Read-Across Assessment Framework Research Articles

Is read-across for chemicals comparable to medical device equivalence and where to use it for conformity assessment?

Novel medical devices must conform to medical device regulation (MDR) for European market entry. Likewise, chemicals must comply with the Registration, Evaluation, Authorization and Restriction of Chemicals (REACh) regulation. Both pose regulatory challenges for manufacturers, but concordantly provide an approach for transferring data from an already registered device or compound to the one undergoing accreditation. This is called equivalence for medical devices and read-across for chemicals.Although read-across is not explicitly prohibited in the process of medical device accreditation, it is usually not performed due to a lack of guidance and acceptance criteria from the authorities. Nonetheless, a scientifically justified read-across of material-based endpoints, as well as toxicological assessment of chemical aspects, such as extractables and leachables, can prevent failure of MDR device equivalence if data is lacking. Further, read-across, if applied correctly can facilitate the standard MDR conformity assessment.The need for read-across within medical device registration should let authorities to reconsider device accreditation and the formulation of respective guidance documents. Acceptance criteria like in the European Chemicals Agency (ECHA) read-across assessment framework (RAAF) are needed. This can reduce the impact of the MDR and help with keeping high European innovation device rate, beneficial for medical device patients.

Incorporating lines of evidence from New Approach Methodologies (NAMs) to reduce uncertainties in a category based read-across: A case study for repeated dose toxicity

A group of triazole compounds was selected to investigate the confidence that may be associated with read-across of a complex data gap: repeated dose toxicity. The read-across was evaluated using Assessment Elements (AEs) from the European Chemicals Agency's (ECHA's) Read-Across Assessment Framework (RAAF), alongside appraisal of associated uncertainties. Following an initial read-across based on chemical structure and properties, uncertainties were reduced by the integration of data streams such as those from New Approach Methodologies (NAM) and other existing data. In addition, addressing the findings of the ECHA RAAF framework, complemented with specific questions concerning uncertainties, increased the confidence that can be placed in read-across. Although a data rich group of compounds with a strong mechanistic basis was analysed, it was clearly demonstrated that NAM data available from publicly available resources could be applied to support read-across. It is acknowledged that most read-across studies will not be so data rich or mechanistically robust, therefore some targeted experimentation may be required to fill the data gaps. In this sense, NAMs should constitute new experimental tests performed with the specific goal of reducing the uncertainties and demonstrating the read-across hypothesis.

The implementation of RAAF in the OECD QSAR Toolbox

The Read-Across Assessment Framework (RAAF) was developed by the European Chemicals Agency (ECHA) as an internal tool providing a framework for a consistent, structured and transparent assessment of grouping of chemicals and read-across. Following a RAAF-based evaluation, also developers and users of read-across predictions outside ECHA can judge whether their read-across rationale is sufficiently robust from a regulatory perspective. The aim of this paper is to describe the implementation of RAAF functionalities in the OECD QSAR Toolbox report. These can be activated in the prediction report after performing a readacross prediction. Once the user manually selects the appropriate scenario, the RAAF assessment elements appear and are automatically aligned with the suitable category elements of the Toolbox report. Subsequently, these are evaluated as part of the category consistency assessment functionality. The implementation of the RAAF functionality is illustrated in practice with two examples.

Grouping of multi-walled carbon nanotubes to read-across genotoxicity: A case study to evaluate the applicability of regulatory guidance

Multi-walled carbon nanotubes (MWCNTs) consist of multiple layers of graphene sheets in a tubular shape. Depending on the synthesis and purification method, MWCNTs may differ in size, shape, rigidity and other properties. Previous research has shown that physicochemical properties can influence the translocation and toxicity of MWCNTs.Extensive in vitro and in vivo testing may be required to characterise the hazard of various physical forms of MWCNTs. Grouping of MWCNTs to read-across data for toxicological endpoints could efficiently contribute to reduce and focus MWCNT testing.This paper describes a case study to explore and illustrate read-across of genotoxicity data by following the “Recommendations for nanomaterials applicable to the Guidance on QSARs and Grouping”, developed by the European Chemicals Agency (ECHA). The grouping hypothesis was supported by the use of chemoinformatics techniques such as hierarchical clustering and principal components analysis. The uncertainties of the present case study were evaluated using the Read-Across Assessment Framework (RAAF) developed by ECHA.While the aim of this study was not to conduct a hazard assessment, the study data chosen for illustrative purposes suggest that the MWCNTs analogues selected are not genotoxic. No (major) differences between the analogues were observed which could be attributed to differences in physicochemical properties such as length, diameter or rigidity/straightness. Such properties, however, may have an impact on other hazard endpoints such as carcinogenicity.This study shows the practical application of the ECHA framework for grouping of nanomaterials (NMs) as well as use of the ECHA RAAF for NMs, and how this can be supported by chemoinformatics techniques. Some adaptations to the workflow are suggested for a more practical and straightforward narrative in the reporting.

Grouping of nanomaterials to read-across hazard endpoints: from data collection to assessment of the grouping hypothesis by application of chemoinformatic techniques

BackgroundAn increasing number of manufactured nanomaterials (NMs) are being used in industrial products and need to be registered under the REACH legislation. The hazard characterisation of all these forms is not only technically challenging but resource and time demanding. The use of non-testing strategies like read-across is deemed essential to assure the assessment of all NMs in due time and at lower cost. The fact that read-across is based on the structural similarity of substances represents an additional difficulty for NMs as in general their structure is not unequivocally defined. In such a scenario, the identification of physicochemical properties affecting the hazard potential of NMs is crucial to define a grouping hypothesis and predict the toxicological hazards of similar NMs. In order to promote the read-across of NMs, ECHA has recently published “Recommendations for nanomaterials applicable to the guidance on QSARs and Grouping”, but no practical examples were provided in the document. Due to the lack of publicly available data and the inherent difficulties of reading-across NMs, only a few examples of read-across of NMs can be found in the literature. This manuscript presents the first case study of the practical process of grouping and read-across of NMs following the workflow proposed by ECHA.MethodsThe workflow proposed by ECHA was used and slightly modified to present the read-across case study. The Read-Across Assessment Framework (RAAF) was used to evaluate the uncertainties of a read-across within NMs. Chemoinformatic techniques were used to support the grouping hypothesis and identify key physicochemical properties.ResultsA dataset of 6 nanoforms of TiO2 with more than 100 physicochemical properties each was collected. In vitro comet assay result was selected as the endpoint to read-across due to data availability. A correlation between the presence of coating or large amounts of impurities and negative comet assay results was observed.ConclusionThe workflow proposed by ECHA to read-across NMs was applied successfully. Chemoinformatic techniques were shown to provide key evidence for the assessment of the grouping hypothesis and the definition of similar NMs. The RAAF was found to be applicable to NMs.

Read-across in REACH and the read-across assessment framework (RAAF)

Read-across in REACH and the read-across assessment framework (RAAF)

Improving the Safety Assessment of Chemicals and Drug Candidates by the Integration of Bioinformatics and Chemoinformatics Data.

The application of read-across and in silico tools for regulatory decision-making has been limited for pharmaceutical compounds to the assessment of genotoxic impurity. In contrast, the broad availability of toxicity data for industrial chemicals has triggered regulatory frameworks for read-across (e.g. ECHA Read-Across Assessment Framework), software tools and public databases for an automated process of gap filling in the context of safety assessment. This MiniReview provides an overview of the currently existing in silico and read-across approaches for chemicals together with recent developments for pharmaceutical compounds in these areas. It also highlights the differences and commonalities in the in silico safety assessment of industrial chemicals and drug candidates. Whereas toxicity data collection and sharing is now common practice for chemicals falling under the European REACH regulation (Registration, Evaluation, Authorisation and Restriction of Chemicals), the biggest hurdle for establishing preclinical safety databases for pharmaceutical compounds is the unwillingness to share proprietary data and lack of published data sets. In a recent consortium approach, thirteen pharmaceutical companies, eleven academic partners and six small to medium size enterprises (SMEs) of the bioinformatics sector joined forces over the last 7years within the European Innovative Medicines Initiative project eTOX ('electronic toxicity') to design and implement a strategy for leveraging these preclinical data for small molecules and sharing them across project partners. The eTOX database has evolved as the largest preclinical toxicity database for drugs and drug candidates and currently contains more than 1900 different chemical structures and more than 8000 invivo toxicity study data sets. It can be foreseen that the development and application of such databases for drugs or drug candidates will in the future also cross-fertilize the read-across and the in silico assessment of industrial or consumer chemicals particularly as soon as human safety data from clinical trials are integrated too.

Innovative Strategies to Develop Chemical Categories Using a Combination of Structural and Toxicological Properties.

Interest is increasing in the development of non-animal methods for toxicological evaluations. These methods are however, particularly challenging for complex toxicological endpoints such as repeated dose toxicity. European Legislation, e.g., the European Union's Cosmetic Directive and REACH, demands the use of alternative methods. Frameworks, such as the Read-across Assessment Framework or the Adverse Outcome Pathway Knowledge Base, support the development of these methods. The aim of the project presented in this publication was to develop substance categories for a read-across with complex endpoints of toxicity based on existing databases. The basic conceptual approach was to combine structural similarity with shared mechanisms of action. Substances with similar chemical structure and toxicological profile form candidate categories suitable for read-across. We combined two databases on repeated dose toxicity, RepDose database, and ELINCS database to form a common database for the identification of categories. The resulting database contained physicochemical, structural, and toxicological data, which were refined and curated for cluster analyses. We applied the Predictive Clustering Tree (PCT) approach for clustering chemicals based on structural and on toxicological information to detect groups of chemicals with similar toxic profiles and pathways/mechanisms of toxicity. As many of the experimental toxicity values were not available, this data was imputed by predicting them with a multi-label classification method, prior to clustering. The clustering results were evaluated by assessing chemical and toxicological similarities with the aim of identifying clusters with a concordance between structural information and toxicity profiles/mechanisms. From these chosen clusters, seven were selected for a quantitative read-across, based on a small ratio of NOAEL of the members with the highest and the lowest NOAEL in the cluster (< 5). We discuss the limitations of the approach. Based on this analysis we propose improvements for a follow-up approach, such as incorporation of metabolic information and more detailed mechanistic information. The software enables the user to allocate a substance in a cluster and to use this information for a possible read- across. The clustering tool is provided as a free web service, accessible at http://mlc-reach.informatik.uni-mainz.de.

Evaluation of read-across argumentation according to the ECHA Read-Across Assessment Framework (RAAF)

The reactions of 4,4-bipyridine and 5-Hydroxyisophthalic acid with Zn(NO3)2·3H2O in N,N′-dimethylacetamide lead to the formation of [Zn(5-hip)(bpy)]·2DMA (1). Compound 1 possesses a non-interpenetrating pillar-layer framework with 1D rectangular-shape channels. The experimental results show that the luminescent intensity of 1 highly depends on small solvent molecules, particularly CH3OH and acetone. Compound 1 can be used as a luminescent probe to detect small molecule acetone.

Toward Good Read-Across Practice (GRAP) guidance

SummaryGrouping of substances and utilizing read-across of data within those groups represents an important data gap filling technique for chemical safety assessments. Categories/analogue groups are typically developed based on structural similarity and, increasingly often, also on mechanistic (biological) similarity. While read-across can play a key role in complying with legislation such as the European REACH regulation, the lack of consensus regarding the extent and type of evidence necessary to support it often hampers its successful application and acceptance by regulatory authorities. Despite a potentially broad user community, expertise is still concentrated across a handful of organizations and individuals. In order to facilitate the effective use of read-across, this document presents the state of the art, summarizes insights learned from reviewing ECHA published decisions regarding the relative successes/pitfalls surrounding read-across under REACH, and compiles the relevant activities and guidance documents. Special emphasis is given to the available existing tools and approaches, an analysis of ECHA's published final decisions associated with all levels of compliance checks and testing proposals, the consideration and expression of uncertainty, the use of biological support data, and the impact of the ECHA Read-Across Assessment Framework (RAAF) published in 2015.

Building scientific confidence in the development and evaluation of read-across

Read-across is an alternative approach exploited to address information requirements for risk assessment and for regulatory programmes such as the European Union’s REACH regulation. Whilst read-across approaches are accepted in principle, difficulties still remain in applying them consistently in practice. Recent work within Cefic LRI and ECETOC attempted to summarize the state-of-the-art and identify some of the barriers to broader acceptance of read-across approaches to overcome these. Acceptance is undoubtedly thwarted partly by the lack of a systematic framework to characterize the read-across justification and identify the uncertainties particularly for complex regulatory endpoints such as repeated-dose toxicity or prenatal developmental toxicity. Efforts are underway by the European Chemical’s Agency (ECHA) to develop a Read-Across Assessment Framework (RAAF) and private sector experts have also considered the development of a similar framework. At the same time, mechanistic chemical categories are being proposed which are underpinned by Adverse Outcome Pathways (AOPs). Currently such frameworks are only focusing on discrete organic substances, though the AOP approach could conceivably be applied to evaluate more complex substances such as mixtures. Here we summarize the deliberations of the Cefic LRI read-across team in characterizing scientific confidence in the development and evaluation of read-across.