Methanaminium, N,N,N-trimethyl-, 2,2-dimethylpropanoate (1:1)

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

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 followed

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, Methanaminium,N,N,N-trimethyl-,salt with 2,2-dimethylpropanoic acid a.k.a Tetramethylammonium Privalate Salt. 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:

-

EC Number:

478-310-4

EC Name:

-

Cas Number:

53803-13-7

Molecular formula:

C9H21NO2

IUPAC Name:

Methanaminium N,N,N-trimethyl-, salt with 2,2-dimethylpropanoic acid

Test material form:

solid: crystalline

Details on test material:

Description: white solid
Batch: 13AP016
Expiry 2015-11-13

Results and discussion

Preliminary studies:

The substance is a white solid has a low/moderate log octanol/water partition coefficient (0.312) and water solubility that indicates 10-90% miscibility with water. The test item has a low vapour pressure value suggesting that inhalation of volatile products is unlikely at normal temperatures but toxic organic vapours can be produced if the material is exposed to flames. Although particle size distribution of the test item is not known it is reported that high concentrations of the test item in the atmosphere will result in toxic effects centrally and therefore absorption via inhalation cannot be discounted
Results of acute toxicity studies or prediction of likely oral/dermal toxicity suggests that the test item is expected to have evidence of acute toxicity and therefore absorption following oral ingestion is expected.
A twenty-eight day repeated dose toxicity study in the rat showed evidence of absorption with target organ effects identified. The level of toxicity to rats was confirmed from findings seen in a prenatal development toxicity study in the pregnant rat
In the presence/absence of auxiliary metabolising system, the test item was non-clastogenic in mammalian cells in vitro (human lymphocytes) and was not mutagenic or clastogenic in the mouse lymphoma assay.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Inhalation is considered to be a potential route of exposure based on the fact that the substance, whilst being non-volatile, it is reported that absorption at high atmospheric concentrations will result in toxic effects. The evidence of slight irritancy to the skin of a 50% solution of test item plus a predicted dermal toxicity value suggest that exposure through the dermis may also be possible
Absorption from the gastrointestinal tract following oral ingestion is supported by the results from oral toxicity studies. The predicted oral toxicity value shows the likelihood of systemic toxicity following a single dose of test item. In an oral repeated dose toxicity study (28-day) there was some evidence of absorption. The evidence of hepatic change as indicated by the histopathology of the liver plus changes in blood chemistry values for circulating enzyme values (alanine aminotransferase and aspartate aminotransferase) and altered bile acid values are indicators of effects of test item following absorption.
The moderate/low log Pow and high water solubility of the substance suggest that dermal absorption will be possible but at a limited rate. The quoted figure for an LD50 value in a rabbit dermal toxicity study suggests that absorption through the dermis can take place

Details on distribution in tissues:

The appreciable water solubility of the test item would suggest that it may be readily distributed in the water compartment of the circulatory system. The material does not appear to be a sensitizer as there was no response in the Mouse Local Lymph Node Assay and so binding to circulatory proteins is not expected.
The limited Log Octanol: water partition coefficient value would suggest the substance has limited affinity to accumulate in fatty tissues.

Details on excretion:

There is no evidence to indicate the route of excretion but water-soluble products are favourable for urinary 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. As the material is readily water soluble it is unlikely that significant hepatic metabolism is required. It is however of note that hepatic changes observed microscopically in rats from a repeated dose toxicity study together with changes in blood chemistry profiles of specific enzymes/substrates suggest that there is some change to the metabolic processes in the liver. This may therefore be a secondary consequence of metabolism of the test item. The lack of evidence of enzyme induction would suggest that this potential metabolism may be non-microsomal.

Applicant's summary and conclusion

Conclusions:

The available information suggests that absorption of the test substance from the gastrointestinal tract is possible. Absorption via the skin or through the respiratory system can also take place. Widespread distribution of any absorbed substance can occur through simple processes involving distribution in the water compartments. Any substance absorbed may have limited potential to accumulate in fatty tissues. Changes to hepatic processes in the livers of rats would suggest that metabolism may take place as a detoxification process. Urinary excretion may well be the significant route of excretion.

Executive summary:

The available information suggests that absorption of the test substance from the gastrointestinal tract is possible. Absorption via the skin or through the respiratory system can also take place. Widespread distribution of any absorbed substance can occur through simple processes involving distribution in the water compartments. Any substance absorbed may have limited potential to accumulate in fatty tissues. Changes to hepatic processes in the livers of rats would suggest that metabolism may take place as a detoxification process. Urinary excretion may well be the significant route of excretion.