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
PROPYLENE GLYCOL ALGINATE
Biological data
Biochemical aspects
In vitro hydrolysis by simulated gastric and intestinal juices shows
practically no effect of gastric juice, while intestinal juice
hydrolyses 25 per cent. of the ester in 4 h., 65 per cent. in 12 h.
and 80 per cent. in 24 h. (MeNeely & Shepherd, 1966).
Alginic acid and alginates and also the algae from which these
substances derive have been used in man for many years. Propylene
glycol is rapidly absorbed from the gut and metabolized in a variety
of ways to acetate, lactate or glycogen.
Propylene glycol alginate, labelled uniformly with 14C either in the
alginate or the propylene glycol moiety, was administered to 8 mice.
Absorption, distribution through the body tissues and excretion of the
radio-label was followed from 1 hour to 5 days after administration by
whole body autoradiography. The alginate moiety and unhydrolysed
ester are not absorbed from the gastrointestinal tract. Any
hydrolysed propylene glycol is absorbed and metabolized by the usual
pathways. A single dose of 1000 mg/kg is virtually completely
eliminated within 5 days but after 5000 mg/kg traces of activity were
still noted in the rectum. Absorbed labelled propylene glycol had
disappeared completely from the body after 3 days (Sharratt & Dearn,
1971). 14C-labelled alginate prepared from Laminaria digitata was
not absorbed to any significant extent by rats when fed at 10 per
cent. of their diet (Humphreys & Triffit, 1968).
Acute toxicity
No LD50s are available. Rabbits injected intravenously,
intraperitoneally, intramuscularly or subcutaneously with 6.2 mg, 12.5
mg or 25 mg/kg body-weight showed no toxic effects systematically or
at the site of injection (Steiner & MeNeely, 1951). When injected
subcutaneously or intramuscularly with up to 2 ml of sterile aqueous 2
per cent. solutions of the compound no gross or histological
abnormalities occurred at the injection site. Intraperitoneal and
intravenous injections of similar amounts produced no abnormal
systemic effects (Ouer, 1949).
Of 50 human subjects known to be allergic to numerous other substances
11 showed very slight to moderate skin reactions to the intradermal
test. When 5 of those that showed the greatest reactions were fed
propylene glycol alginate 3 showed mild allergic reactions which were
duplicated in repeated tests. Of 50 non-allergic individuals 3 showed
very slight skin reactions, but none had reactions to oral
administration (Ouer, 1949).
Special studies
1, 2-propylene glycol has a no-effect level of 2000 ppm level when
tested for embryo toxicity in the chick (McLaughlin et al., 1965)
while 1,3-propylene glycol appeared to produce chondrodystrophy in a
high percentage of embryos (Gebhardt, 1968). The toxicology of
propylene glycol has been reviewed (FAO/WHO, 1970; Bost & Ruckebusch,
1962).
Bacteriological examination of the intestinal flora of 2 rats after 6
months on basal diet and 21 days of 5 per cent. added propylene glycol
alginate showed a fall in lacto-bacilli and aerobic counts with a rise
in coliforms and no change in anaerobic counts (Woodard, 1959).
Short-term studies
Rat
Two groups of 6 female rats each were fed either a diet containing
21.5 per cent. of the compound and 21.5 per cent. glucose or a normal
diet with additional 21.5 per cent. glucose for 4 weeks. After
sacrificing 2 animals in each group the remaining 4 animals per group
were fed a normal diet for 4 weeks. Thereafter, the original control
group was fed a diet containing 21.5 per cent. of the compound and the
original test group was kept on control diet for 2 weeks. The test
group showed slight growth retardation but appearance and behaviour
remained normal. The faeces of the test group tended to be slimy.
Histopathology of intestine, kidney and liver of the 2 sacrificed
animals (test and controls) showed no abnormalities (MRCL, 1951).
Guinea-pig
Four groups of 3 animals each were fed a diet containing 0, 5, 10 and
15 per cent. of the compound for 26 weeks. No adverse effects on
weight gain, food intake, were seen and histopathology of various
organs demonstrated no significant lesions (Nilson & Wagner, 1951).
Cat
Eight cats and 1 control were fed a diet with 0, 5, 10 and 15 per
cent. of the compound for 88-100 days. At dietary levels of 10 and 15
per cent. animals showed frequent soft stools. No signs of toxicity
were noted, autopsy and histopathology revealed nothing of
significance (Nilson & Wagner, 1951).
Dog
Three groups of 3 male and 3 female beagles were fed diets containing
0, 5 and 15 per cent. of the compound for 1 year. All groups showed
normal weight gains, food consumption, haemograms, blood urea
nitrogen, serum alkaline phosphatase, blood glucose and urinalysis. A
complete histopathological examination showed no significant lesions
(Woodard, 1959).
Chick
Four groups of 13-day-old chicks were fed on a diet containing 0, 5,
10 and 15 per cent. of the compound for 3-7 weeks. All treated groups
showed reduced growth rate due to difficulty with the diet but no
evidence of toxic effects. Histopathology showed slight evidence of
transient reversible tissue changes in all groups (Nilson & Wagner,
1951).
Long-term studies
Mouse
Four groups of mice were kept on diets containing 0, 5, 10 and 25 per
cent. of the compound for 12 months. At the high levels mortality was
increased and weight gain as well as food intake reduced but
histopathology was unremarkable (Nilson & Wagner, 1951).
Rat
Four groups of 10 male and female rats were fed over their life span
diets containing 0, 5, 15 and 25 per cent. propylene glycol alginate.
A fifth group received 15 per cent. of the compound in a different
basal diet. Life span was slightly reduced at the 15 per cent. and 25
per cent. level. The bulky diet caused loose faeces. The group on 15
per cent. in a different basal diet had normal faeces and was
sacrificed at 37 weeks. No adverse effects on weight gain, food or
water consumption were noted. Histology showed no lesions
attributable to the compound (Nilson & Wagner, 1951).
Forty male and 40 female rats were kept on a diet containing 0 and 5
per cent. of the compound for 2 years. After 4-5 months feeding some
animals were mated. The F1 generation was fed on similar diets,
mated after 4 months, and the F2 generation also kept on similar
diets. At the end of 2 years the survival rates were 67 per cent.
male and 78 per cent. female in test groups and 56 per cent. and 50
per cent. in the respective control groups. The P generation survived
761 days, the F1 and F2 generations were sacrificed at 202 and 212
days respectively. No difference from the controls was noted
regarding mean body-weight, general condition, mortality, fertility,
lactation and survival of the three generations. Haematology was
normal; gross and histopathology showed nothing significant (Morgan,
F. C.).
Comments
Long-term studies in two species are available although the mouse
study extends over only 12 months. Effects upon reproduction were
assessed in the long-term study on rats through two filial
generations. In vivo metabolic studies using labelled alginate and
propylene glycol moieties show that only the propylene glycol moiety
is absorbed and metabolized. The alginate moiety is excreted
unchanged in rats and mice. A true estimate of the extent of in vivo
gastrointestinal hydrolysis is desirable to help in estimating the
contribution by propylene glycol alginate to the total dietary
propylene glycol intake.
EVALUATION
Level causing no significant toxicological effects in the rat
Five per cent. (50 000 ppn) in the diet equivalent to 2500 mg/kg
body-weight/day.
Estimate of acceptable daily intake for man mg/kg body-weight
Unconditional acceptance 0-251
REFERENCES
Bost, J. & Ruckebusch, Y. (1962) Thérapie, 17, 83
FAO/WHO (1970) WHO/Food Add./70.36
Gebhardt, D. 0. E. (1968) Teratology, 1, 153
Humphreys, S. E. R. & Triffit, J. T. (1968) Nature (Lond.), 219,
1172
McLaughlin et al., (1965) Toxicol. appl. Pharmacol., 7, 491
McNeely, W. H. & Shepherd, V. M. (1966) Report to Kelco Co. Labs.
Medical Research Council Laboratories (1951) Unpublished report
Morgan, F. C. cited in Woodard, G. (1959) Unpublished report
Nilson, H. W. & Wagner, J. A. (1951) Proc. Soc. exp. Biol. (N.Y.),
76, 630
Ouer, R. A. (1949) Ann. Allergy, 7, 681
Sharratt, M. & Dearn, P. (1971) Unpublished report submitted by
BIBRA
Steiner, A. B. & MeNeely, W. H. (1951) Ind. Eng. Chem., 43, 2073
Woodard, G. (1959) Unpublished report
1 The contribution from propylene glycol alginate to total dietary
propylene glycol intake from all sources should be included in the ADI
for propylene glycol.
See Also:
Toxicological Abbreviations
Propylene glycol alginate (FAO Nutrition Meetings Report Series 46a)
Propylene glycol alginate (WHO Food Additives Series 5)
Propylene glycol alginate (WHO Food Additives Series 32)
PROPYLENE GLYCOL ALGINATE (JECFA Evaluation)