The value of acute toxicity testing of pharmaceuticals for estimation of human response

The determination of single high doses of active pharmaceutical ingredients (API) is used mostly to fulfill regulatory demands. Oral LD50 values in animals for over 300 API were compared to the minimal effective therapeutic doses (METD) in humans in order to find a correlation between animal and human data. The highest correlation between human METD and animal LD50 was found for the dog (R = 0.323), the lowest for the rat (0.287). It was determined that acute oral LD50 of rats have poor correlation with the METD, and cannot be used as a classification criteria into official acute toxic categories. Only 13% of API has been classified as fatal if swallowed according to the EU CLP regulation, none of the substances with very low therapeutic dose have been identified as EU CLP acute toxicity category 1. Substances with very low therapeutic doses, which could potentially have toxic effects in humans, are not identified with the use of oral LD50 and current classification system. We propose that the acute toxicity based on rat LD50 dose is not used as a basis for classification of pharmaceuticals, and that the METD is applied as basis for classification.

► Acute oral LD50 of rats have poor correlation with the METD, and cannot be used as a classification criteria. ► Substances with very low therapeutic doses are not identified with the use of oral LD50. ► We propose that the acute toxicity based on rat LD50 dose is not used as a basis for classification of pharmaceuticals.