Monograph: |
Benzyl Alcohol
A clear, colourless, oily, refractive liquid with a slightly aro-
fnatic odour. Soluble or sparingly soluble in water: freely sol-
uble in alcohol (50%); miscible with alcohol, chloroform.
pther, and fatty and essential oils. It is neutral to litmus.
penzyl alcohol oxidises to produce benzaldehyde and benzoi
c acid and oxidation may take place slowly on exposure to
lir. Benzaldehyde may also be produced on autoclaving. The
ph. Eur. has a limit of not more than 0.05% of benzaldehyde
ind 0.1% of other related substances for benzyl alcohol in-
ended for use in the manufacture of a parenteral dosage form.
Β»tore in completely filled airtight containers and prevent ex-
iosure to excessive heat. Protect from light. Benzyl alcohol is
incompatible with oxidising agents and strong acids. The ant-
imicrobial activity may be reduced by nonionic surfactants
and benzyl alcohol may be lost from solutions stored in poly-
ethylene containers.
Adverse Effects and Precautions
There have been a few reports of hypersensitivity re-
actions to benzyl alcohol when used as a preserva-
ive.
The pure alcohol is irritant and requires handling
with care; ingestion or inhalation can cause nausea.
/vomiting, diarrhoea, headache, vertigo, and CNS
depression. However, concentrations of benzyl aleo-
iol normally used for preservation are not associat-
ed with such effects.
There have been some instances of neurotoxic ef-
fects in patients given intrathecal injections that
contained benzyl alcohol.
A fatal toxic syndrome in premature infants was at-
ributed to benzyl alcohol present as a preservative
in solutions used to flush intravenous catheters. This
has led to restriction on the use of benzyl alcohol in
neonates. see below.
effects on the lungs. Severe bronchitis and haemoptysis
was reported in a patient with obstructive pulmonary disease
who, over a period of 2 years, had inhaled salbutamol nebulis-
er solution diluted with a bacteriostatic sodium chloride solu-
tion containing benzyl alcohol.'
effects on the nervous system. Rapid development of
flaccid areflexic paraplegia, total anaesthesia below the groin.
[nd radicular abdominal pain occurred in a 64-year-old man
following a lumbar intrathecal injection of cytarabine which
contained 1.5% benzyl alcohol.' The patient recovered fully
after 100 mL of CSF was replaced with sodium chloride in-
jection (0.9%) and 40 mg of methylprednisolone. Intrathecal
lections of cytarabine dissolved in sterile distilled water he-
ore and after the episode of paraplegia caused no neurologic
symptoms. On reviewing 20 other cases of paraparesis asso-
ciated with methotrexate or cytarabine intrathecal injections.
benzyl alcohol had been used as a preservative in 7. Of the 7,
4 developed neurotoxicity immediately, in the other 3 it did
not develop until 6 to 48 hours after administration. The du-
ration varied. One patient did not improve, one made a partial
recovery, a third took 6 weeks lo recover, another took 5 days;
yet 2 patients recovered within I 'A to 2'~ hours while the
final patient experienced only transient effects.
Hypersensitivity. Some reports of hypersensitivity reac-
tions to benzyl alcohol.
Neonates. During 1981 and 1982 reports were published
from 2 centres in the USA of 20 deaths in low-birth-weight
neonates attributed to the use of benzyl alcohol as a preserv-
ative in solutions used to flush their umbilical catheters and
in
some cases also to dilute their medication. The neonates suf-
fered a toxic syndrome whose features included metabolic ac-
idosis. symptoms of progressive encephalopathy. intracranial
haemorrhage, and respiratory depression with gasping.
These deaths prompted the FDA* to recommend that benzyl
alcohol should not be used in such flushing solutions: sodium
chloride injection (0.9%) without preservative should be used
instead. The PDA had also advised against the use of benzyl
alcohol or any preservative in fluids being used for the dilu-
tion or reconstitution of medicines for the newborn.
Those reporting the deaths' considered that the toxic syn-
drome could have been caused by the accumulation of the
benzoic acid metabolite of benzyl alcohol, which could not be
handled effectively by the immature liver: given the very low
weight of the neonates they would have been receiving a high
dose of benzyl alcohol. In commenting on the problem, the
American Academy of Pediatrics' agreed that the FDA's
warning was warranted, but pointed out that there was no ev-
idence from controlled studies to confirm that benzyl alcohol
was responsible.
Pharmacokinetics
Benzyl aicohol is meiabolised to benzoic acid. This
is conjugated with glycine in the liver to form hippu-
ric acid which is excreted in the urine. Benzalde-
hyde and benzoic acid are degradation products in
vitro.
Uses
Benzyl alcohol is used as an antimicrobial preserva-
tive. It is bacteriostatic mainly against Gram-posi-
tive organisms and some fungi. It is used in a range
of pharmaceutical preparations in concentrations up
to 2%. Concentrations of 5% or more are employed
when it is used as a solubiliser. Benzyl alcohol is
also used as a preservative in foods and cosmetics.
In addition to its antiseptic properties, diluted ben-
zyl alcohol possesses weak local anaesthetic and an-
tipruritic activity and this is the reason for its
inclusion in some preparations.
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