• Toxicological Research
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• v.34 no.4
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• pp.355-361
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• 2018

Methylisothiazolinone (MIT) has been used in combination with methylchloroisothiazolinone (CMIT) for cosmetic products such as shampoo, body lotion, and skin care products. The mixture of CMIT/MIT has been found to cause allergic contact dermatitis and is thus no longer permitted for use as a preservative in leave-on cosmetics. However, MIT itself was approved as a stand-alone preservative at a maximum concentration of 100 ppm as the toxicity was derived from CMIT rather than MIT. However, in many countries, allergic skin irritation caused by MIT remains a social concern. In this study, skin irritation was assessed for the presence of MIT, propylene glycol, and their mixture using a 3D human skin model $EpiDerm^{TM}$. Although non-diluted MIT causes serious skin toxicity, skin irritation was not observed at a concentration of 100 ppm, the maximum permissible level for cosmetics and personal care products according to European regulations. Propylene glycol, the most widely used vehicle for MIT, did not cause skin irritation in the 3D skin model. The results are expected to provide information for regulatory policies and guidelines on the use of biocides in consumer products.

• Journal of Environmental Health Sciences
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• v.46 no.3
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• pp.312-323
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• 2020

Objective: This study aimed to summarize the physiochemical properties, toxicity, and legal regulation of chloromethylisothiazolinone (CMIT) and/or methylisothiazolinone (MIT), review the health effects caused by exposure to CMIT/MIT, and evaluate the individual association of lung injury with the use of humidifier disinfectants (HD) containing a mixture of CMIT and MIT. Method: A literature review was conducted by searching keywords such as CMIT, MIT, health effect, dermatitis, asthma, and lung injury, either singly or combined. Results: Both CMIT and/or MIT were found to be associated with the development of several types of adverse health effects. In particular, respiratory diseases including asthma, nasal symptoms, cough, and rhinitis were caused by the use of products including CMIT or/and MIT. The mixture of CMIT/MIT has been banned in cosmetics. As of the end of 2017, nine patients who were confirmed to have HD associated lung injury (HDLI) were found to have used only an HD brand containing CMIT and MIT. Their responses regarding the name of the HD used could be trustworthy based on the short duration of HD use (less than six months) before the onset of HDLI and frequent use of HD per day. Conclusion: According to the toxicity and HDLI cases, the use of HD containing CMIT and /or MIT can cause fatal lung injury. Further study with manufacturers' assistance is necessary in order to obtain more clear evidence on the causal relationship since HDLI cases are being reported continuously.

• Analytical Science and Technology
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• v.33 no.3
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• pp.125-133
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• 2020

Methylisothiazolinone (MIT) and chloromethylisothiazolinone (CMIT) cause allergic contact dermatitis and are banned cosmetics ingredients, except in rinse-off products. However, their presence has been detected in cosmetics. We report a UPLC-tandem MS/MS screening method for their simultaneous determination in cosmetics. To facilitate extraction from various matrices, pretreatment methods were developed for each sample type. The method was optimized through a series of assessments, including specificity, LOD, LOQ, linearity, recovery, stability, precision, and accuracy. The LODs and LOQs for MIT ranged from 0.054 and 0.163 ㎍ mL^-1 whereas those for CMIT ranged from 0.040 and 0.119 ㎍ mL^-1. The linear correlation coefficients (r²) were higher than 0.999. Relative standard deviations (RSDs) for both intra- and inter-day measurements ranged from 0.3 ~ 13.6 %. Recoveries at three different concentrations were within 87.9 ~ 118.9 %. The RSD for stability measurements of spiked samples was within 7 %. These results confirm the suitability of the developed method for the simultaneous quantitation of MIT and CMIT in cosmetics. Samples of 320 color cosmetics, including eyeshadows, solid lipsticks, liquid lipsticks, and nail polishes were analyzed using the developed method, and two of them were found to contain both MIT and CMIT and one of them was found to contain only MIT. This data and the method will aid the regulation of ingredients used in cosmetics.

• Journal of Environmental Health Sciences
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• v.44 no.5
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• pp.468-479
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• 2018

Objectives: Recently, a report was published that the humidifier disinfectant CMIT/MIT did not cause developmental toxicity and was not detected in systemic circulation as a result of an inhalation toxicity test. Therefore, this study was carried out to investigate any associations between CMIT/MIT exposure and developmental toxicity using the in vivo apical toxicity test method. Methods: Groups of pregnant ICR mice were instilled in the trachea with chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT) using a visual instillobot over a period of seven days from days 11 to 17 days post-coitum. For the in vivo apical toxicity test method, an $LD_{50}$-based dose-range finding model was applied to decide the dose range for inducing developmental toxicity. Results: Among the groups of 0, 0.1, 0.5, 1.0, and 1.5 mg ai/kg/day CMIT/MIT, the exposure groups of 0.5 mg and 1.0 ai/kg/day CMIT/MIT were estimated to reflect the thresholds for the stillbirth and death of pregnant mice, respectively. The groups of 0.5, 1.0, and 1.5 mg ai/kg/day CMIT/MIT induced stillbirth rates of 2.57, 10, and 53.8%, respectively. Another exposure group of 0.75 mg ai/kg/day CMIT/MIT did not induce any deaths of pregnant mice and resulted in a stillbirth rate of 8% in only one of six pregnant mice. Conclusions: CMIT/MIT can induce stillbirth in pregnant mice. It was also concluded that CMIT/MIT moves through the pulmonary circulation system and then continues on through systemic circulation and the placenta. There is a possibility of stillbirth and other health causalities in humans beyond the lungs caused by CMIT/MIT exposure.

• Journal of Environmental Health Sciences
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• v.43 no.4
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• pp.247-256
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• 2017

Objectives: The deaths of Korean victims exposed to the disinfectant CMIT/MIT have remained unresolved. This is mainly due to a lack of concordance between the few available toxicity tests and the abundant epidemiological data, making it difficult to establish a cause-and-effect relationship. Therefore, this study was carried out to investigate any potential associations between CMIT/MIT exposure and death. Methods: Groups of experimental and control C57BL/6 mice were instilled (in the trachea) with chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT) using a visual instillobot. CMIT/MIT was instilled over a period of three days and eight weeks, respectively, to achieve acute and chronic exposures. A threshold dose-response model was applied for estimating the threshold level as one line of evidence for a causal association between CMIT/MIT and death. Results: An acute exposure of 1.2 mg ai/kg/day of CMIT/MIT was estimated to reflect the threshold for death. The dose-response curve with this threshold showed a very steep slope and a narrow range of CMIT/MIT exposures. The narrow range of CMIT/MIT exposures, in particular, indicated an evident boundary between survival and death, thus implicating a strong causal association. A similar threshold dose-response relationship observed following acute exposure was also seen following chronic exposure to CMIT/MIT. Airborne disinfectant exposure was visible as minimal or mild lung damage with no fibrosis, as shown by histopathological tests. However, many observations are considered to be functional respiratory tract or lung failure due to death, as observed in necropsies of the mice that died due to CMIT/MIT exposures. Conclusions: There are two strong lines of evidence for a causal association between death and CMIT/MIT exposure: 1) The threshold dose-response curve, with a very steep slope and a narrow range of CMIT/MIT exposures showing a visible boundary between survival and death; and 2) many cases of functional respiratory or lung failure.

• Journal of Environmental Health Sciences
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• v.49 no.3
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• pp.169-177
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• 2023

Background: The Korea Centers for Disease Control and Prevention (KCDC) has identified cases of people suspected of suffering lung disease potentially caused by chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT) used in humidifier disinfectants (HDs). The Korean Ministry of Environment (MoE) epidemiological investigation and toxicity test study found that HDs caused health damage such as asthma and lung disease. Objectives: The main purposes of this study were to classify the HD exposure rating and to analyze the exposure characteristics that affect exposure to CMIT/MIT HDs. Methods: The exposure characteristics and socio-demographic characteristics of victim participants using CMIT/MIT HDs were investigated through questionnaires. An inhalation no observed adverse effect level (NOAEL) for CMIT/MIT was produced based on inhalation toxicity values. Exposure ratings (class 1~class 2) were cross-tabulated with clinical ratings (acceptable~unacceptable). A correlation analysis was conducted with the main exposure characteristics that affect the exposure concentration of CMIT/MIT HDs. Results: The concentration in indoor air of CMIT/MIT was 8.75±25.40 ㎍/m³, and the exposure concentration was 2.30±6.29 ㎍/m³. The CMIT/MIT exposure rating of 67 participants with high exposures of not more than MOE 100 were evaluated as 14.5%, while the damage participants who matched the clinical rating made up 4.5%. The exposure concentration of CMIT/MIT showed a positive correlation with the daily usage amount and usage frequency, and a negative correlation with volume of the indoor environment. Conclusions: A new exposure rating could be suggested and calculated based on the MOE, and the factors affecting the exposure concentration could be identified.

• Journal of Environmental Health Sciences
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• v.48 no.1
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• pp.36-43
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• 2022

Background: Preservatives are used to prevent product deterioration in modeling clay. Parabens, a representative preservative, have been found to be endocrine disruptors and cause skin irritation and allergic reactions. Isothiazolinone preservatives can be irritating to the skin, respiratory tract, and eyes. Thorough investigation and regulation of clay are necessary because clay is marketed to children, who are more sensitive to the toxic effect of chemicals. Objectives: In this study, the presence of 16 preservatives was analyzed in modeling clay and the results were compared with current standards. Methods: A total of 200 samples were collected from 28 children's clay products sold in South Korea (13 from Korea and 15 imported from overseas). Twelve preservatives, such as parabens, were analyzed using high-performance liquid chromatography (HPLC). Isothiazolinone preservatives (chloromethylisothiazolinone; CMIT, methylisothiazolinone; MIT, octylisothiazolinone; OIT, and benzisothiazolinone; BIT) were analyzed using ultra performance liquid chromatography-tandem mass spectrometery (UPLC-MS/MS). Results: Dehydroacetic acid (DHA) was detected the most in the clays at 51.50% (103 cases) detection; 38 cases (median 190.42 ㎍/g) in Korean products and 65 cases (median 169.62 ㎍/g) in Chinese products. CMIT, which is prohibited in Korea, was detected in 14 (median 16.28 ㎍/g) Chinese products. OIT, which has a chemical structure similar to CMIT was found in 28 (median 68.38 ㎍/g) samples in Korean products. Conclusions: The use of CMIT and MIT in children's products is prohibited in Korea and the European Union (EU). The detection of CMIT in Chinese clay products suggests that management is necessary for imported products. It is necessary to review the safety and regulatory status for OIT because OIT was used as a substitute for CMIT and MIT in Korean products.

• Korean Journal of Environmental Biology
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• v.38 no.2
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• pp.271-277
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• 2020

Toxicities to many organs caused by humidifier disinfectants have been reported. Recently, humidifier disinfectants have been reported to cause cardiovascular, embryonic, and hepatic toxicities. This study was designed to investigate the toxic mechanism of humidifier disinfectants and compare toxicity in a cellular model and a zebrafish animal model. Because brain toxicity and skin toxicity have been less studied than other organs, we evaluated toxicity in a human dermal cell line and zebrafish under various concentrations of humidifier disinfectants that included polyhexamethyleneguanidine phosphate (PHMG), oligo-[2-(2-ethoxy)-ethoxyethyl-guanidinium-chloride] (PGH) and methylchloroisothiazolinone/methylisothiazolinone (CMIT/MIT). A human dermal fibroblast cell line was treated with disinfectants (0, 2, 4, 6, 8, and 16 mg L^-1) to compare their cytotoxicity. The fewest PHMG-treated cells survived (up to 33%), while 49% and 40% of the PGH- and CMIT/MIT-treated cells, respectively, survived. The quantification of oxidized species in the media revealed that the PHMG-treated cells had the highest MDA content of around 28 nM, while the PGH- and CMIT/MIT-treated cells had 13 and 21 nM MDA, respectively. As for brain toxicity, treatment of the zebrafish tank water with CMIT/MIT (final 40 mg L^-1) for 30 min resulted in a 17-fold higher production of reactive oxygen species (ROS) than in the control. Treatment with PGH or PHMG (final 40 mg L^-1) resulted in 15- and 11-fold higher production, respectively. The humidifier disinfectants (PHMG, PGH, and CMIT/MIT) showed severe dermal cell toxicity and brain toxicity. These toxicities may be relevant factors in understanding why some children have language disorders, motor delays, and developmental delays from exposure to humidifier disinfectants.

• Journal of Environmental Health Sciences
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• v.46 no.5
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• pp.481-494
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• 2020

Objectives: No study has been conducted to review characteristics of humidifier disinfectants (HD) products, such as real numbers, levels and types of HD substances contained, or the volume marketed. We aimed to review the characteristics of HD through a literature review. Methods: We collected literature reporting the names, numbers, and ingredients of HD and discussed them with a focus on the number of HD products and the chemicals used as a disinfectant. Results: A total of eight publications has reported the names of HD brands or types of disinfectants from 2011 to 2020. To date, a total of 40 HD products have been used, excluding four products. Eight HD products used polyhexamethylene guanidine phosphate (PHMG) and 14 used a mixture of chloromethylisothiazolinone (CMIT) and methylisothiazolinone (MIT) as disinfectants. Benzalkonium chloride (BKC) and sodium dichloroisocyanurate (NaDCC) were also used as a disinfectant in several HD products. A total of 19 HD products were associated with the development of HD associated lung injury (HDLI). The Oxy Saksak HD product containing PHMG showed the highest number of HD associated health effects. The type of disinfectant from a total of 14 HD products has not been identified. Conclusions: A total of 40 HD products have been marketed in South Korea since 1994. Further studies should be conducted to identify the association of product characteristics, including type of HD ingredients, with health effects.

• Journal of Environmental Health Sciences
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• v.46 no.2
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• pp.128-135
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• 2020

Objective: The objectives of this study are to report the number of humidifier disinfectant (HD) associated health problems, including HD associated lung injury (HDLI), by year. This data was analyzed by the type of HD and HD brand. Methods: A total of 530 patients registered with the national program on HD through its third round were distributed based on the year when they developed their first health problem including HDLI (N=221). The distribution of health problems at diagnosis was clinically evaluated in order to examine the association between their lung injury and the use of HD. Results: The number of HD associated victims and HDLI patients was found to rise sharply from 2008 to 2011, with a peak in 2011. This trend was found not only for HD brands containing polyhexamethylene guanidine phosphate (PHMG), but also chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT). The number of patients who responded as developing health problems in the specific year was 35 for 2008, 51 for 2009, 108 for 2010 and 182 for 2011. Other types of HD brands and HD chemicals did not follow the trend of abrupt increase in HD associated patients since 2008. Conclusion: This study found the number of HD associated victims and HDLI patients who used HD brands containing PHMG sharply increased starting in 2008. A significant change in the process of manufacturing PHMG can be suspected with the abrupt rise in HD associated patients in specific years.