Phenol, 4-amino-, reaction products with aniline, 4-methyl-1,3-benzenediamine, p-phenylenediamine, sodium sulfide (Na2S) and sulfur

Basic toxicokinetics

Administrative data

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

Data source

Reference

Reference Type:

other: Expert Statement

Title:

Unnamed

Year:

2019

Report date:

2019

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Phenol, 4-amino-, reaction products with aniline, 4-methyl-1,3-benzenediamine, p-phenylenediamine, sodium sulfide (Na2S) and sulfur

EC Number:

274-987-3

EC Name:

Phenol, 4-amino-, reaction products with aniline, 4-methyl-1,3-benzenediamine, p-phenylenediamine, sodium sulfide (Na2S) and sulfur

Cas Number:

70892-38-5

Molecular formula:

not applicable

IUPAC Name:

Reaction product of 4-aminophenol, aniline, 4-​methyl-​1,​3-​benzenediamine and p-​phenylenediamine with polysulfide

Test material form:

solid: particulate/powder

Details on test material:

CAS No.: 70892-38-5
EC No.: 274-987-3
Description: dark green powder
Storage: room temperature

Test animals

Details on species / strain selection:

not applicable

Details on test animals or test system and environmental conditions:

not applicable

Administration / exposure

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

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 Green 16 has a number-average molecular weight of 42 919 g/mol and weight-average molecular weight of 139 587 976 g/mol. Less than 1% of the fraction shows a molecular weight < 1000 g/mol. The water solubility was determined to be 0.041 mg/L, therefore not favouring absorption. Taken together, the physiochemical properties indicate that Leuco Sulfur Green 16 is not bioavailable following the oral route. This assumption is confirmed by the results of an acute toxicity study (OECD 423) and of a repeated dose toxicity study (OECD 422) with a read-across substance Leuco Sulphur Yellow 22 (CAS: 90268-98-7). No substance related effects or mortality were observed up to the limit dose in the OECD 423 and OECD 422 study. In both studies no coloration of internal organs occurred. In the acute oral toxicity study dark faeces were observed on the first day after administration of the test substance.
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 was determined to > 500 °C. Together with the extremely high molecular weight a low vapour pressure is expected and absorption of Leuco Sulfur Green 16 via inhalation route is not expected to occur.
Dermal uptake is favoured for substances with a molecular weight < 100 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. Leuco Sulfur Green 16 has a water solubility of 0.041mg/L and a molecular weight exceeding 100 g/mol by far. Thus, dermal absorption is not expected to occur.

Details on distribution in tissues:

In general, the smaller the molecule, the wider the distribution. Due to the hihg molecular weight of Leuco Sulfur Green 16 a wide distribution is not expected, in case the substance would become systemically available. Furthermore, distribution would be limited to the aqueous compartment due to its negative log Pow.

Details on excretion:

Leuco Sulfur Green 16 is most excreted via faeces due to its very high molecular weight and its poor water solubility (0.041 mg/L). This assumption is confirmed by the results of the acute toxicity study (OECD 423). Dark staining of the faeces related to staining properties of the test substance was observed.

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 would 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 an Ames test and a HPRT and Chromosomal Aberration test with a read across substance (CAS: 90268-98-7), 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.

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 of the substance is expected. This assumption is further supported by the results of an oral acute toxicity study and a repeated dose toxicity study with a read across substance, revealing no substance related effects and no coloration of 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 neither increase the toxicity of the test substance in an Ames test nor the toxicity of a read across substance in a HPRT and Chromosomal Aberration test. Excretion of Leuco Sulfur Green 16 occurs via faeces evidenced by stained faeces observed in the acute oral toxicity study.