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Specific investigations: other studies

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mechanistic studies
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well-documented mechanistic investigation which meets basic scientific principles

Data source

Reference Type:
Evaluation of the Potential of Triethanolamine to Alter Hepatic Choline Leveis in Female B6C3F1 Mice
Stott, W.T. et al
Bibliographic source:
Toxicological sciences 79, 242-247

Materials and methods

Test guideline
no guideline followed
Principles of method if other than guideline:
The potential of TEA to cause choline deficiency in the liver of 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® rats were also administered 0 or an MTD dosage of 250 mg/kg/day TEA (Trial II) in a similar manner.
GLP compliance:
not specified
Type of method:
in vivo
Endpoint addressed:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Details on test material:
Two samples of TEA ware used, one supplied by The Dow Chemical Company (Seadrift, TX; Lot QB1955R8S4) for use in the first mouse trial und the other a generous gift of the National Toxicology Program (RTI International, Research Triangle Park, NC; Lot 7G-60/02) for use in the second mouse und die rat trials. Both had greater than 99% purity; however, analyses identified differences in DEA impurity levels, 0.04% and 0.45%, respectively.

Test animals

other: Mouse and rat
other: B6C3F1 (mouse) and CDF (rat)
Details on test animals or test system and environmental conditions:
Female B6C3F1/CrIBR® (B6C3F1) mice and CDF® (Fischer 344/CrIBR) (CDF) rats were obtained from Charles River Laboratories Inc. (Portage. MI). Animals were housed one per cage in appropriate stainless steel cages in rooms designed to maintain adequate conditions (temperature, humidity, and photocycle). Animals ware provided LabDiet® Certified Rodent Diet #5002 (PMI Nutrition International, St. Louis, MO) in pelleted form in a hanging feeder und municipal water from a pressure-activated nipple-type watering system ad libitum. This diet contains approximately 1800 ppm choline. Following acclimation, animals (8-12 weeks of age) were stratified using preexposure body weights und ware randomly assigned to treatment groups.

Administration / exposure

Route of administration:
Details on exposure:
An area on the back of each mouse or rat, between the scapulae and stretching posterior approximately halfway to the ileum, was clipped free of hair at least 24 h prior to initiation of dosing. This area was reclipped over the course of the dosing period, as needed, at least 24 hours prior to resumption of dosing. Care was taken to avoid abrasion or nicking of skin. Dosing was as described by NTP (1999a; 2003), by applying (“painting") solutions or vehicle (acetone) directly on the skin using a blunt syringe. Dose solutions in acetone vehicle were applied at a volume of 4 ml/kg (250 mg/ml) in the first mouse trail, 2 ml/kg (5-500 mg/ml) in the second mouse trial, and 0.5 ml/kg (500 mg/ml) in the rat trial. The exposure site was not occluded, nor was any restraining device employed to prevent grooming.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
3 weeks
Frequency of treatment:
5 days per week
Post exposure period:
Doses / concentrationsopen allclose all
Doses / Concentrations:
0 or 1000 mg/kg/day
nominal conc.
Trial I (mouse)
Doses / Concentrations:
0, 10, 100, 300 or 1000 mg/kg/day
nominal conc.
Trial II (mouse)
Doses / Concentrations:
0 or 250 mg/kg/day
nominal conc.
Trial II (rat)
No. of animals per sex per dose:
Trial I: 10
Trial II: 8 (mouse and rat)
Control animals:
yes, concurrent vehicle

Results and discussion

Details on results:
Clinical Observations and Body Weights
No effects of dosing upon the clinical appearance, body weights, or weight gains of mice or rats were noted. In addition, no evidence of dermal irritation of dosing solutions was noted during the dosing period.

In Vivo Choline and Choline-Related Metabolites
In the initial mouse trial (Trial I), a 1000 mg/kg/day TEA dosage caused statistically identified decreases in betaine (26%) and PCho (35%) levels relative to vehicle treated controls. A smaller decrease in hepatic choline concentration (13%) was also observed, which was not statistically identified. In a subsequent dose-response experiment (Trial II mice), all three measured parameters were statistically identified by Trend Test as changing over the dose range, despite a noticeable degree of variability in the data. PCho levels were decreased by 18-20% at 100-300 mg/kg/day and by 42% at 1000 mg/kg/day compared to controls. Hepatic betaine levels were also decreased across most dosages, with minimal levels observed at the high dosage (29% decrease), and choline levels of high-dose-group mice were depressed by 35% compared to controls. Pairwise statistically significant changes were limited to high-dose groups. Administration of 250 mg/kg/day TEA to male CDF rats failed to cause a significant change in any measured parameter.

In Vitro Choline Uptake
TEA caused a statistically identified decrease in the uptake of 3H-choline by growing CHO cells. A dose-related decrease in uptake occurred from 0.67 mM to 1.34 mM concentrations, reaching a maximal inhibition of approximately 60-70% of control at 1.34 to 3.4 mM over the 10-min dosing period. A more pronounced response to DEA was observed, with a dose-related decrease in 3H-choline uptake observed from 0.048 to 0.15 mM, reaching a maximal inhibition of approximately 75% of control at 0.19 to 1.9 mM.

Applicant's summary and conclusion