Reaction mass of (disodium 4-[[4-(acetylmethylamino)-2-sulphonatophenyl]amino]1-amino-9,10-dihydro-9,10-dioxoanthracene-2-sulphonate and sodium sulphate and sodium chloride)

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: Expert statement

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: All available information on Physical , chemical and toxicological properties of the tet material was used to deduce probable toxicokinetic peroperties.

Justification for type of information:

No other information required

Data source

Reference

Reference Type:

other: Expert statement

Title:

Evaluation and Assessment of the Basic Toxicokinetic Properties of Acid Blue 182

Author:

Colorants Solutions Deutschland GmbH

Year:

2020

Report date:

2020

Materials and methods

Objective of study:

other: General evaluation of toxicokinetic behavior based on available information

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

All available data from in vitro and in vivo studies were evaluated regarding indications of toxicokinetic behaviour of a Acid Blue 182

GLP compliance:

no

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

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. Acid Blue 182 has a solubility in water of 4.5g/L due to its ionic character. The partition coefficient (lg Pow) is -4,5 and indicates no or mini-mal solubility in fat/lipids. Therefore, it is unlikely that Acid Blue 182 becomes systemically bioavailable after oral, dermal or inhalation exposure.
Based on the sub-acute oral toxicity study with Acid Blue 182 absorption of toxicologically significant amounts of Acid Blue 182 via the gastrointestinal tract is considered unlikely, since Acid Blue 182 did not show any effects on inner organs and blood or urine.
The skin sensitisation studies with Acid Blue 182 indicate no local dermal bioavailability. Systemic availability also seems to be negligible after dermal exposure since no systemic signs of intoxication were seen after occlusive administration of 500 mg Acid Blue 182 per kg body weight in rabbits in the acute dermal irritation study.
Dermal absorption is, therefore, considered unlikely
In the unlikely event of exposure to aerosolized colorant in respirable form, the substance is considered to behave like an soluble, inert dust. Therefore, the deposited colorant particles will mostly be cleared from the lung via dissolution and the mucocilliary transport. The in-ternal dose delivered via this mechanism can be considered negligible as the material insol-uble in lipid will not be able to transit cellular membranes.

Details on distribution in tissues:

Distribution:
The Repeated Dose Toxicity Study did not indicate any relevant systemic effects or histo-pathological changes in any of the investigated organs. This may indicate that the colorant either does not affect special organs as targets, i.e., is non-toxic, or is not distributed within the body in significant amounts. As indicated above, the physico-chemical parameters of the colorant support the conclusion that it is not absorbed into the body and thus does not be-come systemically available. There were also no other signs of deposition of the colorant in any organ including excretory organs, like the kidney, indicating that even exposure to high doses of the substance does not 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 unlikely and specific hotspots of distribution cannot be identified.
Thus, it is concluded, that Acid Blue 182 is not systemically available at relevant concentra-tions within the organism.
There were no signs of bioaccumulation of the test material. This view is supported by the physical-chemical properties (solubility in water).

Details on excretion:

Excretion:
Taking into account the physico-chemical properties and the molecular structure of the mate-rial and the absence of any indication of absorption and/or metabolism it is assumed that ex-cretion, if any, is likely to occur via urine and faeces. This notion is confirmed by the discol-oration of faeces observed in the subacute study as the only alteration.

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

Metabolism:
Since the solution of the substance in cellular fluid or cellular membranes is a prerequisite for its metabolism, it is unlikely that the colorant, which is insoluble in lipids, becomes ac-cessible for metabolizing systems in relevant amounts.
The results of the mutagenicity tests provide useful indications for qualitative consideration of the metabolic fate of Acid Blue 182. In the mutagenicity tests, the colorant proved to be non-mutagenic in the absence as well as in the presence of an exogenous metabolizing sys-tem, indicating that the colorant is not converted into toxic or genotoxic metabolites. This conclusion is also supported by the lack of any morphological and histopathological chang-es of organs involved in xenobiotic metabolism, such as the liver, in the Repeated Dose Toxicity Study as well as the Reproduction/ Develop-mental Toxicity Screening Test with the test material. Furthermore, the missing skin or eye irritating or skin sensitizing properties argue against any interaction with biological material.
Therefore, Acid Blue 182 is considered to just pass through the intestinal tract without sig-nificant metabolism.

Applicant's summary and conclusion

Conclusions:

Based on all available data, Acid Blue 182 does not exhibit conspicuous toxicokinetic behav-iour in the sense of accumulative and/or delayed effects with regard to the individual param-eters absorption, distribution, metabolism and excretion.
The results from studies with dermal exposure indicate that Acid Blue 182 has a no relevant dermal absorptive potential. Acid Blue 182 is most probably not absorbed from the gastroin-testinal tract in significant amounts.
Indications of an intense metabolism or a bio-accumulative potential do not exist as no tox-icity occurred. Additionally, no systemic effects were observed in the subacute oral toxicity study, which points to no bio-accumulation potential and complete excretion of all possibly available Acid Blue 182 and/or metabolites.

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. Acid Blue 182 has a solubility in water of 4.5g/L due to its ionic character. The partition coefficient (lg Pow) is -4,5 and indicates no or minimal solubility in fat/lipids. Therefore, it is unlikely that Acid Blue 182 becomes systemically bioavailable after oral, dermal or inhalation exposure.

Based on the sub-acute oral toxicity study and a reproduction/developmental toxicity screening test (OECD TG 421) with Acid Blue 182 absorption of toxicologically significant amounts of Acid Blue 182 via the gastrointestinal tract is considered unlikely, since Acid Blue 182 did not show any effects on inner organs and blood or urine.

The skin sensitisation studies with Acid Blue 182 indicate no local dermal bioavailability. Systemic availability also seems to be negligible after dermal exposure since no systemic signs of intoxication were seen after occlusive administration of 500 mg Acid Blue 182 per kg body weight in rabbits in the acute dermal irritation study.

Dermal absorption is, therefore, considered unlikely

In the unlikely event of exposure to aerosolized colorant in respirable form, the substance is considered to behave like a soluble, inert dust. Therefore, the deposited colorant particles will mostly be cleared from the lung via dissolution and the mucocilliary transport.The internal dose delivered via this mechanism can be considered negligible as the material insoluble in lipid will not be able to transit cellular membranes.

 

Distribution:

The Repeated Dose Toxicity Study did not indicate any relevant systemic effects or histopathological changes in any of the investigated organs. This may indicate that the colorant either does not affect special organs as targets, i.e., is non-toxic, or is not distributed within the body in significant amounts. As indicated above, the physico-chemical parameters of the colorant support the conclusion that it is not absorbed into the body and thus does not become systemically available. There were also no other signs of deposition of the colorant in any organ including excretory organs, like the kidney, indicating that even exposure to high doses of the substance does not 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 unlikely and specific hotspots of distribution cannot be identified.

Thus, it is concluded, that Acid Blue 182 is not systemically available at relevant concentrations within the organism.

There were no 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 unlikely that the colorant, which is insoluble in lipids, becomes accessible for metabolizing systems in relevant amounts.

The results of the mutagenicity tests provide useful indications for qualitative consideration of the metabolic fate of Acid Blue 182. In the mutagenicity tests, the colorant proved to be non-mutagenic in the absence as well as in the presence of an exogenous metabolizing system, indicating that the colorant is not converted into toxic or genotoxic metabolites.This conclusion is also supported by the lack of any morphological and histopathological changes of organs involved in xenobiotic metabolism, such as the liver, in the Repeated Dose Toxicity Study as well as the Reproduction/ Develop-mental Toxicity Screening Testwith the test material. Furthermore, the missing skin or eye irritating or skin sensitizing properties argue against any interaction with biological material.

Therefore, Acid Blue 182 is considered to just pass through the intestinal tract without significant metabolism.

 

Excretion:

Taking into account the physico-chemical properties and the molecular structure of the material and the absence of any indication of absorption and/or metabolism it is assumed that excretion, if any, is likely to occur via urine and faeces. This notion is confirmed by the discoloration of faeces observed in the subacute study as the only alteration.

 

 

Conclusion:

 

Based on all available data, Acid Blue 182 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 Acid Blue 182 has a no relevant dermal absorptive potential. Acid Blue 182 is most probably not absorbed from the gastrointestinal tract in significant amounts.

Indications of an intense metabolism or a bio-accumulative potential do not exist as no toxicity occurred. Additionally, no systemic effects were observed in the subacute oral toxicity study, which points to no bio-accumulation potential and complete excretion of all possibly available Acid Blue 182 and/or metabolites.