Foreword 

isothiazolone is a generic term for a class of derivatives whose structural formula is a five-membered isothiazolone ring (Figure 1). If R1 is H, it usually exists in the form of 3-hydroxyisothiazole, and isothiazolone is tautomeric (Figure 2); Among them, R2 and R3 can be the same group or different, can be alkyl, cyanogroup, halogen or cyclic cycloalkyl, aromatic ring and so on.

Isothiazolinone is a new type of efficient broad-spectrum fungicide, with the advantages of high efficiency, low toxicity and environmental friendliness. Since it was developed, the field of biocidal agents has entered a revolutionary development stage, gradually replacing many toxic and inefficient fungicides such as mercury. Commonly used isothiazolinone mainly has the following varieties (Figure 3). At present, it is widely used in many fields of industrial sterilization, corrosion and mildew prevention.

We all know that isothiazolinones are extremely effective as industrial fungicides, but a growing number of studies have reported that they are also strong sensitizers, which can produce skin irritation and allergy, and may cause ecotoxicological hazards. As a result, their use has been restricted by increasing legislation at home and abroad. Taking into account the usage habits and market share of isothiazolinone fungicides, this review collates their chemical synthesis, analytical methods, biological effects, toxicological safety, market overview and domestic and foreign regulations and other relevant information for your reference.

5. Stability of isothiazolinone derivatives 

The European Union's Biocidal Products Regulation (Regulation (EU) 528/2012) is also known as the EU BPR. The EU BPR came into force on 1 September 2013. The EU BPR aims to harmonize the operation and management of the biocidal market at the EU level to protect human health and environmental safety. All biocidal products require authorisation before being placed on the market, and the active substances contained in the biocidal product must be approved in advance. In order to obtain approval for an active substance, the applicant must provide stability data, including changes in the active substance under external factors such as temperature, humidity or light, in order to ensure the conditions of use and storage of the active substance, and to assess the degree of environmental impact of the biocide. Isothiazolinone as the main biocide is designed to protect humans, animals, materials or articles from harmful organisms such as pests or bacteria. However, there are few studies on its stability and degradation in the literature, and the literature data basically believe that the stability of isothiazolinone in water system is affected by the presence of nucleophiles (such as metals, amines, mercaptans and sulfides) under environmental conditions. Once this interaction occurs, the five-membered heterocyclic ring opens and transformation/degradation occurs.

I. Isothiazolinone (CMIT/MIT, commonly known as Casson) 

The results showed as follows: ① The hydrolysis rate of CMIT increases with the increase of pH and temperature. The compound is stable under acidic conditions, but the decomposition rate increases about 2000 times when pH is from 4.5 to 11, and 1-2 orders of magnitude when pH is from 7℃ to 40℃ . In addition, it was observed that the rate of CMIT degradation through biological mechanisms was concentration dependent and decreased with the increase of concentration. (2) The bactericidal efficacy of MIT was significantly lower than that of CMIT, but the biodegradation rate was faster than that of CMIT in river water or simulated sewage treatment plants. ③ Both of these compounds are degraded by ultraviolet radiation and have little adsorption in river mud, but are easily absorbed and metabolized by aquatic ferns. The authors suggest that the main degradation pathways of the CMIT/MIT mixture include dissociation from CaCl2, ring opening, loss of chlorine and sulfur, and formation of n-methylpropionamide acid. The degradation then proceeds through the formation of propionamide, malonic, acetic and formic acid and their conversion to CO2. Other products on the degradation pathway have been provisionally identified as 5-chloro-2-methyl-4-isothiazolin-1-oxide, n-methylacetaldehyde amide, glycol, and urea

Park and Kwon performed hydrolysis and photolysis tests on isothiazolinones (CMIT and MIT) (pH 4, 7, and 9 at 25 ° C) to assess their stability in consumer products. The results showed that: ① CMIT is relatively stable under acidic or neutral hydrolysis conditions; The concentration of CMIT decreased in different degrees (7-35%) under alkaline conditions and photolysis under acidic or alkaline conditions. ③ In comparison, the photolysis rate of CMIT is much slower than the hydrolysis rate. (4) MIT is stable, and no significant decrease in MIT concentration was observed under any test conditions.

Barman and Preston studied the stability of 5-chloro-2-methyl-4-isothiazoline-3-one (CMIT), the active ingredient in Kathon 886 MW and Kathon MWC fungicides, in acidic and alkaline solutions. The study found that these fungicides were stable in acidic media. However, degradation of the active ingredient occurs in alkaline solutions, and the rate of degradation is faster as the pH level increases. Further analysis showed that the chemical degradation of Kathon fungicide was caused by the hydrolysis of CMIT. Barman also studied the effect of temperature on the degradation of Kathon 886 MW and Kathon MWC fungicides in aqueous media and metalworking fluid concentrates. In aqueous medium, the half-life value is less than two hours at pH 9.6 and 60 ° C; At room temperature and pH 8.5, its half-life is 46 days. It was also found that the active ingredient (CMIT) is very stable at room temperature in typical gold processing fluid concentrates, with an estimated half-life of six months. However, the same concentration of CMIT is rapidly consumed at 40 ° C and 60 ° C, with half-life values of only 12 and less than 2 days, respectively

benzoisothiazolinone (BIT) 

Benzoisothiazolinone (BIT) is generally considered to be very stable in water-based systems, Li, A. Et al. reported a BIT half-life of more than 30 days in the environment, BIT can be transported through soil and reach surface water, and can still maintain its bactericidal properties after 3 months of exposure to sunlight. Wang et al. Evaluated the photodegradation of BIT under UVC irradiation and verified the influence of several parameters, including initial BIT concentration, solution pH, and HCo3-anion, with the following results:

①The photolysisrateof BIT inacidic solutions (pH5and6) is much slower than that inneutral solutions(pH7and8) and alkaline solutions(pH10).

②At pH7(20mM phosphate buffering),thephotolys is BIT under UV Cirradiationhasa removal efficiency of 94.5% at aninitial BIT=20µM and 15min irradiation time.

③The hydrolys is of BIT under dark conditions was negligible.

2-n-octyl-4-isothiazolin-3-one (OIT) 

Arning, J, et al., reported that octylisothiazolin-3-one (OIT) has hydrolytic stability with a halflife of over 40 days at 25 ° C and pH 7.4. Borman et al studied the leaching and incidence of OIT for exterior wall coatings under natural conditions. The results show that the photolysis half-life of OIT in tap water is 28 h and the photolysis rate constant is 0. 026 h-1 under the test conditions. Several photolysis products were identified and verified by analytical criteria. As described for other isothiazol- 3 (2H) -ketones, the photodegradation of OIT is also triggered by a break in the ring structure. In addition to the 3-octylthiazol-2 (3H)-one produced by OIT photoisomerization, the breaking of the N-S- bond leads to progressive degradation of the ring, resulting in n-octylmalonic acid, noctylpropionate 2-acrylamide, n-octylacetamide and n-octylformamide, as well as octylamine as the final product.

4, 5-dichloro-2-n-octyl-3-isothiazolinone (DCOIT) 

It was found that Sea-Nine 211 (containing 30%DCOIT) is rapidly biodegradable and chemically degraded in natural seawater, and the half-life of DCOIT in natural seawater is < 1 day, according to Shade, W.D. et al. Chen et al. studied the degradation kinetics of DCOIT under different environmental conditions, such as pH, temperature, dissolved oxygen, sunlight, and Marine organisms: Conclusion 1: In a buffered solution with pH 4, the half-life is 6.8 days; In a buffer solution with pH 7, the half-life is 1.2 days; In a buffer solution with pH 9, the half-life is 3.7 days; Conclusion 2: The degradation rate of DCOIT increases with the increase of temperature. At 4℃ , 25℃ and 40℃ , the half-life of DCOIT was > 64 days, 27.9 days and 4.5 days, respectively. Conclusion 3: Exposure to sunlight can accelerate the degradation of DCOIT. The photolysis half-life of DCOIT was 6.8 days and 14.4 days for dark control. The half-life of Sea-Nine 211 in different environmental substrates has been summarized in the literature. Under natural sunlight, the light conversion of Sea-Nine 211 in natural water increases in the following order: lake water > river water > seawater > distilled water, showing a strong dependence on the composition of the irradiated medium. Simulating solar radiation for 30 hours resulted in a 97%, 92%, 87%, and 77% decrease in Sea-Nine 211 concentration, respectively. Two main conversion pathways of Sea-Nine 211 light conversion are proposed (Figure 43). The first pathway (a) is the cleavage of the isothiazolone ring, followed by dechlorination, hydroxylation and oxidation to produce n-n-octyl propanamide, followed by decarboxylation to produce the corresponding n-n-octyl acetamide. N-octylacetamide is further oxidized to n-octyloxamic acid, which is then photoconverted to the corresponding N-molecule - n-octylcarbamic acid, followed by decarboxylation to n-octylamine. The second pathway (b) produces 4, 5-dichloro-3-n-octylthiazolin-2-ketone from Sea-Nine 211, whose N-C alkyl bond breaks and alkyl oxidation produces n-octylaldehyde. A number of other conversion products were detected but not identified in the photodegradation experiment.