More than just methylisothiazolinone: Retrospective analysis of patients with isothiazolinone allergy in North America, 2017-2020.

BACKGROUND: Isothiazolinones are a common cause of allergic contact dermatitis. OBJECTIVE: To examine the prevalence of positive patch test reactions to isothiazolinones from 2017-2020 and characterize isothiazolinone-allergic (Is+) patients compared with isothiazolinone nonallergic (Is-) patients. METHODS: Retrospective cross-sectional analysis of 9028 patients patch tested to methylchloroisothiazolinone (MCI)/methylisothiazolinone (MI) 0.02% aqueous, MI 0.2% aqueous, benzisothiazolinone (BIT) 0.1% petrolatum, and/or octylisothiazolinone (OIT) 0.025% petrolatum. Prevalence, reaction strength, concurrent reactions, clinical relevance, and source of allergens were tabulated. RESULTS: In total, 21.9% (1976/9028) of patients had a positive reaction to 1 or more isothiazolinones. Positivity to MI was 14.4% (1296/9012), MCI/MI was 10.0% (903/9017), BIT was 8.6% (777/9018), and OIT was 05% (49/9028). Compared with Is-, Is+ patients were more likely to have occupational skin disease (16.5% vs 10.3%, P <.001), primary hand dermatitis (30.2% vs 19.7%, P <.001), and be >40 years (73.1% vs 61.9%, P <.001). Positive patch test reactions to >1 isothiazolinone occurred in 44.1% (871/1976) of Is+ patients. Testing solely to MCI/MI would miss 47.3% (611/1292) of MI and 60.1% (466/776) of BIT allergic reactions. LIMITATIONS: Retrospective cross-sectional study design and lack of follow-up data. CONCLUSION: Sensitization to isothiazolinones is high and concurrent sensitization to multiple isothiazolinone allergens is common.

Influence of Surfactant on the Skin Permeation of Methylisothiazolinone and Methylchloroisothiazolinone.

Patch tests are often used in safety evaluations to identify the substance causing skin irritation, but the same substance can sometimes give positive or negative results depending on the test conditions. Here, we investigated differences in the skin penetration of two test compounds under different application conditions. We studied the effects of the anionic surfactant sodium dodecyl sulfate (SDS) and the nonionic surfactant polysorbate 80 (PS) on skin penetration of the preservatives methylisothiazolinone (MT) and methylchloroisothiazolinone (MCT), which are used in cosmetics such as shampoos. The skin permeation of MT was enhanced by SDS but was unchanged by PS. Skin impedance decreased in the presence of SDS whereas PS had the same effect as the control aqueous solution, suggesting that SDS reduction of the barrier function of skin affects the permeation of MT, a hydrophilic drug. Application of a mixture of MCT and MT in the presence of SDS did not affect the skin permeation of MCT whereas the permeation of MT was enhanced by SDS, indicating that the skin permeation of MCT is less affected by SDS than is MT. Thus, attention should be paid to the possible effect of co-solutes, especially hydrophilic drugs.

Current frequency of contact allergy to isothiazolinones (methyl-, benz- and octylisothiazolinone) across Europe.

BACKGROUND: The use of methylisothiazolinone (MI) as a preservative in cosmetic products caused an alarming increase in MI contact allergy across Europe in the 2010s. This was followed by regulations of use with a total ban on leave-on (implemented in 2017) and reduced use concentrations in rinse-off cosmetics (2018). OBJECTIVE: To follow-up on the prevalence of contact allergy to MI and the related benzisothiazolinone (BIT) and octylisothiazolinone (OIT) in consecutively patch-tested patients in Europe. METHODS: A cross-sectional audit following the design of two previous audits on MI contact allergy from 1 May 2022 to 31 October 2022 included all patients patch tested with the European baseline series, including or supplemented with MI, BIT and OIT across 10 departments in eight European countries. RESULTS: A total of 2554 patients were consecutively patch tested with the three isothiazolinones during the study period. The prevalence of MI and BIT contact allergy was 2.9% (95% confidence interval [CI]: 2.3%-3.7%; range 1.1%-5.8%) and 3.1% (95% CI: 2.4%-3.9%; range 0.0%-6.6%), respectively; that of OIT was 0.7% (95% CI: 0.4%-1.1%; range 0%-3.2%). Rinse-off cosmetic (73.3%) and leave-on cosmetic products (13.3%) were still associated with eliciting allergic contact dermatitis to MI. CONCLUSION: We confirmed a positive impact of regulatory measures on the prevalence of MI contact allergy in Europe, which halved compared to 2015. However, our data suggest that consumers may still be exposed to older cosmetic products containing MI. BIT has superseded MI in causing contact allergy, despite not being allowed for use in cosmetic products.

Methylisothiazolinone sensitisation in New Zealand is decreasing.

BACKGROUND/OBJECTIVES: In the last 10 years methylisothiazolinone (MI) emerged as a global cause of preservative-related ACD. New Zealand has liberal regulations for the MI concentration limit in cosmetic products compared to Europe and Australia. The aim of this study was to evaluate the prevalence of MI sensitisation in New Zealand, explore sources of MI exposure and make recommendations on New Zealand regulations for MI use. METHODS: This retrospective study included data from patients who underwent patch testing with MI from 2008 to 2021 in a tertiary hospital dermatology clinic and a private dermatology clinic in Auckland, New Zealand. Patient baseline characteristics were recorded along with results of patch testing. Sources of MI exposure were identified from medical records. RESULTS: Over the study period, 1049 patch tests were performed in 1044 patients. MI was only tested as a stand-alone allergen from 2015; positive reactions to MI increased from 5.3% in 2015 to a peak of 11.9% in 2017 and then decreased to 6.4% in 2021. The most common source of MI exposure was shampoo or conditioner (27.7% of all relevant reactions) followed by occupational exposures to paints, biocides or glue (19.1%). CONCLUSION: Both sensitisation and ACD to MI appear to be decreasing, likely secondary to changes in product compounding due to stricter concentration limits internationally. We recommend New Zealand adopt lower MI concentration limits for cosmetics to match the limits of Australia and Europe.

Four-year Epidemiological Surveillance of the Spanish Registry of Research in Contact Dermatitis and Cutaneous Allergy: Current Situation and Trends. / Vigilancia epidemiológica en los últimos 4 años del Registro Español de Investigación en Dermatitis de Contacto y Alergia Cutánea: situación actual y tendencias.

BACKGROUND: The epidemiological surveillance of contact dermatitis is one of the objectives of the Spanish Registry of Research in Contact Dermatitis and Cutaneous Allergy. Knowing whether the prevalence of positive tests to the different allergens changes over time is important for this monitoring process. OBJECTIVES: To describe the various temporary trends in allergen positivity in the GEIDAC standard series from 2018 through December 31, 2022. METHODS: This was a multicenter, observational trial of consecutive patients analyzed via patch tests as part of the study of possible allergic contact dermatitises collected prospectively within the Spanish Registry of Research in Contact Dermatitis and Cutaneous Allergy. The data was analyzed using 2 statistical tests: one homogeneity test (to describe the changes seen over time) and one trend test (to see whether the changes described followed a linear trend). RESULTS: A total of 11327 patients were included in the study. Overall, the allergens associated with a highest sensitization were nickel sulfate, methylisothiazolinone, cobalt chloride, methylchloroisothiazolinone/methylisothiazolinone, and fragrance mix i. A statistically significant decrease was found in the percentage of methylisothiazolinone positive tests across the study years with an orderly trend. CONCLUSIONS: Although various changes were seen in the sensitizations trends to several allergens of the standard testing, it became obvious that a high sensitization to nickel, methylchloroisothiazolinone/methylisothiazolinone and fragrances mix i remained. Only a significant downward trend was seen for methylisothiazolinone.

Synergy between UV light and trichloroisocyanuric acid on methylisothiazolinone degradation: Performance, kinetics and degradation pathway.

Methylisothiazolinone (MIT) is widely used in daily chemicals, fungicides, and other fields and its toxicity has posed a threat to water system and human health. In this study, ultraviolet (UV)/trichloroisocyanuric acid (TCCA), which belongs to advanced oxidation processes (AOP), was adopted to degrade MIT. Total chlorine attenuation detection proved that TCCA has medium UV absorption and a strong quantum yield (0.49 mol E-1). At a pH of 7.0, 93.5% of MIT had been decontaminated after 60 min in UV/TCCA system (kobs = 4.4 × 10-2 min-1, R2 = 0.978), which was much higher than that in the UV alone system and TCCA alone system, at 65% (1.7 × 10-2 min-1, R2 = 0.995) and 10% (1.8 × 10-3 s-1, R2 = 0.915), respectively. This system also behaved well in degrading other five kinds of contaminants. Tert-butanol (TBA) and carbonate (CO32-) were separately used in quenching experiments, and the degradation efficiency of MIT decreased by 39.5% and 46.5% respectively, which confirmed that HO• and reactive chlorine species (RCS) were dominant oxidants in UV/TCCA system. With TCCA dosage increasing in a relatively low concentration range (0.02-0.2 mM) and pH decreasing, the effectiveness of this AOP system would be strengthened. The influences of coexisting substances (Cl-, SO42-, CO32-, NO2- and NO3-) were explored. MIT degradation pathways were proposed and sulfur atom oxidation and carboxylation were considered as the dominant removal mechanisms of MIT. Frontier orbital theory and Fukui indexes of MIT were employed to further explore the degradation mechanism.

Sensitization to isothiazolinones in the Spanish Contact Dermatitis Registry (REIDAC): 2019-2021 epidemiological situation.

BACKGROUND: Current frequency and risk factors for sensitization to methylisothiazolinone (MI), methylchloroisothiazolinone/methylisothiazolinone (MCI/MI), benzisothiazolinone (BIT) and octylisothiazolinone (OIT) in Spain are not well known. OBJECTIVES: To study the frequency of sensitization, risk factors and simultaneous sensitization between the four isothiazolinones. MATERIALS AND METHODS: We analysed all 2019-2021 consecutive patients patch-tested with MI (0.2% aq.), MCI/MI (0.02% aq.), BIT (0.1% pet.) and OIT (0.1% pet) within the Spanish Contact Dermatitis Registry (REIDAC). RESULTS: A total of 2511 patients were analysed. Frequencies of sensitization were: any isothiazolinone 15.7%, MI 6.8%, MCI/MI 4.8%, BIT 3.5% and OIT 0.5%. MI and MCI/MI sensitization was associated with being occupationally active, hand dermatitis, detergents and age over 40. BIT sensitization was associated with leg dermatitis and age over 40. About one in nine MI-positive patients were positive to BIT, whereas one in five BIT-positive patients were positive to MI. CONCLUSIONS: Sensitization to MI, MCI/MI and BIT is still common in Spain, while sensitization to OIT is rare. Currently, sensitization to MI and MCI/MI seems to be occupationally related. Although its origin is unknown, sensitization to BIT is more frequent in patients aged over 40 years. Simultaneous sensitization between MI and BIT is uncommon.

Novel insights into contact dermatitis.

Contact dermatitis is a common disease that is caused by repeated skin contact with contact allergens or irritants, resulting in allergic contact dermatitis (ACD) and/or irritant contact dermatitis. Attempts have been made to identify biomarkers to distinguish irritant and allergic patch test reactions, which could aid diagnosis. Some promising candidates have recently been identified, but verification and validation in clinical cases still need to be done. New causes of ACD are constantly being recognized. In this review, 10 new contact allergens from recent years, several relating to anti-aging products, have been identified. Frequent allergens causing considerable morbidity in the population, such as the preservative methylisothiazolinone, have been regulated in the European Union. A significant drop in the number of cases has been seen, whereas high rates are still occurring in other areas such as North America. Other frequent causes are fragrance allergens, especially the widely used terpenes and acrylates found in medical devices for control of diabetes. These represent unsolved problems. Recent advances in immunology have opened the way for a better understanding of the complexity of contact dermatitis, especially ACD-a disease that may be more heterogenous that previous understood, with several subtypes. With the rapidly evolving molecular understanding of ACD, the potential for development of new drugs for personalized treatment of contact dermatitis is considerable.

Quantification of Methylisothiazolinone and Methylchloroisothiazolinone Preservatives by High-Performance Liquid Chromatography.

Isothiazolinone preservatives (methylisothiazolinone (MIT) and methylchloroisothiazolinone (CMIT) are commonly used in cosmetics, industrial and household products. However, these isothiazolinone derivatives are known to cause allergic contact dermatitis. Hence, a sensitive, accurate, and reliable method for the detection of these compounds is thus warranted. The study aims to analyze concentrations of MIT and CMIT by high performance liquid chromatography. The analytical method used for quantification of MIT and CMIT in cosmetic products (leave-on-baby wet wipes) complies with the validation acceptance criteria (international standards ISO 5725, EU25 European Union for cosmetic regulations). MIT and CMIT were extracted and analyzed in leave-on baby wet-wipes collected from different stores in Riyadh city. Extraction was performed by ultrasonication of the samples, solid-phase extraction, and liquid-liquid extraction. Ten (10) µL of the sample was injected into the HPLC system and samples were analyzed with a mixture of acetic acid and methanol (80:20 v/v) in an isocratic mode. The flow rate was maintained at 1 mL/min. UV detection was performed at 274 nm. The results demonstrated recoveries between 90 and 106%, measurement uncertainty of C +/- 0.4% for methylisothiazolinone and C +/- 0.03% for methylchloroisothiazolinone, repeatability limit (r = 0.2%) and intermediate precision limit; R = 2% and R2 of 0.9996.

Perivascular clusters of Th2 cells and M2 macrophages in allergic contact dermatitis to methylchloroisothiazolinone and methylisothiazolinone.

BACKGROUND: Methylisothiazolinone (MI) and Methylchloroisothiazolinone (MCI) are among the most common skin sensitizers, yet the immunological events that occur during MCI/MI allergic contact dermatitis (ACD) are still poorly understood. OBJECTIVES: To analyse dendrocytes, macrophage subtypes and T cells in skin during the elicitation phase of MCI/MI ACD. METHODS: Thirteen patients with positive patch test reactions to MCI/MI (ACD group) and 11 individuals with negative patch test results were selected. Skin biopsies were only performed at 48 hours of patch testing. Immunohistochemistry was conducted to assess T cells, dendrocytes (Factor XIIIa), M1 (p-Stat1, CD68) and M2 (c-Maf, CD163) macrophages. Transcriptional analyses were performed for cytokines and related factors, and further compared to atopic dermatitis samples (n=4). Immunofluorescence assays addressed T cells location, along with IL-4 or IL-13, within the skin. RESULTS: MCI/MI elicited dermal dendrocytes and macrophages, pronouncedly the M2 subtype. T cells, majorly CD4+ T cells, accumulated in the perivascular areas. Similarly, abundant IL-4 protein was detected in these areas. There was an upregulation of IL-4 and IL-13 mRNA expression, a mild increase in IFNG mRNA levels and a down-regulation of RORC in the ACD group. Immunofluorescence revealed dermal clusters of T cells co-localized with IL-4. CONCLUSIONS: M2 macrophages and Th2 cells participate in the immunopathogenesis of MCI/MI ACD. Dermal dendrocytes and M2 macrophages may assist the formation of CD4+ T cells perivascular clusters. These findings render a mechanistic insight into the MCI/MI reaction. Further analysis at different timepoints of patch testing is required to fully comprehend this ACD kinetics.

Quantification of preservatives in tattoo and permanent make-up inks in the frame of the new requirements under the REACH Regulation.

BACKGROUND: According to the REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals) restriction, tattoo and permanent make-up (PMU) inks placed on the European Union market after January 4, 2022, shall not contain methylisothiazolinone, benzisothiazolinone (BIT), octylisothiazolinone (OIT), or other skin sensitizers in concentrations of 10 mg/kg or higher and phenoxyethanol (PE) or other eye irritants or damaging substances in concentrations of 100 mg/kg or higher. In addition, preservatives and other substances enlisted in Annex II to Cosmetic Product Regulation shall not be present in concentrations of 0.5 mg/kg or higher. OBJECTIVES: This study aims to quantify 14 preservatives in 99 tattoo and 39 PMU inks from the Italian market and presents a comparison with concentration limits set by the REACH restriction. METHODS: Inks were analysed by applying validated analytical methods based on liquid chromatography techniques. RESULTS: About 24.0%, 15.2% and 1.5% of the overall samples contained BIT, PE and OIT, respectively, at concentrations exceeding REACH concentration limits. The number of noncompliant tattoo inks (49.5%) would be significantly greater than that of the PMU inks (17.9%). CONCLUSIONS: About 40.6% of the samples would be noncompliant with the restriction for the presence of preservatives above the permitted level. Additional concentration limits will apply to skin sensitizing preservatives for proper labelling of inks under CLP (Classification, Labelling and Packaging) Regulation.

Contact allergy to haptens in the Swedish baseline series: Results from the Swedish Patch Test Register (2010 to 2017).

BACKGROUND: Allergic contact dermatitis has considerable public health impact and causative haptens vary over time. OBJECTIVES: To report the prevalence of contact allergy to allergens in the Swedish baseline series 2010 to 2017, as registered in the Swedish Patch Test Register. METHODS: Results and demographic information for patients tested with the Swedish baseline series in 2010 to 2017 were analysed. RESULTS: Data for 21 663 individuals (females 69%) were included. Females had significantly more positive patch tests (54% vs 40%). The reaction prevalence rates were highest for nickel sulfate (20.7%), fragrance mix I (7.1%), Myroxylon pereirae (6.9%), potassium dichromate (6.9%), cobalt chloride (6.8%), methylchloroisothiazolinone/methylisothiazolinone (MCI/MI; 6.4%), MI (3.7%), colophonium (3.5%), fragrance mix II (3.2%), and formaldehyde (3.2%). Myroxylon pereirae reaction prevalence increased from 5% in 2010 to 9% in 2017 and that for methyldibromo glutaronitrile from 3.1% to 4.6%. MCI/MI and MI reactions decreased in prevalence after 2014. Nickel reaction prevalence decreased among females aged 10 to 19 years. CONCLUSIONS: Nickel remains the most common sensitizing agent, with reaction prevalence decreasing among females younger than 20 years. The changes in MCI/MI and MI reaction prevalence mirrored those in Europe. The register can reveal changes in contact allergy prevalence over time among patients patch tested in Sweden.

Cosmetic Preservatives: Hazardous Micropollutants in Need of Greater Attention?

In recent years, personal care products (PCPs) have surfaced as a novel class of pollutants due to their release into wastewater treatment plants (WWTPs) and receiving environments by sewage effluent and biosolid-augmentation soil, which poses potential risks to non-target organisms. Among PCPs, there are preservatives that are added to cosmetics for protection against microbial spoilage. This paper presents a review of the occurrence in different environmental matrices, toxicological effects, and mechanisms of microbial degradation of four selected preservatives (triclocarban, chloroxylenol, methylisothiazolinone, and benzalkonium chloride). Due to the insufficient removal from WWTPs, cosmetic preservatives have been widely detected in aquatic environments and sewage sludge at concentrations mainly below tens of µg L-1. These compounds are toxic to aquatic organisms, such as fish, algae, daphnids, and rotifers, as well as terrestrial organisms. A summary of the mechanisms of preservative biodegradation by micro-organisms and analysis of emerging intermediates is also provided. Formed metabolites are often characterized by lower toxicity compared to the parent compounds. Further studies are needed for an evaluation of environmental concentrations of preservatives in diverse matrices and toxicity to more species of aquatic and terrestrial organisms, and for an understanding of the mechanisms of microbial degradation. The research should focus on chloroxylenol and methylisothiazolinone because these compounds are the least understood.

Electrochemical Characterization and Voltammetric Determination of Methylisothiazolinone on a Boron-Doped Diamond Electrode.

The electrochemical properties of methylisothiazolinone (MIT), the most widely used preservative, were investigated by cyclic (CV) and differential pulse voltammetry (DPV) to develop a new method for its determination. To our knowledge, this is the first demonstration of a voltammetric procedure for the determination of MIT on a boron-doped diamond electrode (BDDE) in a citrate-phosphate buffer (C-PB) environment. The anodic oxidation process of methylisothiazolinone, which is the basis of this method, proved to be diffusion-controlled and proceeded with an irreversible two-electron exchange. The radical cations, as unstable primary products, were converted in subsequent chemical reactions to sulfoxides and sulfones, and finally to more stable final products. Performed determinations were based on the DPV technique. A linear calibration curve was obtained in the concentration range from 0.7 to 18.7 mg L-1, with a correlation coefficient of 0.9999. The proposed procedure was accurate and precise, allowing the detection of MIT at a concentration level of 0.24 mg L-1. It successfully demonstrated its suitability for the determination of methylisothiazolinone in household products without the need for any separation steps. The proposed method can serve as an alternative to the prevailing chromatographic determinations of MIT in real samples.

Contact dermatitis associated with preservatives: Retrospective analysis of North American Contact Dermatitis Group data, 1994 through 2016.

BACKGROUND: Preservatives are often necessary components of commercial products. Large-scale North American studies on preservative allergy are limited. OBJECTIVE: To evaluate demographics, positive patch test reactions (PPTRs), clinical relevance, and trends for preservatives tested by the North American Contact Dermatitis Group. METHODS: We conducted a retrospective cross-sectional analysis of North American Contact Dermatitis Group patch testing results of preservatives from 1994 through 2016. RESULTS: A total of 50,799 patients were tested; 11,338 (22.3%) had a PPTR to at least 1 preservative. The most frequent reactions were to methylisothiazolinone 0.2% aqueous (aq) (12.2%), formaldehyde 2% aq (7.8%), formaldehyde 1% aq (7.8%), quaternium-15 2% petrolatum (pet) (7.7%), and methyldibromo glutaronitrile/phenoxyethanol 2% pet (5.1%). Paraben mix 12% pet (1%), iodopropynyl butylcarbamate 0.1% pet (0.4%), benzyl alcohol 1% pet (0.3%), and phenoxyethanol 1% pet (0.2%) had the lowest PPTRs. Linear regression analysis of preservatives tested showed that only methylchloroisothiazolinone/methylisothiazolinone 0.01% aq (parameter estimate, 0.42; 95% CI, 0.17-0.66; P < .005) had a significant increase in PPTRs over time. LIMITATIONS: Collected variables are dependent on clinical judgment. Results may be prone to referral selection bias. CONCLUSIONS: This large North American study provides insight on preservative PPTRs and trends from 1994 through 2016.

Contact dermatitis to personal care products is increasing (but different!) in males and females: North American Contact Dermatitis Group data, 1996-2016.

BACKGROUND: Personal care products (PCPs) are commonly responsible for allergic contact dermatitis and irritant contact dermatitis. PCP use was historically associated with females, but male-targeted PCPs are increasingly being marketed. OBJECTIVE: To characterize and compare males with PCP-related contact dermatitis (MPCPs) and females with PCP-related contact dermatitis (FPCPs). METHODS: This was a retrospective cross-sectional analysis of North American Contact Dermatitis Group data (1996-2016). RESULTS: Four thousand six hundred eighty of 16,233 men (28.8%) and 12,730 of 32,222 (39.5%) women had a PCP identified as a source of irritant contact dermatitis or a positive patch test reaction. The proportion of PCP-related dermatitis in both sexes significantly increased (>2.7-fold) over the decade of study. Compared with FPCPs, a larger proportion of MPCPs were older or had trunk or extremity dermatitis (P < .0001). MPCPs were twice as likely to have soaps as a source while FPCPs were twice as likely to have hair care products (P < .0001). The most common PCP-related North American Contact Dermatitis Group allergens for both sexes were methylisothiazolinone (MPCP 28.8% and FPCP 21.5%), fragrance mix I (MPCP 22.3% and FPCP 20.1%), balsam of Peru (MPCP 18.5% and FPCP 14.1%), quaternium-15 (MPCP 16.1% and FPCP 12.3%), and paraphenylenediamine (MPCP 11.5% and FPCP 11.1%). LIMITATIONS: Patient population referred for suspected contact dermatitis. CONCLUSIONS: PCP-related dermatitis is increasing. Sites of involvement and relevant PCP sources are distinct between sexes. Male and female variation in exposure history may explain differences in reactivity to some allergen groups.

A mixture of chloromethylisothiazolinone and methylisothiazolinone impairs rat vascular smooth muscle by depleting thiols and thereby elevating cytosolic Zn2+ and generating reactive oxygen species.

Chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) are biocidal preservatives and the active ingredients in Kathon CG, which contains ca. 1.5% mixture of CMIT and MIT at a ratio of 3:1 (CMIT/MIT). CMIT/MIT was misused as humidifier disinfectant products, which caused serious health problems in Korea. Here, the vascular effects of CMIT/MIT were investigated to evaluate claims of putative cardiovascular toxicity observed in humidifier disinfectant users. CMIT/MIT did not affect the basal tension of the rat thoracic aorta up to 2.5 µg/mL in myograph experiments. Instead, pretreatment with CMIT/MIT impaired phenylephrine- or 5-hydroxytryptamine-induced vasoconstriction in a range of 0.5-2.5 µg/mL, which was largely irreversible and not recovered by washing out the CMIT/MIT. Similarly, the application of CMIT/MIT to pre-contracted aorta caused a gradual loss of tension. In primary cultured vascular smooth muscle cells (VSMCs), CMIT/MIT caused thiol depletion, which in turn led to cytosolic Zn2+ elevation and reactive oxygen species (ROS) formation. CMIT/MIT-induced shrinkage, detachment, and lysis of VSMCs depending on the concentration and the treatment time. All events induced by CMIT/MIT were prevented by a thiol donor N-acetylcysteine (NAC). Cytolysis could be inhibited by a Zn2+ chelator TPEN and a superoxide scavenger TEMPOL, whereas they did not affect shrinkage and detachment. In accordance with these results, CMIT/MIT-exposed aortas exhibited dissociation and collapse of tissue in histology analysis. Taken together, CMIT/MIT causes functional impairment and tissue damage to blood vessels by depleting thiol and thereby elevating cytosolic Zn2+ and generating ROS. Therefore, exposure to CMIT/MIT in consumer products may be a risk factor for cardiovascular disorders.

Monitoring and risk assessment of hazardous chemicals in toy-slime and putty in the Netherlands.

In 2019, the Dutch Food and Consumer Product Safety Authority performed a market surveillance for toy-slime (23 samples) and putty (16 samples). For 35% of the toy-slimes and 13% of the putties, the migration of boron exceeded the European legal limit of 300 and 1200 mg/kg respectively. In 36% of the toy samples, methylisothiazolinone (MI) and chloromethylisothiazolinone (CMI) were detected in levels up to 25 and 38 mg/kg, respectively, much higher than the European legal limit for aqueous toys intended for children younger than three. 59% of the toys contained other preservatives such as 2-phenoxyethanol, p-hydroxybenzoic acid and parabens. In 2 toy-slimes and 2 putties N-nitrosodiethanolamine (NDELA) was found in amounts up to 2.3 mg/kg. A risk assessment was performed for boron and NDELA. The estimated exposure to boron did not exceed the health based guidance value. The estimated exposure to NDELA from 2 toy-slimes may pose a health risk. For 2 putties the estimated exposure to NDELA was somewhat lower, but health risks could not be excluded. The presence of isothiazolinones may lead to skin sensitisation. It is recommended to extend the legal limit for NDELA, MI and CMI in finger-paint and labelling requirements to other aqueous toys.

The epidemic of contact allergy to methylisothiazolinone-An analysis of Danish consecutive patients patch tested between 2005 and 2019.

BACKGROUND: In 2005, methylisothiazolinone (MI) was allowed as a stand-alone preservative in cosmetics. This resulted in an epidemic of allergic contact dermatitis to MI, mainly affecting women exposed to leave-on cosmetics. Consequently, a regulation of Annex V in the European Union in 2017 banned the use of MI in leave-on cosmetics and reduced the allowed concentration in rinse-off products. OBJECTIVE: To analyze the temporal trends in contact allergy to MI in Danish patients in relation to key events including European regulations over time. METHODS: A retrospective study of consecutive patients patch tested with methylisothiazolinone from 2005 to 2019. Demographics and clinical characteristics in terms of MOAHLFA (male, occupational, atopic dermatitis, hand dermatitis, leg dermatitis, facial dermatitis and age >40 years), sources of exposure, and clinical relevance were analyzed in relation to key historical events. RESULTS: Three hundred eighty of 12 494 patients (3.0%, 95CI: 2.7-3.4%) tested from 2005 to 2019 were sensitized to MI. An increasing trend in the prevalence of MI contact allergy from 2005 to 2019 (P < .01) was observed, although a decline in the absolute number of patch-test positive patients was seen from 2013 and onward. A reduction in leave-on cosmetics as a source of exposure was observed following the legislative ban in 2017, from 24.8% from in 2010 to 2013 to 6.2% in 2017 to 2019 (P < .01). CONCLUSION: The epidemic of MI contact allergy is declining in absolute terms, although the prevalence in the patch-tested population has not returned to its pre-epidemic levels. The legislative regulation of MI in 2017 has been effective in terms of leave-on cosmetics as a source of exposure in MI allergic patients. The process of post-marketing risk assessment of contact allergens in the European Union needs improvement.

Occupational contact dermatitis in painters and varnishers: Data from the Information Network of Departments of Dermatology (IVDK), 2000 to 2019.

INTRODUCTION: Painters and varnishers ("painters") are exposed to various contact allergens and skin irritants, and therefore, are at risk for developing occupational dermatitis (OD). OBJECTIVE: To describe the spectrum of occupational sensitizations in painters and revise the corresponding current patch test recommendations. PATIENTS AND METHODS: Retrospective analysis of Information Network of Departments of Dermatology (IVDK) data from 2000 to 2019 with focus on male painters with OD, ages 20-59 years (n = 557) in comparison to age-matched male painters without OD (n = 422) and male OD patients who have had never worked as painters (n = 13 862). RESULTS: Male painters with OD have a significantly higher rate of allergic contact dermatitis and face dermatitis than male patients with OD who work in other professions. Positive patch tests to epoxy resin, methylisothiazolinone (MI), and methylchloroisothiazolinone (MCI)/MI were significantly more frequent in painters with OD than in the other groups. Epoxy resin sensitization was significantly associated with face dermatitis. CONCLUSIONS: Epoxy resin, MI, and MCI/MI represent the most important occupational sensitizers in painters. In addition to baseline, resins and glues, and industrial biocides series, the patients' own workplace materials should be tested in painters with suspected OD.