National Toxicology Program

TOX-20
Toxicity Studies of Diethanolamine (CASNo. 111-42-2) Administered Topically and in Drinking Water to F344/N Ratsand B6C3F₁ Mice

Diethanolamine is a high-production chemical used in cosmetics, in cuttingfluids, as a dispersing agent for agricultural chemicals, and as anabsorbent for acidic gases. Toxicology studies of diethanolamine wereconducted in F344/N rats and B6C3F₁ mice of both sexes for 2 weeks(5/sex/species/dose) and 13 weeks (10/sex/species/dose) to characterize andcompare the effects of oral and dermal exposure. In addition tohistopathology, evaluations included clinical pathology, urinalyses, andsperm morphology or vaginal cytology. In vitro genetic toxicity studiesincluded assessments of mutagenicity in Salmonella typhimurium and mouselymphoma L5178Y cells, analysis of chromosomal aberrations and sisterchromatid exchange in Chinese hamster ovary cells, and determination ofmicronuclei formed in mice during the 13-week dermal exposure study.

Groups of rats and mice received drinking water containing diethanolamineat concentrations of up to 10000 ppm during studies of 2 or 13 weeksduration. In the 2-week studies, rats and mice of both sexes received inthe were 0, 630, 1250, 5000, and 10000 ppm diethanolamine in the drinkingwater. In the 13-week studies, rats received 0, 320, 630, 1250, 2500, and5000 ppm (males) or 0, 160, 320, 630, 1250, and 2500 ppm (females) indrinking water; male and female mice received 0, 630, 1250, 2500, 5000, and10000 ppm. All female rats in the 2 highest dose groups and 2 males in the10000 ppm group in the 2-week study died before the end of the study. Inthe 13-week study, deaths of mice occurred in the 3 highest dose groups; 2male rats in the top dose group also died. Surviving animals in the higherconcentration groups in both studies exhibited depressed weight gains.Rats receiving diethanolamine developed a poorly regenerative, microcyticanemia in both studies. In the 2-week study, dosed male and female ratshad increased kidney weights, renal tubular cell necrosis, and decreasedrenal function; rats in the 13-week study also showed increased incidencesor severity of nephropathy, tubular necrosis, and mineralization.Degeneration of the seminiferous tubules of the testis was noted in dosedmales in both the 2- and 13-week studies, and sperm motility and count weredecreased in the 13-week study. Demyelination in the brain (medullaoblongata) and spinal cord was observed in male and female rats in the13-week study. In mice, dose-dependent increases in liver weight wereobserved in males and females in the 2-week study; cytologic alteration andnecrosis of individual hepatocytes were observed in the highest dose group.In the 13-week drinking water study in mice, nephropathy and tubularnecrosis were observed in males, and degeneration of cardiac myocytes, andhepatocellular necrosis were seen in males and females. Cytologicalteration in the submandibular salivary gland was noted in male and femalemice. Hepatocyte cytologic alteration also was noted in all dosed groupsof mice.

In the 2-week dermal studies, groups of rats and mice were administereddaily doses of diethanolamine in 95% ethanol, ranging from 160 to 2500mg/kg for mice, and from 125 to 2000 mg/kg for rats, 5 days per week. In13-week studies, dermal doses ranged from 32 to 500 mg/kg for rats, andfrom 80 to 1250 mg/kg for mice. In the 2-week study, early deaths of malerats and male and female mice occurred in the highest dose groups and infemale rats in the 2 highest dose groups (1000 and 2000 mg/kg). Bodyweight gains were reduced in rats and mice in the higher dose groups.Early deaths in the 13-week study were observed in the highest dose groupsof rats (500 mg/kg) and mice (1250 mg/kg). Body weight gains were reducedin rats and mice given the higher doses. Rats in the dermal studiesexhibited dose-dependent hematologic and renal function changes similar tothose observed in rats in the drinking water study. In addition, in the2-week study, rats exhibited ulcerative skin lesions at the site ofapplication, accompanied by inflammatory cell infiltration, hyperkeratosis,and acanthosis (hyperplasia) of the epidermis. Hyperkeratosis, withoutulceration, was observed in some animals. Ulceration at the site ofapplication was observed in male and female mice. Acanthosis, withoutulceration or inflammatory cell infiltration, was observed in mice in alllower dose groups. In the 13-week study, skin lesions at the site ofapplication included ulceration and inflammation, hyperkeratosis, andacanthosis. Liver weights were increased in male and female rats, butthere were no associated histopathological changes. Othertreatment-related effects observed in rats included demyelination in thebrain and spinal cord, and nephropathy, renal tubular necrosis, and/ortubular mineralization; mice exhibited cytological alterations in the liverand/or hepatocellular necrosis, renal tubular epithelial necrosis, andcardiac myocyte degeneration.

In in vitro genetic toxicity studies, diethanolamine was not mutagenic inSalmonella typhimurium or mouse L5178Y TK^+/- cells. Diethanolamine did notinduce sister-chromatid exchanges or chromosomal aberrations in Chinesehamster ovary cells, nor did it induce micronuclei in peripheral blooderythrocytes in mice exposed by topical application for 13 weeks. All invitro studies were conducted with and without S9 activation.

Target organs of diethanolamine toxicity identified in these studiesincluded bone marrow, kidney, brain, spinal cord, testis, and skin in rats,and liver, kidney, heart, salivary gland, and skin in mice. Ano-observed-adverse-effect-level (NOAEL) was not achieved for hematologicalchanges or nephropathy in rats (<160 ppm), or for cytologic alteration ofthe liver in mice (<630 ppm) in the drinking water studies. In the dermalstudies, a NOAEL was not achieved for hematological changes, nephropathy,or hyperkeratosis of the skin in rats (<32 mg/kg), or for cytologicalteration of the liver or acanthosis of the skin in mice (<80 mg/kg).

Synonyms: 2,2'-iminodiethanol; 2,2'-iminobisethanol; diethylolamine;bis(hydroxy-ethyl)amine; 2,2'dihydroxydiethylamine; 2,2'-aminodiethanol

Report Date: October 1992

Growth & Survival Curves for NTP 13-Week Toxicity Studies

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