ON THE RELATION BETWEEN THE TOXICITY AND CHEM-

ICAL CONSTITUTION OF A NUMBER OF DERIVATIVES

OF CHOLINE AND ANALOGOUS COMPOUNDS

REID HUNT AND R. DE M. TAVEAU.

From the 1)ivision of Pharmacology, Hygienic Lahoratory, Public Health and Marine
Hospital Service, Washington, D. C.

Received for publication, June 28, 1909.

INTRODUCTION

One of the present writers found in 1899 that the fall of blood-
pressure caused by the injection of suprarenal extract from which
the epinephrine had been removed was due in part to choline; the
latter was isolated in large amounts and analyzed by means of the
platinum salt.1 Hunt also found choline in extracts of the brain and
sympathetic ganglia. He also obtained evidence2 that extracts of
the suprarenals and brain contained a substance which readily yielded
choline upon chemical manipulation, but which was more toxic than
choline itself and the physiological action of which differed from
that of the latter in that it caused a fall of blood pressure after atropine.
It has been found by many observers, that the extracts of various
organs cause a fall of blood pressure upon injection into the circula-
tion; in a number of cases choline has been isolated from such extracts.
A number of observers have also found that the effect of most of
these extracts is not abolished completely by atropine (a very char-
acteristic property of choline) and have assumed that the fall of
blood pressure was due in part to the presence of potassium and
other salts, histones, etc. From the facts given above and also since
we have prepared a number of choline derivatives which cause a fall
‘Hunt: Amer. Jour. Physiol., 1899, iii, p. xviii. The fact was overlooked at
that time that Marino-Zuco had isolated choline (using the name neurine, however)
from the suprarenals.
2 Hunt: 1. c.; also Amer. Jour. Physiol., v, p. vi, 1901. Cf. Hunt and Taveau,
Bnt. Med. Jour., ii, p. 1788, 1906.
304 REID HUNT AND 11. DE M. TAVEAU

of pressure after atropine we think it probable that in many cases

the fall of blood pressure is in reality due to compounds of choline
or closely related bodies. Further, as one of the present writers sug-
gested,3 if choline is an etiological factor in certain of the symptoms
of some diseases of the nervous system, as has been suggested, it is
probable that some compound or compounds of choline rather than
choline itself is responsible, for several derivatives of the latter far
more toxic than choline itself have been prepared by the present
writers.
Choline derivatives may prove of interest in other connections.
Thus several writers have called attention to certain similarities in
the action of “secretin” and choline. v. F#{252}rthand Schwarz4 have
studied this question carefully and reached the conclusion that while
choline is contained in secretion the two are not identical since the
action of the former is completely prevented by atropine whereas
that of secretin is only weakened by this drug. In the light of experi-
ments to be described in this and succeeding papers on this subject
we think it not improbable that the activity of secretin is due to
choline derivatives or closely related compounds. The same is per-
haps true of certain other internal secretions.
Some of the compounds with which we have worked are so extra-
ordinarily active physiologically (0.00000001 gram acetyl choline per
kilogram animal, for example, causes a fall of blood pressure) and
yet are not very toxic that it seems not improbable that some may
prove of value in therapeutics. Before taking up the subject, however,
it seemed desirable to determine the general laws governing the tox-
icity of such compounds, for when these are determined it may be
possible to make compounds which, while preserving the desired
physiological action, have a low degree of toxicity.

EXPERIMENTAL

Nearly all of the compounds the toxicity of which is discussed in

this communication are new; the methods by which they were pre-
pared will be described later. The purity of the compounds was, in

‘Hunt: Reference Handbook of the Medical Sciences, iii, p. 37, 1901.

v. F#{252}rthand Schwarz: Pfl#{252}ger’s Archiv, cxxiv, p. 427, 1908.
 TOXICITY AND CHEMICAL CONSTITUTION OF CHOLINE 305

every case, carefully determined by the analysis of the carefully

purified platinum or gold double salts.
The substances were dissolved in water or a 0.8 per cent sodium
chloride solution and injected subcutaneously into white mice. The
latter were weighed to within a centigram and the doses expressed
in terms of milligrams per gram body weight. Only young adult
mice which had been kept under uniform conditions and which had
received the same diet were employed.5
Many experiments were made with each compound but only the
largest non-fatal and the smallest fatal doses are cited. This treat-
ment is necessary for the sake of clearness and brevity for, as each
of the compounds belongs to two or more groups, there is necessarily
much repetition.

I. Influence of the (CH2 + 1)3 Groups upon the Toxicity of Come-

pounds of the Choline Type and Some of their Derivatives

All of the compounds of this series belong to the “choline type”

inasmuch as they are quartenary ammonium compounds and con-
tain a group (CH2 + ), in combination with nitrogen, and a side
chain consisting either of an oxyethyl, oxypropyl, dioxypropyl or
monochloroxypropyl group.

‘The necessity of paying close attention to such details in determining the toxic
dose of drugs was much impressed upon us in connection with the work which one
of us has been doing with acetonitrile (See Hunt and Seidell, Bulletin 47, Hgyienic
Laboratory, p. 27); we have not found, however, that the toxic dose of any of the
compounds described in this paper is so dependent upon the condition of the animal
as is the case with acetonitrile.
306 REID HUNT AND R. DE M. TAVEAU

a. Compounds contairnug the group-CH2CH,OH

a
N
, r,.
0 -
o o Coil
DOSE IN MOM. N
PER GM. MOt1SE
a-I
COMPOUNDS N
N N N 5 0
ao
_________ N -I 0c)
05 0 I
N,. N
.15 ..I-I5.
N
u-
Survived Died II .c
5, z

,(CH3)3
Cl-N 0.72 0.75 0.735 1.000 139.57 1.000

CH,CH,OH
,(C2H5).
Cl-N 0.06 0.07 0.065 0.088 181.61 0.068

\CH,CH2OH

Cl-N 0.142 0.17 0.156 0.210 223.66 0.131

\CH2CH,OH

Cl-N 0.11 0.15 0.130 0.177 307.75 0.080

\dH,,oH
,(CH3)2
Cl-N--(5H,,)iso 0.60 0.63 0.615 0.837 195.63 0.597

\CH2CH2OH

(1) The mean of the largest non-fatal and the smallest fatal dose is taken as the average fatal
dose.

Summary: The least toxic of this series is choline itself which con-
tains three methyl groups; the most toxic is the tri-ethyl compound.
The compound containing two methyl and one iso-amyl group is
abou+. times less toxic than the tri-amyl and nearly twice as
toxic as choline.
 TOXICITY AND CHEMICAL CONSTITUTION OF CHOLINE 307

b. Compounds containing the group-CH,CH,O(CH3CO)

‘4

5-
COMPOUNDS

‘RI.,

,(CH3)3
Cl-N 0.30 0.32 0.31 1.000 181.58 1.000

\CH,CH20(dH,co)

Cl-N Not Prep ared

\dH2cH2o(CH,co)
,(C3H7)3
Cl-N . . . Not Prep ared

\CH,CH2O(CH,CO)

Cl-N 0.130 0.145 0.138 0.445 349.76 0.231

\cH,CH,o(cH,co)

Cl-N-C,H,1 iso 0.37 0.40 0.385 1.242 237.64 0.949

\CH,cH,o(dH,Co)

Summary: Of the compounds of this series prepared, that containing

three methyl groups was the least toxic and that containing the three
amyl the most toxic. The compound containing two methyl and one
iso-amyl was only slightly more toxic than choline and only about
one-fourth as toxic as the tri-amyl compound.
308 REID HUNT AND R. DE M. TAVEAU

c. Compounds containing the - CH,CH,O(C6H,CO) group

DOSE IN MOM.
PER GM. MOUSE N
COMPOUNDS
O
55.
0

Survived Died

,(CH3)3 I
,

Cl-N ... 1.80 2.00 1.90 1.000 243.60 1.000

\CH,CH,O(C6H3C0
,(C2H6)3
Cl-N ... 0.27 0.28 0.275 0.145 285.64 0.124
\CH2cH,o(c5H3Co)
,(C3H7)
Cl-N ... 0.18 0.19 0.185 0.0974 327.69 0.0724

\CH,cH,o(C,H,co)
(C5H11)3
Cl-N ... 0.032 0.036 0.034 0.018 411.78 0.011
\CH,cH,o(C4H,co)
,(CH3)2
Cl-N--C5H,,iso ... 1.10 1.20 1.15 0.605 299.66 0.492

\CH,CH,O(C6H,CO)

Summary: The compound containing three methyl groups was the

least toxic. The toxicity increased up to the tri-amyl compound
which was 90 times as great as that of the tri-methyl compound. The
compound containing two methyl and one amyl group was twice as
toxic as benzoyl-choline, but less than one-fortieth as toxic as the tn-
amyl compound.
 TOXICITY AND CHEMICAL CONSTITUTION OF CHOLINE 309

d. Compounds containing a - CH2CFJOHCH, group

14 0Z

z
DOSE IN MGM. - .1 - . .1 14
PERGM.MOUSE 14

COMPOUNDS

_____________ I4
0
5.
CaN
.1
P C
45 . 5
51 S...
Survived Died 5
4 4 5 4

Cl-N 0.60 0.63 0.615 1.000 153.58 1.000

\CH,CHOHCH,

Cl-N 0.18 0.18 0.18 0.293 195.63 0.230

\CH2CHOHCH,
,(C3H7)3
Cl-N 0.09 0.11 0.10 0.163 237.67 0.105

\CH,CHOHCH,

Cl-N 0.07 0.09 0.08 0.130 321.76 0.062

\CH,CHOHCH,

Summary: The toxicity increased from the tn-methyl compound (the

least toxic) to the tni-amyl (the most toxic).
 r - -; ‘...-..

310 REID HUNT AND R. DE M. TAVEAU

e. Compounds containing a - CH,CHOHCH2C1 group

0
1.1
a
DOSEINMGM.
PEROM. MOUSE 0

COMPOUNDS . ±
__________ 51 O
CC
.I

Survived Died II N
________________ ___- 4 5,

(CH3)3

Cl-N ... 0.52 0.50 0.510 1.000 188.02 1.000

\CH,CHOHCH,CI

Cl-N ... 0.36 0.37 0.365 0.716 230.06 0.585

\CH,.CHOH.CH,C1
,(C3117)3

Cl-N ... 0.06 0.065 0.063 0.123 272.12 0.085

\CH2.CHOH.CH2C1

Cl-N ... 0.20 0.21 0.205 0.402 356.21 0.212

\CH,.CHOH.CH,C1

Summary: The tri-methyl was the least and the tri-propyl the most
toxic compound.
 TOXICITY AND CHEMICAL CONSTITUTION OF CHOLINE 311

f. Compounds containing a CH,CHO(CH,CO)CH, group

51
S .I

DOSE IN MOM. N C
.1 N
-‘ C N
PER GM. MOUSE. 14 . 14

COMPOUNDS 51 5
5,
____________ .1 0
CC 0

Survived Died H

Cl-N ... 0.163 0.175 0.169 1.000 195.60 1.000

\CH,CHO(CH,COCH.

Cl-N 0.086 0.101 0.094 0.556 237.64 0.458

\dH,.cHo(cH3codH,

Cl-N 0.15 0.16 0.155 0.918 279.69 0.642

\CH,.CHO(CH,CO)CH,

Cl-N 0.135 0.150 0.143 0.846 363.78 0.455

\CH,.CHO(CH,COCHJ

Summary: The tri-methyl compound was the least toxic; the others
were about twice as toxic.
-r ‘r’ - .- - -- -. - -

312 REID HUNT AND R. DE M. TAVEAU

g. Compounds containing a -CH2CHO(C5H5CO)CH, group

0 ,
51
.I . 14
.1 .1
N C
o
DOSE IN MGM. N C

PER GM. MOUSE 4 0 4 N

F51 L5 C4
COMPOUNDS 1
45, a
5 4
51S o I
CC 0
45 . Q -I.I.

Survived Died 0 .1
‘‘
4 C
4 5, N 5,

,(CH3)3

Cl-N 1.026 1.080 1.053 1.000 257.61 1.000

\CH,CHO(C8H6CO)CH,
,(C2H5)3
Cl-N 0.30 0.32 0.31 0.294 299.66 0.253
\CH2CHO(COHICO)CHI,
,(C3H7)3
Cl-N 0.050 0.052 0.051 0.048 341.70 0.036

“CH2CHO(CeHsCO)CHs
(C,H,,),

Cl-N 0.034 0.038 0.036 0.034 425.79 0.020

CH,CHO(C6H5CO)CH,

Summary: The toxicity increases from the tri-methyl (the least

toxic) to the tri-amyl (the most toxic).
 - - .-

TOXICITY AND CHEMICAL CONSTITUTION OF CHOLINE 313

h. Compounds containing a - CH,CHO(CH3CO)CH,C1 group

a -
51
a
51 ,5
0. .1
. 05 5 0
DOSEINMGM. 1C
PER GM. MOUSE 0 51 5.
51 I.)5 0
COMPOUNDS 4s
515
5,
14 0E’ .1
CC a51N_
.1.Ifr
5 fri
I I
Survived Died H
4 5, 5 5,

,(CH3)3
Cl-N 0.356 0.365 0.360 1.000 230.04 1.000
\cH2CH0(dH,co)CH2C1
,(C2H5)3
Cl-N 0.191 0.209 0.200 0.555 272.08 0.469
\CH,cHo(CH,Co)dH,cl
(C3H7)3

Cl-N 0.16 0.17 0.165 0.431 314.13 0.316

\CH2CHO(CH,CO)CH,C1

Cl-N 0.14 0.15 0.145 0.403 398.22 0.233

\CH,CHO(CH,CO)CH2C1

Summary: The toxicity increased from the tri-methyl to the tri-

amyl compound.
 - 5.. WT’T .. - - .- -.-,.- ..-

314 REID HUNT AND R. DE M. TAVEAU

i. Compounds containing a -CH2CHO(C6H5CO)CH,Ct group

a
51 51
M, 5’ .1
05’ .1
0. 45, 5
5 C 551N
DOSE IN MOM. 0 5
PERGM.UOUSE 4 0
5,g u5 0
COMPOUNDS 4, 511
a
0 ouS’
051 0
5 .i5, .IE.
#{149}
Survived Died 5, H
4
4 5. 5 5,

,(C113)3
Cl-N .... 0.356 0.368 0.362 1.000 292.05 1.000

\CH3CHO(C.H5COCH,Cl
,(C2115)3

Cl-N .... 0.113 0.122 0.118 0.326 334.10 0.285

\CH,CHO(C6H5COCH,C1
,(C3H7)3

Cl-N .... 0.055 0.060 0.058 0.160 376.15 0.124

\CH,CHO(C6H5COCH,C1
,(C5H11)3

Cl-N .... 0.037 0.039 0.038 0.105 460.24 0.067

\CH,cHo(c5H,Co)CH,C1

Summary: The toxicity increased from the tri-methyl to the tn-

amyl compound.
 -. .‘ $.

TOXICITY AND CHEMICAL CONSTITUTION OF CHOLINE 315

j. Compounds containing a - CH,.CHOH.CH,OH group

a
51 51 51

R
DOSEINMGM. .10 50’ 5 NM5’
PEROM.MOUSE . o
5’i .)5 o,5
COMPOUNDS ,
____________ 05’
0 0515
N P15’”’
Survived Died I

,(CH3)
Cl-N 1.60 1.80 1.70 1.000 169.58 1.000
\CH,.CHOH.CH2OH

Cl-N 0.57 0.62 0.60 0.353 211.63 0.283

\0H2.CHOH.CH2OH
,(C3H7)3
Cl-N 0.23 0.25 0.24 0.141 253.67 0.094
\CH2.CHOH.CH,OH

Cl-N 0.37 0.40 0.39 0.229 337.76 0.115

\CH,.CHOH.CH,OH

Summary: The tri-methyl compound was the least and the tn-
propyl the most toxic.
 ‘y’ T

316 REID HUNT AND R. DE M. TAVEAU

k. Compounds containing a - CH,CHO(CH,CO)CH2O(CH8CO) group

a
1.1 111
.1 5’ .1 .1
0 i. 0a5’
N55
DOSEINMOM. 0
PEROM.MOUSE 0 5,N
0
COMPOUNDS s. MN-
a a5
M 05’ 0u5’
a5 p 0
CC
N .1.15’

Survived Died H H
4 s, N F.,

,(CH3)3
Cl-N 0.90 1.00 0.95 1.000 253.61 1.000

CH2CHO(CH3COCH2O
(CH3CO)

Cl-N 0.40 0.46 0.43 0.453 295.66 0.389

CH,CHOCH3COCH,O-
(CH3CO)
,(C3H7)3
Cl-N 0.20 0.20 0.20 0.210 337.70 0.158

CH2CHOCH3COCH2O-
(CH3CO)

Cl-N 0.22 0.25 0.24 0.253 421.79 0.152

CH,CHOCH3COCH2O-
(CH3CO)

Summary: The toxicity increased from the tri-methyl to the tni-

amyl compound; there was, however, almost no difference between
the toxicity of the tri-propyl and tri-amyl compounds.
 TOXICITY AND CHEMICAL CONSTITUTION OF CHOLINE 317

1. Compounds containing a CH2CHO(C6H5CO)CH2O(C6116C0) group

14 0
5’
Z 05 01.5’
DOSEINMGM. - . 5,. -
PER GM. MOUSE

COMPOUNDS C5 4u
014
_________ .1
0. Ca5 P 0
.15 55
C Mo F.
Survived Died N c II a u
4 5

,(CH3)3

Cl-N 1.00 1.20 1.100 1.000 377.64 1.000

\CH,CHO(C0H5CO)CH,O..
(CeH5CO)

Cl-N 0.13 0.15 0.140 0.127 419.69 0.114

\CH2CHO(C6H5CO)CH20
(C5H5CO)
,(C3H7)3
Cl-N . 0.09 0.10 0.095 0.086 461.73 0.070

\CH2CHO(C6H5CO)CH2O-
(CeH3CO)

Cl-N ... .. 0.12 0.144 0.132 0.120 545.83 0.083

\CH,CHO(C.,H6COCH2O-
(C6H5CO)

Summary: The tri-methyl was the least and the tni-propyl the most
toxic; the latter was, however, but slightly more toxic than the tri-
amyl compound.
318 REID HUNT AND H. DE M. TAVEAU

Summary of I: In each of the above twelve groups of compounds

the compound containing the three methyl groups was the least toxic.
In eight of the cases the tri-amyl, in three, the tri-propyl, in one the
tri-ethyl was the most toxic. As a rule the toxicity increased from
the tri-methyl to the tri-amyl compound, but there was no regularity
in the degnee of the increased toxicity. In the case of the compounds
containing two methyl groups and one amyl group the toxicity was
intermediate between that of the compounds containing three methyl
groups and those containing three amyl groups (ci. VI).
The practical deduction to be dnawn from these experiments is
that in seeking fon compounds in this series which may have a desir-
able pharmacological action it is advisable to investigate first those
containing methyl groups, for these are the least toxic.

II. Effect of Various Side Chains upon the Toxicity of Compounds

Containing the (CH3)3 Group

It having been found that in any given group of compounds of this

series that containing three methyl groups was the least toxic, the
compounds are arranged in the following table so as to bring out the
relations between the toxicity of compounds in which the three methyl
groups are retained but in which the side chain is changed.6

Another reason for choosing this form of tabulation is that compounds containing
the three methyl groups have special relations to the vascular system as will be shown
in a subsequent communication.
 TOXICITY AND CHEMICAL CONSTITUTION OF CHOLINE 319

a. Compounds containing hydroxyl (or certain other oxygen-containing groups)

DOSE IN MOM.
PER GM. MOUSE

COMPOUNDS

5urvived Died

,(CH3)3

Cl-N 0.07 0.075 0.073 1.000 125.55 1.000

\CH2OH
,(CH3)3
Cl-N 0.037 0.040 0.038 0.521 139.57 0.469
\CH,OCH3

Cl-N 2.60 3.00 2.80 38.356 153.55 31.361

\cH,COOH
,(CH3)3
Cl-N 0.72 0.75 I 0.735 10.069 139.57 9.058
\CH,CH,OH
,(CH3)3
Cl-N 0.13 0.17 0.150 2.057 153.58 1.682
\CH,CH,CH2OH
,(CH3)3
Cl-N 0.60 0.63 0.615 8.425 153.58 6.889
\CHICHOHCHa
,(CH)3
(‘I-N 0.52 0.50 0.510 6.986 188.02 4.667
\CH2CHOHCH,C1
,(CH3)3
Cl-N . 1.60 1.80 1.700 23.288 169.58 17.241
\CH2CHOHCH2OH

Summary: The most toxic of this series is the methyl ether of

formocholine, which is eighteen times as toxic as choline itself.7 The
least toxic is betaine
,(CH3)3
Cl-N

CH2COOH
The great toxicity of the ethyl ether of formocholine was, already known (Fr#{228}nkel,
Arzneimittelsynthese, 2d ed., p. 334, 1906.)

4
320 REID HUNT AND H. DE M. TAVEAU

Of the compounds containing one or more hydroxyl groups formo-

choline was the most toxic; it was nine times as toxic as choline itself.
The least toxic was the di-oxy-propyl compound, which was about
one-half as toxic as choline.8 Thus it is possible to pnesenve the
(CIT3)3 group (with which, as will be shown later, certain marked and
perhaps therapeutically useful physiological properties are associated)
and materially reduce the toxicity.
The following tables show to what extent the laws governing the
toxicity of the above compounds apply to certain of the derivatives.

b. Acetyl Derivatives

I1

Z Q5 N ooa
-
aN
.1 C
DOSE IN MOM.
. M a
PERGM. MOUSE ‘ N_
5 0e
COMPOUND 14 1 5, I
145. 41 . ©CS
I C. Ca I
45 45I
C 50a I 14 55,4
Survived Died N 51 u a I 0 5.

4 4 5 t
- -.............

(CH3)3
a. Cl-N 0.72 0.75 0.735 1.000 139.57 1.000

\CH,CH,OH
,(CH3)3

b. Cl-N 0.30 0.32 0.310 0.422 181.58 p.324

\CH,CH2OCH3CO
,(CH3)3

a. Cl-N 0.13 0.17 0.150 1.000 153.581 1.000

CH,CH2CH,OH
(CH3)3
b. Cl-N 0.065 0.070 0.068 0.453 195.60 0.356

CH,CH,CH2O(CH3CO)
(CH3)3
a. Cl-N 0.60 0.63 0.615 1.000 153.58 1.000

CHCHOHCH,

8The slight toxicity of this compound (homoisomuscarine) has been pointed out

by Hans Meyer (in article by Schmidt, Liebig’s Annalen, 337, p.48, 1904).
 1

TOXICITY AND CHEMICAL CONSTITUTION OF CHOLINE 321

b. Acetyl derivatives (continued)

Z 0N
DOSE IN MOM. PER - .1 fl .1 M

GM. MOUSE C

COMPOUNDS 0
_______ 51 M1 .1

05.
Survived Died N u a 14 o a 5’
4 4 5 4

b. Cl-N . 0.163 0.175 0.169 0.275 195.60 0.216

CH,CHO(CH8CO)CH,

a. ClN 0.52 0.50 0.510 1.000 188.02 1.000

CH,CHOHCH,C1
(CH3)3
b. Cl-N 0.356 0.356 0.356 0.698 230.04 0.571

CH,CHO(CH,CO)
CH,C1
,(CH3)3
a. Cl-N 1.60 1.80 1.70 1.000 169.58 1.000
\CH2CHOHCH,OH
,(CH3)3
b. Cl-N 0.90 1.00 0.95 0.553 253.61 0.370
\CH,CHO(CH3CO)
CH2O - (CH,CO)

Summary: The toxicity of all the above compounds containing the

tri-methyl group is somewhat increased by the acetyl group; the degree
of increase varies in different cases.
322 REID hUNT AND R. DE M. TAVEAU

c. Benzoyl derivatives

14
a -

DOSE IN MOM. S fl.15

PER GM. MOUSE 0 4
5’
COMPOUNDS M 4
51 5.
51
C. C
4
N C S
Survived Died M 1.1

4 4

a. Cl-N 0.72 0.75 0.735 1.000 139.57 1.000

\CH2CH2OH
,(CH3)3

b. Cl-N 1.80 2.00 1.900 2.585 243.60 1.481

\CH2CH20C6115C0
,(CH3)3

a. Cl-N 0.13 0.17 0.150 1.000 153.58 1.000

CH2CH2CII2OH

b. Cl-N 0.23 0.27 0.250 1.666 257.61 0.993

CH2CH,CH2OC6H5CO

a.Cl-N 0.60 0.63 0.615 1.000 153.58 1.000

CH2CHOHCH3

b. Cl-N 1.026 1.080 1.053 1.712 257.61 1.021

CH2CHO(C.,H5COCH3

a. Cl-N 0.52 0.50 0.510 1.000 188.02 1.000

CH2CHOHCH2C1
(CH3)3
b. Cl-N 0.356 0.356 0.356 0.698 292.05 0.449

‘CH2CHo(C6H6CO)CH2
Cl

,(CH3)3

a. Cl-N 1.60 1.80 1.70 1.000 169.58 1.000

\CH,CHOHCH,OH

b. Cl-N 1.00 1.200 1.10 0.647 377.64 0.291

\CH2CHO(C6H5CO)
CH2O(C6H5CO)
 I

TOXICITY AND CHEMICAL CONSTITUTION OF CHOLINE 323

Summary: In some cases the henzoyl group diminished, in others

increased the toxicity of the compounds. The greatest increase in
toxicity was in the case of the di-oxy-propyl compounds.
Summary of II: The only general law that can be deduced from
this series is that the introduction of an acetyl group invariably in-
creased the toxicity.

III. Effect of Various Side Chains upon the Toxicity of Compounds

Containing the (C2H5)3 Group

a. Compounds containing one or more hydroxyl groups

14 0 ‘5

DOSE IN MOM. .1 C S - a
PER GM. MOUSE

COMPOUNDS a 5’ 57 5.

05,-4

.15’

Survived Died

,(C2H5)3
a. Cl-N 0.06 0.07 0.065 1.000 181.61 1.000

\CH2CH2OH

b. Cl-N 0.18 0.18 0.18 2.769 195.63 2.571

\CH,CHOHCH3

c. Cl-N 0.36 0.37 0.365 5.615 230.06 4.431

CH2CHOHCH2C1

d. Cl-N 0.57 0.62 0.600 9.231 211.63 7.922

\CH,CHOHCH2OH

Summary: The toxicity diminishes as the length of the side chain

increases. The compound containing two hydroxyl groups is the
least poisonous.
324 REID HUNT AND R. DE M. TAVEAU

b. Acetyl derivatives
N C ‘:

DOSE IN MOM. .1 C
h
N
P- II
PER GM. MOUSE C

COMPOUNDS a N
.

C0 0N N

. N :i
Survived Died a p
4 a N a

,(C2H6)3
a. Cl-N 0.06 0.07 0.065 1.000 181.61 1.000
\CH,C112011

,(C2115)3
b. Cl-N Unpre pared

\CH2CH2O(CH3CO)
,(C2H6)3
0.18 0.18 0.18 1.000 195.63 1.000
a. Cl-N

\CH,CHOHCH3
,(C2116)3
0.086 0.101 0.094 0.522 237.64 0.430
b. Cl-N

\CH,CHO(CH,CO)CH3

,(CH5)3
0.36 0.37 0.365 1.000 230.06 1.000
a. Cl-N

\CH2CHOHCH,C1
,(C2115)8
0.191 0.209 0.200 0.548 272.08 0.463
b. Cl-N
\CH,CHO(CH,CO)C1
,(C2H5)3 0.57 0.62 0.60 1.000 2ll.63 1.000
a. Cl-N
\CH2CHOHCH,OHCH,
,(C2115)3 0.40 0.46 0.43 0.717 295.66 0.513
b. Cl-N .
I

\CH2CHO(CH3CO)
CH2O(CH3CO) ,

Summary: In each case the toxicity is increased by the introduc-

tion of the acetyl group; the increase was not as great in most cases
as it was in the case of the tri-methyl compounds.
 TOXICITY AND CHEMICAL CONSTITUTION OF CHOLINE 325

c. Benzoyl derivatives
a
0
as
.. C
N
DOSE IN MOM. 4
PER GM. MOUSE 57 0 14 0 ‘ 57

COMPOUNDS r.1

0 a a515
4 .1.75’
Survived Died H

,(C2H6)3
a. Cl-N 0.06 0.07 0.065 1.000 181.61 1.000
\CH2CH,OH
,(C2H5)3
b. Cl-N 0.27 0.28 0.275 4.231 285.64 2.690
\CH2CH,O(C6H5C0
,(C,H5),
a. Cl-N 0.18 0.18 0.18 1.000 195.63 1.000

\CH2CHOHCH3
,(C2H5)3
h. Cl-N 0.30 0.32 0.31 1.722 299.66 1.124

\CH2CHO(C6H5CO)CH,
,(C2H5)3
a. Cl-N 0.36 0.37 0.365 1.000 230.06 1.000

\CH,CHOHCH,C1
,(C2H5)3
b. Cl-N 0.113 0.122 0.118 0.323 334.10 0.222

\CH,CHO(C6H,C0
CH,C1
,(C2H5)3
a. Cl-N .... 0.57 0.62 0.60 1.000 211.63 J.000

\CH2CHOHCH2OH
,(C2H5)3

b. Cl-N 0.13 0.15 0.14 0.233 419.69 0.117

\CH,CHO(C0H,CO)
CH,O(C6H5CO)

Summary: The introduction of the benzoyl group diminished the

toxicity of the first two but increased that of the second two com-
pounds.
326 REID HUNT AND R. DE M. TAVEAU

JV. Effect of Various Side Chains upon the Toxicity of Compounds

Containing the - (C3H7)3 Group

a. Compounds containing one or more hydrox-yl groups

14 -
N a5’ aN5’
0 OX N COX
N 0
DOSEINMGM. .3P S
PER GM. MOUSE

COMPOUNDS 0
.7 F.,

SN

Survived Died

,(C5H7)8
Cl-N 0.142 0.170 0.156 1.000 223.66 1.000

\bH2CH2OH
,(C3H7)3

Cl-N 0.09 0.11 0.100 0.641 237.67 0.603

\CH2CHOHCH3

Cl-N 0.060 0.065 0.063 0.404 272.12 0.332

\CH2CHOHCH2C1

Cl-N .. .. 0.23 0.25 0.24 1.539 253.67 1.357

\CH2CHOHCH2OH

Summary: The toxicity increases as the length of the side chain is

increased except in the case of the di-hydroxyl compound, which is
the least toxic. This is in marked contrast with the tri-ethyl com-
pounds (see III).
 TOXICITY AND CHEMICAL CONSTITUTION OF CHOLINE 327

b. Compounds containing one or more acetyl groups

. 51 57
N a 5’ aN
C 0 - 5 00’.
N a1 a.’5.

DOSRINMGM. S 57 .157
PER GM. MOUSE 57 S
a 4U5’
COMPOUNDS #{149} 5.’.

o 14 aa
4 4 57
Survived Died 57

,(C3H7)3

a. Cl-N 0.142 0.170 0.156 1.000 223.66

\CH2CH,OH
,(C3H7)3

b. Cl-N not pre pared

\CH,CH2O(CH,CO)
(C3H7)3
a. Cl-N 0.090 0.110 0.100 1.000 237.67 1.000
\CH,CHOHCH8
,(C3H7)3
b. Cl-N 0.150 0.160 0.155 1.550 279.69 1.317

\CH,CHO(CH,CO)CH3
,(C3H7)3

a. Cl-N 0.060 0.065 0.063 1.000 272.12 1.000

\CH,CHOHCH3CI
,(C3H7)3
b. Cl-N 0.160 0.170 0.165 2.619 314.13 2.269
\CH,CHO(CH8CO)CH,CI
,(C3H7)3
a. Cl-N 0.230 0.250 0.240 1.000 253.67 1.000

\CH,CHOHCH2OH
,(C3H7)3

b. Cl-N 0.200 0.200 0.200 0.833 337.70 0.626

\CH2CHO(CH,CO) -

C1120(CH3CO)

Summary: The acetyl group diminished the toxicity of all the com-
pounds prepared with the exception of the di-hydroxy-compounds, in
which it was increased. The effect of the acetyl group is thus, in
general, the reverse of its effect in the corresponding tri-methyl and
tri-ethyl compounds.
328 REID HUNT AND R. DE M. TAVEAU

c. Compounds containing one or more benzoyl groups

14
I
- 5’ R SI
CS N C a
05,11 o
DOSEINMGM. . .705
PER GM. MOUSE ‘. N U N

COMPOUNDS
5’”
Na .7
0 Oaa
45 45a U
0 o’. N

Survived Died N U5 Na5’

4 N

,(C3117)3
a. Cl-N . ... 0.142 0.170 0.156 1.000 223.66 1.000

\CH2CH2OH
,(C3H7)11
b. Cl-N .... 0.180 0.190 0.185 1.186 327.69 0.810
\CH2CHIOCSHSCO
,(C3H7)3

a. Cl-N .... 0.090 0.110 0.100 1.000 237.67 1.000

\CII2CHOHCHS
,(C3117)3
b. Cl-N 0.050 0.052 0.051 0.510 341.70 0.355

\CH2CHOCGHSCOCII3
,(C3H7)8
a. Cl-N .... 0.060 0.065 0.063 1.000 272.12 1.000

\CH2CHOHCHIC1
,(C8117)3
b. Cl-N .... 0.055 0.060 0.058 0.921 376.15 0.666

“\CH2CHO(C6115C0)
CH2C1

,(C3H7)3
a. Cl-N .... 0.230 0.250 0.240 1.000 253.67 1.000
,
\CH3CHOHCH2OH
,(C3H7)3

b. Cl-N 0.09 0.11 0.10 0.416 461.73 0.229

\CH2CHOC6H5CO
CH2O(C6H5CO)

Summary: The benzoyl group increased the toxicity in each case.

The effect was thus more uniform than in the case of the tn-methyl
and tri-ethyl compounds.
 TOXICITY AND CHEMICAL CONSTITUTION OF CHOLINE 329

V. Effect of Various Side Chains upon the Toxicity of Compounds

Containing the (C5H11)3 Group

a. Compounds containing one or more hydrox-yl groups

57
a

DOSE IN MOM.
S
PER GM. MOUSE -N 4Q
0
COMPOUNDS O 5’!
057 5.’.ISI
‘.7 57a 57Oa,
C5.,5
4N5’p
50 OXo 57 S.,45’
Survived Died N U0a Ca57fl
4 4 5 4

Cl-N 0.11 0.15 0.13 1.000 307.75 1.000

\CH2CH2OH

Cl-N 0.07 0.09 0.08 0.616 321.76 0.589

\CH2CHOHCH,

Cl-N 0.20 0.21 0.205 1.577 356.21 1.363

\CH,CHOHCH2C1

Cl-N 0.37 0.40 0.385 2.962 337.76 2.699

\CH2CHOHCH,OH

Summary: The most toxic of these compounds is the oxy-iso-

propyl; the least toxic is the di-oxy-propyl.
330 REID HUNT AND R. DE M. TAVEAU

b. Compounds containing one or more acetyl groups

57 -
a 5’ 00,
5fl C
CUS,..,
DOSEINMGM. .75
.114
PERGM.MOUSE. 4.7i

COMPOUNDS S 5.57SI
4 .15’
- 8,
NC
0. Ca5 U
N 4Na U
0 O57 S5.4,
Survived Died N US .7 14
05.a
4 4 5 4

a. Cl-N .... 0.11 0.15 0.140 1.000 307.75 1.000

\CH2CH2OH

b. Cl-N .... 0.13 0.145 0.138 0.986 349.76 0.868

\CH2CH2O(C118C0)

a. Cl-N .... 0.07 0.09 0.080 1.000 321.76 1.000

\CH,CHOHCH3

b. Cl-N .... 0.135 0.15 0.143 1.787 363.78 1.581

\CH2CHO(CH3CO)C113

a. Cl-N .... 0.20 0.21 0.205 1.000 356.21 1.000

\CH2CHOHCH2C1

b. Cl-N .... 0.14 0.15 0.145 0.707 #{149}398.220.632

\CII2CH0(CH3C0)
CH3C1

a. Cl-N .... 0.37 0.40 0.385 1.000 337.76 1.000

\CH2CHOHCH2OH

b. Cl-N .... 0.22 0.25 0.235 0.610 421.79 0.489

\CH2CH0(CH8C0)
CH2O(CH8CO)

Summary: In all but one case the acetyl group increased the tox-
icity.
 TOXICITY AND CHEMICAL CONSTITUTION OF CHOLINE 331

c. Compounds containing one or more bensoyl groups

57
a
. 0”’
5 0,
DOSE IN MOM. .., .
PER GM. MOUSE 57
a 5’
COMPOUNDS 0 4
a57 5.
515 57
C. 0
45
SC
Survived Died N
4 4

,(C6H11)3
a. Cl-N .... 0.11 0.15 0.130 1.000 307.75 1.000
\CH2CH2OH
,(C7H11)3
b. Cl-N .... 0.032 0.036 0.034 0.262 411.78 0.196

\CH2CH2O(C6H5CO)
,(C5H11)3
a. Cl-N .... 0.07 0.09 0.080 1.000 321.76 1.000
\CH,CHOHCH3
,(C5H11)3

b. Cl-N .... 0.034 0.038 0.036 0.450 425.79 0.340

\CH2CHO(C6H5CO)CHS
,(C5H11)3
a. Cl-N .... 0.20 0.21 0.205 1.000 356.21 1.000
\CH,CHOHCH,C1
,(C5H11)3
b. Cl-N .... 0.037 0.039 0.038 0.185 460.24 0.143

\CH,cHo(C6115co)
CH2C1
,(C5H11)3
a. Cl-N .... 0.37 0.40 0.385 1.000 337.76 1.000
\CH,CHOHCH2OH
(C5H11)3
b. Cl-N .... 0.144 0.168 0.156 0.405 545.83 0.251

\CH2CHO(C6H5CO)
CH2O(C6H5CO)

Summary: The toxicity was increased in each case by the benzoyl

group. The effect is thus the same as with the tri-propyl.
 332 REID HUNT AND H. DE M. TAVEAU

VI. Effect of Various Side Chains upon the Toxicity of Compounds

Containing the Groups <(CHS)2

C5H11 (ios)

51 1.15’ I ‘.
a a
0 0 5, 005’
0. 0X
. DOSEINMGM. .1 .757C
PER GM. MOUSE H
COMPOUNDS
457 5’
400 5’p’I
5 5NZ 5

M .1 57C
CC Caa U CNa
45 U
1.1
Survived Died U U .1
0 14 0 a U
4 4 5 4

,(CH3)2
Cl-N-C5H11 (iso) 0.60 0.63 0.615 1.000 195.63 1.000
\CH2CII,OH
(CH3)2
Cl-N-C5H,, (iso) 0.37 0.40 0.385 0.626 237.64 0.515

\CH,CH2O(CH,CO)
,(CH3)2
Cl-N-C5H11 (iso) 1.10 1.20 1.150 1.869 299.66 1.220

\CH2CH2O(C6H6CO)

Summary: The acetyl group increased and the benzoyl group

diminished the toxicity. Comparing these results with those of II,
b and c; and V, b and c, it is seen that these compounds resemble the
tn-methyl rather than the tni-amyl derivatives.
 TOXICITY AND CHEMICAL CONSTITUTION OF CHOLINE 333

VII. Toxicity of Compounds Containing Two Methyl and One Iso-amyl

Group
57
. a -
0
aH 5’
DOSEIN MOM. .1
PER GM. MOUSE. C

COMPOUNDS 57

1.1 574
Ca
. 50
45
Survived Died N U

4 4

a. Cl-N .... 0.72 0.75 0.735 1.000 139.57 1.000

CH,CH,OH

b. Cl-N .... 0.11 0.15 0.130 0.177 307.75 0.080

\CH2CH,OH
,(CH3)2
c. Cl-N--C51111 (iso) .... 0.60 0.63 0.615 0.837 195.63 0.597

\CH2CH2OH

,(CH3)3
a. Cl-N .... 0.30 0.32 0.310 1.000 181.58 1.000

\CH,CH2O(CH3CO)

b. Cl-N .... 0.13 0.145 0.138 0.445 349.76 0.231

CH,CH,OCH,CO

c. Cl-N-C,H11 (iso) .... 0.37 0.40 0.385 1.242 237.64 0.949

CH,CH2OCH,CO
(CH3)3
a. Cl-N .... 1.80 2.00 1.900 1.000 243.60 1.000

CH,CH,o(C6H,CO)

h. Cl-N .... 0.032 0.036 0.034 0.018 411.78 0.011

CH,CH2OC6H5CO
,(CH8)2
c. C1-N-C5HII (iso) .... 1.10 1.20 1.150 0.605 299.66 0.492

CH2CH2OC6H5CO

Summary: In all cases the toxicity of the compound containing

one iso-amyl and two methyl groups lay between that of the tri-methyl
and tni-amyl compounds, being however nearer the former than the
latter.
334 REID HUNT AND R. DE M. TAVEAU

VIII. Effect of Chlorine in the Side Chain

a. Hydroxyl compounds
a‘. U
a
0
0
C
DOSE IN MGM. - a
PER GM. MOUSE 57
aC 5’Hs 5’US_
4U5’
COMPOUNDS 5.51 S
S1’
514 .1 1.1
0. Ca U C
.IN 4Na U
SC 051
Survived Died N U S .1 51 5.
4 4 5 4

i. Methyl group
,(CH3)3

a. Cl-N 0.60 0.63 0.615 1.000 153.58 1.000

\CH,CHOHCH3

,(C113)3

b. Cl-N 0.52 0.50 0.510 0.829 188.02 0.677

\CH,CHOHCH2C1
ii. Ethyl group

a. Cl-N 0 .18 0.18 0.18 1.000 195.63 1.000

\CH,CHOHCH3

b. Cl-N ‘ 0.36 0.37 0.365 2.028 230.06 1.724

\CH2CHOHCH2C1
iii. Propyl group

,(C3H7)3
a. Cl-N 0.09 0.11 0.100 1.000 237.67 1.000

CH,CHOHCH3

b. Cl-N 0.06 0.065 0.063 0.630 272.12 0.550

CH,CHOHCH2C
iv. Amyl group

a. Cl-N 0.07 0.09 0.080 1.000 321.76 1.000

\CII,CHOHCH3

b. Cl-N 0.20 0.21 0.205 2.563 356.21 2.316

\CH2CHOHCH2C1

Summary: Chlorine increased the toxicity in the case of the tn-

methyl and tni-propyl compounds, but diminished it in the tn-ethyl
and tni-amyl compounds.
 ‘--- r-’-’ - -

TOXICITY AND CHEMICAL CONSTITUTION OF CHOLINE 335

b. Acetyl groups
57’
N a57
C S 5’ 01.1
N a5,., N aU
S C 57
DOSE IN MOM. .7 .15751
57
PER GM. MOUSE 57 4 4.1
a 5’ a
COMPOUNDS 0
5751 S
a
S5’ 4 5.p
C 514- .7 57O5
Ca 0N57
4 451
57 S’.,4
.1
5urvived Died NUa
0
05.5’
5,
4 4 N 4

i. Methyl group
,(CH3)3
a. Cl-N .... 0.163 0.175 0.169 1.000 195.60 1.000
\CH2CHO(CH300)CH,
,(CH3)3
b. Cl-N .... 0.356 0.365 0.361 2.136 230.04 1.817

\CH2CHO(CH3CO)
CH2C1
ii. Ethyl group
,(C2H5)3
a. Cl-N .... 0.18 0.18 0.180 1.000 237.64 1.000
\CH,CHO(CH,CO)CH3
,(C2H5)3

b. Cl-N .... 0.36 0.37 0.365 2.028 272.08 1.771

\CH,CHO(CH,CO)
CH,C1
iii. Propyl group

a. Cl-N .... 0.09 0.11 0.100 1.000 279.69 1.000

\CH,CHO(CH3CO)CH3
,(C3H7)3

b. Cl-N .... 0.06 0.065 0.063 0.630 314.13 0.561

\CH,CHO(CH8CO)
CH,C1
iv. Amyl group

a. Cl-N .... 0.135 0.150 0.142 1.000 363.78 1.000

\CH,CHO(CH3CO)CH3

b. Cl-N .... 0.14 0.15 0.145 1.021 398.22 0.933

/CH,CHO(CH,CO)
CH2CI ________________ _____

Summary: Chlorine diminished the toxicity in the tri-methyl and

tri-ethyl compounds, but increased that of the tri-propyl and tri-amyl
groups.
336 REID HUNT AND R. DE M. TAVEAU

c. Benzoyl groups

1.7
a - 51514
C 5’ E05
N 2U -
DOSE IN MOM. a 51
PER GM. MOUSE 57 o -
COMPOUNDS N

____________ ‘.7S
C.
57
05.a
45 45 U 4 SN
50 ‘. 5a4a
Survived Died N U S C 5
4 4 N 4

i. Methyl group
,(CH3)3

a. Cl-N 1.026 1.080 1.053 1.000 257.61 1.000

\CH2CHO(C6H5CO)CH3

b. Cl-N 0.356 0.356 0.356 0.338 292.05 0.298

\CH2CHOC6H5CO
CH2C1
ii. Ethyl group

a. Cl-N 0.30 0.32 0.310 1.000 299.66 1.000

\CH2CHO(C6H5CO)CH3

b. Cl-N 0.113 0.122 0.118 0.381 334.l0 0.342

\CH,CHO(C6H5CO)
CH2C1
iii. Propyl group
,(C3117)3
a. Cl-N 0.050 0.052 0.051 1.000 341.70 1.000
\CH,CHO(C6H5CO)CH3
(C3H7)3

b. Cl-N 0.055 0.060 0.058 1.137 376.15 1.033

\CH2CHO(C6H5CO)
CH2C1
iv. Amyl group

a. Cl-N 0.034 0.038 0.036 1.000 425.79 1.000

\CH,CHOC6H5CO)CH3

b. Cl-N 0.037. 0.039 0.038 1.055 460.24 0.976

\CH2CHO(COH5CO)
CH2C1

Summary: Chlorine markedly increased the toxicity of the tn-

methyl and tri-ethyl compounds, but had little effect upon the tn-
propyl and tri-amyl compounds.
 TOXICITY AND CHEMICAL CONSTITUTION OF CHOLINE 337

Summary of Effect of Chlorine

The effect of chlorine upon the toxicity of the above compounds
is shown in the following table.
Hydroxyl-group. Acetyl-group Benzoyl-group

CIT3 increased decreased increased

C2H5 decreased decreased increased
C3H7 increased increased 0
C5H11 decreased ? 0

Thus chlorine diminishes the toxicity of the acetyl derivative of

the tri-methyl and tri-ethyl compounds, but increases that of the
benzoyl derivatives of these compounds.

VIII. Relative Toxicity of Oxy-normal and Oxy-iso-propyl

Derivatives

a5’ C 0U
DOSE IN MOM. .1 I
PER GM. MOUSE 57 -

COMPOUNDS

S 51
Survived Died 0 5
4 4 4

,(CH3)3

a. Cl-N 0.13 0.17 0.150 1.000 153.58 1.000

\CH,CH,CH2OH
,(CH3)3

b. Cl-N 0.60 0.63 0.615 4.100 153.58 4.100

\CH,CHOHCH,
,(CH3)3

a. Cl-N 0.065 0.070 0.068 1.000 195.60 1.000

\CH2CH2CH,O(CH3CO)
,(C113)3

b. Cl-N 0.163 0.175 0.169 2.485 195.60 2.485

\CH,CHO(CH3CO)CH3
,(CH3)3

a. Cl-N 0.23 0.27 0.250 1.000 257.61 1.000

\CH,CH,CH,O(C6H5CO)
,(CH3)3

b. Cl-N 1.026 1.080 1.053 4.212 257.61 4.212

\CH2CHO(C6115C0)CH3

Summary: The normal were invariably more toxic than the iso
compounds.
338 REID HUNT AND R. DE M. TAVEAU

IX. Effect of Two Hydroxyl Groups

SI 57
a -
C N
z 0.Q L
DOSE IN MOM. - .

PER GM. MOUSE N 51 51 757

4.7 H
aC 5’ 57
COMPOUNDS 4 0 5’
5.57 S
4
575. 57.) 7
o”
C. Ci, CS51
4 557
S S57 57 55.4a
Survived Died S US .7 C5.a
4 4 5 4

a. Cl-N 0.60 0.63 0.615 1.000 153.58 1.000

\CH,CHOHCH3
,(CH3)3

b. Cl-N 1.60 1.80 1.700 2.764 169.58 2.603

\CH2CHOHCH2OH
,(C2H5)3
a. Cl-N 0.18 0.18 0.180 1.000 195.63 1.000

\CH,CHOHCH3
,(C2H6)3

b. Cl-N 0.57 0.62 0.600 3.333 211.63 3.081

\CH,CHOHCH2OH

a. Cl-N 0.09 0.11 0.100 1.000 237.67 1.000

\CH2CHOHCH3
,(C3H7)3

b. Cl-N 0.23 0.25 0.240 2.400 253.67 2.249

\CH2CHOHCH2OH

a. Cl-N 0.07 0.09 0.080 1.000 321.76 1.000

\CH,CHOHCH8

b.Cl-N 0.37 0.40 0.385 4.813 337.76 4.585

\CH2CHOHCH2OH

Summary: The di-oxy compounds were invariably less toxic than

the mon-oxy compounds.
 TOXICITY AND CHEMICAL CONSTITUTION OF CHOLINE 339

RESUME

(I) In each of twelve groups of homologous compounds the corn-

pound containing a tri-methyl group was less toxic than that con-
taming a tri-ethyl, a tni-pnopyl, or a tni-amyl group.
(II) In eight of the twelve groups the tri-amyl, in three the tri-
propyl and in one the tri-ethyl was the most toxic.
(III) Compounds containing two methyl and one amyl group had
a toxicity greater than that of the tn-methyl but less than that of
the tri-amyl compounds.
(IV) Compounds containing the oxy-ethyl group were less toxic
than those containing a shorter or a longer side chain with one
hydroxyl group (except in the case of the tri-ethyl compounds).
(V) In all cases compounds containing two hydroxyl groups in the
side chain were less toxic than those containing but one hydroxyl.
This was true also of compounds containing two acetyl but not of
those containing two benzoyl groups.
(VI) The acetyl group increased the toxicity of all the compounds
containing tri-methyl and tri-ethyl groups; with the tri-propyl and
tni-amyl groups the effect varied in different compounds.
(VII) The benzoyl group increased the toxicity of the compounds
containing tri-propyl and tri-amyl groups. The effect varied in the
case of the tn-methyl and tri-ethyl compounds.
(VIII) A chlorine atom in the side chain diminished the toxicity
of the acetyl derivatives of the tri-methyl and tri-ethyl compounds;
the increased toxicity caused by the introduction of an acetyl group
may thus, to a certain extent, be overcome by the introduction of a
chlorine atom.
(IX) A chlorine atom in the side chain increased the toxicity of
the benzoyl derivatives of the tri-methyl and tri-ethyl compounds.
(X) The normal oxy-propyl compound and its derivatives were
invariably more toxic than the oxy-iso compounds.