POLYDEXTROSES MODIFIED
Explanation
Polydextrose or Polydextrose A is formed by melt polycondensation
in vacuo of food grade glucose and sorbitol (approximately 89:10) in
the presence of about 10% of food grade citric acid as a catalyst.
Polydextrose N is the potassium-neutralized solution form of
Polydextrose. Polydextrose is decolorized with hydrogen peroxide and
neutralized with potassium hydroxide.
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
To study the disposition of Polydextrose in humans four healthy
volunteers received 10 g non-labelled Polydextrose incorporated into a
chocolate milk drink daily, for seven days. On the eighth day each
received the standard 10 g portion containing 72 microcuries of
14C-Polydextrose. On the two subsequent days after receiving the
labelled material, each subject continued to receive 10 g non-labelled
Polydextrose. The recovery of radioactivity as 14CO2 in the breath
was 16% of the dose for the subject 2. Conversion of these results
into estimated caloric utilization for 14C-Polydextrose indicates
that the average value is 26.6% of the dose. Serum radioactivity was
detectable one hour after the labelled dose, declined to a minimum
value by four hours, and then slowly increased to a maximum level at
24 hours. Urinary recovery of radioactivity averaged 1.4% of the dose.
Most of the radioactivity found in urine is due to 14C-urea and
other normal endogenous metabolism products. Faecal recovery of
radioactivity accounted for an average of 50% of the administered
dose. The overall recovery or accountability of radioactivity was 78%.
The observed recovery does not take into account losses of 14CO2 as
flatus (Anon., 1978a).
Three subjects received 10 g 14C labelled-Polydextrose
containing 69.4 µCi of radioactivity as a water solution. Faeces were
collected for three or four successive 24-hour periods after the
radioactive dose. Each 24-hour collection was pooled for each subject.
Radioactive VFA have been found in human faeces after oral
14C-Polydextrose administration. In vitro incubations with human
faeces convert significant quantities (approximately 17%) of
14C-Polydextrose to VFA within 22-30 hours. Polydextrose is fermented
by the microflora in the lower intestinal tract, resulting in the
production of volatile fatty acids (Anon., 1978b).
Three rats received an intravenous dose of 14C-Polydextrose at
25 mg/kg or 50 mg/kg in the tail vein. Each rat was placed in a sealed
metabolism cage. Total 14CO2 was collected for 24 hours, and urine
and faeces were separately collected for three days. An average of
1.16% of the administered dose was recovered as 14CO2 indicating
that 1.93% of dose was available to the rat and used as calories. Most
of the 14CO2 exhaled occurs within the first three hours. Within the
same time, the major portion of administered radioactivity (90%) is
excreted in urine. Recovery of radioactivity in faeces was extended
from 0.5% to 10.5%. The total balance of radioactivity by all routes
was 97.1% (Anon., 1978c).
Groups of six rats received a single dose of 14C-Polydextrose by
oral intubation. Each rat received 55 mg/kg (12.6 µCi) and was placed
into a sealed metabolism cage. Total 14CO2, urine and faeces were
separately collected for three days. More than 20% of the dose is
recovered as 14CO2, less than 2% in urine, and the remainder in
faeces, within the first 24 hours after dosing. The low urinary
recovery of label shows the very poor Polydextrose absorption as such.
Most of the radioactivity present in urine represents normal waste
products (i.e. urea) labelled by incorporation of 14C by the usual
metabolic processes (Anon., 1978d).
To determine the extent of absorption of intact Polydextrose, one
rat was fed for three days by oral intubation with a daily dose of
non-labelled Polydextrose at 5 g/kg per day. On the fourth day the rat
received 5 g/kg 14C-Polydextrose containing 23 µCi of radioactivity,
and was immediately placed in a metabolism cage. The 0-24 hour urine
collection contained 0.6% of the administered dose. The eluted
patterns of radioactivity resulting from gel filtration compared with
an authentic sample of Polydextrose, shows that the 14C-Polydextrose
is approximately 41% of the total radioactivity eluted from the
column. Since the total urinary radioactivity recovered from the rat
after 14C-Polydextrose administration was 0.6% of the dose, a maximum
of 0.24% of the dose could have been Polydextrose-related material
(Anon., 1978e).
Rats received 28 µCi of 14C-Polydextrose by oral intubation.
Faeces were collected during the interval 0-24 hours. Analysis of the
steam distillate demonstrated the presence of radioactive acetic,
propionic and burytic acids. The total steam distillate contained 2.5%
of the faecal radioactivity. Five hours after receiving an oral dose
of 14C-Polydextrose the caecum contents of a rat contained 58% of the
administered radioactivity. The steam distillate residue contained 13%
of the administered label. The relative abundance of volatile fatty
acids in this experiment was acetic burytic propionic acids (Anon.,
1978b).
In one experiment it has been determined whether rats that have
been fed large daily oral doses of Polydextrose for 90 days adapt to
this agent and show altered caloric utilization or metabolism of
Polydextrose. Rats stressed by feeding Polydextrose at 1 g/kg per day
or 10 g/kg per day for 90 days metabolize a test dose of 14.7 mg
14C-Polydextrose radioactivity = 36.7 µCi/dose quantitatively and
qualitatively the same as control rats which were not fed
Polydextrose. No induction of metabolism was observed. The pattern and
time course of excreted 14CO2 from the treated rats is
indistinguishable from the non-treated control rats. In each of the
three test groups (two rats per group) approximately 19% of the
administered radioactivity was recovered as 14CO2 indicating that
approximately 31% of the dose was calorically utilized. Urinary
recovery of label was also identical for the three groups and averaged
1-2% of administered dose. The faecal recovery was virtually the same
for the control and 1 g/kg rats, averaging approximately 50%. Those
rats receiving 10 g/kg Polydextrose demonstrated somewhat lowered
faecal recovery; however this was due mainly to problems associated
with collection. Overall, approximately 85% of the administered
radioactivity was collected or accounted for (Anon., 1978f).
In order to estimate the extent of utilization during the second
passage through a rat, three rats received a water solution of
14C-Polydextrose by oral intubation. Appropriate Sephadex fractions
resulted from a purification of the 0-24 hour faecal collection and
containing an average of 3.2 µCi were fed to the same three rats by
oral intubation. The result shows that less than 6% of the dose is
recovered as 14CO2. Approximately 1.4% was eliminated with
urine. The faecal recovery accounted for the major portion of the
administered radioactivity, approximately 90% of the dose. In this
experiment the caloric utilization of 14C-Polydextrose was
approximately 10% less than one-third the value of 35% obtained with
"new" Polydextrose. The first passage of Polydextrose through the rat
intestine removes by fermentation a substantial fraction of those
Polydextrose molecules that serve as a substrate for bacterial enzymes
(Anon., 1978g).
C-14 Polydextrose, Types A and N were tested in the standard 13
hours 14CO2 exhalation test using three rats for each Polydextrose.
Rats received an oral dose of 63 mg/kg of 14C-Polydextrose, Type A or
Type N. The caloric utilization of Polydextrose Type A was 38.1% and
that for Type N was 37.1%. The urinary and faecal recoveries for Types
A and N Polydextrose respectively were 1.6% and 1.7% (urine) and 62.6%
and 59.5% (faeces) (Anon., 1978h).
To determine the extent of absorption of intact Polydextrose by
the dog, two dogs each received a daily oral dose of 200 mg/kg non-
labelled Polydextrose for six days and then received an oral dose of
14C-Polydextrose at 200 mg/kg; urine and faeces were separately
collected for three days. Expired breath (14CO2) was not collected.
Dogs excrete approximately twice as much urinary radioactivity as
the rat and nearly three times as much as man; 3.71% of the
administered dose for the dog versus 1.85% for rats and 1.27% for man.
Of the total radioactivity found in dog urine approximately 50% is
unchanged Polydextrose as compared to 41% in the rat and less than 5%
in man. The dog also excretes more radioactivity with faeces than the
rat indicating that the caloric utilization of Polydextrose in the dog
is approximately 25% of the dose, somewhat less than the caloric
utilization of approximately 35% of the dose observed in the rat.
All three species excrete the major portion of radioactivity
within the first 24 hours after administration. The recovery of
unchanged Polydextrose found in the 0-24 hour urine of dog, rat and
man, is 1.72%, 0.24% and 0.03% of the dose respectively; it is clear
therefore that man absorbs substantially less and excretes into the
urine less Polydextrose than the dog and rat (Anon., 1978g).
Effects on calcium balance
Two groups of five fasted and anaesthetized beagle dogs
administered intraduodenal infusions of calcium gluconate 34 g/l;
final pH = 6.38 with and without 50% Polydextrose-N (0.5 litre of 70%
solution Polydextrose-N per litre of infusion solution) showed that
Polydextrose-N significantly decreased the pH of the duodenal fluid
and slightly increased mesenteric blood calcium and phosphate levels
(Anon., 1977a).
Oral administration of radio-labelled calcium (150 µCi of
calcium-45 with 35 mg of calcium as calcium chloride) to four male
beagle dogs prior to, twice during and after feeding a diet containing
22.5% Polydextrose Type N for 19 days demonstrated that Polydextrose
Type N enhanced to a slight but significant degree the absorption of
the orally administered radioactive calcium, as shown by an increase
in the level of radioactivity and calcium specific activity in serum
(Anon., 1977b).
TOXICOLOGICAL STUDIES
Special studies on cytopathology
Polydextrose in either the A or N forms do not exercise an
adverse effect on mouse peritoneal macrophages cultured in vitro.
The lysosomal activity of macrophages treated with Polydextrose
(A or N) was comparable to controls (Hooson et al., undated).
Special studies on mutagenicity
Polydextrose was evaluated in a series of assays for assessing
the mutagenic potential of chemicals. Point mutation assays in
histidine auxothrophs of Salmonella typhimurium did not produce
significant or reproducible increases in mutation frequency.
These assays included spot tests as well as quantitative plate
determinations. An assay using Polydextrose at 10 mg/plate produced no
significant increases in the number of revertant colonies per plate
with S. typhimurium TA 1535, TA 1536, TA 1537, TA 1538 and C340,
Type N was assayed at 20 mg/plate with TA 1536, no increase above the
spontaneous rate of revertant colonies per plate was seen.
Host-mediated assays were performed at 200 mg/kg using several strains
of Salmonella typhimurium. Polydextrose was given orally to mice
whose peritoneal cavities contained one of five different
S. typhimurium strains. No significant increase in mutation
frequency was seen. Cytogenetic studies were conducted both in vivo
in mouse bone marrow and in vitro in human lymphocytes. For
in vivo studies, groups of five CD-1 male mice were given oral doses
of 2 mg/kg of Polydextrose or Polydextrose acid. Mice were sacrificed
at 6, 12, 24, 48 or 72 hours post-treatment. Subacute treatment
consisted of 1 mg/kg per day for seven days with sacrifice at 24 hours
after the last dose. At three hours prior to sacrifice, each animal
received colchicine. Animals were sacrificed and femur bone marrow
was flushed. Cell suspension was stained. Fifty metaphase figures
were examined for chromosome damage from each mouse. In all of the
treatment regimes there is no indication of compound-induced
chromosome breakage over that observed in the experimental controls.
In vitro studies were conducted on human lymphocytes, cultured
Polydextrose acid or bleached neutral was added at 500 or 1000 µg/ml
of culture medium. Cells were stained and scored as described above
for mouse bone marrow. Fifty or 100 metaphase figures were examined
for structural aberration from each culture. Polydextrose did not
produce any evidence of genetic toxicity in the in vitro
assessments. Chromosome damage in the treated cultures was not
statistically elevated over control levels. Polydextrose N was
evaluated in the dominant-lethal assay. Polydextrose was administered
orally in distilled water to male mice at a level of 1.0 g/kg per day
for seven days. Both control and compound-treated groups contained 15
male mice which were caged with three virgin females each on the
seventh day of dosing. These females were replaced at seven-day
intervals for an eight-week period. All females were autopsied 11 days
after removal from the mating cages. Polydextrose N did not produce
evidence of dominant lethality at a level of 1 g/kg. The number of
dead implants/pregnant females was not elevated in a statistically
significant manner compared to controls in any of the seven-week
mating periods of the study (Anon., 1978j).
Special studies on reproduction
Polydextrose was administered to four groups of 50 male and 50
female rats for three successive generations. In each generation, male
and female rats received 0, 5, 10% Polydextrose or 10% sucrose in the
diet. The F0 generation was treated for approximately 100 days and
the F1 generation for 24 months. As the females of the F0 generation
received supplemented diet throughout gestation and lactation, the F1
generation was exposed in principle to the test substance initially
in utero and subsequently via the mother's milk until weaning. The
F1 dams were bred twice to produce F2a and F3a generations. The
general health of the rats, both parental and live offspring, was
unaffected by the treatment with Polydextrose. The treatment with
Polydextrose had no effect on the fertility of either males or
females. A decrease of the copulation rate was seen in the last
parental generation (F2) treated with either Polydextrose or sucrose.
The litter size was similar in control and treated groups and remained
constant through the generations. No drug-related mortality was
observed. No drug-related malformation or lesion was seen when pups
were examined for ocular lesions or were autopsied. Continuous
administration of Polydextrose did not produce any adverse effect on
growth, fertility and postnatal development of parents and litter
offsprings (Anon., 1975a).
Polydextrose was administered to five groups of 15 male rats for
79 days before mating and to five groups of 30 female rats for 14 days
prior to mating and throughout the gestation at doses of 0, 1, 2,
4 g/day/animal representing about 0, 5, 10 and 20% of average daily
food consumption sucrose, at the dose of 4 g/day/animal was used as a
positive control. The reproductive performance of the treated animals
and the growth of their progeny was recorded. The administration of
Polydextrose had no adverse effect on the male rats except for
softness of the faeces at the 4 g/day level. The reproductive
behaviour was normal. One male with athropic testes and vacuolization
of 20% of the spermatogenic cells was observed at the top dose
(4 g/day) but this case was not related to Polydextrose
administration. The litter size at birth and the viability of the pups
were similar in the control and treated groups. The mean body weight
of the treated pups was slightly higher than that of controls and the
growth rate of pups born from males treated at 4 g/day Polydextrose
was slightly higher than in the other groups. The gestation and
parturition of treated females was normal. The litter size and the
survival rate of their progeny was similar to that of control.
Polydextrose did not show any adverse effect on the gonadal function,
mating behaviour and conception rate. The treatment had no effect on
the development of the offspring which presented no lesions,
abnormalities or growth delay (Anon., 1975b).
Polydextrose when administered to five groups of 20 female rats
during the last third of pregnancy, lactation and until weaning,
at the daily doses of 0, 1, 2 and 4 g per animal representing
approximately 0, 10 and 20% of the average daily food consumption did
not produce any adverse effects on the adults. The parturition of the
females treated with Polydextrose or with sucrose (4 g/day/animal) was
normal, with no difference between any of the groups. Polydextrose
administration did not increase the mortality. During the lactation
period, the viability of the pups in the treated groups appeared
slightly better than in the controls, with a dose-dependent relation
for the Polydextrose groups. The growth of the Polydextrose pups was
slower than controls for the females at the three dose levels and the
males at the top dose of 4 g, compared with the controls. A slight
delay in the postnatal development as manifested by the dates of
appearance of some reflexes was noticed in the Polydextrose treated
groups. This apparent delay is related to the shortening of the length
of the gestation period and the most prominent delays were observed in
the Polydextrose 1 g group which had the shortest (mean) gestation
period (Anon., 1974).
Special studies on teratogenicity
Polydextrose was administered to five groups of 20 pregnant rats
during the critical period of organogenesis from day 6 to day 15 at
the daily dose of 0, 1, 2, 4 g/animal representing approximately 0, 5,
10 and 20% of the average daily food consumption. No maternal toxicity
was observed. Maternal toxicity and teratogenic effects, which could
be related to Polydextrose, were not observed in rat foetuses. The
foetal growth was similar in control and treated animals. The
placental weight of Polydextrose treated foetuses was slightly
increased. Sucrose was administered for comparison to rats at 4 g per
day. A slightly negative effect on growth was observed (Anon., 1973a).
Polydextrose was administered to five groups of 15 pregnant
rabbits during the critical period of organogenesis from day 7 to
day 18 at the daily dose of 0, 3, 6 and 12 g/animal, corresponding
approximately to 0, 1.5, 3 and 6% of the mean daily consumption of a
pregnant rabbit. No maternal toxicity was observed. The only
Polydextrose related symptomatology was an increase of water
consumption and a slightly reduced body weight gain. Maternal toxicity
and teratogenic effects, which could be related to Polydextrose, were
not observed in rabbit foetuses. The foetal growth was similar in
control and treated animals. The placental weight of Polydextrose
foetuses was slightly increased. Sucrose was administered for
comparison to rabbits at 12 g per day. A negative effect on growth was
pronounced in pregnant rabbits. This growth depressant effect is
described by several authors as a decrease of food conversion
efficiency, and is reflected also in the foetuses in this trial which
have a lower weight and show a delayed ossification (Anon., 1973a).
Acute toxicity
LD50(mg anhydrous Polydextrose/kg bw)
Animal Route Type A (50% Type N (70% Type A Reference
solution) solution) (bulk)
Mouse Oral > 30 000 > 47 300 Anon., 1978k
Rat Oral > 18 920 Anon., 1978k
Dog Oral > 20 000a > 20 000b Anon., 1978k
i.v. > 2 000 Anon., 1978k
a 10 000 mg/kg b.i.d. or a total dose of 20 000 mg/kg bw per day.
b 5000 mg/kg q.i.d. or a total dose of 20 000 mg/kg bw per day in
gelatin capsules.
No mortality was produced at all the doses. At the higher doses
the symptom noted was diarrhoea (Anon., 1978k).
Short-term studies
Rat
Forty male and 40 female rats were divided into four groups of 10
males and 10 females each. One group of 10 males and 10 females served
as control and were fed ground rat food seven days a week for 92 days.
The other three groups of 10 males and 10 females each received, mixed
in the daily ration, Polydextrose at doses of 10, 2 or 1 g/kg per day
for 92 days. Haematology and urinalysis examinations were made once
prior to beginning treatment and on days 29, 57 and 85. The
haematological parameters evaluated consisted of red blood cell (RBC),
white blood cell (WBC), and WBC differential counts; haemoglobin
concentrations; haematocrits; and clotting times. Clinical chemistry
determinations were made on two rats per sex per dose level on days 36
and 64 and six rats per sex per dose level at day 92. The parameters
evaluated consisted of blood glucose, total bilirubin, blood urea
nitrogen (BUN), alkaline phosphate, serum glutamic oxalacetic and
glutamic pyruvic transaminases (SGOT and SGPT), creatinine, uric acid,
sodium, potassium and calcium. Slit-lamp ophthalmoscopic examinations
were made on each animal once prior to commencing treatment and on
days 29, 57 and 85. Polydextrose produced no signs of compound induced
toxicity. The rate of weight gain was less than control values in low
dose males and females and in high dose females. There were no
remarkable physical, clinical pathological, ophthalmological, or
histopathological changes and there were no compound-related lesions
(Anon., 1973b).
Dog
Polydextrose at 50% dry weight of the diet (23 g/kg bw per day)
was fed for 98 days to a group of six male beagle dogs. Two dogs were
used as control animals. Serum chemistry determinations consisted of
the following parameters: sodium, potassium, calcium, glucose, blood
urea nitrogen, uric acid, creatinine, total bilirubin, alkaline
phosphatase, lactic dehydrogenase, aspartate transaminase, chloride,
CO2, total protein, albumin, inorganic phosphate, pH, and pCO2.
Haematology parameters consisted of white blood cell and red blood
cell counts, haemoglobin concentration, haematocrit, and mean
corpuscular volume. Urine was analysed for volume, pH, sodium,
potassium, calcium, and phosphates. In a 90-day feeding study,
Polydextrose induced loose stools and compensatory water imbibition
throughout the study. Intensive study of serum and urinary
biochemistry of these animals failed to reveal significant shifts in
vascular fluid volume, electrolyte excretion or in serum calcium
levels such as occurred, secondary to chronic watery diarrhoea, in
previous experiments with high dietary levels of type N, the bleached
and neutralized form of Polydextrose (Anon., 1978l).
Monkey
Eight male and eight female monkeys were separated into four
groups of two males and two females each. Three of these groups
received Polydextrose N by gavage at doses of 10, 2 and 1 g/kg per
day, seven days a week for 91 days. The fourth group received
distilled water. The 10 g/kg per day dose was administered as 5 g/kg
twice a day. The 2 and 1 g/kg dose levels were administered once a
day. The 10 mg/kg animals were dosed with a 50% solution and the 2 and
1 g/kg animals were dosed with a 70% solution. Haematology, serum
chemistry and urinalysis examinations were made on each monkey twice
prior to start of treatment and at 29, 57 and 85 days. The
haematological parameters evaluated consisted of red blood cell (RBC),
white blood cell (WBC), and WBC differential counts; haemoglobin
concentration; haematocrits; and whole blood clotting times. Clinical
chemistry determinations consisted of fasting blood sugar, blood urea
nitrogen (BUN), serum glutamic pyruvic and serum glutamic oxalacetic
transaminases (SGPT and SGOT), serum alkaline phosphatase, total
bilirubin, serum lactic dehydrogenase (LDH), serum creatine
phosphokinase (CPK), serum sodium (Na+), serum potassium (K+), serum
calcium (Ca++), serum creatinine and uric acid levels.
Ophthalmoscopic examinations and electrocardiographic tracings were
made twice prior to treatment and on days 29, 57 and 85. All animals
remaining at the end of the test were sacrificed and necropsied on day
92, 24-28 hours after the ninety-first dose. Protracted diarrhoea
occurred in animals at the high dose level only. There was a decrease
in serum calcium levels to the lower range of normal and focal areas
of haemosiderin-containing macrophages in the colonic mucosa were
detected on microscopic examinations. Both of these biologically
insignificant changes occurred only at the highest dose level and both
are considered a secondary consequence of the continuous diarrhoea. No
signs of compound-induced toxicity were noted and all animals
maintained good physical condition during the course of the experiment
(Anon., 1973c).
Long-term studies
Mouse
Four groups of 50 male and female mice were fed with a diet
containing Polydextrose at 0, 5 and 10% concentrations. Positive
control received a diet containing sucrose 10%. No adverse clinical
symptoms or behavioural changes which could be related to the
ingestion of Polydextrose were observed during the trial except for a
slight but not significant increase of the blood glucose in the
Polydextrose or sucrose treated groups. No variations in haematology
parameters were recorded which could be the consequence of the intake
of Polydextrose or sucrose. No obvious differences were seen between
control or treated animals in the examination of the fundus, lens and
cornea of the control, 10% Polydextrose and sucrose groups. There were
no significant differences in mortality rate between control and
treated animals. The sucrose treated females were the only groups
which differed from any of the others by being significantly heavier.
There was no evidence of any lesion which could be related to the
administration of Polydextrose or sucrose. There were no obvious
differences in the frequency of tumours between the different groups
(Anon., 1975c).
Rat
Four groups of 50 male and 50 female rats received either 0, 5 or
10% of Polydextrose, 10% sucrose. The F0 generation was treated for
about 100 days and from this F1 generation 50 rats of both sexes from
the corresponding groups were used for the 24-month period. All
animals of the F1 generation were mated at the age of 90 and 140 days
and in males and females there were no compound-related malformations
or gross lesions. Soft and dark faeces were noted in the animals which
received either Polydextrose or sucrose in their diet. Mortality or
morbidity rates were similar among the four groups. No differences in
growth and food consumption of any importance were noted. Examination
of the cornea, iris, vitreous, lens and fundus were normal. In
clinical chemical and haematological tests no regularly recurring
modifications were noted. At autopsy and histopathology no evidence
was obtained of a Polydextrose or sucrose-related effect on the total
incidence of tumours or of malignant tumours or in the latency of
tumour appearance. No treatment-related histopathological change was
found (Anon., 1977c).
Dog
Beagle dogs, six males and six females per group, were
administered nominally 0, 10, 20 or 50% Polydextrose Type N or 0, 20
or 50% sucrose in the diet (9, 16 or 33% of total dry weight of the
diet), for periods up to two years in two experiments. Most of the
dogs treated with Polydextrose (50%) showed sporadic anorexia, which
was severe at times. This was not noticeable at the lower Polydextrose
levels and disappeared as soon as the drug was withdrawn.
Administration of Polydextrose at 10 and 20% of the diet had no effect
on body weight relative to the control group. At the 50% level,
however, Polydextrose-treated dogs did not gain weight during the
administration period, in contrast to controls which gained
approximately 3-4 kg during this 18-month period. The Polydextrose
Type N administration produced a chronic watery diarrhoea (with
concomitant effect on water and electrolyte balance) and gradual
increases in serum levels of calcium (beginning at three months at the
20 and 50% levels) which resulted in clinical hypercalcaemic
nephropathy. The diarrhoea stopped completely within three days of
compound withdrawal. The renal lesion was made up of wedge-shaped
areas of scarring in the cortex or just below the corticomedullary
junction. Tubular dilation was often present in the cortical portion
of the lesion and moderate mineralization more prominent in the
medulla. All effects seen were considered secondary to the chronic
diarrhoea and not a direct effect of Polydextrose. Some elevated
plasma urea concentrations were also observed in the top dose group
and, at the end of treatment only, for the mid-dose group. There were
no other changes in clinical chemistry parameters which could be
attributed to an action of the compound (Anon., 1978m).
In the 24-month dog experiments aforementioned, Polydextrose
containing 1% potassium ion induced watery diarrhoea, polydypsia, loss
of electrolytes, a gradually developing hypercalcaemia and consequent
nephropathy. To ascertain the contribution of the potassium content of
the product to the severity of the watery diarrhoea, Polydextrose Type
N was administered to four beagle dogs in dog food to provide 50% dry
weight of the diet (23 g/kg bw per day) until hypercalcaemia developed
(135 days) and then was replaced with the same amount of Type A, the
acidic potassium-free Polydextrose for 60 additional days. The
severity of the diarrhoea and serum calcium levels decreased and
urinary sodium and calcium concentrations increased after replacement
with Type A. The two dogs which developed clinical hypercalcaemia
while receiving Polydextrose N were found upon sacrifice to have renal
lesions similar to those previously observed in long-term studies in
dogs with Polydextrose Type N. These results support the hypothesis
that the renal lesions in dogs result from hypercalcaemia which
develops with chronic watery diarrhoea induced by Polydextrose Type N
(potassium salt). Fluid shifts result in contracted extracellular
fluid volume and electrolyte imbalance with increased renal
reabsorption of sodium and calcium. When the watery diarrhoea is
abated by replacement of Type N with Type A, urinary sodium and
calcium excretion increase and serum calcium levels decline (Anon.,
1978n).
OBSERVATIONS IN MAN
To determine the incidence of diarrhoea or emesis 20 volunteers
received Polydextrose in increasing dosage (75 g per day to 150 g per
day) over a period of three weeks with a parallel control group of
nine volunteers receiving a "placebo". Polydextrose was administered
in the form of a chocolate milk drink three times a day after meals,
the placebo consisted of a chocolate milk drink with dextri-maltose
administered in the same fashion. Patients were checked daily for
side-effects and weekly for laboratory and cardiodynamic parameters.
The determining factor for termination from the study was persistent
diarrhoea. Eleven volunteers from the Polydextrose group were taken
off the study because of diarrhoea, five during the first week (75 g
per day), three during the second week (75 g per day) and three during
the last week (150 g per day). Five volunteers from the placebo group
were taken off the study because of diarrhoea, all at the end of the
third week. Gastrointestinal transit time as measured by the
faecal dye marker technique was not significantly altered by the
consumption of Polydextrose. Analysis of faecal samples indicated that
Polydextrose ingestion did not interfere with the absorption of amino
acids or minerals (potassium and calcium). Elevated serum-free fatty
acids and triglycerides existed in the majority of the volunteers
during the baseline period. The chocolate milk drink test vehicle and
the abnormally high carbohydrate diet available to the volunteers
(manifested by the high serum triglyceride values) probably
contributed to the high incidence of side-effects in this study
(Anon., 1979a).
To measure acceptability patterns in a normal diet which included
35 g per day (0.5 g/kg bw) or 75 g per day (1.0 g/kg bw) Polydextrose,
57 volunteers were divided into a control group (fed sucrose or
dextri-maltose based foods), a group receiving 35 g of Polydextrose
per day and a group receiving 75 g of Polydextrose per day. The
volunteers consumed the test foods at breakfast, lunch and an
afternoon coffee break for a two-week period excluding the weekend.
All volunteers willingly completed the trial and no toxicity of any
sort was observed in clinical chemistry parameters. While there was no
significant diarrhoea related to Polydextrose ingestion, there was an
appreciable increase in flatulence and stools were less firm and in
addition, at 75 g per day stools were passed more frequently (Knirsch,
1979).
To measure the upper toleration limit a study was conducted with
21 adults using Polydextrose sorbitol as a positive control and
dextri-maltose as a placebo. The test substances were administered in
foods at breakfast, lunch and an afternoon coffee break. The
volunteers consumed increasing doses of the test materials in their
food until they reached a pre-established level of laxative effect or
reported other intolerable side-effects. Under rather conservative
test conditions the mean laxative threshold was 90 g (1.3 g/kg bw per
day) (range 50-130 g) for Polydextrose and 70 g (1.0 g/kg bw per day)
(range 40-110 g) for sorbitol (Anon., 1979a).
To determine any effects from prolonged ingestion of Polydextrose
a group of 51 volunteers participated in a study of three months
duration. In this study the volunteers were limited to a maximum
dosage of 30 g per day during the first month, 45 g per day during the
second month and 60 g per day during the third month. Each individual
was allowed to adjust his (or her) Polydextrose (or placebo) daily
intake to a convenient level. As a result of this the actual doses of
Polydextrose consumed during the study ranged from 20 to 60 g per day
(0.28-0.83 g/kg). All clinical and laboratory parameters measured
during the study showed no significant change. The Polydextrose
experienced a slight but significant loss in weight during the study
in comparison to the placebo group (Anon., 1979b).
A group of 106 children aged from two to 16 years participated in
a four-week toleration study. Based on the results available from the
adult toleration studies the dosages for the children's study were
conservatively set at 500 mg/kg per day for the first week, 750 mg/kg
per day for the second week and 1000 mg/kg per day for the third and
fourth weeks. The test substances were consumed in foods throughout
the day. All of the children tolerated these dosages and completed the
study. Both laboratory and clinical parameters showed no significant
changes. As expected the children experienced a wide range of
transient effects during the study but the only side-effect relating
to Polydextrose and persisting for two or more days that had
statistical significance was flatulence (Anon., 1979e).
To verify the absence of insulin demand a study was conducted
with a group of maturity-onset diabetics. All of the 10 subjects
received in a fasted state a 50 g (0.69 g/kg) dose of Polydextrose
either alone and also in a mixture with 50 g or 100 g of glucose. This
quantity of Polydextrose did not affect plasma glucose or insulin
kinetics under standard glucose tolerance test conditions. These 50 g
slug doses of Polydextrose caused no significant gastrointestinal
side-effects. Isolated instances of diarrhoea and flatulence were
reported but the frequency was similar to that found with the glucose
control group (Anon., 1979f).
To more carefully evaluate possible effects of Polydextrose
ingestion on the absorption and utilization of essential nutrients a
group of 16 volunteers participated in a metabolic balance study. This
study lasted for eight weeks during which the volunteers subsisted on
a carefully regulated and constant diet based on a single daily menu.
After a two-week baseline period the Polydextrose sub-group ingested
30 g of Polydextrose per day. The dosage was raised to 40 g per day
during the fourth week, 50 g per day (0.78 g/kg) during the fifth week
and was kept at this level for the remaining three weeks of the study.
The placebo sub-group received corresponding amounts of foods made
from sucrose and dextri-maltose. While some of the volunteers reported
increased flatulence, there were no significant gastrointestinal
symptoms. Clinical observations, blood chemistries and haematological
indices revealed no significant clinical changes. The balance data for
calcium, sodium, potassium, iron, zinc and nitrogen indicated no
significant differences between the Polydextrose sub-group and the
controls. Urinary thiamine and riboflavin excretion and faecal fat
output were the same for the two groups. Ingestion of Polydextrose in
healthy young adults leads to no detectable change in nutrient
utilization. The lack of significant change in calcium utilization is
in sharp contrast to results observed in dog studies where
Polydextrose was shown to enhance the intestinal absorption of calcium
(Anon., 1979g).
ADDENDUM
A thirteen-month feeding study with Polydextrose A in beagle dogs
Thirty dogs (5/sex/level) received Polydextrose Type A in
concentrations of 0, 20 and 50% in the diet daily for 13 consecutive
months. Unformed stools and watery diarrhoea were more prominent in
the 50% than the Polydextrose 20% groups. In 2/5 high-level male dogs,
hypercalcaemia (> 12 mg/dl), calciuria and increased serum creatinine
levels gradually developed over the course of the experiment. One
of these dogs also showed elevated BUN values. After sacrifice
characteristic calcium nephropathy was observed grossly and
microscopically in the kidneys of the same two animals. These changes
did not occur in the remaining high-level dogs or in those at the 20%
intake level (Anon., 1980).
These compounds were evaluated in the twenty-fourth report of the
Expert Committee and an ADI of 0-70 mg/kg bw was allocated. The
Committee regarded this ADI as being applicable to general food uses
of Polydextroses and considered that higher levels could be taken in
dietetic foods. The Committee confirmed the ADI of 0-70 mg/kg bw
for Polydextrose A and Polydextrose N, singly or in combination.
The specifications were revised to include a limit of 0.05% for
5-hydroxymethylfurfural in Polydextroses.
EVALUATION
Estimate of acceptable daily intake for man
0-70 mg/kg bw.
REFERENCES
Anon. (1973a) Study of the action of Polydextrose on pregnancy and
foetal development in rats and rabbits. Unpublished reports from
Pfizer Central Research submitted to the World Health
Organization by Pfizer Central Research
Anon. (1973b) Three-month, oral dose study in rats with CP-31,081.
Unpublished reports from Pfizer Central Research submitted to the
World Health Organization by Pfizer Central Research
Anon. (1973c) A three-month study in monkeys with CP-31,081.
Unpublished reports from Pfizer Central Research submitted to the
World Health Organization by Pfizer Central Research
Anon. (1974) Study of the action of MPD (Modified Polydextrose) on the
perinatal and postnatal development of the rat. Unpublished
reports from Pfizer Central Research submitted to the World
Health Organization by Pfizer Central Research
Anon. (1975a) 3-generation study in rats. Unpublished reports from
Pfizer Central Research submitted to the World Health
Organization by Pfizer Central Research
Anon. (1975b) Action of MPD (Polydextrose Type A) on fertility and
general reproductive performance in the rat. Unpublished reports
from Pfizer Central Research submitted to the World Health
Organization by Pfizer Central Research
Anon. (1975c) 18-month carcinogenicity study with MPD (Polydextrose
Type A). Unpublished reports from Pfizer Central Research
submitted to the World Health Organization by Pfizer Central
Research
Anon. (1977a) Effect of MPD on the intestinal absorption of calcium in
anaesthetized dogs. MPD Type N. Unpublished reports from Pfizer
Central Research submitted to the World Health Organization by
Pfizer Central Research
Anon. (1977b) Calcium absorption study in beagle dogs with
Polydextrose. Unpublished reports from Pfizer Central Research
submitted to the World Health Organization by Pfizer Central
Research
Anon. (1977c) 24-month carcinogenicity study in rats with Polydextrose
A (MPD). Unpublished reports from Pfizer Central Research
submitted to the World Health Organization by Pfizer Central
Research
Anon. (1978a) Metabolism of 14C-Polydextrose in man. Unpublished
reports from Pfizer Central Research submitted to the World
Health Organization by Pfizer Central Research
Anon. (1978b) Formation of radioactive volatile fatty acids (VFA) from
14C-Polydextrose in the intestinal flora of rats and man.
Unpublished reports from Pfizer Central Research submitted to the
World Health Organization by Pfizer Central Research
Anon. (1978c) Intravenous administration of 14C-Polydextrose to rats.
Unpublished reports from Pfizer Central Research submitted to the
World Health Organization by Pfizer Central Research.
Anon. (1978d) Oral administration of 14C-Polydextrose to rats.
Unpublished reports from Pfizer Central Research submitted to the
World Health Organization by Pfizer Central Research
Anon. (1978e) Oral absorption of unchanged Polydextrose by rats.
Unpublished reports from Pfizer Central Research submitted to the
World Health Organization by Pfizer Central Research
Anon. (1978f) Metabolism of 14C-Polydextrose in stressed rats.
Unpublished reports from Pfizer Central Research submitted to the
World Health Organization by Pfizer Central Research
Anon. (1978g) Recycled 14C-Polydextrose in rats. Unpublished reports
from Pfizer Central Research submitted to the World Health
Organization by Pfizer Central Research
Anon. (1978h) Comparison of caloric utilization of 14C-Polydextrose
and 14C-Polydextrose-N in rats. Unpublished reports from Pfizer
Central Research submitted to the World Health Organization by
Pfizer Central Research
Anon. (1978j) Genetic toxicologic report. Unpublished reports from
Pfizer Central Research submitted to the World Health
Organization by Pfizer Central Research
Anon. (1978k) Acute studies mouse oral LD50 - 50% solution (Type A)
rat oral LD50 - 70% solution (Type N) dog intravenous LD50 70%
solution (Type N) oral LD50's - mouse, rat, dog - 70% solution
(Type N) dog oral LD50 - (Type A) - dry powder. Unpublished
reports from Pfizer Central Research submitted to the World
Health Organization by Pfizer Central Research
Anon. (1978l) A 90 day feeding study in beagle dogs with CP-31,081,
Polydextrose (PD) Type A. Unpublished reports from Pfizer Central
Research submitted to the World Health Organization by Pfizer
Central Research
Anon. (1978m) MPD 24-month toxicity study in beagle dogs (10% and 20%
of the diet) (Polydextrose Type N) and sucrose (20% of diet) and
MPD 2-year study in dogs with Modified Poly-Dextrose (MPD)
administered at 50% of diet - MPD Type N. Unpublished reports
from Pfizer Central Research submitted to the World Health
Organization by Pfizer Central Research
Anon. (1978n) A six month feeding study with CP-31,081, Polydextrose
(PD Type N followed Type A) in beagle dogs (50% of dry weight of
the diet) low caloric food ingredient. Unpublished reports from
Pfizer Central Research submitted to the World Health
Organization by Pfizer Central Research
Anon. (1979a) Determination of incidence of diarrhoea or emesis at
dose levels of 0, 75, 150 g/day. Unpublished reports from Pfizer
Central Research submitted to the World Health Organization by
Pfizer Central Research
Anon. (1979b) Determination of whether gastrointestinal symptoms
result from ingestion as part of a regular diet dose levels 0,
35, 75 g/day. Unpublished reports from Pfizer Central Research
submitted to the World Health Organization by Pfizer Central
Research
Anon. (1979c) Upper toleration limit or laxative threshold, comparison
with sorbitol. Unpublished reports from Pfizer Central Research
submitted to the World Health Organization by Pfizer Central
Research
Anon. (1979d) Effects of long-term ingestion (12 weeks) at dose levels
from 30-60 g/day. Unpublished reports from Pfizer Central
Research submitted to the World Health Organization by Pfizer
Central Research
Anon. (1979e) Effects in children and adolescents, dose levels 0.5 to
1.0 g/day, four weeks. Unpublished reports from Pfizer Central
Research submitted to the World Health Organization by Pfizer
Central Research
Anon. (1979f) Effects on insulin and glucose kinetics in diabetics
50 g dose level. Unpublished reports from Pfizer Central Research
submitted to the World Health Organization by Pfizer Central
Research
Anon. (1979g) Effects on absorption and utilization of certain
essential nutrients as determined by the metabolic balance
technique; dose levels 0, 30, 40, 50 g/day, eight weeks.
Unpublished reports from Pfizer Central Research submitted to the
World Health Organization by Pfizer Central Research
Anon. (1980) A thirteen month feeding study with Polydextrose A in
beagle dogs. Unpublished reports from Pfizer Central Research
submitted to the World Health Organization by Pfizer Central
Research
Hooson, J., Roberts, M. & Grasso, P. Comparison of cytopathological
effects of MPD and other polysaccharides on cells in culture.
Unpublished report from the British Industrial Biological
Research Association submitted to the World Health Organization
by Pfizer Central Research
See Also:
Toxicological Abbreviations
POLYDEXTROSES (JECFA Evaluation)