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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics, other
Type of information:
other: statement on availability of information
Remarks:
Evaluation of all available information with regard to information on ADME.
Adequacy of study:
supporting study
Study period:
2020
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 toxicokinetic purposes but for general toxicology. Nevertheless information on ADME can be deduced. This is in compliance with REACH requirements at this tonnage level.
Objective of study:
absorption
distribution
excretion
metabolism
toxicokinetics
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
Type:
metabolism
Results:
See Summary and discussion of toxicokinetics
Type:
excretion
Results:
See Summary and discussion of toxicokinetics
Type:
distribution
Results:
See Summary and discussion of toxicokinetics
Type:
absorption
Results:
See Summary and discussion of toxicokinetics
Metabolites identified:
not measured
Details on metabolites:
This information is not available.

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 168 given below is based on the results obtained for the following toxicological endpoints:



  • Acute oral toxicity

  • Acute dermal toxicity

  • Skin irritation

  • Eye Irritation

  • Skin sensitisation

  • HGPRT-test

  • Ames-test

  • In vitro chromosomal aberration 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 Pow and hydrolytic stability are considered in the evaluation. This information gives additional indications regarding special toxicokinetic parameters, e.g. distribution, metabolism and excretion.


Toxicological Profile:


C.I. Pigment Red 168 was tested for acute oral toxicity in male and female rats. The rats were subjected to test acute oral toxicity according to a protocol similar to OECD TG 401 (limit test). The test item was administered at one dose level of 5000 mg/kg bw to 5 male and 5 female rats. During the 14 days observation period no animals died and there were no ab normalities found in necropsy, thus leading to an LD50 > 5000 mg/kg bw.


C.I. Pigment Red 168 was tested for acute dermal toxicity in the Wistar strain rat according to OECD TG 402 “Acute Dermal Toxicity”. A group of ten animals (five males and five females) was given a single, 24 hour, semi-occluded dermal application of the test item to intact skin at a dose level of 2000 mg/kg bodyweight. There were no deaths and no signs of systemic toxicity. The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg bodyweight.


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 C.I. Pigment Red 168 is a no skin sensitizer.


C.I. Pigment Red 168 gave negative results in Ames tests with S. typhimurium with and without metabolic activation. C.I. Pigment Red 168 did not induce gene mutations at the HPRT locus in V79 cells. The clastogenic potential of the test item to induce chromosomal aberrations in mammalian cells was evaluated according to OECD TG 473. The test item did not induce structural chromosome aberrations in V79 cells (Chinese hamster cell line) in vitro. Therefore, the test item is considered to be non-clastogenic in this chromosome aberration test in the absence and presence of metabolic activation, when tested up to the highest evaluable concentration.


Based on the results of a sub-acute oral and reproductive toxicity study (OECD 422) with C.I. Pigment Red 168, daily administration of doses of 0, 100, 300 and 1000 mg/kg body weight to rats has not caused compound-related toxicity. The NOAEL (No Observed Adverse Effect Level) and NOEL (No Observed Effect Level) for general toxicity in males and females was considered to be 1000 mg/kg bw/day. The NOEL (No Observed Effect Level) for reproduction/developmental toxicity was considered to be 1000 mg/kg/day.


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


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. Pigment Red 168 can be considered insoluble because it has an extremely low solubility in water and n-octanol. Therefore, it is unlikely that Pigment Red 168 becomes systemically bioavailable after oral, dermal or inhalation exposure.


Based on the sub-acute oral toxicity study, absorption of toxicologically significant amounts of C.I. Pigment Red 168 via the gastrointestinal tract is considered unlikely, since C.I. Pigment Red 168 did not show any effects on inner organs and blood or urine.


The skin sensitisation studies with C.I. Pigment Red 168 indicate no local dermal bioavailability. Systemic availability also seems to be negligible after dermal exposure since no systemic signs of intoxication were seen acute dermal toxicity study and 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. 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 Red 168 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 168 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 C.I. Pigment Red 168. 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. Furthermore, the missing skin or eye irritating or skin sensitizing properties argue against any interaction with biological material.


Therefore, C.I. Pigment Red 168 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.


Conclusion:


Based on all available data, C.I. Pigment Red 168 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 168 has a no relevant dermal absorptive potential. C.I. Pigment Red 168 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 168 and/or metabolites.

Conclusions:
Specific studies on toxicokinetics are not available. Assessment of the toxicokinetic behaviour of the substance was derived from the relevant available information.
Based on all available data, C.I. Pigment Red 168 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 168 has a no relevant dermal absorptive potential. C.I. Pigment Red 168 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 168 and/or metabolites.
Executive summary:

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 168 given below is based on the results obtained for the following toxicological endpoints:



  • Acute oral toxicity

  • Acute dermal toxicity

  • Skin irritation

  • Eye Irritation

  • Skin sensitisation

  • HGPRT-test

  • Ames-test

  • In vitro chromosomal aberration 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 Pow and hydrolytic stability are considered in the evaluation. This information gives additional indications regarding special toxicokinetic parameters, e.g. distribution, metabolism and excretion.


The substance is available in non-nano- as well as nano-form. The available data have been generated with non-nano material, but the conclusions drawn are considered valid for the nano form as well, because the material is chemically identical, and the physical properties are widely overlapping.


Toxicological Profile:


C.I. Pigment Red 168 was tested for acute oral toxicity in male and female rats. The rats were subjected to test acute oral toxicity according to a protocol similar to OECD TG 401 (limit test). The test item was administered at one dose level of 5000 mg/kg bw to 5 male and 5 female rats. During the 14 days observation period no animals died and there were no ab normalities found in necropsy, thus leading to an LD50 > 5000 mg/kg bw.


C.I. Pigment Red 168 was tested for acute dermal toxicity in the Wistar strain rat according to OECD TG 402 “Acute Dermal Toxicity”. A group of ten animals (five males and five females) was given a single, 24 hour, semi-occluded dermal application of the test item to intact skin at a dose level of 2000 mg/kg bodyweight. There were no deaths and no signs of systemic toxicity. The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg bodyweight.


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 C.I. Pigment Red 168 is a no skin sensitizer.


C.I. Pigment Red 168 gave negative results in Ames tests with S. typhimurium with and without metabolic activation. C.I. Pigment Red 168 did not induce gene mutations at the HPRT locus in V79 cells. The clastogenic potential of the test item to induce chromosomal aberrations in mammalian cells was evaluated according to OECD TG 473. The test item did not induce structural chromosome aberrations in V79 cells (Chinese hamster cell line) in vitro. Therefore, the test item is considered to be non-clastogenic in this chromosome aberration test in the absence and presence of metabolic activation, when tested up to the highest evaluable concentration.


Based on the results of a sub-acute oral and reproductive toxicity study (OECD 422) with C.I. Pigment Red 168, daily administration of doses of 0, 100, 300 and 1000 mg/kg body weight to rats has not caused compound-related toxicity. The NOAEL (No Observed Adverse Effect Level) and NOEL (No Observed Effect Level) for general toxicity in males and females was considered to be 1000 mg/kg bw/day. The NOEL (No Observed Effect Level) for reproduction/developmental toxicity was considered to be 1000 mg/kg/day.


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


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. Pigment Red 168 can be considered insoluble because it has an extremely low solubility in water and n-octanol. Therefore, it is unlikely that Pigment Red 168 becomes systemically bioavailable after oral, dermal or inhalation exposure.


Based on the sub-acute oral toxicity study, absorption of toxicologically significant amounts of C.I. Pigment Red 168 via the gastrointestinal tract is considered unlikely, since C.I. Pigment Red 168 did not show any effects on inner organs and blood or urine.


The skin sensitisation studies with C.I. Pigment Red 168 indicate no local dermal bioavailability. Systemic availability also seems to be negligible after dermal exposure since no systemic signs of intoxication were seen acute dermal toxicity study and 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. 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 Red 168 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 168 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 C.I. Pigment Red 168. 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. Furthermore, the missing skin or eye irritating or skin sensitizing properties argue against any interaction with biological material.


Therefore, C.I. Pigment Red 168 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.


Conclusion:


Based on all available data, C.I. Pigment Red 168 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 168 has a no relevant dermal absorptive potential. C.I. Pigment Red 168 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 168 and/or metabolites.

Description of key information

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. Pigment Red 168 can be considered insoluble because it has an extremely low solubility in water and n-octanol. Therefore, it is unlikely that Pigment Red 168 becomes systemically bioavailable after oral, dermal or inhalation exposure.


Based on the sub-acute oral toxicity study, absorption of toxicologically significant amounts of C.I. Pigment Red 168 via the gastrointestinal tract is considered unlikely, since C.I. Pigment Red 168 did not show any effects on inner organs and blood or urine.


The skin sensitisation studies with C.I. Pigment Red 168 indicate no local dermal bioavailability. Systemic availability also seems to be negligible after dermal exposure since no systemic signs of intoxication were seen acute dermal toxicity study and 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. 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 Red 168 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 168 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 C.I. Pigment Red 168. 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. Furthermore, the missing skin or eye irritating or skin sensitizing properties argue against any interaction with biological material.


 


Therefore, C.I. Pigment Red 168 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. 


 


Conclusion:


Based on all available data, C.I. Pigment Red 168 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 168 has a no relevant dermal absorptive potential. C.I. Pigment Red 168 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 168 and/or metabolites.


 


 

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information