2- Fluoroethanol, toxicity

Toxic compounds that can be absorbed to a marked degree by a living plant through either its roots or its leaves have been called by British investigators systemic insecticides. Schrader (38) first found this peculiar property in certain acetals of 2-fluoroethanol and bis-(2-fluoroethoxy) methane, as well as in certain compounds of his organic phosphorus series, notably bis(dimethylamido)fluophosphate and octamethyl pyrophosphoramide. 

In this work on compounds containing the C—F link, it was obviously desirable to prepare 2-fluoroethanol, both for toxicity tests on the compound itself, and as a starting material for the production of other fluorine compounds. Swarts1 was unable to obtain 2-fluoroethanol by the action of silver fluoride or mercuric fluoride on either ethylene chlorohydrin or ethylene bromohydrin. He obtained acetaldehyde in each case. He ultimately obtained fluoroethanol in very poor yield by the indirect method of hydrolysing fluoroacetin (from bromoacetin and mercuric fluoride) for 80 hr. with dilute mineral acid. 

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... 

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. 

All the toxic compounds mentioned above are either hydro-lysable or oxidizable to fluoroacetic acid.1 In this connexion it should be noted that l-chloro-2-fluoroethane was relatively nontoxic. The chlorine atom in this compound was shown to be rather unreactive chemically, hence hydrolysis to the toxic fluoroethanol in the animal body would be unlikely. 

Fluoroethyl fluoroacetate is a compound of considerable toxicity. Its l.c. 50 for rabbits (inhalation) is 0-05 mg./l., i.e. about half as great as for M.F.A. It is therefore placed in class A. Other factors apart from hydrolysis to fluoroethanol and fluoroacetic acid appear to be operative, and it seems that the molecule is toxic per se. The related fluoroacetylimino-2-fluoro-ethyl ether hydrochloride, [CH2F C( NH2) O CH2 CH2F]+CT, is also placed in class A. This is understandable as it is readily hydrolysed by water to 2-fluoroethyl fluoroacetate. Other fluoroacetylimino ether hydrochlorides containing, however, only one fluorine atom fall into class B, as does also fluoroacet-amidine hydrochloride itself. 

A good example of the fact that a considerable number of fluorinated chemicals are not toxic per se, but elicit toxicity only after metabolic modifications, is the toxic behavior of tri-fluoroethanol and/or its derivatives, e.g. the anesthetic Fluoroxene (CF3CH2OCH = CH2)4 43 and analogs, 2.2,2-trifluoroethyl ethyl ether and others.44,45... 

Monofluoroacetic acid (fluoroacetate, figure 7,39) is a compound found naturally in certain South African plants, and which causes severe toxicity in animals eating such plants. The compound has also been used as a rodenticide. The toxicity of fluoroacetate was one of the first to be studied at a basic biochemical level, and Peters coined the term lethal synthesis to describe this biochemical lesion. Fluoroacetate does not cause direct tissue damage and is not intrinsically toxic but requires metabolism to fluoroacetyl CoA (figure 7,39). Other fluorinated compounds which are metabolized to fluoroacetyl CoA therefore produce the same toxic effects. For instance, compounds such as fluoroethanol and fluorofatty acids with even numbers of carbon atoms may undergo /1-oxidation to yield fluoroacetyl CoA. 

CAUTION Monofluoroacetates are intermediates for some literature syntheses of fluorinated heterocycles. Fluoroacetic acid and its derivatives, such as fluoroacetamide and ethyl fluoroacetate, and compounds which could be metabolically converted into fluoroacetate, such as 2-fluoroethanol, are extremely toxic and have no antidote. A lethal dose of the acid in humans may be as low as 100 mg. They should be avoided if at all possible, but if their use is essential, they must only be used under rigorous control. 

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. 

Monofluoroacetic acid is one of the most toxic compounds known. Its toxicity is related to blocking the citric acid cycle by hindering the enzyme acotinase. Compounds which can readily be hydrolyzed or oxidized to fluoroacetic acids (e.g., esters of fluoroacetic acid and fluoroethanol) are also highly toxic. 

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