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acid or cetyl palmitate. Bees wax consists chiefly of myricil
alcohol and cerotic and melissic acids in ester combination.

Waxes are of both animal and vegetable origin. The surfaces
of all organisms, both plant and animal, are covered with a layer
of wax. The secretion is found in greater abundance in some
plants than others. The function of it is to protect the plant or
animal from over-wetting or over-drying and against changes in
temperature. For these reasons waxes are important in the pro-
tection of the eggs and larvae of insects. It is well known that
wax is a poor conductor of heat as Well as electricity.

Lanolin or wool fat, or more correctly, wool wax, consists
largely of monatomic alcohol, cholesterol in the free state. There
is also some of this combined with myristic, cerotic, and lanoceric
acids to form true wax.

The fact that waxes generally have a harder consistency than
fats has given rise to incorrect nomenclature in some cases. For
instance, wool fat, which is in reality a wax, is not usually re-
garded as such, while Japan wax, produced by a species of Rhus,
is actually a fat. True fats are esters of glycerine, but waxes
are esters of higher fatty acids and monatomic alcohols. There
is a great variation in the alcohols and the fatty acids in waxes
as the following list will show:

(Composition op the Waxes — Taken prom Mathews Physiological
Chemistry, 1915, p. 80.)



Acids. Saturated.



Formula



Melting point



Wax



Picocerylic

'Myristic

Palmitic

Carnaubic

Cerotic

Melissic

Psyllostearylic



CuHjeOi


57«C.


CiiHisOt


63.8°


CieHaiOi


62.6<»


C«4H4iO»


72.5°


Cs«Hm0>


77.8°


CsoHeoOt


91°


CmH«60«


94-96°



Gundang.

Wool.

Bees. Spermaceti.

Carnauba. Wool.

Bees. Wool. Insect.

Bees.

Psylla.



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STEROLS



166



II. Aoryllic series.

Physetoleic

Doeglic (?)

Lanopalmic

Cocceric

Lanoceric

III. Alcohols. Sterols,

Pisan ceryl • • •

Cetyl (Ethal)

Octodecyl

Carnaubyl »

Ceryl

Myricyl (Melissyl)

Psyllostearyl

Lanolin alcohol

Ficoceryl

Cholesterol

Cocceryl

Iso-cholesterol



ChHioOj
Ci9Hi«0«
CuHijOa
CiiHbjOi
CaoHioO*



30"

87-88*

92-93°

104-105<»



Sperm oil.
Sperm oil.
Wool.

Wool.



CibHmO
CieHieO
CitHitO
CjiHftoO
C38H94O
Ci(»H«jO
CisHmO
CuHmO
CitHjiO
CjTHieO
CioHssOs

Cl6H4«0



78«»
50°
59°



79°

85-88°

68-70°

102-104°

198°

148.4-150.8°

101-104°

137-138°



Pisang.

Spermaceti.

Spermaceti.

Wool.

Wool Chinese.

Bees. Carnauba.

PsyUa.

Wool.

Gundang.

Wool.

Cochineal.

Wool.



Waxes are soluble in the ordinary fat solvents, benzene, ether,
chloroform, etc. but are less soluble than the fats.

When heated, waxes give no smell of acrolein, since they contain
no glycerine. They are saponifiable like the fats, but with iriore
diflSculty.

STEROLS

These are solid alcohols, "steros," meaning solid, and "ol"
the chemical ending signifying, alcohol. Cholesterol C27H46OH
was the first discovered member of the group, and the most im-
portant. It is a secondary alcohol, since it oxidizes to a ketone.
Compounds closely related to cholesterol are found in plants,
phytosterols, and also in feces, coprosterols.

Cholesterol can be taken as a type of the sterols, which are
important as constituents of waxes. The relation of the sterols
to waxes is the same as glycerine to fats.

CHOLESTEROL

This sterol was first prepared from gall stones in 1785 by Four-
croy and studied by Chevreul in 1814, who named it cholesterin
from the Greek chole, bile, and steros, solid. Some gall stones
are almost pure cholesterol. It is also found in brain tissue.
The important source of it is lanolin or wool fat, "lana,"



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166 CHEMICAL PHARMACOLOGY

wool, oleum, oil, or adeps lan» hydrosus. This contains some
free cholesterol and some combined with myristic, cerotic, lano-
eerie, and lanopalmitic acids in the form of wax. Wool wax also
contains other sterols, as camabuyl, and lanolin alcohols.

Cholesterol is insoluble in water and alkalies, sparingly soluble
in cold, but readily soluble in hot alcohol, ether, acetone, chloro-
form, and other organic solvents, slightly soluble in soap solutions
and much more soluble in solutions of bile salts. It is readily
soluble in oleic acid and oils. Solutions of it jeact neutral. It
is tasteless, odorless, cannot be saponified, and is remarkably
stable toward oxidation. These reasons, and the additional one
that it does not become rancid, recommend its use in ointments,
etc. Because of its penetrative power, it is used as the base to
carry drugs through the skin.

Cholesterol is found to some degree in every cell, probably as a
protective agent. The structure of it is not satisfactorily known.
Mauthner' assigns to it the following formula:

CHsv

yCH.CH2CH2 — C17H26CH: CH2
CHs/ /\

H2C CII2

CH(OH)
Windaus^ gives
CHsv

yCH — CH2 — CH2 — ^iilli7

CH CH

H2C CH CH — CH3

III

H2C CH2 CH

c\ (1

HOH CH2
From these formulas it is seen to be closely related to the
terpenes, which are also important in drug chemistry.

^ Zeit. f. physiologische chemie, 1901, 34, 426.

* Ber. Deutsche, chem. gesellschaft, 1912, 45, 2421.



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CHOLESTEROL 167

This constitution ig not yet definitely settled. It is evidently a
terpene compound. The formation of terpenes in the animal
body is hard to explain, and it seems probable that it does not
originate in the animal organism. Animal cholesterol is ap-
parently plant cholesterol, utilized by the body.^ The metabol-
ism of it in the body is as unknown, as is its fimction, though it
possesses certain definite properties which are pharmacologic
importance. Lecithin accelerates the activity of cobra poison
and cholesterol retards the action of lecithin. Snake venom
added to washed red blood corpuscles suspended in water, will
not cause laking. If, however, a trace of lecithin be added, laking
results. A trace of cholesterol dissolved in methyl alcohol will
neutraUze the influence of the lecithin in this case. Since lecithin
and cholesterol exist in all cells and especially in red blood cor-
puscles, it seems that the function of the cholesterol is protective.

Preparation and Tests for Cholesterol
Place 2 grams of wool fat in a 100 cc. Erlenmeyer flask, add
25 cc. of 25 per cent, alcoholic (KOH) and boil under a reflux
condenser for two hours with frequent shaking. This saponifies
the fats but not the cholesterol. Pour the mixture into an eva-
porating dish and evaporate oflf the alcohol. Dissolve the resid-
ual soap in 50 cc. of hot water and transfer to a 200 cc. separating
funnel, cool and add 50 cc. of ether and shake several times.
The ether dissolves the cholesterol. If separation does not occur
readily, add 5 cc. alcohol and shake again. Run oflf the soap
solution and collect the ether solution in a dry evaporating dish
and evaporate to dryness on a water bath.

1. Examine the residue under a microscope on a glass sUde for
the characteristic crystals.

2. Cholesterol on oxidation yields pigments. The Lieber-
mann-Burchard test is the most delicate and characteristic.
The test is as follows:

Dissolve a few crystals of cholesterol in 2-3 cc. of chloroform in

1 Recently, Gamble and Blackfan (J. Biol. Chem., 1920, 42, 401-9),
from analysis of the nonnsaponifiable fraction of the feces of undernourished
children for three days found the excretion of cholesterol larger than the
amount in the food. They interpreted this result as indicating a S3mthesis of
cholesterol in the body. This is confirmation of an older observation of
Mueller, but does not satisfactorily account for the excretion of a probable
storage from previous feeding.



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168 CHEMICAL PHARMACOLOGY

a dry test tube or in the depression of a test tablet. Add about
10 drops of acetic anhydride, shake and add concentrated H2SO4
drop by drop. A transient pink color first develops, which on the
addition of more acid changes to blue and finally to green.

3. Schiff's reaction: A few crystals of cholesterol are placed
on a porcelain dish and treated with a few drops of a mixture of
1 volume 10 per cent, ferric, chloride and 3 volumes of concen-
trated H2SO4. It is then evaporated carefully to dryness over a
free flame. A reddish violet residue changing to bluish is
obtained.

4. Crystals of cholesterol on a white surface, when moistened
with a mixture of 5 parts H2SO4 and 1 part water, turn pink.
On the oxidation of a drop of very dilute solution of iodine a play
of colors violet, blue, green, and red, results.

All animal fats contain cholesterol while vegetable fats con-
tain phytosterol, and sitosterol. The isolation and identification
of the unsaponifiable residue, therefore, is of considerable im-
portance, in establishing whether or not a fat is of animal or
plant origin. In food products the more expensive animal fats
are sometimes substituted by or adulterated with, the cheaper
vegetable fats. Recently vegetable fats have been hydrogen-
ated to make them more nearly like animal fats — ^see p. 154, but
such hydrogenated fats are used only as foods.

XIX. VOLATILE, ETHEREAL OR ESSENTIAL OILS

The sources of the volatile oils are mainly the flowers, fruit
and leaves of many plants. They differ from the fixed oils
chemically, physically, pharmacologically, and economically.

The composition of volatile oils is very variable and not fully
understood. Terpene is the most common constituent. Many
are composed mainly of terpenes either of the aliphatic or aro-
matic series. But mixtures of terpene derivatives which include
alcohols, aldehydes, ketones, acids, esters, ethers, phenols, lac-
tones, quinones, oxides, nitrogen and sulphur compounds occur.
Some non-terpene hydrocarbons have also been foimd and in
some oils no terpene has been found (Attar of Roses). The
only common characteristic of the volatile oils as a class is their
volatility. They all contain hydrogen and carbon and most of
them also oxygen. A few contain nitrogen or sulphur or both.



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TBRPENES 169

The characteristic odor of the oil is associated with the oxygenated
part of the molecule, and especially with the oxygenated aliphatic
terpene.

CHEMICAL CLASSIFICATION
Dumas in 1833, classified volatile oils as follows:

1. Those containing carbon and hydrogen only, hke turpen-
tine.

2. Those that contain oxygen, like camphor and eucalyptus.

3. Those that contain sulphur, like mustard oil or

4. Nitrogen, like oil of bitter almonds. While this classifica-
tion may still be used in a modified form, it is to general to give one
any information regarding the composition of any volatile oil.

ALIPHATIC HYDROCARBONS IN VOLATILE OILS
Heptane C7H16 is the lowest member of this series found in
volatile oils. It has been found in the distillate of the oleoresin
of some California pines. Higher members of this series and of
the olefin series occur quite generally in the wax-like secretions
of leaves, flowers and fruits. They occur mixed with other
homologues and not as pure products. Octylene CgHie has been
found in the oils of bergamot and lemon. A number of terpene
hydrocarbons have been isolated.

TERPENES
Terpenes were formerly defined as hydrogenated derivatives
of ijymene and its substituted products (true terpenes). More
recent work however has discovered some olefine terpenes.
These can readily be converted into aromatic terpenes. All
terpenes are unsaturated compounds and can be hydrogenated
readily and yield addition products with halogens. On exposure
to the air they are oxidized to resins, and this has given rise to
the opinion that natural resins are oxidized products of volatile
oils. As a group they appear to be derived from hydrocarbons
of the composition CsHg. They are classified as:

Hemiterpenes CsHs

Terpenes CioHie

Sesquiterpenes C16H24

Diterpenes. C20H32

Polyterpenes (C5H8)n

These may be divided into two groups:
1. The olefine terpenes.



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170 CHEMICAL PHARMACOLOGY

2. The aromatic terpenes.

(a) Monocyclic.
(6) Dicyclic.

The monocyclic are represented by cymene or menthol and the
dicyclic by camphor and camphane.

The most important terpenes of the aliphatic or olefine series
are:



CH2V yCHs



\ C— CHr-CHr-CHj— CH (
CH,'^ ^CHr-CHjOH

Citronellol (Lemon oil)
CH,. /CH,

)C=CH— CH,— CH2— C{
CHa'^ ^CH— CH2OH

Geraniol (Oil of geranium)

CHsv yUH.3

)C=CH— CH^CH^C^CH=CHi

Linalool (Oil of lavender)

CH3. xCHs

)C=CH— CHi— CH2— C (f
CHs/ \CH=CH2

Myrcene (Oil of lignaloes, etc.)

CHsv yCHs

CH

The nucleus of true terpene /\
is cymene



CH3
or paramethyl isopropyl benzene^ which can be derived easily
from some of the volatile oils, stearoptenes and camphors.

CioHieO + P2O5 -> CioHu + H2O
Camphor Cymene

C10H16 + -> CioHi4 + H2O
Turpentine Cymene



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ABOMATIC TERPENBS 171

Cymene is a pleasant smelling liquid — specific gravity 0.87
and boils at 175"176''C. On oxidation with dilute HNOs the
isopropyl end of the ring is first oxidized and para toluic acid is
formed CH8.C6H4.COOH. Further oxidation yields terephthalic
acid COOH.C6H4COOH (1 : 4). In the body the methyl end
of the chain is first attacked and cumic acid is formed:

•CH (0x13)2
C6H4V

^COOH
Cumic acid

and excreted as the glycocoU conjugate, cuminuric acid

(CH3)2CH.C5H4CO.NH.CH2COOH

AROMATIC TERPENES

True terpenes have the formula CioHic. They seem to be
polymerides of the hemi-terpene (CsHg). Two or more mole-
cules of this compound may polymerize to form terpenes or
polyterpenes.

In the destructive distillation of india rubber, or when tur-
pentine is passed through a tube heated to redness, isoprene
(CsHs) which is methyl divinyl, is formed

This is a Kquid B.P. 37"^. It polymerizes readily to the
terpene dipentene,

CH3V CHsv yCH — CH K

2 ^C— CH = CH2-> ^C— CH^^ \C.CH,

CH2 CH.2 CI12 — 0X12

Isoprene Dipentene



On treatment with acids, isoprene polymerizes, forming rubber
again, which is considered as a resin.

The terpenes may be considered as being derived from iso-
prene or an isomeric hydrocarbon. The true terpenes all con-
tain the dipentene or cymene nucleus.



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172



CHEMICAL PHARMACOLOGY

CHs QH3



Cymene
nucleus



Dipentene
nucleus



C

/\
CH3 CH3



c

CH2 "CH3



The terpenes being unsaturated bodies, unite with HCl or
HBr to form addition products. The unsaturated condition
also imparts great reactivity to them. They absorb oxygen
readily and resinify. HNO3 or iodine and other oxidizing sub-
stances mixed with them may cause explosions. Weaker oxidiz-
ing may break them down with the formation of acetic, propionic,
butyric, oxalic, and other acids while bromine and iodine convert
them into cymene. One of the easiest ways to prepare cymene
is to treat camphor with P2S5,ZnCl2, or P2O5 (p. 170).

The main characteristics of this ill-defined group of true
terpenes are:

1. Their composition CioHie.

2. Their unsaturated condition.

3. Their great reactivity.

4. Their tendency to polymerize and resinify.

5. On reduction they yield hydroterpenes.

6. On oxidation with potassium, they yield, in many cases,
benzene derivatives.

7. The presence of the cymene ring or nucleus.

8. They boil without decomposition at 155-180°C.

9. When taken into the body, they as a rule, are excreted
combined with glycuronic acid, as conjugated glycuronates.

Fior convenience of study, the true terpenes have been sub-
divided as follows:

1. The terpenogen group

2. Terpan or menthan group



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VOLATILE OILS 173

3. Camphan group.

Group I. consists of alcohols, aldehydes, acids, etc., combina-
tions of terpenes from which the hydrocarbon can readily be
prepared.

Group II. Menthol is a prominent member of this group,
and has certain reactions which distinguish it from the first group.
It is not so easily converted into the hydrocarbon.

Group III. Camphor is the typical representative. Cam-
phor yields camphene which is the only solid terpene known.

ALIPHATIC ALCOHOLS IN VOLATILE OILS

Methyl alcohol occurs frequently and has been found in aque-
ous distillates of the oils of cypress, savin, vetiver, orris, etc.
Ethyl alcohol has been observed only in a few instances. N
butyl, isobutyl, isoamyl, n hexyl, heptyl, n octyl, n nonyl and
undecyl have also been found. Various other less known alipha-
tic alcohols have been reported.

AROMATIC ALCOHOLS IN VOLATILE OILS

Benzyl, phenyl ethyl, phenyl propyl, and cinnamic occur;
also salicyclic alcohols, are more or less commonly foimd.

DIFFERENCES BETWEEN FIXED AND VOLATILE OILS
The chief differences are:

Fixed Oils Volatile Oils

1. Ijeave a greasy spot on paper. Evaporate completely.

2. Can be saponified. Cannot be saponified.

3. Will not explode when May explode when brought

brought together with ni- together with nitric and

trie acid, iodine, or other other oxidizing agents,
oxidizing agents.

4. Chemical composition — esters Chemical composition,

of glycerine and fatty acids mainly terpenes and deriv-
atives.

5. Almost insoluble in alcohol. Soluble in ether, chloroform,

except castor oil. Soluble benzene, and other oils,
in ether, chloroform, ben-
zene, and in other oils.



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174 CHEMICAL PHABMACOLOOY

6. More easily emulsified. Not so easily emulsified.

7. Used in medicine as laxatives, Used in medicine as flavors,

emollients, vehicles for oint- carminatives, stomachics,
ments, liniments, etc. correctives, rubifacients,

deodorants, antiseptics, etc.

8. Are foodstuffs. Are not foodstuffs.

9. Completely oxidized in the Not oxidized but are excreted,

body and excreted as CO2 mainly combined with
and H2O. glycuronic acid.

THE GENERAL ACTION OF THE VOLATILE OILS

All volatile oils attack protoplasm and are antiseptic for this
reason. This is a general action of benzene derivatives, and most
volatile oils are such. The volatility of the oil aids in its penetra-
tion and action. When applied to the skin, they produce itching,
redness, some anesthesia, and if volatilization be prevented they
will cause bhstering. The turpentine stupe, which is essentially,
oil of turpentine, sprinkled on a woolen cloth wrung out of hot
water, and applied to a part of the body, gives one a good idea of
the local action of volatile oils. Some oils, such as oil of mustard
act after they are broken down into active ingredients, and others
such as menthol have a specific action on the nerves conveying
the sensation of cold. In general however the action resembles
that of turpentine.

Action on the Alimentary Tract

Oils generally have an agreeable taste. They are slightly
irritating and cause a flow of saliva. They are readily absorbed
and may increase the appetite. When swallowed small doses in-
crease moderately the activity of the gastro-intestinal tract and
act as carminatives. Excessive doses produce symptoms of
inflammation with vomiting and diarrhoea.

The oils circulate in the blood for the most part unchanged,
but due to their action on the intestine a leucocytosis may be pro-
duced. If very large doses are taken the central nervous system
is influenced and convulsions may occur. This is readily demon-
strated by giving rabbits large doses of camphor which acts like a
volatile oil. The harmful effects of absinthe (a volatile oil) are
due to its action on the central nervous system. The continued



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GLYCimONIC ACID



175



use of any volatile oil may lead to fatty degeneration of the liver
and kidneys.

Volatile oils are excreted mainly in combination with glycu-
ronic acid — as glycuronates, but this is not characteristic as many
other substances are excreted in this way.

Substances Excreted Combined with Glycuronic Acid, — ^In ad-
dition to terpenes the following substances, when ingested, may
be excreted as glycuronates:



Isopropyl alcohol Chloral


Methylpropyl


carbinol Butylchloral


Methylhexyl carbinol Bromal


Tertiary butyl alcohol Dichloracetone


Tertiary amyl alcohol


Pinacone




Saccharin




Benzene


Turpentine oil


Nitrobenzene


Camphor


Aniline


Borneol ,


Phenol


Menthol


Resorcinol


Pinene


Thymol


Antipyrine


a-and jS-


Etc.


naphthol





The Significance of Glycuronic Acid in the Urine

In the normal metabolism of glucose, the aldehyde end of the
chain is first oxidized. Glycuronic acid is formed from glucose
by oxidation of the CH2OH end of the chain. It is thought by
some to be formed in small quantities in normal metabolism,
but this does not seem to be correct, since glycuronic acid
administered parenterally appears in the urine quantitatively
(Biberfeld, 1914). Its appearance in the urine following the
administration of drugs indicates a derangement of carbohydrate
metabolism. The formation of the glycuronic acid may be due
primarily to the drug uniting with the aldehyde end of the
chain which prevents its oxidation.

According to their uses in medicine volatile oils may be classi-
fied as:



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176 CHEMICAL PHARMACOLOGY

1. Flavoring agents or carminatives:

Cloves Peppermint

Coriander Rose

Lavender etc.
Lemon

2. Malodorous oils, used mainly for their psychic effect:

Asafcetida
Valerian

3. Genito-urinary disinfectants. All volatile oils are mildly
antiseptic but those especially valuable here are:

Copaiba

Cubebs

Sandalwood.

Tests
Any fixed and volatile oil may be used. Oil of turpentine is'
taken as a representative of the volatile oils and cottonseed as
a type of the fixed oils.

1. Place a drop of each on a piece of glazed paper and note the .
difference.

2. Test the solubility of each in water, alcohol, and acetic
acid, chloroform. Repeat this, using croton or castor oil.

3. Add 1 cc. of oil of turpentine to water in a test tube, shake
and let settle. Draw off the water and note the odor. What are
aquae?

4. Sapoaification. — In an extractor place 200 cc. of cotton-
seed oil and 100 cc. of 10 per cent, alcoholic solution of KOH.
Heat on water bath for 30 minutes, cool and add 15 grams of
NaCl in 50 cc. of water. This converts the soft green soap into
hard soap. Green soap (sapo viridis) was so named because the
vegetable oil from which it was first prepared contained enough
chlorophyll to color it green. Soft soap as now prepared is not
colored green.

5. Heat a little fixed oil with a crystal of KHSO4 in a test
tube over a free flame. Note the odor of acrolein (acer,
sharp and oleum, oil). Repeat, using glycerine instead of oil.

CH2OH.CH2OH.CHOH - H20-^CH2:CHCHO
Glycerine Acraldehyde or acrolein

Fats and oils become rancid on standing, especially when ex-



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STEAROPTENES 177

posed to light, of if there is a small amount of protein present.
For this reason in the preparation of ointments, ,benzoinated
lard, lanolin, or petrolatum is often substituted.

Lanolin or wool fat, C27H45OH, is cholesterol, a monatomic
alcohol obtained from sheep's wool. It resembles fat in appear-
ance and solubility, and does not become rancid, but is expensive.
It is used in plasters and ointments.

The cholesterols are closely related to the terpenes.

STEAROPTENES

Stearoptenes from their pharmacological action may be con-
sidered as solid volatile oils. When volatile oils are allowed to
stand at low temperatures, they separate into two layers. The
top or lighter layer is known as eleoptene and the lower crystal-
line deposit, as stearoptene. The latter is an oxidized product
of the oil. Camphor, menthol, and thymol are the most impor-
tant stearoptenes. Some unimportant stearoptenes are liquid
at ordinary temperature.

Camphora or camphor is a saturated ketone derived from
cinnamomum camphora. It is said to be saturated because it
will not form addition products. It has the formula — CioHieO.
The form of camphor in white masses of crystalline structure
which have the same solubilities as the volatile oils.
GH2 CH CH.2




, CH3
Camphor-menthol of the National Formulary is a solution pro-
duced by triturating equal amounts. of camphor and menthol.
Its uses are as an antiseptic, and as a local anodyne.

Camphor monobromata CioHisBr.O is a substitution product
of camphor. It occurs as prismatic needles or scales, the solu-
bility being the same as camphor. Borneol camphor: CioHieO is



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