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Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics, other
Type of information:
other: Expert Statement
Study period:
2021
Reliability:
2 (reliable with restrictions)
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. Pigment Orange 34 can be considered insoluble because it has an extremely low solubility in water and n-octanol. Therefore, it is unlikely that Pigment Orange 34 becomes systemically bioavailable after oral, dermal or inhalation exposure. Based on the chronic oral toxicity study with Pigment Orange 34 absorption of toxicologically significant amounts via the gastrointestinal tract is considered unlikely, since Pigment Orange 34 did not show any effects on inner organs and blood or urine. No metabo-lites could be detected. The skin sensitisation studies with Pigment Orange 34 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 Pigment Orange 34 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 ma crophages 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.
Details on distribution in tissues:
Distribution
The Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxici-ty Screening Test as well as all older studies employing repeated exposure with Pigment Or-ange 34 did not indicate any relevant histopathological changes in any of the investigated organs. This may indicate that the pigment either does not affect specific 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 pig-ment 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 or-gans, 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 infor-mation 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 Pigment Orange 34 is not systemically available at relevant concentrations within the organ-ism. There were no signs of bioaccumulation of the test material. This view is supported by the physical-c hemical properties (solubility in water and octanol).
Metabolites identified:
no
Details on metabolites:
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 qualitative infor-mation on the metabolic fate of Pigment Orange 34. In the mutagenicity tests, the pigment proved to be non-mutagenic in the absence as well as in the presence of an exogenous me-tabolizing system, indicating that the pigment, even directly exposed to metabolizing en-zymes, 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 xeno-biotic metabolism, such as the liver, in the Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test and with Pigment Orange 34. Fur-thermore, the missing skin or eye irritating or skin sensitizing properties argue against any interaction with biological material. Therefore, Pigment Orange 34 is considered to just pass through the intestinal tract without significant metabolism.

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 Pigment Orange 34 given below is based on the results obtained for the toxicological endpoints:

 

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 34 can be considered insoluble because it has an extremely low solubility in water and n-octanol. Therefore, it is unlikely that Pigment Orange 34 becomes systemically bioavailable after oral, dermal or inhalation exposure. Based on the chronic oral toxicity study with Pigment Orange 34 absorption of toxicologically significant amounts via the gastrointestinal tract is considered unlikely, since Pigment Orange 34 did not show any effects on inner organs and blood or urine. No metabolites could be detected. The skin sensitisation studies with Pigment Orange 34 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 Pigment Orange 34 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 ma crophages 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 as well as all older studies employing repeated exposure with Pigment Orange 34 did not indicate any relevant histopathological changes in any of the investigated organs. This may indicate that the pigment either does not affect specific 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 Pigment Orange 34 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-c hemical properties (solubility in water and octanol).

 

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 qualitative information on the metabolic fate of Pigment Orange 34. In the mutagenicity tests, the pigment proved to be non-mutagenic in the absence as well as in the presence of an exogenous metabolizing system, indicating that the pigment, even directly exposed to metabolizing enzymes, 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 Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test and with Pigment Orange 34. Furthermore, the missing skin or eye irritating or skin sensitizing properties argue against any interaction with biological material. Therefore, Pigment Orange 34 is considered to just pass through the intestinal tract without significant metabolism.

 

Excretion

Considering the physico-chemical properties and the molecular structure and size of the molecules and the absence of any indication of absorption and/or metabolism it is assumed that excretion, if any, is likely to occur via faeces.

 

Conclusions:
Based on all available data, Pigment Orange 34 does not exhibit conspicuous toxicokinetic behaviour in the sense of accumulative and/or delayed effects with regard to the individual parameters ab sorption, distribution, metabolism and excretion. The results from studies with dermal exposure indicate that Pigment Orange 34 has a no relevant dermal absorptive poten-tial. Pigment Orange 34 is most probably not absorbed from the gastrointestinal tract in sig-nificant amounts. Indications of an intense metabolism or a bio-accumulative potential do not exist as no toxicity occurred even after chronic exposure, which points to no bio-accumulation potential and complete excretion of all possibly available Pigment Orange 34 and/or metabolites.
Executive summary:

Based on the available data base on Pigment Orange 34 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 substance is available in nano-form. The available data have mostly been generated with nano material, but the conclusions drawn are considered valid for the bulk form as well, because the material is chemically identical, and the physical properties are widely overlapping. The results of basic toxicity testing give no reason to anticipate unusual characteristics regarding the toxico-kinetics of Pigment Orange 34. Pigment Orange 34 is not absorbed from the gastrointestinal tract in toxicologically significant amounts. The data indicate that there is no relevant dermal absorption. After inhalation unspecific reactions to unreactive dust can be expected. Indications of a bioaccumulative potential as well as metabolism towards genotoxic sub-structures do not exist. Excretion of traces of possibly systemically available Pigment Orange 34 and/or metabolites via faeces is likely.

 

Description of key information

Based on all available data, Pigment Orange 34 does not exhibit conspicuous toxicokinetic behaviour in the sense of accumulative and/or delayed effects with regard to the individual parameters ab sorption, distribution, metabolism and excretion. The results from studies with dermal exposure indicate that Pigment Orange 34 has a no relevant dermal absorptive potential. Pigment Orange 34 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 even after chronic exposure, which points to no bio-accumulation potential and complete excretion of all possibly available Pigment Orange 34 and/or metabolites.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Based on the available data base on Pigment Orange 34 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 substance is available in nano-form. The available data have mostly been generated with nano material, but the conclusions drawn are considered valid for the bulk form as well, because the material is chemically identical, and the physical properties are widely overlapping. The results of basic toxicity testing give no reason to anticipate unusual characteristics regarding the toxico-kinetics of Pigment Orange 34. Pigment Orange 34 is not absorbed from the gastrointestinal tract in toxicologically significant amounts. The data indicate that there is no relevant dermal absorption. After inhalation unspecific reactions to unreactive dust can be expected. Indications of a bioaccumulative potential as well as metabolism towards genotoxic sub-structures do not exist. Excretion of traces of possibly systemically available Pigment Orange 34 and/or metabolites via faeces is likely.

 

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