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