Dimethyl(octyl)amine

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

(Q)SAR

Adequacy of study:

key study

Study period:

(Q)SAR analysis, no study period available

Reliability:

other: Reliability of report to be confirmed when QSAR justifcation is updated - refer to justification for type of information

Rationale for reliability incl. deficiencies:

other: Rationale for reliability of report to be confirmed when QSAR justifcation is updated - refer to justification for type of information

Justification for type of information:

The attached study report ismissing the QSAR model and justification for using QSAR model. Requests for an updated version of the report to include the justification have been sent to the performing laboratory - Eurofins and W L Gore is waiting for the amended report. When it is completed, W L Gore will submit a spontaneous dossier update to include the missing justification data.

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 required

Principles of method if other than guideline:

QSAR mdoel to be confirmed with spontaneous dossier update.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Dimethyl(octyl)amine

EC Number:

230-939-3

EC Name:

Dimethyl(octyl)amine

Cas Number:

7378-99-6

Molecular formula:

C10H23N

IUPAC Name:

dimethyl(octyl)amine

Specific details on test material used for the study:

The toxicokinetic assessment of N, N -dimethyloctylamine is predicted based on its physico-chemical properties and available toxicological study data. The OECD QSAR application toolbox v4.0 was also utilized to make a qualitative prediction of metabolites formed in vivo in rat and in the skin.
physico-chemical properties:
Molecular weight: 157

Water solubility: 255.8 mg/L at 20° C, in ultra-pure water (pH = 10.75)

Octanol-water 2.17
partition coefficient
(log Pow):

Vapour pressure: Predicted value of 0.564 mm Hg (Episuite)

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

N,N -dimethyloctylamine is very likely to be absorbed via the oral route. N,N -dimethyloctylamine is very likely to be absorbed via the inhalation route. N,N -dimethyloctylamine is very likely to be absorbed via the dermal route.

Main ADME results 2

Type:

distribution

Results:

Indications are that distribution of N,N –dimethyloctylamine and/or its metabolites would be extensive.

Main ADME results 3

Type:

metabolism

Results:

A significant number of potential metabolites are predicted using the OECD toolbox

Main ADME results 4

Type:

excretion

Results:

Excretion of N,N –dimethyloctylamine and its predicted metabolites is expected via urine due to their relatively low molecular weight and (expected/known) water solubility (known from test on parent and assumed as similar/higher for metabolites).

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Oral route

At the low pH in the human stomach (approximately pH 2), N,N -dimethyloctylamine is likely to be converted from the free amine to the hydrochloride salt, which is expected to have a higher water solubility than the free amine. However, the pH in the GI tract moves from acidic to alkaline, so the hydrochloride salt is expected to convert back to the free amine which is more likely to undergo absorption via the small intestine (ileum). The moderate log Pow and the low molecular weight (less than 200 g/mol) indicate that N, N -dimethyloctylamine is likely to be absorbed by passive diffusion.

A dose-range finding study (BSL Munich Study No. 154453) for oral administration in Wistar rat, provided qualitative evidence – in the form of treatment-related effects on internal organs (increase in liver and uterus weight) - that this molecule is absorbed in the GI tract.

A reproduction/developmental toxicity screening test was performed in Wistar rats (BSL Munich Study No 154454). No mortality occurred in the control or any of the dose groups during the study period (apart from one due to accidental dosage via gavage). No adverse effects were seen for systemic or reproductive toxicity, but the NOAEL for developmental toxicity was set at the low dose level. This indicates that – as concluded in the dose rangefinder test – absorption via the oral route must have occurred in order to have systemic toxicity. As previously, there is no information to deduce the extent of oral absorption.

The OECD QSAR application toolbox was used to apply Lipinski's Rule of Five which predicts the likelihood of bioavailability. For clarification, bioavailability is not the same as absorption in this context. For example, a molecule can be absorbed in the GI tract but then be fully metabolised in the liver and therefore not be bioavailable to the systemic circulation.

N,N -dimethyloctylamine is predicted to be bioavailable i.e. will enter the systemic circulation.

The toolbox is also designed to predict possible metabolites that can be produced by phase 1(e.g. oxidation/reduction) and phase 2 (e.g. conjugation) biotransformations in the liver, based on the structure of the parent molecule. This biotransformation can occur during the first pass effect, but can also occur if the unmetabolised molecule passes into the systemic circulation and returns through the liver.

The predicted metabolites (table 1) are all expected to be bioavailable.

Based on the available evidence, it can be concluded that N,N -dimethyloctylamine is absorbed via the oral route and the observed toxicity is likely to be due to this absorption, not to local effects in the GI tract. This conclusion is supported by evidence of systemic toxicity after dermal exposure (see dermal route below), where mortality resulting from dermal application of N,N -dimethyloctylamine is highly unlikely to have been due to local effects on the ear-skin.


Inhalation route

Moderate log P values (between -1 and 4) are favourable for absorption directly across the respiratory tract epithelium by passive diffusion. In the case of this substance, the log P is 2.17 and therefore likely to be passively absorbed via the lungs.
An acute toxicity inhalation study (PSL study number 42517) showed acute toxicity and gross necropsy revealed discolouration of lungs, liver, stomach and/or intestines and/or distention of the stomach. This is indicative that absorption via lungs occurred, but it is not possible to quantify such absorption.

Dermal route

Dermal absorption is influenced inter alia by water solubility, log Pow and molecular weight. REACH endpoint specific guidance (R.7c) indicates that the water solubility (100-10000 mg/L), low molecular weight (< 200 g/mol) and log Pow (>1, < 4) of N,N –dimethyloctylamine all favour dermal absorption.

This expected dermal absorption is supported by the observations from a local lymph node assay (BSL Munich Study No 154449) which indicated that absorption of N,N –dimethyloctylamine occurred. This was very clearly demonstrated in the pre-screen test prior to the main test. At an application of 100% substance to the entire dorsal area of each ear, in both animals exposed to the 100% substance, one was dead on day 1 and the other showed clinical signs of systemic toxicity and was euthanised for ethical reasons on day 1. Use of diluted substance did not have the same effect, thus demonstrating a dose-response systemic effect via dermal absorption. The main test also demonstrated that classification as a sensitiser (cat 1B) was indicated, again indicating dermal absorption must have occurred to some degree.

The overall data from the pre-screen and main LLNA test show that the substance can be absorbed via skin. Quantification of the dermal absorption is not possible from the data

Details on distribution in tissues:

Distribution

There is minimal information available relating to the distribution of N,N –dimethyloctylamine.

The available oral toxicity studies clearly indicate that absorption does occur and therefore there is the possibility of distribution around the body unless the substance is completely metabolised in the liver before any can enter the systemic circulation. In the reproductive/developmental screening study (BSL Munich Study No 154454) no gross lesions could be attributed to the test item, although this does not necessarily mean that the substance did not distribute to the examined organs after absorption – only that it did not affect it macroscopically. Microscopic findings were observed in the stomach, but this might be expected as direct local contact would have occurred during gavage.

Overall, given the water solubility, molecular weight and log P values together with evidence of systemic toxicity, it is probable that systemic distribution of N,N -dimethyloctylamine occurs. However, the magnitude, location and residence time of distribution into a particular part of the body cannot be determined from the available data. In addition, it cannot be totally excluded that the observed systemic toxicity effects may be due to skin and GI/liver metabolites entering the systemic circulation, rather than the parent.

Details on excretion:

Excretion

Excretion of N,N – dimethyloctylamine and its predicted metabolites is expected to occur predominantly via urine, on the basis of their low molecular weights. In addition the parent is known to be reasonably water soluble and its metabolites are expected to be at least as water soluble.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

N,N –dimethyloctylamine was stable to hydrolysis at pH 4-9, therefore no abiotic degradation is expected at the various pH changes occurring in the GI tract.

Potential metabolites of N,N –dimethyloctylamine in vivo and in skin have been predicted using OECD Toolbox (table 1). Fourteen metabolites were predicted by the in vivo rat metabolism simulator (which includes 5 metabolites also predicted by the S9 liver metabolism simulator) and 2 metabolites for rat skin metabolism simulator. All metabolites were predicted to be bioavailable.

The main predicted biotransformations in vivo and for skin include hydroxylation reactions, demethylation and oxidation, which are considered as the normal types of phase I and phase II transformations. It is clear from the number of predicted metabolites that N,N – dimethyloctylamine can potentially undergo a significant degree of metabolism before and/or after absorption (by GI tract flora and/or enzymes in liver/skin).

The SMILES codes for all the above predicted metabolites were entered into the ChemSpider website, but no identification was found with the exception of those structures that are specifically named in table 1 of the attached report.

Applicant's summary and conclusion

Conclusions:

The absorption, distribution, metabolism and excretion of N,N -dimethyloctylamine have been predicted using QSAR in the absence of toxicokinetic studies.

Absorption
N,N -dimethyloctylamine is very likely to be absorbed via the oral route.
N,N -dimethyloctylamine is very likely to be absorbed via the inhalation route.
N,N -dimethyloctylamine is very likely to be absorbed via the dermal route.

Distribution
Indications are that distribution of N,N –dimethyloctylamine and/or its metabolites would be extensive.

Metabolism
A significant number of potential metabolites are predicted using the OECD toolbox (table 1 of the report).

Excretion
Excretion of N,N –dimethyloctylamine and its predicted metabolites is expected via urine due to their relatively low molecular weight and (expected/known) water solubility (known from test on parent and assumed as similar/higher for metabolites).

Executive summary:

The absorption, distribution, metabolism and excretion of N,N -dimethyloctylamine have been predicted using QSAR in the absence of toxicokinetic studies.

Absorption

N,N -dimethyloctylamine is very likely to be absorbed via the oral route.

N,N -dimethyloctylamine is very likely to be absorbed via the inhalation route.

N,N -dimethyloctylamine is very likely to be absorbed via the dermal route.  

Distribution

Indications are that distribution of N,N –dimethyloctylamine and/or its metabolites would be extensive.

Metabolism

A significant number of potential metabolites are predicted using the OECD toolbox (table 1 of the report).

Excretion

Excretion of N,N –dimethyloctylamine and its predicted metabolites is expected via urine due to their relatively low molecular weight and (expected/known) water solubility (known from test on parent and assumed as similar/higher for metabolites).