[No public or meaningful name is available]

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: Assessment based on existing data

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2018

Report date:

2018

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

In accordance with Annex VIII (point 8.8) of Regulation (EC) No 1907/2006 (REACH), a paper-based toxicokinetic assessment has been conducted for the substance, Benzylated Polyamine. Summaries of studies and available literature were reviewed by a qualified toxicologist with a view to fulfilling the requirements of Annex VIII, point 8.8 of REACH. The assessment of the likely toxicokinetic behaviour of the substance was provided to the extent that can be derived from the relevant available information at the time of the assessment. The assessment is based on the Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, June 2017).

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

{2-[(2-aminoethyl)amino]ethyl}(benzyl)amine

Cas Number:

39549-34-3

Molecular formula:

C11H19N3

IUPAC Name:

{2-[(2-aminoethyl)amino]ethyl}(benzyl)amine

Constituent 2

Reference substance name:

benzyl(2-{[2-(benzylamino)ethyl]amino}ethyl)amine

Cas Number:

17327-80-9

Molecular formula:

C18H25N3

IUPAC Name:

benzyl(2-{[2-(benzylamino)ethyl]amino}ethyl)amine

Constituent 3

Reference substance name:

Piperazine-1,4-diethylamine

EC Number:

229-428-8

EC Name:

Piperazine-1,4-diethylamine

Cas Number:

6531-38-0

Molecular formula:

C8H20N4

IUPAC Name:

2,2'-piperazine-1,4-diyldiethanamine

Constituent 4

Reference substance name:

2-piperazin-1-ylethylamine

EC Number:

205-411-0

EC Name:

2-piperazin-1-ylethylamine

Cas Number:

140-31-8

Molecular formula:

C6H15N3

IUPAC Name:

2-piperazin-1-ylethanamine

Constituent 5

Reference substance name:

N-(2-aminoethyl)-N'-[2-(benzylamino)ethyl]ethylenediamine

EC Number:

244-734-1

EC Name:

N-(2-aminoethyl)-N'-[2-(benzylamino)ethyl]ethylenediamine

Cas Number:

22029-44-3

Molecular formula:

C13H24N4

IUPAC Name:

N-(2-aminoethyl)-N'-[2-(benzylamino)ethyl]ethane-1,2-diamine

Constituent 6

Reference substance name:

2-{4-[(benzylamino)methyl]piperazin-1-yl}ethan-1-amine

Molecular formula:

C14H24N4

IUPAC Name:

2-{4-[(benzylamino)methyl]piperazin-1-yl}ethan-1-amine

Constituent 7

Reference substance name:

[2-(benzylamino)ethyl][2-(piperazin-1-yl)ethyl]amine

Molecular formula:

C15H26N4

IUPAC Name:

[2-(benzylamino)ethyl][2-(piperazin-1-yl)ethyl]amine

Constituent 8

Reference substance name:

1,12-diphenyl-2,5,8,11-tetraazadodecane

Cas Number:

140840-03-5

Molecular formula:

C20H30N

IUPAC Name:

1,12-diphenyl-2,5,8,11-tetraazadodecane

Constituent 9

Reference substance name:

benzyl(2-{4-[2-(benzylamino)ethyl]piperazin-1-yl}ethyl)amine

Cas Number:

176906-02-8

Molecular formula:

C22H32N4

IUPAC Name:

benzyl(2-{4-[2-(benzylamino)ethyl]piperazin-1-yl}ethyl)amine

Test material form:

liquid: viscous

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The results from the repeated dose oral toxicity studies gave no indication of systemic toxicity which could therefore not confirm absorption of the test item following oral ingestion. The limited water solubility of the test item suggests that significant absorption of test item in a practically aqueous environment is unlikely to be favoured. The toxic signs that were observed including mortality are likely to relate back to the irritant characteristics of the test item. In direct contact with the gastric mucosa the test item may induce characteristic events such as gaseous distention of stomach and intestine particularly at the higher doses seen in the repeated dose range- finding study that was performed. A lack of significant histopathological changes in other tissues indicates that a lack of absorption following ingestion; despite the gastric mucosa being compromised.
The moderately high vapour pressure value for the test item suggests that absorption of volatile products via inhalation is a potential route of exposure to the test item as indicated by the odour that is associated with the test item. If the volatile material that can be detected has the same limited water solubility as for the parent material then there is likelihood that this material will only be absorbed to a limited extent from the lungs into the systemic system
The test item is a strong dermal irritant and therefore absorption across a compromised dermal barrier could be a potential event. The limited water solubility will however restrict any systemic absorption even if the dermis is breached.

Details on distribution in tissues:

The lack of appreciable water solubility of the test item would suggest that it may not be readily distributed in the water compartment of the circulatory system as a result of passive diffusion processes. This will inhibit systemic distribution. The moderate log Octanol: Water partition coefficient value suggests only limited active absorption across biological membranes may potentially take place
.
The lack of skin sensitization data cannot confirm if the test material is likely to bind to circulatory proteins.
The test material gives no indication as to whether it may accumulate in body fat. The insolubility in water does question whether the test material is lipophilic and therefore have the potential to accumulate in body fat. For this to happen there would need to be sufficient absorption of the test item initially.

Details on excretion:

There is no evidence to indicate the route of excretion but water-insoluble products are favourable for biliary excretion. Any substance that is not absorbed following oral ingestion will probably be excreted in the faeces.

Metabolite characterisation studies

Details on metabolites:

The results of the genotoxicity assays have shown that genotoxicity is neither enhanced nor diminished in the presence of a metabolising system. Examination of treated animals from a repeated dose toxicity study showed no evidence to suggest that metabolism has been affected by the test material and that liver induction has not taken place. Test items that are insoluble in water are more likely to be metabolised in order to facilitate urinary excretion. Alternatively such water insoluble materials may pass through the liver to allow for biliary excretion.

Applicant's summary and conclusion

Conclusions:

Paper-based toxicokinetic assessment has been conducted for the substance, Benzylated Polyamine. The results of the repeated dose oral toxicity studies do not confirm that significant absorption of the test item has taken place following oral ingestion. The toxic effects that were observed were likely to have resulted from direct contact of the test item with the mucosal membranes in the stomach and potentially the small intestine and may be a result of the irritant properties of the test item. The limited water solubility will inhibited free passage of test item via diffusion across the gut and is likely to limit the systemic distribution of test item. There was no indication of metabolism of test item in either in vitro or in vivo. Likewise, no indications of potential routes of excretion of test item although it may be speculated that biliary excretion may be favourable for water insoluble materials

Executive summary:

Paper-based toxicokinetic assessment has been conducted for the substance, Benzylated Polyamine. The results of the repeated dose oral toxicity studies do not confirm that significant absorption of the test item has taken place following oral ingestion. The toxic effects that were observed were likely to have resulted from direct contact of the test item with the mucosal membranes in the stomach and potentially the small intestine and may be a result of the irritant properties of the test item. The limited water solubility will inhibited free passage of test item via diffusion across the gut and is likely to limit the systemic distribution of test item. There was no indication of metabolism of test item in either in vitro or in vivo. Likewise, no indications of potential routes of excretion of test item although it may be speculated that biliary excretion may be favourable for water insoluble materials