PESTICIDE RESIDUES IN FOOD - 1984 Sponsored jointly by FAO and WHO EVALUATIONS 1984 The monographs 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 Rome 1985 MALEIC HYDRAZIDE Explanation 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 TOXICOLOGICAL STUDIES Special Study on Teratogenicity Rabbit 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 & Blair, 1983). Special Studies on Carcinogenicity Mouse 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, 1981). Comments 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). FURTHER INFORMATION Desired Observations in humans. REFERENCES 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. (Unpublished)
See Also: Toxicological Abbreviations Maleic hydrazide (Pesticide residues in food: 1976 evaluations) Maleic hydrazide (Pesticide residues in food: 1977 evaluations) Maleic hydrazide (Pesticide residues in food: 1980 evaluations) Maleic hydrazide (Pesticide residues in food: 1984 evaluations) Maleic hydrazide (Pesticide residues in food: 1996 evaluations Part II Toxicological) Maleic Hydrazide (IARC Summary & Evaluation, Volume 4, 1974)