Abstract
Quantitative Structure-Property Relationships (QSPR) are predictive methods of macroscopic properties of substances based on their only molecular structures. If these methods were initially mainly devoted to biology and toxicology, they are nowadays increasingly used for the prediction of physico-chemical properties.
In the framework of the European REACH regulation (2006), their developments are encouraged as alternative to experimental tests. Indeed, this regulation requires the evaluation of the physico-chemical properties of a large number of existing substances (143 000 pre-registered substances in 2008) in order to allow their use before 2018. Due to the number of substances and properties, the timing, the economic costs, the feasibility at the R&D level and the risks for the manipulator, in particular for the characterization of the dangerous physico-chemical properties (explosibility, flammability), the complete gathering of the data solely based on experimental measurements is not realistic. Thus, the use of such alternative predictive methods was recommended by REACH for the evaluation of the properties of substances.
In this context, INERIS developed QSPR models for the prediction of hazardous physico-chemical properties of chemical substances like explosibility of nitro compounds, thermal stability of organic peroxides or flammability of amines. To this end, quantum chemical tools allowed calculating relevant molecular descriptors (notably issued from Conceptual DFT) and to evidence subjacent chemical mechanisms. These models were developed according to the five validation principles of QSPR models proposed by OECD for regulatory use. During the French PREDIMOL (molecular modeling prediction of physico-chemical properties of products) project (2015) funded by ANR (National Research Agency), it was demonstrated that molecular modeling, notably the use of QSPR models, was a credible alternative approach to experimental characterization to access, in a reliable and fast manner, physico-chemical properties of substances required by REACH (annexes VII and IX).
This paper presents an overview of existing validated QSPR models for hazardous physico-chemical properties including those developed recently by INERIS. Then, the different ways towards the acceptance and use of QSPR in a regulatory assessment of chemicals are discussed and exemplified with the first QSPR model implemented into the QSAR Toolbox of ECHA and OECD (2015) (in its version 3.3 of December 2014) for the prediction of a hazardous physico-chemical property. This model is a simple multilinear model (based only on constitutional descriptors) dedicated to the prediction of one property of explosibility which is the impact sensitivity of nitroaliphatics (Prana et al. 2012).
