MALTOL
Explanation
This substance was evaluated for acceptable daily intake for man
(ADI) by the Joint FAO/WHO Expert Committee on Food Additives in 1967
and 1978 (see Annex, Refs. 14 and 48). Toxicological monographs were
issued in 1968 and 1978 (see Annex, Refs. 15 and 50).
Since the previous evaluation, additional data have become
available and are summarized and discussed in the following monograph.
The previously published monograph has been expanded and reproduced in
its entirety below.
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS
No data available.
TOXICOLOGICAL STUDIES
Special studies on mutagenicity
Maltol gave a positive response when tested for mutagenicity in
the Ames plate assay system using Salmonella typhimurium strain
TA-100. The mutagenic activity was not affected by the addition of a
liver activation system. Maltol was not mutagenic to the TA-98 strain
(Bjeldanes et al., 1979).
Special studies on reproduction
Rat
A three-generation reproduction study was carried out on rats
[Charles River Crl:COBS-CD(SD)BR(France)] 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 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.,
1978b).
Acute toxicity
LD50
Animal Route (mg/kg bw) Reference
Mouse Oral 550 Dow Chemical Company, 1967
Rat Oral 1 410 Dow Chemical Company, 1967
Guinea-pig Oral 1 410 Dow Chemical Company, 1967
(male)
Rabbit Oral 1 620 Dow Chemical Company, 1967
(male)
Short-term studies
Mouse
Charles River CD-1 mice in groups of 50 animals per sex per dose
group were given 0, 100, 200 or 400 mg/kg maltol in the diet for up to
six months. An interim sacrifice was conducted on half the animals in
each group at three months and the liver, kidney and testes examined
microscopically. A complete range of tissues was examined in the
animals sacrificed at the end of the study. At the beginning of the
study two animals in the 400 mg/kg group and one in the 100 mg/kg
group died and another animal in the 100 mg/kg group was sacrificed in
moribund condition. Body weight gain was lower in the high and mid
dose males, but the effect was not statistically significant. No
differences between dosed and control animals were reported with
respect to gross or microscopic pathology organ weights, clinical
signs or clinical chemistry (Marshall & Bouchard, 1980).
Rat
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
Company, 1967).
Groups of Charles River rats, 25/sex, were fed diets containing
0, 100, 200 or 400 mg/kg bw maltol in the diet for six months.
No treatment-related effects were reported on mortality, gross or
microscopic pathology or clinical signs. There were no statistically
significant differences in body weight gain between dosed and control
animals, although body weights were lower in the high dose female
throughout the study. There were small but statistically significant
increases in cholesterol and creatinine levels in the high dose males.
Small statistically significant increases were also observed in the
absolute and relative liver weights of the high dose males (Marshall &
Bouchard, 1980).
Dog
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 dogs at the 500 mg/kg dose 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 midzonal 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 dose level
group and at 30 days in the 250 mg/kg dose level group. Histologically
the 250 mg/kg dose level group 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 (Gralla et al., 1969).
Beagle dogs in groups of 4/sex were given daily for three months
0, 100, 200 or 300 mg/kg bw of maltol by capsule. No treatment-related
effects were noted on gross or microscopic pathology, clinical
chemistry, haematology or clinical signs. Compared to controls, the
treated females exhibited lower body weights throughout the study. The
high dose group had the lowest body weights (Marshall & Bouchard,
1980).
Long-term studies
Mouse
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 mg/kg for a period of 18 months.
There were not significant differences in survival between test
and control groups. The mean body weights of male mice in the
400 mg/kg 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 mg/kg
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 six, 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).
Rat
A two-year study was carried out in the F1 generation of rats
[Charles River Crl:COBS-CD(SD)BR(France)] 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 not 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).
Comments
In an 18-month study in the mouse at the highest dose tested
(400 mg/kg bw), focal testicular atrophy was significantly greater
than in controls. This effect has not been observed in the rat, and
there were no compound-related effects in a three-generation
reproduction study in the rat. A two-year feeding study in the rat
showed some changes in serum clinical chemistry in the high dose
groups. However, there were no gross or microscopic compound-related
lesions.
Elevated serum bilirubin and the occurrence of Kupffer cells
containing haemasiderin was reported in dogs fed maltol at 250 and
500 mg/kg/day for 30 days. However, this effect was not observed in
another study in which dogs were dosed with maltol at levels up to
300 mg/kg/day for a period of three months.
Although maltol has been shown to be mutagenic in one strain of
S. typhimurium (TA-100), there is no indication that maltol had an
effect on tumour incidence in the two-year study in rats, and an
18-month study in mice.
EVALUATION
Level causing no toxicological effect
Rat: 100 mg/kg bw.
Estimate of acceptable daily intake for man
1 mg/kg bw.
REFERENCES
Bjeldanes, L. F. & Chew, H. (1979) Mutagenicity of 1,2-dicarbonyl
compounds: maltol, kojic acid, diacetyl and related studies,
Mutagenic Research, 67, 367-371
Dow Chemical Company (1967) Unpublished report
Gralla, E. J. et al. (1969) Toxicity studies with ethyl maltol,
Toxicol. appl. Pharmacol., 15, 604-613
King, T. O. et al. (1978) Three-generation and carcinogenicity study
in rats. Unpublished data. Research Center, Pfizer, France
Protocol 74107-Maltol
King, T. O. et al. (1978a) 18-month mouse study with maltol.
Unpublished data. Research Center, Pfizer, France Protocol 75-009
Marshall, G. A. & Bouchard, E. F. (1980) Six-month oral toxicity study
in rats. Unpublished data. Research Center, Pfizer, France
Protocol 79031
Marshall, G. A. & Bouchard, E. F. (1980) Six-month oral toxicity study
in mice. Unpublished data. Research Center, Pfizer, France
Protocol 79031
Marshall, G. A. & Bouchard, E. F. (1980) Six-month oral toxicity study
in dogs. Unpublished data. Research Center, Pfizer, France
Protocol 79031
See Also:
Toxicological Abbreviations
Maltol (FAO Nutrition Meetings Report Series 44a)
Maltol (WHO Food Additives Series 13)
MALTOL (JECFA Evaluation)