How valid are old repeated dose toxicity studies for chemical risk assessment?

An essential endpoint for assessing human health effects also within the REACH process is the repeated toxicity in rodents. In many cases experimental studies are already available. However, these studies often have not been performed according to (current) guidelines, or without GLP. The question is, if the NOAELs and LOAELs derived from these old studies are valid, or if the studies must be repeated. To answer this question the RepDose database on repeated dose toxicity in rodents (Bitsch et al. 2006) created by Fraunhofer ITEM with funding from Cefic LRI was analysed. As expected, the extensive examination in recent Guideline studies usually results in effects in several organs/targets already at the LOAEL of a study. However, the number of organs affected is not crucial for the validity of the NOAEL or LOAEL, as long as one of the organs, which determines the LOAEL, has been examined. The most frequently affected targets at the LOAEL of high quality studies are liver, kidney, haematology, clinical chemistry and clinical symptoms, or body weight is reduced. In inhalation studies nose and lung are also affected quite often. If only one target organ triggers the LOAEL, in >80% of the cases it is one of the frequently affected target organs. Based on these findings it can be concluded that in most cases also older studies can be used to derive a reliable NOAEL or LOAEL, if the frequently affected target organs of the respective guideline study have been investigated. A repetition of studies should be considered carefully.