An unexpected challenge: ionizable compounds in the REACH chemical space
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- Franco, A., Ferranti, A., Davidsen, C. et al. Int J Life Cycle Assess (2010) 15: 321. doi:10.1007/s11367-010-0165-6
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About 143,000 industrial chemicals have been pre-registered at the European Chemical Agency for registration according to REACH. The tools, models, and regressions employed for the chemical safety assessment of the registered compounds have limited applicability domains. Thus, it is an important question which fraction of the pre-registered compounds falls into these applicability domains.
A random sample of 1,510 compounds out of the ∼117,000 chemicals pre-registered at the European Chemicals Agency and due to registration by 2010 and 2013 was analyzed to investigate the physico-chemical domain of REACH substances. The chemical structure was identified from the CAS number, and the software ACD/Labs was used to calculate dissociation constant(s) (pKa), octanol–water partition coefficient (log P) and vapor pressure of the neutral molecule.
Four hundred ninety-one (33%) of the 1,510 compounds are mostly ionized at pH 7 (i.e., acids pKa < 7, bases pKa > 7). Twenty-seven percent of compounds are acids with pKa < 12, 14% bases with pKa > 2, and 8% ampholytes or zwitterionics. Almost half of the ionizable compounds (267 out of 1,510 compounds or 18%) with pKa between 2 and 12 are even multivalent. There is a high occurrence of hydrophilic chemicals (30% with log P < 1), but super-lipophilic chemicals are frequent as well (10% with log P > 6). Most chemicals are non- or semi-volatile: the vapor pressure is <1 Pa for 65% and >100 Pa only for 13%.
This preliminary characterization of the REACH chemical space helps to identify most urgent gaps of existing in silico tools that are going to be applied in the context of REACH. These data may also be used to select representative sets of test chemicals for the development of new QSARs and models.