Abstract
One of the most challenging areas in regulatory science is assessment of the substances known as UVCB (unknown or variable composition, complex reaction products and biological materials). Because the inherent complexity and variability of UVCBs present considerable challenges for establishing sufficient substance similarity based on chemical characteristics or other data, we hypothesized that new approach methodologies (NAMs), including in vitro test-derived biological activity signatures to characterize substance similarity, could be used to support grouping of UVCBs. We tested 141 petroleum substances as representative UVCBs in a compendium of 15 human cell types representing a variety of tissues. Petroleum substances were assayed in dilution series to derive point of departure estimates for each cell type and phenotype. Extensive quality control measures were taken to ensure that only high-confidence in vitro data were used to determine whether current groupings of these petroleum substances, based largely on the manufacturing process and physico-chemical properties, are justifiable. We found that bioactivity data-based groupings of petroleum substances were generally consistent with the manufacturing class-based categories. We also showed that these data, especially bioactivity from human induced pluripotent stem cell (iPSC)-derived and primary cells, can be used to rank substances in a manner highly concordant with their expected in vivo hazard potential based on their chemical compositional profile. Overall, this study demonstrates that NAMs can be used to inform groupings of UVCBs, to assist in identification of representative substances in each group for testing when needed, and to fill data gaps by read-across.
Highlights
Substance identification is required before exposure, hazard or risk evaluations are performed by industry or regulatory authorities
We found that new approach methodologies (NAMs) data can be used to rank individual UVCBs in a manner highly concordant with their expected in vivo hazard potential based on their chemical composition
We reasoned that bioactivity “signatures” of these substances in a large number of human cell types will be informative to (i) assess the validity of existing groupings, and (ii) determine whether “representative” substances can be identified in each category so that they can be further considered for regulatory-required assays and that information used for read-across in each group
Summary
Substance identification is required before exposure, hazard or risk evaluations are performed by industry or regulatory authorities. Other types are deemed to be “multi-constituent” substances and “UVCBs” (Unknown or Variable composition, Complex reaction products, and Biological materials). The latter comprise about 20% of all recent substance registrations in the European Union (ECHA, 2017) under Regulation on Registration, Evaluation and Authorisation of Chemicals (REACH). Petroleum substances are prototypical UVCBs (Clark et al, 2013), and their complex and variable nature is the consequence of their manufacturing processes They are primarily produced by the distillation of petroleum feed stocks, typically followed by additional processing steps such as solvent extraction, hydro-desulfurization, or hydrogenation (McKee et al, 2015). The challenge of grouping petroleum-substances is further complicated by the reality that currently used substance nomenclature, due to the inherent chemical complexity of UVCBs, is not uniquely associated with chemical composition, but relies on manufacturing process, associated physico-chemical characteristics, and product performance specifications
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
