Reaction mass of (2E)-Tridec-2-enenitrile and (2Z)-Tridec-2-enenitrile and (3E)-Tridec-3-enenitrile and (3Z)-Tridec-3-enenitrile

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Remarks:

Expert statement

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

Principles of method if other than guideline:

Expert statement

GLP compliance:

no

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

Remarks:

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. The poor water solubility of 0.27 mg/L limits the amount of substance that might be dissolved in the gastrointestinal fluids. Still the low molecular weight of less than 200 g/mol might enable the dissolved test substance to pass through aqueous pores or to be carried through the epithelial barrier by the bulk passage of water. The high log Pow value of ca. 6 indicates lipophilic properties and those favour the formation of micells and pinocytosis and thereby absorption of the substance into the lymphatic system. Taken together, the physicochemical 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, while the observed effects in the oral repeated dose study indicate an uptake into the body. Assuming that some amount of the test substance becomes 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). This is further supported by the repeated NOAEL for systemic toxicity of 60 mg/kg bw/day for rats.
Due to the relatively low vapour pressure of the test substance it is unlikely that the substance will be available as a vapour to a large extend, but if it is the case absorption via inhalation route the low water solubility and the high log Pow value, indicate a limitation of absorption via inhalation route directly across the respiratory tract epithelium by passive diffusion, while uptake of the substance by micellular solubilisation might occur. The limited availability of the substance via inhalation might also be indicated by the observation of no mortality after exposure to saturated vapour of the test substance (48.6 mg/m3).
Dermal absorption might also take place albeit partition from stratum corneum into the epidermis will be slow due to the low water solubility. The log Pow indicates a previous high uptake of the substance into the stratum corneum. It also 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. Still the small molecular weight of the substance stands in favour of the partition between those compartments of the skin. The occurrence of dermal absorption is also likely as the substance was found to be sensitising to skin and therefore it has to pass into the lower parts of the epidermis and into the dermis to induce inflammatory/ immune cell responses.

Details on distribution in tissues:

The physicochemical properties of the test substance favour systemic absorption following oral, inhalative and dermal uptake at least to a small extent.
Direct transport through aqueous pores is likely to be an entry route to the systemic circulation as well as the formation of micells and pinocytosis. After being absorbed into the body, the test substance is most likely distributed into the interior part of cells due to its lipophilic properties (log Pow ca. 6) and in turn the intracellular concentration may be higher than extracellular concentration particularly in adipose tissues.
The log Pow 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. Nevertheless, 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 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 involvement of Phase II metabolism. Substances with a molecular weight below 300 g/mol are prone for excretion via urine and the molecular weight is 193.33 g/mol, therefore it is the likely pathway. As the substance on the other hand is more or less lipophilic, as indicated by the log Pow, excretion via bile and faeces might take place. For substance that was absorbed via dermal uptake, a small portion will be processed via the systemic route after passage into the epidermis, while a likely higher portion will remain within the stratum corneum and be sloughed off with skin cells without entering into the body beforehand.

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. No changes were observed for blood chemistry, in the liver and kidneys after repeated oral exposure to the test substance. This indicates that no specific metabolism or interaction mechanism of the test substance and proteins occurs. Therefore it is likely that common protein interaction such as 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 substanceis not considered critical based on expert statement.

Executive summary:

Based on physicochemical characteristics, particularly water solubility and octanol-water partition coefficient, limited absorption by the dermal, oral and inhalation route is expected. 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 and through bile and faeces.

Description of key information

Based on physicochemical characteristics, particularly water solubility and octanol-water partition coefficient, limited absorption by the dermal, oral and inhalation route is expected. 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 and through bile and faeces.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Toxicokinetic Assessment

The test substance is a colourless to pale yellow liquid at room temperature with a molecular weight of 193.33 g/mol. The substance is poorly soluble in water (0.27 mg/L at 20 °C). The log Pow was determined to be around 6. The test substance has a low vapour pressure of 0.11 hPa at 20 °C. The test substance is a multi-constituent substance consisting mostly of two constituents with their respective two enantiomers. A different distribution of the individual constituents results in two different compositions of the test substance, referred to as Composition A and Composition B. As physical-chemical properties of those compositions have proved to be in the same ranges the compositions are considered together for the test substance and have no impact on the outcome of the toxicokinetic evaluation.

 

Absorption

Generally, oral absorption is favoured for molecular weights below 500 g/mol. The poor water solubility of 0.27 mg/L limits the amount of substance that might be dissolved in the gastrointestinal fluids. Still the low molecular weight of less than 200 g/mol might enable the dissolved test substance to pass through aqueous pores or to be carried through the epithelial barrier by the bulk passage of water. The high log Pow value of ca. 6 indicates lipophilic properties and those favour the formation of micells and pinocytosis and thereby absorption of the substance into the lymphatic system. Taken together, the physicochemical 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, while the observed effects in the oral repeated dose study indicate an uptake into the body. Assuming that some amount of the test substance becomes 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). This is further supported by the repeated NOAEL for systemic toxicity of 60 mg/kg bw/day for rats.

Due to the relatively low vapour pressure of the test substance it is unlikely that the substance will be available as a vapour to a large extend, but if it is the case absorption via inhalation route the low water solubility and the high log Pow value, indicate a limitation of absorption via inhalation route directly across the respiratory tract epithelium by passive diffusion, while uptake of the substance by micellular solubilisation might occur. The limited availability of the substance via inhalation might also be indicated by the observation of no mortality after exposure to saturated vapour of the test substance (48.6 mg/m3).

Dermal absorption might also take place albeit partition from stratum corneum into the epidermis will be slow due to the low water solubility. The log Pow indicates a previous high uptake of the substance into the stratum corneum. It also 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. Still the small molecular weight of the substance stands in favour of the partition between those compartments of the skin. The occurrence of dermal absorption is also likely as the substance was found to be sensitising to skin and therefore it has to pass into the lower parts of the epidermis and into the dermis to induce inflammatory/ immune cell responses.

 

Distribution

The physicochemical properties of the test substance favour systemic absorption following oral, inhalative and dermal uptake at least to a small extent.

Direct transport through aqueous pores is likely to be an entry route to the systemic circulation as well as the formation of micells and pinocytosis. After being absorbed into the body, the test substance is most likely distributed into the interior part of cells due to its lipophilic properties (log Pow ca. 6) and in turn the intracellular concentration may be higher than extracellular concentration particularly in adipose tissues.

The log Pow 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. Nevertheless, 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 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. No changes were observed for blood chemistry, in the liver and kidneys after repeated oral exposure to the test substance. This indicates that no specific metabolism or interaction mechanism of the test substance and proteins occurs. Therefore it is likely that common protein interaction such as 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 involvement of Phase II metabolism. Substances with a molecular weight below 300 g/mol are prone for excretion via urine and the molecular weight is 193.33 g/mol, therefore it is the likely pathway. As the substance on the other hand is more or less lipophilic, as indicated by the log Pow, excretion via bile and faeces might take place. For substance that was absorbed via dermal uptake, a small portion will be processed via the systemic route after passage into the epidermis, while a likely higher portion will remain within the stratum corneum and be sloughed off with skin cells without entering into the body beforehand.