Amines, tri-C8-10-alkyl

Endpoint summary

Description of key information

The bioavailability of the substance can be confirmed through different routes. But the uptake may be limited for some routes due to the physicochemical behavior. Possible uptake routes are dermal, oral and inhalation, whereas via dermal route absorption is expected to be limited. Absorption via inhalation route may be possible but not of favor as the vapor pressure is low and mist a more difficult to generate than for water. The oral bioavailability was thereby confirmed in various studies. It can be assumed that the substance is wide distributed in the organism and maybe able to accumulate in adipose tissues. A main route of elimination could not be concluded, but renal and bile excretion are assumed to be the main path for excretion. Furthermore some metabolites may be exhaled as carbon dioxide at the end of their metabolic pathway. 

Key value for chemical safety assessment

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

100

Additional information

There were no studies available in which the toxicokinetic properties (distribution, metabolism, elimination) of the Amines, tri-C8-10-alkyl were investigated.

 

The expected toxicokinetic behavior is derived from the physicochemical properties, the results from the available toxicological studies and the available literature following the information given in guidance document 7c.

Please note that the real behavior may be different but can only be determined with ADME studies, which aren’t justified based on the low toxicity of the substance.

 

Amines, tri-C8-10-alkyl having a molecular weight of ~ 395 g/mol is a viscose liquid (viscosity 12.38 mPa s) with a water solubility of less than 100 mg/l. The substance has a low volatility of <0.0001 Pa and a very lipophilic character (log Pow = 10.35-13.3). The structure shows a free electron pair on a nitrogen atom which may be protonated in acid ambient. The surface tension is 65.3 mN/m .

 

Oral and GI absorption:

Based on the physicochemical data the substance is suspected to be less dissolvable in GI and absorbed via micellular solubilisation. As the substance contains a free electron pair it may be protonated in acids increasing the water solubility and changing the absorption character as well as the toxicological behavior. Due to the molecular mass an GI absorption is possible but limited by the low solubility. Oral and dermal acute toxicity studies showed some effects and underline the possible absorption as well as a OECD 422 which shows effects at low concentration. In summary due to the molecular weight and physicochemical behavior and the result of animal studies the substance may be absorbed orally / via GI tract in noteable amounts.

 

Inhalation absorption:

Derived from the physicochemical data the substance has a very low volatility and is therefore only inhaled in very low concentration if no mist are generated. The further limiting factor is the possibility of creating mists. As the substance has a higher viscosity than water s the development of mist is less expected (viscosity 12.38 mPa). Nevertheless if the substance is inhaled the substance may reach the lower respiratory system as a retaining in the upper mucosa is not expected due to the low water solubility and high lipophilic character. In this region an uptake via micellular solubilisation may happen but is expected to be limited. Due to the neutral ambient no protonation can be expected an respiratory absorption of the parent compound must be assumed. Nevertheless the low toxicity seen in acute toxicity test points to a low oral / dermal absorption and gives hints for an also low inhalation absorption and /or a general low systemic toxicity. Summarising the inhalation of mist is not a favor route of exposure due to viscosity of the substance but possible. If the substance is inhaled it may reach lower respiratory system and parent compound may be absorbed but absorption maybe limited.

 

Dermal absorption:

Triggered by the physicochemical data the following dermal absorption behavior is expected. Due to liquid state of the substance it can be easily distributed on the skin surface and the low vapor pressure increases the dermal contact time. But the very low water solubility and the very high log pow are limiting the dermal absorption. Effects seen in dermal irritation test are quiet strong but not corrosive. These effects may increase a dermal absorption, but as no damage happen this increase may also be limited. In acid milieu the substance may has the ability to be protonated which increases the water solubility. But the pH value of the skin may be not sufficient enough to trigger protonation of the substance. Furthermore acute dermal toxicity test show no systemic effects. If this result is compared to the results of the acute oral toxicity test a less dermal absorption must be assumed (higher than 60% reduction). In summary a low dermal absorption is expected, but dermal absorption cannot fully exclude.

Second it is known for cosmetic ingredients having a MW above 300 g/mol and a log pow below -1 or above 5 that an dermal absorption of 10% can be expected (Kroes et al., Food Chem Toxicol 2007 Dec; 45(12): 2533-62). These physicochemical parameters are fulfilled for the above mentioned substance and therefore the assumption from Kroes et al. may also hold true for the substance registered here, hence for exposition calculation 10% dermal absorption is used.

 

Distribution:

Based on the physicochemical data the substance is expected to be less distributed in the organism due to their low water solubility. The molecular mass may also limit the distribution and the very high lipophilic character favors the substance for cellular uptake and increased intracellular concentration. Result from a OECD 422 indicate that substance may be wide distributed. Special targets for distribution could not be identified but effects were observed in the heart and reproduction organs. In summary a wide distribution is assumed but nevertheless all this behavior is estimated, detailed information can only be obtained by ADME investigations.

 

Accumulative potential:

Based on the available data the substance may not accumulate in the lung as micellular solubilisation makes a uptake possible and furthermore lung cleaning systems my transport the substance away. The accumulation of the substance in adipose tissue may be represent the most suitable possible accumulation due to the high log pow. Nevertheless it stays unclear if high amounts of the substance are transported to adipose tissues. Accumulation in stratum corneum may be possible but is not assumed as the favored log pow for accumulation is between 4 and 6.

 

Metabolism:

Based on based on the general structure of the molecule the normal cleavage process as seen for alkyl chains (ß-oxidation) is expected. Further the central nitrogen atom may be oxidise by flavin depending monooxygnese to N-oxid. It is also possible that the substance may be protonated in acid containing ambience. This may increase the solubility and alter the toxicological behavior (and the substance identity which is afterwards a ammonium salt).

 

Reactivity:Available studies on genotoxicity were negative, i. e. there is no indication of a reactivity under the test conditions.

 

Excretion:

Based on the available information the expected behavior of the substance is estimated: The high molecular mass points to an excretion via bile but partly it may be also excreted via urine as the molecular mass is not that high and ß-oxidation may shorten the chain length. Furthermore the substance contains a free electron pair on a nitrogen atom which can be protonated in acid ambience (especially after oral uptake). The build ammonium ion may be more water soluble and excreted predominantly via urine. Therefore both routes are expected. As the substance is expected to not wide distributed, less amount in breast milk or saliva are expected. If the substance is applied dermally a low amount is expected to be absorbed. Nevertheless as the substance may than reach the stratum corneum an exfoliation may be possible. Further ß-oxidation may lead carbon dioxide as an end product. Therefore to some extend the substance may be also transformed into an exhalable product. This expected behavior is only estimated based on the few available physicochemical information, only detailed ADME investigation can confirm these behavior.

 

In summary:The bioavailability of the substance can be confirmed through different routes. But the uptake may be limited for some routes due to the physicochemical behavior. Possible uptake routes are dermal, oral and inhalation, whereas via dermal route absorption is expected to be limited. Absorption via inhalation route may be possible but not of favor as the vapor pressure is low and mist a more difficult to generate than for water. The oral bioavailability was thereby confirmed in various studies. It can be assumed that the substance is wide distributed in the organism and maybe able to accumulate in adipose tissues. A main route of elimination could not be concluded, but renal and bile excretion are assumed to be the main path for excretion. Furthermore some metabolites may be exhaled as carbon dioxide at the end of their metabolic pathway.