PESTICIDE RESIDUES IN FOOD - 1984
Sponsored jointly by FAO and WHO
Data and recommendations of the joint meeting
of the FAO Panel of Experts on Pesticide Residues
in Food and the Environment and the
WHO Expert Group on Pesticide Residues
Rome, 24 September - 3 October 1984
Food and Agriculture Organization of the United Nations
Maleic Hydrazide (MH) was evaluated by the Joint Meeting on
Pesticide Residues in 1976 and 1977 (FAO/WHO, 1977, 1978) wherein it
was determined that data submitted were inadequate for the estimation
of an acceptable daily intake (ADI). At the Joint Meeting in 1980
(FAO/WHO, 1981) further data on carcinogenicity and mutagenicity were
evaluated and a temporary ADI of 0-1.0 mg/kg bw was allocated, noting
the need for further studies on teratogenicity. This temporary ADI was
for Maleic Hydrazide of 99 percent purity containing less than
1.5 mg/kg free hydrazine. Additional toxicological data have been
submitted on the potassium salt of Maleic Hydrazide and are reviewed
in the following monograph addendum.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
Special Study on Teratogenicity
Groups of artificially inseminated Dutch Belted rabbits (16 per
group) were intubated with potassium Maleic Hydrazide at 0, 100, 300
and 1 000 mg/kg bw on days 6 through 27 of gestation, at a constant
volume of 5 mg/kg. The does were sacrificed on day 28 and pups
delivered by caesarean section for external, visceral and skeletal
examinations. No treatment-induced mortality occurred. One control and
two low-dose females aborted. The high-dose females exhibited slight
inhibition of maternal body weight gain, an increase in the incidence
of alopecia and soft stools. These findings were not evident among
females in other groups.
The mean number of viable foetuses, early and later resorptions,
post-implantation loss, total implantations, corpora lutea, foetal sex
ratio and mean foetal body weight were comparable to the controls. The
incidence of external, visceral and skeletal malformations and
developmental variations were comparable between treated and control
groups. Potassium Maleic Hydrazide, at 1 000 mg/kg bw did not induce a
teratogenic response in Dutch Belted rabbits (Aldrige, Schardein &
Special Studies on Carcinogenicity
Maleic Hydrazide (purity 98.5 percent as free acid, containing
0.6 ppm hydrazine) was administered orally or by subcutaneous (s.c.)
injection to C57BL/B6 mice from the IARC colony.
Oral administration: 40 male and 42 female mice were given oral
doses of 510 mg/kg bw/week of Maleic Hydrazide in olive oil from
weaning (at age four weeks) for life. A group of 13 male and 13 female
mice received only olive oil, and 51 males and 49 females formed the
untreated control group.
Subcutaneous injection: Maleic Hydrazide suspended in tricaprylin
was injected s.c. into 163 newborn mice on days 1, 7, 14 and 21 after
birth at single doses of 5, 10, 20 and 30 mg Maleic Hydrazide per
mouse. The equivalent amount of solvent was given to a control group
of 61 newborn mice.
At 120 weeks all surviving mice were autopsied. Major organs
as well as those showing gross abnormalities were examined
histologically. Oral treatment had no effect on growth or survival and
there were no significant differences in the number of tumour-bearing
animals. The number of tumours found in the s.c.-treated mice was not
significantly different from that in the solvent control group.
However, the corresponding comparison between treated and untreated
control groups demonstrated a significant increase in liver cell
tumours in the high dose group. The incidence of other types of
tumours was similar in MH treated, vehicle control and untreated
control groups. Considering the potential contribution from free
hydrazine, the results provide insufficient evidence of
carcinogenicity of MH to mice (Cabral & Ponomarkov, 1982).
Groups of Charles River CD-1 mice (50/sex/group) were fed diets
containing potassium Maleic Hydrazide (purity 97 percent Maleic
Hydrazide and 1.63 ppm hydrazine), at concentrations yielding 0,
1 000, 3 200, and 10 000 ppm Maleic Hydrazide for 98 weeks. The
control group was offered the basal diet mixed with an appropriate
amount of potassium buffer (to equal the concentration of potassium in
the high-dose test diet).
Observations were made routinely for signs of toxicity,
moribundity, mortality, body weight change and food consumption. No
compound-related changes in appearance or behaviour, mortality, body
weight or food consumption were noted. There were no macroscopic or
microscopic lesions which could be attributed to the compound (Jessup,
The 1980 JMPR considered carcinogenicity and mutagenicity data
and allocated a temporary ADI, since further studies on teratogenicity
were required. An acute toxicity study of the free acid and of the
sodium or potassium salt were similar. New data on the potassium salt
have now been presented and reviewed.
Potassium Maleic Hydrazide, administered orally, was not
teratogenic in rabbits at 1 000 mg/kg/day. A 98-week study of the
potassium salt (97 percent pure; 1.6 ppm hydrazine) in CD-1 mice at
doses up to 10 000 ppm was not oncogenic. A 120-week study of free
Maleic Hydrazide (98.5 percent pure; 0.6 ppm hydrazine) administered
orally to C57BL/B6 mice at 510 mg/kg/week showed no increased
tumorigenicity; a similar study in which the Maleic Hydrazide was
administered subcutaneously was considered to be negative. The free
hydrazide and the potassium salt were evaluated and the results were
considered applicable to the sodium salt, 99.9 percent pure and with
not more than 1 ppm of hydrazine.
Level Causing no Toxicological Effect
Rat: 20 000 ppm equivalent to 1 000 mg/kg bw.
Dog: 20 000 ppm equivalent to 500 mg/kg/bw.
Estimate of Acceptable Daily Intake for Humans
0 - 5.0 mg/kg bw (sodium or potassium salt, 99.9 percent pure
with less than 1 ppm hydrazine).
Observations in humans.
Aldrige, B.S., Schardein, J.L. and Blair, M. Teratology study in
1983 rabbits with potassium salt of Maleic Hydrazide.
International Research and Development Corporation,
Mattawan, Michigan. Submitted by Uniroyal Inc., Bethany, USA
to WHO. (Unpublished)
Cabral, J.R.P. and Ponomarkov, V. Carcinogenicity study of the
1982 pesticide Maleic Hydrazide. Toxicology, 24: 169-173.
Submitted by Uniroyal Inc., Bethany, USA, to WHO.
Jessup, C. Lifetime oncogenicity study of potassium Maleic Hydrazide
1981 in mice. International Research and Development Corporation.
Submitted by Uniroyal Inc., Bethany, USA, to WHO.