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Key value for chemical safety assessment

Additional information

No key study for repeated dose toxicity of geranyl acetate is available. However , the respective endpoint is assessed by weight of evidence based on a set repeated dose studies in rats and mice tested with a mixture of geranyl acetate and citronellyl acetate. 

Repeated dose toxicity was analyzed in a 91 day oral toxicity study in rats performed by the National Toxicity Program of the US National Institutes of Health (NTP, 1987) In this study, doses of 250, 500, 1000, 2000 and 4000 mg/kg bw/d of food-grade geranyl acetate (71 % geranyl acetate (CAS 105-87-3) and 29 % citronellyl acetate (CAS 150-84-5)) in corn oil was administered by gavage to ten male and female Fischer 344 rats for 13 weeks. 1/10 female and 2/10 male of the 4000 mg/kg bw/d group died, in addition to one animal accidently killed by gavage error in the 500 mg/kg bw/d group. Besides mortality, the observed substance related toxic effect was a depressed mean body weight of the animals of the 4000 mg/kg bw/d group compared to control (19% for the males, 8% for the females). Three males showed reddened mucosa of the stomach, however no test substance related histopathological changes were observed. Thus, a NOAEL of 2000 mg/kg bw/d of food-grade geranyl-acetate has been set, corresponding to 1420 mg/kg bw/d geranyl acetate.

In the associated range finding study, five Fischer 334 rats per sex and dose were also administered with the same test substance at doses of 62, 125, 250, 500 and 1000 mg/kg bw/d by gavage for 14 days (NTP, 1987). No mortality as well as no other toxic effects were noted up to 1000 mg/kg bw.

Both studies have been used for dose selection of a 2 year carcinogenicity study (NTP 1987).

In this study, 50 F344 rats per sex and dose were gavaged with doses of 1000 and 2000 mg/kg bw/day of the respective solution of food-grade geranyl acetate (71% geranyl acetate and 29% citronellyl acetate). 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 at 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.

Considering these findings from this 2 year study in rats a NOAEL is to be set at 1000 mg/kg bw/d, corresponding to 710 mg/kg bw/d geranyl acetate.

For neoplastic lesions, please refer to the chapter “Carcinogenicity”.

 

In the same publication, repeated dose toxicity studies in mice were reported (14 day and 13 week dosing study). In both studies, five male and female B6C3F1 mice received 125, 250, 500, 1000 and 2000 mg/kg bw of food-grade geranyl acetate (71 % geranyl acetate (CAS 105-87-3) and 29 % citronellyl acetate (CAS 150-84-5)) by gavage application.

Application for 14 days resulted in mortalities in 3/5 females in the 2000 mg/kg bw/d dose group. One of 5 male mice of the 2000 mg/kg bw group was found to have a thickened duodenal wall and 3 of 5 females of the same group showed a thickened wall of the cardiac stomach.

In the 13 week study seven males and nine females of the 2000 mg/kg bw group died. Also, three females of the lower dose groups died, but this was accidentally due to an error of gavage. No other clinical signs of toxicity were noted during the study. The males of the 2000 mg/kg bw group exhibit a delay in body weight gain. Liver, kidney and myocardium of males and females of the 2000 mg/kg bw group displayed cytoplasmic vacuolization with lipid inclusions indicative of fatty degeneration. Furthermore, stomach lesions including inflammation and edema were reported in this group. Thus, the NOAEL was set at 1000 mg/kg bw/d food-grade geranyl-acetate corresponding to 710 mg/kg bw/d geranyl acetate.

The listed studies in mice have been performed for dose selection of a 2 year carcinogenicity study (NTP 1987). Fifty 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.

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 were 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 (low/ high dose animals) and kidneys (low/high dose females and high dose males). Geranyl acetate induced lipidosis seems to be species specific since these findings were not observed in rats. Overall, as mentioned above, the respective study had limitations in study execution and does not form a valid basis for the derivation of a NOAEL.

For neoplastic lesions, please refer to the chapter “Carcinogenicity”.

Justification for classification or non-classification

In a weight of evidence, the present data on repeated dose toxicity do not fulfill the criteria laid down in 67/548/EEC and regulation (EU) 1272/2008, and therefore, a non-classification is warranted.