2,2'-Iminodiethanol, propoxylated

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: Assessment of the toxicokinetic behaviour as can be derived from the available information.

Adequacy of study:

weight of evidence

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2009

Materials and methods

Principles of method if other than guideline:

Review of reports summarised in the dataset

Test material

Test material information

Constituent 1

Reference substance name:

2,2'-Iminodiethanol, propoxylated

EC Number:

500-085-9

EC Name:

2,2'-Iminodiethanol, propoxylated

Cas Number:

35176-06-8

Molecular formula:

C4H11O2N(C3H6O)n; n = 1 – 6.5

IUPAC Name:

2,2’-Iminodiethanol, propoxylated

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Given the vapour pressure and water solubility of the commercial preparation, it is likely that absorption of some of the lower molecular weight components may occur via the lung.

2,2’-Iminodiethanol is absorbed by passive diffusion, when administered orally. Propane-1,2-diol, oxydipropanol and [(methylethylene)bis(oxy)]dipropanol are also absorbed, probably by passive diffusion, when administered orally. Further, 2,2’,2”-nitrilotriethanol is well absorbed orally. 2,2’-Iminodiethanol, propoxylated, 1-6.5 mol propoxylated (the NLP polyol) contains very little material of the molecular size that may result in significant lymphatic absorption. Thus it is probable that low number oligomers will be absorbed and the principal mechanism of absorption for these NLP polyols is passive diffusion. The calculated logP suggests that the component representing the mean toxicity of the commercial preparation is likely to be absorbed orally.

As explained previously, the first propoxylation is likely to be to the stronger nucleophile, i.e. the amine group. This implies that the most relevant core substance for comparison purposes may be 2,2’,2”-nitrilotriethanol, and this substance is well absorbed when administered dermally.

Details on distribution in tissues:

There is evidence from the literature that 2,2’-iminodiethanol accumulates in the liver and kidney due to incorporation into and inhibition of the metabolism of phospholipids. However, if the substance is propoxylated, then the first product (1 mol propoxylated) is a close analogue of 2,2’,2”-nitrilotriethanol, a substance that is not accumulated. Thus bioaccumulation is not expected for the NLP polyol.

Details on excretion:

Unmetabolised oligomer and metabolites are likely to be excreted in urine, especially as 2,2’,2”-nitrilotriethanol is excreted extensively in urine, irrespective of route of administration. Some carbon dioxide might be formed from hydrolysis of the propane-1,2-diol groups and exhaled.

Metabolite characterisation studies

Details on metabolites:

Although N-methylation is the principal metabolic pathway for 2,2’-iminodiethanol, followed by incorporation into and perturbation of phospholipid metabolism, this is unlikely to occur for the NLP polymer as 2,2’,2”-nitrilotriethanol is excreted unchanged or conjugated with glucuronic acid. It can be assumed that the 1 mol propoxylated 2,2’-iminodiethanol will behave similarly to 2,2’,2”-nitrilotriethanol.

Propane-1,2-diol, oxydipropanol and [(methylethylene)bis(oxy)]dipropanol it is likely some material may be hydrolysed, some oxidation of one or both of the terminal alcohol groups to the corresponding mono and di-carboxylic acids may occur or, possibly some conjugation of the terminal alcohol groups with glucuronic acid and/or sulphate may also be possible. At low doses some further metabolism to carbon dioxide may occur.

Any other information on results incl. tables

There are no experimental studies on the toxicokinetics of propoxylated 2,2’-iminodiethanol. The toxicokinetics of the core substance is examined in Appendix 1. The toxicokinetics of the repeating unit is summarised in Illing and Barratt (2007 revised 2009). The core substance has two free hydroxy groups and a secondary amine group, thus NLP polyols are likely to consist predominantly of chains of between one and two repeating units, with some chains containing three repeating units. As the first mol of propoxylation is likely to attach to the secondary amine, the substance containing one mol of propoxylation (one repeating unit) is a structural analogue of 2,2’,2”-nitrilotriethanol. Thus the toxicokinetics of 2,2’,2”-nitrilotriethanol (outlined in Illing and Barratt, 2007 revised 2009) are also relevant.

For the calculations of bioavailability of the commercial NLP polyol, logP values were calculated using the incremental fragment method of Suzuki and Kudo (1990).

The propoxy groups have an important effect on the toxicity by modulating any toxicity arising from the core substance. The substitution of a hydroxyl group on a core compound by a propoxy group increases its logP value by 0.24 units and its molecular weight by 58. The combined effect of these changes is to reduce the bioavailability by a factor of 1.53 (calculated using the Potts and Guy equation).