Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

Key value for chemical safety assessment

Additional information

To analyze the metabolic pathway of geraniol, male IISc rats were given [3H]geraniol in daily doses of 800 mg/kg bw by gavage for 20 consecutive days (Chadha, 1984). As a result, five urinary metabolites were identified via two primary pathways. In one pathway, the alcohol was oxidized to yield geranic acid (3,7-dimethyl-2,6-octadienoic acid) which is subsequently hydrated to yield 3, 7-dimethyl-3-hydroxy-6-octenoic acid (3-hydroxy citronellic acid). In a second pathway, the alcohol underwent selective omega-oxidation of the C8-methyl to yield 8-hydroxygeraniol and 8-carboxygeraniol, the latter of which underwent further oxidation to the principal urinary metabolite 2,6-dimethyl-2,6-octadienedioic acid (Hildebrandt acid). In the same study, it was demonstrated that administration of geraniol at a dose of 600 mg/kg bw by gavage for 1, 3 or 6 days induced expression of rat liver microsomal cytochrome P450 and geraniol hydroxylation, but not the activities of rat liver microsomal cytochrome b5, NADPH-cytochrome c reductase, and NADH-cytochrome c reductase, nor the activities of these enzymes in rat lung microsomes (Chadha, 1984).

In earlier study by the same author, lung ribosomes were prepared from male IISc rats which were injected intraperitoneally with either PB in 1 ml of 0.9% NACl solution (80 mg/kg body weight) or BNF in 1 ml of peanut oil (80 mg/kg body weight) once daily for 4 days (Chadha, 1982). The microsomes were shown to ω-hydroxylate acyclic monoterpene alcohols in the presence of NADPH and O2. Hydroxylation was specific to the C-8 position in geraniol and has a pH optimum of 7.8. The inhibition of the hydroxylase activity by SKF-525A, CO, N-ethylmaleimide, ellipticine, alpha-naphthoflavone, cyt. c and p-CMB indicated the involvement of the cyt. P-450 system. However, NaN3 stimulated the hydroxylase activity to a significant level. Rat kidney microsomes were also capable of ω-hydroxylating geraniol although the activity was lower than that observed with lungs.

In a publication from 1959, the detoxification of geraniol was described (Willimas, 1959). Following hydrolysis, geraniol underwent a complex pattern of alcohol oxidation, ω-oxidation, hydration, selective hydrogenation and subsequent conjugation to form oxygenated polar metabolites, which are rapidly excreted primarily in the urine. Alternatively, the corresponding carboxylic acids formed by oxidation of the alcohol function may enter the beta-oxidation pathway and yield shorter chain carboxylic acids that are completely metabolized to carbon dioxide.

In another study, the activity of UDP-glucuronosyltransferase of rat and guinea pig microsomes was enhanced 2.7 times over control by application of 0.25 mM geraniol (Noutin, 1985). Geraniol and other monoterpenoid alcohols are conjugated by a phenobarbital inducible UDP glucuronosyltransferase in liver of rats and guinea pigs.

The authors describe this enzyme as a new isoform of UDP glucuronosyltransferase I.

In another study, geraniol was found to be metabolized by ω-oxidation and by reduction of an alpha-beta-unsaturated bond in the rabbit (Perke, 1968).

Also, another study found that the products of geraniol metabolism were 'Hildebrandt acid' and 7-carboxy-3-methylocta-6-enoic acid, which is optically active (Williams, 1959).

Also, an enzymatic system capable of reducing citral to geraniol was identified in rat liver soluble fraction (Sporn, 1976). The activity of this enzyme was determined spectrophotometrically by the rate of NADH oxidation (340 nm) and by the hypsocromic changes of citral (234 nm) to geraniol (208 nm). The enzyme system was found to belong to the aldehyde reductase type NADH dependent group.

In another metabolism study, male Sprague-Dawley rats were treated for seven days with a diet containing 5% cholestyramine (Westfall, 1997). Animals were also treated for two weeks with a diet containing 2% cholesterol. The animals were fasted overnight and sacrificed two hours into their light cycle. Liver homogenates were first fractionated by differential centrifugation to obtain a peroxisome-enriched fraction (also containing smaller mitochondria and microsomes), a cytosolic fraction, a mitochondrial fraction and a microsomal fraction. The peroxisome-enriched fraction was further purified by equilibrium density centrifugation on a linear Nycodenz (20-50%) gradient except that ethanol was not included in the sucrose homogenization buffer. All fractions were analyzed for marker enzyme activities and protein concentration. Isolated peroxisomes were at least 93% pure as determined by marker enzyme distribution and contained 1% mitochondrial protein and 3 - 5% microsomal protein. As a result, there was no measurable cytosolic contamination of peroxisomes as determined by phosphoglucose isomerase activity. Farnesyl pyrophosphatase, farnesyl diphosphate kinase and alcohol dehydrogenase activity were determined, and geraniol was found to be a substrate for ADH.

In another study, the physicochemical criteria were investigated which are required to predict the elimination of molecules including geraniol by the UDP-glucuronosyltransferases (Thomassin, 1987). These enzymes possess a low specificity, particularly towards exogenous compounds. For this purpose, the kinetic constants (Vmax, Km, V/K) in non-treated and 3-methylcholanthrene-treated rat liver microsomes were determined. The results for geraniol were a Vmax of 13.5, Km of 4.0 and V/K values of 3.4 compared to control values of Vmax of 11.5, Km of 11.0 and V/K values of 1.0.

The inhibition of noradrenaline induced respiration in isolated hamster brown fat cells was measured as an indication of effect on cell metabolism (Pettersson, 1980). Geraniol was incubated at 37°C with the brown adipocytes, isolated from adult hamsters, for exactly 5 minutes where the oxygen consumption was registered. After this preincubation, noradrenaline was added and the oxygen consumption of the cells was registered for another 5 minutes. The noradrenaline concentration was 1 uM, which is approximately twice the dose known to induce maximal respiratory rate. While 0.1 mM geraniol resulted in a 38% inhibition of noradrenaline induced respiration, geraniol at 1 mM reduced inhibition of noradrenaline induced respiration by 96%.

A dermal absorption study was conducted with 230 male mice, using an area on the shaved abdominal skin measuring 2.2 cm2 (Meyer, 1959).  Absorption was noted over a period of up to 2 hours, and Eserine (0.23%) was used as an indicator as it has a characteristic and easily recorded effect on striated muscles. Geraniol was used as a carrier for Eserine, and the latency period between the application to the skin and the appearance of Eserine's effect in the periodically stimulated masticatory muscles was used as a measure of the absorption time. The time to absorption was recorded, and experiments were conducted 3 – 6 times. As result, no absorption was noted.