QSAR Use in REACH Analyses of Alternatives to Predict Human Health and Environmental Toxicity of Alternative Chemical Substances.

In 2006, the European Union (EU) enacted the Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH) to address growing concerns of hazardous chemicals in the EU market. Under REACH, companies seeking authorization to use priority substances identified as substances of very high concern (SVHCs) and included in the authorization list must apply and submit health and environmental effects data in analyses of alternatives (AoAs) to the European Chemicals Agency (ECHA). To assess safer alternatives, especially in AoA hazard assessment cases where vital information could be missing or insufficient, quantitative structure-activity relationship (QSAR) nontesting methods have gained increasing acceptance and importance. This article assesses AoA applicants' use of QSAR sources and documentation while looking for meaningful trends. In this assessment, usage and frequency of QSAR sources were evaluated in 189 analyses of alternatives for 15 physicochemical properties and 19 human health and environmental endpoints to determine the scope of purpose of QSAR use in AoAs. We found that only 24 out of 189 applications cited QSAR sources to rank or evaluate the safety of their alternative substances relative to the REACH Annex XIV chemical. For human health and environmental hazard endpoints, applicants cited the Danish (Q)SAR Database (n = 63) and unidentified QSARs (n = 36) most frequently. While QSARs were not used to eliminate an alternative, 7.9% and 1.4% per maximum opportunity (MOP) of hazard endpoint and physicochemical QSAR predictions reported background information on alternatives using weight of evidence (WoE). In addition, 3.0% per MOP of hazard endpoint QSAR predictions supported the safety of the alternative while 0.7% per MOP of physicochemical QSAR predictions gave mixed support for their alternative's safety. Documentation regarding QSARs was absent in all 24 AoAs that used QSARs. Limited QSAR use and missing documentation may be the result of several factors, including inconsistent regulatory guidance. Integr Environ Assess Manag 2020;16:745-760. © 2020 SETAC.