Citronellal

Endpoint summary

Additional information

No key study is available to assess the toxicokinetic behavior and dermal absorption of citronellal and experimental information is restricted to the identification of some metabolites and possible metabolic pathways.

In general, citronellal was found to be excreted in urine after biotransformation to hydrophilic metabolites after absorption from the gastro-intestinal tract.

In rabbits, citronellal is metabolized to dihydro-Hildebrandt acid after subcutaneous injection (Asano Y, 1950). and oral administration (Ishida T, 1989). This indicates oxidation of the aldehyde function of citronellal andω-oxidation. As a result of cyclization of citronellal, trans- and cis-menthane-3,8-diol and isopregol were found in the urine of rabbits after oral administration but these accounted to <10% of the administered dose.

After subcutaneous application to rabbits, dihydro-Hildebrandt acid ((+)-3,7 -dimethyl-6 -octene-1,8 -dioic acid) was excreted in urine (Asano 1950). After oral administration of 6 g (+)-citronellal to rabbits, 0.6 g neutral and 1.5 g acidic metabolites (dihydro-Hildebrandt acid) were found in the urine (Ishida 1989). (-)-Isopregol, (-)-trans- and (+)-cis-menthane-3,8 -diol, as well as their corresponding acetates, represented 16%, 42% and 24% of the neutral metabolites, respectively. Furthermore (-)-trans- and (+)-cis-menthane-3,8 –diol were found to be formed in vitro during incubation of citronellal with gastric juice (Ishida 1989; Kuhn 1938). In vitro, 2,6-dimethyl-1,5-heptadiene was a product from the reaction of citronellal and cytochrome P-450 2B4 isoenzyme, but was not detected upon incubation with P-450 isoenzymes 1A2, 2E1, 2C3 or 2G1 (Roberts 1991).

Other than the structurally related citral, citronellal did not induce glutathione-S-transferase activity (GST) in cultures of the rat liver cell line RL34 (Nakamura 2003).

 

There are no quantitative data on absorption, distribution, elimination and toxicokinetics. However, some general conclusions can be drawn from the physical-chemical properties in combination with a read-across of the structurally related substance citral.

The molecular structures of citronellal and citral differ only in the aspect that citral has an additional C-C double bond in alpha,beta-position to the terminal carbonyl group. Molecular weight and molecule size are very similar (152 and 154 g/mol). The lipophilicity of citronellal is somewhat higher than for citral with log Pow values of 3.6 and 2.8, respectively. Consequently, the water solubility of citronellal (88 mg/L) is somewhat lower than that of citral (420 mg/L). The volatility of citronellal (vapour pressure of 16 Pa at 20 °C) is slightly higher than for citral (vapour pressure of 4.6 Pa at 20 °C).

Consequently, concerning absorption and distribution after oral, dermal and inhalative exposure a behaviour of citronellal similar to citral is considered. Absorption of citral from the gastro-intestinal tract was rapid and almost complete (Diliberto 1988). Five to 9 % of the oral dose was not absorbed from the gastrointestinal tract and was eliminated via the faeces. The lipophilicity of the substance facilitates passive diffusion across cell membranes and results in wide dispersion throughout the body tissues with no evidence of a major depot. Overall tissue amounts were below 2% of the applied citral 72 h after administration. For dermal exposures, a considerable part of an applied dermal dose of citronellal may be lost before percutaneous absorption may occur due to its volatility. On the basis of the log Pow and the data of the structurally similar citral, citronellal remaining on the skin, is expected to be fairly well absorbed. In line to assumptions made for citral, a dermal penetration rate of 50% is assumed for derivation of the systemic dermal DNEL.

 

Concerning excretion, citronellal was found to be excreted in the urine after biotransformation to polar metabolites. Overall, long-term storage or bioaccumulation of citronellal is not expected to occur in the body.