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SCCS OPINION ON the safety of cosmetic ingredients HEMA and Di-HEMA Trimethylhexyl Dicarbamate (CAS 41137-60-4 / 72869-86-4) - Submission I - (Sensitisation only)" SCCS/1592/17 - Final version

June 2018

Publisher: SCCS/EC (https://ec.europa.eu/health/sites/health/files/scientific_committees/consumer_safety/docs/sccs_o_214.pdf)

Authors:

Ulrike Bernauer

Bundesinstitut für Risikobewertung

Laurent Bodin

Atomic Energy and Alternative Energies Commission

Qasim Chaudhry

University of Chester

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The SCCS adopted this Opinion at its plenary meeting on 21-22 June 2018 (40 pages) https://ec.europa.eu/health/sites/health/files/scientific_committees/consumer_safety/docs/sccs_o_214.pdf

: Overview on patch test results from case reports and other clinical studies with HEMA among patients with skin problems due to nail styling.

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SCCS/1592/17

Final version

Scientific Committee on Consumer Safety

SCCS

OPINION ON

the safety of cosmetic ingredients HEMA and Di-HEMA

Trimethylhexyl Dicarbamate

Submission I

(Sensitisation only)

The SCCS adopted this Opinion at its plenary meeting on 21-22 June 2018

SCCS/1592/17

Final Opinion on the safety of cosmetic ingredients HEMA (CAS 868-77-9) and Di-HEMA Trimethylhexyl

Dicarbamate (CAS 41137-60-4 / 72869-86-4) - Submission I (Sensitisation only)

___________________________________________________________________________________________

ACKNOWLEDGMENTS

SCCS members listed below are acknowledged for their valuable contribution to the

finalisation of this Opinion.

For the Preliminary Opinion

SCCS Members

Dr U. Bernauer

Dr L. Bodin

Dr L. Celleno (1st Rapporteur)

Prof. Q. Chaudhry

Prof. P.J. Coenraads (Chairperson)

Prof. M. Dusinska

Dr J. Ezendam

Dr E. Gaffet

Prof. C. L. Galli

Dr B. Granum

Prof. E. Panteri

Prof. V. Rogiers

Dr Ch. Rousselle

Dr M. Stepnik

Prof. T. Vanhaecke

Dr S. Wijnhoven

For the Final Opinion

SCCS Members

Dr U. Bernauer

Dr L. Bodin

Prof. Q. Chaudhry

Prof. P.J. Coenraads (Chairperson and 2nd Rapporteur)

Prof. M. Dusinska

Dr J. Ezendam

Dr E. Gaffet

Prof. C. L. Galli

Dr B. Granum

Prof. E. Panteri

Prof. V. Rogiers

Dr Ch. Rousselle

Dr M. Stepnik

Prof. T. Vanhaecke

Dr S. Wijnhoven

All Declarations of Working Group members are available on the following webpage:

http://ec.europa.eu/health/scientific_committees/experts/declarations/sccs_en.htm

This Opinion has been subject to a commenting period of a minimum eight weeks after its

initial publication (from 22 December 2017 until 26 February 2018). Comments received

during this time were considered by the SCCS.

For this Opinion, comments received resulted mainly in the following changes: sections

3.3.11 human data and discussion part on sensitisation, as well as the 2nd conclusion on

scientific concerns.

SCCS/1592/17

Final Opinion on the safety of cosmetic ingredients HEMA (CAS 868-77-9) and Di-HEMA Trimethylhexyl

Dicarbamate (CAS 41137-60-4 / 72869-86-4) - Submission I (Sensitisation only)

___________________________________________________________________________________________

1. ABSTRACT

The SCCS concludes the following:

1. In light of the data provided, does the SCCS consider monomers of HEMA and Di-HEMA

Trimethylhexyl Dicarbamate, safe at concentrations of up to 35% and 99% respectively

when used in topically applied UV-cured artificial nail modelling systems?

The available evidence suggests that normal nail plate acts as a good barrier to penetration

of chemical substances in general, and that both methacrylate monomers (HEMA and di-

HEMA-TMHDC) polymerise rapidly under UV curing when applied as part of an artificial nail

modelling system. This leaves very little chance for the monomers to be absorbed in any

appreciable amount through the nail plate. In view of this, the SCCS is of the opinion that

HEMA and di-HEMA-TMHDC, when applied appropriately to the nail plate at concentrations

of up to 35% and 99% respectively as part of an artificial nail modelling system, are not

likely to pose a risk of sensitisation, provided that their use is restricted to the nail plate

only and contact with the adjacent skin is avoided.

2. Does the SCCS have any further scientific concerns with regard to the use of HEMA and

Di-HEMA Trimethylhexyl Dicarbamate monomers in cosmetic products?

 More analytical data are needed to exclude the possibility of the presence of other

sensitisers that may be present as impurities or degradation products alongside the

two methacrylate monomers.

 Both HEMA and di-HEMA-TMHDC are weak to moderate sensitisers and pose a risk of

sensitisation from misuse of the products or from inappropriately carried out

application or from unintentional contamination of the skin adjacent to the nails

under normal and reasonably foreseeable conditions of use.

 Filing or sanding nails to remove/replace previous applications may generate particle

dust that may lead to respiratory exposure of the professionals if appropriate

protective measures are not in place.

 The potential for sensitisation to the methacrylate monomers is likely to be higher

amongst the professionals who carry out routine applications of artificial nail

modelling systems without appropriate protective measures.

 In view of the growing popularity of artificial nail fashions and the potential use by

consumers at home, and considering the observations of several professional

dermatological organisations that the prevalence of contact dermatitis from artificial

nail products (among which HEMA is an important constituent) is rising, a further

increase of the prevalence of sensitisation is possible.

Keywords: SCCS, scientific opinion, cosmetic ingredients, 2-hydroxyethyl methacrylate

HEMA (CAS 868-77-9 and EC 212-782-2), Di-HEMA Trimethylhexyl Dicarbamate (CAS

41137-60-4 / 72869-86-4 and EC 276-957-5), SCCS/1592/17, Regulation 1223/2009

Opinion to be cited as: SCCS (Scientific Committee on Consumer Safety), Opinion on the

safety of cosmetic ingredients HEMA (CAS 868-77-9) and Di-HEMA Trimethylhexyl

Dicarbamate (CAS 41137-60-4 / 72869-86-4) - Submission I (Sensitisation only),

SCCS/1592/17, preliminary version adopted on 22 December 2017, final version adopted on

21-22 June 2018.

SCCS/1592/17

Final Opinion on the safety of cosmetic ingredients HEMA (CAS 868-77-9) and Di-HEMA Trimethylhexyl

Dicarbamate (CAS 41137-60-4 / 72869-86-4) - Submission I (Sensitisation only)

___________________________________________________________________________________________

About the Scientific Committees

Two independent non-food Scientific Committees provide the Commission with the scientific

advice it needs when preparing policy and proposals relating to consumer safety, public

health and the environment. The Committees also draw the Commission's attention to the

new or emerging problems that may pose an actual or potential threat.

These Committees are the Scientific Committee on Consumer Safety (SCCS) and the

Scientific Committee on Health, Environmental and Emerging Risks (SCHEER) and are made

up of scientists appointed in their personal capacity.

In addition, the Commission relies upon the work of the European Food Safety Authority

(EFSA), the European Medicines Agency (EMA), the European Centre for Disease prevention

and Control (ECDC) and the European Chemicals Agency (ECHA).

SCCS

The Committee shall provide Opinions on questions concerning health and safety risks

(notably chemical, biological, mechanical and other physical risks) of non-food consumer

products (for example cosmetic products and their ingredients, toys, textiles, clothing,

personal care and household products such as detergents, etc.) and services (for example:

tattooing, artificial sun tanning, etc.).

Scientific Committee members

Bernauer Ulrike, Bodin Laurent, Chaudhry Mohammad Qasim, Coenraads Pieter-Jan,

Dusinska Maria, Ezendam Janine, Gaffet Eric, Galli Corrado Lodovico, Granum Berit, Panteri

Eirini, Rogiers Vera, Rousselle Christophe, Stępnik Maciej, Vanhaecke Tamara, Wijnhoven

Susan

Contact

European Commission

Health and Food Safety

Directorate C: Public Health, country knowledge, crisis management

Unit C2 – Country Knowledge and Scientific Committees

Office: HTC 03/073

L-2920 Luxembourg

SANTE-C2-SCCS@ec.europa.eu

ISSN ISBN

Doi ND

The opinions of the Scientific Committees present the views of the independent scientists

who are members of the committees. They do not necessarily reflect the views of the

European Commission. The opinions are published by the European Commission in their

original language only.

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

SCCS/1592/17

Final Opinion on the safety of cosmetic ingredients HEMA (CAS 868-77-9) and Di-HEMA Trimethylhexyl

Dicarbamate (CAS 41137-60-4 / 72869-86-4) - Submission I (Sensitisation only)

___________________________________________________________________________________________

TABLE OF CONTENTS

1. BACKGROUND ............................................................................................. 6

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

3. OPINION ..................................................................................................... 7

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

3.1.1 Chemical identity .................................................................... 7

3.1.2 Physical form ......................................................................... 9

3.1.3 Molecular weight .................................................................... 9

3.1.4 Purity, composition and substance codes .................................... 9

3.1.5 Impurities / accompanying contaminants ................................... 9

3.1.6 Solubility ............................................................................... 9

3.1.7 Additional physical and chemical specifications .......................... 10

3.1.8 Homogeneity and Stability ..................................................... 10

3.2 Function and uses .............................................................................. 12

3.3 Toxicological evaluation ...................................................................... 13

3.3.1 Acute toxicity ....................................................................... 13

3.3.2 Irritation and corrosivity ........................................................ 13

3.3.3 Skin sensitisation .................................................................. 14

3.3.4 Dermal / percutaneous absorption........................................... 15

3.3.5 Repeated dose toxicity .......................................................... 16

3.3.6 Mutagenicity / Genotoxicity .................................................... 16

3.3.7 Carcinogenicity ..................................................................... 16

3.3.8 Reproductive toxicity ............................................................. 16

3.3.9 Toxicokinetics ...................................................................... 16

3.3.10 Photo-induced toxicity ........................................................... 16

3.3.11 Human data ......................................................................... 16

3.3.12 Discussion ........................................................................... 25

4. CONCLUSION ............................................................................................ 27

5. MINORITY OPINION .................................................................................... 27

6. REFERENCES ............................................................................................. 28

SCCS/1592/17

Final Opinion on the safety of cosmetic ingredients HEMA (CAS 868-77-9) and Di-HEMA Trimethylhexyl

Dicarbamate (CAS 41137-60-4 / 72869-86-4) - Submission I (Sensitisation only)

___________________________________________________________________________________________

2. BACKGROUND

The cosmetic ingredients HEMA, with chemical name 2-hydroxyethyl methacrylate (CAS

868-77-9, EC 212-782-2), and Di-HEMA Trimethylhexyl Dicarbamate, with chemical name

7,7,9 (or 7,9,9)-trimethyl-4,13-dioxo-3,14-dioxa-5,12-diazahexadecane-1,16-diyl

bismethacrylate (CAS 41137-60-4/72869-86-4, EC -/276-957-5) are active components of

topically applied artificial nail modelling systems cured by ultraviolet (UV) light. The

methacrylate ester monomers HEMA and Di-HEMA Trimethylhexyl Dicarbamate are used as

film forming ingredients in nail products, where they are consumed within a few seconds to

minutes during the polymerization induced by the UV-curing process.

In August 2014, the Commission was informed of a decision of the Swedish authorities to

withdraw and prohibit the sale and delivery of a range of nail polishes, according to Article

27 (Safeguard clause) of Regulation (EC) No 1223/2009 on cosmetic products. These

products were notified through the RAPEX system, pursuant to Article 12 of Directive

2001/95/EC on general product safety, as posing a serious risk to consumers (RAPEX

notification A12/1226/14).

The Swedish authorities consider that the above-mentioned products, which are hardened

with the use of a LED lamp after application, constitute a serious risk for consumers as they

can lead to contact allergy and result in damage to nails and/or hands. Available scientific

evidences suggest that the sensitising potential could be related to the uncured (not fully

reacted), unpolymerised reactive monomers HEMA and Di-HEMA Trimethylhexyl

Dicarbamate.

In 2016, the Commission launched a public call for data to retrieve safety information on

HEMA, Di-HEMA Trimethylhexyl Dicarbamate and in addition on the class of compounds

termed "urethane acrylates".

Following this call for data, several contributions from Member States' national authorities,

clinicians and industry experts have been submitted to the Commission services.

The two substances Di-HEMA Trimethylhexyl Dicarbamate and HEMA are used as cosmetics

ingredients and listed in CosIng, the European Commission database for cosmetic

ingredients, while "urethane acrylates" indicates a class of substances that is not registered

in CosIng as such. Further clarifications are needed on the specific substances of this class

that are used as cosmetic ingredients and that could represent a concern for consumer

safety. Therefore the scope of this current safety evaluation is limited to the monomers of

HEMA and Di-HEMA Trimethylhexyl Dicarbamate.

3. TERMS OF REFERENCE

1. In light of the data provided, does the SCCS consider monomers of HEMA and Di-HEMA

Trimethylhexyl Dicarbamate, safe at concentrations of up to 35 % and 99% respectively

when used in topically applied UV-cured artificial nail modelling systems?

2. Does the SCCS have any further scientific concerns with regard to the use of HEMA and

Di-HEMA Trimethylhexyl Dicarbamate monomers in cosmetic products?

SCCS/1592/17

Final Opinion on the safety of cosmetic ingredients HEMA (CAS 868-77-9) and Di-HEMA Trimethylhexyl

Dicarbamate (CAS 41137-60-4 / 72869-86-4) - Submission I (Sensitisation only)

___________________________________________________________________________________________

4. OPINION

4.1 Chemical and Physical Specifications

4.1.1 Chemical identity

4.1.1.1 Primary name and/or INCI name

INCI names: HEMA and Di-HEMA TRIMETHYLHEXYL DICARBAMATE

4.1.1.2 Chemical names

HEMA

Chemical name: 2-Hydroxyethyl methacrylate

IUPAC name: 2-Hydroxyethyl methacrylate

Di-HEMA Trimethylhexyl Dicarbamate

Chemical name: Di-HEMA trimethylhexyl dicarbamate

IUPAC name: 11,14-Dioxa-2,9-diazaheptadec-16-enoic Acid, 4,4,6,16-tetramethyl-10,15-

dioxo,2-[(2-methyl-1-oxo-2-propenyl)oxy]ethyl ester

Ref: CosIng

4.1.1.3 Trade names and abbreviations

HEMA

2-HEMA

2-Hydroxyethyl ester, methacrylic acid

Ethylene glycol methacrylate

HEMA

Hydroxyethyl methacrylate

Di-HEMA Trimethylhexyl Dicarbamate

Depositor-Supplied Synonyms:

Urethane dimethacrylate

2-Propenoic acid, 2-methyl-, 7,7,9(or 7,9,9)-trimethyl-4,13-dioxo-3,14-dioxa-5,12-

diazahexadecane-1,16-diyl ester

7,7,9(or 7,9,9)-trimethyl-4,13-dioxo-3,14-dioxa-5,12-diazahexadecane-1,16-diyl

bismethacrylate

11,14-Dioxa-2,9-diazaheptadec-16-enoic acid, 4,4,6,16-tetramethyl-10,15-dioxo-, 2-((2-

methyl-1-oxo-2-propen-1-yl)oxy)ethyl ester

11,14-Dioxa-2,9-diazaheptadec-16-enoic acid, 4,4,6,16-tetramethyl-10,15-dioxo-, 2-((2-

methyl-1-oxo-2-propenyl)oxy)ethyl ester

11,14-Dioxa-2,9-diazaheptadec-16-enoic acid, 4,4,6,16-tetramethyl-10,15-dioxo-, 2-[(2-

methyl-1-oxo-2-propenyl)oxy]ethyl ester

CCRIS 8223

SCCS/1592/17

Final Opinion on the safety of cosmetic ingredients HEMA (CAS 868-77-9) and Di-HEMA Trimethylhexyl

Dicarbamate (CAS 41137-60-4 / 72869-86-4) - Submission I (Sensitisation only)

___________________________________________________________________________________________

MeSH Entry Terms:

1,6-di-(methacryloxy-2-ethoxycarbonylamino)-3,5,5-trimethylhexane

Lumin-X

Opalux

UDMA compound

urethane dimethacrylate

urethane dimethacrylate luting resin

urethane-di-methacrylate

Visioform

Ref: PubChem: https://pubchem.ncbi.nlm.nih.gov/compound/170472#section=Synonyms,

CIR, 2005; OECD SIDS, 2001

4.1.1.4 CAS / EC number

HEMA:

CAS: 868-77-9

EC: 212-782-2

Di-HEMA Trimethylhexyl Dicarbamate:

CAS: 41137-60-4, 72869-86-4

EC: 276-957-5

4.1.1.5 Structural formula

HEMA

Di-HEMA Trimethylhexyl Dicarbamate

Ref: ChemSpider, PubChem

4.1.1.6 Empirical formula

Formula HEMA: C6H10O3

Formula Di-HEMA: C23H38N2O8

SCCS/1592/17

Final Opinion on the safety of cosmetic ingredients HEMA (CAS 868-77-9) and Di-HEMA Trimethylhexyl

Dicarbamate (CAS 41137-60-4 / 72869-86-4) - Submission I (Sensitisation only)

___________________________________________________________________________________________

4.1.2 Physical form

Physical form HEMA: Clear liquid

4.1.3 Molecular weight

Molecular weight HEMA: 130.14 g/mol

Molecular weight Di-HEMA: 470.56 g/mol

4.1.4 Purity, composition and substance codes

HEMA:

Purity: 97.0 - >99%

SCCS comment

Additional information on the analytical method used to evaluate peak purity is needed.

Data on the purity of Di-HEMA Trimethylhexyl Dicarbamate was not provided.

4.1.5 Impurities / accompanying contaminants

HEMA:

Diethylene glycol mono-methacrylate: < 2.0%

Ethylene glycol di-methacrylate: < 0.2%

Water: < 0.04%

Methacrylic acid: < 0.04%

Ethylene oxide: < 0.001%

4-Methoxy phenol (syn. Hydroquinone Methylether (MeHQ)): 40 – 80 ppm (additive for

prevention of polymer formation). Noteworthy to mention that in commercial nail products

for professional and for non-professional use, the MeHQ content will be at maximum 200

ppm and thus in line with the current cosmetics regulation.

SCCS comments

Additional information on the analytical method used for the chemical characterisation of

impurities is needed. Data on the impurities of Di-HEMA Trimethylhexyl Dicarbamate have

not been provided.

4.1.6 Solubility

HEMA:

Water solubility: Miscible with water and soluble in common organic solvents

(PubChem reference: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th

ed. New York, NY: Van Nostrand Rheinhold Co., 1993, p. 622)

Di-HEMA Trimethylhexyl Dicarbamate:

Soluble in water: 30 mg/L at 37 °C (experimental, ChemIdPlus)

Reference: OECD SIDS, 2001; Keystone, 2016

SCCS/1592/17

Final Opinion on the safety of cosmetic ingredients HEMA (CAS 868-77-9) and Di-HEMA Trimethylhexyl

Dicarbamate (CAS 41137-60-4 / 72869-86-4) - Submission I (Sensitisation only)

___________________________________________________________________________________________

4.1.7 Partition coefficient (Log Pow)

HEMA:

Log Pow: measured: 0.42 at 25 °C and pH ≥ 5.9 – ≤ 6.1 (OECD

107)

DI-HEMA Trimethylhexyl Dicarbamate:

LogPow = 4.69 (estimated, ChemIdPlus)

4.1.8 Additional physical and chemical specifications

HEMA

Melting point: -12 °C (experimental, Alfa Aesar, ChemSpider)

Boiling point: 250 °C (experimental, Alfa Aesar, ChemSpider)

Flash point: 101 °C (experimental, Alfa Aesar, ChemSpider)

Density: 1.1±0.1 g/cm3 (predicted, ACD/Labs, ChemSpider)

Vapour pressure: 0.2±0.7 mmHg at 25°C (predicted, ACD/Labs, ChemSpider)

Viscosity: /

pKa: /

Refractive index: 1.453 (experimental, Alfa Aesar, ChemSpider)

UV_Vis spectrum: /

Di-HEMA Trimethylhexyl Dicarbamate (Di-HEMA-TMHDC):

Melting point: /

Boiling point: 594.3±45.0 °C at 760 mmHg (predicted, ACD/Labs, ChemSpider)

Flash point: 313.2±28.7 °C (predicted, ACD/Labs, ChemSpider)

Vapour pressure: 0.0±1.7 mmHg at 25°C (predicted, ACD/Labs, ChemSpider)

Density: 1.1±0.1 g/cm3 (predicted, ACD/Labs, ChemSpider)

Viscosity: /

Surface Tension: 37.6±3.0 dyne/cm (predicted, ACD/Labs, ChemSpider)

pKa: /

Refractive index: 1.479 (predicted, ACD/Labs, ChemSpider)

Molar Refractivity: 122.0±0.3 cm3 (predicted, ACD/Labs, ChemSpider)

UV_Vis spectrum: /

Ref: www.chemspider.com

4.1.9 Homogeneity and Stability

HEMA:

The product is stable

Ref: Keystone, 2016

SCCS comment

Additional information on the stability studies (conditions, any stabiliser added, analytical

method used to evaluate stability) is not provided. Data on the stability of Di-HEMA

Trimethylhexyl Dicarbamate are also not provided.

SCCS/1592/17

Final Opinion on the safety of cosmetic ingredients HEMA (CAS 868-77-9) and Di-HEMA Trimethylhexyl

Dicarbamate (CAS 41137-60-4 / 72869-86-4) - Submission I (Sensitisation only)

___________________________________________________________________________________________

Polymerisation

The polymerization of 22 methacrylates including HEMA was measured in an ethyl

methacrylate based system using Differential Scanning Calorimetry (DSC). Maximum peak

exotherm and total exotherm were measured as indications for the polymerization process,

while the nail enhancement product reacted in the test chamber. Maximum peak exotherm

occurs at gelation (gel point) of a curing nail enhancement system. The gelation point is

reached when at least 50% of the monomer has reacted and the material has a hardened

surface. This process starts immediately and takes 2 to 4 minutes in most commercially

available professional monomer-based nail enhancement systems. Changes in gel point

time and total exotherm are both directly proportional to the test monomers’ reactivity.

In the experiment, the Radical® artificial nail monomer/polymer system was modified by

adding 5% ethyl methacrylate to establish a normalised baseline to compare reactivity of

various test monomers including HEMA. Each of the 22 test monomers were added at a

concentration of 5% and 50% (by weight) to the Radical® artificial nail monomer/polymer

system.

The results show that polymerization of HEMA was fast in general and even faster at a

higher concentration (Table 1). This can be considered as an indication of strong reactivity.

Table 1. Results of differential scanning calorimetry regarding HEMA in nail

product

HEMA concentration

50%

Polymerization set

time

2.85 ± 5.0 min

1.82 ± 1.0 min

Total exotherm

672.07 ± 4.4 mJ/m²

1130.3 ± 6.3 mJ/m²

Ref: Creative Nail Design, 2001; Schoon, 1994a +b

Extraction

Explorative analytical screening investigations to mimic use conditions are available. The

amount of extractable Hydroxyethyl Methacrylate (HEMA) amongst other methacrylates

from cured films of UV/LED full coat system, an acrylic and a builder system, applied on a

glass slide, was analysed using a 0.1% salt water solution or acetone as extraction solvent.

The salt water extracts were analysed by High Performance Liquid Chromatography (HPLC)

and the acetone extracts were analysed by Gas Chromatography (GC).

The HEMA containing samples were prepared as follows:

Preparation of Samples

NC6195M: Base coat was applied to a glass slide using a 5 mil drawdown bar and cured for

3 minutes in Young Nails UV lamp. The first colour coat was applied to the glass slide using

a 10 mil drawdown bar and cured for 3 minutes. The second colour coat was applied to the

glass slide using a 15 mil drawdown bar and cured for 3 minutes. The top coat was applied

using a 20 mil drawdown bar and then cured for 3 minutes. The surface was then wiped

with isopropyl alcohol. The slide was left to sit at room temperature for 72 hours.

NC6195N: Base coat was applied to a glass slide using a 5 mil drawdown bar and cured for

1 minute in OPI Studio LED lamp. The first colour coat was applied to the glass slide using a

10 mil drawdown bar and cured for 1 minute. The second colour coat was applied to the

glass slide using a 15 mil drawdown bar and cured for 1 minute. The top coat was applied

using a 20 mil drawdown bar and then cured for 1 minute. The surface was then wiped with

isopropyl alcohol. The slide was left to sit at room temperature for 72 hours.

SCCS/1592/17

Final Opinion on the safety of cosmetic ingredients HEMA (CAS 868-77-9) and Di-HEMA Trimethylhexyl

Dicarbamate (CAS 41137-60-4 / 72869-86-4) - Submission I (Sensitisation only)

___________________________________________________________________________________________

NC61950-1 & -2: A nail brush was dipped in J2 monomer to wet it. The brush was then

dipped into P3 acrylic powder. The wet powder was then applied to a glass slide and left to

sit at room temperature for 72 hours. Thereafter, the cured film was scraped off the glass

slide and transferred to a glass vial. The weight of the cured film was recorded. The salt

water solution was added to one of the duplicate samples and acetone was added to the

other. The samples were allowed to extract at room temperature for approximately 24

hours. Then, the salt water solution extracts were analysed on an Agilent 1290 HPLC with a

diode array detector and the acetone extracts were analysed on an Agilent 6890 GC with an

FID detector.

All HPLC and GC system suitability requirements were met. The detector response to

concentration was linear for the range tested in all standards. The limit of detection (LOD)

was 1.0 ppm for both the HPLC and GC analysis.

Table 2. HEMA Extraction Results

There was no significant difference between the curing time, the light source, the applied

product or the extraction medium, when normal analytical variation was considered. Curing

for 1 min using LED light resulted in a comparable extractable amount of HEMA compared to

3 min curing under UV light. Even following a hardening process without artificial light

exposure led to a comparable amount of extractable HEMA.

In any case the extractable HEMA portions were in the same order of magnitude and ranged

between 0.28 % – 0.49 % using salt water and between 0.3 % – 0.49 % with acetone as

extraction medium (Reference: Steffier, 2016).

However, these explorative analytical screening data represent a worst case situation and

should therefore not be used for general regulatory purposes, e.g., not to fix specific limit

values.

SCCS comment

Information on the speed and completeness of the polymerisation and extraction of Di-

HEMA-TMHDC monomer under use conditions along with information on the concentration

and the type of polymerisation inhibitor and polymerisation activator is not provided.

Information on various commercial systems used for polymerising HEMA and DiHEMA-

TMHDC is also not provided.

4.2 Function and uses

From the submission:

The HEMA monomer is a methacrylate ester and is used in nail products to form a film. In

principle, two major processing systems for nail modelling systems are available, two

SCCS/1592/17

Final Opinion on the safety of cosmetic ingredients HEMA (CAS 868-77-9) and Di-HEMA Trimethylhexyl

Dicarbamate (CAS 41137-60-4 / 72869-86-4) - Submission I (Sensitisation only)

___________________________________________________________________________________________

component powder/liquid systems (self- or light curing) and light-curing single component

gel systems (composites). The current and anticipated use concentrations of HEMA are up

to 10% in powder/liquid systems and up to 35% in gel systems. The artificial nail modelling

systems are used for fingernails- and toenails.

HEMA will be consumed rapidly during the polymerisation process (within 1.82 minutes).

Explorative screening investigations showed that under worst-case conditions, the

extractable monomer portion is at maximum in the order of about 0.49 % (4900 ppm).

For both nail modelling systems, quantities of 2 to 4 g are used for the first application and

approximately 1 g for filling up after approximately 2 to 3 weeks, corresponding to a

maximum of 1400 mg HEMA in total for all nail plates. Contact is meant to be limited to the

keratin of the nail plate.

Clear use instructions and adequate training of professional users should ensure that these

nail products are properly applied, i.e. exclusively to the nail plate and not to the

surrounding skin by ensuring a small space between the cuticle and the nail. Thus, there is

no contact to skin when carefully applied to the nail plate. In case of unintended skin

contact at the cuticle and the side of the nails, the use instructions call for removing it

immediately from the skin, especially prior to radiation.

For the two-component systems the curing reaction is triggered by mixing the liquid and the

powder. Since the reaction starts immediately and is completed after a maximum of 2 to 3

minutes, processing possibilities are limited in time. The reaction occurs with heating and

odour development.

For the light-curing gel systems, which represent a further development of the composites

from dental medicine, curing is started after the decomposition of the added photo

initiators, and the actual curing process is already completed after 30 to 45 seconds. In

practice there is, however, a curing period of 2 to 3 minutes in order to ensure optimum

strength and adhesion of the nail.

For the application of the systems there are detailed descriptions, which are selectively

intended to ensure not only optimum application of the nail modelling but also the highest

possible protection of the users.

The application of the liquid/powder systems is carried out by means of a special brush,

frequently using a template. With the tip of the brush previously immersed in the liquid, the

powder is absorbed in a slight circulating movement. This forms a wax-like bead. These and

possibly other beads are placed in the centre of the nail and modelled into a slight so-called

C curve. The material thickness is selected in such a way that the entire nail modelling has

at the so-called stress point a maximum height of 1 mm. For the gel systems the principle is

similar, whereby curing by UV light is carried out between the different work steps (gel

applications).

Filing is then used to optimise the form, polish and in most cases an additional top coat is

applied to bring about optimum gloss. If necessary, a filling up of the acrylic modelling is

carried out after a few weeks.

Ref: Creative Nail Design, 2001; Schoon, 1994a+b, Creative Nail Design, 2013, IKW, 2016

4.3 Toxicological evaluation

4.3.1 Acute toxicity

4.3.2 Irritation and corrosivity

SCCS/1592/17

Final Opinion on the safety of cosmetic ingredients HEMA (CAS 868-77-9) and Di-HEMA Trimethylhexyl

Dicarbamate (CAS 41137-60-4 / 72869-86-4) - Submission I (Sensitisation only)

___________________________________________________________________________________________

4.3.3 Skin sensitisation

Guinea pig maximisation tests (GMPT)

A GMPT (Clemmensen 1985) investigated the influence of concentration, vehicle, and

cyclophosphamide on the skin sensitising potential of HEMA. The vehicles used for

elicitation were petrolatum, soybean oil, and a mixture of s o y b e an oil and 2-butanone

(sbomek). Ten to twenty guinea pigs (Scc:AL) were used per dose group. The following

materials were used for intradermal induction (day 0): 1% HEMA (in soybean oil), 25%

HEMA (in soybean oil), 25% HEMA (in sbomek), 1% HEMA (aqueous), 10% HEMA

(aqueous), and 25% HEMA (aqueous). Dermal induction w as pe r f ormed on days 7 and

8 using a 10% sodium lauryl sulfate pre-treatment and 400 µl of HEMA applied via a 48

h patch. Challenge was performed on day 21 using 25% HEMA (in petrolatum), 25%

HEMA (aqueous), 25% HEMA (sbomek), 25% HEMA (in soybean oil), and 100% HEMA.

Effects were scored at 48 h and 72 h post-challenge.

The major determining factor for sensitisation was the concentration used for intradermal

induction. Induction with 10% HEMA or greater caused a reaction in 4 to 10 guinea pigs

out of 12 challenged per dose group.

There was no c h a l l e n g e response to challenge when an intradermal injection had been

given with 1% HEMA in soybean oil. When HEMA was used at concentrations of 25 % or

higher, the vehicles did not influence the response.

Other guinea pig studies showed (Katsuno 1995, Katsuno 1996) that HEMA produced

positive delayed hypersensitivity reactions: 6 out of 10 albino guinea pigs induced and

challenged with HEMA (100%) showed a positive reaction at 24 hours and 5 out of 10

showed a positive reaction at 48 hours.

The optimum concentration of HEMA for sensitisation and elicitation was established by

testing HEMA at 0.01, 0.02, 0.1, 0.2, 0.5, 1.0, and 5.0%. Challenge concentrations were

10, 25, 50, and 100%.

It was shown that the optimum concentration to induce sensitisation was 0.2%; five of five

guinea pigs had a positive challenge reaction to HEMA at 24 hours and 48 hours after patch

removal with a mean skin response of 5.0 (Katsuno, 1996).

In an unpublished report (Roehm 1982, cited in OECD-SIDS 2001), HEMA was negative in

the Buehler test when tested undiluted under occlusive conditions.

A study (Van der Walle 1982) with 8 albino female guinea pigs of the Himalayan white

spotted outbred strain investigated the skin sensitisation potential of HEMA in a Freund’s

Complete Adjuvant Test (FCAT). Four guinea pigs were positive to HEMA on day 21 but all

animals were negative on day 35 .

Cross-reactivity patterns of methacrylates including HEMA were studied in guinea pigs using

a Freund’s Complete Adjuvant Test (FCAT) (Rustemeyer 1998). HEMA led to strong cross-

reactions to all other methacrylates [methacrylate (MMA), 2-hydroxypropyl methacrylate (2-HPMA)

and ethyleneglycol dimethacrylate (EGDMA)], while cross-reactions to Ethylene Glycol

Dimethacrylate were weak. Hydroxypropyl Methacrylate had only weak to moderate cross

reactivity with HEMA.

Local lymph node assay (LLNA) on Di-HEMA-TMTDC)

Guideline/method: OECD 429

Species/strain: Mouse/CBA

Group size: 4 females per group

Test substance: Di-HEMA-TMHDC (referred to as UDMA)

SCCS/1592/17

Final Opinion on the safety of cosmetic ingredients HEMA (CAS 868-77-9) and Di-HEMA Trimethylhexyl

Dicarbamate (CAS 41137-60-4 / 72869-86-4) - Submission I (Sensitisation only)

___________________________________________________________________________________________

Batch: 81106228 (purity: 96.99%)

Vehicle: Dimethylformamide (DMF)

Concentrations: 0, 10, 25, 50%

Positive control: hexyl cinnamic aldehyde

Route: Epidermal (topical) application on the surface of the dorsal ear lobe

GLP: Yes

Published: No

Remark: The study is currently in a negotiation process.

The sensitising potential of Di-HEMA-TMHDC was tested at concentrations of 10, 25 and

50% (w/w) solution in DMF (dimethylformamide). The 50% concentration was the highest

non-irritant test concentration which did not show any signs of irritation or systemic toxicity

up to day 8 after three-day exposure to two animals. The application volume 25 µL was

spread over the dorsal surface of the ear lobes once daily for three consecutive days. Five

days after the first application, all mice were intravenously injected with 250 µL of [3H]-

thymidine.

Results

Stimulation Indices (SIs) of 1.58, 1.70 and 4.44 were determined at concentrations of 10,

25, and 50% (w/w) in DMF, respectively. A clear dose response was observed. Based on the

SI values, an EC3 value of 36.9% was calculated. A statistically significant increase in the

DPM values was observed in all dose groups in comparison to the vehicle control group.

Based on the calculated EC3 value, Di-HEMA-TMTDC was, under the condition of this LLNA,

considered as a weak sensitiser.

Ref: information taken from the submission

SCCS comment on the animal studies

Studies in guinea pigs:

While for most studies it is unclear whether the OECD guidelines were followed, induction of

sensitisation was achieved in a number of tests with injection of Freund’s adjuvant.

Although guinea pig tests are not suitable to establish potency, the available data point

toward HEMA being a moderate skin sensitiser.

LLNA

HEMA was not tested in the LLNA. Therefore, no information on the skin sensitising potency

is available.

The LLNA with Di-HEMA-TMHDC indicates that it is a weak sensitiser.

4.3.4 Dermal / percutaneous absorption

From the submission dossier

There is no dermal penetration study available for HEMA.

However, exposure to HEMA is negligible when adhering to proper use conditions, i.e. no

contact to skin by careful application to the nail plate only as well as reduction of exposure

to residual monomers by fast polymerization within a few seconds to minutes. Since this

kind of product is not meant to be applied on the skin, but on nails only, there is no risk

from systemic exposure, even if insignificant amounts will have contact with the skin. In

case of unintended skin contact, the instructions call for its immediate removal from the

skin, especially prior to radiation.

After application of HEMA-containing nail products to the nail plate, the polymerisation

process starts immediately and is completed within less than 2 minutes. HEMA will be

consumed rapidly during the polymerisation process. Explorative screening investigations

showed that under worst-case conditions, the extractable monomer portion is at maximum

in the order of about 0.49 % (4900 ppm), irrespectively of product, curing time and light

source. Only this tiny amount would theoretically be available for penetration through the

SCCS/1592/17

Final Opinion on the safety of cosmetic ingredients HEMA (CAS 868-77-9) and Di-HEMA Trimethylhexyl

Dicarbamate (CAS 41137-60-4 / 72869-86-4) - Submission I (Sensitisation only)

___________________________________________________________________________________________

nail plate. Considering the anatomical structure and the functional characteristics of the nail

(see section 7 in the submission dossier: Nail structure and function), proper application to

the nail plate will not result in any bioavailable portion of the residual HEMA fraction.

SCCS comment

The SCCS agrees that the nail plate has a very low permeability and that it is unlikely that

sufficient amounts of monomers of HEMA and Di-HEMA-TMHDC that are needed to induce

sensitisation will reach the nail-bed. However, the problem of an incorrect application by the

consumers who may apply the substance not only on the nail plate but also to the

surrounding skin remains as a possibility leading to sensitisation. Contact dermatitis to

(meth)acrylates has been observed on fingers, probably due to removal of excess polish by

rubbing it off with unprotected fingers. It is as yet unknown whether filing or sanding

(‘roughening’) of the nails before application of the monomers will lead to enhancement of

penetration.

Only a summary of the above-mentioned explorative screening investigations on extractable

monomers was available (see 3.1.9).

Ref.: Gatica-Ortega et al., 2017

4.3.5 Repeated dose toxicity

4.3.6 Mutagenicity / Genotoxicity

4.3.7 Carcinogenicity

4.3.8 Reproductive toxicity

4.3.9 Toxicokinetics

4.3.10 Photo-induced toxicity

4.3.11 Human data

A. HEMA

Sensitisation data from several patch test studies conducted on patients suspected to be

affected by contact dermatitis to acrylates in nail styling products are summarised in Table

3. Not all studies distinguish clearly between consumers and professionally exposed subjects

(‘nail stylists’, beauticians etc).

SCCS/1592/17

Final Opinion on the safety of cosmetic ingredients HEMA (CAS 868-77-9) and Di-HEMA Trimethylhexyl

Dicarbamate (CAS 41137-60-4 / 72869-86-4) - Submission I (Sensitisation only)

___________________________________________________________________________________________

Table 3: Overview on patch test results from case reports and other clinical

studies with HEMA among patients with skin problems due to nail styling.

Patients

No. of positive

reactions to HEMA

Exposure/Remark

Reference

1 patient

Positive

Cosmetician

Conde-Salazar 1986

5 patients

5/5 positive to HEMA

5 women with dermatitis

from photo-bonded

acrylic nails

Hemmer 1996

337 patients out of 440

were patch tested with

HEMA

29/337 were positive

440 patients identified

with exposure to acrylates

and methacrylates out of

14000 records.

67/440 patients showed at

least one relevant reaction

to acrylate patch tests.

47/67 patients were

sensitized at work (3/47

were beauty therapists);

of the remaining patients,

16 were sensitised via

artificial nails.

Tucker 1999

55 patients

21/55 female patients

positive to allergens from

the methacrylate artificial

nail series (14/22 were

professional beauticians).

Of the 55 patients, 17 had

a positive reaction to

HEMA. Of these, 9 were

consumers and 8 were

professionally exposed

All 55 patients were

women professionally and

non-professionally

exposed to artificial nail

products. Study period

2001 to 2004.

Lazarov

2007

122 patients

37/122 patients were

positive to

(meth)acrylates.

HEMA was positive in 30.

Of the 37 positive cases,

20 were beauty

technicians and 8 were

consumers.

Observational and

retrospective study (2006-

2013). Among 2263 patch-

tested patients, 122

underwent testing with an

extended meth(acrylate)

series

Ramos 2014

SCCS/1592/17

Final Opinion on the safety of cosmetic ingredients HEMA (CAS 868-77-9) and Di-HEMA Trimethylhexyl

Dicarbamate (CAS 41137-60-4 / 72869-86-4) - Submission I (Sensitisation only)

___________________________________________________________________________________________

241 patients

16 positive to a

(meth)acrylate or

cyanoacrylate

12/16 positive to HEMA

A retrospective

observational study on

241 consecutive

patients patch tested

with (meth)acrylates

or cyanoacrylates

between January

2012- February 2015

Muttardi 2014

87 patients

27/87 positive to HEMA

87 female patients worked

as nail

artists/cosmetologists and

suspected nail cosmetics

as the cause of dermatitis

Uter 2015

8 patients

6/8 positive

8 patients who had

reported severe skin

reactions after the use of

the UV-curing polish,

patch tested at five

dermatology

departments in Sweden

Dahlin 2016

113 patients

37/113 positive

299 patients out of >

110,000 patients were

selected as “nail”

patients. 113 were

specifically tested on

HEMA allergy, of which

37 were sensitised.

Schnuch 2016

475 patients

52 positive to

(meth)acrylates (24

occupation related).

29 positive to HEMA,

for which acrylate

nails were responsible

in 22)

Retrospective review.

A series of 28

(meth)acrylates was

applied to 475 patients

Spencer 2016

455 patients

54 were positive to

acrylates. Of these, 44

were positive to HEMA. Of

the 54 positives to

acrylates, 16 were

beauticians and 30 had

non-professional exposure

to nail acrylates.

A retrospective review of

all patients tested with

acrylates from 2008 to

2014. Not clear how

many (12 or 13) of the

beauticians and how

many of the non-

professionally exposed

had a positive reaction to

HEMA.

Montgomery 2016

SCCS/1592/17

Final Opinion on the safety of cosmetic ingredients HEMA (CAS 868-77-9) and Di-HEMA Trimethylhexyl

Dicarbamate (CAS 41137-60-4 / 72869-86-4) - Submission I (Sensitisation only)

___________________________________________________________________________________________

230 patients tested on

methacrylates; of these,

220 were patch tested to

HEMA

198/220 (90%) positive to

HEMA

Retrospectively reviewed

files of patients with ACD

caused by

(meth)acrylates related

to nail cosmetic products

who were patch tested

between 2011-2015 in 13

departments of

dermatology in Portugal.

Not specified the

number of consumer

positive. Of the 230

investigated patients,

55 were nail stylists,

56 were consumers,

and 119 had mixed

exposure.

Raposo 2017

18228 patients

136 positive to nail

acrylates,

124 to HEMA

Retrospective study

about allergic contact

dermatitis from

acrylates and

methacrylates due to

artificial nails

diagnosed from 2013-

15 in several clinics

whose members belong

to EECDRG

Goncalo 2017, Goncalo

2018

908 patients

97/908 positive to at least

one acrylate

(21 cases were nail-

related cosmetic

reactions)

Out of 4758 patients

908 were patch tested

to an acrylates series

Rajan 2017

2353 patients

43 patients were

diagnosed with

allergic contact

dermatitis caused by

(meyh)acrylates.

39/43 were positive to

HEMA

The files of patients

with ACD caused by

(meth)acrylates in

long-lasting nail polish

diagnosed between

2013 and 2016 in four

dermatology

departments in Spain

were reviewed

Gatiga-Ortega 2017

4 patients

3 of these 4 sensitised

to HEMA

All 4 had positive

patch-tests to other

acrylates

Gatica-Ortega 2018

SCCS/1592/17

Final Opinion on the safety of cosmetic ingredients HEMA (CAS 868-77-9) and Di-HEMA Trimethylhexyl

Dicarbamate (CAS 41137-60-4 / 72869-86-4) - Submission I (Sensitisation only)

___________________________________________________________________________________________

Hemmer et al. (1996) investigated five women with damages of nails and of the skin around

nails induced by the application of artificial nails with acrylic glues. They showed pruritic

dermatitis around and under the nails for several months. Two out of these patients had

dermatitis of the lower lids and cheeks. The symptoms developed 6 months to 3 years after

the first applications of artificial nails. Monthly renewal of the nails caused a strong

exacerbation of the dermatitis within 24 hours.

In the patch test performed with a standard series and a special battery including HEMA and

Di-HEMA-TMHDC and other acrylates and (meta) acrylates, all five patients (5) had a

positive patch-test to HEMA.

Two patients were positive to Di-HEMA-TMHDC.

Kanerva et al. (1996) also reported a case of 47-year-old female cosmetician who

developed dermatitis on her right thumb that subsequently spread to both hands and face

after she started to work with photo-bonded nails and chemically cured nail cosmetics.

HEMA and other but not all acrylates resulted in a positive skin reaction (+2). The patient

had also a positive allergic patch test result to her own nail strengthener preparation that

contained 2.2% Butyl Methacrylate and her own monomer liquid for sculptured nails with

5% Triethylene Glycol Dimethacrylate.

A retrospective study (Tucker 1999) over a 15-year period identified 440 patients

(professionally and non-professionally exposed) out of approximately 14,000 records with a

history of exposure to acrylates and methacrylates. All 440 had been patch tested with

HEMA; in 67 (15.2%) there was a positive reaction. 19 out of the 67 positive patients had

been exposed to nail-styling products.

Lazarov (2007) conducted a 4-year retrospective study of patients with suspected ACD from

artificial nails (ANs). Patients were tested with the methacrylate artificial nail series and

were evaluated clinically and with patch test examination.

About half of the patients were beauticians specialising in nail sculpturing who developed

Occupationally-related ACD.

Of the 55 patients reacting to acrylates, 17 had a positive reaction to HEMA. Of these, 9

were consumers and 8 were professionally exposed.

Uter (2015) conducted a retrospective analysis (2004-2013) of patch test results with

(meth)acrylates, along with clinical and demographic data. These were used to subdivide

patients according to (i) a potentially exposed occupation and (ii) nail cosmetics as the

suspected cause of contact dermatitis and patterns of co-sensitisation. Among the 114 440

patients patch tested, 72 244 were female and were considered further. 87 patients worked

as nail artists or cosmetologists. In this group 31% responded with a positive patch test to

HEMA. Among the total number of patients, 47.1% reacted to at least one (meth)acrylate,

most often to HEMA (n = 27), 2-hydroxypropyl methacrylate and hydroxyethyl acrylate (n

= 26 each), with marked coupled reactivity. In other subgroups of interest, frequencies of

sensitisation to (meth)acrylates were less elevated but higher than in all remaining female

patients (n = 69 419). The authors concluded that the results indicate a fairly uncommon,

but potentially serious, problem, especially concerning professionally exposed and sensitised

nail artists.

Ramos (2014) performed an observational and retrospective study (January 2006-April

2013) to evaluate and correlate epidemiological and clinical parameters and positive patch

test results with (meth)acrylates. Among 2263 patch-tested patients, 122 underwent

testing with an extended (meth)acrylate series. Twenty-eight cases were related to artificial

nails. In their sample, beauty technicians working with artificial nails were the most affected

group (80% of occupational cases including industrial workers and dentists).

SCCS/1592/17

Final Opinion on the safety of cosmetic ingredients HEMA (CAS 868-77-9) and Di-HEMA Trimethylhexyl

Dicarbamate (CAS 41137-60-4 / 72869-86-4) - Submission I (Sensitisation only)

___________________________________________________________________________________________

Dahlin (2016) reported severe undesirable effects in 8 patients caused by methacrylate

ultraviolet-curing nail polish for non-professional use. Out of these, 6 had a positive patch

test to HEMA.

The same 8 patients were also patch-tested with Di-HEMA-TMHDC in 2% petrolatum; 7

were positive and one had a doubtful reaction.

Geier (2016) performed a retrospective analysis of patch test results with (meth-) acrylates

including clinical and demographic data to analyse the frequency of contact allergy to

(meth) acrylates used in artificial nails in nail artists as well as in consumers. Altogether

72,244 female patients were patch tested between 2004 and 2013. Only in 398 out of

72,244 female patients (0.55%), this product category was explicitly mentioned. If nail

artists and cosmetologists were added, the patient portion increased to 732 cases (1.01%).

The investigators concluded that contact allergy to (meth‐)acrylates was much more

common among nail artists with suspected allergic contact dermatitis to nail materials

(47.1%) than among consumers with suspected allergic contact dermatitis to nail materials

(18.0%).

The authors state that their data are the result of clinical epidemiology (and not population‐

based epidemiology), and have therefore to be put into perspective by a quantitative view.

For general risk considerations, the authors pointed out that patients attending their skin

clinic are a highly selected subgroup of the general population, with a selection driven by

morbidity. Thus, in absolute terms, the risk in the general population is much lower than

0.55% as in their data, at least by a factor of ten.

Schnuch (2016) provided results from a dermatological (Dermatological surveillance of the

Information Network of Departments of Dermatology (IVDK) on contact allergies with 56

departments participating, and with an annual entry of data from about 12,000 patients

based also on data Uter (2015). The analysis on nail cosmetics during a ten year period of

total accumulated data comprised 112,327 patients. Out of this collective, 299 patients

were selected as “nail” patients on the base of clinical symptoms, 113 of whom were

specifically tested for HEMA contact allergy; of these, 37 (33 %) were shown to be

sensitised. With regards to the overall patients, the authors considered this as a negligible

proportion of 0.03% if compared to the total number of patients tested. They commented

on this percentage because only 300 patients were selected as nail patients and 113 were

specifically tested for HEMA.

Spencer (2016) applied a series of 28 (meth)acrylates to 475 patients. Results were positive

in 52 cases, with occupational sources being identified in 24.

29/52 patients were positive to HEMA. 22 of the 29 positive patients were exposed to

acrylates for nails application. These were both consumers and nail professionals.

Montgomery (2016) reported from the UK a retrospective review of all patients tested with

acrylates over a 6-year period (200-2014). 4710 patients underwent patch testing and 455

of these were tested with an acrylates series. Of the 455 tested with acrylates, 54 showed

positive reactions. Of these, 44 (81.2%) were allergic to HEMA. Seventeen (31.5%) of the

54 were occupationally-related and all but one of these patients were beauticians. Among

occupational cases, 13 (92.9%) were allergic to HEMA. Thirty-seven patients had non-

occupational allergic contact dermatitis. Of these, 30 (81%) cases were deemed to be

related to nail products containing acrylates.

Raposo (2017) published the results of a retrospective review on patients patch tested for

acrylate contact dermatitis related to nail cosmetic products, summarising the results from

13 departments of Dermatology in Portugal from 2011 - 2015.

Of 230 cases of ACD, 55 cases were professionally exposed as technicians, 56 were

consumers and 119 had mixed exposure from professional and non-professional contact

with acrylates. Most of the patients presented with chronic hand eczema (93%).

HEMA was tested in 220 patients, of which 190 tested positive.

SCCS/1592/17

Final Opinion on the safety of cosmetic ingredients HEMA (CAS 868-77-9) and Di-HEMA Trimethylhexyl

Dicarbamate (CAS 41137-60-4 / 72869-86-4) - Submission I (Sensitisation only)

___________________________________________________________________________________________

In a Spanish study (Gatica-Ortega 2017) on 2353 patients patch tested positive to

(meth)acrylates, 43 (1.82%) were diagnosed with allergic contact dermatitis caused by

(meth)acrylates in long-lasting nail polish. The most frequent positive allergens were HEMA,

2-hydroxypropyl methacrylate (HPMA), and tetrahydrofurfuryl methacrylate (THFMA). In all

patients with allergic contact dermatitis to (meth)acrylates, the fingers were involved,

where eczema on the dominant hand usually was more severe. This was probably related to

excess polish being removed without the use of appropriate material. The excess material

was usually removed by rubbing it off with the unprotected dominant fingertips. Face

dermatitis was observed in 15 of 40 (37.5%) patients, and was probably mainly attributable

to accidental transfer of excess polish material by contaminated fingers or objects. Most

cases were diagnosed in an occupational setting. This study gives evidence that

professionals handling the substance without safety measures are likely to expose their

skin.

Following a call for data by the European Commission the reports described below were

submitted:

On behalf of the European Environmental Contact Dermatitis Research Group (EECDRG),

Gonçalo (2017) reported retrospective studies on allergic contact dermatitis (ACD) from

acrylates and methacrylates due to artificial nails diagnosed during the years 2013-15 in

several clinics.

During the commenting period for this opinion, updated figures were published (Gonçalo

2018). ACD from nail (meth)acrylates was diagnosed in 135 females and one male out of

18228 patients. Exposure to nail (meth)acrylates occurred mostly in an occupational setting

(77 cases – 57%, but higher in southern Europe – 84%). Fifty-nine patients were exposed

to (meth)acrylates only during the process of sculpting their own artificial nails. Most

patients reacted to two or more acrylates, while HEMA was the most common allergen

(124/135) found both in occupational and non-occupational cases

In a UK multicentre audit (Rajan 2017), HEMA was the most common acrylate causing

positive reactions (positive in 97 of 4758 consecutive unselected patch test patients and

10.5% of 908 selected patients).

Nail-cosmetic related reactions were observed in 21 cases.

During the commenting period on the draft opinion, the SCCS was informed about

additional cases of contact dermatitis from nail (meth)acrylates: 4 (3/4 reacting to HEMA)

from Spain (Gatica-Ortega 2018) and 16 from the Netherlands (13/16 reacting to HEMA,

half of them professionally exposed).

SCCS comment on human studies with HEMA

Several clinical studies have been conducted with the 72-hour patch test method to test

acrylate sensitisation in large patient populations. These patients were selected based on a

diagnosis of suspected allergic contact dermatitis to acrylates. The patients in these studies

were made up of a mixed population comprising patients exposed for professional reasons

(dentists, industry workers), those working as professional nail stylists, and consumers

exposed to contact with artificial nails that require an adhesive application based on

acrylates. Not all of the studies have a clear division between patients that are just

consumers and professional nail stylists; often the patients seem to have mixed exposure as

both a consumer and professional nail stylist

Compared to the professional users of artificial nail systems, the positive reactions to HEMA

seem to be less common among those who are only consumers. Although the number of

users is not known, the data should be interpreted in the context of the apparently

widespread exposure among consumers and the number of professional users of artificial

nail products.

SCCS/1592/17

Final Opinion on the safety of cosmetic ingredients HEMA (CAS 868-77-9) and Di-HEMA Trimethylhexyl

Dicarbamate (CAS 41137-60-4 / 72869-86-4) - Submission I (Sensitisation only)

___________________________________________________________________________________________

The publications indicate that there is often co-sensitisation to other (meth)acrylates.

B. Di-HEMA-TMHDC

In Table 4 the patch test studies with Di-HEMA-TMHDC, mostly conducted on populations

other than users of nail-styling products, are summarised.

Table 4: Overview on patch test results from case reports and other clinical studies

regarding Di-HEMA-TMHDC exposed patients (professionally and not

professionally exposed)

Subjects

No. of positive

reactions

Exposure/Remark

Reference

1 dentist,6 dental nurses

0/5

Assumed acrylate

sensitisation towards

plastic resins, positive

reactions towards other

(meth)acrylates

Kanerva 1989

5 patients with photo-

bonded acrylic nails and

dermatitis

2/5

Patients developed

symptoms 6 months to 3

years after first

applications; monthly

renewal caused strong

exacerbation within 24

hours.

Hemmer 1996

1 cosmetician

1/1

A 47-year-old female

cosmetician developed

dermatitis on her right

thumb that subsequently

spread to both hands

and face after she

started to work with

photo-bonded nails and

chemically cured nail

cosmetics

Kanerva 1996

268 patients

2 positive

Patients out of 440 in

total from about 14,000

records with a history of

acrylates and

methacrylates exposure

Tucker 1999

13833 patients

54/13833 showed

positive patch test to 1 or

more (meth)acrylates

(23 were non-

occupationally exposed

and 31 were

occupational) Out of the

54 positive patients , one

(1.4%) reacted to Di-

13833 patients suspected

of contact dermatitis

examined during 1978 –

1999

Geukens 2001

SCCS/1592/17

Final Opinion on the safety of cosmetic ingredients HEMA (CAS 868-77-9) and Di-HEMA Trimethylhexyl

Dicarbamate (CAS 41137-60-4 / 72869-86-4) - Submission I (Sensitisation only)

___________________________________________________________________________________________

HEMA

8 patients

7/8 showed positive

reactions and 1/8 showed

a doubtful reaction

8 patients who had

reported severe skin

reactions after the use of

the UV-curing nail polish

were patch tested at five

dermatology departments

in Sweden.

Dahlin 2016

6775 patients who were

dental technicians

47/6775 (0.7%)

Di-HEMA-TMHDC is

contained in tests for

dental technicians. Least

frequent allergen among

(meth)acrylates. Tests

between 2008 – 2015.

Geier 2016

10 patients reacting to

‘urethane dimethacrylate’

Not clear how many

patients had been patch-

tested with Di-HEMA-

TMHDC

Gonçalo 2018

Kanerva (1989) reported that none of five patients (4 dental nurses and 1 dentist)

occupationally sensitised to dental resin products reacted to Di-HEMA-TMHDC 2% in

petrolatum when patch tested with the European standard and special acrylates series.

Hemmer (1996) investigated five women with photo-bonded acrylic nails who had pruritic,

paronychial and subonychial dermatitis. In the patch tests performed with a standard series

and a special battery including acrylates and methacrylates, one patient and two patients

reacted positively to 0.2% and 0.6% Di-HEMA-TMHDC.

Kanerva (1996), reported a positive reaction in a 47-year-old female cosmetician who

developed dermatitis on her right thumb that subsequently spread to both hands and face

after she started to work with photo-bonded nails and chemically cured nail cosmetics. The

patient also had a positive patch test to other (meth)acrylates and to her own nail

strengthener preparation..

Tucker (1999) reported that, over a 15-year period, in total 440 patients out of

approximately 14,000 records with a history of exposure to acrylates and methacrylates

were identified. Two out of 268 patients (0.7%) who were patch tested with 2% Di-HEMA-

TMHDC showed a positive response.

Geukens (2001) reported that among 13,833 patients suspected of contact dermatitis

examined during the years 1978-1999, 54 patients showed a positive patch test to one or

more (meth)acrylates (23 subjects were non-occupationally exposed and 31 were

occupationally exposed). Out of the 54 positive patients, one (1.4%) reacted to Di-HEMA-

TMHDC.

Dahlin (2016) investigated eight patients who had reported severe skin reactions after the

use of the UV-curing polish; they were patch tested at five dermatology clinics Sweden. It

was shown that all 8 patients showed contact allergic reactions towards Di-HEMA-TMHDC.

SCCS/1592/17

Final Opinion on the safety of cosmetic ingredients HEMA (CAS 868-77-9) and Di-HEMA Trimethylhexyl

Dicarbamate (CAS 41137-60-4 / 72869-86-4) - Submission I (Sensitisation only)

___________________________________________________________________________________________

Geier (2016) performed a study on dental technicians with occupational dermatitis. Di-

HEMA-TMHDC has been patch tested in this series in 6775 patients during the years 2008 to

2015 (total number of patients: 99,130). 47/6775 (0.7%) patients showed a reaction. Thus,

it was the least frequent allergen among the (meth‐)acrylates in this series. Therefore, the

authors concluded that there is no conclusive indication that Di-HEMA-TMHDC represents a

special, frequent, or particularly severe allergological problem, compared to other

methacrylates.

In the retrospective study of records from 18228 patients in 13 departments participating in

the EECDR, there were 10 patients with a positive reaction to ‘urethane dimethacrylate’

(Gonçalo 2018). It was not clear how many had been patch-tested with Di-HEMA-TMHDC.

SCCS comment on human (patch-test) studies with Di-HEMA-TMHDC

There are only a few reports with information on sensitisation to Di-HEMA-TMHDC among

users of nail-styling products. Di-HEMA-TMHDC is commonly used in dentistry and more

reports are available from this professional group. The LLNA indicates that it is a weak

sensitiser. This is reflected in the clinical studies in humans, especially the study among

dental technicians (Geier 2016) which indicates that this was the least frequent allergen

among the acrylates. The human studies do not indicate that sensitisation to Di-HEMA-

TMHDC is of concern among users of nail-styling products.

Respiratory effects among professional users

Several epidemiological studies among professionals applying and sculpturing artificial nails

point towards an increased risk of asthma (Kreiss 2006; Reutman 2009; Roelofs 2008). A

clinical study with simulated inhalation exposure to nail-styling work using different

acrylates among two professionals with asthmatic complaints established occupational

asthma (Sauni 2008). Interestingly, one of these cases had also been diagnosed with

allergic contact dermatitis with contact sensitisation to 2-HEMA and to ethylene glycol

dimethylacrylate (EGDMA). Three out of 10 nail-stylists with occupational allergic contact

dermatitis to acrylates experienced exacerbation of pre-existing asthma (Lazarov 2007). In

a study among 71 nail stylists who responded to an invitation for a clinical respiratory

examination, rhinitis (in 21%) was detected, as well as an overall tendency to reduced

expiratory flow (FEV) and diffusion (Dessalces 2014).

4.3.12 Discussion

Physicochemical properties

Data on the impurities in HEMA and Di-HEMA-TMHDC, in particular the presence of possible

sensitisers, have not been provided.

Additional information on the stability studies (conditions, any stabiliser added, analytical

method used to evaluate stability) is not provided.

Information on the speed and completeness of the polymerisation and persistence of Di-

HEMA-TMHDC monomer under use conditions along with information on the concentration

and the type of polymerisation inhibitors and polymerisation activators is not provided.

Information on various commercial systems used for polymerising HEMA and Di-HEMA-

TMHDC is also not provided.

Nail penetration

SCCS/1592/17

Final Opinion on the safety of cosmetic ingredients HEMA (CAS 868-77-9) and Di-HEMA Trimethylhexyl

Dicarbamate (CAS 41137-60-4 / 72869-86-4) - Submission I (Sensitisation only)

___________________________________________________________________________________________

Penetration of the nails by pharmaceuticals (mainly anti-fungal agents) has generally been

insufficient to deliver the desired dosage. Several studies show that the nail plate behaves

like a hydrophilic-gel barrier and is not lipophilic (Mertin 1997, Brown 2009. Kobayashi

2004, Kobayashi 1999). Nail permeability is however independent of lipophilicity, but clearly

decreases with increasing molecular weight (Kobayashi 2004). Flux through the nail plates

of caffeine, methylparaben and Terbenafine are in the order of 0.55 to 6.5 microgram per

cm2 per hour (Brown 2009). The flux of p-Hydroxybenzoic acid methyl ester -

methylparaben - (which has a molecular weight close to that of HEMA) was estimated to be

approx. 15 microgram per cm2 per half a day (Kobayashi 2004).

In view of these studies, and considering that polymerisation is initiated immediately after

application, it can be assumed that monomers of HEMA and di-HEMA-TMHDC penetrate the

nails only in negligible amounts. In view of the moderate sensitisation potency, it can also

be assumed that induction of sensitisation is unlikely from the very small amounts that

could theoretically be presented to the immune system at the level of the nail bed.

It is as yet unknown whether filing or sanding (‘roughening’) of the nails before application

will lead to nail penetration by methacrylate monomers. A study on components of the nail

plate of one human subject indicates that the main nail barrier to drug permeation may be

the low diffusivity of drugs in the dorsal (upper) layer of the nail plate (Kobayashi 1999).

Sensitisation

HEMA

The animal studies indicate that HEMA can be considered as an allergen with weak to

moderate potency.

The human studies conducted by patch testing among patients in dermatology clinics

indicate that this substance can be considered an allergen of concern. However it should be

noted that among consumers the sensitisation most likely results from contamination of the

skin adjacent to the nails (with a relatively short exposure to a high concentration) or

contamination of other skin areas because penetration through the nail plate is likely to be

negligible. This means that application that is restricted to the nail plate is safe.

It is as yet unknown whether induction of sensitisation among consumers is driven by

unintentional contamination by uncured monomers of the skin adjacent to the nail plates, or

by contamination of other skin areas (such as fingertips) by inappropriate handing of the

product.

Compared to the consumers (those having their nails treated), the potential for sensitisation

to HEMA is considerably higher amongst the professional users when protective measures

are neglected. The clinical studies (in patch-tested populations) support this. Besides skin

exposure due to inadequate handling of the monomers, the removal of excess nail-polish

material using unprotected fingers is also likely to occur.

It should also be noted that the data obtained in clinical studies do not reflect the real

incidence in the general population of HEMA contact allergy, which is at the moment

unknown. An increase in prevalence may occur due to the increasing popularity of artificial

nails. The recent publications seem to point towards an increase.

These publications also indicate that many of the patients reacting to nail acrylates are also

sensitised to other (meth)acrylates.

Di-HEMA-TMHDC

There are only a few reports with information on sensitisation to Di-HEMA-TMHDC among

users of nail-styling products. Di-HEMA-TMHDC is commonly used in dentistry. The LLNA

indicates that it is a weak sensitiser. This is reflected in the clinical studies in humans. The

human studies do not indicate that sensitisation to Di-HEMA-TMHDC is of concern among

users of nail-styling products.

Respiratory problems have been reported among professional users of nail-styling products,

but the causative chemicals are often not identified.

SCCS/1592/17

Final Opinion on the safety of cosmetic ingredients HEMA (CAS 868-77-9) and Di-HEMA Trimethylhexyl

Dicarbamate (CAS 41137-60-4 / 72869-86-4) - Submission I (Sensitisation only)

___________________________________________________________________________________________

For ‘metacrylates’ the evidence for respiratory allergy was denoted as limited or

contradictory in one review (Baur 2013) and absent in an updated version (Baur 2014).

For professional users, guidelines for the prevention of skin sensitisation and respiratory

problems are available (NIOSH 2011). A recent report from the French Authorities (ANSES

2017) reviews and discusses a range of exposures to various chemicals in nail-styling

professionals.

5. CONCLUSION