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Statistical evaluation of the revised fixed-dose procedure

Medical and Pharmaceutical Statistics Research Unit, The University of Reading, Reading, UK; MPS Research Unit, The University of Reading, PO Box 240, Earley Gate, Reading RG6 6FN, UK; n.stallard{at}reading.ac.uk

A Whitehead

Medical and Pharmaceutical Statistics Research Unit, The University of Reading, Reading, UK

P Ridgway

Health Directorate, Health and Safety Executive, Bootle, Merseyside L20 3QZ, UK

The fixed-dose procedure (FDP) was introduced as OECD Test Guideline 420 in 1992, as an alternative to the conventional median lethal dose (LD₅₀) test for the assessment of acute oral toxicity (OECD Test Guideline 401). The FDP uses fewer animals and causes less suffering than the conventional test, while providing information on the acute toxicity to allow substances to be ranked according to the EU hazard classification system. Recently the FDP has been revised, with the aim of providing further reductions and refinements, and classification according to the criteria of the Globally Harmonized Hazard Classification and Labelling scheme (GHS). This paper describes the revised FDP and analyses its properties, as determined by a statistical modelling approach. The analysis shows that the revised FDP classifies substances for acute oral toxicity generally in the same, or a more stringent, hazard class as that based on the LD₅₀ value, according to either the GHS or the EU classification scheme. The likelihood of achieving the same classification is greatest for substances with a steep dose–response curve and median toxic dose (TD₅₀) close to the LD₅₀. The revised FDP usually requires five or six animals with two or fewer dying as a result of treatment in most cases.

Key Words: acute oral toxicity testing • LD50 test • OECD Test Guideline 420

Human & Experimental Toxicology, Vol. 21, No. 4, 183-196 (2002)
DOI: 10.1191/0960327102ht239oa


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