Comparative Metabolism and Toxicokinetics of 14C-ResorcinoI Bis-Diphenylphosphate (RDP) in the Rat, Mouse, and Monkey

Abstract

As part of a comprehensive program to examine the safety and toxicokinetics of the flame retardant, resorcinol bis-diphenylphosphate (RDP), the metabolism and toxicokinetics of RDP was determined after exposure of rats and monkeys to 14C-RDP via intravenous, inhalation, oral, or dermal routes. The metabolism of RDP was also determined in mice. Blood, urine, and fecal samples were collected at specified times for the quantification of 14C levels. Expired air was collected from rats. Excreta samples were quantitatively extracted. Chromatographic profiles of urinary and fecal metabolites were generated for multiple animals from each group. The major metabolites were isolated and then purified by a multistep chromatographic process. Structures of urinary and fecal metabolites were determined by HPLC-mass spectrometry (MS), MS-MS, and MS-MS-MS techniques. The metabolic pattern in all three species is complex. In certain urine and feces samples, radioactivity was associated with more than 30 HPLC peaks. There was little interanimal variability in metabolic profiles. No differences between species or sexes were apparent. The parent molecule, RDP, was present in significant amounts only in the feces of animals exposed by inhalation or gavage; this appears to reflect unabsorbed ingested material. Structures of all major urinary and fecal metabolites (representing 5% of the administered dose) in rats and primates were identified. The major fecal metabolites were resorcinol diphenylphosphate (RDP half ester), hydroxy-RDP half ester, dihydroxy-RDP, and hydroxy-RDP. Major urinary metabolites were identified as resorcinol, resorcinyl glucuronide, and resorcinyl sulfate. A small amount of 14CO2 was expired. This study confirms that RDP is metabolized in an identical manner by rats, mice, and primates, and that the rat and mouse are appropriate surrogates (animal models) in which to assess the toxicity of RDP. In both rats and primates, the highest peak plasma concentration (Cmax) and greatest area under the curve (AUC) was obtained with intravenous (TV) administration. In rats the Cmax for inhalation, oral, and dermal exposures were 42%, 10%, and 1%, respectfully. The AUC values for these three routes were 60%, 58%, and 15% of the IV AUC. Approximately 20% of the dermal dose was absorbed in the rat whereas primates absorbed only 10% of the applied dermal dose. Tissue accumulation and retention of radioactivity was minimal, indicating complete clearance of the administered dose.