Natl Toxicol Program Tech Rep Ser. 1999 Jul;478:1-212.
Diethanolamine is widely used in the preparation of diethanolamides and diethanolamine salts of long-chain fatty acids that are formulated into soaps and surfactants used in liquid laundry and dishwashing detergents, cosmetics, shampoos, and hair conditioners. Diethanolamine is also used in textile processing, in industrial gas purification to remove acid gases, as an anticorrosion agent in metalworking fluids, and in preparations of agricultural chemicals. Aqueous diethanolamine solutions are used as solvents for numerous drugs that are administered intravenously. Diethanolamine was selected for evaluation because its large-scale production and pattern of use indicate the potential for widespread human exposure. Male and female F344/N rats and B6C3F1 mice received dermal applications of diethanolamine in 95% ethanol for 2 years. Genetic toxicology studies were performed in Salmonella typhimurium, L5178Y mouse lymphoma cells, cultured Chinese hamster ovary cells, and B6C3F1 mouse peripheral blood erythrocytes. RATS: Groups of 50 male rats were administered 0, 16, 32, or 64 mg diethanolamine/kg body weight in ethanol dermally for 2 years. Groups of 50 female rats were administered 0, 8, 16, or 32 mg/kg in ethanol dermally for 2 years. Survival, Body Weights, and Clinical Findings Survival of vehicle control and dosed male and female rats was similar. Mean body weights of 64 mg/kg males were less than those of the vehicle controls beginning week 8, and mean body weights of females were generally similar to those of the vehicle control group. The only clinical finding attributed to diethanolamine administration was irritation of the skin at the site of application. Pathology Findings: Minimal to mild nonneoplastic lesions occurred at the site of application in the epidermis of dosed male and female rats. The incidence of acanthosis in 64 mg/kg males, the incidences of hyperkeratosis in 32 and 64 mg/kg males and in all dosed female groups, and the incidences of exudate in 64 mg/kg males and in all dosed female groups were greater than those in the controls. The incidences and severities of nephropathy were significantly increased in dosed female rats compared to the vehicle controls. MICE: Groups of 50 male and 50 female mice were administered 0, 40, 80, or 160 mg diethanolamine/kg body weight in ethanol dermally for 2 years. Survival, Body Weights, and Clinical Findings Survival of dosed male groups was similar to that of the vehicle control group; survival of dosed female groups was significantly less than that of the vehicle control group. Mean body weights of 80 and 160 mg/kg males were less than those of the vehicle controls after weeks 88 and 77, respectively. Mean body weights of dosed groups of females were generally less than those of the vehicle controls during the second year of the study. Pathology Findings: In male mice, the incidences of hepatocellular adenoma and of hepatocellular adenoma or carcinoma (combined) in all dosed groups and of hepatocellular carcinoma and hepatoblastoma in 80 and 160 mg/kg males were significantly increased compared to the vehicle controls. The incidences of hepatocellular neoplasms were significantly greater in dosed groups of female mice than in the vehicle control group. The incidences of hepatocellular neoplasms in all dosed groups of males and females exceeded the historical control ranges. Nonneoplastic hepatocyte changes were seen only in dosed male and female mice. Changes consisted of cytoplasmic alteration and syncytial alteration. The incidences of renal tubule adenoma in males occurred with a positive trend; however, the incidences of carcinoma and hyperplasia did not follow this pattern. An extended evaluation of kidney step sections revealed additional adenomas and hyperplasias in all dosed groups. The combined analysis of single and step sections indicated a dose-related increase in the incidences of renal tubule hyperplasia and renal tubule adenoma or carcinoma (combined), and an increase in the incidences of renal tubule adenoma in male mice. Incidences of thyroidthyroid gland follicular cell hyperplasia were increased in dosed male and female mice compared to vehicle controls. Hyperkeratosis, acanthosis, and exudate were treatment-related changes in the skin at the site of application. The incidences of hyperkeratosis were significantly greater than those in the vehicle control groups in all dosed groups except 40 mg/kg females. GENETIC TOXICOLOGY: Diethanolamine was not mutagenic in any of four strains of Salmonella typhimurium, in the presence or absence of S9 metabolic activation enzymes. No induction of trifluorothymidine resistance was observed in L5178Y mouse lymphoma cells treated with diethanolamine with or without S9. Diethanolamine did not induce significant sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells, with or without S9. Peripheral blood samples collected from male and female mice exposed to 80 to 1,250 mg/kg diethanolamine dermally for 13 weeks showed no increase in micronucleated normochromatic erythrocytes. CONCLUSIONS: Under the conditions of these 2-year dermal studies, there was no evidence of carcinogenic activity of diethanolamine in male F344/N rats administered 16, 32, or 64 mg/kg diethanolamine or in female F344/N rats administered 8, 16, or 32 mg/kg. There was clear evidence of carcinogenic activity of diethanolamine in male and female B6C3F1 mice based on increased incidences of liver neoplasms in males and females and increased incidences of renal tubule neoplasms in males. Dermal administration of diethanolamine to rats was associated with increased incidences of acanthosis (males only), hyperkeratosis, and exudate of the skin and increased incidences and severities of nephropathy in females. Dermal administration of diethanolamine to mice was associated with increased incidences of cytoplasmic alteration (males only) and syncytial alteration of the liver, renal tubule hyperplasia (males only), thyroid gland follicular cell hyperplasia, and hyperkeratosis of the skin. Synonyms: Bis-2-hydroxyethylamine; DEA, diethylolamine; 2,2'-dihydroxydiethylamine; diolamine; 2,2'-iminobisethanol; 2,2'-iminodiethanol; iminodiethanol
二乙醇胺广泛用于制备二乙醇酰胺和长链脂肪酸的二乙醇胺盐，这些盐被配制成用于液体洗衣和餐具洗涤剂、化妆品、洗发水和护发素的肥皂和表面活性剂。二乙醇胺还用于纺织加工、工业气体净化以去除酸性气体、作为金属加工液中的防腐剂以及用于制备农用化学品。二乙醇胺水溶液用作多种静脉给药药物的溶剂。选择二乙醇胺进行评估是因为其大规模生产和使用模式表明存在广泛的人类接触可能性。将雄性和雌性F344/N大鼠以及B6C3F1小鼠在95%乙醇中经皮涂抹二乙醇胺，持续2年。在鼠伤寒沙门氏菌、L5178Y小鼠淋巴瘤细胞、培养的中国仓鼠卵巢细胞和B6C3F1小鼠外周血红细胞中进行了遗传毒理学研究。
将50只雄性大鼠分为几组，分别以0、16、32或64毫克二乙醇胺/千克体重的剂量在乙醇中经皮给药2年。将50只雌性大鼠分为几组，分别以0、8、16或32毫克/千克的剂量在乙醇中经皮给药2年。
存活情况、体重和临床发现：赋形剂对照组以及给药的雄性和雌性大鼠的存活率相似。64毫克/千克雄性大鼠的平均体重从第8周开始低于赋形剂对照组，雌性大鼠的平均体重通常与赋形剂对照组相似。唯一归因于二乙醇胺给药的临床发现是给药部位皮肤出现刺激。
给药的雄性和雌性大鼠表皮给药部位出现轻微至轻度的非肿瘤性病变。64毫克/千克雄性大鼠的棘皮症发生率、32和64毫克/千克雄性大鼠以及所有给药雌性组的角化过度发生率，以及64毫克/千克雄性大鼠和所有给药雌性组的渗出物发生率均高于对照组。与赋形剂对照组相比，给药雌性大鼠的肾病发生率和严重程度显著增加。
将50只雄性和50只雌性小鼠分为几组，分别以0、40、80或160毫克二乙醇胺/千克体重的剂量在乙醇中经皮给药2年。
存活情况、体重和临床发现：给药雄性组的存活率与赋形剂对照组相似；给药雌性组的存活率显著低于赋形剂对照组。80和160毫克/千克雄性大鼠的平均体重分别在第88周和第77周后低于赋形剂对照组。在研究的第二年，给药雌性组的平均体重通常低于赋形剂对照组。
在雄性小鼠中，与赋形剂对照组相比，所有给药组的肝细胞腺瘤、肝细胞腺瘤或癌（合并）以及80和160毫克/千克雄性大鼠的肝细胞癌和肝母细胞瘤的发生率均显著增加。给药雌性小鼠组的肝细胞肿瘤发生率显著高于赋形剂对照组。所有给药雄性和雌性组的肝细胞肿瘤发生率均超过历史对照范围。仅在给药的雄性和雌性小鼠中观察到非肿瘤性肝细胞变化。变化包括细胞质改变和多核细胞改变。雄性肾小管腺瘤的发生率呈上升趋势；然而，癌和增生的发生率未呈现此模式。对肾脏连续切片的进一步评估显示，所有给药组均有额外的腺瘤和增生。对单张切片和连续切片的综合分析表明，雄性小鼠肾小管增生、肾小管腺瘤或癌（合并）的发生率呈剂量相关增加，肾小管腺瘤的发生率也增加。与赋形剂对照组相比，给药雄性和雌性小鼠的甲状腺滤泡细胞增生发生率增加。角化过度、棘皮症和渗出物是给药部位皮肤的治疗相关变化。除40毫克/千克雌性组外，所有给药组的角化过度发生率均显著高于赋形剂对照组。
在有或无S9代谢激活酶的情况下，二乙醇胺在四种鼠伤寒沙门氏菌菌株中均无致突变性。在用二乙醇胺处理的L5178Y小鼠淋巴瘤细胞中，无论有无S9，均未观察到三氟胸苷抗性的诱导。在有或无S9的情况下，二乙醇胺在培养的中国仓鼠卵巢细胞中均未诱导显著的姐妹染色单体交换或染色体畸变。从经皮暴露于80至1250毫克/千克二乙醇胺13周的雄性和雌性小鼠采集的外周血样本中，未观察到微核正染红细胞增加。
在这些为期2年的经皮研究条件下，没有证据表明在给予16、32或64毫克/千克二乙醇胺的雄性F344/N大鼠或给予8、16或32毫克/千克的雌性F344/N大鼠中，二乙醇胺具有致癌活性。基于雄性和雌性肝脏肿瘤发生率增加以及雄性肾小管肿瘤发生率增加，有明确证据表明二乙醇胺对雄性和雌性B6C3F1小鼠具有致癌活性。对大鼠经皮给予二乙醇胺与棘皮症（仅雄性）、角化过度和皮肤渗出物的发生率增加以及雌性肾病的发生率和严重程度增加有关。对小鼠经皮给予二乙醇胺与细胞质改变（仅雄性）、肝脏多核细胞改变、肾小管增生（仅雄性）、甲状腺滤泡细胞增生以及皮肤角化过度的发生率增加有关。
双-2-羟乙基胺；DEA，二乙醇胺；2,2'-二羟基二乙胺；二醇胺；2,2'-亚氨基双乙醇；2,2'-亚氨基二乙醇；亚氨基二乙醇
