2,6-dimethyloct-7-en-2-ol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Remarks:

Expert statement

Type of information:

other: Expert statement based on physicochemical and toxicity data.

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Expert statement based on physicochemical and toxicity data

Data source

Reference

Reference Type:

other: Expert statement

Title:

Unnamed

Year:

2021

Report date:

2021

Applicant's summary and conclusion

Conclusions:

Based on physicochemical characteristics, absorption by the oral and dermal routes is likely. This assumption is supported by the results of toxicokinetic studies with the analogue substances linalool (oral absorption) and dimyrcetol (dermal absorption) as well as by the results of the subacute and subchronic oral toxicity studies, the latter revealing a NOAEL of 30 mg/kg bw/day. Bioaccumulation of the substance is rather unlikely. After being absorbed into the body, 2,6-dimethyloct-7-en-2-ol is most likely distributed into the interior part of cells due to its lipophilic properties (log Pow = 3.25) and in turn, the intracellular concentration may be higher than extracellular concentration, particularly in adipose tissues. Due to the effects observed in the subchronic oral toxicity study, 2,6-dimethyloct-7-en-2-ol or its metabolites may target the liver, kidneys and the bone marrow. Ambiguous results on potential metabolic transformation to more toxic metabolites were obtained from the genotoxicity studies but results from the read-across substance linalool, however, indicate conjugation to non-toxic metabolites. On the basis of the molecular substance characteristics as well as of the results from toxicokinetic studies with the analogue substance linalool, excretion via urine is favoured.

Executive summary:

2,6-dimethyloct-7-en-2-ol is a mono-constituent substance. It is a colourless viscous liquid at room temperature with a molecular weight of 156.27 g/moL. The substance shows a good solubility in water (939 mg/L at 20 °C). The log Pow was determined to be 3.25. The test substance has a vapour pressure of 20 Pa at 25 °C.

 

Absorption

According to the ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7c (Endpoint specific guidance), oral absorption is favoured for molecules with molecular weights of less than 500 g/moL. The substance is assumed to readily dissolve in gastrointestinal fluid due to its good water solubility of 939 mg/L and the log Pow of 3.25 favours absorption by passive diffusion. Taken together, the physiochemical properties indicate that 2,6-dimethyloct-7-en-2-ol becomes bioavailable following the oral route. This assumption is confirmed by read-across to toxicokinetics studies with linalool (CAS 201-134-4), an analogue substance, which showed a rapid excretion of the substance, after intragastric administration to rats, suggesting also a rapid absorption from the gut. Also the subacute oral toxicity study with 2,6-dimethyloct-7-en-2-ol  and the subchronic oral toxicity study with the read-across substance dimyrcetol (mixture of 2,6-dimethyloct-7-en-2-yl and 2,6-dimethyloct-7-en-2-yl formate ester, CAS 18479-58-8), where a dose-dependent decrease in body weights was noted (both in the subacute and subchronic study). Furthermore, an increase in relative liver and kidney weights as well as hematological changes, adipose infiltration of bone marrow and diuresis were observed in the subchronic toxicity study.

 

Due to the low volatility (vapour pressure of 20 Pa at 25 °C and high boiling point of 193 °C) of 2,6-dimethyloct-7-en-2-ol, it is unlikely that the substance will be available as a vapour. As the substance is a liquid, no particle formation is expected. Hydrophilic substances are likely to be retained within the mucus and thus, because of the good water solubility of the substance, penetration may be reduced. Although the logPow of 3.25 would favour uptake through the respiratory tract epithelium by passive diffusion, it is very unlikely that the substance reaches the respiratory tract due to the previously mentioned properties.

 

Dermal uptake is favoured by a liquid state of the substance, a molecular weight of less than 100 g/moL and a water solubility between 100-10,000 mg/L. 2,6-dimethyloct-7-en-2-ol is a non-volatile liquid with a relatively low molecular weight of 156.27 g/moL, a logPow of 3.25 and good water solubility of 939 mg/L, thus dermal absorption may be a potential uptake route. Especially the high water solubility enables a partition of the substance from the stratum corneum into the epidermis. This assumption is supported by the fact that the substance is classified for skin and eye irritation (category 2), indicating that the substance is absorbed to a certain extend. Furthermore, two in vitro dermal absorption studies with the analogue substance dimyrcetol using human skin, showed a dermal absorption of 2,6-dimethyloct-7-en-2-ol of up to 2.5±0.2 % (unoccluded conditions) or up to 10.4 % (occluded conditions).

 

 

Distribution

As mentioned above, the physicochemical properties of 2,6-dimethyloct-7-en-2-ol favour absorption by the oral and dermal route. The systemic absorption and distribution within the body is also demonstrated by the dose-dependent effects on body weight (subchronic and subacute study) and by effects on absolute and relative liver and kidney weights, the presence of adipose infiltration of bone marrow, haematological changes and diuresis effects in the subchronic study using the read-across substance. After being absorbed into the body, 2,6-dimethyloct-7-en-2-ol is most likely widely distributed due to its relatively low molecular weight and may enter into the interior part of cells due to its lipophilic properties (log Pow 3.25) and in turn, the intracellular concentration may be higher than extracellular concentration, particularly in adipose tissues. Due to effects on liver/kidneys/bone marrow observed in the subchronic repeated-dose toxicity study, it can be assumed that liver, kidneys and bone marrow may be target organs of the substance. In toxicokinetic studies with the analogue substance linalool, linalool was found in liver, gut, skin and skeletal muscles. Enterohepatic circulation may play a role as, after intragastric administration of the analogue substance linalool, 40% of the biliary conjugates were hydrolyzed and reabsorbed in the first pass. 

 

Although the log Pow of 2,6-dimethyloct-7-en-2-ol indicates a weak potential bioaccumulation potential, the rapid excretion observed for the analogue substance linalool suggests no tissue accumulation.

 

 

Metabolism

There is no direct experimental data to characterize the metabolism of the test substance. Instead, the anticipated metabolism is derived from expert judgement and reapplication of metabolic properties of related substances.

 

As some liver effects were observed in the subchronic repeated dose oral toxicity study, the substance is principally able to reach the liver and its metabolic capacities.

 

The genotoxicity studies indicated no remarkable differences in genotoxicity between treatments with or without metabolic activation. Higher cytotoxicity was observed in the presence of metabolic activation systems (Ames test and in vitro mammalian chromosome aberration test) but the opposite effect was observed in an in vitro mammalian cell gene mutation test. Therefore, no clear statement can be made on the metabolic (de)toxification of the substance but metabolism seems to occur to a certain extent.

 

This assumption is supported by toxicokinetic studies with the analogue substance linalool which showed increased microsomal cytochrome P-450 enzymes and metabolism of linalool mainly into 8-hydroxy-linalool and 8-carboxy-linalool. This suggests also conjugation of 2,6-dimethyloct-7-en-2-ol to non-toxic metabolites in the liver.

 

 

Excretion

The physicochemical properties of the substance favour excretion via urine (low molecular weight and high water solubility). In two toxicokinetic studies with the analogue substance linalool, its metabolites 8-hydroxy-linalool and 8-carboxy-linalool were excreted via urine (approx. 58% of the applied dose) whereas 23% were found to be exhaled in form of CO₂ and up to 15% were eliminated by fecal excretion after enterohepatic circulation, suggesting a similar excretion pattern for 2,6-dimethyloct-7-en-2-ol.