Information Sources Day 1. Adam Peters and Graham Merrington 2017

Information SMILES QSAR Tests Reliability Fate 2017

Information Sources ECHA dissemination portal 2017

Predicting Chemical Properties USEPA EPI Suite – suite of QSAR models Generally suitable for non-ionisable organic chemicals Structures for most substances available in a database SMILES codes may be available on the internet Derive the SMILES code yourself Always check that the structure produced is the substance you are working on 2017

SMILES Codes Simplified Molecular-Input Line-Entry System Summarises the molecular structure in a way which can be entered into a model Try to join every atom with a single continuous line Cyclohexane or benzene? End Start 2017

EPI Suite 2016

EPI Suite Outputs Original Structure SMILES from structure CN1C(=O)N(C)C(=O)c2N(C)C=Nc12 SMILES from CAS RN CN1C(=O)N(C)c2ncn(C)c2C1(=O) SMILES codes are not unique, they could start (and end) at any part of the structure. Both sets of predictions resulted in the same structure despite different notations 2017

EPI Suite Predictions Log KOW, from structure Vapour pressure, from structure Water solubility, from KOW & structure (2 models) Baseline toxicity (apolar narcosis) Henrys Law Constant KOC, from KOW & structure (2 models) Biodegradation (readily biodegradable?) Based on results of several models 2017

Test Methods Usually according to OECD standard tests Different methods depending upon nature of the substance (e.g. solubility in solvents) May be limited by analytical capabilities Water solubility in pure water may be quite different to solubility in natural waters There is an upper limit to measureable values of log KOW due to the solubility of water in octanol and vice versa 2017

Reliability of Information Original study reports may not be available There may be several studies for a single endpoint Critical study or weight of evidence? Justification and recording of decisions made can be critical because some parameters can have a large influence on risk assessment outcomes 2017

Partitioning Indicated by log KOW, log KOC, and KD Usually assumed to be controlled by organic carbon content of medium (soil/sediment) Limited predictability for substances with no reliable log KOW value Empirical measurements usually required for ionisables, inorganics, and metals Can be highly variable between different environments 2017

Ionisable Organic Substances Tend to behave differently to non-polar substances in the environment Properties tend not to be predictable by QSAR Often identifiable from the structure of the substance Dissociation constant – pKa pKa is equal to the pH at which both forms (ionised and unionised) of the substance (or functional group) are present at equal concentrations 2016

Partition Coefficients for Ionisable Substances May be measured in buffered solutions Several pH levels may need to be tested Should cover a range of ionisation of the substance Substances may have more than one ionisable functional group Amino acids have at least 2 ionisable functional groups -COOH, and –NH2 Ionisation affects water solubility 2016

Degradation Ready biodegradability test Rapid mineralisation under favourable conditions Usually limited other test data Important to distinguish between mineralisation (to CO2 and H2O) and primary degradation (original substance not present) Degradation products are usually more soluble and more degradable than the original substance 2017

Bioaccumulation Accumulation in biota and food chains Indicated by partition coefficient Bioconcentration factor BCF Accumulation from water Bioaccumulation factor BAF Accumulation from both food and water Biomagnification factor BMF Accumulation from food 2017

2016