Methylisothiazolinone

Methylisothiazolinone
Skeletal formula of methylisothiazolinone
Space-filling model of the methylisothiazolinone molecule
Names
IUPAC name
2-Methylisothiazol-3(2H)-one
Other names
2-Methyl-4-isothiazolin-3-one
Identifiers
2682-20-4 YesY
Abbreviations MIT
ChEBI CHEBI:53620 YesY
ChemSpider 36393 YesY
EC Number 220-239-6
Jmol 3D model Interactive image
PubChem 39800
UNII 229D0E1QFA YesY
Properties
C4H5NOS
Molar mass 115.1 g/mol
Hazards
S-phrases (S2) S26 S28 S36/37/39 S45 S60 S61
R/S statement R23/24/25 R34 R43 R50/53
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
YesY verify (what is YesYN ?)
Infobox references

Methylisothiazolinone, MIT, or MI, (sometimes erroneously called methylisothiazoline), is a powerful synthetic biocide and preservative within the group of isothiazolinones, which is used in numerous personal care products and a wide range of industrial applications.

It is a cytotoxin that may affect different types of cells. Its use for a wide range of personal products for humans, such as cosmetics, lotions, moisturizers, sanitary wipes, shampoos, and sunscreens, more than doubled during the first decade of the twenty-first century and is proving to be a concern because of sensitization and allergic reactions as well as cell and nerve damage.

Industrial manufacturing and distribution of the biocide has resulted in more severe health hazards to the humans involved in the handling of large concentrated quantities of the biocide.

Industrial applications also are quite wide ranging, from preservative and sanitizing uses to antimicrobial agents, energy production, metalworking fluids, mining, paint manufacturing, and paper manufacturing, many of which increase potential exposure to it by humans as well as organisms, both terrestrial and marine. Industrial applications in marine environments are proving to be toxic to marine life, for instance, when the effect of its now almost-universal use in boat hull paint was examined.[1]

Applications

Methylisothiazolinone and other isothiazolinone-derived biocides are used 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. Kathon is supplied to manufacturers as a concentrated stock solution containing from 10-15% of CMIT/MIT. For applications the recommended use level is from 6 ppm to 75 ppm active isothiazolones. Biocidal applications range from industrial water storage tanks to cooling units, in processes as varied as mining, paper manufacturing, metalworking fluids and energy production.

Kathon also has 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.[3]

Other isothiazolinones

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.[4] Of environmental concern, DCOI levels predicted in marinas now are considered a threat to various marine invertebrate species.[5] Isothiazolinones also are extremely toxic to fish.[1]

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.[6] This occurs primarily, but not exclusively, when workers are exposed to stock solutions during the dilution process, usually resulting in chemical burns, contact dermatitis, and allergic sensitization.[7] Inhalation exposure also is very common.[8]

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,[9] and are present in a very large number of commonly used cosmetics.[10] “Leave-on” cosmetics (hand-creams, lotions, etc.) contain 15 parts per million (100 micromolar) of combined CMIT/MIT.

The long-term consequences of low-level chronic exposure to isothiazolinones on the central nervous system have not been thoroughly investigated.

Human health

MIT is allergenic and cytotoxic, and this has led to some concern over its use.[11][12] 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 of extracellular signal-regulated kinase (ERK) and NADPH oxidase. This activity led to production of reactive oxygen species (free radicals), DNA damage, and the overactivization of the DNA repair enzyme poly (ADP-ribose) polymerase, or PARP. Overactivization 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 Cosmetic, Toiletry, and Fragrance Association issued a response statement asserting that MIT is safe in cosmetic formulas, and attacking the findings reported in an abstract presented at the 2004 meeting of the American Society for Cell Biology as lacking "a credible scientific basis".[14] The results described in the abstract were published later in a peer-reviewed scientific journal.[15] A report released by the European Scientific Committee on Cosmetic Products and Non-food Products Intended for Consumers (SCCNFP) in 2003 also concluded that insufficient information was available to allow for an adequate risk assessment analysis of MIT.[16]

Rising reports of consumer impact led to new research, including a study released in 2014 by the European Commission Scientific Committee on Consumer Safety which reported: "The dramatic rise in the rates of reported cases of contact allergy to MI, as detected by diagnostic patch tests, is unprecedented in Europe; there have been repeated warnings about the rise (Gonçalo M, Goossens A. 2013). The increase is primarily caused by increasing consumer exposure to MI from cosmetic products; exposures to MI in household products, paints and in the occupational setting also need to be considered. The delay in re-evaluation of the safety of MI in cosmetic products is of concern to the SCCS; it has adversely affected consumer safety."[17]

"It is unknown what proportion of the general population is now sensitized to MI and has not been confirmed as sensitized."[17]

Allergic contact dermatitis

Methylisothiazolinone is used commonly in products in conjunction with methylchloroisothiazolinone, a mixture sold under the registered trade name Kathon CG. A common indication of sensitivity to Kathon CG is allergic contact dermatitis. Sensitization to this family of preservatives was observed as early as the late 1980s.[18][19] Due to increased use of isothiazolinone-based preservatives in recent years, an increase in reported incidences of contact allergy to this product has been reported. In 2013 the substance was declared the 2013 Contact Allergen of the Year by the American Contact Dermatitis Society.[20] In 2016 the Dermatitis Academy launched a call to action for patients to report their isothiazolinone allergy to the FDA.[21]

On December 13, 2013 the trade group, Cosmetics Europe,[22] following discussions with the European Society of Contact Dermatitis (ESCD),[23] recommended to its members "that the use of Methylisothiazolinone (MIT) in leave-on skin products including cosmetic wet wipes is discontinued. This action is recommended in the interests of consumer safety in relation to adverse skin reactions. It is recommended that companies do not wait for regulatory intervention under the Cosmetics Regulation but implement this recommendation as soon as feasible."[24]

On March 27, 2014, the European Commission’s Scientific Committee on Consumer Safety issued an opinion on the safety of Methylisothiazolinone. This report only considered the issue of contact sensitization. The committee concluded:

“Current clinical data indicate that 100 ppm MI in cosmetic products is not safe for the consumer.

"For leave-on cosmetic products (including ‘wet wipes’), no safe concentrations of MI for induction of contact allergy or elicitation have been adequately demonstrated.

"For rinse-off cosmetic products, a concentration of 15 ppm (0.0015%) MI is considered safe for the consumer from the view of induction of contact allergy. However, no information is available on elicitation.”[25]

Physiopathological effects 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 the FAK 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.[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.

Ingredient in mouthwash

Although many companies that had begun using the biocide in personal care products, such as Kimberly-Clark, Johnson and Johnson, and Unilever are removing methylisothiazolinone from their lotions and wipes, Colgate-Palmolive has added it as an ingredient in a mouthwash put onto the market in August 2014 with the name Colgate Total Lasting White.[26] Adverse reactions are triggering coverage of the frequent and new uses of methylisothiazolinone in newspapers such as the New York Times at the same time as it notes that some companies even are considering removing the biocide from products that routinely are rinsed off shortly after application.

References

  1. 1 2 Rohm and Haas, Toxicology Department, “Evaluation of the toxicity of Kathon biocide,” August, 1984
  2. ↑ Collier PJ. Ramsey A. Waigh RD. Douglas KT. Austin P. Gilbert P.; Ramsey; Waigh; Douglas; Austin; Gilbert (1990). "Chemical reactivity of some isothiazolone biocides". Journal of Applied Bacteriology 69 (4): 578–584. doi:10.1111/j.1365-2672.1990.tb01551.x. PMID 2292521.
  3. ↑ "Cosmetic Ingredient Review. Final Report on the Safety Assessment of Methylisothiazolinone and Methylchloroisothiazolinone". J. American Col. Toxicol. 11 (1): 75–128. 1992. doi:10.3109/10915819209141993.
  4. ↑ Harino H. Mori Y. Yamaguchi Y. Shibata K. Senda T.; Mori; Yamaguchi; Shibata; Senda (2005). "Monitoring of antifouling booster biocides in water and sediment from the port of Osaka, Japan". Arch Environ Contam Toxicol 48 (3): 303–310. doi:10.1007/s00244-004-0084-2. PMID 15750770.
  5. ↑ Bellas J. (2006). "Comparative toxicity of alternative antifouling biocides on embryos and larvae of marine invertebrates". Sci Total Environ 367 (2–3): 573–85. doi:10.1016/j.scitotenv.2006.01.028. PMID 16545431.
  6. ↑ Podmore P. (1998). "An epidemic of isothiazolinone sensitization in a flax spinning mill". Contact Dermatitis 38 (3): 165–1666. doi:10.1111/j.1600-0536.1998.tb05687.x. PMID 9536412.
  7. ↑ Isaksson M. Gruvberger B. Bruze M., M; Gruvberger, B; Bruze, M (2004). "Occupational contact allergy and dermatitis from methylisothiazolinone after contact with wall covering glue and after a chemical burn from a biocide". Dermatitis 15 (4): 201–205. doi:10.2310/6620.2004.04017. PMID 15842065.
  8. ↑ Environmental Protection Agency (1998). R.E.D. Facts, Methylisothiazolinone. Publication EPA-738-F-98-008
  9. ↑ Nagorka R. Rosskamp E. Seidel K. [Evaluation of humidifier units within the scope of room climate modification]. [German] Offentliche Gesundheitswesen. 52:168-73, 1990
  10. ↑ Rastogi SC, SC (1990). "Kathon CG and cosmetic products". Contact Dermatitis 22 (3): 155–160. doi:10.1111/j.1600-0536.1990.tb01551.x. PMID 2335088.
  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; McLaughlin; Pal; 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 (17): 7408–7416. PMID 12196562.
  14. ↑ "Study on methylisothiazolinone in shampoo lacks a credible scientific basis" 2004
  15. 1 2 K. He, J. Huang, C. F. Lagenaur, E. Aizenman; Huang; Lagenaur; Aizenman (2006). "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 (3): 1320–1329. doi:10.1124/jpet.106.103044. PMID 16547166.
  16. ↑ European Scientific Committee on Cosmetic Products and Non-food Products Intended for Consumers (SCCNFP), adopted 2004
  17. 1 2 SCCS (Scientific Committee on Consumer Safety), Opinion on Methylisothiazolinone (P94) – Submission II, 12 December 2013, SCCS/1521/13, revision of 27 March 2014 (PDF)
  18. ↑ Hannuksela, M. (1986). "Rapid increase in contact allergy to Kathon CG in Finland". Contact dermatitis 15 (4): 211–214. doi:10.1111/j.1600-0536.1986.tb01338.x. PMID 3802805.
  19. ↑ De Groot, A. C.; Weyland, J. W. (1988). "Kathon CG: A review". Journal of the American Academy of Dermatology 18 (2 Pt 1): 350–358. doi:10.1016/s0190-9622(88)70051-1. PMID 3279090.
  20. ↑ Castanedo-Tardana, M. P.; Zug, K. A. (2013). "Methylisothiazolinone". Dermatitis : contact, atopic, occupational, drug 24 (1): 2–6. doi:10.1097/DER.0b013e31827edc73. PMID 23340392.
  21. ↑ MCI/MI/BIT Call To Action!
  22. ↑ Cosmetics Europe Recommendation on MIT
  23. ↑ European Society of Contact Dermatitis
  24. ↑ Cosmetics Europe Recommendation on MIT
  25. ↑ European Commission Scientific Committee on Consumer Safety Opinion on Methylisothiazolinone (P94) Submission II (Sensitization only) SCCS/1521/13
  26. ↑ Abrams, Rachel, Growing Scrutiny for an Allergy Trigger Used in Personal Care Products, The New York Times, January 23, 2015, and in the print edition of the New York edition, as An Unexpected Reaction, January 24, 2015, p. B1

External links

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