FAO Nutrition Meetings
Report Series No. 40A,B,C
WHO/Food Add./67.29
TOXICOLOGICAL EVALUATION OF SOME
ANTIMICROBIALS, ANTIOXIDANTS, EMULSIFIERS,
STABILIZERS, FLOUR-TREATMENT AGENTS, ACIDS AND BASES
The content of this document is the result of the deliberations of the
Joint FAO/WHO Expert Committee on Food Additives which met at Rome,
13-20 December, 19651 Geneva, 11-18 October, 19662
1 Ninth Report of the Joint FAO/WHO Expert Committee on Food
Additives, FAO Nutrition Meetings Report Series, 1966 No. 40;
Wld Hlth Org. techn. Rep. Ser., 1966, 339
2 Tenth Report of the Joint FAO/WHO Expert Committee on Food
Additives, FAO Nutrition Meetings Report Series, 1967, in press;
Food and Agriculture Organization of the United Nations
World Health Organization
1967
MANNITOL
Synonyms D-Mannitol; Mannitol
Chemical name 1,2,3,4,5,6-Hexanehexol
Empirical formula C6H14O6
Structural formula H H OH OH
' ' ' '
HOCH2 - C - C - C - C - CH2OH
' ' ' '
OH OH H H
Molecular weight 182.17
Definition Mannitol consists of D-mannitol and
contains, after drying, not less than 98
per cent. and not more then the
equivalent of 102 per cent. of
C6H14O6.
Description Mannitol is a white crystalline solid
which is odourless and has a sweet
taste.
Uses Sweetening agent, humectant,
sequestrant.
Biological Data
Biochemical aspects
D-mannitol occurs widely in nature in a variety of plants, algae
fungi and certain bacteria. L-Mannitol does not occur naturally.
Traces of mannitol have been identified occasionally in human urine
(Pitkänen Pitkänen, 1964).
D-mannitol has a slow rate of absorption from the intestinal
tract and exerts laxative properties. The laxative threshold for man
was found to lie between 10 and 20 g of D-mannitol per single dose
(Ellis & Krantz, 1941). D-mannitol fed to dogs was excreted in large
quantities in the urine (Jaffe, 1883). When 14C-D-mannitol was given
at a rate of 240 mg/rat orally to non-fasted rats, about 50 per cent.
of the radioactivity was recovered in the expired 14CO2 (Wick et
al., 1954). In similar experiments, also using 14C-D-mannitol at a
rate of 500 mg/kg body-weight, fasted rats oxidized 40 per cent. of
the dose to 14CO2, non-fasted rats 68 per cent,; 9.74 per cent. was
stored in the carcass; 1.28 per cent. in the liver and 6.32 per cent.
was excreted in the urine (Gongwer, 1963). Feeding D-mannitol to rats
and dogs led to a small but significant increase of liver glycogen
(Carr et al., 1933; Todd et al., 1939; Silberman & Lewis, 1933; Carr &
Krantz, 1938).
When 14C-D-mannitol was administered to rats by i.p.injection,
77-97 per cent. of the dose was excreted in the urine within 24 hours,
and only 2-3 per cent. of the mannitol carbon was oxidized to 14CO2.
Additional experiments using injection directly into the portal vein
showed that mannitol could be oxidized by the liver only (Wick et al.,
1954.
I.v. administered D-mannitol was completely cleared by the
kidneys of 2 dogs at rates identical to inulin and creatinine (Smith
et al., 1940). Mannitol did not elevate the blood sugar level of dogs
upon i.v. injection at a rate of 22.5 g/dog (Todd et al., 1939.
In man, i.v. administration of D-mannitol is practiced for
induction of diuresis in oliguria or for forced diuresis in poisoning
cases or to measure the extracelluar fluid compartment. There is an
extensive literature available on these aspects (Milne, 1965;
Widdowson et al., 1964). Following, the. i.v. injection of 10 g
D-mannitol into man, 81 per cent. of the dose was excreted unchanged
in the urine and up to 80 g, produced no toxic effect (Smith et al.,
1940). Administration of 25 g of D-mannitol on 3 subsequent days to
man did not significantly influence either the blood sugar level or
the respiratory quotient (Ellis & Krantz, 1941). When 100 g D-mannitol
was fed to man, the maximum rise in blood sugar level was 10 mg per
cent. (Field, 1919).
Acute toxicity
Animal Route LD50 References
(mg/kg
body-weight)
Mouse oral 22 000 Gongwer, 1960
i.v. 16 800 Robb, 1964
i.p. 14 000-16 000 Deck et al., 1936
Rat oral 17 300 Gongwer, 1960
Mice diet with signs of central nervous system depression and
gastrointestinal tract mucosal damage; rats died with predominantly
gastrointestinal tract signs (Gongwer, 1960; Gongwer, 1961).
Short-term studies
Rat. Groups of 20 male rats were fed 35 per cent. sucrose plus
5 5 per cent. D-mannitol or 40 per cent. sucrose (control group) over
a period of 3 months. The growth curves showed that D-mannitol was
nutritionally inferior to sucrose (Ellis & Krantz, 1941). These
results are in accordance with earlier findings, that mannitol is
inferior to sucrose, as judged by weight gain of rats (Ariyama et al.,
1929)
Monkey. Three rhesus monkeys were each fed 3 g of D-mannitol
daily,. for 3 months. Two animals were employed as controls. No toxic
signs nor pathological changes were observed (Ellis & Krantz, 1941).
Man. The i.v. injection of 10 g of D-mannitol daily over a
period of 1 month produced no significant changes in non-protein
nitrogen, or CO2- combining power of blood, red cell count or renal
function (Ellis & Krantz, 1941).
Long-term studies
No data are available.
Comments
The poor absorption shown in the metabolic studies and a long
clinical experience in man support the safety of D-mannitol.
Evaluation
The many studies that have bean carried out in man provide a
basis for evaluation.
Estimate of acceptable daily intake for man
mg/kg body-weight
Unconditional acceptance 0-50
Conditional acceptance 50-150
REFERENCES
Ariyama, T. & Takahashi, K. (1929) J. agric. chem. Soc. Japan, 5,
674
Beck, F. F., Carr, C. J. & Krantz, J. C. jr (1936) Proc, Soc. exp.
Biol. Med., 35, 98
Carr, C. J., Musser, R., Schmidt, J. E. & Krantz, J. C. jr (1933)
J. biol. Chem., 102, 721
Carr, C. J. & Krantz, J. C. jr (1938) J. biol. Chem., 124, 221
Ellis, F. & Krantz, J. C. jr (1941) J, biol. Chem., 141, 147
Field, C. W. (1919) Proc. Soc. Exp. Biol. Med., 17, 29
Gongwer, L. E. (1960) Unpublished report submitted by Atlas Chemical
Industries Ltd
Gongweg L. E. (1961) Unpublished report submitted by Atlas Chemical
Industries Ltd
Gongwer, L. E. (1963) Unpublished report submitted by Atlas Chemical
Industries Ltd
Jaffe, M. (1883) Z. physiol. Chem., 7, 297
Milne, M. D. (1965) Ann. Rev. Pharmac., 5, 125
Pitkänen, E. & Pitkänen, A. (1964) Ann. med. exp. Fenn., 42, 113
Robb, B. J. (1964) Unpublished report submitted by Atlas Chemical
Industries Ltd
Silberman, A. K. & Lewls, H. B. (1933) Proc. Soc. exp. Biol. Med.,
31, 253
Smith, W.W., Finkelstein, N. & Smith, H. W. (1940) J. biol. Chem.,
135, 231
Todd, W. R., Myers, J. & West, E. S. (1939) J. biol. Chem., 127,
275
Wick, A. N., Morita, T. N. & Joseph, L. (1354) Proc. Soc. exp. Biol.
Med.,85, 188
Widdowson, E. M. & Dickerson, J. W. T. (1964) In: Comar, L. C. &
Brommer, F. "Mineral Metabolism" New York-London, Vol. IIA p. 13
See Also:
Toxicological Abbreviations
Mannitol (WHO Food Additives Series 21)
MANNITOL (JECFA Evaluation)