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:
2010
Report Date:
2010

Materials and methods

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

Test material

Reference
Name:
Unnamed
Type:
Constituent

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. "

Based on data for toluene-2,4-diamine and toluene-2,6-diamine, toluene-2,3-diamine and 4-methyl-o-phenylene diamine should be readily absorbed orally. Ethane1,2-diol, oxydiethanol, propane-1,2-diol, oxydipropanol and [(methylethylene)bis(oxy)]dipropanol are also absorbed, probably by passive diffusion, when administered orally. Thus it is probable that low number oligomers will be absorbed. The calculated logP suggests that the component representing the mean toxicity of the commercial preparation is likely to be absorbed orally.

Details on distribution in tissues:
"Given the logP values, it is likely that any absorbed oligomers of ethoxylated and propoxylated diaminotoluene will be widely distributed in the body. As metabolism is likely, it is unlikely that they will accumulate in tissues."
Details on excretion:
"In the event that higher molecular weight material is absorbed, it is likely to be excreted in bile. Lower molecular weight unmetabolised oligomer is likely to be excreted in 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. Some carbon dioxide might be formed from hydrolysis of the propane-1,2-diol groups and exhaled."

Metabolite characterisation studies

Details on metabolites:
"Based on information from ethane-1,2-diol, oxydiethanol, and (ethylenedioxy)diethanol, 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 toxicokinetic data for ethoxylated and propoxylated o-diaminotoluene. The ethoxylated and propoxylated diaminotoluene is made from o-diaminotoluene. Commercial o-toluenediamine is a mixture of 40% toluene-2,3-diamine and 60% 4-methyl-o-phenylenediamine. The toxicokinetics of propoxylated diaminotoluene is inferred from the read across from toluene-2,4-diamine and toluene-2,6-diamine to the toluene-2,3-diamine and 4-methyl-o-phenylene diamine and from propane-1,2-diol, oxydipropanol and [(methylethylene)bis(oxy)]-dipropanol. Diaminotoluene has two free amino groups, thus no longer polymer oligomers are likely to consist predominantly of chains of between one and two monomers.

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 58Daltons. 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 44Daltons. 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. TDA + 3EO + 3PO indicates the component representing the mean toxicity for the NLP polyol.

 

Applicant's summary and conclusion