3,3'-oxybis(ethyleneoxy)bis(propylamine)

Endpoint summary

Description of key information

No experimental data on absorption, metabolism and distribution are available for the substance. Therefore, the toxicokinetic behavior was evaluated based on the structure and the physico-chemical properties of the substance as well as data from experimental in vivo toxicity studies.

The test substance belongs as low molecular weight polyetherdiamine to the structural class of etherdiamines.

Absorption is expected for the oral, dermal and inhalation route. Since the test substance is excellent miscible in water, a distribution through extracellular body fluids is likely. Moreover, the corrosive properties of the test substance might increase absorption. Metabolism might occur, e.g. via N-acetylation. Excretion will most likely occur via the urine. No bioaccumulation is expected.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

The main toxicokinetic properties of the polyetherdiamine 3,3'-oxybis(ethyleneoxy)bis(propylamine) (EC-No. 224-207-2) are assessed on the basis of its physico-chemical properties and with special regard to the results of the standard toxicity studies performed with this substance. Substance specific toxicokinetic or dermal absorption studies are not available.

 

1. Relevant physico-chemical properties of 3,3'-oxybis(ethyleneoxy)bis(propylamine

Molecular weight:   220.3 g/mol

Physical state:          liquid at room temperature

Boiling point:            not applicable (decomposes before boiling)

logPow:                    -1.25 (at 25 °C, pH 11.1)

Water solubility:      miscible with water in any ratio

pKa:                           10.0 (at 20 °C)

Vapour pressure:     0.00005 hPa at 20 °C

Hydrolysis:               Hydrolysis is not expected due to the absence of hydrolysable groups.

Surface tension:       Based on chemical structure, no surface activity is predicted.

 

 

2. Absorption:

Oral absorption

The molecular weight of the substance (below 500) favours absorption after oral exposure. In contrast, the following factors are more in favour of a limited oral absorption: It is generally thought that ionised substances do not readily pass biological membranes. As the pKa is 10, most of the substance will be ionized at the pH range present in the gastro-intestinal tract. The very high water solubility and the log Pow below -1 indicate that passive diffusion through membranes might be limited by the rate at which the substance partitions out of the gastrointestinal fluid. Furthermore, the molecular weight of > 200 g/mol might restrict passage through the aqueous pores or transport through the epithelial barrier by the bulk passage of water.

Following single or repeated oral gavage administration, the substance causes corrosive and/or irritating effects in stomach and intestine. Thus, it is possible that oral absorption is enhanced due to damage to cell membranes. It is therefore concluded that a higher oral aborption can be assumed following administration of irritant/corrosive substance doses whereas a lower oral absorption can be assumed at non-irritating substance doses.

In a repeated dose toxicity study (combined with the reproduction / developmental toxicity test, OECD 422) in rats the substance caused signs of systemic toxicity (decreased food consumption and decreased body weight parameters), revealing that absorption has occurred. However, apart from that, no specific data concerning oral absorption of the test substance are available

Dermal absorption

Dermal absorption of the pure substance can be assumed because of its corrosive properties, which leads to the destruction of the skin barrier (as observed in the acute dermal toxicity study on rat skin as well as in the skin irritation/corrosion study on rabbit skin). In contrast, the dermal absorption at non-irritating substance concentrations can be assumed to be very low. This is due to the fact that at the skin’s slightly acidic pH the substance will be ionised and thus, not be able to penetrate through the intact skin.

 

Inhalation absorption

The low volatility (vapour pressure of 0.00005 hPa at 20 °C) indicates that a vapour inhalation exposure is unlikely.

If exposure to respirable aerosol occurs, the very high water solubility and log Pow below -1 indicate that the substance may be retained in the mucus of the respiratory tract, thus, limiting inhalation absorption. However, the corrosive properties of the substance could cause a destruction of epithelial membranes, which would lead to an enhanced absorption.

Overall, it is concluded that inhalation absorption at a similar rate to oral absorption can be assumed.

Altogether, due to the lack of data concerning the absorption of the test substance a worst case of 100 % absorption after oral uptake, dermal exposure, and inhalation is assumed.

 

 

3. Distribution/Metabolism:

At physiological pH the highly water soluble substance will be mostly ionised. Thus, diffusion across membranes might be limited and distribution throughout the body via the extracellular aqueous compartment seems likely. Distribution to the central nervous system and testis is likely to be restricted by the blood-brain and blood-testis barriers.

The clinical signs observed in toxicity studies are mainly indicative for local irritating/corrosive effects and do not allow a conclusion regarding distribution.

For diamines N-acetylation has been described (e.g. Leung, 2000). Furthermore, the sensitising properties of diamines such as ethylenediamine and 3-dimethylaminopropylamine have been assigned to desamination reactions leading to the respective aldehydes and subsequent reaction with proteins (e.g. Aptula et al., 2005). These metabolic pathways are also likely for the present diamine.

The conversion into a metabolite that was more cytotoxic or more genotoxic than the parent substance was not noted when comparing in vitro test results with metabolic activation to in vitro test results without metobolic activation system (genetic toxicity tests). Based on this, an indication is not given that the formation of cytotoxic metabolites is likely.

 

4. Excretion:

The relative low molecular weight (below 300 g/mol) and high water solubility of 3,3' oxybis(ethyleneoxy)bis(propylamine) lead to the conclusion that urinary excretion will be the most relevant route of excretion in the rat. Furthermore, the logPow indicates no potential for accumulation in the tissues.

References

Aptula AO, Patlewicz G and Roberts DW (2005). Skin sensitization: Reaction mechanistic applicability domains for structure-activity relationship. Chem. Res. Toxicol. 18: 1420 -1426.

Leung HW (2000). Pharmacokinetics and metabolism of ethylenediamine in the swiss webster mouse following oral or intravenous dosing. Toxicol Lett. 117(1 -2):107 -14.