Brussels, 10 March 2021 – In 21st century toxicology practice, there isn’t any scientific justification for selecting high doses of chemicals in animal tests which could result in lethality, pain, suffering or other forms of profound toxicity in any of the experimental subjects, according to a new Technical Report from the Centre for chemical safety assessment (ECETOC).
Prior to registering and marketing any new pharmaceutical, chemical, agricultural chemical or food ingredient products, manufacturers must by law generate data to ensure human and environmental safety. The testing requirements to ensure human safety vary by sector, product type and geographical region or country and many require repeat-dose testing in animals.
Dose level selection is the most important aspect of the specification of repeat dose toxicity studies. It is about identifying relevant hazards, determination of a dose response, at which dose level there are no (adverse) effects and what level of exposure leads to risk for humans or the environment.
Repeat dose studies range in duration from 28-day systemic toxicity tests to 2-year carcinogenicity studies. Rats and mice are generally used for systemic toxicity testing, while assessments of reproductive and developmental toxicity are done in rats and rabbits.
The advice on dose level selection given in test guidelines and by regulatory authorities globally for most sectors often vary; the pharmaceutical sector is the closest to having a globally aligned approach through the International Council for Harmonisation (ICH).
The criteria used to set the highest dose level are even less well harmonised across the range of studies and geographies. These range from approaches that can be interpreted to allow a proportion of deaths at the highest dose tested to those that encourage high dose level selection based on signs of evident toxicity.
The new report’s recommendations provide pragmatic approaches to selecting dose levels that allow accurate risk assessment and also the identification of relevant hazards, which can then be used for classification purposes.
The report recognises that different sectors have differing degrees of freedom to operate in dose level selection and this is reflected in the overall recommended approaches. These can be applied within the current regulatory frameworks, and also provide future options and approaches to science-based dose level selection. Dose selection should be based on best scientific practises as well as on social acceptance of the appropriate level of toxicity in animals to serve the above-mentioned purposes of testing
Olivier De Matos, ECETOC Secretary General, said: “The Task Force’s report provides guidance to achieve a good balance between chemical safety assessment requirements and animal welfare, while also supporting the appropriate design and interpretation of toxicity studies.”
Download the report here.