Natl Toxicol Program Tech Rep Ser. 2004 May(518):5-163.
[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.
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.
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.
[结构——见正文]三乙醇胺广泛用于家用洗涤剂和上光剂、纺织品、农用除草剂、矿物油和植物油、石蜡和蜡、药用软膏、石油破乳剂、合成树脂、增塑剂、粘合剂和密封剂的生产。它用作阴离子和非离子表面活性剂的化学中间体、硫化促进剂、保湿剂和软化剂以及许多其他工业应用。美国国立癌症研究所将三乙醇胺列入研究对象，因为它在化妆品和其他消费品中广泛使用，由于其众多工业用途，工人接触的可能性很高，并且有可能转化为致癌物N-亚硝基二乙醇胺。美国国家毒理学计划此前在F344/N大鼠和B6C3F1小鼠中对三乙醇胺进行了为期3个月和2年的研究；两年期大鼠研究结果表明，基于肾小管腺瘤发病率的轻微增加，有模棱两可的致癌活性证据（NTP，1991年）。小鼠两年期研究结果的解释因肝螺杆菌感染而变得复杂，促使对小鼠进行重复的两年期研究。雄性和雌性B6C3F1小鼠通过皮肤涂抹接受三乙醇胺（纯度大于99%），持续2年；在另外的小鼠中进行了吸收、分布、代谢和排泄研究。在鼠伤寒沙门氏菌、培养的中国仓鼠卵巢细胞、黑腹果蝇和小鼠外周血红细胞中进行了遗传毒理学研究。
每组50只雄性和50只雌性小鼠每周5天通过皮肤涂抹0、200、630或2000mg/kg（雄性）和0、100、300或1000mg/kg（雌性）的三乙醇胺丙酮溶液，持续104周（雄性）或104至105周（雌性）。所有给药组的存活率与赋形剂对照组相似。2000mg/kg雄性小鼠的体重在第17至37周以及研究结束时低于赋形剂对照组；给药组雌性小鼠的体重在整个研究过程中与赋形剂对照组相似。与治疗相关的临床发现包括涂抹部位的皮肤刺激，其随剂量增加而增加，且雄性比雌性更严重。尸检时观察到的大体病变包括给药雌性小鼠肝脏中的结节和肿块。所有给药组雌性小鼠的肝细胞腺瘤和肝细胞腺瘤或癌（合并）的发生率均显著增加。630mg/kg雄性小鼠肝脏血管肉瘤的发生率略有增加。所有给药组小鼠嗜酸性病灶的发生率均高于赋形剂对照组。尸检时观察到的大体病变包括所有给药组小鼠涂抹部位可见的结痂。大多数给药组小鼠涂抹部位出现与治疗相关的表皮增生、化脓性炎症、溃疡和皮肤慢性炎症，这些病变的发生率和严重程度通常随剂量增加而增加。
三乙醇胺在任何体外或体内试验中均无致突变性。它在鼠伤寒沙门氏菌中未诱导突变，在暴露于三乙醇胺的培养中国仓鼠卵巢细胞中未观察到姐妹染色单体交换或染色体畸变的诱导。这些体外试验均在有和没有S9代谢活化的情况下进行。三乙醇胺在通过喂食或注射暴露的成年雄性黑腹果蝇生殖细胞中未诱导性连锁隐性致死突变。在接受三乙醇胺皮肤涂抹13周后，雄性或雌性小鼠外周血样本中微核红细胞频率未增加。
在本两年期皮肤研究的条件下，基于肝脏血管肉瘤的发生，有模棱两可的证据表明三乙醇胺在雄性B6C3F1小鼠中具有致癌活性。基于肝细胞腺瘤发生率的增加，有一些证据表明三乙醇胺在雌性B6C3F1小鼠中具有致癌活性。通过皮肤涂抹接触三乙醇胺导致雄性和雌性小鼠肝脏嗜酸性病灶的发生率增加。给药小鼠在涂抹部位出现与治疗相关的非肿瘤性病变。
