Toxicological evaluation of some food
additives including anticaking agents,
antimicrobials, antioxidants, emulsifiers
and thickening agents
WHO FOOD ADDITIVES SERIES NO. 5
The evaluations contained in this publication
were prepared by the Joint FAO/WHO Expert
Committee on Food Additives which met in Geneva,
25 June - 4 July 19731
World Health Organization
Geneva
1974
1 Seventeenth Report of the Joint FAO/WHO Expert Committee on
Food Additives, Wld Hlth Org. techn. Rep. Ser., 1974, No. 539;
FAO Nutrition Meetings Report Series, 1974, No. 53.
PROPYLENE GLYCOL ALGINATE
Explanation
This substance has been evaluated for acceptable daily intake by
the Joint FAO/WHO Expert Committee on Food Additives (see Annex 1,
Refs Nos 10 and 27) in 1969 and 1971.
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.
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
In vitro hydrolysis by simulated gastric and intestinal juices
shows practically no effect of gastric juice, while intestinal juice
hydrolyzes 25% of the ester in 4 hours, 65% in 12 hours and 80% in 24
hours (McNeely & 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 eight
mice. Absorption, distribution through the body tissues and excretion
of the radio-label was followed from one hour to five days after
administration by whole body autoradiography. The alginate moiety and
unhydrolyzed ester are not absorbed from the gastrointestinal tract.
Any hydrolized propylene glycol is absorbed and metabolized by the
usual pathways. A single dose of 1000 mg/kg is virtually completely
eliminated within five 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 three days (Sharratt &
Dearn, 1971). 14C-labelled alginate prepared from Laminaria
digitata was not absorbed to any significant extent by rats when fed
at 10% of their diet (Humphreys & Triffit, 1968).
TOXICOLOGICAL STUDIES
Special studies on teratogenicity
1, 2-propylene glycol has a no-effect level of 2000 ppm (0.2%)
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; Best & Ruckebusch,
1962).
Bacteriological examination of the intestinal flora of two rats
after six months on basal diet and 21 days of 5% added propylene
glycol alginate showed a fall in lacto-bacilli and aerobic counts with
arise in coliforms and no change in anaerobic counts (Woodard, 1959).
Groups of 22 to 32 pregnant female albino CD-1 mice were dosed
daily by oral intubation with propylene glycol alginate at levels 0,
8, 36, 170 and 780 mg/kg from day 6 to 15 of gestation. At dose levels
up to 170 mg/kg, there was no effect on nidation or maternal or fetal
survival. The number of abnormalities seen in either soft or skeletal
tissues did not differ from the number occurring spontaneously in
controls. At the 780 mg/kg level there were 7/32 maternal deaths.
Surviving dams and fetuses carried to term appeared normal in all
respects (Food and Drug Research Lab. Inc., 1972). Groups of 24
pregnant adult Wistar rats were dosed with propylene glycol alginate
at levels 0, 7, 33, 155 or 720 mg/kg from day 6 to 15 of gestation. On
day 20 dams were subjected to caesarian section and dams and fetuses
were examined for pathological and teratological effects. No compound-
related effects were observed (Food and Drug Research Lab. Inc.,
1972). In a similar study in which groups of 20 to 23 pregnant golden
hamsters were dosed daily by oral intubation, with propylene glycol
alginate at levels of 0, 7, 33, 150 or 700 mg/kg from day 6 to 10 of
pregnancy, and mother and fetuses examined on day 14, no compound-
related effects were observed (Food and Drug Research Lab. Inc.,
1972).
Acute toxicity
No LD50s are available. Rabbits injected intravenously,
intraperitoneally, intramuscularly or subcutaneously with 6.2 mg,
12.5 mg or 25 mg/kg bw showed no toxic effects systematically or at
the site of injection (Steiner & McNeely, 1951). When injected
subcutaneously or intramuscularly with up to 2 ml of sterile aqueous
2% 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 five of those that showed the greatest
reactions were fed propylene glycol alginate three showed mild
allergic reactions which were duplicated in repeated tests. Of 50
non-allergic individuals three showed very slight skin reactions, but
none had reactions to oral administration (Ouer, 1949).
Groups of rats were given by oral intubation 5 g/kg propylene
glycol alginate, or fed a diet containing 50 to 70% of the alginate
for 24 hours. No adverse effects were observed, and autopsy on day 14
post-treatment did not reveal any compound-related effects (Woodward,
1972).
Rats dosed orally with propylene glycol alginate at a level of
10 g/kg, prepared as a suspension in corn oil, showed a transient
depression. No other effects were noted (Newell & Maxwell, 1972).
Short-term studies
Rat
Two groups of six female rats each were fed either a diet
containing 21.5% of the compound and 21.5% glucose or a normal diet
with additional 21.5% glucose for four weeks. After sacrificing two
animals in each group the remaining four animals per group were fed a
normal diet for four weeks. Thereafter, the original control group was
fed a diet containing 21.5% of the compound and the original test
group was kept on control diet for two 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 two sacrificed
animals (test and controls) showed no abnormalities (MRCL, 1951).
Guinea-pig
Four groups of three animals each were fed a diet containing 0,
5, 10 and 15% 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 one control were fed a diet with 0, 5, 10 and 15%
of the compound for 88 to 100 days. At dietary levels of 10 and 15%
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 three male and three female beagles were fed
diets containing 0, 5 and 15% of the compound for one 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% of the compound for three to seven 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% 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% propylene glycol alginate.
A fifth group received 15% of the compound in a different basal diet.
Life-span was slightly reduced at the 15% and 25% level. The bulky
diet caused loose faeces. The group on 15% 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% of the compound for two years. After four to five months
feeding some animals were mated. The F1 generation was fed on similar
diets, mated after four months, and the F2 generation also kept on
similar diets. At the end of two years the survival rates were 67%
male and 78% female in test groups and 56% and 50% 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
as well as in a teratogenicity study. 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 the faeces of rats and mice.
EVALUATION
Level causing no toxicological effect
Rat: 50 000 ppm (5%) in the diet equivalent to 2500 mg/kg bw.
Estimate of acceptable daily intake for man
0-25 mg/kg bw.*
REFERENCES
Bost, J. & Ruckebusch, Y. (1962) Thérapie, 17, 83
FAO/WHO (1970) WHO/Food Add./70.36
Food and Drug Research Lab., Inc. (1972) Unpublished report submitted
to DHEW/Public Health Service, U.S. FDA
Gebhardt, D. O. E. (1968) Teratology, 1, 153
Humphreys, S. E. R. & Triffit, J. T. (1968) Nature (Lond.), 219, 1172
McLaughlin, J. 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
* The contribution from propylene glycol alginate to total dietary
propylene glycol intake from all sources should be included in the ADI
for propylene glycol.
Newell, G. W. & Maxwell, W. A. (1972) Unpublished report from Stamford
Research Institute, Menlo Park Co., submitted to DHEW/Public
Health Service, U.S. FDA
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. & McNeely, W. H. (1951) Ind. Eng. Chem., 43, 2073
Woodard, G. (1959) Unpublished report
Woodward Research Corp. (1972) Unpublished report submitted to Kelco
Co.