AromaChemistry and Applications of Tea Tree Oil – Part 4 of 4

Absorption of Tea Tree Oil Applied Topically

Tea Tree Oil has long since been used topically for a variety of conditions and is widespread in formulations of the cosmetic industry. However, little is actually known about its absorption and penetration through human skin and the consequential risks of application.  Due to the lipophilic nature of many of the constituents, it has been generally accepted that Tea Tree Oil readily penetrates through the skin. A study conducted by S.E. Cross et al. evaluated penetration for both neat TTO (pure) and a 20% solution in ethanol. The 20% TTO solution in ethanol was selected, as it is a formulation believed to disrupt the barrier properties of the skin and possibly ease penetration (15).

This study observed the penetration and retention of TTO over a 24-hour period and used the skin of three female donors. The TTO used contained the ISO amounts for the 15 standard components. Another aspect of the study looked to determine evaporation rates, as when TTO evaporates there is a less concentrated amount that can then penetrate through the skin, thereby affecting absorption values. Due to the volatile nature of TTO, two different settings were established: non-occluded and partially occluded application. In partial occlusion, the top of the donor chamber was partially covered to reduce evaporation and observe the resulting effects in penetration. Penetration was determined based on passage through the epidermal membrane into the receptor phase of the skin.  Samples were taken at the receptor phase throughout the 24-hour period. Gas Chromatography-Mass Spectrometry (GC-MS) was used to help identify individual molecules (15).

The non-occluded application exhibited penetration in only terpinen-4-ol and α-terpineol, as shown from receptor phase samples. However, there were wide variations between the donors in the values. The penetration of terpinen-4-ol corresponded to only 3.6-8.0% of the applied amount and the penetration of α-terpineol corresponded to only 3.6-8.4%. With the partially-occluded application, 1,8-cineole levels could be detected. Additionally, the mean increase in terpinen-4-ol was ~2.5x, and for a-terpineol, ~2x. (15).

In terms of epidermal retention, extracted skin samples were taken at 24-hours. For the partially occluded applications, terpinen-4-ol and a-terpineol were most prominently identified, as well as a mixture of other sesqui-terpenes. Terpinen-4-ol corresponded to approximately 0.1-0.2% of the applied amount. The observed mixture of sesqui-terpenes indicates that although some of the components may have not penetrated, it appears as though some remained on the skin after 24-hours. The total retention for identifiable components of TTO resided between 0.23% and 0.37% of the originally applied amount (15).

The partially occluded applications exhibited very different results. With this application, although very low, all 15 standard components of TTO were identified, compared to the non-occluded where only terpinen-4-ol and a-terpineol were identifiable. For the partial occlusion, the total epidermal retention correlated to 0.27% of the original applied amount. Also, there was a 3x increase in retention of terpinen-4-ol (15).

As part of this study, a brief experiment was performed to determine the rate of evaporation of TTO. At 30ºC, small filter papers were used with two applications: 1.43 mg/cm² and 7.37 mg/cm². The latter was used to mimic dermal penetration.  The results showed that the 1.43 mg/cm² application evaporated within 1 hour and the 7.37 mg/cm² application evaporated within 4 hours. With the rapid rates of evaporation, there is an inverse relationship with penetration. Therefore, with an increase in evaporation rate, there is a decrease in penetration as there is less substance available to penetrate, and as seen with the prior assay, TTO is best absorbed under high concentrations. (15).

The study suggests that TTO is not as readily absorbed as once thought. It is also clear that there are significant variations in absorption between individuals. Although penetration can be determined in general terms, actual rates will vary from person to person. In addition, terpinen-4-ol and α-terpineol seem to be the main agents that penetrate into the receptor phase of the skin.  As observed with the differences between the non-occluded and occluded applications, it appears that higher concentrations of TTO and its components allow for increased diffusivity through the epidermis. High concentrations are hard to maintain, as TTO is speculated to evaporate from the skin within 4 hours. It is important to keep in mind that due to the in vitro nature of this study, other variables are not accounted for, such as perfusion by blood vessels, and actual penetration and retention may differ in vivo. (15).

Toxicity Of Tea Tree Oil

Even though Tea Tree Oil has been used rather safely for thousands of years, externally, the topic of toxicity must be addressed and studied. Cases of oral poisoning, irritation, and allergic reaction have been reported for humans with ingestion and topical application, but, are relatively rare. No human deaths from TTO have been reported in the literature. Additionally surveying the issue of toxicity, various studies have been performed, and predominantly so on rats (16).

TTO can be toxic if ingested. This has been seen through human reports, as well as experimental studies. One study determined that 50% of the oral lethal dosage of TTO for rats is 1.9-2.6 mL/kg body weight. In a subsequent study, rats dosed with </ 1.5 g TTO/kg body weight appeared ataxic and lethargic. Additionally, rats continued to exhibit depressed activity after 72 hours of dosage. Again, no human deaths have been reported, but cases of poisoning exist for both children and adults. Cases with children are, however, more dramatic, as even a relatively low amount may provide an increased effect due to their low body weight in comparison to an adult (16).

One case study documented a 23-month old boy who consumed less than 10 mL. Upon awakening from a 30-minute nap immediately following consumption, he appeared drunk and was unsteady on his feet. He was taken to a hospital and treated with activated charcoal and sorbitol via a naso-gastric tube, and after 5 hours he appeared asymptomatic. Another reporting involved an adult who drank half of a cup of TTO, or in terms of their body weight, 0.5-1.0 mL/kg. The individual was comatose for 12 hours, and then became semi-conscious and hallucinatory and remained so for another 36 hours (16).

Cases of dermal toxicity have also been reported and involve both dermal irritation and allergic reactions. To determine how frequent and severe irritant reactions are, several studies have been conducted. One study patch tested 217 patients with 10% TTO, none of which suffered irritant reaction. The same group of people was asked to apply a 5% TTO lotion. This time, however, weak irritant reactions were exhibited in 44 patients (20%). This raises two very important questions: a) are there ingredients present in a given medium, such as lotion, which are truly the cause of irritation and not actually the oil itself?, and b) are products on the shelves stored properly to minimize the oxidation of TTO components and thereby reduce adverse reactions (16)?

Additional studies have been performed and have looked to survey allergic reactions. In one study, neat TTO (100% pure) was applied to 550 patients, and allergic reactions were observed in just 13 patients (2.4%). In another study, which involved 725 patients, TTO was applied in concentrations of 5%, 1%, and 0.1%.  Only one patient suffered irritation from 5% and 1%. No patients exhibited irritation at 0.1%. Further research suggests that the greatest likelihood of allergic reactions is from improper storage conditions of Tea Tree Oil or its related products. Over time, and with exposure to light, oxidation of the oil occurs and, with this, alteration of the original chemical composition. Research suggests that the new components present are more likely to cause adverse reactions.  It is also suggested that some of the major agents that play a role in allergic reactions may be terpinolene, α-terpinene, ascardiole, and 1,2,4-trihydroxymethane (16).

Tea Tree Oil does, in fact, exhibit dermal and oral toxicity, although most commonly in extreme situations. Practical applications with a properly stored product are likely to have mild to no effect on individuals with TTO sensitivity. Additionally, it also appears that lower dosages are always more appropriate and will help to minimize serious adverse reactions (16).

Gaps In Research

Research shows that 1,8-cineole does have antibacterial properties, and as seen in some studies, its effect has been stronger than other TTO components at their MIC levels. However, 1,8-cineole has been erroneously identified as a skin and mucous membrane irritant, and was also believed to have little to no antimicrobial activity (1, 5).  Due to these facts, little research has been conducted emphasizing the mode of action of 1,8-cineole. Yet, if studies were conducted, 1,8-cineole might enhance the antibacterial effects.

Recent research has shown that 1,8-cineole does, in fact, play a very important role in the action on S. aureus.  At its MIC levels, 1,8-cineole provided significantly stronger effects on the bacteria’s salt tolerance and loss of 260-nm absorbing material (6).  Furthermore, research suggests that although 1,8-cineole may not promote immediate cellular death, as seen with S. aureus, it is hypothesized that it may play a role in assisting other components’ efficacy. With the variations in chemotypes available, it would be reasonable to extract those with high cineole levels for experimentation purposes.

Although studies have looked at TTO alone, as well as its individual components, very little is understood about the interactions of the constituents as a holistic system. It is possible that a combination of select molecules may provide synergistic or antagonistic effects, compared to TTO alone. Additionally, the removal of a specific molecule or group of molecules may increase the efficacy.

References

1. Carson, C.F., K.A. Hammer, and T.V. Riley. “Melaleuca alternifolia (Tea Tree) Oil: A Review of Antimicrobial and Other Medicinal Properties.” Clinical Microbiology Reviews (2006): 50-62.
2. Kirste, B. 2 February 2002. 7 October 2008 <http://www.chemie.fu-berlin.de/chemistry/oc/terpene/terpene_en.html>.
3. International Organisation for Standardisation. 2004. ISO 4730:2004. Oil of Melaleuca, terpinen-4-ol type (tea tree oil). International Organisation for Standardisation, Geneva, Switzerland.
4. Brophy, J.J., N.W. Davies, I.A. Southwell, I.A. Stiff, and L.R. Williams. “Gas Chromatographic Quality Control for Oil of Melaleuca Terpinen-4-ol Type (Australian Tea Tree).” Journal of Agricultural and Food Chemistry (1989): 1330-1335.
5. Carson, C.F. and T.V. Riley. “Antimicrobial activity of the major components of the essential oil of Melaleuca alternifolia.” Journal of Applied Bacteriology (1995): 264-269.
6. Carson, C.F., B.J. Mee, and T.V. Riley. “Mechanism of Action of Melaleuca alternifolia (Tea Tree) Oil on Staphylococcus aureus Determined by Time-Kill, Lysis, Leakage, and Salt Tolerance Assays and Electron Microscopy.” Antimicrobial Agents and Chemotherapy (2002): 1914-1920.
7. Cox, S.D., J.E. Gustafson, C.M. Mann, J.L. Markham, Y.C. Liew, R.P. Hartland, H.C. Bell, J.R. Warmington, and S.G. Wyllie. “Tea tree oil causes K+ leakage and inhibits respiration in Escherichia coli.” Letters in Applied Microbiology (1998): 355-358.
8. Gustafson, J.E., Y.C. Liew, S. Chew, J. Markham, H.C. Bell, S.G. Wyllie, and J.R. Warmington. “Effects of tea tree oil on Escherichia coli.” Letters in Applied Microbiology (1998): 194-198.
9. Mann, C.M., S.D. Cox, and J.L. Markham. “The outer membrane of Pseudomonas aeruginosa NCTC 6749 contributes to its tolerance to the essential oil of Melaleuca alternifolia (tea tree oil).” Letters in Applied Microbiology (2000): 294-297.
10. Bassett I.B., D.L. Pannowitz, and R.S. Barnetson. “A comparative study of tea-tree oil versus benzoylperoxide in the treatment of acne.” Medical Journal of Austrailia (1990): 455-458.
11. Satchell, A.C., A. Saurajen, C. Bell, and R. Barnetson. “Treatment of dandruff with 5% tea tree oil shampoo.” American Academy of Dermatology (2002): 852-855.
12. Golab, M., and K. Skwarlo-Sonta. “Mechanisms involved in the anti-inflammatory action of inhaled tea tree oil in mice.” Experimental Biology and Medicine (2007): 420-426.
13. Koh, K.J., A.J. Pearce, G. Marshman, J.J. Finlay-Jones, and P.H. Hart. “Tea tree oil reduces histamine-induced skin inflammation.” British Journal of Dermatology (2002): 1212-1217.
14. Halcon, L., and K. Milkus. “Staphylococcus aureus and wounds: A review of tea tree oil as a promising antimicrobial.” American Journal of Infection Control (2004): 402-408.
15. Cross, S.E., M. Russell, I. Southwell,and M.S. Roberts. “Human skin penetration of the major components of Australian tea tree oil applied in its pure form and as a 20% solution in vitro.” European Journal of Pharmaceutics and Biopharmaceutics 69 (2008): 214-222.
16. Hammer, K.A., C.F. Carson, T.V. Riley, and J.B. Nielsen. “A review of the toxicity of Melaleuca alternifolia (tea tree) oil.” Food and Chemical Toxicology (2006): 616-625.