** Evaluation in CCPR periodic review programme
TOXICOLOGY
Ferbam was evaluated for toxicological effects by the Joint Meeting in 1965, 1967, 1970, 1974, 1977, and 1980. A temporary ADI of 0-0.025 mg/kg bw for ferbam or ferbam in combination with other dimethyldithiocarbamates was allocated in 1967, on the basis of 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.
Ferbam is well absorbed after oral administration to rats and is extensively metabolized. Most of the administered radiolabel was found in the urine, expired air, and bile. In pregnant rats, a small but significant amount crossed the placenta into the fetus. In lactating rats the radiolabel was secreted into the milk, absorbed by the pups, and excreted in the pups' urine. In expired air the main product was carbon disulfide; in the urine the main products were inorganic sulfate, a salt of dimethylamine, and the glucuronide conjugate of dimethyldithiocarbamic acid.
Ferbam has low acute toxicity and has been classified by WHO as unlikely to present an acute hazard in normal use.
In two four-week studies, rats were fed diets providing ferbam at concentrations of 0, 100, 500, 2500, or 5000 ppm or 0 or 2500 ppm. The NOAEL was 100 ppm, equivalent to 10 mg/kg bw per day, on the basis of growth depression at 500 ppm and above. Post-mortem examination revealed no thyroid abnormalities. In another four-week study in which one dog was given ferbam and ziram together, each at a dose of 5 mg/kg bw per day, the only adverse effect was slight anaemia. In another study a dog remained healthy, except for slight anaemia, when given ferbam alone at a dose of 25 mg/kg bw per day for one month or 50 mg/kg bw per day for one week. An attempt to raise the dose to 100 mg/kg bw per day immediately provoked severe vomiting and malaise.
In a study in which dogs were treated with ferbam at doses of 0.5, 5, or 25 mg/kg bw per day for one year, the NOAEL was 5 mg/kg bw per day, on the basis of convulsions at 25 mg/kg bw per day.
In a two-year study of toxicity and carcinogenicity in rats treated 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 depressed growth rate, shortened life span, neurological changes, cystic brain lesions, and testicular atrophy at 2500 ppm. Carcinogenicity was not demonstrated.
Sperm quality was investigated in mice given oral doses of 0, 250, 500, or 1000 mg/kg bw per day for five consecutive days. The NOAEL was 500 mg/kg bw per day, on the basis of an increased frequency of sperm abnormalities at 1000 mg/kg bw per day.
In a three-generation study of reproductive toxicity in rats fed dietary concentrations of 0 or 250 ppm, the NOAEL was 250 ppm, equivalent to 12 mg/kg bw per day.
Few data were available on genotoxicity. Ferbam did not induce reverse mutation in bacteria.
Ferbam was slightly irritating to the skin and eyes of rabbits. It has weak skin-sensitizing properties in guinea-pigs.
The Meeting concluded that the toxicological data specifically generated for ferbam were inadequate to estimate an ADI. However, because of the similarity of the chemical structure of ferbam to that of ziram and the comparable toxicological profile of the two compounds, ferbam was included in the group ADI of 0-0.003 mg/kg bw for ferbam and ziram, which was derived from the information available on ziram.
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: |
500 mg/kg bw per day (study of sperm quality) |
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Rat: |
100 ppm, equivalent to 10 mg/kg bw per day (one-month study of toxicity) |
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250 ppm, equivalent to 12 mg/kg bw per day (two-year study of toxicity and carcinogenicity) |
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250 ppm, equivalent to 12 mg/kg bw per day (study of reproductive toxicity) |
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Dog: |
5 mg/kg bw per day (one-year 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. Studies on dissociation in aqueous solutions.
2. Observations in humans.
Toxicological criteria for setting guidance values for dietary and non-dietary exposure to ferbam.
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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, mouse |
LD50 = 1000 mg/kg bw |
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Oral toxicity, rat |
LD50 = 11 000 mg/kg bw |
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Inhalation toxicity, rat |
LC50 = 0.3 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 |
Weakly sensitizing |
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Repeated oral, 5 days, testicular toxicity, mouse |
NOAEL = 500 mg/kg bw per day, increased sperm abnormalities |
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Medium-term (1-26 weeks) |
Repeated oral, 4 weeks, toxicity, rat |
NOAEL = 10 mg/kg bw per day, reduced body weight |
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Repeated oral, reproductive toxicity, rat |
NOAEL = 12 mg/kg bw per day, reproductive toxicity |
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Long-term (> one year) |
Repeated oral, two years, toxicity and carcinogenicity, rat |
NOAEL = 12 mg/kg bw per day, reduced body weight, shortened life span, neurological changes, cystic brain lesions, and atrophied testes. No carcinogenicity |
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Repeated oral, one year, toxicity, dog |
NOAEL = 5 mg/kg bw per day, convulsions |
RESIDUE AND ANALYTICAL ASPECTS
Ferbam was originally evaluated in 1965 (toxicology) and 1967 (toxicology and residues) and is included in the dithiocarbamate group of compounds. The compound was evaluated at the present Meeting within the CCPR periodic review programme.
Ferbam is a broad-spectrum fungicide used for the control of certain diseases in fruit trees, small fruits and berries, ornamentals, conifers and tobacco.
The Meeting received information on the metabolism of ferbam in goats and sheep, methods of residue analysis, the stability of residues in stored analytical samples, approved use patterns, notably on fruits and potatoes, and supervised residue trials on mangoes.
When lactating goats were dosed with radiolabelled ferbam the total residues in milk increased for 2 or 3 days and then reached a plateau. Levels of the radiolabel were higher in the liver than in other tissues.
The analytical methods for ferbam residues are the same as those for other dithiocarbamates. They rely on acid hydrolysis to release CS2, which may then be measured by head-space gas chromatography or by spectrophotometry. These methods were used to analyse samples from the supervised trials. The Meeting agreed that the definition of the residue of the dithiocarbamates should apply also to ferbam.
Ferbam residues in macerated apples fortified at 1 mg/kg and stored at -20°C were stable for 22 weeks.
The Meeting received data from two supervised residue trials with ferbam on mangoes in the USA, but the data could not be evaluated because information on the relevant GAP was not available.
Generally, the information on ferbam was quite limited. Because of the lack of critical supporting studies the Meeting would not have been able to recommend MRLs for dithiocarbamates based on applications of ferbam even if adequate information on GAP and data from supervised trials were available for some commodities. Recommendations for MRLs for dithiocarbamates are derived from supervised trials with specific dithiocarbamate compounds applied according to the relevant GAP. The compounds for which data have been evaluated and found to be adequate to support the recommended MRLs are indicated in the Table in Annex I. Because of the lack of critical supporting studies ferbam is not included in the list of dithiocarbamates with adequate data to support recommended MRLs for dithiocarbamates.
FURTHER WORK OR INFORMATION
Desirable
1. An adequate set of critical supporting studies for ferbam is needed before it can be included in the list of compounds supporting recommended MRLs for dithiocarbamates (See report of 1995 JMPR, Section 2.5.2).
2. Information on attempts to develop specific methods of analysis for ferbam, whether successful or not.
