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Toxicological information

Specific investigations: other studies

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Administrative data

Endpoint:
mechanistic studies
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well-documented mechanistic investigation which meets basic scientific principles

Data source

Reference
Reference Type:
publication
Title:
Development of a Transgenic Mouse Model for Carcinogenesis Bioassays: Evaluation of Chemically Induced Skin Tumors in Tg.AC Mice
Author:
Spalding, J.W. et al
Year:
1999
Bibliographic source:
Toxicological Sciences 49, 241-254

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
TEA was solubilized in acetone and applied topically in a total volume of 200 µl with an automatic pipette. That volume, when applied in an anterior to posterior manner along the dorsal midline, spread evenly over the shaved area. The frequency of administration of acetone matched that of TEA.
GLP compliance:
not specified
Type of method:
in vivo
Endpoint addressed:
carcinogenicity

Test material

Constituent 1
Reference substance name:
triethanolamine
IUPAC Name:
triethanolamine
Constituent 2
Chemical structure
Reference substance name:
2,2',2''-nitrilotriethanol
EC Number:
203-049-8
EC Name:
2,2',2''-nitrilotriethanol
Cas Number:
102-71-6
Molecular formula:
C6H15NO3
IUPAC Name:
2,2',2''-nitrilotriethanol
Details on test material:
Triethanolamine (TEA) was obtained from the National Toxicology Program, NIEHS.

Test animals

Species:
mouse
Strain:
other: Tg.AC
Sex:
female
Details on test animals or test system and environmental conditions:
Four or five week old female homozygous Tg.AC mice were received from an NTP-maintained colony at Taconic Farms Inc., Germantown, NY.
The ages of the mice at initiation of treatment ranged from 7 to 18 weeks. Mice were maintained in groups of 4 or 5, in polycarbonate shoebox-style cages containing hardwood bedding (Beta Chips, Northeastern Products Corp., Warrensbury, NY). Husbandry practices were carried out in compliance with NIH Guidelines for Humane Care and Use of Laboratory Animals. Room temperature was 72±2°F; humidity ranged from 40-60%; and fluorescent lighting was on a 12-h light-dark cycle. Purina Pico Chow No. 5058 (Ralston Purina, St. Louis, MO) and tap water were available ad libitum. Animals were uniquely identified with tattoo numbers on their tails (Animal Identification and Marking System, Piscataway, NJ). Prior to beginning chemical exposure, 15-20 animals were randomly allocated to each treatment group, the mice remaining with their originally assigned cage mates.

Administration / exposure

Route of administration:
dermal
Vehicle:
acetone
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
20 weeks
Frequency of treatment:
5x/week
Post exposure period:
no data
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 3, 10, 30 mg/animal
Basis:

Remarks:
Doses / Concentrations:
0, 120, 400, 1200 mg/kg bw
Basis:

No. of animals per sex per dose:
13-20
Control animals:
yes, concurrent vehicle

Examinations

Positive control:
TPA was administered at a dose of 1.25 ug in 200ul 2x/week

Results and discussion

Details on results:
Homozygous Tg.AC mice in the negative control groups treated with acetone developed a very low frequency of papillomas. The average papilloma incidence among animals treated 5 days per week with 3.0 to 30 mg of TEA was not significantly different from the incidence observed in animals treated with acetone, the negative control and solvent vehicle. There was no significant difference in weight gain among vehicle-control or TEA-treated groups. Survival was slightly reduced in the TEA-treated groups, but this was mainly due to removal of animals with odontomas from the study.

Any other information on results incl. tables

Transgenic rodent models have emerged as potentially useful tools in the assessment of drug and chemical safety. The transgenic Tg.AC mouse carries an inducible v-Ha-ras oncogene that imparts the characteristic of genetically initiated skin to these animals. The induction of epidermal papillomas in the area of topically applied chemical agents, for duration of not more than 26 weeks, acts as a reporter phenotype that defines the activity of the test article. We describe here the activity of six chemicals that have been previously characterized for activity in the standard 2 -year bioassay conducted by the National Toxicology Program (NTP). Homozygous female Tg.AC mice were treated with benzene (BZ), benzethonium chloride (BZTC), o-benzyl-p- chlorophenol (BCP), 2 -chloroethanol (2 -CE), lauric acid diethanolamine (LADA) and triethanolamine (TEA). BZ and LADA induced skin papillomas in adose-dependent manner, while BCP induced papillomas only at the highest dose. BZTC, 2-CE, and TEA exhibited no activity. The correspondence of chemical activity in Tg.AC mice with that in the 2 - year bioassay was high. A comparison of responsiveness to BZ and LADA was made between hemizygous and homozygous female Tg.AC mice. Both genotypes appear to be equally sensitive to maximum doses of active compounds. The results reported here indicate that the Tg.AC transgenic mouse model can discriminate between carcinogens and noncarcinogens and that both mutagenic and nonmutagenic chemicals can be detected. These studies provide support for the adjunctive use of the Tg.AC transgenic mouse skin tumor model in drug and chemical safety assessment and for the prediction of the carcinogenic potential of chemicals.

Treatment

Incidence of animals with tumors (%)

Mean weeks to first tumor (±SD)

Mean tumor/animals at risk (±SD)

Mean weeks to maximal tumor yield (±SD)

Survival at 20 weeks (%)

Acetone

4/14 (29%)

13.3±2.1

0.3±0.0

13.3±2.1

14/14 (100%)

3.0 mg TEA

4/14 (29%)

11.8±7.3

±0.5

13.8±6.7

11/14 (79%)

10.0 mg TEA

5/13 (38%)

13.4±4.9

0.8±2.2

14.8±5.4

12/13 (92%)

30.0 mg TEA

4/19 (21%)

8.8±2.6

0.5±1.7

13.5±4.4

15/19 (79%)

TPA 1.25 ug

19/20 (95%)

7.4±2.4

19.5±12.4

13.6±3.5

9/20 (45%)

Applicant's summary and conclusion

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