Registration Dossier

Toxicological information

Carcinogenicity

Currently viewing:

Administrative data

Description of key information

Key value for chemical safety assessment

Additional information

No key study for carcinogenicity data is available for geraniol. As supportive information, carcinogenicity studies with structural similar compounds were taken into account.

A 2 year study with citral performed by NTP (2001) was taken into account for classification, since citral is metabolized to geraniol (Boyer, 1990; Sporn, 1976). In this study citral was fed to 50 female and 50 male F344 rats per dose with geraniol concentrations of 1000, 2000, and 4000 ppm (corresponding to: 50, 100, 210 mg/kg bw/d) daily for two years (NTP, 2001). Additional groups of 50 male and 50 female rats received untreated feed (untreated controls) or feed containing placebo microcapsules (vehicle controls). All animals were observed twice daily and clinical findings and body weights were recorded initially (body weights only), on day 8, day 33 (rats), every 4 weeks thereafter and at the end of the study. Complete necropsies and microscopic examinations were performed on all rat where all organs and tissues were examined for grossly visible lesions All major tissues were fixed and preserved in 10% neutral buffered formalin, processed and trimmed, embedded in paraffin, sectioned to a thickness of 4 to 6 μm, and stained with hematoxylin and eosin for microscopic examination. For all paired organs (e.g., adrenal gland, kidney, ovary), samples from each organ were examined. The results showed that the survival of all exposed groups of males was significantly greater than that of the vehicle control group, while the survival of exposed groups of females was similar to that of the vehicle control group. The mean body weights of rats exposed to 4,000 ppm  were generally less than those of the vehicle controls from week 49 (males) or week 25 (females) to the end of the study. Thereby, the feed consumption by all exposed groups was similar to that by the vehicle controls. Regarding carcinogenicity, no neoplasms or non neoplastic lesions were attributed to exposure to citral. Because the vehicle control incidence of renal mineralization was 84%, the increased incidences observed in the exposed groups are believed to reflect an exacerbation of this spontaneously occurring lesion. These renal changes are considered to have minimal toxicologic significance. As a consequence, the NOAEL was estimated as 4000 ppm for male and female rats.

In the same study, groups of 50 male and 50 female B6C3F1 mice were fed diets containing 500, 1,000, or 2,000 ppm microencapsulated citral for 2 years (NTP, 2001). Additional groups of 50 male and 50 female mice received untreated feed (untreated controls) or feed containing placebo microcapsules (vehicle controls). All animals were observed twice daily for clinical findings. Body weights were recorded initially (body weights only), on day 8, day 36, every 4 weeks thereafter, and at the end of the study. Complete necropsies and microscopic examinations were performed on all rats and mice where all organs and tissues were examined for grossly visible lesions. All major tissues were fixed and preserved in 10% neutral buffered formalin, processed and trimmed, embedded in paraffin, sectioned to a thickness of 4 to 6 μm, and stained with hematoxylin and eosin for microscopic examination. For all paired organs (e.g., adrenal gland, kidney, ovary), samples from each organ were examined.

As a result of this study, the survival of exposed males and females was similar to that of the vehicle control groups. Thereby, the mean body weights of mice exposed to 1,000 or 2,000 ppm were generally less than those of the vehicle controls throughout the study. Also, the mean body weights of 500 ppm females were less from week 30 to the end of the study, but the feed consumption by the exposed groups was similar to that by the vehicle controls. The incidences of malignant lymphoma occurred with a positive trend in female mice, and the incidence in 2,000 females was significantly greater than that in the vehicle control group but was within the historical ranges in controls (all routes) given NTP-2000 diet or feed controls given NIH-07 diet. Tissues most commonly affected by malignant lymphoma were the spleen, mesenteric lymph node, thymus, and, to a lesser extent, the ovary.

In addition to the studies with citral, studies with the structural analogue geranyl acetate (CAS 105-87-3) could be taken into account for assessment, as it is also known to be metabolized to geraniol (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 papliloma 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 groups of 50 mice were treated 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. 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.

Because the 2 year cancer studies with rats and mice showed, that citral and geranyl acetate were not carcinogenic, the same result could be expected for geraniol due to the structural similarities.

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.

Geraniol 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 geraniol, 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 gernaniol in a carcinogenicity study.

Justification for classification or non-classification