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.
MODIFIED CELLULOSES
(Includes; hydroxypropyl cellulose, hydroxypropyl methylcellulose,
methylcellulose, methylethylcullulose, sodium carboxymethyl-cellulose)
Explanation
These substances have been evaluated for acceptable daily intake
by the Joint FAO/WHO Expert Committee on Food Additives (see Annex 1,
Refs Nos 7, 13 and 20) in 1963, 1966 and 1969.
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
(a) Hydroxypropyl cellulose
14C-labelled hydroxypropyl cellulose was administered to four
rats in a 5% aqueous solution. One male and one female rat received
0.25 g/kg bw, the other two rats received 1 g/kg bw. Urine, faeces and
expired air were collected over the next 120 hours. Then all organs
were assayed for residual radioactivity. No activity (<0.01% of the
administered dose) was detected in organs, urine and expired air due
to administered material. Recoveries of activity in the faeces varies
from 98.32 to 102.7%. Hence orally ingested material is not absorbed
from the gastrointestinal tract of the rat and is excreted
quantitatively in the faeces principally in the first 48 hours.
To check on enterohepatic circulation two additional rats with
ligated bile ducts were administered 1 g/kg of radio-labelled
material. Bile was collected for 72 hours but no significant activity
was found (Industrial Bio-Test Lab., 1964).
(b) Methylcellulose
Methylcellulose is usually resistant to microbial attack (Bargen,
1949). In rats it was not hydrolyzed to cellulose and methanol in the
intestinal tract and it did not appear to be absorbed (Bauer & Lehman,
1951).
Investigations on two male adults and one 10-year-old girl showed
that methylcellulose passed through the digestive tract practically
unaltered, when 5-10 g of methylcellulose were ingested the recovery
of methoxyl groups from the faeces was almost quantitative. Methanol
formation after the taking of methylcellulose was not significantly
different from that under normal conditions (Machle et al., 1944).
It has been stated that methylcellulose could be partly
hydrolyzed in the digestive tract to units of lower molecular weight,
as indicated by a decrease in viscosity. Such intermediate products
obtained after acid hydrolysis were fed to mice at a dose of 1 g daily
for 28 days without any demonstrable effect on growth rate (Letzig,
1943).
There is some evidence for the excretion of methylcellulose into
the milk of pregnant rats and this causes transient anaemia in
suckling rats (Baldini, 1958).
(c) Methylethylcellulose
After feeding a single dose of 0.6 g of methylethylcellulose in
the diet of rats some 90% of the dose was recovered from the faeces by
the end of the fourth day. Nearly all alkoxyl groups remained attached
to the cellulose chain during passage through the gut (Gage, 1962).
(d) Sodium carboxymethylcellulose
Sodium carboxymethylcellulose (CMC) is readily hydrolyzed by
micro-organisms (Reese et al., 1950). Diastase and cellulases are
stated to bring about the breakdown of this compound (Letzig, 1943).
Pepsin and pancreatin, separately or in combination, do not attack the
substance (Massatsch & Steudel, 1941).
In five rats fed 5 g of CMC collectively, approximately 90% of
the dose was recovered in the faeces (Shelanski & Clark, 1948).
Experiments on six rats during four periods of 10 days each showed
that CMC given in the diet at levels of 5%, 10% and 14% was reclaimed
quantitatively in the faeces (Ziegelmayer et al., 1951).
14C-tagged CMC, containing up to 0.34% radioactive sodium
glycolate, was given orally to two groups of five male rats each in a
dose of 400 mg. No detectable activity (less than 0.02% of the dose)
was found in the livers and kidneys and about 0.14% of the
administered radioactivity was found in the 48-hour urine samples.
This amount, however, could be accounted for by the free radioactive
glycolate present in the test compound (Wiebe et al., 1962).
Only about 50% of the intake of CMC could be recovered from the
faeces of two rabbits on diets containing 4.76% and 9% CMC.
Two dogs received 10 g of CMC for one day and 20 g daily for the
following five days. The total, doses were recovered quantitatively in
the faeces (Ziegelmayer et al., 1951).
Two human adults were given 30 g of CMC by mouth daily for four
days and a third was given 20 g/day. About 90% of the compound was
recovered from the faeces (Ziegelmayer et al., 1951).
TOXICOLOGICAL STUDIES
Special studies on carcinogenicity
Methylcellulose
Subcutaneous implantation of 500 mg of methylcellulose as a
powder in 25 rats failed to demonstrate carcinogenic properties
(Hueper, 1959).
Acute toxicity
(a) Hydroxypropyl cellulose
Animal Route LD50 mg/kg bw Reference
Rat Oral 10 200 Industrial Bio-Test Lab., 1962
(b) Hydroxypropyl methylcellulose (type B)
Animal Route LD50 mg/kg bw References
Mouse i.p. 5 000 Hodge et al., 1950
Rat i.p. 5 000 Hedge et al., 1950
(c) Methylcellulose
LD50 values have not been found in the literature. In dogs,
single intravenous injections of 40 ml of 0.7 to 2.8% solutions of
methylcellulose in saline resulted, within 24 hours in a moderate
anaemia and leucopenia and an increased sedimentation rate (Hueper,
1944). In rabbits, intravenous injections of 10 mg/kg were followed by
leucopenia. Injections of 10 to 100 mg/kg in a 1% solution had no
effect on the blood pressure or respiration (Wiedersheim, 1953). In
man, single oral doses of 5 g and 10 g were well tolerated (Maohle et
al., 1944),
Intravenous injection of a 1% solution in rabbits induced
subintimal deposits of methylcellulose at arterial walls followed by
extensive calcification, ossification, cartilage formation and lipid
deposition (Stehbens & Silver, 1966).
(d) Methylethylcellulose
No data are available but from short-term tests it can be
inferred that 3 g daily in the diet had no effect in rats (Imperial
Chemical Industries, 1966).
(e) Sodium carboxymethylcellulose
Animal Route LD50 mg/kg bw Reference
Rat oral 27 000 Shelanski & Clark, 1948
Guinea- oral 16 000 Shelanski & Clark, 1948
pig
Rats, guinea-pigs and rabbits showed no symptoms after
administration by stomach tube of 3000 mg/kg in three divided doses
(Rowe et al., 1944).
Six rats given an intravenous injection of 40 ml of a 1.6%
solution of CMC showed 48 hours later the presence of particles
localized in cells of the reticulo-endothelial system (Jasmin & Bois,
1961).
Four dogs given an intravenous injection of 40 ml of 0.25% CMC in
1% sodium chloride solution reacted with a transitory leucopenia
(Hueper, 1945).
Short-term studies
(a) Hydroxypropyl cellulose
Rat
Groups of five male and five female rats received in their diet
0.2%, 1.0% and 5.0% of hydroxypropyl cellulose for 90 days. Controls
received unmodified cellulose at the same levels. There were no
differences observed between tests and controls as regards mortality,
growth, food utilization, urinalysis, haemotological indices, organ
weight, gross pathology and histopathology. At higher dietary levels
there was increased food consumption and decreased food utilization
consequential to the inertness of the material (Industrial Bio-Test
Lab., 1963).
(b) Hydroxypropyl methylcellulose
Rat
Groups of 10 male and 10 female weanling rats were fed diets
containing 0, 2, 10 and 25% type B for 30 days. Only in the highest
dose were interference with body weight gain and diarrhoea observed.
There were no histological lesions nor were there abnormal findings in
urine and blood (Hodge et al., 1950).
Groups of 10 male and 10 female young rats were fed 0, 1, 3, 10
and 30% of type A for 121 days. Body weight gain was markedly retarded
at the 30% level, with 50% mortality attributed to under-nutrition.
Only the male rats showed slight body weight gain retardation at the
10% dietary level, while the weight gain was normal at the lower
levels. Histological examination of internal organs revealed no
abnormalities in any of the five groups (McCollister & Oyen, 1954).
Groups of 10 male and 10 female young rats were fed diets
containing 0, 0.3, 1, 10 and 20% of type C for 90 days. At the 20%
level both sexes showed marked retardation of body weight gain, with
30% mortality. At the 10% level male rats only showed slight but
significant weight gain retardation. At the lower levels there were no
adverse effects. The microscopic appearance of tissues was normal at
all levels (McCollister et al., 1961).
Groups of 10 male and 10 female young rats were fed 0, 0.3, 1, 3,
10 and 20% of type D for 84 days. No adverse effects were noted with
female rats at all levels. Male rats showed a definite retardation of
body weight gain at the 20% level and a slight retardation at 10%.
Organ weights and gross and microscopic examination revealed no
adverse effects (McCollister et al., 1961).
Rabbit
Groups of six rabbits were fed diets containing 0, 10 and 25%
type B for 30 days. The group on the highest dose maintained, but did
not increase, their body weight. Normal results were obtained from
urine and blood analyses, comparison of organ weights and histological
examination (Hodge et al., 1950).
Dog
Groups of two dogs were fed for one year 0.1, 0.3, 1.0 and
3.0 g/kg bw daily of type B without effect on body and organ weights,
urine, blood and microscopic appearance of internal organs. One dog
fed 25 g/kg bw daily for 30 days suffered no ill effects. Another dog
fed 50 g/kg bw daily for 30 days exhibited some diarrhoea, slight
weight loss and slight depression of red blood cell count without any
histological changes (Hodge et al., 1950).
(c) Methylcellulose
Rat
A group of 10 rats (five male and five female) was fed a diet
containing 10% methylcellulose for 95 days. The male rats gained
weight at the same rate as the controls. The females showed lower food
intake and slight growth depression. No abnormalities were found at
autopsy or on microscopic examination. Weights of heart, liver, spleen
and kidney were normal. The stomachs were 15% heavier in the
experimental group than in the controls (Tainter, 1943).
Eighty rats received methylcellulose at the level of 0.8%
in the diet and 1% in the drinking-water for eight months. This
was equivalent to an average total daily intake of 436 mg of
methylcellulose per animal. No effect on growth rate was observed in
any of the animals. Water and food intake were normal. No gross or
microscopic pathological changes were found post mortem (Deichmann &
Witherup, 1943).
Groups of five female rats were fed diets containing 1.66% and 5%
methylcellulose for six months without any adverse effects (Bauer et
al., 1944).
Three groups of 10 rats (five male and five female) were given
diets containing 0.17% (changed after six weeks to 0.5%) and 5%
methylcellulose for eight months. No deleterious effect on growth
was recorded, and macroscopic and microscopic examination of
representative animals revealed essentially normal tissues. Deposition
of abnormal material in the tissues was not observed. Reproduction was
unimpaired through three generations. Second and third generation rats
were fed a diet containing 5% methylcellulose for four months and
responded normally (Bauer & Lehman, 1951).
A modified paired feeding experiment was conducted on three
groups of rats for 90 days: one group received a diet containing 50%
methylcellulose, one a diet containing 50% cellulose powder, and one
the basal diet. Growth depression was seen in the first two groups.
Subsequent replacement of the methylcellulose or cellulose diet by the
basal diet resulted in marked weight gain (Bauer & Lehman, 1951).
In 28-day experiments with groups of 10 rats, some normal and
others vitamin-depleted, the oral administration of 50 mg of
methylcellulose did not affect the absorption of either 6 µg of
thiamine or 3 units of vitamin A per day, as determined by weight gain
(Ellingson & Massengale, 1952).
Four intraperitoneal injections over 10 days of a maximal total
dose of 160 mg of methylcellulose produced arterial hypertension and
glomerulonephritis in rats given a 1% NaCl solution to drink.
In a further experiment on rats methylcellulose was shown to
deposit within the renal glomeruli leading to reduction of filtration
and sodium accumulation if the latter is given as well. Hypertension
and glomerular lesions developed (Hall & Hall, 1962a).
Intravenous injections of 1% methylcellulose were made into rats
at three-day intervals and produced splenic enlargement 21 days after
the last injection. Survival time studies on red cells showed that the
enlarged spleens destroyed red cells more quickly (Fitch et al.,
1962). Intraperitoneal injections of 2.5% methylcellulose solution
twice weekly into adult rats for one to 16 weeks reduced haematocrit
and increased spleen weight in a dose-dependent manner. Foamy
histiocytes accumulated in the spleen pulp and sinusoids. E.M.
observations suggested lysosomal ingestion with phagolysosome
formation (Lawson & Smith, 1968).
Dog
Two dogs were fed doses of methylcellulose increasing from 2 g to
100 g daily for one month without any noticeable effect (Bauer, 1945).
Solutions containing 0.7 to 2.8% of methylcellulose of different
molecular weights in 1% NaCl were administered by intravenous
injection to 18 dogs in doses of 40 to 130 ml for five days a week.
The maximum total dose of 5720 ml was injected within six months. Most
of the animals died. Haematological reactions and the formation of
foam cells were observed (Hueper, 1944).
(d) Methylethylcellulose
None available.
(e) Sodium carboxymethylcellulose
Rat
Ten rats received 300 to 500 mg of CMC daily for two months
without any adverse effect (Werle, 1941).
One group of rats (10 male and 15 female) was fed on a diet
containing 5% CMC for 201 to 250 days. Judged by growth rate,
mortality, organ weight and the results of histopathological
examination of the liver, kidney, spleen, pancreas, adrenal gland,
testis and gastrointestinal tract, there was no significant difference
between the treated and the control group (Rowe et al., 1944).
Another group of 10 rats received a diet containing 20% of CMC
for 63 days. Slight growth retardation and a laxative effect were
observed. Organ weights and both gross and microscopic pathological
examination revealed no abnormalities (Rowe et al., 1944).
Two groups of 100 rats received daily 500 and 1000 mg/kg bw of
CMC mixed in their diets for six months. No adverse effects were
observed in any of the experimental animals as determined by growth
rate, fertility and examination of the blood, urine, and main tissues
(Shelanski & Clark, 1948).
Six rats were fed 14% of CMC in the diet for five weeks without
demonstrable deleterious effect (Ziegelmayer et al., 1951).
Ten rats given subcutaneous injections of CMC showed
mast-cell-like elements within the adrenal medulla. Changes in the
adrenocortical cells and the presence of granules in the adrenal-vein
were noted occasionally (Selye, 1955).
Guinea-pig
Two groups of 100 animals were fed CMC for six months at the
levels of 500 and 1000 mg/kg bw daily mixed in the diet. No signs of
toxicity were observed.
Two groups of 20 guinea-pigs received CMC in their diet at rates
of 500 and 1000 mg/kg bw daily for one year. As judged by weight gain,
gross and histopathological examination, no adverse effects were noted
(Shelanski & Clark, 1948).
Rabbit
Three rabbits were fed CMC at levels of 4.8% and 9% in their diet
for two periods of 15 days without any detectable toxic effects
(Ziegelmayer et al., 1951).
Dog
Two dogs were given daily doses of CMC (0.3-0.4 g/kg bw) in water
by mouth for two months without adverse effects (Werle, 1941).
Groups of 10 dogs were fed CMC daily in the diet at levels of 500
and 1000 mg/kg bw for six months. Growth rate was the same in all
groups. Six animals from each group were examined post mortem.
Histologically the stomach, intestines, spleen, kidney, heart, lung
and pancreas in the treated animals were no different from those of
the controls (Shelanski & Clark, 1948).
Five dogs received intravenous injections of 0.25% CMC in 1%
sodium chloride solution in doses increasing from 40 ml to 150 ml for
a maximum of three months. There were no gross pathological changes.
Histopathological studies revealed uptake in the reticuloendothelial
cells in the aorta (Hueper, 1945).
Chickens
Groups each of 20 one-day-old chicks were maintained on diets
containing 0 or 2% sodium carboxymethylcellulose for 20 days. Addition
of sodium carboxymethylcellulose to the diet resulted in decreased
growth rate (Vohra et al., 1964).
Long-term studies
(a) Hydroxypropyl cellulose
None available.
(b) Hydroxypropyl methylcellulose
Rat
Groups of 50 male and 50 female rats were fed for two years on
diets containing 0, 1, 5 and 20% of type B. There was a slight
retardation of body weight gain in the male group at the highest dose.
Mortality ranged from 60 to 84% with no significant difference between
the groups. Tumour incidence was the same in the experimental groups
as in controls (Hodge et al., 1950).
(c) Methylcellulose
None available.
(d) Methylethylcellulose
Mouse
Groups of 50 male and 50 female mice were fed 0, 0.1 and 1% of
methylethylcellulose for two years. Body weight was slightly reduced
in both sexes at the 1% level in the latter part of the test period.
There was no difference between the groups in survival, tumour
incidence, blood picture and gross and microscopic appearance of
internal organs (Imperial Chemical Industries, 1966).
Rat
Groups of 50 male and 50 female rats were fed 0, 0.1 and 1% of
methylethylcellulose for two years. Body weight was reduced in males
at the 1% level in the latter part of the test period. There was no
difference between the groups in survival, tumour incidence, blood
picture and gross and microscopic appearance of internal organs
(Imperial Chemical Industries, 1966).
(e) Sodium carboxymethylcellulose
Mouse
Groups of 50 male and 50 female mice were maintained for up to
100 weeks on ad lib. diets containing 0, 0.1 and 1% of sodium
carboxymethylcellulose. There was no apparent difference in mortality
and tumour incidence between the groups (Imperial Chemical Industries,
1966).
Rat
Groups of 50 male and 50 female rats were maintained for up to
two years on ad lib. diets containing 0, 0.1 and 1% of sodium
carboxymethylcellulose. No difference in mortality and tumour
incidence was apparent between the groups (McElligot & Hurst, 1968).
Thirty rats were given weekly injections of 1 ml of a 2% aqueous
solution of CMC subcutaneously. After 73 weeks, 43% of the animals
showed tumours at the site of injection, characterized as
fibrosarcomas of moderate malignancy by histological standards (Lusky
& Nelson, 1957).
Twenty rats were given subcutaneous injections once a week of 2%
aqueous solution of CMC. In four animals tumours developed at the site
of injection within 13 to 16 months. Two of the neoplasms were
fibromas and two fibrosarcomas (Jasmin, 1961).
Groups of 25 rats, divided about equally for sex, were placed for
two years on diets containing CMC in concentrations providing 100, 500
and 1000 mg/kg bw daily. Three generations of litters were produced
and kept on the same diet as their parents. According to growth rates,
monthly urine and blood examinations, fertility, and histopathological
examination of the main organs, there were no differences between the
test rats and the controls. No neoplasms were found in any of the
experimental animals (Shelanski & Clark, 1948).
OBSERVATIONS IN MAN
(a) Hydroxypropyl methylcellulose
Twenty-five young human adults ingested doses ranging from 0.6 to
8.9 g of type B on three separate occasions. Only a mild laxative or
constipating effect was noted in several cases. About 97% of the dose,
determined as methoxy groups, was recovered from faeces (Knight et
al., 1952).
(b) Methylcellulose
In three healthy adults 5 g of methylcellulose given twice a day
for eight days approximately doubled the volume of the stools and
increased their frequency slightly (Tainter, 1943).
There was no evidences of toxicity when 1-6 g were taken daily
as a laxative for four to 240 days (maximum 6 g for 240 days) by
37 patients (Schweig, 1948), but doses of 2.5 to 5.25 g of
methylcellulose taken orally as a gel in 250 ml of water were mildly
constipating (Bauer, 1945).
Patients have been given 2 g of methylcellulose before meals
without toxic reactions (Bargen, 1949).
Two patients given 60-90 ml of a methylcellulose preparation
daily for five days developed generalized oedema, visual disturbances
and neurological signs which disappeared within 72 hours of cessation
of intake. Symptoms were paralleled by sodium and water retention,
increased serum osmolality and reduced urinary aldosterone excretion
(Crane et al., 1969).
(c) Sodium carboxymethylcellulose
Daily oral doses of 20 to 30 g for seven days were well tolerated
by three human subjects (Ziegelmayer et al., 1951).
Eleven patients received 10 g daily for six months without
complaint, but in seven further cases the dose had to be reduced owing
to abdominal discomfort. No haematological changes were observed
(Brick, 1952).
Adult patients have been treated for more than a year with daily
oral doses of 2-6 g of CMC as a laxative and there were no ill-effects
(Brick, 1949; Fittipoldi & Davis, 1948; Schultz, 1949).
Skin tests on 100 men and 100 women demonstrated that sodium
carboxymethylcellulose is not a primary irritant, nor a sensitizer
(Shelanski & Clark, 1948).
Comments:
(a) Hydroxypropyl cellulose
There is adequate evidence of the biochemical inertness of
hydroxylpropyl cellulose and of the lack of absorption of the
substance from the gastrointestinal tract. It resembles closely other
modified celluloses.
(b) Hydroxypropyl methylcellulose
No significant amounts appear to be absorbed from the digestive
tract in man. A long-term study has been done on one particular type.
Short-term studies have been done with four slightly different types,
and gave consistent results.
(c) Methylcellulose
The results of the short-term studies in rats, two of them for
periods of eight months, are supported by evidence from the treatment
of human patients demonstrating no adverse effects. As metabolic
studies show no absorption from the intestinal tract, toxic reactions
resulting from parenteral administration can be left out of
consideration.
(d) Methylethylcellulose
In view of the metabolic inertness and the virtual non-
absorbability of this compound, evaluation is based on data provided
for other members in addition to those referable to
methylethylcellulose alone.
(e) Sodium carboxymethylcellulose
Studies with radio-labelled CMC have shown that significant
amounts of label are not absorbed from the digestive tract in man. The
injurious properties that have been demonstrated in animals following
parental administration can therefore be left out of consideration.
EVALUATION
Level causing no toxicological effect
Rat: 50 000 ppm (0.005%) in the diet, equivalent to
2500 mg/kg bw.
Estimates of acceptable daily intake for man
0-25* mg/kg bw.**
* As sum of total modified celluloses.
** ADI may be exceeded for dietetic purposes. Dietetic in this
context refers to a situation where use is primarily intended to take
advantage of the non-caloric property of these additives.
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