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Description of key information

Key value for chemical safety assessment

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No valid key study is available for the assessment of all toxicokinetic aspects of citronellol.

The physicochemical properties of citronellol, i.e. small molecular weight, LogPow and moderate water solubility at room temperature (MW = 156.3, Log Kow = 3.41; Water solubility = 307 mg/L), favour bioavailability via the oral route. On the basis of the low vapour pressure at room temperature (vapour pressure 8.6 Pa), the exposure of citronellol via inhalation as a vapour is low. Oral bioavailability of citronellol is qualitatively indicated by mortalities observed in an acute oral toxicity study.

In a key in vitro skin penetration study taken from literature, radiolabeled citronellol (2% or 5% in 3:1 diethylphtalate:ethanol) has been applied under occlusion to human cadaver skin (4 donors, n=3 replicates each per concentration used) for 24 hours (Gilpin 2010). Residual doses on skin (first and second tape strip), content in stratum corneum (next 3 to10 tape strips), separated epidermis, dermis, receptor fluid and surrounding edge skin was determined together with covers, chamber washes and skin surface washes in order to obtain a total recovery value. The amount absorbed after administration of 2% or 5 % citronellol was 3.8+/-2.1% or 4.7+/-1.9% respectively, considering the sum of amounts measured in the receptor fluid, dermis, epidermis, stratum corneum and surrounding edged skin. These values represent a worst case, since the total amount in the stratum corneum was considered as bioavailable although elimination via desquamation could be taken into account. The total recovery (removed dose in% + penetrated dose in%) was found at 90.1% and 86.3% after administration of 2% or 5 % citronellol respectively.

In a supportive study reported in literature, penetration of dl-citronellol through human epidermis was evaluated using human thorax skin excised from one cadaver (Cal, 2003). 500 mg of pure citronellol was applied onto 0.65 cm2 skin (total dose 769231 µg/cm2) and after 1–4 h its content in the stratum corneum, epidermis/dermis and receptor fluid was determined. Accumulation of citronellol into skin layers was found, without penetration to the receptor medium. Taking into account the test substance dermal load applied, the percentage of dectectable citronellol in total skin was low and ranged between 0.1 and 0.2% of the applied citronellol. Excluding the fraction found in the stratum corneum, the bioavailable fraction is found to be around 0.1% of the amount applied. In an additional elimination experiment (test substance application for 1 hour), a constant drop in the total amount in the skin was observed, although no citronellol was detected in the acceptor buffer. This may suggest, that elimination could occur by evaporation rather than by percutaneous penetration.

Overall, these data demonstrate a low dermal bioavailability of citronellol, and absorption of 7% has been taken for derivation of respective DNELs.

Concerning metabolism and elimination, the following information is taken from the revised test plan for Terpenoid Primary Alcohols and Related Esters (The Flavor and Fragrance High Production Volume Consortia - The Terpene Consortium; March 2004):

Citronellol, related terpenoid alcohols (geraniol and nerol), and the related aldehydes (geranial and neral) exhibit similar pathways of metabolic detoxication in animals. Terpenoid alcohols are rapidly absorbed in the GI tract. Geraniol, nerol, and citronellol undergo a complex pattern of alcohol oxidation, omega-oxidation, hydration, selective hydrogenation and subsequent conjugation to form oxygenated polar metabolites, which are rapidly excreted primarily in the urine of animals. Alternately, the corresponding carboxylic acids formed by oxidation of the alcohol function may enter the beta-oxidation pathway and eventually undergo cleavage to yield shorter chain carboxylic acids that are completely metabolized to carbon dioxide.

In a study reported in literature, male IISc rats were given [3H]geraniol and 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).

Data derived by an in vitro hydroxylase assay with different terpenoid alcohols (citronellol, geraniol, nerol and linalool) using lung, liver or kidney microsomes from male albino IISc rats was reported in literature, which addresses one aspect of the metabolic pathways of these compounds involved (Chadra 1982). These microsomal preparations were found to catalyse the hydroxylation of these compounds to form the respective 8-hydroxy form via the cytochrome P450 system. Although no absolute quantitative data for all compounds were reported here, there was no indication of the authors concerning evident differences in hydroxylation activities between these compounds that would substantiate a putative steric hindrance dependent on the position and number of double bonds.  

Further data in literature are available addressing certain aspects of the metabolic fate of citronellol but are only presented as short summary in this dossier.

When groups of four female Swiss mice were exposed to air containing 1.5 ml of citronellol, 2.9 ng/ml could be found in blood samples collected 0, 20, 60 and 90 minutes after inhalation (Buchbauer, 1993). In another metabolism study, 0.25 mM citronellol was found to induce UDP-glucuronosyltransferase activities in Wistar and Gunn rats and Guinea pigs (Boutin, 1985). In rabbits given citronellol by gavage, dihydro-Hildebrandt acid and an alcohol precursor (8-hydroxy-3,7-dimethyl-6-octenoic acid) have been reported as urinary metabolites (Fischer, 1940). In another study with Saccharomyces cerevisiae IWD72, Kluyveromyces lactis IFO1267 and Torulaspora delbrueckii NCYC696, citronellol was a conversion product of geraniol in S. cerevisiae. With K. lactis, citronellol was a conversion product of 25 ug/ml geraniol and 25 ug/ml nerol (King, 2000). In another study by the same author, 100 µg/ml (100 mg/kg) citronellyl acetate and geraniol were identified as conversion products of citronellol. Citronellol was identified as a conversion product of geraniol and nerol and as a conversion product of geraniol with both S. cerevisiae and S. bayanus (King, 2003).

Based on the information given above, there is no evidence for a bioaccumulative potential of citronellol.