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

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

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

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

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

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

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

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.

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

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

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

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

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.

    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.

    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

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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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,
Washington, DC: National Academies Press.
5. USEPA, USFDA, and USDA. Modernizing the Regulatory System for
Biotechnology Products: Final Version of the 2017 Update to the
Coordinated Framework for the Regulation of Biotechnology. 2017;
Available from: https://www.epa.gov/regulation-biotechnology-under-tsca-and-fifra/update-coordinated-framework-regulation-biotechnology.
6. USEPA, Natural Toxicants in Food From Plants. 2019. EPA-HQ-OPP-
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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
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the December 18, 1992 Meeting. 1993.
9. The Biotechnology Science Advisory Committee (BSAC) Subcommittee
on Plant Pesticides, Report: BSAC Subcommittee on Plant Pesticides,
July 13, 1993 Meeting. 1993.
10. National Research Council, Genetically Modified Pest Protected
Plants: Science and Regulation. 2000, Washington, DC: National
Academy Press.
11. National Research Council and Institute of Medicine, Safety of
Genetically Engineered Foods: Approaches to Assessing Unintended
Health Effects. 2004, Washington, DC: National Academies Press.
12. National Academies of Science Engineering and Medicine,
Preparing for Future Products of Biotechnology. 2017, Washington,
DC: National Academies Press.
13. Hajjar, R. and T. Hodgkin, The use of wild relatives in crop
improvement: A survey of developments over the last 20 years.
Euphytica, 2007. 156(1-2): p. 1-13.
14. Harlan, J.R., Genetic Resources in Wild Relatives of Crops. Crop
Science, 1976. 16(3): p. 329-333.
15. Tanksley, S.D., et al., Advanced backcross QTL analysis in a
cross between an elite processing line of tomato and its wild
relative L-pimpinellifolium. Theoretical and Applied Genetics, 1996.
92(2): p. 213-224.
16. Xiao, J.H., et al., Genes from wild rice improve yield. Nature,
1996. 384(6606): p. 223-224.
17. Ghorbani, M., E.A. Jonckheere, and P. Bogdan, Gene Expression Is
Not Random: Scaling, Long-Range Cross-Dependence, and Fractacl
Characteristics of Gene Regulatory Networks. Frontiers in
Phsyiology, 2018. 22.
18. Hamner, K.C. and R.Q. Parks, Effect of light intensity on
ascorbic acid content of turnip greens. Journal of the American
Society of Agronomy, 1944. 36: p. 269-273.
19. Orr, H.A., Dobzhansky, Bateson, and the genetics of speciation.
Genetics, 1996. 144(4): p. 1331-1335.
20. Ouyang, Y.D. and Q.F. Zhang, The molecular and evolutionary
basis of reproductive isolation in plants. Journal of Genetics and
Genomics, 2018. 45(11): p. 613-620.
21. Servedio, M.R., The role of linkage disequilibrium in the
evolution of premating isolation. Heredity, 2009. 102(1): p. 51-56.
22. Glenn, K.C., et al., Bringing New Plant Varieties to Market:
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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).

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_ADDRESS>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