[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