PESTICIDE RESIDUES IN FOOD - 1980
Sponsored jointly by FAO and WHO
Joint meeting of the
FAO Panel of Experts on Pesticide Residues
in Food and the Environment
WHO Expert Group on Pesticide Residues
Rome, 6-15 October 1980
Maleic hydrazide was reviewed by the 1976 and 1977 Joint Meeting
(FAO/WHO 1977, 1978). The data were not adequate for the
estimation of an acceptable daily intake for man and the following
studies were required:
1. The results of the carcinogenicity study with rats, which was
currently in progress.
2. Teratogenicity study with the sodium salt or the free acid.
Part of these studies have been provided and are summarised in the
following monograph addendum.
DATA CONSIDERED FOR DERIVATION OF ACCEPTABLE DAILY INTAKE
Special studies on carcinogenicity
Before the carcinogenicity study a breeding experiment was
performed with groups of 50 female and 25 male rats, which were fed
diets containing 0, 1.0 or 2.0% maleic hydrazide from 1 week before
mating onwards. After a one-week mating period the dams were
separated from the males. The dams were given the respective diets
throughout pregnancy and lactating period. The fertility index,
viability, lactation index and the number of infertile rats were
comparable between groups.
The carcinogenicity study was conducted with one group of 65 males
and 65 females (2% maleic hydrazide) and 2 groups of 55 animals of
each sex (control and 1%). The rats were kept on their respective
diets for a period of 28 months after weaning.
No clear differences between control and test groups were seen in
respect to mortality, food consumption, haematology and organ
weights. The body weight gain of the females of both treated groups
was decreased especially during the first half of the experiment.
The males of the 2% group showed a tendency to a lower growth rate.
There was a significant increase in water consumption at the 2%
level, measured during week 18 and 25. In the 1% dietary level
group a tendency to an increased water consumption was observed.
Urinalysis revealed that 1 and 2% maleic hydrazide caused
proteinuria and increased protein/oreatinin ratios in both males
and females after 6 and 12 months. However no histopathological
lesions in the kidneys and other tissues were observed. There was
no treatment-related tumour incidence. The malaic hydrazide used
in the study contained less than 1.5 mg/kg hydrazine as impurity
(van der Heijden et al, 1979).
Special studies on mutagenicity
The cytotoxic effects of maleic hydrazide (MH), its potassium
(K-MH) and diethanolamine (DEA-MH) salt and hydrazine
dihydrocholoride (HDC) were tested in a Chinese hamster cell line.
The purity of the compounds tested is not given. The LD50 values
were, in µg/ml: 1100 (MH), 20,000 (K-MH) and 12,000 (DEA-MH). HDC
was more toxic with LD50 of 230 µg/ml. The MH compounds showed
weak but dose-related cytogenetic effects. At the LD50 dose
maximal frequencies of aberrant cells were 18% for MH and KMH
compared with 4% for the controls.
The cytogenetic effect of ethylmethanesulphonate was about equal to
MH and its salts, whereas the positive control
N-methyl-N'-nitrosoguanidine at 5 µg/ml induced 97% cells with
The suspected carcinogenic and mutagenic compound HDC did not show
an increased number of aberrant cells (Nishi et al, 1979).
Six groups of either 2 or 4 male Swiss mice were injected
intraperitoneally with DMSO, 100 or 200 mg/kg bw maleic hydrazide,
and 40, 80 or 120 mg/kg bw hycanthone methane sulphonate. The
dosing was repeated after 24 hours after the second injection, the
mice were killed and bone-marrow preparations made.
Hycanthone showed a clear but not dose-related increase in the
frequency of micronuclei, whereas maleic hydrazide did not show any
mutagenic effect (Chaubey et al, 1977)
The previous toxicological evaluation of maleic hydrazide in 1976
(FAO/WHO 1977b) was not completed because studies on
carcinogenicity were unfinished. From the data now submitted it
appears that maleic hydrazide containing less than 1.5 mg/kg
hydrazine as impurity is not carcinogenic to rats. Two new
mutagenicity studies have been reviewed. In a micronucleus test
maleic hydrazide showed no mutagenic effect, whereas in a
cytotoxicity test with Chinese hamster cells the number of
chromosomal aberrations was slightly increased at a dose level
similar to the LD50. However, from this result it cannot be
concluded that maleic hydrazide is a mutagen, which agrees with
previous data on mutagenicity mentioned in the monograph of 1976,
showing that maleic hydrazide is not mutagenic.
No teratogenicity study was made available, but a reproduction
study in 1976 showed no adverse effects. In the present long-term
carcinogenicity study with maleic hydrazide in rats, increased
protein in the urine, and inhibition of growth in female animals
were seen at doses of 10,000 and 20,000 mg/kg in the diet. It was
concluded that the study did not reveal a no-effect level.
In the monograph of 1976 a no-effect level of 21% in the diet was
found for the sodium salt of maleic hydrazide. The data on the
sodium salt are now adequate for toxicological evaluation.
However, owing to the lack of a teratogenicity study and the
apparent difference in toxicity between the sodium salt and the
free acid, only a temporary ADI with a high safety factor can be
allocated. It has to be stressed that this ADI is for maleic
hydrazide of 99% purity, containing less than 15 mg/kg of free
hydrazine. No ADI was allocated for the diethanolamine salt.
Level in the diet causing no toxicological effect (sodium salt)
Rat: 20,000 mg/kg equivalent to 1,000 mg/kg bw/day.
Dog: 20,000 mg/kg equivalent to 500 mg/kg bw/day.
Estimate of temporary acceptable daily intake for man
0-1 mg/kg bw/day (sodium or potassium salt)
FURTHER WORK OR INFORMATION
Required (by 1984)
1. Teratogenicity study with the sodium or potassium salt.
2. Short-term toxicological study with maleic hydrazide as free
acid and as sodium or potassium salt to establish a no-effect level
and to study the apparent difference in toxicity.
3. Carcinogenicity study with the diethanolamine salt of maleic
hydrazide before an ADI can be established for this salt.
Chaubey, R.C., Kavi, B.R., Chauhan, P.S. and Sundaram, K. The
effect of hycanthone and maleic hydrazide on the frequency of
micronuclei in the bone-marrow erythrocytes of mice. Mut. Res. 51:
Heijden, C.A. van der, Berkvens, J.M., Tonkelaar, E.M. den, Droes,
R. Nesselrooy, J.H.J., Vries, Th. de and Esch, G.J. van. Maleic
hydrazide: an oral carcinogenicity study in rats. (1979)
Unpublished report nr. 7/79 Tox/Path of the National Institute of
Public Health, The Netherlands.
Nishi Y., Mori, M. and Inui, N. Chromosomal aberrations induced by
maleic hydrazide and related compounds in chinese hamster cells in
vitro. Mut. Res. 67: 245-257.