Carbazole

Endpoint summary

Additional information

Genetic toxicity In vitro

Bacterial assays

Even though all Ames tests conducted exhibit some deviations from today valid test guidelines, there is consistent and unequivocal evidence that carbazole does not induce any mutagenic response (Purchase et al. 1978, LaVoie et al. 1982, Florin et al. 1980, Epler et al . 1979). In addition, no mutagenicity was observed in a bacterial forward mutation assay (not validated test system) (Kaden et al., 1979).

 

UDS test with primary hepatocytes

Carbazole administered at graduated concentrations from 0.167 to 167 mg/L was demonstrated not to induce unscheduled DNA synthesis in primary rat hepatocytes up to the highest concentration tested where toxic effects and precipitation of carbazole were observed (Weyand et al. 1993). Carbazole is not active in the Unscheduled DNA Synthesis/Repair assay indicating not to cause genetic mutations or DNA damage.

 

Genetic toxicity in vivo

 

Three different tests have been performed to investigate the genetic toxicity of carbazole in vivo (executed by one and the same working group). In contrast to the in vitro tests, carbazole was tested positive in vivo after i.p. treatment in mouse.

 

Mouse bone marrow chromosome aberration test (Jha et al. 2002)

In an in vivo mammalian bone marrow cell chromosome aberration test similar to OECD test guideline 475, carbazole was tested in mice using five graduated doses (25 to 200 mg/kg bw) and two sampling regimens (after 14 and 42 h). The test results show that carbazole is moderately clastogenic to bone marrow cells of mouse under the test conditions used. Statistically significant changes compared to solvent controls in mitotic index (decrease) and in the frequency of chromosome aberrations (increase) could be demonstrated for the two highest doses administered (150 and 200 mg/kg).

 

Rodent Dominant Lethal Assay (Jha et al. 2002)

In the Rodent Dominant Lethal Test similar to OECD test guideline 478, carbazole was administered to two groups of 20 male mice each by intraperitoneal injection at 5 consecutive days at doses of 30 and 60 mg/kg bw/day (150 and 300 mg/kg bw total). Males were mated with two females each after the end of administration for four 7-day periods. At both doses, carbazole induced significant effects on reproductive performance of the male mice: The number of successful pregnancies (fertility) was reduced; the number of implants and live implants per female was significantly reduced especially for mating period 1 and 2 as well as mating period 3 for the high dose group. Effects were more pronounced for the high dose group than for the low dose group.

Mouse sperm morphology assay (Jha et al. 2002)

Carbazol induced a dose-related increase in the incidence of mouse-sperm head abnormalities for all three sampling times (1, 3, and 5 weeks after i.p. injection of graduated single doses from 50 to 300 mg/kg bw), somewhat more pronounced after 3 week.

Short description of key information:
Available information on the genetic toxicity of carbazole is inconsistent.
In all in vitro genotoxicity tests (backward and forward bacterial gene mutation, unschelduled DNA synthesis in primary hepatocytes), carbazole did not induce any mutagenic response.
In three in vivo genetic toxicity assays following i.p. injection (bone marrow chromosomal aberration, dominat lethal, and mouse sperm morphology test), carbazol proved to be positive.

Endpoint Conclusion: Adverse effect observed (positive)

Justification for classification or non-classification

The experimental positive results of in-vivo mutagenesis in mice justify classification for the possibility of irreversible damage:

Proposal: R68, Possible risk of irreversible effects