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.

Occurrence and Transport of Isothiazolinone-Type Biocides from Commercial Products to Aquatic Environment and Environmental Risk Assessment.

This study investigated the occurrence and transport of four isothiazolinone-type biocides from commercial products to wastewater treatment plants (influents, sludges, and effluents) and to natural emissaries (upstream and downstream the wastewater treatment plants) in Romania. All four biocides were determined in personal care and household products, with the highest concentration of 76.4 µg/L OIT (2-octyl-4-isothiazolin-3-one). For environmental samples, three of the four isothiazolinones were determined, CMI (5-chloro-2-methyl-4-isothiazolin-3-one) being the prominent compound for water samples. The maximum concentration of 84.0 µg/L in influent, 122 µg/L upstream, and 144 µg/L downstream the wastewater treatment plants were obtained for CMI. Unlike water samples, in the sewage sludge samples, OIT proved to be the dominant compound, with concentration up to 5.80 µg/g d.w. The extremely high levels of isothiazolinone determined in different WWTPs from Romania may be due to the COVID-19 pandemic situation, during which a much larger amount of cleaning, hygiene, and personal care products was used. The isothiazolinone-type biocides were readily removed from the influents of the five WWTPs, with the mean removal rate up to 67.5%. The mean mass loading value for the targeted biocides based on influent was 20.4 µg/day/1000 people, while the average environmental emissions were 6.93 µg/day/1000 people for effluents. The results obtained for riverine water combine with statistical analysis showed that the anthropogenic activities are the major contamination sources of the surface waters. Preliminary ecological risk evaluation showed that BIT (1,2-benzisothiazol-3(2H)-one), OIT, and CMI could pose a very high risks to different aquatic species living in the receiving aquatic environments.

Effect of Cosmetics Use on the In Vitro Skin Absorption of a Biocide, 1,2-Benzisothiazolin-3-one.

1,2-Benzisothiazolin-3-one (BIT) is a commonly used organic biocide containing an isothiazolone ring. However, it may have adverse effects on human health and its risk needs to be properly evaluated. Dermal exposure is the main route of BIT exposure, and co-exposed substances may affect its absorption. The dermal permeation profile of BIT has not been well-studied. This study aimed to investigate the dermal permeation profiles of BIT with or without cosmetic use. Dermal permeation profiles of BIT were investigated after infinite- (100 µg/cm2), or a finite-dose (10 µg/cm2) application with or without cosmetics using a minipig skin and Strat-M®, an artificial membrane. A cream, lotion, and essence (namely, face serum) were pre-treated as representative cosmetics on minipig skin for 30 min, with BIT treatment afterward. After the treatment, BIT left on the skin surface was collected by cotton swabbing, BIT in the stratum corneum, by sequential tape stripping, and BIT retained in the remaining skin was extracted after cutting the skin into pieces before LC-MS/MS analysis. When an infinite dose was applied, permeation coefficients (Kp, cm/h) for minipig skin and Strat-M® were 2.63 × 10-3 and 19.94 × 10-3, respectively, reflecting that skin permeation was seven to eight times higher in Strat-M® than in the minipig skin. BIT, in the presence of cosmetics, rapidly permeated the skin, while the amount in the stratum corneum and skin deposit was reduced. We performed a risk assessment of dermally applied BIT in the absence or presence of cosmetics by calculating the skin absorption rate at 10 h based on the toxicological data from several references. The risk level was higher in the presence of essence as compared to lotion, which was higher than cream, which was higher than the control (non-treated). However, all of the margins of safety values obtained were greater than 100, suggesting that BIT is safe for use in dermally exposed consumer products. We believe that this research contributes to a greater understanding of the risk assessment of isothiazolinone biocides.

Gastrointestinal tract and skin permeability of chemicals in consumer products using parallel artificial membrane permeability assay (PAMPA).

Some chemicals commonly used in personal care products, household items, food vessels, cosmetics, and other consumer products are potentially harmful, and several reviews of epidemiological studies have suggested the associations between the chemical exposure from consumer products, and respiratory diseases, skin sensitization, and reproductive problems. Therefore, risk assessment is essential for management of consumer products safety. Necessarily, the estimation of human exposure is an essential step in risk assessment, and the absorption rate of those chemicals via the gastrointestinal tract, respiratory tract, and skin are very critical in determining the internal dose of the exposed chemicals. In this study, parallel artificial membrane permeability assays (PAMPA) for the gastrointestinal tract and skin were performed to evaluate the permeability of parabens (4-hydroxybenzoic acid, methyl-, propyl-, and butyl paraben), bisphenols (bisphenol A, bisphenol F, and bisphenol S), isothiazolinones (methyl-, chloromethyl-, benz-, octyl-, and dichlorooctyl isothiazolinone), and phthalates [diethyl-, dibutyl-, Di-isononyl-, and bis(2-ethylhexyl) phthalate]. Lipid solubility of test chemicals indicated by log P values was shown as the most critical factor and showed a positive association with the permeability of parabens, bisphenols, and isothiazolinones in PAMPA assay. However, phthalate showed a reverse-association between lipophilicity and permeability. The permeability of all the tested chemicals was higher in the gastrointestinal tract membrane than in the skin membrane. The pH in donor solution did not show significant effects on the permeability in all the chemicals, except the chemicals with a free hydrophilic moiety in their chemical structures.

Development and validation of a UPLC-MS/MS method for the quantification of isothiazolinones in the composition and emissions from consumer products.

Isothiazolinones, a family of biocides, are used as preservatives for their fungicidal, bactericidal, and algacidal properties. These compounds can be found in a wide range of consumer and building products, such as paints, varnishes, shampoos, and liquid detergents. A robust analytical UPLC-MS/MS method to identify and quantify seven isothiazolinones (MIT, CMI, BIT, MBIT, BBIT, OIT, and DCOIT) in consumer products and their emissions was developed and validated according to ISO/IEC 17025. The limits of detection (LODs) ranged from 0.14 µg L-1 (BIT) to 0.54 µg L-1 (CMI). The method was applied for the quantification of the seven isothiazolinones in four types of consumer products (i.e., cosmetics, air fresheners, cleaning products, and building products) and the indoor emissions from a paint. Matrix effects were observed for the shampoo (63-74%), the shower gel (67-84%), and the ceramic glass cleaner (53-57%). All isothiazolinones indicated by the manufacturer (i.e., MIT, CMI, BIT, OIT, and DCOIT) were detected in the products and successfully quantified by the UPLC-MS/MS method.

Allergic contact dermatitis and other occupational skin diseases in health care workers in the Finnish Register of Occupational Diseases in 2005-2016.

BACKGROUND: Health care workers are an important risk group for occupational skin disease (OSD). AIMS: To study diagnoses and causes of OSDs in health care workers in the Finnish Register of Occupational Diseases (FROD) in 2005-2016. METHODS: We searched the FROD for dermatological cases (a) in health care-related occupations defined by ISCO-08 and (b) in the industrial branch of health care defined by European industry standard classification system (NACE rev. 2). RESULTS: Health care workers comprised 19% of all OSD cases in the FROD, and irritant contact dermatitis dominated the diagnoses. Nurses and assistant nurses were the largest occupational groups with incidence rates of 3.3 and 2.7/10 000 person years, respectively. Rubber chemicals were by far the most common causative agents of allergic contact dermatitis (ACD) followed by preservatives, the latter mainly comprising isothiazolinones and formaldehyde. Acrylates were important allergens in dental professions. Metals and coconut fatty acid derivatives were the next largest causative groups for ACD. Drugs caused only 1% of the ACD cases. CONCLUSIONS: Workers in different health care occupations do not have a uniform risk for OSD, but they share the risk for ACD due to rubber chemicals and various preservatives.

Simultaneous Determination of Isothiazolinones and Parabens in Cosmetic Products Using Solid-Phase Extraction and Ultra-High Performance Liquid Chromatography/Diode Array Detector.

Isothiazolinones methylisothiazolinone (MI) and methylchloroisothiazolinone (MCI), and parabens methylparaben (MP), ethylparaben (EP), propylparaben (PP) and butylparaben (BP) are the most common synthetic preservatives. They are all known to be potential skin allergens that lead to contact dermatitis. Thus, the identification of these unsafe chemicals in cosmetic products is of high importance. In the present study, solid-phase extraction (SPE) based on HyperSep reversed-phase C8/benzene sulfonic acid ion exchanger (HyperSep C8/BSAIE) and Sep-Pak C18 sorbents, and ultra-high performance liquid chromatography/diode array detector (UHPLC/DAD) were optimized for the simultaneous determination of MI, MCI, MP, EP, PP and BP in cosmetic products. HyperSep C8/BSAIE and UHPLC/DAD with the eluting solvent mixture (acetonitrile/methanol, 2:1, v/v) and detection wavelength (255 nm) were found to be the optimal conditions, respectively. The method illustrates the excellent linearity range (0.008-20 µg/mL) with coefficient of determination (R2, 0.997-0.999), limits of detection (LOD, 0.001-0.002 µg/mL), precision in terms of relative standard deviation (RSD < 3%, intra-day and <6%, inter-day) when examining a standard mixture at low (0.07 µg/mL), medium (3 µg/mL) and high (15 µg/mL) concentrations. A total of 31 cosmetic samples were studied, achieving concentrations (MI, not detected (nd)-0.89 µg/g), (MCI, nd-0.62 µg/g), (MP, nd-6.53 µg/g), (EP, nd-0.90 µg/g), (PP, nd-9.69 µg/g) and (BP, nd-17.80 µg/g). Recovery values ranged from 92.33 to 101.43% depending on the types of sample. To our knowledge, this is the first specific method which covers the theme and describes background amounts of such preservatives in cosmetics.

[Allergy to isothiazolinones in recent years]. / Alergia na izotiazolinony w ostatnich latach.

BACKGROUND: Isothiazolinones are preservatives which are present in cosmetics, household chemicals and many other industrial products. Initially, a mixture of methylchloroisothiazolinone and methylisothiazolinone (MCI/MI - Kathon CG) was used, and then, from the beginning of the 21st century, only methylisothiazolinone. Due to a significant increase in the number of contact dermatitis caused by allergy to this compound, it was withdrawn from leave-on cosmetics, and its concentration in rinse-off cosmetics was reduced. The aim of the study was to analyze the incidence of contact allergy to isothiazolinones among patients in the Nofer Institute of Occupational Medicine, Lódz, the intensification of patch test results and hypersensitivity depending on the occupation, and to assess the contribution of immediate allergy to the occurrence of that hypersensitivity. MATERIAL AND METHODS: In a group of 1137 patients (832 females and 305 males) with suspected contact dermatitis, diagnosed in 2014-2018, patch tests series including methylchloroisothiazolinone/methylisothiazolinone (0.01%) and methylisothiazolinone (0.2%), produced by Chemotechnique Diagnostics, Sweden, were performed. In a group of 29 individuals with contact allergy to isothiazolinones, prick tests with methylisothiazolinone (0.001%, 0.01%, 0.1%, 1%) (Sigma-Aldrich, Germany) were conducted. RESULTS: Of the 1137 subjects, 95 (8.3%) were allergic to isothiazolinones, slightly more often females - 71 (8.5%) than males - 24 (7.9%). In total, 150 positive patch tests with isothiazolinones (13.2%) were obtained. The number of positive results with methylisothiazolinone alone (7.8%) was higher than the number with methylisothiazolinone from Kathon CG (5.4%). Among the subjects sensitized to methylisothiazolinone alone strongly positive patch tests (+++) concerned 60.7%. In the female group, office workers (42.3%) and medical staff (18.3%) predominated, and in the male group - locksmiths, turners, mechanics and similar ones (45.8%), and construction workers (25.0%). Prick tests with methylisothiazolinone were negative, and they became positive after 3-5 h. CONCLUSIONS: Isothiazolinones, particularly methylisothiazolinone, are significant causal factors of contact allergy, including that of occupational origin. They have strongly allergenic properties, and in patch tests they often give very severe inflammatory reactions. The issue of the role of immediate allergy in the pathogenesis of isothiazolinones sensitization requires further research. Med Pr. 2020;71(5):603-11.

Construction workers' skin disorders in the Finnish Register of Occupational Diseases 2005-2016.

BACKGROUND: Construction workers are a known risk group for occupational skin disease (OSD). OBJECTIVES: To study diagnoses and causes of OSD in construction workers in the Finnish Register of Occupational Diseases (FROD) 2005-2016. MATERIALS AND METHODS: We searched the FROD for dermatological cases in (a) construction-related occupations defined by the International Standard Classification of Occupations (ISCO-08) and (b) in the industrial branch of construction defined by the Statistical Classification of Economic Activities in the European Community (NACE Rev. 2). RESULTS: The two searches yielded the same number of cases, 329, although they were not identical subgroups. The number of allergic contact dermatitis (ACD) cases was 235 (71%) in construction-related occupations and 228 (69%) in the industrial branch of construction. In the latter analysis, synthetic resin systems caused 66% of ACD cases and 46% of all OSDs, epoxy compounds being the leading cause (122 cases; 54% of ACD cases; 37% of all OSDs). Metals were the second most common group of causes of ACD with 31 cases (chrome 22 cases; cobalt 8 cases). Isothiazolinones caused ACD in 21 cases, many of whom were painters. CONCLUSIONS: ACD dominated the OSDs of construction workers and epoxy products were by far the leading cause comprising 37% of all OSDs. Chrome and isothiazolinones were also prominent causes of ACD.

12-year data on dermatologic cases in the Finnish Register of Occupational Diseases I: Distribution of different diagnoses and main causes of allergic contact dermatitis.

BACKGROUND: Skin diseases are among the most common occupational diseases, but detailed analyses on their epidemiology, diagnoses, and causes are relatively scarce. OBJECTIVES: To analyze data on skin disease in the Finnish Register of Occupational Diseases (FROD) for (1) different diagnoses and (2) main causes of allergic contact dermatitis (ACD). METHODS: We retrieved data on recognized cases with occupational skin disease (OSD) in the FROD from a 12-year-period 2005-2016 and used national official labor force data of the year 2012. RESULTS: We analyzed a total of 5265 cases, of which 42% had irritant contact dermatitis (ICD), 35% ACD, 11% contact urticaria/protein contact dermatitis (CU/PCD), and 9% skin infections. The incidence rate of OSD in the total labor force was 18.8 cases/100 000 person years. Skin infections concerned mainly scabies in health care personnel. Twenty-nine per cent of the ACD cases were caused by plastics/resins-related allergens, mainly epoxy chemicals. Other important causes for ACD were rubber, preservatives, metals, acrylates, and hairdressing chemicals. Cases of occupational ACD due to isothiazolinones reached a peak in 2014. CONCLUSION: Our analysis confirms that epoxy products are gaining importance as causes of OSD and the isothiazolinone contact allergy epidemic has started to wane.

Isothiazolinone Biocides: Chemistry, Biological, and Toxicity Profiles.

The importance of isothiazole and of compounds containing the isothiazole nucleus has been growing over the last few years. Isothiazolinones are used in cosmetic and as chemical additives for occupational and industrial usage due to their bacteriostatic and fungiostatic activity. Despite their effectiveness as biocides, isothiazolinones are strong sensitizers, producing skin irritations and allergies and may pose ecotoxicological hazards. Therefore, their use is restricted by EU legislation. Considering the relevance and importance of isothiazolinone biocides, the present review describes the state-of-the-art knowledge regarding their synthesis, antibacterial components, toxicity (including structure-activity-toxicity relationships) outlines, and (photo)chemical stability. Due to the increasing prevalence and impact of isothiazolinones in consumer's health, analytical methods for the identification and determination of this type of biocides were also discussed.

Contact allergy to isothiazolinones epidemic: Current situation.

BACKGROUND: Since 2009, an increasing number of published cases of allergic contact dermatitis (ACD) from isothiazolinones in Europe was observed, amounting to an epidemic. However, only few studies have assessed the current situation after changes in European regulation. OBJECTIVES: To analyze the incidence of isothiazolinone-related ACD in our area in the last decade. METHODS: A retrospective study analyzed all patients patch tested in the allergy unit in a tertiary hospital in Spain between January 2010 and June 2019. Positive patch-test reactions to methylchloroisothiazolinone (MCI)/methylisothiazolinone (MI) and/or MI alone were recorded. RESULTS: A total of 243 patients (9.55%) with positive patch-test reactions to MCI/MI and/or MI alone among 2544 consecutively patch-tested patients were recorded. An initial increase in the prevalence of MCI/MI allergy was observed, from 4.5% in 2010 reaching a peak in 2015, which was followed by a significant decrease until July 2019 with 3.1% prevalence in 2019. CONCLUSIONS: As shown in our data, regulatory interventions have resulted in a dramatic decrease in the prevalence of MCI and MI ACD, reaching a pre-epidemic level of 3.1% in 2019.

Isothiazolinones in cleaning products: Analysis with liquid chromatography tandem mass spectrometry of samples from sensitized patients and market.

BACKGROUND: Methylchloroisothiazolinone (MCI) and methylisothiazolinone (MI) contact dermatitis is a severe problem. The high concentrations of these substances and other isothiazolinones such as benzisothiazolinone (BIT) and octylisothiazolinone (OIT) contained in cleaning products may cause allergic contact dermatitis in sensitized patients. OBJECTIVES: To evaluate the exposure to isothiazolinones contained in cleaning products on the market and from sensitized patients, and to verify the accuracy of labeling. METHODS: A total of 34 cleaning products were collected (17 supplied by sensitized patients and 17 bought randomly). Analysis was made of the concentrations of MI, MCI, BIT, and OIT using liquid chromatography tandem mass spectrometry (LC-MS/MS). RESULTS: MI and BIT were the components most frequently detected. Of all the products analyzed, 76.5% contained at least one isothiazolinone. Twelve products had an MI concentration above the permitted level for rinse-off cosmetics. Most of them were coming into direct contact with the skin in daily use. Mislabeling occurred in eight products. CONCLUSIONS: Some cleaning products with high concentrations of isothiazolinones may cause cutaneous symptoms in sensitized patients, especially in spray form. The labeling should be correct, also regarding the use of each article.

Ultrafast photodegradation of isoxazole and isothiazolinones by UV254 and UV254/H2O2 photolysis in a microcapillary reactor.

The photodegradation process of methylisothiazolinone (MIT), benzisothiazolinone (BIT), and isoxazole (ISOX) in ultrapure water and synthetic wastewater by means of UV254 photolysis and by UV254/H2O2 advanced oxidation process were investigated in a microcapillary photoreactor designed for ultrafast photochemical transformation of microcontaminants. For the first time, we estimated key photo-kinetic parameters, i.e. quantum yields (35.4 mmol·ein-1 for MIT, and 13.5 and 55.8 mmol·ein-1 for BIT at pH = 4-6 and 8, respectively) and rate constants of the reaction of photo-generated OH radicals with MIT and BIT (2.09·109 and 5.9·109 L mol-1·s-1 for MIT and BIT). The rate constants of the reaction of photo-generated OH radicals with ISOX in MilliQ water was also estimated (2.15·109 L mol-1·s-1) and it was in good agreement with literature indications obtained in different aqueous matrices. The models were extended and validated to the case of simultaneous degradation of mixtures of these compounds and using synthetic wastewater as an aqueous matrix. High resolution-accurate mass spectrometry analysis enabled identification of the main intermediates (BIT200, B200, saccharin, BIT166) and enabled proposal of a novel degradation pathway for BIT under UV254/H2O2 treatment. This study demonstrates an ultrafast method to determine key photo-kinetic parameters of contaminants of emerging concern in water and wastewater, which are needed for design and validation of photochemical water treatment processes of municipal and industrial wastewaters.