On 26 September 2017 the FEEDAP Panel adopted three new Guidances that are intended to assist applicants in preparing a dossier.
At the same time these guidances also reflect what data FEEDAP expects in an application for authorisation and that are indispensable for a final opinion. The adoption was preceded by a relatively long process lasting over a year of deliberation and reflection (review of the need for new guidances, review of alternative ideas and drafts), coordination with the Risk Manager and the stakeholders, and internal discussion. The new guidances take into account the scientific progress achieved since the first versions of 2008 (the amendments in the second versions of 2011 were chiefly of an editorial nature) and FEEDAP’s experiences with the applications since use of the guidances (and the overarching Regulations on feed law). The process of revising guidances has not yet been completed. The first new guidances published in the EFSA Journal are the Guidance on the assessment of the safety of feed additives for the target species (EFSA Journal 2017;15(10):5021), Guidance on the assessment of the safety of feed additives for the consumer (EFSA Journal 2017;15(10):5022), and Guidance on the identity, characterisation and conditions of use of feed additives (EFSA Journal 2017;15(10):5023).
These guidances, that are regrettably only available in English, enter into force on 1 May 2018. If applicants believe they do not have to or cannot follow the requirements of the guidance, they must provide acceptable justification for this.
The Guidance summarises the requirements that have so far been scattered across different guidances on how the safety of an additive can be determined for the target species and this should consequently make it easier for applicants to obtain an overview of the respective requirements. However, all the FEEDAP Guidances do not relieve applicants of their obligation to comply with the requirements of REG (EC) No. 1831/2003 with its Implementation Rules (REG (EC) No. 429/2008). The new Guidance reinforces the obligation of applicants to take the RRR (Reduction, Replacement, Refinement) principles into account in the planning of animal experiments. Whereas so far the tolerance trial on the target species de facto represented the sole possibility of demonstrating the safety of the additive for the target species, a three-phase procedure is now being introduced.
For a series of additives no supporting evidence of their safety in the target species is required. Such safety is assumed a priori. This concerns for instance all nutritional additives authorised so far and the microorganisms that qualify for the criteria of QPS (Qualified Presumed Safety). If the exemptions do not apply and so evidence of the safety of the additive for the target species is required, the guidances recommend extensive research in the appropriate literature as a first and simplest step. The critical point here is the requirement that the substance in the publications must be – if not identical – at least similar to the substance for which the application is being made, so that conclusions can be extrapolated. Alternatively the safety of additives (with the exception of live microorganisms) can be derived from toxicological data (NOAEL (No Observed Adverse Effect Level) or BMDL (BenchMark DoseLlevel) from sub-chronic testing on laboratory animals). The data for converting the various dimensions (NOAEL in mg/kg bodyweight, safe application concentration for the target animal in mg/kg straight feed) must comply with certain specifications that are summarised for the feed consumption (g dry matter/kg bodyweight) for the potential target species in a table. If no toxicological data are available for the substance, TTC (Thresholds of Toxicological Concern) levels can be used for (most) flavouring substances on the basis of their allocation to certain (Cramer) classes. However, this method only allows very low “safe maximum concentrations” in the feed (between 0.02 and 1.5 mg/kg depending on the Cramer class and target species). If the safety of an additive cannot be (satisfactorily) documented (the applicant insists on higher application concentrations) in accordance with the above methods, an in vivo tolerance study – generally on the (healthy) target species – must be presented. The purpose of this is to determine a kind of short-term toxicity and a safety margin for the application concentration. For this, at least three trial groups are set up – one control group without the addition of the test substance, one trial group with the maximum substance concentration applied for, and one overdose group with a multiple of the application concentration in the feed. The depth of the examination (nature and number of the experimental parameters) depends on the amount by which the substance concentration in the overdose group exceeds the concentration in the application without any detrimental effects being observed. If the overdose is a hundredfold or more of the application concentration, clinical symptoms, performance parameters and possibly product quality are sufficient. If the overdose is only tenfold to one hundredfold of the concentration in the application, a blood analysis and clinical routine analyses in the blood are required in addition. If the overdose is less than tenfold, pathological examinations are also called for. The Guidance covers the trial planning and the statistics to be applied (to determine the sample size as well), the minimum duration of the tolerance study for the individual animal species/categories and the nature of the trial parameters in depth. Theoretically, tolerance studies should be available for each species or category named as target. As this is an unrealistic expectation, especially when the application is submitted for all animal species and categories, rules for extrapolating from one animal species/category to others are provided. For example, the results of a tolerance study on broiler hens can be transferred to other growing poultry species, the results for layer hens are assumed to be valid for other egg-laying poultry species. Special supplementary examinations are required for reproduction (sitting hens). However, extrapolation between physiologically different species is also possible. For example, if the application refers to all terrestrial animal species, it is sufficient to conduct one study each on broiler hens, pigs and dairy cattle.
The Guidance provides detailed directions for organising the trial report, draws attention to the documentation of possible interactions between the additive and other additives and medicaments, and describes under what circumstances microbiological examinations are also necessary to establish a safe dose for the target species.
The authors – Gerhard Flachowsky and Jürgen Gropp – are long-serving members of the EFSA Panel on Additives and Products or Substances in Animal Feed (FFEDAP). They report on the work of the FEEDAP Panel. The articles contain personal views and representations, not those of EFSA or the EU. Consequently they do not necessarily coincide with the viewpoints of EFSA or the EU. As experts working on behalf of EFSA, the authors are subject to certain confidentiality obligations.