INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
WORLD HEALTH ORGANIZATION
SUMMARY OF TOXICOLOGICAL DATA OF CERTAIN FOOD ADDITIVES
WHO FOOD ADDITIVES SERIES NO. 13
The data contained in this document were examined by the
Joint FAO/WHO Expert Committee on Food Additives*
Rome, 3-12 April 1978
Food and Agriculture Organization of the United Nations
World Health Organization
* Twenty-second Report of the Joint FAO/WHO Expert Committee on Food
Additives, Geneva, 1978, WHO Technical Report Series No. 631
This compound has been evaluated for acceptable daily intake by
the Joint FAO/WHO Expert Committee on Food Additives in 1967.
Since the previous evaluation additional data have become
available and are summarized below.
No data available.
Animal Route mg/kg bw References
Mouse Oral 550 Dow Chemical Company, 1967
Rat Oral 1 410 Dow Chemical Company, 1967
(male) Oral 1 410 Dow Chemical Company, 1967
Rabbit Oral 1 620 Dow Chemical Company, 1967
Groups of 15 males and 15 females were fed 0 and 1.0% maltol for
six months without adverse effect on growth, survival, organ weights,
haematology and microscopic appearance of major organs (Dow Chemical
Groups of four dogs, not necessarily distributed according to
sex, were given maltol by capsule at levels of 0, 125, 250 and
500 mg/kg/day, for 90 days.
By day 41 all dogs at the 500 mg/kg level had died. Signs of
death suggested liver damage and red cell destruction, in addition to
which emesis, ataxia and finally prostration were noted.
Histological examination revealed pulmonary oedema, pericentral
and mid-zonal hepatic necrosis, fatty degeneration of the myocardium,
adrenal cortical and medullary necrosis and testicular degeneration.
Elevated serum bilirubin was seen in the 500 mg/kg and at 30 days
in the 250 mg/kg. Histologically the 250 mg/kg showed a moderate
number of Kupffer cells containing haemosiderin and small amounts of
intracellular bilirubin. At the 125 mg/kg level only a moderate number
of haemosiderin-laden Kupffer cells were observed.
As effects at the lowest level appeared to be marginal, a
conservative no-effect level could be estimated at 100 mg/kg (Gralla
et al., 1969).
Groups each of 100 mice (Charles River CDI) equally divided by
sex were maintained on diets containing maltol at levels of 0, 100,
200 or 400 ppm for a period of 18 months.
There were no significant differences in survival between test
and control groups. The mean body weights of male mice in the 400 ppm
group were significantly lower than controls. Blood chemistry at
sacrifice was within normal limits with the exception of plasma urea
which was significantly elevated in males in the 400 ppm maltol group,
and a dose-related increase in serum alkaline phosphatase in all
female test groups. No dose-related haematological changes were
observed. Ophthalmic observations at 6, 12 and 18 months showed no
compound-related ocular lesions. At autopsy, the relative organ/body
weight ratio was similar for test and control animals with the
exception of the kidney and testes weights of males in the 400 mg/kg
group, which were significantly lower than controls. Histological
examination of tissues and organs did not show any compound-related
lesions except for the testes. Focal testicular atrophy was observed
in both control and test males, but was most severe in the 400 mg/kg
group (King et al., 1978a).
A two-year study was carried out in the F1 generation of rats
(Crl:CD-COB 5 (SD)), derived from parents exposed to diets containing
maltol at 0, 100, 200 or 400 mg/kg of diet. After weaning the rats
(groups of 100 equally divided by sex) were maintained on the
appropriate diets containing maltol. The rats were mated on days 189
and 245 respectively of the study to provide the F2a and F2b
generations of a three-generation reproduction study. During the
course of the study on days 134 and 418 respectively all animals
showed signs of sialodacryodenitis, a contagious disease of viral
origin. No deaths occurred from this disease and signs regressed
within 10 days.
There were no significant differences in survival between test
and control animals. Ophthalmic examinations of the high and control
groups performed at months 12, 18 and 24 showed no compound-related
eye lesions. Blood chemistry and haematology at sacrifice showed that
test and control animals were similar and within normal limits with
the exception of significant increases in K+, Cl-, urea and
bilirubin in the 400 mg/kg male and female groups, and urea and K+
in the 200 mg/kg male group. The gross and microscopic examination of
tissues and organs showed no compound-related lesions, nor was there
any indication that maltol had an effect upon tumour incidence (King
et al., 1978b).
Special studies on reproduction
A three-generation reproduction study was carried out on rats
(Crl:CD-COB 5 (SD)) using groups of 20 male and 20 female rats for the
production of each generation. Dosage levels of 0, 100, 200 or
400 mg/kg of maltol was administered in the diet. During the course of
the study on day 134 (F1 generation) all animals showed signs of
sialodacryodenitis, a contagious disease of viral origin. No deaths
occurred from this disease and signs regressed within 10 days.
Criteria evaluated were body weight and food consumption of
parents, fertility index, mating index, gestation index, survival
index and sex ratio of each generation. At birth all offspring were
examined for gross morphological abnormalities. Maltol had no effect
on copulation rate, mating index, fertility index, gestation index and
length of gestation. The viability index, lactation index, 21-day
survival index and sex ratios were within normal limits. Differences
in growth rate of the pups appears to be related to the outbreak of
sialodacryodenitis in the colony. No specific compound-related
abnormalities or lesions were reported in the pups (King et al.
Dow Chemical Co. (1967) Unpublished report
Gralla, E. J., Stebbins, R. B., Coleman, G. L. and Delahunt, C. S.
(1969) Toxicity studies with ethyl maltol, Toxicol. appl.
Pharmacol., 15, 604-613
King, T. O., Reinert, H., Pelé, M. F., Chvedoff, M., Taradach, C.,
Nachbaur, J., Faccini, J. M., Irisarri, E., Clarke, M. R. and Monro,
A.M. (1978a) Unpublished data. Research Center, Pfizer, France
Protocol 75-009. 18-month mouse study with maltol
King, T. O., Perraud, J., Faccini, J. M., Nachbaur, J. and Monro, A.M.
(1978b) Unpublished data. Research Center, Pfizer, France Protocol
74107-Maltol. 3 generation and carcinogenicity study in rats