Methylisothiazolinone

Methylisothiazolinone or MIT, sometimes erroneously called methylisothiazoline, is a powerful biocide and preservative within the group of isothiazolinones, used in shampoos and body care products. Though long considered safe for use in cosmetics, two recent in vitro studies have shown that MIT is neurotoxic, causing damage to rat brain cells in tissue culture. Long-term health and safety studies have been conducted on animals, and thus far there is no published evidence of nerve damage or neurological effects associated with MIT for consumers or workers. None of the animal safety studies, however, are published in the primary scientific literature in peer-reviewed journals. Regulatory authorities in the USA, Japan and Europe and more than 25 other countries have all independently concluded the product is safe. Despite these claims, the studies published in scientific journals suggest that additional testing may be needed. Initially, a similar conclusion was reached by the European Scientific Committee on Cosmetic Products and Non-Food Products Intended for Consumers in 2003 (link below). However, in 2004, after receiving additional studies, the European Scientific Committee on Cosmetic Products and Non-Food Products Intended for Consumers concluded "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."^[1]

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Applications

Methylisothiazolinone and other isothiazolinone-derived biocides are utilized for controlling microbial growth in water-containing solutions. ^[2] 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. ^[3] Of environmental concern, DCOI levels predicted in marinas are now considered a threat to various marine invertebrate species. ^[4] Isothiazolinones are also extremely toxic to fish (Rohm and Haas, Toxicology Department, “Evaluation of the toxicity of Kathon biocide,” August, 1984). 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. ^[5] 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. ^[6] Kathon is supplied to manufactures as a concentrated stock solution containing 1.5% of CMIT/MIT (equal to 15 g/l, 100 milimolar, or 15 part per thousand). Inhalation exposure is also very common (EPA).^[7])

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^[8] and are present in a very large number of commonly used cosmetics.^[9] “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.^[10] 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.^[11][12] In early December, 2004, a news broadcast from WNYT in Albany, NY reported that methylisothiazolinone had been linked to nerve cell death in scientific studies. In 2002, there was an in vitro study of the neurotoxicity of MIT in the department of Neurobiology at the University of Pittsburgh.^[13] 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 that MIT. 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."

It is noteworthy, however, that 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 and are summarized later on this article ^[14].

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."

It must also be mentioned, however, that 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.

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 recently published in the Journal of Pharmacology and Experimental Therapeutics.^[15] 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

1. ^ European Scientific Committee on Cosmetic Products and Non-Food Products Intended for Consumers (SCCNFP)
2. ^ Collier PJ. Ramsey A. Waigh RD. Douglas KT. Austin P. Gilbert P. Chemical reactivity of some isothiazolone biocides. Journal of Applied Bacteriology. 69:578-584, 1990.
3. ^ Harino H. Mori Y. Yamaguchi Y. Shibata K. Senda T. Monitoring of antifouling booster biocides in water and sediment from the port of Osaka, Japan. Arch Environ Cont Toxicol. 48(3):303-10, 2005
4. ^ Bellas J. Comparative toxicity of alternative antifouling biocides on embryos and larvae of marine invertebrates. Sci Total Environ. Epub. 2006
5. ^ Podmore P. An epidemic of isothiazolinone sensitization in a flax spinning mill. Contact Dermatitis. 38(3):165-6, 1998
6. ^ 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
7. ^ Environmental Protection Agency (1998). R.E.D. Facts, Methylisothiazolinone. Publication EPA-738-F-98-008
8. ^ Nagorka R. Rosskamp E. Seidel K. [Evaluation of humidifier units within the scope of room climate modification]. [German] Offentliche Gesundheitswesen. 52:168-73, 1990
9. ^ Rastogi SC. Kathon CG and cosmetic products. Contact Dermatitis. 22:155-60, 1990
10. ^ Cosmetic Ingredient Review. Final Report on the Safety Assessment of Methylisothiazolinone and Methylchloroisothiazolinone. J. American Col. Toxicol. 11(1):75-128, 1992
11. ^ 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).
12. ^ 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).
13. ^ Shen Du, BethAnn McLaughlin, Sumon Pal, Elias Aizenman (2002): 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 of Neuroscience 22:7408-7416; 2002.
14. ^ K. He, J. Huang, C. F. Lagenaur, E. Aizenman: "Methylisothiazolinone, a neurotoxic biocide, disrupts the association of Src family tyrosine kinases with focal adhesion kinase in developing cortical neurons", J. Pharmacol. Exp. Therap. 317:1320-1329; 2006
15. ^ K. He, J. Huang, C. F. Lagenaur, E. Aizenman: "Methylisothiazolinone, a neurotoxic biocide, disrupts the association of Src family tyrosine kinases with focal adhesion kinase in developing cortical neurons", J. Pharmacol. Exp. Therap. 317:1320-1329; 2006