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RIRDC Completed Projects in 2006-2007 & Research in Progress as at June 2007
To tea Tree Oil Research in Progress
1.7 TEA TREE OIL - COMPLETED PROJECTS PROJECT No PROJECT TITLE RESEARCHER PHONE ORGANISATION To improve existing products and develop new ones UJC-13A Fabrication of electronic materials from the Australian essential oils Dr Mohan Jacob (07) 4781 4379 James Cook University To enhance the ability of the industry to provide products that meet appropriate safety and efficacy CIN-1A Preparation of SCCP submission for tea tree oil Mr John Issa (02) 9705 9909 CINTOX Pty Ltd GUI-1A Skin sensitisation: Local lymph node assay Mrs Patricia Bolster (02) 6674 2991 P Guinane Pty Ltd USC-9A Stability testing of tea tree oil A/Prof David Leach (02) 6622 3211 Southern Cross University To establish production systems that are both ecologically sustainable and profitable DAN-199A Breeding and cloning tea tree for greater profitability Dr Trevor Olesen (02) 6626 1224 NSW Department of Primary Industries To improve existing products and develop new ones
Project Title: Fabrication of electronic materials from the Australian essential oils RIRDC Project No.: UJC-13A Researcher: Dr Mohan Jacob Organisation: James Cook University Phone: (07) 47814379 Fax: (07) 4781 5177 Email: mohan.jacob@jcu.edu.au Objectives 1. Fabricate high quality plasma polymerised thin films from essential oils available in Australia. 2. Procure an Ellipsometer and study the optical properties of the fabricated thin films to find suitable applications.
3. Fabrication of thin film and study the semi-conducting properties.
Background More than 60 billion pounds of polymer products is used per year only in USA, which includes the polymers like Polyethylene. The total polymer industry around the world is worth billions of dollars and employs several million people. Most of the commercially available polymers are made out of chemicals and are not biodegradable, and are hazardous to the environment. The aim of this research is to fabricate polymers from natural resources and hence adding value to our resources. Research A plasma polymerisation unit has been fabricated and installed to develop polymer thin films from essential oils. The deposition parameters were changed to optimise the thin film properties. Different essentials oils were tested to find the feasibility of polymerisation. a-Pinene and d-Limonene and tea tree oil were used as monomers for fabrication of the thin films. The Atomic Force Microscope was used to study the surface properties and found that very smooth films can be obtained from tea tree oil. We have also tried different substrate materials. An ellipsometer was ordered to study the optical properties. We have installed an electrical characterisation set up for the measurement of electrical properties. Outcomes Even though we could polymerise the monomers, the quality of the thin film was different. Some of the cheapest essential oils like a-pinene and d-Limonene could produce polymer thin films under ideal conditions but the roughness of the surface was very high. The optical properties of the thin films derived from Tea Tree Oil was studied and found that the refractive index of the thin film is close to that of glass. A setup is made ready for electrical characterisation. Implications The properties of the thin polymer films show that they are potential candidates for electrical and biomedical applications. More tests are under progress to study the behaviour of the films under ideal and varying physical and environmental conditions. Initial studies show a biodegradable nature of the fabricated thin film. Publications We are waiting for more results before communicating the results in the public domain. To enhance the ability of the industry to provide products that meet appropriate safety and efficacy
Project Title Preparation of SCCP submission for TTO-Stage 1 RIRDC Project No.: CIN-1A Researcher: Mr John Issa Organisation: Cintox Pty Ltd
PO Box 168
SUMMER HILL NSW 2130.Phone: (02) 9705 9909 Fax: (02) 9705 9919 Email: johnissa@cintox.com.au Objectives To prepare a safety dossier on tea tree oil for submission to the Scientific Committee on Consumer Products (SCCP) in conjunction with the tea tree oil industry. Background The European SCCP (Scientific Committee on Consumer Products) recently concluded that insufficient data was available on the safety and stability of tea tree oil. The industry is addressing this situation by commissioning approved tests in order to obtain a more complete safety dossier on tea tree oil. Research A comprehensive review of the available scientific literature on the toxicity of tea tree oil and its main constituents has been conducted. This review was conducted independently by Dr Jesper Bo Nielsen, Associate Professor, Institute of Public Health, Environmental Medicine, University of Southern Denmark. Several literature studies, not previously considered by the SCCP, have been identified and presented in this dossier. Additional new studies have been either conducted by ATTIA/RIRDC or have been contributed by individual companies in response to the SCCP request:
·1 Percutaneous absorption ·2 Mouse micronucleus assay
·3 Mouse Local Lymph Node Assays (LLNA)
·4 Serial dilution patch test and Repeated Open Application Test (ROAT)
·5 Predictive testing for irritancy and allergenicity of tea tree oil in normal subjects (Aspres and Freeman 2003)
·6 In-use stability study
·7 Method for the characterisation of tea tree oil and determination of peroxide levels and p-cymene as markers for oil degradation status in neat oil and in formulated products
·8 Stability of formulated products
·9 Peroxide levels of retained samples
·10 Company adverse event data
To enhance the ability of the industry to provide products that meet appropriate safety and efficacy
Project Title Skin sensitisation: Local lymph node assay RIRDC Project No.: GUI-1A Researcher: Mrs Patricia Bolster Organisation: P Guinane Pty Ltd
PO Box 20
Tweed Heads NSW 2485Phone: (02) 6674 2991 Fax: (02) 6674 2475 Email: pcb@gelair.com.au Objectives To undertake a Local Lymph Node Assay in Mice (OECD429) to identify the contact allergenic potential of tea tree oil in order to provide a rational basis for risk assessment to the sensitising potential of tea tree oil to humans. Background The European SCCP (Scientific Committee on Consumer Products) recently concluded that insufficient data was available on the safety and stability of tea tree oil. The industry is addressing this situation by commissioning approved tests in order to obtain a more complete safety dossier on tea tree oil. Research In order to study a possible contact allergenic potential of tea tree oil, a number of LLNA tests were undertaken in accredited laboratories in Europe and the United States of America. Concentrations of 5%, 25% and 50% of tea tree oil were tested in the LLNA assay.
Topical applications at 25% and 50% in PEG 400 resulted in a stimulation index greater than three which classifies tea tree oil as an extremely weak sensitiser at those concentrations.
Outcomes While tea tree oil has been shown to be an extremely weak skin sensitiser, oxidised tea tree oil has a much greater propensity to cause skin sensitisation. Thus, the use of oxidised tea tree oil should be avoided. When used and stored properly, tea tree oil is not expected to pose a risk to human health. Implications The scientific testing undertaken in the preparation of this submission will be of economic benefit to the tea tree oil industry as a more acceptable oil will lead to more sales as a direct result of the safety and stability of the oil being better defined. Publications Submission to the Scientific Committee on Consumer Products (ACCP) - Toxicological summary and safety assessment for tea tree oil: A joint submission made by the Australian Tea Tree Industry Association and the Rural Industries Research & Development Corporation. A summary booklet outlining the major findings in the above submission is currently under development.
To enhance the ability of the industry to provide products that meet appropriate safety and efficacy
Project Title: Stability testing of tea tree oil RIRDC Project No.: USC-9A Researcher: Associate Professor David Leach Organisation: Centre for Phytochemistry & Pharmacology
Southern Cross University
PO Box 157
Lismore NSW 2480Phone: (02) 6622 3211 Fax: (02) 6622 3459 Email: dleach@scu.edu.au Objectives The objective of this study is to determine the changes in tea tree oil composition and peroxide value over 12 months under simulated in-use conditions. The proposed study protocol is based on principles outlined by the EMEA (European Agency for the Evaluation of Medicinal Products) in 'Guidance On In-Use Stability of Human Medicinal Products'. Analysis methods are based on authoritative European reference texts and should be acceptable to the SCCP and related relevant European authorities. Background Tea tree products are successfully marketed abroad and have become popular in Europe and North America. With this popularity has come increased scrutiny. Some tea tree oil products have been shown anecdotally and scientifically to cause dermal irritation and allergic sensitisation. Previous studies have indicated that intermediate peroxides formed by the oxidation of specific monoterpenes resulting in dimers and ultimately monoterpene polymers which crystallise, making the degraded oil yellow and viscous. The degraded tea tree oils are shown to have very high peroxide values. Tea tree oil, like all essential oils, is a blend of different, but closely related molecules called monoterpenes and sesquiterpenes. However, approximately 75% of the oil is comprised of only 4 molecules: a-terpinene (10%); ?-terpinene (20%); terpinen-4-ol (40%); p-cymene (1 – 3%); and 1,8-cineole (3%). In the presence of oxygen monoterpenes gradually oxidise forming peroxyl radicals.
Research Oil of Melaleuca, terpinen-4-ol type (tea tree oil) from two separate production batches (60175 and 60176) supplied to CPP by TP Health Ltd., Ballina, Australia. The oil samples conform to the definition and identification/quality profile of the European Pharmacopoeia (EP) monograph 04/2002:1837 ‘Tea Tree Oil – Melaleuca aetheroleum’ and ISO 4730 ‘Oil of Melaleuca, terpinen-4-ol type (Tea Tree oil). Tea tree oil was stored in 100 mL capped (airtight), amber glass bottles completely filled (no initial air space), and stored at room temperature (25°C) in a suitable space away from heat sources and light.
At the start of the study the bottles were removed from the storage cabinet and 0.15 mL and 6.17 mL of tea tree oil for GC analysis and peroxide value determination were withdrawn from each bottle which was then recapped after a total exposure to air for 1 minute and returned to the cabinet. Every seven days for three weeks each bottle was removed from the storage cabinet to an area within the laboratory illuminated by normal room lighting and opened for the duration of 1 minute while 0.5 mL oil was removed to simulate ongoing regular product usage before the bottle was tightly recapped and returned to the cabinet. On the 28th day only the 0.15 mL and 6.17mL aliquots of oil were removed from each bottle for testing and each bottle remained uncapped for 1 minute before being sealed again and returned to the dark cabinet. This procedure was repeated for the next 11 months. The analysis test results over the specified 12 x 28 day periods provide a compositional profile and information with respect to changes in peroxide value of tea tree oil under a defined simulated in-use regime.
Outcomes The results from the in-use stability testing of the two tea tree oil batches indicated that both samples remained relatively stable over the 12 month test period. There was a gradual increase in peroxide value over the 12 month period from 2 to 9 meqO2/kg. The major components of tea tree oil remained stable for 6 months after which time downward trends in ?-terpinene and ?-terpinene and an upward trend in p-cymene were observed. There was no significant change in the minor tea tree oil components over the 12 month period. At the end of the 12 month storage period both batches of oil still conformed to monograph specifications for tea tree oil. Implications This in-use stability study confirmed that neat tea tree oil is stable for 12 months and therefore presents no additional health hazards. Publications RIRDC Final report. To establish production systems that are both ecologically sustainable and profitable
Project Title: Breeding and cloning tea tree for greater profitability RIRDC Project No.: DAN-199A Researcher: Dr Trevor Olesen Organisation: NSW Department of Primary Industries
PO Box 72
Alstonville, NSW, 2477.Phone: (02) 6626 2422 Fax: (02) 6628 5209 Email: trevor.olesen@dpi.nsw.gov.au Objectives To improve the profitability of the tea tree industry by production and distribution of highly improved seed and selected clones. Background The project builds on two earlier RIRDC/ATTIA tea tree breeding projects (1993-1996; 1996-2000) that substantially improved the quality of seed available to industry. Research The main breeding strategy is based on establishing large trials which, after culling inferior trees, are converted to orchards to supply genetically improved seed. Complementing this, interim measures (best bush seed and a clonal seed orchard) have also delivered genetically improved seed to industry. Outcomes Oil yield from project seed has been progressively increased from 148 kg/ha at the beginning of the breeding program to c. 250 kg/ha, equivalent to a gain of 70% in 12 years. Desirable changes in oil quality have also been achieved in parallel with the increase in yield. Even greater gains are expected from elite clonal selections, which are currently being field assessed, and through improved seed from the project’s seed orchard program. Implications Adoption of project seed would result in improved profitability to the industry equivalent to c. $4M at current prices and costs, increasing the long-term viability of the Australian tea tree industry. Publications Doran JC, Baker GR, Williams ER, Southwell IS (2006) Genetic gains in oil yields after nine years of breeding Melaleuca alternifolia (Myrtaceae). Aust. J. Exp. Ag. 46, 1521-1527. To improve existing products and develop new ones
Project Title Tea tree oil to prevent staphylococcal infections in dialysis patients RIRDC Project No.: UWA-100A Start Date: 06/11/06 Finish Date: 10/11/08 Researcher: Professor Thomas V. Riley Organisation: The University of Western Australia Phone: (08) 9346 3690 Fax: (08) 9346 2912 Email: triley@cyllene.uwa.edu.au Objectives 1. To demonstrate that tea tree oil products are efficacious in the prevention of staphylococcal infections associated with dialysis catheters. 2. To demonstrate that tea tree oil products are a suitable alternative to existing products used to prevent staphylococcal infections associated with dialysis catheters.
3. To provide clinical data on the efficacy and safety of tea tree oil products.
Current Progress The protocol, information sheet and consent form were considered by the Clinical Drugs Trials Committee (CDTC) of Sir Charles Gairdner Hospital on 19th April 2007. They had some minor revisions and these were accepted by the Chair of the committee, Associate Prof. D A Joyce on 22 June, 2007. The application to the Human Research Ethics Committee (HREC) was considered at their meeting on the 8th May 2007. The Committee raised the question of gynecomastia and tea tree oil and the chief investigator Dr Brian Hutchison was asked to comment. A reply was drafted and sent to the HREC on 6th June. Dr Hutchison is awaiting their reply and approval for the trial to commence.
The Research Governance Unit (RGU) of Sir Charles Gairdner Hospital has recently been instituted and now oversees the standards of research at the hospital. A meeting was held with their representative on 2nd May 2007. They raised the issues of indemnity and insurance as the hospital now requires 10 million dollars in clinical trial insurance and indemnity before any trial can proceed. Novsel Australia who are supplying the tea tree ointment to be used in the trial have kindly agreed to supply both. We are waiting for this to be finalised. Once this has been done the RGU will give their approval for the trial.
Once approval has been obtained from the HREC and RGU the CTN form can be lodged with the TGA. Once permission from the TGA has been received by Dr Hutchison, the trial can begin.
1.7 TEA TREE OIL - RESEARCH IN PROGRESS PROJECT No PROJECT TITLE RESEARCHER PHONE ORGANISATION To improve existing products and develop new ones UWA-100A Tea tree oil to prevent staphylococcal infections in dialysis patients Prof Thomas Riley (08) 9346 3690 University of Western Australia To enhance the ability of the industry to provide products that meet appropriate safety and efficacy SCF-1A Allergy to tea tree oil: Qualitative aspects and risk assessment Dr Lisa O’Brien (02) 8353 3000 Skin and Cancer Foundation Australia UWA-90A Effects of tea tree oil on biofilm formation Dr Kate Hammer (08) 9346 1986 University of Western Australia UWA-93A Pilot study of tea tree oil in the decolonisation of MRSA positive wounds Dr Christine Carson (08) 9346 3288 University of Western Australia To establish production systems that are both ecologically sustainable and profitable ANU-74A Diagnostic tools for quality enhancement in Australian essential oil industries Dr William Foley (02) 6125 2866 Australian National University DAN-254A Improved tea tree varieties for a competitive market Dr Trevor Olesen (02) 6626 2422 NSW Department of Primary Industries To enhance the ability of the industry to provide products that meet appropriate safety and efficacy
Project Title Allergy to tea tree oil: Qualitative aspects and risk assessment RIRDC Project No.: SCF-1A Start Date: 1/6/06 Finish Date: 30/6/07 Researcher: Dr Lisa O’Brien Organisation: Skin and Cancer Foundation Australia
277 Bourke St
DARLINGHURST NSW 2010Phone: (02) 8353 3000 Fax: (02) 83533040 Email: lobrien@scfa.edu.au Objectives To evaluate the safety profile of tea tree oil by elicitation of dose-response patch testing and use testing. Current Progress A study was carried out to evaluate the safety profile of tea tree oil by elicitation dose-response patch testing and use testing in subjects who had been previously fount to be allergic to tea tree oil. A total o14 study subjects and 7 control subjects were tested. An additional two study subjects (currently being sought) are required to produce the necessary statistical power to provide conclusive results. To enhance the ability of the industry to provide products that meet appropriate safety and efficacy
Project Title Effects of tea tree oil on biofilm formation RIRDC Project No.: UWA 90A Start Date: 04/07/05 Finish Date: 06/07/07 Researcher: Dr Katherine Hammer Organisation: The University of Western Australia Phone: (08) 9346 1986 Fax: (08) 9346 2912 Email: khammer@cyllene.uwa.edu.au Objectives 1. Demonstrate that tea tree oil can inhibit the formation of microbial biofilm. 2. Investigate the effects of tea tree oil on existing biofilm.
3. Investigate the mechanism(s) by which biofilm formation is inhibited.
4. Explore potential medical and industrial applications of biofilm inhibition.
Current Progress Objective 1 has been achieved, with tea tree oil shown to inhibit biofilm formation by the Gram negative bacteria Pseudomonas aeruginosa, Stenotrophomonas maltophilia and Vibrio harveyi, the Gram positive bacterium Staphylococcus epidermidis and the yeast Candida albicans. However, there is some data from experiments with V. harveyi indicating that the inhibition of biofilm formation may simply be a direct result of reduced microbial growth, rather than an effect specifically against biofilm. This possibility requires further investigation and can be addressed to some extent under Objective 3. Objective 2 has largely been achieved, with work showing that the treatment of existing biofilm with tea tree oil for 24 hours results in the loss of viability within the biofilm, but not necessarily loss of the biofilm structure itself, also referred to as the biofilm biomass. This means that although the organisms may no longer be alive within the biofilm, its structure remains intact.
Objectives 3 and 4 have yet to be achieved. Protocols for investigating whether tea tree oil interferes with the cell-to-cell communication that is critical for biofilm initiation and development (also known as quorum sensing) have been developed and these experiments will commence in the final stages of the project.
To enhance the ability of the industry to provide products that meet appropriate safety and efficacy
Project Title Pilot study of tea tree oil in the decolonisation of MRSA positive wounds RIRDC Project No.: UWA-93A Start Date: 01/11/05 Finish Date: 31/10/07 Researcher: Dr Christine Carson Organisation: The University of Western Australia Phone: Mon-Wed, Fri: (08) 9314 5189 Thu: (08) 9346 3288 Fax: (08) 9346 2912 Email: ccarson@cyllene.uwa.edu.au Objectives 1. To determine if tea tree oil (TTO) can eliminate methicillin-resistant Staphylococcus aureus (MRSA) from colonised wounds. 2. To determine if TTO is a beneficial treatment for chronic wounds.
Current Progress Final approvals to conduct the pilot study were received from both the UWA and Silver Chain Human Research Ethics Committees and recruitment began in April. To date, four participants have been recruited and all commenced treatment with the tea tree oil product as planned. Two of the participants were subsequently shown to not be carrying MRSA and were withdrawn from the study in keeping with protocol. A third participant was MRSA positive but developed a wound infection and commenced antibiotics which necessitated withdrawing from the study. Results from the primary swab on the fourth participant are pending. If they are MRSA positive, their TTO treatment will continue. Additional strategies to enhance recruitment are being developed. These include getting Silver Chain staff from other nursing bases to recruit participants.
To establish production systems that are both ecologically sustainable and profitable
Project Title Diagnostic tools for quality enhancement in Australian essential oil industries RIRDC Project No.: ANU-74A Start Date: 01/06/06 Finish Date: 30/05/07 Researcher: Dr William Foley Organisation: Australian National University Phone: (02) 61252866 Fax: (02) 61255573 Email: william.foley@anu.edu.au Objectives The project aims to exploit the recent discovery of genes that control the production of terpenes in Melaleuca. The discovery of these genes provides a means of identifying the genetic differences responsible for the chemotypic variation among species and genotypes of Melaleuca plantation cultivars. It is expensive and slow. This project will correlate variations in the terpene profiles of Melaleuca chemotypes with variations in the sequences of terpene synthase genes. With this information it will be possible to identify diagnostic genetic variation that can ultimately be converted into diagnostic assays for use by breeders. Current Progress We have completed the collection of Melaleuca alternifolia leaf samples, covering its natural distribution. The leaf oils have been analysed and the presence of individuals of all known chemotypes has been confirmed. RNA has been extracted from individuals representing all chemotypes, and the construction of cDNA libraries has commenced. DNA has been extracted from all samples collected, and has been tested for purity and quantity. We currently have consistent results in isolating four distinct terpene synthases from genomic DNA, covering up to 60% of the open reading frame with sufficient specificity to allow for direct sequencing.
Furthermore, we have been able to apply recently obtained sequence information from Eucalyptus as well as publicly available Melaleuca sequence to isolating the mevalonate kinase and isopentenyl diphosphate isomerase genes responsible for upstream steps in the terpene biosynthesis pathway.
Presently, population wide sequencing of close to 100 individuals is underway to ascertain variation in the sequences available, while further effort is being put into completing the sequence information of all genes to obtain 100% coverage. We are thus close to being able to correlate variations in gene sequences with variations in oil profiles to provide a diagnostic test of high value oils in Melaleuca.
To establish production systems that are both ecologically sustainable and profitable
Project Title Improved tea tree varieties for a competitive market RIRDC Project No.: DAN-254A Start Date: 01/07/06 Finish Date: 01/07/09 Researcher: Dr. Trevor Olesen Organisation: NSW Department of Primary Industries
PO Box 72
Alstonville NSW 2477Phone: (02) 6626 2422 Fax: (02) 6628 5209 Email: trevor.olesen@dpi.nsw.gov.au Objectives To release improved seed and clones to maximise profit and market access for Australian the tea tree oil producers. Current Progress The tea tree breeding project has continually released seed to the industry since 1997. Seed sales total over 7.8kg (enough to plant over 1000 ha). Seed made available is from the best provenances, together with improved seed from both seedling and clonal orchards. Over 970g ($80/g) of seed from the clonal orchard have been sold since 2004 when yield gains of over 70% (averaged over 4 harvests) were confirmed for this seedlot. A yield trial established in 2002 for project released seed showed a 45% increase in yield on the fourth harvest compared with an industry standard. This increase comprised a 7% increase in growth and a 29% increase in oil concentration. The best performing release for the first, second, third and fourth harvests was the clonal seed orchard seed which achieved 91, 75, 43 and 79% (mean 72%) increases in oil yield for the four harvests, respectively. Accompanying these yield improvements were desirable changes in oil quality with project releases giving lower 1,8 cineole and higher terpinen-4-ol levels.
Improved seed from second-generation seedling seed orchards is now available. The progeny is to be tested in a yield trial to be established at Bungawalbin later this year.
A second clonal orchard for commercial seed production, using 24 elite families, was established at Wollongbar in February 2007. The first available seed from this orchard is expected in 2011.
Twenty elite clones are being assessed in a series of plant density/progeny trials at Bungawalbin. Early results suggest that reducing plant density from 33K to 16K plants per ha will have the potential to reduce yields.
At first and second harvests, clones (as physiologically mature plants) demonstrated 50% and 9% higher oil concentrations than seedlings respectively. The implication for growers is that clones may return higher early yields than seedlings but this advantage appears to diminish by the second harvest.
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