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January 07, 2008

Coumarin Again

We have a new developments over allegations of coumarin toxicity to humans. To recap, coumarin is commonly found in perfumes & cosmetics, because of its deliberate addition as a perfumery synthetic ingredient, and because of its widespread distribution in added natural aromatic materials (see Cropwatch article at http://www.cropwatch.org/nlet4art4.htm). Coumarin is not restricted IFRA, although it has been wrongly classified as a sensitiser by the SCCP [see Floc'h (2002) & Vocansen et al (2006)], but nevertheless must be labelled according to an adaptation of 7th Amendment of the Cosmetics Directive 76/768/EEC if its concentration in the final retailed product from whatever source is greater than 0.01% in products intended for rinsing off the skin, or 0.001% in leave-on products. 

In the EU, flavourings are regulated according to the Articles of the European Council’s Directive on food flavourings 88/388/EEC, 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, 0.5mg/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 heptatoxic 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 heptacarcinogenic effect. Lake's fairly thorough (1999) review paper pointed out (amongst other things) that dietary exposure to coumarin (0.02mg/day) plus cosmetic exposure to coumarin (0.04mg/day) sill adds up to a TDI which is still approx. 100 times less than the minimum figure causing observed adverse reactions in humans, and between 2000 and 3000 times lower than the dose necessary to produce liver tumours in rats. (Lake 1999). 

Now enter the Federal Institute for Risk Assessment (BfR), who just recently (20.12.2007) have maintained that they have "evaluated the analytical results of the controlling bodies of the federal states in order to assess the scale on which cosmetics contribute to consumer exposure to coumarin." They find that "it has not been fully elucidated whether coumarin taken in via the skin has a similarly harmful effect on the liver to coumarin ingested from the gastro-intestinal tract". Presumably they would cite in their defence of this position, the paper by Yourick & Bronaugh (1997) who found that coumarin rapidly penetrated rat & human skin and is not metabolised by enzymes in the skin. Coumarin is thereby presumed by rapidly enter the systemic circulation to be metabolised by the liver. So what, you may ask? Humans still are not at risk from heptacarcinogenic effects according to figures given by Lake (1999). But the BfR also states that consumers could already exceed the tolerable daily intake (TDI) of coumarin just by using cosmetics with high coumarin levels, an opinion at therefore at variance with Lake's (1999) findings. The president of the BfR Prof. Hesel says that coumarin should not be used in products for infants & toddlers as a precautionary measure. That statement you might think, comes 130 years too late, since coumarin has been extensively used at fairly  high concentrations in many fragrances for infant care products, since its commercial production in 1876, and infant toxicity has not been revealed to be a problem thus far. 

At least one perfumery organisation has commented internally to its members that Prof. Hesel has not understood the species differences relevant to coumarin metabolism. However Cropwatch can take a broader view. Firstly we don't know for sure that detoxification mechanisms in babies/very young children are exactly similar to those for adults. Secondly, the perfumery organisation that made the comment was only slightly acquainted with coumarin metabolism (as I was until recently) and hadn't allowed for the fact that not all humans metabolise coumarin via the 7-hydroxylation route - there some may a proportion of 'low 7-hydroxylators' (see Hadidi et al 1997).who may be more at rise to coumarin exposure. Further, all of use may use a proportion of other routes other than the major 7-hydroxylation route to detoxify coumarin. Obviously we need more research.to properly assess the risks. It is a matter of judgement how precautionary we need to be on restricting coumarin levels in cosmetics -obviously a harsh coumarin limit would severely affect not only the types of perfumes that could be sold (i.e. no traditional chypres) and the number of essential oils & absolutes that could be used. One further piece for consideration is contained in a paper published by Givel in 2003, who gives an insight into information on coumarin toxicity in tobacco perfumes, who continued use until 10 or 20 years ago demonstrates the conflict between a duty to protect the health of the people of the nation against the right to keep trade secrets (tobacco fragrance formulation). Givel reports that "despite known severe toxic and carcinogenic risks to humans, coumarin was also reportedly used as an additive in pipe tobacco in the USA at least as late as 1996 (and from cigarettes supposedly in 1985).   

References: 

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. 

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 

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

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 Assessement.” 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. 

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 

Further to my previous comments, now lets look further at The National Toxic Encephalopathy Foundation (NTEF) case which continues to generate a considerable amount of media coverage in their campaign against L'Oreal and the coumarin-containing perfume Angel in particular. Their case looks increasingly badly realised - Cropwatch has been sifting through some of the published papers cited by the President of the NTEF, Angel de Fazio to support her case that coumarin is a harmful perfumery ingredient (in the NTEF news release of Oct 27th 2007), supported by Jack D. Thrasher, Ph.D., who is described as a "Toxicologist/Immunotoxicologist/Fetaltoxicologist". We have found that most of the references do not actually concern coumarin at all - they concern coumarins - a world of difference. Here they are in detail 

1. Albert RE Allergic contact sensitizing chemicals as environmental carcinogens. Environ Health Perspect. 1997 September; 105(9): 940–948.
2. Gerard Van Den Berg*, Marius L. De Winter†, Wybo A. De Boer and Wijbe Th. Nauta. Inhibition of ß-glucuronidase by 2-diarylmethyl- 1,3-indandiones. Received 23 June 1975; accepted 23 October 1975. Available online 5 November 2002. Biochem Pharmacol. 1976 Jun 15;25(12):1397-403.
3. http://www.usp.org/pdf/EN/veterinary/phenylbutazone.pdf
4. Peter G. Dayton, Yavuz Tarcan, Theodore Chenkin, and Murray Weiner
The Influence of Barbiturates on Coumarin Plasma Levels and Prothrombin Response, J Clin Invest. 1962 February; 41(2): 300.
5. Ren, P, Stark, PY, Johnson, RL, Bell, RG. Mechanism of action of anticoagulants: correlation between the inhibition of prothrombin synthesis and the regeneration of vitamin K1 from vitamin K1 epoxide. J Pharmacol Exp Ther 1977 201: 541-546.
6. Wallin R, Martin L F Vitamin K-dependent carboxylation and vitamin K metabolism in liver. Effects of warfarin. J Clin Invest. 1985 November; 76(5): 1879–1884.
7. Marek LJ, Koskinen WC. Multiresidue analysis of seven anticoagulant rodenticides by high-performance liquid chromatography/electrospray/mass spectrometry. J Agric Food Chem. 2007 Feb 7;55(3):571-6.
8. A Taylor and M G Townsend, Some biochemical studies on warfarin resistance in the rat. Biochem J. 1970 July; 118(3): 56P–57P.
9. http://en.wikipedia.org/wiki/Coumarin
10. Wesseling J, Van Driel D, Heymans HS, Van der Veer E, Sauer PJ, Touwen BC, Smirkovsky M. Behavioural outcome of school-age children after prenatal exposure to coumarins. Early Hum Dev. 2000 Jun;58(3):213-24
11. Wesseling J, Van Driel D, Smrkovsky M, Van der Veer E, Geven-Boere LM, Sauer PJ, Touwen BC. Neurological outcome in school-age children after in utero exposure to coumarins. Early Hum Dev. 2001 Jul;63(2):83-9 

Working in reverse order, reference 11 deals with acenocumarol & phenprocoumarol exposure, whilst reference 10 deals with the after-effects of acenocoumarol, phenprocoumon & coumadin (Warfarin) exposure to prenatal etc. children. These findings are of interest to rat-poison users, but making an inference that coumarin would behave similarly to say, warfarin, is to say the least, unproven, if not pure conjecture. Reference 9 deals with a Wikipedia entry which isn't particularly damning about coumarin. References 8, 7, 6 & 5 also relate more to warfarin and anti-coagulant coumarin derivatives. Reference 2 concerns 2-aryldimethyl-indandiones which we will assume are absent in most perfumes - unless proof is furnished to the contrary. 

So really then there are slim pickings for a case against coumarin here, and to make any sort of case, it might have been far wiser to expand the 'low 7-hydroylators' hypothesis and other troubling aspects of coumarin metabolism set out in the first section of this note. 

Tony Burfield.

Posted by Tony Burfield on January 7, 2008 in Regulatory Issues, Research, Safety/Toxicity | Permalink

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