PBT assessment under REACH: Screening for low aquatic bioaccumulation with QSAR classifications based on physicochemical properties to replace BCF in vivo testing on fish.

Aquatic bioconcentration factors (BCFs) are critical in PBT (persistent, bioaccumulative, toxic) and risk assessment of chemicals. High costs and use of more than 100 fish per standard BCF study (OECD 305) call for alternative methods to replace as much in vivo testing as possible. The BCF waiving scheme is a screening tool combining QSAR classifications based on physicochemical properties related to the distribution (hydrophobicity, ionisation), persistence (biodegradability, hydrolysis), solubility and volatility (Henry's law constant) of substances in water bodies and aquatic biota to predict substances with low aquatic bioaccumulation (nonB, BCF<2000). The BCF waiving scheme was developed with a dataset of reliable BCFs for 998 compounds and externally validated with another 181 substances. It performs with 100% sensitivity (no false negatives), >50% efficacy (waiving potential), and complies with the OECD principles for valid QSARs. The chemical applicability domain of the BCF waiving scheme is given by the structures of the training set, with some compound classes explicitly excluded like organometallics, poly- and perfluorinated compounds, aromatic triphenylphosphates, surfactants. The prediction confidence of the BCF waiving scheme is based on applicability domain compliance, consensus modelling, and the structural similarity with known nonB and B/vB substances. Compounds classified as nonB by the BCF waiving scheme are candidates for waiving of BCF in vivo testing on fish due to low concern with regard to the B criterion. The BCF waiving scheme supports the 3Rs with a possible reduction of >50% of BCF in vivo testing on fish. If the target chemical is outside the applicability domain of the BCF waiving scheme or not classified as nonB, further assessments with in silico, in vitro or in vivo methods are necessary to either confirm or reject bioaccumulative behaviour.

[1]  Helmut Segner,et al.  Integrated testing strategy (ITS) for bioaccumulation assessment under REACH. , 2014, Environment international.

[2]  L. R. Dice.  Measures of the Amount of Ecologic Association Between Species , 1945 .

[3]  S. Tanabe,et al.  Bioaccumulation of Butyltin Compounds in Marine Mammals: The Specific Tissue Distribution and Composition , 1997 .

[4]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings , 1997 .

[5]  S Dimitrov,et al.  Base-line model for identifying the bioaccumulation potential of chemicals , 2005, SAR and QSAR in environmental research.

[6]  Emilio Benfenati,et al.  A comparative survey of chemistry-driven in silico methods to identify hazardous substances under REACH. , 2013, Regulatory toxicology and pharmacology : RTP.

[7]  Konrad Hungerbühler,et al.  USING CONDITIONAL INFERENCE TREES AND RANDOM FORESTS TO PREDICT THE BIOACCUMULATION POTENTIAL OF ORGANIC CHEMICALS , 2013, Environmental toxicology and chemistry.

[8]  Watze de Wolf,et al.  Animal Use Replacement, Reduction, and Refinement: Development of an Integrated Testing Strategy for Bioconcentration of Chemicals in Fish , 2007, Integrated environmental assessment and management.

[9]  W. Russell,et al.  Ethical and Scientific Considerations Regarding Animal Testing and Research , 2011, PloS one.

[10]  M Nendza,et al.  Screening for low aquatic bioaccumulation (2): physico-chemical constraints , 2011, SAR and QSAR in environmental research.

[11]  Helmut Segner,et al.  Use of In Vitro Absorption, Distribution, Metabolism, and Excretion (ADME) Data in Bioaccumulation Assessments for Fish , 2007 .

[12]  T. Springer,et al.  Assessment of an approach to estimating aquatic bioconcentration factors using reduced sampling , 2008, Environmental toxicology and chemistry.

[13]  Adam Lillicrap,et al.  A tiered assessment strategy for more effective evaluation of bioaccumulation of chemicals in fish. , 2016, Regulatory toxicology and pharmacology : RTP.

[14]  L. Lai,et al.  Calculating partition coefficient by atom-additive method , 2000 .

[15]  Jon A Arnot,et al.  A quantitative structure‐activity relationship for predicting metabolic biotransformation rates for organic chemicals in fish , 2009, Environmental toxicology and chemistry.

[16]  M. Nendza,et al.  Screening for low aquatic bioaccumulation (1): Lipinski's ‘Rule of 5’ and molecular size , 2010, SAR and QSAR in environmental research.

[17]  Wenjing Fu,et al.  Methods for estimating the bioconcentration factor of ionizable organic chemicals , 2009, Environmental toxicology and chemistry.

[18]  Watze de Wolf,et al.  Animal Use Replacement, Reduction, and Refinement: Development of an Integrated Testing Strategy for Bioconcentration of Chemicals in Fish , 2007 .

[19]  Yuki Sakuratani,et al.  Workgroup Report: Review of Fish Bioaccumulation Databases Used to Identify Persistent, Bioaccumulative, Toxic Substances , 2006, Environmental health perspectives.

[20]  R. Mason,et al.  Factors Controlling the Bioaccumulation of Mercury, Methylmercury, Arsenic, Selenium, and Cadmium by Freshwater Invertebrates and Fish , 2000, Archives of environmental contamination and toxicology.

[21]  A. Ghose,et al.  Prediction of Hydrophobic (Lipophilic) Properties of Small Organic Molecules Using Fragmental Methods: An Analysis of ALOGP and CLOGP Methods , 1998 .

[22]  Lyn Denison,et al.  Stockholm Convention on Persistent Organic Pollutants , 2013 .

[23]  J. Dearden,et al.  Predicting Fate-Related Physicochemical Properties , 2007 .

[24]  Ralph Kühne,et al.  Estimation of Compartmental Half‐lives of Organic Compounds – Structural Similarity versus EPI‐Suite , 2007 .

[25]  Mark Bonnell,et al.  Bioaccumulation Assessment Using Predictive Approaches , 2009, Integrated environmental assessment and management.

[26]  Ralph Kühne,et al.  Chemical Domain of QSAR Models from Atom-Centered Fragments , 2009, J. Chem. Inf. Model..

[27]  Scott A Mabury,et al.  Bioconcentration and tissue distribution of perfluorinated acids in rainbow trout (Oncorhynchus mykiss) , 2003, Environmental toxicology and chemistry.

[28]  Gergana Dimitrova,et al.  A Stepwise Approach for Defining the Applicability Domain of SAR and QSAR Models , 2005, J. Chem. Inf. Model..

[29]  G. Schüürmann,et al.  Development and application of screening tools for biodegradation in water-sediment systems and soil. , 2016, The Science of the total environment.