1,3-Benzenediamine, 4-methyl-, reaction products with 4-nitrobenzenamine, p-phenylenediamine and sodium sulfide (Na2(Sx))

Endpoint summary

Link to relevant study record(s)

Reference

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

Objective of study:

absorption

distribution

excretion

metabolism

Details on test animals or test system and environmental conditions:

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:

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. The test item is an UVCB substance and does not have a defined molecular structure but consists of large molecules well above 500 g/mol. The water solubility of 0.95 mg/L does not favour absorption. Taken together, the physiochemical properties indicate that the substance is not bioavailable following the oral route. This assumption is confirmed by the results of the acute toxicity study (OECD 423) and the repeated dose toxicity studies with the read across substance Leuco Sulphur Yellow 22 (DRF to OECD 422 and OECD 422). No substance related effects were observed.
The volatility indicates whether a substance may be available for inhalation as a vapour. Volatility decreases with increased molecular weight. In particular due to the high molecular weight absorption of the test item 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 thus too large. In addition, the substances must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Absorption is anticipated to be low to moderate if water solubility is between 1 and 100 mg/L. The test item has a water solubility of 0.95 mg/L, therefore not supporting dermal absorption.

Details on distribution in tissues:

In general, the smaller the molecule, the wider the distribution. Based on its molecular weight distribution (no fractions below 3460 Da) and the hydrophilicity (log Pow <-0.3) it is assumed, that if absorbed, the test substance is not widely distributed and that distibution is limited to the aqueous compartment of the organism. Furthermore, an accumulation within adipose tissue can be excluded.

Details on excretion:

Due to the high molecular weight, low water solubility and negative low Pow the substance will be ecreted in the faeces.

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. 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.

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. The substance is excreted in faeces.

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 acute oral toxicity study, revealing no substance related effects. 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. Due to the size of the molecule and the poor water solubility excretion via feces is assumed.

Description of key information

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 acute oral toxicity study and the repeated dose toxicity study with the read across substance Leuco Sulphur Yellow 22, 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 (read across to CAS 90268 -98 -7) and Chromosome Aberration test (read across to CAS 90268 -98 -7). Due to the size of the molecule and the poor water solubility excretion via feces is assumed.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

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. The test item is an UVCB substance and does not have a defined molecular structure but consists of large molecules well above 500 g/mol. The water solubility of 0.95 mg/L does not favour absorption. Taken together, the physiochemical properties indicate that the test substance is not bioavailable following the oral route. This assumption is confirmed by the results of the acute toxicity study (OECD 423) and the repeated dose toxicity studies (DRF to OECD 422 and OECD 422) with the read across substance Leuco Sulphur Yellow 22. No substance related effects were observed.

The volatility indicates whether a substance may be available for inhalation as a vapour. Volatility decreases with increased molecular weight. In particular due to the high molecular weight absorption of the test item 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 thus too large. In addition, the substances must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Absorption is anticipated to be low to moderate if water solubility is between 1 and 100 mg/L. The test substance has a water solubility of 0.95 mg/L, therefore not supporting dermal absorption.

Distribution:

In general, the smaller the molecule, the wider the distribution. Based on its molecular weight distribution (no fractions below 3460 Da) and the hydrophilicity (log Pow <-0.3) it is assumed, that if absorbed, the test substance is not widely distributed and that distibution is limited to the aqueous compartment of the organism. Furthermore, an accumulation within adipose tissue can be excluded.

Metabolism:

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. 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.

Excretion:

According to the physicochemical properties of the test substance, molecular weight, hydrophilic characteristics and water solubility, the main route of excretion is expected to be via faeces.