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Description of key information

TOXICOKINETIC ANALYSIS:

 

There are no specific toxicokinetics or dermal absorption studies available for Pigment Red 81:5 (Xanthylium, 9-[2-(ethoxycarbonyl)phenyl]-3,6-bis(ethylamino)-2,7-dimethyl-, molybdatesilicate). Therefore, in line with ECHA's Guidance on Information Requirements and Chemical Safety Assessment chapter R.7c [1] the main toxicokinetic properties of Pigment Red 81:5 are assessed on the basis of its physico-chemical properties and with special regard to the results of the standard toxicity studies performed with this substance.

 

Pigment Red 81:5 is a dark red powder at room temperature with a molecular weight of ≥ 3700 ≤ 8200 g/mol. A log Pow of 1 was estimated from the estimates of solubilities of the substance in n-octanol and water.

 

The vapour pressure could not be determined as the substance is a solid with a melting point > 350 °C.

 

The test substance is a UVCB with a purity of 100% (w/w).

 

Absorption

 

Oral route

 

Based on its high molecular weight of ≥ 3700≤ 8200g/mol Pigment Red 81:5 is not likely to be quantitatively absorbed in the GI tract since large molecules with a molecular weight above 1000 g/mol do not favour absorption. However, this assumption is not supported by the results of the acute and repeated dose oral toxicity studies with Pigment Red 81:5 indicating signs of systemic toxicity after exposure to the test substance. Pink coloured faeces (due to the test item) was seen from day 3 in males and females of all dose levels indicating unabsorbed test item or excretion of unchanged test item. However, following repeated exposure up to the limit dose of 1000 mg/kg bw/day, histopathological findings in kidneys (tubular basophilia found at all dose levels) which correlated with an increase observed at 1000 mg/kg/day in creatinine in males and in urea in males and females when compared to controls indicated that the test item was able to pass the intestinal wall in toxicologically relevant amounts. Also an increase was observed in albumin at 300 and 1000 mg/kg/day and in females, a trend to higher kidneys weight was observed when increasing the dose.

In conclusion, oral absorption is considered to be have occurred.


 

Inhalation route

 

The vapour pressure of Pigment Red 81:5 could not be determined because the melting point of the substance was >350°C. Therefore, the substance is not volatile, and inhalation to vapours is not relevant.

 

The particle size distribution of Pigmemt Red 81:5 was determined by laser scattering/diffraction to be VMD = 80.97 µm (D10 = 14.37 µm, D50 = 58.47µm and D90 = 185.47 µm), as the particle size of the material is 100% greater than 10 µm, all of the test substance, if inhaled, would be expected to be deposited in the upper respiratory tract and may be transported to the stomach via the mucociliary escalator. From here, it would be subjected to the same fate as any test substance that was dosed orally. Hazard identification and characterization for airborne exposures may, therefore, be extrapolated from data collected following oral administration. No experimental study was performed.

In conclusion, absorption via the inhalation route is assumed to be negligible.

 

Dermal route

 

Based on the molecular weight of > 500 g/mol, low solubility in water, and absence of skin corrosion properties, skin permeability of Pigment Red 81:5 is expected to be very poor.

 

No indication of systemic availability (i.e. systemic toxicity or discoloured urine) was observed in the LLNA with Pigment Red 81:5 in mice.

 

In conclusion, absorption via the dermal route is assumed to be negligible.

 

Distribution

 

As clinical signs were observed in a repeat dose oral toxicity studies with Pigment Red 81:5, a distribution to potential target organs is considered to have occurred. Furthermore, there was an indication of distribution to certain target organs based on macroscopic and histopathology examinations following repeated oral exposure of Pigment Red 81:5. Due to the molecular weight of > 3700 g/mol, distribution through aqueous channels and pores is restricted.

An accumulative potential in adipose tissue can be excluded due to the estimated very low solubility in water and n-octanol (value of <0.1 mg/L).

 

 

Metabolism

 

In the Ames test and the in vitro gene mutation test in mammalian cells with Pigment Red 81:5 and the in vitro micronucleus test with Pigment Red 81:5 no remarkable differences in regard to genotoxicity and cytotoxicity were seen in the presence or absence of metabolic activation systems. The results indicate that neither genotoxic nor more cytotoxic metabolites were formed in those test systems.

 

Generally, metabolism will render a xenobiotic molecule more polar and harmless, leading to fast and quantitative excretion.

 

Excretion

 

In the acute and repeated dose oral toxicity studies with Pigment Red 81:5 in rats pink/red discoloration of feces was observed. These results indicate that a direct excretion via the feces without former GI tract absorption of the test substance represents the main excretion route after oral exposure.

 

Substance characteristics favourable for urinary excretion are low molecular weight (below 300 g/mol in the rat), good water solubility, and ionization at the pH of urine. Pigment Red 81:5 does not fulfil these characteristics. Also, no discoloured urine was observed in the acute and repeated dose oral toxicity studies with Pigment Red 81:5.

 

References

 

[1] ECHA (2017), Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance, Version 3.0, June 2017

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information