Registration Dossier

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
Reference
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:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
only male rats
GLP compliance:
not specified
Species:
rat
Strain:
other: CD strain
Sex:
male
Details on test animals 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:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
haematology
clinical biochemistry
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
histopathology: neoplastic
Dose descriptor:
LOAEL
Effect level:
109 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
mortality
histopathology: non-neoplastic
Critical effects observed:
not specified

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  -  -  -  -
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.

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
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
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
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
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
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.