“L.I. Medved’s Research Center of Preventive Toxicology, Food and Chemical Safety, Ministry of Health, Ukraine (State Enterprise)”, Kyiv, Ukraine

ABSTRACT. Objective is to summarise current literature data on the adverse effects of triclosan (TCS) biocide on human and animal health and potential risk for the development of endocrine-disruptor effects forjustification of the necessity to improve regulatory measures for its use in consumer products.

Material and Methods. Analysis of literature data on the ways of influence of metabolic transformation in the body and toxicokinetics of TCS, its influence on human health and environment was performed. Targets and biomarkers of TCS exposure, its toxic properties and potential risk for the formation of endocrine-disruptor effects were described.

Results. Necessity to optimise regulatory measures for the use of TCS in the personal hygienic means, general and curative beauty products, woven fabric for bedlinen and underwear, etc. has been justified.

Key Words: triclosan biocide, toxic properties, endocrine-disruptor effects, regulatory measures.

Triclosan, Irgasan DP 300 (trade name) 2,4,4’-trichloro-2’-hydroxy diphenyl ester; 5-chloro-2-(2,4-dichlorophenoxy) phenol is a diphenyl ester by its chemical structure. By the parameters of acute toxicity, triclosan administered intragastrically belongs to moderately hazardous substances: DL ₅₀ for rats is 4,300 mg/kg, for mice — 4,500 mg/kg, for dogs — 5,000 mg/kg (class 3 according to GOST 12.1.007-76). Upon application on the rabbit skin, DL₅₀ is more than 6,000 mg/kg (class 4 of low-hazardous substances by this GOST). Experimental and accumulated clinical data obtained in 1990–2000 suggested low irritating and sensitization action of triclosan, about the lack of mutagenic, carcinogenic, teratogenic effects, and reproductive toxicity [1, 4, 5, 6, 11, 12].

For many tears triclosan was known as a pesticide, and during the last 30 years — as s synthetic antimicrobial agent of the wide spectrum of action, commonly used in different consumer products, including all sorts of soap (liquid, gel, bar), toothpastes, liquids for mouth rinsing (orosepts), disinfecting liquids for hands, deodorants, beauty care products, cleaning and disinfecting agents, and other hygienic items [1-4]. It was shown that triclosan (TCS) shows bacteriostatic or bactericidal action on many representatives of Gram-positive and Gram-negative flora, as well as on fungi [1-7]. Small concentrations of TCS (up to dozens of micrograms per litre) used in many consumer product — personal hygiene products, has bacteriostatic action. At the same time, its high concentrations (0.2–2 %) has bactericidal effect resulting in disorders in membranes and in the range of cytoplasmic structures of bacterial cells that is accompanied by the inhibition of mitochondrial functions and impaired synthesis of fatty acids required for recovery of membranes and reproduction of bacteria [1-6].

In the late 2000s, TCS as an active ingredient was found in 93 % of different soaps (hard, liquid, gels or foams). Soled products containing TCS in the concentration from 3.5 to 17 mM just from September 2008 till 2009 amounted to USD 132 million (FDA, 2013). At the same time, articles were published showing that TCS containing soaps did not provide any additional benefits in terms of skin disinfection compared to TCS free soaps TCS [8]. This apparently associated with the fact that bacterial resistance is rapidly formed to TCS that decreases the bacteriostatic effect of this biocide [9]. Furthermore, increased resistance to TCS is responsible for further increase in the resistance to many other antibacterial agents [10]. Bactericidal action of TCS is stipulated by the impaired synthesis of fatty acids and formation of mitochondrial dysfunctions in bacteria upon the use of TCS containing personal hygiene and other products, and at the same time, its main target is fatty acids synthase (enoyl-acyl carrier protein reductase, Fab I) [11]. Formation of antibacterial resistance to TCS is associated with the mutation of the gene of this fatty acid synthase [11]. TCS biocide is widely used not only in personal hygiene products (soaps, shower gels, toothpastes, orosepts, hair colours), but also in products for nail cleaning, especially before the use of artificial nail systems and in other beauty care products: creams, emulsions, skin oils, deodorants, depilators, antiperspirants, sun care products, shaving products, etc. [5, 6, 12, 13, 16].

However, an experimental, clinical and epidemiological study conducted during the recent years suggests potential hazard of TCS for human, animal health and environment.

The range of studies has shown a constant presence of TCS in human biological media [1-5, 26-27], including blood and milk of breastfeeding women [26]. In the US, TCS was found within the period from 2003 till 2004 in 75 % of urine samples of the population in the concentrations from 7.9 nM to 13.1 µM [27]. TCS was found in 100 % of 181 blood samples of pregnant females and 51 % of umbilical blood samples of the newborns in New York [31]. In 100 % of 2,400 urine samples collected among the population of Australia, TCS was found in the concentration ranged from 0.08 to 0.71 µM [28]. In Canada, TCS was found in 87 % of urine samples from 80 healthy pregnant females [29]. TCS was also found in the liver, fatty tissue and brain, while the liver is the organ with the highest TCS concentration [30].

TCS has high lipophilic properties, therefore, it easily penetrates the skin, mucous membranes of the oral cavity and upon the use of oroseptics — gastrointestinal mucosa. It was shown that about 12 % of TCS dose is present in the human skin 24 hours after its exposure, and in rats — 26 % of dose [32]. TCS is metabolised in the skin, and after penetration, in other organs also, predominantly in the liver, to TCS sulphate, TCS glucuronide and to the main metabolite — 2,4-dichlorophenol [32].

TCS is extensively found in the environmental objects (water bodies, soils) and in animal tissues, especially its high concentrations are found in wastewater and bottom sediments — biosolids (up to 30,000 µg/kg of dry weight) [33]. Considering that wastewater similar to biosolids are commonly used in agricultural practice on the fields, therefore, TCS is the potential pollutant of the agricultural crops. Its half-life in the soil is 20 to 58 days and is significantly longer under anaerobic conditions [33, 34, 36]. The range of studies has shown that biotic degradation of TCS in environmental objects produces such toxic compounds as 2,4-dichlorophenol, 4-chlorophenol, hydroquinones, etc. with their subsequent bioaccumulation [33, 34]. Furthermore, under exposure to sunlight and upon burning, TCS is transformed intro polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans [34]. Dioxin and dioxin-like compounds in turns activate aryl hydrocarbon receptor (AhR) that is accompanied by gene expression associated with the development of different types of cancer, formation of teratogenic effect, impaired reproductive and immune function [35].

During the last 5–8 years, the number of publications on the adverse consequences of TCS exposure to human, animal health and environment has significantly grown. It is reported that TCS in mice liver activates production of reactive oxygen species (ROS), increases proliferation of hepatocytes, therefore, acting as the tumorogenesis promotor [38]. Upon the use of skin cells exposed to TCS and UV radiation, two dioxin-like products were found suggesting that TCS may be subjected to phototransformation to dioxin-like substances on the human skin also [37]. Furthermore, it was shown that the formation of polychlorinated dibenzodioxins in the commercial textile treated with TCS [41], which use for fabrication of bedding, underwear, etc. are known. It was found that the ROS level in the liver is also correlated with increased content of TCS in the human urine samples [39]. Furthermore, TCS increases expression of such proinflammatory cytokines in the mice liver as TNF-α, IL-6, IL-1α [38]. Based on in vitro studies, a range of authors believes that TCS contributes to the development of cancer [39, 40]. Authors associated the potential carcinogenic risk upon exposure to TCS with its stimulation of tumour growth ovarian factor that regulates gene expression of the cellular cycle and apoptosis [39].

A range of human epidemiological studies has found a relationship of TCS action — its increased urine level with the rate of allergic conditions both in children and adults: bronchial asthma, allergic rhinitis, dermatosis and food hypersensitivity [42-46]. It was noted that TCS contributes to the formation of contact hypersensitivity and development of contact dermatitis [48], and also TCS induces production of thymic stromal lymphopoietin in the skin, which is Th₂ allergic response promotor [46].

During recent years, it was shown that TCS is an active endocrine disruptor both in some species of animals and in human. For example, exposure of different species of fish to nanomolecular TCS levels in water bodies results in an intense increase of the content of hepatic vitellogenin (Vtg) that is the precursor of egg yolk widely used as the biomarker of impairments in the endocrine system under exposure to xenobiotics [47]. Reduction of progesterone, oestradiol and testosterone level in the blood serum of rats is reported after oral exposure to TCS. This biocide reduces the level of thyroid hormones (Т₄) in female rats after oral administration [50]. Endocrine-disruptor effects of TCS are associated with its interaction with hormonal nuclear receptors, especially oestrogen and androgen [51, 55]. Under exposure to TCS, oestrogen receptor-associated signalling pathways contribute not only to the formation of endocrine disorders but also to the proliferation of breast cancer cells [49]. Depending on the TCS level in the blood serum, the impaired balance of testosterone was also reported in children of both genders [52]. Furthermore, the relationship between the increased urea TCS levels and the rate of the impaired menstrual cycle and reduced fertility was found [53, 54, 55].

Especially pronounced impairments under exposure to TCS are registered in the functioning of the thyroid gland with the reduction of Т ₄ level not only in female rats [50] but also in puppies on oral TCS [55], in male juvenile rats and mice. Epidemiological studies in human have found a relationship between the reduction of T₄ level in mother and cognitive disorders in a child. Chronic exposure of newborn rats to TCS is accompanied by the formation of impaired thyroid and reproductive function [55]. In a range of works, researchers are disturbed with endocrine-disruptor effects of TCS on the population, in particular, upon chronic exposure [56-58]. Special concern is raised by the data that TCS is a reason of spontaneous abortions [51, 57] that is mediated by interaction with oestrogen receptors and reduction of the activity of oestrogen sulfotransferase [57]. Furthermore, increased TCS levels in the maternal blood stipulate more common formation of teratogenic effects with an increased rate of congenital malformations [51, 56, 58]. Endocrine-disruptor effects of TCS include both an increase in the overweight detected upon its increased concentrations in urine, and obesity in children and adolescents [59]. Unfavourable reproductive effects and endocrine disorders are associated with the formation of mitochondrial dysfunction under exposure to TCS both in the experiment on the cellular culture, and in vivo [29, 56, 60, 61], and also with impaired function of hormonal nuclear receptors [51, 55, 57, 60].

Therefore, clinical and experimental studies of TCS biocide have revealed its pronounced unfavourable action on human and animal health, associated with a potential carcinogenic risk, increase in the rate of allergic conditions, the formation of endocrine-disruptor, obesogenic and teratogenic effects, impairment of the reproductive function. Study results necessitate correction of regulatory measures upon the use of this biocide in the consumer products.

Considering TCS resistance in the environmental objects and obtained new data about its toxicity and unfavourable action on human health, a range of countries has performed correction of legislation on its use in consumer products. For example, in the US, the FDA prohibited the use of TCS in soap products (hard, liquid, gels, foams) since September 2016 [62]. In 2017 and 2019 similar decisions were made by the FDA in terms of TCS use in antiseptics applied in healthcare and antiseptics for consumer use, respectively [63, 64]. However, TCS is still allowed in the US in toothpaste, face masks, dry shampoos, after-shave products and mouthwashes in the concentrations below 0.3 %. Furthermore, in the US TCS as a biocide is still allowed for use as bacteriostatic and fungistatic in plastics, polymers and textile products, as well as for hard non-porous surfaces of devices used for heating, ventilating and air conditioning systems. Currently, EPA performs so called registration revision process. In April 2019, a draft document on TCS risk evaluation for human health and ecology was published [65]. Upon risk evaluation, among other things, studies suggesting TCS effect on the hypothalamic-pituitary-thyroid axis of the endocrine system were taken into account [68]. However, in the final statements of this document authors came to the need of further study of TCS potential risk for human health and environment.

In the European Union, the possibility to use TCS as biocide was reviewed within the program of revision of approved active substances of biocidal agents, however in April 2014 it was decided not to approve TCS as active substance in biocidal agents for use in healthcare, veterinary, as a preservative for films, fibres, leather, rubber, and polymeric materials [66, 67].

The conducted analysis of literature data obtained in recent years on the unfavourable effects of TCS on human, animal health and environment, as well as the analysis of regulations for its use in the US and Europe suggests the necessity of the revision of regulations for TCS use in Ukraine in a wide range of consumer products.

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