1,6-Hexanediamine, N1,N1,N6,N6-tetramethyl-, propoxylated (>1 < 4,5 mol PO)

Endpoint summary

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

There are no studies available that investigate the toxicokinetic behaviour of the substance. However, based on the molecular structure and physicochemical properties a toxicokinetic assessment can be performed. The anticipated toxicokinetic profile of the substance is described below for each ADME process individually.

 

Substance description

The substance has a hexane backbone, which is substituted with an amine group on position 1 and 6. The amine groups are propoxylated, and the actual substance consists of a mixture of 1, 2, 3 and 4 times propoxylated molecules (referred to as 1PO, 2PO, 3PO and 4PO, respectively), as is indicated in Section 1. The substance has a molecular weight range between 231.41 and 406.66 g/mol (1PO: 231.41; 2PO: 290.49; 3PO: 348.57; 4PO: 406.66 g/mol). The substance is miscible in water) has a melting point of -10°C, a boiling point of 98°C and a vapour pressure of 980 Pa at 20°C. The density is 1.026 g/cm³ and the partition coefficient is determined to be below -1.73 at 23 °C.

Absorption

Uptake of the substance in the intestines is expected to be high, based on the miscibility in water and the molecular weight range which is for all propoxate variants (1PO to 4PO) in the favourable range for absorption (< 500 Da) (ECHA guidance R7c Table R.7.12-1). Based on these properties, uptake of the smaller molecules is likely to be more efficient. With a log Kow below -1.73 the partition coefficient is outside the favourable domain for intestinal absorption, which is between -1 and 4. Uptake based on this property is therefore considered to be less. Since no systemic effects are observed in the acute oral toxicity study and the OECD422 study, no experimental confirmation on oral bioavailability is available. However, based on the physico-chemical properties of the substance, oral absorption cannot be ruled out.

The physical state (liquid) is favourable for dermal absorption and the molecular weight (below 500 Da) does allow absorption through the skin. In addition, the corrosive properties of the substance might enhance skin penetration. However the combination of the relatively low partition coefficient and the miscibility in water, indicating that the  substance might be too hydrophilic, makes dermal absorption unlikely (ECHA guidance R7c Table R.7.12-3).

Although not highly volatile, exposure of the substance via the inhalation route is expected based on the moderate vapour pressure (980 Pa) and boiling point (98°C) but these values may also be attributed to the high water containt of the substance and therefore exposure via inhalation may be limited. As for absorption in the GI tract, the partition coefficient is outside the favourable range for alveolar absorption. Due to the high hydrophilicity and miscibility in water, the substance might retain in the mucus (ECHA guidance R7c Table R.7.12-2). Therefore, absorption via inhalation is expected to be inefficient.

Distribution

Once absorbed the substance is expected to be widely distributed through the body based on the high water solubility and relatively small molecular weight. The partition coefficient (< -1.73) however indicates that the substance might not be able to cross cell membranes due to its hydrophilic nature, which limits the distribution (ECHA guidance R7c Table R.7.12-4). The partition coefficient does not indicate bioaccumulation risk.

Metabolism

3PO and 4PO contain ether bonds which are generally stable with regard to pH-dependent hydrolysis at pH values present in the GI tract. These substances will therefore be metabolically stable in the gastrointestinal tract. The simulation of rat S9 metabolism using the OECD QSAR Toolbox (version 4.1) predicts oxidation of the hydroxy groups to aldehydes and carboxylic acids. For the tertiary amine, which is only present in 1PO, several additional reactions are predicted including oxidations and dealkylation. Hydroxy groups and carboxylic acids might be prone to subsequent phase II metabolism such as conjugation touridine 5′-diphosphoglucuronic acid and further facilitate biliary excretion.

Excretion

The part of the ingested dose which is not absorbed is directly excreted in the faeces from the GI mucosa. The absorbed fraction might, based on the miscibility in water and molecular weight be excreted via the urine (more likely for the smaller constituents 1PO and 2PO). In addition the substance might be excreted via the biliary route in the faeces, which might be facilitated by metabolic conversion to glucuronide conjugates.

Conclusion

Oral absorption is anticipated and considered more efficient compared to absorption via the skin and lungs. Based on the miscibility in water and molecular weight the substance is expected to be widely distributed through the body, however due to the hydrophilic nature the substance might not be able to cross membranes, which limits the distribution. The substances are considered to be metabolically stable in the GI tract. After absorption several phase I and II metabolic reactions are predicted, which might enhance (biliary) excretion. Excretion in faeces might occur directly (unabsorbed oral fraction) or via biliary excretion. Urinary excretion is also possible based on the molecular properties.