Are toxicological analysis still mandatory according to the proposed regulation from EC ?

Are toxicological analysis still mandatory according to the proposed regulation from EC to Member states on GMP’s risks assessment ?

« SANCO/12462/2011 Rev. 2 (POOL/E1/2011/12462/12462R2-EN.doc [...](2012) XXX draft
of XXX on applications for authorisation of genetically modified food and feed in accordance with Regulation (EC) No 1829/2003 of the European Parliament and of the Council and amending Regulations (EC) No 641/2004 and (EC) No 1981/2006 »

Inf’OGM’s analysis of the text
Concerning toxicological analysis, the proposed regulation is written with a main paragraph and 4 sub-sections pushing forward « the specific information requirements and testing strategies ». 
The main paragraph, which applies to the whole paragraph 1.4., establishes one principle : "The toxicological impact of any changes resulting from the expression of introduced genes or any other type of genetic modification, (such as gene silencing or over-expression of an endogenous gene) shall be assessed".

Although this principle seems quite clear, one question needs relevantly to be answered : do the word “changes” concern those directly linked to the newly introduced gene (the new property conferred to the plant) or do it concern all the possible changes in the plant following the gene’s introduction ? For those latter, as the companies usually conclude to the substantial equivalence of the GM plant with its isogenic comparator, the answer will certainly be that no changes are coming from the gene’s introduction. Considering that the new protein is analysed, will companies be able to read this principle as not making mandatory analysis on the whole plants, in addition to the comparison of composition analysis ?

Reading the proposed regulation, the main principle appears to be subjected to special provisions (or to be confirmed depending on the answer to the first question quoted above) :

- "The applicant shall consider the need of toxicological testing based on the outcome of the molecular and comparative analysis referrer to in Section 1.2 and 1.3, namely the differencies identified between the GM products and its conventional counterpart, including intended as well as unintended changes" 
The applicant will therefore decide on the need and relevancy to conduct a toxicological analysis. To do so, it will use the results of comparative analysis (also called substantial equivalence). To Inf’OGM, this is a serious limitation of the main principle if this latter should make mandatory those analysis.

- "As regards applications of which the scope include or is restricted to genetically modified food and feed produced from genetically modified plants, toxicological studies with the processed products shall not be provided under the condition that the applicant provides a risks assessment of the genetically modified plants (or relevant parts of it) demonstrating its safety and provided that there are no indications that the processed genetically modified food and feed would be any different from their respective conventional counterpart. The applicant shall provide adequate justicication in this regard".
Concerning processed products, toxicological analysis won’t be requested if the applicant provides a risk assessment which conclude to the absence of risk associated with the GMP, and under condition of substantial equivalence.

The sub-section of the main paragraph works the same way : establishing a principle which is then subjected to special provisions : 

1.4.1. Testing of newly expressed proteins  
Principe : "The applicant shall provide an evaluation of all newly expressed proteins."
Exceptions : "As regards proteins expressed in the genetically modified plant, in the case where the history of safe use for consumption as food and/or feed of both the plant and the newly expressed proteins is duly documented, specific toxicity testing as provided for in this Section shall not be required."
"Acute toxicity testing of the newly expressed proteins of genetically modified plants is of little additional value for the risk assessment of the repeated human and animal consumption of genetically modified food and feed and shall not be provided as part of the studies performed under this Point."

1.4.2. Testing of new constituents other than proteins 
"The applicant shall provide a risk assessment of identified new constituents other than proteins. This shall include, on a case-by-case basis an evaluation of their toxic potency and of the need of toxicological testing as well as a determination of their concentration in the genetically modified food and feed."
The need of toxicological analysis is here to be considered. It seems that this paragraph 1.4.2. doesn’t make it mandatory, with the exception that it is considered needed (who’s deciding that ?).

1.4.3. Information on altered levels of food and feed constituents  
This paragraph applies only when "the intended or unintended effect of the genetic modification would result in an alteration of the levels of food and feed constituents beyond the natural variation."
The toxicological analysis is to be conducted based on the results of the risk assessment : "The result of that risk assessment shall determine if, and to what extent, the applicant shall provide toxicological tests on selected food and feed constituents.".

1.4.4. Testing of the whole genetically modified food and feed
The circumstances for specific toxicological analysis are to be conducted are described here : "Under the circumstances set out in Points, and of this Section, specific toxicological studies with the whole genetically modified food and feed shall be carried out."
The sub-paragraph of this one are providing, on a case by case basis, the situations where toxicological analysis are required. This sub-paragraph is subjected to the main paragraph 1.4. and the special provisions of this latter. 90-day feeding study in rodents with whole genetically modified food/feed :
This paragraph list the situation when toxicological analysis are required. But this sub-paragraph is subjected to the main paragraph 1.4. and the specific provisions of this latter.
« The applicant shall include a 90-day feeding study with whole food and feed in rodents for the assessment of food and feed containing, consisting of or produced from genetically modified plants with a single transformation event or with stacked transformation events which are not obtained by conventional crossing of genetically modified plants containing a single transformation event ».
Once again, if this paragraph seems to imply that toxicological analysis on whole plants (with one transgenic event) are to be done, it is nonetheless subjected to the main paragraph 1.4. and the special provisions of this latter.

« In the case of stacked transformation events obtained by conventional crossing of genetically modified plants containing one or several transformation event(s), a 90-day feeding study with whole food and feed in rodents shall be included for each of the genetically modified plant with a single transformation event which was used. An additional 90-day feeding study with whole food and feed in rodents with the genetically modified plant with the stacked transformation events shall be included where indications of potential adverse effects are identified during the assessment of (i) the stability of the inserts, (ii) the expression of the inserts and (iii) the potential synergistic or antagonistic effects resulting from the combination of the transformation events. »
This paragraph states that toxicological analysis are not mandatory for stacked GM plants, meaning containing more than one transgenic event, all introduced by conventional crossing, and considering that single event GM plants have been assessed (still under the main paragraph 1.4). The question to be raised here is the number of transgenic events that can be considered (two, three, eights, more ?).

This regulation seems to establish one principle : toxicological analysis are mandatory. But it needs to be clarified.
This principle is subjected to many and important special provisions (or is confirmed, depending on its understanding), notably those stated in the main paragraph which are referring to substantial equivalence, which applies in a broader way and limit the sub-paragraph. Those special provisions cancel the main principle in its potential objective to make toxicological analysis mandatory.