LACTITOL*
Explanation
Lactitol has not previously been evaluated by the Joint FAO/WHO
Expert Committee on Food Additives.
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
Absorption, distribution and excretion
Three male rats (150-200 g; six to eight weeks of age; one not
pretreated and two habituated to a diet containing 7% lactitol) were
orally intubated with about 2 mg D-(sorbitol-1-14C) lactitol. In the
studies with the rats habituated to lactitol, 9-15% of the
radioactivity was recovered from the air exhaled in the period 0-5
hours and 48% from the air exhaled in the period 0-24 hours. The urine
and the faeces contained a minor proportion of the administered
radioactivity (urine, 2.3% after five hours and 6.8% after 24 hours;
faeces, 11.7% after 24 hours). The gastrointestinal tract contained
33% of the radioactivity after five hours and 5% after 24 hours; the
remainder of the body contained 20% after five hours and 9% after 24
hours. It was concluded that lactitol is extensively degraded in the
rat after oral administration presumably mainly by the intestinal
microflora and that habituation of the rats to unlabelled lactitol did
not essentially affect the rate and extent of degradation (Leegwater,
1978).
The utilization of lactitol was determined in two successive
feeding periods of seven days each, using male rats adapted to a diet
containing 20% lactitol. It was concluded that, in adapted rats,
lactitol is digested and utilized to such an extent that it may
support a growth rate of more than 50% of that supported by an equal
amount of sucrose (van Beck, 1977).
The effect of lactitol on the characteristics of the faeces was
investigated as a satellite study of the long-term study performed
over a one-week period (starting at week 125) on 11-15 rats/sex/group,
obtained from mothers which had been exposed to 2, 5 or 10% lactitol
* Lactitol (4-ß-D-galactopyranosyl-D-sorbitol) is a sweet-tasting
sugar alcohol. It is formed from lactose, which is hydrogenated
in the presence of Raney-Nickel catalyst. After sedimentation (to
settle the catalyst) the solutions is filtered, purified,
concentrated and crystallized.
or 20% lactose during gestation and lactation. The feeding of lactitol
or lactose was accompanied by increased production of faecal dry
matter, increased water content, decreased faecal pH, and a lowering
of apparent protein digestibility. These changes were attributed to
relatively slow digestibility of lactitol and lactose in the small
intestine. There were no noticeable changes in the composition of the
faecal microflora or in the levels of lactic and volatile fatty acids
in the caecal and faecal contents. The levels of lactitol and lactose
in the caecum and faecal content were very low, indicating almost
complete degradation in the gastrointestinal tract (Sinkeldam et al.,
1982).
In a patent application (Hayashibara, 1974), it was demonstrated
in rats that lactitol inhibits the absorption of sucrose and the
formation of cholesterol. The increase of the blood glucose content,
after consumption of a 1:1 mixture of sucrose and lactitol, was about
half of the increase after consumption of sucrose only (the amount of
sucrose intake was the same); however, the formation of liver glycogen
with the 1/1 mixture was only one-fifth of that with only sucrose.
When added to diets containing cholesterol, it was shown that lactitol
reduced the liver and serum cholesterol levels in rats by as much as
50%.
Enzymatic hydrolysis
Karrer & Buchi (1937) have studied the action of ß-galactosidase-
containing enzyme preparations on the splitting of lactitol into
galactose and sorbitol. They found that lactitol is only hydrolysed
very slowly by these enzymes. Later it was confirmed that lactitol is
only slowly split by enzymes with about a tenth of the speed at which
lactose is split (Maizena, 1971).
Biodegradability
In a modified OECD degradation test, biodegradation (based on
dissolved organic carbon) was complete within five days, whereas only
50% of the theoretically required oxygen was used. This points to
lactitol being mainly used for the growth of microorganisms. Lactitol
must be considered as rapidly biologically degradable (de Kreuk,
1980).
Special effects
The laxative effects of lactitol, xylitol and sorbitol were
compared with that of lactose in feeding tests with young male rats.
In the initial stages of the study, lactitol (10%) induced
considerably less diarrhoea than xylitol and sorbitol. Rats showed a
rapid adaptation to the diets, which resulted in comparable scores on
the laxative effect at the end of the seven-day period. It was
concluded that each of the sugar alcohols, when fed at the 10% level,
was a stronger laxative than lactose, while xylitol was more active
than lactitol or sorbitol. When fed at the 5% level, lactitol was
considerably less laxative than xylitol and sorbitol and comparable to
10% lactose (de Groot & Andringa, 1976).
The effect of lactitol on dental plaque formation was examined at
the University of Utrecht, School of Dentistry. Streptococcus mutans
and other bacteria isolated from human dental plaques were shown to
form acid from lactitol, but at a much slower rate than with glucose.
The bacteria were not able to synthesize extracellular polysaccharides
from lactitol. It could not be established from these experiments
whether lactitol is a better sugar substitute than sorbitol (Havenaar,
1976).
In a study at the University of Wurzburg on the cariogenic
properties of lactose, rats were given test diets, one of which
contained lactitol. It was concluded that rats fed 45% lactitol in
basal diets had a significantly lower caries incidence than rats fed
lactose, fructose or sucrose in their basal diet. However, the caries
incidence was higher than that in the control group (Gehring, 1978).
It was claimed that lactitol has no caloric value "because it is
not digested or absorbed by digestive organs of the higher animal".
This was demonstrated by experiments with live rabbits. The intestines
of fasted rabbits were closed at both ends and were injected with a
20% aqueous solution of lactitol or an equimolecular amount of a
sucrose solution. After several hours, the sugar or sugar alcohol
remaining in the intestines was estimated. It was found that, while
85% of the sucrose intake had been lost due to absorption and
digestion, lactitol had shown no loss (Hayashibara, 1976).
TOXICOLOGICAL STUDIES
Special studies on Carcinogenicity
See under long-term studies.
Special studies on dermal irritation
A Draise test was conducted with six rabbits, using intact and
abraded skin. 0.5 g lactitol caused a very slight oedema in two out of
six rabbits on intact skin. At 24 hours, erythema and very slight
oedema were observed on abraded skin-test sites in six rabbits (van
Beek, 1980).
Special studies on the effects of different carbohydrates and
polyols in the alloxan diabetic rat
In man, diabetes mellitus, if not treated properly, is known to
induce cataract, retinopathy, nephropathy and angiopathy. A major
objective of the study was to investigate whether and to what extent
these effects also occur in alloxan diabetic rats fed diets containing
lactitol, lactose, sorbitol, sucrose or fructose for three months.
Experimental diets were prepared by replacing 15 or 30% of wheat
starch (control) by the test products. The rats were made diabetic by
a single, intravenously administered dose of 40 mg alloxan/kg bw. Only
animals with blood glucose levels between 20 and 30 mmol/litre were
used. Induction of alloxan diabetes resulted in decreased growth,
increased food and water intake, elevated blood glucose levels,
development of cataracts, increased liver and kidney weight and caecum
enlargement.
In the rats fed lactitol, lactose or sorbitol diets, only an
isolated case of cataract occurred. In the rats fed the wheat starch,
sucrose or fructose diets, cataracts were seen in five to 14 in each
group of 20. In general, it was shown that lactitol and sorbitol had a
dose-related favourable effect on the typical symptoms of diabetes
mellitus in the alloxan diabetic rat. The same applies to lactose,
although to a lesser extent (Leegwater et al., 1982).
Special studies on eye irritation
In a Draise test with six rabbits, 100 mg of lactitol was
instilled into the conjunctiva of one eye. The eye was not washed.
Conjunctival redness was observed in three rabbits (with chemosis in
one) after 24 hours, clearing up after three days (van Beek, 1980).
Special studies on mutagenicity
The mutagenic activity of lactitol was examined in the
Salmonella/microsome mutagenicity test, using a set of five histidine-
requiring mutants of S. typhimurium (TA-1535, TA-1537, TA-1538,
TA-98 and TA-100) and liver homogenate of Aroclor-induced rats.
Incorporation of the test compound up to 10 mg per plate did not
increase the number of histidine revertants in any of the five tester
strains, either in the presence or in the absence of the liver
microsome activation system. It was concluded that the present results
did not reveal any mutagenic activity of lactitol in the
Salmonella/microsome mutagenicity test (Willems, 1979).
Special studies on reproduction
Rat
A one-generation reproduction study was carried out by feeding
10% lactitol or 20% lactose to two groups of eight female and four
male rats; a third groups was fed basal diet only, with starch and
sucrose added so as not to change the carbohydrate levels for the
treatment groups. The results of this pilot study did not show any
obvious deleterious effects of lactitol or lactose on reproduction of
rats. Fertility indices were 100% and viability indices at days 1 and
4 were not adversely affected by the test materials. Body weights of
the parent rats tended to be decreased with both lactitol and lactose
in the diet. No diarrhoea was observed in any group. The only change
observed in the litters was a slightly smaller litter size in the test
groups than in controls, resulting in increased birth weights of the
pups in these groups and a slight growth retardation in both lactitol
and lactose fed groups - not accompanied by diarrhoea (Sinkeldam,
1979).
A multigeneration study in Wistar rats was conducted by feeding
diets containing 0, 2, 5 or 10% of the test substance over three
successive generations. Because of the tendency of lactitol to induce
diarrhoea, the animals of the F0 generation were adapted to the
ingestion of this sugar. Initially each group of parent rats consisted
of 20 males and 40 females. Weanling rats of the F1a litters were
used to constitute the groups for a chronic toxicity/carcinogenicity
study and for a teratogenicity study. The number of parent rats per
group was then reduced to 10 males and 20 females for the second
mating of the F1 generation and the same numbers were maintained in
successive generations. One group of rats, fed a diet with 20%
lactose, served as an additional control during the F0 generation.
Body weights of the F1 male parents were somewhat decreased at
the 5% and 10% lactitol levels. No unfavourable effects were observed
in fertility, gestation period, gestation index, resorption quotient
and litter size. Viability (day 4) and lactation indices were reduced
at the 5% and 10% levels in most generations. F3b rats fed 5% or 10%
lactitol for four weeks after weaning showed caecum enlargement, which
was attributed to poor digestibility of lactitol. Growth rate during
and after lactation was decreased in pups of groups fed 10% lactitol,
which was also attributed to poor digestibility. Treatment-related
changes were observed in the livers of F3b males of all treated
groups, characterized by a uniform and homogeneous cytoplasm of the
liver cells. There was no dose-response relationship (Sinkeldam et
al., 1982).
Special studies on skin sensitization
Guinea-pig
A maximization test was carried out on 15 young male guinea-pigs.
The maximum concentration of lactitol, suitable for intradermal
injection and topical application, was found to be 40% w/v in water;
these concentrations were utilized. From the reaction to the challenge
dose, it was concluded that the test substance exhibited slight
sensitization properties (Til & Keizer, 1981).
Special studies on teratogenicity
Rat
Four groups of 25 pregnant rats each were used. They originated
from the corresponding test diet groups of Fla young of the multi-
generation study and were continuously fed with the test substance
until day 21 of pregnancy at levels of 0, 2, 5 and 10% in the diet.
Growth rate, food intake, autopsy findings, macroscopic examination of
foetuses, organ weights and litter data did not reveal any defect that
could be attributed to the feeding of lactitol. All foetuses were
stored, but not microscopically examined (Koëter, 1980). Lactitol was
fed to female rats which were pretreated in utero and subsequently,
after birth, for 15 weeks prior to mating. Pregnant females (25
rats/group) were fed the test diets until day 21 of pregnancy at
levels of 0, 2, 5 and 10% in the diet. (The rats were selected from
the F2a generation of the multigeneration study.)
Body weights of animals in the 10% lactitol group lagged behind
during the premating period and subsequently during pregnancy. Weight
gain during gestation was similar in all groups. Autopsy findings,
organ weights, litter data and macroscopic examination of the foetuses
did not reveal any effect attributable to treatment. Neither skeletal
nor visceral examination of the foetuses revealed any malformation
that could be related to lactitol feeding. However, there was an
increased incidence in numbers of supernumerary lumbar ribs and
incomplete thoracic vertebral bodies in the 10% lactitol groups which
might point to an embryotoxic or foetotoxic effect (Koëter, 1981).
Acute toxicity
Species Route LC50 Reference
(mg/l)
Poecilia reticulata Water >10 000 Adema, 1980
Daphnia magna Water >10 000 Adema, 1980
Rat p.o. >10.0 Spanjers & Til, 1980
Rabbit Dermal > 4.5 van Beek et al., 1980
Short-term studies
Rat
Five groups of 10 male and 10 female rats were fed diets
containing either 0, 5, 10 or 20% lactitol or 25% lactose. Body
weights were recorded weekly and food intake of each group determined
during the first four weeks, and in weeks 11 and 12. Haematology,
urinalysis and clinical chemistry were carried out terminally. At week
13, the rats were killed, examined grossly and 10 organs were weighed.
Over 20 organs and tissues were examined microscopically. A dose-
related growth reduction (by less than 10%) was observed in all rats
receiving lactitol and the food intake showed a treatment-related
decrease during the first four weeks. Food efficiency figures were
decreased both at 20% lactitol and 25% lactose levels. Haematological
indices and urine composition did not show any toxicologically
significant differences between the test groups and the controls.
Minimal increase of serum glutamic-pyruvic transaminase and serum
alkaline phosphatase in treated groups was statistically significant,
but, in most cases, not biologically significant. The weight of the
caecum was increased at each treatment level. The relative weight of
the kidney and liver was increased at the 10 and 20% levels.
Microscopically, swollen liver cells showing homogeneous and cloudy
cytoplasm were observed in the rats fed 10 or 20% lactitol (Sinkeldam
et al., 1976).
In another study, the rats were randomly selected from the first
litter of parent rats which had already been treated with lactitol or
lactose during 12 weeks before mating. Five groups of 10 male and 10
female rats were fed lactitol in the diet at levels of 0, 2, 5 and 10%
and lactose at 20% for one year. General condition and behaviour were
checked "frequently" and body weights recorded once every week during
the first 12 weeks and once every four weeks thereafter. Food
consumption was measured weekly and food efficiency calculated in the
first four weeks of the study. Water consumption was determined daily.
Faeces production was measured during weeks 1, 2, 3, 4, 17 and 27.
After 52 weeks, all rats were killed and examined grossly. Ten organs
were weighed and tissue samples of over 20 organs examined
microscopically. Body weights of all treated groups were lower than
that of controls; the difference was 10% at the lowest lactitol level.
Food intake was slightly reduced at the 10% level. Faeces dry matter
showed a dose-related increase in lactitol fed groups. There was a
treatment-related increase in the relative weight of the filled and
empty caecum. Gross and microscopic examinations did not reveal
compound-related pathological changed (Sinkeldam et al., 1981).
Dog
At the end of week 10 of a feeding study planned for six months,
male dogs were stolen by a group of activists against the use of
animals for research. All remaining male dogs were abandoned and a new
study with male dogs was started and conducted in exactly the same way
as the study in females, four months later.
Lactitol was fed at dietary levels of 0, 5, 10 and 15% and
lactose at 15% to groups of six male and six female beagle dogs for 26
weeks (dry pellets). Condition and behaviour of dogs were checked
daily. Ophthalmoscopy was conducted on control and highest level
groups at weeks 3 and 17 and on all dogs at end of study. Body weight
and food consumption was determined weekly. Haematological parameters
(haemoglobin, haematocrit, erythrocyte number and indices total and
differential leucocyte count, prothrombin time and sedimentation rate)
were determined at weeks 0, 7, 13-14 and 26. At the same time periods,
SGOT, SGPT, SAP, total plasma protein, plasma albumin, glucose, urea
and electrolyte measurements were made. Urinalyses (including
microscopy of the sediment) were performed four times during the
study. All dogs were autopsied, 14 organs weighed and about 40 tissues
examined histologically.
Diarrhoea was observed in the dogs fed 10 and 15% lactitol and in
those fed 15% lactose. Body weight did not show treatment-related
differences. There was slight anaemia, as evidenced by the relatively
low haemoglobin levels, haematocrit and red blood cell counts observed
terminally in males fed 15% lactitol or lactose. SAP levels were
decreased in females of the 15% lactitol group. In other groups of
treated females, the decrease did not reach statistical significance.
Retention of phenosulfophthalein or bromosulfophthalein did not
suggest any impairment of the kidney or liver function. The most
marked treatment-related effect was an increase in the weight of the
caecum, colon and small intestine in males of all lactitol groups and
an increase in caecum weight in females of the 10 and 15% lactitol
group (small intestines and colon were not weighed in females). Gross
and microscopic examination did not reveal any pathological changes
that Could be attributed to the feeding of lactitol or lactose (Til et
al., 1981).
Long-term studies
Mouse
Lactitol-dihydrate was fed at levels of 0, 2, 5 and 10% in the
diet to groups of 50 males and 50 females (selected by computer
randomization) for two years. Fresh diet was provided every week;
lactitol was included at the expense of sucrose and wheat starch in
the basal diet. A number of diet batches were analysed for stability
and concentration of lactitol and were found satisfactory. Mice were
observed daily and examined for signs of illness and rumours every two
weeks. Body weight of each animal was recorded weekly for three months
and once every four weeks thereafter. Food consumption was measured 14
times (up to week 78) and water consumption four times. Urinalyses
were conducted on urine samples collected individually from 10
mice/sex/group in weeks 13, 26, 52 and 78 for determination of
density. Semi-quantitative tests and sediment examination were carried
out from pooled urine samples from 10 mice/sex/group. All surviving
mice were autopsied, and brain, caecum, heart, kidneys, liver, spleen
and testes weighed. All nodules and macroscopically abnormal tissues
were preserved along with over 40 tissues. Detailed microscopic
examination was performed on tissues of the control and highest level
groups; of the mid-dose and low-dose groups the liver, spleen,
ovaries, pituitary, thyroid and adrenals were examined
microscopically. All grossly observed rumours and lesions suspected of
being tumours were examined in all groups; special attention was paid
to the occurrence of bladder stones. A thorough autopsy was also
performed on mice that died intercurrently and tissue samples
preserved; the organs of these animals were not weighed.
No distinct deleterious effect was found. There was no evidence
of lactitol affecting condition, behaviour, survival, growth, food and
water intake or urine parameters. Incidence, location and type of
rumours did not reveal any treatment-related differences amongst the
groups. The only treatment-related effect was an increase in the
weight of the filled and empty caecum in males of all lactitol groups
and in females of the 5 and 10% lactitol groups (Til et al., 1982).
Rat
Groups of 50 male and 50 female rats were fed lactitol in the
diet at levels of 0, 2, 5 and 10% and with lactose at 20%.
Main observations were as follows. In both sexes body weight was
somewhat lower in the treated groups (except at 2%) than in controls.
Caecum weight (both filled and empty) was increased in the 5 and 10%
lactitol and 20% lactose group. In males (data on females were not yet
available), foci of basophilic cells in the adrenal medulla of treated
rats were somewhat elevated compared to controls and the incidence of
benign as well as malignant pheochromocytomas in the adrenals of some
of the lactitol and lactose fed groups was higher than that in the
controls. The number of benign tumours was 9, 61, 6, 17 and 16, and
the number of malignant pheochromocytomas was 2, 4, 1, 2 and 9 in the
controls, 2, 5 and 10% lactitol and 20% lactose groups respectively
(Sinkeldam et al., 1982).
OBSERVATIONS IN MAN
Lactitol, 24 g/day orally, was well tolerated by healthy or
diabetic persons and it did not influence blood glucose and blood
insulin levels. It did not induce diarrhoea in diabetic patients
(Doorenbos, 1977).
Loading tests with equal amounts of sucrose, lactose, lactitol,
and lactitol and sucrose have been carried out on eight healthy
adults. The average maximal increases in blood glucose concentration
after the different loadings were 63, 43, 6 and 40 mg% respectively.
All subjects experienced diarrhoea after lactitol (50 g) as well as
lactitol and sucrose ingestion (Zaal & Ottenhof, 1977).
So far, four patients with portal-systemic encephalopathy have
been treated with lactitol (instead of lactulose) and it has been
found that lactitol has the same therapeutic effect. With dosages of
36-96 g/day administered for three to 64 weeks, the patients did not
have diarrhoea, only mild flatulence. Lactitol did not influence
haemoglobin, serum glucose, sodium or potassium levels (Bircher,
1982).
Comments
Lactitol is a sweet-tasting sugar alcohol which is claimed to be
a suitable sugar substitute for diabetics. It is not metabolized in
humans or animals as a carbohydrate, as it is not absorbed in the
small intestines and is only very slowly split by enzymes. In the rat,
lactitol is extensively degraded, presumably mainly by the intestinal
microflora.
The animal and human studies reveal that lactitol is of a very
low general toxicity following single or repeated large doses. The
most marked treatment-related effect in all animal species studied in
short- or long-term feeding experiments was an increase in the weight
of the caecum. Some depression of growth was observed in the rat at
higher levels. Diarrhoea in man occurred following ingestion of 50 g,
but not following 24 g of lactitol.
Lactitol was not mutagenic in microbial systems with or without
metabolic activation. In the rat, it was not teratogenic. The
multigeneration study, however, revealed some embryotoxicity or
foetotoxicity at the 5 and 10% levels. The life-time feeding study on
the mouse did not show any important toxicological effect. In the
life-time oral toxicity rat study, the incidence of adrenal medullary
pheochromocytomas in treated males was increased in a non-dose-related
manner. Since histopathology on female rats was not submitted, final
evaluations of the study will be possible only upon receipt of these
data.
The no-effect level in the mouse study was 10%. In the dog study
it was 5%. Since in the multigeneration rat study these levels did
show toxicity, the 2% level was taken as the level causing no
toxicological effect.
EVALUATION
Level causing no toxicological effect
Rat: 2% (20 000 ppm) in the diet, equivalent to 1000 mg/kg bw.
Estimate of acceptable daily intake for man
Not specified.*
* The statement "ADI not specified" means that, on the basis of the
available data (chemical, biochemical, toxicological, and other),
the total daily intake of the substance, arising from its use at
the levels necessary to achieve the desired effect and from its
acceptable background in food, does not, in the opinion of the
Committee, represent a hazard to health. For this reason, and for
reasons stated in the individual evaluations, the establishment
of a numerical figure for an acceptable daily intake (ADI) is not
deemed necessary.
REFERENCES
Adema, D. M. M. (1980) The acute aquatic toxicity of lactitol-
dihydrate. Unpublished report by TNO, submitted by CCA to WHO
van Beek, L. (1977) The utilization of lactitol in rats. Unpublished
report from CIVO-TNO, submitted by CCA to WHO
van Beek, L. (1980) Primary skin irritation and eye irritation tests
with lactitol in albino rabbits. Unpublished report by CIVO-TNO,
submitted by CCA to WHO
van Beek, L., Bruintjes, J. P. & Beems, R. B. (1980) Acute dermal
toxicity study with lactitol in albino rabbits. Unpublished
report by CIVO-TNO, submitted by CCA to WHO
Bircher, J. (1982) Treatment of portal systemic encephalopathy with
lactitol. Unpublished letter from the University of Bern,
submitted by CCA to WHO
Doorenbos, H. (1977) Metabolism of lactitol. Unpublished report from
the University of Groningen, submitted by CCA to WHO
Gehring, F. (1978) Prüfung der Kariogenität von Lactose. Unpublished
report submitted by CCA to WHO from the University of Würzburg
de Groot, A. P. & Adringa, Marian (1976) Comparison of the laxative
properties of lactose, lactitol, xylitol and sorbitol in rats.
Unpublished report from CIVO-TNO, submitted by CCA to WHO
Havenaar, R. (1976) Microbiological investigations one the
cariogenicity of the sugar-substitute lactitol. Unpublished
report from the University of Utrecht, submitted by CCA to WHO
Hayashibara, K. K. (1974) Method for the preparation of sucrose
containing sweeteners and sucrose containing groceries. Dutch
patent application No. 7313151, submitted by CCA to WHO
Hayashibara, K. K. (1976) Containing lactitol as a sweetener.
USA Patent No. 3,973.050, submitted by CCA to WHO
Karrer, P. & Buchi, J. (1937) Reductions producte von Disacchariden:
Maltit, Lactit, Cellobit, Helvetica Chim. Acta., 20, 86-90
Koëter, H. B. W. M. (1980) Tentative oral embryotoxicity/
teratogenicity study with lactitol in rats. Unpublished report
from CIVO-TNO, submitted by CCA to WHO
Koëter, H. B. W. M. (1981) Oral embryotoxicity/teratogenicity study
with lactitol in second generation rats. Unpublished report from
CIVO-TNO, submitted by CCA to WHO
de Kreuk, J. F. (1980) Determination of the biodegradability of
lactitol. Unpublished report from TNO, submitted by CCA to WHO
Leegwater, D.C. (1978) Studies on the metabolic fate of orally
administered (14C) lactitol in the rat. Unpublished report from
CIVO-TNO, submitted by CCA to WHO
Leegwater, D.C., Spanjers, M. T. & Kuper, C. F. (1982) Effects of
different carbohydrates and polyols in the alloxan diabetic rat.
Unpublished report from CIVO-TNO, submitted by CCA to WHO
Maizena GMBH (1971) German Patent. Auslegeschrift 2133428
Sinkeldam, E. J. (1979) One generation study with high dietary levels
of lactitol and lactose in rats. Unpublished report from
CIVO-TNO, submitted by CCA to WHO
Sinkeldam, E. J., Till, H. P. & van der Heijden, C. A. (1976)
Suchronic (90-day) toxicity study with lactitol in rats.
Unpublished report by CIVO-TNO, submitted by CCA to WHO
Sinkeldam, E. J., Hollanders, V. M. H. & Woutersen, R. A. (1981)
One year feeding study with lactitol in rats. Unpublished report
by CIVO-TNO, submitted by CCA to WHO
Sinkeldam, E. J., Hollanders, V. M. H. & Woutersen, R. A. (1982)
Multigeneration study with lactitol in rats. Unpublished report
from CIVO-TNO, submitted by CCA to WHO
Sinkeldam, E. J. (1982) Life span oral toxicity and carcinogenicity
study with lactitol in rats pretreated in utero. Unpublished
report by CIVO-TNO, submitted by CCA to WHO
Spanjers, M. Th. & Til, H. P. (1980) Determination of the acute oral
toxicity of lactitol in rats. Unpublished report by CIVO-TNO,
submitted by CCA to WHO
Til, H. P. & Keizer, A. M. M. (1981) Sensitization test with lactitol
in guinea pigs (maximization test). Unpublished report from
CIVO-TNO, submitted by CCA to WHO
Til, H. P., Bosland, M. C. & Hollanders, V. M. H. (1981) Six month
feeding study with lactitol in dogs. Unpublished report by
CIVO-TNO, submitted by CCA to WHO
Til, H. P., Hollanders, V. M. H. & Woutersen, R. A. (1982) Life-span
oral carcinogenicity study with lactitol in mice. Unpublished
report by CIVO-TNO, submitted by CCA to WHO
Willems, M. I. (1979) Evaluation of lactitol in the salmonella/
microsome mutagenicity test. Unpublished report from CIVO-TNO,
submitted by CCA to WHO
Zaal, J. & Ottenhof, A. (1977) Influence of lactitol in blood sugar
levels after sucrose intake. Unpublished report by CIVO-TNO,
submitted by CCA to WHO