** Evaluation in CCPR periodic review programme
TOXICOLOGY
Ziram was evaluated for toxicological effects by the Joint Meeting in 1965, 1967, 1970, 1974, 1977, and 1980. A temporary ADI (0-0.025 mg/kg bw) for ziram or ziram in combination with other dimethyldithiocarbamates was allocated in 1967, on the basis of the NOAEL in a one-year study in dogs. This temporary ADI was lowered to 0.005 mg/kg bw in 1974. A group ADI of 0-0.02 mg/kg bw for ferbam and ziram was allocated in 1977 and confirmed in 1980. The compound was reviewed by the present Meeting within the CCPR periodic review programme.
In experiments with 14C-labelled ziram in rats, elimination was essentially complete within 48 h. Elimination occurred mainly in expired air, urine, and faeces. Less than 2% of the administered dose remained in the tissues. The biotransformation of ziram has not been studied in rodents. In goats, it is metabolized at least in part via a single-carbon pathway, which results in extensive radiolabelling of natural products.
The primary effect of short- and long-term treatment with ziram in mice, rats, and dogs was on the liver, thyroid gland, and testes. The hepatic effects were increased liver weight, degeneration, and focal-cell necrosis. Effects in the thyroid were C-cell hyperplasia and carcinomas, and that on the testes was sterility.
Ziram had moderate acute oral toxicity in rats and rabbits (LD50 = 200-400 mg/kg bw). WHO has classified ziram as 'slightly hazardous'.
In a four-week study of toxicity in mice given dietary concentrations of 0, 3000, 4000, or 5000 ppm, an NOAEL was not identified. Reductions in body weight, food intake, efficiency of food use, and brain and heart weight occurred at all doses.
In a 13-week study of toxicity in mice given dietary concentrations of 0, 100, 300, 900, or 2700 ppm, the NOAEL was 100 ppm, equal to 15 mg/kg bw per day, on the basis of lowered spleen weight at higher doses. At 900 and 2700 ppm, the number of corpora lutea was reduced, which was consistent with cellular changes in the uterus.
In two four-week studies of toxicity in rats either given diets containing 0, 100, 500, 2500, or 5000 ppm or treated by gavage with 0, 3, 15 or 100 mg/kg bw per day, the NOAEL was 3 mg/kg bw per day, on the basis of degenerative liver changes. At 100 mg/kg bw per day, degenerative changes in the kidneys and reductions in body weight, food intake, efficiency of food use, and absolute weights of the liver, pituitary, testes, brain, and uterus were seen.
In a 13-week study of toxicity in which rats received dietary levels of 0, 100, 300, or 1000 ppm, the NOAEL was 100 ppm, equal to 7.4 mg/kg bw per day, on the basis of reduced body-weight gain, food intake, and food use and increased brain and spleen weights at higher doses.
In a four-week study of toxicity in dogs given diets providing doses of 0, 1000, 2000, or 5000 ppm, an NOEL was not identified. Increased liver weight occurred at all doses. At 2000 ppm, convulsive episodes were observed.
In a 13-week study of toxicity in dogs given diets providing 0, 100, 300, or 1000 ppm, the NOAEL was 100 ppm, equal to 4.1 mg/kg bw per day, on the basis of increased liver weight, focal liver necrosis, pigment in Kupffer cells, activated partial thromboplastin time, and elevated cholesterol level at higher doses.
In a one-year study of toxicity in which dogs were fed diets providing doses of 0, 50, 180, or 500 ppm, the NOAEL was 50 ppm, equal to 1.6 mg/kg bw per day, on the basis of reductions in body-weight gain, degeneration of hepatocytes, and increased activity of alanine and aspartate aminotransferases and alkaline phosphatase at 180 ppm and above. At 500 ppm, single liver-cell necrosis was observed, and the liver weight and cholesterol values were increased; albumin values were reduced. Inflammatory cell infiltration around the hepatic veins and its branches and aggregates of pigmented Kupffer cells were observed in the liver.
Two long-term studies of toxicity and carcinogenicity in mice have been reported. One was considered inadequate for evaluating the carcinogenicity of ziram. In the other, mice were given diets containing 0, 25, 75, 220, or 680 ppm for 80 weeks. The NOAEL was 25 ppm, equal to 3 mg/kg bw per day, on the basis of reduced brain weight at 75 ppm and above. There was no evidence of carcinogenicity.
In a two-year study of toxicity and carcinogenicity in rats at dietary concentrations of 0, 25, 250, or 2500 ppm, the NOAEL was 250 ppm, equivalent to 12 mg/kg bw per day, on the basis of testicular atrophy and thyroid hyperplasia at 2500 ppm. There was no evidence of carcinogenicity.
In a two-year study of toxicity and carcinogenicity in Fischer 344 rats with dietary concentrations of 0, 300, or 600 ppm, an NOAEL was not identified since the combined incidence of C-cell adenoma and carcinoma of the thyroid in males showed a positive trend. This finding was considered to represent an extension of the known toxicity of the compound to the thyroid, to which the rat is particularly sensitive, and not to indicate carcinogenic potential for humans.
In a study of toxicity and carcinogenicity in CD rats treated with 0, 60, 180, or 540 ppm in the diet for 12-24 months, an NOEL was not identified because dose-related changes in organ weights and histopathological and haematological changes were observed at 60 ppm, equal to 2.5 mg/kg per day. Other effects included reduced body weight, erythrocyte counts, and tri-iodothyronine and thyroxine activity. Cysts in the thyroids, epithelial hyperplasia, hypertrophy with vacuolation, cortical cystic degeneration of the adrenals, and C-cell hyperplasia of the thyroid were also observed. The tumour incidence was not increased.
In a study of sperm quality in mice treated intraperitoneally with ziram at single doses of 0, 50, or 100 mg/kg bw or repeated doses of 25 mg/kg bw per day for five days, severe morphological abnormalities were observed. The frequency of abnormal sperm was 1.6% in the controls, 5.6% at 50 mg/kg bw, 8.2% at 100 mg/kg bw, and 8.4% after repeated doses of 25 mg/kg bw per day.
In a two-generation study of reproductive toxicity and developmental neurotoxicity, rats were fed ziram at concentrations of 0, 72, 210 or 540 ppm. The NOAEL for maternal toxicity was 210 ppm, equal to 10 mg/kg bw per day, based on reduced food consumption and body-weight gain at 540 ppm. The NOAEL for neonatal toxicity was 210 ppm, equal to 10 mg/kg bw per day, based on reduced body-weight gain at 540 ppm. The NOAEL for reproductive toxicity and developmental neurotoxicity was 540 ppm, equal to 25 mg/kg bw per day.
In a study of developmental toxicity, rats were administered ziram at 0, 1, 4, 16, or 64 mg/kg bw per day on days 6-15 of gestation. The NOAEL for maternal toxicity was 4 mg/kg bw per day, on the basis of decreased body-weight gain and food intake, and increased water intake and salivation at 16 mg/kg bw per day and above. The NOEL for developmental toxicity was 16 mg/kg bw per day, on the basis of decreased litter weight and fetal weight at 64 mg/kg bw per day. No teratogenicity was seen.
In a study of teratogenicity in hamsters treated with single oral doses of 0, 31, 63, 120, or 500 mg/kg bw per day on day 7 or 8 of gestation, the NOAEL was 63 mg/kg bw per day, on the basis of fused ribs and deformed tails and heads, including all degrees of exencephaly, at 120 mg/kg bw per day.
In a study of developmental toxicity in rabbits given ziram at doses of 0, 3, 7.5, or 15 mg/kg bw per day on days 7-19 of gestation, the NOAEL for maternal toxicity and developmental toxicity was 7.5 mg/kg bw per day, on the basis of decreased body-weight gain and food intake in the dams and post-implantation loss, reduced litter size, litter weight, fetal weight, and crown-rump length at 15 mg/kg bw per day. There was no evidence of developmental toxicity.
Ziram is mutagenic in bacteria. It induced chromosomal aberrations in some, but not all, studies with cultured mammalian cells but did not induce unscheduled DNA synthesis in hepatocytes. In vivo, ziram induced single-strand breaks of DNA in the livers of rats but not mice. Chromosomal aberrations were not induced in mice in vivo in bone-marrow cells or spermatogonia, and micronuclei were not induced in bone-marrow cells or peripheral erythrocytes. Studies for clastogenicity have not been conducted in rats in vivo. In an old study of nine workers exposed for three to five years to ziram at a concentration of 2-4 mg/m3 air, the percentage of peripheral leucocytes with chromosomal aberrations was 5.9%; in a control group the percentage was 0.75%. The Meeting was unable to reach a conclusion about the genotoxicity of ziram.
Ziram caused severe eye irritation but no dermal irritation in rabbits and moderate skin sensitization in guinea-pigs.
In two studies of neurotoxicity in rats treated with single doses of 0, 15, 300, or 600 mg/kg bw or 0, 72, 210, or 540 ppm for 91 days, behavioural effects indicative of neurotoxicity were apparent after single high doses but not after repeated dosing at a lower level. The NOAEL was 210 ppm, equal to 14 mg/kg bw per day, on the basis of reduced body weight and food consumption and inhibition of brain neuropathy target esterase activity at 540 ppm.
An ADI of 0-0.003 mg/kg bw was established on the basis of long-term toxicity in the rat. In this study, effects were seen at all doses, the LOAEL being 60 ppm, equal to 2.5 mg/kg bw per day. In view of the absence of an NOAEL, a safety factor of 1000 was used. The NOAEL of 1.6 mg/kg bw per day observed in a long-term study of toxicity in dogs supported this ADI, which served as the basis for the group ADI that was established for ziram alone or in combination with ferbam.
A toxicological monograph was prepared, summarizing the data received since the previous evaluation and relevant data from the previous monograph and monograph addendum.
TOXICOLOGICAL EVALUATION
Levels that cause no toxic effect
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Mouse: |
25 ppm, equal to 3 mg/kg bw per day (80-week study of toxicity and carcinogenicity) |
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210 ppm, equal to 10 mg/kg bw per day (maternal toxicity in a study of reproductive toxicity) |
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10 mg/kg bw per day (study of reproductive toxicity) |
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Rat: |
NOAEL could not be determined: lowest effective dose 60 ppm, equal to 2.5 mg/kg bw per day (12-24-month study of toxicity, various effects) |
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100 ppm, equal to 7.4 mg/kg bw per day (13-week study of toxicity) |
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250 ppm, equivalent to 12 mg/kg bw per day per day (two-year study of toxicity and carcinogenicity) |
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Hamster: |
63 mg/kg bw per day (study of teratogenicity) |
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Rabbit: |
7.5 mg/kg bw per day (maternal toxicity and embryotoxicity in a study of developmental toxicity) |
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Dog: |
50 ppm, equal to 1.6 mg/kg bw per day (one-year study of toxicity) |
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100 ppm, equal to 4.1 mg/kg bw per day (13-week study of toxicity) |
Estimate of acceptable daily intake for humans
0-0.003 mg/kg bw (group ADI for ferbam and ziram)
Studies that would provide information useful for the continued evaluation of the compound
1. Further studies on long-term toxicity in rats.
2. Further studies on genotoxicity in rats.
3. Further studies on male reproductive toxicity.
4. Further observations in humans.
Toxicological criteria for setting guidance values for dietary and non-dietary exposure to ziram
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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 = 270 mg/kg bw |
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Inhalation toxicity, rat |
LC50 = 0.06 mg/litre |
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Dermal irritation, rabbit |
Not irritating |
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Ocular irritation, rabbit |
Severely irritating |
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Dermal sensitization, guinea-pig |
Moderately sensitizing |
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Medium-term (1-26 weeks)
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Repeated oral, 13 weeks, toxicity, mouse |
NOAEL = 15 mg/kg bw per day, decreased spleen weight |
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Repeated oral, 4 weeks, toxicity, rat |
NOAEL = 3 mg/kg bw per day, reduced body weight, food consumption, and degenerative hepatic changes |
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Repeated oral, 13 weeks, toxicity, dog |
NOAEL = 4.1 mg/kg bw per day, hepatic toxicity |
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Repeated oral, reproductive toxicity and developmental neurotoxicity, rat |
NOAEL = 25 mg/kg bw per day, reproductive toxicity and development neurotoxicity NOAEL = 10 mg/kg bw per day, maternal and neonatal toxicity (reduced body weight) |
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Repeated oral, developmental toxicity, rat |
NOAEL = 16 mg/kg bw per day, developmental toxicity (reduced fetal weight) NOAEL = 4 mg/kg bw per day, maternal toxicity (reduced body weight) |
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Repeated oral, developmental toxicity, hamster |
NOAEL = 63 mg/kg bw per day, developmental toxicity (deformed fetuses) |
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Repeated oral, developmental toxicity, rabbit |
NOAEL = 7.5 mg/kg bw per day, developmental and maternal toxicity (reduced fetal and maternal weight) |
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Repeated oral, neurotoxicity, rat |
NOAEL = 14 mg/kg bw per day, inhibition of neuropathy target esterase activity |
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Long-term (> one year) |
Repeated oral, 18 months, toxicity, mouse |
NOAEL = 3 mg/kg bw per day, reduced brain weight and hepatic toxicity |
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Repeated oral, two years, toxicity and carcinogenicity, rat |
No NOAEL identified, LOAEL = 2.5 mg/kg bw per day, haematological toxicity and toxic effects on the thyroid |
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Repeated oral, one year, toxicity, dog |
NOAEL = 1.6 mg/kg bw per day, reduced body weight and hepatic toxicity |
RESIDUE AND ANALYTICAL ASPECTS
Ziram was originally evaluated in 1965 (toxicology) and 1967 (toxicology and residues) and is included in the dithiocarbamate group of compounds. It was evaluated at the present Meeting within the CCPR periodic review programme.
Ziram is a dithiocarbamate contact fungicide with protective action and is registered for use on fruit, vegetables, tree nuts and ornamentals in many countries. Ziram applied to dormant fruit trees is also used to repel hares and rabbits.
The Meeting received information on the metabolism of ziram in goats and apples, methods of residue analysis, the stability of residues in stored analytical samples, approved use patterns, supervised residue trials and the fate of residues during the processing of apples.
In a study on lactating goats with radiolabelled ziram the total residues in milk reached a plateau within 2-3 days. Levels of the radiolabel were higher in the liver than in other tissues.
The metabolism study on apples demonstrated that ziram residues are essentially on the surface. Most of the residue which becomes incorporated into the tissues no longer contains the CS2 structure.
Studies of the environmental fate were not provided for review by the FAO Panel, but the Meeting was informed that such studies were available and had been supplied to the Environmental Core Assessment Group. They would be supplied for future evaluation by the FAO Panel. The Meeting agreed to recommend only temporary MRLs pending a review of the data on environmental fate by the FAO Panel.
The analytical methods for ziram rely on acid digestion and CS2 evolution, as do those for other dithiocarbamates. The Meeting agreed that the definition of the residue of the dithiocarbamates should apply to ziram.
Ziram in fortified macerated apples and peaches stored at -20°C for 3 months was of marginal stability.
The Meeting received data on ziram residues from supervised trials on apples, pears, apricots, cherries, nectarines, peaches, plums, almonds (kernels and hulls analysed), and pecans.
In an apple-processing study, residue levels of ziram in apple juice were about 10% of those in the apples.
FURTHER WORK OR INFORMATION
Required (by 1997)
Information on the environmental fate of ziram in soil and in water/sediment systems.
Desirable
1. Information on the effect of washing on ziram residues on fruits.
2. Final reports of freezer storage stability studies now in progress on peaches, apples and almonds.
3. Information on attempts to develop specific methods of analysis for ziram, whether successful or not.
