1-Octadecanamine, reaction products with 1,1'-methylenebis[4-isocyanatobenzene]

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

not specified

Adequacy of study:

supporting study

Study period:

12 May 2015 to 12 January 2016

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study was conducted according to well established method, but not a GLP guideline study.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2016

Report date:

2016

Materials and methods

Objective of study:

absorption

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The aim of these studies was to develop a sensitive analytical method for the quantification of the registered substance 'Polurea Thickener' capable of supporting In vitro absorption studies across everted gut sac measured as estimation of absorption from the small intestine via the oral route

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Polyurea Thickener

IUPAC Name:

Polyurea Thickener

Test material form:

other: Beige solid peices

Details on test material:

- Name of test material (as cited in study report): Polyurea Thickener
-Date of receipt: 27th April 2015
- Physical state: Beige solid peices
- Batch number: VPSG011
- Expiration date of the lot/batch: Originally 14 December 2015. Expiry date extended by Sponsor to 28 February 2016
- Storage condition of test material: Room temperature in the dark

Radiolabelling:

no

Administration / exposure

Details on study design:

The aim of these studies was to develop a sensitive analytical method for the quantification of the registered substance 'Polyurea thickener' capable of supporting absorption studies. Initially, CXR's intention was to develop an assay for the registered substance in rat plasma. CXR identified an ion at m/z 817 which appeared to be associated with the registered substance. The initial observed limit of detection in rat plasma extracts, monitoring the m/z 817 ion, was 2 μg/mL (2.5 μM) and this was regarded to be unacceptable for toxicokinetic studies as it represents 30 μg compound in blood of an average rat, or 1 % of a 10 mg/kg dose, at one time.

CXR then attempted to develop an assay for the registered substance in Fed State Simulated Intestinal Fluid (FeSSIF) to assess its stability at gastric pH and absorption potential in-vitro using everted gut sacs. The rationale for assessing the in-vitro method was that the external concentration would only be limited by solubility and the assay sensitivity requirement would be less than that for an in-vivo approach.

Subsequently, it was suggested that the m/z 817 entity was an impurity from the manufacture of the registered substance and it was concluded that the registered substance does not dissolve in xylene or any of the other 7 additional solvents tested (acetonitrile, DMSO, hexane, isooctane, diethyl ether, acetone, chloroform). As CXR were unable to identify a solvent suitable for the preparation of calibration and quality control standards for the registered substance in rat plasma and FeSSIF media it was not possible to develop a quantitative analytical method.

The analytical techniques assessed during this work were GC/MS, direct infusion electrospray ionisation (ESI MS, atmospheric pressure chemical ionisation (APCI) MS and matrix-assisted laser desorption/ionization (MALDI)-Tof. The most abundant entity in xylene extracts of the registered susbtance was tentatively identified as an unusual by-product of isocyanate, hence it was concluded that all method development be terminated due to the fact that no quantitative assay could be established for the polyurea thickener itself.

Further information on the study design and conclusiuons can be found in the attached study report.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The registered substance appears to be insoluble in all solvents tested. A component of the mixture was detected in xylene solutions but the Sponsor has suggested that this is an impurity from the manufacture of the registered substance.

As no quantitative analytical method could be developed, attempts to assess the absorption of the registered substance in-vivo or in-vitro had to be abandoned for this reason. It was decided not to terminate any rats for the collection of fresh intestine for ethical reasons as no analytical technique was available. The procedure for the everted rat intestinal sac incubations did not proceed due to this fact.

Although it was not possible to proceed with absorption testing due to the difficulties in finding a suitable solvent/quantitative analytical method it is believed that the insolubility of the regsistered substance can be used as evidence to support the lack of bioavailability that this compound would have.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no data

Executive summary:

The aim of this non-GLP compliant, non-guideline studies was to develop a sensitive analytical method for the quantification of the registered substance capable of supporting absorption studies. Initially, CXR's intention was to develop an assay for the registered substance in rat plasma. However as this proved impossible CXR attempted to develop an assay for the registered substance in Fed State Simulated Intestinal Fluid (FeSSIF) to assess its stability at gastric pH and absorption potential in-vitro using everted gut sacs. The rationale for assessing thein-vitro method was that the external concentration would only be limited by solubility and the assay sensitivity requirement would be less than that for an in-vivo approach.

The studies demonstrated that the registered substance appears to be insoluble in all solvents tested. A component of the mixture was detected in xylene solutions but this was considered by the registrant to be an impurity from the manufacture of the registered substance.

 

As no quantitative analytical method could be developed, attempts to assess the absorption of BP’s Polyurea Thickener in-vivo or in-vitro had to be abandoned for this reason. It was decided not to terminate any rats for the collection of fresh intestine for ethical reasons as no analytical technique was available. The procedure for the everted rat intestinal sac incubations did not proceed due to this fact.

 

Although it was not possible to proceed with absorption testing due to the difficulties in finding a suitable solvent/method of detection, it is believed that the insolubility of the registered substance can be used as evidence to support the lack of bioavailability that this compound would have. Further information on the study design and conclusiuons can be found in the attached study report.