title: Evaluation of the dermal subchronic toxicity of diphenyl ether in the rat.
abstract: 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.
authors.affiliation: Research Institute for Fragrance Materials, Inc., 2 University Plaza Drive, Suite 406, Hackensack, NJ 07601-6209, USA. api@rifm.org
authors.forename: A M
authors.initials: AM
authors.lastname: Api
authors.forename: R A
authors.initials: RA
authors.lastname: Ford
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D009929:Organ Size / Q000187:drug effects; D010476:Perfume / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D010647:Phenyl Ethers / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D010710:Phosphates / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D012709:Serum Albumin / Q000187:drug effects; D012869:Skin Absorption / Q000187:drug effects*; D015430:Weight Gain / Q000187:drug effects
chemical_list: D010476:Perfume; D010647:Phenyl Ethers; D010710:Phosphates; D012709:Serum Albumin; C031538:phenyl ether; D002784:Cholesterol