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EC number: 238-484-2 | CAS number: 14484-64-1
- Life Cycle description
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- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
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- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
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Endpoint summary
Administrative data
Description of key information
The subchronic oral toxicity of the test item ferbam was studied in male rats. Administration of ferbam in the diet for 13 weeks reduced weight gain, parraleled with reduced food consumption. Ferbam intake of 109 mg/kg*d killed 6 of 20 rats between the 3d and 5th wk and 331 mg/kg-d killed all rats during the 1st wk. No adverse effects on clinical chemistry parameters or examined organs were observed in rats treated with 66 mg/kg*d. Based on mortality and lesions in spleen and lymph nodes observed in rats fed 109 mg/kg*d ferbam, a NOAEL of 66 mg/kg*d can be derived.
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- not mentioned
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
- Deviations:
- yes
- Remarks:
- only male rats
- GLP compliance:
- not specified
- Species:
- rat
- Strain:
- other: CD strain
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratory, Wilmington, Massachusetts
- Females (if applicable) nulliparous and non-pregnant: [yes/no] no females
- Age at study initiation: young rats
- Weight at study initiation: 120 - 190 g
- Housing: The rats were housed, two per cage, in plastic cages with filter tops in temperature- and humidity-controlled quarters on a 12-h light cycle. Hardwood bedding material was used.
- Diet (e.g. ad libitum): Wayne Laboratory Animaf Dieis, Allied Mills, Chicago.
- Water (e.g. ad libitum): no details given
- Acclimation period: no details given
DETAILS OF FOOD AND WATER QUALITY: Regular chow was analyzed for metals, trace elements, and various pesticides. The diets were prepared every 2-3 wk.
ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12-h light cycle
- Route of administration:
- oral: feed
- Details on route of administration:
- Regular chow was analyzed for metals, trace elements, and various pesticides. The diets were prepared every 2-3 wk. Ferbam was found to be stable in the diets at room temperature for 8 wk.
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- - PREPARATION OF DOSING SOLUTIONS:
- DIET PREPARATION
- Rate of preparation of diet (frequency): The diets were prepared every 2-3 wk.
- Mixing appropriate amounts with (Type of food): powdered regular rodent chow
- Storage temperature of food: room temperature
- Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- Food intake was measured throughout the study.
- Duration of treatment / exposure:
- 13 weeks
- Frequency of treatment:
- Daily
- Dose / conc.:
- 23 mg/kg bw/day (nominal)
- Dose / conc.:
- 66 mg/kg bw/day (nominal)
- Dose / conc.:
- 109 mg/kg bw/day (nominal)
- Dose / conc.:
- 331 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 20 male rats per dose
- Control animals:
- yes, plain diet
- Positive control:
- not specified
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: checked daily for behavioural changes and adverse effects
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Not specified
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Not specified
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at termination
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals: 12 rats of each group
- Parameters examined: total red blood cells, white blood cell and reticulocyte counts, differential leukocyte count, hematocrit, and hemoglobin
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at termination
- Animals fasted: Not specified
- How many animals: 12 rats of each group
- Parameters examined: fasting glucose, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase, and blood urea nitrogen (BUN)
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: observed daily
OTHER: organ weights, microscopic examination - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
The liver, spleen, kidneys, adrenals, thyroids, and gonads were removed and weighed; organ weight/body weight ratios were calculated.
HISTOPATHOLOGY: Yes
The liver, spleen, kidneys, adrenals, thyroids, gonads, heart, lung, salivary gland, pancreas, fundic and pyloric stomach, intestines, urinary bladder, accessory sex organs, diaphragm and gracilis muscle, rib bone with marrow smears, pituitary, and brain were stained with hematoxylin and eosin (H&E) for microscopic examination. - Statistics:
- Differences between treated and control groups were tested for significance according to Dunnett's (1955) multiple comparison procedure.
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Six deaths occurred in rats fed 109 mg/kg'd between the 3d and 5th wk. In a fourth group, 331 mg/kg*d ferbam killed all 20 rats during the 1st wk.
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- Six deaths occurred in rats fed 109 mg/kg'd between the 3d and 5th wk. In a fourth group, 331 mg/kg*d ferbam killed all 20 rats during the 1st wk.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Ferbam intake of 23, 66, or 109 mg/kg*d significantly reduced the weight gain and food consumption of male rats.
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- Ferbam intake of 23, 66, or 109 mg/kg*d significantly reduced the weight gain and food consumption of male rats.
- Food efficiency:
- not specified
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Rats in the two high-dose groups had golden pigmentation of the reticuloendothelial (R-E) cells of the spleen and mesenteric lymph nodes.
- Histopathological findings: neoplastic:
- no effects observed
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 66 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- body weight and weight gain
- clinical biochemistry
- clinical signs
- food consumption and compound intake
- gross pathology
- haematology
- histopathology: neoplastic
- histopathology: non-neoplastic
- mortality
- organ weights and organ / body weight ratios
- Dose descriptor:
- LOAEL
- Effect level:
- 109 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- histopathology: non-neoplastic
- mortality
- Critical effects observed:
- not specified
- Conclusions:
- The most obvious effect of ferbam in rats was the reduced weight gain. This was significant in males fed ferbam at all dosages (23, 66, and 109 mg/kg'd) for 13 wk. Food consumption was reduced and paralleled the reduced weight gain, thus the depressed weight gain could be a result of decreased palatability of the ferbam-containing feed. Ferbam intake of 109 mg/kg*d killed 6 of 20 rats between the 3d and 5th wk and 331 mg/kg-d killed all rats during the 1st wk. No adverse effects on clinical chemistry parameters or examined organs were observed in rats treated with 66 mg/kg*d. Based on mortality and lesions in spleen and lymph nodes observed in rats fed 109 mg/kg*d ferbam, a NOAEL of 66 mg/kg*d can be derived.
- Executive summary:
The subchronic oral toxicity of the test item ferbam was studied in male rats. Administration of ferbam in the diet for 13 weeks reduced weight gain, parraleled with reduced food consumption. Ferbam intake of 109 mg/kg*d killed 6 of 20 rats between the 3d and 5th wk and 331 mg/kg-d killed all rats during the 1st wk. No adverse effects on clinical chemistry parameters or examined organs were observed in rats treated with 66 mg/kg*d. Based on mortality and lesions in spleen and lymph nodes observed in rats fed 109 mg/kg*d ferbam, a NOAEL of 66 mg/kg*d can be derived.
Reference
Summary of subactute toxicities of ferbam in rats.
23 mg/kg*d | 66 mg/kg*d | 109 mg/kg*d | 331 mg/kg*d | |
Total weight gain, % of control | 90 | 79 | 58 | |
Average feed intake, % of control | 91 | 83 | 63 | |
Number of deaths | 0 | 0 | 6 | 20 |
Clinical chemistry | - | - | - | |
Lesions |
||||
- Spleen, lymph node | - | - | + | + |
- Testes | - | - | - | - |
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 66 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- rat
- Quality of whole database:
- Well documented study similar to OECD TG 408. Study was conducted prior to establishment of GLP.
- System:
- immune system
- Organ:
- lymph node
- spleen
Repeated dose toxicity: inhalation - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: inhalation
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- other:
Reference
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: inhalation
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- other:
Reference
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: dermal
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- a short-term toxicity study does not need to be conducted because exposure of humans via the dermal route in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment
Reference
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: dermal
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- a short-term toxicity study does not need to be conducted because exposure of humans via the dermal route in production and/or use is not likely as based on the provided thorough and rigorous exposure assessment
Reference
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
The subchronic (13 weeks) study was selected as key study, because the selected doses in the chronic study do not allow the derivation of a NOAEL for male and female rats, as required by the guideline. The chronic study shows that males are more sensitive than females. Therefore, the sub-chronic study, which was performed only with male rats, provides the hazard value for the most sensitive sex. When applying Haber's Law, the NOAEL from the sub-chronic study is in the same magnitude as the NOAEL from the chronic study.
Justification for classification or non-classification
The subchronic oral toxicity of the test item ferbam was studied in male rats. Administration of ferbam in the diet for 13 weeks reduced weight gain, parraleled with reduced food consumption. Ferbam intake of 109 mg/kg*d killed 6 of 20 rats between the 3d and 5th wk and 331 mg/kg-d killed all rats during the 1st wk. No adverse effects on clinical chemistry parameters or examined organs were observed in rats treated with 66 mg/kg*d. Based on mortality and lesions in spleen and lymph nodes observed in rats fed 109 mg/kg*d ferbam, a NOAEL of 66 mg/kg*d can be derived.
Concerning possible systemic effects by dermal route of exposure, they can be ruled out because no significant dermal absorption is expected for ferbam due to its physico-chemical properties and the evidence from the acute dermal toxicity study (Rejinders, 1987b) in which no toxicity was observed at the dose of up to 4000 mg/kg bw.
The inhalation route is also a not relevant route of exposure for ferbam due to its physico-chemical properties. Although treatment-related effects were observed in the acute inhalation studies in rats (McDonald, 188; Hardy, 1988), according to gross pathological examination they seem to be rather local than systemic effects: extensive haemorrhage in the lungs and resultant pulmonary oedema
Based on these subchronic oral toxicity data and in accordance with Regulation (EC) No 1272/2008 (CLP Regulation), no classification and labelling is required for specific target organ toxicity after repeated exposure (STOT-RE) for ferbam.
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