Natural preservatives: myth or magic?

They repeat and exaggerate claims shown to be false, such as:

Another claim that is on quite a number of natural product websites is:

This statement also appears with “cruel” added in the appropriate place, and despite being used by a number of sites, no user has determined that it makes no sense and corrected it, unless they consider bacteria and fungi to be animals. The Scientific Committee on Cosmetic Products and Non-food Products intended for Consumers prepared a document titled Notes on Guidance for the Testing of Cosmetic Ingredients and Their Safety Evaluation. The 5th Edition was released in October 2003. The toxicity data requirements for preservatives are established in section 3.5.1 and the areas shown in Table 2.

Despite the large amount of testing, opponents of synthetic chemicals claim it is not necessarily the active components that are problematic. They say that unknown contaminants, which may only be present in miniscule amounts but which are taken into the body over many years, cause tragic effects. It appears that opponents of synthetic chemicals believe that all chemicals are absorbed through the skin and once inside remain there, none being degraded, altered or excreted. No amount of testing will prove safety. There is also the obvious and very real problem that animals do not necessarily react to chemicals the same as humans do.

The fact that most botanicals do not undergo such rigorous testing, that they contain many active compounds, and that large numbers of impurities and concentrations vary with the season is not significant. They are natural and therefore safe, it is considered.

Preservatives

Preservatives are chemical compounds added to products to prevent the growth of microorganisms. As such, whether they are natural or synthetic, they are toxic compounds capable of killing microorganisms by interfering with cell walls, internal structures or processes to cause death of the cell. Anything that kills microorganisms is potentially toxic to mammalian cells, and it is the concentration, contact time and point of contact that determines if there are any side effects from their use, not whether they are synthetic or natural. Synthetic and natural preservatives are compared in Table 3.

Preservatives permitted for use in cosmetics marketed in the EU must be listed in Annex VI of the EU Cosmetics Directive, List of Preservatives Which Cosmetic Products May Contain. The preamble to this annex states: “1. Preservatives are substances which may be added to cosmetic products for the primary purpose of inhibiting the development of microorganisms in such products.”

“3. Other substances used in the formulation of cosmetic products may also have anti-microbial properties and thus help in the preservation of the products, as, for instance, many essential oils and some alcohols. These substances are not included in this Annex.”

A number of substances used in cosmetics that are not listed in Annex VI are now claimed to have preservative activity and one of their selling points is that they can be used in products labelled as preservative free. Clause 3 of Annex VI allows the use of these non-listed compounds provided they are added to the cosmetic for some other reason. However, the claim of preservative free is only correct if you accept that only products listed as allowed preservatives in Annex VI should be called preservatives.

Any compound added to a cosmetic to control the growth of microorganisms by toxicity to the organisms, i.e., not including controlling of water activity or pH, is there as a preservative with potential toxicity, and consumers deserve to have them declared as preservatives.

This should cause an ethical problem for manufacturers and users of these products. Marketing a product as a natural preservative and stressing its antimicrobial activity as the real or only reason for including it in a product, while hiding behind clause 3 and labelling it as a fragrance or other additive is quite simply deliberately misleading and against what is a basic tenant of consumers wanting to use natural products. Stretching the truth in small ways leads to the justified suspicion of the cosmetics industry by consumers. There is little evidence that there is any ethical dilemma: natural preservatives are openly marketed and have evasive labelling.

If natural preservatives are so safe, the users of them should be willing to proudly pronounce that their products contain them and highlight which compounds or extracts in a formulation are there as preservatives so that consumers can research and decide if they want to use them, in the same way that they consider products containing synthetic preservatives. Unfortunately, due to adverse publicity, often by the same people promoting natural products, “preservative” is a term that carries undesired and often undeserved connotations.

The European Commission is concerned with this trend and has proposed a change in the definition of a preservative to further restrict “non-preservatives” preservatives. The proposed new definition is: “Preservatives mean substances which are exclusively or mainly intended to inhibit the development of microorganisms in the cosmetic product”.

The proposed revised regulation also removes clause 3 as quoted above, requiring that any compound added to a cosmetic for its preserving ability must be listed in Annex VI, including natural preservatives or fragrances added for their antimicrobial activity. If they are not listed in Annex VI, they may not be added to cosmetics.

The ASEAN Harmonised Cosmetic Regulatory Scheme (AHCRS) is an agreed standard for regulating cosmetic products in ASEAN Countries and finally came into force on 1 January 2008. Schedule B of the regulatory scheme is the ASEAN Cosmetics Directive (ACD) and Annex VI of the ACD is the List of Preservatives which cosmetic products may contain. The ACD Annex VI is the EU Cosmetics Directive Annex VI updated as at September 2007. So, regulations covering cosmetics and preservatives able to be used in cosmetics in the ASEAN countries are now the same as regulations in the EU. Annex VI lists approved preservatives with any limitations on their use in certain product types, maximum allowable concentrations or special labelling requirements. Cosmetics in Australia are now regulated by NICNAS which sets national standards for cosmetics imported into, or manufactured in Australia. The Cosmetics Guidelines propose to prohibit or restrict cosmetic ingredients based on existing controls and bans for cosmetic ingredients such as SUSDP and international negative lists such as those of the US FDA and the EU Cosmetics Directive. Australian manufacturers therefore tend to follow the Annex VI list of approved preservatives including its restrictions.

Some multinational companies, or those manufacturing for export, must also meet the specific requirements for other markets, particularly for Japan and the US.

Natural

Natural has become a marketing word to a large extent with different meanings to different people. At one end of the spectrum it means any product that contains some component that was once part of a plant or animal, or was reacted/ converted/synthesised from something that was once part of a plant or animal. At the other extreme a product will only be considered natural if 100% of the ingredients are plant based, cold pressed, non-chemically refined or bleached, fragranced only with essential oils or CO2 extracts and that the product is produced with the lowest possible heat to preserve the botanical properties of each component.

NICNAS sets national standards for cosmetics imported into, or manufactured in, Australia and NICNAS legislation defines natural ingredients, including oils, extracts and essences of plants, as: “An unprocessed chemical occurring in a natural environment; or a chemical occurring in a natural environment, being a substance that is extracted by: manual, mechanical or gravitational means; or dissolution in water; or flotation; or a process of heating for the sole purpose of removing uncombined water; all without chemical change in the substance”. This definition does not include steam extraction and a number of objections have been raised with NICNAS concerning this. It also does not allow for solvent or CO2 extraction. This definition is rather specific and, as NICNAS has noted, would exclude most products claimed to be natural cosmetic ingredients.

Natural preservatives

Natural preservatives have become prized by preservative suppliers and cosmetic producers. If a truly natural preservative with all the required traits was discovered it would immediately capture a huge market share. There are a number of natural preservatives, or products claiming to be natural preservatives, currently available on the market.

Many essential oils also, it is claimed, are proficient natural preservatives, and these include neem seed oil, bitter orange extract, sweet orange oil and thyme oil, various root, flower and leaf extracts and, lately, extracts from trees known to have protection from fungal attack.

The essential oils and plant extracts need to be used in combination or at high concentrations and care must be taken to avoid fragrance allergens. The method of extraction of the active compounds needs to be checked to ensure it meets the NICNAS definition of natural.

Plants are vulnerable to microbial attack and have developed several defence measures. The last line of defence is the production of antimicrobial compounds, usually most effective against fungi. Strawberries, like most rosaceous plants, contain protoanthocyanidines, effective antifungal agents to protect the berries from rotting until the seeds have developed and matured. When the berries are ripe, the protoanthocyanidines are converted to anthocyanidines, a group of polyphenolic compounds, which gives the strawberry its characteristic red colour. The red colour attracts insects and animals to devour the strawberry and spread the seeds far and wide, and, if this fails, the loss of the fungal protection allows attack by fungi to rot the fruit and liberate the seeds.

Timber from several species of trees are known to be resistant to microbial attack due to the presence of antimicrobial compounds in the timber. These actives include tannins, such as the protoanthocyanidines and tannic acid, isolated from many species, and the phenolic compounds thujaplicin or hinokital from the Western Red Cedar (Thuja plicata) and totarol from Podocarpus totara. Totarol is a phenolic diterpene extracted from the heartwood of the totara tree by the use of an organic solvent or near critical fluid, commercially available preparations using CO2. The resultant extract shows good antibacterial activity but needs to be included with a fungicide to offer complete protection against microbial contamination. Bacterial cells contain a protein FtsZ in cell walls that is involved in the formation of the Z-ring, responsible for engineering cytokinesis, the process whereby the cytoplasm of a cell divides to form two new cells. Totarol appears to function by inhibiting bacterial reproduction by targeting the FtsZ protein.29

Formaldehyde and parabens, in particular 4-hydroxybenzoic acid and methyl paraben, also have some claim to being natural preservatives. They are contained at various concentrations in an enormous number of fruits and plants. Japanese honeysuckle (Lonicera japonica) is sold as a natural preservative and contains a complex mixture including lonicerin and natural p-hydroxy benzoic acid.2 Although parabens and formaldehyde have as much claim to being natural preservatives as many others natural ingredients, they are not claimed as such and are not discussed in this article. They are probably the two synthetic chemical preservatives most hated by many purveyors of natural cosmetics, although, interestingly, quite a number of handcrafters do use parabens. David Steinberg has suggested that if formaldehyde was renamed as Fruit Aldehyde Extracts it might make it more acceptable.3 Unfortunately, it would still not be natural as extraction of formaldehyde and p-hydroxy benzoic acid from natural sources would be rather uneconomical.

Acid preservatives

There is an increase in the use of acid preservatives, especially benzoic and sorbic acids. These two preservatives are only effective as the free acids so only provide protection if the pH of the finished product is below the pKa value, the pH at which there is 50% dissociation and loss of activity. Both have maximum activity at pH 3 and show significant loss of activity at pH >4. Sorbic acid may show activity up to pH 6 as it can undergo partial intramolecular cyclisation to the delta lactone of 5-hydroxy-2-hexene acid, a substance whose activity is not as pH dependent as the acid.13 They show good fungal protection but have limited protection against bacteria especially pseudomonads. Previous use in leave-on cosmetics resulted in frequent reports of sensitisation for sorbic acid and an increase in the use of these compounds to replace the parabens is expected to show this problem resurfacing. Benzoic and sorbic acid both occur in nature – however, commercial products are synthesised and are often listed as nature identical. The same could be claimed for methyl paraben and formaldehyde.

Tea tree oil

Tea tree oil is extracted from the foliage of Melaleuca alternifolia by steam distillation and has been known for its antiseptic powers for many years. Tea tree oil has a very complex makeup but the principal antimicrobial ingredient is terpinen-4-ol. Tea tree oil also contains 1,8-cineole and p-cynene but doubt has been raised on the antimicrobial effectiveness of these two components.4 Tea tree oil also contains limonene, an EU fragrance allergen.

Tea tree oil has a rather strong and distinctive odour that limits its acceptance by some consumers and has recently come under criticism from some sectors with claims of causing allergic contact dermatitis,5 weak on intact skin, but increasing with age of the oil. It has also been reported that exposing microorganisms to sublethal concentrations of tea tree oil has reduced the susceptibility of some human pathogens to antibiotics.6 (Editor’s note: another article in this edition of Personal Care covers assessment of tea tree oil skin penetration).

Grapefruit seed extract (GSE)

Grapefruit seeds contain limonoids, a group of triterpine derivatives, including limonin, nomilin, obacunone and deacetylnomilin while the peel contains relatively high concentrations of flavanone glycosides.8 GSE has been tested for preserving fruit, reducing Salmonella contamination on chicken skin and also as a preservative for cosmetics. GSE has shown good antimicrobial activity for all of these applications.

Grapefruit seed extract is claimed to be nontoxic by oral ingestion, is listed as GRAS (generally regarded as safe) and is not a primary skin irritant, non-sensitising and non-carcinogenic. It is also sold as a dietary supplement.

It is recommended to be used at between 0.2% to 1.0% and although cationic, is compatible with most raw materials used in cosmetics. It is effective against gram positive and gram negative bacteria, yeast and mould with limited effect against aerobic spore formers and Lactobacilli. It exerts it antimicrobial effect by disrupting the function of the microbial cell membrane.

The name grapefruit seed extract sounds like a natural product extracted from the seeds of grapefruit. However, GSE is not produced by extracting the natural ingredients from grapefruit seeds, juice or skins. Instead grapefruit pulp, a waste from grapefruit juice production, is subjected to a chemical process to convert the natural phenolic compounds into synthetic quaternary ammonium compounds. Investigations into commercial GSE products have found that most samples analysed contained the synthetic preservative benzethonium chloride, plus a number also contained methyl-phydroxybenzoate (methyl paraben) and 2,4,4’-trichloro-2’-hydroxydiphenylether (triclosan).9

A report by the US Department of Agriculture8 confirmed that the quaternary ammonium compound was benzethonium chloride at concentration of 8% in liquid formulations.

The antimicrobial efficacy of GSE was found to be related to the concentration of the synthetic preservatives identified in commercial products by a German study.10 This study found that 5 of 6 samples tested contained the preservatives and showed good antimicrobial efficacy, while the sixth extract contained no preservatives and exhibited no activity.

One manufacturer of GSE is fighting back against the negative press and has posted the following response at its website:11

“Newsgroups and email groups have received postings to the effect that GSE contains triclosan, benzelthonium chloride, or methyl paraben. The source of this type of report comes from both Germany and Japan, where Citricidal is not approved for human consumption. The reason is that Citricidal is very similar in molecular weight to both benzelthonium chloride and triclosan, both of which are effective disinfectants, but are toxic to human and animal life. In Germany, their test (which is not well documentedl) for BC, triclosan, and methyl paraben came up positive (which is more correctly called a “false positive”) and in Japan, the same is happening for triclosan. USDA found benzelthonium chloride in its 2001 test. Was this a simple error or a deliberate attempt to scare people away from Citricidal and NutriBiotic products? “Meanwhile, Citricidal has been tested for the presence of these toxins by independent labs, and has been proven clean. (Ex: Weston Gulf Coast Laboratories, Inc., University Park, IL, test completed in March of 1992. Tested for heavy metals, cyanides, pesticides and PCBs and benzelkonium chloride. Results: none detected.) In fact, the accusations about triclosan (used in many dish and hand soaps in the US) became so frequent a few years ago, that Citricidal began specifically testing each batch of GSE for its absence, and providing a Certificate of Analysis to that effect.

“Triclosan has recently been compared to ‘Agent Orange’ in toxicity. The EPA rates triclosan as ‘highly toxic’. The US FDA made inspections of the NutriBiotic manufacturing facility back in the 1990s and found no chemical preservatives; and the formula is the same today. Such rumours are false, and are not a threat to those armed with accurate information. The test reports from Germany and Japan and the USDA are certainly bothersome, but they have produced ‘false positives’, not accurate profiles. The vast body of evidence from many years of use by thousands of satisfied consumers, doctors, manufacturers, and veterinarians, speaks most loudly against such reports. (The German report does suggest that some suppliers of ‘GSE’ may, in fact, be fraudulent. But Citricidal and NutriBiotic GSE are both proven, safe, and effective products).

“Factory tours are not allowed as the manufacturing process is proprietary in nature. And it’s just a factory, anyway. It’s the product that counts”. Another site has the following information:

“Citricidal® is synthesised from the polyphenolic compounds found in grapefruit seed and pulp. Numerous reactions are involved, including distillation, catalytic conversion, and ammoniation. The active component of Citricidal is a quaternary ammonium chloride (a diphenol hydroxybenzene reacted with ammonium chloride) similiar to benzethonium chloride when analysed in accordance with USP XXII/NF XVII.12

The US Department of Agriculture´s (USDA) National Organic Program defines synthetic as: “A substance that is formulated or manufactured by a chemical process or by a process that chemically changes a substance extracted from naturally occurring plant, animal, or mineral sources.” Grapefruit seed extract is a synthetic chemical compound, and does not meet the NICNAS definition of a natural ingredient.

Potential users need to determine whether GSE contains a unique active compound or existing synthetic preservatives and if a particular supplier is adding extra goodness. The molecular weight of triclosan (C12H7Cl3O2) and benzethonium chloride (C27H42ClNO2) are significantly different and the chemical structures would not allow mistaking them for each other in the analytical techniques employed in the referenced reports. Either way, grapefruits seed extract it is not a natural preservative.

Sodium hydroxymethyl glycinate

Sodium hydroxymethyl glycinate is a broad spectrum preservative used for a variety of applications including cosmetics, surface coatings, adhesives and janitorial products. It shows good activity against bacteria and mould, but shows some weakness against yeast. It is produced from the amino acid glycine through a series of chemical reactions. Synthetic glycine is reacted with sodium hydroxide in water with formaldehyde to form sodium hydroxymethyl glycinate (Fig.1). The solution may be characterised as an equilibrium mixture of compounds produced by the reaction of the sodium salt of glycine with formaldehyde.13 Sodium hydroxymethyl glycinate is listed in Annex VI of the EU Cosmetic Directive as an allowed preservative up to a concentration of 0.5% of active ingredient. It is sold as a 50% solution, meaning that up to 1% of the product can be used in cosmetic applications. It is not permitted to be used in Japan. It is active at both alkaline and acid pH levels and is regarded as non-irritating, non-sensitising at use concentrations and non-mutagenic.

A search on the internet will reveal many supporters of the preservative as natural, often included in formulation claimed to be 100% natural and chemical free. Just as many sites list it in with all the other toxic synthetic preservatives to be avoided.

The EU Scientific Committee on Cosmetic Products and Non-food Products Intended for Consumers released two opinions on formaldehyde and formaldehyde releasers in 2002, which included sodium hydroxymethyl glycinate. The opinions claim that sodium hydroxymethyl glycinate decomposes in aqueous solutions to release formaldehyde with one molecule of formaldehyde being released for each molecule of sodium hydroxymethyl glycinate (Fig. 2). This will result in a total free formaldehyde content of 0.118% in a product containing 0.5% sodium hydroxymethyl glycinate, the maximum allowed concentration.14,15 The opinions reference a previous opinion from 1995 which states: “Experimental data demonstrate that this compound is a potential allergen according to the guinea pig maximisation test. At the current usage levels, there is no evidence of unacceptable risk of sensitisation to the consumers. However, any background of sensitivity to the compound may be assessed at the later date if it becomes more widely used as a cosmetic preservative”.

Sodium hydroxymethyl glycinate is not a natural preservative by almost any definition of natural, and most certainly not by the definition of NICNAS. It is classed as a formaldehyde releaser.

The future

Bacterial cells can increase their tolerance to antimicrobial actives in 3 ways, active inactivation, target modification or reducing intracellular concentration of the active compound. This can occur by reducing cellular permeability by the reduction of porin proteins in the outer membrane of Gram negative bacteria, but does not occur in Gram positives due to the lack of an outer membrane.

Both Gram positive and Gram negative bacterial cells may contain multi-drug efflux pumps, which when activated pump a variety of unrelated chemical compounds from inside of the cell. In this manner the cell may efflux active compounds that are toxic to the cell, along with a wide range of non-toxic compounds. A number of workers have found that compounds isolated from plants have the ability to inhibit the efflux pumps allowing a buildup of the antimicrobial actives in the cell. Polyacrylated neohesperidosides from Geranium caespitosum were found to potentiate the activity of a number of antibiotics against Staphylococcus aureus even though they exhibited no activity on their own.16

Isoflavones isolated from Lupinus argenteus were found to potentiate the activity of a-linolenic acid from the same plant against Staphylococcus aureus.17 Work indicated that disabling the multi-drug resistant efflux pumps from a number of Gram negative organisms, including Pseudomonas aeruginosa and E. coli showed a marked increase in activity of plant antimicrobials. The activity of rhein, from rhubarb, was potentiated 100 to 2,000 fold depending on the organism. Comparable activity was seen with plumbagin, reseratrol, gossypol, commestrol and berberine.18 Totarol, an extract from totara wood, has been shown to inhibit the multi-drug efflux pump of Staphylococcus aureus and sub-inhibitory concentrations were found to reduce the MICs of selected antibiotics.30 These results hold the promise of the use of plant extracts that may allow reduced concentrations of synthetic preservatives by potentiating their activity by blocking the effect of efflux pumps. Although the entire preservative package may not be natural, the use of natural helpers may make for safer products due to lower concentrations of synthetic preservatives.

Are natural preservatives a myth?

Are natural preservatives a myth? No, there are natural products with potential to preserve cosmetics, but they are not really suitable for the vast majority of products on the market. However, the most popular, or notorious ones, certainly are not natural. Tea tree oil may classify as a true natural preservative if NICNAS alters their definition and the EU authorities accept the dossier submitted to them and do not place unworkable restrictions on the concentration that may be added. Grapefruit seed extract and sodium hydroxymethyl glycinate will never be classified as natural.

Are natural preservatives magic?

Are natural preservatives magic? No, unfortunately the currently available ones posses no great attributes that would classify them as anything but mundane. Interesting to note during the internet searching reveals several sites for producers of natural cosmetics that strongly address the need for preservatives and outline clearly why they use synthetic preservatives in their products, including parabens. Particularly good is the site for Treasured Locks, with an article entitled The Truth About Preservatives. Much is taken from other websites, but put together in a way that most people could read and hopefully understand.19 Also valuable is the site is for ‘Natural Compatibles makeup’ which supports its use of titanium dioxide, talc and parabens. Also addressed is the use of “all natural” as a marketing term, and promoted are the benefits of having well-made, well-preserved and tested products.20

Conclusion

Studies conducted on personal care products in the 1960s and 1970s found up to 24% of unopened products were contaminated, mainly with Pseudomonas, while up to 49% of used samples were also contaminated. These studies highlighted the need for the incorporation of preservatives into water-based formulations along with improvements to manufacturing practices. Following introduction of preservative systems, development of challenge test methods and improvements to factory hygiene, the US FDA reported in 1984 that microbiological contamination was no longer an issue.

In August 2005, an outbreak of severe nosocomial infections in the intensive care unit at the Universitari del Mar Hospital in Barcelona was caused by the use of moisturising body milk contaminated with Burkholderia cepacia.28

The desire to move away from preservatives with proven track records for protecting personal care products from microbial contamination due to dubious technical reports and scare campaigns may result in a return to the failure rate seen in the 1960s.

The spread of the internet into most homes has enabled the spread of truth, half truths and outright false information to consumers unable to tell which is which. The influence of current affairs programmes just intensifies this attack. The wish for safer and natural products will likely continue, and so will the search for natural preservatives, despite the inherent potential toxicity in any preservative active.

All preservatives incorporated into personal care products have limitations on the organisms they are active against. They are affected by the physical characteristics of the products they will be incorporated into, and also by the manufacturing processes utilised during production of the finished goods. It is critical to ensure that the preservative active selected for a particular product is matched to the physical and chemical requirements of the product and will provide protection against the full spectrum of microorganisms likely to be encountered.

It may well be that there will be no natural preservatives developed in the foreseeable future, and, rather than trying to make non-working ingredients work, or using deceptive labelling, the better way forward may be education of the end user.

References

1 What’s New in Food Technology and Manufacturing. Jan/Feb 2008, 8.

2 Dweck A. Natural Preservatives. Cosmetics and Toiletries, August 2003.

3 Steinberg D. Preservatives for Cosmetics, 2nd Edition, 2006, Allured Publishing Corporation.

4 Markham J. Antimicrobial effectiveness of tea tree oil. Cosmetics, Aerosols & Toiletries in Australia.

5 Fritz T.M., Burg G., Krasovec M. Allergic contact dermatitis to cosmetics containing Melaleuca alternifolia (tea tree oil). Ann Dermatol Verereol. 2001 Feb;128(2):123-6.

6 McMahon M.A.S., Blair I.S., Moore J.E., McDowell D.A. Habituation to sub-lethal concentrations of tea tree oil (Melaleuca alternifolia) is associated with reduced susceptibility to antibiotics in human pathogens. Journal of Antimicrobial Chemotherapy (2007) 59, 125-127.

7 www.naturalingredient.org/Articles/ tea_tree_oil.html

8 Takeoka G., Dao L., Wong R.Y., Lundin R. and Mahoney N. Identification of Benzethonium Chloride in Commercial Grapefruit Seed Extracts. J. Agric. Food Chem. 2001, 49, 3316-3320.

9 Sakamoto S., Sato K., Maitani T., Yamada T. Analysis of components in natural food additive “grapefruit seed extract” by HPLC and LCMS, Bull. Natl. Inst. Health Sci 1996: (114): 38-42.

10 von Woedtke T., Schluter B., Pflegel P., Lindequist U., Julich W. Aspects of the antimicrobial efficacy of grapefruit seed extract and its relation to preservative substances contained. Pharmazie 1999, 54, 452-456.

11 www.nutriteam.com/faq.htm

12 The Citricidal Story. www.gseinformation.com/citricidal.htm

13 Paulus W. Editor, Directory of Microbiocides for the Protection of Materials 2005, Springer.

14 Opinion concerning the determination of certain formaldehyde releasers in cosmetic products, adopted by the SCCNFP during the 22nd plenary meeting of 17 December 2002. http://ec.europa.eu/health/ph_risk/committees/ sccp/documents/out188_en.pdf

15 Opinion concerning a clarification on the formaldehyde and para-formaldehyde entry in Directive 76/768/EEC on cosmetic products, adopted by the SCCNFP during the 22nd plenary meeting of 17 December 2002.

16 Sternitz F., Cashman K., Halligan K., Morel C., Tegos G., Lewis K. Polyacryltated neofesperidosides from Geranium caespitosum: bacterial multidrug resistance pump inhibitors. Bioorganic and Medicinal Chemistry Letters, Volume 13, Issue 11, 2003, 1915-1918.

17 Morel C., Stermitz F., Tegos G., Lewis K. Isoflavones As Potentiators of Antimicrobial Activity. J. Agric. Food Chem, 51 (19) 5677-5679. 2003.

18 Tegos G., Sternitz F., Lomovskaya O., Lewis K. Miltidrug Pump Inhibitors Uncover Remarkable Activity of Plant Antimicrobials. Antimicrobial Agents and Chemotherapy, 2002, 3233-3141.

19 www.treasuredlocks.com/trabpringrse.html

20 www.naturalcompatibles.com.au/benefits.html

21 www.foodauthority.nsw.gov.au/ mr-Feb-08-vegetable-chip-cracker-recalltest- results-prompt-warning.asp

22 www.foodauthority.nsw.gov.au/consumer/ c-cassava-based-chips.asp#action

23 Cyanogenic Glycosides in Cassava and Bamboo Shoots, A Human Health Risk Assessment. Technical Report Series No. 28, Food Standards Australia New Zealand, July 2004.

24 Kruszelnicki K. Please Explain. 2007. Harper Collins Publishers.

25 A portfolio of illustrations of some plants known to be poisonous in S.E. Australia. Australian National Botanical Gardens. www.anbg.gov.au/poison-plants/index.html

26 Johnson A., Johnson S. Garden Plants Poisonous to People. NSW DPI, Primefacts, Primefact 358, November 2006.

27 Poisonous Plants. Factsheet, Kidsafe Qld (inc).

28 Alvarez-Lerma F., Maull E., Terradas R., Segura C., Planells I., Coll P., Knobel H., Vazquez A. Moisturizing body milk as a reservoir of Burkholderia cepacia: outbreak of nosocomial infection in a multidisciplinary intensive care unit. Critical Care. 2008; 12(1): R10.

29 Jaiswal R., Beuria T., Mohan R., Mahajan S., Panda D. Totarol Inhibits Bacterial Cytokinesis by Perturbing the Assembly Dynamics of FtsZ. Biochemistry, 46 (14), 4211-4220, 2007.

30 Smith E., Kaatz G., Seo S., Wareham N., Williamson E., Gibbons S. The Phenolic Diterpene Totarol Inhibits Multidrug Efflux Pump Activity in Staphylococcus aureus. Antimicrobial Agents and Chemotherapy, December 2007, p. 4480-4483, Vol. 51, No. 12.

31 Toxic Honey Sickens 10 in New Zealand. Sydney Morning Herald, March 25, 2008.

32 New Zealand Food Safety Authority. Background to Toxic Honey. www.nzfsa.govt.nz/animalproducts/publications/ info-pamphlet/bee-products/toxic-honey.htm