[Federal Register Volume 62, Number 95 (Friday, May 16, 1997)]
[Proposed Rules]
[Pages 27142-27149]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-12786]
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ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 180
[OPP-300371A; FRL-5716-7]
RIN 2070-AC02
Plant-Pesticides; Nucleic Acids; Supplemental Notice of Proposed
Rulemaking
AGENCY: Environmental Protection Agency (EPA).
ACTION: Supplemental notice of proposed rulemaking.
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SUMMARY: This document announces the availability of information for
additional public comment regarding a proposed exemption from the
requirement of a tolerance under the Federal Food, Drug, and Cosmetic
Act (FFDCA) for residues of nucleic acids (i.e., deoxyribonucleic acid
and ribonucleic acid) produced in plants as part of a plant-pesticide.
Comments on this document may also affect EPA's final determination on
three proposed exemptions under the Federal Insecticide, Fungicide, and
Rodenticide Act (FIFRA). In 1994, EPA proposed to exempt from the
requirement of tolerance residues of nucleic acids produced in plants
as part of a plant-pesticide because such a tolerance would not be
necessary to protect the public health. Since publication of the
proposal, Congress enacted the Food Quality Protection Act (FQPA) which
amended FFDCA and FIFRA. EPA is issuing this document today to provide
the public with an opportunity to comment on EPA's analysis of how
certain FQPA amendments to FFDCA and FIFRA apply to the proposed
exemption from the requirement of a tolerance for residues of nucleic
acids produced in plants as part of a plant-pesticide. EPA believes
that it considered most of the substantive issues associated with the
FQPA amendments when it issued the proposal in 1994. EPA is, thus, in
this document, specifically seeking comment only on its evaluation of
the requirements imposed by FQPA that the Agency did not address in the
proposal.
DATES: Comments, identified by the docket control number ``OPP-
300371A,'' must be received on or before June 16, 1997.
ADDRESSES: By mail, submit written comments to: Public Information and
Records Integrity Branch, Information Resources and Services Division
(7506C), Office of Pesticide Programs, Environmental Protection Agency,
401 M St., SW., Washington, DC 20460. In person deliver comments to:
Rm. 1132, Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA
22202.
Comments and data may also be submitted electronically by following
the instructions under Unit VI. of this document. No Confidential
Business Information (CBI) should be submitted through e-mail.
FOR FURTHER INFORMATION CONTACT: Elizabeth Milewski, Office of Science,
Coordination and Policy, Office of Prevention, Pesticides and Toxic
Substances (7101), Environmental Protection Agency, 401 M St., SW.,
Washington, DC 20460, Telephone: (202) 260-6900, e-mail:
[email protected].
SUPPLEMENTARY INFORMATION:
I. Introduction
EPA issued in the November 23, 1994 Federal Register a package of
five separate Federal Register proposals (59 FR 60496, 60519, 60535,
60542 and 60545) (FRL-4755-2, FRL-4755-3, FRL-4758-8, FRL-4755-5, and
FRL-4755-4) which together described EPA's approach to substances
produced in plants that enable the plants to resist pests or disease.
EPA's package of proposals indicated that these substances are
pesticides under section 2 of FIFRA (7 U.S.C. 136(u)) if they are
``intended for preventing, destroying, repelling, or mitigating any
pest'' or if they are ``. . . intended for use as a plant regulator,
defoliant, or desiccant'' regardless of whether the pesticidal
capabilities evolved in the plants or were introduced by breeding or
through the techniques of modern biotechnology. These substances, and
the genetic material necessary to produce them, were designated
``plant-pesticides'' by EPA in the November 23, 1994, Federal Register
notices. The notices defined a ``plant-pesticide'' as ``a pesticidal
substance that is produced in a living plant and the genetic material
necessary for the production of the pesticidal substance where the
pesticidal substance is intended for use in the living plant'' (59 FR
at 60534).
One of the five documents (59 FR 60542) proposed to exempt from the
requirement of a tolerance residues of nucleic acids (i.e.,
deoxyribonucleic acid (DNA) and ribonucleic acid (RNA)) when such
nucleic acids are produced in plants as part of a plant-pesticide
(i.e., the genetic material necessary to produce the pesticidal
substance). This supplemental notice addresses the nucleic acids
portion of plant-pesticides produced in food plants. Because FQPA
modified FIFRA ( 7 U.S.C. 136 et seq.) by incorporating the FFDCA
safety standard into the FIFRA test for determining whether a pesticide
poses an unreasonable adverse effect, comments on this supplemental
notice may also affect EPA's final determination on proposed exemptions
under FIFRA for three categories of plant-pesticides (59 FR at 60535):
(1) Those that are derived from a plant that is sexually compatible
with the recipient plant, (2) those that act primarily by affecting the
plant, and (3) those that are coat proteins from plant viruses.
EPA is publishing this supplemental notice to ensure that the
public has had adequate opportunity to comment on certain new
considerations raised by the FQPA amendments to FFDCA as these
considerations relate to the proposed exemption from a tolerance for
residues of the nucleic acid portion of plant-pesticides produced in
food plants. In evaluating a pesticide chemical residue for exemption
from FFDCA tolerance requirements, EPA must now explicitly address
certain factors, and make a determination that there is a reasonable
certainty that aggregate exposure to the residue will cause no harm to
the public. The factors to be considered are iterated in Unit II. of
this supplemental notice. EPA's evaluation of these factors relative to
the proposed exemption (59 FR 60535) is contained in Unit IV. of this
supplemental notice. Consistent with FFDCA section 408(c)(2)(B), EPA
has reviewed the available scientific data and other relevant
information in support of this action. In today's supplemental notice,
EPA requests comment only on the new conclusions identified in Unit
V.C.
In light of FQPA, EPA is engaged in a process, including
consultation with registrants, states, and other interested
stakeholders, to make decisions on the
[[Page 27143]]
new policies and procedures that will be appropriate as a result of
enactment of FQPA. In establishing this exemption from the requirement
of a tolerance for residues of nucleic acids produced in plants as part
of a plant-pesticide, EPA does not intend to set precedents for the
application of section 408 and the new safety standard to other
tolerances and exemptions. This exemption from the requirement of a
tolerance will not restrict EPA's options with regard to general
procedures and policies for implementation of the amended FFDCA section
408.
II. Statutory Authority
Under FFDCA, EPA regulates pesticide chemical residues by
establishing tolerances limiting the amounts of residues that may be
present in food, or by establishing exemptions from the requirement of
a tolerance for such residues. Pesticide chemical residues subject to
regulation under FFDCA are defined by reference to the definition of
pesticide under FIFRA. FFDCA section 201(q)(1) defines a ``pesticide
chemical residue'' to mean the residue in or on food of a pesticide
chemical or other added substance resulting primarily from the
metabolism or degradation of a pesticide chemical (21 U.S.C. 321
(q)(2)). A ``pesticide chemical'' means ``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 authorizes EPA to regulate the sale and distribution of
pesticides in the United States and to exempt a pesticide from the
requirements of FIFRA if it is not of a character requiring regulation
(7 U.S.C. 136a(a) and 136w(b)). 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)).
FQPA amends both FFDCA and FIFRA. FQPA, which took effect on August
3, 1996, among other things, amends FIFRA such that a registration
cannot be issued for a pesticide to be used on or in food unless the
residue of the pesticide in food qualifies for a tolerance or exemption
from the requirement for a tolerance. FQPA modified FIFRA section 2(bb)
by incorporating the FFDCA section 408 safety standard into the test
for determining whether a pesticide poses an unreasonable adverse
effect (7 U.S.C. 136(bb)). FIFRA section 2(bb) defines the term
``unreasonable adverse effects on the environment'' to mean (1) any
unreasonable risk to man or the environment, taking into account the
economic, social, and environmental costs and benefits of the use of
any pesticide, or (2) a human dietary risk from residues that result
from a use of a pesticide in or on any food inconsistent with the
standard under section 408 of the FFDCA. Thus, a pesticide used in or
on food that does not meet the FFDCA section 408 safety standard also
would pose an unreasonable adverse effect under FIFRA and would not
qualify for an exemption from the requirements of FIFRA under FIFRA
section 25(b)(2).
FQPA amends FFDCA section 408(c)(2)(A)(i) to allow EPA to establish
an exemption from the requirement of a tolerance for a ``pesticide
chemical residue'' only if EPA determines that the exemption is
``safe'' (21 U.S.C. 346a(c)(2)(A)(i)). Section 408(c)(2)(A)(ii) 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, but does not include
occupational exposure. In establishing an exemption from the
requirement of a tolerance, FFDCA section 408(c), like the statute
prior to FQPA, does not require EPA to consider benefits that might be
associated with use of the pesticide chemical.
FFDCA section 408 requires EPA to give special consideration to
exposure of infants and children to the pesticide chemical residue in
establishing an exemption and to ``ensure that there is a reasonable
certainty that no harm will result to infants and children from
aggregate exposure to the pesticide chemical residue'' (21 U.S.C.
346a(b)(2)(C)(ii)(I)) and (c)(2)(B). Section 408(b)(2)(D) specifies
other, general factors EPA is to consider in establishing an exemption.
Section 408(c)(3)(B) 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
(21 U.S.C. 346a(c)(3)(B)).
Specifically, EPA must consider the following in deciding whether
to grant an exemption:
1. The validity, completeness, and reliability of the available
data from studies of the pesticide chemical and chemical pesticide
residue.
2. Nature of any toxic effect shown to be caused by the pesticide
chemical or residues in studies.
3. Available information concerning the relationship of the results
of such studies to human risk.
4. Available information concerning the dietary consumption
patterns of consumers (and major identifiable subgroups of consumers).
5. Available information concerning the cumulative effects of such
residues and other substances that have a common mechanism of toxicity.
6. Available information concerning the aggregate exposure levels
of consumers to the pesticide chemical residue and to other related
substances, including dietary exposure and non-occupational exposures.
7. Available information concerning the variability of the
sensitivities of major identifiable subgroups of consumers.
8. Such information as the Administrator may require on whether the
pesticide chemical may have an effect in humans that is similar to an
effect produced by a naturally-occurring estrogen or other endocrine
effects.
9. Safety factors which in the opinion of experts qualified by
scientific training and experience to evaluate the safety of food
additives are generally recognized as appropriate for the use of animal
experimentation data (21 U.S.C. 346a(b)(2)(D)).
Additionally, with respect to exposure of infants and children,
consistent with section 408(b)(2)(C), EPA must assess the risk of the
pesticide based on available information concerning:
1. Consumption patterns that are likely to result in
disproportionately high consumption of food with pesticide residues.
2. Special susceptibility of infants and children to such residues.
3. Cumulative effects of residues with other substances that have a
common mechanism of toxicity (21 U.S.C. 346a(b)(2)(C) and (c)(2)(B)).
III. Summary of Proposed Regulation
The proposal (59 FR 60542) described how EPA would view: (1)
Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), (2) nucleic
acid analogues (e.g., altered purine or pyrimidine bases) that may be
considered ``nucleic acids'' by their chemical composition, and (3) DNA
sequences that code for the RNA complement (anti-sense) of the
messenger RNA (mRNA) for an essential enzyme or other component of an
obligate parasite.
[[Page 27144]]
In the November 23, 1994 Federal Register, EPA proposed to exempt
nucleic acids (i.e., deoxyribonucleic acid (DNA) and ribonucleic acid
(RNA)) from the requirement of a tolerance when such nucleic acids are
produced in plants as part of a plant-pesticide (59 FR 60542). In the
proposal, EPA stated that the proposed exemption from the requirement
of a tolerance for the nucleic acids portion of plant-pesticides
produced in food plants is based on the ubiquity of nucleic acids in
all forms of life, their presence in human and domestic animal food and
the consequent large scale exposure of the human population with no
evidence nucleic acids have caused any adverse health effects when
consumed as part of a food plant. The Agency knows of no instance where
nucleic acids naturally occurring in plants have been associated with
any toxic effects related to the consumption of foods.
In the 1994 proposal, EPA recognized that nucleic acid analogues
(e.g., altered purine or pyrimidine bases) may be considered ``nucleic
acids'' by their chemical composition. Certain analogues are being
developed as therapeutic agents for human diseases and nucleic acid
analogues could conceivably be developed as pesticides. The proposed
exemption does not extend to such nucleic acid analogues. The 1994
proposal only proposed to exempt the naturally occurring, non-modified
nucleic acids (ribosides or deoxyribosides of A, T, G, C, and U) and
polymers of such substances commonly found in living cells that encode
the information necessary to make the pesticidal substances produced by
plants.
The 1994 proposal also discussed how EPA proposed to view the
introduction into plants of DNA sequences that code for the RNA
complement (anti-sense) of the messenger RNA (mRNA) for an essential
enzyme or component of an obligate parasite. One mechanism by which
this RNA complement or anti-sense RNA is believed to work is to bind to
the target mRNA and prevent it from binding to ribosomes, effectively
terminating synthesis of the essential enzyme or other enzymes for
making other essential cellular components necessary to survival of the
parasite. This methodology is currently being developed for introducing
pest-resistance into plants. As was noted in the proposed exemption,
the Agency believes that the introduction and expression in plants of
nucleic acids in this anti-sense technology do not present a hazard to
the public health and such nucleic acids would qualify for this food
tolerance exemption.
IV. Risk Assessment and Safety Determinations
A. Risk Assessment in Proposal
This unit reviews the analysis that EPA used to support its 1994
proposal (59 FR 60535) to exempt nucleic acids (DNA and RNA, including
DNA and RNA used in anti-sense technology) produced in plants as part
of a plant-pesticide from the requirement of a tolerance under FFDCA.
EPA also relied upon the analysis in the 1994 FFDCA proposal to
evaluate human dietary risks in support of its proposal (59 FR 60519)
to exempt three categories of plant-pesticides (59 FR at 60535) from
most FIFRA requirements. Non-dietary human risks from exposure to
nucleic acids as part of plant-pesticides were examined under the
analysis for the proposed FIFRA exemption and are discussed in this
supplemental notice only as they pertain to the dietary risks.
EPA's 1994 proposal (59 FR 60542) to exempt nucleic acids produced
in plants as part of a plant-pesticide from the requirement of a
tolerance was based on the ubiquity of nucleic acids and their presence
in human and domestic animal food without observed adverse health
effects.
Nucleic acids encode the information necessary for the functioning
of the organism. Chemically, nucleic acids occur in two types:
deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). DNA and RNA can
be thought of as a ``tape'' containing information. DNA and RNA are
polymers composed of small units, called ``nucleotides.'' A nucleotide
is made up of a sugar, a phosphate group, and one of four heterocyclic
bases. The heterocyclic bases in DNA are adenine, thymine, cytosine,
and guanine. The heterocyclic bases in RNA are adenine, uracil,
cytosine and guanine. The sugars and phosphates form a long chain or
``backbone'' with one heterocyclic base attached to each sugar. The
information encoded in the nucleic acid is determined by the sequence
in which the heterocyclic bases are attached to the sugar-phosphate
backbone. Thus, the ``genetic material necessary for the production of
the pesticidal substance'' are the nucleic acids encoding the
information necessary for a plant cell to make the pesticidal
substance.
Nucleic acids are also the chemical basis for heritable traits.
When nucleic acids encoding the genetic information needed for the
production of a pesticidal substance is stably integrated into the
plant, that plant and its progeny will have the potential to produce
the pesticidal substance.
Nucleic acids are widespread in foods and have not, by themselves,
been associated with toxic or pathogenic effects on animals or humans.
None of the constituents of nucleic acids are known to be acute
toxicants, but like proteins and other normal constituents of food, may
cause indirect, adverse metabolic effects if consumed exclusively at
high doses over a long period of time in the absence of a normal
balanced diet. Nucleic acids never occur at these high amounts in food
plants and have not been associated with any toxic effects related to
consumption of foods.
In the proposal, the Agency made clear that it is not proposing to
exempt nucleic acid analogues from the requirement of a food tolerance.
These analogues are not naturally occurring and those used as
therapeutic agents frequently have significant toxicity associated with
their use. The intent of EPA's 1994 proposal was to exempt only the
naturally occurring, non-modified nucleic acids, and polymers of such
substances, commonly found in living cells that serve as the mechanisms
of encoding traits associated with pesticidal substances produced by
plants.
EPA proposed to extend this exemption (59 FR 60542) from the
requirement of a tolerance to the mRNA used in anti-sense technology
based on the consideration that these mRNAs are analogous to naturally
occurring, non-modified nucleic acid polymers commonly found in living
cells. The rationale applied in the proposal to other naturally
occurring, non-modified nucleic acid polymers applies equally to these
mRNAs; the ubiquity of nucleic acids and their presence in human and
domestic animal food and no observed adverse health effects associated
with consumption of foods containing nucleic acids.
B. Risk Assessment in Light of Amendment to FFDCA
After EPA issued its proposed exemption from the requirement of a
tolerance for nucleic acids produced in plants as part of a plant-
pesticide (59 FR 60542), Congress enacted FQPA and amended certain
FFDCA provisions governing pesticide chemical residues and FIFRA
provisions governing pesticides (See Unit II. of this supplemental
notice). Congress revised the specific wording of the section 408
standard for exemptions and provided more specific guidance regarding
some of the factors that EPA should consider in establishing such
exemptions (see
[[Page 27145]]
Unit II. of this supplemental notice). When EPA proposed the exemption
for residues of nucleic acids produced in plants as part of a plant-
pesticide (59 FR 60535), it considered most of the safety factors
spelled out in FQPA even though the Agency may not have explicitly
discussed all those factors using the terminology specified in the FQPA
amendments. This supplemental notice describes how the Agency took
account of most of the FQPA factors in issuing its 1994 proposal to
exempt from the requirement of a tolerance nucleic acids produced in
plants as part of a plant-pesticide, and indicates which factors were
considered in that proposal. The information the Agency relied on in
considering these factors is part of the public record which was
available to the public when EPA issued the proposed exemption from the
requirement of a food tolerance. The supplemental notice also
identifies the factors that were not considered in the proposal.
Because FQPA amended FIFRA by incorporating the section 408 safety
standard, commenters should be aware that comments on this supplemental
notice may also affect EPA's final determination on the proposed
exemptions (59 FR at 60535) under FIFRA for three categories of plant-
pesticides: (1) Those that are derived from plants sexually compatible
with the recipient plant, (2) those that act primarily by affecting the
plant, and (3) those that are coat proteins from plant viruses.
1. Validity, completeness, and reliability of available data. EPA
considered in 1994 the validity, completeness, and reliability of the
available data with regard to nucleic acids produced in plants as part
of a plant-pesticide in the proposals (59 FR 60519 and 60542) and has
described the evaluation in Unit IV.A. of this supplemental notice.
2. Nature of toxic effect. EPA in 1994 considered the nature of the
toxic effects caused by nucleic acids produced in plants as part of a
plant-pesticide in the proposals (59 FR 60519 and 60542) and has
described its evaluation in Unit IV.A. of this supplemental notice.
3. Relationship of studies to humans. EPA in 1994 considered the
available information concerning the relationship of available data on
toxicity of nucleic acids produced in plants as part of a plant-
pesticide to humans when it issued the proposal to exempt these
substances from the requirement of a tolerance. EPA has summarized its
evaluation in Unit IV.A. of this supplemental notice. The nature of the
toxic effect of nucleic acids was assessed in light of the known
presence of nucleic acids in all consumed foods (Ref. 1) and the
history of human consumption of food derived from crop plants, and from
products such as meat and milk from animals that consume forage and
other crops (e.g., corn and other grains) that contain residues of
nucleic acids. EPA determined in the proposal that nucleic acids
produced in plants as part of a plant-pesticide do not have a toxic
effect and have no adverse effects to humans. Because knowledge of
human consumption of food containing nucleic acids was available and
adequately addressed the issues of hazard and exposure, the Agency did
not use, for the proposed exemption (59 FR 60542), data generated in
the laboratory through animal testing.
4. Dietary consumption patterns. EPA considered in the 1994
proposal the available information on the varying dietary consumption
patterns of major identifiable consumer subgroups as it pertains to
nucleic acids in food from plants. As described in the 1994 proposal,
nucleic acids are ubiquitous in nature and in the food supply. Nucleic
acids that make up the genetic material in plant-pesticides will not
alter this baseline consumption pattern of nucleic acids. The Agency's
evaluation is summarized in Unit IV.A. of this supplemental notice.
5. Available information concerning cumulative effects of the
pesticide chemical residue and other substances that have a common
mechanism of toxicity. EPA in 1994 examined the available information
on the cumulative effect of nucleic acids in food from plants and other
substances that have a common mechanism of toxicity. EPA summarizes
this information and its analysis in Unit IV.A. of this supplemental
notice.
Nucleic acids are widespread in food and have not been associated
with direct toxic or pathogenic effects to animals or humans. Because
nucleic acids in foods have no human toxicity, no cumulative effects
can be identified for nucleic acids produced in plants as part of a
plant-pesticide. FQPA also directs the Agency to examine whether there
are other substances that have a common mechanism of toxicity with
nucleic acids produced in plants as part of a plant-pesticide. Based on
available information which indicates that nucleic acids in food have
no human toxicity, EPA is not aware of any other substances that might
have a common mechanism of human toxicity with nucleic acids produced
in plants as part of a plant-pesticide.
EPA is not aware of any substances outside of the food supply that
may have a common mechanism of toxicity with nucleic acids produced in
plants as part of a plant-pesticide since nucleic acids in plant food
are not toxic. EPA has identified nucleic acid analogues as substances
having some level of toxicity; however, their mechanism of toxicity is
not cumulative with that of naturally occurring nucleic acids (DNA and
RNA).
EPA considered the safety of foods containing residues of nucleic
acids when it issued the proposal and is not requesting additional
comment on that topic. Comments are only requested on EPA's conclusion
that there are no substances outside of the food supply that may have a
cumulative toxic effect with residues of nucleic acids produced in
plants as part of a plant-pesticide.
6. Aggregate exposures of consumers including non-occupational
exposures. EPA considered the available information on the aggregate
exposure level of consumers to nucleic acids produced in plants as part
of a plant-pesticide in the 1994 FFDCA and FIFRA proposals (59 FR 60519
and 60542). This included a consideration of exposures from dietary
sources (59 FR 60542) as well as from other non-occupational sources
(59 FR 60519). As indicated in EPA's policy statement, ``plant-
pesticides are likely to present a limited exposure of the pesticidal
substance to humans. In most cases, the predominant, if not the only,
exposure route will be dietary. Significant respiratory and dermal
exposures will be unlikely'' (59 FR at 60513). As explained in the
FFDCA and FIFRA proposals and EPA's policy statement (59 FR 60496) and
associated dockets, plant-pesticides present negligible exposure of
pesticidal substances to humans outside of the dietary route because
the substances are in the plant tissue and thus are found either within
the plant or in close proximity to the plant. This is particularly true
for the nucleic acid portion of plant-pesticides. EPA considered
dietary exposure to nucleic acids produced in plants as part of a
plant-pesticide in the proposed FFDCA exemption (59 FR 60542) and
summarized its evaluation in Unit IV.A. of this supplemental notice.
Despite EPA's belief that, because of the nature of nucleic acids
produced in plants as part of a plant-pesticide, there is little
likelihood of exposure other than through the dietary route, EPA in
this supplemental notice sets forth in greater detail its
considerations concerning other exposure routes. With regard to the
dermal route of exposure, nucleic acids produced in plants as part of a
plant-pesticide may in some cases be present in sap or other exudates
from the plant or the food and thus may
[[Page 27146]]
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. However, on a per person basis, the potential amounts involved
in these exposures are negligible in comparison to potential exposure
through the dietary route. Moreover, substances that occur naturally in
food, including the nucleic acids produced in plants as part of plant-
pesticides, are unlikely to cross the barrier provided by the skin.
This is particularly true for nucleic acids produced in plants as part
of a plant-pesticide as they are large polymers.
With regard to exposure through inhalation, nucleic acids produced
in plants as part of a plant-pesticide may in some cases be present in
pollen and some individuals (those near enough to farms, nurseries, or
other plant-growing areas to be exposed to wind-blown pollen) may be
exposed, through inhalation, to the pollen. On a per person basis, the
potential amounts of pollen involved in these exposures are negligible
in comparison to potential exposure through the dietary route.
Moreover, it is unlikely that exposure to the pollen is equivalent to
exposure to nucleic acids produced in plants as part of a plant-
pesticide. In pollen, nucleic acids will likely be integrated into the
tissue of the pollen grain and not bound to the surface of the pollen
grain. Pollen grains and the substances that occur naturally in pollen
are unlikely to cross the barrier provided by the mucous membrane of
the respiratory tract and thus are not additive to dietary exposure.
EPA also evaluated potential non-occupational exposures in drinking
water. As noted in the preceding paragraphs, the substances in plants
or parts of plants, including nucleic acids produced in plants as part
of a plant-pesticide, are produced inside the plant itself. Nucleic
acids are an integral 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 digest it, using the
components of the tissue (including nucleic acids produced in plants as
part of plant-pesticides) as building blocks for making their own
tissues or for fueling their own metabolisms. Nucleic acids produced in
plants as part of a plant-pesticide are subject to the same processes
of degradation and decay that all organic matter undergoes. This
turnover of biochemical materials in nature through a process of
degradation occurs fairly rapidly. Indeed, nucleic acids are highly
unstable outside of the cellular environment and are very quickly
broken down. Therefore, nucleic acids produced in plants as part of a
plant-pesticide do not persist in the environment or bioaccumulate.
There is no indication that naturally occurring nucleic acids produced
in plants as part of plant-pesticides, are resistant to this
degradation. Because of the very rapid turnover of these substances,
even if they reach surface waters (e.g., through plant parts falling
into bodies of water), they are unlikely to present anything other than
a very negligible exposure in drinking water drawn either from surface
or ground water sources. Therefore, the potential for non-dietary
exposure (i.e., non-food oral, dermal and inhalation) in non-
occupational settings is extremely limited and EPA expects such
exposure to be negligible.
With regard to exposure to ``other related substances,'' EPA is not
aware of any other substances either in food or outside the food supply
that may be related, via a common mechanism of toxicity, to nucleic
acids produced in plants as part of a plant-pesticide since nucleic
acids are not toxic. With regard to non-occupational exposure through
routes other than dietary exposure, since nucleic acids have no
mechanism of toxicity, EPA is not aware of substances in food or
outside the food supply that may be related via a common mechanism of
toxicity to the nucleic acids that are produced in plants as a plant-
pesticide. No evidence indicates that adverse effects due to aggregate
exposure of nucleic acids with these substances through the dietary,
non-food oral, dermal and inhalation routes occurs.
EPA considered exposure to nucleic acids produced in plants as a
part of a plant-pesticide when it issued the proposal and it is not
requesting additional comment on this topic. Comments are requested
only on EPA's conclusion that there are no additional substances
outside the food supply that are related, via a common mechanism of
toxicity, to residues of nucleic acids produced in plants as part of a
plant-pesticide for which EPA must consider exposure in aggregate with
nucleic acids.
7. Sensitivities of subgroups. In 1994, EPA considered available
information on the sensitivities of subgroups as it pertains to the
nucleic acids produced in plants as part of a plant-pesticide in the
proposal (59 FR 60542). The Agency's evaluation is summarized in Unit
IV.A. of this supplemental notice.
8. Naturally occurring estrogen or other endocrine effects. FFDCA
now directs EPA, in establishing an exemption from the requirement of a
tolerance, to consider ``such information as the Administrator may
require on whether the pesticide chemical may have an effect in humans
that is similar to an effect of a naturally occurring estrogen or other
endocrine effect'' (21 U.S.C. 346(a)(q)). Congress allowed EPA 2 years
to establish a screening program to determine whether certain pesticide
chemicals may have estrogenic effects and an additional year to
implement the program (21 U.S.C. 408(p)). As part of the screening and
implementation process, EPA is determining what information might be
required and how it will address estrogenic effects from pesticide
residues in general.
Based on available information concerning their structure and mode
of action, EPA does not expect nucleic acids produced in plants as part
of a plant-pesticide to cause estrogen or other endocrine effects.
There is some information on estrogenic effects by exposure to
pesticides but the data are limited and do not pertain to nucleic
acids. If EPA becomes aware of a potential for estrogenic or endocrine
effect from exposure to nucleic acids produced in plants as part of a
plant-pesticide, EPA will reexamine this tolerance exemption in light
of that information.
9. Safety factors. In the 1994 proposal, EPA did not rely on the
available animal data in reaching its determination that a tolerance is
not necessary to protect the public from nucleic acids produced in
plants as part of a plant-pesticide (59 FR 60542). As discussed in Unit
IV.A. of this supplemental notice, EPA relied on the long history of
safe human consumption of food containing nucleic acids produced in
plants as part of a plant-pesticide and in food derived from animals
that consume forage and other crops (e.g., corn and other grains). EPA
continues to believe that long-term evidence of human consumption, not
animal experimentation data, is the appropriate information base for
the proposed exemption (59 FR 60542). Because EPA did not rely on
animal experimentation data, the Agency did not consider which safety
factors would be appropriate to use in assessing risk to humans based
on data generated through experiments on animals.
10. Infants and children.--a. Dietary consumption patterns. In the
1994 proposal (59 FR 60542), EPA considered available information on
the dietary consumption pattern of infants and children as it pertains
to nucleic acids produced in plants as part of a plant-
[[Page 27147]]
pesticide and has summarized the evaluation in Unit IV.A. of this
supplemental notice. 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 soy-based products. Infants begin as early as 4-
months of age to consume specific types of solid foods. Subsequent to 4
months of age, apart from processing to facilitate swallowing, the
diets of infants are 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. All
foods consumed by infants and children contain nucleic acids.
b. Special susceptibility. In the 1994 proposal (59 FR 60542), EPA
considered available information on the potential for susceptibility of
infants and children, including pre- and post-natal toxicity, as these
factors pertain to the nucleic acids produced in plants as part of a
plant-pesticide. There is no scientific evidence that nucleic acids as
a component of food would have a different effect on children than they
would on the adult population. EPA summarizes its analysis of the
effect of consumption in food of nucleic acids on human health in Unit
IV.A. of this supplemental notice.
c. Cumulative effects of residues with other substances with a
common mechanism of toxicity. In the 1994 proposal (59 FR 60542), EPA
examined the available information on the cumulative effect of residues
of nucleic acids produced in plants as part of a plant-pesticide as
well as other substances in food that may have a common mechanism of
toxicity. The Agency's consideration in the proposal of the effects of
the residues of nucleic acids produced in plants as part of a plant-
pesticide on the general population also included consideration of
effects for infants and children. See Unit IV.B.5. of this supplemental
notice for a discussion of cumulative effects of nucleic acids and
other substances that have a common mechanism of toxicity.
Because EPA already considered the safety of food containing
residues of nucleic acids produced in plants as part of a plant-
pesticide and other constituents of food when it issued the proposal
(59 FR 60542), the Agency is not requesting additional comment on that
topic. Comments are requested only on EPA's conclusion that there are
no substances outside of the food supply with a common mechanism of
toxicity to the residues of nucleic acids produced in plants as part of
a plant-pesticide.
d. Margin of safety. In determining whether the residues of nucleic
acids produced in plants as part of a plant-pesticide are safe, FFDCA
section 408(b)(2)(C) directs EPA to apply a tenfold margin of safety
for the residues and other sources of exposure to infants and children
to account for potential pre- and post-natal toxicity and completeness
of data on threshold effects with respect to exposure and toxicity to
infants and children, unless a different margin will be safe. In
proposing the exemption, EPA based its assessment of exposure and
toxicity upon reliable information (Ref. 1) including the long history
of safe human consumption of food containing residues of nucleic acids
produced in plants as part of a plant-pesticide and other substances in
food, and the unique nature of plant-pesticides. EPA did not rely on
animal data. EPA relied on observations concerning whole food
consumption by humans and did not rely on single entity testing,
wherein substances are isolated from a plant source, and fed to animals
at high concentrations (Ref. 1). EPA relied on the vast base of the
human experience with actual food consumption rather than limited
testing situations. EPA thus, did not utilize animal or other studies
that would yield data that could be subjected to an additional margin
of safety. (See Units IV.A. and IV.B.3. of this supplemental notice).
As a result, the FQPA amendments to FFDCA do not affect EPA's analysis.
C. Safety Determinations in Light of FFDCA Amendment
Based on the information discussed in the 1994 proposals (59 FR
60496 through 60547), the discussion in Unit IV.A. and the analysis in
Unit IV.B. of this supplemental notice, EPA concludes that there is a
reasonable certainty that no harm will result to the U.S. population in
general, and U.S. infants and children, from aggregate exposure to
residues of nucleic acids produced in plants as part of a plant-
pesticide, including all anticipated dietary exposures and all other
exposures for which there is reliable information. Under the proposed
exemption from the requirement for a tolerance (59 FR 60542), EPA would
exempt residues of nucleic acids produced in plants as part of a plant-
pesticide. Extensive use and experience show the safety of foods
containing these substances. No evidence, in the many years of human
experience with the growing and consumption of food from plants
containing residues of nucleic acids produced in plants as part of a
plant-pesticide, indicates that adverse effects due to aggregate
exposure through the dietary, non-food oral, dermal and inhalation
routes occur.
The conclusion that residues of nucleic acids produced in plants as
part of a plant-pesticide should be exempt from tolerance requirements
under the FFDCA section 408 safety standard also lends support to EPA's
proposed FIFRA exemptions (59 FR 60519) with respect to human dietary
risks. These exemptions are: (1) Plant-pesticides that are derived from
a plant that is sexually compatible with the recipient plant, (2)
plant-pesticides that act primarily by affecting the plant, and (3)
plant-pesticides that are coat proteins from plant viruses (59 FR at
60535). In the FIFRA proposal, EPA utilized two criteria to determine
whether plant-pesticides should be exempt; (1) whether they posed a low
probability of risk, and (2) whether they caused unreasonable adverse
effects on the environment. Based upon the determination that residues
of the three categories of pesticidal substances subject to the
proposed exemptions (59 FR 60535) and the nucleic acid component of a
plant-pesticide (59 FR 60542) meet the FFDCA section 408 safety test,
EPA concludes plant-pesticides in the three proposed categories of
exemption would pose only a low probability of human dietary risk and
also would not pose an unreasonable adverse effect with respect to such
risks.
D. Other Considerations.
When the Agency proposed to establish an exemption from the
requirement of a tolerance for nucleic acids produced in plants as part
of a plant-pesticide (59 FR 60542), EPA did not propose any numerical
limitation on the amount of nucleic acids that could be present in food
containing these residues. EPA consulted in 1994 with the Department of
Health and Human Services (DHHS) in developing the proposed exemption
and this supplemental notice and will consult with the Secretary of HHS
prior to issuing the final rule. Because the 1994 proposal was an
exemption from the requirement of a tolerance, the Agency has concluded
that an analytical method for detecting and measuring the levels of the
residues of nucleic acids in or on food is not required.
[[Page 27148]]
V. Comments
A. Confidential Business Information
Information submitted as a comment concerning this supplemental
notice may be claimed confidential by marking any part or all of that
information as ``Confidential Business Information'' (CBI). CBI should
not be submitted through e-mail. Information marked as CBI will not be
disclosed except in accordance with procedures set forth in 40 CFR part
2. A copy of the comment that does not contain CBI must be submitted
for inclusion in the public record. Information not marked confidential
may be disclosed publicly by EPA without prior notice.
B. 30-Day Comment Period
EPA is allowing a 30-day comment period because it has determined
that such a period will provide the public with an adequate opportunity
to respond to the additional issues raised in this supplemental notice.
FFDCA and FIFRA do not specify a comment period for this type of
notice. EPA has decided that a 30-day comment period is reasonable
because this supplemental notice raises very few new issues that were
not already available for public comment. As discussed in Unit IV. of
this supplemental notice, EPA effectively considered most of the
factors required by the FQPA amendments of FFDCA and FIFRA relevant to
the proposed exemptions when it issued the proposed package of notices
describing EPA's approach in 1994 (59 FR 60496, 60519, 60535, 60542 and
60545). At that time, the public had an opportunity to review both the
Agency's rationale for the proposals and the underlying support
documents during a 90-day public comment period. Only a limited number
of new issues have been raised by the FQPA amendments to FFDCA and
FIFRA and the Agency continues to rely upon the information already in
the docket for the 1994 proposals and thus 30 days should provide
adequate time for public comment. In addition, EPA believes that it is
in the interest of the public to publish the final exemption from the
requirement of a tolerance in a timely manner.
C. Request for Comments
Interested persons are invited to submit written comments on the
new issues raised in this supplemental notice specifically on:
(1) EPA's conclusion that there are no substances outside of the
food supply that may have a cumulative toxic effect with residues of
nucleic acids produced in plants as part of a plant-pesticide.
(2) EPA's conclusion that there are no additional substances
outside the food supply that are related, via a common mechanism of
toxicity, to residues of nucleic acids produced in plants as part of a
plant-pesticide for which EPA must consider exposure in aggregate with
nucleic acids.
Commenters who possess information on nucleic acids causing
estrogenic effects are requested to send such information to EPA.
In this supplemental notice, EPA describes in greater detail the
rationale supporting the statement made in the 1994 Federal Register
(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 official comment
period. Commenters may comment on this more detailed rationale.
In this supplemental notice, EPA also describes in greater detail
how the rationale presented in the 1994 Federal Register (59 FR at
60538) concerning the safety for human consumption of food containing
nucleic acids produced in plants as part of a plant-pesticide applies
to infants and children. No comments were received on this statement
during the official comment period. Commenters may comment on this more
detailed rationale specifically addressing infants and children as part
of the larger human population.
VI. Public Docket
The official record for this rulemaking, as well as the public
version, has been established for this rulemaking under docket control
number number ``OPP-300371A'' (including comments and data submitted
electronically as described below). A public version of this record,
including printed, paper versions of electronic comments, which does
not include any information claimed as CBI, is available for inspection
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal
holidays. The official rulemaking record is located at the address in
``ADDRESSES'' at the beginning of this document.
Electronic comments can be sent directly to EPA at:
[email protected]
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption. Comment and data
will also be accepted on disks in WordPerfect 5.1 file format or ASCII
file format. All comments and data in electronic form must be
identified by the docket number ``OPP-300371A.'' Electronic comments on
this supplemental notice may be filed online at many Federal Depository
Libraries.
VII. References
(1) 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.
VIII. Regulatory Assessment Requirements
This supplemental notice merely seeks additional comments on the
proposed rules with regard to the potential impact that the new
statutory amendments imposed by the August 3, 1996 Food Quality
Protection Act (FQPA) might have on the provisions as proposed. As
such, this notice does not contain any new proposed requirements that
would require additional consideration by the Office of Management and
Budget (OMB) under Executive Order 12866, entitled Regulatory Planning
and Review (58 FR 51735, October 4, 1993) or the Paperwork Reduction
Act (PRA), 44 U.S.C. 3501 et seq. It does not require any other action
under Executive Order 12875, entitled Enhancing the Intergovernmental
Partnership (58 FR 58093, October 28, 1993), Executive Order 12898,
entitled Federal Actions to Address Environmental Justice in Minority
Populations and Low-Income Populations (59 FR 7629, February 16, 1994),
or the Regulatory Flexibility Act (RFA) (5 U.S.C. 601 et seq.). The
Agency's activities related to these regulatory assessment requirements
are discussed in the proposed rules.
EPA did not consider Title II of the Unfunded Mandates Reform Act
of 1995 (UMRA) (Pub. L. 104-4) at the proposal stage because the
proposed rules were issued prior to its enactment. Although this
supplemental notice is not subject to UMRA because it neither proposes
or finalizes any regulatory requirements, the applicability of the UMRA
requirements will be addressed in the final rules.
List of Subjects in 40 CFR Part 180
Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Plants, Plant-
pesticides, Reporting and recordkeeping requirements.
[[Page 27149]]
Dated: May 7, 1997.
Lynn R. Goldman,
Assistant Administrator for Prevention, Pesticides and Toxic
Substances.
[FR Doc. 97-12786 Filed 5-15-97; 8:45 am]
BILLING CODE 6560-50-F