4-(1-methoxy-1-methylethyl)-1-methylcyclohexene

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 the substance 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. In view of the conservative nature of the measured log Kow and the anticipated metabolism of the substance into Terpineol (multi), there is no bioaccumulation potential.

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

Orange Flower Ether (14576-08-0) and the assessment of its toxico-kinetic behaviour

Introduction

The test material Orange Flower Ether (14576-08-0) is an ether attached to a cyclohexyl ring with one double bond with a methyl-group attached at the para-position (see section 1 on identity). Orange Flower Ether is liquid with a melting point <-20°C and a boiling point of 222.2°C. The molecular weight of 168.28 g/mol does not preclude absorption. The substance is readily biodegradable. The log Kow is 4.5 at 25°C (but considered to be conservative, EpiSuite and Sparc predict 4.0 and 3.4, respectively), the solubility in water is 85 mg/L at 23°C and the vapour pressure is 9.91 Pa at 23°C.

Absorption

Oral: The relatively low molecular weight and the moderate octanol/water partition coefficient (measured Log Kow 4.5) and water solubility (85 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 Orange Flower Ether is likely to be absorbed by the GI-tract and the oral absorption is therefore expected to be >50%.

Skin: Based on the physical-chemical characteristics of the substance, being a liquid with a molecular weight of 168.28 g/mol, a log Kow of 4.5 and water solubility of 85 mg/L the absorption is expected to be low to moderate. The optimal MW and log Kow for dermal absorption is <100 g/mol and in the range of 1-4, respectively (ECHA guidance, 7.12, Table R.7.12-3). Orange Flower Ether is just outside the optimal range and therefore the skin absorption is not expected to exceed 50%.

Lungs: Absorption via the lungs is also based on these physico-chemical properties. Though the inhalation exposure route is to be minor, because of its low volatility (9.91 Pa), the octanol/water partition coefficient (4.5), indicates that inhalation absorption is possible. The blood/air (B/A) partition coefficient is another partition coefficient indicating lung absorption. Buist et al. 2012 have developed B/A portioning model for humans using the most important and readily available parameters:

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

For Orange Flower Ether the B/A partition coefficient would result in:

Log P(BA) = 6.96 – 1.04 x 0.996 – 0.533 x 4.5 – 0.00495 x 168.28 = 2.69

This means that Orange Flower Ether has a slight 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 Orange Flower Ether being somewhat out of the applicability domain and the exact B/A portioning may not be fully correct, it can be seen that the substance will be readily absorbed via the inhalation route.

Distribution

The moderate water solubility of the test substance would limit distribution in the body via the water channels. The log Kow would suggest that the substance would pass through the biological cell membrane. The substance is not expected to accumulate in the body fat, despite its log Kow of 4.5 because the log Kow is conservative and the substance is anticipated to be readily metabolized.

Metabolism

Orange Flower Ether metabolises into Terpineol (multi) by demethylation of the ether CH3 group, resulting in Terpineol-alpha (Toxicological handbooks). See Figure below.

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Excretion

As Orange Flower Ether has a low molecular weight urinary excretion is favourable. Any unabsorbed substance will be excreted via the faeces

Discussion

Orange Flower Ether 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 physico-chemical properties. The MW and the log Kow are higher than the favourable range for dermal absorption but significant absorption is likely. The IGHRC (2006) document of the HSE and mentioned in the ECHA guidance Chapter 8 will be followed to derive the final absorption values for the risk characterisation.

Conclusion

Orange Flower Ether 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

Buist, H.E., Wit-Bos de, L., Bouwman, T., Vaes, W.H.J., 2012, Predicting blood:air partition coefficient using basic 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