Citronellol

Carcinogenicity

Description of key information

Carcinogenicity:
- not carcinogenic (2y, NTP; Analogy CAS 150-84-5)

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Dose descriptor:

NOAEL

2 000 mg/kg bw/day

Justification for classification or non-classification

Since citronellol is a metabolite of citronellyl acetate, which is negative for carcinogenicity in a 2 year study with rats, similar results are expected for citronellol and no classification as carcinogenic is required.

Additional information

No valid carcinogenicity study for citronellol is available, however, data from the metabolically related acetates of citronellol and geraniol; i.e. citronellyl acetate (CAS 150-84-5) and geranyl acetate (CAS 105-87-3), are taken into account for assessment. These acetates are expected to hydrolyze to geraniol or citronellol and acetic acid. In animals, hydrolysis of aliphatic esters are catalyzed by classes of enzymes recognized as carboxylesterases or esterase. Citronellyl acetate was reported to be completely hydrolyzed within 2 hours by simulated intestinal fluid containing pancreatin at pH 7.5.

In the key carcinogenicity 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 (NTP; 1987).

For analysis, all animals were observed twice daily for signs of morbidity or mortality and clinical signs and body weights by cage were recorded every week for the first 12 weeks and monthly thereafter. The mean body weight of each group was calculated by dividing the total weight of all animals in the group by the number of surviving animals in the group. Moribund animals and animals that survived to the end of the studies were killed using carbon dioxide and necropsied. Major tissues or organs were examined for grossly visible lesions. Tissues were preserved in 10% neutral buffered formalin, embedded in paraffin, sectioned, and stained with hematoxylin and eosin. Necropsies were performed on all animals found dead and on those killed at the end of the study, unless precluded in whole or in part by autolysis or cannibalization.

Increased mortality was evident 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 addition to the in vivo study, citronellol was found to be unlikely carcinogenic in a computerized optimized molecular parametric analysis (Lewis, 1994).