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Key value for chemical safety assessment

Additional information

The genotoxic activity of citral has been well investigated in several in vitro and in vivo studies performed according to or comparable to OECD guidelines.

In the chosen key study the mutagenic activity of citral (concentration range: 1 to 220 µg/plate) was investigated in Salmonella typhimurium strains TA98, TA100, TA1535 and TA1537 both in the absence or presence of metabolic activation (rat or hamster liver S9-mix) with a preincubation assay (test protocol comparable to OECD Guideline 471). No mutagenic activity was observed up to cytotoxic concentrations (NTP 1982).

In a further key study with Salmonella typhimurium strains TA98, TA100, TA97a and TA102 (concentration range: 5 to 700 µg/plate) using a plate incorporation assay (test protocol comparable to OECD Guideline 471) no mutagenic activity was observed up to cytotoxic concentrations (Gomes-Carneiro 1997).

In the key study for mutagenicity in mammalian cells according to OECD tG 476 and GLP, citral showed no mutagenicity activity at the HPRT locus in CHO cells up to cytotoxic concentrations, both in the absence and presence of a metabolic activation system (BASF 2008_50M0410/074062 ).

In the key study for cytogenicity in mammalian cells, a chromosomal aberration test in CHO cells performed in the absence and presence of a metabolic activation system using a test protocol comparable to OECD Guideline 473, there was no significant increase of chromosomal aberrations up to cytotoxic concentrations of citral (test concentration range: -S9 12.5-40.3 µg citral/mL; +S9 30.3-70.7 µg/mL) (NTP 1984_881385).

A sister chromatid exchange test in CHO cells was performed with citral in the absence and presence of a metabolic activation system using a test protocol comparable to OECD Guideline 479. A significant and concentration dependent increase of SCE above the solvent control was observed up to cytotoxic concentrations with and witout metabolic activation (NTP 1984_881385 ).

In the key and supportive study comparable to OECD Guideline 474, the induction of micronuclei in peripheral blood (NTP 1993_A84250) and in bone marrow polychromatic erythrocytes (NTP 1993_A66944) was investigated in B6C3F1 mice. There was no clastogenic activity in erythrocytes of male and female mice after 13 weeks of continuous feeding of a microencapsulated preparation of citral up to toxic doses of 8110 mg/kg bw/d in males and 7550 mg/kg bw/d in females (animals from the NTP subchronic toxicity study: NTP 2003b). Furthermore, citral showed no clastogenic activity in the micronucleus test in bone marrow of male mice in vivo after intraperitoneal injection (three doses of 0, 250, 500, 750, or 1000 mg/kg bw/d). The highest dose of 1000 mg/kg bw/d was lethal for all animals.

Based on the majority of the present in vitro data, there is no indication for mutagenic or clastogenic activity in bacteria and mammalian cells in vitro both in the presence and absence of metabolic activation. The absence of a clastogenic activity in vivo was confirmed in two micronucleus tests in peripheral blood and bone marrow cells of mice.


Short description of key information:
Bacterial mutagenicity test: negative in Ames test (NTP 1982, Gomes-Carneiro 1997)
Mammalian cell mutagenicity test: negative in HPRT assay in CHO cells (BASF 2008_50M0410/074062)
Mammalian cell aberration test: negative in CHO cells (NTP 1984_881385)
In vivo micronucleus test: negative in mouse peripheral blood erythrocytes (NTP 1993_A84250)

Endpoint Conclusion: No adverse effect observed (negative)

Justification for classification or non-classification

Cital has been found to be not mutagenic in bacteria and mamalian cells in vitro. Furthermore, no clastogenic effects of citral have been observed in the majority in vitro and in vivo studies.

Taken together, the present data on genotoxicity do not fulfill the criteria laid down in 67/548/EEC and CLP, and a non-classification is warranted.