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Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics, other
Type of information:
other: Expert statement
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Expert statement
Principles of method if other than guideline:
Expert statement based on toxicological and toxicokinetic data provided in IUCLID section 7.
Details on absorption:
Oral route:
Following oral administration, the likelihood of systemic absorption through the walls of the intestinal tract depends on several physicochemical substance properties. Generally, the smaller the molecule the more easily it may be absorbed through the walls of the gastrointestinal tract. As the molecular weight of C.I. Pigment Brown 24 is 90.67 g/mol, an uptake of the compound into the systemic circulation via the gastro-intestinal (GI) tract is likely (ECHA 2014). But C.I. Pigment Brown 24 has a very low water solubility of < 1 ug/L and therefore, the pigment can be regarded as not bioavailable.
With regard to the toxicological data, no signs of systemic toxicity were observed in the three acute oral toxicity studies (BASF 1978, Bayer 1972, Ishihara Sangyo Kaisha 1985) as well as in the repeated-dose study (Bomhard et al. 1982). Administered to rats via gavage in the acute oral toxicity studies, C.I. Pigment Brown 24 led to LD50 values of greater than 5000 mg/kg bw and 10000 mg/kg bw, without any clinical signs or mortality. Furthermore, the results of a long-term toxicity studies in rats (90d: NOAEL = 500 mg/kg bw/d in male and female) confirmed the results of the in vitro leaching studies that organ translocation of ions from the crystal lattice could not be demonstrated.

Inhalation route
Since no inhalation data are available for the test substance, read-across with the rutile pigment C.I. Pigment Yellow 53 (Nickel antimony titanate yellow) was performed. The available inhalation data show that absorption via the inhalation route is not to be expected for C.I. Pigment Yellow 53. In a subacute inhalation study, male Wistar rats were exposed for 5 days to 60 mg/m³ of C.I. Pigment Yellow 53. The observation period was 0, 3, 10, 31 and 60 d (BASF 1994). Nickel and antimony levels in the lung declined following first-order kinetics with a clearance of 50 d. In liver and kidneys, antimony and nickel were present in the range of the limit of quantification or below. In conclusion, study results indicate a negligible bioavailability of Ni and Sb after inhalation of the test substance.

Dermal route
The dermal exposure pathway is assessed as not relevant, because no relevant leaching of Sb and Cr ions was detected in a leaching study (BASF 2017). Furthermore, the substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Since the pigment is nearly insoluble, dermal uptake is likely to be low.
Details on distribution in tissues:
Based on the low water solubility and the results from the comprehensive toxicity testing, it is unlikely that the test substance becomes systemically available. If absorbed, the metal ions will most likely be transported within the body via blood stream and gain access to the body tissues potentially bound to macromolecules due to its low water solubility. This only happens to a very small degree because organ translocation of the ions from the crystal lattice could not be demonstrated in the repeated-dose studies.
A leaching study was performed at different pH conditions (pH 1.5 and 6.5) in artificial gastric fluid and artificial sweat solution. The study showed leaching concentrations significantly below the prescribed threshold level for EN 1811 (0.5 µg/cm2/week). Since the test covers the pH extrema in the human organs and for dermal contact, the leaching fraction of metals can be regarded as of no concern for distribution.
Details on excretion:
Chemicals can be excreted via various routes and mechanisms. The excretion depends on the physical and chemical properties of the compound. The inert pigment will most likely be excreted via faeces. Due to the lack of adsorption, urinary excretion will not occur and bioaccumulation can most likely be excluded due to the neglible bioavailability of the test substance.
Metabolites identified:
no
Details on metabolites:
As already described above, due to its insolubility in water and inert character, if any, only very low amounts of the test substance may be absorbed and become available for metabolisation. Metal ions are not metabolised in the body but are bound to carrier proteins and are transported to the target location. In addition, based on the results of the Ames test (BASF, 1995), Mouse lymphoma assay (BASF, 1996) and Micronucleus test (BASF, 2001) it can be assumed that the test substance is not enzymatically activated (toxified) during the metabolism as the parent compound showed no higher toxicity compared to the metabolic activated substance.

Description of key information

Most pigments behave like inert dusts and thus oral, dermal and inhalative adsorption can be considered as not very likely. This is also supported by the low water solubility and the results of the leaching studies. The heavy metal oxides are absorbed by the spinel lattice and thus lose their chemical, physical, and physiological properties. If the substance is inhaled, it will be cleared without being absorbed due to the effective clearance capacity of the lung. Based on the low water solubility and the results from the comprehensive toxicity testing, it is unlikely that the test substance become systemically available. If any, there might be only a very small proportion available for metabolization and biotransformation. The practically insoluble pigment is most likely be excreted via faeces. Bioaccumulation is unlikely due to the neglible bioavailability of the test substance.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

General background and toxicological profile
C.I. Pigment Brown 24 is a complex inorganic coloured pigment based on titanium dioxide with the molecular formula (Ti, Cr, Sb) O2. In the rutile lattice, titanium ions are partially replaced by chromium (III) and antimony (V) ions. The substance has a very low water solubility of <1 ug/l (loading 100mg/l, 28d, pH 8.5).

Toxicokinetic analysis of C.I. Pigment Brown 24
C.I Pigment Brown 24 is a yellow-orange powder at room temperature with a molecular weight of 90.67 g/mol, a density 4-5 g/cm³ and a melting point >1000 °C. The substance has a very low water solubility of <1 ug/l.

Absorption
Oral route:
Following oral administration, the likelihood of systemic absorption through the walls of the intestinal tract depends on several physicochemical substance properties.  Generally, the smaller the molecule the more easily it may be absorbed through the walls of the gastrointestinal tract. As the molecular weight of C.I. Pigment Brown 24 is 90.67 g/mol, an uptake of the compound into the systemic circulation via the gastro-intestinal (GI) tract is likely (ECHA 2014). But C.I. Pigment Brown 24 has a very low water solubility of <1 ug/L and therefore, the pigment can be regarded as not bioavailable.
With regard to the toxicological data, no signs of systemic toxicity were observed in the three acute oral toxicity studies (BASF 1978, Bayer 1972, Ishihara Sangyo Kaisha 1985) as well as in the repeated-dose study (Bomhard et al. 1982). Administered to rats via gavage in the acute oral toxicity studies, C.I. Pigment Brown 24 led to LD50 values of greater than 5000 mg/kg bw and 10000 mg/kg bw, without any clinical signs or mortality. Furthermore, the results of a long-term toxicity studies in rats (90d: NOAEL = 500 mg/kg bw/d in male and female) confirmed the results of the in vitro leaching studies that organ translocation of ions from the crystal lattice could not be demonstrated.

Inhalation route
Since no inhalation data are available for the test substance, read-across with the rutile pigment C.I. Pigment Yellow 53 (Nickel antimony titanate yellow) was performed. The available inhalation data show that absorption via the inhalation route is not to be expected for C.I. Pigment Yellow 53. In a subacute inhalation study, male Wistar rats were exposed for 5 days to 60 mg/m³ of C.I. Pigment Yellow 53. The observation period was 0, 3, 10, 31 and 60 d (BASF 1994). Nickel and antimony levels in the lung declined following first-order kinetics with a clearance of 50 d. In liver and kidneys, antimony and nickel were present in the range of the limit of quantification or below. In conclusion, study results indicate a negligible bioavailability of Ni and Sb after inhalation of the test substance.

Dermal route
The dermal exposure pathway is assessed as not relevant, because no relevant leaching of Sb and Cr ions in sweat simulated medium was detected in a leaching study (BASF 2017). Furthermore, the substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Since the Pigment is nearly insoluble, dermal uptake is likely to be low.

Distribution
Based on the low water solubility and the results from the comprehensive toxicity testing, it is unlikely that the test substance becomes systemically available. If absorbed, the metal ions will most likely be transported within the body via blood stream and gain access to the body tissues potentially bound to macromolecules due to its low water solubility. This only happens to a very small degree because organ translocation of the ions from the crystal lattice could not be demonstrated in the repeated-dose studies.
A leaching study was performed at different pH conditions (pH 1.5 and 6.5) and different media (artificial gastric fluid, artificial sweat solution). The release of Sb was zero after substraction of the blanks. The release of Cr was ~ 0.5 ug/l after 24h in GST and zero after 2h and in AST. Since the test covers the pH extrema in the human organs and for dermal contact, the leaching fraction of metals can be regarded as of no concern for distribution.

Metabolism
As already described above, due to its insolubility in water and inert character, if any, only very low amounts of the test substance may be absorbed and become available for metabolisation. Metal ions are not metabolised in the body but are bound to carrier proteins and are transported to the target location. In addition, based on the results of the Ames test (BASF 1995), Mouse lymphoma assay (BASF 1996) and Micronucleus test (BASF 2001) it can be assumed that the test substance is not enzymatically activated (toxified) during the metabolism as the parent compound showed no higher toxicity compared to the metabolic activated substance.

Excretion
Chemicals can be excreted via various routes and mechanisms. The excretion depends on the physical and chemical properties of the compound. The inert pigment will most likely be excreted unchanged via faeces. Due to the lack of adsorption, urinary excretion will not occur and bioaccumulation can most likely be excluded due to the neglible bioavailability of the test substance.