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Gene mutation in bacteria

In the key study according to OECD TG 471 and GLP, Nerolidol was not mutagenic with and without metabolic activation when tested up to 5000μg/plate using Salmonella typhimurium TA 1535, TA 100, TA 1537, TA 98, E. coli WP2 uvrA (BASF40M0004/974021).


No further data for genetic toxicity in-vitro are available for nerolidol. However, reliable studies which were conducted with the structurally related linalool (CAS No. 78-70-6) were adopted for the assessment of nerolidol via read-across.

Inclusion of linalool into the assessment of genotoxicity is justified by the structural similarity between linalool and nerolidol. Both structures are terpenes, share the same functional groups, except for an additional isoprene unit found in nerolidol.


Gene mutation in mammalian cells

In the key study, linalool was tested in the L5178Y mouse lymphoma forward mutation assay using a current protocol in which osmolality was controlled and the pH maintained at or above 7.0. Doses up to 200 µg/ml (with activation) and up to 224 µg/ml (without activation) did not induce a mutant frequency that exceeded the minimum criterion for a positive response and were evaluated as negative under conditions of the test (Lorillard 15880 -0 -4 -311R).

Further studies in literature, reporting positive results for linalool in mouse lymphoma assay are considered to be associated with changes in physiologic culture conditions (pH and osmolarity).


Cytogenicity in mammalian cells

In the key study, i.e. an in-vitro mammalian chromosome aberration test, a Chinese hamster fibroblast cell line was exposed to linalool at 0.0625, 0.125, 0.250 mg/ml for 24 and 48 hours in the absence of a metabolic activation system. Linalool did not cause chromosomal abberations up to the highest concentration tested (Ishidate 1984).

In the key study, i.e an in-vitro sister chromatid exchange assay, Chinese hamster Ovary (CHO) cells were exposed to linalool at 0, 33.3, 100, 333, 1000 µM for 21 hours in the absence of a metabolic activation system (Sasaki 1989). No increase of the frequency for sister chromatid exchange levels were observed at any dose level.



In the chosen key study, nerolidol was assessed in NMRI mice using the micronucleus test method acc. to OECD 474 and GLP (BASF 2013; 26M0466/09M030). Nerolidol was administered once orally to male animals at dose levels of 250, 500, 1 000 and 2 000 mg/kg body weight in a volume of 10 mL/kg body weight in each case. The animals were sacrificed and the bone marrow of the two femora was prepared 24 and 48 hours after administration in the highest dose group and in the vehicle controls. In the test groups of 250, 500 and 1 000 mg/kg body weight and in the positive control groups, the 24-hour sacrifice interval was investigated only. As additional parameter the subcutaneous body temperature was determined.

As vehicle control, male mice were administered merely the vehicle, corn oil, by the same route and in the same volume as the animals of the dose groups, which gave frequencies of micronucleated polychromatic erythrocytes within the historical vehicle control data range. Both positive control substances, cyclophosphamide for clastogenicity and vincristine sulfate for spindle poison effects, led to the expected increase in the rate of polychromatic erythrocytes containing small or large micronuclei. No relevant inhibition of erythropoiesis determined from the ratio of polychromatic to normochromatic erythrocytes was detected. Besides, the body temperature was not relevantly influenced in any dose group at both sacrifice intervals.

According to the results of the present study, the single oral administration of nerolidol did not lead to any relevant increase in the number of polychromatic erythrocytes containing either small or large micronuclei. The rate of micronuclei was close to the range of the concurrent vehicle control in all dose groups and at all sacrifice intervals and within the range of the historical vehicle control data.

Thus, under the experimental conditions of this study, the test substanceNerolidoldoes not induce cytogenetic damage in bone marrow cells of NMRI mice in vivo.

Further in vitro mutagenicity studies on the trans-isomer of nerolidol (CAS 40716-66-3; not further specified) are available as publications, i.e. a Comet-assay and a Micronucleus test (Piculo, 2011). Swiss Albino mice have been treated orally (gavage) with a single dose of 250, 500 and 2000 mg/kg bw nerolidol in DMSO and peripheral blood cells were collected 4 and 24 h after the treatments and liver cells 24 h after treatment. At least 100 nucleoids per cell type/animal were analyzed to determine the DNA damage scores and 2000 PCEs per animal for micronuclei in PCEs. The positive control was N-nitroso-N-ethylurea 50 mg/kg bw. Cytotoxicity was assessed by scoring 200 consecutive total polychromatic (PCE) and normochromatic (NCE) erythrocytes (PCE:NCE ratio).

ENU induced a statistically significant increase in micronucleated polychromatic erythrocytes (MNPCE) in the micronucleus assay. A weak and dose-related enhancement in the mean number of MNPCE with statistical significance for doses of 500 and 2000 mg/kg body weight, was observed.The PCE:NCE ratio showed no cytotoxicity up to the highest dose tested.According to the authors, the test substance induced a clastogenic effects on bone marrow cells of mice. However, this result could not be confirmed in a guideline conform study according to GLP principles with the registered substance, i.e. cis-trans-nerolidol (BASF SE 2013, 26M0466/09M030, see above) containing approx. 60% trans-nerolidol.

In the comet assay, ENU induced statistically significant increases in DNA migration of all cells and conditions investigated. Furthermore, DNA damage was statistically significantly increased in peripheral blood and liver cells after treatment with trans-nerolidol in comparison to the vehicle control group. However, the increase in DNA damage was weak when compared to the positive control values. To evaluate the extent of DNA damage, cells were analyzed visually and assigned to different classes according to tail size. This subjective method represents a point of criticism concerning the validity of this study and is no longer state of the art. Despite the performed blind analysis, this approach may lead to inaccurate results. In particular, it can be difficult to distinguish between spontaneous damaged cells (“background noise”) and cells with minor damage. The calculation of cell damage (“scores”) via multiplying the number of cells in each class by the damage class is arbitrary and difficult to justify. Therefore, the comparison of mean values of different test groups is contestable. Furthermore, no information on historical vehicle control data range is given for the animal strain and the respective laboratory. The observed weak increase of DNA migration in the comet assay of test substance treated samples cannot be correlated without doubt to trans-nerolidol treatment. The authors interpreted their results of the micronucleus test and the comet assay with caution. In their final conclusion they summarized: “…, analyzing high doses of one monosubstance, indicates a clastogenic (MNT in vivo) and weak genotoxic potency (comet assay in vivo) of nerolidol in mouse cells”.

Overall, this publication has only limited importance for the assessment of genotoxicity.


In support, a reliable study which was conducted with the structurally related linalool (CAS No. 78-70-6), which was adopted to nerolidol by read-across: An oral in vivo mouse micronucleus test was conducted (acc. to GLP requirements and OECD 474; DSM 328826). The test substance was administered once orally to male and female NMRI mice at doses of 500, 1000 and 1500 mg/kg body weight. No significant difference has been reported between the vehicle control and any of the linalool dosage groups. Clinical signs of toxicity (lethargy and ataxia) were seen at doses ≥ 500 mg/kg bw.


Overall, based on the key studies available for the registered substance, i.e. cis/trans-nerolidol (CAS 7212-44-4) and structurally related compound linalool, nerolidol is determined to be non-genotoxic.

Justification for classification or non-classification

The present data on genetic toxicity do not fulfill the criteria laid down in 67/548/EEC and 1272/2008/EEC and therefore, a non-classification is warranted.