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Repeated dose toxicity: dermal

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Administrative data

sub-chronic toxicity: dermal
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: NTP study

Data source

Reference Type:
study report

Materials and methods

Test guideline
equivalent or similar to guideline
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
GLP compliance:
not specified
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Constituent 2
Reference substance name:
Constituent 3
Reference substance name:

Test animals

Fischer 344
Details on test animals or test system and environmental conditions:
Male and female Fischer 344/N rats were obtained from Simonsen Laboratories (Gilroy, CA). On receipt, the rats were 4 weeks old. Animals were quarantined for 11 to 14 days and were 6 weeks old on the first day of the studies. Feed and water were available ad libitum. Rats were housed individually.

Administration / exposure

Type of coverage:
Details on exposure:
Based on the results of the earlier NTP studies, groups of 10 male and 10 female rats were topically administered 0, 125, 250, 500, or 1,000 mg
triethanolamine per kilogram body weight, in acetone, or 2000 mg/kg neat triethanolamine . For rats, if the dose volume exceeded 320 µL, half the total
volume was administered in the morning and the remainder was administered in the afternoon. Doses were applied 5 days per week for 13 weeks to an area extending from the animal’s mid-back to the dorsal intrascapular region; the site of application was clipped weekly during the studies. Additional groups of 10 male and 10 female rats designated for clinical pathology evaluations received the same dermal exposures as the core study rats.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
5 days per week
No. of animals per sex per dose:
10 males and 10 females


Observations and examinations performed and frequency:
Blood was collected from all clinical pathology group animals from the retroorbital sinus for hematology and clinical chemistry. Urine was collected overnight (16 hours) from clinical pathology group rats during weeks 1, 3, 7, and 13 and from clinical pathology group mice during weeks 7 and 12. Hematology: hematocrit; hemoglobin concentration; erythrocyte, reticulocyte, and nucleated erythrocyte counts; mean cell volume; mean cell hemoglobin; mean cell hemoglobin concentration; platelet count; and total leukocyte count and differentials.
Clinical chemistry: urea nitrogen, creatinine, glucose, total protein, albumin, alanine aminotransferase, aspartate aminotransferase, and sorbitol dehydrogenase
Urinalysis: glucose, protein, volume, and specific gravity
Sacrifice and pathology:
Complete histopathology was performed on core study rats in the vehicle control and 2,000 mg/kg groups. 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, uterus, and vagina (females in vaginal cytology studies only). Additionally, the kidney of female rats, pituitary gland of male and female rats, and skin (site of application) of male and female rats in the lower exposure groups were examined until a no-effect level was reached.
The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1958) and is presented in the form of graphs. Statistical analyses for possible dose-related effects on survival used Cox’s (1972) method for testing two groups for equality and Tarone’s (1975) life table test to identify dose-related trends.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
Clinical findings were observed only in mice in the 4,000 mg/kg groups and included scaliness, irritation, and discoloration at the site of triethanolamine application for males and females and skin erosion at this site in one male
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The final mean body weight and weight gain of males in the 250 mg/kg group were less than those of the vehicle controls.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
slightly elevated kidney weights in males and females administered 500, 1000 or 2000 mg/kg, compared to controls.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
hypertrophy of pituitary gland (males and females, only at 2000 mg/kg). Kidney nephropathy (females, all dose groups)
Details on results:
Clinical findings related to triethanolamine administration occurred only at the site of application and included irriation, scaliness and crustiness for males and females. Males had also discoloration and two males (2000 mg/kg) had ulceration at application site. Mild pathological effects were attributable to skin inflammation and only observed at 2000 mg/kg.

Effect levels

Dose descriptor:
Effect level:
125 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: slight increased body weight

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Microscopic examination of the skin of dosed rats indicated acanthosis and inflammation at the site of application. Acanthosis occurred in males (starting at dose group 125 mg/kg) and females (starting at dose group 500 mg/kg); the severity increased with increasing dose in males and females. Inflammation was observed in males and females in the 1,000 mg/kg groups.

Applicant's summary and conclusion

Effects observed in this study do not warrant classification for STOT-repeteated dose according to CLP.
Executive summary:

In the 13-week rat study, topical application of 2,000 mg triethanolamine per kilogram body weight resulted in a significant decrease in body weight gain, and grossly visible crusts at the site of application were noted in males and females administered 1,000 or 2,000 mg/kg. Hematologic changes were consistent with the presence of skin inflammation in rats in the 2,000 mg/kg groups, and clinical chemistry findings of very mild but generally dose-related increases in serum alanine and aspartate aminotranferase activities were suggestive of liver injury. However, sorbitol dehydrogenase activity, which is generally considered to be a better gauge of liver damage

was not increased, and histopathology revealed no evidence of hepatic injury. Aspartate aminotransferase has a wider tissue distribution than sorbitol dehydrogenase, and increased serum activity could be related to minor injury at another site, such as the muscle, rather than to hepatotoxicity. Additionally, some compounds can cause increases in alanine aminotransferase activity in the liver or serum without causing hepatic injury.

Kidney weights increased with increasing dose in male and female rats in the 13 -week study. Dosed males

study, had decreased urinary protein excretion which likely reflected a change in renal function or an increase in protein reabsorption, as serum protein concentrations were not affected. Although these findings suggest the possibility of protein droplet accumulation or some other form of renal dysfunction or injury, no evidence of hyaline droplet nephropathy or other histopathologic changes that might account for the weight changes was noted.

Lesions at the site of application in rats in the 13-week study ranged from no discernable change, through minimal to mild epidermal thickening (acanthosis), to chronic active inflammation, erosion, and ulceration. The dermis was also thickened with inflammation and

fibrosis at the higher doses. There was no histologic evidence to suggest the development of skin sensitization or contact dermatitis. This does not, however, rule out the possibility that triethanolamine might cause contact sensitization in a more sensitive animal model such as the guinea pig.