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

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

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.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

year of study report: 1991

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: secondary source, original study report not available

Objective of study:

toxicokinetics

Principles of method if other than guideline:

Tissue distribution of radioactivity was determined by whole body autoradiography at selected time points up to 48 hours after dosing of rats.

GLP compliance:

not specified

Radiolabelling:

yes

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

not specified

Duration and frequency of treatment / exposure:

single exposure and analysis of tissue distribution by autoradiography up to 48 h post exposure

No. of animals per sex per dose / concentration:

not stated

Control animals:

other: not required

Details on absorption:

Based on the distribution data there is no absorption by the oral route.

Details on distribution in tissues:

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 (according to the authors).

Details on excretion:

- "Most of the radioactivity was eliminated from the rats at 24 hours and it was virtually undetected at 18 hours post-dose."
- excretion seems to be via faeces

Metabolites identified:

not measured

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Under the conditons of this study, the systemic absorption of the test item (Pigment Violet 19) was negligible.

Executive summary:

In this toxicokinetic study, the radiolabelled test item (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.

Reference 3

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

year of study report: 1991

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: secondary source, original study report not available

Objective of study:

toxicokinetics

Principles of method if other than guideline:

Toxicokinetic study with oral administration of the radiolabelled test item and examination of the excretion via urine and feces.

GLP compliance:

not specified

Radiolabelling:

yes

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Duration and frequency of treatment / exposure:

single exposure with excreta collection up to 72 h post exposure

Remarks:

Doses / Concentrations:
3.22 mg/kg (33.68 uCi/kg) for males, 5.44mg/kg (56.81 uCi/kg) for females

Control animals:

other: not required

Details on absorption:

Based on the excretion data there is no oral absorption

Details on excretion:

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.

Metabolites identified:

not measured

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Under the conditons of this study, the systemic absorption of the test item was negligible.

Executive summary:

In this toxicokinetic study, the radiolabelled test item was administered orally per gavage to male and female F-344 rats as a suspension in aqueous 1% carboxymethyl cellulose (3.22 mg/kg (33.68 uCi/kg) for males, 5.44 mg/kg (56.81 uCi/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.

Reference 4

Endpoint:

basic toxicokinetics in vivo

Type of information:

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

Adequacy of study:

weight of evidence

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
[Please provide information for all of the points below. Indicate if further information is included as attachment to the same record, or elsewhere in the dataset (insert links in 'Cross-reference' table)]

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Please refer to attached read across justification document (Chapter 13).

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Please refer to attached read across document (Chapter 13).

3. ANALOGUE APPROACH JUSTIFICATION
Please refer to attached read across justification document (Chapter 13).

4. DATA MATRIX
Please refer to attached read across justification document (Chapter 13).

Reason / purpose for cross-reference:

read-across source

Control animals:

other:

Details on absorption:

Based on the distribution data there is no absorption by the oral route.

Details on distribution in tissues:

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 (according to the authors).

Details on excretion:

- "Most of the radioactivity was eliminated from the rats at 24 hours and it was virtually undetected at 18 hours post-dose."
- excretion seems to be via faeces

Metabolites identified:

not measured

Conclusions:

The toxicity profile of Pigment Violet 19 is assessed based on analogue approaches: : no bioaccumulation potential based on study results
Under the conditons of this study, the systemic absorption of the test item (Pigment Violet 19) was negligible.

Executive summary:

In this toxicokinetic study, the radiolabelled test item (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.

Reference 5

Endpoint:

basic toxicokinetics in vivo

Type of information:

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

Adequacy of study:

weight of evidence

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
[Please provide information for all of the points below. Indicate if further information is included as attachment to the same record, or elsewhere in the dataset (insert links in 'Cross-reference' table)]

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Please refer to attached read across justification document (Chapter 13).

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Please refer to attached read across document (Chapter 13).

3. ANALOGUE APPROACH JUSTIFICATION
Please refer to attached read across justification document (Chapter 13).

4. DATA MATRIX
Please refer to attached read across justification document (Chapter 13).

Reason / purpose for cross-reference:

read-across source

Details on absorption:

Based on the excretion data there is no oral absorption

Details on excretion:

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.

Metabolites identified:

not measured

Conclusions:

The toxicity profile of Pigment Red Violet 19 is assessed based on analogue approaches: no bioaccumulation potential based on study results
Under the conditons of this study, the systemic absorption of the test item was negligible.

Executive summary:

In this toxicokinetic study, the radiolabelled test item was administered orally per gavage to male and female F-344 rats as a suspension in aqueous 1% carboxymethyl cellulose (3.22 mg/kg (33.68 uCi/kg) for males, 5.44 mg/kg (56.81 uCi/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.

Reference 6

Endpoint:

basic toxicokinetics in vivo

Type of information:

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

Adequacy of study:

weight of evidence

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
[Please provide information for all of the points below. Indicate if further information is included as attachment to the same record, or elsewhere in the dataset (insert links in 'Cross-reference' table)]

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Please refer to attached read across justification document (Chapter 13).

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Please refer to attached read across document (Chapter 13).

3. ANALOGUE APPROACH JUSTIFICATION
Please refer to attached read across justification document (Chapter 13).

4. DATA MATRIX
Please refer to attached read across justification document (Chapter 13).

Reason / purpose for cross-reference:

read-across source

Conclusions:

The toxicity profile of Pigment Violet 19 is assessed based on analogue approaches: 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 results of the registration substance and the analobue substance, the registration substance is not likely bioavailable and no bioaccumulation potential is expected.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential