• 한국환경보건학회지
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• 제44권5호
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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.

• 한국환경보건학회지
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• 제43권4호
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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.

• Toxicological Research
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• 제35권2호
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• pp.103-117
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• 2019

The mixture of 5-chloro-2-methylisothiazol-3(2H)-one (CMIT) and 2-methylisothiazol-3(2H)-one (MIT), CMIT/MIT, is a preservative in cosmetics. CMIT/MIT is a highly effective preservative; however, it is also a commonly known skin sensitizer. Therefore, in the present study, a risk assessment for safety management of CMIT/MIT was conducted on products containing 0.0015% of CMIT/MIT, which is the maximum MIT level allowed in current products. The no observed adverse effect level (NOAEL) for CMIT/MIT was 2.8 mg/kg bw/day obtained from a two-generation reproductive toxicity test, and the skin sensitization toxicity standard value for CMIT/MIT, or the no expected sensitization induction level (NESIL), was $1.25{\mu}g/cm^2/day$ in humans. According to a calculation of body exposure to cosmetics use, the systemic exposure dosage (SED) was calculated as 0.00423 mg/kg bw/day when leave-on and rinse-off products were considered. Additionally, the consumer exposure level (CEL) amounted to $0.77512{\mu}g/cm^2/day$ for all representative cosmetics and $0.00584{\mu}g/cm^2/day$ for rinse-off products only. As a result, the non-cancer margin of safety (MOS) was calculated as 633, and CMIT/MIT was determined to be safe when all representative cosmetics were evaluated. In addition, the skin sensitization acceptable exposure level (AEL)/CEL was calculated as 0.00538 for all representative cosmetics and 2.14225 for rinse-off products; thus, CMIT/MIT was considered a skin sensitizer when all representative cosmetics were evaluated. Current regulations indicate that CMIT/MIT can only be used at concentrations 0.0015% or less and is prohibited from use in other cosmetics products. According to the results of this risk assessment, the CMIT/MIT regulatory values currently used in cosmetics are evaluated as appropriate.

• 한국환경보건학회지
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• 제46권3호
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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.

• 한국환경보건학회지
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• 제47권2호
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• pp.111-122
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• 2021

Objectives: There was a judgment of acquittal for the manufacturer SK Chemical and the vendor Aekyung regarding humidifier disinfectant (HD) containing 5-chloro-2-methylisothiazol-3(2H)-one/2-methylisothiazol-3(2H)-one (CMIT/MIT). The rationale used in this judgement is discussed here in the light of scientific consideration. Methods: The sentencing document for the judgements was obtained from the Korea Supreme Court Service. In particular, the judgements made by the court related to the risk of HD and external and internal exposure to CMIT/MIT are discussed based on scientific evidence. Results: Rendering a determination in a criminal trial of insufficient evidence of causation, the court dismissed the prosecution's motion that humidifier disinfectant-associated lung injuries (HDLI) and asthma were associated with the utilization of these products. However, CMIT/MIT, a strong sensitizing and corrosive substance, has been reported to be associated with brain toxicity, allergic contact dermatitis, and asthma. Furthermore, the judgment did not consider total consumption amounts or the cumulative dose of CMIT/MIT in the humidifier. Lastly, there are several cases supporting the fact that exposure to water-soluble substances including CMIT/MIT can cause lower respiratory tract diseases. In addition to cases of asthma among the workers exposed to CMIT/MIT, we identified lung injury victims who were exposed to HDs exclusively containing CMIT/MIT. Conclusions: We conclude that there is sufficient evidence supporting the assertion that HDs containing CMIT/MIT cause lung injuries, including asthma, contrary to the court's judgement.

• 한국환경보건학회지
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• 제49권3호
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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.

• 환경생물
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• 제38권2호
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• pp.271-277
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• 2020

가습기 살균제 성분(PHMG, PGH, CMIT/MIT)의 노출에 의한 다양한 장기에 대한 독성들에 대해서 피해사례는 계속 증가하고 있으나, 세포모델과 동물모델에서의 연구와 보고는 아직 부족한 실정이다. 심혈관 독성, 간 독성, 배아 독성에 대해서는 최근 알려져 있으나 뇌신경 독성과 피부 독성에 대해서는 상대적으로 적게 알려져 있다. 본 연구에서는 이들 세 가지 성분들의 피부 독성과 뇌신경 독성을 사람 피부섬유세포와 제브라피쉬 동물모델을 대상으로 각각 평가하였다. 사람피부섬유세포에 세 가지의 성분들을 0, 2, 4, 6, 8, 16 mg L^-1 (최종농도)로 처리하였을 때, 세포 생존율은 PHMG가 33%로 가장 낮았고, PGH가 49%, CMIT/MIT가 40%의 생존율을 보였다. 세포배양액 내의 산화물을 정량해본 결과, PHMG 처리된 세포가 28 nmol MDA로 가장 높았고, PGH가 13 nmol MDA, CMIT가 21 nmol MDA를 보였다. 제브라피쉬 사육수조에 PHMG, PGH, CMIT를 40 mg L^-1의 최종농도가 되도록 희석한 후, 제브라피쉬를 30분간 노출시킨 후 중뇌의 광시개영역(optic tectum)을 횡면 미세절단하여 산화물의 생성정도를 비교해본 결과, CMIT/MIT를 처리한 그룹에서 대조군 대비 17배 많은 산화물의 생성이 있었고, PGH를 처리한 그룹에서는 15배, PHMG를 처리한 그룹에서는 11배 많은 산화물이 관찰되어 심각한 뇌신경계 독성을 보여주었다. 결론적으로 세 가지 종류의 가습기 살균제 성분들에서 모두 심각한 피부세포 독성과 뇌신경계 독성이 나타났는데, 피부 독성은 특히 PHMG가, 뇌신경계 독성은 특히 CMIT/MIT가 가장 심각하였다. 이들 결과들은 가습기 살균제에 노출된 어린이들이 뇌신경계 독성을 통하여 언어장애, 운동장애, 발달장애 등을 겪게 될 수도 있음을 실험적으로 제시한다.

• 한국환경보건학회지
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• 제47권3호
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• pp.193-204
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• 2021

Objectives: In January 2021, the former heads of the manufacturer SK Chemical and the vendor Aekyung were acquitted for manufacturing and selling humidifier disinfectant (HD) containing 5-chloro-2-methylisothiazol-3(2H)-one/2-methylisothiazol-3(2H)-one (CMIT/MIT). In this article, we analyzed the rationale used in this judgement in the light of scientific consideration. Methods: The sentencing document for the judgements was obtained from the Korea Supreme Court Service. In particular, the judgements made by the court related to the toxicological and individual association with HD perspectives were discussed based on scientific evidence. Results: The ruling stated that the necessary conditions for causality between CMIT/MIT and such diseases were not met based on the fact that asthma and lung damage were not found in the inhalation exposure animal experiments. The judgment overlooked the inevitable limitations of using animal experiments for verifying health effects in humans, which are often inconsistent with the observations in animals. Among 11 governmentaffirmed lung injury cases with CMIT/MIT usage, three patients' humidifier disinfectant-associated lung injury (HDLI) pathology proved that CMIT/MIT could cause lung injury similar to that caused by PHMG and PGH. In addition, five children showed decreased lung function related to damage caused by humidifier disinfectant exposure. Conclusions: We conclude that there is sufficient evidence supporting the assertion that HDs containing CMIT/MIT cause lung injuries, including asthma, contrary to the court's decision.

• Toxicological Research
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• 제34권4호
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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.

• 한국환경보건학회지
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• 제48권1호
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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.