Geraniol

Endpoint summary

Description of key information

Oral Repeated Dose Toxicity:
- BASF 2023: NOAEL = 50 mg/kg bw/day, LOAEL = 800 mg/kg bw (subacute)
- Hagan 1967: NOAEL = 10,000 ppm (corresponding to approx. 550 mg/kg bw/day) (subchronic)

Additional information

The oral repeated dose toxicity was evaluated in a study, where a mixture of 3,7-dimethyl-2,6-octadienol and 3,7-dimethyl-1,6-octadienol was feed to five male and five female individually housed Osborne-Mendel rats per dose group (Hagan, 1967). Thereby, a concentrations of 1000 (= ca. 55 mg/kg bw/day) was administered for 189-169 days and a concentration of 10000 ppm (= ca. 550 mg/kg bw/day) was given for 112 days. During the study, the food consumption was monitored and blood was collected at the end of study and was subjected analysis of white cell counts, red cell counts and hemoglobin and hematocrit content. Also, animals were necropsied and histopathology was performed. Since no clinical signs, no effects on body weight as well as no histopathological changes were observed, the NOEL could be estimated as 10000 ppm. Thus the NOAEL would be > 550 mg/kg bw/day.

 

In a supporting mechanistic subacute toxicity study in rats similar to OECD TG 407 and according to GLP, the thyroid effects of Geraniol Extra via enzyme induction in the liver was assessed (BASF 2023; 99C0046/10X450). Geraniol Extra was administered to groups of 5 Wistar rats per sex and dose at doses of 0, 50, 800 and 1000 mg/kg bw/day (Control, Low, Mid and High Dose group) via gavage over a period of 14 days (Subset A) and 28 days (Subset B). During the course of the study, blood samples were taken and examined for thyroid hormone levels (T3, T4 and TSH; Subsets A and B). Blood samples for the analyzes of hormone levels (T3, T4, TSH) were taken on study days -3, 11 and 13 for all animals of Subset A and on study days -3,11, 14, 21 and 28 for all animals of Subset B. Shortly before necropsy, blood samples were taken for the examination of hematology and clinical chemistry parameters (Subset B, only). At necropsy, weights of liver, adrenals, thyroids with parathyroid glands and pituitary were determined, and histopathological examinations of liver and thyroid were performed (Subsets A and B). Parts of the liver tissue were fixed for histopathology, others were deep frozen in liquid nitrogen for bioanalytical examinations. For bioanalytical examinations (Subset A), liver microsomes were prepared and characterized for their protein content, total cytochrome P450-content as well as for the activities of 7-ethoxyresorufin-O-deethylase (EROD), 7-pentoxyresorufin-O-dealkylase (PROD), 7-benzyloxyresorufin-O-dealkylase (BROD), alcohol dehydrogenase (ADH), hydroxy biphenyl (HOBI)-glucuronidase, 4-methylumbeliferone (4-MU)-glucuronidase and T4-glucuronidase. In addition, homogenized intestinal samples were characterized for protein content and 4-methylumbeliferone (4-MU)-glucuronidase. Bioanalytical examinations were carried out without GLP status.

No mortality occurred during the study.

Treatment related clinical sign of increased salivation, noisy respiration, rooting in bedding and tiptoe gait was observed in the Mid and High Dose group, these effects were not considered as adverse.

No test item related effects were detected on bodyweight or bodyweight gains or in food consumptions during the study in any of the treated groups when compared to the controls. Increased water consumption was observed in the Mid and High dose groups compared to the control during the study.

No test item related effects were observed in clinical pathology parameters in any of the dosed groups and there were no test item related effects on the T3 and TSH hormone levels. Statistically significantly decreased T4 concentration was observed in the Mid and High dose male animals and High dose female animals compared to the control.

Liver microsomes from male and female Wistar rats exposed to Geraniol Extra showed a significant increase for several CYP and UGT enzyme activities. For both male and female Wistar rats exposed to Geraniol Extra, a statistically significant increase was observed for PROD and BROD activity in Mid Dose groups (per mg protein only) and High Dose groups compared to the Control group. A statistically significant increase was observed in all animals for HOBI-glucuronidation and liver microsomal 4-MU-glucuronidation activity for Mid and High Dose groups. T4-glucuronidation activity showed a statistically significant increase in activity for the group exposed to 1000 mg/kg bw/day test substance in male rats and for the groups exposed to 50, 800 and 1000 mg/kg bw/day test substance in female rats compared to the control group. For ADH activity a statistically significant increase was observed in male rats of the High Dose group and in female rats of the Mid and High Dose groups. However, results for the ADH activity should be interpreted with due care. High background signals in the liver microsome samples were observed, which also increased during the incubation. A possible explanation for this observation is that the microsomal preparation contained additional substrates which were introduced during the preparation of the microsomes and could also metabolized to produces NADH. For the assay with rat intestinal samples, the formation of 4-MU-glucuronide was low and for a number of samples under the limit of quantification. This resulted in high variation within the exposure groups and therefore, results should be interpreted with due care.

No test item-related gross findings were noted at necropsy. Increased liver weights were observed in males and females in the Mid and High Dose groups after 14 or 28 days of treatment, which correlated with minimal centrilobular hypertrophy. The test item caused minimal centrilobular, hypertrophy of the hepatocytes in the Mid and High Dose males at 14 days dosing, and minimal/mild centrilobular, hypertrophy of the hepatocytes in the Mid and High Dose males and females after 28 days of dosing. The hepatic change was considered to be an adaptive change with enzyme induction. The minimal, multifocal hypertrophy of the follicular cells of the thyroid in the High Dose animals after 28 days of dosing is considered to be secondary to hepatic enzyme induction.

In conclusion, under the conditions of this 28-day study, there were minor non-systemic effects on in-life parameters (e.g. increased salivation, noisy respiration, tiptoe gait) in Mid and High Dose (800 and 1000 mg/kg bw/day) animals.

After 14 or 28 days of treatment increased liver weights in both sexes dosed at 800 and 1000 mg/kg bw/day corelated with minimal centrilobular hypertrophy seen at histology, and with liver enzyme induction.

Statistically significantly decreased T4 concentration was observed in the Mid and High Dose male animals and High Dose female animals compared to the control, correlated with liver enzyme induction.

The no observed effect level (NOAEL) for systemic effects of Geraniol Extra is considered to be 50 mg/kg bw/day, the Low Dose in this study.

 

To investigate the human relevance of the changes in rat thyroid hormone metabolism by UGT induction, a comparative study in rat and human hepatocytes has been initiated to evaluate the enzyme activity induced by the test item in different species. As soon as results will be avaible, they will be reported in a dossier update. 

 

In another study, ten rats per dose were fed with 0.1% geraniol for 28 weeks and with 1% for 16 weeks (FDA, 1954). Since no effects were reported, a NOEL of 1% could be estimated. However, this data could not be considered for assessment since only concentrations of 1% and 0.1% were used and only limited data were given.

 

In an inhalative repeated-dose toxicity study, eight complex fragrance mixtures consisting of approximately 200 ingredients (close to one-half of the ingredients present at a level of 1% or more) were tested (Fukayama, 1999). Geraniol was present in 3 out of the eight mixtures and was tested in Syrian hamster and CD and Sprague-Dawley rats. They were whole-body exposed to the mixtures at 5, 9 or 50 mg/m³ for 4 h/day, 5 days/week for 6 or 13 weeks. The concentrations of fragrance in the chamber used were monitored and the found particle size ranged from 0.5 to 4.3 µm. Thereby, the highest determined exposure levels were 5.7 and 37.8 µg/m³. No gross pathological or histopathological findings related to test material exposures were observed. However, because different mixtures of substances were used in this study, the data could not be taken into account for assessment.

 

Geraniol Extra was administered via dermal administration to groups of 10 male and 10 female Wistar rats (F0 animals) at dose levels of 0 (vehicle control; test group 0), 50 (test group 1), 150 (test group 2) and 450 mg/kg bw/d (test group 3) in order to observe the possible effects of the test substance on the integrity and performance of the reproductive system in both sexes. Due to severe dermal findings, the dose level for test group 3 was decreased to 300 mg/kg bw/d from study day 10 onwards. Regarding clinical examinations, only signs of local dermal toxicity were observed for males and females at all dose levels. No changes in food consumption and body weight data were seen at any dose level. Fertility indices for male and female animals as well as development of the offspring were not impaired by test-substance administration. Regarding pathology, there were no treatment-related necropsy or histological findings in ovaries, testes or epididymides associated with dermal administration of the test substance. The local minimal inflammatory reactions in the skin of treated males (test groups 1-3) and females (test group 3 only) were regarded as related to treatment and adverse.

Justification for classification or non-classification

Based on the results from repeated dose toxicity testing no classification for specific target organ toxicity after repeated exposure is warranted according to Regulation (EC) No 1272/2008.