(E)-7,11-dimethyl-3-methylenedodeca-1,6,10-triene

Endpoint summary

Description of key information

The potential for uptake of farnesene following oral administration has been investigated in an in-vitro everted rat gut-sac model. Results suggest minimal absorption is likely following oral exposure. 
In the absence of further information on farnesene, data on related compounds (farnesol and β-myrcene) have been used to inform on likely toxicokinetic behaviour.  See section 13 for read across justification.
 By analogy, farnesene has the potential to be absorbed via the skin. Any material absorbed is expected to be distributed to adipose tissue, kidney and liver. Metabolic conversion to polar species and excretion via the urine is expected to be relatively rapid, based on data available for the metabolism and excretion of farnesol.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

The only toxicokinetic data available for farnesene is an in-vitro study to investigate the potential for uptake following oral administration. The study was performed using sections of isolated rat proximal small intestine, formed into gut-sacs; three sacs from each of two rats were used. The sacs were filled with “fed state” simulated intestinal fluid (FeSSIF) and incubated in FeSSIF containing 10 mM farnesene for 1hr. Samples of external media and serosal fluid were collected and analysed for the presence of farnesene. Under the conditions of this test, only low amounts of farnesene were detected in the serosal fluid, indicating minimal absorption (between 1.2 and 1.3% of the incubation concentration).

In the absence of further information on farnesene, data on farensol, the alcohol of farnesene and the structurally related compound β-myrcene, have been used to inform on the toxicokinetic behaviour of farnesene.

Based on analogy, farnesene would be expected to be absorbed by skin given its lipophilic nature. In-vivo and in-vitro dermal absorption studies (Doan et al 2009) have shown that farnesol is absorbed through skin (~ 39% of applied dose within 24 hrs) and suggest that that lipophilic chemicals initially form a reservoir in skin, and the material in the reservoir may ultimately diffuse out of the skin into the receptor fluid within 72 h.

Following ingestion, only a small amount of farnesene would be expected to be absorbed by the gastrointestinal tract. Any farnesene absorbed via the gut would be expected to be to distributed to adipose tissue and organs such as the kidney and liver and be converted to more polar metabolites. Urinary excretion products for orally administered myrcene and farnesol have been experimentally determined. For myrcene these include 3(10)-glycol, uroterpenol, myrcene-1,2-glycol, 1-hydroxymyrcene-1-carboxylic acid, and 3-hydroxymyrcene-10-carboxylic acid (Ishida, 1981). For farnesol, measured urinary metabolites in rats were dicarboxylic acids (Bostedor, 1997). The half-life for such excretion is expected to be relatively short. For myrcene, female rats administered 1 g/kg body weight orally, the blood level of myrcene at 60 minutes was 14.1 ± 3.0 :g/mL, and the elimination half-life was 285 minutes (Delgado et al., 1993) For farnesol, the enzyme kinetics point to rapid elimination in vivo (Staines et al, 2004).

 

There has been much research on the metabolism of myrcene, a food additive, and farnesol owing to its role in endogenous cholesterol synthesis, regulation of cell functioning, and potential anti-cancer properties (Staines,2004). Myrcene is a substrate/inducer as well as a competitive inhibitor of the cytochrome P450 enzyme CYP2B (De Oliviera, 1997a,b).  Likewise, farnesol is metabolized by P450. It was metabolized by in vitro human tissue microsomes to farnesyl glucuronide, hydroxyfarnesol and hydroxyfarnesyl glucuronide. Farnesol is a good substrate for glucuronidation in the microscomes of human liver, kidney, and intestines. Specific human UGTs (uridine diphosphoglucuronosyltransferases) are involved. UGT1A1 is primarily responsible for farnesol glucuronidation; however, in intestines and kidney microsomes, UGT2B7 is probably the major isoform involved (Staines et al,2004).