Safety Assessment of Dichlorophene and Chlorophene1

Abstract

Dichlorophene is a halogenated phenolic compound that functions as a bacteriocide and fungicide in cosmetics. Chlorophene is a halogenated phenolic compound that functions as a biocide and preservative in cosmetics. Dichlorophene was reported to be used in a total of five cosmetic formulations at concentrations of 0% to 1.0%, but Chlorophene was not reported to be used. Dichlorophene is prohibited for use in cosmetic ingredients in Japan. In Europe, the maximum authorized concentration allowed for Dichlorophene is 0.5% and for Chlorophene is 0.2%. The major impurity of Dichlorophene is the trimer 4-chloro-2,6-bis(5-chloro-2-hydroxy-benzyl)phenol. In rats, Dichlorophene sulfate, Dichlorophene monoglucuronide, and Dichlorophene diglucuronide were the major metabolites of Dichlorophene and were excreted, mainly in the urine. The glucuronic acid conjugate, the sulfate ester conjugate, and two minor metabolites of Chlorophene were the metabolites found in rat urine. Chlorophene was incompletely absorbed through the rat skin. These chemicals exhibited low toxicity in acute oral toxicity studies in several animal species. Some evidence of toxicity with both chemicals was found in short-term oral toxicity studies in mice and rats; nephropathy was the principal finding. Chronic toxicity data were not available for Dichlorophene. Rats and mice dosed with Chlorophene for 2 years had a dose-related and sex-related increase in the severity of nephropathy. In animal tests, Dichlorophene and Chlorophene were ocular irritants. No inhalation toxicity data were available for these ingredients. Dichlorophene up to 10% concentration resulted in no to minimal irritation when applied to the intact and abraded skin of rabbits. Chlorophene was severely irritating to rabbits in most dermal irritation studies. Studies on guinea pigs gave positive and negative results in sensitization tests of Dichlorophene. A dose-related contact hypersensitivity response to Chlorophene was reported in mice. No reproductive or developmental toxicity data were available for Dichlorophene, but there was some evidence of non-dose-dependent developmental toxicity with Chlorophene in rabbits. Dichlorophene was positive in the Ames mutagenicity assay, but not in mammalian or fruit fly test systems. Chlorophene was mutagenic in four in vitro mammalian test systems. Carcinogenicity studies for Dichlorophene were not found. Neoplasms were not observed in rats treated with Chlorophene for 2 years; however a significant incidence of neoplasms was observed in mice so treated. A 1-year National Toxicology Program (NTP) study concluded that Chlorophene was a cutaneous irritant and a weak skin tumor promoter but had no activity as an initiator or complete carcinogen. Dichlorophene was not a sensitizer in clinical dermal sensitization tests. Some reactions to Chlorophene occurred in some, but not all, clinical dermal sensitization tests. Positive photopatch tests to Dichlorophene were found in 13/469 patients. Although these ingredients were ocular irritants at high concentrations, the risk at concentrations which are actually used in cosmetic formulations was uncertain. Overall, the available data were insufficient to support safety of Dichlorophene or Chlorophene. Additional data needed include (1) method of manufacture and impurities data (especially the trimer in Dichlorophene); (2) photosensitization and photo-carcinogenicity data for Dichlorophene; (3) dermal reproductive and developmental toxicity data for Dichlorophene (as a function of dose); and (4) ocular irritation at concentration of use, if available.

Repositioning of the Anthelmintic Drugs Bithionol and Triclabendazole as Transthyretin Amyloidogenesis Inhibitors

“…35 is currently used as an external medicine to eliminate tapeworms from animals. However, 35 has been superseded in this capacity by niclosamide, which has fewer side effects . Although the discovery that 35 functions as a TTR stabilizer motivates us to investigate this compound further, 35 may be difficult to reposition as a clinical amyloidogenesis inhibitor due to its substantial side effects .…”

“…However, 35 has been superseded in this capacity by niclosamide, which has fewer side effects. 39 Although the discovery that 35 functions as a TTR stabilizer motivates us to investigate this compound further, 35 may be difficult to reposition as a clinical amyloidogenesis inhibitor due to its substantial side effects. 39 In Japan, 42 was administered orally to diphyllobothriasis patients until the early 1980s.…”

“…39 Although the discovery that 35 functions as a TTR stabilizer motivates us to investigate this compound further, 35 may be difficult to reposition as a clinical amyloidogenesis inhibitor due to its substantial side effects. 39 In Japan, 42 was administered orally to diphyllobothriasis patients until the early 1980s. The tolerability of 42 in children is low because of abdominal pain and nausea, and today, 42 has been superseded by praziquantel.…”

“…Compounds 11 and 30 were purchased from FUJIFILM Wako Chemicals. Compounds 4,12,14,19,29,34,35,38,39,40, and 43 were purchased from Tokyo Chemical Industry. All chemicals were supplied in greater than 95% purity with a certificate of analysis by high-performance liquid chromatography (HPLC), gas chromatography, or NMR except for 35 (>85% by HPLC).…”

Triclocarban, Triclosan, Bromochlorophene, Chlorophene, and Climbazole Effects on Nuclear Receptors: An in Silico and in Vitro Study

“…farming plants, and it can thus enter the water environment at high concentrations and with seasonal dependence (Arlos et al 2015;Benitez et al 2013). It was shown to be mutagenic in in vitro bacterial and mammalian assays and to increase incidence of neoplasms in mice (Yamarik 2004), and it was rejected by the European Chemicals Agency in 2017 (ECHA 2017) as a biocidal product type 2 and 3 due to hazards it might pose to operators handling such products. A previously shown IC 50 of 0:54 lM for chlorophene as an AR antagonist in anti-YAS assays (Rostkowski et al 2011) is lower than the IC 50 of 2:4 lM obtained in the present study using an OECD-validated assay.…”