Summary: Background: In recent years, a steep increase in the frequency of occupational contact allergy to isothiazolinones has been reported from several European countries. Objective: To examine the extent and occurrence of isothiazolinones in different types of product at Danish workplaces. Methods: Seven different isothiazolinones were identified in the Dictionary ofContactAllergens:ChemicalStructures,Sources, andReferences from Kanerva'sOccupationalDermatitis. By use of the chemical names and Chemical Abstracts Service numbers for these chemicals, information on products registered in the Danish Product Register Database (PROBAS) was obtained. Results: All seven isothiazolinones were registered in PROBAS. The top three isothiazolinones registered were: benzisothiazolinone (BIT), registered in 985 products, methylisothiazolinone (MI), registered in 884 products, and methylchloroisothiazolinone (MCI)/MI, registered in 611 products. The concentration ranges were 0.01 ppm to 45% for BIT, 0.01 ppm to 10% for MI, and 0.01 ppm to 14.1% for MCI/MI. The most common product type was ‘paint and varnish’; five of the seven isothiazolinones were registered in this type of product. Conclusion: Isothiazolinones are present in multiple products registered for use at workplaces, and may occur in high concentrations.
2 ‐ methyl ‐ 4,5 ‐ trimethylene ‐ 4 ‐ isothiazolin ‐ 3 ‐ one; allergic contact dermatitis; benzisothiazolinone; dichlorooctylisothiazolinone; isothiazolinones; methylchloroisothiazolinone; methylisothiazolinone; octylisothiazolinone
Knowledge regarding the individual and general exposures to hazardous chemicals in our environment is pivotal for understanding the individual and general disease risk related to these chemicals. Such information is also essential for the planning of preventive initiatives. Information on the production and use of the chemicals may be retrieved from national and international statistical offices, databases, and manufacturers; this data collection is difficult and time ‐ consuming. The Scandinavian countries have developed registers that contain information on the contents of hazardous chemicals in products registered for occupational use in the respective countries.
The isothiazolinones are preservatives (Table [NaN] ) that have been in use for > 30 years in products for both occupational and consumer use [
Marketed isothaizolinones and their regulation
Isothiazolinones CAS numbers Regulations Cosmetics REACH CLP BPR Benzisothiazolinone (INCI) (1,2 ‐ benzisothiazolin ‐ 3 ‐ one) 2634 ‐ 33 ‐ 5 Not allowed 22,23 Intended but not registered 24 Harmonized classification: R43/H317 with specific concentration limit: 0.05% 25 Review programme: PT 2, 6, 9, 11, 12, and 13 26 Non ‐ included: PT 7, 10, and 22 27 4,5 ‐ Dichloro ‐ 2 ‐ n ‐ octyl ‐ 4 ‐ isothiazolin ‐ 3 ‐ one 64359 ‐ 81 ‐ 5 Not allowed 23 Intended but not registered 24 Not classified Approved: PT 8 Review programme: PT 7, 9, 10 11, and 21 26 Non ‐ included: PT 6, and 12 27 2 ‐ Methyl ‐ 4,5 ‐ trimethylene ‐ 4 ‐ isothiazolin ‐ 3 ‐ one 82633 ‐ 79 ‐ 2 Not allowed 23 — Harmonized classification: R43/H317 25 Not allowed Methylchloroisothiazolinone (INCI) (5 ‐ chloro ‐ 2 ‐ methyl ‐ 4 ‐ isothiazolin ‐ 3 ‐ one) 26172 ‐ 55 ‐ 4 Not allowed 23 Preregistered for 2010, but not registered 28 Not classified Not allowed Methylchloroisothiazolinone (INCI) (5 ‐ chloro ‐ 2 ‐ methyl ‐ 4 ‐ isothiazolin ‐ 3 ‐ one) and methylisothiazolinone (INCI) (2 ‐ methyl ‐ 4 ‐ isothiazolin ‐ 3 ‐ one) 55965 ‐ 84 ‐ 9 and 96118 ‐ 96 ‐ 6 Allowed at 15 ppm (3:1) 29,23 Preregistered for 2010, but not registered Harmonized classification: R43/H317 with specific concentration limit: 15 ppm 25 RoI France, concerning environmental classification: by end of 2014 30 First product: Review programme: PT 2, 4, 6, 11, 12, and 13 26 Non ‐ included: PT 3, 7, 9, and 10 27 Second product: not allowed Methylisothiazolinone (INCI) (2 ‐ methyl ‐ 4 ‐ isothiazolin ‐ 3 ‐ one) 2682 ‐ 20 ‐ 4 Allowed at 100 ppm 23,31 Preregistered for 2010, but not registered 28 Harmonized classification: R43/H317 with non ‐ specific concentration limit Inventory (self ‐ classification): R43/H317 with specific concentration limit: 0.1% Slovenia by end of 2013 32 Review programme: PT 2, 6, 11, 12, and 13 26 Non ‐ included: PT 4, 7, 9, 10, and 22 27 Octylisothiazolinone (INCI) (2 ‐ n ‐ octyl ‐ 4 ‐ isothiazolin ‐ 3 ‐ one) 26530 ‐ 20 ‐ 1 Not allowed 23 Preregistered for 2010, but not registered 28 Harmonized classification: R43/H317 with specific concentration limit: 0.05% 25 Review programme: PT 6, 7, 9, 10, 11, and 13 26 Non ‐ included: PT 4, 8, and 12 27
1 BPR, biocidal products regulation; CLP, the regulation on classification, labelling and packaging of substances and mixtures; INCI, International Nomenclature of Cosmetic Ingredients; PT, product type; REACH, Registration, Evaluation, Authorization and Restriction of Chemical substances; RoI, registry of intention – ‘warning’ of future proposal.
- 2 * According to CLP there is non ‐ specific concentration limit for MI but according to the inventory there is a “self ‐ classification” with a specific concentration limit on 0.1%. This concentration is not validated or authorized but is used by some manufactures because of the allergenic potency of MI. For those manufacturer this concentration will be effective from 1st of June 2015.
- 3 ** The European Commission requested Slovenia to classify MI according to the Annex XV dossier in REACH. The deadline was December 2013.
In view of the above, we provide an overview of the occurrence of isothiazolinones in registered chemical products, and discuss the clinical and general health implications.
We selected the isothiazolinones listed in the Dictionary of Contact Allergens: Chemical Structures, Sources, and References from Kanerva's Occupational Dermatitis[
In the examination of product types registered with content of the isothiazolinones, the chemical names and the Chemical Abstract Service (CAS) numbers for these isothiazolinones were searched for in the Danish Product Register Database (PROBAS) (September 2012).
PROBAS is a database in which the composition of, primarily, hazardous chemical products for occupational use is registered. Products are registered: (i) if the product/substance is manufactured or imported for occupational use in a quantity of > 100 kg annually; (ii) if the product contains at least one chemical that is registered as harmful according to the Danish Ministry of the Environment and the Danish Working Environment Authority (WEA); (iii) if the product contains ≥ 1% of the substance (for preservatives, the limit is 0.1%); (iv) if the product/substance is assigned an occupational exposure limit in the WEA list of limit values for substances and materials; and/or (v) if materials contain ≥ 1% of a substance that has been assigned an occupational exposure limit in the WEA list of limit values for substances and materials [
PROBAS is updated at the end of every odd year with data collected from the manufacturers in even years. In cases where there were fewer than three manufacturers, the specific product types were classified as confidential.
In PROBAS, the chemicals are categorized according to the Use Categories Nordic (UCN) code system [
All confidential information was omitted from the dataset. No main groups were deleted, but subgroups that had a ratio of < 2% between the main group and the subgroup were deleted by the authors to maintain a more relevant overview.
The isothiazolinones included in this study are shown in Table [NaN] . All seven isothiazolinones were registered in PROBAS. The results of the search in the database for different types of registered product are shown in Tables [NaN] and [NaN] . The concentrations listed in the two tables are in the same format as used in PROBAS. It is not possible to compare the different product types, because some of them are raw materials and others are products for the downstream user.
The results from the Danish Product Register Database (PROBAS) for benzisothiazolinone, methylisothiazolinone, methylchloroisothiazolinone, and Methylchloroisothiazolinone/ methylisothiazolinone
Main group No. of products in group Benzisothiazolinone; CAS no. 2634 ‐ 33 ‐ 5 Methylisothiazolinone; CAS no. 2682 ‐ 20 ‐ 4 Methylchloroisothiazolinone; CAS no. 26172 ‐ 55 ‐ 4 Methylchloroisothiazolinone/methylisothiazolinone; CAS no. 55965 ‐ 84 ‐ 9 No. of products % of main group Concentration (minimum) (ppm) Concentration (maximum) (%) Mean (ppm) No. of products % of main group Concentration (minimum) (ppm) Concentration (maximum) (%) Mean (ppm) No. of products % of main group Concentration (minimum) (ppm) Concentration (maximum) (%) Mean (ppm) No. of products % of main group Concentration (minimum) (ppm) Concentration (maximum) (%) Mean (ppm) Absorbents and adsorbents 90 3 3.3 75 0.1 369 6 6.7 4 0.02 147 — — — — — — — — — — Air cleaners and anti ‐ odour agents 45 — — — — — 6 6.7 4 0.02 147 — — — — — — — — — — Biocides 1174 26 2.2 0.04 45 5.5 34 2.9 0.05 10 1.1 25 2.1 0.11 17.2 0.9 27 2.3 0.03 14.1 1.6 Car care products 96 21 21.9 2.5 5.4 0.26 18 18.8 2 0.008 33.5 — — — — — — — — — — Binding agents 366 20 5.5 0.6 0.1 201 21 5.7 0.4 0.138 182 5 1.4 0.9 0.01 21.4 19 5.2 4.71 0.01 23.3 Binding agents for paints, adhesives, etc. 184 15 4.1 0.6 0.1 254 14 3.8 8 0.138 282 — — — — — 10 2.7 11 0.01 24.2 Other binding agents 168 — — — — — — — — — — 4 1.1 0.9 0.01 21.3 8 2.2 4.71 0.004 21.7 Softeners 59 — — — — — — — — — — — — — — — 5 8.5 12 0.01 33.8 Other softeners 32 — — — — — — — — — — — — — — — 4 6.8 12 0.01 38.8 Colouring agents 324 25 7.7 12.5 1 486 36 11.1 0.25 0.05 56.4 22 6.8 0.75 0.01 38.8 7 2.2 1.4 0.015 29.2 Pigments for paints and printing inks 191 16 4.9 12.5 0.1 265 25 7.7 1.4 0.01 50.5 17 5.2 4.2 0.01 46.1 4 1.2 1.4 0.001 8.7 Other colouring agents 125 8 2.5 14.7 1 0.13 10 3.1 0.25 0.05 83.2 — — — — — — — — — — Flooring materials 146 6 4.1 93.9 0.05 199 5 3.4 7.5 0.05 137 — — — — — — — — — — Impregnation/proofing 122 7 5.7 10.5 0.03 126 8 6.6 1.36 0.013 22.1 4 3.3 0.01 0.0037 10.0 — — — — — Cosmetics 484 — — — — — 9 1.9 0.75 0.085 174 — — — — — 8 1.7 0.01 0.003 4.9 Construction materials 201 3 1.5 500 0.29 0.13 — — — — — — — — — — — — — — — Adhesives 752 28 3.7 0.23 0.10 173 17 2.3 0.5 0.023 47.6 6 0.8 0.96 0.003 7.6 24 3.2 0.09 0.05 30.9 Paint and varnish 3567 544 15.3 0.01 0.33 176 471 13.2 0.01 0.085 36.3 275 7.7 0.01 0.07 12.9 363 10.2 0.01 3.9 103 Paint: water ‐ based, decorative/protection, industrial use 219 144 4.0 0.01 0.05 196 110 3.1 0.01 0.024 20.3 75 2.1 0.04 0.001 1.5 105 2.9 0.02 0.022 25.4 Paint and varnishes: additives 77 6 7.8 0.55 0.03 118 7 9.1 0.86 0.018 65.9 — — — — — — — — — — Metal surface treatment remedies 468 — — — — — — — — — — — — — — — 4 0.9 40 0.2 816 Solvents 797 — — — — — 4 0.5 1 0.1 251 4 0.5 3 0.1 254 — — — — — Surface active agents 517 16 3.1 0.1 0.04 73.2 16 3.1 0.53 0.01 36.0 6 1.2 0.98 0.001 6.0 5 1.0 2.7 0.001 7.6 Surface treatment for paper, cardboard, and other non ‐ metals 106 3 2.8 0.15 0.02 56.4 4 3.8 1.35 0.012 47.8 3 2.8 3.6 0.01 37.3 8 7.5 2 0.023 31.3 Surface treatment for paper and cardboard 73 — — — — — — — — — — — — — — — 6 5.7 2 0.023 38.1 Polishing agents 350 65 18.6 0.66 0.04 76.9 60 17.1 0.25 0.024 31.3 20 5.7 0.15 0.9 433 32 9.1 0.08 1 345 Polishing agents for lacquers (car wax) 93 18 5.1 0.78 0.02 57.4 22 6.3 1.4 0.024 60.1 7 2.0 4.2 0.07 281 — — — — — Wax and other polishing preparations for floors 81 27 7.7 0.66 0.02 51.3 24 6.9 0.25 0.009 9.41 10 2.9 0.39 0.001 5.4 18 5.1 0.08 0.048 41.8 Other polishing agents 71 9 2.6 35.4 0.04 194 — — — — — — — — — — — — — — — Cleaning/washing agents 3560 108 3.0 0.06 0.17 83.4 87 2.4 0.02 0.19 55.8 34 1.0 0.03 0.6 156 50 1.4 0.04 0.9 363 Cracking indicators 56 2 3.6 0.75 0.0045 30.3 — — — — — — — — — — — — — — — Rust inhibitors 421 11 2.6 0.7 0.06 90.7 12 2.9 0.01 0.06 48.8 3 0.7 0.04 0.001 3.4 — — — — — Corrosion inhibitors 169 10 2.4 0.7 0.06 93.0 — — — — — — — — — — — — — — — Raw materials and intermediate products 572 — — — — — 3 0.7 75 0.01 91.7 — — — — — — — — — — Rinsing agents 95 11 11.6 160 0.1 263 3 3.2 1.8 0.0004 3.56 6 6.3 2.3 0.001 6.1 — — — — — Rinsing agents (for dishwashing machines) 50 — — — — — 3 3.2 1.8 0.0004 3.56 3 3.2 5.3 0.001 9.9 — — — — — Lubricants 1225 3 0.2 0.21 0.02 127 — — — — — — — — — — 5 0.4 2.8 0.071 173 Toners 56 10 17.9 26.4 0.05 271 6 10.7 3.9 0.049 98.3 — — — — — 4 7.1 1.07 0.001 10.8 Printing inks 293 10 3.4 8 0.13 413 14 4.8 2.4 0.07 62.1 12 4.1 7.4 0.07 65.6 13 4.4 1 0.43 834 Filling agents 956 16 1.7 5.4 0.17 206 18 1.9 0.28 0.1 78.8 13 1.4 0.76 0.5 343 8 0.8 0.14 0.002 7.5 Viscosity changers 71 — — — — — 3 4.2 9.9 0.005 30.0 — — — — — — — — — — Total — 985 — 0.01 45 — 884 — 0.01 10 — 474 — 0.01 17.2 — 611 — 0.01 14.1 —
4 * Percentages.
The results from the D anish P roduct R egister D atabase (PROBAS) for dichlorooctylisothiazolinone and octylisothiazolinone
Main group No. of products in group Dichlorooctylisothiazolinone; CAS no. 64359 ‐ 81 ‐ 5 Octylisothiazolinone; CAS no. 26530 ‐ 20 ‐ 1 No. of products % of main group Concentration (minimum) (ppm) Concentration (maximum) (%) Mean (ppm) No. of products % of main group Concentration (minimum) (ppm) Concentration (maximum) (%) Mean (ppm) Biocides 1174 12 1 0.11 28.1 11.1 16 1.4 7.1 16 1.7 Binding agents 366 — — — — — 2 0.5 10 0.02 71.2 Cooling agents for metal processing 201 — — — — — 3 1.5 100 0.03 177 Adhesives 752 — — — — — 4 0.5 67.5 16.3 4.1 Paint and varnish 3567 38 1.1 405 0.2 0.11 60 1.7 0.02 0.1 177 Filling agents 956 5 0.5 94 0.1 368 5 0.5 25 0.5 0.13 Total — 58 — 94 28.1 — 111 — 0.02 16.3 —
5 * Percentages.
BIT was registered in 985 different products registered in PROBAS, and was the isothiazolinone most often found in products registered in PROBAS. The top three product types containing BIT were paints and varnishes (
MI was the second most frequently registered isothiazolinone, with 884 different products registered in PROBAS. The top three product types containing MI were paints and varnishes (
MCI/MI was the third most frequently registered isothiazolinone, with 611 different products registered in PROBAS. The top three product types containing MCI/MI were paints and varnishes (
MCI was the fourth most frequently registered isothiazolinone, with 474 different products registered in PROBAS. The top three product types containing MCI were paints and varnishes (
OIT was the fifth most frequently registered isothiazolinone, with 111 different products registered in PROBAS. The top three product types containing OIT were paints and varnishes (
DCOIT was registered in 58 different products, which was the second lowest number among the isothiazolinones in this study. The top three product types containing DCOIT were paints and varnishes (
MTMIT was the only isothiazolinone for which all of the use categories (UCN codes) were confidential. The chemical was registered in seven products in concentrations from 47.6 to 150 ppm.
The present study shows that thousands of products are registered in PROBAS as containing isothiazolinones.
BIT and MI were registered in 985 and 884 products, respectively; MCI/MI was registered in 611 products.
The most prominent product type containing these three isothiazolinones was paints and varnishes (with a total of 3567 products), in which BIT, MI and MCI/MI were the predominant isothiazolinones. This is in accordance with clinical experience (Table [NaN] ), where isothiazolinone allergies have been reported in painters [
Clinical effects of cutaneous and airborne exposures to the isothiazolinone preservatives
Exposures Concentrations Clinical symptoms Duration of eczema/consequence Reference Cosmetic products MCI/MI < 15 ppm MI < 100 ppm Allergic contact dermatitis: face and hands One event: 4–6 months Repeated events: chronic disease 18,19,20,21 Paint, glues, oils, etc. MCI/MI < 14 ppm MI < 300 ppm BIT < 360 ppm 43 Severe allergic contact dermatitis: face and hands Airborne dermatitis, respiratory symptoms 6–12 months Change or loss of job 11,12,13,14,36,37,38,42,44,45,46 Biocides MCI > 0.5% MI > 0.5% BIT > 0.5% Chemical burns, generalized severe allergic contact dermatitis with subjective symptoms Systemic allergic dermatitis, respiratory symptoms Chronic disease, risk of disability 11,15,45 Airborne exposure Probably < 60 mg/m243 Primary sensitization may be possible Flare ‐ ups of facial and systemic allergic dermatitis Acute and chronic disease 15,36,37,38,42,43,47
6 BIT, benzisothiazolinone; MCI, methylchloroisothiazolinone; MI, methylisothiazolinone.
Preservative exposure from paints has changed since 2000, when MI was introduced as a stand ‐ alone preservative and, to some extent, replaced MCI/MI. The reason may be that, whereas MCI/MI is on the list of dangerous substances, labelled R43/H317 (may cause sensitization), and has to be declared on the label if it is present in amounts > 15 ppm, no such requirements exist for MI (Table [NaN] ); instead, there is self ‐ classification, with a specific concentration limit of 0.1% in industrial products [
The products registered with the highest content of isothiazolinones were car care products, BIT being present in 21.9% of products, and MI in 18.8%; a similar pattern was seen for polishing agents for cars and floor products (Tables [NaN] and [NaN] ). We have not found any reports concerning contact allergy related to the use of such products.
Contact allergy to isothiazolinones in the paper and textile industry has also been reported [
Contact allergy to BIT and OIT has been reported in metalworkers [
Exposure to high concentrations of isothiazolinones (Table [NaN] ) can cause chemical burns followed by contact sensitization resulting from a single exposure [
A part of the problem is that much emphasis and reliance has been put on the results of animal assays, in particular the LLNA, to predict the sensitization potency of these substances. The reporting of these results is very brief in the scientific literature, as EC3 values only, not supported by data, and has also been shown to be misleading [
In three product categories, namely paints and varnishes, biocides, and filling agents, all six isothiazolinones were registered, whereas, for all other product categories, some but not all isothiazolinones were used.
There are only few studies on cross ‐ reactions between the different isothiazolinones. In 1992, Damstra et al. found, in an analysis of 556 patch tested patients, that 8 of 10 patients who reacted to BIT also reacted to MCI/MI, and 8 of 56 patients who reacted to MCI/MI also reacted to BIT [
It is very important for the physician and the clinical procedure that all information concerning the product be on the product label and/or in the Material Safety Data Sheet (MSDS) or other product datasheets, so that exposures to allergens can be identified, appropriate patch testing performed, and the correct diagnosis made. Otherwise, important allergens can be missed. The correct diagnosis is very important for patients with occupational allergic contact dermatitis, both for the medical prognosis and for the compensation, depending on national laws [
In conclusion, isothiazolinones are present in multiple products registered for use at the workplace, and may occur in high concentrations. BIT was the most frequent isothiazolinone, being registered in the most products (
Knowledge of the use and exposure to the isothiazolinone preservatives, together with the contact allergic potential and the clinical disease related to the exposure, leads to the following points to be addressed:
The use concentrations in the different exposure scenarios need to be revised.
All types of isothiazolinone, independently of concentration, should be labelled on the product and included in the MSDS.
The use of concentrated solutions of isothiazolinones should only be permitted in closed systems, and the workers involved need proper education.
Is the margin of safety for isothiazolinones so low that future use should be abolished?
We thank the Danish Working Environment Research Fund for funding this project, and give special thanks to Peter Herskind (chief consultant in the work environment at the Confederation of Danish Industry) and Jan Toft Rasmussen (consultant at the Danish Metalworkers' Union) for participating in the steering group and for valuable help throughout the project, to Lea Stine Tobiassen (toxicologist at the Danish Environmental Protection Agency) for valuable help throughout the project, and to Poul Erik Andersen at the Danish Product Register for performing the analysis in PROBAS.
By Ulrik Fischer Friis; Torkil Menné; Mari ‐ Ann Flyvholm; Jens Peter Ellekilde Bonde; Jean ‐ Pierre Lepoittevin; Christophe J. Le Coz and Jeanne Duus Johansen