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Since Amix TE (CAS 68953-70-8) is composed of at least 75 % of TEA (CAS 102-71-6) and the available data for Amix TE are limited, a read-across to TEA was conducted.

In addition to the acute toxicity studies for TEA mentioned below, another acute oral toxicity study with Amix TE was performed: in rats the oral LD 50 was >2000 mg/kg bw, no mortality and no abnormal clinical signs were observed (BASF AG 10A0444/951087).

1. Physical-chemical properties

TEA (MW 149.2 g/mol) is a liquid with a measured melting point of 20.5°C, a measured boiling point of 336.1°C at 1013.25 hPa, a measured vapour pressure of 0.00029 hPa at 21°C, and a dissociation constant (pKa) of 7.86 at 25°C. The octanol-water partition coefficient (log Pow) is -2.3 at 25°C, and the substance is fully miscible with water.

2. Data from acute and repeated dose toxicity studies

Acute toxicity data indicate low toxicity: in rats the oral LD50 was 6400 mg/kg bw, no mortality was observed at or below 5000 mg/kg bw. Clinical signs (elevated respiration, anancasm to chew, apathy, reduced grooming) disappeared 2 days after dosing, and gross pathology at necropsy revealed no abnormalities (BASF AG, 1966). In an acute dermal toxicity study in rabbits, no mortality was observed up to the limit concentration and the LD50 was established to be > 2000 mg/kg bw (TSCATS, 1989). Due to its extremely low vapour pressure, exposure to TEA vapour is very unlikely. One report stated that whole-body exposure of rats to an atmosphere saturated with TEA vapour (concentration not given) at 20°C for 8 hours failed to cause any deaths, therefore no LC50 value was established (BASF AG, 1966).

In an oral repeated dose study, rats were administered 0 - 1000 mg/kg bw/day in the diet for 91 days. Since no adverse effects were observed, the NOAEL was established to be 1000 mg/kg bw/day (TSCATS, 1989). In a sub-chronic dermal toxicity study, rats were treated with 0 - 2000 mg/kg bw/day on the skin for 90 days (Battelle, 1987). At the highest doses, decreases in body weight, irritation and inflammation at the site of application were observed - ranging from minimal acanthosis at the lower doses to chronic active inflammation, erosion and ulceration in higher dose groups - accompanied by hematologic changes. NOAEL's for local effects were determined to be 125 and 250 mg/kg bw/day for males and females, respectively. The NOAEL for systemic effects was established at 125 mg/kg bw/day, based on renal effects (i.e. increased kidney weight). Similar effects were observed in a sub-chronic dermal toxicity study in mice, receiving 0 - 4000 mg/kg bw/day TEA on the skin for 90 days (Battelle, 1987). The kidneys were identified as the target organ at lower doses, accompanied by increased liver weights at the top dose level. Dermal irritation and inflammation was noted at the site of application. In an 28 -day inhalation toxicity study in rats, exposed to 0 - 0.5 mg/L TEA for 6 hours/day and 5 hours/week, the NOAEL for systemic effects was established at 0.5 mg/L since no adverse systemic effects were observed. The NOAEL for local effects (laryngeal inflammation) was determined to be 0.02 mg/L for females; since slight inflammation was still observed in males, this concentration was designated the LOAEL for local effects in males (BASF AG, 1993).

3. Absorption, distribution, metabolism, excretion

Studies in experimental animals indicated that triethanolamine is absorbed through the skin and in the gastrointestinal tract. In oral studies, 63% of TEA administered to Wistar rats was absorbed from the gastrointestinal tract within one hour after administration (IARC (2000), IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Some Industrial Chemicals, Vol. 77, pp. 381-401). In the skin, differences in the rate of absorption between F344 rats and C3H/HeJ mice have been described. In mice, most of the topically applied [14C]-TEA is absorbed, and only 6% to 11% is detected at the site of application after 48 hours (Dow 1989; Stott, 2000). In rats, absorption occurs more slowly and is less extensive (IARC, 2000; Melnick and Tomaszewski (1990), Triethanolamine. In Ethel Browning’s Toxicity and Metabolism of Industrial Solvents. Vol. 2: Nitrogen and Phosphorus Solvents, 2nd ed. (D.R. Buhler and D.J. Reed, Eds.), pp. 441-450. Elsevier Science Publishers,.). Stott et al. (2000) reported similar levels of dermal absorption between C3H/HeJ mice and F344 rats 24 to 48 hours after dosing. In contrast, an absorption, distribution, metabolism, and excretion study by the NTP (2004) found that after 72 hours of exposure, only 20% to 30% of the applied dose of TEA (68 or 276 mg/kg) was absorbed in rats and 80% was absorbed in mice (79 or 1120 mg/kg). These differences in absorption have been attributed either to the different doses used in comparative studies or to species-specific factors. In fact, an analysis of absorption data reveals that a 14-fold increase in concentration gives a 23-fold increase in absorption in mice; whereas in rats, a fourfold increase gives a sixfold increase in absorption. No differences in tissue distribution were noted after iv or dermal exposure (NTP, 2004). The elimination of [14C]-TEA-derived radioactivity from the blood of mice after a 1 mg/kg intravenous injection displays two-phase elimination kinetics with an initial rapid distribution phase (0.3-hour half-life) followed by a slower elimination phase (10-hour half-life). Kinetics following an unoccluded dermal application of neat TEA (200 mL/kg) was described as an initial rapid absorption phase (0.7-hour half-life) and two elimination phases with half-lives of 1.9 and 31 hours (Dow, 1989; Stott, 2000). The dermal absorption study was unoccluded, so it may be expected that some TEA was orally absorbed through grooming. Excretion of [14C]-TEA is similar among rats and mice. Following a dermal dose of 1000 mg/kg, mice excreted approximately 60% of the radioactivity in the urine and 20% in the feces 48 hours after dosing; rats excreted 54% and 9% in the urine and feces, respectively (Dow, 1989; Stott, 2000). Kohri et al. (1982) reported that urinary excretion of [14C]-triethanolamine in rats occurred primarily as the parent compound with a small amount of glucoronide metabolite.

In addition to animal studies, human skin penetration of TEA was tested in vitro using diffusion cell techniques (Kraeling, 2003). Oil-in-water emulsions containing 1% or 5% 14C-TEA were added to the stratum corneum side of 200 -300 µm thick human skin sections and penetration of radioactivity into and through the skin (into a receptor fluid, sampled up to 24 hours after application) was determined. At pH 8.0, 1.1 and 1.2% of the dose was absorbed into the receptor fluid with a total penetration of 22.0 and 16.5% for 1 and 5% TEA, respectively. At pH 7.0, 0.43 and 0.28% was absorbed into the receptor fluid with a total penetration of 9.8 and 5.8% after 24 hours for 1 and 5% TEA, respectively. After 48 hours at pH 7.0, 0.68 and 0.60% was absorbed into the receptor fluid with a total penetration of 9.6 and 6.9%, for 1 and 5% TEA respectively. This pH-related diffence reflects the higher percentage of unionized test material pH 8.0.