430 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Dose and effect The use of colourings in food is regarded as self-limiting and, subject to good manufacturing practice, no attempt is usually made to prescribe upper limits for the levels of application in particular foods. This factor, taken together with the possible presence of colourings in many articles of diet, consumed by both the very young and the very old, makes the task of safety evaluation much more exacting than it need be with cosmetics colours, where maximum levels of use can be prescribed for various appli- cations. Thus Davis and Fitzhugh (39) were able to establish 0.05øfo as a satisfactory no-effect level for Lithol red (D & C Red No. 10) in rats. Accepting that in such circumstances a reasonable safety factor (i.e. ratio between the maximum tolerated dose producing no ill-effects in animals and the likely total daily intake in man) such as 100 can be agreed upon, the levels of testing in animals are readily arrived at. Provided the maximum no-effect level is thus established in long-term lifespan studies in the animals, what happens at higher levels is of less importance as long as carcinogenesis is not involved. The colouring matters testing programme initiated by the Toilet Goods Association U.S.A., has been based on this approach (40). Finally, there exists the need to discriminate between colourings in- corporated in preparations whose use involves the likelihood of ingestion, and those products intended solely for external application. (Received: 14th April 1966) REFERENCES (1) Golberg, L. J. Soc. Cosmetic Chemists 15 177 (1964). (2) Cainan, C. D. J. Soc. Cosmetic Chemists 18 3 (1967). (3) Hansen, W. H., Davis, K. J., Fitzhugh, O. G. and Nelson, A. A. Toxicol. Appl. Pharmacol. 5 105 (1963). (4) Radomski, J. L. and Mellinger, T. J. J. Pharmacol. Exptl. Therap. 130 259 (1962). (5) Scheline, R. R. and Longberg, B. Acta Pharmacol. Toxicol. 9,11 1 (1965). (6) Ryan, A. J. and Wright, S. E. Nature 195 1009 (1962). (7) Daniel, J. W. Toxicol. Appl. Pharmacol. 4 572 (1962). (8) Ryan, A. J. and Wright, S. E. J. Phar•n. Pharmacol. 13 492 (1961). (9) Priestly, B. G. and O'Reilly, W. J. ,[. Pharm. Pharmacol. 18 41 (1965). (10) Webb, J. M., Fonda, Margaret and Brouwer, E. A. J. Pharmacol. Exptl. Therap. 137 141 (1962). (11) Webb, J. M. and Brouwer, E. A. Federation Proc. 21 449 (1962). (12) Andersen, C. J., Keiding, N. R. and Nielsen, A. B. Scan& J. Clin. Lab. Invest. 16 249 (1964). (13) Hess, S. M. and Fitzhugh, O. G. J. Pharmacol. Exptl. Therap. 11{ 38 (1955). (14) Fours, J. R., Kamm, J. J. and Brodie, B. B. J. Pharmacol. Exptl. Therap. 19,0 291 (1957). 1.q• Lindstrom, H. V., Hansen, W. H., Nelson, A. A. and Fitzhugh, 0. G. J. Pharmacol. Exptl. Therap. 1{9, 257 (1963).

THE TOXICOLOGY OF ARTIFICIAL COLOURING MATERIALS 431 (16) Lindstrom, H. V., Wallace, W. C., Hansen, W. H., Nelson, A. A. and Fitzhugh, O. G. Federation Proc. 22 188 (1963). (17) Tegeris, A. S. Toxicol. Appl. Pharmacol. 8 6 (1966). (18) Stokinger, H. E. and Mountain, J. T. Arch Env. Health 6 495 (1963). (19) Farmer, Madge, Grasso, P. and Colberg, L. Unpublished observations (1966). (20) Bowie, W. C., Arnault, L. T. and Lindstrom, H. V. Federation Proc. 24 392 (1965). (21) Colberg, L. Proc. Europ. Soc. Study Drugs Toxicol. 7 69 (1966). (22) BIBRA Annual Report. 22 (1965). (23) Levenstein, I. and Draize, J. H. In "Cosmetics and the Skin" Ed. by I. Lubowe and F. V. Wells, p.539 (1964). Reinhold, New York. (24) Levenstein, I. J. Soc. Cosmetic Chemists lõ 377 (1964). (25) Clayson, D. B. Chemical Carcinogenesis. 245 (1962). J. & A. Churchill, London. (26) Grice, H. C., Mannell, W. A. and Allmark, M. G. Toxicol Appl. Pharmacol. •1 509 (1961). (27) Mannell, W. A. Food Cosmet. Toxicol. 2 169 (1964). (28) Bonser, Georgians M. and Clayson, D. B. Rep. Br. Emp. Cancer Campn. No. 42. 457 (1964). (29) Grasso, P. and Colberg, L. Food Cosmet. Toxicol. 4 No. 3 in press (1966). (30) Grasso, P. and Colberg, L. Food Cosmet. Toxicol. 4 No. 3 in press (1966). (31) Hueper, W. C. and Payne, W. W. Arch. Env. Health 6 484 (1963). (32) Well, C. S., Carpenter, C. P. and Smyth, H. F. Arch. Env. Health ll 616 (1965). (33) Hansen, W. H., Fitzhugh, O. G., Nelson, A. A. and Davis, K. J. Toxicol. Appl. Phar- macol. 8 29 (1966). (34) Beck, F. and Lloyd, J. B. Adv. Teratol. 1 131 (1965). (35) Beaudoin, A. R. and Pickering, M. J. Anat. Rec. 137 297 (1960). (36) Christie, G. A. Nature 208 1219 (1965). (37) Luck, H., Walln6fer, P. and Bach, H. Pathol. g•licrobiol. 26 206 (1963). (38) Nagai, S. Science 130 1188 (1959). (39) Davis, K. J. and Fitzhugh, O. G. Toxicol. Appl. Pharmacol. 5 728 (1963). (40) Goulden, H. D. Drug Cosmetic Ind. 91 286 (1962). Introduction by the lecturer One of the weaknesses of this paper is that it makes very little reference to cosmetic colours as distinct from food colours, and there are good reasons for this: the lack of published work, of which many of you must be aware also the lack of practical experience in our own institute on these D & C and Ext. D & C colours. However, the general features are very much the same, and if one surveys the present situation there are really two key questions that one has to ask. Firstly, are the existing colourings, and particularly food colourings, capable of acting as sensitizers, and there Professor Calnan (41) gave us an indication. The question has also been raised whether colourings in cosmetics or in food are doing harm other than by causing sensitization, but of this I do not think that we have any evidence whatsoever. There are, however, differences in metabolic routes when materials of this sort are ingested or are introduced into the body by other means. For example, in the case of oral administration of tartrazine, sulphanic acid is excreted in the urine of man and the rat but no intact colouring. There is reduction of the azo-linkage in the intestinal tract by the bacterial flora, with decomposition of the molecule into two halves. When the material is given intraperitoneally there is free colouring in the urine and no sulphanilic acid, i.e. the tartrazine goes through the system intact. It is conceivable that if a colouring is absorbed from the skin, the ß (41) Cainan, C D., J. Soc. Cosinetic Chemists 18 3 (1967).