General Overview of the Safety Evaluation of Chemicals

PAUL ILLING

1 Introduction

Society demands that chemicals be 'safe'. This requirement is exercised through legislation concerned with the safety of chemicals, usually introduced post hoc, in response either to disasters or to perceived inadequacies in the previous legislation. Public perceptions of risk drive priorities and legislative agendas. Generally legislatures are concerned with setting frameworks and setting up bodies to develop detailed requirements, evaluate the evidence and enforce the legislation.

When human health is the issue, the aim is to prevent ill health. In order to do this it is necessary to have means of predicting ill health. Ethically, it is difficult to justify predictive testing in humans unless a substance is intended for administration to humans. Thus tests are normally conducted in laboratory animals as surrogates for humans. Even when testing in humans is possible, preliminary testing in animals is usually required. The bodies concerned with evaluating safety therefore set minimum testing requirements for those who wish to place on the market a chemical substance or to market it for a specified use. These requirements include:

• when and what tests should be conducted (testing strategies);

• the protocols setting out how the tests should be conducted (test methods); and

• the audit procedures to ensure that tests have been properly conducted and reported ('Good Laboratory Practice'; GLP).

Furthermore, the bodies may either evaluate the results of the tests or set guidance as to how the results should be interpreted.

In the context of safety testing, chemicals includes natural products as well as synthetic chemicals. While the general public may consider 'natural' as good (less harmful) and 'synthetic' as bad (more harmful), there is no scientific reason to differentiate between 'natural' and 'synthetic' chemicals. Ricin (from castor beans), the toxins produced by Cl. botulinus and a number of mycotoxins are examples of natural materials of great potency as toxic agents. Generally, therefore, legislation does not differentiate between 'natural' and 'synthetic' chemicals.

One of the main tools used to predict what the potential ill health effects of chemicals might be is animal testing. A second societal demand, sometimes expressed with considerable force by groups within society who are against conducting work with animals, is associated with the welfare of animals used in experimental procedures. The aim is to prevent, or, at least, to minimize experiments on, usually, vertebrates. Generally, society has been less tolerant of animal testing for substances intended for use as cosmetics or cosmetic ingredients than for substances as a whole.

This clash between the demand for safety and the limitations on human experimentation is the reason why testing is undertaken in animals. The requirements concerning animal welfare dictate that, wherever possible, alternatives to animal testing should be sought.

2 Legislation and Regulatory Requirements

Predictive testing is best instigated when a licence or some other form of permission is required before a substance can be used. It may also be required in law prior to marketing even when there is no formal assessment of the data by a regulator. Thus, predictive testing is required for 'new substances' about to be placed on the market. It is also required prior to use for substances intended for specific uses, such as drugs, veterinary medicines, cosmetics/personal care products, food additives, plant-protection products and biocides. In these cases the person or corporate body desiring to market the substance carries out the required testing. Predictive testing almost always includes experiments in animals.

Legislation may also cover the presence of chemicals in air, water or soil. This legislation generally deals with evaluating existing situations rather than new ones and post hoc information from studies in humans should be available. Under these circumstances, predictive testing may be required for endpoints not easily addressed through studies in humans. However, in these cases it is usually Government that sponsors and finances this work.

Originally legislation concerning the safety of chemicals was based on the individual national government. Nowadays it is mostly based on regional (e.g. European Union [EU]) or international (Organization for Economic Co-operation and Development [OECD]; World Trade Organization [WTO] or United Nations [UN]) groupings.

Two areas of legislation are particularly pertinent to the current debate on alternatives to animal testing as the testing requirements associated with them are currently being revised. The first is that concerned with the placing on the market of chemicals generally. Currently this is governed by EU Council Directive 67/548/EEC. A Council Directive, implemented in the UK as the 'Notification of New Substances Regulations' deals with 'new substances', i.e. those placed on the market after 1981. Under the seventh amendment, a dossier, containing, inter alia, information on testing in animals, is required prior to placing the substance on the market. Testing is tiered, some testing being conducted before the substance is placed on the market and further testing being required as the amounts placed on the market increase. Currently testing strategies are given in Directive 92/32/EEC and in a technical guidance document and test protocols are given in Annex V of Directive 67/548/EEC. The test protocols are those set up by the OECD. Tests have to be conducted to these protocols and audited in accordance with the principles of good laboratory practice. Animal welfare considerations, set out in Directive 86/609/EC, should be taken into account when deciding on the need for a specific test.

Existing substances are still classified and labelled on the basis of existing information.

The Registration, Evaluation, Authorization and restriction of CHemicals (REACH) proposals currently before the EU Council and Parliament, intend to bring the regulation of both new and existing substances into a common scheme, and to require that specific information is available under specified conditions. For existing substances this implies those placing on the market the substance or preparations containing it may need to set up consortia to conduct testing to fill data gaps. The REACH proposals also have a testing strategy contained within them, and the test protocols are those set out in the OECD Guidelines. Although currently the classification is that for Directive 67/548/EEC, it is likely that the UNECE Globally Harmonized System (GHS) will be substituted before implementation of the proposals. It is claimed that the REACH proposals should encourage the use of alternatives to animal...