Propionamide

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 absorption:

Absorption is a property of a substance to diffuse across biological membranes. Generally, oral absorption is favored for molecular weights below 500 g/mol and log Pow values between -1 and 4. The good water solubility of 720 g/L enables the substance to dissolve in the gastrointestinal fluids. In combination with the low molecular weight of less than 200 g/mol the substance can pass through aqueous pores or can be carried through the epithelial barrier by the bulk passage of water. The log Pow value shows that passive diffusion is also possible. Taken together, the physiochemical properties indicate that the substance becomes bioavailable following the oral route. This assumption is neither confirmed nor rebutted by the results of the acute toxicity study conducted with the test substance, as no mortality or clinical signs have been reported after acute oral administration to rats. However, the results of repeated oral exposure show that the substance becomes systemically available by this route.

Due to the melting point of the substance above 70 °C, no availability as a vapour under standard environmental conditions is expected. Still the vapour pressure was determined and is low. It is 1.06 Pa at 25 °C. As the substance is a solid formation and inhalation of dusts is unlikely but might occur during handling. Generally particles with an aerodynamic diameter below 100 μm have the potential to be inspired, below 50 μm may reach the thoracic region and those below 15 μm can pass into the alveolar region of the respiratory tract. For the test substance a D50 value of 1131 µm and a D10 of 386 µm were determined. As demonstrated by the distribution of the particle size no inhalable amount of the test substance is expected and the substance’s particles are not expected to possess the ability to reach the alveolar region. In the unlikely event of substance particles reaching the thoracic region adsorption directly across the respiratory tract epithelium is possible based on the moderate logPow and good water solubility.

As a solid, the substance is not readily taken up by the skin. However, once moistened on the skin surface, absorption is possible, due to the high water solubility determined for the test substance. The molecular weight (73 g/mol) of the substance also favours dermal uptake. Considering the moderate log Pow of -0.7 of the test substance, poor lipophilicity will limit penetration into the stratum corneum, resulting in low dermal absorption.

Details on distribution in tissues:

As mentioned above, the physicochemical properties of the test substance favour systemic absorption following oral, inhalative and dermal uptake to a certain extent.

Direct transport through aqueous pores is likely to be an entry route to the systemic circulation. After being absorbed into the body, the distribution into the interior part of cells is most likely limited due to the slightly hydrophilic properties (log Pow between -0.7) and in turn the extracellular concentration is expected to be higher than intracellular concentration.

The test substance does not have a bioaccumulative potential. The log Pow of the test substance indicates no bioaccumulation potential, as it is well below 3.

Details on excretion:

In general, urinary excretion in favored by low molecular weight (below 300 g/mol in the rat) and good water solubility. Therefore, the test substance is expected to be excreted mostly via urine.

Details on metabolites:

The genotoxicity studies with the test substance indicate no remarkable differences in regard to genotoxicity and cytotoxicity in the presence or absence of metabolic activation systems. Thus, no metabolic activation is expected. Generally 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 substance. The resulting compounds might be further processed into polar compounds during the metabolism in Phase II. The changes observed in the liver and on liver-related blood parameters 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. Thereby pointing towards metabolisation of the substance by Phase I and II metabolism within liver cells.

Conclusions:

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

Executive summary:

No experimental data on absorption, distribution, metabolism and excretion are available for the substance. Based on physicochemical characteristics, particularly water solubility, molecular weight and octanol-water partition coefficient, systemic absorption following oral, inhalative and dermal uptake is favoured to a certain extent. Bioaccumulation of the test substance is not considered critical, as log Pow of the test substance indicates no bioaccumulation potential. Phase I and II metabolism within liver cells with involvement of cytochrome P450 is likely and excretion will presumably occur after renal passage via urine.

Description of key information

No experimental data on absorption, distribution, metabolism and excretion are available for the substance. Based on physicochemical characteristics, particularly water solubility, molecular weight and octanol-water partition coefficient, systemic absorption following oral, inhalative and dermal uptake is favoured to a certain extent. Bioaccumulation of the test substance is not considered critical, as log Pow of the test substance indicates no bioaccumulation potential. Phase I and II metabolism within liver cells with involvement of cytochrome P450 is likely and excretion will presumably occur after renal passage via urine (reference 7.1.1-1).

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Toxicokinetic assessment

The substance is a solid with a molecular weight of 73 g/mol. The test item has good water solubility of 720 g/L at 20 °C. The log P_ow is -0.7 and the vapour pressure is 1.06 Pa at 25 °C. The substance melts at 80 - 82 °C and starts boiling at 222 °C. The median particle size (D50) is 1131 µm.

 

Absorption

Oral

Absorption is a property of a substance to diffuse across biological membranes. Generally, oral absorption is favored for molecular weights below 500 g/mol and log P_ow values between -1 and 4. The good water solubility of 720 g/L enables the substance to dissolve in the gastrointestinal fluids. In combination with the low molecular weight of less than 200 g/mol the substance can pass through aqueous pores or can be carried through the epithelial barrier by the bulk passage of water. The log Pow value shows that passive diffusion is also possible. Taken together, the physiochemical properties indicate that the test substance becomes bioavailable following the oral route. This assumption is neither confirmed nor rebutted by the results of the acute toxicity study conducted with the test substance, as no mortality or clinical signs have been reported after acute oral administration to rats. However, the results of repeated oral exposure show that the substance becomes systemically available by this route.

 

Inhalative

Due to the melting point of the substance above 70 °C, no availability as a vapour under standard environmental conditions is expected. Still the vapour pressure was determined and is low. It is 1.06 Pa at 25 °C. As the substance is a solid formation and inhalation of dusts is unlikely but might occur during handling. Generally particles with an aerodynamic diameter below 100 μm have the potential to be inspired, below 50 μm may reach the thoracic region and those below 15 μm can pass into the alveolar region of the respiratory tract. For the test substance a D50 value of 1131 µm and a D10 of 386 µm were determined. As demonstrated by the distribution of the particle size no inhalable amount of the test substance is expected and the substance’s particles are not expected to possess the ability to reach the alveolar region. In the unlikely event of substance particles reaching the thoracic region adsorption directly across the respiratory tract epithelium is possible based on the moderate logPow and good water solubility.

 

Dermal

As a solid, the substance is not readily taken up by the skin. However, once moistened on the skin surface, absorption is possible, due to the high water solubility determined for the test substance. The molecular weight (73 g/mol) of the substance also favours dermal uptake. Considering the moderate log Pow of -0.7 of the test substance, poor lipophilicity will limit penetration into the stratum corneum, resulting in low dermal absorption.

 

Distribution

As mentioned above, the physicochemical properties of the test substance favour systemic absorption following oral, inhalative and dermal uptake to a certain extent.

 

Direct transport through aqueous pores is likely to be an entry route to the systemic circulation. After being absorbed into the body, the distribution into the interior part of cells is most likely limited due to the slightly hydrophilic properties (log Pow between -0.7) and in turn the extracellular concentration is expected to be higher than intracellular concentration.

 

The test substance does not have a bioaccumulative potential. The log Pow of the test substance indicates no bioaccumulation potential, as it is well below 3. 

 

Metabolism

The genotoxicity studies with the test substance indicate no remarkable differences in regard to genotoxicity and cytotoxicity in the presence or absence of metabolic activation systems. Thus, no metabolic activation is expected. Generally 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 substance. The resulting compounds might be further processed into polar compounds during the metabolism in Phase II. The changes observed in the liver and on liver-related blood parameters 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. Thereby pointing towards metabolisation of the substance by Phase I and II metabolism within liver cells.

 

Excretion

In general, urinary excretion in favored by low molecular weight (below 300 g/mol in the rat) and good water solubility. Therefore, the test substance is expected to be excreted mostly via urine.