Methylisothiazolinone: Difference between revisions

| verifiedrevid = 444012977

| ImageSize = 120px

| IUPACName = 2-Methylisothiazol-3(2''H'')-one

| OtherNames = 2-Methyl-4-isothiazolin-3-one

| Section1 = {{Chembox Identifiers

| Abbreviations = MIT

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| Section2 = {{Chembox Properties

| C=4|H=5|N=1|O=1|S=1

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| SPhrases = {{(S2)}} {{S26}} {{S28}} {{S36/37/39}} {{S45}} {{S60}} {{S61}}

| RSPhrases = {{R23/24/25}} {{R34}} {{R43}} {{R50/53}}

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'''Methylisothiazolinone''' or '''MIT''', sometimes erroneously called methylisothiazo''line'', is a powerful [[biocide]] and [[preservative]] within the group of [[isothiazolinone]]s, used amongst others in [[shampoo]]s and body care products.

==Applications==

Methylisothiazolinone and other isothiazolinone-derived biocides are utilized for controlling microbial growth in water-containing solutions.<ref>{{cite journal | author = Collier PJ. Ramsey A. Waigh RD. Douglas KT. Austin P. Gilbert P. | title = Chemical reactivity of some isothiazolone biocides | journal = Journal of Applied Bacteriology | volume = 69 | pages = 578–584 | year = 1990 | pmid = 2292521 | issue = 4}}</ref> 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.<ref>{{cite journal | author = Harino H. Mori Y. Yamaguchi Y. Shibata K. Senda T. | title = Monitoring of antifouling booster biocides in water and sediment from the port of Osaka, Japan | journal = Arch Environ Cont Toxicol | volume = 48 | issue = 3 | pages = 303–310 | year = 2005 | doi = 10.1007/s00244-004-0084-2 | pmid = 15750770}}</ref> Of environmental concern, DCOI levels predicted in marinas are now considered a threat to various [[marine invertebrate]] species.<ref>{{cite journal | author = Bellas J. | title = Comparative toxicity of alternative antifouling biocides on embryos and larvae of marine invertebrates | journal = Sci Total Environ | year = 2006}}</ref> Isothiazolinones are also extremely toxic to fish.<ref>Rohm and Haas, Toxicology Department, “Evaluation of the toxicity of Kathon biocide,” August, 1984</ref> 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.<ref>{{cite journal | author = Podmore P. | title = An epidemic of isothiazolinone sensitization in a flax spinning mill | journal = Contact Dermatitis | volume = 38 | issue = 3 | pages = 165–1666|year = 1998 | doi = 10.1111/j.1600-0536.1998.tb05687.x | pmid=9536412}}</ref> 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. <ref>Isaksson M. Gruvberger B. Bruze M. Occupational contact allergy and dermatitis from methylisothiazolinone after contact with wall covering glue and after a chemical burn from a biocide. Dermatitis. 15(4):201-5, 2004</ref> 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.<ref>Environmental Protection Agency (1998). R.E.D. Facts, Methylisothiazolinone. Publication EPA-738-F-98-008</ref>

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<ref>Nagorka R. Rosskamp E. Seidel K. [Evaluation of humidifier units within the scope of room climate modification]. [German] Offentliche Gesundheitswesen. 52:168-73, 1990</ref> and are present in a very large number of commonly used cosmetics.<ref>Rastogi SC. Kathon CG and cosmetic products. Contact Dermatitis. 22:155-60, 1990</ref> “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.<ref>Cosmetic Ingredient Review. Final Report on the Safety Assessment of Methylisothiazolinone and Methylchloroisothiazolinone. J. American Col. Toxicol. 11(1):75-128, 1992</ref> 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.<ref>A. Schnuch, J. Geier, W. Utur, P. J. Frosch: "Patch testing with preservatives, antimicrobials and industrial biocides. Results from a multicentre study", ''British Journal of Dermatology'', 137(3), 467-476 (1998).</ref><ref>A. C. De Groot, A. Herxheimer: "Isothiazolinone Preservative: Cause Of A Continuing Epidemic Of Cosmetic Dermatitis", ''[[The Lancet]]'', Volume 333, Issue 8633, Pages 314-316 (1989).</ref> In 2002, there was an [[in vitro]] study of the [[neurotoxicity]] of MIT in the department of [[Neurobiology]] at the [[University of Pittsburgh]].<ref name="Du">{{cite journal | author = Shen Du, BethAnn McLaughlin, Sumon Pal, Elias Aizenman | year = 2002| url = http://www.jneurosci.org/cgi/content/abstract/22/17/7408 | title = ''In vitro'' neurotoxicity of methylisothiazolinone, a commonly used industrial and household biocide, proceeds via a zinc and extracellular signal-regulated kinase mitogen-activated protein kinase-dependent pathway | journal = Journal of Neuroscience | volume = 22 | pages = 7408–7416 | pmid = 12196562 | issue = 17}}</ref> 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. A CFTA (Cosmetic, Toiletry, and Fragrance Association) response statement has come out, strongly 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 of these safety tests have never been published in the peer-reviewed literature, nor are they easily available to the average consumer. Furthermore, the results from the abstract presented at the ASCB meeting were later published in a peer-reviewed scientific journal.<ref name="He">{{cite journal | author = K. He, J. Huang, C. F. Lagenaur, E. Aizenman | year = 2006 | url = http://jpet.aspetjournals.org/cgi/content/abstract/317/3/1320 | title = Methylisothiazolinone, a neurotoxic biocide, disrupts the association of Src family tyrosine kinases with focal adhesion kinase in developing cortical neurons | journal = J. Pharmacol. Exp. Therap. | volume = 317 | pages = 1320–1329 | doi = 10.1124/jpet.106.103044 | pmid = 16547166 | issue = 3}}</ref>

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 was of the opinion that insufficient information was available to allow for an adequate risk assessment analysis of MIT (see link below). Clearly additional studies are warranted. 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."<ref name="SCCNFP">[http://ec.europa.eu/health/ph_risk/committees/sccp/documents/out270_en.pdf European Scientific Committee on Cosmetic Products and Non-Food Products Intended for Consumers (SCCNFP)]</ref> The caveats and limitations of this conclusion are listed earlier.

Typically, methylisothiazolinone is used in products in conjunction with methylchloroisothiazolinone, this mixture is sold under the registered trade name of Kathon CG. A common indication of an allergic reaction to Kathon CG is eczema-like symptoms 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==

The physiopathological effects of MIT and its closely related analog, [[chloromethylisothiazolinone]] or CMIT, reside in affecting the ability of young or developing neurons to grow processes (axons and dendrites) in tissue culture. The specific protein that is affected by MIT is called focal adhesion kinase, or FAK. Normal FAK function is required for the growth of axons and dendrites. But FAK has to be modified by a process called phosphorylation to perform its function, so [[phosphates]] are added to FAK’s [[amino acid]] 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.<ref name="He" /> 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.

==References==

<references/>

==External links==

* {{HPD|198}}

* [https://www.roche-applied-science.com/MSDS/us/1089161.pdf Material Safety Data Sheet for product containing 0.1-1% MIT]

* [http://ec.europa.eu/health/ph_risk/committees/sccp/documents/out_201.pdf European Scientific Committee on Cosmetic Products and Non-Food Products Intended for Consumers (SCCNFP)]

[[Category:Isothiazoles]]

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