9 October 2017

EMA/CHMP/508188/2013
Committee for Human Medicinal Products (CHMP)

Questions and answers on benzyl alcohol used as an

excipient in medicinal products for human use

Draft agreed by Excipients Drafting group 19 November 2013

Adopted by CHMP for release for consultation 23 January 2014

Start of public consultation 24 February 2014

End of consultation (deadline for comments) 31 May 2014

Agreed by Excipients Drafting group 6 October 2014

Adopted by CHMP 23 October 2014

Date of publication 9 October 2017

Keywords Excipients, Package leaflet, Benzyl alcohol

This document should be read in the context of the revision of the Annex of the European Commission
guideline ‘Excipients in the labelling and package leaflet of medicinal products for human use’
(EMA/CHMP/302620/2017) [1].

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Questions and answers on benzyl alcohol used as an
excipient in medicinal products for human use
Table of contents
1. What is benzyl alcohol and why is it used as an excipient? ..................... 3
2. Which medicinal products contain benzyl alcohol? .................................. 3
3. What are the safety concerns? ................................................................ 3
4. What are the reasons for updating the information in the package
leaflet? ........................................................................................................ 4
5. Proposal for an updated information in the package leaflet .................... 5
References .................................................................................................. 7
Annex 1 - Information in the package leaflet as per 2003 Guideline ........... 8

Questions and answers on benzyl alcohol used as an excipient in medicinal products for human use
EMA/CHMP/508188/2013 Page 2/8
1. What is benzyl alcohol and why is it used as an excipient?
Benzyl alcohol is an aromatic alcohol with the formula C 7 H 8 O. In the body, benzyl alcohol is
metabolised into benzoic acid (for more information on benzoic acid see the dedicated questions and
answers document [9]).

It is used as an excipient for its preservative properties, as a solubilising agent or as a fragrance 1

(cutaneous use).

Other use as active ingredient in antiseptic and local anaesthetic products will not be discussed in this
document (not in the scope).

2. Which medicinal products contain benzyl alcohol?

Benzyl alcohol is mainly used as an excipient in medicinal products that are administered
intramuscularly, such as antibiotics, anti-inflammatory or antipsychotic medicines where its anaesthetic
properties reduce pain at the injection site. Benzyl alcohol is also present in medicinal products
administered intravenously (anti-cancer drugs, heparins, cardiovascular drugs). Finally, benzyl alcohol
is used as a preservative in many topical preparations, such as antifungal and anti-inflammatory
products.

3. What are the safety concerns?

The main problem associated with the use of benzyl alcohol is the risk of accumulation in newborn
babies (pre-and full-term) due to metabolic immaturity. Benzyl alcohol administered intravenously in
the range of 100 to 200 mg/kg/day has been linked to the “gasping syndrome” in several pre-term
newborns with metabolic acidosis that resulted in deterioration of the neurological status, cardio-
vascular failure and haematological anomalies [3, 6]. This syndrome is associated with the
accumulation of benzyl alcohol and the majority of poisonings were fatal.

There are no animal toxicological data for parenteral or topical use of benzyl alcohol. However, oral
absorption is close to 100%, hence recommendations for oral use are considered applicable for other
routes of administration. Regarding oral juvenile studies, only one short-term study has been
performed in juvenile rats [5], which established a NOAEL of 300 mg/kg/day which is close to the
adult. There are no juvenile animal toxicity studies related to long-term use.

Based on animal toxicity data, the SFC (Scientific Committee on Food) of the European Commission,
has reviewed the data on benzyl alcohol in 2002 [10] and has added benzyl alcohol to the ADI group of
0-5 mg/kg bw. This position was based on a previous position given by EPA (the US Environmental
Agency) in 1989 [4]. The EPA’s review relied on toxicology studies performed by the NTP published in
1989 [8]. In 2002 the Scientific Committee on Food (SCF) has reviewed the data on benzyl alcohol in
2002. The SCF confirmed the inclusion of benzyl alcohol in the group ADI of 0–5 mg/kg for benzoic
acid and benzoates, as agreed in its previous opinion of 1981. Young children (< 3 years old) may not
be sufficiently mature to metabolize and eliminate benzyl alcohol as efficiently as adults. Therefore the
upper limit of the ADI should be considered with caution in this age group [10].

1
See also ‘Information for the package leaflet for fragrances containing allergens used as excipients in medicinal products
for human use’ (EMA/CHMP/273718/2014).

Questions and answers on benzyl alcohol used as an excipient in medicinal products for human use
EMA/CHMP/508188/2013 Page 3/8
4. What are the reasons for updating the information in the
package leaflet?
The recommendations in the 2003 guideline are incomplete and too strict (see annex 1). While this
excipient should not be used in neonates, it may be used for children aged older than 4 weeks with
caution. In addition, the thresholds needed to be revised.

Questions and answers on benzyl alcohol used as an excipient in medicinal products for human use
EMA/CHMP/508188/2013 Page 4/8
5. Proposal for an updated information in the package leaflet
Name Route of Threshold Information for the Package Leaflet Comments
Administration

Benzyl alcohol All routes of Zero This medicine contains x mg benzyl alcohol in each
administration <dosage unit><unit volume> <which is equivalent
to x mg/<weight><volume>>.

Benzyl alcohol may cause allergic reactions.

Oral, parenteral Zero Benzyl alcohol has been linked with the risk of Intravenous administration of benzyl
severe side effects including breathing problems alcohol has been associated with serious
(called “gasping syndrome”) in young children. adverse events and death in neonates
(“gasping syndrome”). The minimum
Do not give to your newborn baby (up to 4 weeks
amount of benzyl alcohol at which
old), unless recommended by your doctor.
toxicity may occur is not known.

Warning in section 4.4 in the SmPC

should be given if used in neonates.

Do not use for more than a week in young children Increased risk due to accumulation in
(less than 3 years old), unless advised by your young children.
doctor or pharmacist.

Ask your doctor or pharmacist for advice if you are

pregnant or breast feeding. This is because large
amounts of benzyl alcohol can build-up in your body
and may cause side effects (called “metabolic
acidosis”).

Questions and answers on benzyl alcohol used as an excipient in medicinal products for human use
EMA/CHMP/508188/2013 Page 5/8
Name Route of Threshold Information for the Package Leaflet Comments
Administration

Ask your doctor or pharmacist for advice if you have High volumes should be used with
a liver or kidney disease. This is because large caution and only if necessary, especially
amounts of benzyl alcohol can build-up in your body in subjects with liver or kidney
and may cause side effects (called “metabolic impairment because of the risk of
acidosis”). accumulation and toxicity (metabolic
acidosis).

Topical Zero Benzyl alcohol may cause mild local irritation.

Further scientific background is available in the report entitled ‘Benzyl alcohol and benzoic acid group used as excipients’ [2].

Questions and answers on benzyl alcohol used as an excipient in medicinal products for human use
EMA/CHMP/508188/2013 Page 6/8
References
1. Annex of European Commission guideline ‘Excipients in the labelling and package leaflet of
medicinal products for human use’ (EMA/CHMP/302620/2017).

2. Benzyl alcohol and benzoic acid group used as excipients (EMA/CHMP/272866/2013).

3. Brown, W.J., Buist, N.R., Gipson, H.T., Huston, R.K., Kennaway, N.G., ‘Fatal benzyl alcohol
poisoning in a neonatal intensive care unit’, Lancet, Vol. 1(8283), 1982, p. 1250.

4. EPA (Environmental Protection Agency), Health and environmental effects document for benzyl
alcohol, September 1989.

5. Foulon, O., Mungapen, L., Gaoua, W., Forster R., ‘Benzyl alcohol: safety assessment in
juvenile rats’, The Toxicologist, Volume 84: S-1, Abstracts of the 44th annual Meeting &
Toxexpo, New Orleans, Abstract 265, March 2005.

6. Gershanik, J., Boecler, B., Ensley, H., McCloskey, S., George, W., ‘The gasping syndrome and
benzyl alcohol poisoning’, N Engl J Med., Vol 307(22), 1982, p. 1384–1388.

7. Guideline on excipients in the label and package leaflet of medicinal products for human use
(CPMP/463/00 Rev.1), July 2003.

8. NTP (National Toxicology Program), Technical report on the toxicology and carcinogenesis
studies of benzyl alcohol (CAS No. 100-51-6) in F344/n rats and B6C3F1 mice (gavage
studies), 1989.

9. Questions and answers on benzoic acid and benzoates used as excipients in medicinal
products for human use (EMA/CHMP/508188/2013).

10. SCF (Scientific Committee on Food) 2002, Opinion of the Scientific Committee on Food on
Benzyl alcohol, 2002. Available at: http://ec.europa.eu/food/fs/sc/scf/out138_en.pdf

Questions and answers on benzyl alcohol used as an excipient in medicinal products for human use
EMA/CHMP/508188/2013 Page 7/8
Annex 1 - Information in the package leaflet as per 2003 Guideline [7]

Name Route of Threshold Information for the Package Leaflet Comments

Administration

Benzyl alcohol Parenteral Exposures less Must not be given to premature babies or neonates. SPC: ‘allergic’ should be
than 90 mg/kg/day expressed as ‘anaphylactoid’
May cause toxic reactions and allergic reactions in
infants and children up to 3 years old. The amount of benzyl
alcohol in mg per <volume>
should be stated in the
package leaflet and SPC.

90 mg/kg/day Must not be given to premature babies or neonates. The amount of benzyl
alcohol per <volume>
Due to the risk of fatal toxic reactions arising from
should be stated in the
exposure to benzyl alcohol in excess of 90 mg/kg/day,
package leaflet and SPC.
this product should not be used in infants and children
up to 3 years old.

Questions and answers on benzyl alcohol used as an excipient in medicinal products for human use
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