Studies on the effect of the solvents dimethylsulfoxide and ethyleneglycoldimethylether on the mutagenicity of four types of diisocyanates in the Salmonella/microsome test.
The mutagenicity of isomers and homologs of diphenylmethanediisocyanate (4,4'-diisocyanatodiphenylmethane, 2,4'-diisocyanatodiphenylmethane, a mixture of monomeric MDI isomers, and polymeric MDI), containing 55-100% of monomeric MDI, was determined in the Salmonella/microsome test using dimethylsulfoxide (DMSO) and ethyleneglycoldimethylether (EGDE) as solvents. Positive results were obtained for DMSO solutions of all four diisocyanates in the presence of S9 mix containing 30% S9 fraction. Uniformly negative results were found when the diisocyanates were dissolved in EDGE. These results correspond to those of analytical investigations. A small amount of diaminodiphenylmethane (MDA) is one of the reaction products formed when MDI is dissolved in commercial DMSO. No MDA could be detected in solutions of MDI in EGDE. It is therefore concluded that the positive results obtained with diisocyanates in DMSO solutions are due to the formation of MDA. This is artificially formed through the hydrolysis of MDI, caused by traces of water that are always present in DMSO. These findings indicate that DMSO is an inappropriate solvent and should therefore not be used in any in vitro study with diisocyanates. EGDE may be a suitable replacement. The positive test results reported so far for DMSO solutions of MDI are thus only of limited relevance for risk evaluation.
Herbold
B
B
PH-PD Toxicology, Wuppertal, Germany.
Haas
P
P
Seel
K
K
Walber
U
U
D004121:Dimethyl Sulfoxide / Q000494:pharmacology*; D004347:Drug Interactions; D004355:Drug Stability; D005019:Ethyl Ethers / Q000494:pharmacology*; D017953:Isocyanates / Q000737:chemistry / Q000633:toxicity*; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D012997:Solvents / Q000494:pharmacology*; D001559:Benzhydryl Compounds
D004121:Dimethyl Sulfoxide; D005019:Ethyl Ethers; D017953:Isocyanates; D009153:Mutagens; D012997:Solvents; C005969:4,4'-diphenylmethane diisocyanate; D001559:Benzhydryl Compounds; C024683:1,2-dimethoxyethane