3,7-dimethyloctan-3-ol

Endpoint summary

Additional information

There were no valid studies available in which the toxicokinetic properties of tetrahydrolinalool were investigated.

 

Tetrahydolinalool (synonyms: 2,6-dimethyl-6-octanol; 3,7-dimethyloctan-3-ol; 3-octanol, 3,7-dimethyl) having a molecular weight of 158.29 g/mol is a colorless oily liquid, which is soluble in water (320 mg/l at 25 °C). It has a vapor pressure of 0.111 hPa (20°C) and a log P_o/wof 3.8.

 

In an acute oral toxicity study, rats were administered ca.10 ml/kg bw tetrahydrolinalool (eq. to 8270 mg/kg bw) by gavage. 4/10 animals died within 48 h and clinical signs of toxicity were observed; therefore bioavailibility of tetrahydrolinalool is indicated (BASF 1980).

In an acute dermal toxicity study a dose level of 5000 mg/kg bw tetrahydrolinalool was administered to rabbits (1976). No deaths and no signs of toxicity were reported, being indicative of dermal absoprtion. However, when considering molecular weight and P_o/wof tetrahydrolinalool, a dermal penetration cannot be excluded.

When considering the vapour pressure of tetrahydrolinalool, limited adsorption of the substance via the inhalative route can be assumed. In a standardized inhalation hazard test with a saturated vapour atmosphere, 0/12 rats died after 8 h exposure (BASF 1980). No clinical signs were observed and there were no necropsy findings in the survivors after 2 d observation period.

Evidence for systemic availability of tetrahydrolinalool via the oral route can be derived from toxikokinetic data and the key repeated dose toxicity study in rats. In the subchronic toxicity study, rats received 1500, 5000 or 15000 ppm tetrahydrolinalool (BASF 2019; 50C0267/10C194), resulting in changes in body weights, clinico-chemical parameters and alpha-2µ-globulinuria.

Labelled linalool (14C) was administered orally (gavage, 500 mg/kg bw) and intraperitoneally (20 mg/animal) to male Wistar rats (Parke 1974). Linalool was rapidly and completely absorbed in rats after oral administration. The majority was excreted via urine (60% of administered radioactivity), expired air (23%) and faeces (15%) 72 hours after application, whereas only 3% of the dose were detected in tissues, i.e. brain, lung, liver, heart, spleen, gastro-intestinal tract, kidney, skin and skeletal muscle. Intraperitoneal administration with a subsequent collection of bile revealed, that approx. 25% of the dosed linalool is excreted via the bile probably by formation of respective glucuronide and sulfate conjugates. Transfer of the bile from a linalool treated animal into the duodenum of an untreated animal further indicated the occurrence of enterohepatic circulation.

In a subchronic dermal study, linalool was administered dermally to rats over a 91 day period at doses of 250, 1000 and 4000 mg/kg bw/day (T&O 79-201), resulting in increases in mortality and changes of liver and kidney weights. Considering molecular weight and Po/w of tetrahydrolinalool, a certain rate of dermal penetration is to be expected.

Taken together, rapid and complete oral absorption and indications for bioavailablility after topical application are given for tetrahydrolinalool and the structurally related substance linalool and consequently, systemic availability of tetrahydrolinalool is to be expected via these exposure routes.

Considering the chemical structure of tetrahydrolinalool, metabolism may consist of conjugation of the C3 hydroxy group with glucuronic acid and/or sulfatation, or of an oxidation at the C1 position to the acid via intermediate formation of the respective aldehyde, or of an oxidation at the C7 position and formation of alcohol.

All potential metabolites of the metabolic pathway described above are more polar and more water soluble than the parent chemical and are expected to be excreted predominantly via the urine.

 

Studies on genotoxicity (Ames-Test, gene mutation in mammalian cells in-vitro) were negative, i.e. there is no indication of a reactivity of tetrahydrolinalool or its metabolites under the test conditions.

 

Taking into account the log P_o/w, the water solubility and the considerations on the metabolism, accumulation of tetrahydrolinalool is considered to be unlikely.