A TOXICOLOGICAL STUDY OF SOME ALCOHOLS, WITH

ESPECIAL REFERENCE TO ISOMERS

DAVID I. MACHT

From the Pharmacological Laboratory, the Johns Hopkins University

Received for publication May 25, 1920

The comparative pharmacological, and, more particularly,

toxicological, properties of various alcohols have been the sub-.
ject of investigations on the part of many authors. The work
on the subject has, for the most part, been confined to the first
five members of the aliphatic series, and almost entirely to the
primary alcohols in the cases in which several isomers are known.
The most significant and important observation on the compara-
tive pharmacology of these alcohols was made as early as 1869.
Richardson, in 1869, stated, in the Medical Times and Gazette,
volume 2, page 705, that the toxicity of the alcohols belonging
to the fatty acid series increased ‘in proportion to their molecular
weight. This observation, known as Richardson’s law, has been
confirmed and amplified by all the later observers. Among the
most important investigators along these lines may be mentioned
Dujardin-Baumetz (1), Joifroy and Servaux (2), Picaud (3),
and Baer (4), who studied the comparative ‘lethal doses; while
Efron (5), Schneegans and v. Mering (6), Breyer (7), Dold (8),
Kuno (9) and others investigated the effects of the various
alcohols on special organs.
Dujardin-Baumetz and Audige found the toxicity of ethyl,
propyl, butyl and amyl alcohols to be in the ratio of 1.0, 2.0,
4.2 and 5.2, respectively. According to these authors, the
toxicity of methyl alcohol was found to be about the same or
slightly higher than that of ethyl. Most authors, however,
find that in acute experiments methyl alcohol is less poisonous
than ethyl alcohol. Thus, Joifroy found the relation between
1

THE JOUR. OP PHARM. AND EXPER. THERAP., VOL. XVI, NO. 1

2 DAVID I. MACHT

the lethal doses of alcohol-methyl, ethyl, propyl, butyl and

amyl-to be expressed by the ratios 0.46, 1.0, 3.5, 8.0 and 18.5.
Picaud gives the following figures for the same relationship:
0.66, 1.0, 1.0, 3.0 and 16.0. According to Baer, the ratios are
s follows: 0.8, 1.0, 2.0, 3.0 and 4.0. It will be noted that accord-
ing to the last three authors, the toxicity of the various alcohols
increases in proportion to their molecular weight. The actual
figures obtained by various observers are different, according to
the methods of administration. Some injected the drugs in-
travenously, which is, on the whole, the most satisfactory method

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FIG. 1.’ FROG’S HEART SUSPENSION PREPARATION

A, Perfusion with propyl alcohol 1 per cent in Locke; B, perfusion with isopro-
pyl alcohol 1 per cent in Locke.

of studying the lethal doses for acute toxic experiments. This

is the method, as is well known, now employed for standardizing
the digitalis bodies. Dujardin-Baumetz found the same relation-.
ship to hold good after administering the alcohols by stomach.
Efron (1885) studied the pharmacological action of the various
alcohols on nerve and muscle. This author found that Richard-
son’s law applies also to the behavior of these organs. All
the alcohols produce a more or less marked primary excitation,
followed by paralysis, and the relative toxicity increases with
the molecular weight. Schneegans and v. Mering found the
 TOXICOLOGICAL STUDY OF SOME ALCOHOLS 3

narcotic action of the various alcohols to follow’ more or less

Richardson’s law. Picaud studied the effects of various alcohols
on fishes, amphibians and other animals. Dold studied the
comparative effects of the various alcohols on the frog’s heart,
while Hermeter investigated the effects of the same on the
mammalian heart. All these authors found a relationship be-
tween the toxicities to be very much in accordance with Richard-
son’s earlier observations. Further work by Kuno on mam-

FIG. 2. FROG’S HEART SUSPENSION PREPARATION

N, Normal contractions; systole, down; lB., isobutyl alcohol 0.5 per cent;
B, butyl alcohol 0.5 per cent.

malian hearts, by Breyer 011 motor nerves and ciliated epithelium,

by F#{252}hner (10) on the eggs of the sea-urchin, by Blumenthal
(11), and by Verzar (12), all corroborated, broadly speaking, the
original law enunciated by Richardson. The chief exception
noted was that by Blumenthal, who claimed that methyl alcohol
is more poisonous than ethyl. Many other interesting pharma-
cological facts concerning the various alcohols may be found
in Professor Abel’s monograph on the subject (13).
4 DAVID I. MACHT

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 TOXICOLOGICAL STUDY OF SOME ALCOHOLS 5

While the comparative physiological effects of the primary,

or normal, alcohols have been studied extensively, very little,
indeed, is known concerning the pharmacological action of the
secondary alcohols. The present author became interested in
this subject in connection with a study of isopropyl alcohol,
which he has undertaken at the suggestion of Prof. Ira Remsen.
In order to obtain a comprehensive idea of the toxicological effects
of isopropyl alcohol, the author made experiments with primary
alcohols, on the one hand, and secondary alcohols, on the other.
The compounds studied were the following: Methyl alcohol,
ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol,
isobutyl alcohol, amyl alcohol, isoamyl alcohol, and, to some
extent also, benzyl alcohol.
The first investigation undertaken by the author was to
determine the lethal doses of the various alcohols. For this
purpose the cat method was employed. This method, which is
extensively followed for the testing of various drugs, is now
recognized as the most convenient method of assaying digitalis
and other heart drugs. It consists, briefly, in injecting into the
vein of a cat, under light ether anesthesia, at regular intervals
of time, a solution of the drug to be tested. The amount of the
drug necessary to kill the cat, expressed in terms of its weight,
is the lethal dose. In performing the experiment, care is taken
to note the form of death produced-whether through paralysis
of the heart, paralysis of the respiratory center, etc.
It was found, on testing methyl, ethyl, propyl, butyl, and
amyl alcohols, that their toxicity increased, broadly speaking,
with their molecular weight. In other words, Richardson’s law
was found to hold good. In the experiments performed, 1 and
5 per cent solution of the various alcohols were made in physi-
ological saline, and injected rather rapidly, but at regular intervals
of time (2 cc. per minute). The figures obtained are shown in
the subjoined table. It will be noted that while the absolute
fatal doses may be different from those obtained by other authors
(due to the rapidity of administration and concentration of the
solution), Richardson’s law was confirmed completely.
6 DAVID 1. MACHT

Following the injections of the primary alcohols just men-

tioned, the lethal dosage of the secondary alcohols was determined
by the same method, and the figures compared with those
obtained in case of the normal propyl, butyl and amyl alcohols.
It was found, in case of the three groups of isomers, that the
primary or normal alcohols were always more toxic than the
secondary, or the isopropyl, isobutyl and isoamyl alcohols.
After studying the lethal dosage of the various compounds
mentioned above, a comparative study of their solutions on the
isolated frog’s heart was undertaken. It was interesting to find
that on this isolated organ Richardson’s law held good, and,

TABLE I

LETHAL DOSE LETHAL DOSE RATIO IN TERMS

CONCENTRATION
ALCOHOL
INJECTED
KflO WEIGHT ETHYL ALCOHOL

per cent cc. cc.

Methyl 5 118.0 5.9 0.8

Ethyl 5 100.0 5.0 1.0
Propyl 5 40.0 2.0 2.5
Butyl 5 6.0 0.3 16.6
Amy! 1 14.8 0.15 33.2
Isopropyl 5 5.0 2.5 2.0
Isobutyl 5 18.0 0.9 5.5
Isoamyl 1 26.0 0.26 19.2
Benzy! 1 60.0 0.60 8.3

furthermore, that in every case the normal alcohols were more

toxic than the secondary ones, as illustrated by the curves.
In order to test the curious relationship between the normal
and secondary alcohols further, observations were made on their
action on isolated plain muscle. It was found that in case of the
ureter, which, in many respects, as has been shown by the author
elsewhere, is
the most convenient smooth muscle organ for
quantitative comparisons, the same relationship held good (14).
In every case the primary alcohol paralyzed the smooth muscle
more quickly than the secondary ones.
Inasmuch as the author was especially interested in the prop-
erties of isopropyl alcohol, some special studies were made
 TOXICOLOGICAL STUDY OF SOME ALCOHOLS 7

with that compound. The toxicity of isopropyl alcohol through

inhalation was compared with that of methyl and ethyl alcohols.
This was studied on rats. The animals were confined in a
chamber containing an open vessel, suitably screened off, filled
with the above alcohols, so that the air of the chamber was
saturated with their fumes. It was found that methyl alcohol
quickly killed the rats, the latter succumbing in a day or two.

LtLUJkLLLL A

FIG. 4. PIG’s URETER

NP., Normal propyl alcohol 1:500; IF., isopropyl alcohol 1:C0

Ethyl alcohol proved also fatal to the animals, after exposure

to its fumes for several days in a warm room. Rats confined
in a chamber containing an open vessel with isopropyl alcohol,
in a wTarin room, were very little affected, and were found to be
apparently in normal health after a week’s exposure. No blind-
ness or defects in vision were noted after exposure of the rats to
the fumes of isopropyl alcohol in these experiments.
The peculiar relationship between the primary and secondary
alcohols noted by the author has not been described elsewhere.
8 DAVID I. MACHT

It is interesting to note, however, that the properties of one of

the isomers, namely, isopropyl alcohol, have been investigated
by Efron. That author found that isopropyl alcohol is less
depressant that the normal propyl alcohol for nerve fibers, and
his observations harmonize with the findings of the present
investigation.
It will be seen that a comparative study of the various alcohols
reveals the fact, on the one hand, that their toxicity increases

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Fio. 5. Pic’s URETER

N.B., Norma! butyl alcohol 1 per cent, paralyzed after three closes 1 cc. each
in 30 cc. Locke. No response to epinephrin after that. lB., Isobutyl alcohol
1 per cent, contraction inhibited after 4 cc. but still revived by epinephrin.

with their molecular weight, and, on the other hand, that the
normal propyl, butyl and arnyl alcohols are more toxic than
the isopropyl, isobutyl and isoamyl alcohols, as revealed by
studies of the killing dose for cats, by experiments on isolated
frog hearts, and by observations on the contractions of isolated
plain muscle.
 TOXICOLOGICAL STUDY OF SOME ALCOHOLS 9

Furthermore, it should be noted that the lethal (loses obtained

in this investigation are those for acute intoxications. This is
important to bear in mind in connection, especially, with wood
alcohol. Methyl alcohol is known to be extremely poisonous,
and is regarded as a more violent poison than grain alcohol.
This is true only in respect to its remote effects, as commonly
seen when it is ‘taken by mouth. When introduced into the
alimentary canal, wood alcohol acts not as such, but exerts its
most deleterious effects through its decomposition products,

jjjjJiftULjJjLUMJJJuJJJk
iA L

FIG. 6. PIG’S URETER

A., Amy! alcohol 1 per cent; l.A., isoaniyl alcohol 1 per cent

especially formaldehyde and formic acid. It is these secondary

products that render wood alcohol more poisonous than ethyl
alcohol, when taken by mouth. When injected into the vein,
however, and acting acutely upon the heart and the brain,
methyl alcohol is considerably less toxic than ethyl alcohol.
It is interesting to compare this difference between the im-
mediate and remote or indirect effects of methyl alcohol with the
immediate and secondary, or remote, effects of benzyl alcohol.
Benzyl alcohol, which the present author has shown to be a
 10 DAVID I. MACHP

valuable local anesthetic, is a comparatively little toxic drug

(15). The lethal dose of benzyl alcohol, as obtained by intraven-
ous injections of its solutions, is, however, very much greater
than the toxic dose of it, when administered even in pure form
and undiluted by mouth. Indeed, the author has not been
able to kill dogs by administering even large quantities of benzyl
alcohol through the stomach tube. The difference between the
intravenous and oral administrations of the drug is due to the
metabolism of benzyl alcohol and its excretion in the form of
hippuric acid, when taken by mouth.

SUMMARY

1. The toxicity of the normal alcohols-methyl, ethyl, butyl

and amyl-increases with their place in the aliphatic series,
as indicated by the lethal dosage for cats, and by their effects
on isolated frogs’ hearts and plain muscle preparations.
2. The secondary propyl, butyl and amyl alcohols were found
to be less toxic than the corresponding primary alcohols.
3. In discussing the toxicity of alcohols, a distinction should
l)e made between the acute or immediate, and the secondary
‘or remote effects of the drugs, as is well illustrated by the studies
on methyl and benzyl alcohols.

REFERENCES

(1) DtJJARDIN-BAUMETZ: Comp. R. Acad., 1875 and 1876. Also, Recherches

experiinentales sur la puissance toxique des alcohols, Paris, 1879.
(2) JOFFROY ET SERVAUX: Arch. d. Med. et d’Anat. Path., 1895, vii, 569.
(3) PicAun: Comp. R., 1897, cxxiv, 830.
(4) BAER: Diss. 1erlin, 1898.
(5) EFRON: Pfluger’s Archiv, 1885, xxxvi, 467.
(6) SCHNEEGANS AND V. Therap.
MERLNG Monatsheft.e, 1892, 327.
(7) BREYER: Pfluger’s Archiv, xcix, 481.
(8) D0LD: Pfluger’s Archiv, 1906, cxii, 600.
(9) KuNo: Arch. Exp. Path. u. Pharmakol., 1913, lxxiv, 399; 1914, lxxvii, 206.
(10) FiJUNER: Arch. Exp. Path. u. Pharmakol., 1904, Ii, 1.
(11) BLUMENTHAL: PfiUger’s Archiv, 1896, lxxii, 513.
(12) VERZAR: Pfluger’s Archiv, 1909, cxxv, 398.
(13) ABEL: Physiological Aspects of the Liquor Problem, ii, 1903, 1.
(14) rv1.cHT: Pharmacology of the Ureter. Numerous papers in Jour. Pharma-
col. & Exp. Therap.
(15) Micuv: Jour. Pharmacol. & Exp. Therap., 1918, xi, 263.