Sucrose, 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:

2007

Materials and methods

Principles of method if other than guideline:

Review of reports summarised in the dataset

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Sucrose, propoxylated

EC Number:

500-029-3

EC Name:

Sucrose, propoxylated

Cas Number:

9049-71-2

Molecular formula:

C12H14O11-(C3H6O)nH8 sum of n: >1 - <16.5 mol PO

IUPAC Name:

Sucrose, propoxylated

Constituent 2

Reference substance name:

not applicable

Molecular formula:

>= C102H156N30O18

IUPAC Name:

not applicable

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Given the vapour pressure and the logP of the commercial material, some of the lower molecular weight material may be absorbed via the lung if inhaled. No useful prediction concerning oral absorption can be made on the basis of the logP of the commercial material as there should be a range of values, one for each of the components. It is possible that absorption of the oligomers may occur following oral administration, but it is more likely that any absorption is of hydrolysis products derived from the oligomers. If absorption of parent substance took place it would occur in the stomach. In vitro and in vivo studies rat (Shigeoka et al., 1984) suggest that hydrolysis to sucrose and fatty acid (in his study, stearate, C18) is needed for absorption of esters of sucrose. Only about 1.3% of orally administered sucrose polyesters containing 28% penta or lower short chain (58% C12-14; 39% C16-C18) polyesters was absorbed, probably after intestinal hydrolysis of the short chain esters to fructose and glucose (Miller et al., 1995). C12-C14 is equivalent to an oligomer of approximately 4 monomers, thus the pentaester is equivalent to a polymer (sucrose+20 PO). These esters are therefore equivalent to the polymer, rather than the NLP polyol.
Absorption decreases with increasing size of polyol, thus it is possible that limited amounts of the smaller polyols may be absorbed orally, presumably by passive diffusion.
Given the both the predicted and the measured logP values, dermal absorption is likely to be limited.

Details on distribution in tissues:

Given the logP values, it is likely that any absorbed oligomers of propoxylated sucrose will be widely distributed in body water and it is unlikely that they will accumulate in tissues.

Details on excretion:

In the unlikely event that unmetabolised higher molecular weight material is absorbed, it is likely to be excreted in bile. 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

Metabolites identified:

yes

Details on metabolites:

Based on information from the propane-1,2-diol and trimer, if absorbed, the propane-1,2-diol moiety of the propoxylated sucrose could be further conjugated (with glucuronic acid or sulphate) or stepwise hydrolysed. The three-carbon elements are likely to be taken into intermediary metabolism. If hydrolysis occurs, it eventually yields sucrose which can be hydrolysed to its component monosaccharides and enter endogenous carbohydrate metabolism. The ultimate end product from carbohydrate metabolism will be carbon dioxide.

Any other information on results incl. tables

There are no experimental studies on the toxicokinetics of propoxylated sucrose. Sucrose (the core substance) and propane-1,2-diol and oligomers (the propoxylated side chains) are possible models for the absorption of the propoxylated sucrose. Sucrose has eight free hydroxy groups, thus oligomers in the NLP polyol are likely to consist of chains of between one and three monomers.

Sucrose is unlikely to be absorbed by passive diffusion, but, if absorbed by passive diffusion, absorption would be in the stomach and upper intestine where the alcohol groups are unionised. Sucrose is hydrolysed in the brush border of the intestine and the two monosaccharides, fructose and glucose, and these carbohydrates are absorbed by active transport. Propane-1,2-diol

and [(methylethylene)bis(oxy)]dipropanol (and, presumably oxydipropanol) are absorbed when administered orally, probably by passive diffusion. Essentially, the NLP polyol (propoxylated sucrose) is non-toxic.

For the calculations of bioavailability the composition of the commercial NLP polyol was obtained and 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 propoxyl- 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). The substitution of a hydroxyl group on a core compound by an ethoxyl- group decreases its logP value by 0.083 units and increases its molecular weight by 44. The effect of these changes is to reduce the bioavailability by a factor of about 2.12. Thus the molecular weight changes are more significant than the logP changes in determining the bioavailability. The relative bioavailabilities are in the text table.

 

Molecule	Molecular weight	Weight fraction (%)	Mole fraction	Relative bioavailability	% Contribution to toxicity
Sucrose + 3PO	534	0.56	0.012	1	8.93
Sucrose + 4PO	592	1.13	0.023	0.65	11.17
Sucrose + 5PO	650	2.95	0.053	0.47	18.84
Sucrose + 6PO	708	4.8	0.08	0.28	16.68
Sucrose + 7PO	766	7.13	0.11	0.18	14.97
Sucrose + 8PO	824	8.87	0.127	0.12	11.32
Sucrose + 9PO	882	10.77	0.144	0.078	8.34
Sucrose + 10PO	940	9.05	0.113	0.051	4.32
Sucrose + 11PO	998	10.2	0.12	0.033	2.98
Sucrose + 12PO	1056	7.01	0.078	0.022	1.27
Sucrose + 13PO	1114	6.1	0.064	0.01	0.67
Sucrose + 14PO	1172	5.04	0.051	0.009	0.37
Sucrose + 15PO	1230	2.73	0.026	0.006	0.15

The value in red (logP [calculated] –0.70) indicates the component representing the mean toxicity for the NLP polyol.

 

The representative single entity for the toxicity of this NLP polyol is sucrose with 5 propoxy groups attached. QSAR comparisons for the bioavailability of propoxylated sucrose are based on the molecules present in the commercial NLP polyol. SAR predictions are that the relative bioavailability falls off rapidly, such that the bioavailability of sucrose + 5PO is less than half of that of sucrose + 3PO. The logP for sucrose is considerably less than that for propane-1,2-diol, thus it is likely that sucrose + 3PO is less well absorbed than the propane-1,2-diol trimer. Given this, the amounts absorbed of the propoxylated sucrose representing the mean toxicity of commercial propoxylated sucrose are likely to be small (<5%). Thus it is likely that the propoxylated sucrose NLP polyol is not well absorbed.

Lipinski et al (1997) have 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) the number of hydrogen bond acceptors >10.

Oligomers of sucrose with seven or more propoxy units (MW 766 or higher) and containing more than five hydrogen bond donating hydroxyl groups are unlikely to be absorbed to any great extent. The QSAR calculations are consistent with the literature information on related substances.

Applicant's summary and conclusion

Executive summary:

There are no experimental studies on the toxicokinetics of propoxylated sucrose. Sucrose (the core substance) and propane-1,2-diol and oligomers (the propoxylated side chains) are possible models for the absorption of the propoxylated sucrose. Sucrose has eight free hydroxy groups, thus oligomers are likely to consist of chains of between one and three monomers.

 

Sucrose is unlikely to be absorbed by passive diffusion, but, if absorbed by passive diffusion, absorption would be in the stomach and upper intestine where the alcohol groups are unionised. Sucrose is hydrolysed in the brush border of the intestine and the two monosaccharides, fructose and glucose, and these carbohydrates are absorbed by active transport. Propane-1,2-diol and [(methylethylene)bis(oxy)]dipropanoloxydipropanol are absorbed when administered orally, probably by passive diffusion. Essentially, the propoxylated sucrose is non-toxic.(partly cited fromIlling, H P A, Barratt, M D (2007 revised 2009). Grouping of NLP ‘Polyols’ and their Toxicokinetics Assessments. Confidential report to the European Diisocyanate and Polyols Producers Association. December 2007, revised 2009.)