3-methyl-5-phenylpent-2-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:

Doses / Concentrations:
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 moderate water solubility of 119 mg/L enables the substance to dissolve in the gastrointestinal fluids. In combination with the low molecular weight of less than 200 g/mol the test substance can pass through aqueous pores or can be carried through the epithelial barrier by the bulk passage of water. The moderate log Pow value is also favourable for passive diffusion. Taken together, the physiochemical properties indicate that the test substance becomes bioavailable following the oral route. This assumption is confirmed by the results of the acute and repeated dose toxicity studies. These results did lead to classification of the substance for acute oral toxicity (category 4) as mortality was observed and the oral LD50 was established to be between 300 to 2000 mg/kg bw.

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 might be possible due to the moderate water solubility and the moderate log Pow value, enabling uptake directly across the respiratory tract epithelium by passive diffusion. This is also supported by the mortality observed after exposure of rats to the substance’s aerosol.

Dermal absorption will also take place, favoured by the water solubility and the log Pow value, and also by the size of the molecule. 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. The systemic absorption is also demonstrated by changes detected in the liver and especially within ovary after repeated oral application in rats.
Direct transport through aqueous pores is likely to be an entry route to the systemic circulation. After being absorbed into the body, the test substance is most likely distributed into the interior part of cells due to its slightly lipophilic properties (log Pow 2.93) and in turn the intracellular concentration may be higher than extracellular concentration particularly in adipose tissues. The proposed intake into cells is also supported by the observed changes in the cytoplasm of hepatocytes.
The test substance does not undergo significant pH-dependent hydrolysis. A study established that less than 10 % of the test substance was hydrolysed after 5 days at 50 °C and pH 4, 7 and 9. The logPow indicates no bioaccumulation potential. It is below 3 and the most likely uptake mechanism into cells is passive diffusion, therefore the test substance is not considered to be bioaccumulative.

Details on excretion:

The test substance will be excreted in its unhydrolised but most likely metabolised form as it was found to be stable against pH-dependent hydrolysis.
The likely excretion pathway of the test substance is via urine. As substances with a molecular weight below 300 g/mol are prone for this pathway and the substance’s molecular weight is 171.23832 g/mol. In addition histopathological changes seen in kidneys demonstrate a passage of the substance through this organ and thereby raise the likelihood of renal excretion.

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. The changes observed in the liver, especially the foamy cytoplasm within the hepatocytes, after repeated oral exposure to the test substance indicate a possible metabolism or at least interaction mechanism of the test substance and liver cell proteins. Therefore it is likely that during Phase I metabolism cytochrome P450 oxidases introduce a reactive or polar group in the enantiomers. Those might be further processed into polar compounds during the metabolism in Phase II.

Conclusions:

Bioaccumulation of the test substance is not to be expected after continuous exposure based on expert statement.

Executive summary:

Based on physicochemical characteristics, particularly water solubility and octanol-water partition coefficient, absorption by the dermal, oral and inhalation route is expected. This assumption is further supported by the results of the oral, inhalation and dermal acute toxicity studies, revealing some effects. Bioaccumulation of the test substance is not to be expected after continuous exposure. Phase I and II metabolism within liver cells is likely and excretion will presumably occur after renal passage via urine.

Description of key information

Based on physicochemical characteristics, particularly water solubility and octanol-water partition coefficient, absorption by the dermal, oral and inhalation route is expected. This assumption is further supported by the results of the oral, inhalation and dermal acute toxicity studies, revealing some effects. Bioaccumulation of the test substance is not to be expected after continuous exposure. Phase I and II metabolism within liver cells is likely and excretion will presumably occur after renal passage via urine.

 

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 171.23832 g/mol. The substance is soluble in water (119 mg/L at 20 °C). The log Pow was determined to be 2.93. The test substance has a low vapour pressure of 0.21 hPa at 20 °C. The test substance is a multi-constituent substance consisting mostly of the two enantiomers (62.6 % (w/w) and 34.9 % (w/w)).

 

Absorption

Generally, oral absorption is favoured for molecular weights below 500 g/mol. The moderate water solubility of 119 mg/L enables the substance to dissolve in the gastrointestinal fluids. In combination with the low molecular weight of less than 200 g/mol the test substance can pass through aqueous pores or can be carried through the epithelial barrier by the bulk passage of water. The moderate log Pow value is also favourable for passive diffusion. Taken together, the physiochemical properties indicate that the test substance becomes bioavailable following the oral route. This assumption is confirmed by the results of the acute and repeated dose toxicity studies. These results did lead to classification of the substance for acute oral toxicity (category 4) as mortality was observed and the oral LD50 was established to be between 300 to 2000 mg/kg bw.

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 might be possible due to the moderate water solubility and the moderate log Pow value, enabling uptake directly across the respiratory tract epithelium by passive diffusion. This is also supported by the mortality observed after exposure of rats to the substance’s aerosol.

Dermal absorption will also take place, favoured by the water solubility and the log Pow value, and also by the size of the molecule. 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. The systemic absorption is also demonstrated by changes detected in the liver and especially within ovary after repeated oral application in rats.

Direct transport through aqueous pores is likely to be an entry route to the systemic circulation. After being absorbed into the body, the test substance is most likely distributed into the interior part of cells due to its slightly lipophilic properties (log Pow 2.93) and in turn the intracellular concentration may be higher than extracellular concentration particularly in adipose tissues. The proposed intake into cells is also supported by the observed changes in the cytoplasm of hepatocytes.

The test substance does not undergo significant pH-dependent hydrolysis. A study established that less than 10 % of the test substance was hydrolysed after 5 days at 50 °C and pH 4, 7 and 9. The logPow indicates no bioaccumulation potential. It is below 3 and the most likely uptake mechanism into cells is passive diffusion, therefore the test substance is not considered to be bioaccumulative. 

 

Metabolism

The genotoxicity studies indicated no remarkable differences in regard to genotoxicity and cytotoxicity in the presence or absence of metabolic activation systems. The changes observed in the liver, especially the foamy cytoplasm within the hepatocytes, after repeated oral exposure to the test substance indicate a possible metabolism or at least interaction mechanism of the test substance and liver cell proteins. Therefore it is likely that during Phase I metabolism cytochrome P450 oxidases introduce a reactive or polar group in the enantiomers. Those might be further processed into polar compounds during the metabolism in Phase II.

 

Excretion

The test substance will be excreted in its unhydrolised but most likely metabolised form as it was found to be stable against pH-dependent hydrolysis.

The likely excretion pathway of the test substance is via urine. As substances with a molecular weight below 300 g/mol are prone for this pathway and the substance’s molecular weight is 171.23832 g/mol. In addition histopathological changes seen in kidneys demonstrate a passage of the substance through this organ and thereby raise the likelihood of renal excretion.