Canadian Food Inspection Agency
Plant Products Directorate
Plant Biosafety Office

INTERIM AMENDMENT TO DIR2000-07 FOR CONFINED RESEARCH FIELD TRIALS OF PNTs FOR PLANT MOLECULAR FARMING

DIRECTIVE 2000-07

Section 1.2 DEFINITIONS

Add the following definition:

PLANT MOLECULAR FARMING:
The use of plants in agriculture for the production of pharmaceutical or industrial compounds and not intended for general use as food and/or feed.

Add new Section 1.4:

Section 1.4 PLANT MOLECULAR FARMING

The Government of Canada is currently initiating a broad policy review of plant molecular farming. Until this consultation and analysis is complete, applications for confined research field trials for PNTs intended for plant molecular farming will be addressed on a case-by-case basis, with authorizations granted according to this amendment. Applicants should note the following interim recommendations:

• The use of major food or feed crop species for plant molecular farming is not recommended.
• The use of crop species that are pollinated by bees that contribute to commercial honey production is also not recommended for plant molecular farming.
• Developers are encouraged to consider fibre crops, crops with only minor food or feed use, small-acreage specialty food or feed crops, or new crops as production platforms.
• The host species should also be as amenable to confinement as possible, i.e. developers should consider level of outcrossing, mode of pollination, weediness, seed dormancy, seed dispersal, harvest efficiency, tendency to volunteer, and available reproductive control mechanisms in choosing a host plant species.
• Genetic mechanisms such as tissue-specific or post-harvest inducible expression of the compound may be useful in mitigating environmental exposures.

Section 2.4 WHEN TO APPLY

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Please take into account that for submissions for confined research field trials of PNTs intended for plant molecular farming using crop species traditionally used for food or feed, additional time will be required for assessment by Health Canada (if a food crop species is used), and/or the Feed Section, CFIA (if a feed crop species is used), of potential risks to food and feed supplies (see Section 3.10.6). Note that Health Canada and the Feed Section, CFIA require 60 days for this assessment. Where submitted data is incomplete, additional data will be requested and a new 60 day assessment period will commence when the additional data is received. Applicants are encouraged to consult with the Plant Biosafety Office as early as possible to avoid planting delays.

Section 3.4 RECORDS AND REPORTING OF CONFINED TRIALS

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In the case of PNTs intended for plant molecular farming, these records must be submitted to the Plant Biosafety Office within 60 days of harvest.

 Section 3.5.1 ISOLATION DISTANCES (SPATIAL, SEPARATION) AND DESTRUCTION ZONES

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Please note that minimum isolation distances of PNTs intended for plant molecular farming may be greater than that required for other PNTs (see Appendix 4). Minimum distances from plant molecular farming trials to seed production fields, or to food or feed crops or pasture are also required (see Appendix 4).

Section 3.6 DISPOSITION OF PLANT MATERIAL FROM CONFINED TRIALS

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In the case of PNTs for plant molecular farming, disposal and destruction of all residual plant materials must be witnessed by a CFIA inspector (see Section 3.10.6).

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CONTINGENCY PLANS

Applicants must also provide contingency plans for responding to accidental breaches of containment. These plans must include immediate notification of regulatory authorities and commodity handlers, and provide for monitoring, tracking, recall and destruction of accidentally-released plant material from the environment and/or food or feed supply chains.

Section 3.7 POST-HARVEST LAND USE

Add the following paragraph:

Developers are encouraged to avoid cultivation of crops for food or feed use in post-harvest years following trials of PNTs intended for plant molecular farming. Some additional post-harvest land use restrictions, including restrictions of cultivation of food or feed crops, may be imposed in some cases following trials of PNTs intended for molecular farming (see Appendix 4 section 1).

Add new section 3.10.6:

Section 3.10.6 PNTs FOR PLANT MOLECULAR FARMING

As with all confined research field trials of PNTs, seed logs must be kept and all plant material used or harvested from the trial must be accounted for. Where the intended use of the PNT is for plant molecular farming, disposal of residual material must be witnessed by a CFIA inspector. The seed log showing tracking of seed or propagules from multiplication through planting, harvest and disposal must be presented to the inspector at that time.

If the PNT is a modification of a food or feed crop species and intended for plant molecular farming rather than for food or feed, the developer must submit exposure and hazard data for human and livestock health effects assessments. For species traditionally used for human food, data to assess human exposure and hazards of unintentional introduction by various means of the plant material into food supplies must be provided (see Appendix 6). This data will be sent by the Plant Biosafety Office immediately on receipt to Health Canada for a 60-day assessment period. Likewise, for species traditionally used for animal feed, data to assess livestock animal exposure and hazards of unintentional introduction by various means of the plant material in feed supplies must be provided (see Appendix 7). This data will be sent by the Plant Biosafety Office immediately on receipt to the Feed Section, CFIA for a 60-day assessment period. Both sets of data will be requested for species that are traditionally used for both food or feed. Where submitted data is incomplete, additional data will be requested and a new 60 day assessment period will commence when the additional data is received.

If there is any question as to whether this data is required, developers are encouraged to consult with the Plant Biosafety Office early in the application process and to be prepared to provide any necessary data at least 60 days before the anticipated planting date, to avoid planting delays.

 APPENDIX 4 Section 1

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THE FOLLOWING TERMS AND CONDITIONS WILL BE IMPOSED ON CONFINED RESEARCH FIELD TRIALS OF PNTs INTENDED FOR PLANT MOLECULAR FARMING:

(i) For traditional food or feed crop species the minimum isolation distances are two times that prescribed for the species as listed in Section 2 of this appendix. These distances may be reduced if alternative methods of reproductive isolation are used (see Section 3.5.2).

(ii) For any species, the trial must be isolated from any seed production field of the same or related species by a distance of four times the isolation distance listed for the species in Section 2 of this appendix..

(iii) Land within 50m of the trial perimeters may not be used for food or feed production, including grazing of livestock. It is not necessary that this 50m be left black. For example, ornamental species, or any other plant that will not be grazed or harvested for food or feed, may be cultivated in this area. Research trials of material that will not enter the food or feed chain will also be permitted within the 50m area.

(iv) The Plant Biosafety Office may in some cases impose restrictions on cultivation of crops for food or feed use or on grazing of livestock during post-harvest years of sites of trials of PNTs intended for plant molecular farming. These restrictions will be imposed on a case-by-case basis. Developers are encouraged to consult with the Plant Biosafety Office early in the application process to ensure appropriate planning for post-harvest land use.

APPENDIX 5 CONFINED FIELD TRIAL FORM

Add new point 1.7:

1.7 PNTs for Plant Molecular Farming. If the PNT is intended for plant molecular farming, indicate whether human or livestock toxicology and allergenicity data have been submitted, as according to Appendix 6 and/or Appendix 7.

Add new point in Section 3, for each trial site location included in the application:

Where required minimum isolation distances are two or more times those provided in Appendix 4 as for trials of PNTs intended for plant molecular farming, indicate previous land use of the trial site and isolation area, including crop species planted, in the year(s) prior to the proposed trial. The number of years of land use history required is the number of years of post-harvest land use restriction required for the species of the PNT.

APPENDIX 6

EXPOSURE AND HAZARD DATA THAT MAY BE REQUIRED FOR PNTs IN TRADITIONAL FOOD CROP SPECIES INTENDED FOR PLANT MOLECULAR FARMING RATHER THAN FOR FOOD USE

1. Potential exposure

1.1 Describe the plant tissues in which the novel compound(s) are expressed. Describe the extent to which these plant tissues may traditionally be present in human food.

1.2 Provide expression levels of the novel compound(s) in any plant tissues from which human food may be derived, or which may be inadvertently present in human food.

1.3 Describe if the novel compound(s) is present in an active form in the plant. If not, describe the trigger or procedure for activation.

2. Potential hazard

If any human food intentionally or unintentionally derived from or containing material derived from the PNT may contain the novel compound(s) as per section 1 above, please address the following:

2.1 Toxicity and other biological activity. Provide data or valid scientific rationale to show the anticipated human toxicity and/or biological activity of any human food derived from or containing material derived from the PNT if inadvertently consumed by humans, as follows:

For protein expression products, the assessment of potential toxicity should focus on amino acid sequence similarity between the protein and known protein toxins and anti-nutrients (e.g. protease inhibitors, lectins) as well as stability to heat or processing and to degradation in appropriate/representative gastric or intestinal model systems. Acute oral toxicity studies using gram/kg bw doses of the novel protein are appropriate for assessing the potential toxicity of proteins. A negative result using doses in the gram/kg body weight range together with evidence that the protein is digested to small peptides and amino acids would provide assurance that the protein is not a toxin and is digested to nutrients as are the vast majority of dietary proteins.

Different types of in vivo or in vitro studies would be needed to assess the toxicity of introduced substances other than proteins that will be used for industrial purposes (e.g. oils, plastics). The types of studies are determined on a case-by-case basis and depend on the original source of the introduced substances and their function. Such studies may include assays of metabolism, toxicokinetics, chronic toxicity/carcinogenicity, impact on reproductive function, and teratogenicity.

2.2 Allergenicity

Expression products of protein origin would require assessment for their potential to cause allergic reactions. This assessment should include consideration of whether a newly expressed protein is one to which certain individuals may already be sensitive as well as whether a protein is likely to induce allergic reactions in some individuals.

The steps in assessing possible allergenicity of any newly expressed proteins involve determination of: the allergenicity of the source of the introduced protein; any similarity between the amino acid sequence of the protein and that of known allergens; and certain physicochemical properties, including but not limited to, its susceptibility to enzymatic degradation. The endpoint of the assessment is a conclusion as to the likelihood of the expressed protein being a food allergen. For more information on the assessment of potential allergenicity, please refer to Health Canada’s Guidelines for the Safety Assessment of Novel Foods Derived from Plants and Microorganisms (2003).

2.3 Processing of plant material

Provide a description of the processing of the plant material highlighting areas where by-products are produced.

2.4 Information on donor organism

Provide any available information on the history of use in food of the donor organism(s).

Provide a critical assessment of the ability of the donor organism(s) to produce potentially toxic compounds, anti-nutritional compounds and/or endogenous allergens.

APPENDIX 7

EXPOSURE AND HAZARD DATA THAT MAY BE REQUIRED FOR PNTs IN TRADITIONAL FEED CROP SPECIES INTENDED FOR PLANT MOLECULAR FARMING RATHER THAN FOR FEED USE

1. Potential exposure

1.1 Describe the plant tissues in which the novel compound(s) are expressed. Describe the extent to which these plant tissues may traditionally be present in livestock feed.

1.2 Provide expression levels of the novel compound(s) in any plant tissues from which livestock feed may be derived, or which may be inadvertently present in livestock feed.

1.3 Describe if the novel compound(s) is present in an active form in the plant. If not, describe the trigger or procedure for activation.

2. Potential hazard

If any livestock feed intentionally or unintentionally derived from or containing material derived from the PNT may contain the novel compound(s) as per section 1 above, please address the following:

2.1 Toxicity and other biological activity. Provide data or valid scientific rationale to show the anticipated livestock toxicity and biological activity of any livestock feed derived from or containing material derived from the PNT if inadvertently fed to livestock, as follows:

Describe the mode of action of the novel compound(s) in humans and animals.

Provide any available toxicology data for the expressed compound. Data on the compound does not need to be from the plant-expressed source; however, if it is not, provide data to demonstrate similarity of the plant-expressed compound to products produced from traditional sources.

Compare the amino acid sequence of the plant-expressed compound to amino acid sequences of known toxins to determine any potential homology.

2.2 Allergenicity

Compare the amino acid sequence of the plant-expressed compound to amino acid sequences of known allergens to determine any potential homology.

Based on those endogenous allergens known to be present in the host plant, parental lines, or donor organisms, provide any available data on levels of endogenous allergen(s) in the modified plant compared to that of an appropriate comparator.

2.3 Processing of plant material

Provide a description of the processing of the plant material highlighting areas where by-products are produced.

2.4 Information on donor organism

Provide any available information on the history of use in livestock feed of the donor organism(s).

Provide a critical assessment of the ability of the donor organism(s) to produce potentially toxic compounds, anti-nutritional compounds and/or endogenous allergens.