Fluoroacetate symptoms

Fluoroethanol, in contrast to ethanol, is only weakly oxidized by purified alcohol dehydrogenases, the rate being one-tenth to one-twentieth. Nevertheless, this rate appears sufficient to produce a typical fluoroacetate poisoning. A fairly long lag period in the development of the fluoroacetate symptoms possibly masks the time required for oxidation of fluoroethanol. 

Methyl fluoroacetate, a mobile liquid, has an extremely faint odour. Animals did not usually exhibit any symptoms while being exposed to lethal concentrations of this vapour, and no obvious effects were noted until some 30-60 min. (depending upon the concentration) after exposure. Violent convulsions then took place and death usually followed within a few hours. For rabbits and guinea-pigs the lethal concentration (l.c. 50) for a 10 min. exposure was of the order of 0-1 mg./l. Mice were rather more resistant. Intravenous injection produced symptoms similar to those displayed after exposure to the vapour. Even with large doses a delayed action was observed. The l.d. 50 for rabbits (intravenously) was found to be about 0-25 mg./kg. 

Methyl fluoroacetate (M.F.A.) is a liquid of b.p. 104° and f.p. ca. — 32° and is almost odourless. During a 10 min. exposure to a lethal concentration of the vapour, small animals did not appear to be affected in any way. After exposure, no very obvious symptoms developed until some 30-60 min. later (depending upon the concentration). The symptoms then shown depended to some extent upon the species, but all animals suffered convulsions, from which a partial recovery was sometimes made. Finally, however, a recurrence of the convulsions would cause death. 

In the phosphorofluoridate series, we found that the diphenyl ester (p. 53) was relatively non-toxic. Phenyl fluoroacetate, however, was toxic with an l.d. 50 of 6-10 mg./kg. for subcutaneous injection into mice. The symptoms were similar to those displayed by methyl fluoroacetate. 

Injection of (V) into mice showed that the l.d. 50 was similar to that of fluoroacetamide or of fluoroacetic acid, and the symptoms produced appeared to be similar in each case (V), however, showed no vesicant action. It is probable then that hydrolysis of the molecule occurs in vivo, resulting in the formation of fluoroacetic acid and the relatively harmless 2-chloroethylamine. 

In order to prove the identity of (XI), it was synthesized in a different manner. Ethylene dibromide was converted into ethylene dithiol, which was then heated with bromofluoroethane in the presence of sodium hydroxide. The yield by this method was small. The compound (XI), otherwise called sesqui-fluoro-H , is a liquid. It is neither a vesicant nor does it produce fluoroacetate-like symptoms in the animal body. 

The hydrochloride (XIII) had a l.d. 50 of ca. 10 mg./kg. by subcutaneous injection into mice. The corresponding figure for 2-fluoroethyl betaine hydrochloride was 45 mg./kg. Both (XIII) and (XIV) produced fluoroacetate-like symptoms. 

Broadly speaking herbivorous animals (guinea-pig excepted) show cardiac symptoms and carnivores develop central nervous system convulsions or depression with omnivores both heart and central nervous system may be affected. Cold-blooded vertebrates are usually less sensitive to fluoroacetate, but frogs are more sensitive in summer than in winter.2 Fish appear to be insensitive to fluoroacetate dissolved in water.3 Insects are easily killed by fluoroacetate, and the use of sodium fluoroacetate as a systemic insecticide is described on p. 182. 

The very high toxicity of ethyl 5-fluoropentanecarboxylate and its derivatives and the fluoroacetate-like symptoms produced seemed to us to be of particular interest, since by a process of /9-oxidation in the animal body 5-fluoropentanecarboxylic acid would readily give rise to the toxic fluoroacetic acid. Similar remarks apply to y-fluorobutyric acid and its derivatives prepared independently by American workers. The non-toxicity of /9-fluoropropionic acid and its derivatives may, on the other hand, be due to the inability of this acid to give the toxic fluoroacetic acid by a process of /9-oxidation. 

We see from the above that there is a striking alternation in the physiological properties of w-fluorocarboxylic esters of the general formula of F- [CH2]w-C02.R. Thus when n is an odd number the compound is highly toxic to animals, whereas when n is even the compound is non-toxic. All the toxic compounds are powerful convulsant poisons and showed symptoms of the fluoroacetate type. 

The term non-toxic is used relatively to the highly toxic methyl fluoroacetate. At high concentrations (e.g. several hundred mg./kg.) it is probable that some symptoms would be observed even with the non-toxic materials. 

Sherley, M. (2004). The traditional categories of fluoroacetate, poisoning signs and symptoms belie substantial underlying similarities. Toxicol. Lett. 151 399-406. 

In view of these facts and of the known toxic action of fluoro-acetates it seemed worth while investigating compounds containing both fluorine and the above-mentioned groups. We prepared the flrst of a series of nitrogen compounds in 1943, namely, ethyl jluoroacetamidoacetate, CHjF CO NH CHg COjEt (XH). It was a colourless crystalline solid which, when injected into mice, had a l.d. 50 of 20 mg./kg. The corresponding figure for methyl fluoroacetate is 6 mg. /kg. The symptoms were similar in each case (delayed convulsant action). 

In class B are placed all simple esters, CHjF CO i , of fluoro-aoetic acid, where iZ = Me, Et, Pr , Pr , Ph, etc. When substitution takes place in the a-hydrogen atoms, e.g. in methyl a-fluoropropionate or a-fluoroisobutyrate, then the compound is devoid of toxicity. This indicates the importance of the unsubstituted fluoromethyl group. On pp. 125 et seq. it was shown that fluoroacetamide and a variety of substituted amides such as CHjF CO NH CHg CHjCl were, molecule for molecule, equally toxic with fluoroacetic acid and produced the same symptoms. The 2 chloroethyl group therefore contributed nothing appreciable to the toxicity of the molecule. The majority of the esters of fluoroethanol showed the toxicity of the parent alcohol, e.g. 2-fluoroethyl chlorosulphonate, CHgF CHg O SOjCl, di-(2-fluoroethyl) sulphate and 2-fluoroethylglycine hydrochloride. 

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