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19640 Federal Register / Vol. 72, No.

74 / Wednesday, April 18, 2007 / Proposed Rules

inserted only in an inverted repeat Programs, Attention: PVCP-PIP ENVIRONMENTAL PROTECTION


orientation or lacking an initiation Exemption. Any such statement must be AGENCY
codon for protein synthesis such that no submitted at the time of a first
PVC-protein is produced in the plant. submission, if any, of information under 40 CFR Part 174
(2) The Agency determines after paragraph (d)(2) of this section for a [EPA–HQ–OPP–2006–0643; FRL–8100–5]
review that viruses that naturally infect particular PVCP-PIP. If a PVCP-PIP
the plant containing the PVCP-PIP are satisfies paragraphs (a)(1), (b)(1), and RIN 2070–AD49
unlikely to acquire the coat protein (c)(1)) of this section and §§ 174.21(b)
sequence through recombination and and (c), the developer must submit a Exemption from the Requirement of a
produce a viable virus with significantly notification to the Agency of that Tolerance under the Federal Food,
different properties than either parent determination and certify that the Drug, and Cosmetic Act for Residues
virus. PVCP-PIP qualifies for exemption under of Plant Virus Coat Proteins that are
(c) The criterion in paragraph (c) of FIFRA, i.e., that the PVCP-PIP meets Part of a Plant-Incorporated Protectant
this section is satisfied if either §§ 174.21(a), (b), and (c).This (PVC-Proteins); Supplemental
paragraph (c)(1) or paragraph (c)(2) of certification must contain: Proposal
this section applies: (i) The name of the crop (including AGENCY: Environmental Protection
(1) The genetic material that encodes genus and species) containing the Agency (EPA).
the pesticidal substance or leads to the PVCP-PIP. ACTION: Proposed rule.
production of the pesticidal substance:
(i) Is inserted only in an inverted (ii) The name of the virus from which
the coat protein gene was derived. SUMMARY: EPA is proposing to exempt
repeat orientation or lacking an from the Federal Food, Drug, and
initiation codon for protein synthesis (iii) The name of the virus(es) to
Cosmetic Act (FFDCA) section 408
such that no PVC-protein is produced in which resistance is conferred.
requirement of a tolerance, residues of
the plant, or (iv) When available, a unique coat proteins from viruses that naturally
(ii) Encodes only a single virtually identifier. infect plants that humans consume
unmodified viral coat protein. Multiple 5. By revising § 174.480 to read as when such coat proteins are produced
PVC-proteins could each separately follows: in living plants as part of a plant-
meet this criterion. Chimeric PVC- incorporated protectant (PIP) and the
proteins do not qualify. § 174.480 Scope and purpose.
criteria proposed for this exemption are
(2) The Agency determines after This subpart lists the inert ingredients met. EPA believes there is a reasonable
review that the genetic material that that may be used in a plant-incorporated certainty that no harm will result from
encodes the pesticidal substance or protectant listed in subpart B of this part aggregate exposure to such residues,
leads to the production of the pesticidal and whose residues are either exempted including all anticipated dietary
substance: from the requirement of a tolerance exposures and all other exposures for
(i) Encodes a protein that is minimally under FFDCA or no tolerance would which there is reliable information. This
modified from a coat protein from a otherwise be required. proposed exemption would eliminate
virus that naturally infects plants, or 6. By adding § 174.486 to read as the need to establish a maximum
(ii) Produces no protein. follows:
(d)(1) Records to support exemption permissible level in food for these
determinations made by the developer residues.
§ 174.486 Inert ingredients that may be
of a PVCP-PIP under paragraphs (a)(1), used with PIPs in certain plants. DATES: Comments must be received on
(b)(1), or (c)(1) of this section; to support The following must be used in a plant or before July 17, 2007.
a submission of information under that satisfies § 174.27(a) in order to be ADDRESSES: Submit your comments,
paragraphs (a)(2), (b)(2), or (c)(2) of this exempt from the requirements of FIFRA. identified by docket identification (ID)
section; or to support a certification number EPA–HQ–OPP–2006–0643, by
(a) Beta-D-glucuronidase (GUS) from
made by the developer that a PVCP-PIP one of the following methods:
Escherichia coli and the genetic material
meets § 174.21(b) and/or § 174.21(c) • Federal eRulemaking Portal: http://
necessary for its production.
must be maintained by the developer of www.regulations.gov. Follow the on-line
the product for the duration of time that (b) Neomycin phosphotransferase II instructions for submitting comments.
the PVCP-PIP is sold or distributed. (NPTII) and the genetic material • Mail: Office of Pesticide Programs
Such records must be made available for necessary for its production. (OPP) Regulatory Public Docket (7502P),
inspection and copying, or otherwise (c) Phosphomannose isomerase (PMI) Environmental Protection Agency, 1200
submitted to the Agency for review and the genetic material necessary for Pennsylvania Ave., NW., Washington,
upon request by EPA or its duly its production. DC 20460–0001.
authorized representative. (d) CP4 enolpyruvylshikimate-3- • Delivery: OPP Regulatory Public
(2) Information adequate to support phosphate (CP4 EPSPS) and the genetic Docket (7502P), Environmental
claims for an Agency-determined material necessary for its production. Protection Agency, Rm. S–4400, One
exemption must be submitted for review (e) Glyphosate oxidoreductase (GOX Potomac Yard (South Bldg.), 2777 S.
to the Office of Pesticide Programs, or GOXv247) and the genetic material Crystal Dr., Arlington, VA. Deliveries
Attention: PVCP-PIP Exemption. necessary for its production. are only accepted during the Docket’s
(3) A statement notifying the Agency (f) Phosphinothricin acetyltransferase normal hours of operation (8:30 a.m. to
and certifying the accuracy of any (PAT) and the genetic material 4 p.m., Monday through Friday,
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determination made by the developer necessary for its production. excluding legal holidays). Special
that a PVCP-PIP meets § 174.21(b), arrangements should be made for
(g) Partial tetracycline resistance gene
§ 174.21(c), paragraph (a)(1) of this deliveries of boxed information. The
under the control of a bacterial promoter
section, paragraph (b)(1) of this section, Docket Facility telephone number is
as present in papaya line 55–1.
and/or paragraph (c)(1) of this section (703) 305–5805.
must be signed by the developer and [FR Doc. E7–7297 Filed 4–17–07; 8:45 am] • Instructions: Direct your comments
submitted to the Office of Pesticide BILLING CODE 6560–50–S to docket ID number EPA–HQ–OPP–

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2006–0643. EPA’s policy is that all SUPPLEMENTARY INFORMATION: Public Docket in Rm. S–4400, One
comments received will be included in Potomac Yard (South Bldg.), 2777 S.
I. General Information
the docket without change and may be Crystal Dr., Arlington, VA. The hours of
made available on-line at http:// A. Does this Document Apply to Me? operation of this docket facility are from
www.regulations.gov, including any You may be potentially affected by 8:30 a.m. to 4 p.m., Monday through
personal information provided, unless this action if you are a person or Friday, excluding legal holidays. The
the comment includes information company involved with agricultural Docket Facility telephone number is
claimed to be Confidential Business biotechnology that may develop and (703) 305–5805.
Information (CBI) or other information market PIPs. Potentially affected entities 2. Tips for preparing your comments.
whose disclosure is restricted by statute. may include, but are not limited to: When submitting comments, remember
Do not submit information that you • Pesticide and other agricultural to:
consider to be CBI or otherwise chemical manufacturing (NAICS code i. Identify the document by docket ID
protected through regulations.gov or e- 32532), e.g., establishments primarily number and other identifying
mail. The regulations.gov website is an engaged in the formulation and information (subject heading, Federal
‘‘anonymous access’’ system, which preparation of agricultural and Register date and page number).
means EPA will not know your identity household pest control chemicals. ii. Follow directions. The Agency may
or contact information unless you • Food manufacturing (NAICS code ask you to respond to specific questions
provide it in the body of your comment. 311), e.g., establishments primarily or organize comments by referencing a
If you send an e-mail comment directly engaged in the manufacturing of food or Code of Federal Regulations (CFR) part
to EPA without going through feed. or section number.
regulations.gov, your e-mail address • Crop production (NAICS code 111), iii. Explain why you agree or disagree;
will be automatically captured and e.g., establishments primarily engaged suggest alternatives and substitute
included as part of the comment that is in growing crops, plants, vines, or trees language for your requested changes.
placed in the docket and made available and their seeds.
on the Internet. If you submit an iv. Describe any assumptions and
• Colleges, universities, and provide any technical information and/
electronic comment, EPA recommends professional schools (NAICS code
that you include your name and other or data that you used.
611310), e.g., establishments of higher
contact information in the body of your v. If you estimate potential costs or
learning which are engaged in
comment and with any disk or CD-ROM burdens, explain how you arrived at
development and marketing of virus-
you submit. If EPA cannot read your your estimate in sufficient detail to
resistant plants.
comment due to technical difficulties allow for it to be reproduced.
• Research and development in the
and cannot contact you for clarification, physical, engineering, and life sciences vi. Provide specific examples to
EPA may not be able to consider your (NAICS code 54171), e.g., illustrate your concerns and suggest
comment. Electronic files should avoid establishments primarily engaged in alternatives.
the use of special characters, any form conducting research in the physical, vii. Explain your views as clearly as
of encryption, and be free of any defects engineering, or life sciences, such as possible, avoiding the use of profanity
or viruses. agriculture and biotechnology. or personal threats.
Docket: All documents in the docket This listing is not intended to be viii. Make sure to submit your
are listed in the docket index. Although exhaustive, but rather provides a guide comments by the comment period
listed in the index, some information is for readers regarding entities likely to be deadline identified.
not publicly available, e.g., CBI or other affected by this action. Other types of
information whose disclosure is II. What Action is the Agency
entities not listed in this unit could also Proposing?
restricted by statute. Certain other be affected. The North American
material, such as copyrighted material, Industrial Classification System EPA is proposing to exempt the
is not placed on the Internet and will be (NAICS) codes have been provided to following from the FFDCA section 408
publicly available only in hard copy assist you and others in determining requirement of a tolerance: Residues of
form. Publicly available docket whether or not this action might apply coat proteins from viruses that naturally
materials are available either in the to certain entities. To determine infect plants that humans consume as
electronic docket at http:// whether you or your business may be part of a normal diet, including any
www.regulations.gov, or, if only affected by this action, you should metabolites or degradates of those coat
available in hard copy, at the OPP carefully examine the applicable proteins, when such coat proteins are
Regulatory Public Docket in Rm. S– provisions of 40 CFR part 174. If you produced in living plants as part of a
4400, One Potomac Yard (South Bldg.), have questions regarding the PIP and the criteria proposed for this
2777 S. Crystal Dr., Arlington, VA. The applicability of this action to a exemption are met. The proposed
hours of operation of this docket facility particular entity, consult the person criteria are intended to clearly identify
are from 8:30 a.m. to 4 p.m., Monday listed under FOR FURTHER INFORMATION and exempt only those residues for
through Friday, excluding legal CONTACT. which a long history of safe exposure
holidays. The Docket Facility telephone and consumption can support
number is (703) 305–5805. B. What Should I Consider as I Prepare exemption. EPA believes there is a
FOR FURTHER INFORMATION CONTACT:
My Comments for EPA? reasonable certainty that no harm will
Melissa Kramer, Hazard Assessment 1. Docket. EPA has established a result from aggregate exposure to such
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Coordination and Policy Division docket for this action under docket ID residues, including all anticipated
(7202M), Office of Science Coordination number EPA–HQ–OPP–2006–0643. dietary exposures and all other
and Policy, 1200 Pennsylvania Ave., Publicly available docket materials are exposures for which there is reliable
NW., Washington, DC 20460–0001; available either in the electronic docket information. This proposed exemption
telephone number: (202) 564–8497; fax at http://www.regulations.gov, or, if only would eliminate the need to establish a
number: (202) 564–8502; e-mail address: available in hard copy, at the Office of maximum permissible level in food for
kramer.melissa@epa.gov. Pesticide Programs (OPP) Regulatory these residues.

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III. What is the Agency’s Authority for exposure through drinking water and in As such, residues of PVCP-PIPs in or on
Taking this Action? residential settings, but does not include food (hereinafter simply ‘‘in food’’) are
EPA is proposing to establish this occupational exposure. Pursuant to subject to FFDCA section 408.
tolerance exemption on its own section 408(c)(2)(B) of FFDCA, in Since PVCP-PIPs are a relatively
initiative under sections 408(e) and (c) establishing or maintaining in effect an newly described type of pesticide, the
of FFDCA, 21 U.S.C. 346a(c) and (e). exemption from the requirement of a discussion in this unit provides
Under FFDCA section 408, EPA tolerance, EPA must take into account information explaining how this FFDCA
regulates pesticide chemical residues by the factors set forth in section proposed action on residues of the plant
establishing tolerances limiting the 408(b)(2)(C) of FFDCA, which require virus coat protein portion of a PVCP-PIP
amounts of residues that may be present EPA to give special consideration to (called here the ‘‘PVC-protein’’) would
in or on food or by establishing exposure of infants and children to the affect the FFDCA and FIFRA status of
exemptions from the requirement of a pesticide chemical residue in the complete PVCP-PIP. To this end,
tolerance for such residues. Food establishing a tolerance and to ‘‘ensure several pieces of information are
includes articles used for food or drink that there is a reasonable certainty that presented: A description of the
by humans or animals. A food no harm will result to infants and anticipated residues of PVCP-PIPs; a
containing pesticide residues may not children from aggregate exposure to the discussion of the FFDCA status, either
be moved in interstate commerce pesticide chemical residue. . . .’’ current or proposed, of all anticipated
without an appropriate tolerance or an Additionally, section 408(b)(2)(D) of PVCP-PIP residues; a discussion of what
exemption from the requirement of a FFDCA requires that the Agency would be considered in determining the
tolerance. consider ‘‘available information FFDCA status of the complete PVCP-
Section 408 of FFDCA applies to all concerning the cumulative effects of a PIP; and a discussion of how the FFDCA
‘‘pesticide chemical residues,’’ which particular pesticide’s residues’’ and status of PVCP-PIP residues relates to
are defined as residues of either a ‘‘other substances that have a common the FIFRA status of the PVCP-PIP.
‘‘pesticide chemical’’ or ‘‘any other mechanism of toxicity.’’ 1. What are the components of a PIP?
added substance that is present on or in EPA performs a number of analyses to A PIP is defined at 40 CFR 174.3 as ‘‘a
the commodity or food primarily as a determine the risks from aggregate pesticidal substance that is intended to
result of the metabolism or other exposure to pesticide residues. First, be produced and used in a living plant,
degradation of a pesticide chemical’’ (21 EPA determines the toxicity of or in the produce thereof, and the
U.S.C. 321(q)(2)). FFDCA defines pesticides. Second, EPA examines genetic material necessary for
‘‘pesticide chemical’’ as: ‘‘any substance exposure to the pesticide through food, production of such a pesticidal
that is a pesticide within the meaning of drinking water, and through other substance. It also includes any inert
the Federal Insecticide, Fungicide, and exposures that occur as a result of ingredient contained in the plant, or
Rodenticide Act, including all active pesticide use in residential settings. produce thereof.’’
and inert ingredients of such pesticide’’ Section 408(e)(1)(C) of FFDCA also 2. What are the anticipated residues
(21 U.S.C. 321(q)(1)). The Federal grants EPA the authority to establish of PVCP-PIPs? Based on the definition
Insecticide, Fungicide, and Rodenticide ‘‘general procedures and requirements of a PIP, EPA anticipates residues of a
Act (FIFRA) section 2(u) defines to implement this section’’ (21 U.S.C. PVCP-PIP would include residues of
‘‘pesticide’’ as: ‘‘(1) any substance or 346a(e)(1)(C)). any PVC-protein; the nucleic acids
mixture of substances intended for IV. Context associated with the PVCP-PIP, e.g., the
preventing, destroying, repelling, or genetic material encoding the PVC-
mitigating any pest, (2) any substance or A. What is the Relationship of this protein; and any inert ingredient as
mixture of substances intended for use Proposal to Other Regulatory defined for PIPs at 40 CFR 174.3. Each
as a plant regulator, defoliant, or Requirements under FIFRA and FFDCA? of these three classes of residues will
desiccant, and (3) any nitrogen When the genetic material that also include any metabolite and
stabilizer. . .’’ (7 U.S.C. 136(u)). Under encodes an entire or a portion of a plant degradate of that class in accordance
FIFRA section 2(t), the term ‘‘pest’’ virus coat protein is introduced into with FFDCA section 201 that defines a
includes: ‘‘(1) any insect, rodent, living plants with the intention of ‘‘pesticide chemical residue’’ as ‘‘a
nematode, fungus, weed, or (2) any preventing or mitigating viral disease in residue in or on raw agricultural
other form of terrestrial or aquatic plant the plants, the genetic material and any commodity or processed food of (A) a
or animal life or virus, bacteria, or other substances produced from the genetic pesticide chemical; or (B) any other
microorganism. . . which the material constitute a type of pesticide added substance that is present on or in
Administrator declares to be a pest. . .’’ termed a ‘‘plant virus coat protein plant- the commodity or food primarily as a
subject to certain exceptions (7 U.S.C. incorporated protectant’’ or ‘‘PVCP- result of the metabolism or other
136(t)). PIP.’’ PVCP-PIPs meet the FIFRA section degradation of a pesticide chemical’’ (21
Section 408(c)(2)(A)(i) of FFDCA 2(u) definition of ‘‘pesticide’’ because U.S.C. 321(q)(2)).
allows EPA to establish an exemption they are introduced into plants with the 3. What is the FFDCA status of each
from the requirement for a tolerance (the intention of ‘‘preventing, destroying, identified class of residues? For the
legal limit for a pesticide chemical repelling, or mitigating any pest. . .’’ (7 complete PVCP-PIP to be exempt from
residue in or on a food) only if EPA U.S.C. 136(u)) and plant viruses meet FFDCA section 408, all three classes of
determines that the exemption is ‘‘safe.’’ the FIFRA section 2 definition of ‘‘pest’’ PVCP-PIP residues listed above must be
Section 408(c)(2)(A)(ii) of FFDCA (7 U.S.C. 136(t)). PVCP-PIPs are exempt, i.e., residues of the PVC-
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defines ‘‘safe’’ to mean that ‘‘there is a considered pesticide chemicals under protein, the nucleic acids associated
reasonable certainty that no harm will FFDCA which defines a ‘‘pesticide with the PVCP-PIP, and any inert
result from aggregate exposure to the chemical’’ as ‘‘any substance that is a ingredient as defined for PIPs at 40 CFR
pesticide chemical residue, including pesticide within the meaning of the 174.3. The units below discuss the
all anticipated dietary exposures and all Federal Insecticide, Fungicide, and status of residues of the PVC-protein
other exposures for which there is Rodenticide Act, including all active under this proposed action, the status of
reliable information.’’ This includes and inert ingredients of such pesticide.’’ residues of the nucleic acids associated

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with the PVCP-PIP, and the status of adenine, thymine, guanine, cytosine, FIFRA at 40 CFR 174.21(b).) The FIFRA
residues of inert ingredients. and uracil; polymers of the deoxyribose- status of a PVCP-PIP is determined
i. Residues of PVC-proteins. Residues 5’-monophosphates of thymine, based on factors in addition to FFDCA
in this category consist of residues of cytosine, guanine, and adenine linked section 408 considerations because
the PVC-protein and any metabolites or by successive 3’-5’ phosphodiester FIFRA requires the Agency to consider
degradates of that protein. This proposal bonds (also known as deoxyribonucleic additional risk and benefit issues
would exempt from tolerance acid); and polymers of the ribose-5’- beyond those addressed under section
requirements residues of PVC-proteins monophosphates of uracil, cytosine, 408 of FFDCA. Concurrently with this
that meet certain criteria. guanine, and adenine linked by proposed FFDCA exemption, the
Coat proteins are those substances successive 3’-5’ phosphodiester bonds Agency is publishing a proposal under
that viruses produce to encapsulate and (also known as ribonucleic acid). The which PVCP-PIPs might meet the
protect the viral nucleic acid and to term does not apply to nucleic acid general qualification for FIFRA
perform other important tasks for the analogues (e.g., dideoxycytidine), or exemption at 40 CFR 174.21(a) based on
virus, e.g., assistance in viral polymers containing nucleic acid different criteria than the criteria in this
replication, movement within the plant, analogues.’’ Nucleic acids are currently proposal.
and transmission of the virus from plant exempt from FFDCA tolerance
to plant by insects (Ref. 1). Current B. What is the History of this Proposal?
requirements. See 40 CFR 174.475 and
scientific information suggests that 66 FR 37817 (July 19, 2001) (FRL–6057– 1. Scientific input. EPA sponsored (or
prevention or mitigation of disease by 5). EPA is not proposing to amend this cosponsored with other Federal
some PVCP-PIPs may be protein- exemption. agencies) six conferences relevant to
mediated because for certain PVCP-PIPs iii. Residues of any inert ingredient. development of this proposed rule: On
efficacy is correlated with the Residues in this category consist of October 19–21, 1987, a meeting on
concentration of coat protein produced residues of any inert ingredient that is ‘‘Regulatory Considerations:
by the transgene (Ref. 2). In protein- part of a PVCP-PIP and any metabolite Genetically-Engineered Plants’’ at
mediated resistance, the coat protein is or degradate of an inert ingredient. An Cornell University in Ithaca, NY; on
thought to impede the infection cycle by inert ingredient for a PIP is defined at September 8–9, 1988, a ‘‘Transgenic
interfering with the disassembly of 40 CFR 174.3 as ‘‘any substance, such as Plant Conference’’ in Annapolis, MD; on
infecting viruses (Ref. 3). In such cases, a selectable marker, other than the November 6–7, 1990, a conference on
EPA would consider the PVC-protein to active ingredient, where the substance is ‘‘Pesticidal Transgenic Plants: Product
be the pesticidal substance. Residues of used to confirm or ensure the presence Development, Risk Assessment, and
such PVC-proteins and their metabolites of the active ingredient, and includes Data Needs’’ in Annapolis, MD; on April
and degradates that meet the proposed the genetic material necessary for the 18–19, 1994, a ‘‘Conference on
criteria would be covered by this production of the substance, provided Scientific Issues Related to Potential
proposal. that genetic material is intentionally Allergenicity in Transgenic Food Crops’’
In transgenic plants employing a introduced into a living plant in in Annapolis, MD; on July 17–18, 1997,
second mechanism of resistance called addition to the active ingredient.’’ a ‘‘Plant Pesticide Workshop’’ in
post-transcriptional gene silencing A tolerance or tolerance exemption is Washington, DC; and on December 10–
(PTGS), prevention or mitigation of viral required for residues of any substance in 12, 2001, a conference on ‘‘Assessment
disease is not correlated with the level food that meets the 40 CFR 174.3 of the Allergenic Potential of
of PVC-protein expression. Indeed, virus definition of an inert ingredient (e.g., a Genetically Modified Foods’’ in Chapel
resistance can occur even when a coat selectable marker intentionally Hill, NC. Information from these
protein gene expresses untranslatable introduced into the plant as part of a conferences has been incorporated as
RNA sequences and no PVC-protein is PVCP-PIP such as a protein conferring appropriate in development of this
detected. In PTGS, RNA fragments resistance to an herbicide). Part 180 and proposed rule.
appear to be pesticidal substances (Ref. part 174, subpart W, of 40 CFR list inert EPA has requested the advice of two
3). (See Unit II.E. of the companion ingredients for which tolerance scientific advisory groups at five
document published elsewhere in this exemptions have been established. If an meetings while developing its approach
Federal Register for a more detailed inert ingredient is not listed at part 180 to PIPs. On December 18, 1992, EPA
description of PTGS.) Even when PTGS or part 174, subpart W, an applicant convened the FIFRA Scientific Advisory
is the mechanism of resistance, any would need to petition the Agency in Panel (SAP) to review a draft policy on
PVC-protein that might be produced is accordance with 40 CFR 180.7 to obtain PIPs (then called plant-pesticides) and
part of the PVCP-PIP. Residues of such a tolerance or tolerance exemption for to respond to a series of related
PVC-proteins and their metabolites and residues of that particular inert questions posed by the Agency dealing
degradates that meet the proposed ingredient in order for food containing primarily with EPA’s approach under
criteria are also covered by this residues of the PVCP-PIP to move in FIFRA. On July 13, 1993, EPA requested
proposal. interstate commerce—even if all other the advice of a Subcommittee of the
ii. Residues of nucleic acids. Residues residues of the PIP are exempt. EPA Biotechnology Science Advisory
in this category include residues of the 4. What is the relationship between Committee (BSAC) on a series of
genetic material necessary for the the FIFRA status of a PVCP-PIP and the scientific questions dealing with EPA’s
production of the pesticidal substance FFDCA status of its residues? A approach to PIPs under FFDCA. On
and the genetic material for any inert tolerance exemption does not exempt a January 21, 1994, EPA asked for advice
ingredient as defined at 40 CFR 174.3. PVCP-PIP from FIFRA regulation. on the Agency’s approach to PIPs under
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Residues in this category would also However, in order for a PVCP-PIP in both statutes at a joint meeting of the
include residues of any nucleic acids food plants to be exempted from FIFRA SAP and the BSAC. To evaluate more
effecting the pesticidal action of the regulation, a tolerance exemption must recent scientific advances, EPA again
PVCP-PIP, e.g., residues of nucleic acids exist for all residues associated with a brought these issues to the SAP on
involved in PTGS. PVCP-PIP or FFDCA requirements must October 13–14, 2004. On December 6–
‘‘Nucleic acids’’ are defined at 40 CFR be otherwise met. (See the general 8, 2005, EPA requested the SAP to
174.3 as ‘‘ribosides or deoxyribosides of qualification for exemption under respond to a series of scientific

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questions related to this proposal. EPA a. EPA’s conclusion that there are no is relying to support this proposed
carefully considered advice from all five substances outside of the food supply tolerance exemption for residues of
meetings in the development of this that may have a cumulative toxic effect PVC-proteins in food. First, virus-
proposed rule. with residues of PVC-proteins, infected plants have always been a part
2. Federal Register documents. The b. EPA’s conclusion that there are no of the human and domestic animal food
history of this proposal consists of the substances outside of the food supply to supply. Most crops are frequently
original proposed exemption that which humans might be exposed infected with plant viruses, and food
appeared in the November 23, 1994 through non-occupational routes of from these crops has been and is being
Federal Register (59 FR 60545) (FRL– exposure that are related via a common consumed without adverse human or
4755–4), a supplemental document that mechanism of toxicity to residues of animal health effects. Second, plant
appeared in the May 16, 1997 Federal PVC-proteins, viruses are not infectious to humans,
Register (62 FR 27149) (FRL–5716–6), c. Any available information on PVC- including children and infants, or to
and a supplemental document which proteins causing estrogenic effects, other mammals. Third, plant virus coat
appeared in the July 19, 2001Federal d. EPA’s rationale, described in proteins, while widespread in food,
Register (66 FR 37855) (FRL–6760–4). greater detail, for concluding that PIPs have not been associated with toxic or
i. November 23, 1994. EPA published are likely to present a limited exposure allergenic effects to animals or humans.
a package of five separate documents in of pesticidal substances to humans in These conclusions are derived from a
the November 23, 1994 Federal Register which the predominant, if not the only, base of experience and information
which described EPA’s policy and route of exposure will be dietary, and sufficient to support this proposed
proposals for PIPs under FIFRA and e. EPA’s rationale, described in tolerance exemption.
FFDCA (59 FR 60496, 60519, 60535, greater detail, for concluding that the 1. Always been part of food supply
60542, and 60545). In one of these Agency’s analysis concerning the without adverse effects. Virus-infected
documents (59 FR 60545), EPA dietary safety of food containing PVC- food plants have always been a part of
proposed to exempt from the proteins applies to infants and children the human and domestic animal food
requirement of a tolerance, residues of as well as adults. supply (Refs. 5, 6, 7, 8, 9, and 10). Most
iii. July 19, 2001. In July of 2001, EPA plants are infected by at least one virus,
plant virus coat proteins produced and
published a supplemental document in and components of plant viruses,
used in living plants as a plant-
the Federal Register (66 FR 37855) to including coat proteins, are often found
incorporated protectant (then called a
provide the public with additional in the produce of crop plants. For
plant-pesticide). The proposed
opportunity to comment on the FIFRA example, at the beginning of this
exemption from the requirement of a
and FFDCA exemptions for PIPs that the century virtually every commercial
tolerance read as follows:
Agency proposed in 1994 but had not cultivar of potatoes grown in the United
‘‘Residues of coat proteins from plant yet finalized by 2001. EPA also States and Europe was infected with
viruses, or segments of the coat proteins, requested comment on the information, either one or a complex of potato
produced in living plants as plant- analyses, and conclusions pertaining to viruses (Ref. 10). Even plants that show
pesticides are exempt from the PVCP-PIPs contained in the NRC report no disease symptoms are often found to
requirement of a tolerance’’ (59 FR entitled ‘‘Genetically Modified Pest- be infected with viruses (Refs. 9 and 11).
60547). Protected Plants: Science and In addition, a common agricultural
ii. May 16, 1997. In August of 1996, Regulation’’ (Ref. 4). In addition, the practice used since the 1920s for
Congress enacted the Food Quality public was given an opportunity to protection against viral disease involves
Protection Act (FQPA), which amended comment on a clarification of the intentionally inoculating healthy plants
FFDCA and FIFRA. On May 16, 1997, language in the original 1994 proposal with a mild form of a virus in order to
EPA published a supplemental on PVCP-PIPs that EPA was considering prevent infection by a more virulent
document in the Federal Register (62 in response to public comment. The form (Ref. 11). A recent analysis of viral
FR 27149) to provide the public with an purpose of the clarification was to sequences isolated from fecal samples of
opportunity to comment on EPA’s circumscribe more clearly those healthy humans showed the presence of
analysis of how certain FQPA residues proposed for exemption. large quantities of plant pathogenic
amendments to FFDCA and FIFRA The documents, including associated viruses from 35 different plant virus
apply to the proposed exemption from public comments, and the reports of the species with evidence suggesting dietary
the requirement of a tolerance for meetings described above are available origins for the most prevalent (Ref. 12).
residues of PVC-proteins. in the public dockets established for A great deal of information supports the
In that supplemental document, EPA each of the associated rulemakings as ubiquitous appearance of plant viruses
explained how most of the substantive described in Unit XII.B. in foods, and to date there have been no
factors that the amended FFDCA This proposed rule completely reports of adverse human or animal
requires EPA to consider in evaluating supersedes these previous proposals. health effects associated with
pesticide chemical residues had been EPA does not intend to respond to consumption of plant viruses in food.
considered in the Agency’s 1994 comments submitted on those The National Research Council (NRC)
proposed tolerance exemption. Even proposals. Thus, individuals who observed in its 2000 report that
though the Agency may not have used believe that any comments submitted on ‘‘[h]uman or animal consumption of
the terminology specified in FQPA, EPA any of the earlier proposals remain plants with viral coat proteins is widely
did take into account most of the same germane to this proposal should submit considered to be safe, on the basis of
factors in issuing its 1994 proposal to them (or relevant portions) again during common exposure to these types of
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exempt residues of PVC-proteins, or this comment period. proteins in nontransgenic types of food’’
segments of such proteins, from FFDCA (Ref. 4). The FIFRA SAP addressed the
tolerance requirements. EPA therefore C. Rationale Supporting the Proposed issue of dietary risk at its December 18,
sought comment on the requirements FFDCA Tolerance Exemption 1992 meeting (Ref. 13). The SAP stated,
imposed by FQPA that the Agency had EPA’s base of experience with viruses ‘‘Since viruses are ubiquitous in the
not addressed in its 1994 proposal, infecting food plants has led the Agency agricultural environment at levels
specifically: to draw three conclusions on which it higher than will be present in transgenic

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plants, and there has been a long history cellular machinery. Plant viruses plant virus coat protein in the
of ‘contamination’ of the food supply by therefore do not and cannot infect environment where PVCP-PIPs are
virus coat protein, there is scientific mammals and other vertebrates. In deployed.
rationale for exempting transgenic addition, multiple virus components in
D. Key Issue: Determination of Natural
plants expressing virus coat protein addition to the coat protein have a role Virus Variation
from the requirement of a tolerance.’’ in and are necessary for plant infection.
The FIFRA SAP again discussed PVC- Plant viral coat proteins alone are not A key issue facing EPA in developing
proteins on October 11–13, 2004, and infectious to plants, and whole, intact this exemption is how to clearly
‘‘agreed that (because of the human plant viruses are not infectious to describe for regulatory purposes those
history of consuming virus infected humans. Therefore, it is reasonable to PVC-proteins that are within the range
food), unaltered PVCPs do not present assume that a single component of plant of naturally occurring plant virus coat
new dietary exposures’’ (Ref. 14). The viruses, e.g., the PVC-protein, will not proteins and to which the rationale
2005 SAP also agreed that be infectious to humans. discussed in Unit IV.C. therefore
‘‘[h]istorically, virus infected plants applies. If a plant virus coat protein
3. No toxic or allergenic effects to
have been a part of the human and gene is isolated in nature and not
animals or humans. Humans and
domestic animal food supply without modified, the PVC-protein would
domestic animals have been and are
adverse human or animal health effects’’ clearly be within the range of natural
exposed to plant viruses in the food
(Ref. 15). variation. However, many coat protein
supply because most crops are genes are modified in creating a PVCP-
In general, EPA anticipates that frequently infected with plant viruses.
dietary exposure through human and PIP, e.g., to increase product efficacy or
Food from these crops has been and is allow appropriate expression in the
animal consumption of plants
being consumed with no indication of plant. Some of these modifications may
containing residues of PVC-proteins that
human or animal toxicity related to affect a PVC-protein, although most of
would qualify for the proposed
plant virus infections. Additionally, in these variations would not be expected
exemption will be similar to or less than
experiments where purified plant virus to differ significantly (e.g., in terms of
the dietary exposure to plant virus coat
preparations have been injected into toxicity or allergenicity) from the
proteins currently found in food plants
laboratory animals, no adverse effects naturally occurring coat protein. In fact,
naturally infected with viruses.
have been reported (Ref. 17). given the considerable variation in
Experiments have shown the amount of
Furthermore, the Agency is not aware of naturally occurring viral coat proteins, it
PVC-protein found in plants containing
a PVCP-PIP to be as much as one any coat protein from a virus that is also possible that naturally occurring
hundred- to one thousand-fold lower naturally infects plants that has been plant viruses exist with some of the
than the amount of plant virus coat identified as a food allergen for humans. minor modifications that could
protein found naturally in virus-infected Finally, the amount of PVC-protein conceivably be introduced into PVC-
plants, even when the resistance is likely to be found in food is anticipated proteins.
believed to be mediated by the PVC- to generally be lower than the amount However, EPA’s task of defining this
protein itself (Refs. 8 and 16). The of virus coat protein found in food variation is complicated by the variable
difference in amount of PVC-protein naturally infected with plant viruses (as nature of plant virus genomes and the
present is even more marked for virus- discussed in Unit IV.C.1.).The 2005 SAP fact that the full extent of variation for
resistant plants employing resistance questioned whether an increased even a single plant virus is currently
mediated by RNA. In such cases, little propensity for allergies in humans unknown. Sequencing of plant virus
to no detectable coat protein is affects the relevance of the history of genomes has revealed that a large
produced in a plant containing a PVCP- safe use to the current safety of virus number of variants exist within most
PIP (Refs. 3 and 17). Such information coat proteins. Several studies have populations of both RNA and DNA
conforms to information EPA has documented a general increase in atopy viruses. Due to this inherent
received from the scientific advisory in human populations; these studies heterogeneity in virus populations, they
groups the Agency has consulted (see show that over the last several decades are often described as ‘‘quasispecies’’
Unit IV.B.1.). Although the Agency there has been an increasing proportion that exist as a pool of different
believes that the PVC-proteins which of human populations that have an sequences varying around a consensus
qualify for this proposed tolerance allergic sensitization to particular sequence (Refs. 23, 24, and 25).
exemption are safe at any level given the allergens (Refs. 20, 21, and 22). Genetic variation in virus populations
long history of human dietary exposure However, there is no reason to believe arises due to several processes including
to high levels of such proteins, the that PVC-proteins in the environment mutation, recombination, and
anticipated low levels of exposure to would have any impact on this reassortment. Mutation is a change in
PVC-proteins in food lend additional phenomenon. EPA is aware of no the genetic material that most
support to this proposed exemption. evidence that previously nonallergenic commonly occurs when replication
2. Not infectious to humans. Any substances are now able to elicit an errors lead to incorporation of an
virus/host relationship is characterized immune response, and no plant virus incorrect nucleotide into the daughter
by a high degree of specificity (Ref. 8). coat proteins have ever been identified sequence (Ref. 26). New virus variants
Plant viruses usually infect plants only as allergens. Moreover, the amount of are also generated by recombination, the
within a certain taxonomic group and plant virus coat protein in the natural process that occurs during
are unable to infect humans or other environment is not expected to increase replication of DNA or RNA whereby
vertebrates (Refs. 18 and 19). Cellular due to the use of PVCP-PIPs. On the new combinations of genes are
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machinery for processing genetic contrary, PVCP-PIPs generally express produced. Recombination is more likely
material is highly specific. For example, PVC-protein at levels below that found to occur the more closely related viruses
plant viruses are unable to recognize in natural virus infections, and the are, but recombination between
and attach to the specific sites on virus-resistant phenotype conferred by different viral species is also believed to
mammalian cells needed to penetrate PVCP-PIPs should significantly reduce occur (Refs. 27 and 28). Evidence of past
the cell membrane, and plant viruses levels of natural virus infection in recombination having led to the creation
cannot be processed by mammalian plants, thereby decreasing the amount of of new DNA and RNA viruses has been

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found in a number of different groups natural variability of plant virus coat (except as described below by the
including bromoviruses (Ref. 29), proteins found in virus populations definition of virtually unmodified), as
caulimoviruses (Ref. 30), luteoviruses either generally or for any species in well as chimeric PVC-proteins that are
(Ref. 31), nepoviruses (Ref. 32), particular. In light of this, and relying encoded by a sequence constructed by
cucumoviruses (Ref. 33), and extensively on the advice of the 2005 fusing portions of two or more plant
geminiviruses (Refs. 27 and 34). FIFRA SAP meeting (Ref. 15), EPA has virus coat protein genes. EPA is
Sequence analysis of viruses from the developed two proposals to exempt proposing to exclude such PVC-proteins
family Luteoviridae indicated that this PVC-protein residues from the from the categorical exemption because
family has evolved via both intra- and requirement of a tolerance: of advice from the 2005 SAP that
inter-familial recombination (Ref. 35). In 1. A categorical exemption for a insufficient information exists at this
viruses with segmented genomes, subset of PVC-proteins based on time to allow EPA to describe a priori
variation may also be caused by developer self-determination that the a single standard articulating which of
reassortment whereby entire segments encoded PVC-protein is virtually these types of changes would be
are exchanged between viruses (Ref. 36). unmodified when compared to an entire consistently expected to fall within the
Attempts to describe the range of unmodified coat protein from a virus natural range of variation of viruses
variation for naturally occurring plant that naturally infects plants that humans and/or which types of changes could be
virus coat proteins are complicated not consume in toto or in part, and determined not to affect toxicity or
only by variation within species but also 2. An exemption for more extensively allergenicity without any EPA review
by variation among species (See Ref. 37 modified proteins that is conditional on (see Unit IV.D.).
for review). For example, cucumber an Agency determination after review
The Agency proposes to define the
mosaic cucumovirus (CMV) has a that the encoded PVC-protein is
term ‘‘unmodified’’ to mean, ‘‘having or
relatively high degree of variation (Ref. minimally modified when compared to
an unmodified coat protein from a virus coding for an amino acid sequence that
38) compared to tobacco mild green
that naturally infects plants that humans is identical to an entire coat protein of
mosaic tobamovirus (Ref. 39). The
consume in toto or in part. a naturally occurring plant virus.’’ The
greater variability in CMV would be
Agency is considering several options
expected based on the relatively wide E. Structure of the Proposed FFDCA for defining the term virtually
host range and relatively high Tolerance Exemption unmodified. Under this proposal, any
recombination rate of this virus. Such
1. Proposed categorical exemption. virtually unmodified PVC-protein
wide-ranging, inherent variability
confounds attempts to establish Under the proposed exemption at would qualify for a tolerance exemption
meaningful estimates of normal § 174.477(a), when the encoded PVC- without Agency review. Under one
variability for coat proteins of plant protein is virtually unmodified when option, this term would mean, ‘‘having
viruses as a group. compared to an entire unmodified coat or coding for an amino acid sequence
A large number of viral coat protein protein from a virus that naturally that is identical to an entire coat protein
sequences are currently available in the infects plants that humans consume in of a naturally occurring plant virus,
literature and in public sequence toto or in part, the residues of the PVC- except for the addition of one or two
repositories, e.g., the National Center for protein would be exempt from the amino acids at the N- and/or C-terminus
Biotechnology Information. However, requirement of a tolerance without other than cysteine, asparagine, serine,
EPA has concluded that no single Agency review. If the PVC-protein is and threonine and/or the deletion of one
standard could capture the degree of expressed from a plant virus coat or two amino acids at the N- and/or C-
variation across all viruses, and protein gene that was isolated from a terminus.’’ As noted by the 2005 SAP,
hundreds of plant viruses have been virus found naturally in a food plant in the terminal ends of a protein ‘‘are the
identified to date (Ref. 40). It would be the United States and was not modified, least structurally constrained regions of
at best impractical for EPA to describe the PVC-protein would meet this a protein. As such, the ends can be
individually for all virus groups all criterion. Additionally, a PVC-protein thought of as being essentially
potential modifications that would would meet this criterion if the ‘unstructured,’ and therefore unlikely to
produce a PVC-protein that falls within developer has evidence showing it has serve as allergenic epitopes or to make
the range of natural variation given the an amino acid sequence that is virtually major contributions to the overall
vast (and yet still incomplete) amount of unmodified when compared to an structure of the molecule. Addition (or
data that currently exists. The 2005 SAP unmodified plant virus coat protein deletion) of one or two amino acids is
concurred with these conclusions: sequence from a virus that naturally unlikely to change this.’’ However, the
‘‘Currently, it is extremely difficult to infects plants that humans consume, SAP also noted the possibility that the
identify modifications that would be e.g., as found in a database. Although addition of amino acids such as cysteine
expected to be ‘within the range of EPA cannot a priori identify all existing with side chains that could promote
natural variation for all virus families’. natural coat protein variants, the cross-linking or aggregation between
This would require prior knowledge of requirement of being virtually molecules or other amino acids that can
the natural variation limits of the unmodified when compared to an entire serve as sites for post-translational
individual PVC proteins, which is not unmodified coat protein ensures that modifications should be evaluated on a
available. Specific modifications can be the exempted PVC-protein falls within case-by-case basis (Ref. 15). EPA has
identified that would raise potential the existing base of experience on which identified cysteine, asparagine, serine,
concerns, but it is not clear that it is the proposed exemption relies. and threonine as the amino acids
possible to create a comprehensive list EPA intends, with the requirement containing side chains that could
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of these changes for all virus families’’ that the PVC-protein be virtually promote cross-linking or serve as sites
(Ref. 15). unmodified when compared to ‘‘an for post-translational modifications.
At the present time, insufficient entire unmodified coat protein,’’ to EPA therefore excludes the addition of
information exists to develop a standard exclude from the categorical exemption these amino acids from the proposed
that would describe a priori the degree residues of modified PVC-proteins, e.g., definition of virtually unmodified. The
to which a PVC-protein could be PVC-proteins containing insertions, 2005 SAP report mentioned alanine as
modified and yet still remain within the deletions, or amino acid substitutions an amino acid involved in

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

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

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almost certain that all viral gene currently feasible because the Agency appropriate in evaluating individual
products are expressed at higher levels knows of no generally applicable, exemption petitions to determine
in virus-infected than transgenic plants’’ established baseline for what constitutes whether a protein is minimally
(Ref. 15). the range of natural variation of a virus. modified.
2. Proposed exemption conditional on EPA thus does not believe that Regarding the 2005 SAP suggestion
Agency determination. The Agency proposing an exemption that would that EPA might wish to consider
recognizes that product developers allow developers to self-determine expression levels in determining
frequently modify the genetic material eligibility of modified PVC-proteins whether to exempt a PVC-protein from
of a PVCP-PIP, e.g., in order to achieve would be supportable. Rather, EPA is tolerance requirements, the Agency
greater efficacy (Ref. 50) and that most proposing that under proposed believes that such an evaluation is not
of these changes would be unlikely to § 174.477(b), the residues of such a PVC- necessary to determine whether a PVC-
result in proteins affecting potential protein would be exempt only if the protein is minimally modified. EPA
dietary risk. However, the Agency Agency determines after review that the would necessarily have to find such
cannot at this time articulate a criterion encoded PVC-protein is minimally proteins to be similar to a natural viral
that would ensure all PVC-proteins with modified when compared to an coat protein in order for them to qualify
such modifications fall within the base unmodified coat protein from a virus for this proposed exemption. EPA
of experience supporting the proposed that naturally infects plants that humans believes that minimally modified PVC-
exemption. consume in toto or in part. proteins are safe at any level for the
The question of how to objectively In determining whether a PVC-protein same reasons discussed above for
define criteria on which the regulated is minimally modified from a natural virtually unmodified proteins (Unit
community may rely to determine a viral coat protein, EPA will consider IV.E.1.). In both cases, the hazard
priori how much a virus coat protein first how similar the PVC-protein is to associated with PVC-proteins qualifying
may be modified and still fall within the a natural viral coat protein by evaluating for this proposed tolerance exemption is
range of natural variation is a key information on the PVCP-PIP genetic sufficiently low that it does not rise to
challenge. EPA first considered the construct, PVC-protein deduced amino the level warranting regulation, even if
question of how to describe residues acid sequence, and biochemical in some cases exposure to a PVC-protein
that fall within the base of experience characterization of the PVC-protein as might be greater than the exposure to
supporting exemption when the Agency expressed in the plant (e.g., molecular the corresponding natural plant virus
issued its proposal on November 23, weight to evaluate potential post- coat protein. (However, see Unit XI. for
1994 (59 FR 60539). In the July 19, 2001 translational modifications). EPA might a discussion of how exposure level
supplemental notice (66 FR 37865), EPA also evaluate developer-submitted could possibly be considered under the
again addressed the question of how to analyses that characterize the PVC- proposed exemption structure when
describe PVCP-PIPs that fall within the protein sequence relative to the range of reviewing minimally modified
recognized base of experience natural coat protein variation found in proteins.)
supporting the proposed categorical public sequence databases. Those PVC- Under proposed § 174.477(b), the
exemption. proteins determined to be similar to a procedures for obtaining a
In October 2004, the FIFRA SAP was natural viral coat protein would be determination that a PVC-protein fits
asked to consider the degree and ways further evaluated to determine whether under the tolerance exemption would be
a plant virus coat protein gene might be the modified PVC-protein is as safe as no different than those currently
modified while still retaining scientific an unmodified protein by considering provided under the statute for obtaining
support for the idea that humans have information from an amino acid a tolerance exemption. A person can file
consumed the products of such genes sequence comparison with known a submission requesting a determination
for generations and that such products protein toxins and allergens. The type (21 U.S.C. 346a(d)) of whether a
therefore present no new dietary and extent of information that would particular PVC-protein fits under the
exposures (Ref. 14). They responded, need to be provided in order for EPA to tolerance exemption, or the Agency can
‘‘There was no clear consensus on how determine whether a PVC-protein is initiate an action to issue a
much change would be necessary to minimally modified and therefore determination (21 U.S.C. 346a(e)). After
invalidate this assumption, although qualifies for the exemption would be a person files a submission under
there was general agreement that the determined on a case-by-case basis. FFDCA section 408(d)(1) proposing that
appropriate comparison is to the range The 2005 SAP identified certain a particular PVC-protein falls under this
of natural variation in the virus modifications that might raise potential exemption because it is minimally
population.’’ The 2005 SAP also concerns when considering if a protein modified from a natural plant virus coat
addressed this question. They concurred is minimally modified, including ‘‘the protein, FFDCA section 408(d)(3)
that, ‘‘it is extremely difficult to identify addition or removal of protease requires that the Administrator
modifications that would be expected to recognition sites, the addition or determine whether a petition meets the
be ‘within the range of natural variation removal of cysteine residues involved in requirements of the statute and publish
for all virus families’. . . . Given the internal cross-links, the addition or a summary of the petition and other
possible range of natural variations for removal of proline residues that act as required information in the Federal
PVC proteins, it would be appropriate to secondary structure ‘break points,’ and Register within 30 days of making that
assess whether specific modifications the addition or removal of asparagines determination. Alternatively, the
are within natural variation limits of the and alanines involved in glycosylation’’ Administrator may publish a notice of
PVC protein on a case-by-case basis’’ (Ref. 37). By contrast, the report proposed rulemaking and provide a
hsrobinson on PROD1PC76 with PROPOSALS2

(Ref. 15). identified ‘‘[m]odifications such as period of generally not less than 60 days
EPA believes that developing single amino acid substitutions with for public comment. In either case, EPA
objectively defined criteria on which the biochemically similar amino acids that will publish any final rule exempting a
regulated community could rely to do not affect secondary or tertiary PVC-protein from the requirement of a
determine whether a modified PVC- structure’’ as potentially being of tolerance in the Federal Register and
protein falls within the natural range of relatively little concern (Ref. 37). EPA allow 60 days for any person to file
variation for a particular virus is not would consider this guidance as objections thereto (21 U.S.C. 346a(g)(2)).

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Currently no fees would be associated some point after commercialization plant tissue in which gene silencing
with either the proposed categorical even though PVC-protein may not have does not occur showed normal levels of
exemption under § 174.477(a) or the been detected and/or produced during transgene mRNA, and transgenic protein
Agency’s determination under proposed product development. For example, it is was produced.
§ 174.477(b) that a particular PVC- known that in some cases PTGS must be It has been shown that PTGS can be
protein fits under the tolerance triggered before transgene RNA suppressed by viruses that encode
exemption. production can be effectively certain suppressor proteins leading to
For residues of a PVC-protein that suppressed. Lindbo et al. (Ref. 51) used loss of the virus-resistant phenotype
would not qualify for this proposed tobacco etch virus (TEV) to infect conferred by a PVCP-PIP. For example,
exemption under either § 174.477(a) or transgenic tobacco plants containing a Savenkov and Valkonen (Ref. 55)
(b) because the Agency cannot TEV coat protein gene. Plants showed that resistance to Potato virus A
determine that the encoded PVC-protein temporarily developed symptoms but (PVA) in Nicotiana benthiana could be
is minimally modified from an were able to recover from infection. overcome when plants were challenged
unmodified coat protein from a virus Recovered transgenic plant tissue with Potato virus Y (PVY). Although
that naturally infects food plants, an showed significantly reduced levels of levels of transgene mRNA in healthy
applicant may petition the Agency for transgene mRNA, and PVC-protein was transgenic plants were extremely low or
an individual tolerance exemption undetectable. However, plant tissues below the detection limit, transgene
under FFDCA section 408 (see also 40 unchallenged with virus did express mRNA was readily detectable in PVY-
CFR 180.7). PVC-protein, suggesting that in at least infected plants where suppression of
some cases of PTGS-induced virus gene silencing had apparently occurred.
F. Tolerance Issues Associated with
resistance, PVC-protein may be The study did not report whether PVC-
Unintended Protein Production when
produced until virus infection occurs. protein was produced from the
Virus Resistance is Mediated through
Béclin et al. (Ref. 52) showed that in transgene mRNA.
Post-Transcriptional Gene Silencing The 2005 SAP was asked to comment
transgenic tobacco lines expressing a b-
Section 408 of the FFDCA does not glucuronidase (uidA) transgene, on issues associated with protein
require a tolerance or tolerance suppression of transgene expression production in the case of plants
exemption if residues will not be always occurs but is initiated at containing a PVCP-PIP that confers
present in food moving in interstate different plant developmental stages: resistance through an RNA-mediated
commerce. However, with the exception Either 15 days after germination or 2 mechanism. The Panel responded that
of residues that meet the requirements months post-germination. Prior to PTGS ‘‘[g]iven the wide variety of conditions
proposed at § 174.477(a), the mere fact initiation, transgenic protein is that can modulate the transition from
that a developer may not detect residues expressed, suggesting that in at least PTGS to no PTGS for non-[inverted
during product development will not some cases lack of protein production repeat (IR)] transgenes. . .it is likely that
protect the food from seizure if residues may only occur after a certain a non-IR transgene insertion that retains
are subsequently found following developmental stage is reached. an initiation codon for protein synthesis
commercialization, either because Likewise, Pang et al. (Ref. 53) found that will make at least a low level of protein
detection techniques improve or plant developmental stage plays an in at least some plant tissues over the
because the protein is unexpectedly important role in the timing of PTGS course of its development, especially in
produced. If such an event occurs and initiation. the field where there is exposure to
no tolerance exemption exists for Experiments demonstrating that plant environmental extremes and virus
residues of that PVC-protein (regardless developmental stage determines PTGS infections. Thus, these PVCP-PIP plants
of its safety), any food containing the initiation suggest that any may accumulate virus-derived mRNA
PVC-protein residues would be environmental factors influencing plant and proteins in these situations’’ (Ref.
adulterated and subject to seizure. In growth would also affect the amount of 15). EPA notes that the Panel further
addition, any FIFRA exemption that time before RNA and protein production concluded that ‘‘[b]ecause of low levels
may have been applicable for the PVCP- is effectively suppressed. At least one of accumulation and sequence identity
PIP would no longer be valid because 40 experiment has looked more directly at to the natural viral pathotypes. . .these
CFR 174.21(b) would no longer be the influence of environmental factors PVCP-PIPs pose similarly low risks’’ as
satisfied. Any sale or distribution of on PTGS. Szittya et al. (Ref. 54) PVCP-PIPs that produce no protein (Ref.
such a PVCP-PIP would constitute sale demonstrated that cold temperatures 15). However, any PVC-protein residue
and distribution of an unregistered inhibited transgene-induced RNA in food that is not covered by a
pesticide, in violation of FIFRA section silencing leading to increased levels of tolerance or tolerance exemption would
12(a)(1). transgene mRNA, although they did not constitute an adulterant of the food
The 2005 SAP suggested that the report on the level of transgenic protein. supply irrespective of the protein’s
construction of certain PVCP-PIPs may In addition to temporal changes in safety or the level at which it is
offer a reasonable level of assurance that protein production that may be detected.
PVC-protein production would not influenced by varying environmental The above considerations suggest that
occur, i.e., transgene insertions where conditions, PTGS may also be many factors should be considered in
the transcribed segment lacks an associated with variation in protein making a determination of whether
initiator codon or insertions of expression across different plant tissues. residues of a PVC-protein will be
transcribed inverted repeat constructs Plant lines expressing a nitrate present in food derived from a crop
that constitutively produce transcripts reductase transgene were found to containing a PVCP-PIP. Due to the
hsrobinson on PROD1PC76 with PROPOSALS2

that are folded into double-stranded display PTGS in leaves and stem tissue serious consequences of having an
RNA as the immediate product of but not in shoot apical or axillary unapproved residue in the food supply
transgene transcription (Ref. 15). meristems (Ref. 52). As in other (as discussed earlier in this unit), EPA
However, for other types of constructs, experiments (Ref. 51), transgene protein strongly recommends that developers
questions remain about circumstances was not detectable and transgene mRNA consult with the Agency before
under which PVC-protein might be levels were significantly reduced in determining that no tolerance or
detected and/or produced in food at plant tissue displaying PTGS. However, tolerance exemption for the PVC-protein

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would be necessary based solely on the residues of the PVC-protein, that food tests for protein detection are ELISA and
premise that no residues of the protein would be adulterated and subject to immunoblot (‘Western’ blot) analyses
are anticipated to be present. EPA seizure unless and until EPA could with specific antibodies. Triplicate
expects that the Agency would conclude make a determination that the PVC- experiments should be sufficient to
no PVC-protein tolerance exemption protein is minimally modified and is determine that the results of these tests
would be necessary for insertion events therefore covered by this proposed are reproducible’’ (Ref. 15). Given that
where the transgene either lacks an tolerance exemption. FFDCA does not require a developer to
initiation codon for protein synthesis or Any adulterant in the food supply demonstrate that no tolerance
is inserted in an inverted-repeat would likely cause public concern and exemption is necessary, EPA would
orientation, provided that evidence is great expense—whether or not the PVC- require such testing as a condition of
given to the Agency to verify the protein were subsequently determined either registering or exempting the
characteristics of the insertion event. to be safe. The Agency also notes that PVCP-PIP under FIFRA.
For such constructs, the 2005 SAP these costs are not necessarily borne by If the developer detects a PVC-protein
indicated the PVCP-PIP ‘‘could be safely the product developer, but rather may during the course of investigating
determined to have no [PVC-protein] disproportionately affect farmers and/or potential PVC-protein production, e.g.,
expression regardless of plant tissue, food producers because any adulterated through challenge with a suppressor
developmental stage, environmental food would be subject to seizure or protein, this protein would only be
conditions, or exposure to virally- recall. The Agency is considering this covered under the proposed categorical
encoded suppressors of PTGS’’ (Ref. 15). tolerance exemption, i.e., without any
approach under the assumption that the
For all other types of PVCP-PIP Agency action, if the protein falls within
absence of detectable protein using
insertion events, EPA is considering the definition of a virtually unmodified
rigorous testing could give reasonable
several approaches under FFDCA for PVC-protein. Therefore, unless the
assurance that PVC-protein residues
PVC-proteins that are not readily protein is virtually unmodified from a
would not be found in food and
detectable, but which the SAP indicated natural plant virus coat protein, EPA
therefore a tolerance determination
would likely be produced under some would expect a developer to provide the
would be unnecessary to prevent
circumstances (Ref. 15), some of which Agency with information for a
adulteration of the food supply. EPA
might result in the PVC-protein being in determination of whether the PVC-
would expect developers to provide the
food. EPA does not currently have a protein qualifies as minimally modified
Agency with data acquired during
preferred approach and presents several and meets the proposed conditional
options to promote full consideration of product development that demonstrates tolerance exemption. (See Unit IV.E.2.
the issues. These options are not no PVC-protein residues in food would for a discussion of the factors EPA
necessarily mutually exclusive, and the be reasonably anticipated during the intends to consider in making this
approach pursued may vary depending commercial life of the PVCP-PIP. For determination.)
on the characteristics of the PVCP-PIP example, such data could be obtained When possible, EPA would expect to
under consideration. The discussion by testing for protein and/or mRNA see biochemical characterization of the
below relates only to proteins that EPA production in all plant tissues and all PVC-protein. However, EPA recognizes
review would determine to be developmental stages that are harvested that such characterization may be
minimally modified, i.e., proteins that for food production under a variety of difficult or even impossible in some
are similar, but not identical to natural circumstances and environmental cases. For example, when only very low
plant virus coat proteins. Virtually conditions representative of those that levels of protein are produced, it may be
unmodified PVC-proteins would be the plant may experience during its difficult to obtain sufficient amounts of
covered under the proposed tolerance commercial cultivation. Challenge with protein for biochemical
exemption without any Agency action. a known PTGS suppressor protein characterization. In addition, EPA
The discussion is not relevant to introduced by a replicating virus vector, recognizes the cost and burden of
proteins that would not be able to genetic crosses, or agro-infiltration (Ref. producing sufficient protein for such
qualify under this proposal as either 56) may also in some cases be a characterization may not be warranted
virtually unmodified or minimally sufficient and less burdensome for PVC-proteins given that an
modified because the proposed technique to show that no PVC-protein evaluation based on the construct
tolerance exemption would not cover is able to be translated from the PVCP- sequence alone could consider most of
such proteins regardless of how EPA PIP. The potential to elicit protein the issues EPA intends to evaluate when
implements the exemption. production from silenced transgenes has determining whether a PVC-protein is
Under one approach, when no PVC- been shown by studies investigating minimally modified (see Unit IV.E.2.).
protein is detected during product whether particular proteins are able to EPA is therefore also considering a
development, EPA would not issue a suppress such silencing (Ref. 56). The second approach to addressing PVC-
determination of whether the PVC- 2005 SAP discussed such a technique, proteins that are not detected during
protein is minimally modified (and indicating that ‘‘[t]o determine if PTGS- product development but whose
therefore falls under this proposed based PVCP-PIP plants have the presence as residues in food cannot be
tolerance exemption). Section 408 of potential to produce proteins, the most ruled out for the commercial life of the
FFDCA does not require a tolerance or effective test is to use viral suppression PVCP-PIP. Under this approach, EPA
tolerance exemption for foods that do of PTGS. In this type of assay, the PVCP- would evaluate the PVC-protein to
not bear any residues, and such an PIP plants are infected with viruses determine whether it qualifies as
approach would be consistent with from the potyvirus, cucumovirus, and minimally modified from a natural plant
hsrobinson on PROD1PC76 with PROPOSALS2

current EPA practice regarding chemical tombusvirus genera. These viruses virus coat protein and is thus eligible for
pesticide residues in that tolerance encode different classes of PTGS this proposed tolerance exemption
determinations are not generally issued suppressor proteins. . . Protein and RNA based only on its amino acid sequence
for substances when residue studies are then extracted from the infected as deduced from the sequence of the
demonstrate that detectable residues plant tissue and assayed for the inserted gene. EPA notes the advice of
will not be present in food. However, if presence of the PVCP-PIP accumulated the 2005 SAP that ‘‘[i]t is critical to
food is subsequently found bearing full-length RNA and protein. Standard evaluate the protein as expressed in the

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host, including factors such as post- ‘‘pose similarly low risks’’ as those that consuming food containing coat
translational modifications’’ (Ref. 15). would have no protein expression under proteins from viruses that naturally
Nevertheless, EPA considers evaluating any circumstances (Ref. 15), giving infect plants with knowledge of plant
the protein as expressed in the host to scientific support for this option. genetics, plant physiology,
be less important for minimally However, the Agency notes that this phytopathology, microbial ecology,
modified PVC-proteins than for many advice is not entirely consistent with ecology, biochemistry, and plant
other types of proteins. A PVC-protein advice regarding PVC-protein safety breeding to evaluate the potential risks
would not be expected to have received by the Panel. For one, both the of the residues of PVC-proteins
significantly different post-translational 2004 and 2005 SAPs were unable to qualifying for this proposed exemption.
modifications than a plant virus coat endorse a tolerance exemption for PVC- EPA considered the nature of any
protein produced in a virus-infected proteins other than those that are toxic effects that might be caused by
plant. Because plant viruses replicate in virtually unmodified from a natural residues of PVC-proteins proposed for
plant cells as part of their normal life plant virus coat protein unless the exemption. As mentioned above, coat
cycle, any post-translational Agency performed a case-by-case review proteins from plant viruses that
modifications are expected to be the of some nature. PVC-proteins could be naturally infect plants are widespread in
same for a PVC-protein expressed from encoded for by a nucleic acid sequence foods (Refs. 6, 7, and 10) and are not
a plant transgene as for a plant virus that meets the 90% similarity required associated with toxic or pathogenic
coat protein expressed from a viral for PTGS to function but fail to be effects in humans or vertebrates (Refs.
genome in a virus-infected plant. virtually unmodified from a natural 18 and 19). Residues of PVC-proteins
virus coat protein (see Unit IV.E.1.). qualifying for this proposed exemption
As a third alternative, EPA is
Moreover, the 2005 SAP recommended are virtually unmodified or minimally
considering whether the Agency could
that ‘‘[d]etermining whether PVC- modified from other coat proteins from
expand this proposed tolerance
proteins containing terminal deletions, viruses that naturally infect food plants
exemption to cover all PVC-proteins
or any other modifications, are within and that have been safely consumed for
that would be produced from constructs
the range of natural variation would hundreds if not thousands of years.
where resistance is demonstrated to
require the development of a database of Given this long history of safe use and
EPA to be mediated through PTGS, e.g.,
the natural variation and truncated the fact that toxicity is an unusual
those that confer virus resistance in the
forms of PVC-proteins that occur property among proteins in general (Ref.
absence of detectable protein 59), consumption of food containing
naturally’’ (Ref. 15). While PTGS
production for at least some period of residues of PVC-proteins qualifying for
requires a relatively high sequence
time. The rationale for this alternative this proposed exemption is not expected
similarity with natural virus coat
would be, as indicated by the 2005 SAP, to present a toxic effect on humans or
proteins to function, only a portion of
that ‘‘PTGS-based virus resistance animals.
the coat protein gene is necessary,
requires greater than 90% RNA EPA considered the available
suggesting that many truncated proteins
sequence homology between the PVCP- information on the various dietary
would be encompassed in this
PIP transgene and the target virus, exemption without any review of consumption patterns of consumers and
indicating that the viral mRNA and whether they occur naturally. (See, major identifiable consumer subgroups
protein produced in PVCP-PIP plants however, EPA’s discussion of whether as it pertains to residues of PVC-
will be nearly identical to the viral truncated proteins could be determined proteins in food. Plant virus coat
pathotype that occurs in the United to be exempt without Agency review in proteins are, and always have been,
States’’ (Ref. 15). To implement this Unit IV.E.2.) The 2005 SAP also widespread in all food from crop plants
alternative, the Agency would have to suggested that a low level of protein since most plants are susceptible to
be able to conclude, without any case- expression would indicate low risk, but infection by one or more viruses. Thus,
by-case examination, that any PVC- prior SAPs and other scientific experts all consumers and all major identifiable
protein produced from a PVCP-PIP that have been unable to establish a consumer subgroups are, and have been,
mediates resistance through PTGS threshold below which the level of exposed to plant virus coat proteins.
would be safe. Even if a PVC-protein protein would not present concerns Implementation of this proposed
were detected before product with respect to food allergenicity (Refs. exemption is not expected to alter the
deployment, such a protein would not 57 and 58). current consumption patterns of plant
need any evaluation by the Agency in virus coat proteins except perhaps to
order to be covered by this tolerance V. Toxicological Profile reduce exposure through a decrease in
exemption. The rationale for this Consistent with section 408(b)(2)(D) virus-infected plants. Therefore, EPA
approach would be that any such PVC- of FFDCA, EPA has reviewed the does not expect any special sensitivities
protein would meet the conditions of a available scientific data and other to arise due to the consumption of
minimally modified protein (as relevant information in support of this residues of PVC-proteins that are
discussed in Unit IV.E.2.) given the proposed action and considered its proposed to be exempted.
necessity for transgene transcript validity, completeness, and reliability
sequence similarity to natural plant and the relationship of this information VI. Aggregate Exposures
virus coat protein sequences in order for to human risk. EPA has also considered In examining aggregate exposure,
PTGS to effectively function. Although available information concerning the section 408 of FFDCA directs EPA to
EPA does not believe it could identify variability of the sensitivities of major consider available information
a priori which modifications would be identifiable subgroups of consumers, concerning exposures from the pesticide
hsrobinson on PROD1PC76 with PROPOSALS2

within the range of natural variation for including infants and children. residue in food and all other non-
the protein, under this rationale the EPA’s risk assessment was based occupational exposures, including
induction of PTGS would be an a priori primarily on an analysis of human drinking water from ground water or
indicator that such a PVC-protein is experiences with the breeding and surface water and exposure through
within the range of natural variation of cultivation of agricultural plants as well pesticide use in gardens, lawns, or
the protein. The 2005 SAP suggested as food preparation and consumption. buildings (residential and other indoor
that all PTGS-based PVCP-PIPs would EPA combined human experience in uses).

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EPA considered the available exists, including information on human in ornamental plants or in plants grown
information on the likely aggregate dietary exposure, for foods that contain in home gardens. Such exposure to
exposure level of consumers to PVC- coat proteins from viruses that naturally PVC-proteins is expected to be
proteins qualifying for this proposed infect plants. As plant virus coat negligible on a per-person basis
exemption and to other related proteins are ubiquitous in food, EPA compared to exposure to PVC-proteins
substances, including exposures to plant concluded that all humans are exposed and natural plant virus coat proteins in
virus coat proteins occurring through to plant virus coat proteins throughout the diet. Furthermore, PVC-proteins
natural processes such as viral infection their lives as part of their diet. Neither qualifying for this exemption would not
of a food plant. This analysis included naturally occurring plant virus coat be toxic, and there is no evidence that
a consideration of exposures from proteins nor the PVC-proteins qualifying exposure to such PVC-proteins would
dietary sources as well as from other for this exemption are toxic, and there lead to any harm.
non-occupational sources. is no evidence that consumption in food 1. Dermal exposure. Residues of PVC-
The PVC-proteins qualifying for this of residues of PVC-proteins qualifying proteins qualifying for this proposed
proposed exemption and plant virus for this proposed exemption would lead exemption may be present in sap or
coat proteins that occur naturally are to any harm. other plant exudates and thus may
both produced in living plants and are 1. Food. As mentioned in Unit IV.C.1., present some limited opportunity for
subject to the natural processes of the Agency has concluded that dietary dermal exposure to persons coming
degradation and decay that all biological exposures to PVC-proteins qualifying for physically into contact with the plant or
materials undergo. They are broken this proposed exemption will be similar raw agricultural food from the plant.
down by enzymatic processes of living to or less than the amounts of plant Individuals preparing meals are those
organisms into constituent parts that are virus coat proteins currently found and most likely to experience dermal contact
used as building blocks for other consumed in food plants that have been with the residues on a non-occupational
biological substances (Ref. 60). Because naturally infected by viruses. Even if basis. As noted by the 2005 SAP, PVC-
of their biodegradable nature, neither there were notable exposure to PVC- proteins’ ‘‘natural exposure route may
PVC-proteins nor naturally occurring proteins, there is no evidence that PVC- be via oral ingestion. However,
plant virus coat proteins bioaccumulate proteins are toxic to humans. Moreover, genetically modified expression of
(i.e., build up in tissues because the the Agency is not aware of any coat PVCP-PIPs would lead to the presence
body is unable to either break the protein from a virus that naturally of [PVC-proteins] in other plant
substance down or eliminate it) or infects plants that has been identified as compartments such as pollen grains
biomagnify (i.e., progressively build up a food allergen for humans. The which lead to other sites of exposure
in successive trophic levels because it residues that are proposed to be including respiratory and cutaneous
bioaccumulates in the bodies of exempted by this Federal Register surfaces’’ (Ref. 15). However, the
organisms lower in the food chain). document would not differ substantially potential amount involved in such
Humans ingesting naturally occurring from residues of naturally occurring exposure on a per person basis is likely
plant virus coat proteins and residues of plant virus coat proteins. to be negligible in comparison to
PVC-proteins qualifying for this 2. Drinking water exposure. EPA also potential exposure through the dietary
proposed exemption in food are likely evaluated potential non–occupational route to PVC-proteins and natural plant
to quickly degrade them and use their exposures in drinking water. Residues virus coat proteins (Ref. 61). Moreover,
constituent elements as nutrients. of PVC-proteins that qualify for this PVC-proteins qualifying for this
Because of these characteristics, there proposed exemption are produced proposed exemption or naturally
is limited potential for exposures to inside the plant itself. When the plant occurring plant virus coat proteins that
PVC-proteins qualifying for this dies or a part is removed from the plant, occur in food are unlikely to cross the
proposed exemption beyond direct microorganisms colonizing the tissue barrier provided by the skin (Ref. 62).
physical exposure to a plant. In most immediately begin to degrade it using 2. Inhalation exposure. Pollen could
cases, the predominant exposure route the components of the plant tissue potentially contain residues of PVC-
will be dietary. In general, EPA (including residues of PVC-proteins) as proteins qualifying for this proposed
anticipates that dietary exposure to building blocks for making their own exemption. Individuals (e.g., those
PVC-proteins qualifying for this cellular components or for fueling their visiting, living, or working near enough
proposed exemption through human own metabolisms. PVC-proteins and to farms, nurseries, or other plant-
and animal consumption of plants naturally occurring plant virus coat growing areas to be exposed to wind-
expressing PVC-proteins will be similar proteins are subject to the same blown pollen) may be exposed to the
to, or less than the amounts of plant processes of biodegradation and decay pollen through inhalation. On a per
virus coat proteins currently consumed that all biological materials undergo and person basis, the potential amount of
through food plants that are infected are not known to either bioaccumulate pollen involved in these exposures is
naturally with viruses (see Unit IV.C.1.). or biomagnify (Ref. 60). Even if they likely to be negligible in comparison to
Exposure through other routes is were to reach surface waters (e.g., potential exposure through the dietary
unlikely because the substances are in through plant parts or pollen falling into route (Ref. 61). Some members of the
the plant tissue and thus are found bodies of water), they are unlikely to 2005 SAP indicated that ‘‘[i]ntroduction
either within the plant or in close present anything other than a very of new proteins to pollens and other
proximity to the plant. EPA expects negligible exposure in drinking water plant materials may have the potential
non-dietary exposure (i.e., non-food drawn either from surface water or to cause problems, and consideration by
oral, dermal, and inhalation) in non– ground water sources due to the Agency is warranted’’ (Ref. 15). As
hsrobinson on PROD1PC76 with PROPOSALS2

occupational settings to be negligible. biodegradation of these residues. the Panel explained, ‘‘While plant
viruses systemically infect plant tissues,
A. Dietary Exposure B. Other Non-Occupational Exposure there is tissue specific regionalization of
EPA considered the consequences of Residential exposure to PVC-proteins viruses. Therefore [plant virus coat
dietary exposure to PVC-proteins that qualifying for this proposed exemption proteins] would be restricted within
are the subject of this proposed would be limited. Residential exposure certain compartments. Transgenic
exemption. A large base of experience could occur through use of PVCP-PIPs expression of some PVC-PIPs would

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19654 Federal Register / Vol. 72, No. 74 / Wednesday, April 18, 2007 / Proposed Rules

promote [PVC-protein] expression in VIII. Safety Factor for Infants and amount of exposure to such PVC-
different plant tissues relative to what Children proteins in food would lead to any
would naturally occur (i.e., all cells). harm.
A. In General EPA considered available information
This could lead to heightened levels of
[PVC-proteins] in certain tissues (i.e., Section 408(b)(2)(C) of FFDCA on the potential for special
pollen grains) and the effects provides that EPA shall apply an susceptibility of infants and children,
additional tenfold margin of safety for including prenatal and postnatal
(specifically to allergenicity) are not yet
infants and children in the case of toxicity, to residues of PVC-proteins
known. This has implications for non-
threshold effects to account for prenatal qualifying for this proposed exemption.
dietary exposure of plant proteins. In and postnatal toxicity and the PVC-proteins in food are not toxic.
some instances, [plant virus coat completeness of the information base on There is no scientific evidence that
protein’s] natural exposure route may be toxicity and exposure unless EPA residues of such PVC-proteins in food
via oral ingestion. However, genetically determines that a different margin of would have a different effect on infants
modified expression of PVCP-PIPs safety will be safe for infants and and children than adults due to
would lead to the presence of [PVC- children. Margins of safety are neurological differences between
proteins] in other plant compartments incorporated into EPA risk assessments infants, children, and adults.
such as pollen grains which lead to either directly through use of a MOE The Agency’s consideration of
other sites of exposure including analysis or through using uncertainty cumulative effects of the residues of
respiratory and cutaneous surfaces’’ (safety) factors in calculating a dose PVC-proteins qualifying for this
(Ref. 15). However, other Panel level that poses no appreciable risk to proposed exemption on the general
members felt that ‘‘unless there is humans. population also included consideration
evidence that PCVP-PIPs are expressed of effects for infants and children.
B. Prenatal and Postnatal Sensitivity
on the surface of pollen grains in a Neither naturally occurring plant virus
manner different from expression in EPA considered available information coat proteins nor PVC-proteins
on the dietary consumption patterns of qualifying for this proposed exemption
wild-type plants, the risk of increased
infants and children as it pertains to are toxic when consumed as part of the
allergy from exposure to pollen is non- residues in food of PVC-proteins
existent’’ (Ref. 15). The Agency also diet, and EPA is not aware of any
qualifying for this proposed exemption. substances that might have a common
notes that in order for expression of a The range of foods consumed by infants mechanism of toxicity with these PVC-
PVC-protein to be a concern, the protein and children is in general more limited proteins. There is no scientific evidence
would have to be expressed on the than the range of foods consumed by indicating any potential for adverse
surface of the pollen grain, it would adults. Most newborns rely on breast effects on infants and children due to
have to actually be an antigenic protein, milk or formula-based products for cumulative exposure to residues of such
and it would have to elicit an allergic nutrition, although some infants are fed PVC-proteins. EPA concludes that there
response through secondary exposure. soy-based products. Infants may begin is no evidence of a common mechanism
The Agency considers that this as early as 4 months of age to consume of toxicity between PVC-proteins
sequence of events is very unlikely to solid foods that are based on foods qualifying for this proposed exemption
occur, in part because no plant virus consumed by the general adult and any other substances, and therefore,
coat proteins have been identified as population albeit in different no cumulative effects of these PVC-
being allergenic, and PVC-proteins proportions and with processing to proteins would reasonably be
qualifying for this exemption are facilitate swallowing. As infants and anticipated.
virtually unmodified or minimally children mature, more and more of the
foods normally consumed by adults C. Conclusion
modified from natural plant virus coat
proteins. Therefore, it is unlikely that become part of their diets, and the There is a complete toxicity base of
relative proportions of the different information for PVC-proteins that are
inhalation exposure to PVC-proteins in
types of food consumed change to more the subject of this proposed exemption,
pollen would result in adverse effects.
closely resemble an adult diet. Because and exposure data are estimated based
VII. Cumulative Effects plant viruses are ubiquitous in plant on data that reasonably account for
foods, EPA concluded that infants and potential exposures. For residues of
EPA examined the available children are exposed to plant virus coat PVC-proteins qualifying for this
information on residues of PVC-proteins proteins from the time they begin to eat proposed exemption, EPA has
qualifying for this proposed exemption food of plant origin. As the diets of determined that a tenfold margin of
for cumulative effects with other humans change from infancy through safety is not necessary to protect infants
substances, including natural plant childhood and into adulthood, there is and children. As noted in Unit IV.C.,
virus coat proteins. Plant virus coat some possibility that the amount of EPA based its assessment of exposure
proteins are nontoxic proteins that are plant virus coat proteins being and toxicity on the long history of safe
widespread in food from plants. They consumed may change, with those human and animal consumption of food
have not been associated with toxic consuming the greatest amounts of food containing plant virus coat proteins.
effects to animals or humans (see Unit of plant origin most likely exposed to EPA also relied upon information from
IV.C.3.). EPA is therefore not aware of the most plant virus coat protein. the disciplines of plant genetics, plant
any other substances that could have a However, there is no evidence that such physiology, plant virology, microbial
common mechanism of human toxicity changes are likely to result in ecology, ecology, biochemistry,
hsrobinson on PROD1PC76 with PROPOSALS2

with residues of PVC-proteins disproportionately high consumption of molecular biology, and plant breeding.
qualifying for this exemption and foods containing plant virus coat Based on all of this information, EPA
cannot identify any cumulative effects proteins among infants and children in concludes that PVC-proteins qualifying
comparison to the general population. for this proposed exemption in food are
of such residues with any other
Furthermore, PVC-proteins qualifying not toxic and may be safely consumed,
substances.
for this proposed exemption are not including by infants and children. There
toxic, and there is no evidence that any is no evidence that exposure to such

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Federal Register / Vol. 72, No. 74 / Wednesday, April 18, 2007 / Proposed Rules 19655

PVC-proteins in food, including changes C. Codex Maximum Residue Level be truncated from either end of a PVC-
in exposure because of changes in the protein.
relative proportions of the different There are no Codex maximum residue 2. In addition to the types of changes
types of food consumed from infancy levels established for PVC-proteins. discussed in the paragraph above, EPA
through childhood and into adulthood, X. Preliminary Determination of Safety requests comment on whether any other
leads to any harm. Thus, on the basis of for U.S. Population, Infants, and class of potential PVC-protein
valid, complete, and reliable Children modifications (e.g., a particular number
information, EPA has concluded that of amino acid substitutions) would
residues in food of PVC-proteins Based on the information discussed in always be expected to produce a PVC-
qualifying for this proposed exemption this document and that discussed in the protein as safe as an unmodified plant
are safe for infants and children and that 1994 Federal Register documents, the virus coat protein such that the protein
an additional margin of safety need not supplemental documents, and the would not warrant a case-by-case
be applied. associated record as described in Unit Agency review for a tolerance
XII.B., EPA preliminarily concludes that exemption. The Agency also requests
IX. Other Considerations there is a reasonable certainty that no that commenters indicate whether the
harm will result to the U.S. population, number and combination of such
A. Endocrine Disruptors infants, and children from aggregate modifications has any relevance to the
Based on available information that exposures to residues of PVC-proteins product’s safety. In October 2004, the
plant virus coat proteins are ubiquitous that qualify for this proposed FIFRA SAP was asked to consider the
in foods and have no known adverse exemption. Many years of experience degree and ways a plant virus coat
with growing, preparing, and protein gene might be modified while
effects when consumed as part of the
consuming food from plants containing still retaining scientific support for the
diet (see Unit IV.C.), EPA does not
plant virus coat proteins and idea that humans have consumed the
expect residues of PVC-proteins
information generated through years of products of such genes for generations
qualifying for this proposed exemption and that such products therefore present
study of the food supply (Refs. 6, 7, 8,
to cause estrogenic or other endocrine no new dietary exposures (Ref. 14).
9, 10, and 66) indicate that adverse
effects. In the May 16, 1997 They responded that ‘‘[t]here was no
effects due to aggregate exposure to
supplemental document, EPA clear consensus on how much change
PVC-proteins qualifying for this
specifically requested comment on PVC- would be necessary to invalidate this
proposed exemption through dietary,
proteins causing estrogenic effects. No assumption, although there was general
non-food oral, dermal, and inhalation
information was received indicating that routes are highly unlikely. agreement that the appropriate
either naturally occurring plant virus comparison is to the range of natural
coat proteins or PVC-proteins that XI. Request for Comment variation in the virus population.’’ This
qualify for this proposed exemption question was also addressed by the 2005
EPA requests comment on whether
might cause estrogenic or other SAP which concurred that ‘‘it is
this proposed tolerance exemption
endocrine effects. If EPA becomes aware extremely difficult to identify
identifies those PVC-proteins that are
of a potential for estrogenic or endocrine modifications that would be expected to
unlikely to result in new dietary
effects from exposure to residues of exposures. When commenting, please be ‘within the range of natural variation
such PVC-proteins, the Agency will use the terminology conventions for all virus families’. . . Given the
reexamine this proposed tolerance adopted in this document, i.e., use possible range of natural variations for
exemption in light of that information. ‘‘plant virus coat protein’’ when PVC proteins, it would be appropriate to
referring to the protein produced assess whether specific modifications
B. Analytical Method(s) are within natural variation limits of the
naturally from a plant virus, and use
EPA has concluded that even though PVC protein on a case-by-case basis’’
‘‘PVC-protein’’ when referring to the
methodology exists to detect residues of (Ref. 15). Commenters should
protein component of a PVCP-PIP. The
PVC-proteins (Refs. 63, 64, and 65), specifically address this advice when
Agency requests comment on the
formulating comments.
there is no need to employ a practical following specific issues: 3. EPA requests comment on whether
method for detecting and measuring the 1. EPA requests comment on the there would be any safety issues
level of residues of PVC-proteins options discussed in Unit IV.E.1. for associated with exposure to PVC-
qualifying for this exemption. There is defining virtually unmodified. Under proteins if the virus used to create the
no reason to believe that the residues of the Agency’s proposed rule, virtually PVCP-PIP does not naturally infect the
PVC-proteins proposed to be exempted unmodified proteins would be exempt particular plant species into which the
in this Federal Register document from the requirement of a tolerance PVCP-PIP is inserted. A PVC-protein
would behave any differently than without Agency review. Under one may be expressed in a food plant that
naturally occurring plant virus coat option, virtually unmodified would be the virus does not naturally infect when
proteins in food. There is a reasonable defined as having or coding for an heterologous resistance to a particular
certainty that no harm will result from amino acid sequence that is identical to virus is conferred through a different
exposure to any amount of residues in an entire coat protein of a naturally virus’ coat protein gene (e.g., Ref. 45).
food of such PVC-proteins. Because occurring plant virus; except for the Such PVC-proteins could be safely
these residues may be present in food at addition of one or two amino acids at exempted from tolerance requirements
any level without causing harm, EPA the N- and/or C-terminus other than if these proteins are reasonably expected
hsrobinson on PROD1PC76 with PROPOSALS2

has concluded that an analytical method cysteine, asparagine, serine, and to be part of the current diet, as
is not required for detecting and threonine and/or the deletion of one or discussed in Unit IV.E.1. In light of the
measuring the level of residues of these two amino acids at the N- and/or C- uncertainty surrounding the SAP’s
PVC-proteins in food. EPA consulted terminus. However, the Agency is remarks concerning this issue (see Unit
with the Department of Health and considering removing the limitations on IV.E.1.), EPA requests comment on
Human Services (HHS) in making this which amino acids may be added and whether there would be any safety
determination. on the number of amino acids that may issues associated with exposure tothe

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19656 Federal Register / Vol. 72, No. 74 / Wednesday, April 18, 2007 / Proposed Rules

PVC-proteins themselves if the virus assurance that such events would not minimally modified and therefore are
used to create a PVCP-PIP does not occur, e.g., any key environmental exempt from the requirement of a
naturally infect the particular plant parameters that should be varied during tolerance under proposed § 174.477(b)
species into which the PVCP-PIP is testing. should be listed in the CFR as is the
inserted. EPA also requests comment on current practice for individual tolerance
4. EPA requests comment on whether whether obtaining characterization data exemptions associated with other types
the Agency should consider the level of of a plant-produced PVC-protein for a of PIPs. If so, EPA requests comment on
PVC-protein expression in determining tolerance review is scientifically feasible whether the listing should indicate the
whether a PVC-protein is virtually in all cases where the PVCP-PIP specific modifications of the reviewed
unmodified or minimally modified and insertion event contains a translation proteins, given that each determination
thus exempt from tolerance initiation codon and is not present in an would apply only to proteins with those
requirements. EPA concurs with the inverted repeat orientation. The Agency modifications. EPA is aware that in the
2005 SAP that ‘‘exposure level is an would like to know for any given crop past, developers have found such
important component of an allergenicity how technically difficult it would be to listings to be useful for international
risk assessment’’ (Ref. 15). However, it attempt to induce protein production trade reasons, as governments rely on
can be argued that PVC-proteins that are through challenge with a known PTGS EPA tolerances to support import
virtually unmodified or minimally suppressor protein, e.g., through decisions.
modified when compared to natural introduction by a replicating virus
plant viral coat proteins are of vector, genetic crosses, or agro- XII. References
sufficiently low hazard that the infiltration (Ref. 56). In addition, EPA A. Books, Articles, and Reports Used in
potential risk does not rise to the level would like to know how likely it is that Preparing this Proposed Rule
warranting regulation, even in the rare such techniques could yield sufficient 1. Callaway A., Giesman-Cookmeyer
case that exposure to a PVC-protein quantities of PVC-protein for analysis D., Gillock E.T., Sit T.L., Lommel S.A.
might be greater than the exposure to (e.g., mass spectrometry or glycosylation The multifunctional capsid proteins of
the corresponding natural plant virus analysis). The Agency would also be plant RNA viruses. Annual Review of
coat protein. Although EPA’s review of interested in hearing of additional Phytopathology 2001; 39:419-60.
PVC-proteins to determine if they are techniques that could be employed to 2. Powell P.A., Sanders P.R., Tumer
minimally modified could allow the obtain plant-produced PVC-protein in N., Fraley R.T., Beachy R.N. Protection
Agency to consider PVC-protein cases where PTGS normally prevents against tobacco mosaic virus infection
expression level relative to natural accumulation of protein but is not in transgenic plants requires
levels of plant virus coat proteins, the expected to be consistently activated, accumulation of coat protein rather than
Agency is unsure how this factor could thereby leading to PVC-protein coat protein RNA sequences. Virology
be readily incorporated into the criteria production. 1990; 175:124-30.
for a developer-determined tolerance Regarding the second alternative 3. Goldbach R., Bucher E., Prins M.
exemption; EPA anticipates needing to presented for PVC-proteins associated Resistance mechanisms to plant viruses:
consider the appropriateness of data with PTGS, EPA requests comment on an overview. Virus Research 2003;
designed to address these questions on the value of the additional information 92:207-12.
a case-by-case basis. Therefore, if gained by analyzing an actual PVC- 4. National Research Council.
protein expression level is considered a protein as produced in the plant where Genetically Modified Pest-Protected
necessary factor in evaluating whether the inserted nucleotide sequence Plants: Science and Regulation.
to exempt a virtually unmodified PVC- suggests it would be minimally Washington, DC: National Academy
protein from tolerance requirements, modified from a natural plant virus coat Press, 2000.
EPA seeks comment on how such protein, e.g., to consider potential post- 5. Dewan C., Pearson M.N. Natural
considerations could be articulated in a translational modifications, relative to field infection of garlic by garlic yellow
clear, unambiguous criterion. the reduced burden and cost of streak virus in the Pukekohe area of
5. EPA requests comment on the analyzing safety based on the deduced New Zealand and associated problems
Agency’s options for how to view a amino acid sequence from the insert with the introduction of new garlic
PVC-protein that would not meet the alone. cultivars. New Zealand Journal of Crop
definition of virtually unmodified and is Regarding the third alternative and Horticultural Science 1995; 23:97-
not detected during product presented, EPA requests comment on 102.
development if the construct suggests the rationale that would be used to 6. McKinney H.H. Mosaic diseases in
that its production is likely to occur in support expanding this tolerance the Canary Islands, West Africa, and
at least some plant tissue at some point exemption to cover all PVC-proteins Gibraltar. Journal of Agricultural
in time (see Unit IV.F.). Specifically, produced by a PVCP-PIP that mediates Research 1929; 39:557-78.
EPA requests comment on the relative resistance through PTGS, i.e., that any 7. Provvidenti R., Gonsalves D.
costs and benefits of allowing a PVCP- such protein would meet the conditions Occurrence of zucchini yellow mosaic
PIP that does not produce detectable of a minimally modified protein as virus in cucurbits from Connecticut,
PVC-protein residues in food during discussed in this document given the New York, Florida, and California. Plant
product development to be sold or necessity for transgene transcript Disease 1984; 68:443-6.
distributed without a PVC-protein sequence similarity to natural plant 8. Palukaitis P. Virus-mediated
tolerance exemption in place. EPA is virus coat protein sequences in order for genetic transfer in plants. In: Levin M,
particularly interested in information PTGS to effectively function. In Strauss H. Risk Assessment in Genetic
hsrobinson on PROD1PC76 with PROPOSALS2

about the likelihood that protein would particular, EPA requests comment on Engineering. New York: McGraw-Hill,
fail to be detected during product how to reconcile this option with prior 1991:140-62.
development but subsequently be advice of the SAP (as discussed in Unit 9. Jones L., Anderson E., Burnett G.
detected in food. The Agency is also IV.F.). The latent virus of potatoes. Journal of
interested in comments on conditions 6. EPA requests comment on whether Phytopathology 1934; 7:93-115.
under which protein detection protocols PVC-proteins that the Agency has 10. Beemster A.B.R., de Bokx J.A.
could be conducted to provide adequate reviewed and has determined are Survey of properties and symptoms. In:

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Immunology 2004; 113:821-30. Clarke N. Biochemistry, 5th ed. New Proposed Rule’’ (59 FR 60519,
49. Ebner C., Hoffmann- York: W. H. Freeman and Company, November 23, 1994) (FRL–4755–3).
Sommergruber K., Breiteneder H. Plant 2002. 3. The docket identified by the docket
food allergens homologous to 61. Environmental Protection Agency. control number OPP–300368 for the
pathogenesis-related proteins. Allergy Issue Paper on Dermal and Inhalation document entitled ‘‘Plant-Pesticides;
2001; 56:43-4. Exposure to Plant Substances. 2000. Proposed Exemption From the
50. Davis M., Ying Z. Development of 62. Guy R.H., Hadgraft J. Principles of Requirement of a Tolerance Under the
papaya breeding lines with transgenic skin permeability relevant to chemical Federal Food, Drug, and Cosmetic Act’’
resistance to Papaya ringspot virus. exposure. In: Hobson DW. Dermal and (59 FR 60535, November 23, 1994)
Plant Disease 2004; 88:352-8. Ocular Toxicology: Fundamentals and (FRL–4758–8).
51. Lindbo J.A., Silva-Rosales L., Methods. Boca Raton: CRC Press, 4. The docket identified by the docket
Proebsting W.B., Dougherty W.G. 1991:221-46. control number OPP–300371 for the
Induction of a highly specific antiviral 63. Huguenot C., van den Dobbelsteen document entitled ‘‘Plant-Pesticides;
state in transgenic plants: Implications G., de Haan P., Wagemakers C., Drost G., Proposed Exemption From the
for regulation of gene expression and Osterhaus A. et al. Detection of tomato Requirement of a Tolerance Under the
virus resistance. The Plant Cell 1993; spotted wilt virus using monoclonal Federal Food, Drug, and Cosmetic Act
5:1749-59. antibodies and riboprobes. Archives of for Nucleic Acids Produced in Plants’’
52. Béclin C., Berthomé R., Palauqui (59 FR 60542, November 23, 1994)
Virology 1990; 110:47-62.
J.C., Tepfer M., Vaucheret H. Infection (FRL–4755–5).
64. Rocha-Pena M., Lee R., Niblett C.
of tobacco or Arabidopsis plants by 5. The docket identified by the docket
Development of a dot-immunobinding
CMV counteracts systemic post- control number OPP–300367 for the
assay for detection of citrus tristeza
transcriptional silencing of nonviral document entitled ‘‘Plant-Pesticides;
virus. Journal of Virological Methods
(trans)genes. Virology 1998; 252:313-7. Proposed Exemption From the
53. Pang S-Z, Jan F.J., Carney K., Stout 1991; 34:297-309.
Requirement of a Tolerance Under the
J., Tricoli D.M., Quemada H. et al. Post- 65. Sukhacheva E., Novikov V.,
Federal Food, Drug, and Cosmetic Act
transcriptional transgene silencing and Plaksin D., Pavlova I., Ambrosova S.
for Viral Coat Proteins Produced in
consequent tospovirus resistance in Highly sensitive immunoassays for
Plants’’ (59 FR 60545, November 23,
transgenic lettuce are affected by detection of barley stripe mosaic virus
1994) (FRL–4755–4).
transgene dosage and plant and beet necrotic yellow vein virus. 6. The docket identified by the docket
development. Plant Journal 1996; 9:899- Journal of Virological Methods 1996; control number OPP–300370A for the
909. 56:199-207. document entitled ‘‘Plant-Pesticide
54. Szittya G., Silhavy D., Molnár A., 66. Hull R., Covey S.N., Dale P. Subject to the Federal Insecticide,
Havelda Z., Lovas A, Lakatos L. et al. Genetically modified plants and the 35S Fungicide, and Rodenticide Act and the
Low temperature inhibits RNA promoter: assessing the risks and Federal Food, Drug, and Cosmetic Act;
silencing-mediated defence by the enhancing the debate. Microbial Ecology Reopening of Comment Period’’ (61 FR
control of siRNA generation. The EMBO in Health and Disease 2000; 12:1-5. 37891, July 22, 1996) (FRL–5387–4).
Journal 2003; 22:633-40. B. Additional Information 7. The docket identified by the docket
55. Savenkov E.I., Valkonen J.P.T. control number OPP–300368A for the
Coat protein gene-mediated resistance to EPA has established an official record document entitled ‘‘Plant-Pesticides;
Potato virus A in transgenic plants is for this rulemaking. The official record Supplemental Notice of Proposed
suppressed following infection with includes all information considered by Rulemaking’’ (62 FR 27132, May 16,
another potyvirus. Journal of General EPA in developing this proposed rule 1997) (FRL–5717–2).
Virology 2001; 82:2275-8. including documents specifically 8. The docket identified by the docket
56. Li W.X., Ding S.W. Viral referenced in this action, any public control number OPP–300371A for the
suppressors of RNA silencing. Current comments received during an applicable document entitled ‘‘Plant-Pesticides;
Opinion in Biotechnology 2001; 12:150- comment period, and any other Nucleic Acids; Supplemental Notice of
4. information related to this action, Proposed Rulemaking’’ (62 FR 27142
57. FIFRA Scientific Advisory Panel. including any information claimed as May 16, 1997) (FRL–5716–7).
Minutes of the July 17-18, 2001 Meeting CBI and any information received in any 9. The docket identified by the docket
on A Set of Scientific Issues Being of the related dockets mentioned in this control number OPP–300367A for the
Considered by the Environmental unit. This official record includes all document entitled ‘‘Plant-Pesticides;
Protection Agency Regarding: information physically located in the Viral Coat Proteins; Supplemental
Assessment of Additional Scientific dockets described in the following Notice of Proposed Rulemaking’’ (62 FR
Information Concerning StarLinkTM paragraphs, as well as any documents 27149, May 16, 1997) (FRL–5716–6).
Corn. 2001. that are referenced in the documents in 10. The docket identified by the
58. FIFRA Scientific Advisory Panel. the dockets. docket control number OPP-300369A
Minutes of the November 28, 2000 1. The docket identified by the docket for the document entitled ‘‘Plant-
hsrobinson on PROD1PC76 with PROPOSALS2

Meeting on A Set of Scientific Issues control number OPP–300370 for the Pesticides, Supplemental Notice of
Being Considered by the Environmental document entitled ‘‘Proposed Policy: Availability of Information’’ (64 FR
Protection Agency Regarding: Plant-Pesticides Subject to the Federal 19958, April 23, 1999) (FRL–6077–6).
Assessment of Scientific Information Insecticide, Fungicide, and Rodenticide 11. The docket identified by the
Concerning StarLinkTM Corn. 2000. Act and the Federal Food, Drug, and docket control number OPP-300368B for
59. Pariza M., Johnson E. Evaluating Cosmetic Act’’ (59 FR 60496, November the document entitled ‘‘Exemption
the safety of microbial enzyme 23, 1994) (FRL–4755–2). From the Requirement of a Tolerance

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Federal Register / Vol. 72, No. 74 / Wednesday, April 18, 2007 / Proposed Rules 19659

Under the Federal Food, Drug, and XIII. Statutory and Executive Order action will not have a substantial direct
Cosmetic Act for Residues Derived Reviews effect on States or tribal governments,
Through Conventional Breeding From This proposed rule would establish an on the relationship between the national
Sexually Compatible Plants of Plant- exemption from therequirement of a government and the States or tribal
Incorporated Protectants (Formerly tolerance under section 408 of FFDCA. governments, or on the distribution of
Plant-Pesticides)’’ (66 FR 37830, July 19, The Officeof Management and Budget power and responsibilities among the
2001) (FRL–6057–6). (OMB) has exempted these types of various levels of government or between
12. The docket identified by the actionsfrom review under Executive the Federal Government and Indian
docket control number OPP–300371B Order 12866, entitled Regulatory tribes. Thus, the Agency has determined
for the document entitled ‘‘Exemption Planning and Review (58 FR 51735, that Executive Order 13132, entitled
from the Requirement of a Tolerance October 4, 1993). Because this proposed Federalism (64 FR 43255, August 10,
Under the Federal Food, Drug, and rule has been exempted from review 1999) and Executive Order 13175,
Cosmetic Act for Residues of Nucleic under Executive Order 12866, this entitled Consultation and Coordination
Acids that are Part of Plant-Incorporated proposal is not subject to Executive with Indian Tribal Governments (65 FR
Protectants (Formerly Plant-Pesticides)’’ Order 13211, Actions Concerning 67249, November 6, 2000) do not apply
(66 FR 37817, July 19, 2001) (FRL– Regulations That Significantly Affect to this rule. In addition, this rule does
6057–5). Energy Supply, Distribution, or Use (66 not impose any enforceable duty or
13. The docket identified by the FR 28355, May 22, 2001) or Executive contain any unfunded mandate as
docket control number OPP–300369B Order 13045, entitled Protection of described under Title II of the Unfunded
for the document entitled ‘‘Regulations Children from Environmental Health Mandates Reform Act of 1995 (UMRA)
Under the Federal Insecticide, Risks and Safety Risks (62 FR 19885, (Public Law 104–4).
Fungicide, and Rodenticide Act for April 23, 1997). This proposed rule does As with all aspects of its proposal,
Plant-Incorporated Protectants not contain any new information EPA invites your comments on these
(Formerly Plant-Pesticides)’’ (66 FR collections subject to OMB approval determinations.
37772, July 19, 2001) (FRL–6057–7). under the Paperwork Reduction Act List of Subjects in 40 CFR Part 174
14. The docket identified by the (PRA), 44 U.S.C. 3501 et seq., nor does
it require any special considerations Environmental protection,
docket control number OPP-300370B for Administrative practice and procedure,
the document entitled ‘‘Plant- under Executive Order 12898, entitled
Federal Actions to Address Agricultural commodities, Pesticides
Incorporated Protectants (Formerly and pests, Plants, Reporting and
Plant-Pesticides), Supplemental Environmental Justice in Minority
Populations and Low-Income recordkeeping requirements.
Proposal’’ (66 FR 37855, July 19, 2001)
(FRL–6760–4). Populations (59 FR 7629, February 16, Dated: April 9, 2007.
1994). This action does not involve any Stephen L. Johnson,
15. The docket identified by the technical standards that would require
docket ID number EPA–HQ–OPP–2006– Administrator.
Agency consideration of voluntary
0642 for the companion document Therefore, it is proposed that 40 CFR
consensus standards pursuant to section
entitled ‘‘Exemption under the Federal part 174 be amended as follows:
12(d) of the National Technology
Insecticide, Fungicide, and Rodenticide Transfer and Advancement Act of 1995
Act for Certain Plant-Incorporated PART 174—[AMENDED]
(NTTAA) (15 U.S.C. 272 note). Pursuant
Protectants Derived from Plant Viral to the Regulatory Flexibility Act (RFA) 1. The authority citation for part 174
Coat Protein Gene(s) (PVCP-PIPs)’’ (5 U.S.C. 601 et seq.), the Agency would continue to read as follows:
(FRL–8100–7) published elsewhere in previously assessed whether Authority: 7 U.S.C. 136–136y and 21
this issue of the Federal Register. establishing tolerances, exemptions U.S.C. 346a and 371.
16. The docket identified by the from tolerances, raising tolerance levels
docket ID number EPA–HQ–OPP–2006– 2. By adding § 174.477 to read as
or expanding exemptions might
0643 for this document (FRL–8100–5). follows:
adversely impact small entities and
Also included in the complete official concluded, as a general matter, that § 174.477 Plant virus coat protein portion
public record are: there is no adverse economic impact of a PVCP-PIP (PVC-protein); exemption
• Public comments submitted in associated with tolerance actions. The from the requirement of a tolerance.
response to the proposals and factual basis for the Agency’s generic (a) Residues of a PVC-protein from a
supplemental documents cited in the certification for tolerance actions PVCP-PIP are exempt from the
above paragraphs. published on May 4, 1981 (46 FR requirement of a tolerance if the
• Reports of all meetings of the 24950). Since this proposed rule will encoded PVC-protein is virtually
Biotechnology Science Advisory not have an adverse economic impact, unmodified when compared to an entire
Committee and the FIFRA Scientific EPA hereby certifies under section unmodified coat protein from a virus
Advisory Panel pertaining to the 605(b) of the RFA that this action will that naturally infects plants that humans
development of this final rule. not have a significant adverse economic consume in toto or in part.
impact on a substantial number of small (b) When the genetic material that
• Support documents and reports. entities. Tolerance actions, such as this encodes the pesticidal substance or
• Records of all communications proposed exemption, directly regulates leads to the production of the pesticidal
between EPA personnel and persons growers, food processors, food handlers substance has been modified (e.g.,
hsrobinson on PROD1PC76 with PROPOSALS2

outside EPA pertaining to the proposed and food retailers, not States or tribes. through internal deletions, addition of
rule. (This does not include any inter- Tolerance actions do not alter the nucleotides from other virus coat
and intra-agency memoranda, unless relationships or distribution of power protein genes, or substitutions leading
specifically noted in the indices of the and responsibilities established by to amino acid changes), residues of the
dockets). Congress in the preemption provisions PVC-protein may be exempt if the
• Published literature that is cited in of section 408(n)(4) of FFDCA. As such, Agency determines, after review, that
this document. the Agency has determined that this the encoded PVC-protein has been

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19660 Federal Register / Vol. 72, No. 74 / Wednesday, April 18, 2007 / Proposed Rules

minimally modified when compared to (c) Agency determinations made provisions of 40 CFR part 177 or on the
an entire unmodified coat protein from under paragraph (b) of this section may Agency’s own initiative.
a virus that naturally infects plants that be made in response to a petition [FR Doc. E7–7296 Filed 4–17–07; 8:45 am]
humans consume in toto or in part. submitted in accordance with the BILLING CODE 6560–50–S
hsrobinson on PROD1PC76 with PROPOSALS2

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