SCCS/1550/15

Version S

Scientific Committee on Consumer Safety
SCCS

OPINION ON
β-arbutin

The SCCS adopted this Opinion at its 9th plenary meetingon 25 March 2015

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Opinion on β-arbutin________________________________________________________________________________________

About the Scientific Committees
Three independent non-food Scientific Committees provide the Commission with thescientific 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.
They are: the Scientific Committee on Consumer Safety (SCCS), the Scientific Committee
on Health and Environmental Risks (SCHER) and the Scientific Committee on Emerging and
Newly Identified Health Risks (SCENIHR) and are made up of external experts.
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).
SCCSThe Committee shall provide opinions on questions concerning all types of health and safety
risks (notably chemical, biological, mechanical and other physical risks) of non-foodconsumer products (for example: cosmetic products and their ingredients, toys, textiles,
clothing, personal care and household products such as detergents, etc.) and services (forexample: tattooing, artificial sun tanning, etc.).
Scientific Committee members
Ulrike Bernauer, Qasim Chaudhry, Pieter Coenraads, Gisela Degen, Maria Dusinska, Werner
Lilienblum, Elsa Nielsen, Thomas Platzek, Suresh Chandra Rastogi, Christophe Rousselle,
Jan van Benthem.
Contact
European Commission
Health & Food safety
Directorate C: Public Health
Unit C2 – Health Information/ Secretariat of the Scientific Committee
Office: HTC 03/073
L-2920 Luxembourg
SANTE-C2-SCCS@ec.europa.eu©

European Union, 2015

ISSN 1831-4767

ISBN 978-92-79-56125-2

Doi:10.2875/10211

EW-AQ-16-002-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 theEuropean Commission. The opinions are published by the European Commission in their
original language only.

http://ec.europa.eu/health/scientific_committees/consumer_safety/index_en.htm

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Opinion on β-arbutin________________________________________________________________________________________ACKNOWLEDGMENTSSCCS Members
Dr. U. Bernauer
Prof. P.J. Coenraads
Prof. G. Degen
Dr. M. Dusinska
Dr. W. Lilienblum
Dr. E. Nielsen
Prof. T. Platzek
Dr. S. Ch. Rastogi
Dr. Ch. Rousselle
Dr. J. van Benthem(rapporteur)(chairman)

Former SCCS Member
Prof. A. Luch
External experts
Prof. A. Bernard
Prof. A.M. Giménez-Arnau
Prof. T. Vanhaecke

Keywords: SCCS, scientific opinion, β-arbutin, Regulation 1223/2009, CAS:
EC: 207-850-3

497-76-7,

Opinion to be cited as: SCCS (Scientific Committee on Consumer Safety), Opinion on βarbutin, SCCS/1550/15, 25 March 2015

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Opinion on β-arbutin________________________________________________________________________________________TABLE OF CONTENTS

1.

BACKGROUND ............................................................................................. 6

2.

TERMS OF REFERENCE.................................................................................. 6

3.

OPINION ..................................................................................................... 7
3.1

Chemical and Physical Specifications....................................................... 7

3.1.1
Chemical identity .................................................................... 7
3.1.2
Physical form ......................................................................... 8
3.1.3
Molecular weight .................................................................... 8
3.1.4
Purity, composition and substance codes .................................... 8
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
3.2
Function and uses .............................................................................. 14
3.3

Toxicological Evaluation ...................................................................... 14

4.

3.3.1
Acute toxicity ....................................................................... 14
3.3.2
Irritation and corrosivity ........................................................ 16
3.3.3
Skin sensitisation .................................................................. 17
3.3.4
Dermal / percutaneous absorption........................................... 18
3.3.5
Repeated dose toxicity .......................................................... 23
3.3.6
Mutagenicity / Genotoxicity .................................................... 25
3.3.7
Carcinogenicity ..................................................................... 27
3.3.8
Reproductive toxicity ............................................................. 28
3.3.9
Toxicokinetics ...................................................................... 30
3.3.10
Photo-induced toxicity ........................................................... 30
3.3.11
Human data ......................................................................... 32
3.3.12
Special investigations ............................................................ 36
3.3.13
Safety evaluation (including calculation of the MoS) ................... 36
3.3.14
Discussion ........................................................................... 37
CONCLUSION ............................................................................................ 44

5.

MINORITY OPINION.................................................................................... 45

6.

REFERENCES ............................................................................................. 45

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1. BACKGROUND
Submission I for β-Arbutin (CAS 497-76-7) with the chemical name 4-hydroxy-phenyl-β-Dglucopyranoside and the INCI name Arbutin was submitted in July 2005 by COLIPA1.
The effect of Arbutin seems to be due to the fact that it hydrolyses to Hydroquinone.
However, Hydroquinone (CAS 123-31-9) is listed in Annex II/1339 of the Cosmetic
Regulation No 1223/2009; it means it is banned as cosmetic ingredient with the exception ofentry 14 in Annex III. Its permitted use is restricted to professional use in artificial nailsystems in a concentration in the final product up to 0.02%. Since Hydroquinone could not
be used as a skin whitener after introduction of a ban, other substances have been used forthat purpose, including Arbutin.
The first opinion (SCCP/1158/08) on beta-arbutin was adopted the 15 April 2008 with theconclusion: "Although the general toxicological assessment of β-arbutin suggests that thesubstance may be safe, the bioavailability of hydroquinone under conditions of intended useof the substance is of concern. Whereas hydroquinone was initially permitted at aconcentration of 2%, a 1998 opinion of the SCCNFP recommended that the substanceshould not be used any more as a depigmentating agent in cosmetic products due toobserved clinical side effects, among which exogenous ochronosis [41].
Consequently, the SCCP considers the currently requested use of β-arbutin in cosmetic
products unsafe. In addition, it is the opinion of the SCCP that the same concern can be
expressed for other products that result in the release and/or formation of hydroquinone
before or upon application on the skin."The substance is used as a chemical ingredient alone and as a component of plant extracts
like Arctostaphylos Uva Ursi, Vaccinium Vitis-Idaea, Chimaphila Umbellata etc, all rich incontent of arbutin, according to the information on skin lightening products available to theCommission Services.
The current submission II is a response to the first opinion on beta-Arbutin.

2. TERMS OF REFERENCE(1)

Does the SCCS consider on the basis of the provided scientific data, the use of β-arbutin
to be safe for consumers in cosmetic products in a concentration up to 7% in facecreams?

(2)

Does the SCCS have any further scientific concerns with regard to the use of β-arbutin in
cosmetic products?

1

COLIPA – The European Cosmetics Association, now Cosmetics Europe

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3. OPINION
The previous SCCP 2008 Opinion (SCCP/1158/08) was based on Submission I of theapplicant (Shiseido via COLIPA) from July 2005. The present Opinion also includes
Submission II from May 2009 and information provided thereafter (Cover Letter Shiseido to
EU COM of April 2012 with “Final Expert statement SCCS Arbutin requests KS 26-04-2012”)

3.1

Chemical and Physical Specifications

3.1.1

Chemical identity

3.1.1.1 Primary name and/or INCI nameArbutin (INCI name)
Ref.: 8, 9, 15
3.1.1.2 Chemical names
4-Hydroxyphenyl--D-Glucopyranoside
Ref.: 8, 9, 15
3.1.1.3 Trade names and abbreviations
Arbutin

Ref.: 8, 9, 15

3.1.1.4 CAS / EC number
CAS: 497-76-7
EC: 207-850-3

Ref.: 93.1.1.5 Structural formula
OH

HOH2C
O

HO
HO

O
OH

Ref: Schindler et al. 2002
3.1.1.6 Empirical formulaC12H16O7
3.1.2

Physical form

White to light grey powder

Ref.: Appendix 1 in Submission I
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3.1.3

Molecular weight272.25 g/mol
Ref.: 8, 9, 15
3.1.4

Purity, composition and substance codes

Purity: 97.0 - 102.0 %β -arbutin:
Lot A: 99.7%
Lot B: 97.8%
Lot C: 99.8%

Batches used:

Lot TDA-361: 100.3%
Lot TDD-422: 100.0%
Lot TPG-412: 99.8%
Lot TGJ-225: 100.4%

Ref.: Appendix 1 in Submission I

Lot A, B, C:
Lot A:

stability testing
acute oral and dermal toxicity testskin and eye irritation in the rabbit
skin sensitisation assay
28 day oral & 90 day dermal toxicity test
mutagenicity testing
1-generation reproduction toxicity test
phototoxicity & photosensitisation assay
human patch test
Lot TDD-422: carcinogenicity study
Lot TPG-412: human skin metabolism (repeated topical application)
Lot TDA-361: human (patch) tests with 7-10% β -arbutin formulations


3.1.5

Impurities / accompanying contaminants

Hydroquinone:

Chloride:
Heavy metals:
Arsenic:
Iron:

3.1.6

≤ 0.030%:
Lot A: 0.0129%
Lot B: 0.0208%
Lot C: 0.0094%≤ 0.036%≤ 20 ppm≤ 2 ppm≤ 20 ppm

Lot TDA-361: 0.0064%
Lot TDD-422: 0.0033%
Lot TPG-412: 0.0019%
Lot TGJ-225: 0.0043%

Ref.: Appendix 1 in Submission I

Solubility

Water, propylene glycol:
Ethanol, glycerine:
Squalane, olive oil:≥ 10g/100g
1-10g/100g≤ 1g/100g
Ref.: 15

Comment
The water solubility has not been measured by the EC method A.6

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3.1.7

Partition coefficient (Log Pow)

- 1.35 (probably calculated, no details given).

Ref.: 8Comment
The Log Pow has not been determined by the EC method A.8.

3.1.8

Additional physical and chemical specifications

UV light absorption spectrum:
Melting point:pH:

Specific rotation:(method not
specified)

3.1.9

spectrum not availablemax = 285 nm (in summary report)
197-201°C:
Lot A: 198.3°C Lot TDA-361: 201.2°C
Lot B: 198.0°C Lot TDD-422: 200.0°C
Lot C: 198.7°C Lot TPG-412: 201.0°C
Lot TGJ-225: 201.0°C
5-7:
Lot A: 5.78
Lot TDA-361: 6.00
Lot B: 5.63
Lot TDD-422: 6.10
Lot C: 5.75
Lot TPG-412: 6.10
Lot TGJ-225: 6.10
[]D25 = -62 to -68°:
Lot A: -64.2
Lot TDA-361: -65.8
Lot B: -66.1
Lot TDD-422: -65.7
Lot C: -64.8
Lot TPG-412: -65.0
Lot TGJ-225: -65.4

Homogeneity and Stability

3.1.9.1 Stability of β-arbutin as a raw material
Data from submission II
Photostability test in aqueous solution (Test of 2006)
Sample preparation: Concentration of β-Arbutin (Lot TQI-771, TQI-772, TQI-773) were 3%
and 6.3%; dissolved in 10% ethanol and water
Light Source - a white fluorescent lamp and near ultraviolet lamp
Procedure - Samples were kept in transparent glass bottle of 50mL. Protected samples
wrapped in aluminium foil were used as controls. Samples were exposed to light providing
an overall illumination of no less than 1.2 million lux hours and an integrated near
ultraviolet energy of no less than 200 w·h/m2 at 25οC then measured instantly in compliancewith ICH guidelines, the analysis being repeated 3 times for each lot of product, using an
HPLC assay with detection at 280 nm.
Test results are provided in the Summary Table below.
The quantitation limit of hydroquinone (HQ) in the samples was 1 ppm.

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Conclusion
The photostability of β-arbutin (3% and 6.3% solutions) was investigated in 10% ethanoland pure water. Following the ICH guideline for the photostability testing, the solutions were
exposed to light providing an overall illumination of no less than 1.2 million lux hours andan integrated near-ultraviolet energy of no less than 200 w･h/m2 at 25°C. No apparentchange in the amount of β-arbutin was observed between light-exposed and control
samples. A slight increase of hydroquinone, on the other hand, was observed in lightexposed 6.3% solutions although those levels were always below 2.5 ppm after light
exposure.
Ref. 1 in subm II
Photostability at different pH values and temperatures (Test date 2008-9)
Sample type: 7% β-arbutin in phosphate buffers ranging from pH 2.0-11.0
Samples prepared from Lot TTG-305 were subdivided and kept in transparent glass bottles(30ml). Protected samples wrapped in aluminium foil were used as dark controls. Samples
were exposed to light (white fluorescent lamp) providing an overall illumination of no lessthan 1.2 million lux hours and an integrated near ultraviolet energy of no less than 200 w･
h/m2 at 25ο (ICH guidelines). The effects of temperature were studied at 50οC for 1 monthand 40οC for 3 months. The analyses were repeated 3 times for each lot of product.
Results (for pH of solutions, parent compound and hydroquinone content) at various
conditions are summarised below:

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Opinion on β-arbutin________________________________________________________________________________________* The quantitation limit of HQ in these samples was 1 ppm.

The authors concluded that for both the heat and light conditions, no apparent change on
the amount of β-arbutin was observed at pH 4-11. β-Arbutin levels were slightly decreased
at pH 3 accompanied by a rapid increase of hydroquinone. The degree of hydroquinone
generation was higher at low pH (~4,300ppm at 50°C 1 month and 3,700ppm at 40°C 3
months at pH 2); however only trace levels of hydroquinone were detected in neutral tobasic solutions (pH 6-11).
Ref. 2 in subm II

3.1.9.2 Stability of β-arbutin in a cosmetic formulation
Data from subm II
A. β-arbutin in a finished cosmetic product (accelerated test conditions for 6 months)
Date of study:
Method:Test substance:
Temperature:
Relative Humidity
Analytical method:

2008-2009
Internal protocol Shiseido Co, Japan.
Shiseido Product C (Lot 0804A, B, C) containing
5.67-6.93% β-arbutin at pH 5.0-7.0
40οC
75%
HPLC

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Samples were kept in a transparent glass bottle at 40°C and 75% relative humidity for6 months. β-Arbutin and hydroquinone concentrations were measured in threefold by HPLC
for each batch at the start of the study, after 3 months and after 6 months.
Results (for pH, parent compound and hydroquinone) at various conditions are summarised
below:

Conclusions
Since the concentrations of β-arbutin were stable and those of hydroquinone remained
below 1 ppm (detection limit), the study authors conclude that β-arbutin is stable in final
cosmetic formulations and that no hydroquinone is released under accelerated ageing
conditions for 6 months.
Ref.: 20 Ref. 3 in subm II
B. β-arbutin in a finished cosmetic product (ambient test conditions for 36 months, i.e.,
long-term testing)Date of study:
Method:Test substance:
Temperature:
Relative Humidity:
Analytical method:

2003-6
Internal protocol Shiseido Co, Japan.
Shiseido Product C (lot A, B, C) containing 5.67-6.93% β-arbutin (pH
5.0-7.0),
25οC
60%
HPLC

Samples of Shiseido Product C were kept in a transparent glass bottle at ambient conditionsfor 3 years. β-Arbutin and hydroquinone concentrations were measured in threefold by
HPLC at the start and at the end of the study.

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Results

Since the concentrations of β-arbutin were stable and those of hydroquinone remained
below 1 ppm (detection limit), the study authors conclude that β-arbutin is stable in theusual cosmetic formulation and that no hydroquinone is released under normal storage
conditions for 3 years.
Ref.: 20-1 Ref. 3 in subm II
Overall conclusions (applicant)β-arbutin was relatively stable to light when dissolved in a 10% ethanol aqueous solution.
No significant change in the amount of β-arbutin was detected and only trace levels ofhydroquinone (<0.25 ppm) were detected under the conditions of the ICH photostability
test. β-arbutin was found to be unstable in low pH solutions, decrease of β-arbutin andsignificant increase of hydroquinone was observed, especially at pH 2.
On the other hand, β-arbutin was stable in the finished product: hydroquinone content in
the finished product was no more than 1 ppm (LLOQ) throughout the accelerated and longterm storage conditions (40°C, 75% relative humidity for 6 months and (25°C, 60% relative
humidity for 36 months).
A recently published study tested ß-Arbutin (and deoxy-arbutin) at 10-4 M (<0.003 % w/v)
in aqueous solution with 10% propylene glycol and UV irradiation (narrow band UVB light
unit at 312 nm) at 2.65 mW/cm2: under these conditions (pH not given), ß-arbutin was
reduced to 43.5% of the initial level after 2 h of irradiation, and hydroquinone was detected
at significant levels (up to 20%) over the test period (up to 12 h).
Add. Ref.: Yang CH et al. 2013
SCCS remark
As the test concentration is far below that used in cosmetic products, this study is
considered to be of limited relevance.
SCCS comment
The results presented in the respective studies regarding photostability testing (according to
ICH guideline) and pH- or temperature-dependent stabilities of β-arbutin sound conclusive
and reliable. In cosmetic formulations hydroquinone as impurity remained below 1 ppm(detection limit). Yet, aside from reduced photostability under certain UV irradiation
conditions (Yang et al. 2013), it is to be considered that β-arbutin may also undergo
cutaneous hydrolysis into hydroquinone due to enzymatic activity through β-glucosidases inskin (Mier & van den Hurk 1976; Redoules et al. 2005) or via the activity of microbes
residing on the surface of the skin (Bang et al. 2008). This is further discussed in section
3.3.4.2.

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3.2

Function and uses

The naturally occurring compound β-arbutin (4-hydroxyphenyl-β-D-glucopyranoside,hydroquinone-β-glucopyranoside, CAS 497-76-7) is a β-D-glucopyranoside derivative ofhydroquinone that can be found in the leaves and bark of many plants. It has been
proposed for use as a skin-lightening agent, inhibiting production of the skin pigment
melanin which is formed through a series of oxidative reactions involving the amino acidtyrosine and the enzyme tyrosinase. This enzyme catalyses the hydroxylation of tyrosine to
L-DOPA (dihydroxyphenylalanine) and the oxidation of DOPA to dopaquinone which is thenfurther metabolised to melanin. β-Arbutin is thought to act by inhibition of the activity ofmelanosomal tyrosinase, where the inhibition may be due to structural similarities to thesubstrate tyrosine (Zhu and Gao, 2008). β-Arbutin can be hydrolysed both in acid solution
and by enzymic action to hydroquinone which also acts as a skin lightening agent, again by
inhibiting tyrosinase. Extended use of ≥2% hydroquinone, topically applied, has been
associated with adverse effects including exogenous ochronosis in dark-skinned people [27,38]. Hydroquinone, like β-arbutin, is present in many dietary components in trace amounts
and is metabolised in vivo to its glucuronide and sulphate conjugates.
β-Arbutin is proposed to be used as a skin-lightening agent in cosmetic face creams or facelotions at concentrations up to 7%.

3.3

Toxicological Evaluation

3.3.1

Acute toxicity

From SCCP/1158/08 with minor corrections
3.3.1.1 Acute oral toxicity
Guideline:
Date of test:
Species/strain:
Group size:
Test substance:
Batch:
Purity:Dosages:Observation period:
GLP/QAU:

OECD TG 401 (1981)
3-17 December 1985
Sprague Dawley (Crj:CD, SPF) rats and ICR (Crj:CD-1, SPF) mice
5 rats or mice/sex/dose
β-arbutin
Lot A
99.7%
1792, 2509, 3513, 4919, 6886, 9641, 13496, 18895 mg/kg bw
14 days/

The test substance was applied by oral gavage at dosages of 1792, 2509, 3513, 4919,
6886, 9641, 13496, 18895 mg/kg bw to groups of 5 male and/or 5 female rats and mice.
The animals were checked daily for mortality and clinical signs. Body weights were recordedon days 1 to 5, 7, 8, 11 and 15. Animals were observed for 14 days. Animals that diedduring the test and all surviving animals at the end of the observation period were
submitted to gross necropsy.
Results
Lethality is summarised in the following table:
Dosage(mg/kg bw)
1792
2509

Lethality
male rats
0/5
0/5

Lethality
female rats
0/5
0/5
13

Lethality
male mice
0/5
0/5

Lethality
female mice
0/5
0/5

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3513
4919
6886
9641
13496
18895

0/5
0/5
2/5
3/5
4/5
5/5

0/5
0/5
1/5
3/5
4/5
5/5

0/5
1/5
1/5
1/5
3/5
5/5

0/5
0/5
1/4*
3/5
3/5
5/5

* one of the five 6886 mg/kg bw male mice died by gavage accident

Liver changes associated with the test substance were observed at 4149 mg/kg bw in miceand at 9641 mg/kg bw in rats, though not at lower dosage levels.
There were no deaths in mice given  3513 mg/kg bw or in rats given  4919 mg/kg bw.
Few toxic signs were observed in either species at dosage levels up to 3513 mg/kg bw.
Conclusion
The study authors conclude that the oral LD50-value for β-arbutin is 9804 mg/kg bw for themouse and 8715 mg/kg bw for the rat. These values indicate a low level of acute oral
toxicity.
Ref.: 1

3.3.1.2 Acute dermal toxicity
Guideline:
Date of test:
Species/strain:
Group size:
Test substance:
Batch:
Purity:Dosages:Observation period:
GLP/QAU:

OECD TG 402 (1981)
January-April 1986
Sprague Dawley (Crj:CD, SPF) rats and ICR (Crj:CD-1, SPF) mice
10 rats or mice/sex
β-arbutin, 30% (w/w) in a 50:50 ethanol:water solution
Lot A
99.7%
928 mg/kg bw (technically applicable maximal dosage)
14 days/For both rats and mice, the test substance was applied evenly on the back after fur clipping(treatment area not mentioned). The applied volume was 3 ml/kg, the maximum technicallyachieved. 30% β-arbutin in 50% ethanol aqueous solution led to a dosage of 928 mg
β-arbutin/kg bw.
For mice, clinical signs were recorded for 14 days except for holidays, and body weight wasmeasured on day 1 to 3, 5 to 8, 12 and 15. For rats, clinical signs were recorded for 14days, and body weight was measured on day 1 to 3, 5 to 8 and 15. Since no animal diedduring the observation period, all animals were sacrificed with chloroform at the end theobservation period and subjected to necropsy.
Results
No lethality occurred during the test and no abnormalities in clinical signs were seen. Body
weight gain was normal throughout the observation period. There were no remarkablefindings at necropsy for either mice or rats.
Conclusion
For rats and mice, the LD50 value via the dermal route showed to be greater than
928 mg/kg bw (the technically applicable maximal dose).
Ref.: 2SCCS comment
The SCCS noted that there is no justification in relation to the ‘the maximum technicallyfeasible’ dose volume of 3 ml/kg (recalculated to a dose of 928 mg/kg bw. According toOECD TG 402 (Acute dermal toxicity) a dose level of 2000 mg/kg is the cut-off for the limit
test.
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3.3.1.3 Acute inhalation toxicity
No data submitted

3.3.2

Irritation and corrosivity

From SCCP/1158/08 (with minor modifications)3.3.2.1 Skin irritation
Guideline:
Date of test:
Species/strain:
Group size:
Test substance:
Batch:
Purity:Dosages:Observation period:
GLP/QAU:

Draize method (1959), no official guideline
April 1986
Japanese white rabbits
6 malesβ-arbutin, dissolved as a 10% (w/w) solution in distilled water
Lot A
99.7%
300 µl of the 10% solution was applied on patch of 4.9 cm²
72 hours
before introduction of GLP (1987), thus not applicable.

A 4.9 cm² (2.5 cm diameter) patch test plaster with 300 µl test material (10% β-arbutin indistilled water) was placed on shaved intact and abraded (by needle scratching not deep
enough to cause bleeding) dorsal skin sections of six male rabbits for 24 hours. After the
24-hour application time, the patch was removed. No rinsing was done. Skin reactions were
evaluated for erythema and oedema after 48 and 72 hours.
Results
Slight erythema (score 1) was observed in one rabbit after 24 and 72 hours on intact andabraded skin. No oedema was observed during the test period.
Conclusion
The study authors conclude that a 10% aqueous solution of β-arbutin can be considered ashaving ‘little primary irritation potential’.
Ref.: 3
SCCS comment
A 10% aqueous solution of β-arbutin was slightly irritating to the skin.

3.3.2.2 Mucous membrane irritation / Eye irritation
Guideline:
Date of test:
Species/strain:
Group size:
Test substance:
Batch:
Purity:Dosages:Observation period:
GLP/QAU:

Internal protocol performing laboratory (Japan), no official guideline
March-April 1986
Japanese white rabbits
3 males
-arbutin, dissolved as a 10% (w/w) solution in water
Lot A
99.7%
100 µl of the 10% solution
72 hours/

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100 µl of test substance (10% -arbutin in distilled water) was instilled to the right eye ofthree rabbits. The eyes were left unrinsed and the untreated left eyes served as control.
Ocular reactions were measured for one week according to the Draize method. Reading
times were at 1, 4, and 24 hours, 2, 3, 6, and 7 days after instillation. Parameters checked
included cornea (opacity, area of cornea involved), iris (morbidity value) and conjunctiva(redness, chemosis, discharge).
Results
No reactions were observed in the cornea, iris or conjunctiva during the test period on any
animal treated with test substance.
Conclusion
Under the conditions of the study, a 10% aqueous solution of -arbutin was not irritating to
the rabbit eye.

3.3.3

Skin sensitisation

Taken from SCCP/1158/08 (with minor modifications)
Guideline:
Date of test:
Species/strain:
Group size:

Test substance:
Batch:
Purity:Dosages:Observation period:
GLP/QAU:

Magnusson Kligman Guinea Pig Maximisation Test (1970)
May-June 1986
Hartley albino guinea pig
10 females treated with -arbutin
10 females treated with hydroquinone
5 females treated with positive control (DNCB)
10 females treated with distilled water (control group)-arbutin, dissolved as a 10% (w/w) solution in water
Lot A
99.7%
dermal induction: -arbutin
10% in water:ethanolhydroquinone: 5% in water:ethanol
DNCB:
0.1% in liquid paraffindermal challenge: -arbutin
1, 3, 10% inwater:ethanolhydroquinone: 1, 3, 10% in water:ethanol
DNCB:
0.001%, 0.1% in acetone
72 hours/

On the first day, three samples were intradermally injected on the upper dorsal region:
1) 0.1 ml of Freund’s complete adjuvant (FCA):water (1:1)
2) 0.1 ml of 10% - Arbutin in distilled water
3) 0.1 ml of 10% -arbutin emulsified in FCA
One week after the injections, 50 mg of 10% sodium lauryl sulfate in petrolatum wasapplied to the upper dorsal region. On the next day, 0.2 ml of 10% -arbutin was
occlusively applied for 48 hours. Distilled water was used as negative control, 5% HQ wasused as reference control, and 0.2% 2,4-dinitrochlorobenzene (DNCB) was used as positive
control.
Three weeks after the first induction, 0.01 ml of 10, 3, and 1% -arbutin in aqueous/ethanol(50/50) solution were topically applied on the flank of animals. 0.01 ml of 10, 3, and 1% HQ
in aqueous/ethanol (50/50) solution were applied as reference control, and 0.01 mL of 0.01
and 0.1% DNCB in acetone were applied as positive control. The reaction was evaluated 24
and 48 hours after challenge application.

16

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Results
No positive reactions were observed at any reading time in animals in either the treated orcontrol groups challenged with 10, 3, or 1% -arbutin in aqueous/ethanol (50/50) solution.
All the animals challenged with 3 or 10% hydroquinone and 9 of 10 tested with 1%hydroquinone showed allergic reactions on challenge. Five out of five guinea pigs sensitised
to DCNB showed an allergic reaction when challenged with 0.01 and 0.1% DNCB. No
positive reactions were observed with the control group at any challenge concentration.
Conclusion
The study authors conclude that -arbutin does not possess skin sensitising potential under
the test conditions.
Ref.: 7SCCS comment
Apparently no preliminary study for induction and challenge concentration determination
has been performed. Challenge with 3 different concentrations is unusual. The scores after
induction are not stated, thus the adequacy of the concentrations used cannot be checked.
The question can be raised whether an aqueous/ethanol (50/50) solution is an appropriate
solvent. An aqueous solution with slightly acidic pH would be more suitable.

3.3.4

Dermal / percutaneous absorption

3.3.4.1 In vitro dermal / percutaneous absorption
Guideline:
Date of test:
Test system:
N° of samples:
Receptor fluid:
Test substances:

Purity:Applied amount:
Reference compound:
Duration of study:
GLP/QAU:

Draft OECD TG 428: Percutaneous Absorption: in vitro Method(2000) and SCCNFP Notes of Guidance (SCCNFP/0321/00)
August-September 2002
Excised dermatomed human skin (combination of freshly isolated
and frozen skin) from 3 donors
flow-through diffusion cells, exposure area 0.64cm².
6 per test substance (each formulation was applied to 2 skinsamples of 3 different donors)
mixture of 2 culture media (DMEM & Ham F12, 3:1), supplemented
with epidermal growth factor (10µg/l), hydrocortisone (400µg/l),
gentamycin (50mg/l) and foetal calf serum (10%, w/w)
Cream-CBP-H (batchS-1601):
6.3% [14C] β-arbutinCream-CBP-L (batch S-1602):
3.0% [14C] β-arbutin
Cream-BOP-H (batch S-1603):
6.3% [14C] β-arbutin
Cream-BOP-L (batch S-1604):
3.0% [14C] β-arbutin
Gel-H(batch S-1605):
6.3% [14C] β-arbutin
Gel-L(batch S-1606):
3.0% [14C] β-arbutin
97.6% (ring labelled ß-arbutin)
2.2-5.5 mg/cm²
Testosterone
24 hours
In compliance

Human skin membranes, 875 µm (experiment 1), 793 µm (experiment 2) and 848 µm(experiment 3) in thickness, were mounted in 9 mm flow-through type diffusion cells. The
exposure area of the skin membranes in these cells was 0.64 cm2. The temperature of thecells was approximately 32 °C, at ambient humidity. The receptor fluid (culture medium
continuously gassed with 95% O2 and 5% CO2) was pumped at a speed of approximately
1.5 ml/h. Prior to each experiment, a skin integrity test was conducted using the marker
substance tritiated water. Only skin membranes with a permeability coefficient (Kp) of lessthan 1.98 x 10-3 cm.h-1 for tritiated water were used. The test formulation was applied to17

SCCS/1550/15
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the skin membranes at doses ranging between 1.4 and 3.5 mg/membrane; (2.25.5 mg/cm²) for an exposure period of 24 h. In all experiments, the receptor fluid wascollected at 1, 2, 4, 6, 8, 12, 16, 20, and 24 h after application. Each skin membrane wasseparated into the following compartments 24 h after application: donor cell, skin wash area
(exposed and non-exposed), tape strips (stratum corneum), epidermis and dermis. The
radioactivity in all samples was determined using a liquid scintillation counter. Total relative
absorption (% of dose applied) was calculated as the sum of radioactivity in epidermis,
dermis and the receptor fluid.
Results
The following table shows the tissue distribution of β-arbutin, the mean flux constants andthe mean lag times as measured:Test
formulation
β-arbutin
concentration
Donor cell (%)
Skin wash
exposed area(%)
Tape strips
exposed area(%)
Skin wash nonexposed area(%)
Tape strips
non-exposedarea (%)
Epidermis (%)
Dermis (%)
Rest skin (%)
Receptor fluid
samples (%)
Receptorcompartment(%)
Total recovery
(%)
Total
absorption (%)
Mean flux
constant(µg/cm².h)
Mean lag time(hours)CreamCPB-H

CreamCPB-L

CreamBOP-H

CreamBOP-L

Gel-H

Gel-L

6.3%

3%

6.3%

3%

6.3%

3%

1.842
± 2.3240.901± 0.745

1.807± 3.4963.041± 3.4548.240± 8.408

10.394± 8.336

93.9
± 6.3

99.4
± 4.4

97.3
± 6.2

95.2
± 6.9

89.1
± 10.9

88.3
± 3.7

0.071
± 0.0960.154± 0.1320.162± 0.206

0.217± 0.175

0.187± 0.2660.106± 0.0390.109± 0.0420.162± 0.1090.172± 0.084

0.162± 0.076

0.493± 0.504

0.464± 0.3300.023± 0.0420.005± 0.004

0.004± 0.0030.005± 0.003

0.006± 0.0030.007± 0.006

0.057± 0.0930.034± 0.058
0.052± 0.106
0.015± 0.0190.070± 0.0360.027± 0.0260.011± 0.0090.015± 0.0140.077± 0.077
0.029± 0.0180.014± 0.0050.020± 0.0160.109± 0.0670.050± 0.0290.015± 0.0100.036± 0.0360.050± 0.0410.034± 0.0210.028± 0.0150.020± 0.0110.042± 0.0210.044± 0.0290.040± 0.0160.034± 0.0200.002± 0.004

0.002± 0.0020.002± 0.001

0.003± 0.0020.003± 0.0020.005± 0.004

96.1
± 6.2
0.160
± 0.255

100.8
± 4.3
0.126
± 0.060

99.6
± 3.0
0.143
± 0.083

98.9
± 7.2
0.214
± 0.114

98.2
± 7.7
0.135
± 0.066

99.4
± 8.8
0.164
± 0.0160.00160.00090.00250.00190.00220.0017

0.8

1.2

0.9

1.3

0.7

1.4

With respect to the reference compound (testosterone), no considerable differences wereobserved based on flux constants and Kp value between freshly isolated skin and frozenskin samples.
Conclusion
The study authors conclude that the mean total absorption of radioactivity from the three
formulation types used in the present study was very low, ranging from 0.126 to 0.214% of
the applied dose over a 24-h exposure period.
Ref.: 8

TNO (2003) TNO Report V4768, In vitro percutaneous absorption of [14C]-Arbutin using human skin membranes,
TNO Chemistry, Zeist, The Netherlands for Shiseido Research Center, Safety Research Laboratories, Fukuura,
Japan, 11 February 2003

18

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Opinion on β-arbutin________________________________________________________________________________________SCCS comment
The study has some limitations: exact composition of the test formulations is not given andno information is provided on the pH and impurities (hydroquinone). The tested
concentrations of 3.0 and 6.3% β-arbutin are below the requested maximum concentrationof 7%, and the number of human skin samples (2 replicates from 3 donors) is lower thanthat usually required (triplicate samples from 3 donors). The variability of the results ishigh. All the tape strips were discarded. Thus the measured dermal absorption (0.126 0.214 % in 24 h) may be underestimated. For calculation of SED the upper value of 0.214%of the dose or 0.339 µg/cm2 will be used.
This is in line with similar values for in vivo dermal absorption of β-arbutin as calculated by
the SCCS based on the analysis of human biopsy samples from a study (ref. 9, below) withvolunteers after repeated application.

3.3.4.2 In vivo dermal / percutaneous absorption - human
Skin metabolism after repeated topical application of β-arbutin in humanvolunteers
Date of study:
Method:Subjects:
Group size:
Test substance:

09-13 Jan 2005
Multiple topically dosed open study (4 days application)
Healthy volunteers, age 18-45 years (mean: 30 years)
9 female and 9 male subjects
CP-SEN, a 6.3% β-arbutin-containing gel (full quantitative
composition available)
Batch:
CP-SEN: Lot 043
β-arbutin: Lot A, B, C
Purity of β-arbutin:
Lot A: 99.7%, Lot B: 97.8%, Lot C: 99.8%
Hydroquinone content: Lot A: 0.0129%, Lot B: 0.0208%, Lot C: 0.0094%
CP-SEN Lot 043: 0.1 ppm
Doses:
2.8 mg/cm² of 6.3% β-arbutin-containing gel
Exposure time:
Open application, once/day, unoccluded for 30 minutes
Volunteers:
18 healthy volunteers (9 females and 9 males)
GCP/QAU:
Undersigned statements available, including ethical approvals
Volunteers (9 females and 9 males) were chosen according to set in- and exclusion criteria,
pre-study check-up and physical examination results. They were treated daily for
4 consecutive days with 141.5 mg of a 6.3 %(w/w) β-arbutin-containing gel on a delineatedarea of 50 cm² (10 x 5 cm) on the right side of the upper part of the buttock. Their diet was
not restricted; they only needed to keep a diary of their daily food and drink intake. The useof hair dyes was prohibited from 3 days prior to the study till the end of the study. During
the whole topical treatment period, showering and bathing was only allowed in the morning
just prior to visiting the performing facility. The application period was determined based on
the excreting profile of hydroquinone in human studies (ref. 23 and 24).
The applied dose of 141.5 mg on 50 cm² corresponds to about 2.83 mg of test formulation
per cm². This results in a daily application of ~8.9 mg of β-arbutin. The subjects were
instructed to leave the application area unoccluded for 60 minutes after each application
and were therefore confined to the testing facility.
Prior to the first application (day 1), an area at the upper left buttock was tape-stripped andthree skin biopsies were obtained as controls from each volunteer. Approximately
24-30 hours after the last application (Day 5), three treated skin biopsies were taken fromthe right buttock as well. From either the untreated or treated skin area, 4 mm punch
biopsies (n=3) were taken.
Control and treated skin samples taken from each day (Day 1 and Day 5) were frozen inliquid nitrogen. β-arbutin and hydroquinone (HQ) were extracted from the dismembratedskin and analysed by high-resolution GC-MS.
19

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Within each study day (Day 1 and Day 5), calibration line (CAL) and quality control (QC)
samples for HQ and β-arbutin were prepared and analysed separately.
It is well known that human subjects take HQ from food and excrete it in urine. To describe
the possible changes in urinary HQ levels, spot urine samples were collected daily during
the study. Urine samples were collected each morning (prior to application until
approximately 24-30 hours after the last application). Total HQ levels of acid-hydrolysed
urine samples, a total of 90 samples, were determined quantitatively by an LC systemequipped with electrochemical detector (LC-ECD). For measuring HQ, CAL and QC samples
were prepared and analysed.
Results:- In all control skin biopsy samples very low levels of HQ (<1.1 ng quantitative limit) and
β-arbutin (<8.9 ng quantitative limit) were present.
- In all treated skin samples, average HQ content of 177 ± 149 ng/g (32.0 – 602 ng/g)
and average β-arbutin content of 3735.8 ng/g ± 2137.5 (863.0-9809.0 ng/g) could beestablished.
- In a number of spot urine samples (24/90) detectable HQ levels, corrected by creatinine
for diuresis (< 4.19 – 9.16 mmol/mol), were established.
The following table shows the amount of β-arbutin and HQ and the percentage of HQ
present in skin, together with the urinary total HQ analysis results (detection limit
urinanalysis = 0.974 mg/l).
β-arbutin and HQ skin biopsy
Subject
number

HQ urinanalysis results

resultsβ -arbutin
(ng/g
skin)

HQ
(ng/g
skin)

HQ/(Ar
b+HQ)
(%)

Day 1
(mg/l)

Day 2(mg/l)

Day 3(mg/l)

Day 4(mg/l)

Day 5(mg/l)

01

3048.784

2.69< 0.974< 0.974<
0.974< 0.974< 0.974023185.489

2.73< 0.974< 0.974

1.32< 0.9742.37

034132.8196

4.53< 0.974< 0.974<
0.974< 0.974< 0.974

04

863.0

32

3.57

1.59

1.54

<
0.974

< 0.9741.16

057744.6

133

1.69

1.51

1.19

2.54

< 0.974< 0.97406

1652.674

4.26< 0.974< 0.974

1.36< 0.974< 0.974073321.290

2.64< 0.974< 0.974<
0.974< 0.974< 0.974084102.5140

3.29< 0.974< 0.974<
0.974< 0.974< 0.974094140.6134

3.13< 0.974< 0.974

<
0.974

1.46

< 0.974103543.6

473

11.77

2.32

< 0.974

3.05< 0.974< 0.974

11

1851.935

1.86< 0.974< 0.974

<
0.974

1.22

< 0.974124239.0

142

3.24

1.15

2.38

2.97

< 0.974< 0.974134865.1

602

11.01

1.77

2.01

1.32

< 0.974< 0.974

14

2366.3168

6.61< 0.974< 0.974<
0.974< 0.974< 0.97415

3486.5

162

4.43

1.09

1.32

<
0.974

< 0.974< 0.974162860.5253

8.14< 0.974

1.60

1.39

< 0.974< 0.97420

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β-arbutin and HQ skin biopsy
Subject
number

HQ urinanalysis results

resultsβ -arbutin
(ng/g
skin)

HQ
(ng/g
skin)

HQ/(Ar
b+HQ)
(%)

Day 1
(mg/l)

Day 2(mg/l)

Day 3(mg/l)

Day 4(mg/l)

Day 5(mg/l)

179809.0286

2.83< 0.974< 0.974<
0.974< 0.974< 0.974182031.088

4.15< 0.974< 0.974

1.05< 0.974< 0.974

Mean± S.D.

3735.8± 2137.5

177
± 149

4.6
± 2.9

Conclusion
The study authors conclude that:- Repeated topical application of gel containing 6.3% (w/w) β-arbutin leads to detectableamounts of β-arbutin and HQ in skin.
- The statistical tests showed significant differences (p<0.0001) between Day 1 and Day 5
for the variables: analysed amount (ng) and corrected amount (ng/g) for HQ as well as
for β-arbutin.
- Based on the large variation in the established urinary total HQ results, changes inurinary HQ levels due to topical treatment of β-arbutin could not be established.
- When the HQ content in the skin samples is taken relative, on a weight to weight basis,to the β-arbutin + HQ content, on average 4.6% (± 2.9) (range: 1.69-11.77) of HQ ispresent in these skin samples.
- Actual levels of HQ in treated skin amounted on average to 0.018 ± 0.016 µg/cm² (range
0.003 – 0.072).
Ref.: 9SCCS comment
Under the in-use conditions described in human volunteers2, hydroquinone is released in theskin to a relative level of 4.6% (compared to the β-arbutin + HQ content) and as high as
11.8% (w/w). This wide variation may reflect enzymatic action from skin bacteria (Bang etal., 2008) as well as the action of β-glucosidases in skin fibroblasts (Mier & van den Hurk,
1976; Redoules et al., 2005).
There is wide variation in urinary excretion of HQ. It may result from absorption of HQ
across the skin, together with a component resulting from dietary intake, since many
foodstuffs contain HQ or its precursor β-arbutin, resulting in mean urinary HQconcentrations of 1.2±0.54 mg/L (Deisinger et al. 1996). In any individual, there is poorcorrelation between skin HQ and urinary HQ measured in spot urine samples; the volunteers
kept a food diary but the contribution of dietary HQ intake to urinary HQ excretion is notassessed so that it is not possible from the data provided to determine which part of theexcreted HQ is derived from food or from dermal application of β-arbutin.
Moreover, the method used for HQ determination was not sensitive enough to quantify thisanalyte in the urine samples, since a large proportion (70%) of samples had concentrations
below the detection limit of 0.974 mg/l. Much lower detection limits are reported in otherstudies (e.g. Schindler et al. 2002; Quintus et al. 2005). Because of this lack of sensitivity,
no conclusion can be drawn from the measurement of urinary HQ in this experiment.
Another study assessed the relative amounts of HQ in tape strips from the skin ofvolunteers after application of a gel with either 3% alpha-arbutin or 3% beta-arbutin or
1.9% hydroquinone (Mamabolo et al., unpublished data). The results, discussed in more

2

The β-arbutin concentration tested (6.3%) is slightly lower than the required 7%.

21

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depth in the alpha-arbutin Opinion (SCCS/1552/153 section 3.3.11.3), indicate low
conversion of arbutins to HQ, but this data allows no conclusions on percutaneousabsorption.

3.3.5

Repeated dose toxicity

3.3.5.1 Repeated Dose (28 days) oral toxicity
Taken from SCCP/1158/08 (with minor corrections)
Guideline:

Date of test:
Species/strain:
Group size:
Test substance:
Batch:
Purity:Dosages:Observation period:
GLP/QAU:Not stated, though mainly according to Annex V to Dir. 67/548/EEC,
Method B.7: Repeated dose (28 days) toxicity (oral), OECD
Guideline 407: Repeated Dose 28-Day Oral Toxicity Study inRodents
September - November 1986
Sprague Dawley rat (SPF Crj:CD)
16 animals/sex/dosage group, out of which 6/sex were scheduled
for the 28-day recovery measurements
-arbutin
Lot A
99.7%
0 - 40 - 200 - 1000 mg/kg bw/day
56 days/Groups of 10 male and 10 female rats received 0, 40, 200 and 1000 mg/kg bw/day of
-arbutin by oral gavage for 28 days (7 days per week). Control and high dose groups were
supplemented with 6 rats/sex in order to study the reversibility of treatment-related effects
after a subsequent 28-day treatment-free period. Clinical signs were monitored at every
dosing. Body weights and food consumption were recorded weekly.
Haematology, serum chemistry, and urine measurements were performed at the end of thedosage period (day 28) and after the recovery period (day 56), and included:- for haematology: red blood cell count, haemoglobin, haematocrit, platelet count, whiteblood cell count, mean red blood cell volume, mean red blood cell haemoglobin amount,mean red blood cell haemoglobin concentration, basophils, eosinophils, neutrophils,
lymphocytes, monocytes, reticulocytes;- for serum chemistry: alkaline phosphatase, calcium, total cholesterol, creatinine, glucose,glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, phosphorus, total
protein, triglyceride, blood urea nitrogen, sodium, potassium, chloride, albumin/globulin;- for urine: pH, protein, glucose, ketone bodies, bilirubin, occult blood, nitrite,
urobilinogen.
Absolute and relative weights of brain, pituitary gland, salivary gland, thymus, heart, liver,spleen, kidney, adrenal gland, testis, prostate and ovary were determined at the end of thedosage period (day 28) and after the recovery period (day 56). In addition tissues were
fixed for histopathological examination.
Results
No test substance-related clinical signs or deaths were observed. Neither did body weightgain and food consumption differ between control and treated animals during the dosing
period.

3

Planned to be published later

22

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Some slight changes in haematological, serum chemistry and urine parameters wereobserved, though no dose-dependency could be observed and the observed changes were
small and reported to be within the normal ranges for the tested species.
Necropsy at the end of the dosing period revealed some spontaneous anomalies, but no test
compound-related changes. There were no histopathological findings related toadministration of the test substance.
Conclusion
The study authors conclude that, since no changes attributed to -arbutin were observed up
to a dosage of 1000 mg/kg bw/day, this can be considered as the NOEL value.
Ref.: 10

3.3.5.2 Sub-chronic (90 days) dermal toxicity
Guideline:
Date of test:
Species/strain:
Group size:
Test substance:
Batch:
Purity:Dosages:Observation period:
GLP/QAU:

OECD Guideline 411: Repeated Dose 90-Day Dermal Toxicity Studyin Rodents
February - May 1986
Sprague Dawley rat (SPF Crj:CD)
10 animals/sex/dosage group-arbutin dissolved in 50% aqueous ethanol solution (vehicle)
Lot A
99.7%
0 (untreated) - 0 (vehicle) - 56 - 294 - 618 mg/kg bw/day in 2.0
mL/kg bw
90 days/

Prepared test substance or vehicle was applied to the dorsal skin (clipped of fur) of 10 maleand 10 female rats per dosage group, 6 days per week for 90 days. Fur clipping was
performed once per week. Clinical signs were monitored at the time the test substance orvehicle was applied.
Body weights and food consumption were recorded weekly. Haematology, serum chemistry,
and urine measurements were performed at the end of the dosage period (day 90) andincluded:- for haematology: red blood cell count, white blood cell count, platelet count,
haemoglobin, mean red blood cell volume, mean red blood cell haemoglobin, mean red
blood cell haemoglobin concentration, haematocrit, reticulocyte count and white blood
cell differential count;- for serum chemistry: total protein, albumin/globulin ratio, glutamic oxaloacetictransaminase, glutamic pyruvic transaminase, alkaline phosphatase, total cholesterol,
triglyceride, blood urea nitrogen, creatinine, glucose, chloride, calcium, sodium,
potassium, inorganic phosphorus;- for urine: pH, protein, glucose, ketone bodies, bilirubin, occult blood, nitrite,
urobilinogen.
Absolute and relative brain, pituitary gland, salivary gland, thymus, heart, liver, spleen,kidney, adrenal gland, testis, prostate and ovary weights were determined at the end of thedosage period (day 90) and after the recovery period (day 56). In addition tissues were
fixed for histopathological examination.
Results
All animals survived the test. Observations:56 mg/kg bw/day:
reduced body weight in males week 6-8; increased relative weights
for spleen, thymus and adrenal gland
23

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294 mg/kg bw/day:
618 mg/kg bw/day:decrease in Ca++ in females; decrease in absolute pituitary glandweight in males; decreased absolute and relative pituitary gland andthymus weights in females;
increase in monocyte ratio in females; decreased relative thymus
weight.

No substance-related abnormalities were observed in clinical signs and in the urinanalysis.
There were no remarkable findings at necropsy in either sex at any dose level. No
histopathological changes were observed.
The study authors consider the reduced body weight at 56 mg/kg/day within the normal
range of variation (no dose-dependency observed). The same is claimed for the increased
monocyte ratio (618 mg/kg bw/day) and the decreased Ca2+ level in females(294 mg/kg bw/day), which are regarded as being within normal physiological variation.
Conclusion
The study authors conclude that, since no test substance-related changes attributed to-arbutin were observed up to a dosage of 618 mg/kg bw/day (the maximum technicallyapplicable dosage), this can be considered as the NOEL value.
Ref.: 11SCCS comment
The change in the relative thymus weight (increase at lower dosage level and decrease at
higher dosage levels) did not occur in the 28-day oral study, supporting the authors' findingthat the observed variations were within the normal range of variation and not substancerelated.
SCCS conclusion on repeated dose toxicity
A repeated dose 28-day oral study and 90-day dermal study with the rat only revealed
some sporadic observations that could not be related to the test substance. Therefore inboth tests, the highest dosage tested could be designated as NOEL, i.e. 1000 mg/kg bw/day
for the repeated dose oral study and 618 mg/kg bw/day for the repeated dose dermal
study.

3.3.5.3 Chronic ( 12 months) toxicity
No data.

3.3.6

Mutagenicity / Genotoxicity

Taken from SCCP/1158/08 (with minor modifications)
3.3.6.1 Mutagenicity/Genotoxicity in vitro
Gene mutation test in bacteria
Guideline:
OECD 471 (1997)
Species/strain:
Salmonella typhimurium, TA98, TA100, TA1535, TA1537 and Escherichia
coli WP2 uvrA
Replicates:
Triplicates per test concentration
Test substance:β-arbutin
Batch:Lot A
Purity:99.7%
24

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Vehicle:Concentrations:
GLP:
Date of study:

distilled water
0, 156.25, 312.5, 625.0, 2500 and 5000 µg/plate, with and without
metabolic activation (rat S9-mix)/
9 February 1987 -19 February 1987

Beta-arbutin was investigated for the induction of gene mutations in strains of Salmonella
typhimurium and Escherichia coli (Ames test). Concentrations were based on the results ofa concentration determination test; no toxicity of β-arbutin was observed in any of the test
strains at 5000 µg/plate. Therefore, the maximum concentration was set at 5000 µg/plateand 6 concentrations were set at a common ratio of 2. In the main study, the strains were
exposed to β-arbutin in the presence and absence of rat liver metabolic activating system.
Liver S9 fraction was prepared from livers of male Sprague-Dawley rats that had received
the intraperitoneal injections of sodium phenobarbital and 5,6-benzoflavone. Distilled water
alone served as negative control. As a positive standard requiring metabolic activation 2aminoanthracene was used. N-ethyl-N'-nitro-N-nitrosoguanidine, ICR-191 and 2-(2-furyl)3-(5-nitro-2-furyl) acrylic amide were used as positive standards without metabolic
activation.
Results
A biologically relevant increase in the number of revertant colonies was not observed in anyof the test strains at any concentration, irrespective of metabolic activation. The number ofrevertant colonies was similar to that for the solvent control. Positive control substances
induced mutagenic responses in respective test strains.
Conclusion
Under the experimental conditions used, β-arbutin can be considered non-mutagenic in all
tested strains under all tested conditions.
Ref.: 12
In vitro mammalian chromosome aberration test
Guideline:
OECD 473 (1997)
Cells:
Chinese hamster lung (CHL) fibroblast cells
Replicates:
duplicate cultures
Test substance:
β -arbutin
Batch:Lot A
Purity:99.7%
Solvent:
physiological saline
Concentrations:0, 0.34, 0.68, 1.36 and 2.72 mg/ml with and without metabolic
activation (rat S9-mix)
Treatment:
6 h treatment without and with S9-mix; harvest time 24 h after thestart of treatment
24 and 48 h treatment without S9-mix; harvest time immediately after
the end of treatment
GLP/QAU:/
Date of study:
11 April 1986 - 5 September 1986
Beta-arbutin has been investigated for the induction of chromosomal aberrations in CHL
cells in the absence and presence of metabolic activation. As exogenous metabolic
activation system, liver S9 fraction from sodium phenobarbital and 5,6-benzoflavone
induced rats was used. In the main study, cells were incubated with β-arbutin atconcentrations of 0, 0.34, 0.68, 1.36 and 2.72 mg/ml without and with S9-mix for 6 h and aharvest time of 24 h after the start of treatment. Additionally, cells were treated with thesame concentrations for 24 and 48 h without S9-mix and harvested immediately after theend of treatment. Two hours before the end of the incubation period, colcemid was added tothe cultures. N-Methyl-N’-nitro-N-nitrosoguanidine and benzo[a]pyrene were used as
positive controls for the direct and the metabolic activation methods, respectively. Per
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culture, 100 metaphases were scored for structural chromosomal aberrations andpolyploidy.
Results
There were no biologically relevant and statistically significant increases in cells withstructural aberrations and polyploidy after treatment with β-arbutin at any concentration or
incubation time, irrespective of the presence of a metabolic activation system. The
reference mutagens used as positive controls showed distinct increases in cells withstructural chromosome aberrations.
Conclusion
Under the experimental conditions used, β-arbutin was not genotoxic (clastogenic) in thischromosome aberration test in CHL cells.
Ref.: 13Overall conclusion on mutagenicity
The genotoxicity of β-arbutin is sufficiently investigated in valid genotoxicity tests for genemutations in bacteria and structural chromosomal aberrations and polyploidy in mammaliancells. β-arbutin did not induce gene mutations in bacteria nor an increase in cells withchromosomal aberrations or polyploidy in CHL cells. Although a gene mutation test in
mammalian cells is lacking, based on the present reports β-arbutin can be considered tohave no in vivo genotoxic potential and additional tests are unnecessary.
Arbutins are considered to be metabolised differently by different glycosidases or byspontaneous hydrolysis, yet they all form hydroquinone. The latter is considered as the
genotoxic moiety; therefore a read across approach based on HQ release is a possibility toassess the genotoxic potential of the arbutins as a group.

3.3.7

Carcinogenicity

Dermal study
Guideline:
Date of test:
Species/strain:
Group size:
Test substance:
Batch:
Purity:Dosages:Observation period:
GLP/QAU:

National official protocol (Japan), partly according to Annex V to
Dir. 67/548/EEC, Method B.32: Carcinogenicity test, OECD
Guideline 451: Carcinogenicity Studies.
Apr 1993 - Oct 1994
Crj:CD1 (ICR) mice
50 animals/sex/dosage group-arbutin, dissolved in 50% ethanol solution in water
Lot TDD-422
100.0%
0 - 45 - 135 - 400 mg/kg bw/day in 2 mL/kg bw
78 weeks (18 months)
reported to be present, but not included in the submission.

Groups of 50 male and 50 female mice were treated with 0, 45, 135 and 400 mg/kg bw/dayof -arbutin through dermal application for 78 weeks (6 days per week). The application site
was the interscapular skin (≈ 2 x 2 cm), clipped with an electrical clipper once every one or
two weeks. Control animals received 10 ml of distilled water. Clinical signs and presence ofdead or moribund animals were checked twice per day. In addition, body surface waspalpated for masses once per week. Documentation of detected masses included date, sizeand progression. Body weights and food consumption were recorded once per week until
week 26 and once every two weeks thereafter.
Haematology was performed at the end of the dosage period (week 78) and after therecovery period (day 56), and included red blood cell count, white blood cell count,

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differential count, eosinophil, basophil, monocyte, band neutrophil and segment neutrophil
count. Haematology was also performed whenever possible on moribund animals.
All surviving animals were sacrificed and body surfaces, intracranial tissues, and internalorgans were examined. Observed masses were documented as to site, shape, size andnumber. Absolute and relative brain, heart, lung, liver, kidney, spleen, testis and ovary
weights were determined. Histopathology was performed on organs and tissues of all
animals.
Results
Mortality rates, clinical signs and food consumption did not show significant differences
between control and treated animals. Red blood cell count, white blood cell count, whiteblood cell differential count, absolute and relative organ weight measurements and necropsy
and microscopic examination did not reveal substance-related differences.
Non-tumour lesions included hyperplasia of mucosal epithelium in the glandular stomach,myocardial degeneration and necrosis in the heart, excessive extramedullaryhaematopoiesis in the spleen, calcification in brain thalamus, subcapsular hyperplasia in theadrenal gland, ovary cysts, cystic endometrial hyperplasia in the uterus and detachment or
hypertrophy of articular chondrocytes in the joint.
Tumour lesions included hepatocellular adenoma, bronchiolar/alveolar adenoma andmalignant lymphoma. These lesions occurred in all groups (also in the control group).
Conclusion
The study authors conclude that, since the observed (non-)tumour lesions are the ones
frequently observed in aging mice, the NOEL value for -arbutin in the present study isestimated to be 400 mg/kg bw/day in male and female mice. It is also concluded that thetest substance is not carcinogenic under the conditions of the performed study.
Ref.: 14SCCS comment
No rationale is given for the choice of another species than the one used in the 28-day or
90-day repeated dose study (mice instead of rats). In addition, the weight variation in the
animals at the beginning of the study exceeded 20% ( 50%) and the intermediatehaematological examination (after 12 months) was not performed. The non-tumour and thetumour lesions observed in all animals (including the control group) reveal that, whether or
not caused by aging alone, the general condition of the animals appeared to be poor. As theincidence of tumour and non-tumour lesions did not show an increasing dose-relationship,and since they are frequently observed in aging mice, they are regarded as spontaneous
lesions. No positive control group has been included. This is not necessary, but historical
data from the testing facility to detect carcinogens with the method used, are lacking.
No conclusion with regard to carcinogenicity can be drawn from this study.

3.3.8

Reproductive toxicity

Taken from SCCP/1158/08
3.3.8.1 1-generation reproduction toxicity
Guideline:
Date of test:
Species/strain:
Group size:
Test substance:
Batch:
Purity:Not stated, though partly according to Annex V to Dir. 67/548/EEC,
Method B.34: One-generation reproduction toxicity test.
Not specified, around April 1986
Sprague Dawley rat (SPF Crj:CD)
35 animals/sex/dosage group-arbutin
Lot A
99.7%
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Dosages:Route:
Observation period:
GLP/QAU:0 - 25 - 100 - 400 mg/kg bw/day in salines.c. injection (of 2 mL/kg bw)
up to 10 weeks
probably before introduction of GLP (1987), thus not applicable.

-arbutin or vehicle was injected subcutaneously into male rats for 9 weeks prior to mating,from 6 to 15 weeks of age. Dosing continued until the rats were observed to havesuccessfully copulated. For female rats, dosing was performed for 2 weeks before mating,i.e. from 8 to 10 weeks of age, after which it continued during the mating period. A group of
20 pregnant rats were subjected to a caesarean section after daily dosages from days 0 to
19 of pregnancy. The remaining animals that were scheduled to go to term (+ 10) were
dosed daily from day 0 of pregnancy till day 21 after parturition.
Observations for the parent (P) rats included clinical signs, mortality, body weight and foodintake on a daily basis. To examine the oestrous cycle, vaginal smears were examined. For
the males, testis, epididymis, and prostate were weighed. Ovary and uterus from female
rats that did not successfully mate and from non-pregnant female rats were examinedhistopathologically.
In the caesarean section group, foetuses were fixed in alcohol for either skeletal
examination or visceral examination. Pups from the delivery groups were lactated andclinical signs, body weights, physical and behavioural development were observed up to day
21 after parturition. One male and female pair from each litter was mated at 10 weeks ofage to evaluate reproductive function. One rat/sex from each litter was sacrificed at 7 and
10 weeks of age and the organs were weighed. The number of corpora lutea, implantations,
live and dead foetuses, and the number of resolved embryos were counted. Male F1 rats
used for mating were sacrificed for post-mortem examination to measure the weight oftestis, epididymis and prostate.
Results
No clinical or body weight abnormalities related to the test substance were observed in theparent rats. Food intakes were slightly lower on Days 51 and 58 for the 100 mg/kg groupand on Days 2 and 58 for the 400 mg/kg group, though only for the male rats.
Oestrous cycles, copulation indices, and fertility indices in the treatment groups were similar
to the control group.
For ovulation, implantation, foetal development, number of ovulations (number of corpora
lutea), implants, live foetuses, implantation rate, embryo-lethality rate, placental weights,
and sex ratios, the measurements in the treatment groups were similar to the ones in thecontrol group. Body weights of female foetuses in the 400 mg/kg bw/day group weresignificantly lower than the control group. Gross findings, organ weight checks,
histopathological examinations and examination of female parent rats at delivery, revealed
no abnormalities related to the test substance.
The live foetuses showed no abnormalities in external, visceral, and skeletal examination.
The degrees of ossification and the incidences of skeletal variations of the treatment groups
were similar to the control group. Mean numbers of F1 pups, viability indices at 4 days ofage, weaning indices at 21 days of age, body weights of F1 pups during the lactation period,
behavioural and physical development parameters did not differ between treated andcontrol animals. After weaning, the F1 rats showed no adverse clinical signs or altered bodyweight gain and food intake values. With regard to absolute and relative organ weights (7or 10 weeks of age), no significant differences were observed in the 25 and 100 mg/kg
groups. Absolute and relative organ weights of the left ovary of the 400 mg/kg group weresignificantly lower, but no significant differences were observed with the total absolute andrelative weight of the right ovary.
Conclusion
It is concluded that 400 mg/kg/day of -arbutin does not affect reproductive functions of
the parent animals and F1 rats, but caused body weight decrease in female foetuses,
decreased organ weights of the unilateral ovary of female F1 rats. Therefore the study
authors estimate the no observable effect dose of -arbutin to be 100 mg/kg/day.
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Ref.: 15SCCS comment
This is the lowest NOEL for -arbutin; yet, subcutaneous injection is an uncommon
application route in one-generation reproductive toxicity tests.

3.3.8.2 Teratogenicity
No data submitted.

3.3.9

Toxicokinetics

ß-Arbutin is hydrolysed into hydroquinone and glucose in the presence of weak acids.
Cosmetics with ß-arbutin may contain small amounts of hydroquinone (HQ) as impurity.
Hydrolysis of dermally applied arbutin may also occur to some extent on the skin surface(by microflora) and in the skin (by hydrolases). Data on skin metabolism, however, arescarce.
Dermal route:See section 3.3.4.2 for a study in human volunteers with repeated topical application of agel with 6.3 % ß-arbutin (Ref. 9). The results show some release of hydroquinone fromß-arbutin in the skin.
Oral Route:
Many foodstuffs contain HQ or its precursor β-arbutin, resulting in mean urinary HQconcentrations of 1.2±0.54 mg/L (Deisinger et al. 1996; Ref 28, subm. I). The metabolism of
ß-arbutin was also assessed in studies which measured urinary excretion in humanvolunteers after oral administration of herbal preparations which are used to treat urinary
tract infections.
(A) Three human volunteers were dosed with bearberry leaf extract (containing 150 mg ßarbutin), and the metabolites of arbutin were measured in urine; >50% of the arbutin was
excreted within 4 hours as HQ glucuronide and HQ sulphate while >75% of the arbutin (asHQ metabolites) was excreted in 24 hours. In one volunteer only, 5.6% of the total arbutin
was found as free HQ (Quintus et al. 2005).
(B) Sixteen human volunteers were dosed with bearberry leaf extract as film-coated tablet
or as aqueous solution containing equal amounts of ß-arbutin (210 mg). HQ glucuronide
and HQ sulphate were the main urinary metabolites; free HQ was also detected, but
represented only 0.1 % of the applied dose (Schindler et al. 2002).
(C) An earlier study on the metabolism of arbutin in 12 subjects after ingestion of 420 mg
arbutin, reported that 70% of the administered dose was excreted as conjugates of
glucuronide and sulphuric acid and only 0.6% as free hydroquinone (Siegers et al., 1997).
SCCS comment
Despite intersubject variability observed in these studies with oral application, the main
metabolic route is apparently phase II metabolism of hydroquinone (HQ). This implies thatany ß-arbutin absorbed across the skin when hydrolysed to HQ is then also predominantly
excreted by systemic conjugation as glucuronide and sulphate.

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3.3.10 Photo-induced toxicity
Taken from SCCP/1158/08 (with minor modifications)3.3.10.1

Phototoxicity / photo-irritation and photosensitisation

Guideline:
Date of test:
Species/strain:
Group size:
Test substance:
Batch:
Purity:Positive control:
Dose:
Observation period:
GLP/QAU:

Morikawa et al. 1974 (Ref. 34)
24-28 Mar 1986
Hartley male albino guinea pigs
10 animals
ß-arbutin, 10% solution in 50% v/v ethanol solution in water
Lot A
99.7%
8-Methoxypsoralen (8-MOP) at 0.02% in ethanol
20 µl applied to a skin surface area of 1.5cm x 1.5cm
72 hours/

The fur of the back of 10 guinea pigs was clipped with an electric clipper and depilated with
Shiseido hair remover. The test was carried out 24 hours after depilation. 20 µl of either
10% ß-arbutin in 50% ethanol or 8-MOP were applied to two 1.5cm x 1.5cm skin areas.
Immediately after application, one side was covered with aluminium foil and 30 minutes
later, the other side was irradiated with six Toshiba model FL-40 BLB lamps (emission: 300400 nm, max=360 nm) arranged in parallel and fitted with a window-glass filter to eliminate
radiation below 320 nm. The distance from the light source to the skin was 10 cm and theenergy used was 14.0 Joule/cm2. Erythema and oedema were evaluated at 24, 48, and72 hours after irradiation. Phototoxicity was evaluated by comparing scores of the irradiatedand non-irradiated sections.
Results
No skin reactions were observed in either irradiated or non-irradiated sections treated with
ß-arbutin. Conversely, a strong phototoxicity reaction was observed with the positive control
substance 8-MOP.
Conclusion
The study authors conclude that ß--arbutin has little phototoxicity potential.

3.3.10.2

Ref.: 17

Photosensitisation test

Guideline:
Date of test:
Species/strain:
Group size:
Test substance:
Batch:
Purity:Positive control:
Dose:

Observation period:
GLP/QAU:

Ichikawa et al. 1981 (Ref. 35)
10 Mar - 2 Apr 1986
Hartley male albino guinea pigs
10 animals (treatment & control), 5 animals (positive control)ß-arbutin, 10% solution in 50% v/v ethanol solution in water
Lot A
99.7%
6-methylcoumarin (6-MC) at 1.0% and 0.1% in ethanol
induction: 100 µl of 10% ß-arbutin in 50% ethanol
100 µl of 5% 6-MC in ethanol
challenge: 20 µl of 10% ß-arbutin in 50% ethanol
20 µl of 1 and 0.1% 6-MC in ethanol
24 daysbefore introduction of GLP (1987), thus not applicable.

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100 µl of emulsified Freund’s Complete Adjuvant (FCA) was injected intradermally at the
4 corners of the clipped and shaved 2cm x 4cm nuchal area of the guinea pigs. 100 µl of
10% ß-arbutin in 50% ethanol solution was then applied to the area defined by the injection
sites. Subsequently the area was irradiated with 10.2 Joule/cm2 of UVA. Whereas FCA wasinjected once at the start of the induction exposure, the remaining procedures wererepeated for 5 consecutive days. The light source used composed of six tubes of Black Light
Lamp (=300-400 nm, max=360 nm) had a glass filter to eliminate radiation below 320 nm.
The distance from the light source to the skin was 10 cm. Three weeks after first induction,
20 µl of 10% ß-arbutin in 50% ethanol was applied to the dorsal site. One side wasirradiated with 10.2 Joule/cm2 of UVA, while the other side was covered with aluminium foil
thus serving as unirradiated control. 20 µl of 1% and 0.1% 6-Methylcoumarin (6-MC) inethanol was applied as positive control. Erythema and oedema formation were evaluated 24
and 48 hours after irradiation.
Results
No positive reactions were observed in either irradiated or non-irradiated sections treatedwith ß-arbutin. Conversely, strong photosensitisation reactions were observed with thepositive control substance 6-MC.
Conclusion
The study authors conclude that ß-arbutin does not possess photoallergic potential under
the test conditions.
Ref.: 16

3.3.11 Human data
Taken from SCCP/1158/08 (with minor modifications and updated)
A. Single patch test with ß-arbutin on human volunteers
Method:Subjects:
Group size:
Test substance:
Batch:
Purity:Doses:
Exposure time:
Scoring system:

GCP:
Date of study:

48-hour closed patch test in human volunteers
Healthy volunteers, age 25-47 years (mean: 35 years)
43 male subjects
ß-arbutin, 10% solution in distilled water
Lot A
99.7%
50 μl of 10% ß-arbutin solution
48 hours
negative:no reaction
pseudo-positive:
mild erythema+
positive, weak:erythema++positive, medium:
erythema + oedema+++
positive, strong:erythema + oedema + (serious) papules
or small vesicles++++ positive, strongest: large vesicles
No statement (performed before issue GCP guidelines)
01-03 Apr 1986

50 µl of 10% ß-arbutin solution was placed on a piece of lint which was attached to the backof each subject. The application site was subsequently immobilized using Nichiban Keepsilk
plasters (16 mm in diameter). After 48 hours, the plasters were removed.
The first reading was performed 30 minutes after the removal (48-hour reading), and theseverity of skin reactions was scored. A second reading was performed 24 hours later (72hour reading).

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Results
No positive reactions were seen in any subjects at 48 or 72 hours after application of 10%
ß-arbutin solution.
Conclusion
The study authors conclude that ß-arbutin displays low irritation potential.
Ref.: 4
B. Single patch test with ß-arbutin-containing finished products on human volunteers
Method:Subjects:
Group size:
Test substance:

Batch:
Purity:Doses:
Exposure time:
Scoring system:

GCP:
Date of study:

24-hour closed patch test in human volunteers
Healthy volunteers, age 19-59 years (mean: 32 years)
24 female and 23 male subjects
1) AR-91 SWT Essence (containing 7% ß-arbutin),2) AR-91 SWT Essence A10 (containing 10% ß-arbutin),3) AR-91 SWT Essence AC (containing 0% ß-arbutin).
No details on qualitative and/or quantitative compositions.For ß-arbutin: Lot TDA-361
100.3%
30 μl of above-mentioned formulations (0%, 7% or 10% ß-arbutin)
24 hours
negative:no reaction
pseudo-positive:
mild erythema+
positive, weak:erythema++positive, medium:
erythema + oedema+++
positive, strong:erythema + oedema + (serious) papules
or small vesicles++++ positive, strongest: large vesicles
No statement (performed before issue GCP guidelines)
29 Jun - 01 Jul 1992

The irritation potential was assessed in a closed patch test with Finn chambers: 30 µl ofeach product was placed on a filter paper positioned on an aluminium plate with petroleum
jelly, which was subsequently attached to the flexor side of the forearm of each volunteer.
The application site was immobilised using an elastic bandage. Elastic and adhesive
bandages were removed three hours before the first reading (24 hours) and the severity ofskin reactions was scored. A second reading was performed 24 hours later (48 hourreading).
Results
No positive reactions were seen at 24 or 48 hours after application of the 0%, 7% or 10%
ß -arbutin products and the positive rate was 0% in all cases.
Conclusion
The study authors conclude that 0%, 7% and 10% ß-arbutin-containing products display
low irritation potential.
Ref.: 5
C. Repeated open application test with ß-arbutin-containing finished products, without
exposure to sunlight on human volunteers
Method:Subjects:
Group size:

24-week repeated open application test in human volunteers
Healthy volunteers, age 18-53 years (mean: 34 years) without skindiseases
23 female and 23 male subjects
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Test substance:

Batch:
Purity:Doses:
Exposure time:
Scoring system:

GCP:
Date of study:1) AR-91 SWT Essence (containing 7% ß-arbutin),2) AR-91 SWT Essence A10 (containing 10% ß-arbutin),3) AR-91 SWT Essence AC (containing 0% ß-arbutin).
No details on pH or qualitative and/or quantitative compositions.For ß-arbutin: Lot TDA-361
100.3%
20 mg of above-mentioned formulations (0%, 7% or 10% ß-arbutin)
Open test, 3 applications/day, thus continuous exposure for 24 weeks
Skin colour reading criteria: 0
no1
slight2
significant
Adverse reactions reading criteria:noneslight+mild++
moderate+++ severe (indicates termination of the test)
No statement
30 Jul 1992 - 20 Jan 1993

Test samples were applied at least three times daily for 24 consecutive weeks. The 0%
ß-arbutin product was applied randomly to either the upper or lower area of each arm, while
the 7 and 10% ß-arbutin product were randomly assigned to the left or right arm, thus
ensuring that product application was left-right symmetric. Four tubes were labelled "upper
right", "lower right", "upper left" and "lower left". For each application, subjects were
instructed to apply about 20 mg of product (about the size of a rice grain) using theirfingers. Readings were performed at 4, 8, 12, 16, 20 and 24 weeks after the start ofapplication. Severity of pigmentation and discoloration were assessed in relation to skincolour of adjacent areas. Adverse reactions due to the application of test materials (forexample irritation, itching, redness, oedema, papules/vesicles, and desquamation) wereassessed for each area and graded.
Results
Of the 64 subjects, two women withdrew from the study (after 8 and 20 weeks,
respectively). Data obtained from these subjects were analysed until their last reading.
Application of test products was not terminated due to the onset of adverse reactions in anyof the subjects, and none of the subjects violated any of the restrictions.
For all reading periods after the start of application, there were no differences in relative
skin colour for the 7%, 10%, and 0% ß-arbutin products and no pigmentation/discoloration
was observed. No adverse reactions caused by the application of test materials were seen inany subject at any reading period.
Conclusion
The study authors conclude that there were no safety-related problems with the tested 7%
and 10% ß-arbutin product.
Ref.: 18
D. Repeated open application test with a 10% ß-arbutin-containing finished product, with
exposure to sunlight on human volunteers
Date of study:
Method:Subjects:
Group size:

24 Sep 1992 - 09 Mar 1993
24-week repeated open application test in human volunteers, with
exposure to sunlight
Healthy volunteers, age 32-60 years (mean: 43 years) without skindiseases
59 female subjects
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Test substance:
Batch:
Purity:Doses:
Exposure time:
Scoring system:

GCP:1) AR-91 SWT Essence A10 (containing 10% ß-arbutin),2) AR-91 SWT Essence AC (containing 0% ß-arbutin).
No details on qualitative and/or quantitative compositions.For ß-arbutin: Lot TDA-361
100.3%
50 mg of above-mentioned formulations (0% or 10% ß-arbutin)
Open test, 4 applications/day, thus continuous exposure for 24 weeks
Skin colour reading criteria:0
no1
slight2
significant
Adverse reactions reading criteria:noneslight+mild++
moderate+++ severe (indicates termination of the test)
No statement

Test substances were applied at least four times daily for 24 consecutive weeks. The 10%
and 0% ß-arbutin products were randomly assigned so that one product was applied to theright hand while the other was applied to the left hand. In case the hands came in contact
with water, products were reapplied. Subjects were instructed to apply about 50 mg (size ofa soybean) of product to the back of the respective hand. Readings were performed at 4, 12
and 24 weeks after the start of application.
The presence and severity of adverse reactions at the application sites were scored andadverse reactions such as irritation, itching, flushing, swelling, papules/vesicles, dry skin,desquamation, discoloration and pigmentation were graded.
Results
None of the subjects experienced adverse reactions severe enough to terminate applicationof the products, and as a result, data obtained from all 59 subjects were analysed.
Skin readings conducted at 4 and 12 weeks after the start of application revealed no skinreactions. Skin readings conducted at 24 weeks after the start of application revealed a few
reactions in two subjects. However, it was determined that these reactions were not causedby the 10% or 0% ß-arbutin products.
Conclusion
The study authors conclude that no safety-related problems resulted from applying the 10%
ß-arbutin product to the backs of the hands of 59 healthy women for 24 consecutive weeks.
Ref.: 19
E. Post marketing surveillanceSome side effects from the use of Shiseido Product A or Shiseido Product B were reported
by 30 out of 1,382 users surveyed. However, based on the results of subsequent
investigations, the majority of these people were able to continue using the product with notrouble. In addition, the skin symptoms experienced by a user with a sensitive skin were
probably not caused by allergic contact but may have been an irritation response.
Based on the results above, it was concluded that Shiseido Product A and Shiseido ProductB are safe and in particular with no reactions attributable to arbutin.
Ref. 5 (PMS Shiseido in house data) in subm. II files.
A case report on contact allergy to ß-arbutin could be identified (Matsuo et al. 2015).
Contact allergy to hydroquinone has been described, notably in hairdressers and theirclients reacting to hair-dye (Uter et al. 2014).
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The sensitising potential of ß-arbutin is negligible. It is not an irritant.

3.3.12 Special investigations
In vitro studies
ß-Arbutin inhibits melanin production in guinea pig B16 cells and decreases tyrosinase
activity in a cell-free system (Lim et al. 2005). Using A375 human malignant melanoma
cells in a proteomic approach, ß-arbutin was shown to have a role in tumour suppression, as
found by regulation of p53 and cell apoptosis (Nawarak et al. 2005).

3.3.13 Information on the toxicity of hydroquinone
Taken in part from the SCCP/1158/08 Opinion and updated
LD50-oral-rat = 298 mg/kg
Slightly irritating to the eye
Sensitising to the skin
NOEL (28d/90d-oral-rat) =20 mg/kg/day
NOAEL (28d/90d-dermal-rat) =74 mg/kg/day
NOEL (developmental toxicity-rabbit) =25 mg/kg/day (dams)
NOEL (developmental toxicity-rabbit) =75 mg/kg/day (teratogenic effects).
NOEL (1-generation reproduction toxicity-rat) =15 mg/kg/day (general toxicity).
NOEL (1-generation reproduction toxicity-rat) = 150 mg/kg/day (reproductive toxicity).
Negative in the Ames test, the dominant lethal assay and the mouse spot test.
Positive in the in vitro chromosome aberration test (+S9)
Positive (i.p.) and weakly positive (oral) in the in vivo micronucleus test.
Equivocal conclusions on potential carcinogenic effects at dosage levels  25 mg/kg/day.
Ref.: 26, 29
Hydroquinone has been used for many years in skin-bleaching preparations up to 2%. It
does not directly bleach the skin, but acts through competitive inhibition of tyrosinase
resulting in gradual fading of hyperpigmented spots by a reduction in the formation of new
pigment.
With regard to potential adverse effects caused by hydroquinone, covalent binding andoxidative stress are mechanisms postulated to be induced by the molecule. Oxidisedhydroquinone metabolites may covalently bind cellular macromolecules or alkylate low
molecular weight nucleophiles (e.g. glutathione) resulting in enzyme inhibition, alterations
in nucleic acids and oxidative stress. Cell proliferation associated with nephrotoxicity in asensitive strain of animals (male F344 rat) has been postulated to be involved in the
production of renal tumours in rats.
Ref.: 26
According to IARC, hydroquinone is not classifiable as to its carcinogenicity to humans. Thisconclusion was based upon limited evidence in experimental animals and inadequate
evidence in humans (IARC 1999, Ref. 37). In the EU, hydroquinone is classified as Carc Cat
2 H351 (suspected of causing cancer) based on Regulation (EC) No 1272/2008 (CLP
Regulation), Annex VI4.
4

The SCCS is aware that HQ is presently evaluated under REACH, and further data isrequested
on
its
in
vivo
oral
genotoxicity(http://echa.europa.eu/documents/10162/7e36b2f6-80c6-42fb-9d67-7f7c7a86ee10)35

SCCS/1550/15
Opinion on β-arbutin________________________________________________________________________________________A more recent literature review on the carcinogenicity of hydroquinone concludes thatindeed renal tumours were observed in male rats, but that the mode of action (exacerbatedchronic progressive nephropathy) appears to be a rat-specific disease that appears to lack ahuman counterpart. The available cohort studies (all involving occupational exposure) failed
to show a clear causal relationship between exposure to hydroquinone and the developmentof several types of malignancies.
Ref.: 36
A final side effect linked to the use of hydroquinone as a skin bleaching agent is ochronosis,
the darkening of the skin accompanied by changes in the papillary dermis. Recently aliterature review from 1966 to 2007 on the topic of human exposure to topically applied
pharmaceutical hydroquinone preparations was published. Data on more than 10,000
patients were screened. Applied hydroquinone concentrations ranged from 1 to 30% andthe duration of exposure from 1 day to 20 years. More than 9,500 patients usedhydroquinone for a period longer than one month. In total, 789 cases of ochronosis werereported, of which 756 arose from Africa.
When hydroquinone is used at relatively high concentrations (>2%) in the medicinal world
to treat for example dyschromia, a risk-benefit analysis is performed.
Ref.: 38
The Cosmetic Ingredient Review (CIR) Expert Panel conducted a safety assessment ofhydroquinone as used in cosmetics and concluded that it is safe at concentrations ≤ 1% inhair dyes and is safe for use in nail adhesives. Hydroquinone should not be used in otherleave-on cosmetics. With regard to the use of HQ in topical formulations as skin bleachingand depigmenting agent, the CIR report (2010) points out that this use is considered in the
USA as drug use and thus falls under the purview of the FDA. Prescription and over-thecounter-products range in concentration from 0.4 to 5% (Anderson et al. 2010 new Ref.?#)Studies on the kinetics (ADME) of hydroquinone (HQ) in humans and rodents (reviewed by
McGregor 2007 and CIR/Anderson et al. 2010 new Ref.?#) indicate rather high bioavailability
and rapid clearance after oral or dermal administration. The dermal penetration in humans
was examined for 2% HQ in cream in vitro and in vivo with similar results [ref.24, Wester etal. 1998]: Total permeation of HQ after 24h was 43.3% of the dose in vitro; flux was 2.93µg/h-cm2. An average of 45.3±11.2% of the dose was recovered in urines of volunteers
after application of HQ to forehead skin. It is worth noting that dermal penetration of HQ isconsiderably higher than that of ß-Arbutin.
For the safety evaluation of HQ exposure resulting from the use of skin bleaching products
in comparison to internal HQ doses which may induce ochronosis, the SCCS will use 50%
dermal absorption for HQ.

3.3.14 Safety evaluation (including calculation of the Margin of Safety)
Safety evaluation for ß-arbutin (7% a.i. in face creams, applied 2 times per day)The systemic exposure dose (SED) was calculated for µg/cm2 derived from the in vitro
dermal penetration study (ref. 8). The no observed effect level (NOEL) from the 28-day oral
toxicity rat study (ref. 10) of 1000 mg/ kg bw was adjusted by a factor of 3 for time.
Absorption through the skin
Skin Area surface
Dermal absorption per treatment
Typical body weight of human
Systemic exposure dose (SED)A
SAS
SAS x A x 0.001
SAS x A x 0.001/bw

36

=
=
=
=
=

0.339 µg/cm²
565 cm2
0.192 mg (x 2)
60 kg
0.0064 mg/kg bw

SCCS/1550/15
Opinion on β-arbutin________________________________________________________________________________________

No observed effect levelfor 28-day, oral, rat : 3

NOEL

Margin of Safety

NOEL/SED=

333 mg/kg bw/d

=

52082

Additional MOS calculations for the NOAEL of 100 mg/kg bw from the rat reprotoxicity study
with subcutaneous administration (ref. 15) also arrive at very high value (MOS=15625).
An SED calculation based on a dermal absorption of 0.214% of dose (instead of µg/cm2)
arrives at 0.004 mg/kg bw (lower than the 0.0064 mg/kg bw above). Accordingly, the MoS
values for ß-arbutin would be even higher (83250 and 25000).
Further safety considerations will focus on ingredient-related exposure to hydroquinone as
resulting from topical application of β-arbutin.
Safety evaluation for the Hydroquinone (HQ) formed
Below the exposure to hydroquinone from application of β-arbutin containing products is
assessed and compared to risks related to 1.) repeated dose toxicity, 2.) induction ofochronosis and 3.) carcinogenicity.
Dermal penetration of β-arbutin, either expressed in % of dose (A) or in µg/cm2 (B), areused as starting points in the following calculation of internal amounts of HQ.
1. Based on repeated toxicity study and reproductive toxicity tests for HQA) Exposure to hydroquinone (HQ) from application of products containing up to 7%
β-arbutin (and its dermal penetration in % of dose) is derived as follows:– The amount of cream applied is 1.6 g with 7% a.i. = 112 mg ß-arbutin (external);– then 0.214 % of β-arbutin (ref. 8) is absorbed or 240 µg/person/day (internal);– the fraction of HQ in skin, relative to total absorbed, was up 12 parts (11.8% ref. 9)
or in total 29 µg HQ.
– For a possible presence of HQ as impurity (<1 ppm) in the applied product, one may
add another 1.6 µg HQ (if 1 ppm in 1.6 g product as worst case) and use 50%
dermal absorption for HQ, resulting in an extra 0.8 µg HQ per day.
The internal HQ exposure amounts to ≤31 µg per day; divided by 60 kg body weight= (SED) 0.517 µg/kg bw/d or 0.0005 mg/kg bw/d
NOAEL reported for HQ repeated toxicity (section 3.3.13) are 15 or 20 mg/kg bw/d
NOAEL / SED results in MOS of 25000 or 33333
B) Exposure to hydroquinone (HQ) from application of products containing up to 7%
β-arbutin (and its dermal absorption in µg/cm2 instead of % of dose) is derived as follows:– For ß-arbutin (see above) SED = 0.0064 mg/kg bw/d or 6.4 µg/kg bw/d– the fraction of HQ in skin, relative to total absorbed, is up to 11.8% (ref. 9) which isequivalent to 0.755 µg/kg bw HQ (x 60 kg = 45 µg HQ per day)
– For a possible presence of HQ as impurity (below 1 ppm) in the applied product (i.e.
1.6 g creme), one may add 1.6 µg HQ (external) and use 50% dermal absorption for
HQ, resulting in an extra 0.8 µg HQ per day
The internal HQ exposure amounts to 45.8 µg per day; divided by 60 kg body weight
SED = 0.763 µg/kg bw/d or 0.00076 mg/kg bw/d
NOAEL reported for HQ repeated toxicity (section 3.3.13) are 15 or 20 mg/kg bw/d
NOAEL / SED results in MOS of 19737 or 26315

37

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Opinion on β-arbutin________________________________________________________________________________________

2. For exogenous ochronosis
HQ is suspected to cause exogenous ochronosis. As a NOAEL has not been established forexogenous ochronosis (EO), the lowest effect level described in a case report was used to
calculate the Exposure Dose of HQ that might cause ochronosis: 1% has been adopted as
the minimum exposure level of HQ causing EO since no publication available suggests EO
with products formulated with 1% or less HQ.
Exposure Dose of HQ that may cause ochronosis was calculated as 8 mg/day[1 x 0.8 x 1000 x 2 x 50 / 100 x 100]
– Lowest concentration in product1%– Maximum quantity of application
0.8 g– Frequency of application per day2– Average absorption of HQ through skin50%
Based on dermal absorption from the in vitro percutaneous absorption study and the in vivo
conversion ratio from β-arbutin to HQ (11.8 % as individual maximum value) plus possible
extra exposure from HQ impurities in the formulation, the total HQ exposure when using
7% β-arbutin formulation was 0.046 mg/day (section 1. above)
The Exposure Dose of HQ that might cause ochronosis (8 mg/day) and the Exposure Doseof HQ formed on and in skin when using cosmetic product with 7% ß-arbutin (0.048
mg/day) is calculated as Ratio: 8 / 0.046 = 174
The minimum exposure level of HQ causing exogenous ochronosis is calculated as being 174
times higher than the maximum HQ exposure level formed from β-arbutin. Therefore it canbe concluded that ß-arbutin does not pose a risk with regard to induction of exogenous
ochronosis in humans (under the conditions of use specified in the terms of reference).
3. For carcinogenicity
According to IARC (1999) HQ is not classifiable as to its carcinogenicity for humans (group3). In more recent reviews on the carcinogenicity of HQ (McGregor 2007; CIR 2010) a
nongenotoxic mode of action that involves exacerbation of a spontaneously occurring rodent
renal disease, chronic progressive nephropathy (CPN), has been proposed. CPN isparticularly prominent in male rats and the evidence is consistent with an absence of ahuman counterpart.
In the EU, hydroquinone is classified as Carc Cat 2 H351 (suspected human carcinogen)Muta Cat 2 H341 (suspected of causing genetic defects) based on Regulation (EC) No
1272/2008 (CLP Regulation), Annex VI.
The SCCS has carried a calculation to determine lifetime cancer risk (as in section 3-7.4 of
the SCCS Notes of Guidance). First an animal dose descriptor (T25) for carcinogenic
potency is determined and then converted to a human dose descriptor (HT25) based oncomparative metabolic rates by using the following formula:

For the critical effect (renal tubular cell adenomas in male F344 rats; NTP study 1989), theT25 dose descriptor for hydroquinone is 61.4 mg/kg bw/day.
From this a HT25 value of 18.2 mg/kg bw/d was obtained.
Lifetime cancer risk =SED
HT25 / 0.25

38

SCCS/1550/15
Opinion on β-arbutin________________________________________________________________________________________For a systemic HQ exposure dose of 0.0005 mg/kg bw/d (section 1 A above), the risk is
calculated to be 6.8 x 10-6.
For a systemic HQ exposure dose of 0.00076 mg/kg bw/d (section 1 B above), the risk is
calculated to be 1 x 10-5.
However, it has to be taken into account that this tumour type may be considered rodent
specific and may have little relevance for humans and risk has been calculated by linear
extrapolation (in this case a highly conservative approach). Therefore, hydroquinone (HQ)
exposure resulting from use of cosmetic products which can release HQ is not of concern
with regard to carcinogenicity.
HQ exposure from dermal application as compared with oral intake:
The applicant argues that systemic exposure to HQ that is released from ß-arbutin
containing cosmetic products is low/negligible in relation to HQ amounts ingested with diet.
The SCCS considered the following values for such a comparison:
Dermal route (see above)
45.8 µg HQ per day / 60 kg bw = 0.76 µg/kg bw or ≤0.0008 mg/kg bw/day
Oral intake of HQ (from ß-Arbutin) with food (coffee, wheat products, fruits)(from Deisinger et al. Ref. 28 subm. I, value range 783.9 – 1278.7 µg):
average 1020 µg HQ day / 60 kg bw = 17 µg/kg bw or 0.017 mg/kg bw/day
Comparing these HQ exposures, HQ derived from ß-arbutin in cosmetic products is about
22-fold lower than the estimated dietary intake of HQ. Therefore, the use of ß-arbutin in
cosmetics would not substantially increase the plasma concentrations of HQ.

3.4

Discussion

Physico-chemical properties
In acidic medium, β-arbutin is easily hydrolysed into hydroquinone [42, 43]. This may be of
relevance if β-arbutin is incorporated in aqueous lotions with a slightly acidic pH, facilitatinghydrolysis into hydroquinone within the formulation. Data are now presented on the stabilityof the product, which appears to be photostable and temperature stable in the pH range ofthe formulation. The concentrations of hydroquinone in the formulations studied remain
below 1 ppm.
Yet, it is to be considered that ß-arbutin might be also undergo cutaneous hydrolysis intohydroquinone due to enzymatic activity (through ß-glucosidases: Mier & van den Hurk
1976; Redoules et al. 2005) or via the activity of microbes residing in or on the surface ofthe skin (Bang et al. 2008).
A study of the degradation by beta-glucosidase has not been performed.
Toxicity
A general remark is that the majority of the toxicological tests have been performed inJapan. In practical terms, this means that the presented corresponding test reports consistof translated summaries only. The company's toxicologist certifies that they truthfully
represent the original Japanese duly-signed in-house test reports.
Local toxicity
The skin irritation study in the rabbit was not completely performed according to current
standards. Nevertheless, since the skin was abraded and the 10% solution did not show any
irritating properties, β-arbutin can be considered as non-irritating to the rabbit skin at
dilutions up to 10%. That same solution moreover was shown to be non-irritating to therabbit eye.

39

SCCS/1550/15
Opinion on β-arbutin________________________________________________________________________________________In a single patch test on human volunteers with β-arbutin at 10% in water and at 7 and
10% in a cosmetic formulation, the substance revealed to be non-irritating. Repeated open
application tests with and without sunlight exposure showed that the 10% β-arbutincontaining cosmetic formulation was well-tolerated by the volunteers. No adverse reactions
related to the test substance were noted.
Skin sensitisation
Although the available Magnusson & Kligman test was not entirely performed according tocurrent guidelines, it used β-arbutin concentrations up to 10%. The tested concentrations
showed to be negative, whereas the positive control clearly elicited an allergic reaction.
Therefore, β-arbutin as such is not expected to be a skin sensitiser.
Since hydroquinone has been identified to be a skin sensitiser, its release from ß-arbutin
containing products could cause sensitisation. Yet, no problems were reported in the study
with human volunteers or in post-marketing surveillance with β-arbutin.
Dermal absorption
The study authors conclude for the in vitro dermal absorption test performed that the mean
total absorption was very low, ranging from 0.126 to 0.214% of the applied dose over a
24 h exposure period, and an upper value for dermal absorption of 0.339 µg/cm². It was
further noted that the number of skin samples was lower than that usually required and thatthe concentration of β-arbutin in the test formulation (6.3%) was slightly below therequested maximum concentration (7.0%).
Although the in vitro percutaneous penetration study has some (minor) limitations, it isconsidered as sufficiently valid. A low absorption of the applied ß-arbutin related
radioactivity was measured over 24h. Although specific analysis of parent compound and its
cleavage products was not performed, it can be considered likely that the great majority ofthe measured radioactivity relates to β-arbutin. This view is supported by results from an invivo study in humans with repeated topical application and analysis of skin biopsies for
β-arbutin and hydroquinone content (see below “Toxicokinetics”).
Systemic toxicity
The acute oral toxicity profile of β-arbutin can be considered low, viewing the LD50-oral-rat
value of 8715 mg/kg/day whereas the LD50-dermal-rat was >928 mg/kg (maximum
practically applicable dosage).
A repeated dose 28-day oral study and 90-day dermal study with the rat only revealed
some sporadic observations which could not be related to the test substance. Therefore inboth tests, the highest dosage tested could be designated as NOEL, i.e. 1000 mg/kg bw/day
for the repeated dose oral study and 618 mg/kg bw/day for the repeated dose dermal
study.
Toxicokinetics
Hydrolysis to hydroquinone (HQ) has been described as significantly taking place in the caseof oral intake of β-arbutin (stomach acids), but also to a lesser extent after dermal exposure[43, 38]. Subsequent enzymatic biotransformation (by phase II enzymes) of HQ may be
expected in both cases [40, 42].
A human skin metabolism study revealed that daily topical application for 4 consecutive
days of a gel containing 6.3% (w/w) β-arbutin led to detectable amounts of β-arbutin and
HQ in skin. Based on a large variation in the established urinary total HQ concentrations(yet determined by a rather insensitive analytical method with a high LOD), changes inurinary HQ levels due to topical treatment of β-arbutin could not be established.
When the HQ content in the skin samples was taken relative to the total (β-arbutin + HQ)
content, on average 4.6% of HQ was present in these skin samples going up as high as
11% in two samples. Actual levels of HQ in treated skin amounted on average to 0.018 ±0.016 µg/cm², with a top level of 0.060 µg/cm² in one sample. This exposure to HQ reflectsa realistic in use situation in man and the release of HQ cannot be ignored.

40

SCCS/1550/15
Opinion on β-arbutin________________________________________________________________________________________

Mutagenicity/genotoxicity
The Ames test did not reveal any increase in the number of revertant colonies with any of
the test strains at any concentration, irrespective of metabolic activation. Neither were
there any biologically relevant and statistically significant increases in cells with structuralaberrations and polyploids after treatment with β-arbutin at any concentration or incubation
time, irrespective of the presence of metabolic activation system in the presented in vitro
mammalian chromosome aberration test. Therefore β-arbutin is considered to be nonmutagenic.
Arbutins (alpha-, beta- and deoxy-arbutin), are considered to be metabolised differently bydifferent glycosidases or by spontaneous hydrolysis, yet they all form hydroquinone. The
latter is considered as the genotoxic moiety; therefore a read across approach based on HQ
release is a possibility to assess the genotoxic potential of the arbutins as a group.
Carcinogenicity
A dermal carcinogenicity study in mice revealed that dosages up to 400 mg/kg bw/day
failed to induce dose-related tumour formation due to the administration of β-arbutin. Yet,no rationale is given for the choice of another species than the one used in the 28 day or
90 day repeated dose study (mice instead of rats). In addition, the weight variation in the
animals at the beginning of the study exceeded 20% (50%) and the intermediatehaematological examination (after 12 months) was not performed. Finally, the non-tumour
and the tumour lesions observed in all animals (including the control group) reveal that,whether or not caused by aging alone, the general condition of the animals appeared to bepoor.
No conclusion with regard to carcinogenicity can be drawn from this study.
Reproductive toxicity
A one-generation reproduction study with β-arbutin revealed a NOEL for reproduction
toxicity of 100 mg/kg bw/day based upon the observation of body weight decrease infemale foetuses and decreased organ weights of the unilateral ovary of female F1 rats at
400 mg/kg bw/day.
Photo-induced adverse effects
The presented summaries of a phototoxicity and photosensitisation assay with β-arbutin in
the guinea pig conclude that the substance displays neither phototoxic nor photoallergic
potential.
The human repeated open application test with so-called "exposure to sunlight" lacks
standardisation of the intensity and duration of the sunlight exposure. The volunteers were
only exposed to sunlight through their normal daily activities with the product applied on
the back of their hands.
Issues related to hydroquinone (HQ) in skin lightening products
If HQ is released in relevant amounts either in the product or during the use of arbutins (βarbutin or similar ingredients), the product could not be considered safe, since HQ has beenassessed as being unsafe for use in skin lightening applications due to the danger ofexogenous ochronosis and leukomelanoderma [41] and consequently is currently banned
for this use in the EU. The HQ product concentrations at which ochronosis has been
described are of 1% and higher [44]. A 2% formulation of 14C–hydroquinone was shown tohave 45.3% +/- 11.2% availability with a 24-hour application in human volunteers (6). The
bioavailability was calculated as 43.3% of the dose with a flux of 2.85 μg/cm2/h.
As no data is available on HQ concentration levels below 1%, a lower threshold for theoccurrence of ochronosis is difficult to establish. Although the risk for ochronosis may berelatively low and largely confined to individuals with very dark skin, the occurring cases
can be severe and irreversible.
The use of arbutins (alpha-, beta- and deoxy-arbutin) in skin bleaching products is acomplex situation for which the application level and the local availability of hydroquinone
cannot be generalised. The factors causing HQ release at the skin surface will depend on theactivity of skin bacteria and enzymes (glycosidases) in any one individual and there is41

SCCS/1550/15
Opinion on β-arbutin________________________________________________________________________________________

insufficient information on their quantitative variation. Moreover, dermal penetration of theactive ingredient and its stability in formulations can differ. Therefore, a case-by-caseevaluation is needed.
Dermal absorption of β-arbutin is rather low (max. 0.214 % of the applied dose or 0.339µg/cm2), which is considerably lower than that of HQ itself. It is noted that the ratiohydroquinone/(β-arbutin + hydroquinone) in the skin averaged 4.6% and amounted up to
11.8% in the skin metabolism study in human volunteers which is clearly higher than theratio of the two substances (<1 ppm HQ) in the applied product. If formation ofhydroquinone from β-arbutin in the skin is taken with an upper value of 12%, then a 7%
level of arbutin in cosmetic products, applied twice per day to face and neck (an area of 565
cm2), could give rise to a systemically available dose of about 30 to 45 µg of hydroquinone
per person and day, including also the HQ present as impurity in the cosmetic product.
This internal exposure value for HQ was used in safety assessments related to ochronosis
and other endpoints.
In comparison, the internal exposure resulting from use of a product with 1% hydroquinone(taking a dermal penetration of about 50%) would amount to about 8 mg hydroquinone.
This dose (which may elicit ochronosis) is 174-times higher than that resulting from the useof products with ß-arbutin. Therefore it can be concluded that ß-arbutin does not pose a risk
with regard to induction of exogenous ochronosis in humans (under the conditions of use
specified in the terms of reference).
The general potential toxicity of HQ has been reported (7; ref. xy) as being highly sex-,
species- and strain- specific, with nephrotoxicity and carcinogenicity primarily limited tomale F-344 rats. Epidemiology and occupational studies of workers with extensive exposure
to HQ have not reported any evidence of adverse systemic health effects.
Since hydroquinone is classified in the EU as Carc Cat 2 H351 (suspected of causing cancer)
based on Regulation (EC) No 1272/2008 (CLP Regulation), Annex VI, the SCCS has carried acalculation to determine a lifetime cancer risk. Risk was calculated to be 10-5, based on asystemic exposure dose of 0.00076 mg/kg bw/day and a HT25 dose derived from the T25
dose descriptor for renal tubular cell adenomas in male F344 rats (NTP study 1989).
Taking into account that risk has been calculated by linear extrapolation (in this case ahighly conservative approach), and that the tumour type considered may have little
relevance for humans, hydroquinone (HQ) exposure resulting from ß-arbutin containing
cosmetic products (under the conditions of use specified in the terms of reference) is not ofconcern with regard to carcinogenicity.

References - cited above (#) in the “old” SCCP conclusions
1. Charlin R et al.
2. Zhu W and Gao J
3. Sugimoto K et al.
4. Bang SH et al.
5. Allanson JE et al.
6. Wester RC et al.
7. O’Donoghue JL
8. Quintus J et al.
9. Lim YJ et al.
10 Nawarak J et al.

Int J Dermatol 47 19-23 (2008)
J Invest Dermatol (Symp Proc) 13 20-24 (2008)
Biol Pharm Bull 27 510-4 (2004)
J Cosmet Dermatol 7(3) 189-93 (2008)
Am J Med Genet (1988)
J Tox Env Health pt A 54(4) 301-17 (1998)
J Cosmet Dermatol 5(3) 196-203 (2006)
Planta Medica 71 (2) 147-52 (2005)
Arch Pharmacol Res 32 (3) 367-73 (2009)
BBA 1794(2) 159-67 (2009)42

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4. CONCLUSION(1)Does the SCCS consider on the basis of the provided scientific data, the use of β-arbutin to
be safe for consumers in cosmetic products in a concentration up to 7% in face creams?
The SCCS considers the use of β-arbutin to be safe for consumers in cosmetic
products in a concentration up to 7% in face creams provided that the contaminationof hydroquinone in the cosmetic formulations remain below 1 ppm.

(2) Does the SCCS have any further scientific concerns with regard to the use of β-arbutin in
cosmetic products?
A potential combined use of β-arbutin and other hydroquinone releasing substances incosmetic products has not been evaluated in this Opinion.

5. MINORITY OPINION/
6. REFERENCES
Submission I
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.

Koya Shiratori, Hiroaki Eiro, Hiroko Matsumoto, Shin-ichi Hirama, Kumi Yoshihara,
Masashi Yanagi, and Yoshikuni Wakisaka. Acute Oral Toxicity Test of Arbutin in Miceand Rats. SHISEIDO in house data.
Koya Shiratori, Hiroaki Eiro, Hiroko Matsumoto, Shin-ichi Hirama, Kumi Yoshihara,
Masashi Yanagi, and Yoshikuni Wakisaka. Acute Percutaneous Toxicity Test of Arbutinin Mice and Rats. SHISEIDO in house data.
Junko Tanaka, Masato Kuramoto, Hiroshi Tanaka, and Toshiaki Kobayashi. Primary
Skin Irritation Test of Arbutin in Rabbits. SHISEIDO in house data.
Hiroko Tamura, Rie Ikeda, Hiroshi Tanaka and Toshiaki Kobayashi. Patch test of
Arbutin in humans. SHISEIDO in house data.
Shotaro Harada, Rie Inada, Yasuyuki Umino, Nozomiko Seki, Osamu Yagame andShinobu Kato. Patch test of AR-91 S WT ESSENCE in humans. SHISEIDO in housedata.
Junko Tanaka, Masato Kuramoto, Hiroshi Tanaka, and Toshiaki Kobayashi. Eye
Irritation Test of Arbutin in Rabbits. SHISEIDO in house data.
Hideyuki Ichikawa, Yoshio Katsumura, Shinobu Ishii, and Toshiaki Kobayashi. Skin
Sensitization Test of Arbutin in Guinea Pigs. SHISEIDO in house data.
J.J.M. van de Sandt. In vitro percutaneous absorption of [14C]arbutin using human skinmembranes  identical to TNO report 2003 as Ref.17 in KS 2012
W.J.A Meuling. Skin metabolism after repeated topical application of Arbutin in humanvolunteers  identical to TNO report 2003 as Ref.18 in KS 2012
Koya Shiratori, Hiroaki Eiro, Hiroko Matsumoto, Shin-ichi Hirama, Kumi Yoshihara,
Masashi Yanagi, and Yoshikuni Wakisaka. 28-day Repeated-dose Oral Toxicity Study of
SL-16 in Rats with a 28-Day Recovery Period. SHISEIDO in house data.
Koya Shiratori, Hiroaki Eiro, Hiroko Matsumoto, Shin-ichi Hirama, Kumi Yoshihara,
Masashi Yanagi, and Yoshikuni Wakisaka. 90-day Repeated-dose Percutaneous Toxicity
Study of Arbutin in Rats. SHISEIDO in house data.
Osamu Yagame, Shinobu Kato and Toshiaki Kobayashi. Reverse Mutation Test of
Arbutin in Bacteria. SHISEIDO in house data.
43

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13.

Chiyomi Sugiyama, Hiroshi Kobayashi and Toshiaki Kobayashi. Chromosome
Aberration Test of Arbutin using Mammalian Cells in Culture. SHISEIDO in house data.
14. Kenji Suzuki. Percutaneous Carcinogenicity Study of Arbutin in Mice.
15. Masafumi Itabashi, Hiroyuki Aihara, Tsutomu Inoue, Jyoji Yamate, Sadako Sannai,
Masanori Tajima, Chiaki Tanaka, and Yoshikuni Wakisaka.(1988), Reproduction studyof Arbutin in Rats by Subcutaneous administration, IYAKUHIN KENKYU. 19 (2), 282297.
16. Yoshio Katsumura, Mariko Uchiyama, and Toshiaki Kobayashi. Skin Photosensitization
Test of Arbutin in Guinea Pigs. SHISEIDO in house data.
17. Yoshio Katsumura, Mariko Uchiyama, and Toshiaki Kobayashi. Phototoxicity Test of
Arbutin in Guinea Pigs. SHISEIDO in house data.
18. Yasuyuki Umino, Osamu Yagame, Nozomiko Seki, Rie Inada, Shinobu Kato, Hiromi
Masuda and Kuninobu Okazaki. Twenty-four-week continuous application of AR-91 S
WT ESSENCE to the medial side of the upper arm of healthy individuals. SHISEIDO inhouse data.
19. Shotaro Harada, Osamu Yagame, Yasuyuki Umino, Nozomiko Seki, Rie Inada, Shinobu
Kato, Hiromi Masuda and Kuninobu Okazaki. Twenty-four-week continuous applicationof AR-91 S WT ESSENCE A10 to the backs of the hands of healthy individuals.
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20. Stability tests under accelerated aging conditions of a final cosmetic formulation
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24. Wester R.C., et al. (1998). Human in vivo and in vitro hydroquinone topicalbioavailability, metabolism and disposition. J Toxicol Env Health PartA, 54, 301-317.
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35.

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Mahé A., Ly F., Aymard G., Dangou J.M. Skin diseases associated with the cosmetic
use of bleaching products in women from Dakar, Senegal. J Dermatol. 2003
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Adebajo SB. An epidemiological survey of the use of cosmetic skin lightening
cosmetics among traders in Lagos, Nigeria. West Afr J Med. 2002 Jan-Mar;21(1):51-5.
Levin CY, Maibach H. Exogenous ochronosis. An update on clinical features, causative
agents and treatment options. Am J Clin Dermatol. 2001;2(4):213-7.
Bowman PH, Lesher JL Jr. Primary multiple miliary osteoma cutis and exogenous
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Jacyk WK. Annular granulomatous lesions in exogenous ochronosis are manifestationof sarcoidosis. Am J Dermatopathol. 1995 Feb;17(1):18-22.
Camarasa JG, Serra-Baldrich E. Exogenous ochronosis with allergic contact dermatitis
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Snider RL, Thiers BH. Exogenous ochronosis. J Am Acad Dermatol. 1993
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dans un produit cosmetique (GT ingredients du 14.11.2006 – Sortie des industriels sauf
la FIP autorisee a rester par la firme), Commission de Cosmétologie No. 30, 07
December 2006, unpublished data
2. Albrecht CF, Theron EJ, Kruger PB (1995) Morphological characterization of the46

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Opinion on β-arbutin________________________________________________________________________________________

cellgrowth inhibitory activity of rooperol and pharmacokinetic aspects of hypoxoside as
an oral prodrug for cancer therapy, S. Af. Med. J., 85, 853-860
3. Council of Europe (2008) Safety survey of active ingredients used in cosmetics: 3.
Arbutin, prepared by the Committee of Experts on Cosmetic Products, Health Protectionof the Consumer, Council of Europe, Strasburg, France, March 2008
4. Bang SH, Han SJ, Kim DH (2008) Hydrolysis of Arbutin to hydroquinone by human skinbacteria and its effect on antioxidant activity, J. Cosmetic Dermatology, 7, 189-193
5. BfR (Bundesinstitut für Risikobewertung, 2008) 73., 74. und 75 Sitzung der vorläufigen
Kommission für kosmetische Mittel, Tagungsbericht, Bundesinstitut für Risikobewertung,
Berlin, Germany, 20 November 2008 including translation of relevant Arbutin parts [73.,74 and 75 meeting of the provisonal commission for cosmetics, meeting protocol,
German Institute for risk assessment, Berlin, Germany, 20 November 2008]
6. BfR (Bundesinstitut für Risikobewertung, 2009a) 3. Sitzung der BfR-Kommission fürkosmetische Mittel, Protokoll, Bundesinstitut für Risikobewertung, Berlin, Germany, 05
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7. BfR (Bundesinstitut für Risikobewertung, 2009b) Translation with regards to topic 2: ßArbutin and exogenous ochronosis, 3. meeting of the BfR commission for cosmetics,
meeting protocol, German Institute for risk assessment, Berlin, Germany, 05 May 2009
8. Daiichi Pure Chemicals (2002) Certificate of analysis on [14C] Arbutin, Technical data,
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9. European Commission (2012) Letter – Scientific committee on consumer safety (SCCS) –Request for additional data on Arbutin and its derivatives, European Commission, Healthand Consumer Directorate General, Brussels, Belgium, 25 January 2012
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uvaursi, Integrated Laboratory Systems, Inc., Research Triangle Park, NC, Under
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DeViguerie N (2005) Slow internal release of bioactive compounds under the effect ofskin enzymes. J. Investigative Dermatol., 125, 270-277
13. SCCP (Scientific Committee on Consumer Products, 2008) Opinion on ß-Arbutin,
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15. Shiseido (2005) Safety assessment for ß-Arbutin as a cosmetic ingredient, Hitoshi Sasa,
Shiseido Co., Ltd., Fukuura, Japan, 30 June 2005
16. Shiseido (2009) Additional submission for SCCP opinion on ß-Arbutin as a cosmetic
ingredient, Hitoshi Sasa, Shiseido Co., Ltd., Fukuura, Japan, 30 April 2009
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human skin membranes, TNO Chemistry, Zeist, The Netherlands for Shiseido ResearchCenter, Safety Research Laboratories, Fukuura, Japan, 11 February 2003
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19. TNO (2012) Statement on fetal calf serum (FCS) used as 10% (w/w) constituent of thereceptor fluid, TNO report V4768, In vitro percutaneous absorption of [14C] Arbutinusing human skin membranes, TNO, Zeist, The Netherlands for Shiseido Europe,
Boulogne, France, 02 March 201247

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References added by SCCS
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Bang et al. (2008) see above: Schilling Ref #4“CIR 2010” on HQ: Andersen FA et al. …Final amended safety assessment ofhydroquinone as used in cosmetics. Intl J Toxicol. 29 (suppl 4): 274S-287S
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Exogenous ochronosis: case report and literature review. An Bras Dermatol. 2012
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Matsuo Y, Ito A, Masui Y, Ito M (2015) A case of allergic contact dermatitis causedby arbutin. Contact Dermatitis (doi:10.111/cod.12375)
Nawarak J et al. BBA 1794(2) 159-67 (2009)
Redoules et al (2005) see above: Schilling Ref #12
Schindler G, Patzak U, Brinkhaus B, von Nieciecki A, Wittig J, Krähmer N, Glöckl I,
Veit M (2002) Urinary excretion and metabolism of arbutin after oral
administration of Arctostaphylos uva ursi extract as film-coated tablets andaqueous solution in healthy humans. J Clin Pharmacol 42:920-927.
Siegers CP, Siegers JP, Pentz R, Bodinet C, Freudenstein J (1997): Metabolism ofarbutin from Uvae ursi extracts in humans. Pharm. Pharmacol. Lett. 7 (2-3): 9092
Uter W, Gefeller O, John SM, Schnuch A, Geier J (2014) Contact allergies toingredients of hair cosmetica – comparison of female hairdressers and clients
based in IVDK 2007-2012 data. Contact Dermatitis 71:13-20
Yang CH, Chang NF, Chen YS, Lee SM, Lin PJ, Lin CC (2013) Comparative study
on the photostability of arbutin and deoxy arbutin: sensitivity to ultraviolet
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Zhu W and Gao J (2008) see above: Subm II Ref #33

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