title: Multiparameter toxicity assessment of novel DOPO-derived organophosphorus flame retardants.
abstract: 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-6H-dibenzo[c,e][1,2]oxaphosphinin-6-yl)amino)ethoxy)-6H-dibenzo[c,e][1,2]oxaphosphinine 6-oxide (ETA-DOPO) and 6,6'-(ethane-1,2-diylbis(oxy))bis(6H-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(6H-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.
authors.affiliation: Particles-Biology Interactions Laboratory, Swiss Federal Laboratories for Materials Science and Technology (Empa), Lerchenfeldstrasse 5, 9014, St. Gallen, Switzerland. Cordula.Hirsch@empa.ch.
authors.forename: Cordula
authors.initials: C
authors.lastname: Hirsch
authors.affiliation: ZHAW, Life Sciences and Facility Management, Einsiedlerstr. 31, 8820, Waedenswil, Switzerland.
authors.forename: Britta
authors.initials: B
authors.lastname: Striegl
authors.affiliation: ZHAW, Life Sciences and Facility Management, Einsiedlerstr. 31, 8820, Waedenswil, Switzerland.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Mathes
authors.affiliation: ZHAW, Life Sciences and Facility Management, Einsiedlerstr. 31, 8820, Waedenswil, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Adlhart
authors.affiliation: ZHAW, Life Sciences and Facility Management, Einsiedlerstr. 31, 8820, Waedenswil, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Edelmann
authors.affiliation: ZHAW, Life Sciences and Facility Management, Einsiedlerstr. 31, 8820, Waedenswil, Switzerland.
authors.forename: Epifania
authors.initials: E
authors.lastname: Bono
authors.affiliation: Additives and Chemistry Group, Advanced Fibers, Swiss Federal Laboratories for Materials Science and Technology (Empa), Lerchenfeldstrasse 5, 9014, St. Gallen, Switzerland.
authors.forename: Sabyasachi
authors.initials: S
authors.lastname: Gaan
authors.affiliation: Additives and Chemistry Group, Advanced Fibers, Swiss Federal Laboratories for Materials Science and Technology (Empa), Lerchenfeldstrasse 5, 9014, St. Gallen, Switzerland.
authors.forename: Khalifah A
authors.initials: KA
authors.lastname: Salmeia
authors.affiliation: University of Konstanz, Universitaetsstr. 10, 78457, Konstanz, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Hoelting
authors.affiliation: University of Konstanz, Universitaetsstr. 10, 78457, Konstanz, Germany.
authors.forename: Alice
authors.initials: A
authors.lastname: Krebs
authors.affiliation: University of Konstanz, Universitaetsstr. 10, 78457, Konstanz, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Nyffeler
authors.affiliation: University of Konstanz, Universitaetsstr. 10, 78457, Konstanz, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Pape
authors.affiliation: University of Konstanz, Universitaetsstr. 10, 78457, Konstanz, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Bürkle
authors.affiliation: University of Konstanz, Universitaetsstr. 10, 78457, Konstanz, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Leist
authors.affiliation: Particles-Biology Interactions Laboratory, Swiss Federal Laboratories for Materials Science and Technology (Empa), Lerchenfeldstrasse 5, 9014, St. Gallen, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Wick
authors.affiliation: University of Konstanz, Universitaetsstr. 10, 78457, Konstanz, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schildknecht
mesh_terms: D000072283:A549 Cells; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003498:Cyclic P-Oxides / Q000633:toxicity; D005411:Flame Retardants / Q000633:toxicity*; D000066449:Human Embryonic Stem Cells / Q000166:cytology; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000633:toxicity*; D039904:Pluripotent Stem Cells / Q000166:cytology; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D012869:Skin Absorption; D023422:Skin Irritancy Tests; D034421:Sus scrofa; D054457:Tissue Scaffolds / Q000737:chemistry; D018675:Toxicity Tests
chemical_list: D003498:Cyclic P-Oxides; C000614748:EDA-DOPO compound; C000614747:EG-DOPO compound; C000614746:ETA-DOPO compound; D005411:Flame Retardants; D009943:Organophosphorus Compounds
keywords: Dermal absorption; Flame retardants; Neurotoxicity; Organophosphate; Polybrominated diphenyls