National Industrial Chemicals Notification and
Assessment Scheme
Glycolic Acid
_______________________________________________________
Priority Existing Chemical
Assessment Report No. 12
April 2000
Commonwealth of Australia 2000
ISBN 0 642 43258 9
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Preface
This assessment was carried out under the National Industrial Chemicals Notification and
Assessment Scheme (NICNAS). This Scheme was established by the Industrial Chemicals
(Notification and Assessment) Act 1989 (the Act), which came into operation on 17 July
1990.
The principal aim of NICNAS is to aid in the protection of people at work, the public and
the environment from the harmful effects of industrial chemicals.
NICNAS assessments are carried out in conjunction with Environment Australia and the
Therapeutic Goods Administration, which carry out the environmental and public health
assessments, respectively.
NICNAS has two major programs: the assessment of the health and environmental effects
of new industrial chemicals prior to importation or manufacture; and the other focussing on
the assessment of chemicals already in use in Australia in response to specific concerns
about their health/or environmental effects.
There is an established mechanism within NICNAS for prioritising and assessing the many
thousands of existing chemicals in use in Australia. Chemicals selected for assessment are
referred to as Priority Existing Chemicals.
This preliminary assessment report has been prepared by the Director (Chemicals
Notification and Assessment) in accordance with Section 60A of the Act. Under the Act
manufacturers and importers of Priority Existing Chemicals are required to apply for
assessment. Applicants for assessment are given a draft copy of the report and 28 days to
advise the Director of any errors. Following the correction of any errors, the Director
provides applicants and other interested parties with a copy of the draft assessment report
for consideration. This is a period of public comment lasting for 28 days during which
requests for variation of the report may be made. Where variations are requested the
Director's decision concerning each request is made available to each respondent and to
other interested parties (for a further period of 28 days). Notices in relation to public
comment and decisions made appear in the Commonwealth Chemical Gazette.
In accordance with the Act, publication of this report revokes the declaration of this
chemical as a Priority Existing Chemical, therefore manufacturers and importers wishing to
i n t r o d u c e this chemical in the future need not apply for assessment. However,
manufacturers and importers need to be aware of their duty to provide any new information
to NICNAS, as required under section 64 of the Act.
For the purposes of Section 78(1) of the Act, copies of assessment reports for New and
Existing Chemical assessments may be inspected by the public at the Library, NOHSC, 92-
94 Parramatta Road, Camperdown, Sydney, NSW 2050 (between 10 am and 12 noon and 2
pm and 4 pm each weekday). Summary reports are published in the Commonwealth
Chemical Gazette, which are also available to the public at the above address.
Copies of this and other assessment reports are available from NICNAS either by using the
prescribed application form at the back of this report, or directly from the following
address:
iii
Glycolic acid
GPO Box 58
Sydney
NSW 2001
AUSTRALIA
Tel: +61 (02) 9577 9437
Fax: +61 (02) 9577 9465 or +61 (02) 9577 9465 9244
Other information about NICNAS (also available on request) includes:
? NICNAS Service Charter;
? information sheets on NICNAS Company Registration;
? information sheets on Priority Existing Chemical and New Chemical assessment
programs;
? subscription details for the NICNAS Handbook for Notifiers; and
? subscription details for the Commonwealth Chemical Gazette.
Information on NICNAS, together with other information on the management of workplace
chemicals can be found on the NOHSC Web site:
http://www.nohsc.gov.au/nicnas
iv Priority Existing Chemical Number 12
Overview
Glycolic acid (CAS No. 79-14-1) was declared a Priority Existing Chemical for preliminary
assessment on 7 April 1998. The reason for the declaration was concern about the health
effects of the chemical following consumer complaints that some cosmetic products
containing glycolic acid caused irritation of the skin. The declaration applied to cosmetic
uses of the chemical.
Glycolic acid is prepared by chemical synthesis or extraction from plants and has both
industrial and domestic applications that utilise its acidity and ability to dissolve
encrustations.
In Australia, annual imports for cosmetic purposes amount to 5.7 metric tonnes per year, of
which about 2/3 is imported in finished cosmetic products and the remainder as raw
materials used by local formulators. Cosmetic grade raw materials include crystalline
glycolic acid, 70% aqueous solutions and plant extracts containing 2.5-17% glycolic acid.
An industry survey identified 180 cosmetic products on the Australian market that contain
glycolic acid, of which 25 are used in beauty salons and 155 are sold to consumers for use
at home. Apart from 11 consumer hair care products, all products are intended for
application to the skin. Salon products contain from 4-60% glycolic acid at pH 1.5-4.5.
Consumer products contain 0.01-20% glycolic acid at pH 3.0-6.6.
Glycolic acid is absorbed by ingestion, inhalation and through the skin. In humans, it is
mainly excreted unchanged in the urine while smaller amounts are metabolised to glyoxylic
and oxalic acids, which are also excreted in the urine. The kinetics and metabolism are
qualitatively similar in rats and humans; however, rats metabolise a greater proportion to
carbon dioxide and eliminate the chemical faster than humans.
In laboratory animals, glycolic acid is harmful by single-dose ingestion or inhalation of
high doses. Depending on concentration and pH, it may be corrosive or irritating to the
skin, eyes and respiratory system. It is toxic to the kidneys by repeated oral administration.
When glycolic acid is given to pregnant rats by mouth on a daily basis, it induces
malformations at high, maternally toxic doses. In two studies, there was an 8-9% reduction
in foetal body weight and a substantial increase in minor skeletal abnormalities at dose
levels associated with mild maternal toxicity. In another study, a marginal increase in foetal
abnormalities was seen at a dose associated with marginal maternal toxicity, with no effects
on foetal development seen at lower doses. Glycolic acid is not mutagenic. It does not
impair fertility or neonatal growth during lactation. There are no animal studies of systemic
or developmental toxicity from dermal exposure and no carcinogenicity studies.
Glycolic acid is a metabolite of ethylene glycol and is the immediate cause of the metabolic
acidosis and kidney failure associated with ethylene glycol poisoning in humans. Cosmetic
formulations with glycolic acid have been extensively tested in human tolerability studies.
There is no evidence of contact sensitisation; however, glycolic acid causes stinging and
skin irritation in a dose- and/or pH-dependent manner. In use studies of products with 0.5-
50% glycolic acid at pH 1.2-5.5, 13% of subjects had signs of skin irritation and 10%
complained of stinging. In one study glycolic acid increased the sensitivity of human skin to
sunburn by up to 50% in some individuals.
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Glycolic acid
Occupational exposure to glycolic acid in the cosmetic industry is predominantly through
skin contact as the chemical is practically non-volatile and the formation of aerosols (mists)
is likely to be insignificant during formulation and beauty salon use of cosmetic products.
Occupational control measures such as isolation, engineering controls and/or the use of
personal protective equipment are in place in most formulation plants. Control measures in
beauty salons include the substitution of solutions with gels or creams to minimise
dispersion and the use of gloves to reduce hand exposure. Current MSDS and labels are
satisfactory for synthetic raw materials. In the case of plant extracts and salon-only
products, MSDS and labels generally do not comply with the NOHSC National Model
Regulations for the Control of Workplace Hazardous Substances.
The public is exposed to skin contact with a variety of cosmetic products that contain the
c h e m i c a l . Under the Trade Practices (Consumer Product Information Standards)
(Cosmetics) Regulations, consumer cosmetics must be labelled with their ingredients. Ten
of 66 labels assessed (15%) did not comply with the ingredient labelling requirements and
18 (27%) did not explicitly disclose the presence of glycolic acid in the formulation.
The no observed adverse effect level (NOAEL) based on a 3-month oral rat toxicity test and
on maternal and developmental toxicity in pregnant rats is 150 mg/kg/day.
External exposures obtained from reasonable worst-case workplace scenarios are estimated
at 1.7 mg/kg/day in beauty salon workers and 6.3 mg/kg/day in formulation workers. As
such, the known uses of glycolic acid in the cosmetic formulation and beauty salon
industries are considered unlikely to present a significant risk to occupational health in
Australia if exposure is appropriately controlled.
External exposures obtained from reasonable worst-case consumer scenarios are estimated
at 10 mg/kg/treatment for skin peels of large areas of the body and at 28 mg/kg/day from at-
home use of glycolic acid cosmetics. Based on the same scenarios, the estimated internal
exposure level is 4.7 mg/kg/day on the day of a salon treatment and 3.4 mg/kg/day for use
at home. Compared with the NOAEL determined in rats, this represents a margin of
exposure below the recommended level for chemicals which are widely used by the general
population. However, considerations relating to the route and frequency of exposure, the
blood levels known to be associated with systemic toxicity in humans and the pH of
commercial formulations relative to the test materials used in animal studies justify the
conclusion that the use of glycolic acid in salon and consumer cosmetics is unlikely to pose
a significant risk to the general public, although skin and eye irritation may occur at high
concentrations and low pH values.
Based on the assessment findings and the NOHSC Approved Criteria for Classifying
Workplace Hazardous Substances, it is recommended that glycolic acid for use at work be
classified as `Harmful by inhalation and if swallowed' (Risk phrase R20/22), `Causes
burns' (R34), `Risk of serious damage to eyes' (R41), `Irritating to eye and skin' (R36/38),
and `Irritating to respiratory system' (R37).
It is recommended that glycolic acid be included in the NOHSC List of Designated
Hazardous Substances with the above classification. The reference cut-off levels for
mixtures are given in section 15.1 of the main report.
Suppliers of the chemical for workplace use should update their MSDS and labels in
a c c o r d a n c e with the recommended hazard classification. As with other hazardous
workplace chemicals, employers should conduct a risk assessment of their individual
workplace and, where necessary, implement appropriate control measures.
vi Priority Existing Chemical Number 12
Glycolic acid in cosmetic products used by the general public may cause skin and eye
irritation when present at high concentrations and low pH values. As such, it is
recommended that glycolic acid be considered for listing in the Standard for the Uniform
Scheduling of Drugs and Poisons. In addition, manufacturers, importers and suppliers of
consumer products should inform consumers that the use of skin exfoliant cosmetic
products may result in an enhanced sensitivity to sunburn, and that use of sunscreen
protection is advised.
On the basis of the assessed hazard, exposure information and current controls, NICNAS
does not recommend a full (risk) assessment of glycolic acid in cosmetic products at this
time.
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Glycolic acid
Contents
PREFACE iii
OVERVIEW v
ABBREVIATIONS AND ACRONYMS xiv
1. INTRODUCTION 1
1.1 Declaration 1
1.2 Scope of the assessment 1
1.3 Objectives 1
1.4 Sources of information 2
1.5 Peer review 2
2. BACKGROUND 3
2.1 International perspective 3
2.2 Australian perspective 4
2.3 Assessment by other national or international bodies 4
3. APPLICANTS 5
4. CHEMICAL IDENTITY AND COMPOSITION 7
4.1 Chemical name (IUPAC) 7
4.2 Registry numbers 7
4.3 Other names 7
4.4 Trade names of cosmetic raw materials 7
4.4.1 Pure substance 7
4.4.2 AHA blends 7
4.5 Molecular formula 8
4.6 Structural formula 8
4.7 Molecular weight 8
4.8 Concentration units 8
4.9 Composition 8
5. PHYSICAL AND CHEMICAL PROPERTIES 10
5.1 Physical state 10
5.2 Physical properties 10
5.3 Chemical properties 10
5.4 Concentration of undissociated acid in cosmetic formulations 11
6. METHODS OF DETECTION AND ANALYSIS 13
6.1 Identification 13
6.2 Quantitative analysis 13
6.2.1 General methods 13
6.2.2 Raw materials 13
viii Priority Existing Chemical Number 12
6.2.3 Cosmetic products 13
6.2.4 Biological monitoring 14
7. MANUFACTURE, IMPORTATION AND USE 15
7.1 Manufacture of glycolic acid 15
7.2 Overview of the Australian cosmetic industry 15
7.3 Importation for cosmetic use 17
7.4 Types of cosmetic products containing glycolic acid 17
7.5 Non-cosmetic uses 18
7.6 Glycolic acid in foods 18
8. ESTIMATED OCCUPATIONAL AND PUBLIC EXPOSURE TO GLYCOLIC 19
ACID RESULTING FROM COSMETIC USES
8.1 Methods of use 19
8.1.1 Formulation of cosmetic products 19
8.1.2 Application of cosmetic products 20
8.2 Occupational exposure 20
8.2.1 Methodology 20
8.2.2 Exposure during storage and transportation 21
8.2.3 Exposure during formulation 21
8.2.4 Occupational exposure from salon use 23
8.3 Public exposure 23
8.3.1 Methodology 23
8.3.2 Exposure from personal use 24
8.3.3 Public exposure from salon use 24
8.4 Conclusions 24
9. KINETICS AND METABOLISM 26
9.1 Absorption 26
9.1.1 Through the skin 26
9.1.2 By inhalation 28
9.1.3 By ingestion 29
9.2 Distribution 29
9.3 Metabolism 30
9.4 Elimination and excretion 32
9.5 Comparative kinetics and metabolism 32
10. EFFECTS ON LABORATORY MAMMALS AND OTHER TEST SYSTEMS 34
10.1 Acute toxicity 34
10.1.1 Lethality 34
10.1.2 Oral toxicity 34
10.1.3 Inhalation toxicity 35
10.1.4 Intravenous toxicity 36
10.2 Corrosivity and irritation 36
10.2.1 Skin 37
10.2.2 Eyes 37
10.3 Sensitisation 38
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Glycolic acid
10.4 Repeated dose toxicity 38
10.4.1 Oral toxicity 38
10.4.2 Inhalation toxicity 40
10.5 Developmental and reproductive toxicity 41
10.5.1 Developmental toxicity studies 41
10.5.2 Reproductive toxicity studies 45
10.6 Genetic toxicity 46
10.6.1 In vitro 46
10.6.2 In vivo 46
10.7 Carcinogenicity 47
10.8 Other test systems 47
10.9 Special skin investigations 47
10.9.1 Effects on the epidermis 47
10.9.2 Effects on the skin barrier 48
10.9.3 Effects on the dermis 48
10.10 Summary of toxicological data 49
11. HUMAN HEALTH FFECTS 51
11.1 Systemic effects 51
11.1.1 From oral administration 51
11.1.2 From ethylene glycol intoxication 51
11.2 Skin effects 52
11.2.1 Stinging tests 52
11.2.2 Contact irritation tests 53
11.2.3 Contact sensitisation tests 55
11.2.4 Tests for phototoxicity 55
11.2.5 Tests for photosensitisation 56
11.2.6 Comedogenicity tests 56
11.2.7 Use studies 56
11.2.8 Case reports and customer complaints 57
11.2.9 Conclusions 57
11.3 Special skin investigations 58
11.3.1 Intact skin 58
11.3.2 The stratum corneum 58
11.3.3 The viable epidermis 61
11.3.4 Skin barrier function 62
11.3.5 The dermis 63
11.3.6 Sensitivity to UV light 65
11.3.7 Discussion 67
12. HAZARD ASSESSMENT AND CLASSIFICATION 70
12.1 Toxicokinetics and metabolism 70
12.2 Health hazards 71
12.2.1 Acute lethal effects 71
12.2.2 Corrosion/irritation 71
12.2.3 Sensitisation and photosensitisation 73
x Priority Existing Chemical Number 12
12.2.4 Effects after repeated or prolonged exposure 73
12.2.5 Reproductive effects 74
12.2.6 Genetic toxicity 77
12.2.7 Carcinogenicity 77
12.2.8 Summary of hazard classification 78
13. CURRENT CONTROLS 79
13.1 Workplace control measures 79
13.1.1 Elimination 79
13.1.2 Substitution 79
13.1.3 Isolation 80
13.1.4 Engineering controls 80
13.1.5 Safe work practices 81
13.1.6 Personal protective equipment 81
13.2 Emergency procedures 82
13.3 Hazard communication 82
13.3.1 Assessment of MSDS 82
13.3.2 Assessment of labels 83
13.3.3 Education and training of workers 83
13.3.4 Consumer information materials 84
13.4 Occupational and public health regulatory controls 84
13.4.1 Exposure standards and health surveillance 84
13.4.2 Australian Code for the Transport of Dangerous Goods by Road 84
and Rail (ADG Code)
13.4.3 Standard for the Uniform Scheduling of Drugs and Poisons 84
(SUSDP)
13.5 Voluntary standards and guidelines 85
13.5.1 Australian Standards 85
13.5.2 Industry guidelines 86
14. DISCUSSION AND CONCLUSIONS 88
14.1 Health effects 88
14.2 Current use in Australia 89
14.3 Occupational exposure 90
14.4 Public exposure 90
14.5 Current regulations and controls 92
14.5.1 Occupational measures 92
14.5.2 Labelling of products for consumer use 93
14.6 Data gaps 93
14.7 Conclusions 93
15. RECOMMENDATIONS 95
15.1 NOHSC occupational hazard classification 95
15.2 Further studies 96
15.3 Hazard communication 96
15.3.1 MSDS 96
15.3.2 Workplace labels 96
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Glycolic acid
15.3.3 Education and training of workers 98
15.4 Occupational control measures 99
15.5 Public health recommendations 99
15.6 Uses outside the scope of the assessment 99
16. SECONDARY NOTIFICATION 100
APPENDIX 1 Cosmetic products containing glycolic acid 101
APPENDIX 2 Exposure calculations 105
APPENDIX 3 Studies excluded from assessment 111
REFERENCES 114
LIST OF TABLES
Table 4.1 Composition of technical and cosmetic grade glycolic acid 9
Table 4.2 Composition of some AHA blends for cosmetic use 9
Table 5.1 Physical properties 10
Table 7.1 Types of glycolic acid containing cosmetic products marketed in 17
Australia in 1998/99
Measured and predicted airborne concentrations of glycolic acid (mg/m3) 22
Table 8.1
in raw material and formulation manufacture facilities and a beauty salon
in USA and Australia
Table 8.2 Typical use levels of selected cosmetics 23
24
Table 8.3 Potential external exposure of workers with and without gloves and/or
long-sleeved protective clothing and of consumers to glycolic acid
resulting from cosmetic uses
Summary of in vivo and in vitro studies of skin absorption of 14C-labelled
Table 9.1 27
glycolic acid in animals and humans
Elimination of 14C-labelled glycolic acid in animals and humans
Table 9.2 32
Table 9.3 Summary of kinetics and metabolism in rats, non-human primates and 33
humans
Table 10.1 Summary of acute lethality studies 35
Table 10.2 Summary of in vivo corrosivity and irritation studies 36
Table 10.3 Mean body weight, body weight gain, food consumption and food 38
efficiency in rats given glycolic acid by mouth for 3 months
Table 10.4 44
Summary of structural abnormalities in rat embryos exposed to
glycolic acid or sodium glycolate in vitro
Table 10.5 Summary of toxicological data 50
Table 11.1 57
Incidence of adverse skin events in 869 subjects using glycolic acid
containing cosmetics for 7 days to 6 months
59
Table 11.2 Stratum corneum thickness, viable epidermis thickness, collagen
deposition and glycosaminoglycan content in 20 subjects with
moderately severe dryness of the skin after 3 weeks twice-daily treatment
with glycolic acid or vehicle control
Table 11.3 The effect of glycolic acid on stratum corneum hydration as measured by 61
electrical capacitance testing
Table 11.4 The effect of glycolic acid on skin barrier function as measured by trans- 63
epidermal water loss
Table 11.5 The effect of glycolic acid on skin response to UV irradiation 65
xii Priority Existing Chemical Number 12
67
Table 11.6 Geometric mean number of sunburn cells per high power field in
histological sections of human epidermis exposed to 1 MED of UV light
following treatment with a 10% glycolic acid gel
Table 12.1 Foetal and maternal findings in 3 developmental toxicity studies in the rat 76
Table 12.2 Summary of hazards and lowest or no observed adverse effect levels of 78
glycolic acid, with assigned risk phrases as per the Approved Criteria
Table 13.1 Control measures in 5 small and 6 large Australian formulation 81
manufacturing facilities for glycolic acid containing cosmetics
Table 13.2 Type of voluntary consumer information supplied with 39 cosmetic 85
products containing glycolic acid
Table A.1.1 Input to EASE model used to estimate glycolic acid air levels in various 105
occupational settings
LIST OF FIGURES
Figure 5.1 pH of aqueous solutions of glycolic acid 12
Figure 5.2 Undissociated glycolic acid in % of total concentration in aqueous 12
solutions at pH 2-6
Figure 5.3 Undissociated glycolic acid in the aqueous phase of octanol-in-water 12
emulsions at pH 2 and pH 4 in % of total concentration in the product
Figure 7.1 Schematic representation of the flow of glycolic acid for cosmetic use 16
from manufacturers through to end users
Figure 9.1 28
Time-averaged skin absorption and penetration as a function of the
concentration of undissociated glycolic acid in aqueous solutions
Figure 9.2 Metabolic pathways of glycolic acid 32
Figure 11.1 Stinging potential of a glycolic acid lotion at various concentrations and 53
pH values
Figure 11.2 Irritation potential of a 10 % glycolic acid lotion at various formulation 54
pH values
60
Figure 11.3 Average reduction of stratum corneum turnover time in groups of at least
8 subjects treated with a glycolic acid lotion at various concentrations and
pH values
xiii
Glycolic acid
Abbreviations and Acronyms
ADG Australian Dangerous Goods
AHA alpha-hydroxy acid
ALD approximate lethal dose
ALT alanine aminotransferase
AS Australian Standard
AS/NZS Australian/New Zealand Standard
ASCC Australian Society of Cosmetic Chemists
AST aspartate aminotransferase
CAS Chemical Abstracts Service
CIR Cosmetic Ingredient Review
cm centimeter
cm2 square centimeter
CTFA Cosmetic, Toiletry, and Fragrance Association
DNA deoxyribonucleic acid
EASE Estimation and Assessment of Substances Exposure
EINECS European Inventory of Existing Chemical Substances
FDA Food and Drug Administration
FXIIIa(+) Factor XIIIa positive
g gram
GLP Good Laboratory Practices
GMP Good Manufacturing Practices
h hour
HPLC high-pressure liquid chromatography
IUPAC International Union for Pure and Applied Chemistry
kg kilogram
Michaelis-Menten constant
Km
L litre
LOAEL lowest observed adverse effect level
M molar (moles/L)
m3 cubic meter
MED minimal erythemal dose
mg milligram
min minute
mL millilitre
mm millimeter
mM millimolar
mRNA messenger RNA
MSDS material safety data sheet
NDPSC National Drugs and Poisons Schedule Committee
NICNAS National Industrial Chemicals Notification and Assessment Scheme
nm nanometer
NOAEL no observed adverse effect level
NOHSC National Occupational Health and Safety Commission
OECD Organisation for Economic Co-Operation and Development
Pa Pascal (0.0075 mm Hg)
PPE personal protective equipment
ppm parts per million
RNA ribonucleic acid
RTECS Registry of Toxic Effects of Chemical Substances
xiv Priority Existing Chemical Number 12
s second
SPF sun protection factor
SUSDP Standard for the Uniform Scheduling of Drugs and Poisons
t metric tonne
TAFE Technical and Further Education
TEWL trans-epidermal water loss
TGA Therapeutic Goods Administration
TNF- tumour necrosis factor alpha
TWA time-weighted average
UN United Nations
UV ultraviolet
maximum velocity
Vmax
y year
? cubic angstrom
礸 microgram
祄 micrometer
礛 micromolar
祄ole micromole
xv
Glycolic acid
xvi Priority Existing Chemical Number 12
1. Introduction
1.1 Declaration
The chemical glycolic acid (CAS No. 79-14-1) was declared a Priority Existing
C h e m i c a l for preliminary assessment under the Industrial Chemicals
(Notification and Assessment) Act 1989 on 7 April 1998. The declaration applied
to the cosmetic uses of glycolic acid. The reason for the declaration was concern
about the health effects of the chemical following consumer complaints that some
cosmetic products containing glycolic acid caused irritation of the skin.
1.2 Scope of the assessment
The Industrial Chemicals (Notification and Assessment) Act 1989 prescribes
which matters may be taken into account and addressed in a preliminary
assessment. Risk assessment and risk management are not covered in preliminary
assessments. However, as an outcome of a preliminary assessment, the Act
requires the National Industrial Chemicals Notification and Assessment Scheme
(NICNAS) to determine the significance of the assessment findings for risk. This
consideration may be facilitated by undertaking a reasonable worst-case risk
estimate for adverse effects resulting from the importation, manufacture, use,
storage, handling or disposal of the chemical. If the findings indicate that there
may be a significant risk of adverse health or environmental effects, then a full
(risk) assessment may be recommended.
The declaration of glycolic acid as a Priority Existing Chemical for preliminary
assessment applied to the cosmetic uses of the chemical. As such, the scope of the
assessment was limited to potential adverse health effects of glycolic acid
resulting from the manufacture, handling and use of `cosmetic products' as
defined in the Trade Practices (Consumer Product Information Standards)
(Cosmetics) Regulations (Statutory Rules 1991 No. 327, as amended). The use of
glycolic acid for therapeutic purposes by, or as directed by, members of the
medical profession was excluded from the assessment, as were the potential
effects of glycolic acid on the environment.
1.3 Objectives
The objectives of this assessment were to:
? critically review the available scientific data with regard to the properties of
glycolic acid, particularly data of relevance to toxicity;
? characterise the intrinsic capacity of glycolic acid to cause adverse health
effects;
? determine the likely uses of glycolic acid in cosmetics in Australia;
? determine the extent of occupational and public exposure to glycolic acid
resulting from its use in the cosmetics industry; and
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Glycolic acid
? determine whether or not the significance for risk is such that a full (risk)
assessment should be undertaken.
1.4 Sources of information
Relevant scientific data were submitted by applicants and notifiers, obtained from
a comprehensive literature survey, or retrieved from other sources. In particular, a
large number of unpublished reports were obtained from the Cosmetic Ingredient
Review (CIR), which is a self-regulatory program sponsored by the US industry
association, the Cosmetic, Toiletry, and Fragrance Association (CTFA). In these
reports, references to the identity, composition and pH of experimental or
commercial products were often blacked out for reasons of confidentiality.
However, information about the type of formulation, glycolic acid content and pH
was usually included in the CIR's published review of the studies (CIR, 1998).
Information on product specifications, labelling and use patterns and on
occupational exposure and control measures was made available by applicants
and notifiers. Information on the training and work practices of beauty therapists
was obtained through telephone interviews and correspondence with a small
sample of beauty therapy teachers and practitioners.
1.5 Peer review
During all stages of preparation, the report has been subject to internal peer
review by NICNAS and the Therapeutic Goods Administration (TGA). Sections
of the report relating to cosmetic technologies were also peer reviewed by
Richard J.E. Williams, Technical Manager, Vetsearch International & Medical
Research Pty Ltd. Sections of the report relating to the developmental toxicity of
glycolic acid were also peer reviewed by Dr William S. Webster of the
Department of Anatomy and Histology at the University of Sydney. Dr David
Cutler of the University of Sydney's Department of Pharmacology calculated
estimated blood levels of glycolic acid in animals and humans exposed to the
chemical.
2 Priority Existing Chemical Number 12
2. Background
2.1 International perspective
The use of glycolic acid in cosmetic products is believed to have derived from so-
called `chemical peels' that dermatologists and plastic surgeons have been using
for years to remove undesirable signs of skin ageing, such as discolouration,
roughness and wrinkling (Kurtzweil, 1998). The peels, typically trichloroacetic
acid, phenol, resorcinol, and salicylic acid, cause the skin to lose its outermost
layer, revealing a fresher-looking layer of skin. Also known as `chemical
exfoliation', the procedure is performed in doctors' surgeries under close
supervision to avoid deep skin burns from the highly acidic solutions.
In the late 1980s, cosmetic manufacturers in USA began to market similar but
milder versions of chemical peels containing alpha-hydroxy acids (AHAs) for
salon use by cosmetologists and beauticians. These products quickly caught on
and led to the introduction of AHA-containing cosmetics for the consumer
market, such as face creams and body lotions. A dermatologist, Dr Van Scott, and
a pharmacologist, Dr Yu, were instrumental in promoting this development. They
published the first clinical paper on the use of AHAs to control keratinisation
(Van Scott & Yu, 1974), took out a number of US and European patents relating
to the use and formulation of AHA preparations and founded a pharmaceutical
and cosmetics company to commercialise their invention.
AHAs comprise several chemicals, all of which are natural carboxylic acids with
a hydroxy group at the two, or alpha, position. They are mostly manufactured by
chemical synthesis or fermentation, but because of their abundance in sources
such as citrus fruits, apricots, apples, grapes and sugar cane, they are sometimes
referred to as `fruit acids' rather than AHAs. With only two carbon atoms,
glycolic acid is the smallest molecule within the homologous series of AHAs. It
is commercially available at low cost and is used in a wide range of cosmetic
products.
In 1992, the US Food and Drug Administration (FDA) cautioned consumers
about possible hazards associated with the use of AHA-based skin peeling
products. The warning was issued after FDA received reports of several injuries
caused by skin peeling procedures done by non-medical professionals. At the
same time, FDA announced its intention to commission a review of all products
marketed with a skin peeling claim. The review concluded that additional
scientific investigation was needed to establish the safety of cosmetic products
containing AHAs and in particular to address concerns that AHAs might sensitise
the skin to ultraviolet (UV) rays (KRA, 1996). Consequently, the National
Toxicology Program of the US National Institute of Environmental Science
accepted FDA's proposal to conduct a long-term study in hairless mice to
investigate the effect of AHAs on the risk of cancer associated with sunlight and
UV radiation. This study is scheduled to commence in 1999 and will take 3 years
to complete.
3
Glycolic acid
Meanwhile, the Cosmetic Ingredient Review (CIR) Panel of the CTFA conducted
a separate review of the safety of AHAs. The final report was released in 1997
and published in 1998 (CIR, 1998). CIR concluded that glycolic acid and lactic
acid and their common salts and esters are safe for use in cosmetic products at
concentrations 10%, at final formulation pH values 3.5, when formulated to
avoid increasing sun sensitivity or when directions for use include the daily use of
sun protection. For salon use products, CIR considered the same ingredients safe
at concentrations 30%, at final formulation pH values 3.0, in products designed
for brief, discontinuous use followed by thorough rinsing from the skin, when
applied by trained professionals, and when application is accompanied by
directions for the daily use of sun protection.
2.2 Australian perspective
The first lines of salon and consumer cosmetics containing glycolic acid were
launched in Australia in the early 1990s.
In Australia, specific legislation concerning cosmetic products is limited to the
T r a d e Practices (Consumer Product Information Standards) (Cosmetics)
Regulations which came into effect on 31 October 1993. The information
standard deals with requirements concerning ingredient labelling information. It
defines `cosmetic product' as a substance or preparation intended for placement
in contact with any external part of the body, with a view to:
? altering the odours of the body;
? changing its appearance;
? cleansing it;
? maintaining it in good condition;
? perfuming it; or
? protecting it.
Chemicals contained in cosmetic products are considered industrial chemicals
and are subject to the Industrial Chemicals (Notification and Assessment) Act.
The Trade Practices (Consumer Product Information Standards) (Cosmetics)
Regulations as well as the Industrial Chemicals (Notification and Assessment)
Act specifically exempt products which are therapeutic goods in the meaning of
the Therapeutic Goods Act 1989, that is, products intended to treat or prevent
disease or modify a physiological process in humans. Therapeutic goods are
subject to pre-market review and approval by TGA and are required to be
included in the Australian Register of Therapeutic Goods; cosmetics are not. In
some cases, the classification of a product as cosmetic or therapeutic depends on
subtle differences in the wording of the actions and benefits the product is
claimed to provide (NCCTG, 1997).
2.3 Assessment by other national or international bodies
Except for the FDA-sponsored review referred to in section 2.1, glycolic acid has
not been assessed by other national agencies or international organisations
involved in reviewing or evaluating data pertaining to health hazards posed by
chemicals.
4 Priority Existing Chemical Number 12
3. Applicants
Following the declaration of glycolic acid as a PEC, 38 companies importing
glycolic acid into Australia for cosmetic or other uses applied for assessment of
the chemical. The applicants supplied information on the properties, import
quantities and cosmetic uses of the chemical. In accordance with the Industrial
Chemicals (Notification and Assessment) Act 1989, NICNAS provided the
a p p l i c a n t s with a draft copy of the report for comments during the
corrections/variation phase of the assessment. Data for the assessment were also
provided by 22 notifiers, that is, companies which purchase glycolic acid in
Australia and formulate it into various products.
The applicants were, as follows:
Advanced Skin Technology Pty Ltd ICN Biomedicals Australasia
1606 High St 12/167 Prospect Hwy
Glen Iris VIC 3143 Seven Hills NSW 2147
Allergan Australia Pty Ltd Internatio-M黮ler Australia/New
22 Rodborough Rd Zealand Pty Ltd
Frenchs Forest NSW 2086 64 Trenerry Cr
Abbotsford VIC 3067
Amway of Australia International Beauty Supplies Pty
46 Carrington Rd Ltd
Castle Hill NSW 2154 6 Narrabang Way
Belrose NSW 2085
Johnson & Johnson Pacific Pty
Beiersdorf Australia Ltd
4 Khartoum Rd Ltd
North Ryde NSW 2113 Stephen Rd
Botany NSW 2019
Bio Scientific Pty Ltd Kandas International Australia
28 Munroe Ave Pty Ltd
Kirrawee NSW 2232 Level 2, 762 George Street
Haymarket NSW 2000
Bioscor International Pty Ltd Lever J H & Co Pty Ltd
6 Bond St
184 Huntingdale Rd
Oakleigh East VIC 3166 Richmond SA 5033
Lever Rexona
Bronson & Jacobs Pty Ltd
Parkview Drv Australia Cntr 219 North Rocks Rd
Homebush NSW 2140 North Rocks NSW 2151
Clariant (Australia) Pty Ltd 3M Australia Pty Ltd
675 Warrigal Rd 950 Pacific Hwy
Chadstone VIC 3148 Pymble NSW 2073
5
Glycolic acid
Clinical Skincare & Equipment Pty Merck Pty Ltd
Ltd 207 Colchester Rd
PO Box 649 Kilsyth VIC 3137
Alderley QLD 4051
Cosmetic Products Pty Ltd Montcove Pty Ltd
1 Wella Way 101 Allambi Ave
Sommersby NSW 2250 Florida Gardens QLD 4218
Crampton RVB Nutri-Metics International
29 Antlia St (Australia) Pty Ltd
Regents Park QLD 4118 102 Elliott St
Balmain NSW 2041
Crown Scientific Pty Ltd Salon Marketing Services Pty Ltd
144 Moorebank Ave Unit 6/165 Rookwood Rd
Moorebank NSW 2170 Bankstown NSW 2200
Cussons Pty Ltd Sanofi Beaute Australia Pty Ltd
282 Hammond Rd 166 Epping Rd
Dandenong VIC 3175 Lane Cove NSW 2066
Doctors Formula Pty Ltd Scental Pacific Pty Ltd
1/182 Euston Rd 53 Jersey Rd
Alexandria NSW 2015 Bayswater VIC 3153
Du Pont (Australia) Ltd Sigma Aldrich Pty Ltd
168 Walker St 14 Anella Ave
North Sydney NSW 2060 Castle Hill NSW 2154
Eckstein Australia Pty Ltd Specialty Supply Australia Pty
66c Maryborough St Ltd
Fyshwick ACT 2609 9/10-12 Yalgar Rd
Kirrawee NSW 2232
Goldwell Cosmetics (Australia) Pty Universal Aesthetics Pty Ltd
Ltd 1/14 Roseberry St
103 Yerrick Rd Balgowlah NSW 2093
Lakemba NSW 2195
Hamilton Laboratories Victor Paul Direct Marketing Pty
217 Flinders St Ltd
Adelaide SA 5000 561 Botany Rd
Waterloo NSW 2017
Heavenly Beauty Yves Rocher
46 South St
12/300B Burns Bay Rd
Rydalmere NSW 2116
Lane Cove NSW 2066
6 Priority Existing Chemical Number 12
4. Chemical Identity and
Composition
4.1 Chemical name (IUPAC)
Hydroxyethanoic acid
4.2 Registry numbers
Glycolic acid is listed on the Australian Inventory of Chemical Substances
(AICS) as hydroxyethanoic acid.
CAS number 79-14-1
EINECS number 201-180-5
RTECS number MC5250000
4.3 Other names
Acetic acid, hydroxy-
Alpha-hydroxyacetic acid
Gluco-hydroxy-acid
Glycollic acid (Approved Australian Name)
Hydroxyacetic acid
2-Hydroxyacetic acid
4.4 Trade names of cosmetic raw materials
4.4.1 Pure substance
Glycolic acid
Glypure
4.4.2 AHA blends
-HydroxyAcids `AHA'
Amidroxy Apple
Amidroxy Sugar Cane
Fruitlange
Multifruit BSC
7
Glycolic acid
NAB Apricot Extract
Sugar Cane AHA
4.5 Molecular formula
C2H4O3
4.6 Structural formula
HO
|
HO--C--C--OH
H
4.7 Molecular weight
76.05
4.8 Concentration units
It is customary to state the concentration of glycolic acid in cosmetic products in
% w/w. Thus, the concentration of glycolic acid in a 1% solution, gel, cream or
lotion is 10 mg/g. A 1 M solution contains 7.6% or 76 mg/mL glycolic acid.
4.9 Composition
Glycolic acid is a naturally occurring substance formed during photosynthesis.
Blends of glycolic acid and other AHAs are made by extraction of plant materials
but may be standardised by the addition of man-made chemicals. It is made
synthetically by treating formaldehyde with carbon monoxide and water or by
hydrolysis of monochloroacetic acid with sodium hydroxide (Miltenberger,
1989). The composition of some raw materials is shown in Tables 4.1-4.2.
Compared with cosmetic grade glycolic acid, the technical quality has a higher
content of process impurities such as formic acid, formaldehyde, diglycolic acid
and methoxyacetic acid.
8 Priority Existing Chemical Number 12
Table 4.1: Composition of technical and cosmetic grade glycolic acid
(DuPont, 1995b)
Technical grade Cosmetic grade
70% solution 70% solution 99% crystalline
Total acid (%) 70.0-72.2 69.7-72.0 99.8-100.5
Heavy metals (ppm) <4 <4 <4
Sulfates (ppm) <150 <25 <100
Formic acid (ppm) <3800 <150 <10
Formaldehyde (ppm) <750 <15 <3.5
Iron (ppm) <7.0 <1.0 <1.0
Chloride (ppm) <1.7 <1.0 <1.0
Sodium (ppm) <32 <2.5 <10
Ammonia (ppm) <110 <3.9 <5.0
Diglycolic acid <1.1% <140 ppm <115 ppm
Methoxyacetic acid <1.9% <190 ppm <170 ppm
Free acid (%) 62.8-65.2 64.0-67.0 >95.0
pH <0.5 <0.5 -
Table 4.2: Composition of some AHA blends for cosmetic use (Bronson &
Jacobs, 1999; Lever, 1998; Sohume, 1998; Specialty Supply, 1999)
-Hydroxy NAB Sugar
Multifruit Apricot Cane
Acids
Fruitlange BSC Extract AHA
`AHA'
10
Glycolic acid (%) ~2.5 12-17 10-15 ~15
Lactic acid (%) ~23.5 28-32 13-18 ~5
13
4
Malic acid (%) ~2.5 <1 1-3 ~2.5
Tartaric acid (%) ~0.1 <1 <1 -
4
Citric acid (%) ~5.0 2-6 1-3 ~2.5
13
Pyroglutamic acid (%) ~5.0 - - - -
Pyruvic acid (%) ~0.2 - - - -
Glycerol (%) ~6.0 - - - -
Propylene glycol (%) - - - - 30-40
Water (%) 51-56 52-60 ~40 ~69 30-40
pH 3.4-4.6 3.5-4.5 4-5 ~2 1-2
9
Glycolic acid
5. Physical and Chemical
Properties
5.1 Physical state
Glycolic acid is a crystalline, colourless, odourless, somewhat hygroscopic solid
(Budavari, 1996).
Conversion factors (at 25癈):1 mg/m3 = 0.32 ppm; 1 ppm = 3.1 mg/m3.
5.2 Physical properties
Table 5.1: Physical properties
Property Value Reference
Boiling point 100癈 (decomposes) Miltenberger (1989)
112癈 (70% solution) DuPont (1998e)
Melting point 78-80癈 Miltenberger (1989)
-1.38 Barratt (1996)
Partition coefficient
(logPo/w) -1.11 Hansch & Leo (1987)
Density 1.49 g/mL (at 25癈) Miltenberger (1989)
1.27 g/mL (70% solution at DuPont (1998e)
15.6癈)
Vapour pressure
?solid form Nil (at 25癈) DuPont (1999b)
143 Pa (at 91癈) DuPont (1999b)
779 Pa (at 119癈) DuPont (1999b)
?70% aqueous solution 1.92 Pa (at 45癈) DuPont (1999b)
Dissociation constant 3.83 (at 25癈) Budavari (1996)
(pKa)
3
Molecular volume 55? Barratt (1996)
Flammability limits Non-flammable DuPont (1999b)
5.3 Chemical properties
Glycolic acid is freely soluble in water, methanol, ethanol, acetone, ethyl acetate,
ether and acetic acid (Budavari, 1996; Miltenberger, 1989).
The pH of unbuffered solutions of glycolic acid in water is illustrated in Figure
5.1.
Glycolic acid contains acid as well as primary alcohol functional groups. It
undergoes typical oxidation reactions to give glyoxylic acid and oxalic acid and
reduction reactions with active metals to form acetic acid. As an acid it forms
salts, esters, amides etc. As an alcohol it forms esters, acetals and ethers. It uses
both functional groups to form complexes with polyvalent metal ions. In acid
environments, glycolic acid can undergo self-esterification to form cyclic and
10 Priority Existing Chemical Number 12
linear polymers known as glycolides. There are no readily hydrolysable groups in
glycolic acid.
Glycolic acid is non-flammable. Its combustion products include formaldehyde,
formic acid, carbon monoxide and carbon dioxide.
Crystalline glycolic acid begins to lose water and polymerise at temperatures
above 50篊 (DuPont, 1998e). When heated to its melting point, the chemical
emits acrid smoke and irritating fumes (Lewis, 1996). Concentrated aqueous
solutions of glycolic acid are chemically stable at normal temperatures (DuPont,
1998e).
5.4 Concentration of undissociated acid in cosmetic formulations
G l y c o l i c acid is a moderately strong acid and in aqueous environments
dissociates into glycolate and hydrogen ions:
HOCH2COOH HOCH2COO- + H+
The relative concentrations of undissociated acid and glycolate ion depend on the
pH of the solution and are governed by the following equation:
[undissociated acid]/[glycolate] = [H+]/ Ka
where [molecule] denotes the molar concentration of the molecule and Ka is the
dissociation constant of glycolic acid (1.48 x 10-4 (Budavari, 1996)).
Thus, in an unbuffered 10% (100 mg/mL) solution of glycolic acid with a pH of
1.73 (Budavari, 1996), the ratio [undissociated acid]/[glycolate] is 126/1 and the
concentration of undissociated glycolic acid is >9.9% (>99 mg/mL). If the pH is
increased by the addition of a base, then the concentration of undissociated
glycolic acid decreases, as shown in Figure 5.2.
Most formulations of glycolic acid are not aqueous solutions but oil-in-water
emulsions such as creams and lotions. In emulsions, undissociated glycolic acid
m o l e c u l e s distribute to the oil phase, decreasing the concentration of
undissociated glycolic acid, glycolate ion and hydrogen ion in the aqueous phase.
In this case, the concentration of undissociated acid in the aqueous phase can be
calculated from the following equation (CIR, 1998):
C
[undissociated acid]w =
Ko/a x q + 1 + Ka/[H+]w
where C is the total concentration of glycolic acid in the formulation, Ko/a is the
oil/water partition coefficient of glycolic acid, q is the volume ratio of the oil and
water phases, Ka is the dissociation constant of glycolic acid and [H+]w is the
hydrogen ion concentration in the aqueous phase.
No information was available on the Ko/a of glycolic acid for cosmetic oil phase
ingredients. However, the octanol/water partition coefficient is known (Table
5.1). A graph constructed from data from a series of octanol-in-water emulsions
at pH 2 and 4 shows that the concentration of undissociated glycolic acid in the
aqueous phase of a given product is much more susceptible to changes in pH than
to variations in the oil/water phase ratio (Figure 5.3).
11
Glycolic acid
Figure 5.1: pH of aqueous solutions of glycolic acid (Budavari, 1996; Yu &
Van Scott, 1994)
3
2.5
2
pH
1.5
1
0.5
0
0 10 20 30 40 50 60 70 80
Con entration (%)
c
Figure 5.2: Undissociated glycolic acid in % of total concentration in
aqueous solutions at pH 2-6
100
90
% undissociated acid
80
70
60
50
40
30
20
10
0
2 2.5 3 3.5 4 4.5 5 5.5 6
pH
Figure 5.3: Undissociated glycolic acid in the aqueous phase of octanol-in-
water emulsions at pH 2 and pH 4 in % of total concentration in the product
100
90
% undissociated acid
80
pH = 2
70
pH = 4
60
50
40
30
20
10
0
0 10 20 30 40 50
Octanol conce tration (% v/v)
n
12 Priority Existing Chemical Number 12
6. Methods of Detection and
Analysis
6.1 Identification
Glycolic acid can be characterised by nuclear magnetic resonance, infrared and
mass spectroscopy. The chemical may be detected qualitatively in a spot test with
2,7-dihydroxynaphtalene in concentrated sulphuric acid (Eegriwe, 1932, as cited
in Miltenberger, 1989).
6.2 Quantitative analysis
6.2.1 General methods
Quantitative determination of glycolic acid can be performed by acidimetric
titration or a variety of spectroscopic and chromatographic methods. A frequently
employed assay utilises the Eegriwe colour reaction described above, followed by
measurement of the absorbance of the solution at 540 nm (Calkins, 1943, as cited
in Hackney & Hensley, 1987). The Calkins method has a detection limit of
approximately 1 礛 (76 礸/L) but its specificity is low because of interference
by formaldehyde, ammonium and nitrate ions, carbohydrates and other naturally
occurring substances. A less sensitive (about 4 礛) but more specific assay
employs glycolate oxidase to catalyse the conversion of glycolic acid to glyoxylic
acid, which then reacts with phenylhydrazine to form a coloured derivative with
an absorbance peak at 324 nm (Hackney & Hensley, 1987). The most sensitive
method developed to date uses extraction with ethyl acetate, derivatisation with
bis-trimethylsilyl trifluoroacetamide and quantification by gas chromatography-
mass spectrometry (Leboulanger et al., 1998). This method has a limit of
detection below 0.05 礛 (4 礸/L) glycolic acid.
6.2.2 Raw materials
Blake et al. (1987) have developed a method for the quantitative analysis of
organic acids in sugar cane juice which allows the simultaneous determination of
glycolic, lactic, malic, tartaric, citric, pyroglutamic, pyruvic and other commonly
occurring 'fruit acids'. The acids in the sample are passed through a cation-
exchange column, isolated on an anion-exchange column and eluted with dilute
sulphuric acid. After filtration of the eluate, the acids are separated by high-
p r e s s u r e liquid chromatography (HPLC) on 2 cation-exchange columns
connected in series and equilibrated at 35癈 and 85癈 respectively and quantified
by refractive index monitoring. The system is calibrated using external standards
and has a detection limit of about 50 mg/L.
6.2.3 Cosmetic products
A method has been developed for routine analysis of commercial cosmetics such
as creams and lotions (Scalia et al., 1998). A sample of the product is dispersed in
13
Glycolic acid
tetrahydrofuran-water by sonication, purified by solid-phase extraction on a
silica-based, strong anion-exchange cartridge and directly analysed by HPLC
using an UV detector set at 210 nm. The sensitivity of the assay was determined
at 15 礸/mL, which corresponds to a concentration of 0.4% glycolic acid in the
cosmetic product. The peaks representing glycolic, lactic, malic, tartaric and citric
acid were well separated and the average recovery of glycolic acid was 92-96%.
6.2.4 Biological monitoring
Blood glycolic acid may be measured by high-performance ion chromatography
of a plasma or serum ultrafiltrate, using monitoring of the column eluant with a
conductivity cell and an external standard (Hagen et al., 1993). The ion-exchange
method can be automated and has a high degree of sensitivity (approximately 3
礛), precision and specificity. It can also be applied to urine (Wandzilak et al.,
1991).
Fraser & MacNeil (1993) have developed colourimetric and gas chromatographic
procedures for the measurement of glycolic acid in blood from ethylene glycol
poisoned patients (see section 11.1.2). These assays are rapid and can be run on
standard equipment, but have a much higher detection limit than the ion-
chromatographic method (1.0 mM).
Serum and urine samples can also be analysed directly for glycolic acid content
by proton magnetic resonance spectroscopy (Wahl et al., 1998).
14 Priority Existing Chemical Number 12
7. Manufacture, Importation and
Use
7.1 Manufacture of glycolic acid
Glycolic acid manufacture does not occur in Australia, but is reported in USA,
Europe and Japan. Glycolic acid is on the OECD list of high production volume
chemicals (OECD, 1997), which means that at least one OECD member state
imports and/or produces more than 1000 metric tonnes per year (t/y) of the
chemical. In the late 1980s, worldwide consumption (all grades and uses) was
estimated at 2000-3000 t/y (Miltenberger, 1989). Manufacture of AHA blends by
extraction of plant materials is on a much smaller scale, mainly in Europe and
USA, and is not known to occur in Australia.
7.2 Overview of the Australian cosmetic industry
As shown in Figure 7.1, the entities involved with cosmetic uses of glycolic acid
in Australia are:
? chemical suppliers who purchase glycolic acid raw materials overseas and
resell them to product formulators;
? product formulators who manufacture salon and consumer cosmetics and sell
them to cosmetic wholesalers and distributors;
? cosmetic wholesalers and distributors who purchase products from overseas
and/or domestic formulators and resell them to beauty and hair salons or
retailers;
? beauty and hair salons who purchase products for in-salon end use or resale
to clients;
? retailers such as pharmacies, supermarkets and department stores; and
? consumers.
Industry sources estimate that there are 2500-3000 full-service beauty salons and
12,000 hair salons in Australia. In addition, there are over 15,000 pharmacies,
supermarkets and department stores (Australian Bureau of Statistics, 1993), most
of which would stock one or more lines of glycolic acid consumer cosmetics.
Many businesses are both importers and formulators of finished goods and some
also control the distribution and retailing of their products:
? Business A distributes a total of 29 glycolic acid containing cosmetic products, of
which 23 are for the retail and 6 for the salon market. Twenty-eight of the products
a r e manufactured in USA and imported in finished form. One product is
manufactured in Australia by a contract manufacturer who purchases the raw
material from a local chemical supplier.
15
Glycolic acid
Figure 7.1: Schematic representation of the flow of glycolic acid for
cosmetic use from manufacturers through to end users
Overseas
Raw material manufacturers Product
formulators
----------------------------------------------------------------------------------------------
Australia
Product Cosmetic
Chemical
formulators wholesalers and
suppliers
distributors
Retailers
Beauty/hair
salons
Consumers
? Business B is the Australian subsidiary of a large multinational company specialising
in beauty and related products which are sold and distributed directly to the
consumer. The business imports most of its products in finished form, however 5
formulations containing glycolic acid are manufactured in Australia by a contract
manufacturer from raw materials purchased from a local chemical supplier.
? Business C, which is owned by two physicians, makes and distributes 16 different
glycolic acid products, which are sold to about 30 beauty salons where they are either
consumed or resold to the public. The business also uses and retails the products in
its own beauty salon. The finished products are manufactured in the business' own
laboratory from raw materials purchased from a local chemical supplier.
? Business D, a pharmacy, retails a number of branded cosmetics containing glycolic
acid but also manufactures two extemporaneous formulations, which are packaged in
glass jars with typewritten labels and sold to the general public. The raw material is
purchased from a local chemical supplier.
The industry comprises a large number of small formulators and importers of
finished products that are not subscribers to the Chemical Gazette or members of
the industry association (Cosmetic, Toiletry and Fragrance Association of
Australia) and may not have been aware of the declaration of glycolic acid as a
PEC. As such, the quantity of glycolic acid imported in finished form, the number
of salon and consumer products marketed in Australia and the number of
formulators and importers of finished products are likely to be higher than
reported below.
16 Priority Existing Chemical Number 12
7.3 Importation for cosmetic use
Cosmetic grade raw materials (synthetic and natural) were imported by 8 of the
applicants for this assessment, whereas 17 imported the chemical as an ingredient
in finished cosmetic products. Information submitted by the applicants indicates
that glycolic acid is imported at annual levels 1500 kg in synthetic, cosmetic
grade raw materials, 500 kg as an ingredient in natural raw materials (AHA
blends) and 3700 kg as an ingredient in cosmetic products for salon or consumer
use.
7.4 Types of cosmetic products containing glycolic acid
Based on information collected from applicants and notifiers, it is estimated that
180 different cosmetic products containing glycolic acid were marketed in
Australia in 1998/99 (Table 7.1 and Appendix 1). This number does not include
different pack sizes of the same brand, formulation, glycolic acid content, pH and
recommended use. Also, 20 products which 3 importers distribute directly to
physicians for use in their practice were not considered. Although the database is
unlikely to be complete, it probably includes most, if not all, major brands and
high volume products. As the cosmetics market is dynamic, some of the products
may no longer be commercially available.
Table 7.1: Types of glycolic acid containing cosmetic products marketed in
Australia in 1998/99
Range of glycolic
End users Formulation Number acid content (%) Range of pH
Beauty salons Cream 3 4-10 3.0-3.5
Gel 8 10-60 2.0-3.5
Lotion 2 10 3.5
Solution 12 5-50 1.5-4.5
Total 25 4-60 1.5-4.5
Consumers Cream 56 0.06-20 3.0-6.6
Gel 22 0.1-20 3.0-5.8
Hair products 11 0.01-8 4.3-6.0
Lotion 40 0.7-20 3.0-5.8
Oil 1 5 3.5
Scrub 9 0.3-15 3.0-6.0
Solution 16 0.2-6.5 3.5-5.8
Total 155 0.01-20 3.0-6.6
Grand total 180 0.01-60 1.5-6.6
By comparison, a FDA survey of the US cosmetics market conducted in 1997
identified 62 different formulations containing glycolic acid (CIR, 1998).
All cosmetics containing glycolic acid are used in the care of the skin and its
appendages (hair and nails). According to their end users, they can be divided
into salon products and consumer products. All salon and most consumer
products are recommended for skin care, that, is application to the skin of the
face, body, hands or feet as moisturising and exfoliating agents and to improve
skin texture, smooth fine lines and wrinkles and reduce the appearance of age
17
Glycolic acid
spots. All hair products are for consumer end use. They include shampoos,
conditioners and intensive hair treatments, most of which contain very small
amounts of glycolic acid, either for the purposes of pH adjustment or to provide a
`fruit acid' marketing platform.
7.5 Non-cosmetic uses
In Australia, technical grade glycolic acid is used in household and industrial
cleaners, paint strippers, textile finishing solutions and oil and water well flow
enhancers. These uses are outside the scope of the present assessment.
7.6 Glycolic acid in foods
Glycolic acid is found in the fruit, leaf, stem and root portions of all plants.
Commonly consumed fruits and vegetables are reported to contain from 0.45-7.4
mg glycolic acid per 100 g fresh wet weight (Harris & Richardson, 1980). Tea,
coffee, fruit juice and other beverages derived from plant sources may contain 5-7
mg glycolic acid per 100 mL. Foods of animal origin are generally low in
glycolic acid, with milk and beef reported to contain 0.06-0.12 mg per 100 g of
the chemical.
18 Priority Existing Chemical Number 12
8. Estimated Occupational and
Public Exposure to Glycolic
Acid Resulting from Cosmetic
Uses
In Australia, exposure to glycolic acid resulting from its use in the cosmetics
industry may occur to:
? workers handling glycolic acid raw materials during storage or transportation;
? workers involved with the manufacture of cosmetic products;
? workers handling finished cosmetic products during storage or transportation;
? workers in beauty salons;
? consumers treated with glycolic acid products in beauty salons; and
? consumers who use cosmetics with glycolic acid at home.
8.1 Methods of use
8.1.1 Formulation of cosmetic products
Of the 60 applicants and notifiers, 19 formulated skin or hair care products with
glycolic acid in Australia or had such products formulated by local contract
manufacturers.
The products are generally manufactured from liquid raw materials (70% glycolic
acid solution or AHA blends) which are imported in polyethylene jerry cans, pails
or drums containing 1-250 kg. The quantity of raw material required to formulate
a batch is pre-weighed and decanted into smaller containers. Where the raw
material is partially neutralised before final mixing, water is first weighed into a
vessel to which the base (usually ammonium hydroxide) is slowly added. The raw
material is then slowly poured into the basic solution and the premix is stirred for
10-15 min. Solutions and gels are manufactured by adding additional water and
the remaining ingredients to the premix at room temperature whilst keeping the
b a t c h under slow/medium sweep blade mixing. Lotions and creams are
manufactured by heating and homogenising the oil phase and aqueous phase
ingredients together at 60-95癈. The batch is then cooled to 40-65癈 and the raw
material or partially neutralised premix is poured manually or pumped into the
batch and mixed in. After further cooling, the batch is pumped or decanted into a
storage tank from which it is dispensed into bottles, tubes or jars by gravity feed
or pneumatic filling. The primary containers may be packaged into individual
cartons. The finished product is stored and distributed in multiunit cardboard
boxes or shrink-wrapped in plastic foil.
In a few cases, the starting material is crystalline glycolic acid which is imported
in 20 kg disposable fibre drums. The solid raw material is weighed into a sealed
19
Glycolic acid
container, transferred to an open vessel and dissolved in water using a hand
stirrer. The solution is then processed as above.
8.1.2 Application of cosmetic products
In salons, beauticians first cleanse and rinse the skin area to be treated and then
apply the glycolic acid solution or gel with the fingertips or a cotton tip or brush.
When treating the face, the solution/gel is left in place for 5-10 min and then
washed off with gauze dipped in cold water. Occasionally, the solution/gel is
applied a second time and left in place for another 5-10 min before being washed
off. Hands, feet and other body parts are treated similarly. According to industry
sources, products applied to body parts other than the face are usually washed off
after about 15 min. The treatment is concluded with the application of a
moisturising cream, which usually contains a sunscreen with a sun protection
factor (SPF) 15. A typical treatment course includes 6-10 peels over a period of
4-6 weeks.
When used at home, skin care solutions, gels, lotions and creams are applied to
the skin with the fingertips or a small cotton ball once or twice a day. Scrubs,
which are lotions or creams that contain polishing granules, are rubbed into the
skin with a cloth or a sponge and then rinsed off with water.
Hair products such as shampoos and conditioners are lathered into the hair, left
on for a few minutes, and rinsed off with water. Intensive hair treatment products
are usually applied to the hair and left in. In some cases, the manufacturer
recommends to cover the head with plastic film or a towel for 15 min before
rinsing out the product under the shower.
8.2 Occupational exposure
8.2.1 Methodology
Given the uses of glycolic acid in the cosmetics industry, workers are potentially
exposed to the chemical by both skin contact and inhalation.
The theoretical external exposures by skin contact were estimated for reasonable
worst-case scenarios, using occupational exposure parameters derived from the
EASE (Estimation and Assessment of Substances Exposure) model developed by
t h e UK Health and Safety Executive (EC, 1996). The assumptions and
calculations used to arrive at these estimates are described in Appendix 2, section
A2.1. The EASE model is designed to provide a conservative estimation of
potential exposure.
Cosmetic products formulated in Australia contain a maximum of 40% glycolic
acid and the most widely used raw material is a 70% solution of the chemical in
water. For formulation plant workers, the EASE model predicted a maximum
dermal exposure to glycolic acid assessed as external dose rate to predominantly
the hands and forearms that varied between 140 mg/day for incidental exposure
to a 70% solution and 800 mg/day for intermittent exposure to solutions
containing 40% of the chemical.
During manual application of formulations of glycolic acid in beauty salons or
skin clinics, the maximum external exposure predominantly to the hands and
20 Priority Existing Chemical Number 12
forearms predicted by the EASE model was 800 mg/day for application of a 40%
formulation in beauty salons and 1400 mg/day for a 70% formulation as used in
skin clinics.
Data on airborne exposure were provided by a major manufacturer, based on air
monitoring conducted at two US and three Australian sites handling various
glycolic acid products (DuPont, 1999b). The air monitoring program also
included a laboratory simulation of the blending of a commercial 70% glycolic
acid solution in a 20 L gas-sparged, agitated, translucent open-air vessel equipped
with baffles, a turbine propeller and a single-point sparging line and run with
process parameters representing typical commercial-scale values. Aerosol
formation was measured with an 11-stage cascade impactor placed 4-15 cm
above the surface of the mixing liquid. There was visible splashing and churning
in the vessel, but no mist could be seen with the naked eye. However, chemical
analysis of the impactor filters identified the presence of very fine aerosol
particles with a mean diameter of 0.4-1 祄 in a quantity corresponding to an
airborne concentration of glycolic acid ranging from 1.1-1.9 mg/m3.
The measured air levels were comparable to estimates obtained by the EASE
model as described in Appendix 2. The maximum exposure levels were estimated
to equal the lowest rounded value encompassing all relevant UTL95%,95%1
values and EASE estimates given in Table 8.1. A breathing zone concentration of
2 mg/m3 was taken to be the maximum airborne exposure from the commercial
70% raw material, whereas a breathing zone concentration of 1 mg/m3 was taken
to be the maximum airborne exposure from formulated products containing 45%
glycolic acid.
The maximum predicted dermal exposure is equivalent to the exposure resulting
from the application of a standard amount (1-2 x 7.5 g; see Table 8.2) of a body
lotion with 10% glycolic acid. The estimated maximum air concentrations of
glycolic acid are 5-10 times lower than the workplace control level of 10 mg/m3
(8- and 12-h TWA) established by one large manufacturer of the chemical
(DuPont, 1999b).
8.2.2 Exposure during storage and transportation
Cosmetic raw materials and finished products containing glycolic acid are
packaged into closed containers and as such the likelihood of occupational
exposure during storage and transportation is negligible, except in case of
accidental spills or leaks.
8.2.3 Exposure during formulation
Workers involved in the formulation of cosmetic products may be exposed to
glycolic acid during pre-weighing of raw materials, during the preparation of
premixes and final formulations, and during filling operations. As some
formulators are small businesses with a limited number of staff, one worker could
be involved in the entire formulation process. On the other hand, exposure is
unlikely to occur repeatedly, as even the largest formulators do not manufacture
glycolic acid containing cosmetics on a daily basis.
1
Upper tolerance limit encompassing 95% of exposures with a certainty of 95%.
21
Glycolic acid
3
Table 8.1: Measured and predicted airborne concentrations of glycolic acid (mg/m ) in raw material and formulation manufacture
facilities and a beauty salon in USA and Australia
Average
glycolic acid
Analytical results
concentration
Duration EASE in product
N Range Median UTL95%,95%*
Site Process Monitoring Description (min) estimate handled
Belle, VA, USA Manufacture Personal Operators Full-shift** 10 <0.1-1.2 0.20 1.5 0-0.3 70%
Purification Personal Operators Full-shift 3 <0.1 <0.1 - 0-0.3 70%
Road tanker loading Personal Operators Full-shift 11 <0.1-1.4 0.20 1.6 Negligible 70%
Drumming Personal Operators Full-shift 19 <0.1-0.6 0.10 0.53 Negligible 70%
Wilmington, DE, Simulated blending Static 50 cm above tank 180-240 8 0.14-0.33 0.28 0.52 Negligible 70%
USA at 45?angle
USA, not further Cosmetic formulation Static 15-45 cm from 85-280 4 <0.1-0.15 0.085 0.60 0-0.2 40%
specified manufacture vessel surfaces
Household cleaner
Tomago, NSW Personal Operator 300 1 <0.1 - - Negligible 5%
formulation manufacture
Household cleaner Static 50 cm above open 270-280 2 <0.1 <0.1 - Negligible 5%
formulation manufacture mixing vessel
Nowra, NSW Industrial cleaner Personal Operator 240 1 <0.1 - - Negligible 45%
formulation manufacture
and filling
Industrial cleaner Static 50 cm above open 240 1 0.15 - - Negligible 45%
formulation manufacture mixing vessel
Industrial cleaner Static Proximity of filling 240 1 <0.1 - - Negligible 45%
formulation filling area
Sydney, NSW Beauty salon Static Inside cubicle 310 1 0.1 - - Negligible 20%
* Upper tolerance limit encompassing 95% of exposures with a certainty of 95% (calculated according to Mulhausen & Damiano (1998), with non-detectable results assigned a value of
0.7 times the detection limit)
** 12-hour shifts
22 Priority Existing Chemical Number 12
In a reasonable worst-case scenario based on the manufacture of a 40% solution
from a raw material containing 70% glycolic acid, one worker would spend 2 h at
pre-weighing and mixing followed by 4 h at the filling line. As shown in
Appendix 2, section A2.1.3, the estimated potential exposures are:
? inhalation: 0.1 mg/kg/day
? skin contact: 6.2 mg/kg/day
? total: 6.3 mg/kg/day.
8.2.4 Occupational exposure from salon use
Workers in beauty salons may be exposed to inhalation of vapours originating
from and to intermittent skin contact with products containing glycolic acid. In a
reasonable worst-case scenario, a beautician may perform 3 applications per day,
each lasting 15-20 min, corresponding to a maximum of 1 h of exposure to the
chemical. As shown in Appendix 2, section A2.1.3, this would result in the
following potential exposures from a product containing 40% glycolic acid:
? inhalation: 0.02 mg/kg/day
? skin contact: 1.7 mg/kg/day
? total: 1.7 mg/kg/day.
8.3 Public exposure
8.3.1 Methodology
The public will be exposed to skin contact with a variety of cosmetic products
such as face creams, body lotions and gels, scrubs, shampoos and conditioners.
Inhalation may also occur, but vaporisation of glycolic acid from cosmetic
formulations is expected to be negligible.
For a selection of relevant cosmetics, the typical use levels employed in the
assessment of consumer exposure in Europe are shown in Table 8.2.
Table 8.2: Typical use levels of selected cosmetics (EC, 1996; ECETOC,
1993)
Product type Amount/application (g) Frequency of application
Non-rinse products
? 0.8 2/day
face cream
? 1* 1-2/day
general purpose cream
? 1.2 1-2/day
after-shave
? 7.5 1-2/day
body lotion
? 12 1-2/week
setting product
? 2.5 1-2/day
make-up remover
? 0.25 2-3/week
nail products
Rinse-off products
? 10 1-4/week
shower gel
? 12 1-7/week
shampoo
? 14 1-3/week
hair conditioner
2
* mg/cm
23
Glycolic acid
8.3.2 Exposure from personal use
In a reasonable worst-case scenario, home use of cosmetics with glycolic acid
would imply 2 daily applications of a 10% leave-on face cream and a 10% leave-
on body lotion (the highest concentration sold directly to consumers is 20%, but
in general manufacturers do not recommend twice daily application for products
containing >10% glycolic acid).
According to Table 8.2, this would result in the following external exposure for a
60 kg person: 10 x (0.8 + 7.5) x 2 x 1000 / 100 x 60 = 28 mg/kg/day.
8.3.3 Public exposure from salon use
Products used in salons for face peels contain up to 60% glycolic acid. However,
as the surface area of the face is relatively small and it is customary to rinse off
the product after a contact time of 5-10 min, face peels do not represent a
reasonable worst-case scenario. As such, it is assumed that salon treatment
involves 2 applications to the arms, legs and back of the hands and feet of a 40%
formulation applied in a standard quantity of 1 mg/cm2 (Table 8.2) and rinsed off.
Assuming that 10% of the formulation is left on the skin after rinsing, this would
result in the following external exposure for a person weighing 60 kg, in whom
the surface area of the arms, legs and back of the hands and feet is approximately
7800 cm2 (EPA, 1997): 40 x 7800 x 1 x 2 x 10 / 100 x 100 x 60 = 10 mg/kg/day.
8.4 Conclusions
In practice, workers involved with the manufacturing of cosmetic products would
usually wear protective clothing in the form of long-sleeved overalls or coats and
impervious gloves, which would minimise exposure to the hands and forearms.
Workers in beauty salons may wear gloves, which would reduce skin exposure by
about one-third.
Table 8.3: Potential external exposure of workers with and without gloves
and/or long-sleeved protective clothing (GPC) and of consumers to glycolic
acid resulting from cosmetic uses
Total potential exposure
(mg/kg/day)
Type of Frequency of
exposure Scenario exposure Without GPC With GPC*
Occupational Formulation plant Intermittent 6.3 2.1
Beauty Salon Repeated 1.7 1.1
Public Salon skin peel Intermittent 10 NA
Home use Repeated 28 NA
NA = not applicable
Table 8.3 above presents a summary of the estimated maximum external
exposure of workers and consumers to glycolic acid as used in the cosmetics
industry. The table also includes information on the likely frequency of exposure,
which may be intermittent or repeated, that is, occur at intervals of several days to
several weeks or on a daily or almost daily basis. The table may be used to
estimate the impact of combined exposure scenarios. For example, a beautician
24 Priority Existing Chemical Number 12
who also consumes glycolic acid products at home could be subject to repeated
exposures to the chemical at a level of 30 mg/kg/day.
Although physician use of glycolic acid falls outside the scope of this assessment,
occupational exposure also occurs in clinical practice where nurses and other staff
may handle and apply solutions containing up to 70% glycolic acid. As shown in
Appendix 2, section A2.1.3, if such workers handle glycolic acid formulations
manually for 1 h/day, their estimated maximal total exposure (repeated) would be
2.9 mg/kg/day without protective clothing. It would be 1.9 mg/kg/day if gloves
are used and negligible if both gloves and long-sleeved coats are worn.
It should be emphasised that the above exposure estimates are conservative and
do not include any form of absorption, which will be considered in the following
section.
25
Glycolic acid
9. Kinetics and Metabolism
The toxicokinetics of glycolic acid has been well investigated in laboratory
animals and humans. This is primarily because glycolic acid is both a precursor
of oxalic acid, which is a common component of kidney stones, and the major
toxic metabolite of ethylene glycol, which is an ingredient in antifreeze products
and a frequent cause of poisoning by ingestion in many parts of the world.
However, there are also studies of the absorption and metabolism of glycolic acid
applied to the skin.
9.1 Absorption
9.1.1 Through the skin
Absorption is defined as the rate and extent to which a substance is taken up by
the body when it is applied to a body surface. Dermal absorption in vivo may be
determined indirectly by measuring radioactivity in excreta following topical
application of the labelled substance. Alternatively, it is determined in vitro by
mounting a piece of skin in a diffusion cell, adding labelled substance to the
surface and measuring the amount of radioactivity which is taken up by the skin
(the retention) or passes through the skin to the medium in the collection chamber
(the penetration).
The available skin absorption data for glycolic acid are summarised in Table 9.1.
As there are no differences in absorption between fresh (live) and frozen (dead)
skin specimens, it is considered that dermal absorption of glycolic acid is a
passive diffusion process (Jiang & Qureshi, 1998). As shown in Table 9.1, the
a b s o r p t i o n process is influenced by time, pH, concentration, type and
composition of the formulation, and by the degree of occlusion of the site of
application.
A graphic representation of the absorption rates determined by Jiang & Quareshi
(1998) indicates that the most important factor in determining the rate of skin
penetration is the concentration of undissociated glycolic acid in the test sample
(Figure 9.1). The permeability coefficient (P) of glycolic acid can be calculated
from the slope of the regression line through the linear portion of the penetration
curve in Figure 9.1, after conversion of the unit of the abscissa (the concentration
of undissociated glycolic acid) from % to mg/mL. In this case the result is
approximately 3 x 10-4cm/h.
The permeability coefficient through human skin of small non-electrolytes in
aqueous solution can also be estimated from the following equation:
log[P (cm/s)] = -6.36(?.18) + 0.74(?.07) x log Po/w ?0.006(?.0006) x MW
where Po/ w is the octanol/water partition coefficient and MW the molecular
weight (Guy, 1995).
26 Priority Existing Chemical Number 12
14
Table 9.1: Summary of in vivo and in vitro studies of skin absorption of C-labelled glycolic acid (GA) in animals and humans
Species Study design Test samples Results Comments Reference
In vivo
Ohta et al.
At 1 h, 10-60% of the applied quantity was found on the skin One liposome
Hairless mice, Test samples rinsed off at 250 礸/cm_ GA in a 4%
(1996)
surface, 30-70% in the stratum corneum, 1-3% in the living formulation had a
SKH-hr-1, 1 h. One animal per aqueous solution, 2 liposome
skin layers and <1% in the urine and liver. At 9 h, the significantly higher
5 males per group killed at 1, 2, 3, 5 formulations, 30% propylene
corresponding values were 10-70, 20-50, 0.3-1 and 0.3-4%. absorption than all
group and 9 h. Skin, bladder glycol in water, an oil-in-water
other formulations
and liver analysed for and a water-in-oil emulsion
radioactivity.
In vitro
After 16 h, the penetration was 3% for the aqueous solution, Ohta et al.
Hairless mice, Full thickness skin in 565 礸/cm_ GA in a 4%
13-20% for the liposome formulations and 10% for the (1996)
SKH-hr-1, static diffusion cell, no aqueous solution, 2 liposome
propylene glycol/water mixture
3 males per occlusion formulations and 30%
group propylene glycol in water
20 mg/cm_ GA in a 10% Without occlusion, lag time was >15 min, penetration non- Goldstein &
Full thickness skin in Summary only
Hairless mice
Brucks (1994)
aqueous solution, pH 3.8 linear and 8-h penetration = 0.6-0.9%. With occlusion, lag
static diffusion cell ?br>
time was <15 min, penetration linear and 8-h penetration =
occlusion
1.8-2.3%.
Goldstein &
20 mg/cm_ GA in a 10% Without occlusion, lag time was >15 min, penetration non-
Separated epidermis in Summary only
Pigs
aqueous solution, pH 3.8 linear and 8-h penetration = 0.7-1.1%. With occlusion, lag Brucks (1994)
static diffusion cell ?br>
time was <15 min, penetration linear and 8-h penetration =
occlusion
0.8-1.8%.
2
2 mg/cm_ GA in a 10%
Humans, Epidermal membranes At 24 h, total absorption was <1%. An-eX (1994)
Only 20 礚/cm solution
aqueous solution, pH 3.7
1 subject from frozen abdominal was applied and GA
skin in static diffusion cell, may have crystallised
no occlusion on the surface
At 24 h, total absorption was 27-35%, retention 23-25% and Study conducted by Kraeling &
Humans, Viable split thickness 150 礸/cm_ GA in 2 different
penetration 3-12% at pH 3.0 and 2-3, 1-3 and <2% at pH 7.0 FDA Bronaugh
3-5 subjects abdominal skin in flow- 5% oil-in-water emulsions, pH
(1997)
per group through diffusion cell, no 3.0 and 7.0
occlusion
Jiang &
Study conducted by
With a 20%, pH 1.9 solution, absorption was 12% at 6 h and
4.4, 11.1 22.2 and 66.7
Humans, Fresh and frozen split
Qureshi
Therapeutic Products
37% at 24 h. For solutions at their native pH (0.7-2.0),
mg/cm_ GA in 4, 10, 20 and
3-4 subjects thickness breast and
(1998)
Directorate, Health
absorption was directly proportional to GA concentration. At
60% aqueous solutions at
per group abdominal skin in flow-
pH 3.8 there was no difference in the total amount absorbed
through diffusion cell, no Canada
various pH levels
from a 4, 10 and 20% solution. At constant concentration
occlusion
(4%), absorption, retention and penetration were significantly
higher at pH 2.0 and 2.6 than at pH 3.3 and 3.8.
27
Glycolic acid
Figure 9.1: Time-averaged skin absorption and penetration as a function of
the concentration of undissociated glycolic acid in aqueous solutions
(based on data from Jiang & Qureshi (1998) and Qureshi (1999))
2.5
2
Absorption
mg/cm2h
1.5
/
Penetration
1
0.5
0
0 10 20 30 40 50 60 70
Undissociated glycolic acid (%)
For glycolic acid, whose MW = 76.05 and whose log Po/w is ?.38 to ?.11, the
estimated permeability coefficient ranges from 3 x 10-5 to 2 x 10-4 cm/h, which is
in reasonable agreement with the experimentally determined permeability
coefficient of 3 x 10-4cm/h. The slightly higher value of the measured coefficient
could be due to glycolic acid inducing some loosening or thinning of the stratum
corneum (see section 11.3), which would shorten the diffusion path across the
skin.
The permeability coefficient can be used to estimate the absorption from aqueous
solutions containing a practically infinite quantity of glycolic acid.
Kraeling & Bronaugh (1997) measured the in vitro penetration from two oil-in-
water emulsions containing 5% glycolic acid at pH 3.0 and 7.0 which were
applied in an amount equal to 3 mg/cm2 to skin specimens from 5 human donors.
The two formulations were the same, except that in Formulation B 1%
ammonium laureth (or lauryl) sulfate, an ionic surfactant, replaced an equivalent
quantity of Laureth-4 in Formulation A. The mean recovery of glycolic acid from
the receptor fluid was 2.6% of the applied dose of Formulation A (pH 3.0), with a
standard error of ?.7% (corresponding to a 95% confidence interval of 1.2-
4.0%), whereas the mean recovery from the receptor fluid was 12.2% of the
applied dose of Formulation B (pH 3.0), with a standard error of ?.2%
(corresponding to a 95% confidence interval of 2.0-22.4%). At a formulation pH
of 7.0, the mean recovery from Formulations A and B was 0.8% and 1.4%
respectively. There was a high correlation (r2 = 0.92) between glycolic acid and
water absorption values. As water permeability is an indicator of the integrity of
the skin, the authors speculated that the inter-individual variability in glycolic
acid absorption was due to normal differences in the barrier function of the skin.
9.1.2 By inhalation
There were no quantitative studies of the rate or extent of uptake of glycolic acid
from inhalation of vapours or aerosols of the chemical. However, the available
28 Priority Existing Chemical Number 12
inhalation studies in laboratory animals indicate that glycolic acid is readily
absorbed from the airways (see sections 10.1.3 and 10.4.2).
9.1.3 By ingestion
Absorption by ingestion has been determined in rats and Rhesus monkeys by
measuring radioactivity in excreta after oral administration of 14C-glycolic acid.
Groups of fasted and non-fasted male Wistar rats were dosed with 50-900 mg/kg
14
C-labelled sodium glycolate in an aqueous solution administered by gavage
(Harris & Richardson, 1980). Urine, faeces and expired air were collected for 48
h, with food and water being withheld during the collection period. Only 2% of
the radioactivity was recovered in faeces. At the lowest dose level, 50% of the
administered dose was recovered as respiratory carbon dioxide and approximately
7% as glycolic, glyoxylic and oxalic acids in the urine. At the highest dose level,
22% of the administered dose was recovered as respiratory carbon dioxide, 51%
as glycolic acid in the urine and 3% as glyoxylic and oxalic acids in the urine (see
Table 9.2).
Two female Rhesus monkeys dosed orally with 500 mg/kg labelled glycolic acid
in aqueous solution excreted around 3% of total radioactivity in faeces over a 72-
96 h collection period (McChesney et al., 1972).
Intestinal absorption has also been studied in vitro using everted rat intestinal
rings exposed to 0-10 mM (0-1.0 mg/mL) 14C-labelled sodium glycolate (Talwar
et al., 1984). Saturation kinetics was observed, with a Km of 6.25 mM and a Vmax
of 11 祄oles/30 min/g wet weight. Absorption was not influenced by sulfhydryl
binding agents or inhibitors of cellular respiration; however, it was competitively
inhibited by glyoxylic and lactic, but not oxalic or pyruvic acids. The absorption
rate was somewhat higher in specimens from the jejunum and ileum than from
the duodenum and colon.
In conclusion, these findings indicate that glycolic acid is readily absorbed from
the small intestine by a saturable carrier mechanism, which is shared by lactic
acid and probably belongs to the family of monocarboxylate transporters referred
to below.
9.2 Distribution
No experimental data were available about the distribution of glycolic acid to
various organs and tissues following systemic administration or uptake.
Based on kinetic data from a reproductive toxicity study (Carney et al., 1997,
1999), the volume of distribution in pregnant rats can be determined at 0.66 L/kg.
In humans, blood contains glycolic acid of dietary origin, with plasma or serum
levels having a reference interval of 1.4-7.5 礛 (0.1-0.6 mg/L) (Hagen et al.,
1993). The concentration is about 10 times higher in cerebrospinal fluid than in
plasma, possibly due to formation of glycolic acid from certain neurotransmitters
such as glycine and -aminobutyric acid (Hoffmann et al., 1993). Kinetic
o b s e r v a t i o n s in 2 patients with ethylene glycol intoxication indicated a
distribution volume of 0.56 L/kg, that is, glycolic acid is distributed in total body
water (Jacobsen et al., 1988). This is expected since at physiological pH (7.4)
29
Glycolic acid
99.9% of the chemical is present as glycolate anion, which is miscible with water
but insoluble in lipids.
Glycolic acid is taken up by rat liver cells by means of a monocarboxylate
transporter which exchanges glycolate for inorganic anions (Jackson & Halestrap,
1996). Such transporters are found in many other mammalian organs and tissues,
including the intestine, heart and skeletal muscle, the brain, the retina and red
blood cells. Except for the liver and intestine, their function is to transport lactic
acid into the extracellular fluid (Price et al., 1998).
9.3 Metabolism
The biotransformation of glycolic acid has been studied by oral or parental
administration of glycolic acid labelled with 14C at the 1 or 2 position to intact
rats and monkeys followed by determination of labelled molecules in blood, urine
and exhaled air. Exhaled air was found to contain labelled carbon dioxide (Harris
& Richardson, 1980; Weinhouse & Friedman, 1951), whereas urine contained
labelled glyoxylic acid, oxalic acid and hippuric acid as well as unmetabolised
glycolic acid (Harris & Richardson, 1980; King & Lehner, 1971; McChesney et
al., 1972; Weinhouse & Friedman, 1951). Hippuric acid is a conjugate of benzoic
acid with the amino acid glycine which is formed from glyoxylic acid by
transamination. Hepatectomy significantly altered the metabolism of labelled
glycolic acid in the rat, reducing the formation of urinary metabolites and exhaled
carbon dioxide by approximately 30-50% and 60-90% respectively (Farinelli &
Richardson, 1983; Varalakshmi & Richardson, 1983).
In isolated perfused rat livers and rat liver homogenates, glycolic acid is oxidised
to oxalic acid via glyoxylic acid (Richardson, 1973; Yanagawa, 1990). These
reactions proceed at a rate which is twice as high in male as in female rats
(Richardson, 1965; Runyan, 1971, Yoshihara et al., 1999). The oxidation of
glycolic acid to glyoxylic acid is catalysed by glycolate oxidase, which is a
hydrogen peroxide generating enzyme found in the peroxisome fraction of liver
and kidney cells. Hydrogen peroxide is a co-substrate for catalase which catalyses
the oxidation of formic acid to carbon dioxide. In vitro, glycolate oxidase also
oxidises glyoxylic acid to oxalic acid; however, under physiological conditions,
this reaction is more likely to be catalysed by lactate dehydrogenase (Poore et al.,
1997).
When single doses of 1-4 g/kg of unlabelled or 14C-labelled ethylene glycol was
administered intraperitoneally to pigtail monkeys, the only detectable metabolite
in blood and urine was glycolic acid (although the assay used would not have
determined oxalic acid complexed with calcium) and the rate of CO2 formation
per h was 0.03% of the ethylene glycol dose (Clay & Murphy, 1977).
Following intravenous administration of 14 C-glycolic acid to healthy human
subjects, labelled glyoxylic and oxalic acids as well as unmetabolised glycolic
acid were recovered from the urine (King, 1970). In human liver homogenates,
labelled glycolic acid is metabolised to glyoxylic acid, oxalic acid and carbon
dioxide (Dean et al., 1967; Richardson, 1965). There is no evidence of sex
differences in the metabolic rate of glycolic acid in humans.
In various in vitro studies of human skin absorption, no metabolites of labelled
glycolic acid were detected in the skin or the collecting fluid (FDA, 1996).
30 Priority Existing Chemical Number 12
14
Table 9.2: Elimination of C-labelled glycolic acid (GA) in animals and humans
In urine (%)
Through
Metabolites the lungs
Unchanged
(%)
Species Dose and route Total GA Reference
Glyoxylic Oxalic Hippuric Others
Rat 50 mg/kg PO ND 3 <1 3 ND ND 50 (48 h) Harris &
Richardson (1980)
900 mg/kg PO ND 51 1 2 ND ND 22 (48 h)
Rat 380 mg/kg IV 67 (6 h) 61 1.2 3.5 ND 1.0 16 (6 h) Varalakshmi &
Richardson (1983)
Rat 10-110 mg/kg + ND ND ND 0.8-1.1 7.2-12.5 ND 32-13 Weinhouse &
1mmole sodium (24 h) (24 h) (5 h) Friedmann (1951)
benzoate IP
Goat Trace IV ND ND ND ND ND ND 40 (5 h) Peters et al. (1971)
Cattle Trace IV 11 (4 h) ND ND ND ND ND 37 (4 h) Peters et al. (1971)
37-52 McChesney et al.
Monkey 500 mg/kg PO 34-44 0.3-2.2 0.3-1.3 0.3 6 ND
(72-96 h) (1972)
Monkey Trace IV ND 61* (3 h) 12* 24* - 3* ND King & Lehner
(1971)
Human Trace IV 9-14 5-10 1 3 - - ND King (1970)
(2 h)
* % of count excreted in urine
IP = intraperitoneal administration
IV = intravenous administration
ND = not determined
PO = oral administration
31
Glycolic acid
In summary, glycolic acid metabolism is qualitatively similar in rats, non-human
p r i m a t e s and humans and follows the pathways set out in Figure 9.2.
Decarboxylation of glyoxylic acid to formic acid and CO2 does not occur
extensively in primates.
Figure 9.2: Metabolic pathways of glycolic acid
Glycolic acid HOCH2COOH
COOH
H2NCH2COOH Glyoxylic acid OCHCOOH
Glycine COOH
Oxalic acid
+ Benzoic Formic acid HCOOH + CO2
acid
C6H6CONHCH2COOH
Hippuric acid Carbon dioxide CO2
9.4 Elimination and excretion
The available studies of the elimination of 14C-labelled glycolic acid in animals
and humans are summarised in Table 9.2. Glycolic acid and its polar metabolites
glyoxylic and oxalic acids are excreted in the urine, whereas the metabolite
carbon dioxide is eliminated through the lungs. The amino acid glycine is
normally preserved by the body but forms conjugates with aromatic acids such as
benzoic acid that facilitate their excretion in the urine. This explains the high
elimination as hippuric acid in the study in which glycolic acid was co-
administered with sodium benzoate (Weinhouse & Friedmann, 1951). The data
indicate that a substantial portion of glycolic acid is excreted unchanged in the
urine, particularly at higher dose levels, where the metabolic processes tend to
become saturated.
In pregnant rats, the elimination half-life of glycolic acid is 3 h (Carney et al.,
1997, 1999).
In humans, the elimination half-life was determined at 7-10.5 h in a small
number of patients with ethylene glycol intoxication (Jacobsen et al., 1988;
Moreau et al., 1998). The reference interval for urinary excretion of glycolic acid
in healthy men and women is in the order of 1-100 mg/24 h (Hagen et al., 1993;
Wandzilak et al., 1991).
9.5 Comparative kinetics and metabolism
The key findings characterising the kinetics and metabolism of glycolic acid in
rats, non-human primates and humans are summarised in Table 9.3.
32 Priority Existing Chemical Number 12
Table 9.3: Summary of kinetics and metabolism in rats, non-human
primates and humans
Non-human
Parameter Rats primates Humans
Absorption
? Almost complete Almost complete No data
ingestion
No direct data No data No data
? inhalation
No data No data Significant
? through skin
Main metabolites Glyoxylic acid Glyoxylic acid Glyoxylic acid
Oxalic acid Oxalic acid Oxalic acid
Carbon dioxide
Distribution volume 0.66 L/kg No data 0.56 L/kg
Route of elimination Kidney Kidney Kidney
Lung (as carbon dioxide)
Elimination half-life 3 h (pregnant females) No data 7-10.5 h
Sex differences Rate of metabolism 2 times No record No record
higher in males
33
Glycolic acid
10. Effects on Laboratory
Mammals and Other Test
Systems
Toxicology studies with glycolic acid have been conducted to characterise the
g e n e r a l toxicity of the chemical, investigate the mechanisms of oxalate
urolithiasis and of poisoning with ethylene glycol, or to determine the effects of
the chemical on the skin. In this section, the emphasis is on studies which were
conducted in accordance with Good Laboratory Practices (GLP) and employed
internationally recognised methods such as OECD's Test Guidelines (OECD,
1981 as amended)1. Where such studies were not available, other test reports or
published papers have been considered, provided they furnished enough scientific
detail to permit a critical appraisal of their findings. Studies that were excluded
from assessment because they did not meet the above criteria are listed in
Appendix 3.
In some reports, dose levels were stated in mg/kg of commercially available
solutions of glycolic acid. For purposes of comparison, these have been adjusted
for concentration and expressed in mg/kg of 100% glycolic acid, unless otherwise
indicated in the text.
10.1 Acute toxicity
10.1.1 Lethality
A number of acute lethality studies have been conducted with glycolic acid using
different routes of administration and are summarised in Table 10.1. The rat
studies were conducted in three different strains, namely Holzman (Bove, 1966),
Sprague-Dawley (DuPont, 1963, 1998a*, 1998c*), and Wistar rats (Smyth et al.,
1941).
10.1.2 Oral toxicity
The acute toxic effects from a single intragastric administration of glycolic acid
or sodium glycolate included loss of appetite, weight loss, gastrointestinal
irritation, kidney and liver damage and neuromuscular disturbances. Clinical
signs comprised loss of appetite in all species, ataxia and flaccid paralysis in
mice, lethargy, noisy breathing, ocular discharge and prostrate posture in rats, and
vomiting, ataxia and convulsions in cats. Generally, the signs took about an hour
to appear, progressed in intensity during the next 24 h, and either subsided
gradually over several days or worsened and proved fatal (DuPont, 1998a*,
1998d*; Laborit et al., 1971; Riker & Gold, 1942).
The cat was the only species in which a no observed adverse effect level
(NOAEL) was determined (Riker & Gold, 1942). Following oral administration
1
These studies are marked with an asterisk ().
34 Priority Existing Chemical Number 12
of sodium glycolate by gavage, 5/5 animals dosed with 100 mg/kg showed no
signs of intoxication, whereas 4/5 animals dosed with 250 mg/kg showed mild
weakness, ataxia and anorexia. As such, the NOAEL was 100 mg/kg sodium
glycolate corresponding to 78 mg/kg glycolic acid.
In rats dosed with 70% glycolic acid by gavage, there were signs of dose-related
gastric irritation such as acute ulcerative and haemorrhagic gastritis (DuPont,
1963) or distended and discoloured stomachs lined with a black, unidentified
fluid (DuPont, 1998a*). In one rat study, microscopic examination of the liver
revealed hepatocyte necrosis in the paraportal region, increased mitosis and
cytoplasmic eosinophilia (DuPont, 1963). In rats and guinea pigs, kidney weight
was increased in surviving animals and microscopic examination revealed
interstitial nephritis and calcium oxalate crystals in the tubules (Bove, 1966;
DuPont, 1963; Smyth et al., 1941). In cats, tubular degeneration and increased
blood urea nitrogen and creatinine were found (Riker & Gold, 1942).
Table 10.1: Summary of acute lethality studies
Route Species Results Comments Reference
Oral Mouse (f) ALD = 1120 mg/kg GA 70% technical DuPont
grade by gavage (1998d)*
Mouse (m) ALD = 840 mg/kg GA
Rat (f) LD50 = 5000 mg/kg GA 25% analytical Bove (1966)
grade by gavage
LD50 = 2968 mg/kg GA 70% technical DuPont
Rat (m)
grade by gavage (1963)
LD50 = 1357 mg/kg GA 70% technical DuPont
Rat
grade by gavage (1998a)*
LD50 = 1950 mg/kg GA 5% commercial Smyth et al.
Rat (m)
grade by gavage (1941)
5% commercial Smyth et al.
Guinea LD50 = 1920 mg/kg GA
grade by gavage (1941)
pig
9.8% solution by Riker & Gold
Cat ALD = 500 mg/kg NaG
gavage (1942)
Dermal No data
3
Aerosolised 70% DuPont
LC50 > 3640 mg/m GA
Inhalation Rat (f)
technical grade (1998c)*
3
Rat (m) LC50 = 2520 mg/m
GA
Intra- Cat ALD = 1000 mg/kg 9.8% solution Riker & Gold
venous NaG (1942)
LD50 = 2000 mg/kg Unknown purity Laborit et al.
Intra- Mouse
NaG (1971)
peritoneal
ALD = approximate lethal dose (the lowest dose LC50 = median lethal concentration
administered that causes mortality in at least one animal) LD50 = median lethal dose
f = females only m = males only
GA = glycolic acid NaG = sodium glycolate
10.1.3 Inhalation toxicity
Groups of 5 male and 5 female or 10 male Sprague-Dawley rats were exposed
nose-only to aerosols of a 70% solution of technical grade glycolic acid for a
single 4-h exposure period (DuPont, 1998c*). The aerosols provided exposure
levels equal to 0, 420, 1470, 2660 and 3640 mg/m3 glycolic acid. The animals
were weighed and observed for clinical signs for 14-15 days before they were
35
Glycolic acid
sacrificed for gross pathological examination and microscopy of the nose, larynx,
pharynx and lungs. Satellite groups of 5 male rats each were sacrificed
approximately 24 h after exposure for microscopic examination of the same
organs.
Time of death varied from 0-12 days post-exposure. Weight loss and clinical
signs were evident at all dose levels and increased in severity with concentration.
Immediately post-exposure, gasping, noisy breathing, hunched posture, and nasal
and ocular discharges were observed. During the recovery period, in addition to
the effects seen in the immediate post-exposure period, clinical signs included
lethargy, sore eyes, sore nose, sore chin, vocalisation, hair loss, and stained
and/or wet fur and/or perineum. No target organ gross changes were observed,
whereas microscopic changes including dose-related degrees of ulceration and
inflammation were observed in the mucosal membranes lining the larynx and the
nose, with mild subacute-chronic inflammation of the lungs.
10.1.4 Intravenous toxicity
Intravenous administration of a solution of sodium glycolate to cats produced
signs that were similar in type, strength and time course to those observed after
oral administration of the same chemical (Riker & Gold, 1942).
10.2 Corrosivity and irritation
A number of in vivo skin and eye corrosivity and irritation studies have been
conducted with glycolic acid in different formulations and are summarised in
Table 10.2.
Table 10.2: Summary of in vivo corrosivity and irritation studies
Organ Species Test substance Results Reference
Skin Rabbit 99% cosmetic grade Corrosive DuPont (1993a)*
Rabbit 70% technical grade Corrosive DuPont (1993b)*
Rabbit 70% cosmetic grade, Mild irritant DuPont (1998f)
adjusted to pH 7.0
Rabbit 10, 30 and 40% Mild to moderate DuPont (1994)*
cosmetic grade, irritant
adjusted to pH 3.5
Rabbit 57% technical grade Irritant Hoechst (1984a)*
Rabbit 15, 25 and 50% in Non-irritant Natura Biss?br>
cosmetic products, pH (1996)
4.5
Mini pig 50% cosmetic grade Sloughing of the Moy et al. (1996b)
epidermis
70% cosmetic grade Epidermal and
dermal necrosis
Eye Rabbit 64% technical grade Corrosive DuPont (1977)
Rabbit 57% technical grade Corrosive Hoechst (1984b)*
Rabbit 10% cosmetic grade Moderate irritant Ohno (1999)*
Rabbit 4 and 8% in cosmetic Non- or practically Tox Monitor
products, pH 3.8-4.0 non-irritant (4%) Laboratories
(1994a-h, 1995)*
Minimal to mild
irritant (8%)
36 Priority Existing Chemical Number 12
10.2.1 Skin
Glycolic acid has been evaluated for skin corrosion/irritation potential in rabbits
in several studies conducted according to OECD Guideline No. 404 or similar
protocols (DuPont 1993a*, 1993b*, 1994*; 1998f; Hoechst, 1984a*). Crystalline
glycolic acid and a solution containing 70% glycolic acid at its natural pH (<0.5)
caused visible necrosis through the epidermis and into the dermis after a 1-h
exposure and were classified as corrosive. Solutions containing 10%, 30% or
40% glycolic acid at pH 3.5, 57% glycolic acid at pH 1.8 or 70% glycolic acid at
pH 7.0 caused slight to moderate erythema, no or slight oedema, and no or
superficial sloughing and skin necrosis after a 4-h exposure. When tested in
rabbits according to European guidelines, a commercial face cream and two
peeling solutions containing 15, 25 and 50% glycolic acid at pH 4.5 produced
some erythema but no oedema and were classified as non-irritant (Natura Biss?
1996).
In mini pigs exposed to 50% and 70% glycolic acid, histological examination of
the skin 8 h after application showed epidermal sloughing and epidermal and
dermal necrosis respectively (Moy et al., 1996b).
Solutions of glycolic acid have also been evaluated for skin corrosion potential in
a non-biological system using the InVitro International Corrositex assay1
(DuPont, 1997a-b). Solutions containing 30%, 50% and 70% cosmetic grade
glycolic acid at their natural pH and a 70% solution adjusted to pH 3 were
assigned to Packing Group II (moderate corrosives), whereas a 70% solution
adjusted to pH 11 was assigned to Packing Group I (severe corrosive).
10.2.2 Eyes
Pure glycolic acid has been evaluated for eye corrosion/irritation potential in
rabbits in three studies conducted according to protocols consistent with OECD
Guideline No. 405. A solution containing 64% glycolic acid (pH not reported)
caused severe, irreversible effects including total blindness and was classified as
corrosive (DuPont, 1977). A solution containing 57% glycolic acid at pH 1.8
caused irreversible opacity and vascularisation of the cornea in addition to
reversible conjunctival erythema and oedema (Hoechst, 1984b*), whereas a 10%
solution at pH 1.8 was classified as moderately irritating (Ohno, 1999*). A total
of 12 commercial creams or lotions containing 4% or 8% glycolic acid at pH 3.8-
4.0 were reported to be at worst mildly irritating, even when they were not rinsed
off after the standard exposure time of 15 sec (Tox Monitor Laboratories, 1994a-
h*, 1995*).
When tested in a non-biological system, several commercial cosmetics containing
2-10% glycolic acid at pH 3.5-5.5 produced readings similar to substances known
to be mild to severe irritants to the eye (Avon Products, Inc., 1995).
1
Corrositex is a rapid in vitro test that permits assignment of UN Packing Group classes to corrosive
(class 8) substances. The method is accepted by several transport agencies, including the Federal Office
of Road Safety.
37
Glycolic acid
10.3 Sensitisation
The potential of technical grade glycolic acid to induce contact skin sensitisation
in guinea pigs was assessed by the modified Buehler method (White Eagle,
1998*). The chemical was dissolved in normal saline and applied repeatedly to
clipped intact skin under occlusion. No delayed responses were observed.
10.4 Repeated dose toxicity
10.4.1 Oral toxicity
Subchronic toxicity with immunotoxicity and neurotoxicity evaluation
A 3-month oral gavage study was conducted in Sprague-Dawley rats given
solutions containing technical grade glycolic acid at doses of 0, 150, 300 or 600
mg/kg/day of glycolic acid (DuPont, 1999a*). Each dosage group was divided
into subchronic toxicity, immunotoxicity, neurotoxicity, and reproductive toxicity
subsets (10 animals/sex/subset/dose level). The findings in the reproductive
toxicity subset are reviewed in section 10.5.2.
Body weights and individual food consumption were determined weekly. Clinical
observations were recorded at weighing and by daily cage-site examinations.
Ophthalmoscopic examinations were conducted on all rats prior to the start of the
study and on surviving subchronic toxicity rats on test day 86. Clinical pathology
evaluations were performed on subchronic toxicity animals near the middle and
the end of the study. In the immunotoxicity subset, humoral immune function was
evaluated. Rats in the neurotoxicity subset underwent functional observation
battery and motor activity assessments once prior to study start, then near the
beginning, middle and end of the study. All rats were given a gross pathological
examination and selected tissues were examined microscopically.
Table 10.3: Mean body weight, body weight gain, food consumption and
food efficiency in rats given glycolic acid by mouth for 3 months (DuPont,
1999a*)
Dose level (mg/kg/day)
Parameter 0 150 300 600
Mean body weight (g)
? 553.3 539.6 510.6* 481.0*
male rats
318.1 306.2 298.4* 284.1*
? female rats
Overall body weight gain (g)
? 323.1 308.3 280.4* 252.5*
male rats
153.7 140.0 131.6* 119.8*
? female rats
Mean daily food consumption (g)
? 28.1 27.8 26.5* 25.2*
male rats
20.6 20.0 19.5 18.7*
? female rats
Mean food efficiency
? 0.126 0.121 0.116* 0.110*
male rats
0.081 0.077 0.074* 0.070*
? female rats
* Significantly different from controls (p <0.05).
38 Priority Existing Chemical Number 12
Mean body weight at day 92 and overall mean body weight gain, food
consumption and food efficiency (weight gain divided by food consumption) over
days 1-92 are shown in Table 10.3. There were no clinical signs indicative of
systemic toxicity, although irregular respiration or lung noise attributed to
aspiration of glycolic acid occurred in all treatment groups. There were no
treatment-related ophthalmological findings in any of the groups. In all subsets
combined, there were 2 deaths from kidney lesions, both in high-dose males.
Eight animals died as a result of dosing accidents and one from a disease that was
unrelated to the substance.
In the subchronic toxicity subset, blood neutrophils were slightly increased in
male rats treated with 300 and 600 mg/kg/day, that is, the groups with kidney
lesions and the most severe cases of pulmonary inflammation. Increased serum
urea nitrogen, creatinine and phosphorous and an increased volume of less
concentrated urine, which are indicative of renal pathology, were also observed in
male rats treated with 300 and 600 mg/kg/day.
In males, absolute/relative kidney weights were increased by 6/15% at 300
mg/kg/day and by 14/25% at 600 mg/kg/day. Gross and microscopic kidney
lesions were observed in male rats at 300 or 600 mg/kg/day. These included dose-
related increases in the incidence of dilatation of the renal pelvis, oxalate crystal
nephrosis, unilateral hydronephrosis and hyperplasia of the transitional cell
epithelium of the renal pelvis. In addition, there were microscopic lesions in the
respiratory tract in both sexes in all treatment groups. These were compatible
with broncho-pulmonary irritation and most likely the result of aspiration of
glycolic acid.
In the immunotoxicity subset, the animals were inoculated with sheep red blood
cells on day 23 and sacrificed on day 29. Serum was collected and tested for
specific antibody formation and the spleen and thymus were weighed. There were
no treatment-related changes in any of these parameters.
In the neurotoxicity subset, functional tests included forelimb and hindlimb grip
strength, footsplay and a series of quantified observations of behaviour and motor
activity. In addition, a histopathological examination was conducted on nervous
system and skeletal muscle tissue specimens from 6 animals/sex from the control
and high-dose groups that underwent whole body perfusion fixation at sacrifice.
There were no substance-related microscopic observations or changes in the
functional test parameters.
In conclusion, this study determined an overall NOAEL equal to 150 mg/kg/day,
based on body weight, body weight gain, food consumption and food efficiency
in both sexes and on kidney lesions in males. There was no indication of
immunotoxicity or neurotoxicity in animals treated with up to 600 mg/kg/day for
4 and 13 weeks respectively.
Special studies
A number of feeding studies have investigated the effects of glycolic acid on the
kidneys and the metabolism of lipids.
I n male rats fed diets with 2-3% glycolic acid (approximately 200-300
mg/kg/day) for 3-6 weeks there was a significant increase in kidney weight and in
kidney content and urinary excretion of oxalic acid, with deposition of calcium
39
Glycolic acid
oxalate calculi in the renal tubules, pelvis and papilla, the ureters, and urinary
bladder (Chow et al., 1975, 1978; Richardson, 1965, 1967). Rabbits and dogs
were considerably less sensitive to the nephrotoxic effects of the chemical
(DuPont, 1940; Silbergeld, 1960).
In mice and rats fed diets with 1.3-3% glycolic acid (approximately 130-450
mg/kg/day) for 6-30 days there were significant changes in lipid metabolism in
the liver and kidneys (Crane et al., 1980; Saravanan et al., 1995; Subha &
Varalakshmi, 1993; Sumathi et al., 1993). The changes included increased
catabolism of triglycerides, neutral lipids and phospholipids, increased levels of
total and esterified cholesterol and increased lipid peroxidation. Glycolic acid
also decreased the activity of the enzymes catalase, superoxide dismutase and
gluthathione peroxidase and the content of reduced glutathione, total thiols and
ascorbic acid. In addition, glycolic acid has been shown to stimulate the
metabolism of ethanol in isolated rat hepatocytes as well as in intact rats (Harris
et al., 1982; Oshino et al., 1975).
These metabolic effects may be related to the induction of peroxisomal enzymes
and/or the generation of hydrogen peroxide from the oxidation of glycolic acid to
g l y o x y l i c acid by glycolic acid oxidase. Hydrogen peroxide can induce
peroxidation of unsaturated fatty acids and is a co-substrate for catalase, which is
one of three enzymes that catalyse the oxidation of ethanol to acetaldehyde.
10.4.2 Inhalation toxicity
Groups of 10 male Sprague-Dawley rats were exposed to nasal inhalation of
aerosolised 70% technical grade glycolic acid at levels providing exposures equal
to 0, 160, 510 and 1400 mg/m3 glycolic acid for 6 h per day, 5 days per week for
2 weeks, with a 2-week recovery period for 3-5 animals per group (DuPont,
1983).
The highest level exposures were terminated after the 8th exposure. In the
highest dose group, 7 rats were sacrificed in extremis 0-12 days after the 8th
exposure. In the middle dose group, one animal died 13 days after the 10th
exposure. In the 510 and 1400 mg/m3 groups, findings included significant
weight loss; decreased absolute liver, spleen, kidney and thymus weights; and
dose-related clinical signs such as laboured breathing, noisy breathing, ruffled
and discoloured fur, red and clear nasal and ocular discharges and general
weakness. At 510 mg/m3, urine volume was decreased and serum AST activity
was increased. Serum protein, urine volume and pH were decreased and serum
ALT and AST increased at 1400 mg/m3 . All of these clinical chemistry
measurements reverted to normal at the end of the recovery period. At the end of
the exposure period, the only gross pathological abnormality was a distended
gastrointestinal tract and small spleen and thymus in the highest dose group.
Microscopically, a very mild, diffuse liver cell degeneration was found in all dose
groups. Atrophy and degeneration of the thymus were noted in the intermediate
and high dose animals.
The only effect seen at 160 mg/m3 was a very mild, diffuse hepatocellular
degeneration in 1/10 animals by the end of the 2-week recovery period. Based on
the steepness of the dose-response curve (disappearance of mortality, weight loss
and clinical signs with concentration), 160 mg/m3 was considered practically a
no-effect level (DuPont, 1983). In a subsequent publication, this concentration
40 Priority Existing Chemical Number 12
was described as approaching and being essentially a NOAEL for exposure
through inhalation (Kennedy & Burgess, 1997).
10.5 Developmental and reproductive toxicity
10.5.1 Developmental toxicity studies
The developmental toxicity of glycolic acid has been investigated in rats in two
standard studies conducted by DuPont (1995a*, 1996*) and two special studies
aimed at elucidating the mechanisms of the developmental toxicity of ethylene
glycol conducted by researchers at Dow Chemical Company (Carney et al., 1996,
1997, 1999). All studies were conducted in compliance with GLP. In this section,
structural abnormalities in the foetuses are described as malformations or
variations in accordance with the terminology used in the source documents.
The DuPont studies
The DuPont studies comprised a pilot and a main study. In both studies the test
substance was given to groups of pregnant Sprague-Dawley rats by gavage from
day 7 to day 21 of gestation and the foetuses were examined on day 22.
In the pilot study, glycolic acid (70% technical solution) was administered to 5
groups of 8 pregnant rats at dose levels of 0, 125, 250, 500, or 1000 mg/kg/day.
Chemical analysis of the gavage solutions showed these doses to be equivalent to
0, 77, 157, 332, and 697 mg/kg/day of the 100% chemical.
At 1000 mg/kg/day there was evidence of maternal toxicity, specifically lung
noise, abnormal gait, stained and wet fur and increased salivation. Lung noise
was also heard in two rats at the 500 mg/kg/day dose and there was also wet fur.
In both groups maternal body weight decreased during the first few days (days 7-
9) while in the other groups and controls there was increased weight. Final
maternal body weight minus the weight of the products of conception was also
decreased in the 1000 and 500 mg/kg/day groups. There were no remarkable
post-mortem or clinical chemistry findings in any of the dams.
There was a significantly increased incidence of resorptions at 1000 mg/kg/day
(1.5%) compared to controls (0.4%). At 1000 and 500 mg/kg/day mean foetal
weight was significantly decreased by 18% and 9% respectively. At the 1000
mg/kg/day dose there were 6 litters containing 74 foetuses. Three of the foetuses
had major malformations (1 septal defect (1.4%) and 2 cases of gastroschisis
(2.7%)) and 4 (5.4%) had hydrocephaly. Twenty-two foetuses had skeletal
malformations, mainly fused ribs and fused or hemi-vertebrae. At 500 mg/kg/day
there were 69 foetuses from 5 litters. Only one foetus (1.4%) had hydrocephaly.
The incidence of retarded ossification was significantly higher at 1000 and 500
mg/kg/day than in the controls (64% and 77% compared to 53%). At 250 and 125
mg/kg/day there were 87 and 122 foetuses respectively but no malformations and
the incidence of retarded ossification was lower than in the controls. In the
controls there were 102 foetuses, 5 of which had skeletal malformations similar to
those seen at 1000 mg/kg/day. The study report did not provide historical control
data for the DuPont laboratory. However, a collection of historical control data
f o r the same strain (Sprague-Dawley CRL) obtained from a number of
laboratories gives the incidence of septal defects, gastroschisis and hydrocephaly
as 0.016, 0.01 and 0.02% respectively (Hood, 1997).
41
Glycolic acid
Overall, the pilot study showed that at 1000 mg/kg/day glycolic acid (70%
technical solution) caused a significantly increased incidence of embryonic death,
foetal growth retardation and congenital malformations. At 500 mg/kg/day
glycolic acid (70% technical solution) there was a significant reduction of mean
foetal weight and a significant increase of retarded sternebral ossification, that is,
signs of foetotoxicity but no teratogenic effects. As there was evidence of
maternal toxicity at both these dose levels, the authors concluded that the
maternal and developmental NOAEL was 250 mg/kg/day (70% technical
solution) and that technical grade glycolic acid is unlikely to be uniquely toxic to
the rat conceptus.
In the main study, groups of 25 pregnant rats were dosed with cosmetic grade
glycolic acid (99.6%) at dose levels of 0, 75, 150, 300 or 600 mg/kg/day.
At 600 mg/kg/day, there was evidence of maternal toxicity with loss of maternal
weight over the first few days of dosing and decreased food intake. Some of the
high dose animals showed clinical signs of toxicity including lung noise,
abnormal gait and irregular respiration. In the 300 mg/kg/day group 2 rats had
noisy breathing. There were no remarkable post-mortem findings in any of the
dams.
Mean foetal weight was significantly decreased at 600 mg/kg/day (by 13%) and
the incidence of total malformations was significantly increased (10.6%)
compared to controls (0.8%). There were 9 major malformations (heart septal
defects (3), microphthalmia (1), absent kidney (1), cleft palate (1), gastroschisis
(2) and omphalocoele(1)) in 352 high dose foetuses compared to 2 cases of septal
defects in 366 control foetuses. There were also 5 foetuses (all from one litter)
with distended brain ventricles and 3 foetuses with clubbed legs. Twenty-two of
3 5 1 foetuses examined had skeletal malformations mainly affecting the
sternebrae and vertebrae. At the 300 mg/kg/day dose there was marginal evidence
of an increase in the skeletal malformations of fused ribs and fused vertebrae. In
the remaining treatment groups, the incidence of malformations was similar to the
controls. The incidence of foetuses with retarded skeletal development was
31.5% in the controls, 41.8% at 75 mg/kg/day, 32.1% at 150 mg/kg/day, 42.0% at
300 mg/kg/day and 67.9% at 600 mg/kg/day. The study report did not provide
historical control data for the DuPont laboratory. However, a collection of
historical control data for the same strain (Sprague-Dawley CRL) obtained from a
number of laboratories gives the incidence of septal defects, microphthalmia,
absent kidney, gastroschisis and omphalocoele as 0.016, 0.027, 0.003, 0.01 and
0.01% respectively (Hood, 1997).
The main study indicated that at maternally toxic doses (600 mg/kg/day) glycolic
acid caused an increased incidence of foetal growth retardation and skeletal
malformations, mainly affecting the sternebrae and vertebrae. The dose of 300
mg/kg/day was not associated with foetal growth retardation or major soft tissue
malformations, but there was a marginal (p = 0.0555) increase in the incidence of
two skeletal malformations and marginal (p = 0.0553) evidence of maternal
toxicity. The authors concluded that both the maternal and the developmental
NOAEL was 150 mg/kg/day and that glycolic acid is unlikely to be uniquely
toxic to the rat conceptus.
In a subsequent publication of key findings from the DuPont studies, the
investigators stated that while this was a conservative interpretation, they
42 Priority Existing Chemical Number 12
believed that the marginally significant maternal and foetal effects observed at
300 mg/kg/day represented the bottom of the dose-response curve for the
following reasons: (1) Noisy breathing or wheezing as a maternal observation is
rarely, if ever, seen in control group animals and was consistent with effects seen
at 600 mg/kg/day; (2) lung noise/wheezing was statistically significantly
increased at 500 mg/kg/day 70% solution and higher in the pilot study; (3) the
skeletal malformations observed were consistent with malformations observed at
600 mg/kg/day; (4) skeletal effects were also observed at 500 mg/kg/day 70%
solution and above in the pilot study (Munley et al., 1999).
Others have argued that the fused ribs and fused vertebrae observed in the 300
mg/kg/day dosage group in the main study were spontaneous in origin and
unrelated to exposure to glycolic acid as the litter and foetal incidences were not
significant and the pattern of effect was not dose-dependent (Christian, 1999).
For the purposes of this assessment, a NOAEL of 150 mg/kg/day is taken forward
for assessment of the significance of risk to human health of exposure to glycolic
acid.
The Dow studies
Ethylene glycol, which is metabolised to glycolic acid, is known to induce
skeletal malformations when given orally in high doses to pregnant rats and mice
(Carney, 1994).
Carney et al. (1996) used a Sprague-Dawley derived rat gestation day 10.5 whole
embryo culture system to discriminate between the developmental effects of
ethylene glycol, the metabolite glycolic acid acting indirectly via an acidic pH
and a direct chemical toxicity of the glycolate anion. In one experiment, groups of
10 embryos were incubated at 37癈 for 46 h in media containing 0.5, 2.5, 12.5,
25.0, or 50.0 mM ethylene glycol or glycolic acid (corresponding to 38-3800
mg/L glycolic acid) or 1.0 mM sodium valproate as a positive control. In another
experiment, groups of 12 embryos were cultured under similar conditions in
control media adjusted to pH 6.74 or 7.41, medium containing 12.5 mM (950
mg/L) glycolic acid at pH 6.74, or medium containing 12.5 mM sodium glycolate
at pH 7.41. At the end of the incubation period, embryos were evaluated for
v i a b i l i t y , morphology (using an investigator-blind system), growth (by
measurement of the visceral yolk sac diameter, crown-rump length and head
length) and protein content in the body and visceral yolk sac.
In the first experiment, ethylene glycol at all concentrations and glycolic acid at
0.5 mM and 2.5 mM appeared to be without effect. Half the embryos in the 25
mM and all embryos in the 50 mM glycolic acid group were non-viable. In the
12.5 mM and 25 mM glycolic acid groups, somite number, crown-rump length,
head length and embryo and visceral yolk sac protein content were significantly
reduced in a concentration-dependent manner. Furthermore, the percentage of
structurally abnormal embryos was significantly increased, with the most
commonly observed alterations being a bilateral, cyst-like enlargement of the
maxillary process and various abnormalities in the mid-facial region. In the
second experiment, somite number, crown-rump length, head length and embryo
and visceral yolk sac protein content were significantly reduced in the glycolic
acid and sodium glycolate groups compared with the pH 7.41 controls. Head
length and embryo and visceral yolk sac protein content were significantly
43
Glycolic acid
reduced in the pH 6.74 control group compared with the pH 7.41 controls. The
incidence and type of structural abnormalities in all groups are shown in Table
10.4.
Table 10.4: Summary of structural abnormalities in rat embryos exposed to
glycolic acid or sodium glycolate in vitro (from Carney et al., 1996)
1
% of embryos with abnormality of
Cranio-facial
No. abnormal/
Treatment group region Yolk sac Other
no. evaluated (%)
Control, pH 7.41 0/12 (0%) 0 0 0
Glycolic acid, 12.5 mM, 8/12 (67%)* 50 33 25
pH 6.74
Sodium glycolate, 12.5 7/12 (58%)* 58 8 0
mM, pH 7.42
Control, pH 6.74 1/12 (8%) 8 0 0
1
Some embryos had multiple abnormalities
* Statistically different from the pH 7.41 control group (p < 0.05)
The authors concluded that glycolic acid is the primary toxicant for ethylene
g l y c o l - i n d u c e d developmental toxicity in rats and that the glycolic acid
metabolite can act through an inherent toxicity of the glycolate anion as well as
via induction of metabolic acidosis.
In pregnant Sprague-Dawley derived rats, single oral doses of 2500 mg/kg
ethylene glycol or 650 mg/kg glycolic acid administered by gavage or 833 mg/kg
sodium glycolate (pH 7.4) injected subcutaneously were shown to produce
similar peak serum glycolate levels (8.4-8.8 mM, corresponding to approximately
650 mg/L glycolic acid) (Carney et al., 1997, 1999). Also, both ethylene glycol
and glycolic acid induced a clear, but mild, metabolic acidosis. These treatments,
or distilled water by gavage, were then given to 4 groups of 25 time-mated rats
from day 6 to day 15 of gestation and the foetuses were examined on day 21.
In the glycolic acid group there was clear evidence of maternal toxicity. Several
dams developed mouth breathing, noisy or deep respiration, facial soiling,
salivation and/or nasal discharge and 3 of them were sacrificed because of their
respiratory difficulties. A fourth dam was found dead on day 8 with no prior
clinical symptoms observed. At necropsy, these dams had mucoid exudate in the
nasal turbinates, blood-soiled face and nose regions, distended stomachs,
congestion of the liver, lungs and kidneys and dilated renal pelvis, indicating that
their respiratory problems might have been due to nasal reflux of small amounts
of glycolic acid as a complication of oral gavage dosing. Maternal body weight
gain was depressed compared with controls and relative kidney and absolute and
relative liver weights were increased.
In the sodium glycolate-treated dams there was little evidence of maternal
toxicity. There was no mortality, no treatment-related clinical symptoms, and
maternal bodyweight gain and organ weights were not affected, except for an
increase in absolute and relative liver weights.
In the glycolic acid group mean foetal body weight was significantly decreased
(17%) compared to controls and the resorption rate was slightly increased (5.7%)
compared to controls (2.5%) although within the historical range (3.5-14.1%).
44 Priority Existing Chemical Number 12
There were 264 foetuses of which 137 underwent visceral examination. There
was a small number of major malformations including umbilical hernia (1),
abnormal limb rotation (1), absent tail (1), diaphragmatic hernia (1) and
hydroureter (1). Seven foetuses from 4 litters had dilated brain ventricles. In 128
foetuses examined for skeletal malformations, there were 30 foetuses with
hemivertebrae, 16 with fused ribs and 30 with missing ribs and many of the
foetuses had evidence of delayed ossification. Overall, there was a significant
increase in the incidence of total malformations (23.5%) compared to controls
(0.3%).
In the sodium glycolate group mean foetal body weight was significantly
decreased (8%) compared to controls and the resorption rate was slightly
increased (4.3%) compared to controls (2.5%) although within the historical
range (3.5-14.1%). There were 314 foetuses of which 163 underwent visceral
examination. There was a small number of external malformations including
absent tail (1) and rudimentary tail (3), but no cases of dilated brain ventricles. In
1 5 1 foetuses examined for skeletal alterations, there was 1 foetus with
hemivertebrae, none with fused ribs, 20 with wavy ribs, 1 with missing and 4
with calloused ribs and many of the foetuses had evidence of delayed ossification.
Overall, there was a small, but significant increase in the incidence of total
malformations (3.8% versus 0.3% in controls), whereas the incidence of delayed
ossification of the skull, vertebrae and ribs and irregular pattern of ossification of
the sternebrae was markedly increased (23.8, 92.7, 39.7 and 5.3% respectively)
compared to controls (8.6, 32.2, 2.0 and 0.7% respectively).
According to the authors, these findings clearly showed that some of the well-
known developmental effects of ethylene glycol can be induced by the glycolate
anion in the absence of maternal metabolic acidosis. However, as the incidence
and severity of skeletal abnormalities were considerably greater in the glycolic
acid than in the sodium glycolate group, they concluded that metabolic acidosis is
a major contributing factor in the developmental toxicity of large oral doses of
ethylene glycol.
10.5.2 Reproductive toxicity studies
The subchronic oral toxicity study in rats described in section 10.4.1 included a
subset of 10 animals/sex/dose level given 0, 150, 300 or 600 mg/kg/day of
glycolic acid for 18-22 weeks (DuPont, 1999a*). These animals were mated on or
after day 97. Pups in each litter were counted and weighed as soon as possible
after delivery and on days 7, 14 and 21, when they were sacrificed and underwent
gross pathological evaluation. Parental rats were sacrificed on day 131 (males) or
o n days 142 through 153 (females) and subjected to gross pathological
examination. The testes of each male rat were weighed and the uteri of female
rats examined for the presence and number of implantation sites.
There were no dose-related differences in mating, fecundity, or gestation indices,
implantation efficiency, or gestation length in rats at any dose level compared to
controls. In the males, an increase in the relative testis weight was observed in all
dose groups, but attributed to the decrease in body weight at all dose levels. Four
high-dose males had gross and microscopic kidney lesions.
Compared to controls, the number of pups born per litter was 106% at 150
mg/kg/day, 92% at 300 mg/kg/day and 88% at 600 mg/kg/day, resulting in a
45
Glycolic acid
statistically significant trend being assigned to the 300 and 600 mg/kg/day
groups. The mean pup weight was not adversely affected at any time during
lactation. There were no dose-related differences in the incidences of any clinical
signs among the litters or in mortality or gross observations in the pups.
As such, there was no indication of impaired fertility or of retarded neonatal
growth during lactation in animals treated with up to 600 mg/kg/day of glycolic
acid for 18-22 weeks.
10.6 Genetic toxicity
10.6.1 In vitro
Gene mutation assays
At concentrations varying from 1-10,000 礸 per plate, glycolic acid was not
mutagenic in Salmonella typhimurium strains TA97a, TA98, TA100, TA1535,
TA1537 and TA 1538 or in Escherichia coli strain WP2 uvrA (pKM101) with
a n d without metabolic activation (DuPont, 1998b*; Hoechst, 1993*;
Microbiological Associates, 1994b*).
Technical grade glycolic acid was tested for induction of forward mutation at the
TK locus of L5178Y mouse lymphoma cells (Covance, 1998*). There were no
increases in mutant frequency at or below concentrations of 10mM (760 mg/L),
w h e r e a s concentrations from 32.9-65.8 mM (2500-5000 mg/L) produced
increases in mutant frequency in the presence of metabolic activation.
Assay for chromosomal aberration
When tested in Chinese hamster ovary cells at concentrations ranging from 625-
5000 mg/L at pH 6.5, toxicity (mitotic inhibition) at the highest concentration
level was <10% with and 43% without metabolic activation (Microbiological
Associates, 1994a*). The percentage of cells with chromosomal aberrations in the
test groups, both with and without metabolic activation, was not statistically
increased compared to the solvent control. Clastogenic responses to mitomycin C
and cyclophosphamide confirmed the sensitivity of the assay.
10.6.2 In vivo
Bone marrow micronucleus test
Groups of Crl:CD-1 (ICR) BR mice were given glycolic acid (70% technical
grade diluted in water) by gavage at dose levels of 0, 210, 420, or 840 mg/kg
(males), or 0, 280, 560, or 1120 mg/kg (females) (DuPont, 1998d*). Bone
marrow smears were prepared from 5 mice/sex from the control and all treatment
groups 24 h post-dosing and from the control and high-dose treatment groups 48
h post-dosing. Two thousand polychromatic erythrocytes per animal were
evaluated for micronuclei. There were no statistically significant increases in
micronucleated polychromatic erythrocytes in any of the exposed groups at either
time point.
Five/15 males and 3/13 females from the highest dose groups were found dead 1-
2 days post-dosing. Treatment-related clinical signs included lethargy,
46 Priority Existing Chemical Number 12
moribundity and/or abnormal gait and persisted for up to 2 days post-dosing. At
the 48-h time point, there was an 18-25% reduction in the proportion of
polychromatic erythrocytes per 1000 erythrocytes in smears from high-dose
males and females respectively. Although the differences were not statistically
significant, the authors concluded that the finding might be indicative of bone
marrow toxicity.
10.7 Carcinogenicity
No carcinogenicity studies with glycolic acid were available for assessment.
10.8 Other test systems
Bruschi & Bull (1993) assessed the cytotoxicity of glycolic acid by measuring the
proportion of total lactate dehydrogenase activity released into the medium from
i s o l a t e d hepatocytes exposed to the chemical. When added to cultured
hepatocytes from B6C3F1 mice or Sprague-Dawley rats in a pH 7.4 solution,
glycolic acid had no effect at a concentration of 1.0 mM (76 mg/L) but produced
significant release of the enzyme at 5.0 mM (380 mg/L). Glycolic acid also
produced a dose-related depletion of intracellular reduced glutathione. In
hepatocytes from animals pre-treated with clofibrate to induce peroxisome
proliferation, there was a significant increase in cytotoxicity, which was
paralleled by an increased depletion of reduced glutathione and a dose-dependent
increase in intracellular formation of oxidised glutathione. As the conversion of
reduced glutathione to oxidised glutathione requires hydrogen peroxide, these
findings indicate that the cytotoxicity of glycolic acid to isolated liver cells is
associated with the production of hydrogen peroxide that occurs concomitantly
with its oxidation (see section 9.3). It has subsequently been demonstrated that
clofibrate-induced peroxisome proliferation stimulates the oxidation of glycolic
acid to oxalic acid and the urinary excretion of oxalate in rats in vivo (Sharma &
Schwille, 1997).
10.9 Special skin investigations
10.9.1 Effects on the epidermis
Hood et al. (1996, 1999) studied the effect of two oil-in-water emulsions
containing 5% or 10% glycolic acid at pH 3.0 on stratum corneum turnover time,
epidermal thickness and percutaneous absorption of water, hydroquinone and
musk xylol in hairless guinea pigs.
The emulsions, or a commercial moisturising lotion, were applied to the backs of
3 groups of 2-3 animals once daily 6 days per week. After 2 weeks, the stratum
corneum was labelled with fluorescent dansyl chloride by a standard technique
(Jansen et al., 1974). The clearance of the fluorescence was examined daily under
UV illumination and treatment continued until all fluorescence had disappeared.
Stratum corneum turnover time was defined as the time in days between staining
and fluorescence disappearance. Compared to the vaseline-treated controls,
stratum corneum turnover time was reduced by 36% and 39% in the animals
exposed to 5% and 10% glycolic acid respectively.
47
Glycolic acid
In a subsequent study, 3 mg/cm2 of the 5% emulsion, 10% emulsion, or
moisturising lotion was applied to the backs of 3 groups of animals once daily 6
days per week for 3 weeks, with a 4th group of animals used as untreated
controls. At the end of the treatment period, the skin was examined visually and
skin specimens collected for microscopic examination and in vitro determination
of percutaneous absorption of 3H-labelled water or 14C-labelled hydroquinone or
musk xylol. Compared with the control lotion and untreated skin, both glycolic
acid emulsions produced some erythema and/or flaking of the skin as well as a 4-
fold increase in viable epidermal thickness and a 2-fold increase in the number of
epidermal cell layers. No significant differences in the absorption of any of the
test compounds were found for skin treated with the glycolic acid formulations or
the moisturising lotion.
In a small number of SKH-hairless-1 (albino) female mice treated once daily 5
days a week for 6 months with a 30% solution of glycolic acid in water (pH not
specified), microscopic examination of the exposed skin revealed marked cellular
atypia and intercellular oedema of the epidermis, with a dense lymphocytic
infiltrate in the dermis accompanied by an increased amount of fine, curled elastic
fibres (Kligman & Kligman, 1998).
10.9.2 Effects on the skin barrier
Two experimental oil-in-water emulsions containing 5% glycolic acid at pH 3 or
7 and two commercial products containing 5% or 10% glycolic acid at pH 2.5 and
3.5 respectively were compared for their effects on the barrier properties of
hairless guinea pig skin (FDA, 1996). Steady-state 3H-water absorption through
the skin was measured in vitro following 24-h in vivo exposure to the test
s u b s t a n c e s and the permeability constant was calculated. The average
permeability constant for all formulations was determined at 7.5 x 10-4 cm/h,
which was significantly higher that the permeability constant of 4.6 x 10-4 cm/h in
untreated controls.
10.9.3 Effects on the dermis
Solutions of 50% and 70% glycolic acid at their natural pH (and other peeling
agents) were applied to separate sites of the shaved back skin of 2 mini pigs after
the skin had been cleansed by scrubbing it for 15 min with acetone-soaked cotton
swabs (Moy et al., 1996b). The quantity applied is not reported and there was no
negative (vehicle) control. Skin biopsies were taken from each site at 8 h, 7 days
and 21 days after application and examined microscopically. At 8 h, there was
some epidermolysis (small blebs in the epidermis) at both glycolic acid sites. In
addition, there was sloughing of the epidermis at the 50% site and epidermal and
dermal necrosis and a slight inflammatory infiltrate at the 70% site. At 7 and 21
days, both sites showed thickening of the granular layer of the epidermis,
markedly thickened collagen fibres in the upper dermis and a slight inflammatory
infiltrate. Compared with other peeling agents included in the test (phenol and
trichloroacetic acid), 70% glycolic acid was reported to have induced a
comparable amount of collagen deposition with less inflammation of the skin.
Twelve hairless mice (Hr+/kud) were treated twice daily for 14 days on the back
area with 200 礚 of a solution of 10% glycolic acid (pH 3.9), 10% lactic acid (pH
6.0), or a vehicle control (Kim et al., 1998). Twenty-four hours after the final
48 Priority Existing Chemical Number 12
application, skin specimens were taken for microscopic examination and RNA
extraction. Microscopically, the glycolic and lactic acid sites had a thinner
epidermis and a thicker dermis and appeared to contain more collagen than the
control sites. RNA analysis revealed 2 pro -1 (I) collagen mRNA transcripts,
which appeared to be expressed at a higher level in skin from glycolic acid sites
compared with the lactic acid and vehicle control sites. No statistical analysis was
reported.
Three studies were conducted in SKH-hairless-1 (albino) mice which were
irradiated thrice weekly for 10 weeks with UV light to photoage the skin and then
treated with various glycolic acid formulations. A commercial glycolic acid lotion
(10%, pH 3.8) applied once daily 5 days a week for 10 weeks did not induce any
statistically significant deposition of new subepidermal collagen or type III
p r o c o l l a g e n and did not increase skin content of soluble or insoluble
hydroxyproline (Kligman et al., 1996). Treatment with a 15% glycolic acid oil-
in-water emulsion (pH not specified) once daily for 10 weeks resulted in a
significant increase of about 60% in the thickness of the upper dermis and in
collagen synthesis as measured by incubating homogenised skin specimens with
3
H-proline in vitro (Moon et al., 1999). Five fortnightly treatments with a highly
acidic solution containing 50% or 70% glycolic acid produced concentration-
r e l a t e d epidermal thickening and moderate inflammation of the dermis
characterised by moderate to severe fibrosis and the presence of dense mats of
fine elastic fibres (Kligman et al., 1999).
10.10 Summary of toxicological data
Table 10.5 summarises the results of all assessed studies.
49
Glycolic acid
Table 10.5: Summary of toxicological data
Test
species and
Type of study Effects and effect levels Section
Route system
Acute toxicity
ALD = 1120 mg/kg GA 10.1.2
Lethality Oral Mouse (f)
Mouse (m) ALD = 840 mg/kg GA
Rat LD50 = 1357 mg/kg GA
Guinea pig LD50 = 1920 mg/kg GA
Cat ALD = 500 mg/kg NaG
3
Inhalation Rat (f) LC50 (4hr) > 3640 mg/m GA 10.1.3
3
Rat (m) LC50 (4hr) = 2520 mg/m GA
Intra- Mouse LD50 = 2000 mg/kg NaG 10.1.2
peritoneal
Intra- Cat ALD = 1000 mg/kg NaG 10.1.4
venous
Irritation Skin Rabbit Corrosive (70% GA) 10.2.1
Mini pig Corrosive (70% GA)
Eye Rabbit Corrosive (57% GA) 10.2.2
Sensitisation Skin Guinea pig Negative 10.3
Repeated dose toxicity
3
Subacute Inhalation Rat (m) NOAEL = 160 mg/m GA 10.4.2
Subchronic Oral Rat NOAEL = 150 mg/kg/day GA 10.4.1
Reproductive effects
Development Oral Rat NOAEL = 150 mg/kg/day GA 10.5.1
In vitro Rat embryo NOAEL = 190 mg/L GA 10.5.1
Fertility Oral Rat NOAEL = 600 mg/kg/day GA 10.5.2
Lactation Oral Rat NOAEL = 600 mg/kg/day GA 10.5.2
Genetic toxicity
Gene mutation In vitro S. typhi- Negative 10.6.1
murium
E. coli Negative
Mouse Negative
lymphoma
cells
Chromosomal In vitro Chinese Negative 10.6.1
aberration hamster
ovary cells
Bone marrow Oral Rat Negative 10.6.2
micronucleus test
ALD = approximate lethal dose LD50 = median lethal dose
f = females only m = males only
GA = glycolic acid NaG = sodium glycolate
LC50 = median lethal concentration NOAEL = no observed effect level
50 Priority Existing Chemical Number 12
11. Human Health Effects
The commercial success of glycolic acid as a cosmetic ingredient has stimulated
much research into the effects of the chemical on human skin. This section
contains a critical review of all human studies that provide meaningful data on the
nature, incidence and/or causes of adverse health effects of glycolic acid. It is
beyond the scope of this assessment to review data on the desired effects of the
chemical. In consequence, use studies that exclusively address the cosmetic or
therapeutic efficacy of glycolic acid have not been considered, but are listed in
Appendix 3 for easy reference. The citation or listing of a use study in this report
does not constitute an endorsement of its quality or results. Indeed, very few of
them are well-controlled trials conducted in accordance with Good Clinical
Practices and published in peer-reviewed scientific journals.
The available data on human health effects resulting from systemic exposure to
glycolic acid are limited to two studies conducted some 60 years ago. However,
clinical observations from cases of ethylene glycol poisoning provide well-
documented information on the potential toxic effects of glycolic acid in humans.
11.1 Systemic effects
11.1.1 From oral administration
For 4-5 consecutive days, 190-450 mg/kg/day of glycolic acid was added to the
diet of 4 patients with progressive muscular dystrophy in whom the ingestion of
glycine was followed by a definite increase in the urinary excretion of creatinine
(Milhorat & Toscani, 1936). The treatment induced a modest increase in the
output of creatinine, indicating that only a small fraction of glycolic acid was
converted to glycine (see section 9.3). When measured in 2 of the patients,
glycolic acid had no effect on urinary output of oxalic acid. There was no record
of other effects of the exposure.
In a study aimed at determining the safety of a baking powder containing partially
polymerised glycolic acid, 10 healthy volunteers ingested an average dose
equivalent to 38 mg/kg/day of the chemical for 12 (2 females and 3 males) or 36
weeks (3 females and 2 males) (DuPont, 1940). Physical examinations were done
pre-treatment and at 12 and 36 weeks; fasting urine and blood samples were
collected at regular intervals. No treatment-related signs were observed. There
were no significant changes in urine albumin, sugar, occult blood, casts, epithelial
cells, red or white blood cells, or pH, and no excessive excretion of oxalate
crystals. Blood counts and haemoglobin levels were normal throughout, and
plasma carbon dioxide combining power (which is diminished in metabolic
acidosis) stayed within the normal range.
11.1.2 From ethylene glycol intoxication
The systemic toxic effects of ethylene glycol poisoning include cardiopulmonary
and renal effects that correlate directly with blood levels of glycolic acid (Brent et
al., 1999; Davis et al., 1997; Jacobsen & McMartin, 1986; Keyes, 1998). The
51
Glycolic acid
cardiopulmonary effects include increased heart rate and ventilation and may
progress to cyanosis and coma caused by pulmonary oedema and congestive heart
failure attributed to metabolic acidosis and hypocalcaemia induced by glycolic
acid and its metabolites. At plasma glycolate levels exceeding approximately 10
mM (760 mg/L), kidney failure ensues. Urine production decreases and the urine
is of low specific gravity and contains protein, blood cells, and cylinders and/or
calcium oxalate crystals. Blood urea nitrogen and creatinine are increased and
kidney biopsies show cortical necrosis, diffuse oedema, dilated proximal tubules,
degeneration of tubular epithelium, and intra-tubular casts. These effects may
occur in the absence of calcium oxalate precipitation and it therefore appears that
glycolic acid itself, or its metabolic products other than calcium oxalate, may
have a direct toxic action on the kidneys. In most cases, the kidney lesions are
reversible, but full recovery may take 45 days or longer.
11.2 Skin effects
11.2.1 Stinging tests
Cosmetic products may elicit subjective sensations of stinging, burning or
tingling shortly after their application, particularly to the face, as a result of a
direct stimulation of sensory nerves in the skin. The stinging response is transient,
not associated with visible alterations of the skin and is not predictive of a
positive irritation test to the same chemical (Frosch, 1992).
The standard test for stinging is performed on a panel of 10-20 `stingers', that is,
healthy subjects who consistently experience acute discomfort from a 5-10%
aqueous solution of lactic acid. With a cotton wool bud, a small amount of test
substance is applied to one nasolabial fold and distilled water to the other. The
panellists then record any sensory effects on a 3-point self-rating scale every 1-2_
min for 5-15 min after the application. A product is classified as non-stinging, or
mildly, moderately, or severely stinging if the average score is <0.4, 0.4-1.0, 1.1-
2.0, or 2.1-3.0 respectively.
Smith (1996) examined the stinging potential of 9 formulations that employed the
same vehicle (water, ethanol, ethoxydiglycol and butylene glycol) but differed in
glycolic acid content and pH. As shown in Figure 11.1, although all 9
formulations were classified as mildly to moderately stinging, the stinging
potential was clearly a function of the concentration and pH of the formulation1.
In tests of 50 commercial creams and lotions containing 2-10% glycolic acid at
pH 3.25-5.5, about 42% of the products were classified as mildly and 18% as
moderately stinging (Consumer Product Testing Co., 1993b; CTFA, 1995b;
DiNardo, 1994; Morganti et al., 1996). Although there was a tendency for the
higher concentrations to cause more stinging, there were also examples of sets of
creams or lotions that differed considerably in stinging potential in spite of
identical concentrations of glycolic acid and similar pH values. Thus, the nature
and concentration of excipients also have an impact on the likelihood that a
product causes stinging.
1
Smith used a 4-point rating scale. For purposes of comparison, the average score has been converted to
correspond to the more conventional 3-point scale.
52 Priority Existing Chemical Number 12
Figure 11.1: Stinging potential of a glycolic acid lotion at various
concentrations and pH values (data from Smith (1996))
2
1.8
Glycolic acid
1.6
concentration
Average score
1.4
3.80%
1.2
7.60%
1
0.8 11.40%
0.6
0.4
0.2
0
pH = 3 pH = 5 pH = 7
11.2.2 Contact irritation tests
Cumulative irritation tests
The cumulative irritation test is a common method for testing the potential of a
cosmetic product to produce skin irritation (KRA, 1996). The test substance is
applied to the back of 10-25 healthy subjects, under either an occluded or semi-
occluded patch, and the patches are reapplied to the same site daily, usually for
14-21 consecutive days. Each site is examined visually before patch reapplication
and signs of irritation are scored on a 6-point scale. Patches are occluded until a
score of 1 (minimal erythema) is reached whereupon semi-occluded patches are
used. When a score of 3 (definite erythema and papules) is reached, the site is no
longer treated and the score of 3 is recorded for the remainder of the test. The
irritation score is calculated by adding all the scores for the product over the
duration of the test and comparing them to a maximum possible score if the
product had produced maximum irritation (score 3) at all readings. Sodium lauryl
sulphate and normal saline may be used as positive and negative controls. The
overall score, expressed in % of the theoretical maximum, is usually interpreted,
as follows: <8% = non-irritant/mild; 8-32% = probably mild in normal use; 33-
71% = possibly mild in normal use; 72-92% = experimental cumulative irritant;
>92% experimental primary irritant (Hill Top Research, 1995).
Hilltop Research (1994, 1995) conducted three separate 21-day tests on various
creams and lotions containing 4% (4 products) or 8% (10 products) glycolic acid
(pH not specified). All 4% products were classified as probably mild in normal
use. Three 8% products were classified as probably mild and the remaining 7 as
possibly mild in normal use.
In a 14-day test, in which semi-occluded patches were used throughout, the
irritation score of a 10% glycolic acid formulation was shown to be inversely
correlated with the pH of the formulation (Figure 11.2), whereas the scores of 3
formulations containing 10%, 15% or 20% glycolic acid at pH 3.8 were very low
with little difference between them (DiNardo, 1995, 1996). Of 12 commercial
creams and lotions, 5 products containing 5-10% glycolic acid at pH 2.4-3.6 were
classified as probably or possibly mild in normal use, whereas 7 products
53
Glycolic acid
containing 8-13% glycolic acid at pH 3.8-4.4 were classified as non-irritant/mild
(DiNardo, 1995). As such, the author concluded that a product's pH appears to
contribute more to its cumulative irritation potential than its glycolic acid content.
Figure 11.2: Irritation potential of a 10 % glycolic acid lotion at various
formulation pH values (data from DiNardo (1995, 1996))
90
80
Score (% of maximum)
70
60
50
40
30
20
10
0
pH = 2.0 pH = 2.5 pH = 3.0 pH = 3.25 pH = 3.8 pH = 4.4
Alfieri (1996) conducted a 14-day test on two commercial face lotions of
identical glycolic acid concentration (8.4%) and similar pH (3.3 and 4.0). One
was an oil-in-water suspension whereas the other used a non-phospholipid
liposome delivery system. Both products were found to be possibly mild in
normal use and there was little difference between them.
In the so-called mini-cumulative test, the product is applied for 4 consecutive
days only. Treatment is discontinued if a reading produces a score 2 (definite
erythema). Scoring is done 5 h after removal of the last patch. The overall score,
expressed in % of the theoretical maximum, is usually interpreted, as follows:
<15% = non-irritating; 15-25% = slightly irritating; 26-40% = mildly irritating;
41-75% = moderately irritating; >75% = severely irritating (CTFA, 1995e). In a
mini-cumulative test in 19-20 subjects of 41 commercial creams and lotions
containing 2-10% glycolic acid at pH 3.7-4.0, about 12% of the products were
rated as slightly irritating, 22% as mildly irritating, 29% as moderately irritating,
and 5% as severely irritating (CTFA, 1995e). There appeared to be no correlation
between irritation score and glycolic acid concentration or type of formulation.
Follicular irritation chest tests
The potential of a commercial gel containing 2% or 4% glycolic acid at pH 3.9 to
cause folliculitis (inflammation of the hair follicles) was tested by applying the
products or a vehicle control to the chest of groups of healthy subjects once or
twice daily for 7-14 days (CTFA, 1991c). Throughout the test period, the treated
sites were examined visually for the presence of bumps, papules or pustules. The
gel caused follicular irritation in 3/30 and 10/30 subjects treated with the 2% and
4% strength respectively. No follicular reactions were observed in 20 subjects
treated with the vehicle only.
54 Priority Existing Chemical Number 12
Other tests for irritation
Murad et al. (1995) investigated the histopathological effects of glycolic acid at 2
days, 2 weeks, 2 months and 19 months after a single application of a 70%
aqueous solution at its natural pH (0.6) to the arm of a single healthy subject. At 2
days, there was epidermolysis, necrosis of individual epidermal cells, and oedema
and a perivascular infiltrate of lymphocytes and macrophages in the dermis. At 2
weeks, the epidermis was somewhat thickened and oedema persisted in the outer
layer of the dermis. At 2 months, there were patches of thickened stratum
corneum and increased thickness of collagen fibres in the dermis. At 19 months,
all changes had reverted back to normal.
In a similar study, solutions containing 50% glycolic acid at pH 1.0 or 70%
glycolic acid at pH 0.6, 1.8, 2.25 and 2.75 were applied to different areas of the
face of 2 elderly subjects with sun-damaged skin and rinsed off 30 min later
(Becker et al., 1996). After 48 h, biopsies were obtained and processed for
microscopic examination. In case of the 70% solution, there was partial epidermal
necrosis and epidermal crusting at pH 0.6, epidermal crusting at pH 1.8, and
partial loss of stratum corneum at pH 2.25 and 2.75. The site treated with the 50%
solution (pH 1.0) had lost its stratum corneum, but had no crusting or epidermal
necrosis. The authors concluded that the irritant effect of a glycolic acid peel is
both concentration- and pH-dependent.
11.2.3 Contact sensitisation tests
The repeat insult patch test is a standard method for testing the potential of a
substance to induce allergic contact dermatitis (CIR, 1998; KRA, 1996). Various
protocols are used, but in general subjects are treated with 24-h, 48-h or 72-h
occluded and/or semi-occluded patches containing 0.1-0.2 mL of the test
formulation 2-3 days per week for a total of 5-10 applications. After a rest period
of 10-14 days, subjects are challenged by re-patching on both treated and
untreated sites and examined for the presence of erythema, papules and blisters at
1 and 24-48 h after removal of the challenge patches. A reaction to the challenge
that exceeds the reactions during the treatment phase or spreads beyond the patch
site indicates sensitisation. The so-called maximisation test is a variation in which
the sensitivity is increased by pre-treatment of the test sites with the skin irritant
sodium lauryl sulphate.
Repeat insult patch testing has been performed on a total of 23 products
containing from 0.5-50% glycolic acid at pH values ranging from 2.2-5.5, in
g r o u p s comprising from 25-198 healthy volunteers per product (AMA
Laboratories, 1993a-c, 1994; Consumer Product Testing Co., 1993a; CTFA,
1995d; Essex Testing Clinic, 1994a-i; Kanengiser et al., 1994a-b; Richerche e
Technologie Cosmetologiche, 1996). All results were negative, except in the case
of a 1.25% solution of a glycolic acid-cyclodextrin complex at pH 2.2, which
induced strong irritation in most subjects and challenge reactions suggestive of
sensitisation (Richerche e Technologie Cosmetologiche, 1996).
11.2.4 Tests for phototoxicity
Phototoxicity is defined as a non-immunological, light-induced dermatitis caused
by a photoactive chemical. It is determined by applying the test product to 2 skin
sites under occlusion for 24 h, irradiating one treated and an untreated control site
55
Glycolic acid
with UV light and comparing the degree of erythema and oedema of all 3 sites at
15 min, 24 h and 48 h post-irradiation (CIR, 1998; KRA, 1996).
Three commercial products containing 0.5-4% glycolic acid at pH 3.6-4.1 were
tested in separate groups of 10 healthy volunteers (Consumer Product Testing
Co., 1994b; CTFA, 1994e; Harrison Research Laboratories, 1994b). No evidence
of phototoxicity was observed.
11.2.5 Tests for photosensitisation
A chemical is a photosensitiser if it reacts with light to produce one or more
s u b s t a n c e s that induce allergic contact dermatitis. The standard test for
photosensitisation is similar to the repeat insult patch test described above.
However, the test sites are irradiated with UV light immediately after patch
removal during the induction as well as the challenge phase and non-irradiated
treated and irradiated untreated sites are included in the test as negative controls
(CIR, 1998; KRA, 1996).
Five commercial products containing 0.5-6% glycolic acid at pH 3.6-4.2 were
tested in separate groups of 25-27 healthy volunteers (Consumer Product Testing
Co., 1994a; CTFA, 1994d; Harrison Research Laboratories, 1994a). No evidence
of photosensitising potential was observed.
11.2.6 Comedogenicity tests
S u b s t a n c e s applied to the skin may induce the formation of comedones
(blackheads). The standard test for comedogenicity involves applying the test
substance and a negative control under occlusive or semi-occlusive patches to the
upper back of healthy volunteers (Mills & Kligman, 1982). The patches are
changed 3 times per week for 4 weeks, providing 28 days of continuous exposure.
At the end of the test period, a piece of stratum corneum with follicular
extensions is lifted off from each site and examined for horny cylinders under a
dissecting microscope. When so tested in 6 subjects, 5 commercial cosmetics (3
creams and 2 lotions) containing from 2-10% glycolic acid at pH 3.7-3.8 showed
no potential to induce blackheads (CTFA, 1995c).
11.2.7 Use studies
A total of 22 studies provided information on the incidence of treatment-emergent
adverse skin events during regular use of cosmetics with glycolic acid (CTFA,
1989, 1990a-c, 1991a-b, 1991d, 1992a-d, 1993, 1994b-c; Effendy et al., 1995;
Hill Top, 1996; Kopera et al., 1996; Milmark Research, 1994; Morganti et al.,
1996; Thibault et al., 1998; TKL Research, 1994a-b; Wang et al., 1997). These
studies had a duration of 7 days to 6 months and monitored the use of various
formulations and commercial products containing 0.5-50% glycolic acid at pH
1.2-5.5 by 770 healthy subjects, 59 subjects with photoaged skin, and 40 patients
with acne. As shown in Table 11.1, adverse events were recorded in 24% of the
subjects, with stinging accounting for 42% and signs of skin irritation for 55% of
the total. None of the use studies provided information on systemic tolerability.
56 Priority Existing Chemical Number 12
Table 11.1: Incidence of adverse skin events in 869 subjects using glycolic
acid containing cosmetics for 7 days to 6 months
Adverse event Number Per cent
Stinging 87 10.0
Itching 37 4.3
Mild skin irritation (unspecified) 35 4.0
Erythema 20 2.3
Bumps 8 0.9
Flaking/scaling 7 0.8
Follicular erosions with oedema 6 0.7
Activation of local herpes simplex infection 3 0.3
Hyperpigmentation 3 0.3
Hypopigmentation 1 0.1
Skin necrosis 1 0.1
Total 208 24.0
11.2.8 Case reports and customer complaints
Isolated cases of hyperpigmentation in dark-skinned people have been reported in
the trade press (Boschert, 1994).
Altomare et al. (1997) described 3 cases of recurrent, intensely burning
oedematous dermatitis of the eyelids resulting from application to the face of two
different creams containing 6% or 8% glycolic acid. Patch testing with the cream
was done in one case and was negative. Two of the patients agreed to a challenge
test which consisted in applying the cream to one eyelid after full recovery had
occurred. In both cases, the challenge resulted in an intense inflammatory
response. The authors concluded that the reaction was clearly irritant.
For the purposes of the present assessment, NICNAS asked all 36 applicants and
notifiers importing or manufacturing glycolic acid containing cosmetics to
provide information on any adverse events reported to them. Two large consumer
goods companies selling creams and lotions containing 0.5-8% glycolic acid at
pH 3.5-6.6 reported customer complaint rates of 140-455 per 1 million units sold.
These complaints related to adverse events varying from slight stinging, over
itchiness and redness, to rashes and presumed allergic reactions. Two importers
stated that a tiny percentage of customers had reported stinging, reddened or dry
skin from products containing 2.5-14% glycolic acid at pH 4.4. Nine importers
and manufacturers stated that they had not received any adverse event reports
relating to their products, whereas the remaining importers and manufacturers did
not address the question. By comparison, the average rate of adverse skin events
from topical cosmetics has been estimated at 10-200 per 1 million items sold
(Meynadier et al., 1994).
11.2.9 Conclusions
A substantial number of experimental and commercial glycolic acid formulations
have been tested for their potential to induce stinging, contact irritation, follicular
irritation, contact sensitisation, phototoxicity, photosensitisation and comedone
(blackhead) formation. The tests have employed methods that are generally
57
Glycolic acid
recognised as reliable and have been conducted in an adequate number of
subjects.
The results of these tests indicate that cosmetic products containing glycolic acid
do not induce contact sensitisation, phototoxicity or photosensitisation and are
non-comedogenic. However, at concentrations 2% they induce stinging in a
dose- and pH-related manner, skin irritation to a degree that appears to depend
more on pH than glycolic acid content, and dose-related follicular irritation. The
frequency and severity of these effects also depend on the choice of excipients, in
ways which are not well understood.
The relevance of the test results is borne out by a high incidence of stinging
(10%) and signs of skin irritation (13%) in a number of use studies involving 869
subjects. These effects were also frequent causes of spontaneous consumer
complaints.
11.3 Special skin investigations
A number of in vivo and in vitro studies have investigated various biological skin
effects of glycolic acid in humans, including effects that have been interpreted as
indicative of a potential risk that glycolic acid may increase skin sensitivity to
sunlight exposure.
11.3.1 Intact skin
Skin thickness was measured with micrometer callipers in 17 subjects with
photoaged skin treated with a lotion containing 25% citric, glycolic or lactic acid
adjusted to pH 3.5 and a placebo lotion applied to either forearm twice daily for
4-8 months (Ditre et al., 1996). On the AHA-treated side, 2-layer skin thickness
increased by 24% from 11.5 to 14.3 mm, whereas it decreased from 12.2 to 11.9
mm on the vehicle control side. The difference was statistically significant and
easily discerned by comparative pinching of the forearm skin. There were no
differences between the thickening induced by citric, glycolic or lactic acid.
Twice-daily application of 2 creams containing 5.7% glycolic acid (pH not
specified) or one cream with 10% glycolic acid at pH 5.5 for 6-8 weeks produced
significant increases in skin firmness in healthy volunteers, whereas once-daily
application of a 6% cream (pH not specified) for 4 weeks did not improve skin
elasticity in a group of women with photodamaged skin (Morganti et al., 1996;
Pi閞ard et al., 1996; Smith, 1996).
11.3.2 The stratum corneum
The outermost, horny layer of the skin consists of several tiers of flat cells that
are filled with keratin and have no nuclei or metabolic activity. These cells are
continuously sloughed off or worn away and replaced by cells from the viable
epidermis beneath them. In histological preparations the stratum corneum appears
to be divided into an innermost layer of compacted cells (stratum compactum)
and an outermost layer of loosely connected cells with empty spaces between
them (stratum disjunctum).
58 Priority Existing Chemical Number 12
Thickness
Van Scott and Yu (1974) observed that ointments or solutions containing 5-10%
glycolic acid or other AHAs induced a remarkable thinning of the stratum
corneum in patients with a variety of skin diseases in which the stratum
disjunctum is pathologically thickened.
Stratum corneum thickness was determined microscopically in biopsies from
healthy subjects treated with commercial cosmetic products containing glycolic
acid (CTFA, 1994a,c). Twice daily applications of an 8% cream, pH 3.9 to 10
subjects for 4 weeks or a 4% formulation, pH 3.9 to 8 subjects for 6 months were
not associated with significant stratum corneum alterations when compared with
vehicle or untreated control sites.
DiNardo et al. (1996) treated 20 subjects with moderately dry skin with a
formulation containing 8% glycolic acid at pH 3.25, 3.8 or 4.4; 3.25%, 6.5%,
9.75% or 13% glycolic acid at pH 3.8; or a vehicle control. The thickness of the
stratum corneum was measured by microscopic examination of superficial skin
biopsies. The changes in stratum corneum thickness after 3 weeks of twice daily
application of the test formulations are showed in Table 11.2; no data were given
on their statistical significance.
Table 11.2: Stratum corneum thickness, viable epidermis thickness,
collagen deposition and glycosaminoglycan content in 20 subjects with
moderately severe dryness of the skin after 3 weeks twice-daily treatment
with glycolic acid (GA) or vehicle control (DiNardo et al., 1996)
% change compared with vehicle control site
Test Stratum Viable Glycosamino-
formulation corneum epidermis Collagen glycan
thickness thickness deposition content
%GA pH
3.25 3.8 -44 +50 +29 +267
6.5 3.8 -55 +56 +21 +167
8.0 3.25 -22 +18 +54 +350
8.0 3.8 -32 +21 +128 +33
8.0 4.4 -25 +36 +160 +300
9.75 3.8 -22 +42 +55 +25
13.0 3.8 +23 -25 +250 +167
In a double-blind study in 41 subjects with photoaged skin, a 50% glycolic acid
or placebo gel was applied to either side of the face, dorsal forearms and hands
for 5 min once weekly for 4 weeks (Newman et al., 1996). Skin biopsies were
taken before treatment and one week after the last application and used for
microscopic measurement of skin thickness. Compared to baseline, the thickness
of the stratum corneum was decreased by 53% in skin treated with glycolic acid
and unchanged at the vehicle control sites. The decrease in stratum corneum
thickness mainly affected the outermost layer of loosely connected cells (stratum
disjunctum). No statistical analysis was reported.
Fartasch et al. (1997) looked at the morphology of skin biopsies from 4 healthy
subjects treated twice daily for 4 weeks with a lotion containing 4% glycolic acid
at pH 3.8 or the vehicle formulation. Using light microscopy, the horny layer of
glycolic acid treated skin appeared more compact than that of vehicle treated
59
Glycolic acid
skin. However, when examined by electron microscopy the number of layers in
the stratum corneum was similar in both groups and the only discernible
difference was an acceleration of the normal degradation of desmosomal plugs
(which hold the cells together) in the stratum disjunctum of subjects treated with
glycolic acid.
Turnover time
Effendy et al. (1995) measured stratum corneum turnover time in 6 healthy
subjects using the dansyl chloride labelling technique described in section 10.9.1.
The test substance was a 12% aqueous solution of glycolic acid at its natural pH
(approximately 1.6) applied under occlusion for 60 min 5 days per week until the
disappearance of the fluorescence. At untreated, vehicle control and glycolic acid
sites, the mean turnover time was 18.3, 18.0 and 12.8 days respectively. The
reduction in turnover time induced by glycolic acid was statistically significant.
Smith (1996) used the same technique to determine turnover rate in groups of at
least 8 healthy subjects treated twice daily with 2 mg/cm2 of 9 test products that
employed the same vehicle, but differed in glycolic acid content and pH. The
reduction in turnover time compared with an untreated control site is shown in
Figure 11.3.
In a separate study, a test product containing 4% glycolic acid at pH 3, 5 or 7
decreased turnover time by 34%, 23% and 10% respectively (Smith, 1994). When
a test product with 3% glycolic acid (pH not specified) was applied for 20 weeks,
the decrease in turnover rate fell from 29% at the start of the treatment to 17% at
10 weeks and 10% at 20 weeks. The author concluded that the effect on turnover
time diminished over time and with increasing pH of the formulation. Statistical
details were not reported.
Figure 11.3: Average reduction of stratum corneum turnover time in groups
of at least 8 subjects treated with a glycolic acid lotion at various
concentrations and pH values (data from Smith (1996))
35
% reduction in turnover time
30
Glycolic a id
c
25 concentra ion
t
3.80%
20
7.60%
15
11.40%
10
5
0
pH = 3 pH = 5 pH = 7
Hydration
The resistance of the stratum corneum to the flow of an alternating electrical
current is inversely proportional to its water content. Measurement of skin
capacitance is commonly used to assess the ability of cosmetic products to
60 Priority Existing Chemical Number 12
hydrate or moisturise the skin. The available studies on the effect of glycolic acid
on skin capacitance are summarised in Table 11.3. The data indicate that glycolic
acid has a modest effect on stratum corneum hydration.
Table 11.3: The effect of glycolic acid (GA) on stratum corneum hydration
as measured by electrical capacitance testing
Skin type
(number of Test Treatment
subjects) product protocol Effect on hydration Reference
Moderately Lotion with Twice daily Increased 1.5-fold DiNardo et al.
dry (10 per 3.25-13% application for 3 (13% GA, pH 3.8) to (1996)
group) GA at pH weeks 3-fold (8% GA, pH
3.8-4.4 4.4) (no statistical
analysis)
12% GA in Applied under Modest increase Effendy et al.
Normal (6)
water, pH occlusion for 60 until 4th application, (1995)
min 5 days per followed by a slight
1.6
week for 2 but significant
weeks decrease
Normal (3) Lotion with Twice daily No change Fartasch et
4% glycolic application for 3 al. (1997)
acid, pH 3.8 weeks
Normal (6) Cream with Twice daily Modest, but Smith (1966)
5.7% GA, application for 6 significant increase
pH not weeks
specified
11.3.3 The viable epidermis
The viable epidermis consists of several layers of nucleated, metabolically active
cells which from the stratum corneum inwards include the stratum granulosum,
the stratum spinosum and the stratum germinativum or basal cell layer. The latter
contains a single tier of columnar cells that, on division, are pushed up into the
stratum spinosum, start accumulating keratin and eventually reach the outer part
of the stratum corneum in approximately 26-28 days. Including the stratum
corneum, the epidermis is about 0.1 mm thick, except on the palms and soles
where it is several times thicker.
Thickness
The thickness of the viable epidermis was determined microscopically in biopsies
from healthy subjects treated with commercial cosmetic products containing
glycolic acid (CTFA, 1994a, 1994c). Twice daily application of an 8% cream, at
pH 3.9 to 10 subjects for 4 weeks or of a 4% cream at pH 3.9 to 14 subjects for 6
months was not associated with significant epidermal alterations when compared
with vehicle treated or untreated control sites. When a portion of the biopsies
from the 6-month study was examined by electron microscopy, no abnormalities
were observed (CTFA, 1995g).
The thickness of the viable epidermis was measured by microscopic examination
o f biopsies from 20 subjects with moderately dry skin treated with an
experimental formulation containing 8% glycolic acid at pH 3.25, 3.8 or 4.4;
3.25%, 6.5%, 9.75% or 13% glycolic acid at pH 3.8; or a vehicle control
(DiNardo et al., 1996). After 3 weeks of twice daily application of the test
61
Glycolic acid
formulations, the viable epidermis was, on average, about 30% thicker at the
treated than at the control sites (Table 11.2); statistical details were not reported.
In a double-blind study in 41 subjects with photoaged skin, a 50% glycolic acid
or placebo gel was applied for 5 min once weekly for 4 weeks (Newman et al.,
1996). In biopsies taken before treatment and one week after the last application,
microscopic measurements showed a 19% increase in epidermal thickness
compared to baseline. No statistical analysis was reported.
In 8 subjects with photoaged skin who were treated with a lotion containing 25%
citric, glycolic or lactic acid adjusted to pH 3.5 and a placebo lotion twice daily
for 4-8 months, the mean epidermal thickness was 62% greater in AHA-treated
than in control specimens (Ditre et al., 1996). Statistically, this difference was
highly significant.
None of the above studies identified any other structural effects on the epidermis.
Cell proliferation
Epidermal cell proliferation was measured in superficial skin biopsies from 6
healthy subjects treated twice daily for 24 weeks with a 4% glycolic acid
emulsion, pH 3.9 and a conventional moisturiser, pH 6.6 (CTFA, 1995f).
Following incubation with 3H-labelled thymidine for 2 h, DNA-synthesising cells
were visualised by autoradiography. The mean labelling index, that is, the
percentage of DNA-synthesising cells, was 5.3 at the glycolic acid treated sites,
6.2 at the moisturiser treated sites, and 4.1 in biopsies from untreated skin areas.
These indices were not statistically different. In an abstract, Bartolone et al.
(1994) described an in vitro experiment in which glycolic and lactic acid
s i g n i f i c a n t l y stimulated the proliferation of cultured human epidermal
keratinocytes as compared to control cells. However, detailed study data were not
available for assessment.
11.3.4 Skin barrier function
The skin barrier is a physiological concept that includes all the elements that
enable the skin to protect the body from dehydration and restrict foreign
chemicals from entering the systemic circulation. The barrier has been likened to
a `brick wall', with the keratin-filled, mature corneocytes being the bricks and the
thin intercellular film of lipids, free fatty acids and cholesterol the mortar that fills
the crevices between them (Guy, 1995). It has been calculated that the diffusion
path of water across the barrier is about 0.9 mm long, whereas the stratum
corneum itself is only 10-20 祄 thick in most places. It is therefore conceivable
that water and other small non-electrolytes do not cross the cells of the epidermis,
but follow a tortuous route through the intercellular film of relatively polar lipids.
Skin barrier function is usually assessed by quantitative trans-epidermal water
loss (TEWL) assays. Several studies have examined the effect of glycolic acid
treatment on TEWL and are summarised in Table 11.4.
Two studies looked at the potential of repeated applications of glycolic acid
formulations to modulate the increase in TEWL induced by sodium lauryl
sulphate, which is known to disrupt skin barrier function.
62 Priority Existing Chemical Number 12
Table 11.4: The effect of glycolic acid (GA) on skin barrier function as
measured by trans-epidermal water loss (TEWL)
Skin type
(number of Treatment
subjects) Test product protocol Effect on TEWL Reference
Normal (11) Cream with 8% Twice daily No significant Berardesca
GA, pH 4.4 application of 2 changes after 1, 2, 3 et al.
2
mg/cm cream or 4 weeks of (1997)
for 4 weeks application
Moderately Lotion with Twice daily Slight increase (no DiNardo et
dry (10 per 3.25-13% GA application for statistical analysis) al. (1996)
group) at pH 3.8-4.4 3 weeks
Normal (6) 12% GA in Applied under Significant increase Effendy et
water, pH 1.6 occlusion for which had not al. (1995)
60 min 5 days reverted to normal at
per week for 2 7 days post-
weeks treatment
Normal (3) Lotion with 4% Twice daily No significant Fartasch et
glycolic acid, application for change al. (1997)
pH 3.8 3 weeks
Slight but significant KGL Skin
Normal (19) Formulation Twice daily
increase after 6, Study
containing 4% application of 2
2
mg/cm cream 12,18 and 24 weeks Center
GA, pH 3.9
for 24 weeks of application (1995b)
In one study, 8 healthy subjects were treated twice daily for 4 weeks with a 4%
glycolic acid formulation at pH 3.7-4.0 (CTFA, 1995a). In the other study, 2
mg/cm2 of a cream with 8% glycolic acid, pH 4.4 was applied twice daily for 4
weeks (Berardesca, 1997). Vehicle treated and/or untreated control sites were
used. At the end of the treatment period, TEWL was measured before and after
application to the treated and control skin sites of an occluded patch containing
sodium lauryl sulphate. In both studies, prior treatment with glycolic acid
significantly reduced the barrier damage induced by sodium lauryl sulphate.
The impact of glycolic acid on the ability of the skin to keep out foreign
substances was addressed in an investigation of the influence of a 10% glycolic
acid lotion (pH 3.5) on the percutaneous penetration of model penetrants through
human skin (Hill Top Reearch, 1996). Twenty healthy subjects were pre-treated
with the test product or a vehicle control once daily 6 days a week for 15 weeks.
14
C-labelled model penetrants (hydrocortisone and glycerol) dissolved in acetone
were then applied to separate sites on the treated skin area. One and 4 h later,
sites were tape-stripped for a total of 21 times to remove the stratum corneum and
the tape strips analysed for radioactivity. There were no significant differences in
the amount of 14C-hydrocortisone or 14C-glycerol recovered from treated, vehicle
control or untreated control sites, indicating that glycolic acid did not enhance
absorption of the test substances.
11.3.5 The dermis
The dermis is a dense fibrous network of collagen and elastin, which serves as a
supporting unit and reservoir of nutrients for the epidermis.
63
Glycolic acid
Thickness
Compared with vehicle control specimens, the mean thickness of the outer layer
of the dermis was almost doubled in biopsies from 8 subjects with photoaged skin
who were treated twice daily with a lotion containing 25% citric, glycolic or
lactic acid adjusted to pH 3.5 for 4-8 months (Ditre et al., 1996).
In vitro fibroblast proliferation
Kim et al. (1998) studied the effect of glycolic acid on cultured fibroblasts
obtained from circumcised neonatal foreskin. After incubation for 24 h in a
medium containing glycolic acid at 0.001, 0.01 and 0.1 礛 (0.076, 0.76 and 7.6
礸/L respectively), cell growth was measured using a commercially available
assay kit. Glycolic acid induced a statistically significant, concentration-
dependent, 1.2- to 1.4-fold increase in the number of viable cells. A similar
proliferative response to glycolic acid in cultured human fibroblast was reported
in abstract form by Bartolone et al. (1994).
Collagen and glycosaminoglycan synthesis in vitro and in vivo
Glycolic acid has been shown to stimulate the incorporation of 3H-labelled
hydroxyproline into type I collagen and to augment the synthesis of procollagen
type I C-peptide in human skin fibroblasts cultured in vitro (Bartolone et al.,
1994; Kim et al., 1998; Moy et al., 1996a).
In an in vivo study, DiNardo et al. (1996) estimated the dermal content of
collagen and glycosaminoglycans in selectively stained histological slides
prepared from biopsies from 20 subjects with moderately dry skin, who had been
treated twice daily for 3 weeks with a formulation containing 8% glycolic acid at
pH 3.25, 3.8 or 4.4; 3.25%, 6.5%, 9.75% or 13% glycolic acid at pH 3.8; or a
vehicle control. As shown in Table 11.2, there was a slight to marked increase in
both collagen and glycosaminoglycan content; statistical details were not
r e p o r t e d . In another in vivo study, the dermal content of collagen and
glycosaminoglycans appeared increased in biopsies from 8 subjects with
photoaged skin who were treated twice daily with a lotion containing 25% citric,
glycolic or lactic acid adjusted to pH 3.5 for 4-8 months (Ditre et al., 1996). By
image analysis, however, the mean collagen fibre density at AHA-treated sites
(53%) was not statistically different from that at control sites (43%).
FXIIIa(+) dendrocytes
Dendrocytes are connective tissue cells which populate the outer layer of the
dermis in a perivascular distribution, are closely associated with mast cells and
express Factor XIIIa, a coagulation enzyme that facilitates fibrin cross-linking
and contributes to wound healing. They show enhanced FXIIIa expression in
response to mast cell degranulation and their number is increased in a variety of
skin diseases, including radiation dermatitis (Moretto et al., 1998; Sueki et al.,
1993).
Immunoperoxidase and toluidine blue staining and electron microscopy were
used to evaluate FXIIIa expression and mast cell degranulation in skin biopsies
from 8 subjects with photoaged skin treated with a pH 3.5 lotion containing 25%
citric, glycolic or lactic acid twice daily for 4-8 months (Griffin et al., 1996).
64 Priority Existing Chemical Number 12
Compared to vehicle control sites, AHA-treated skin appeared to have both an
increased number of FXIIIa(+) cells and an increase in the size of these cells. By
image analysis, FXIIIa expression was increased 50-600% over controls in 6 of
the 8 subjects. The increase was statistically significant in 4 of the subjects and
was seen with all 3 AHAs studied. There was also a statistically significant
increase in mast cell degranulation. By electron microscopy, the dendrocytes in
A H A - t r e a t e d skin appeared markedly enlarged with dilatation of rough
e n d o p l a s m i c reticulum, particularly when they were positioned close to
degranulated mast cells.
11.3.6 Sensitivity to UV light
The available studies on the effect of post- or pre-exposure treatment with
glycolic acid on the skin response to UV radiation are summarised in Table 11.5.
Table 11.5: The effect of glycolic acid on skin response to UV irradiation*
No. of
subjects Test product Treatment protocol Effect Reference
Post-irradiation treatment
5 Cream with Applied 4 times daily Markedly reduced Perricone &
12% GA, pH beginning 4 h after erythema at 48 h; DiNardo
4.2 exposure to 3 MEDs hyperpigmentation (1996)
(vehicle control) observed at 72 h
5 Two lotions Applied once daily 7-16% reduction Perricone &
with 8% GA, beginning 24 h after in irritation DiNardo
pH 3.25 exposure to 3 MEDs (1996)
(untreated control)
Pre-irradiation treatment
20 Lotion with Test product applied SPF = 8.82 Consumer
approximately 15-30 min before Product
1.5% GA, pH irradiation Testing Co.
3.7-4.1 (1993c)
19 Cream with Test product applied SPF = 0.87 KGL Skin
4% GA, pH twice daily for 12 Study
not specified weeks prior to Center
irradiation (1995a)
5 Two lotions Test products SPF = 2.4 Perricone &
with 8% GA, applied once daily DiNardo
for 3 weeks prior to
pH 3.25 (1996)
irradiation
5 Two lotions Test products SPF = 1.7 Perricone &
with 8% GA, applied once daily DiNardo
pH 3.25/50% for 3 weeks; 6-min (1996)
GA peel, pH peel 15 min prior to
2.75 irradiation
* GA = glycolic acid SPF = sunlight protection factor
MED = minimal erythemal dose UV = ultraviolet
When administered after UV irradiation, 3 products containing 8-12% glycolic
acid were reported to reduce erythema and irritation from UV irradiation when
applied to the skin at intervals commencing 4-24 h post-exposure, although 6-
hourly application of the 12% product was associated with hyperpigmentation.
With pre-exposure treatment, the effect was assessed in standard sunscreen
efficacy tests and expressed as the mean sun protection factor (SPF), that is, the
65
Glycolic acid
minimal erythemal dose (MED) for the treated site divided by the MED for the
untreated control site1. Vehicle controls were not used. Most test products were
found to offer some degree of sun protection. However, in one study conducted
by KGL Skin Study Center (1995a), twice-daily treatment with a 4% glycolic
acid cream for 12 weeks induced a statistically significant reduction in the
amount of UV radiation required to induce sunburn, yielding a mean SPF of 0.87.
There was considerable inter-individual variation in the effect, with UV
sensitivity being increased in 9 subjects (by 48-50% in 3 of them), unchanged in
9 subjects and decreased in 1 of the 19 panellists.
The study protocol included tests for skin hydration as measured by electrical
capacitance and semi-quantitative analysis of skin scaling using the D-Squames?br>
method2. Skin sites treated with the 4% cream had a higher capacitance (that is,
stratum corneum hydration) and less scaling than control sites (KGL Skin Study
Center, 1995a-b). Other studies showed that seasonal variations in sunburn
sensitivity coincide with variations in skin dryness/roughness and that treatment
with moisturisers or emollients or smoothing of the skin surface by scrubbing or
shaving increase UV light sensitivity by 5-12% (KGL Skin Study Center, 1995c;
TKL Research, 1995a-b). As such, the laboratory testing the cream concluded
that the increase in sensitivity in the smoother, glycolic acid treated areas was a
physiological phenomenon caused by reduced light scattering from the skin
surface and the consequent increase in light absorbency.
This interpretation was contested by the research organisation whom FDA
contracted to make an assessment of the published and unpublished literature on
the effects of AHAs on the skin (KRA, 1996). They reanalysed the study data and
c o n c l u d e d that there was hardly any correlation between an individual's
sensitivity to UV light and skin capacitance and none at all between light
sensitivity and the score for scaling. They also pointed out that 3/19 tested
subjects had a MED of about 0.5 after glycolic acid treatment, meaning close to a
doubling of the sensitivity to sunburn, and that individual MED reductions of that
magnitude were not observed at skin sites smoothed by moisturisers, emollients
or mechanical means.
Subsequent studies investigated the production of sunburn cells in subjects
treated with glycolic acid before exposure to UV light. Sunburn cells occur in
mammalian epidermis after exposure to UV radiation and are easily recognised
by their pyknotic (small and dark-staining) nuclei and eosinophilic cytoplasma
(Young, 1987). Sunburn cell production was examined in 3 groups of 15-16
healthy subjects who had been treated once daily for 4 days or 12 weeks with a
10% glycolic acid gel, pH 3.5-4.0, which was applied at a dose of 2 mg/cm2 and
rubbed into the skin (KGL, Inc., 1996a-b). Control sites were treated with a
placebo gel, a glycerol-based moisturiser, a mineral oil emollient, rubbed with a
moistened mechanical exfoliating sponge for 15 sec, or left untreated. Fifteen min
after the last application, each site was irradiated with UV light equivalent to 1
individually determined MED. Within 16-24 h of irradiation, a biopsy was taken
from each site and the number of sunburn cells determined by microscopic
examination. The results of these studies are summarised in Table 11.6.
1
One MED is defined as the minimal amount of UV radiation required to cause distinct redness of the
skin.
2
The D-Squames?kit comprises a transparent adhesive disk that is applied directly onto the body area
to be tested, removed and analysed after it has been pressed onto a black control card, which collects
and visualises the scales adhering to its surface.
66 Priority Existing Chemical Number 12
Table 11.6: Geometric mean number of sunburn cells per high power field
in histological sections of human epidermis exposed to 1 MED of UV light
following treatment with a 10% glycolic acid gel (KGL, Inc., 1996a-b)
Duration Type of treatment
of
Glycolic No
Vehicle Moisturiser Sponge
treatment
acid Emollient treatment
4 days 0.27 - 0.16 - 0.24 0.18
12 weeks 0.77* - 0.38 - 0.44 0.37
12 weeks 0.85** 0.31 - 0.26 - 0.37
* Statistically significant compared to skin treated with moisturiser and to untreated skin
** Statistically significant compared to any other group
Whereas treatment for 4 days had no effect, treatment for 12 weeks caused a
small increase in sunburn cell production which was significantly different from
untreated control sites as well as sites treated with a moisturiser, an emollient, or
a vehicle control. Sunburn cells are not cancerous, but are generally recognised as
an objective, easily quantified marker of acute skin damage elicited by UV
irradiation. As such, the sunburn cell studies invalidate the hypothesis that
increased sensitivity to UV irradiation following long-term treatment with topical
glycolic acid is secondary to smoothing of the surface of the skin.
In a similar study, there was no increase in the number of sunburn cells in 4
healthy subjects treated once daily for 4 days with 2 creams containing 1.5%
octyl methoxycinnamate (a sunscreen) and either 4% or 8% glycolic acid (DeLeo,
1996).
11.3.7 Discussion
The special skin investigations in humans reviewed above demonstrate that
glycolic acid has a number of effects on the structure and function of human skin
at concentrations and pH levels that are commonly encountered in cosmetic
products on sale in Australia.
Epidermis
Topically applied glycolic acid was consistently found to increase stratum
corneum turnover in a dose- and pH-related manner and to decrease the thickness
of the outermost layer of loosely connected cells (stratum disjunctum) where the
latter is unusually prominent, such as in dry or photoaged skin. It also increased
the thickness of the viable epidermis in dry or photoaged skin, although the only
study of its potential to stimulate epidermal cell proliferation concluded that the
impact on DNA-synthesis in healthy epidermal cells was slight and non-
significant. In tests for TEWL or absorption of model penetrants, formulations
containing 10 % glycolic acid had at most a modest impact on skin barrier
function tests, whereas exposure to a solution with 12% glycolic acid at pH 1.6
was associated with a long-lasting increase in skin permeability to water.
Overall, these effects of glycolic acid on the structure and function of the
epidermis appear to represent a combination of physiological repair mechanisms
in response to superficial damage to the stratum corneum and to insults to the
living layers of the skin.
67
Glycolic acid
Dermis
Concentrations of <1 礸/L glycolic acid induced s small, but dose-related
increase in skin fibroblast proliferation and collagen synthesis in vitro. However,
the significance of this finding may be tenuous as few studies provide convincing
in vivo evidence of increased collagen deposition and thickening of the dermis
and only at concentrations in the 15-70% range. Although there was no
histological evidence of skin inflammation in humans using commercially
available cosmetics (other than an increase in FXIIIa(+) dendrocytes), the dermal
effects in animals were preceded by corrosive or irritant reactions and associated
w i t h a slight inflammatory infiltrate (see section 10.9.3). It is therefore
conceivable that any increase in skin thickness or firmness caused by glycolic
acid is in response to a mild primary skin irritation.
Sensitivity to UV radiation
When 3 commercial creams and lotions containing 8-12% glycolic acid were
applied to experimentally sunburned skin, they were found to reduce erythema
compared to vehicle or untreated controls. These findings were claimed to be the
result of anti-inflammatory, antioxidant and photoprotective effects of glycolic
acid (Perricone & DiNardo, 1996). However, the weight of evidence indicates
that glycolic acid may cause inflammatory reactions in the skin and is unlikely to
act as an antioxidant or photoprotective agent as it is not metabolised in human
skin (FDA, 1996) and does not contain chromophores that absorb light in the
visible or UV spectrum (KRA, 1996).
There is ample evidence that UV irradiation of human skin results in a significant
release of tumour necrosis factor (TNF-) and that sunburn cell production can
be blocked by neutralising antibodies to TNF- and by cromolyn sodium, an
asthma drug impeding mast cell degranulation (Walsh, 1995). TNF- also
appears to mediate some of the immunosuppresive effects of UV irradiation,
which are believed to facilitate the progression of DNA-damaged cells to
increasingly malignant cancer cells. There are no studies on the effect of glycolic
acid on TNF- release, but a significant increase in mast cell degranulation and
FXIIIa expression in dermal dendrocytes (which is enhanced by mast cell
degranulation and TNF-) was reported in skin exposed repeatedly to AHAs in
relatively high concentrations. It is therefore conceivable that glycolic acid and
UV irradiation can have an additive effect on the release of TNF- from mast
cells in the dermis and thereby on sunburn cell production in the epidermis.
Whether there are any adverse long-term effects from repeated combined
exposure to glycolic acid and UV light will be investigated in a FDA-initiated
lifetime study in hairless mice, which is scheduled to commence in 1999 and will
take 3 years to complete.
Conclusions
In conclusion, topical treatment with glycolic acid may lead to smoothing of the
stratum corneum and a slight increase in the thickness and firmness of the skin.
These effects appear to involve subtle mechanisms similar to those caused by
mild abrasion and wounding and can usually be achieved at exposure levels that
are not associated with skin corrosion or irritation or indeed with any of the
classical signs of inflammation: erythema, oedema and cellular infiltration.
68 Priority Existing Chemical Number 12
Use of cosmetics with glycolic acid may increase the sensitivity of the skin to
sunburn, possibly because glycolic acid and UV light have an additive effect on
the release of TNF- from mast cells in the dermis. At present, however, there is
no evidence that glycolic acid facilitates any of the mechanisms that contribute to
the development of sunlight-induced cancers of the skin.
69
Glycolic acid
12. Hazard Assessment and
Classification
This section integrates data on kinetics and metabolism, animal toxicity and
human effects in order to characterise the potential adverse human health effects
of glycolic acid resulting from its use in the cosmetics industry. Any health
hazards that were identified have been classified in accordance with the NOHSC
Approved Criteria for Classifying Hazardous Substances (the Approved Criteria)
(NOHSC, 1999a). The Approved Criteria are cited in the NOHSC National
M o d e l Regulations for the Control of Workplace Hazardous Substances
(NOHSC, 1994c) and provide the mandatory criteria for determining whether a
workplace chemical is hazardous or not.
Where adequate human data were unavailable, information from experimental
studies (animal and in vitro bioassays) formed the basis for assessment. In
extrapolating results from experimental studies to humans, consideration has been
given to relevant issues such as quality of data, weight of evidence, metabolic and
mechanistic profiles, inter- and intra-species variability and relevance of exposure
levels.
12.1 Toxicokinetics and metabolism
In vitro investigations of human skin have shown that percutaneous absorption of
glycolic acid is a passive diffusion process whose extent is proportional to time,
concentration of undissociated acid, and degree of occlusion of the site of
application. It is also influenced by formulation type and composition. The
available data indicate that the permeability coefficient for undissociated glycolic
acid in aqueous solutions is approximately 3 x 10- 4 cm/h. For oil-in-water
emulsions containing 5% glycolic acid at pH 3, maximum penetration through the
skin averaged 12%, with a 95% confidence interval of 2-22%. No information
was available about absorption in humans following inhalation or ingestion of
glycolic acid. However, animal data show that absorption of the chemical from
the intestinal tract is virtually complete and a comparison of its oral and
inhalation toxicity in rats indicates that it is likely to be readily absorbed through
the lungs as well.
The distribution volume of glycolic acid is small (0.56 L/kg) and corresponds to
the size of the body water compartment. The chemical is taken up by liver cells
by a transport mechanism and metabolised to glyoxylic acid by glycolic acid
o x i d a s e , which is a peroxisomal, hydrogen peroxide generating enzyme.
Glyoxylic acid may be oxidised further to oxalic acid, transaminated to glycine,
or decarboxylated to formic acid and carbon dioxide, although the latter route is
of little significance in primates. The oxidation of glycolic acid to glyoxylic acid
is rate-limiting and easily saturated, and at higher dose levels glycolic acid is
predominantly excreted unchanged in the urine.
Healthy subjects have plasma concentrations of glycolic acid in the 0.1-0.6 mg/L
range and excrete 1-100 mg/day in the urine. This is primarily of dietary origin.
70 Priority Existing Chemical Number 12
Based on the tables published by Harris & Richardson (1980), the estimated
average daily intake from dietary sources for a 60 kg adult is about 68 mg
glycolic acid (1.1 mg/kg/day), based on a mean intake of 500 g fresh fruit and
vegetables and 4 cups of beverages (tea, coffee, fruit juice) per day (ANZFA,
1999). The half-life of plasma glycolic acid has been determined at 7-10.5 h in a
limited number of patients with ethylene glycol poisoning.
12.2 Health hazards
12.2.1 Acute lethal effects
In animal studies, glycolic acid was found to cause lethality by ingestion,
inhalation or injection in all species tested. Deaths occurred up to 12 days
following exposure, with kidney lesions being the most common finding at
necropsy. In GLP studies in the rat conducted according to OECD's Test
Guidelines or similar protocols, the oral LD50 was 1357 mg/kg and the LC50 from
nasal inhalation of aerosolised glycolic acid was 2520 mg/m3 (2.5 mg/L) in male
and >3640 mg/m3 (>3.6 mg/L) in female rats. No dermal toxicity studies were
available. In mice and rats, lethal dose levels were consistently lower in males
than in females, apparently because the metabolite oxalic acid, which is prone to
precipitate as calcium oxalate in the kidney and urinary tract of rodents, is formed
at a faster rate in male as compared to female animals.
Cases of human intoxication have not been reported. However, there is a
considerable body of data on the effects of acute poisoning from ingestion of
ethylene glycol, which is of low toxicity in itself, but is slowly metabolised to
glycolic acid. The estimated lethal dose of ethylene glycol in humans is
approximately 1600 mg/kg, with death occurring from metabolic acidosis,
cardiopulmonary collapse and/or renal failure within one to several days of
exposure (Cavender & Sowinski, 1994).
There is no evidence of non-lethal irreversible effects from single exposures to
glycolic acid in animals, or in humans from ethylene glycol poisoning.
Classification. Glycolic acid meets the Approved Criteria for classification as
harmful by inhalation and if swallowed (R20/22).
12.2.2 Corrosion/irritation
Skin
In several GLP studies for skin corrosion/irritation potential in rabbits conducted
according to OECD Guideline No. 404, crystalline glycolic acid and a 70%
solution at pH <0.5 caused full thickness destruction of skin tissue after a 1-h
e x p o s u r e , whereas solutions of 70% neutralised glycolic acid or 57%
unneutralised glycolic acid caused visible irritation after a 4-h exposure.
The histopathological effects of a single, non-occluded application of skin peel
solutions were investigated in 3 human subjects, 2 of whom were exposed for 30
min only. Solutions containing 70% glycolic acid at pH 0.6 caused crusting and
partial necrosis of the epidermis and acute dermal inflammation, consistent with a
strong irritant reaction.
71
Glycolic acid
A large number of experimental formulations and commercial cosmetic products
have been tested for skin irritation in humans according to various cumulative
irritation test protocols. Out of a total of 77 formulations containing 2-20%
glycolic acid at pH 2.0-4.4, 5% were classified as severely irritant and 16% as
moderately irritant. By comparison, signs of skin irritation such as redness,
swelling or itching were reported by 13% of 869 subjects taking part in use tests
of a number of cosmetic products covering a wide range of concentrations and
formulation pH values. This was about 55% of all recorded adverse skin events.
Tests for phototoxicity with a small number of commercial products containing
0.5-4% glycolic acid at pH 3.6-4.1 were negative.
Follicular irritation chest tests with a single product containing 2% or 4% glycolic
acid at pH 3.9 showed a dose-dependent positive response.
Classification. Glycolic acid meets the Approved Criteria for classification as
corrosive (R34).
Eyes
In rabbit studies consistent with OECD Guideline No. 405, a solution of 64%
glycolic acid at unknown pH caused destruction of the eye, whereas a solution of
57% glycolic acid at pH 1.8 caused irreversible lesions of the cornea.
Classification. Glycolic acid meets the Approved Criteria for classification as a
severe eye irritant (R41).
Respiratory system
In a study conducted according to OECD Guideline No. 403 and to GLP
standards, male and female rats were exposed to nose-only inhalation of an
aerosolised solution of 70% glycolic acid for 4 h. Nasal discharge and soreness
with ulceration of the mucosal membranes of the larynx and nose occurred at all
dose levels (420-3640 mg/m3). Clinical signs included gasping, noisy breathing
and ocular discharge which may have been secondary to irritation of the nasal
cavity as rats are obligatory nose-breathers and swelling of the nasal turbinates
may block the drainage of the tear ducts. Noisy breathing and nasal and ocular
discharge were also observed in male rats exposed to nasal inhalation of an
aerosolised solution of glycolic acid at 510 mg/m3 and above for 2 weeks. These
effects were not observed in animals exposed to 160 mg/m3 glycolic acid.
Moreover, noisy respiration accompanied by mouth breathing, nose bleeding,
ocular discharge and/or a mucoid exudate in the nasal turbinates were observed in
one acute lethality and 3 10- to 15-day developmental toxicity studies in rats.
Irregular respiration and lung noise were also recorded in a 3-month toxicity test
in rats. These were all studies in which aqueous solutions of unneutralised
glycolic acid were administered by stomach tube. As such, the above clinical
signs may have been due to nasal reflux or aspiration of small amounts of
glycolic acid as a complication of oral gavage dosing.
Classification. Glycolic acid meets the Approved Criteria for classification as
causing serious irritation to the respiratory system (R37).
72 Priority Existing Chemical Number 12
12.2.3 Sensitisation and photosensitisation
One skin sensitisation study in guinea pigs conducted according to OECD
Guideline No. 406 and to GLP standards was negative, as were repeat insult patch
tests of numerous cosmetic products covering a wide range of concentrations and
pH values in groups comprising 25-198 healthy human subjects per product.
When a small number of commercial cosmetic products containing 0.5-6%
glycolic at pH 3.6-4.2 were tested by repeat insult patching followed by UV
irradiation, no evidence of photosensitising potential was observed.
There were no findings indicating that glycolic acid may be a respiratory
sensitiser.
C l a s s i f i c a t i o n . Glycolic acid does not meet the Approved Criteria for
classification as a sensitiser.
12.2.4 Effects after repeated or prolonged exposure
According to the Approved Criteria, risk phrase R48 (Danger of serious damage
to health by prolonged exposure) is assigned when serious damage (clear
functional disturbance or morphological changes which have toxicological
significance) is likely to be caused by repeated or prolonged exposure. Workplace
chemicals are classified at least as harmful when these effects are observed at the
following dose ranges:
? Oral, rat 50 mg/kg/day; and
? Inhalation, rat 0.25 mg/L, 6h/day.
These guide values apply directly when severe lesions have been observed in a
90-day test. The guide values are at least 3 times higher in a 28-day test, that is, at
least 150 mg/kg/day by mouth or 0.75 mg/L, 6h/day by inhalation.
The NOAEL for oral exposure in male and female rats was 150 mg/kg/day in a
90-day toxicity test.
The repeated-dose inhalation study provided for assessment was a 14-day test in
male rats exposed to aerosols containing 160, 510 or 1400 mg/m3 glycolic acid
for 6 h per day, 5 days per week. In this study, clear treatment-related effects
( s i g n i f i c a n t weight loss, dyspnoea, elevated serum liver enzymes and
hepatocellular degeneration) leading to the sacrifice of 7/10 rats in extremis were
seen at 1400 mg/m3 (1.4 mg/L). At 510 mg/m3 (0.51 mg/L), serum AST and ALT
levels were increased and microscopic examination of the liver showed a mild
hepatocellular degeneration. At the end of a 14-day recovery period, the liver
enzyme levels had reverted to normal in the 1400 mg/m3 group and in all but 2/10
animals in the 510 mg/m3 group. Decreased urinary output was reported in the
510 mg/m3 group, but no microscopic changes were seen in the kidneys. No
treatment-related changes were seen at 160 mg/m3 (0.16 mg/L), except for a very
mild, diffuse hepatocellular degeneration in 1/10 animals by the end of the 2-
week recovery period. These effects could be due to the acute toxicity of glycolic
acid, as deaths occurred up to 12 days post-exposure in the single-dose inhalation
study reviewed in section 10.1.3. However, it cannot be excluded that chronic
effects would have developed at 160 mg/m3 (0.16 mg/L) if exposure had occurred
for a longer period such as 28 or 90 days. As such, it is not possible to determine
73
Glycolic acid
the potential of glycolic acid to cause serious damage by prolonged inhalation
exposure from this 14-day study.
No repeated dose toxicity studies by dermal exposure were available for
assessment.
Classification. Glycolic acid does not meet the Approved Criteria for
classification as causing danger of serious damage to health by prolonged
exposure if swallowed. Based on the limited inhalation data available for
assessment, glycolic acid is not classifiable with regard to serious damage to
health by prolonged exposure through inhalation.
12.2.5 Reproductive effects
There were no human case reports or studies indicating any link between
exposure to glycolic acid and birth defects or impaired fertility in humans.
Developmental toxicity
T h e findings in the available in vivo developmental toxicity studies are
summarised in Table 12.1.
The classification system prescribed by the Approved Criteria applies a broad
d e f i n i t i o n of developmental toxicity and does not distinguish between
malformations and variations, allocate relative weights to particular findings or
set cut-off levels for continuous variables such as the incidence of alterations or
percentage reduction in foetal body weights.
A workplace chemical is included in Category 1 if there is sufficient evidence to
establish a causal relationship between human exposure to the substance and
subsequent developmental toxic effects in the progeny. It is included in Category
2 if there is sufficient evidence to provide a strong presumption that human
exposure to the substance may result in developmental toxicity, generally on the
basis of: (1) clear results in appropriate animal studies where effects have been
observed in the absence of signs of marked maternal toxicity, or at around the
same dose levels as other toxic effects but which are not a secondary non-specific
consequence of the other toxic effects; (2) other relevant information.
Classification into Category 3 is based on similar criteria as for Category 2 but
may be used where the experimental design has deficiencies which make the
conclusions less convincing, or where the possibility that the effects may have
been due to non-specific influences such as generalised toxicity cannot be
excluded.
In general, classification in Category 3 or no category would be assigned on an ad
hoc basis where the only effects recorded are small changes in the incidence of
spontaneous defects, small changes in the proportions of common variants such
as are observed in skeletal examinations, or small differences in postnatal
developmental assessments.
Glycolic acid has not been linked with birth defects in humans. As shown in
Table 12.1, there was statistically significant developmental toxicity as defined in
the Approved Criteria in five dose groups administered 332 mg/kg/day glycolic
acid by mouth or 833 mg/kg/day sodium glycolate by subcutaneous injection.
There were signs of marked maternal toxicity at oral dose levels 600 mg/kg/day,
74 Priority Existing Chemical Number 12
whereas signs of maternal toxicity were mild in the 332 mg/kg/day glycolic acid
group in the DuPont pilot study and in the 833 mg/kg/day sodium glycolate group
in the Dow study. In dams given 332 mg/kg/day glycolic acid by oral gavage,
they included a decrease in weight gain limited to the last two days of gestation,
wet fur, which is usually due to treatment-induced diarrhoea, and lung noise,
presumably as a result of aspiration of small quantities of glycolic acid. In dams
injected subcutaneously with 833 mg/kg/day sodium glycolate, the only effects
recorded were small changes in the absolute and relative weight of the liver,
which is the main site of glycolate metabolism. In the DuPont main study, there
w a s developmental toxicity as well as marked maternal toxicity at 600
mg/kg/day, a marginal increase in foetal abnormalities and marginal maternal
toxicity at 300 mg/kg/day, and no effects on either foetuses or dams at 150
mg/kg/day and below.
The DuPont study was a pilot study with only 5 pregnant animals per group and
the Dow study did not follow OECD guidelines as there was only one dose level.
Furthermore, the mechanistic studies reviewed in section 10.5.1 indicate that
whereas the glycolate ion is a developmental toxicant in its own right, oral
administration of unbuffered glycolic acid leads to generalised metabolic acidosis
which is associated with a substantial increase in the incidence and severity of
developmental effects.
As shown in Table 12.1, the effects recorded in the 332 mg/kg/day dose group in
the DuPont pilot study included reduced foetal body weight and a substantial
increase in skeletal variations (77 vs. 53%). In the Dow study, there was reduced
foetal body weight and a substantial increase in skeletal variations of up to 93 vs.
32% in the sodium glycolate group. There was also an increase in total
malformations in this exposure group. However, the increase was small (3.8 vs.
0.3%) and due to tail malformations which may also occur spontaneously.
The biological significance of these findings is supported by the fact that ethylene
glycol, which is extensively metabolised to glycolic acid, induced foetal growth
retardation and abnormalities of the axial skeleton and cranio-facial region in
several developmental toxicity studies in rats and mice (Carney, 1994). One such
study indicated that reduced body weights and abnormalities such as delayed
ossification and fused ribs in rat pups of dams exposed to a large oral dose of
ethylene glycol were reversible by day 63 after birth (Marr et al., 1992).
The molecular basis for the effects of glycolate and metabolic acidosis on foetal
growth and skeletal development is unknown, although it is acknowledged that
skeletal development is very susceptible to chemical agents that inhibit oxidative
r e s p i r a t i o n (Faustman et al., 1997). Several other chelating agents are
developmentally toxic and have pronounced effects on mineral metabolism and
bone mineralisation in animal embryos, apparently because they induce zinc
and/or copper deficiencies that inhibit the activity of a number of metallo-
enzymes (Domingo, 1998).
In summary, both the DuPont pilot study and the Dow study (1) provide clear
evidence of developmental toxicity in the form of reduced foetal body weight and
a substantial increase in the incidence of skeletal variations at dose levels not
associated with marked maternal toxicity; (2) have formal deficiencies in their
experimental design; and (3) determined effects which may in part be due to non-
specific influences. These studies conducted by two independent laboratories
75
Glycolic acid
using different chemical forms of the substance (free acid and sodium salt) and
different routes of administration (oral and subcutaneous), clearly demonstrate
that glycolic acid is a foetotoxic developmental toxicant.
Table 12.1: Foetal and maternal findings in 3 developmental toxicity studies
in the rat*
Dose group Foetal findings Maternal findings
DuPont pilot study (DuPont, 1995a; Munley et al., 1999), 5 pregnant rats/group
697 mg/kg/day Increased resorptions (1.5 vs. 0.4%) Reduced weight gain GD7-22 (38%)
Reduced foetal weight (18%) Reduced body weight GD22 (12%)
Increased incidence of total Reduced feed consumption GD9-22
malformations (39 vs. 5%) (17%)
Increased incidence of skeletal Lung noise (88%), stained and wet
variations (64 vs. 53%) fur (75%), salivation (50%),
abnormal gait (25%)
332 mg/kg/day Reduced foetal weight (9%) Reduced weight gain GD21-22
(38%)
Increased incidence of skeletal
variations (77 vs. 53%) Wet fur (50%), lung noise (25%)
157 mg/kg/day None None
77 mg/kg/day None None
DuPont main study (DuPont, 1996; Munley et al., 1999), 5 pregnant rats/group
600 mg/kg/day Reduced foetal weight (13%) Reduced weight gain GD7-22 (20%)
Increased incidence of total Reduced body weight GD22 (12%)
malformations (10.6 vs. 0.8%) Reduced feed consumption GD21-
Increased incidence of retarded 22
ossification (67.9 vs. 31.5%)
Lung noise (32%), abnormal gait
(20%), irregular respiration (8%),
lethargy (8%)
Marginally increased incidence of
Marginally significant incidence of
300 mg/kg/day
lung noise (8%), p = 0.0553
skeletal malformations (fused ribs and
vertebrae in 2/339 foetuses from 2/23
litters), p = 0.0555
150 mg/kg/day None None
75 mg/kg/day None None
Dow study (Carney et al., 1997, 1999), 25 pregnant rats/group
650 mg/kg/day Reduced foetal weight (17%) Reduced body weight gain GD9-21
GA (14%)
Increased resorptions (5.7 vs. 2.5 vs. a
Reduced body weight on GD16,
historical range of 3.5-14.1%)
GD21 (6%)
Increased total malformations (23.5 vs.
0.3%) Increased relative kidney (8%) and
liver (13%) weights
Increased skeletal malformations (10.6
vs. 0.8) Mortality (16%), abnormal
respiration (8%)
Increased skeletal variations (24,6,90,
72,39,13,10,13,23,46,41 vs. 0,0,32,2,0,
0,2,0,0,16,1%)
833 mg/kg/day Reduced foetal weight (8%) Increased absolute (9%) and relative
NaG by (11%) liver weight
Increased resorptions (4.3 vs. 2.5 vs. a
subcutaneous
historical range of 3.5-14.1%)
injection
Increased total malformations (3.8 vs.
0.3%)
Increased skeletal variations (24,93,40,
8,9,5 vs. 9,32,2,0,2,1%)
* All dose indications refer to 100% glycolic acid (GA) or sodium glycolate (NaG). All results given
were statistically significant unless otherwise stated. All structural abnormalities (malformations and
variations) are reported in accordance with the terminology used in the study reports. GD = gestation
day.
76 Priority Existing Chemical Number 12
However, according to article 4.108 of the Approved Criteria, even when clear
effects have been demonstrated in animal studies the relevance for humans may
be doubtful because of the doses administered, for example, where effects have
been demonstrated only at high doses, or where marked toxicokinetic differences
exist, or the route of administration is inappropriate.
With glycolic acid, statistically significant developmental toxicity occurred at
doses of 332 mg/kg/day glycolic acid by mouth and 833 mg/kg/day sodium
glycolate by subcutaneous injection. As shown in Appendix 2, section A2.3, these
doses are assessed to be high as they correspond to an internal dose that is
estimated to be unattainable in humans exposed to glycolic acid by skin contact
and/or inhalation in the occupational environment.
C l a s s i f i c a t i o n . Based on the above, glycolic acid is not classified for
developmental toxicity.
Effects on fertility
No impairment of fertility was observed in a well-conducted study involving the
oral administration of up to 600 mg/kg/day of glycolic acid to male and female
rats for 18-22 weeks.
C l a s s i f i c a t i o n . Glycolic acid does not meet the Approved Criteria for
classification as toxic to reproduction.
Lactation effects
Neonatal growth during lactation was not retarded in a well-conducted rat study
in which the dams were dosed orally with up to 600 mg/kg/day of glycolic acid
for 3 months prior to mating and during pregnancy and lactation.
C l a s s i f i c a t i o n . Glycolic acid does not meet the Approved Criteria for
classification as having effects on lactation.
12.2.6 Genetic toxicity
Glycolic acid has been tested in a number of assays for genetic toxicity in
accordance with OECD's Test Guidelines and to GLP standards. The tests
available for assessment included in vitro assays for reverse mutation in bacteria,
forward mutation in mouse lymphoma cells and chromosomal aberration in
Chinese hamster ovary cells. An in vivo somatic cell mutagenicity test (mouse
bone marrow micronucleus test) was also available. All tests were negative,
except the in vitro assay for gene mutation in mouse lymphoma cells which was
positive at high concentrations of glycolic acid (2500-5000 mg/L) in the presence
of metabolic activation.
Glycolic acid is not structurally related to any known germ cell mutagens.
C l a s s i f i c a t i o n . Glycolic acid does not meet the Approved Criteria for
classification as mutagenic.
12.2.7 Carcinogenicity
No carcinogenicity studies were available for assessment and it is not possible to
classify glycolic acid for carcinogenic effects. Ethylene glycol did not induce
77
Glycolic acid
tumours in carcinogenicity studies in rats and mice and is not suspected of having
carcinogenic effects in humans (Cavender & Sowinski, 1994).
12.2.8 Summary of hazard classification
The identified human health hazards and their classification according to the
Approved Criteria are summarised in Table 12.2.
Table 12.2: Summary of hazards and lowest or no observed adverse effect
levels of glycolic acid, with assigned risk phrases as per the Approved
Criteria (NOHSC, 1999a)
Hazard Effect level* Species Classification from review
Acute lethal effects
?ingestion R20/22: Harmful by inhalation
LD50 = 1350 mg/kg Rat
and if swallowed
3
?inhalation LC50 = 2500 mg/m Rat
Corrosion
?skin LOAEL = 70% Rabbit R34: Causes burns
?eyes LOAEL = 57% Rabbit R41: Risk of serious damage
to eyes
Irritation
3
?respiratory R37: Irritating to respiratory
LOAEL = 420 mg/m Rat
system
system
Sensitisation
?skin Negative Guinea pig None
?respiratory system No data Not classifiable
Systemic toxicity
?ingestion Rat None
LOAEL = 300 mg/kg/day
3
Not classifiable
LOAEL = 510 mg/m
?inhalation
?dermal No data Not classifiable
Developmental NOAEL = 150 mg/kg/day Rat None
toxicity
Fertility effects NOAEL = 600 mg/kg/day Rat None
Lactation effects NOAEL = 600 mg/kg/day Rat None
Genetic toxicity Negative Various None
Carcinogenicity No data Not classifiable
* LC50 = median lethal concentration LOAEL = lowest observed adverse effect level
LD50 = median lethal dose NOAEL = no observed adverse effect level
78 Priority Existing Chemical Number 12
13. Current Controls
This section discusses currently employed measures to reduce the likelihood of
adverse human health effects from occupational and consumer exposure to
glycolic acid. The information reviewed includes national and international
standards and guidelines, material safety data sheets (MSDS), labels, and
consumer information materials. Where appropriate, measures for reducing
exposure to glycolic acid are dealt with separately for formulation facilities and
beauty salons.
Relevant information was provided by importers and users of cosmetic grade raw
materials, manufacturers and importers of glycolic acid containing cosmetics in
finished form, a small sample of beauty therapists and beauty therapy schools,
and national and international industry associations.
They key issues discussed in this section include: workplace control measures;
emergency procedures; hazard communication, including MSDS, labels for
workplace and consumer products, education and training of workers, and
consumer information materials; occupational and public health regulatory
controls; and voluntary standards and guidelines.
13.1 Workplace control measures
Based on this assessment, glycolic acid is a hazardous substance in accordance
with the NOHSC Approved Criteria (NOHSC, 1999a). According to the NOHSC
National Model Regulations for the Control of Workplace Hazardous Substances
(NOHSC, 1994c), exposure to hazardous substances should be prevented or,
where this is not practicable, adequately controlled, so as minimise risks to health
and safety.
In general, the control of worker exposure to any hazardous substance should be
achieved through a hierarchy of control strategies comprising elimination,
substitution, isolation, engineering controls, safe work practices, and personal
protective equipment. Control measures are not mutually exclusive and effective
control usually requires a combination of these measures. In relation to glycolic
acid and the cosmetic industry, particular attention must to be paid to control
measures that minimise skin contact with the chemical.
13.1.1 Elimination
Elimination implies the removal of a chemical from a process, such as the use of
a non-chemical process in skin beautification. Such methods exist, but are
generally more expensive and less convenient than the use of chemicals.
13.1.2 Substitution
Substitution includes substituting a less hazardous substance, the same substance
in a less hazardous form or the same substance in a less hazardous process.
79
Glycolic acid
A comparative evaluation of the health effects of chemicals that may be
substituted for glycolic acid in cosmetic products is beyond the scope of this
assessment. However, below is a summary of relevant literature sources. As a
general principle, caution should be exercised when substituting an unknown
hazard for a known hazard, particularly when replacing one material with another
having similar chemical properties.
Lactic acid, which is the closest homologue of glycolic acid, is an ingredient in
many cosmetic products, particularly moisturising creams and lotions. There is
substantial evidence from human in vivo studies that glycolic acid and lactic acid
have essentially similar skin effects (Berardesca et al., 1997; CIR, 1998; Ditre et
al., 1996; Griffin et al., 1996; Johnson et al., 1997; KRA, 1996; Smith, 1994,
1996; Van Scott & Yu, 1974). The toxicology of lactic acid has been reviewed by
the British Industrial Biological Research Association (BIBRA, 1990), CIR
(1998) and in a literature survey commissioned by FDA (KRA, 1996).
A limited number of investigations have compared the human skin effects of
g l y c o l i c acid with other AHAs such as citric acid, 2-hexanoic acid, 2-
hydrobutyric acid, malic acid and tartaric acid (Berardesca et al., 1997; Ditre et
al., 1996; Griffin et al., 1996; Smith, 1996; Van Scott & Yu, 1974).
Derivatives of glycolic acid such as citric acid esters and glycolic acid polymers
are being promoted as safe alternatives to glycolic acid. However, there is no
published evidence to support such claims.
In some beauty salons, glycolic acid is applied in viscous gel or cream
formulations rather than in aqueous solutions as a simple and practicable way of
reducing the risk of dispersion.
13.1.3 Isolation
Importers generally store glycolic acid raw materials in tightly closed containers
in a separate corrosive materials store, in accordance with Australian Standard
(AS) 3780-1994 (see section 13.5.1). As shown in Table 13.1, some small and all
large cosmetics manufacturers employ a partially enclosed formulation process,
with one or more unit operations such as neutralisation, dilution, mixing or
transport taking place in closed vessels or pipework. In all but the smallest
facilities, the filling and packaging processes are automated. These measures will
to a large extent isolate workers from the chemical.
There is limited scope for isolation of beauty salon workers from potential
exposure to glycolic acid as the application of the chemical to the skin of the
client requires manual handling.
13.1.4 Engineering controls
In formulation plants, exhaust ventilation may be installed in weighing and
mixing rooms and occasionally in filling and/or packaging areas (Table 13.1).
No exhaust ventilation is employed in beauty salons, apart from standard air
conditioning.
80 Priority Existing Chemical Number 12
13.1.5 Safe work practices
In formulation, filling and packaging facilities, no work practices were identified
that can be characterised as unique to glycolic acid. Although there is no
requirement to manufacture cosmetics in accordance with Good Manufacturing
Practices (GMP), some facilities also manufacture therapeutic goods and operate
to GMP standards (Table 13.1). These include strict observation of standard
operating procedures for the handling of hazardous substances and training of
staff in safe work practices.
Beauty salon workers are generally trained to handle all products they use exactly
as prescribed in the manufacturer's instruction (see section 13.3.3).
Table 13.1: Control measures in 5 small and 6 large Australian formulation
manufacturing facilities for glycolic acid containing cosmetics
Maximum batch size
200 kg (n = 5)
Control measure 500-1100 kg (n = 6)
Isolation
? 0 1
corrosive raw materials store
? 1 6
partially enclosed process
? 3 6
automated filling/packaging
Engineering controls
? 2 4
exhaust ventilation
Safe work practices
? 1 3
GMP observed
Personal protective equipment
? 2 4
eye protection
? 2 3
face protection
? 4 6
rubber gloves
? 0 3
protective clothing
? 1 3
respiratory protection
13.1.6 Personal protective equipment
Where other control measures are not practicable or adequate to control exposure,
p e r s o n a l protective equipment (PPE) should be used. Appropriate PPE
recommended in available MSDS for glycolic acid raw materials includes eye
and face protection, rubber gloves, protective clothing, and respiratory protection
if there is a possibility of airborne exposure from mists. In practice, whereas
rubber gloves are widely used, only half of the facilities surveyed employ eye and
face protection and only a quarter require their workers to wear protective
clothing (Table 13.1).
A guide for the hairdressing and beauty industry published by the Queensland
Workplace Health and Safety Authority (Anon, 1994) recommends the wearing
of cotton-lined protective gloves to prevent contact with irritating chemicals and
of safety glasses where there is a slight chance of a chemical entering the eye.
Information provided by a small sample of beauty therapists indicates that only a
minority of salon workers wear gloves and that safety glasses are hardly used at
all.
81
Glycolic acid
13.2 Emergency procedures
For any hazardous chemical an emergency response plan is an essential
component of occupational health and safety risk management. In the event of a
substantial leak, spill, release or fire, a written procedure is necessary for workers
and emergency services. Although such plans were not submitted for assessment,
the following emergency procedures have been described in available MSDS:
? neutralise spills with lime or soda ash;
? collect into suitable container and dispose of, or incinerate, in accordance
with applicable regulations;
? clean spill area with plenty of water;
? use carbon dioxide, dry chemical powder, foam or water spray for
firefighting; and
? provide safety showers and eye washes in areas where glycolic acid is used.
With regard to storage of corrosive chemicals, AS 3780-1994 provides guidance
on the preparation of emergency plans. With regard to transport, appropriate
emergency procedures for corrosive substances are contained in AS 1678.8A1-
1987, which is intended to be used in conjunction with the Australian Dangerous
Goods (ADG) Code (FORS, 1998).
13.3 Hazard communication
13.3.1 Assessment of MSDS
MSDS are the primary source of information for workers involved in the
handling of chemicals. Under the NOHSC National Model Regulations for the
C o n t r o l of Workplace Hazardous Substances (NOHSC, 1994c) and the
corresponding State and Territory legislation, suppliers of hazardous chemicals
for use at work are obliged to provide a current MSDS to their customers.
A total of 22 MSDS were provided for assessment, including 6 MSDS for
synthetic, cosmetic grade glycolic acid (70-99%), 7 MSDS for AHA extracts
containing 2.5-17% glycolic acid and 9 MSDS for finished products for salon end
use containing 4-40% glycolic acid.
The MSDS were assessed against the NOHSC National Code of Practice for the
Preparation of Material Safety Data Sheets (NOHSC, 1994b). The most common
deficiencies were:
? lack of date and page numbers;
? no Australian emergency telephone number;
? no information on classification according to the ADG Code;
? insufficient or no supporting toxicological data;
? lack of advice to doctor;
? no reference to engineering controls; and
? inadequate recommendations for PPE, particularly eye and face protection
and protective clothing.
82 Priority Existing Chemical Number 12
13.3.2 Assessment of labels
Raw materials and products for workplace use
Under the NOHSC National Model Regulations for the Control of Workplace
Hazardous Substances (NOHSC, 1994c) and the corresponding State and
Territory legislation, suppliers or employers shall ensure that all containers of
hazardous substances used at work are appropriately labelled in accordance with
the NOHSC Code of Practice for the Labelling of Workplace Substances
(NOHSC, 1994a).
Five labels for synthetic, cosmetic grade raw materials provided for assessment
conformed with all requirements of the NOHSC Code of Practice and the ADG
Code. Three labels for AHA blends containing 5-10%, 10% and 12-17% glycolic
acid respectively provided details of the overseas manufacturer and one of them
also contained safety phrases relating to the use of PPE. They did not comply
with any of the other requirements of the NOHSC Code of Practice.
Seven labels for salon end use products were available for assessment. None of
these complied with the NOHSC Code of Practice, although two contained a
safety phrase and a first aid procedure relating to eye irritation.
Finished products for consumer end use
Where products containing glycolic acid are intended for consumer end use, they
need only comply with the ingredient labelling requirements in the Trade
Practices (Consumer Product Information Standards) (Cosmetics) Regulations.
According to these regulations, cosmetic products must be labelled with a list
indicating their ingredients in descending order by volume or mass1. The names
of the ingredients must be either their English names or their International
Nomenclature Cosmetic Ingredient names and the list must be prominently
shown and clearly legible. There is no requirement to declare the concentration of
any ingredient or the pH of the formulation.
A total of 66 labels for consumer end use products were provided for assessment.
Ten of these did not comply with the Trade Practices (Consumer Product
Information Standards) (Cosmetics) Regulations. Four of the non-compliant
products had no ingredient list at all, whereas one product listed glycolic acid but
no other ingredients. Three products containing plant extracts listed these
ingredients under the Latin name of their source, for example, Saccharum
officinarum in lieu of sugar cane extract. Two labels were not clearly legible
because the print was extremely small or covered by a sticker with the name and
address of the Australian distributor. Nine products complied formally with the
ingredient labelling requirements, but used ingredient names such as sugar cane
extract, mixed fruit acids or mixed fruit AHA extracts, which the average
consumer may not associate with glycolic acid.
13.3.3 Education and training of workers
Four formulation facilities that operate according to GMP stated that they train
their workers in the handling of hazardous chemicals and safe work practices.
1
Ingredients in concentrations of <1% and colour additives may be listed separately in any order.
83
Glycolic acid
Vocational training of beauty therapists is offered by a number of Technical and
Further Education (TAFE) institutes and private beauty schools. TAFE courses
c o n t a i n a module on occupational health and safety, including general
information and standard safety measures relating to hazardous chemicals. These
courses teach students to handle all products exactly as prescribed in the
manufacturer's instruction and generally do not address the use of specific
chemicals such as glycolic acid. Course material for facial treatment classes in
one TAFE institute contained information about adverse effects of AHAs in
clients, but did not mention the potential hazards to beauticians (Moreton, 1999).
The Queensland Workplace Health and Safety Authority has published a fact
sheet on hazardous substances in the hairdressing and beauty industry, which is
also available on the Internet (Anon, 1996). The fact sheet provides general
information about MSDS, labels and control measures and contains a list of
hazardous substances that are common in the hairdressing and beauty industry.
13.3.4 Consumer information materials
Some consumer products provide product information in excess of the ingredient
labelling requirements of the Trade Practices (Consumer Product Information
Standards) (Cosmetics) Regulations. This information may appear on the label of
the primary container, on the outer packaging or in a leaflet supplied with the
product.
Table 13.2 summarises the extent of such additional information supplied with 39
of 66 products that were available for assessment.
13.4 Occupational and public health regulatory controls
13.4.1 Exposure standards and health surveillance
There are no formal requirements for health surveillance programs in workplaces
using glycolic acid and an exposure standard has not been established in Australia
or overseas.
13.4.2 Australian Code for the Transport of Dangerous Goods by Road and Rail
(ADG Code)
Glycolic acid is not listed in the ADG Code (FORS, 1998). However, when tested
by the Corrositex method, crystalline glycolic acid and solutions containing
30% glycolic acid at their natural pH meet the criteria for classification as
corrosive substances (Class 8) and for assignment to Packing Group II (DuPont,
1993; DuPont, 1997a). Such goods would therefore come under UN Number
3260 (corrosive solid, acidic, organic, not otherwise specified) or UN Number
3265 (corrosive liquid, acidic, organic, not otherwise specified) and must comply
with the corresponding requirements of the ADG Code with regard to packaging,
storage, labelling etc.
13.4.3 Standard for the Uniform Scheduling of Drugs and Poisons (SUSDP)
Glycolic acid is not listed in the current SUSDP (Australian Health Ministers'
Advisory Council, 1999).
84 Priority Existing Chemical Number 12
Table 13.2: Type of voluntary consumer information supplied with 39
cosmetic products containing glycolic acid
Products supplied with this
information
Type of information Number %
Identification
? 26 67
name of active ingredient(s)
? 21 54
cosmetic form
? 5 13
glycolic acid content by weight or volume
? 0 0
pH
What the product is used for 36 92
How the product works 12 31
Advice before using the product
? 21 54
contraindications*
? 0 0
precautions for use
? 5 13
special warnings
How to use the product properly
? 18 46
dosage
? 37 95
method of administration
? 33 85
frequency of administration
? 1 3
duration of use
Unwanted effects
?br>
? 32 82
description of undesired effects
? 32 82
action to be taken if experienced
Storage conditions 0 0
Where to go for further information 19 49
Name and address of the Australian product 24 62
sponsor
Date of information 0 0
* Use on sensitive or irritated skin
Effects on sun sensitivity
?br>
Eye and/or skin irritation and/or stinging
13.5 Voluntary standards and guidelines
13.5.1 Australian Standards
The following Australian Standards (AS) and Australian and New Zealand
Standards (AS/NZS) contain information that is relevant to the handling of
glycolic acid in the cosmetic industry, given the corrosive nature of the chemical:
? AS/NZS 1337:1992 ?Eye protectors for industrial application;
? AS 1678.8A1-1987 ?Emergency procedure guide ?transport ?group text
card 8A1 ?corrosive; and
? AS/NZS 2161.2:1998 ?Occupational protective gloves ?general
requirements.
85
Glycolic acid
13.5.2 Industry guidelines
Occupational exposure standards
One large raw material manufacturer has established a control level of 10 mg/m3
(8- and 12-h TWA) glycolic acid in workroom air (DuPont, 1999b). This level
was based on the results of a subacute inhalation study in rats in which the only
e f f e c t in the lowest dose group (160 mg/m3) was a very mild, diffuse
hepatocellular degeneration in 1/10 animals by the end of the recovery period
(DuPont, 1983). As such, this concentration was considered to approach a
NOAEL for exposure through inhalation (Kennedy & Burgess, 1997).
Salon products
The Esthetics Manufacturers and Distributors Alliance of the American Beauty
Association recommends that the concentration of glycolic acid products for
salon end use not exceed 30%, with a pH of at least 3.0 (EMDA, 1996).
The safety of glycolic acid in cosmetic products was reviewed by the CIR Expert
Panel under the US Cosmetic, Toiletry and Fragrance Association (CIR, 1998).
Based on the information included in the CIR report, the Expert Panel concluded
t h a t glycolic acid was safe for use by professional beauty therapists at
concentrations 30%, at pH values 3.0, in products designed for brief,
infrequent, rinse-off use, when application was accompanied by directions for
daily use of sun protection. This conclusion was intended to address concerns
about adverse health effects on clients such as potential irritation, enhancement of
the penetration of other ingredients and increase in sensitivity to sunlight. The
Expert Panel did not consider potential adverse health effects on beauty salon
workers.
Consumer products
With regard to cosmetic products for consumer end use, the CIR Expert Panel
concluded that glycolic acid was safe at concentrations 10%, at final pH values
3.5, when formulated to avoid increasing sun sensitivity or when directions for
use include the daily use of sun protection (CIR, 1998). This conclusion was
intended to address concerns about adverse health effects such as potential
irritation, enhancement of the penetration of other ingredients and increase in
sensitivity to sunlight.
The European Cosmetic Toiletry and Perfumery Association has suggested an
industry code of practice that limits the concentration of AHAs including but not
limited to glycolic acid in retail non-rinse skin care cosmetics to a maximum of
12% and the pH to a minimum of 3.0 (COLIPA, 1996).
In 1996, the Australian Society of Cosmetic Chemists (ASCC) issued a position
paper on AHAs, -hydroxy acids and -keto acids (ASCC, 1996). The paper did
not set concentration or pH limits, but recommended that formulators carry out
the appropriate development, clinical and dermatological tests to determine
efficacy and potential irritancy so as to be able to bring to the consumer AHA-
based products which are effective and safe to use. This position paper is
currently under review. According to a spokesperson for the ASCC Technical
Committee, the revised paper will agree with the CIR findings and suggest limits
86 Priority Existing Chemical Number 12
for the concentration of glycolic acid (and lactic acid) and pH in consumer
products for skin renewal. These limits are likely to be a concentration >2% but
10% and a pH >3.5 (ASCC, 1999). The aim of the 2% limit is to keep the
widespread use of lactic acid and, to a lesser extent, glycolic acid as a pH
adjustment agent exempt from regulations.
Neither the Cosmetic, Toiletry and Fragrance Association nor any other
Australian beauty industry association have established guidelines for the
formulation or use of glycolic acid containing products.
87
Glycolic acid
14. Discussion and Conclusions
14.1 Health effects
The acute lethality of glycolic acid by oral or inhalation exposure, its potential to
cause skin, eye and respiratory system corrosion or irritation, and its subchronic,
developmental and reproductive toxicity have been investigated in well designed
and well conducted animal studies. However, there were no acute or repeated-
dose animal studies of the toxic effects from dermal exposure, other than single-
dose tests for skin corrosion/irritation.
The available animal studies indicate that glycolic acid is harmful by single-dose
ingestion or inhalation. Depending on concentration and pH, it may be either
corrosive or irritating to the skin, eyes and respiratory system. Furthermore, it is
toxic to the kidneys by prolonged or repeated oral administration. When glycolic
acid is given by mouth on a daily basis, it induces malformations at high,
maternally toxic doses. A marginal increase in foetal abnormalities was seen at a
dose of 300 mg/kg/day, which was also associated with marginal maternal
toxicity, with no effects on foetal development at lower doses. There is little
information on the systemic health effects of glycolic acid in humans. In acute
ethylene glycol poisoning, the severity of clinical and biochemical abnormalities
are proportional to the plasma concentration of the metabolite glycolic acid and
plasma levels in excess of 760 mg/L are associated with kidney injury. There are
no case reports in the published literature of systemic or developmental toxicity
resulting from exposure to glycolic acid itself.
A large number of experimental and commercial cosmetic formulations
containing glycolic acid have been tested in humans, mainly in studies conducted
by cosmetic manufacturers to ensure the acceptability of their products. Overall,
these tests have shown a high incidence of adverse events from regular, short- or
long-term use of glycolic acid skin care products, with irritation and stinging
recorded in 13% and 10% of subjects respectively.
Skin irritation is related to glycolic acid concentration, pH, the nature of
excipients and time of residence on the skin. Products containing 20% glycolic
acid or less, at pH 3.5 or above, are not expected to cause skin irritation, although
they may cause a mild to moderate transient stinging sensation in certain
individuals. Products formulated at 20-40% glycolic acid and pH 3.5 may cause
slight irritation. Products formulated at 40% glycolic acid at pH 3.5, or 10% at
pH 3.0 may cause moderate skin irritation. At pH 2.5 and below, products
containing 10% or more glycolic acid may be severe skin irritants. Salon products
formulated at concentrations of 40-60% where the pH is <3.5 may be moderate to
severe skin irritants; at these concentrations, irritation is inversely correlated to
pH. Concentrations of 50% glycolic acid cause sloughing of the epidermis, while
70% glycolic acid is corrosive.
Although stinging is a relatively frequent adverse effect, it is short-lived, not
associated with visible skin lesions and not predictive of more severe reactions to
the chemical.
88 Priority Existing Chemical Number 12
Products formulated at 10-20% glycolic acid, pH 3.8-4.0 would be expected to
cause mild to moderate eye irritation. If the concentration is greater than 10% and
the pH lower than 3.8, it is expected that eye irritation would be moderate to
severe.
One study showed that long-term use of a skin cream with 4% glycolic acid
increased sensitivity to sunburn by up to 50% in some subjects. Glycolic acid has
the dual effects of increasing skin thickness by hydration, while removing the
topmost layer of the epidermis. Thus, immediately following use of cosmetic
products containing glycolic acid, increased hydration of the dermis may afford
protection against sunburn. However, it is reasonable to assume that increased
sensitivity to sunburn may occur if hydration is not maintained and the stratum
c o r n e u m has been thinned by exfoliation, or if skin irritation develops.
Mechanistically, this is likely to represent an additive effect of glycolic acid and
UV light on the release of mediators of inflammation.
A lifetime study in hairless mice investigating the long-term effects from repeated
combined exposure to topically applied glycolic acid and UV irradiation will
begin in 1999 and be completed by 2002. At present there is no evidence from
animal or human studies that glycolic acid facilitates any of the mechanisms that
contribute to the development of sun-induced skin cancers.
14.2 Current use in Australia
Information collected from applicants at the beginning of 1999 indicates that the
consumption of glycolic acid for cosmetic uses in Australia is at least 5.7 t/y, of
which about 2/3 is imported as an ingredient in products manufactured overseas
and the remainder in raw material form.
The chemical is an ingredient in at least 180 cosmetic products, of which 1/7 is
for end use in beauty salons and 6/7 is sold to the public for use at home. Salon
products contain from 4-60% glycolic acid and consumer products between
0.01% and 20% of the chemical. All salon products and more than 90% of
consumer products are used to beautify the skin, with the balance accounted for
by shampoos, conditioners and other hair products used at home. Cosmetic grade
raw materials include crystalline glycolic acid, aqueous solutions containing 70%
glycolic acid and a number of AHA blends containing 2.5-17% glycolic acid
mixed with other AHAs such as lactic, citric, malic and tartaric acids.
There are at least 8 importers of glycolic acid in cosmetic raw materials, 17
importers of finished cosmetic products containing glycolic acid, and 19
businesses that manufacture such products locally. Many of the latter contract out
the formulation. Although some contract formulators manufacture for several
distributors, even the largest facilities do not usually produce more than one batch
per month. Some of the businesses that import, formulate or distribute cosmetics
with glycolic acid are local subsidiaries of, or agents for, large multinational
companies with considerable expertise in the testing of cosmetic products for
safety and acceptability. The majority, however, are small businesses, which do
not have access to such expertise and, in most cases, do not belong to the national
industry association: The Cosmetic, Toiletry and Fragrance Association of
Australia.
89
Glycolic acid
It is estimated that skin treatments with glycolic acid formulations are available in
the majority of Australia's 2500-3000 full-service beauty salons. These salons
also sell glycolic acid skin care products to their customers for home use, as do
most of Australia's 15,000 pharmacies, supermarkets and department stores. Hair
care products with glycolic acid are predominantly distributed through hair
salons, which number about 12,000 nation-wide, although a few are available
from pharmacies and supermarkets.
14.3 Occupational exposure
In Australia, glycolic acid containing cosmetics are formulated at less than 20
facilities, with a maximum of 5 workers per facility who handle the chemical. As
such, the total number of formulation workers exposed to glycolic acid is low.
Furthermore, exposure occurs at intervals of several days to several months.
There are 2500-3000 full-service beauty salons in Australia. The percentage of
salons that use glycolic acid and the average number of workers per salon are
unknown, but as a rough estimate it can be assumed that the number of
Workers in the cosmetic industry are unlikely to be exposed to glycolic acid by
beauticians who use glycolic acid, in some cases on a daily basis, is at least 1000-
2000. ingestion. Skin contact may occur as a result of accidental splashes or
spills. Exposure through inhalation is likely to be low to negligible as the
volatility of glycolic acid is very limited and respirable aerosols formed under
vigorous mixing conditions would contain minimal concentrations of the
chemical. As with other corrosive substances, accidental burns to the skin and
eyes from glycolic acid raw materials are potentially serious and may lead to
disfiguration and time off work.
I n reasonable worst-case scenarios, the potential external exposure is
conservatively estimated at 6.3 mg/kg/day in workers in formulation facilities and
at 1.7 mg/kg/day in beauty salon staff. The NOAEL based on a 3-month oral rat
toxicity test and on maternal and developmental toxicity in pregnant rats given
oral bolus doses of glycolic acid is 150 mg/kg/day.
As such, it is concluded that the known uses of glycolic acid (and products
containing glycolic acid) in the cosmetic industry in Australia are unlikely to pose
significant risks to the health of workers if exposure is appropriately controlled
and that a full occupational risk assessment by NICNAS is not required.
Nonetheless, as glycolic acid is a hazardous chemical, employers of formulation
and beauty salon workers (and self-employed beauticians) should conduct a risk
assessment of their individual workplace and, where necessary, give due
consideration to the control measures discussed in section 13.
14.4 Public exposure
The public will be exposed from skin contact with a variety of cosmetic products
such as face creams, body lotions and gels, scrubs, shampoos, conditioners and
skin peeling solutions. Inhalation exposure may also occur, but vaporisation from
cosmetic formulations would be very low, and public exposure via this route is
expected to be negligible.
90 Priority Existing Chemical Number 12
In reasonable worst-case scenarios, the maximum skin exposure is calculated as
10 mg/kg in clients undergoing treatment in beauty salons and 28 mg/kg/day in
consumers using glycolic acid cosmetics at home, based on the following
estimates of exposure:
? In beauty salons, a single treatment of the arms, legs and backs of the hands
and feet (an area of approximately 7800 cm2) with two applications of a 40%
gel in an amount of 1 mg/cm2 of the product per application, massaged into
the skin, and then rinsed off; and
? For use at home, twice daily application of 0.8 g of a 10% face cream and of
7.5 g of a 10% body lotion massaged into the skin and left on without being
rinsed off.
In both cases, it is assumed that the exposed person has a body weight of 60 kg.
The NOAEL based on a 3-month oral rat toxicity test and on maternal and
developmental toxicity in pregnant rats given oral bolus doses of glycolic acid is
150 mg/kg/day. As such, the calculated margin of exposure (the NOAEL divided
by the estimated human exposure) for the above scenarios would be in the range
of 5.4-15, based on external exposure.
Based on the calculations detailed in Appendix 2, section A2.2, the estimated
maximum systemic absorption in reasonable worst-case scenarios are 4.7 mg/kg
on the day of a salon treatment and 3.4 mg/kg/day for home-use. Exposure
margins calculated from these estimates for systemic uptake range from 32-44.
Absorption through the skin is slower than absorption from the intestine and
therefore would be expected to lead to lower peak blood levels. Although
experimental data are not available, it is possible to estimate the blood levels of
glycolic acid from percutaneous absorption of the chemical in humans and
compare them to the estimated blood levels from ingestion of doses that represent
a reliable NOAEL in animals in vivo. This can be achieved by means of a simple,
one-compartment kinetic model based on the available human and animal data
relating to the absorption, elimination and distribution of the chemical (for
details, see Appendix 2, section A2.2). The modelling indicates that in the skin
exposure scenarios outlined above, blood levels would peak at 2.6 mg/L and 2.5
mg/L respectively1. By comparison, peak blood levels in animals are estimated at
130 mg/L for oral administration of 150 mg/kg/day, which is the NOAEL
obtained in a well-conducted 3-month oral rat toxicity test as well as the NOAEL
based on maternal and developmental toxicity in pregnant rats given oral bolus
doses of glycolic acid on day 7-21 of gestation. Based on the estimated peak
blood levels of glycolic acid, the calculated margin of exposure is 50 for beauty
salon and 52 for at-home applications.
As a rule, for chemicals that are widely used by the general population a margin
of exposure <100 is an indication that problems may arise. However, when
considering the significance for risk of the exposure margins referred to above,
the following particulars should be taken into account:
? The highest internal exposure and estimated peak blood level are in
consumers undergoing treatment in beauty salons which is taken at intervals
1
In normal adult subjects, blood levels of glycolic acid (originating predominantly from dietary intake)
range from 0.1-0.6 mg/L (see Section 9.2).
91
Glycolic acid
of one to several weeks. A NOAEL for single exposures in rats is not
available but is likely to be higher than 150 mg/kg. As such, the true margins
of exposure are likely to be higher than the estimates provided above.
? The target organs for toxicity of glycolic acid in the rat are the kidney and, to
a lesser extent, the liver. Studies of a number of cases of human intoxication
with ethylene glycol indicate that kidney damage in humans is absent or
slight at plasma concentrations of glycolic acid below 760 mg/mL and
significant liver effects have not been recorded.
? The developmental effects in rats are aggravated by the metabolic acidosis
induced by oral bolus doses of glycolic acid solutions at their natural pH. By
contrast, all cosmetic products with glycolic acid for salon or consumer use
are pH-adjusted and only a part of the content of glycolic acid is present as
undissociated acid. Moreover, absorption of glycolic acid through the skin is
slower than from the gastro-intestinal tract and therefore less likely to exhaust
the physiological mechanisms that maintain the acid-base balance of the
body.
As such, it is concluded that the possibility of systemic and/or developmental
toxicity in humans is remote and that normal professional and domestic use of
cosmetic products containing glycolic acid is unlikely to present a significant risk
to public health. Nonetheless, given the potential of glycolic acid to cause skin
and eye irritation at high concentrations and low pH values, this report should be
referred to the National Drugs and Poisons Schedule Committee (NDPSC) for
their consideration. In addition, manufacturers, importers and suppliers of
consumer products should inform consumers that the use of skin exfoliant
cosmetic products may result in an enhanced sensitivity to sunburn, and that use
of sunscreen protection is advised.
14.5 Current regulations and controls
14.5.1 Occupational measures
A survey of workplace control measures showed that none of 11 Australian
formulation facilities employ the full spectrum of measures available to control
exposure to glycolic acid, such as keeping corrosive raw materials in a separate
store, using partially enclosed processes and automated filling and packaging,
installing exhaust ventilation where aerosols may be formed, and providing
workers with appropriate PPE. Control measures are most deficient in the
smallest facilities and least deficient in facilities operating to GMP.
In beauty salons, control measures are limited to the occasional substitution of
solutions with gels or creams to minimise dispersion and of gloves to reduce hand
exposure to the chemical.
An assessment of MSDS and labels for workplace chemicals containing glycolic
acid found a number of deficiencies, particularly with respect to MSDS and labels
for AHA blends and beauty salon products. No MSDS was available for 16/25
products (64%) intended exclusively for in-salon use and of 7 labels available for
examination none was found to comply with the requirements for workplace
chemicals.
92 Priority Existing Chemical Number 12
14.5.2 Labelling of products for consumer end use
Unless one of their ingredients is listed on the SUSDP, cosmetic products for
consumer end use have to comply only with the ingredient labelling requirements
in the Trade Practices (Consumer Product Information Standards) (Cosmetics)
Regulations. These regulations are enforced by the Australian Competition and
Consumer Commission through surveys conducted at regular intervals (DIST,
1998). Nonetheless, 10/66 (15%) of the labels that were available for assessment
did not meet the ingredient labelling requirements and 18/66 products examined
(27%) were labelled in a way that did not explicitly disclose the presence of
glycolic acid in the formulation.
Almost 60% of the products examined were labelled or supplied with voluntary
information over and above the prescribed ingredient labelling. In general, these
consumer information materials were found to provide adequate instructions
about the method and frequency of administration, common undesired effects,
and actions to be taken should such effects occur. None of 39 labels or leaflets
examined provided information on the pH of the product, 34 (87%) did not state
the concentration of the active ingredient, and only 5 (13%) contained a warning
about the possible risk of increased sensitivity to sunburn.
14.6 Data gaps
Glycolic acid has substantial biological and physiological effects, some of which
have not been investigated in detail. The most important data gaps identified
during this assessment of glycolic acid in cosmetic products relate to studies of:
? the systemic toxicity of glycolic acid when applied in repeated doses to the
skin of laboratory animals, with toxicokinetic measurements as required to
extrapolate the findings to humans;
? a developmental toxicity study of glycolic acid in a second species by dermal
administration which would confirm or otherwise the occupational exposure
estimates for the dermal route utilised in the hazard classification in section
12.2.5;
? chronic toxicity and carcinogenicity, with toxicokinetic measurements as
required to extrapolate the findings to humans; and
? the rate and extent of systemic absorption of glycolic acid through human
skin in vivo, including peak and steady state blood concentrations in humans
exposed to standardised at-home and salon treatments, which would confirm
or otherwise the skin absorption parameters estimated from human in vitro
data and utilised in the public exposure assessment in section 14.4.
It is noted that a lifetime study in hairless mice to investigate the effects of
repeated combined skin exposure to glycolic acid and UV irradiation is scheduled
to commence in 1999.
14.7 Conclusions
In conclusion, this preliminary assessment has identified the following health and
safety issues relating to the use of glycolic acid for cosmetic purposes:
93
Glycolic acid
? Moderate to severe skin and eye irritation may result from the use of
c o s m e t i c s containing glycolic acid at high concentrations and low
formulation pH values.
? Glycolic acid may thin the stratum corneum by exfoliation and if skin
hydration is not maintained or skin irritation develops, increased sensitivity to
sunburn could occur.
? Glycolic acid is a hazardous workplace chemical.
? Many MSDS and workplace labels are incomplete and several options
available to reduce worker exposure are not pursued.
? Notwithstanding the statutory requirement for ingredient labelling of
cosmetics, a quarter of the labels examined failed to inform the consumer that
the product contained glycolic acid.
? Many products are supplied without any accompanying consumer
information and when written health and safety advice is provided, it is often
incomplete.
94 Priority Existing Chemical Number 12
15. Recommendations
NICNAS does not recommend a full (risk) assessment of glycolic acid in
cosmetic products at this time. Nevertheless, given the findings discussed in the
previous section, the following recommendations are made:
15.1 NOHSC occupational hazard classification
In accordance with the NOHSC Approved Criteria for Classifying Hazardous
Substances (NOHSC, 1999a) and based on an assessment of health hazards, the
recommended classification for any use of glycolic acid in the workplace is as
follows:
R20/22 Harmful by inhalation and if swallowed
R34 Causes burns
R41 Risk of serious damage to eyes
R36/38 Irritating to eyes and skin
R37 Irritating to respiratory system
It is recommended that glycolic acid be included in the NOHSC List of
Designated Hazardous Substances (NOHSC, 1999b).
The overall classification of a mixture, product or preparation for use at work
depends on the concentration of the hazardous chemicals it contains. It is usually
based on cut-off concentration levels which are tabulated in the NOHSC
Approved Criteria for Classifying Hazardous Substances (NOHSC, 1999a).
However, where a mixture has been tested and classified as a whole, the
classification can be based on the test results rather than on the reference cut-off
concentration levels.
In case of glycolic acid, it should be taken into account that the available skin and
eye corrosivity and irritation studies indicate that the chemical is not corrosive at
concentrations <30% and is only slightly irritant at concentrations <10%. As
such, it is recommended to establish concentration cut-off levels for corrosive and
irritant effects of glycolic acid that are similar to those applied to other
moderately strong organic acids listed in the NOHSC List of Designated
Hazardous Substances (NOHSC, 1999b), such as acetic and propionic acids1.
As such, the recommended reference cut-off levels for each of the classified
hazards of glycolic acid are as follows: 10% and <25% for R36/38; 20% for
R37; and 25% for R20/22, R34 and R41.
As an acid placed on the market in mixtures at various concentrations which
require different labelling, glycolic acid should be listed with labelling note B.
This note requires the supplier to state on the label of workplace chemicals the
1
For acetic and propionic acids the cut-off points for R36/38 are 10% and <25%, whereas the cut-off
point for R34 (which implies R41) is 25%.
95
Glycolic acid
percentage concentration of the hazardous chemical in the mixture (for example,
70% glycolic acid). As there is no precedent in the NOHSC Designated List of
D e s i g n a t e d Hazardous Substances (NOHSC, 1999b) for taking the pH of a
mixture into account in the classification of hazardous workplace substances, the
p e r c e n t a g e concentration would mean the sum of the concentration of
undissociated glycolic acid and of glycolate ion, expressed as glycolic acid.
Mixtures, products or preparations containing other hazardous substances should
be classified by taking into account the health effects of all ingredients, or, if they
have been tested as such, according to the actual test results.
15.2 Further studies
Glycolic acid is not classifiable with regard to serious damage to health by
prolonged exposure in contact with skin or through inhalation because of no or
l i m i t e d data respectively. It is recommended that testing be carried out
investigating the systemic toxicity of glycolic acid following repeated dose
administration by the dermal and inhalation administration route.
15.3 Hazard communication
As glycolic acid is a hazardous substance, employers and suppliers are required
to provide information, such as MSDS and labels, about the hazards of the
chemical. Details of these obligations, consistent with employers' general duty of
care, are provided in the NOHSC National Model Regulations for the Control of
Workplace Hazardous Substances (NOHSC, 1994c).
15.3.1 MSDS
The NOHSC National Code of Practice for the Preparation of Material Safety
Data Sheets (NOHSC, 1994b) provides guidance for the preparation of MSDS.
It is recommended that suppliers amend their MSDS to take account of the
classification and cut-off levels recommended in section 15.1 and, where
necessary, rectify the deficiencies identified in this assessment. Particular
attention needs to be paid to the following:
? inclusion of a statement of hazardous nature;
? appropriate risk and safety phrases;
? inclusion of an Australian emergency contact number;
? inclusion of appropriate advice to doctor;
? inclusion of appropriate engineering controls such as exhaust ventilation if
there is a possibility of aerosol formation; and
? inclusion of appropriate recommendations for PPE, including, in addition to
rubber gloves, the use of eye and face protection, protective clothing, and
respiratory protection if there is a possibility of exposure to aerosols (mists).
15.3.2 Workplace labels
It is recommended that suppliers of glycolic acid raw materials or products for
use at work update their labels to take account of the classification and cut-off
l e v e l s recommended in section 15.1 and, where necessary, rectify the
96 Priority Existing Chemical Number 12
deficiencies identified in this assessment. The labelling requirements are outlined
below:
NOHSC requirements
T h e NOHSC National Code of Practice for the Labelling of Workplace
Substances (NOHSC, 1994a) provides guidance for the labelling of workplace
hazardous substances. Requirements for glycolic acid are as follows:
Signal word (hazard category)
In accordance with NOHSC requirements, a `signal word' should be used in the
l a b e l l i n g of hazardous substances. For glycolic acid the signal words
`HARMFUL' or `HAZARDOUS' are appropriate for workplace chemicals.
Ingredient disclosure
The presence of glycolic acid in a mixture or preparation must be disclosed on
the label (together with its concentration) when present in a mixture at or above
25% w/w.
Risk phrases
T h e risk phrases recommended for mixtures, products and presentations
containing various concentrations of glycolic acid are as follows:
Risk phrase:
Concentration (w/w):
10% but <25% R36/38 Irritating to eyes and skin
20% R37 Irritating to respiratory system
25% R34 Causes burns
Risk of serious damage to eyes1
R41
Safety phrases
The recommended safety phrases for raw materials for industrial use are:
S7 Keep container tightly closed; and
S36/37/39 W e a r suitable protective clothing, gloves and eye/face
protection.
The following safety phrases are recommended for products that are likely to be
used in places to which members of the general public have access, such as
beauty salons:
S2 Keep out of reach of children;
S7 Keep container tightly closed;
S25 Avoid contact with eyes; and
S37 Wear suitable gloves.
1
When an ingredient or mixture is classified as corrosive and assigned R34, the risk of severe damage
to the eye is considered implicit and R41 may be omitted from the label.
97
Glycolic acid
First aid statements
The following first aid statements are recommended for raw materials for
industrial use as well as for products that are likely to be used in places to which
members of the general public have access, such as beauty salons:
S26 In case of contact with eyes, rinse immediately with plenty of water and
contact a doctor or Poisons Information Centre; and
S45 In case of accident or if you feel unwell, contact a doctor or Poisons
Information Centre immediately (show the label where possible).
Decanting
Where glycolic acid (or a mixture, product or preparation containing 10% w/w
of the chemical) is decanted into non-original containers and not consumed
immediately, such containers must be labelled with the name of the product and
the appropriate risk and safety phrases.
Other hazardous ingredients
Glycolic acid products containing other hazardous ingredients should be
classified and labelled accordingly.
Dangerous goods requirements
The following information should also appear on the label for glycolic acid in
mixtures, products or preparations containing 30% of the chemical in order to
comply with the requirements of the ADG Code (FORS, 1998):
? UN Number 3260 (if in solid form in containers with a capacity 500 g)
? UN Number 3265 (if in liquid form in containers with a capacity 500 mL)
? Dangerous Goods Class ?Class 8.
15.3.3 Education and training of workers
Guidelines for the induction and training of workers potentially exposed to
hazardous substances are provided in the NOHSC National Model Regulations
for the Control of Workplace Hazardous Substances (NOHSC, 1994c).
Workers potentially exposed to glycolic acid need to be trained in safe handling,
storage, transportation and disposal of the chemical. Training should provide
information on the health and safety hazards of glycolic acid and should address
appropriate control and safety measures required to minimise occupational
exposure. It is recommended that beauty therapy teachers and employers of
b e a u t y salon workers refer to the following publication: Guide for the
hairdressing and beauty industry. Brisbane, QLD, Division of Workplace Health
and Safety, Department of Employment, Vocational Education, Training and
Industrial Relations (Anon, 1994).
MSDS for glycolic acid and/or glycolic acid containing products should be made
freely available to all workers with potential exposure.
98 Priority Existing Chemical Number 12
15.4 Occupational control measures
Under the NOHSC National Model Regulations for the Control of Workplace
Hazardous Substances (NOHSC, 1994c), an employer shall ensure that an
assessment is made of the risks to health at any workplace using a hazardous
chemical. Where the assessment indicates that it is necessary, the employer shall
ensure that exposure is either prevented or, where that is not practicable,
adequately controlled so as to minimise risks to health. With regard to glycolic
acid, particular attention should be paid to worker exposure via skin contact and
the inhalation of aerosols (mists). A number of relevant control measures such as
isolation, ventilation and the use of PPE are described in section 13.
15.5 Public health recommendations
Given the potential of glycolic acid to cause skin and eye irritation when used in
cosmetic products at high concentrations and low pH values, this report should be
referred to the National Drugs and Poisons Schedule Committee (NDPSC) for
their consideration.
It is also recommended that importers and manufacturers of cosmetic products
comply with the ingredient labelling requirements in the Trade Practices
(Consumer Product Information Standards) (Cosmetics) Regulations and clearly
indicate whether such products contain glycolic acid. Furthermore, importers and
manufacturers that supply a consumer information document with their products
should amend the information to rectify the deficiencies identified in this
assessment. In particular, consumers should be advised that the use of skin
exfoliant cosmetic products may result in an enhanced sensitivity to sunburn and
that use of sunscreen protection is advised, and to immediately discontinue use of
the product if skin irritation or increased sensitivity to sunburn occurs.
15.6 Uses outside the scope of the assessment
The scope of this assessment was limited to glycolic acid in cosmetic products.
However, many of the recommendations set out above are applicable to other
industrial or domestic uses of the chemical. As such, this report will be
forwarded to agencies and government bodies responsible for the use of
chemicals in other industries, in non-cosmetic products for domestic use, or by or
as directed by members of the medical profession.
99
Glycolic acid
16. Secondary Notification
Under Section 65 of the Industrial Chemicals (Notification and Assessment) Act
1 9 8 9 , secondary notification of glycolic acid may be required where an
introducer of the chemical becomes aware of any circumstances that may warrant
a reassessment of its hazards and risks. Specific circumstances include:
? the function or use of glycolic acid has increased, or is likely to change,
significantly;
? the amount of glycolic acid introduced into Australia has increased, or is
likely to increase, significantly;
? manufacture of glycolic acid has begun in Australia; and
? additional information has become available to the introducer as to the
adverse health effects of glycolic acid, such as the results of any of the
studies identified in sections 14.6 and 15.2.
The Director (Chemicals Notification and Assessment) must be notified within
28 days of the manufacturer/importer becoming aware of any of the above or
other circumstances prescribed under section 65 of the Act.
100 Priority Existing Chemical Number 12
Appendix 1
Cosmetic Products Containing Glycolic Acid
This appendix provides a list of cosmetic products containing glycolic acid that were marketed in
Australia in 1998/99. The list includes the trade name of each product and, where available, the
concentration of glycolic acid in the product (in % w/w) and the pH of the formulation. Where the
notified pH covered a range of values, the pH listed is the mean of that range.
The list was compiled during the first half of 1999 from information supplied by applicants and
notifiers. It is not intended to be a comprehensive listing. Formulations may have changed since
the preparation of the list and some products may no longer be commercially available.
Trade name % glycolic acid pH
ADN Revitalising Skin Renewal Complex 1.20 6.30
AHA Biofruit Liposome 0.23 4.10
AHA Booster Complex 2.50 4.40
Anew All-In-One Intensive Complex Cream 2.00 3.90
Anew All-In-One Perfecting Complex Cream 1.00 3.80
Anew All-In-One Perfecting Complex Lotion 1.00 3.80
Anew Intensive Line Minimiser 8.00 3.80
Anew Peel Off Mask 6.00 4.50
Antioxidant Performance Night Cream 0.48 4.25
Antioxidant Triple Performance AHA Fruit Peel 1.45 4.25
Aqua Glycolic Astringent 6.50 3.80
Aqua Glycolic Body Cleanser 8.00 4.40
Aqua Glycolic Body Scrub 8.00 4.40
Aqua Glycolic Face Cream 5.60 4.40
Aqua Glycolic Facial Cleanser 6.50 4.40
Aqua Glycolic Hand & Body Lotion 8.00 4.40
Aqua Glycolic Shampoo 8.00 4.40
Arbre Fruit Extracts Booster Serum 6.30
Arbre Fruit Extracts Cleanser and Tonic 0.20
Arbre Fruit Extracts Hand & Body Lotion 9.50
Arbre Fruit Extracts Masque 30.00
Beta Alistine Skin Science AHA Treatment Serum 9.00
Better Body Works Facial Cream 5.00 5.50
BiON Glycolic Acid Exfoliator 30% 30.00 2.30
BiON Glycolic Acid Exfoliator 40% 40.00 2.30
BiON Glycolic Acid Exfoliator 60% 60.00 2.00
BiON Glycolic Cleanser 4.00 3.70
BiON Glycolic Gel 15.00 3.20
BiON Glycolic Salicylic Gel 10.00 3.20
Body Works Shower Gel 0.01 5.20
Bodysilk Exfoliating Gel 20.00 3.40
Buffered Alphahydroxy Peel 40.00 3.00
C'est Ravir AHA Revitalising Body Lotion 10.00 4.00
C'est Ravir Glyco-Excell 30.00 3.50
101
Glycolic acid
Trade name % glycolic acid pH
C'est Ravir Glyco-Gel 15.00 3.50
C'est Ravir Glycolic Body Scrub 8.00 3.80
C'est Ravir Glycolic Cleanser 8.50 3.80
C'est Ravir Glycolic Complex Serum 6.00 3.50
C'est Ravir Glycolic Eye & Lip Cr鑝e 1.00 4.00
C'est Ravir Glycolic Facial Lotion 8.50 4.00
C'est Ravir Glycolic Pro-Gel 10.00 3.50
C'est Ravir Glycolic Transformation 5.00 3.50
C'est Ravir Renu Skin Defense 6.00 3.80
C'est Ravir Soft Grain Scrub 1.00 3.70
Colored & Permed Conditioner 0.01 5.30
Colored & Permed Shampoo 0.03 5.95
David Jones Natural Extracts Skin Repair Cream 1.00 4.20
Demineralising Shampoo 0.03 5.45
Dermasilk Exfoliating Clay Mask 15.00 3.30
Dermasilk Eyecare Complex 3.60
Dermasilk Resurfacing Cleanser 10.00 3.50
Dermasilk Resurfacing Cream 5% 5.00 3.60
Dermasilk Resurfacing Cream 10% 10.00 3.40
Dermasilk Resurfacing Cream 15% 15.00 3.20
Dermasilk Resurfacing Cream 20% 20.00 3.00
Dermasilk Resurfacing Gel 10% 10.00 3.30
Dermasilk Resurfacing Gel 15% 15.00 3.20
Dermasilk Resurfacing Gel 20% 20.00 3.10
Dermasilk Resurfacing Lotion 10% 10.00 3.30
Dermasilk Resurfacing Lotion 15% 15.00 3.20
Dermasilk Resurfacing Lotion 20% 20.00 3.10
Dermasilk Toning Mist 10.00 3.50
Dermline Selftanning Lotion 5.00 3.70
Elucent Skin Refining Day Cream 4.00 4.00
Elucent Skin Refining Face & Body Lotion 4.00 4.00
Elucent Skin Refining Gentle Cleanser 4.00 4.00
Elucent Skin Refining Night Cream 4.00 4.00
Energy Lift Body Wash 0.01 5.20
Equalise Shampoo 0.01 5.25
Fleur de Mer Fruit Acid Active Hand & Body Cream 1.45 4.00
Fleur de Mer Fruit Acid Active Moisturising Cream 1.00 4.00
Fleur de Mer Fruit Acid Active Solution 14.50 4.50
Frith's Pharmacy's Glycollic Acid 5% 5.00
Frith's Pharmacy's Glycollic Acid 10% 10.00
Glycolic Polymer Cr鑝e 5% 5.00 3.50
Glycolic Polymer Cr鑝e 10% 10.00 3.00
Glycolic Polymer Eye Cr鑝e 4.00 3.50
Glycolic Polymer Solution 5% 5.00 3.00
Glycolic Polymer Solution 10% 10.00 2.50
Glycolic Polymer Solution 20% 20.00 1.50
Glymed Plus Active Exfoliator 15.00 3.20
Glymed Plus AHA Accelerator 9.60 3.70
Glymed Plus AHA Exfoliating Masque 5.10 3.70
Glymed Plus Alpha Therapeutic Foot Cream 5.00 3.80
102 Priority Existing Chemical Number 12
Trade name % glycolic acid pH
Glymed Plus Alpha Therapeutic Hand & Body Lotion 9.20 3.80
Glymed Plus Eye & Lip Renewal Complex 3.20 4.50
Glymed Plus Facial Hydrator 8.70 3.70
Glymed Plus Gentle Facial Wash 8.60 3.70
Glymed Plus Prep Solution 7.00 3.20
Glymed Plus Serious Skin Action Gel 9.40 3.80
Glymed Plus Therapeutic Body Scrub 9.50 3.80
Glymed Plus Treatment Cream 9.80 3.70
Hair Energising Complex 0.01 4.95
Hand & Nail Treatment Cr鑝e 5.00 5.00
Intensive Hair Treatment 0.01 4.25
Juvena Skin Balancer Gel 0.10 4.50
MD Body Scrub 8.90 3.80
MD Facial Cleanser 7.10 3.80
MD Facial Cream 8.30 3.80
MD Facial Lotion 7.10 3.80
MD Glycare 10 8.30 3.80
MD Glycare 5 4.20 3.80
MD Glycare Cleansing Gel 7.10 3.80
MD Glycare Perfection Gel 3.20 3.25
MD Glycare Shampoo & Body Gel 7.10 3.80
MD Glycolic Facial Gel 25.80 3.25
MD Hand & Body Cream 8.30 3.80
MD Hand Treatment Gel 25.80 3.25
MD Nail & Cuticle Complex 6.00 3.80
MD Pedicream 10.70 3.80
MD Sensitive Skin Cleanser 6.70 4.40
MD Sensitive Skin Cream 7.80 4.40
MD Sensitive Skin Lotion 6.70 4.40
MD Skin Bleaching Gel 5.60 4.40
MD Skin Cleansing & Prepping Scrub 9.70 3.25
MD Skin Cleansing & Prepping Solution 4.50 3.25
MD Smoothing Complex 6.50 3.25
MD Vit-A-plus 2.80 4.40
Medi-Care Shampoo 0.03 5.25
Natio Wrinkle Defence Cream 1.00 4.40
Natura Biss?Glyco Eye 10.00 4.50
Natura Biss?Glyco-Peeling 25.00 4.50
Natura Biss?Glyco-Peeling Plus 50.00 4.50
Natural Care Skin Balancing Lotion 0.10 4.10
Natural Care Skin Renewal Lotion 0.10 4.10
Neostrata AHA Skin Smoothing Cream 8.00 3.50
Neostrata AHA Skin Smoothing Lotion 10.00 3.80
Neostrata AHA Solution for Oily/Acne Prone Skin 8.00 4.00
Neutrogena Healthy Skin Eye Cream 0.50 6.60
Neutrogena Healthy Skin Face Lotion 8.00 3.50
Neutrogena Healthy Skin Face Lotion Delicate Skin 4.00 4.10
Peaceful Moment Body Wash 0.01 5.20
Pevonia After Shaving Cream 5.00 4.50
Pevonia After Shaving Gel 5.00 4.50
103
Glycolic acid
Trade name % glycolic acid pH
Pevonia Body Moisturizer 5.00 4.00
Pevonia Clarifyl Care Cream 5.00 3.50
Pevonia Clarifyl Purifying Mask 5.00 4.00
Pevonia Clarifyl Spot Treatment 9.80 3.60
Pevonia Desincrustation Gel 9.80 3.60
Pevonia Eye Cream 2.00 4.50
Pevonia Foot Dry Oil 5.00 3.50
Pevonia Multi Active Foot Cream 10.00 3.50
Pevonia Multi Active Hand Cream 8.00 4.50
Pevonia O2-Oxygenating Treatment 9.70 3.60
Pevonia Radiance Glycocides Cream 8.00 4.50
Pevonia Radiance Lightening Fluid 5.00 4.00
Pevonia Radiance Lightening Mask 5.00 4.00
Poly Glyco Body Lotion 10.00 3.50
Pond's Age Defying Complex Cream - Delicate 4.00 3.80
Pond's Age Defying Complex Cream - Normal 8.00 3.80
Pond's Age Defying Lotion 4.00 3.80
Principal Secret AHA Booster Complex 2.50 4.40
Refining Body Cleanser 4.00 4.10
Refining Facial Cleanser 6.00 4.00
Revelery Skin Logics AHA Cream 1.00 4.20
Revitalising Cr鑝e 7.00 5.80
Revitalising Lotion 10.00 5.80
Riche Cr鑝e Anti-Wrinkle 1.00 4.70
RVB Fluid Smoother 5.50
RVB Opalising Cream 0.06 4.50
RVB Opalising Intensive Drops 1.12 5.75
RVB Opalising Mask 1.12 5.75
RVB Restructuring Cream 1.12 4.50
RVB Restructuring Intensive Drops 1.12 4.75
RVB Restructuring Mask 1.12 5.75
RVB Soothing Cream 1.12 4.60
RVB Soothing Intensive Drops 1.12 5.40
RVB Vitalising Cream - Dry Skin 1.12 4.40
RVB Vitalising Cream - Oily Skin 0.06 5.75
Sanctum Firming Clay Mask 0.30 6.00
Sanctum Skin Rejuvenation Fruit-Acid Night Lotion 0.75 6.00
Shine & Volume Conditioner 0.01 5.30
Shine & Volume Shampoo 0.03 5.25
Skinbiance Daily Moisterising Cream with AHAs 0.70 4.25
Skinbiance Daily Moisturising Lotion with AHAs 0.70 4.25
Spa Dynamique Cellulite Smoothing Gel 1.00 5.00
Tropical Escape Body Wash 0.01 5.20
Wild Mate Naturally Rich Moisturising Lotion w/ AH 1.50 5.00
Works Moiturising Liquid Keratin Complex 0.01 3.00
Yves Saint Laurent Fruit Jeunesse 2.50
104 Priority Existing Chemical Number 12
Appendix 2
Exposure Calculations
A2.1 Occupational exposure
A2.1.1 Modelling of airborne levels
The EASE model was used to provide an independent estimate of glycolic acid air
concentrations for all scenarios for which measured levels were available. The input to
the model for each of these scenarios is summarised in Table A1.1. For liquids, the input
also included the vapour pressure of glycolic acid over a 70% aqueous solution at 45癈
given in Table 5.1.
Table A1.1: Input to EASE model used to estimate glycolic acid air levels in various
occupational settings
Average
Process glycolic acid
Setting temperature concentration Use pattern Control pattern LEV*
Synthesis 200癈 70% Closed system Full containment No
Purification 50癈 70% Closed system Full containment No
Road tanker Out-
25癈 70% Non-dispersive Segregation
loading doors
Drumming 25癈 70% Non-dispersive Segregation No
Simulated 25癈 70% Non-dispersive Segregation No
blending
Formulation 40癈 40% Closed system Full containment No
with significant
manufacture
breaching
Formulation 25癈 5% Non-dispersive Segregation No
manufacture
Formulation 28癈 45% Non-dispersive Segregation No
manufacture
Beauty salon 25癈 20% Non-dispersive Direct handling No
use
* Local exhaust ventilation
The output was converted from ppm to mg/m3 by multiplication with 3.1 (see section 5.1)
and reduced proportionally to account for process mixtures containing <70% glycolic
acid, as recommended in the EASE manual (EC, 1996). The final estimates are shown in
Table 8.1.
Based on the measured and modelled data reproduced at section 8.2.1, a breathing zone
concentration of 2 mg/m3 was taken to be the maximum airborne exposure from mixtures
containing 70% glycolic acid, whereas a breathing zone concentration of 1 mg/m3 was
taken to be the maximum airborne exposure from any mixture containing 45% glycolic
acid.
A2.1.2 Dermal exposure
Dermal exposure was estimated for occupational exposure to a 70% raw material and a
40% final formulation. In case of the former, direct skin contact was assumed to be
105
Glycolic acid
incidental (one event per day, typically resulting from splashes or spills). In case of the
final formulation, skin contact was assumed to be intermittent, that is, 2-10 events per
day.
When these variables were entered into the EASE model, the predicted maximum dermal
exposures amounted to 0.1 mg/cm2/day of the raw material and 1 mg/cm2/day of the final
formulation. These values were then converted to mg/day glycolic acid by factoring in the
concentration of glycolic acid (70% and 40% respectively) and the exposed skin area,
which by convention was assumed to be predominantly the hands and forearms (2000
cm2).
As such, the calculated dermal exposure was 140 mg/day from the raw material (70%
glycolic acid) and 800 mg/day from the final formulation (40% glycolic acid). Dermal
exposure from a final formulation containing 70% glycolic acid as used in skin clinics
under medical supervision was calculated at 1400 mg/day.
A2.1.3 Combined inhalation and skin exposure
Combined exposure through inhalation and skin contact expressed as mg/kg/day was
calculated as the sum of AL x T x R/BW and DE x T/8/BW, where AL is the airborne
level, T the exposure time in hours, R the standard inhalation rate of 1.3 m3/h for
occupational exposure during light work activities (OECD, 1993), BW the standard
bodyweight of 70 kg for men and 60 kg for women, and DE the dermal exposure in
mg/day.
Formulation plant workers
In a reasonable worst-case scenario based on the manufacture of a 40% formulation from
a raw material containing 70% glycolic acid, one worker would spend 2 h at pre-weighing
and mixing followed by 4 h at the filling line. The resulting exposures are:
inhalation: [(2 mg/m3 x 2 h + 1 mg/m3 x 4 h) x 1.3 m3/h] / 70 kg = 0.1 mg/kg/day
?br>
? skin contact: [(140 mg/day x 2/8) + (800 mg/day x 4/8)] / 70 kg = 6.2 mg/kg/day
? total: 6.3 mg/kg/day.
Beauty salon workers
Workers in beauty salons may be exposed to inhalation of vapours originating from, and
to intermittent skin contact with, products they work with. In a reasonable worst-case
scenario, a beautician may perform 3 skin peels per day, each lasting 15-20 min,
corresponding to a maximum of 1 h of direct handling of glycolic acid. Assuming that all
peels are done with a 40% formulation, the resulting exposures are:
inhalation: (1 mg/m3 x 1 h x 1.3 m3/h) / 60 kg = 0.02 mg/kg/day
?br>
? skin contact: [800 mg/day x 1/8] / 60 kg = 1.7 mg/kg/day
? total: 1.7 mg/kg/day.
Skin clinic workers
Nurses and other staff in skin clinics handle and apply formulations containing up to 70%
glycolic acid. In a reasonable worst-case scenario, it is assumed that such staff, like
beauty salon workers, may perform 3 applications per day, each lasting 15-20 min,
corresponding to a maximum of 1 h of direct handling of glycolic acid. During this time
they would be exposed to air levels of glycolic acid equal to a maximum of 2 mg/m3 and
106 Priority Existing Chemical Number 12
have intermittent skin contact with the formulation corresponding to a maximum dermal
exposure to the hands and forearms (2000 cm2) of 1 mg/cm2/day of the formulation or
1400 mg/day of glycolic acid. This would result in the following total exposure:
inhalation: (2 mg/m3 x 1 h x 1.3 m3/h) / 60 kg = 0.04 mg/kg/day
?br>
? skin contact: [1400 mg/day x 1/8] / 60 kg = 2.9 mg/kg/day
? total: 2.9 mg/kg/day.
A.2.2 Estimated internal exposure and blood levels of glycolic acid in consumers
Blood levels were calculated from a simple, one-compartment kinetic model based on the
available human or animal data relating to the absorption, elimination and distribution of
glycolic acid. The simulations were carried out using the Micromath Scientific Software.
Programming involved modification of package routines to reflect the timing of dosing
and the particular input for the various scenarios.
For at-home treatment with leave-on products, systemic uptake was estimated at 3.4
mg/kg/day by multiplying the external exposure (28 mg/kg/day, see section 8.3.1) by
0.12, which was the maximum in vitro penetration from a 5% glycolic acid cream applied
to skin specimens from several human donors in an amount equal to 3 mg/cm2 (Kraeling
& Bronaugh, 1997). Furthermore, absorption through the skin was assumed to occur at a
constant rate, that is, 3.4/24 = 0.14 mg/kg/h for twice daily application of a 10% face
cream and body lotion.
The reasonable worst-case scenario for beauty salon treatment was defined as the
application of a 40% glycolic acid formulation at pH 3.0 to the arms, legs and back of the
hands and feet, massaged into the skin and then rinsed off. According to industry sources,
the rinse off takes place after 15 min in the case of neck and hand treatments. For a
treatment of the arms, legs and back of the hands and feet the maximum contact time was
estimated at 20 min to allow for the additional time needed to manually rinse off a larger
skin area. Because of the high concentration of glycolic acid and short exposure time,
skin absorption was calculated from the experimentally determined permeability
coefficient given in section 9.1.1, the concentration of free glycolic acid in a 40% solution
at pH 3.0 estimated from the graph in Figure 5.2, the area of treated skin, and the
exposure time, as follows: (3 x 10-4 cm/h x 0.9 x 400 mg/mL x 7800 cm2 x 1/3 h)/60 kg =
4.7 mg/kg.
Other kinetic parameters included the distribution volume of glycolic acid determined at
0.56 L/kg by Jacobsen et al. (1988) and the elimination half-life, which was assumed to
be the lower of the two values reported in the literature (see section 9.4), that is, 7 h. For
absorption through the skin, the absorption half-life was assumed to be 10 h.
The calculation of a reference blood level in animals was based on a NOAEL of 150
mg/kg, which was the highest oral dose level that did not cause systemic toxicity in a 3-
month rat study or maternal or developmental toxicity in pregnant rats exposed to glycolic
acid on day 7-21 of gestation (DuPont, 1996, 1999a). Other kinetic parameters included a
distribution volume of 0.66 L/kg and an elimination half-life of 3 h as determined by
Carney et al. (1997, 1999) in pregnant rats1. Absorption was assumed to be complete,
with an absorption half-life of 1 h.
The results of the toxicokinetic modelling are shown in the graphs below. The peak blood
levels were as follows:
1
The distribution volume was calculated from the dose (650 mg/kg or 8.55 mmol/kg), the area under the curve (55.9
mmol_h/L) and the elimination half-life.
107
Glycolic acid
(A) 2.5 mg/L in humans from twice daily application of a standard quantity of a face
cream and a body lotion containing 10% glycolic acid;
(B) 2.6 mg/L in humans from weekly skin peels of the arms, legs and back of the
hands and feet with a formulation containing 40% glycolic acid; and
(C) 130 mg/L in rats from a daily oral bolus dose of 150 mg/kg glycolic acid.
A2.3 Factors limiting occupational exposure
T h e following sections provide detailed considerations in relation to doses for
classification of glycolic acid for developmental toxicity.
In assessing the potential harmful effects from inhalation or skin contact with glycolic
acid in the workplace, consideration must be given to a number of factors that tend to
limit the quantity of glycolic acid that is likely to enter the body. These include the
physical properties of the chemical (see section 5.1), the permeability of human skin to
glycolic acid (section 9.1.1), and the tendency for concentrated formulations and aerosols
(mists) of glycolic acid to cause acute irritation of the skin and respiratory system
respectively (section 12.2.2).
A.2.3.1 Potential for volatilisation
Glycolic acid can be characterised as a practically non-volatile substance, with zero
vapour pressure in solid form at 25癈 and a partial vapour pressure of approximately 2 Pa
(0.0144 mm Hg) over a 70% solution at 45癈 (Table 5.1). Even upon boiling of pure or
dissolved glycolic acid, which causes the chemical to decompose, the vapour pressure
does not exceed 1 kPa (7.5 mm Hg). As such, significant airborne exposure to glycolic
acid can only occur with substantial mist formation, that is, the generation of aerosols of
tiny, air-suspended droplets of an aqueous solution of the chemical. During formulation,
the potential for aerosol formation is limited even in worst-case process scenarios such as
vigorous stirring and mixing, with air levels of glycolic acid not exceeding 2 mg/m3 a few
cm above an open vessel (DuPont, 1999b). However, the aerosol was found to consist of
particles in the 0.4-1 祄 or respirable range.
It should be noted that the above findings do not necessarily apply to other uses of
glycolic acid in other industries. An analysis of this subject is beyond the scope of this
assessment. However, it is known that glycolic acid is an ingredient in water-based
industrial cleaning products, which may be applied in spray form or to hard surfaces
under pressure, thus resulting in mist formation. Therefore, the possibility of occupational
exposure to significant air levels of glycolic acid, although unlikely in the cosmetic
industry, cannot be excluded in a wider context.
A2.3.2 Absorption and local irritation from skin contact
Skin absorption from glycolic acid solutions containing >10% glycolic acid at their
natural pH (<0.1) is a linear function of concentration, time and the exposed skin area. Its
extent in mg/day can be estimated by multiplication of the concentration (mg/mL) with
the permeability coefficient (3 x 10-4 cm/h), duration of exposure (8 h/day), and exposed
skin area (by convention, the hands and forearms = 2000 cm2). The likelihood of systemic
toxic effects from occupational skin exposure to glycolic acid can then be determined
from the lowest glycolic acid concentration (Cmin) that would lead to an internal exposure
equal to the NOAEL for developmental effects in experimental animals (150 mg/kg/day,
see Table 12.2).
108 Priority Existing Chemical Number 12
For a person weighing 70 kg the applicable equation is:
Cmin mg/mL x 3 x 10-4 cm/h x 2000 cm2 x 8 h/day = 150 mg/kg/day x 70 kg
which solved for C min gives a concentration of 2200 mg/mL (or 1500 mg/mL for a 12-h
exposure). It corresponds to a concentration in excess of 100%1. It can therefore be
concluded that developmental toxicity from occupational skin exposure to glycolic acid is
unlikely to constitute a practical hazard.
This is supported by animal and in vitro observations indicating that formulations
containing 30% glycolic acid are corrosive (section 10.2.1). Spills on the skin would
therefore cause acute discomfort and most likely be rinsed off immediately.
A.2.3.3 Absorption and local irritation from aerosol inhalation
Internal exposure to glycolic acid from the inhalation of aerosols can be calculated in a
similar manner. The bioavailability of inhaled glycolic acid is unknown, although the
small particle size of aerosols from cosmetic grade raw materials means that it may be
high. For the purposes of this evaluation it will be assumed to be 100%.
For a 70-kg worker with an inhalation rate of 1.3 m3/h (OECD, 1993), the lowest airborne
concentration (ACmin) of glycolic acid leading to an internal exposure equivalent to 150
mg/kg/day can be calculated from the following equation:
ACmin mg/m3 x 1.3 m3/h x 8 h/day = 150 mg/kg/day x 70 kg
which solved for ACmin gives an airborne concentration of 1000 mg/m3 (or 670 mg/m3 for
a 12-h exposure)2. An aerosol concentration of 1000 mg/m3 is physically feasible as air
l e v e l s as high as 3640 mg/m3 have been achieved experimentally by means of
nebulisation (DuPont, 1998c). On the other hand, the available inhalation studies in
experimental animals showed serious irritation of the respiratory tract at airborne
exposures 420 mg/m3 (DuPont, 1998c). It is therefore unlikely that a worker would
tolerate more than very brief periods of inhalation of glycolic acid aerosols at the levels
required to attain an internal dose that is equivalent to the NOAEL for developmental
effects in experimental animals.
A.2.3.4 Absorption from combined skin contact and aerosol inhalation
Similar calculations can be applied to scenarios involving combined skin contact and
inhalation of glycolic acid. An airborne exposure equal to the level associated with
respiratory system irritation in animals (420 mg/m3) would result in an internal dose of
420 mg/m3 x 1.3 m3/h x 8 h/day / 70 kg = 62 mg/kg/day, which means that the balance of
150 ?62 mg/kg/day = 88 mg/kg/day would have to come from skin contact. Substituting
this dose for the NOAEL in the equation given in section A2.3.2 and solving for Cm a x
gives a concentration of 1280 mg/mL glycolic acid for an 8-h and of 860 mg/mL for a 12-
h exposure (or 1170 mg/mL and 740 mg/mL respectively for a 60-kg worker). Even the
lowest of these Cmax values corresponds to a solution containing about 60% glycolic acid.
Therefore, combined airborne exposure and skin contact is unlikely to result in an internal
dose equivalent to the NOAEL in animals based on developmental effects from repeated
exposure.
1
For a female worker weighing 60 kg, Cmin is 1900 mg/mL (or 1250 mg/mL for a 12-h exposure). This corresponds
to a solution containing >100% or, for a 12-h exposure, >80% glycolic acid.
2
For a female worker weighing 60 kg, ACmin is 865 mg/m3 (or 575 mg/m3 for a 12-h exposure).
109
Glycolic acid
[Graphs]
110 Priority Existing Chemical Number 12
Appendix 3
Studies Excluded from Assessment
This appendix provides a list of references to animal and human studies that were available for
assessment but were not reviewed for the reasons set out in sections 10 and 11.
Acute toxicity
Delphaut J (1951) A study of hepato-renal diuresis. VIII. Pharmacodynamic studies. M閐icin
Tropical, 12:641.
Delphaut J, Bernard P (1951) A study of hepato-renal diuresis. IV. Trials with glycolic acid.
M閐icin Tropical, 12:634-638.
DuPont (1940) Report No. MR-86-1, HL-2-40. Newark, DE, Haskell Laboratory.
DuPont (1962) Hydroxyacetic acid 70% technical: Federal Hazardous Substances Labelling Act
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DuPont (1964) Report No. MR-712-1, HL-33-64.
DuPont (1973) Report No. MR-1968-1, HL-418-73. Newark, DE, Haskell Laboratory.
DuPont (1981) Acetic acid, hydroxy-: Inhalation median lethal concentration (LC50) in rats.
Report No. MR-3817-1, HL-862-81. Newark, DE, Haskell Laboratory.
Corrosivity and irritation
Carpenter CP, Smyth HF (1946) Chemical burns of the rabbit cornea. American Journal of
Ophthalmology, 29:1363-1372.
Dermatech (1993) Mixed fruit acid (MFA) dermal safety: 10 day primary irritancy study.
Unpublished data submitted by CTFA (95-AHA-0108). Washington, DC, Cosmetic Ingredient
Review.
DuPont (1940) Corneal cloudiness (eye fog) from material formed in the glycol process at Belle.
Report No. MR-86-1, HL-2-40. Newark, DE, Haskell Laboratory.
DuPont (1962) Hydroxyacetic acid 70% technical: Federal Hazardous Substances Labelling Act
tests. Report No. MR-644-1, HL-44-62. Newark, DE, Haskell Laboratory.
DuPont (1964) Hydroxyacetic acid (70%), phosphoric acid (85%): Eye irritation test. Report No.
MR-712-2, HL-33-64. Newark, DE, Haskell Laboratory.
DuPont (1968) Preliminary test record. Dosing for variety of injury ?demonstration. Report No.
MR-0010-131. Newark, DE, Haskell Laboratory.
DuPont (1973) Hydroxyacetic acid 70%: Department of Transportation skin corrosion test on
rabbit skin. Report No. MR-1968-1, HL-418-73. Newark, DE, Haskell Laboratory.
111
Glycolic acid
Skin sensitisation
Unilever (1994) Glycolic acid: Safety assessment for use in skin care products (draft).
Unpublished data submitted by CTFA. Washington, DC, Cosmetic Ingredient Review.
Subacute-chronic toxicity
Conner RT (1943) Chronic toxicity study of sodium hydroxyacetate in rats. General Foods
Corporation. Cited in CIR (1998).
Krop S, Gold H (1945) On the toxicity of hydroxyacetic acid after prolonged administration:
Comparison with its sodium salt and citric and tartaric acids. Journal of the American
Pharmaceutical Association, 34:86-89.
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Sanchez IM, Bull RJ (1990) Early induction of reparative hyperplasia in the liver of B6C3F1 mice
treated with dichloroacetate and trichloroacetate. Toxicology, 64:33-46.
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Biochemistry and Biophysics, 84:183-187.
Genetic toxicity
DuPont (1981) Acetic acid, hydroxy-: Mutagenicity evaluation in Salmonella typhimurium. Report
No. MR-3815-1, HL-608-81. Newark, DE, Haskell Laboratory.
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and glyoxal derivatives. Agricultural and Biological Chemistry, 47:2461-2465.
Human studies
Ash K, Lord J, Zukowski M, McDaniel DH (1998) Comparison of topical therapy for striae alba
(20% glycolic acid/0.05% tretinoin versus 20% glycolic acid/10% L-ascorbic acid). Dermatologic
Surgery, 24:849-856.
Bernstein EF, Uitto J (1995) Connective tissue alterations in photoaged skin and the effects of
alpha hydroxy acids. Journal of Geriatric Dermatology, 3:7A-18A.
Ellis DAF, Tan AKW, Ellis CS (1995) Superficial micropeels: Glycolic acid and alpha-hydroxy
acid with kojic acid. Facial Plastic Surgery, 11, 15-21.
Elson, ML (1992) The utilization of glycolic acid in photoaging. Cosmetic Dermatology, 5:12-15.
Leyden JJ, Lavker RM, Grove G, Kaidbey K (1995) Alpha hydroxy acids are more than
moisturizers. Journal of Geriatric Dermatology, 3:33A-37A.
Morganti P, Randazzo SD, Palombo P, Bruno C (1994) Topical gelatin-glycine and alpha hydroxy
acids for photoaged skin. Journal of Applied Cosmetology, 12:1-10.
Moy LS, Murad H, Moy RL (1993) Glycolic acid peels for the treatment of wrinkles and
photoaging. Journal of Dermatologic Surgery and Oncology, 19:243-246.
Perricone, NV (1993) An alpha hydroxy acid acts as an antioxidant. Journal of Geriatric
Dermatology, 1:101-104.
112 Priority Existing Chemical Number 12
Perricone NV (1993) Treatment of pseudofolliculitis barbae with topical glycolic acid: A report of
two studies. Cutis, 52:232-235.
Piacquadio D, Dobry M, Hunt S, Andree C, Grove G, Hollenbach KA (1996) Short contact 70%
glycolic acid peels as a treatment for photodamaged skin. Dermatologic Surgery, 22:449-452.
Rubin MG (1994) The clinical use of alpha hydroxy acids. Australasian Journal of Dermatology,
35:29-33.
Stiller MJ, Bartolone J, Stern R, Smith S, Kollias N, Gillies R, Drake LA (1996) Topical 8%
glycolic acid and 8% lactic acid creams for the treatment of photodamaged skin. Archives of
Dermatology, 132:631-636.
Van Scott EJ, Yu RJ (1984) Hyperkeratinization, corneocyte adhesion, and alpha hydroxy acids.
Journal of the American Academy of Dermatology, 11:867-879.
Yu RJ, Van Scott EJ (1996) Bioavailability of alpha-hydroxy acids in topical formulations.
Cosmetic Dermatology, 9:54-62.
113
Glycolic acid
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