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Screening for low aquatic bioaccumulation (1): Lipinski's 'Rule of 5' and molecular size

: Nendza, M.; Müller, M.


SAR and QSAR in Environmental Research 21 (2010), No.5&6, pp.495-512
ISSN: 1062-936X
ISSN: 1029-046X
Journal Article
Fraunhofer IME ()
QSAR; BCF; logKOW; molecular weight; molecular diameter; hydrogen bonding

Aquatic bioconcentration factors are critical in PBT assessment of industrial chemicals under REACH. Reliable indicators based on physico-chemical properties and molecular attributes of chemicals with low bioconcentration potential have been searched to de-prioritize non-accumulative chemicals in order to avoid unnecessary biotests that do not produce risk-relevant information. Developed to screen drug candidates, Lipinski's 'Rule of 5' identifies chemicals with poor oral absorption based on criteria in partitioning, molecular weight and hydrogen bonding. This parameter ensemble has been supplemented with molecular diameter and tested for its adequacy to filter chemicals with low bioconcentration potential. Perhaps (not) surprisingly, the application of the 'Rule of 5' fails to protectively identify non-accumulative compounds because other processes dominate the uptake in aquatic environments as compared with oral absorption. No robust evidence was found for cut-offs in bioconcentration related to molecular size. However, pragmatic thresholds in molecular weight (>650 g mol-1) and lipophilicity (logKOW <3 or >10) have been verified to securely de-prioritize 30-40% of chemicals of low concern with regard to the B criterion.