Reaction mass of 2,6-Octadien-1-ol, 3,7-dimethyl-, (E) and 2,6-Octadien-1-ol, 3,7-dimethyl-, (Z)-

Carcinogenicity

Additional information

No data on carcinogenicity were found on geraniol, nerol, or the respective reaction mass. As supportive information, carcinogenicity studies with structural similar compounds were taken into account.

A 2 year study (NTP, 1987) with rats and mice exists, in which a mixture of geranyl acetate and citronellyl acetat had been tested. Since acetates are known to be metabolised to the respective alcohols, meaning that geranyl acetate is metabolised to geraniol, this study is used for read across:

To evaluate the carcinogenic potential of geranyl acetate a two year study performed by the National Toxicity Program of the US National Institutes of Health was taken into account (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 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 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.

In both dose groups increased mortality was seen, as 21/50 males and 22/50 females died in the low dose group and 32/50 males and 17/50 females died in the 2000 mg/kg bw group compared to the control group (16/50 males and 15/50 females). The body weight was significant reduced after 40 weeks and the depression in bodyweight gain was dose related. The observed retinopathy or cataracts in females of the low dose group and males of the high dose group were not related to the test substance but to the proximity of the rats to a source of fluorescent light.

Regarding carcinogenicity, two males of the low dose group displayed kidney tubular cells adenoma. The incidence of kidney tumors in male rats within the vehicle control group of this study was similar to the historical incidence observed in the laboratory (0.4%). Also, six males of this group displayed epidermal tumors, which was not statistically significant increased compared to control (three). One male displayed squamous cell papilloma at 2000 mg/kg bw. According to the authors of this study, the observed increased mortality of males in the high dose group lowered the sensitivity of the study for detecting neoplastic substance-related changes.

The marginal increased incidence of epidermal tumors (particularly squamous cell papillomas of the skin) and of tubular cell adenomas in the kidney may have been substance-related.

In the same study, 50 male and female B6C3F1 mice were treated with doses of 500 and 1000 mg/kg bw/day for 103 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. The histological examination of the liver and kidney tissue revealed increased cytoplasmic vacuolization. The incidence of this effect was particularly conspicuous in the high dose group (e.g., in the liver of males 94 % versus 2 % in control males) and was considered to be substance-related.  According to the authors of this study, 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. However, no evidence of carcinogenic effect was found, so that under the conditions of the present study, the test substances geranyl acetate / citronellyl acetate were not carcinogenic.

According to REACH, additional data on carcinogenicity need to be provided if the substance has a widespread dispersive use or frequent/long-term human exposure is given and the substance is a mutagen category 3 or there is evidence for a capacity to induce hyperplasia and/or preneoplastic lesions from repeated dose studies.

The reaction mass of geraniol and nerol was determined to be non-genotoxic in bacterial and mammalian cell mutagenicity tests in vitro and in vivo. Additionally, there is no evidence from repeated dose studies using the reaction mass of geraniol and nerol, that the substance is able to induce hyperplasia and/or pre-neoplastic lesions, beyond its local topical irritative effects.

As a consequence, there is no indication for further testing the reaction mass of geraniol and nerol in a carcinogenicity study.