The benchmark approach applied to a 28-day toxicity study with Rhodorsil Silane in rats: the impact of increasing the number of dose groups

The OECD study design, aimed at obtaining a no-observed-adverse-effect leve l (NOAEL), may be suboptimal for deriving a benchmark dose. Therefore the p resent subacute (28-day) study was carried out to evaluate a multiple dose study design and to compare the results with the common OECD design. Seven groups of 10 female rats each were intragastrically administered corn oil w ithout (controls) or with 50, 150, 300, 450, 600 or 750 mg Rhodorsil Silane /kg body weight/day, once daily (7 days/week) for 4 weeks. From the complet e dataset, two subsets were selected, one representing a study design with seven dose groups of five animals (7 x 5 design), the other representing a study design with four dose groups of 10 animals (4 x 10 design). Under the conditions of the present study, the NOAEL for Rhodorsil Silane 198 was as sessed at 50 mg/kg body weight/day, based on the data of the 4x10 design. T he benchmark approach resulted in a benchmark dose of 19 mg/kg body weight/ day, based on the data of the 7x5 design. Comparison of the results demonst rated that the multiple dose (7x5) design led to a more reliable result tha n the OECD (4x10) design, despite the smaller total number of animals. The dose-response analysis showed that at "the NOAEL" the effect on relative sp leen weight was larger than 10%, illustrating that at the NOAEL, adverse ef fects may occur. (C) 2001 Elsevier Science Ltd. All rights reserved.