NTP toxicology and carcinogenesis studies of triethanolamine (Cas No. 102-71-6) in B6C3F1 mice (dermal studies).
[structure--see text] Triethanolamine is widely used in the manufacturing of household detergents and polishes, textiles, agricultural herbicides, mineral and vegetable oils, paraffin and waxes, pharmaceutical ointments, petroleum demulsifiers, synthetic resins, plasticizers, adhesives, and sealants. It is used as a chemical intermediate for anionic and nonionic surfactants, a vulcanization accelerator, a humectant and softening agent and in many other industrial applications. The National Cancer Institute nominated triethanolamine for study because of its widespread use in cosmetics and other consumer products, its high potential for worker exposure due to its many industrial uses, and its potential for conversion to the carcinogen N-nitrosodiethanolamine. Previous 3-month and 2-year studies of triethanolamine were conducted by the National Toxicology Program in F344/N rats and B6C3F1 mice; results from the 2-year rat study indicated equivocal evidence of carcinogenic activity based on a marginal increase in the incidence of renal tubule adenoma (NTP, 1991). Interpretation of the results from the 2-year study in mice was complicated by Helicobacter hepaticus infection, prompting a repeat 2-year study in mice. Male and female B6C3F1 mice received triethanolamine (greater than 99% pure) by dermal application for 2 years; a study of absorption, distribution, metabolism, and excretion was performed in additional mice. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, Drosophila melanogaster, and mouse peripheral blood erythrocytes. 2-YEAR STUDY: Groups of 50 male and 50 female mice received dermal applications of 0, 200, 630, or 2,000 mg/kg (males) and 0, 100, 300, or 1,000 mg/kg (females) triethanolamine in acetone, 5 days per week, for 104 (males) or 104 to 105 (females) weeks. Survival of all dosed groups was similar to that of the vehicle control groups. Body weights of 2,000 mg/kg males were less than those of the vehicle controls from weeks 17 to 37 and at the end of the study; body weights of dosed groups of females were similar to those of the vehicle controls throughout the study. Treatment-related clinical findings included skin irritation at the site of application, which increased with increasing dose and was more severe in males than in females. Gross lesions observed at necropsy included nodules and masses of the liver in dosed females. The incidences of hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined) were significantly increased in all dosed groups of females. The incidence of hemangiosarcoma of the liver in 630 mg/kg males was marginally increased. The incidences of eosinophilic focus in all dosed groups of mice were greater than those in the vehicle controls. Gross lesions observed at necropsy included visible crusts at the site of application in all dosed groups of mice. Treatment-related epidermal hyperplasia, suppurative inflammation, ulceration, and dermal chronic inflammation occurred at the site of application in most dosed groups of mice, and the incidences and severities of these lesions generally increased with increasing dose.


RESULTS
Triethanolamine was not mutagenic in any of the in vitro or in vivo tests. It did not induce mutations in Salmonella typhimurium, and no induction of sister chromatid exchanges or chromosomal aberrations was noted in cultured Chinese hamster ovary cells exposed to triethanolamine. These in vitro tests were all conducted with and without S9 metabolic activation. Triethanolamine did not induce sex-linked recessive lethal mutations in germ cells of adult male Drosophila melanogaster exposed by feeding or injection. No increase in the frequency of micronucleated erythrocytes was observed in peripheral blood samples of male or female mice that received dermal applications of triethanolamine for 13 weeks.


CONCLUSIONS
Under the conditions of this 2-year dermal study, there was equivocal evidence of carcinogenic activity of triethanolamine in male B6C3F1 mice based on the occurrence of liver hemangiosarcoma. There was some evidence of carcinogenic activity in female B6C3F1 mice based on increased incidences of hepatocellular adenoma. Exposure to triethanolamine by dermal application resulted in increased incidences of eosinophilic focus of the liver in males and females. Dosed mice developed treatment-related nonneoplastic lesions at the site of application.
D018248:Adenoma, Liver Cell / Q000139:chemically induced / Q000473:pathology; D000279:Administration, Cutaneous; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000633:toxicity*; D004983:Ethanolamines / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D006394:Hemangiosarcoma / Q000139:chemically induced / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009152:Mutagenicity Tests; D009374:Neoplasms, Experimental / Q000139:chemically induced* / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D036401:Toxicity Tests, Chronic
D002273:Carcinogens; D004785:Environmental Pollutants; D004983:Ethanolamines; C009546:triethanolamine