2,2'-oxydi(ethylamine)

Endpoint summary

Description of key information

For the test substance, no study is available for the determination of toxicokinetics, metabolism and distribution. Therefore, a qualitative assessment is performed on the basis of the physico-chemical properties of the substance.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

The test substance BAEE is a liquid with a high water solubility (100 g/l), a low log Kow (-2.12 at pH 11; at physiological pH the substance will be charged and hence more hydrophilic) and a moderate vapour pressure (239 Pa). Its pKa is 9.71. The substance is found to be corrosive to the skin.

No toxicokinetic data (animal or human studies) are available on this substance. The data present in this dossier are based on physico-chemical parameters and will allow a qualitative assessment of the toxicokinetic behaviour of the test substance.

Absorption

Oral/GI absorption

Following its high water solubility, the test substance will readily dissolve into the gastrointestinal fluids and subsequently pass through aqueous pores or be carried through the epithelial barrier by the bulk passage of water. 

Based on its molecular weight which is <200 (104 g/mol), absorption by passive diffusion will be favoured, although the low log Kow indicates that this process might be hampered.

It is generally thought that ionized substances do not readily diffuse across biological membranes. The pKa of the test substance suggests that this substance will be predominantly in its ionized form at physiological pH and hence diffusion could be hampered.

The substance is corrosive and therefore it could enhance penetration by local necropsy of GI tissues.

In an acute oral toxicity study with the test substance (Mallory VT, 1983), some animals showed haemorrhagic and fluid filled stomachs and intestines, congested and oedematous lungs, discoloured organs (testes, spleen, pancreas) and haemorrhages of testicular connective tissues at necropsy. Although some of the findings (e.g. haemorrhagic stomach, oedematous lungs) could be link to the corrosive properties of the test substance (local effect), findings on testes, spleen and pancreas could be considered as signs of systemic toxicity, giving an indication that absorption could occurred after oral intake.

In the gastro-intestinal tract hardly any degradation of the substance is expected.

The oral absorption factor is therefore set to 50%, based on the anticipated hampered diffusion of the test substance as an ionized substance and to reflect the variability of the analysis due to the corrosive properties of the substance. The results of the toxicity studies do not provide reasons to deviate from this proposed value. 

Respiratory absorption

Given the vapour pressure of 239 Pa, the test substance is not a highly volatile substance and the availability for inhalation as a vapour is limited.

Once in the respiratory tract, the very hydrophilic substance may be retained within the mucus, and subsequently absorption may occur. Absorption directly across the respiratory tract epithelium by passive diffusion will occur but might be hampered in view of the low log Kow value.

There is no repeated inhalation toxicity study with the test substance available. However, a repeated toxicity study in rats (14 weeks exposure to vapour) has been performed with BDMAEE, a very similar substance to which BAEE can be read-across (see supporting information in the Read Across document). Local effects (irritation of the eye and respiratory track) were observed in the exposure site. Minor, non-specific systemic toxicity was observed at the highest dose (5.8 ppm). The target organs in this study were the adrenal gland and the testes.

Based on the above considerations, it could be concluded that absorption can occur in some extent after inhalation. Therefore, the inhalatory absorption factor is set to 100% (default value).

Dermal absorption

Because of its high water solubility and low log Kow, penetration into the lipid-rich stratum corneum and hence dermal absorption might be limited although its physical form (liquid) and low molecular weight (104 g/mol) favours dermal absorption. In addition, as BAEE is a corrosive substance, absorption/penetration might be enhanced.

In an acute dermal toxicity study (Mallory VT, 1983), the test substance BAEE was tested at very high doses (up to 8000mg/kg b.w.). Some animals showed pale kidneys, dark red fluid-filled bladders and pale livers with multiple small irregular yellow nodules, haemorrhages in the cortex of both kidneys, fluid-filled intestines and erosions in the stomach mucosa at necrospy. Fluid in the thoracic cavity, discoloured adrenals, distended bladders, congested lungs and distended fluid-filled intestines were also observed. Terminal necropsy of surviving animals also revealed haemorrhages of the muscle layers in the application sites, fluid in the abdominal cavity, liver adhered to abdominal walls and kidneys pitted with surface haemorrhages. Although some of the findings (e.g. erosion in the stomach mucosa, haemorrhages of the muscle layers) could be link to the corrosive properties of the substance (local effect), findings on kidneys and liver could be considered as signs of systemic toxicity. Therefore absorption could occur in some extent after acute dermal exposure at high doses.

There is no repeated dermal toxicity study available with BAEE, but BDMAEE has been tested in a 90-day repeated toxicity study in rabbits (Bushy Run Research Center, 1984a). Local effects as irritation were observed in the exposure site but no systemic toxicity was observed when tested up to 2.0% (8 mg/kg bw based on active ingredient). Although the results of the 90-day study do not suggest that dermal absorption occurred, this could be explained by the low concentrations tested. This is supported by the results of a subacute dermal toxicity study where BDMAEE was tested at 2.5%, 5% and 10% and no NOAEL could be identified (Bushy Run Research Center, 1984b).Based on the above considerations, it could be concluded that absorption can occur in some extent after dermal exposure.

Generally default values of 10% or 100% are used for dermal absorption, based on molecular weight and log Kow values (ECHA guidance on IR&CSA, R.7c). For BAEE, the dermal absorption factor might be set to 100% based on a molecular weight < 500, although the log Kow is outside the applicable range of -1 to 4 (log Kow = -2.12 at pH 11). However, it is also generally acknowledged that dermal absorption will not be higher compared to oral absorption; as a result, the dermal absorption factor for BAEE is set to 50%. The results of the toxicity studies do not provide reasons to deviate from this proposed value.

Distribution

In general, the smaller the molecule, the wider the distribution. Small water-soluble molecules, like BAEE, will diffuse through aqueous channels and pores. In view of its log Kow < 0 the substance will not likely distribute into cells and hence the intracellular concentration is not expected to be higher than the extracellular concentration. Based on the test-item related findings observed in toxicity studies on kidneys, lungs, liver, testes, spleen, pancreas and adrenal gland, it is expected that the absorbed fraction of BAEE is distributed over these organs.

Accumulation

In view of the low log Kow and the high water solubility, BAEE is not expected to accumulate in the body.

Metabolism

Once absorbed, the aliphatic carbons as well as the primary nitrogens will undergo extensive hydroxylation, followed by rapid sulfation or glucuronidation. Direct conjugation at the nitrogens in the parent compound is expected. Also extensive cleavage of the ether bound is anticipated.

Excretion

Given the high water solubility and low molecular weight, BAEE and its metabolites will be mainly excreted via the urine.