Methyl fluoroacetate toxicity

Ethyl, n-propyl and isopropyl fluoroacetates were also readily prepared by heating the corresponding esters of chloroacetic acid with potassium fluoride in the rotating autoclave. Their toxicities were similar to that of methyl fluoroacetate. (It... 

These findings were in accordance with expectation, and it was now obvious that the toxicity was bound up with the FCHjCO group, whereas the FCO group was ineffective. Farther confirmation of this point was provided by the observation that ethyl fluoroformate, FCOOEt, was non-toxic. Fluoro-aoetic anhydride was slightly more toxic (by inhalation) than methyl fluoroacetate. 

It was obviously of interest to determine whether other esters of fluoroacetic acid would prove to be more or less toxic than the methyl ester. In the phosphorofluoridate series, for example, we found that esters of secondary alcohols were far more potent than those of primary alcohols for instance, di-isopropyl fluorophosphonate (I) was a compound of considerable activity. Accordingly ethyl, ra-propyl and isopropyl fluoroacetates were prepared by heating the corresponding esters of chloroacetic acid in the rotating autoclave with potassium fluoride. The toxicity figures of these esters were very similar to those of methyl fluoroacetate. 

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. 

It is interesting to compare the toxicity of fluoroacetyl chloride with the isomeric chloroacetyl fluoride. The former possessed a toxicity comparable to that of methyl fluoroacetate, whereas the latter was relatively non-toxic. This is readily understandable in that fluoroacetyl chloride gives the toxic fluoroacetic acid, whereas chloroacetyl fluoride hydrolyses to chloroacetic acid and the relatively non-toxic (at the concentrations employed) hydrogen fluoride. Fluoroacetyl fluoride also possessed a toxicity comparable with that of fluoroacetyl chloride or of methyl fluoroacetate, again showing that the COF group contributed practically nothing. Acetyl fluoride was also non-toxic. 

Chloro-2-fluoroethane, easily obtained3 from fluoroethanol, was found to be non-toxic. A concentration of 0-184 mg./l. failed to kill any animals, whereas a similar concentration of fluoroethanol or of methyl fluoroacetate would have killed some 50 per cent of a batch of rabbits, guinea-pigs or rats. The chlorine atom in chlorofluoroethane was found to be un-reactive towards a variety of reagents, and this fact no doubt... 

In view of the fact that fluoroethanol is as toxic as methyl fluoroacetate (or as fluoroacetic acid), it seemed worth while preparing a compound in which the active parts of these molecules were combined, in the hope of obtaining a compound of increased potency. Such a compound is 2-fluoroethyl fluoroacetate, first prepared and described by us in 1943.1 This ester was readily prepared by the action of fluoroacetyl chloride on fluoroethanol. It is a stable, mobile liquid possessing an extremely faint odour. 

Fluoroethyl fluoroacetate was found to possess rather enhanced toxic properties. The l.c. 50 by inhalation for rabbits was 0-05 mg./l. This shows that it is about twice as toxic (weight for weight) as fluoroethanol or methyl fluoroacetate. This seems to indicate that the toxicity of 2-fluoroethyl fluoroacetate cannot be due entirely to that of its hydrolysis products according to the equation... 

In view of the biological importance of nicotinic acid, it was decided to prepare a quaternary salt from the acid or ester and bromofluoroethane. S Carbethoxy- N-2-fluoroethylpyridinium bromide (XIX) was therefore prepared and examined. The l.d. 50 for subcutaneous injection into mice was 200 mg. /kg., i.e. it was relatively non-toxic compared with methyl fluoroacetate. 

It seems possible to draw certain deductions from the above toxicities. It is to be noted that ethyl fluoroacetamidoacetate (XII) would almost certainly be hydrolysable in the animal body to free fluoroacetic acid, and that (XIII) and (XIV) would similarly give 2-fluoroethanol (oxidizable in vivo to fluoroacetic acid). These three compounds do, in fact, show toxicities of the same order as that of methyl fluoroacetate (or of fluoroacetic acid) (XIV) is, however, rather less toxic than might be expected. 

From a study of the fluoroacetates so far mentioned, it appears that any compound which can give rise to fluoroacetic acid (or the fluoroacetate ion), either by hydrolysis or by oxidation (or both), is toxic. The toxic grouping is thus F-CH2-CO, and any substitution in this radical destroys the toxicity as far as relatively simple compounds are concerned. We had reached this conclusion by May 1943.1 We subsequently showed that esters of / -fluoropropionic acid were non-toxic, whereas esters of y-fluorobutyric acid were shown by American workers to be toxic. In 19442 we reported the synthesis of ethyl 5-fluoro-pentanecarboxylate, F,[CH2]g C02Et (I). This is a stable, colourless liquid and we showed that it possessed very potent toxic properties of the fluoroacetate type. By subcutaneous injection of the propylene glycol solution into mice the l.d. 50 was 4 mg./kg. Methyl fluoroacetate (II) may be taken as a convenient standard (p. 115) and has a l.d. 50 of about 6 mg./kg. for saline solutions, and 15 mg./kg. for propylene glycol solution.3 Therefore ethyl 5-fluoropentanecarboxylate was about 7 times as toxic as methyl fluoroacetate (molecule for molecule).4... 

On p. 129 it was shown that 2-fluoroethyl fluoroacetate was about twice as toxic as methyl fluoroacetate (M.F.A.) by inhalation. By analogy then it seemed that 2-fluoroethyl-5-fluoropentanecarboxylate (III) might be a compound of exceptionally high toxicity. This proved to be correct, for its l.d. 50... 

The compounds in a suitable solvent were subcutaneously injected into mice. Methyl fluoroacetate was always injected, under the same conditions, into a batch of mice as a control. The /9-carbon atom in /9-2-fluoroethoxypropionic acid and in /9-3-fluoropropoxypropionic acid is linked to the ether oxygen atom, and if/9-oxidation of these compounds takes place in vivo, the hydrogen carbonate of the fluoro alcohol is formed. One would expect this to have approximately the same toxicity as the alcohol itself, since the latter would be produced either by hydrolysis or by elimination of carbon dioxide ... 

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. 

Toxicity compared to that of methyl fluoroacetate Similar Rather higher... 

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). 

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