title: Short-term oral toxicity of pentyl ether, 1,4-diethoxybutane, and 1,6-dimethoxyhexane in male rats.
abstract: Pentyl ether (PE) and two newly synthesized polyoxy ethers, 1,4-diethoxybutane (DEB) and 1,6-dimethoxyhexane (DMH), have been proposed as candidate diesel fuel additives. To characterize and compare their toxicity and to provide information for risk assessment, a 4-week oral study was conducted on these compounds. Male Sprague-Dawley rats (288 +/- 20 g) were divided into groups of seven animals each, and were administered by gavage low (2 mg/kg body weight), medium (20 mg/kg body weight), or high (200 mg/kg body weight) doses of PE, DEB, or DMH, respectively, 5 days/week for 4 weeks. Animals in the control group received the vehicle (corn oil, 1 ml/100 g body weight) only. At the end of the exposure period, relative testis and thymus weights were reduced by 30 and 46%, respectively, in animals treated with the high dose of DMH. Significant reductions in serum lactate dehydrogenase (LDH), serum uric acid, and blood platelet counts were also observed in the high dose of DMH. Serum corticosterone was significantly depressed in the high doses of PE and DEB and in the low dose of DMH. Serum thiobarbituric acid-reactive substances (TBARS) were decreased (p < 0.05) in all DMH treatment groups and in the medium and high dose PE and DEB groups, while liver TBARS were unaffected by treatment. In the liver, increased glutathione (GSH) level and glutathione-S-transferases activity were detected in the high dose DMH group. Urinary ascorbic acid levels were markedly increased in animals receiving the high doses of PE, DEB, and DMH. Urinary formic acid was increased by 13 times in the high dose PE and DEB groups. Testes of all animals receiving the high dose of DMH showed a moderate to marked degree of degeneration of the seminiferous tubules, including a mild degree of vacuolation. At the same time, the epididymis of these animals had substantially reduced sperm density with prominent presence of spermatid giant cells. Mild histological changes were seen in the liver at all dose levels for all three chemicals. Thyroid effects were also observed in the high dose PE and DEB groups and in the medium and high dose DMH groups. It was concluded that DMH is the most toxic of the three ethers tested, with testicular, epidiymal, and thymic effects being the most prominent at 200 mg/kg. Other significant changes included depressed platelet counts and serum biochemical changes. Increased production of formic acid, an ocular toxin, from PE and DEB treatments may also be of toxicological concern.
authors.affiliation: Environmental Health Science Bureau, Health Canada, Ottawa, Ontario, Canada. raymond_poon@hc-sc.gc.ca
authors.forename: Raymond
authors.initials: R
authors.lastname: Poon
authors.forename: Marc
authors.initials: M
authors.lastname: Rigden
authors.forename: Ih
authors.initials: I
authors.lastname: Chu
authors.forename: Victor E
authors.initials: VE
authors.lastname: Valli
mesh_terms: D000284:Administration, Oral; D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D002073:Butanes / Q000008:administration & dosage / Q000633:toxicity*; D019963:Clinical Chemistry Tests; D004305:Dose-Response Relationship, Drug; D004987:Ethers / Q000008:administration & dosage / Q000633:toxicity*; D005019:Ethyl Ethers / Q000008:administration & dosage / Q000633:toxicity*; D005742:Gasoline; D006403:Hematologic Tests; D006586:Hexanes / Q000008:administration & dosage / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013737:Testis / Q000187:drug effects / Q000473:pathology; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D013950:Thymus Gland / Q000187:drug effects / Q000473:pathology; D013961:Thyroid Gland / Q000187:drug effects / Q000473:pathology; D023382:Toxicity Tests, Acute
chemical_list: C488840:1,4-diethoxybutane; C488841:1,6-dimethoxyhexane; D000393:Air Pollutants; D002073:Butanes; D004987:Ethers; D005019:Ethyl Ethers; D005742:Gasoline; D006586:Hexanes; D017392:Thiobarbituric Acid Reactive Substances; C488839:pentyl ether