Trisodium bis[3-hydroxy-4-[(2-hydroxy-1-naphthyl)azo]-7-nitronaphthalene-1-sulphonato(3-)]chromate(3-)

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: expert statement

Adequacy of study:

key study

Study period:

2013

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Information is derived from existing toxicological studies.

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

Trisodium bis[3-hydroxy-4-[(2-hydroxy-1-naphthyl)azo]-7-nitronaphthalene-1-sulphonato(3-)]chromate(3-)

EC Number:

260-906-9

EC Name:

Trisodium bis[3-hydroxy-4-[(2-hydroxy-1-naphthyl)azo]-7-nitronaphthalene-1-sulphonato(3-)]chromate(3-)

Cas Number:

57693-14-8

Molecular formula:

C40H20CrN6O14S2.3Na

IUPAC Name:

trisodium bis[3-hydroxy-4-[(2-hydroxy-1-naphthyl)azo]-7-nitronaphthalene-1-sulphonato(3-)]chromate(3-)

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Based on the subacute (28-day) oral toxicity study absorption of toxicologically significant amounts of the substance via the gastrointestinal tract has to be assumed since obvious discoloration of inner organs was observed throughout the body.
The skin sensitisation studies indicate some local dermal bioavailability. However, systemic availability seems to be negligible after dermal exposure since no systemic signs of intoxication were seen after occlusive administration of 2000 mg test item per kg body weight in rats in the acute dermal toxicity study. Indications of a significant dermal absorptive potential were also not revealed by testing for primary irritation in rabbits.

Details on distribution in tissues:

Based on the results of the subacute oral toxicity study, discolorations were observed in liver, kidney, lymph nodes, reproductive organs, thymus and salivary glands. Thus it can be concluded, that test item is absorbed through the gastrointestinal tract and systemically available within the organism. Histopathological findings indicate a deposition of the dye mainly in interstitial macrophages of the affected tissues.
There were no signs of bioaccumulation of the test material although the dose-response-relationship of the macroscopic as well as the microscopic discolorations after dosing in the subacute toxicity study indicates some retention of the dye. This view is supported by the physical-chemical properties (solubility in water) and the molecular structure.

Details on excretion:

Taking into account the physico-chemical properties and the molecular structure of the dye it can be assumed that the main route of excretion will be the kidney. This notion is confirmed by the discoloration of kidneys observed in the subacute study.

Metabolite characterisation studies

Metabolites identified:

no

Details on metabolites:

Test substance proved to be weakly active in the Ames-test with and without exogenous metabolic activation. This indicates that it does not need metabolic activation. It was not genotoxic in the HPRT in vitro and the micronucleus assay in vivo. Thus metabolites, if any are formed, are not more toxic than the parent compound.
In the skin sensitisation test positive reactions were seen, which indicate some reactivity e. g. protein binding.
No effects were seen in the subacute study except for a discoloration of tissues histologically allocated to tissue macrophages. No functional or structural impairments were detected. Therefore, the substance is considered to just pass through the organism without significant metabolism. The only interaction being some binding to bio-molecules giving rise to the hypersensitivity reactions and the accumulation observed in macrophages. Depending on the dose, the capacity of the excretion mechanisms may become exhausted leading to deposition of the dye in tissue macrophages.

Applicant's summary and conclusion

Conclusions:

Based on all available data, test substance does not exhibit conspicuous toxicokinetic behaviour in the sense of accumulative and/or delayed effects with regard to the individual parameters absorption, distribution, metabolism and excretion.
The results from studies with dermal exposure indicate that it has a small but definite dermal absorptive potential. It is absorbed from the gastrointestinal tract in significant amounts and distributed throughout the body.
Indications of an intense metabolism or a bio-accumulative potential do not exist as no delayed toxicity occurred. Additionally no increase in severity of systemic effects was observed in the subacute oral toxicity study, which also points to no bio-accumulation potential as well as to excretion.

Executive summary:

Absorption:

Based on the subacute (28-day) oral toxicity study absorption of toxicologically significant amounts of test substance via the gastrointestinal tract has to be assumed since obvious discoloration of inner organs was observed throughout the body.

The skin sensitisation studies indicate some local dermal bioavailability. However, systemic availability seems to be negligible after dermal exposure since no systemic signs of intoxication were seen after occlusive administration of 2000 mg test substance per kg body weight in rats in the acute dermal toxicity study. Indications of a significant dermal absorptive potential were also not revealed by testing for primary irritation in rabbits.

 

Distribution:

Based on the results of the subacute oral toxicity study discolorations were observed in liver, kidney, lymph nodes, reproductive organs, thymus and salivary glands. Thus it can be concluded, that test substance is absorbed through the gastrointestinal tract and systemically available within the organism. Histopathological findings indicate a deposition of the dye mainly in interstitial macrophages of the affected tissues.

There were no signs of bioaccumulation of the test material although the dose-response-relationship of the macroscopic as well as the microscopic discolorations after dosing in the subacute toxicity study indicates some retention of the dye. This view is supported by the physical-chemical properties (solubility in water) and the molecular structure.

 

Metabolism:

Test substance proved to be weakly active in the Ames-test with and without exogenous metabolic activation. This indicates that it does not need metabolic activation. It was not genotoxic in the HPRT in vitro and the micronucleus assay in vivo. Thus metabolites, if any are formed, are not more toxic than the parent compound.

In the skin sensitisation test positive reactions were seen, which indicate some reactivity e. g. protein binding.

No effects were seen in the subacute study except for a discoloration of tissues histologically allocated to tissue macrophages. No functional or structural impairments were detected. Therefore, it is considered to just pass through the organism without significant metabolism. The only interaction being some binding to bio-molecules giving rise to the hypersensitivity reactions and the accumulation observed in macrophages. Depending on the dose the capacity of the excretion mechanisms may become exhausted leading to deposition of the dye in tissue macrophages.

 

Excretion:

Taking into account the physico-chemical properties and the molecular structure of the dye it can be assumed that the main route of excretion will be the kidney. This notion is confirmed by the discoloration of kidneys observed in the subacute study.