Sensory irritation mechanisms investigated from model compounds : trifluoroethanol, hexafluoroisopropanol and methyl hexafluoroisopropyl ether

• Published in: Archives of toxicology Vol. 70; no. 6; pp. 319 - 328
• Main Authors: NIELSEN, G. D, ABRAHAM, M. H, HANSEN, L. F, HAMMER, M, COOKSEY, C. J, ANDONIAN-HAFTVAN, J, ALARIE, Y
• Format: Journal Article
• Language: English
• Published: Berlin Springer 1996
• Subjects: 1-Propanol - toxicity; Animals; Biological and medical sciences; Dose-Response Relationship, Drug; General aspects. Methods; Irritants - toxicity; Male; Medical sciences; Methyl Ethers - toxicity; Mice; Mice, Inbred Strains; Models, Chemical; Propanols; Respiration - drug effects; Toxicology; Trifluoroethanol - toxicity; Volatile compound; Upper respiratory tract; Respiratory disease; Toxicity; Chemical compound; Rodentia; Eye disease; Vertebrata; Mammalia; Structure activity relation; Mouse; Animal; Irritant compound; Organic compounds; Irritation; Hydrogen bond
• ISSN: 0340-5761; 1432-0738
• DOI: 10.1007/s002040050281

Quantitative structure-activity relationships (QSAR) have suggested the importance of hydrogen bonding in relation to activation of the sensory irritant receptor by nonreactive volatile organic chemicals. To investigate this possibility further, three model compounds with different hydrogen bond acidity, trifluoroethanol, hexafluoroisopropanol and methyl hexafluoroisopropyl ether, were selected for study. The potency of each chemical is obtained from the concentration necessary to reduce respiratory rate in mice by 50% (RD50). The RD50 values obtained were: methyl hexafluoroisopropyl ether (> or = 160,000 ppm), trifluoroethanol (11,400-23,300 ppm), and hexafluoroisopropanol (165 ppm). QSAR showed that trifluoroethanol and methyl hexafluoroisopropyl ether behaved as predicted as nonreactive sensory irritants, whereas hexafluoroisopropanol was much more potent than predicted. The higher than predicted potency of hexafluoroisopropanol could be due to a coupled reaction, involving both strong hydrogen bonding and weak Brönsted acidity. A concerted reaction could thus be more efficient in activation of the receptor. Hydrogen bonding properties and concerted reactions may be important in the activation of the sensory irritant receptor by nonreactive volatile organic chemicals.