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, 19640-19660 [E7-7296]

Agencies

• ENVIRONMENTAL PROTECTION AGENCY

[Federal Register Volume 72, Number 74 (Wednesday, April 18, 2007)]
[Proposed Rules]
[Pages 19640-19660]
From the Federal Register Online via the Government Printing 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:
      Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the on-line instructions for submitting comments.
      Mail: Office of Pesticide Programs (OPP) Regulatory 
Public Docket (7502P), Environmental Protection Agency, 1200 
Pennsylvania Ave., NW., Washington, DC 20460-0001.
      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.
     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 
https://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 https://
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: kramer.melissa@epa.gov.

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this Document Apply to Me?

    You may be potentially affected by this action if you are a person 
or company involved with agricultural biotechnology that may develop 
and market PIPs. Potentially affected entities may include, but are not 
limited to:
     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.
     Food manufacturing (NAICS code 311), e.g., establishments 
primarily engaged in the manufacturing of food or feed.
     Crop production (NAICS code 111), e.g., establishments 
primarily engaged in growing crops, plants, vines, or trees and their 
seeds.
     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.
     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 https://
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 pro