FAO Nutrition Meetings
Report Series No. 48A
WHO/FOOD ADD/70.39
TOXICOLOGICAL EVALUATION OF SOME
EXTRACTION SOLVENTS AND CERTAIN
OTHER SUBSTANCES
The content of this document is the
result of the deliberations of the Joint
FAO/WHO Expert Committee on Food Additives
which met in Geneva, 24 June -2 July 19701
Food and Agriculture Organization of the United Nations
World Health Organization
1 Fourteenth report of the Joint FAO/WHO Expert Committee on Food
Additives, FAO Nutrition Meetings Report Series in press; Wld Hlth
Org. techn. Rep. Ser., in press.
SACCHARIN
The previous assessment was based on work performed in the 1950s
and a large number of new studies on saccharin alone are being
undertaken or are presently in progress. The results of further
experiments using mixtures of cyclamate and saccharin have now become
available for evaluation. These should be evaluated when the full data
have become available.
Comments
Calcium and sodium cyclamate have been evaluated previously by
the Eleventh Joint FAO/WHO Expert Committee on Food Additives in 1967.
The additional data now reviewed have thrown little further light on
the exact mechanism of the laxative effect or on the changes observed
in the cellular and subcellular structures of the gastro-intestinal
tract. These two problems have been left unanswered at the time of the
first review. There is now good evidence that a proportion of the
human population is able to convert cyclamate to cyclohexylamine and
it is likely that this conversion takes place as a result of the
activity of the microbial flora of the gut. Recent work has raised the
problem of mutagenicity of cyclamate as observed under various
conditions of testing but it is not possible to interpret these
findings in terms of human risk when taken in isolation. There is some
doubt whether the observed chromosomal changes are specific to
cyclamate. More serious are the findings reported in relation to
bladder carcinoma found after feeding very high doses of
cyclamate/saccharin mixtures and the more recent reports of the
production of bladder carcinoma following feeding of cyclamate alone.
it is difficult to extrapolate these findings to man on the data
available. Nonetheless, the new information together with the
previously available evidence on toxicity as well as the discovery of
the metabolic fate of cyclamate and the toxicity of cyclohexylamine,
counsels prudence in the future use of cyclamates in food and drink.
Cyclohexylamine, a known metabolite of cyclamate in some animals
and man, is itself further metabolized but not all of these
metabolites have been identified. One long-term study has resulted in
the production of a single bladder tumour but the number of survivors
was too small to allow adequate evaluation. Cyclohexylamine may have
been involved in the appearance of bladder carcinoma following
ingestion of large doses of cyclamate and cyclamate/saccharin mixture
by rats.
Evaluation
Because of the possible carcinogenic potential of cyclamate in the
rat, an ADI for this compound cannot be established at the present
time, and therefore the previously established temporary ADI is now
withdrawn. The use of cyclamate in the management of diabetes and
gross obesity was beyond the purview of food additive consideration.
REFERENCES
Abbott Laboratories (1967) Unpublished report submitted to WHO
Abbott Laboratories (1968) Unpublished report Submitted to WHO
Abbott Laboratories (1970) Unpublished report submitted to WHO
Bajusz, E. (1969) Nature, 223, 406
Batterman, R. C. (1966) Unpublished report to Abbott Laboratories,
326602 & 326723
Bein, H. J. et 1. (1967) Unpublished report submitted to WHO
Blocktüs, L. E. et al. (1968) Unpublished report to Abbott
Laboratories, 316811
Bryan, G. T. & Ertuürk, E. (1970) Science, 117
Buchel, L. & Guyonneau, M. (1963) Thérapie, 18, 953
Burbank, F. & Fraugment, J. F. (1970) Nature, in press
Carswell, T. S. & Morrill, H. L. (1937) Ind. Eng. Chem., 29, 1247
Chung, C. W. (1969) FDA report to NAS-NRC
Classen, H. G., Marquardt, P. & Späth, M. (1968) Arzneimittel-Forsch,
18, 590
Davis, T. R. A., Adler, N. & Opsall, J. C. (1969) Toxicol. appl:
Pharmacol., 15, 10
Dick, C. & Brava, C. G. (1970) Environ. Mutagen. Soc., 1st Ann.
Meeting, Abstr. 35
Dubois, K. P. & Kinoshita, F. (1968) Unpublished report to Abbott
Laboratories, 316807
Elliott, T. H. Lee, N. Y. & Tao, R. C. C. (1968) Biochemistry,
109; 11P-12P
FAO/WHO (1967) FAO Nutrition Meetings Report Series 44A; WHO/Food
Add./68.33
Fels Research Laboratory (1969) FDA Report to NAS-NRC
Feingold, B. F. (1968) Ann. Allergy, 26, 309
Ferrando, R., Hachet, B. & Boivin, M. R. (1968) Bull. Acad. Med.,
152, 36
Flinn, F. B. (1937) Unpublished report from FDA
Food and Drug Research Laboratories, Inc. (1969) Unpublished report to
Abbott Laboratories
Food and Drug Research Laboratories, Inc. (1970) Unpublished report to
Abbott Laboratories
Foster D. Snell, Inc. (1968) Food Cosmet. Toxicol., 6, 313
Freese, H., Jencke, T. S. & Rubenkoenig, H. (1964) Unpublished report
to Abbott Laboratories, 326401, 326723
Fritz H. & Hess, R (1968) Experiential (Zasel), 24, 1140
Ghiani, P. & Accame, R. (1969) Unpublished report submitted to WHO
Goldberg, L. et al.(1969) Soc. Tox. 8th Ann. Meeting, Abst. 107
Goldberg, L. et al. (1969) Toxicol. appl. Pharmacol., 14, 6541 (?)
Göttinger, E. et al. (1968)Wien. Kl. Wschr., 80, 329
Hellauer, H. (1968) 5th Int. Conf. Hyg. Prev. Med., Rome 1968
Huntingdon Research Centre (1967) Unpublished report submitted to WHO
Industrial Bio-test Lab. Inc. (1967) Unpublished report to Abbott
Laboratories
Industrial Bio-test Lab. Inc. (1968) Unpublished report to Abbott
Laboratories
Industrial Bio-test Lab. Inc. (1969a) Unpublished report to Abbott
Laboratories
Industrial Bio-test Lab. Inc. (1969b) Unpublished report to Abbott
Laboratories
Jackson, G. (1968) Unpublished report to Abbott Laboratories, 316812
Kennedy P. Arnold (1967) Unpublished report to Abbott Laboratories,
316748
Klotsche, C. (1969) Arzneimittel-Forsch, 19, 925
Lamberg, S. I.(1967) J. Amer. med. Ass., 201, 747
Lee, I. P. & Dixon, R. L. (1969) Toxicol. appl. Pharmacol., 14,
Abst. p. 654
Legator, M.S. et al. (1969) Science, 165, 1139
Lethco, E., Wallace, W. & Braunberg, R. (1969) FDA report to NAS-NRC
Lomonova, G. V. (1963) Gig. Trüda Prof. Zabol., 7, 51
Lorke, D. (1969) Arzneimittel-Forsch, 19, 923
Loser, E. (1970) Unpublished report submitted to WHO
Malletto, F. S. & von Haam, E. (1952) Arch. ind. Hyg. Occ. Med.,5,
311
Mauer, R. E & Szymauski, E.T. (1968) Unpublished report to Abbott
Laboratories, 316806
Mollet, M. (1966) Unpublished report to Abbott Laboratories, 316611-4
Olson, W. H. (1955) Unpublished report to Abbott Laboratories
Oser, B. L. (1968) Unpublished report to Abbott Laboratories, 316804
Oser, B. L. (1969) Unpublished report submitted to WHO and to Abbott
Laboratories, 316901
Oser, B, L., Carson, S. & Vogin, E. E. (1968) Nature, 220, 179
Palmer, K. (1968) 7th Conf. Manual Cytol. & Somatic Cell Genetics
Pitkin, R. M., Reynolds, W. A. & Filer, J. (1969) Proc. Soc. exp.
Biol. Med., 132, 993
Pitkin, R. M., Reynolds, W. A. & Filer, L. J. (1970) JAMA, in press
Pliss, G. B. (1958) Vop. Onkol., 4, 659
Price, J. M. et al. (1969) BIBRA Bull., 8(9), 456
Prosky, L. & 0'Dell, R. G. (1970) Fed. Abstr., 29, 1797
Radding, R. S. (1967) Unpublished report to Abbott Laboratories Ltd.,
326702, 326723
Renwick, A. G. & Williams, R. T. (1969) Proc. Bioch. Soc., 114,
Abst. 44
Roe, F. J. C., Levy, L. S. & Carter, R. L. (1970) Food Cosm. Tox.
8, 135
Rosenblum, I. (1968) Soc. Toxicol. 7th Ann. Meeting, Abst. 11
Rosenblum, I. & Rosenblum G. (1968) Toxicol. appl. Pharmacol., 12,
260 and 13, 339
Rudali, G., Coezy, E. & Muranyi-Kovacs, I. (1969) C. R. Acad. Sci.,
Paris, 269, 1910
Sax, K. & Sax. H. J. (1968) Japan J. Genetics, 43, 89
Sonders, R. C. (1969) Am. Soc. Pharm, Exp. Ther., August 1969
Sonders, R. C. & Wiegand, R. G. (1968) Soc. tox., 7th Ann. Meeting,
Abst. 16
Sonders, R. G. Netwal, J. C. & Wiegand, R. G. (1970) Unpublished
report to Abbott Laboratories
Stern, S. B. (1967) Unpublished report to Abbott Laboratories,
326706-8, 326723
Stoltz, D. R. et al. (1970) Science, 167, 1501
Stone, D., Lamson, E. & Chang, Y. S. (1969) Science, 164, 568
Tanaka, R. (1964a) Jap. J. Publ. Health, 11, 909
Tanaka, R. (1964b) J. Iwate Med. Ass., 16, 330
Tremolières (1964) Unpublished report to Abbott Laboratories, 316401
Unilever Research Laboratories (1970) Unpublished report submitted to
WHO
US Food and Drug Admin. (1969) Unpublished report submitted to WHO
US Food and Drug Admin. (1969) Report to NAS-NRC
Verrett, M. J. (1969) FDA report to NAS-NRC
Wagner, J. G. (1969) The Sciences, 9, 20
Watrons, R. M. & Schulz, H. N. (1950) Ind. Med. Surg., 19, 317
Wechsler, A. S., Epstein, S. E. & Click, G. (1969) J. Pharmac. exp.
Ther., 170(1), 62
Weinberg, M. S. & Harrington, E. M. (1968) Toxicol. appl.
Pharmacol., 12, 290
Wills, J. H. et al. (1968) Toxicol. appl. Pharmacol., 12, 292
Woodward Research Lab. (1963) Unpublished report to Abbott
Laboratories
Woodward Research Lab. (1964) Unpublished report to Abbott
Laboratories
Wortman, B., Locke, R. K. & Schrogie, J. J. (1968) Soc. Toxic 8th
Ann. Meeting, Abst. 108
Yamamura, H. I. & Dixon, R. L. (1968) Soc. Toxic. 7th Ann. Meeting,
Abst. 12
Yamamura, H. I., Lee, I. P. & Dixon, R. L. (1968) J. Pharm. Sci.,
571, 1132
Zollner, N. & Pieper, M. (1970) Unpublished report submitted to WHO
Zollner, N. & Schuelle, K. (1969) Arzneimittel-Forsch, 19, 913