Coumarins carcinogenicity

Lake B. 1999. Coumarin metabolism, toxicity and carcinogenicity, relevance for human risk assessment. Food Chem Toxicol 37(4) 423-453. 

No epidemiological data relevant to the carcinogenicity of coumarin were available. There is limited evidence in experimental animals for the carcinogenicity of coumarin. 

Ueno, 1. Hirono, 1. (1981) Non-carcinogenic response to coumarin in Syrian golden hamsters. 

The carcinogenic properties of coumarins have been reviewed (74MI22401, B-80MI22404), as has their toxicity (B-72MI22400, 79MI22403). 

In workers, dusts may be irritating to the respiratory system. Coumarin may be a weak dermal sensitizer in sensitive individuals. Purity of the material can play a significant role in this regard. No other longterm effects of coumarin have been reported in humans. The International Agency for Research on Cancer (lARC) reviewed coumarin in 2000 and classified it in group 3, not classifiable as a carcinogen in humans. 

Bom S, Caudill D, Smith BJ, and Lehman-McKeeman LD (2000) In vitro kinetics of coumarin 3,4-epoxidation Application to species differences in toxicity and carcinogenicity. Toxicological Sciences 58 23-31. 

Among the synthetic musks used as perfumery fixatives, musk ambrette made from m-cresol is still very popular though it has been reported that many companies no longer use it as it has been declared as carcinogenic. Coumarin a major perfumery fixative and also a food additive is made from o-cresol. 

C-Substitution of coumarins and chromones has been observed in both rings in strongly acidic media, in which presumably it is a hydroxy-benzopyrylium cation that is attacked, substimtion takes place at C-6, for example nitration. This can be contrasted with the dimethylaminomethylation of chromone, iodin-ation of flavones or the chloromethylation of coumarin where hetero-ring substitution takes place, presumably via the non-protonated (non-complexed) heterocycle (CAUTION CH2O/HCI also produces some CICH2OCH2CI, a carcinogen). 

Inhibition of chemical carcinogen-induced neoplasia by coumarins and alpha-angelicalactone. Cancer Res. 39, 1651-1654. 

About 80 lactones have been identified in tobacco smoke. These compounds, especially they-butyrolactones, andothers, have alkylating potential and some have been reported to be carcinogenic in laboratory animals [Lawley (6A12)]. [see also Appendix 2, pp. 387-394) in (1870)]. Quantitatively, about half the lactones in the smoke consist of y-butyrolactone [lARC (6A10)] (about 10 pg/cigarette) and its derivatives 5-valerolactone and some alkylated and unsaturated 5-valerolactones, as well as coumarin [see pp. 427-430 in Wynder and Hoffmann (4332)], 6-methylcoumarin, and 3,4-dihydrocoumarin have also been isolated [Schumacher et al. (3553)]. The occurrence of coumarin derivatives in smoke could be due to pyrolysis of polyphenols with a coumarin structure. .. or of plant extracts added to tobacco to enhance flavour [see pp. 427-430 in Wynder and Hoffmann (4332)]. Coumarin itself is carcinogenic to rats after oral administration [lARC (6A10)]. 

As noted in the quotation from the 1986 lARC monograph, orally administered coumarin (2//-l-benzopyran-2-one) had been reported as carcinogenic in rats. The results reported from several studies on the tumorigenicity of coumarin eventually resulted in coumarin being removed from... 

According to lARC, no data were available to its Working Group on the carcinogenicity of coumarin in humans. After assessment of various studies in which coumarin was administered to laboratory animals, lARC concluded that the evidence was limited in laboratory animals on the carcinogenicity of coumarin. lARC described its overall evaluation of coumarin as a carcinogen as follows Coumarin is not classifiable as to its carcinogenicity to humans. ... 

Dickens, F. and H.E.H. Jones Further studies on the carcinogenic action of certain lactones and related substances in the rat and mouse Brit. J. Cancer 19 (1965) 392-403. Griepentrog, R Pathological-anatomical results on the effect of coumarin in animal experiments Toxicology 1 (1973) 93-102. 

Aflatoxins are highly toxic and carcinogenic coumarin derivatives of a complex structure, e.g. aflatoxin 17. It is formed as a secondary metabolite by Aspergillus flavus which occurs in mouldy food. 

European authorities have raised concern over the cou-marin content of cassia (BfR 2006 EFSA 2008). In the 1980s, coumarin was suspected to have genotoxic and carcinogenic effects, although more recent evidence suggests that coumarin is not genotoxic (Lake 1999 Sproll et al. 2008). As of 2008, the European Food Safety Authority indicated that the appropriate total daily intake (TDI) level of coumarin in foods was 0.1 mg/kg, and that intake of three times this amount for 1 to 2 weeks posed no concerns (EFSA 2008). The German Federal Institute for Risk Assessment (BfR)... 

---