Chemical name: 1-Propanol, 2,3-dibromo-, phosphate (3:1) Final regulatory action has been taken for the category: Industrial Final regulatory action: The chemical is Severely Restricted Use or uses prohibited by the final regulatory action: The placing into the market of textiles containing TBPP and which are carried directly or indirectly on the skin (clothes, wigs, costumes etc) or which are intended to be used as decoration (bed sheets, table clothes, carpets, curtains etc) is banned The final regulatory action was based on a risk or hazard evaluation: Yes Summary of the final regulatory action: The placing on the market of textiles containing Tris(2,3-dibromopropyl) phosphate (TBPP) and which are carried directly or indirectly on the skin (clothes, wigs, costumes, etc) or which are intended to be used as decoration (bed sheets, table clothes, carpets, curtains, etc) is banned (Ordinance on the Reduction of Risks linked Chemical products, ORRChem). TBPP is considered as a substance particularly dangerous for human health. According ot the article 79 of the Ordinance on Chemicals (OChem), which is not specific for TBPP, a particularly dangerous substance can only be supplied to adults or authorized persons. The reasons for the final regulatory action were relevant to: Human health Summary of known hazards and risks to human health: Exposure data: The primary routes of potential human exposure to TBPP are inhalation, dermal contact and ingestion. When released to soil, it leaches slowly to groundwater, and under basic conditions it will hydrolyse. In water, it will rapidly hydrolise. In the atmosphere it will sorb to particulate matter and react with photochemically produced hydroxyl radicals (half-life of 3.74 days). TBPP does not occur naturally, but it has been detected in food and water. Children wearing TBPP-treated sleepwear were the group of the general population particularly exposed to this flame retardant. The estimated intake via the skin of children wearing TBPP-treated sleepwear in the USA was calculated to be 9 ug/kg bodyweight per day. The Consumer Product Safety Commission of the USA calculated that, over a 6-year period, as child wearing TBPP-treated clothing could absorb a total of 2-77 mg TBPP/kg bodyweight or more. Kinetics and metabolism in laboratory animals and humans: TBPP is absorbed readily from the gastrointestinal tract and at a moderate rate via the skin in rats and rabbits. In rats, TBPP or its metabolites are eliminated within 5 days. Approximately 50% is eliminated via the urine, 10% via the faeces, and 10-20% is exhaled as carbon dioxide. One day after oral administration of labeled TBPP to rats, radioactivity was found in the blood, liver, kidneys, muscles, fat and skin, in a range of 0.2 - 6.6%. The half-life clearance of radioactivity from these organs was approximately 2-4 days. After 8 h, only bis(2,3-dibromopropyl (BBPP) phophate was still present in substantial concentrations in most tissues. After oral administration of TBPP to rats, six metabolites were identified in the urine and bile. The main metabolite in the urine, faeces, bile and tissues was BBPP. The metabolite 2,3-dibromopropanol (DBP) was also identified in rats and in children wearing TBPP-treated clothing. Liver microsomes metabolize TBPP in the presence of NADPH and oxygen. The main metabolites are BBPP and 2,3-dibromopropanol (DBP). In addition to BBPP, 2-bromoacrolein, 2-bromoacrylic acid, and propyl-hydroxylated compounds and metabolites conjugated with glutathione have been found. S-(2,3-dihydroxypropyl) gluathione was identified in the bile of rats, and it was suggested that TBPP and/or BBPP are conjugated directly with glutathione by glutathione S-transferase with the formation of episulfonium ion metabolites. Toxicity: The acute and short-term oral, and the acute dermal, toxicities of TBPP are low. The oral LD50 for the rat >2 g/kg and dermal LD50 for the rabbit >8 g/kg body weight. Extensive kidney damage (necrosis of renal proximal tubular cells) was noted in male rats following a single IP injection of 100 mg TBPP/kg bodyweight. In rabbits, daily dermal application of 2.2 g TBPP/kg bodyweight or more, for 4 weeks, resulted in degenerative changes in the liver and kidneys. All rabbits died within 4 weeks. No deaths occurred in another study with dose levels of up to 250 mg/kg bodyweight. Mutagenicity: TBPP has been shown to be activated to form products that bind covalently to proteins and DNA in vivo and in vitro. TBPP is mutagenic in bacteria and causes genetic damage in cultured mammalian cells, Drosophila melanogaster and mice, probably via metabolism to a number of intermediates of which 2-bromoacrolein may be particularly important. After intraperitoneal injections of tritiated-TBPP, male mice, hamsters, and guinea-pigs, which are less sensitive to TBPP-induced nephrotoxicity than rats, showed similar levels of covalent binding to proteins in the liver and kidneys. in the male rat, which is highly susceptible to TBPP induced nephrotoxicity, much higher amounts of radiolabel were bound to kidney proteins that to liver proteins. Liver microsomes form mice, guinea-pigs, hamster, and humans all metabolised TBPP to genotoxic intermediates. However, the rate of formation of reactive TBPP metabolites with human liver microsomes was lower than with liver microsomes from the rodents. The binding of labelled TBPP and analogues in rats as a nephrotoxic dose showed that the covalent protein binding was highest in the kidneys followed by the liver and testes. The results of comparative in vivo and in vitro studies on renal DNA damage suggested that BBPP is formed in the liver by P450-mediated oxidation at either C2 or C3 of TBPP. BBPP is transported to the kidneys, where it is metabolized to reactive intermediates that cause DNA damage and bind to kidney proteins. The activation occurring in the kidney appears not to involve P450 but seems to be mediated by GSH-dependent metabolism. In vitro studies with labelled TBPP and analogues showed that oxidation of TBPP incorporates one atom of oxygen from water. This implies that oxidation at C2 of the propyl moiety yields a reactive alphabromoketone that can alkylate protein directly or hydrolyse to BBPP and a reactive bromo-alpha-hydroxyketone. Extensive DNA damage was found in various organs of rats administered TBPP. In vitro, TBPP has been shown to induce DNA strand breaks in human KB cells. It induced unscheduled DNA synthesis in rat liver hepatocytes, but not in human foreskin epithelial cells. TBPP was mutagenic in several studies on Salmonella typhimurium, especially in base-pair substituting strains with, and without, metabolic activation. Forward gene mutation assays using Chinese hamster V79 cells, with and without metabolic activation were negative. However, a positive effect in the presence of liver microsomes of rats pretreated with phenobarbital was obtained. TBPP increased the number of sister chromatid exchanges (SCEs) in Chinese hamster V79 cells, but no chromosomal aberrations were induced in Chinese hamster cells, mouse bone marrow cells, or in cultured human lymphoid cells. SCEs but no chromosomal aberrations were found with diploid human fibroblastic cells without metabolic activations. However, in an in vitro chromosome aberration test with teh Chinese hamster cell line (CHL), TBPP was positive. A positive result was obtained with TBPP in a micronucleus test on Chinese hamster bone marrow cells. Another micronucleus study with mice showed a weak positive effect. Teratogenicity Two teratogenicity studies were carried out on rats. In one study with dose levels of up to 125 mg/kg body weight, no teratogenicity was observed. In another study with a dose level of 200 mg/kg bodyweight, a significant increase in skeletal variations in the fetuses was observed, and, with 50 and 100 mg/kg bodyweight, a significantly lower viability index was found. Animal carcinogenicity data: TBPP was tested for carcinogenicity in mice and rats by oral administration. In mice, it produced benign and malignant tumours of the forestomach and lung in animals of each sex, benign and malignant liver tumours in females and benign and malignant tumours of the kidneys in males. In rats, it produced benign and malignant tumours of the kidneys in males and benign kidney tumours in females. In a study of limited duration in male rats, benign tumours of the colon were reported. After skin application to female mice, it produced tumours of the skin, lung, forestomach and oral cavity. BBPP was tested for carcinogenicity in rats by oral administration and another metabolite, DBP, was tested in mice and rats by skin application. They produced a variety of tumours, including skin, forestomach and hepatocellular tumours, in mice and rats, and tumours of the oesophagus, intestine, nasal mucosa and Zymbal gland in rats. From these studies, it can be concluded that TBPP has carcinogenic potential in mice and rats. Effects on humans Limited data are available regarding the effects of TBPP on humans. TBPP has been tested for skin sensitization potential in a few studies on humans. The results of these studies indicate that TBPP has a low sensitization potential and no skin irritation was reported. However, persons who showed a positive sensitization response to pure BPP also reacted when exposed to fabrics treated with TBPP. Date of entry into force of the final regulatory action: 01/08/2005 |