COD
Contact Dermatitis • Original Article
Contact Dermatitis
Coupled exposure to ingredients of cosmetic products: II. Preservatives ´ 2 Wolfgang Uter1 , Kerem Yazar2 , Eva-Maria Kratz3 , Gerd Mildau3 and Carola Liden 1 Department of Medical Informatics, Biometry and Epidemiology, Friedrich-Alexander-University Erlangen/Nurnberg, ¨ D-91054 Erlangen, Germany, 2 Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden, and 3 Chemical and Veterinary Investigation Office (CVUA Karlsruhe),
D-76187 Karlsruhe, Germany doi:10.1111/cod.12165
Summary
Background. The use of cosmetics exposes consumers to mixtures of ingredients, many of which are potential allergens. Many cosmetics contain one or several preservatives, some being important contact allergens. Objective. To examine the pattern of co-exposure to preservatives in different categories of cosmetics. Methods. A survey of products marketed in Germany, conducted in 2006–2009 by the Chemical and Veterinary Investigation Office in Karlsruhe, identified 4680 products categorizable according to Annex I to the Cosmetics Directive with information on the presence of preservatives. The occurrence and co-occurrence of preservatives were analysed and presented in tabular and graphical format. Results. Thirty per cent of all products were not declared to contain any preservatives; for 8%, no INCI labelling was present. For the remainder, the number of preservatives used tended to be higher in leave-on than in rinse-off products. Most often, combinations of (up to all five) parabens were used (39% of all products). Combinations with phenoxyethanol were also frequent. Formaldehyde releasers were found in 8% of products overall. Conclusions. The pattern of co-exposure to preservatives in important categories of cosmetic products illustrates the ‘cocktail’ of allergens that may facilitate sensitization, although, conversely, the combination of preservatives allows individual use levels to be kept lower, thereby possibly reducing sensitization risk. Key words: cosmetics; exposure analysis; ingredient label; preservatives.
In real life, people are usually not exposed to only one substance at a time, but to a multitude of substances, either occupationally or as consumers. Concomitant skin exposure to allergens, irritants and penetration enhancers occurs daily from many products and other
Correspondence: Wolfgang Uter, Department of Medical Informatics, Biom¨ etry and Epidemiology, Friedrich-Alexander University Erlangen-Nurnberg, Erlangen, Waldstr. 4–6, D-91054 Erlangen, Germany. Tel: +49 9131 8522750; Fax: +49 9131 8522721. E-mail: [email protected] Conflicts of interest: W.U. has accepted honoraria for presentations or travel reimbursement from cosmetic industry associations for presentations given to these. C.L., K.Y., E.-M. K. and G.M. have no conflict of interests to disclose. Accepted for publication 24 September 2013
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Contact Dermatitis, 70, 219–226
sources. Recent experimental findings have indicated that exposure to such a ‘cocktail’ of substances may enhance sensitization (1). Therefore, an estimation of the extent of co-exposure may improve our understanding of the exposure to allergens that actually occurs in daily life. The present study addresses this research question by analysing coupled exposure to preservatives, an important group of allergens in cosmetics, on the basis of a large survey of the German market. Thereby, it extends the scope of a previous publication on the co-occurrence of labelled fragrances in different categories of cosmetics (2).
Methods The Chemical and Veterinary Investigation Office (CVUA) in Karlsruhe, Germany is a state laboratory for risk
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PRESERVATIVES CO-OCCURRING IN COSMETICS • UTER ET AL.
analysis and assessment. In 2006–2009, the CVUA analysed various types of cosmetic product for an official investigation of the conformity of cosmetic products with legal provisions (5667 in the 4 years); see (2). In short, INCI labelling was studied with regard to the presence of preservatives permitted for use in cosmetics (Annex VI to the Cosmetics Directive); thus, qualitative information on the presence of substances was collected. All products were categorized into a hierarchical system of product types, with, effectively, 170 items. For the present analysis, these product type categories were aggregated to the items of Annex I of the Cosmetics Directive valid at the time of writing, with effectively 23 different categories (‘hair-setting products’ and ‘tinted bases’ were not applicable; a separate category, ‘not categorizable’, has been introduced). The present analysis includes those product data where (i) the above categorization was possible, thus excluding products that were ‘not categorizable’ (n = 250), and (ii) the presence (or absence) of preservatives was recorded in terms of an INCI declaration. Because, in 395 products, no INCI labelling was present, 4680 products could be included in the present analysis. Data management and analysis were performed with the statistical software r [version 3.0.1 (3)], in particular with the r-package ‘igraph’ (http://igraph.sourceforge.net/index.html) for producing so-called social network diagrams, which we have previously used to present similar data (2, 4), and the package ‘VennDiagram’.
Results The frequencies of occurrence of the different aggregated product types are shown in Table 1. Evidently, the most common type of product in the sample was leaveon creams. The proportion of products (i) without and (ii) with preservatives and (iii) the distribution of the number of preservatives in products with > 0 preservatives is given. Additionally, the percentage of products containing at least one of the five paraben esters is indicated, as is the percentage of products containing (one of) the formaldehyde releaser(s) included, namely, quaternium-15, imidazolidinyl urea, DMDM hydantoin, diazolidinyl urea, 5-bromo-5-nitro-1,3-dioxane, and bromo-2-nitropropane-1,3-diol. Generally, each paraben is counted as one in these analyses. However, as parabens are usually used combined with each other, we specifically addressed the overall co-occurrence of parabens with a Venn diagram (Fig. 1). The distribution of preservatives is shown in Table 2, both overall and across the product categories included
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in further analyses. The four original product categories – ‘hairdressing products’, ‘hair-conditioning products’, ‘hair tints and bleaches’, and ‘products for waving, straightening and fixing hair’ (Table 1) – have been combined to form a ‘hair (cosmetics)’ category. For this analysis, the five parabens (butylparaben, ethylparaben, isobutylparaben, methylparaben, and propylparaben) have additionally been aggregated to form a ‘parabens’ category, that is, the presence of at least one of the five compounds. In a similar fashion, ‘formaldehyde releasers’ have been aggregated, that is, the presence of at least one of the six substances listed above. The frequencies of different preservatives in important product categories subjected to further in-depth analysis are shown as a modified ‘violin plot’ in Fig. 2, again with each paraben (and each formaldehyde releaser) counting as one. Moreover, a number of special issues were addressed: (1) Beyond the product categories considered in Table 2 and further analyses, triclosan was present in only a limited proportion of products: in 6.5% of deodorants and antiperspirants, in 1% of toothpastes and related products (n = 207), and in single instances of a few other product categories. (2) If formaldehyde releasers are combined, the resulting increased exposure to formaldehyde may be an issue (formaldehyde itself was not used in the cosmetics evaluated). Hence, overall co-occurrence was analysed and found to be very limited: Bromo-2-nitropropane-1,3-diol and imidazolidinyl urea: n = 5, Diazolidinyl urea and DMDM hydantoin: n = 2, DMDM hydantoin and imidazolidinyl urea: n = 2 and 5-Bromo-5-nitro1,3-dioxane and imidazolidinyl urea: n = 1. (3) Methylisothiazolinone (MI), after its approval as cosmetic preservative in use concentrations up to 100 ppm (see Discussion), has been increasingly used in recent years. In the study period, a significant (p < 0.001) increase among the total samples was observed, with 0.4% of 1390 products containing MI in 2006, an identical proportion in 2007, a slight increase in 2008 (0.6% of 1123 products), and a substantial increase in 2009 (2.4% of 1076 products). The increase remained significant after adjustment, in a logistic regression model, for the proportion of rinse-off and ‘sun’ products containing MI most often, the proportions being 37%, 17%, 17%, and 26%, respectively, in the 4 successive years. The co-occurrence of MI and methylchloroisothiazolinone (MCI), according to label information, is difficult to interpret. It is not
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Contact Dermatitis, 70, 219–226
PRESERVATIVES CO-OCCURRING IN COSMETICS • UTER ET AL.
Table 1. Types of cosmetic product included in the analysis, aggregated to the categories of Annex I to the Cosmetics Directive, with frequency
of occurrence and (i) proportion of products without preservatives, (ii) proportion of products containing parabens, and (iii) proportion of products containing formaldehyde releasers. On the right, the distribution of the number of preservatives in products with > 0 preservatives, in terms of first quartile, median, third quartile and maximum is given, each paraben counting as one Distribution of number of preservatives
Category
Short
n
% no preservatives
% paraben
% Formaldehyde releasers
Creams, emulsions, lotions, gels and oils for the skin (hands, face, feet, etc.) Sunbathing products Products for making up and removing make-up from the face and the eyes Bath and shower preparations (salts, foams, oils, gels, etc.) Hair-cleansing products (lotions, powders, shampoos) Products for care of the teeth and the mouth Products intended for application to the lips Perfumes, toilet waters, and eau de Cologne Products for nail care and make-up Hairdressing products (lotions, lacquers, brilliantines) Deodorants and antiperspirants Hair-conditioning products (lotions, creams, oils) Hair tints and bleaches Anti-wrinkle products Products for waving, straightening and fixing hair Toilet soaps, deodorant soaps, etc. Face masks (with the exception of peeling products) Make-up powders, after-bath powders, hygienic powders, etc Products for tanning without sun Shaving products (creams, foams, lotions, etc.) Depilatories Products for external intimate hygiene Skin-whitening products Overall
Cream
1500
20.5
47.9
9.9
2
4
6
10
Sun Make-up
463 415
16.2 14.7
44.1 67.7
1.5 11.6
2 2
4 2
6 5
7 9
Shower*
384
23.7
18.0
3.9
2
2
4
8
Shampoo*
245
4.1
33.5
13.9
2
3
4
9
–
207
56.0
18.8
0.0
1
1
2
7
–
174
19.0
67.8
0.6
1
2
2
6
–
156
84.6
1.9
0.6
1
1
1
5
– Hair
146 144
93.8 16.0
0.7 51.4
2.0 23.6
1 1
1.5 2
2 4
4 9
– Hair
114 111
57.9 27.9
1.8 31.5
1.8 12.6
1 1
2 2
2 3
6 10
Hair – Hair
101 88 98
59.4 10.2 35.7
9.9 60.2 33.7
6.9 9.1 6.1
1 2 1
1 3.5 1.5
3.25 6 4
7 9 6
Soap* –
87 48
47.1 18.8
5.8 62.5
13.8 4.2
2 2
2 4
2 6
5 8
Make-up
44
29.5
65.9
4.5
2
2
3
7
– –
38 34
7.9 35.3
57.9 38.2
15.8 17.6
1 1
3 2
4.5 5
9 7
– – – –
33 27 23 4680
84.8 0.0 17.4 29.8
6.1 33.3 56.5 39.4
0.0 18.5 26.1 7.9
4 1.5 2 2
6 4 2 3
6 4 3 5
*
Q1
Median
Q3
Maximum
6 6 6 10
Aggregated to ‘rinse-off’.
possible to determine whether or not MI has been added in addition to the MCI/MI 3:1 mixture (e.g. Kathon® CG). (4) Methyldibromo glutaronitrile (MDBGN) was banned first from use in leave-on cosmetics and later also for use in rinse-off cosmetics in Europe (see Discussion). Nevertheless, according to ingredient labelling, MDBGN was present in 31 cosmetic products. Although a significant (p = 0.033) overall downward trend was observed, in 2008 one leave-on
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Contact Dermatitis, 70, 219–226
product and four rinse-off products, and in 2009 three leave-on products and one rinseoff product, were still labelled as containing MDBGN. (5) A number of products are specifically applied to vulnerable anatomical sites (see Discussion). A closer look at deodorants reveals that the majority do not contain preservatives at all (Table 1). Among the preservatives included, those found most commonly (in > 1%) were: sodium benzoate (8.8%), potassium sorbate (7.9%), triclosan
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PRESERVATIVES CO-OCCURRING IN COSMETICS • UTER ET AL.
Butyl 3
4
23 16
8
0
2 6
Ethyl
7
67
2
1 499
3
5 0
Propyl
0
249
2
0 0 11 0
0
3 0
0
552 132 24
227
Methyl
Isobutyl
Fig. 1. Venn diagram illustrating the co-occurrence of five different
parabens (butylparaben, ethylparaben, isobutylparaben, methylparaben, and propylparaben) across all product categories. The numbers in the areas representing single and coupled occurrence, respectively, indicate the frequency of (co-)occurrence. For instance, all five parabens were identified in 499 products (figure in the centre area with overlap of all five areas).
(6.1%), phenoxyethanol (4.4%), and benzyl alcohol (3.5%), in addition to parabens and formaldehyde releasers (Table 1). (6) Only few products for external intimate hygiene were sampled (n = 27), including only three wet wipes, the majority being ‘washing lotions’ intended for this particular body region. This limited sample illustrates that such products are heavily preserved, for example compared with other rinse-off products (see also Table 1); the preservatives used include sodium benzoate (48.1%), MCI/MI (44.4%), phenoxyethanol (44.4%), potassium sorbate (22.2%), benzoic acid (18.5%), benzyl alcohol (18.5%), salicylic acid (14.8%), diazolidinyl urea (11.1%), imidazolidinyl urea (7.4%), iodopropynyl butylcarbamate (7.4%), chlorhexidine (3.7%), ethylparaben (3.7%), and MI (3.7%). The main focus of the present analysis, however, is to present the combinations of preservatives in certain cosmetic product types. Figure 3a,b shows the various combinations in a semi-quantitative, graphical manner, including constituents occurring in at least 1% of products. The diameter of circles (nodes) representing single preservatives is scaled to represent the frequency
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of occurrence in the product category (Table 2). The width and darkness of the lines (links) varies with the frequency of bivariate occurrence – the more frequently two preservatives are used together, the wider and darker the line. To give a reference, the highest frequency, corresponding to the widest and darkest line, is given in the figure legend for each plot. It is evident that the combination of parabens with 2-phenoxyethanol is the most common one, except for rinse-off products, in which potassium sorbate and sodium benzoate is the most frequent combination, closely followed by combinations with phenoxyethanol and parabens. It is of note that MDBGN was always (and only) combined with phenoxyethanol in the products considered in this analysis.
Discussion This analysis extends a previous approach of analysing the co-occurrence of hair dye components (4) and the occurrence of fragrances (5) and preservatives (5, 6), respectively, in products on the market, and, in particular, of the co-occurrence of fragrances in cosmetics, the latter being based on the same data sample (2). This is the first analysis of the co-occurrence of preservatives in all categories of cosmetic product. Many of these preservatives are the most used, well-known and potent allergens. Parabens were found in almost 40% of all assessed products, and two or more parabens generally occurred together. This actual combined exposure resembles the use of a mixture of parabens in diagnostic patch testing. The paraben mix in the European and international baseline series for patch testing presently contains butylparaben, ethylparaben, methylparaben, and propylparaben, but not isobutylparaben. Such combined exposure may possibly elicit contact allergy reactions not produced by any one of the single constituents alone. This puts the notion of ‘false-positive’ reactions to the mix into perspective, when none of the single ingredients elicits a positive patch test reaction, which is quite often observed (8). On the other hand, parabens are known to be relatively weak allergens, affecting mainly elderly patients who have undergone long-lasting treatments because of stasis dermatitis/leg ulcer (7, 8). Another commonly used group of preservatives are the formaldehyde releasers, the actual release of formaldehyde varying and depending on matrix conditions, such as the pH. Contact sensitization as a clinical endpoint has recently been reviewed (9). In the review, a lack of exposure data concerning use in cosmetics in Europe had been noted; the present analysis is aimed at filling
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PRESERVATIVES CO-OCCURRING IN COSMETICS • UTER ET AL.
Number of Products in Category 1500
459
245
384
87
454
463
Cream
Make−up
Shampoo
Shower
Soap
Hair
Sun
10 9
Number of Preservatives
8 7 6 5 4 3 2 1 0
Product Category Fig. 2. Distribution of the number of preservatives in the product categories chosen for further analysis as a modified ‘violin plot’, accounting for the discrete nature of the count data, corresponding to centred histograms. For instance, the bottom set of rectangles indicates the proportion of products with no preservative listed.
this gap, at least for Germany. de Groot et al. mention that, in the United States, where contact sensitization to formaldehyde releasers is much more common than in Europe, ‘approximately 20% of cosmetics and personal care products (stay-on products: 17%, rinse-off products 27%) contain a formaldehyde-releaser’. Considering the relatively low overall use frequency according to our data (Table 1; 7.9%), the relatively low frequency of sensitization according to Information Network of Departments of Dermatology data (6) appears to be plausibly explained. However, in a previous analysis of the risk of sensitization to preservatives in leave-on cosmetics, based on the same CVUA data, bromo-2-nitropropane-1,3-diol was shown to have the highest estimated sensitization risk, and thus the least favourable ‘Sensitisation Exposure Quotient’, of the formaldehyde releasers (6). The combined use of formaldehyde releasers is, according to the present study, a rare exception, and will hopefully remain so.
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Contact Dermatitis, 70, 219–226
Two observations regarding single preservatives need to be commented on. First, MDBGN was banned in leave-on cosmetic products in March 2005 (Commission Directive 2003/83/EC), and, following a Scientific Committee on Consumer Products (SCCP) opinion of 2006 (SCCP/1013/06), in June 2008 also in rinse-off products (Commission Directive 2007/17/EC). Hence, MDBGN played only a marginal role in the present sample, and was still more prevalent in rinse-off products. However, the fact that products still contained MDBGN in the years when it was already banned underscores the need for continual surveillance schemes, such as the one ¨ used in Germany (‘Bundesweiter Uberwachungsplan’; see http://www.bvl.bund.de, last accessed 22 July 2013). Second, there is a current upsurge in MI contact allergy, mostly resulting from cosmetic exposure in females (10), owing to the increased use of MI since its approval in 2005 (Commission Directive 2005/42/EC), after an SCCNFP opinion (SCCNFP/0805/04). We conclude, on
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PRESERVATIVES CO-OCCURRING IN COSMETICS • UTER ET AL.
Table 2. Overall occurrence of preservatives and occurrence in those products considered for further analysis by their INCI name. Multiple
occurrences of preservatives are possible (see Table 1 and Fig. 2), hence, column percentages may add up to > 100%. For aggregation of categories to ‘make-up’ and ‘hair’, see Table 1 Product type Shower
Soap
Hair
Sun
Abbreviation
CAS no.
n = 4680
n = 1500
n = 459
n = 245
n = 384
n = 87
n = 454
n = 463
Benzalkonium chloride (benzyl-C8-18-alkyldimethyl chlorides)
Balk
63449-41-2, 68391-01-5, 68424-85-1, and 85409-22-9
0
0.1
0
0
0.3
0
0
0
Benzethonium chloride
Beth
121-54-0
0
0
Benzoic acid
Baci
65-85-0
3.1
2.4
Preservative
Benzyl alcohol
Overall
Cream
Make-up
Shampoo
Balc
100-51-6
7.8
9.3
Chloroacetamide
Clace
79-07-2
0.1
0
Chlorhexidine
Clhex
55-56-1
0.2
Climbazole
Clim
38083-17-9
Formic acid
Facid
Iodopropynyl butylcarbamate
0
0
0
0
0
0
1.7
7.8
4.9
2.3
4
2.4
2.8
8.6
12.8
11.5
5.1
8.2
0
0
0.3
2.3
0
0
0.3
0.2
0
0
0
0.2
0
0.5
0.1
0
9.8
0
0
0
0
64-18-6
0.5
0.1
0
4.5
2.1
0
0.7
0
IPBC
55406-53-6
3.1
3.7
2.6
2
2.9
12.6
3.7
3.2
Methyldibromo glutaronitrile
MDBGN
35691-65-7
0.7
0.7
0.2
2.9
1
3.4
0.2
0.2
Methylchloroisothiazolinone/ methylisothiazolinone
MCI/MI
55965-84-9; alternatively 26172-55-4 and 2682-20-4
4
4.1
0.7
11.8
7
0
5.5
21.8
Methylisothiazolinone
MI
2682-20-4
0.9
0.3
0.2
1.6
1.8
0
0.4
3.7
Phenoxyethanol
PE
122-99-6
30.1
41.9
30.5
30.2
19.5
10.3
20.5
54.6
Piroctone olamine
Piroc
68890-66-4
0.9
0.1
0
10.6
0
0
3.3
0
Potassium sorbate
Psorb
24634-61-5 and 590-00-1
8.4
10.8
5
29.8
21.6
0
2.4
0.9
Propionic acid
Propi
79-09-4
0
0
0
0
0
0
0
0
Sali
69-72-7
2.1
1.2
0
11
2.3
0
4
0
Sbenz
532-32-1
10.6
7.6
8.5
49
24.2
3.4
8.6
2.6
Salicylic acid Sodium benzoate Sorbic acid
Sorb
110-44-1
1.5
2
0.9
2
1.3
0
1.3
2.8
Triclocarban
Trica
101-20-2
0
0
0
0
0
0
0
0
Triclosan
Triclo
3380-34-5
1
2
0.4
0.4
0.8
0
0
0
Undecylenic acid
Undec
112-38-9
0
0
0
0
0
0
0
0
0.4
0
0
7.3
0
0
0
0
18
Zinc pyrithione Paraben(s)
Zpyri
13463-41-7
39.4
47.9
67.5
33.5
Bpara
94-26-8
17.7
26.9
24.8
11.8
7.3
Ethylparaben
Epara
120-47-8
19.9
31.1
22.2
15.9
9.6
5.7
9.5
32.2
Isobutylparaben
iBpara
4247-02-3
11.3
18.7
19.4
4.9
4.4
0
4.8
12.5
Methylparaben
Mpara
99-76-3
37.3
47
61.9
33.1
17.4
5.7
32.6
43.6
Propylparaben
Ppara
94-13-3
32.9
43.1
59.3
20
14.8
5.7
19.6
38.7
Formaldehyde
Fald
50-00-0
0
0
0
0
0
Formaldehyde releasers
F.rel
–
7.9
9.9
10.9
13.9
Butylparaben
Para
5.7 0
33.5
44.1
7.7
28.9
0
0
3.9
13.8
13.4
1.5
0
Bromo-2-nitropropane-1,3-diol
Brono
52-51-7
1.7
2.5
0.7
3.3
2.3
13.8
0.9
0.4
5-Bromo-5-nitro-1,3-dioxane
Brdio
30007-47-7
0.1
0
0.2
0
0.8
0
0.4
0
Diazolidinyl urea
Diazo
78491-02-8
1.9
2.3
4.8
2.4
0
0
3.1
0.2
DMDM hydantoin
DMDMh
6440-58-0
1.3
0.6
0.2
7.8
0.8
0
4.8
0.4
Imidazolidinyl urea
Imida
39236-46-9
2.9
4.6
4.4
0.8
0
0
4.8
0.4
Quaternium-15
Qua15
4080-31-3 and 51229-78-8
0.1
0.1
0.9
0
0
0
0.2
0
the basis of the present analysis, that the increased use of MI gained momentum in 2009; unfortunately, current use frequencies and concentrations in different categories of cosmetic are unknown. It is very likely that the use of MI increased further in 2010 and subsequent years, giving rise to the epidemic of cosmetic-related sensitization observed in many countries [e.g. (10)]. It should also
224
be noted that neither MI nor MDBGN have yet been classified as skin sensitizers (H 317, R 43) according to the regulation on classification, labelling and packaging of substances and mixtures. These two important skin sensitizers are thus used without restriction, ingredient information or warning labelling in product types other than cosmetics.
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Contact Dermatitis, 70, 219–226
PRESERVATIVES CO-OCCURRING IN COSMETICS • UTER ET AL.
a
Cream
Make−up
MCIMI 62
Baci 36
Balc 139
Brono 37
MI 17
Diazo 22
Balc 38
Sbenz 39 IPBC 15
Para 719
Sorb 30
Psorb 23
Imida 69
Sbenz 114
Sun
PE 628
Triclo Diazo30 35
IPBC 56
Psorb 162
Imida 20
Para 310
PE 140
Para 204
PE 253 Sorb 13
Balc 13
Baci 8
Sali 18
Sbenz 12
IPBC 12
Rinse−off
b
Brono 29
MCIMI 69
Baci 11
Hair DMDMh 22
MI 11 Imida 22
IPBC 27
Baci 40 Balc Para 80 Psorb 156 156 PE Sbenz Zpyri 158 216 18 Facid Piroc 19 Sali 26 36 Sorb 10 Clim 24
MDBGN 14
Balc 23
DMDMh 22
MCIMI 32 Sbenz 39
Baci 18 PE 93
Para 152 Sali 18
Sorb 6 IPBC 17 Piroc 15
Diazo 14
Psorb 11
Fig. 3. (a) Co-occurrence of the most commonly used preservatives, identified by INCI name on the label, in different product categories according to Annex I of the Cosmetics Directive. Abbreviations are explained in Table 2. The two vertices connected by the widest edge, and the respective frequency of co-occurrence, are indicated for reference (see text): Creams: ‘creams, emulsions, lotions, gels and oils for the skin (hands, face, feet, etc.)’ (n = 1500). Most frequent co-occurrence: parabens with phenoxyethanol: 526. Make-up: ‘products for making up and removing make-up from the face and the eyes’ and ‘make-up powders, after-bath powders, hygienic powders, etc.’ (n = 459). Most frequent co-occurrence: parabens with phenoxyethanol: 119. Sun: ‘sunbathing products’ (n = 463). Most frequent co-occurrence: parabens with phenoxyethanol: 185. (b) Co-occurrence of the most commonly used biocides, identified by INCI name on the label, in different product categories according to Annex I of the Cosmetics Directive; ‘rinse-off’ combines three categories. Abbreviations are explained in Table 2. The two vertices connected by the widest edge, and the respective frequency of co-occurrence, are indicated for reference (see text): Rinse-off : combination of three categories; see Table 1 (n = 716). Most frequent co-occurrence: potassium sorbate with sodium benzoate: 108. Hair: combination of four categories; see Table 1 (n = 454). Most frequent co-occurrence: parabens with phenoxyethanol: 84.
Triclosan was found in 48 products. The safety of triclosan has been assessed by the Scientific Committee on Consumer Safety (SCCS) and its predecessors. Triclosan is not considered to be a skin sensitizer. The current use of triclosan at a maximum concentration of 0.3% in toothpastes, soaps and deodorant sticks has been considered to be safe, whereas additional use in other leave-on products is not considered to be safe. The main concern about triclosan is the development of antimicrobial resistance (SCCP/1040/06, SCCP/1251/09, SCCS/1414/11).
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Contact Dermatitis, 70, 219–226
A number of general aspects pertaining to preservatives and their combined use have been discussed in the previous article on coupled exposure to fragrances (2), and are not reiterated here. One particular limitation on the interpretability of data on co-exposure to preservatives stems from the fact that actual use concentrations are not available from the ingredient labelling according to the INCI, which is purely qualitative (see Methods) and not always accurate (11). This implies that preservatives may have been (i) introduced by preserved components of the final product, (ii) added to the final product with the aim
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PRESERVATIVES CO-OCCURRING IN COSMETICS • UTER ET AL.
of preserving it, or (iii) introduced by a component and added to the final product. In the case of preservatives, there is some rationale for combining several preservatives, namely, exploiting synergistic antimicrobial action spectra, and avoiding excessive levels of single preservatives that would otherwise be necessary under the manufacturing and use conditions, and that would entail an increased sensitization
risk. Nevertheless, from the point of view of primary prevention of contact sensitization, all substances that are biologically active as preservatives seem to be also biologically active as allergens. Hence, further development of the composition of cosmetics, manufacturing conditions, quality of ingredients, and dispensing systems, allowing safe and non-sensitizing levels of preservatives, or even their complete avoidance, appears to be an attractive target for qualitative improvement of cosmetic products.
References 1 Bonefeld C M, Nielsen M M, Rubin I M et al. Enhanced sensitization and elicitation responses caused by mixtures of common fragrance allergens. Contact Dermatitis 2011: 65: 336–342. 2 Uter W, Yazar K, Kratz E M, Mildau G, Lid´en C. Coupled exposure to ingredients of cosmetic products: I. fragrances. Contact Dermatitis 2013: 69: 335–341. 3 R Team. R: A Language and Environment for Statistical Computing: Wien, The R Project for Statistical Computing, 2012. 4 Yazar K, Boman A, Lid´en C. p-Phenylenediamine and other hair dye sensitizers in Spain. Contact Dermatitis 2012: 66: 27–32. 5 Yazar K, Johnsson S, Lind M L, Boman A, Lid´en C. Preservatives and fragrances in selected consumer-available cosmetics
226
and detergents. Contact Dermatitis 2011: 64: 265–272. 6 Schnuch A, Mildau G, Kratz E M, Uter W. Risk of sensitization to preservatives estimated on the basis of patch test data and exposure, according to a sample of 3541 leave-on products. Contact Dermatitis 2011: 65: 167–174. 7 Uter W, Schnuch A, Geier J, Agathos M. Epikutantest-Reaktionen auf Paraben-Mixe und ihre ¨ Aufschlusselungen. Studien der Deutschen Kontaktallergie-Gruppe (DKG) und des Informationsverbundes dermatologischer Kliniken (IVDK), 1990–2000. Allergologie 2002: 25: 194–202. 8 Uter W, Geier J, Pfahlberg A, Effendy I. The spectrum of contact allergy in elderly
patients with and without lower leg dermatitis. Dermatology 2002: 204: 266–272. 9 de Groot A C, White I R, Flyvholm M A, Lensen G, Coenraads P J. Formaldehyde-releasers in cosmetics: relationship to formaldehyde contact allergy. Part 1. Characterization, frequency and relevance of sensitization, and frequency of use in cosmetics. Contact Dermatitis 2010: 62: 2–17. 10 Uter W, Geier J, Bauer A, Schnuch A. Risk factors associated with methylisothiazolinone contact sensitisation. Contact Dermatitis 2013: 69: 231–238. 11 Rastogi S C. Analytical control of preservative labelling on skin creams. Contact Dermatitis 2000: 43: 339–343.
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Contact Dermatitis, 70, 219–226
Contact Dermatitis • Original Article
Contact Dermatitis
Coupled exposure to ingredients of cosmetic products: II. Preservatives ´ 2 Wolfgang Uter1 , Kerem Yazar2 , Eva-Maria Kratz3 , Gerd Mildau3 and Carola Liden 1 Department of Medical Informatics, Biometry and Epidemiology, Friedrich-Alexander-University Erlangen/Nurnberg, ¨ D-91054 Erlangen, Germany, 2 Institute of Environmental Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden, and 3 Chemical and Veterinary Investigation Office (CVUA Karlsruhe),
D-76187 Karlsruhe, Germany doi:10.1111/cod.12165
Summary
Background. The use of cosmetics exposes consumers to mixtures of ingredients, many of which are potential allergens. Many cosmetics contain one or several preservatives, some being important contact allergens. Objective. To examine the pattern of co-exposure to preservatives in different categories of cosmetics. Methods. A survey of products marketed in Germany, conducted in 2006–2009 by the Chemical and Veterinary Investigation Office in Karlsruhe, identified 4680 products categorizable according to Annex I to the Cosmetics Directive with information on the presence of preservatives. The occurrence and co-occurrence of preservatives were analysed and presented in tabular and graphical format. Results. Thirty per cent of all products were not declared to contain any preservatives; for 8%, no INCI labelling was present. For the remainder, the number of preservatives used tended to be higher in leave-on than in rinse-off products. Most often, combinations of (up to all five) parabens were used (39% of all products). Combinations with phenoxyethanol were also frequent. Formaldehyde releasers were found in 8% of products overall. Conclusions. The pattern of co-exposure to preservatives in important categories of cosmetic products illustrates the ‘cocktail’ of allergens that may facilitate sensitization, although, conversely, the combination of preservatives allows individual use levels to be kept lower, thereby possibly reducing sensitization risk. Key words: cosmetics; exposure analysis; ingredient label; preservatives.
In real life, people are usually not exposed to only one substance at a time, but to a multitude of substances, either occupationally or as consumers. Concomitant skin exposure to allergens, irritants and penetration enhancers occurs daily from many products and other
Correspondence: Wolfgang Uter, Department of Medical Informatics, Biom¨ etry and Epidemiology, Friedrich-Alexander University Erlangen-Nurnberg, Erlangen, Waldstr. 4–6, D-91054 Erlangen, Germany. Tel: +49 9131 8522750; Fax: +49 9131 8522721. E-mail: [email protected] Conflicts of interest: W.U. has accepted honoraria for presentations or travel reimbursement from cosmetic industry associations for presentations given to these. C.L., K.Y., E.-M. K. and G.M. have no conflict of interests to disclose. Accepted for publication 24 September 2013
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Contact Dermatitis, 70, 219–226
sources. Recent experimental findings have indicated that exposure to such a ‘cocktail’ of substances may enhance sensitization (1). Therefore, an estimation of the extent of co-exposure may improve our understanding of the exposure to allergens that actually occurs in daily life. The present study addresses this research question by analysing coupled exposure to preservatives, an important group of allergens in cosmetics, on the basis of a large survey of the German market. Thereby, it extends the scope of a previous publication on the co-occurrence of labelled fragrances in different categories of cosmetics (2).
Methods The Chemical and Veterinary Investigation Office (CVUA) in Karlsruhe, Germany is a state laboratory for risk
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PRESERVATIVES CO-OCCURRING IN COSMETICS • UTER ET AL.
analysis and assessment. In 2006–2009, the CVUA analysed various types of cosmetic product for an official investigation of the conformity of cosmetic products with legal provisions (5667 in the 4 years); see (2). In short, INCI labelling was studied with regard to the presence of preservatives permitted for use in cosmetics (Annex VI to the Cosmetics Directive); thus, qualitative information on the presence of substances was collected. All products were categorized into a hierarchical system of product types, with, effectively, 170 items. For the present analysis, these product type categories were aggregated to the items of Annex I of the Cosmetics Directive valid at the time of writing, with effectively 23 different categories (‘hair-setting products’ and ‘tinted bases’ were not applicable; a separate category, ‘not categorizable’, has been introduced). The present analysis includes those product data where (i) the above categorization was possible, thus excluding products that were ‘not categorizable’ (n = 250), and (ii) the presence (or absence) of preservatives was recorded in terms of an INCI declaration. Because, in 395 products, no INCI labelling was present, 4680 products could be included in the present analysis. Data management and analysis were performed with the statistical software r [version 3.0.1 (3)], in particular with the r-package ‘igraph’ (http://igraph.sourceforge.net/index.html) for producing so-called social network diagrams, which we have previously used to present similar data (2, 4), and the package ‘VennDiagram’.
Results The frequencies of occurrence of the different aggregated product types are shown in Table 1. Evidently, the most common type of product in the sample was leaveon creams. The proportion of products (i) without and (ii) with preservatives and (iii) the distribution of the number of preservatives in products with > 0 preservatives is given. Additionally, the percentage of products containing at least one of the five paraben esters is indicated, as is the percentage of products containing (one of) the formaldehyde releaser(s) included, namely, quaternium-15, imidazolidinyl urea, DMDM hydantoin, diazolidinyl urea, 5-bromo-5-nitro-1,3-dioxane, and bromo-2-nitropropane-1,3-diol. Generally, each paraben is counted as one in these analyses. However, as parabens are usually used combined with each other, we specifically addressed the overall co-occurrence of parabens with a Venn diagram (Fig. 1). The distribution of preservatives is shown in Table 2, both overall and across the product categories included
220
in further analyses. The four original product categories – ‘hairdressing products’, ‘hair-conditioning products’, ‘hair tints and bleaches’, and ‘products for waving, straightening and fixing hair’ (Table 1) – have been combined to form a ‘hair (cosmetics)’ category. For this analysis, the five parabens (butylparaben, ethylparaben, isobutylparaben, methylparaben, and propylparaben) have additionally been aggregated to form a ‘parabens’ category, that is, the presence of at least one of the five compounds. In a similar fashion, ‘formaldehyde releasers’ have been aggregated, that is, the presence of at least one of the six substances listed above. The frequencies of different preservatives in important product categories subjected to further in-depth analysis are shown as a modified ‘violin plot’ in Fig. 2, again with each paraben (and each formaldehyde releaser) counting as one. Moreover, a number of special issues were addressed: (1) Beyond the product categories considered in Table 2 and further analyses, triclosan was present in only a limited proportion of products: in 6.5% of deodorants and antiperspirants, in 1% of toothpastes and related products (n = 207), and in single instances of a few other product categories. (2) If formaldehyde releasers are combined, the resulting increased exposure to formaldehyde may be an issue (formaldehyde itself was not used in the cosmetics evaluated). Hence, overall co-occurrence was analysed and found to be very limited: Bromo-2-nitropropane-1,3-diol and imidazolidinyl urea: n = 5, Diazolidinyl urea and DMDM hydantoin: n = 2, DMDM hydantoin and imidazolidinyl urea: n = 2 and 5-Bromo-5-nitro1,3-dioxane and imidazolidinyl urea: n = 1. (3) Methylisothiazolinone (MI), after its approval as cosmetic preservative in use concentrations up to 100 ppm (see Discussion), has been increasingly used in recent years. In the study period, a significant (p < 0.001) increase among the total samples was observed, with 0.4% of 1390 products containing MI in 2006, an identical proportion in 2007, a slight increase in 2008 (0.6% of 1123 products), and a substantial increase in 2009 (2.4% of 1076 products). The increase remained significant after adjustment, in a logistic regression model, for the proportion of rinse-off and ‘sun’ products containing MI most often, the proportions being 37%, 17%, 17%, and 26%, respectively, in the 4 successive years. The co-occurrence of MI and methylchloroisothiazolinone (MCI), according to label information, is difficult to interpret. It is not
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Contact Dermatitis, 70, 219–226
PRESERVATIVES CO-OCCURRING IN COSMETICS • UTER ET AL.
Table 1. Types of cosmetic product included in the analysis, aggregated to the categories of Annex I to the Cosmetics Directive, with frequency
of occurrence and (i) proportion of products without preservatives, (ii) proportion of products containing parabens, and (iii) proportion of products containing formaldehyde releasers. On the right, the distribution of the number of preservatives in products with > 0 preservatives, in terms of first quartile, median, third quartile and maximum is given, each paraben counting as one Distribution of number of preservatives
Category
Short
n
% no preservatives
% paraben
% Formaldehyde releasers
Creams, emulsions, lotions, gels and oils for the skin (hands, face, feet, etc.) Sunbathing products Products for making up and removing make-up from the face and the eyes Bath and shower preparations (salts, foams, oils, gels, etc.) Hair-cleansing products (lotions, powders, shampoos) Products for care of the teeth and the mouth Products intended for application to the lips Perfumes, toilet waters, and eau de Cologne Products for nail care and make-up Hairdressing products (lotions, lacquers, brilliantines) Deodorants and antiperspirants Hair-conditioning products (lotions, creams, oils) Hair tints and bleaches Anti-wrinkle products Products for waving, straightening and fixing hair Toilet soaps, deodorant soaps, etc. Face masks (with the exception of peeling products) Make-up powders, after-bath powders, hygienic powders, etc Products for tanning without sun Shaving products (creams, foams, lotions, etc.) Depilatories Products for external intimate hygiene Skin-whitening products Overall
Cream
1500
20.5
47.9
9.9
2
4
6
10
Sun Make-up
463 415
16.2 14.7
44.1 67.7
1.5 11.6
2 2
4 2
6 5
7 9
Shower*
384
23.7
18.0
3.9
2
2
4
8
Shampoo*
245
4.1
33.5
13.9
2
3
4
9
–
207
56.0
18.8
0.0
1
1
2
7
–
174
19.0
67.8
0.6
1
2
2
6
–
156
84.6
1.9
0.6
1
1
1
5
– Hair
146 144
93.8 16.0
0.7 51.4
2.0 23.6
1 1
1.5 2
2 4
4 9
– Hair
114 111
57.9 27.9
1.8 31.5
1.8 12.6
1 1
2 2
2 3
6 10
Hair – Hair
101 88 98
59.4 10.2 35.7
9.9 60.2 33.7
6.9 9.1 6.1
1 2 1
1 3.5 1.5
3.25 6 4
7 9 6
Soap* –
87 48
47.1 18.8
5.8 62.5
13.8 4.2
2 2
2 4
2 6
5 8
Make-up
44
29.5
65.9
4.5
2
2
3
7
– –
38 34
7.9 35.3
57.9 38.2
15.8 17.6
1 1
3 2
4.5 5
9 7
– – – –
33 27 23 4680
84.8 0.0 17.4 29.8
6.1 33.3 56.5 39.4
0.0 18.5 26.1 7.9
4 1.5 2 2
6 4 2 3
6 4 3 5
*
Q1
Median
Q3
Maximum
6 6 6 10
Aggregated to ‘rinse-off’.
possible to determine whether or not MI has been added in addition to the MCI/MI 3:1 mixture (e.g. Kathon® CG). (4) Methyldibromo glutaronitrile (MDBGN) was banned first from use in leave-on cosmetics and later also for use in rinse-off cosmetics in Europe (see Discussion). Nevertheless, according to ingredient labelling, MDBGN was present in 31 cosmetic products. Although a significant (p = 0.033) overall downward trend was observed, in 2008 one leave-on
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Contact Dermatitis, 70, 219–226
product and four rinse-off products, and in 2009 three leave-on products and one rinseoff product, were still labelled as containing MDBGN. (5) A number of products are specifically applied to vulnerable anatomical sites (see Discussion). A closer look at deodorants reveals that the majority do not contain preservatives at all (Table 1). Among the preservatives included, those found most commonly (in > 1%) were: sodium benzoate (8.8%), potassium sorbate (7.9%), triclosan
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PRESERVATIVES CO-OCCURRING IN COSMETICS • UTER ET AL.
Butyl 3
4
23 16
8
0
2 6
Ethyl
7
67
2
1 499
3
5 0
Propyl
0
249
2
0 0 11 0
0
3 0
0
552 132 24
227
Methyl
Isobutyl
Fig. 1. Venn diagram illustrating the co-occurrence of five different
parabens (butylparaben, ethylparaben, isobutylparaben, methylparaben, and propylparaben) across all product categories. The numbers in the areas representing single and coupled occurrence, respectively, indicate the frequency of (co-)occurrence. For instance, all five parabens were identified in 499 products (figure in the centre area with overlap of all five areas).
(6.1%), phenoxyethanol (4.4%), and benzyl alcohol (3.5%), in addition to parabens and formaldehyde releasers (Table 1). (6) Only few products for external intimate hygiene were sampled (n = 27), including only three wet wipes, the majority being ‘washing lotions’ intended for this particular body region. This limited sample illustrates that such products are heavily preserved, for example compared with other rinse-off products (see also Table 1); the preservatives used include sodium benzoate (48.1%), MCI/MI (44.4%), phenoxyethanol (44.4%), potassium sorbate (22.2%), benzoic acid (18.5%), benzyl alcohol (18.5%), salicylic acid (14.8%), diazolidinyl urea (11.1%), imidazolidinyl urea (7.4%), iodopropynyl butylcarbamate (7.4%), chlorhexidine (3.7%), ethylparaben (3.7%), and MI (3.7%). The main focus of the present analysis, however, is to present the combinations of preservatives in certain cosmetic product types. Figure 3a,b shows the various combinations in a semi-quantitative, graphical manner, including constituents occurring in at least 1% of products. The diameter of circles (nodes) representing single preservatives is scaled to represent the frequency
222
of occurrence in the product category (Table 2). The width and darkness of the lines (links) varies with the frequency of bivariate occurrence – the more frequently two preservatives are used together, the wider and darker the line. To give a reference, the highest frequency, corresponding to the widest and darkest line, is given in the figure legend for each plot. It is evident that the combination of parabens with 2-phenoxyethanol is the most common one, except for rinse-off products, in which potassium sorbate and sodium benzoate is the most frequent combination, closely followed by combinations with phenoxyethanol and parabens. It is of note that MDBGN was always (and only) combined with phenoxyethanol in the products considered in this analysis.
Discussion This analysis extends a previous approach of analysing the co-occurrence of hair dye components (4) and the occurrence of fragrances (5) and preservatives (5, 6), respectively, in products on the market, and, in particular, of the co-occurrence of fragrances in cosmetics, the latter being based on the same data sample (2). This is the first analysis of the co-occurrence of preservatives in all categories of cosmetic product. Many of these preservatives are the most used, well-known and potent allergens. Parabens were found in almost 40% of all assessed products, and two or more parabens generally occurred together. This actual combined exposure resembles the use of a mixture of parabens in diagnostic patch testing. The paraben mix in the European and international baseline series for patch testing presently contains butylparaben, ethylparaben, methylparaben, and propylparaben, but not isobutylparaben. Such combined exposure may possibly elicit contact allergy reactions not produced by any one of the single constituents alone. This puts the notion of ‘false-positive’ reactions to the mix into perspective, when none of the single ingredients elicits a positive patch test reaction, which is quite often observed (8). On the other hand, parabens are known to be relatively weak allergens, affecting mainly elderly patients who have undergone long-lasting treatments because of stasis dermatitis/leg ulcer (7, 8). Another commonly used group of preservatives are the formaldehyde releasers, the actual release of formaldehyde varying and depending on matrix conditions, such as the pH. Contact sensitization as a clinical endpoint has recently been reviewed (9). In the review, a lack of exposure data concerning use in cosmetics in Europe had been noted; the present analysis is aimed at filling
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PRESERVATIVES CO-OCCURRING IN COSMETICS • UTER ET AL.
Number of Products in Category 1500
459
245
384
87
454
463
Cream
Make−up
Shampoo
Shower
Soap
Hair
Sun
10 9
Number of Preservatives
8 7 6 5 4 3 2 1 0
Product Category Fig. 2. Distribution of the number of preservatives in the product categories chosen for further analysis as a modified ‘violin plot’, accounting for the discrete nature of the count data, corresponding to centred histograms. For instance, the bottom set of rectangles indicates the proportion of products with no preservative listed.
this gap, at least for Germany. de Groot et al. mention that, in the United States, where contact sensitization to formaldehyde releasers is much more common than in Europe, ‘approximately 20% of cosmetics and personal care products (stay-on products: 17%, rinse-off products 27%) contain a formaldehyde-releaser’. Considering the relatively low overall use frequency according to our data (Table 1; 7.9%), the relatively low frequency of sensitization according to Information Network of Departments of Dermatology data (6) appears to be plausibly explained. However, in a previous analysis of the risk of sensitization to preservatives in leave-on cosmetics, based on the same CVUA data, bromo-2-nitropropane-1,3-diol was shown to have the highest estimated sensitization risk, and thus the least favourable ‘Sensitisation Exposure Quotient’, of the formaldehyde releasers (6). The combined use of formaldehyde releasers is, according to the present study, a rare exception, and will hopefully remain so.
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Contact Dermatitis, 70, 219–226
Two observations regarding single preservatives need to be commented on. First, MDBGN was banned in leave-on cosmetic products in March 2005 (Commission Directive 2003/83/EC), and, following a Scientific Committee on Consumer Products (SCCP) opinion of 2006 (SCCP/1013/06), in June 2008 also in rinse-off products (Commission Directive 2007/17/EC). Hence, MDBGN played only a marginal role in the present sample, and was still more prevalent in rinse-off products. However, the fact that products still contained MDBGN in the years when it was already banned underscores the need for continual surveillance schemes, such as the one ¨ used in Germany (‘Bundesweiter Uberwachungsplan’; see http://www.bvl.bund.de, last accessed 22 July 2013). Second, there is a current upsurge in MI contact allergy, mostly resulting from cosmetic exposure in females (10), owing to the increased use of MI since its approval in 2005 (Commission Directive 2005/42/EC), after an SCCNFP opinion (SCCNFP/0805/04). We conclude, on
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PRESERVATIVES CO-OCCURRING IN COSMETICS • UTER ET AL.
Table 2. Overall occurrence of preservatives and occurrence in those products considered for further analysis by their INCI name. Multiple
occurrences of preservatives are possible (see Table 1 and Fig. 2), hence, column percentages may add up to > 100%. For aggregation of categories to ‘make-up’ and ‘hair’, see Table 1 Product type Shower
Soap
Hair
Sun
Abbreviation
CAS no.
n = 4680
n = 1500
n = 459
n = 245
n = 384
n = 87
n = 454
n = 463
Benzalkonium chloride (benzyl-C8-18-alkyldimethyl chlorides)
Balk
63449-41-2, 68391-01-5, 68424-85-1, and 85409-22-9
0
0.1
0
0
0.3
0
0
0
Benzethonium chloride
Beth
121-54-0
0
0
Benzoic acid
Baci
65-85-0
3.1
2.4
Preservative
Benzyl alcohol
Overall
Cream
Make-up
Shampoo
Balc
100-51-6
7.8
9.3
Chloroacetamide
Clace
79-07-2
0.1
0
Chlorhexidine
Clhex
55-56-1
0.2
Climbazole
Clim
38083-17-9
Formic acid
Facid
Iodopropynyl butylcarbamate
0
0
0
0
0
0
1.7
7.8
4.9
2.3
4
2.4
2.8
8.6
12.8
11.5
5.1
8.2
0
0
0.3
2.3
0
0
0.3
0.2
0
0
0
0.2
0
0.5
0.1
0
9.8
0
0
0
0
64-18-6
0.5
0.1
0
4.5
2.1
0
0.7
0
IPBC
55406-53-6
3.1
3.7
2.6
2
2.9
12.6
3.7
3.2
Methyldibromo glutaronitrile
MDBGN
35691-65-7
0.7
0.7
0.2
2.9
1
3.4
0.2
0.2
Methylchloroisothiazolinone/ methylisothiazolinone
MCI/MI
55965-84-9; alternatively 26172-55-4 and 2682-20-4
4
4.1
0.7
11.8
7
0
5.5
21.8
Methylisothiazolinone
MI
2682-20-4
0.9
0.3
0.2
1.6
1.8
0
0.4
3.7
Phenoxyethanol
PE
122-99-6
30.1
41.9
30.5
30.2
19.5
10.3
20.5
54.6
Piroctone olamine
Piroc
68890-66-4
0.9
0.1
0
10.6
0
0
3.3
0
Potassium sorbate
Psorb
24634-61-5 and 590-00-1
8.4
10.8
5
29.8
21.6
0
2.4
0.9
Propionic acid
Propi
79-09-4
0
0
0
0
0
0
0
0
Sali
69-72-7
2.1
1.2
0
11
2.3
0
4
0
Sbenz
532-32-1
10.6
7.6
8.5
49
24.2
3.4
8.6
2.6
Salicylic acid Sodium benzoate Sorbic acid
Sorb
110-44-1
1.5
2
0.9
2
1.3
0
1.3
2.8
Triclocarban
Trica
101-20-2
0
0
0
0
0
0
0
0
Triclosan
Triclo
3380-34-5
1
2
0.4
0.4
0.8
0
0
0
Undecylenic acid
Undec
112-38-9
0
0
0
0
0
0
0
0
0.4
0
0
7.3
0
0
0
0
18
Zinc pyrithione Paraben(s)
Zpyri
13463-41-7
39.4
47.9
67.5
33.5
Bpara
94-26-8
17.7
26.9
24.8
11.8
7.3
Ethylparaben
Epara
120-47-8
19.9
31.1
22.2
15.9
9.6
5.7
9.5
32.2
Isobutylparaben
iBpara
4247-02-3
11.3
18.7
19.4
4.9
4.4
0
4.8
12.5
Methylparaben
Mpara
99-76-3
37.3
47
61.9
33.1
17.4
5.7
32.6
43.6
Propylparaben
Ppara
94-13-3
32.9
43.1
59.3
20
14.8
5.7
19.6
38.7
Formaldehyde
Fald
50-00-0
0
0
0
0
0
Formaldehyde releasers
F.rel
–
7.9
9.9
10.9
13.9
Butylparaben
Para
5.7 0
33.5
44.1
7.7
28.9
0
0
3.9
13.8
13.4
1.5
0
Bromo-2-nitropropane-1,3-diol
Brono
52-51-7
1.7
2.5
0.7
3.3
2.3
13.8
0.9
0.4
5-Bromo-5-nitro-1,3-dioxane
Brdio
30007-47-7
0.1
0
0.2
0
0.8
0
0.4
0
Diazolidinyl urea
Diazo
78491-02-8
1.9
2.3
4.8
2.4
0
0
3.1
0.2
DMDM hydantoin
DMDMh
6440-58-0
1.3
0.6
0.2
7.8
0.8
0
4.8
0.4
Imidazolidinyl urea
Imida
39236-46-9
2.9
4.6
4.4
0.8
0
0
4.8
0.4
Quaternium-15
Qua15
4080-31-3 and 51229-78-8
0.1
0.1
0.9
0
0
0
0.2
0
the basis of the present analysis, that the increased use of MI gained momentum in 2009; unfortunately, current use frequencies and concentrations in different categories of cosmetic are unknown. It is very likely that the use of MI increased further in 2010 and subsequent years, giving rise to the epidemic of cosmetic-related sensitization observed in many countries [e.g. (10)]. It should also
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be noted that neither MI nor MDBGN have yet been classified as skin sensitizers (H 317, R 43) according to the regulation on classification, labelling and packaging of substances and mixtures. These two important skin sensitizers are thus used without restriction, ingredient information or warning labelling in product types other than cosmetics.
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Contact Dermatitis, 70, 219–226
PRESERVATIVES CO-OCCURRING IN COSMETICS • UTER ET AL.
a
Cream
Make−up
MCIMI 62
Baci 36
Balc 139
Brono 37
MI 17
Diazo 22
Balc 38
Sbenz 39 IPBC 15
Para 719
Sorb 30
Psorb 23
Imida 69
Sbenz 114
Sun
PE 628
Triclo Diazo30 35
IPBC 56
Psorb 162
Imida 20
Para 310
PE 140
Para 204
PE 253 Sorb 13
Balc 13
Baci 8
Sali 18
Sbenz 12
IPBC 12
Rinse−off
b
Brono 29
MCIMI 69
Baci 11
Hair DMDMh 22
MI 11 Imida 22
IPBC 27
Baci 40 Balc Para 80 Psorb 156 156 PE Sbenz Zpyri 158 216 18 Facid Piroc 19 Sali 26 36 Sorb 10 Clim 24
MDBGN 14
Balc 23
DMDMh 22
MCIMI 32 Sbenz 39
Baci 18 PE 93
Para 152 Sali 18
Sorb 6 IPBC 17 Piroc 15
Diazo 14
Psorb 11
Fig. 3. (a) Co-occurrence of the most commonly used preservatives, identified by INCI name on the label, in different product categories according to Annex I of the Cosmetics Directive. Abbreviations are explained in Table 2. The two vertices connected by the widest edge, and the respective frequency of co-occurrence, are indicated for reference (see text): Creams: ‘creams, emulsions, lotions, gels and oils for the skin (hands, face, feet, etc.)’ (n = 1500). Most frequent co-occurrence: parabens with phenoxyethanol: 526. Make-up: ‘products for making up and removing make-up from the face and the eyes’ and ‘make-up powders, after-bath powders, hygienic powders, etc.’ (n = 459). Most frequent co-occurrence: parabens with phenoxyethanol: 119. Sun: ‘sunbathing products’ (n = 463). Most frequent co-occurrence: parabens with phenoxyethanol: 185. (b) Co-occurrence of the most commonly used biocides, identified by INCI name on the label, in different product categories according to Annex I of the Cosmetics Directive; ‘rinse-off’ combines three categories. Abbreviations are explained in Table 2. The two vertices connected by the widest edge, and the respective frequency of co-occurrence, are indicated for reference (see text): Rinse-off : combination of three categories; see Table 1 (n = 716). Most frequent co-occurrence: potassium sorbate with sodium benzoate: 108. Hair: combination of four categories; see Table 1 (n = 454). Most frequent co-occurrence: parabens with phenoxyethanol: 84.
Triclosan was found in 48 products. The safety of triclosan has been assessed by the Scientific Committee on Consumer Safety (SCCS) and its predecessors. Triclosan is not considered to be a skin sensitizer. The current use of triclosan at a maximum concentration of 0.3% in toothpastes, soaps and deodorant sticks has been considered to be safe, whereas additional use in other leave-on products is not considered to be safe. The main concern about triclosan is the development of antimicrobial resistance (SCCP/1040/06, SCCP/1251/09, SCCS/1414/11).
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Contact Dermatitis, 70, 219–226
A number of general aspects pertaining to preservatives and their combined use have been discussed in the previous article on coupled exposure to fragrances (2), and are not reiterated here. One particular limitation on the interpretability of data on co-exposure to preservatives stems from the fact that actual use concentrations are not available from the ingredient labelling according to the INCI, which is purely qualitative (see Methods) and not always accurate (11). This implies that preservatives may have been (i) introduced by preserved components of the final product, (ii) added to the final product with the aim
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PRESERVATIVES CO-OCCURRING IN COSMETICS • UTER ET AL.
of preserving it, or (iii) introduced by a component and added to the final product. In the case of preservatives, there is some rationale for combining several preservatives, namely, exploiting synergistic antimicrobial action spectra, and avoiding excessive levels of single preservatives that would otherwise be necessary under the manufacturing and use conditions, and that would entail an increased sensitization
risk. Nevertheless, from the point of view of primary prevention of contact sensitization, all substances that are biologically active as preservatives seem to be also biologically active as allergens. Hence, further development of the composition of cosmetics, manufacturing conditions, quality of ingredients, and dispensing systems, allowing safe and non-sensitizing levels of preservatives, or even their complete avoidance, appears to be an attractive target for qualitative improvement of cosmetic products.
References 1 Bonefeld C M, Nielsen M M, Rubin I M et al. Enhanced sensitization and elicitation responses caused by mixtures of common fragrance allergens. Contact Dermatitis 2011: 65: 336–342. 2 Uter W, Yazar K, Kratz E M, Mildau G, Lid´en C. Coupled exposure to ingredients of cosmetic products: I. fragrances. Contact Dermatitis 2013: 69: 335–341. 3 R Team. R: A Language and Environment for Statistical Computing: Wien, The R Project for Statistical Computing, 2012. 4 Yazar K, Boman A, Lid´en C. p-Phenylenediamine and other hair dye sensitizers in Spain. Contact Dermatitis 2012: 66: 27–32. 5 Yazar K, Johnsson S, Lind M L, Boman A, Lid´en C. Preservatives and fragrances in selected consumer-available cosmetics
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and detergents. Contact Dermatitis 2011: 64: 265–272. 6 Schnuch A, Mildau G, Kratz E M, Uter W. Risk of sensitization to preservatives estimated on the basis of patch test data and exposure, according to a sample of 3541 leave-on products. Contact Dermatitis 2011: 65: 167–174. 7 Uter W, Schnuch A, Geier J, Agathos M. Epikutantest-Reaktionen auf Paraben-Mixe und ihre ¨ Aufschlusselungen. Studien der Deutschen Kontaktallergie-Gruppe (DKG) und des Informationsverbundes dermatologischer Kliniken (IVDK), 1990–2000. Allergologie 2002: 25: 194–202. 8 Uter W, Geier J, Pfahlberg A, Effendy I. The spectrum of contact allergy in elderly
patients with and without lower leg dermatitis. Dermatology 2002: 204: 266–272. 9 de Groot A C, White I R, Flyvholm M A, Lensen G, Coenraads P J. Formaldehyde-releasers in cosmetics: relationship to formaldehyde contact allergy. Part 1. Characterization, frequency and relevance of sensitization, and frequency of use in cosmetics. Contact Dermatitis 2010: 62: 2–17. 10 Uter W, Geier J, Bauer A, Schnuch A. Risk factors associated with methylisothiazolinone contact sensitisation. Contact Dermatitis 2013: 69: 231–238. 11 Rastogi S C. Analytical control of preservative labelling on skin creams. Contact Dermatitis 2000: 43: 339–343.
© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Contact Dermatitis, 70, 219–226
