Saghir Shakil A, Brzak Kathy A, Markham Dan A, Bartels Michael J, Stott William T
Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, MI 48642, USA.
Regul Toxicol Pharmacol. 2005 Oct;43(1):10-8. doi: 10.1016/j.yrtph.2005.04.002.
To determine potential nitrosation of triethanolamine (TEA) to N-nitrosodiethanolamine (NDELA) at different physiological conditions of the GI tract, in vitro NDELA formation was examined in aqueous reaction mixtures at several pHs (2-10) adjusted with acetic, sulphuric or hydrochloric acids or in cultures of mouse cecal microflora incubated. In vivo NDELA formation was also determined in blood, ingesta, and urine of female B6C3F1 mice after repeated dermal, most relevant human route, or single oral exposure to 1000 mg/kg TEA in the presence of high oral dosages of NaNO(2). Appropriate diethanolamine (DEA) controls were included to account for this impurity in the TEA used. Samples were analyzed for NDELA using GC/MS. The highest degree of nitrosation of TEA to NDELA ( approximately 3%) was observed in the in vitro cultures at pH 4 and acetic acid with lower amounts obtained using sulphuric acid ( approximately 1.3%) and hydrochloric acid ( approximately 1.2%). At pH 7, <1% of the TEA was nitrosated to NDELA and at pH 2 (HCl) or pH 10 (NaOH) no NDELA was found above the limit of detection. In incubated cultures containing cecal microflora and nutrient broth, only 0.68% of TEA was nitrosated to NDELA. No NDELA was formed in rats repeatedly dermally dosed with TEA at the limits of detection in blood (0.001 microg/ml, ppm), ingesta (0.006 microg/ml, ppm), and urine (0.47 microg/ml, ppm). Levels of NDELA measured in blood and ingesta after a single oral dose of TEA and NaNO(2) were less than those in DEA controls. These findings in toto confirm the lack of any significant formation of NDELA from TEA in vivo.
为了确定在胃肠道不同生理条件下三乙醇胺（TEA）向N-亚硝基二乙醇胺（NDELA）的潜在亚硝化作用，通过用乙酸、硫酸或盐酸调节至几种pH值（2 - 10）的水性反应混合物，或在小鼠盲肠微生物培养物中检查体外NDELA的形成。在雌性B6C3F1小鼠经反复皮肤给药（最相关的人体途径）或单次口服1000 mg/kg TEA且同时口服高剂量NaNO₂后，还测定了其血液、食糜和尿液中NDELA的体内形成情况。使用了合适的二乙醇胺（DEA）对照来考虑所使用的TEA中的这种杂质。使用气相色谱/质谱联用仪（GC/MS）分析样品中的NDELA。在体外培养物中，在pH 4和乙酸条件下观察到TEA向NDELA的亚硝化程度最高（约3%），使用硫酸（约1.3%）和盐酸（约1.2%）时获得的量较低。在pH 7时，<1%的TEA被亚硝化生成NDELA，在pH 2（HCl）或pH 10（NaOH）时，未发现高于检测限的NDELA。在含有盲肠微生物和营养肉汤的培养物中，仅0.68%的TEA被亚硝化生成NDELA。在大鼠经TEA反复皮肤给药后，在血液（检测限为0.001微克/毫升，ppm）、食糜（检测限为0.006微克/毫升 ppm）和尿液（检测限为0.47微克/毫升，ppm）中未检测到NDELA的形成。单次口服TEA和NaNO₂后，在血液和食糜中测得的NDELA水平低于DEA对照中的水平。这些总体发现证实了体内TEA不会显著形成NDELA。
