Phenol, 4-[[4-(dimethylamino)phenyl]azo]-, reaction products with sodium sulfide (Na2(Sx)), leuco derivatives

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:

2018

Report date:

2018

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test material

Test material information

Constituent 1

Reference substance name:

Phenol, 4-[[4-(dimethylamino)phenyl]azo]-, reaction products with sodium sulfide (Na2(Sx)), leuco derivatives

EC Number:

235-517-2

EC Name:

Phenol, 4-[[4-(dimethylamino)phenyl]azo]-, reaction products with sodium sulfide (Na2(Sx)), leuco derivatives

Cas Number:

12262-25-8

Molecular formula:

not applicable

IUPAC Name:

Reaction product of 4-[4-(dimethylamino)anilino]phenol with sodium polysulfide, leuco derivatives

Test material form:

solid: particulate/powder

Details on test material:

Test item: Leuco Sulfur Blue 9
Appearance: Black, solid

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 Blue 9 has a number-average molecular weight above 2000 g/mol and weight-average molecular weight above 1 000 000 g/mol. Less than 2.5 % of the fractions was determined to be < 520 g/mol. The water solubility was determined to be of 0.65 mg/L, therefore not favouring absorption. Taken together, the physiochemical properties indicate that Leuco Sulfur Blue 9 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 (DRF, OECD 422) with a read-across substance (CAS: 1040873-93-5). 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 was observed.
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 > 300 °C and the average number molecular weight of the test substance is > 2 000 g/mol. Based on these data a low vapour pressure is expected and absorption of Leuco Sulfur Blue 9 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 the substances is > 2 000 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 Blue 9 has a water solubility of 0.65 mg/L, therefore not supporting dermal absorption.

Details on distribution in tissues:

In general, the smaller the molecule, the wider the distribution. Leuco Sulfur Blue 9 has a high averagenumber molecular weight of > 2 000 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:

Leuco Sulfur Blue 9 is most likely excreted via faeces due to its very high molecular weight (mean MW > 1 000 000 and mean Mn > 2000 g/mol) and its poor water solubility (0.65 mg/L).

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 an Ames test and a HPRT and Chromosomal Aberration test with a read across substance (CAS: 1040873-93-5), 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 as well as no wide distribution of the test 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. Due to the size of the high molecular weight and the poor water solubility excretion via faeces is assumed.