HYDROXYPROPYL DISTARCH GLYCEROL Explanation This modified starch was previously evaluated for an ADI for man by the Joint FAO/WHO Expert Committee on Food Additives in 1969, 1971 and 1973 (see Annex I, Refs. 19, 26 and 29). Toxicological monographs were published in 1969, 1972 and 1974 (see Annex I, Refs. 20, 27 and 30). Since the previous evaluation, additional data have become available and are summarized and discussed in the following monograph. The previously published monograph has been expanded and is reproduced in its entirety below. Introduction Modification is performed by the use of 0.1% epichlorohydrin and up to 10% propylene oxide. Cross-linking would be no greater than expected on modification with 0.1% epichlorohydrin. Substitution by treatment with 10% propylene oxide would probably add no more than 15-20 ether linkages per 100 glucopyranose units. BIOLOGICAL DATA BIOCHEMICAL ASPECTS The in vitro digestibility of a hydroxypropyl distarch glycerol (degree of substitution 0.04) by pancreatin and porcine intestinal mucase was found to be 86% of that of the native starch (Leegwater, 1971). TOXICOLOGICAL STUDIES Special studies on reproduction Groups each of 10 male and 20 female rats were fed the modified starch at a level of 10% in their diet for a period of 3 generations. Rats were mated (P1, F1 and F2) at weeks 12 and 20 after weaning. Each generation was mated twice and the litter from the second generation used to produce the next generation. No adverse effects were noted on fertility, number of pups per litter, body weight of young, mortality experience or resorption quotient that could be ascribed to treatment. The average relative caecum weight (filled) of females of the P and F2 generation was greater than controls, but empty caecum weight did not differ from controls. The relative caecum weight (filled and empty) of males of the F1 generation did not differ from controls. Growth of the F3b generation maintained on the test diet for 3 weeks was normal. Relative organ weights were comparable to control, with the exception of decreased thyroid weight and distinctly increased caecal weight (both filled and empty) in male pups, and increased empty caecal weight in female pups. Gross examination of organs at autopsy did not show any compound-related changes. Gross and microscopic examination of F3b rats did not show any compound-related changes (de Groot et al., 1974; Til et al., 1971b). In a modified 13-week subacute 1-generation reproduction study, hydroxypropyl distarch glycerol or cornstarch was fed at 10% of the diet to Charles River albino rats from 2 weeks prior to mating for the F1a generation until the sacrifice of the parental females for the caesarean delivery of the F1b generation (Olson & Ferrell, 1970). Twenty-five weanling F1a males and 25 weanling F1a females were randomly selected to be placed on a 13-week subacute dietary study. The reproduction indices for the F1a litter were comparable between the modified starch fed and unmodified starch groups. Skeletal evaluation of the F1b litter did not show any compound-related alternations. Organ weight, necropsy, and microscopic examination of the F1a pups did not show any compound-related effects. The modified starch-fed P females had elevated spleen and kidney weight ratios. The F1a generation fed for 13 weeks did not show any consistent effect which could be compound related. However, blood chemistry analyses showed elevated glucose for the females at the initial and 13-week intervals and for the males at 13 weeks. BUN was also slightly higher for both males and females at 13 weeks. Statistical analysis showed lower values for male terminal body weight, absolute thyroid and relative thyroid in the test animals as compared to controls, and higher values for female kidney weight and kidney ratio, and male kidney ratio than controls. No specific pathological alterations which could be attributed to the test procedure was seen in the animals maintained on either diet for 13 weeks after weaning (Olson & Ferrell, 1970). Short-term studies Rat Groups of 10 male and 10 female rats were fed for 8 weeks on a diet containing 25 or 50% modified starch. Although the body weights of males at the higher level tested were slightly lower than those of the controls, the differences were not statistically significant. The faecal dry matter content was increased at both test levels in both sexes and there was considerable diarrhoea at the 50% level in both sexes. Slight diarrhoea occurred at the 25% level in both sexes. Caecal weights were increased in a dose-related manner at all levels in all test groups but no histological abnormalities could be detected in the caeca (de Groot & Spanjers, 1970). Groups of 25 male and 25 female rats were fed for 13 weeks on a diet containing 1 and 5% of modified starch or 5% of native starch. The general appearance and behaviour of test rats was comparable with the controls. One male and 1 female rat died at the lower test level. Growth, feed consumption, body weight, haematology at and 3 mouths, urinalysis at 1 and 3 months, and gross and histopathological findings were comparable in all groups (Knapp, 1967a). In another experiment, groups of 10 male and 10 female rats were fed for 90 days diets containing 0, 5, 10 or 30% modified starch. No differences between test and control animals were noted with regard to appearance, behaviour, growth, food consumption, haematology serum chemistry, or urinalysis. No definite diarrhoea occurred at any test level. The amounts of dry matter in the faeces did not vary significantly between controls and treated animals, only at the 30% level were the caecal weights increased in both sexes. Gross and histopathology were otherwise unremarkable in all groups. Histopathology of the enlarged caeca showed no recognizable abnormality (de Knecht-van Eekelen et al., 1970). Dog Three groups of 4 male and 4 female beagle dogs were given in their diet 1 and 5% of modified starch or 5% of native starch for 13 weeks. Haematological studies, blood sugar, blood urea, serum GPT and alkaline phosphatase as well as urinalysis were comparable for all groups. Appearance and behaviour were normal. Body weight changes were unrelated to the administration of the test substance. Gross and histopathology showed no consistent abnormalities. Organ weights of thyroid, heart, liver, spleen, kidneys, ardenals and testes showed no test-related changes (Knapp, 1967b). In a second study with dogs (Olson & Voelker, 1970), groups of 4 male and 4 female beagles were maintained on diets containing 10% hydroxypropyl distarch glycerol or cornstarch for a period of 13 weeks. Food consumption and weight gain were comparable between the 2 groups. Haematology, blood chemistry and urinalysis of the test and control groups were carried out at the beginning of the study and at week 13. There were no significant differences between the groups, and values were within normal limits. At autopsy, organ weights were measured and a microscopic examination made of the principal organs and tissues. No compound-related effects were observed (Olson & Voelker, 1970). Pig Groups of 8 Pitman-Moore miniature pigs were weaned at 3 days of age, and were fed formula diets containing 5.4% unmodified starch or 4.9% hydroxypropyl distarch glycerol for 25 days. Growth was normal during the test period. At termination of the study, biochemical analyses of blood (haemoglobin) and serum (cholesterol, triglyceride, calcium, phosphorus, alkaline phosphatase, urea nitrogen, total protein, albumin and globulin) were similar for test and control animals. Relative organ weight as well as carcass composition (water, fat, protein, ash, Ca, PO4, Na, Mg) and liver composition (water, fat, protein and ash), were similar for test and control animals (Anderson et al., 1973a,b). Long-term studies Groups of 30 male and 30 female rats were fed for 104 weeks modified starch at 0, 5, 10 and 30% of their diet. No differences were noted between test and control animals with regard to appearance, behaviour, food consumption, haematology, serum chemistry and urinalysis. The mortality of females at the 30% level was slightly higher than in the control group. The growth rate was slightly reduced for both sexes at the 30% level when compared with controls. Caecal weight was increased at 30% in males and at 10% and 30% in females. Microscopic examination revealed no noticeable changes in the caecal wall. Renal calcification accompanied by focal hyperplasia of the pelvic epithelium was more marked in males fed 30% of the test compound than in control males. No distinct compound-related gross or microscopic changes were encountered in any of the organs examined (de Groot et al., 1974; Til et al., 1971a). Roe (1979) has conducted an extensive review of this type of mineral deposition in the renal pelvis of rats and concluded that pelvic nephrocalcinosis, corticomedullary nephrocalcinosis, acute tubular nephropathy, and calculus formation are manifestations of mineral imbalances and are of relatively common occurrence in untreated laboratory rats (particularly older animals). OBSERVATIONS IN MAN Twelve volunteers consumed 60 g modified starch on each of 4 successive days. No adverse effects were noticed and no abnormalities occurred in regard to frequency or amount of faeces or faecal water and lactic acid content (Pieters et al., 1971). Comments The feeding studies with rats, dogs and pigs show that the modified starch is well utilized. The studies with radio-labelled hydroxypropyl starch provide some information in the rat on the metabolic fate of the hydroxypropyl moiety. Several short-term studies in the rat and dog show no adverse effects even at high dietary levels. The available evidence for the group of modified starches considered indicates that caecal enlargement without associated histopathological changes is without toxicological significance. The long-term and reproduction studies in the rat indicate no significant adverse effects and may be used for evaluation. The increased incidence of renal calcification accompanied by focal hyperplasia in test male rats in the long-term study is considered to be associated with imbalances in the Ca/P/ and Mg in the diet. EVALUATION Estimate of acceptable daily intake for man Not specified.* * The statement "ADI not specified" means that, on the basis of the available data (toxicological, biochemical, and other), the total daily intake of the substance, arising from its use or uses at the levels necessary to achieve the desired effect and from its acceptable background in food, does not, in the opinion of the Committee, represent a hazard to health. For this reason, and for the reasons stated in individual evaluations, the establishment of an acceptable daily intake (ADI) in mg/kg bw is not deemed necessary. REFERENCES Anderson, T. A. et al. (1973a) Unpublished data submitted to Corn Refiners Ass., Inc. Anderson, T. A., Filer, L. J., Fomon, S. J., Andersen, D. W., Jensen, R. L. & Rogers, R. R. (1973b) Effect of waxy corn starch modification on growth, serum biochemical values and body composition of Pitman-Moore miniature pigs, Fd. Cosmet. Toxicol., 11, 747-754 de Groot, A. P. & Spanjer, M. Th. (1970) Observations in rats fed on diets containing five different chemically modified starches. Report No. R 3096. Centraal Instituut voor Voedingsonderzoek, Zeist, Holland de Groot, A. P., Til, H. P., Feron, V. J., Van der Meullen, H. C. D. & Willems, M. I. (1974) Two-year feeding and multigeneration studies in rats on five chemically modified starches, Fd. Cosmet. Toxicol., 12, 651-664 Knapp, W. A., Jr (1967a) Three-month dietary administration - rats, AR-197. Report of Hazleton Laboratories, Inc., Falls Church, Va., to International Latex and Chemical Corporation, Hawthorne, N.J. Submitted to Federation of American Societies for Experimental Biology, Bethesda, Md., by A. E. Staley Manufacturing Company, Decatur, Ill. Knapp, W. A., Jr (1967b) 13-week dietary administration - dogs: AR-197 (test compound); tapioca fluor (reference compound). Report of Hazleton Laboratories, Inc., Falls Church, Va., to International Latex and Chemical Corporation, Hawthorne, N.J. Submitted to Federation of American Societies for Experimental Biology, Bethesda, Md., by A. E. Staley Manufacturing Company, Decatur, Ill. de Knecht-van Eekelen, A., Willems, M. & de Groot, A. P. (1970) Subchronic (90-day) toxicity study with a hydroxypropyl distarch glycerol in rats. Report No. R 3093. Centraal Instituut voor Voedingsonderzoek, Zeist, Holland Leegwater, D. C. (1971) Report No. 3431 by Centraal Instituut voor Voedingsonderzoek, Zeist, Holland. Submitted to WHO Olson, W. A. & Voelker, R. W. (1970) 13-week dietary administration - dogs: modified starch (F4-231); unmodified starch (control). Report of Hazleton Laboratories, Inc., Falls Church, Va. Submitted to A. E. Staley Manufacturing Company, Decatur, Ill. Olson, W. A. & Ferrell, J. F. (1970) Modified 13-week subacute one- generation reproduction study-rats. Unmodified starch. Modified starch (F4-231). Report of Hazleton Laboratories, Inc., Falls Church, Va. Submitted to A. E. Staley Manufacturing Company, Decatur, Ill. Pieters, J. J. L., van Staveren, W. A. & Brinkhuis, B. G. A. M. (1971) Report No. 3433 of the Centraal Instituut voor Voedingsonderzoek, Zeist, Holland. Submitted to WHO Roe, F. J. C. (1979) Mineral deposition in the renal pelvis of rats: A brief review, unpublished report. Submitted to WHO Til, H. P. et al. (1971a) Chronic (2-year) feeding study in rats with two chemically modified starches (starch acetate and hydroxypropyl distarch glycerol). Report No. R 3363. Centraal Instituut voor Voedingsonderzoek, Zeist, Holland Til, H. P., Spanjers, J. Th. & de Groot, A. P. (1971b) Unpublished report No. 3403 by Centraal Instituut voor Voedingsonderzoek, Zeist, Holland. Submitted to WHO
See Also: Toxicological Abbreviations Hydroxypropyl distarch glycerol (FAO Nutrition Meetings Report Series 46a) Hydroxypropyl distarch glycerol (WHO Food Additives Series 1) Hydroxypropyl distarch glycerol (WHO Food Additives Series 5) HYDROXYPROPYL DISTARCH GLYCEROL (JECFA Evaluation)