Registration Dossier

Toxicological information

Carcinogenicity

Currently viewing:

Administrative data

Description of key information

An increase in tumor incidence was neither observed in rats treated dermally or orally with TEA for 2 years, nor in mice exposed to TEA by oral administration for 2 years. In a dermal mouse carcinogenicity study there was an increased incidence of liver tumors in females at all doses tested. Mechanistic research specifically on TEA indicates that, to the extent TEA can potentially induce tumors in mice, it does so by a mechanism that is not relevant to humans. Therefore, based on the available data, TEA is not considered carcinogenic for humans.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
Groups of rats were dosed (in drinking water) for 104 weeks, and thereafter tap water was given to animals in all groups, observation being continued until wk 113 when all survivors were sacrificed. Moribund or dead animals were autopsied completely and examined pathologically for the development of tumours.
GLP compliance:
not specified
Species:
rat
Strain:
Fischer 344/DuCrj
Sex:
male/female
Route of administration:
oral: drinking water
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
2 years
Frequency of treatment:
Daily
Post exposure period:
9 weeks
Dose / conc.:
667 mg/kg bw/day
Remarks:
1 % in drinking water, (from week 69: 0.5 % and 1 %, in females, ca. 333 and 667 mg/kg)
Dose / conc.:
1 333 mg/kg bw/day
Remarks:
2 % in drinking water, (from week 69: 0.5 % and 1 %, in females, ca. 333 and 667 mg/kg)
No. of animals per sex per dose:
50
Control animals:
yes, concurrent no treatment
Details on study design:
At about experimental wk 60, loss of body weight gain and animal deaths increased in the female 2% group. Therefore, administration of triethanolamine was ceased in females at wk 68 for 1 wk, and thereafter from wk 69 doses in females were reduced by half.
Positive control:
None
Details on results:
A variety of tumors developed in all groups, including the control group, and all tumors observed were histologically similar to spontaneous tumors in this strain of rats. No statistically significant increase of the incidence of any tumor was observed in the treated groups of both sexes by the chi-square test. In this study, however, there was an increase in nephrotoxicity, which appeared to have an adverse effect on the life expectancy of the treated animals, especially of females. Therefore, an age-adjusted statistical analysis on incidences of main tumors or tumor groups of both sexes was also done by methods recommended by Peto et al.(1980). The result showed that a positive trend (p < 0.05) was noted in the occurrence of hepatic tumors (neoplastic nodule/hepatocellular carcinoma) in males and of uterine endometrial sarcomas and renal-cell adenomas in females. These tumors, however, have been observed spontaneously in this strain of rats, and their incidences in the control group of the present study were lower than those of our historical controls. These results may indicate that a positive trend in the occurrence of these tumors is not attributable to triethanolamine administration. Increased incidence of renal tumors in the female high-dose group may have been connected with renal damage. Histological examination of renal damage observed in the treated groups, especially in the female high-dose group, revealed acceleration of so-called chronic nephropathy. In addition, mineralization of the renal papilla, nodular hyperplasia of the pelvic mucosa, and pyelonephritis with or without papillary necrosis were also observed. Thus, it is concluded that under these experimental conditions triethanolamine is not carcinogenic in F344 rats but is toxic to the kidneys.
Key result
Dose descriptor:
NOAEL
Effect level:
2 other: % in drinking water (corresponding to 1333 mg/kg bw/day)
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Key result
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 333 mg/kg bw/day
Study duration:
chronic
Species:
rat

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
carcinogenicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
GLP compliance:
yes
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 7G-60



Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Simonsen Laboratories, Inc. (Gilroy, CA)
- Age at study initiation: 6 weeks
- Weight at study initiation: male 21 gram / female 17.5 gram
- Housing: Polycarbonate (Lab Products, Inc., Maywood, NJ), changed weekly
- Diet (e.g. ad libitum): NIH-07 open formula pelleted diet (Zeigler Brothers, Inc., Gardners, PA), available ad libitum, changed weekly
- Water (e.g. ad libitum): Tap water (City of Columbus municipal supply) via automatic watering system (Edstrom Industries, Waterford, WI), available ad libitum
- Acclimation period: 11 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.0 - 23.9
- Humidity (%): 35 - 76
- Air changes (per hr): minimum of 10
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: 14 November 1988 To: 2 November 1990
Route of administration:
dermal
Vehicle:
acetone
Details on exposure:
TEST SITE
- Area of exposure: area extending from the animal’s mid-back to the intrascapular region
- Time intervals for shavings or clipplings: approximately once per week
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Periodic analyses of dose formulations of triethanolamine were conducted by the study laboratory and the analytical chemistry laboratory with gas chromatography. The dose formulations were analyzed at the beginning of the study and every 6 to 10 weeks thereafter; animal-room samples were analyzed every 22 to 26 weeks. Of the doses analyzed, 95% (59/62) of the formulations were within 10% of the target concentrations. All animal-room samples were within 10% of the target concentrations. Results of periodic referee analyses performed by the analytical chemistry laboratory agreed with the results obtained by the study laboratory.
Duration of treatment / exposure:
103 weeks
Frequency of treatment:
5 days per week
Post exposure period:
None
Dose / conc.:
0 mg/kg bw/day
Remarks:
males
Dose / conc.:
32 mg/kg bw/day
Remarks:
males
Dose / conc.:
63 mg/kg bw/day
Remarks:
males
Dose / conc.:
125 mg/kg bw/day
Remarks:
males
Dose / conc.:
0 mg/kg bw/day
Remarks:
females
Dose / conc.:
63 mg/kg bw/day
Remarks:
females
Dose / conc.:
125 mg/kg bw/day
Remarks:
females
Dose / conc.:
250 mg/kg bw/day
Remarks:
females
No. of animals per sex per dose:
60
Control animals:
yes, concurrent vehicle
Details on study design:
Dermal application was chosen as the route of exposure to mimic the principal means of human exposure to triethanolamine and because considerable systemic exposure is achieved with this route.
Positive control:
None
Observations and examinations performed and frequency:
Observed twice daily; clinical findings were recorded monthly. Animals were weighed initially, weekly for 13 weeks, monthly thereafter, and at the end of the studies.
Sacrifice and pathology:
Necropsy performed on all animals. Organs weighed were left and right kidneys and liver.
Complete histopathology was performed on all rats. In addition to gross lesions and tissue masses, the tissues examined included: adrenal gland, bone and marrow, brain, clitoral gland, epididymis, esophagus, gallbladder (mice), heart, kidney, large intestine (cecum, colon, and rectum), liver, lung, lymph nodes (mandibular and mesenteric), mammary gland, nose, ovary, pancreas, parathyroid gland, pituitary gland, preputial gland, prostate gland, salivary gland, seminal vesicle, skin (lesions and unaffected skin from site of application; inguinal skin), small intestine (duodenum, jejunum, and ileum), spinal cord and sciatic nerve (if neurologic signs were present), spleen, stomach (forestomach and glandular stomach), testis, thymus, thyroid gland, trachea, urinary bladder, and uterus.
Other examinations:
None
Statistics:
The probability of survival was estimated by the product-limit procedure of Kaplan and Meier.
Statistical analyses for possible dose-related effects on survival used Cox’s method for testing two groups for equality and Tarone’s life table test
to identify dose-related trends.
Neoplasm prevalence was modeled as a logistic function of chemical exposure and time.
Prevalence analysis of Dinse and Lagakos.
Life table test.
Fisher exact test.
Cochran-Armitage trend test.
Parametric multiple comparison procedures of Dunnett and Williams.
Nonparametric multiple comparison methods of Shirley and Dunn.
Jonckheere’s test.
Mann-Whitney U test.
Multivariate analysis of variance.
Dermal irritation (if dermal study):
effects observed, treatment-related
Description (incidence and severity):
Male and female rats receiving triethanolamine had irritated skin at the site of application; in dosed females, the site of application also had a crusty appearance. The number of animals in which these findings were observed increased with increasing dose.
Mortality:
mortality observed, treatment-related
Description (incidence):
The survival rates of males receiving 32 mg/kg and females receiving 250 mg/kg were slightly less than those of the vehicle controls.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The mean body weight of females administered 250 mg/kg ranged from 9% to 12% less than that of the vehicle controls between weeks 73 and 93; however, at the end of the study, the mean body weight of this group was only 7% less than that of the vehicle controls. Mean body weights of dosed males were similar to those of the vehicle controls throughout the study.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
At the 15-month interim evaluation, the absolute left and right kidney weights and relative right kidney weight of females administered 250 mg/kg were slightly greater than those of the vehicle controls; the organ weights of dosed males were similar to those of the vehicle controls.
Details on results:
PATHOLOGY AND STATISTICAL ANALYSES
Skin
Gross lesions attributed to triethanolamine administration consisted of multiple, small, randomly located, red or brown lesions or crusts at the site of application in females. Increased incidences of nonneoplastic lesions at the site of application in dosed rats were observed at the 15-month interim evaluation and at the end of the 2-year study. Lesions occurred more frequently in females than in males receiving equivalent doses. Lesions consisted of thickened epidermis (acanthosis) and ulceration with associated chronic active inflammation in dosed males and females, as well as erosion in dosed females.
At the 15-month interim evaluation, two males in the 125 mg/kg group had minimal acanthosis at the site of application. Females receiving 125 or 250 mg/kg had acanthosis, inflammation, and ulceration. Acanthosis and inflammation were of mild average severity; the average severity of ulceration was mild in the 125 mg/kg group and moderate in the 250 mg/kg group. At 2 years, the incidence of acanthosis in males administered 125 mg/kg and the incidences of acanthosis, inflammation, and ulceration in dosed cell females were greater than in the vehicle controls; additionally, males in the 125 mg/kg group had greater incidences of inflammation and ulceration than the vehicle controls. The incidences of erosion, which was diagnosed only in areas distinctly removed from ulceration, were significantly greater in females receiving 125 or 250 mg/kg than in the vehicle controls at 2 years.
The epidermis covering the entire site of application was generally mildly thickened (two to four times) relative to that of the vehicle controls, with neutrophils occasionally observed within the epidermis. Ulcers were random and multifocal and were of mild to moderate severity. Ulcers were characterized by complete segmental necrosis of epidermis, with variable erosion of the dermis and associated chronic active inflammation (neutrophils, lymphocytes, and macrophages). Ulcerated areas were covered with cellular debris, keratin, fibrin, and inflammatory cells composing the “crusts” noted grossly. Erosion consisted of necrosis of the superficial layers of epidermis and did not extend into the dermis.
At 2 years, one male in the 125 mg/kg group had a keratoacanthoma at the site of application. However, the incidences of keratoacanthoma and squamous cell papilloma of the skin (all sites) were slightly less in dosed males than in the vehicle controls. No keratoacanthomas or squamous cell papillomas occurred in vehicle control male rats in the only other dermal study with an acetone vehicle in the NTP database; however, the incidences of keratoacanthoma (10%) and squamous cell papilloma (6%) in the vehicle controls in the present study fall within the historical range for these neoplasms in male rats in NTP feed studies (keratoacanthoma, 0%-10%; squamous cell papilloma, 0%-8%). One vehicle control male had a basal cell adenoma at the site of application; this neoplasm did not occur in dosed males. Additionally, one vehicle control female had a squamous cell papilloma and one female in the 63 mg/kg group had a keratoacanthoma away from the site of application; no skin neoplasms occurred in females administered 125 or 250 mg/kg triethanolamine. Squamous cell papillomas were observed in 6 of 1,202 females in NTP feed studies (range 0%-2%) but did not occur in the other dermal study.

Kidney
No kidney lesions were observed at the 15-month interim evaluation; however, the absolute kidney weights of females in the 250 mg/kg group were greater than those of the vehicle controls. At 2 years, the incidence of adenoma of the renal tubule epithelium in males in the 63 mg/kg group was marginally greater than that in the vehicle controls. No renal tubule adenomas occurred in vehicle control male F344/N rats in other dermal study in the NTP database with an acetone vehicle; the incidence of this neoplasm in untreated control males ranged from 0% to 6%. Although the neoplasm incidence observed in the 63 mg/kg group exceeds the incidence in untreated controls in the NTP database, an equal or greater incidence did not occur in males in the 125 mg/kg group, and the neoplasms in all groups were small and were detected only microscopically. Additionally, the incidences of hyperplasia were not increased in dosed males. Because of these uncertain findings, an extended evaluation of the kidneys of vehicle control and dosed males was conducted. In this extended evaluation, additional proliferative lesions (hyperplasia and adenoma) were identified, with similar incidences in all groups; however, the incidence of adenoma was marginally, although not significantly, greater in the 125 mg/kg group than in the vehicle controls. Nephropathy was observed in nearly all male rats in all groups; there was no apparent difference in the severity of this lesion between dosed and vehicle control groups.
The proliferative lesions were phenotypically similar to those spontaneously occurring in F344/N rats. Focal renal tubule hyperplasia consisted of single or multiple adjacent tubule profiles containing three or more layers of epithelial cells that partially or completely filled the tubule lumens and that usually caused slight dilatation of the tubule. The hyperplastic cells were generally slightly larger than normal epithelial cells and were polygonal, with abundant eosinophilic cytoplasm. All adenomas were small (less than 0.9 cm) and expansile and usually consisted of multiple, variably sized tubule profiles, some with necrotic centers. Cells of adenomas were generally the larger than normal and polygonal, with abundant eosinophilic cytoplasm.

Thyroid Gland
The incidence of C-cell adenoma or carcinoma (combined) was marginally greater in female rats in the 250 mg/kg group than in the vehicle controls (0 mg/kg, 1/50; 63 mg/kg, 2/50; 125 mg/kg, 2/50; 250 mg/kg, 6/49). This greater incidence was not considered to be related to the administration of triethanolamine. Thyroid gland C-cell neoplasms are relatively common, spontaneously occurring neoplasms in male and female rats, occurring in 6 of 46 vehicle control females (13%) in the other NTP dermal study with an acetone vehicle and in 175 of 1,196 untreated control females (15%) in NTP feed studies. Further, of the 24 feed studies in the database, no control group had an incidence of less than 6% for C-cell neoplasms. Additionally, proliferative lesions of the thyroid gland C-cells generally represent a morphological and biological continuum, with progression from hyperplasia to adenoma to carcinoma. In this study, there was often difficulty in determining whether the proliferative lesions were adenomas or hyperplasia. The incidences of hyperplasia in dosed females (8/50, 4/50, 10/50, 2/49; Table B4) did not support a treatment effect, and when the incidences of hyperplasia and neoplasms were combined, the results indicated no increased incidences of proliferative thyroid gland C-cell lesions in dosed female rats.

Uterus
The incidence of stromal polyp of the uterus was marginally increased in females in the 125 mg/kg group, but not in the 250 mg/kg group (2/50, 1/50, 8/50, 5/50). Stromal polyps are relatively common, spontaneously occurring, benign neoplasms in female rats, occurring in 3 of 50 vehicle control females (6%) in the other study with an acetone vehicle in the NTP database and in 178/1,202 untreated control females (16%) in NTP feed studies. Also, the vehicle control incidence of 4% is well below the historical incidence for untreated controls, and the incidence in the 125 mg/kg group is the same as the historical incidence for untreated controls. Therefore, the increased incidence of stromal polyp in females in the 125 mg/kg group was not considered to be related to triethanolamine administration,

Pituitary gland
The incidences of hemosiderin pigment in the pituitary gland pars distalis increased with increasing dose in male rats (0 mg/kg, 23/50; 32 mg/kg, 24/50; 63 mg/kg, 32/48; 125 mg/kg, 35/50), and the incidence of angiectasis was also marginally greater in males administered 125 mg/kg than in the vehicle controls (30/50, 36/50, 29/48, 39/50). These are minimal changes in the incidence of common incidental lesions of uncertain biological significance. Conversely, the incidences of these lesions were lower in females administered 250 mg/kg than in the vehicle controls (hemosiderin pigmentation: 33/50, 29/50, 27/50, 22/50; angiectasis: 37/50, 35/50, 36/50, 29/50).

Key result
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: no treatment related carcinogenic effects were observed
Key result
Dose descriptor:
NOAEL
Effect level:
125 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: increased relative kidney weight in females (not in males, tested up to 125 mg/kg bw/day)
Key result
Dose descriptor:
NOAEL
Remarks:
local
Effect level:
63 mg/kg bw/day
Sex:
male
Basis for effect level:
other: acanthosis, ulceration, and chronic active inflammation at the site of application
Key result
Dose descriptor:
NOAEL
Remarks:
local
Effect level:
< 63 mg/kg bw/day
Sex:
female
Basis for effect level:
other: acanthosis and chronic active inflammation at the site of application
Key result
Critical effects observed:
not specified

Although the results of the 13-week rat study led to the selection of doses for female rats in the 2-year study that were twice those administered to males, the females were clearly more sensitive to triethanolamine administration, as shown by the much greater incidences and severities of inflammation and irritation at the site of application in females compared to males in the 2-year study. Ulceration occurred in about half the female rats receiving 125 or 250 mg/kg, while only 5 of 50 males receiving 125 mg/kg had similar lesions. The survival rate of female rats receiving 250 mg/kg was less than that of the other groups, although the mean body weight of this group was only slightly decreased during the study, and this decrease was observed only around week 90. There were no skin neoplasms in male or female rats at or away from the site of application that were considered to be related to triethanolamine administration.

Histopathologic findings which were evaluated to determine their relationship with triethanolamine exposure included renal tubule adenomas in male rats and thyroid gland C-cell adenomas and carcinomas and uterine stromal polyps in female rats. The increased incidences of thyroid gland C-cell neoplasms and uterine stromal polyps were not considered to be related to triethanolamine administration. The evidence for a relationship between the renal tubule neoplasms in male rats and triethanolamine administration was considered equivocal. The total number of male rats identified in the combined single and step-section evaluations as having proliferative lesions (hyperplasia and adenoma) of the renal tubule epithelium was 10/50 (vehicle controls), 8/50 (32 mg/kg), 11/49 (63 mg/kg), and 8/50 (125 mg/kg). Although the proliferative lesions were observed only microscopically, those that were identified as adenomas were clearly larger lesions; these appeared in one vehicle control male, two males in the 32 mg/kg group, six males in the 63 mg/kg group, and four males in the 125 mg/kg group. Four of the six adenomas in the 63 mg/kg group were noted during the standard histopathologic evaluation, and thus this incidence may be compared to historical control data. The 8% incidence in the 63 mg/kg group exceeds the historical mean (0.8%) and range (0%-6%) observed in previous untreated control groups from feed studies. However, the lack of both a clear dose response and an increase in incidences of total proliferative lesions in dosed rats leaves doubt that this result could be attributed to triethanolamine administration with certainty. Other examples of the use of an extended evaluation of the kidney and their interpretation have been discussed by Eustiset al.(1994).

In a previous carcinogenicity study in which triethanolamine was administered in drinking water at concentrations of 1% and 2% to groups of 47 to 50 F344/DuCrj rats (Maekawaet al.,1986), two renal tubule adenomas were observed in females in the 2% group; none occurred in the controls or in the 1% group. This finding was discounted by the authors because renal toxicity was observed in females in the 2% group. Doses were halved for females after week 68 because of toxicity. The total triethanolamine intake during the study was reported to be 119 or 232 mg (actually grams) for female rats. For comparison, assuming 100% absorption of material from the skin and average body weights of 350 g for males and 200 g for females, rats in the 125 (male) and 250 mg/kg (female) groups in the current studies would have received total doses of approximately 23 g for males and 26 g for females. Thus, the lack of kidney toxicity in the current study is consistent with the findings of Maekawaet al.(1986). These authors also reported increased incidences of hepatic neoplasms in males and uterine endometrial sarcoma in females. However, these findings were not attributed to triethanolamine administration because in compar­ison to historical incidences, the neoplasm trends reflected low incidences in the control groups rather than increased incidences in the exposed groups.

Endpoint:
carcinogenicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
GLP compliance:
yes
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 7G-60

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: stored at room temperature in amber glass containers with Teflon®-lined lids
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 6 weeks
- Fasting period before study: none
- Housing: individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 14 (males) or 13 (females) days

ENVIRONMENTAL CONDITIONS
- standardized
Route of administration:
dermal
Vehicle:
acetone
Details on exposure:
Doses were applied to an area extending from the animal’s mid-back to the intrascapular region; the site of application was clipped approximately once per week during the study
Duration of treatment / exposure:
104 (males) or 105 (females) weeks
Frequency of treatment:
5 days per week
Dose / conc.:
100 mg/kg bw/day
Remarks:
dermal doses (females)
Dose / conc.:
300 mg/kg bw/day
Remarks:
dermal doses (females)
Dose / conc.:
1 000 mg/kg bw/day
Remarks:
dermal doses (females)
Dose / conc.:
200 mg/kg bw/day
Remarks:
dermal doses (males)
Dose / conc.:
630 mg/kg bw/day
Remarks:
dermal doses (males)
Dose / conc.:
2 000 mg/kg bw/day
Remarks:
dermal doses (males)
No. of animals per sex per dose:
50
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
Cages and racks were rotated every 2 weeks. All mice were observed twice daily and were weighed initially, weekly for 13 weeks, monthly thereafter, and at the end of the study. Clinical findings were recorded on day 29, monthly thereafter, and at the end of the study. Complete necropsies and microscopic examinations were performed on all mice.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

At necropsy, all organs and tissues were examined for grossly visible lesions, and all major tissues were fixed and preserved in 10% neutral buffered formalin, processed and trimmed, embedded in paraffin, sectioned to a thickness of 4 to 6 um, and stained with hematoxylin and eosin for microscopic examination. For all paired organs (e.g. adrenal gland, kidney, ovary), samples from each organ were examined.
Statistics:
product-limit procedure of Kaplan and Meier
Cox’s method for testing two groups for equality
Tarone’s life table test to identify dose-related trends
Poly-k test
pairwise comparisons
Mann-Whitney U test
Details on results:
100 mg/kg carcinogenic effects , irritant effects , liver , micropathology in organs other than list , skin effects
This dose was administered to female mice only. Treatment-related clinical findings included skin irritation with visible crusts. Microscopic examination showed epidermal hyperplasia, supparative inflammation, ulceration and dermal chronic inflammation with an incidence and severity that was related to dose. The incidence of eosinophilic focus in the liver was increased relative to controls. There was some evidence for carcinogenic activity based on increased incidences of hepatocellular adenoma (18/50 vs control, 9/50) or hepatocellular adenoma or carcinoma combined (23/50 vs control, 12/50).

200 mg/kg irritant effects , liver , photoallergy , skin effects
This dose was administered to male mice only. Treatment-related clinical findings included skin irritation with visible crusts. Microscopic examination showed epidermal hyperplasia, supparative inflammation, ulceration and dermal chronic inflammation with an incidence and severity that was related to dose. The incidence of eosinophilic focus in the liver was increased relative to controls.

300 mg/kg carcinogenic effects , irritant effects , liver , micropathology in organs other than list , skin effects
This dose was administered to female mice only. Treatment-related clinical findings included skin irritation with visible crusts. Microscopic examination showed epidermal hyperplasia, supparative inflammation, ulceration and dermal chronic inflammation with an incidence and severity that was related to dose. The incidence of eosinophilic focus in the liver was increased relative to controls. There was some evidence for carcinogenic activity based on increased incidences of hepatocellular adenoma (20/50 vs control, 9/50) or hepatocellular adenoma or carcinoma combined (24/50 vs control, 12/50).

630 mg/kg carcinogenic effects , irritant effects , liver , micropathology in organs other than list , skin effects
This dose was administered to male mice only. Treatment-related clinical findings included skin irritation with visible crusts. Microscopic examination showed epidermal hyperplasia, supparative inflammation, ulceration and dermal chronic inflammation with an incidence and severity that was related to dose. The incidence of eosinophilic focus in the liver was increased relative to controls. There was equivocal evidence of carcinogenic activity based on the occurrence of liver hemangiosarcoma (1/50, 0/50, 6/50 and 1/50 at 0, 200, 630 and 2000 mg/kg, respectively).

1000 mg/kg carcinogenic effects , irritant effects , liver , micropathology in organs other than list , skin effects
This dose was administered to female mice only. Treatment-related clinical findings included skin irritation with visible crusts. Microscopic examination showed epidermal hyperplasia, supparative inflammation, ulceration and dermal chronic inflammation with an incidence and severity that was related to dose. The incidence of eosinophilic focus in the liver was increased relative to controls. There was some evidence for carcinogenic activity based on increased incidences of hepatocellular adenoma (33/50 vs control, 9/50) or hepatocellular adenoma or carcinoma combined (34/50 vs control, 12/50).

2000 mg/kg body weight changes , irritant effects , liver , micropathology in organs other than list , skin effects
This dose was administered to male mice only. Body weights were less than those of the vehicle controls from weeks 17 to 37 and at the end of the study. Treatment-related clinical findings included skin irritation with visible crusts. Microscopic examination showed epidermal hyperplasia, supparative inflammation, ulceration and dermal chronic inflammation with an incidence and severity that was related to dose. The incidence of eosinophilic focus in the liver was increased relative to controls.
Key result
Dose descriptor:
NOAEL
Effect level:
<= 100 mg/kg bw/day (nominal)
Sex:
female
Basis for effect level:
other: increased incidences of hepatocellular adenoma (18/50 vs control, 9/50) or hepatocellular adenoma or carcinoma combined (23/50 vs control, 12/50)
Key result
Dose descriptor:
NOAEL
Effect level:
<= 100 mg/kg bw/day (nominal)
Sex:
female
Basis for effect level:
other: see 'Remark'
Key result
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
250 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
similar OECD TG 451

Additional information

In a dermal carcinogenicity study in rats performed to a similar method as OECD guideline 451 and under GLP, Fischer rats (60/sex/dose) were dermally exposed to 0, 32, 63, or 125 mg/kg bw/day (males) and 0, 63, 125, or 250 mg/kg bw/day (females) TEA in acetone, 5 days/week for 103 weeks (NTP, 1999). Ten male and ten female rats from each group were evaluated at 15 months for organ weights and histopathology.The survival rate of females in the 250 mg/kg bw group was slightly less than that of the vehicle controls. The mean body weight of females administered 250 mg/kg bw ranged from 9% to 12% less than that of the vehicle controls between weeks 73 and 93. Male and female rats receiving triethanolamine had irritated skin at the site of application; in dosed females, the site of application also had a crusty appearance. The number of animals in which these findings were observed increased with increasing dose. At the 15-month interim evaluation, the absolute left and right kidney weights and relative right kidney weight of females administered 250 mg/kg bw were significantly greater than those of the vehicle controls.

The incidence of acanthosis at the site of application in males administered 125 mg/kg bw and the incidences of acanthosis, inflammation, and ulceration in dosed females were greater than in the vehicle controls at the 15-month interim evaluation and at the end of the 2-year study. Males in the 125 mg/kg bw group also had greater incidences of inflammation and ulceration than the vehicle controls, and females receiving 125 or 250 mg/kg bw had greater incidences of epidermal erosion than the vehicle controls at 2 years. There were no skin neoplasms at or away from the site of application that were considered related to treatment with triethanolamine. At the end of the study, renal tubule adenomas were observed in seven dosed males and in one vehicle control female and one female in the 63 mg/kg group. One male in the 125 mg/kg bw group and one female in the 250 mg/kg bw group had renal tubule hyperplasia. Extended (step-section) evaluation of the kidneys of all male rats revealed additional renal tubule adenomas in one vehicle control male, one male in the 32 mg/kg bw group, two males in the 63 mg/kg bw group, and three males in the 125 mg/kg bw group (including one male from the 15-month interim evaluation). An oncocytoma was also identified in one male in the 32 mg/kg bw group. Hyperplasia was identified in eight additional vehicle control males and in 19 additional dosed males. The total incidences (combined standard and extended evaluations) of renal tubule adenoma in dosed male rats were slightly greater than the vehicle control incidence (vehicle control, 1/50; 32 mg/kg bw, 2/50; 63 mg/kg bw, 6/49; 125 mg/kg bw, 4/50). The total incidence of hyperplasia in dosed and vehicle control males was similar (9/50, 8/50, 7/49, 6/50). The severity of hyperplasia in males in the 32 and 125 mg/kg bw groups was greater than that in the vehicle controls.

Under the conditions of these dermal studies, there was equivocal evidence of carcinogenic activity of TEA in male rats based on a marginal increase in the incidences of renal tubule cell adenoma. There was no evidence of carcinogenic activity in female rats receiving 63, 125, or 250 mg/kg bw TEA. Based on these results, IARC (2000) concluded that there was no significant increase in the incidence of tumours at any site. Dosed rats had varying degrees of acanthosis and inflammation and ulceration, female rats had epidermal erosion at the site of skin application. 63 mg/kg bw/day was established to be the NOAEL for local effects in males, and the LOAEL in females, based on acanthosis and chronic active inflammation at the application site.

In a dermal carcinogenicity study in mice performed to a similar protocol as OECD guideline 451 and under GLP, B6C3F1 mice (50/sex/dose) were dermally exposed to 0, 200, 630, or 2000 mg/kg bw/day (males) and 0, 100, 300, or 1000 mg/kg bw/day (females) TEA in acetone, 5 days/week for 104 (males) or 105 (females) weeks (NTP, 2004). Survival of all dosed groups was similar to that of the vehicle control groups. Body weights of 2000 mg/kg bw males were less than those of the vehicle controls from weeks 17 to 37 and at the end of the study; body weights of dosed groups of females were similar to those of the vehicle controls throughout the study. Treatment-related clinical findings included skin irritation at the site of application, which increased with increasing dose and was more severe in males than in females. Gross lesions observed at necropsy included nodules and masses of the liver in dosed females. The incidences of hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined) were significantly increased in all dosed groups of females. The incidence of hemangiosarcoma of the liver in 630 mg/kg bw males was marginally increased. The incidences of eosinophilic focus in all dosed groups of mice were greater than those in the vehicle controls. Gross lesions observed at necropsy included visible crusts at the site of application in all dosed groups of mice. Treatment-related epidermal hyperplasia, suppurative inflammation, ulceration, and dermal chronic inflammation occurred at the site of application in most dosed groups of mice, and the incidences and severities of these lesions generally increased with increasing dose.

Under the conditions of this 2-year dermal study, there was equivocal evidence of carcinogenic activity of TEA in male B6C3F1 mice based on the occurrence of liver hemangiosarcoma. There was some evidence of carcinogenic activity in female B6C3F1 mice based on increased incidences of hepatocellular adenoma. Exposure to TEA by dermal application resulted in increased incidences of eosinophilic focus of the liver in males and females. Dosed mice developed treatment-related non-neoplastic lesions at the site of application.

In an oral carcinogenicity study in rats, Fischer rats (50/sex/dose) were daily exposed to 0, 1, or 2% TEA via the drinking water (corresponding to a dose of approximately 667 and 1333 mg/kg bw/day) for 2 years (Maekawa et al, 1986). In week 69, dose levels in females were reduced to 0.5 and 1% (corresponding to ca. 333 and 667 mg/kg bw/day), because of associated nephrotoxicity. A variety of tumours developed in all groups, but no statistically significant differences were observed to control levels. A positive trend towards increased occurrence of hepatic tumours in males and of uterine endometrial sarcomas and renal-cell adenomas in females was judged as not related to the treatment. It was concluded that TEA is not carcinogenic under these conditions in the Fischer rat, but is toxic to the kidneys.

In another oral carcinogenicity study, B6C3F1 mice (50/sex/dose) were administered 0, 1, or 2% TEA in the drinking water (corresponding to a dose of ca. 1600 and 3200 mg/kg bw/day) for 82 weeks (Konishi et al, 1992). Neoplasms developed in all groups including the control group, but no dose-related increase in tumour incidence was observed. No adverse effects were noted on survival and organ weights. Thus, no evidence for carcinogenic potential of TEA upon oral administration was found in mice.

TEA was evaluated in a genetically modified mouse skin papilloma model (Spalding, 1999, 2000). Doses up to 30 mg of TEA were administered topically to groups of 15 to 20 female Tg.AC mice five times per week for 20 weeks. The experimental design also included positive and negative controls. In contrast to the positive controls, which developed multiple papillomas, there were no increases in the incidences of skin tumours in mice receiving TEA.

Thus, TEA has been reported to cause an increased incidence of liver tumours in female B6C3F1 mice after dermal application, but not in males nor in Fischer 344 rats (NTP 1999, 2004). Effects on choline metabolism have been suggested to play a role in hepatic tumorigenesis in mice. Choline deficiency induces liver cancer in rodents, and TEA could compete with choline uptake into tissues. In a mechanistic study, the potential of TEA to cause choline deficiency in the liver of mice as a mode of tumorigenesis was investigated (Stott, 2004). Groups of female B6C3F1 mice were administered TEA at 0 or the maximum tolerated dose (MTD) of 1000 mg/kg bw/day (trail I), and 0, 10, 100, 300 or 1000 mg/kg bw/day (trial II) in acetone, 5 days/week for 3 weeks. Female CDF rats were also administered 0 or an MTD dose of 250 mg/kg bw/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 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 3H-choline by cultured Chinese hamster ovary cells revealed a dose-related effect upon uptake. It was concluded that TEA may cause liver tumours in mice via a choline-depletion mode of action and that this effects is likely caused by inhibition of choline uptake. A similar mechanism was identified for hepatic tumorigenesis in mice upon exposure to the structural analogue substance DEA. This non-genotoxic mechanism displays interspecies differences in sensitivity with humans being much more resistant. Therefore, based on the available data, TEA is not considered carcinogenic for humans.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

The available data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on the available data, the substance is not considered to be classified for carcinogenicity under Regulation (EC) No 1272/2008, as amended for the tenth time in Regulation (EU) No 2017/776.