(I have added a sub-title to this talk: and how it affects the Aromatherapist)
Safety is defined as freedom from danger, injury or damage. There is a fundamental contexting of the term "safety" in this paper in terms of hazard and risk. We can say, for our purposes, these latter terms mean the following:
(Essential oils are potentially hazardous materials)
(If handled in an appropriate manner, the risk involved in safe use of essential oils can be extremely small).
Leading perceptions of safety issues in Aromatherapy are probably not influenced by opinions of figures from backgrounds which are specifically in health & safety, or yet toxicology. Rather they tend to be the views of Aromatherapy educators. In my value judgement, we can place many of these Aromatherapy (AT) writers into two categories:
We will first examine these points in relation to legislational issues surrounding AT in its’ natural setting. Some relevant Health and Safety Legislation for the UK is as follows:
§1. Health & Safety Policy: The Law
Legally set by:
Acts of Parliament (Statutes). e.g.:
Health & Safety @ Work Act 1974
COSSH regulations (Control of Substances Hazardous toHealth 1994) and later versions of…
CHIPS (Chemicals(Hazard Information & Packaging)Regulations 1993)
The Medicines (Retail Sale or Supply of Herbal Remedies Order
1977): prohibits sale of Chenopodium oil: Chenopodium
ambrosoioides var. anthelminticum; Savin oil: Juniperus
sabina; Jaborandi oil: Pilocarpus jaborandi & P. microphyllus
amongst others.
Reporting of Industrial Diseases and Dangerous Occurrences
1995 etc. etc.
Secondary legislation
Regulations therein (of Acts of Parliament above)
ACOPS (Approved Codes of Practice) which have quasi-legal status.
SCOPS (Statutory Codes of Practice)
Guidance Notes. (may be issued by the Health & Safety Executive
(HSE), industry etc.)
EC Directives for National Governments. (Instructions for governments of member states to enact a particular law).
§2 Management Of Health & Safety @ Work Regulations 1992 (MHSW regs). Employers must:
Definition of terms:
The term "risk" is used to imply the elements of both probability and impact. The use of the probability component only should be discouraged.
Risk profile: some things to think about:
Risk Characterisation.
The social perception of risk is especially important to AT. Different viewpoints on risk may well be taken, say, by a casualty department doctor who has just pumped out the stomach contents of a child who has accidentally swallowed a quantity of essential oil, as opposed to an AT who has a vested interest in the continued & unrestricted public/professional use of essential oils.
I give two examples of toxicity perceptions, which involve essential oils:
Identification of risk.
In order to carry risk identification, we need to be aware of several factors:
The manner in which you carry out your duties as an Aromatherapist or supplier affects clients, downstream customers etc.
The tools of the Aromatherapists’ trade are certain essential oils, hydrosols, absolutes and other raw materials. Lists of approved and cautionary essential oils are generated by some professional Aromatherapy organisations (e.g. the IFA). Help in assessing risks can be obtained from information gleaned from:
1. Suppliers MSDS’s are a legal requirement for delivered chemical goods (e.g. essential oils).
MSDS sheets were originally written in complex technical language for persons responsible for Health & Safety matters in the chemical industry. Requirements for openness, and US State right-to-know information (the COSSH regulations in Britain) has lead to a wider audience for this sort of information. In recent years the Chemical Manufacturers Association (CMA) has developed a standard aimed at international acceptability, and the American National Standards Committee (ANSI) has adopted this format. The sixteen sections according to ANSI are as follows:
Sec 1. Chemical Product & Company information.
Sec 2. Composition/Information on Ingredients
Sec 3. Hazards identification
Sec 4. First Aid measures
Sec 5. Fire Fighting measures
Sec 6. Accidental release measures
Sec 7. Handling & Storage
Sec 8. Exposure controls/personal protection
Sec 9. Physical & chemical properties
Sec 10. Stability & reactivity
Sec 11. Toxicological information
Sec 12. Ecological information
Sec 13. Disposal considerations
Sec 14. Transport information
Sec 15. Regulatory information
Sec 16. Other information
As a customer you have a legal right to return an MSDS sheet from a supplier if you cannot understand the information, and ask that it be re-written in terms that you can understand. Similarly, you have rights to information where blank sections occur or if you think that the information is poor, and you are legally entitled to a re-submission.
The following "Burfield rules" apply to MSDS sheets:
1. They are constructed on a basic template. There is an absolute minimum of data about the properties of the individual oil.
2. The job of assembling the data sheets usually falls to a clerk rather than a chemist, and the task is usually of low priority within the company.
3. MSDS sheets are notorious for mistakes, especially regarding Chemical Abstract Service (CAS) Nos., incorrect Latin names, incomprehensible toxicological information and incorrect transport labelling details. Do not rely on the absolute accuracy of the information: you have a legal requirement to check the information independently before use. In any case there is in any case usually a disclaimer!
4. Downplaying information on toxicity might have occurred in the past to allay public fears. The law does now require a personal written evaluation and updating process, so this is clearly not a legally acceptable policy.
Aromatherapists and Aromatherapy companies who supply oils are legally bound to supply MSDS sheets to customers, and Aromatherapists in their working (clinical) setting are required to have safety information to hand. This is important! In the US a similar situation applies with Occupational Safety & Health Administration (OSHA) Hazard Standard 1910.1200 requiring private employees to provide information and training to employers: OSHA legislation additionally requires that MSDS’s shall be kept & maintained in a marked and accessible area).
Aromatherapists could follow the following scheme:
1. Collect MSDS sheets, file them and have them readily available.
2. Follow up references to safety information for each oil and construct a written safety assessment for each material used.
3. Encourage Aromatherapy organisations to compile data and generate their own written assessments of every raw material used in Aromatherapy.
4. If possible ask a suitably qualified person or expert on any safety queries regarding oils.
5. Encourage your professional organisation, or a group of Aromatherapy associates to produce guidelines on the use of essential oils, preferably with expert input.
6. Make links with other professional & trade organisations, and review the Guidelines as and when necessary.
2. Professional Organisations
Aromatherapy Organisations often do not have the individual written assessments of the substances used in their trade mentioned above, a necessary stage in the process in order to carry out risk assessments. Other professional organisations which use essential oils may be more advanced in this respect, or can draw on expertise within their (often extensive) battery of members.
The European Flavours & Fragrance Association (EFFA): represents the interests of its member associations to the authorities & professional bodies of the European Union. It works with member states and their scientific advisers to establish a workable legislative framework and generally works & co-operates with associations in other countries i.e. US, Japan and the International Organisation of the Flavour Industry (IOFI)
Further, each member state may have its own national trade associations
e.g. in the UK, BEMA (British Essence Manufacturers Association); BFA (British
Fragrance Association). My view is that EFFA has effectively built bridges
between a great number of bodies in order to achieve common aims.
The American Fragrance Manufacturers Association set up RIFM (Research Institute for Fragrance Manufacturers) which is described extensively below.
FEMA: the US based Flavour Essence Manufacturers Association). Of some interest to AT’s is the fact that Fragrance & Flavour Data Sheets, including many on essential oils, are produced by the USA organisations FEMA/RIFM/FMA (USA’s Food Manufacturing Association): a set of 1500 is available at around $1000, or they can be purchased in sets of 10, choosing from a published list.
It is sometimes advantageous for professional organisations to associate with one another to achieve common aims, share information, formulate strategies to deal with forthcoming legislation etc. and it will be interesting to see if AT organisations eventually evolve in this direction.
OTHER ORGANISATIONS: There are a huge number of additional organisations that are directly involved, or interact with the essential oils trade and its’ user groups, for example, International Federation of Essential Oil & Aroma Trades (IFEAT), The European Cosmetic,Toiletry & Perfumery Association (COLIPA) in America the SDA & The Cosmetic Toiletary & Fragrance Association (CTFA) and of interest to Aromatherapy the Food & Drugs Authority (FDA) and the American Medical Association (AMA), It is impossible in a short paper to cover the work, policies & influence of all these organisations.
3. Internet Data-Bases
Information about the safety and toxicological properties of raw materials of interest to Aromatherapists is widely spread. A few pointers are given below. A useful data-base list may be obtainable by searching the NAHA site: (http://www.naha.org).
Botanical Dermatology Database http://bodd.cf.ac.uk/search/all_bodd
Medline http://www.nlm.nih.gov/medlineplus/ A searchable data-base
of some 9 million medical papers. Abstracts available to many documents.
IFRA Guidelines: http://www.ifraorg.org/GuideLines.asp. See below.
ToxLine: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?TOXLINE. A searchable data-base containing 2.1 million toxicity related papers.
Dialog OneSearch http://library.dialog.com/products/datastar/4002-3.html
4. Scientific Literature. See appendix.
- To return to the management of H&S @ Work Regulations 1992 employers should carry out:
Hazards Identification:
Strategy
§3 COSSH regulations Control of Substances Hazardous to Health 1994 applies to:
[MEL: maximum exposure limit as the air based concentration that must not be succeeded
OEL as the air-based concentration for other slightly less hazardous substances which the employer should aim to keep as far below as possible.]
COSSH regulations require employers
§4. CHIP 2 The Chemicals (Hazard Information and Packaging for supply) Regulations 1994 and amended CHIP 1996 defines 5 categories of chemicals:
Requires employers to carry out COSSH assessments, identifying and listing substances, physicals, classification, determine hazard, assess risk, determine medical treatment needed etc.
Packaging for dangerous substances, should:
Be suitable; prevent leakage; be able to withstand expected handling; have reusable closures
Labels must have following information:
Name address telephone number of supplier
Name of substance/blend
Hazard symbol, danger indications
Risk phrases in full e.g. R28 Very toxic if swallowed
Safety phrases in full e.g. S24/25 Toxic in contact with skin and if swallowed.
EEC no
Substance classification as carcinogenic/mutagenic/toxic for reproduction: must be labelled as restricted to professional users.
There are also stipulations on childproof fastenings, packaging not to be of a shape to attract children.
Professional Expertise
RIFM is The Research Institute for Fragrance Materials established in 1966 by the American Fragrance Manufacturers Association, and is a non-profit-making international organisation, whose expert panel is wholly independent of any manufacturing interests. RIFM collects, produces & publishes data on fragrance materials, which includes data on essential oils. From this above-described base for risk analysis, RIFM makes a risk assessment & recommendations for individual substances used in fragrances. The decision tree approach of Cramer et al. 1978 underlies much of the approach RIFM have used for toxicity assessment.
IFRA (the International Fragrance Research Association) receives & considers these recommendations & produces guidelines for the individual fragrance ingredients for its’ members in the fragrance industry. We can say that IFRA therefore is concerned with the management of risk (for more about IFRA see below).
Some 1300 substances have been tested by RIFM and some 50 have been subsequently not recommended for use in perfumes ("banned IFRA"). A further 58 are subject to quantitative limits in formulations, or have special criteria governing their use. A number of these substances, in both categories, are essential oils. Results of the toxicity findings are published as monographs in the Food & Chemical Toxicity journal. Reputable fragrance companies widely adhere to this voluntary self-regulation (i.e. the strict following of IFRA guidelines), especially when selling to IFRA compliant markets. In practice however some analysed skin fragrances have been found to be breaking the rules.
As one of the principle investigative programs on fragrant substance toxicology, RIFM data has been widely adopted & referenced by industry, and perhaps not surprisingly, by authors of books on essential oils. This may be because the data is widely available, whereas other toxicological sources may be less comprehensive, and difficult to access. As part of its’ on going activity, it has been stated in the public domain that RIFM is re-evaluating the original 1300 materials that it investigated, as the original data is now looking considerably out-dated - and additionally is evaluating another 1400 materials in common use. It is also undertaking a worldwide survey of volume usage of all materials on the European indicative inventory. Again, via material put out in the public domain, RIFM originally agreed to keep the results of this survey confidential, and was soliciting for unpublished safety data from manufacturers. It was hard to see how this confidentiality arrangement fits in with the second phrase of the RIFM charter "To distribute descriptions & other information relating to the uniform standards of testing and evaluation and the results thereof" (my emphasis). A reconsidering of their position on a purely restrictive release of a top materials list might eventually be more widely available to the general public.
IFRA: Established in 1973, members of IFRA are the national associations from a number of countries including the US. The fragrance industries work loosely on a system of voluntary self-regulation implementing the findings of RIFM regarding perfume ingredient use, a policy which has avoided wholesale imposition of legislation without consultation. Self-policing under IFRA’s voluntary regulatory system can be seen working in practice continually as companies analyse competitors products and customers analyse the products from their supplier. In fact a major perfume launch in recent years was perceived by other major fragrance houses to actually breach the rules, and provoked an immediate trade reaction. Other countries such as the Netherlands, Denmark & USA have (additional) mechanisms to regulate at Government level.
It has to be said that IFRA’s voluntary self-regulation system has inevitably changed the face of perfumery. We can think of formerly used powerful materials like MOC (methyl octine carbonate: a chemical which has a powerful violet note), styrax resinoid and oakmoss products which at one time had unrestricted status in formulae (Oakmoss products are now limited to 0.1% when working with the 20% rule in formulae). Amongst others, perfumes like Miss Dior with its high level of oakmoss, could not be put on the market now in original form. Of course, the continuing pace of regulation may have future implications for Aromatherapy best practice as well.
IFRA recommendations are regularly published in the bi-monthly trade magazine "Perfumer & Flavourist". IFRA recommendations are at last posted on the internet at http://www.ifraorg.org/GuideLines.asp.
RIFM testing:
The organisation designed basic set of tests:
In addition RIFM also carries out investigations into chronic effects, and the metabolism of fragrant substances as and when necessary.
Essential oils and Aromatherapy
An essential oil is:
Types of Hazard.
The following might apply to certain essential oils:
Chemical Exposure
Evaluation of exposure in a risk analysis will consider:
And routes of exposure:
Basic toxicology
Before looking at chemical exposure in more detail, we are going to run through a brief toxicology intro. For our purposes, we can divide toxicity into
The toxicity of a particular individual substance tested in isolation may be modified by the presence of other substances because the following effects may operate:
Biotransformation may involve:
Consequences of biotransformtion:
Types of metabolism:
In the skin, cutaneous enzymes help detoxify harmful chemicals. These enzymes may be esterases or cytochromes P-450. Although specific activity of cutaneous cytochromes P-450may be only 10% of that of the liver, the large surface area of the skin (2m2) may mean in effect that biotransformation may be significant in effect.
Microsomal oxidation may be divided into a number of functions:
Aromatic hydroxylation
Acyclic hydroxylation
Heterocyclic hydroxylation
N-, S- and O-dealkylation
N-oxidation
N-hydroxylation
S-oxidation
Desulphuration
Deamination
Dehalogenation
Most of these oxidations are carried out by the cytochromes monooxygenase P-450 system, a series of isoenzymes all of which have an iron porphyrin IX entity. The enzymes are found in the membrane of the smooth endoplasmic reticulum (SER) part of the cell as well as the rough endoplasmic reticulum and nuclear membrane, especially in the liver, but basically in all tissues.
The battery of available enzymes enables the essentially lipophilic molecules of essential oils (such as monoterpene hydrocarbons and monoterpene alcohols) to become more water soluble via reactions including hydroxylations, oxidations and by coupling, glcuronidation, so that the resulting metabolites are more water soluble, and can be excreted more easily.
Non-microsomal oxidations:
Amine oxidation
Alcohol & aldehyde oxidation
Aromatisation
Purine oxidation
These oxidations represent a compliment of reactions, which enable a diverse range of substrates to be metabolised in sites all over the body, as required.
Inhalation
The practice of Aromatherapy is necessarily concerned with the intake of odiferous substances and for their physiological effects. The lungs themselves are highly efficient at exchanging gases between ambient air and blood therefore will absorb air-born odiferous substances rapidly. The surface area of the lung is approximately 70m2 in adult and exchange takes place in the alveoli, a division of the bronchioles, themselves a fine division of the bronchi. The pores in the alveolar membranes are small 8-10Å radius, so that small molecules can pass through directly, or alternatively lipid-soluble materials may be able to pass through the membrane by diffusion.
Entry of substances past the blood-brain barrier and into the brain itself is a more difficult route than for other tissues. Ionised compounds are effectively kept out, but lipid soluble compounds may permeate e.g. the anaesthetic: thiopental. In neo-nates there is an increased permeability compared with the adult situation. A more direct absorption route for airborne chemicals would seem to be directly through via the olfactory mucosa to the brain, thereby by-passing the blood-brain barrier as in inhalation.
Inhalation toxicity
Various statements have been made about essential oil (e.o.) inhalation toxicity. In 1962, Kowalski Z et al. made a somewhat worrying declaration "In view of the relatively high systemic toxicity of the vapours of certain essential oils, the hazards of excessive inhalation of these oils should not be disregarded." It is perhaps the quantitation of "excessive" which is important. In their search for data on the toxic effects of VOC’s, Cooper SD et al (1995) found information which relates to various e.o.components (9-14mg/Kg for benzaldehyde, benzyl acetate, a -terpineol and ethanol). The conclusion was that, from the literature health effects are unclear, although the levels of exposure that they were considering look extraordinarily high. Pappas G.P. et al (2000) concluded that reductions in levels of VOCs to substantially less than 25 mg/m3 are required if a "non-irritating" work environment is desired. In a more extreme example of exposure, in Swedish sawmills, it has been noted that the air-levels of a -pinene, b -pinene and d -3-carene were found to be from 80-550mg/m3 – these are relatively high figures. Exposure to terpenes and heating products from coniferous woods is significantly associated with the risk of respiratory cancer after 5 years duration of exposure ref: Kauppinen TP et al (1986). Other studies on a -pinene enantiomers by Falk AA et al. (1990) indicate that for short term exposures at from 10 to 450mg/m3 no acute changes in lung function occur after 20 minutes of exposure.
In trying to calculate the likely dosing levels in AT consider as an example 5dr/hr of a Eucalyptus oil (say 0.25g) is dispensed from a nebulisor into a 4mx4mx4m room. This would give a concentration of 3.91mg/m3 if the whole amount were vapourised instantly. Note that there is a difference between concentration and dose. In our above example, we will assume the 1,8 cineol content of the Eucalyptus oil to be 80%, and we have a 5 minute inhalation session. Even assuming 100% of the aerially dispersed oil is actually breathed in and absorbed by the lungs, 20.8 mg of eucalyptus oil would be inhaled, 16.6mg of which is 1,8-cineol. The actual dose would only be a small proportion of that.
Pharmokinetic studies on prolonged inhalation are not too common. For our Eucalyptus example, of relevance are Jaeger W. (1996)’s findings that 1,8 cineol is easily absorbed from breathing air, plasma concentration peaking at 18 mins. Elimination from the blood is biphasic, with mean distribution half-life of 6.7 mins and elimination half-life of 104.6 mins. These sorts of figures are useful in considering the metabolic fates of substances with regard to elimination and accumulation.
Limits for dietary intake of 1,8-cineol had been proposed at 0.07mg/Kg bw/day (private communication) =4.9 mg/day for a 70Kg adult. This proposed (low) limit was envisaged to cause problems for confectionery manufacturers from dietary intake of products containing Peppermint (piperita) and Eucalyptus oils. Subsequently the Council of Europe have approved the use of Eucalyptus oil as a food additive at 15 ppm. In this context, the likely inhalation doses of 1,8-cineol from a 5-15 minute session from a vapouriser loaded with Eucalyptus oil in a small room as calculated above, look over the recommended daily oral intake, assuming a worst case scenario. To put this in context, however there are figures suggesting Eucalyptus oil is (only) relatively orally toxic (NIOSH 1975) compared with other routes of administration.
In conculsion there is some widely scattered data on inhalation toxicity, but little in the way of MEL, OES or TLV data for essential oils set out in a comprehesive manner. There is also some data set out for individual essential oil components such as alpha -pinene, but not for a toxic compound like thujone. Thus we have to search out data case by case, and taking thujone as an example, the National Occupational Exposure Survey (NOES) and National Institute for Occupational Safety & Health (NIOSH) between 1981 and 1983 noted that almost 11,000 workers were exposed to thujone via Dalmation Sage oil, and over 43,000 to Cedarleaf oil in their workplaces. The most comprehensive account of thujone toxicity that I could find seems to be via the FDA Priority-based Assessment of Food Additives Database (PAFA) published via FDA p64.
Inhalation & allergy
Whilst the acute toxicity effects from inhalation might give less cause for concern, the allergic effects of airborne chemicals continue to pose problems.
M.M. Schaller et al (1993) investigated contact allergy in a 53-year old woman suffering from relapsing eczema. Sensitization from previous exposure to Lavender, Jasmine & Rosewood oils, and discovered new positive sensitivity testing to Laurel, Eucalyptus and Pomerance oils without previous exposure history. Perfume allergy has been verified by Kumar P. et al (1995) who submitted 29 asthma patients and 13 normal subjects to 4 bronchial inhalation challenge tests from perfume scented strips. Authors found 36%,17% and 8% of severe, moderate & mild asthma patients had exacerbations of symptoms and obstruction of airways.
Millqvist followed this in 1996 in a study where nine patients with respiratory symptoms after non-specific irritant stimuli were subjected to perfume provocation or placebo, with and without a carbon filter mask (nose clamped) The conclusion was that hyper-reactivity of the respiratory tract can be produced by perfume, and that a carbon filter had no effect. The mechanism was independent of the olfactory nerve, but perhaps operated via a trigeminal reflex of the respiratory tract or by the eyes. Fukayama MY et al (1999) showed that for perfumes at least, subchronic inhalation of complex fragrance mixtures did not constiute a risk even when inhaled under repeated and exaggerated exposure levels.
Attempts have also been made to quantify the inhalation dose of applied perfumes. Pybus D & Sell C. (1999) attempt to estimate the inhalation dose where 0.2ml of 10% fragrance in ethanol is applied behind the ear. Assuming that the fragrance can be detected at up to 1 metre away, then 0.02ml fragrance volatises immediately into 8 cubic metres of air, giving a concentration of 2.5 mg/m3. Since the perfume might be detectable for several hours, obviously the concentration will be much lower than this. The authors remark that if perfumes were toxic at this level, they would be classified as chemical warfare agents! As a comparison, Camphor has a long term OES level of 12mg/m3 Reynolds J.E.F (1993).
In an AT context, we are taking a scenario where 5-25 ml of massage oil would be used in a whole-body application, at a maximum level of 2.5% e.o. concentration. Using the maximum 25 ml, this would give us a total of 0.625 g of essential oil applied to the body. If this was all suddenly volatised at once using the 8 cubic metre model above that would give us a concentration of 78.1 mg/litre. Clearly this does not happen as we would be choking and our eyes would be streaming at this level! In practice, say 25% of the essential oil would be absorbed by the skin, and if 5% of this oil evaporated in the first minute, again using the 8 cubic meter analogy we would above would give us a more reasonable 2.93 mg/litre, at that point in time. The actual concentration would be much lower in reality, and in relative terms would represent a low toxicity body-burden. Tisserand & Balacs have stated however, that because giving a massage involves physical effort, the AT may absorb more EO than the client!
Conclusions
We are left assuming that although e.o. doses from inhalation in conventional AT procedures (massage, nebulisers) may be small, but where higher exposure levels are regular there might be a small risk of accumulation of essential oil components, which may lead to chronic toxicity. This could be of concern where neurotoxic oils are regularly employed – however this is pretty unlikely in normal practice. A more realistic risk scenario concerns the air-borne levels of essential oils which are present in the AT’s place of work being sufficient to cause allergic inhalation reactions in susceptible clients. These individuals may be identified as often having a pre-disposition to atopic skin conditions, having respiratory problems such as asthma or respiratory allergy, or having a history of perfume sensitivity.
R65: Aspiration Hazards
This has been further put into the spotlight by the R65 Aspiration hazard labelling requirement for essential oils (the potential to cause lung damage after swallowing based on the inherent low viscosity of materials containing more than 10% of aliphatic, alicylic and aromatic hydrocarbons). Requirements for R65 labelling came in on 31 May 1988. The 3rd Edition of the Health & Safety Executive’s Approved Guide to the Classification & Labelling of Substances & Preparations dangerous for supply-Guidance regulations sets out criteria for R65 classification.
Many essential oils have more than 10% of hydrocarbons: here is a small selection:
Angelica 95%
Bay 30%
Bergamot 55%
Cajuput 40%
Carrot Seed 50%
Cascarilla 30%
Cedarwood 60%
Celery Seed 80%
Cistus 10%
Copaiba Balsam Oil 90%
Chamomile 15%
Citronella Sri Lanka 15%
Clove Leaf 15%
Clove Stem !5%
Costus 30%
Cubebs 70%
Cumin 50%
Cypress 70% etc. etc.
The EC does supply a list of substances approved for classification, most of which do not concern AT, but the onus is on the supplier to correctly identify and classify materials which constitute a hazard.
§4.2 Acute Oral Toxicity:
Adaptation
Koala bears thrive on a diet of Eucalyptus leaves & branches. Their digestive metabolic processes have presumably evolved to tolerate and safely metabolise the large amounts of essential oil that they consume daily. This is a simple example of adaptation. A graphic illustration of this effect in rats is provided by Uehleke (1979) who fed myrtle oil to rats and found that its toxicity reduced considerably by adaptive liver stimulation after 3 weeks pretreatment feeding of myrtle oil in the daily diet. (N.B. this does not always happen! Depending on the nature of the oils, and the species consuming it etc., toxicity can actually increase when oils are consumed regularly).
General Remarks
Glossing over possible gastric irritation effects from oral dosing of essential oils, as they pass through the digestive tract, solubiliszation with bile acids occurs, and proportion of ingested essential oil will be absorbed and transported to the liver. Here phase 1 reactions P-450 occur as indicated in the basic toxicology section, and some conversion to alcohols or carboxylic acids occurs. Conjugation with glycine for carboxylic acid containing metabolites, or glucuronic acid for metabolites with alcohol groupings is common, and elimination may occur via the bile or urine.
LD50 Issues
To decide our tolerance of oils & chemicals we have to rely on testing procedures. The determination of LD50 values are one of the major factors in deciding the acute toxicity of substances including essential oils. Data exists for different doses which are administered to matched pairs of animals (rats, guinea pigs, rabbits, mice etc.). The dose that kills 50% of the animals is the LD50 value, and is calculated on body weight of the animal and expressed as mg/Kg. Data is often available for oral, dermal and intraperitoneal methods of administration.
Determinations of LD50 values seemingly vary from source to source, but we can construct a table of relative toxicity's which would range from less than 1g/Kg to over 5g/Kg (e.g. Boldo oil from Peumus boldus at 0.3mg/Kg at one end of the scale, to say Rose oil at over 5g/Kg at the other). Some of the oils with LD50 values of less than 1g/Kg are not recommended for use in perfumery by IFRA. These are:
Mustard oil, Boldo, Chenopodium, & Calamus oils, amongst others. Similarly, the above oils are not recommended for use in AT.
Assumptions are made when interpreting animal data to the human situation i.e. more toxic/less toxic. The differences in metabolism between species are quantitative rather than qualitative, but this may mean different metabolic routes are favoured in one species over another. It would be more appropriate therefore, given sufficient resources, to choose a particular animal model for a particular essential oil. In the absence of appropriate modelling, we start to draw conclusions on the relative toxicity of the material from poisoning records i.e. by estimation of the (fatal) dose received, or better by clinical measurement of substrates in target organs. In this manner we are sometimes able to derive the relative toxicity: animals to humans and derive a ratio.
Examples:
An example of toxicity in an older but important paper: Hyssop oil was found to be more toxic than sage oil by Millet Y. et al (1981) working on diet-induced convulsions in rats: the dose at which cortical events became sub-clinical was 0.08g/Kg for hyssop; 0.3g Kg for Sage. i.e. 0.8 g dose for 10 Kg child for Hyssop oil if animal: human child toxicity were similar. Convulsions occurred at 0.13g/Kg for Hyssop and 0.5g/Kg for sage oil which became lethal above 1.25/Kg for Hyssop and 3.25g/Kg for sage. Interestingly, repeated daily injection of sub-clinical does revealed a cumulative toxic effect. This paper indicated the neurotoxicity of thujone & pinocamphone in rats for the first time but also indicates untoward effects occur at levels well below (6.4% of) the lethal dose. As an aside, in the EC the standard permitted portion of thujone(s) in food flavourings is 0.5 ppm in food and beverages. Humans don’t eat many kilos of food per day, so Acceptable Daily Intake (ADI) is set extremely low for these thujone isomers. This is presumably the reason behind Tisserand & Balacs’s statement that thujone containing oils such as Armoise (Artemisia herba-alba) and Wormwood (Artemisia absinthium) should not be used in Aromatherapy. Presumably the same remarks should apply to Hyssop (Hyssopus officinalis) which appears even more toxic from the above data (Miller Y. 1981).
An evaluation of 109 pediatric poisoning accidents involving Eucalyptus oil in Victoria by Day et al (1997) revealed that 74% gained access via a home vapouriser unit, often placed at ground level, and in most instances between 5 and 10 ml was consumed. (In fact Eucalyptus oil is much more toxic by the oral route than by any other: oral-child TDLo=218 mg/Kg; oral-man TDLo= 375 mg/Kg NIOSH 1975).
Potential countermeasures proposed by day et al. included discontinuing use of Eucalyptus oil as a therapeutic agent, improving child resistant closures, discouraging vapouriser use for respiratory infections in children. If AT had widely promoted the use of say Pennyroyal oil instead of Eucalyptus as an acceptable mucolytic, we would be looking at far more serious misadventure consequences in this one district alone. I would suggest therefore there is a global social responsibility here: either the universal promotion of child-proof closures on bottles and equipment has to be more effective, or AT as a profession needs to discourage the use of hazardous essential oils. With something like 3.8 million reported accidents with essential oils now documented globally, potential hazard is now equating with unacceptable risk in the minds of many of those who are dealing with the consequences of essential oil ingestion.
Summarising things to remember about LD50’s:
Metabolic factors can also influence susceptibility to toxins. as well as sex, genetic and dietary factors, age and stress can also play a part. This may go some way to explaining the apparent variability of dose-response data. For example, in a harrowing account by Bakerink J.A. et al (1984) of the multiple organ failure after ingestion of Pennyroyal oil from herbal tea in two infants, possible influence of influenza to the response picture is discussed in one case.
LDLo is often seen quoted in toxicological data. It is the lowest dose of material introduced by any route over a given period of time reported to have caused death. Lo is frequently used where the number of subjects is low.
Oral dosing. Many practicing Aromatherapists will find themselves unable to legally prescribe essential oils for oral intake within the country/state in which they operate, unless they are appropriately medically qualified. In any case, oils should be carefully administered in the correct manner: intake of concentrated and volatile substances into the mouth should not be embarked upon casually. Oils should generally be administered in minute amounts and by appropriate dilution. A suitable vehicle for this can be difficult to find because of the poor water solubility of most oils. Sometimes one or two drops of oil can be dissolved in strong sugar syrup, and then quickly stirred into a full tumbler of water, and the oil will stay "dissolved". Other factors to take into account are the toxicity of the oils (many oils should never be taken orally e.g. Hyssop, Wormwood, Wintergreen etc.), the possibility of interaction with medications, whether the treatment is appropriate (during pregnancy for example). In conclusion, my message is, unless you are very clear on what you are doing, stay away from oral prescribing.
4.3 Dermal LD50 (Limit test rabbit)
Dermal LD50 are concerned with mortality following application of a toxin to the skin rather than being taken orally. The concept of damaging the skin as target organ changed as we became aware that the skin was permeable to chemicals - previously it was thought to be a non-permeable barrier. The ability to penetrate the skin and the metabolic changes that occur in the skin vary from substance to substance: for example coumarin is rapidly absorbed by the skin and passes through the barrier unchanged ref: Yourick J.J. (1997), but some esters may be totally modified. We now realise that LD50 values tell us more about systemic toxicity than anything else. Also, there are worries that data from rabbit skin LD50 tests may give a distorted view when applied to the human situation, due to the greater apparent permeability of rabbit skin to a variety of chemicals. Curiously dermal LD50 studies, however flawed, must be potentially of great interest to AT’s, because they are closely allied to what is carried out in AT massage practice. Yet they have been left out of Tisserand & Balacs "Essential Oil Safety", and results obtained have elsewhere described as not very relevant to human exposure. Ref: Schnaulbelt K (1986).
However we do know of course that the skin as a target organ is capable of being damaged – phototoxicity is a case in point, but other oils which are dermal toxins include Wormseed, Bitter Almond and Wintergreen oils.
Permeation of substances through the skin (specifically across the stratum corneum) is a diffusion controlled process where absorbtion of individual substances are related to lipophilicity (represented by the partition coefficient for an octanol/water) and the molecular volume (molecular weight can be used here). The effect of one substance on another must also be taken into account i.e. in the above example for coumarin absorption it was found that the take up of coumarin was greater from an oil-in-water emulsion than from an ethanolic solution.
Additional evidence of bioavailability being proportional to method of application was provided by Weyers W (1989).
(N.B. application under occlusion has been shown to alter the permeation kinetics because:
All these factors may increase the absorption of the applied substance.
Thus we have the following important factors in skin absorption:
For the mixture of substances present in an oil, many small lipophilic materials may quickly permeate the skin and eventually pass into the receptor fluid and on to the systemic circulation. Less more polar components with high molecular weights may penetrate much slower, perhaps infinitely slowly, resulting in the "fractional absorption" of essential oil components i.e. some are absorbed at a greater rate than others. Counter to this, smaller, more volatile components evaporate more quickly from the skin surface. Aromatherapy writers who have been quick to dismiss the skin absorption route as being of little significance in terms of physiological effects (mainly supporting the inhalation route) have often pointed gleefully at the fact that only 3% of limonene is absorbed. However coumarin, present in Cassia and other oils is rapidly absorbed to 46% (human unoccluded), b -phenylethanol 64% (rat unoccluded), benzyl acetate 12%.(human unoccluded), cinnamaldehyde to 24% (human unoccluded).
In more detail, some components will accumulate to form a cutaneous reservoir pool Hewitt P.G. et al (1993) in the lipid-rich strateum corneum. Others components permeate deeper into the skin to be biotransformed by the P-450 enzyme systems in the dermis and epidermis, and eventually this mixture of biotransformed and unchanged molecules will reach the systemic circulation via the dermal microvasculature. The cutaneous reservoir model of a pool of applied substances, which are slowly released into the systemic circulation, is an important concept because it allows for continued systemic exposure after dermal application has ceased.
Chronic Toxicity.
Adverse effects of repeated essential oil usage can be quantified in terms of the TD50 (toxic response in 50% of cases) or LD50 concepts. Comparisons with the acute oral LD50 give an idea of accumulation in vivo. Chronic toxicity testing is often carried out over 90 days or other specified time period. The chronicity factor is the LD50 1 dose /LD50 90 doses: if the value = 90 the material is absolutely cumulative, if over 2 relatively cumulative, less than two relatively non-cumulative. We have few readily available figures on chronic toxicity for essential oils, but Von Skramlik’s 1959 studies indicate a chronicity factor of approximately 5-10 for a range of oils.
Skin Sensitization
One of the original RIFM tests was the determine the potential for skin sensitization: the 1966 Kligman human maximisation test (Kligman A.M. 1966) was used as a screening method using petrolatum as a solvent. The word potential is important: this is a predictive test and does not indicate hazard. The word maximization refers to a maximum level of exposure to identify even weak sensitzers which might have been previously missed in former procedures. Ten times the maximum use levels of the substance in consumer products was used in order to give a safety margin and to account for the fact that only 25 volunteers were used in the test, and also to compensate for the fact that the material was applied under semi-occlusion. In a modification, details of which were published in 1969 (Magnussan et al.), guinea pigs replaced humans when finding volunteers became problematic. A number of problems with the test subsequently came to light:
1. Irritants have often been misidentified as sensitizers.
2. Common vehicles (carriers) can be sensitizers.
3. Inter-lab variability was very high
4. Private sector information on the subject remains unpublished.
5. There is little distinction between mild and severe sensitizers.
6. Further, epicutaneous testing has suffered from the use of impure materials and many substances classes as sensitizers may have been wrongly described on the basis of impurities they contain. Mixtures of compounds can lead to increased or decreased reactivity.
Misidentification of irritants as sensitizers has been the subject of much dispute, and it would appear that skin hypersensitivity or angry back syndrome and other factors are to blame. Interestingly RIFM does not have a cross-reactivity testing regime.
In 1995 RIFM switched to the modified Draize procedure (Human Repeat Injury Patch Test). Volunteers were treated with 24hr patch test on Mondays, Wednesdays & Fridays over a three week period followed by a two week rest, then a 24 hr challenge under total occlusion. In fact the original Draize procedure used ten applications, but for convenience three applications for three weeks has more often been used. RIFM relies on this human screening for final decision on sensitivity potential. (It is important to note this latter fact: there is confusion in the Aromatherapy community on this point. Some writers on the Aromatherpay newsgroups have erroneously maintained that these tests are not carried out on humans, and therefore (breath-takingly!) dismissed RIFM data as irrelevant!). Materials are initially screened however Buerler’s guinea pig sensitization test (1965) where materials are applied under total occlusion. This procedure was said to give better predictions of eventual performance in HRIPT tests than other tests. An external review tells a different story however, of poor result compatibility between RIFM’s maximization data and the Draize HRIPT test however: see the reference Marzulli F.N. & Maibach H.I. (1980).
[A note on looking at data (for example on MSDS sheets). Doses are given in mg or other appropriate unit/duration period of exposure i.e. 500mg/24H. Skin reaction result tests are expressed as:
MLD: ("mild") well defined erythema & slight edema
MOD: ("moderate") mod to severe erythema & slight edema
SEV: ("severe") severe to slight escher form. & severe edema].
The protocols of Bueler and the maximisation test are recommended in EU & OECD guidelines, but variable results are still encountered. The mouse local lymph node assay (LLNA) (Kimber & Basketter 1992) depends on measuring cell growth in lymph nodes draining the dermal site to which to the potential sensitizer have been applied. This test gives good inter-laboratory correlation, although may be less sensitive than the maximization test and can still apparently yield false positive results. It has had full international validation, and by measuring threshold concentrations of applied substances required to produce skin sensitization gives information, gives data on relative sensitizing abilities of different substances.
All about Haptens.
We know there are low molecular weight allergens, called haptens, in a number of oils and we can often remove these by physical treatment rendering the oils non-sensitizing. The aroma industry has not adopted this practice to any great extent commercially, in order to use the IFRA banned or restricted materials freely, however. The skin is an organ which has a surface area of approx. 2m2 in the adult and which contains many xenobiotic metabolising enzymes and P450 cytochrome systems just as the liver does. In a simplified model to illustrate skin sensitivity:
1. The chemical is first absorbed into the epidermis
2. It is either metabolized by cutaneous enzymes or other processes to form a reactive metabolite, or often may be chemically modified through the reaction of UV light, or remains unchanged.
3. It binds to dermal proteins. Haptens are often electrophilic and can bind covalently with -NH2 groups and -SH groups on proteins, modifying the protein, which when presented to the immune system, will react with antigen presenting cells in the dermis.
4. The Langerhans cells react with the allergen: the hapten-protein complex. They then migrate to the thymus.
5. The Langerhans cells teach T-cells to recognise the allergen and when they leave the thymus they are sensitized.
6. When they encounter the allergen they release lymphokines.
Attempts have been made to define sensitization potential from structure, and at an elementary level we can classify haptens from their functional groups: this listing include epoxides, and may partly explain why oxidised bitter orange and turpentine oils have an associated sensitizing potential. Oxidation of d-limonene, present at up to 96% in bitter orange oil leads to the formation of cis- and trans- limonene oxides, and limonene hydroperoxide, carveol and l-carvone amongst others, all of which except carveol have been found to be sensitizing. Additionally unsaturated compounds are often sensitizers, and initially this was thought to go towards explaining why turpentine oil, which contains the unsaturated compound d -3-carene, is a sensitiser. It is now believed that unknown hydroperoxides are more likely the cause.
Sensitizers: banned IFRA: Costus root oil, absolute & concrete, Elecampane oil, Thea sinesis absolute, Verbena oil, Fig leaf absolute.
Restricted by IFRA: Cinnamon bark oil Sri Lanka, Cassia oil, Oakmoss extracts, Treemoss extracts, Fennel oil, Opoponax derivatives, Peru balsam, Styrax, Verbena absolute, Pinaceae derivatives. Oakmoss products have come under a temporary restriction to a concentration 0.1% in the final product until new methods of extraction can produced materials which are not (so) sensitizing.
Pinaceae derivatives including oils of the Pinus & Abies genera, should only be used when the level of peroxides is kept to the lowest practical level, preferably by adding anti-oxidants at the time of production. They should in any case only be used when the level of peroxides is less than 10mmol/l determined by the EOA method.
Quenching is a phenomenon where the sensitization properties of fragrant substances can be quenched when other compounds are present e.g. cinnamic aldehyde is quenched by an equivalent amount of eugenol. Studies of even simple mixes of fragrance chemicals have shown non-predictive sensitization behavior. It is presumptuous therefore to predict the likely sensitizing potential of a complex mix of hundreds of components, as is the case with an essential oil, based on the inclusion of one or more chemicals with known sensitivity problems.
What is more thought provoking perhaps are the findings of Nakayama H. (19741-1984) (3 references) who embarked on a screening program to find the contact allergens in cosmetics. The findings have been widely discussed and amongst the essential oils include Jasmine oil, Patchouli oil, Geranium oil, Cananga and Ylang ylang oils, Sandalwood oil, and Costus amongst others. By cutting out these substances in perfume formulations, cosmetics could be produced with a buit-in allergen-control system. It will be interesting to see if IFRA eventually validate these findings.
Skin/eye irritation
An irritant is an agent which can cause cell damage if applied in sufficient concentration and for a long enough period. Immunological processes are not involved, and basically the chemical insult releases a potent vascodilator called histamine from mast cells producing erythma and increased vascular permeability, accompanied by eventual migration of polymorphonuclear leucocytes to the area. Dermatitis can follow without prior sensitization. Those with fair skin are more easily irritated, but the irritant reaction can also be shown to decline with increasing age, and to increase with increasing temperature, such that irritant dermatitis may only occur in some individuals in summer. The irritant must exceed a certain threshold to produce a reaction, but the dose response curve is less acute for allergens. Based around the original 1944 Draize test, the FDA report of the procedure uses albino rabbits clipped free of hair. A minimum of 6 animals are used in abraded and intact skin tests. Materials are introduced under a square surgical gauze (skin or eyes) and the entire trunk of the animal is wrapped up in an impervious material for 24 hours. to keep the patch in place and to prevent the easy evaporation of the volatile substance. After 24hrs the patch is removed to predict irritation potential.
The test often failed to distinguish between marginal & low-grade irritants and in the Philipis modification, cumulative low grade irritants are tested with a cumulative irritancy test, the application time of which may be up to 21 days. The test gives good results for single application testing because strong & moderate irritants are easily recognised. Other animals besides rabbits have been tried, but good comparisons between human & rabbit test results have made a major change unlikely (until the end of animal testing?). Alternatives to animal testing are likely to become to be an EU requirement soon, and the management team of the European Cosmetic Toiletry & Perfumery Association (COLIPA) are working on a validation study on eye irritation presently which converts results in vitro tests to in vivo standards via a number of prediction model algorithms.
Irritation effects may be encountered with neat oils containing components like eugenol, (Clove bud, Pimento etc), menthol (Cornmint, Peppermint) and aldehydes (10-fold orange, cassia etc). In general the following oils have been found to be strongly irritant: Horseradish, Mustard, Garlic, Massoia. A larger number of oils have a moderate irritant risk, including the essential oils of Savoury, Clove leaf, bud & stem oils, Pimento leaf and Thyme. Many perfume companies self-impose a final 0-0.5% skin concentration limit on phenolic oils in fragrances (this does not include application to facial areas). In today’s climate, similar restrictions might be considered appropriate by aromatherapists.
Photo-toxicity.
Sunlight in the form of UVA or UVB is responsible for a number of cutaneous pathologies including phototoxicity and skin cancer. Photo-toxicity itself is a light-related irritation which is due to the percutanous penetration of a light activated chemical (the photo-toxic agent) followed by skin exposure to light of the appropriate intensity and wavelength. It does not involve the immune system. In more simple terms it is can be regarded as accelerated tanning of the skin by a chemical UV absorber. The carrier or solvent in which the material is dissolved strongly affects the percutanous penetration and chemical release, and therefore availability of the agent, in a complex manner. Testing is therefore has previously been carried out with vehicles likely to release the photo-toxic agent effectively, such as ethanol.
Furanocoumarins (also called psoralens) in expressed citrus oils, and certain other oils like Rue, (and fig leaf absolute) are perhaps the best investigated photo-toxins, in particular bergaptene (0.30 to 0.39%) and xanthotoxin in bergamot oil. The time following chemical exposure and, the intensity of the light exposure are also variables. Animals produce maximum responses to photo-toxins after a few minutes; in humans 1 hour is usually optimal, fading away to zero response at 24 hours. Human testing is usually carried out on areas on the back or arm. As the response can be produced in virtually every person, only small testing panels are employed.
A important original finding by Forbes et al (1977) was that following a screening of 161 raw materials used in fragrances, 21 gave a phototoxic response, and 20 of these 21 were in either the botanical families of the Rutaceae (citrus oils) or the Apiaceae. For cosmetic safety professionals this leaves a very large number of cosmetic ingredients to test, so that even at this stage the overall potential & frequency of the photo-toxic response is still unclear. Response is affected by the body test site, the treatment protocol, test concentration, application frequency and the time & duration of chemical/light exposure.
We can rank photo-toxic oils in common Aromatherapy use. Distillation or chemical treatments are available options to bring the furanocoumarin concentration down to very low levels (often below 0.05% for distilled Bergamot oil). Fig leaf absolute & Verbena oil are banned IFRA and these products are not recommended for Aromatherapy use. Tagete, Bergamot oil expressed Lime oil expressed and Angelica root oil are all phototoxic and should not be used at concentrations greater than recommended by IFRA. In my opinion Rue oil and Tagete oil should not be used at all in this situation. Orange oil bitter, Lemon oil expressed and Grapefruit oil expressed are less phototoxic and IFRA guidelines reflect this. Paradoxically Bergamot oil itself is sometimes found in sunscreens. This is because tanned skin is more protective against UV.
Photocarcinogenesis
Bergamot oil is carcinogenic in the presence of UV light when applied to mouse skin, but when applied with a sunscreen the carcinogenic effect disappears. Little data is available in the public domain for oils other than Bergamot at present.
Photoallergens.
Photo-allergy is similar to allergy but involves the binding of a protein with a metabolite which has penetrated the skin and been transformed by UV light. Many photoallergens are also contact allergens, although there are fewer photoallergens. The former fragrance compound 6-methylcoumarin is well-known example here.
Carcinogens.
A carcinogen is a chemical which may give rise to tumor production, which is an unrestrained malignant proliferation of a somatic cell, resulting in a progressively growing mass of abnormal tissue.
At the simplest level carcinogenic testing might involve adding substances to rodents’ diets over a period of time, at the end of which they are killed and examined for tumors etc. This in vivo approach still accounts for a considerable proportion of pharmacological testing at least (for screening new drugs etc.). Ethical demands have driven the wider use of in vitro alternatives to animal tests. Unfortunately the standard of information given by in vitro testing falls below that offered by in vivo tests. Quantitative Structure-Activity Relationship (QSAR) modeling - which relates the magnitude of one particular property of a series of related chemicals to one or more other physiochemical or structural parameters of the chemicals in question - is helping to complement in vivo testing. It is hoped that this approach will eventually get to a stage which will be accepted by regulatory authorities.
Mutagen: A substance which may cause inheritable defects arising from their action on mammalian germ cells. Tumour formation may result from their action on somatic cells via cellular disruption. Many mutagens are carcinogens, but not all carcinogens are mutagens.
A mutation is defined as any heritable change in generic material. In vitro testing methods for mutagens include examining the action of the substance on chromosomal DNA and bacterial testing for gene mutation often takes the form of reverse mutation assay in Salmonella typhimurium and Escherichia coli with & without metabolic activation (Ames test). The problem with using the Ames test to predict potential carcinogens is that the mutagens identified in the Ames test are not necessarily carcinogens, and some carcinogens are not mutagenic. Interpretation of data in this whole area is frequently both complex and controversial, for example safrole which is labeled as a carcinogen would have had to have satisfied a number of criteria before classification.
Teratogen . Substances that interfere with the normal development of either the embryo or foetus in utero, giving rise to abnormalities in the neonate.
Notes on Specific oils/natural chemicals
Safrole containing oils.
Cannot be legally used in many countries. Sassafras oil is controlled (as Safrole) under the Controlled Drugs (Scheduled Substances Used in Manufacture)(Intra-Community Trade) Regulations 1993 in conformity with subsequent European Directives 3677/90 as amended by Council Regulation 900/92 as a Category 1 substance. It is controlled together with a number of other substances, as it is a pre-cursor to the illicit manufacture of psychotropic & narcotic drugs (esp. in this case Ecstasy), as part of a world-wide effort to restrict unauthorized movement of these substances. This means that licenses are required to engage in the import/export of these substances, and end-user declarations have to be filled in annually.
Hazard:
Safrole is categorised as a category 2 carcinogen (i.e. carcinogenic to man) under the 22nd commission directive para 1.7.2 of Labeling guide (annex VI to Commission Directive 93/21/EEC) as Oils containing more than 0.1% safrole i.e. Nutmeg, Brown Camphor oil & Ylang ylang oil should be classified and labeled as category 2 carcinogen. However this should not apply if safrole is not an impurity (it is a constituent).
Similar restrictions apply in the US, and it is probable that Brown Camphor Oil (Cinnamomum camphora) and Cangerana oil (Cabralea cangerana) are also subject to this legislation. Aside from trading restrictions, safrole metabolism in rats proceeds via formation of 1’-hydroxysafrole in rat & mouse liver from he hydroxylation of safrole via the microsomal P450 enzymes and has been indicated as the likely carcinogen. However work by Primedetti has shown that the major excretion product in man is 4-allyl catechol. 1’-hydroxy safrole was not detected.
In fact the safrole limit in many legislation’s are not based on the ADI for safrole but on the technical need to continue to use nutmeg. Lowering the ADI would reduce the use of nutmeg. Nutmeg oil may have 0.1-2% safrole, and mace oil is broadly similar. The effect of safrole and myristicin in producing hepatic DNA adducts from cola drinking have raised concerns Randerath K et al (1993).
ß-asarone. Calamus oil is (severely) restricted IFRA. Triploid and tetroid varieties of Acorus calamus contain ß-asarone which damages human lymphocytes and has mutagenic effects on bacteria and has demonstrable carcinogenic activity in rats. Although diploid varieties are claimed to have little or no ß-Asarone content, Calamus oil should not be used in Aromatherapy.
Citral. Known to be a powerful contact allergen. Occurs in Backhousia citriodora, Lemongrass, Litsea cububa and Melissa oils. Restricted IFRA: should be used with quencher e.g. Lemongrass 80%, citrus terpenes 20%.
Methyl chavicol.
Occurs as major component in (95%) Mexican Avacado leaf oil, Basil & Tarragon oils and Fennel oils. Methyl chavicol (=estragole) has been shown to produce heptacellular carcinomas in mice (Drinkwater et al. 1976), but investigations of genotoxicity of two Basil oils & one Tarragon oil by Tateo (1989), whilst showing Tarragon to be genotoxic, did not the show Basil oils to be genotoxic at all. The author here concluded that methyl chavicol was not the only factor in considering the genotoxic effects in Basil oil, and in another study highly purified methyl chavicol was found free from mutagenic effects to Salmonella T100, whereas 96% was positive to Salmonella TA100 TA 1535, TA98 and TA1537 (Ames test)(Sekizawa 1982). We probably do not have enough data to predict the carcinogenic effects of methyl chavicol in Fennel and in Basil oil reliably, but when considering exposure of children these oils caution is advised. Tarragon & high methyl chavicol type Basil oils are important contributors to the top notes in men's fragrances, but are not recommended for aromatherapy use.
Other substances causing concerns in
Essential oils
It can be very difficult for Aromatherapists to decide about the safety of particular oils, especially where there is conflicting advice. It is as well to be aware of what the problems are, and exercise caution if you decide to use these oils. It is always to debate "personal professional use" positive & negative lists of oils with fellow users. This paper cannot give space to more than a few discussion points:
Geraniol. Sensitizer. Consistently causes problems as a component of perfumes & cosmetics. Occurs in many oils including Palmarosa, Geranium, and Rose. Not currently restricted IFRA. Ref: Nakayama H et al (1974.)
Ylang ylang oil. 5 year worldwide study of cosmetics reactions shows frequent allergic reaction to this material. Ref: Nakayama H et al (1974.)
Methyl eugenol.
Hazard: Genotoxic. Occurs in a few oils as a major component (Huon Pine and in Melaleuca bracteata (95% methyl eugenol) and in a number of essential oils as a minor component from e.g. Nutmeg, Myristica fragrans, Russian Tarragon, Rose oils (Rosa spp.) Ylang ylang (Cananga odorata subsp. genuina) Laurel Leaf and others. Investigations have confirmed genotoxicity and carcinogenicity in rats (e.g. Chan V.S.W. et al (1992)), probably due to strong DNA-binding reactions. Many perfume companies impose in-house restrictions on the use of this material in perfume formulations, and will be pressurising professional bodies for a position statement.
Risk: Such that it is suggested that high methyl eugenol containing oils should not be used by Aromatherapists.
Eugenol.
Component of clove and thyme oils. Frequent allergic reactions when used as ingredient of fragrance formulations. LLNA tests shows 14.5% threshold concentration (cf. Citral= 13%). No current IFRA restriction. Ref: Loveless et al (1996)
R-(+)-Pulegone.
Hazard: Hepatotoxic. Major constituent of Pennyroyal oil (both from Hedeoma pulegioides and Mentha pulegium), & Buchu oil from Agothosma crenulata. Also present in Spearmint, Catnip, Peppermint & Cornmint oils, amongst others. The acute oral LD50 for rats for Pennyroyal oil is 0.5g/Kg Many workers have indicated that the substance is hepatoxic, but it would appear that the damaging effect on the liver of large oral doses may involve the depletion of glutathione, which is needed in one of several detoxification steps. This depletion leads to the overwhelming of the liver by excess pulegone and centrilobar necrosis of the hepatocytes occurs.
Some Aromatherapy authors have played down the risk associated with pulegone, although the food regulations in the EC limit the amount of pulegone in food flavourings to 0.025g/Kg food (The Flavourings in Food Regulations Statutory Instrument no 1971 (1992). Risk: It is probably important that the AT profession is not seen to be out of step with regulations imposed in other sectors: co-incidentally (or not!) Tisserand & Balacs 1995 indicate that the oil should not be used in Aromatherapy especially in pregnancy.
Sandalwood Oil. 5 year worldwide study of cosmetic reactions shows Sandalwood causes frequent allergic reactions. This may be related to the ß-santalol content, which is thought to be a sensitiser. Ref: Nakayama H et al (1974.)
Menthofuran
Hazard: Hepatoxic. Newer legislation limits its’ concentration in chewing-gum, where is occurs as a component of mint oils. It has previously been found to be hepatoxic and lung-toxic, and occurs in water mint (Mentha aquatica) in many other wild mints, and formerly in Japanese peppermint oil. Fortunately perhaps, Western consumers have never cared much for the taste of high menthofuran-containing peppermint oils, and this characteristic has been successfully curtailed in many commercial strains of peppermint oil, so that menthofuran occurs at much lower levels. It is a metabolite of pulegone detoxification in the liver (for example from Pennyroyal oil), and contributes to the toxicity of this substance.
Anethol.
Hazard: trans-Anethol occurs especially in Aniseed oil, where levels may exceed 95%. There has been much debate about the toxicity of anethol. Much of this is to be centered around its’ commercial purity. The cis-form is much more toxic, and can form on aging, especially in the presence of light. It is the principle flavouring agent in Pernod & Ouzo, but there are no current restrictions on its’ use in beverages. Star anise oil may contain additionally contain 5-6% methyl chavicol, although rectified oils may contain less. Other substances, such as photoanethol may be responsible for its’ alleged toxicity.
Risk: It would seem prudent in the absence of further data to only use fresh oils, with caution, and to restrict intakes for children.
Methyl salicylate
Hazard
Methyl salicylate occurs in up to 98% Wintergreen and Sweet Birch oils, the former being commercially obtainable from China amongst other places. Most oils on the market are actually synthetic methyl salicylate. It is very toxic to man, and according to Pribble (1988) children are very susceptible to salicylate poisoning.
Methyl salicylate is used as a counter-irritant in many over-the-counter
preparations. Its' use in topical rubefacients for the relief of muscle pain by
their action in producing a feeling of relief and "glowing-skin" has
been estimated at generating £7 million in sales in the UK alone. The toxicity
of methyl salicylate is of concern however, especially where children are a
consideration, as the substance directly interferes with glucose metabolism, and
exhibits CNS toxicity. There is some evidence that absorption from the
intestines is erratic, and hence we get a range of toxicity estimations and
variability in fatalities and effects. Gleason et al (1969) puts the lethal dose
for a 70Kg man at between 5 and 30ml. NIOSH (1975) recorded a human oral LDLo
value of 170 mg/Kg (LD50 oral-rat for methyl salicylate is 887mg/Kg).
Pribble et al (1988) in his book "Applied Therapeutics: the clinical use of
drugs" notes that children under five are especially susceptible to
salicylate poisoning, and can quickly go to show physiological symptoms
associated with advanced poisoning.
There are a large number of studies on skin absorption of methyl salicylate from
skin; from Brown and Scott's 1934 investigation through to more modern work e.g.
Skin absorption Levine (1984) J. Anal Toxicol 8: 239-241. The
general picture is that methyl salicylate absorption can be rapid. Evidence
suggests that blood salicylate levels are highest at 20-30 mins after
application. Davidson J. Pharmacol Exp Ther 132: 207-211
show that most conversion of methyl salicylate to salicylic acid occurs in the
liver and little in the blood.
Absorption through the skin is much more rapid that intestinal absorption and
metabolism seems to occur mainly in the liver. Collins et al (1984) did some
interesting work on topical absorption of "Deep-Heat" an aerosol
preparation for relief of rheumatic pain which includes methyl and ethyl
salicylate in its formulation. After a one-shot 500 micro-litre spray on the
forearm, erythma production was correlated with salicylate concentration and
blood salicylate levels reached a maximum after 20 minutes. In their work blood
salicylates appeared to affect the prostaglandin system. So, to cut this short,
the worst case scenario is that methyl salicylate is a CNS poison with acute
salicylate poisoning manifesting in disorientation, irritability,
hallucinations, stupor, coma etc. So: don’t imbibe the oil, if you sell
Wintergreen oil sell it in containers with child-proof lids, where used for
topical application use minimal doses which will do the job, do not use in whole
body applications, and do not use if client is using anti-coagulant drugs such
as warfarin.
Exposure to methyl salicylate generally (national annual consumption ratios)
would appear to be especially high in the US and Philippines and to a lesser
extent UK. This is perhaps due to a predisposition in the US especially to use
methyl salicylate in toothpaste, candies, soft drinks, dental preparations,
chewing gum cough drops and in over 50 proprietary over the counter
non-prescriptive medicines (liniments, ointments, rheumatic remedies etc). Over
50% of all toothpaste sold in N. America contains methyl salicylate at average
levels around 0.4%, whilst liniment levels average between 15 and 18%. Also
methyl salicylate occurs in many beverages in the US, following the demise of
sarsaparilla (contains the toxic principle safrole)
The manifestations of salicysm are mainly related to patients with a history of asprin use and appears as CNS disturbances disorientation, stupor, hallucinations and worse see Pribble JP et al (1988).
Risk:
We know there are problems with chronic salicylate ingestion in pregnancy in humans which makes petty morbid reading (several references including Turner G et al (1975). Basically pregnant and lactating women should avoid methyl salicylate/Wintergreen.
Neurotoxic issues.
Many oils have a direct action on the CNS: Hyssop, Camphor, Cedarleaf, Tansy etc., and the worrying element here is irreversible damage of over-exposure, as spontaneous self-repair is not generally possible. With the same perception of possible CNS damage in mind, The No Observable Adverse Effect Level (NOEAL) was used by RIFM for considering the possible neurotoxic effects of the synthetic perfumery musk chemical 6-acetyl-7-ethyl-1,1,4,4-tetramethyltetralin. The material was subsequently banned IFRA.
This minimum level concept at which there are "no observable effects" is generally used in setting exposure limits such as Acceptable Daily Intake (ADI) for chemicals used as food additives, or Threshold Limit Values (TLV values) for chemicals used in an industrial context. Usually a built-in safety factor of x 100 applies, to account for difference between species, and to account for idiosyncratic metabolism and other factors. Where these figures are available, this would seem to be a very useful concept to apply to the AT situation with regard to neurotoxic/toxic compounds in essential oils, such as alpha- and beta-thujones, rather than rely on computations based on LD50 values. Children, for example, are especially vulnerable from CNS effects, and in our own lifetimes many of use will have experienced the removal of lead from petrol. This move followed evidence where even levels as low as 0.3 micrograms of blood lead/ml were proven to affect neuronal transmission.
I worry seriously about AT authors who proclaim the "no risk" scenario in using potentially neurotoxic oils such as Hyssop, Armoise and to some extent Sage oils. Just as concerning, is the fact that there are still many herbals in circulation, which, for example mention pennyroyal use as an abortifacient, with no mention of inevitable cellular injury, or recommend pennyroyal tea with no mention of the potential of fulminant hepatic failure to young children.
Reproductive toxicity.
It is probable that essential oil metabolites cross the placenta because of the intimate (but not direct) contact between maternal and embryonic or foetal blood. Lipophilic substances can migrate by passive diffusion between these two bloodstream’s and reach equivalent levels in foetal blood, but if these substances are biotransformed into polar compounds, they can accumulate in the foetus. In addition, the high water: lipid ratio in the foetus, the lower amount of available plasma protein for binding foreign compounds, and the reduced rate of glomerular filtration are all factors, amongst others, which mitigate against toxin clearance in neonates. We therefore do not necessarily know the consequences of direct exposure to many substances during pregnancy, and oral, vaginal and rectal administration should be avoided.
ß-Phenylethyl alcohol (PEA) (major constituent of rose absolute) was found to cause reproductive effects at high doses in animals by the oral route: Mankes R.F. et al (1983), & Ford RA (1990). By studying oral and dermal routes of exposure, it was ascertained in the skin that conversion to phenylacetic acid quickly occurs (phenylacetic cid is a naturally occurring compound in blood). Further it was determined that increases in blood levels of phenyl acetic acid were relatively minute and posed no risk: thereby adequate safety margins were demonstrable, and no restrictive guidelines have been issued by IFRA.
Teratogens that have been positively identified amongst the essential oils have included the embryotoxic Savin oil from Juniperus sabina ref: Pages N. et al (1989) and Spanish lavender (Salvia lavandulifolia) oil ref: Fournier G et al (1993). Here the offending substance appears to be the sabinyl acetate content, which may occur up to 24% in Spanish lavender oil. Sabina oil is banned IFRA and as mentioned above, its’ sale in the UK is contrary to The Medicines (Retail Sale or Supply of Herbal Remedies) Order 1977. Spanish lavender oil is not similarly restricted.
To my thinking the responsible attitude is to discourage the use of essential oils completely during the first few months of pregnancy. Critics of this policy have said that the amount of dietary essential oil intake (in flavourings) outweighs intake from AT practice. I might think that dietary intake of essential oils was undesirable under these circumstances anyway, but in any case, current AT practice uses oils which are not used in flavourings, and involves different routes of absorption. It has always to be considered that the greatest number of mitoses take place in the foetus, and exposure to substances which might possibly act as mutagens should particularly be avoided in the first trimester of pregnancy.
I hope in this widely ranging talk, I have given some pointers to enable practising AT’s explore safety issues further.
References:
Bakerink J.A. et al. (1996) "Multiple organ failure after ingestion of Pennyroyal oil from herbal tea in two infants." Paediatrics 98(5), 944-7.
Brown and Scott's (1934) J. Pharm. & Exptl. Therapeutics 50: 32-50
Chan V.S.W. et al (1992) "Comparitive induction of unscheduled DNA synthesis in cultured rat hepatocytes by allylbenzenes and their 1’-hydroxy metabolites" FCT 30(10) 831-836
Collins et al (1984) Annals of the Rheumatic Diseases 43, 411-415
Conway G.A. et al (1979). J. Ethnopharmacol Oct 1(3) 241-6.
Cooper SD et al (1995). "The identification of polar organic compounds found in consumer products and their toxicological properties" J. Expo Anal Environ Epidemiol 1995 Jan-Mar 5(1) 57-75.
Cramer GM, Ford RA, Hall RL (1978) "Estimation of Toxic Hazard – a decision Tree Approach" FCT 16, 255-276.
Davidson J. Pharmacol Exp Ther 132: 207-211
Ford RA (1990) "Metabolic and kinetic criteria for assessment of reproductive hazard" In: Volans GF, Sis J. Sullivan FM, Turner P (eds) Basic Science in Toxicology. Tylor & Francis NY pp59-68. Centre for Aromatic Medicine 1998.
Falk AA et al. (1990) "Uptake, distribution and elimination of alpha -pinene in man after exposure by inhalation" Scand. J. Work Environ Health 16, 372-8.
Fukayama MY et al. "Subchronic inhalation studies of complex fragrance mixtures in rats and hamsters" Toxicol Letters 20, 111(1-2) 175-87.
Gleason et al (1969): Clinical toxicology of acute poisoning 3rd edn. (1969)
Hewitt P.G. et al. 1993 "Cutaneous retopical application of 4,4’-methylene –bis-(2-cloroaniline) and 4,4’-methylenedianiline to rat and human skin in vitro." From Brain K.R et al Prediction of percutaneous penetration: methods, measurements and modeling , Vol 3b STS Cardiff p638-645).
Jaeger W et al. (1996)"Pharmokinetic studies of the fragrance compound 1,8-cineole in humans during inhalation" Chem. Senses 21, 477-80.
Kauppinen TP et al (1986) "Respiratory cancers and chemical exposure in the wood industry: a nested case-control study Br. J. Ind. Med. 43: 84-90
Kimber I., Basketter D.A. (1992) "The Murine Local Lymph Node Assay: a commentary on collaborative studies and new directions" FCT 30 165-169.
Kligman A.M. (1966) "The identification of Human Contact Allergens by Human" Exposure J. Invest. Derm. 47: 399
Koren G (1993) "Medications which can kill a toddler with one tablet or teaspoonful." J Toxicol Clin Toxicol, 31(3):407-13
Kowalski Z et al. (1962) Medycyna Pr. 13, 69.
Kumar P. et al (1995)"Inhalation challenge effects of perfume scent strips in patients with asthma" Ann Allergy Asthma Immunol 75(5) 429-33.
Levine (1984) "Skin absorption" (1984) J. Anal Toxicol 8: 239-241.
Loveless S.E et al (1996) "Further evaluation of the Local Lymph Node Assay in the final phase of an international collaborative trial" Toxicology 108, 141-152
Mankes R.F. et al (1983). "Effects of various exposure levels of 2-phenylethanol on foetal development and survival in Long-Evan rats". J. Toxicol & Environ. Health 12: 235-244.
Millet Y. et al 1981 Clinical Toxicol 18(12) 1485-98.
Millqvist (1996) "Placebo controlled challenges with perfume in patients with asthma-like symptoms" Allergy 51(6) 434-9.
Nakayama H. (1974) 2Perfume allergy and cosmetic dermatitis." Jap J. Dermatol. 84, 659-667.
Nakayama H. et al Allergen controlled system 1-42 Kanehara Shuppan, Tokyo
Nakayama et al (1984) "Pigmented Cosmetic Dermatitis" Int. J. Dermatol. 23, 299-305.
Pages N., Fournier G., Chamorro G., Slazar M. Paris M. Boudene C. "Teratological evaluation of Juniperus sabina essential oil in mice" Planta Med. 1989 Apr. 55(2) 144-6.
Pappas GP, Herbert RJ, Henderson W, Koenig J, Stover B, Barnhart S "The respiratory effects of volatile organic compounds." : Int J Occup Environ Health 2000 Jan-Mar; 6(1):1-8.
Pribble JP et al 1988 Poisoning. In Applied Therapeutics Vancouver : Applied Therapeutics Inc. 1988).
Pybus D. & Sell C. (1999) The Chemistry of Fragrances RSC Paperbacks 1999.
Randerath K et al (1993) "Flavour constituents in cola drinks induce hepatic DNA adducts in adult and fetal mice" Biochem Biophys Res Commun 192(1) 61-8.
Reynolds JEF (Ed) 1993 The Extra Pharmacopoeia The Pharmaceutical Press, London.
Schnaulbelt K (1986): Aromatherapy Course 2nd edn. p116 Kurt Schnaubelt Ph.D. San Raphel.
M. M. Schaller & H.C. Korting (1993) "Allergic airborne contact dermatitis from essential oils used in aromatherapy" Clinical & Experimental Dermatology 20, 143-145.
Smith A. & Margolis G. (1954) "Camphor Poisoning" American Journal of Pathology 30, 857-869.
Uehleke H. Brinkschulte-Freitas M. "Oral toxicity of an essential oil from myrtle and adaptive liver stimulation". Toxicology 1979 12(3): 335-42.
Tateo F. (1989) J. Ess. Oil Res. 1, 111-118 (May/June 1989)
Tisserand R. & Balacs T. (1995) Essential Oil Safety- a guide for Health Care Professionals pub: Churchill Livingstone 1995.
Turner G., Collins E. (1975) "Fetal effects of regular salicylate ingestion in pregnancy" Lancet 2: 338-339).
Weyers W (1989) "Skin absorbtion of Volatile Oils. Pharmokinetics." Pharm. Unserer Zeit 18(3), 82-6
Von Skamlik E.V. (1959) "Uber die Giftigkeit und Vertraglichkeit von atherischen Olen". Pharmazie 14, 435-445
Yourick J.J. (1997) J. Appl. Toxicol 17(3) 153-8
Safety Literature:
N.B. Some of these publications may only have small sections which are directly relevant to AT.
1. Essential Oil Safety- a guide for Health Care Professionals
R. Tisserand & Tony Balacs. Pub: Churchill Livingstone 1995.
2. Clinical Toxicology of Commercial Products: Acute Poisoning
Gosselin R.E. et al 1976 4th edn. pub: Williams & Wilkins,
Baltimore.
3. Potters New Cyclopaedia of Botanical Drugs & Preparations:
Wren R.C., revised by E.M. Williamson & F..J. Evans (1988)
C.W. Daniel Co. Essex.
4. Adverse Effects of Herbal Drugs Vol 1-3. Ed: P.A.G.M/ De Smet,
K. Keller R. Hansel & R.F. Chandler. pub: Springer-Verlag
5. Sax’s Dangerous Properties of Industrial Materials 9th edn.
Richard J. Lewis pub: Van Nostrand Reinhold.
(& Sax N.I Hazardous Chemicals Desk Reference
pub: Van Nostrand Reinhold 1987).
6. Compendium of SDS sheets for Research & Industrial Chemists
ed. Lawrence H. Keith et al.
Part VII Flavour & Fragrance Substances ed. T.C. Zebovitz.
7. Opdyke D.L.J. Food & Cosmetics Toxicology: Monographs on
Fragrance Raw Materials Sp Issues I-VII
8. Flavour & Fragrance Extract Manufacturers Association of U.S.
Inc. Flavour & Fragrance Materials. pub. Allured Publishing
Co. Illinois 1987.
9. Food Chemicals Codex IV edn. National Academy Press
Washington.
Copyright © 2000 by Tony Burfield. All Rights reserved.