Opinion on Benzyl Salicylate (CAS No. 118-58-1, EC No. 204-262-9).
Date: 2024-07-26
Institutions: Directorate-General for Health and Food Safety
Subjects: chemical product, chemicals legislation, consumer protection, cosmetic product, endocrine disruptor, environmental impact, health risk, research, safety standard, scientific report, toxic substance

SCCS/1656/23 
Final Opinion 

Scientific Committee on Consumer Safety 

SCCS 

OPINION on 

Benzyl Salicylate 

 (CAS No. 118-58-1, EC No. 204-262-9) 

The SCCS adopted this document 
during the plenary meeting on 26 October 2023 

 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Opinion on Benzyl Salicylate (CAS No. 118-58-1, EC No. 204-262-9) 
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SCCS/1656/23 
Final Opinion 

ACKNOWLEDGMENTS 

SCCS  members  listed  below  are  acknowledged  for  their  valuable  contribution  to  the 
finalisation of this Opinion. 

For the preliminary and for the final version of the Opinion 

SCCS members   
Dr U. Bernauer   
Dr L. Bodin  
Prof. Q. Chaudhry 
Prof. P.J. Coenraads 
Prof. M. Dusinska 
Dr J. Ezendam 
Dr E. Gaffet 
Prof. C. L. Galli 
Dr B. Granum 
Prof. E. Panteri   
Prof. V. Rogiers   
Dr Ch. Rousselle  
Dr M. Stepnik  
Prof. T. Vanhaecke  
Dr S. Wijnhoven  

SCCS external experts 
Dr. E. Benfenati 
Dr N. Cabaton    
Prof. E. Corsini 
Dr A. Koutsodimou 
Dr. H. Louro 
Prof. W. Uter 
Dr N. von Goetz  

(SCCS Chair) 
(SCCS Vice-Chair, Chairperson of the WG)  

(SCCS Vice-Chair) 
(Rapporteur) 

(Rapporteur) 

This Opinion has been subject to a commenting period of min eight weeks after its initial 
publication (from 13 June to 24 August 2023). Comments received during this period were 
considered by the SCCS. For this Opinion, main changes occurred in the following sections: 
3.2.1.1 SCCS comment, 3.3.2.2. SCCS comment, SCCS comments under Table 10 and 
Table 11, SCCS conclusion on endocrine activity, 3.5 safety evaluation, as well as special 
investigation and safety evaluation under discussion section.  

All Declarations of Working Group members are available on the following webpage: 
Register of Commission expert groups and other similar entities (europa.eu)  

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1.  ABSTRACT  

The SCCS concludes the following: 

(1) 

In light of the data provided and taking under consideration the concerns related to 
potential endocrine disrupting properties of Benzyl Salicylate, does the SCCS consider 
Benzyl Salicylate safe when used up to the maximum concentrations provided in the 
dossier submission by the Benzyl Salicylate Consortium? 

Based on the assessment of data provided and taking under consideration the concerns 
related  to  potential  endocrine  disrupting  properties,  the  SCCS  considers  Benzyl 
Salicylate safe when used up to the maximum concentrations as provided in Table 1 
of this Opinion. 

(2) 

Alternatively, what is according to the SCCS the maximum concentration considered 
safe for use of Benzyl Salicylate in cosmetic products?  

/ 

(3) 

Does the SCCS have any further scientific concerns with regard to the use of Benzyl 
Salicylate in cosmetic products?  

The available data on Benzyl Salicylate provide some indications for an endocrine mode 
of action, but there is no evidence to suggest that this results in endocrine effects.  

The  SCCS  mandates  do  not  address  environmental  aspects.  Therefore,  this 
assessment did not cover the safety of Benzyl Salicylate for the environment. 

Keywords: SCCS, scientific opinion, Benzyl Salicylate, Regulation 1223/2009, CAS No. 118-
58-1, EC No. 204-262-9 

Opinion to be cited as: SCCS (Scientific Committee on Consumer Safety), Opinion on Benzyl 
Salicylate (CAS No. 118-58-1, EC No. 204-262-9), preliminary version of 6-7 June 2023, final 
version of 26 October 2023, SCCS/1656/23 

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Opinion on Benzyl Salicylate (CAS No. 118-58-1, EC No. 204-262-9) 
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About the Scientific Committees 
Two independent non-food Scientific Committees provide the Commission with the scientific 
advice it needs when preparing policy and proposals relating to consumer safety, public health 
and the environment. The Committees also draw the Commission's attention to the new or 
emerging problems, which may pose an actual or potential threat. 
These  Committees  are:  the  Scientific  Committee  on  Consumer  Safety  (SCCS)  and  the 
Scientific Committee on Health, Environmental and Emerging Risks (SCHEER) and they are 
made up of scientists appointed in their personal capacity. 

In  addition,  the  Commission  relies  upon  the  work  of  the  European  Food  Safety  Authority 
(EFSA), the European Medicines Agency (EMA), the European Centre for Disease prevention 
and Control (ECDC) and the European Chemicals Agency (ECHA). 

SCCS 
The  Committee  shall  provide  Opinions  on  questions  concerning  health  and  safety  risks 
(notably  chemical,  biological,  mechanical  and  other  physical  risks)  of  non-food  consumer 
products  (for  example  cosmetic  products  and  their  ingredients,  toys,  textiles,  clothing, 
personal care and household products such as detergents, etc.) and services (for example: 
tattooing, artificial sun tanning, etc.). 

Scientific Committee members 
Ulrike  Bernauer,  Laurent  Bodin,  Qasim  Chaudhry,  Pieter  Jan  Coenraads,  Maria  Dusinska, 
Janine Ezendam, Eric Gaffet, Corrado Lodovico Galli, Eirini Panteri, Vera Rogiers, Christophe 
Rousselle, Maciej Stepnik, Tamara Vanhaecke, Susan Wijnhoven 

Contact 
European Commission 
Health and Food Safety 
Directorate B: Public Health, Cancer and Health security 
Unit B3: Health monitoring and cooperation, Health networks 
L-2920 Luxembourg
SANTE-SCCS@ec.europa.eu
© European Union, 2024 

PDF   ISSN 1831-4767    ISBN 978-92-68-19384-6     doi:10.2875/160899     EW-AQ-24-001-EN-N

The opinions of the Scientific Committees present the views of the independent scientists who 
are members of the committees. They do not necessarily reflect the views of the European 
Commission.  The  opinions  are  published  by  the  European  Commission  in  their  original 
language only. 

SCCS - Opinions (europa.eu) 

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Final Opinion 

TABLE OF CONTENTS 

ACKNOWLEDGMENTS .......................................................................................................... 2 

1. 

2. 

3. 

ABSTRACT ................................................................................................................ 3 

MANDATE FROM THE EUROPEAN COMMISSION.............................................................. 6 

OPINION ................................................................................................................... 8 

3.1 

CHEMICAL AND PHYSICAL SPECIFICATIONS ........................................................ 8 

3.1.1 Chemical identity .............................................................................................. 8 
3.1.2 Physical form.................................................................................................... 8 
3.1.3 Molecular weight ............................................................................................... 9 
3.1.4 Purity, composition and substance codes ............................................................. 9 
3.1.5 Impurities / accompanying contaminants ............................................................. 9 
3.1.6 Solubility 9 
3.1.7 Partition coefficient (Log Pow) .............................................................................. 9 
3.1.8 Additional physical and chemical specifications ..................................................... 9 
3.1.9 Homogeneity and Stability ............................................................................... 10 
TOXICOKINETICS ............................................................................................ 10 

3.2 

3.2.1 Dermal / percutaneous absorption .................................................................... 10 
3.2.2 Other studies on Toxicokinetics ......................................................................... 17 
3.2.2.1 Oral absorption, distribution, metabolism, excretion and kinetics ............................... 17 

3.2.2.2 Inhalation absorption, distribution, metabolism, excretion and kinetics ....................... 19 

3.3 

EXPOSURE ASSESSMENT .................................................................................. 19 

3.3.1 Function and uses ........................................................................................... 19 
3.3.2 Calculation of SED/LED .................................................................................... 19 
TOXICOLOGICAL EVALUATION .......................................................................... 28 

3.4 

3.4.1. Irritation and corrosivity ................................................................................. 28 
3.4.2 Skin sensitisation ............................................................................................ 32 
3.4.3 Acute toxicity ................................................................................................. 38 
3.4.4 Repeated dose toxicity .................................................................................... 39 
3.4.5 Reproductive toxicity ....................................................................................... 41 
3.4.6 Mutagenicity / genotoxicity .............................................................................. 45 
3.4.7 Carcinogenicity ............................................................................................... 52 
3.4.8 Photo-induced toxicity ..................................................................................... 52 
3.4.9 Special investigations / Endocrine Activity .......................................................... 54 
SAFETY EVALUATION (INCLUDING CALCULATION OF THE MOS) ............................ 57 

DISCUSSION ................................................................................................... 59 

CONCLUSION ........................................................................................................... 62 

MINORITY OPINION ................................................................................................... 62 

REFERENCES ............................................................................................................ 63 

GLOSSARY OF TERMS ................................................................................................ 69 

LIST OF ABBREVIATIONS ........................................................................................... 69 

3.5 

3.6 

4. 

5. 

6. 

7. 

8. 

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2.  MANDATE FROM THE EUROPEAN COMMISSION  

Background on substances with endocrine disrupting properties 

On 7 November 2018, the Commission adopted the review1 of Regulation (EC) No 1223/2009 
on cosmetic products (‘Cosmetics Regulation’) regarding substances with endocrine disrupting 
(ED) properties. The review concluded that the Cosmetics Regulation provides the adequate 
tools  to  regulate  the  use  of  cosmetic  substances  that  present  a  potential  risk  for  human 
health, including when displaying ED properties. 
The Cosmetics Regulation does not have explicit provisions on EDs. However, it provides a 
regulatory  framework  with  a  view  to  ensuring  a  high  level  of  protection  of  human  health. 
Environmental concerns that substances used in cosmetic products may raise are considered 
through the application of Regulation (EC) No 1907/2006 (‘REACH Regulation’).  
In  the  review,  the  Commission  commits  to  establishing  a  priority  list  of  potential  EDs  not 
already  covered  by  bans  or  restrictions  in  the  Cosmetics  Regulation  for  their  subsequent 
safety assessment. A priority list of 28 potential EDs in cosmetics was consolidated in early 
2019 based on input provided through a stakeholder consultation. The Commission carried 
out  a  public  call  for  data2  in  2019  on  143  of  the  28  substances  (to  be  treated  with  higher 
priority-Group  A  substances)  in  preparation  of  the  safety  assessment  of  these  substances. 
Benzyl Salicylate is one of the above-mentioned 14 substances for which the call for data took 
place. 

Background on Benzyl Salicylate 

Benzyl  Salicylate  (CAS  No.  118-58-1,  EC  No.  204-262-9)  with  the  chemical  name  ‘2-
hydroxybenzoic acid phenylmethyl ester’ is produced naturally in a variety of plants and plant 
extracts where it can be extracted. In addition, Benzyl Salicylate can be synthesised for use, 
typically as a fragrance ingredient, in a range of manufactured goods (cosmetics, household 
goods  and  medicines).  In  cosmetics,  Benzyl  Salicylate  is  used  for  its  fragrance/perfuming 
function.  

Benzyl  Salicylate  was  assessed  by  the  SCCNFP  in  19994  and  by  SCCS  in  20125  and  it  is 
considered as an established contact allergen in humans. It is currently regulated for labelling 
purposes as an allergen in entry 75 of Annex III to the Cosmetics Regulation. In particular, 
“its  presence  must  be  indicated  in  the  list  of  ingredients  when  its  concentration  exceeds 
0.001% in leave-on products and 0.01% in rinse-off products”. 
During the call for data, stakeholders submitted scientific evidence to demonstrate the safety 
of Benzyl Salicylate as a fragrance ingredient in cosmetic products. The Commission requests 
the SCCS to carry  out  a safety assessment on  Benzyl Salicylate in view  of the information 
provided, taking into account the maximum concentration of Benzyl Salicylate in the different 
categories of cosmetic products listed in the table below:  

1 https://ec.europa.eu/transparency/regdoc/rep/1/2018/EN/COM-2018-739-F1-EN-MAIN-PART-1.PDF 
2https://ec.europa.eu/growth/content/call-data-ingredients-potential-endocrine-disrupting-properties-used-
cosmetic%20products_en   
3 Benzophenone-3, kojic acid, 4-methylbenzylidene camphor, propylparaben, triclosan, Homosalate, octocrylene,  
triclocarban, butylated hydroxytoluene (BHT), benzophenone, homosalate, benzyl salicylate, genistein and daidzein 
4 https://ec.europa.eu/health/archive/ph_risk/committees/sccp/documents/out98_en.pdf 
5 https://ec.europa.eu/health/scientific_committees/consumer_safety/docs/sccs_o_102.pdf  
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Table 1: Maximum use concentrations of Benzyl Salicylate in cosmetic products 

Type of cosmetic product exposure 

Maximum % 
concentration 
used 

Hydroalcoholic-based fragrances (spray and non-spray) 

Rinse-off skin & hair products (except rinse off body products) 

Rinse off body products 

Leave on skin & hair products (non-spray/non-aerosol)(except body 
lotion) 

Leave on hair products (spray/aerosol) 

Leave on body products (non-spray/spray/aerosol) 

Face make-up products and make-up remover 

Oral care 

Deodorant products (spray/aerosol) 

4 

0.5 

1.3 

0.5 

0.5 

0.7 

0.2 

0.004 

0.91 

Terms of reference 

1.  In light of the data provided and taking under consideration the concerns related to 
potential endocrine disrupting properties of Benzyl Salicylate, does the SCCS consider 
Benzyl Salicylate safe when used up to the maximum concentrations provided in the 
dossier submission by the Benzyl Salicylate Consortium? 

2.  Alternatively, what is according to the SCCS the maximum concentration considered 

safe for use of Benzyl Salicylate in cosmetic products?  

3.  Does the SCCS have any further scientific concerns with regard to the use of Benzyl 

Salicylate in cosmetic products?  

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3.  OPINION 

3.1 

CHEMICAL AND PHYSICAL SPECIFICATIONS 

3.1.1 Chemical identity 

3.1.1.1 Primary name and/or INCI name 

Benzyl Salicylate 

3.1.1.2 Chemical names 

IUPAC: benzyl 2-hydroxybenzoate 

Synonyms: salicylic acid benzyl ester; 2-Hydroxybenzoic acid phenylmethyl ester; 
phenylmethyl 2-hydroxybenzoate; Benzyl o-hydroxybenzoate; Salicylic acid, benzylester;) 

3.1.1.3 Trade names and abbreviations 

Benzyl 2-hydroxybenzoate 
Benzyl o-hydroxybenzoate 
Benzyl Salicylate 

Ref: ECHA: https://echa.europa.eu/el/substance-information/-/substanceinfo/100.003.876 

3.1.1.4 CAS / EC number 

CAS number:   118-58-1 
EC number: 

 204-262-9 

3.1.1.5 Structural formula 

The chemical structure of Benzyl Salicylate is shown in Figure 1  

Figure 1. Chemical structure of Benzyl Salicylate  

3.1.1.6 Empirical formula 

Empirical formula: C4H12O3 

3.1.2 Physical form 

Thick, colourless to pale yellow liquid. 

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Ref: 2021-11-18 SCCS Benzyl Salicylate Dossier_FINAL 

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3.1.3 Molecular weight 

228.25 g/mol 

3.1.4 Purity, composition and substance codes  

> 99% 

SCCS comment 
A full report of the chemical characterisation of Benzyl Salicylate in terms of purity and identity 
in representative batches should be provided and the validity of the analytical methodologies 
used should be shown. 

3.1.5 Impurities / accompanying contaminants 

/ 

SCCS comment   
A full report on the impurity tests in representative batches of the test substance should be 
provided  and  the  validity  of  the  analytical  methodologies  used  shown.  Identity  and 
concentration of any impurities that may be present should also be stated. 

3.1.6 Solubility 

Slightly soluble in water (8.8 mg/L at 20 °C). Soluble in organic solvents and oils. 

3.1.7 Partition coefficient (Log Pow) 

4.31 at 35 °C 

3.1.8 Additional physical and chemical specifications 

Where relevant: 

- 

- 
- 
- 
- 
- 
- 
- 
- 
- 
- 

organoleptic properties: Benzyl Salicylate has a faint, sweet odour. 

melting point: 24 °C 
boiling point: 320 °C 
flash point: / 
vapour pressure: 7.8 x 10-5 mmHg at 25 °C; 0.0104 Pa at 25 °C (ECHA, 2020) 
density: / 
viscosity: / 
pKa: 9.82 
pH: 6.8-7.1 
refractive index: / 
UV/visible light absorption spectrum: / 

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3.1.9 Homogeneity and Stability 

Stable  under  recommended  storage  conditions.  Predicted  to  be  stable  in  most  organic 
solvents. 

SCCS comment 
Data on the stability of the test substance under the experimental conditions of the reported 
studies and under conditions of use, and information on any hydrolysis products,  should be 
provided. 

3.2 

TOXICOKINETICS 

3.2.1 Dermal / percutaneous absorption 

3.2.1.1  In vitro human skin absorption studies 

Two  studies  have  been  used  to  investigate  absorption  of  Benzyl  Salicylate  in  vitro  using 
human skin: Jimbo (1983) and a new OECD Test Guideline 428 study (BASF, Oct 2021). 

The skin absorption of Benzyl Salicylate through human epidermis was studied in vitro using 
a static cell glass chamber (Jimbo, 1983). The experiment was repeated six times. 0.2 mL of 
Benzyl Salicylate was applied neat to the skin. The upper  surface  of human epidermis was 
fixed  to  a  glass  tube  which  was  then  placed  inside  one  arm  of  a  U-shaped  glass  chamber. 
0.5 mL  saline  was  in  contact  with  the  underside  of  the  epidermis.  Parafilm  was  applied  to 
occlude the skin. The chamber was kept at 21°C and 55% relative humidity for 72 h. Material 
that  had  penetrated  into  the  receptor  fluid  was  extracted  in  ether  and  analysed  by  gas 
chromatography. The amount of Benzyl Salicylate that penetrated human skin in this study 
was  minimal;  the  percent  penetration±S.E.  through  excised  human  skin  was  0.031%  ± 
0.004%.  This  study  did  not  meet  the  basic  criteria  for  skin  absorption  in  SCCS  Notes  of 
Guidance (2021) and therefore a new study was performed using human skin in vitro. 

An  OECD  Test  Guideline  428  skin  absorption  study  was  performed  (BASF,  Oct  2021).  In 
preparation, prior to the performance of the main study, a stability study was performed that 
showed  5  mg/g  (0.5%  w/w)  of  Benzyl  Salicylate  was  homogenously  formulated  and  was 
stable in a representative blank (i.e without Benzyl Salicylate) body lotion formulation for at 
least 24 hours at 32°C. Benzyl Salicylate was also stable in receptor fluid (physiological saline 
with 5% bovine serum albumin (BSA)) for 24 hours at target concentrations of 0.09 mg/mL 
and  0.01  μg/mL  at  32°C.  The  solubility  of  the  test-substance  in  the  receptor  fluid  was 
determined to be 0.91 mg/mL. 

[14C]-Benzyl  Salicylate  was  applied  to  n=12  human  skin  samples  (previously  frozen  and 
dermatomed, from 4 donors) at a target dose of 10 μg/cm2 (actual 9.5 μg/cm2) in application 
of  representative body  lotion formulation at 2 mg/cm2 in Franz-type diffusion  cells in  flow-
through  mode  (surface  skin  area  approximately  1cm2),  using  receptor  fluid  (physiological 
saline with 5% BSA and 0.01% (w/v) sodium azide (NaN3)). The integrity of the skin barrier 
was  checked  via  TEER  (impedance  value).  A  summary  of  the  mean  recoveries  and  kinetic 
parameters from this study is shown in Table 2. 

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Table  2:  Mean  recoveries  and  kinetic  parameters  for  skin  penetration  of  [14C]-Benzyl 
Salicylate as applied to human skin in vitro (BASF, Oct 2021) 

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Final Opinion 

N.B. Mean values were  calculated from  cells 1-7 and 9-11. Cells 8 and 12 were  excluded 
from statistics due to failed application (resulting in invalid recoveries that were calculated 
to be >120%). 

The majority of the applied test substance was recovered as dislodgeable, calculated as the 
sum of skin wash and donor chamber washing (85.11 ± 3.10%). The amount associated to 
tape  strips  resulted  in  1.11  ±  0.87%  of  the  applied  dose.  Minor  amounts  of  the  test 
substance were associated with the skin after the exposure period. This amount accounted 
to 1.64 ± 0.79% of the applied dose. The recovery from the sum of absorbed dose and dose 
associated to remaining skin was 9.01 ± 1.46% of applied dose. The mean total recovery 
fulfilled  the  quality  criteria  put  forward  in  the  test  guidelines,  resulting  in  a  mean  total 
recovery of 95.23 ± 2.02 %. A value for skin absorption can be calculated from this study 
using the mean + 1SD i.e. 9 + 1.5 = 10.5% 

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SCCS comment 
The results of the skin penetration study are based on radiolabelled compound ([14C] on one 
of the benzyl rings) and as such it is not clear whether the amounts measured were for the 
intact compound or a breakdown product. This needs to be clarified. Apart from this, the study 
was well performed and follows the OECD 428 guidance and the SCCS basic criteria for skin 
penetration study (SCCS/1358/10). Assuming the amounts measured were for the worst case 
that  included  intact  substance  as  well  as  breakdown  products  (salicylic  acid),  the  value  of 
mean+1SD i.e. 9±1.5 = 10.5% can be used for the MoS calculation.  

3.2.1.2  In vitro animal skin absorption studies 

Studies that have been used to investigate skin absorption of Benzyl Salicylate in vitro using 
animal skin are summarised in Table 3. There are two studies performed at Hoffmann LaRoche 
laboratories  from  1983  and  1984,  including  data  for  rat  and  pig  skin,  respectively.  These 
experiments used radiolabelled 14C-Benzyl Salicylate in a static cell system with physiological 
saline as receptor fluid. These studies show that as expected, the skin absorption through pig 
skin (which is most like human skin) is much less than is observed with naked rat skin (Figure 
2).  As  outlined  in  the  SCCS  document  ‘Basic  criteria  for  the  in  vitro  assessment  of  dermal 
absorption  of  cosmetic  ingredients’  (SCCS/1358/10),  rat  skin  is  not  recommended  for  skin 
absorption studies given that rat skin is more permeable than human skin (mean difference 
about  10-fold)  (van  Ravenzwaay  and  Leibold,  2004),  whereas  pig  skin  is  regarded  as  a 
suitable surrogate for human skin. Hence, the greatest weight in these available animal skin 
absorption studies should be given to the pig skin data. 

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Table 3: Summary of observations for Benzyl Salicylate from in vitro skin absorption studies 
using animal skin 

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The extent of skin penetration into receptor fluid was dependent upon the application dose, 
time of application and the species of skin used (Figure 2). 

Figure 2. The skin absorption profile for a) naked shaved rat skin and b) intact pig skin over 
time, when a 10% dose of Benzyl Salicylate is applied for 1, 6, 16 (rat and pig) or 24h (rat 
only). (Hoffmann LaRoche study 1984) 

Taking the pig skin data (Hoffmann LaRoche, 1984) as the most relevant for human exposure, 
more than 85% of the applied dose is removable from the surface of pig skin at all time points 
and  all  dose  levels.  The  material  removed  and  that  in  the  stratum  corneum  are  not 
bioavailable, and are not considered as ‘absorbed’. The material measured within the skin and 
in  receptor  fluid  is  considered  as  absorbed  and  bioavailable.  For  the  three  doses  tested  at 
16h, the % absorbed is 8.2, 5.8 and 4.7%, respectively. 

A conservative skin absorption value of 10% is supportable from the in vitro pig skin study to 
account  for  the  study  duration  only  being  16h  and  not  the  usual  24h.  No  metabolism  or 
speciation  was  investigated  in  these  studies,  these  data  are  for  total  radioactive  counts 
therefore there is no underestimation, although, it is not  known what proportion  of  Benzyl 
Salicylate has been metabolised in the skin by esterases to benzyl alcohol and salicylic acid. 

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3.2.1.3  In vivo human skin absorption/kinetics studies 

A  study  where  100  μL  neat  Benzyl  Salicylate  was  applied  to  skin  in  humans,  and 
measurements made in urine, is summarised in Table 4. 

Table 4: Summary of observations in urine from in vivo skin absorption/kinetics studies in 
humans 

James et al. (2019) developed a new GC-MS based bioanalytical method for the detection of 
parent unmetabolized methyl salicylate and Benzyl Salicylate and applied it to analyse urine 
following human skin application (James et al., 2020). 

Six participants (n =3 female, n = 3 male; age range 22-44 years, median age 27.5 years) 
participated in the trial during April 2018. All participants were healthy and were instructed 
to avoid foodstuffs suspected to contain methyl salicylate and cosmetic  products suspected 
to contain Benzyl Salicylate for 24 hours before and after the study during the urine collection 
period. 

Participants provided a baseline urine sample ten minutes prior to the start of the study. Test 
material was pipetted (100μl of each simulant) onto the upturned forearm of each participant; 
Benzyl Salicylate was applied to the right forearm while the methyl salicylate was applied to 
the  left  forearm.  The  simulant  was  applied  as  a  long  droplet  (~10cm).  Participants  were 
instructed to stay as still as possible to avoid simulant run-off until the simulant had dried. 

At 60 minutes, the first of eight post-application urine samples were collected. Over the next 
24 hours, urine samples were collected from each participant (at 2-hour, 4-hour, 6-hour, 8-
hour, 12.5-hour, 21-hour, and 24-hour post-dose). Urine samples were returned shortly after 
24 hours by all participants. 

All 54 urine samples collected during the study contained detectable levels of methyl salicylate 
and  Benzyl  Salicylate  above  the  assay  limits  of  quantification  (4.6 ng/mL).  Recoveries  are 
given as total Benzyl Salicylate excreted (μg) per urine sample provided. Baseline recoveries 
ranged between 8μg and 34μg (concentrations 257.5 ng/mL – 370.3 ng/ml non-normalized) 
with an average recovery of 21μg. The peak excretion of Benzyl Salicylate occurred in the 21-
hour sample (Figure 3), with the highest value being 557 μg. Samples taken at 12.5 hours 
and 21 hours were both significantly higher than baseline levels (P < 0.0001). Cumulative 
excretion of Benzyl Salicylate over 24 hours ranged between 773 μg and 1430 μg. 

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Figure  3.  a)  Total  measured  excretion  and  b)  cumulative  excretion  over  24  h  of  Benzyl 
Salicylate in urine for all n=6 participants. Note: Values given have been normalized against 
total volume of  each urination. 12.5-hour and  22-hour samples are the average values for 
urine collected before and after bed. Box and whisker plot shows the median and inter-quartile 
range, together with the maximum and minimum values. * = P <.0001 compared to baseline. 
Abbreviation: BeS, Benzyl Salicylate. (As appears in James et al., 2020) 

No significant increase in excreted Benzyl Salicylate levels was observed compared to baseline 
until four hours, when all participants’ urinary Benzyl Salicylate levels increased (Figure 3). 
Levels of Benzyl Salicylate slowly increased between four hours and 12.5 hours, followed by 
a large increase overnight and into the post-sleep sample (21 hours) for all participants before 
dropping  to  near  baseline  levels  at  the  24-hour  mark.  Benzyl  Salicylate  was  detectable  in 
urine after skin exposure, with reproducible values across the 24 hours for all six participants 
and cleared effectively within 24 hours. 

No metabolism was accounted for in this study, as the authors were looking for detectable 
Benzyl  Salicylate  as  a  qualitative  marker  substance  only  rather  than  considering  total 
absorption, and it is likely that some absorption of benzyl alcohol and salicylic acid as the first 
pass primary metabolites via the skin would also have occurred and was not measured using 
this method. 

SCCS comment 
This study is of limited  use as only the parent  compound  Benzyl Salicylate  was measured, 
without measuring any metabolites, although it is well known that Benzyl Salicylate will be 
rapidly and extensively metabolised once absorbed by any route of exposure.  

3.2.1.4  In vivo animal skin absorption studies 

/ 

3.2.1.5  Dermal Metabolism data 

It is expected that Benzyl Salicylate, once absorbed by any route of exposure, will be rapidly 
and extensively metabolised by ubiquitous carboxylesterases in vivo (Williams 1985; Oesch 
et  al.,  2018),  thus,  only  salicylic  acid  and  benzyl  alcohol  will  be  systemically  available. 
Generally, skin esterase activity was shown to be predominantly localized in the  epidermis 
and  near  hair  follicles  (using  fluorescein-  5-isothiocyanate  diacetate  as  substrate) 
(Sugibayashi et al., 1999). As was seen above in the James  et al., 2020 study, a very low 
level of parent Benzyl Salicylate (<1.5%) is excreted in urine after a ~100 mg dermal dose. 
Benzyl Salicylate itself is not regarded as the main toxicant in animal toxicology studies, but 
salicylic acid as the chief hydrolysis product (Belsito et al., 2007). 

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Conclusion from the Applicant on skin absorption: 
Data from an OECD Test guideline 428 skin absorption study performed to GLP (BASF, Oct 
2021)  indicates  that  a  value  of  10.5%  absorption  can  be  used  in  the  safety  evaluation  for 
Benzyl  Salicylate.  It  is  expected  that  the  majority  of  systemic  exposure  is  in  the  forms  of 
salicylic acid and benzyl alcohol. Subsequent phase 2 conjugation of both leads to effective 
clearance. 

SCCS overall comment on skin absorption 
A value of 10.5% was calculated following a recent in vitro study using human skin that meets 
the basic criteria for skin absorption in SCCS Notes of Guidance (2021) (BASF, 2021) (see 
section 3.2.1.1). This value will be used for the calculation of the MoS. 

3.2.2 Other studies on Toxicokinetics 

3.2.2.1 Oral absorption, distribution, metabolism, excretion and kinetics 

Salicylates are known to be well absorbed across the gut (Goodman & Gilman, 2006). There 
are no specific quantitative in vivo studies available on the ADME properties and kinetics of 
Benzyl  Salicylate  via  the  oral  route  in  animals  and  humans,  but  oral  absorption  studies 
conducted  on  closely  related  hydroxy-  and  alkoxy-substituted  benzyl  derivatives  indicate  a 
rapid and nearly complete absorption following ingestion. As a result, for the assessment of 
potential effects of oral exposures to the salicylates from their use as cosmetic ingredients, 
an  oral  bioavailability  of  100%  is  assumed  (Belsito  et  al.,  2007).  This  is  supported  by  the 
2018  SCCS  opinion  on  salicylic  acid,  where  a  100%  oral  absorption  was  assumed  (SCCS, 
2018a).  In  addition,  in  vitro  investigations  demonstrate  the  rapid  hydrolysis  of  Benzyl 
Salicylate to salicylic acid in rat and human tissues and plasma (see below). 

•  Oral ADME/kinetic data in animals or humans 

No data 

•  Oral ADME/kinetic data in vitro 

Ozaki et al. (2015) examined the hydrolysis of Benzyl Salicylate to salicylic acid (and benzyl 
alcohol)  by  various  tissue  microsomes  and  plasma  of  rats,  and  by  human  liver  and  small-
intestinal  microsomes.  Benzyl  Salicylate  was  readily  hydrolysed  by  human  and  rat 
microsomes;  this  was  most  extensive  in  small  intestine  microsomes,  followed  by  liver 
microsomes. It is evident that microsomal hydrolysis of Benzyl Salicylate in vivo leads to rapid 
production of salicylic acid in rats and humans. 

Figure 4. Rapid formation of salicylic acid from 100 nmol Benzyl Salicylate incubations in rat 
liver microsomes (Ozaki et al., 2015). 

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A similar experiment was performed by Givaudan (Givaudan study, 2018), Benzyl Salicylate 
was  incubated  (100 μM)  with  rat  and  human  hepatocytes.  Rat  hepatocytes  were  thawed, 
checked  for  viability  by  Trypan  blue  exclusion  and  adjusted  to  106  cells  per  ml  in  WEM 
medium. Viability was at > 90%. Benzyl Salicylate was dissolved in methanol at 10 mM and 
a final concentration of 100 μM was added to the cells to start the experiment. Experiments 
were  run  in  closed  glass  vials.  To  stop  the  reaction,  samples  were  mixed  with  1M  HCl 
containing d4-deuterated salicylic acid as internal standard. Samples were then purified over 
SPE columns prior to injection into HR-LC-MS. With HR LC-MS the peak of salicylic acid and 
the internal reference d4-salicylic acid was determined, and calibration was performed with 
an external calibration row. Benzyl Salicylate was completely hydrolysed within 15 mins. The 
extent of hydrolysis was the same in both rat and human hepatocytes. 

Table 5: Release of salicylic acid (given in % of added parent) from different salicylates in 
rat and human hepatocytes 

•  Salicylic acid metabolite - ADME 

The oral ADME properties of salicylic acid were covered in the SCCS Opinion from 2018. The 
data will not be repeated here. Briefly, it was concluded that available evidence suggests that 
oral  absorption  can  be  regarded  as  100%  and  that  clearance  of  salicylic  acid  is  rapid  and 
complete within 24 hours in both rats and humans, after any route of exposure (Goodman & 
Gilman, 2006). 

•  Benzyl alcohol metabolite - ADME 

A  dossier  has  been  prepared  for  benzyl  alcohol  by  the  Cosmetics  Ingredient  Review  (CIR, 
2017)  and  by  OECD  SIDS  (2001).  The  OECD  evaluation  of  benzyl  alcohol  toxicokinetics 
concludes: ‘The studies clearly show that the compound is rapidly absorbed from the GI tract 
of rats and mice, and about 90% of the total dose is recovered as urinary metabolites after 
24h.  More  than  90%  of  the  radiolabel  in  the  urine  is  present  as  hippuric  acid,  with  minor 
amounts  of  benzyl  alcohol  and  benzylmercapturic  acid  (up  to  4%);  no  unchanged  benzyl 
acetate  was  found.  Only  at  very  high  doses,  saturation  of  these  pathways  will  occur.  All 
supports very rapid ADME of these substances. 

Conclusion on Oral ADME data:  
Benzyl Salicylate is expected to be rapidly and completely absorbed and metabolised, in both 
gut and liver tissue by first pass metabolism, to salicylic acid and benzyl alcohol following oral 
exposure  in  both  rat  and  humans.  With  rapid  hydrolysis  in  the  gut  and  liver,  systemic 
exposure is primarily to salicylic acid and benzyl alcohol, which do not accumulate in the body, 
and are rapidly excreted. This means that any point of departure from an oral toxicology study 
on either Benzyl Salicylate, salicylic acid or benzyl alcohol can be regarded as a systemic point 
of departure (PODsys). 

SCCS comment 
Based on the available  data, the SCCS  considers that an absorption value by oral  route  of 
100% can be used in the risk assessment. 

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3.2.2.2 Inhalation absorption, distribution, metabolism, excretion and kinetics  

There are no data on the extent of Benzyl Salicylate absorption in the lung. 

Ozaki  et  al.  (2015)  also  used  rat  lung  microsomes  to  investigate  the  hydrolysis  of  Benzyl 
Salicylate  to  salicylic  acid  and  found  lung  microsomes  to  be  equally  as  active  as  small 
intestinal microsomes and liver at hydrolysing Benzyl Salicylate. 

SCCS comment 
Due  to  the  lack  of  data  available  data,  the  SCCS  considers  that  an  absorption  value  by 
inhalation of 100% can be used in the risk assessment. 

3.3 

EXPOSURE ASSESSMENT 

3.3.1 Function and uses 

Benzyl Salicylate (CAS RN 118-58-1; EC No. 204-262-9) occurs naturally in a variety of plants 
and  plant  extracts  such  as  ylang-ylang  oil,  carnation  oil  and  tuberose  absolute.  It  can  be 
extracted  or  synthesised  for  use,  typically  as  a  fragrance  ingredient,  in  a  range  of 
manufactured  goods  (cosmetics,  household  goods  and  medicines)  and  its  use  in  Europe  is 
greater than 1000 tonnes but less than 10000 tonnes per annum (ECHA, 2020).  

•  Cosmetic uses 

Benzyl Salicylate has been used safely in cosmetic preparations for decades. It is used in the 
formulation  of  fragrances  in  cosmetics  as  it  has  a  sweet  odour.  Benzyl  Salicylate  is  used 
globally in a wide range of cosmetics [Lapczynski et al., 2007; CIR 2019a]. The EU Cosmetic 
Regulation  (Annex  III-entry  75)  does  not  restrict  the  use  of  Benzyl  Salicylate  in  cosmetics 
and  personal  care  products,  but  states  that  “its  presence  must  be  indicated  in  the  list  of 
ingredients when its concentration exceeds 0.001% in leave-on products and 0.01% in rinse-
off products”. It can also be used as an UV absorber (CosIng database, consulted 04/05/23). 

•  Other non-cosmetic dermatological uses  

Benzyl Salicylate can also be used in pediculicides for treatment of lice in humans and animals. 

•  Other non-cosmetic uses  

Benzyl Salicylate is also used as a fragrance in household cleaners and it has been approved 
as a flavour by the US FDA in accordance with (21 CFR 172.515). Benzyl Salicylate has been 
granted Generally Recognized as Safe (GRAS) status as a flavouring ingredient by the Flavor 
and  Extract  Manufacturers  Association  (FEMA)  (Adams  et  al.,  2005).  In  addition,  the  Joint 
FAO/WHO Expert Committee on Food Additives (JECFA) concluded that the substance does 
not present a safety concern at current low levels of intake when used as a flavouring agent 
(JECFA, 2001). 

3.3.2 Calculation of SED/LED 

Separate  exposure  assessments  were  performed  by  the  Applicant  for  the  dermal  and 
inhalation routes. The use in oral care products is low and leads to negligible exposure. As 

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the deterministic approach yields a favourable outcome, further exposure modelling was not 
necessary to refine exposure. 

3.3.2.1 Calculation of Systemic Exposure Dose (SED) following dermal exposure 

To  estimate  an  SED  following  dermal  exposure,  the  standard  worst  case  deterministic 
aggregate Tier 1 exposure assessment approach, as per the SCCS 11th revision of the notes 
of  guidance,  has  been  performed  by  the  Applicant  and  is  presented  in  Table  6,  with  the 
addition of an 18th product type – hydroalcoholic fragrances.  

Scenario A uses the maximal concentrations of Benzyl Salicylate in products in weight %, and 
Scenario B uses the P90 of concentrations used in products. Maximal and P90 use levels are 
taken from an RIFM survey performed in 2018. In this approach the exposures for individual 
product  types  are  calculated,  but  also  aggregated  in  a  worst-case  assumption.  Exposure 
Scenarios A and B assume 100% occurrence of Benzyl Salicylate at the maximum potential 
% use concentration in all cosmetics products used simultaneously by an individual in a day. 

A  measured  value  of  10.5%  (see  section  3.2)  is  used  for  skin  absorption  of  the  dermally 
applied substance from all products. 

•  Deterministic worst case aggregated exposure assessment for the dermal route  

The  starting  point  is  a  Tier  1  Scenario  A  deterministic  exposure  assessment  based  on 
maximum concentrations of Benzyl Salicylate that are used in products in Europe, in each of 
the standard 17 product types as included in an aggregate exposure assessment (according 
to the SCCS Notes of Guidance 2021). These levels have been provided in a recent use survey 
by  the  members  of  the  ‘Benzyl  Salicylate  consortium’  and  are  used  to  calculate  the  total 
systemic  exposure  to  Benzyl  Salicylate  (in  mg/kg/day)  from  each  product  for  adults  (see 
Table 6).  

Benzyl  Salicylate  is  also  used  as  a  fragrance  ingredient  in  hydroalcoholic  fragrances  (e.g. 
aftershave,  eau  de  toilette,  cologne)  and,  therefore,  this  is  added  in  this  case  into  the 
calculation  as  an  18th  product  type  in  Table  6.  The  exposure  to  product  (Eproduct)  value 
normalised  by  weight  is  calculated  by  including  the  respective  retention  factor  for  each 
product type (SCCS, 2021).  

A measured value  for  skin penetration  of  Benzyl Salicylate  of 10.5% (see  section 3.2) has 
been used for all products in these calculations where dermal absorption needs to be factored 
in to calculate a systemic exposure dose (SED). For lipstick and oral care products a worst-
case value of 100% absorption is used to account for passage across the oral mucosa and/or 
ingestion. A SED via the dermal route was calculated for each product in mg/kg/day and also 
an aggregate systemic exposure dose for the 18 products (see Table 6).  

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Table 6: Tier 1 Scenario A Deterministic worst case systemic exposure dose calculation for 
the  dermal  route  using  maximum  %  levels  of  Benzyl  Salicylate.  (NB.  exposure  to 
spray/aerosol products are taken into account in section 3.3.2.3 on inhalation below) 

SCCS/1656/23 
Final Opinion 

Table 7 shows the outcomes following a similar method but using P90 % use levels for the 
same  set  of  product  types  as  determined  in  a  RIFM  survey  from  2018.  This  provides 
reassurance that current use levels are in reality lower than the maximal values. 

Table 7: Tier 1 Scenario B Deterministic aggregate exposure calculations for the dermal route 
using P90 use levels as defined by RIFM in 2018. Values of SED are calculated according to 
the SCCS 11th notes of guidance approach to calculating aggregate exposure on the basis of 
deterministic  additive  methods.  Benzyl  Salicylate  is  assumed  to  undergo  10.5%  skin 
penetration for all product types (except oral care and lipstick where 100% is assumed) in 
this assessment. 

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SCCS comment  
The SCCS considers Scenario A “Deterministic worst case systemic exposure dose calculation 
for the dermal route using maximum % levels of Benzyl Salicylate” as the more appropriate 
as it also covers some highly concentrated products. Therefore, the SCCS will use Scenario A 
for the MoS calculation. 

3.3.2.2 Calculation of Systemic Exposure Dose (SED) – inhalation route 

Based on the vapor pressure of Benzyl Salicylate, inhalation exposure through volatilisation 
is not expected.  

Therefore, the systemic exposure through inhalation will be performed only for the sprayed 
fraction of finished products. 

A systemic exposure dose from the potential for inhalation (SEDinh) from spray products can 
be calculated by assuming instant release of the ingredient in a defined box (1-Box model) or 
by applying a 2-Box model based on principles in Rothe  et al. (2011). In Section 3-3.5.4.1 

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and Appendix 11 of the 11th Notes of Guidance (2021), a deterministic approach for 2-box 
modelling  was  presented  for  propellant  and  pump  spray  products  according  to  the  generic 
equations and associated parameters in the box above on page 27. 

SCCS/1656/23 
Final Opinion 

SEDinh = (IA1 + IA2) x G x RF x DA/BW 

Where: 

SEDinh = Systemic Exposure Dose from the inhalation route (mg/kg/day) 

IA1 = the potential amount inhaled during the first 2 min (in mg) 

IA1 (EA/V1*BR*t1) 

IA2 = the potential amount inhaled during the subsequent 10-20 min (in mg) 

IA2 (EA/V2*BR*t2) 

EA = potential amount to be inhaled 

EA = (A*C*P*AF)/100 

A = Amount of product by application (mg/application) (user defined or default SCCS 2021)* 

C = Percentage concentration of ingredient in product (%) (user defined)* 

P  =  Proportion  of  non-propellant  in  formulation  (no  units)  (user  defined)*  or  default  60% 
(propellant, 100% pump spray) (Bremmer/RIVM 2006) 

AF  =  airborne  fraction  (no  units);  1  (propellant  spray);  0.2  (pump  spray)  (Bremmer/RIVM 
2006) 

V1 = First step: near-field, 1m3 (SCCS 2021) 

V2 = Second step: far-field, 10m3 (SCCS 2021) 

BR = breathing rate, 13 L/min (SCCS 2021;)** 

t1 = 2 minutes in near field (SCCS 2021; Rothe et al., 2011) 

t2 = 10-20 minutes in far field (SCCS 2021; Rothe et al., 2011) 

G = default factor substance lung retention 0.75 (25% is exhaled) (Rothe et al., 2011; SCCS 
2021) 

RF = respirable fraction: propellant & pump spray specific (user defined experimental value*) 

DA = Daily frequency of application (user defined* or SCCS 2021) 

BW = body weight = adult 60 kg (SCCS 2021) 

*Product-dependent parameter value 

** highest median among several adult age categories 

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Calculation  of  SEDinh  for  Benzyl  Salicylate  in  four  main  spray  products  (hydroalcoholic 
fragrance spray, deodorant spray, hair spray and body lotion spray) are presented in Table 
8, 9, 10and 11, respectively. 

Table  8:  Deterministic  systemic  exposure  dose  after  inhalation  exposure  (SEDinh)  to  4% 
Benzyl Salicylate in a hydroalcoholic fragrance spray formulation (e.g. eau de toilette, 
perfume, cologne etc) 

SCCS comment 
The amount of 280 mg/application refers to the arithmetic mean for the use amounts. Also, 
the frequency  of application refers to a  mean  value, according to Ficheux  & Roudot, 2017. 
Therefore,  the  SCCS  has  recalculated  the  presented  exposure  with  the  P95  of  618 
mg/application.  This  results  in  an  exposure  of  0.032  µg/kg/d  to  hydroalcoholic  fragrance 
spray. 
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Table 9: Deterministic systemic exposure dose after inhalation exposure (SEDinh) to 0.91% 
Benzyl Salicylate in a deodorant spray formulation 

SCCS/1656/23 
Final Opinion 

SCCS comment 
The  value  of  0.886  for  the  airborne  fraction  has  been  derived  based  on  a  2012  study  by 
Steiling  et  al.  that  reports  a  worst  case  for  dermal  exposure  to  deodorant  (i.e.  11.4% 
deposited). Since the worst-case inhalation exposure cannot be derived from subtracting a 
worst-case dermal  exposure from 100%,  and  since no data were provided,  the SCCS uses 
100%  availability  as  a  worst  case.  The  resulting  exposure  is  4.64  µg/kg/day  for  inhalation 
exposure to deodorant. 

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Table 10: Deterministic systemic exposure dose after inhalation exposure (SEDinh) to 0.5% 
Benzyl Salicylate in hair spray formulations 

SCCS/1656/23 
Final Opinion 

SCCS comment 
The use amount derived from Steiling et al., 2014 goes back to Bremmer et al., 2006 and is 
a P75. Therefore, for propellant spray SCCS uses the P95 (9890 mg/application) of Loretz et 
al., 2006 for daily use combined with a frequency of 1. This results in an exposure value of 
3.86  µg/kg/d.  For  pump  spray,  the  amount  is  a  P50  derived  from  Loretz  et  al.,  2006.  The 
SCCS therefore uses the P95 (15620 mg/application) from Loretz et al., 2006 for daily use in 
combination  with  a  frequency  of  1.  This  results  in  an  exposure  value  of  0.102  µg/kg/d  for 
pump spray. 

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Table 11: Systemic exposure dose (SED) after inhalation exposure to 0.7% Benzyl Salicylate 
in a body lotion spray formulation 

SCCS/1656/23 
Final Opinion 

SCCS comment 
The SCCS agrees with the Applicant’s calculation of systemic exposure dose from the use of 
Benzyl Salicylate in sprayable body lotion. 

Overall Exposure Assessment conclusion (from the Applicant)  

A deterministic worst case systemic exposure dose (SED) estimate from aggregated dermal 
exposure modelling of Benzyl Salicylate in cosmetic products is 179 μg/kg/day. This value will 
be taken forward into the safety evaluation. 

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It is not necessary to add the dermal aggregate  outcome for  Total SED to the SED values 
from inhaled spray products, as on any one day, only one (spray or non-spray versions) of 
the type of products in Table 7 will be used, not both simultaneously. Typically, the non-spray 
version of a product leads to the higher SED, and inhalation exposure (in the range here from 
0.015 to 7.11 μg/kg/day) is often much lower than dermal exposure. 

SCCS comment 

SCCS agrees that for  most  of the products, the non-spray products  lead to a much higher 
systemic exposure when compared to the spray products. The exceptions are the hair styling 
products: systemic exposure via non sprayed hair styling products is 3 µg/kg/d whereas it is 
3.86 µg/kg/d when using hair styling spray products. Therefore, for the MoS calculation, for 
all  products  except  hair  styling  products,  only  non-spray  products  will  be  considered  in  a 
worst-case scenario.   

3.4 

TOXICOLOGICAL EVALUATION 

For  the  hazard  assessment  of  Benzyl  Salicylate,  the  Applicant  mainly  relied  on  several 
literature reviews such as Belsito et al., 2007; Lapczynski et al. (2007); Cosmetics Ingredient 
Review 
substance  dossier  available  at 
https://echa.europa.eu/registration-dossier/-/registered-dossier/16100  

(2019a)  and  on 

the  EU  REACH 

3.4.1. Irritation and corrosivity 

3.4.1.1 Skin irritation 

• 

Animal data 

The available irritation studies in animals are listed in Table 12. 

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Table 12: Skin irritation studies in animals 

SCCS/1656/23 
Final Opinion 

In a study according to OECD guideline 404 (RIFM 1985), approximately 0.5mL of neat Benzyl 
Salicylate was applied to the shorn flanks of three rabbits, wrapped in semi-occlusive dressing 
for a period of 4 hours. One hour after the dosing period, well defined erythema of the treated 
skin was apparent in one rabbit and very slight erythema was observed in the remaining three 
rabbits  of  the  group.  Slight  oedema  was  noted  in  one  rabbit  and  very  slight  oedematous 
reaction  was  observed  in  the  treated  skin  of  the  second  rabbit  at  this  time.  Very  slight 
erythema remained in three rabbits at  24-hour observation, very slight oedema also being 
observed  in  two  rabbits.  This  response  declined,  very  slight  erythema  remaining  in  two 
animals 72 hours after dosing and no irritation remaining visible 7 days after dosing.  

The averages calculated from the numerical values given to the irritation observed at the 24, 
48 and 72 -hour observations were 0.6 for erythema and 0.2 for oedema.  

The  effects  seen  do  not  trigger  classification  according  to  Regulation  (EC)  No. 
1272/2008 (CLP). 

• 

Human data 

A range of skin irritation tests in humans are presented in Table 13.  

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_________________________________________________________________________________ 

Table 13: Skin irritation studies with Benzyl Salicylate in humans 

SCCS/1656/23 
Final Opinion 

Human repeat insult patch test (HRIPT) studies:  

In agreement with earlier studies (RIFM 1968, 1975c), RIFM (2004a) observed no irritation 
in the induction phase of a HRIPT (n = 29 males and n = 72 females). 0.3 ml of 15% Benzyl 
Salicylate  in  3:1  DEP:EtOH  vehicle  was  applied  to  an  adhesive  patch  (25  mm  Hilltop® 
Chamber System) and then applied to the back of each subject for 24h. Nine induction patches 
were completed based on Monday, Tuesday, Wednesday and Friday schedule over a period 
of approximately three weeks. Reactions were scored at patch removal. No irritation was 
observed. 

Human maximisation tests:  

No  irritation  was  observed  following  48-h  closed  patch  with  30%  Benzyl  Salicylate  in 
petrolatum applied to normal sites on the volar forearms of five volunteers (RIFM, 1975a). In 
a second study, two irritant reactions were observed from 22 male volunteers conducted with 
30% Benzyl Salicylate in petrolatum in a 48h patch under occlusion (RIFM, 1975b). 

Closed patch tests:  

Benzyl Salicylate at 20% in vaseline or unguentum cream applied to the back of each subject 
(n = 5 males; n  = 5  females) produced no irritation (Fujii  et al., 1972). Irritation was not 
observed when a 24–72h closed patch with 2% Benzyl Salicylate in an unguentum cream was 
applied to the upper inside of arm of 30 male and female volunteers (Fujii et al., 1972). Five 
(5/313) positive reactions were observed when 0.2% Benzyl Salicylate in 99% ethanol 
was applied under occlusion for 24–48h to the upper inside of arm of 313 volunteers (Fujii et 
al., 1972). 

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SCCS/1656/23 
Final Opinion 

Opinion on Benzyl Salicylate (CAS No. 118-58-1, EC No. 204-262-9) 
_________________________________________________________________________________ 

Benzyl Salicylate at 5% in petrolatum was applied to adhesive patches  for 1  or 24h which 
were then applied to the upper arms of each subject (n = 12 males; n = 13 females).  No 
irritation was observed (RIFM, 1997a). 

The potential of Benzyl Salicylate to produce irritation was  evaluated in a patch test which 
was conducted on 30 volunteers. A 0.2 ml aliquot of neat Benzyl Salicylate was applied using 
25 mm Hilltop® Chambers which were then applied to the skin of the upper outer arm for up 
to 4h. Benzyl Salicylate was applied progressively for 15 and 30 min through 1, 2, 3 and 4h, 
each, to a new skin site. Reactions were scored at 24, 48 and 7 h after patch removal.  No 
irritation was observed (Basketter et al., 2004). 

Skin Irritation & Corrosivity Applicant Conclusion:  

Overall, there is no evidence of a skin irritation potential of Benzyl Salicylate in humans at a 
range of high concentrations, including neat. Consequently, there is no risk of skin irritation 
at the maximum concentrations used in cosmetic products. 

3.4.1.2 Mucous membrane irritation / eye irritation 

• 

In vitro data 

A  GLP-compliant  OECD  Guideline  437  (Bovine  Corneal  Opacity  and  Permeability  Test  for 
Identifying Ocular Corrosives and Severe Irritants) is available (Givaudan report, 2012). 

Method:  

0.75  mL  of  the  neat  Benzyl  Salicylate  was  applied  to  triplicate  corneas.  The  undiluted  test 
material was applied for 10 minutes followed by an incubation period of 120 minutes. At the 
end  of  the  exposure  period  the  test  material  was  removed  from  the  anterior  chamber  and 
each cornea was rinsed three times with fresh complete MEM containing phenol red before a 
final  rinse  with  complete  MEM.  Results  from  the  two  test  method  endpoints,  opacity  and 
permeability,  were  combined  in  an  empirically  derived  formula  to  generate  an  In  Vitro 
Irritancy Score. Opacity Measurement- The change in opacity for each cornea (including the 
negative  control)  was  calculated  by  subtracting  the  initial  opacity  reading  from  the  final 
opacity  reading.  These  values  were  then  corrected  by  subtracting  from  each  the  average 
change in opacity observed for the negative control corneas. The mean opacity value of each 
treatment group was then calculated by averaging the corrected opacity values of each cornea 
for that treatment group. 

Permeability  Measurement  -  The  corrected  OD492  was  calculated  by  subtracting  the  mean 
OD492  of  the  negative  control  corneas  from  the  OD492  value  of  each  treated  cornea.  The 
OD492  value  of  each  treatment  group  was  calculated  by  averaging  the  corrected  OD492 
values  of  the  treated  corneas  for  the  treatment  group.  The  following  formula  was  used  to 
determine the in vitro score:  

In Vitro Irritancy Score = mean opacity value + (15 x mean OD492 value)  

A test material that induces an in vitro irritancy score > than or equal to 55.1 is defined as 
an ocular corrosive or severe irritant. Additionally, the opacity and permeability values were 
evaluated independently to determine whether the test material induced a response through 
only one of the two endpoints. The condition of the cornea was visually assessed immediately 
after rinsing and at the final opacity measurement. 

The test results are summarised in Table 14. 

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Table 14: Summary of results from the OECD Guideline 437 study on Benzyl Salicylate 

SCCS/1656/23 
Final Opinion 

• 

In vivo data 

A  Draize  rabbit  eye  study  is  available,  that  was  performed  pre-GLP  but  as  the  study  was 
similar  to  OECD  guideline  405  and  conducted  in  accordance  with  good  scientific  principles, 
the  data  reported  was  sufficient  to  classify  the  substance  as  a  mild  to  moderate  eye 
irritant,  and  in  the  interest  of  animal  welfare  it  was  considered  unecessary  to  repeat  the 
study (ECHA, 2020). 

Approximately 0.5mL of neat test substance was instilled into the eyes of three albino rabbits. 
1,  2,  3,  4,  7  and  10  days  after  exposure  reactions  were  recorded.  The  effects  on  the 
conjunctivae (redness) were sufficient in 2 out of 3 animals tested to trigger classification as 
category 2 eye irritation in accordance with Regulation (EC) 1272/2008 (CLP).  

All adverse reactions were reversed between 3-7 days. 

Eye Irritation Applicant Conclusion:  
Benzyl Salicylate was not an eye irritant in vitro/ex vivo, but did show irritant properties in a 
pre-GLP  in  vivo  Draize  rabbit  eye  test  in  undiluted  form.  However,  there  is  no  risk  of  eye 
irritation at the maximum concentrations used in cosmetic products. 

SCCS comment 
SCCS considers that Benzyl Salicylate is non irritating to the skin but may cause eye irritation. 

3.4.2 Skin sensitisation 

• 

Animal data 

All of the available skin sensitisation studies in guinea-pig are listed in Table 15 below. And 
two murine LLNA studies in Table 16. 

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Table 15: Available skin sensitisation studies for Benzyl Salicylate in guinea-pigs 

SCCS/1656/23 
Final Opinion 

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Table 16: Murine local lymph node assays (LLNA) for Benzyl Salicylate 

SCCS/1656/23 
Final Opinion 

A GLP compliant OECD Guideline 429 murine LLNA is available (RIFM, 2005) and acts as the 
pivotal animal sensitisation assay for Benzyl Salicylate. 

Five  groups  of  n=4  animals  received  Benzyl  Salicylate  at  2.5,  5,  10,  25  or  50%  in  1:3 
ethanol/diethylphthalate  and  a  negative  control  group  of  n=4  animals  received  vehicle.  α-
hexylcinnamaldehyde (HCA) was used successfully as a positive control to validate the study. 
25  μL  of  benzyl  benzoate  or  vehicle  was  applied  to  each  ear  for  three  consecutive  days. 
Following  two  rest  days,  each  animal  received  a  single  intravenous  injection  of  250  μl  of 
phosphate buffered saline containing 20 μci of 3H-TdR. Approximately 5 hours later, auricular 
lymph nodes were excised, and lymphocyte proliferation was quantified by beta scintillation 
counting. The Stimulation Index (SI) was obtained by mean dpm per node of treated divided 
by mean dpm per node of vehicle control group. The SI of 2.6, 5.5, 6.0, 18.9 and 26.2 were 
observed for 2.5, 5, 10, 25 or 50% w/v Benzyl Salicylate, respectively.  

Under conditions of this study, Benzyl Salicylate induced contact sensitization and 
an EC3 value was calculated to be 2.9%, or 725 μg/cm2. 

• 

Human data 

There have been a few case reports indicating Benzyl Salicylate exposure may lead to contact 
allergy (Fernández-Canga et al., 2017; Tous-Romero et  al., 2018). However, this is a rare 
observation; Benzyl Salicylate is not a common allergen in the population (Schnuch, 2007). 
This  is  supported  by  the  results  of  human  repeated  insult  patch  tests  (HRIPT)  and 
maximization (HMT) tests for Benzyl Salicylate indicating that Benzyl Salicylate may be only 
a weak sensitiser in humans, if any (Table 17). 

Table 17: Confirmative human in vivo study data for skin sensitisation 

Human repeat insult patch test (HRIPT); human maximization test (HMT) 

Diagnostic patch testing in human volunteers has also been performed for Benzyl Salicylate  

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Table 18: Summary of human diagnostic patch test studies 

SCCS/1656/23 
Final Opinion 

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SCCS/1656/23 
Final Opinion 

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SCCS/1656/23 
Final Opinion 

• 

In silico and in vitro data 

The chemical structure of Benzyl Salicylate indicates that it theoretically has intrinsic reactive 
properties, and it would be expected to react with skin proteins directly (Roberts, 2007; OECD 
toolbox v 4.3), but it would have to penetrate the skin to act as a skin sensitiser. 

Benzyl  Salicylate  was  found  to  be  negative  in  the  in  vitro  direct  peptide  reactivity  assay 
(DPRA);  1%  and  2.65%  mean  depletion  of  cysteine  and  lysine  peptides  was  observed, 
respectively,  demonstrating  minimal  reactivity  of  Benzyl  Salicylate  to  skin  proteins  (RIFM, 
2014; Urbisch, 2015; Avonto, 2019). 

In two KeratinoSens assays, Benzyl Salicylate induced ARE dependent gene activity with an 
EC1.5 of 9.63 μM and 8.42 μM, respectively (RIFM, 2015; Emter, 2010) and in the U-Sens 
assay, induced CD86 expression with an EC150 of 63 μg/mL (276.03 μM) (Piroird, 2015). In 
an in vitro assay looking at the upregulation of IL-18, Benzyl Salicylate showed no response 
(Galbiati et al., 2017). These assays represent key events in the adverse outcome pathway 
(AOP) for skin sensitisation as developed by the OECD (2012). 

Sensitisation Applicant Conclusion:  

The skin sensitisation potential of Benzyl Salicylate has been extensively investigated. Overall, 
from the weight of evidence, the available data indicate that Benzyl Salicylate is only a weak 
sensitiser in humans. This is supported by the available data from in vitro or in chemico new 
approach methodologies (NAMs) predicting the lack of a relevant sensitisation hazard as well 
as the absence of a skin sensitisation potential of salicylic acid. In addition, in both animal 
tests  and  studies  in  humans,  a  relevant  sensitisation  response  was  only  induced  at 
concentrations higher than the maximum concentrations used in cosmetic products.  

Nevertheless, the SCCS opinion on fragrance materials (SCCS, 2011) lists Benzyl Salicylate 
as a contact allergen in humans that is less frequently reported compared to other allergens. 
Consequently, it is one of the 26 fragrance allergens currently requiring individual labelling in 
the  EU.  Risk  management  of  the  use  of  Benzyl  Salicylate  as  a  fragrance  material  is  very 
effective through the use  of quantitative risk assessment (QRA) within the IFRA Standards 
and  its  use  is  not  considered  to  present  a  significant  problem  in  the  consumer  population. 
Such  QRA  method  has  been  further  refined  within  the  International  Dialogue  for  the 
Evaluation of Allergens IDEA (www.ideaproject.info). 

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SCCS comment 
Benzyl Salicylate is classified as a Category 1B skin sensitiser in CLP. 
Benzyl Salicylate is listed as a contact allergen in humans (SCCS, 2011). Consequently, it is 
one of the fragrance allergens that currently require individual labelling in the EU.  

SCCS/1656/23 
Final Opinion 

3.4.3 Acute toxicity 

3.4.3.1 Acute oral toxicity 

There  is  one  study  in  animals  covering  the  acute  oral  toxicity  of  Benzyl  Salicylate  as 
summarised in Table 19. 

Table 19: Acute oral toxicity studies for Benzyl Salicylate 

Three groups of rats (6/dose) weighing approximately 100–200 g were dosed orally (gavage) 
at  levels  of  1.25,  2.5,  or  5.0  g/kg.  The  calculated  LD50  was  2.23  g/kg  (1.93–2.58  g/kg). 
Observations for mortality and systemic effects were made over a 7-day period. At 1.25 g/kg, 
no deaths (0/6) were observed; 4/6 deaths were observed at 2.5 g/kg and all (6/6) animals 
died  at  5.0  g/kg.  The  principal  toxic  effect  observed  before  death  was  depression  (RIFM, 
1970a). 

3.4.3.2 Acute dermal toxicity 

The acute dermal data is summarised in Table 20. 

Table 20: Acute dermal toxicity study for Benzyl Salicylate 

The  animals  in  this  study  were  observed  daily  for  a  period  of  seven  days  for  any  signs  of 
systemic toxicity. On day 5, blood was drawn from the marginal ear vein for haematology and 
clinical chemistry evaluation. No effects were observed at 5.0 g/kg. Animals that received the 
10 and 20 g/kg dosage were depressed and showed slow respiration. On day 5, one of three 
rabbits (1/3) at the 10 g/kg level and two (2/3) at the 20 g/kg level died. Among animals 
dying,  intoxication  persisted,  and  gradually  deepened  to  severe  depression,  loss  of  the 
righting reflex, coma and death. Survivors appeared normal on day  5. No significant gross 
pathology  was  noted  in  animals  that  died  during  the  study.  Haematological  and  clinical 
chemistry  values  from  the  survivors  were  within  normal  limits  when  compared  to  control 

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animals, except for a low hemoglobin value that was noted for the only survivor animal treated 
at the 20 g/kg level (RIFM, 1970b). 

SCCS/1656/23 
Final Opinion 

3.4.3.3 Acute inhalation toxicity 

There are no acute inhalation toxicity data available in animals for Benzyl Salicylate. The use 
of Benzyl Salicylate in consumer products for decades has revealed no adverse effects in the 
lung.  Benzyl  Salicylate  is  not  irritating  to  the  skin  and  eye  at  the  concentrations  used  in 
cosmetic products and therefore, is not expected to be irritating or toxic to respiratory tract 
and lung at the concentrations used in cosmetic products. 

Given hydrolysis of Benzyl Salicylate has been shown to occur via lung microsomes in vitro 
(Ozaki et al., 2015), it may be relevant to consider the benzyl alcohol data that is available, 
showing  the  very  low  toxicity  of  benzyl  alcohol  in  the  lung.  Also,  there  are  data  on  acute 
inhalation for methyl salicylate to provide supporting evidence that salicylates in general are 
not acute lung toxicants. 

Conclusion from the Applicant on acute Toxicity 

Benzyl Salicylate is only acutely toxic at very high doses. 
The LD50 via the oral route in rabbits was 2.23 g/kg. 
The LD50 via the dermal route was g/kg was in the range 4.6 to 43.9 g/kg. 
Benzyl Salicylate is not expected to be irritating or toxic to respiratory tract and lung. 

SCCS comment 
Benzyl Salicylate is acutely toxic at high doses. 

3.4.4 Repeated dose toxicity 

No  repeat  dose  toxicity  data  were  available  on  Benzyl  Salicylate,  as  performed  before  the 
March 2013 animal testing ban. For the purposes of performing a cosmetics safety assessment 
and given that Benzyl Salicylate itself is not regarded as the main toxicant, but salicylic acid 
as the chief hydrolysis product, this section also discusses the available repeat dose toxicity 
data and conclusions for the primary Benzyl Salicylate metabolites salicylic acid and benzyl 
alcohol (Belsito et al., 2007). 

All  data  for  salicylic  acid  were  recently  reviewed  by  the  SCCS  in  its  recent  opinion 
(SCCS/1646/22) and therefore are not reported in this opinion. 

Concerning  benzyl  alcohol,  a  summary  of  the  repeat  dose  oral  studies  cited  in  the  ECHA 
REACH registration dossier for benzyl alcohol (https://echa.europa.eu/registration-dossier/-
/registered-dossier/14748/7/6/2) are presented in Table 21. 

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Table 21: Oral (gavage) repeat dose studies in animals for benzyl alcohol 

SCCS/1656/23 
Final Opinion 

The  NOAEL  from  these  studies  was  regarded  as  400  mg/kg/day  which  was  subsequently 
confirmed  in  an  OECD  451  carcinogenicity  study.  EFSA  (2019)  also  used  this  NOAEL  to 
determine an ADI for benzyl alcohol in foods of 4 mg/kg/day. 

3.4.4.1 Repeated dose (28 days) oral / dermal / inhalation toxicity 

14 days range finding study mentioned in the reach dossier. 

3.4.4.2 Sub-chronic (90 days) oral / dermal / inhalation toxicity 

• 

Oral route 

Following  ECHA  decision  (CCH-D-2114379324-45-01/F)  on  Benzyl  Salicylate  it  was

  requested to conduct additional toxicological studies: 

Sub-chronic toxicity study (90-day), oral route (Annex IX, Section 8.6.2.; test method: EU 
B.26./OECD TG 408) in rats with the registered substance. 

The  objective  of  the  following  study  was  to  evaluate  the  potential  toxicity  of  the  Benzyl 
Salicylate when administered via the diet to Sprague Dawley rats for at least 90 consecutive 
days.  

Guideline:  

Species/strain:    
Group size:  
Test substance:   
Physical form: 
Batch:  
Purity:  
Vehicle:  
Dose levels:  

Route:  
Administration:   
GLP:   
Observation period:    
Study period: 

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study 
in Rodents) 
female and male Sprague-Dawley rats 
4 groups of 10 male and 10 female rats 
Benzyl Salicylate 
/ 
/ 
/ 
not need (dietary study) 
1500, 3000, and 6000 ppm equivalent to 86, 177 and 357 
mg/kg for males and 106, 204 and 429 for females  
oral feed 
continuously 
Yes  
90 days 
IN-LIFE DATES: From:02 Jan 2019 To: 04 Apr 2019 

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Final Opinion 

Opinion on Benzyl Salicylate (CAS No. 118-58-1, EC No. 204-262-9) 
_________________________________________________________________________________ 

Taken from the REACH dossier 

Animals  were  administered  the  test  substance  continuously  in  the  diet  for  at  least  90 
consecutive  days.  The  following  parameters  and  end  points  were  evaluated  in  this  study: 
clinical  signs,  body  weights,  body  weight  gains,  food  consumption,  ophthalmology,  clinical 
pathology parameters (haematology, coagulation, serum chemistry, and urinalysis), thyroid 
hormone  concentration  (T3,  T4,  and  TSH),  gross  necropsy  findings,  organ  weights,  and 
histopathologic examinations. Average compound consumption for the 1500, 3000, and 6000 
ppm groups was 86, 177, and 357 mg/kg/day for males and 106, 204, and 429 mg/kg/day 
for females, respectively. All animals survived to the scheduled necropsy.  

There were no direct test substance-related clinical, ophthalmic, macroscopic, or microscopic 
observations  or  effects  on  serum  chemistry,  haematology,  coagulation,  urinalysis,  thyroid 
hormone  concentration,  and  organ  weights.  Adverse  test  substance-related  lower  body 
weights  and  body  weight  gains  were  noted  in  the  6000  ppm  group  males  and  females 
generally  throughout  the  dosing  period.  In  the  6000  ppm  group  males,  lower  food 
consumption was noted during the first week of dosing and lower food efficiency was noted 
throughout the first month of the dosing period. Lower mean food efficiency was also noted 
for females in the 6000 ppm group during 7 of the 13 weekly intervals during the study.  

Effects on mean food efficiency were considered adverse as they were a contributing factor 
to  the  adverse  effects  on  body  weights  in  males  and  females  at  6000  ppm.  Based  on  the 
results  of  this  study,  dietary  administration  of  Benzyl  Salicylate  to  Crl:CD(SD)  rats  at 
concentrations of 1500, 3000, and 6000 ppm for a minimum of 90 days resulted in adverse 
lower body weights, lower body  weight gains, and decreased  food  efficiency  for males and 
females at 6000 ppm.  

Therefore, the no-observed-effect level (NOEL) was considered to be 3000 ppm (equivalent 
to 177 and 204 mg/kg/day for males and females, respectively). 

Ref: https://echa.europa.eu/de/registration-dossier/-/registered-dossier/16100/7/6/1 

• 

Inhalation route 

There are no specific repeat dose toxicity data by the inhalation route for Benzyl Salicylate. 

Given hydrolysis has been shown to occur via lung microsomes (Ozaki et al., 2015), it may 
be relevant to consider the benzyl alcohol data that is available. Also, there are data on acute 
inhalation for methyl salicylate to provide supporting evidence that salicylates in general are 
not acutely toxic to respiratory tract and lung. 

• 

Dermal route 

No study available 

3.4.4.3 Chronic (> 12 months) toxicity 

3.4.5 Reproductive toxicity 

No reproductive toxicity data were available on Benzyl Salicylate, as performed before the 
March 2013 animal testing ban.  

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Taken from the REACH dossier on Benzyl Salicylate 

SCCS/1656/23 
Final Opinion 

to  conduct  additional 

Following  ECHA  decision  (CCH-D-2114379324-45-01/F)  on  Benzyl  Salicylate  it  was 
- 
for 
requested 
reproductive/developmental  toxicity  (Annex  VIII,  Sections  8.6.1  and  8.7.1.;  test  method: 
OECD TG 421) in rats, oral route 
- 
B.31./OECD 414) in a first species (rat or rabbit), oral route. 

a  Pre-natal  developmental  toxicity  study  (Annex  IX,  Section  8.7.2.;  test  method:  EU 

toxicological  studies:  a  Screening  study 

3.4.5.1 Fertility and reproduction toxicity 

The objective of the following study was to provide preliminary information on the potential 
adverse effects of the test substance on male and female reproduction within the scope of a 
screening  study.  This  encompassed  gonadal  function,  mating  behavior,  conception, 
parturition, and lactation of the parental generation and the development of offspring from 
conception through day 13 of postnatal life. 

Guideline:  

Species/strain:    
Group size:  
Test substance:   
Physical form: 
Batch:  
Purity:  
Vehicle:  
Dose levels:  

Route:  
Administration:   
Exposure period:  

GLP:   
Study period: 

OECD Guideline 421 (Reproduction / Developmental Toxicity 
Screening Test) 
female and male Sprague-Dawley rats 
4 groups of 10 male and 10 female rats 
Benzyl Salicylate 
/ 
/ 
/ 
not need (dietary study) 
500, 750, and 2500 ppm equivalent to 32, 48 and 158 mg/kg 
for males and 34, 49 and 166 for females  
oral feed 
continuously  
FO males for 14 days prior to mating and continuing through 
the day of euthanasia (minimum 28 days of dose 
administration); F0 females were dosed for 14 days prior to 
mating and continuing through Lactation Day 13. The F1 
animals were not directly exposed to the test substance at any 
time during the study; the offspring of the F0 parental 
generation were potentially exposed to the test substance in 
utero and while nursing. 
Yes    
IN-LIFE DATES: from 30 May 2019 to 27 Aug 2019 

Taken from the REACH dossier 

Animals were administered the test substance continuously in the diet. F0 males were dosed 
for 14 days prior to mating and continuing through the day of euthanasia. F0 females were 
dosed  for  14  days  prior  to  mating  and  continuing  through  Lactation  Day  13.  The  following 
parameters and end points were evaluated in this study: clinical signs, body weights, body 
weight gains, food consumption, oestrous cycles, reproductive performance, parturition, litter 
viability and survival, anogenital distance, areolae/nipple anlagen, thyroid hormones, gross 
necropsy findings, organ weights, and histopathologic examinations. 

Mean  compound  consumption  was  34,  49,  and  166  mg/kg/day  in  the  500,  750,  and  2500 
ppm  group  F0  males  during  the  premating  treatment  period  (Study  Days  0–14).  Mean 
compound consumption was 32, 48, and 158 mg/kg/day during the premating period (Study 
Days  0–14),  33,  51,  and  170  mg/kg/day  during  gestation  (Gestation  Days  0–20),  and  67, 
101, and 324 mg/kg/day during lactation (Lactation Days 1–13) in the 500, 750, and 2500 

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Final Opinion 

Opinion on Benzyl Salicylate (CAS No. 118-58-1, EC No. 204-262-9) 
_________________________________________________________________________________ 

ppm group females, respectively. All F0 males and females in the control, 500, 750, and 2500 
ppm groups survived to the scheduled necropsy. There were no test substance-related clinical 
observations noted at the daily examinations at any exposure level. 

No test substance-related effects on F0 body weight or food consumption parameters were 
noted for males and throughout the study at any exposure concentration.  

F0  male  and  female  mating  and  fertility,  male  copulation  and  female  conception  indices, 
oestrous cycle lengths, mean number of days between pairing and coitus, gestation lengths, 
and the process of parturition were unaffected by test substance administration at all dietary 
concentrations.  

No test substance-related effects on mean T4 levels were noted in the 500, 750, and 2500 
ppm group F0 males on Study Day 28.  

There  were  no  test  substance-related  effects  on  gross  observations,  organ  weights,  or 
histologic changes observed in the F0 generation.  

There  were  no  test  substance-related  effects  on  the  mean  number  of  former  implantation 
sites or unaccounted-for sites at any exposure level.  

Mean absolute F1 birth weights (PND 1) in the 2500 ppm group males and females were 4.9% 
and 5.2% lower, respectively, than the control group. Lower mean body weight gains in these 
pups during PND 4–13 resulted in mean absolute male and female body weights that were up 
to 7.8% and 10.4% lower, respectively, than the control group. These differences were not 
statistically significantly different compared to the control group except for female F1 pups in 
the 2500 ppm group on PND 13. Also, the lower mean pups body weight in the 2500 ppm 
group was mainly due to lower body weights in a single litter (No. 4892) and the body weight 
mean in other litters in the 2500 ppm group were all within Charles River historical control 
data range; therefore, the effects on mean body weights and body weight gains at 2500 ppm 
were considered test substance-related and no adverse. 

Mean  pup  body  weights  and  body  weight  gains  in  the  500  and  750  ppm  groups  were 
unaffected by test substance administration. 

There were no test  substance-related  effects on mean number  of pups born, pup  survival, 
liver  litter  size,  mean  sex  ratio,  anogenital  distance,  areolae/nipple  anlagen  (males  only), 
thyroid  hormone  levels  (total  T4)  on  PND  13,  and  thyroid  weights.  There  were  no  clinical 
observations or necropsy findings that could be attributed to F0 maternal administration of 
the test substance at any exposure concentration. 

Under the conditions of this screening study, no test substance-related effects were noted on 
reproductive performance in F0 males and females at any exposure concentration. Based on 
the lack of F0 parental toxicity at any exposure concentration, an exposure concentration of 
2500  ppm  (the  highest  dose  level  tested)  was  considered  to  be  the  no-observed-adverse-
effect  level  (NOAEL)  for  F0  systemic  and  reproductive  toxicity  of  Benzyl  Salicylate  when 
administered  in  the  diet  to  Crl:CD(SD)  male  and  female  rats.  Based  on  the  lack  of  test 
substance-related  effects  at  any  dose  level,  an  exposure  concentration  of  2500  ppm  (the 
highest dose level tested) was considered to be the no-observed-adverse-effect level (NOAEL) 
for F1 neonatal toxicity. The 2500 ppm dose level corresponded to actual consumption of 166 
mg/kg/day  for  males  during  the  pre-mating  period  and  158,  170,  and  324  mg/kg/day  for 
females during pre-mating, gestation, and lactation, respectively. 

Ref: https://echa.europa.eu/de/registration-dossier/-/registered-dossier/16100/7/9/2 

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Opinion on Benzyl Salicylate (CAS No. 118-58-1, EC No. 204-262-9) 
_________________________________________________________________________________ 

SCCS comment  
The SCCS agrees that the NOAEL derived from this study should be 166 mg/kg/day for male 
rats and 158 mg/kg/day for female rats. 

3.4.5.2 Developmental Toxicity 

The objectives of the following study were to determine the potential of the test substance to 
induce  developmental  toxicity  after  maternal  exposure  from  implantation  to  expected 
parturition, to characterize maternal toxicity at the exposure levels tested and to determine 
a no-observed-adverse-effect level (NOAEL) for maternal and developmental toxicity. 

Guideline:  
Species/strain:    
Group size:  
Test substance:   
Physical form: 
Batch:  
Purity:  
Vehicle:  
Dose levels:  

Route:  
Administration:   
Exposure period:  
GLP:   
Study period: 

OECD Guideline 414 (Prenatal Developmental Toxicity Study) 
female Sprague-Dawley rats 
4 groups of 25 female rats 
Benzyl Salicylate 
/ 
/ 
/ 
not need (dietary study) 
1000, 3000, and 4000 ppm equivalent to 72, 214 and 289 
mg/kg  
oral feed 
continuously 
From gestation Day 6 to through 21.  
Yes    
IN-LIFE DATES: From: 04 March 2019 To: 29 March 2019 

All  females  survived  to  the  scheduled  necropsy  on  Gestation  Day  21;  there  were  no  test 
substance‑related clinical observations during the study. 

Mean maternal body weight loss in the 4000 ppm group and lower mean body weight gain in 
the 3000 ppm group were noted following administration of the first dose (Gestation Days 6–
7), and lower mean food consumption was noted in these groups during Gestation Days 6–9 
(both groups) and 9–12 (3000 ppm only).  

Mean absolute body weights in the 4000 ppm group were up to 6.4% lower than the control 
group  during  Gestation  Days  7–21.  Some  of  the  aforementioned  differences  in  mean  body 
weight  changes  and  food  consumption  and  all  of  the  differences  in  mean  absolute  body 
weights were statistically significant compared to the control group. The effects on mean body 
weights,  body  weight  gains,  and  food  consumption  at  4000  ppm  were  considered  test 
substance-related and adverse due to the magnitude of the changes.  

Mean  body  weights  in  the  3000  ppm  group  were  slightly  lower  than  the  control  group 
(sporadically statistically significant) during Gestation Days 7–15; however, the values were 
≤ 4.3% lower than the control group. The effects on mean body weights, body weight gains, 
and food consumption at 3000 ppm were considered test substance-related but not adverse 
due  to  the  low  magnitude  of  the  changes  and  the  transient  nature.  There  were  not  test 
substance-related effects on maternal body weight and food consumption parameters in the 
1000 ppm group. 

There were no test substance-related macroscopic findings noted at the scheduled necropsy. 

Mean foetal body weights (male, female, and combines sexes) were 7.1% and 10.7% lower 
in  the  4000  ppm  group  compared  to  the  concurrent  control  group  and  resulted  in  a  lower 
mean gravid uterine weight in the 4000 ppm group; the differences in mean  foetal weights 
were  statistically  significant,  and  the  values  were  below  the  minimum  mean  values  in  the 
Charles  River  Ashland  historical  control  data,  therefore  were  considered  test  substance-
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Final Opinion 

Opinion on Benzyl Salicylate (CAS No. 118-58-1, EC No. 204-262-9) 
_________________________________________________________________________________ 

related and adverse. Intrauterine growth in the 1000 ppm group and intrauterine survival in 
the 1000, 3000, and 4000 ppm groups were unaffected by test substance administration. 

There were no test substance-related foetal malformations noted in any group. A higher mean 
litter  proportion  of  14th  rudimentary  rib(s)  was  noted  in  the  4000  ppm  group  (statistically 
significant) and higher mean litter proportions of bent rib(s) were noted in the 3000 and 4000 
ppm  groups  compared  to  the  concurrent  control  group;  the  values  were  also  above  the 
maximum mean values in the Charles River Ashland historical control data.  

These findings corresponded to the test substance-related lower mean  foetal body weights 
observed at 3000 and 4000 ppm but were not considered adverse because both have been 
noted to resolve postnatally and should not be used in risk assessment to set standards for 
exposure to chemical agents (Kimmel, et al., 2014). 

Ref: https://echa.europa.eu/de/registration-dossier/-/registered-
dossier/16100/7/9/3/?documentUUID=59df934a-3aff-4c34-b016-61e23a9c1936 

SCCS comment  
Based on adverse mean body weight loss, lower mean body weights and food consumption 
at 4000 ppm, a dosage level of 3000 ppm, equivalent to 214 mg/kg/day, was considered 
to be the NOAEL for maternal toxicity.  

Based  on  lower  mean  foetal  body  weights  in  the  4000  ppm  group,  a  dosage  level  of  3000 
ppm, equivalent to 214 mg/kg/day, was considered to be the NOAEL for embryo/foetal 
development when Benzyl Salicylate was administered orally (via the diet) to time-mated 
Crl:CD(SD) rats.  

3.4.6 Mutagenicity / genotoxicity 

3.4.6.1 Mutagenicity / genotoxicity in vitro 

Bacterial gene mutation tests 

Three  Ames  tests  in  Salmonella  typhimurium  were  performed  for  Benzyl  Salicylate  in  the 
presence  and  absence  of  metabolic  activation,  using  the  following  strains:  TA98,  TA100, 
TA1535, and TA1537, and/or TA97 (Zeiger et al., 1987; NTP (2018a,b)). Doses of 3.3 to 333 
μg  Benzyl  Salicylate/plate  in  dimethyl  sulfoxide  (DMSO)  vehicle  did  not  produce  any 
mutagenic effects with or without metabolic activation. 

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Opinion on Benzyl Salicylate (CAS No. 118-58-1, EC No. 204-262-9) 
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Table 22: In vitro bacterial assays for Benzyl Salicylate 

SCCS/1656/23 
Final Opinion 

Mammalian gene mutation test 

The following in vitro assays were available using mammalian cells (summary in Table 23 and 
abstracts of the studies below the Table). 

Table 23: In vitro mammalian clastogenicity and gene mutation 

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Opinion on Benzyl Salicylate (CAS No. 118-58-1, EC No. 204-262-9) 
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SCCS/1656/23 
Final Opinion 

In Vitro Mammalian Cell Gene Mutation Test (according to OECD Guideline 476) (2019) 

The test substance, Benzyl Salicylate (CAS# 118-58-1), was evaluated for its ability to induce 
forward  mutations  at  the  hypoxanthine-guanine  phosphoribosyl  transferase  (HPRT)  locus 
(hprt) of Chinese hamster ovary (CHO) cells, in the presence and absence of an exogenous 
metabolic activation system, as assayed by colony growth in the presence of 6-thioguanine 
(TG resistance, TGr). Dimethyl sulfoxide (DMSO) was used as the vehicle. 

In the preliminary toxicity assay, the concentrations tested were 3.91, 7.81, 15.6, 31.3, 62.5, 
125, 250, 500, 1000 and 2000 μg/mL. The maximum concentration evaluated approximated 
the limit dose for this assay. Visible precipitate was observed at concentrations ≥31.3 μg/mL 
at the beginning of treatment and at concentration 2000 μg/mL by the end of treatment with 
S9. Adjusted relative survival was 44.74 and 64.94% at a concentration of 2000 μg/mL with 
and  without  S9,  respectively.  Based  upon  these  results,  the  concentrations  chosen  for  the 
definitive mutagenicity assay were 125, 250, 500, 1000 and 2000 μg/mL with and without 
S9. 

In the definitive mutagenicity assay, visible precipitate was observed at all concentrations at 
the beginning of treatment and at concentrations ≥1000 μg/mL by the end of treatment with 
S9. The average adjusted relative survival was 21.80 and 78.14% at a concentration of 2000 
μg/mL  with  and  without  S9,  respectively.  Cultures  treated  at  all  concentrations  with  and 
without S9 were chosen for mutant selection. No statistically significant increases in mutant 
frequency,  as  compared  to  the  concurrent  vehicle  controls,  were  observed  at  any 
concentration  evaluated  with  or  without  S9  (p  >  0.01).  The  positive  controls  induced 
significant increases in mutant frequency (p < 0.01). 

These  results  indicate  Benzyl  Salicylate  (CAS#  118-58-1)  was  negative  for  the  ability  to 
induce  forward  mutations  at  the  hypoxanthine-guanine  phosphoribosyl  transferase  (HPRT) 
locus  (Hprt)  of  Chinese  hamster  ovary  (CHO)  cells,  in  the  presence  and  absence  of  an 
exogenous metabolic activation system. 

Conclusion: 

Under the conditions of the assay, Benzyl Salicylate (CAS# 118-58-1) was concluded to be 
negative for the induction of forward mutations at the hypoxanthineguanine phosphoribosyl 
transferase (HPRT) locus (Hprt) of Chinese hamster ovary (CHO) cells, in the presence and 

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Final Opinion 

Opinion on Benzyl Salicylate (CAS No. 118-58-1, EC No. 204-262-9) 
_________________________________________________________________________________ 

absence of an exogenous metabolic activation system, in the in vitro mammalian cell forward 
gene mutation (CHO/HPRT) assay. 

Ref: BioReliance Corporation, BioReliance Study Number AF45GY.783.BTL (2019) 

SCCS comment  
In the main (definitive) experiment with S9-mix, the concentrations 250 and 500 μg/mL gave 
high cytotoxicity (9.1 and 10.9% of viability, respectively), which is not in accordance with 
the OECD Guideline. Historical positive control B(a)P has a high range of mutant frequency 
from 6-323 mutants per million of cells, while the negative control shows a much lower range 
from 0-15 mutants per million of cells. The SCCS therefore considers this study as not valid.  

New study submitted by Applicant in March 2023 

In vitro Cell Gene Mutation Test (according to OECD Guideline 476)  

An in vitro mammalian cell gene mutation assay was performed in CHO K1 Chinese hamster 
ovary  cells  at  the  Hprt  locus  to  evaluate  the  potential  of  Benzyl  Salicylate  (batch  number 
VE00790747)  to  cause  gene  mutation.  Treatments  were  carried  out  for  5  hours  with  and 
without metabolic activation (±S9-mix – rat metabolic activation induced by phenobarbital) 
and  for  24  hours  without  metabolic  activation  (-S9-mix).  The  study  was  performed  in 
compliance with the OECD Principles of Good Laboratory Practice.  

Positive controls without metabolic activation - Ethyl methanesulfonate (EMS, 0.4 μL/mL) was 
used. For metabolic activation 7,12 dimethylbenz[a]anthracene (DMBA, 15 μg/mL) was used. 
Dimethyl  sulfoxide  (DMSO,  1%)  was  used  as  the  vehicle  (solvent)  of  the  test  item  in  this 
study. Stock solution 200mg/mL was prepared.  Treatment concentrations for the mutation 
assays of the main tests were selected based on the results of a preliminary toxicity test as 
follows: 

Assay 1 
5-hour treatment in the presence of S9-mix: 2000, 1000, 500, 250, 125, 62.5, 31.25, 15.625, 
7.813 and 3.906 μg/mL. 
5-hour treatment in the absence of S9-mix: 2000, 1000, 500, 250, 125, 62.5, 31.25, 15.625, 
7.813 and 3.906 μg/mL. 

Assay 2 
5-hour treatment in the presence of S9-mix: 2000, 1000, 500, 250, 125, 62.5, 31.25, 15.625, 
7.813 and 3.906 μg/mL. 
24-hour  treatment  in  the  absence  of  S9-mix:  2000,  1000,  500,  250,  125,  62.5,  31.25, 
15.625, 7.813 and 3.906 μg/mL. 

In the main assays, a measurement of the survival (colony-forming ability at the end of the 
treatment  period)  and  viability  (colony-forming  ability  at  the  end  of  the  7  day  expression 
period following the treatment) and mutagenicity (colony-forming ability at the end of the 7 
day expression period following the treatment, in the presence of 6-thioguanine as a selective 
agent) was determined. 

In Assay 1, insolubility (precipitate) was detected in the final treatment medium at the end 
of the treatment in the experiments with and without metabolic activation at the concentration 
range of 2000 - 125 and/or 62.5 μg/mL.  

In Assay 2, insolubility (precipitate) was detected in the final treatment medium at the end 
of the treatment in the experiment with and without metabolic activation at the concentration 
range of 2000 - 500 and/or 250 μg/mL. There were no large changes in pH and osmolality 
after treatment in any cases. 
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Final Opinion 

Opinion on Benzyl Salicylate (CAS No. 118-58-1, EC No. 204-262-9) 
_________________________________________________________________________________ 

In Assay 1, in the presence of S9-mix (5-hour treatment), marked cytotoxicity of the test 
item was observed at only 500 μg/mL concentrations (with a relative survival of 44%). In the 
absence  of  S9-mix  (5-hour  treatment),  cytotoxicity  was  observed  in  2000,  1000,  500  and 
250 μg/mL, with a relative survival of 38%, 33%, 37% and 49%, respectively. 

In Assay 2, in the presence of S9-mix (5-hour treatment), cytotoxicity of the test item 
was observed in 2000, 1000, 500 and 250 μg/mL, with a relative 
survival  of  79%,  51%,  30%  and  59%,  respectively.  In  the  absence  of  S9-mix  (24-hour 
treatment), cytotoxicity was observed in 2000, 1000, 500, 250 and 125 μg/mL, with a relative 
survival of 25%. 28%, 23%, 35% and 58%, respectively. Therefore, the evaluation was made 
using data of all ten concentrations (up to the recommended maximum concentration).  

No statistically significant increases in the mutant frequency were observed at any examined 
concentrations when compared to the negative (vehicle) control data and there was no dose 
response to the treatment (a trend Test Facility analysis showed no effect of treatment (R2 
= 0.447)). This experiment is considered to be negative. 

In Assay 1, without metabolic activation, statistically significant increase in the mutation 
frequencies was observed in this experiment at a single value (at the concentration of 31.25 
μg/mL, at p< 0.05 level), but the observed increase was within the general historical control 
range.  Furthermore,  the  observed  mutant  frequency  (8.4  x  10-6)  was  within  the  expected 
range  of  the  negative  control  samples  according  to  the  relevant  OECD  guideline  (expected 
range:  5-20  x  10-6).  No  dose  response  to  the  treatment  was  observed  (a  trend  analysis 
showed  no  effect  of  treatment  (R2  =  0.021)).  This  experiment  is  considered  to  be 
negative. 

In  Assay  2,  with  metabolic  activation  statistically  significant  increase  in  the  mutation 
frequencies  (at  p  <  0.01  level)  was  observed  in  this  experiment  at  a  single  value  (at  the 
concentration  of  62.5  μg/mL),  but  the  observed  increase  was  within  the  general  historical 
control  range.  Furthermore,  the  observed  mutant  frequency  (10.7  x  10-6)  was  within  the 
expected  range  of  the  negative  control  samples  according  to  the  relevant  OECD  guideline 
(expected  range:  5-20  x  10-6).  No  dose  response  to  the  treatment  was  observed  (a  trend 
analysis showed no effect of treatment (R2 = 0.067)). This experiment is considered to 
be negative. Moreover, it confirmed the result of the Assay 1. 

In  Assay  2,  in  the  absence  of  S9-mix  (24-hour  treatment)  no  statistically  significant 
increases  in  the  mutation  frequency  were  observed  at  any  examined  concentrations  when 
compared  to  the  negative  (vehicle)  control  data  and  there  was  no  dose  response  to  the 
treatment (a trend analysis showed no effect of treatment (R2 = 0.003)). This experiment is 
considered to be negative. 

The spontaneous mutant frequency of the negative (vehicle) control was in accordance with 
the general historical control range in all assays. The positive controls gave the anticipated 
increases in mutation frequency over the controls in line with the historical data in all assays. 
Ten  evaluated  concentrations  were  presented  in  all  assays.  The  cloning  efficiencies  for  the 
negative controls at the beginning and end of the expression period were within the target 
range. The evaluated concentration ranges were considered to be adequate (concentrations 
were tested up to the maximum achievable cytotoxicity, which plateaued well below the target 
10-20% survival as concentrations increased. The overall study was considered to be valid. 

In conclusion, no mutagenic effect of Benzyl Salicylate was observed either in the 
presence or absence of a metabolic activation system under the conditions of this 
HPRT  assay.  The  study  was  considered  valid  based  on  the  negative  and  positive 
control values. 

Ref: Charles River Laboratories Hungary Kft. Final report.  
Study Code: 22/215-015C, (2023) 

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Opinion on Benzyl Salicylate (CAS No. 118-58-1, EC No. 204-262-9) 
_________________________________________________________________________________ 

SCCS comment  
According to OECD TG 476, the top concentration should be considered based on cytotoxicity 
and  precipitation.  If  no  precipitate  or  limiting  cytotoxicity  is  observed,  the  highest  test 
concentration should correspond to 10 mM, 2 mg/mL or 2 μL/mL, whichever is the lowest. As 
stated in the Guideline, it is advisable to test only one concentration producing turbidity or 
with  a  visible  precipitate  because  artifacts  may  result  from  the  precipitate.  However,  in  all 
preliminary as well as the main experiments (5h treatment with and without S9-mix) and 24h 
treatment without S9-mix, the precipitates appeared already in lower/middle concentrations 
(65.5  -125-250ug/mL)  before  and  after  the  treatment.  Nevertheless,  the  study  was 
considered valid by the SCCS.  

In  Vitro  Mammalian  Chromosomal  Aberration  Test  in  Chinese  hamster  cells 
(according to OECD Guideline 473) (2018) 

In order to evaluate the clastogenic potential of Benzyl Salicylate, a chromosomal aberration 
test using cultured Chinese hamster (CHL/IU) cells was conducted (Study period: December 
14, 2016 to March 27, 2017). 

As a preliminary study to select dose levels for the chromosomal aberration test, a cell-growth 
inhibition  test  was  conducted  setting  the  highest  dose  level  at  2000  μg/mL,  and  this  dose 
diluted using a common ratio of 2 to prepare a total of 8 concentrations. In the results, cell 
growth inhibition effects of more than 50% were recorded at the dose levels of 125 μg/mL 
and  above  for  the  short-term  treatment  method  without  metabolic  activation  and  for  the 
continuous treatment method and at the dose levels of 250 μg/mL and above for the short-
term  treatment  method  with  metabolic  activation,  and  thus  the  50%  cell  growth  inhibition 
concentration  (approximate  value)  was  calculated  to  be  92  μg/mL  for  the  short-term 
treatment  method  without  metabolic  activation,  178  μg/mL  for  the  short-term  treatment 
method with metabolic activation, and 97 μg/mL for the continuous treatment method.  

Based on these results, chromosome aberration study was conducted setting the maximum 
dose concentration at 120 μg/mL and using 5 dose concentrations with common difference of 
20  μg/mL  for  the  short-term  treatment  method  without  metabolic  activation  and  for  the 
continuous treatment method, and setting the maximum dose concentration at 200 μg/mL 
and  using  5  dose  concentrations  with  common  difference  of  30  μg/mL  for  the  short-term 
treatment method with metabolic activation. 

In the results of the chromosome aberration study, the incidence of the occurrence of cells 
with chromosomal aberrations not containing gaps, an index for the chromosome structural 
aberration (TA value), and the incidence of the occurrence of cells with polyploidy (poly value) 
were not higher than those in the negative control group with statistical significance for any 
treatment  method,  and  the  values  for  the  negative  control  group  within  the  range  of  95% 
probability distribution of the negative control values in the historical background data of the 
test facility. Therefore, the test article was judged to be negative for chromosome aberration 
effects. 

For  all  the  treatment  methods,  the  incidence  of  the  occurrence  of  cells  with  chromosome 
structural aberrations and the incidence of the occurrence of polyploidy in the negative control 
group were within the range of 95% probability distribution of the historical background data 
of  the  test  facility.  In  the  positive  control  group,  a  statistically  significant  increase  in  the 
incidence  of  cells  with  chromosome  structural  aberration  was  recorded  in  comparison  with 
that  of  the  negative  control  group.  Therefore,  it  was  judged  that  the study  was  conducted 
appropriately. 

Conclusion:  It  was  concluded  that  Benzyl  Salicylate  had  neither  chromosome  structural 
aberration inducibility nor chromosome numerical aberration inducibility under the conditions 
of this study. 

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Opinion on Benzyl Salicylate (CAS No. 118-58-1, EC No. 204-262-9) 
_________________________________________________________________________________ 

Ref: Tokyo Laboratory, BoZo Research Center Inc., Study Number: T-G239 (2018) 

SCCS comment 
The SCCS agrees that Benzyl Salicylate was negative in the chromosome aberration test.  

In Vitro Mammalian Cell Micronucleus Assay in human peripheral blood 
lymphocytes (according to OECD Guideline 487)  

The  test  substance, Benzyl  Salicylate,  was  tested  to  evaluate  the  potential  to  induce 
micronuclei in human peripheral blood lymphocytes (HPBL) in both the absence and presence 
of an exogenous metabolic activation system. HPBL were treated for 4 hours in the absence 
and  presence  of  S9  mix,  and  for  24 hours  in  the  absence  of  S9  mix. Dimethyl  sulfoxide 
(DMSO) was used as the vehicle. 

In the preliminary toxicity assay (A1), the doses tested ranged from 0.2 to 2000 µg/mL, which 
was the limit dose for this assay. Cytotoxicity [>= 55± 5%cytokinesis-blocked proliferation 
index  (CBPI)  relative  to  the  vehicle  control]  was  observed  at  doses  >=200  µg/mL  in  the 
non-activated and S9-activated 4-hour exposure groups, and at doses >= 60 µg/mL in the 
non-activated  24-hour  exposure  group. At  the  conclusion  of  the  treatment  period,  visible 
precipitate was observed at doses >= 600 µg/mL in all three exposure groups. Based upon 
these results, the doses chosen for the micronucleus assay ranged from 38.8 to 156 µg/mL 
for the non-activated 4-hour exposure group, from 38.8 to 280 µg/mL for the S9-activated 
4-hour exposure group, and from 9.70 to 69.6 µg/mL for the non-activated 24-hour exposure 
group. 

In  the  initial  micronucleus  assay  (B1),  cytotoxicity  (55±  5%  CBPI  relative  to  the  vehicle 
control)  was  observed  at  doses  >=  50.7  µg/mL  in  the  non-activated  24-hour  exposure 
group. At the conclusion of the treatment period, visible precipitate was not observed at any 
dose in any of the exposure groups. In the non-activated and S9-activated 4-hour exposure 
group,  due  to  lack  of  requisite  cytotoxicity,  the  micronucleus  assay  was  repeated  at  doses 
ranging from 22.5 to 100 µg/mL for the non-activated 4-hour exposure group and from 45 to 
250 µg/mL for the S9-activated 4-hour exposure group. 

In  the  repeat  assay  (B2),  cytotoxicity  (55±  5%  CBPI  relative  to  the  vehicle  control)  was 
observed at doses >= 81 µg/mL in the non-activated 4-hour exposure group and at doses 
>= 180 µg/mL in the S9-activated 4-hour exposure group. At the conclusion of the treatment 
period, visible precipitate was not observed at any dose in both exposure groups. 

The  doses  selected  for  evaluation  of  micronuclei  were  19.4,  38.8,  and  56.4  µg/mL  for  the 
non-activated  24-hour  exposure  group;  22.5,  65.6,  and  81  µg/mL  for  the  non-activated 
4-hour exposure group; and 90, 162, and 180 µg/mL for the S9-activated 4-hour exposure 
group. 

Neither  statistically  significant  nor  dose-dependent  increases  in  micronuclei  induction  were 
observed at any dose in treatment groups wth or without S9 (p > 0.05; Fisher’s Exact and 
Cochran-Armitage  tests). The  results  were  within  the  95%  control  limit  of  the  historical 
negative control data. 

These results indicate Benzyl Salicylate was negative for the induction of micronuclei in the 
presence and absence of the exogenous metabolic activation system.  

Conclusion: Under the conditions of the assay described in this report, Benzyl Salicylate was 
concluded  to  be  negative  for  the  induction  of  micronuclei  in  the  non-activated  and  S9-
activated test systems in the in vitro mammalian micronucleus test using human peripheral 
blood lymphocytes. 

Ref: BioReliance Corporation. BioReliance Study Number AF45GY.348REACH.BTL (2021) 

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SCCS comment 
The SCCS agrees that Benzyl Salicylate was negative in the in vitro mammalian micronucleus 
test.  

SCCS/1656/23 
Final Opinion 

3.4.6.2 Mutagenicity / genotoxicity in vivo 

There are no in vivo data for Benzyl Salicylate. 

The Applicant’s conclusion on mutagenicity and genotoxicity of Benzyl Salicylate  

Benzyl Salicylate is not genotoxic or mutagenic in any of the OECD guideline in vitro assays 
performed. The mutagenicity and genotoxicity data for salicylic acid were recently reviewed 
by the SCCS (SCCS, 2018) and benzyl alcohol is also not genotoxic or mutagenic (CIR, 2017). 
There are no concerns from these endpoints for Benzyl Salicylate. 

The SCCS overall comment on mutagenicity and genotoxicity of Benzyl Salicylate 
Benzyl Salicylate was tested in 3 bacterial gene mutation tests with negative results. However, 
the SCCS noted that in the studies 1 strain combination recommended by the OECD TG 471 
was  not  represented  (E.  coli  WP2  uvrA,  or  E.  coli  WP2  uvrA  (pKM101),  or  S.  typhimurium 
TA102). 

Benzyl Salicylate was tested in 2 mammalian gene mutation tests in Hprt locus on Chinese 
hamster ovary (CHO) cells with negative results. However, the first study was not considered 
valid due to  several  shortcomings highlighted above.  The second  in vitro mammalian gene 
mutation  study  was  considered  valid  even  if  precipitation  appeared  already  in  middle 
concentrations.  

Benzyl Salicylate was tested in 1 valid in vitro mammalian chromosomal aberration test on 
Chinese  hamster  cells  and  1  valid  in  vitro  mammalian  cell  micronucleus  assay  on  human 
lymphocytes, both with negative results. 

After analysis of the available data, the SCCS considers that Benzyl Salicylate does not pose 
a genotoxic/ mutagenic potential. 

3.4.7 Carcinogenicity 

There  are  no  carcinogenicity  studies  for  Benzyl  Salicylate.  However,  given  there  are  no 
genotoxicity/  mutagenicity  concerns  from  in  vitro  assays  with  or  without  S9,  and  it  is  also 
highly  unlikely  that  the  main  metabolites  salicylic  acid  and  benzyl  alcohol  may  act  as 
carcinogens, then there are no known concerns to address for Benzyl Salicylate. 

Conclusion from the Applicant: Benzyl Salicylate is not expected to be a carcinogen in animals. 

SCCS comment 
After analysis of the available in vitro mutagenicity studies, the SCCS considers that Benzyl 
Salicylate is not likely to be a human carcinogen. 

3.4.8 Photo-induced toxicity 

3.4.8.1 Phototoxicity / photo-irritation and photosensitisation 

Based on the available in vivo and human data Benzyl Salicylate does not present a concern 
for phototoxicity or photoallergenicity. 

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Final Opinion 

Opinion on Benzyl Salicylate (CAS No. 118-58-1, EC No. 204-262-9) 
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UV Spectra Analysis: UV/Vis absorption spectra (OECD test guideline  101) were generated 
for Benzyl Salicylate. Benzyl Salicylate absorbs in the range of 290 to 700 nm. Furthermore, 
the molar absorption coefficient for λ max within this range is above 1000 L ∙ mol-1 ∙ cm-1, 
the benchmark of concern for phototoxic effects (Henry, 2009). 

Studies in mouse 

Forbes (1977); In a phototoxicity study, 12 Skh:hairless mice (6/group) received 1 application 
of  20  μl/5  cm2  of  25%  and  100%  Benzyl  Salicylate  in  methanol.  Thirty  minutes  later  the 
animals  were  irradiated.  One  group  was  irradiated  at  a  distance  of  0.65  meters  or  less  by 
fluorescent blacklight (a bank of 6 Sylvania F40T12BL PUVA lamps with a broad band output 
of  350  nm)  for  1  hour  to  provide  a  measure  dose  of  200  RB  units.  The  second  group  was 
irradiated at a distance of 1 meter from a simulated sunlight (Atlas Xenon light source, 6.5 
KW long-arc xenon high pressure burner with power supply, igniter and water-cooling system) 
for 1 hour providing a dose of 200 RB units. The treated areas were examined for presence 
or  absence  of  erythema,  scaling,  edema,  or  fissuring  at  4,  24,  48,  72,  and  96  hours  after 
exposure. No effects were observed. 

Studies in guinea-pig 

RIFM/Givaudan  (1982);  Two  open  applications  of  0.025  mL/2  cm2  of  1  and  3%  Benzyl 
Salicylate  in  ethanol  with  2%  DMSO  were  made  to  a  2  cm2  area  of  the  skin  of  10  shaved 
outbred Himalayan white spotted guinea pigs (300-450 grams) per dose. Thirty minutes after 
application,  one  site  was  irradiated  with  UV  light  (Westinghouse  FS  40  “Black  Lamp”  with 
energy of 1x10(4) Ergs/cm2/sec and spectrum of 320-400 nm). The radiation dose was 20 
J/cm2.  Reactions  were  graded  at  4,  24,  and  48  hours  after  application.  No  reactions  were 
observed at 1%. At 3% a slight reaction was seen in all 10 guinea pigs at the 4 and 24 hour 
readings. Eight (8/10) guinea pigs scores returned to normal at the 48 hour reading. 

RIFM/Rhodia (1983); Phototoxicity and photoallergy were evaluated in twenty (10/sex) adult 
albino  Dunkin  Hartley  guinea  pigs  weighing  300-400  grams.  The  animals  received  a  single 
application of 0.5 mL of 10% Benzyl Salicylate in absolute ethanol under an occlusive patch 
for 1 hour 30 minutes on the anterior part of the back. Irradiation was carried out using a 
system  of  fluorescent  lamps  with  continuous  spectrum  emission:  4000-3100,  Mazadaflour 
black  light  fluorescent  map:  3500-2850  Westinghouse  sun  fluorescent  lamp.  Radiation 
emitted by these lamps was principally in the UVA range (wavelength from 4000-3150 A) and 
in the UVB range (wavelength from 3150-2900 A). The 2 lamps used were placed 10 cm from 
the back of each animal and irradiated for 5 minutes. The total energy was 12.5 J/cm2 and 
the  rage  of  UVS  was  1%.  Evaluation  of  the  test  sites  was  made  at  6  and  24  hours  after 
irradiation. No effects were observed. 

RIFM/Takasago International (1997); In a phototoxicity study, open applications of 5%, 10% 
and  30%  Benzyl  Salicylate  in  acetone  were  made  to  clipped  skin  sites  on  5  female  albino 
Hartley-Dunkin  guinea  pigs.  The  application  sites  were  irradiated  with  UV  light  (array  of  5 
National  FL  20  S.BLB  tubes  (UV-A  black  light  300-400  nm,  max  360nm))  at  10  cm  for  60 
minutes. All irradiation energy was about 13 J/cm2. Reactions were graded according to Draize 
method at 24 & 48 hours after application. No effects were observed. 

Study in humans 

RIFM/Givaudan  (1983);  A  phototoxicity  test  was  conducted  on  6  volunteers.  Patches  were 
prepared with 0.025 mL/cm2 of 3% and 10%  Benzyl Salicylate in 1:1 ethanol/acetone was 
applied to the left and right side on the back of each subject. The right test side was covered 
and  served  as  an  irritancy  control  site.  Thirty  minutes  after  application  the  test  sites  were 
exposed to non-erythrogenic UVA irradiation at 1, 2.5, 5, 10 and 20 J/cm2. The light source 
was  a  bank  of  4  “blacklight”  fluorescent  tubes  with  an  emission  spectrum  of  320-400  mm 

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housed in a reflector unit. Following irradiation, each test site was examined 4, 24, 48, and 
72 hours after application. No phototoxic responses were observed. 

SCCS/1656/23 
Final Opinion 

3.4.8.2 Photomutagenicity / photoclastogenicity 

No data were provided 

3.4.9 Special investigations / Endocrine Activity 

Benzyl  Salicylate  has  been  identified  by  the  European  Commission  (and  via  the  German 
regulatory authorities in the CoRAP process) as a substance in cosmetic products that merits 
further  review  as  a  suspected  endocrine  disrupting  chemical  (EDC),  based  on  some 
observations reporting endocrine activity (Miller et al., 2001; Charles & Darbre 2009; Zhang 
et al., 2012), and one in relation to fish (Kunz & Fent, 2006).  

The  available  data  as  published  for  Benzyl  Salicylate  looking  at  the  potential  for  endocrine 
activity in vitro and in an uterotrophic assay, as relevant to mammalian systems, are reviewed 
below. In addition, new in vitro evidence has been provided by the Applicant (Natsch et al., 
2021). 

Endocrine activity in vitro – OECD level 2 studies  

Benzyl Salicylate has been included in the US EPA’s Endocrine Disruptor Screening Program 
for  the  21st  Century  (EDSP21)  and  returned  positive  results  in  9  Estrogen  Receptor  (ER) 
assays (out  of 33), in 0 Androgen Receptor (AR) assays (tested in 17), 0 out  of 9  Thyroid 
Receptor  (TR)  assays  and  3  out  of  26  steroidogenesis  assays.  The  relative  potency  was 
significantly  lower  for  Benzyl  Salicylate  compared  to  endogenous  endocrine  modulators. 
Based  on  the  US  EPA’s  EDSP  ToxCast  Estrogen  Receptor  (ER)/Androgenic  receptor  (AR) 
Model, Benzyl Salicylate was considered inconclusive for estrogenic potential and negative for 
androgen activity. 

In  the  study  from  Charles  and  Darbre  (2009),  Benzyl  Salicylate  was  reported  to  have 
estrogenic activity in assays using the estrogen-responsive MCF7 human breast cancer cell 
line. At 3 000 000-fold molar excess, they were able to partially displace [3H]-estradiol from 
recombinant human estrogen receptors Erα and Erβ, and from cytosolic ER of MCF7 cells. At 
concentrations in the range of 5 × 10−5 to 5 × 10−4 M, Benzyl Salicylate was able to increase 
the  expression  of  a  stably  integrated  estrogen-responsive  reporter  gene  (ERE-CAT)  and  of 
the endogenous estrogen-responsive pS2 gene in MCF7 cells, albeit to a lesser extent than 
with 10−8 M 17β-estradiol.  

In the study from Miller et al. (2001), the authors have used a recombinant yeast estrogen 
assay  to  assess  the  activity  of  73  phenolic  additives  that  were  used  as  sunscreens, 
preservatives,  disinfectants,  antioxidants,  flavorings,  or  for  perfumery.  Benzyl  Salicylate 
showed a very weak response (600,000 times weaker than 17β-estradiol), as shown in the 
table underneath.  

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Table  24:  Estrogenic  potency  values  (10%  response  level)  for  compounds  displaying 
submaximal responses 

SCCS/1656/23 
Final Opinion 

Zhang  et  al.  (2012)  have  evaluated  the  estrogenic  potentials  of  phenyl  salicylate  (PhS), 
Benzyl Salicylate (BzS), phenethyl salicylate (PES), ethyl salicylate (ES) and methyl salicylate 
(MS) using an in vitro human estrogen receptor α (hERα)-coactivator recruiting assay. They 
found that PhS, BzS and PES showed obvious in vitro hERα agonistic activities. BzS has the 
highest  activity  among  the  tested  Ses.  The  REC10  value  of  BzS  is  1.58×10−8  M,  which  is 
approximately 257- and 0.06-fold that of E2 and BPA, respectively. 

In  their  study,  Jimenez-Diaz  et  al.  (2013)  have  applied  a  new  liquid  chromatography–
tandem mass spectrometry (LC–MS/MS) method to assess the presence of six UV-filters in 
current  use  (Benzyl  Salicylate,  phenyl  salicylate,  octyl  salicylate,  homosalate,  3-(4-
methylbenzylidene)  camphor,  and  3-benzylidene  camphor)  in  human  placental  tissue. 
Moreover,  the  interactions  of  these  compounds  with  the  human  estrogen  receptor  alpha 
(hERα)  and  androgen  receptor  (hAR),  using  two  in  vitro  bioassays  based  on  reporter  gene 
expression and cell proliferation assessment, were also investigated. All tested compounds, 
except  Benzyl  Salicylate  and  octyl  salicylate,  showed  estrogenic  activity  in  the  E-Screen 
bioassay whereas only homosalate and 3-(4- methylbenzylidene) camphor were potent hAR 
antagonists. 

SCCS comment 
Benzyl Salicylate is not listed in the Annex VI  of the EU Cosmetic Regulation (allowed UV-
filters) but is listed in the Cosing database as a UV-Absorber. 

Natsch et al. (2021) reviewed the in vitro evidence for Benzyl Salicylate. Given the limited 
data,  two  new  in  vitro  assays  were  performed  to  assess  the  relative  potency  of  Benzyl 
Salicylate vs. Estradiol (E2) at binding the estrogen receptor (ER). The 2 tests are i) a T47D-
Kbluc cell-based assay with luciferase reporter gene under control of the estrogen response 
element (ERE) and ii) 6 days MCF-7 cell proliferation assay, cell yield by PrestoBlue®. In both 
assays, very similar results for BS were found. In the T47D-Kbluc cell assay Benzyl Salicylate 
was a partial agonist with a weak potency of 21,000,000- fold below E2; in the MCF-7 cell 
assay  Benzyl  Salicylate  was  a  partial  agonist  with  potency  for  equal  proliferation  ca. 
36,000,000- fold below E2. The authors concluded that this potency is significantly below the 
agonistic activity of known chemicals which cause estrogenic effects in in vitro assays.  

Applicant conclusion: 

In vitro assays confirm that Benzyl Salicylate is an extremely weak partial agonist of the ER, 
seven  orders  of  magnitude  lower  than  the  natural  substrate  E2.  It  is  highly  unlikely  given 
such a weak potency, that any effects are exerted in vivo by an ER mechanism. That potency 
makes the difference in relation to endocrine activity was highlighted in the review by Borgert 
et  al.  (2013).  Chemicals  with  low  potency  such  as  Benzyl  Salicylate  are  not  able  to  exert 

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Final Opinion 

Opinion on Benzyl Salicylate (CAS No. 118-58-1, EC No. 204-262-9) 
_________________________________________________________________________________ 

detectable endocrine activity against the background of highly potent endogenous hormones 
already occupying receptors, especially not at relatively low use concentrations. 

Endocrine activity in vivo – mouse uterotrophic assay (OECD Level 3 studies) 

Uterotrophic assay :  

Zhang  et  al.  (2012)  have  evaluated  the  estrogenic  potentials  of  phenyl  salicylate  (PhS), 
Benzyl Salicylate (BzS), phenethyl salicylate (PES), ethyl salicylate (ES) and methyl salicylate 
(MS) using an in vivo immature rodent uterotrophic bioassays. They found that PhS, BzS and 
PES  showed  obvious  in  vitro  hERα  agonistic  activities;  BzS  in  particular  exhibited  a  higher 
estrogenic  activity  compared  to  bisphenol  A  (BPA).  The  uterine  weights  were  significantly 
increased in mice treated with 11.1, 33.3, 100 and 300 mg/kg/day BzS and 33.3mg/kg/day 
PES and rats treated with 3.7, 11.1, 33.3 and 100mg/kg/day BzS for 3 days (P<0.05).  

Figure 5. uterine weight of mice administered SE chemical for 3 days beginning on PND21. 
Values shown are the mean +/- SD. *Significantly different from to the corresponding control 
(vehicle control) at P < 0.05. ** *Significantly different from to the corresponding control) at 
P < 0.01 

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SCCS/1656/23 
Final Opinion 

Figure  6.  uterine  weight  of  rats  administered  E2  or  BzS  for  3  days  beginning  on  PND21. 
Values  shown  are  the  mean  +/-  standard  error.  *Significantly  different  from  to  the 
corresponding  control  (vehicle  control)  at  P  <  0.05.  **  *Significantly  different  from  to  the 
corresponding control (vehicle control) at P < 0.01. 

Finally, the authors have transformed the daily intakes and the dermal exposures of Ses in 
the “real world” into estradiol equivalent concentrations (EEQs). They found that the EEQ of 
BzS  daily  intake  in  consumers  in  the  U.S.  and  the  EEQs  of  dermal  BzS  and  PES  exposure 
among high-volume users worldwide were higher than the maximum secure daily estradiol 
intake recommended by the U.S. Food and Drug Administration (FDA). In particular, the EEQ 
for dermal BzS exposure was up to 162 ng EEQ/kg, which is 3.3 times higher than the maximal 
acceptable daily E2 intake recommended by the Joint FAO/WHO Expert Committee on Food 
Additives (JECFA). 

Applicant observation  

It  has  to  be  noted  that  a  positive  response  in  an  uterotrophic  assay  only  indicates  some 
biological activity, but it does not indicate an adverse effect. Furthermore, the variability of 
the measured estrogen-dependent parameters is a major potential confounding factor for the 
scientific evaluation of this assay (Ashby, 2003). 

SCCS conclusion on endocrine activity  
In  vitro  results  on  Benzyl  Salicylate  did  not  show  androgenic  activity,  and  only  a  weak 
estrogenic activity. The estrogenic activity is confirmed by the in vivo studies in mouse. The 
uterotrophic assay is the gold standard to demonstrate an estrogenic effect in vivo, and the 
in vivo studies used in the Opinion clearly showed a weak estrogenic potential.  

3.5 

SAFETY EVALUATION (INCLUDING CALCULATION OF THE MOS) 

Selection of the Key study and the POD 

There are no repeat dose toxicity data for Benzyl Salicylate from before 11 March 2013 to use 
in a cosmetic safety assessment. However, as Benzyl Salicylate itself is not regarded as the 
main toxicant, but salicylic acid as the main hydrolysis product via all routes of exposure. 

Salicylic acid was reviewed recently by the SCCS in its opinion from SCCS/1646/22. The POD 
for salicylic acid was selected as a no observed adverse effect level (NOAEL) of 75 mg/kg/day 

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Final Opinion 

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based upon the most sensitive observations in orally dosed rats, of teratogenic effects, in the 
Tanaka et al., 1973 study. Using molecular weight correction (Salicylic acid MW = 138 g/mol 
; Benzyl Salicylate MW = 228 g/mol) the adjusted POD (that would yield the same amount of 
salicylic  acid  systemically)  for  Benzyl  Salicylate  is  123  mg/kg/day  (=  75  mg/kg/day  x 
(228/138)). 

Based  on  the  exposure  information  in  section  3.3.2,  the  Margins  of  Safety  for  consumer 
exposures to Benzyl Salicylate in cosmetic products are shown for Scenario A maximum % 
use levels: 

Table 24: Margins of Safety for consumer exposures to Benzyl Salicylate in cosmetic products 
based on Scenario A and maximum % use levels 

* values taken from the exposure via spray see section 3.3 

For systemic effects, considering all applied cosmetic products either directly on the skin or 
by spray, at the maximum concentrations of Benzyl Salicylate reported in Table above, taken 
individually and also the aggregated exposure, the margin of safety is above 100. 

As  an  estrogenic  effect  of  Benzyl  Salicylate  at  relatively  high  doses  of  exposure  has  been 
observed (see section 3.4.9 above), following the Note of Guidance 12th recommendations, 
specific calculations for children of different categories of ages have been considered by the 
SCCS.  However,  in  view  of  the  high  values  of  the  MoS  for  all  product  categories,  even  if 
specific scenario of exposure in children may lead to higher exposure (due to the difference 
of ratio in body surface and body weight depending of the ages) the MoS will still be above 
100 and therefore these specific calculations are not included in the opinion. 

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58 

Product familiesProduct categoriesMaximum conc BzSDermal absorptionEproduct normalized Tier 1, dermal/oral SEDNOAEL MOS(w/w %)(%)(mg/kg bw /d)(mg/kg bw /d)(mg/kg bw /d)Hydroalcoholic-based fragrances410.54.670.0196141236271Rinse-off skin & hair cleansing products (except hand wash)Shower gel1.310.52.790.0038083512332297Hair conditioner0.510.50.670.00035175123349680Shampoo0.510.51.510.00079275123155156Hand wash soapHand wash soap0.510.53.330.0017482512370356Leave on skin and hair productsBody lotion0.710.5123.20.0905521231358Face cream0.510.524.140.01267351239705Hand cream0.510.532.70.01716751237165Deodorant non-spray0.510.522.080.01159212310611Hair styling*0.510.55.740.0038612331865Face make-up productsLiquid foundation0.210.57.90.00165912374141Make-up remover0.210.58.330.001749312370314Eye make up Eye make-up0.210.50.330.00006931231774892Mascara0.210.50.420.00008821231394558Eyeliner0.210.50.080.00001681237321429oral care productsToothpaste0.0041002.160.00008641231423611Mouthwash0.00410032.540.001301612394499Lip productsLipstick, lip salve0.21000.90.001812368333Mouthspray0.00410026.70.001066667123115313273.4900.170123724aggregate dermal/oral 
 
 
 
 
 
 
 
 
 
Opinion on Benzyl Salicylate (CAS No. 118-58-1, EC No. 204-262-9) 
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SCCS/1656/23 
Final Opinion 

3.6 

DISCUSSION 

Physicochemical properties 

Benzyl  Salicylate  (CAS  No.  118-58-1,  EC  No.  204-262-9)  with  the  chemical  name  ‘2-
hydroxybenzoic acid phenylmethyl ester’ is produced naturally in a variety of plants and plant 
extracts where it can be extracted. In addition, Benzyl Salicylate can be synthesised.   

A full report of the chemical characterization of Benzyl Salicylate in terms of purity and identity 
in representative batches is missing and therefore should be provided and the validity of the 
analytical methodologies used shown. 
A  full  report  in  terms  of  impurity  tests  in  representative  batches  of  the  test  substance  is 
missing  and  therefore  should  be  provided  and  the  validity  of  the  analytical  methodologies 
used must be shown. Identity and concentration of any impurities that may be present should 
also be stated. 
Moreover, data on the stability of the test substance under the experimental conditions of the 
reported studies and under conditions of use, and information on any hydrolysis are missing 
and therefore, should be provided. 

Toxicokinetics  

Skin absorption 

Data from an OECD Test guideline in vitro skin absorption study performed following the GLP 
(BASF, Oct 2021) indicates a value of 10.5% absorption, which is used in this opinion for the 
safety evaluation of Benzyl Salicylate. It is expected that the majority of systemic exposure 
is in the forms of salicylic acid and benzyl alcohol.  

Oral exposure 

Benzyl Salicylate is expected to be rapidly and completely absorbed and metabolised, in both 
gut and liver tissue by first pass metabolism, to salicylic acid and benzyl alcohol following oral 
exposure  in  both  rat  and  humans.  With  rapid  hydrolysis  in  the  gut  and  liver,  systemic 
exposure is primarily to salicylic acid and benzyl alcohol, which do not accumulate in the body, 
and are rapidly excreted. Therefore, based on the available data, the SCCS considers that an 
absorption value by oral route of 100% can be used in the risk assessment. 

Exposure by inhalation 

Due  to  the  lack  of  data  available  data,  the  SCCS  considers  that  an  absorption  value  by 
inhalation of 100% can be used in the risk assessment. 

Exposure  

Benzyl Salicylate can be used typically as a fragrance ingredient, in a range of manufactured 
goods (cosmetics, household goods and medicines). In cosmetics,  Benzyl Salicylate is used 
for its fragrance/perfuming function. 

Separate exposure assessments were performed for the dermal, oral and inhalation routes. 
As the deterministic approach - based on maximal concentrations used (scenario A) - yields 
a  favourable  outcome,  further  exposure  modelling  was  not  necessary  to  refine  exposure. 
Scenario A is based on maximum concentrations of Benzyl Salicylate that are used in products 
in Europe, in each  of the standard 17 product types  as included in an aggregate exposure 
assessment  (according  to  the  SCCS  Notes  of  Guidance  2021).  These  levels  have  been 
provided in a recent use survey by the members of the ‘Benzyl Salicylate consortium’, and 
are used to calculate the total systemic exposure to  Benzyl Salicylate (in mg/kg/day) from 

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each product for adults. In addition to the 17th cosmetic products usually considered, an 18th 
product type – hydroalcoholic fragrances was included in the scenario.  

A measured value  for  skin penetration  of  Benzyl Salicylate  of 10.5% (see  section 3.2) has 
been used for all products in these calculations where dermal absorption needs to be factored 
in to calculate a systemic exposure dose (SED). For lipstick and oral care products a worst-
case value of 100% absorption is used to account for passage across the oral mucosa and/or 
ingestion. A SED via the dermal route was calculated for each product in mg/kg/day and an 
aggregate systemic exposure dose for the 18 products (see Table 7). 

Exposure via inhalation for products used in spray or pump forms was also calculated. It is 
not necessary to add the dermal aggregate outcome for Total SED to the SED values from 
inhaled spray products, as on any one day, only one (spray or non-spray versions) of the type 
of products in Table 7  will be used, not both simultaneously.  For most of the products the 
non-spray products lead to a much higher systemic exposure when compared to the spray 
products. The exception are the hair styling products: systemic exposure via non sprayed hair 
styling  products  is  3  µg/kg/d  whereas  it  is  3.86  µg/kg/d  when  using  hair  styling  spray 
products. Therefore, for the MoS calculation, for all products except hair styling products only 
non-spray products will be considered in a worst-case scenario.   

A deterministic worst case systemic exposure dose (SED) estimate from aggregated dermal 
exposure modelling of Benzyl Salicylate in cosmetic products is 179 μg/kg/day. This value will 
be taken forward into the safety evaluation. 

Toxicological Evaluation 
For the toxicological evaluation of Benzyl Salicylate, SCCS mainly relied on the dossier from 
the Applicant and on the EU REACH substance dossier available at 
https://echa.europa.eu/registration-dossier/-/registered-dossier/16100  

Irritation and corrosivity 

SCCS  considers  that  Benzyl  Salicylate  is  non  irritating  to  the  skin  but  it  may  cause  eye 
irritation. 

Skin sensitisation  

Benzyl Salicylate is currently regulated for labelling purposes as an allergen in entry 75 of 
Annex III to the Cosmetics Regulation. In particular, “its presence must be indicated in the 
list of ingredients when its concentration exceeds 0.001% in leave-on products and 0.01% 
in rinse-off products”. 

Acute toxicity 

Benzyl Salicylate is acutely toxic at high doses. 

Repeated dose toxicity 

No repeat dose toxicity data were available on Benzyl Salicylate, performed before the March 
2013  animal  testing  ban.  For  the  purposes  of  cosmetics  safety  assessment  and  given  that 
Benzyl  Salicylate  itself  is  not  regarded  as  the  main  toxicant,  but  salicylic  acid  as  the  main 
hydrolysis  product,  this  section  also  discusses  the  available  repeat  dose  toxicity  data  and 
conclusions for the primary Benzyl Salicylate metabolites salicylic acid and benzyl alcohol. 

All  data  for  salicylic  acid  were  recently  reviewed  by  the  SCCS  in  its  recent  opinion  (SCCS, 
2023) and therefore are not reported in this opinion. 

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Concerning  benzyl  alcohol,  a  summary  of  the  repeat  dose  oral  studies  cited  in  the  ECHA 
REACH registration dossier for benzyl alcohol (https://echa.europa.eu/registration-dossier/-
/registered-dossier/14748/7/6/2) has been provided to SCCS. 
A no-observed-effect level (NOEL) was of 3000 ppm (equivalent to 177 and 204 mg/kg/day 
for  males  and  females,  respectively).  This  was  derived  from  an  oral  90  days  study  in  rats 
performed after 2013 following a request from ECHA to comply with the Reach regulation. 

Reproductive toxicity  

Following  ECHA  decision  (CCH-D-2114379324-45-01/F)  on  Benzyl  Salicylate,  additional 
toxicological studies were performed in 2019: 

- 
 a Screening study for reproductive/developmental toxicity (Annex VIII, Sections 8.6.1 
and  8.7.1.;  test  method:  OECD  TG  421)  in  rats,  oral  route  leading  to  a  NOAEL  of  166 
mg/kg/day for males and 158 mg/kg/day for females 

a  Pre-natal  developmental  toxicity  study  (Annex  IX,  Section  8.7.2.;  test  method:  EU 
- 
B.31./OECD  414)  in  a  first  species  (rat  or  rabbit),  oral  route  leading  to  a  NOAEL  of  214 
mg/kg/day for maternal toxicity and for embryo/fetal development, when  Benzyl Salicylate 
was administered orally (via the diet) to time-mated Crl:CD(SD) rats. 

Mutagenicity / genotoxicity 

Benzyl Salicylate was tested in 3 bacterial gene mutation tests with negative results. However, 
the SCCS noted that in the studies 1 strain combination recommended by the OECD TG 471 
has not been represented (E. coli WP2 uvrA, or E. coli WP2 uvrA (pKM101), or S. typhimurium 
TA102). 
Benzyl Salicylate was tested in 2 mammalian gene mutation tests in  Hprt locus on Chinese 
hamster  ovary  (CHO)  cells  with  negative  results.  However,  first  study  was  not  considered 
valid due to  several  shortcomings highlighted above. The second  in vitro mammalian gene 
mutation  study  was  considered  valid  even  if  precipitation  appeared  already  in  middle 
concentrations.  
Benzyl Salicylate was tested in 1 valid in vitro mammalian chromosomal aberration test on 
Chinese  hamster  cells  and  1  valid  in  vitro  mammalian  cell  micronucleus  assay  on  human 
lymphocytes, both with negative results. 

The SCCS, after analysis of the available data, considers that Benzyl Salicylate does not pose 
a genotoxic/ mutagenic potential. 

Carcinogenicity 

The SCCS, after analysis of the available in vitro mutagenicity studies, considers that Benzyl 
Salicylate is not likely to be a human carcinogen. 

Photo-induced toxicity  

Based on the available in vivo and human data Benzyl Salicylate does not present a concern 
for phototoxicity or photoallergenicity. 

Special investigation  

In vitro results on Benzyl Salicylate did not show androgenic activity but a weak estrogenic 
activity. The estrogenic activity is confirmed by the in vivo studies in mouse. The uterotrophic 
assay is the gold standard in vivo to demonstrate an estrogenic effect and the in vivo studies 
used in the opinion showed a weak estrogenic potential. 

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Safety evaluation 

Considering  all  cosmetic  products  applied  either  directly  on  the  skin  or  by  spray,  at  the 
maximum concentrations of  Benzyl Salicylate  reported in Table 1 above, taken individually 
and also the aggregated exposure, the margin of safety is above 100. As an estrogenic effect 
of  Benzyl  Salicylate  has  been  observed  at  relatively  high  doses  of  exposure,  specific 
calculations  for  children  of  different  categories  of  ages  have  been  considered  by  the  SCCS 
(see  section  3.4.9  above),  following  the  12th  revision  of  the  SCCS  Notes  of  Guidance 
(SCCS/1647/22). However, in view of the high values of the MoS for all product categories, 
even  if  specific  scenario  of  exposure  in  children  could  lead  to  higher  exposure  (due  to  the 
difference of ratio in body surface and body weight depending on the ages), the MoS will still 
be far above 100, and therefore these specific calculations have not been considered in the 
Opinion. 

4.  CONCLUSION 

1.  In light of the data provided and taking under consideration the concerns related to 
potential endocrine disrupting properties of Benzyl Salicylate, does the SCCS consider 
Benzyl Salicylate safe when used up to the maximum concentrations provided in the 
dossier submission by the Benzyl Salicylate Consortium? 

Based on the assessment of data provided and taking under consideration the concerns 
related  to  potential  endocrine  disrupting  properties,  the  SCCS  considers  Benzyl 
Salicylate safe when used up to the maximum concentrations as provided in Table 1 
of this Opinion. 

2.  Alternatively, what is according to the SCCS the maximum concentration considered 

safe for use of Benzyl Salicylate in cosmetic products?  

/ 

3.  Does the SCCS have any further scientific concerns with regard to the use of Benzyl 

Salicylate in cosmetic products?  

The available data on Benzyl Salicylate provide some indications for an endocrine mode 
of action, but there is no evidence to suggest that this results in endocrine effects.  

The  SCCS  mandates  do  not  address  environmental  aspects.  Therefore,  this 
assessment did not cover the safety of Benzyl Salicylate for the environment. 

5.  MINORITY OPINION 

/ 

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Final Opinion 

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7.  GLOSSARY OF TERMS 

See SCCS/1647/22, 12th Revision of the SCCS Notes of Guidance for the Testing of Cosmetic 
Ingredients and their Safety Evaluation – Appendix 15 - from page 158 

8.  LIST OF ABBREVIATIONS 

See SCCS/1647/22, 12th Revision of the SCCS Notes of Guidance for the Testing of Cosmetic 
Ingredients and their Safety Evaluation – Appendix 15 - from page 158 

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