Bisbenzimidazo[2,1-b:1',2'-j]benzo[lmn][3,8]phenanthroline-6,9-dione

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: expert statement

Remarks:

Evaluation of all available information with regard to information on ADME.

Adequacy of study:

other information

Study period:

2023

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

The study is a theoretical evaluation of data not specifically created for toxikokinetic purposes but for general toxicology. Nevertheless information on ADME can be deduced. This is in compliance with REACH requirements at this tonnage level.

Data source

Reference

Title:

Evaluation and Assessment of the Basic Toxicokinetic Properties of C.I. Pigment Red 194

Author:

Heubach Colorants Germany GmbH

Year:

2023

Report date:

2023

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

toxicokinetics

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Evaluation of all available information on the toxicology of the test material with regard to ADME- properties.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Bisbenzimidazo[2,1-b:1',2'-j]benzo[lmn][3,8]phenanthroline-6,9-dione

EC Number:

224-152-4

EC Name:

Bisbenzimidazo[2,1-b:1',2'-j]benzo[lmn][3,8]phenanthroline-6,9-dione

Cas Number:

4216-02-8

Molecular formula:

C26H12N4O2

IUPAC Name:

bisbenzimidazo[2,1-b:1',2'-j]benzo[lmn][3,8]phenanthroline-6,9-dione

Test material form:

solid: nanoform

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

See Summary and discussion of toxicokinetics

Main ADME results 2

Type:

distribution

Results:

See Summary and discussion of toxicokinetics

Main ADME results 3

Type:

metabolism

Results:

See Summary and discussion of toxicokinetics

Main ADME results 4

Type:

excretion

Results:

See Summary and discussion of toxicokinetics

Toxicokinetic / pharmacokinetic studies

Details on 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. PR 194 can be considered insoluble be-cause it has an extremely low solubility in water and n-octanol. Therefore, it is unlikely that PR 194 becomes systemically bioavailable after oral, dermal or inhalation exposure.
Based on the sub-acute oral toxicity study with the close analogue C.I. Pigment Orange 43 absorption of toxicologically significant amounts of C.I. Pigment Red 194 via the gastrointestinal tract is considered unlikely, since C.I. Pigment Orange 43 did not show any effects on inner organs and blood or urine.
The skin sensitisation studies with the close analogue C.I. Pigment Orange 43 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 C.I. Pigment Red 194 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 pigment in respirable form, the substance is considered to behave like an inert dust. Therefore, the deposited pigment particles will mostly be cleared from the lung via the mucocilliary transport. As the pigment will not dis-solve in the lung surfactant, the only way the pigment can enter the body is via phagocytosis of pigment particles by lung macrophages followed by migration of the macrophages into the interstitium and into the draining lymph nodes. This is supported by the acute inhalation toxicity study in rats exposed to 5.02 mg C.I. Pigment Red 194 per litre air for 4 hours which revealed no compound-related toxicity. However, the internal dose delivered via this mechanism can be considered negligible.

Details on distribution in tissues:

The Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test with the close analogue C.I. Pigment Orange 43 did not indicate any relevant histopathological changes in any of the investigated organs. This may indicate that the pigment 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 pigment support the conclusion that the pigment is not absorbed into the body and thus does not become systemically available. There were also no other signs of deposition of the pigment in any organ including excretory organs, like the kidney, indicating that even exposure to high doses of the pigment 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 C.I. Pigment Red 194 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).

Details on 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 faeces. This notion is confirmed by the discoloration of faeces observed in the subacute study as the only alteration.

Metabolite characterisation studies

Metabolites identified:

not measured

Any other information on results incl. tables

Evaluation and Assessment of the Basic Toxicokinetic Properties of

Pigment Red 194

 

 

Introduction:

Toxicokinetic parameters such as uptake, distribution, metabolism and excretion form part of the essential toxicological profile of a substance. Although the toxicokinetic behaviour of substances does not describe a toxicological endpoint itself, an approximate indication of the individual toxicokinetic parameters absorption, distribution, metabolism and excretion (ADME) can be gained from the results of basic toxicity testing. In this respect, the following evaluation discusses results and observations from basic toxicity studies, which can be used as approximate indications for the description of every individual toxicokinetic parameter. Such an approach is also justified by animal welfare considerations because herewith additional animal testing can be avoided. The assessment of the toxicokinetic properties of C.I. Pigment Red 194 given below is based on the results obtained for the following toxicological endpoints:

  

• Acute oral toxicity


• Acute inhalation toxicity


• Skin irritation


• Eye Irritation


• Skin sensitisation


• HGPRT-test


• In vitro cytogenetic assay


• Combined subacute oral toxicity and reproductive toxicity screen (OECD 422)

  

Many of these studies were carried out according to the principles of Good Laboratory Practice and most met the requirements of the OECD and EU-Guidelines for the Testing of Chemicals.

Simultaneously physico-chemical data such as solubility, log P_ow and hydrolytic stability are considered in the evaluation. This information gives additional indications regarding special toxicokinetic parameters, e.g. distribution, metabolism and excretion.

 

Substance Identity:  C.I. Pigment Red 194 is the Color Index name for bisbenzimidazo[2,1-b:1',2'-j]benzo[lmn][3,8]phenanthroline-6,9-dione (CAS: 4216-02-8). The purity of C.I. Pigment Red 194 was > 80% and the material was available as a red powder.

 

Toxicological Profile:

 C.I. Pigment Red 194 was tested for acute oral toxicity in female rats. After application of 15000 mg/kg body weight by gavage no dose-related lethality were observed. Clinical symptoms were limited to transient diarrhoea and squatting posture. Body weight development was not influenced. Macroscopically visible changes were not observed. Based on these results the median lethal doses (oral, LD₅₀) of the test material in the rat are greater than 15000 mg/kg body weight. In addition, C.I. Pigment Red 194 was tested for acute inhalation toxicity and revealed no mortality and no clinical symptoms after single 4 hours inhalation exposure in rats up to 5.02 mg/L air. Therefore, the median lethal concentration (LC50) of the test material in rats is greater than 5.02 mg/L air.

 

The test material is not irritating to the skin and is not irritating to eyes.

 

Testing for sensitizing properties in mice using the LLNA test revealed that the close analogue C.I. Pigment Orange 43 is a no skin sensitizer.

  

C.I. Pigment Red 194 gave negative results in Ames tests with S. typhimurium and E.coli with and without metabolic activation. In addition, the close analogue C.I. Pigment Orange 43 did not induce point-mutations at the HGPRT locus in CHO-K1 cells of the Chinese hamster in vitro with and without S9-mix and was not clastogenic in CHO-K1 cells of the Chinese hamster in vitro with and without S9-mix.

 Based on the results of a sub-acute oral and reproductive toxicity study (OECD 422) with C.I. Pigment Orange 43, daily administration of doses of 0, 100, 300 and 1000 mg/kg body weight to rats has not caused compound-related toxicity. The general health status of the animals was not altered. The only finding relevant for the assessment of ADME was an orange discoloration of faeces at necropsy not indicating bioavailability of the material. A `No Observed Adverse Effect Level` (NOAEL) of 1000 mg test material per kg body weight per day was established.

 

Evaluation and Assessment of the Toxicokinetic Profile:

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. PR 194 can be considered insoluble because it has an extremely low solubility in water and n-octanol. Therefore, it is unlikely that PR 194 becomes systemically bioavailable after oral, dermal or inhalation exposure.

Based on the sub-acute oral toxicity study with the close analogue C.I. Pigment Orange 43 absorption of toxicologically significant amounts of C.I. Pigment Red 194 via the gastrointestinal tract is considered unlikely, since C.I. Pigment Orange 43 did not show any effects on inner organs and blood or urine.

The skin sensitisation studies with the close analogue C.I. Pigment Orange 43 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 C.I. Pigment Red 194 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 pigment in respirable form, the substance is considered to behave like an inert dust. Therefore, the deposited pigment particles will mostly be cleared from the lung via the mucocilliary transport. As the pigment will not dissolve in the lung surfactant, the only way the pigment can enter the body is via phagocytosis of pigment particles by lung macrophages followed by migration of the macrophages into the interstitium and into the draining lymph nodes. This is supported by the acute inhalation toxicity study in rats exposed to 5.02 mg C.I. Pigment Red 194 per litre air for 4 hours which revealed no compound-related toxicity. However, the internal dose delivered via this mechanism can be considered negligible. 

Distribution:

The Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test with the close analogue C.I. Pigment Orange 43 did not indicate any relevant histopathological changes in any of the investigated organs. This may indicate that the pigment 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 pigment support the conclusion that the pigment is not absorbed into the body and thus does not become systemically available. There were also no other signs of deposition of the pigment in any organ including excretory organs, like the kidney, indicating that even exposure to high doses of the pigment 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 C.I. Pigment Red 194 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 insoluble pigment 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 Pigment Red 194 and the close analogue C.I. Pigment Orange 43. In the mutagenicity tests, the pigments proved to be non-mutagenic in the absence as well as in the presence of an exogenous metabolizing system, indicating that the pigments are 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 Combined Repeated Dose Toxicity Study with the Reproduction/ Develop-mental Toxicity Screening Test with the close analogue C.I. Pigment Orange 43. Furthermore, the missing skin or eye irritating or skin sensitizing properties argue against any interaction with biological material.

Therefore, C.I. Pigment Red 194 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 faeces. This notion is confirmed by the discoloration of faeces observed in the subacute study as the only alteration.

Executive summary:

Based on the available database on C.I. Pigment Red 194 relevant information exists to make a qualitative evaluation of the toxicokinetic profile of this compound. This is in line with animal welfare considerations because additional animal tests can be avoided by such an evaluation.

The results of basic toxicity testing give no reason to anticipate unusual characteristics about the toxicokinetics of C.I. Pigment Red 194. The data indicate that there is no relevant dermal absorption. C.I. Pigment Red 194 is not absorbed from the gastrointestinal tract in toxicologically significant amounts. Indications of a bio-accumulative potential as well as metabolism towards genotoxic sub-structures do not exist. Excretion of small amounts of possibly systemically available C.I. Pigment Red 194 and/or metabolites via faeces is likely.

 

Conclusion:

Based on all available data, C.I. Pigment Red 194 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 C.I. Pigment Red 194 has a no relevant dermal absorptive potential. C.I. Pigment Red 194 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 to excretion of all possibly available C.I. Pigment Red 194 and/or metabolites.

Applicant's summary and conclusion

Conclusions:

Based on all available data, C.I. Pigment Red 194 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 C.I. Pigment Red 194 has a no relevant dermal absorptive potential. C.I. Pigment Red 194 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 to excretion of all possibly available C.I. Pigment Red 194 and/or metabolites.

Executive summary:

Based on the available database on C.I. Pigment Red 194 relevant information exists to make a qualitative evaluation of the toxicokinetic profile of this compound. This is in line with animal welfare considerations because additional animal tests can be avoided by such an evaluation.

The results of basic toxicity testing give no reason to anticipate unusual characteristics about the toxicokinetics of C.I. Pigment Red 194. The data indicate that there is no relevant dermal absorption. C.I. Pigment Red 194 is not absorbed from the gastrointestinal tract in toxicologically significant amounts. Indications of a bio-accumulative potential as well as metabolism towards genotoxic sub-structures do not exist. Excretion of small amounts of possibly systemically available C.I. Pigment Red 194 and/or metabolites via faeces is likely.