Methylisothiazolinone
Encyclopedia
Methylisothiazolinone or MIT, sometimes erroneously called methylisothiazoline, is a powerful biocide
and preservative
within the group of isothiazolinone
s, used amongst others in shampoo
s and body care products.
Non-occupational exposure to isothiazolinones by the general population also occurs, albeit at much lower concentrations. These compounds can be detected in air-conditioned indoor air and are present in a very large number of commonly used cosmetics. “Leave-on” cosmetics (hand-creams, lotions, etc.) contain 15 parts per million (100 micromolar) of combined CMIT/MIT. Kathon has also been used to control slime in the manufacture of paper products that contact food. In addition, this product serves as an antimicrobial agent in latex adhesives and in paper coatings that also contact food. The long-term consequences of low-level chronic exposure to isothiazolinones on the central nervous system have not been thoroughly investigated.
study of the neurotoxicity
of MIT in the department of Neurobiology at the University of Pittsburgh
. In that study, it was shown that a short exposure (10 min) to concentrations of MIT of 30-100 micromolar (or 4-12 parts per million) were lethal to mature neurons in tissue culture, but not to other brain cells, such as astrocytes (support cells). The lethal actions of MIT were due to its ability to liberate the metal zinc from intracellular metal-binding sites. The liberated zinc, in turn, triggered a cell death cascade in neurons that was characterized by the sequential activation extracellular signal-regulated kinase (ERK) and NADPH oxidase. This activity led to production of reactive oxygen species (free radicals), DNA damage and the overactivation of the DNA repair enzyme poly(ADP-ribose)polymerase, or PARP. Overactivation of PARP has been linked by many investigators to cell death due to its consumption of reduced equivalents and depletion of cellular energy sources (ATP). Additional studies from the same laboratory have observed that CMIT may be significantly (30-100 times) more potent than the MIT observations. All these studies were performed on rat brain cells in culture.
The CFTA (Cosmetic, Toiletry, and Fragrance Association) issued a response statement asserting that MIT is safe in cosmetic formulas. The CFTA response is as follows: "The abstract on Methylisothiazolinone (MI), presented at the Cell Biology 2004 meeting of the American Society for Cell Biology (ASCB) lacks a credible scientific basis in suggesting that MI could be a safety issue for consumers using personal care products. In determining the safety of any ingredient, a major factor is exposure. Cosmetic exposure is so much lower than what is presented in this abstract as to make the study meaningless for safety evaluation purposes regarding cosmetic products. The experiments conducted with MI on extracted rat nerve cells in laboratory containers do not remotely resemble the possible consumer exposure to this preservative. Reports have suggested that safety testing with animals has demonstrated that application of MI does not result in systemic toxicity to the preservative. Clinical and functional effects on the nervous system have reportedly not been observed in relevant safety tests."
The results from the abstract presented at the ASCB meeting were later published in a peer-reviewed scientific journal.
The CFTA response continues: "MI is a preservative that has been specifically approved for use as a biocide by the US Environmental Protection Agency (EPA), by Japan, and by the European Commission for use in cosmetics. It is used at very low levels, parts per million (one part per million = one drop in a 55 gallon drum) in cosmetic products, including shampoos and other products. MI was reviewed by the Cosmetic Ingredient Review (CIR)* in 1992 as a component of a preservative mixture with methylchloroisothiazolinone (MCI) and found safe for use in cosmetics. Cosmetics are regulated under the Food, Drug and Cosmetic Act, which is enforced by the U.S. Food and Drug Administration (FDA). The Food and Drug Administration (FDA) has abundant legal authority to regulate the safety of cosmetic products."
A report released by the European Scientific Committee on Cosmetic Products and Non-Food Products Intended for Consumers (SCCNFP) in 2003 concluded that insufficient information was available to allow for an adequate risk assessment analysis of MIT. In 2004, after receiving additional studies, committee said "The SCCNFP is of the opinion that the proposed use of Methylisothiazolinone as a preservative at a maximum concentration of 0.01% (100 ppm) in the finished cosmetic product does not pose a risk to the health of the consumer."
Typically, methylisothiazolinone is used in products in conjunction with methylchloroisothiazolinone, a mixture sold under the registered trade name Kathon CG. A common indication of an allergic reaction to Kathon CG is dermatitis
on the hands and wrists. These symptoms will disappear several weeks after exposure is ceased. A common point of exposure in household items is shampoos and soaps.
chain (a process called tyrosine phosphorylation). MIT inhibits the tyrosine phosphorylation of FAK by another kinase called Src, preventing the growth of axons and dendrites, at least in culture. These findings were published in the Journal of Pharmacology and Experimental Therapeutics. The toxic actions of MIT on developing neurons occurs at much lower concentrations than those inducing lethal injury (1-3 micromolar). CMIT is even more potent, working at concentrations as low as 0.1 micromolar. One micromolar is approximately 0.115 parts per million.
Biocide
A biocide is a chemical substance or microorganism which can deter, render harmless, or exert a controlling effect on any harmful organism by chemical or biological means. Biocides are commonly used in medicine, agriculture, forestry, and industry...
and preservative
Preservative
A preservative is a naturally occurring or synthetically produced substance that is added to products such as foods, pharmaceuticals, paints, biological samples, wood, etc. to prevent decomposition by microbial growth or by undesirable chemical changes....
within the group of isothiazolinone
Isothiazolinone
Isothiazolinone is a heterocyclic chemical compound. Derivatives of isothiazolinone are used as biocides, including:* Methylisothiazolinone * Chloromethylisothiazolinone * Benzisothiazolinone * Octylisothiazolinone...
s, used amongst others in shampoo
Shampoo
Shampoo is a hair care product used for the removal of oils, dirt, skin particles, dandruff, environmental pollutants and other contaminant particles that gradually build up in hair...
s and body care products.
Applications
Methylisothiazolinone and other isothiazolinone-derived biocides are utilized for controlling microbial growth in water-containing solutions. Two of the most widely used isothiazolinone biocides are 5-chloro-2-methyl-4-isothiazolin-3-one (chloromethylisothiazolinone or CMIT) and 2-methyl-4-isothiazolin-3-one (methylisothiazolinone or MIT), which are the active ingredients in a 3:1 mixture (CMIT:MIT) sold commercially as Kathon. Biocidal applications range from industrial water storage tanks to cooling units, in processes as varied as mining, paper manufacturing, and energy production. In addition, one isothiazolinone, Sea-Nine 211 (4,5-dichloro-2-n-octyl-4-isothiazolino-3-one, DCOI), has quickly replaced tributyltin as the antifouling agent of choice in ship hull paint. A recent study reported the presence of DCOI in both port water and sediment samples in Osaka, Japan, especially in weakly circulating mooring areas. Of environmental concern, DCOI levels predicted in marinas are now considered a threat to various marine invertebrate species. Isothiazolinones are also extremely toxic to fish. The widespread use of isothiazolinones in industrial settings has resulted in a very large number of reported cases of human occupational exposure, sometimes reaching epidemic proportions. This occurs primarily, but not exclusively, when workers are exposed to stock solutions during the dilution process, usually resulting in caustic burns, contact dermatitis, and allergic sensitization. Kathon is supplied to manufactures as a concentrated stock solution containing 1.5% of CMIT/MIT (equal to 15 g/l, 100 millimolar, or 15 part per thousand). Inhalation exposure is also very common.Non-occupational exposure to isothiazolinones by the general population also occurs, albeit at much lower concentrations. These compounds can be detected in air-conditioned indoor air and are present in a very large number of commonly used cosmetics. “Leave-on” cosmetics (hand-creams, lotions, etc.) contain 15 parts per million (100 micromolar) of combined CMIT/MIT. Kathon has also been used to control slime in the manufacture of paper products that contact food. In addition, this product serves as an antimicrobial agent in latex adhesives and in paper coatings that also contact food. The long-term consequences of low-level chronic exposure to isothiazolinones on the central nervous system have not been thoroughly investigated.
Human health
Some studies have shown MIT to be allergenic and cytotoxic, and this has led to some concern over its use. In 2002, there was an in vitroIn vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
study of the neurotoxicity
Neurotoxicity
Neurotoxicity occurs when the exposure to natural or artificial toxic substances, which are called neurotoxins, alters the normal activity of the nervous system in such a way as to cause damage to nervous tissue. This can eventually disrupt or even kill neurons, key cells that transmit and process...
of MIT in the department of Neurobiology at the University of Pittsburgh
University of Pittsburgh
The University of Pittsburgh, commonly referred to as Pitt, is a state-related research university located in Pittsburgh, Pennsylvania, United States. Founded as Pittsburgh Academy in 1787 on what was then the American frontier, Pitt is one of the oldest continuously chartered institutions of...
. In that study, it was shown that a short exposure (10 min) to concentrations of MIT of 30-100 micromolar (or 4-12 parts per million) were lethal to mature neurons in tissue culture, but not to other brain cells, such as astrocytes (support cells). The lethal actions of MIT were due to its ability to liberate the metal zinc from intracellular metal-binding sites. The liberated zinc, in turn, triggered a cell death cascade in neurons that was characterized by the sequential activation extracellular signal-regulated kinase (ERK) and NADPH oxidase. This activity led to production of reactive oxygen species (free radicals), DNA damage and the overactivation of the DNA repair enzyme poly(ADP-ribose)polymerase, or PARP. Overactivation of PARP has been linked by many investigators to cell death due to its consumption of reduced equivalents and depletion of cellular energy sources (ATP). Additional studies from the same laboratory have observed that CMIT may be significantly (30-100 times) more potent than the MIT observations. All these studies were performed on rat brain cells in culture.
The CFTA (Cosmetic, Toiletry, and Fragrance Association) issued a response statement asserting that MIT is safe in cosmetic formulas. The CFTA response is as follows: "The abstract on Methylisothiazolinone (MI), presented at the Cell Biology 2004 meeting of the American Society for Cell Biology (ASCB) lacks a credible scientific basis in suggesting that MI could be a safety issue for consumers using personal care products. In determining the safety of any ingredient, a major factor is exposure. Cosmetic exposure is so much lower than what is presented in this abstract as to make the study meaningless for safety evaluation purposes regarding cosmetic products. The experiments conducted with MI on extracted rat nerve cells in laboratory containers do not remotely resemble the possible consumer exposure to this preservative. Reports have suggested that safety testing with animals has demonstrated that application of MI does not result in systemic toxicity to the preservative. Clinical and functional effects on the nervous system have reportedly not been observed in relevant safety tests."
The results from the abstract presented at the ASCB meeting were later published in a peer-reviewed scientific journal.
The CFTA response continues: "MI is a preservative that has been specifically approved for use as a biocide by the US Environmental Protection Agency (EPA), by Japan, and by the European Commission for use in cosmetics. It is used at very low levels, parts per million (one part per million = one drop in a 55 gallon drum) in cosmetic products, including shampoos and other products. MI was reviewed by the Cosmetic Ingredient Review (CIR)* in 1992 as a component of a preservative mixture with methylchloroisothiazolinone (MCI) and found safe for use in cosmetics. Cosmetics are regulated under the Food, Drug and Cosmetic Act, which is enforced by the U.S. Food and Drug Administration (FDA). The Food and Drug Administration (FDA) has abundant legal authority to regulate the safety of cosmetic products."
A report released by the European Scientific Committee on Cosmetic Products and Non-Food Products Intended for Consumers (SCCNFP) in 2003 concluded that insufficient information was available to allow for an adequate risk assessment analysis of MIT. In 2004, after receiving additional studies, committee said "The SCCNFP is of the opinion that the proposed use of Methylisothiazolinone as a preservative at a maximum concentration of 0.01% (100 ppm) in the finished cosmetic product does not pose a risk to the health of the consumer."
Typically, methylisothiazolinone is used in products in conjunction with methylchloroisothiazolinone, a mixture sold under the registered trade name Kathon CG. A common indication of an allergic reaction to Kathon CG is dermatitis
Dermatitis
-Etymology:Dermatitis derives from Greek derma "skin" + -itis "inflammation" and genetic disorder.-Terminology:There are several different types of dermatitis. The different kinds usually have in common an allergic reaction to specific allergens. The term may describe eczema, which is also called...
on the hands and wrists. These symptoms will disappear several weeks after exposure is ceased. A common point of exposure in household items is shampoos and soaps.
Physiopathological effects of MIT on developing neurons
MIT and its closely related analog, chloromethylisothiazolinone or CMIT, affect the ability of young or developing neurons to grow processes (axons and dendrites) in tissue culture. The specific protein affected by MIT is called focal adhesion kinase, or FAK. Normal FAK function is required for the growth of axons and dendrites. FAK has to be modified by a process called phosphorylation to perform its function, so phosphates are added to FAK’s amino acidAmino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
chain (a process called tyrosine phosphorylation). MIT inhibits the tyrosine phosphorylation of FAK by another kinase called Src, preventing the growth of axons and dendrites, at least in culture. These findings were published in the Journal of Pharmacology and Experimental Therapeutics. The toxic actions of MIT on developing neurons occurs at much lower concentrations than those inducing lethal injury (1-3 micromolar). CMIT is even more potent, working at concentrations as low as 0.1 micromolar. One micromolar is approximately 0.115 parts per million.