1.1.1. Nomenclature

• Chem. Abstr. Serv. Reg. No.: 102-71-6
• Deleted CAS Reg. Nos: 36549-53-8; 36549-54-9; 36549-55-0; 36659-79-7; 10565527-4; 126068-67-5
• Chem. Abstr. Name: 2,2′,2″-Nitrilotris[ethanol]
• IUPAC Systematic Name: 2,2′,2″-Nitrilotriethanol
• Synonyms: Alkanolamine 244; nitrilotriethanol; TEA; TEA (amino alcohol); TEOA; triethanolamin; tris(β-hydroxyethyl)amine; tris(2-hydroxyethyl)amine

1.1.2. Structural and molecular formulae and relative molecular mass

1.1.3. Chemical and physical properties of the pure substance

(a)

Description: Hygroscopic crystals, or colourless, viscous liquid with a mild ammoniacal odour (Lide & Milne, 1996; Budavari, 1998)

(b)

Boiling-point: 335.4 °C (Lide & Milne, 1996)

(c)

Melting-point: 20.5 °C (Lide & Milne, 1996)

(d)

Density: 1.1242 g/cm³ at 20 °C (Lide & Milne, 1996)

(e)

Spectroscopy data: Infrared (proton [10636]; grating [18547]), nuclear magnetic resonance (proton [7209]; C-13 [1871]) and mass spectral data have been reported (Sadtler Research Laboratories, 1980; Lide & Milne, 1996)

(f)

Solubility: Miscible with water, acetone, ethanol and methanol; soluble in chloroform; slightly soluble in benzene, diethyl ether and lignans (Lide & Milne, 1996; Budavari, 1998)

(g)

Volatility: Vapour pressure, < 1.3 Pa at 20 °C; relative vapour density (air = 1), 5.14 (Verschueren, 1996); flash-point, 185 °C (Budavari, 1998)

(h)

Stability: Incompatible with metals such as aluminium and copper, halogenated organics, strong acids, oxidizing materials and absorbent materials (cellulose, sawdust) (Dow Chemical Company, 1999a)

(i)

Octanol/water partition coefficient (P): log P, –2.3 (Verschueren, 1996)

(j)

Conversion factor¹: mg/m³ = 6.10 × ppm

1.1.4. Technical products and impurities

Triethanolamine is commercially available with the following specifications: purity, 99.0% min.; monoethanolamine, 0.05% max.; diethanolamine, 0.40% max. (see monograph in this volume); and water content, 0.20% max. (Dow Chemical Company, 1999b). Triethanolamine is also available in several other grades, including a blend of 85% triethanolamine and 15% diethanolamine [TEA 85]; a low freeze-grade blend (85% TEA 85 and 15% deionized water) for use in colder temperatures; and a blend of 85% triethanolamine and 15% deionized water [TEA 99 Low Freeze Grade] (Dow Chemical Company, 1998).

Trade names for triethanolamine include Daltogen, Sterolamide, Sting-Kill, Thiofaco T-35, and Trolamine.

1.1.5. Analysis

Triethanolamine can be determined in workplace air by drawing the air sample through aqueous hexanesulfonic acid and analysing by ion chromatography. The limit of detection for this method is 20 µg per sample (Eller, 1994).

Triethanolamine can be determined in metalworking and cutting fluids by gas chromatography–mass selective detection of silylated derivatives, by isotachophoresis, by capillary zone electrophoresis with indirect ultraviolet detection, and by spectrophotometry (Kenyon et al., 1993; Fernando, 1995; Schubert et al., 1996; Sollenberg, 1997); and in cosmetics and pharmaceuticals by ion-exclusion chromatography and by reversed-phase high performance liquid chromatography (Fukui et al., 1992; Maurer et al., 1996).

1.4.1. Natural occurrence

Triethanolamine is not known to occur as a natural product.

1.4.2. Occupational exposure

No data on the number of workers exposed to triethanolamine were available from the 1981–83 National Occupational Exposure Survey (NOES, 1999) conducted by the National Institute for Occupational Safety and Health (NIOSH).

Triethanolamine is present in machining and grinding fluids and has been measured in the metal manufacturing industry. It was present in bulk cutting fluids at levels ranging from 0.3 to 40%. Personal air exposures ranged from 0.02 to 244 µg/m³ (n = 110) (Kenyon et al., 1993). Concentrations were generally higher for workers engaged in transfer operations and lowest for assembly workers (who did not use machining fluids themselves).

In a German study (1992–94), triethanolamine was measured in metalworking fluid samples (n = 69). The proportion of samples containing triethanolamine varied over time between 50 and 85% (Pfeiffer et al., 1996).

1.4.3. Environmental occurrence

The broad utility of triethanolamine in a large number of industrial applications and consumer products may result in its release to the environment through various waste streams (Beyer et al., 1983; Santa María et al., 1996; West & Gonsior, 1996).

Dermal exposure to triethanolamine-containing products (principally personal care products) is the primary route of general population exposure to triethanolamine (Jones & Kennedy, 1988; Batten et al., 1994).

In 1981, triethanolamine was reported to be an ingredient (generally at a concentration of less than or equal to 5%) in 2720 out of 22 572 cosmetic products which may be applied to or come into contact with skin, eyes, hair, nails, mucous membrane and respiratory epithelium. Small amounts may be ingested from lipsticks. Product formulations containing also monoethanolamine (triethanolamine–ethanolamine) may be in contact with the skin for variable periods of time following each application. Daily or occasional use may extend over many years (Beyer et al., 1983).

3.1.1. Mouse

Groups of 40 male and 40 female ICR-JCL mice, six weeks of age, were fed diets prepared by adding 0.03 (low dose) or 0.3% w/w (high dose) triethanolamine (analytical grade) to a powdered diet (heated for 40 min at 100 °C and formed into pellets) throughout their lifespan. Control animals received untreated diet [heating not specified]. The survival rate was 50% at 85 weeks in females and at 65 weeks in males for both treated and control animals. There was a statistically significant (p < 0.05, test unspecified) increase in the incidence of lymphomas in female mice (controls, 1/36; low dose, 7/37; high dose, 9/36), but no increase in the incidence of tumours at any site in male mice (Hoshino & Tanooka, 1978). [The Working Group noted the lack of historical control data on the incidence of lymphomas in female mice, as well as the possibility that heating of the triethanolamine in the diet may have produced degradation products.]

Groups of 50 male and 50 female B6C3F₁ mice, six weeks of age, were given drinking-water containing triethanolamine (reagent grade, containing 1.9% diethanolamine as a contaminant) at concentrations of 0% (control), 1% (low dose) or 2% (high dose) for 82 weeks, at which time the study was terminated. The high dose was estimated to be the maximum tolerated dose. The percentage of mice surviving at week 82 was: females—all groups, 100%; males—control, 86%; low-dose, 92%; high-dose, 96%. There was no significant difference between the body weights of treated and untreated mice. There was no treatment-related increase in tumour incidence in either sex (Konishi et al., 1992).

3.1.2. Rat

Groups of 50 male and 50 female Fischer (F344/DuCrj) rats, six weeks of age, were given drinking-water containing triethanolamine (reagent grade, containing 1.9% diethanolamine as a contaminant) at concentrations of 0% (control), 1% (low dose) or 2% (high dose) for two years. At approximately experimental week 60, loss of body weight gain and mortality increased in the female 2% group. Administration of triethanolamine was therefore ceased in both female treatment groups at week 68 for one week and thereafter, from week 69, dietary concentrations in both female treatment groups were reduced by half. After week 104, untreated drinking-water was given to all rats and observation was continued until week 113, when all surviving animals were killed. Treatment with triethanolamine produced a reduction in weight in both males and females and, in females, a dose-dependent increase in mortality due to nephrotoxicity was seen. The percentage mortality in the control, low- and high-dose groups was 32, 32 and 34 in males, and 16, 32 and 42 in females, respectively. No treatment-related increase in the incidence of tumours was observed (Maekawa et al., 1986).

3.2.1. Mouse

Groups of 60 male and 60 female B6C3F₁ mice, six weeks of age, were administered triethanolamine (purity, 99%) topically in acetone on five days per week for 103 weeks. Male mice received 0, 200, 630 or 2000 mg/kg bw and female mice received 0, 100, 300 or 1000 mg/kg bw triethanolamine. Although there was an apparent association with hepatocellular tumours in both sexes and hepatoblastomas in males, the authors noted that the mice were chronically infected with Helicobacter hepaticus, an organism that is known to induce hepatitis, so that interpretation of any relationship between triethanolamine and liver neoplasms was inconclusive (Fox et al., 1998; National Toxicology Program, 1999). [The Working Group did not consider this study in its evaluation of carcinogenicity since it was considered inadequate by the National Toxicology Program.]

3.2.2. Genetically modified mouse

Groups of 15–20 female Tg.Ac mice, which carry a zeta-globin v-Ha-ras gene on an FVB background, 14 weeks of age, were administered triethanolamine in acetone topically (the triethanolamine used was from the same chemical batch as that used in the National Toxicology Program mouse study (National Toxicology Program, 1999)). Triethanolamine was administered in 200-µL volumes, five times per week for 20 weeks. The concurrent negative control groups were treated with 200 µL acetone. The positive control group was treated with 1.25 µg 12-O-tetradecanoylphorbol 13-acetate (TPA; approximately 99% pure) three times per week or with 1.5 µg twice per week for 20 weeks. The doses of triethanolamine selected were based on the maximum tolerated dose (MTD) used earlier (National Toxicology Program, 1999) and were 3, 10 or 30 mg triethanolamine per mouse per application. Lesions were diagnosed as papillomas when they reached at least 1 mm in size and persisted for at least three weeks. Animals that did not survive until the end of week 10 were not included in the data summaries or calculations. Six weeks after the last application, all surviving mice were killed. There was no evidence of chronic irritation or ulceration at the site of application during the exposure period. In contrast to the positive controls, which developed multiple papillomas in 19/20 animals, there was no increase in the incidence of skin tumours in triethanolamine-treated animals (Spalding et al., 2000).

3.2.3. Rat

Groups of 60 male and 60 female Fischer 344/N rats, six weeks of age, were administered triethanolamine (purity, 99%) topically in acetone on five days per week for 103 weeks. Male rats received 0, 32, 63 or 125 mg/kg bw and females received 0, 63, 125 or 250 mg/kg bw triethanolamine. The survival rates of males were 21/50, 11/50, 18/49 and 19/50 and of females were 25/50, 29/50 and 18/50 in the control, low-, mid- and high-dose rats respectively. The mean body weight of females receiving 250 mg/kg bw ranged from 9% to 12% lower than that of the vehicle controls from weeks 73 to 93, and by the end of the study, was 7% lower than that of the vehicle control group. There was no significant increase in the incidence of tumours at any site (National Toxicology Program, 1999).

4.1.1. Humans

No toxicokinetic data related directly to triethanolamine were available.

4.1.2. Experimental systems

4.2.1. Humans

Triethanolamine appeared to be without irritating effects below a concentration of 5% in most people; above this concentration (mild) skin irritation is observed. In some volunteers, however, skin irritation was observed at lower concentrations of triethanolamine, particularly in persons who had a history of contact dermatitis and scarified skin (Beyer et al., 1983). Among patients with contact dermatitis, triethanolamine was found to be the most frequent sensitizer (Tosti et al., 1990). When a total of 1357 patients suspected of having allergic eczematous contact dermatitis were patch-tested with triethanolamine, 41 had positive reactions. Of these, 29 had applied lotion-based medicaments locally for some time (Scheuer, 1983). Many case reports on people exposed to cosmetics and investigations in groups of workers exposed to cutting fluids (containing triethanolamine among many other components) indicate that contact dermatitis and allergic reactions to triethanolamine occur (e.g., Calas et al., 1978; Herman, 1983; Shrank, 1985; Jones & Kennedy, 1988; Batten et al., 1994; Hüner et al., 1994; Hamilton & Zug, 1996; Blum & Lischka, 1997).

Triethanolamine has been clinically tested with other model irritant compounds for potency to stimulate signal release of proinflammatory mediators in human skin in order to find biomarkers of irritancy. Neat or aqueous triethanolamine was applied to the lower arm of 12 male volunteers; after 24 h, suction blister fluid specimens were taken from the site of treated skin. Triethanolamine caused no significant increase in arachidonic acid and prostaglandin concentrations in suction blister fluid samples, in contrast to the irritants sodium lauryl sulfate, benzalkonium chloride and Tween 80 that gave positive test results (Müller-Decker et al., 1998).

4.2.2. Experimental studies

The toxicology of triethanolamine has been reviewed (Knaak et al., 1997). In general, rather high doses of triethanolamine are well tolerated by rats and mice. Major sites of toxicity in rats and mice are liver and kidney, while skin toxicity occurs after dermal application, especially when undiluted triethanolamine is applied.

Irritation to the eye and skin was minimal to slight 72 h after application of pure (98%) triethanolamine to New Zealand White rabbits (Dutertre-Catella et al., 1982).

Subchronic inhalation exposure to triethanolamine aerosols has been studied in both male and female Fischer 344 rats and B6C3F₁ mice at concentrations of 125– 2000 mg/m³ for 6 h per day on five days a week over a 16-day period (an unpublished study reported by Mosberg et al., 1985, Battelle Columbus Division Laboratories, and reviewed in Knaak et al., 1997). In rats, several minor changes were observed such as a decrease in body weight and an increase in kidney weight, but no histopathological changes were apparent, indicating little toxicity under these conditions. In mice, various haematological changes were considered not to be dose-related.

Signs of kidney and liver toxicity were observed by Kindsvatter (1940) in guinea-pigs and albino rats during oral administration of triethanolamine (200–1600 mg/kg bw per day). Maekawa et al. (1986) reported that exposure to triethanolamine in the drinking-water led to kidney toxicity at a concentration of 1–2% (approximately 1000 mg/kg bw per day intake) in both male and female Fischer 344 rats. Body weight gain was depressed by 10–14% after two years on this regimen, compared with controls. Kidney weights were greatly increased, and major histopathological changes were observed in the kidneys, suggesting a dose-related acceleration of chronic nephropathy, which is common in ageing Fischer 344 rats. Mineralization and necrosis of the renal papilla were found. In a 14-day study, no histopathological changes were observed in Fischer 344 rats exposed to 2% triethanolamine in the drinking-water, equivalent to an intake of approximately 2500–2800 mg/kg bw per day (an unpublished study reported by Hejtmancik et al., 1985, cited by Knaak et al., 1997).

In a chronic study in B6C3F₁ mice given 1 or 2% triethanolamine (containing 2% diethanolamine) in the drinking-water (see Section 3.1.1), little toxicity was observed in either sex (Konishi et al., 1992). [The mice consumed up to 3000 mg/kg bw per day at the high dose.]

Dermal application of high concentrations and, in particular, of undiluted triethanolamine to rats and mice in (sub-)chronic studies led to a necrotizing, chronic– active inflammatory process on the skin as observed in several studies and reported extensively in a National Toxicology Program (1999) study. In a 13-week study in Fischer 344 rats given 125–2000 mg/kg bw dermally per day on five days per week, animals receiving 2000 mg/kg bw per day showed body weight gain reductions and kidney weight increases. Hypertrophy of the pars intermedia of the pituitary gland also occurred. The effects were dose-related and were similar in both males in females. In a subsequent 103-week study, doses of 32–125 mg/kg bw per day were applied to the skin of males and of 63–250 mg/kg per day to the skin of females. At the 15-month interim evaluation, inflammation and ulceration were present at the site of application in both males and females. In females, kidney weights increased after application of 250 mg/kg bw per day. At the end of the study, hyperplasia in the kidney was observed, which was more severe in males than in controls, although the incidence of hyperplasia was the same.

The National Toxicology Program (1999) study also included B6C3F₁ mice. In the 13-week study (250–4000 mg/kg bw per day on five days per week), acanthosis and inflammation at the site of application were observed in both males and females at 4000 mg/kg bw per day, and liver and kidney weights were increased at that dose. In the subsequent 103-week study, females received doses of 100–1000 mg/kg bw per day and males 200–2000 mg/kg bw per day. Skin inflammation was found in both males and females at the site of application. Infection with Helicobacter hepaticus in these mice (Fox et al., 1998) complicates the interpretation of the results. Another subchronic study of triethanolamine administered dermally to C3H/HeJ mice (140–2000 mg/kg bw in males and 160–2300 mg/kg bw in female mice, three times per week for 95 days) found no signs of toxicity except for slight epidermal hyperplasia at the application site; the internal organs showed no change in weight and no histopathological signs were observed (DePass et al., 1995).

4.3.1. Humans

No data were available to the Working Group.

4.3.2. Experimental systems

Triethanolamine was administered to groups of 10 male and 10 female Fischer 344/N rats and B6C3F₁ mice for 13 weeks by topical application at dose levels of 0, 500, 1000 or 2000 mg/kg bw per day and 0, 1000, 2000 or 4000 mg/kg bw per day, respectively. Body weight gains were significantly lower in the highest-dose group of male and female rats, but there was no change in mice at any dose level. In neither rats nor mice was there any significant change in sperm motility, morphology or number and there was no change in the mean duration of the estrous cycle (National Toxicology Program, 1999).

No embryotoxic or teratogenic effects were produced when pregnant rats were exposed by topical administration to their shaved skin of semipermanent hair-dye preparations containing 0.1–1.5% triethanolamine on gestational days 1, 4, 7, 10, 13, 16 and 19 (Burnett et al., 1976). [This study was not reviewed in detail by the Working Group because of the low proportion of triethanolamine in the complex mixtures tested.]

The reproductive and developmental toxicity of triethanolamine tested without the complication of many other accompanying substances has been reviewed (Knaak et al., 1997). This review is used as the reference source to the following studies because they have not been reported in the open literature (Battelle reports).

Triethanolamine was administered as a solution in acetone to the skin of male and female Fischer 344 rats at dose levels of 0 or 500 mg/kg bw per day for 10 weeks before mating and then to the females during gestation and lactation. No effect on mating, fertility or offspring growth and survival was observed. In a similar study with CD-1 mice administered triethanolamine doses of 0 or 2000 mg/kg bw per day, no effect of treatment was observed.

4.4.1. Humans

No data were available to the Working Group.

4.4.2. Experimental systems (see Table 4 for references)

Triethanolamine was not mutagenic to Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 or TA1538 in the presence or absence of exogenous metabolic activation in a number of studies. Triethanolamine did not induce mutations in Escherichia coli WP2 uvrA and WP2 try^– in the presence or absence of exogenous metabolic activation in two studies. In a single study, triethanolamine was not mutagenic to Bacillus subtilis strains carrying uvrA or uvrA and polA mutations in the presence or absence of exogenous metabolic activation. However, when triethanolamine was mixed with sodium nitrite, mutations were induced in this system without exogenous metabolic activation; this activity was lost in the presence of exogenous metabolic activity.

Triethanolamine did not induce gene conversion in Saccharomyces cerevisiae in the presence or absence of exogenous metabolic activation in one study. In a single study, sex-linked recessive lethal mutations were not induced in Drosophila melanogaster by treatment with triethanolamine either by diet or injection.

Unscheduled DNA synthesis was not induced in rat primary hepatocytes exposed to triethanolamine in two studies.

Triethanolamine did not induce sister chromatid exchanges in Chinese hamster ovary cells in either the presence or absence of exogenous metabolic activation. Chromosomal aberrations were not induced in rat liver cells, Chinese hamster lung cells or Chinese hamster ovary cells by in-vitro exposure to triethanolamine. It did not induce cell transformation in Syrian hamster embryo cells.

Treatment of male and female mice with triethanolamine for 13 weeks by dermal application did not result in any change in the frequency of micronuclei in their blood cells.

Overall evaluation

Triethanolamine is not classifiable as to its carcinogenicity to humans (Group 3).