2023 年 10 巻 7 号 p. 295-300
The amidine compound 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) is a strong organic base, is non-nucleophilic, and has been widely used in the organic synthesis of pharmaceuticals as a base catalyst. In the present study, we propose the permitted daily exposure (PDE) values of DBU by the oral, parenteral, and inhalation routes based on toxicological information in animals from the database of the European Chemicals Agency (ECHA). DBU exhibited mainly stomach toxicity caused by the corrosive effect of this strong alkali in rats. Although it is unlikely that stomach toxicity is induced in patients by DBU contamination of pharmaceuticals because most pharmaceutical products are adjusted to a near neutral pH, we calculated the PDE values conservatively based on the dosage at which no stomach-related findings were observed because no other noteworthy findings caused by systemic exposure were included in toxicity studies. By applying adjustment factors to the no-observed-adverse-effect-level (NOAEL) (120 mg/kg/day) in animal studies during the longest treatment period (3 months), we estimated the PDE values for oral, parenteral, and inhalation routes as 24, 12, and 6 mg/day, respectively. Derivation of the PDE was performed according to the concepts described by the International Conference on Harmonisation (ICH) Q3C(R8) and Q3D(R2) guidelines.
