REACH read across – mechanistic studies to address REACH data gaps

At CXR, we 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 recommend designing and performing short-term, mechanistic studies on the compounds to support read-across conclusions.  This involves characterising all (structurally-related) substances in the class for key attributes such as absorption and metabolism, then potentially using this ranking to select a subset of chemicals for further characterisation, e.g. additional repeat dose testing or toxicogenomic screening. Based on such a mechanistic approach, a representative subset of chemicals can be selected for full toxicology testing, rather than every chemical in the class, thus significantly reducing both test animal numbers and costs.

The REACH legislation

REACH (Registration, Evaluation, Authorisation and restriction of CHemicals) is a European Union Regulation which addresses the production and use of chemical substances, and their potential impacts on both human health and the environment. REACH entered into force in June 2007, with a phased implementation over the next decade.

REACH requires 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. In the registration dossier an evaluation of that data is given, defining how it should be classified for health, safety and environmental hazards. A substance may only be registered with ECHA if the risks related to its usage are shown to be adequately controlled. 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 which have been well studied over a long period of time. Many others, which have a more limited use or are substances where there was data on a similar analogue, do not have all the data that is formally required by REACH.

The challenge in REACH has often been to find the best way to fulfil the information requirement without using excessive experimentation (something written into the REACH regulation), with all its attendant costs. Any alternative approaches used need to be acceptable to ECHA.  ECHA in turn needs to demonstrate that companies are meeting their statutory requirements as described in the regulation, its annexes and ECHA’s own many guidance documents.

Read Across

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, and defines 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)’. Read-across can therefore be a key input into the hazard identification phase of REACH.

However, it has been reported that many read-across concepts presented to ECHA under REACH have achieved mixed acceptance. Frequently, this was because there was not sufficient data to support the underlying scientific hypothesis and hence the proposed substance groupings.1

Read Across – CXR’s mechanistic approach

CXR has experience of designing and running studies that provide robust read across data in a cost-effective way.

As outlined above, data is required to provide a credible and plausible read across hypothesis, in order to provide regulators with the confidence that the proposed approach is acceptable and meets the requirements of REACH.

Conceptually, our 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 following figure outlines this approach.

Flow of data and potential work to demonstrate category coherence

REACH-flowchart-1

Case Study

An example of the successful application of the initial stages of this approach was outlined in an article by CXR Biosciences and Penman Consulting in Specialty Chemicals Magazine 2, and presented as a poster at the US Society of Toxicology 3.  The read across data generated at CXR was used by the 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 programme used less than one sixth of the animals that might have been used otherwise, some thousands of animals.

References:

1. N. Jansen-Bouriatchenko & D. Dierolf, Specialty Chemicals Magazine, December 2014
2. M Penman & M Piper, Specialty Chemicals Magazine, May 2015, pages 46 to 47.
3. R. Powrie et al., US Society Of Toxicology 2014, Poster Presentation
Download the REACH Read Across Brochure

For further information about our services, or to discuss a specific issue, please contact us.