The Next Frontier of Environmental Unknowns: Substances of Unknown or Variable Composition, Complex Reaction Products, or Biological Materials (UVCBs)

Abstract

Substances of unknown or variable composition, complex reaction products, or biological materials (UVCBs) are over 70 000 "complex" chemical mixtures produced and used at significant levels worldwide. Due to their unknown or variable composition, applying chemical assessments originally developed for individual compounds to UVCBs is challenging, which impedes sound management of these substances. Across the analytical sciences, toxicology, cheminformatics, and regulatory practice, new approaches addressing specific aspects of UVCB assessment are being developed, albeit in a fragmented manner. This review attempts to convey the "big picture" of the state of the art in dealing with UVCBs by holistically examining UVCB characterization and chemical identity representation, as well as hazard, exposure, and risk assessment. Overall, information gaps on chemical identities underpin the fundamental challenges concerning UVCBs, and better reporting and substance characterization efforts are needed to support subsequent chemical assessments. To this end, an information level scheme for improved UVCB data collection and management within databases is proposed. The development of UVCB testing shows early progress, in line with three main methods: whole substance, known constituents, and fraction profiling. For toxicity assessment, one option is a whole-mixture testing approach. If the identities of (many) constituents are known, grouping, read across, and mixture toxicity modeling represent complementary approaches to overcome data gaps in toxicity assessment. This review highlights continued needs for concerted efforts from all stakeholders to ensure proper assessment and sound management of UVCBs.

Keywords: UVCB; cheminformatics; complex substances; environmental pollutants; mixtures; testing and assessment.

Figure 1

Examples of chemical structure representations for UVCBs available in REACH registration dossiers, depicted using CDK Depict.

Figure 2

Examples of cheminformatics representations of UVCBs: (A) G SMILES. (Modified with permission from ref (50). Copyright 2015 John Wiley and Sons.) (B) Mixture InChI (MInChI). The highlighted character strings are machine-readable formats, color coded according to the different components of G SMILES and MInChI, respectively, as indicated by their labels.

Figure 3

(left) Graphical illustration of the proposed UVCB data structure expressing constituents, concentrations/composition, and hierarchy, shown representing a “mixture of ‘coconut oil, polymer with glycerol and isophthalic acid’ (CASRN 68132-70-7) and ‘(R)-12-hydoxyoleic acid, compound with 2,2′-iminodiethanol (1:1)’ (CASRN 94232-00-5) dissolved in xylenes (CASRN 1330-20-7)” for demonstrative purposes. (bottom right) Different specificity levels of available information on UVCB constituent structural representation, in decreasing order of preference from 1 to 5.

Figure 4

Schematic representation of the three main experimental approaches prescribed for PBT assessment of UVCB substances.^,