CXR Biosciences, the CRO specialising in investigative toxicology, and Penman Consulting, one of Europe’s leading Product Stewardship and Regulatory service providers, are pleased to announce the publication of a joint article in the May issue of Speciality Chemicals Magazine.
The article1 outlines a mechanistic approach to read-across and minimising animal testing, and outlines how this approach was utilised by the Higher Olefins and Polyalphaolefins REACH Consortium (HOPA, c/o Penman Consulting bvba, Brussels).
The REACH regulations require that an extensive, tonnage-dependant set of toxicological and environmental data should be submitted to the European Chemicals Agency (ECHA) on each substance manufactured or imported within the EU in quantities of >1 tonne/year. This process can be lengthy and costly but is a prerequisite for any EU chemicals business’s licence to operate.
Whilst some substances are data-rich and have information on most of the endpoints required for the REACH evaluation process to start, these tend to be major commodity chemicals. Many others do not have all the data that is formally required by REACH. The challenge then becomes finding the best way to fulfil the information requirement without using excessive experimentation (something written into the REACH regulation), with all its attendant costs.
Read Across – a mechanistic approach
The process of using the available data from one substance to inform on another is known as read-across and has been used informally by toxicologists and ecotoxicologists within industry and regulatory agencies for years. ECHA specifically permits read-across as one alternative method for addressing the information requirements under REACH, defining it as ‘a technique for predicting endpoint-specific information for one substance (target substance), by using data from the same endpoint from (an)other substance(s)’. However, many read-across concepts presented to ECHA to date have achieved mixed acceptance, frequently because there was not sufficient data to support the underlying scientific hypothesis and hence the proposed substance groupings. The read across approach described in the article is specifically designed to address those concerns.
Conceptually, the approach involves using short-term mechanistic studies to characterise all of the (structurally related) substances in a category for key attributes such as absorption and metabolism, then grouping substances based on this and selecting a small subset of chemicals for further characterisation, e.g. combined screening studies for reproduction and repeat dose toxicity. This can be further extended to include toxicogenomic screening, if required, to elucidate any toxicological effects that may be seen in the screening studies or longer-term studies on the selected category members. Toxicogenomic studies allow the identification of putative pathways of toxicity and the remaining compounds can then be tested specifically for their ability to perturb these pathways. Based on this mechanistic approach, a representative subset of substances can be selected for full toxicology testing.
The article describes how the initial stages of this approach was used by the HOPA consortium to strengthen its category approach, and to devise a focused testing programme that read across to all members of the category. This focused testing program used less than one sixth of the animals that might have been used otherwise.
1. M Penman & M Piper, Speciality Chemicals Magazine, May 2015, pages 46 to 47.
CXR Biosciences® offers tailored preclinical services in the areas of investigative & mechanistic toxicology, exploratory & discovery toxicology and PK & metabolism. We have particular expertise in experimental read across approaches, and have the mechanistic toxicology expertise required to support your REACH read across needs. Where limited animal data exists on a class of structurally-related compounds, we run short-term, mechanistic studies on the compounds to support read-across conclusions. Our customers include leading pharmaceutical, agrochemical, chemical, consumer product and biotechnology companies. CXR Biosciences® is located in Dundee, Scotland, United Kingdom. CXR is funded by Archangel Investors Limited and is a Scottish Enterprise supported company.
About Penman Consulting
We are one of Europe’s leading Product Stewardship and Regulatory service providers. With a strategic partner we created the de facto standard SIEF management software. Since 2007 we have set the standard in REACH services and our 2007-2010 customers all successfully completed 2010 registration.