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Description of key information

There was no data available for the determination of toxicokinetics, metabolism and distribution. An assessment was done based on physico-chemical properties of the test substance and available data on acute and repeated dose toxicity.

Key value for chemical safety assessment

Additional information

There was no data available for the determination of toxicokinetics, metabolism and distribution.

Assessment of Toxicokinetic Behaviour 

Bis(2-ethylhexyl)amine (CAS-No. 106-20-7) is a colorless liquid with a molecular weight of 241.46 g/mol and a vapour pressure of 0.0023 hPa at 20°C. It has a low water solubility of 14 mg/L at 20°C, the log Pow is 7.3 at 25°C and the pH is 7.5. The high logPow indicates that a general accumulation of the test substance is possible.

The substance is described with a purity of generally >/= 99%, with water (</= 0.1%) as further component.

 

Absorption

Data for absorption can be taken from acute (oral, inhalative and dermal) and chronic toxicity studies.

 

In an acute oral toxicity study (BASF AG 1967) a LD50 of 1008 mg/kg bw for male and female rats was determined. The female animals appeared to be more sensitive. Main clinical signs observed were irregular/ accelerated respiration, heavy ruffled fur, anogenital region smeared with feces (diarrhea), squatting posture, apathy, red eye and nose crusts. All survivors recovered. At necropsy of the dead animals, dilated stomach, atony and blood smeared snouts were observed. The sacrificed animals showed uneven faded liver, adhesion between liver, stomach, spleen and left kidney; bronchitis or bronchopneumonia with emphysema.

Additionally, a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test was conducted. The test substance was administered in corn oil as vehicle at dosages of 7.5, 25, and 75 mg/kg body weight/day, and controls received the vehicle only. At 75 mg/kg bw/day, bedding in mouth, accompanied by slight salivation in some isolated animals was noted. Furthermore, there was a slight decrease in mean body weight gain after treatment start in males, which was considered to be not adverse. Hematological and clinical chemistry examinations did not reveal any adverse effects. Increased liver and kidney weights were observed in females at 25 and 75 mg/kg bw/day. However, there were no hints for an impaired function of these organs by clinical chemistry and histopathology. All microscopic findings recorded were within the range of normal background lesions which may be recorded in animals of this strain and age. No effects on reproduction and development were observed at any dose level. The general NOAEL was considered to be 75 mg/kg body weight/day.

 

The findings reported above may indicate bioavailability of bis(2-ethylhexyl)amine after oral uptake. But the acute study may also represent side effects of the corrosive potential of the test item. Due to the lipophilic nature of the compound, it may be taken up by micellular solubilisation (ECHA guidance document R.7c, 2017).

 

An acute inhalation toxicity test was performed (BASF AG 1991) with a test substance as aerosol and a LC50 of 0.91 mg/Lfor male and female rats was observed. Main clinical signs were local irritation of the airways and of the eyes. 30 min post application tonic-clonic convulsions, restlessness, pain reflex and intermittent respiration were noted. Also effects on body weight were noted. At necropsy, general congestion and pulmonary hyperemia with edema were observed. Additional data were available from inhalation risk tests (IRT). The inhalation of a saturated vapour-air mixture (0.2 mg/L) for 8 h caused no mortality in male and female rats (strain not specified). Symptoms described included signs of irritation of the mucous membranes and post mortem examination revealed occasional bronchopneumonia (BASF AG 1967; reliability score 2). In a second IRT, groups of six male albino rats (strain unspecified) were exposed to a flowing stream of air substantially saturated with vapours of the test material. No mortality was observed (Smyth et al. 1949; reliability score 2).

In the described inhalation studies, it seems that the main effects were local effects due to the corrosive potential of the test substance. Due to the low vapour pressure of 0.0023 hPa (at 20°C) the exposure to this substance via the inhalation route might be of less importance. However, if inhaled the high logPow value of 7.3 and the low water solubility may favor uptake by micellular solubilisation (ECHA guidance document R.7c, 2017).

A dermal LD50 value of 1.19 mL/kg, equivalent to 958 mg/kg bw, was reported for rabbits, with no further details provided (Union Carbide 1968). According to the ECHA guidance document R.7c, 2017, the dermal absorption of test substances with water solubility between 1-100 mg/L is anticipated to be low to moderate. Additionally, the results of the acute oral and acute inhalative toxicity tests indicated, that local effects caused by the corrosive properties of the test substance which might led to destruction of membrane barriers during the acute dermal toxicity study were more important than toxicity via systemic availability.

 

Taken together, bis(2-ethylhexyl)amine resulted in mortality after oral, inhalative and dermal exposure. Thus, the substance might be systemic available via these routes of exposure. However, as bis(2-ethylhexyl)amine is also caustic the existing data indicate that corrosion and also irritation of the respiratory tract (local effects) are the primary effects.

 

All available in vitro studies on genotoxicity, with or without metabolic activation, were negative. Therefore, there is no indication of a strong reactivity of bis(2-ethylhexyl)amine and/ or its metabolites under the chosen test conditions.

 

Distribution

Because of the high logPow value of 7.3 the substance is likely to reach the intracellular compartment. Further, even though data for the body half-life of the substance is not available, bioaccumulation in adipose tissue under repeated exposure conditions cannot be excluded.

Metabolism

If not excreted unchanged, secondary amines like bis(2-ethylhexyl)amine could be N-dealkylated and also N-oxygenated with oxidative N-dealkylation as predominant process which lead to aldehydes as products (Mayer R.T., 2007; Seto J., 1993; Yamada H., 1997). The aldehyde is further metabolized to the respective carboxylic acid.              

 

Excretion 

Due to its molecular weight, as well as its vapour pressure, bis(2-ethylhexyl)amine is expected to be excreted predominantly via the urine (ECHA guidance document R.7c, 2017).Urinary excretion is also assumed for the metabolic end product carboxylic acid.