** Evaluation in CCPR periodic review programme
TOXICOLOGY
Maleic hydrazide was previously evaluated for toxicological effects by the Joint Meeting in 1976, 1980, and 1984. In 1984, an ADI of 0-5 mg/kg bw was established for maleic hydrazide (sodium or potassium salt, 99.9% pure containing <1 mg hydrazine/kg).
The toxicology of the compound was reviewed at the present Meeting within the CCPR periodic review programme.
Maleic hydrazide was rapidly and extensively absorbed after oral administration of single doses of 2 or 100 mg/kg bw or 2 mg/kg bw per day for 15 days. Excretion is rapid (>80% in 24 h) after either oral or intravenous administration, with urinary excretion predominating (>80%). The metabolism of maleic hydrazide is minimal, the parent compound accounting for over 60% in males and 80% in females of the urinary radiolabel; conjugation to sulfate is the only significant reaction. There was no evidence that absorption or metabolism was affected by dose or by repeated administration in rats. The total tissue residues in rats represented < 1% of the administered dose after seven days.
The acute toxicity of maleic hydrazide after administration by the oral, dermal, or inhalation route is low, with LD50 and LC50 values greater than the limit doses (5 g/kg bw orally, 20 g/kg bw dermally, and 20 mg/litre by inhalation). No target organs were identified. Maleic hydrazide was only slightly irritating to the skin and eyes and is not a skin sensitizer. The compound has been classified by WHO as unlikely to present an acute hazard in normal use.
After administration of repeated oral doses of maleic hydrazide to rats (0, 30, 100, 300, or 1000 mg/kg bw per day or 0, 0.5, 1, 2 or 5% in the diet) and dogs (0, 750, 2500, or 25,000 ppm) for 12-13 weeks, no marked adverse effects were seen at doses up to 1000 mg/kg bw per day; however, the extent of the examinations performed in these studies was inadequate to permit a reliable NOAEL to be determined.
In rats treated dermally for three weeks, no significant effects were seen on gross or histopathological examination at doses up to 1000 mg/kg bw per day. An increased lymphocyte count in males at 500 or 1000 mg/kg bw per day was considered to be of questionable biological significance in the absence of similar findings in other studies. The NOAEL was 1000 mg/kg bw per day.
In a one-year study of toxicity in dogs treated in the diet at levels of 0, 750, 2500, or 25,000 ppm, reduced body-weight gain, thyroid hypertrophy, and inflammatory lesions of the liver were seen at 25,000 ppm (equal to 500 mg/kg bw per day), with changes in urinary pH, serum enzyme activities, and albumin level. As significant reductions in body-weight gain were seen at 25,000 ppm (35%) and 2500 ppm (20%), the NOAEL was 750 ppm, equal to 25 mg/kg bw per day. Earlier studies with limited protocols were inadequate for deriving reliable NOAELs for dogs but showed no marked effects at doses up to 500 mg/kg bw per day over two years.
In a 23-month study in mice fed diets containing 0, 1000, 3200 or 10,000 ppm, there was a dose-related increase in the prevalence of amyloidosis in males, which also occurred in females at the highest dose. The frequencies of adrenal hyperplasia and carditis or myocarditis were increased in females at the two higher doses. Increases in the frequencies of alveolar adenomas and uterine haemangiomas in females at the highest dose were not statistically significant and do not represent clear evidence of carcinogenic potential. The NOAEL was 1000 ppm (equal to 160 mg/kg bw per day) on the basis of cardiac and adrenal changes in females at 3200 ppm and above. A small increase in the frequency of amyloidosis at 1000 ppm was observed in males, which was not considered to be significant. An earlier long-term study in mice treated by oral or subcutaneous administration provided no evidence of carcinogenicity.
In a two-year study of toxicity and carcinogenicity in rats in which the levels incorporated in the diet were varied to give 0, 25, 500 or 1000 mg/kg bw per day, there was no evidence of an increase in tumour incidence. Reductions in body-weight gain, despite increased food consumption, were noted at 500 and 1000 mg/kg bw per day. An altered pattern of renal lesions, myocarditis, adrenal hyperplasia, and thyroid hyperplasia was seen at 1000 mg/kg bw per day. The NOAEL was 25 mg/kg bw per day on the basis of clear effects on weight gain at doses of 500 mg/kg bw per day and above. Earlier long-term studies in rats provided no evidence of carcinogenicity at doses up to 2% in the diet (equivalent to 1000 mg/kg bw per day).
In a two-generation study of reproductive toxicity in rats given 0, 1000, 10,000, 30,000 or 50,000 ppm in the diet, significant effects on the body-weight gain of parents and pups were evident at the two highest doses, to such an extent that the dose of 50,000 ppm was discontinued after the first generation. There were no adverse effects on reproductive parameters. Increases in organ weight and histological findings indicated a slight effect on the kidneys at 30,000 ppm. The NOAEL was 10,000 ppm (equivalent to 750 mg/kg bw per day).
In a study of developmental toxicity, rats were given 0, 30, 300, or 1000 mg maleic hydrazide/kg bw per day by gavage on days 6-16 of gestation. There was no clear evidence of effects on the fetus or of maternal toxicity, even at the highest dose tested. In a similar study in rabbits treated with 0, 100, 300, or 1000 mg/kg bw per day by gavage on days 7-27 of gestation, there was no clear evidence of fetotoxicity or teratogenicity. Reduced maternal body-weight gain and an increased frequency of late resorptions were seen at 1000 mg/kg bw per day. The NOAEL was 300 mg/kg bw per day.
A wide range of tests for genotoxicity in vitro with high concentrations of maleic hydrazide resulted in several positive findings. No positive findings were recorded in four studies in vivo. The Meeting concluded that maleic hydrazide is not genotoxic.
An ADI of 0-0.3 mg/kg bw was established on the basis of the NOAEL of 25 mg/kg bw per day in the two-year study of toxicity and carcinogenicity in rats and the one-year study of toxicity in dogs, using a 100-fold safety factor.
A toxicological monograph was prepared, summarizing the data reviewed since the previous evaluation and including summaries from the previous monograph and monograph addendum.
TOXICOLOGICAL EVALUATION
Levels that cause no toxic effect
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Mouse: |
1000 ppm, equal to 160 mg/kg bw per day (toxicity in a 23-month study of toxicity and carcinogenicity) |
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Rat: |
25 mg/kg bw per day (toxicity in a two-year study of toxicity and carcinogenicity) |
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1000 mg/kg bw per day (highest dose tested in a study of developmental toxicity) |
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10,000 ppm, equivalent to 750 mg/kg bw per day (toxicity in a two-generation study of reproductive toxicity) |
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Rabbit: |
300 mg/kg bw per day (maternal toxicity in a study of developmental toxicity) |
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Dog: |
750 ppm, equal to 25 mg/kg bw per day (one-year study of toxicity) |
Estimate of acceptable daily intake for humans
0-0.3 mg/kg bw
Toxicological criteria for setting guidance values for dietary and non-dietary exposure to maleic hydrazide
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EXPOSURE |
RELEVANT ROUTE, STUDY TYPE, SPECIES |
RESULT/REMARKS |
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Short-term (1-7 days)
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Oral toxicity, rat |
LD50 >5000 mg/kg bw |
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Dermal toxicity, rabbit |
LD50 >20000 mg/kg bw |
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Inhalation, 1 h, toxicity, rat |
LC50 >20 mg/litre |
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Dermal irritation, rabbit |
Slightly irritating |
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Ocular irritation, rabbit |
Slightly irritating |
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Dermal sensitization, guinea-pig |
Not sensitizing |
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Medium-term (1-26 weeks)
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Repeated dermal, 21 days, toxicity, rat |
NOAEL = 1000 mg/kg bw per day (highest dose tested) |
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Repeated oral, reproductive toxicity, rat |
NOAEL = 750 mg/kg bw per day, reduced weight gain; no effects on reproduction |
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Repeated oral, developmental toxicity, rat |
NOAEL = 1000 mg/kg bw per day (highest dose tested), |
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Repeated oral, developmental toxicity, rabbit |
NOAEL = 1000 mg/kg bw per day (highest dose tested), embryotoxicity and teratogenicity NOAEL = 300 mg/kg bw per day, maternal toxicity (increased resorptions and decreased weight gain) |
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Long-term (> one year) |
Repeated oral, two years, toxicity and carcinogenicity, rat |
NOAEL = 25 mg/kg bw per day, decreased weight gain, increased food intake, and clinical chemical changes |
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Repeated oral, one year toxicity, dog |
NOAEL = 25 mg/kg bw per day, reduced body-weight gain |
