Nitrile toxicity, mechanism

As a class of compounds, the two main toxicity concerns for nitriles are acute lethality and osteolathyrsm. A comprehensive review of the toxicity of nitriles, including detailed discussion of biochemical mechanisms of toxicity and stmcture-activity relationships, is available (12). Nitriles vary broadly in their abiUty to cause acute lethaUty and subde differences in stmcture can greatly affect toxic potency. The biochemical basis of their acute toxicity is related to their metaboHsm in the body. Following exposure and absorption, nitriles are metabolized by cytochrome p450 enzymes in the Hver. The metaboHsm involves initial hydrogen abstraction resulting in the formation of a carbon radical, followed by hydroxylation of the carbon radical. MetaboHsm at the carbon atom adjacent (alpha) to the cyano group would yield a cyanohydrin metaboHte, which decomposes readily in the body to produce cyanide. Hydroxylation at other carbon positions in the nitrile does not result in cyanide release. 

The relevance of the QSAR shown in Equation 4.2 to this discussion is that since the logPe/w and kacorr values can be determined computationally, Equation 4.2 can be used to predict the acute toxicities of nitriles yet to be synthesized, or of existing nitriles for which measured toxicity data are not available. This examples also demonstrates the importance of first having a qualitative understanding of any existing relationships between structure and toxicity, and the mechanism of toxicity, before attempting to quantify the relationships. 

One mechanism of nitrile toxicity requires that the cyano moiety be released from the molecule (Figure 4). This particular example illustrates the in vivo transformation by cytochrome P450, a very common oxidation enzyme found primarily in the liver but also in other tissues. 

Tanii H, Hashimoto K. 1984b. Studies on the mechanism of acute toxicity of nitriles in mice. Arch Toxicol 55 47-54. 

H. Tanii, K. Hashimoto, Studies on the Mechanism of Acute Toxicity of Nitriles in Mice , Arch. Toxicol. 1984, 55, 47 - 54. 

Organonitriles are organic substances that contain the cyano (-C = N) group. Nitriles have wide commercial applications that include solvents, synthetic intermediates, pharmaceuticals, and monomers, to name just a few. As a class of substances, there are two types of toxicity associated with exposure to nitriles acute lethality and osteolathyrism. Some nitriles are known to cause both. The mechanisms by which nitriles cause these toxic effects, the corresponding relationships between nitrile structure and toxic potency for each effect, and the use of this information as a basis to design substances that may need to contain the functionality of the cyano group but will cause minimal toxicity have been discussed in detail [7]. Only the biochemical mechanism and SARs related to acute lethality of nitriles are discussed here. More detailed discussions are available [7, 8, 61]. 

Scheme 4.4 Mechanism by which organonitriles are acutely lethal. Nitriles that can form a more stable radical on the a-carbon tend to be more lethal because they form the cyanohydrin intermediate more readily, which decomposes to release cyanide, which is highly toxic.

WALLIG, M.A., GOULD, D.H., FETTMAN, M.J., Comparative toxicities of the naturally occuring nitrile l-cyano-3,4-epithiobutane and the synthetic nitrile n-valeronitrile in rats differences in target organs, metabolism and toxic mechanisms., Fd. Chem. Toxic., 1988,26, 149-157. 

Acute and subchronic toxicity, teratogenicity, and biochemical mechanism studies of a series of structurally similar aliphatic nitriles indicated that although the toxicological profiles were generally the same for most of the compounds, there were unique differences, too (Johannsen and Levinska, 1986). In this respect, acetonitrile was different from the other nitriles within the homologous series. Nitriles liberated cyanide both in vivo and in vitro. Tanii and Hashimoto (1984a,b, 1985) observed a dose-cyanide liberation relationship in liver and hepatic microsomal enzyme system in mice pretreated with carbon tetrachloride. For most nitriles, the toxicity was greatly reduced by carbon tetrachloride pretreatment. By contrast, certain nitriles, exhibited an increase of toxicity as a result of such pretreatment. 

The Schmidt reaction of aldehydes has some features as follows. (1) Aldehydes react with hydrazoic acid faster than carboxylic acids. (2) The formation of for-mamides is often observed as side reaction. The factors that affect the distribution of nitriles and formamides in products have been figured out nowadays because the mechanism has been finally established [34]. (3) Since the reaction requires acidic conditions to achieve high yields, the using of aldehydes is usually limited to aromatic aldehydes due to stability reasons. For aliphatic aldehydes, only acetaldehyde could work to give acetonitrile in the presence of aqueous sulfuric acid. (4) Hydrazoic acid, handled either as a solution or generated in situ, is publicly acknowledged to be toxic and explosive especially on large scale. 

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