## EPA Response to Public Comments on

Biopesticides Registration Action Document

Proposed Decision



## Coat Protein Gene of Plum Pox Virus

PC Code: 006354



## May 10 , 2010

U.S. Environmental Protection Agency Office of Pesticide Programs Biopesticides and Pollution Prevention DivisionEPA Respon se to Public Comments on BRAD Proposed Decision: Plum Pox

May 10, 2010

2 The Biopesticides and Pollution Prevention Division (BPPD) of the Office of Pesticide Programs, EPA, has anal yz ed and considered all comments submitted on the Agency 's preliminary registration decision for the C5 Honey Sweet Plum, containing the new plant

- incorporated protectant active ingredient, Coat Protein Gene of the Plum Pox Virus (CPG

- PPV). These comments were submitted to docket EPA

- HQ

- OPP

- 2008

- 0742. This document responds to significant comments received.
General Issues Support for the registration A number of comments were received on matters generall y related to the Agency's preliminary

decision to register the C5 Honey Sweet Plum. F ifty

- o ne comments expressed support for the registration of this PI P pesticide. Representative of these comments was number 0016: " I concur with the panel of regulators that this product does not pose an y undue risks to the environment or human health. Quite the contrary , the ‘Honey sweet’ is a promising technolog y that has great potential to mitigate a devastating invasive virus. " Similarl y, number 0018 noted: " Viral coat protein genes have been known for over 20 years to provide lasting

— and very

safe

--

- resistance in plants against viruses (Fuchs & Gonsalves, 20 07 Annu al Rev. Phy topathology

45:173

- 202.). There is a compelling need for this genetically modified tree with plum pox resistance, since the only other known means to control the virus are economically damaging quarantine and eradication measures. Once a tree is infected, it must be destroyed. Eradication of plum pox in Pennsylvania in 1999 resulted in destruction of 1600 acres of trees at a cost of $40 million (Scorza et al., 2007. Acta Hortic. 738:669

- 671). Eradication of plum pox in Canada has result ed in destruction of 354,798 trees at a cost of Can.$180 million (U.S.$174 million) by

the end of March 2011 ." [ citation omitted ] [ emphasis in original ] Also, number 63: " Honey Sweet plum is highly resistant to Plum pox virus (PPV), a devastating virus of stone fruits worldwide. Resistance to PPV in Honey Sweet is due to the expression of a plant

- incorporated protectant that activates the anti

- viral pathway s of RNA silencing, a natural and potent defense mechanism of plants against viruses. Since no host resistance to PPV is known in European plum, Honey Sweet offers a practical and unique solution to manage PPV. Extensive field risk assessment studies done in various ecos ys tems have shown that HoneySweet does not pose undue risks to the environment and human health. Also, the safe use of summer squash and papay a that express similar plant

- incorporated protectants and are grown for more than a decade on thousands of acres further supports a safe use of Honey Sweet. " In addition to the comments providing a s ubstantive rationale for supporting the registration of C5 Honey Sweet Plum, there were a number of comments expressing general agreement with the decision. Comment 0013 illustrates these comments: " I have reviewed the data for this plum. It poses no thre at to the environment nor to people. I recommend that it be deregulated and released as a new cultivar. It should be of great use to consumers. "EPA Respon se to Public Comments on BRAD Proposed Decision: Plum Pox

May 10, 2010

3 EPA Response : EPA agrees that the C5 Honey Sweet Plum should be registered pursuant to our authorit y under Sec tion 3 of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) . The C5 Honey Sweet Plum registration application is supported by

adequate data and/or rationales for waiver of data requirements (in accordance with 40 C.F.R. section 152.45), and w e have determined that use of this product consistent with the terms of the registration will not result in unreasonable adverse effects on the environment. Opposition to the Registration One comment expressed general opposition to the registration. Comment 0036 stated "Say

no to GMOs!" (Other comments expressed opposition to the Agency registering this pesticide under FIFRA; but, supported the sale and distribution of the C5 Honey Sweet Plum. These comments will be addressed separatel y below.)
EPA Res ponse: Pursuant to Section 3 of FIFRA, EPA grants registrations permitting the sale and distribution o f pesticides that we have determined will not result in unreasonable adverse effects to the environment when used consistent with the terms and/or condit ions of the registration. The Agency does not have the legal authority to categorically deny

registration to any

class of pesticides for which it is demonstrated that they

can be used in a manner that does not result in unreasonable adverse effects to the environment.
FI FRA S ection 3 registration comments A number of commenters asserted that the C5 Honey Sweet Plum should not be subject to registration under FIFRA. Commenter 0017 noted that Honey Sweet Plum does not contain an y novel product that could b e considered a toxin. The comment further states that the fact that the transgenic component here does not produce an y toxic effect "provides EPA ample justification to exempt" this product from registration requirements. Commenter 0064 stated that "the molecular components of resistance bred into plants" should not be classified as pesticides. Commenter 0069 stated that "there is no scientificall y justifiable reason for EPA to even consider the [CPG

- PPV] to be a plant incorporated protectant". In parti cular, because no virus coat proteins are intended to be produced, the C5 plum does not "in any meaningful sense contain a 'substance' that should be classified as a PI P." Commenters 0070 , 0072, and 0074 made similar points. EPA Response: Whether a substance is a toxin or has a toxic effect is not dispositive as to whether it is a pesticide for purposes of FIFRA regulation. FIFRA section 2(u) defines “pesticide” as: “(1) any

substance or mixture of substances intended for preventing, destroy ing, r epelling, or mitigating any pest, (2) any

substance or mixture of substances intended for use as a plant regulator, defoliant, or desiccant, and (3) an y nitrogen stabilizer”

. 7 U.S.C. section 136(u). Under FIFRA section 2(t), the term “pest” includes “(1) an y insect, rodent, nematode, fungus, weed, or (2) an y otherEPA Respon se to Public Comments on BRAD Proposed Decision: Plum Pox

May 10, 2010

4 form of terrestrial or aquatic plant or animal life or virus, bacteria, or other micro

organism (except viruses, bacteria, or other micro

- organisms on or in living man or other living animals ) which [EPA] declares to be a pest under section 25(c)(1) of [FIFRA]. ” 7 U.S.C. section 136(t). Thus, an y substance the intent of which is to mitigate a pest is, b y definition, a pesticide under the statute. There is no requirement that the substance be toxic, or, as relevant here, that it be "present" in a particular form. Where, as here, the CPG

- PPV has the effect of initiating a host plant defense mechanism that functions to mitigate the harmful effects of a pest, it is appropriatel y determined to be, and regulated as, a pesticide. As to whether there was sufficient evidence presented to exempt the CPG

- PPV from the requirements of FIFRA, that question was not before the Agency . The Applicant submitted a registration application, not a petition to ex empt this active ingredient. The Agency

reasonabl y proceeded to make a decision on the application before it, rather than effectuate an regulatory decision other than what was requested. It is useful to provide some explanation as to why the CPG

- PPV is a PI P. EPA explained the definition of a PI P at 66 Fed. Reg. 37771 ( July 19, 2001)

. As discussed therein, when traits from an y living organism that have pesticidal properties are introduced into novel organisms, the substances are pesticides under the FIF RA definition of pesticide, regardless of whether the pesticidal capability evolved in the plants or was introduced b y breeding or through the techniques of modern biotechnology

. The genetic material necessary for the production of such a pesticidal subst ance also meets the FIFRA statutory definition of a pesticide. Such genetic material is introduced into a plant with the intent of ultimately producing a pesticidal effect even though the genetic material may not, itself, directly

affect pests. The pesti cidal substance, along with the genetic material necessary to produce it, produced and used in living plants, is designated a “ plant

- incorporated protectant ” by EPA. Plant

- incorporated protectants are primarily distinguished from other ty pes of pesticides because they are intended to be produced and used in the living plant. FFDCA tolerance exemption comments A number of commenters made the point that the CPG

- PPV protein should not be regulated b y EPA. Comment 0017 stated that EPA should not assess the safet y of a

" hy pothetical coat protein ," and that it is not “ even an inert ingredient (since it is absent)

. ” Comment 0061 noted that “without a pox virus coat protein product in C5 plants, there is no chance of an allergenic reaction from the engineered DNA construct. Further there is also very little reason to expect any hy persensitivity reactions from contact with C5 plants.” Comm ent 0069 noted that the C5 plum does not express any novel protein prior to initiation of the plant’s defense mechanism and that, moreover, the C5 plum is not intended to produce novel proteins

. Comment 0070 stated that EPA should not “require safet y assessments of the proteins per se. As noted above humans safel y ingest large amounts of coat proteins of numerous plant viruses , and it is not the active ingredient intended to produce the PI P effect (it is the DNA that invokes RNAi, not the protein). Earlier work had tried to produce resistance via coat proteins, but these have largel y been superseded by RNAiEPA Respon se to Public Comments on BRAD Proposed Decision: Plum Pox

May 10, 2010

5 induction using the coat protein

- encoding DNA or targeting other viral sequences.” Comment 0074 noted that “the CP coding mRNAs elicit natural plant defense responses conferring post

- transcriptional gene silencing (PTGS) to subdue viral development. As such, CP mRNAs are me rel y elicitors while innate plant compounds are the key

play ers in the resistance reaction. Further, translational products of the transgene are undetectab le. ” EPA Response Essentially , these comments address a key point considered in regulation of C5 Honey Sweet Plum trees

– if the protein is undetectable, wh y is it regulated? EPA decided to approach this issue with caution noting that conditions where PTGS in plants is generall y known to occur include during times of plant stress, cold weather, and up on infection with plant viruses that express PTGS

- inhibitors. Therefore, insertion of an open reading frame theoreticall y able to produce translatable mRNAs led to anal ys is of the putative protein, in other words the protein that would be produced under unknown (though probabl y unlikely) circumstances. It is the putative coat protein from genes inserted into the C5 Honey Sweet Plum, therefore, that are exempt from a food tolerance under FFDCA as an inert ingredient

. EPA agrees with the commenters that muc h of the dietary safet y assessment for the coat protein of plum pox virus is based on the safe consumption of the current food supply , which has been demonstrated to have significant levels of plant virus present. The dietary

safet y assessment for plum po x virus resistant C5 plum and other PI Ps dependent on the RNAi gene silencing phenomenon is also facilitated b y the reduced potential for an y virus coat protein production from this trait. The safet y issue comes from the fact that, during production of th e DNA for insertion into the plant, there may be amino acids added to the plum pox coat protein or variations in the amino acid sequence in the plum pox coat protein. The dietary assessment is based on the existing plum pox coat protein exposure. The Age ncy acknowledges that there is natural variability

in the population of viruses infecting plants and possibly variant coat proteins. However, the possible production and presence of a new protein related to the use of a PIP requires an examination of the new protein for dietary safet y if it differs from that currently found in the food supply.
Label comments A number of comments were received asserting that the C5 Honey Sweet Plum should not be distributed with a FIFRA label and that an y label that did ac company the product should not include the statement “PPVR: not intended for use in organic agriculture”. EPA Response: As a point of clarification, we note that the proposed label included in the docket was not intended to be a label to accompan y the product in commerce. Consistent with our practice with other registered PI Ps, the FIFRA label for the C5 Honey Sweet Plum is not required to accompan y the product distributed in commerce. Rather, theEPA Respon se to Public Comments on BRAD Proposed Decision: Plum Pox

May 10, 2010

6 label is approved concomitant with the registration and is held by the registrant. We placed the label in the docket because this is our normal practice for all products for which we have made a preliminary decision to register and which are subject to public comment. We did not intend to inadvertently send a signal that this is a label that would be required as a term of the registration to accompan y the product in commerce. Consistent with practice for other registered PIPs, the C5 Honey Sweet Plum will be accompanied b y labeling developed b y the registrant. This labeling will set forth specific terms of agreement between USDA and the distributors of the budwood. This is consistent with the current practice for other registered PIP products.
S imilarly , with respect to the statement regarding whether th e C5 Honey Sweet Plum may be used in organic production, we are not requiring as a term of the registration granted to USDA that the statement “not intended for use in organic agriculture” be included on the C5 Honey Sweet Plum label.