Nitrile toxicity

Grogan J, DeVito SC, Pearlman RS, et al. Modeling cyanide release from nitriles prediction of cytochrome P450 mediated acute nitrile toxicity. Chem Res Toxicol 1992 5(4) 548-552. 

Figure 4.5 Acute lethality values of some commonly used nitriles. Nitrile toxic potency is measured in mice, and expressed as oral median lethal dose (LD50) in millimoles of the nitrile per kilogram body weight [7].

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. 

Grogan, J., DeVito, S.C. Pearlman, R.S. Korzekwa, K.R. Modeling Cyanide Release From Nitriles Prediction of Cytochrome P450 Mediated Acute Nitrile Toxicity. Chem. Res, in Tex. 1992.5, pp. 548-552. 

Nickel Catalyst, dry Nickel Cyanide Nickel Nitrate Nickel Nitrite Nicotine Nicotine Compound, liquid, n.o.s. 2881 1653 2725 2726 1654 3144 1655 37 53 35 35 55 55 Nitriles, toxic, n.o.s. (solid) Nitrites, inorganic, aqueous solutions, n.o.s. Nitrites, inorganic, n.o.s. Nitroanilines Nitroanisole 3276 3219 2627 1661 2730 55 35 35 55 55... 

Nitriles, toxic, flammable, n.o.s. 3275 57 with more than 1 % but not more than 5% nitroglycerin ... 

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 propensity of nitriles to release cyanide subsequent to metaboHsm is the basis of their acute toxicity. Nitriles that form tertiary radicals at their alpha carbon atoms (eg, isobutyronitrile, 2-methylbutyronitrile) are substantially more acutely lethal than nitriles that form secondary radicals at their alpha carbons (eg, butyronitrile, propionitnle). Cyanohydrins are acutely toxic because they are unstable and release cyanide quickly. Alpha-aminonitriles are also acutely toxic, presumably by analogy with cyanohydrins. 

Cyanohydrins are highly toxic by inhalation or ingestion, and moderately toxic through skin absorption (21). AH a-hydroxy nitriles are potential sources of hydrogen cyanide or cyanides and must be handled with considerable caution. Contact with the skin and inhalation should be rigorously avoided. Special protective clothing should be worn and any exposure should be avoided (18,20). The area should be adequately ventilated. Immediate medical attention is essential in case of cyanohydrin poisoning. 

Hydrolysis of Nitriles. The chemical hydrolysis of nitriles to acids takes place only under strong acidic or basic conditions and may be accompanied by formation of unwanted and sometimes toxic by-products. Enzymatic hydrolysis of nitriles by nitrile hydratases, nittilases, and amidases is often advantageous since amides or acids can be produced under very mild conditions and in a stereo- or regioselective manner (114,115). 

Nitriles, or alkyl cyanides, are compounds in which carbon is bound to nitrogen by triple bonds. They tend to be stable, neutral substances with pleasant smells and are less toxic than hydrogen cyanide. The smallest compounds are water soluble liquids and all are soluble in organic solvents. 

Acetone cyanohydrin (Oxyisobutyric nitrile) (CH3)2C(0H)CN Highly toxic by inhalation or ingestion Irritating and moderately toxic upon skin contact Readily decomposes to HCN and acetone at 1 20°C, or at lower temperatures when exposed to alkaline conditions Colourless combustible liquid Elash point 73°C Ignition temperature 68.7°C Completely soluble in water... 

Cyanides are dangerously toxic materials that can cause instantaneous death. They occur in a number of industrial situations but are commonly associated with plating operations, and sludges and baths from such sources. Cyanide is extremely soluble and many cyanide compounds, when mixed with acid, release deadly hydrogen cyanide gas. Cyanide is sometimes formed during the combustion of various nitrile, cyanohydrin, and methacrylate compounds. Cyanides (CN ) are commonly treated by chlorine oxidation to the less toxic cyanate (CNO ) form, then acid hydrolyzed to COj and N. Obviously, care should be taken that the cyanide oxidation is complete prior to acid hydrolysis of the cyanate. 

The imidazole nucleus is often found in biologically active molecules,3 and a large variety of methods have been employed for their synthesis.4 We recently needed to develop a more viable process for the preparation of kilogram quantities of 2,4-disubstituted imidazoles. The condensation of amidines, which are readily accessible from nitriles,5 with a-halo ketones has become a widely used method for the synthesis of 2,4-disubstituted imidazoles. A literature survey indicated that chloroform was the most commonly used solvent for this reaction.6 In addition to the use of a toxic solvent, yields of the reaction varied from poor to moderate, and column chromatography was often required for product isolation. Use of other solvents such as alcohols,7 DMF,8 and acetonitrile9 have also been utilized in this reaction, but yields are also frequently been reported as poor. 

The product of the reaction in Entry 8 was used in the synthesis of the alkaloid pseudotropine. The proper stereochemical orientation of the hydroxy group is determined by the structure of the oxazoline ring formed in the cycloaddition. Entry 9 portrays the early stages of synthesis of the biologically important molecule biotin. The reaction in Entry 10 was used to establish the carbocyclic skeleton and stereochemistry of a group of toxic indolizidine alkaloids found in dart poisons from frogs. Entry 11 involves generation of a nitrile oxide. Three other stereoisomers are possible. The observed isomer corresponds to approach from the less hindered convex face of the molecule. 

Tanii H, Hashimoto K. 1984a. Structure-toxicity relationship of aliphatic nitriles. Toxicol Lett 22 267-272. 

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

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