Isothiazolinone (; sometimes isothiazolone) is an

organic compound Some chemical authorities define an organic compound as a chemical compound that contains a carbon–hydrogen or carbon–carbon bond; others consider an organic compound to be any chemical compound that contains carbon. For example, carbon-co ...

with the formula (CH)₂SN(H)CO. A white solid, it is structurally related to

isothiazole Isothiazole, or 1,2-thiazole, is an organic compound consisting with the formula . The ring is unsaturated and features an S-N bond. The isomeric thiazole, where the S and N are not directly bonded are far more common. Isothiazones are produced ...

. Isothiazolone itself is of limited interest, but several of its derivatives are widely used preservatives and

antimicrobial An antimicrobial is an agent that kills microorganisms (microbicide) or stops their growth (bacteriostatic agent). Antimicrobial medicines can be grouped according to the microorganisms they are used to treat. For example, antibiotics are used aga ...

Synthesis

Compared to many other simple heterocycles, the discovery of isothiazolinone is fairly recent, with reports first appearing in the 1960s. Isothiazolinones can be prepared on an industrial scale by the ring-closure of 3-mercaptopropanamides. These in turn are produced from

acrylic acid Acrylic acid (IUPAC: prop-2-enoic acid) is an organic compound with the formula CH2=CHCOOH. It is the simplest unsaturated carboxylic acid, consisting of a vinyl group connected directly to a carboxylic acid terminus. This colorless liquid has ...

via the 3-mercaptopropionic acid: : Ring-closure of the thiol-amide is typically effected by chlorination or oxidation of the 3-sulfanylpropanamide to the corresponding

disulfide In chemistry, a disulfide (or disulphide in British English) is a compound containing a functional group or the anion. The linkage is also called an SS-bond or sometimes a disulfide bridge and usually derived from two thiol groups. In inorg ...

. : Many other routes have been developed, including addition of thiocyanate to propargyl amides.

Mechanism of action

The antimicrobial activity of isothiazolinones is attributed to their ability to inhibit life-sustaining enzymes, specifically those enzymes with

thiol In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl grou ...

s at their

active site In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate, the ''binding s ...

s. It is established that isothiazolinones form mixed disulfides upon treatment with such species.

Applications

The principal isothiazolones are: *

Methylisothiazolinone Methylisothiazolinone (), MIT, or MI, is the organic compound with the formula S(CH)2C(O)NCH3. It is a white solid. Isothiazolinones, a class of heterocycles, are used as biocides in numerous personal care products and other industrial applicatio ...

(MIT, MI) *

Chloromethylisothiazolinone Methylchloroisothiazolinone, also referred to as MCI, is the organic compound with the formula S(C2HCl)C(O)N(CH3). It is a white solid that melts near room temperature. The compound is an isothiazolinone, a class of heterocycles used as biocides. ...

(CMIT, CMI, MCI) * Benzisothiazolinone (BIT) * Octylisothiazolinone (OIT, OI) * Dichlorooctylisothiazolinone (DCOIT, DCOI) * Butylbenzisothiazolinone (BBIT) These compounds all exhibit

properties. They are used to control

bacteria Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...

fungi A fungus (: fungi , , , or ; or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and mold (fungus), molds, as well as the more familiar mushrooms. These organisms are classified as one ...

, and

algae Algae ( , ; : alga ) is an informal term for any organisms of a large and diverse group of photosynthesis, photosynthetic organisms that are not plants, and includes species from multiple distinct clades. Such organisms range from unicellular ...

in cooling water systems, fuel storage tanks,

pulp Pulp may refer to: * Pulp (fruit), the inner flesh of fruit * Pulp (band), an English rock band Engineering * Pulp (paper), the fibrous material used to make paper * Dissolving pulp, highly purified cellulose used in fibre and film manufacture ...

and

paper mill A paper mill is a factory devoted to making paper from vegetable fibres such as wood pulp, old rags, and other ingredients. Prior to the invention and adoption of the Fourdrinier machine and other types of paper machine that use an endless belt ...

water systems,

oil extraction Petroleum is a fossil fuel that can be drawn from beneath the Earth's surface. Reservoirs of petroleum are formed through the mixture of plants, algae, and sediments in shallow seas under high pressure. Petroleum is mostly recovered from oil ...

systems,

wood preservation Wood preservation refers to any method or process, or even technique, used to protect the wood and extend its service life. Most wood species are susceptible to both biological (''biotic'') and non-biological (''abiotic'') factors that cause d ...

, and some paints. They are

antifouling Biofouling or biological fouling is the accumulation of microorganisms, plants, algae, or small animals where it is not wanted on surfaces such as ship and submarine hulls, devices such as water inlets, pipework, grates, ponds, and rivers that ...

agents. They are frequently used in

shampoo Shampoo () is a hair care product, typically in the form of a viscous liquid, that is formulated to be used for cleaning (scalp) hair. Less commonly, it is available in solid bar format. (" Dry shampoo" is a separate product.) Shampoo is use ...

s and other

hair care Hair care or haircare is an overall term for hygiene and cosmetology involving the hair which grows from the human scalp, and to a lesser extent Facial hair, facial, Pubic hair, pubic and other body hair. Hair care routines differ according to a ...

products.

(CMIT) and 2-methyl-4-isothiazolin-3-one (methylisothiazolinone or MIT) are popular derivatives. A 3:1 mixture of CMIT:MIT is sold as ''Kathon''. Kathon is supplied as a concentrated stock solution containing from 1.5 to 15% of CMIT/MIT. For applications the recommended use level is from 6 ppm to 75 ppm active isothiazolones. 4,5-Dichloro-2-n-octyl-4-isothiazolino-3-one (DCOI or Sea-Nine 211) is used especially as an antifouling agent, i.e. paint for ship hulls to prevent the formation of barnacles, etc.

Safety and environmental aspects

Together with their wanted function, controlling or killing

microorganism A microorganism, or microbe, is an organism of microscopic scale, microscopic size, which may exist in its unicellular organism, single-celled form or as a Colony (biology)#Microbial colonies, colony of cells. The possible existence of unseen ...

s, isothiazolinones also have undesirable effects. Many countries are looking at partial or full bans of the substance due to the known dangers in using the biocide.

Environmental

Isothiazolinones have a high aquatic

toxicity Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacteria, bacterium, or plant, as well as the effect o ...

. DCOI has been detected in both port water and sediment samples in Osaka, Japan, especially in weakly circulating mooring areas. DCOI levels threaten various

marine invertebrate Marine invertebrates are invertebrate animals that live in marine habitats, and make up most of the macroscopic life in the oceans. It is a polyphyletic blanket term that contains all marine animals except the marine vertebrates, including the ...

s. Isothiazolinones also are extremely toxic to fish.Rohm and Haas, Toxicology Department, “Evaluation of the toxicity of Kathon biocide,” August, 1984

Dermatitis

In 2014 the European Commission Scientific Committee on Consumer Safety 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." "It is unknown what proportion of the general population is now sensitized to MI and has not been confirmed as sensitized." In 2014, the European Commission Scientific Committee on Consumer Safety further issued a voluntary ban on "the mixture of Methylchloroisothiazolinone (and) Methylisothiazolinone (MCI/MI) from leave-on products such as body creams. The measure is aimed at reducing the risk from and the incidence of skin allergies. The preservative can still be used in rinse-off products such as shampoos and shower gels at a maximum concentration of 0.0015 % of a mixture in the ratio 3:1 of MCI/MI. The measure will apply for products placed on the market after 16 July 2015." Shortly thereafter, Canada moved to adopt similar measures in its Cosmetic Ingredients Hotlist. Additionally, new research into cross reactivity of MI-sensitized patients to variants benzisothiazolinone and octylisothiazolinone have found that reactions may occur if present in sufficient amounts.

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 Allergic contact dermatitis (ACD) is a form of contact dermatitis that is the manifestation of an allergic response caused by contact with a substance; the other type being irritant contact dermatitis (ICD). Although less common than ICD, ACD ...

. Sensitization to this family of preservatives was observed as early as the late 1980s.The use of isothiazolinone-based preservatives has resulted in many incidences of contact allergy. In 2013 the substance was declared the ''2013 Contact Allergen of the Year'' by the American Contact Dermatitis Society. In 2016 the Dermatitis Academy launched a call to action for patients to report their isothiazolinone allergy to the FDA. On December 13, 2013, the trade group, Cosmetics Europe, following discussions with the European Society of Contact Dermatitis (ESCD), 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." 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.” Colgate-Palmolive had added it as an ingredient in a mouthwash put onto the market in August 2014 with the name Colgate Total Lasting White. In industrial use, the greatest occupational inhalation exposure occurs during open pouring. Non-occupational exposure to isothiazolinones by the general population also occurs, albeit at much lower concentrations. These compounds are present in a number of commonly used cosmetics.

References

External links

*{{Commonscatinline, Isothiazolinone Preservatives Isothiazolinones