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Cropwatch Claims Victory Regarding “26 Allergens” Legislation

Feb 2008

Pre-amble. Cropwatch has been campaigning for a number of years to reverse the “26 allergens” legislation, founded as it is, on “bad science”. We were assured in a face-to-face meeting with the EU Cosmetics Regulator in Brussels in 2007 that this subject would be re-examined, and it appears that this is now the case, as the EU Commission have reportedly agreed to consider the Schnuch evidence (see below). If this is all the evidence on alleged allergens that the Commission is going to review, it will be a disappointment, since further scientific papers on fragrance chemicals originally misclassified as allergens by the SCCNFP (now the SCCP) are piling up, as indicated below.

To recap (Burfield 2008) 26 alleged allergens, 16 occurring in natural complex substances, were identified in SCCNFP Opinion 0329/00 (rubber stamping previous IFRA-RIFM information) and passed into EU legislation under the Directive 2003/15/EC, amending Directive 76/768/EEC. The criteria for the inclusion of these materials as allergens by the SCCP has never been satisfactorily explained. The legislation requires a labeling obligation for finished cosmetic products containing any of the 26 identified allergens present at 0.01% in products rinsed off the skin, or 0.001% in leave-on products.

The Schnuch Evidence (taken from Burfield 2007). The July edition of the German consumer magazine Öko-Test, No. 7/2004, 55, reported on studies done by the IVDK, an information network association of dermatologists, headed up by Prof. Schnuch. It concluded that not all the 26 allergens identified by SCCNFP Opinion, and enshrined in the 7th Amendment to the Cosmetics Act, bear the same risk, and criticises the EU Commission for treating them all as equal. The report classifies allergens accordingly.

Ingredient type	Strong potent allergens (I)	Less potent allergens (II)	Rarely found as allergens (III)	Risk of being allergens to small to consider (IV)
Naturals	oakmoss, treemoss
Synthetic Fragrance materials also occurring in complex biological substances	isoeugenol, cinnamic aldehyde	cinnamic alcohol	citral, eugenol, farnesol	benzyl alcohol, benzyl salicylate, geraniol, anisyl alcohol, benzyl benzoate, benzyl cinnamate, citronellol, d-limonene, linalool, coumarin
Synthetics		HMPCC, hydroxyl-citronellal	lilial, methyl heptine carbonate	amyl cinnamic alcohol, hexyl cinnamic aldehyde, alpha-keton

Table 1. Classification of the ‘26 allergens’ according to IVDK, 2004

The Oko-test report for July 2004 gives details on criteria & an internal ranking system for allergic fragrance ingredients. This penalises the presence of strong allergens (column I above) by two points & penalizes less potent allergens by one point (column II above). Weaker (column III) allergens do not gather points but must be named. Non-allergens (column IV) do not gather points or have to be named.

Schnuch et al. (2007) report in a further study conducted in four periods of six months from Jan 2003 to Dec 2004, on the frequency of sensitisation to the 26 allergens. The authors conducted the patch-testing studies with a large number of consecutive, unselected patients with suspected allergic dermatitis to these 26 compounds. Schnuch et al. concluded that for some of the alleged allergens amongst the 26, neither restriction nor labeling seem justified, and that EU regulators should review the previous decisions taken.

Further Evidence (taken from Burfield 2007). Hostynek & Maibach have critically reviewed the evidence on SCCP alleged allergens, and called into question whether a number of fragrance substances can actually cause allergic contact dermatitis, in a series of articles:

Anisyl alcohol (Hostynek & Maibach 2003a)
Amylcinnamic aldehyde (Hostynek & Maibach 2003b)
Linalool (Hostynek & Maibach 2003c)
Geraniol (Hostynek & Maibach 2004a)
Citronellol (Hostynek & Maibach 2004b)
Alpha-iso-methyl-ionone (Hostynek & Maibach 2004c)
Methyl heptine carbonate (Hostynek & Maibach 2006).

Reviewing the scientific evidence for geraniol, for example, Hostynek & Maibach conclude that they found no cases where a patient had been brought to a clinic directly because of geraniol contact dermatitis. The authors go on to discuss patch-testing mixtures in general, where concentrations of elicitating chemicals are deemed too high, which decreases specificity without greatly affecting sensitivity. Consumers, they argue, may acquire benign allergies after everyday exposure to low doses of geraniol, which are only revealed under patch-testing conditions.

Storrs (2007) also comments that dermatologists help patient’s needs most, when they critically evaluate patients reactions. Storrs concludes that positive reactions to patch-testing (using fragrance mixes) rarely indicates clinical contact dermatitis caused by specific fragrance ingredients.

The position of pure coumarin as non-allergen has been extensively reviewed by Cropwatch at http://www.cropwatch.org/Coumarin - the real story update.pdf (also on this blog here). Aroma trade associations have tried to belittle the finding that pure coumarin in not an allergen, by stating that the situation of coumarin non-allergy may only apply to (pure) Rhone-Poulenc derived material. However the status of coumarin-containing natural materials, like lavender absolute & tonka bean absolute (previously found non-sensitising by RIFM, remember), is far from clear. Is it safe that finished fragrances containing these coumarin-containing substances as ingredients, have to be labeled to show the presence of allergens, as required under the EU Cosmetics Directive, or not? The EC’s regulations have advanced, but the necessary scientific backing is not there.

Friedrich et al. (2008) looking at a number of monoterpenes using the rat Popliteal Lymph Node Assay (PLNA) concluded that although citral, a-terpinene, b-myrcene and (-)-a-pinene induced a clear immuno-stimulatory response due to their irritant properties, no monoterpene proved to be a sensitizing agent in the PLNA. Further work may reinforce the hypothesis whereby weak irritants such as citral above are often misclassified by techniques such as the LLNA, as weak or moderate sensitizers. Again it underlines the point that we may have been misled by a culture of toxicological imperialism, into forms of precautionary fragrance ingredient legislation which may not ultimately prove to be scientifically robust.

SCCP ‘Out of Touch’.

Although the chairman of the SCCP was quoted as saying words to the effect that he expected the 26 allergens legislation to have little effect on industry, it has lost the industry € millions in labeling & reformulating costs, computer reprogramming costs & lost revenue to natural ingredient producers, as nervous perfume buyers initially demanded the elimination of all allergens from their suppliers’ fragrances, on the basis that by operating this policy, they would escape media attention in the event of any adverse effect complaints about their products. When fragrance houses started offering substandard perfumes as a result of leaving out natural materials containing those dreaded allergens, perfume buyers started to realise that they would have to allow at least some allergens to be present. Although it may not generally realised, a second list of alleged allergens (Frosch et al. 2002) was quickly drawn up by some prominent toxicologists ‘jumping on the bandwagon’ (the authorship team including Ian White, the chairman of the SCCP). This paper included a number of ingredients rarely used in perfumery, and the paper itself was riddled with scientific errors of fact. So this further list of alleged allergens was quietly dropped, following the industry storm that the original 26 allergens legislation created.

Cropwatch believes corporate toxicologists and industry-funded-bodies such as EFFA, are still trying to sneak further allergens into the Cosmetics Directive by the back-door, under the guise of 40^th IFRA amendment / QRA methodology. It is difficult to see whose interests they are serving by doing this. Whatever the toxicologists say, the animal-based tests (such as the LLNA) underpinning the science in this area, are not sufficiently robust to use as a basis for further over-hasty legislation. 

Curiously industry seems to have no appetite to openly challenge the shaky science frequently supported by those regulatory officers & career toxicologists who seem to have become spokespeople for the entire aroma industry. Yet Cropwatch has, just lately, had a flurry of meeting with top industry officials who worry that cosmetics legislation has now reached such an unnecessary pitch that it is going to destroy the very industry that they have helped create. But since it is the aroma industry which is funding the safety agenda, the answer is quite plain.

References:

Burfield T. (2007) “Over-regulation is Destroying Natural aromatics.” Lecture to the 38^th meeting of the ISEO, Graz, Austria on 12^th Sept. 2007.

Burfield T. (2008) “Regulation of Flavours & Fragrances in Europe.” Specialities Chemical Magazine 28(1), 34-36. 

Friedrich K., Delgado I.F., Santos L.M.F., Francisco J.R. Paumgartten J.R.(2007) "Assessment of sensitisation potential of monoterpenes using the rat popliteal lymph node assay" Food & Chem Toxicol 45, 1516-1522.

Frosch P.J., Johansen J.D., Menné T., Pirker C., Rastogi S.C., Andersen K.E., Bruze M., Goosens A., Lepitoittevin J.P. & White I.R. (2002) “Further important sensitisers in patients sensitive to fragrances” II. Reactivity to essential oils.” Contact Dermatitis 47, 279-287.

Hostynek J.J. & Maibach H.I. (2003) “Operational definition of a causative contact allergen – a study with six fragrance allergens.” Exog. Dermatol. 2, 279-285. 

Hostynek J.J. & Maibach H.I. (2003a) "Is there evidence that anisyl alcohol causes allergic dermatitis?" Exog. Dermatol. 2, 230-33.

Hostynek J.J. & Maibach H.I. (2003b) "Is there evidence that amylcinnamic aldehyde causes allergic dermatitis?" Exog. Dermatol. 3, 35-46.

Hostynek J.J. & Maibach H.I. (2003c) "Is there evidence that linalool causes allergic dermatitis?" Exog. Dermatol. 2, 223-229.

Hostynek J.J., Maibach H.I. (2004a) “Is there evidence that geraniol causes allergic contact dermatitis?” Exog. Dermatol. 3(6), 318-331. 

Hostynek J.J., Maibach H.I. (2004b) “Sensitisation potential of citronellol” Exog Dermatol 3(6), 307-312.

Hostynek J.J., Maibach H.I. (2004c) “Is there evidence that alpha-methyl-ionone causes allergic contact dermatitis?” Exog. Dermatol. 3(3), 121-143. 

Hostynek J.J., Maibach H.I. (2006) “Is there evidence that alpha-methyl-ionone causes allergic contact dermatitis?” Cutaneous & Ocular Toxicol. 25(4), 259-271. 

Schnuch A., Uter W., Geier J., Lessmann H., Frosch P.J. (2007) “Sensitization to 26 fragrances to be labelled according to current European regulation. Results of the IVDK and review of the literature.” Contact Dermatitis. 57(1),1-10.

Storrs (2007) “Allergen of the year: fragrance.” Dermatitis 18(1), 3-7.

Technorati Tags: 26 allergans legislation,Schnuch evidence,Anisyl alcohol,Amylcinnamic aldehyde,Linalool,Geraniol,Citronellol,Alpha-iso-methyl-ionone,Methyl heptine carbonate,coumarin,monoterpenes

Givaudan & Those Natural Product Sourcing Media Write-ups

Cropwatch tries hard to cut through the aromatic marketing hype presented by parts of the aroma trade, and to maintain an independent position, on the basis that somebody has to. For example the megacorp Givaudan, which you will remember recently acquired the aroma giant Quest (hence the floods of Quest employees who have been looking for jobs of late), disclosed a bolstered global turnover of € 888 million for 2007. Shortly before we learned of this figure, we also read about a partnership, (dressed up as it was in sustainable & natural product media hype terms, between Givaudan & Mount Romance in Australia, for Australian sandalwood oil supply futures (in spite of the high carbon footprint associated with sandalwood oil production). The negative effects of  sandalwood plantations on the Australian environment have been previously discussed by Cropwatch at http://www.cropwatch.org/cropwatch2.htm which drew for information, amongst other sources, on the fairly forthright & critical report on the W. Australian sandalwood industry by Tonts & Selwood (2002). Considering that land clearance for sheep & wheat farming devastated existing natural Australian sandalwood tree numbers, and caused huge salinity problems for the water table, it makes the trade rag reporting of 'sustainable production' even more laughable. Further, you may recall that Bleimann (2007) spoke for many of us in the aroma trade, when he commented that Sandalwood oil Australian is not a practical replacement for Sandalwood oil EI in perfumery formulae. Mount Romance  are still emphasising the use of aboriginal labour, this time publicising aboriginal sandalwood sourcing. As we mention in the v 1.04 update mentioned above, the MD of Mount Romance was previously associated with crocodile & turtle farming, and even now Mount Romance has a strong connection with emu oil promotion (previously, in 1981, Birkbeck reportedly took charge of a "forgotten peoples" emu company in Wiluna, W. Australia). Opposition to emu farming in Australia by the Australian Royal Society for the Prevention of Cruelty to Animals, can be viewed at http://www.rspca.org.au/pdf/B_policystatements.pdf

So, at a time when the cosmetics industry is getting out of animal products (for example, see the shark liver oil saga in v 1.04), just what do the decision-makers at Givaudan think they will achieve with this controversial buying arrangement? Cropwatch predicts (in our humble opinion of course) that the agreement is not exactly going to be ecstatically received by animal lovers, vegetarians, vegans, eco-supporters and perhaps not even by the green movement in general. Unfortunately, Givaudan are not the first to want to get into bed with Mount Romance over Australian sandalwood oil - Aveda have reportedly entered a similar arrangement (see v 1.04 update).  But now we also learn that Lush are reportedly joining the goldrush too, by signing up with the Australian sandalwood producer TFS Corporation, in anticipation of their commercial sandalwood oil production starting in 2011. All this activity is pretty strange, because up to now, the major market for Australian sandalwood oil has been, err, Australia! Further, direct buying by end-users from the producers may well cut out the middle man, but it further reduces the already fragile position of essential oil traders, who serve to buffer the market in times of shortage, provide forward cost-stability under contract, and provide superior ingredient location services to many buyers. It is another sign that the fragrance industry used to be more a professionally run, mutually co-operative endeavour, but now some puffed-up corporate big-shots are pursuing their own individual company agendas to the detriment of all others, which can only fragment & weaken the industry overall. 

Givaudan do seem to have entered a vote of confidence in coumarin's future, however, with the recent announcement of a 3-cornered arrangement for the 'sustainable' sourcing of tonka beans (for the production of tonka bean absolute, a rich source of natural coumarin) between the Criollo people of the Caura basin in Venezuela, the charity Conservation International & Givaudan themselves.

Meanwhile the debate about coumarin toxicity continues, Oko-test (the German consumer organisation's organ) has also run the story on the BfR opinion. We understand (if we have translated correctly) that in another section of the current magazine there is news that highest coumarin content found in a retailed cosmetic products by Oko-test was in a self-tanning lotions (37mg coumarin/Kg) which approximated to a 0.18 mg application of coumarin from one single eight gram application of tanning lotion for the body (per day). This is so far under the TDI that Oko-test recommend the BfR drop the regulation of coumarin in cosmetics altogether (thanks to Kendra for the translation).
Tony Burfield.

Refs:

Bleimann K .(2007) - see http://www.cropwatch.org/Kim Bleimann's lecture.pdf

Tonts M & Selwood J (2002) “Niche Markets, Regional Diversification and the Reinvention of Western Australia’s Sandalwood Industry” Tijdschrift voor Economische en Sociale Geografie 94(5), 564-575.

Technorati Tags: Givaudan,Quest,Mount Romance,sandalwood,emu oil,coumarin,coumarin toxicity

Cropwatch Threatened Species Update Feb 2008

Cropwatch Threatened Aromatic Plants Used in the Aroma & Cosmetic Industries v 1.04 Feb 2008

The fourth update of Cropwatch's Threatened Species used in the Aroma Industry is out & can be found at http://www.cropwatch.org/v 1.04.pdf Its scope is now broadened to cover both the Aroma & Cosmetic Industries. For those of you who have not browsed the 81-page feature, it is divided into two parts. The first is a brief summary of topics relevant to aromatic plant conservation, and the second larger part is an alphabetical listing of the threatened aromatic species, covering geographic distribution,  IUCN status and any listings by other conservation organisations, with notes about the materials themselves. This new version also contains an updated section on unethical animal products used in cosmetics - such as oils derived from shark-livers, green turtles and emus. We have also slightly extended the biopiracy section to cover the activities of a US company which has copyrighted a Peruvian natural product used as a foodstuff and in indigenous medicine, as previously first reported in Herbalgram. 

Technorati Tags: Cropwatch,Threatened Aromatic Plants,biopiracy

Let's Talk About Free Trade in the Aromatic Industry:

Theobroma cacao

I've been mulling over the somewhat obscure issues of fair trade in our industry, however, Valentines Day presented the perfect opportunity to end my procrastination and begin a conversation here.  Rob and I start our weekday mornings with a cup of coffee and Amy Goodman on Democracy Now.  If you are not familiar with this acclaimed journalist and Harvard University graduate, she's a champion of  peace and human rights, with battle scars from her work in East Timor in 1991 where she and fellow journalist Allan Nairn were badly beaten while witnessing a mass killing of Timorese demonstrators, now known as the Dili Massacre.  Usually, on Thursdays and Fridays Democracy Now is co-hosted by another award-winning journalist, Juan Gonzales, whose work includes Ground Zero illnesses and EPA coverups after 9/11.  Amy and Juan got right to the underbelly of the chocolate industry.  While mostly concerned with the chocolate you might get for a Valentine gift, our industry cannot ignore the fact that the very same cacao is harvested for cacao oleoresin and absolute, much sought after in the perfume and cosmetic industries.  Their guests were Christian Parenti, a correspondent for The Nation magazine and author of "Chocolate's Bittersweet Economy" in the February 4th edition of Fortune and William Guyton, President of the World Cocoa Foundation,  whose members comprise some of the big corporations who basically control the ports and set the prices.  I refreshed my coffee and settled in for what promised to be an interesting and juxtaposed debate.

Parenti began with his trip to the Ivory Coast (70% of the world's cacao comes from West Africa with 40% originating in the Ivory Coast).  He cited the Harkin-Engel protocol developed after real legislation failed, with the hope of volunteer participation from chocolate and cocoa industries.   The protocol was signed by industry leaders in 2001 and laid out a series of date-specific actions to eliminate the worst forms of child labor in the growing and processing of cacao beans and their derivative products, with a deadline of July 1, 2005 for reporting labor practices in cacao farming in West Africa.  The deadline was extended to July 2008 after the industry failed to reach substantial goals.   Parenti went to the Ivory Coast last October to fact check the claims of changes by the WCF and found them wanting.  He observed no substantive changes . . . "there were still many children working, using pesticides, machetes, carrying heavy loads. . . unable to attend school and being injured due to their labor."   He also cites the First Annual Report: Oversight of Public and Private Initiatives to Eliminate the Worst Forms of Child labor in the Cocoa Sector in Cote d'Ivoire and Ghana, prepared by Payson Center for Intentional Development and Technology Transfer/Tulane University.  This 271 page document is worth a complete read for those of you who like to follow the threads of bureaucratic intrigue.  The conclusion on page 50 summarizes the lack of attention or activity given (in spite of reams of reports from the companies, their trade organizations, NGO's and West African government officials) to the primary problem of child labor . . . "There is evidence that child labor is a problem in the cocoa supply chain and that the work of children is being used in Cote d'Ivoire and Ghana in a large number of agricultural tasks and at all times of the year."

The WCF claims to have spent tens of millions of dollars to eliminate child labor.  An NGO (International Cocoa Initiative) , identified by William Guyton as providing successful benchmarks, was established and Parenti found it in Ivory Coast to consist of one employee who shared an office in a basement of a law firm.  Parenti says the many claims of successful development projects did not pan out and he could find only one orphanage where most of the kids were not from the cacao sector and cited the head of the orphanage as saying perhaps 8 children over the last several months had been from the cacao sector.  William Guyton agreed with most of the findings in the Fortune  article, however, he spent a lot of time avoiding the key issue of child labor and attempting to focus on other issues - farming techniques for productivity, environmental conditions and social/health issues like HIV-AIDS.

When asked directly if raising the prices to the farmers themselves wouldn't address the need to employ child labor, Guyton cited that these are family farms with children working with their parents, not hired from other places.  He seemed to miss the point that if the farmers could afford to hire workers, it would benefit the children and free them to attend school.  The only successful program that he might be able to tout is the Sustainable Tree Crops Program, claiming that the farmers are receiving income improvements between 25-50%.  I would ask, if this is true, then why have the conditions for children (as well as the farmers themselves) not changed and improved?

What I've come away with (from the Democracy Now presentation, Christian Parenti's investigation, The Tulane Report and my own research) is:

1.)  Although farmers have attempted to establish co-operatives in attempts to circumvent the large companies who control ports/prices and establish collective bargaining for price structure as their own middle men, they are thwarted by international companies who loan them money and then claim that their crops are inferior, paying them less than needed to pay back their loans, many falling into debt.

2.)  The Cote d'Ivoire government is corrupt and not standing up to the international cocoa firms to establish better conditions for their own citizens, farmers and children.  In some instances the co-op members are arrested, after bribes are paid by the international companies to the police. 

3.)  The world market price determined globally on commodity exchanges and cocoa prices are favorable to the big companies, at about $2500 per metric ton.  International cocoa companies joined in a successful lobby in 1999 to eliminate minimum prices for farmers.  The farmers have no say in what they receive in payment, leaving them in a slave condition. 

We will address more of these issues in the future and hope that you will join the conversation as well as pass information on.

Cosmetic industry bullying & consumer victims

Tony Burfield Feb 2008.

The tendency of powerful corporations to pursue their marketing aims by totally ignoring consumer resistance or preference is becoming a worrying feature of modern society. And instead of taking a neutral stance on controversial safety issues, regulators in the US or EU bureaucracies may well side with the money-makers. We see this, for example, in the FDA’s failure to regulate cosmetic ingredient safety & so protect the US cosmetic & beauty product consuming public, and we see it in the EU Commissions determination to force GM technology on a reluctant Europe, most of which is markedly averse to buying GM products. Indeed on this point the UK is set for a forthcoming battle this year, as BASF attempts to plant GM potatoes for trials in a small field near Cambridge to the considerable annoyance of GM protestors, who will doubtless attempt to wreck the trial, as previously.

In the cosmetics area, the issue of phthalates as unsuitable or hazardous cosmetic ingredients raises the same degree of concern from many cosmetics  consumers as GM products do for food consumers in Europe. The cosmetic industry does not now defend, does not use (because it not allowed to) and keeps very quiet about the former use of those phthalates as diluents for resinoids, essential oils & perfumes – such as DIOP (di-isooctyl phthalate), DNBP (di-n-butyl phthalate), DEHP (di-2-ethylhexyl phthalate) etc. In fact in 2001 the EU passed regulations restricting the use of 6 phthalates (excluding DEP) in children’s products intended for age 0 to 3 years. But industry does continue to arrogantly defend the use DEP (diethyl phthalate) in the face of continued consumer opposition, which it thinks it can brush aside.

Diethyl phthalate (DEP) was given a clean bill of safety by the Cosmetic Ingredient Review Expert Panel (CIR) in 2002, & by the SCCP in 1992 (SCCNFP/0411/01) & in March 2007 – but Cropwatch had established in late 2007 that up to that point, the SCCP was incapable of conducting an independent literature search on any safety issue laid before it. It cannot be ruled out that its “expert” committee wasn’t prone to potentially be spoon-fed skewed or biased information. However that said, evidence of adverse health effects for DEP are pretty sparse. The National Resources Defence Council (NRDC) report on phthalates in air fresheners, & petition to the Environmental Protection Agency (EPA) & Consumer Product Safety Commission (CPSC), was summarily dismissed by the Fragrance Manufacturers Association of the United States (FMA) who, in a statement on Nov 7th 2007, called on the EPA to deny the citizens petition, maintaining that their conclusions on phthalates in air fresheners were ‘baseless & irresponsible’. Sathyanarayana et al (2008) claim to have found phthalates in infant diapers,citing baby care products as possible sources of exposure. Again the FMA have been quick to criticize this study. In an earlier study (TNO 2005), Greenpeace Netherlands commissioned the TNO to analyse 36 perfumes, 35 of which contained phthalates, 34 of which contained DEP, and 19 of which contained DEHP.  The TNO report eliminates the polymer spraying parts of the perfume containers as a source of phthalates.

If it is (now) true that the majority of the fragrance industry does not use phthalates other than diethyl phthalate, it still needs to explain why a range of phthalates often appears in the detailed analysis of perfumes. However in spite of the virtual dismissal of the problem by industry trade associations, many of us who aren’t career toxicologists making second-hand reassurances, but who actually work hands-on within the cosmetic industry, can name a handful of companies who still occasionally use phthalates other than DEP. Further, ingredient processing where molecular distillation employs co-solvents, or leaching from processing & storage containers & pipework, could still prove to be the source of some of these minor phthalate contaminants It is certainly not good enough to for the assemblers of perfumes who manufacture perfume compounds from bought-in ingredients to throw their hands up in the air and say “we’re not guilty.” There is more to the story than this.

Finally, the fragrance manufacturing industry has to face the fact that however safe they may maintain diethyl phthalate to be, consumers don’t want the ingredient in their purchased cosmetics, and they don’t necessarily want to be bullied by industry into having to accept its presence. Ultimately, of course, it may be up to the consumers to buy their cosmetics from manufacturers with a “no phthalates” policy.

References

Sathyanarayana S., Karr C.J., Lozano P., Brown E., Calafat A.M., Liu F., Swan S.H. (2008) "Baby care products: possible sources of infant phthalate exposure." Pediatrics 121(2), 260-268, or available on-line at http://www.pediatrics.org/cgi/content/full/121/2/e260

Scientific Committee on Consumer Products (SCCP), “Opinion on Phthalates in Cosmetic Products," FR/07/69, adopted at its 11th plenary meeting of March 21, 2007. Available online here in PDF format.

TNO-report R&I-A R 2005/011 "Phthalates & Artificial Musks in Perfumes" Greenpeace Netherlands, available online here in PDF format.

Technorati Tags: phthalates,perfume safety,perfume toxicity,fragrance safety,cosmetic safety

New pepper species found

Indian scientists report  the discovery of a new subspecies of pepper that has an essential oil yield from the fruit of up to 4 times the usual yield of cultivated peppers. With development it could lead to greater production and availability of oil. Not too many details in this article from the Financial Express, but it was found in the wild in the Agasthyamala belt of the Western Ghats in Kerala State.

Probably not much effect on the aromatherapy community right now, but it may bring out a new chemotype of pepper oil.

The pepper species was found by scientists from the Tropical Botanic Garden & Research Institute in Kerala, which is dedicated to the preservation of the biodiversity in Kerala state. The institute has active research ongoing in Phytochemistry and Ethnomedicine.

Coumarin: The Real Story (Updated Jan. 2008).

Copyright © Tony Burfield 2006-2008
A PDF copy of this paper is available on the Cropwatch web site.

What is it?

Coumarin (2H-1-benzopyran-2-one) CAS No 91-64-5, is a crystalline white solid when seen pure, with a hay-like, sweet aromatic creamy odour with certain nutty shadings, much used in synthetic form as a fragrance chemical for perfumes and for fragranced soaps and detergents. Coumarin has a widespread occurrence in natural products too (see separate section below), and is a representative of the lactones (where a lactone is an ester group integrated into a carbon ring system).

 

References:

BfR (2007) – see http://www.bfr.bund.de/cd/10569

Born S. L., Rodriguez P. E., Eddy C. L. & Lehman-McKeeman L. D. (1997) “Synthesis and reactivity of coumarin 3,4-epoxide.” Drug Metabolism and Disposition 25, 1318-1323.

Carlton B. D., Aubrun J-C. & Simon G. S. (1996) “Effects of coumarin following perinatal and chronic exposure in Sprague-Dawley rats and CD-1 mice.” Fundamental and Applied Toxicology 30, 145-151.

Cohen A.J. (1979) “Critical Review of the toxicology of coumarin with special reference to interspecies differences in metabolism and hepatoxic response & their significance to man” Food Cosmet. Toxicol. 17, 277-289.

Fentem J. H. & Fry J. R. (1991) “Comparison of the eˇects of inducers of cytochrome P450 on Mongolian gerbil and rat hepatic microsomal monooxygenase activities.” Xenobiotica 21, 895-904.

Floc’h F. (2002) “Coumarin in Plants and Fruits: Implications in Perfumery.” Perf. & Flav. 27 (Mar/Apr 2002), 32-36.

Givel M. (2003) “A comparison of US and Norwegian regulation of coumarin in tobacco products.” Tobacco Control 12, 401-405

Hadidi H., Zalsen K., Idle J.R. & Cholerton S. (1997) "A single amino acid substitution (Leu160His) in Cytochrome P450 CYP2A6

IKW (2008) – see http://www.ikw.org/pages/prodgr_details.php?info_id=304&navi_id=km&subnavi_id=aktuelles&page_title=Körperpflegemittel

Kaighen M. & Williams R.T. (1961) "The metabolism of 3-14C coumarin" Journal of Med. Chem 3, 25-43.

Lake B. G., Gaudin H., Price R. J. and Walters D. G. (1992a) “Metabolism of [3-14C]coumarin to polar and covalently bound products by hepatic microsomes from the rat, Syrian hamster, gerbil and humans.” Food and Chemical Toxicology 30, 105-115.

Lake B. G., Osborne D. J., Walters D. G. and Price R. J. (1992b) “Identification of ohydroxyphenylacetaldehyde as a major metabolite of coumarin in rat hepatic microsomes.” Food and Chemical Toxicology 30, 99-104.

Lake B.G., Gray T.B.G., Evans J.G., Lewis D.F.V., Beamand J.A. & Hue K.L. (1989) "Studies on the mechanism of coumarin-based toxicity in rat hepatocytes: comparison with dihydrocoumarin and other coumarin metabolites.” Toxicology & Applied Pharmacology 97, 311-323.

Lake B.G. (1999) “Coumarin Metabolism, Toxicity & Carcinogenicity: Relevance for Human Risk Assessment.” Food & Chemical Toxicology 37(4), 423-453.

Lake B.G., Gray T.J.B. (1999) "Studies on the mechanism of coumarin-induced toxicity in rat hepatocytes: Comparison with dihydrocoumarin and other coumarin metabolites." Toxicology and Applied Pharmacology 97(2), 311-323.

Norman R. L. & Wood A. W. (1984) “o-Hydroxyphenylethanol, a novel lactone ring-opened metabolite of coumarin.” Drug Metabolism and Disposition 12, 543-549.

Steensma A., Beamand D.G., Walters D.G. et al. (1994) “Metabolism of Coumarin and 7-ethoxycoumatrin by rat, mouse, guinea pig, Cynomolgus monkey & human precusion-cut liver slices” Xenobiotica 24, 893-907.

Vocanson M., Goujon C., Chabeau G., Castelain M., Valeyrie M., Floc’h F., Maliverney C., Gard A. & Nicolas J.F. (2006) “The Skin Allergenic Properties of Chemicals may depend on Contaminants” Int Arch Allergy Immunol 140, 231-238

2. The NTEF’s campaign against the coumarin-containing Angel perfume2.

The Las-Vegas based NTEF (National Toxic Encephalopathy Foundation) has received some media attention over allegations that Clarins Angel perfume (Thierry Mugler) contains toxic ingredients causing (amongst others) ocular damage. It appears that NTEF president Angel de Fazio had filed a lawsuit in the District Court in Clark County Nevada against Clarins in October 2004 claiming that one spray of the company's Angel Parfum had left her permanently disabled (Montague-Jones 2007b). The same report reveals that, again allegedly according to Clarin’s legal spokesperson, de Fazio's claims had been dismissed in January 2007, the court ruling “that the allegations were without merit and brought in bad faith. She was ordered to pay Clarins $77,851 in costs, fees and sanctions”.

Earlier, Montague-Jones (2007a) had reported that the NTEF had stated that Angel Parfum fits the FDA definition of a health hazard because it contains the scent coumarin, which it considers to be a dangerous poison. The Aromaconnection blog (www.aromaconnection.org) also reported the story on 12th Nov 2007, informing that the FDA has accepted a petition from the National Toxic Encephalopathy Foundation (NTEF) to have Angel Perfume declared "Misbranded", and had asked that its importation be halted until the issue is resolved. Nina Immers posted a long comment to this carried item (Immers 2007) reeling off some well-known toxicology studies on the potential hazards associated with the uncontrolled use of perfumery ingredients. Searching for any comments relevant to Angel perfume, there is a statement that coumarin is hepatotoxic in mice because it is metabolised to coumarin 3,4-epoxide, which has been linked to tumour formation in rats, and it is claimed that there is evidence that this metabolic route occurs in humans. Although Cropwatch was initially doubtful about the validity of this point, we do think that this area needs to be clarified by further research, to examine whether there is a quantifiable risk to the small number of people that cannot detoxify coumarin by the 7–hydroxycoumarin route, as mentioned elsewhere in this document.

Cropwatch had some previous correspondence with de Fazio in Jan 2007, where we commented that the analysis of Angel perfume available at http://www.national-toxic-encephalopathy-foundation.org/oculartest0001.pdf. was extremely poor and that perhaps Cropwatch could have provided a more comprehensive analysis3. We also asked if any the components allegedly responsible for ocular damage caused by Angel perfume had been identified (actually stated as damage to the cornea), Angel de Fazio indicated (at the time)that this information was not available.

3 You could take the view that Angel by Thierry Mugler (Clarins) has the elements of a chypre fragrance (patchouli-evernyl accord), but more importantly is perhaps the first ground-breakingly successful "gourmand" fine fragrance. It is very sweet, having chocolate, red berry, praline, vanilla & cassis aspects. In a comprehensive analysis, you might expect to find veltol, patchouli, evernyl, hedione, frambinone, vanillin, canthoxal, a cassis base and certain lactones present.

Cropwatch was uncertain why Angel perfume had been particularly identified for criticism since there are fragrances still currently available arguably with higher coumarin contents - for example the original "Joop Homme" (Joop 1989) or "Le Male" (Jean Paul Gaultier 1995). Further, an NTEF press release on Aug 27th 2007 seemed to confuse the actual ingredients in Angel perfume with allergens required to be disclosed by labeling. A further NTEF news release of 27th Oct 2007 by de Fazio that maintaining that coumarin is a harmful perfumery ingredient is supported by Jack D. Thrasher, Ph.D., who is described as a "Toxicologist/Immunotoxicologist/Fetaltoxicologist". Unfortunately almost all the supplied references supposedly supporting the case do not actually concern coumarin at all - they concern coumarins such as warfarin, so Cropwatch can’t see this feature actually contributes anything to the case. Nevertheless Montague-Jones picked up the NTEF suggestion that coumarin affected prenatal development & reported it in Cosmetic-Design (Montague-Jones 2007c), & subsequently the article was circulated to the membership of several perfumery trade organisations. We believe this story, which has nothing to do with coumarin, originates from two studies by Wesseling et al. (Wesseling et al 2000; Weisling et al. 2001) which refer to pre-natal etc. exposure studies to the oral anti-coagulants acenocoumarol, phenprocoumon & coumadin (WarfarinÔ) (“coumarins”), and acenocumarol & phenprocoumarol respectively, all of which are capable of crossing the placenta and may affect the central nervous system. Coumarin however is not an anti-coagulant (Feuer 1974).

To summarise, Cropwatch believes that the NTEF haven’t (yet) made a convincing case that coumarin is a dangerous perfumery ingredient presenting quantifiable risks to cosmetic users.

2.Adapted from the author’s blog posting on www.aromaconnection.org

Coumarin-containing Natural Products.

Coumarin occurs widely in natural products, generally being liberated from the corresponding glycoside (melilotoside) on drying coumarin-containing herb material. Dicoumarol is a microbiological biotranformation product in spoiled Melilotus Clover and other hay products, and its presence in fodder at >10ppm is cause for concern, as it is responsible for fatalities by hemorrhaging in cattle. This is because dicoumarol interferes with vitamin K reductase in the liver and the liver is unable to reactivate vitamin K, which leads to a decrease in vitamin K-dependent clotting proteins. The study of this compound paved the way to the discovery of anti-coagulant drugs such as warfarin.

Coumarin occurs widely in natural products; the following natural aromatic materials are of note:

Some Natural Coumarin Sources	Notes
Anthoxanthum odoratum L. Flouve oil	Both essential oil and absolute produced.
Carphephorus odoratissmus (J.F. Gemel)syn Liatris odoratissima Mich. syn. Trilisia odoratissima (J.F. Gmel.)Cass. Deer tongue or Liatris	1.6% coumarin. Ratio of coumarin: dihydrocoumarin: 2,3 benzofuran in volatile fraction of extract 1:3:20(Appleton & Enzell 1971).
Cinnamomum cassia J. Presyl. Cassia oil	Coumarin 4-11% (Burfield 1999). Coumarin to 8.73% (TNO 1996) Eu Pharm V (2) allows 1.5 to 4.0% coumarin in cassia oil monograph.
Cinnamomum zeylanicum Cinnamon bark & leaf oils	To 0.3%; rarely to 0.7%.
Dipteryx odorata (Aubl.) Wild. & sometimes D.oppositifolia Tonka bean absolute	1-3%, or up to 10% coumarin in tonka beans (Hagers Handbuch 1973); also dihydrocoumarin, o-coumaric acid, ethyl & methyl meliotate etc (Ehlers et al. 1996). Tonka absolute contains up to 65% coumarin
Galium odoratum L. syn. Asperula odorata Woodruff absolute & concrete	Variable; coumarin content develops on drying herb, although headspace of freshly cut woodruff found to be 80% coumarin (Surburg et al. 1993). Used in alcoholic beverage flavourings (e.g. vodka).
Hierochloe odorata (L.) Beauv Sweet grass	Use to flavour vodka in Russia.
Lavandula spp. Lavender & Lavandin qualities.	Lavender absolute to 8.0% coumarin; lavandin absolute to 5.0% coumarin. Spike lavender oil to 0.3% coumarin.
Lolium perenne L. & other spp. incl. Phleum pratense (Timothy grass), Poa pratensis L. (Meadow grass), Cynosurus cristatus (Crested Dog’s-Tail), Anthoxylum odoratum L. and Melilotus spp. Foin oil.	Essential oil and absolute produced. Foin essential oil contains some 8% coumarin.
Melilotus alba Medik. Bokhara Clover, or White Sweet Clover	Less used than Common Melilot (q.v.)
Melilotus officinalis L. (Pallas) Common Melilot or Yellow Sweet Clover	0.9% coumarin on dry weight basis. Wagner (1996) says 0.25-0.45% coumarin in herb, together with umbelliferone, scopolin etc.
Mentha spp. Peppermint oil	20 ppm (TNO 1996)

Table 1: The occurrence of coumarin in some common herbs & natural products.

Coumarin also occurs in trace amounts in the oils of:

Billy Goat Weed Ageratum conyzoides L.
Sweet wormwood Artemisia annua L.
Mugwort Artemisia vulgaris L..
Carrot Seed oil Daucus carota L. ssp sativus (Hoffm.) Arcang.
Champaca Michelia champaca L.,
Narcissus spp.
Clary sage Salvia sclarea L.

Melilotus leaves from Melilotus officinalis L. have been used to flavour snuff & tobacco. Tonka bean absolute, deertongue absolute & melilotus absolute find some uses in perfumery, but woodruff absolute is no longer much used, apart from flavouring wines. Coumarin derivatives such as the sweetly herbaceous 7-hydroxycoumarin (umbelliferone) also occur in natural products (e.g. in lavender absolute from Lavandula angustifolia) but derivatives like herniaren are banned by IFRA.

Coumarin in Flavourings.

Use of coumarin and coumarin-containing herb extracts was common in earlier times. Walter (1916) relates the use of woodruff extract from the fresh flowering herb in the preparation of lemonade, but remarks that it tends to be weak and prone to cause turbidity, and gives an alternative recipe for woodruff flavouring constructed from synthetic coumarin, alcohol and tonka bean tincture. Use of woodruff extract in cola, caramel, gooseberry and other flavourings is also detailed, and the use of tonka essence containing coumarin, vanillin etc is also outlined for flavouring of fondants.

Earlier reports of the toxicity and carcinogenicity of coumarin are now believed to be due to impurities, but coumarin is banned in foods in USA (21CFR 189.130), Japan, India, & the EC, and was banned in Germany from 1970 to 1991 (the ban is now replaced by a concentration limit) etc. Since many derivatives of coumarin are commercial poisons, e.g. warfarin, the well-known rat poison, it has been difficult to persuade people of coumarin’s safety. However a detailed discussion of the beneficial uses of Melilotus extract & coumarin in phytotherapy (and there are many) & any remaining toxicological issues are given in a Meliltotus monograph by Mills and Bone (2000).

The FDA dubiously identified coumarin as a carcinogen in 1954. Subsequent studies initially upheld this opinion, but then disproved it. The net result is that because of the controversy (see elsewhere in this document), it cannot be added to foods (although it is famously naturally present in many, including spices (cinnamon), cherries, apricots, green tea, licorice & strawberries!).

In the EU, flavourings are regulated according to the Articles of the European Council’s Directive on food flavourings. Coumarin was placed in Annex II of this Directive (88/388/EEC) in 1988, which was subsequently amended by 91/71/EEC and implemented into UK national law in the Flavourings in Food Regulations 1992: You might remember, that coumarin had been restricted with respect to its allowable concentration in foodstuffs because of allegations of (non-linear dose related) rat & dog carcinogenicity which occurred at high levels of coumarin administration. These considerations caused the regulators to limit coumarin concentrations in food & beverages to 2 mg/Kg, except for limits for chewing gum (50 mg/Kg), alcoholic drinks (10mg/Kg) & caramel confectionery (10mg/Kg). However the EU Scientific Committee for Food (1997) recommended the lowering the coumarin limit to the limit of detection in food, (then 0.5 mg/Kg). However, we know that the metabolism of coumarin proceeds through a different major route of 7-hydroxylation in humans compared with the 3-hydroxylation pathway in rats (Cohen 1979, Fentem & Fry 1993, Kaighen & Williams 1961, Lake et al 1989), further species to species differences being investigated for example by Fenton & Fry (1993), who found that a hepatotoxic route involving 3-hydroxylation and involving a 3,4-epoxide occurs in the rat, but not in baboons, gerbils, some strains of mice, and man. This hypothesis had also been muted by Steensma (1994) amongst others, and was further explored in Lake's paper with Gray (1999), who fed dihydrocoumarin to rats (which cannot form the 3,4 epoxide metabolite) and found no hepatocarcinogenic effect. As was discussed in detail earlier in this document, the existence of genetic polymorphism in humans with regard to the existence of different metabolic detoxification routes for coumarin has brought us to a situation where EFSA has recommended at TDI for coumarin of 0-0.1 mg/Kg body weight.

Coumarin in Perfumery.

Coumarin has a history of importance in perfumery, being the first synthetic (synthesised by W.H. Perkin 1868) to be used in a fragrance - Fougère Royale (Houbigant), where coumarin was combined with lavender, citrus and woody notes.- and since that time coumarin has been fundamental to the fougère perfumery accord, together with lavender and bergamot oils. Synthetic coumarin is used in large volumes in fragrances.

Coumarin has been approved for perfumery use, but was identified as a fragrance allergen by the SCCNFP/0017/98, although many perfumery professionals have refused to believe that pure coumarin is an allergen (see below). Coumarin has been regulated within the 7th Amendment of the Cosmetics Directive (76/768/EEC) such that coumarin requires labeling if present at concentrations of >10ppm in fragrances leave on products, or >100 ppm in fragranced products washed off the skin. Floc’h et al. (2002), Vocanson et al. (2006) & Vocanson et al. (2007) have published data supporting their view that pure coumarin is not a sensitiser, but rather it is impurities that elicit any alleged reaction (see below), an opinion which is widely accepted by the technically-minded in industry, but not, apparently, by the SCCP.

Coumarin as a Sensitiser (?).

An article by François Floc’h et al. (2002), of Rhodia Perfumery & Specialities, looked at pure coumarin applied in homogenous form to the skin of animals and humans, and concluded that coumarin is not a dermal allergen. Coumarin was one of the items you will remember cited in the SCCNFP position paper for Fragrance Allergy in Consumers (SCCNFP/0017/98 final Dec 1999) as being a skin sensitiser, this being the conclusion of previous COLIPA and RIFM opinions. Previous work by Malten K.E. et al. (1984), De Groot A.C. et al. (1988), Larsen W. et al. (1996), and Van Joost T et al. (1985) on coumarin was also reviewed by François Floc’h et al. who commented, amongst other things, on the lack of scientific rigor, and found no statements of the purity of the materials previously used, and who questioned the homogeneity and the stability of the coumarin in petrolatum suspension. Floc’h et al. further indicated the above work failed to distinguish allergy to coumarin and cross-reaction to allergens for which coumarin might be an indicator.

The SCCP Opinion on coumarin as a sensitiser SCCP/0935/05 (adopted 20th June 2006) considers whether coumarin of >99.99% purity had any sensitising properties (industry claims that it doesn’t), & if it doesn’t, whether the Opinion on Fragrance Allergy SCCNFP/0017/98 would need to be changed. The committee concluded that coumarin of 99.9% purity when patch tested at 2% would be able to elicit allergic contact reactions in humans.

A further published paper from Vocansen et al. (2007) on the non-allergenicity of pure coumarin, indicates that dihydrocoumarin, an contaminant of impure coumarin, promotes cell proliferation in the LLNA test whereas pure coumarin does not. The authors state that “that pure coumarin is endowed with very weak sensitizing capacities, if any, and suggest that the presence of contaminants in coumarin preparations may account for the previously reported allergenic properties of coumarin.” All we need now is for the SCCP policy on this issue to come in line with the available evidence (don’t hold your breath).

Cropwatch Comments (from July 2006).

Although the SCCP Opinion heavily criticises various published papers/abstracts/posters by Vocanson et al. (2006), Masamoto (2001), CIT (2001) & INSERM (2003/2004) on regarding alleged coumarin sensitisation on various grounds (i.e. is confusing, there is lack of evidence etc.), those very same remarks apply to their own Opinion. The SCCP document is poorly laid out with lack of clear headings, so that it is not immediately apparent what study you are reading about (until the reader has gone over the paper several times). [The key to understanding the Opinion is that new evidence is considered under various headings: Patch testing, Animal data & LLNA (local lymph node assay) studies, with the identity of the study under consideration confusingly set out in normal type face towards the right hand margin at the bottom of the relevant text (instead of as a heading at the top)]. The discussion 3.3.14 needs rewriting with clear references to the work they are criticising.looks half finished – sloppily, the Vocanson et al. paper is not fully referenced (full details below)

The SCCP Opinion that coumarin of 99.9% purity when patch tested at 2% would be able to elicit allergic contact reactions in humans, seem to us to be largely based on the findings of the study by Vocanson et al. (2006), who claim that they found a reaction of only one subject in 512 hospital patients to pure coumarin (although, on a quick read-through, the SCCP Opinion seemingly only accounts for 510). Commercial samples of coumarin with coumarin derivatives as impurities were found to be weak or moderate sensitisers by the Vocanson team. The SCCP seems to have seized on this one reaction and on the reaction of an individual positive from 101 patients positive to the fragrance mix (of which coumarin is not a component) as evidence that coumarin is a sensitiser. Crucially, the discrepancy between the Vocanson team’s finding of one positive and the SCCP’s reading of two positives is not explained, and presumably the SCCP did not bother to contact the authors for an explanation of why they had dismissed one of these positive reactions.

The SCCP wastes our time reporting on the evaluating an abstract by Masamoto (2001) and concludes, unsurprisingly, there is not enough evidence presented. The SCCP do not provide an explanation of why they were unable to obtain the full paper (maybe they are unable to cope with articles written in Japanese ?).

Cropwatch can only conclude the following:

1. That this SCCP Opinion SCCP/0935/05 only further establishes that the evidence for pure coumarin as a sensitiser is extremely weak. The SCCP defended their previous Opinion on coumarin only by nit-picking at the paper by Vocanson et al. (2006).

2. That criticism by the SCCP of the determinations of the purity of coumarin presented in the publications considered is a bit rich, considering Floc’h’s remarks (Floc’h 2002) that previous work up by Malten KE et al. (1984), De Groot AC et al. (1988), Larsen W. et al. (1996), and Van Joost T et al. (1985) had not paid any/sufficient attention to the issue. If the SCCNFP themselves had looked at the coumarin purity issue more closely in the first place, they would not have classified coumarin as a sensitiser in SCCNFP/0017/98 final Dec 1999.

3. We feel that the SCCP are now adopting a different set of evaluative criteria towards new submitted evidence on coumarin, in order to make judgments that support their previous Opinions – clearly they are being defensive rather than objective.

4. If the SCCP had contacted the authors of the papers on coumarin sensitisation that they were reviewing in SCCP/0935/05 for clarification/further information, it is probable that a different outcome would have resulted. The fact that this was not done has to be seen as having a political dimension.

5. The matter of whether it should be required by law that coumarin – a weak sensitiser at best - should need labeling as required under the 7th Amendment to the Cosmetics Directive, now needs investigation by Judicial Review. Further, the assumption that natural botanical products which contain coumarin are sensitising also needs reviewing; deertongue incoloure (which has a high coumarin content) was after all, previously reported non-sensitising by RIFM (Opdyke D.L.J. 1976)

References.

Appleton R.A. & Enzell C.R. (1971) “Triterpenoids & aromatic components of deer tongue leaf” Phytochemistry 10, 447-449.

CIT (2001): CIT/Study No. 21214 TSS/RhodiascentTM Coumarine/Rhodia Services – RSP 13 Dec 2001

Cohen A.J. (1979) “Critical Review of the toxicology of coumarin with special reference to interspecies differences in metabolism and hepatoxic response & their significance to man” Food Cosmet. Toxicol. 17, 277-289.

Clarke G.S. (1995) “Coumarin” Perf & Flav. 20, (Nov/Dec 1995) 23-34.

de Groot, A.C. et al. (1988) “Allergens in Cosmetics” Arch. Dermatol. 124, 1525-1529.

Ehlers D. et al. (1996) “Reducing the coumarin content of tonka bean extracts using supercritical CO2.” Int J. Food Sc & Techn 31, 93-95.

Felter S.P., Vassallo J.D., Carlton B.D. & Daston G.P. (2006). “A safety assessment of coumarin taking into account species-specificity of toxio-kinetics”. Food & Chem. Toxicol. 44, 462-475.

Fentem J. H. and Fry J. R. (1991) “Comparison of the e€ects of inducers of cytochrome P450 on Mongolian gerbil and rat hepatic microsomal monooxygenase activities.” Xenobiotica 21, 895-904.

Feuer G. (1974) “The metabolism & biological actions of coumarins.” Progress in Medicinal Chemistry 10, 85-158.

Floc’h F. (2002) “Coumarin in plants and fruits: implications in perfumery.” Perf. & Flav. 27 (Mar/Apr 2002), 32-36.

Feuer G (1974). “The metabolism & biological actions of coumarins.” Progress in Medicinal Chemistry 10, 85-158.

Immers N. (2007) http://www.aromaconnection.org/2007/11/ntef-attacks-an.html#comments

INSERM U503/Société Rhodia Services. “Evaluation du potential de sensibilisation cutanée des coumarines à l’aide du Local Lymph Node Assay murin.” 10th Dec 2003/26 mai 2004.

Kaighen M. and Williams R. T. (1961) The metabolism of [3-14C]coumarin. Journal of Medicinal Chemistry 3, 25-43.

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Larsen W. et al. (1996) “Fragrance contact dermatitis. A worldwide multi-centre investigation (part 1).” Am. J. of Contact Dermatitis 7, 77-83.

Malten K.E. et al. (1984) “Reactions in selected patients to 22 fragrance materials” Contact Dermatitis 11, 1-10.

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Montague-Jones (30th Oct 2007a) “Controversial safety attack on Clarins' perfume” - see http://www.cosmeticsdesign-europe.com/news/ng.asp?n=80996-clarins-fragrance-coumarin

Montague-Jones G. (6th Dec 2007b) “Clarins defends itself against interest group attacks”. Cosmetics-Design see http://www.cosmeticsdesign.com/news/ng.asp?id=81896-clarins-ntef-legal

Montague-Jones G. 21st Dec 2007c “Research group raises alarm over coumarin” Cosmetics-Design – see http://www.cosmeticsdesign-europe.com/news/ng.asp?n=82247-health-cosmeticscoumarin

Opdyke D.L.J. (1976) Food Chem Toxicol 14, (Suppl.) 743.

Steensma A., Beamand D.G., Walters D.G. et al. (1994) “Metabolism of coumarin and 7-ethoxycoumatrin by rat, mouse, guinea pig, Cynomolgus monkey & human precision-cut liver slices” Xenobiotica 24, 893-907.

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Vocanson M., Goujon C., Chabeau G., Castelain M., Valeyrie M., Floc’h F., Maliverney C., Gard A. & Nicolas J.F. (2006) “The skin allergenic properties of chemicals may depend on contaminants” Int Arch Allergy Immunol 140, 231-238.

Vocanson M., Valeyrie M., Rozières A., Hennino A., Floc'h F., Gard A. & Nicolas J.F. (2007) "Lack of evidence for allergenic properties of coumarin in a fragrance allergy mouse model." Contact Dermatitis 57(6), 361-4.

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Walter E. (1916) Manual for the Essence Industry John Wiley.