Terpene hydrocarbon alcohols, terpene processing by-products

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

Toxico-kinetic behaviour of Terpene hydrocarbon alcohols

Introduction

Terpene hydrocarbon alcohols have the following constituent types of substances: Solely hydrocarbons-terpene type, Alcohol-type, Ketone-type and Ether-type all having a saturated or unsaturated cyclic hydrocarbon backbone. These types have a MW around 150, they are all liquids, vapour pressures are around 10 Pa, water solubility around 1000 mg/l and log Kow around 3.5. All substances have a hydrocarbon backbone. For the toxico-kinetic assessment, the Solely hydrocarbons present the more extreme values and the measured values for vapour pressure and log Kow are considered to represent this group: 51.9 Pa and log Kow is 4.33. The latter value is derived based on the measured log Kow of Terpinolene being between 4.2 and 4.5, with 4.33 as the arithmetical mean value. For the water solubility the measured of the substance is used to also present the other more water soluble constituent types.

Absorption

Oral: The physico-chemical properties indicate high oral absorption based on results the relatively low molecular weight (136) and the moderate octanol/water partition coefficient (Log Kow 4.33) and water solubility (622 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 all constituent types are likely fully absorbed orally and therefore the oral absorption is expected to be >> 50%. 

Skin: Based on the physico-chemical characteristics of Terpinolene being a liquid, molecular weights (ca 136), log Kow (4.33) and water solubility (662), 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 and physico-chemical value are just outside optimal range and therefore the skin absorption is not expected to exceed the oral absorption. 

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 (51.9 Pa), the octanol/water partition coefficient (4.33), 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. 

For the substance the B/A partition coefficient would result in: 

Log P (BA) = 6.96 – 1.04 (log 51.9) – 0.533 (4.33) – 0.00495 (136) = 2.2 

This means that the constituents have 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 constituents 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 of the substance indicates that some transport via the water channels in the body can occur. The log Kow would suggest that these constituents would pass through the biological cell membrane. Based on the log Kow the substance can accumulate somewhat in the body fat. Based on the metabolic profile such accumulation is not likely.

Metabolism: The metabolites of the Terpene hydrocarbon alcohol constituents are all quite similar. The substances that have external methyl groups can oxidise into primary alcohols and further into acids (e.g. alpha Terpineol). The metabolites of the hydrocarbon type result mainly in secondary and some in tertiary alcohols (e.g. Terpinolene). Alcohols present are secondary or tertiary alcohols (alpha-Terpineol). Ketones (e.g. Camphor) will be reduced to secondary alcohols to make them susceptible for conjugation. Methyl ethers attached to aromatics will metabolise into secondary phenol type (e.g. cis-Anethole, WHO on trans-Anethole, 1999). There are some published in vitro data on alpha-Terpineol, which may oxidise into Perilyc acid (Madhave and Srivatsan, 1988) among other oxidised metabolites.

 

Fig. 1   The metabolic pathway of Terpenyl hydrocarbon alcohols and their constituent types. All will result in an alcohol type metabolite which can be further oxidized or becomes conjugated for excretion (conjugation pathway is not shown).

Excretion

Terpene hydrocarbon alcohols and the oxidised metabolites will result in kidney being the key excretion route. This key excretion pathway. Primary alcohols may be excreted as such. Secondary and Tertiary alcohols are partly conjugated with alpha-2u globulin and will be excreted via the kidneys via this mechanism because we see for a number of secondary alcohols alpha hydrocarbon nephropathy in the kidneys. Tertiary alcohols and ketones (the latter need first reduction into alcohols) are likely to follow a similar mechanism. Excretion via the bile and is not expected because of the limited fatty characteristics of the metabolites. In view of the expected >>50% excretion via the faeces without being absorbed is not an important route.

Discussion

Terpene hydrocarbons alcohols will be readily absorbed, orally and via inhalation based on Terpinolene as a guiding constituent, because of its higher log Kow and higher vapour pressure. The MW and the log Kow are higher than the favourable range for dermal absorption and therefore dermal absorption will not exceed oral absorption. The IGHRC (2006) document of the HSE mentioned in the ECHA guidance Chapter 8 will be followed to derive the final absorption values for the risk characterisation.

Oral to dermal extrapolation: The substance is absorbed orally. Since dermal absorption will be (s)lower and the substance will also pass the liver during systemic circulation, it is assumed that the oral absorption will equal dermal absorption as a conservative approach. Using the asymmetric handling of uncertainty, the oral absorption will be considered 50% (though likely to be higher) and the dermal absorption is not expected to exceed the oral absorption (IGHRC, 2006).

Oral to inhalation extrapolation: Although the substance is not volatile, exposure via inhalation will be considered. In the absence of bioavailability data it is most precautionary that 100% of the inhaled vapour is bioavailable. For inhalation absorption 100% will be used for route to route extrapolation, because this is worst case the inhalation route.

 

References

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.

 

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

 

Madhava Madyastha, K., and Srivatsan, V., Biotransformation of a-Terpineol in the rat, 1988, Its effects on the liver microsomal cytochrome P-450 system, Bull. Environ. Contam. Toxicol., 41 17-25.

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.

 

Trans-Anethole, 1999, Review by WHO on food additives, No 42,

http://www.inchem.org/documents/jecfa/jecmono/v042je02.htm