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Reference
Endpoint:
basic toxicokinetics in vivo
Type of information:
other: Expert statement
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Expert statement
Objective of study:
toxicokinetics
Details on absorption:
Following oral administration, the likelihood of systemic absorption through the walls of the intestinal tract depends on several physico-chemical substance properties. In order to obtain a conclusive judgement of a substance’s potential to be able to reach the systemic circulation, important physico-chemical factors such as molecular weight, water solubility and the log Pow value need to be considered. Generally, the smaller the molecule the more easily it may be absorbed through the walls of the gastrointestinal tract. As the molecular weight of the test substance is 533 g/mol, an uptake of the compound into the systemic circulation via the gastro-intestinal (GI) tract is limited but possible (ECHA, 2014). The compound is lipophilic (log Pow = 4.66) and has a low water solubility. Furthermore, substance particles have a MMD of 82.06 µm. Therefore the absorption is limited by the extent to which such substances dissolve into the GI fluids and hence set in contact with the mucosal surface The absorption can however be enhanced via micellular solubilisation by bile salts. The substance is not readily biodegradable, indicating no microbial degradation. A bacterial degradation in the intestinal tract and uptake of the degradation products is unlikely.
No signs of systemic toxicity were observed in oral acute or repeated dose studies giving no indication for substance absorption.
Considering the low vapour pressure of the test substance and the resulting low volatility, exposure of the substance as vapour is very limited if handled at room temperature. Even if inhaled, only a small fraction of the substance will reach the thoracic or even the alveolar region of the respiratory tract, based on the MMD of 82.06 µm (ECHA, 2014). Furthermore, the poor water solubility of the compound would prevent that particles dissolve into the mucus lining of the respiratory tract. The log Pow of 4.66 does not favour absorption directly across the respiratory tract epithelium by passive diffusion, which is additionally limited by the MW of 533 g/mol. Therefore, direct absorption will be negligible. Instead of being absorbed, inhaled particles could be coughed or sneezed out of the respiratory tract and might be swallowed.
In general, substances with a molecular weight below 100 are favoured for dermal uptake. Above 500 the substances are considered to be too large to be readily absorbed through the skin. As the test substance has a molecular weight of 533 g/mol a dermal uptake is limited. Dermal penetration is further confined by the high lipophilicity of the compound (log Pow 4.66). As the chemical consists of a particulate at room temperature, it has to dissolve into the surface moisture of the skin before systemic uptake can begin. These pre-requisites will drastically limit the bioavailable amount of the chemical when placed in contact to the skin.
The assumption that low or no dermal absorption occurs is strengthened by the results achieved from the dermal toxicity testing. In an acute dermal toxicity study, the test substance did not cause any toxic effects. The LD50 was determined to be greater than 1000 mg/kg bw.
Topical application of the test substance onto the skin of rabbits also caused no sign of irritation as observed in a skin irritation study. No evidence of tissue damage was observed which in turn could have favoured direct absorption into the systemic circulation. A negative skin sensitization assay (EU Method B.6) in guinea pigs additionally supports the assumption of low dermal absorption.
Details on distribution in tissues:
Based on the physico-chemical properties and the results achieved from the comprehensive toxicity testing, it cannot be excluded that small amounts of the test substance become systemically available. Once adsorbed, the substance will most likely be transported within the body via the blood stream and gain access to the body tissues potentially bound to macromolecules due to its low water solubility. Due to the highly lipophilic properties, the substance might be enriched in body fats if no metabolism and formation of more polar metabolites takes place.
Details on excretion:
Based on the chemicals characteristics, excretion via urine can be regarded as negligible for the parent compound. The high molecular weight of over 300 g/mol and the low water solubility limit the urinary excretion drastically. Biliary excretion is assumed to be the major way of excretion of theoretically absorbed molecules. However, the intestinal excretion via feces of the unchanged/unmodified parent substance can be anticipated. According to the calculated BCF value, bioaccumulation is unlikely for the test substance.
Conclusions:
Based on its physico-chemical properties systemic available test item will be limited. When taken up by the oral route, the substance absorption through the walls of the gastrointestinal tract could take place by micellular solubilisation. The physico-chemical properties do not favour transdermal absorption. Considering the low vapour pressure and the particle size distribution no relevant amounts of the test substance are expected to be inhalable under normal use conditions. The substance is expected to be distributed and metabolised within the body if becoming systemically available. Based on the chemical characteristics biliary excretion via feces is assumed to be the major route. According to the calculated BCF value, bioaccumulation is unlikely for the test substance.
Executive summary:

Absorption

Following oral administration, the likelihood of systemic absorption through the walls of the intestinal tract depends on several physico-chemical substance properties. In order to obtain a conclusive judgment of a substance’s potential to be able to reach the systemic circulation, important physicochemical factors such as molecular weight, water solubility and the log Pow value need to be considered. Generally, the smaller the molecule the more easily it may be absorbed through the walls of the gastrointestinal tract. As the molecular weight of the test substance is 533 g/mol, an uptake of the compound into the systemic circulation via the gastro-intestinal (GI) tract is limited but possible (ECHA, 2014). The compound is lipophilic (log Pow = 4.66) and has a low water solubility. Furthermore, substance particles have a MMD of 82.06 µm. Therefore the absorption is limited by the extent to which such substances dissolve into the GI fluids and hence set in contact with the mucosal surface The absorption can however be enhanced via micellular solubilisation by bile salts. The substance is not readily biodegradable, indicating no microbial degradation. A bacterial degradation in the intestinal tract and uptake of the degradation products is unlikely.

No signs of systemic toxicity were observed in oral acute or repeated dose studies giving no indication for substance absorption.

Considering the low vapour pressure of the test substance and the resulting low volatility, exposure of the substance as vapour is very limited if handled at room temperature. Even if inhaled, only a small fraction of the substance will reach the thoracic or even the alveolar region of the respiratory tract, based on the MMD of 82.06 µm (ECHA, 2014). Furthermore, the poor water solubility of the compound would prevent that particles dissolve into the mucus lining of the respiratory tract. The log Pow of 4.66 does not favour absorption directly across the respiratory tract epithelium by passive diffusion, which is additionally limited by the MW of 533 g/mol. Therefore, direct absorption will be negligible. Instead of being absorbed, inhaled particles could be coughed or sneezed out of the respiratory tract and might be swallowed.

In general, substances with a molecular weight below 100 are favoured for dermal uptake. Above 500 the substances are considered to be too large to be readily absorbed through the skin. As the test substance has a molecular weight of 533 g/mol a dermal uptake is limited. Dermal penetration is further confined by the high lipophilicity of the compound (log Pow 4.66). As the chemical consists of a particulate at room temperature, it has to dissolve into the surface moisture of the skin before systemic uptake can begin. These pre-requisites will drastically limit the bioavailable amount of the chemical when placed in contact to the skin.

The assumption that low or no dermal absorption occurs is strengthened by the results achieved from the dermal toxicity testing. In an acute dermal toxicity study, the test substance did not cause any toxic effects. The LD50 was determined to be greater than 10000 mg/kg bw.

Topical application of the test substance onto the skin of rabbits also caused no sign of irritation as observed in a skin irritation study. No evidence of tissue damage was observed which in turn could have favoured direct absorption into the systemic circulation. A negative skin sensitization assay (EU Method B.6) in guinea pigs additionally supports the assumption of low dermal absorption.

Distribution

Based on the physico-chemical properties and the results achieved from the comprehensive toxicity testing, it cannot be excluded that small amounts of the test substance become systemically available. Once adsorbed, the substance will most likely be transported within the body via the blood stream and gain access to the body tissues potentially bound to macromolecules due to its low water solubility. Due to the highly lipophilic properties, the substance might be enriched in body fats if no metabolism and formation of more polar metabolites takes place.

Metabolism

Absorbed amounts of the test substance may be transformed within the body by Phase I enzymes while undergoing functionalisation reactions aiming to further increase the hydrophilicity. Furthermore, Phase II conjugation reactions may covalently link an endogenous substrate to the absorbed chemical, the respective Phase I metabolites or to the OH groups of the parent molecule in order to ultimately facilitate excretion. The chemical is most likely not enzymatically activated (toxified) during metabolism. The assumption is supported by the negative cytotoxicity results of two chromosome aberration assays. The cytotoxicity of the test substance was not higher as compared to the metabolically activated test substance.

Excretion

Based on the chemicals characteristics, excretion via urine can be regarded as negligible for the parent compound. The high molecular weight of over 300 g/mol and the low water solubility limit the urinary excretion drastically. Biliary excretion is assumed to be the major way of excretion of theoretically absorbed molecules. However, the intestinal excretion via feces of the unchanged/unmodified parent substance can be anticipated. According to the calculated BCF value, bioaccumulation is unlikely for the test substance.

Description of key information

Based on its physico-chemical properties systemic availability 2'-anilino-6'-(dibutylamino)-3'-methyl-3H-spiro[2-benzofuran-1,9'-xanthen]-3-one will be limited. When taken up by the oral route, the substance absorption through the walls of the gastrointestinal tract could take place by micellular solubilisation. The physico-chemical properties do not favour transdermal absorption. Considering the low vapour pressure and the particle size distribution no relevant amounts of the test substance are expected to be inhalable under normal use conditions. The substance is expected to be distributed and metabolised within the body if becoming systemically available. Based on the chemical characteristics biliary excretion via feces is assumed to be the major route. According to the calculated BCF value, bioaccumulation is unlikely for the test substance.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Toxicokinetic analysis of 2'-anilino-6'-(dibutylamino)-3'-methyl-3H-spiro[2-benzofuran-1,9'-xanthen]-3-one

The test substance is a white powder at room temperature with a molecular weight of 533 g/mol. Particles of the substance have a mass median diameter (MMD) of 82.06 µm, covering a range from 0.73 µm to 413.6 µm (1.13 % were < 2.0 µm ; 16.79 % of the particles were > 200 µm). The water solubility is very low (0.021 mg/L at 20 °C). In contrast, the solubility in standard fat is good (139.2 mg/g at 37 °C). A log Pow of above 4.66 was determined and a BCF value of 552.0 L/kg was calculated. The test substance has a very low vapour pressure of 2.6E-4 Pa at 25 °C.

Absorption

Following oral administration, the likelihood of systemic absorption through the walls of the intestinal tract depends on several physico-chemical substance properties. In order to obtain a conclusive judgment of a substance’s potential to be able to reach the systemic circulation, important physicochemical factors such as molecular weight, water solubility and the log Pow value need to be considered. Generally, the smaller the molecule the more easily it may be absorbed through the walls of the gastrointestinal tract. As the molecular weight of the test substance is 533 g/mol, an uptake of the compound into the systemic circulation via the gastro-intestinal (GI) tract is limited but possible (ECHA, 2014). The compound is lipophilic (log Pow = 4.66) and has a low water solubility. Furthermore, substance particles have a MMD of 82.06 µm. Therefore the absorption is limited by the extent to which such substances dissolve into the GI fluids and hence set in contact with the mucosal surface The absorption can however be enhanced via micellular solubilisation by bile salts. The substance is not readily biodegradable, indicating no microbial degradation. A bacterial degradation in the intestinal tract and uptake of the degradation products is unlikely.

No signs of systemic toxicity were observed in oral acute or repeated dose studies giving no indication for substance absorption.

Considering the low vapour pressure of the test substance and the resulting low volatility, exposure of the substance as vapour is very limited if handled at room temperature. Even if inhaled, only a small fraction of the substance will reach the thoracic or even the alveolar region of the respiratory tract, based on the MMD of 82.06 µm (ECHA, 2014). Furthermore, the poor water solubility of the compound would prevent that particles dissolve into the mucus lining of the respiratory tract. The log Pow of 4.66 does not favour absorption directly across the respiratory tract epithelium by passive diffusion, which is additionally limited by the MW of 533 g/mol. Therefore, direct absorption will be negligible. Instead of being absorbed, inhaled particles could be coughed or sneezed out of the respiratory tract and might be swallowed.

In general, substances with a molecular weight below 100 are favoured for dermal uptake. Above 500 the substances are considered to be too large to be readily absorbed through the skin. As the test substance has a molecular weight of 533 g/mol a dermal uptake is limited. Dermal penetration is further confined by the high lipophilicity of the compound (log Pow 4.66). As the chemical consists of a particulate at room temperature, it has to dissolve into the surface moisture of the skin before systemic uptake can begin. These pre-requisites will drastically limit the bioavailable amount of the chemical when placed in contact to the skin.

The assumption that low or no dermal absorption occurs is strengthened by the results achieved from the dermal toxicity testing. In an acute dermal toxicity study, the test substance did not cause any toxic effects. The LD50 was determined to be greater than 2000 mg/kg bw.

Topical application of the test substance onto the skin of rabbits also caused no sign of irritation as observed in a skin irritation study. No evidence of tissue damage was observed which in turn could have favoured direct absorption into the systemic circulation. A negative skin sensitization assay (EU Method B.6) in guinea pigs additionally supports the assumption of low dermal absorption.

Distribution

Based on the physico-chemical properties and the results achieved from the comprehensive toxicity testing, it cannot be excluded that small amounts of the test substance become systemically available. Once adsorbed, the substance will most likely be transported within the body via the blood stream and gain access to the body tissues potentially bound to macromolecules due to its low water solubility. Due to the highly lipophilic properties, the substance might be enriched in body fats if no metabolism and formation of more polar metabolites takes place.

Metabolism

Absorbed amounts of the test substance may be transformed within the body by Phase I enzymes while undergoing functionalisation reactions aiming to further increase the hydrophilicity. Furthermore, Phase II conjugation reactions may covalently link an endogenous substrate to the absorbed chemical, the respective Phase I metabolites or to the OH groups of the parent molecule in order to ultimately facilitate excretion. The chemical is most likely not enzymatically activated (toxified) during metabolism. The assumption is supported by the negative cytotoxicity results of two chromosome aberration assays. The cytotoxicity of the test substance was not higher as compared to the metabolically activated test substance.

Excretion

Based on the chemicals characteristics, excretion via urine can be regarded as negligible for the parent compound. The high molecular weight of over 300 g/mol and the low water solubility limit the urinary excretion drastically. Biliary excretion is assumed to be the major way of excretion of theoretically absorbed molecules. However, the intestinal excretion via feces of the unchanged/unmodified parent substance can be anticipated. According to the calculated BCF value, bioaccumulation is unlikely for the test substance.

Summary

Based on its physicochemical properties systemic availability 2'-anilino-6'-(dibutylamino)-3'-methyl-3H-spiro[2-benzofuran-1,9'-xanthen]-3-one will be limited. When taken up by the oral route, the substance absorption through the walls of the gastrointestinal tract could take place by micellular solubilisation. The physicochemical properties do not favour transdermal absorption. Considering the low vapour pressure and the particle size distribution no relevant amounts of the test substance are expected to be inhalable under normal use conditions. The substance is expected to be distributed and metabolised within the body if becoming systemically available. Based on the chemical characteristics biliary excretion via feces is assumed to be the major route. According to the calculated BCF value, bioaccumulation is unlikely for the test substance.

 

References

ECHA (2014) Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.