D-Glucitol, 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

Cross-reference

Reason / purpose for cross-reference:

reference to same study

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:

D-Glucitol, propoxylated

EC Number:

500-118-7

EC Name:

D-Glucitol, propoxylated

Cas Number:

52625-13-5

Molecular formula:

(C3 H6 O)n (C3 H6 O)n (C3 H6 O)n (C3 H6 O)n (C3 H6 O)n (C3 H6 O)n C6 H14 O6 sum of n: >1 - <12.5 mol PO

IUPAC Name:

D-Glucitol, propoxylated

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Given the vapour pressure and water solubility of the commercial material, it is likely that some of the lower molecular weight elements of propoxylated D-glucitol may be absorbed via the lung if inhaled.
It is likely that only limited quantities of propoxylated D-glucitol are absorbed orally. D-Glucitol is well absorbed, probably by passive diffusion rather than active transport. Propane-1,2-diol and [(methylethylene)bis(oxy)]-dipropanol are also absorbed when administered orally. However, the relatively large number of propoxyl groups attached to the type member of this group representing the commercial preparation probably means that the type member for this group is poorly absorbed.
Given the water solubility and logP it is likely that propoxylated D-glucitol is absorbed dermally.

Details on distribution in tissues:

Given the logP values, It is likely that any absorbed oligomers of propoxylated D-glucitol will be widely distributed and it is unlikely that they will accumulate in tissues.

Details on excretion:

In the event that unmetabolised material is absorbed, it could be excreted in bile as well as urine. In rat the molecular weight threshold for biliary excretion is around 350, in human it is about 500 (Illing, 1989). The material most likely to be absorbed is likely to be hydrolysed and the products appear in urine, except when the end point of metabolism is carbon dioxide. Carbon dioxide will be exhaled.

Metabolite characterisation studies

Details on metabolites:

Based on information from propane-1,2-diol and trimer, if absorbed, the propane-1,2-diol moiety of the propoxylated glucitol could be further conjugated (with glucuronc acid or sulphate) or stepwise hydrolysed. The three carbon elements are likely to be taken into intermediary metabolism. If hydrolysis occurs, it eventually yields glucitol. D-Glucitol is oxidised to fructose, either directly or following conversion to glucose. It therefore enters
endogenous intermediary metabolism, one end point of which is carbon dioxide. Pathways to carbon dioxide include those concerned with glycolysis, leading to metabolism via the citric acid cycle.

Any other information on results incl. tables

There are no experimental studies on the toxicokinetics of propoxylated Dglucitol. The toxicokinetics of propoxylated glucitol are inferred from the core substance and propane-1,2-diol, oxydipropanol and [(methylethylene)bis(oxy)]dipropanol. Glucitol has six free hydroxy groups, thus NLP polyols are likely to consist predominantly of chains of between one and two monomers, with some chains containing three monomers.

For the calculations of bioavailability LogP values of the commercial NLP polyol were calculated using the incremental fragment method of Suzuki and Kudo (1990). The propoxyl- 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 propoxyl- group increases its logP value by 0.24 units and its molecular weight by 58 Daltons. The combined effect of these changes is to reduce the bioavailability by a factor of 1.53 (calculated using the Potts and Guy equation). Thus the molecular weight changes are more significant than the logP changes in determining the bioavailability.

The trimer of propane-1,2-diol is 84% absorbed. As D-glucitol has a lower logP it is less likely to be well absorbed. The absorption of D-glucitol + 3 PO (3 moles propoxylation, MW 356) is less than 40% of that of the propane-1,2- diol trimer whilst that of Glucitol + 6PO, the type molecule used for toxicity purposes even lower (< 8%).

Lipinski et al (1997) proposed the so-called ‘rule-of-five’ for identifying chemicals that would have poor absorption. This rule states that poor absorption is likely when any two of the following conditions are satisfied: a) molecular weight >500; b) log P > 5.0; c) number of hydrogen bond donors >5; and d) number of hydrogen bond acceptors >10.

Higher molecular weight polyols with seven or more propoxyl units (MW 588 or higher) are containing more than five hydrogen bond donating hydroxyl groups are unlikely to be absorbed in significant amounts.

See Illing and Barrat (2009 and 2009) in Section 13 for further information.