3,7-dimethylnona-1,6-dien-3-ol

Endpoint summary

Additional information

Background

Ethyllinalool is widely used as flavour and fragrance ingredient and no experimental data are available on toxicokinetic behaviour, metabolism and dermal absorption; however considerable information is available for linalool (CAS 78-70-6). Those two substances are structural homologues which differ only by a methyl-group. Their physical-chemical properties are comparable and available experimental data on same toxicological endpoints, showed identical toxicological properties. Therefore, it is assumed that all toxicological properties are as well comparable and thus read-across is justified.

Toxicokinetic data were identified for Linalool which was shown to be rapidly and completely absorbed and excreted upon oral administration. Excretion is via urine, air and faeces. To some extent Linalool may be subject to enterohepatic recirculation. Metabolism investigations have shown that Linalool is extensively conjugated (glucuronidation and sulfonation) at its hydroxyl-group in position 3. In addition, phase I metabolism introduces a further hydroxyl-group at position 8 of the molecule. This hydroxyl-group can be further oxidised or conjugated to a glucuronide or sulfate. Other metabolites were found but could not be identified. Linalool is able to induce Phase I and Phase II metabolizing enzymes in the liver of rats. Due to its vapour pressure most dermally applied Linalool evaporates rapidly thereby significantly reducing dermal absorption to a minimum (0.17% of applied dose). Pulmonary absorption was shown.

Studies on toxicokinetics in the dossier

The oral absorption of linalool in rats was rapid after an oral dose of 500 mg/kg bw linalool (radiolabelled). Within 2 days after treatment, radioactivity was excreted via urine (approx. 60%), expired air (approx. 23%), and faeces (approx. 15%) indicating that at least 85% of the applied dose was absorbed. A separate experiment showed that considerable enterohepatic circulation is possible, and that bilary conjugates and non-polar ether extractable metabolites are formed and excreted via faeces. Overall, this may indicate that radioactivity was completely absorbed. Three percent of the dose was distributed in tissues after 72 h of dosing; linalool was detected in liver (0.5%), gut (0.6%), skin (0.8%) and skeletal muscle (1.2%). Other organs including kidneys contained insignificant residual radioactivity. Metabolites detected in urine and bile indicated that linalool is largely excreted in the form of glucuronic acid conjugates (Parke et al., 1974a).

 

After exposure to linalool by inhalation, linalool could be detected in blood of exposed mice (7-9 ng/mL serum) (Jirovetz et al., 1991). Other reports showed that after inhalation of linalool at 3.21 mg/L for 30, 60, and 90 min, mice plasma levels were around 1, 2.5, and 3 ng/mL plasma (Buchbauer et al., 1991).

 

To determine dermal absorption, two in vitro studies were performed that were both similar to guideline OECD 428. In the first study, human skin was exposed to radiolabelled linalool (4% in a solution of ethanol /water (70/30)) for 24 hours both open and occluded. 12.7% of the applied dose were found in receptor fluid excluding epidermis when exposure was occluded. Open exposure resulted in 3% of the applied dose recovered from receptor fluid. When linalool was applied open, approximately 97% of the applied dose evaporated within 24 hours (Green, 2007).

A second in vitro dermal absorption study studied the absorption of pure linalool in human skin after 4 hours of (occluded) exposure. Linalool easily penetrated into the skin, however it was not detected in the receptor fluid. The dermal absorption of linalool was determined to be 0.17% (Cal and Sznitowska, 2003).

An in vivo dermal absorption study confirms the limited dermal absorption of linalool. In this study the dermal absorption of linalool from lavender oil was studied in one male human subject. The applied dose was about 7 mg linalool. Results showed that linalool present in plasma peaks approximately after 20 min (ca. 120 ng/mL). Plasma levels return to almost background after 90 min indicating rapid elimination from plasma (Jäger et al., 1991).

 

In four studies, metabolism of linalool was studied, mainly by investigating enzyme induction upon oral exposure with linalool. Increased activity of cytochrome P450, cytochrome b5, biphenyl-4-hydroxylase and 4-methylumbelliferone glucuronyltransferase were observed in rats that were exposed to linalool for 64 days at a dose level of 500 mg/kg bw/d (Parke et al., 1974b).

In another in vivo study in which rats (600 mg/kg bw/d) were exposed to linalool orally for six days, increased P450-activity was observed up to three days of dosing, whereas activities had returned to normal after six days of dosing. In the same study, the metabolites 8-hydroxy linalool and 8-carboxy linalool were identified in urine (after acidic hydrolysis) after 20 days of exposure, indicating that 8-hydroxylation seems to be the major Phase I metabolism pathway. Other minor metabolites could not be characterised (Chadha and Madhava Madyastha, 1984).

The metabolism of linalool by human skin P450 enzymes CYP2C19 and CYP2D6 was studied in another in vitro study. Linalool was metabolized to (R/S)-furanoid-linalool oxide, (R/S)-pyranoid-linalool oxide and (cis/trans)-8-hydroxylinalool, dependent on time, linalool, and enzyme concentration (Meesters et al., 2007).

Phase II metabolism was also studied using an in vitro experiment. It was shown that when the phase II enzyme UDP-glucuronosyltransferase (UDPGT) was induced by phenobarbital, UDPGT specific activity towards linalool was higher than when UDPGT was induced by 3-methylcholanthrene. These experiments indicate that linalool is conjugated with glucuronic acid (Boutin et al., 1985).

 

It can be concluded that linalool is rapidly and completely absorbed after oral administration. After 72h, 97% of the administered radioactivity were excreted. 3% of the dose was detected in tissues (liver, gut, skin and skeletal muscle) 72 h after dosing. Linalool was excreted mainly via urine (60%), exhaled air (23%) and faeces due to bile excretion (15%) and is subject to enterohepatic recirculation. Both phase I and phase II enzymes (mainly glucuronidation) are responsible for the metabolism of linalool, 8-hydroxylation seems to be the major Phase I pathway. The dermal absorption of linalool is low: 0.17% after 4 hours exposure (occluded). Experiments show that most of the dermally applied linalool evaporates from skin.

 

Information from public literature

The most reliable references from literature were included in the dossier and summarized in the paragraph above. Additionally, an OECD SIDS assessment is available in which the toxicokinetics of linalool is discussed. In the document the rapid oral absorption of linalool is confirmed, as well as the excretion in urine, faeces, and via the expired air. The conclusion of the OECD SIDS assessment is that the relatively rapid overall excretion of linalool and its metabolites suggests no long-term hazard.

 

Information from other studies

Physical/chemical parameters such as log Kow, water solubility, vapour pressure, and molecular weight, as well as parameters like hydrolysis can provide useful information regarding the behaviour of a substance in the body. Linalool has a log Kow of 2.9 and a water solubility of 1.56 g/l. The vapour pressure is 0.273 hPa and the molecular weight is 154.24. No information on hydrolysis is available.

The moderate log Kow and good water solubility, as well as the relatively low molecular weight would favour oral, respiratory and dermal absorption. This confirms the findings found for oral absorption, as well as the presence of systemic effects in a 28-day repeated dose toxicity study. However, dermal absorption is low according to the available data. This can be explained by the high vapour pressure of linalool. This finding is confirmed by the available data on dermal absorption. The results of a 90-day dermal toxicity study partly confirm this, effects were mostly local on the skin (skin irritation), however, decreases in body weight, and increases in liver and kidney weight were also observed in the highest dose tested, indicating that some absorption may occur esp. on irritated skin.

 

Conclusions

Although toxicokinetic data on ethyllinalool were not identified, it can be reasonably assumed that ethyllinalool is absorbed, distributed, metabolized and excreted via the same mechanisms as linalool.

Based on (i) physical-chemical data, (ii) experimental information from a structurally related compound i.e. Linalool, and (iii) in silico metabolism prediction, the following can be predicted:

Upon dermal exposure Ethyllinalool will evaporate quickly from skin limiting systemic exposure via skin to a minimum.

After inhalation exposure Ethyllinalool will be partly absorbed from the airways and will be systemically available.

After oral ingestions, the substance will be quickly and completely absorbed. It will be distributed widely in the body. Metabolism pathways will consist of (i) hydroxylation either at the allylic position or at terminal methyl group, (ii) glucuronidation of primary and secondary aliphatic alcohol, (iii) oxidation of secondary alcohol to corresponding ketone, (iv) oxidation of primary alcohol to corresponding aldehyde and carboxylic acid, the latter being glucuronidated. Excretion will be fast and almost complete within 48h, the majority will be excreted via urine (60%) followed by expired air (20%) and feces (10-15%).

Ethyllinalool as Linalool is likely able to induce liver enzymes such as cytochrome P450, cytochrome b5, or UDPGT.

Therefore it can be concluded that ethyllinalool is rapidly absorbed, metabolized to inconspicuous metabolites and excreted.