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    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
    


    See Also:
       Toxicological Abbreviations
       LACTITOL (JECFA Evaluation)