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.
1,2 - PROPYLENE GLYCOL
Explanation
This substance has been evaluated for acceptable daily intake by
the Joint FAO/WHO Expert Committee on Food Additives (see Annex 1,
Ref. No. 7) in 1963.
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
Propylene glycol is rapidly absorbed after oral administration
and appears in the blood-stream. After a dose of 8 ml/kg bw had been
administered to dogs approximately 24 hours were required for complete
elimination from the blood-stream (Hanzlik et al., 1939a). Propanediol
phosphate occurs in brain and liver (Rudney, 1954a) and may be
metabolized by dephosphorylation followed by oxidation Huff & Rudney,
1959).
Propanediol and propanediol phosphate are intermediates in the
catabolism of acetone to acetate and formate: propanediol added to a
liver slice preparation is converted to lactic acid (Rodney, 1954b).
Liver alcohol dehydrogenase oxides the glycol to lactaldehyde (Huff,
1961). Propylene glycol is glycogenic in the fasted rat (Opitz, 1958).
Definite increases in liver glycogen occurred after giving 1 ml/kg bw,
but 0.5 ml produced no change (Hanzlik et al., 1939b). Dogs given
propylene glycol excreted 25 to 50% unchanged in the urine (Hanzlik et
al., 1939a; Lehman & Newman, 1937). In experiments on three human
subjects, 20 to 25% of the dose (1 ml/kg bw) was excreted in the urine
within 10 hours (Hanzlik et al., 1939a). The propylene glycol content
of the saliva was about three times as high as that in the blood.
In the body, propylene glycol stearate esters undergo enzymatic
hydrolysis and absorption in a similar manner to stearate glycerides
(Long et al., 1958).
TOXICOLOGICAL STUDIES
Acute toxicity
Animal Route LD50 References
(per kg bw)
Rat oral 21.0 ml Laug et al., 1939;
26.3 ml Smyth et al., 1941;
33.5 ml Weatherby & Haag, 1938
Mouse oral 23.9 ml Laug et al., 1939;
22.0 ml Latven & Moliter, 1939
Guinea-pig oral 18.9 ml Laug et al., 1939;
18.3 ml Smyth et al., 1941
Rabbit oral 18.5 ml Lehman & Newman, 1937
In the rat, a single large oral dose produced minimal microscopic
changes in the kidney. The liver showed slight congestion and
hyperaemia (Laug et al., 1939).
The intravenous lethal dose for dogs was 25 ml/kg bw, and the
anaesthetic dose was 21.2 ml/kg (Hanzlik et al., 1939a).
Short-term studies
Rat
Six rats wore given 3.58% propylene glycol in the drinking-water
for 11 weeks. One rat died at the tenth week, one was ill and others
were beginning to lose weight (Holck, 1937).
When all the carbohydrate in the diet of a group of four rats was
replaced by propylene glycol, giving a concentration of 48.5%, all the
animals died within a month. When three-quarters of the carbohydrate
was replaced by propylene glycol, giving a concentration of 31%, all
the animals in another group died within 14 weeks. With half-and-half
proportions of carbohydrate and propylene glycol, giving a
concentration of 25%, the rats in a third group grew more slowly than
those in a control group, and at five-and-a-half months their weight
was less. With 13% propylene glycol in the diet, there was no
mortality during the feeding period of five months and weight gain was
about the same as in the controls. Paired-fed rats given 12.8%
propylene glycol in the diet and the same level of carbohydrate grew
faster and attained a greater weight than the control animals. Part of
this difference might have been due to the greater caloric value of
the propylene glycol. The spontaneous activity of rats fed large doses
of propylene glycol was somewhat greater than that of the control
group. Propylene glycol had no effect on the respiratory quotient of
rats (Hanzlik et al., 1939b).
Paired-fed rats kept for 127 to 163 days on a diet in which
one-quarter of the carbohydrate had been replaced by the caloric
equivalent of propylene glycol (total propylene glycol intake 89.2 to
130.7 g) grew better than the controls (Winkle & Newman, 1941).
Rats in groups of five tolerated up to 10% of propylene glycol in
the drinking-water over about one-eighth of the normal life span
(corresponding to a daily intake of 10 to 13 g/kg bw but when the
drinking-water contained 25% or 50% of propylene glycol they died
within nine days (Weatherby & Haag, 1938; Seidenfeld & Hanzlik, 1932).
Groups of 10 rats were each given six weeks of treatment with 5%
or 10% propylene glycol in their drinking-water. Liver weights were
significantly increased. The red cell count was significantly
decreased. There was considerable hyperglycaemia and a slight decrease
in blood urea (Vaille et al., 1971).
Rabbit
Doses of 1, 2, 3, 4 or 8 ml of propylene glycol per kg bw were
administered daily by stomach tube to 11 young rabbits over a period
of 50 days. A satisfactory growth rate was established (Braun &
Carland, 1936).
Seven rabbits were given 5% propylene glycol in drinking-water
for eight weeks, the mean amount ingested daily being 14.8 ml per
rabbit. There was induction of hyperglycaemia in this species (Vaille
et al., 1971).
Dog
Four dogs consumed 5% of propylene glycol in drinking-water for
five to nine months. The average daily intake of propylene glycol was
5.1 ml/kg bw. All dogs remained in good health and no significant
changes were noted in the functional efficiency of tho liver and
kidneys (galactose excretion, uric acid excretion, rose bengal test,
phenolsulfonphthalein test). Histopathological examination showed no
changes in the livers and kidneys. No alterations in serum calcium
were observed (Winkle & Newman, 1941).
Long-term studies
Rat
Groups of 10 rats (males and females) were fed for two years on
diets containing 2.45% or 4.9% of propylene glycol, corresponding to a
daily intake of 0.9 or 1.8 ml/kg bw. There was no influence on growth,
food utilization or survival. The histopathological examination of the
liver, kidney, lung, heart, spleen, lymph nodes, pancreas, stomach,
intestine and adrenals showed no lesions attributable to the glycol,
although slight chronic liver damage was reported (Morris et al.,
1942).
Groups of 30 male and 30 female rats were fed for two years on
diets containing 0, 6250, 12 500, 25 000 and 50 000 ppm (0%, 0.625%,
1.25%, 2.50%, and 5%) of propylene glycol. The highest level
corresponds to 2.5 g/kg per day. There were no statistically
significant effects on death rate, weight gain or food consumption.
There were no significant effects on haemoglobin or differential white
cell counts after two years, nor on haematocrit values, red cell and
white cell counts and reticulocyte counts after one year of treatment.
Urine cell counts, urine concentrating power and urinary capacity were
not affected in rats on the two higher dosage levels after 13, 30 or
52 weeks. At the end of the two-year trial, there were no significant
effects on absolute or relative weights of organs (brain, heart,
liver, spleen, stomach, small intestine, caecum, kidneys, adrenals,
gonads), and no histopathological effects or neoplasia attributable to
the substance (Gaunt et al., 1972).
Dog
Groups of five male and five female beagles were given propylene
glycol, in the diet, at dosage levels of 2.0 and 5.0 g/kg for two
years. In control groups, the calorific equivalent of dextrose was
given. At the 5 g/kg level, there were findings suggestive of an
increased erythrocyte destruction with a compensatory increased rate
of haematopoiesis: slightly reduced cell count, haemoglobin and
haematocrit values, slightly increased bilirubin, and increased
incidence of anisocytosis, poikilocytosis and reticulocytosis. There
was no evidence of damage to spleen or bone marrow. Dosage with
2 g/kg per day produced no adverse effect. Liver function tests
(bromosulfthalein retention, serum alkaline phosphatase, serum
glutamate-oxalacetate and glutamate-pyruvate transaminases, liver
glycogen and lipids) and liver histology were not significantly
affected by either dose level of propylene glycol (Weil et al., 1971).
OBSERVATIONS IN MAN
Propylene glycol had no effect upon basal metabolism (Hanzlik et
al., 1939a).
Comments:
Conversion to lactic acid has been shown to be the normal
metabolic pathway. This observation, together with the results of the
long-term studies, was used as the basis for the evaluation.
EVALUATION
Level causing no toxicological effect
In the rat and in the dog: 2500 mg/kg bw.
Estimate of acceptable daily intake for man
0 to 25 mg/kg bw.
REFERENCES
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See Also:
Toxicological Abbreviations