Lactitol

• benefits of lactitol
• beneficial to people with diabetes
• does not cause dental caries
• safety
• multiple ingredient approach to calorie control
• future
• references

Lactitol, a polyol (sugar alcohol), is currently used as a bulk sweetener in calorie-controlled

foods. Discovered in 1920, it was first used in foods in the 1980's. Lactitol has a clean sweet
taste that closely resembles the taste profile of sucrose. It has only 40 percent of sucrose's
sweetening power. This mild sweetness makes it an ideal bulk sweetener to partner with low-
calorie sweeteners, such as acesulfame K, aspartame, neotame, saccharin and sucralose.
Lactitol is produced by two manufacturers. DANISCO SWEETENERS markets lactitol in both
anhydrous and monohydrate forms and PURAC BIOCHEM markets several forms of lactitol
under the trade name LACTY®.

Due to its stability, solubility and similar taste to sucrose, lactitol can be used in a variety of
low-calorie, low-fat and/or sugar-free foods such as ice cream, chocolate, hard and soft
candies, baked goods, sugar reduced preserves, chewing gums and sugar substitutes. Lactitol
is manufactured by reducing the glucose part of the disaccharide lactose. Unlike the
metabolism of lactose, lactitol is not hydrolyzed by lactase. It is neither hydrolyzed nor
absorbed in the small intestine. Lactitol is metabolized by bacteria in the large intestine, where
it is converted into biomass, organic acids, carbon dioxide and a small amount of hydrogen.
The organic acids are further metabolized resulting in a caloric contribution of 2 calories per
gram (carbohydrates generally have about 4 calories per gram).

A GRAS (Generally Recognized As Safe) affirmation petition submitted by PURAC biochem has
been accepted for filing by the U.S. Food and Drug Administration (FDA). This allows
manufacturers to produce and sell foods with lactitol in the United States. Internationally, it is
approved for use in many countries, including the European Union (EU), Canada, Japan, Israel
and Switzerland.

Benefits of Lactitol
Sweet and clean taste: Lactitol has a clean sweet, sugar-like taste with no aftertaste. The
relative sweetness of lactitol rises as its concentration in a food is increased. Its mild sweet
taste allows other flavors to be clearly perceived. Lactitol is a white crystalline powder.

High quality low-calorie foods: Lactitol's many attributes as a bulk sweetener with mild
sweetness make it a versatile ingredient for high quality low-calorie, low-fat and sugar-free
foods. Lactitol is not hygroscopic, meaning it will not absorb moisture into products, will
maintain crispness and extend the shelf life of cookies and chewing gum. It also has similar
solubility to glucose, is stable in acid and alkaline conditions and remains stable under the high
temperatures of food processing. Due to lactitol's mild sweetness profile, it can be paired with
low-calorie sweeteners commonly used in today's low-calorie, sugar-free foods (e.g.
acesulfame K, aspartame, neotame, saccharin and sucralose).

Low in calories: Lactitol is not metabolized like a typical carbohydrate (or like sugar) and
therefore does not contribute the usual 4 calories per gram. Lactitol is metabolized in the large
intestine and yields, according to tests, only 2 calories per gram. This value has been accepted
for labeling purposes in the U.S. by the FDA. The EU Nutrition Labeling Directive states that all
sugar alcohols, including lactitol, have a caloric value of 2.4 calories per gram.

Improving gut health: Lactitol is fermented in the colon and consequently has beneficial
effects on the colonic microflora. A reduction in the pH of the colon, along with an increase in
probiotic bacteria and a significant reduction in potential pathogens emphasizes the beneficial
effects of lactitol. In essence, lactitol functions as a prebiotic.

Facts About Lactitol

• Bulk sweetener which can be blended with low-calorie sweeteners (e.g., acesulfame K,
aspartame, neotame, saccharin and sucralose) and/or other polyols (e.g., sorbitol, xylitol)
• Clean and mild sweet taste with no aftertaste
• Reduced-calorie sweetener with 2 calories per gram
• Potential use in a variety of low-calorie, low-fat and sugar-free foods
• Beneficial for people with diabetes because it does not raise blood glucose or insulin
levels
• Does not contribute to the formation of dental caries
• Functions as a prebiotic

Beneficial to People With Diabetes

As a sweetening ingredient, lactitol has a low glycemic index, does not induce an increase in
blood glucose or insulin levels and contributes half the calories of most other carbohydrates (2
calories per gram). Control of blood glucose, lipids and weight are the three major goals in
diabetes management today. Foods using lactitol to replace sugar can be used by people with
diabetes, giving them a wider variety of low-calorie and sugar-free choices. However, people
should understand that foods sweetened with lactitol contain other ingredients that contribute
calories and other nutrients. These must be considered in meal planning.

Does Not Cause Dental Caries

Lactitol is not metabolized by oral bacteria which break down sugars and starches to release
acids that may lead to cavities or erode tooth enamel. The usefulness of polyols, including
lactitol, as alternatives to sugars and as part of a comprehensive program including proper
dental hygiene has been recognized by the American Dental Association. The FDA has
approved the use of a "does not promote tooth decay" health claim in labeling for sugar-free
foods that contain polyols, including lactitol.

Safety

The safety of lactitol as a food additive has been substantiated by numerous animal and
human studies. Safety studies in experimental animals include long-term feeding studies at
high dietary levels for 2 1/2 years in rats and for 2 years in mice.

The safety research on lactitol has been reviewed by several

international authoritative bodies. In April 1983, the World
Health Organization's Joint Expert Committee on Food
Additives (JECFA) reviewed the scientific data on lactitol and
allocated an Acceptable Daily Intake (ADI) of "not specified"
to lactitol. JECFA's decisions are often adopted by many small
countries, which do not have their own agencies to review
food additive safety. In 1984, the Scientific Committee on
Food of the European Union evaluated lactitol and stated that
consumption of 20 grams per day of polyols, including
lactitol, is unlikely to cause undesirable laxative symptoms.
The Committee allocated lactitol an ADI "not specified." ADI,
expressed in terms of body weight, is the amount of a food additive that can be consumed
daily over a lifetime without risk. An ADI "not specified" is the safest category in which JECFA
can place a food additive.

In the United States, a GRAS (Generally Recognized As Safe) affirmation petition for the use of
lactitol in chewing gum, hard and soft candy and frozen dairy desserts was accepted for filing
by the Food and Drug Administration in September 1993. Once a GRAS affirmation petition
has been accepted for filing, food manufacturers can use the ingredient in the applications
specified in the petition.

Multiple Ingredient Approach to Calorie Control

Today, more Americans are striving to maintain a healthy lifestyle by consuming less calories
and fat. To achieve today's nutrition and health goals, Americans are continually searching for
new calorie-controlled foods and beverages. Good taste remains a vital factor in consumer
acceptance of new healthier foods.

Lactitol is a novel ingredient that allows food manufacturers to develop new foods that both
taste good and are lower in calories, fat and/or sugar. Lactitol's qualities as a bulk sweetener
make it optimal to blend with low-calorie sweeteners that are several hundred times sweeter
than sucrose (but do not provide the necessary volume). Lactitol can also be used with other
bulk sweeteners or polyols. Blending two or more polyols gives food manufacturers the
flexibility to take advantage of each sweetener's individual attributes. Lactitol offers food
manufacturers the beneficial characteristics of mild sweetness, stability, solubility, bulk and
reduced calories.

Future

Lactitol's unique attributes make it a versatile reduced-calorie sweetener for a wide variety of
food applications from baked goods to hard and soft candy and frozen dairy desserts. With an
ever growing focus on healthier eating, the demand for low-calorie foods is rising. With the
relatively new introduction of lactitol, many innovative products are on the horizon.

[ More information about lactitol ]

References

European Economic Community Council (EEC). 1990. Directive on food labeling. Off. J. Eur.
Communities No. L 276/40 (Oct.6).

Grenby, T.H., Phillips, A., Mistry, M.: Studies of the dental properties of lactitol compared with
five other bulk sweeteners in vitro. Caries Research. 23:315-319, 1989.

Grenby, T.H., Phillips, A.: Dental and metabolic observations on lactitol in laboratory rats.
British Journal of Nutrition. 61:17-24, 1989.

Grenby, T.H., Desai, T.: A trial of lactitol in sweets and its effects on human dental plaque.
British Dental Journal. 164:383-387, 1988.

Joint FAO/WHO Expert Committee on Food Additives, IPCS Toxicological evaluation of certain
food additives and contaminants: Lactitol, 27th report Geneva, WHO Food Additives Series,
1983, pp.82-94

U.S. Food and Drug Administration. PURAC biochem b.v.; Filing of petition for affirmation of
GRAS status (lactitol) Federal Register, Vol. 58 No.174:47746, 1993

Van Es, A.J.H., de Groot, L., Vogt, J.E.: Energy balances of eight volunteers fed on diets
supplemented with either lactitol or saccharose. British Journal of Nutrition. 56:545-554,
1986.

van Velthuijsen, J.A., Blankers, I.H.: Lactitol: A new reduced-calorie sweetener. In:
Alternative Sweeteners (2ed.), L.O. Nabors & R.C. Gelardi eds., Marcel Dekker, Inc., N.Y.,
1991.

Lactitol is a bulk sweetener with a sugar-like taste. Its stability, solubility and reduced
calories make it suitable for a variety of low-calorie, low-fat and/or sugar-free foods. Its
mild sweet taste makes it ideal for use with low calorie sweeteners.

Lactitol was discovered in 1920 and it was first used in foods in the 1980's. Lactitol is a
disaccharide polyol (sugar alcohol), derived from lactose. As being a unique bulk
sweetener with very similar technical and handling properties to those of sucrose, lactitol
is very suitable to replace sucrose on a 1 : 1 basis in calorie-controlled foods.

Lactitol is an odorless white crystalline powder with very high purity and good
flowability. Lactitol has a clean sweet taste that closely resembles the taste profile of
sucrose, while no aftertaste is observed. The sweetening power of lactitol is only 40% of
that of sucrose. Due to the mild sweetness of lactitol, it is an ideal bulk sweetener to
combine with low-calorie sweeteners commonly used in today's low-calorie, sugar-free
foods (e.g. acesulfame K, aspartame, neotame, saccharin and sucralose). Additionally, its
mild sweet taste allows other flavors to be clearly perceived. The relative sweetness of
lactitol rises as its concentration in a food is increased.

Lactitol is not hygroscopic, meaning it will not absorb moisture into products. It will
maintain crispness and extend the shelf life of cookies and chewing gum. In chocolate,
where a cooling effect is undesirable, lactitol is highly useful due to its very small cooling
effect. Compared to sucrose, lactitol has reasonably good solubility. This can help
minimize modifications to the process, making substituting sucrose very easy. Lactitol
can be dissolved at lower temperatures than sucrose, and thereby save on energy and
processing costs. In acid and alkaline conditions, lactitol is stable and it also remains
stable under the high temperatures of food processing.

Lactitol's unique attributes make it a versatile reduced-calorie sweetener for a wide

variety of food applications. Due to its stability, solubility and similar taste to sucrose,
lactitol can be used in a variety of low-calorie, low-fat and/or sugar-free foods such as
ice cream, chocolate, hard and soft candies, baked goods, sugar-reduced preserves,
chewing gums and sugar substitutes. As versatile ingredient lactitol can also be applied in
certain pharmaceutical applications, in food for diabetics or as cryoprotectant in surimi,
or as prebiotic in cultured dairy foods.

Lactitol is manufactured by reducing the glucose part of the disaccharide lactose. Lactitol
is produced by two manufacturers. PURAC BIOCHEM markets several forms of lactitol
under the trade name LACTY® and DANISCO SWEETENERS markets lactitol in both
anhydrous and monohydrate forms.

Benefits of Lactitol

Besides replacing sugar, lactitol can be beneficial for your food products due to its other
unique properties.

Low in Calories
Lactitol is not metabolized like a typical carbohydrate. Unlike the metabolism of lactose,
lactitol is not hydrolyzed by lactase. It is neither hydrolyzed nor absorbed in the small
intestine. Lactitol is metabolized by bacteria in the large intestine, where it is converted
into biomass, organic acids, carbon dioxide and a small amount of hydrogen. The organic
acids are further metabolized resulting in a caloric contribution of 2 calories per gram
(carbohydrates generally have about 4 calories per gram). The FDA has accepted this
caloric value for labeling purposes in the U.S. The EU Nutrition Labeling Directive states
that all sugar alcohols, including lactitol, have a caloric value of 2.4 calories per gram.

Improving Gut Health

Since lactitol can pass the upper gastrointestinal tract without being hydrolyzed and
absorbed, it is capable of promoting the growth of beneficial bacteria in the colon such as
Bifidobacteria and Lactobacilli. The intestinal bacteria ferment lactitol, resulting in the
establishment of an acidic environment in the colon due to the formation of short chain
fatty acids. At these acidic conditions, the beneficial bacteria, better known as probiotics,
grow in preference over disease causing organisms or pathogens. As excellent prebiotic
ingredient, lactitol can help to keep your colonic microflora healthy.

Low Glycemic and Insulinemic Response

As a sweetening ingredient, lactitol has a low glycemic index and does not induce an
increase in blood glucose or insulin levels after consumption. Control of blood glucose,
lipids and weight are the three major goals in diabetes management today. Not just
people with diabetes can use low GI foods comprising lactitol to replace sugar to give
them a wider variety of low-calorie and sugar-free choices in their diabetic diet.
Consuming low GI foods could also provide health benefits to people who are health
conscious. However, people should understand that foods sweetened with lactitol contain
other ingredients that contribute calories and other nutrients. These must be considered in
meal planning.

Does Not Cause Dental Caries

Lactitol is not metabolized by oral bacteria, which break down sugars and starches to
release acids that may lead to cavities or erode tooth enamel. As tooth-friendly
ingredient, lactitol does not cause dental caries. The American Dental Association has
recognized the usefulness of polyols, including lactitol, as alternatives to sugars and as
part of a comprehensive program including proper dental hygiene. The FDA has
approved the use of a "does not promote tooth decay" health claim in labeling for sugar-
free foods that contain polyols, including lactitol.

Lactitol

• Bulk sweetener with a clean sweet taste

• Made from lactose
• Useful in formulating a variety of low-calorie, low-fat and sugar-
 free foods
• Provides only 2 calories per gram
• Promotes a healthy colonic micro flora
• Does not cause dental caries

• Does not increase blood glucose or insulin levels

Regulatory Status

In the United States, a GRAS (Generally Recognized As Safe) affirmation petition

submitted by PURAC BIOCHEM has been accepted for filing by the Food and Drug
Administration (FDA). This allows food manufacturers to produce and sell foods with
lactitol in the United States. Internationally, it is approved for use in many countries,
including the European Union (EU), Canada, Japan, Israel and Switzerland.

Safety

Numerous animal and human studies have substantiated the safety of lactitol as a food
additive. Safety studies in experimental animals include long-term feeding studies at high
dietary levels for 2 1/2 years in rats and for 2 years in mice.

Several international authoritative bodies have reviewed the safety research on lactitol. In
April 1983, the World Health Organization's Joint Expert Committee on Food Additives
(JECFA) reviewed the scientific data on lactitol and allocated an Acceptable Daily Intake
(ADI) of "not specified" to lactitol. JECFA's decisions are often adopted by many small
countries, which do not have their own agencies to review food additive safety. In 1984,
the Scientific Committee on Food of the European Union evaluated lactitol and stated
that consumption of 20 grams per day of polyols, including lactitol, is unlikely to cause
undesirable laxative symptoms. The Committee allocated lactitol an ADI "not specified."
ADI, expressed in terms of body weight, is the amount of a food additive that can be
consumed daily over a lifetime without risk. An ADI "not specified" is the safest
category in which JECFA can place a food additive.

Multiple Ingredient Approach to Calorie Control

Today, more Americans are striving to maintain a healthy lifestyle by consuming less
calories and fat. To achieve today's nutrition and health goals, Americans are continually
searching for new calorie-controlled foods and beverages. Good taste remains a vital
factor in consumer acceptance of new healthier foods.

Lactitol is a versatile ingredient that allows food manufacturers to develop new foods that
both taste good and are lower in calories, fat and/or sugar. Lactitol's qualities as a bulk
sweetener make it optimal to blend with low-calorie sweeteners that are several hundred
times sweeter than sucrose (but do not provide the necessary volume). Lactitol can also
be used with other bulk sweeteners or polyols. Blending two or more polyols gives food
manufacturers the flexibility to take advantage of each sweetener's individual attributes.
Lactitol offers food manufacturers the beneficial characteristics of mild sweetness,
stability, solubility, bulk and reduced calories.

Future

With an ever-growing focus on healthier eating, the demand for low-calorie foods is
rising. With the unique health benefits of lactitol with respect to calorie control, diabetes
management and gut health improvement, many innovative products are on the horizon.

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)