Division II.4.2

The detailed and critical summary shall:

1. (a)

   include a clear position on the adequacy of the data presented, in light of current scientific knowledge;

2. (b)

   have an introduction describing the actual or proposed pattern of use of the substance under review in animal husbandry and a summary of any other experience of its use;

3. (c)

   consider the extent to which the substance concerned has similarities to other known substances, which may be relevant for the evaluation;

4. (d)

   cover all standard data requirements, as set out in the Commission Implementing Regulation (EU) 2017/12^f1, provide a critical evaluation of the available experimental studies and an interpretation of the results;

5. (e)

   provide scientific justification for the omission of any studies that are described in this section;

6. (f)

   discuss requirements for additional studies;

7. (g)

   provide a description and explanation of the key findings for each study. The following issues shall be discussed: the animal species used, the number(s) of animals used, the route(s) of administration, the dosage(s), the duration of treatment, the exposure achieved, the dose response relationship, the nature of the adverse effects (their onset and duration, their dose dependency and reversibility and any species related or sex-related differences), known relevant structure-activity relationships and relevance of the findings for human consumers;

8. (h)

   give a justification for the NO(A)EL or LO(A)EL or BMDL proposed for each study;

9. (i)

   summarise and discuss relevant scientific literature, including reports of evaluations undertaken by other scientific bodies (such as the European Food Safety Authority (‘EFSA’), European Chemicals Agency (‘ECHA’) and the Joint Food and Agriculture Organisation (‘FAO’)/World Health Organisation (‘WHO’) Expert Committee on Food Additives (‘JECFA’)). If detailed references to published scientific literature are used, all the requirements set out under point I.5 shall be met, as far as possible;

10. (j)

    include information on the quality of batches of test substances used in the safety studies. Any association between findings and the quality of the test substances and/or the medicinal products shall be indicated. When necessary, a critical evaluation of the impurities present in the active ingredient shall be presented and information on their potential biological effects shall be given. The implications of any differences of the chirality, chemical form and impurity profile between the substance used in the safety studies and the form to be marketed shall be discussed;

11. (k)

    discuss the GLP status of the studies submitted;

12. (l)

    discuss possible deficiencies in the design and conduct of the studies and their documentation, making reference to published F1... guidance. Any deviations from applicable guidance shall be highlighted and the impact of the deviation discussed and scientifically justified;

13. (m)

    comment on the use of experimental animals in the studies and whether the studies were conducted in accordance with F2the Animals (Scientific Procedures) Act 1986;

14. (n)

    provide a justification for the selection of critical NO(A)EL(s) or BMDL(s) and the derivation of the acceptable daily intake (‘ADI’), justifying the selection of uncertainty factors. If no ADI is proposed, or if an alternative toxicological reference value is selected, this shall be thoroughly justified.