Acute airway irritation of methyl formate in mice

Methyl formate (MF) is a volatile solvent with several industrial applications. The acute airway effects of MF were evaluated in a mouse bioassay, allowing the assessment of sensory irritation of the upper airways, airflow limitation of the conducting airways and deep lung (pulmonary) irritation. MF was studied at vapour concentrations of 202-1,168 ppm. Sensory irritation was the only effect observed, which developed slowly over the 30-min exposure period. The potency at steady state was at least 10-fold higher than expected from a hypothetically similar, but non-reactive compound. Methyl formate may be hydrolysed in vivo to formic acid, a potent sensory irritant, and methanol, a low-potent sensory irritant. Hydrolysis may be catalysed by carboxyesterases, and therefore, the role of the esterases was studied using the esterase inhibitor tri-ortho-cresyl phosphate (TOCP). TOCP pre-treatment reduced the irritation response of MF, suggesting that carboxyesterase-mediated hydrolysis plays a role in the irritative effect. However, even after administration of TOCP, MF was considerably more irritating than expected from a quantitative structure-activity relationship (QSAR) model. The slope of the concentration-effect relationship for formic acid was lower than that for the MF in the low-dose range, suggesting that different receptor activation mechanisms may occur, which may include an effect of MF itself, in addition to an effect of formic acid and potentially an effect from formaldehyde.