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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 Yellow 53 is 94.24 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 Yellow 53 has a very low water solubility of <0.1 mg/L. Due to the insolubility in water, the pigment can be regarded as not bioavailable.
With regard to the toxicological data, no signs of systemic toxicity were observed in the two acute oral toxicity studies (MHLW 2002, BASF 1978) as well as in the repeated-dose study (Bomhard et al. 1982, MHLW 2002). Administered to rats via gavage in two acute oral toxicity studies, C.I. Pigment Yellow 53 led to LD50 values of greater than 2000 mg/kg bw and above 10000 mg/kg bw without any clinical signs or mortality. Furthermore, the results of two long-term toxicity studies in rats (1st study: 90d rat: NOAEL ≥450 mg/kg bw/day; no bioavailability (OECD 408, Bomhard et al. 1982); 2n study: 46d (males)/ 41-45d (females) rat: NOAEL ≥1000 mg/kg bw/day (OECD 422, MHLW 2002)) confirmed the results of the in vitro leaching studies that organ translocation of ions from the crystal lattice could not be demonstrated.

Inhalation route
The test substance has low volatility potential due to its very low vapour pressure of 3.9E-09 Pa at 20 °C and 1.1E-08 Pa at 25 °C. Thus, inhalation as a vapour to a relevant extent is very unlikely. The available inhalation data also show that absorption via the inhalation route is not to be expected for the test substance. 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 metal ions was detected in a leaching study with C.I. Pigment Yellow 53 (BASF 2005). Furthermore, the substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Because the pigment is nearly insoluble, dermal uptake is assumed to be very 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.
Leaching studies with C.I. Pigment Yellow 53 were performed under different pH conditions (pH 1, 8.5 and 6.5) and in different type of media. The release of Sb is zero after substraction of the blanc. Leaching of Ni was only seen in artificial sweat at a very low level (14 ug/l after 2h, 28 ug/l after 24h). 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), Chromosome Aberration test (MHLW 2001) and HPRT test (BASF 1996) 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 Yellow 53 is a complex inorganic coloured pigment based on titanium dioxide with the molecular formula (Ti, Ni, Sb) O2. In the rutile lattice, titanium ions are partially replaced by nickel (II) and antimony (V) ions. The substance has a very low water solubility of <0.1 mg/L.

Toxicokinetic analysis of C.I. Pigment Yellow 53
C.I Pigment Yellow is a yellow powder at room temperature with a molecular weight of 91.24 g/mol, a density of 4-5 g/cm³ and a melting point >1000 °C. The substance has a very low water solubility of <0.1 mg/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 Yellow 53 is 94.24 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 Yellow 53 has a very low water solubility of <0.1 mg/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 two acute oral toxicity studies (MHLW 2002, BASF 1978) as well as in the repeated-dose study (Bomhard et al. 1982, MHLW 2002). Administered to rats via gavage in two acute oral toxicity studies, C.I. Pigment Yellow 53 led to LD50 values of greater than 2000 mg/kg bw and above 10000 mg/kg bw without any clinical signs or mortality. Furthermore, the results of two long-term toxicity studies in rats (1st study: 90d rat: NOAEL 450 mg/kg bw/day; no bioavailability (OECD 408, Bomhard et al. 1982); 2n study: 46d (males)/ 41-45d (females) rat: NOAEL 1000 mg/kg bw/day (OECD 422, MHLW 2002)) confirmed the results of the in vitro leaching studies that organ translocation of ions from the crystal lattice could not be demonstrated.

Inhalation route:
The test substance has low volatility potential due to its very low vapour pressure of 3.9E-09 Pa at 20 °C and 1.1E-08 Pa at 25 °C. Thus, inhalation as a vapour to a relevant extend is very unlikely. The available inhalation data also show that absorption via the inhalation route is not to be expected for the test substance. 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 leaching of metal ions in artificial sweat medium for 24h was very poor for Sb ions (1.2 ppm, approx. 0.00012 ug/cm2/week) and low for Ni ions (28 ppm, approx. 0.0028 ug/cm2/week) (BASF 2017). The value obtained for Ni is very well below the treshold of Ni-containing alloys regarding skin sensitization (CLP, Annex I, Note U, 7). 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.
Leaching studies with C.I. Pigment Yellow 53 were performed at different pH conditions (pH 1, 8.5 and 6.5) and in different test media (artificial sweat, artificial gastric juice). The values obtained in these assays reflect a poor release of the ions from the rutile structure. Leaching of all ions (Ni, Sb and Ti, respectively) in artificial sweat is below the skin sensitization threshold for Ni-containing alloys. The release under low pH condistions (gatric juice simulant) for 2h and 24h remains also within the low ppm range. 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), Chromosome Aberration test (MHLW 2001) and HPRT test (BASF 1996) 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 which is supported by the observation of yellow stained feces after single oral administration. 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.