Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics, other
Type of information:
other: expert statement
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Evaluation of all available data with regard to txicokintic properties.

Data source

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline required
Principles of method if other than guideline:
Evaluation of all available data with regard to toxicokinetic properties
GLP compliance:
no

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
A prerequisite for a relevant absorption is that the substance can be dissolved in either aque-ous (e.g., gastrointestinal fluid, blood plasma, sweat) or lipophilic (e.g., lipoproteins, lipid membranes, triglycerides) media or in both. Sanoline Lave Blue A is very soluble and shows solubility in water of > 1000 g/L. Therefore, it is likely that the test itembecomes systemically bioavailable after oral or inhalation exposure, although even after the low dose (100 mg/kg) a significant part of the oral dose was excreted directly with faeces.
Based on the sub-acute oral toxicity study absorption of toxicologically significant amounts of Sanoline Lave Blue A via the gastrointestinal tract is assumed, since inner organs and urine were obviously bluish discoloured and there were microscopic effects on inner organs (liver, kidney) and blood.
It is not considered likely that Sanoline Lave Blue A could penetrate skin because of its very hydrophilic character. The skin sensitisation studies also indicate no dermal bioavailability. Systemic availability also seems to be negligible after dermal exposure since no systemic signs of intoxication were seen after occlusive administration of 2000 mg Sanoline Lave Blue A per kg body weight in rats in the acute dermal toxicity study. Dermal absorption, there-fore, is considered unlikely.
In the unlikely event of exposure to aerosolized dye in respirable form, the substance is considered to dissolve in the surfactant and become at least to some degree bio-available.
Details on distribution in tissues:
The Repeated Dose Toxicity Study and the Reproduction Toxicity Screening Test did indi-cate relevant histopathological changes in liver and kidney. This may indicate that the dye does not affects these organs as targets and is distributed within the body in significant amounts. As indicated above, the physico-chemical parameters of the dye support the con-clusion that the dye is absorbed into the body and thus does become systemically available. There were signs of deposition of the dye in liver, kidneys and skin organ (blue coloration) indicating that prolonged exposure to high doses of the dye could lead to bioaccumulation in special compartments of the body.
Based on the available information on absorption distribution of the test material in the body in significant amounts is likely and specific hotspots of distribution can be identified.
Thus it is concluded, that Sanoline Lave Blue A is systemically available at relevant concen-trations within the organism.
There were signs of bioaccumulation of the test material. This view is supported by the phys-ical-chemical properties (solubility in water).
Details on excretion:
Taking into account the physico-chemical properties and the molecular structure of the mate-rial and the presence of many indications of absorption and metabolism it is assumed that excretion is likely to occur via kidney and faeces. This notion is confirmed by the discolora-tion of urine as well as faeces observed in the subacute study.

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
Since the solution of the substance in cellular fluid or cellular membranes is a prerequisite for its metabolism, it is likely that the soluble dye becomes accessible for metabolizing sys-tems in relevant amounts.
In the mutagenicity tests, the dyes proved to be non-mutagenic in the absence as well as in the presence of an exogenous metabolizing system, indicating that the dyes are not convert-ed into toxic or genotoxic metabolites. This conclusion is also supported by the lack of any adverse morphological and histopathological changes of organs involved in xenobiotic me-tabolism, such as the liver, in the Repeated Dose Toxicity Study and the Reproduction/ Develop-mental Toxicity Screening Test. However, the presence of hepatocellular hypertro-phy in the liver indicates activation of metabolizing enzymes in this organ..
Therefore, The test item is considered to induce metabolic activity in the liver sig-nificantly.

Bioaccessibility

Bioaccessibility testing results:
The test item is considered to be bioavailable after oral exposure. After dermal contact the probability of dermal absorption is considered very low.

Applicant's summary and conclusion

Conclusions:
Based on all available data, the test item does exhibit conspicuous toxicokinetic behaviour with regard to the individual parameters absorption, distribution, metabolism and excretion.
The results from studies with dermal exposure indicate that the test item has a no relevant dermal absorptive potential. The test item is obviously absorbed from the gastrointestinal tract in significant amounts.
Indications of metabolism and a bio-accumulative potential exist as slight toxicity as well as histopathological changes in the liver were detected. Systemic effects were observed in the subacute oral toxicity study, which point to some bioaccumulation potential and delayed excretion of available the test item and/or metabolites via the kidney.

Executive summary:

Taking all available toxicological tests into account, qualitative estimates for ADME-parameters are possible.

Absorption:

A prerequisite for a relevant absorption is that the substance can be dissolved in either aqueous (e.g., gastrointestinal fluid, blood plasma, sweat) or lipophilic (e.g., lipoproteins, lipid membranes, triglycerides) media or in both. Sanoline Lave Blue A is very soluble and shows solubility in water of > 1000 g/L. Therefore, it is likely that Sanoline Lave Blue A becomes systemically bioavailable after oral or inhalation exposure, although even after the low dose (100 mg/kg) a significant part of the oral dose was excreted directly with faeces.

Based on the sub-acute oral toxicity study absorption of toxicologically significant amounts of Sanoline Lave Blue A via the gastrointestinal tract is assumed, since inner organs and urine were obviously bluish discoloured and there were microscopic effects on inner organs (liver, kidney) and blood.

It is not considered likely that Sanoline Lave Blue A could penetrate skin because of its very hydrophilic character. The skin sensitisation studies also indicate no dermal bioavailability. Systemic availability also seems to be negligible after dermal exposure since no systemic signs of intoxication were seen after occlusive administration of 2000 mg Sanoline Lave Blue A per kg body weight in rats in the acute dermal toxicity study. Dermal absorption, therefore, is considered unlikely.

In the unlikely event of exposure to aerosolized dye in respirable form, the substance is considered to dissolve in the surfactant and become at least to some degree bio-available.

 Distribution:

The Repeated Dose Toxicity Study and the Reproduction Toxicity Screening Test did indicate relevant histopathological changes in liver and kidney. This may indicate that the dye does not affects these organs as targets and is distributed within the body in significant amounts. As indicated above, the physico-chemical parameters of the dye support the conclusion that the dye is absorbed into the body and thus does become systemically available. There were signs of deposition of the dye in liver, kidneys and skin organ (blue coloration) indicating that prolonged exposure to high doses of the dye could lead to bioaccumulation in special compartments of the body.

Based on the available information on absorption distribution of the test material in the body in significant amounts is likely and specific hotspots of distribution can be identified.

Thus it is concluded, that Sanoline Lave Blue A is systemically available at relevant concentrations within the organism.

There were signs of bioaccumulation of the test material. This view is supported by the physical-chemical properties (solubility in water).

 Metabolism:

Since the solution of the substance in cellular fluid or cellular membranes is a prerequisite for its metabolism, it is likely that the soluble dye becomes accessible for metabolizing systems in relevant amounts.

In the mutagenicity tests, the dyes proved to be non-mutagenic in the absence as well as in the presence of an exogenous metabolizing system, indicating that the dyes are not converted into toxic or genotoxic metabolites.This conclusion is also supported by the lack of any adverse morphological and histopathological changes of organs involved in xenobiotic metabolism, such as the liver, in the Repeated Dose Toxicity Study and the Reproduction/ Develop-mental Toxicity Screening Test. However, the presence of hepatocellular hypertrophy in the liver indicates activation of metabolizing enzymes in this organ..

Therefore, Sanoline Lave Blue A is considered to induce metabolic activity in the liver significantly.

 Excretion:

Taking into account the physico-chemical properties and the molecular structure of the material and the presence of many indications of absorption and metabolism it is assumed that excretion is likely to occur via kidney and faeces. This notion is confirmed by the discoloration of urine as well as faeces observed in the subacute study.