Phenol, 4-(phenylamino)-, sulfurized, leuco deriv.

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Remarks:

Expert Statement

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

Data source

Reference

Reference Type:

other: Expert statement

Title:

Unnamed

Year:

2017

Report date:

2017

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test material

Test material information

Constituent 1

Reference substance name:

phenol, 4-(phenylamino)-, sulfurised, leuco deriv.

Molecular formula:

not applicable

IUPAC Name:

phenol, 4-(phenylamino)-, sulfurised, leuco deriv.

Test animals

Details on test animals or test system and environmental conditions:

not applicable

Administration / exposure

Positive control reference chemical:

not applicable

Details on study design:

not applicable

Details on dosing and sampling:

not applicable

Statistics:

not applicable

Results and discussion

Toxicokinetic / pharmacokinetic studies

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. Leuco Sulfur Brown 96 has a mean molecular weight of 64000 g/mol and a water solubility of 22 mg/L, therefore not favouring absorption. Taken together, the physiochemical properties indicate that Leuco Sulfur Brown 96 is not bioavailable following the oral route. This assumption is confirmed by the results of the acute toxicity study (OECD 423) and the combined repeated dose and reproduction/developmental study (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 (OECD 422). In both studies no coloration of urine or internal organs occurred.

T he 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 range of the test substance was determined to be 99.1 to 101.7 °C and the molecular weight of the test substance is > 60000 g/mol. In particular due to the high molecular weight absorption of Leuco Sulfur Brown 96 via inhalation route is not expected to occur.

Dermal uptake is favoured for substances with a molecular weight < 100 g/mol. The molecular weight of the substances is > 60000 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 10000 mg/L. Leuco Sulfur Brown 96 has a water solubility of 22 mg/L, therefore not supporting dermal absorption. No mortality and no clinical signs related to the test substance as well as no staining of urine, faces or internal organs were observed in the acute dermal toxicity study (OECD 402).

Details on distribution in tissues:

In general, the smaller the molecule, the wider the distribution. Leuco Sulfur Brown 96 has a very high molecular weight of > 60000 g/mol. Therefore, no distribution is expected. This assumption was supported by the results of the acute toxicity study (OECD 423) and the combined repeated dose and reproduction/developmental study (OECD 422). No coloration of internal organs was observed, but faeces were stained black.

Details on excretion:

Leuco Sulfur Brown 96 is most likely excreted via faeces due to its very high molecular weight (> 60000 g/mol) and its poor water solubility (22 mg/L). This assumption is confirmed by the results of the acute toxicity study (OECD 423) and the combined repeated dose and reproduction/developmental study (OECD 422). Black staining of the faeces related to staining properties of the test substance was observed in both studies.

Metabolite characterisation studies

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.

Applicant's summary and conclusion

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 distribution of the test substance is expected. This assumption is further supported by the results of the oral and dermal acute toxicity studies as well as by the results of thecombined repeated dose and reproduction/developmental study, revealing no substance related effects and no coloration of urine and internal organs 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. Renal excretion of Leuco Sulfur Brown 96 was confirmed by stained faeces observed in the oral acute toxicity study as well as in the combined repeated dose and reproduction/developmental study.