3,3'-[butane-1,4-diylbis(oxy)]bispropanamine

Endpoint summary

Description of key information

The test substance belongs as low molecular weight polyetherdiamine to the structural class of etherdiamines. Absorption was demonstrated for the oral route and inhalation route and is expected in case of dermal route. Since the test substance is described as miscible in water at any ratio, a distribution through extracellular body fluids is likely. Metabolism might occur, e.g. via N-acetylation. Excretion of this aliphatic polyetherdiamine will most likely occur via the urine. No bioaccumulation is expected.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The main toxicokinetic properties of the low molecular weight polyetherdiamine 3,3'-[butane-1,4-diylbis(oxy)]dipropan-1-amine (EC-No. 7300-34-7) 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'-[butane-1,4-diylbis(oxy)]dipropan-1-amine

Molecular weight: 204.3 g/mol

Physical state: liquid at room temperature

Boiling point: approximately 300°C

logPow: -0.4 at 25°C, pH 11.1; < -2.5 at 25°C, pH 7.1

Water solubility: miscible with water in any ratio

pKa: 10.3 (at 20°C)

Vapour pressure: 0.00067 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 to be expected. 

 

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. Due to the high pKa most of the substance will be ionized at the pH range present in the gastro-intestinal tract. The water solubility indicates that passive diffusion through membranes might be limited by the rate at which the substance partitions out of the gastrointestinal fluid. Furthermore, passage through the aqueous pores or transport through the epithelial barrier by the bulk passage of water is also possible as the MW is only about 200 g/mol..

Following single 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 absorption can be assumed following administration of irritant/corrosive substance doses whereas a lower oral absorption can be assumed at non-irritating substance doses.

 

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 the at the skin’s slightly acidic pH the substance will be ionised and thus, not be able to penetrate through the intact skin.

This is supported by the findings of a study on acute dermal toxicity in rats (focal skin lesions, focal erythema, crust formation, but no clinical signs were recorded; BASF, 2001). 

 

Inhalation absorption

The relative volatility (vapour pressure of 0.067 Pa at 20°C) indicates a very low fugacity. Thus it is concluded that a vapour inhalation exposure is unlikely.

If exposure to respirable aerosol occurs, the substance may be retained partially in the mucus of the respiratory tract, thus, limiting the amount which can react with the alveolar region. However, the corrosive properties of the substance could cause a destruction of epithelial membranes, which would lead to an enhanced absorption. Effects demonstrating the corrosive potential of the substance have been observed in the acute aerosol inhalation toxicity study where in decedent animals exposed to 3.7 mg/L strong hyperemia of the lung was found. Overall, it is concluded that inhalation absorption at a similar rate to oral absorption can be 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.

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 test, here: Ames-test +/- S9; BASF, 1999). Based on this, an indication is not given that the formation of cytotoxic metabolites is likely. 

4. Excretion

The relative low molecular weight (ca. 200 g/mol) and high water solubility of 3,3'-[butane-1,4-diylbis(oxy)]dipropan-1-amine lead to the conclusion that urinary excretion will be the most relevant route of excretion. Furthermore, the high water solubility and low logPow indicate no potential for accumulation in organisms. 

 

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.