[Federal Register: July 19, 2001 (Volume 66, Number 139)]
[Rules and Regulations]
[Page 37830-37854]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr19jy01-21]

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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 174

[OPP-300368B; FRL-6057-6]
RIN 2070-AC02


Exemption From the Requirement of a Tolerance Under the Federal
Food, Drug, and Cosmetic Act for Residues Derived Through Conventional
Breeding From Sexually Compatible Plants of Plant-Incorporated
Protectants (Formerly Plant-Pesticides)

AGENCY: Environmental Protection Agency (EPA).

ACTION: Final rule.

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SUMMARY: The substances plants produce for protection against pests,
and the genetic material necessary to produce these substances, are
pesticides under the Federal Insecticide, Fungicide and Rodenticide Act
(FIFRA), if humans intend to use these substances for ``preventing,
destroying, repelling or mitigating any pest.'' These substances,
produced and used in living plants, along with the genetic material
necessary to produce them, are also ``pesticide chemical residues''
under the Federal Food, Drug, and Cosmetic Act (FFDCA). EPA calls these
substances, along with the genetic material necessary to produce them,
plant-incorporated protectants. In this final rule, EPA exempts from
the FFDCA section 408 requirement of a tolerance, residues of the
pesticidal substance portion and residues of any inert ingredient of
any plant-incorporated protectant derived through conventional breeding
from a plant sexually compatible with the recipient food plant. EPA has
determined that there is a reasonable certainty that no harm will
result from aggregate exposure to these residues.

DATES: This rule is effective September 17, 2001. Objections and
requests for hearings must be received by EPA on or before September
17, 2001.

ADDRESSES: Objections and hearing requests may be submitted by regular
mail, electronically, or in person. Please follow the detailed
instructions for each method as provided in Unit II. of the
SUPPLEMENTARY INFORMATION.

FOR FURTHER INFORMATION CONTACT: By mail: Philip Hutton, Biopesticides
and Pollution Prevention Division, Office of Pesticide Programs
(7511C), Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,
Washington DC 20460; telephone number: (703)

[[Page 37831]]

308-8260; e-mail address: hutton.phil@epa.gov.

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this Document Apply to Me?

    You may be potentially affected by this action if you are a person
or company involved with agricultural biotechnology that may develop
and market plant-incorporated protectants. Potentially affected
categories and entities may include, but are not limited to:

------------------------------------------------------------------------
                                                         Examples of
           Categories                NAICS codes         potentially
                                                      affected entities
------------------------------------------------------------------------
Pesticide manufacturers          32532               Establishments
                                                      primarily engaged
                                                      in the formulation
                                                      and preparation of
                                                      agricultural and
                                                      household pest
                                                      control chemicals
------------------------------------------------------------------------
Seed companies                   111                 Establishments
                                                      primarily engaged
                                                      in growing crops,
                                                      plants, vines, or
                                                      trees and their
                                                      seeds
------------------------------------------------------------------------
Colleges, universities, and      611310              Establishments of
 professional schools                                 higher learning
                                                      which are engaged
                                                      in development and
                                                      marketing of plant-
                                                      incorporated
                                                      protectants
------------------------------------------------------------------------
Establishments involved in       54171               Establishments
 research and development in                          primarily engaged
 the life sciences                                    in conducting
                                                      research in the
                                                      physical,
                                                      engineering, or
                                                      life sciences,
                                                      such as
                                                      agriculture and
                                                      biotechnology
------------------------------------------------------------------------

    This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed above could also be
affected. The North American Industrial Classification System (NAIC)
codes have been provided to assist you and others in determining
whether or not this action might apply to certain entities. To
determine whether you or your business may be affected by this action,
you should carefully examine the applicable provisions of part 174 in
title 40 of the Code of Federal Regulations (CFR). If you should have
any questions regarding the applicability of this action to a
particular entity, consult the technical person listed in the FOR
FURTHER INFORMATION CONTACT.

B. How Can I Get Additional Information , Including Copies of This
Document and Other Related Documents?

    1. Electronically.You may obtain electronic copies of this
document, and certain other related documents that might be available
electronically, from the EPA Internet Home Page at http://www.epa.gov/.
To access this document, on the Home Page select ``Laws and
Regulations,'' ``Regulations and Proposed Rules,'' and then look up the
entry for this document under the ``Federal Register--Environmental
Documents.'' You can also go directly to theFederal Register listings
at http://www.epa.gov/fedrgstr/. To access information about the EPA's
program for biopesticides go directly to the Home Page for the Office
of Pesticide Programs at http://www.epa.gov/pesticides/biopesticides.
    2. In person. The Agency has established an official record for
this action under the docket control number OPP-300368B. The official
record consists of the documents specifically referenced in this
action, any public comments received during an applicable comment
period, and other information related to this action, including any
information claimed as Confidential Business Information (CBI). This
official record includes the documents that are physically located in
the docket, as well as the documents that are referenced in those
documents. The public version of the official record, which includes
printed, paper versions of any electronic comments submitted during an
applicable comment period, is available for inspection in the Public
Information and Record Integrity Branch (PIRIB), Rm. 119, Crystal Mall
#2, 1921 Jefferson Davis Highway, Arlington, VA, from 8:30 a.m. to 4
p.m., Monday through Friday, excluding legal holidays. The PIRIB
telephone number is (703) 305-5805.

C. How Should I Handle CBI that I Want to Submit to the Agency?

    Do not submit any information electronically that you consider to
be CBI. You may claim information that you submit to EPA in response to
this document as CBI by marking any part or all of that information as
CBI. Information so marked will not be disclosed except in accordance
with procedures set forth in 40 CFR part 2. In addition to one complete
version of the comment that includes any information claimed as CBI, a
copy of the comment that does not contain the information claimed as
CBI must be submitted for inclusion in the public version of the
official record. Information not marked confidential will be included
in the public version of the official record without prior notice. If
you have any questions about CBI or the procedures for claiming CBI,
please consult the person listed under FOR FURTHER INFORMATION CONTACT.

II. Objections and Hearing Requests

    Under section 408(g) of the FFDCA, as amended by the Food Quality
Protection Act (FQPA), any person may file an objection to any aspect
of this regulation and may also request a hearing on those objections.
The EPA procedural regulations which govern the submission of
objections and requests for hearings appear in 40 CFR part 178.
Although the procedures in those regulations require some modification
to reflect the amendments made to the FFDCA by the FQPA of 1996, EPA
will continue to use those procedures, with appropriate adjustments,
until the necessary modifications can be made. The new section 408(g)
provides essentially the same process for persons to ``object'' to a
regulation for an exemption from the requirement of a tolerance issued
by EPA under new section 408(d), as was provided in the old FFDCA
sections 408 and 409. However, the period for filing objections is now
60 days, rather than 30 days.

A. What Do I Need to Do to File an Objection or Request a Hearing?

    You must file your objection or request a hearing on this
regulation in accordance with the instructions provided in this unit
and in 40 CFR part 178. To ensure proper receipt by EPA,

[[Page 37832]]

you must identify docket control number OPP-300368B in the subject line
on the first page of your submission. All requests must be in writing,
and must be mailed or delivered to the Hearing Clerk on or before
September 17, 2001.
    1. Filing the request. Your objection must specify the specific
provisions in the regulation that you object to, and the grounds for
the objections (40 CFR 178.25). If a hearing is requested, the
objections must include a statement of the factual issues(s) on which a
hearing is requested, the requestor's contentions on such issues, and a
summary of any evidence relied upon by the objector (40 CFR 178.27).
Information submitted in connection with an objection or hearing
request may be claimed confidential by marking any part or all of that
information as CBI. Information so marked will not be disclosed except
in accordance with procedures set forth in 40 CFR part 2. A copy of the
information that does not contain CBI must be submitted for inclusion
in the public record. Information not marked confidential will be
included in the public version of the official record without prior
notice.
    Mail your written request to: Office of the Hearing Clerk (1900),
Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,
Washington, DC 20460. You may also deliver your request to the Office
of the Hearing Clerk in Rm. C400, Waterside Mall, 401 M St., SW.,
Washington, DC 20460. The Office of the Hearing Clerk is open from 8
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The
telephone number for the Office of the Hearing Clerk is (202) 260-4865.
    2. Tolerance fee payment. If you file an objection or request a
hearing, you must also pay the fee prescribed by 40 CFR 180.33(i) or
request a waiver of that fee pursuant to 40 CFR 180.33(m). You must
mail the fee to: EPA Headquarters Accounting Operations Branch, Office
of Pesticide Programs, P.O. Box 360277M, Pittsburgh, PA 15251. Please
identify the fee submission by labeling it ``Tolerance Petition Fees.''
    EPA is authorized to waive any fee requirement ``when in the
judgement of the Administrator such a waiver or refund is equitable and
not contrary to the purpose of this subsection.'' For additional
information regarding the waiver of these fees, you may contact James
Tompkins by phone at (703) 305-5697, by e-mail at tompkins.jim@epa.gov,
or by mailing a request for information to Mr. Tompkins at Registration
Division (7505C), Office of Pesticide Programs, Environmental
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460.
    If you would like to request a waiver of the tolerance objection
fees, you must mail your request for such a waiver to: James Hollins,
Information Resources and Services Division (7502C), Office of
Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania
Ave., NW., Washington, DC 20460.
    3. Copies for the docket. In addition to filing an objection or
hearing request with the Hearing Clerk as described in Unit II., you
should also send a copy of your request to the PIRIB for its inclusion
in the official record that is described in Unit I.B.2. Mail your
copies, identified by docket control number OPP-300368B, to: Public
Information and Records Integrity Branch, Information Resources and
Services Division (7502C), Office of Pesticide Programs, Environmental
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460.
In person or by courier, bring a copy to the location of the PIRIB
described in Unit I.B.2. You may also send an electronic copy of your
request via e-mail to: opp-docket@epa.gov. Please use an ASCII file
format and avoid the use of special characters and any form of
encryption. Copies of electronic objections and hearing requests will
also be accepted on disks in WordPerfect 6.1/8.0 file format or ASCII
file format. Do not include any CBI in your electronic copy. You may
also submit an electronic copy of your request at many Federal
Depository Libraries.

B. When Will the Agency Grant a Request for a Hearing?

    A request for a hearing will be granted if the Administrator
determines that the material submitted shows the following: There is a
genuine and substantial issue of fact; there is a reasonable
possibility that available evidence identified by the requestor would,
if established resolve one or more of such issues in favor of the
requestor, taking into account uncontested claims or facts to the
contrary; and resolution of the factual issues(s) in the manner sought
by the requestor would be adequate to justify the action requested (40
CFR 178.32).

III. Under What Authority Is EPA Issuing this Final Rule?

    This exemption from the requirement of a tolerance is being issued
under the authority of section 408(c) of the FFDCA (21 U.S.C. 346a(c)).
Under FFDCA section 408, EPA regulates pesticide chemical residues by
establishing tolerances limiting the amounts of residues that may be
present in or on food, or by establishing exemptions from the
requirement of a tolerance for such residues. Food includes articles
used for food or drink by humans or other animals. A food containing
pesticide residues may not be moved in interstate commerce without an
appropriate tolerance or an exemption from the requirement of a
tolerance.
    Section 408 of the FFDCA applies to all ``pesticide chemical
residues '' which are defined as residues of either a ``pesticide
chemical'' or ``any other added substance that is present on or in a
commodity or food primarily as a result of the metabolism or other
degradation of a pesticide chemical'' (21 U.S.C. 321(q)(2)). The FFDCA
defines ``pesticide chemical'' as: ``any substance that is a pesticide
within the meaning of the Federal Insecticide, Fungicide, and
Rodenticide Act, including all active and inert ingredients of such
pesticide.'' (21 U.S.C. 321(q)(1)). FIFRA section 2(u) defines
``pesticide'' as: ``(1) any substance or mixture of substances intended
for preventing, destroying, repelling, or mitigating any pest, (2) any
substance or mixture of substances intended for use as a plant
regulator, defoliant, or desiccant, and (3) any nitrogen stabilizer''
(7 U.S.C. 136(u)). Under FIFRA section 2(t), the term ``pest'' includes
``(1) any insect, rodent, nematode, fungus, weed, or (2) any other form
of terrestrial or aquatic plant or animal life or virus, bacteria, or
other microorganism'' with certain exceptions (7 U.S.C. 136(t)).
    Under FFDCA section 408(c), EPA can establish an exemption from the
requirement of a tolerance for a ``pesticide chemical residue'' only if
EPA determines that granting such an exemption is ``safe'' (21 U.S.C.
346a(c)(2)(A)(i)). The FFDCA defines ``safe'' to mean that ``there is a
reasonable certainty that no harm will result from aggregate exposure
to the pesticide chemical residue, including all anticipated dietary
exposures and all other exposures for which there is reliable
information'' (21 U.S.C. 346a(c)(2)(A)(ii)). This includes exposure
through drinking water, and residential and other indoor uses, but does
not include occupational exposure. In establishing an exemption from
the requirement of a tolerance, FFDCA section 408(c) does not authorize
EPA to consider potential benefits associated with use of the pesticide
chemical in determining whether the pesticide chemical may be exempted.
    FFDCA section 408 requires EPA to give special consideration to
exposure of infants and children to the pesticide chemical residue in
establishing an exemption and to ``ensure that there is a reasonable
certainty that no harm will

[[Page 37833]]

result to infants and children from aggregate exposure to the pesticide
chemical residue'' (21 U.S.C. 346a(b)(2)(C)(ii)(I)) and (c)(2)(B)).
FFDCA section 408(b)(2)(D) specifies other general factors EPA must
consider in establishing an exemption (21 U.S.C. 346a(b)(2)(D)). FFDCA
section 408(c)(3) prohibits an exemption unless there is either a
practical method for detecting and measuring levels of pesticide
chemical residue in or on food or there is no need for such a method,
requiring EPA to state the reason for this determination (21 U.S.C.
346a(c)(3)).

IV. Context

A. What Role Does this Exemption Play in EPA's Approach to Plant-
Incorporated Protectants?

    The substances plants produce for protection against pests are
pesticides under the FIFRA definition of pesticide, if humans intend to
use these substances for ``preventing, destroying, repelling or
mitigating any pest.'' These substances, produced and used in living
plants, along with the genetic material necessary to produce them, are
designated ``plant-incorporated protectants'' by EPA.
    To understand the role this exemption plays in EPA's approach to
plant-incorporated protectants, the following two considerations must
be understood. First, what constitutes the residues of plant-
incorporated protectants derived through conventional breeding from
plants sexually compatible with the recipient plant and why EPA is
exempting them from the requirement of a tolerance. Second, how this
exemption from the FFDCA requirement of a tolerance for residues of
plant-incorporated protectants derived through conventional breeding
from sexually compatible plants relates to the exemption from the FFDCA
requirement of a tolerance published elsewhere in this issue of the
Federal Register for residues of nucleic acids that are part of a
plant-incorporated protectant.
    1. What constitutes the residues of plant-incorporated protectants
derived through conventional breeding from sexually compatible plants
and why is EPA exempting them? In developing its approach to plant-
incorporated protectants, EPA took into account the properties of
pesticidal and other substances produced and used in plants. In
particular, EPA recognized that plants have evolved, and thus naturally
possess, various mechanisms to resist pests. The mechanisms of
resistance can be varied, including, for example, structural
characteristics of the plant, the production of general metabolites
that have toxic properties, or the production of specific toxic
substances in response to pest attack. In breeding plant varieties,
humans have frequently intentionally used these mechanisms to create
varieties with varying abilities to prevent, destroy, repel or mitigate
pests. Based on human experience in breeding, growing, preparing, and
consuming food from such plant varieties and the large and varied
information developed through systematic scientific study available in
the literature, EPA recognized that residues of many plant-incorporated
protectants, in or on food or feed, would qualify for exemption from
regulation under FFDCA section 408. (Hereafter, EPA will use the term
``in food'' to represent the concept of ``in or on food or feed'' in
this preamble).
    For EPA to exempt any residue of a pesticide, including any residue
of a plant-incorporated protectant, EPA must find that there is a
reasonable certainty that no harm will result from aggregate exposure
to the residue, including all anticipated dietary exposures and all
other exposures for which there is reliable information. EPA takes this
action today with regard to residues of plant-incorporated protectants
derived through conventional breeding from sexually compatible plants
because it has determined that there is a reasonable certainty that no
harm will result from aggregate exposure to the residues, including all
anticipated dietary exposures and all other exposures for which there
is reliable information.
    Under FFDCA section 408, the term residue is defined broadly to
include residues of the active and inert ingredients of the pesticide
itself and residues that are present in the food as a result of the
metabolism or other degradation of the pesticide (21 U.S.C. 321(q)).
For plant-incorporated protectants derived through conventional
breeding from sexually compatible plants, EPA anticipates the residues
will consist of the pesticidal substance and the genetic material
necessary for production of the pesticidal substance, and any substance
that might function as an inert ingredient as defined for plant-
incorporated protectants (e.g., any selectable marker), and the genetic
material necessary for production of the inert ingredient.
    This action exempts from the requirement of a tolerance under FFDCA
section 408, residues of the pesticidal substance portion of plant-
incorporated protectants derived through conventional breeding from
plants sexually compatible with the recipient plant, and residues of
any inert ingredient introduced through conventional breeding from
plants sexually compatible with the recipient plant. For plant-
incorporated protectants, the recipient plant is the living plant that
receives the genetic material necessary to produce the pesticidal
substance and in which the plant-incorporated protectant is intended to
be produced and used.
    2. How does this exemption relate to the exemption from the FFDCA
requirement of a tolerance for residues of nucleic acids? This
exemption can be paired with EPA's tolerance exemption for residues of
nucleic acids that are part of a plant-incorporated protectant,
published elsewhere in a companion document in this issue of the
Federal Register. That exemption applies to residues of the genetic
material portion of all plant-incorporated protectants, and, thus, also
applies to residues of the genetic material necessary for the
production of the pesticidal substance portion of plant-incorporated
protectants derived through conventional breeding from sexually
compatible plants, and the residues of the genetic material necessary
for the production of any inert ingredient introduced through
conventional breeding from plants sexually compatible with the
recipient plant. Because of these actions, all residues of plant-
incorporated protectants derived through conventional breeding from
sexually compatible plants are exempt from FFDCA section 408
requirements.

B. Does this Final Rule Have Any Relevance to Other Types of
Pesticides?

    Nonviable plant tissues, organs or parts that are used as
pesticides, will not be covered by this exemption. Residues of such
pesticides are subject to the regulations found in 40 CFR parts 177
through 180 rather than 40 CFR part 174. An example of this type of
pesticide would be the powder, produced by drying and grinding cayenne
pepper, dusted on plants to protect them from pests.
    Residues of substances that are isolated from a plant's tissues and
then applied to plants and/or to food for pest control will not be
covered by this exemption. Residues of these types of pesticides in
formulations such as those for foliar application are subject to
regulations found in 40 CFR parts 177 through 180 rather than 40 CFR
part 174. An example of this type of pesticide would be pyrethrum
isolated from chrysanthemum plants, formulated with other ingredients
for foliar application, and sprayed onto other plants for pest control.

[[Page 37834]]

    Residues of substances that are synthesized will not be covered by
this exemption. Residues of such pesticides are subject to regulations
found in 40 CFR parts 177 through 180 rather than 40 CFR part 174. An
example of this type of pesticide is the herbicide, atrazine.

C. What Is the History of this Final Rule?

    This final rule is an additional step in fully implementing the
``Coordinated Framework for Regulation of Biotechnology'' of the United
States of America which was published in the Federal Register by the
Office of Science and Technology Policy (OSTP) on June 26, 1986 (51 FR
23302).
    EPA sponsored, or co-sponsored with other Federal agencies, three
conferences dealing with plant related issues: On October 19-21, 1987,
a meeting on``Genetically Engineered Plants: Regulatory
Considerations'' at Cornell University, Ithaca, New York; on September
8-9, 1988, a ``Transgenic Plant Conference'' in Annapolis, Maryland; on
November 6-7, 1990, a conference on ``Pesticidal Transgenic Plants:
Product Development, Risk Assessment, and Data Needs'' in Annapolis,
Maryland. Information from these conferences has been incorporated as
appropriate in development of this final rule.
    In developing its approach to plant-incorporated protectants, EPA
requested the advice of two scientific advisory groups at three
meetings. On December 18, 1992, pursuant to section 25 of FIFRA, a
subpanel of the FIFRA Scientific Advisory Panel (SAP) was convened to
review a draft policy on plant-pesticides (now called plant-
incorporated protectants) and to respond to a series of questions posed
by the Agency, primarily on EPA's approach under FIFRA. On July 13,
1993, EPA requested the advice of a subcommittee of the EPA
Biotechnology Science Advisory Committee (BSAC) on a series of
scientific questions dealing with EPA's approach to plant-pesticides
under FFDCA. On January 21, 1994, a joint meeting of the subpanel of
the SAP and the BSAC subcommittee was held and EPA asked advice on
approaches to plant-pesticides under both FIFRA and FFDCA. Advice from
these scientific advisory groups was considered in finalizing this
rule.
    EPA published in the November 23, 1994, Federal Register a package
of five separate documents (59 FR 60496, 60519, 60535, 60542, 60545)
(FRL-4755-2, FRL-4755-3, FRL-4755-4, FRL-4755-5, FRL-4755-8) which
described EPA's policy and proposals for plant-pesticides under FIFRA
and FFDCA. Included in that package was a proposal to exempt from the
FFDCA requirement of a tolerance, residues of the pesticidal substance
portion of plant-pesticides derived from closely related plants.
    On July 22, 1996, EPA published a supplemental document in the
Federal Register (61 FR 27891) (FRL-5387-4) on one aspect of its
November 23, 1994, Federal Register documents; i.e., how the concept of
inert ingredient related to plant-pesticides.
    In August of 1996, Congress enacted the FQPA which amended the
FFDCA and FIFRA. On May 16, 1997, EPA published in the Federal Register
a supplemental document (62 FR 27132) (FRL-5717-2) to provide the
public with an opportunity to comment on EPA's analysis of how certain
FQPA amendments to the FFDCA and FIFRA apply to the proposed tolerance
exemption for pesticide chemical residues derived from closely related
plants.
    On April 23, 1999, EPA published a supplemental document (64 FR
19958) (FRL-6077-6) in the Federal Register soliciting comment on
whether to change the name of this type of pesticide.
    The documents and the reports of the meetings described above are
available in the record for the rulemaking for plant-incorporated
protectants as described in Unit X.

V. What are the Key Features of the Proposed Exemption?

    The development of this exemption consists of a proposed rule which
appeared in the November 23, 1994, Federal Register (59 FR 60535), and
two supplemental documents; one document that appeared on July 22,
1996, in the Federal Register (61 FR 37891), and a second that appeared
in the May 16, 1997, Federal Register (62 FR 27132).

A. November 23, 1994, Federal Register Proposed Rule

    In the 1994 Federal Register document (59 FR 60535, November 23,
1994), EPA proposed to exempt residues of a category of plant-
pesticides it believed would qualify for an exemption. The proposed
exemption was based upon the premise that new dietary exposures would
not likely arise for these residues if the genetic material leading to
the production of the pesticide chemical residues is derived from a
plant that is closely related to the recipient plant; i.e., if the
plant that is the donor of the genetic material is closely related to
the plant receiving the genetic material.
    In the 1994 Federal Register document, EPA presented two options
for describing a standard based on the relatedness of plants. Option 1,
the Agency's preferred option proposed at 40 CFR 180.1137(a), used
sexual compatibility as a measure of relatedness between plants. Under
this option, residues of a pesticidal substance produced in a living
plant as part of a plant-pesticide would be exempt from the requirement
of a tolerance if the genetic material that encodes for the pesticidal
substance or leads to the production of the pesticidal substance is
derived from a plant that is sexually compatible with the recipient
plant and has never been derived from a source that is not sexually
compatible with the recipient plant.
    Option 2 would utilize the rank of genus as the taxonomic standard
for describing closely related plants, as well as sexual compatibility.
This option would exempt residues of a pesticidal substance derived
from a plant classified in the same genus as the recipient plant, as
well as residues of a pesticidal substance derived from a plant
sexually compatible with the recipient plant. Under both Options 1 and
2, residues of the pesticidal substance derived from plants sexually
compatible with the recipient plant would be exempt, even if the source
and recipient plants are classified in different genera.
    EPA proposed that ``sexually compatible,'' when referring to
plants, would mean ``capable of forming a viable zygote through the
fusion of two gametes, including the use of bridging and/or wide
crosses between plants.'' EPA proposed that ``bridging crosses between
plants'' would mean the ``utilization of an intermediate plant in a
cross between the intermediate plant and the first plant, in order to
cross the plant resulting from that zygote with a third plant that
would not otherwise be able to produce viable zygotes from the fusion
of its gametes with those of the first plant. The result of the
bridging cross is the mixing of the first and third plant through the
formation of an intermediate zygote.'' EPA proposed that ``wide crosses
between plants'' would mean ``to facilitate the formation of viable
zygotes through the use of surgical alteration of the plant pistil, bud
pollination, mentor pollen, immunosuppression, in vitro fertilization,
pre-pollination and post-pollination hormone treatments, manipulation
of chromosome numbers, embryo culture, or ovary and ovule cultures or
any other technique that the Administrator determines meets this
definition.''

[[Page 37835]]

    Neither of the options was intended to exempt residues of a
pesticidal substance that is significantly different functionally from
the pesticidal substance as it occurs in the source plant.
    The Agency also requested comment on the utility of an exemption
criterion based on the process (e.g., rDNA) used to introduce the
plant-incorporated protectant into a plant (59 FR at 60514, 60540,
60541). This approach was discussed by the SAP Subpanel and BSAC
Subcommittee at the joint meeting of these scientific advisory groups
held on January 21, 1994. In this approach, residues of plant-
incorporated protectants developed through techniques other than those
of modern biotechnology would be exempted, e.g., residues of those
plant-incorporated protectants developed through conventional plant
breeding would be exempted. Residues of those plant-incorporated
protectants that were not exempted could subsequently be considered for
exemption on the basis of risk potential.
    The joint Subcommittee/Subpanel report justified such an approach
on the following three considerations. First, the National Institutes
of Health Guidelines for Research Involving Recombinant DNA Molecules
established a precedent that has worked well. Second, although new
techniques, such as rDNA are more precise than conventional plant
breeding, it is possible to make with rDNA novel genetic modifications
never before possible. The novel combinations possible with modern
genetic techniques create uncertainties about how the gene will
function and how its products may affect the plant's phenotype and its
impact upon the environment and human health. Third, establishing rDNA
methodologies as a criterion for oversight may give the public more
confidence that risk potential is being evaluated. As a result,
approved products may move to the marketplace more easily (Ref. 6).

B. What Issues Were Discussed in the Supplemental Documents?

    Subsequent to publication of the November 23, 1994 Federal Register
document (59 FR 60535), EPA published two supplemental documents
directly relevant to this exemption: one on July 22, 1996 (61 FR
37891), and another on May 16, 1997 (62 FR 27132).
    1. July 22, 1996. The July 22, 1996, supplemental document (61 FR
37891) discussed how the concept of inert ingredient related to plant-
pesticides.
    2. May 16, 1997. In August of 1996, the FFDCA and FIFRA were
amended by the FQPA. On May 16, 1997, EPA published in the Federal
Register, a supplemental document (62 FR 27132) to provide the public
with an opportunity to comment on EPA's analysis of how certain FQPA
amendments to the FFDCA and FIFRA affect this proposed exemption.
    EPA stated in the May 16, 1997, supplemental document its belief
that most of the substantive factors the FFDCA now requires EPA to
consider when evaluating pesticide residues were considered when the
Agency proposed the exemption in 1994. EPA, thus, in the supplemental
document, specifically sought comment only on its evaluation of the
requirements imposed by FQPA that the Agency had not addressed in the
proposed rule. EPA sought comment on the following five considerations.
First, whether there are substances, outside of the food supply,
sharing a common mechanism of toxicity with residues of pesticidal
substances derived from sexually compatible plants. Commenters were
asked to submit information on the cumulative effects of such
substances and the pesticidal substances that were the subject of the
proposed exemption (59 FR 60535). Second, whether there are substances,
outside of the food supply, related via a common mechanism of toxicity
to such residues to which humans might be exposed through non-
occupational routes of exposure. Commenters were asked to describe
routes through which such exposure might occur, including exposure to
major identifiable subgroups of human populations (e.g., infants and
children). Commenters were requested, if such routes were identified,
to provide information on the nature and levels of expected exposures.
Comments were also sought on these two issues with regard to Option 2,
the alternative option for describing closely related plants (described
in Unit V.A.). Third, commenters who possess information on substances
occurring in food from plants that may have estrogenic effects and may
be used as plant-incorporated protectants were requested to send such
information to EPA. Fourth, EPA described in greater detail the
rationale supporting the statement made in the 1994 Federal Register
document (59 FR at 60513) that ``plant-pesticides are likely to present
a limited exposure of pesticidal substances to humans. In most cases,
the predominant, if not the only, route of exposure will be dietary.
Significant respiratory and dermal exposures will be unlikely.'' No
comments were received on this statement during the first comment
period for the proposed rule. The public was given the opportunity to
comment on EPA's more detailed rationale supporting the statement.
Fifth, EPA also described in greater detail how the rationale presented
in the 1994 Federal Register document (59 FR at 60538) concerning the
safety for human consumption of food from plants that meet the sexually
compatible standard applies to infants and children. The public was
given the opportunity to comment on the more detailed rationale
specifically addressing infants and children as part of the larger
human population.

VI. What are the Key Features of this Final Rule?

    In this final rule, EPA exempts residues of the pesticidal
substance and inert ingredient portion of plant-incorporated
protectants derived through conventional breeding from plants sexually
compatible with the recipient plant. The following language is added to
40 CFR 174.479:

    Residues of a pesticidal substance that is part of a plant-
incorporated protectant from a sexually compatible plant are exempt
from the requirement of a tolerance if all the following conditions
are met:
    (a) The genetic material that encodes for the pesticidal
substance or leads to the production of the pesticidal substance is
from a plant that is sexually compatible with the recipient food
plant.
    (b) The genetic material has never been derived from a source
that is not sexually compatible with the recipient food plant.
    (c) The residues of the pesticidal substance are not present in
food from the plant at levels that are injurious or deleterious to
human health.

    Pertinent associated definitions in 40 CFR 174.3 are discussed in
greater detail in a companion document published elsewhere in this
issue of the Federal Register on FIFRA regulations for plant-
incorporated protectants.
    In this final rule, plant means an organism classified using the 5-
kingdom classification system of Whittaker (Ref. 1) in the kingdom,
Plantae. Therefore, the term ``plant'' includes, but is not limited to,
bryophytes such as mosses, pteridophytes such as ferns, gymnosperms
such as conifers, and angiosperms such as most major crop plants.
    Also included in the regulatory text at Sec. 174.485, subpart X, is
an exemption for residues of inert ingredients in plants derived
through conventional breeding from sexually compatible plants.

VII. How Do the Proposed Rule and Final Rule Differ?

    This exemption from the requirement of a tolerance is adopted with
several

[[Page 37836]]

changes from the proposed rule published in 1994 (59 FR 60535, November
23, 1994). EPA has changed the name of this type of pesticide from
``plant-pesticide'' to ``plant-incorporated protectant'' as described
in the companion document on FIFRA regulations for plant-incorporated
protectants published elsewhere in this issue of the Federal Register.
EPA exempts at this time only a subgroup of the category it proposed to
exempt in 1994: Residues of pesticidal substances and inert ingredients
derived through conventional breeding from plants sexually compatible
with the recipient plant. In a companion document published elsewhere
in this issue of the Federal Register, EPA solicits additional comment
on alternative options for the plant-incorporated protectants derived
through modern biotechnology, e.g., recombinant DNA techniques, from
plants sexually compatible with the recipient plant.
    In response to concerns expressed in comments and to make EPA's
approach more consistent with the policy of the Food and Drug
Administration (FDA), EPA has added a condition to the exemption that
addresses levels of substances that are injurious or deleterious to
human health in food from plants in sexually compatible populations. A
few other modifications have been made to the text of the exemptions,
for purposes of clarification. A discussion of modifications to other
relevant definitions, including an analysis of comments on those
definitions, can be found in a companion document published elsewhere
in this issue of the Federal Register on FIFRA regulations for plant-
incorporated protectants. Discussion of all modifications can be found
in the documents summarizing public comments and EPA responses on
issues associated with plant-incorporated protectants (Ref. 2) located
in the record for this rule as described in Unit X.
    When EPA proposed the exemption in 1994 at 40 CFR 180.1137(a), it
also stated its intention (59 FR at 60520) to establish a new 40 CFR
part 174 specifically for plant-incorporated. This new 40 CFR part 174
is being established in a companion document published elsewhere in
this issue of the Federal Register. EPA adds this tolerance exemption
to 40 CFR 174.479, subpart W, rather than adding it to 40 CFR part 180
as proposed.

VIII. Discussion of Final Rule and Public Comments

    In this unit, EPA discusses the final rule and summarizes the
comments it received on the November 23, 1994 proposed rule and the May
16, 1997 supplemental document. EPA reviewed and considered all
comments received on the proposed rule and supplemental document and
prepared detailed responses to these comments. These responses can be
found at appropriate points in this preamble and in the Agency's
summary of public comments and EPA's response on issues associated with
plant-incorporated protectants (Ref. 2).

A. From Whom Did EPA Receive Comments?

    In response to the package of documents published in the Federal
Register in 1994, EPA received letters from industry, academia,
professional and trade associations, government agencies, state
regulatory authorities, public interest groups and private citizens.
Some of the commenters sent separate letters for each of the five
dockets associated with the 1994 Federal Register documents. Other
commenters sent a single letter addressing all five dockets. EPA
received comments on the July 22, 1996, supplemental document, and on
the May 16, 1997, supplemental document, which provided the public an
opportunity to comment on EPA's analysis of how certain amendments to
the FFDCA and FIFRA by FQPA affected this proposed exemption. Copies of
all comments received are available in the record for this rule as
described in Unit X.

B. Exemption of Residues of Plant-Incorporated Protectants Derived
Through Conventional Breeding from Sexually Compatible Plants

    On November 23, 1994 (59 FR 60535), EPA proposed to exempt from the
FFDCA requirement of a tolerance, all residues of a category of plant-
incorporated protectants based on the premise that new dietary
exposures would be unlikely if the genetic material leading to the
production of the plant-incorporated protectant is derived from a plant
closely related to the recipient plant. EPA offered two options for
defining plant-incorporated protectants derived from plants closely
related to the recipient plant. The options were somewhat different
approaches to describing a high degree of relatedness between the
genetic donor and the recipient plant. Neither of the options was based
on the process by which a plant-incorporated protectant was introduced
into the recipient plant. Option 1, based upon sexual compatibility,
was EPA's preferred option (59 FR 60542). Option 2, used taxonomy
(genus) in conjunction with sexual compatibility to define closely
related plants. The Agency also requested comment on the utility of an
exemption criterion based on the process (e.g., rDNA) used to introduce
the plant-incorporated protectant into a plant (59 at FR 60514, 60540,
60541).
    During the comment period for the 1994 proposed rule, EPA received
19 comments addressing the options for describing pesticidal substances
derived from closely related plants. Nine of these comments supported
Option 1 and generally agreed that the sexual compatibility standard is
reasonable and adequately addresses food safety issues. Three comments
favored Option 2, with one of these comments arguing that species
belonging to the same genus are closely related and thus have a high
degree of biochemical similarity even though they may not be sexually
compatible. The commenter also cited the history of safe use of foods
from plant varieties developed through plant breeding. EPA also
received comments expressing serious reservations about using, for this
exemption, a taxonomic standard for describing closely related plants
(i.e., Option 2), because taxonomic categories, and the relationship of
a given plant species to a given taxon, may be transient since
taxonomic categories may change as information accrues. Others
expressed concern that dietary risk may be presented by such a
standard.
    EPA received 37 comments on the use of the process by which the
genetic material is introduced into the plant as an exemption
criterion. Twenty of these comments supported an approach based on
process, i.e., that those plant-incorporated protectants introduced by
rDNA would be regulated. The arguments advanced by these commenters can
be represented by the comment that:

    Genetic engineering (particularly recombinant DNA [rDNA]
methodologies), represents a fundamental technical advance over
traditional plant breeding in the ability to manipulate plants
genetically. Genes which code for production of plant-pesticides can
be readily turned `on' or `off' to dramatically increase the
existing levels of plant-pesticides within plants, turning plants
into pesticide factories and delivery systems. . . . given the fact
that rDNA technologies represent such a fundamental technical
advance over plant breeding, and given that plant-pesticides are by
their very nature toxic substances, all plant-pesticides produced
via rDNA methodologies should undergo some form of review under both
FIFRA and FFDCA . . . (Ref. 3).

    Several letters described quantitative changes in the levels of
plant-incorporated protectants as specific

[[Page 37837]]

instances in which the commenter believed risk would be better
addressed by an approach based on process. One of these commenters did
not agree with EPA's analysis that levels of the plant-incorporated
protectants (and thus of their residues) are likely to fall, in the
vast majority of cases, within ranges currently found in safely
consumed food from plants. Another of these commenters urged EPA to
modify the proposed exemption so that the Agency would be notified if
levels of pesticidal substances are ``deliberately increased through
the introduction or modification of promoters or other noncoding
regulatory sequences or there is reason to believe that levels of a
plant-pesticide in food or feed derived from a particular crop will be
increased by an order of magnitude or more'' (Ref. 3).
    In response to the May 16, 1997, supplemental document, EPA
received six comments. Five comments supported exemption of residues of
plant-incorporated protectants derived from sexually compatible plants,
with four comments addressing specific questions posed by EPA. One
commenter, however, opposed any exemption that did not take into
account quantitative changes in the levels of these residues, stating
that ``current knowledge is certainly inadequate to sanction greatly
increased levels of these substances'' in food (Ref. 4).
    Some comments urging regulation based on whether rDNA had been used
to introduced the plant-incorporated protectant, supported exempting
conventional breeding. One commenter, for example, stated ``that a long
record of experience with the products of natural evolution and
traditional breeding shows that they typically do not present new
dietary exposures and should be exempt from tolerance requirements''
(Ref. 5).
    Based on the advice of the BSAC and SAP at the joint meeting held
January 21, 1994, and the comments received in response to the November
23, 1994 Federal Register document, EPA has determined that it is
appropriate at this time to exempt from the FFDCA tolerance requirement
those residues of the pesticidal substance portion of plant-
incorporated protectants, as well as any inert ingredients derived
through conventional breeding from plants sexually compatible with the
recipient plant. In a companion document published elsewhere in this
issue of the Federal Register, EPA solicits public comment on
alternative options for the category of residues of pesticidal
substances derived through the techniques of modern biotechnology,
e.g., recombinant DNA, from plants sexually compatible with the
recipient plant. The Agency is considering these options in response to
public comment on its earlier proposals. One of these options would
establish notification procedures, and as the public has not had an
opportunity to comment on either the procedures themselves, or the
criteria on which EPA would base its regulatory decisions, the Agency
believes it would be appropriate to seek additional public comment
prior to adopting a particular option. In addition, as these
alternatives would distinguish between categories of residues of plant-
incorporated protectants based solely on the processes by which they
are derived, the public will also have an opportunity to present
comments on whether this is an appropriate distinction for regulatory
purposes.

C. What is the Language of the Exemption?

    In this final rule, EPA is, at 40 CFR 174.479, exempting only a
subgroup of the category of residues it proposed to exempt in 1994,
pesticide chemical residues derived through conventional breeding from
plants sexually compatible with the recipient plant. EPA discusses the
language of the exemption as it applies to this subcategory.
    1. Why is sexual compatibility an appropriate standard? EPA
believes that sexual compatibility is an appropriate standard because
sexually compatible plants share a common pool of genetic material,
even though there may be some variability among plants in sexually
compatible populations. Sexual compatibility, the ability to produce
viable offspring, is only possible in nature for plants that possess
many traits in common. Traits, and the genetic material encoding them,
can be passed through sexually compatible plant populations by
hybridization, and the mixing of genetic material that occurs through
this process of mating tends to a situation where the members of
sexually compatible population have similar traits and similar genetic
material. This is particularly true with crop plants where generations
of selection and breeding have tended to increase the homogeneity of
traits used to produce agriculturally important cultivars. Sexual
compatibility thus presents a natural grouping of plants which can be
readily described and used as a regulatory standard, and about which a
large amount of information exists in the scientific literature. This
information can be used in assessing risk.
    Using sexual compatibility as a standard affords a clear
delineation of whether the residues of a plant-incorporated protectant
meet the conditions of the exemption. In most cases, whether two plants
are sexually compatible is known; thus, testing to determine whether
the plants are sexually compatible is not likely to be necessary. If,
in rare cases, it is not known whether two plants are sexually
compatible, the means of determining sexual compatibility is
straightforward and simple. Sexual compatibility is empirically
demonstrable. EPA believes that the criterion of sexual compatibility
provides a high level of regulatory clarity and the greatest ease of
implementation, while at the same time presenting the lowest
probability of novel dietary exposure. This standard allows the public,
industry, and EPA to easily and readily identify those plant-
incorporated protectants that meet the criterion of being derived from
plants closely related to the recipient plant.
    i. Why is sexual compatibility limited to conventional breeding? As
explained in a companion document published elsewhere in this issue of
the Federal Register, EPA is soliciting additional comment on the
various options it is considering in response to the significant
comments it has received raising issues specific to plant-incorporated
protectants derived through genetic engineering. Because none of the
comments raised significant issues relative to pesticide chemical
residues of plant-incorporated protectants derived through conventional
breeding, the Agency is finalizing its proposals with respect to
residues of this subgroup of products. In a final rule under FIFRA
described elsewhere in a companion document in this issue of the
Federal Register, EPA includes in the definition of sexually compatible
at 40 CFR 174.3 the clause ``through conventional breeding.'' EPA also
provides a definition of conventional breeding that equates it to 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. Conventional breeding 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.
EPA believes that this

[[Page 37838]]

definition addresses the recommendation of the SAP/BSAC that ``the
Agency define methodologies in a way that clearly delineates to the
scientific community and the public what is and is not included in the
regulatory scope'' (Ref. 6).
    In the 1994 proposed rule (59 FR at 60538) and in the 1997
supplemental document (62 FR at 27135), EPA states that its proposed
rule is based on ``experience with the exposure of human populations to
crops developed through the breeding process, i.e., crops developed
through 50 to 100 years of scientific breeding among sexually
compatible plant populations using Mendelian genetics.'' In its 1994
proposed rule, EPA calls this type of breeding, ``traditional
breeding'' (see e.g., 59 FR 60519). When the Agency determined that it
would exempt a subgroup of residues of the sexually compatible
grouping, while allowing additional comment on how the Agency should
treat the residues of those plant-incorporated protectants introduced
into the plant through the techniques of modern biotechnology, EPA
chose to describe the exempt group of residues in the most
straightforward manner, as those derived through breeding in sexually
compatible populations. Recognizing that many consider the modern
techniques of biotechnology as simply an extension of breeding
techniques, EPA determined that an adjective was needed to modify the
word ``breeding'' to adequately describe the exempt group. Although the
Agency used the word ``traditional'' in its 1994 proposed rule, EPA
chose the word ``conventional'' to describe this type of breeding in
this rule because the SAP/BSAC in the report of their January 21, 1994
joint meeting used the adjective ``conventional'' in its advice to EPA
(Ref. 6), and the word ``conventional'' might more readily connote
techniques such as wide crosses.
    ii. Why is conventional breeding described by processes such as
pollination and vegetative reproduction? One comment received on the
1994 proposed rule suggested that there is ambiguity in the proposed
regulatory language at 40 CFR 174.5(a) in the November 23, 1994,
Federal Register document (59 FR 60535). The commenter indicated the
perceived ambiguity could lead to questions about whether plant-
incorporated protectants that are ``native'' to a food crop would meet
the criteria of exemption.
    Because of the use of the word ``food'' in the comment, it was not
clear whether the comment is directed toward EPA's proposed exemption
under FIFRA or that under the FFDCA for residues of plant-incorporated
protectants derived from plants sexually compatible with the recipient
plant. EPA assumes this comment is directed at both exemptions, and
that the commenter's suggestion is that EPA ensure that the regulatory
language exempts from the FFDCA tolerance requirements, residues of
those plant-incorporated protectants that normally occur in a plant
(i.e., are ``native'' to the plant) and will be used in that plant. For
example, if corn normally produced a plant-incorporated protectant, the
regulatory text should be clear that the residues of the plant-
incorporated protectant would be exempt when produced and used in corn.
EPA believes inclusion of the word ``pollination'' as an example of a
process leading to syngamy in the definition of conventional breeding
addresses this concern. EPA believes the word ``pollination'' is
appropriate because pollination is the process through which
traditional breeding occurs (see e.g., 59 FR 60537) (Ref. 7). Inclusion
of the word ``pollination'' in the definition emphasizes that plant-
incorporated protectants that occur naturally in a plant growing from a
viable zygote that arises by the mating in conventional breeding of one
corn variety with another, or the mating of a corn plant with a corn
plant of the same variety, are exempt.
    EPA recognizes that this same concern also applies to plant-
incorporated protectants in plants that are propagated vegetatively.
EPA believes inclusion of the phrase ``vegetative reproduction'' in the
definition of conventional breeding addresses this concern. The
language of the exemption for pesticide chemical residues derived
through conventional breeding from sexually compatible plants
specifically exempts residues in plants reproduced vegetatively. For
example, residues of a plant-incorporated protectant in a plant
propagated only vegetatively, (e.g., bananas), are exempt. Also exempt
are residues of a plant-incorporated protectant in a plant propagated
primarily vegetatively (e.g., potatoes), as long as, under conditions
of reproduction through hybridization, the plant donating the genetic
material is sexually compatible with the recipient plant as defined in
at 40 CFR 174.3, and the other conditions described at 40 CFR 174.479
are met. Inclusion of this term in the definition of conventional
breeding reflects EPA's statement in the 1994 proposed rule (59 FR
60524) on the status of crop plant varieties propagated vegetatively.
    iii. Will wide and bridging crosses be part of the definition of
conventional breeding? In the final rule under FIFRA described
elsewhere in a companion document in this issue of the Federal
Register, EPA defines ``conventional breeding'' to include wide and
bridging crosses. These definitions are also important to this FFDCA
tolerance exemption, and thus, EPA discusses them in this preamble.
    In the final rule, wide crosses include use of surgical alteration
of the plant pistil, bud pollination, mentor pollen,
immunosuppressants, in vitro fertilization, pre-pollination and post-
pollination hormone treatments, manipulation of chromosome numbers,
embryo culture or ovary and ovule cultures. Generations of artificial
hybridizations through these techniques have taken place in the well-
established practices of plant breeding (Ref. 8). Wide crosses, have
been in the past and are currently, commonly used to expand the plant
gene pool for varietal improvement, and a history of safe use has been
associated with plant varieties developed through the use of wide cross
techniques (Ref. 8). A fairly high degree of relatedness between the
parental plants is indicated when a wide cross produces a viable
zygote. This high degree of relatedness indicates a low probability of
new exposures. Agricultural plants safely consumed as food have been
developed in the past 100 years utilizing wide crosses in the breeding
process.
    The definition of ``bridging crosses between plants'' is intended
to convey the concept that an intermediate plants could be used in a
cross to move traits from a source plant into a desired recipient
plant. The intermediate plant can form viable zygotes with both the
source and recipient plants, whereas the source and recipient plant
cannot form viable zygotes. The intermediate plant serves as a bridge
for gene flow between the two incompatible plants. The result of the
bridging cross is the mixing of genetic material of the first and third
plant through the formation of an intermediate zygote. No comments were
received on the proposed definition of bridging crosses between plants,
also part of the definition of conventional breeding for sexually
compatible. EPA is adopting this definition as proposed.
    iv. Will cell or protoplast fusion be part of the definition of
wide crosses? EPA received one comment suggesting that protoplast
fusion should be included in the definition of wide crosses between
plants. That request was made in the context of the proposal to exempt
plant-incorporated protectants derived from plants sexually

[[Page 37839]]

compatible with the recipient plant from FIFRA requirements, but as the
definition of wide crosses is also relevant for this FFDCA exemption,
EPA will discuss that comment in this preamble.
    In the technique of protoplast fusion, protoplasts are made in the
laboratory through the removal of the cell walls of somatic cells. A
somatic cell is a type of cell that forms plant vegetative tissues and
organs and is distinguished from a germ cell which undergoes meiosis to
produce reproductive tissues (e.g., pollen and egg cells). In the
technique of protoplast fusion, protoplast are made from the somatic
tissues of two different plants. The membranes of the different
protoplasts are then fused together mechanically through processes such
as treatment with polyethylene glycol, producing a hybrid somatic cell
with a genetic make-up resulting from the combination and sorting of
the two plant genomes. The somatic hybrid cell is then grown on
specialized media into a mature plant.
    In support of the request, the commenter argued that the
hybridization of somatic cells (i.e., protoplast fusion) has a history
of use to artificially induce sexual compatibility. The commenter
argued that movement of genetic material by this means has historically
been considered safe.
    EPA did not, in its 1994 proposed rule include protoplast fusion in
the definition of wide crosses between plants, nor did it perform an
analysis of the potential for new dietary exposures when protoplast
fusion is used to perform wide crosses between plants. The commenter
did not provide such information in response to the 1994 proposed rule
nor the 1997 supplemental document. EPA does not believe information
currently in the record supports inclusion of protoplast fusion in the
definition of wide crosses. Therefore, EPA does not include protoplast
fusion in the definition of wide crosses and specifically excludes cell
fusion from the definition of conventional breeding. However, EPA
requests comment on whether protoplast fusion should be included in the
definition of wide crosses in a supplemental document published
elsewhere in this issue of the Federal Register. EPA would welcome
submission of information on protoplast fusion. If the Agency obtains
sufficient information demonstrating a low probability of risk, EPA may
initiate notice-and-comment rulemaking under FIFRA section 25(b) and
FFDCA section 408 to include protoplast fusion in the definition of
wide crosses between plants.
    v. ``Recombinant DNA'' and genetic material ``extracted from an
organism and introduced into the genome of the recipient plant.'' As
explained previously, EPA restricted this exemption to conventionally
bred plant-incorporated protectants while the Agency solicits
additional comment on the alternatives it is considering in response to
the comments received on the 1994 proposal. Thus, in order to fully
describe which plant-incorporated protectants are exempt under this
exemption, EPA includes limiting phrases. EPA in the 1994 Federal
Register document (59 FR 60541, November 23, 1994) discussion of the
advice of the joint SAP/BSAC at the January 21, 1994 meeting on the use
of a process-based criterion to define a category of plant-incorporated
protectants that would be subject to review, stated that the Agency
would define such a process-based criterion in the following way: ``The
genetic material that encodes for the pesticidal substance or leads to
the production of the pesticidal substance is extracted from an
organism and introduced into the genome of the recipient plant or is
synthesized in vitro and introduced into the genome of the recipient
plant.'' EPA in this action uses the language it put forth in the 1994
Federal Register to fashion two of the exclusions from the conventional
breeding definition at 40 CFR 174.3. One exclusion is for techniques
involving the direct introduction into an organism of genetic material
extracted from the source and introduced into a recipient plant.
Processes such as micro-injection, macro-injection and micro-
encapsulation would be excluded from the conventional breeding
definition because they are used to introduce such extracted genetic
material into the recipient plant. These processes have been included
in the definition as examples to assist in understanding the concept.
    The second exclusion from the conventional breeding definition uses
the term ``recombinant DNA'' to represent the concept of ``extracted
from an organism. . ., synthesized in vitro and introduced into the
genome of the recipient plant.'' To provide greater technical accuracy,
EPA provides a definition at 40 CFR 174.3 for recombinant DNA as
follows: ``Recombinant DNA means the genetic material has been
manipulated in vitro through the use of restriction endonucleases and/
or other enzymes that aid in modifying genetic material, and
subsequently introduced into the genome of the plant.''
    2. Why is the concept of ``functionally modified from the source''
important and how does the definition of conventional breeding address
it? In the November 23, 1994 Federal Register document (59 FR at
60539), EPA explained that in proposing the exemptions the Agency did
not intend to exempt residues of a pesticidal substance that is
significantly different functionally, from the pesticidal substance as
it occurs in the source plant. EPA believed this limitation is
appropriate because rearrangements or modifications of the genetic
sequence encoding a pesticidal substance made through the use of
techniques such as rDNA could, for example, result in a plant-
incorporated protectant, and/or residues of such a plant-incorporated
protectant, with significantly different functions from the function in
the source plant. For example, if the pesticidal substance is an
enzyme, it could be modified so that it acts on a different substrate
in the recipient plant than it did in the source plant (Refs. 8 and 9).
Residues of such a significantly modified pesticidal substance would
not necessarily present risks similar to the substance prior to
modification, nor would the base of experience on which EPA relies for
support of the exemption necessarily be relevant. If the genetic
material encoding the pesticidal substance has been modified in such a
way that the pesticidal substance functions differently in the
recipient plant than it did in the source plant, the analysis performed
to determine that there is a reasonable certainty that no harm will
result from aggregate exposure to the residues of the plant-
incorporated protectant, would not apply.
    In this final rule, this concern is addressed by the limitation
placed on the definition of sexually compatible. Under this definition,
residues of pesticidal substances from sexually compatible plants are
only exempt if the genetic material is introduced into the plant
through conventional breeding as defined at 40 CFR 174.3. The types of
changes discussed above (Refs. 8 and 9) that can be made through modern
molecular techniques, are very unlikely to be made through conventional
breeding as defined at Sec. 174.3, and residues of plant-incorporated
protectants modified through modern molecular techniques are not
eligible for today's exemption.
    3. Why is the phrase ``never derived from source not sexually
compatible with recipient plant'' important? EPA discussed the
relevance of this phrase to the proposed exemption in the November 23,
1994 Federal Register

[[Page 37840]]

document (59 FR 60539). The phrase, ``has never been derived from a
source that is not sexually compatible with the recipient plant,'' was
included in the proposed regulatory text to clearly indicate that
pesticide chemical residues of a plant-incorporated protectant would
not qualify for the exemption if the genetic material is introduced
into a recipient plant from a sexually incompatible source and then
subsequently introduced from this recipient plant into other plants
sexually compatible with the recipient plant. For example, the
exemption does not extend to a situation where the genetic material
encoding the Bacillus thuringiensis delta endotoxin is introduced into
wheat, and the endotoxin-producing wheat is subsequently hybridized
with rye using wide cross techniques to produce triticale. The residues
of the endotoxin produced in the triticale would not be eligible for
the exemption because the genetic material encoding the endotoxin
originated from a bacterium, a source that is not sexually compatible
with the original recipient plant (wheat in this example).
    One commenter suggested that the Agency delete this phrase from the
regulatory text and instead include a period of time after which a
plant-incorporated protectant would be treated as part of a plant's
``accessible'' gene pool. EPA disagrees and will continue to include
this language in the final rule at 40 CFR 174.479. Further, EPA
disagrees with the commenter's suggestion that a gene, derived from a
phylogenetically distant source and successfully used in a crop, be
treated after a period of time as though it had become part of the
crop's gene pool (i.e., equivalent to a gene that had evolved in a
sexually compatible population of plants). The commenter does not
suggest what an appropriate period of time would be nor how this would
correlate with the potential for dietary exposures. Without additional
information, EPA cannot find that there is a ``reasonable certainty
that no harm will result from aggregate exposure to the pesticide
chemical residue'' as required by FFDCA section 408(c).
    4. Why is EPA placing a condition on the exemption limiting the
levels of pesticidal substances? To address concerns raised in comment
on its original proposal concerning the possibility that certain
substances normally present in plants in sexually compatible
populations may in rare circumstances be present in food at levels that
are hazardous, EPA is limiting this exemption by requiring that the
residues of the pesticidal substance not be present in food from the
plant at levels that are injurious or deleterious to human health. EPA
is including at 40 CFR 174.479, the following condition to the language
of the exemption: ``(c) The residues of the pesticidal substance are
not present in food from the plant at levels that are injurious or
deleterious to human health.''
    If the residues of the plant-incorporated protectant do not meet
this criterion, they are not exempt from the requirement of a
tolerance, nor would a tolerance have been established for them. A food
containing residues of a pesticide may not be moved in interstate
commerce without either an appropriate tolerance or an exemption from
the requirement of a tolerance. Should such an occurrence be
identified, the condition will allow expeditious removal of the
offending food from the market. EPA does not believe that such an
occurrence will result a priori in a reevaluation of the categorical
exemption for pesticidal substances derived through conventional
breeding from sexually compatible plants under FFDCA section 408
because any problem will likely be associated with a single variety.
    Producers who wish to increase the levels of pesticidal substances
in plants in sexually compatible populations beyond the ranges of
levels generally seen in plant varieties currently on the market and
known to produce food safe for consumption are strongly encouraged to
consult with EPA to determine whether their plant-incorporated
protectant is eligible for the exemption from the requirement of a
tolerance, or whether a tolerance, and therefore, a registration is
necessary. Based on the record compiled for this rulemaking on the
historical safety of food from plants in sexually compatible
populations, as described in Unit IX.A. and Unit IX.B.1., EPA believes
that such a circumstance, will be extremely unlikely for residues
derived through conventional breeding from plants sexually compatible
with the recipient plant.
    This condition makes EPA's approach to plant-incorporated
protectants more consistent with FDA's regulatory approach, and allows
the agencies to act more expeditiously in the rare circumstance that a
risk associated with higher levels of substances normally part of a
plant in a sexually compatible population is identified in food.
    This condition, in conjunction with the reporting requirement at 40
CFR 174.71, is conceptually similar to the suggestion of one commenter
that the Agency be notified if levels of pesticidal substances are
significantly increased. EPA disagrees, however, with the commenter's
suggestion that notification be required only when levels of pesticidal
substances are increased by 10 fold. There is natural variability in
levels of expression in a plant of any substance, including plant-
incorporated protectants, influenced by factors such as genetic
composition, soil composition, climate and weather. Humans are
currently being exposed to variation in the food they consume. The
commenter did not provide information to support the suggestion that a
10-fold increase would represent an unacceptable risk, and broad
adoption of such a standard would be arbitrary. The variations normally
seen in food from plants, such as the 20-fold variation for ascorbic
acid in muskmelon depending on variety planted, and the variation in
the levels of carotene in carrots which can range from none detectable
to 370 mg/100 g tissue depending on the variety (Ref. 8), are greater
than the 10-fold increase suggested by comment. Other examples can be
offered where the variation falls within a more narrow range, for
example, one researcher (Ref. 8) reported that depending on maturity of
the fruit, the level of ascorbic acid in tomato can range from 2.7 mg/
100 g tissue to 7.6 mg/100 g tissue, a 2.8-fold variation. The
conditions on the exemption at Sec. 174.479 and reporting requirement
at Sec. 174.71, on the other hand, have no numerical standards.
Nevertheless, the Agency believes that the adverse effects reporting
requirement will allow the Agency to monitor for any rare instances in
which significant increases in levels of plant-incorporated protectants
might present a hazard, and that the condition at Sec. 174.479 will
allow EPA and FDA to act expeditiously. (The adverse effects reporting
requirement is described in a companion document published elsewhere in
this issue of the Federal Register on FIFRA regulations for plant-
incorporated protectants).
    The historical safety of the food supply as described by the record
EPA has compiled for this exemption, the reporting requirement imposed
as a condition of the FIFRA exemption, taken in conjunction with the
strong likelihood that manufacturers and companies will choose to
consult with EPA rather risk seizure of their food by FDA, cause EPA to
believe that the condition placed on the exemption sufficiently address
the commenters' concerns.
    5. Why does 40 CFR 174.479 include language limiting the recipient
to food plants? In the preamble to the 1994

[[Page 37841]]

proposed rule (see e.g., 59 FR 60537), EPA discussed the premise for
this exemption; that ``new dietary exposures would not likely arise for
plant-pesticides produced in recipient food plants if the genetic
material leading to the production of the pesticidal substance is
derived from closely related plants.'' In addition, the BSAC in its
report on the July 13, 1993 meeting (Ref. 10) emphasized to the Agency
that the focus of an exemption should be on plant-incorporated
protectants in food plants. They suggested that ``plant-pesticides in
plants commonly consumed by humans as food be exempt as long as the
plant's genetic material is derived from related plants within the same
family that have contributed traits to the food plant through the
mechanism of sexual recombination (including wide crosses and embryo
rescue)'' (59 FR 60540). In this final rule, EPA has revised
Sec. 174.479 to clearly state that the recipient plant must be a food
plant by including the phrase ``recipient food plant'' in the
regulatory text at Sec. 174.479(a) and (b). In the final rule, EPA has
revised the definition of ``food plant'' proposed in the 1994 proposed
rule at 40 CFR 180.1137 (59 FR at 60542) to read: ``Food plant means a
plant which, either in part or in toto, is used as food''. EPA includes
this definition at 40 CFR 174.3. EPA also includes at Sec. 174.3 the
definition of food found in the FFDCA. Thus, for these regulations for
plant-incorporated protectants: Food includes articles used for food or
drink by humans or other animals.
    6. What is the status of substances within sexually compatible
plant populations that might be used as inert ingredients? In a
companion document published elsewhere in this issue of the Federal
Register, EPA describes its consideration of inert ingredients in light
of existing regulations and comments received in response to both the
November 23, 1994 Federal Register document (59 FR 60534) and a 1996
supplemental document (61 FR 37891) discussing the Agency's treatment
of selectable markers as inert ingredients for plant-incorporated
protectants. In the companion document published elsewhere in this
Federal Register on FIFRA regulations, EPA describes its determination
that it will apply the concept of inert ingredients to plant-
incorporated protectants consistent with the 1994 proposal.
    The preamble discussion in the 1994 Federal Register document (59
FR at 60523) of the rationale supporting the proposal to exempt plant-
incorporated protectants derived from sexually compatible plants
extends to any substance that is derived from plants sexually
compatible with the recipient plant, including substances such as a
selectable marker, used to confirm or ensure the presence of the active
ingredient. EPA's analysis in Unit IX., applies equally to all the
substances that normally are found in a population of sexually
compatible plants, including inert ingredients as long as these are
derived through conventional breeding from plants sexually compatible
with the recipient plant, and have never been derived from a source
that is not sexually compatible with the recipient plant. An example of
such an inert ingredient in sexually compatible populations could be
tightly linked traits, such as unusual leaf pigmentation always found
with a pest resistance trait.
    EPA includes these residues at 40 CFR part 174, subpart X, to
ensure that readers understand that any trait used as a selectable
marker, and the genetic material necessary to produce it, that occurs
normally in a plant sexually compatible with the recipient plant or is
introduced through conventional breeding, is exempt from the FFDCA
section 408 requirement of a tolerance, as well as FIFRA requirements
on inert ingredients when used with a plant-incorporated protectant
derived through conventional breeding from a plant sexually compatible
with the recipient plant. EPA believes this interpretation is a logical
implication of the preamble discussion in the 1994 proposed rule (59 FR
at 60538).
    Because the Agency recognizes that a substance described in Unit
IX.B.2. (i.e., a toxicant) could theoretically be used as an inert
ingredient, EPA places the same limiting condition on residues of the
inert ingredient in food as is placed on residues of the pesticidal
substance portion of the active ingredient; i.e., the residues of the
inert ingredient do not qualify for the exemption if they are present
in food from the plant at levels that are injurious or deleterious to
human health.
    Discussion supporting this exemption can also be found in a
companion document published elsewhere in this issue of the Federal
Register on FIFRA regulations for plant-incorporated protectants.
Regulatory text has been established at 40 CFR 174.485, subpart X,
which is entitled ``Inert ingredients from sexually compatible
plant,''in a companion document on FIFRA regulations for plant-
incorporated protectants published elsewhere in this issue of the
Federal Register.

D. What Were the Other Potential Approaches to the Scope of Exemption?

    In the November 23, 1994 Federal Register document (59 FR 60537),
EPA discussed the merits of an approach using taxonomy, along with
sexual compatibility (Option 2), as a standard for describing closely
related plants, and received comment on use of such a criterion. EPA
also received a comment, made in the context of the FIFRA regulations,
suggesting that the criterion of sequence homology be used to limit the
concept of sexual compatibility. In light of the relevance of this
comment to this FFDCA exemption, EPA discusses this suggestion, as well
as the comments on taxonomy, here. EPA also discusses a comment
suggesting that EPA consider extending the exemption, on a case-by-case
basis, to residues of plant-incorporated protectants derived from
plants unrelated to the recipient plant, and a suggestion that
exemptions should be based on a documented history of safe use.
    1. Taxonomy. Two commenters expressed reservation about using a
taxonomic standard for describing closely related plants. They pointed
out that taxonomic categories, and the relationship of a given plant
species to a given taxon, may be transient since taxonomic
classification may change as information accrues. EPA agrees. In the
1994 Federal Register document, EPA noted (59 FR at 60524) that a
taxonomy- based standard (e.g., Option 2) may be artificial:
classification of plants in different taxonomic genera is not fixed and
could change over time and between scientific authorities. Taxonomy
reflects current observations about phenotypic, and to some extent,
genotypic, differences between organisms. Currently, some plant genera
are narrowly defined; for other plant genera, membership is based on
broader criteria. These differences in classification criteria may lead
to different probabilities between genera that new exposures may occur
when genetic material from one species in a genus is introduced into
another species in the genus. In recent years new tools have become
available to taxonomists, allowing them to better clarify phylogenetic
relationships among organisms. New information, particularly that
obtained through the use of new genetic tools, concerning organisms'
properties and relationships may in the future alter current taxonomic
designations. In light of these advances, EPA anticipates there may be
some reorganizations among the Plantae, and that these
reclassifications will better reflect the relationships

[[Page 37842]]

among plants, and the probability of new exposures in intrageneric
crosses.
    The possibility that taxonomic classification may change as
information accrues would add an extra layer of complexity to any
regulations based on a taxonomic standard, and EPA probably would not
be able to structure an exemption to accommodate for potential changes
in classification. The possibility of reclassification also creates
some uncertainty within the regulated community about the future status
of a product.
    Furthermore, under the FFDCA, an exemption must be examined
specifically within the context of the food supply and dietary
consumption. Although some species in a genus might be food plants,
others in that genus might not. Moreover, in a genus containing food
plants, there may be such barriers to hybridization that some of the
non-food species in that genus would never have contributed to the food
supply. Thus, there may be no experience with the potential dietary
risks associated with such non-food species. In addition, knowledge of
whether substances such as naturally-occurring toxicants are present
is, in general, more limited for all the plant species constituting a
genus than it is for species used to produce the major food crops.
Consequently, there is a greater degree of uncertainty in any finding
applicable to all potential members of taxonomic categories. The large
body of information supporting this exemption was generated for food
crops in sexually compatible populations (Refs. 8, 11, 12, 13, 14, 15,
16, 17, 18, and 19, for example). Overall, the base of dietary
experience is not as broad or as deep for populations of plants
described by the taxonomic standard of genus as it is for populations
of plants described by sexual compatibility. EPA does not believe it
possesses sufficient information at this time to allow the Agency to
issue an exemption based on taxonomy.
    2. Sequence homology. EPA received one comment suggesting that an
additional criterion be used to limit the concept of sexual
compatibility. While this suggestion was made in the context of a
comment made on the proposal to exempt plant-incorporated protectants
derived from plants sexually compatible with the recipient plant from
FIFRA requirements, EPA discusses that suggestion here because of its
relevance to EPA's decision to exempt residues of pesticidal substances
derived through conventional breeding from plants sexually compatible
with the recipient plant. The suggested criterion of sequence homology
would base relatedness on the degree of sequence homology between the
source and recipient plant. Sequence homology refers to the extent that
the sequence of deoxynucleotides in two pieces of genetic material are
the same. A deoxynucleotide is made up of a sugar, a phosphate, and one
of four purine or pyrimidine bases (adenine, cytosine, guanine,
thymine). The sugars and phosphates of the deoxynucleotides are
covalently linked by phosphodiester bonds to form the ``backbone'' of
the deoxynucleotide polymer (DNA). One base is attached to each sugar
in the sugar-phosphate backbone. The information encoded in the genetic
material is determined by the sequence in which the bases are attached
to the sugar-phosphate backbone. The extent to which two pieces of
genetic material have the same base sequence is often described in
terms of percent homology, with 100% homology meaning the pieces of
genetic material have an identical sequence. The Agency currently
believes that DNA sequence homology is a less straightforward standard
for regulatory purposes than a standard such as sexual compatibility.
Sexual compatibility is known in most cases, and if it is not, it is
less burdensome and simpler to demonstrate than is relatedness based on
DNA sequence homology. Use of homology as a criterion presents the
following complex issues. First, where should homology be assessed? For
example, how many genes of the source and recipient plants should be
compared to determine the degree of homology? All the genes of both
plants? A few genes? If only a few, which genes? Second, what degree of
homology would be sufficient to indicate a high degree of relatedness?
Third, under what conditions should homology be measured? Fourth,
appropriate test procedures would need to be developed and validated in
order to set a standard procedure for measuring homology. All of these
issues would need to be resolved, and converted into regulatory text,
in order to develop an exemption standard based on DNA sequence
homology.
    3. Other potential exemptions suggested by comment. One comment
suggested that EPA consider extending the exemption, on a case-by-case
basis, to residues of the pesticidal substance portion of plant-
incorporated protectants derived from plants unrelated to the recipient
plant: ``Should a gene be taken from a commonly consumed food plant and
inserted into another commonly used food plant, and the trait is
expressed at approximately the same (or lower) level, an exemption
would be warranted.'' A second commenter proposed that exemptions
should be based on a documented history of safe use.
    With regard to the suggestion that EPA consider extending
exemptions on a case-by-case basis to residues of pesticidal substances
of plant-incorporated protectants derived from plants unrelated to the
recipient plant, the Agency has the option to exempt residues of
pesticides from the requirement of a tolerance on a case-by-case basis
provided that the residues meet the exemption standard in FFDCA section
408(c). In addition, any person may petition EPA to establish a
tolerance exemption pursuant to section 408(d). Section 408(d)(2)(A)
establishes the minimum requirements for such a petition. As additional
information becomes available, EPA will consider, in future, exempting
from the FFDCA requirement of a tolerance, residues of plant-
incorporated protectants derived from plants unrelated to the recipient
plant when these can be shown to meet the FFDCA section 408 safety
standard. EPA also has the option of exempting residues of plant-
incorporated protectants based on a history of safe use where there is
sufficient information to meet the FFDCA section 408(c) test.

IX. Statutory Finding

A. What Methodology Did EPA Use to Assess these Residues?

    For most pesticides (e.g., 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 end-points (e.g., acute toxicity, carcinogenicity, developmental
toxicity). Conclusions from animal models are used to assess dose-
response and describe such endpoints for potential human hazard. 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. Uncertainty factors
are often used in the risk assessment to account for extrapolation from
animal models to human toxicity and from limited studies using humans
to the larger population. The data requirements describing the types of
information to be generated and other guidance for assessing dietary
risk are detailed in 40 CFR part 158.
    The questions posed as part of the risk assessment in evaluating
residues of

[[Page 37843]]

most pesticides (e.g., chemical pesticides) can also be posed for the
pesticide chemical residues that are the subject of this exemption, and
40 CFR part 158 can be used as guidance in evaluating these residues
for hazard end-points (including, for example, acute toxicity,
carcinogenicity, and developmental toxicity). To address the hazard
endpoints described in 40 CFR part 158 for residues of plant-
incorporated protectants derived through conventional breeding from
sexually compatible plants, EPA relied on a very large body of
information found, for the most part, in the public scientific
literature. In performing the assessment for this exemption from the
requirement of a tolerance, EPA did not need to rely as much on
information generated from animal models as it would in assessing other
pesticides (e.g., chemical pesticides). A very large body of experience
with actual human dietary consumption over hundreds, if not thousands,
of years exists for the substances that are the subject of this
exemption. And thus, a large and varied amount of information developed
through systematic scientific study exists in the literature, and can
be used for assessing the risk of exempting these residues. Numerous
epidemiological studies on humans show the health benefits of consuming
foods containing residues of the plant-incorporated protectants that
are the subject of this exemption (Refs. 11, 12, 13, 14, 15, 16, 17,
18, and 19). The epidemiological studies in particular provide
information on the effects of chronic exposure of a far longer term
than is possible with animal model experimentation, given the large
differences in life span between humans and most animals used in animal
model testing. The results of many nutritional assessment studies using
human volunteers are available on the effects of either whole foods
from plants in sexually compatible populations or isolated constituents
from food from such plants (Refs. 11, 12, 13, 14, 15, 16, 17, 18, and
19). Studies have also been performed using animal models to test the
effects of either whole foods from crops in sexually compatible
populations or constituents from food from such crops (Refs. 11, 12,
13, 14 15, 16, 17, 18, and 19). There is a large literature on
constituents of food from plants in sexually compatible populations
accumulated by a century of systematic study (Ref. 8), and EPA also
used these sources of information.
    EPA also considered other information in the literature in
evaluating the potential for exposure to residues of plant-incorporated
protectants derived through conventional breeding from sexually
compatible plants. Plant-incorporated protectants are produced within
the living plant itself and the pesticidal substance is used in situ in
a living plant to protect against pests, in contrast to most other
pesticides which must be applied to the plant (Ref. 20). Because a
plant-incorporated protectant is produced and used within the plant,
physiological constraints limit the amounts of residues produced by the
plant (Ref. 20). Because the plant-incorporated protectant is within
the plant, routes by which other organisms may be exposed to the plant-
incorporated protectant may be more limited, e.g., dietary exposure is
likely to be the predominant route of exposure.
    EPA used experimental data derived from the science of
phytopathology to characterize the disease and pest resistance
mechanisms known to occur in plants (Ref. 21). EPA also considered
information from the field of plant physiology regarding plant
metabolism, the production of substances that may have pesticidal
effects, and conditions that may limit the plant's production of such
substances (Refs. 7 and 20). This information also provided a basis for
EPA's estimation of the physiological limitations to production in
plants of substances that may be pesticidal and thus to production of
their residues. EPA also used information from the fields of
biochemistry, microbial ecology, and ecology (Refs. 7, 21, and 37).
    EPA's conclusion that the vast majority of plant varieties
developed by conventional breeding in sexually compatible populations
produce foods that are safe for human consumption is based on this
information and the historical consumption of crops since the
prehistorical origins of agriculture. EPA also considered its knowledge
of the practices that plant breeders routinely employ in selecting and
developing plant varieties in sexually compatible plant populations,
such as chemical analyses, taste-testing, and visual analyses, and that
such practices have historically proven reliable for ensuring the
safety of food from such plants (Refs. 8 and 22). EPA also considered
that appropriate processing procedures are widely known and are
routinely used by consumers in preparation of food containing residues
that are the subject of this exemption, including those foods which
require specific processing and/or preparation steps to avoid dietary
problems.
    Residues of plant-incorporated protectants derived through
conventional breeding from sexually compatible plants were evaluated
for dietary risk within the context of the food supply and dietary
consumption patterns. In performing its assessment, the Agency
considered that the diet includes all of the food items that are
customarily eaten by human populations or subpopulations as part of a
normal diet. (EPA did not consider that the normal diet includes plants
or plant parts consumed in times of deprivation, for religious reasons,
in substance abuse or by misidentification. The information base on
which EPA relied in performing its risk assessment (Refs. 8, 11, 12,
13, 14, 15, 16, 17, 18, and 19, for example) did not address such
plants.)
    EPA considered health risks to the general population, including
infants and children. Children, and to some extent infants, have always
and currently consume food containing residues that are the subject of
this exemption. EPA's risk assessment also included subgroups as part
of the general population, (i.e., differences in diet due to the
influence of culture), and allowed for consumption pattern differences
of such subgroups. The consumption of food plants is part of a balanced
and varied diet.
    EPA believes that the numerous epidemiological and nutritional
assessment studies found in the literature of human experience in
consuming food containing residues that are the subject of this
exemption, combined with information generated from animal model
testing and biochemical studies and knowledge from the disciplines of
plant genetics, plant physiology, phytopathology, microbial ecology,
ecology, biochemistry, and plant breeding form the appropriate
information base for evaluating the potential risks of such residues.

B. What Factors Has EPA Considered in Making the Findings Required by
408(c) of the FFDCA?

    FFDCA section 408(c)(2)(B) requires EPA to consider several factors
in determining whether to exempt a pesticide from the requirement of a
tolerance (21 U.S.C. 346a(c)(2)(B)). Information relevant to EPA's
consideration of these factors with regard to this exemption of the
pesticide chemical residues of a plant-incorporated protectant derived
through conventional breeding from sexually compatible plants, is
contained in this document, as well as in other

[[Page 37844]]

documents in the record for this rule as described in Unit X.
    The preamble discussion in the 1994 Federal Register document (59
FR at 60538), and in the May 16, 1997, supplemental document (62 FR
27132), of the rationale supporting the proposal to exempt residues of
plant-incorporated protectants derived from sexually compatible plants
extends to any substance that is normally a component of a population
of sexually compatible plants. It thus, applies to any substance, such
as a selectable marker, used to confirm or ensure the presence of the
active ingredient, that is also derived from plants sexually compatible
with the recipient plant. EPA's analysis in Unit IX., applies equally
to all the substances that are normally a component of a population of
sexually compatible plants, including inert ingredients as long as
these are derived through conventional breeding from plants sexually
compatible with the recipient plant, and have never been derived from a
source that is not sexually compatible with the recipient plant.
    1. Validity, completeness and reliability of available data. As
described in Unit IX.A., EPA's risk assessment for residues of plant-
incorporated protectants derived through conventional breeding from
sexually compatible plants was based primarily on an analysis of the
long human experience with breeding and growing agricultural plants and
preparing and consuming food from such plants, and associated
epidemiological studies, nutritional assessments with human volunteers
and animal model testing (Refs. 8, 11, 12, 13, 14, 15, 16, 17, 18, and
19). EPA combined this information with knowledge from the disciplines
of plant genetics, plant physiology, phytopathology, microbial ecology,
ecology, biochemistry (including studies on the constituents of food),
and plant breeding to evaluate the potential risks of pesticide
chemical residues of plant-incorporated protectants derived through
conventional breeding from sexually compatible plants. EPA considered
the validity, completeness and reliability of the available information
on human consumption of food containing substances that are the subject
of this exemption including epidemiological studies, nutritional
assessments with human volunteers and animal model testing, as well as
information from the disciplines of plant genetics, plant physiology,
phytopathology, microbial ecology, ecology, biochemistry (including
studies on the constituents of food) and plant breeding. EPA concluded
that this information was valid, complete and reliable, and adequately
addressed the issues of hazard and exposure with regard to residues in
food of plant-incorporated protectants derived through conventional
breeding from sexually compatible plants.
    2. Nature of toxic effect. In light of comments raising concern
about possible adverse effects from increases in the levels of
substances that naturally occur at low levels in food from plants, EPA
considered the nature of toxic effects shown by the data described in
Unit IX.B.1., above to be caused by substances that might potentially
be residues of plant-incorporated protectants derived through
conventional breeding from sexually compatible plants, should these
substances be used as pesticides (i.e., if humans intend to use these
substances for preventing, repelling or mitigating any pest) and
present at high levels. The examination led EPA to conclude that as the
vast majority of substances in plants are not toxic, any of these
nontoxic substances, should they be used as plant-incorporated
protectants, would not present toxic effects. EPA has identified 21
substances of plant origin that are in foods that could be considered
part of a normal diet and could potentially present toxic effects if
present at high levels (Ref. 8). (The normal diet does not include
plants, or parts of plants, consumed in times of deprivation, for
religious reasons, in substance abuse, or by misidentification. The
normal diet is considered to be balanced and varied and include food
from a variety of sources.) This analysis is based on an accumulation
of millennia of human experience and a century of systematic scientific
study of food constituents (Ref. 8). The conclusion of the analysis
described in Unit IX.B.2., for these 21 substances indicates that they
are either: Beyond the scope of the exemption; in foods that are not
part of the normal diet of the United States population; and/or,
millennia of human experience and use have given rise to procedures, on
the part of the plant breeder, the food processor and/or the consumer,
that combined with the condition determining eligibility for this
exemption, adequately address the risk posed by these substances.
    These 21 substances, of the hundreds of thousands of plant-produced
substances in food, represent less than one-tenth of 1% of the total
number of constituents of food (Ref. 8). Of these 21 substances, seven
(acetylandromedol, andromedol, anhydroandromedol, desacetylpireistoxin
B, gelsamine, tutin, hyenanchin) are in honey, being ``pass-through''
contaminants of honey introduced by bees collecting pollen from
rhododendron, azalea, yellow jasmine, or the tutu tree. (The substances
from the tutu tree, tutin and hyenanchin, can cause delirium and
convulsions). Similarly, four (cicutoxin, coiinine, methylconiine,
conhydrine) of the 21 substances capable of causing toxic effects in
the normal diet are pass-through contaminants in the milk of cows that
have consumed water hemlock or hemlock. These substances are nervous
system stimulants. None of the plant sources of these 11 pass-through
contaminants are used or intended to be used as food plants and thus
this section 408 exemption does not apply to them. Another of the 21
substances in the normal diet identified as potentially causing toxic
effects is nitrate. Exposure to excessive amounts of nitrates can cause
methemoglobinemia, a condition in which some portion of the hemoglobin
molecules become incapable of binding oxygen. Levels of nitrates high
enough to cause such effects can be found in spinach and other green,
leafy vegetables subjected to intensive application of high-nitrate
fertilizers. Nitrates that enter the plant through uptake of fertilizer
applied intensively are not ``produced'' by the plant per se, i.e.,
they are not biosynthesized by the plant. This exemption is not
relevant to such nitrates. The toxic effect presented by high levels of
nitrates is generally addressed in agriculture by use of proper
fertilization practices.
    Of the 21 substances originally identified (Ref. 8), nine of these
(solanine, linamarin, lotaustralin, cucurbitacin, vicine, convicine,
hypoglycin A, sparteine, beta-N-oxalylamino-L-alanine) are
biosynthesized by plants that could be used as food in a normal diet
somewhere in the world, and, thus, if used by humans for pesticidal
purposes, could potentially be pesticide chemical residues derived
through conventional breeding from sexually compatible plants. Three of
these nine substances (sparteine, hypoglycin A, beta-N-oxalylamino-L-
alanine) are found in food not customarily consumed as part of the
normal diet in the United States. Their risks appear to be well known
locally where plants containing such substances are consumed, and
native methods of processing exist to reduce the potential for toxic
effects (Ref. 22).
    Sparteine is a quinolizidine alkaloid found in the lupines. The
lupines are forage or range crops, but can also be cultivated for feed
and have some limited use in human food, primarily as

[[Page 37845]]

a ``traditional'' grain used by indigenous cultures in South America
and the Mediterranean. The presence in the plant of the quinolizidine
alkaloids appears to protect the plant against fungal infection.
Reduction of the levels of quinolizidine alkaloids in the plant can
result in increased levels of potentially more hazardous mycotoxins.
Toxic effects from consumption of food containing higher levels of
sparteine include breathing problems, weakness and loss of motor
control (Ref. 22, 23). These alkaloids can be removed by cooking, or by
rinsing for several days (Ref. 22, 24).
    Beta-N-oxalylamino-L-alanine is found in the seeds of the chickling
vetch. It is a neurotoxin that can cause spastic paralysis, probably by
interfering with the action of the neurotransmitter, glutamate (Ref.
22, 25). Reported cases of toxicity are mostly confined to the Indian
subcontinent. Most of the toxin can be leached out by soaking the seeds
in hot water for several minutes, followed by cooking.
    Hypoglycin A is an amino acid analogue found in the immature ackee
fruit that can result in severe hypoglycemia and vomiting. Ackee fruit
is primarily consumed in Africa and Jamaica (Ref. 22). The primary
method of dealing with the potential adverse effect presented by
hypoglycin A is avoidance of (i.e., not consuming) immature ackee
fruit.
    Of the remaining six substances, two (vicine and convicine) affect
a small subpopulation of the United States population. Vicine and
convicine are found in the fava bean. Exposure of individuals with the
Mediterranean form of an inherited deficiency of the enzyme, glucose-6-
phosphate dehydrogenase (G6PD), to these substances in the fava bean
can result in an hemolytic anemia. The anemia is manageable (Ref. 26).
Physicians attempt to prevent hemolytic episodes by warning patients
with the Mediterranean form of G6PD deficiency about the risks of
consuming fava beans (Ref. 27). Thus, the primary strategy employed by
persons with this G6PD deficiency with regard to food is avoidance of
(i.e., not consuming) foods containing fava beans. Drying the beans or
exposing them to sunlight reduces the potential for hemolytic episodes
(Ref. 22).
    Several strategies, including breeding for varieties that produce
low levels of the substances and monitoring, as well as general
knowledge in the population, reduce the potential for toxic effects to
occur with the remaining four toxicants (cucurbitacin, linamarin,
lotastralin, solanine). Cucurbitacins are naturally present in edible
squash and cucumbers at very low levels. Cucurbitacins are purgatives
and impart a bitter taste to the fruit. Cucurbitacins if consumed at
extremely high concentrations may cause stomach aches or cramps (Refs.
22 and 28). On rare occasions, in producing seed for cultivated
varieties, pollen from a wild relative may contaminate the seed plot,
resulting in seeds that may produce higher levels of cucurbitacin.
Breeding isolation is employed by seed producers to ensure that such
contamination does not occur (Refs. 7 and 22).
    Linamarin and lotaustralin (also called phaseolutin) are cyanogenic
glycosides (Refs. 8 and 22) biosynthesized by cassava and lima beans.
When the plant tissue is damaged, enzymes are released that act on the
cyanogenic glycoside to produce hydrogen cyanide. The toxicity of
cyanide is due to its ready reaction with the iron atom of the enzyme,
cytochrome oxidase. The ability of the cell to utilize oxygen is
inhibited by formation of the cytochrome oxidase-cyanide complex. Toxic
effects associated with cyanide include neurological disorders,
breathing difficulties, and thyroid enlargement (Ref. 22). The lima
bean varieties on the United States market today were bred and are
monitored to ensure that they produce very low levels of cyanogenic
glycosides (Refs. 22 and 29). Imported lima beans are monitored to
ensure only low levels of cyanogenic glycosides (Refs. 22 and 29).
Similarly, cassava used in the United States today comes from varieties
that were bred and are monitored to ensure that they produce very low
levels of cyanogenic glycosides. Populations outside of the United
States (e.g., Africa) that consume cassava from varieties that produce
higher levels of cyanogenic glycoalkaloids are aware of the risk
associated with this food and use native methods of processing
(peeling, chopping and grinding in running water, also boiling and
fermentation) to reduce the cyanogenic glycoside content. Cases of
toxicity are observed primarily in these populations when the cassava
is eaten without adequate processing, because a scarcity of other food
items causes individuals to risk consuming inadequately processed
cassava to ease their hunger (Ref. 26). There are also ongoing breeding
and monitoring efforts to assist these populations to reduce the
cyanogenic glycoside content in cassava varieties grown in their
countries.
    The glycoalkaloids collectively referred to in this document as
solanine are biosynthesized by potatoes, and to some extent eggplant
and peppers. A related glycoalkaloid, tomatine, can be found in green
tomatoes. The solanines are membrane disruptors. Some members of the
class have been shown in vitro and through intraperitoneal and
intravenous injection to be weak to moderate cholinesterase inhibitors
(Ref. 30). While solanine poisoning is very rare, in large doses
solanine can cause gastrointestinal tract irritation, including
moderate nausea, vomiting and diarrhea, as well as headaches,
drowsiness, sweating, changes in blood pressure and heart rate, and
edema (Ref. 22). Solanine imparts a bitter taste to the tuber, and at
high concentrations solanine can leave a persistent irritation and
burning sensation on the tongue (Ref. 22). Potato varieties are bred
and monitored in the United States to ensure that they produce only low
levels of solanine (Refs. 22 and 31). Monitoring for these
glycoalkaloids also occurs during the grading and shipping of potatoes.
Peeling or removing any damaged portion of the potato is the best way
to reduce solanine levels. In an undamaged, unsprouted potato, thirty
to eighty percent of the solanine is found in, and directly under, the
skin. Cooking, e.g., boiling in steam or water or deep frying in oil at
170 degrees, may lower solanine concentrations (Refs. 22 and 32).
    For the reasons described in the preceding paragraphs, EPA does not
believe that this exemption would result in levels in food of residues
of these four substances significantly different from those observed in
food currently safely consumed. That there have been few instances in
the United States of toxic effects on humans due to substances normally
found in food from plants in sexually compatible populations in the
past 50 years, despite the hundreds of food plant varieties from
sexually compatible plant populations going onto the market each year
(Ref. 8), supports a conclusion that the probability of risk is low
even for the few substances discussed in this Unit. As an added
protection, EPA has placed a condition limiting the exemption to
residues present in food from the plants at levels that are not
injurious or deleterious to human health.
    3. Relationship of studies to humans. EPA considered the available
information concerning the relationship to human risk of this
information on residues in food of plant-incorporated protectants
derived through conventional breeding from sexually compatible plants.
The effect of these residues on humans was assessed in light of the
long history of human

[[Page 37846]]

consumption of food derived from plants, and from products such as meat
and milk from animals that consume forage and other crops (e.g., corn
and other grains), containing residues that are the subject of this
exemption, and associated epidemiological studies, nutritional
assessments with human volunteers and animal model testing (Refs. 8,
11, 12, 13, 14, 15, 16, 17, 18, and 19). The epidemiological studies
and nutritional assessments performed with human volunteers supply data
generated on humans and, thus, directly applicable to humans.
Information from animal model testing as well as information from the
disciplines of plant genetics, plant physiology, phytopathology,
microbial ecology, ecology, biochemistry (including studies on the
constituents of food) and plant breeding were also used to predict
effects on humans. Because information on human consumption of food
derived from plants comprising sexually compatible populations was
available and adequately addressed the issues of hazard and exposure
for residues that are the subject of this exemption, the Agency relied
primarily on the epidemiological and other information generated
directly from humans rather than relying on data generated in the
laboratory through animal testing.
    4. 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
that are the subject of this exemption. The consumption of food from
plants is part of a balanced and varied diet (Ref. 33). Humans have
been consuming food containing substances that may be residues of
plant-incorporated protectants derived through conventional breeding
from sexually compatible plants and thus, all consumers, and all major
identifiable consumer subgroups, are, and have been, exposed to the
substances that are the subject of this exemption. It is not
anticipated that publication of this exemption from the requirement of
a tolerance 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.
    5. Available information concerning cumulative effects of the
pesticide chemical residue and other substances that have a common
mechanism of toxicity. EPA examined available information on the
cumulative effect of residues of plant-incorporated protectants derived
through conventional breeding from sexually compatible plants, as well
as other substances present in food that may have a common mechanism of
toxicity with such residues.
    i. What information is available on the cumulative effects of the
residues that are the subject of this exemption? A large amount of
information exists for the residues that are the subject of this
exemption. The extensive information described in Unit IX.A. and Unit
IX.B.1., e.g., epidemiological studies, nutritional assessment studies
and animal model testing (Refs. 11, 12, 13, 14, 15, 16, 17, 18, and 19)
indicates a very low probability of harm. The few substances occurring
naturally in food from plants that EPA has identified as being
problematic are discussed in Unit IX.B.2. A discussion of the variation
in the levels of substances that may be pesticide chemical residues and
may occur naturally among the plants of a sexually compatible
population, and the potential consequences of that variation are
discussed in Unit IX.B.6.
    If information becomes available that indicates its analysis of
cumulative effects in Unit IX.B.5., is no longer consistent with the
FFDCA exemption standard for residues of a pesticidal substance in this
category, EPA will consider the validity of the new information and may
act to amend this tolerance exemption.
    ii. Are there substances that occur naturally in food that may
share a common mechanism of toxicity with residues that are the subject
of this exemption? Because of the conditions of this exemption, i.e.,
the genetic material leading to the production of the plant-
incorporated protectant is derived through conventional breeding from
plants sexually compatible with the recipient plant, the potential for
new dietary exposures is low. Thus, EPA considered the effects of all
the substances in food from plants when it addressed the safety of food
from plants in sexually compatible populations, including those that
occur naturally in plants along with the substances that are the
subject of this exemption. Food from plants has hundreds of thousands
of constituents, and EPA cannot rule out the possibility that in the
foods humans consume, common mechanisms of action might exist between
some of these substances and the various residues that are the subject
of this exemption. For example, the word ``solanine'' generically
refers to a group of related steroid glycoalkaloids that naturally
occur in plants in the nightshade family such as potatoes, eggplant,
peppers and green tomatoes. EPA's analysis considered the effects of
these substances in food from plants cumulatively when it addressed the
safety of food from plants in sexually compatible populations.
    Food from plants in sexually compatible populations is being safely
consumed by humans 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). The history of safe
consumption and the information base described in Unit IX.A. and Unit
IX.B.1. indicates that any cumulative effects between substances in
food that may have a common mechanism with residues that are the
subject of this exemption present a very low probability of harm. The
analysis made in this preamble in Unit IX.B.6., concerning potential
increases in levels of residues apply equally to constituents of food
that may have a common mechanism of action with residues that are the
subject of this exemption. Variations in the levels of these substances
are not expected to be any different than those currently observed in
conventional breeding. Experience has shown that food from crop plants
in sexually compatible populations is safe for human consumption and/or
appropriate processing procedures are widely known and routinely used
by processors and consumers in preparing food from such sources. Should
EPA in the future identify substances with a common mechanism of
toxicity with the residues that are the subject of this exemption, both
FIFRA and the FFDCA give the Agency adequate authority to take
appropriate action to address any risks these substances may present to
human health. Should substances in food that may share a common
mechanism of toxicity with residues that are the subject of this
exemption present cumulative effects resulting in food safety concerns,
the condition limiting this exemption at 40 CFR 174.479 and the
requirement to report adverse effects at Sec. 174.71 will provide a
mechanism to monitor the effects of this class of products and allow
the EPA and FDA to act expeditiously.
    iii. Are there substances that do not occur naturally in food that
may share a common mechanism of toxicity with residues that are the
subject of this exemption? EPA examined two groups of substances to
determine whether these substances have a common mechanism of toxicity
with residues that could be the subject of this exemption.
    a. Do the organophophate and carbamate pesticides have a common
mechanism of toxicity with the naturally occurring toxicants solanine?
EPA examined certain of the

[[Page 37847]]

organophosphate and carbamate pesticides and the naturally-occurring
toxicants, solanine (described in Unit IX.B.2.). EPA examined these
substances because many members of these two classes of pesticides
inhibit the cholinesterase enzymes (Refs. 30 and 34), and some in vitro
and intraperitoneal and intravenous injection studies have shown that
some of the glycoalkaloids comprising the solanines also can inhibit
these enzymes (Refs. 22 and 30). The solanines have also been shown to
disrupt cell membranes (Ref. 30).
    EPA examined available information generated both in vitro and
through in vivo animal studies on solanine. EPA gave greater weight in
its analysis to information generated by animal studies where the
animals were exposed through oral ingestion, as such studies are far
more likely to provide physiologically significant information. Animal
studies performed with the solanines administered to the animals in
similar manner that plant-incorporated protectants would be presented
in the diet (i.e., through ingestion) show that death could not be
attributed to cholinesterase inhibition and its neurotoxic consequences
but was due to severe gastrointestinal necrosis from cell membrane
disruption (Ref. 35).
    Given this information, EPA has concluded that available
information is insufficient to create a presumption of the existence of
a common mechanism of toxicity between solanine and the organophosphate
and carbamate pesticides (Ref. 36), particularly as animal studies
suggest the solanines, when used as plant-incorporated protectants,
lead to the endpoint of death through membrane disruption.
    b. Do microorganisms have metabolic pathways in common with plants?
One commenter, in response to the May 16, 1997, supplemental document,
suggested that some microorganisms may have some metabolic pathways in
common with plants, although the commenter was of the opinion that this
is not likely to be problematic. EPA agrees that this route of exposure
to any substances that may be related to residues that are the subject
of this exemption is unlikely to be problematic, and notes that
possession of the same metabolic pathways does not equate to expression
of the same characteristics. Raw plant foods commonly contain hundreds
to several million microorganisms per gram (Ref. 8). Some of these
microorganisms are commensals of the plant, others come from the
natural environment of the plant (e.g., soil, water, air, other
plants). Such microorganisms are routinely consumed with raw
agricultural produce. Certain microorganisms are deliberately consumed
routinely in high numbers by humans with no ill effects (e.g., Marmite
based on a yeast, natto based on the bacterium Bacillus subtilis,
yogurt made with bacteria of the genus Lactobacillus, cheese made with
the fungus Penicillium roquefortii). This base of experience with
actual human consumption indicates that should such microbes have any
metabolic pathways in common with foodstuffs from plants, the
cumulative effect of substances from these pathways with residues that
are the subject of this exemption, presents a very low probability of
harm.
    c. Are there any other substances? EPA cannot rule out the
possibility that there may be other substances outside of the food
supply that may have a common mechanism of toxicity with the residues
that are the subject of this exemption, although it is not aware of any
other such substances. Should EPA in future identify substances with a
common mechanism of toxicity other than those found in food plants,
both FIFRA and the FFDCA give the Agency adequate authority to take
appropriate action.
    6. Aggregate exposures of consumers including non-occupational
exposures. EPA considered the available information on the aggregate
exposure level of consumers to the residues of plant-incorporated
protectants derived through conventional breeding from sexually
compatible plants, including exposure to these substances in plants
when they are not intended to be used as plant-incorporated protectants
(i.e., when humans are not intending to use the substance for a
pesticidal purpose). This evaluation included a consideration of
exposures from dietary sources as well as from other non-occupational
sources. Plant-incorporated protectants and their residues are likely
to present a limited exposure to humans. In most cases, the
predominant, if not the only, exposure route will be dietary. Exposure
through other routes is likely to be negligible because the substances
are in the plant tissue and thus are found either within the plant or
in close proximity to the plant.
    In addition, the substances evolved by populations of sexually
compatible plants are part of the metabolic cycles of these plants.
These substances are biotic and are subject to the processes of
biodegradation and decay that all biotic materials undergo (Ref. 37).
Biotic materials are broken down to constituent parts through the
enzymatic processes of living organisms, and these constituent parts
used as the building blocks to make other biotic substances.
    Because of their biodegradable nature, the residues that are the
subject of this exemption do not bioaccumulate (bioaccumulation occurs
when a substance is taken into the body through processes such as
eating, and as the body is unable to either break the substance down or
eliminate it, the substance accumulates in the tissues) or biomagnify
in the tissues of living organisms (biomagnification occurs when a
substance bioaccumulates in the bodies of organisms lower in the food
chain, and as predators higher in the food chain consume organisms
lower in the food chain, more and more of the substance accumulates in
the bodies of organisms higher in the food chain) as do such long-lived
persistent substances such as DDT (Ref. 38). Humans ingesting the
substances that are the subject of this exemption are likely to quickly
degrade them and use their constituent elements as nutrients. Because
of these characteristics, the potential for exposures to the residues
to occur, beyond direct physical exposure to, or consumption of, the
plant, is limited. This also contributes to EPA's conclusion that non-
dietary exposure (i.e., non-food oral, dermal and inhalation) in non-
occupational settings is likely to be negligible.
    i. Dietary exposures? As described in Unit IX.A. and Unit IX.B.1.,
a large base of experience exists, including information on human
dietary exposure, for the residues exempted by this action. Moreover,
dietary exposures other than those for which a large base of
information exists, are unlikely to result from this exemption for
residues of plant-incorporated protectants derived through conventional
breeding from sexually compatible plants. Plants in a sexually
compatible population are likely to have similar genetic information
and have many traits in common. Generations of directed breeding to
produce improved crops for cultivation have tended to increase the
relatedness, and reduce the genetic variability, of populations of
agricultural crop plants (Ref. 6). Sexually compatible plants share a
common pool of genetic material, and movement of genetic material
encoding pesticidal substances between plants in a sexually compatible
population through conventional breeding is unlikely to result in
exposure of humans consuming food from such plants to residues to which
no humans previously has been exposed and to which the information base
underlying this exemption cannot be applied. The SAP Subpanel and the
BSAC

[[Page 37848]]

Subcommittee at the joint meeting held on January 21, 1994, supported
this conclusion and noted that genetic mapping of the genomes of both
wild and crop plants reinforce the thesis that plants in sexually
compatible populations are likely to possess similar genetic
information (Ref. 6). It is likely that substances that are the subject
of this exemption are present at low concentrations in the edible parts
of plants, and that such substances have long been part of the human
diet. There is no evidence at present in the many studies performed on
the relationship of diet to health that food from plants in sexually
compatible populations, properly handled, has any significant adverse
health effect (Refs. 8, 11, 12, 13, 14, 15, 16, 17, 18, and 19).
    The primary exposure consideration associated with the substances
that are the subject of this exemption is whether the substances,
identified in Unit IX.B.2. as toxic at higher concentrations, are
likely to be present in food from plants in sexually compatible
populations at such concentrations. EPA carefully examined whether
there are variations, within and among food plant varieties in sexually
compatible plant populations, in levels of plant-incorporated
protectants and thus in the residues that are the subject of this
exemption from the FFDCA requirement of a tolerance (Ref. 20). The
amount of any substance produced by plants normally varies among
members of a sexually compatible plant population because of the
effects of conditions such as genetic constitution and environment
(e.g., weather) (Refs. 8 and 20). Indeed, such variation is observed
among plants of the same variety. For example, one researcher (Ref. 8)
has shown a 20-fold variation in the amount of ascorbic acid (3 to 61
mg/100g tissue) in different varieties of muskmelon. Because such
variation is ubiquitous in populations, differences in the levels of
exposure to substances in plants are likely when humans consume food
from plants, including differences in exposure to residues that are the
subject of this exemption. Such variation is a natural phenomenon
common to all plants, however, in controlled food production the
variation in the substances identified in Unit IX.B.2. is limited (Ref.
22).
    EPA also examined whether the levels of substances any variety
within a sexually compatible population could produce are likely to
exceed the range of low concentrations found in crop plant varieties
safely consumed. For the following reasons, the Agency concluded that
such occurrences were unlikely. First, there are several constraints on
the extent to which expression of any substance can be increased in
highly managed food crop plants without unwanted effects on other,
desirable characteristics of the plant such as yield or palatability.
In general, breeders balance a number of characteristics (e.g., yield,
palatability, height, uniformity of seed drop) in developing marketable
plant varieties. Solanine and cucurbitacin, for example, affect
palatability as they taste bitter to humans.
    Moreover, in conventional breeding, plant breeders assess the new
cultivar for food safety, based in part on knowledge of and familiarity
with the characteristics of agricultural plants in sexually compatible
populations (Ref. 22). EPA's assessment of the likelihood of breeders
ensuring that plants developed through conventional breeding will
continue to be safe for consumption 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, within the past 50 years, conventional plant breeding of plants
in sexually compatible populations has recorded very few instances of
plant varieties causing food safety problems. The two identified
instances (Ref. 8), high psoralen expressing celery that in the 1980s
caused dermatitis in grocery employees and the Lenape potato in the
late 1960s with increased glycoalkaloid levels, involved increases in
the level of known toxicants (which may or may not be plant-
incorporated protectants depending on whether humans intend to use
these substances for preventing, destroying, repelling or mitigating
any pest). In both cases, the problem was identified and the
appropriate measures taken to protect the public health. In the case of
the Lenape potato, food processors in routine screening detected the
high levels of solanine and the potatoes were removed from the market
before exposure of consumers (Ref. 8). In contrast to these few
problematic occurrences, there are many studies indicating the health
benefits of consuming plant foods that likely contain residues that are
the subject of this exemption (Refs. 8, 11, 12, 13, 14, 15, 16, 17, 18,
and 19).
    A second exposure consideration is whether this exemption will
affect the ability of individuals with food sensitivities to manage
these sensitivities. To protect themselves, individuals with food
sensitivities generally avoid the food, and related foods, that cause
them problems (Ref. 39). This exemption will not affect the efficacy of
this strategy of avoidance, because the exemption will not affect the
ability of individuals to recognize and avoid foods that cause them
problems (Refs. 27, 39, and 40). For example, the ability of persons
who have the Mediterranean form of the inherited G6PD deficiency to
deal with their disease by avoiding (i.e., 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 will be exempt
only if they are moved through conventional breeding among fava bean
plants and plant varieties sexually compatible with fava beans; a
population of plants in which such substances normally occur, and the
food of which individuals with the inherited G6PD deficiency avoid
(Ref. 27). Similarly, the efficacy of the strategy of avoidance will
not be affected for individuals suffering from food allergy (Ref. 39)
or enteropathies such as celiac disease (gluten-sensitive enteropathy)
(Ref. 40). Moreover, the efficacy of the monitoring, processing, and
preparation methodology which humans are familiar with and have been
adequate in the past to produce food safe for consumption will not be
affected by publication of the exemption, e.g., the monitoring
procedures for solanine used in the breeding and marketing of potatoes.
    EPA believes the history of familiarity with agricultural plants in
sexually compatible populations, and thus with the likely progeny of
genetic exchanges between plants in such populations (Ref. 8), and the
procedures currently employed in plant breeding to screen out
undesirable traits in such populations, support a tolerance exemption
for residues of plant-incorporated protectants derived through
conventional breeding from sexually compatible plants. However, to
ensure that the Agency can act expeditiously should any rare instances
of risk arise, EPA is placing at 40 CFR 174.479 a condition on this
exemption from the requirement of a tolerance limiting the
concentrations in food of substances such as toxicants that may be
injurious or deleterious to human health. EPA is also implementing an
adverse effects reporting requirement at Sec. 174.71 that will serve to
alert the Agency to any such rare instances of risk.
    One comment received in response to the May 16, 1997, supplemental
document (62 FR 27132), suggested that plant extracts might be used in
some pharmaceutical preparations. The commenter did not provide any
examples of these types of situations, nor any information on such
extracts. Without such additional information, it

[[Page 37849]]

is difficult to determine whether the extracts would contain substances
related to residues that are the subject of this exemption. However,
even if such related substances are present in some pharmaceutical
preparations, on a per person basis, the potential amounts involved in
these exposures are likely to be a negligible contribution to aggregate
exposure. The commenter also was of the opinion that such uses are not
likely to be problematic.
    ii. Dermal exposure. With regard to the dermal route of exposure,
residues of plant-incorporated protectants derived through conventional
breeding from sexually compatible plants may in some cases be present
in sap or other exudates from the plant or the food 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. Individuals preparing meals are those most likely to
experience dermal contact with the substances on a non-occupational
basis. Although contact dermatitis can occur from such exposure (Refs.
41 and 42), these reactions are generally mild, of a self-limiting
nature or self-diagnosed and treated.
    Most of the substances that could be the subject of this exemption
are unlikely to pass through the skin to affect other organ systems
(Refs. 41, 42, and 43). For those substances which possess to some
degree properties that allow some penetration of the skin, the
potential amounts of such exposures, on a per person basis, are likely
to be a negligible contribution to aggregate exposure, or do not
present adverse effects.
    There are a few substances with the ability to present an effect on
dermal exposure on a non-occupation basis, that might be residues of
plant-incorporated protectants, if humans intend to use these
substances as pesticides. For example, one substance present in a food
(condiment) Americans might use in preparing meals and identified as a
potential skin irritant (Refs. 8 and 22) is the phenolic, capsaicin,
found in cayenne pepper. Capsaicin is used medically in a topically
applied cream, which facilitates passage of the capsaicin across the
barrier of the outer layer of the skin, at concentrations of 0.025 to
0.075% capsaicin. The cream is applied up to four times daily for pain
control and treatment of psoriasis (Refs. 22 and 44). Cayenne pepper
can be used liberally in the diet. Currently, cayenne pepper is exempt
from the requirement of tolerance when it is used on food crops (40 CFR
180.1165). Acute toxicity through the oral route has been examined in
several animal species, and it is estimated that the lethal dietary
dose for a 150 pound individual is 2.2 kilograms (Refs. 22 and 45).
Given the low toxicity of capsaicin, even if capsaicin should penetrate
through the barrier of the skin, aggregate exposure through the dermal
and dietary routes is not anticipated to present harm.
    A second substance examined because of known effects beyond mild
dermatitis with dermal exposure are the psoralens. These substances
occur naturally in a wide range of plants but occur in the highest
concentrations in celery, dill and parsley (Refs. 22 and 41). Psoralens
can be phototoxic to the skin in conjunction with sunlight (UV light).
Due to their relative solubility in oils, psoralens can penetrate into
the skin cells, where they intercalate into the genetic material of the
skin cell (Refs. 22 and 41). Subsequent exposure to sunlight (UV light)
causes the genetic material to ``cross link,'' affecting the ability of
the cell to further process its genetic material. This may result in
skin blisters and rashes. This UV-dependent phototoxicity has also been
implicated in mutations that may lead to skin cancer (Refs. 22 and 41).
In spite of the potential for this type of adverse effect with the
psoralens, there are few reported incidents for substances derived
through conventional breeding from sexually compatible plants (Ref. 8).
    Psoralens (supervised and in small doses) are also used in the
treatment of a variety of skin diseases, including vitiligo and
psoriasis (Ref. 22), primarily through topical application.
    The primary route through which humans in general are exposed to
psoralens is dietary, and the psoralens are not toxic when ingested.
Given the low oral toxicity, the supervised use of psoralen in
medicine, the low concentrations of psoralen in celery, dill and
parsley currently on the market, and the condition EPA has placed on
this exemption limiting the amount of substances in food that may have
an injurious or deleterious effect on human health, EPA finds that for
psoralen, were this substance to be used as a plant-incorporated
protectants derived through conventional breeding from sexually
compatible plants, there is a reasonable certainty that no harm will
result from aggregate exposure.
    Those few substances from food plants discussed in Unit IX.B.2.,
which might be present in foods Americans might use in preparing meals
and which at higher concentrations can cause adverse effects, do so
when ingested (Refs. 22, 26, 29, and 31). Substances that are the
subject of this exemption are unlikely to pass through the skin to
affect target organs. For those substances which possess to some degree
properties that allow some penetration of the skin, the potential
amounts of such exposures, on a per person basis, are likely to be
negligible in comparison to potential exposure through the dietary
route, or do not cause adverse effects. Dermal exposures are, thus,
unlikely to contribute significantly to aggregate exposure.
    One comment received in response to the May 16, 1997, supplemental
document (62 FR 27132) suggested that plant extracts might be used in
some cosmetic preparations. The commenter was of the opinion that such
uses are not likely to be problematic. The commenter did not provide
any examples of these types of extracts, nor any information on the
source or composition of such extracts. Without such additional
information, it is difficult to determine whether the extracts would
contain substances related to residues that are the subject of this
exemption. EPA is aware that some floral extracts are used in perfumes,
e.g., lavender, jasmine, rose. However, lavender, jasmine and rose are
not generally consumed as staple foods, although parts of these plants
can be brewed into teas or tisane. The amounts ingested through the
tisane or by passing through the skin from perfumes is likely to be
very small. Further, EPA is not aware of any reports of adverse effects
from use of these flowers in tisane or perfumes. Even if such
substances are present in some cosmetic preparations, on a per person
basis, the potential amounts involved in these exposures are likely to
be negligible.
    EPA is also aware of other extracts used in perfumes from plants
consumed as food, e.g., carrot, fennel, garlic, lemon. Even if such
substances are present in some cosmetic preparations, on a per person
basis, the potential amounts involved in these exposures are likely to
be a negligible contribution to potential exposure through the dietary
route.
    iii. Inhalation exposure. With regard to exposure through
inhalation, residues of plant-incorporated protectants derived through
conventional breeding from sexually compatible plants may in some cases
be present in pollen and some individuals (e.g., those living or
working near enough to farms, nurseries or other plant-growing areas to
be exposed towind-blown pollen, or visiting such areas) may be exposed,
through inhalation, to the pollen. On a per person basis, the potential
amounts of pollen involved in these exposures are likely to be
negligible in comparison

[[Page 37850]]

to potential exposure through the dietary route. Residues of the
pesticidal substance will not in every case be present in the pollen.
When present in pollen, the residues are likely to be integrated into
the tissue of the pollen grain. Pollen grains are solid, insoluble
particles of sufficiently large diameter that they are filtered out in
the nasopharynx or in the upper respiratory tract (Refs. 41 and 46).
This exemption will not change current exposures nor affect strategies
for dealing with residues that are the subject of the exemption. (Ref.
41).
    iv. Drinking water. EPA also evaluated potential non-occupational
exposures in drinking water. The substances in plants or parts of
plants, including residues of plant-incorporated protectants derived
through conventional breeding from sexually compatible plants, are
produced and used inside the living plant itself. The residues are part
of the living tissue of the plant. When the plant dies or a part is
removed from the 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 exemption in the
tissue) as building blocks for making their own cellular components or
for fueling their own metabolisms. The residues that EPA is exempting
in this action, including those identified at Unit IX.B.2., as toxic at
higher concentrations, 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 occurs fairly rapidly (Ref. 37). There is no indication
that naturally-occurring plant biotic materials, including the residues
that are the subject of this exemption, are resistant to
biodegradation. Because of the fairly rapid turnover of these residues,
even if they reach surface waters (through pollen dispersal or parts of
the plants (leaves, fruits etc.) falling into bodies of water), they
are unlikely to present anything other than a negligible exposure in
drinking water drawn either from surface or ground water sources.
    v. Residential exposure. EPA is not aware of any residential uses
of plant-incorporated protectants that might result in exposure to
residues that are the subject of this exemption.
    7. Sensitivities of subgroups. EPA considered available information
on the sensitivities of subgroups as it pertains to residues of plant-
incorporated protectants derived through conventional breeding from
sexually compatible plants. In performing its assessment, the Agency
considered that the diet includes all of the food items that are
customarily eaten by human populations or subpopulations. As discussed
in this preamble, this exemption will not affect the current pattern of
exposure to residues that are the subject of this exemption.
Individuals recognize and are familiar with the plant-derived food they
consume, and, based on prior experience with food, individuals avoid
consuming foods containing substances they know, either through
personal experience or through acquired knowledge, cause them problems
(Refs. 8, 39, and 40). Because the exposure pattern will not be
affected by publication of this exemption, the efficacy of the current
strategy whereby sensitive individuals recognize and avoid foods known
to cause them problems will not be affected by this exemption (Ref. 39,
40). For example, the ability of persons who have the Mediterranean
form of the inherited G6PD deficiency to deal with their disease by
avoiding (i.e., not consuming) fava beans will not be affected. Thus,
no subgroup should be adversely affected by the exemption.
    8. Estrogenic or other endocrine effects. While there is some
information on estrogenic effects from exposure to certain pesticides,
the data are limited. It is known that 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 no information was submitted
to EPA on this issue despite the Agency specifically soliciting it in
the May 16, 1997, supplemental document (62 FR 27132), EPA cannot rule
out the possibility that such phytoestrogens could be used as plant-
incorporated protectants. Potential exposure of humans via consumption
of plant tissue to phytoestrogens exerting estrogenic effects and used
as plant-incorporated protectants may need to be considered as EPA
examines the issue of endocrine disruptors. If dietary exposure to
phytoestrogens (that are also plant-incorporated protectants) is
discovered to be a significant factor, the Agency will re-examine this
exemption from the requirement of a tolerance in light of that
information.
    9. Safety factors. EPA did not rely solely on available animal data
in reaching its determination that residues of plant-incorporated
protectants derived through conventional breeding from sexually
compatible plants can be exempted from the requirement of a tolerance.
There is a long history of safe human consumption of food containing
residues that are the subject of this exemption, and of food derived
from animals that consume forage and other crops containing these
residues (e.g., corn and other grains). EPA thus was able to rely on
epidemiological studies on humans, nutritional assessments with human
volunteers and animal model testing generated through a century of
systematic scientific study and available in the public literature
(Refs. 8, 11, 12, 13, 14, 15, 16, 17, 18, and 19). EPA also relied on
knowledge from the disciplines of plant genetics, plant physiology,
phytopathology, microbial ecology, ecology, biochemistry (including
studies on plant constituents) and plant breeding. EPA believes that
long-term evidence of human consumption and the large base of
scientific data generated by epidemiological studies on humans and
nutritional assessments with human volunteers, with a more limited
reliance on animal experimentation data, is the appropriate information
for evaluating whether residues of plant-incorporated protectants
derived through conventional breeding from sexually compatible plants
warrant exemption. Because EPA was able to rely on data from humans,
the Agency concluded that a safety factor designed to account for
uncertainties in extrapolating from animal data would not be necessary.
In addition, because the available epidemiological and other
information generated on humans was based on studies employing very
large numbers of individuals, the Agency concluded that a ten-fold
safety factor to account for uncertainties in analyzing the human data
would not be necessary.
    10. Infants and children. EPA considered available information on
consumption patterns of infants and children, including special
sensitivity, cumulative effects of residues of plant-incorporated
protectants derived through conventional breeding from sexually
compatible plants with other substances that may have a common
mechanism of toxicity with these residues, and the need for a margin of
safety for infants and children.
    i. Dietary consumption patterns. EPA considered available
information on the dietary consumption pattern of infants and children
as pertains to residues of plant-incorporated protectants derived
through conventional breeding from sexually compatible plants. 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

[[Page 37851]]

soy-based products. Soy-based products may contain residues that are
the subject of this exemption. Infants begin as early as four months of
age to consume specific types of solid foods from plants that may
contain residues that are the subject of this exemption. Subsequent to
four months of age, apart from processing to facilitate swallowing, the
diets of infants 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 normally consumed by adults
become part of their diets and the relative proportions of the
different types of food consumed changes to more closely resemble an
adult diet. The substances that are the subject of this exemption occur
in the normal diet. They have been consumed by infants and children
over very long periods of time and currently are being consumed by
infants and children. Exposure as part of a normal diet to these
substances is highly unlikely to lead to harm to infants and children.
As the diets of humans change from infancy through childhood and into
adulthood, there is some possibility that the amount of the substances
that are the subject of this exemption being consumed may change with
those consuming the greatest amounts of food of plant origin receiving
the highest exposure to substances that are the subject of this
exemption. There is no evidence that such changes are likely to result
in disproportionately high consumption of these residues in comparison
to the general population. The evidence strongly suggests that
consumption of foods containing the substances that are the subject of
this exemption, including changes in exposure because of changes in the
relative proportions of the different types of food consumed from
infancy through childhood and into adulthood, is highly unlikely to
lead to any harm.
    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 plant-
incorporated protectants derived through conventional breeding from
sexually compatible plants. The substances that are the subject of this
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, in light of
neurological differences between infants and children and adults, than
they would present for the adult population.
    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 plant-incorporated protectants
derived through conventional breeding from sexually compatible plants
as well as other substances in food that may have a common mechanism of
toxicity with these residues. The Agency's consideration of the effects
of the residues that are the subject of this exemption, and other
substances that have a common mechanism of toxicity, in Unit IX.B.5.
and Unit IX.B.6., included consideration of effects on infants and
children.
    iv. Margin of safety. In determining whether the residues of plant-
incorporated protectants derived through conventional breeding from
sexually compatible plants are safe, FFDCA section 408(b)(2)(C) directs
EPA in the case of threshold effects to apply a tenfold margin of
safety for the residues and other sources of exposure to infants and
children to account for potential prenatal and postnatal toxicity and
completeness of data effects with respect to exposure and toxicity to
infants and children, unless a different margin will be safe (21 U.S.C.
346a(b)(2)(C)). For residues of plant-incorporated protectants derived
through conventional breeding from sexually compatible plants, EPA has
determined that a tenfold margin of safety is not necessary to protect
infants and children. EPA reaches this determination based on valid,
complete and reliable information. EPA based its assessment of exposure
and toxicity upon the information base described in Unit IX.A. and Unit
IX.B.1. (Refs. 8, 11, 12, 13, 14, 15, 16, 17, 18, and 19) that arose
through the long history of human consumption of food containing
substances which are the subject of this exemption, and other animals
that consume plants containing these substances, and other substances
in food that may have a common mechanism of toxicity (Ref. 8). EPA also
relied upon knowledge from the disciplines of plant genetics, plant
physiology, phytopathology, microbial ecology, ecology, biochemistry
(including the constituents of food) and plant breeding. Based on all
of this information, EPA concludes that it is unlikely that consumption
of food containing residues that are the subject of this exemption,
including changes in exposure because of changes in the relative
proportions of the different types of food consumed from infancy
through childhood and into adulthood, would lead to any harm. Thus, EPA
has concluded that consumption of food containing residues of plant-
incorporated protectants derived through conventional breeding from
sexually compatible plants is safe for infants and children, and that a
margin of safety need not be applied for these residues in food.
    11. Analytical methods. EPA has decided that there is no need to
employ a practical method for detecting and measuring the levels of
most of the substances in plants that might be used as plant-
incorporated protectants and thus might be residues of plant-
incorporated protectants derived through conventional breeding from
sexually compatible plants. It is not anticipated that these substances
would cause adverse effects. EPA has identified nine substances of
plant origin that are found in plants that are part of the normal
American diet and if present at high levels can present toxic effects.
These are discussed in Unit IX.B.2. Practical methods exist for
detecting and measuring the concentration of these substances in food
(Ref. 22). EPA consulted with the Department of Health and Human
Services (DHHS) in developing the proposed exemption and in issuing
this final rule.

C. Determination of Safety for United States Population, and Infants
and Children

    Based on the information discussed in this document today and that
discussed in the 1994 Federal Register documents and the supplemental
documents and the associated record as described in Unit X., EPA
concludes that there is a reasonable certainty that no harm will result
to the United States population in general, and infants and children in
the United States, from aggregate exposure to any residues of the
pesticidal substance portion, or inert ingredients, of plant-
incorporated protectants derived through conventional breeding from
plants sexually compatible with the recipient plant, including all
anticipated dietary exposures and all other exposures for which there
is reliable information. This finding is based on extensive use and
experience, and the large associated literature on epidemiological
studies, nutritional assessments with human volunteers and animal model
testing of foods from plant varieties developed by moving traits among
plants in sexually compatible populations. This information shows that
adverse effects due to aggregate exposure through the dietary, non-food
oral, dermal and inhalation routes are highly unlikely for pesticidal
substances, or inert ingredients, derived through

[[Page 37852]]

conventional breeding from plants sexually compatible with the
recipient plant. And in the unlikely event such adverse effects do
occur, EPA has implemented mechanisms to ensure that it will be
notified, and that FDA will be able to seize the adulterated food;
i.e., the adverse effects reporting requirement at 40 CFR 174.71 and
the condition limiting this exemption at Sec. 174.479.

X. Documents in the Official Record

    As indicated in Unit I.B.2., the official record for this rule has
been established under docket control number OPP-300368B, the public
version of which is available for inspection as specified in Unit
I.B.2.

A. References

    The following books, articles and reports were used in preparing
this final rule and were cited in this document by the number
indicated:
    1. Whittaker, R. H. 1969. New concepts of kingdoms of organisms.
Science, 163:150-160.
    2. Environmental Protection Agency. 2000. Summary of public
comments and EPA responses on issues associated with plant-incorporated
protectants (formerly plant-pesticides) for docket OPP-300368 and OPP-
300368A.
    3. Hanson, M., and J. Halloran. In a letter dated February 22, 1995
on dockets OPP-300367 through OPP-300371.
    4. Goldburg, R. In a letter dated February 6, 1995 on dockets OPP-
300367 through OPP-300371.
    5. Rissler, J., and M. Mellon. In a letter dated January 23, 1995
on dockets OPP-300367 through OPP-300371.
    6. Environmental Protection Agency. 1994. Joint meeting of the
FIFRA Scientific Advisory Panel (SAP); Subpanel on plant-pesticides,
and the EPA Biotechnology Science Advisory Committee (BSAC);
Subcommittee on plant-pesticides. January 21, 1994. Final Report.
    7. Raven, P. H., R. F. Evert, and S. E. Eichhorn. 1992. Biology of
Plants. Fifth Edition. Worth Publishers, New York, New York.
    8. International Food Biotechnology Council. 1990. Biotechnologies
and food; Assuring the safety of foods produced by genetic
modification. In: Regulatory Toxicology and Pharmacology. Vol 12.
Academic Press, New York, New York.
    9. Wilks, H. M., A. Cortes, D. C. Emery, D. J. Halsall, A. R.
Clarke and J. J. Holbrook. 1992. Opportunities and limits in creating
new enzymes. In: Enzyme Engineering XI. Edited by D. S. Clark and D. A.
Estell. Annals of the New York Academy of Sciences. Vol. 672. The New
York Academy of Sciences. New York, New York.
    10. Environmental Protection Agency. Meeting of the EPA
Biotechnology Science Advisory Committee (BSAC); Subcommittee on plant-
pesticides. July 13, 1993. Final Report.
    11. World Cancer Research Fund and American Institute for Cancer
Research. 1997. Food, Nutrition and the Prevention of Cancer: A Global
Perspective. BANTA Book Group, Menasha, Wisconsin.
    12. Lampe, J. M. 1999. Health effects of vegetables and fruit:
assessing mechanisms of action in human experimental studies. American
Journal of Clinical Nutrition. Sep;70(3 Suppl):475S-490S.
    13. Ogomoto, I. A. Shibata and K. Fukuda. 2000. World Cancer
ResearchFund/American Institute of Cancer Research 1997 recommendation:
applicability to digestive tract cancer in Japan. Cancer Causes Control
Jan;11(1):9-23.
    14. Joseph, J. A., B. Shukitt-Hale, N. A. Denisova, D. Bielinski,
A. Martin, J. J. McEwen and P. C. Bickford. 1999. Reversals of age-
related declines in neuronal signal transduction, cognitive, and motor
behavioral deficits with blueberry, spinach, or strawberry dietary
supplementation.Journal of Neuroscience. Sep 15;19(18):8114-21.
    15. Segasothy, M. and P. A. Phillips. 1999. Vegetarian diet:
panacea for modern lifestyle diseases? QJM Monthly Journal of the
Association of Physicians. Sep;92(9):531-44.
    16. Joshipura, K. J., A. Ascherio, J. E. Manson, M. J. Stampfer, E.
B. Rimm, F. E. Speizer, C. H. Hennekens, D. Spiegelman and W. C.
Willett. 1999. Fruit and vegetable intake in relation to risk of
ischemic stroke. Journal of the American Medical Association.
Oct6;282(13)1233-9.
    17. Thompson, H. J., J. Heimendinger, A. Haegele, S. M. Sedlacek,
C. Gillette, C. O'Neill, P. Wolfe and C. Conry. 1999. Effect of
increased vegetable and fruit consumption on markers of oxidative
cellular damage. Carcinogenesis. Dec;20(12):2261-6.
    18. New, S. A., S. P. Robins, M. K. Campbell, J. C. Martin, M. J.
Garton, C. Boltin-Smith, D. A. Grubb, S. J. Lee and D. M. Reid. 2000.
Dietary influences on bone mass and bone metabolism: further evidence
of a positive link between fruit and vegetable consumption and bone
health?American Journal of Clinical Nutrition. Jan;71(1):142-51.
    19. Michaud, D. S., D. Spiegelman, S. K. Clinton, E. B. Rimm, W. C.
Willett and E. L. Giovannucci. 1999. Fruit and vegetable intake and
incidence of bladder cancer in a male prospective cohort. Journal of
the National Cancer Institute. Apr7;91(7):605-13.
    20. Environmental Protection Agency issue paper. 1994. FIFRA:
Benefit and environmental risk considerations for inherent plant-
pesticides.
    21. Agrios, George. 1988. Plant Pathology. Third Edition. Academic
Press. New York, New York.
    22. Environmental Protection Agency issue paper. 2000. Natural
toxicants in food.
    23. USDA Agricultural Research Service Poisonous Plant Research
Laboratory. Bulletin 415: Poisonous plants of the western United
States: Neurotoxic and mycotoxic plants. [http://www.pprl.usu.edu/
bulletin.htm]
    24. Hernando, J. E. and J. Leon (eds) Neglected Crops: 1492 from a
different perspective. FAO Plant production and protection series No.
26. Rome Italy, p. 131-148. 1994.
    25. Shibamoto, T. And L.F. Bjeldanes. 1993. Introduction to Food
Toxicology. Academic Press, Inc. San Diego, New York, Boston.
    26. Ellenhorn, M. J. S. Schonwald, G. Ordog and J. Wasserberger.
1997. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human
Poisoning. Second Edition. Williams and Wilkins. Baltimore, MD
    27. Cooper, R. A., and H. F. Bunn. Hemolytic anemias. 1980. In:
Harrison's Principles of Internal Medicine. Edited by. K. J.
Isselbacher, R. D. Adams, E. Braunwald, R. G. Petersdorf and J. D.
Wilson. McGraw-Hill Company.
    28. Coulston, F., and A. C. Kolbye. 1990. (Eds) Regulatory
Toxicology and Pharmacology. 12(3), S20-S30.
    29. Concon, J. M. 1988. Food Toxicology: Principles and Concepts.
Marcel Decker Inc. New York and Basel.
    30. Environmental Protection Agency issue paper. 2000. The
glycoalkaloid class; solanine and chaconine: Mechanisms of action.
    31. D'Mello, J. P. F. 1997. Handbook of Plant and Fungal Toxicants.
CBC Press. Boca Raton, New York.
    32. Tice, R. 1998. Chacoline and solanine: Review of the
Toxicological Literature. Prepared for E. Zeiger, National Toxicology
Program, National Institute of Environmental Health Sciences, National
Institutes of Health. [http://ntp-server.niehs.nih.gov/htd. ...und/
ExecSumm/ChaconineSolanine.html
    33. Environmental Protection Agency. 2000. Benefits of fruits and
vegetables.
    34. Taylor, P. 1996. Anticholinesterase agents. In: Goodman and
Gilman's The Pharmacological Basis of Therapeutics. Ninth Edition.
Edited by J. G. Hardman, L. E. Limbird,

[[Page 37853]]

P. B. Molinoff, and R. W. Rudden. McGraw-Hill Health Profession
Division. New York, New York.
    35. Baker, D. C., R. F. Keeler, and W. P. Gaffield. 1988. Mechanism
of death in syrian hamsters gavaged potato sprout material. Toxicologic
Pathology. Vol. 16:333
    36. Environmental Protection Agency. 1999. Guidance for identifying
pesticide chemicals and other substances that have a common mechanism
of toxicity. FAX-on-Demand Number : (202) 401-0527. Item: 6055.
    37. Atlas, R. and R. Bartha. 1987. Microbial Ecology. Benjamin/
Cummings Publishing Company, Inc. Menlo Park, California.
    38. National Research Council. 1999. Hormonally Active Agents in
the Environment. National Academy Press. Washington DC.
    39. Yunginger, J. W. 1991. Food Antigens. In: Food Allergy: Adverse
Reactions to Foods and Food Additives. Edited by D. D. Metcalfe, H. A.
Sampson, and R. A. Simon. Blackwell Scientific Publications. Cambridge,
Massachusetts.
    40. O'Mahony, S. And A. Ferguson. 1991. Gluten-Sensitive
Enteropathy (Celiac Disease). In: Food Allergy: Adverse Reactions to
Foods and Food Additives. Edited by D. D. Metcalfe, H. A. Sampson, and
R. A. Simon. Blackwell Scientific Publications. Cambridge,
Massachusetts.
    41. Environmental Protection Agency issue paper. 2000. Dermal and
inhalation exposure to plant substances.
    42. Lovell, C. R. 1993. Plants and the skin. First edition. Oxford,
Blackwell Scientific Publications.
    43. Guy, R. H., and J. Hadgraft. 1991. Principles of skin
permeability relevant to chemical exposure. In: Dermal and Ocular
Toxicology: Fundamentals and Methods. Edited by D. W. Hobson. CRC Press
Boca Raton, Florida.
    44. Murray, M. T. 1995. The Healing Power of Herbs. Prima
Publishing, Rocklin, California.
    45. Glinsukon, T., Stitmunnaithum, V., Toskulkao, C., Buranawuti,
T., and V. Tangkrisanavinont. Acute toxicity of capsaicin in several
animal species. Toxicon. 18(2):215-20. 1980.
    46. Environmental Protection Agency. 1997. Exposure Factors
Handbook. Volume 1. National Center for Environmental Assessment. EPA/
600/P-95/002Fa.
    47. Environmental Protection Agency. 2000. Economic analysis of the
plant-incorporated protectant regulations under the Federal
Insecticide, Fungicide, and Rodenticide Act.

B. Additional Information

    The complete official record for this rulemaking includes:
    The docket identified by the docket control number OPP-300370 for
the document entitled ``Proposed Policy: Plant-Pesticides Subject to
the Federal Insecticide, Fungicide, and Rodenticide Act and the Federal
Food, Drug, and Cosmetic Act'' (59 FR 60496, November 23, 1994) (FRL-
4755-2).
    The docket identified by the docket control number OPP-300369 for
the document entitled ``Plant-Pesticides Subject to the Federal
Insecticide, Fungicide and Rodenticide Act; Proposed Rule'' (59 FR
60519, November 23, 1994) (FRL-4755-3).
    The docket identified by the docket control number OPP-300368 for
the document entitled ``Plant-Pesticides; Proposed Exemption From the
Requirement of a Tolerance Under the Federal Food, Drug, and Cosmetic
Act'' (59 FR 60535, November 23, 1994) (FRL-4758-8).
    The docket identified by the docket control number OPP-300371 for
the document entitled ``Plant-Pesticides; Proposed Exemption From the
Requirement of a Tolerance Under the Federal Food, Drug, and Cosmetic
Act for Nucleic Acids Produced in Plants'' (59 FR 60542, November 23,
1994) (FRL-4755-5).
    The docket identified by the docket control number OPP-300367 for
the document entitled ``Plant-Pesticides; Proposed Exemption From the
Requirement of a Tolerance Under the Federal Food, Drug, and Cosmetic
Act for Viral Coat Proteins Produced in Plants'' (59 FR 60545, November
23, 1994) (FRL-4755-4).
    The docket identified by the docket control number OPP-300370A for
the document entitled ``Plant-Pesticide Subject to the Federal
Insecticide, Fungicide, and Rodenticide Act and the Federal Food, Drug,
and Cosmetic Act; Reopening of Comment Period'' (61 FR 37891, July 22,
1996) (FRL-5387-4).
    The docket identified by the docket control number OPP-300368A for
the document entitled ``Plant-Pesticides; Supplemental Notice of
Proposed Rulemaking'' (62 FR 27132, May 16, 1997) (FRL-5717-2).
    The docket identified by the docket control number OPP-300371A for
the document entitled ``Plant-Pesticides; Nucleic Acids; Supplemental
Notice of Proposed Rulemaking'' (62 FR 27142, May 16, 1997) (FRL-5716-
7).
    The docket identified by the docket control number OPP-300367A for
the document entitled ``Plant-Pesticides; Viral Coat Proteins;
Supplemental Notice of Proposed Rulemaking'' (62 FR 27149, May 16,
1997) (FRL-5716-6).
    The docket identified by the docket control number OPP-30069A for
the document entitled ``Plant-Pesticides, Supplemental Notice of
Availability of Information'' (64 FR 19958, April 23, 1999) (FRL-6077-
6).
    The docket identified by the docket control number OPP-300371B for
the companion document entitled ``Exemption from the Requirement of a
Tolerance Under the Federal Food, Drug, and Cosmetic Act for Residues
of Nucleic Acids that are Part of Plant-Incorporated Protectants
(Formerly Plant-Pesticides)'' (FRL-6057-5) published elsewhere in this
issue of the Federal Register.
    The docket identified by the docket control number OPP-300369B for
the document entitled ``Regulations Under the Federal Insecticide,
Fungicide, and Rodenticide Act for Plant-Incorporated Protectants
(Formerly Plant-Pesticides)'' (FRL-6057-7)published elsewhere in this
issue of the Federal Register.
    The docket identified by the docket control number OPP-300368B for
this document (FRL-6057-6).
    Also include in the complete official public record are:
    1. Public comments submitted in response to the proposals and
supplemental documents cited in this Unit X.B.
    2. Reports of all meetings of the Biotechnology Science Advisory
Committee and the FIFRA Science Advisory Panel pertaining to the
development of this final rule.
    3. The Economic Analysis (EA) for the final rule on FIFRA
regulations for plant-incorporated protectants, and documents
supporting the EA (Ref. 47).
    4. Support documents and reports.
    5. Records of all communications between EPA personnel and persons
outside EPA pertaining to the final rule. (This does not include any
inter-agency and intra-agency memoranda, unless specifically noted in
the Indices of the dockets).
    6. Published literature that is cited in this document.
    7. The response to comments document pertaining to the development
of this final rule (Ref. 2).

XI. Regulatory Assessment Requirements

    This final rule establishes an exemption from the tolerance
requirement under FFDCA section 408 and does not impose any other
regulatory requirements. As such, The Office of Management and Budget
(OMB) has exempted these types of actions from review under Executive

[[Page 37854]]

Order 12866, entitled Regulatory Planning and Review (58 FR 51735,
October 4, 1993).
    This action does not contain any information collections subject to
OMB approval under the Paperwork Reduction Act (PRA), 44 U.S.C. 3501 et
seq., nor does it require OMB review or any Agency action under
Executive Order 13045, entitled Protection of Children from
Environmental Health Risks and Safety Risks (62 FR 19885, April 23,
1997).
    This action does not require any special considerations under
Executive Order 12898, entitled Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations (59 FR 7629, February 16, 1994), nor does it involve any
technical standards that would require Agency consideration of
voluntary consensus standards pursuant to section 12(d) of the National
Technology Transfer and Advancement Act of 1995 (NTTAA), Public Law
104-113, section 12(d) (15 U.S.C. 272 note).
    This action does not impose any enforceable duty or contain any
unfunded mandate, and will not otherwise significantly or uniquely
affect small governments as described under Title II of the Unfunded
Mandates Reform Act of 1995 (UMRA) (Public Law 104-4). This rule does
not significantly or uniquely affect the communities of Indian trial
governments, nor does it involve or impose any requirements that affect
Indian Tribes. Accordingly, the requirements of section 3(b) of
Executive Order 13084, entitled Consultation and Coordination with
Indian Tribal Governments (63 FR 27655, May 19, 1998), do not apply to
this rule. Executive Order 13175, entitled Consultation and
Coordination with Indian Tribal Governments (65 FR 67249, November 6,
2000), which took effect on January 6, 2001, revokes Executive Order
13084 as of that date. EPA developed this rulemaking, however, during
the period when Executive Order 13084 was in effect; thus, EPA
addressed tribal considerations under Executive Order 13084. For the
same reasons stated for Executive Order 13084, the requirements of
Executive Order 13175 do not apply to this rule either. For the same
reasons, this rule does not have any substantial direct effect on
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, as specified in Executive Order 13132,
entitled Federalism (64 FR 43255, August 10, 1999). This rule directly
regulates growers, food processors, food handlers and food retailers,
not States. This action does not alter the relationships or
distribution of power and responsibilities established by Congress in
the preemption provisions of FFDCA section 408(n)(4).
    Pursuant to section 605(b) of the Regulatory Flexibility Act (RFA)
(5 U.S.C. 601 et seq.), the Agency hereby certifies that this final
rule will not have a significant economic impact on a substantial
number of small entities. The Agency's determination is based on the
fact that an exemption from the requirement of a tolerance under FFDCA
section 408, such as that contained in this rule, will not adversely
affect any small businesses. Additional information about the Agency's
determination may be found in the small entity impact analysis prepared
as part of the economic analysis for the FIFRA rulemaking, which is
available in the public version of the official record under OPP-
300368B (Ref. 47). The Agency has also previously assessed whether
establishing tolerances, exemptions from tolerances, raising tolerance
levels or expanding exemptions might adversely impact small entities
and concluded, as a general matter, that there is no adverse economic
impact associated with these actions. See 46 FR 24950, May 4, 1981.
    This rule is not subject to Executive Order 13211, entitled Actions
Concerning Regulations That Significantly Affect Energy Supply,
Distribution, or Use (66 FR 28355, May 22, 2001), because this action
is not expected to affect energy supply, distribution, or use.

XII. Submission to Congress and the Comptroller General

    The Congressional Review Act, 5 U.S.C. 801 et seq., as added by the
Small Business Regulatory Enforcement Fairness Act of 1996, generally
provides that before a rule may take effect, the agency promulgating
the rule must submit a rule report, which includes a copy of the rule,
to each House of the Congress and to the Comptroller General of the
United States. EPA will submit a report containing this rule and other
required information to the U.S. Senate, the U.S. House of
Representatives, and the Comptroller General of the United States prior
to publication of this final rule in the Federal Register. This final
rule is not a ``major rule'' as defined by 5 U.S.C. 804(2).

List of Subjects in 40 CFR Part 174

    Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Plants, Reporting and
recordkeeping requirements.

    Dated: July 12, 2001.
Christine T. Whitman,
Administrator.

    Therefore, 40 CFR chapter I is amended as follows:

PART 174--[AMENDED]

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

    Authority: 7 U.S.C. 136-136y and 21 U.S.C. 346a and 371.

    2. Section 174.479 is added to subpart W to read as follows:

Sec. 174.479  Pesticidal substance from sexually compatible plant;
exemption from the requirement of a tolerance.

    Residues of a pesticidal substance that is part of a plant-
incorporated protectant from a sexually compat
    Pursuant to section 605(b) of the Regulatory Flexibility Act (RFA)
(5 U.S.C. 601 et seq.), the Agency hereby certifies that this final
rule will not have a significant economic impact on a substantial
number of small entities. The Agency's determination is based on the
fact that an exemption from the requirement of a tolerance under FFDCA
section 408, such as that contained in this rule, will not adversely
affect any small businesses. Additional information about the Agency's
determination may be found in the small entity impact analysis prepared
as part of the economic analysis for the FIFRA rulemaking, which is
available in the public version of the official record under OPP-
300368B (Ref. 47). The Agency has also previously assessed whether
establishing tolerances, exemptions from tolerances, raising tolerance
levels or expanding exemptions might adversely impact small entities
and concluded, as a general matter, that there is no adverse economic
impact associated with these actions. See 46 FR 24950, May 4, 1981.
    This rule is not subject to Executive Order 13211, entitled Actions
Concerning Regulations That Significantly Affect Energy Supply,
Distribution, or Use (66 FR 28355, May 22, 2001), because this action
is not expected to affect energy supply, distribution, or use.

XII. Submission to Congress and the Comptroller General

    The Congressional Review Act, 5 U.S.C. 801 et seq., as added by the
Small Business Regulatory Enforcement Fairness Act of 1996, generally
provides that before a rule may take effect, the agency promulgating
the rule must submit a rule report, which includes a copy of the rule,
to each House of the Congress and to the Comptroller General of the
United States. EPA will submit a report containing this rule and other
required information to the U.S. Senate, the U.S. House of
Representatives, and the Comptroller General of the United States prior
to publication of this final rule in the Federal Register. This final
rule is not a ``major rule'' as defined by 5 U.S.C. 804(2).

List of Subjects in 40 CFR Part 174

    Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Plants, Reporting and
recordkeeping requirements.

    Dated: July 12, 2001.
Christine T. Whitman,
Administrator.

    Therefore, 40 CFR chapter I is amended as follows:

PART 174--[AMENDED]

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

    Authority: 7 U.S.C. 136-136y and 21 U.S.C. 346a and 371.

    2. Section 174.479 is added to subpart W to read as follows:

Sec. 174.479  Pesticidal substance from sexually compatible plant;
exemption from the requirement of a tolerance.

    Residues of a pesticidal substance that is part of a plant-
incorporated protectant from a sexually compatible plant are exempt
from the requirement of a tolerance if all the following conditions are
met:
    (a) The genetic material that encodes for the pesticidal substance
or leads to the prodhat encodes for the pesticidal substance
or leads to the production of the pesticidal substance is from a plant
that is sexually compatible with the recipient food plant.
    (b) The genetic material has never been derived from a source that
is not sexually compatible with the recipient food plant.
    (c) The residues of the pesticidal substance are not present in
food from the plant at levels that are injurious or deleterious to
human health.

[FR Doc. 01-17983 Filed 7-16-01; 11:42 am]
BILLING CODE 6560-50-S