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Carcinogenicity

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Description of key information

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The in-vitro and in-vivo experiments described in the dataset are in very good agreement with regards to the negligible level of bioavailability of the element Pr contained in the pigment, indicating a lack of any concern for carcinogenic properties.

(1) no signs of local toxicity in an acute inhalation toxicity test at the limit dose of 5.5 mg/L. The study has been performed according to OECD TG 403 and which shows no signs of acute toxicity after inhalation exposure to the pigment, indicating a LC50 > 5.5 mg/L. No mortality occurred. An acute oral toxicity test according to OECD 401 afforded a LD50 value of >2000 mg/kg.bw.

No signs of mutagenic or clastogenic potential in three different genetic toxicity test systemscould be observed.

(2) In in-vitro dissolution experiments in five different artificial physiological media, dissolved Zr, Si and Pr concentrations from this pigment were very low, corresponding to a solubility of less than 0.4%.

(3) In a 28-day oral toxicity study with 1,000 mg/kg pigment no increase in Pr plasma and urine concentrations were observed when sampled at the end of the 28-day exposure period. From a final dose of 1,000 mg/kg of the pigment that the animals received on the last day of the study, only cumulated relative amounts of < 0.00001 % (m/f) were found in the terminal 24-h urine collection period. 

(4)  In a mass balance study with a single oral dose of 1,000 mg/kg of the pigment, 102% Pr of the dose and 74.3% Zr were excreted via faeces within 3 days, with only <0.00001% Pr and < 0.002% Zr of the dose being excreted via urine at the same time.

(5)   In a bioavailability study, the absolute and relative bioavailability of orally administered pigment was calculated 0.00005/0.000007% Pr (m/f) in relation to a soluble Pr3+compound (PrCl3)injected i.v..

Comparing the findings ofin-vitrodissolution testing (2) within-vivoresults (1,3-5), thein-vivodata consistently demonstrates slightly lower bioavailability. This is in agreement with the general understanding thatin-vitroexperiments in simulated gastric juice provide a conservative estimate of actual (in-vivo) bioavailability.

In conclusion, the oral absolute and relative bioavailability of the pigment "Zirconium praseodymium yellow zircon" can be assumed to be negligible, as demonstrated in three independent in-vivo studies in rats yielding very comparable results, supported by in-vitro dissolution experiments in five different artificial physiological media.

A rounded value of <<0.01% for oral absorption can be taken forward from (i) terminal urine/plasma sampling in a study involving 28 repeated oral doses of 1,000 mg pigment/kg bw/d (<<0.00001%)and (ii) a mass balance study involving a single dose of 1,000 mg pigment/kg bw (0.00003% for Pr and <<0.00001% for Zr).

It is concluded that the pigment was well tolerated and that no signs of systemic toxicity whatsoever were observed in rats when administered at a dose of 1000 mg/kg bw/day for up to 28 days. Either no or only marginal increases in Pr plasma concentrations were observed, and only a minor fraction (<<0.001%) of the total administered dose of Pr was collected via urine, documenting the lack of bioavailability of this pigment. The no observed adverse effect level (NOAEL) in rats is 1000 mg/kg/day.

 

Overall conclusions

Considering the well-documented poor bioavailability, the absence of any indication of genotoxicity and the lack of any adverse findings in a 28d oral toxicity study, there is no concern for carcinogenicity to be anticipated.

Justification for classification or non-classification

It is concluded that the pigment was well tolerated and that no signs of systemic toxicity whatsoever were observed in rats when administered at a dose of 1000 mg/kg bw/day for up to 28 days. Either no or only marginal increases in Pr plasma concentrations were observed, and only a minor fraction (<<0.001%) of the total administered dose of Pr was collected via urine, documenting the lack of bioavailability of this pigment. The no observed adverse effect level (NOAEL) in rats is 1000 mg/kg/day.

No classification for carcinogenicity according toEC Regulation No. 1272/2008 is anticipated.