Ethylenediamine, ethoxylated and propoxylated

Basic toxicokinetics

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Administrative data

Endpoint:

basic toxicokinetics

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Study period:

2016

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: QSAR prediction

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2016

Report date:

2016

Materials and methods

Test guideline

Guideline:

other: REACH guidance on QSARs R.6 May/July 2008

Principles of method if other than guideline:

QSAR programs ADMET predictor and Gastro Plus (v8.5, Simulations Plus Inc, Lancaster, CA, USA).

Test material

Test material information

Constituent 1

Details on test material:

- SMILES: EDA + 3EO +1PO CC(O)CN(CCN(CCO)CCO)CCO; EDA + 2EO +2PO CC(O)CN(CCN(CC(C)O)CCO)CCO; EDA + 1EO +3PO CC(O)CN(CCN(CC(C)O)CC(C)O)CCO; EDA + 4PO CC(O)CN(CC(C)O)CCN(CC(C)O)CC(C)O

Results and discussion

Main ADME results

Type:

other: fractional absorption (Fa%), bioavailability (F%), maximum plasma concentration (Cmax) at steady state, and area under curve (AUC0-t) values

Results:

The major components of Ethylenediamine, ethoxylated and propoxylated (>1 - <8.5 mol of EO and PO) {EDA/EO/PO} were comparable or higher than the corresponding values from the major components of Ethylenediamine, propoxylated (>1 - <8.5 mol of PO).

Any other information on results incl. tables

Domains:Defined by GastroPlus and ADMET Predictor.

i. Descriptor domain:In general, GastroPlusTM(version 8.5) applies only to small organic molecules composed of the following elements: C, N, O, S, P, H, F, Cl, Br, I, B and their isotopes. Other elements (in particular metals) are not supported. In addition, the program limits to certain degree the size and complexity of input molecules to no more than 256 bonds and no more than 20 ionizable groups.

ii. Structural fragment domain:GastroPlusTM(version 8.5) use calculated descriptors for each structure of the individual components of Ethylenediamine, ethoxylated and propoxylated (>1 - <8.5 mol of EO and PO) {EDA/EO/PO} and Ethylenediamine, propoxylated (>1 - <8.5 mol of PO){EDA/PO} as inputs to its predictive models, not structural fragments.

iii. Mechanism domain:GastroPlusTMmodel uses QSAR/QSPR methodology, which is a subset of statistical-correlative modeling. It does not consider mechanisms of action, at least not explicitly.

 iv. Metabolic domain:Metabolism is considered relevant and is considered in the assessment.

b. Structural analogues:Ethylenediamine, ethoxylated and propoxylated (>1 - <8.5 mol of ESMKO and PO) {EDA/EO/PO} and Ethylenediamine, propoxylated (>1 - <8.5 mol of PO){EDA/PO} are analogs.

c. Considerations on structural analogues:Ethylenediamine, ethoxylated and propoxylated (>1 - <8.5 mol of EO and PO){EDA/EO/PO} and Ethylenediamine, propoxylated (>1 - <8.5 mol of PO) {EDA/PO} both contain similar C-N-C (amine) and C-O-C (ether) bonds.

Applicant's summary and conclusion

Conclusions:

The overall predicted fractional absorption (Fa%), bioavailability (F%), maximum plasma concentration (Cmax) at steady state, and area under curve (AUC0-t) values for the major components of Ethylenediamine, ethoxylated and propoxylated (>1 - <8.5 mol of EO and PO) {EDA/EO/PO} were comparable or higher than the corresponding values from the major components of Ethylenediamine, propoxylated (>1 - <8.5 mol of PO) {EDA/PO} in the 28-day rat oral gavage dose simulation conditions. As the major components of Ethylenediamine, ethoxylated and propoxylated (>1 - <8.5 mol of EO and PO) {EDA/EO/PO} and Ethylenediamine, propoxylated (>1 - <8.5 mol of PO) {EDA/PO} have similar chemical structures, based these QSAR results, it can be predicted that Ethylenediamine, propoxylated (>1 - <8.5 mol of PO) {EDA/PO} should have similar or lower systemic toxicity than Ethylenediamine, ethoxylated and propoxylated (>1 - <8.5 mol of EO and PO){EDA/EO/PO}.

Executive summary:

Experimental data on bioavailability are not available for the reaction mixtures of Ethylenediamine, ethoxylated and propoxylated (>1 - <8.5 mol of EO and PO){EDA/EO/PO}and Ethylenediamine, propoxylated (>1 - <8.5 mol of PO) {EDA/PO}. To evaluate the oral bioavailability of in rats, the major toxicokinetic parameters of the major components of both mixtures were estimated by the widely accepted QSAR programs ADMET predictor and Gastro Plus (v8.5, Simulations Plus Inc, Lancaster, CA, USA).

The overall predicted fractional absorption (Fa%), bioavailability (F%), maximum plasma concentration (Cmax) at steady state, and area under curve (AUC0-t) values for the major components of Ethylenediamine, ethoxylated and propoxylated (>1 - <8.5 mol of EO and PO) {EDA/EO/PO} were comparable or higher than the corresponding values from the major components of Ethylenediamine, propoxylated (>1 - <8.5 mol of PO) {EDA/PO} in the 28-day rat oral gavage dose simulation conditions. As the major components of Ethylenediamine, ethoxylated and propoxylated (>1 - <8.5 mol of EO and PO) {EDA/EO/PO} and Ethylenediamine, propoxylated (>1 - <8.5 mol of PO) {EDA/PO} have similar chemical structures, based these QSAR results, it can be predicted that Ethylenediamine, propoxylated (>1 - <8.5 mol of PO) {EDA/PO} should have similar or lower systemic toxicity than Ethylenediamine, ethoxylated and propoxylated (>1 - <8.5 mol of EO and PO){EDA/EO/PO}.