2-dimethylaminoethanol

Carcinogenicity

Administrative data

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well documented publication which meets basic scientific principles

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1988

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

10 mM dimethylaminoethanol (DMAE) was administered to mouse sub-lines, the C3H/HeN which carries a germinal mammary tumor provirus and the C3H/He J(+) which also carries the exogenous mammary tumor virus. Both types of mice have a high incidence of tumor appearing. The present study was undertaken to determine the effect of DMAE on aging and lifespan of female mice of two sub-lines and to assess whether it reduced their cryptogenic neoplasm incidence or, conversely, induced neoplasms.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-dimethylaminoethanol

EC Number:

203-542-8

EC Name:

2-dimethylaminoethanol

Cas Number:

108-01-0

Molecular formula:

C4H11NO

IUPAC Name:

2-(dimethylamino)ethanol

Details on test material:

DMAE (Sigma Chemical Company, St. Louis, MO)

Test animals

Species:

mouse

Strain:

other: C3H/HeN and C3H/HeJ(+)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: National Institutes of Health Bethesda, MD
- Age at study initiation: 4 weeks
- Weight at study initiation: not reported
- Fasting period before study:
- Housing: 5/10.5 × 19.5 × 8"polycarbonate cage. The bedding was heat-treated hardwood chips. Cages and food were changed three times a week.
- Diet (e.g. ad libitum): not reported
- Water (e.g. ad libitum): not reported
- Acclimation period: not reported

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21°C ± 1°C)
- Humidity (%): 50 ± 10%
- Air changes (per hr): 14
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

unchanged (no vehicle)

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Solutions of 10 mM (group 2) and 15 mM (group 4) were prepared by adding 8.9 and 13.4 g DMAE to 10 1 of tap water, respectively. The solutions were neutralized to pH 7 using hydrochloric acid and kept refrigerated until use. The drinking water containing DMAE was given in amber glass bottles and made freely available.

VEHICLE - Justification for use and choice of vehicle (if other than water): No, water is the vehicle

Details on analytical verification of doses or concentrations:

Statistical analyses were performed using the X² test with one degree of freedom.

Duration of treatment / exposure:

105 weeks for groups 1 and 2 and 123 weeks for groups 3 and 4 (Table 1 in "any other information on material and methods").

Frequency of treatment:

continuos

Post exposure period:

no

No. of animals per sex per dose:

C3H/HeN mice - 120 animals (60 - treated, 60 - untreated)
C3H/HeJ(+) mice - 100 animals (50 - treated, 50 - untreated)

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The dose of DMAE used in the first study (study with C3H/HeN mice is the first study) was chosen to avoid toxicity. Lifetime administration to female C3H/HeN mice of 10 mM DMAE in the drinking water had no effect on the initial weight gain or mature body weights in treated mice. Therefore, in the second study in C3H/HeJ(+) female mice, a 50% higher dose, i.e. 15 mM was used.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
The survival of DMAE-treated C3H/HeN mice (group 2) or C3H/HeJ(+) mice (group 4) as compared to controls (groups 1 and 3) was not appreciably affected. If anything, in treated groups, a slightly higher mortality was seen in older animals.

BODY WEIGHT AND WEIGHT GAIN
The dose of DMAE used in the first study (study with C3H/HeN mice is the first study) was chosen to avoid toxicity. Lifetime administration to female C3H/HeN mice of 10 mM DMAE in the drinking water had no effect on the initial weight gain or mature body weights in treated mice. Therefore, in the second study in C3H/HeJ(+) female mice, a 50% higher dose, i.e. 15 mM was used. This also did not affect body weights.

GROSS PATHOLOGY
DMAE treatment did not induce any notable changes in the structure or appearance of different organs or in their microscopical morphology using conventional methods. Only the extent of lipofuscin appeared less distinct in the livers in DMAE-treated groups 2 and 4, when evaluated in hematoxylin and eosin stained sections, but this could not be quantified.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
A large number of neoplasms developed in all groups (Table 1) and the influence of the exogenous mammary tumor virus in the C3H/HeJ(+) mice was evident from the high incidence of mammary tumors (Table II). The number of neoplasms in most organs was similar in the control and treated animals (Table II). However, in DMAE-treated mice a possible slight, though not statistically significant, decrease in the incidence of mammary neoplasms was observed, i.e. 16% in treated C3H/HeN mice vs. 24% in controls and 68% in treated C3H/HeJ(+) mice vs. 73% in controls. Histological study of the neoplasms in the different groups did not show effects related to DMAE in either mouse strain. Mammary neoplasms were mostly well-differentiated solid adenocarcinomas in DMAE-treated mice as well as in untreated animals. Liver neoplasms, adenomas and hepatocellular carcinomas, were morphologically similar in both treated and untreated groups. Hemangiomas were present in several tissues, i.e. liver, subcutaneous tissues and lymph nodes in DMAE-treated mice as well as controls, although the total number was low. Lung adenomas were nodular lesions comprised of cuboidal cells, which were similar in DMAE-treated animals and controls. Neoplasms of the genital system were numerous in all groups. These included mainly ovarian neoplasms, granulosa cell tumors, tubular adenomas, and a few luteomas as well as a few neoplasms of the uterus and cervix. Ovarian cysts, were numerous, 117 in total. Most were of the simple type with low flattened epithelium, only a few cystadenomas of serous or mucinous types were found. Cysticovarian follicles were common, apparently as a result of failure of normal luteinization of Graafian follicles.

Relevance of carcinogenic effects / potential:

This study provides information on the lack of carcinogenicity of DMAE.

Effect levels

1

Dose descriptor:

conc. level:

Effect level:

10 other: mM

Based on:

act. ingr.

Sex:

female

Basis for effect level:

other: DMAE did not induce any neoplasms in C3H/HeN mice

Remarks on result:

other: Effect type: carcinogenicity

2

Dose descriptor:

conc. level:

Effect level:

15 other: mM

Based on:

act. ingr.

Sex:

female

Basis for effect level:

other: DMAE did not induce any neoplasms in C3H/HeJ(+) mice

Remarks on result:

other: Effect type: carcinogenicity

Any other information on results incl. tables

TABLE I
NUMBER OF NEOPLASM-BEARING ANIMALS AND NEOPLASMS IN FEMALE MICE EXPOSED TO DIMETHYLAMINOETHANOL AND CONTROLS
Group	Exposure	Subline	Initial No.	Effective No.	No. Bearing a Tumor	Total Neoplasms
1	None	C3H/HeN	60	58	33	49
2	DMAE	C3H/HeN	60	50	30	39
3	None	C3H/HeJ(+)	50	44	39	57
4	DMAE	C3H/HeJ(+)	50	40	35	53

TABLE II
TYPES OF NEOPLASMS OCCURRING IN DIMETHYLAMINOETHANOL TREATED FEMALE MICE AND CONTROLS
Group	Subline	Exposure	Effective No.	Mammary Carcinoma	Lymphoma	Liver Neoplasm	Lung Neoplasm	Hemangioma	Ovaries			Other
									Granulosa cell tumor	Tubular Adenoma	Cyst
1	C3H/HeN	None	58	14	4	6	7	1	4	6	33	7^a
2	C3H/HeN	DMAE	50	8^c	8	7	4	1	4	3	22	4^b
3	C3H/HeJ(+)	None	44	32	0	4	3	4	2	9	35	3^c
4	C3H/HeJ(+)	DMAE	40	27^f	1	5	1	4	3	5	27	7^d
^a2 ovarian luteomas, 1 cervical polyp, 1 endometrial polyp, 1 uterine adenocarcinoma, 2 adrenal tumors. ^b1 ovarian teratocarcinoma, 2 subcutaneous sarcomas, 1 adrenal tumor. ^c2luteomas; 1 endometrial adenocarcinoma. ^d2 stomach squamous cell carcinomas, 1 duodenal adenocarcinoma, 1 renal carcinoma, 3 subcutaneous sarcomas. ^eNot different from group 1,P =0.42. ^fNot different from group 3,P= 0.776.

Applicant's summary and conclusion

Conclusions:

Administration of DMAE in drinking water to two sublines of female mice for lifetime did not have a significant effect on longevity. However, a decrease in histologically detected lipofuscin pigment in the liver seemed to occur with DMAE treatment (antiaging effect). DMAE did not inhibit the formation of most neoplasms, although the number of mammary neoplasms tended to be lower in treated groups. DMAE was given for lifetime with no increase of any type of neoplasm in either strain.

Executive summary:

The effects of lifetime treatment with dimethylaminoethanol (DMAE) on longevity and cryptogenic neoplasm formation were studied in females of two mouse sub-lines, the C3H/HeN which carries a germinal mammary tumor provirus and the C3H/ He J(+) which also carries the exogenous mammary tumor virus. Administration in the drinking water of 10 mM dimethylaminoethanol to the C3H/HeN mice or 15 mM to the C3H/HeJ(+) mice did not result in significant differences between treated and untreated groups in average survival. No changes in age-related organ structure or morphology were observed with dimethylaminoethanol treatment, except for an apparent decrease in the amount of lipofuscin in the liver judged in histological sections. Among untreated C3H/HeJ(+) females, 89% developed neoplasms of the mammary gland, ovary, liver, lung and reticuloendothelial system, while the incidence was 88% in the treated mice. In C3H/HeN females, neoplasms of the mammary gland, ovary, liver, lung and lymphatic system occurred in 57% and in 60%of treated mice. Also, there was no statistically significant difference between control and treated animals in the age of onset or the type of specific neoplasms. Dimethylaminoethanol did not induce any neoplasms.