2,6-dimethyloctan-2-ol

Endpoint summary

Description of key information

No experimental toxico-kinetic data are available for assessing adsorption, distribution, metabolisation and excretion of the substance. Based on effects seen in the human health toxicity studies and physico-chemical parameters Tetrahydromyrcenol is expected to be readily absorbed via the oral and inhalation route and somewhat lower via the dermal route. Using the precautionary principle for route to route extrapolation the final absorption percentages derived are: 50% oral absorption, 50% dermal absorption and 100% inhalation absorption.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

Toxico-kinetic behaviour of Tetrahydromyrcenol

Introduction

Tetrahydromyrcenol Cas no18479-57-7) has a branched alkyl chain back bone to which a tertiairy alcohol is attached. This tertiairy alcohol is thefunctional group. It is liquid with a molecular weight of 158 that does not preclude absorption. The test material is unlikely to hydrolyse because there are no hydrolysable groups (e.g. such as esters). The substance has a low volatility of 9.3 Pa.

Absorption

Oral:The results of the repeat dose oral toxicity of the analogue Dihydromyrcenol show that the substance is being absorbed by the gastro-intestinal tract following oral administration, because some liver and kidney effects were seen. The relatively low molecular weight (158) and the moderate octanol/water partition coefficient (Log Kow 3.2) and water solubility (282 mg/l) would favour absorption through the gut. According to Martinez and Amidon (2002) the optimal log Kow for oral absorption falls within a range of 2-7. This shows that the substance is likely to be absorbed orally and therefore the oral absorption is expected to be much > 50% but 50% will be used as a default value. 

Skin: Based on the substance having a molecular weight of 158, being a liquid, the physico-chemical characteristics of the substance, log Kow (3.2) and water solubility (282), indicate that dermal absorption is likely to occur. The optimal MW and log Kow for dermal absorption is < 100 and in the range of 1-4, respectively (ECHA guidance, 7.12, Table R.7.12-3). The molecular weight of the substance is just outside optimal range and therefore the skin absorption is expected to be similar to oral absorption but will not exceed this. Therefore 50% will be used as a default value.

Lungs: Absorption via the lungs is also indicated based on these physico-chemical properties. Though the inhalation exposure route is thought minor, because of its low volatility (9.3 Pa), the octanol/water partition coefficient (3.2), indicates that inhalation absorption is possible. The blood/air (BA) partition coefficient is another partition coefficient indicating lung absorption. Buist et al. 2012 have developed BA model for humans using the most important and readily available parameters:

Log PBA = 6.96 – 1.04 Log (VP) – 0.533 (Log) Kow – 0.00495 MW.

ForThe substancethe B/A partition coefficient would result in:

Log P (BA) = 6.96 – 1.04 Log (9.3)– 0.533*3.2 – 0.00495*158 = 3.47

This means that the substance has a tendency to go from air into the blood. It should, however, be noted that this regression line is only valid for substances which have a vapour pressure > 100 Pa. Despite the substance being somewhat out of the applicability domain and the exact B/A may not be fully correct, it can be seen that the substance will be readily absorbed via the inhalation route and will be close to 100%.

Distribution

The moderate water solubility (282) of the test substance may present some distribution in the body via the water channels. The log Kow (3.2) would suggest that the substance would pass through the biological cell membrane. In view of this log Kow the substance as such would not accumulate in the body fat.

Metabolism

There are no actual data on the metabolisation of the substance but the anticipated metabolism using OECD Toolbox is summarized in Fig. 1, which is in accordance with Belsito review on non-cyclic terpene alcohols (Belsito et al., 2010). During Phase 1 metabolism, the methyl C atoms may become oxidized towards primary alcohols which may further oxidise into acids. During Phase 2 metabolism these alcohols can be conjugated by glucuronation. It is also anticipated that in the lysosomes the alcohol become conjugated with alpha2u-globulins.

Fig. 1   The metabolisation pathway of the substance as summarized from OECD Toolbox.

 

Excretion

In view of the anticipated higher water solubility of the metabolites the kidney is the main route of excretion. Alpha2u-globulin precipitation is seen in male rats causing alpha-hydrocarbon nephropathy indicate also that the kidney is the main route of excretion. Acidic metabolites may also be excreted as such.

Discussion

Tetrahydromyrcenol is expected to be readily absorbed, orally and via inhalation, based on the human toxicological information and physico-chemical parameters. The substance also is expected to be absorbed dermally based on the physic-chemical properties. The MW and the log Kow are higher than the favourable range for dermal absorption but significant absorption is likely.

In view of the absence of adverse effect in the repeated dose / reproscreen study route to route extrapolation is not needed.

Conclusion

Tetrahydromyrcenol is expected to be readily absorbed via the oral and inhalation route and somewhat lower via the dermal route based on toxicity and physico-chemical data. Using the precautionary principle for route to route extrapolation the final absorption percentages derived are: 50% oral absorption, 50% dermal absorption and 100% inhalation absorption.

References

D. Belsito, D. Bickers, M. Bruze, P. Calow, H. Greim, J.M. Hanifin, A.E. Rogers, J.H. Saurat,

I.G. Sipes, H. Tagami: The RIFM Expert Panel. A safety assessment of branched chain saturated alcohols when used as fragrance ingredients. Food and Chemical Toxicology 48 (2010) S1–S46

 

Buist, H.E., Wit-Bos de, L., Bouwman, T., Vaes, W.H.J., 2012, Predicting blood:air partion coefficient using basis physico-chemical properties, Regul. Toxicol. Pharmacol., 62, 23-28. 

 

Martinez, M.N., And Amidon, G.L., 2002, Mechanistic approach to understanding the factors affecting drug absorption: a review of fundament, J. Clinical Pharmacol., 42, 620-643.

IGHRC, 2006, Guidelines on route to route extrapolation of toxicity data when assessing health risks of chemicals,http://ieh.cranfield.ac.uk/ighrc/cr12[1].pdf