INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
WORLD HEALTH ORGANIZATION
SAFETY EVALUATION OF CERTAIN
FOOD ADDITIVES AND CONTAMINANTS
WHO FOOD ADDITIVES SERIES 40
Prepared by:
The forty-ninth meeting of the Joint FAO/WHO Expert
Committee on Food Additives (JECFA)
World Health Organization, Geneva 1998
MICROCRYSTALLINE CELLULOSE
First draft prepared
by Dr J.B. Greig
Department of Health,
Skipton House, 80 London Road, London, SE1 6LW, UK
1. Explanation
2. Biological data
2.1 Biochemical aspects
2.1.1 Absorption, distribution and excretion
2.1.1.1 Rats
2.1.1.2 Humans
2.1.2 Presorption in animal species
2.2 Toxicological studies
2.2.1 Acute toxicity studies
2.2.2 Short-term toxicity studies
2.2.2.1 Rats
2.2.3 Long-term toxicity/carcinogenicity studies
2.2.3.1 Rats
2.2.4 Reproductive toxicity studies
2.2.4.1 Rats
2.2.5 Special studies on embryotoxicity and
teratogenicity
2.2.5.1 Rats
2.2.6 Special studies on genotoxicity
2.2.7 Special studies on sensitization
2.2.8 Special studies on skin and eye irritation
2.2.9 Special studies on effects of cellulose fibre
on tumour growth
2.3 Observations in humans
2.3.1 Toxicity consequent to substance abuse
2.3.2 Changes in gastrointestinal function and
nutrient balance
3. Comments
4. Evaluation
5. References
1. EXPLANATION
Microcrystalline cellulose was evaluated at the fifteenth,
seventeenth and nineteenth meetings of the Committee (see Annex 1,
references 26, 32 and 38). At the nineteenth meeting an ADI "not
specified" was allocated. In the light of concern about possible
persorption and consequential adverse effects of fine particles, the
substance was re-evaluated at the present meeting.
2. BIOLOGICAL DATA
2.1 Biochemical aspects
2.1.1 Absorption, distribution and excretion
2.1.1.1 Rats
Four rats were fed 14C-labelled microcrystalline cellulose at 10
or 20% of their diet. No evidence of degradation or digestion was
noted. Faecal recoveries of radioactivity ranged from 96-104% and were
complete for all labelled material. No radioactivity appeared in the
urine (Baker, 1966).
A study was specifically designed to investigate the possibility
that persorption of microcrystalline cellulose might induce
toxicological effects. Groups of male and female Sprague-Dawley CD
rats (20 per group) from Charles River Laboratories were administered,
by gavage, suspensions of a special fine particle-size
microcrystalline cellulose (median particle size 6 µm). The rats were
dosed orally daily for 90 consecutive days at a level of 5000 mg/kg bw
per day by means of a 25% suspension in tap water. The animals were
killed on study days 91-94 and necropsies were carried out under
conditions that reduced the possibility of contamination of tissues
with fine particulates. The birefringent microcrystalline cellulose
particles were not detected in any organ or tissue, including
gut-associated lymphoid tissue, liver, lung, spleen and brain. The
size limit for detection of the particles was considered to be < 1 µm
(Kotkoskie et al., 1996; FMC Corporation N.V., 1996).
2.1.1.2 Humans
One human subject received 150 g of microcrystalline cellulose
daily in two portions for a 15-day adaptation period. He then received
14C-labelled microcrystalline cellulose (47.6 µCi) in two portions on
one day. Supplementation of the diet with unlabelled microcrystalline
cellulose continued for 10 days. Twenty-four-hour faecal and urine
collections were examined for radioactivity. No radioactivity appeared
in the urine or in the expired CO2. All administered radioactivity
(98.9 ± 3.0%) was recovered from the faeces within two days (Baker,
1968).
Metabolism of a preparation of 14C-labelled cellulose by four
volunteers has been shown to be increased by the consumption, for a
period of 3 months, of an additional 7 g/per day of dietary fibre. In
six subjects with an ileostomy, the cumulative excretion of 14CO2
was lower than in controls. In two constipated subjects metabolism
appeared to be more extensive and occurred over a longer period
(Walters et al., 1989).
Examination of the stools of one male and one female patient
given 30 g microcrystalline cellulose as dry flour or gel for 5´ weeks
showed the presence of undegraded material of the same birefringence
as the original microcrystalline cellulose administered. No
significant effects on the human gastrointestinal tract were noted
during the administration (Tusing et al., 1964).
Most (87%) of the radiolabel associated with 131I-labelled
alpha-cellulose fibres (retained by a sieve with pores of 1 mm diam)
was excreted by 4 male and 4 female volunteers within 5 days of
ingestion. Less than 2% of the faecal radiolabel was unbound; urinary
excretion of unbound radio-iodine accounted for another 1.9% of the
total dose (Carryer et al., 1982).
Other studies have been carried out to demonstrate the
relationship between persorbability and size and consistency of
granules. Using quartz sand, the upper limit for persorbability was
shown to be 150 µm. Starch granules must be structurally largely
intact to possess the property of persorbability. Persorbed starch
granules may be eliminated in the urine, pulmonary alveoli, peritoneal
cavity, cerebrospinal fluid, via lactating milk and transplacentally
(Volkheimer et al., 1968).
In another study, dyed plant foods (oatmeal, creamed corn) were
fed to human subjects, and blood and urine were examined for coloured
fibres. Dyed fibres were shown to be present (Schreiber, 1974).
Lycopodium spores and pollen grains have also been shown to be
persorbed by humans (Linskens & Jorde, 1974).
Mean intake of dietary microcrystalline cellulose in the USA has
been estimated to range from 2.7 g/person per day (children 2 years of
age) to 5.1 g/person per day (young adult males). For heavy consumer
intake of microcrystalline cellulose (90th percentile) the values are
5.4 to 10.2 g/person per day for the same age groups (CanTox Inc.,
1993).
The mean intake of dietary microcrystalline cellulose in the
United Kingdom has been estimated as 0.65 g/person per day. The
highest mean intake, 0.90 g/person per day, was for children aged
10-11 (the youngest group for which data were available). For heavy
consumer intake of microcrystalline cellulose (90th percentile) the
values ranged from 1.13 g/person per day for adults age 16-24 to 1.83
g/person per day for males age 10-11 (Egan & Heimbach, 1994).
2.1.2 Persorption in animal species
Rats, pigs and dogs were used to study the persorption of
microcrystalline cellulose. The animals were not fed for 12 hours
prior to oral administration of the test compound. Rats, dogs and pigs
were given 0.5, 140 and 200 g, respectively, of the test compound.
Venous blood was taken from the animals 1-2 hours after administration
of the test compound, and examined for particles. Persorbed particles
were demonstrated in the blood of all three species. The average
maximum diameter for persorbed particles was greater in rats than in
dogs or pigs (Pahlke & Friedrich, 1974).
Orally administered poly(DL-lactide-co-glycolide) microspheres of
diameter 1-10 µm were specifically taken up into the Peyer's patch
tissue of the gut of BALB/c mice. Those larger than or equal to 5 µm
diameter remained in the Peyer's patches; those < 5 µm were
translocated to the mesenteric lymph nodes and spleen (Eldridge
et al., 1989).
These microspheres degrade slowly and can be used for the
delivery of antigens to the gut-associated lymphoid tissue of BALB/c
mice, males and females, and the initiation of a secretory IgA
response in other organs and tissues (Eldridge et al., 1990).
The use of particles with differing sizes, i.e. styrene
divinylbenzene microspheres (5.7 ± 1.5 µm, mean ± SE) and carbonized
styrene divinylbenzene microspheres (15.8 ± 1.4 µm), indicated that
smaller particles are more readily translocated to the lungs and
mesenteric lymph nodes than are those of a larger size. Unlike earlier
workers, the authors considered that the orally administered particles
do not reach the peripheral blood but are transported to the lungs via
the lymphatic system (LeFevre et al., 1980).
Orally administered titanium dioxide particles of nominal size
500 nm are taken up by gut-associated lymphoid tissue of female
Sprague-Dawley rats and are translocated to liver, spleen, lung and
peritoneal tissues (Jani et al., 1994).
The same research group has investigated the persorption of
polystyrene microspheres with diameters of 50 nm to 3 µm administered
by gavage for 10 days to female Sprague-Dawley rats at a dose of 1.25
mg/kg bw per day. The extent of persorption of the 50 and 100 nm
particles was 34 and 26%, respectively; the uptake of larger particles
was less than 14%. The 50 nm particles were detected in stomach, small
intestine, colon, liver, spleen, kidney and blood. The 3.0 µm
particles were detected only in the stomach, small intestine and colon
(Jani et al., 1990).
Fluorescent polystyrene microparticles of nominal diameters 0.15
and 1.0 µm were injected intraduodenally in the region of a Peyer's
patch in male Wistar rats in which a cannula had been implanted in the
mesenteric lymph duct. Uptake and detection in lymph was rapid for
both sizes of particle, with the time of maximal uptake being 65 min
after the start of the infusion (Jenkins et al., 1994).
Sprague-Dawley rats, 10 per group, aged 25 days, 5 months or 15
months, were dosed with a suspension of fluorescent polystyrene
microparticles of nominal diameter 2.247 µm for 5 days. There was no
significant difference between age groups in the number of particles
that were transferred into gut-associated lymphoid tissue (Simon
et al., 1994)
2.2 Toxicological studies
2.2.1 Acute toxicity studies
Acute toxicity studies of various cellulose preparations are
summarized in Table 1.
Table 1. Acute toxicity of microcrystalline cellulose in animals
Species Sex Route LD50 Reference
(mg/kg bw)
Rat 1 M oral > 3160 Pallotta, 1959
Rat 2 M & F oral > 5000 Freeman, 1991a
Rat 3 M & F oral > 5000 Freeman, 1996d
Rat 1 M intraperitoneal > 3160 Pallotta, 1959
Rat 4 M & F dermal > 2000 Freeman, 1991b
Rat 5 M & F dermal > 2000 Freeman, 1996e
LC50
(mg/litre)
Rat 6 M & F inhalation > 5.35 Signorin, 1996
1 Test material Cellan 300, five male rats per group.
2 Based on no deaths in 10 rats of each sex administered 5000 mg/kg of Avicel RCN-15.
3 Based on no deaths in 5 rats of each sex administered 5000 mg/kg of Avicel AC-815.
4 Based on no deaths in 5 rats of each sex treated with 2000 mg/kg of Avicel RCN-15.
5 Based on no deaths in 5 rats of each sex treated with 2000 mg/kg of Avicel AC-815.
6 Based on no deaths in 5 rats of each sex exposed to 5.35 mg/litre of Avicel AC-815.
In the studies summarized in Table 1, there was no evidence of
toxicity of microcrystalline cellulose preparations administered
either orally or dermally to rats at doses of 5000 or 2000 mg/kg bw,
respectively. The observations seen at necropsy in animals treated
intraperitoneally with Cellan 300 at 3160 mg/kg bw are consistent with
an irritant reaction caused by the presence of foreign material. An
inhalation toxicity study showed only transient effects at a
concentration of 5.35 mg/litre.
Groups of five male Sprague-Dawley rats received a single oral
dose, by stomach tube, of 10.0, 31.6, 100, 316, 1000 or 3160 mg/kg bw
of a suspension of Cellan 300 (refined alpha-cellulose) in either
distilled water or Mazola corn oil. The animals were observed for 7
days following administration. No differences were observed among the
groups as regards the average body weight, appearance and behaviour
compared to untreated rats. No observable gross pathology was revealed
at autopsy in animals dosed with either suspension. Therefore, the
acute oral LD50 was >3160 mg/kg (Pallotta, 1959).
Similar single doses of refined alpha-cellulose were given i.p. in
distilled water suspension to five male rats. During 7 days
observation there were no abnormalities in the rats given 316 mg/kg bw
or less. At 1000 and 3160 mg/kg bw inactivity, laboured respiration
and ataxia were observed 10 min after administration and, at 3160
mg/kg bw, ptosis and sprawling of the limbs were observed. These
animals appeared normal after 24 hours and for the remainder of the
observation period. At sacrifice body weights were higher than normal
and gross autopsy revealed adhesions between the liver, diaphragm and
peritoneal wall and congestion of the kidneys. Masses resembling
unabsorbed compound were also observed and these were found to a small
extent in the mesentery of the animals administered 316 mg/kg bw.
There were no deaths and therefore the acute i.p. LD50 was >3160
mg/kg bw (Pallotta, 1959).
Ten male and ten female Sprague-Dawley rats fasted overnight were
fed Avicel RCN-15 (a mixture of 85% microcrystalline cellulose with
15% guar gum) at a dose level of 5000 mg/kg bw mixed with parmesan
cheese. Six of ten males and five of ten females consumed the mixture
within 24 hours. After a 14-day period during which all rats gained
weight normally they were killed. There were no gross lesions at
necropsy. Under the specified conditions of administration the LD50
was >5000 mg/kg bw (Freeman, 1991a).
An acute inhalation toxicity study using a preparation of Avicel
AC-815 (composed of 85% microcrystalline cellulose and 15% calcium
alginate) with mass median aerodynamic diameter of 8.48-8.61 µm (range
of measures) was dispersed and delivered at a mean concentration of
5.35 mg/litre in a nose-only inhalation exposure chamber to 5 male and
5 female Crl:CDBR VAF Plus rats for a period of 4 hours. The rats were
observed over the 14 days after removal from the chamber. The only
signs of toxicity were on removal from the chamber and consisted of
chromodacryorrhea, chromorhinorrhea and, in one male rat, decreased
locomotion; these signs had resolved by the next day. After 14 days no
gross lesions were observed at necropsy (Signorin, 1996).
2.2.2 Short-term toxicity studies
2.2.2.1 Rats
Groups of four male rats were kept on diets containing 0.25, 2.5
or 25% of various edible celluloses for 3 months. No differences were
observed among the groups with regard to growth and faecal output.
Histopathology of the gastrointestinal tract revealed no
treatment-related abnormalities (Frey et al., 1928).
Three groups of five male rats received 0.5 or 10%
microcrystalline cellulose in their diet for 8 weeks. Growth was
comparable to controls but the 10% group showed slightly lower body
weights. Haematology, serum chemistry and vitamin B1 levels in blood
and faeces showed no differences from controls (Asahi Chemical
Industry Co., 1966).
Groups of five male weanling Sprague-Dawley rats received 0, 5, 10
or 20% of acid-washed cellulose in their diet during three consecutive
nutrient balance trials over a period of 17 days. Absorption of
magnesium and zinc were significantly lower in the animals that were
receiving the 10 and 20% cellulose diets. Histopathology of the
gastrointestinal tract revealed increased mitotic activity and the
presence of increased numbers of neutrophils in crypt epithelial
cells, particularly of the duodenum and jejunum (Gordon et al.,
1983).
A mixture of four types of Elceme (in the ratio of 1:1:1:1) was
fed to groups of Wistar rats for 30 days at a dietary level of 50%,
and for 90 days at a dietary level of 10% (Elceme is a
microcrystalline cellulose, and the four types are identified by
particle size, namely, 1-50 (powder), 1-100 (powder), 1-150
(fibrillar), 90-250 (granulate)). All test animals were observed for
food intake and weight gain. For animals in the 10% group, urinalysis,
haematological tests and serum biochemical tests were carried out at
weeks 6 and 13 of the test. A complete autopsy including
histopathology was carried out at the end of the study. Animals in the
50% group were subjected to a persorption test, on the last day of the
study, by addition of a cellulose staining dye (Renal, Wine-red) to
the food of the test animals at a level equivalent to 5% of the
Elceme. The animals were sacrificed 24 hours after administration of
the diet, and a careful histological examination was made of the
gastrointestinal tract, spleen, liver, kidney and heart for stained
particles.
Animals in the 10% group gained significantly less weight than
those in the control group; the marked decrease commenced in the third
or fourth week of the study. Food intake was similar in test and
control groups. Urinalysis, haematological values and biochemical
values were similar for test and control group 1. At autopsy some of
the rats on the test diet had distended stomachs, which often
contained considerable amounts of the test diet. The absolute liver
and kidney weights and the ratio of the weight of these organs to
brain weight was increased in test animals when compared with control
animals. No compound-related pathology was reported. Animals in the
50% group showed considerable less weight gain than control animals in
spite of a marked increase in food consumption. No persorption of dyed
fibres was observed (Ferch, 1973a,b).
Randomly bred rats of both sexes were divided into groups that
received a control diet or the control diet with 330 mg/kg
microcrystalline cellulose for a period of 6 months. Six rats in each
group were then killed, their organs were examined, and tissues were
taken for histopathology. No effects of the treatment were observed
(Yartsev et al., 1989).
Groups of Crl:CD(R) BR/VAF/Plus rats (20/sex per group) were
administered 0 (control), 25 000 or 50 000 mg/kg Avicel RCN-15 in the
diet for 90 days. A few test animals were noted as having
chromodacryorrhea/ chromorhinorrhea, but this was not considered to be
biologically significant. In some early weeks the rats increased diet
consumption, probably to allow for the increased dietary fibre
content. Body weight gain was unaffected. During the study and at
necropsy there was no evidence of treatment-related changes. Clinical
chemistry, haematology and organ weights were unaffected by treatment.
Histopathology of 34 organs or tissues, including gastrointestinal
tract and gut-associated lymphoid tissue of the ileum, provided no
evidence of toxicity of microcrystalline cellulose. The calculated
daily consumption of microcrystalline cellulose was 3769 mg/kg bw per
day for males and 4446 mg/kg bw per day for females. The author noted
that the NOEL exceeded 50 000 mg/kg diet (Freeman, 1992a).
Groups of Sprague-Dawley CD rats (20 rats/dose per sex) from
Charles River Laboratories were administered 0 (control), 25 000 or 50
000 mg/kg Avicel CL-611 in the diet for 90 days. (Avicel CL-611 or
Avicel(R) Cellulose Gel is composed of 85% microcrystalline
cellulose and 15% sodium carboxymethyl cellulose). There were no
differences in weight gain of the males; a body weight gain decrement
in females was attributed to a decreased caloric intake. No adverse
effects attributable to the treatment were observed. At necropsy organ
weights of the test groups were normal other than changes to adrenals
of males receiving 50 000 mg/kg and to absolute brain and kidney
weights in females receiving 25 000 mg/kg, but these were not
attributed to the treatment. Histopathology of 36 organs or tissues
from the control and high-dose groups, including gastrointestinal
tract and gut-associated lymphoid tissue of the ileum, provided no
evidence of toxicity of the microcrystalline cellulose. The mean
nominal consumptions, averaged over weekly periods, of Avicel CL-611
by males and females of the top-dose groups ranged from 2768 to 5577
and 3673 to 6045 mg/kg bw per day, respectively (Freeman, 1994a).
Microcrystalline cellulose (Avicel) was used as a positive control
in a short-term toxicity study (approximately 13 weeks) of Cellulon, a
cellulose fibre. Sprague-Dawley Crl:CB (SD) BR rats, 20 rats/sex per
group, received a diet containing 0, 5 or 10% of the appropriate fibre
ad libitum. Animals were checked daily, and body weights and food
consumption were monitored weekly. Haematology (10 parameters) and
clinical chemistry (14 parameters) were performed on blood samples
taken from 10 rats/sex per group. All animals were necropsied, and
gross observations and the weights of liver, testes with epididymes,
adrenals and kidneys were recorded. Histological examination was
carried out on tissue sections from control and high-dose groups.
Food consumption was increased in the groups fed cellulose fibre,
although there were no differences in body weight between the
fibre-fed and control groups. This effect was attributed to the
altered nutritional value of the diet. From the haematology and
clinical chemistry there was only one significant difference of a
microcrystalline cellulose group from the control value; this was in
the group of female rats fed 5% microcrystalline cellulose in which
there was an elevation of the haematocrit. There was no evidence of a
dose response.
Study of the necropsy results and the histological observations
indicated that there was no evidence of any treatment-related effects
of microcrystalline cellulose during the 13-week feeding study in rats
at either 5 or 10% in the diet (Schmitt et al., 1991).
Groups of Sprague-Dawley (CD) rats (20 rats/dose per sex) from
Charles River Laboratories were administered, by gavage, suspensions
of a special, fine particle size, microcrystalline cellulose (median
particle size 6 µm). The dose levels were 0 (control), 500, 2500 or
5000 mg/kg per day as a 25% suspension in tap water. Dosing was
performed daily for 90 consecutive days. No treatment-related deaths
occurred during the study and the only treatment-related clinical sign
(pale faeces) was not attributed to toxicity. There were no
toxicologically significant effects in treated animals with respect to
body weight, absolute and relative organ weights (5 organs weighed),
food consumption, clinical chemistry measurements, haematology
measurements or opthalmoscopic examinations. In animals that had
received 5000 mg/kg per day there were no treatment-related lesions
detected histopathologically (in 36 tissues including gut-associated
lymphoid tissue, liver, lung, spleen and brain) nor was there any
macroscopic or microscopic finding of microemboli or granulomatous
inflammatory lesions (Kotkoskie et al., 1996).
2.2.3 Long-term toxicity/carcinogenicity studies
2.2.3.1 Rats
Three groups of 50 male and 50 female rats received in their diet
for 72 weeks either 30% ordinary cellulose or dry microcrystalline
cellulose or micro-crystalline cellulose gel. Appearance and behaviour
was comparable in all groups. No adverse effects were noted. The body
weights of males given microcrystalline cellulose gel were higher than
those of the controls. Food efficiency, survival and haematology were
comparable in all groups. The liver and kidney weights of males
receiving microcrystalline cellulose gel were higher than the
controls. Gross and histopathology showed some dystrophic
calcification of renal tubules in females on microcrystalline
cellulose but all other organs appeared unremarkable. Tumour incidence
did not differ between the groups (Hazleton Labs, 1963).
The Committtee was aware of a study in which a microcrystalline
cellulose preparation, of which 90% of the particles had a diameter
< 20 µm, was fed to male and female rats at 0 (control), 30, 100 or
200 g/kg diet. The high mortality during the course of the study, the
evidence of confounding infection, the limited number of animals for
which there was histopathological examination, and the absence of
details of the first year of feeding do not provide adequate
reassurance as to the ability of this study to detect other than gross
effects (Lewerenz et al., 1981).
A review article makes reference to what may be the earlier, first
year portion of the above study; however, inadequate referencing did
not permit a firm conclusion (Steege et al., 1980).
2.2.4 Reproductive toxicity studies
2.2.4.1 Rats
Groups of eight male and 16 female rats were used to produce P,
F1a, F1b, F2 and F3 generations after having been fed on diets
containing 30% microcrystalline cellulose flour or gel or ordinary
cellulose as a control. The presence in the diet of such an amount of
non-nutritious material, which contributed no calories, had an adverse
effect on reproduction. Fertility and numbers of live pups were
relatively depressed, and lactation performances in all three
generations, as well as survival and the physical condition of the
pups, were unsatisfactory throughout the study. The new-born pups
appeared smaller, weak and showed evidence of disturbed motor
coordination. Liver weights were increased in the group receiving
microcrystalline cellulose gel in all generations but other organ
weights showed no consistent patterns. At autopsy female rats of all
generations showed kidney changes comprising pitting, occasional
enlargement and zonation of the cortex. Other organs showed no
consistent changes. No teratological deformities were seen (Hazleton
Labs, 1964).
2.2.5 Special studies on embryotoxicity and teratogenicity
2.2.5.1 Rats
Seventy-two rats (Sprague-Dawley CD) divided into eight groups
were fed a mixture of four types of Elceme in the ratio of 1:1:1:1 in
the diet at a level of 0, 2.5, 5 or 10% for 10 days, between days 6
and 15 of pregnancy. Rats of four test groups were killed on day 21 of
pregnancy and the following parameters studied: number of fetuses and
resorption sites, litter size and average weight of rats, average
weight of fetuses and average backbone length. Fetuses were also
examined for soft tissue or skeletal defects. The remaining groups
were allowed to bear young, which were maintained to weaning (21
days). The following parameters were studied: litter size, weight of
pups at days 7 and 21, and there was a histological study of the
offspring. Although there is some suggestion that administration of
dietary Elceme resulted in a dose-dependent increase in resorption
sites, as well as a change in sex ratio, and possible defects such as
opaque crystalline lenses, the data has not been presented in a manner
that permits a meaningful interpretation. However, the author
concluded that Elceme is non-teratogenic (Ferch, 1973a,b).
Groups of 25 presumed pregnant Crl:CD(R) BR VAF/Plus rats were
administered 0 (control), 25 000 or 50 000 mg Avicel RCN-15/kg diet
(equal to 2.1 and 4.5 g/kg bw per day, respectively) ad libitum on
days 6 to 15 of gestation. Animals received basal diet at all other
times. In the group receiving 50 000 mg/kg the food consumption on
days 6 to 15 was significantly higher than that of controls, probably
because of the increased fibre content. On day 20 of gestation the
dams were killed by carbon dioxide inhalation and the following
parameters studied: number and distribution of implantation sites,
early and late resorptions, live and dead fetuses and corpora lutea.
External, visceral and skeletal examinations of the fetuses were also
performed. There was no evidence of any adverse effects of the test
material on either the dams or the fetuses. Due to a protocol error
fetal sex was not recorded (Freeman, 1992b).
Groups of 25 presumed pregnant Charles River Sprague-Dawley CD
rats were administered 0 (control), 25 000 or 50 000 mg Avicel
CL-611/kg (equal to 2.2 and 4.6 g/kg bw per day, respectively) diet
ad libitum on days 6 to 15 of gestation. Animals received basal diet
at all other times. In the test groups the food consumption on days 6
to 15 was significantly higher than for controls, probably because of
the increased fibre content. The parameters studied and examinations
performed were the same as in the study of Freeman (1992b). There was
no evidence of any effects of the Avicel treatment on the fetuses, and
there was no evidence of a change of sex ratio in the pups or of eye
defects. Under the conditions of the study, the maternal and fetal
NOEL was > 50 000 mg/kg diet (equal to 4.6 g/kg bw per day) (Freeman,
1994b).
2.2.6 Special studies on genotoxicity
Various microcrystalline cellulose preparations have been tested
for genotoxicity in several different assay systems. The results, all
of which were negative, are summarized in Table 2.
Table 2. Results of genotoxicity assays of microcrystalline cellulose
Test system Test cells Concentration Results Reference
Reverse mutation 1,2 Salmonella typhimurium 50-5000 µg/plate negative Batt, 1992
TA98, TA100, TA1535,
TA1537, TA1538
Reverse mutation 1,3 Salmonella typhimurium 10-5000 µg/plate negative Lawlor, 1996
TA98, TA100, TA1535,
TA1537, TA1538
Escherichia coli 10-5000 µg/plate negative
WP2uvrA
Forward mutation 1,2 Mouse lymphoma 100-1000 µg/ml negative Cifone, 1992
L5178Y cells, TK locus
Forward mutation 1,4 Mouse lymphoma 125-1000 µg/ml negative Cifone, 1994
L5178Y cells, TK locus
UDS with confirmatory Rat liver primary cell 10-1000 µg/ml inactive McKeon, 1992
assay 2 cultures
In vivo mammalian Bone marrow polychromatic 5000 mg/kg bw, negative Murli, 1992
micronucleus assay 2,5 erythrocytes of ICR mice oral
In vivo mammalian Bone marrow polychromatic 5000 mg/kg bw, negative Murli, 1994a
micronucleus assay 6 erythrocytes of CD-1 oral
(ICR) mice
In vivo mammalian Bone marrow polychromatic 5000 mg/kg bw, negative Murli, 1994b
micronucleus assay 4 erythrocytes of CD-1 oral
(ICR) mice
Table 2. Continued...
1 With and without rat liver S9 metabolic activation
2 Test material: Avicel RCN-15
3 Test material: Avicel AC-815
4 Test material: Avicel CL-611
5 Test material: Avicel RCN-15
6 Test material: Avicel PH101 Pharmaceutical
In the reverse mutation assays the microcrystalline cellulose
formulations produced a heavy precipitate on the plate at the highest
concentration. Solubility also affected the forward mutation assays
and it was not possible to include concentrations of the test material
that were cytotoxic. In the in vivo mammalian micronucleus assays it
is improbable that there was appreciable persorption of the test
materials, and, therefore, there was little exposure of the bone
marrow cells. In the test in which Avicel RCN-15 was used it was
administered admixed with the diet of male and female ICR mice. Only
mice that had consumed all the diet within 10 hours were retained in
the study and were killed after 24, 48 or 72 hours. Because one group
of control mice had 0 micronuclei per 1000 polychromatic erythrocytes,
the comparison with the test group was statistically significant. This
was not considered to be a valid observation.
There is no evidence that microcrystalline cellulose is genotoxic.
2.2.7 Special studies on sensitization
Avicel RCN-15 was determined to be non-sensitizing when topically
applied to ten male and ten female Hartley guinea-pigs (Freeman,
1991e).
Avicel AC-815 was determined to be non-sensitizing when topically
applied to ten male Hartley guinea-pigs (Freeman, 1996c).
2.2.8 Special studies on skin and eye irritation
Avicel RCN-15 was judged to be minimally irritating after
instillation into the eyes of four male and two female New Zealand
White rabbits (Freeman, 1991c).
Avicel AC-815 was judged to be minimally irritating after
instillation into the eyes of four male and two female New Zealand
White rabbits (Freeman, 1996a).
Avicel RCN-15 was judged to be non-irritating after a 4-hour
occlusive contact with the skin of three male and three female New
Zealand White rabbits (Freeman, 1991d).
Avicel AC-815 was judged to be non-irritating after a 4-hour
occlusive contact with the skin of three male and three female New
Zealand White rabbits (Freeman, 1996b).
2.2.9 Special studies on effects of cellulose fibre on tumour growth
The effect of artifical diets containing varied concentrations of
either wheat bran or pure cellulose fibre on the induction of mammary
tumours by N-nitrosomethylurea (i.v., 40 mg/kg) was studied in
female F344 rats. The wheat bran diet appeared to possess
anti-promotion properties that pure cellulose lacked. The
concentrations of serum estrogens, urinary estrogens and faecal
estrogens did not vary in a consistent, statistically significant
manner (Cohen et al., 1996).
The effect of a high-fibre diet containing 45 000 mg/kg Avicel PH-
105 on the development of colon tumours was investigated in male
Wistar rats that were injected with 1,2-dimethylhydrazine
dihydrochloride (25 mg/kg, s.c., once weekly for 16 weeks). The test
and control diets were administered for 2 weeks prior to the first
injection of the carcinogen. There was a reduction in the number of
animals bearing colon tumours and a statistically significant
reduction in the number of colon tumours/rat in the high-fibre dietary
group. However, for small bowel tumours and tumours of the ear canal
there was no significant difference between the dietary groups Freeman
et al., 1978).
A later study by the same authors demonstrated that there was no
significant effect of increasing the level of cellulose in the diet to
90 000 mg/kg (Freeman et al., 1980).
2.3 Observations in humans
2.3.1 Toxicity consequent to substance abuse
Intravenous abuse of drugs available in tablet form has led to the
detection of excipients, e.g., talc, magnesium stearate or
microcrystalline cellulose, in the tissues of a series of 33 fatality
cases of intravenous drug addicts. Microcrystalline cellulose (21
cases) and talc (31 cases) were detected most frequently and, in some
cases, were associated with granulomatous lesions (Kringsholm &
Christoffersen, 1987).
In one case intravenous abuse of the drug pentazocine, possibly
for longer than six months, led to a fatal pulmonary granulomatosis
(Zeltner et al., 1982).
In other cases of pentazocine abuse, in addition to pulmonary
granulomas there were granulomas at the injection site and in the
right ventricular endocardium. The principal vascular lesion was
thrombosis (Tomashefski et al., 1981).
2.3.2 Changes in gastrointestinal function and nutrient balance
A number of clinical studies using refined cellulose as roughage
in the human diet for the treatment of constipation showed no
deleterious effects. Groups of 18 children received regular amounts of
edible cellulose instead of normal cereal for three months. The only
effect noted was an increase in bowel movements but no diarrhoea or
other gastrointestinal disturbances were seen (Frey et al., 1928).
Eight male and eight female volunteers supplemented their normal
diet with 30 g microcrystalline cellulose per day as either dry powder
or gel (15% aqueous) for 6 weeks followed by 2 weeks without
supplementation. No adverse findings were reported regarding
acceptance or body weight but most subjects complained of fullness and
mild constipation. Haematology was normal in all subjects. Biochemical
blood values showed no differences between treatment and control
periods, nor was there evidence of liver or kidney function
disturbance. Urinalysis produced normal findings. The faecal flora
remained unchanged. The cellulose content of faeces increase five to
eight times during the test period. Microscopy revealed the presence
of microcrystalline cellulose (Hazleton Labs, 1962).
In another study, eight healthy males received 30 g
microcrystalline cellulose daily as supplement to their diet for 15
days. D-xylose absorption varied between pretest, test and post-test
periods, being lower during microcrystalline cellulose ingestion. The
absorption of 131I-triolein was unaffected by microcrystalline
cellulose ingestion. No change was noted in the faecal flora nor was
there any significant effect on blood chemistry during ingestion of
microcrystalline cellulose. Examination of urine, blood and faecal
levels of vitamin B1 during microcrystalline cellulose ingestion
showed no difference from control periods (Asahi Chemical Industry
Co., 1966).
Twelve men consumed diets containing fibres from various sources
for periods of 4 weeks. There was no significant difference between
values of serum cholesterol, triglyceride and free fatty acid levels
measured after consumption of the basal diet, compared with the values
measured after consumption of a diet containing cellulose fibres (90%
cellulose, 10% hemicellulose; James River Corp., Berlin, New
Hampshire, USA). There were no significant differences in plasma VLDL
and HDL cholesterol or in the ratio of HDL/VLDL+LDL cholesterol.
However, the increase in plasma LDL cholesterol after the cellulose
diet was significant (Behall et al., 1984).
A similar study in a group of four men and six women could detect
no effect of a diet containing added alpha-cellulose (15 g daily) on
serum total cholesterol, triglycerides, HDL cholesterol and the ratio
of HDL to total cholesterol. The cellulose was well tolerated (Hillman
et al., 1985).
A double-blind cross-over trial of the effects of guar gum and
microcrystalline cellulose on metabolic control and serum lipids in 22
Type 2 diabetic patients has been carried out. The fibre preparations
were given at 15 g/day for a 2-week period and then at 5 g/day for the
remaining 10-week period of each treatment phase. There was no effect
of the microcrystalline cellulose diet on fasting blood glucose level,
glycosylated haemoglobin, serum HDL-cholesterol, serum triglycerides,
serum zinc or ferritin, or urinary magnesium excretion (Niemi
et al., 1988).
The effect of various dietary fibres, including microcrystalline
cellulose (40 g), on the uptake of vitamin A (approximately sixty
times the daily requirement) from a test meal was investigated in 11
female subjects aged 19 to 22. All the dietary fibres significantly
increased the absorption of the vitamin A over a period of 9 hours
(Kasper et al., 1979).
A study of apparent mineral balance in a group of eleven men
revealed that there was no significant effect of cellulose, added to
the diet at 7.5 g per 1000 kcal for 4 weeks, on the mineral balance of
calcium, magnesium, manganese, iron, copper or zinc. However, in this
report the source of the cellulose fibre was not specified (Behall
et al., 1987).
The addition of nutritional grade cellulose (21 g) to the daily
diet of healthy adolescent girls resulted in reduction of the serum
calcium, phosphorus and iron concentrations. The authors suggested
that high-fibre diets may not be advisable (Godara et al., 1981).
A study of only three men on a low-fibre diet claimed changes in
mineral balance consequent on the consumption of additional cellulose
fibre, 10 g of Whatman No. 3 filter paper daily, in the diet
(Ismail-Beigi et al., 1977).
Microcrystalline cellulose (5 g) did not appear to inhibit the
uptake of iron in women who were neither pregnant nor lactating
(Gillooly et al., 1984).
A group of twenty women, aged 27-48, who were given 20 g packs of
alpha-cellulose to be consumed daily for three months, were included
in a study of the effect of indole-3-carbinol on estrogen metabolite
ratios. Because the control group and the group fed indole-3-carbinol
received capsules, the cellulose group could not be blinded; in
addition, an unspecified number of subjects in this group dropped out
as they found that the cellulose suspension was unpalatable. However,
the authors suggest that the estrogen metabolite ratio in the high-
fibre group was not different from that in the control group (Bradlow
et al., 1994).
3. COMMENTS
Persorption of microcrystalline cellulose was reported in various
species, which included rats, in early studies. A recent study in
which a special fine particle size preparation of microcrystalline
cellulose (median diameter of particles 6 µm) was administered orally
to rats (5 g/kg bw per day) for 90 days has failed to confirm the
earlier observations. In this study precautions were taken to ensure
that, at autopsy, there was no cross-contamination of the tissues with
fine particulate matter.
In various parenteral studies of the acute toxicity of
microcrystalline cellulose in animals there have been signs consistent
with a tissue response to foreign particles. Similarly,
microcrystalline cellulose has been associated with the formation of
granulomas in human lung when it has been injected intravenously
during drug abuse. No such lesions have been described as a
consequence of oral ingestion of microcrystalline cellulose by rats or
humans.
In 90-day toxicity tests during which microcrystalline cellulose
was administered to rats in the diet at concentrations of 2.5 to 50%,
increased consumption of food to compensate for the content of this
material was observed. Although this may have some effects on mineral
absorption there was, in general, no compound-related systemic
toxicity. The NOEL exceeded 50 g/kg diet, at which dose level the mean
intakes of microcrystalline cellulose by male and female rats were 3.8
and 4.4 g/kg bw per day, respectively.
A two-year feeding study of microcrystalline cellulose in rats was
brought to the attention of the Committee. Despite a lack of evidence
of toxic effects, the Committee considered that the execution and
reporting of the study were not adequate to identify a NOEL.
In vitro and in vivo genotoxicity studies were negative.
In a three-generation reproductive toxicity study in rats that had
been reviewed by an earlier Committee, there were some effects of
using 30% microcrystalline cellulose in the diet; these had been
considered to be a consequence of the quantity of material reducing
the energy density of the diet. However, in recent embryotoxicity and
teratogenicity studies in rats there was no evidence of
compound-related effects at dietary levels up to 50 g of
microcrystalline cellulose per kg diet (equal to 4.6 g/kg bw per day),
given on days 6 to 15 of pregnancy.
In some human studies there have been reports of alterations to
gastrointestinal function following ingestion of microcrystalline
cellulose. The changes do not appear to be related to systemic
toxicity.
4. EVALUATION
The Committee concluded that the toxicological data from humans
and animals provided no evidence that the ingestion of
microcrystalline cellulose can cause toxic effects in humans when used
in foods according to good manufacturing practice.
It is recognized that small particles of other materials may be
persorbed and that the extent of persorption is greater with
sub-micrometre particles. Despite the absence of any demonstrated
persorption of microcrystalline cellulose in the recent study in rats,
the Committee, as a precautionary measure, revised the specifications
for microcrystalline cellulose at the present meeting to limit the
content of particles less than 5 µm in diameter. The Committee
retained the ADI "not specified" for microcrystalline cellulose
conforming to these specifications.
5. REFERENCES
Asahi Chemical Industry Co. (1966) Effect of ingestion of
avicel-contained foods on living organisms. Unpublished report from
Yoshitoshi Internal Seminar (Submitted to WHO by Asahi Chemical
Industry Co., Ltd).
Baker, E.M. (1966) Microcrystalline cellulose: oral administration -
Rats. Unpublished report from Fitzsimmons General Hospital (Submitted
to WHO by FMC Corporation).
Baker, E.M. (1968) Microcrystalline cellulose: oral administration -
Humans. Unpublished report from Fitzsimmons General Hospital
(Submitted to WHO by FMC Corporation).
Batt, K.J. (1992) Avicel RCN-15 - Salmonella/mammalian microsome
plate incorporation assay (Ames test). Unpublished report No. I91-1214
from FMC Corporation Toxicology Laboratory, Princeton, New Jersey, USA
(Submitted to WHO by FMC Europe N.V.).
Behall, K.M., Lee, K.H., & Moser, P.B. (1984) Blood lipids and
lipoproteins in adult men fed four refined fibers. Am. J. Clin.
Nutr., 39: 209-214.
Behall, K.M., Scholfield, D.J., Lee, K., Powell, A.S., & Moser, P.B.
(1987) Mineral balance in adult men: effect of four refined fibers.
Am. J. Clin. Nutr., 46: 307-314.
Bradlow, H.L., Michnovicz, J.J., Halper, M., Miller, D.G., Wong,
G.Y.C., & Osborne, M.P. (1994) Long-term response of women to
indole-3-carbinol or a high fiber diet. Cancer Epidemiol.
Biomarkers Prev, 3: 591-593.
CanTox Inc. (1993) Estimated consumption of microcrystalline cellulose
and sodium carboxymethylcellulose from current and proposed food uses
of Avicel cellulose gel. Unpublished report dated December 1993,
prepared by CanTox Inc. for FMC Corporation (Submitted to WHO by FMC
Europe N.V.).
Carryer, P.W., Brown, M.L., Malagelada, J.-R., Carlson, G.L., &
McCall, J.T. (1982) Quantification of the fate of dietary fiber in
humans by a newly developed radiolabeled fiber marker.
Gastroenterology, 82: 1389-1394.
Cifone, M.A. (1992) Mutagenicity test on Avicel RCN-15 in the L5178Y
TK+/- mouse lymphoma forward mutation assay with an independent
repeat. Unpublished report by Hazleton Washington Inc., Vienna,
Virginia, USA (FMC Study No. 191-1230) (Submitted to WHO by FMC Europe
N.V.
Cifone, M.A. (1994) Mutagenicity test on Avicel CL-611, E329N in the
L5178Y TK+/- mouse lymphoma forward mutation assay with a confirmatory
assay. Unpublished report by Hazleton Washington Inc., Vienna,
Virginia, USA (FMC Study No. 194-1834) (Submitted to WHO by FMC Europe
N.V.)
Cohen, L.A., Zhao, Z., Zang, E., & Rivenson, A. (1996) Dose-response
effects of dietary fiber on NMU-induced mammary tumorigenesis,
estrogen levels and estrogen excretion in female rats.
Carcinogenesis, 17: 45-52.
Egan, S.K. & Heimbach, J.T. (1994) Microcrystalline cellulose, MCC,
E460(i). Part four: Exposure data - Estimated intake of MCC in the
United Kingdom. Unpublished report dated April 11, 1994, prepared by
TAS, Inc., Washington, DC, USA for FMC Corporation (Submitted to WHO
by FMC Europe N.V.).
Eldridge, J.H., Gilley, R.M., Staas, J.K., Moldoveanu, Z., Meulbroek,
J.A., & Tice, T.R. (1989) Biodegradable microspheres: vaccine delivery
system for oral immunization. Curr. Top. Microbiol. Imunol., 146:
59-66.
Eldridge, J.H., Hammond, C.J., Meulbroek, J.A., Staas, J.K., Gilley,
R.M. & Tice, T.R. (1990) Controlled vaccine release in the
gut-associated lymphoid tissues: I. Orally administered biodegradable
microspheres target the Peyer's patches. J. Control. Release, 11:
205-214.
Ferch, H. (1973a) Innocuity of Elceme (R). Part I. Pharm. Ind.,
35(9): 578-583.
Ferch, H. (1973b) Innocuity of Elceme (R). Part II. Pharm. Ind.,
35(9): 658-661.
FMC Corporation N.V. (1996) Microcrystalline cellulose. MCC, Ins 460
(i). Technical and Scientific Dossier. Unpublished report from FMC
Europe N.V., Brussels, Belgium, dated November 1996 (Submitted to WHO
by FMC Europe N.V.).
Freeman, C. (1991a) Avicel RCN-15. Acute oral toxicity study in rats.
Unpublished report No. I91-1217 from FMC Corporation Toxicology
Laboratory, Princeton, New Jersey, USA (Submitted to WHO by FMC Europe
N.V.).
Freeman, C. (1991b) Avicel RCN-15. Acute dermal toxicity study in
rats. Unpublished report No. I91-1219 from FMC Corporation Toxicology
Laboratory, Princeton, New Jersey, USA (Submitted to WHO by FMC Europe
N.V.).
Freeman, C. (1991c) Avicel RCN-15. Primary eye irritation study in
rabbits. Unpublished report No. I91-1218 from FMC Corporation
Toxicology Laboratory, Princeton, New Jersey, USA (Submitted to WHO by
FMC Europe N.V.).
Freeman, C. (1991d) Avicel RCN-15. Primary skin irritation study in
rabbits. Unpublished report No. I91-1220 from FMC Corporation
Toxicology Laboratory, Princeton, New Jersey, USA (Submitted to WHO by
FMC Europe N.V.).
Freeman, C. (1991e) Avicel RCN-15. Skin sensitisation study in guinea
pigs. Unpublished report No. I91-1216 from FMC Corporation Toxicology
Laboratory, Princeton, New Jersey, USA (Submitted to WHO by FMC Europe
N.V.).
Freeman, C. (1992a) Avicel RCN-15. Ninety-day feeding study in rats.
Unpublished report No. I91-1202 from FMC Corporation Toxicology
Laboratory, Princeton, New Jersey, USA (Submitted to WHO by FMC Europe
N.V.).
Freeman, C. (1992b) Avicel RCN-15. Teratology study in rats (dietary).
Unpublished report No. I91-1213 from FMC Corporation Toxicology
Laboratory, Princeton, New Jersey, USA (Submitted to WHO by FMC Europe
N.V.).
Freeman, C. (1994a) Avicel CL-611. Ninety-day feeding study in rats.
Unpublished report No. I92-1711 from FMC Corporation Toxicology
Laboratory, Princeton, New Jersey, USA (Submitted to WHO by FMC Europe
N.V.).
Freeman, C. (1994b) Avicel CL-611. Teratology study in rats (dietary).
Unpublished report No. I92-1712 from FMC Corporation Toxicology
Laboratory, Princeton, New Jersey, USA (Submitted to WHO by FMC Europe
N.V.).
Freeman, C. (1996a) Avicel AC-815. Primary eye irritation study in
rabbits. Unpublished report No. I95-2042 from FMC Corporation
Toxicology Laboratory, Princeton, New Jersey, USA (Submitted to WHO by
FMC Europe N.V.).
Freeman, C. (1996b) Avicel AC-815. Primary skin irritation study in
rabbits. Unpublished report No. I95-2043 from FMC Corporation
Toxicology Laboratory, Princeton, New Jersey, USA (Submitted to WHO by
FMC Europe N.V.).
Freeman, C. (1996c) Avicel AC-815. Skin sensitization study in guinea
pigs. Unpublished report No. I95-2044 from FMC Corporation Toxicology
Laboratory, Princeton, New Jersey, USA (Submitted to WHO by FMC Europe
N.V.).
Freeman, C. (1996d) Avicel AC-815. Acute oral toxicity study in rats.
Unpublished report No. I95-2040 from FMC Corporation Toxicology
Laboratory, Princeton, New Jersey, USA (Submitted to WHO by FMC Europe
N.V.).
Freeman, C. (1996e) Avicel AC-815. Acute dermal toxicity study in
rats. Unpublished report No. I95-2041 from FMC Corporation Toxicology
Laboratory, Princeton, New Jersey, USA (Submitted to WHO by FMC Europe
N.V.).
Freeman, H.J., Spiller, G.A., & Kim, Y.S. (1978) A double-blind study
on the effect of purified cellulose dietary fiber on 1,2-
dimethylhydrazine-induced rat colonic neoplasia. Cancer Res., 38:
2912-2917.
Freeman, H.J., Spiller, G.A., & Kim, Y.S. (1980) A double-blind study
on the effects of differing purified cellulose and pectin fiber diets
on 1,2-dimethylhydrazine-induced rat colonic neoplasia. Cancer
Res., 40: 2661-2665.
Frey, J.W., Harding, E.R., & Helmbold, T.R. (1928) Dietetic
investigations of edible pure cellulose. Med. J. Rec., 127: 585-589.
Gillooly, M., Bothwell, T.H., Charlton, R.W., Torrance, J.D., Bezwoda,
W.R., MacPhail, A.P., Derman, D.P., Novelli, L., Morrall, P., & Mayet,
F. (1984) Factors affecting the absorption of iron from cereals.
Br. J. Nutr., 51: 37-46.
Godara, R., Kaur, A.P., & Bhat, C.M. (1981) Effect of cellulose
incorporation in a low fiber diet on fecal excretion and serum levels
of calcium, phosphorus, and iron in adolescent girls. Am. J. Clin.
Nutr., 34: 1083-1086.
Gordon, D.T., Besch-Williford, C., & Ellersieck, M.R. (1983) The
action of cellulose on the intestinal mucosa and element absorption by
the rat. J. Nutr., 113: 2545-2556.
Hazleton Labs (1962) Microcrystalline cellulose; oral administration -
Human. Unpublished report from Hazleton Labs, Inc. (Submitted to WHO
by FMC Corporation).
Hazleton Labs (1963) Long-term nutritional balance study - Rats.
Unpublished report from Hazleton Labs, Inc. (Submitted to WHO by FMC
Corporation).
Hazleton Labs (1964) Microcrystalline cellulose: reproduction study -
Rats. Unpublished report from Hazleton Labs, Inc. (Submitted to WHO by
FMC Corporation).
Hillman, L.C., Peters, S.G., Fisher, C.A., & Pomare, E.W. (1985) The
effects of the fiber components pectin, cellulose and lignin on serum
cholesterol levels. Am. J. Clin. Nutr., 42: 207-213.
Ismail-Beigi, F., Reinhold, J.G., Faraji, B., & Abadi, P. (1977)
Effects of cellulose added to diets of low and high fiber content upon
the metabolism of calcium, magnesium, zinc and phosphorus by man.
J. Nutr., 107: 510-518.
Jani, P., Halbert, G.W., Langridge, J., & Florence, A.T. (1990)
Nanoparticle uptake by the rat gastrointestinal mucosa: quantitation
and particle size dependency. J. Pharm. Pharmacol., 42: 821-826.
Jani, P.U., McCarthy, D.E., & Florence, A.T. (1994) Titanium dioxide
rutile particle uptake from the rat GI tract and translocation to
systemic organs after oral administration. Int. J. Pharm., 105:
157-168.
Jenkins, P.G., Howard, K.A., Blackhall, N.W., Thomas, N.W., Davis,
S.S., & O'Hagan, D.T. (1994) The quantitation of the absorption of
microparticles into the intestinal lymph of Wistar rats. Int. J.
Pharm., 102: 261-266.
Kasper, H., Rabast, U., Fassl, H., & Fehle, F. (1979) The effect of
dietary fiber on the postprandial serum vitamin A concentration in
man. Am. J. Clin. Nutr., 32: 1847-1849.
Kotkoskie, L.A., Butt, M.T., Selinger, E., Freeman, C., & Weiner, M.L.
(1996). Qualitative investigation of uptake of fine particle size
microcrystalline cellulose following oral administration in rats.
J. Anat., 189: 531-535.
Kringsholm, B. & Christoffersen, P. (1987) The nature and the
occurrence of birefringent material in different organs in fatal drug
addiction. Forensic Sci. Int., 34: 53-62.
Lawlor, T.E. (1996) Mutagenicity test with Avicel AC-815 in the
Salmonella-Escherichia coli/mammalian microsome reverse mutation
assay with a confirmatory assay. Unpublished report by Corning
Hazleton Inc., Vienna, Virginia, USA (FMC Study No. I95-2047)
(Submitted to WHO by FMC Europe N.V.).
LeFevre, M.E., Hancock, D.C., & Joel, D.D. (1980) Intestinal barrier
to large particulates in mice. J. Toxicol. Environ. Health, 6: 691.
Lewerenz, H.J., Bleyl, D.W.R., & Plass, R. (1981) Report on
investigations in the second test year of continuous administration of
microcrystalline cellulose into rats with their feed. Translation (and
German original) of an unpublished report from the Academy of Sciences
of the German Democratic Republic, Research Center for Molecular
Biology and Medicine, Central Institute for Nutrition,
Potsdam-Rehbrücke (Submitted to WHO by FMC Europe N.V.).
Linskens, H.F. & Jorde, W. (1974) Persorption of lycopodium spores and
pollen grains, Naturwissenschaften, 61: 275-276.
McKeon, M.E. (1992). Genotoxicity test on Avicel RCN-15 in the assay
for unscheduled DNA synthesis in rat liver primary cell cultures with
a confirmatory assay. Unpublished report by Hazleton Washington Inc.,
Kensington, Maryland, USA (FMC Study No. I91-1229) (Submitted to WHO
by FMC Europe N.V.).
Murli, H. (1992) Mutagenicity test on Avicel RCN-15 in vivo
mammalian micronucleus assay. Unpublished report by Hazleton
Washington Inc., Kensington, Maryland, USA ( FMC Study No. I91-1228)
(Submitted to WHO by FMC Europe N.V.).
Murli, H. (1994a) Mutagenicity test on Avicel pH101 Pharmaceutical in
an in vivo mouse micronucleus assay. Unpublished report by Hazleton
Washington, Inc., Vienna, Virginia, USA (FMC Study No. I94-1837)
(Submitted to WHO by FMC Europe N.V.).
Murli, H. (1994b) Mutagenicity test on Avicel CL-611 in an in vivo
mouse micronucleus assay. Unpublished report by Hazleton Washington,
Inc., Vienna, Virginia, USA (FMC Study No. I94-1835) (Submitted to WHO
by FMC Europe N.V.).
Niemi, M.K., Keinänen-Kiukaanniemi, S.M., & Salmela, P.I. (1988)
Long-term effects of guar gum and microcrystalline cellulose on
glycaemic control and serum lipids in Type 2 diabetes. Eur. J.
Clin. Pharmacol., 34: 427-429.
Pahlke, G. & Friedrich, R. (1974) Persorption of microcrystalline
cellulose, Naturwissenschaften, 61: 35.
Pallotta, A.J. (1959) Acute oral administration - Rats; and acute
intraperitoneal administration - Rats, of microcrystalline cellulose.
Unpublished report from Hazleton Labs, Inc. (Submitted to WHO by FMC
Corporation).
Schmitt, D.F., Frankos, V.H., Westland, J., & Zoetis, T. (1991)
Toxicologic evaluation of Cellulon fiber; genotoxicity, pyrogenicity,
acute and subchronic toxicity. J. Am. Coll. Toxicol., 10: 541-554.
Schreiber, G. (1974) Ingested dyed cellulose in the blood and urine of
man. Arch. Environ. Health, 29: 39.
Signorin, J. (1996) Avicel AC-815. Acute inhalation study in rats.
Unpublished report No. I95-2045 by FMC Corporation Toxicology
Laboratory, Princeton, New Jersey, USA (Submitted to WHO by FMC Europe
N.V.).
Simon, L., Shine, G., & Dayan, A.D. (1994) Effect of animal age on the
uptake of large particulates across the epithelium of the rat small
intestine. Int. J. Exp. Pathol., 75: 369-373.
Steege, H., Lewerenz, H.J., Philipp, B., & George, J. (1980)
Characterization of cellulose powders with special attention to the
physiological aspects. International Dissolving Pulp Conference,
German Democratic Republic, 5, 169-183.
Tomashefski, J.F., Hirsch, C.S., & Jolly, P.N. (1981) Microcrystalline
cellulose pulmonary embolism and granulomatosis. A complication of
illicit intravenous injections of pentazocine tablets. Arch.
Pathol. Lab. Med., 105: 89-93.
Tusing, T.W., Paynter, O.E., & Battista, O.A. (1964) Birefringence of
plant fibrous cellulose and microcrystalline cellulose in human stools
freezer-stored immediately after evacuation. Agric. Food Chem.,
12(3): 284-287.
Volkheimer, G., Schultz, F.H., Lehmann, H., Aurich, I., Hubner, R.,
Hubner, M., Hallmayer, A., Munch, H., Opperman, H., & Strauch, S.
(1968) Primary portal transport of persorbed starch granules from the
intestinal wall. Med. Exp., 18: 103-108
Walters, M.P., Kelleher, J., Findlay, J.M., & Srinivasan, S.T. (1989)
Preparation and characterisation of a [14C]cellulose suitable for
human metabolic studies. Br. J. Nutr., 62: 121-129.
Yartsev, N.M., Ivanova, V.S., Altymyshev, A.A., Sarybayeva, R.I., &
Vasil'kova, T.V. (1989) Anatomical and histological state of rats
given microcrystalline cellulose in long-term experiments.
Izvestiya AN Kirgizskoi SSR, 3: 63-65.
Zeltner, T.B., Nussbaumer, U., Rudin, O., & Zimmermann, A. (1982)
Unusual pulmonary vascular lesions after intravenous injections of
microcrystalline cellulose. A complication of pentazocine tablet
abuse. Virchows Arch. [Pathol. Anat.], 395: 207-216.