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Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics, other
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
Objective of study:
absorption
distribution
excretion
metabolism
Details on species / strain selection:
not applicable
Details on test animals and environmental conditions:
not applicable
Details on exposure:
not applicable
Duration and frequency of treatment / exposure:
not applicable
No. of animals per sex per dose:
not applicable
Positive control:
not applicable
Details on study design:
not applicable
Details on dosing and sampling:
not applicable
Statistics:
not applicable
Details on absorption:
Bioavailability via oral route is strongly linked to physico-chemical properties of the substance. Generally, oral absorption is favoured for molecular weights below 500 g/mol. Furthermore, a high water solubility of more than 100 mg/L enables the substance to readily dissolve in the gastrointestinal fluids, allowing direct uptake into the systemic circulation through aqueous pores or via carriage of the molecules across membranes with the bulk passage of water. Blue Sema consists of two fractions with a number-average molecular weight of 301 293 g/mol (major fraction) and 1762 g/mol (minor fraction). The weight-average molecular weight of the two fractions was determined to be 34 711 643 g/mol (major fraction) and 4104 g/mol (minor fraction). The values represent the mean of two GPC determinations measured at 270 nm. Comparable results were obtained at 550 nm, the characteristic absorbtion maximum of the dye. Less than 1% of the substance shows a molecular weight < 570 g/mol. The water solubility was determined to be 0.57 mg/L, therefore not favouring absorption. Taken together, the physiochemical properties indicate that Blue Sema is not bioavailable following the oral route. This assumption is confirmed by the results of the acute oral toxicity study (OECD 423) and the repeated dose toxicity study (DRF, OECD 422). No substance related effects or mortality were observed up to the highest test concentration of 2000 mg/kg bw (OECD 423) or 1000 mg/kg bw/d (DRF, OECD 422). In both studies no coloration of internal organs occurred.
The volatility indicates whether a substance may be available for inhalation as a vapour. Highly volatile substances are those with a boiling point below 50 °C and low volatile substances those with a boiling point above 150 °C. Furthermore, volatility decreases with increased molecular weight. The boiling point of the test substance is> 300 °C and the number- as well as weight-average molecular weight of the test substance fractions was determined to be > 1 700 g/mol. Based on these data a low vapour pressure is expected and absorption of Blue Sema via inhalation route is not expected to occur.
Dermal uptake is favoured for substances with a molecular weight < 100 g/mol. The average molecular weight of Blue Sema is > 1 700 g/mol. In addition, the substances must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Absorption is anticipated to be moderate to high if water solubility is between 100 and 10000 mg/L. Blue Sema has a water solubility of 0.57 mg/L, therefore not supporting dermal absorption.
Details on distribution in tissues:
In general, the smaller the molecule, the wider the distribution. Blue Sema has a high average molecular weight of > 1 700 g/mol. Therefore, no wide distribution is expected, in case the substance would become systemically available. Distribution is assumed to be restricted to the aqueous compartment and no bioaccumulation is expected due to the negative log Pow of the substance.
Details on excretion:
Blue Sema is most likely excreted via faeces due to its high molecular weight (average > 1 000 g/mol) and its poor water solubility (0.57 mg/L).
Details on metabolites:
The test substance is not expected to be bioavailable following oral, inhalative or dermal exposure. In case minor amounts become systemically bioavailable, a prediction of the metabolism is not possible as the test item is a UVCB substance with unknown structure. Based on the results of the Ames test, HPRT test and Chromosome Aberration test it can be assumed that the test substance is not enzymatically activated (toxified) during the metabolism as the metabolic activated test substance showed no higher toxicity compared to the test substance without metabolic activation. Furthermore, available data indicate that the test substance is not susceptible to hydrolysis. Therefore an unaltered passage of the parent substance through the stomach can be presumed.
Conclusions:
Due to the high molecular weight and low water solubility of the test substance no absorption is expected by the oral, inhalative or dermal route.
Executive summary:

Based on physicochemical characteristics (very high molecular weight, low water solubility) no absorption by the oral, inhalative or dermal route as well as no wide distribution of the test substance is expected. This assumption is further supported by the results of the oral acute toxicity study and the repeated dose toxicity study, revealing no substance related effects up to the highest tested concentrations. In case minor amounts become systemically bioavailable, enzymatic activation (toxification) yielding in cytotoxic metabolites is not expected to occur as metabolic activation did not increase the toxicity of the test substance in an Ames test, HPRT test and Chromosome Aberration test. Due to the size of the molecule and the poor water solubility excretion via feces is assumed.

Description of key information

Based on physicochemical characteristics (very high molecular weight, low water solubility) no absorption by the oral, inhalative or dermal route as well as no wide distribution of the test substance is expected. This assumption is further supported by the results of the oral acute toxicity study and the repeated dose toxicity study, revealing no substance related effects up to the highest tested concentrations. In case minor amounts become systemically bioavailable, enzymatic activation (toxification) yielding in cytotoxic metabolites is not expected to occur as metabolic activation did not increase the toxicity of the test substance in an Ames test, HPRT test and Chromosome Aberration test. Due to the size of the molecule and the poor water solubility excretion via feces is assumed.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Absorption:

Bioavailability via oral route is strongly linked to physico-chemical properties of the substance. Generally, oral absorption is favoured for molecular weights below 500 g/mol. Furthermore, a high water solubility of more than 100 mg/L enables the substance to readily dissolve in the gastrointestinal fluids, allowing direct uptake into the systemic circulation through aqueous pores or via carriage of the molecules across membranes with the bulk passage of water. Blue Sema consists of two fractions with a number-average molecular weight of 301 293 g/mol (major fraction) and 1762 g/mol (minor fraction). The weight-average molecular weight of the two fractions was determined to be 34 711 643 g/mol (major fraction) and 4104 g/mol (minor fraction). The values represent the mean of two GPC determinations measured at 270 nm. Comparable results were obtained at 550 nm, the characteristic absorbtion maximum of the dye. Less than 1% of the substance shows a molecular weight < 570 g/mol. The water solubility was determined to be 0.57 mg/L, therefore not favouring absorption. Taken together, the physiochemical properties indicate that Blue Sema is not bioavailable following the oral route. This assumption is confirmed by the results of the acute oral toxicity study (OECD 423) and the repeated dose toxicity study (DRF and OECD 422). No substance related effects or mortality were observed up to the highest test concentration of 2000 mg/kg bw (OECD 423) or 1000 mg/kg bw/d (DRF, OECD 422). In both studies no coloration of internal organs occurred.

The volatility indicates whether a substance may be available for inhalation as a vapour. Highly volatile substances are those with a boiling point below 50 °C and low volatile substances those with a boiling point above 150 °C. Furthermore, volatility decreases with increased molecular weight. The boiling point of the test substance is > 300 °C and the number- as well as weight-average molecular weight of the test substance fractions was determined to be > 1 700 g/mol. Based on these data a low vapour pressure is expected and absorption of Blue Sema via inhalation route is not expected to occur.

Dermal uptake is favoured for substances with a molecular weight < 100 g/mol. The average molecular weight of Blue Sema is > 1 700 g/mol. In addition, the substances must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Absorption is anticipated to be moderate to high if water solubility is between 100 and 10000 mg/L. Blue Sema has a water solubility of 0.57 mg/L, therefore not supporting dermal absorption.

 

Distribution:

In general, the smaller the molecule, the wider the distribution. Blue Sema has a high average molecular weight of > 1 700 g/mol. Therefore, no wide distribution is expected, in case the substance would become systemically available. Distribution is assumed to be restricted to the aqueous compartment and no bioaccumulation is expected due to the negative log Pow of the substance.

 

Metabolism:

The test substance is not expected to be bioavailable following oral, inhalative or dermal exposure. In case minor amounts become systemically bioavailable, a prediction of the metabolism is not possible as the test item is a UVCB substance with unknown structure. Based on the results of the Ames test, HPRT test and Chromosome Aberration test it can be assumed that the test substance is not enzymatically activated (toxified) during the metabolism as the metabolic activated test substance showed no higher toxicity compared to the test substance without metabolic activation. Furthermore, available data indicate that the test substance is not susceptible to hydrolysis. Therefore an unaltered passage of the parent substance through the stomach can be presumed.

Excretion:

Blue Sema is most likely excreted via faeces due to its high molecular weight (average > 1 700 g/mol) and its poor water solubility (0.57 mg/L).