INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
WORLD HEALTH ORGANIZATION
TOXICOLOGICAL EVALUATION OF SOME
FOOD COLOURS, EMULSIFIERS, STABILIZERS,
ANTI-CAKING AGENTS AND CERTAIN
FAO Nutrition Meetings Report Series
No. 46A WHO/FOOD ADD/70.36
The content of this document is the result of the deliberations of the
Joint FAO/WHO Expert Committee on Food Additives which met in Rome,
27 May - 4 June 19691
Food and Agriculture Organization of the United Nations
World Health Organization
1 Thirteenth report of the Joint FAO/WHO Expert Committee on Food
Additives, FAO Nutrition Meetings Report Series, in press;
Wld Hlth Org. techn. Rep. Ser., in press.
SILICON DIOXIDE, AMORPHOUS; ALUMINIUM, CALCIUM, MAGNESIUM, AND SODIUM
(includes: silica aerogel, hydrated silica, silicic acid, dehydrated
silica gel, Kaolin, Talc and magnesium trisilicate)
Silica, silicic acid and the (calcium, magnesium and aluminum salts
occur ubiquitously in the environment and some have been used for many
years medically. Food contains various amounts of SiO2, for example:
potatoes 10.1, milk 2.1, drinking water 7.1, mineralwater 22.5, beer
131 gamma SiO2 per g or cm3 (Bauman 1960).
Very small amounts of silica are normally present in all body tissues
but there is no evidence that they play any physiological role.
Silicic acid is a normal constituent of the union, where it is found
as early as a few days after birth. The amount excreted in the urine,
which varies considerably according to the diet, is in the order of
10-30 mg per day (Thomas 1965). The silica content of human tissue
varies from 10-200 mg/100 g dry weight (spleen 15 mg, lung 140 mg)
(Unilever Research Laboratory 1964). The normal level of silicic acid
in human blood is below 1 µg SiO2/cm3; the concentration in the
corpuscles is practically the same as that in the plasma. Silicic acid
is present in plasma in a molybdate reactive form and is not bound to
protein or any other substance of high molecular weight. Ingested
monomeric silicic acid rapidly penetrates the intestinal wall and
becomes distributed throughout the whole extracellular fluid. It
enters the blood corpuscles at a slower rate (Baumann 1960).
Silica dust was administered intragestrically to rabbits and dogs
leading to a rise in urinary silica output without significant
variation in blood silica levels. Considerable absorption took place
with peak excretion in dogs occurring between four to eight hours
after administration. There appears to be little retention in any
organ of the body even if animals ingest large amounts of silicates in
their food. Intragastric five per cent. silicic acid administered to
dogs leads to considerable absorption and urinary excretion, peak
excretion occurring between three to eight hours after dosing. I.V.
infusion of neutralized sodium silicate (1 mg/ml) in dogs leads to
rapid urinary elimination of about 50 per cent. of the dose (King et
In experiments with two volunteers, it was shown that, after ingestion
of 50 mg of monomeric silicic acid in 50 cm3 liquid, the renal
excretion of SiO2 per time unit was not related to the quantity of
urine excreted in the same time unit. Maximum excretion appeared after
one to two hours. Even at high concentrations up to more than 700µg
SiO2/cm3 urine, the silicic acid was still present in a molybdate
reactive form. Silicic acid polymerizes above 100-150 gamma
SiO2/cm3. The speed of polymerization is dependent on ph and
concentration. The experiment was designed so as to exclude damage to
the urinary tract through precipitation of proteins by polymeric
silicic acid formed by polymerization of monomeric silicic acid at
high concentrations. If the urine at concentration. in the order of
700 gamma SiO2/cm3 was taken at longer intervals, such as two
hours, the concentration of monomeric silicic acid as below the total
SiO2 concentration, thus suggesting that some polymerization had
taken place, There was no indication of storage breakdown of
reabsorption (Baumann 1960).
Administration of 5 g of the siliceous materials listed below in 20 ml
of milk by stomach tube to cats showed the following urinary excretion
within 120 hours; silicic acid (fresh) 43.3, calcium silicate 37.2,
magnesium trisilicate 34.1, silicic acid (moist) 29.0, SiO2 (quarz)
(air sediment very fine) 20.8, magnesium silicates (talc) 9.2,
diatomaceous earth 8.8 and calcium silica aluminate hydrate (kaolin)
7.6 mg SiO2. From this it can be observed that free silica is
attacked to a variable extent depending on its physical and chemical
condition. Several silicates are apparently unattacked, as non-treated
animals excreted an average of 8.6 mg in 120 hours. Some complex
silicates appear to suffer partial decomposition by the hydrochloric
acid of the stomach, with partial solution of same of the products in
the intestine (King et al. 1938).
Oral administration of a single dose of 2.5 g of amorphous polymeric
silicon dioxide (99.8 per cent. SiO2 content of the water free
compound) to 12 volunteers caused a slight but statistically
insignificant increase in the silicon dioxide level of the urine
(Langendorf et al., 1966).
"Quarz water" (water in which silicic acid had been dissolved as a
result of contact with quarz powder) given to rats over a prolonged
period as the only source of liquid intake did not show any SiO2
storage in tissues (Klösterkotter 1956).
In vitro investigations on slices of tissue showed that monomeric
silicic acid penetrated liver and kidney cells easily, whereas spleen
and muscle cells were more or less impenetrable (Kirsch 1960).
Ten gamma mononmeric SiO2/cm3 was shown in vitro to damage the
enzymes of isolated mitochondria in rat liver (Hanger et al., 1963).
Animal Route LD50 Reference
Rat Oral 3.16 Elsea, 1958a
The oral LD5 in mice of finely ground silicic acid is > 5 g/kg body
weight (Kimmerle 1968).
Rabbits receiving 3 mg of silicon in their conjunctival sac showed
mild irritation for 48 hours (Elsea 1958a).
A single dose of 50 mg of monomeric silicic acid in 50 cm3 liquid was
tolerated by two volunteers. Higher doses should be taken either with
more liquid or at intervals of about 20 mins. in order to avoid
polymerization of silicic acid in the urine (Baumann 1960). A single
dose of 2.5 g of amorphous polymeric silicon dioxide to volunteers did
not significantly raise the SiO2 excretion in the urine thus
suggesting poor absorption of the compound (Langendorf 1966).
The probable lethal dose of silica (oral) for man is over 15 g/kg body
weight. The probable oral lethal dose of magnesium trisilicate for man
is over 15 g/kg body weight. There is same doubt as to whether large
doses cause laxation. The probable oral dose for man of sodium
silicate lies lower at between 0.5 and 5 g/kg and may well be due to
its alkalinity (Unilever Research Laboratories 1964). Data on
inhalation toxicity of silica and silicates are not relevant to
consideration of toxic hazard by the oral route.
Rat. Oral administration of 50 mg amorphous silica to rats for three
months did not cause any toxic effects but no experimental details are
available (Malten et al., 1964). Micronized silica gel was fed to four
groups of ten male rats each in their diet at 0 per cent., 0.2 per
cent., 1.0 per cent. and 2.5 per cent. levels for 28 days. No adverse
effects on mortality or abnormal gross autopsy findings were
discovered. Body weight gain was significantly reduced at the 2.5 per
cent. level and nearly significantly at the 1.0 per cent. level. No
other parameters were examined (W. R. Grace & Co., 1958).
Fifteen male and 15 female rats received daily 50 mg of amorphous
polymeric silicone dioxide (99.8 SiO2 content of water free
compound) by stomach tube for three months. There was no adverse
effect an body weight gain and mortality. Pathology of organs not
enumerated showed no abnormalities in comparison with the controls
Groups of 15 male and 15 female rats were fed diets containing silica
at concentrations of 0.0, 1.0, 3.0 and 5.0 per cent. for 90 days. A
fifth positive control group received a diet containing 3.0 per cent.
cosmetic talc. No evidence of systemic toxicity caused by silica was
found in terms of survival, body weights and food consumption. No
appreciable deposition of silicon dioxide was seen in the kidney,
livers, spleen, blood and urine in the animals fed at the five per
cent. level. No gross or microscopic pathology attributable to silicon
were seen (Elsea 1958b).
The same compound was fed to 20 male and 20 female rats at a
concentration of 500 mg/kg body weight per day for six months. The
same number of animals served as the control. After four and a half
months five females were mated. No adverse effects were noted on
mortality, body weight gain, haematology (haemoglobin, erthrocyte- and
leucocyte-count) and reproductive performance. Histopathology of
stomach, intestines, pancreas, liver and kidney of the test group
showed no significant difference to that of the control group. Litter
size, birth weight and morphological development of the offspring as
well as weight gain were normal (Leuschner 1963).
In a similar experiment (see Leuschner 1963) the same results were
obtained when feeding a hydrophobic preparation of amorphous polymeric
SiO2 in which some of the silanol groups on the surface reacted with
dimethyl-dichlorosilane (98.5 per cent. SiO2 content of water free
compound) (Leuschner 1965).
The compound (see Leuschner 1965) was also fed to groups of five male
and five female rats at levels of 0, 500, 1000, 2000 mg/kg body weight
for five weeks. The highest level was raised after 14 days to 4000,
after 28 days to 8000 and after 42 days to 16 000 mg/kg body weight.
When the level was raised to 16 g/kg, all animals lost weight and four
animals died. Seven days after the level had been raised to 8000
mg/kg, the animals did not gain weight normally. At 1000 mg/kg two
rats out of 10 showed slight changes in the liver epithelia. At higher
levels atrophy of the liver epithelia, regression of the basophilic
structure and glycogen content were observed. Histopathology of other
organs (not enumerated) including the kidney of the animals at all
levels showed no significant changes compared with the controls
Rabbit. The dermal effects of silica was tested on groups consisting
of two male and two female rabbits at levels of five and 10 g/kg/day.
A negative control group received methyl cellulose solution (0.5 per
cent. w/w) and a positive control group received 10 g/kg/day of
cosmetic talc. Applications were made five days/week for three weeks.
No evidence of systemic toxicity caused by silica was found in terms
of body weight, behaviour, silicon content of blood, urine, spleen,
liver and kidney. No gross or microscopic pathology was seen in the
major organs examined or in the skin (Elsea 1958c).
Man. 60-100 g daily for three to four weeks of 12 per cent.
amorphous silicic acid administered orally to patients suffering from
gastritis or enteritis were tolerated without adverse effects. Only
one thousandth of the substance administered was excreted in the urine
The available data on orally administered silica and silicates,
including flumed silicate dioxide, appear to substantiate the
biological inertness of these compounds. Any silicate absorbed is
excreted by the kidneys without evidence of toxic emulation in the
body. Methods for estimating silica in body tissues have been greatly
improved in recent years making some of the earlier data somewhat less
valuable. A number of short-term studies in two species are available.
This information taken together with human clinical experience and the
ubiquitous occurrence of these compounds in the environment does not
point to any significant toxic effects when these substances are used
as food additives.
Not limited except for good manufacturing practice.
Baumann, H. (1960) Hoppe-Seylers Z. physiol. Cbemie., 320, 11
Elsea, J.R. (1958a) Unpublished report, January 8, from Hazleton
Elsea, J. R. (1958b) Unpublished report, July 11, from Hazleton
Elsea, J.R. (1958c) Unpublished report, May 6, from Hazleton
Hanger, R., Kirsch, K. & Standinger, Hj. (1963)
Beitr.Silikose-Forsch.S-Bd Grundfragen Silikoseforsch Bd. 5, 69
Keller, J. G. (1958) Unpublished report to W. R. Grace & Co.
Kimmerle (1968) unpublished report submitted by Bayer
King, E. J. Stantial, H. & Dolan, M. (1933) Biochem. J., 27, 1002
King, E. J. &, McGeorge, M. (1938) Biochem. J., 32, 426
Kirsch, K. (1960) Beitr. Silikose-Forsch. S-Bd. Grundfragen der
Silikoseforsch., 4, 33
Klosterkötter (1956) Diskussionsbemerkung, Beitr. Silikose-Forsch.
S-Bd. Grundfragen Silikoseforsch. Bd., 2, 348
Kuschinsky, G. (1955) Unpublished summary report submitted by Degussa
Langendorf, H. von & Lang, K. (1966) Zeitschrift für
Ernährungswissenschaft, 8, 27
Leuschner, F. (1963) Unpublished report submitted by Degussa
Leuschner, F. (1964) Unpublished report submitted by Degussa
Leuschner, F. (1965) Unpublished report submitted by Degussa
Malten, K. E. & Zielhuis, R. L. (1964) Industrial Toxicology and
Dermatology in the Production and Processing of Plastics, Elsevier,
Sarre, H. (1953) Unpublished summary report submitted by Degussa
Thomas, K. (1965) Dtsch. Zeitschr. f. Verdaunngs-u.
Stoffwechsel-Krankheiten 25, 260
Unilever Research Laboratory (1964) Report No. CH 64888, dated 21