Five studies examined the toxicity of ketene in various animal species. These studies indicate that the inhalation route of exposure is of particular
concern for ketene and that the chemical has similarities to phosgene in clinical effects and mode of action. Ketene is a respiratory poison that can
exhibit delayed toxicity to alveolar structures (mainly capillaries) to produce death by pulmonary edema. Ketene has been shown to acetylate free
amino (and other functional) groups of proteins in aqueous solution. Like phosgene, the pulmonary effects of inhalation exposure to ketene may be
manifested in the absence of direct irritation by ketene or its breakdown product, acetic acid. For all species tested, the toxicologic profile of
ketene is similar. Ketene is lethal at high concentrations; at lower concentrations, minor irritation during exposure and central nervous system
impairment have been observed. However, severe damage to the lungs (at the alveolar level) may manifest as long as 24 h after exposure. The central
nervous system effects are likely due to cerebral anoxia secondary to alveolar damage. Toxicity is greatest in mice, followed by rats, guinea pigs,
cats, and rabbits. Ketene appears to exhibit a steep concentration-response relationship
AEGL-3 values are based on the mouse studies of Treon et al. (1949). A 50-min exposure to ketene at 50 ppm caused 100% mortality in mice. A 30-min
exposure at 23 ppm was lethal to 7/10 mice, but a 2-h exposure at this concentration was 100% lethal. A 4.5-h exposure at 12 ppm (the next lower test
concentration) did not result in deaths, but 3/7 mice died during a 5.5-h exposure at the same concentration on the subsequent day of exposure.
Because the time of death during the second exposure was not reported, whether the deaths were a delayed effect of the first exposure or caused by the
second exposure is uncertain. In a second repeated-exposure study (Treon et al. 1949), no deaths occurred in mice after a single 7-h exposure at 1 ppm
and 1/10 mice died 3 days after the tenth exposure. The concentration of 1 ppm was considered a threshold for lethal effects caused by a single
exposure to ketene and was chosen as the point of departure for calculating AEGL-3 values. A total uncertainty factor of 10 was used. Mice appeared to
be the most susceptible species, so an interspecies factor of 3 was considered adequate to account for interspecies differences. An intraspecies
factor of 3 was used because the mode of action (acylation of functional groups on proteins and enzymes in the lung) is not expected to vary greatly
among individuals. Human studies examining the toxicity of phosgene, which appears to have a mode of action similar to ketene, did not identify
sensitive subpopulations and used an intraspecies uncertainty factor of 3 in the derivation of the AEGL-2 and AEGL-3 values (NRC 2002). AEGL-3 values
were derived by time scaling according to the equation Cn × t = k, using default values of n = 3 to extrapolate from longer to shorter durations and
n = 1 to extrapolate from shorter to longer durations. The 10-min AEGL-3 value was set equal to the 30-min value because of the uncertainty associated
with extrapolating a 7-h point of departure to a 10-min AEGL value
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