Isothiazolinones are employed in the preservation of cosmetic, consumer and industrial products, with the objective of preventing deterioration and spoilage. However, the utilization of isothiazolinones is associated with an elevated risk of developing contact allergy (CA). Herein, we assess the epidemiology of CA to isothiazolinones among dermatitis patients from year 2000 onwards. We systematically searched PubMed, Embase, and Web of Science from 1 January 2000 to 19 April 2025 yielding 115 studies comprising 1 514 781 dermatitis patients. The prevalence of CA to methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) was 4.58%, methylisothiazolinone (MI) was 5.48%, and benzisothiazolinone (BIT) was 2.09%. The clinical relevance ranged from 60.1% for MCI/MI, 55.6% for MI, and 35.3% for BIT. Asia and North and South America exhibited the highest rates of CA to isothiazolinones, whereas Europe showed lower rates. These findings underscore the efficacy of proactive risk management for post-marketed substances such as MI, underscoring substantial regional variations in usage patterns, which are contingent on the strictness or permissiveness of their incorporation into everyday consumer products. There is an indication of a decline, particularly regarding MI and MCI/MI. However, there has been an increase in the use of substances such as BIT, which necessitates enhanced surveillance measures.

Human biomonitoring provides direct measures of internal exposure to environmental chemicals, but translating biomarker concentrations into quantitative external exposure and risk estimates remains challenging. Chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) are widely used biocides, and population exposure is typically assessed via urinary biomarkers. However, a quantitative framework connecting biomonitoring data to external dose and health risk is currently lacking. This study aims to quantitatively reconstruct external CMIT/MIT exposures from human urinary biomonitoring data using a population pharmacokinetic (PopPK) model and to assess human health risk via integrating reverse dosimetry with an internal dose-based reference dose (RfD). A human-scale PopPK model capable of quantitatively describing urinary excretion of N-methylmalonamic acid and the mercapturic acid metabolite M-12 following oral CMIT/MIT exposure was developed. Model parameters were estimated using nonlinear mixed-effects modeling and evaluated via bootstrap analysis, visual predictive checks, goodness-of-fit diagnostics, and normalized prediction distribution error analysis. The validated model was then applied to adult biomonitoring data from the German Environmental Sample Bank and to pediatric and adolescent survey data. External exposure doses were reconstructed via reverse dosimetry, accounting for inter-individual PK variability. Human health risk was quantified using the margin of exposure (MOE) approach, referencing an internal dose-derived oral RfD of 0.02mg/kg/day. The final PopPK model reliably captured urinary biomarker excretion dynamics at population and individual levels. Parameter estimates were robust, with bootstrap medians closely aligned with the final model values. Reconstructed external exposures exhibited no consistent long-term increasing or decreasing trend in adults and no systematic age- or sex-related pattern in pediatric and adolescents. Most exposure scenarios yielded MOE values > 10, while only extreme upper-bound conditions yielded MOEs of approximately 2-5. Even under conservative assumptions, all MOE values remained above 1. This study demonstrates that human biomonitoring data can be quantitatively translated into external exposure and risk metrics using a PopPK-based reverse dosimetry framework. The findings indicate that current CMIT/MIT exposure levels in the general population are unlikely to pose health concerns under typical environmental conditions. The integrated biomonitoring-modeling approach offers a regulatory-relevant framework for linking internal biomarkers to external exposure and health risk assessment.

Translational toxicokinetics of chloromethylisothiazolinone/methylisothiazolinone: Radioactivity-associated materials-physiologically based toxicokinetic modeling and human dose extrapolation.

Contact allergy to benzisothiazolinone (BIT) has increased in recent years, but exposure to it is not always found. It's important to know whether the gloves might be an isothiazolinone source especially in patients with symptoms from gloves and isothiazolinone contact allergy with or without allergy to rubber chemicals. To present results of chemical analysis of isothiazolinones in disposable rubber gloves of patients in an occupational dermatology clinic. We went through our chemical analysis record from 2018-2025 and identified isothiazolinone analyses done from disposable rubber gloves. The chemical analysis of glove extracts was done by liquid chromatography-mass spectrometry (LC-MS). We screened the respective patients' files and collected information on their occupation, glove usage, patch test reactions as well as basic information on their hand eczema. We discovered BIT in 30/54 (60%) analysed gloves (27 nitrile rubber gloves, 2 neoprene rubber gloves and 1 natural rubber glove) in concentrations of 0.3-73.7 ppm (mean 12.7 ppm, median 4.2 ppm). Methylisothiazolinone (MI) was found in solitary gloves in small concentrations. Isothiazolinone-containing gloves were samples from altogether 21 patients, and six of them had several gloves that contained isothiazolinones. Many patients had also other isothiazolinone sources at work or at home. Disposable rubber gloves are a possible BIT source. Several gloves contained BIT in a concentration that may be enough to induce contact allergy when gloves are used frequently.

Endocrine disruptive effects and mechanisms of isothiazolinone analogs in marine medaka (Oryzias melastigma) embryos and H295R cells.

Methylisothiazolinone (MIT) degradation performance of an air-lift moving bed electro-Fenton reactor: Homogeneous and heterogeneous phases

Methylisothiazolinone (MIT), a prevalent antimicrobial agent utilized in pharmaceuticals, cosmetics, and industrial contexts, presents potential toxicity concerns. Recent investigations have corroborated its neurotoxic effects in zebrafish and suggested involvement of the Hedgehog signaling pathway, although the specific regulatory mechanisms remain to be elucidated. In this study, transcriptome-based gene-pathway network analysis identified hhip within the Hedgehog pathway. Expression profiling and in situ hybridization revealed it is suppressed by MIT exposure and displays high expression in the zebrafish midbrain and hypothalamus. Dual-luciferase reporter assays in the zebrafish Pac2 cell line demonstrated that hhip suppresses transcription of the Hedgehog target gene gli1 and modulates reactive oxygen species (ROS) levels and oxidative stress-related gene expression. Moreover, pharmacological inhibition of the Hedgehog pathway with Ciliobrevin A (CA) during MIT exposure ameliorated anxiety-like behaviors in zebrafish, such as aberrant edge preference (thigmotaxis). This intervention downregulated Hedgehog pathway activity, elevated expression of oxidative stress genes (e.g., gpx4), reduced expression of the ferroptosis marker gene tf, attenuated the loss of Nissl bodies in brain tissue, and decreased brain iron content. These findings suggested that MIT exposure is associated with molecular signatures indicative of Hedgehog pathway activation. This cascade of molecular events is associated with subsequent anxiety-like behaviors, implying its potential contribution to the behavioral phenotype. In vitro studies using Pac2 cells further corroborated that inhibition of the Hedgehog pathway alleviates the increase in lipid peroxidation induced by the ferroptosis inducer Erastin. Collectively, these results elucidated the molecular regarding MIT-induced neurotoxicity and offer potential preventive and interventional strategies for addressing toxicity associated with this class of compounds.

IntroductionAllergic contact dermatitis (ACD) is a cutaneous inflammatory disorder mediated by allergen-specific memory T cells. Methylisothiazolinone (MI), a preservative widely used in industrial and cosmetic products and a component of Kathon CG, has led to a substantial rise in ACD cases. Despite increasing sensitization rates, the innate immune mechanisms and transcriptional responses induced by MI in the skin remain poorly understood.MethodsIndividuals with positive patch tests exclusively to MI were recruited at the Contact Dermatitis Clinic of Hospital das Clínicas (São Paulo). Participants were re-exposed to MI or saline, and skin biopsies were collected 48 hours later. Healthy MI-negative controls were also exposed to MI and saline. Histopathology and RNA-sequencing were performed. Differentially expressed genes (DEGs) were analyzed, and key findings were validated by qPCR and protein expression of IL-9 and IL-24.ResultsTwo distinct MI-responsive groups emerged among ACD patients:ACD-A (high responders): pronounced histopathology (spongiosis, microvesicles). ACD-B (low responders): milder reactions with absence of spongiosis. In ACD-A, MI exposure resulted in 1,588 upregulated and 2,090 downregulated genes compared to ACD-B. DEGs were enriched for innate immune and inflammatory pathways, including IL-24, IL-9, IL-13, and NTRK1 (upregulated), while IL-37 and IL-18 were downregulated. Compared to MI-negative ACD controls, ACD-A showed 1,169 upregulated and 321 downregulated genes. qPCR confirmed increased NTRK1 and IL-9 expression and reduced IL-18 levels. IL-9 and IL-24 protein levels were higher in the dermal layer of ACD-A.Discussion and ConclusionMI-sensitized individuals exhibit heterogeneous innate immune responses despite uniformly positive patch tests. IL-9, IL-24, and NTRK1 appear to play important roles in the heightened inflammatory response observed in high-responder individuals, while downregulation of IL-18 and IL-37 may contribute to impaired regulatory pathways. These findings highlight previously undescribed heterogeneity in MI-induced ACD and identify potential targets for better understanding disease pathogenesis.

Contact allergy is a clinically relevant condition already present in early childhood, yet longitudinal European data remain scarce. This updated ESSCA analysis (2011-2022) offers the most comprehensive pediatric patch test dataset to date, enabling comparison with the previous 2002-2010 ESSCA study. Standardized patch test data from 6961 children and adolescents (1-16 years) across 11 European countries was analyzed retrospectively. Sensitization rates, age distribution, allergen patterns, and associations with atopic dermatitis were assessed. Contact sensitization was identified in 29.3% of children and adolescents, similar to the 28.9% reported in 2015. The youngest children (1-5 years) showed an unexpectedly high sensitization rate (34.3%). Across age groups, sensitization to nickel sulfate and methylisothiazolinone (MI) was higher among children aged 1-5 years (19.7% and 4.2%, respectively) compared with adolescents aged 13-16 years (7.3% and 3.2%). Similarly, cobalt chloride sensitization was lower in the oldest group (4.3%) than in the youngest (13.1%). Sensitization to 2-hydroxyethyl methacrylate (HEMA) was 1.4% in children aged 1-5 years and 0.7% in adolescents aged 13-16 years. Moreover, adolescents (13-16 years) exhibited a threefold increase in sensitization to para-phenylenediamine (PPD) compared to the 6-12-year age group. Notably, nickel positivity was highest in the northeast (27.2%) and lowest in the western region (e.g., UK, 6.6%), reflecting regional differences in product exposure. Contact allergy remains common in the pediatric population but reveals evolving sensitization profiles shaped by regulation and societal change. Sensitization to nickel and acrylates was higher in the youngest children compared to adolescents, whereas PPD sensitization was higher in adolescents. Younger children showed the highest overall prevalence, and regional differences persist. These findings highlight the need for ongoing surveillance and periodic updates to pediatric patch test series to inform prevention and public health strategies.

The rapid development of industry has led to the discharge of large quantities of organic pollutants into water bodies, posing a significant threat to aquatic safety. It is imperative to develop efficient and environmentally friendly methods for the elimination of organic pollutants. The integration of hydrogel membranes with advanced oxidation processes (AOPs) for water purification has attracted considerable interest due to their high efficiency. However, conventional wet membrane materials stored in aqueous environments are more prone to swelling and leakage of loaded metal species. This limits its application in the degradation of organic pollutants. This study employs a vacuum drying strategy for wet hydrogels, incorporating molybdenum disulfide as a cocatalyst and Co2+ cross-linking within the alginate matrix, resulting in a dried MoS2-cobalt alginate hydrogel membrane (D-MoS2-CoAlg). The drying process of the D-MoS2-CoAlg membrane not only significantly enhanced its mechanical strength and anti-swelling capacity but also effectively mitigated the leaching of Co2+. Throughout five consecutive cycles, the concentration of leached Co2+ remained below 0.032 mg/L. This enables the membrane to achieve a balance between reusability and environmental compatibility. Under the conditions of a drying time of 60 min, a peroxymonosulfate (PMS) dosage of 0.2 mmol/L, and an initial methylisothiazolinone (MIT) concentration of 20 mg/L, the D-MoS2-CoAlg membrane exhibited exceptional catalytic performance, achieving a degradation rate of MIT as high as 92.14% within 5 min. The D-MoS2-CoAlg membrane demonstrates high catalytic activity and good stability, showing promising potential for application in the field of organic wastewater treatment.

Nontarget screening and identification of emerging preservatives and their metabolites in human urine.

North American Contact Dermatitis Group Patch Test Results: 2021-2022.

Antimicrobial compounds enter freshwater systems via municipal wastewater, potentially affecting aquatic life. While the toxicity of triclosan (TCS), a legacy antimicrobial, is well-documented, less is known about emerging alternatives such as chloroxylenol (PCMX) and methylisothiazolinone (MIT). This study evaluated the developmental and molecular effects of these compounds on early-life stage rainbow trout (Oncorhynchus mykiss). Embryos were exposed to nominal concentrations of 0.39-400 µg/L from hatch to 28 days post-hatch (dph). Mortality and sublethal endpoints (edema, spinal curvature, jaw deformities, swim-up time) were assessed, and transcriptomic responses were measured at 96 h using the EcoToxChip RT-qPCR platform. TCS and PCMX reduced survivability, with 28-d LC50 values of 107 and 254 µg/L, respectively. TCS increased jaw deformities and edema, while PCMX induced spinal deformities and edema at ≥241 µg/L. MIT had no observable effects on survival or development. No significant changes were detected in swim-up time or histopathology of gill, liver, or intestine across treatments. Transcriptomic analysis revealed 55, 25, and 3 differentially expressed genes (DEGs) in response to TCS, PCMX, and MIT, respectively. TCS and PCMX shared regulation of 19 genes linked to metabolic, endocrine, and reproductive pathways, suggesting similar modes of action. These findings indicate that TCS and PCMX exert low but distinct sublethal and molecular toxicity, while MIT showed minimal effects. The EcoToxChip effectively detected early transcriptomic responses, supporting its application in rapid chemical hazard assessment of both legacy and emerging antimicrobials.

Nociceptive effects and gene alterations of CMIT/MIT mixture in zebrafish embryos and larvae.

Abstract Baby wipes contain water and low levels of preservatives, fragrances, surfactants and emollients, which remain on the skin and contribute to irritant and allergic contact dermatitis in infants and caregivers. Historically, the preservatives methylisothiazolinone (MI) and methylchloroisothiazolinone (MCI) were significant allergens [Chang MW, Nakrani R. Six children with allergic contact dermatitis to methylisothiazo­linone in wet wipes (baby wipes). Pediatrics 2014; 133: e434–8; Soriano LF, Chowdhury MMU, Cooper SM et al. Current prevalence and relevance of positive patch test reactions to cosmetic and noncosmetic isothiazolinones in the UK. Br J Dermatol 2021; 185: 223–5]. However, their ban in leave-on cosmetics in the European Union since 2018 has shifted the allergen landscape. This study investigates the prevalence of current ingredients in UK baby wipes. In January 2025, a survey of baby wipe products was conducted across nine major supermarkets and health and beauty retailers in a UK city. Product names, ingredients, marketing claims (e.g. ‘fragrance-free/sensitive’) and compliance with the International Nomenclature of Cosmetic Ingredients (INCI) were documented. Unique ingredients were identified using Python (version 3.13.1). In total, 85 products were identified, containing 120 unique ingredients, with a mean of 10 ingredients per product (range 1–20). Five products were noncompliant with INCI labelling standards, with terms including ‘bamboo’, ‘aloe vera’, ‘apple’ and ‘apple extract’. The most frequently occurring ingredients included sodium benzoate (66 of 85), citric acid (60 of 85), sodium citrate (47 of 85), ‘aloe barbadensis’ (aloe vera) (46 of 85) and glycerine (41 of 85). MI and MCI were absent from all surveyed products. Preservatives and antimicrobials were common, particularly sodium benzoate (66 of 85), phenoxyethanol (22 of 85), benzoic acid (26 of 85), dehydroacetic acid (24 of 85), potassium sorbate/sorbic acid (19 of 85) and benzalkonium chloride (11 of 85). Plant extracts, including chamomile, citrus and Asteraceae derivatives, appeared in 41 of 85 products. Fragrances were present in 20 of 85 products, primarily as parfum (18 of 85), with gamma-nonalactone and pentadecalactone identified in two of 85. Three fragranced products lacked explicit labelling, including one marketed as ‘sensitive and fragrance-free’. Other allergens identified included glycols (30 of 85), carboxylic acids and salts (19 of 85), betaine derivatives (eight of 85), cetearyl alcohol (six of 85) and lauryl glucoside (three of 85). Although MI and MCI were absent, preservatives, fragrances and botanical extracts were prevalent. Noncompliance with INCI standards and misleading marketing claims may obscure consumer awareness of potential sensitizers. Given the allergen burden in baby wipes in 2025, clinicians should consider them as a cause of infant allergic perineal dermatitis and hand dermatitis in their caregivers. A targeted patch testing series may improve diagnostic accuracy and early intervention and overcome the limitations imposed by infant size, while minimizing unnecessary hapten exposure.

Abstract A 51-year-old atopic female toolmaker presented with recurrent dermatitis affecting her hands, forearms and face, episodic facial and lip swelling, breathlessness and wheezing. She had worked in a metal workshop for 30 years, and her symptoms began within 2 weeks of relocating to a new work facility, where she was involved in metal grinding and etching. Despite wearing gloves, she developed pruritic rashes, facial swelling and wheezing late in the working day, requiring repeated courses of oral corticosteroids. Her symptoms improved when away from work and resolved completely after transitioning to an office-based role. The respiratory team confirmed occupational asthma, based on work-related peak flow variability and elevated fraction of exhaled nitric oxide, both of which normalized in her office-based role, in conjunction with her clinical presentation and exposures to known asthmagens [Iskandar IYK, Gawkrodger DJ, Byrne L et al. Trends in work-related respiratory diseases attributed to nickel, chromium and cobalt in the UK: descriptive findings from The Health and Occupation Research (THOR) network 1996–2019. Occup Environ Med 2024; 81: 220–4]. Metalworking fluid was identified as the new exposure likely responsible for her respiratory presentation. Patch testing using the British Society for Cutaneous Allergy standard series, along with local metal, oils and cosmetic series, revealed positive reactions to metals (cobalt, nickel, palladium), rubber chemicals (thiuram mix, para-phenylenediamine) and preservatives [methylisothiazolinone (MI) and methylchloroisothiazolinone (MCI)]. She confirmed occupational exposure to nickel and cobalt from metal grinding, isothiazolinones from metalworking fluids, and rubber accelerators from gloves. She was diagnosed with occupational ACD. The UK SWORD (Surveillance of Work-Related and Occupational Respiratory Disease) scheme attributed 1% of occupational respiratory diseases to nickel, chromium or cobalt, with most cases being occupational asthma, due to inhalation of fine metal dust generated from hard metal manu­facturing. Workers frequently report cough, wheezing and dyspnoea, which improve away from work. Occupational ACDs are common in metalworkers; common allergens include nickel, cobalt, chromium, rubber accelerators and preservatives from metalworking fluids (including MCI and MI) [Schubert S, Brans R, Reich A et al. Contact sensitization in metalworkers: data from the information network of departments of dermatology (IVDK), 2010–2018. Contact Dermatitis 2020; 83: 487–96]. This case highlights the coexistence of ACD and occupational asthma, conditions with distinct immunological mechanisms. ACD is a type IV hypersensitivity reaction, while occupational asthma is type I hypersensitivity. Their simultaneous presentation is rare, and patch testing, although primarily used for type IV hypersensitivity, provided supporting evidence for occupational asthma by confirming significant exposure to known respiratory sensitizers for which skin prick or IgE testing is not available.

Methylisothiazolinone (MIT) is a known inducer of allergic contact dermatitis that is used as a preservative and a biocide in consumer products. Transient receptor potential ankyrin 1 (TRPA1) is a non-selective cation channel expressed in neurons and in some nonneuronal cells including keratinocytes. In neurons, TRPA1 mediates itch, pain and neurogenic inflammation. It has also been shown that TRPA1-deficient animals have reduced expression of inflammatory cytokines in experimental models of allergic contact dermatitis. Therefore, we aimed to test the hypothesis that TRPA1 is activated by MIT and mediates MIT-induced inflammatory conditions. In Fluo 3-AM intracellular Ca2+ measurements MIT caused a dose-dependent increase in the intracellular calcium which was inhibited with the TRPA1-antagonist A-967079. In whole-cell patch clamp recordings, MIT was confirmed to induce currents blocked by A-967079. EC50 values were 2.17 μM at +70 mV and 6.28 μM at -70 mV in Ca2+-free conditions. Mutation of the cysteine 621 in TRPA1 lowered the potency of MIT to activate the channel. In the mouse model of MIT-induced acute inflammatory paw edema, mice treated with a TRPA1 antagonist as well as TRPA1-deficient mice had reduced edema formation. In addition, TRPA1-deficient mice sensitized to MIT had reduced elevation of IL-4 expression in skin following exposure to MIT when compared to wild-type mice. In conclusion, we report here, for the first time, that the preservative and known contact sensitizer MIT is a potent agonist of TRPA1 and that TRPA1 mediates some of the effects of MIT in inflammatory conditions. These results together with the previous findings suggest that TRPA1 is a factor in the pathogenesis of type 2 T-helper cell (Th2)-skewed contact allergy and as such a potential drug target to treat Th2-driven diseases.

Objectives: To evaluate the prevalence of methylisothiazolinone (MI) sensitivity and associated factors in individuals with suspected allergic contact dermatitis. Methods: Cross-sectional study based on patch tests, including methylisothiazolinone 0.2%, in 286 participants with suspected allergic contact dermatitis, in Brasília/DF, Brazil, between March/2020 and March/2022. Results: 13.6% of participants were diagnosed with allergic contact dermatitis and sensitive to MI. The mean age was 43.7 years, and the majority were women (71,8%). The average duration of the disease was 60 months. The most common location was hands (76.9%) and upper limbs (33.3%). In 97.4%, allergy to methylisothiazolinone was considered of current relevance. In the multivariate model, being domestic/household increased the chance of presenting sensitivity to MI by 4.2 (95% CI= 1.36 - 13.5). Presenting lesions in several places of the body was also significantly associated (OR=2.84; CI 95%=1.17 - 6.86) to be sensitive to the test substance. Conclusion: The findings confirm the epidemic of allergy to methylisothiazolinone. They reinforce the need for the inclusion of this isolated substance in the Brazilian baseline series. We emphasize the need for regulations on the use of methylisothiazolinone in industrial products and household detergents, as is done for cosmetics. Studies in other centers are needed to confirm these results. Keywords: Prevalence; Methylisothiazolinone; Allergic contact dermatitis; Allergy; Epidemiology; Detergents; Industrial products.

Allergic Contact Dermatitis in Skin of Color: A Retrospective Study from a Comprehensive Patch Testing Center.

The following case report highlights the importance of the diagnosis and treatment of contact allergies caused by isothiazolinones such as methylisothiazolinone (MI) and methylchloroisothiazolinone (MCI).Recently, there has been a significant increase in the prevalence of MI/MCI-related contact allergies, a form of allergic contact dermatitis.This is mainly due to the prevalence of MI/MCI as a preservative in a variety of products, including cosmetics, detergents and paints [1,2].Despite regulatory measures to limit concentrations in certain products, the risk of sensitization remains, especially in the case of occupational exposure, unlabeled products or circumvention of regulatory measures.We present a case that highlights the complex challenges and importance in the diagnosis and management of such allergies.It also highlights the need for improved education and stricter regulation of MI/MCI in products and compliance.The patient's written consent for the case report and images are available.