Evaluation of the dermal subchronic toxicity of diphenyl ether in the rat

Diphenyl ether (DPE) was investigated to determine the dermal absorption parameters and subchronic toxicity of this fragrance ingredient. For the absorption, distribution and elimination study, Sprague–Dawley rats received a dermal application of [14C]DPE under a semi-occlusive dressing for 6 h. DPE was diluted in diethyl phthalate (DEP) to administer a total application volume of 2 ml/kg and concentrations of 0.5, 5 and 50% (≅10, 100 and 1000 mg DPE/kg body weight). Approximately 17.7% of the administered dose was eliminated in the urine, with small amounts also found in the feces (1.18–3.79%). At 72 h post-dosing, approximately 0.2% of the applied dose was retained in the body with low levels also measured in the liver, kidney and gastrointestinal tract (≅ 0.04, 0.02 and 0.3%, respectively). The 13-week subchronic toxicity study was performed with groups of 12 Sprague–Dawley rats/sex/dose that received semi-occluded daily dermal applications of DPE for 6 h/day. All groups were dosed at a constant 2 ml/kg body weight volume of DPE in the DEP vehicle at concentrations to administer 0, 100, 300 or 1000 mg DPE/kg body weight/day. At the high dose level, there was a slight reduction in body weight gain in males (13%), increase in albumin (5–6%) and phosphate (10–15%) levels in both sexes, a reduction of cholesterol in females (14%), an increase in kidney (17%) and brain (8%) weights in males, and an increase in liver weight (18–19%) in both sexes. No histopathological lesions were seen in any organ examined. At 300 mg/kg body weight/day, the only notable findings were an increase in liver weight (10%) in both sexes and a slight increase in albumin (5%) in females. In addition, skin irritation reactions at the site of application were observed in all DPE dose groups. The systemic no-observed-effect level (NOEL) in this study is 100 mg/kg body weight/day. Owing to mitigating factors, the systemic findings were judged to lack biological significance and the no-observed-adverse-effect level (NOAEL) was determined to be 1000 mg/kg body weight/day.