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Various specific investigations regarding thyroid effects were performed with the substance itself and read-across substances. The substance is an inducer of the liver-thyroid axis in rats. It does not directly inhibit hepatic deiodinase activity as in tested with rat and monkey liver homogenate.

Additional information

The species-specific mechanisms causing the thyroidal stimulation following uptake of 2,6-substituted phenols (and similar compounds) in rats have been described in standard textbooks and are generally acknowledged by the scientific community (Davies, D.T. (1996). Thyroid Endocrinoloy. Animal Clinical Chemistry: A primer for Toxicologists. Ed: A.O. Evans,and Francis,). From basic research performed over several years, it became clear, that the stimulation of glycuronidyl-transferase synthesis is used to facilitate excretion of 2,6-substituted phenolic antioxidants. However, glycuronidyl-transferase is also able to promote the excretion of thyroid hormones. This has remarkable consequences for the physiology of the rat upon exposure to phenolic antioxidants:

- In the rat, the thyroid hormones T3 and T4 are not bound to a specific carrier protein in the plasma. Therefore, increased levels of glycuronidyl-transferase (induced e.g. by 2,6-substituted phenolic antioxidants) speed up the elimination of T3 and T4. This causes a drop of the plasma concentrations of T3 and T4. By feedback mechanism, reduced levels of T3 and T4 hormone subsequently lead to a stimulation of the thyroid to produce new hormone. The chronic stimulation of the thyroid can cause hyperplasia and can lead in extreme cases to thyroid tumours.

- In primates, about 90% of the thyroid hormones T3 and T4 are bound to a specific protein (thyroxine binding protein) in the plasma. Due to this protein, primates are protected from significant changes of thyroid hormone levels in the plasma, even in the presence of high levels of glycuronidyl-transferase. Consequently, in primates thyroid hormone concen­trations are not affected, no feedback mechanisms are induced to produce new T3 and T4 and no thyroid hyperplasia occurs.

The active, bioavailable substructure of the test item is closely related to 2’,6’-di-tertiary butylmethylphenole (=butylated hydroxytoluene, BHT). BHT is a direct food additive used world-wide since decades and causes - similar to the test article - a stimulation of the thyroid in rodents. BHT is known to be safe for humans due to the long-lasting experience and due to the well investigated mechanisms of toxicity (see above).