Commission Regulation (EC) No 429/2008Show full title

4.2.3. Section III: studies concerning the safety of the additives

4.2.3.1. Studies concerning the safety of use of the additive for the target animals

The whole of subsection 3.1.1 of Annex II applies.

Applicants are encouraged to use, wherever possible, at least a 100-fold overdose in the experimental group and consequently reduce the number of end-points required. A concentrated form of the additive can be used for this purpose. Concentration shall be adjusted by reducing the amount of carrier present but the ratio of active agent(s)/substance(s) to the other fermentation products must remain the same as in the final product. For enzymes, the diet shall provide the appropriate substrate(s).

The whole of subsection 3.1.2 of Annex II applies for all micro-organisms and for those enzymes with a direct catalytic effect on elements of the microbiota or which otherwise are claimed to affect the gut microbiota.

Where there is novel exposure or a substantial increase in the extent of exposure to micro-organisms, additional studies may be necessary to demonstrate the absence of adverse effects on the commensal microbiota of the digestive tract. For ruminants, direct counts of the microbiota will be necessary only if indicted by evidence of an adverse change to rumen function (measured in vitro as a change in volatile fatty acid concentrations, reduction in propionate concentration or reduced cellulolysis).

4.2.3.2. Studies concerning the safety of the additive use for consumer

(1)

Metabolic and residue studies are not required.

(2)

Toxicological studies, according to subsection 3.2.2 of Annex II.

Enzymes and micro-organisms form only a part of the whole additive which, in most cases, can include other components originated from the fermentation process. Consequently, it is necessary to test the additive to ensure it does not contain mutagenic or otherwise materials that can harm human consumers of food derived from animals feed with feedingstuffs or water treated with these additives.

However, most viable bacteria intended for direct or indirect ingestion by mammals (including humans) are selected from groups of organisms with a history of apparent safe use or from groups where the toxic hazards are well defined. Similarly, the hazards associated with micro-organisms currently used for the production of enzymes generally are well recognised and substantially reduced by modern production methods. Therefore, for enzymes from microbial sources and for micro-organisms with a history of apparent safe use and where the components of fermentation process are well defined and know, toxicity tests (e.g. oral toxicity or genotoxicity testing) are not considered necessary. However, for both live organisms and those used for the production of enzymes, the specific concerns in section 2.2.2.2 of Annex II shall always be addressed.

When the organism or its application is novel and insufficient is known about the biology of the (production) organism to exclude a potential for the production of toxic metabolites, genotoxicity and oral toxicity studies made with additives containing viable micro-organisms or enzymes shall be introduced. In this case, they shall take the form of genotoxicity studies including mutagenicity and a subchronic oral toxicity study. It is recommended that such studies are performed with the cell-free fermentation broth or in the case of a solid state fermentation, an appropriate extract.

4.2.3.3. Studies concerning the safety of the additive for users/workers

The whole of subsection 3.3 of Annex II applies except:

• enzymes and micro-organisms, as proteinaceous substances, are assumed to be respiratory sensitisers unless convincing evidence to the contrary is provided. Therefore, no direct testing is required.

• the formulation of the product (e.g. micro-encapsulation) may obviate the need for some or all tests. In such cases, appropriate justification shall be provided.

4.2.3.4. Studies concerning the safety of the additive for the environment

The whole of subsection 3.4 of Annex II fully applies for micro-organisms which are not of gut origin or are not ubiquitous in the environment.