This article is available online at http://dmd.aspetjournals.org ABSTRACT:Among the group of polybrominated diphenyl ethers used as flame-retardants, the fully brominated diphenyl ether, decabromodiphenyl ether (decaBDE), is the most commonly used. Despite the large usage of decaBDE, neither the metabolic pathways nor the absorption have been addressed, and there are very few studies on its toxicology. In this work, it is shown that after a single oral dose of 14 C-labeled decaBDE to rats, at least 10% of the decaBDE dose is absorbed. The major excretion route in conventional rats is via feces that contained 90% of the decaBDE dose. The excretion in bile was close to 10% of the dose and represented mainly metabolites. It cannot be excluded that greater than 10% of the oral dose had been absorbed since 65% of the radioactivity excreted in feces was metabolites. The highest concentrations on a lipid weight basis were found in plasma and blood-rich tissues, and the adipose tissue had the lowest concentration of decaBDE. After derivatization of a phenolic fraction, gas chromatography-mass spectrometry (GC/MS) analyses indicated that metabolites with five to seven bromine atoms had formed, and they possessed a guaiacol structure (a hydroxy and a methoxy group) in one of the rings. In addition, traces of nonabrominated diphenyl ethers and monohydroxylated metabolites were found by GC/MS. Metabolites, characterized by their chemical properties, were interpreted to be covalently bound to macromolecules, either proteins or lipids. In addition, water solubility was suggested. The metabolic pathway was indicated to include a reactive intermediate.

The tissue distribution, metabolism, and excretion of 14C-labeled 2,4,4'-trichlorobiphenyl (CB-28) were studied in the rat. Following intravenous administration, radioactivity was removed from the blood rapidly and distributed to tissues. The time-courses of varying concentrations of CB-28 in tissues and blood were described mathematically using nonlinear regression analysis. The highest concentrations of radioactivity were found in the adipose and skin, which showed distinct uptake phases. High levels were seen at 30 minutes in liver and brain, but quickly declined. Fifty-two percent of the given dose was excreted in feces within 14 days. Intraperitoneal administration to three female rats for five consecutive days provided tissues which were analyzed for metabolites.

1. After an oral dose of (14)C-labelled 3,3',4,4'-tetrachlorobiphenyl (CB-77), the conventional germ-free and bile-duct cannulated male Sprague-Dawley rat excreted approximately 80% of the dose in faeces and/or bile within 3 days. 2. For the germ-free and conventional rat, 15% of the dose was excreted via the faeces as metabolites covalently bound to lipids. Bile-duct-cannulated rats excreted similar amounts of lipid-bound metabolites in the bile. The lipid-bound metabolites appear to be formed in the liver and excreted via the bile, and the microflora did not seem essential for the formation of lipid-bound metabolites. 3. The novel CB-77 metabolites had chemical and physical properties similar to those of lipids with regard to solubility and polarity, as determined by partition characteristics on various chromatographic systems. 4. In addition to identification of hydroxylated CB-77 metabolites, several fatty acid esters of hydroxy-chlorobiphenyls were indicated and one hydroxy-tetrachlorobiphenylol palmitoate was identified, but fatty acid esters were minor metabolites. 5. Approximately 70% of the lipid-bound metabolites were present in the fraction that contained phospholipids. The formation of lipid-bound CB-77 metabolites seems a spontaneous reaction rather than an enzymatically catalysed reaction, as indicated by the large number of different lipid-bound metabolites.