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Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics in vitro / ex vivo
Type of information:
other: expert statement
Adequacy of study:
key study
Study period:
2016
Reliability:
1 (reliable without restriction)
Details on absorption:
Following oral administration, the likelihood of systemic absorption through the walls of the intestinal tract depends on several physicochemical substance properties. In order to obtain a conclusive judgement 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 1,1’-(1,1,2,2-tetramethylethylene)dibenzene is 238.7 g/mol, an uptake of the compound into the systemic circulation via the gastro-intestinal (GI) tract is likely (ECHA, 2008). The compound is highly lipophilic (log Pow = 6.68) and has a low water solubility. 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. An uptake of nanosized particles by pinocytosis can be neglected because the measured particle size distribution indicates that 1,1’-(1,1,2,2-tetramethylethylene)dibenzene does not contain particles in the nanosize region.
The possible gastrointestinal absorption is further strengthened by the results achieved in the oral toxicity studies with rats. Although no effects were seen in the acute oral toxicity study the repeated dose tests showed some toxic effects after oral administration of the substance (the NOAEL in the 90-day repeated dose toxicity study was 10 mg/kg bw/day based on reduced body weight development at 30 mg/kg bw/d which was not reversible in female animals). In the prenatal developmental toxicity study (OECD 414) the NOAEL was also found to be 10 mg/kg bw/day based on effects found at 30 mg/kg bw/day such as reduced food consumption and body weights in both dams and offspring.
 Considering the low vapour pressure of 1,1’-(1,1,2,2-tetramethylethylene)dibenzene and the resulting low volatility, exposure of the substance as vapour is very limited if handled at room temperature. Based on the particle size distribution, it is unlikely that dust particles are inhaled or reach the lower lung region in order to become systemically available. Even if inhaled, the poor water solubility of the compound would prevent that particles dissolve into the mucus lining of the respiratory tract. Therefore, direct absorption will be negligible. Instead of being absorbed, inhaled particles could be coughed or sneezed out of respiratory tract and 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 1,1’-(1,1,2,2-tetramethylethylene)dibenzene has a molecular weight of 238 g/mol a dermal uptake can be expected. Due to a high lipophilicity of the test item, it will not easily pass the skin layers and therefore shows a rather limited skin penetration. 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, 1,1’-(1,1,2,2-tetramethylethylene)dibenzene did not cause any toxic effects. The LD50 was determined to be greater than the limit dose (2000 mg/kg bw).
Topical application of 1,1’-(1,1,2,2-tetramethylethylene)dibenzene 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.
Considering the positive immunological response obtained in the LLNA assay, at least small amounts of 1,1’-(1,1,2,2-tetramethylethylene)dibenzene seem to become systemically available.
Based on the physical-chemical properties and the results of the testing with dermal application, 1,1’-(1,1,2,2-tetramethylethylene)dibenzene is considered to be systemically available to a small degree by absorption or penetration through skin.
Details on distribution in tissues:
Based on the physicochemical properties and the results achieved from the comprehensive toxicity testing, small amounts of 1,1’-(1,1,2,2-tetramethylethylene)dibenzene can 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:
After oral intake, parts of the substance will be excreted via the faeces in its unchanged form. After absorption, the parent compound as well as its metabolites are likely to be excreted via the urine as its molecular weights are well below 500 Da or via the faeces, if intrinsic Phase II conjugation takes place. According to the calculated BCF value, bioaccumulation cannot be totally excluded for 1,1’-(1,1,2,2-tetramethylethylene)dibenzene.
Details on metabolites:
Absorbed amounts of 1,1’-(1,1,2,2-tetramethylethylene)dibenzene 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 chemicals or the respective Phase I metabolites in order to ultimately facilitate excretion. Potential reactions are e.g. hydroxylation of the phenyl rings forming phenols and to a minor extent hydroxylation of the methyl groups forming the respective alcohols can be expected.
According to the published data a structural analogue (Diphenylmethane) is mainly excreted unchanged via the urine and to a lesser extent via feces. Present metabolites in the urine were 2- and 4-hydroxydiphenylmethane showing Phase I functionalisation as indicated above. A similar metabolism can also be assumed for 1,1’-(1,1,2,2-tetramethylethylene)dibenzene.
Conclusions:
Absorption of the test substance after oral administration is very low due to the lipophilic character of the reference item. Adsorption via dermal uptake or inhalation is negligible due to its physico-chemical properties. The substance is distributed via the blood stream and gains access to the body tissues potentially bound to macromolecules due to its low water solubility. Potential metabolism reactions, that can be expected, are e.g. hydroxylation of the phenyl rings forming phenols and to a minor extent hydroxylation of the methyl groups forming the respective alcohols. After absorption, the parent compound as well as its metabolites are likely to be excreted via the urine as its molecular weights are well below 500 Da or via the faeces, if intrinsic Phase II conjugation takes place. According to the calculated BCF value, bioaccumulation cannot be totally excluded for 1,1’-(1,1,2,2-tetramethylethylene)dibenzene.
Executive summary:

Absorption:

Following oral administration, the likelihood of systemic absorption through the walls of the intestinal tract depends on several physicochemical substance properties. In order to obtain a conclusive judgement 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 1,1’-(1,1,2,2-tetramethylethylene)dibenzene is 238.7 g/mol, an uptake of the compound into the systemic circulation via the gastro-intestinal (GI) tract is likely (ECHA, 2008). The compound is highly lipophilic (log Pow = 6.68) and has a low water solubility. 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. An uptake of nanosized particles by pinocytosis can be neglected because the measured particle size distribution indicates that 1,1’-(1,1,2,2-tetramethylethylene)dibenzene does not contain particles in the nanosize region.

The possible gastrointestinal absorption is further strengthened by the results achieved in the oral toxicity studies with rats. Although no effects were seen in the acute oral toxicity study the repeated dose tests showed some toxic effects after oral administration of the substance (the NOAEL in the 90-day repeated dose toxicity study was 10 mg/kg bw/day based on reduced body weight development at 30 mg/kg bw/d which was not reversible in female animals). In the prenatal developmental toxicity study (OECD 414) the NOAEL was also found to be 10 mg/kg bw/day based on effects found at 30 mg/kg bw/day such as reduced food consumption and body weights in both dams and offspring.

 Considering the low vapour pressure of 1,1’-(1,1,2,2-tetramethylethylene)dibenzene and the resulting low volatility, exposure of the substance as vapour is very limited if handled at room temperature. Based on the particle size distribution, it is unlikely that dust particles are inhaled or reach the lower lung region in order to become systemically available. Even if inhaled, the poor water solubility of the compound would prevent that particles dissolve into the mucus lining of the respiratory tract. Therefore, direct absorption will be negligible. Instead of being absorbed, inhaled particles could be coughed or sneezed out of respiratory tract and 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 1,1’-(1,1,2,2-tetramethylethylene)dibenzene has a molecular weight of 238 g/mol a dermal uptake can be expected. Due to a high lipophilicity of the test item, it will not easily pass the skin layers and therefore shows a rather limited skin penetration. 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, 1,1’-(1,1,2,2-tetramethylethylene)dibenzene did not cause any toxic effects. The LD50 was determined to be greater than the limit dose (2000 mg/kg bw).

Topical application of 1,1’-(1,1,2,2-tetramethylethylene)dibenzene 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.

Considering the positive immunological response obtained in the LLNA assay, at least small amounts of 1,1’-(1,1,2,2-tetramethylethylene)dibenzene seem to become systemically available.

Based on the physical-chemical properties and the results of the testing with dermal application, 1,1’-(1,1,2,2-tetramethylethylene)dibenzene is considered to be systemically available to a small degree by absorption or penetration through skin.

 

Distribution:

Based on the physicochemical properties and the results achieved from the comprehensive toxicity testing, small amounts of 1,1’-(1,1,2,2-tetramethylethylene)dibenzene can 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 1,1’-(1,1,2,2-tetramethylethylene)dibenzene 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 chemicals or the respective Phase I metabolites in order to ultimately facilitate excretion. Potential reactions are e.g. hydroxylation of the phenyl rings forming phenols and to a minor extent hydroxylation of the methyl groups forming the respective alcohols can be expected.

According to the published data a structural analogue (Diphenylmethane) is mainly excreted unchanged via the urine and to a lesser extent via feces. Present metabolites in the urine were 2- and 4-hydroxydiphenylmethane showing Phase I functionalisation as indicated above. A similar metabolism can also be assumed for 1,1’-(1,1,2,2-tetramethylethylene)dibenzene.

 

Excretion:

After oral intake, parts of the substance will be excreted via the faeces in its unchanged form. After absorption, the parent compound as well as its metabolites are likely to be excreted via the urine as its molecular weights are well below 500 Da or via the faeces, if intrinsic Phase II conjugation takes place. According to the calculated BCF value, bioaccumulation cannot be totally excluded for 1,1’-(1,1,2,2-tetramethylethylene)dibenzene.

Description of key information

Absorption of the test substance after oral administration is very low due to the lipophilic character of the reference item. Adsorption via dermal uptake or inhalation is negligible due to its physico-chemical properties. The substance is distributed via the blood stream and gains access to the body tissues potentially bound to macromolecules due to its low water solubility. Potential metabolism reactions, that can be expected, are e.g. hydroxylation of the phenyl rings forming phenols and to a minor extent hydroxylation of the methyl groups forming the respective alcohols. After absorption, the parent compound as well as its metabolites are likely to be excreted via the urine as its molecular weights are well below 500 Da or via the faeces, if intrinsic Phase II conjugation takes place. According to the calculated BCF value, bioaccumulation cannot be totally excluded for 1,1’-(1,1,2,2-tetramethylethylene)dibenzene.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information

Absorption:

Following oral administration, the likelihood of systemic absorption through the walls of the intestinal tract depends on several physicochemical substance properties. In order to obtain a conclusive judgement 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 1,1’-(1,1,2,2-tetramethylethylene)dibenzene is 238.7 g/mol, an uptake of the compound into the systemic circulation via the gastro-intestinal (GI) tract is likely (ECHA, 2008). The compound is highly lipophilic (log Pow = 6.68) and has a low water solubility. 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. An uptake of nanosized particles by pinocytosis can be neglected because the measured particle size distribution indicates that 1,1’-(1,1,2,2-tetramethylethylene)dibenzene does not contain particles in the nanosize region.

The possible gastrointestinal absorption is further strengthened by the results achieved in the oral toxicity studies with rats. Although no effects were seen in the acute oral toxicity study the repeated dose tests showed some toxic effects after oral administration of the substance (the NOAEL in the 90-day repeated dose toxicity study was 10 mg/kg bw/day based on reduced body weight development at 30 mg/kg bw/d which was not reversible in female animals). In the prenatal developmental toxicity study (OECD 414) the NOAEL was also found to be 10 mg/kg bw/day based on effects found at 30 mg/kg bw/day such as reduced food consumption and body weights in both dams and offspring.

 Considering the low vapour pressure of 1,1’-(1,1,2,2-tetramethylethylene)dibenzene and the resulting low volatility, exposure of the substance as vapour is very limited if handled at room temperature. Based on the particle size distribution, it is unlikely that dust particles are inhaled or reach the lower lung region in order to become systemically available. Even if inhaled, the poor water solubility of the compound would prevent that particles dissolve into the mucus lining of the respiratory tract. Therefore, direct absorption will be negligible. Instead of being absorbed, inhaled particles could be coughed or sneezed out of respiratory tract and 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 1,1’-(1,1,2,2-tetramethylethylene)dibenzene has a molecular weight of 238 g/mol a dermal uptake can be expected. Due to a high lipophilicity of the test item, it will not easily pass the skin layers and therefore shows a rather limited skin penetration. 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, 1,1’-(1,1,2,2-tetramethylethylene)dibenzene did not cause any toxic effects. The LD50 was determined to be greater than the limit dose (2000 mg/kg bw).

Topical application of 1,1’-(1,1,2,2-tetramethylethylene)dibenzene 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.

Considering the positive immunological response obtained in the LLNA assay, at least small amounts of 1,1’-(1,1,2,2-tetramethylethylene)dibenzene seem to become systemically available.

Based on the physical-chemical properties and the results of the testing with dermal application, 1,1’-(1,1,2,2-tetramethylethylene)dibenzene is considered to be systemically available to a small degree by absorption or penetration through skin.

 

Distribution:

Based on the physicochemical properties and the results achieved from the comprehensive toxicity testing, small amounts of 1,1’-(1,1,2,2-tetramethylethylene)dibenzene can 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 1,1’-(1,1,2,2-tetramethylethylene)dibenzene 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 chemicals or the respective Phase I metabolites in order to ultimately facilitate excretion. Potential reactions are e.g. hydroxylation of the phenyl rings forming phenols and to a minor extent hydroxylation of the methyl groups forming the respective alcohols can be expected.

According to the published data a structural analogue (Diphenylmethane) is mainly excreted unchanged via the urine and to a lesser extent via feces. Present metabolites in the urine were 2- and 4-hydroxydiphenylmethane showing Phase I functionalisation as indicated above. A similar metabolism can also be assumed for 1,1’-(1,1,2,2-tetramethylethylene)dibenzene.

 

Excretion:

After oral intake, parts of the substance will be excreted via the faeces in its unchanged form. After absorption, the parent compound as well as its metabolites are likely to be excreted via the urine as its molecular weights are well below 500 Da or via the faeces, if intrinsic Phase II conjugation takes place. According to the calculated BCF value, bioaccumulation cannot be totally excluded for 1,1’-(1,1,2,2-tetramethylethylene)dibenzene.