p-menth-1-en-8-yl acetate

Endpoint summary

Description of key information

No experimental toxico-kinetic data are available for assessing absorption, distribution, metabolisation and excretion of alpha-Terpinyl Acetate. Based on the human toxicological information, physico-chemical parameters and further information from related substances, being discussed in the WHO (2000) review on terpinyl-esters in general and Terpinyl Acetate specifically, this substance is expected to be readily absorbed orally WHO (1999, 2000). The substance is also 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. Inhalation exposure will be limited due to the low vapour pressure but when present the substance will partition into the blood. The IGHRC (2006) document of the HSE and mentioned in the ECHA guidance Chapter 8 is followed to derive the final absorption values for the risk characterisation. 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:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

Alpha-Terpinyl Acetate and the assessment of its toxico-kinetic behaviour,

Introduction

Alpha-Terpinyl Acetate and its impurities are tertiary acetic-esters attached to an unsaturated cyclohexyl ring, with a methyl group attached to the unsaturated bond at the para-position (see section 1 on identity or table A below). It has a melting point of -20^oC and a molecular weight of 196 g/mol that does not preclude absorption. Its viscosity is 6 times higher than water: 6.04 mPa.s (water being 1 mPa.s). The substance has a low volatility 3.5 Pa. Alpha-Terpinyl Acetate is natural occurring in a wide variety of foods, fruits, spices and tea. The substance is also used as a flavour and as such its average oral intake in Europe is circa 5 µg/kg bw as estimated by WHO (2000).

In the table below the structural isomers are presented of alpha-Terpinyl Acetate and Terpinyl Acetate multi including the alcohols to show that these are very similar resulting in the same toxico-kinetic behaviour. The cis-and trans-form may be distributed a bit slower because these are less planar compared to the alpha and the gamma constituents.

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

Terp-inoids/ 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
Cas nu	98-55-5	586-81-2	138-87-4	138-87-4	80-26-2	10235-63-9	59632-85-8	59632-85-8
Alpha-Terpineol	85	11	< 1	< 1	0	0	0	0
Terpineol multi	60	29	9	3	0	0	0	0
Alpha-Terpinyl Acetate	0	0	0	0	87	9	1	1
Terpinyl Acetate multi	0	0	0	0	64	20	7	6

*Chemical structures can be seen in the attached document in IUCLID section 7.1.

Absorption

Oral: A 20-weeks repeated dietary toxicity study indicated a low order of toxicity for alpha-Terpinyl Acetate. The relatively low molecular weight, the moderate octanol/water partition coefficient (Log Kow 4.4) and water solubility (23 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 alpha-Terpinyl Acetate is likely to be absorbed orally and therefore the oral absorption is expected to be > 50%.

Skin: (Some) dermal absorption is likely to occur, based on its molecular weight (196 g/mol) and its physico-chemical characteristics: log Kow (4.4) and water solubility (23 mg/l). 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). Alpha-Terpinyl Acetate is just outside optimal range and therefore the skin absorption is not expected to exceed 50%.

Lungs: Absorption via the lungs is also indicated based on these physico-chemical properties. Though the inhalation exposure route is thought to be minor, because of its low volatility (3.5 Pa), the octanol/water partition coefficient (4.4), 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 Terpinyl Acetate the B/A partition coefficient would result in:

Log P (BA) = 6.96 – 1.04 x 0.56 – 0.533 x 4.4 – 0.00495 x 196= 3.06

This means that alpha-Terpinyl Acetate 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 BA 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 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. Due to the expected metabolisation the substance as such would not accumulate in the body fat.

Metabolism

Though there are no actual data on the metabolisation of alpha-Terpinyl Acetate the metabolism of these substances are well understood (e.g. WHO, 1999, 2000). These acetates are likely to be fully metabolised in the gut and in the liver (as well as in other organs and tissues) into alpha-Terpineol and acetic acid, and while passing no alpha-Terpinyl Acetate will remain (WHO, 2000, Belsito et al., 2008, Yamada et al., 2013 and Wu et al., 2010, see metabolism figure in attached document). Acetic acid is an endogenous component of body; it will be consumed in the Krebs cycle. Alpha-Terpineol will be further metabolised via the glucuronic pathway and subsequently excreted.

Fig. 1   The metabolic pathway of alpha-Terpinyl Acetate is presented. The substance is metabolised via carboxylesterases into alpha-Terpineol and acetic acid (Cas no 98-55-5). Alpha-Terpineol is directly glucuronated (for references see text).

Excretion

The primary route of excretion is expected to be through the urine, though some may occur via the bile into the intestines (WHO, 2000). Any unabsorbed substance will be excreted via the faeces.

Discussion

The substance is expected to be readily absorbed, orally and via inhalation, based on the human toxicological information and physico-chemical parameters and further information from related substances as discussed in the WHO (2000) review on this material. 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.

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-Terpinyl Acetate is expected to be hydrolysed in the gut by micro-organisms because it is an ester. Some first pass effect via the liver may also occur, because of the presence of e.g. carboxylesterases, but because these esterases are also present in the skin, this effect will be minimal. The toxicity of the dermal route will therefore not be underestimated. In addition, the absorption will be slower and the substance will also pass the liver. Therefore it will be assumed that the oral absorption will equal 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-Terpinyl Acetate is not a volatile substance the inhalation exposure will be considered. It is not a skin, an eye irritant or a skin sensitiser and thus local (long-term) effects are not expected and will not need to be considered. 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. For inhalation absorption 100% will be used for route to route extrapolation, because this will be precautionary for the inhalation route.

Conclusion

Alpha-Terpinyl Acetate is expected to be readily absorbed via the oral and inhalation route and somewhat lower via the dermal route based on toxicity information 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.M., Rogers, A.E., Saurat, J.H., Sipes, I.G., Tagami, H., 2008, A toxicologic and dermatologic assessment of cyclic acetates when used as fragrance ingredients, Food and Chemical Toxicology, 10, 46 Suppl 12:S1-27.

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. 

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

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, 1999, Food additive series 42, 1999, Evaluation of certain food additives, Aliphatic acyclic and alicyclic terpenoid tertiary alcohols and structurally related compounds,http://www.inchem.org/documents/jecfa/jecmono/v042je17.htm

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

Wu, S., Blackburn, K., Amburgey, J., Jaworska, J., Federle, F., 2010. A Framework for using structural, reactivity, metabolic and physicochemical similarity to evaluate the suitability of analogs for SAR-based toxicological assessments. Regul. Toxicol. Pharm. 56, 67–81.

Yamada, T., Tanaka, Y., Hasegawa, R., Sakuratani, Y., Yamada, J., Kamata, E., Ono, A., Hirose., A., Yamazoe, Y., Mekenyan, O., Hayashi, M., 2013, A category approach to predicting the repeated-dose hepatotoxicity of allyl esters, Reg. Toxicol. Pharmacol, 65, 189-195.