Registration Dossier

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:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2007

Materials and methods

Principles of method if other than guideline:
Review of findings from reports summarised in the dataset.

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Given the low vapour pressure of the commercial preparation, it is likely that inhalation of the vapour will limited. It is likely that the propoxylated glycerol is well absorbed. Classifiable acute toxicity is seen when oligomers of molecular weight average >700 (i.e. >9 units, equivalent to the fatty acid side chains of >C9 fatty acids) and <~2000 Daltons (~32 units, equivalent to fatty acid side chains of ~C32) are tested. This has been ascribed to entanglement in the processes used for the absorption of dietary lipids (triacylglycerides)( Part 1). However, in molar terms less than 2% of a no longer polymer of Mn 450 is material of MW > 700. Thus this toxicity is seen only with polymeric propoxylated glycerol, not with the NLP polyol.
Glycerol is presumably absorbed by facilitated diffusion during the absorption of dietary fats. Propane-1,2-diol oligomers are probably absorbed by passive diffusion. The short chain (1-6.5 mol) NLP polyols are likely to behave in a manner similar to fats of short chain fatty acids (i.e. those of C8 or less), which are not absorbed by facilitated diffusion. Mu and Hoy (2000) established that the accumulated lymphatic transport of triacylglycerols of medium chain fatty acids increased with increasing carbon length over the C8 to C10 to C12 (from ~7% to ~26% to ~82%) in rats. This implies that the NLP polyols of propoxylated glycerol, if absorbed, are likely to be absorbed by passive diffusion. Given the logP it is likely that the NLP polyols are absorbed dermally.
Details on distribution in tissues:
Given the logP values, it is likely that oligomers of glycerol will be widely distributed and it is unlikely that they will accumulate in tissues.
Details on excretion:
Some higher molecular weight material might be excreted in bile. In rat the molecular weight threshold for biliary excretion is around 350 Daltons and some material from the highest NLP polyols may just exceed this threshold. In humans the threshold is about 500 (Illing, 1989), thus it would be expected that little, if any, of the NLP polyol would be excreted in human bile. Once the material has been hydrolysed, the products below the appropriate threshold will appear in urine, except when the end point of the product is carbon dioxide. Carbon dioxide will be exhaled.

Metabolite characterisation studies

Details on metabolites:
Based on the information on propane-1,2-diol and trimer, it is likely that the oligomers will be stepwise hydrolysed across the ether linkage and the three carbon elements metabolised to lactic acid/pyruvic acid and taken into intermediary metabolism. If the hydrolysis proceeds to completion, the
glycerol thus produced is likely to enter endogenous metabolism and, following conversion to pyruvate, either enter the citric acid cycle under aerobic conditions or be converted to lactic acid under anaerobic conditions. Lactic acid may enter gluconeogenesis.

Applicant's summary and conclusion

Executive summary:

Glycerol is solely a core substance (initiator). However, it is structurally related to propane-1,2-diol (both are C3) and there are similarities in the metabolism of fatty acid esters of both substances by the intestine. There are three free alcohol groups available for formation of the NLP polyols, so the likelihood is that the side chains will be mainly of one or two units, with some of three units. The information on the toxicokinetics of glycerol, propoxylated, 1-6.5 mol (the NLP polyol), and higher oligomers/polymers generally, is based on the information for glycerol, for triglycerides (fats) and for propane 1,2-diol and oligomers. Additional information is derived from studies on the absorption of hydrocarbons. There is some further information in Patty which has also been incorporated into this assessment. In addition, some predictions can be made from the physicochemical and toxicological information on the oligomers