p-menth-1-en-8-ol

Endpoint summary

Description of key information

Alpha-Terpineol 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.

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 information on alpha-Terpineol

Introduction

The test material alpha-Terpineol (CAS no 98-55-6) is a tertiary alcohol attached to an unsaturated cyclohexyl ring. At the para-position a methyl group is attached to the unsaturated bond in the ring. It is liquid at room temperature with a melting point of -20^oC and a molecular weight of 154 g/Mol that does not preclude absorption. The substance has a low volatility 6.5 Pa. Alpha-Terpineol (and its constituents) are natural occurring in a wide variety of food e.g. WHO (1999). Alpha-Terpineol (and similar terpene type of alcohols) are widely used as flavours and has being evaluated as such (WHO, 1999, 2000). A daily intake of 50 ug/kg bw for alpha-Terpineol has been presented by WHO (1999). Some information also exists on its medicinal properties e.g. cholagogic potential (increase in bile release) (Yamahara et al., 1985).

Human health data on alpha-Terpineol are scarce and read across from two sources have been used to predict these. These sources are Terpineol multi (a multi-constituent substance with alpha-Terpineol as its main constituent and gamma-Terpineol as the minor constituent)and alpha-Terpinyl Acetate. The constituents of the target and the source substances are presented below. The similarity and difference in behaviour of these constituents on the absorption, distribution, metabolisation and excretion process, will be discussed.

 Table A: The constituents of alpha-Terpineol, Terpineol multi and alpha-Terpinyl Acetate

Constituents / Dossiers	Alpha-Terpineol	Gamma-Terpineol	Cis-beta-Terpineol	Trans-beta-Terpineol	Alpha-Terpinyl Acetate	Gamma-Terpinyl Acetate	Cis-beta-Terpinyl Acetate	Trans-beta-Terpinyl Acetate
Chemical structures
Alpha-Terpineol	85	11	< 1	< 1	-	-	-	-
Terpineol multi	60	20	9	3	-	-	-
Alpha-Terpinyl Acetate	-	-	-	-	87	9	1	1

*Chemical structures can also be seen in the attached document.

Absorption

Oral:Liver effects were seen in a 20-day repeated dose gavage study of Madyastha and Srivastan (1988) who evaluated the metabolism of alpha-Terpineol. Repeated dose effects on liver were also seen for Terpineol multi in an oral gavage study according to OECD TG 422. These effects show that oral absorption of alpha-Terpineol occurs. Also Belsito et al. (2008) conclude that readily absorption of alpha-Terpineol is likely. They describe for terpene-type of alcohols > 50% orally absorption, being mostly excreted via the urine in a glucuronated conjugate, circa 15% is excreted via the faeces, few percentages in expired air and few percentages residual amount in tissue. The relatively low molecular weight (154) and the low octanol/water partition coefficient (Log Kow 2.6) and moderate water solubility (2870 mg/l) 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 alpha-Terpineol is likely to be absorbed orally and therefore the oral absorption is expected to be > 50% and likely to be close to 100%. Also the constituents are expected to be readily absorbed because they have similar physico-chemical properties, similar chemical structures and similar functional groups.

Skin: Alpha-Terpineol shows skin irritation properties and this indicates skin absorption. Also the physico-chemical characteristics of the substance, being a liquid, its molecular weight (154 g/Mol), log Kow (2.6) and water solubility (2870 mg/l), indicate that dermal absorption is likely to occur (Belsito et al., 2008). The optimal MW and log Kow range for dermal absorption is < 100 g/Mol and 1-4, respectively (ECHA guidance, 7.12, Table R.7.12-3). Though alpha-Terpineol is just outside the optimal range the skin absorption may exceed 50%. In Belsito et al. (2008) references are presented which indicate significant skin absorption for alpha-Terpineol.

Lungs: Absorption via the lungs is also indicated based on the physico-chemical properties. Though the inhalation exposure route is thought to be minor, because of its low volatility (6.5 Pa), the octanol/water partition coefficient (2.6), 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 partition 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 alpha-Terpineol the B/A partition coefficient would result in:

Log P (BA) = 6.96 – 1.04 x 0.8 – 0.544 x 2.6 – 0.00495 x 154= 4

This means that alpha-Terpineol 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 alpha-Terpineol being somewhat out of the applicability domain and the exact BA partition 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 test substance may 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 somewhat planar (flat) structure due to the double bond in the ring and the 1,4-positioned methyl groups of the substance is also expected to increase its distribution (Roberts and Costello, 2003). The log Kow of alpha-Terpineol and of its constituents indicates that the substance as such would not accumulate in the body fat.

Metabolism

The metabolisation of tertiary alcohols, such as alpha and other terpineols, has been described by WHO (2000). Under normal circumstances tertiary alcohols will be directly conjugated with glucuronic acid and will be excreted as can be seen in the figure below.

Fig. 1 The metabolisation of alpha-Terpinyl Acetate into alpha-Terpineol and its glucuronated product.

During gavage dosing the following metabolisation data was retrieved. In a study performed by Madyastha and Srivatsan (1988) it was determined that allylic methyl oxidation of alpha-Terpineol is one route for its biotransformation in rat (see Figure below). In this study, male albino IISc strain rats received alpha-Terpineol orally (gavage) at a daily dose of 600 mg/kg bw for 20 days. Oxidation of the allylic methyl group yielded the corresponding carboxylic acid, which to a small extent, was reduced to yield the corresponding saturated carboxylic acid.

 

Fig. 2 Metabolisation of alpha-Terpineol as presented by Madyastha and Srivatsan (1988)

Besides allylic methyl oxidation, alpha-Terpineol can also be epoxidised and then hydrolysed to yield a triol metabolite (1,2,8-trihydroxy-p-menthane). In this study alpha-Terpineol increased the liver microsomal P450 content and the activity of NADPH-cytochrome reductase suggesting that the oxidation is mediated by CYP450 (Madyastha and Srivatsan, 1988).

The epoxidation route has also been reported in humans following inadvertent oral ingestion of a pine oil disinfectant containing alpha-Terpineol (Horning et al., 1976) and in male Sprague-Dawley rats (Hill et al., 1975). In the latter study with Sprague-Dawley rats, the glucuronide conjugate of alpha-Terpineol was observed in the urine. This glucuronidation of alpha-Terpineol was also observed in sheep fed with alpha-Terpineol (Wright, 1945) and in an in vitro study using human embryonic kidney 293 cells (Green and Tephly, 1996).

During high repeat dosing via dietary route it is expected that alpha-Terpineol will be directly glucuronated and thereafter excreted (WHO, 2000), because no testicular effects were seen with Terpineol multi when dosed via the diet at 750 mg/kg bw. Also alpha-Terpinyl Acetate (which metabolises into alpha-Terpineol) did not show testicular effects during dietary dosing up to 400 mg/kg bw in a 20-week study. At high doses, via gavage, epoxidation of alpha-Terpineol can occur as described by e.g. Madyastha an, Srivatsan (1988).

Excretion

The primary route of excretion is expected to be through the urine, because of the log Kow of 2.6 and the water solubility of 2870 mg/l. In several studies alpha-Terpineol and its metabolites have been found in the urine (see above at metabolisation).

Discussion

Alpha-Terpineol is expected to be readily absorbed, orally and via inhalation, based on the human toxicological information and physico-chemical parameters (e.g. Belsito et al., 2008). The substance also is expected to be absorbed dermally based on the physico-chemical properties (e.g. Belsito et al., 2008). The MW is higher than the favourable range for dermal absorption but significant skin absorption is likely. The IGHRC (2006) document of the HSE and which is mentioned in the ECHA guidance Chapter 8 will be followed to derive the final absorption values for the route to route extrapolation.

Oral to dermal extrapolation:To justify route-to-route extrapolation, situations where the extrapolation of data would underestimate toxicity resulting from human exposure to a chemical by the route to route extrapolation, needs to be avoided. Alpha-Terpineol is expected to be readily absorbed via the oral route based on the information available. The toxicity of the dermal route is expected to be somewhat lower because the molecular weight is slightly above the favourable boundary. Therefore it will be assumed that the oral absorption will be equal to dermal absorption. Using the asymmetric handling of uncertainty the oral absorption will be considered 50% (though likely to be higher) and the dermal absorption will be considered also 50% (though likely to be lower).

Oral to inhalation extrapolation:Though alpha-Terpineol is not a volatile substance the inhalation exposure will be considered. Despite alpha-Terpineol being an eye and a skin irritant respiratory irritation is not expected because it is not a corrosive or a severe irritant (IUCLID section 7.3). In the absence of bioavailability data it is most precautionary that 100% of the inhaled vapour is bioavailable. For the oral absorption 50% has been used for route to route extrapolation to be precautionary for the dermal route.

Conclusion

Alpha-Terpineol 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

Belsito, D, Bickers., D., Bruze, M., Calow, P., Greim, H., Hanifin J.F., Rogers, A.E., Saurat, J.H., Sipes, I.G., Tagami, H.,,Toxicologic and Dermatologic Assessment of Cyclic and Non-Cyclic Terpene Alcohols, Food and Chemical Toxicology 46 (2008) S1–S71

http://www.rifm.org/doc/Assessmnt%20of%20Cyclc%20Non%20Cyclc%20Trpn%20Alcohols-Food%20&%20Chemcl%20Toxiclgy%20112008%20.pdf

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

Green, M.D., Tephly, T.R., 1996. Glucuronidation of amines and hydroxylated xenobiotics and endobiotics catalyzed by expressed human UGT1.4 protein. Drug Metabolism and Disposition 24, 356–363.

Hill, R.M., Barer, J., Hill, L.L., Butler, C.M., Harvey, D.J., Horning, M.G., 1975. An investigation of recurrent pine oil poisoning in an infant by the use of gas chromatographic-mass spectrometric methods. Journal of Pediatrics 87, 115– 118.

Horning, M.G., Butler, C.M., Stafford, M., Stillwell, R.N., Hill, R.M., Zion, T.E., Harvey, D.J., Stillwell, W.G., 1976. Metabolism of drugs by the epoxide-diol pathway. In: Frigerio, A., Catagnoli, N. (Eds.), Advances in Mass Spectroscopy in Biochemistry and Medicine, vol. I. Spectrum Publications, New York, pp. 91–108.

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

Madyastha, K.M., Srivatsan, V., 1988, Studies on the metabolism of L-menthol in rats, Drug Metabolism and Disposition 16, 765–772.

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.

WHO, 2000, Evaluation of certain food additives, Technical Report Series 891, page 53/54,http://whqlibdoc.who.int/trs/WHO_TRS_891.pdf

WHO, 1999, Safety evaluation of certain food additives,http://www.inchem.org/documents/jecfa/jecmono/v042je25.htm

Wright, S.E., 1945. Detoxication mechanisms in the sheep. University Queensland Papers 1, 1–10.

Roberts, D.W., and Costello, J.F., 2003, Mechanisms of action for general and polar narcosis: a difference in dimensions, QSAR Comb. Sci., 22, 226-233.