WORLD HEALTH ORGANIZATION
WHO Food Additives Series 1972, No. 1
TOXICOLOGICAL EVALUATION OF SOME
ENZYMES, MODIFIED STARCHES AND
CERTAIN OTHER SUBSTANCES
The evaluations contained in this publication were prepared by the
Joint FAO/WHO Expert Committee on Food Additives which met in Rome,
16-24 June 19711
World Health Organization
Geneva
1972
1 Fifteenth Report of the Joint FAO/WHO Expert Committee on Food
Additives, Wld Hlth Org. techn. Rep. Ser., 1972, No. 488; FAO
Nutrition Meetings Report Series, 1972, No. 50.
The monographs contained in the present volume are also issued by the
Food and Agriculture Organization of the United Nations, Rome, as FAO
Nutrition Meetings Report Series, No. 50A
(c) FAO and WHO 1972
HYDROXYPROPYL DISTARCH GLYCEROL
Modification is performed by the use of 0.1 per cent. epichlorhydrin
and up to 10 per cent. propylene oxide. Crosslinkage would be no
greater than expected on modification with 0.1 per cent.
epichlorhydrin. Substitution by treatment with 10 per cent. 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
mucose was found to be 86 per cent. of that of the native starch
(Leegwater, 1971).
Short-term studies
Rat
Groups of 10 male and 10 female were fed for 8 weeks on a diet
containing 25 or 50 per cent. 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
per cent. level in both sexes. Slight diarrhoea occurred at the 25
per cent. 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
and Spanjers, 1970).
Groups of 25 male and 25 female rats were fed for 13 weeks on a diet
containing 1 and 5 per cent. of modified starch or 5 per cent. of
native starch. The general appearance and behaviour of test rats was
comparable with the controls. One male and one female rat died at the
lower test level. Growth, feed consumption, body-weight, haematology
at one and three months, urinalysis at one and three months, 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 per cent. modified starch.
No differences between test and control animals were noted with regard
to appearance, behaviour, growth, food consumption, haematology, serum
chemistry 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
per cent. 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 per cent. and 5 per cent. of modified starch or 5 per cent. 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, adrenals and testes showed no test-related changes (Knapp,
1967b).
Man
Twelve volunteers consumed 60 g modified starch on each of 4
successive days. No adverse effects were noticed and no abnormalities
occurred as regards frequency and amount of faeces or faecal water and
lactic acid content (Pieters et al., 1971).
Long-term studies
Groups of 30 male and 30 female rats were fed for 104 weeks modified
starch at 0, 5, 10 and 30 per cent. 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 per cent. level was
slightly higher. The growth rate was slightly reduced for both sexes
at the 30 per cent. level when compared with controls. Caecal weight
was increased in a dose-related manner but occurred only in females at
the 10 per cent. level. The gross pathology has revealed no undue
differences nor was there any obvious evidence of a carcinogenic
effect. The histopathology has not yet been completed (Til et al.,
1971a).
Reproduction studies
Rat
A three generation study was performed using 5 males and 10 females
for the P generation and 10 males and 20 females of the F1b and F2b
to produce successive generations. The F3b generation was kept for 3
weeks after weaning and then sacrificed for histopathological study.
The P, F1b and F2b parents were used for determination of
implantation sites. The test material, fed at 10% of the diet
consisted of starch modified with 5% phosphorus oxide and 0.1%
epichlorhydrin (D.S. of 0.05). No abnormalities were noted regarding
health, behaviour, mortality, body-weights, fertility, little size,
resorption quotient, weaning weight of pups or mortality of young.
Caecal weights were increased in both sexes. Similarly kidney and
thyroid weights in the females differed in a statistically significant
way from the controls. There were no pathological changes on gross
examination at autopsy in the F3b generation but the histopathology
is still outstanding (Til et al., 1971b).
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 week 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 cecum weight (filled) of females of the P and F2
generation was greater than controls, but empty cecum weight did not
differ from controls. The relative cecum weight (filled and empty) of
males of the F1 generation did not differ from controls. Growth of
the F3b generation maintained on test diet for 3 weeks was normal.
Relative organ weights were comparable to control, with the exception
of increased thyroid weight and distinctly increased cecal weight
(both filled and empty) in male pups, and increased empty cecal weight
in female pups. Gross examination of organs at autopsy did not show
any compound related changes. Histopathological studies of organs have
not been completed (Til et al., 1971).
Special studies
Groups of 10 male and 10 female rats were fed for 7 days on a
low-residue diet containing 25 or 50 per cent. modified starch.
Thereafter, they were fed an additional 4 per cent. cellulose.
Body-weight was slightly reduced at the 50 per cent. test level in
both sexes and faecal dry matter was increased in all groups compared
with controls. There was considerable diarrhoea in all test groups
which was unaffected by the additional dietary cellulose. Hair loss
was pronounced at the 50 per cent. test level in both sexes and was
slight at 25 per cent. (de Groot and Spanjers, 1970).
Comments
The feeding studies with rats and dogs 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 propylene glycol released from the starch. 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 suggests that caecal enlargement without
associated histopathological changes is of little toxicological
significance. The long-term and reproduction studies in the rat
indicate no significant adverse effects and may be used for
evaluation.
EVALUATION
Temporarily not limited.*
Further work required by 1973
Histological report to complete the long-term rat study.
Histological report to complete the reproduction study.
REFERENCES
de Groot, A. P. & Spanjers, M. Th. (1970) Unpublished report No. R
3096 by Centraal Instituut voor Voedingsonderzoek
de Knecht-van Eekelen, A., Willems, M. & de Groot, A. P. (1970)
Unpublished report No. R 3093 by Centraal Instituut voor
Voedingsonderzoek
Knapp, W. A. jr (1967a) Report of Hazleton Laboratories Inc.,
submitted by the International Latex and Chemical Corporation
Knapp, W. A. jr (1967b) Report of Hazleton Laboratories Inc., 28
February 1967 submitted by the International Latex and Chemical
Corporation
Leegwater, D. C. (1971) Unpublished report No. R 3431 by Centraal
Instituut voor Voedingsonderzoek
Pieters, J. J. L., van Staveren, W. A. and Brinkhuis, B. G. A. M.
(1971) Unpublished report No. R 3433 by Centraal Instituut voor
Voedingsonderzoek
Til, H. P., Spanjers, M. Th., van der Meulen, H. C. and de Groot, A.
P. (1971a) Unpublished report No. R 3363 by Centraal Instituut voor
Voedingsonderzoek
Til, H. P., Spanjers, M. Th., and de Groot, A. P. (1971b) Report No.
3403 of Centraal Instituut voor Voedingsonderzoek, submitted to WHO
* Except for good manufacturing practice.
See Also:
Toxicological Abbreviations
Hydroxypropyl distarch glycerol (FAO Nutrition Meetings Report Series 46a)
Hydroxypropyl distarch glycerol (WHO Food Additives Series 5)
Hydroxypropyl distarch glycerol (WHO Food Additives Series 17)
HYDROXYPROPYL DISTARCH GLYCEROL (JECFA Evaluation)