Increasing non‐cosmetic exposure and sensitization to isothiazolinones require action for prevention: Review

Frequent use of methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) and MI in cosmetic products has been the main cause of widespread sensitization and allergic contact dermatitis to these preservatives (biocides). Their use in non‐cosmetic products is also an important source of sensitization. Less is known about sensitization rates and use of benzisothiazolinone (BIT), octylisothiazolinone (OIT), and dichlorooctylisothiazolinone (DCOIT), which have never been permitted in cosmetic products in Europe. BIT and OIT have occasionally been routinely patch‐tested. These preservatives are often used together in chemical products and articles. In this study, we review the occurrence of contact allergy to MI, BIT, OIT, and DCOIT over time, based on concomitant patch testing in large studies, and case reports. We review EU legislations, and we discuss the role of industry, regulators, and dermatology in prevention of sensitization and protection of health. The frequency of contact allergy to MI, BIT, and OIT has increased. The frequency of contact allergy to DCOIT is not known because it has seldom been patch‐tested. Label information on isothiazolinones in chemical products and articles, irrespective of concentration, is required for assessment of relevance, information to patients, and avoidance of exposure and allergic contact dermatitis.


| INTRODUCTION 1.| Contact allergy to isothiazolinones
It is well known that the preservatives methylchloroisothiazolinone/ methylisothiazolinone (MCI/MI also termed CMIT/MIT) and methylisothiazolinone (MI also termed MIT) have resulted in global epidemics of contact allergy and associated allergic contact dermatitis.MCI/MI was introduced in chemical products in the beginning of the 1980s, and it was permitted in cosmetic products in 1986.MI was introduced in year 2000 and was permitted in cosmetic products in 2005.Since introduced, their use has increased massively. 1The prevalence of contact allergy to MCI/MI and MI has varied considerably over time and between countries, reaching a peak around 8% of patch-tested dermatitis patients in 2013-2014 in Europe, but continuously increasing in North America. 2,3Currently, around 5% of dermatitis patients in Europe are allergic to MCI/MI and MI, respectively. 4e massive use of these preservatives in cosmetic products is considered the main cause of the widespread sensitization.Their use in non-cosmetic products for the consumer and occupational products is also a source of sensitization of consumers and workers, and occupational exposure to MI seems to be increasing. 2,5Legislative attempts to reduce skin exposure and sensitization to MCI/MI and MI have been taken by the EU Cosmetics Regulation, followed by chemicals regulations. 1her commonly encountered skin sensitizing isothiazolinones are benzisothiazolinone (BIT), octylisothiazolinone (OIT), and dichlorooctylisothiazolinone (DCOIT). 2 Less is known about sensitization rates to them because they have never been permitted in cosmetic products in Europe, and they are not routinely patch tested in most centres as they have not been included in the recommended baseline series; BIT was included in the European baseline series for 2023. 62 | Use of MI, BIT, OIT, and DCOIT Non-cosmetic use of MI, BIT, OIT, and DCOIT during recent decades has been assessed in some European countries adhering to the EU chemicals legislations.Various methodologies have been used, including studies of national registers and assessment of samples of various product categories.

| National products registers
As shown in our recent review Preservatives in non-cosmetic products: Increasing human exposure requires action for protection of health 1 and in Figure 1, the use (by tonnes and number of products) of MI, BIT, OIT, and DCOIT in non-cosmetic products has increased dramatically in recent years.This study was performed by analysing data on use of skin sensitizing preservatives in non-cosmetic products during 1995-2018, based on annual reports by companies to the Swedish Products Register. 7BIT was the most used isothiazolinone by tonnes and number of products.'Paints' was the largest product category for use of all isothiazolinones in 2018, followed by 'adhesives' and 'filling agents'.
Studies have been performed based on notifications to the Danish Product Register for single years 8,9 ; the notification requirements differ, however, between the Danish 10 and Swedish 7 registers.BIT was the most registered isothiazolinone, and 'paint and varnish', followed by 'cleaning/washing agents' were the largest product categories with BIT. 9

| Chemical analysis
Chemical analysis of 69 of the detergents in the Swiss study was performed; isothiazolinones were detected in 52%, and MI and BIT were detected more frequently than MCI and OIT.The concentrations of BIT were the highest (mean 75 ppm; 1000 ppm is 0.1%), followed by MI (mean 44 ppm). 12o studies of indoor paints in five European countries were performed by chemical analysis and assessment of labelling and safety data sheets (SDSs). 13,14In 2014, 71 white wall and wet room paints for consumers or professional use were purchased, and the concentrations of MI, MCI and BIT were analysed. 13BIT was detected in 96% (concentration range 0.1-463 ppm), MI in 93% (0.7-181 ppm), and MCI in 24% (0.3-11 ppm).The concentrations of BIT varied significantly between the countries.A follow-up study was performed by analysing MI, MCI, BIT, and also OIT and DCOIT in 60 paints purchased in 2016. 14No statistically significant differences for MI, MCI, or BIT were shown between the two studies. 13,14OIT was detected in 27%, DCOIT in 50% of the paints; the concentrations were significantly higher in wet-room paints than in wall paints.The concentrations of BIT were significantly higher in environmentally labelled paints than in non-labelled.The information on labels and in SDSs on content of skin sensitizing isothiazolinones was poor in the first study but had improved in the second. 14e study of metalworking fluids was performed in Finland by chemical analysis of 17 metalworking fluid concentrates from 9 machine shops. 15The concentrations of numerous skin sensitizing

| Aggregate exposure
Aggregate exposure of consumers to isothiazolinones was estimated based on use pattern, concentrations in household detergents and cosmetic products, exposure duration, and skin permeability. 16The authors concluded that various detergents are important sources of exposure and sensitization to BIT.They suggested that the model may be used for risk assessment of skin sensitizers and that detergents currently contribute more than cosmetics to isothiazolinone exposure. 162.5 | Summary of use Together, the above studies show that the use of isothiazolinones is massive in common non-cosmetic products intended for consumer and occupational use.They show that BIT is the most frequently used isothiazolinone by number of products and use concentrations, and that isothiazolinones, primarily MI and BIT, often are used together.
The results of the above studies are not directly comparable owing to the mentioned differences.Only one study is suitable for assessing usage trends. 1 MI and BIT were included in all studies, OIT was included in most, while DCOIT was included in only three. 1,9,14e isothiazolinones MI, BIT, OIT, and DCOIT are often used in combination with each other and with other biocides; additional chemically closely related isothiazolinones are also used.A purpose of the combined use is to avoid mandatory warning labelling by using concentrations below the classification limit for labelling.When a new and lower classification limit of MI, OIT, and DCOIT as skin sensitizer has been proposed by the European Chemicals Agency (ECHA), a decrease in use (by tonnes, but not by number of products) has occurred (Figure 1).The classification limit for BIT (0.05%, 500 ppm) was decided in 1998; it remains high and no corresponding decrease in use has been observed.

| Current efforts by regulators
In 2022, the ECHA, promoted by the competent authorities of France, Germany, and Ireland, launched a Call for Evidence on skin sensitizing substances in consumer mixtures. 17The purpose was to assess whether risks are adequately controlled, and what impact additional regulatory risk management would have.
Following the publication of our review on the worrying increase in use of skin sensitizing preservatives, 1

| Aims
In the present study, we review the occurrence of contact allergy to MI, BIT, OIT, and DCOIT over time, based on large patient studies with concomitant patch testing of these substances, and on case reports.We review key elements of the EU regulatory framework concerning conditions for use, and we discuss the role of industry, regulators, and dermatology in prevention of sensitization, consequent allergic contact dermatitis, and protection of health.

| SKIN SENSITIZATION
As the substances BIT, OIT, and DCOIT not are permitted in cosmetics in the EU, they have not generally attracted the attention of dermatologists.A selective literature search was performed to identify pertinent scientific publications, and we have compiled published patch-test data to assess the sensitization rate over time.MI was included for comparison in several compilations.
It should be mentioned that individual cases of allergic contact dermatitis often are described in short articles, for example, case reports (Contact Points) in the journal Contact Dermatitis, when an allergen, exposure, or course may be of particular interest; the focus is often on new, not on well-established knowledge.Such articles are generally searchable on PubMed by title or author name only, but not by abstract, keywords, or content as for original or review articles.
Cases may thus have been missed when gathering information (manually and by search words) on reported cases of contact allergy to BIT, OIT, and DCOIT between 2009 and 2022.

| Large patch test studies and case reports
To estimate whether the increasing use of BIT, OIT, and DCOIT (Figure 1) corresponds to increasing prevalence of contact allergy to these substances, large studies (Table 1 and Figure 2), and scientific articles on individual cases of contact allergy (Table 2) were assessed.
The patch test concentration varied between and within some of the studies.

| Adult dermatitis patients
9][20][21][22] Two similar studies had been performed in North America (NACDG) 2017-2018 and 2019-2020 (Table 1 and Figure 2). 23,24The vast majority of patients in the studies were adults.All testing was performed with their respective baseline series, including MI, with additions of BIT and OIT.DCOIT was not included in any of the studies.
The prevalence of contact allergy to MI and MCI/MI in North America is much higher than in Europe. 239][20][21] The differences are attributed to more frequent skin exposure in North America owing to the lesser restrictions of MI, MCI/MI, and the use of BIT in cosmetic products in North America.
Most studies on the prevalence of contact allergy, based on data for more than 1 year, reported mean values of patch test positivity to MI, BIT, and OIT.Only two studies in Europe reported annual proportions of positive patch test reactions, which is the most useful when analysing trends. 20,25Both these studies, although not directly comparable, showed a steady increase in the prevalence of contact allergy to BIT; from 0.26% to 3.4% in the consecutively patch tested dermatitis patients in the United Kingdom, 20 and from 3.0% to 18.9% in MIsensitized patients in Belgium. 25A steady increase in the prevalence of contact allergy to OIT was also recorded in the MI-sensitized patients in Belgium; from 20.0% to 27.0%. 25 a study by the German group IVDK, sensitization to MI, BIT, and/or OIT was analysed in various subgroups of patients from 2002 through 2021.From 2011, there was an increase in sensitization to BIT; the authors concluded that the increase was independent of variations in MI sensitization. 26

| Peadiatric dermatitis patients
Contact allergy to BIT (0.5%) and OIT (1.9%) was identified in consecutive patch tested peadiatric patients in the Netherlands 2015-2021 (Table 1 and Figure 2). 27The causative exposures were not discussed, but neither BIT nor OIT are permitted in cosmetic products in the EU.Thus, it is likely that the children had been sensitized by exposure to other consumer-available products.The relatively high prevalence of OIT allergy in children, in comparison with other general dermatitis patients, is remarkable notwithstanding the small sample size (Table 1).

| Occupational contact dermatitis
The first cases of contact allergy to BIT, OIT, and DCOIT were occupationally caused and scientifically reported in 1976, 28 1982, 29 and 1993, 30 respectively.In 2022, it was decided to include BIT in the European baseline series for 2023, while keeping OIT as a recommended addition. 6BIT and OIT were added to the NACDG screening series for 2018-2019. 23DCOIT is not included in the European baseline series, and, according to our knowledge, it is not commercially available as a patch test preparation by patch test material suppliers.
The most used patch test concentration of BIT, OIT, and DCOIT is 0.1% (1000 ppm) in petrolatum, and of MI 0.2% (2000 ppm) in aqua.
Patch test concentrations and vehicles vary between substances and may vary over time and between studies; significantly lower concentrations of MI, BIT, and OIT had been used in some of the studies (Table 1).A lower concentration usually results in a lower positivity rate, compared to a higher concentration of the same substance.The most suitable concentration should not cause irritant reactions, false negative reactions, or induce skin sensitization. 58We consider it likely that the current patch test concentration of BIT is too low, rather than too high.

| Concomitant reactions
Concomitant reactions to various isothiazolinones have been analysed 0][61] Concomitant reactions to MI and OIT have been more frequently reported than to MI and BIT or to OIT and BIT.Solitary reactions to BIT have been more frequent than to OIT.Some studies have suggested that concomitant reactions may be indicative of partial crossreactivity, 33,59,61 while others have attributed concomitant reactions to multiple sensitization. 18,26e animal experiment, using a modified local lymph node assay, indicated cross-reactivity between MI and BIT, and between MI and OIT. 62 Abbreviations: non-occ, non-occupational; occ, occupational.Numerous products, for example, paints 13,14 and detergents 12 contain combinations of various isothiazolinones, and the various isothiazolinones are used in numerous product types (PT) 1 (see EU legislations below).We conclude that this results in multiple exposure, multiple-sensitization, and concomitant patch test reactivity.To what extent cross-reactivity contributes is difficult to assess.

| Assessment of clinical relevance
The The relevance of patch test reactions to BIT has sometimes been questioned, referring to that the source of sensitization is unknown or not specified. 20,24It has also been proposed that weak reactions to BIT may be irritant reactions.We consider that both arguments may be affected by the lack of available information on exposure to BIT, and possibly also by inefficient patch test preparations (too low concentration or suboptimal vehicle).Adequate assessment of clinical relevance is, therefore, often difficult to perform.• Chemical is used by ECHA and throughout the EU chemicals legislations for substances and mixtures.

| EU LEGISLATIONS
• Definitions by CLP and REACH: substance: a chemical element and its compounds in the natural state or obtained by any manufacturing process; mixture: a mixture or solution composed of two or more substances; article: an object, which during production, is given a special shape, surface or design that determines its function to a greater degree than does its chemical composition. 63ternationally, the term preparation is sometimes used instead of mixture.In this review, we have sometimes used chemical product instead of mixture.
• BPR uses the terms biocidal active substance, biocidal product, product type, PT, and treated article.

| The regulation on Cosmetic Products
The Cosmetics Regulation (1223/2009/EC) 64 requires that all preservatives in cosmetic products must be permitted for such use (there is stances and mixtures and it mandates information to be included in SDSs, as specified in REACH.CLP does not restrict substances but sets limits for when information on sensitization risk is required; use in cosmetic products, food, medicinal products, and medical devices is not covered by CLP. The generic concentration limit of skin sensitizers in a mixture triggering classification (see below for hazard statement) of the mixture as category 1 and subcategory 1B is ≥1% and as subcategory 1A ≥ 0.1%.Specific concentration limits, lower than the generic, may also be set.Mixtures containing a skin sensitizer above the concentration limit must be labelled with a pictogram and the hazard statement 'H317: May cause an allergic skin reaction'.Mixtures not classified as sensitizing but containing a classified skin sensitizer at a concentration above 10% of the limit for classification shall have a supplemental hazard label statement: 'EUH208: Contains (name of sensitizing substance).
May produce an allergic reaction'.
The current specific concentration limit for classification of BIT (0.05%) was set in 1998, for MCI/MI (0.0015%) in 2004, and was recently agreed for MI, OIT, and DCOIT (0.0015%) (Table 3).We anticipate that the use concentration of MI, OIT and DCOIT will decrease significantly following this, as it did for MCI/MI (Figure 2 in Reference [1]).We consider that this will also facilitate assessment of relevance of MI, OIT, and DCOIT patch test reactions.The relatively high classification limit of BIT (0.05%) will, however, continue to hinder assessment of relevance, owing to lack of label information at concentrations below 0.005% (EUH208).It has been shown that the concentration of BIT is below 0.005% in large proportions of products registered for use in Danish workplaces, 9 in non-cosmetic products in Sweden, 1 and in indoor paints in five European countries. 13,14

| The Biocidal Products Regulation (BPR)
The BPR ((EU) 528/2012) 65 requires that all biocidal active substances must be approved at the EU level.Approved active substances can be used only in certain PTs, and the placing on the market of biocidal products requires authorisation at member state or EU level.The approvals are re-evaluated at least every 10 years if an application for renewal is sent to an evaluating member state.Requirements on hazard labelling of biocidal products are generally based on their CLP classification, but BPR may set stricter requirements.BPR does not apply to cosmetic products, food, medicinal products, or medical devices.
MI, BIT, OIT, and DCOIT are approved for use as preservatives in numerous PTs (Table 3). 66All, except DCOIT, may be used in products during storage (PT6), for example, indoor paints, detergents, and adhesives.Other types of paint, for example, outdoor, wet-room, and antifouling paint, are used for wood (PT8), construction material (PT10), and antifouling products (PT21).Of note is that BIT, OIT, and DCOIT are approved for the treatment of articles not subject to the requirements of CLP since they are not chemical products, without ingredient information or SDS, for example, fibre, leather, rubber, and polymerised materials (PT9).
However, as mentioned above, BPR may set stricter requirements, and that has, for examle, happened for MCI/MI in articles. 67The companies Lanxess, Microbial Control, Thor GmbH, and Troy Chemical are among the largest manufacturers and suppliers of MI, BIT, OIT, and DCOIT in Europe. 68 suggest that requirements, stricter than the current CLP requirements, concerning permitted use and substance information need to be set for isothiazolinones by the BPR.industry cannot manage the risks they pose (Annex XVII). 70til now, isothiazolinones have not been restricted under REACH.
The current, relatively new, and very low harmonised classification limit for MI, OIT, and DCOIT as skin sensitizing (Skin Sens. 1A ≥ 0.0015%) should thus generate SDS information on a large proportion of mixtures (chemical products) containing these.Information on isothiazolinones with higher classification limits, such as BIT (0.05%), are not expected to be identified to the same extent (see above).

| The Detergents Regulation
The Detergents Regulation (Regulation (EC) No 648/2004) 71 requires that all preservatives in detergent products are identified on the label as for cosmetic products, irrespective of concentration and with INCI name.The CLP labelling requirements do also apply to detergents.

| The EU ECOlabel Regulation
The ECOlabel Regulation (Regulation (EC) No 66/2010) 72 sets rules for the voluntary ECOlabel scheme.Criteria are set for ECOlabel product groups to minimise their environmental impacts, including health and safety.The product groups include, for example, paints and varnishes, detergents, textiles and footwear, furniture, and cosmetic products. 73The criteria restrict skin sensitizers (H317) and many other hazard classifications; but the ECOlabel permits, by derogation, isothiazolinones in certain products.Examples of such derogation are the recently set ECOlabel limits for isothiazolinones in paints and varnishes: total sum of isothiazolinones in any paint or varnish (0.05%) except for outdoor wood paints and varnishes (0.20%); BIT (0.05%); MI, MCI/MI and OIT (0.0015% each). 74 suggest removal of the derogation permitting isothiazolinones in ECOlabelled paints and varnishes.It is not reasonable that extremely potent skin sensitizers, affecting numerous professional painters and decorators, and consumers, are used in such products as they do impact health and safety.disagree, however, with the derogations permitting the use of isothiazolinones and other skin sensitizing preservatives in ECOlabelled products.
Industry has often been slow, reluctant, or against introducing voluntary amendments for protection of health and the environment.
Important examples are skin sensitization to nickel in contact with skin, fragrance substances in cosmetic products, and preservatives in cosmetic products and paint.

| Regulatory action for protection of health
Hazard identification, risk assessment, risk management, and enforcement are important tools in chemicals and cosmetics regulations.The situation is complex with numerous substances, and vertical (parallel) legislations that are not harmonised horizontally (between legislations).We consider that current EU legislations on cosmetics and chemicals (CLP, BPR, REACH, Detergents regulation) together cover essential aspects for protection of health.We suggest that legislation should be enhanced to cover a requirement of information on skin sensitizing substances irrespective of concentration, to include solid materials and articles, and to restrict use when necessary for prevention of disease.We welcome ECHA's Integrated Regulatory Strategy and the approach to assessing chemicals in groups. 76amples that we consider could be immediately applied on isothiazolinones are: • Ingredient information on substances and mixtures (chemical products) and in SDSs, irrespective of concentration and CLP classification (as by the Cosmetics and Detergents regulations, and as may be required by BPR); • Ingredient information on solid materials and articles irrespective of concentration; • CLP supplemental hazard label statement irrespective of concentration, by extension of the current EUH208 (as for chromium VI in cement (EUH203), isocyanates (EUH204) and epoxy constituents (EUH205)); • Restriction or prohibition of use of some isothiazolinones (as by the Cosmetics Regulation and REACH); • Group approach for all isothiazolinones by harmonised classification as Skin sens.1A and very low specific concentration limit (in correspondence with the Integrated Regulatory Strategy for structurally related substances).

| Diagnosis, information, avoidance of exposure
Information on content of skin sensitizing isothiazolinones, irrespective of concentration, is crucial for individuals who know that they are sensitized and need to avoid skin contact, for healthcare professionals and dermatologists for diagnosis, assessment of relevance, and informing patients, and for employers to protect their workers.
Patch test patients with a broad range of substances beyond the European baseline series, preferably with samples of materials.Among solids that may contain BIT, OIT, or DCOIT, and are used in contact with skin, are textile, leather, rubber, and plastic articles.
Ideally, identify harmful exposure by workplace visits, chemical analysis, and skin exposure assessment.
Investigate optimal patch test preparations (concentrations and vehicles) for BIT, OIT, and DCOIT, preferably by multicentre studies.
Publish case reports (not only on new experience) and original articles including detailed descriptions of skin symptoms and exposure, patch test results, chemical analysis, and follow-up.Such human evidence is of utmost importance for accurate hazard classification by regulators.

| CONCLUSIONS
The frequency of contact allergy to MI, BIT, and OIT has increased in recent years owing to huge increase in non-cosmetic products for consumer and occupational use that contain them.
The use of DCOIT has increased, but the frequency of contact allergy is not known because it has seldom been patch-tested.
BIT, OIT, and DCOIT are not permitted in cosmetic products in Europe.
Since 2023, BIT is included in the European baseline series for patch testing, and OIT is recommended for addition to the series.
DCOIT should also be made available as a patch test preparation.
Optimal patch test preparations are required for assessment of relevance.
Label information on presence of isothiazolinones in chemi-

F I G U R E 1
Use of methylisothiazolinone (MI), benzisothiazolinone (BIT), octylisothiazolinone (OIT) and dichlorooctylisothiazolinone (DCOIT) in non-cosmetic products in Sweden during 1995-2018.Graphs based on annual reports by companies to the Swedish Products Register on import and manufacture. 1Blue line: tonnes; red dashed line: number of products.substances, including MI, MCI, BIT, and OIT, were assessed.BIT (110 ppm) and OIT (360 ppm) were detected in one product each.
the German competent authority, the Federal Institute for Occupational Safety and Health (BAuA), contacted us (CL) with questions concerning further aspects on the use of preservatives, including the occurrence of skin sensitization to BIT, OIT, and DCOIT, and techniques to avoid preservative use.The request by BAuA stimulated us to write the present review.

T A B L E 1 2 .a
Abbreviations: conc, concentration; ESSCA, European Surveillance System on Contact Allergies; IVDK, Information Network of Departments of Dermatology; NACDG, North American Contact Dermatitis Group.a Generally used patch test concentrations: MI 0.2% in aqua, BIT 0.1% in petrolatum, OIT 0.1% in petrolatum; alternatively used concentrations are mentioned.b A total of 5227 patients patch tested with MI, BIT and OIT 2014-2019.Annual proportions of positive patch test reactions to MI, BIT, and OIT, based on text, Figures 1 and 2 in Reference [20].

a 3 3. 2 |
'positive' list, Annex V, Regulation 1223/2009/EC), and that they must be identified by their INCI (international nomenclature for cosmetic ingredients) name on the ingredient label, irrespective of concentration.In 2014, it was decided that MCI/MI and MI should not be permitted in leave-on cosmetic products.The current maximum use concentration in rinse-off products is 0.0015% (15 ppm).The CLP labelling requirements (see below) do not apply to cosmetic products.BIT, OIT, and DCOIT are not permitted in cosmetic products in the EU.BIT and OIT are permitted in cosmetic products in the United States and Canada; the permitted use of MI and MCI/MI in cosmetic products in North America also differs from their use in the EU.The Classification, Labelling and Packaging (CLP) Regulation The CLP Regulation ((EC) No 1272/2008) 63 states how hazardous substances and mixtures (chemical products) shall be classified and labelled, but solid materials or articles containing hazardous substances are not classified or labelled.Harmonised classifications are decided by the European Commission and are legally binding, while notified classifications ('self-classification') are performed by industry.Hazard classification as skin sensitizing is based on the intrinsic properties of substances shown by human and/or animal experience.CLP is the only legislation in the EU for classification and labelling of sub-

3. 4 |
Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) REACH, (Regulation (EC) No 1907/2006) 69 includes requirements for SDS intended for downstream users of substances and mixtures (including companies, industrial and professional workers, but not consumers).SDSs are sometimes mistaken for ingredient listing, but the CLP concentration limits for classification are decisive for information in SDSs on hazardous substances, H317 as well as EUH208.According to REACH, authorities can restrict the use of hazardous substances if cal products and articles, irrespective of concentration, is likewise required for assessment of relevance and information to patients by healthcare professionals, and for avoidance of skin exposure and allergic contact dermatitis by sensitized individuals.Contact allergy to BIT, OIT, and DCOIT will remain largely unexplained when not always identified on labels of product, including solid materials and articles.Prompt action for risk management by regulators and industry is required for reduction of hazardous skin exposure and prevention of contact allergy.The tools are there, and they should be used.AUTHOR CONTRIBUTIONS Carola Lidén: Conceptualization; investigation; methodology; visualization; writingoriginal draft; writingreview and editing.Ian R. White: Investigation; writingreview and editing.

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HOW CAN PREVENTION OF SKIN SENSITIZATION BE STRENGTHED?Below, are comments on prevention of skin sensitization from noncosmetic exposure to isothiazolinones; what is needed, by whom, b Regulated in various ways for cosmetic products, food, and medicinal products.Praxis and expectations vary between countries.