4,11-dichloro-5,12-dihydroquino[2,3-b]acridine-7,14-dione

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

Please see the attached justification.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Details on absorption:

no bioaccumulation potential, systemic absorption negligible

Details on distribution in tissues:

virtually no bioavailability (substance not detectable in liver and blood of animals exposed orally at 1000 mg/kg/day for 90 days)

Description of key information

The test substance has not been tested for toxicokinetics, metabolism and distribution.

However, in a reliable GLP-conform study according to OECD TG 318 it was observed that the dispersion stability of Pigment Red 207 at low pH values (pH 4) was rather low. Therefore it can be assumed that the Pigment 207 might agglomerate at gastric pHs and is less likely to be absorbed in the gastrointestinal tract. No indication of uptake or reactivity was observed in any study, including acute, irritation, sensitization, repeated dose toxicity and reproduction studies. Studies assessing genotoxicity were negative, i.e. there was no indication of a reactivity of the test substance or potential metabolites with macromolecules under the chosen test conditions.

Additionally, several reliable data are available for other quinacridone pigments (Pigment Violet 19 and Pigments Red 122).

All available data are summarized below:

• The substances of this category have extremely low solubilities in water.


• Body autoradiography of rats which were orally treated with radiolabelled Pigment Violet 19 revealed that radioactivity was only localized in the gastrointestinal tract. No radioactivity was detected in other organs and tissues.


• In rats which received a single oral dose of radiolabelled Pigment Violet 19 more than 90% of the recovered radioactivity was determined in the feces and cage washes (which appeared to contain residual fecal matter) indicating that Pigment Violet 19 was eliminated almost completely in the feces of rats after oral dosing.


• No Pigment Red 122 was quantifiable in blood plasma and liver samples of rats treated with 1000 mg/kg bw by gavage for 90 days.


• No acute toxicity was observed for the substances of this category after oral, dermal or inhalation exposure.


• No toxicity was observed for the substances of this category after subacute or subchronic oral application (NOAEL 1000 mg/kg bw).

Therefore it is concluded, that it is unlikely that the substances of this category become systemically bioavailable after ingestion or skin contact. Upon inhalation of a pigment product with a particle size distribution allowing deposition in the lower respiratory tract, uptake and transport of pigment particles by macrophages may occur as for other inert dust particles.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The test substance has not been tested for toxicokinetics, metabolism and distribution. However, in a reliable GLP-conform study according to OECD TG 318 it was observed that the dispersion stability of Pigment Red 207 at low pH values (pH 4) was rather low. Therefore it can be assumed that the Pigment 207 might agglomerate at gastric pHs and is less likely to be absorbed in the gastrointestinal tract. No indication of uptake or reactivity was observed in any study, including acute, irritation, sensitization, repeated dose toxicity and reproduction studies. Studies assessing genotoxicity were negative, i.e. there was no indication of a reactivity of the test substance or potential metabolites with macromolecules under the chosen test conditions.

 

Additionally, several reliable data are available for other quinacridone pigments (Pigment Violet 19 and Pigments Red 122).

 

In one toxicokinetic study (secondary literature, Klimisch score 4), radiolabeled Pigment Violet 19 was administered orally to groups of male and female Fisher 344 rats by gavage. The tissue distribution of radioactivity was determined by whole body autoradiography at selected times up to 48 hours after dosing. The autoradiogram showed that radioactivity was localized only in the gastrointestinal tract of both male and female rats. No radioactivity was detected in other organs and tissues of the animals. The highest concentrations of radioactivity were found at 2 hours post dosing . Most of the radioactivity was eliminated from the rats at 24 hours and it was virtually undetected at 18 hours post-dose.

Radiolabeled Pigment Violet 19 was also administered as a suspension in aqueous 1 % carboxymethyl cellulose (3.22 mg/kg (33.68 µCi/kg) for males, 5.44 mg/kg (56.81 µCi/kg) for females). Urine and feces were collected from each rat at 2, 8, 24, 48 and 72 hours after dosing; cage washes and gastrointestinal tract of each rat were removed after euthanasia at 72-hour post-dose. Recovery of administered radioactive dose was virtually complete: 91.9 +/- 6.9 % of dose males; 100.5 +/-8.7 % of dose females. There were no gender related differences in the route of excretion. More than 90 % of the recovered radioactivity was eliminated in the feces and cage washes, which appeared to contain residual fecal matter. At 72 hours virtually all radioactivity had been eliminated by the rats. The urine from both groups of rats contained very low amounts of radioactivity, 0.0089 % of dosed males; 0.0020 % of dose females.

 

In a reliable study (Klimisch score 2) the bioavailability of Pigment Red 122 after oral administration was investigated. Liver and blood plasma samples obtained from male and female rats subjected to a 90-day subchronic oral toxicity study were analyzed. The organ samples were extracted and analyzed with high-performance liquid chromatography (HPLC) for the presence of Pigment Red 122. The recovery rates were between 43 % and 59 % for liver samples and between 20 % and 39 % for blood plasma samples. In both cases there was a tendency of the recovery rate to increase with the amount of Pigment Red 122 used for spiking the samples. Attempts to increase the recovery by altering the extraction time or temperature were not successful. Given the extremely low solubility of Pigment Red 122 in water and most organic solvents, the obtained recovery rates were considered acceptable. The limits of detection were estimated at about 1.5 ppm for dried liver and 0.4 / 0.6 ppm for dried blood plasma. Analysis of organ samples from animals of the high dose group that had received 1000 mg Pigment Red 122/kg/day for consecutive 90 days revealed no concentrations of Pigment Red 122 above the detection limits. For both organs, in chromatogram region of the Pigment Red 122 peak at 16.9 minutes, there was a shoulder in the chromatogram caused by extracted blood plasma or liver constituents. This led to some variability in the peak area in this region between the samples. In some samples, a shoulder in the region of the Pigment Red 122 peak was visible. However, the estimated concentration of Pigment Red 122 in dried blood plasma was always below 1 µg/g. No Pigment Red 122 peak was visible in the chromatograms of the extracts of liver samples of the rats that had received 1000 mg Pigment Red 122/kg/day for 90 consecutive days.

 

It can be concluded that it is unlikely that the substances of this category become systemically bioavailable after ingestion or skin contact. Upon inhalation of a pigment product with a particle size distribution allowing deposition in the lower respiratory tract, uptake and transport of pigment particles by macrophages may occur as for other inert dust particles.