Fatal Occupational Exposure to Trimethylsilyl-Diazomethane
Murphy NG,1 Varney SM,2 Tallon JM,1 Thompson JR,1 Blanc PD.3
1IWK Regional Poison Centre, Halifax, NS, Canada; 2Rocky Mountain Poison & Drug Center-Denver Health, Denver, CO, USA; 3Division of Occupational and Environmental Medicine, UCSF, San Francisco, CA, USA.
Background: Diazomethane (DM) is a highly explosive, toxic methylating reagent causing severe pulmonary injury. Trimethylsilyl-diazomethane (TSDM) is a less explosive analogue that may not be less toxic. We describe the first documented case of a fatality following TSDM exposure.
Case report: A 46 year-old male pharmaceutical chemist presented to the ED with progressive dyspnea. At noon on the prior day, as part of a chemical analysis, he had mixed 2 mL of acetone with 25 mL of L-Malic acid to which was added TSDM dissolved in n-hexane. After 1 hour this mix was combined with an inert gas and a small amount of methylene chloride under a fume hood that was later reported to be nonfunctioning.
Although he experienced no immediate mucous membrane irritation, 8 hours post-exposure he developed cough, pleuritic chest pain, hemoptysis, and progressive shortness of breath; by 15 hours, he presented to the ED in respiratory distress, hypoxic (PaO2 67), hypercarbic (PaCO2 46), and acidemic (pH 7.26). A chest radiograph showed an acute lung injury pattern. By 23 hours he required intubation.
At 26 hours postexposure he developed profound bradycardia, refractory hypotension, and asystole.
Case discussion: DM inhalation is known to cause fatal pulmonary edema without an immediate irritant prodrome and with a similar time course to this case. Structural modification of DM with an added trimethylsilyl group makes TSDM less explosive, but its propensity for lung injury is unclear. The chemical admixture as described in this case may have liberated nitrogen gas, but this should not have led to pulmonary injury; nitrogen dioxide should not have evolved. The toxicity may stem from residual DM present in the reagent or a direct effect of TSDM, its metabolites or breakdown products, or potential intracellular formaldehyde formation.
Conclusion: The temporal relationship to exposure with inadequate ventilation and clinical effects similar to the analogue toxicant DM support a causal relationship between TSDM and acute lung injury. Additional safety data for this chemical is warranted, including experimental inhalation testing in animals.The conclusion that I draw from this is not that chemists should not use TMS-diazomethane, but that they should exercise due caution with respect to the potentially fatal consequences of inhaling it. Work practices, engineering controls and PPE are all a part of that.
(Does anyone wonder if there's a misreporting of the scale of whatever test Mr. Daigle was performing? 2 mL of acetone and 25 mL (?) of malic acid does not make a ton of sense.)