Registration Dossier

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:

2017

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

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

Metabolites identified:

not measured

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 Orange 43 given below is based on the results obtained for the following toxicological endpoints:

Acute oral 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 Orange 43 was tested for acute oral toxicity in female rats. After application of 2000 mg/kg body weight by gavage no dose-related lethality were observed. Clinical symptoms were limited to Orange feces observed in all animals from day 2 and persisted in 3 animals until day 3. The body weight of the animals was within the range commonly recorded for this strain and age. Congestion in the lungs was noted in 3 animals whereas no macroscopic findings were recorded in the remaining animals at scheduled necropsy. The median lethal dose of the test item after single oral administration to female rats, observed over a period of 14 days is: LD50 (female rat) > 2000 mg/kg bw

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 Orange 43 is a no skin sensitizer.

C.I. Pigment Orange 43 gave negative results in Ames tests with S. typhimurium with and without metabolic activation. 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. The clastogenic potential of the test item to induce chromosomal aberrations in mammalian cells was evaluated according to OECD TG 473 using cultured Chinese Hamster Ovary (CHO) cells in the presence and absence of an exogenous metabolic activation system. It was concluded that the test item was not clastogenic in CHO cells at the tested concentrations and under the conditions of testing employed.

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.

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 Orange 43 can be considered insoluble because it has an extremely low solubility in water and n-octanol. Therefore, it is unlikely that Pigment Orange 43 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 Orange 43 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 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 Orange 43 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. 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 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 Orange 43 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 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. Furthermore, the missing skin or eye irritating or skin sensitizing properties argue against any interaction with biological material.

Therefore, C.I. Pigment Orange 43 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 Orange 43 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 Orange 43 has a no relevant dermal absorptive potential. C.I. Pigment Orange 43 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 Orange 43 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 Orange 43 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 Orange 43 has a no relevant dermal absorptive potential. C.I. Pigment Orange 43 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 Orange 43 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 Orange 43 given below is based on the results obtained for the following toxicological endpoints:

Acute oral 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 Orange 43 was tested for acute oral toxicity in female rats. After application of 2000 mg/kg body weight by gavage no dose-related lethality were observed. Clinical symptoms were limited to Orange feces observed in all animals from day 2 and persisted in 3 animals until day 3. The body weight of the animals was within the range commonly recorded for this strain and age. Congestion in the lungs was noted in 3 animals whereas no macroscopic findings were recorded in the remaining animals at scheduled necropsy. The median lethal dose of the test item after single oral administration to female rats, observed over a period of 14 days is: LD50 (female rat) > 2000 mg/kg bw

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 Orange 43 is a no skin sensitizer.

C.I. Pigment Orange 43 gave negative results in Ames tests with S. typhimurium with and without metabolic activation. 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. The clastogenic potential of the test item to induce chromosomal aberrations in mammalian cells was evaluated according to OECD TG 473 using cultured Chinese Hamster Ovary (CHO) cells in the presence and absence of an exogenous metabolic activation system. It was concluded that the test item was not clastogenic in CHO cells at the tested concentrations and under the conditions of testing employed.

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.

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 Orange 43 can be considered insoluble because it has an extremely low solubility in water and n-octanol. Therefore, it is unlikely that Pigment Orange 43 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 Orange 43 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 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 Orange 43 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. 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 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 Orange 43 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 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. Furthermore, the missing skin or eye irritating or skin sensitizing properties argue against any interaction with biological material.

Therefore, C.I. Pigment Orange 43 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 Orange 43 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 Orange 43 has a no relevant dermal absorptive potential. C.I. Pigment Orange 43 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 Orange 43 and/or metabolites.