Division 1.1 INTRODUCTION

In the assessment and evaluation of the toxic characteristics of chemicals, it is important to consider the potential for neurotoxic effects. Already the Test Method for repeated dose systemic toxicity includes observations that screen for potential neurotoxicity. This Test Method can be used to design a study to obtain further information on, or to confirm, the neurotoxic effects observed in the repeated dose systemic toxicity studies. However, consideration of the potential neurotoxicity of certain classes of chemicals may suggest that they may be more appropriately evaluated using this Method without prior indications of the potential neurotoxicity from repeated dose systemic toxicity studies. Such considerations include, for example:

• observation of neurological signs or neuropathological lesions in toxicity studies other than repeated dose systemic toxicity studies, or

• structural relationship or other information linking them to known neurotoxicants.

In addition there may be other instances when use of this Test Method is appropriate; for further details see (1).

This Method has been developed so that it can be tailored to meet particular needs to confirm the specific histopathological and behavioural neurotoxicity of a chemical as well as provide a characterization and quantification of the neurotoxic responses.

In the past, neurotoxicity was equated with neuropathy involving neuropathological lesions or neurological dysfunctions, such as seizure, paralysis or tremor. Although neuropathy is an important manifestation of neurotoxicity, it is now clear that there are many other signs of nervous system toxicity (e.g. loss of motor coordination, sensory deficits, learning and memory dysfunctions) that may not be reflected in neuropathy or other types of studies.

This neurotoxicity Test Method is designed to detect major neurobehavioural and neuropathological effects in adult rodents. While behavioural effects, even in the absence of morphological changes, can reflect an adverse impact on the organism, not all behavioural changes are specific to the nervous system. Therefore, any changes observed should be evaluated in conjunction with correlative histopathological, haematological or biochemical data as well as data on other types of systemic toxicity. The testing called for in this Method to provide a characterization and quantification of the neurotoxic responses includes specific histopathological and behavioural procedures that may be further supported by electrophysiological and/or biochemical investigations (1)(2)(3)(4).

Neurotoxicants may act on a number of targets within the nervous system and by a variety of mechanisms. Since no single array of tests is capable of thoroughly assessing the neurotoxic potential of all substances, it may be necessary to utilize other in vivo or in vitro tests specific to the type of neurotoxicity observed or anticipated.

This Test Method can also be used, in conjunction with the guidance set out in the OECD Guidance Document on Neurotoxicity Testing Strategies and Methods (1) to design studies intended to further characterize or increase the sensitivity of the dose-response quantification in order or better estimate a no-observed-adverse effect level or to substantiate known or suspected hazards of the chemical. For example, studies may be designed to identify and evaluate the neurotoxic mechanism(s) or supplement the data already available from the use of basic neurobehavioural and neuropathological observation procedures. Such studies need not replicate data that would be generated from the use of the standard procedures recommended in this Method, if such data are already available and are not considered necessary for the interpretation of the results of the study.

This neurotoxicity study, when used alone or in combination, provides information that can:

• identify whether the nervous system is permanently or reversibly affected by the chemical tested;

• contribute to the characterization of the nervous system alterations associated with exposure to the chemical, and to understanding the underlying mechanism.

• determine dose-and time-response relationships in order to estimate a no-observed-adverse-effect level (which can be used to establish safety criteria for the chemical).

This Test Method uses oral administration of the test substance. Other routes of administration (e.g. dermal or inhalation) may be more appropriate, and may require modification of the procedures recommended. Considerations of the choice of the route of administration depend on the human exposure profile and available toxicological or kinetic information.