MODIFIED CELLULOSES
(Ethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl
cellulose, hydroxypropyl methyl cellulose, methyl cellulose, methyl
ethyl cellulose, sodium carboxymethyl cellulose).
1. EXPLANATION
Modified celluloses were reviewed at the fifth, seventh, tenth,
thirteenth, seventeenth, twenty-sixth, twenty-seventh and thirtieth
meetings of the FAO/WHO Joint Expert Committee on Food Additives.
(Annex 1, references 5, 7, 13, 19, 32, 59, 62, and 73). At the
seventeenth meeting a group ADI of 0-25 mg/kg bw was allocated for the
five previously reviewed modified celluloses which included methyl
cellulose, methyl ethyl cellulose, hydroxypropyl cellulose,
hydroxypropyl methyl cellulose, and sodium carboxymethyl cellulose. A
monograph was prepared discussing these 5 compounds (Annex 1,
reference 33).
The use of microcrystalline cellulose was not included in this
group ADI: no limitation other than that imposed by good manufacturing
practice was deemed necessary for the use of microcrystalline
cellulose as an additive (Annex 1, reference 26).
At the twenty-sixth and twenty-seventh meetings of the committee
ethyl cellulose and ethyl hydroxyethyl cellulose, respectively, were
reviewed and added to the group ADI of 0-25 mg/kg bw. A monograph on
ethyl hydroxyethyl cellulose was prepared after the thirtieth meeting
(Annex 1, reference 74).
Since the previous evaluation, additional data have become
available and are summarized and discussed in the following monograph.
The previously published monographs have been incorporated into the
document below.
2. BIOLOGICAL DATA
ETHYL CELLULOSE
2.2 Toxicological studies
2.2.1 Acute toxicity
Species Sex Route LD50 (mg/kg bw) Reference
Rat ? Oral 5,000 Moreno, 1977
Rabbit ? Dermal > 5,000 Moreno, 1977
2.2.2 Short-term studies
2.2.2.1 Rats
No adverse effects were reported in 80 rats fed a diet containing
1.2% ethyl cellulose, which is equivalent to 182 mg/kg bw/day (Hake &
Rowe, 1963).
2.2.3 Long-term/carcinogenicity studies
No data available.
2.2.4 Reproduction studies
No data available.
ETHYL HYDROXYETHYL CELLULOSE
2.2 Toxicological studies
2.2.1 Acute toxicity
Species Sex Route LD50 (mg/kg bw) Reference
Rat ? Oral 5,000 - 10,000 Cuthbert, 1975
The sensitization potential of 4 types of ethyl hydroxyethyl
celluloses was negative in the guinea pig by Kligman's maximization
test using positive and negative control groups.
In albino rabbits, primary skin irritation was evaluated on
abraded skin using a Draize type of procedure. The ethyl hydroxyethyl
celluloses produced only very mild irritant reactions, with primary
indices between 0.75 and 1.0. The control material, sodium
carboxymethyl cellulose, produced the greatest irritant reactions with
a resulting index of 1.42 (Cuthbert, 1975).
2.2.2 Short-term studies
2.2.2.1 Rats
Ethyl hydroxyethyl cellulose was administered to Charles River CD
rats (20 males and 20 females/group) by continuous dietary
incorporation at dose levels of 0, 250, 1375 or 2500 mg/kg bw/day for
90 consecutive days. All the animals were observed daily and all signs
of toxicity or behavioral changes were recorded. Body weight and food
consumption were recorded weekly. Ophthalmoscopy and hematology
analyses were carried out prior to termination. After 90 days of
treatment the animals were killed and macroscopic examination was
carried out on all tissues from animals in the control and high-dose
groups.
A statistically-significant increase in cumulative food
consumption was recorded in male rats from the high-dose group
throughout the study (weeks 1, 4, 8 and 12) and female rats of the
high-dose group at weeks 4, 8 and 10. The increased food consumption
was considered to represent compensation for the dietary inclusion of
the test substance. A corresponding marginal decrease in the
efficiency of food utilization was noted in rats of this treatment
group throughout the study. After adjustment for final body weight,
a small decrease in liver weight was apparent in male rats of the
high-dose group in comparison with control values. No changes in the
livers of these rats were apparent on histological examination. In
all other respects, including general health, body weight,
ophthalmoscopy, hematology, biochemistry, and macroscopic and
microscopic pathology, rats receiving ethyl hydroxyethyl cellulose
were similar to the controls (Elliot et al., 1985).
2.2.3 Long-term/carcinogenicity studies
No data available.
2.2.4 Reproduction studies
No data available.
2.3 Observations in man
Ethyl hydroxyethyl cellulose was administered in a dose of 1.0 to
1.5 g, three times a day for at least 2 months, in a study of 85 male
and female ambulatory patients (age 21-75 yr) with intestinal
problems. Sixty-eight patients remained on the treatment. X-ray
contrast media were used to study tablet disintegration in several
patients. The disintegration time was greater than 20 minutes. Aside
from minor abdominal discomfort in a few patients, no toxicity was
noted, and restoration to normal bowel movement was seen (Tomenius,
1957).
HYDROXYPROPYL CELLULOSE
2.1 Biochemical aspects
2.2.1 Absorption, distribution and excretion
When 250 or 1,000 mg/kg bw of [14C]hydroxypropyl cellulose was
administered to rats in a 5% aqueous solution, radioactivity no
greater than 0.01% of the administered dose was detected in organs,
urine and expired air. Recovery of activity in the feces varied 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 feces, principally in the first 48 hours.
To check on enterohepatic circulation, two additional rats with
ligated bile ducts were administered 1,000 mg/kg bw of radio-labelled
material. Bile was collected for 72 hours, but no significant activity
was found (Industrial Bio-Test Lab., 1964, not validated).
[14C]hydroxypropylcellulose (12.28% hydroxypropyl group,
2.74 uCi/mg) was administered to 3 male and 3 female rats of
Wistar-Imamichi Strain, weighing approximately 250g, at a dose of
1.3 g/kg bw. Urine and feces were collected for 96 hours, and the
residual radioactivity was measured in the tissues of the rats after
sacrifice. The bile duct was cannulated for bile collections. The
mean urinary excretion of radioactivity over 96 hours was 2.63% in
males and 1.50% in females. The mean fecal excretion was 68.7% and
97.3% in males, and 62.4% and 96.8% in females, over 24 and 96 hrs,
respectively. Total radioactivity in urine and feces over 96 hrs was
99.9% in males and 98.3% in females. Cumulative biliary excretion
over 24 hrs was .015% for males and .0024% for females (Kitagawa
et al., 1976a).
Gel filtration chromatographic patterns of urine were
inconclusive for identification of the single peak of radioactive
material. The elution position showed a molecular weight slightly
higher than glycerol or glucose and it was found at a different
position than propylene glycol, which was present at a level of less
than 2% in the administered material. No radioactivity was detectable
in tissues other than the liver and kidney. The highest radioactivity
in the liver was 1.5% of the dose in male rats at 12 hrs and 0.026% at
24 hrs in females (Kitagawa et al., 1976a).
2.2 Toxicological studies
2.2.1 Acute toxicity
Species Sex Route LD50 (mg/kg bw) Reference
Rat ? Oral 10,200-15,000 Industrial Bio-
Test Lab., 1962
(not validated)
Kitagawa, et
al., 1976b
2.2.2 Short-term studies
2.2.2.1 Rats
Groups of 5 male and 5 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. No differences were
observed between test and control animals as regards mortality,
growth, food utilization, urinalysis, hematological indices, organ
weight, gross pathology and histopathology. At higher dietary levels,
increased food consumption and decreased food utilization was
observed, probably due to dietary dilution (Industrial Bio-Test Lab.,
1963, not validated).
Groups of 10 male and 10 female young adult Wistar rats were fed
hydroxypropyl cellulose in 1% gum arabic at doses of 0, 1.5, 3.0, or
6.0 g/kg bw/day for 30 days and for 6 months. After 30 days, no
effects were observed on body weight and food consumption, serum
chemistry, urinalysis, or histopathology. In females, liver, kidney
and brain weights were decreased at 3.0 g/kg bw/day, but the decrease
did not show a consistent dose-response relationship. After 6 months,
decreased body weight was noted at the high dose level, which was
statistically significant for females. No effects related to dosage
were noted on food consumption, serum chemistry, urinalysis, or
histopathology. The hemoglobin level of male high- and mid-dose rats
was reduced. There were sporadic increases or decreases in organ
weights of a few groups without a dose relationship or associated
pathological change (Kitigawa et al., 1976b).
2.2.2.2 Chickens
Day-old Arbor Acres chicks were apportioned into groups of 10 and
fed low-fat, high-fat or high-protein diets containing 2%
hydroxypropyl cellulose or one of a variety of vegetable gums or other
polysaccharides for 3 wk. The control diet contained 2% cellulose.
Growth of chicks on the hydroxypropyl cellulose diet was depressed by
8% relative to the control diet, but feed intake, nitrogen retention
and fat absorption were unchanged (Kratzer et al., 1967).
2.2.3 Long-term/carcinogenicity studies
No data available.
2.2.4 Reproduction studies
No data available.
2.2.5 Special studies on teratogenicity
2.2.5.1 Rats
Groups of nulliparous female Wistar rats were mated to give 36-37
pregnant rats per dose group. Hydroxypropyl cellulose was administered
daily by gavage in 1% gum arabic at dose levels of 0, 200, 1000, or
5000 mg/kg bw/day between days 7 and 17 post-mating. On day 21 of
gestation, 21-24 females were subjected to Cesarean section. Corpora
lutea, implantations, viable and dead fetuses, and resorbed embryos
were counted and positions of implantations were observed. All viable
fetuses were individually weighed and examined for abnormalities. Two
to three fetuses per group were examined for skeletal abnormalities,
and the remainder were examined for visceral abnormalities. Twelve to
fifteen dams were allowed to deliver spontaneously. Viable pups and
stillborns were counted, and records taken of body weight, sex, and
presence of external anomalies. General behavior of pups was observed
during nursing and individual body weights were recorded at delivery
and weaning. Times for separation of lower incisors and and separation
of eyelids were noted. The pups were weaned at the 28th day after
birth. Each weanling was examined for general behavior and nervous
reflexes. Skeletal examination was done by soft X-ray. One male and
one female per group were killed and wet weights of the brain, heart,
lung, liver, spleen, kidney, thymus, adrenal, testes, epididymis,
prostate, ovary, pituitary and thyroid were obtained. Remaining
weanlings were observed for 5 weeks for body weight gain, and at
maturity for conditioned avoidance response and reproductive ability.
Both mean litter weight and percent pre-implantation loss were
significantly increased in the high dose group. The percent of
skeletal variations was significantly increased for the mid dose only.
At maturity, the progeny showed no effects on reflex behavior or
reproductive ability (Kitagawa et al., 1978a).
2.2.5.2 Rabbits
Groups of 11-12 pregnant Himalayan rabbits received oral doses of
hydroxypropyl cellulose by gavage in 1% gum arabic at levels of 0,
200, 1000, or 5000 mg/kg bw daily from days 6-18 of pregnancy.
Cesarean sections were performed on the 29th day of pregnancy and all
fetuses were examined for skeletal and organ malformations. Up to the
18th day of study a slight body weight loss was noted in the high dose
group. A slight decrease in the number of implants, not dose-related,
was recorded in treatment groups. The resorption rate was
significantly decreased only in the intermediate dosage group. The
mean fetal viable weight was not different between groups. The
pre-implantation loss was significantly increased in the 5000 mg/kg
bw/day group. The incidence of malformations was comparable to
historical controls and was not dose-related (Kitagawa et al.,
1978b).
HYDROXYPROPYL METHYL CELLULOSE
2.1 Biochemical aspects
2.1.2 Absorption, distribution and excretion
The disposition of orally administered 500 mg [14C]hydroxypropyl
methyl cellulose/kg bw (approx. 25 uCi in 3 ml) was examined in 3 male
and 3 female Sprague-Dawley rats either as a single dose, or as a
series of 5 consecutive doses. Radioactivity associated with the
single dose was recovered from the feces (>99%), urine (approx. 1%),
carcass and tissues (approx. 0.2%), expired air (0.07%), and bile
(0.05%). The excretory half life from plasma was approximately 2 hr.
The tissue accumulating the most radioactivity was the
gastrointestinal tract; 0.53% of the administered dose consisted of
cellulose units with an average molecular weight < 1000, which was
thought by the authors to be accounted for entirely (approx. 0.56%
administered dose) in the urine as methyl ethers of glucose and
oligomers. Radioactivity recovered after 5 consecutive doses was found
primarily in the feces (97% in males, 102% in females) with trace
amounts in the urine (approx. 1.0%) and with no evidence of tissue
accumulation (Gorzinski et al., 1986).
The cecal contents from 2 male Wistar rats were incubated
in vitro at 37°C for 0, 6, 12, 24, and 48 hr in complex medium broth
with 2 mg/ml of hydroxypropyl methyl cellulose. Total viable bacteria,
carbohydrate utilization and free reducing-ends were determined.
Hydroxypropyl methyl cellulose remained almost completely unfermented
(5% in 48 hr, no further change by 7 days), and there was no increase
in reducing-ends (i.e., no degradation of the cellulose polymers), or
in viable bacterial counts compared to the control incubations (Wyatt
et al., 1988).
2.2 Toxicological studies
2.2.1 Acute toxicity
Species Sex Route LD50 (mg/kg bw) Reference
Mouse ? i.p. 5,000 Hodge et al.,
Rat F oral >1000 mg/kg 1950 CTFA, 1978a
? i.p. 5,000 Hodge et al.,
1950
2.2.2 Short-term studies
2.2.2.1 Rats
Groups of 10 male and 10 female weanling rats were fed diets
containing 0, 2, 10 and 25% hydroxypropyl methyl cellulose, type B,
for 30 days. Only in the highest dose were interference with body
weight gain and diarrhea 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 hydroxypropyl methyl cellulose, type A, for 121 days. Body
weight gain was markedly retarded at the 30% level, with 50% mortality
attributed to undernutrition. 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 hydroxypropyl methyl cellulose,
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 hydroxypropyl methyl cellulose, 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 20% level
and a slight retardation at 10%. Organ weights and gross and
microscopic examination revealed no adverse effects (McCollister
et al., 1961).
Groups of 10 male and 10 female young rats (unknown strain) were
fed diets containing 0, 1, 3 and 10% hydroxypropyl methyl cellulose
(higher viscosity, 31,800 cP) and 0, 1, 3, and 10% hydroxypropyl
methyl cellulose (lower viscosity, 8,480 cP) for 92 days. No adverse
effects were observed as judged by mortality, growth, general
appearance and behavior, body weights, food consumption, hematological
and serum chemistry analysis, organ weights and gross and histological
examination (McCollister & Copeland, 1967).
Groups of 10 male and 10 female Dow-Wistar rats were fed diets
containing 0, 1, 3 and 10% low viscosity (10 cP) hydroxypropyl methyl
cellulose for 90 days. Groups of 10 male and 10 female Sprague-Dawley
rats were fed diets containing 0, 3 and 10% high viscosity (4000 cP)
hydroxypropyl methyl cellulose for 90 days. No evidence of toxicity
was observed in either strain of rats as judged by mortality, body
weights, food consumption, urine and hematological analyses, serum
chemistry, organ weights and gross and histological examination
(McCollister et al., 1973).
Groups of 15 male and 15 female Sprague-Dawley rats were fed
diets containing 0, 1 and 5% low viscosity (4.22 cP) hydroxypropyl
methyl cellulose for 90-91 days. No evidence of toxicity was observed
in rats as judged by mortality, body weight, food consumption, urine
and hematology analyses, serum chemistry, organ weights and gross and
histological examination (Schwetz et al., 1973).
Groups of 5 male Wistar rats were fed diets containing either 0
or 100 g hydroxypropyl methyl cellulose/kg bw for 12 days. The
hydroxypropyl methyl cellulose diet led to an enlargement of the cecum
and colon associated with increased contents and tissue weight. The
density of bacteria in the cecum and colon of animals fed
hydroxypropyl methyl cellulose was significantly reduced over the
fibre-free controls. The authors concluded that the cecal and colonic
hypertrophy is a physical response to the increased content bulk
(Wyatt et al., 1988).
2.2.2.2 Rabbits
Groups of 6 rabbits were fed diets containing 0, 10 and 25%
hydroxypropyl methyl cellulose, 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).
2.2.2.3 Dogs
Groups of two dogs were fed for one year 0.1, 0.3, 1.0 and
3.0 g/kg bw/day of hydroxypropyl methyl cellulose, type B, without
effect on body and organ weights, urine, blood and microscopic
appearance of internal organs. One dog fed 25 g/kg bw/day for 30 days
suffered no ill effects. Another dog fed 50 g/kg bw/day for 30 days
exhibited some diarrhea, slight weight loss and slight depression of
red blood cell count without any histological changes (Hodge
et al., 1950)
Groups of 2 male and 2 female beagle dogs were fed diets
containing 0, 2 and 6% low viscosity (10 cP) hydroxypropyl methyl
cellulose for 90 days. No evidence of toxicity was observed in dogs as
judged by mortality, body weight, food consumption, urine and
hematological analyses, serum chemistry, organ weights and gross and
histological examination (McCollister et al., 1973).
Groups of 4 male and 4 female beagle dogs were fed diets
containing 0, 1 and 5% low viscosity (4.22 cP) hydroxypropyl methyl
cellulose for 90-91 days. No evidence of toxicity was observed in
dogs as judged by mortality, body weight, food consumption, urine,
hematology, and serum chemistry analyses, organ weights and gross and
histological examination (Schwetz et al., 1973).
2.2.3 Long-term/carcinogenicity studies
Rats
Groups of 50 male and 50 female rats were fed for two years on
diets containing 0, 1, 5 and 20% of hydroxypropyl methyl cellulose,
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).
2.2.4 Reproduction studies
No data available.
2.3 Observations in man
Twenty-five young adults ingested doses ranging from 0.6 to
8.9 g of hydroxypropyl methyl cellulose, 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 feces (Knight et al., 1952).
METHYL CELLULOSE
2.1 Biochemical aspects
2.1.1 Absorption, distribution and excretion
Methyl cellulose 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 methyl cellulose passed through the digestive tract practically
unaltered. When 5-10 g of methyl cellulose were ingested the recovery
of methoxyl groups from the feces was almost quantitative. Methanol
formation after the taking of methyl cellulose was not significantly
different from that observed under normal conditions (Machle et al.,
1944).
It has been stated that methyl cellulose 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 the growth rate
(Letzig, 1943).
There is some evidence for the excretion of methyl cellulose into
the milk of pregnant rats and this causes transient anemia in suckling
rats (Baldini, 1958).
In rats, a one-time dose of 500 mg/kg bw of [14C]methyl
cellulose (labelled in the methoxyl group, and with a viscosity of
3300 cP) was excreted in its entirety (102.2%) in the feces within 48
hours. No radioactivity was detected in the expired air and less than
0.1% of the original dose of radioactivity was found in the urine,
selected tissues and remaining carcass. In rats receiving multiple
doses of labeled methyl cellulose for 5 days, no accumulation of 14C
activity was observed in the body or in selected tissues (Braun
et al., 1974).
When sucrose-based diets containing 8% methyl cellulose of either
low (25 cP), medium (400 cP) or high (1500 cP) viscosity was fed to
male rats (Hooded Wistar strain) for 10-11 days, neither food intake
nor growth were affected by consumption of methyl cellulose.
Tritium incorporation from i.p.-injected tritiated water into
fatty acids and cholesterol in the liver was decreased. The authors
concluded that the decreased hepatic fatty acid synthesis, decreased
serum glucose and increased glycogen storage observed in treated rats
could be explained by a slower absorption rate with increasing
viscosity of the methyl cellulose diets. No effect of methyl
cellulose was noted on cholesterol metabolism, and no evidence was
found to suggest that methyl cellulose is fermented by gut microbial
flora in the rat (Topping et al., 1988).
2.2 Toxicological studies
2.2.1 Acute toxicity
LD50 values for methyl cellulose have not been found in the
literature. In dogs, single intravenous injections of 40 ml of 0.7 to
2.8% solutions of methyl cellulose in saline resulted, within 24
hours, in a moderate anemia and leukopenia and an increased
sedimentation rate (Hueper, 1944). In rabbits, intravenous injections
of 10 to 100 mg methyl cellulose/kg bw in a 1% solution had no effect
on blood pressure or respiration (Wiedersheim et al., 1953). In
man, single oral doses of 5 and 10 g of methyl cellulose were well
tolerated (Machle et al., 1944).
Intravenous injection of a 1% solution of methyl cellulose in
rabbits induced subintimal deposits of methyl cellulose at arterial
walls followed by extensive calcification, ossification, cartilage
formation and lipid deposition (Stehbens & Silver, 1966).
2.2.2 Short-term studies
2.2.2.1 Rats
A group of 10 rats (5 male and 5 female) was fed a diet
containing 10% methyl cellulose 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 the 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 methyl cellulose at the level of 0.8% in the
diet and 1% in the drinking-water for 8 months. This was equivalent to
an average total daily intake of 436 mg of methyl cellulose 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 5 female rats were fed diets containing 1.66% and 5%
methyl cellulose for six months without any adverse effects (Bauer
et al., 1944).
Three groups of 10 rats (5 male and 5 female) were given diets
containing 0.17% (changed after six weeks to 0.5%) and 5% methyl
cellulose 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 fed a diet containing 5% methyl cellulose for 4 months 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%
methyl cellulose, 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 methyl cellulose 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 methyl
cellulose 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 methyl cellulose produced arterial hypertension and
glumerulo-nephritis in rats given a 1% NaCl solution to drink. In a
further experiment on rats, methyl cellulose was shown to deposit in
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, 1962).
Intravenous injections of 1% methyl cellulose were given to rats
at three-day intervals, which 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% methyl cellulose solution
twice weekly into adult rats for one to 16 weeks reduced hematocrits
and increased spleen weights in a dose-dependent manner. Foam
histiocytes accumulated in the spleen pulp and sinusoids. Electron
microscopic observations suggested lysosomal ingestion with
phagolysosome formation (Lawson & Smith, 1968).
Groups of 10 male and 10 female Sprague-Dawley (Spartan strain)
rats were fed for 90 days on diets containing methyl cellulose with a
viscosity of 10 cP (0, 1, 3 and 10%) or a viscosity of 4000 cP (0, 3
and 10%). Male rats consuming 10% methyl cellulose (viscosity of 10
cP) exhibited slight reductions in terminal body weight relative to
controls, but growth was normal in all other 10 cP treatment groups,
and in all rats consuming the 4000 cP methyl cellulose. Food
consumption was significantly elevated (up to 10%) at certain
treatment levels in rats consuming either of the 2 methyl cellulose
preparations as described in the following table:
Food Consumption
Viscosity Dose Males Females
10 cP 3% N N
10% I N
4000 cP 3% I N
10% I I
I = significant increase relative to controls
N = no significant change relative to controls
No significant treatment-related effect was observed on other
toxicological parameters examined in the study, including serum
chemistry, hematology, urinalyses, organ weights and pathology (gross
and microscopic). No accumulation of test material in the
reticuloendothelial system could be detected by histopathologic
examination (McCollister, et al., 1973).
2.2.2.2 Dogs
Two dogs were fed doses of methyl cellulose increasing from 2 to
100 g daily for one month without any noticeable effect (Bauer, 1945).
Solutions containing 0.7 to 2.8% methyl cellulose of different
molecular weights in 1% NaCl were administered by i.v. injection to 18
dogs in doses of 40 to 130 ml for 5 days a week. The maximum total
dose of 5720 ml was injected within six months. Most of the animals
died. Hematological reactions and the formation of foam cells were
observed (Hueper, 1944).
2.2.3 Long-term/carcinogenicity studies
2.2.3.1 Rats
Groups of 30 Sprague-Dawley rats (Spartan strain) of each sex
were fed diets containing 0, 1% or 5% methyl cellulose of viscosity
15, 400 or 4000 cP for 2 yr. Gross pathological examinations were
conducted on terminally ill rats or rats dying during the study, and
on remaining survivors at termination. During necropsy, sections of
grossly visible nodules or masses were preserved for histopathological
examination. There was no indication of increased tumour incidence in
rats receiving the methyl cellulose diets (McCollister et al.,
1973).
Groups of 20 Sprague-Dawley rats (Spartan strain) of each sex
were fed chow diets containing 0, 1% or 5% methyl cellulose of
viscosity 15, 400 or 4000 cP for 2 yr. At termination, gross
pathologic examinations were performed and blood was sampled (5 rats
from each sex) for hematologic evaluation (PCV, Hb, and WBC counts)
and serum chemistry (BUN and AP). Additional groups of rats fed the
same diets were interim sacrificed at 12 and 18 mos. and subjected to
either gross pathologic examination (10 rats of each sex) or tested
for hematology and serum chemistry parameters. During necropsy,
selected tissues (lungs, heart, liver, kidneys, spleen, and testes)
were weighed and, with pancreas and adrenals, preserved for
histopathological evaluation. No treatment-related effect was reported
on mortality or any other test parameters over the course of the study
(McCollister et al., 1973).
Subcutaneous implantation of 500 mg of methyl cellulose as a
powder in 25 rats failed to demonstrate carcinogenic properties
(Hueper, 1959).
2.2.4 Reproduction studies
No data available.
2.2.5 Special studies on teratogenicity
2.2.5.1 Mice
Groups of 12-17 pregnant mice were administered daily gavage
doses of a methyl cellulose suspension in corn oil (70, 153, 330 and
700 mg/kg bw/day) during days 6-15 of pregnancy. Control groups
received daily doses of corn oil (negative control) or acetylsalicylic
acid (110 mg/kg bw, positive control) during the same period of
pregnancy. On day 17 of pregnancy, dams were subjected to Cesarian
section and examination of uterine contents. No dose-related effects
on growth, mortality or incidence of gross lesions were observed in
treated dams. However, significant reductions in the number of
implantations, live fetuses, and corpora lutea were observed in high
dose dams, relative to corn oil controls. No increase in incidence of
external, visceral and skeletal abnormalities, reduced weight or
mortality was observed in fetuses from treated dams (Cannon Labs,
1975).
Groups of 20-22 pregnant mice were administered daily gavage
doses of a methyl cellulose suspension in corn oil (0, 16, 74, 345,
1600 mg/kg bw/day) during days 6-15 of pregnancy. Control groups
received daily doses of corn oil (negative control) or aspirin
(150 mg/kg bw, positive control) during the same period of pregnancy.
On day 17 of pregnancy, dams were subjected to Cesarian section and
examination of uterine contents. Methyl cellulose administered at
levels up to 345 mg/kg bw/day had no effect on nidation or on maternal
or fetal survival. However, a significant increase in mortality was
observed in high dose dams, with a reduced rate of pregnancy in
survivors. At term, resorption sites were markedly increased in
number, and live fetuses were significantly reduced in number and
retarded in maturation and in weight. No evidence of teratogenic
effects was seen in fetuses from high dose dams or from dams receiving
lower levels of treatment (Food and Drug Research Laboratories, Inc.,
1973).
2.2.5.2 Rats
Groups of 13-18 pregnant rats were administered daily gavage
doses of a methyl cellulose suspension in corn oil (120, 260, 550 and
1200 mg/kg bw/day) during days 6-15 of pregnancy. Control groups
received daily doses of corn oil (negative control) or acetylsalicylic
acid (250 mg/kg bw, positive control) during the same period of
pregnancy. On day 20 of pregnancy, dams were subjected to Cesarian
section and examination of uterine contents. No dose-related effects
on growth, mortality or incidence of gross lesions were observed in
treated dams. The incidences of implantations, live fetuses, corpora
lutea, dead fetuses and resorptions in treated dams were within the
normal range. No increase in incidence of external, visceral and
skeletal abnormalities was observed in fetuses from treated dams, with
the exception of an increased incidence of extra centers of
ossification in vertebrae of fetuses from high dose dams. Fetal
weights were not affected by treatment (Cannon Labs, 1977).
Groups of 20-25 pregnant rats were administered daily gavage
doses of a methyl cellulose suspension in corn oil (13, 51, 285, 1320
mg/kg bw/day) during days 6-15 of pregnancy. Control groups received
daily doses of corn oil (negative control) or aspirin (150 mg/kg bw,
positive control) during the same period of pregnancy. On day 20 of
pregnancy, dams were subjected to Cesarian section and examination of
uterine contents. No dose-related effects on growth, mortality or
incidence of gross lesions were observed in treated dams. The
incidences of implantations, live fetuses, dead fetuses and
resorptions in treated dams were within the normal range. No increase
in incidence of external, visceral and skeletal abnormalities was
observed in fetuses from treated dams, with the exception of an
increased incidence of extra centers of ossification in vertebrae of
fetuses from high dose dams, nor were fetal weights affected by
treatment (Food and Drug Research Laboratories, Inc., 1973).
2.2.5.3 Hamsters
Groups of 22-24 pregnant hamsters were administered daily gavage
doses of a methyl cellulose suspension in corn oil (10, 46, 216, 1000
mg/kg bw) during days 6-10 of pregnancy. Control groups received daily
doses of corn oil (negative control) or aspirin (250 mg/kg bw,
positive control) during the same period of pregnancy. On day 24 of
pregnancy, dams were subjected to Cesarian section and examination of
uterine contents. No dose-related effects on growth, mortality or
incidence of gross lesions were observed in treated dams. The
incidence of implantations, live fetuses, dead fetuses and resorptions
in treated dams was within the normal range. No increase in incidence
of external, visceral and skeletal abnormalities was observed in
fetuses from treated dams, nor were fetal weights affected by
treatment (Food and Drug Research Laboratories, Inc., 1973).
2.2.5.4 Rabbits
Groups of 10-17 pregnant rabbits were administered daily gavage
doses of a methyl cellulose suspension in corn oil (7, 32, 148, 685
mg/kg bw) during days 6-18 of pregnancy. Control groups received daily
doses of corn oil (negative control) or 6-aminonicotinamide (7 mg/kg
bw, positive control) during the same period of pregnancy. On day 29
of pregnancy, dams were subjected to Cesarian section and examination
of uterine contents. Dams treated at the highest dose level
experienced increased mortality and a decrease in pregnancy rate in
survivors, but no dose-related effects on growth or incidence of gross
lesions were observed. The incidence of corpora lutea, implantations,
live fetuses, dead fetuses and resorptions in treated dams was within
the normal range. No increase in incidence of external, visceral and
skeletal abnormalities was observed in fetuses from treated dams, nor
were fetal weights affected by treatment (Food and Drug Research
Laboratories, Inc., 1973).
2.2.5 Special studies on genotoxicity
Results of genotoxicity assays on methyl cellulose
Concentration of
Test System Test Object Methyl cellulose Results Reference
Ames test S.typhimurium 50 µg/plate Negative Blevins &
(1) TA98, TA100 Taylor, 1982
TA1535, TA1537,
TA1538
Ames test S.typhimurium <70 mg/plate Negative Ishidate, Jr.,
(1) TA92, TA94, et al.,
TA98, TA100, 1984
TA1535, TA1537,
TA1538
Host-mediated S.typhymurium 1 x 4.75, 47.5 Negative Litton
assay in rats/ TA1530. G46 & 475 mg/kg bw Bionetics,
reverse mutagenesis & 5 x 5000 mg/kg 1974
bw/day
Host-mediated S.cerevisiae 1 x 4.75, 47.5 Negative Litton
assay in rats/ TA1530, G46 & 475 mg/kg bw Bionetics
mitotic & 5 x 5000 mg/kg 1974
re-combination bw/day
Chromosomal Chinese hamster <4.0 mg/ml Negative Ishidate, Jr.,
Aberration fibroblast et al.,
in vitro 1984
Concentration of
Test System Test Object Methyl cellulose Results Reference
Chromosome Human embryonic 80, 800 & 8000 Negative Litton
Aberration lung cells µg/ml Bionetics
Induction (WI-38) 1974
in vitro
Chromosome Rat Bone 1 x 4.75, 47.5 Negative Litton
Aberration Marrow cells 475 mg/kg bw Bionetics
Induction in vivo & 5 x 5000 mg/kg 1974
bw/day
Dominant Male Rats 1 x 4.75, 47.5 Negative Litton
Lethal Assay 475 mg/kg bw Bionetics
& 5 x 5000 mg/kg 1974
bw/day
(1) Both with and without rat liver S-9 fraction.
2.3 Observations in man
In 3 healthy adults, 5 g of methyl cellulose given twice a day
for 8 days approximately doubled the volume of the stools and
increased their frequency slightly (Tainter, 1943).
There was no evidence of toxicity when 1-6 g of methyl cellulose
were taken daily as a laxative for 4 to 240 days (maximum 6 g for 240
days) by 37 patients (Schweig, 1948).
In another study, doses of 2.5 to 5.25 g of methyl cellulose
taken orally as a gel in 250 ml of water were mildly constipating
(Bauer, 1945).
Patients have been given 2 g of methyl cellulose before meals
without toxic reactions (Bargen, 1949).
Two patients given 60-90 ml of a methyl cellulose preparation
daily for 5 days developed generalized edema, 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).
Five adult male volunteers were given 250 mg methyl cellulose/kg
bw daily, divided into 3 equal portions, over a period of 23
consecutive days. The treatment was well tolerated, producing no
allergic responses or alteration in normal elimination patterns.
Methyl cellulose, administered as a prehydrated gel, caused increased
fecal weight (wet and dry basis), but had variable effects on
intestinal transit time, causing increased transit time in three
subjects and decreased transit time in the other two. Hematology,
serum biochemistry and urinalysis parameters remained within normal
limits. Small, but significant, reductions were observed in fecal
volatile fatty acids and neutral sterols, but breath hydrogen levels
were not affected (Eastwood et al., 1988).
Fifty healthy adults (44 women and 6 men, 18-70 yr of age) were
administered daily doses of bulk laxative containing either a placebo
or methyl cellulose (4000 cP, 30% substitution, 2 or 4 g) for a 1 wk
period. All subjects had received placebo for the week preceding
treatment. In a second phase of the study, 59 adults (56 women, 3 men)
suffering from constipation were administered daily doses of either
methyl cellulose (1, 2, or 4 g) or 3.4 g psyllium as a positive
control for a 1 wk period. All stools generated during the study were
weighed and analyzed for solids and moisture content. Stool moisture
content and frequency of bowel movements were increased in normal
adults consuming 4 g of methyl cellulose, but they were unaffected at
the 2 g level of exposure relative to the placebo period of the study.
Stool size was unchanged, and no significant effect on stool
consistency was noted by the patients. Constipated adults experienced
an increase in stool frequency with the psyllium control and with
methyl cellulose at all dose levels. No significant increase in
incidence of abdominal discomfort or flatulence was reported (Hamilton
et al., 1988).
METHYL ETHYL CELLULOSE
2.1 Biochemical aspects
2.1.1 Absorption, distribution and excretion
After feeding a single dose of 0.6 g of methyl ethyl cellulose in
the diet of rats some 90% of the dose was recovered from the feces by
the end of the fourth day. Nearly all alkoxyl groups remained attached
to the cellulose chain during passage through the gut (Gage, 1962).
2.2 Toxicological studies
2.2.1 Acute studies
No data available.
2.2.2 Short-term studies
2.2.2.1 Chicken
Day-old Arbor Acres chicks were apportioned into groups of 10 and
fed low-fat, high-fat or high-protein diets containing 2% methyl ethyl
cellulose or one of a variety of vegetable gums or other
polysaccharides for 3 wks. Cellulose was used in the control diet.
Chicks grew normally on the methyl ethyl cellulose diet. Feed intake
was enhanced by 6% and nitrogen retention was increased by 14%, but
fat absorption was not significantly changed relative to controls
(Kratzer, et al., 1967).
2.2.3 Long-term/carcinogenicity studies
2.2.3.1 Mice
Groups of 50 male and 50 female mice were fed 0, 0.1 and 1% of
methyl ethyl cellulose 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).
2.2.3.2 Rats
Groups of 50 male and 50 female rats were fed 0, 0.1 and 1% of
methyl ethyl cellulose for 2 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).
2.2.4 Reproduction studies
No data available.
SODIUM CARBOXYMETHYL CELLULOSE
2.1 Biochemical aspects
2.1.1 Absorption, distribution and excretion
Sodium carboxymethyl cellulose (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 5 rats fed 5 g of CMC collectively, approximately 90% of the
dose was recovered in the feces (Shelanski & Clark, 1948).
Experiments on 6 rats during 4 periods of 10 days each showed
that CMC given in the diet at levels of 5%, 10% and 14% was reclaimed
quantitatively in the feces (Ziegelmayer et al., 1951).
[14C]-labelled CMC, containing up to 0.34% radioactive sodium
glycolate, was given orally to 2 groups of 5 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
feces 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 5
days. The total doses were recovered quantitatively in the feces
(Ziegelmayer et al., 1951).
Two human adults were given 30 g of CMC by mouth daily for 4 days
and a third was given 20 g/day. About 90% of the compound was
recovered from the feces (Ziegelmayer et al., 1951).
2.2 Toxicological studies
2.2.1 Acute toxicity
Species Route LD50(mg/kg bw) Reference
Rat oral 15,000-27,000 Shelanski & Clark, 1948
CTFA, 1977
CTFA, 1978a,b
CTFA, 1980
Guinea-pig oral 16,000 Shelanski & Clark, 1948
Rats, guinea-pigs and rabbits showed no symptoms after
administration by stomach tube of 300 mg/kg bw in three divided doses
(Rowe et al., 1944).
Six rats given an intravenous injection of 1 ml of a 1.6%
solution of CMC showed the presence of particles localized in cells of
the reticulo-endothelial system 48 hours later (Jasmin & Bois, 1961).
Four dogs given an i.v. injection of 40 ml of 0.25% CMC in 1%
sodium chloride solution reacted with a transitory leukopenia (Hueper,
1945).
2.2.2 Short-term studies
2.2.2.1 Rats
Ten rats received 300 to 500 mg of CMC daily for two months
without any adverse effect (Werle, 1941).
Ten male and 15 female rats were fed a diet containing 5% CMC for
201 to 250 days. Judged by growth rate, mortality, organ weights and
the results of histopathological examination of the liver, kidney,
spleen, pancreas, adrenal gland, testis and gastrointestinal tract,
there were no significant differences between the treated and the
control groups (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 500 and 1000 mg/kg bw/day 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).
Rodents (12 animals per group) were maintained for 21 days on a
high-protein diet containing 0 or 15% sodium CMC of 10 viscosity
grades (35-4500 cP) or 4 other vegetable gums. Animals were weighed on
alternate days. Body weight gain for one sample of CMC exceeded that
of controls and body weight gains for two CMC samples were less than
that of controls. Average fecal water content (measured as %) was
increased in all CMC-fed animals from 1.9-3.0 fold, and average filled
cecal weight (g/kg bw) was increased 1.5-3.3 fold relative to
controls. It was noted that there was a tendency for CMC samples of
low molecular weight to produce high fecal wet weights. Measuring the
viscosities of completely hydrated samples of CMC indicated that CMC
can have large or narrow molecular weight distributions. It was
suggested that different molecular weight distributions in samples of
CMC may produce different physiologic or dietary responses to CMC
(Anderson, 1986).
2.2.2.2 Guinea-pigs
Two groups of 100 animals were fed CMC for six months at levels
of 500 and 1000 mg/kg bw/day 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/day for one year. As judged by weight gain,
gross and histopathological examination, no adverse effects were noted
(Shelanski & Clark, 1948).
2.2.2.3 Rabbits
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).
2.2.2.4 Dogs
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 in the diet at levels of 500 and
1000 mg/kg bw/day 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 treated animals were no different from those of
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 of CMC in the
reticuloendothelial cells in the aorta (Hueper, 1945).
2.2.2.5 Chickens
Groups of 20 one-day-old chicks were maintained on diets
containing 0 or 2% sodium CMC for 20 days. Addition of sodium CMC to
the diet resulted in decreased growth rate (Vohra & Kratzer, 1964).
2.2.3 Long-term/carcinogenicity studies
2.2.3.1 Mice
Groups of 50 male and 50 female mice were maintained for up to
100 weeks on ad libitum diets containing 0, 0.1 and 1% of sodium
CMC. There was no apparent difference in mortality and tumour
incidence between the groups (Imperial Chemical Industries, 1966).
Groups of 50 male and 50 female B6C3F1 mice were used as vehicle-
controls in a carcinogenicity study of selenium sulfide, and received
50 mg/kg bw of CMC by gavage, 5 days per week for 103 weeks. Untreated
mice served as controls. Test animals were observed twice daily and
examined weekly for clinical signs and the presence of palpable
lesions. Mean body weights were recorded every two weeks for the first
12 weeks, then monthly for the remaining 93 weeks. Animals that were
moribund and those that survived to the end of the study were
necropsied. Gross and microscopic examinations were performed on
major organs and all gross lesions. CMC-gavaged animals had
approximately the same or fewer neoplasms than untreated control
animals (NCI, 1979).
2.2.3.2 Rats
Groups of 25 rats, divided about equally by 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).
Groups of 50 male and 50 female rats were maintained for up to
two years on ad libitum diets containing 0, 0.1 and 1% of sodium
CMC. 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 tumour s at the site of injection, characterized as
fibrosarcomas of moderate malignancy (Lusky & Nelson, 1957).
Twenty rats were given subcutaneous injections once a week of 2%
aqueous solution of CMC. In 4 animals, tumours developed at the site
of injection within 13 to 16 months. Two of the neoplasms were
fibromas and two fibrosarcomas (Jasmin, 1961).
Fifty F344 rats of each sex served as the vehicle control for a
carcinogenicity study of selenium sulfide, and received 5 mg/kg bw of
CMC by gavage five days per week for 103 weeks. Untreated rats served
as controls. Test animals were observed twice daily and examined
weekly for clinical signs and the presence of palpable lesions. Mean
body weights were recorded every two weeks for the first 12 weeks,
then monthly for the remaining 93 weeks. Animals that were moribund
and those that survived to the end of the study were necropsied.
Gross and microscopic examinations were performed on major organs and
all gross lesions. Eighty percent of CMC-fed male rats and 76% of
CMC-fed female rats survived until the end of the study. These
percentages were similar to those for untreated rats. CMC-gavaged
animals had approximately the same or fewer neoplasms than untreated
control animals (NCI, 1979).
2.2.4 Reproduction studies
No data available.
2.2.5 Special studies on cecal microflora
Groups of 6 male Sprague Dawley rats with conventional gut
microflora were fed a purified diet containing 0 or 5% of CMC for 4
weeks. After 4 weeks, the rats were killed by cervical dislocation
and the ceca removed; cecal contents from each animal were removed and
maintained under anaerobic conditions for analysis of gut microflora
and measurement of enzyme activities. CMC decreased the final body
weight of the rats by 9% compared to the control group. The weight of
the cecal wall was significantly increased as was the weight of cecal
contents. Feeding CMC to rats significantly increased the total
bacterial population of the cecum. No attempt was made to analyze the
species composition of the microflora. Feeding CMC to rats also
significantly increased in vitro activity of bacterial azoreductase,
beta-glucosidase, beta-glucuronidase, nitrate reductase, and urease.
The greatest effect on for urease activity (elevated 5.3 fold) and
beta-glucosidase activity (elevated 8.2 fold). The authors suggested
that the fact that feeding CMC increased the total activity of all
enzymes studied may indicate that the beta-1,4-glucose backbone of CMC
was susceptible to attack by the intestinal bacteria (Mallett
et al., 1984).
Groups of 5 male Wistar rats were fed a fiber-free synthetic diet
containing 0 or 10% CMC, hydroxypropyl methyl cellulose, or
carboxymethyl guar for 12 days. At termination, rats were anesthetized
and killed by cervical dislocation; cecum and ascending colon were
removed. All diets supplemented with non-digestible polysaccharides
led to a visible enlargement of the cecum, which was associated with
increased wet weight of contents and of tissue. The enlargement in the
CMC-supplemented group was particularly marked, with an almost 8-fold
increase in weight of cecal contents and a doubling of tissue weight.
Animals fed the CMC-supplemented diet had diarrhea (profuse unformed
stools) from the 2nd day of feeding, and the total output of fecal
material was significantly increased.
CMC did not significantly increase the density of bacteria in the
cecum and colon, but because of the increased cecal mass the absolute
number of bacteria per cecum was elevated. The aerobic flora of the
fiber-free controls was composed primarily of Streptococcus spp.,
but aerobic bacteria found in cecal and colonic contents of rats fed
CMC were almost entirely E.coli. No enterotoxin activity was
detected in the E.coli strains isolated from CMC-fed rats with
diarrhoea, and serotyping showed that the strains belonged to groups
that are not commonly associated with diarrhea in man.
A substantial amount of unfermented CMC was present in the
intestinal contents of rats fed the CMC-supplemented diet, and the
proportion of CMC increased distally. The CMC appeared not to have
been hydrolyzed to shorter chain lengths, as no increase in reducing
ends could be demonstrated compared with animals maintained on the
control diet. CMC also was poorly fermented by cecal and colonic
bacteria in vitro. In addition, rats fed the CMC-supplemented diet
had significantly lower short-chain fatty acid concentrations in the
cecum. The authors concluded that enlargement of the rat cecum in
response to dietary non-digestible polysaccharides such as CMC can
occur when the polysaccharide is resistant to fermentation (Wyatt
et al., 1988).
2.2.6 Special studies on genotoxicity
Results of genotoxicity assays on CMC
Concentration
Test System Test Object of CMC Results Reference
Ames test S.typhimurium 5.0% Na CMC Negative Litton
(1,3) TA1535,TA1537 Bionetics
TA1538 1975
Ames test S.typhimutrium 2.5, 5.0 & 10% Negative Litton
(l,4) TA1535,TA1537 Na CMC Bionetics
TA1538 1975
Ames test S.typhimurium 0.5, 1, 10, 100, Negative Litton
(2,3) TA98,TA100, 1000, 2500 & 5000 Bionetics
TA1535,TA1537 µg Na CMC/plate 1980
TA1538
Ames test S.typhimurium <2.5 mg Na Negative Ishidate,
(2,3) TA92,TA94,TA98, Na CMC Jr. et al.
TA100,TA1535, 1984
TA1537
Recombinogenicity S.cerevisiae 0.25, 0.50, 1.00% Negative Litton
D4 - ade Na CMC Bionetics
D4 - try 1975
Concentration
Test System Test Object of CMC Results Reference
Chromosome Chinese Hamster <2.8 mg Na Negative Ishidate,
Aberration fibroblasts Na CMC/ml Jr. et al.
1984
(1) Both with and without rat, mouse or monkey liver, lung or testes
S-9 fraction
(2) Both with and without rat liver S-9 fraction
(3) Plate incorporation assay
(4) Suspension assay
2.2.7 Special studies on teratogenicity
2.2.7.1 Mice
Sodium CMC (0, 16, 74, 345, 1600 mg/kg bw/day) was administered
as a corn oil solution by gavage to groups of 19-24 pregnant mice
(Albino CD-1 outbred females) from days 6-15 of gestation. A positive
control group of 24 pregnant mice received 150 mg aspirin/kg bw/day.
All pregnant females survived until the end of the study. No effects
were observed on nidation or on maternal or fetal survival. The
number of abnormalities seen in either soft or skeletal tissues of the
test groups did not differ from the number occurring spontaneously in
sham-treated controls (Food and Drug Research Laboratories, 1975).
2.2.7.2 Rats
Sodium CMC (0, 16, 74, 345, 1600 mg/kg bw/day) was administered
as a corn oil solution by gavage to groups of 19-22 pregnant rats
(Wistar-derived) from days 6-15 of gestation. Nineteen pregnant rats
(positive control group) were dosed with 250 mg aspirin/kg bw/day. All
pregnant females survived until the end of the study. No effects were
observed on nidation or on maternal or fetal survival. The number of
abnormalities seen in either soft or skeletal tissues of the test
groups did not differ from the number occurring spontaneously in
sham-treated controls (Food and Drug Research Laboratories, 1975).
Twenty male rats (albino, Sprague-Dawley-derived) were treated at
least 60 days and 40 female rats were treated at least 14 days before
mating and during a 6-day mating period with 200 mg/kg bw/day by
gavage; 20 male and 40 female rats were maintained under identical
conditions but were not dosed with CMC (controls) For one half of the
females, treatment was continued until sacrifice on day 14 of
gestation; for the remaining half of the females, treatment continued
until weaning of the progeny (day 28 after birth).
No reactions to treatment with CMC were noted in the parents.
Average body weights were comparable throughout the experiment
(however, the body weight gain for males treated with CMC was less
than the body weight gain for control males at 7 of the 10 weighings).
No difference was observed in mating efficiency or pregnancy rate. The
mean numbers of corpora lutea and implantation sites, as well as the
ratios of corpora lutea to implantation sites, were comparable in both
the CMC-treated and control groups. The rate of resorptions was not
significantly increased in the CMC-treated group. In both groups of
rats, the normal pregnancy duration was maintained (21-22 days) and no
disturbances of parturition were noted. No significant difference was
noted in litter size and sex ratio between the CMC-treated and control
groups.
The body weight gain of the pups was comparable for both groups.
No abnormal nesting behavior (nursing, suckling, and creeping) was
noted, and eye opening and pinna detachment followed the normal course
in both groups. Results of behavioral tests (which included righting
reflex, photophobotaxis, cliff avoidance, palmar grasp ability,
negative geotaxis, and exploratory locomotion pattern in a cylindrical
cage, direct pupillary reflex, and hearing ability by startle
response), were comparable in test and control offspring (Fritz &
Becker, 1981).
2.3 Observations in man
Daily oral doses of 20 to 30 g of Na CMC for seven days were well
tolerated by 3 human subjects (Ziegelmayer et al., 1951).
Eleven patients received 10 g of Na CMC daily for six months
without complaint, but in seven further cases the dose had to be
reduced owing to abdominal discomfort. No hematological 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 CMC
is not a primary irritant or a sensitizer (Shelanski & Clark, 1948).
Twelve men (26-62 years of age; mean age of 38) weighing from
77.5 to 111.5 kg (mean weight 88.7 kg) consumed a basal diet
containing four refined fibers (cellulose, CMC, locust bean gum, or
karaya gum) at a level of 0.75 g fiber/100 calories (19.1 to
26.0 g/day). Each of the four fibers were fed for 4 weeks in a
randomized rotation pattern throughout the study, so that each fiber
was followed by every other fiber. The basal diet contained 14.6% of
calories as protein, 35% of calories as fat (641 mg cholesterol), and
50.4% of calories as carbohydrate, with a relatively low amount of
endogenous fiber. Caloric intake ranged from 2550 to 3600 kcal/day. At
the end of each 4-week dietary period, fasting plasma cholesterol
(HDL, LDL, and VLDL), serum total cholesterol, triglycerides, and free
fatty acids were determined. At the end of 4 weeks, total serum
cholesterol had dropped significantly (from 196 mg/dl base line, to
164 mg/dl after CMC) and plasma LDL decreased significantly (from
131 mg/dl to 107 mg/dl). No statistically significant changes were
observed in triglycerides, free fatty acids, VLDL, or HDL levels. The
HDL/(VLDL+LDL) ratio after consuming CMC-supplemented diets for 4
weeks was significantly higher than the ratios after consumption of
the basal diet alone or of the cellulose-supplemented basal diet
(Behall et al., 1984).
Five healthy men (24-58 yrs of age, weighing 73-84 kg each)
consumed 15 g CMC daily (5 g CMC, 3 times a day) for 23 days following
a 7-day control period. Results of a diet inquiry for the 1st and 4th
weeks of the experiment showed no differences in individual intakes of
protein, fat, carbohydrate, sugar, alcohol, and fiber. CMC was well
tolerated by all subjects and no adverse effects were observed. CMC
had no effect on plasma biochemistry, urinalysis, glucose tolerance,
serum cholesterol, triglyceride and phospholipids, breath hydrogen and
methane concentrations. The average intestinal transit time decreased.
Fecal wet and dry weights increased substantially when CMC was added
to the basal diet. Mean fecal bile acid levels and fecal fat content
increased. The mean excretion of neutral sterols decreased from 48 to
29 umol sterols/g dry weight of feces (Anderson et al., 1986;
Anderson, 1986).
3. COMMENTS
Since the previous evaluation, additional data have become
available. These data include studies in rats on cecal enlargement and
changes in cecal flora, teratology and development, as well as
in vitro mutagenicity studies on methyl cellulose and carboxymethyl
cellulose.
These studies confirmed the conclusion of the earlier meetings of
the Committee that modified celluloses have a low toxicity.
Long-term/carcinogenicity studies on hydroxypropyl methyl
cellulose, methyl cellulose, methyl ethyl cellulose, and sodium
carboxymethyl cellulose in rats and mice are available. No evidence
of mutagenicity or carcinogenicity has been observed. Reproduction
and teratology studies with hydroxypropyl cellulose, methyl cellulose,
and sodium carboxymethyl cellulose have been performed in mice, rats
and rabbits. The consumption of these modified celluloses did not
interfere with the reproductive process, and no embrytoxic or
developmental effects were observed.
A new substantial body of human data was available investigating
the laxative effects of modified celluloses which occurs in some
subjects at levels as low as 5 g/person/day. At higher doses diarrhea
has been reported in some subjects, but in others constipation
developed. Studies in humans did not exceed the addition of 30
g/person/day. An intake of 30 g/day has been recommended as the upper
safe level of dietary fiber in general (NRC, 1989).
4. EVALUATION
Estimate of acceptable daily intake
ADI "not specified". The ability to produce laxation should be
taken into account when using these substances as food additives. See
p.78 for the definition of "ADI not specified".
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See Also:
Toxicological Abbreviations
Modified celluloses (WHO Food Additives Series 5)
MODIFIED CELLULOSES (JECFA Evaluation)