Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: expert statement
Adequacy of study:
disregarded due to major methodological deficiencies
Study period:
2012
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No studies have been performed. The statement is a summary of the knowledge deduced from availible data
Justification for data waiving:
other:

Data source

Reference
Reference Type:
other company data
Title:
Unnamed
Year:
2012

Materials and methods

Objective of study:
other: ADME
Test guideline
Qualifier:
no guideline required
Principles of method if other than guideline:
Evaluation of available data
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: solution
Radiolabelling:
no

Results and discussion

Main ADME results
Type:
absorption

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Leuko Sulphur Brown 37 is soluble only at high pH. Therefore, the solution is expected to act corrosive on living tissues and destroy the natural barriers. The material is soluble in water and, as long as the pH is high, it is expected to be readily bio-available at the portal of entry. However, if the material should diffuse into tissue or be applied in small amounts the pH value will be influenced by the buffering capacity of physiological media, which leads to precipitation of the neutral form of the dye. Thus in the acidic environment of the stomach immediate precipitation will occur. After application to the skin either corrosive action or neutralization with consequent precipitation will occur. The salt form will therefore, not be absorbed systemically. Due to the minimal solubility of the neutral form significant absorption is also not expected.
Details on distribution in tissues:
Due to the low solubility of the neutral form of the dye, which is the only form compatible with living tissue, and the high molecular weight no distribution beyond the portal of entry is expected.
Details on excretion:
As Leuko Sulphur Brown 37 is not expected to become available to metabolism or transport in a living organism, it is also not expected to be excreted via the normal excretory organs (kidney or liver/gall bladder). If applied orally most of the material will be eliminated via the feces. After skin exposure it will be eliminated via the natural turnover of skin cells.

Metabolite characterisation studies

Metabolites identified:
not specified
Details on metabolites:
Leuko Sulphur Brown 37 has mostly a molecular weight above 1000 Dalton and is very poorly soluble at physiologic pH. Significant metabolism is only expected if the substrate is soluble in water at physiological pH and is transported through biological membranes into cells. Due to the high molecular weight, the poor solubility and the polymeric structure such transport is not expected. Significant metabolism is therefore also considered unlikely.

Bioaccessibility

Bioaccessibility testing results:
The test material is not expected to become bioavailable to a relevant degree after oral and dermal exposure

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: No indication of a bioaccumulation potential is expected considering the available information.
Neither absorption, distribution, nor metabolism of the registered substance are expected in undamaged tissue.
Executive summary:

Leuko Sulphur Brown 37 is produced and handled as a strongly alkaline solution of the reaction product of formaldehyde and m-phenylene-diamine with sodium sulfide and sulphur. The pH-value of this solution is about 13. The solution is corrosive and cannot be tested in biological systems. The dye molecules are supposed to have a variable polymeric structure made of a three-dimensional network of sulphur chains connecting the condensates of formaldehyde and the aromatic amine. The molecular weight of this material is mostly between 2000 and 150 000. Less than 1.3 % is below 1000 Dalton.

Absorption: Leuko Sulphur Brown 37 is soluble only at high pH. Therefore, the solution is expected to act corrosive on living tissues and to destroy the natural barriers. The material is soluble in water and, as long as the pH is high, it is expected to be readily bio-available at the portal of entry. However, if the material should diffuse into tissue or be applied in small amounts the pH value will be influenced by the buffering capacity of physiological media, which leads to precipitation of the neutral form of the dye. Thus in the acidic environment of the stomach immediate precipitation will occur. After application to the skin either corrosive action or neutralization with consequent precipitation will occur. The salt form will therefore, not be absorbed systemically. Due to the minimal solubility of the neutral form significant absorption is also not expected.

Distribution: Due to the low solubility of the neutral form of the dye, which is the only form compatible with living tissue, and the high molecular weight no distribution beyond the portal of entry is expected.

Metabolism: Leuko Sulphur Brown 37 has mostly a molecular weight above 1000 Dalton and is very poorly soluble at physiologic pH. Significant metabolism is only expected if the substrate is soluble in water at physiological pH and is transported through biological membranes into cells. Due to the high molecular weight, the poor solubility and the polymeric structure such transport is not expected. Significant metabolism is therefore also considered unlikely.

Excretion: As Leuko Sulphur Brown 37 is not expected to become available to metabolism or transport in a living organism, it is also not expected to be excreted via the main excretory organs (kidney or liver/gall bladder). If applied orally most of the material will be eliminated via the feces. After skin exposure it will be eliminated via the natural turnover of skin cells.