1,2-Benzenediamine, ar-methyl-, reaction products with propylene oxide

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

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:

1,2-Diaminotoluene, propoxylated

EC Number:

918-139-9

Cas Number:

1228577-90-9

Molecular formula:

(C3H6O)n (C3H6O)n (C3H6O)n (C3H6O)n C7H10N2 sum of n: >1 - <8.5

IUPAC Name:

1,2-Diaminotoluene, 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.
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. 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.
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 NLP polyol oligomers and polymers (Mn > 500) with five or more hydrogen bond donating groups are unlikely to be absorbed in significant amounts.
4-Methyl-o-phenylene diamine should be readily absorbed dermally, although dermal permeability is likely to depend on the vehicle chosen.

Details on distribution in tissues:

Given the logP values, it is likely that any absorbed oligomers of 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 the propane-1,2-diol trimer [(methylethylene)bis(oxy)]dipropanol, if absorbed, the propane-1,2-diol moiety of the propoxylated diaminotoluene could be further conjugated (with glucuronic acid or sulphate) or stepwise hydrolysed. Propane-1,2-diol is also further metabolised, entering intermediary metabolism via lactic acid/pyruvic acid, and eventually being eliminated as carbon dioxide. Based on read across, the metabolic pathways identified for the toluene diamine portion of the oligomer are hydroxylation on one of the three available carbon atoms of the phenol ring, followed by glucuronidation. If free toluene diamine is formed, it may also be metabolised by mono-or di-acetylation of the amine groups. Although the benzylic carbon of tolune is oxidised to toluyl alcohol and methylbenzoic acid, which is then conjugated to form methyl hippuric acid, this metabolic route appears to be absent when toluene diamine metabolism is examined.

Any other information on results incl. tables

There are no toxicokinetic data for propoxylated diaminotoluene. The propoxylated diaminotoluene is made from o-diaminotoluene. Commercial otoluenediamine is a mixture of 40% toluene-2,3-diamine and 60% 4-methyl-ophenylenediamine. 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). In the case of toluenediamine, the substitution of each primary aromatic amino group by a propoxyl- group increases the logP value by 0.003 units and the molecular weight by 58 Daltons. The combined effect of these changes is to reduce the bioavailability by a factor of 2.25 (calculated using the Potts and Guy equation). The substitution of each secondary aromatic amino group on (propoxylated) toluenediamine reduces the logP value by a further 0.013 units. Together with the molecular weight increase, the effect is to reduce the bioavailability by a factor of 2.21.

Subsequent additional propoxyl groups are added to the terminal hydroxyls of propoxyl groups. The substitution of a hydroxyl group by an additional 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 for each additional propoxyl group.

In all cases the reduction in bioavailability from increases in molecular weight outweighs any possible increases resulting from small increases in logP.