Phosgene lethality

Lethal human toxicity values have not been established or have not been published. However, based on available information, this material appears to have approximately the same toxicity as Phosgene (C10-A003). 

Phosgene is very poisonous so insidious that it was used as a war gas in World War 1. One deep breath can cause immediate collapse and death, and as it is not irritating there is no gag reflex to prevent one from taking that deep breath. Doses which are not high enough to be immediately lethal may not be noticed at till at the time of exposure, yet lead to death within 24 hours. Sub-lethal doses cause pulmonary edema and serious respiratory disability again, the symptoms can appear well after an exposure which was hardly noticed. 

The 30-min and 1-, 4-, and 8-h AEGL-3 values were based on the highest concentration causing no mortality in the rat after a 30-min exposure (15 ppm) (Zwart et al. 1990). A UF of 3 was applied for interspecies extrapolation because little species variability is observed for lethal and nonlethal end points after exposure to phosgene. A UF of 3 was applied to account for sensitive human subpopulations due to the steep concentration-response curve and... 

In their literature review, Diller and Zante (1982) also identified nonlethal effects from phosgene exposure (lethal effects are described in Section 2.1). Nonlethal information synthesized from this review is presented in Table 1-4. From the above data and from animal data for initial lung damage, Diller and Zante (1982) synthesized information for nonlethal effects of phosgene in humans (Table 1-5). 

Several other acute lethality studies of phosgene in rats have been reported. However, as is the case with the mice, these studies do not contain experimental details such as strain or gender, number of animals exposed, or analytical methodology. These studies are summarized in Table 1-7. 

Thus, partial protection from phosgene-induced lethality was obtained by the phosgene pretreatment. TABLE 1-6 Acute Lethality of Phosgene in Mice ... 

TABLE 1-8 Acute Lethality of Phosgene in Guinea Pigs... 

The concept of a death product was introduced by Haber to explain the relationship between the extent of exposure to phosgene and death (Haber 1924). According to Haber s law, the biological effect of phosgene is directly proportional to the exposure, expressed as the product of the atmospheric concentration (C) and the time of exposure (T), or CT=k, where k can be death, pulmonary edema, or other biological effects of phosgene exposure (EPA 1986). Haber s law has subsequently been shown by other investigators to be valid for both nonlethal and lethal effects within certain limits. 

Rat and mouse lethality data from the well-conducted study of Zwart et al. (1990) also suggest that Haber s law is valid for phosgene. The study by ten Berge et al. (1986) has shown that the concentration-exposure-time relationship for many irritant and systemically acting vapors and gasses can be described by the relationship Cnxt=k. When the 10- to 60-min rat LC50 data are utilized in a linear regression analysis a value of the exponent, n, of 0.93 is obtained. The mouse 10- to 60-min lethality data yield a value of 1.3 for n. 

Karel, L. and Weston, R.E. 1947. The biological assay of inhaled substance by the dosimetric method The retained median lethal dose and the respiratory response in unanesthetized, normal goats exposed to different concentrations of phosgene. J. Ind. Hyg. Toxicol. 29 23— 28. 

Weston, R.E. and Karel, L. 1946. An application of the dosimetric method for biologically assaying inhaled substances The determination of the retained median lethal dose, percentage retention, and respiratory response in dogs exposed to different concentrations of phosgene. J. Pharmacol. Exptl. Ther. 88 195. 

Interspecies 3—little species variability is observed with both lethal and nonlethal end points in many studies after exposure to phosgene... 

The mechanism of carbon tetrachloride hepatotoxicity generally is viewed as an example of lethal cleavage, where the CCh— Cl bond is split in the mixed-function oxidase system of the hepatocytes. After this cleavage damage may occur directly from the free radicals (-CCl and -Cl) and/or from the formation of toxic metabolites such as phosgene." ... 

Phosgene was used as a major CW agent in WW I and was responsible for the greatest number of CW induced mortalities. It causes a lethal pulmonary oedema after an asymptomatic lag phase of up to 24 h. Its specific mechanism of action is unknown, but is assumed to involve reactions with nucleophilic sites on macromolecules. 

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