Multiparameter toxicity assessment of novel DOPO-derived organophosphorus flame retardants

• Published in: Archives of toxicology 2017-01, Vol.91 (1), p.407-425
• Main Authors: Hirsch, Cordula, Striegl, Britta, Mathes, Stephanie, Adlhart, Christian, Edelmann, Michael, Bono, Epifania, Gaan, Sabyasachi, Salmeia, Khalifah A., Hoelting, Lisa, Krebs, Alice, Nyffeler, Johanna, Pape, Regina, Bürkle, Alexander, Leist, Marcel, Wick, Peter, Schildknecht, Stefan
• Format: Article
• Language: English
• Subjects: A549 Cells; Animals; Biomedical and Life Sciences; Biomedicine; Cell Line; Cell Survival - drug effects; Cells, Cultured; Cyclic P-Oxides - toxicity; Cytotoxicity; Daphnia; Environmental Health; Flame retardants; Flame Retardants - toxicity; Human Embryonic Stem Cells - cytology; Humans; In vitro Systems; Keratinocytes - cytology; Keratinocytes - drug effects; Keratinocytes - immunology; Keratinocytes - metabolism; Laboratories; Materials science; Monocytes - cytology; Monocytes - drug effects; Monocytes - immunology; Monocytes - metabolism; Nervous system; Neurons - cytology; Neurons - drug effects; Neurons - immunology; Neurons - metabolism; Occupational Medicine/Industrial Medicine; Organophosphorus Compounds - toxicity; Pharmacology/Toxicology; Phosphorus; Pluripotent Stem Cells - cytology; Polybrominated diphenyl ethers; Respiratory Mucosa - cytology; Respiratory Mucosa - drug effects; Respiratory Mucosa - immunology; Respiratory Mucosa - metabolism; Skin - cytology; Skin - drug effects; Skin - immunology; Skin - metabolism; Skin Absorption; Skin Irritancy Tests; Sus scrofa; Test systems; Tissue Scaffolds - chemistry; Toxicity; Toxicity Tests
• ISSN: 0340-5761; 1432-0738
• DOI: 10.1007/s00204-016-1680-4

Halogen-free organophosphorus flame retardants are considered as replacements for the phased-out class of polybrominated diphenyl ethers (PBDEs). However, toxicological information on new flame retardants is still limited. Based on their excellent flame retardation potential, we have selected three novel 9,10-dihydro-9-oxa-10-phosphaphenanthrene-10-oxide (DOPO) derivatives and assessed their toxicological profile using a battery of in vitro test systems in order to provide toxicological information before their large-scale production and use. PBDE-99, applied as a reference compound, exhibited distinct neuro-selective cytotoxicity at concentrations ≥10 µM. 6-(2-((6-oxido-6 H -dibenzo[ c,e ][1,2]oxaphosphinin-6-yl)amino)ethoxy)-6 H -dibenzo[ c,e ][1,2]oxaphosphinine 6-oxide (ETA-DOPO) and 6,6′-(ethane-1,2-diylbis(oxy))bis(6 H -dibenzo[ c,e ][1,2]oxaphosphinine-6-oxide) (EG-DOPO) displayed adverse effects at concentrations >10 µM in test systems reflecting the properties of human central and peripheral nervous system neurons, as well as in a set of non-neuronal cell types. DOPO and its derivative 6,6′-(ethane-1,2-diylbis(azanediyl))bis(6 H -dibenzo[ c,e ][1,2]oxaphosphinine-6-oxide) (EDA-DOPO) were neither neurotoxic, nor did they exhibit an influence on neural crest cell migration, or on the integrity of human skin equivalents. The two compounds furthermore displayed no inflammatory activation potential, nor did they affect algae growth or daphnia viability at concentrations ≤400 µM. Based on the superior flame retardation properties, biophysical features suited for use in polyurethane foams, and low cytotoxicity of EDA-DOPO, our results suggest that it is a candidate for the replacement of currently applied flame retardants.