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% (approximately equal to 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 (approximately equal to 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.