A No-Observed-Adverse-Effect Level of 1000 Mg/Kg in A 28-Day Repeated-Dose Study as a Limit Value for Acute Toxicity Testing

Abstract

Following the guidelines of the European Community (EC), chemicals are not classified according to acute toxicity if the estimated LD50 exceeds 2000 mg kg-1. Instead of an LD50 test, a limit test is often performed for relatively nontoxic chemicals. Since a short-term repeated-dose study is required in addition to an acute toxicity test, our investigation was aimed at finding out if acute toxicity testing could be omitted under certain circumstances. The latter would contribute to the reduction of (unnecessary) animal use. Data on LD50 and the no-observed-adverse-effect level values of 28-day repeated-dose studies (NO AEL 28-d) were retrieved from EC notifications for new substances. We statistically evaluated the LD50 and the NOAEL28-d values of 766 compounds (rat data only). At a NO AEL28-d of 1000 mg kg-1 there was a 4% probability of the associated LD50 being lower than 2000 mg kg-1. The probability of the LD50 being lower than 200 mg kg-1 was estimated at 0.04%. If such small probabilities of misclassification are considered acceptable, acute toxicity testing could be omitted at a NOAEL28-d of 1000 mg kg-1 or higher. A NOAEL28-d of 1000 mg kg-1 could thus function as a limit value for the acute toxicity testing requirement. Application of this limit value would have made acute toxicity testing redundant for 286 out of 766 compounds reviewed. The use of the limit value may thus form an important contribution to the reduction of animal use.