Triclosan

Endpoint summary

Additional information

Pharmacokinetic data in mice, rats, and hamsters indicate that triclosan is well-absorbed following oral administration, with two Cmax values in mice and rats (at 1 and 4 hours). In hamsters, the Cmax has been reported to occur at 1 hour following administration of the dose of triclosan. While data for single doses of triclosan show that the plasma AUC, as well as the half-life of elimination, in hamsters is greater than in mice or rats, plasma data from repeated-dose studies and from the chronic bioassays in these species have shown that the mouse experiences higher (2- to 5-fold) circulating levels of triclosan compared to the rat or hamster. Based on tissue distribution data following single and repeated dosing, there is no evidence of bioaccumulation/bioretention of triclosan in rats and hamsters.

The metabolism of triclosan is similar between rodents and humans. In all species tested, the formation of glucuronide and sulphate conjugates predominates, with the relative extents to which glucuronide and sulphate conjugates are formed varying with the type of dosing (i.e., single doseversusrepeated doses) and with species under study. The excretion of triclosan in hamsters, primates, and humans is primarilyviathe urine, while excretion is primarily faecal in both mice and rats. There is evidence for the existence of enterohepatic circulation in mice and rats, but not in hamsters. The overall conclusion from a comparison of the rodent and human data is that the hamster is most akin to humans with respect to the pharmacokinetics of triclosan, including elimination half-life, metabolism, and excretion.

Binding of¹⁴C-triclosan to plasma proteins was investigated by equilibrium dialysis at test compound concentrations of 3.2 to 16 µg/mL (Sagelsdorff & Buser, 1995). At equilibrium, independent of the free concentration of the test compound 98.4-99.2% of the recovered test compound was bound to human, mouse and hamster plasma proteins. The ratio of the unbound to the bound fraction remained constant for all plasma samples, indicating no saturation of the protein binding sites in the investigated concentration range.

Purification of plasma proteins by repetitive precipitations with acetone after incubation with¹⁴C-triclosan for up to two hours at a concentration of 6.4 µg/mL demonstrated that only 0.2-0.5% of the test compound was covalently bound to human, mouse arid hamster plasma proteins. However, the lack of time dependence of the protein bound radioactivity indicated that the radioactivity associated with the proteins was due to co-precipitation of the test compound upon acetone precipitation and not to covalent binding of the test compound to plasma proteins.

The results demonstrate a strong non-covalent binding of¹⁴C-triclosan to plasma proteins, whereas no species differences in the binding of the test compound to human, mouse and hamster plasma was observed.

Referring to human data, Triclosan is very well absorbed following oral ingestion. However, limited absorption (approximately 5 to 10% of the dose) occurs following normal toothpaste use (i.e., brushing, expectoration, and rinsing) or following percutaneous application in personal care products.

Regardless of the formulation, only trace amounts of the parent compound are detected in the plasma following exposure to triclosan-containing products. Due to a pronounced first-pass effect, there is a near total conversion of absorbed triclosan to glucuronic and sulphuric acid conjugates. The relative proportions of these metabolites vary depending on the plasma steady-state concentration of total triclosan, with higher concentrations resulting in a shift from predominantly glucuronide- to predominantly sulphate-conjugates. The half-life of elimination for orally administered triclosan was reported to range from approximately 14 hours (single dose) to 20 hours (repeated doses).

Following ingestion, percutaneous application, or intravenous administration, the predominant route of excretion of triclosan is through the urine. In urine, triclosan is present as the glucuronide conjugate. In contrast, triclosan excreted in the faeces is present as the free unchanged compound. Pharmacokinetic data, in particular AUC values after single or repeated oral exposures to triclosan (e.g., through toothpaste use), as well as plasma triclosan levels following percutaneous exposure (e.g., soap use), indicate a lack of bioaccumulation potential.

It is also noteworthy to compare the AUC from the two oral studies bySandborgh-Englundet al.(2006) and Colgate- Palmolive (1989). The first study featured a single oral dose of 4 mg whereas the latter study applied the same dose for 21 days. The AUC in both studies is strikingly similar at 2600 and 2788 ng×h/mL, respectively. This indicates that the capacity for elimination of triclosan from plasma is not saturated at this dose and that no accumulation occurs.

Comparisons between animal and clinical data have shown that humans are exposed to much lower levels of triclosan through normal daily use of consumer products compared to exposure levels in animals in non-clinical toxicology studies. Percutaneous absorption is higher in animals, as expected, compared to in humans. Numerous studies have demonstrated that human exposure to triclosan through the dermal route is minimal and does not result in bioaccumulation.

Comparison of pharmacokinetic data from animals and humans, especially the metabolism and excretion of triclosan, supports that the hamster is the most appropriate animal model for humans in the safety assessment of triclosan.

Considering dermal absorption, a percutaneous absorption study with triclosan was conducted on rat and human skin preparations as well as on living rats (Mosset al., 2000). In rat skin samples, 58% of the applied dose remained on the skin surface and in the stratum corneum (33 and 25%, respectively) and 41.2% of the applied dose was recovered in the receptor fluid and in the epidermis and dermis (23 and 18.2%, respectively) after 24 h of exposure. Thus, it can be considered that 41.2% of the applied dose was absorbed percutaneously within 24 hours (penetration through the stratum corneum into deeper layers of the skin is considered to represent absorption). Likewise, using human skin, 68% of the applied dose remained on the skin surface and in the stratum corneum (46 and 22%, respectively) and 30% of the applied dose was recovered in the receptor fluid and in the epidermis and dermis (6.3 and 23.7%, respectively) after 24 h of exposure. Thus, it can be considered that 30% of the applied dose was absorbed within 24 hours (penetration through the stratum corneum into deeper layers of the skin is considered to represent absorption).

Thein vivorat study revealed a systemic absorption of 21% of dose within 24 h judged by the proportion of dose recovered in excreta and carcass. Main excretory route was via faeces. After 24 h, 7.7% of the dose was found in the carcass, whereas more than 60% of the dose was present on the skin surface and the stratum corneum. This study also investigated the metabolism of triclosan during penetration through skin. Using rat skin explants, triclosan was primarily absorbed through the skin as the parent compound, with some glucuronide and sulphate conjugates being detected in the receptor fluid. With human skin, the majority of radioactivity in receptor fluid (56%) was detected as glucuronide. Some radioactivity in receptor fluid was associated with parent triclosan whereas sulphate conjugates was only a minor metabolite representing only 3% of the radioactivity in the receptor fluid.

Absorption through human skin preparations in vitro was investigated with¹⁴C-triclosan in various formulations representing relevant consumer products. The studies were conducted according to the COLIPA guidelines for percutaneous penetration of cosmetic ingredients. The formulations tested comprised a typical deodorant formulation, a dishwashing liquid, and a soap solution. The deodorant and the dishwashing liquid were kept in contact with the skin sample for 24 h which aims at mimicking leave-on cosmetics or the workday of a professional dishwasher. The soap solution was left on the skin sample for 10 minutes which simulates a typical rinse-off situation.