Reaction mass of geranyl acetate and neryl acetate

Carcinogenicity

Justification for classification or non-classification

The present data on carcinogenicity are not sufficient to fulfill the criteria laid down in 67/548/EEC and regulation (EU) 1272/2008 and therefore, a non-classification is warranted.

Additional information

No data on carcinogenicity are available for the reaction mass. To evaluate the carcinogenic potential of one of the main components, i.e. geranyl acetate, a 2 year study with food grade geranyl acetate performed by NTP (1987) was taken into account for assessment.

In this study, 50 F344 rats per sex and dose were gavaged with doses of 1000 and 2000 mg/kg bw/day of a solution of food-grade geranyl acetate containing 71% geranyl acetate (CAS 105-87-3) and 29% citronellyl acetate (CAS 150-84-5). Administration was 5 times a week for 103 weeks. For analysis, all animals were observed twice daily for signs of morbidity or mortality and clinical signs and body weights were recorded every week for the first 12 weeks and monthly thereafter. Major tissues or organs were examined for grossly visible lesions. A detailed histopathological examination was performed.

Increased mortality was observed in the males group treated with the highest test dose of 2000 mg/kg bw/d, indicating a cumulative toxicity of the test substance. The body weights were reduced after 40 weeks and an evident depression in bodyweight gain was observed in males and females at 2000 mg/kg bw/d. No compound-related clinical signs were observed an any dose level.

Increased incidence of retinopathy or cataracts has been observed in high dose males and low dose females. These findings were stated not to be related to test substance administration but to the proximity of the rats to a source of fluorescent light.

Increased incidence of nephropathy was found in high dose animals. However, an inconsistent dose response relationship, i.e. lower incidences in the low dose group compared to control animals, has been observed, questioning a clear relationship to test substance administration.

A negative trend in the incidences of mammary gland fibroadenomas, pituitary adenomas and pancreas islet cell adenoma/carcinoma was observed in test substance treated animals. Neoplastic lesions of interest were as follows:

Two males of the low dose group displayed kidney tubular cells adenoma which has not been found in high dose and control male animals. Furthermore increased incidences of skin squamous cell papilloma/carcinoma have been observed in the low dose males, which were lower in high dose and control animals. The authors stated that the observed increased mortality in the high dose group lowered the sensitivity of the study for detecting neoplastic substance-related changes, and a relationship to test substance administration cannot be fully excluded.

However, the lesions squamous cell papillomas/carcinomas and kidney tubular cell adenomas, could not be clearly associated with the administration of the test substance and under the conditions of the present study, the test substances geranyl acetate/citronellyl acetate were not found to be carcinogenic.

In the supportive study from the same authors, 50 male and female B6C3F1 mice were treated with food-grade geranyl acetate (71% geranyl acetate and 29% citronellyl acetate) orally via gavage with doses of 500 and 1000 mg/kg bw/day for 102 weeks NTP (1987). The respective study had limitations in study execution.

All mice of the high dose group accidentally died by week 91 because of a dosage error (2800 mg/kg bw administrated during 3 days instead of 1000 mg/kg bw). In both the low dose and the control group, an infection of the genital tract resulted in the death of 8 and 14 females, respectively. Furthermore, mortality due to gavage errors occurred in 3 males of control, 3/3 males/females of low dose and 2 females of the high dose group and mortality by to drowning due to flooding was found in 3 males of the control group. Evident decreases in body weights and body weight gains was found in high dose animals (1000 mg/kg bw/d). No compound-related clinical signs were observed.

Cytoplasmic vacuolisation, i.e. lipidosis due to the presence of lipid droplets, was observed in liver (mid/ high dose animals) and kidneys (mid/high dose females and high dose males). Geranyl acetate induced lipidosis seems to be species specific since these findings were not observed in rats.

No evidence of test substance related carcinogenicity was observed. A negative trend in the incidences of malignant lymphomas and follicular cell adenomas in the thyroid was observed in test substance treated animals. However, according to the authors, the death of all high dose mice as well as of numerous females of the low dose group lowered the sensitivity of the study for detecting neoplastic substance-related changes.

Overall, no evidence of carcinogenic effects were observed, so that under the conditions of the present study, the test substances geranyl acetate / citronellyl acetate were not found to be carcinogenic. Therefore a carcinogenic potential of the discussed reaction mass is not to be expected.