Reaction mixture of hydrogenated tallow alkyl amines with sebacic acid and lithium hydroxide

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Remarks:

expert statement

Type of information:

other: expert statement

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: expert statement based on physical/chemical and toxicology properties, no study on toxicokinetics available

Principles of method if other than guideline:

Expert statement

GLP compliance:

no

Details on species / strain selection:

not applicable

Details on test animals or test system and environmental conditions:

not applicable

Details on exposure:

not applicable

Duration and frequency of treatment / exposure:

not applicable

No. of animals per sex per dose / concentration:

not applicable

Positive control reference chemical:

not applicable

Details on study design:

not applicable

Details on dosing and sampling:

not applicable

Statistics:

not applicable

Details on absorption:

Generally, oral absorption is favoured for molecular weights below 500 g/mol and only molecular weights above 1000 g/mol do no longer favour absorption. The moderate water solubility of 411 mg/L enables the substance to dissolve in the gastrointestinal fluids. In combination with the molecular weight range of 214 g/mol constituent a) might pass through aqueous pores or can be carried through the epithelial barrier by the bulk passage of water. Due to the larger molecular weights constituent b) (459 g/mol) and constituent c) (705 g/mol) favour the formation of micells and pinocytosis and thereby are absorbed into the lymphatic system. Those later mechanisms of uptake are also favoured by the high log Pow values of 6.3 for constituent b) and 18 for constituent c), as generally observed for lipophilic substances. Taken together, the physiochemical properties indicate that the test substance becomes bioavailable though different mechanisms following the oral route. This assumption is neither confirmed nor rebutted by the results of the acute toxicity study conducted with the test substance. Assuming that some compounds of test substance become bioavailable after oral uptake, data from an acute oral toxicity study demonstrated, that absorbed molecules are of low systemic toxicity (an LD50 > 2000 mg/kg bw was obtained).
Due to the low vapour pressure of the test substance it is very unlikely that the substance will be available as a vapour to a large extend. In case such an exposure might occur the diverse log Pow values indicate a limitation of absorption via inhalation route directly across the respiratory tract epithelium by passive diffusion to the main constituent, while the other constituents may be taken up by micellular solubilisation. As no formation of substance’s aerosol is expected during production and handling of the substance, the uptake via inhalation is very unlikely.
Dermal absorption might also take place, favoured by the water solubility of some compounds. The log Pow range indicates an uptake of the substance into the stratum corneum. In addition it shows a possible limitation of the penetration rate by the rate of transfer between the stratum corneum and the epidermis, thereby limiting the dermal absorption of the test substance up to a certain degree. As the test substance was found to be not skin irritating and not sensitising no direct conclusion from these endpoints can be made for dermal absorption. However, at least from the guinea pig assay, in which the skin barrier was artificially compromised (intradermal application), a bioavailability can be expected. Based on the results (no effects) it can therefore be concluded, that the substance if becoming bioavailable after skin contact, is not likely to cause any adverse effects.

Details on distribution in tissues:

As mentioned above, the physicochemical properties of the test substance favour a limited systemic absorption following oral and dermal uptake, while via inhalation practical no systemic uptake is expected.
Dependent on the constituent of the substance direct transport through aqueous pores (constituent a)) is likely to be an entry route to the systemic circulation as well as the formation of micells and pinocytosis (constituents b) and c)). After being absorbed into the body, the constituents b) and c) are most likely distributed into the interior part of cells due to their lipophilic properties and in turn the intracellular concentration may be higher than extracellular concentration particularly in adipose tissues. Constituent a) might be highly distributed through the body fluids due to the low molecular weight (214 g/mol) and it hydrophilic properties (log Pow: -3.1), while the uptake into cells will limited to aqueous channels as diffusion through the lipid membrane layers will not occur.
The log Pow range of the test substance may indicate a possible bioaccumulation potential. Due to the lipophilic tendency, the test substance may be bioaccumulative in individuals that are frequently exposed. Especially the constituents b) and c) are considered for bioaccumulation, while the hydrophilic properties of constituent a) indicate an unlikely bioaccumulation for this constituent. Nevertheless, it is expected that the substance, including constituents b) and c), is metabolized in the human body leading to metabolites with lower log Pow and higher water solubility to facilitate excretion and consequently bioaccumulation is not considered critical.

Details on excretion:

The excretion pathway of the test substance is likely to be via urine or bile/ faeces dependent on the constituent and the involvement of Phase II metabolism. Substances with a molecular weight below 300 g/mol are prone for excretion via urine and constituent a)’s molecular weight is 214 g/mol, therefore it is the likely pathway for the main constituents. As both other constituents, b) and c), have higher molecular weights and are more or less highly lipophilic, as indicated by the log Pows, they are likely to be excreted via bile and faeces.

Details on metabolites:

The genotoxicity studies indicated no remarkable differences in regard to genotoxicity and cytotoxicity in the presence or absence of metabolic activation systems. This lack of cytotoxicity in the presence and absence of S9 mix indicates, that the substance itself has no cytotoxic potential and that cytochrome P450 oxidases mediated processes (metabolism) is also not likely to form reactive molecules, potentially causing toxic effects. Based on the chemical structure it is likely that cytochrome P450 oxidases interaction during Phase I metabolism introduce a reactive or polar group in the test substance. Those might be further processed into polar compounds during the metabolism in Phase II.

Conclusions:

Bioaccumulation of the test substance is not considered critical based on an expert statement.

Executive summary:

Based on physicochemical characteristics, particularly water solubility, molecular weight and octanol-water partition coefficient, limited absorption by the dermal and oral route is expected, while inhalation seems unlikely. Bioaccumulation of the test substance is not considered critical, as it is expected that the substance is metabolized in the human body leading to metabolites with lower log Pow and higher water solubility to facilitate excretion. Phase I and II metabolism within liver cells is likely and excretion will presumably occur after renal passage via urine for the main constituent while the other constituents are most likely execrated via bile and faeces.

Description of key information

Based on physicochemical characteristics, particularly water solubility, molecular weight and octanol-water partition coefficient, limited absorption by the dermal and oral route is expected, while inhalation seems unlikely. Bioaccumulation of the test substance is not considered critical, as it is expected that the substance is metabolized in the human body leading to metabolites with lower log Pow and higher water solubility to facilitate excretion. Phase I and II metabolism within liver cells is likely and excretion will presumably occur after renal passage via urine for the main constituent while the other constituents are most likely execrated via bile and faeces.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Toxicokinetic assessment

The test substance is a white solid at room temperature with a molecular weight in the range of 214 to 705 g/mol. The substance is soluble in water (411 mg/L at 20 °C). The log Pow was determined to be in the range of -3.1 to 18 due to the three different constituents. The test substance has a very low vapour pressure of < 8E-08 Pa at 25 °C. The test substance is a multi-constituent substance consisting of constituent a) (ca. 49.2 % (w/w)), constituent b) (ca. 41.1 % (w/w)) and constituent c) (ca. 9.7 % (w/w)).

 

Absorption

Generally, oral absorption is favoured for molecular weights below 500 g/mol and only molecular weights above 1000 g/mol do no longer favour absorption. The moderate water solubility of 411 mg/L enables the substance to dissolve in the gastrointestinal fluids. In combination with the molecular weight range of 214 g/mol constituent a) might pass through aqueous pores or can be carried through the epithelial barrier by the bulk passage of water. Due to the larger molecular weights constituent b) (459 g/mol) and constituent c) (705 g/mol) favour the formation of micells and pinocytosis and thereby are absorbed into the lymphatic system. Those later mechanisms of uptake are also favoured by the high log Pow values of 6.3 for constituent b) and 18 for constituent c), as generally observed for lipophilic substances. Taken together, the physiochemical properties indicate that the test substance becomes bioavailable though different mechanisms following the oral route. This assumption is neither confirmed nor rebutted by the results of the acute toxicity study conducted with the test substance. Assuming that some compounds of the test substance become bioavailable after oral uptake, data from an acute oral toxicity study demonstrated, that absorbed molecules are of low systemic toxicity (an LD50 > 2000 mg/kg bw was obtained).  

 

Due to the low vapour pressure of the test substance it is very unlikely that the substance will be available as a vapour to a large extend. In case such an exposure might occur the diverse log Pow values indicate a limitation of absorption via inhalation route directly across the respiratory tract epithelium by passive diffusion to the main constituent, while the other constituents may be taken up by micellular solubilisation. As no formation of substance’s aerosol is expected during production and handling of the substance, the uptake via inhalation is very unlikely.

 

Dermal absorption might also take place, favoured by the water solubility of some compounds. The log Pow range indicates an uptake of the substance into the stratum corneum. In addition it shows a possible limitation of the penetration rate by the rate of transfer between the stratum corneum and the epidermis, thereby limiting the dermal absorption of the test substance up to a certain degree. As the test substance was found to be not skin irritating and not sensitising no direct conclusion from these endpoints can be made for dermal absorption. However, at least from the guinea pig assay, in which the skin barrier was artificially compromised (intradermal application), a bioavailability can be expected. Based on the results (no effects) it can therefore be concluded, that the substance if becoming bioavailable after skin contact, is not likely to cause any adverse effects.

 

 

Distribution

As mentioned above, the physicochemical properties of the test substance favour a limited systemic absorption following oral and dermal uptake, while via inhalation practical no systemic uptake is expected.

 

Dependent on the constituent of the substance direct transport through aqueous pores (constituent a)) is likely to be an entry route to the systemic circulation as well as the formation of micells and pinocytosis (constituent b) and c)). After being absorbed into the body, the constituents b) and c) are most likely distributed into the interior part of cells due to their lipophilic properties and in turn the intracellular concentration may be higher than extracellular concentration particularly in adipose tissues. constituent a) might be highly distributed through the body fluids due to the low molecular weight (214 g/mol) and it hydrophilic properties (log Pow: -3.1), while the uptake into cells will limited to aqueous channels as diffusion through the lipid membrane layers will not occur.  

 

The log Pow range of the test substance may indicate a possible bioaccumulation potential. Due to the lipophilic tendency, the test substance may be bioaccumulative in individuals that are frequently exposed. Especially the constituents b) and c) are considered for bioaccumulation, while the hydrophilic properties of constituent a) indicate an unlikely bioaccumulation for this constituent. Nevertheless, it is expected that the substance, including constituent b) and c), is metabolized in the human body leading to metabolites with lower log Pow and higher water solubility to facilitate excretion and consequently bioaccumulation is not considered critical. 

 

 

Metabolism

The genotoxicity studies indicated no remarkable differences in regard to genotoxicity and cytotoxicity in the presence or absence of metabolic activation systems. This lack of cytotoxicity in the presence and absence of S9 mix indicates, that the substance itself has no cytotoxic potential and that cytochrome P450 oxidases mediated processes (metabolism) is also not likely to form reactive molecules, potentially causing toxic effects. Based on the chemical structure it is likely that cytochrome P450 oxidases interaction during Phase I metabolism introduce a reactive or polar group in the test substance. Those might be further processed into polar compounds during the metabolism in Phase II.

 

 

Excretion

The excretion pathway of the test substance is likely to be via urine or bile/ faeces dependent on the constituent and the involvement of Phase II metabolism. Substances with a molecular weight below 300 g/mol are prone for excretion via urine and constituent a)’s molecular weight is 214 g/mol, therefore it is the likely pathway for the main constituents. As both other constituents, constituent b) and c), have higher molecular weights and are more or less highly lipophilic, as indicated by the log Pows, they are likely to be excreted via bile and faeces.