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EPA Set to Announce Revision of Toxicity Test Guidelines to Include Alternative Test Methods

EPA's Office of Prevention, Pesticides, and Toxic Substances (OPPTS) plans to publish Notices of Availability in the Federal Register to announce the revision of two test guidelines in the OPPTS Harmonized Test Guidelines. The guidelines, 870.1100 Acute Oral Toxicity and 870.2600 Skin Sensitization, are being revised to incorporate alternative test methods that have been recently reviewed by the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP). Because the alternative methods are new approaches to testing for these endpoints, interested parties are encouraged to be on the alert for the Federal Register notices and to contact the Agency prior to initiating any such studies. A brief description of the changes is presented in the following paragraphs.

870.1100 Acute Oral Toxicity. An improved Up-and-Down Procedure protocol for acute oral toxicity testing was developed by a team of regulatory and industry scientists to provide the types of testing data needed for U.S. agencies to make regulatory decisions. The Agency strongly recommends the use of the revised Up-and-Down Procedure, as detailed in the revised guideline, to meet the testing requirements for for industrial chemicals and registration of pesticide products registered by the Agency. The revised guideline was reviewed by EPA's Scientific Advisory Panel in a public meeting on December 12, 2001, and recommendations of the Panel have been incorporated into the test protocol.

Acute oral toxicity studies initiated after December 17, 2002 should be conducted in accordance with the Up-and-Down Procedure described in the guideline. This Up-and-Down Procedure was adopted by the Organization for Economic Cooperation and Development (OECD) as Test Guideline 425 in December 2001. A software program to assist laboratory users in the conduct of the test was also developed, and the Agency strongly encourages use of this software program. The test guideline, software package, users' manual and related documentation are available on the Internet at http://www.epa.gov/oppfead1/harmonization.

The Up-and-Down test procedure in this guideline is of value in reducing the number of animals required to determine the acute oral toxicity of a chemical. The revised protocol includes a Primary Test and a Limit Test, and provides for determination of the confidence intervals for the LD50 and observation of toxic signs. Moreover, use of guidance for humane endpoints should reduce the overall suffering of animals in this type of test. This test procedure is optimized when starting doses are set as close as possible to the actual LD50 and when dose spacing is based on the best estimate of the dose-response curve. Therefore, all available information on the test substance should be considered by the testing laboratory prior to conducting the study in order to determine if a preliminary estimate of the LD50 and the slope of the dose-response curve can be made. Initial information may include the identity and chemical structure of the substance; its physical chemical properties; the results of any other in vitro or in vivo toxicity tests on the substance or mixtures; toxicological data on structurally related substances or similar mixtures; and the anticipated use(s) of the substance. Practical guidance for laboratories conducting the test is included in the paper, "Alternative Methods for Acute Oral Toxicity Testing: Practical Guidance for Implementation," in the July/August 2002 issue of the journal Lab Animal.

870.2600 Skin Sensitization. The Local Lymph Node Assay (LLNA) is a test method for assessing the allergic contact dermatitis (skin sensitization) potential of chemicals and compounds. In 1998, upon review by the FIFRA SAP, LLNA was incorporated as a screening test in OPPTS Test Guideline 870.2600 Skin Sensitization. Following additional studies to validate the method, the LLNA was endorsed by the SAP in December 2001 as a full stand-alone assay. The LLNA can be used to predict sensitization potential for a broad range of pesticides and industrial chemicals consisting of single organic substances, but not including aqueous mixtures. The test method provides quantitative data and reduces animal suffering. OPPTS guideline 870.1100 Skin Sensitization has been revised to include LLNA as a stand-alone assay for appropriate applications. The OPPTS guideline has also been harmonized with OECD's Guideline 429 for LLNA, which was adopted in April 2002.

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