Division (2) The identification of a substance as having endocrine-disrupting properties that may cause adverse effect in humans in accordance with point (1) shall be based on all of the following points:

all available relevant scientific data (in vivo studies or adequately validated alternative test systems predictive of adverse effects in humans or animals; as well as in vivo, in vitro, or, if applicable, in silico studies informing about endocrine modes of action):

1. (i)

   scientific data generated in accordance with internationally agreed study protocols, in particular those referred to in Annexes II and III of Regulation (EU) No 528/2012;

2. (ii)

   other scientific data selected applying a systematic review methodology;

an assessment of the available relevant scientific data based on a weight of evidence approach in order to establish whether the criteria set out in point (1) are fulfilled; in applying the weight of evidence determination, the assessment of the scientific evidence shall, in particular, consider all of the following factors:

1. (i)

   both positive and negative results;

2. (ii)

   the relevance of the study designs for the assessment of adverse effects and of the endocrine mode of action;

3. (iii)

   the quality and consistency of the data, considering the pattern and coherence of the results within and between studies of a similar design and across different species;

4. (iv)

   the route of exposure, toxicokinetic and metabolism studies;

5. (v)

   the concept of the limit dose, and international guidelines on maximum recommended doses and for assessing confounding effects of excessive toxicity;

using a weight of evidence approach, the link between the adverse effect(s) and the endocrine mode of action shall be established based on biological plausibility, which shall be determined in the light of current scientific knowledge and under consideration of internationally agreed guidelines;

adverse effects that are non-specific secondary consequences of other toxic effects shall not be considered for the identification of the substance as endocrine disruptor.