Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: Expert statement
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Expert statement, no study available

Data source

Reference
Reference Type:
other: Expert statement
Title:
Unnamed
Year:
2015
Report Date:
2015

Materials and methods

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Details on test animals and environmental conditions:
not applicable

Administration / exposure

Details on exposure:
not applicable
Duration and frequency of treatment / exposure:
not applicable
Doses / concentrations
Remarks:
Doses / Concentrations:
not applicable
No. of animals per sex per dose:
not applicable
Positive control:
not applicable
Details on study design:
not applicable
Details on dosing and sampling:
not applicable
Statistics:
not applicable

Results and discussion

Preliminary studies:
not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Quaternary ammonium substances are poorly absorbed, but systemic effects are possible after all routes of exposure (INCHEM 2009), but were in this case secondary to the irritant effects caused by the test compound.
Generally, oral absorption is favoured for molecular weights below 500 g/mol. Furthermore, the high water solubility enables the substance to readily dissolve in the gastrointestinal fluids, allowing direct uptake into the systemic circulation through aqueous pores or via carriage of the molecules across membranes with the bulk passage of water. Taken together, the physiochemical properties indicate that the substance becomes bioavailable following the oral route. This assumption is confirmed by the results of the acute toxicity studies. The acute oral toxicity study in Sprague-Dawley rats revealed an LD50 value of 207 mg/kg bw.
Due to the low vapour pressure of the test substance it is unlikely that it will be available as a vapour, but if it is the case absorption via inhalation route is possible as absorption following ingestion did also occur. The water solubility would enable dissolving in the mucus lining of the respiratory tract. As the molecules might be too large to be absorbed through aqueous pores and also exhibit hydrophilic properties, uptake at high rates directly across the respiratory tract epithelium by passive diffusion is not likely. With regard to the skin corrosive property of the test substance on the other hand it is likely that some reactions would occur on the site of contact and modify the absorption rate.
According to “Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance” (ECHA, 2008) dermal uptake of quaternary ammonium ions is slow due to their reactivity and binding to skin components. But dermal absorption will in this case take place to a considerably extent, as was demonstrated by the acute dermal toxicity study conducted with New Zealand White rabbits revealing a LD50 value of 429 mg/kg bw. Dermal absorption is supposed to be favoured by the water solubility and also by the size of the molecules.

Details on distribution in tissues:
As mentioned above, the physicochemical properties of the test item allow systemic absorption following oral and dermal uptake. As the molecules are highly water-soluble, the rate of diffusion across membranes could limit their distribution and the extracellular concentration is supposed to be higher than the intracellular concentration. They will most probably not cross the blood-brain barrier, which is confirmed by the test results not indicating distribution to the CNS. Repeated dose toxicity studies did not demonstrate toxicity to specific organs or tissues after oral absorption. No test item related abnormalities were found during necropsy. In contrast to that, after single administration of higher doses in the acute toxicity studies the kidneys, adrenal glands, brain, liver and intestines were found to appear abnormal due to reddening in Sprague-Dawley rats after oral administration. The brain and thymus were found to be haemorrhagic and dark red areas were observed in the stomachs of New Zealand White rabbits that had died after dermal application. These findings indicate that the molecules might be distributed in the body through the bloodstream. Furthermore the haemorrhagic organs and glands demonstrate that blood is leaking out of the vessels due to damage of the capillary endothelium. This damage is presumably caused by lipid peroxidation taking place between the cationic molecules and membrane lipids.
Details on excretion:
The majority of the quaternary ammonium compound will be excreted via faeces after ingestion, as the size of the molecule does not favour renal excretion.

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
No data on metabolism and excretion of the test substance are available.
Based on the structure of the molecule it can be assumed that the substance undergoes oxidation reactions of the alkyl side chain, forming ketones and hydroxyketones, to render the molecules more polar. Due to the molecules already being highly hydrophilic, further conjugation reactions are not to be expected. Due to their polarity and relatively high molecular weights, the molecules are not supposed to undergo enterohepatic circulation.

Bioaccessibility

Bioaccessibility testing results:
Systemic effects were secondary to the irritant effects caused by the test compound.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Local effects observed probably result from the reactive quaternary ammonium cation. The substance is supposed to be metabolized by oxidation reactions and mainly excreted via faeces.