New Technologies to Underpin Category Approaches and Read-across in Regulatory Programmes
Petroleum substances are a prototypical example of UVCBs (Unknown or Variable composition, Complex reaction products and Biological materials), which present enormous challenges for science-informed regulatory decision making. Although UVCBs are identified on global chemical inventories with unique Chemical Abstract Services (CAS) numbers and names, evaluating their potential toxicity remains challenging due to the chemical complexity and multi-constituent nature with largely unknown and variable composition. Therefore, regulators and industry have a common interest to define a process for (petroleum) UVCBs to ensure that there is no underestimation of hazards and at the same time minimize or eliminate the use of animals in toxicology testing to ensure safe use.
All petroleum products were registered in the European Union for the 2010 submission deadline under REACH (≥1000 tonnes registration band), comprising more than 8000 individual registrations.
A number of these submissions were accompanied by testing proposals to fill data gaps in specific toxicity endpoints.To minimize the need for testing in vertebrate animals, the majority of data gaps were addressed by using read-across to similar substances for which the required data were available.
Read-across of petroleum substances within the REACH framework is typically done by grouping the individual substances into product categories with similar manufacturing processes, phys/chem- (including refining history and boiling point/carbon number ranges) and limited analytical chemical properties (such as hydrocarbon classes). However, category read-across approaches for (petroleum) UVCBs that are based solely on such broad similarity parameters may not always be considered sufficient.
The Cat-App project, initiated and funded by Concawe, tackles this specific challenge by investigating practical strategies for grouping and read across approaches with the aim of providing a cost-effective integrative approach to solving the similarity challenges of UVCBs. The concept is to develop a framework based on chemical-biological read-across, a novel direction in regulatory decision making regarding. The approach is to integrate innovations in (i) in vitro testing, (ii) high-throughput genomics and (iii) integrative data analyses and visualisation into a transparent workflow for read-across assessment of UVCBs in regulatory programmes.
This project will address all steps of the proposed workflow within a 24 months period and started on January 2016.
The specific objectives of Cat-App:
- Devising a workflow for chemical-biological grouping and read across of UVCB substances by combining multiple streams of information (production type/refining process, physical-chemical properties, chemical analytical profiles [Substance Identification Profiles, SIPs], existing in-vivo toxicological data and a comprehensive array of the biological/toxicological responses in a broad spectrum of in vitro systems).
- Implementation of the framework in the Concawe REACH strategy by applying the approach to underpin the grouping of petroleum substances, to support chemical-biologically based read across of hazard data in the petroleum REACH dossiers and to develop a pragmatic and more informed testing approach as a last resort (i.e. where read across to fill datagaps is not possible) to address mandatory in-vivo endpoints while significantly reducing the use of vertebrate animals without underestimating hazard
- Translation of the experimental and computational approaches underpinning the implementation of the UVCB read across workflow established in this programme and introduced to the broad spectrum of the stakeholders (commercial entities, regulatory agencies and non-governmental organizations) concerned with public health and wellbeing in the EU and US.
The project is divided into five different work packages (WPs) shown in Figure 1:
Concawe and Texas A&M University will collect and process samples of all UVCBs in WP1. Available information on health hazards and physical-chemical properties of UVCBs are collected and digitized into a flexible database that is inter-operable with the future tools of Cat-App.
WP2 is the laboratory-based R&D work package focused on cell-based assays to outline the toxicological responses of various human in vitro models to petroleum substances as a case study for UVCBs. Texas A&M University will conduct high-content screening on human cells, while Public Health England, an executive body of the Department of Health of the UK, will conduct toxicity phenotyping in a panel of more than ten different human cell lines.
WP3 is tasked with characterising the biological responses of various human in vitro models to petroleum substances as a case study for UVCBs. Texas A&M University will conduct high-throughput transcriptomics profiling of more than 10,000 samples for TempQ-seq.
Data integration and chemical-biological read across in WP 4 will analyse the data and will create
a comprehensive data utilisation and visualisation of the workflow to enable a key element of the framework for category read-across of UVCBs. WP 4 will be a joint work package of North Carolina State University and the University of Ulster.
Project administration, dissemination and outreach activities will be the activities within WP5 undertaken by SYNCOM GmbH.
Project coordination is done by Concawe with responsibility for the overall management of the Project.
Overall, Cat-App will try to make a significant scientific contribution towards identifying an efficient workflow for grouping- and read across assessment of UVCBs with a direct application in regulatory programmes leading to less animal testing, fast and cost effective regulatory decisions in the European Union and the United States.
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