S.C.
346a(b)(2)(D)(vi)).
FIFRA, however, does not provide for exemption of a pesticide in or
on food
[[Page 64314]]
based solely upon consistency with the FFDCA section 408 exemption
standard. At a minimum, EPA also must evaluate risks to the environment
and risks arising from occupational exposure to humans and determine
that such risks meet both exemption criteria (i.e., posing a low
probability of risk to the environment and being not likely to cause
unreasonable adverse effects to the environment even in the absence of
regulatory oversight under FIFRA).
IV. Proposed Regulatory Framework for Exempting PIPs Based on Sexually
Compatible Plants Created Through Biotechnology
In 2001, EPA created a regulatory structure at 40 CFR 174.21, for
exempting PIPs from the requirements of FIFRA, other than the adverse
effects reporting requirement at 40 CFR 174.71. First, the active
ingredient of the PIP must meet codified criteria addressing FIFRA
requirements listed in 40 CFR part 174, subpart B; these provisions
primarily deal with the pesticidal substance of the PIP and the genetic
material necessary for production of that substance (40 CFR 174.21(a)).
Second, when the PIP is intended to be produced and used in a food or
feed crop, an exemption from the requirement of tolerance must be in
place for residues of the PIP (40 CFR 174.21(b)). Third, any inert
ingredient that is part of the PIP must be exempt under 40 CFR 174.705
(174.21(c)).
EPA is proposing to create an exemption from FIFRA requirements for
certain PIPs based on sexually compatible plants created through
biotechnology. These PIPs are created through biotechnology and their
pesticidal substance is found in plants that are sexually compatible
with the recipient plant. To satisfy the requirement of 40 CFR
174.21(a), EPA proposes to create a new section under subpart B for 40
CFR 174.26 containing criteria that an active ingredient of a PIP based
on a sexually compatible plant created through biotechnology must meet
to qualify for the new exemption.
To meet the condition of 40 CFR 174.21(b), EPA is proposing to
exempt from the requirement of a tolerance under the FFDCA residues of
PIPs based on sexually compatible plants created through biotechnology
that are present in or on food or feed. This exemption and the safety
criteria that the residues must meet to qualify for the exemption will
be codified in 40 CFR part 174, subpart W with other PIP-related FFDCA
exemptions.
Per 40 CFR 174.3, an inert ingredient is defined as ``any
substance, such as a selectable marker, other than the active
ingredient, where the substance is used to confirm or ensure the
presence of the active ingredient, and includes the genetic material
necessary for the production of the substance, provided that genetic
material is intentionally introduced into a living plant in addition to
the active ingredient.'' Additionally, in 2001 EPA stated that ``with
regard to the enzymes, precursors, or intermediates in biosynthetic
pathways necessary for anabolizing the pesticidal substance, EPA at
this time considers them to be part of the plant-incorporated
protectant because the substance is intended to ``ensure the presence
of the active ingredient''--i.e., it is an inert ingredient.'' EPA is
therefore proposing to expand the scope of the existing inert
ingredient exemption at 40 CFR 174.705 to include inert ingredients
initiated through a modification made using biotechnology, as EPA
believes the intermediary substances described in the 2001 quote would
be included in this.
Other than these intermediary substances, the Agency does not
expect other, more traditional inert ingredients (e.g., a gene coding
for herbicide tolerance) in PIPs based on sexually compatible plants
created through biotechnology. This is because older methods of
biotechnology that have typically been used to create PIPs use a
bacterial plasmid vector to incorporate a DNA construct into the genome
of the plant. The DNA construct is an artificially constructed segment
of nucleic acid consisting of regulatory elements, the gene coding for
the active ingredient, and sometimes a gene coding for an inert
ingredient. Because the gene coding for the active ingredient and the
gene coding for the inert ingredient are located on the same DNA
construct and will therefore be incorporated into the plant genome
together, the inert ingredient is able to confirm or ensure the
presence of the active ingredient. However, newer biotechnology
techniques, such as CRISPR, that are precise enough to create PIPs
proposed for this exemption do not use DNA constructs in this way.
Instead, these newer techniques allow developers to perform targeted
edits to existing genes, and do not require the incorporation of inert
ingredients in the same way as historically seen in transgenic PIPs.
Modifications coding for substances similar to inert ingredients seen
in transgenic PIPs (e.g., herbicide resistance) would instead be
incorporated into the recipient plant genome independent of the active
ingredient. Because newer techniques allow for these events to be
introduced independently, the modification cannot confirm or ensure the
presence of the active ingredient. The modification therefore would not
meet the definition of an inert ingredient under 40 CFR 174.3 because
it is an independent, non-pesticidal trait not regulated under FIFRA.
EPA expects that any ingredients intentionally added during the
development of PIPs based on sexually compatible plants created through
biotechnology that are specific to the production of the active
ingredient (e.g., guide RNA, DNA nuclease) would either be transiently
transformed or would be removed (e.g., through segregation of the
trait) during the breeding process. If these traits have not been
removed from the final product the product would not meet the criteria
proposed under the new 40 CFR 174.26 and would not qualify for the new
exemptions. The Agency requests comment on whether there are any inert
ingredients other than the intermediary substances described in the
2001 quote that will remain in the final plant products containing PIPs
based on sexually compatible plants created through biotechnology. If
inert ingredients other than the intermediary substances described in
the 2001 quote are identified in the responses to the previous request,
the Agency also requests comment as to whether the inert ingredients in
PIPs based on sexually compatible plants created through biotechnology
require the proposal of an exemption that would be specific to those
created through biotechnology and would allow developer flexibility in
the nucleic acid sequence (see Unit VII.A.). EPA is also proposing to
add a recordkeeping requirement and exemption eligibility determination
process to 40 CFR 174.21 applicable to PIPs based on sexually
compatible plants created through biotechnology that would require a
developer to notify EPA that the PIP meets the criteria for exemption
from the requirements of FIFRA under the conditions of 40 CFR 174.21
and to maintain supporting documentation of its determination. The
exemption eligibility determination can be submitted in two, non-
mutually exclusive ways: a self-determination letter or a request to
EPA for confirmation of the self-determination.
V. Proposed Revisions to the General Provisions (Subpart A)
Provisions that apply to PIPs are codified in 40 CFR part 174,
subpart A. EPA is proposing several changes to these general
provisions.
[[Page 64315]]
A. What are the proposed new definitions?
Definitions that apply to PIPs are codified in 40 CFR part 174,
subpart A, and EPA is proposing to add new definitions for ``gene,''
``native allele,'' and ``native gene.'' Only one term, ``gene,'' is
discussed in this unit. The other proposed definitions are discussed in
detail in Unit VI.
EPA is proposing to define ``gene'' as meaning a ``functional unit
of heritable genetic material that is comprised of the genetic material
necessary for the production of a substance.'' All living organisms
encode the substances they need to perform their normal metabolic
functions in discrete units in their genome, called genes. This
includes the pesticidal substances plants produce to defend against
pests. Genes are further comprised of several functionally distinct
regions within that unit that work in concert to produce the substance
that is encoded by the gene's nucleic acid sequence. The two regions
relevant to the criteria proposed to circumscribe PIPs based on
sexually compatible plants created through biotechnology are the
regulatory and coding regions. Together, they determine the function of
a given gene within the plant. The sequence within the regulatory
region of a gene determines the amount of substance that is produced
and the spatiotemporal pattern of expression within the plant tissues.
The coding region, which is the sequence that is ultimately
transcribed, determines the identity of the substance that is produced
from the gene (e.g., the amino acid sequence of a protein). Because the
regulatory and coding regions of a given gene are inherited together as
a single unit, they have evolved together over evolutionary time. In
proposing the definition of a gene, the Agency clearly identifies and
delineates the physical unit of the genetic material within the plant
genome that encodes the substance and leads to the production of the
pesticidal substance and, in doing so, restricts any genetic
modifications made through biotechnology that would fall under the
proposed exemption to the coding and regulatory regions. Defining the
term ``gene'' was not necessary in the context of PIPs before this
proposed exemption because previous methods employed to create PIPs,
such as particle gun transformation, relied on the integration of a
genetic construct, which included other genetic sequences in addition
to a gene.
B. What is the proposed amendment to the existing definition for
``sexually compatible?''
The term ``sexually compatible'' is currently defined at 40 CFR
174.3 as ``when referring to plants, means a viable zygote is formed
only through the union of two gametes through conventional breeding.''
EPA is proposing to amend the existing definition for ``sexually
compatible'' to instead state ``when referring to plants, means a
viable zygote can be formed through the union of two gametes through
conventional breeding.'' EPA believes this amended definition is more
in line with the biological definition of sexually compatible, in that
being sexually compatible is widely accepted to mean that two organisms
are capable of forming viable progeny. The amended definition also
allows the Agency to use the term ``sexually compatible'' in the
biological sense in the proposed exemption. The proposed clarification
to the sexually compatible definition necessitates changes to the
existing PIP from sexually compatible plant exemption at 40 CFR 174.25,
along with its accompanying exemptions at 40 CFR 174.508 and 174.705;
however, these changes do not result in modifications to the existing
exemption for PIPs moved through conventional breeding. EPA discusses
this proposed clarification in detail in Unit VI.F.
VI. Proposed Exemptions and Exemption Eligibility Determination Process
(Subparts B, D, E, and W)
EPA is proposing to create an exemption from FIFRA requirements for
certain PIPs based on sexually compatible plants created through
biotechnology (described in Unit VI.A.) and to create a companion
exemption from the FFDCA section 408 requirement of a tolerance for
residues of certain PIPs based on sexually compatible plants created
through biotechnology in or on food or feed (described in Unit VI.B.).
EPA is also proposing to add a new subpart (subpart E) to 40 CFR part
174 that would codify the procedures and requirements for the new
exemption eligibility determination process (described in Unit VI.C.).
EPA is proposing a new section in subpart D, 40 CFR part 174.73, that
would codify recordkeeping requirements for exemptions (described in
Unit VI.D.). To accommodate the exemption eligibility determination
process and recordkeeping requirements, EPA is making some clarifying
edits to 40 CFR 174.21 as described in Unit VI.E. Finally, EPA is also
clarifying the relationship between the proposed exemptions for PIPs
based on sexually compatible plants created through biotechnology and
the exemptions currently at 40 CFR 174.25, 174.508, and 174.705 by
modifying 174.25, 174.508, and 174.705 as described in Unit VI.F.
A. What is the proposed FIFRA exemption for the active ingredients of
PIPs based on sexually compatible plants created through biotechnology?
1. What the Proposed Exemption Covers
EPA currently exempts PIPs from sexually compatible plants as
described in 40 CFR 174.25. Because EPA had previously defined sexually
compatible plants as including only those plants that create viable
progeny through conventional breeding, the current exemption excludes
PIPs created through biotechnology, even if they are equivalent to PIPs
that could have been developed through conventional breeding.
Technological advances surrounding genome editing (e.g., meganucleases,
zinc-finger nucleases, transcription activator-like effector nucleases,
and CRISPR-Cas nuclease system) allow for targeted, rapid, and precise
changes directly to chromosomes of living cells (Ref. 12). These
technologies allow for such precise editing of the genome, that the
resulting genes can be indistinguishable from those found in a plant
created through conventional breeding. Given the recent advances in
technology, EPA was able to develop specific criteria proposed in a new
section for 40 CFR 174.26 to exempt certain PIPs developed through the
use of biotechnology that pose no greater risk than the currently
exempt sexually compatible PIPs. The definition of sexually compatible
is also proposed to be amended to refer to the ability of two gametes
to form a viable zygote and thus be more biologically correct in
stating that ``a viable zygote can be formed through the union of two
gametes through conventional breeding.'' This amendment allows for use
of the phrase ``sexually compatible'' in the proposed exemption.
The proposed criteria and supporting proposed definitions of
``native gene'' and ``native allele'' circumscribe the PIPs based on
sexually compatible plants created through biotechnology that would
qualify for the new exemption. The proposed criteria and the proposed
definitions limit the types of PIPs that would be exempt to those that
are found in plants that are sexually compatible with the recipient
plant and meet specific safety criteria, thereby resulting in
negligible risk of novel exposures. It is important to note that
[[Page 64316]]
although the amended definition proposed for ``sexually compatible''
specifically refers to a viable zygote formed through the union of two
gametes, for this proposal EPA includes in its exemption also PIPs
engineered in plants that are propagated vegetatively (e.g., potatoes
and bananas). This approach aligns with the Agency's longstanding
approach for exempting PIPs in vegetatively propagated plants created
through conventional breeding and is consistent with the existing
exemption of PIPs from sexually compatible plants created through
conventional breeding.
The definition of ``native genes'' limits the substances eligible
for exemption to those found in plants that are sexually compatible
with the recipient plant. As genes code for and produce substances,
restricting the genes to only those found in plants that are sexually
compatible with the recipient plant will limit the PIPs eligible for
the new exemption to those found in plants that are sexually compatible
with the recipient plant. The term ``native'' is used in the scientific
literature in the context of cisgenes (e.g., a native promoter is a
promoter endogenous to that gene). However, the Agency seeks comment on
use of the term ``native'' in the names of ``native gene'' and ``native
allele'' and associated definitions as the Agency does not mean to
imply with the use of the term ``native'' that genes which originated
through conventional breeding techniques like mutagenesis would somehow
be excluded from the proposed exemption. It is the Agency's intention
that alleles found in sexually compatible plants that may have been
created through conventional breeding would be included in the
definition of ``native allele'' and ``native gene.''
Native genes comprising the gene pool of sexually compatible plant
populations have been developed through the processes of mutation,
selection, and genetic exchange. The proposed exemption captures
ongoing diversification within gene pools by including within the
proposed criteria a definition for native alleles. The definition of
``native allele'' is similarly limited to only those variants of native
genes that are found in plants that are sexually compatible with the
recipient plant.
EPA also proposes to capture additional ongoing diversification
within existing native genes through the concept of differentially
expressed genes. These are changes to a native gene that result in
alterations in the amount of substance that is produced from that gene.
An additional restriction on differentially expressed genes requires
that the original pesticidal substance is preserved, which again limits
eligible pesticidal substances to only those that are found in plants
that are sexually compatible with the recipient plant. Native genes,
native alleles, and differentially expressed genes represent the
genetic diversity of sexually compatible plants; thus, these criteria
limit exempt pesticidal substances of PIPs based on sexually compatible
plants created through biotechnology to only those substances that are
found in plants that are sexually compatible with the recipient plant.
For agricultural plants, those defined as being sexually compatible
would include existing plant cultivars, landraces (i.e., a locally
isolated variety of a domesticated plant species adapted to the natural
and cultural environment in which it lives), and breeding lines, as
well as plant relatives that can breed with crops but are not currently
used as agricultural plants. Including nonagricultural relatives in the
sexually compatible pool is appropriate, as some traits found in
nonagricultural wild relatives of cultivated plants, although not
expressed in existing agricultural cultivars, have been accessible in
plant breeding by conventional breeding techniques. For example,
nonagricultural plant relatives may express defense mechanisms (i.e.,
pesticidal substances) that have been lost during domestication of crop
plants and thus have not been entirely utilized in agricultural
varieties.
Plant breeders have for many years been following established
practices to ensure safety when moving genes into agricultural
varieties from nonagricultural relatives, particularly from wild
relatives, with no indication that substances resulting from these
genes present higher levels of risk than those from genes moved only
amongst agricultural varieties as long as those established practices
are diligently followed (Ref. 13, 14, 15, 16). The ability to produce
viable offspring is only possible in nature for organisms that possess
many traits (and the genetic material encoding them) in common.
Therefore, many of the traits present in agricultural plants and their
wild relatives are likely to be similar in nature; the fact that the
specific substance from the nonagricultural relative may not be found
in the agricultural variety today does not mean that breeders do not
have the experience and tools to ensure that it will be present in safe
levels if transferred to the agricultural variety. Therefore, the
likelihood is negligible that the transfer of such a substance via
biotechnology from a nonagricultural relative to an agricultural one
would pose a greater risk than if it were transferred through
conventional breeding. The same logic defining the sexually compatible
gene pool for agricultural crop plants also applies to other plants
such as ornamental, turf, and semi-managed plants (e.g., trees).
EPA's proposed criteria and associated definitions are based on the
ability of closely related plants to hybridize and share genetic
information. Because the substances produced by native genes and native
alleles are present in sexually compatible plants, breeders have
experience in ensuring that the substances will be at safe levels. This
is also true for differentially expressed genes (i.e., genes with
modified regulatory regions) because the proposed exemption criteria
require that (a) the substance produced from the genetic material be
not different than what was being produced prior to the modification,
(b) the expression profile of the pesticidal protein does not exceed
the limits seen in the sexually compatible plant population of the
recipient plant. Although the proposed criteria allow for the use of
biotechnology, the associated definitions are written to intentionally
exclude ``transgenes,'' which can be generally defined as derived from
a source organism unable to share genetic material with the recipient
plant through breeding. EPA does not consider transgenes to be native
to the gene pool or a part of the genetic diversity of the recipient
plant. Transgenic traits have been the focus of current PIP
registration activities since 1995 (e.g., those derived from the
bacterium Bacillus thuringiensis), and the registered PIPs generally
present novel exposure scenario considerations for the transgenic
trait.
2. Proposed Criteria and Associated Definitions
The Agency is proposing to define ``native gene'' to mean ``a gene
that is identified in the recipient plant or plants that are sexually
compatible with the recipient plant; and has never been derived from a
source that is not sexually compatible with the source plant.'' The
phrase ``has never been derived from a source that is not sexually
compatible with the source plant'' is meant to clarify that a PIP would
qualify for the proposed exemption only if the native gene is present
in the source plant as a result of conventional breeding. For example,
if a bacterial endotoxin (e.g., from the source Bacillus thuringiensis)
was engineered into plant ``A'' (the source
[[Page 64317]]
plant), this bacterial endotoxin-based PIP would not qualify as a
native gene to be used in plant ``B'' (the recipient plant) under the
proposed exemption, even if plant ``B'' is sexually compatible with
plant ``A''. This is because while plant ``B'' and ``A'' can
interbreed, the bacterium Bacillus thuringiensis (the source) and plant
``A'' (the source plant) are not sexually compatible. This proposed
limitation on the source of the PIP therefore prevents a developer from
claiming that a gene that encodes for a PIP is a ``native gene'' under
the proposed definition when it is not, i.e., when the gene has been
derived from a source that is not sexually compatible with the source
plant. Given this explanation of the intent behind the phrase ``never
derived,'' EPA seeks comment on whether the use of the phrase in the
proposed definition of ``native gene'' is clear.
``Native allele'' means ``a variant of a native gene that is
identified in the genetic diversity of plants that are sexually
compatible with the recipient plant.'' This definition is meant to
clarify that the native allele must be a variant found in plants that
are sexually compatible with the recipient plant, thereby limiting the
potential pesticidal substances to those found in that population. By
stating that the native allele is a variant of a native gene, the
restriction that the genetic material cannot be derived from a source
that is not sexually compatible with the source plant also applies to
native alleles.
Equally important are two considerations, discussed in detail in
the following sections, that are captured by the proposed criteria for
40 CFR 174.26 and that EPA believes together constitute the basis for
meeting the FIFRA section 25(b)(2) standard for exemption: the
pesticidal substance is found in plants that are sexually compatible
with the recipient plant; and limitations on expression profile.
a. The Pesticidal Substance Is Found in Plants That Are Sexually
Compatible With the Recipient Plant
The proposed provisions for 40 CFR 174.26(a) delineate the scope of
the new exemption for PIPs based on sexually compatible plants created
through biotechnology to only include those substances that are found
in sexually compatible plants and substances with which plant breeders
have experience. The regulatory text identifies two major categories
that specify what will qualify as an exempt PIP pesticidal substance:
(i) The insertion of new genetic material; and (ii) The modification of
existing genetic material. Modifications of existing genetic material
are further broken down into: Modifications resulting in the
differential expression of a gene, modifications resulting in a native
allele, and modifications resulting in the differential expression of a
native allele. The restrictions on the intended insertion or
modification, as discussed in this section, ensure that no substance
novel to plants that are sexually compatible with the recipient plant
is produced.
By limiting the types of modifications permissible to those
resulting in a pesticidal substance found in plants that are sexually
compatible with the recipient plant (including substances already in
the recipient plant), EPA can ensure that no substance novel to plants
that are sexually compatible with the recipient plant is produced. This
allows the Agency to ensure that PIPs based on sexually compatible
plants created through biotechnology can meet the FIFRA section
25(b)(2) exemption standard because the modification would present a
low risk of unreasonable adverse effects to humans and the environment
due to the history of ensuring safe exposure through conventional
breeding to the exempt substance. Criteria specific to the permissible
modifications are described as follows.
i. The Insertion of New Genetic Material
For the insertion of new genetic material, 40 CFR 174.26(a)(1)
proposes to limit insertions to native genes. EPA finds it important to
include a native gene insertion option in its proposed exemption of
PIPs based on sexually compatible plants created through biotechnology,
because there may be gene variability among sexually compatible plants.
For example, plant genomes can be highly variable with the presence or
absence of entire genes across different crop lines. If native gene
insertion was excluded from the proposed exemption, EPA would be
excluding a class of modifications that can be found in sexually
compatible plant populations. For native gene insertion, the phrase
proposed for 40 CFR 174.26(a)(1), ``A native gene is engineered into a
non-genic location of the recipient plant genome, resulting in a
pesticidal substance identical to the pesticidal substance identified
in the source plant,'' contains two criteria. First, the phrase
``engineered into a non-genic location'' is intended to preclude the
insertion of the native gene into an existing gene. This is because the
insertion of the native gene in the coding region of an existing gene
within the recipient plant may then lead to production of a novel
substance (e.g., a partial or modified substance) by the existing gene.
Second, the phrase ``resulting in a pesticidal substance identical
to the pesticidal substance identified in the source plant'' ensures
that the substance produced by the inserted native gene does not result
in a substance with which breeders have no experience in preventing
unsafe exposures. The requirement for an identical substance to be
produced, rather than requiring the native gene to be composed of an
identical nucleic acid sequence, allows for some flexibility in the
nucleic acid sequence of the genetic material inserted into the
recipient plant. It is important to allow for this flexibility because
many nucleotide variations found within the coding region of the
genetic material necessary for the production of a proteinaceous
substance are silent, in that they do not result in changes to the
amino acid sequence of the encoded protein. Thus, for proteinaceous
substances, it is therefore permissible to insert a native gene that is
composed of a nucleic acid sequence that is not identical to that found
in the source plant so long as the pesticidal substance for which the
nucleic acid sequence codes is identical to that identified in the
source plant. However, no such flexibility in the modification of the
nucleic acid sequence of the coding region is granted for non-
proteinaceous substances, i.e., in cases when the genetic material
codes for the production of a type of RNA that is not subsequently
translated into a protein (e.g., miRNA), as every nucleic acid in the
coding region is reflected in the final sequence of the non-
proteinaceous substance. For both proteinaceous and non-proteinaceous
substances, flexibility is permissible in the nucleotide sequence of
the regulatory regions. This allows for modifications to the expression
level of the PIP resulting from the native gene insertion, so long as
it meets expression profile criterion 174.26(b) as discussed in Unit
VI.A.2.b.
ii. The Modification of Existing Genetic Material
Proposed provisions for 40 CFR 174.26(a)(2) describe permissible
modifications of existing genetic material and is further delineated
into four possible categories: Modifications resulting in the
differential expression of a gene, modifications resulting in a native
allele, modifications resulting in the differential expression of a
native allele, and modifications resulting in the loss-of-function of
an existing gene.
[[Page 64318]]
(A) Modifications Resulting in the Differential Expression of a Gene
For the first category, the phrase proposed for 40 CFR
174.26(a)(2)(i), ``the existing native gene in the recipient plant is
modified to alter the amount of pesticidal substance produced without
altering the identity of the pesticidal substance produced,'' limits
the permissible modification in three ways. First, the modification
must be made within the existing native gene in the recipient plant.
The types of genes that can be modified only include those that have
never been derived from sources that are not sexually compatible with
the recipient plant; e.g., it is not permissible to adjust the
expression level of a Bt gene. Second, the permissible modification is
limited to changes that result in changes to the amount of pesticidal
substance. While the abundance of a substance in a plant is not solely
determined by its level of expression (i.e., the amount of messenger
RNA produced), it is reasonable to assume that they generally
correlate, e.g., reducing the expression of a gene is expected to also
reduce the abundance of the substance that is encoded by that gene
(Ref. 17).
Third, the phrase ``without altering the identity of the pesticidal
substance produced'' prevents modifications to the coding region of the
gene that result in a partial or modified pesticidal substance. By
requiring that the identity of the pesticidal substance be preserved,
EPA can ensure that the identity of the substance produced by that gene
remains the same as it was before the modification. In other words, a
novel substance cannot be produced as a result of the modification; the
only modification permitted is a change in the expression level of the
substance produced by a gene. This position is consistent with the
advice of the FIFRA SAP in the October 2004 meeting on ``Issues
Associated with Deployment of a Type of Plant-Incorporated Protectant
(PIP), Specifically Those Based on Plant Viral Coat Proteins (PVCP-
PIPs),'' which stated that in the context of maintaining a ``safe
history'' assumption, ``only changes that affect an expressed protein
are of concern and that changes to regulatory and untranslated regions
are not relevant.'' (FIFRA SAP meeting held October 13-15, 2004, page
44 of minutes, Unit VI.A.3.a., Table 1). The statement that ``changes
to regulatory and untranslated regions are not relevant,'' indicates
that modifications to those genetic regions do not result in a novel
substance and therefore are not modifications of concern. Additional
criteria surrounding permitted expression profiles are discussed in
Unit VI.A.2.b.
(B) Modifications Resulting in a Native Allele
For the second category, the phrase in proposed 40 CFR
174.26(a)(2)(ii) ``the genetic material that encodes the substance of
the existing native gene is modified to result in a pesticidal
substance that is identical to the pesticidal substance encoded by a
native allele of that gene,'' limits the types of modifications that
could qualify for exemption. Like the restriction on differentially
expressed genes, modifications to the recipient plant genome resulting
in a native allele must be made within the existing native gene in the
recipient plant. This criterion is intended to limit modifications
solely to a single gene and would therefore exclude from exemption
modifications that would affect more than one gene, e.g., those
affecting chromosomal structure.
Although EPA recognizes that large-scale changes like
translocations may be considered genetic variants, changes that affect
the structure of chromosomes can affect many genes along the chromosome
and are likely to disrupt or change the substances made by those genes.
Insufficient information is available to allow the Agency to a priori
conclude which structural changes would result in novel exposures, and
therefore which changes may or may not result in unreasonable adverse
effects. Thus, at this time, the Agency is unable to make a generic
risk assessment on the consequences of chromosomal structural
modifications and is not proposing an exemption that would allow for
changes such as chromosomal inversions, translocations, or
rearrangements. This does not preclude the Agency from registering
these types of products or proposing an exemption at a later time
should information become available that supports a determination of
low risk.
The second half of the phrase, ``to result in a pesticidal
substance that is identical to the pesticidal substance encoded by a
native allele of that gene,'' is another key limitation applied to
native alleles and is based on the same concepts underlying the no
novel exposure argument articulated for native genes in Unit
VI.A.2.a.i. Briefly, requiring that the pesticidal substance produced
in the recipient plant be identical to the substance encoded by the
native allele ensures that there will be no novel situations for plant
breeders, and therefore no novel exposures. This requirement also
allows for more flexibility in the modifications made to the recipient
plant, in a way that restricting the nucleic acid sequence would not.
Again, no such flexibility in the modification of the nucleic acid
sequence of the coding region is granted for non-proteinaceous
substances, i.e., in cases when the genetic material codes for the
production of a type of RNA that is not subsequently translated into a
protein (e.g., miRNA), as every nucleic acid in the coding region is
reflected in the final sequence of the non-proteinaceous substance.
(C) Modifications Resulting in the Differential Expression of a Native
Allele
For the third category, proposed 40 CFR 174.26(a)(2)(iii) states,
``the existing genetic material is modified pursuant to both (i) and
(ii).'' This phrase is intended to indicate that it is also acceptable
to create a differentially expressed native allele so long as the
criteria under proposed 40 CFR 174.26(a)(2)(i) and 174.26(a)(2)(ii) are
met.
(D) Modifications Resulting in the Loss of Function of a Gene
For the fourth category, the phrase proposed for 40 CFR
174.26(a)(2)(vi), states ``The existing native gene in the recipient
plant is modified to lose function through the reduction or elimination
of the substance encoded by that gene.'' EPA believes a separate
exemption category to allow for instances in which the pesticidal trait
in the plant is created via the loss-of-function of an existing gene
helps clarify that the rule is intended to cover these types of
modifications. To that end, EPA specifically uses the term
``substance'' rather than ``pesticidal substance'' for this exemption
category when referring to the native gene product (e.g., protein). For
example, a gene coding for a receptor protein may be modified to result
in the loss-of-function of that protein to confer disease resistance.
By specifying that the substance must maintain the same identity, EPA
therefore prevents the production of modified proteins not previously
identified in the gene pool while still allowing for modifications in
the coding region that ultimately prevent the production of a protein
(e.g., premature termination codon). Additionally, modifications in the
regulatory region of a gene would be allowed under the proposed
exemption as these do not result in changes to the identity of the
substance produced by the genetic material. EPA requests comment on
whether an exemption category specific to loss-of-function
[[Page 64319]]
traits (rather than including them in proposed 174.26) would be clearer
(see Unit VII.E.).
b. Limitations on Expression Profile
The proposed criterion at 40 CFR 174.26(b), ``the pesticidal
substance is not expressed at higher levels, in different tissues, or
at different developmental stages than identified in a plant that is
sexually compatible with the recipient plant,'' is a key limitation to
prevent novel dietary and environmental exposures. The limitation on
levels is important because endogenous plant compounds that result in
plant resistance to pests can be toxic to mammals or other non-target
organisms (Ref. 11). Limiting the expression profile of pesticidal
substances to that found in a plant capable of being sexually
compatible with the recipient plant ensures that the assumptions used
to justify the proposed exemption (specifically, a long history of
breeder experience with such substances and situations) support the
statutory findings required to exempt PIPs based on sexually compatible
plants created through biotechnology. For example, breeders will be
able to ensure that modifications that lead to an increase in the
expression of a substance are limited to levels accepted in
conventional breeding because of their experience with the levels
observed in plants that are sexually compatible with the recipient
plant. The level of expression of pesticidal substances is expected to
vary among sexually compatible plants depending on environmental
conditions and due to intrinsic variations in their potential to
express a substance (Ref. 17). Variation exists even among plants of
the same variety due to different weather and soil condition (Ref. 18).
As such, limiting changes in the expression of a pesticidal substance
not to exceed levels found within a sexually compatible plant supports
meeting the FIFRA section 25(b)(2) exemption standard because such
changes do not result in exposure levels not otherwise encountered
through conventional breeding.
The proposed phrase also ensures that modifications allowed under
the proposed exemption do not result in changes in the expression
pattern of pesticidal substances. Specifically, this criterion ensures
that pesticidal substances are only expressed in the same plant tissues
and at the same developmental stages as what is found in a sexually
compatible plant. For example, an insect toxin typically produced in
the leaves of a plant would not meet the proposed exemption criterion
if the plant is modified to produce the toxin in the nectar or pollen,
as this may result in novel exposure of pollinators to the toxin. To
ensure that the exempt PIPs are low risk and meet the FIFRA section
25(b)(2) exemption standard, EPA finds it necessary that pesticidal
substances would not exceed expression levels or be expressed in
different tissues or at different developmental stages from the
exposure encountered among sexually compatible plants.
3. Risk Analysis
EPA considered several factors in determining whether PIPs based on
sexually compatible plants created through biotechnology that meet the
criteria under proposed 40 CFR 174.26 could be exempted from FIFRA
requirements in order to meet the 40 CFR 174.21(a) requirement. That
consideration relied upon the large body of knowledge that currently
exists on sexually compatible plants and genetic diversity. The factors
include: ``(1) Low potential for novel exposures; (2) Low potential for
levels of PIPs based on sexually compatible plants created through
biotechnology to exceed levels found in sexually compatible plants; (3)
Low potential for PIPs based on sexually compatible plants created
through biotechnology to move from cultivated plants to wild or weedy
relatives through gene flow and increase weediness; (4) Low potential
for occupational and non-occupational risks to humans; and (5) Low
potential for resistance selection pressure posed by PIPs based on
sexually compatible plants created through biotechnology to exceed that
found in sexually compatible plants.'' EPA also evaluated
considerations specific to newer biotechnology techniques related to
PIPs based on sexually compatible plants created through biotechnology.
In addition to the analyses discussed in this unit for exemption
under FIFRA, EPA also performed similar analyses for the proposed
tolerance exemption under FFDCA discussed in Unit VI.B. EPA refers
readers to the detailed discussions in that unit for information
specific to the dietary safety of PIPs based on sexually compatible
plants created through biotechnology.
a. Large Body of Knowledge
In the issue paper entitled ``FIFRA: Benefit and Environmental Risk
Considerations for Inherent Plant-Pesticides'' (Ref. 23), EPA describes
a large part of the information base on nontarget plants, insects,
birds, mammals and other herbivores that the Agency relied on for its
evaluation of the potential effects of PIPs based on sexually
compatible plants created through biotechnology on the environment. In
addition, to understand the history of exposure of non-target organisms
to substances found in nature that are equivalent to PIPs based on
sexually compatible plants created through biotechnology, EPA used the
large body of literature on the effect on humans of consumption of food
from sexually compatible plants generated from epidemiological studies,
nutritional assessments, animal model testing and biochemical studies
(Ref. 24, 25, 26, 27, 28, 29, 30, 31, 32) to draw conclusions on the
potential risk for animal non-targets, including birds and fish, which
might consume food containing the PIPs proposed for exemption. Testing
in animal models can supply information that is extrapolated to make
conclusions on the effect of a substance on humans; similarly,
information and conclusions drawn in the dietary risk assessment on the
effects on humans can be extrapolated to predict effects on non-human
mammals and other animals in an assessment of environmental risk. In
addition, there is a long history of humans using foods containing PIPs
as food for domesticated and other animals, including birds and fish.
EPA relied on this history of exposure and the large literature
generated by a century of systematic studies of the constituents of
food (Ref. 23) to assess PIPs based on sexually compatible plants
created through biotechnology.
EPA also considered scientific knowledge from a number of
disciplines, including plant genetics, plant physiology,
phytopathology, biochemistry, ecology, evolutionary biology, genomics,
and plant breeding. From the disciplines of plant physiology and
biochemistry, EPA considered, for example, information on plant
metabolism, the production of substances that may have a pesticidal
effect, and conditions that may limit the production of such substances
(Ref. 33). The Agency also used information from the science of
phytopathology to characterize the pest resistance mechanisms in plants
in order to understand the types of traits PIPs based on sexually
compatible plants created through biotechnology may confer to recipient
plants (Ref. 3). The sciences of ecology and evolutionary biology were
considered for information on genetic diversity, mutation, and
reproductive isolation mechanisms in populations (Ref. 34) to
understand the types of genetic changes that are likely to occur when
plants interbreed. Plant breeding and genetics were considered to
[[Page 64320]]
describe the mechanisms of incompatibility and interbreeding (Ref. 35,
36), which aided EPA in determining when plants are likely to
interbreed. Information from genomics and molecular biology were
considered to understand the ability of newer biotechnology techniques
to create traits equivalent to those found in conventionally bred
plants (Ref. 23, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46).
Finally, recommendations from several FIFRA SAPs and NASEM reports
were considered in the development of the proposed exemption criteria
for PIPs based on sexually compatible plants created through
biotechnology, and when describing the types of genetic modifications
in the recipient plant that are unlikely to result in novel exposure to
humans and the environment (see Table 1 in Unit II.C.3.).
b. Low Potential for Novel Exposure
Given that PIPs based on sexually compatible plants created through
biotechnology are intended to represent a subset of substances present
in plants that plant breeders have experience with, EPA does not expect
novel exposures from the substances involved.
Pesticidal traits, and the genetic material encoding them, have
evolved and been developed in plant populations through the processes
of mutation, selection, and genetic exchange among sexually compatible
species (Ref. 47, 48). The ability to produce viable offspring is only
possible for organisms that are genetically similar and possess many
traits in common. Traits, and the genetic material encoding them, can
be passed through a plant population by breeding. The mixing of genetic
material that occurs through breeding results in sexually compatible
plants having similar genetic material and similar traits. Due to the
mixing of traits by mating, similar exposure scenarios are expected for
plants that are capable of being sexually compatible, in other words,
substances in sexually compatible plants are expected to be similar and
therefore, only substances that plant breeders are already familiar
with are expected to be present in sexually compatible plants. This
conclusion is consistent with the 1992, 1993, and 1994 FIFRA SAP
meetings that indicated that sexually compatible plants are more likely
to have a common constitution than unrelated plants and thus movement
of genetic material between sexually compatible plants is less likely
to lead to novel exposures (Ref. 7, 8, 23).
For agricultural plants, those defined as capable of being sexually
compatible would also include existing plant cultivars, landraces, and
breeding lines, as well as plant relatives that interbreed with crops
but that are not currently used as agricultural plants. Plant breeders
have for many years been moving genes into agricultural varieties from
nonagricultural relatives with no indication that substances resulting
from these genes present higher levels of risk than those from genes
moved only amongst agricultural varieties (Ref. 13, 14, 15, 16).
Therefore, the likelihood that the inclusion of nonagricultural
varieties as potential source plants would pose an increased potential
for novel environmental exposures from PIPs based on sexually
compatible plants created through biotechnology is low.
If a population of sexually compatible plants normally possesses a
pesticidal substance, organisms that encounter plants in that
population have likely been exposed to the pesticidal substance in the
past, perhaps over multiple generations. These past exposures,
particularly if they occur over long periods of time, may lead to a
degree of adaptation, or tolerance in the population of organisms
exposed to the pesticidal substance (Ref. 49). Relatedly, the proposed
exemption would not affect exposure patterns because the proposed
criteria require that the pesticidal substance have an expression
profile found in sexually compatible plants (e.g., the pesticidal
substance is expressed in the same developmental stages or tissues).
Any avoidance strategies of nontarget organisms (e.g., avoid eating
certain parts of the plant) would still be protective in the case of
PIPs based on sexually compatible plants created through biotechnology.
Thus, the potential is low that PIPs based on sexually compatible
plants created through biotechnology would pose novel exposures for
organisms that typically encounter related plants.
Genetic diversity is created over time and EPA proposes to capture
some of the ongoing diversification not identified in existing native
genes or native alleles through the inclusion of changes resulting in
the alteration of the amount of substance produced by existing genes,
so long as no novel substance is produced and the substance is not
produced in different tissues or at different developmental stages than
those found in sexually compatible plants. Modifications that lead to
differential expression levels of a substance are not expected to
result in levels that exceed the boundaries of the variation found in
sexually compatible plants due to physiological constraints that are
related to energy expenditure (further discussed in Unit VI.A.3.c.).
Therefore, the potential for novel exposures to occur with the
differential expression of existing genes, or the movement of native
genes and native alleles among sexually compatible plants, is low,
because no substance novel to plants capable of being sexually
compatible with the recipient plant will be produced, nor will the
substance be found at higher levels, in tissues, or at developmental
stages in which it is not currently found.
c. Low Potential for Levels of PIPs Based on Sexually Compatible Plants
Created Through Biotechnology To Exceed Levels Found in Sexually
Compatible Plants
EPA has evaluated whether there are likely to be quantitative
changes in levels of PIPs based on sexually compatible plants created
through biotechnology expressed by the recipient plant, such that
adverse effects to the environment or to humans might occur (see Unit
VI.B. for an analysis on human dietary risk). EPA has determined that
the potential of such an event is low because the highest levels of
pesticidal substances likely to be expressed with PIPs based on
sexually compatible plants created through biotechnology are not likely
to result in significantly different environmental exposure levels.
An analysis discussing the likely range of expression of PIPs in
sexually compatible plants was presented in an EPA issue paper,
entitled: ``FIFRA: Benefit and Environmental Risk Considerations for
Inherent Plant-Pesticides'' (Ref. 23). A summary of the analysis and
how it applies to the proposed exemption is presented here. EPA first
considered whether any increase in the levels of substances, including
PIPs, that plants normally produce is likely to exceed the ranges
normally found within and between plant varieties and uncultivated
plants. The level of production of such substances normally varies
among sexually compatible plants because of differences in potential to
express a substance and environmental conditions. Indeed, variation is
seen even among plants in the same variety because of differences such
as weather and soil condition. For example, one report has shown an
8.3-fold variation in the amount of ascorbic acid in turnip greens
depending on the degree of exposure to light (Ref. 18). EPA's proposal
would exempt PIPs based on sexually compatible plants created through
biotechnology that are not
[[Page 64321]]
expressed above the range of variation on the basis that such exposures
would not be considered novel. EPA considers that nontarget organisms,
such as birds and insect pollinators, that associate with such sexually
compatible plant populations have been and are currently being exposed
to the upper levels of substances that might be used as PIPs based on
sexually compatible plants created through biotechnology.
EPA considered the extent to which any substance can be increased
in highly managed plants without unwanted effects on other, desirable
characteristics of the plant such as yield or palatability of fruit. In
general, breeders balance all of these characteristics in developing
marketable plant varieties. Greatly increased levels of any substance,
including PIPs based on sexually compatible plants created through
biotechnology, generally would only be accomplished at the expense of
the expression of other, agriculturally desirable traits due to
physiological constraints related to energy expenditure in the plant
(Ref. 23). A plant, like any other living organism, has a finite energy
budget, and can only harvest so much energy from the environment to
allocate to all of its activities; therefore, a significant increase in
the production of one substance, like a PIP, would reduce the energy
that could be put towards the production of other substances critical
to the plant's metabolism. Thus, there are practical considerations
that limit the upper expression levels of a PIP based on a sexually
compatible plant created through biotechnology to that found in a plant
that is sexually compatible with the recipient plant. To codify this
principle into regulatory text, EPA is proposing criteria in which the
level of expression of the PIP based on a sexually compatible plant
created through biotechnology is bound by the upper limit of expression
of the pesticidal substance observed in a sexually compatible plant. By
limiting the expression of PIPs based on sexually compatible plants
created through biotechnology in this way, EPA can ensure that the
exposures fall within the normal historical range of exposures with
which plant breeders have experience limiting. EPA also considered
whether the total expression (i.e., expression of the PIP across all
plants capable of producing that PIP) would result in an adverse effect
different than that possible through conventional breeding. Because the
PIP based on a sexually compatible plant created through biotechnology
could have otherwise been created through conventional breeding, EPA
does not expect that the cumulative expression of a PIP based on a
sexually compatible plant created through biotechnology would pose a
higher risk than what is currently possible through conventional
breeding.
The potential for exposure to PIPs is typically lower than for
other types of pesticides because PIPs are produced within the living
plant and used in situ in the plant. Other pesticides, such as
conventional chemicals, must be applied to the plant, or near the
plant. Because a PIP is produced and used within the plant,
physiological constraints limit the amount of pesticidal substance
produced by the plant. Moreover, the routes by which other organisms
may be exposed to the PIP are typically more limited, e.g., dietary
exposure is likely to be the predominant route of exposure; there is a
potential for dermal or inhalation exposure, although that likelihood
is more limited (see Unit VI.A.3.e. for additional discussion of dermal
and inhalation exposure in humans). In addition, PIPs are part of the
metabolic cycles of plants, meaning they are biotic and subject to the
processes of biodegradation and decay. Furthermore, PIPs are
biodegradable to their constituent elements through catabolism by
living organisms. Because they are readily degraded, PIPs do not
bioconcentrate in the tissues of living organisms (Ref. 50) or persist
in the environment. Given these characteristics, the potential for new
exposures to occur, beyond direct physical exposures to the plant or
plant parts, is limited for PIPs generally, including PIPs based on
sexually compatible plants created through biotechnology.
EPA also considered whether variations of expression levels of PIPs
based on sexually compatible plants created through biotechnology
contained in semi-managed systems (e.g., trees) presented any novel
issues for exposure to nontarget organisms (Ref. 23). Semi-managed
systems received specific consideration because their semi-managed
state can result in exposure to a larger variety of nontarget organisms
compared to highly managed row crop systems. For the reasons stated in
the preceding paragraphs in this unit, EPA anticipates that for such
plants, levels of expression of PIPs based on sexually compatible
plants created through biotechnology will continue to fall within the
upper limit of expression currently observed for such substances in
sexually compatible plants. Therefore, it is anticipated that the
levels of PIPs based on sexually compatible plants created through
biotechnology in semi-managed plants would not exceed the levels
observed in sexually compatible free-living relatives (Ref. 23).
Finally, while not necessary to support the Agency's low
probability of risk determination under FIFRA, EPA did nonetheless
consider the role of the plant breeding process in maintaining levels
of substances in plants. Plants containing PIPs based on sexually
compatible plants created through biotechnology will, as would plants
in other development programs, pass through a post-development
screening and selection process. During this process, plants with
undesired or unexpected traits are identified and eliminated from
further development. The development of new plant varieties, whether
through conventional breeding or through biotechnology, begins with the
production of a large number of plants containing the trait of
interest. Plants are cultivated over several propagation cycles in
order to identify those plants that inherit the intended phenotype
across multiple generations while maintaining desirable agronomic
characteristics such as uniform growth characteristics, fertility, and
yield (Ref. 22). The screening and selection practices result in the
selection of plants intended for commercialization that display
desirable behavior, including desired levels of expression of various
traits. Historically, these practices have proven to be reliable for
ensuring safety and plants containing PIPs based on sexually compatible
plants created through biotechnology are expected to also pass through
these same screening and selection processes.
In conclusion, in its assessment, EPA considered the potential of
variations in expression levels of PIPs based on sexually compatible
plants created through biotechnology and whether those variations would
present risk. EPA concluded that although variations in PIP expression
levels will occur in response to environmental conditions in plants
that interbreed, these variances are within exposure levels already
encountered. The purpose of EPA's second criterion limiting expression
levels to no higher than presently found in plants that are sexually
compatible ensures that any exempt PIPs based on sexually compatible
plants created through biotechnology would not pose a higher risk than
what is currently found through conventionally bred plants. Given the
history of safe exposure to those substances, this criterion helps to
ensure that exempt PIPs pose a low probability of risk from
quantitatively different exposures.
[[Page 64322]]
d. Low Potential for PIPs Based on Sexually Compatible Plants Created
Through Biotechnology To Move From Cultivated Plants to Wild or Weedy
Relatives Through Gene Flow and Increase Weediness
Because PIPs based on sexually compatible plants created through
biotechnology are produced and used in the living plant, EPA considered
the possibility that the PIP may be transferred by hybridization from
the crop plant to a cultivated, wild or weedy relative. A large volume
of information is available in the public literature on this
possibility and the likelihood of hybridization (Ref. 36, 51, 52, 53,
54, 55). EPA's issue paper entitled ``Risk Considerations for
Outcrossing and Hybridization'' addresses these considerations for PIPs
in plants in sexually compatible populations (Ref. 56). As the genes
used to create the PIPs proposed for exemption produce the same
substances as found in sexually compatible plant populations, EPA
relied on this analysis to address this aspect of the assessment.
One of the considerations evaluated for this proposed exemption was
whether a PIP based on a sexually compatible plant created through
biotechnology could be transmitted to wild relatives through gene flow
of genetic material. A second and more important consideration is
whether such an outcrossing event could, in turn, increase weediness of
the wild relative. For the following reasons, EPA concluded that the
potential is low for weediness to increase in wild relatives through
the flow of genetic material coding for a PIP based on a sexually
compatible plant created through biotechnology.
There are several factors governing whether gene flow occurs, and
thus governing the potential for hybridization between crops and their
wild relatives (Ref. 53, 54, 57). First, genetic barriers can prevent
hybrids from forming, render them sterile, or reduce the fertility of
hybrids, and thus restrict their contribution to subsequent
generations. The strength of genetic barriers is correlated to the
degree of evolutionary relatedness between the crop and wild relatives,
with the barriers being stronger the more distantly related the plants.
Second, geographic space is an effective barrier to hybridization. For
instance, wild relatives with which corn can hybridize are restricted
to Mexico and Central America. There is no potential of hybridization
between domesticated corn and its wild relatives in other regions of
the globe (Ref. 58). Third, temporal barriers such as time of flowering
also affects hybridization, as hybridization cannot occur when there is
no overlap in the time of flowering of cultivated and wild forms (Ref.
54, 57). For some species (e.g., peanut), the flowers do not ordinarily
open, and self-pollination may be very near 100 percent; thus,
hybridization between cultivated and wild forms is unlikely even if the
cultivated and wild forms are synchronized in flowering and close
enough geographically for pollen to move between them. Fourth, the
ploidy level may differ between a crop and its relatives with many
cultivated plants having higher ploidy than their wild relatives.
Differences in ploidy levels can significantly reduce the likelihood
that the cultivated plant and wild relative will form fertile hybrids
(Ref. 54). Finally, some varieties of certain crop species, such as
banana, are sterile, and thus are incapable of hybridizing not only
with members of other species, but also with members of their own
species (Ref. 59). For some crops in the United States, the probability
of hybridization and gene transfer with the wild relative is zero,
while for other crops, despite the variety of potential barriers to and
selection against hybridization, gene transfer is possible. However,
even in instances where hybridization is possible, wild relatives
generally tend to possess higher levels of resistance to pests and
disease than do the cultivated members of those populations (Ref. 23).
Wild relatives also tend to express a greater range of levels of
inherent plant defense compounds than do cultivated plants, including
the production of higher levels of substances that could potentially be
used as PIPs (Ref. 23).
If an agricultural or semi-managed plant containing a PIP based on
a sexually compatible plant created through biotechnology hybridizes
with a wild relative, it is unlikely that the levels of expression of
the transferred PIP in the wild relative will be substantially
increased. For reasons described in Unit VI.A.3.c., EPA anticipates
that for agricultural, semi-managed, and feral plants, levels of
substance expressed by the PIP based on a sexually compatible plant
created through biotechnology will not exceed levels currently observed
for the substance in sexually compatible plants (Ref. 23, 51). Thus,
because the levels of expression of a PIP based on a sexually
compatible plant created through biotechnology will not exceed levels
currently observed in plant populations pursuant to proposed criteria,
the potential for an increase in weediness in wild relatives is low
should the wild relative acquire the exempted PIP trait.
e. Low Potential for Occupational and Non-Occupational Risk to Humans
In general, PIPs are likely to present a limited exposure to
humans. In most cases, the predominant, if not the only, exposure route
will be dietary. Significant respiratory and dermal exposures are
unlikely in non-occupational settings because most plant substances,
including PIPs based on sexually compatible plants created through
biotechnology, are expressed at relatively low levels and are found
inside the cell, and therefore any human health risks in non-
occupational settings are expected to be negligible. Although a
potential for non-dietary exposure (e.g., dermal and inhalation) in
occupational settings may exist due to the processing of plants
resulting in increased exposure to intracellular substances like PIPs,
EPA expects exposure to be low due to the relatively low levels of such
substances in plants (Ref. 60). Given that PIPs based on sexually
compatible plants created through biotechnology represent a subset of
substances present in sexually compatible plants that breeders have
experience with and must be expressed at or below existing levels, in
the same tissues, and at the same developmental stages, EPA does not
expect novel exposures from the substances involved, as the sexually
compatible plant sources have a history of being safe sources of
genetic diversity for use in cultivated plants. Because these PIPs are
indistinguishable from those found in a sexually compatible plant,
which in many cases is a close relative or even the same plant species,
existing allergen avoidance strategies for certain plants would still
be protective.
Regarding dermal exposure, expressed substances of PIPs based on
sexually compatible plants created through biotechnology may in some
cases be present in sap or other exudates from the plant or the produce
and thus may present some limited opportunity for dermal exposure to
persons physically contacting the plant or raw agricultural food from
the plant. Farmers and food handlers (e.g., individuals harvesting
produce by hand, preparing food for sale, or stocking produce bins in
grocery stores) or floral workers are those most likely to experience
dermal contact with the substances on an occupational basis. However,
because most plant substances, including PIPs, are expressed at
relatively low levels and are found inside the cell, the level of
exposure is still expected to be low.
[[Page 64323]]
Most of the substances that could be the subject of this proposed
exemption are unlikely to pass through the skin to affect other organ
systems or elicit allergenic sensitization (Ref. 60, reviewed in 61).
The most common skin reaction to plant products is likely irritant
contact dermatitis. These dermal reactions are generally mild, of a
self-limiting nature or self-diagnosed, and self-treated (Ref. 60).
Skin penetration of the substances comprising a PIP is dependent on
several characteristics, including the substances molecular structure
and hydrophobicity, accompanying mechanical irritation (e.g., thorns),
the duration and site of contact, and the lipid content of the skin.
For most PIPs, human skin, which is composed of two layers, the
epidermis and the dermis, is a natural barrier. The outer epidermal
layer of the skin consists of dead cells in tight junctions (keratin)
that provide a shield against elements in the outside world. The rapid
shedding and replacement of the keratin layer serves as a further
protective feature of the skin, as any damaged cells are quickly shed
and replaced. For those PIPs based on sexually compatible plants
created through biotechnology that might possess some properties that
allow limited penetration of the skin, the potential amount passing
through the outer epidermal layer of the skin (epidermis) is likely to
be negligible (Ref. 60). Some irritant contact dermatitises are
initiated by mechanical means which allow for limited penetration of
the skin. For example, the small needle-like hairs of some plants
(e.g., stinging nettle) penetrate the skin to deliver small doses of
irritant toxins (e.g., histamine). However, plants with these
characteristics are rare in cultivation, further limiting exposure
(Ref. 60).
Importantly, PIPs based on sexually compatible plants created
through biotechnology represent a subset of substances already present
in related plants. PIPs based on sexually compatible plants created
through biotechnology would therefore not be expected to alter
predicted exposures of workers to plant proteins or other plant
substances. Thus, dermal exposure to residues of PIPs based on sexually
compatible plants created through biotechnology would not be predicted
to alter exposure patterns in occupational settings.
Regarding inhalation exposure, PIPs based on sexually compatible
plants created through biotechnology may in some cases be present in
pollen, and some individuals (e.g., those working on farms in nurseries
or other plant-growing areas) may be exposed through inhalation to
wind-blown pollen. When present in pollen, the pesticidal substance is
likely to be integrated into the tissue of the pollen grain. The
likeliest impact of pollen exposure is rhinitis, or inflammation of the
mucous membranes lining the nose, resulting in symptoms like nasal
congestion, sneezing, itching, post-nasal drainage, and runny nose.
This proposed exemption will not change current exposures or affect
strategies for dealing with reactions to PIPs based on sexually
compatible plants created through biotechnology that may be aero-
allergens or irritants (Ref. 60). Pollen grains are solid, insoluble
particles of sufficiently large diameter that they are filtered out in
the nasopharynx or in the upper respiratory tract (Ref. 60), from which
they are generally swallowed into the gastrointestinal tract. The
gastrointestinal surface forms a barrier between the body and the
lumenal environment and is often described as having two components:
``(1) The intrinsic barrier is composed of the epithelial cells lining
the alimentary canal and the tight junctions that tie them together,
and (2) The extrinsic barrier consists of secretions and other
influences that are not physically part of the epithelium, but which
affect the epithelial cells and maintain their barrier function.''
Regarding the intrinsic barriers, the alimentary canal is lined by
sheets of epithelial cells that form the defining structure of the
mucosa and establish the basic gastrointestinal barrier. Regarding the
extrinsic barriers, the gastrointestinal epithelium is coated with
mucus, which is synthesized by cells that form part of the epithelium.
Mucus contributes to barrier function in several ways by slowing the
diffusion of molecules. Additionally, molecules in food, including
edible plant tissue, are too large to be absorbed by the
gastrointestinal tract and are broken down into smaller molecules to be
absorbed and utilized by the body. Plant materials such as pollen are
also subjected to the processes in the digestive tract that reduce
larger molecules to smaller constituents that can be absorbed by the
membranes of the small intestine. Importantly, pollen characteristics
(e.g., wind vs. insect dispersal, amount produced) are often maintained
within plant families, as is necessary for successful breeding to
occur. Therefore, PIPs based on sexually compatible plants created
through biotechnology should not alter already established
characteristics of any particular species. In cases of occupational
rhinitis, these PIPs would not be expected to significantly alter
already established patterns of exposure to occupational dusts.
f. Low Potential for Resistance Selection Pressure Posed by PIPs Based
on Sexually Compatible Plants Created Through Biotechnology To Exceed
That Found in Sexually Compatible Plants
A component of EPA's oversight historically for PIPs created
through biotechnology has been the requirement for registrants to
implement an insect resistance management plan. Transgenic Bacillus
thuringiensis (Bt) PIPs are likely at greater risk for insects
developing resistance than many conventional pesticides targeting the
same insects because Bt PIPs are expressed throughout all plant tissues
for the entire lifespan of the plant compared to conventional
pesticides, which typically have shorter periods of efficacy and are
applied when pests are likely to cause yield loss. To address
resistance management due to increased exposure, the Agency has
required detailed information for Bt PIPs (e.g., dose expression
levels, cross-resistance potential, modeling scenarios) alongside terms
of registration (e.g., resistance monitoring programs, remedial action
plans, compliance assurance, and grower education activities).
As mentioned in the previous paragraph, the risk of resistance to
Bt PIPs primarily stems from increased exposure to the PIP from
expression across plant tissues and across the plant lifespan, which
are achieved due to transgenic regulatory elements used in the creation
of the PIP. However, in the case of PIPs based on sexually compatible
plants created through biotechnology, the potential to develop
resistance is lower than that of Bt PIPs due to the limitation on
expression profile (e.g., same tissues and developmental stages) to be
within what is found in sexually compatible plants. EPA does not
anticipate an increased resistance risk posed by PIPs based on sexually
compatible plants created through biotechnology compared to those
developed by conventional breeding. The proposed rule does not require
specific resistance management plans from developers of PIPs based on
sexually compatible plants created through biotechnology that qualify
for the new exemption.
g. Are there any considerations associated with newer biotechnology
techniques?
Newer biotechnology techniques using present-day genome editing
techniques (e.g., CRISPR, zinc-finger
[[Page 64324]]
nucleases, transcription activator-like effector nucleases,
oligonucleotide-directed mutagenesis) can present some additional
considerations beyond those discussed previously, and these were taken
into consideration in developing the proposal to exempt PIPs based on
sexually compatible plants created through biotechnology from FIFRA
requirements in order to meet the requirement at 40 CFR 174.21(a).
Present-day genome editing techniques allow for precise modifications
to the plant genome such that the PIP in question meets the proposed
criteria. These new technologies can aid in plant breeding and result
in varieties indistinguishable from those developed through
conventional breeding (Ref. 12).
Although genome editing technologies allow for more precise editing
or insertion compared to older technologies, there is still a
possibility of unintended modifications, also called ``off-target''
mutations. With genome editing technologies, off-target mutations may
occur when the genome editing machinery cuts DNA at sites that share
sequence similarity with the actual target sequence. However, off-
target mutations may occur as a result of any form of plant breeding,
including conventional breeding, and an off-target mutation is not
necessarily significant in a specific PIP/plant combination with regard
to food, feed and/or environmental risk. In plants, off-target
mutations can largely be removed by backcrossing, if necessary,
regardless of the method by which they were introduced (Ref. 62). It is
very likely that the off-target mutation and the desired trait are
inherited separately, which allows for developers to select plants that
have the desired trait, but that do not have the off-target mutation.
A recent comparison of single-base pair substitution mutations
resulting from plant breeding technologies found that the number of
mutations detected after genome editing was not significantly different
from what was found after routine tissue culture (Ref. 63). This
analysis supports the conclusion that off-target mutations from genome
editing are not inherently different or riskier than off-target
mutations occurring through other forms of plant breeding. In addition,
recent studies in rice and maize found that compared to the inherent
variation found in the plant, mutations resulting from genome edited
off-target mutations were negligible and far fewer (Ref. 64, 65).
The majority of unintended changes at the genomic level, whether
due to off-target mutations from plant breeding technologies or through
natural mutations, do not result in significantly deleterious effects
to the plant at the phenotypic level (Ref. 4). This is primarily due to
the highly plastic nature of plant genomes (Ref. 66, 67, 68). The small
percentage of unintended changes that do result in significant
deleterious effects are far more likely to produce an effect
deleterious to the plant itself (e.g., stunted growth) than a novel
exposure to humans or the environment (Ref. 34). Although EPA only
regulates the PIP, FDA regulates the remainder of the plant for food
safety (see Unit II.B.). In the context of the genetic material
encoding the PIP, off-target mutations in the coding region resulting
in protein-level changes would not be eligible for exemption based on
the proposed criteria requiring that the substance be the same as
identified in a source plant. Off-target mutations in the regulatory
region would not be considered a significant risk due to the same
rationale allowing for modifications to regulatory regions as described
in Unit VI.A.2.a. EPA therefore considers off-target mutations
resulting from genome editing technologies to present a negligible risk
to the environment in the context of PIPs based on sexually compatible
plants created through biotechnology.
h. FIFRA Section 25(b)(2): Preliminary Statutory Finding
EPA preliminarily concludes that PIPs based on sexually compatible
plants created through biotechnology as described for proposed 40 CFR
174.26, warrant exemption under FIFRA section 25(b) because these
substances are of a character that is unnecessary to be subject to all
the requirements of FIFRA to carry out the purposes of the Act.
Specifically, EPA has preliminarily concluded that PIPs based on
sexually compatible plants created through biotechnology that meet the
exemption criteria pose a low probability of risks to humans and the
environment.
As discussed in Unit VI.A.3., EPA has preliminarily concluded that
PIPs based on sexually compatible plants created through biotechnology
that meet the exemption criteria pose a low probability of non-dietary
risk to humans and the environment. As explained in this preamble in
Unit VI.B., EPA has also determined that there is a reasonable
certainty that no harm will result from aggregate exposure to the
residues of such products, including all anticipated dietary residues
and all other exposures for which there is reliable information. As
such, EPA has preliminarily determined that use of PIPs based on
sexually compatible plants created through biotechnology is not likely
to cause unreasonable adverse effects on the environment and humans in
the absence of regulatory oversight other than the adverse effects
reporting requirement in existing 40 CFR 174.71. Based on the low
probability of the potential risks coupled with the proposed exemption
eligibility determination process, EPA anticipates minimal societal
benefits would be gained by imposing the full degree of oversight
associated with FIFRA registration (see Unit VI.A.4. for additional
information on benefits). Finally, the adverse effects reporting
requirement at existing 40 CFR 174.71 provides a mechanism that could
alert the Agency to information regarding adverse effects associated
with a PIP based on a sexually compatible plant created through
biotechnology. Based on the information available, the benefits of
exempting PIPs based on sexually compatible plants created through
biotechnology from FIFRA outweigh the potential risk associated with
these PIPs (risk that is low).
4. Benefits
This unit summarizes the benefits that are described in greater
detail in the cost analysis (Ref. 2). This cost analysis quantifies
registration or Pesticide Registration Improvement Extension Act of
2018 (PRIA) related fees as required by FIFRA. These fees represent
savings to developers if the proposed exemption becomes final.
The direct benefit of the proposed rule is the reduced regulatory
burden associated with developing and marketing a PIP based on a
sexually compatible plant created through biotechnology. The proposed
exemption may encourage more research and development in this area of
biotechnology and better enable firms of all sizes to engage in the
development of these types of PIPs.
Entities that support major crops or larger markets can more easily
absorb fixed registration costs. As a portion of the total costs of
researching and developing a new active ingredient, registration costs
often represent a small proportion of the overall costs of bringing a
product to market. However, an outlay of fixed registration costs can
be significant for a firm that supports minor crops. Removal of
registration costs for these entities can be significant, so smaller
entities may feel the most regulatory relief as a result of this rule.
Crop varieties modified for greater pest and disease resistance
could also reduce the use of externally applied pesticides, which in
turn could reduce
[[Page 64325]]
farm expenditures and provide environmental benefits. Finally, the
proposed exemption would also reduce the burden on the Agency to review
applications for registration.
Exempting PIPs based on sexually compatible plants created through
biotechnology from registration while also promulgating an exemption
from the requirement of an FFDCA tolerance for residues of such PIPs in
or on food or feed has an estimated incremental cost savings (the
primary benefit of the rule) of about $444,000-$459,000 per product.
This savings represents the difference between the new costs of the
process to submit a letter of self-determination and the old estimated
costs that developers would have had to incur to meet Agency data
requirements and to register the PIP. The annual number of PIPs based
on sexually compatible plants created through biotechnology cannot be
forecasted, so the Agency based annual and annualized cost savings
estimates on an assumption that there would be one PIP that fit the
exemption category per year for the next ten years. This estimate is
meant to inform the public of the cost savings and their magnitude over
time. The estimate avoids Agency conjecture about how many products
would be registered in the absence of this exemption over time. The
number of future PIPs based on sexually compatible plants created
through biotechnology being developed will depend on the market for
these products.
a. Growers
Growers will have more tools to combat pest pressure because the
proposed exemption might accelerate the development of new plant
varieties containing exempt PIPs based on sexually compatible plants
created through biotechnology that target those pests. Faster marketing
of PIPs based on sexually compatible plants created through
biotechnology will allow the market to respond faster to changes in
disease pressure and the emergence of resistance to existing
pesticides, which can be important to growers. EPA anticipates that the
proposed exemption for PIPs based on sexually compatible plants created
through biotechnology will particularly encourage the development of
PIPs based on sexually compatible plants created through biotechnology
in minor crops. The limited acreage on which minor crops are cultivated
makes it more difficult to recoup investment in research and
development into new varieties, especially if regulatory costs are
high.
b. The Agency
Finally, the proposed exemption would also reduce the burden on the
Agency to review applications for registration. By proposing to exempt
those PIPs based on sexually compatible plants created through
biotechnology due to low probability of risk and lack of unreasonable
adverse effects in the absence of oversight, EPA will concentrate its
regulatory efforts on other PIPs that may pose potential risks. Whereas
the introduction of transgenes into a plant could result in the
exposure of humans and the environment to a new substance or a
previously known substance in a new way, the modifications associated
with qualifying PIPs based on sexually compatible plants created
through biotechnology are unlikely to result in novel exposures. Thus,
concentrating regulatory efforts on PIPs with a higher potential of
novel exposures is a more efficient use of EPA's resources.
B. What is the proposal to exempt residues of PIPs based on sexually
compatible plants created through biotechnology from the requirement of
a tolerance?
Pursuant to its authority under FFDCA section 408(e), 21 U.S.C.
346a(e), EPA is proposing to exempt from the requirement of a tolerance
residues of pesticidal substances from PIPs based on sexually
compatible plants created through biotechnology that meet the
conditions proposed for this exemption. The Agency believes that when
the proposed conditions are met, there is a reasonable certainty that
no harm will result from aggregate exposure to residues of these
pesticidal substances from PIPs based on sexually compatible plants
created through biotechnology, including all anticipated dietary
exposures and all other exposures for which there is reliable
information. The Agency believes the exemption criteria will ensure
that the exempt PIPs would not result in exposures that are
significantly different from what humans are currently exposed to in
the food supply; therefore, the exemption would be safe in light of the
history of safe exposures.
This proposed exemption is intended to address the second condition
for exemption from FIFRA regulation under 40 CFR 174.21(b): The
requirement for a tolerance exemption for the residues of PIPs intended
to be produced and used in a plant used as food or feed. The proposed
rule also includes a process through which developers of PIPs based on
sexually compatible plants created through biotechnology submit either
a self-determination letter or request for EPA confirmation that their
PIP meets the criteria for exemption. That process is proposed at 40
CFR 174.90, and details of the process for and contents of an exemption
eligibility determination submission are found in Unit VI.C. That unit
also describes the circumstances in which submission of a separate
determination for purposes of the FFDCA exemption for a PIP proposed
for use in food or feed is required.
Given that the proposed exemption could potentially cover thousands
of substances, a small fraction of which are known toxicants (for
discussion see Unit VI.B.3.), the Agency is proposing to use certain
guardrails to account for the rare instances in which residues of a
pesticidal substance may reach levels in food or feed that are unsafe.
First, EPA proposes a criterion for exemption under FFDCA that limits
the presence of residues of the pesticidal substance in the recipient
plant. Specifically, residues of a pesticidal substance in plants used
for food are allowed to be present only in the same plant tissues and
developmental stages where such residues are found in a sexually
compatible plant. Additionally, the levels of that pesticidal substance
cannot exceed levels found in a sexually compatible plant, with the
added limitation that those levels may not be injurious or deleterious
to human health. In other words, if levels that are injurious or
deleterious to human health are observed, the PIP and its residues
would not be covered by the proposed exemption from the requirement of
a tolerance. This approach is consistent with the existing exemption
criteria for residues of a pesticidal substance from a sexually
compatible plant, which also limit the levels of residues of exempt
PIPs present in the food from that plant to those that are not
injurious or deleterious to human health (40 CFR 174.508(c)). Second,
under the proposed exemption for PIPs based on sexually compatible
plants created through biotechnology, a developer may wish to request
an exemption for residues of a pesticidal substance whose levels are
commonly screened for in conventional breeding to ensure the safety of
the food. In these instances, the developer of such a PIP would be
required, as part of the exemption eligibility determination process
proposed at 40 CFR 174.90, to describe how conventional breeding
practices have been and will be performed on the recipient food plant
to ensure that the levels of the pesticidal substance are not injurious
or deleterious to human health. This is to
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affirm that PIPs based on sexually compatible plants created through
biotechnology will be held to the same safety standards by the plant
breeders as PIPs in plants created through conventional breeding. This
requirement can be fulfilled by a developer with a confirmation that
the product has been screened for acceptable levels of the pesticidal
substance (e.g., generally accepted safe content for solanine in
potatoes is 20-25 mg/100 g of fresh potato). Breeders have decades of
experience developing new plant varieties and are familiar with the
toxins that may be produced by certain plants used for food and feed,
e.g., by chemically analyzing the components of plants. Because PIPs
based on sexually compatible plants created through biotechnology are
equivalent to those substances found within plants that are sexually
compatible with the recipient plant, these substances are not expected
to be novel to breeders and the existing screening methods are
similarly expected to remain effective. Third, as described further in
Unit VI.C.1., residues of a PIP used in food or feed, which would
include residues of a PIP based on a sexually compatible plant created
through biotechnology, remain subject to the adverse effects reporting
under 40 CFR 174.71 even after the residues have been exempted from the
requirements of FFDCA. Therefore, upon learning of any adverse effects,
which includes injurious or deleterious levels of the pesticidal
substance in food or feed, EPA has the authority to reconsider whether
the PIP and the residues of the PIP continue to meet the criteria for
exemption. Further, as described in the preamble of the July 19, 2001
Federal Register notice implementing 40 CFR 174.71 (66 FR 37772; July
19, 2001), reports involving food or feed (i.e., those subject to
enforcement under FFDCA) would be made to EPA, but EPA will share such
reports with FDA. EPA and FDA will individually determine whether any
action is necessary to protect the public health, and if so, what
constitutes appropriate action based on their respective statutes
(EPA--FIFRA, FDA--FFDCA). Therefore, 40 CFR 174.71 is a means of
ensuring that EPA and FDA can address any potential hazard identified
subsequent to self-determination or EPA confirmation that a PIP meets
the requirements for exemption.
1. Proposed Criteria and Associated Definitions
Unit VI.A.2. outlines the scope of the FIFRA exemption proposal for
PIPs based on sexually compatible plants created through biotechnology.
The criteria and associated definitions discussed in that unit are
equally relevant to the proposed FFDCA exemption for residues of these
PIPs for food and feed use. For example, the proposed definitions of
``native allele,'' and ``native gene'' are discussed in greater detail
in Unit VI.A.2. Also discussed in Unit VI.A.2. are the following
phrases: ``(1) The pesticidal substance is found in plants that are
sexually compatible with the recipient plant; and (2) Limitations on
expression profile.'' The proposed definition of ``gene'' is discussed
in Unit V.A. Thus, the following considerations under the proposed
FFDCA exemption refer to the concepts discussed in other parts of the
exemption proposal when appropriate.
EPA is proposing criteria and supporting definitions that describe
residues from PIPs based on sexually compatible plants created through
biotechnology that the Agency expects to meet the FFDCA safety standard
for establishing exemptions. This proposed exemption covers the
residues of the pesticidal substance of those qualifying PIPs and would
eliminate the need to establish a maximum permissible level in or on
food and feed for these residues.
EPA's basis for its proposal is that the criteria of the exemption
circumscribe a group of PIPs that will not result in novel exposures,
dietary or otherwise. This analysis is based on the large body of
knowledge about the history of safe use from foods containing these
substances that have been consumed by humans for long periods of time.
Because PIPs based on sexually compatible plants created through
biotechnology are equivalent to those that could have been created
through conventional breeding, plant breeders will retain their ability
to ensure that the substances will be at safe levels for humans in the
resulting food plant. EPA concludes that the potential is low that
qualifying PIPs based on sexually compatible plants created through
biotechnology introduce novel exposures (Unit VI.A.3.b.).
a. Large Body of Knowledge
EPA relied on the large body of scientific literature that
describes constituents of food from plants in sexually compatible
populations (Ref. 37). EPA used scientific literature on the effect on
humans of consumption of whole foods from plants generated from
epidemiological studies (Ref. 24, 25, 27, 29, 31, 69, 70, 71, 72, 73)
and animal model testing of the effects of either whole foods, or
constituents from food, contained in these crops (Ref. 26, 28, 30, 74,
75, 76, 77) to draw conclusions on the potential risks to humans
through the dietary (including drinking water) and residential (or non-
occupational) route of exposure to these substances. EPA also
considered scientific knowledge from a number of disciplines including
genetics, plant physiology, phytopathology, toxicology, ecology,
biochemistry, evolutionary biology, genomics, and plant breeding.
Information from the field of plant physiology was considered regarding
plant metabolism to evaluate the production of substances that may have
pesticidal effects and conditions that may limit the plant's production
of such substances, see Unit VI.B.1.c. and Unit VI.A.3.c. (Ref. 33).
EPA considered information from the fields of biochemistry and
toxicology, for example, to identify which substances in food from
plants might pose a dietary risk (Ref. 37, 39, 78). The Agency also
used experimental data derived from the science of phytopathology that
characterize the pest resistance mechanisms in plants to understand the
types of traits through which PIPs may confer resistance or tolerance
to pests (Ref. 3, 79). The sciences of ecology and evolutionary biology
were considered for information on genetic diversity, mutation, and
reproductive isolation mechanisms in populations to understand the
types of genetic changes that are likely to occur when plants
interbreed in nature (Ref. 34). Plant breeding and genetics provided
considerations to help describe the mechanisms of incompatibility and
interbreeding, which aided EPA in determining when plants are likely to
interbreed in nature. As discussed in greater detail in Unit VI.A.3.g.,
information from genomics and molecular biology were considered to
understand the ability of newer biotechnology techniques, such as those
using genome editing techniques, to create traits equivalent to those
found in conventionally bred plants (Ref. 35, 36).
Recommendations from several FIFRA SAP reports were considered in
the development of the proposed exemption criteria for PIPs based on
sexually compatible plants created through biotechnology, and to
circumscribe the types of genetic modifications in the recipient plant
that are unlikely to result in novel exposure to humans, dietary or
otherwise (Unit II.C.3., Table 1).
b. Low Potential for Novel Exposure
All plants, including those commonly consumed as food, naturally
contain pesticidal substances that confer pest
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resistance. Humans have for approximately 10,000 years selected and
bred certain plants for food, feed, and fiber, that have these
pesticidal characteristics. Humans are therefore familiar with and have
been exposed to many plant-produced pesticidal substances and their
residues, such as those that could be developed for use as PIPs based
on sexually compatible plants created through biotechnology, in their
diet and otherwise for millennia. Given that PIPs based on sexually
compatible plants created through biotechnology are intended to
represent a subset of substances present in plants that breeders are
familiar with and that in many instances have been safely consumed by
humans, EPA does not expect that these substances, or residues of these
substances, would result in novel dietary exposures.
Several considerations for assessing the potential for novel risks
for PIPs based on sexually compatible plants created through
biotechnology are discussed in Unit II.C.3. in the context of the
proposed FIFRA exemption. The concepts presented in that unit are
equally relevant to the FFDCA safety assessment of residues of PIPs
based on sexually compatible plants created through biotechnology that
are used for food or feed.
Pesticidal traits have evolved in plant populations over time
through the processes of mutation, selection, and genetic exchange with
sexually compatible species (Ref. 47, 48). The ability to produce
viable offspring is only possible in nature for organisms that are
genetically similar and possess many traits in common. Traits, and the
genetic material encoding them, can be passed through a sexually
compatible plant population by breeding. The mixing of genetic material
that occurs through breeding results in the members of a sexually
compatible population having similar traits and similar genetic
material. Due to the mixing of traits by mating, similar exposure
scenarios are expected for food plants that are sexually compatible--in
other words, substances in sexually compatible plants are expected to
be similar and therefore, only substances that plant breeders are
already familiar with are expected to be present in sexually compatible
plants. This conclusion is consistent with the 1992, 1993, and 1994
FIFRA SAP reports that indicated that sexually compatible plants are
more likely to have a common constitution than unrelated plants and
thus movement of genetic material between sexually compatible plants is
less likely to lead to novel exposures (Unit II.C.3., Table 1).
For agricultural plants, those defined as sexually compatible would
also include existing plant cultivars, landraces, and breeding lines,
as well as plant relatives that interbreed with crops but that are not
currently used as agricultural plants. Plant breeders have for many
years followed established practices to ensure safety when moving genes
into agricultural varieties from nonagricultural relatives,
particularly from inedible relatives, with no indication that
substances resulting from these genes present higher levels of risk
than those from genes moved only amongst agricultural varieties as long
as those established practices are followed (Ref. 13, 14, 15, 16).
Therefore, the likelihood that the inclusion of nonagricultural
varieties as potential source plants would lead to unsafe dietary
exposures from residues of PIPs based on sexually compatible plants
created through biotechnology is low.
Genetic diversity is created over time and EPA proposes to capture
some of the ongoing diversification not identified in existing native
genes or native alleles through the inclusion of novel changes
resulting in the differential expression of existing genes, so long as
no novel substance is produced and the substance is not produced in
different tissues or at different developmental stages than those found
in a sexually compatible plant. Modifications that lead to differential
expression of a substance are not expected to result in levels that
exceed the boundaries of the natural variation found in sexually
compatible plants due to physiological constraints that are related to
energy expenditure (further discussed in Unit VI.B.1.c. and Unit
VI.A.1.c.). The potential for novel dietary exposures to occur with the
differential expression of existing genes, or the movement of native
genes and native alleles among sexually compatible plants, is therefore
low, because no substance novel to plants that are sexually compatible
with the recipient plant will be produced, nor will the substance be
found in tissues or developmental stages at levels, in which it is not
currently found.
c. Low Potential for Levels of PIPs Based on Sexually Compatible Plants
Created Through Biotechnology To Exceed Those Found in Sexually
Compatible Plants
EPA has evaluated whether there are likely to be quantitative
changes in expression levels of PIPs based on sexually compatible
plants created through biotechnology that may pose dietary risks. As
discussed later in this unit, EPA has determined that the probability
is low because the highest levels of pesticidal substances likely to be
expressed by qualifying PIPs based on sexually compatible plants
created through biotechnology is not likely to be significantly
different from those that humans are currently exposed to in the food
supply. To codify this principle into EPA's regulatory text, EPA is
proposing an exemption criterion in which the level of expression of
PIPs based on sexually compatible plants created through biotechnology
is bound by the upper limit of expression of the pesticidal substance
observed in sexually compatible plants. By limiting the level of
expression that qualifies for an exemption in this way, EPA can ensure
that the exposures fall within the normal historical range of exposures
with which plant breeders have experience limiting to ensure safe
exposures when introduced into food plants.
An analysis discussing the likely range of expression of PIPs in
sexually compatible plants was presented in an EPA issue paper,
entitled: ``FIFRA: Benefit and Environmental Risk Considerations for
Inherent Plant-Pesticides.'' A summary of that analysis is presented in
Unit VI.A.3.c. The factors that influence the determination of low
probability of risk under FIFRA that are discussed in that unit are
equally relevant to the FFDCA safety assessment of residues of those
same PIPs in food or feed. Relevant considerations summarized in that
unit include: (1) The level of production of substances normally varies
among sexually compatible plants because of differences in potential to
express a substance and environmental conditions; (2) Physiological and
practical considerations limit the expression levels of PIPs based on
sexually compatible plants created through biotechnology; (3) Humans
have been and are currently exposed to the range of levels of
substances that might be used as PIPs based on sexually compatible
plants created through biotechnology.
Moreover, in varietal development, plant breeders assess the new
cultivar for food safety, based in part on knowledge of and familiarity
with the characteristics of agricultural plants in the relevant
sexually compatible populations (Ref. 6, 37). Because PIPs based on
sexually compatible plants created through biotechnology represent a
subset of substances already present in related plants, the procedures
routinely used in agriculture and food processing would continue to be
efficacious in identifying these substances, and levels
[[Page 64328]]
of these substances, in new food plant varieties.
Although hundreds of new plant varieties enter the market each year
within the past 70 years, conventional plant breeding has recorded very
few instances of plant varieties causing food safety problems (Ref. 37,
80). EPA believes this same demonstrated record of safety can be
applied to the pesticidal substances produced by these plants.
Therefore, the Agency considers it highly unlikely that residues of a
PIP based on a sexually compatible plant created through biotechnology
would occur in or on food or feed at levels that are hazardous. To
account for the rare instances in which a substance may reach levels
that are unsafe, EPA is proposing as a criterion for exemption that
residues of the pesticidal substance are only present in tissues and
developmental stages identified in a plant that is sexually compatible
with the recipient food plant, and do not exceed levels found within
that plant, as long as those levels are not injurious or deleterious to
human health. If levels that are injurious or deleterious to human
health are observed, the PIP and its residues would not be covered by
the proposed exemption from the requirement of a tolerance. In failing
to meet the FFDCA requirements for exemption, the PIP would similarly
fail to meet the exemption requirements under FIFRA.
In conclusion, EPA considered the potential variability of
expression levels of PIPs based on sexually compatible plants created
through biotechnology and whether such variations would be hazardous if
they were to be present in the food or feed supply. EPA concluded that
although variations in the production of plant substances will occur in
response to environmental conditions, there are physiological and
practical considerations that limit the expression level, and thus the
abundance of a particular substance in plants that are sexually
compatible. By limiting the expression of PIPs based on sexually
compatible plants created through biotechnology to not exceed levels
that are found in sexually compatible plants, EPA believes that
breeders will be able to ensure that exposures fall within the normal
historical range of exposures that have proved to be safe through
conventional breeding.
2. Dietary Risk Evaluation
For chemical pesticides, EPA's dietary risk evaluation relies on
data generated by testing in laboratories using representative animal
models to estimate acute, subchronic, or chronic hazard endpoints,
e.g., acute toxicity, carcinogenicity, and developmental toxicity.
Conclusions from animal models are used to assess dose-response and
describe such endpoints for potential human hazards. Other information,
including residue data and information generated by use of mathematical
models, are used to develop human exposure estimates. These exposure
and hazard components are combined to quantify the potential risk
associated with the pesticide's use and to determine the appropriate
maximum residue levels of the chemical in or on food or feed, i.e., to
set the numerical tolerance. Uncertainty factors are often used in the
risk assessment to account for extrapolation from animal models to
human toxicity. If the substance is found to be safe, the Agency may
issue a tolerance or, as proposed here for qualifying PIPs based on
sexually compatible plants created through biotechnology, an exemption
from the requirement of a tolerance for the pesticide chemical
residues. EPA described the information base typically used to assess
the potential risks and safety of PIPs at a public symposium held in
September 2016. The materials developed for this symposium are
available on https://www.regulations.gov in Docket ID No. EPA-HQ-OPP-
2016-0427 and on EPA's website at https://www.epa.gov/pesticides/public-symposium-regulation-plant-incorporated-protectants-rebroadcast-live-webcast.
In some cases, the use of animal model testing may not be required
to support a safety finding for a pesticide chemical residue. For
example, for PIPs that are already part of the food supply but moved
through the use of biotechnology between two distantly related food
plant species (i.e., those that are not sexually compatible and could
not have been moved through conventional breeding), EPA has used
various forms of information aside from animal testing to assess the
safety of PIP residues. These included the open scientific literature
to understand the characteristics of the PIP itself as well as the
biology of the source plant from which the PIP is derived and the
recipient plant in which the PIP will be produced and used. Similarly,
in performing the assessment for the proposed tolerance exemption for
PIPs based on sexually compatible plants created through biotechnology,
the Agency is assessing the substances present in these plants in the
context of the history of human consumption of the whole food, and
animal model testing of the effects of either whole foods, or
constituents from food, contained in these crops (Unit VI.B.1.a.).
EPA's conclusion that qualifying PIPs based on sexually compatible
plants created through biotechnology would be safe for human
consumption is based on this information. EPA considered that
appropriate processing procedures are widely known and are routinely
used by consumers and companies involved in food production and
processing in the preparation of food containing residues that are the
subject of this proposed exemption, including those foods that require
specific processing and/or preparation steps in order to be safely
consumed B.3.). Importantly, the efficacy of the food preparation
techniques, as well as dietary avoidance strategies, are expected to
apply equally to food containing residues of PIPs based on sexually
compatible plants created through biotechnology, since residues of
those pesticidal substances are a subset of substances already present
in related food plants. Similarly, the plant breeding practices that
are routinely employed in selecting and developing new plant varieties,
such as chemical analysis and visual analysis, are not expected to be
affected by this proposed exemption. As a result, the residues are not
expected to pose any risk that differs from what people already are
exposed to in the food supply.
EPA considered health risks to the general population, including
infants and children. Residues of pesticidal substances in or on food
or feed from PIPs based on sexually compatible plants created through
biotechnology that meet the proposed criteria for exemption would not
be new to the food supply, as they are a subset of substances already
present in related plants. Accordingly, this proposal should not change
anything about the way that children, and to some extent infants, are
exposed to substances already found in food that are identical to
residues of PIPs based on sexually compatible plants created through
biotechnology. EPA's risk assessment also included subgroups as part of
the general population, i.e., reflecting differences in diet due to the
influence of culture, and allowed for consumption pattern differences
of such subgroups.
a. Dietary Consumption Patterns
EPA considered the available information on the varying dietary
consumption patterns of consumers and major identifiable consumer
subgroups as it pertains to residues of pesticidal substances from PIPs
based on sexually compatible plants created through biotechnology. The
consumption of food
[[Page 64329]]
from plants is part of a balanced and varied diet (Ref. 81). For
purposes of this proposed exemption, EPA considered a normal diet to be
balanced and varied and to include food from a variety of sources. It
does not include plants or plant parts consumed in times of
deprivation, for religious reasons, in substance abuse, or by accident.
Humans have been consuming food containing pesticidal substances
produced by sexually compatible plants for long periods of time. It is
not anticipated that this proposed exemption from the requirement of a
tolerance, should it be finalized, will affect current consumption
patterns of food from crop plants by consumers or major identifiable
consumer subgroups, and thus no differences in exposure patterns are
anticipated.
b. Validity, Completeness, and Reliability of Available Data
EPA considered the validity, completeness, and reliability of the
available information on human consumption of food containing
substances that would be identical to the expected residues of
pesticidal substances from PIPs based on sexually compatible plants
created through biotechnology, including the extensive history of
humans safely consuming foods from plants containing these substances,
epidemiological studies of human dietary assessments and animal model
testing, as well as information from the disciplines of genetics,
molecular biology, plant physiology, phytopathology, toxicology,
ecology, biochemistry, evolutionary biology, genomics, and plant
breeding (Unit VI.B.1.a.). EPA concluded that this information was
valid, complete, and reliable, and adequately addressed the issues of
hazard and exposure with regard to residues of pesticidal substances
from PIPs based on sexually compatible plants created through
biotechnology in or on food or feed.
3. Toxicological Profile
EPA considered whether toxic effects could be associated with any
pesticidal substances that developers might wish to use as PIPs based
on sexually compatible plants created through biotechnology and that
might be residues in or on food or feed (Ref. 6). The examination led
EPA to conclude that, since the vast majority of substances in plants
that are used for food are not toxic, any of these nontoxic substances,
should they be used as PIPs based on sexually compatible plants created
through biotechnology, would not present any toxic effects.
Plants produce hundreds of thousands of substances of which only
about 200 have been identified as potential toxins in food plants, and
only 10% of those substances (about 0.01% of all substances) may pose a
dietary risk when consumed as part of a normal diet (Ref. 37, 82, 83).
One example is the glycoalkaloid solanine, which is commonly
biosynthesized in potatoes and to some extent eggplant and peppers
(Ref. 6). Solanine poisoning is very rare. However, in large doses it
can cause effects such as gastrointestinal tract irritation and
drowsiness. Solanine imparts a bitter taste to the tuber, and at high
concentrations can even leave a persistent irritation and burning
sensation on the tongue, both of which may to some extent deter
consumption. Potatoes are bred and monitored in the United States to
ensure that they produce only low levels of solanine.
There are several factors that could have contributed to the
relatively low number of toxins in food plants. In crop development,
low toxicant abundance has been a desired trait to increase usability
of a particular plant as a source of nutrition and to enhance its
palatability (Ref. 4, 37). Further, the risk of toxins that may be
present in a particular food crop appears to be well known, and methods
of processing exist to reduce the potential for toxic effects (Ref.
37). For example, as part of the development and characterization of
new plant varieties, plant breeders use methods such as gas and/or
liquid chromatography coupled with mass spectrometry to identify and
quantify toxins in food plants and use this information to identify and
remove new varieties from the development pipeline that contain
potentially harmful levels of these substances. Over the past 50 years,
the sensitivity of some metabolic profiling techniques has increased
over 100,000-fold, enabling the detection of exceedingly small amounts
of these substances (Ref. 37). As a result, the majority of toxicants
in food plants are already known and plant varieties can be screened
for their presence and removed from the market if necessary. In this
context it is relevant to note that no newly released plant variety
exhibited any previously unknown food or feed hazard (Ref. 37, 80).
Because PIPs based on sexually compatible plants created through
biotechnology are a subset of those PIPs found in related plants, these
substances are not novel to plant breeders. Therefore, the efficacy of
the existing monitoring, processing, and preparation methodologies that
have been and are being used to produce food safe for consumption is
expected to be equally effective at screening foods that would contain
PIPs based on sexually compatible plants created through biotechnology.
For the reasons described in Unit VI.B.1.b., EPA expects that PIPs
based on sexually compatible plants created through biotechnology do
not pose novel exposures (dietary or otherwise) compared to pesticidal
substances present in sexually compatible plants. Furthermore, EPA
expects that the levels of PIPs based on sexually compatible plants
created through biotechnology have a low potential to exceed levels
found in sexually compatible plants (Unit VI.B.1.c.) and codifies these
levels in the proposed exemption criteria.
4. Cumulative Effects From Substances With a Common Mechanism of
Toxicity
FFDCA section 408(b)(2)(D)(v) requires that, when considering
whether to establish, modify, or revoke a tolerance, the Agency
consider ``available information'' concerning the cumulative effects of
a particular pesticide's residues and ``other substances that have a
common mechanism of toxicity.'' This factor is also relevant when
considering whether to establish an exemption from the requirement of a
tolerance (21 U.S.C. 346a(c)(2)(B)).
As discussed in Unit VI.B.3., EPA recognizes that there are
toxicants of plant origin that may be part of the human diet, which
could theoretically be used as PIPs based on sexually compatible plants
created through biotechnology and which may cause adverse effects. EPA
has considered available information on the cumulative effects of such
residues and other substances that have a common mechanism of toxicity
and that may be developed as PIPs based on sexually compatible plants
created through biotechnology. EPA also considered whether the
cumulative expression (i.e., expression of the PIP across all plants)
would result in an adverse effect. Because the PIP based on a sexually
compatible plant created through biotechnology could have otherwise
been created through conventional breeding, and by extension would not
be novel to plant breeders, EPA does not consider that the cumulative
expression of a PIP based on a sexually compatible plant created
through biotechnology would pose a higher risk than what is currently
possible through conventional breeding.
For the reasons discussed in Units VI.B.1.a. through c., any
potential cumulative effects from PIPs based on sexually compatible
plants created through biotechnology are not expected
[[Page 64330]]
to be quantitatively different from those present in the current food
supply and the presence of these substances and their residues has
historically been safe.
5. Aggregate Exposures of Consumers Including Non-Occupational
Exposures
EPA considered the available information on the aggregate exposure
of consumers to the residues of PIPs based on sexually compatible
plants created through biotechnology. EPA examines exposure through the
dietary route (including drinking water), and exposure in the
residential non-occupational setting in greater detail in the following
units (Unit VI.B.5.a. through e.).
a. Dietary Exposures From Food
Dietary exposure is the most likely route of exposure to PIPs based
on sexually compatible plants created through biotechnology as these
pesticidal substances are contained within plants consumed as food. As
described in this preamble at Unit VI.B.1.a., a large knowledge base
and experience exists for the residues that are subject of this
proposed exemption, including information on human dietary exposure.
Information from all of these sources can be used in evaluating the
safety of residues of PIPs based on sexually compatible plants created
through biotechnology, as food from a plant engineered to contain such
a PIP is comparable to the situation presented by the natural whole
food from that plant prior to introducing the genetic modification: No
substances new to the sexually compatible plant population would be
introduced, and the introduced substances would be consumed as part of
the whole food.
The exemption criteria prohibit the introduction of substances that
are novel to the sexually compatible plant population and, as discussed
earlier, nothing about the PIP would alter the existing mechanisms for
breeding, processing or preparing the food. Thus, the Agency expects
any exempt PIPs would be consumed as part of the whole food in the same
manner as existing foods currently in the food supply and that plants
containing residues of these PIPs would be subject to the same
procedures plant breeders rely on to ensure the safety of food. There
is no evidence in the many studies performed on the relationship of
diet to health that food containing substances from sexually compatible
plants, when properly processed and prepared, has resulted in adverse
health effects (Unit VI.B.1.a. through c.). The Agency believes this
assumption is supported by the record of safety of the food products
from plants in sexually compatible populations. Although hundreds of
new varieties come on the market each year (Ref. 84), breeding of
plants in sexually compatible populations has recorded very few
instances of exposures to substances that are not safe in food.
Further, no previously unknown food hazard has been observed in new
plant varieties developed through plant breeding (Ref. 37, 80).
The primary exposure consideration associated with the pesticidal
chemical residues that are the subject of this proposed exemption is
whether substances that might be harmful at higher concentrations (or
in different tissues or stages) are likely to be present in food from
sexually compatible plants at such concentrations. EPA considered the
probability of variations in levels of PIPs based on sexually
compatible plants created through biotechnology, and whether such
variations would be hazardous if these PIPs were to be present in the
food supply (Unit VI.B.1.c.). EPA concluded that, based on biological
and agronomic considerations, any variations in the levels of PIPs
based on sexually compatible plants created through biotechnology is
not expected to exceed the levels of these substances currently present
in the food supply, which has been determined to be safe. This
principle is also codified in EPA's proposed regulatory text in which
the level of expression of a PIP based on a sexually compatible plant
created through biotechnology is bound by the upper limit of expression
of the pesticidal substance observed in sexually compatible plants and
that it can only be present at levels that are not injurious or
deleterious to human health.
A second exposure consideration is whether this proposed exemption
will affect the ability of individuals with food sensitivities to
manage these sensitivities. Individuals with food sensitivities,
including food allergies, generally avoid foods from plants that they
are sensitive to. This proposed exemption, if finalized, would not
affect the efficacy of this strategy of avoidance because the proposed
exemption will not affect the ability of individuals to recognize and
avoid foods they are sensitive to. For example, the ability of persons
who have the Mediterranean form of the inherited Glucose-6-phosphate
dehydrogenase (G6PD) deficiency to manage their disease by not
consuming fava beans or foods made with fava beans will not be
affected. The substances in fava beans that can cause hemolytic anemias
in such persons would be exempt only if they are used in fava bean
plants and plant varieties that interbreed with fava beans; a
population of plants in which such substances normally occur (Ref. 85).
In conclusion, qualifying PIPs based on sexually compatible plants
created through biotechnology represent a subset of substances already
present in related plants. Therefore, should residues of these
substances be present in or on food derived from plants, EPA does not
expect them to have any meaningful impact on the already existing
dietary exposure profile for these residues and thus risk from dietary
exposure to such residues in or on food would be low. Moreover, as an
additional measure of safety for residues of qualifying PIPs, the
pesticidal substance can only be present at levels that are not
injurious or deleterious to human health.
b. Residential, Non-Occupational Exposure
Residues of qualifying PIPs based on sexually compatible plants
created through biotechnology may be present in plants grown
residentially for consumption. Consequently, EPA examined the potential
for non-occupational exposures to these substances in the sections for
dermal and inhalation exposure in sections of Unit V.B.5.d. and e.
c. Dietary Exposure From Drinking Water
Dietary exposure through drinking water is considered unlikely. The
substances in plants or parts of plants, including residues of PIPs
based on sexually compatible plants created through biotechnology, are
produced and used inside the living plant itself. As such, the residues
are part of the tissue of the plant. When the plant dies or a part is
removed from the living plant, microorganisms colonizing the tissue
immediately begin to degrade it, using the components of the tissue,
including any residues that are the subject of this proposed exemption,
as building blocks for making their own cellular components or for
fueling their own metabolisms. The residues that EPA is proposing to
exempt in this action are subject to the same processes of
biodegradation and decay that all biotic materials undergo. This
turnover of biotic materials in nature through a process of
biodegradation is expected to occur in rapid fashion and is likely to
preclude these residues from persisting in the environment long enough
to reach the drinking water supply (Ref. 40). There is no indication
that plant biotic materials, including the residues
[[Page 64331]]
that are the subject of this proposed exemption, are resistant to
biodegradation. Even if residues were to reach surface waters, through
pollen dispersal or parts of the plants (leaves, fruits etc.) falling
directly into bodies of water, they are still subject to microbial
degradation and are unlikely to present anything other than a
negligible exposure in drinking water drawn either from surface water
or ground water sources. Importantly, PIPs based on sexually compatible
plants created through biotechnology represent a subset of substances
already present in related plants. Therefore, should these residues be
present in drinking water, they are not expected to meaningfully alter
the already existing pattern of exposure to these residues and thus EPA
expects risk to be negligible.
d. Dermal Exposure
Although a potential for dermal exposure may exist, EPA expects
such exposure to be negligible because PIPs based on sexually
compatible plants created through biotechnology are present in the
plant tissue (Ref. 60). In some cases, residues of PIPs based on
sexually compatible plants created through biotechnology may be present
in sap or other exudates from the plant and thus may present some
limited opportunity for dermal exposure to persons coming physically
into contact with the plant or raw agricultural food from the plant,
e.g., during food preparation (see also Unit VI.A.3.e.). Although
contact dermatitis can occur from such exposure (Ref. 60, 86), these
reactions are generally mild, of a self-limiting nature, or self-
diagnosed and treated. For those substances that possess to some degree
properties that might allow some penetration of the skin, the potential
amount passing through the outer epidermal layer of the skin
(epidermis) is likely to be low (Ref. 60).
Furthermore, most of the substances that could be the subject of
this proposed exemption are unlikely to pass through the skin to affect
other organ systems or elicit allergic sensitization (Ref. 60, 61, 86,
87). Importantly, those substances that do possess properties that
allow some penetration of the skin represent a subset of substances
already present in related plants and would therefore not be expected
to alter the already existing exposures to plant proteins or other
plant substances through handling of the plant containing these
substances. Therefore, EPA does not expect novel hazards or exposures
from residues of the substances involved and thus these PIPs are
expected to represent a low potential of quantitatively different
dermal exposures; therefore, risks from dermal exposures are expected
to be low.
e. Inhalation Exposure
Although a potential for inhalation exposure may exist, EPA expects
such exposure also to be negligible because PIPs based on sexually
compatible plants created through biotechnology are contained within
plant cells, which essentially eliminates this exposure route, or
reduces this exposure route to negligible levels (Ref. 60). However,
residues of PIPs based on sexually compatible plants created through
biotechnology may in some cases be present in pollen and other
agricultural dust and some individuals, e.g., those living or working
in close enough proximity to farms, nurseries or other plant-growing
areas, may be exposed to wind-blown pollen, or through visiting such
areas may be exposed, through inhalation, to the pollen. The most
likely impact of pollen exposure is rhinitis, or inflammation of the
mucous membranes lining the nose, resulting in symptoms like nasal
congestion, sneezing, itching, post-nasal drainage, and runny nose.
On a per person basis, the potential amounts of pollen involved in
these exposures are likely to be low and residues of the pesticidal
substance will not in every case be present in the pollen. Importantly,
pollen characteristics (e.g., wind versus insect dispersal, amount
produced) are often maintained within plant families and, therefore,
residues of PIPs based on sexually compatible plants created through
biotechnology, which are found among sexually compatible plants, should
not alter already established characteristics of any particular plant
species. This proposed exemption will not change current exposures, nor
affect strategies for dealing with reactions to PIPs based on sexually
compatible plants created through biotechnology that may be aero-
allergens or irritants (Ref. 60). Thus, EPA concludes that risk from
inhalation exposure to residues of PIPs based on sexually compatible
plants created through biotechnology is low.
6. Other Considerations
Other considerations for EPA's safety finding under the FFDCA
include the sensitivities of population subgroups, endocrine effects,
and special consideration for risks to infants and children.
a. Sensitivities of Subgroups
EPA considered available information on the sensitivities of
subgroups as it pertains to residues of qualifying PIPs based on
sexually compatible plants created through biotechnology. In performing
its assessment, the Agency considered that the diet includes all of the
food items that are customarily eaten by human populations or
population subgroups. As discussed in this preamble, this proposed
exemption will not affect the current pattern of exposure to residues
that are the subject of this proposed exemption because the substances
at issue are equivalent to substances present in sexually compatible
plants and are limited in their level of expression to those observed
in sexually compatible plants. Relatedly, the expression pattern of
these substances (timing and location of the expression) are limited to
those found in sexually compatible plants through the proposed
criteria. Individuals recognize and are familiar with the plant-derived
food they consume, (e.g., based on prior experience of consumption) and
would avoid consuming foods containing substances they know they are
sensitive to (Ref. 37, 88, 89). Because the exposure pattern to these
foods will not be affected by this proposed exemption, the efficacy of
the current strategy whereby sensitive individuals or subgroups of
sensitive individuals recognize and avoid certain foods would not
similarly not be affected (Ref. 88, 89). Thus, the Agency does not
expect any subgroup to be adversely affected by the proposed exemption.
b. Estrogenic or Other Endocrine Effects
Certain food plants, e.g., soybeans, contain estrogen mimics,
termed phytoestrogens. Such phytoestrogens are currently being consumed
by humans in food derived from plants and are part of the extensive
history of safe human consumption of food from plants. Although the
Agency considers use of these phytoestrogens as PIPs to be unlikely,
EPA cannot rule out the possibility that such phytoestrogens could be
developed as PIPs based on sexually compatible plants created through
biotechnology. Based on available information concerning levels of
phytoestrogens that must be consumed before effects can be seen (Ref.
90), the natural limitations of gene expression (Unit VI.A.3.c.), and
the limitations the Agency is proposing on the levels and expression
pattern of these substances at 40 CFR 174.541(b), EPA expects that this
exemption, as proposed, will not result in levels of phytoestrogens in
foods that would be quantitatively different from those currently being
safely consumed.
[[Page 64332]]
c. Infants and Children
FFDCA section 408(b)(2)(C) provides that EPA shall assess the risk
of pesticide residues based on available information about infants' and
childrens' consumption patterns, special susceptibility to pesticide
chemical residues, and the cumulative effects. EPA's evaluation of
these factors is presented in the following units (Unit VI.B.6.c.i.
through iii.).
In addition, this section of the FFDCA requires that, in the
context of threshold effects, EPA apply an additional tenfold margin of
safety to take into account potential pre- and postnatal toxicity and
completeness of the toxicity and exposure databases with respect to
infants and children. This safety factor is most relevant when the
Agency conducts a quantitative risk assessment upon identifying
threshold effects of concern and employs various uncertainty factors,
including this safety factor, to ensure an appropriate margin of safety
in its risk analysis. For residues of PIPs based on sexually compatible
plants created through biotechnology, EPA has concluded that
consumption of food containing residues of PIPs based on sexually
compatible plants created through biotechnology is safe for infants and
children, and that a margin of safety need not be proposed for these
residues in food. EPA based its assessment of exposure and toxicity
upon the information base described in this preamble in Unit VI.B.1.
i. Dietary Consumption Patterns
EPA considered available information on the dietary consumption
pattern of infants and children as it pertains to residues of PIPs
based on sexually compatible plants created through biotechnology. The
range of foods consumed by infants and children is in general more
limited than the range of foods consumed by adults. Most newborns rely
on milk products for nutrition, although some infants are fed with soy-
based products. Soy-based products may contain residues that are the
subject of this proposed exemption. Infants begin as early as 4 months
of age to consume specific types of solid foods, including foods from
plants that may contain residues that are the subject of this proposed
exemption. Later on, apart from processing to facilitate swallowing,
the diets of toddlers begin to be based on foods consumed by the
general adult population albeit in different proportions. As infants
and children mature, more and more of the foods consumed by adults
become part of their diets and the relative proportions of the
different types of food consumed change to more closely resemble an
adult diet.
Foods that may contain residues that are the subject of this
proposed exemption are part of a normal diet. They have been consumed
by infants and children over long periods of time. The likelihood that
exposure as part of a normal diet to these substances could lead to
harm to infants and children is low. As the diets of humans change from
infancy through childhood and into adulthood, there is some possibility
that the amount of foods that contain residues that are the subject of
this proposed exemption being consumed may change, with those consuming
the greatest amounts of plant-based foods being the most exposed to
substances that may be subject of this proposed exemption. There is no
evidence, however, that such changes are likely to result in
disproportionately high consumption of these residues in comparison to
the general population. Thus, there is no evidence that any exposures
would be different from those currently in existence. The evidence
suggests that consumption of foods containing residues from PIPs based
on sexually compatible plants created through biotechnology, including
changes in exposure (i.e., relative proportions of the different types
of food consumed from infancy through childhood and into adulthood) is
highly unlikely to lead to any harm (Units VI.B.1. through 5.).
ii. Special Susceptibility
EPA considered available information on the potential for special
susceptibility of infants and children, including prenatal and
postnatal toxicity, to residues of qualifying PIPs based on sexually
compatible plants created through biotechnology. The substances that
are the subject of this proposed exemption occur in the normal diet,
and there is no evidence that exposure to such residues, as components
of food, present a different level of dietary risk for infants and
children.
iii. Cumulative Effects of Residues With Other Substances With a Common
Mechanism of Toxicity
EPA examined the available information on the cumulative effect of
residues of PIPs based on sexually compatible plants created through
biotechnology, as well as other substances in food that may have a
common mechanism of toxicity with these residues, and considered
effects on infants and children (Unit VI.B.4.). Food from sexually
compatible crop plants is being safely consumed by humans, including
infants and children, either directly or indirectly in products such as
meat and milk that are derived from animals that consume forage and
other crops, e.g., corn and other grains. Considering the history of
safe consumption and the information base described in Unit VI.B.4.,
EPA has not found that substances in food from plants share common
mechanisms of toxicity with other substances.
d. Safety Conclusion
Based on the information discussed in this preamble and in the
associated record, EPA preliminarily concludes that when the proposed
conditions are met, there is reasonable certainty that no harm will
result from aggregate exposure to residues of PIPs based on sexually
compatible plants created through biotechnology, including all
anticipated dietary exposures to humans for which there is reliable
information. This preliminary finding is based on the Agency's
determination that the proposed exemption criteria would only exempt
PIPs that share relevant characteristics with PIPs already found in
sexually compatible plants, thereby ensuring that residues of these
PIPs do not pose different risks to humans. Specifically, the proposed
exemption only applies to substances already found in plants that are
sexually compatible with the recipient food plant, that are present in
tissues and developmental stages identified in those plants, and whose
expression does not exceed levels that are found within those plants.
Moreover, as an additional measure of safety, the exemption
specifically excludes those residues of PIPs from the exemption that
are present in the recipient food plant at levels that are injurious or
deleterious to human health. The safety determination for PIPs based on
sexually compatible plants created through biotechnology is based on a
large body of knowledge about the history of safe use from foods
containing residues of PIPs that are present in plants and EPA's
assessment of scientific literature that describes constituents of food
from plants in sexually compatible populations. To develop the proposed
exemption criteria for PIPs based on sexually compatible plants created
through biotechnology, and to circumscribe the types of genetic
modifications in the recipient plant that are unlikely to result in
novel exposure to humans, dietary or otherwise, EPA relied on
recommendations from several FIFRA SAP reports and considered
information from the public literature to understand the ability of
newer biotechnology techniques to create traits
[[Page 64333]]
equivalent to those found in sexually compatible plants.
e. Analytical Enforcement Methodology
Before issuing an exemption from the requirement of a tolerance,
the FFDCA requires an analytical method for detecting and measuring the
levels of the pesticide chemical residue at issue in food, unless the
Administrator determines that there is no need for such a method and
explains the reasons for that determination in the rulemaking
establishing the exemption (21 U.S.C. 346a(c)(3)). In the case of a
reversal of an exemption decision, established analytical methods could
be critical to enable detection of the affected crop, e.g., should a
recall of foods be necessary. To meet the proposed exemption criteria
at 40 CFR 174.21(d), a developer is likely to already be in possession
of the analytical methods that can be used for the detection of either
the genetic material or the gene product associated with the PIP. For
example, to provide the nucleic acid sequence information of the PIP as
part of the exemption eligibility process, developers may use several
oligonucleotide primers for gene sequencing. These primers can
similarly be used for the specific detection of the PIP in the food
plant using standard PCR methods. Conversely, in those instances in
which primers are not already available, the information provided on
the nucleic acid sequence of the PIP is expected to be sufficient to
promptly design oligonucleotide primers de novo. Therefore, EPA does
not find it necessary to require submission of analytical methods for
the detection in plants of PIPs based on sexually compatible plants
created through biotechnology.
C. What are the proposed exemption eligibility determination procedures
and requirements of 40 CFR part 174, subpart E?
EPA proposes to use currently reserved Subpart E of 40 CFR part 174
for a proposed exemption eligibility determination process related to
the proposed exemptions. Within that subpart, EPA proposes adding four
sections: One to describe the process for determining eligibility for
an exemption, one to describe the general submission process for a
self-determination letter, one to describe the general submission
process for EPA confirmation, and one to describe the information
requirements specific to PIPs based on sexually compatible plants
created through biotechnology. These additions are necessary because
EPA is proposing to make the exemption of PIPs based on sexually
compatible plants created through biotechnology contingent upon
notifying EPA prior to a PIP being brought to market through a self-
determination letter and/or by seeking EPA confirmation that a PIP
meets the exemption criteria (options described in Unit VI.C.1.).
The proposed exemption eligibility determination process will allow
the Agency to maintain a record of the PIPs that meet the criteria for
exemption. This record will aid in inspections conducted by the Agency
to ensure compliance and to confirm that PIPs in the food supply do
indeed meet the standard of safety as defined by the exemption
criteria. Also, if it were determined based on new information that a
PIP was not eligible for exemption, such a record would help inform EPA
and the FDA of the most appropriate steps to protect public health
(including enforcement). As described in Unit VI.A.4., with the
proposed exemption eligibility determination process, exempting PIPs
based on sexually compatible plants created through biotechnology has
an estimated incremental cost saving of about $444,000-$459,000 per
product, compared to traditional registration, due to reductions in
PRIA fees and data generation.
1. Proposed Section for Determining the Eligibility of a PIP To Qualify
for Exemption
The Agency is proposing a new provision in Subpart E, 40 CFR
174.90, entitled ``Determining eligibility for exemption.'' This
provision states that developers have two, non-mutually exclusive
options to notify EPA that their PIP meets the exemption criteria: (1)
Submit a self-determination letter that a PIP meets the exemption
criteria, and (2) seek EPA confirmation that a PIP meets the exemption
criteria. EPA confirmation can be sought instead of, in conjunction
with, or subsequent to the submission of the self-determination letter.
EPA believes that such a confirmation holds multiple potential
benefits, including reduced barriers to international trade, increased
public confidence in product safety, and affirmation for the developer
that it has correctly determined that the PIP meets the criteria for
exemption.
The provision further explains the relationship between the EPA
confirmation processes and a letter of self-determination.
Specifically, if a developer chooses to request EPA confirmation in
accordance with 40 CFR 174.93 in conjunction with or subsequent to
submitting a self-determination letter in accordance with 40 CFR
174.91, the exemption is effective from the time at which the company
receives confirmation of submission of the self-determination letter.
The exemption remains effective if EPA affirms the developer's
determination that the PIP meets the exemption criteria and the self-
determination is superseded by EPA's written confirmation in response
to the confirmation request. However, if at any time after submission
of the self-determination, EPA determines that the PIP was not eligible
for exemption under this proposed rule, the exemption will not have
applied, and EPA may take enforcement against that product to ensure
compliance with FIFRA. Similarly, FDA may take enforcement action if an
incorrect self-determination was made by a developer of a PIP in a
plant used for food or feed. As indicated in Unit VI.C.2., the
developer is responsible for ensuring the accuracy of its self-
determination.
Alternatively, in instances in which no prior self-determination
has been provided to the Agency in accordance with 40 CFR 174.91 and
the developer submits a request for confirmation to the Agency, the
exemption applies only once EPA provides written notice to the
developer confirming that the PIP meets the criteria for exemption. EPA
reserves the right to assess or revisit at any time whether a PIP
meets, or has met, the criteria for exemption regardless of whether the
developer requests EPA confirmation. In particular, as exempt PIPs are
still subject to 40 CFR 174.71, upon learning of any adverse effects
(e.g., injurious or deleterious levels in food), EPA has the authority
to evaluate whether the PIP still meets the criteria for exemption. As
described in the preamble of the July 19, 2001 Federal Register notice
implementing 40 CFR 174.71 (66 FR 37772; July 19, 2001), reports
involving food or feed (i.e., those subject to enforcement under FFDCA)
would be made to EPA, but EPA will share such reports with FDA. EPA and
FDA will individually determine whether any action, including the
possibility of enforcement, is necessary to protect the public health
or the environment, and if so, what constitutes appropriate action
based on their respective statutes (EPA--FIFRA, FDA--FFDCA). Therefore,
40 CFR 174.71 is a means of ensuring that EPA and FDA can address any
potential hazard identified subsequent to self-determination or EPA
confirmation that a PIP meets the requirements for exemption.
The provision also outlines instances in which an exemption
determination
[[Page 64334]]
can be extended to subsequent variations of the PIP. For a PIP based on
a sexually compatible plant created through biotechnology, EPA is
proposing that a determination that the PIP meets the exemption
criteria would be required for each modified gene and plant species
combination, made either by the developer through a self-determination
letter or by EPA through a confirmation request. However, EPA is aware
that a plant species can comprise multiple varieties and does not
intend for the PIP in each variety to require its own submission if a
developer creates the same modification in different varieties. In this
case, that developer would need to notify EPA only for the first
modification in that species. The specific circumstances when an
exemption determination is not required when modifying additional
varieties of a plant species differ slightly depending on whether the
developer is creating the same substance with the modification (e.g.,
native allele) or whether the developer is creating the same phenotype
via a novel mutation. If the developer is creating the same substance
with the modification (e.g., native allele) in other varieties, then
subsequent notifications are not required so long as no additional
modifications were made to the regulatory region. If the developer is
creating the same phenotype by modifying the regulatory region via a
novel mutation in other varieties, then subsequent notifications are
not required. For example, if a developer modifies an existing gene in
a tomato variety to create a native allele, this would require a
determination; however, if the developer subsequently creates the same
native allele in another tomato variety, the developer would not be
required to submit a second determination request for the additional
variety. Similarly, if a developer creates a differentially expressed
gene, subsequent modifications in other varieties would not require a
determination if the developer targets the same nucleic acid sequence
(e.g., uses a guide RNA to target the same location in a gene in a
CRISPR/Cas system) to create a mutation via double stranded DNA break
repaired by non-homologous end joining. Finally, separate submission of
a self-determination or request for EPA confirmation for purposes of
the FFDCA exemption for a PIP proposed for use in food or feed is
required only if it has not already been submitted under FIFRA. This is
because the exemption eligibility determination process already
requires the applicant to certify that the PIP meets the general
qualifications for exemption, which includes exemption under the FFDCA
for PIPs used in food or feed. We envision at least one scenario in
which a developer may need to submit a self-determination or request
for EPA confirmation for the purposes of FFDCA but not FIFRA. That
scenario arises when residues of a PIP will be in or on food imported
into the United States, but the PIP is not intended to be sold or
distributed for pesticidal use (e.g., PIP containing seed or plant sold
for planting) in the United States (and thus is not subject to FIFRA
regulation).
2. Proposed Process for a Letter of Self-Determination for a PIP To
Qualify for Exemption
The Agency is proposing a new provision in Subpart E, 40 CFR
174.91, entitled ``Submitting a letter of self-determination for
exemption.'' The proposed provision describes the requirements and
process of notifying EPA that the developer has determined (or ``self-
determined'') that a PIP qualifies for exemption.
Self-determination letters may be submitted electronically
(guidance for electronic submission can be found in Pesticide
Registration Notice 2011-3 or any subsequent revision or replacement)
or by paper submission. Proposed 40 CFR 174.91 includes information on
how to format the letter and the required contents of the letter,
including a statement certifying the developer's determination of
exemption eligibility. If a developer does not have an EPA company
number they will be required to obtain a company number prior to
submission of a self-determination letter. EPA intends that self-
determination letters will not be submitted under FIFRA section 33
(Pesticide Registration Improvement Extension Act of 2018 (PRIA)) and
will not be subject to application fees.
In addition, this provision explains that a developer must submit
its letter of self-determination prior to engaging in activities
subject to FIFRA for the proposed PIP (e.g., distribution and sale of
the PIP at issue), and the exemption does not apply until EPA confirms
receipt of the self-determination. EPA notes that the developer is
responsible at all times for ensuring its self-determination is
accurate and if at any time EPA determines that a self-determination
was wrongly made, or is no longer accurate due to the availability of
new information that was not available at the time the self-
determination was made, EPA and the FDA can take action to protect
public health or the environment. This includes the possibility of
enforcement under FIFRA or FFDCA. For electronically submitted letters,
this receipt confirmation occurs automatically upon submission and is
considered equivalent to written confirmation of receipt. EPA will
provide written confirmation of receipt within 30 days of receiving a
self-determination letter via mail. EPA will notify FDA when it
receives a letter of self-determination.
3. Proposed EPA Confirmation Submission Process for a PIP To Qualify
for Exemption
The Agency is proposing a new provision in Subpart E, 40 CFR
174.93, entitled ``Obtaining EPA confirmation of eligibility for the
exemption.'' This provision describes the process through which a
developer may seek confirmation from EPA whether a PIP meets the
criteria for exemption codified in 40 CFR 174.21. A developer must
submit information as outlined in 40 CFR 174.91 along with specific
supporting documentation. For example, the information required to
support the request for a PIP based on a sexually compatible plant
created through biotechnology is described in proposed 40 CFR 174.95
and discussed in Unit VI.C.3. The provision also specifies that any
claims of confidentiality for information submitted in the request for
EPA confirmation must be made in accordance with the procedures
outlined in 40 CFR 174.9.
In addition, the provision at 40 CFR 174.93 explains that upon
receipt of the request, EPA will review the submission and determine
whether the PIP meets all necessary criteria to be exempt under 40 CFR
174.21. The Agency proposes to notify the submitter in writing of its
determination. The exemption goes into effect only once the developer
receives EPA's confirmation in writing, unless a self-determination
letter was previously submitted. Once a decision has been made that a
PIP meets the criteria for exemption, this decision applies to all
requirements under FIFRA, except for the adverse effects reporting
under 40 CFR 174.71. As described in Unit VI.C.1., exempt PIPs are
still subject to 40 CFR 174.71 and EPA reserves the right to reassess
whether a PIP meets the criteria for exemption should the Agency learn
of relevant information subsequent to confirming its eligibility to be
exempt under 40 CFR 174.21. EPA intends for requests for EPA
confirmation to be submitted using the current submission category
(M009) and associated fee structure for a Non-FIFRA Regulated
Determination under FIFRA section 33 (PRIA). Currently, under the Non-
FIFRA Regulated Determination
[[Page 64335]]
category, the statutory time for EPA to review and make a determination
is 120 days. The logistics of the submission for a request and EPA
review times may change in the future if PRIA changes or a different
structure for submissions is adopted.
4. Proposed Documentation for an Exemption for PIPs Based on Sexually
Compatible Plants Created Through Biotechnology
The Agency is proposing a new provision in Subpart E, 40 CFR
174.95, entitled ``Documentation for an exemption for a plant-
incorporated protectant based on a sexually compatible plant created
through biotechnology.'' This proposed provision describes the specific
information that must be documented for any PIPs based on sexually
compatible plants created through biotechnology for which a developer
is claiming an exemption. This provision serves two purposes. First,
the provision describes the information that must be submitted to EPA,
pursuant to 40 CFR 174.93, for confirmation that a PIP meets the
exemption criteria. Second, the provision describes the information
that any developer must maintain for 5 years pursuant to the
recordkeeping requirements set forth in 40 CFR 174.73.
For PIPs based on sexually compatible plants created through
biotechnology, the Agency is proposing that the information documented
for recordkeeping and submitted during a request for EPA confirmation
contain three main information elements: (1) Information on the biology
of the plant; (2) a description of the pesticidal trait and how it was
engineered; and (3) information on the molecular characterization of
the PIP. The proposed information elements are necessary to ensure that
the PIP based on a sexually compatible plant created through
biotechnology meets the FIFRA and FFDCA proposed exemption criteria.
Specifically, information that EPA proposes will be needed for each
element is as follows.
The first proposed element, information on the biology of the
plant, will include: The identity of the recipient plant, including
genus and species; and if the PIP was derived from another plant
species, the identity of the source plant, including genus and species,
and information to demonstrate the recipient plant and the source plant
are sexually compatible. EPA anticipates that information fulfilling
the first element will typically be a narrative description to show
that the PIP is found in plants that are sexually compatible with the
recipient plant.
The proposed second element, description of the pesticidal trait
and how it was engineered into the plant, will include a narrative
description of the intended pesticidal function resulting from the
modification of the plant and the technique used to make the
modification (e.g., was the Cas enzyme stably integrated during
development and if so was it segregated out of the final product). This
information ensures that no unapproved ingredients remain in the final
product. In products where the recipient plant is a food plant in which
the levels of the pesticidal substance are commonly screened for in
conventional breeding to ensure safe levels, the second element
requires that the developer describe how conventional breeding
practices have been and will be performed on the product proposed for
exemption. This criterion can be fulfilled with a confirmation that the
developer has screened its product for acceptable levels of the
pesticidal substance (e.g., generally accepted safe content for
solanine is 20-25 mg/100g of fresh potato weight). This criterion
ensures that levels of the pesticidal substance are not present in the
recipient food plant, as the plant is grown and harvested under normal
conditions of use, at levels that are injurious or deleterious to human
health as stated in the FFDCA proposed exemption criteria.
The proposed third element, molecular characterization of the PIP,
includes two components. First, EPA is proposing to require the
nucleotide sequence and the amino acid sequence of the PIP in the
recipient plant, including a sequence comparison between the recipient
plant and the relevant comparator (i.e., the source plant if a source
plant was used or the unmodified plant if no source plant was used).
For a plant-incorporated protectant where the regulatory region has not
been modified, the sequence information will confirm that this is true.
For PIPs where the regulatory region of an existing or inserted native
gene has been modified, the second component is EPA's proposal to
require confirmation that the expression profile (i.e., tissues,
developmental stages, and levels of expression) of the PIP is not
outside that observed in plants that are sexually compatible with the
recipient plant. In this circumstance, the developer must show that the
highest level of expression of the PIP obtained under normal
environmental conditions across the lifespan of the plant does not
exceed the upper limit observed in a plant that is sexually compatible
with the recipient plant. EPA envisions that a developer can meet this
requirement through either rationale or data confirmation: A developer
can document a rationale regarding the expected phenotype given the
type of modification made (e.g., is the modification meant to optimize
an allele and therefore may result in a slight increase in expression
but no change in expression pattern or has something more significant
been done that could lead to altered expression patterns), or the
developer can provide expression data examining the tissue/life stage
in which expression is expected to be highest to corroborate its
expectation. The extent of expression data required is expected to be
directly correlated to the likelihood that the modification could lead
to a novel expression profile. Information described under elements one
through three will inform whether the PIP meets criteria (a) and (b) of
proposed FIFRA exemption and criteria (a) and (b) of proposed exemption
from the requirement of a tolerance.
D. What are the proposed recordkeeping requirements?
EPA proposes to add a new provision in Subpart D, 40 CFR 174.73,
entitled ``General recordkeeping requirements for exemptions.'' This
section describes the documentation and recordkeeping that must be done
for exempted PIPs listed under 40 CFR 174.21(d). Specifically, in order
for a PIP listed under 40 CFR 174.21(d) to be eligible for exemption, a
developer must submit to EPA either a self-determination letter or a
request for EPA confirmation that the PIP is eligible for exemption
prior to engaging in FIFRA regulated activities. Accordingly, proposed
40 CFR 174.73 mandates that the developer maintain documentation of
such a submission along with supporting information. Supporting
information would include the information listed in the exemption
specific section of subpart E. This documentation would need to be
maintained for five years starting from the effective date of the
exemption. Finally, proposed 40 CFR 174.73 states that this information
must be made available to EPA upon request. This request may occur as
part of routine enforcement activities (e.g., auditing, inspections)
conducted by EPA to ensure compliance with EPA regulations or
subsequent to EPA receiving an adverse effects report.
E. What is the proposed clarification to general qualifications for
exemptions?
In 2001, EPA developed ``General Qualifications for Exemptions'' at
40 CFR 174.21, which describes criteria that are required for any PIP
to be
[[Page 64336]]
exempt from the requirements of FIFRA, with the exception of the
adverse effects reporting requirement at 40 CFR 174.71. These criteria
were developed at the same time as the FIFRA and FFDCA exemptions for
PIPs derived through conventional breeding and thus were drafted with
reference to those specific sections. The Agency is proposing edits to
40 CFR 174.21 to clarify the applicability of this framework to other
PIP exemptions, including the language in the proposal.
For paragraph (a), this revision simply clarifies that this
paragraph is specific to the pesticidal substance of the PIP. This
update is necessary to avoid confusion over the current dual use of the
word ``plant-incorporated protectant'' in 40 CFR 174.21 to refer to
both the pesticidal substance and the PIP as a whole, per the
definition in 40 CFR 174.3. For paragraph (b), the current reference to
sections 40 CFR 174.507 through 174.508 only allows for a PIP to be
exempt if the residues of the PIP are nucleic acids or come from a
sexually compatible plant. This restriction was established when the
only exempt PIPs were from sexually compatible plants. EPA is proposing
to revise paragraph (b) to refer to subpart W, rather than the specific
sections. For paragraph (c), the current reference to 40 CFR 174.705
only allows for a PIP to be exempt if the inert ingredients are from
sexually compatible plants. Again, this restriction was established
when the only exempt PIPs were from sexually compatible plants.
Although EPA is not proposing an inert ingredient exemption specific to
this proposal, EPA believes it is important to add flexibility to the
regulatory text to allow PIPs to be exempt based on other inert
ingredient exemptions that EPA may establish in subpart X in the
future. Thus, EPA is proposing to revise paragraph (c) to refer to
subpart X, rather than the specific section of 40 CFR 174.705. Finally,
EPA proposes to add a new paragraph (d) to section 40 CFR 174.21 to
account for the proposed exemption eligibility determination process
(Unit VI.C.) and proposed recordkeeping requirements (Unit VI.D.). This
paragraph specifies that for PIPs listed in the subsequent subparagraph
(i.e., subparagraph (d)(i)), compliance with recordkeeping and
providing an exemption eligibility determination to EPA is a
requirement of the exemption. The addition of paragraph (d) does not
impact the current exemption under section 40 CFR 174.25 for PIPs from
sexually compatible plants, because PIPs from sexually compatible
plants (or the proposed amended title, PIPs from sexually compatible
plants through conventional breeding) are not identified in paragraph
(d).
F. What is the clarification of exemptions for sexually compatible
PIPs?
In 2001, EPA exempted one category of PIPs from all FIFRA
requirements, with the exception of the adverse effects reporting
requirement at 40 CFR 174.71. PIPs derived through conventional
breeding from plants sexually compatible with the recipient plant were
exempted from FIFRA, and a companion FFDCA exemption from the section
408 requirement of a tolerance for residues of this category of PIPs
was also issued. Conventional breeding is defined at 40 CFR 174.3 as
``the creation of progeny through either: the union of gametes, i.e.,
syngamy, brought together through processes such as pollination,
including bridging crosses between plants and wide crosses, or
vegetative reproduction. It does not include use of any of the
following technologies: Recombinant DNA; other techniques wherein the
genetic material is extracted from an organism and introduced into the
genome of the recipient plant through, for example, micro-injection,
macro-injection, micro-encapsulation; or cell fusion.''
The Agency is proposing to clarify the relationship between the
proposal on PIPs based on sexually compatible plants created through
biotechnology and the exemptions currently at 40 CFR 174.25, ``Plant-
incorporated protectant from sexually compatible plant,'' and 40 CFR
174.508 ``Pesticidal substance from sexually compatible plant;
exemption from the requirement of a tolerance.'' To this end, EPA would
insert ``created through conventional breeding'' immediately after the
subject of the exemption (e.g., ``pesticidal substance'') in each
section title, and insert an additional criterion into 40 CFR 174.25
and 174.508 as follows:
``(c) The genetic material is transferred from the source plant to
the recipient plant only through conventional breeding.''
This clarification would explicitly state in the title and criteria
at 40 CFR 174.25 and 174.508 the condition underlying the rationale for
exemption offered in the preamble of the July 19, 2001 Federal Register
notice implementing these paragraphs (66 FR 37772; July 19, 2001).
Although 40 CFR 174.25 has always meant ``only through conventional
breeding,'' this is a necessary clarification now given that the
proposed amended definition for ``sexually compatible'' states that ``a
viable zygote can be formed through the union of two gametes through
conventional breeding,'' which would modify the existing definition
that states that ``a viable progeny is formed only through the union of
two gametes through conventional breeding.'' The clarification would
also explicitly indicate how proposed sections 40 CFR 174.26 and
174.541 on PIPs based on sexually compatible plants created through
biotechnology relate to the existing exemptions for PIPs created
through conventional breeding from sexually compatible plants at 40 CFR
174.25 and 174.508. The Agency is not proposing similar modifications
at 40 CFR 174.705, and instead proposes to expand the scope of that
exemption to include both conventional breeding and biotechnology, as
described in Unit VI.G.
G. What is the proposed expansion of the inert ingredient exemption at
40 CFR 174.705 to include intermediary substances initiated through
biotechnology?
1. Description of the expansion. EPA is proposing to expand the
scope of the existing inert ingredient exemption at 40 CFR 174.705 to
include inert ingredients that are intermediary substances initiated
through biotechnology so long as they still meet the existing criteria.
In the 2001 preamble promulgating 40 CFR 174, EPA stated ``with regard
to the enzymes, precursors, or intermediates in biosynthetic pathways
necessary for anabolizing the pesticidal substance, EPA at this time
considers them to be part of the plant-incorporated protectant because
the substance is intended to ``ensure the presence of the active
ingredient''--i.e., it is an inert ingredient.'' Although the
biochemical pathway may be initiated by a modification created through
biotechnology, EPA believes the plant-produced intermediaries leading
to the ultimate production of the pesticidal substance meet the
scientific rationale of the existing inert ingredient exemption at 40
CFR 174.705. This is because EPA's proposed exemption at 40 CFR 174.26
provides developer flexibility by allowing changes to the nucleic acid
sequence of the PIP as long as those modifications still result in the
same pesticidal substances exempt under 40 CFR 174.25, thereby
maintaining the integrity of such biochemical pathways described in the
2001 preamble. Therefore, although the technique used to initiate such
a biochemical pathway may be different, the intermediary substances
themselves remain the same.
[[Page 64337]]
2. Risk analysis. EPA believes the risk analysis at Unit VI.A.3.
supporting the proposal for exemption from FIFRA requirements and the
risk analysis at Unit VI.B. supporting the FFDCA section 408 proposal
for exemption from the requirement of a tolerance also supports the
exemption from FIFRA and the FFDCA for inerts that meet the criteria
under the proposed expansion of 40 CFR 174.705, because these
substances would be endogenous to plants in sexually compatible
populations and thus would not present novel exposures should inert
ingredient intermediaries be initiated through a modification using
biotechnology.
VII. Request for Comment
EPA is seeking public comment on all aspects of this proposed rule,
including comments on the specific points discussed in this unit and
the specific points raised in Units V. and VI. of this proposal.
A. What inert ingredients could be present in PIPs based on sexually
compatible plants created through biotechnology?
An ``inert ingredient'' is defined in 40 CFR 174.3 to mean ``any
substance, such as a selectable marker, other than the active
ingredient, where the substance is used to confirm or ensure the
presence of the active ingredient, and includes the genetic material
necessary for the production of the substance, provided that genetic
material is intentionally introduced into a living plant in addition to
the active ingredient.'' Additionally, in 2001 EPA stated that ``with
regard to the enzymes, precursors, or intermediates in biosynthetic
pathways necessary for anabolizing the pesticidal substance, EPA at
this time considers them to be part of the plant-incorporated
protectant because the substance is intended to ``ensure the presence
of the active ingredient''--i.e., it is an inert ingredient.'' As
stated in Unit VI.G., the Agency is expanding the current inert
ingredient exemption at 40 CFR 174.705 to be inclusive of both
conventional breeding and biotechnology in order to account for
potential intermediary substances as described in the 2001 quote that
would ultimately lead to the production of the pesticidal substance.
However, outside of these intermediary substances, the Agency does
not anticipate other types of inert ingredients (e.g., herbicide
tolerance) in PIPs based on sexually compatible plants created through
biotechnology. Previous biotechnology approaches that relied on DNA
constructs were constructed with the genetic material encoding for both
the active and the inert ingredient. These DNA constructs ensured that
the inert ingredient could be used to confirm the plants or cells that
successfully integrated the genetic material encoding for the active
ingredient. However, to create PIPs based on sexually compatible plants
created through biotechnology, modifications coding for non-pesticidal
traits in transgenic PIPs (e.g., herbicide resistance) would instead be
incorporated into the recipient plant genome independent of the active
ingredient. Because these events occur independently the modification
cannot confirm or ensure the presence of the active ingredient. The
modification therefore would not meet the definition of an inert
ingredient under 40 CFR 174.3 because it is an independent, non-
pesticidal trait not regulated under FIFRA. EPA expects that any
ingredients intentionally added during the development of PIPs based on
sexually compatible plants created through biotechnology that are
specific to the production of the active ingredient (e.g., guide RNA,
DNA nuclease) and that could function as an inert ingredient would
either be transiently transformed or would be removed (e.g., through
segregation of the trait) during the breeding process and that if these
ingredients have not been removed from the final product the product
would not meet the criteria at proposed under the new 40 CFR 174.26 and
would not qualify for the new exemptions.
The Agency therefore requests comment on whether there are any
inert ingredients other than the intermediary substances described in
the 2001 quote that will remain in the final plant products containing
PIPs based on sexually compatible plants created through biotechnology.
If inert ingredients other than the intermediary substances described
in the 2001 quote are identified in the responses to the previous
request, the Agency also requests comment as to whether the inert
ingredients in PIPs based on sexually compatible plants created through
biotechnology require the proposal of an exemption that would be
specific to those created through biotechnology and would allow
developer flexibility in the nucleic acid sequence. If the Agency
receives comments that indicate inert ingredients other than the
intermediary substances described in the 2001 quote may be present in
the final plant product and/or that developer flexibility in the
nucleic acid sequence of inert ingredients would be beneficial, the
Agency will consider finalizing the proposed rule with exemptions under
FIFRA and FFDCA for inert ingredients derived through biotechnology
from sexually compatible plants. These exemptions would be based on the
proposed exemptions 40 CFR 174.26 and 174.541 in that the use of
biotechnology is permitted and only inert ingredients composed of
genetic material that is derived from sexually compatible plants would
be exempt. The Agency is not currently considering an exemption for
potential inert ingredients that are derived from sources that are not
sexually compatible with the recipient plant (e.g., Cas proteins).
B. What process should EPA use to provide notice that a PIP no longer
meets the criteria for exemption if new information is provided?
EPA is proposing to exempt PIPs based on sexually compatible plants
created through biotechnology from regulation under FIFRA, except for
the adverse reporting effects at 40 CFR 174.71. In the event EPA learns
of information that affects a previous determination that a PIP based
on a sexually compatible plant created through biotechnology meets the
criteria, EPA will reconsider the new information and provide a new
determination in writing whether the PIP continues to meet the criteria
for exemption. EPA requests comment on whether the process outlined is
detailed enough.
C. Should EPA consider other approaches for its confirmation process?
EPA is proposing that the exemption of PIPs based on sexually
compatible plants created through biotechnology include a process
through which developers of PIPs based on sexually compatible plants
created through biotechnology submit either a self-determination letter
or request confirmation that their PIP meets the criteria for
exemption. EPA seeks comment on whether the Agency should consider
different approaches for its proposed exemption eligibility
determination process. For example, one alternative process could be to
require mandatory EPA confirmation so that all developers must submit
information to EPA for EPA confirmation that their PIP meets the
exemption criteria prior to engaging in activities subject to FIFRA.
EPA requests comment on whether or how such a mandatory approach could
be workably implemented, and whether such an approach would be useful
or justified.
[[Page 64338]]
This alternative process would follow the same submission
procedures that are outlined in proposed 40 CFR 174.93, and the
information required to determine the eligibility of exemption would
remain the same as outlined in proposed 40 CFR 174.95. Another
alternative could be a voluntary confirmation process for all PIP
products exempted under the proposed rule similar to that in USDA's
final rule titled ``Movement of Certain Genetically Engineered
Organisms.'' (85 FR 29790; May 18, 2020). Only those developers who
seek EPA's confirmation would be required to submit to the Agency
information and data sufficient to establish that their PIPs are
eligible under the proposed exemptions. Developers who do not seek EPA
confirmation would not be required to submit any documentation to EPA
(and thus this alternative would be different from EPA's proposed
process through which developers submit either a self-determination
letter or request confirmation that their PIP meets the criteria for
exemption). EPA requests comment on whether or how such a voluntary
approach could be workably implemented (e.g., should the recordkeeping
requirements at proposed 40 CFR 174.73 be required for developers who
do not submit for EPA confirmation) and whether such an approach would
be useful or justified?
D. Is EPA's intent behind the use of the terms ``native'' and ``never
derived'' clear?
The Agency is proposing to define ``native gene'' to mean ``a gene
that is identified in the recipient plant or plants that are sexually
compatible with the recipient plant; and has never been derived from a
source that is not sexually compatible with the source plant.'' The
phrase ``has never been derived from a source that is not sexually
compatible with the source plant'' is meant to clarify that a PIP would
not qualify for the proposed exemption if the gene was introduced into
the genome of the source plant through transgenic technology, as those
genes may not be representative of the shared genetic information
between sexually compatible plants. For example, bacterial endotoxin
genes (e.g., from the source Bacillus thuringiensis) are a commonly
engineered pesticidal trait, but EPA does not intend for these genes to
be considered part of the sexually compatible gene pool nor does EPA
intend for these genes to qualify for the proposed exemption. However,
EPA is also aware that horizontal gene transfer from Agrobacterium to
plants can occur and that in some cases, like the domesticated sweet
potato, it may result in a variant so commonly found that it could be
considered part of the gene pool. It is the Agency's intent to exclude
substances that plant breeders do not have experience with (e.g., a
bacterial endotoxin not found in a food plant) from the proposed
exemption. Given the explanation of the intent behind the terms
``native'' and ``never derived,'' EPA seeks comment on whether the
intent behind the use of the terms is clear. The Agency also seeks
comment on whether alternative phrasing rather than ``native'' would be
more appropriate. Similarly, the Agency seeks comment on whether a
definition for ``native gene'' or ``native allele'' is necessary, or if
the criteria included in these definitions should instead be
incorporated into the exemption text.
E. Should EPA issue a clarifying exemption for loss-of-function traits
that result in pesticidal effects?
As described in Unit II.A., the Agency considers the modification
of existing genes in a plant to elicit a loss-of-function trait in
order to confer a pesticidal effect to be a pesticide. EPA recognizes
that this scenario is different from transgenic PIPs that traditionally
produce a pesticidal substance, e.g., PIPs that produce a protein or
other substance that kill a pest. In many instances, for loss-of-
function traits, the genetic material of the recipient plant has been
altered to reduce the production of a substance that would otherwise
facilitate the susceptibility of that plant to a pathogen; therefore,
the reduction or elimination of that substance has a mitigating or
pesticidal effect. For PIPs created through conventional breeding, EPA
considers these loss-of-function traits to be included in the existing
exemption at 40 CFR 174.25. It is also EPA's intention that loss-of-
function traits created through biotechnology are included under the
proposed exemption at 40 CFR 174.26 so long as the exemption criteria
are met (e.g., only substances produced that are found in sexually
compatible plants).
In situations where the existing plant genes are acting as the
pesticidal substance, EPA recognizes that it can be confusing under the
current regulatory definitions in 40 CFR 174.3 to interpret the
pesticidal substance and the genetic material necessary for the
production of the pesticidal substance as applying to the same thing.
Given that it is potentially confusing to refer to both of these as a
``pesticidal substance'' interchangeably, EPA requests comment as to
whether a clarifying exemption specific to ``loss-of-function PIPs,''
where the genetic material is the pesticidal substance, would aid in
reducing ambiguity over the use of the term ``pesticidal substance'' in
the regulatory text. EPA proposes to accomplish this by separating
exempt PIPs into two categories, those where the gene product is the
pesticidal substance and those where the genetic material itself is the
pesticidal substance. Similar to the existing exemption at 40 CFR
174.25 and the proposed exemption at 40 CFR 174.26, the clarifying
exemption specific to loss-of-function PIPs would be written to limit
permissible modifications to those that do not result in the production
of a modified substance. In other words, only the reduced expression of
an unmodified protein or the elimination of the unmodified protein
would be permissible. This is to ensure (1) limitation of substances to
only those with which plant breeders have experience, (2) the
applicability of EPA's risk assessment for the exemption at 40 CFR
174.25 and the risk assessment for the proposed exemption at 40 CFR
174.26 to the proposed ``loss-of-function PIPs'' exemption, and (3)
that if the reduced substance is in fact a pesticidal substance (or its
reduction leads to an increase of another substance that is pesticidal)
it is covered by either the existing tolerance exemption at 40 CFR
174.508 or the proposed tolerance exemption at 40 CFR 174.541. It is
also important to note that when the loss of function of a gene
intentionally results in the increase in production of another gene
which ultimately produces a pesticidal substance, this PIP would fall
under either the existing exemption at 40 CFR 174.25 or the proposed
exemption at 40 CFR 174.26. If EPA were to issue an exemption for loss-
of-function PIPs, EPA would no longer include the category at proposed
40 CFR 174.26(a)(2)(iv). In addition, EPA also requests comment on how
a separate exemption or exemptions (if any) specific to loss-of-
function PIPs might be implemented. Should such a separate exemption(s)
be technique-specific (e.g., should it be specific to loss-of-function
PIPs created through conventional breeding?) or should there be one
exemption that covers loss of function PIPs regardless of the technique
used in their creation?
VIII. References
The following is a listing of the documents that are specifically
referenced in this document. The docket includes these documents and
other information considered by EPA, including documents that are
referenced
[[Page 64339]]
within the documents that are included in the docket, even if the
referenced document is not physically located in the docket. For
assistance in locating these other documents, please consult the person
listed under FOR FURTHER INFORMATION CONTACT.
1. USEPA, Federal Register. 2018. Withdrawal of Proposed Rules;
Discontinuing Several Rulemaking Efforts Listed in the Semiannual
Regulatory Agenda; May 7, 2018. 83 FR 20004. Available online at
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2. USEPA, Cost Analysis of the Proposed Rule Exempting Certain
Plant-Incorporated Protectants (PIPs) from Registration. 2019, EPA:
Washington, DC.
3. Andersen, E.J., et al., Disease Resistance Mechanisms in Plants.
Genes, 2018. 9(7).
4. National Academies of Science Engineering and Medicine,
Genetically Engineered Crops: Experiences and Prospects. 2016,
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5. USEPA, USFDA, and USDA. Modernizing the Regulatory System for
Biotechnology Products: Final Version of the 2017 Update to the
Coordinated Framework for the Regulation of Biotechnology. 2017;
Available from: https://www.epa.gov/regulation-biotechnology-under-tsca-and-fifra/update-coordinated-framework-regulation-biotechnology.
6. USEPA, Natural Toxicants in Food From Plants. 2019. EPA-HQ-OPP-
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7. FIFRA Scientific Advisory Panel (SAP) and Biotechnology Science
Advisory Committee (BSAC) Joint Meeting, Final Report of the Joint
FIFRA Scientific Advisory Panel and Biotechnology Science Advisory
Committee Meeting for January 21, 1994. 1994.
8. FIFRA Scientific Advisory Panel (SAP) Subpanel on Plant
Pesticides, Final FIFRA Scientific Advisory Panel Subpanel Report on
the December 18, 1992 Meeting. 1993.
9. The Biotechnology Science Advisory Committee (BSAC) Subcommittee
on Plant Pesticides, Report: BSAC Subcommittee on Plant Pesticides,
July 13, 1993 Meeting. 1993.
10. National Research Council, Genetically Modified Pest Protected
Plants: Science and Regulation. 2000, Washington, DC: National
Academy Press.
11. National Research Council and Institute of Medicine, Safety of
Genetically Engineered Foods: Approaches to Assessing Unintended
Health Effects. 2004, Washington, DC: National Academies Press.
12. National Academies of Science Engineering and Medicine,
Preparing for Future Products of Biotechnology. 2017, Washington,
DC: National Academies Press.
13. Hajjar, R. and T. Hodgkin, The use of wild relatives in crop
improvement: A survey of developments over the last 20 years.
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14. Harlan, J.R., Genetic Resources in Wild Relatives of Crops. Crop
Science, 1976. 16(3): p. 329-333.
15. Tanksley, S.D., et al., Advanced backcross QTL analysis in a
cross between an elite processing line of tomato and its wild
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92(2): p. 213-224.
16. Xiao, J.H., et al., Genes from wild rice improve yield. Nature,
1996. 384(6606): p. 223-224.
17. Ghorbani, M., E.A. Jonckheere, and P. Bogdan, Gene Expression Is
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ascorbic acid content of turnip greens. Journal of the American
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20. Ouyang, Y.D. and Q.F. Zhang, The molecular and evolutionary
basis of reproductive isolation in plants. Journal of Genetics and
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21. Servedio, M.R., The role of linkage disequilibrium in the
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22. Glenn, K.C., et al., Bringing New Plant Varieties to Market:
Plant Breeding and Selection Practices Advance Beneficial
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23. USEPA, FIFRA: Benefit and environmental risk considerations for
inherent plant-pesticides. 1994.
24. Aune, D., et al., Fruit and vegetable intake and the risk of
cardiovascular disease, total cancer and all-cause mortality-a
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25. Brondani, J.E., et al., Fruit and vegetable intake and bones: A
systematic review and meta-analysis. Plos One, 2019. 14(5).
26. dos Santos Bueno, P.C., et al., Effects of Green Wheat (Triticum
turgidum) and Common Wheat (Triticum aestivum) on the Metabolic
Profile of Wistar Rats. Journal of Medicinal Food, 2019.
27. Oyebode, O., et al., Fruit and vegetable consumption and all-
cause, cancer and CVD mortality: analysis of Health Survey for
England data. Journal of Epidemiology and Community Health, 2014.
68(9): p. 856-862.
28. Ravn-Haren, G., et al., Apple pomace improves gut health in
Fisher rats independent of seed content. Food & Function, 2018.
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29. Schwingshackl, L., et al., Fruit and Vegetable Consumption and
Changes in Anthropometric Variables in Adult Populations: A
Systematic Review and Meta-Analysis of Prospective Cohort Studies.
Plos One, 2015. 10(10).
30. Thangthaeng, N., et al., Tart cherry supplementation improves
working memory, hippocampal inflammation, and autophagy in aged
rats. Age, 2016. 38(5-6): p. 393-404.
31. Wang, X., et al., Fruit and vegetable consumption and mortality
from all causes, cardiovascular disease, and cancer: systematic
review and dose-response meta-analysis of prospective cohort
studies. British Medical Journal, 2014. 349.
32. Wang, P.Y., et al., Higher intake of fruits, vegetables or their
fiber reduces the risk of type 2 diabetes: A meta-analysis. Journal
of Diabetes Investigation, 2016. 7(1): p. 56-69.
33. Berger, S., A.K. Sinha, and T. Roitsch, Plant physiology meets
phytopathology: plant primary metabolism and plant-pathogen
interactions. Journal of Experimental Botany, 2007. 58(15-16): p.
4019-4026.
34. Hartl, D.L., A primer of population genetics. 3rd ed. 2000,
Sunderland, MA: Sinauer Associates, Inc.
35. Harlan, J.R. and J.M.J. de Wet, Toward a rational classification
of cultivated plants. Taxon, 1971. 20(4): p. 509-517.
36. Chen, C., Z.G. E, and H.X. Lin, Evolution and Molecular Control
of Hybrid Incompatibility in Plants. Frontiers in Plant Science,
2016. 7.
37. International Food Biotechnology Council, Biotechnologies and
Food; Assuring the safety of foods produced by genetic modification.
Regulatory Toxicology and Pharmacology. Academic Press. New York
(NY), 1990. 12.
38. Henry J. Thompson, et al., Effect of increased vegetable and
fruit consumption on markers of oxidative cellular damage.
Carcinogenesis, 1999. 20(12): p. 2261-2266.
39. Agrios, G., Plant Pathology. Third Edition. Academic Press, New
York (NY).
40. Atlas, R.a.R.B., Microbial Ecology. 1987: Benjamin/Cummings
Publishing Company, Inc. Menlo Park, California.
41. Varshney, R.K., A. Graner, and M.A. Sorrells, Genomics-assisted
breeding for crop improvement. TRENDS in Plant Science, 2005.
10(12): p. 1360-1385.
42. Kadama, S., et al., Genomic-assisted phylogenetic analysis and
marker development fornext generation soybean cyst nematode
resistance breeding. Plant Science, 2016. 242: p. 342-350.
43. Crossa, J., et al., Genomic Selectionin Plant Breeding: Methods,
Models, and Perspectives. TRENDS in Plant Science, 2017. 22(11): p.
961-975.
44. Shirasawa, K., et al., The genome sequence of sweet cherry
(Prunus avium) for use in genomics-assisted breeding. DNA Research,
2017. 24(5): p. 499-508.
45. Rimbert, H., et al., High throughput SNP discovery and
genotyping in hexaploid wheat. PloS one, 2018. 13(1): p. e0186329.
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46. Chen, K.L., et al., CRISPR/Cas Genome Editing and Precision
Plant Breeding in Agriculture, in Annual Review of Plant Biology,
Vol 70, S.S. Merchant, Editor. 2019. p. 667-697.
47. Dempewolf, H., et al., Past and Future Use of Wild Relatives in
Crop Breeding. Crop Science, 2017. 57(3): p. 1070-1082.
48. Mammadov, J., et al., Wild Relatives of Maize, Rice, Cotton, and
Soybean: Treasure Troves for Tolerance to Biotic and Abiotic
Stresses. Frontiers in Plant Science, 2018. 9.
49. Karban, R. and A.A. Agrawal, Herbivore offense. Annual Review of
Ecology and Systematics, 2002. 33: p. 641-664.
50. Wozniak, C. and J.L. Kough, Safety of Pesticidal Proteins in
Food, in Toxicology and Regulatory Process, S. Green, Editor. 2006,
Marcel Decker, Inc.: NY.
51. Gressel, J., ed. Crop ferality and volunteerism. 2005, CRC
Press: Boca Raton, FL.
52. den Nijs, H.C.M., D. Bartsch, and J. Sweet, eds. Introgression
from genetically modified plants into wild relatives. 2004, CABI
Publishing: Oxfordshire, UK.
53. Abbott, R., et al., Hybridization and speciation. Journal of
Evolutionary Biology, 2013. 26(2): p. 229-246.
54. Rieseberg, L.H. and S.E. Carney, Plant hybridization. New
Phytologist, 1998. 140(4): p. 599-624.
55. Pfennig, K.S., A.L. Kelly, and A.A. Pierce, Hybridization as a
facilitator of species range expansion. Proceedings of the Royal
Society B-Biological Sciences, 2016. 283(1839).
56. USEPA, Risk considerations for outcrossing and hybridization.
1992, Issue paper.
57. Baack, E., et al., The origins of reproductive isolation in
plants. New Phytologist, 2015. 207(4): p. 968-984.
58. Gonzalez, J.D.S., et al., Ecogeography of teosinte. Plos One,
2018. 13(2).
59. Heslop-Harrison, J.S. and T. Schwarzacher, Domestication,
genomics and the future for banana. Annals of Botany, 2007. 100(5):
p. 1073-1084.
60. USEPA, Dermal and inhalation exposure to plant substances. 2000,
Issue paper.
61. Lozano-Ojalvo, D., C. Berin, and L. Tordesillas, Immune Basis of
Allergic Reactions to Food. Journal of Investigational Allergology
and Clinical Immunology, 2019. 29(1): p. 1-14.
62. Hahn, F. and V. Nekrasov, CRISPR/Cas precision: do we need to
worry about off-targeting in plants? Plant Cell Reports, 2019.
38(4): p. 437-441.
63. Tabei, Y., Risk and safety considerations 2: genetic variations
and potential risks-traditional breeding and genome editing.
Transgenic Research, 2019. 28: p. 119-124.
64. Young, J., et al., CRISPR-Cas9 Editing in Maize: Systematic
Evaluation of Off-target Activity and Its Relevance in Crop
Improvement. Scientific Reports, 2019. 9.
65. Tang, X., et al., A large-scale whole-genome sequencing analysis
reveals highly specific genome editing by both Cas9 and Cpf1
(Cas12a) nucleases in rice. Genome Biology, 2018. 19.
66. Leitch, A.R. and I.J. Leitch, Perspective--Genomic plasticity
and the diversity of polyploid plants. Science, 2008. 320(5875): p.
481-483.
67. Henikoff, S., Rapid changes in plant genomes. Plant Cell, 2005.
17(11): p. 2852-2855.
68. Wendel, J.F., et al., Evolution of plant genome architecture.
Genome Biology, 2016. 17.
69. Joshipura, K.J., et al., Fruit and vegetable intake in relation
to risk of ischemic stroke. Journal of the American Medical
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70. Michaud, D.S., et al., Fruit and Vegetable Intake and Incidence
of Bladder Cancer in a Male Prospective Cohort. Journal of the
National Cancer Institute, 1999. 91(7).
71. Segasothy, M. and P.A. Phillips, Vegetarian diet: panacea for
modern lifestyle diseases? QJM: An International Journal of
Medicine, 1999. 92(9): p. 531-544.
72. Ogimoto, I., A. Shibata, and K. Fukuda, World Cancer Research
Fund/American Institute of Cancer Research 1997 Recommendations:
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Control, 2000. 11(1): p. 9-23.
73. Bazzano, L.A., et al., Fruit and vegetable intake and risk of
cardiovascular disease in US adults: the first National Health and
Nutrition Examination Survey Epidemiologic Follow-up Study. American
Journal of Clinical Nutrition, 2002. 76: p. 93-99.
74. Joseph, J.A., et al., Reversals of age-related declines in
neuronal signal transduction, cognitive, and motor behavioral
deficits with blueberry, spinach, or strawberry dietary
supplementation. Journal of Neuroscience, 1999. 18(18): p. 8114-
8121.
75. Galli, R.L., et al., Fruit polyphenolics and brain aging:
nutritional interventions targeting age-related neuronal and
behavioral deficits. Annals of the New York Academy of Sciences,
2006. 959(1).
76. M[uuml]hlbauer, R.C., A. Lozano, and A. Reinli, Onion and a
Mixture of Vegetables, Salads, and Herbs Affect Bone Resorption in
the Rat by a Mechanism Independent of Their Base Excess. Journal of
Bone and Mineral Research, 2002. 17(7): p. 1230-6.
77. Goyarzu, P., et al., Blueberry supplemented diet: effects on
object recognition memory and nuclear factor-kappa B levels in aged
rats. Nutritional Neuroscience, 2004. 7(2): p. 75-83.
78. Raven, P.H., R.F. Evert, and S.E. Eichhorn, Biology of Plants.
Fifth Edition. 1992: Worth Publishers.
79. Das, A., N. Sharma, and M. Prasad, CRISPR/Cas9: A Novel Weapon
in the Arsenal to Combat Plant Diseases. Frontiers in Plant Science,
2019. 9.
80. Weber, N., et al., Editor's choice: Crop genome plasticity and
its relevance to food and feed safety of genetically engineered
breeding stacks. Plant Physiology, 2012. 160(4): p. 1842-53.
81. USEPA, Benefits of fruits and vegetables. 2000. Issue Paper.
82. Dolan, L.C., R.A. Matulka, and G.A. Burdock, Naturally Occurring
Food Toxins. Toxins, 2010. 2: p. 2289-2332.
83. Speijers, G., et al., Evaluation of Agronomic Practices for
Mitigation of Natural Toxins. 2010.
84. Fernandez-Cornejo, J., The seed industry in US agriculture: An
exploration of data and information on crop seed markets,
regulation, industry structure, and research and development. 2004,
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85. Cooper, R.A. and H.F. Bunn, Hemolytic Anemies, in Harrison's
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88. Yunginger, J.W., Food Antigens. In: Food Allergy: Adverse
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IX. Statutory and Executive Order Reviews
Additional information about these statutes and Executive orders
can be found at https://www.epa.gov/laws-regulations/laws-and-executive-orders.
A. Executive Order 12866: Regulatory Planning and Review and Executive
Order 13563: Improving Regulation and Regulatory Review
This action is a significant regulatory action that was submitted
to the Office of Management and Budget (OMB) for review under Executive
Orders 12866 (58 FR 51735, October 4, 1993) and 13563 (76 FR 3821,
January 21, 2011). Any changes made in response to OMB recommendations
have been documented in the docket for this action as required by
section 6(a)(3)(E) of Executive Order 12866.
B. Executive Order 13771: Reducing Regulations and Controlling
Regulatory Costs
This action is expected to be an Executive Order 13771 deregulatory
action. Details on the estimated cost savings of this proposed rule can
be found in EPA's cost analysis (Ref. 2).
[[Page 64341]]
C. Paperwork Reduction Act (PRA)
The information collection activities in this proposed rule have
been submitted for approval to OMB under the PRA, 44 U.S.C. 3501 et
seq. The Information Collection Request (ICR) document that EPA
prepared is assigned EPA ICR No. 2619.01. You can find a copy of the
ICR in the docket for this rule, and it is briefly summarized here.
The information collection activities in this proposed rule are
associated with the proposed exemption eligibility process (i.e., self-
determination or request for EPA-confirmation, and associated
recordkeeping) that would be made available as an alternative to the
existing pesticide registration and tolerance activities that are
already approved by OMB under OMB Control No. 2070-0060 (EPA ICR No.
0277). As such, the ICR accompanying this proposed rule is intended to
amend that existing ICR at the final rule stage, incorporating the
information collection activities for the exemption and related
estimated burden.
Respondents affected entities: See Unit I.A.
Respondent's obligation to respond: Mandatory to obtain the
exemption (40 CFR part 174, as proposed).
Estimated number of respondents: 1.
Frequency of response: Once.
Total estimated burden: 14 hours (per EPA determination). Burden is
defined at 5 CFR 1320.3(b).
Total estimated cost: $1,487 (per EPA determination), includes $0
annualized capital or operation & maintenance costs.
An agency may not conduct or sponsor, and a person is not required
to respond to, a collection of information unless it displays a
currently valid OMB control number. The OMB control numbers for EPA's
regulations in 40 CFR are listed in 40 CFR part 9.
Submit your comments on the Agency's need for this information, the
accuracy of the provided burden estimates, and any suggested methods
for minimizing respondent burden to EPA using the docket identified at
the beginning of this rule. You may also send your ICR-related comments
to OMB's Office of Information and Regulatory Affairs via email to
[email protected], Attention: Desk Officer for the EPA. Since
OMB is required to make a decision concerning the ICR between 30 and 60
days after receipt, OMB must receive comments no later than November 9,
2020. EPA will respond to any ICR-related comments received on the
proposed ICR amendment when issuing the final rule.
D. Regulatory Flexibility Act (RFA)
Pursuant to the RFA section 605(b), 5 U.S.C. 601 et seq., I hereby
certify that this action will not have a significant economic impact on
a substantial number of small entities. In making this determination,
EPA believes that the impact of concern is any adverse economic impact,
and that an agency may certify that a rule will not have a significant
economic impact on a substantial number of small entities if the rule
relieves regulatory burden, has no net burden, or otherwise has a
positive economic effect on the small entities subject to the rule. The
factual basis for this determination is presented in the small entity
impact analysis prepared as part of the cost analysis for this proposed
rule (Ref. 2), which is summarized in Units I.E. and VI.A.4., and a
copy is available in the docket for this rulemaking. The following is a
brief summary of the factual basis for this certification.
The effect of the rule is to reduce costs to developers of PIPs
based on sexually compatible plant created through biotechnology, and
the cost savings per product are approximately $444,000-$459,000. The
cost savings per product would be realized when a letter of self-
determination is sent. The proposed exemption for PIPs based on
sexually compatible plants created through biotechnology reduces the
cost associated with meeting regulatory requirements and so removes a
potential barrier to market entry for small entities. Of the entities
likely to develop PIPs based on sexually compatible plants created
through biotechnology, EPA currently estimates that approximately 80%
are small entities. We have therefore concluded that this action will
relieve regulatory burden for all directly regulated small entities.
Any comments regarding the potential impacts on small entities from
this action should be submitted to the Agency in the manner specified
under ADDRESSES.
E. Unfunded Mandates Reform Act (UMRA)
This action does not contain an unfunded mandate as described in
UMRA, 2 U.S.C. 1531-1538, and does not significantly or uniquely affect
small governments. The action is not expected to impose an enforceable
duty on any state, local or tribal governments, and the requirements
imposed on the private sector are not expected to result in annual
expenditures of $100 million or more for the private sector.
Accordingly, EPA has determined that the requirements of UMRA sections
202, 203, 204, or 205 do not apply to this action.
F. Executive Order 13132: Federalism
This action does not have federalism implications as specified in
Executive Order 13132 (64 FR 43255, August 10, 1999). It will not have
substantial direct effects on the states, on the relationship between
the national government and the states, or on the distribution of power
and responsibilities among the various levels of government. Thus,
Executive Order 13132 does not apply to this proposed rule.
G. Executive Order 13175: Consultation and Coordination With Indian
Tribal Governments
This action does not have tribal implications as specified in
Executive Order 13175 (65 FR 67249, November 9, 2000). It will not have
substantial direct effects on tribal governments, on the relationship
between the Federal government and the Indian tribes, or on the
distribution of power and responsibilities between the Federal
government and Indian tribes. Thus, Executive Order 13175 does not
apply to this proposed rule.
H. Executive Order 13045: Protection of Children From Environmental
Health Risks and Safety Risks
EPA interprets Executive Order 13045 (62 FR 19885, April 23, 1997)
as applying only to those regulatory actions that concern environmental
health or safety risks that EPA has reason to believe may
disproportionately affect children, per the definition of ``covered
regulatory action'' in section 2-202 of the Executive Order. This
action is not subject to Executive Order 13045 because it does not
establish an environmental standard intended to mitigate a health or
safety risk.
I. Executive Order 13211: Actions Concerning Regulations That
Significantly Affect Energy Supply, Distribution, or Use
This action is not a ``significant energy action'' as defined in
Executive Order 13211 (66 FR 28355, May 22, 2001) because it is not
likely to have a significant adverse effect on the supply,
distribution, or use of energy.
J. National Technology Transfer Advancement Act (NITAA)
NTTAA section 12(d), 15 U.S.C. 272 note, does not apply to this
proposed action because it would not impose any technical standards
requiring Agency consideration of voluntary consensus standards. This
regulation proposes the
[[Page 64342]]
types of information to be submitted in a self-determination letter or
EPA confirmation request concerning the exemption of PIPs based on
sexually compatible plants created through biotechnology, but does not
propose to require specific methods or standards to generate that
information.
K. Executive Order 12898: Federal Actions To Address Environmental
Justice in Minority Populations and Low-Income Populations
EPA believes that this action is not subject to Executive Order
12898 (59 FR 7629, February 16, 1994) because it does not establish an
environmental health or safety standard.
L. FIFRA Review Requirements
In accordance with FIFRA section 25(a), EPA submitted the draft
proposed rule to the Secretary of the United States Department of
Agriculture (USDA) and the FIFRA Scientific Advisory Panel (SAP) for
review. A draft of the proposed rule was also submitted to the
appropriate Congressional Committees.
M. Executive Order 13874: Modernizing the Regulatory Framework for
Agricultural Biotechnology Products
This action is intended to further implement section 4(b) of
Executive Order 13874 (84 FR 27899, June 11, 2019). If this proposal is
made final, the final rule may promote future innovation and
competitiveness by efficiently exempting through regulation qualifying
PIPs based on sexually compatible plants created through biotechnology
that meet the FIFRA and FFDCA standards for exemption.
List of Subjects in 40 CFR Part 174
Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Plant-incorporated
protectants, Reporting and recordkeeping requirements.
Andrew Wheeler,
Administrator.
Therefore, it is proposed that 40 CFR chapter I be amended as
follows:
PART 174--[AMENDED]
0
1. The authority citation for part 174 continues to read as follows:
Authority: 7 U.S.C. 136-136y; 21 U.S.C. 321(q), 346a and 371.
0
2. Amend Sec. 174.3 by adding in alphabetical order the following
definitions to read as follows:
Sec. 174.3 Definitions
* * * * *
Gene, and other grammatical variants such as ``genic,'' means a
functional unit of heritable genetic material that is comprised of the
genetic material necessary for the production of a substance.
* * * * *
Native allele means a variant of a native gene that is identified
in the genetic diversity of plants sexually compatible with the
recipient plant.
Native gene means a gene that is identified in the recipient plant
or plants sexually compatible with the recipient plant; and has never
been derived from a source that is not sexually compatible with the
source plant.
* * * * *
Sexually compatible, when referring to plants, means a viable
zygote can be formed through the union of two gametes through
conventional breeding.
* * * * *
0
3. Revise Sec. 174.21 to read as follows:
Sec. 174.21 General qualifications for exemptions.
A plant-incorporated protectant is exempt from the requirements of
FIFRA, other than the requirements of Sec. 174.71, if it meets the
exemption criteria in paragraphs (a) through (d) of this section.
Plant-incorporated protectants that are not exempt from the
requirements of FIFRA under this subpart are subject to all the
requirements of FIFRA.
(a) The pesticidal substance from the plant-incorporated protectant
meets the exemption criteria listed in at least one of the sections in
Sec. Sec. 174.25 through 174.50.
(b) When the plant-incorporated protectant is intended to be
produced and used in a crop used as food, the residues of the
pesticidal substance of the plant-incorporated protectant are either
exempted from the requirement of a tolerance under FFDCA (21 U.S.C. 321
et seq.) as listed in subpart W of this part, or no tolerance would
otherwise be required.
(c) Any inert ingredient that is part of the plant-incorporated
protectant is listed as an approved inert ingredient in subpart X of
this part.
(d) For plant-incorporated protectants listed in the subparagraphs
below, the exemption applies only if the developer is compliant with
the general record keeping requirements specified in Sec. 174.73 and
only after compliance with the relevant eligibility determination
procedures specified in Sec. 174.90:
(1) Plant-incorporated protectant based on a sexually compatible
plant created through biotechnology.
(2) [Reserved]
0
4. Amend Sec. 174.25 by:
0
a. Revising the section heading;
0
b. Revising the introductory paragraph; and
0
c. Adding paragraph (c).
The revisions read as follows:
Sec. 174.25 Pesticidal substance from a plant-incorporated protectant
from a sexually compatible plant created through conventional breeding.
The pesticidal substance from a plant-incorporated protectant from
a sexually compatible plant created through conventional breeding is
exempt if all of the following conditions are met:
* * * * *
(c) The genetic material is transferred from the source plant to
the recipient plant only through conventional breeding.
0
5. Add Sec. 174.26 to read as follows:
Sec. 174.26 Pesticidal substance from a plant-incorporated protectant
based on a sexually compatible plant created through biotechnology.
The pesticidal substance from a plant-incorporated protectant based
on a sexually compatible plant created through biotechnology is exempt
if all of the following conditions are met:
(a) The pesticidal substance is created through biotechnology from
either an insertion of new genetic material as discussed in paragraph
(a)(1) of this section or a modification of existing genetic material
as discussed in paragraph (a)(2) of this section.
(1) A native gene is engineered into a non-genic location of the
recipient plant genome, resulting in a pesticidal substance identical
to the pesticidal substance identified in the source plant.
(2)(i) The existing native gene in the recipient plant is modified
to alter the amount of pesticidal substance produced without altering
the identity of the pesticidal substance produced; or
(ii) The genetic material that encodes the substance of the
existing native gene is modified to result in a pesticidal substance
that is identical to the pesticidal substance encoded by a native
allele of that gene; or
(iii) The existing genetic material is modified pursuant to both
(i) and (ii).
(iv) The existing native gene in the recipient plant is modified to
lose function through the reduction or elimination of the substance
encoded by that gene.
(b) The pesticidal substance is not expressed at higher levels, in
different tissues, or at different developmental stages than identified
in a plant that is sexually compatible with the recipient plant.
[[Page 64343]]
(c) This exemption does not apply until the requirements in subpart
E of this part have been met.
0
6. Add Sec. 174.73 to read as follows:
Sec. 174.73 General recordkeeping requirements for exemptions.
For 5 years, starting with the effective date of a plant-
incorporated protectant exemption, any person who produces an exempt
plant-incorporated protectant listed under Sec. 174.21(d) must do both
of the following:
(a) Maintain documentation of either the letter of self-
determination or the request for EPA confirmation along with all
supporting documentation for the specific exemption listed in subpart
E.
(b) Make the documentation of exemption eligibility available to
EPA upon request.
0
7. Amend subpart E to read as follows:
Subpart E--Exemption Eligibility Determination Process and
Requirements
Sec. 174.90 Determining Eligibility for Exemption
(a) Options for determining eligibility. For a plant-incorporated
protectant listed under Sec. 174.21(d), the developer must do at least
one of the following actions to be eligible for the exemption in Sec.
174.21:
(1) Self-determination. A developer may submit a letter of self-
determination in accordance with Sec. 174.91.
(2) Request for EPA confirmation of eligibility. A developer may
submit a request for EPA confirmation of eligibility in accordance with
Sec. 174.93.
(b) Where to submit a letter of self-determination or request for
EPA confirmation. A letter of self-determination or a request for EPA
confirmation of eligibility must be submitted to the Office of
Pesticide Programs' Document Processing Desk at the appropriate address
as set forth in Sec. 150.17(a) or (b) of this chapter, with the
relevant ``Attention'' line: ``Attention: Plant-Incorporated Protectant
Exemption Self-Determination'' or ``Attention: Plant-Incorporated
Protectant Request for Confirmation of Exemption Eligibility.''
[placeholder for future instructions covering electronic submissions].
(c) Overlapping determinations of eligibility. A developer may
elect to submit a letter of self-determination as well as a request for
EPA confirmation of eligibility concurrently or at a later time. If the
developer so elects, the letter of self-determination will remain in
effect while EPA evaluates the request for confirmation of eligibility.
(d) Revisiting eligibility determination. If, at any time after the
letter of self-determination is submitted or EPA issues a confirmation
of eligibility, EPA becomes aware of information indicating that the
exempt plant-incorporated protectant no longer meets the criteria for
exemption (e.g., adverse effects reports submitted under Sec. 174.71)
or that the self-determination was incorrect, EPA will notify the
original submitter in writing of EPA's intention to initiate a review
of eligibility for exemption and may request additional information
from the developer in order to evaluate that eligibility for exemption.
Upon conclusion of its review, EPA will notify the developer in writing
of its determination whether the plant-incorporated protectant meets
the exemption criteria and any actions that will be required should the
plant-incorporated protectant be found to not meet the exemption
criteria. Under those circumstances, the plant-incorporated protectant
may be considered to be noncompliant with FIFRA and subject to possible
enforcement by EPA.
(e) Extension of exemption to subsequent variations of the plant-
incorporated protectant.
(1) Plant-incorporated protectant based on a sexually compatible
plant created through biotechnology. A letter of self-determination or
EPA's confirmation that the plant-incorporated protectant based on a
sexually compatible plant created through biotechnology meets the
criteria for exemption applies to subsequent engineering of that plant-
incorporated protectant by the submitter into other varieties of that
same plant species as long as the submitter is doing one of the
following:
(i) Producing the identical substance as in the exempt plant-
incorporated protectant, so long as no modifications were made to the
regulatory regions.
(ii) Creating the same phenotype as in the exempt plant-
incorporated protectant by targeting the same nucleic acid sequence in
the regulatory region to result in a mutation via double-strand DNA
break repaired by non-homologous end joining.
(iii) For subsequent engineering events that do not meet either
criterion (e)(1)(i) or (1)(ii), a letter of self-determination or
request for EPA determination must be submitted.
(2) [Reserved]
Sec. 174.91 Submitting a letter of self-determination for exemption.
A developer who elects to self-determine eligibility for the
exemption of a plant-incorporated protectant listed under Sec.
174.21(d) must comply with all of the following requirements.
(a) When to submit a letter of self-determination. A letter of
self-determination for an exemption must be submitted to EPA prior to
engaging in activities subject to FIFRA.
(b) Contents of a letter of self-determination. The letter of self-
determination must:
(1) Provide the name and contact information for the submitter
(including phone and email address), company name, or other
affiliation.
(2) Identify the plant-incorporated protectant and the following
exemption-specific information for the exemption for which eligibility
is self-determined:
(i) Plant-incorporated protectant based on a sexually compatible
plant created through biotechnology. Cite the paragraph under
Sec. Sec. 174.26 or 174.541 that is applicable to the PIP (i.e.,
(a)(1), (a)(2)(i), (a)(2)(ii), (a)(2)(iii), or (a)(2)(iv)).
(ii) [Reserved]
(3) Include the following statement of certification, filling in
the information described in italics:
``I, [name of submitter], on behalf of [name of company] am
submitting this Plant-Incorporated Protectant Exemption Self-
Determination consistent with the provisions of 40 CFR part 174. I
hereby confirm that the plant-incorporated protectant known as [name
of the plant-incorporated protectant] is eligible under 40 CFR
174.21 to be exempt from the requirements of FIFRA, other than the
requirements of 40 CFR 174.71 and 174.73. I understand that it is a
violation of 18 U.S.C. 1001 to willfully make any false statement to
EPA. I further understand that if this self-determination is not
consistent with the provisions of 40 CFR part 174, this plant-
incorporated protectant product may not be exempt from the
requirements of FIFRA, and [name of company] may be subject to
enforcement actions and penalties under FIFRA sections 12, 13, and
14, 7 U.S.C. 136j, 136k, and 136l. Moreover, I also understand that
if this self-determination is not consistent with 40 CFR part 174,
the residues of this plant-incorporated protectant may not be exempt
from the requirement of a tolerance under the FFDCA, and [name of
company], as well as foods containing such residues, may be subject
to enforcement actions and penalties under Chapter III of the FFDCA,
21 U.S.C. 331 et seq.''
(4) The statement must be dated and signed by an authorized
representative of the developer of the plant-incorporated protectant.
(c) EPA response. For electronic submissions, EPA will provide
electronic confirmation of receipt immediately. Electronic confirmation
shall be equivalent to written confirmation. For submissions by mail,
written confirmation of receipt within 30 business days of receipt of a
letter of self-determination.
[[Page 64344]]
(d) Effective date of exemption. The exemption does not apply until
EPA confirms receipt of the letter of self-determination.
Sec. 174.93 Obtaining EPA confirmation of eligibility for the
exemption.
A developer who elects to request EPA confirmation of eligibility
for exemption of a plant-incorporated protectant listed under Sec.
174.21(d) must comply with all of the following requirements.
(a) When to submit a request for EPA confirmation. Unless the
developer has received confirmation of receipt of a letter of self-
determination, the request for EPA confirmation must be submitted prior
to engaging in activities subject to FIFRA.
(b) Contents of a request for EPA confirmation of exemption
eligibility. The request must contain information as specified in Sec.
174.91(b) and supporting documentation demonstrating that the plant-
incorporated protectant meets the criteria for the exemption, as
specified in exemption-specific sections of this subpart. Any claims of
confidentiality for information submitted in the request for EPA
confirmation must be made in accordance with the procedures outlined in
Sec. 174.9 of subpart A.
(c) EPA review and response. Upon receipt of a request, EPA will
review and evaluate the information provided to determine whether the
plant-incorporated protectant meets the exemption criteria in Sec.
174.21. EPA may require additional information to assess whether a
plant-incorporated protectant meets the criteria for exemption. EPA
will notify the submitter in writing of its determination. If EPA
determines that the plant-incorporated protectant does not meet the
criteria for exemption, EPA will notify the submitter in writing of any
actions that will be required.
(d) Effective date for the EPA confirmed exemption. If the plant-
incorporated protectant is not already exempt pursuant to the self-
determination process under Sec. 174.91, this exemption applies once
EPA notifies the submitter in writing, confirming that the plant-
incorporated protectant meets the criteria for exemption.
Sec. 174.95 Documentation for an exemption for a plant-incorporated
protectant based on a sexually compatible plant created through
biotechnology.
A developer requesting EPA confirmation of exemption eligibility
for a plant-incorporated protectant from a sexually compatible plant
created through biotechnology pursuant to Sec. 174.93 must submit the
information in the following paragraphs to EPA along with its request
for exemption confirmation. Any developer required to maintain records
under Sec. 174.73 must maintain the following documentation.
(a) Biology of the plant.
(1) The identity of the recipient plant, including genus and
species.
(2) If the plant-incorporated protectant was derived from another
plant species, provide the identity of the source plant including genus
and species and information to demonstrate the recipient plant and the
source plant are sexually compatible.
(b) Description of the pesticidal trait and how the trait was
engineered into the plant. If the pesticidal substance is a known
mammalian toxin or toxicant (e.g., solanine) describe how conventional
breeding practices are being used to ensure it does not exceed safe
levels in the recipient food plant.
(c) Molecular characterization of the plant-incorporated
protectant.
(1) The nucleotide sequence and the amino acid sequence of the
plant-incorporated protectant in the recipient plant, including a
sequence comparison between the recipient plant and the relevant
comparator (i.e., the source plant if a source plant was used or the
unmodified plant if no source plant was used).
(2) For a plant-incorporated protectant where the regulatory region
of an existing or inserted native gene has been modified, confirmation
that the expression level does not exceed that found in a sexually
compatible plant and the plant-incorporated protectant is not expressed
in tissues or developmental stages outside of that observed in a plant
that is sexually compatible with the recipient plant.
0
8. Amend Sec. 174.508 by:
0
a. Revising the section heading,
0
b. Revising the introductory paragraph,
0
c. Designating paragraph (c) as paragraph (d), and
0
d. Adding a new paragraph (c).
These revisions read as follows:
Sec. 174.508 Pesticidal substance from a plant-incorporated
protectant from a sexually compatible plant created through
conventional breeding; exemption from the requirement of a tolerance.
Residues of a pesticidal substance from a plant-incorporated
protectant from a sexually compatible plant created through
conventional breeding are exempt from the requirement of a tolerance if
all the following conditions are met:
* * * * *
(c) The genetic material is transferred from the source plant to
the recipient plant only through conventional breeding.
(d) The residues of the pesticidal substance are not present in
food from the plant at levels that are injurious or deleterious to
human health.
0
9. Add Sec. 174.541 to read as follows:
Sec. 174.541 Pesticidal substance from a plant-incorporated
protectant based on a sexually compatible plant created through
biotechnology; exemption from the requirement of a tolerance.
Residues of a pesticidal substance from a plant-incorporated
protectant based on a sexually compatible plant created through
biotechnology are exempt if all of the following conditions are met:
(a) The pesticidal substance is created through biotechnology from
either an insertion of new genetic material as discussed in paragraph
(1) or a modification of existing genetic material as discussed in
paragraph (2).
(1) A native gene is engineered into a non-genic location of the
recipient plant genome, resulting in a pesticidal substance identical
to the pesticidal substance identified in the source plant.
(2)(i) The existing native gene in the recipient food plant is
modified to alter the amount of pesticidal substance produced without
altering the identity of the pesticidal substance produced; or
(ii) The genetic material that encodes the substance of the
existing native gene is modified to result in a pesticidal substance
that is identical to the pesticidal substance encoded by a native
allele of that gene; or
(iii) The existing genetic material is modified pursuant to both
(i) and (ii).
(iv) The existing native gene in the recipient plant is modified to
lose function through the reduction or elimination of the substance
encoded by that gene.
(b) The residues of the pesticidal substance are present only in
tissues and developmental stages identified in a plant that is sexually
compatible with the recipient food plant, and do not exceed levels
found within that plant, as long as those levels are not injurious or
deleterious to human health.
(c) This exemption does not apply until the requirements in subpart
E of this part have been met.
[FR Doc. 2020-19669 Filed 10-8-20; 8:45 am]
BILLING CODE 6560-50-P
