Evaluation of the Potential of Triethanolamine to Alter Hepatic Choline Levels in Female B6C3F1 Mice

Abstract

Triethanolamine (TEA), a widely used nongenotoxic alcohol-amine, has recently been reported to cause an increased incidence of liver tumors in female B6C3F1 mice, but not in males nor in Fischer 344 rats. Choline deficiency induces liver cancer in rodents, and TEA could compete with choline uptake into tissues. The potential of TEA to cause choline deficiency in the liver of these mice as a mode of tumorigenesis was investigated. Groups of female B6C3F1 mice were administered 0 (vehicle) or a maximum tolerated dosage (MTD) of 1000 mg/kg/day TEA (Trial I) and 0, 10, 100, 300, or 1000 mg/kg/day TEA (Trial II) in acetone vehicle via skin painting 5 days/week for 3 weeks. Female CDF(R) rats were also administered 0 or an MTD dosage of 250 mg/kg/day TEA (Trial II) in a similar manner. No clinical signs of toxicity were noted, and upon sacrifice, levels of hepatic choline, its primary storage form, phosphocholine (PCho), and its primary oxidation product, betaine, were determined. A statistically significant decrease in PCho and betaine, was observed at the high dosage (26-42%) relative to controls and a dose-related, albeit variable, decrease was noted in PCho levels. Choline levels were also decreased 13-35% at the high dose level in mice. No changes in levels of choline or metabolites were noted in treated rats. A subsequent evaluation of the potential of TEA to inhibit the uptake of (3)H-choline by cultured Chinese Hamster Ovary Cells revealed a dose-related effect upon uptake. It was concluded that TEA may cause liver tumors in mice via a choline-depletion mode of action and that this effect is likely caused by the inhibition of choline uptake by cells.

Diethanolamine alters neurogenesis and induces apoptosis in fetal mouse hippocampus

“…Manufacturers sometimes substitute triethanolamine (TEA) for DEA in products. We found that TEA can also perturb choline metabolism (37), and suggest that it, too, should be evaluated for effects on pregnancy and brain development.…”

Investigation of the formation of N-nitrosodiethanolamine in B6C3F1 mice following topical administration of triethanolamine

“…Previous evaluations of NDELA formation in vivo indicated maximal formation at approximately 2 h post dosing (Stott et al, 2000b). As shown in Table 3, the concentration of NDELA in the blood and ingesta of TEA-treated mice averaged 0.001 § 0.0005 g/g (<detection limit in most samples) and 0.044 § 0.059 g/g, respectively.…”

“…However, a recent dermal (skin paint) oncogenicity study of TEA conducted by the NTP (2003) in B6C3F1 mice at dose levels up to 2000 mg/kg/day in males and at 100, 300, and 1000 mg/kg/day in females for 2 years revealed an increased incidence of liver adenomas in females (only) at all three dose levels. The mode of action (MoA) for liver tumour formation in female B6C3F1 mice has been reported to be related to TEA-induced depletion of choline (Stott et al, 2004), a non-genotoxic threshold-based MoA. However, the frequent suggestion in the literature of in vivo formation of the nitrosamine N-nitrosodiethanolamine (NDELA) from TEA had also raised the question of the potential involvement of this, more serious, MoA in liver tumour formation.…”

Safety Assessment of Triethanolamine and Triethanolamine-Containing Ingredients as Used in Cosmetics

“…It has been reported that choline deficiency induces liver cancer in rodents 51,52 ; therefore, the potential of TEA to cause choline deficiency in the liver of female B6C3F 1 mice was investigated as a mode of tumorigenesis. 53 Female mice were dosed dermally with unoccluded applications of 10, 100, 300, or 1000 mg/kg/d TEA in acetone, 5 d/wk for 3 weeks, and female CDF rats were dosed in a similar manner with 250 mg/kg/d TEA. (Purity of TEA was 99+%; diethanolamine impurity levels were 0.04% and 0.45%.)…”