Revised Up-and-Down Procedure: A Test Method for Determining the Acute Oral Toxicity of Chemicals. Volume 2 of 2

摘要

The acute oral toxicity test is a fundamental component in defining the toxicity of a test material for hazard classification and labeling purposes. There are two types of acute oral tests: (a) those that identify a dose range in which the median lethal dose (LD50) falls, and (b) those that determine a point estimate of the median lethal dose of the material. In tests that estimate the LD50, if sufficient data are available, an estimate of the slope of the dose-response curve and confidence interval can also be determined. In 1981, the Organization of Economic Co-operation and Development (OECD) adopted a test guideline (TG 401) for acute oral toxicity that estimated the LD50 and in many cases, the slope and confidence interval. TG 401 has become the traditional acute oral toxicity test. TG 401 was revised in 1987 to utilize three dose groups of five rats of one sex with confirmation in the other sex using one group of five rats. This resulted in reduced animal use from 50 or more in the 1981 version to 20 in the 1987 version. Since 1987, OECD has adopted three additional acute oral toxicity tests, one of which is the up-and-down procedure (UDP) in 1998. With the new test guidelines adopted, OECD is considering a proposal to delete TG 401. Of the three alternative tests, the UDP is the only test providing a point estimate of the LD50 and does this rather efficiently for many chemicals by only using six or seven animals. However, the UDP does not provide an estimate of the slope of the dose-response curve and confidence interval. With TG 401 to be deleted, there would be no method available to regulatory agencies that provided an estimate of slope and confidence interval. In addition, the global harmonization of the classification scheme has resulted in the need to revise the Fixed-Dose Procedure (FDP) and the Acute Toxic Class Method (ATCM). As a result, OECD agreed to revise all three alternative methods. The U.S. Environmental Protection Agency (EPA) agreed to revise the UDP to include a procedure that would provide slope and corresponding confidence interval estimates. The UDP described in this document has been revised to include: (a) a modified up-and-down procedure with improved performance; (b) a modified Limit Test utilizing only females and providing a limit dose of 5000 mg/kg for specific regulatory purposes; and (c) an added supplemental test for determining the slope and confidence interval.