Disodium hydrogen bis[3-hydroxy-4-[(2-hydroxy-1-naphthyl)azo]naphthalene-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

Test material form:

other: solid and liquid preparations

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 analogue 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 per kg body weight of analogue substance in rats in the acute dermal toxicity study. Indications of 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 analogue 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.

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:

Analogue substance proved to be weakly active in the Ames-test with and without exogenous metabolic activation. This indicates that the analogue substance 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 analogue 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:

Interpretation of results (migrated information): no bioaccumulation potential based on study resultsBased on all available data, analogue 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 analogue substance has a small but definite dermal absorptive potential. The analogue substance 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 of analogue substance.

Executive summary:

Absorption:

Based on the subacute (28-day) oral toxicity study absorption of toxicologically significant amounts of analogue 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 per kg body weight of analogue substance 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 analogue 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:

Analogue substance proved to be weakly active in the Ames-test with and without exogenous metabolic activation. This indicates that the analogue substance 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, analogue 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.

 

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.