[2-(29H,31H-phthalocyaninylmethyl)-1H-isoindole-1,3(2H)-dionato(2-)-N29,N30,N31,N32]copper

Endpoint summary

Description of key information

For the UVCB substance with a higher average substitution grade, a 14-day study in rats with 300 and 1000 mg/kg bw of the substance showed absence of toxicity. No indication of systemic uptake as determined via serum copper concentrations was observed. For support, data on the smaller copper phthalocyanine core (CAS 147-15-8) is used. It shows lack of effects in rats and mice upon subchronic feed exposure. 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

For a similar substance, a 14-day study in rats with 300 and 1000 mg/kg bw of the substance showed absence of toxicity as determined by clincical chemistry, haematology, organ weight determinations, clinical observations and body weight measurements. Intestinal passage was indicated by a blue discoloration of feces; there was no discoloration of internal organs or of urine. For the full subacute toxicity study, read-across is done to the core structure.

Read-across to the blue pigment copper phthalocyanine (CAS 147-14-8) is justified because the target substance phthalimidomethyl copper phthalocyanine is as inert as its core structure. All available toxicological data (acute toxicity, irritation, sensitization, 14-day oral study, genotoxicity) show absence of adverse effects. The measured solubility in water is as low as for copper phthalocyanine. The solubility in octanol is higher, but with 1 mg/L still very low. The phthalimido group is unreactive and does not introduce a new hazard. For details on phthalimide it is referred to the dissiminated ECHA dossier and to the data matrix in the read-across justification. Phthalimide is not classified based on experimental data submitted to ECHA for a 10-100 tpa registration including an OECD 422 study (accessed November 7th, 2015). The same data was also used in the OECD HPV programme (SIAM 20, 2005).

The same pattern of an inert core and a non-reactive derivative is observed for the violet pigment quinacridone and its phthalimido quinacridone derivative (CAS 332142-67-3). The latter is of interest because the molecular weight of both the core and the derivative are lower than that of the target substance. This would make any hypothetical systemic uptake more likely. The phthalimido quinacridone derivative (CAS 332142-67-3) is nontoxic in all studies (subacute oral toxicity at the limit dose, genotoxicity, acute toxicity, irritation and sensitization; see data matrix). If of interest, data on the quinacridone core (Pigment Violet 19, CAS 1047-16-1) it is referred to the dissiminated REACH dossier. No adverse effects are were reported in any study.

 

Organic pigments are poorly soluble in water and organic solvents. For analytical purposes of the target substance, concentrated sulphuric acid needs to be used as other solvents are not suitable. In the absence of solubility, transport processes are not possible and no systemic uptake takes place.

 

For both copper phthalocyanine and its phthalimido derivative, copper concentrations in tissues were determined after 90-day and 14-day oral dosing of doses of 1000 mg/kg bw or higher. For neither substance, there was an increase in systemic copper concentrations. This is a strong indicator that there is no systemic uptake. In case of another organic copper pigment (Pigment Yellow 129) which disintegrates in stomach acid, 14-day oral dosing of 300 and 1000 mg/kg bw caused a clear and dose-dependent increase in liver copper concentrations. Liver is the known organ for copper storage. The fact that even 3-months feed application of up to 4500 mg/kg bw of rats and mice did not result in increased systemic copper concentrations shows that this core structure is inert. Indeed, this result was used as argument by the US authorities not to perform a carcinogenicity study under the US National Toxicology Program.

 

In conclusion, it is predicted that the NOEL for a 28-day oral toxicity study (OECD 407) will be at the limit dose.

A full read-across justification document with data matrix is attached in the toxicokinetic section of IUCLID.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Study on test substance

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)

The available studies are considered reliable and suitable for classification purposes under 67/548/EEC. No serious irreversible effects were observed at dose levels of less than 150 mg/kg bw upon subacute exposure. As a result the substance is not considered to be classified for repeated dose toxicity under Directive 67/548/EEC, as amended for the 31st time in Directive 2009/2/EG.

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. There were no significant toxic effects at doses of less than 300 mg/kg bw upon subacute oral exposure in rats. As a result the substance is not classified for repeated dose toxicity under Regulation (EC) No. 1272/2008, as amended for the third time in Directive EC 618/2012.