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Repeated dose toxicity: other routes

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Administrative data

sub-chronic toxicity: other route
Type of information:
experimental study
Adequacy of study:
key study
Study period:
no information
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Reliable with restriction. Well documented. Not according to GLP nor to specific test guideline
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference Type:
Cadmium-induced osteomalacic and osteopetrotic lesions inovriectomised rats
Katsuta O, Hiratsuka H, Matsumoto J, Iwata H, Toyota N, Tsuchitani M, Umemura T and Marumo F
Bibliographic source:
Toxicol. Appl. Pharmacol.126:58-68

Materials and methods

Principles of method if other than guideline:
The repeated exposure effect of the test material on the bones of rats were determined. Young, ovariectomised, growing female rats were administered cadmium chloride intravenously (1.0 or 2.0 mgCdCl2/kg, 5 d/wk during 13 wk). General clinical observations, body weights and relevant serum levels were measured. Femurs and humerus were examined upon autopsy.
GLP compliance:
not specified
Limit test:

Test material

Details on test material:
-Name of test material-CdCl2

Test animals

Details on test animals and environmental conditions:
- Source: Charles River Japan, Kanagawa, Japan
- Age at study initiation: 4 wk
- Housing: polycarbonate cage in a barrier system

- Temperature (°C): 20-25
- Humidity (%): 40-70
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
physiological saline
Details on exposure:
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
13 wk
Frequency of treatment:
5 d/wk
Doses / concentrations
Doses / Concentrations:
1 and 2 mg/kg/d
No. of animals per sex per dose:
Control animals:
Details on study design:
Post-exposure period: 4, 8 and 13 wk after the treatment was commenced; 6 animals per group were sacrificed


Observations and examinations performed and frequency:
- Clinical observations performed and frequency: body weight frequency: weekly
- Autopsy: microscopic and macroscopic examination: femur, humerus
Dunnett's t test multiple comparisons test

Results and discussion

Results of examinations

Clinical signs:
not specified
not specified
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:

- Body weight: In 2.0 mg/kg group growth retardation was prominent from 2 to 13 wk consistently, weight loss clear from 8 wk. In the 1.0 mg/kg group, decrease of body weight from 10 wk

- Food/water consumption: no information

- Description, severity, time of onset and duration of clinical signs: no information

- Ophthalmologic findings incidence and severity: no information

- Haematological findings incidence and severity: no information

- Clinical biochemistry findings incidence and severity:
* Blood: decreased hematocrit, Hb, MCV, MCH in the 2.0 mg/kg group at 8 and 13 wk. Increases  of AST, ALT in the 2.0 mg/kg group at 13 wk, increase in total protein from 4 to 13 wk. Increases in serum concentrations of  Ca and inorganic P in the 2.0 mg/kg group at 8 and 13 wk. Those changes were less pronounced in the 1.0 mg/kg group.
* Urine: Increase of water consumption and urine volume. NAG and gamma-GT values were markedly increased in treated rats as was the Ca excretion. No dose-dependent change between the 2 dose groups.
* Hormone assays: serum levels of PTH and BGP were not significantly different between treated and control animals

- Mortality and time to death: no information

- Gross pathology incidence and severity: mild fibrosis of the liver and foci of scarring on the kidney found in the 2.0 mg/kg group. No significant difference between the 2 groups in femur length

- Organ weight changes: no information

- Histopathology incidence and severity: Cd –treated rats
Kidneys: vacuolations of proximal convoluted tubular epithelium, single-cell necrosis and/or regeneration of the epithelial cells  observed in teh outer cortical zone at 4 wk. Thereafter, multifocal lesions of tubular atrophy with interstitial fibrosis were distributed throughout this zone. Increased number of coagulating necrotic cells and hypertrohy of collecting tubular epithelium at 13 wk. Incidence and severity of these changes more pronounced in the 2.0 mg/kg group.
Bone: lesions were restricted to the distal portion of the femur and in the proximal portion of the tibia. Cortical bone: dilated haversian canals and surrounded by an increased amount of uncalcified matrix: osteoid seams.
Thickness of the cortical bone was almost normal. In the metaphysis of Cd-treated rats cancellous bone mass increased with time. Trabeculae were thickened and cohered to each other and formed an increased opacity beneath the metaphyseal plates. Changes were more frequent and more severe in the 2.0 mg/kg group. In the 2.0 mg/kg group a slight increase of osteoid seams was also observed in the trabecular bone of the lumbar vertebra of 2 rats at 13 wk.
Liver: diffuse increase of hepatocytic eosinophilia and a few foci of single-cell necrosis of hepatocytes at 4 wk. At a later stage, periportal hepatitis was detected with piecemeal necrosis in the limiting plate, especially in the 2.0 mg/kg group.
No lesions detected in the control rats

Cd, MT, Ca and P contents of organs: hepatic and renal concentrations of Cd and MT increased with dose dependency at 4 wk and the concentrations were not much different between the 2 dose groups. Cd absent in organs of control group. Bone content of Cd increased gradually until termination  of the experiment. Concentrations of Cd and P in controls and exposed rats were not different.

Effect levels

Dose descriptor:
Basis for effect level:
other: Bone toxicity at high dose. Results do not allow discrimination of whether bone effects are due to direct action of cadmium on bone tissue or are a consequence of kidney damage
Remarks on result:
not determinable
no NOAEL identified

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables


Applicant's summary and conclusion

Although an involvement of the indirect action of Cd through renal failure could not be ruled out in this experiment, the biochemical and pathological data suggested that osteomalacia was induced by a direct action of Cd on the bone through abnormal calcium homeostasis
Executive summary:

The repeated exposure effect of the test material on the bones of rats were determined.

Young, ovariectomised, growing female rats were administered cadmium chloride intravenously (1.0 or 2.0 mg CdCl2/kg, 5 d/wk during 13 wk).

This treatment produced severe nephropathy evidenced pathologically by tubular atrophy and interstitial fibrosis as well as clinically by enzymuria and polyuria. The skeletal changes were detected mainly in the femur and tibia where osteomalacic and osteopetrotic changes were detected. Relevant serum hormone levels were not modified by the treatment.

Overall, this study demonstrates the bone toxicity of very high doses of Cd. The results do not allow discriminating whether the bone effects observed are due to a direct action of Cd on the bone tissue or are an indirect consequence of kidney damage (renal osteodystrophy).