5,12-dihydro-2,9-dimethylquino[2,3-b]acridine-7,14-dione

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics, other

Type of information:

other: Expert statement

Adequacy of study:

supporting study

Study period:

2020

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Evaluation of available data with regard to toxico-kinetics

Objective of study:

other: Evaluation and Assessment of the Basic Toxicokinetic Properties of C.I. Pigment Red 122

Qualifier:

no guideline available

Principles of method if other than guideline:

Available toxicologic data were evaluated with regard to toxico-kinetic properties.

GLP compliance:

no

Details on absorption:

A prerequisite for a relevant absorption is that the substance can be dissolved in either aqueous (e.g., gastro-intestinal fluid, blood plasma, sweat) or lipophilic (e.g., lipoproteins, lipid membranes, triglycerides) media or in both. C.I. Pigment Red 122 can be considered insoluble because it has an extremely low solubility in water and n-octanol. Therefore, it is unlikely that C.I. Pigment Red 122 becomes systemically bioavailable after oral, dermal or inhalation exposure. The available data on bio-availability confirm this notion.
Based on the sub-chronic oral toxicity study absorption of toxicologically significant amounts of C.I. Pigment Red 122 via the gastrointestinal tract is considered unlikely, since it did not show any effects on inner organs and blood or urine. No pigment was detected in liver or blood samples.
The skin sensitization as well as the acute dermal data indicate neither local nor systemic dermal bioavaila-bility. Dermal absorption, therefore, is considered unlikely
In the unlikely event of exposure to aerosolized pigment in respirable form, the substance is considered to behave like an inert dust. Therefore, the deposited pigment particles will mostly be cleared from the lung via the mucocilliary transport. As the pigment will not dissolve in the lung surfactant, the only way the pigment can enter the body is via phagocytosis of pigment particles by lung macrophages followed by migration of the macrophages into the interstitium and into the draining lymph nodes. However, the internal dose delivered via this mechanism can be considered negligible. The acute inhalation toxicity study showing no adverse effect at the highest technical achievable concentration of ca. 3 mg/L strongly supports this view.

Details on distribution in tissues:

The Repeated Dose Toxicity Study did not indicate any relevant histopathological changes in any of the investigated organs. This may indicate that the pigment either does not affect spe-cific organs as targets, i.e. is non-toxic, or is not distributed within the body in significant amounts. As indicated above, the physico-chemical parameters of the pigment support the conclusion that the pigment is not absorbed into the body and thus does not become systemi-cally available. There were also no other signs of deposition of the intensely colored pigment in any organ including excretory organs, like the kidney, indicating that even exposure to high doses of the pigment does not lead to bioaccumulation in special compartments of the body. No traces of pigment were found in samples of dried blood and liver tissue by analysis via HPLC with a limit of detection below 1.5 ppm.

Key result

Transfer type:

secretion via gastric mucosa

Observation:

no transfer detectable

Details on excretion:

Taking into account the physico-chemical properties and the molecular structure of the mate-rial and the absence of any indication of absorption and/or metabolism it is assumed that ex-cretion, if any, is likely to occur via faeces. This notion is confirmed by the discoloration of faeces observed in the subchronic study as the only alteration.

Metabolites identified:

not measured

Details on metabolites:

Since the dissolution of the substance in cellular fluid or cellular membranes is a prerequisite for its metabolism, it is unlikely that the insoluble pigment becomes accessible for metaboliz-ing systems in relevant amounts.
The results of the mutagenicity tests provide useful indications for qualitative consideration of the metabolic fate of C.I. Pigment Red 122. In the mutagenicity tests, the pigment proved to be non-mutagenic in the absence as well as in the presence of an exogenous metabolizing system, indicating that the pigment is not converted into toxic or genotoxic metabolites. This conclusion is also supported by the lack of any morphological and histopathological changes of organs involved in xenobiotic metabolism, such as the liver, in the Repeated Dose Toxicity Study. Furthermore, the missing skin or eye irritating or skin sensitizing properties argue against any interaction with biological material.

Therefore, C.I. Pigment Red 122 is considered to just pass through the intestinal tract without significant metabolism.

Bioaccessibility (or Bioavailability) testing results:

See chapter: Absorption

Conclusions:

There were no signs of significant bioavailabilty of pigmnet red 122.

Executive summary:

Based on the available database on C.I. Pigment Red 122 relevant information exists to make a qualitative evaluation of the toxico-kinetic profile of this compound. This is in line with animal welfare considerations because additional animal tests can be avoided by such an evaluation.

The results of basic toxicity testing give no reason to anticipate unusual characteristics with regard to the toxico-kinetics of C.I. Pigment Red 122. The data indicate that there is no relevant dermal absorption. C.I. Pigment Red 122 is not absorbed from the gastro-intestinal tract in toxicologically significant amounts. Indications of a bio-accumulative potential as well as metabolism towards genotoxic sub-structures do not exist. Excretion of small amounts of possibly systemically available C.I. Pigment Red 122 and/or metabolites via faeces is likely.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2009

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: no GLP compliance, low recovery

Reason / purpose for cross-reference:

reference to same study

Objective of study:

other: test for bioavailability

Principles of method if other than guideline:

analysis of test item in liver and blood samples obtained from male and female rats subjected to a 90-day oral toxicity study using HPLC

GLP compliance:

no

Radiolabelling:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

other: 0.5% (w/v) carboxymethylcellulose in distilled water

Duration and frequency of treatment / exposure:

13 weeks + 4 weeks recovery

Remarks:

Doses / Concentrations:
0 (control), 50, 200, 1000 mg/kg bw

No. of animals per sex per dose / concentration:

10 males and 10 females
The high dose group and the control group included 5 additional animals per sex sacrificed after 4 weeks of recovery

Control animals:

yes, concurrent vehicle

Details on dosing and sampling:

- samples were collected at the end of the 90-day exposure period
- liver samples of 4 males and 5 females of the control group and 5 males and 4 females of the 1000 mg/kg bw group were analysed
- blood plasma samples of 2 males and 1 female of the control group and 3 males and 2 females of the 1000 mg/kg bw group were analysed

- liver samples were thawed and freeze dried, dried liver samples were pulverized and mixed with N-methylpyrrolidone (NMP), sonificated for 30 minutes and then filtered using 0.2 µm membrane filters; resulting clear solutions were analysed for the content of Pigment Red 122 by HPLC

- frozen blood plasma was thawed and freeze dried, dried samples were pulverized and mixed with N-methylpyrrolidone; mixtures were stirred at 100°C for 3 hours and then filtered using 0.2 µm membrane filters; resulting clear solutions were analysed for the content of Pigment Red 122 by HPLC

- limit of detection:
- about 1.5 ppm test item in liver
- about 0.4 ppm for male rats (10 ml NMP extraction volume) and about 0.6 ppm for female rats (15 ml NMP extraction volume)

- recovery rates from liver were between 43% and 59% with tendency to increase with the amount of test item used for spiking the liver samples

- no test item was identified in the chromatograms of the samples from the control animals

- no test item was identified in the chromatograms of the samples from the animals that had received 1000 mg/kg bw for 90 days, i.e. the concentration of the test item in dried liver was below the limit of detection of 1.5 µg/g

- recovery rates from blood plasma were between 20% and 39% with tendency to increase with the amount of test item used for spiking the plasma samples

- no test item was identified in the chromatograms of the samples from the control animals

- there was a shoulder in the background peaks that resulted from extracted blood plasma constitutents that interfered with the test item peak leading to some uncertainty in quantification, the estimated concentration of the test item in dried blood plasma was always below 1 µg/g

Conclusions:

Interpretation of results (migrated information): other: test item is not bioavailable
Test item concentrations in liver and blood plasma samples of male and female rats that had received Pigment Red 122 at 1000 mg/kg/day during a 90-day subchronic oral toxicity study (total administered dose 90000 mg/kg) were below quantifiable limit concentrations of 1.5 ug/g dried liver and 0.4 / 0.6 ppm dried blood plasma.

Executive summary:

The study aimed at generating data on the bioavailability of Pigment Red 122 after oral administration. To this end, liver and blood plasma samples were analysed that were obtained from male and female rats subjected to a 90-day subchronic oral toxicity study with Pigment Red 122. The organ samples were extracted and analysed 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.

Description of key information

Based on the available database on C.I. Pigment Red 122 relevant information exists to make a qualitative evaluation of the toxico-kinetic profile of this compound. This is in line with animal welfare considerations because additional animal tests can be avoided by such an evaluation.

The results of basic toxicity testing give no reason to anticipate unusual characteristics with regard to the toxico-kinetics of C.I. Pigment Red 122. The data indicate that there is no relevant dermal absorption. C.I. Pigment Red 122 is not absorbed from the gastro-intestinal tract in toxicologically significant amounts. Indications of a bio-accumulative potential as well as metabolism towards genotoxic sub-structures do not exist. Excretion of small amounts of possibly systemically available C.I. Pigment Red 122 and/or metabolites via faeces is likely.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential