[Federal Register Volume 72, Number 74 (Wednesday, April 18, 2007)]
[Proposed Rules]
[Pages 19640-19660]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E7-7296]


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ENVIRONMENTAL PROTECTION AGENCY

40 CFR Part 174

[EPA-HQ-OPP-2006-0643; FRL-8100-5]
RIN 2070-AD49


Exemption from the Requirement of a Tolerance under the Federal 
Food, Drug, and Cosmetic Act for Residues of Plant Virus Coat Proteins 
that are Part of a Plant-Incorporated Protectant (PVC-Proteins); 
Supplemental Proposal

AGENCY:  Environmental Protection Agency (EPA).

ACTION:  Proposed rule.

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SUMMARY:  EPA is proposing to exempt from the Federal Food, Drug, and 
Cosmetic Act (FFDCA) section 408 requirement of a tolerance, residues 
of coat proteins from viruses that naturally infect plants that humans 
consume when such coat proteins are produced in living plants as part 
of a plant-incorporated protectant (PIP) and the criteria proposed for 
this exemption are met. EPA believes there is a reasonable certainty 
that no harm will result from aggregate exposure to such residues, 
including all anticipated dietary exposures and all other exposures for 
which there is reliable information. This proposed exemption would 
eliminate the need to establish a maximum permissible level in food for 
these residues.

DATES:  Comments must be received on or before July 17, 2007.

ADDRESSES:  Submit your comments, identified by docket identification 
(ID) number EPA-HQ-OPP-2006-0643, by one of the following methods:
     <bullet> Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the on-line instructions for submitting comments.
     <bullet> Mail: Office of Pesticide Programs (OPP) Regulatory 
Public Docket (7502P), Environmental Protection Agency, 1200 
Pennsylvania Ave., NW., Washington, DC 20460-0001.
     <bullet> Delivery: OPP Regulatory Public Docket (7502P), 
Environmental Protection Agency, Rm. S-4400, One Potomac Yard (South 
Bldg.), 2777 S. Crystal Dr., Arlington, VA. Deliveries are only 
accepted during the Docket's normal hours of operation (8:30 a.m. to 4 
p.m., Monday through Friday, excluding legal holidays). Special 
arrangements should be made for deliveries of boxed information. The 
Docket Facility telephone number is (703) 305-5805.
    <bullet> Instructions: Direct your comments to docket ID number 
EPA-HQ-OPP-

[[Page 19641]]

2006-0643. EPA's policy is that all comments received will be included 
in the docket without change and may be made available on-line at 
http://www.regulations.gov, including any personal information 
provided, unless the comment includes information claimed to be 
Confidential Business Information (CBI) or other information whose 
disclosure is restricted by statute. Do not submit information that you 
consider to be CBI or otherwise protected through regulations.gov or e-
mail. The regulations.gov website is an ``anonymous access'' system, 
which means EPA will not know your identity or contact information 
unless you provide it in the body of your comment. If you send an e-
mail comment directly to EPA without going through regulations.gov, 
your e-mail address will be automatically captured and included as part 
of the comment that is placed in the docket and made available on the 
Internet. If you submit an electronic comment, EPA recommends that you 
include your name and other contact information in the body of your 
comment and with any disk or CD-ROM you submit. If EPA cannot read your 
comment due to technical difficulties and cannot contact you for 
clarification, EPA may not be able to consider your comment. Electronic 
files should avoid the use of special characters, any form of 
encryption, and be free of any defects or viruses.
    Docket: All documents in the docket are listed in the docket index. 
Although listed in the index, some information is not publicly 
available, e.g., CBI or other information whose disclosure is 
restricted by statute. Certain other material, such as copyrighted 
material, is not placed on the Internet and will be publicly available 
only in hard copy form. Publicly available docket materials are 
available either in the electronic docket at http://www.regulations.gov, or, if only available in hard copy, at the OPP 
Regulatory Public Docket in Rm. S-4400, One Potomac Yard (South Bldg.), 
2777 S. Crystal Dr., Arlington, VA. The hours of operation of this 
docket facility are from 8:30 a.m. to 4 p.m., Monday through Friday, 
excluding legal holidays. The Docket Facility telephone number is (703) 
305-5805.

FOR FURTHER INFORMATION CONTACT:  Melissa Kramer, Hazard Assessment 
Coordination and Policy Division (7202M), Office of Science 
Coordination and Policy, 1200 Pennsylvania Ave., NW., Washington, DC 
20460-0001; telephone number: (202) 564-8497; fax number: (202) 564-
8502; e-mail address: <a href="/cdn-cgi/l/email-protection#a5ced7c4c8c0d78bc8c0c9ccd6d6c4e5c0d5c48bc2cad3"><span class="__cf_email__" data-cfemail="9cf7eefdf1f9eeb2f1f9f0f5efeffddcf9ecfdb2fbf3ea">[email protected]</span></a>.

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this Document Apply to Me?

    You may be potentially affected by this action if you are a person 
or company involved with agricultural biotechnology that may develop 
and market PIPs. Potentially affected entities may include, but are not 
limited to:
    <bullet> Pesticide and other agricultural chemical manufacturing 
(NAICS code 32532), e.g., establishments primarily engaged in the 
formulation and preparation of agricultural and household pest control 
chemicals.
    <bullet> Food manufacturing (NAICS code 311), e.g., establishments 
primarily engaged in the manufacturing of food or feed.
    <bullet> Crop production (NAICS code 111), e.g., establishments 
primarily engaged in growing crops, plants, vines, or trees and their 
seeds.
    <bullet> Colleges, universities, and professional schools (NAICS 
code 611310), e.g., establishments of higher learning which are engaged 
in development and marketing of virus-resistant plants.
    <bullet> Research and development in the physical, engineering, and 
life sciences (NAICS code 54171), e.g., establishments primarily 
engaged in conducting research in the physical, engineering, or life 
sciences, such as agriculture and biotechnology.
    This listing is not intended to be exhaustive, but rather provides 
a guide for readers regarding entities likely to be affected by this 
action. Other types of entities not listed in this unit could also be 
affected. The North American Industrial Classification System (NAICS) 
codes have been provided to assist you and others in determining 
whether or not this action might apply to certain entities. To 
determine whether you or your business may be affected by this action, 
you should carefully examine the applicable provisions of 40 CFR part 
174. If you have questions regarding the applicability of this action 
to a particular entity, consult the person listed under FOR FURTHER 
INFORMATION CONTACT.

B. What Should I Consider as I Prepare My Comments for EPA?

    1. Docket. EPA has established a docket for this action under 
docket ID number EPA-HQ-OPP-2006-0643. Publicly available docket 
materials are available either in the electronic docket at http://www.regulations.gov, or, if only available in hard copy, at the Office 
of Pesticide Programs (OPP) Regulatory Public Docket in Rm. S-4400, One 
Potomac Yard (South Bldg.), 2777 S. Crystal Dr., Arlington, VA. The 
hours of operation of this docket facility are from 8:30 a.m. to 4 
p.m., Monday through Friday, excluding legal holidays. The Docket 
Facility telephone number is (703) 305-5805.
    2. Tips for preparing your comments. When submitting comments, 
remember to:
    i. Identify the document by docket ID number and other identifying 
information (subject heading, Federal Register date and page number).
    ii. Follow directions. The Agency may ask you to respond to 
specific questions or organize comments by referencing a Code of 
Federal Regulations (CFR) part or section number.
    iii. Explain why you agree or disagree; suggest alternatives and 
substitute language for your requested changes.
    iv. Describe any assumptions and provide any technical information 
and/or data that you used.
    v. If you estimate potential costs or burdens, explain how you 
arrived at your estimate in sufficient detail to allow for it to be 
reproduced.
    vi. Provide specific examples to illustrate your concerns and 
suggest alternatives.
    vii. Explain your views as clearly as possible, avoiding the use of 
profanity or personal threats.
    viii. Make sure to submit your comments by the comment period 
deadline identified.

II. What Action is the Agency Proposing?

    EPA is proposing to exempt the following from the FFDCA section 408 
requirement of a tolerance: Residues of coat proteins from viruses that 
naturally infect plants that humans consume as part of a normal diet, 
including any metabolites or degradates of those coat proteins, when 
such coat proteins are produced in living plants as part of a PIP and 
the criteria proposed for this exemption are met. The proposed criteria 
are intended to clearly identify and exempt only those residues for 
which a long history of safe exposure and consumption can support 
exemption. EPA believes there is a reasonable certainty that no harm 
will result from aggregate exposure to such residues, including all 
anticipated dietary exposures and all other exposures for which there 
is reliable information. This proposed exemption would eliminate the 
need to establish a maximum permissible level in food for these 
residues.

[[Page 19642]]

III. What is the Agency's Authority for Taking this Action?

    EPA is proposing to establish this tolerance exemption on its own 
initiative under sections 408(e) and (c) of FFDCA, 21 U.S.C. 346a(c) 
and (e). Under FFDCA section 408, EPA regulates pesticide chemical 
residues by establishing tolerances limiting the amounts of residues 
that may be present in or on food or by establishing exemptions from 
the requirement of a tolerance for such residues. Food includes 
articles used for food or drink by humans or animals. A food containing 
pesticide residues may not be moved in interstate commerce without an 
appropriate tolerance or an exemption from the requirement of a 
tolerance.
    Section 408 of FFDCA applies to all ``pesticide chemical 
residues,'' which are defined as residues of either a ``pesticide 
chemical'' or ``any other added substance that is present on or in the 
commodity or food primarily as a result of the metabolism or other 
degradation of a pesticide chemical'' (21 U.S.C. 321(q)(2)). FFDCA 
defines ``pesticide chemical'' as: ``any substance that is a pesticide 
within the meaning of the Federal Insecticide, Fungicide, and 
Rodenticide Act, including all active and inert ingredients of such 
pesticide'' (21 U.S.C. 321(q)(1)). The Federal Insecticide, Fungicide, 
and Rodenticide Act (FIFRA) section 2(u) defines ``pesticide'' as: 
``(1) any substance or mixture of substances intended for preventing, 
destroying, repelling, or mitigating any pest, (2) any substance or 
mixture of substances intended for use as a plant regulator, defoliant, 
or desiccant, and (3) any nitrogen stabilizer. . .'' (7 U.S.C. 136(u)). 
Under FIFRA section 2(t), the term ``pest'' includes: ``(1) any insect, 
rodent, nematode, fungus, weed, or (2) any other form of terrestrial or 
aquatic plant or animal life or virus, bacteria, or other 
microorganism. . . which the Administrator declares to be a pest. . .'' 
subject to certain exceptions (7 U.S.C. 136(t)).
    Section 408(c)(2)(A)(i) of FFDCA allows EPA to establish an 
exemption from the requirement for a tolerance (the legal limit for a 
pesticide chemical residue in or on a food) only if EPA determines that 
the exemption is ``safe.'' Section 408(c)(2)(A)(ii) of FFDCA defines 
``safe'' to mean that ``there is a reasonable certainty that no harm 
will result from aggregate exposure to the pesticide chemical residue, 
including all anticipated dietary exposures and all other exposures for 
which there is reliable information.'' This includes exposure through 
drinking water and in residential settings, but does not include 
occupational exposure. Pursuant to section 408(c)(2)(B) of FFDCA, in 
establishing or maintaining in effect an exemption from the requirement 
of a tolerance, EPA must take into account the factors set forth in 
section 408(b)(2)(C) of FFDCA, which require EPA to give special 
consideration to exposure of infants and children to the pesticide 
chemical residue in establishing a tolerance 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. . . 
.'' Additionally, section 408(b)(2)(D) of FFDCA requires that the 
Agency consider ``available information concerning the cumulative 
effects of a particular pesticide's residues'' and ``other substances 
that have a common mechanism of toxicity.''
    EPA performs a number of analyses to determine the risks from 
aggregate exposure to pesticide residues. First, EPA determines the 
toxicity of pesticides. Second, EPA examines exposure to the pesticide 
through food, drinking water, and through other exposures that occur as 
a result of pesticide use in residential settings.
    Section 408(e)(1)(C) of FFDCA also grants EPA the authority to 
establish ``general procedures and requirements to implement this 
section'' (21 U.S.C. 346a(e)(1)(C)).

IV. Context

A. What is the Relationship of this Proposal to Other Regulatory 
Requirements under FIFRA and FFDCA?

    When the genetic material that encodes an entire or a portion of a 
plant virus coat protein is introduced into living plants with the 
intention of preventing or mitigating viral disease in the plants, the 
genetic material and any substances produced from the genetic material 
constitute a type of pesticide termed a ``plant virus coat protein 
plant-incorporated protectant'' or ``PVCP-PIP.'' PVCP-PIPs meet the 
FIFRA section 2(u) definition of ``pesticide'' because they are 
introduced into plants with the intention of ``preventing, destroying, 
repelling, or mitigating any pest. . .'' (7 U.S.C. 136(u)) and plant 
viruses meet the FIFRA section 2 definition of ``pest'' (7 U.S.C. 
136(t)). PVCP-PIPs are considered pesticide chemicals under FFDCA which 
defines a ``pesticide chemical'' as ``any substance that is a pesticide 
within the meaning of the Federal Insecticide, Fungicide, and 
Rodenticide Act, including all active and inert ingredients of such 
pesticide.'' As such, residues of PVCP-PIPs in or on food (hereinafter 
simply ``in food'') are subject to FFDCA section 408.
    Since PVCP-PIPs are a relatively newly described type of pesticide, 
the discussion in this unit provides information explaining how this 
FFDCA proposed action on residues of the plant virus coat protein 
portion of a PVCP-PIP (called here the ``PVC-protein'') would affect 
the FFDCA and FIFRA status of the complete PVCP-PIP. To this end, 
several pieces of information are presented: A description of the 
anticipated residues of PVCP-PIPs; a discussion of the FFDCA status, 
either current or proposed, of all anticipated PVCP-PIP residues; a 
discussion of what would be considered in determining the FFDCA status 
of the complete PVCP-PIP; and a discussion of how the FFDCA status of 
PVCP-PIP residues relates to the FIFRA status of the PVCP-PIP.
    1. What are the components of a PIP? A PIP is defined at 40 CFR 
174.3 as ``a pesticidal substance that is intended to be produced and 
used in a living plant, or in the produce thereof, and the genetic 
material necessary for production of such a pesticidal substance. It 
also includes any inert ingredient contained in the plant, or produce 
thereof.''
    2. What are the anticipated residues of PVCP-PIPs? Based on the 
definition of a PIP, EPA anticipates residues of a PVCP-PIP would 
include residues of any PVC-protein; the nucleic acids associated with 
the PVCP-PIP, e.g., the genetic material encoding the PVC-protein; and 
any inert ingredient as defined for PIPs at 40 CFR 174.3. Each of these 
three classes of residues will also include any metabolite and 
degradate of that class in accordance with FFDCA section 201 that 
defines a ``pesticide chemical residue'' as ``a residue in or on raw 
agricultural commodity or processed food of (A) a pesticide chemical; 
or (B) any other added substance that is present on or in the commodity 
or food primarily as a result of the metabolism or other degradation of 
a pesticide chemical'' (21 U.S.C. 321(q)(2)).
    3. What is the FFDCA status of each identified class of residues? 
For the complete PVCP-PIP to be exempt from FFDCA section 408, all 
three classes of PVCP-PIP residues listed above must be exempt, i.e., 
residues of the PVC-protein, the nucleic acids associated with the 
PVCP-PIP, and any inert ingredient as defined for PIPs at 40 CFR 174.3. 
The units below discuss the status of residues of the PVC-protein under 
this proposed action, the status of residues of the nucleic acids 
associated

[[Page 19643]]

with the PVCP-PIP, and the status of residues of inert ingredients.
    i. Residues of PVC-proteins. Residues in this category consist of 
residues of the PVC-protein and any metabolites or degradates of that 
protein. This proposal would exempt from tolerance requirements 
residues of PVC-proteins that meet certain criteria.
    Coat proteins are those substances that viruses produce to 
encapsulate and protect the viral nucleic acid and to perform other 
important tasks for the virus, e.g., assistance in viral replication, 
movement within the plant, and transmission of the virus from plant to 
plant by insects (Ref. 1). Current scientific information suggests that 
prevention or mitigation of disease by some PVCP-PIPs may be protein-
mediated because for certain PVCP-PIPs efficacy is correlated with the 
concentration of coat protein produced by the transgene (Ref. 2). In 
protein-mediated resistance, the coat protein is thought to impede the 
infection cycle by interfering with the disassembly of infecting 
viruses (Ref. 3). In such cases, EPA would consider the PVC-protein to 
be the pesticidal substance. Residues of such PVC-proteins and their 
metabolites and degradates that meet the proposed criteria would be 
covered by this proposal.
    In transgenic plants employing a second mechanism of resistance 
called post-transcriptional gene silencing (PTGS), prevention or 
mitigation of viral disease is not correlated with the level of PVC-
protein expression. Indeed, virus resistance can occur even when a coat 
protein gene expresses untranslatable RNA sequences and no PVC-protein 
is detected. In PTGS, RNA fragments appear to be pesticidal substances 
(Ref. 3). (See Unit II.E. of the companion document published elsewhere 
in this Federal Register for a more detailed description of PTGS.) Even 
when PTGS is the mechanism of resistance, any PVC-protein that might be 
produced is part of the PVCP-PIP. Residues of such PVC-proteins and 
their metabolites and degradates that meet the proposed criteria are 
also covered by this proposal.
    ii. Residues of nucleic acids. Residues in this category include 
residues of the genetic material necessary for the production of the 
pesticidal substance and the genetic material for any inert ingredient 
as defined at 40 CFR 174.3. Residues in this category would also 
include residues of any nucleic acids effecting the pesticidal action 
of the PVCP-PIP, e.g., residues of nucleic acids involved in PTGS.
     ``Nucleic acids'' are defined at 40 CFR 174.3 as ``ribosides or 
deoxyribosides of adenine, thymine, guanine, cytosine, and uracil; 
polymers of the deoxyribose-5'-monophosphates of thymine, cytosine, 
guanine, and adenine linked by successive 3'-5' phosphodiester bonds 
(also known as deoxyribonucleic acid); and polymers of the ribose-5'-
monophosphates of uracil, cytosine, guanine, and adenine linked by 
successive 3'-5' phosphodiester bonds (also known as ribonucleic acid). 
The term does not apply to nucleic acid analogues (e.g., 
dideoxycytidine), or polymers containing nucleic acid analogues.'' 
Nucleic acids are currently exempt from FFDCA tolerance requirements. 
See 40 CFR 174.475 and 66 FR 37817 (July 19, 2001) (FRL-6057-5). EPA is 
not proposing to amend this exemption.
    iii. Residues of any inert ingredient. Residues in this category 
consist of residues of any inert ingredient that is part of a PVCP-PIP 
and any metabolite or degradate of an inert ingredient. An inert 
ingredient for a PIP is defined at 40 CFR 174.3 as ``any substance, 
such as a selectable marker, other than the active ingredient, where 
the substance is used to confirm or ensure the presence of the active 
ingredient, and includes the genetic material necessary for the 
production of the substance, provided that genetic material is 
intentionally introduced into a living plant in addition to the active 
ingredient.''
    A tolerance or tolerance exemption is required for residues of any 
substance in food that meets the 40 CFR 174.3 definition of an inert 
ingredient (e.g., a selectable marker intentionally introduced into the 
plant as part of a PVCP-PIP such as a protein conferring resistance to 
an herbicide). Part 180 and part 174, subpart W, of 40 CFR list inert 
ingredients for which tolerance exemptions have been established. If an 
inert ingredient is not listed at part 180 or part 174, subpart W, an 
applicant would need to petition the Agency in accordance with 40 CFR 
180.7 to obtain a tolerance or tolerance exemption for residues of that 
particular inert ingredient in order for food containing residues of 
the PVCP-PIP to move in interstate commerce--even if all other residues 
of the PIP are exempt.
    4. What is the relationship between the FIFRA status of a PVCP-PIP 
and the FFDCA status of its residues? A tolerance exemption does not 
exempt a PVCP-PIP from FIFRA regulation. However, in order for a PVCP-
PIP in food plants to be exempted from FIFRA regulation, a tolerance 
exemption must exist for all residues associated with a PVCP-PIP or 
FFDCA requirements must be otherwise met. (See the general 
qualification for exemption under FIFRA at 40 CFR 174.21(b).) The FIFRA 
status of a PVCP-PIP is determined based on factors in addition to 
FFDCA section 408 considerations because FIFRA requires the Agency to 
consider additional risk and benefit issues beyond those addressed 
under section 408 of FFDCA. Concurrently with this proposed FFDCA 
exemption, the Agency is publishing a proposal under which PVCP-PIPs 
might meet the general qualification for FIFRA exemption at 40 CFR 
174.21(a) based on different criteria than the criteria in this 
proposal.

B. What is the History of this Proposal?

    1. Scientific input. EPA sponsored (or cosponsored with other 
Federal agencies) six conferences relevant to development of this 
proposed rule: On October 19-21, 1987, a meeting on ``Regulatory 
Considerations: Genetically-Engineered Plants'' at Cornell University 
in Ithaca, NY; on September 8-9, 1988, a ``Transgenic Plant 
Conference'' in Annapolis, MD; on November 6-7, 1990, a conference on 
``Pesticidal Transgenic Plants: Product Development, Risk Assessment, 
and Data Needs'' in Annapolis, MD; on April 18-19, 1994, a ``Conference 
on Scientific Issues Related to Potential Allergenicity in Transgenic 
Food Crops'' in Annapolis, MD; on July 17-18, 1997, a ``Plant Pesticide 
Workshop'' in Washington, DC; and on December 10-12, 2001, a conference 
on ``Assessment of the Allergenic Potential of Genetically Modified 
Foods'' in Chapel Hill, NC. Information from these conferences has been 
incorporated as appropriate in development of this proposed rule.
    EPA has requested the advice of two scientific advisory groups at 
five meetings while developing its approach to PIPs. On December 18, 
1992, EPA convened the FIFRA Scientific Advisory Panel (SAP) to review 
a draft policy on PIPs (then called plant-pesticides) and to respond to 
a series of related questions posed by the Agency dealing primarily 
with EPA's approach under FIFRA. On July 13, 1993, EPA requested the 
advice of a Subcommittee of the EPA Biotechnology Science Advisory 
Committee (BSAC) on a series of scientific questions dealing with EPA's 
approach to PIPs under FFDCA. On January 21, 1994, EPA asked for advice 
on the Agency's approach to PIPs under both statutes at a joint meeting 
of the SAP and the BSAC. To evaluate more recent scientific advances, 
EPA again brought these issues to the SAP on October 13-14, 2004. On 
December 6-8, 2005, EPA requested the SAP to respond to a series of 
scientific

[[Page 19644]]

questions related to this proposal. EPA carefully considered advice 
from all five meetings in the development of this proposed rule.
    2. Federal Register documents. The history of this proposal 
consists of the original proposed exemption that appeared in the 
November 23, 1994 Federal Register (59 FR 60545) (FRL-4755-4), a 
supplemental document that appeared in the May 16, 1997 Federal 
Register (62 FR 27149) (FRL-5716-6), and a supplemental document which 
appeared in the July 19, 2001Federal Register (66 FR 37855) (FRL-6760-
4).
    i. November 23, 1994. EPA published a package of five separate 
documents in the November 23, 1994 Federal Register which described 
EPA's policy and proposals for PIPs under FIFRA and FFDCA (59 FR 60496, 
60519, 60535, 60542, and 60545). In one of these documents (59 FR 
60545), EPA proposed to exempt from the requirement of a tolerance, 
residues of plant virus coat proteins produced and used in living 
plants as a plant-incorporated protectant (then called a plant-
pesticide). The proposed exemption from the requirement of a tolerance 
read as follows:
     ``Residues of coat proteins from plant viruses, or segments of the 
coat proteins, produced in living plants as plant-pesticides are exempt 
from the requirement of a tolerance'' (59 FR 60547).
    ii. May 16, 1997. In August of 1996, Congress enacted the Food 
Quality Protection Act (FQPA), which amended FFDCA and FIFRA. On May 
16, 1997, EPA published a supplemental document in the Federal Register 
(62 FR 27149) 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 PVC-proteins.
    In that supplemental document, EPA explained how most of the 
substantive factors that the amended FFDCA requires EPA to consider in 
evaluating pesticide chemical residues had been considered in the 
Agency's 1994 proposed tolerance exemption. Even though the Agency may 
not have used the terminology specified in FQPA, EPA did take into 
account most of the same factors in issuing its 1994 proposal to exempt 
residues of PVC-proteins, or segments of such proteins, from FFDCA 
tolerance requirements. EPA therefore sought comment on the 
requirements imposed by FQPA that the Agency had not addressed in its 
1994 proposal, specifically:
    a. EPA's conclusion that there are no substances outside of the 
food supply that may have a cumulative toxic effect with residues of 
PVC-proteins,
    b. EPA's conclusion that there are no substances outside of the 
food supply to which humans might be exposed through non-occupational 
routes of exposure that are related via a common mechanism of toxicity 
to residues of PVC-proteins,
    c. Any available information on PVC-proteins causing estrogenic 
effects,
    d. EPA's rationale, described in greater detail, for concluding 
that PIPs are likely to present a limited exposure of pesticidal 
substances to humans in which the predominant, if not the only, route 
of exposure will be dietary, and
    e. EPA's rationale, described in greater detail, for concluding 
that the Agency's analysis concerning the dietary safety of food 
containing PVC-proteins applies to infants and children as well as 
adults.
    iii. July 19, 2001. In July of 2001, EPA published a supplemental 
document in the Federal Register (66 FR 37855) to provide the public 
with additional opportunity to comment on the FIFRA and FFDCA 
exemptions for PIPs that the Agency proposed in 1994 but had not yet 
finalized by 2001. EPA also requested comment on the information, 
analyses, and conclusions pertaining to PVCP-PIPs contained in the NRC 
report entitled ``Genetically Modified Pest-Protected Plants: Science 
and Regulation'' (Ref. 4). In addition, the public was given an 
opportunity to comment on a clarification of the language in the 
original 1994 proposal on PVCP-PIPs that EPA was considering in 
response to public comment. The purpose of the clarification was to 
circumscribe more clearly those residues proposed for exemption.
    The documents, including associated public comments, and the 
reports of the meetings described above are available in the public 
dockets established for each of the associated rulemakings as described 
in Unit XII.B.
    This proposed rule completely supersedes these previous proposals. 
EPA does not intend to respond to comments submitted on those 
proposals. Thus, individuals who believe that any comments submitted on 
any of the earlier proposals remain germane to this proposal should 
submit them (or relevant portions) again during this comment period.

C. Rationale Supporting the Proposed FFDCA Tolerance Exemption

    EPA's base of experience with viruses infecting food plants has led 
the Agency to draw three conclusions on which it is relying to support 
this proposed tolerance exemption for residues of PVC-proteins in food. 
First, virus-infected plants have always been a part of the human and 
domestic animal food supply. Most crops are frequently infected with 
plant viruses, and food from these crops has been and is being consumed 
without adverse human or animal health effects. Second, plant viruses 
are not infectious to humans, including children and infants, or to 
other mammals. Third, plant virus coat proteins, while widespread in 
food, have not been associated with toxic or allergenic effects to 
animals or humans. These conclusions are derived from a base of 
experience and information sufficient to support this proposed 
tolerance exemption.
    1. Always been part of food supply without adverse effects. Virus-
infected food plants have always been a part of the human and domestic 
animal food supply (Refs. 5, 6, 7, 8, 9, and 10). Most plants are 
infected by at least one virus, and components of plant viruses, 
including coat proteins, are often found in the produce of crop plants. 
For example, at the beginning of this century virtually every 
commercial cultivar of potatoes grown in the United States and Europe 
was infected with either one or a complex of potato viruses (Ref. 10). 
Even plants that show no disease symptoms are often found to be 
infected with viruses (Refs. 9 and 11). In addition, a common 
agricultural practice used since the 1920s for protection against viral 
disease involves intentionally inoculating healthy plants with a mild 
form of a virus in order to prevent infection by a more virulent form 
(Ref. 11). A recent analysis of viral sequences isolated from fecal 
samples of healthy humans showed the presence of large quantities of 
plant pathogenic viruses from 35 different plant virus species with 
evidence suggesting dietary origins for the most prevalent (Ref. 12). A 
great deal of information supports the ubiquitous appearance of plant 
viruses in foods, and to date there have been no reports of adverse 
human or animal health effects associated with consumption of plant 
viruses in food.
    The National Research Council (NRC) observed in its 2000 report 
that ``[h]uman or animal consumption of plants with viral coat proteins 
is widely considered to be safe, on the basis of common exposure to 
these types of proteins in nontransgenic types of food'' (Ref. 4). The 
FIFRA SAP addressed the issue of dietary risk at its December 18, 1992 
meeting (Ref. 13). The SAP stated, ``Since viruses are ubiquitous in 
the agricultural environment at levels higher than will be present in 
transgenic

[[Page 19645]]

plants, and there has been a long history of `contamination' of the 
food supply by virus coat protein, there is scientific rationale for 
exempting transgenic plants expressing virus coat protein from the 
requirement of a tolerance.'' The FIFRA SAP again discussed PVC-
proteins on October 11-13, 2004, and ``agreed that (because of the 
human history of consuming virus infected food), unaltered PVCPs do not 
present new dietary exposures'' (Ref. 14). The 2005 SAP also agreed 
that ``[h]istorically, virus infected plants have been a part of the 
human and domestic animal food supply without adverse human or animal 
health effects'' (Ref. 15).
    In general, EPA anticipates that dietary exposure through human and 
animal consumption of plants containing residues of PVC-proteins that 
would qualify for the proposed exemption will be similar to or less 
than the dietary exposure to plant virus coat proteins currently found 
in food plants naturally infected with viruses. Experiments have shown 
the amount of PVC-protein found in plants containing a PVCP-PIP to be 
as much as one hundred- to one thousand-fold lower than the amount of 
plant virus coat protein found naturally in virus-infected plants, even 
when the resistance is believed to be mediated by the PVC-protein 
itself (Refs. 8 and 16). The difference in amount of PVC-protein 
present is even more marked for virus-resistant plants employing 
resistance mediated by RNA. In such cases, little to no detectable coat 
protein is produced in a plant containing a PVCP-PIP (Refs. 3 and 17). 
Such information conforms to information EPA has received from the 
scientific advisory groups the Agency has consulted (see Unit IV.B.1.). 
Although the Agency believes that the PVC-proteins which qualify for 
this proposed tolerance exemption are safe at any level given the long 
history of human dietary exposure to high levels of such proteins, the 
anticipated low levels of exposure to PVC-proteins in food lend 
additional support to this proposed exemption.
    2. Not infectious to humans. Any virus/host relationship is 
characterized by a high degree of specificity (Ref. 8). Plant viruses 
usually infect plants only within a certain taxonomic group and are 
unable to infect humans or other vertebrates (Refs. 18 and 19). 
Cellular machinery for processing genetic material is highly specific. 
For example, plant viruses are unable to recognize and attach to the 
specific sites on mammalian cells needed to penetrate the cell 
membrane, and plant viruses cannot be processed by mammalian cellular 
machinery. Plant viruses therefore do not and cannot infect mammals and 
other vertebrates. In addition, multiple virus components in addition 
to the coat protein have a role in and are necessary for plant 
infection. Plant viral coat proteins alone are not infectious to 
plants, and whole, intact plant viruses are not infectious to humans. 
Therefore, it is reasonable to assume that a single component of plant 
viruses, e.g., the PVC-protein, will not be infectious to humans.
    3. No toxic or allergenic effects to animals or humans. Humans and 
domestic animals have been and are exposed to plant viruses in the food 
supply because most crops are frequently infected with plant viruses. 
Food from these crops has been and is being consumed with no indication 
of human or animal toxicity related to plant virus infections. 
Additionally, in experiments where purified plant virus preparations 
have been injected into laboratory animals, no adverse effects have 
been reported (Ref. 17). Furthermore, the Agency is not aware of any 
coat protein from a virus that naturally infects plants that has been 
identified as a food allergen for humans. Finally, the amount of PVC-
protein likely to be found in food is anticipated to generally be lower 
than the amount of virus coat protein found in food naturally infected 
with plant viruses (as discussed in Unit IV.C.1.).The 2005 SAP 
questioned whether an increased propensity for allergies in humans 
affects the relevance of the history of safe use to the current safety 
of virus coat proteins. Several studies have documented a general 
increase in atopy in human populations; these studies show that over 
the last several decades there has been an increasing proportion of 
human populations that have an allergic sensitization to particular 
allergens (Refs. 20, 21, and 22). However, there is no reason to 
believe that PVC-proteins in the environment would have any impact on 
this phenomenon. EPA is aware of no evidence that previously 
nonallergenic substances are now able to elicit an immune response, and 
no plant virus coat proteins have ever been identified as allergens. 
Moreover, the amount of plant virus coat protein in the environment is 
not expected to increase due to the use of PVCP-PIPs. On the contrary, 
PVCP-PIPs generally express PVC-protein at levels below that found in 
natural virus infections, and the virus-resistant phenotype conferred 
by PVCP-PIPs should significantly reduce levels of natural virus 
infection in plants, thereby decreasing the amount of plant virus coat 
protein in the environment where PVCP-PIPs are deployed.

D. Key Issue: Determination of Natural Virus Variation

    A key issue facing EPA in developing this exemption is how to 
clearly describe for regulatory purposes those PVC-proteins that are 
within the range of naturally occurring plant virus coat proteins and 
to which the rationale discussed in Unit IV.C. therefore applies. If a 
plant virus coat protein gene is isolated in nature and not modified, 
the PVC-protein would clearly be within the range of natural variation. 
However, many coat protein genes are modified in creating a PVCP-PIP, 
e.g., to increase product efficacy or allow appropriate expression in 
the plant. Some of these modifications may affect a PVC-protein, 
although most of these variations would not be expected to differ 
significantly (e.g., in terms of toxicity or allergenicity) from the 
naturally occurring coat protein. In fact, given the considerable 
variation in naturally occurring viral coat proteins, it is also 
possible that naturally occurring plant viruses exist with some of the 
minor modifications that could conceivably be introduced into PVC-
proteins.
    However, EPA's task of defining this variation is complicated by 
the variable nature of plant virus genomes and the fact that the full 
extent of variation for even a single plant virus is currently unknown. 
Sequencing of plant virus genomes has revealed that a large number of 
variants exist within most populations of both RNA and DNA viruses. Due 
to this inherent heterogeneity in virus populations, they are often 
described as ``quasispecies'' that exist as a pool of different 
sequences varying around a consensus sequence (Refs. 23, 24, and 25).
    Genetic variation in virus populations arises due to several 
processes including mutation, recombination, and reassortment. Mutation 
is a change in the genetic material that most commonly occurs when 
replication errors lead to incorporation of an incorrect nucleotide 
into the daughter sequence (Ref. 26). New virus variants are also 
generated by recombination, the natural process that occurs during 
replication of DNA or RNA whereby new combinations of genes are 
produced. Recombination is more likely to occur the more closely 
related viruses are, but recombination between different viral species 
is also believed to occur (Refs. 27 and 28). Evidence of past 
recombination having led to the creation of new DNA and RNA viruses has 
been

[[Page 19646]]

found in a number of different groups including bromoviruses (Ref. 29), 
caulimoviruses (Ref. 30), luteoviruses (Ref. 31), nepoviruses (Ref. 
32), cucumoviruses (Ref. 33), and geminiviruses (Refs. 27 and 34). 
Sequence analysis of viruses from the family Luteoviridae indicated 
that this family has evolved via both intra- and inter-familial 
recombination (Ref. 35). In viruses with segmented genomes, variation 
may also be caused by reassortment whereby entire segments are 
exchanged between viruses (Ref. 36).
    Attempts to describe the range of variation for naturally occurring 
plant virus coat proteins are complicated not only by variation within 
species but also by variation among species (See Ref. 37 for review). 
For example, cucumber mosaic cucumovirus (CMV) has a relatively high 
degree of variation (Ref. 38) compared to tobacco mild green mosaic 
tobamovirus (Ref. 39). The greater variability in CMV would be expected 
based on the relatively wide host range and relatively high 
recombination rate of this virus. Such wide-ranging, inherent 
variability confounds attempts to establish meaningful estimates of 
normal variability for coat proteins of plant viruses as a group.
    A large number of viral coat protein sequences are currently 
available in the literature and in public sequence repositories, e.g., 
the National Center for Biotechnology Information. However, EPA has 
concluded that no single standard could capture the degree of variation 
across all viruses, and hundreds of plant viruses have been identified 
to date (Ref. 40). It would be at best impractical for EPA to describe 
individually for all virus groups all potential modifications that 
would produce a PVC-protein that falls within the range of natural 
variation given the vast (and yet still incomplete) amount of data that 
currently exists. The 2005 SAP concurred with these conclusions: 
``Currently, it is extremely difficult to identify modifications that 
would be expected to be `within the range of natural variation for all 
virus families'. This would require prior knowledge of the natural 
variation limits of the individual PVC proteins, which is not 
available. Specific modifications can be identified that would raise 
potential concerns, but it is not clear that it is possible to create a 
comprehensive list of these changes for all virus families'' (Ref. 15).
    At the present time, insufficient information exists to develop a 
standard that would describe a priori the degree to which a PVC-protein 
could be modified and yet still remain within the natural variability 
of plant virus coat proteins found in virus populations either 
generally or for any species in particular. In light of this, and 
relying extensively on the advice of the 2005 FIFRA SAP meeting (Ref. 
15), EPA has developed two proposals to exempt PVC-protein residues 
from the requirement of a tolerance:
    1. A categorical exemption for a subset of PVC-proteins based on 
developer self-determination that the encoded PVC-protein is virtually 
unmodified when compared to an entire unmodified coat protein from a 
virus that naturally infects plants that humans consume in toto or in 
part, and
    2. An exemption for more extensively modified proteins that is 
conditional on an Agency determination after review that the encoded 
PVC-protein is minimally modified when compared to an unmodified coat 
protein from a virus that naturally infects plants that humans consume 
in toto or in part.

E. Structure of the Proposed FFDCA Tolerance Exemption

    1. Proposed categorical exemption. Under the proposed exemption at 
Sec.  174.477(a), when the encoded PVC-protein is virtually unmodified 
when compared to an entire unmodified coat protein from a virus that 
naturally infects plants that humans consume in toto or in part, the 
residues of the PVC-protein would be exempt from the requirement of a 
tolerance without Agency review. If the PVC-protein is expressed from a 
plant virus coat protein gene that was isolated from a virus found 
naturally in a food plant in the United States and was not modified, 
the PVC-protein would meet this criterion. Additionally, a PVC-protein 
would meet this criterion if the developer has evidence showing it has 
an amino acid sequence that is virtually unmodified when compared to an 
unmodified plant virus coat protein sequence from a virus that 
naturally infects plants that humans consume, e.g., as found in a 
database. Although EPA cannot a priori identify all existing natural 
coat protein variants, the requirement of being virtually unmodified 
when compared to an entire unmodified coat protein ensures that the 
exempted PVC-protein falls within the existing base of experience on 
which the proposed exemption relies.
    EPA intends, with the requirement that the PVC-protein be virtually 
unmodified when compared to ``an entire unmodified coat protein,'' to 
exclude from the categorical exemption residues of modified PVC-
proteins, e.g., PVC-proteins containing insertions, deletions, or amino 
acid substitutions (except as described below by the definition of 
virtually unmodified), as well as chimeric PVC-proteins that are 
encoded by a sequence constructed by fusing portions of two or more 
plant virus coat protein genes. EPA is proposing to exclude such PVC-
proteins from the categorical exemption because of advice from the 2005 
SAP that insufficient information exists at this time to allow EPA to 
describe a priori a single standard articulating which of these types 
of changes would be consistently expected to fall within the natural 
range of variation of viruses and/or which types of changes could be 
determined not to affect toxicity or allergenicity without any EPA 
review (see Unit IV.D.).
    The Agency proposes to define the term ``unmodified'' to mean, 
``having or coding for an amino acid sequence that is identical to an 
entire coat protein of a naturally occurring plant virus.'' The Agency 
is considering several options for defining the term virtually 
unmodified. Under this proposal, any virtually unmodified PVC-protein 
would qualify for a tolerance exemption without Agency review. Under 
one option, this term would mean, ``having or coding for an amino acid 
sequence that is identical to an entire coat protein of a naturally 
occurring plant virus, except for the addition of one or two amino 
acids at the N- and/or C-terminus other than cysteine, asparagine, 
serine, and threonine and/or the deletion of one or two amino acids at 
the N- and/or C-terminus.'' As noted by the 2005 SAP, the terminal ends 
of a protein ``are the least structurally constrained regions of a 
protein. As such, the ends can be thought of as being essentially 
`unstructured,' and therefore unlikely to serve as allergenic epitopes 
or to make major contributions to the overall structure of the 
molecule. Addition (or deletion) of one or two amino acids is unlikely 
to change this.'' However, the SAP also noted the possibility that the 
addition of amino acids such as cysteine with side chains that could 
promote cross-linking or aggregation between molecules or other amino 
acids that can serve as sites for post-translational modifications 
should be evaluated on a case-by-case basis (Ref. 15). EPA has 
identified cysteine, asparagine, serine, and threonine as the amino 
acids containing side chains that could promote cross-linking or serve 
as sites for post-translational modifications. EPA therefore excludes 
the addition of these amino acids from the proposed definition of 
virtually unmodified. The 2005 SAP report mentioned alanine as an amino 
acid involved in

[[Page 19647]]

glycosylation; however, EPA has found no evidence that alanine is 
involved in glycosylation or promotes cross-linking. The Agency has 
therefore not excluded the addition of alanine under the definition of 
virtually unmodified.
    The Agency is also considering two possible changes to the above 
definition of virtually unmodified. The first change would remove the 
restriction that cysteine, asparagine, serine, or threonine may not be 
added to the naturally occurring protein. Under this alternative, a 
PVC-protein would qualify for the tolerance exemption without Agency 
review if it has an amino acid sequence that is identical to an entire 
coat protein of a naturally occurring plant virus except for the 
addition, substitution, or deletion of one or two amino acids at the N- 
and/or C-terminus. The rationale underlying such an alternative would 
be that addition of any amino acid to the N- or C-terminus, e.g., 
including those that could be glycosylated, is unlikely to introduce 
any concern. In order for an amino acid to be glycosylated, a protein 
must also have a specific enzyme recognition site. The creation of such 
a recognition site by the addition, substitution, or deletion of one or 
two amino acids, particularly at the end of the protein, is expected to 
be extremely rare because it would involve randomly producing a set of 
amino acids involved in a specific interaction. The addition of an 
amino acid with a side group that is capable of forming a covalent 
bond, e.g., cysteine, is likewise unlikely to alter the safety of the 
expressed protein. Such amino acid residues would typically be 
unavailable due to interactions that occur within the protein's normal 
folding conformation. A plant virus coat protein is large enough that 
protein functionality or chemistry would not be dramatically different 
from a PVC-protein that is identical except for its possessing two 
additional amino acids at the N- and/or C-terminus. As previously 
stated, the 2005 SAP said the terminal ends of a protein ``are the 
least structurally constrained regions of a protein'' (Ref. 15). In 
addition, virus coat proteins are self-assembling, structural proteins 
that contain elements necessary for continual infection and replication 
of the entire virus particle. As a structural element of a virus 
particle, one important function of the coat protein is the ability to 
interact with itself to form stable particles. Most if not all plant 
virus coat proteins will naturally aggregate (Refs. 41 and 42), so the 
addition of amino acids that could promote cross-linking or aggregation 
would not fundamentally change the nature of the PVC-protein.
    The second change to the above definition of virtually unmodified 
that the Agency is considering would allow truncated proteins to fall 
under the definition. Under this alternative, a PVC-protein would be 
exempt without Agency review if it has an amino acid sequence that is 
identical to a single contiguous portion of a coat protein of a 
naturally occurring plant virus, except for the addition or 
substitution of one or two amino acids at the N- and/or C-terminus of 
the single contiguous portion other than cysteine, asparagine, serine, 
and threonine. EPA intends that ``identical to a single contiguous 
portion'' would exclude proteins with internal modifications. The 
rationale underlying such an alternative would be that truncated PVC 
proteins have been reported to occur in nature (Ref. 43), as pointed 
out by the 2005 SAP. ``Naturally occurring truncated forms of the PVCs 
could be generated by post-transcriptional and translational events, 
including incomplete translation due to routine errors causing a 
ribosome to dissociate from an mRNA, post-translational processing, the 
presence of a mutation that introduces a premature stop codon, or by 
infrequent translation initiation at downstream AUGs. . . . Whether the 
truncation is at the N- or C-terminus is not relevant to allergenicity 
or toxicity'' (Ref. 15). The SAP also said, ``Determining whether PVC-
proteins containing terminal deletions, or any other modifications, are 
within the range of natural variation would require the development of 
a database of the natural variation and truncated forms of PVC-proteins 
that occur naturally. If a truncated PVC-protein does fall within the 
range of natural variation, the likelihood of increased toxicity and 
allergenicity would be low'' (Ref. 15). However, such a database may 
not be necessary because the potential for toxicity and allergenicity 
of a whole plant virus coat protein is low enough that the likelihood 
of a truncated form of such a protein being toxic or allergenic would 
not rise to the level requiring regulation. Such a change in toxicity 
or allergenicity would require the truncation to expose new allergenic 
epitopes or specific recognition/binding sites in the protein that 
could make the protein toxic, but there is no indication that plant 
virus coat proteins possess such regions. The 2000 SAP indicated that 
``[i]n general, peptide fragments that result from the breakdown of 
proteins are less toxic than the intact protein'' (Ref. 44).
    Either of the changes discussed above could be adopted alone, or 
both could be adopted together. If EPA adopts both changes, a PVC-
protein would be exempt from the requirement of a tolerance without 
Agency review if it has an amino acid sequence that is identical to a 
single contiguous portion of a coat protein of a naturally occurring 
plant virus; except for the addition or substitution of one or two 
amino acids at the N- and/or C-terminus of the single contiguous 
portion.
    EPA is proposing to require that the virus used as the source of 
the coat protein sequence ``naturally infects plants that humans 
consume'' as an additional means of ensuring the proposed exemption is 
limited to PVCP-PIPs that fall within the base of experience discussed 
previously in this unit. This phrase is intended to limit the proposed 
exemption to residues of PVC-proteins that are already part of the 
normal human diet as naturally occurring plant virus coat proteins or 
are minimally modified from such proteins (see Unit IV.C.1.). The 
exemption would not extend to PVC-proteins encoded in part by sequences 
from animal or human viruses.
    EPA proposes to define the term ``naturally infect'' to mean 
``infect by transmission to a plant through direct plant-to-plant 
contact (e.g., pollen or seed), an inanimate object (e.g., farm 
machinery), or vector (e.g., arthropod, nematode, or fungus). It does 
not include infection by transmission that occurs only through 
intentional human intervention, e.g., manual infection in a laboratory 
or greenhouse setting.'' The Agency is proposing this definition 
specifically to exclude transmission that occurs only through 
intentional human intervention because such transmission would have 
little relevance to normal human dietary exposure. Viruses that may be 
able to infect plant species in a laboratory or greenhouse setting 
through manual infection may not ever infect such species in nature. 
EPA intends to include within this definition viruses that are likely 
to have been part of the human diet due to their ability to spread 
without intentional human intervention. EPA recognizes that humans may 
play an inadvertent role in infection (e.g., by transmitting the virus 
on farm machinery). Such unintentional (and often unavoidable) 
transmission can be an important means of virus transmission, leading 
to the presence of natural virus coat proteins in food plants that 
humans consume. EPA therefore includes this mode of transmission in the 
definition of naturally infect to encompass those viruses that would be 
expected to be at

[[Page 19648]]

least occasionally found in the plant and therefore be a normal 
constituent of the human diet. To further clarify that the proposed 
exemption applies only to coat proteins from plant viruses, EPA is 
specifically including the word ``plant'' as an adjective in the name, 
i.e., ``PVC-proteins'' are ``plant virus coat proteins.''
    EPA has considered whether to limit the proposed exemption to PVC-
proteins from PVCP-PIPs based on viruses that naturally infect the 
particular food plant in which the PVC-protein is expressed. EPA must 
address whether there would be any safety issues raised from exposure 
to PVC-proteins if the virus used to create the PVCP-PIP does not 
naturally infect the particular plant species into which the PVCP-PIP 
is inserted. A PVC-protein may be expressed in a food plant that the 
virus does not naturally infect when heterologous resistance to a 
particular virus is conferred through a different virus' coat protein 
gene (e.g., Ref. 45). However, the Agency believes such PVC-proteins 
could be safely exempted from tolerance requirements because these 
proteins would still reasonably be expected to be part of the normal 
diet as long as they naturally infect plants used as food. Based on 
their broad host range, plant viruses are known generally to infect a 
wide variety of plants that humans consume. People generally eat a 
broad range of food plants through which they would reasonably be 
expected to be exposed to a wide variety of plant virus coat proteins 
(Ref. 12). In addition, EPA is not aware that any plant viral coat 
proteins have been identified as allergens, so it is unlikely that a 
person with food allergies avoids a particular food plant because of an 
allergic reaction to a viral coat protein. Based on this rationale and 
in the absence of contravening evidence, EPA concludes that a PVC-
protein expressed in a plant that is not normally infected by the virus 
from which the PVC-protein was derived would raise no safety issues as 
long as the corresponding virus infects other plants that are consumed 
by humans.
    When EPA asked the 2005 SAP to comment on this issue, the Panel 
``expressed some disagreement as to whether the level of risk 
associated with human exposure to any protein is solely dependent on 
the protein itself. One Panel member concluded that the host producing 
the protein is of secondary importance. Others expressed concern 
related to expression of PVC-proteins in plants that are known to be 
highly allergenic such as peanut'' (Ref. 15). The Panel did not 
elaborate on the rationale for such concerns at this point in the SAP 
report. EPA's interpretation of this issue is that the concern is due 
to the possibility, articulated elsewhere in the Panel report, that 
``the changed infectivity status of the plant may also induce changes 
in the overall protein expression pattern of the plant. Thus, in 
various tissues of the plant, natural plant proteins that have been 
identified as allergens may be expressed to a different, and in some 
cases, higher extent compared to a non-infected or a virus-infected 
plant without PVCP-PIP. In particular, pathogenesis-related (PR) 
proteins are known to be very inducible, and their expression levels 
may vary many-fold. Several pathogenesis-related proteins have been 
described as allergens (Breiteneder et al. 2000 and 2004), most notably 
the major birch pollen protein Bet v1 (Breiteneder et al. 1989). An 
increased expression of PR-proteins in pollen could increase both the 
risk of sensitization and the risk of elicitation of allergic 
reactions'' (Refs. 15, 46, 47, and 48). This concern is distinct from 
the concern that EPA addressed above, namely that the PVC-protein 
itself may introduce an allergen into a food source where it is not 
anticipated to be found. The issue the SAP raised would generally be 
addressed by the Food and Drug Administration (FDA) in evaluating food 
composition. However, EPA has not found evidence that introduction of a 
PVCP-PIP would affect induction of PR proteins per se. PR proteins are 
a normal constituent of plants because plants express such proteins in 
response to environmental stresses, including virus infection, exposure 
to certain chemicals, and wounding. Some plant tissues even 
constitutively express such proteins, e.g., those likely to be attacked 
by pests or exposed to environmental stresses such as ultra-violet (UV) 
irradiation (Ref. 49). Moreover, given the large number and variety of 
pathogens (including viruses) encountered by plants in the field, and 
given differences in the virus-infectivity status of plants that occur 
naturally, humans consume varying amounts of PR proteins as part of the 
normal diet. The level found in plants containing a PVCP-PIP is 
therefore expected to be within the range of natural variation.
    EPA has also considered whether a geographic limitation on this 
proposed categorical exemption would be necessary to ensure that the 
exemption extends only to residues that are part of the U.S. diet; 
i.e., that the proposed exemption would only extend to PVC-proteins 
that are part of a PVCP-PIP constructed from a virus that occurs 
naturally in the United States. EPA believes that such a limitation is 
unnecessary to ensure that the PVC-proteins proposed for exemption fall 
within the base of experience supporting the proposal. Humans have long 
consumed viruses infecting food plants with no adverse effects. Given 
the extent of modern market practices in which food is shipped globally 
for human consumption, human dietary exposure to all viruses that 
infect food plants is likely to occur broadly. The lack of any known 
adverse effects attributable to plant viruses suggests that plant virus 
coat proteins in the diet are safe to humans.
    EPA has also considered whether additional conditions are necessary 
to ensure that the expression level of virtually unmodified PVC-
proteins found in plants is no greater than the level of plant virus 
coat protein generally found in a natural virus infection. The 2005 SAP 
suggested that ``for both modified and unmodified proteins, the Agency 
might wish to consider. . . expression levels'' when determining 
whether to exempt a PVC-protein from tolerance requirements (Ref. 15). 
The SAP apparently based this suggestion on the assumption that EPA 
considered exposure level to be an important component of a PVC-protein 
risk assessment given that the Agency's background material for the 
Panel indicated that the dietary exposure to PVC-proteins is 
anticipated to be similar to or less than the dietary exposure to plant 
virus coat proteins currently found in food plants naturally infected 
with viruses. However, even though EPA addresses exposure level in 
evaluating safety (e.g., see Unit IV.C.1.), the Agency also believes 
that the PVC-proteins that qualify for this proposed exemption are safe 
at any level that could be produced in a plant. Humans have been 
exposed to plant virus coat proteins over long periods of time at 
varying and sometimes high levels, and to date there is no indication 
that any plant virus coat protein is an allergen or a toxin. The Agency 
therefore believes that the hazard associated with PVC-proteins that 
are virtually unmodified from natural plant viral coat proteins is 
sufficiently low that it does not rise to the level warranting 
regulation, even if in some cases exposure to a PVC-protein might be 
greater than the exposure to the corresponding natural plant virus coat 
protein. Nevertheless, the Agency regards the anticipated low levels of 
exposure through food to the PVC-proteins covered by this proposal as 
additional support for this proposed categorical exemption. According 
to the 2005 SAP, ``On a per cell basis, it is

[[Page 19649]]

almost certain that all viral gene products are expressed at higher 
levels in virus-infected than transgenic plants'' (Ref. 15).
    2. Proposed exemption conditional on Agency determination. The 
Agency recognizes that product developers frequently modify the genetic 
material of a PVCP-PIP, e.g., in order to achieve greater efficacy 
(Ref. 50) and that most of these changes would be unlikely to result in 
proteins affecting potential dietary risk. However, the Agency cannot 
at this time articulate a criterion that would ensure all PVC-proteins 
with such modifications fall within the base of experience supporting 
the proposed exemption.
    The question of how to objectively define criteria on which the 
regulated community may rely to determine a priori how much a virus 
coat protein may be modified and still fall within the range of natural 
variation is a key challenge. EPA first considered the question of how 
to describe residues that fall within the base of experience supporting 
exemption when the Agency issued its proposal on November 23, 1994 (59 
FR 60539). In the July 19, 2001 supplemental notice (66 FR 37865), EPA 
again addressed the question of how to describe PVCP-PIPs that fall 
within the recognized base of experience supporting the proposed 
categorical exemption.
    In October 2004, the FIFRA SAP was asked to consider the degree and 
ways a plant virus coat protein gene might be modified while still 
retaining scientific support for the idea that humans have consumed the 
products of such genes for generations and that such products therefore 
present no new dietary exposures (Ref. 14). They responded, ``There was 
no clear consensus on how much change would be necessary to invalidate 
this assumption, although there was general agreement that the 
appropriate comparison is to the range of natural variation in the 
virus population.'' The 2005 SAP also addressed this question. They 
concurred that, ``it is extremely difficult to identify modifications 
that would be expected to be `within the range of natural variation for 
all virus families'. . . . Given the possible range of natural 
variations for PVC proteins, it would be appropriate to assess whether 
specific modifications are within natural variation limits of the PVC 
protein on a case-by-case basis'' (Ref. 15).
    EPA believes that developing objectively defined criteria on which 
the regulated community could rely to determine whether a modified PVC-
protein falls within the natural range of variation for a particular 
virus is not currently feasible because the Agency knows of no 
generally applicable, established baseline for what constitutes the 
range of natural variation of a virus. EPA thus does not believe that 
proposing an exemption that would allow developers to self-determine 
eligibility of modified PVC-proteins would be supportable. Rather, EPA 
is proposing that under proposed Sec.  174.477(b), the residues of such 
a PVC-protein would be exempt only if the Agency determines after 
review that the encoded PVC-protein is minimally modified when compared 
to an unmodified coat protein from a virus that naturally infects 
plants that humans consume in toto or in part.
    In determining whether a PVC-protein is minimally modified from a 
natural viral coat protein, EPA will consider first how similar the 
PVC-protein is to a natural viral coat protein by evaluating 
information on the PVCP-PIP genetic construct, PVC-protein deduced 
amino acid sequence, and biochemical characterization of the PVC-
protein as expressed in the plant (e.g., molecular weight to evaluate 
potential post-translational modifications). EPA might also evaluate 
developer-submitted analyses that characterize the PVC-protein sequence 
relative to the range of natural coat protein variation found in public 
sequence databases. Those PVC-proteins determined to be similar to a 
natural viral coat protein would be further evaluated to determine 
whether the modified PVC-protein is as safe as an unmodified protein by 
considering information from an amino acid sequence comparison with 
known protein toxins and allergens. The type and extent of information 
that would need to be provided in order for EPA to determine whether a 
PVC-protein is minimally modified and therefore qualifies for the 
exemption would be determined on a case-by-case basis.
    The 2005 SAP identified certain modifications that might raise 
potential concerns when considering if a protein is minimally modified, 
including ``the addition or removal of protease recognition sites, the 
addition or removal of cysteine residues involved in internal cross-
links, the addition or removal of proline residues that act as 
secondary structure `break points,' and the addition or removal of 
asparagines and alanines involved in glycosylation'' (Ref. 37). By 
contrast, the report identified ``[m]odifications such as single amino 
acid substitutions with biochemically similar amino acids that do not 
affect secondary or tertiary structure'' as potentially being of 
relatively little concern (Ref. 37). EPA would consider this guidance 
as appropriate in evaluating individual exemption petitions to 
determine whether a protein is minimally modified.
    Regarding the 2005 SAP suggestion that EPA might wish to consider 
expression levels in determining whether to exempt a PVC-protein from 
tolerance requirements, the Agency believes that such an evaluation is 
not necessary to determine whether a PVC-protein is minimally modified. 
EPA would necessarily have to find such proteins to be similar to a 
natural viral coat protein in order for them to qualify for this 
proposed exemption. EPA believes that minimally modified PVC-proteins 
are safe at any level for the same reasons discussed above for 
virtually unmodified proteins (Unit IV.E.1.). In both cases, the hazard 
associated with PVC-proteins qualifying for this proposed tolerance 
exemption is sufficiently low that it does not rise to the level 
warranting regulation, even if in some cases exposure to a PVC-protein 
might be greater than the exposure to the corresponding natural plant 
virus coat protein. (However, see Unit XI. for a discussion of how 
exposure level could possibly be considered under the proposed 
exemption structure when reviewing minimally modified proteins.)
    Under proposed Sec.  174.477(b), the procedures for obtaining a 
determination that a PVC-protein fits under the tolerance exemption 
would be no different than those currently provided under the statute 
for obtaining a tolerance exemption. A person can file a submission 
requesting a determination (21 U.S.C. 346a(d)) of whether a particular 
PVC-protein fits under the tolerance exemption, or the Agency can 
initiate an action to issue a determination (21 U.S.C. 346a(e)). After 
a person files a submission under FFDCA section 408(d)(1) proposing 
that a particular PVC-protein falls under this exemption because it is 
minimally modified from a natural plant virus coat protein, FFDCA 
section 408(d)(3) requires that the Administrator determine whether a 
petition meets the requirements of the statute and publish a summary of 
the petition and other required information in the Federal Register 
within 30 days of making that determination. Alternatively, the 
Administrator may publish a notice of proposed rulemaking and provide a 
period of generally not less than 60 days for public comment. In either 
case, EPA will publish any final rule exempting a PVC-protein from the 
requirement of a tolerance in the Federal Register and allow 60 days 
for any person to file objections thereto (21 U.S.C. 346a(g)(2)).

[[Page 19650]]

Currently no fees would be associated with either the proposed 
categorical exemption under Sec.  174.477(a) or the Agency's 
determination under proposed Sec.  174.477(b) that a particular PVC-
protein fits under the tolerance exemption.
    For residues of a PVC-protein that would not qualify for this 
proposed exemption under either Sec.  174.477(a) or (b) because the 
Agency cannot determine that the encoded PVC-protein is minimally 
modified from an unmodified coat protein from a virus that naturally 
infects food plants, an applicant may petition the Agency for an 
individual tolerance exemption under FFDCA section 408 (see also 40 CFR 
180.7).

F. Tolerance Issues Associated with Unintended Protein Production when 
Virus Resistance is Mediated through Post-Transcriptional Gene 
Silencing

    Section 408 of the FFDCA does not require a tolerance or tolerance 
exemption if residues will not be present in food moving in interstate 
commerce. However, with the exception of residues that meet the 
requirements proposed at Sec.  174.477(a), the mere fact that a 
developer may not detect residues during product development will not 
protect the food from seizure if residues are subsequently found 
following commercialization, either because detection techniques 
improve or because the protein is unexpectedly produced. If such an 
event occurs and no tolerance exemption exists for residues of that 
PVC-protein (regardless of its safety), any food containing the PVC-
protein residues would be adulterated and subject to seizure. In 
addition, any FIFRA exemption that may have been applicable for the 
PVCP-PIP would no longer be valid because 40 CFR 174.21(b) would no 
longer be satisfied. Any sale or distribution of such a PVCP-PIP would 
constitute sale and distribution of an unregistered pesticide, in 
violation of FIFRA section 12(a)(1).
    The 2005 SAP suggested that the construction of certain PVCP-PIPs 
may offer a reasonable level of assurance that PVC-protein production 
would not occur, i.e., transgene insertions where the transcribed 
segment lacks an initiator codon or insertions of transcribed inverted 
repeat constructs that constitutively produce transcripts that are 
folded into double-stranded RNA as the immediate product of transgene 
transcription (Ref. 15). However, for other types of constructs, 
questions remain about circumstances under which PVC-protein might be 
detected and/or produced in food at some point after commercialization 
even though PVC-protein may not have been detected and/or produced 
during product development. For example, it is known that in some cases 
PTGS must be triggered before transgene RNA production can be 
effectively suppressed. Lindbo et al. (Ref. 51) used tobacco etch virus 
(TEV) to infect transgenic tobacco plants containing a TEV coat protein 
gene. Plants temporarily developed symptoms but were able to recover 
from infection. Recovered transgenic plant tissue showed significantly 
reduced levels of transgene mRNA, and PVC-protein was undetectable. 
However, plant tissues unchallenged with virus did express PVC-protein, 
suggesting that in at least some cases of PTGS-induced virus 
resistance, PVC-protein may be produced until virus infection occurs. 
B[eacute]clin et al. (Ref. 52) showed that in transgenic tobacco lines 
expressing a [beta]-glucuronidase (uidA) transgene, suppression of 
transgene expression always occurs but is initiated at different plant 
developmental stages: Either 15 days after germination or 2 months 
post-germination. Prior to PTGS initiation, transgenic protein is 
expressed, suggesting that in at least some cases lack of protein 
production may only occur after a certain developmental stage is 
reached. Likewise, Pang et al. (Ref. 53) found that plant developmental 
stage plays an important role in the timing of PTGS initiation.
    Experiments demonstrating that plant developmental stage determines 
PTGS initiation suggest that any environmental factors influencing 
plant growth would also affect the amount of time before RNA and 
protein production is effectively suppressed. At least one experiment 
has looked more directly at the influence of environmental factors on 
PTGS. Szittya et al. (Ref. 54) demonstrated that cold temperatures 
inhibited transgene-induced RNA silencing leading to increased levels 
of transgene mRNA, although they did not report on the level of 
transgenic protein.
    In addition to temporal changes in protein production that may be 
influenced by varying environmental conditions, PTGS may also be 
associated with variation in protein expression across different plant 
tissues. Plant lines expressing a nitrate reductase transgene were 
found to display PTGS in leaves and stem tissue but not in shoot apical 
or axillary meristems (Ref. 52). As in other experiments (Ref. 51), 
transgene protein was not detectable and transgene mRNA levels were 
significantly reduced in plant tissue displaying PTGS. However, plant 
tissue in which gene silencing does not occur showed normal levels of 
transgene mRNA, and transgenic protein was produced.
    It has been shown that PTGS can be suppressed by viruses that 
encode certain suppressor proteins leading to loss of the virus-
resistant phenotype conferred by a PVCP-PIP. For example, Savenkov and 
Valkonen (Ref. 55) showed that resistance to Potato virus A (PVA) in 
Nicotiana benthiana could be overcome when plants were challenged with 
Potato virus Y (PVY). Although levels of transgene mRNA in healthy 
transgenic plants were extremely low or below the detection limit, 
transgene mRNA was readily detectable in PVY-infected plants where 
suppression of gene silencing had apparently occurred. The study did 
not report whether PVC-protein was produced from the transgene mRNA.
    The 2005 SAP was asked to comment on issues associated with protein 
production in the case of plants containing a PVCP-PIP that confers 
resistance through an RNA-mediated mechanism. The Panel responded that 
``[g]iven the wide variety of conditions that can modulate the 
transition from PTGS to no PTGS for non-[inverted repeat (IR)] 
transgenes. . .it is likely that a non-IR transgene insertion that 
retains an initiation codon for protein synthesis will make at least a 
low level of protein in at least some plant tissues over the course of 
its development, especially in the field where there is exposure to 
environmental extremes and virus infections. Thus, these PVCP-PIP 
plants may accumulate virus-derived mRNA and proteins in these 
situations'' (Ref. 15). EPA notes that the Panel further concluded that 
``[b]ecause of low levels of accumulation and sequence identity to the 
natural viral pathotypes. . .these PVCP-PIPs pose similarly low risks'' 
as PVCP-PIPs that produce no protein (Ref. 15). However, any PVC-
protein residue in food that is not covered by a tolerance or tolerance 
exemption would constitute an adulterant of the food supply 
irrespective of the protein's safety or the level at which it is 
detected.
    The above considerations suggest that many factors should be 
considered in making a determination of whether residues of a PVC-
protein will be present in food derived from a crop containing a PVCP-
PIP. Due to the serious consequences of having an unapproved residue in 
the food supply (as discussed earlier in this unit), EPA strongly 
recommends that developers consult with the Agency before determining 
that no tolerance or tolerance exemption for the PVC-protein

[[Page 19651]]

would be necessary based solely on the premise that no residues of the 
protein are anticipated to be present. EPA expects that the Agency 
would conclude no PVC-protein tolerance exemption would be necessary 
for insertion events where the transgene either lacks an initiation 
codon for protein synthesis or is inserted in an inverted-repeat 
orientation, provided that evidence is given to the Agency to verify 
the characteristics of the insertion event. For such constructs, the 
2005 SAP indicated the PVCP-PIP ``could be safely determined to have no 
[PVC-protein] expression regardless of plant tissue, developmental 
stage, environmental conditions, or exposure to virally-encoded 
suppressors of PTGS'' (Ref. 15).
    For all other types of PVCP-PIP insertion events, EPA is 
considering several approaches under FFDCA for PVC-proteins that are 
not readily detectable, but which the SAP indicated would likely be 
produced under some circumstances (Ref. 15), some of which might result 
in the PVC-protein being in food. EPA does not currently have a 
preferred approach and presents several options to promote full 
consideration of the issues. These options are not necessarily mutually 
exclusive, and the approach pursued may vary depending on the 
characteristics of the PVCP-PIP under consideration. The discussion 
below relates only to proteins that EPA review would determine to be 
minimally modified, i.e., proteins that are similar, but not identical 
to natural plant virus coat proteins. Virtually unmodified PVC-proteins 
would be covered under the proposed tolerance exemption without any 
Agency action. The discussion is not relevant to proteins that would 
not be able to qualify under this proposal as either virtually 
unmodified or minimally modified because the proposed tolerance 
exemption would not cover such proteins regardless of how EPA 
implements the exemption.
    Under one approach, when no PVC-protein is detected during product 
development, EPA would not issue a determination of whether the PVC-
protein is minimally modified (and therefore falls under this proposed 
tolerance exemption). Section 408 of FFDCA does not require a tolerance 
or tolerance exemption for foods that do not bear any residues, and 
such an approach would be consistent with current EPA practice 
regarding chemical pesticide residues in that tolerance determinations 
are not generally issued for substances when residue studies 
demonstrate that detectable residues will not be present in food. 
However, if food is subsequently found bearing residues of the PVC-
protein, that food would be adulterated and subject to seizure unless 
and until EPA could make a determination that the PVC-protein is 
minimally modified and is therefore covered by this proposed tolerance 
exemption.
    Any adulterant in the food supply would likely cause public concern 
and great expense--whether or not the PVC-protein were subsequently 
determined to be safe. The Agency also notes that these costs are not 
necessarily borne by the product developer, but rather may 
disproportionately affect farmers and/or food producers because any 
adulterated food would be subject to seizure or recall. The Agency is 
considering this approach under the assumption that the absence of 
detectable protein using rigorous testing could give reasonable 
assurance that PVC-protein residues would not be found in food and 
therefore a tolerance determination would be unnecessary to prevent 
adulteration of the food supply. EPA would expect developers to provide 
the Agency with data acquired during product development that 
demonstrates no PVC-protein residues in food would be reasonably 
anticipated during the commercial life of the PVCP-PIP. For example, 
such data could be obtained by testing for protein and/or mRNA 
production in all plant tissues and all developmental stages that are 
harvested for food production under a variety of circumstances and 
environmental conditions representative of those that the plant may 
experience during its commercial cultivation. Challenge with a known 
PTGS suppressor protein introduced by a replicating virus vector, 
genetic crosses, or agro-infiltration (Ref. 56) may also in some cases 
be a sufficient and less burdensome technique to show that no PVC-
protein is able to be translated from the PVCP-PIP. The potential to 
elicit protein production from silenced transgenes has been shown by 
studies investigating whether particular proteins are able to suppress 
such silencing (Ref. 56). The 2005 SAP discussed such a technique, 
indicating that ``[t]o determine if PTGS-based PVCP-PIP plants have the 
potential to produce proteins, the most effective test is to use viral 
suppression of PTGS. In this type of assay, the PVCP-PIP plants are 
infected with viruses from the potyvirus, cucumovirus, and tombusvirus 
genera. These viruses encode different classes of PTGS suppressor 
proteins. . . Protein and RNA are then extracted from the infected 
plant tissue and assayed for the presence of the PVCP-PIP accumulated 
full-length RNA and protein. Standard tests for protein detection are 
ELISA and immunoblot (`Western' blot) analyses with specific 
antibodies. Triplicate experiments should be sufficient to determine 
that the results of these tests are reproducible'' (Ref. 15). Given 
that FFDCA does not require a developer to demonstrate that no 
tolerance exemption is necessary, EPA would require such testing as a 
condition of either registering or exempting the PVCP-PIP under FIFRA.
    If the developer detects a PVC-protein during the course of 
investigating potential PVC-protein production, e.g., through challenge 
with a suppressor protein, this protein would only be covered under the 
proposed categorical tolerance exemption, i.e., without any Agency 
action, if the protein falls within the definition of a virtually 
unmodified PVC-protein. Therefore, unless the protein is virtually 
unmodified from a natural plant virus coat protein, EPA would expect a 
developer to provide the Agency with information for a determination of 
whether the PVC-protein qualifies as minimally modified and meets the 
proposed conditional tolerance exemption. (See Unit IV.E.2. for a 
discussion of the factors EPA intends to consider in making this 
determination.)
    When possible, EPA would expect to see biochemical characterization 
of the PVC-protein. However, EPA recognizes that such characterization 
may be difficult or even impossible in some cases. For example, when 
only very low levels of protein are produced, it may be difficult to 
obtain sufficient amounts of protein for biochemical characterization. 
In addition, EPA recognizes the cost and burden of producing sufficient 
protein for such characterization may not be warranted for PVC-proteins 
given that an evaluation based on the construct sequence alone could 
consider most of the issues EPA intends to evaluate when determining 
whether a PVC-protein is minimally modified (see Unit IV.E.2.).
    EPA is therefore also considering a second approach to addressing 
PVC-proteins that are not detected during product development but whose 
presence as residues in food cannot be ruled out for the commercial 
life of the PVCP-PIP. Under this approach, EPA would evaluate the PVC-
protein to determine whether it qualifies as minimally modified from a 
natural plant virus coat protein and is thus eligible for this proposed 
tolerance exemption based only on its amino acid sequence as deduced 
from the sequence of the inserted gene. EPA notes the advice of the 
2005 SAP that ``[i]t is critical to evaluate the protein as expressed 
in the

[[Page 19652]]

host, including factors such as post-translational modifications'' 
(Ref. 15). Nevertheless, EPA considers evaluating the protein as 
expressed in the host to be less important for minimally modified PVC-
proteins than for many other types of proteins. A PVC-protein would not 
be expected to have significantly different post-translational 
modifications than a plant virus coat protein produced in a virus-
infected plant. Because plant viruses replicate in plant cells as part 
of their normal life cycle, any post-translational modifications are 
expected to be the same for a PVC-protein expressed from a plant 
transgene as for a plant virus coat protein expressed from a viral 
genome in a virus-infected plant.
    As a third alternative, EPA is considering whether the Agency could 
expand this proposed tolerance exemption to cover all PVC-proteins that 
would be produced from constructs where resistance is demonstrated to 
EPA to be mediated through PTGS, e.g., those that confer virus 
resistance in the absence of detectable protein production for at least 
some period of time. The rationale for this alternative would be, as 
indicated by the 2005 SAP, that ``PTGS-based virus resistance requires 
greater than 90% RNA sequence homology between the PVCP-PIP transgene 
and the target virus, indicating that the viral mRNA and protein 
produced in PVCP-PIP plants will be nearly identical to the viral 
pathotype that occurs in the United States'' (Ref. 15). To implement 
this alternative, the Agency would have to be able to conclude, without 
any case-by-case examination, that any PVC-protein produced from a 
PVCP-PIP that mediates resistance through PTGS would be safe. Even if a 
PVC-protein were detected before product deployment, such a protein 
would not need any evaluation by the Agency in order to be covered by 
this tolerance exemption. The rationale for this approach would be that 
any such PVC-protein would meet the conditions of a minimally modified 
protein (as discussed in Unit IV.E.2.) given the necessity for 
transgene transcript sequence similarity to natural plant virus coat 
protein sequences in order for PTGS to effectively function. Although 
EPA does not believe it could identify a priori which modifications 
would be within the range of natural variation for the protein, under 
this rationale the induction of PTGS would be an a priori indicator 
that such a PVC-protein is within the range of natural variation of the 
protein. The 2005 SAP suggested that all PTGS-based PVCP-PIPs would 
``pose similarly low risks'' as those that would have no protein 
expression under any circumstances (Ref. 15), giving scientific support 
for this option. However, the Agency notes that this advice is not 
entirely consistent with advice regarding PVC-protein safety received 
by the Panel. For one, both the 2004 and 2005 SAPs were unable to 
endorse a tolerance exemption for PVC-proteins other than those that 
are virtually unmodified from a natural plant virus coat protein unless 
the Agency performed a case-by-case review of some nature. PVC-proteins 
could be encoded for by a nucleic acid sequence that meets the 90% 
similarity required for PTGS to function but fail to be virtually 
unmodified from a natural virus coat protein (see Unit IV.E.1.). 
Moreover, the 2005 SAP recommended that ``[d]etermining whether PVC-
proteins containing terminal deletions, or any other modifications, are 
within the range of natural variation would require the development of 
a database of the natural variation and truncated forms of PVC-proteins 
that occur naturally'' (Ref. 15). While PTGS requires a relatively high 
sequence similarity with natural virus coat proteins to function, only 
a portion of the coat protein gene is necessary, suggesting that many 
truncated proteins would be encompassed in this exemption without any 
review of whether they occur naturally. (See, however, EPA's discussion 
of whether truncated proteins could be determined to be exempt without 
Agency review in Unit IV.E.2.) The 2005 SAP also suggested that a low 
level of protein expression would indicate low risk, but prior SAPs and 
other scientific experts have been unable to establish a threshold 
below which the level of protein would not present concerns with 
respect to food allergenicity (Refs. 57 and 58).

V. Toxicological Profile

    Consistent with section 408(b)(2)(D) of FFDCA, EPA has reviewed the 
available scientific data and other relevant information in support of 
this proposed action and considered its validity, completeness, and 
reliability and the relationship of this information to human risk. EPA 
has also considered available information concerning the variability of 
the sensitivities of major identifiable subgroups of consumers, 
including infants and children.
    EPA's risk assessment was based primarily on an analysis of human 
experiences with the breeding and cultivation of agricultural plants as 
well as food preparation and consumption. EPA combined human experience 
in consuming food containing coat proteins from viruses that naturally 
infect plants with knowledge of plant genetics, plant physiology, 
phytopathology, microbial ecology, ecology, biochemistry, and plant 
breeding to evaluate the potential risks of the residues of PVC-
proteins qualifying for this proposed exemption.
    EPA considered the nature of any toxic effects that might be caused 
by residues of PVC-proteins proposed for exemption. As mentioned above, 
coat proteins from plant viruses that naturally infect plants are 
widespread in foods (Refs. 6, 7, and 10) and are not associated with 
toxic or pathogenic effects in humans or vertebrates (Refs. 18 and 19). 
Residues of PVC-proteins qualifying for this proposed exemption are 
virtually unmodified or minimally modified from other coat proteins 
from viruses that naturally infect food plants and that have been 
safely consumed for hundreds if not thousands of years. Given this long 
history of safe use and the fact that toxicity is an unusual property 
among proteins in general (Ref. 59), consumption of food containing 
residues of PVC-proteins qualifying for this proposed exemption is not 
expected to present a toxic effect on humans or animals.
    EPA considered the available information on the various dietary 
consumption patterns of consumers and major identifiable consumer 
subgroups as it pertains to residues of PVC-proteins in food. Plant 
virus coat proteins are, and always have been, widespread in all food 
from crop plants since most plants are susceptible to infection by one 
or more viruses. Thus, all consumers and all major identifiable 
consumer subgroups are, and have been, exposed to plant virus coat 
proteins. Implementation of this proposed exemption is not expected to 
alter the current consumption patterns of plant virus coat proteins 
except perhaps to reduce exposure through a decrease in virus-infected 
plants. Therefore, EPA does not expect any special sensitivities to 
arise due to the consumption of residues of PVC-proteins that are 
proposed to be exempted.

VI. Aggregate Exposures

    In examining aggregate exposure, section 408 of FFDCA directs EPA 
to consider available information concerning exposures from the 
pesticide residue in food and all other non-occupational exposures, 
including drinking water from ground water or surface water and 
exposure through pesticide use in gardens, lawns, or buildings 
(residential and other indoor uses).

[[Page 19653]]

    EPA considered the available information on the likely aggregate 
exposure level of consumers to PVC-proteins qualifying for this 
proposed exemption and to other related substances, including exposures 
to plant virus coat proteins occurring through natural processes such 
as viral infection of a food plant. This analysis included a 
consideration of exposures from dietary sources as well as from other 
non-occupational sources.
    The PVC-proteins qualifying for this proposed exemption and plant 
virus coat proteins that occur naturally are both produced in living 
plants and are subject to the natural processes of degradation and 
decay that all biological materials undergo. They are broken down by 
enzymatic processes of living organisms into constituent parts that are 
used as building blocks for other biological substances (Ref. 60). 
Because of their biodegradable nature, neither PVC-proteins nor 
naturally occurring plant virus coat proteins bioaccumulate (i.e., 
build up in tissues because the body is unable to either break the 
substance down or eliminate it) or biomagnify (i.e., progressively 
build up in successive trophic levels because it bioaccumulates in the 
bodies of organisms lower in the food chain). Humans ingesting 
naturally occurring plant virus coat proteins and residues of PVC-
proteins qualifying for this proposed exemption in food are likely to 
quickly degrade them and use their constituent elements as nutrients.
    Because of these characteristics, there is limited potential for 
exposures to PVC-proteins qualifying for this proposed exemption beyond 
direct physical exposure to a plant. In most cases, the predominant 
exposure route will be dietary. In general, EPA anticipates that 
dietary exposure to PVC-proteins qualifying for this proposed exemption 
through human and animal consumption of plants expressing PVC-proteins 
will be similar to, or less than the amounts of plant virus coat 
proteins currently consumed through food plants that are infected 
naturally with viruses (see Unit IV.C.1.). Exposure through other 
routes is unlikely because the substances are in the plant tissue and 
thus are found either within the plant or in close proximity to the 
plant. EPA expects non-dietary exposure (i.e., non-food oral, dermal, 
and inhalation) in non-occupational settings to be negligible.

A. Dietary Exposure

    EPA considered the consequences of dietary exposure to PVC-proteins 
that are the subject of this proposed exemption. A large base of 
experience exists, including information on human dietary exposure, for 
foods that contain coat proteins from viruses that naturally infect 
plants. As plant virus coat proteins are ubiquitous in food, EPA 
concluded that all humans are exposed to plant virus coat proteins 
throughout their lives as part of their diet. Neither naturally 
occurring plant virus coat proteins nor the PVC-proteins qualifying for 
this exemption are toxic, and there is no evidence that consumption in 
food of residues of PVC-proteins qualifying for this proposed exemption 
would lead to any harm.
    1. Food. As mentioned in Unit IV.C.1., the Agency has concluded 
that dietary exposures to PVC-proteins qualifying for this proposed 
exemption will be similar to or less than the amounts of plant virus 
coat proteins currently found and consumed in food plants that have 
been naturally infected by viruses. Even if there were notable exposure 
to PVC-proteins, there is no evidence that PVC-proteins are toxic to 
humans. Moreover, the Agency is not aware of any coat protein from a 
virus that naturally infects plants that has been identified as a food 
allergen for humans. The residues that are proposed to be exempted by 
this Federal Register document would not differ substantially from 
residues of naturally occurring plant virus coat proteins.
    2. Drinking water exposure. EPA also evaluated potential non-
occupational exposures in drinking water. Residues of PVC-proteins that 
qualify for this proposed exemption are produced inside the plant 
itself. When the plant dies or a part is removed from the plant, 
microorganisms colonizing the tissue immediately begin to degrade it 
using the components of the plant tissue (including residues of PVC-
proteins) as building blocks for making their own cellular components 
or for fueling their own metabolisms. PVC-proteins and naturally 
occurring plant virus coat proteins are subject to the same processes 
of biodegradation and decay that all biological materials undergo and 
are not known to either bioaccumulate or biomagnify (Ref. 60). Even if 
they were to reach surface waters (e.g., through plant parts or pollen 
falling into bodies of water), they are unlikely to present anything 
other than a very negligible exposure in drinking water drawn either 
from surface water or ground water sources due to biodegradation of 
these residues.

B. Other Non-Occupational Exposure

    Residential exposure to PVC-proteins qualifying for this proposed 
exemption would be limited. Residential exposure could occur through 
use of PVCP-PIPs in ornamental plants or in plants grown in home 
gardens. Such exposure to PVC-proteins is expected to be negligible on 
a per-person basis compared to exposure to PVC-proteins and natural 
plant virus coat proteins in the diet. Furthermore, PVC-proteins 
qualifying for this exemption would not be toxic, and there is no 
evidence that exposure to such PVC-proteins would lead to any harm.
    1. Dermal exposure. Residues of PVC-proteins qualifying for this 
proposed exemption may be present in sap or other plant exudates and 
thus may present some limited opportunity for dermal exposure to 
persons coming physically into contact with the plant or raw 
agricultural food from the plant. Individuals preparing meals are those 
most likely to experience dermal contact with the residues on a non-
occupational basis. As noted by the 2005 SAP, PVC-proteins' ``natural 
exposure route may be via oral ingestion. However, genetically modified 
expression of PVCP-PIPs would lead to the presence of [PVC-proteins] in 
other plant compartments such as pollen grains which lead to other 
sites of exposure including respiratory and cutaneous surfaces'' (Ref. 
15). However, the potential amount involved in such exposure on a per 
person basis is likely to be negligible in comparison to potential 
exposure through the dietary route to PVC-proteins and natural plant 
virus coat proteins (Ref. 61). Moreover, PVC-proteins qualifying for 
this proposed exemption or naturally occurring plant virus coat 
proteins that occur in food are unlikely to cross the barrier provided 
by the skin (Ref. 62).
    2. Inhalation exposure. Pollen could potentially contain residues 
of PVC-proteins qualifying for this proposed exemption. Individuals 
(e.g., those visiting, living, or working near enough to farms, 
nurseries, or other plant-growing areas to be exposed to wind-blown 
pollen) may be exposed to the pollen through inhalation. On a per 
person basis, the potential amount of pollen involved in these 
exposures is likely to be negligible in comparison to potential 
exposure through the dietary route (Ref. 61). Some members of the 2005 
SAP indicated that ``[i]ntroduction of new proteins to pollens and 
other plant materials may have the potential to cause problems, and 
consideration by the Agency is warranted'' (Ref. 15). As the Panel 
explained, ``While plant viruses systemically infect plant tissues, 
there is tissue specific regionalization of viruses. Therefore [plant 
virus coat proteins] would be restricted within certain compartments. 
Transgenic expression of some PVC-PIPs would

[[Page 19654]]

promote [PVC-protein] expression in different plant tissues relative to 
what would naturally occur (i.e., all cells). This could lead to 
heightened levels of [PVC-proteins] in certain tissues (i.e., pollen 
grains) and the effects (specifically to allergenicity) are not yet 
known. This has implications for non-dietary exposure of plant 
proteins. In some instances, [plant virus coat protein's] natural 
exposure route may be via oral ingestion. However, genetically modified 
expression of PVCP-PIPs would lead to the presence of [PVC-proteins] in 
other plant compartments such as pollen grains which lead to other 
sites of exposure including respiratory and cutaneous surfaces'' (Ref. 
15). However, other Panel members felt that ``unless there is evidence 
that PCVP-PIPs are expressed on the surface of pollen grains in a 
manner different from expression in wild-type plants, the risk of 
increased allergy from exposure to pollen is non-existent'' (Ref. 15). 
The Agency also notes that in order for expression of a PVC-protein to 
be a concern, the protein would have to be expressed on the surface of 
the pollen grain, it would have to actually be an antigenic protein, 
and it would have to elicit an allergic response through secondary 
exposure. The Agency considers that this sequence of events is very 
unlikely to occur, in part because no plant virus coat proteins have 
been identified as being allergenic, and PVC-proteins qualifying for 
this exemption are virtually unmodified or minimally modified from 
natural plant virus coat proteins. Therefore, it is unlikely that 
inhalation exposure to PVC-proteins in pollen would result in adverse 
effects.

VII. Cumulative Effects

    EPA examined the available information on residues of PVC-proteins 
qualifying for this proposed exemption for cumulative effects with 
other substances, including natural plant virus coat proteins. Plant 
virus coat proteins are nontoxic proteins that are widespread in food 
from plants. They have not been associated with toxic effects to 
animals or humans (see Unit IV.C.3.). EPA is therefore not aware of any 
other substances that could have a common mechanism of human toxicity 
with residues of PVC-proteins qualifying for this exemption and cannot 
identify any cumulative effects of such residues with any other 
substances.

VIII. Safety Factor for Infants and Children

A. In General

    Section 408(b)(2)(C) of FFDCA provides that EPA shall apply an 
additional tenfold margin of safety for infants and children in the 
case of threshold effects to account for prenatal and postnatal 
toxicity and the completeness of the information base on toxicity and 
exposure unless EPA determines that a different margin of safety will 
be safe for infants and children. Margins of safety are incorporated 
into EPA risk assessments either directly through use of a MOE analysis 
or through using uncertainty (safety) factors in calculating a dose 
level that poses no appreciable risk to humans.

B. Prenatal and Postnatal Sensitivity

    EPA considered available information on the dietary consumption 
patterns of infants and children as it pertains to residues in food of 
PVC-proteins qualifying for this proposed exemption. 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 breast milk or 
formula-based products for nutrition, although some infants are fed 
soy-based products. Infants may begin as early as 4 months of age to 
consume solid foods that are based on foods consumed by the general 
adult population albeit in different proportions and with processing to 
facilitate swallowing. 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 change 
to more closely resemble an adult diet. Because plant viruses are 
ubiquitous in plant foods, EPA concluded that infants and children are 
exposed to plant virus coat proteins from the time they begin to eat 
food of plant origin. As the diets of humans change from infancy 
through childhood and into adulthood, there is some possibility that 
the amount of plant virus coat proteins being consumed may change, with 
those consuming the greatest amounts of food of plant origin most 
likely exposed to the most plant virus coat protein. However, there is 
no evidence that such changes are likely to result in 
disproportionately high consumption of foods containing plant virus 
coat proteins among infants and children in comparison to the general 
population. Furthermore, PVC-proteins qualifying for this proposed 
exemption are not toxic, and there is no evidence that any amount of 
exposure to such PVC-proteins in food would lead to any harm.
    EPA considered available information on the potential for special 
susceptibility of infants and children, including prenatal and 
postnatal toxicity, to residues of PVC-proteins qualifying for this 
proposed exemption. PVC-proteins in food are not toxic. There is no 
scientific evidence that residues of such PVC-proteins in food would 
have a different effect on infants and children than adults due to 
neurological differences between infants, children, and adults.
    The Agency's consideration of cumulative effects of the residues of 
PVC-proteins qualifying for this proposed exemption on the general 
population also included consideration of effects for infants and 
children. Neither naturally occurring plant virus coat proteins nor 
PVC-proteins qualifying for this proposed exemption are toxic when 
consumed as part of the diet, and EPA is not aware of any substances 
that might have a common mechanism of toxicity with these PVC-proteins. 
There is no scientific evidence indicating any potential for adverse 
effects on infants and children due to cumulative exposure to residues 
of such PVC-proteins. EPA concludes that there is no evidence of a 
common mechanism of toxicity between PVC-proteins qualifying for this 
proposed exemption and any other substances, and therefore, no 
cumulative effects of these PVC-proteins would reasonably be 
anticipated.

C. Conclusion

    There is a complete toxicity base of information for PVC-proteins 
that are the subject of this proposed exemption, and exposure data are 
estimated based on data that reasonably account for potential 
exposures. For residues of PVC-proteins qualifying for this proposed 
exemption, EPA has determined that a tenfold margin of safety is not 
necessary to protect infants and children. As noted in Unit IV.C., EPA 
based its assessment of exposure and toxicity on the long history of 
safe human and animal consumption of food containing plant virus coat 
proteins. EPA also relied upon information from the disciplines of 
plant genetics, plant physiology, plant virology, microbial ecology, 
ecology, biochemistry, molecular biology, and plant breeding. Based on 
all of this information, EPA concludes that PVC-proteins qualifying for 
this proposed exemption in food are not toxic and may be safely 
consumed, including by infants and children. There is no evidence that 
exposure to such

[[Page 19655]]

PVC-proteins in food, including changes in exposure because of changes 
in the relative proportions of the different types of food consumed 
from infancy through childhood and into adulthood, leads to any harm. 
Thus, on the basis of valid, complete, and reliable information, EPA 
has concluded that residues in food of PVC-proteins qualifying for this 
proposed exemption are safe for infants and children and that an 
additional margin of safety need not be applied.

IX. Other Considerations

A. Endocrine Disruptors

    Based on available information that plant virus coat proteins are 
ubiquitous in foods and have no known adverse effects when consumed as 
part of the diet (see Unit IV.C.), EPA does not expect residues of PVC-
proteins qualifying for this proposed exemption to cause estrogenic or 
other endocrine effects. In the May 16, 1997 supplemental document, EPA 
specifically requested comment on PVC-proteins causing estrogenic 
effects. No information was received indicating that either naturally 
occurring plant virus coat proteins or PVC-proteins that qualify for 
this proposed exemption might cause estrogenic or other endocrine 
effects. If EPA becomes aware of a potential for estrogenic or 
endocrine effects from exposure to residues of such PVC-proteins, the 
Agency will reexamine this proposed tolerance exemption in light of 
that information.

B. Analytical Method(s)

    EPA has concluded that even though methodology exists to detect 
residues of PVC-proteins (Refs. 63, 64, and 65), there is no need to 
employ a practical method for detecting and measuring the level of 
residues of PVC-proteins qualifying for this exemption. There is no 
reason to believe that the residues of PVC-proteins proposed to be 
exempted in this Federal Register document would behave any differently 
than naturally occurring plant virus coat proteins in food. There is a 
reasonable certainty that no harm will result from exposure to any 
amount of residues in food of such PVC-proteins. Because these residues 
may be present in food at any level without causing harm, EPA has 
concluded that an analytical method is not required for detecting and 
measuring the level of residues of these PVC-proteins in food. EPA 
consulted with the Department of Health and Human Services (HHS) in 
making this determination.

C. Codex Maximum Residue Level

    There are no Codex maximum residue levels established for PVC-
proteins.

X. Preliminary Determination of Safety for U.S. Population, Infants, 
and Children

    Based on the information discussed in this document and that 
discussed in the 1994 Federal Register documents, the supplemental 
documents, and the associated record as described in Unit XII.B., EPA 
preliminarily concludes that there is a reasonable certainty that no 
harm will result to the U.S. population, infants, and children from 
aggregate exposures to residues of PVC-proteins that qualify for this 
proposed exemption. Many years of experience with growing, preparing, 
and consuming food from plants containing plant virus coat proteins and 
information generated through years of study of the food supply (Refs. 
6, 7, 8, 9, 10, and 66) indicate that adverse effects due to aggregate 
exposure to PVC-proteins qualifying for this proposed exemption through 
dietary, non-food oral, dermal, and inhalation routes are highly 
unlikely.

XI. Request for Comment

    EPA requests comment on whether this proposed tolerance exemption 
identifies those PVC-proteins that are unlikely to result in new 
dietary exposures. When commenting, please use the terminology 
conventions adopted in this document, i.e., use ``plant virus coat 
protein'' when referring to the protein produced naturally from a plant 
virus, and use ``PVC-protein'' when referring to the protein component 
of a PVCP-PIP. The Agency requests comment on the following specific 
issues:
    1. EPA requests comment on the options discussed in Unit IV.E.1. 
for defining virtually unmodified. Under the Agency's proposed rule, 
virtually unmodified proteins would be exempt from the requirement of a 
tolerance without Agency review. Under one option, virtually unmodified 
would be defined as having or coding for an amino acid sequence that is 
identical to an entire coat protein of a naturally occurring plant 
virus; except for the addition of one or two amino acids at the N- and/
or C-terminus other than cysteine, asparagine, serine, and threonine 
and/or the deletion of one or two amino acids at the N- and/or C-
terminus. However, the Agency is considering removing the limitations 
on which amino acids may be added and on the number of amino acids that 
may be truncated from either end of a PVC-protein.
    2. In addition to the types of changes discussed in the paragraph 
above, EPA requests comment on whether any other class of potential 
PVC-protein modifications (e.g., a particular number of amino acid 
substitutions) would always be expected to produce a PVC-protein as 
safe as an unmodified plant virus coat protein such that the protein 
would not warrant a case-by-case Agency review for a tolerance 
exemption. The Agency also requests that commenters indicate whether 
the number and combination of such modifications has any relevance to 
the product's safety. In October 2004, the FIFRA SAP was asked to 
consider the degree and ways a plant virus coat protein gene might be 
modified while still retaining scientific support for the idea that 
humans have consumed the products of such genes for generations and 
that such products therefore present no new dietary exposures (Ref. 
14). They responded that ``[t]here was no clear consensus on how much 
change would be necessary to invalidate this assumption, although there 
was general agreement that the appropriate comparison is to the range 
of natural variation in the virus population.'' This question was also 
addressed by the 2005 SAP which concurred that ``it is extremely 
difficult to identify modifications that would be expected to be 
`within the range of natural variation for all virus families'. . . 
Given the possible range of natural variations for PVC proteins, it 
would be appropriate to assess whether specific modifications are 
within natural variation limits of the PVC protein on a case-by-case 
basis'' (Ref. 15). Commenters should specifically address this advice 
when formulating comments.
    3. EPA requests comment on whether there would be any safety issues 
associated with exposure to PVC-proteins if the virus used to create 
the PVCP-PIP does not naturally infect the particular plant species 
into which the PVCP-PIP is inserted. A PVC-protein may be expressed in 
a food plant that the virus does not naturally infect when heterologous 
resistance to a particular virus is conferred through a different 
virus' coat protein gene (e.g., Ref. 45). Such PVC-proteins could be 
safely exempted from tolerance requirements if these proteins are 
reasonably expected to be part of the current diet, as discussed in 
Unit IV.E.1. In light of the uncertainty surrounding the SAP's remarks 
concerning this issue (see Unit IV.E.1.), EPA requests comment on 
whether there would be any safety issues associated with exposure tothe

[[Page 19656]]

PVC-proteins themselves if the virus used to create a PVCP-PIP does not 
naturally infect the particular plant species into which the PVCP-PIP 
is inserted.
    4. EPA requests comment on whether the Agency should consider the 
level of PVC-protein expression in determining whether a PVC-protein is 
virtually unmodified or minimally modified and thus exempt from 
tolerance requirements. EPA concurs with the 2005 SAP that ``exposure 
level is an important component of an allergenicity risk assessment'' 
(Ref. 15). However, it can be argued that PVC-proteins that are 
virtually unmodified or minimally modified when compared to natural 
plant viral coat proteins are of sufficiently low hazard that the 
potential risk does not rise to the level warranting regulation, even 
in the rare case that exposure to a PVC-protein might be greater than 
the exposure to the corresponding natural plant virus coat protein. 
Although EPA's review of PVC-proteins to determine if they are 
minimally modified could allow the Agency to consider PVC-protein 
expression level relative to natural levels of plant virus coat 
proteins, the Agency is unsure how this factor could be readily 
incorporated into the criteria for a developer-determined tolerance 
exemption; EPA anticipates needing to consider the appropriateness of 
data designed to address these questions on a case-by-case basis. 
Therefore, if protein expression level is considered a necessary factor 
in evaluating whether to exempt a virtually unmodified PVC-protein from 
tolerance requirements, EPA seeks comment on how such considerations 
could be articulated in a clear, unambiguous criterion.
    5. EPA requests comment on the Agency's options for how to view a 
PVC-protein that would not meet the definition of virtually unmodified 
and is not detected during product development if the construct 
suggests that its production is likely to occur in at least some plant 
tissue at some point in time (see Unit IV.F.). Specifically, EPA 
requests comment on the relative costs and benefits of allowing a PVCP-
PIP that does not produce detectable PVC-protein residues in food 
during product development to be sold or distributed without a PVC-
protein tolerance exemption in place. EPA is particularly interested in 
information about the likelihood that protein would fail to be detected 
during product development but subsequently be detected in food. The 
Agency is also interested in comments on conditions under which protein 
detection protocols could be conducted to provide adequate assurance 
that such events would not occur, e.g., any key environmental 
parameters that should be varied during testing.
    EPA also requests comment on whether obtaining characterization 
data of a plant-produced PVC-protein for a tolerance review is 
scientifically feasible in all cases where the PVCP-PIP insertion event 
contains a translation initiation codon and is not present in an 
inverted repeat orientation. The Agency would like to know for any 
given crop how technically difficult it would be to attempt to induce 
protein production through challenge with a known PTGS suppressor 
protein, e.g., through introduction by a replicating virus vector, 
genetic crosses, or agro-infiltration (Ref. 56). In addition, EPA would 
like to know how likely it is that such techniques could yield 
sufficient quantities of PVC-protein for analysis (e.g., mass 
spectrometry or glycosylation analysis). The Agency would also be 
interested in hearing of additional techniques that could be employed 
to obtain plant-produced PVC-protein in cases where PTGS normally 
prevents accumulation of protein but is not expected to be consistently 
activated, thereby leading to PVC-protein production.
    Regarding the second alternative presented for PVC-proteins 
associated with PTGS, EPA requests comment on the value of the 
additional information gained by analyzing an actual PVC-protein as 
produced in the plant where the inserted nucleotide sequence suggests 
it would be minimally modified from a natural plant virus coat protein, 
e.g., to consider potential post-translational modifications, relative 
to the reduced burden and cost of analyzing safety based on the deduced 
amino acid sequence from the insert alone.
    Regarding the third alternative presented, EPA requests comment on 
the rationale that would be used to support expanding this tolerance 
exemption to cover all PVC-proteins produced by a PVCP-PIP that 
mediates resistance through PTGS, i.e., that any such protein would 
meet the conditions of a minimally modified protein as discussed in 
this document given the necessity for transgene transcript sequence 
similarity to natural plant virus coat protein sequences in order for 
PTGS to effectively function. In particular, EPA requests comment on 
how to reconcile this option with prior advice of the SAP (as discussed 
in Unit IV.F.).
    6. EPA requests comment on whether PVC-proteins that the Agency has 
reviewed and has determined are minimally modified and therefore are 
exempt from the requirement of a tolerance under proposed Sec.  
174.477(b) should be listed in the CFR as is the current practice for 
individual tolerance exemptions associated with other types of PIPs. If 
so, EPA requests comment on whether the listing should indicate the 
specific modifications of the reviewed proteins, given that each 
determination would apply only to proteins with those modifications. 
EPA is aware that in the past, developers have found such listings to 
be useful for international trade reasons, as governments rely on EPA 
tolerances to support import decisions.

XII. References

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2004 Meeting on Issues Associated with Deployment of a Type of Plant-
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Coat Proteins (PVCP-PIPs). 2004.
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quasispecies is controlled by host-virus interactions. Journal of 
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of luteoviruses probably induced by base-pairing between the genomes of 
two distinct viruses. Virology 1995; 206:1129-32.
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sequence of the RNA-2 of an isolate of the English serotype of tomato 
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quadripartite hybrid virus by interspecific exchange and recombination 
between replicase components of two related tripartite RNA viruses. 
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Fauquet C.M. Recombination, pseudorecombination and synergism of 
geminiviruses are determinant keys to the epidemic of severe cassava 
mosaic disease in Uganda. Journal of General Virology 2001; 82:655-65.
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an emerging virus that has evolved by recombination between luteoviral 
and poleroviral ancestors. Virology 2000; 269:156-71.
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in RNA viruses. Journal of General Virology 1999; 80:2535-43.
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and genetic structure of plant virus populations. Annual Review of 
Phytopathology 2001; 39:157-86.
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pepper isolates of cucumber mosaic virus. Plant Disease 1995; 79:450-5.
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Garca-Arenal F. Genetic diversity in tobacco mild green mosaic 
tobamovirus infecting the wild plant Nicotiana glauca. Virology 1996; 
223:148-55.
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L., and Zurcher, E. Plant Viruses Online: Descriptions and Lists from 
the VIDE Database Version: 20\th\ August 1996. http://image.fs.uidaho.edu/vide/.
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aggregation of tobacco mosaic virus coat protein. Biochemistry (Moscow) 
2002; 67:525-33.
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the movement and coat proteins of Maize streak virus: implications for 
the transport of viral DNA. Journal of General Virology 2001; 82:35-44.
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basic arm of brome mosaic virus coat protein on RNA packaging and 
systemic infection. Journal of Virology 1989; 63:4545-52.
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Meeting on Mammalian Toxicity Assessment Guidelines for Protein Plant 
Pesticides. 2000.
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J. Heterologous resistance to potato virus Y in transgenic tobacco 
plants expressing the coat protein gene of lettuce mosaic potyvirus. 
Phytopathology 1993; 83:819-24.
    46. Breiteneder H., Pettenburger K., Bito A., Valenta R., Kraft D., 
Rumpold H. et al. The gene coding for the major birch pollen allergen 
Betv1, is highly homologous to a pea disease resistance response gene. 
The EMBO Journal 1989; 8:1935-8.
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allergens. The Journal of Allergy and Clinical Immunology 2000; 106:27-
36.
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allergens. The Journal of Allergy and Clinical Immunology 2004; 
113:821-30.
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allergens homologous to pathogenesis-related proteins. Allergy 2001; 
56:43-4.
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transgenic resistance to Papaya ringspot virus. Plant Disease 2004; 
88:352-8.
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Induction of a highly specific antiviral state in transgenic plants: 
Implications for regulation of gene expression and virus resistance. 
The Plant Cell 1993; 5:1749-59.
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Vaucheret H. Infection of tobacco or Arabidopsis plants by CMV 
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(trans)genes. Virology 1998; 252:313-7.
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H. et al. Post-transcriptional transgene silencing and consequent 
tospovirus resistance in transgenic lettuce are affected by transgene 
dosage and plant development. Plant Journal 1996; 9:899-909.
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Lakatos L. et al. Low temperature inhibits RNA silencing-mediated 
defence by the control of siRNA generation. The EMBO Journal 2003; 
22:633-40.
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resistance to Potato virus A in transgenic plants is suppressed 
following infection with another potyvirus. Journal of General Virology 
2001; 82:2275-8.
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Opinion in Biotechnology 2001; 12:150-4.
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2001 Meeting on A Set of Scientific Issues Being Considered by the 
Environmental Protection Agency Regarding: Assessment of Additional 
Scientific Information Concerning StarLink\TM\ Corn. 2001.
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2000 Meeting on A Set of Scientific Issues Being Considered by the 
Environmental Protection Agency Regarding: Assessment of Scientific 
Information Concerning StarLink\TM\ Corn. 2000.
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preparations used in food processing: update for a new century. 
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to chemical exposure. In: Hobson DW. Dermal and Ocular Toxicology: 
Fundamentals and Methods. Boca Raton: CRC Press, 1991:221-46.
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Drost G., Osterhaus A. et al. Detection of tomato spotted wilt virus 
using monoclonal antibodies and riboprobes. Archives of Virology 1990; 
110:47-62.
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Highly sensitive immunoassays for detection of barley stripe mosaic 
virus and beet necrotic yellow vein virus. Journal of Virological 
Methods 1996; 56:199-207.
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the 35S promoter: assessing the risks and enhancing the debate. 
Microbial Ecology in Health and Disease 2000; 12:1-5.

B. Additional Information

    EPA has established an official record for this rulemaking. The 
official record includes all information considered by EPA in 
developing this proposed rule including documents specifically 
referenced in this action, any public comments received during an 
applicable comment period, and any other information related to this 
action, including any information claimed as CBI and any information 
received in any of the related dockets mentioned in this unit. This 
official record includes all information physically located in the 
dockets described in the following paragraphs, as well as any documents 
that are referenced in the documents in the dockets.
    1. The docket identified by the docket control number OPP-300370 
for the document entitled ``Proposed Policy: Plant-Pesticides Subject 
to the Federal Insecticide, Fungicide, and Rodenticide Act and the 
Federal Food, Drug, and Cosmetic Act'' (59 FR 60496, November 23, 1994) 
(FRL-4755-2).
    2. The docket identified by the docket control number OPP-300369 
for the document entitled ``Plant-Pesticides Subject to the Federal 
Insecticide, Fungicide and Rodenticide Act; Proposed Rule'' (59 FR 
60519, November 23, 1994) (FRL-4755-3).
    3. The docket identified by the docket control number OPP-300368 
for the document entitled ``Plant-Pesticides; Proposed Exemption From 
the Requirement of a Tolerance Under the Federal Food, Drug, and 
Cosmetic Act'' (59 FR 60535, November 23, 1994) (FRL-4758-8).
    4. The docket identified by the docket control number OPP-300371 
for the document entitled ``Plant-Pesticides; Proposed Exemption From 
the Requirement of a Tolerance Under the Federal Food, Drug, and 
Cosmetic Act for Nucleic Acids Produced in Plants'' (59 FR 60542, 
November 23, 1994) (FRL-4755-5).
    5. The docket identified by the docket control number OPP-300367 
for the document entitled ``Plant-Pesticides; Proposed Exemption From 
the Requirement of a Tolerance Under the Federal Food, Drug, and 
Cosmetic Act for Viral Coat Proteins Produced in Plants'' (59 FR 60545, 
November 23, 1994) (FRL-4755-4).
    6. The docket identified by the docket control number OPP-300370A 
for the document entitled ``Plant-Pesticide Subject to the Federal 
Insecticide, Fungicide, and Rodenticide Act and the Federal Food, Drug, 
and Cosmetic Act; Reopening of Comment Period'' (61 FR 37891, July 22, 
1996) (FRL-5387-4).
    7. The docket identified by the docket control number OPP-300368A 
for the document entitled ``Plant-Pesticides; Supplemental Notice of 
Proposed Rulemaking'' (62 FR 27132, May 16, 1997) (FRL-5717-2).
    8. The docket identified by the docket control number OPP-300371A 
for the document entitled ``Plant-Pesticides; Nucleic Acids; 
Supplemental Notice of Proposed Rulemaking'' (62 FR 27142 May 16, 1997) 
(FRL-5716-7).
    9. The docket identified by the docket control number OPP-300367A 
for the document entitled ``Plant-Pesticides; Viral Coat Proteins; 
Supplemental Notice of Proposed Rulemaking'' (62 FR 27149, May 16, 
1997) (FRL-5716-6).
    10. The docket identified by the docket control number OPP-300369A 
for the document entitled ``Plant-Pesticides, Supplemental Notice of 
Availability of Information'' (64 FR 19958, April 23, 1999) (FRL-6077-
6).
    11. The docket identified by the docket control number OPP-300368B 
for the document entitled ``Exemption From the Requirement of a 
Tolerance

[[Page 19659]]

Under the Federal Food, Drug, and Cosmetic Act for Residues Derived 
Through Conventional Breeding From Sexually Compatible Plants of Plant-
Incorporated Protectants (Formerly Plant-Pesticides)'' (66 FR 37830, 
July 19, 2001) (FRL-6057-6).
    12. The docket identified by the docket control number OPP-300371B 
for the document entitled ``Exemption from the Requirement of a 
Tolerance Under the Federal Food, Drug, and Cosmetic Act for Residues 
of Nucleic Acids that are Part of Plant-Incorporated Protectants 
(Formerly Plant-Pesticides)'' (66 FR 37817, July 19, 2001) (FRL-6057-
5).
    13. The docket identified by the docket control number OPP-300369B 
for the document entitled ``Regulations Under the Federal Insecticide, 
Fungicide, and Rodenticide Act for Plant-Incorporated Protectants 
(Formerly Plant-Pesticides)'' (66 FR 37772, July 19, 2001) (FRL-6057-
7).
    14. The docket identified by the docket control number OPP-300370B 
for the document entitled ``Plant-Incorporated Protectants (Formerly 
Plant-Pesticides), Supplemental Proposal'' (66 FR 37855, July 19, 2001) 
(FRL-6760-4).
    15. The docket identified by the docket ID number EPA-HQ-OPP-2006-
0642 for the companion document entitled ``Exemption under the Federal 
Insecticide, Fungicide, and Rodenticide Act for Certain Plant-
Incorporated Protectants Derived from Plant Viral Coat Protein Gene(s) 
(PVCP-PIPs)'' (FRL-8100-7) published elsewhere in this issue of the 
Federal Register.
    16. The docket identified by the docket ID number EPA-HQ-OPP-2006-
0643 for this document (FRL-8100-5).
    Also included in the complete official public record are:
    <bullet> Public comments submitted in response to the proposals and 
supplemental documents cited in the above paragraphs.
    <bullet> Reports of all meetings of the Biotechnology Science 
Advisory Committee and the FIFRA Scientific Advisory Panel pertaining 
to the development of this final rule.
    <bullet> Support documents and reports.
    <bullet> Records of all communications between EPA personnel and 
persons outside EPA pertaining to the proposed rule. (This does not 
include any inter- and intra-agency memoranda, unless specifically 
noted in the indices of the dockets).
    <bullet> Published literature that is cited in this document.

XIII. Statutory and Executive Order Reviews

    This proposed rule would establish an exemption from therequirement 
of a tolerance under section 408 of FFDCA. The Officeof Management and 
Budget (OMB) has exempted these types of actionsfrom review under 
Executive Order 12866, entitled Regulatory Planning and Review (58 FR 
51735, October 4, 1993). Because this proposed rule has been exempted 
from review under Executive Order 12866, this proposal is not subject 
to Executive Order 13211, Actions Concerning Regulations That 
Significantly Affect Energy Supply, Distribution, or Use (66 FR 28355, 
May 22, 2001) or Executive Order 13045, entitled Protection of Children 
from Environmental Health Risks and Safety Risks (62 FR 19885, April 
23, 1997). This proposed rule does not contain any new information 
collections subject to OMB approval under the Paperwork Reduction Act 
(PRA), 44 U.S.C. 3501 et seq., nor does it require any special 
considerations under Executive Order 12898, entitled Federal Actions to 
Address Environmental Justice in Minority Populations and Low-Income 
Populations (59 FR 7629, February 16, 1994). This action does not 
involve any technical standards that would require Agency consideration 
of voluntary consensus standards pursuant to section 12(d) of the 
National Technology Transfer and Advancement Act of 1995 (NTTAA) (15 
U.S.C. 272 note). Pursuant to the Regulatory Flexibility Act (RFA) (5 
U.S.C. 601 et seq.), the Agency previously assessed whether 
establishing tolerances, exemptions from tolerances, raising tolerance 
levels or expanding exemptions might adversely impact small entities 
and concluded, as a general matter, that there is no adverse economic 
impact associated with tolerance actions. The factual basis for the 
Agency's generic certification for tolerance actions published on May 
4, 1981 (46 FR 24950). Since this proposed rule will not have an 
adverse economic impact, EPA hereby certifies under section 605(b) of 
the RFA that this action will not have a significant adverse economic 
impact on a substantial number of small entities. Tolerance actions, 
such as this proposed exemption, directly regulates growers, food 
processors, food handlers and food retailers, not States or tribes. 
Tolerance actions do not alter the relationships or distribution of 
power and responsibilities established by Congress in the preemption 
provisions of section 408(n)(4) of FFDCA. As such, the Agency has 
determined that this action will not have a substantial direct effect 
on States or tribal governments, on the relationship between the 
national government and the States or tribal governments, or on the 
distribution of power and responsibilities among the various levels of 
government or between the Federal Government and Indian tribes. Thus, 
the Agency has determined that Executive Order 13132, entitled 
Federalism (64 FR 43255, August 10, 1999) and Executive Order 13175, 
entitled Consultation and Coordination with Indian Tribal Governments 
(65 FR 67249, November 6, 2000) do not apply to this rule. In addition, 
this rule does not impose any enforceable duty or contain any unfunded 
mandate as described under Title II of the Unfunded Mandates Reform Act 
of 1995 (UMRA) (Public Law 104-4).
    As with all aspects of its proposal, EPA invites your comments on 
these determinations.

List of Subjects in 40 CFR Part 174

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


    Dated: April 9, 2007.
Stephen L. Johnson,
Administrator.
    Therefore, it is proposed that 40 CFR part 174 be amended as 
follows:

PART 174--[AMENDED]

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

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

    2. By adding Sec.  174.477 to read as follows:


Sec.  174.477  Plant virus coat protein portion of a PVCP-PIP (PVC-
protein); exemption from the requirement of a tolerance.

     (a) Residues of a PVC-protein from a PVCP-PIP are exempt from the 
requirement of a tolerance if the encoded PVC-protein is virtually 
unmodified when compared to an entire unmodified coat protein from a 
virus that naturally infects plants that humans consume in toto or in 
part.
     (b) When the genetic material that encodes the pesticidal 
substance or leads to the production of the pesticidal substance has 
been modified (e.g., through internal deletions, addition of 
nucleotides from other virus coat protein genes, or substitutions 
leading to amino acid changes), residues of the PVC-protein may be 
exempt if the Agency determines, after review, that the encoded PVC-
protein has been

[[Page 19660]]

minimally modified when compared to an entire unmodified coat protein 
from a virus that naturally infects plants that humans consume in toto 
or in part.
     (c) Agency determinations made under paragraph (b) of this section 
may be made in response to a petition submitted in accordance with the 
provisions of 40 CFR part 177 or on the Agency's own initiative.

[FR Doc. E7-7296 Filed 4-17-07; 8:45 am]
BILLING CODE 6560-50-S


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