Tetrachloro-μ-hydroxy(μ-methacrylato-O:O')dichromium

Endpoint summary

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

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

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:

Oral route:
Generally, oral absorption is favoured for molecular weights below 500 g/mol. Moderate log Pow values between -1 and 4 are favourable for absorption by passive diffusion. 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.
The complexation reaction product of tetrachloro-μ-hydroxy(μ-methacrylato-O:O')dichromium, isopropylalcohol and water has a molecular weight of 469.09 g/mol, a log Pow of 0.28 and a water solubility of 2324 mg/L, therefore favouring absorption. Taken together, the physiochemical properties indicate that the complexation reaction product of tetrachloro-μ-hydroxy(μ-methacrylato-O:O')dichromium, isopropylalcohol and water becomes bioavailable following the oral route. This assumption is confirmed by the results of the acute toxicity studies. These results did not lead to classification of the substance (LD50 > 2000 mg/kg bw), but clinical signs were observed.

Inhalation route:
Respiratory absorption is favoured for highly volatile substances with a vapour pressure greater than 250 hPa. The vapour pressure of the complexation reaction product or its constituents is well below this value. However, the constituents may in part become available as vapour. Then absorption via inhalation route is possible due to the moderate log Pow value, enabling uptake directly across the respiratory tract epithelium by passive diffusion. However, due to the high water solubility the substance may be retained within the mucus.

Dermal route:
Dermal uptake is favoured for substances with a molecular weight < 100 g/mol and log Pow values between 1 and 4. Therefore, based on the molecular weight of 469.09 g/mol and a log Pow of 0.28 dermal absorption is not favoured for the complexation reaction product of tetrachloro-μ-hydroxy(μ-methacrylato-O:O')dichromium, isopropylalcohol and water. However, with a moleculare weight < 500 g/mol the substance is still small enough to be absorbed by skin. The water solubility of the complexation reaction product of tetrachloro-μ-hydroxy(μ-methacrylato-O:O')dichromium, isopropylalcohol and water is > 10.000 mg/L. Taking this together with the log Pow of about 0, the substance may be to hydrophilic to cross the lipid rich environment of the stratum corneum. The dermal uptake is expected to be low.

Details on distribution in tissues:

As mentioned above, the physicochemical properties of the complexation reaction product of tetrachloro-μ-hydroxy(μ-methacrylato-O:O')dichromium, isopropylalcohol and water favour systemic absorption following oral and to a less extend inhalative and dermal uptake. Direct transport through aqueous pores is likely to be an entry route to the systemic circulation. In general, the smaller the molecule, the wider the distribution. Taken into account the log Pow and the water solubility, accumulation of the complexation reaction product of tetrachloro-μ-hydroxy(μ-methacrylato-O:O')dichromium, isopropylalcohol and water is very unlikely. In a repeated dose toxicity study no gross lesions or histological findings were revealed that could be attributed to treatment with the test item. The available study data revealed no indications of the substance to cross the blood-brain barrier.

Details on excretion:

The decay products and metabolites of the complexation reaction product of tetrachloro-μ-hydroxy(μ-methacrylato-O:O')dichromium, isopropylalcohol and water are most likely excreted via urine due to their small molecular weight and their good water solubility. The excretion via bile will be only of minor importance.

Metabolites identified:

no

Details on metabolites:

The complexation reaction product of tetrachloro-μ-hydroxy(μ-methacrylato-O:O')dichromium, isopropylalcohol and water will be degraded in the human body. The component tetrachloro-μ-hydroxy(μ-methacrylato-O:O')dichromium is only stable in the present of isopropylalcohol and water. An decrease in the concentration of isopropylalcohol and water in the human body will result in decay of tetrachloro-μ-hydroxy(μ-methacrylato-O:O')dichromium to chromium trichloride and methylacrylic acid. Methylacrylic acid can react with glutathione and the glutathion adduct can be further degraded to the corresponding mercapturic acid. Isopropylalcohol will mainly be metabolised to acetone. From methylacrylaid acid as well as from isopropylalcohol the formation of CO2 is conceivable. For the decay products chromium trichloride and methylacrylic acid and for isopropylalcohol data concerning the metabolism are publically available and sufficient evaluated.

Conclusions:

Absorption by the oral route is expected and absorption via dermal and inhalation route is unlikely, but cannot be excluded. Bioaccumulation of the decay products and metabolites will not occur. After enzymatic conversion the metabolites will mainly be excreted via urine.

Executive summary:

Based on physicochemical characteristics, particularly molecular weight, water solubility and octanol-water partition coefficient, absorption by the oral route is expected. This assumption is further supported by the results of the oral acute toxicity study, revealing some clinical signs at very high doses (6000 - 8000 mg/kg bw). Absorption via dermal and inhalation route is unlikely, but cannot be excluded. Bioaccumulation of the decay products and metabolites of the complexation reaction products of tetrachloro-μ-hydroxy(μ-methacrylato-O:O')dichromium, isopropylalcohol and water will not occur. After enzymatic conversion the metabolites will mainly be excreted via urine.

Description of key information

Based on physicochemical characteristics, particularly molecular weight, water solubility and octanol-water partition coefficient, absorption by the oral route is expected. This assumption is further supported by the results of the oral acute toxicity study, revealing some clinical signs at very high doses (6000 - 8000 mg/kg bw). Absorption via dermal and inhalation route is unlikely, but cannot be excluded. Bioaccumulation of the decay products and metabolites will not occur. After enzymatic conversion the metabolites will mainly be excreted via urine (reference 7.1.1 -1).

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Toxicokinetic Assessment

The complexation reaction product of tetrachloro-μ-hydroxy(μ-methacrylato-O:O')dichromium, isopropylalcohol and water is a bluish-green liquid at 20 °C and 1013.25 hPa with a molecular weight of 469.09 g/mol.The substance is soluble in water (2324 mg/L at 25 °C) and its log Pow was determined to be 0.28 at 25 °C.

 

Absorption

Oral route:

Generally, oral absorption is favoured for molecular weights below 500 g/mol. Moderate log Pow values between -1 and 4 are favourable for absorption by passive diffusion. 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.

The complexation reaction product of tetrachloro-μ-hydroxy(μ-methacrylato-O:O')dichromium, isopropylalcohol and water has a molecular weight of 469.09 g/mol, a log Pow of 0.28 and a water solubility of 2324 mg/L, therefore favouring absorption. Taken together, the physiochemical properties indicate that the complexation reaction product of tetrachloro-μ-hydroxy(μ-methacrylato-O:O')dichromium, isopropylalcohol and water becomes bioavailable following the oral route. This assumption is confirmed by the results of the acute toxicity studies. These results did not lead to classification of the substance (LD50 >2000 mg/kg bw), but clinical signs were observed.

 

Inhalation route:

Respiratory absorption is favoured for highly volatile substances with a vapour pressure greater than 250 hPa. The vapour pressure of the complexation reaction product or its constituents is well below this value. However, the constituents may in part become available as vapour. Then absorption via inhalation route is possible due to the moderate log Pow value, enabling uptake directly across the respiratory tract epithelium by passive diffusion. However, due to the high water solubility the substance may be retained within the mucus.

 

Dermal route:

Dermal uptake is favoured for substances with a molecular weight < 100 g/mol and log Pow values between 1 and 4. Therefore, based on the molecular weight of469.09 g/mol and a log Pow of 0.28 dermal absorption is not favoured for the complexation reaction products of tetrachloro-μ-hydroxy(μ-methacrylato-O:O')dichromium, isopropylalcohol and water. However, with a moleculare weight < 500 g/mol the substance is still small enough to be absorbed by skin. The water solubility ofthe complexation reaction products of tetrachloro-μ-hydroxy(μ-methacrylato-O:O')dichromium, isopropylalcohol and water is > 10.000 mg/L. Taking this together with the log Pow of about 0, the substance may be to hydrophilic to cross the lipid rich environment of the stratum corneum. The dermal uptake is expected to be low.

 

Distribution

 

As mentioned above, the physicochemical properties of the complexation reaction product of tetrachloro-μ-hydroxy(μ-methacrylato-O:O')dichromium, isopropylalcohol and water favour systemic absorption following oral and to a less extend inhalative and dermal uptake. Direct transport through aqueous pores is likely to be an entry route to the systemic circulation. In general, the smaller the molecule, the wider the distribution. Taken into account the log Pow and the water solubility, accumulation of the complexation reaction products of tetrachloro-μ-hydroxy(μ-methacrylato-O:O')dichromium, isopropylalcohol and water is very unlikely. In a repeated dose toxicity study no gross lesions or histological findings were revealed that could be attributed to treatment with the test item. The available study data revealed no indications of the substance to cross the blood-brain barrier.

 

Metabolism

 

The complexation reaction product of tetrachloro-μ-hydroxy(μ-methacrylato-O:O')dichromium, isopropylalcohol and water will be degraded in the human body. The component tetrachloro-μ-hydroxy(μ-methacrylato-O:O')dichromium is only stable in the present of isopropylalcohol and water. An decrease in the concentration of isopropylalcohol and water in the human body will result in decay of tetrachloro-μ-hydroxy(μ-methacrylato-O:O')dichromium tochromium trichloride and methylacrylic acid. Methylacrylic acid can react with glutathione and the glutathion adduct can be further degraded to the corresponding mercapturic acid. Isopropylalcohol will mainly be metabolised to acetone. From methylacrylaid acid as well as from isopropylalcohol the formation of CO₂ is conceivable. For the decay products chromium trichloride and methylacrylic acid and for isopropylalcohol data concerning the metabolism are publically available and sufficient evaluated.

 

Excretion

 

The decay products and metabolites of the complexation reaction product of tetrachloro-μ-hydroxy(μ-methacrylato-O:O')dichromium, isopropylalcohol and water are most likely excreted via urine due to their small molecular weight and their good water solubility. The excretion via bile will be only of minor importance.