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Toxicological information

Toxicity to reproduction: other studies

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Administrative data

Endpoint:
toxicity to reproduction: other studies
Type of information:
experimental study
Adequacy of study:
key study
Study period:
No information
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: reliable with restrictions. Compatible with guidelines.
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
publication
Title:
Behavioural and functional neurotoxicological changes caused by cadmium in a three-generational study in rats
Author:
Nagymajtenyl L, Schulz H and Desi I
Year:
1997
Bibliographic source:
Human Experim. Toxicol. 16:691-699

Materials and methods

Principles of method if other than guideline:
A study was conducted to evaluate the behavioural neurotoxicity of the test material in rats. Three consecutive generations of Wistar rats were orally treated by gavage with 3.5, 7.0, or 14.0 mg Cd/kg bw/d (as cadmium chloride diluted in distilled water) over the period of pregnancy, lactation, and 8 weeks after weaning. Behavioral (open field behavior) andelectrophysiological (spontaneousand evoked cortical activity, etc.) parameters of male rats from each generation were investigated at the age of 12 wk.
GLP compliance:
not specified
Type of method:
in vivo

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
-Name of test material-Cadmium chloride (CdCl2.2.5H2O)
PURITY: 99.5%

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: SPF breeding colony of the research institute of laboratory animals, Gödöllö, Hungary
- Age at study initiation: 11 wk
- Housing: cages
- Diet ( ad libitum): rodent food
- Water (ad libitum): water
- Acclimation period: 3 wk


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2
- Humidity (%): 60±10
- Photoperiod (hrs dark / hrs light): 12/12


Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
No information
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No information
Duration of treatment / exposure:
approx. 49 d
Frequency of treatment:
cft test design
Duration of test:
approx. 49 d
Doses / concentrations
Remarks:
Doses / Concentrations:
3.5, 7.0 and 14.0 mg/kg bw/d
Basis:
nominal conc.
No. of animals per sex per dose:
A total of 260 rats were used in the experiments. Experiments were only performed on male offspring. Behavioral tests were done with 10 male 
animals per group. Three generations and four dose groups resulted in 12 test groups. 
Control animals:
yes
Details on study design:
Oral cadmium treatment started at the age of 4 wk in the F1 generation, which was bred out of the parental generation in the laboratory. The F1 generation was then split : 10 males per dose for behavioral tests, ten males per dose for "neurotoxicological" evaluations  (the authors probably refer to the neurophysiological tests), 5 males per dose for breeding, and 10 females per dose for breeding. Animals received treatment for 5 d/wk, with a dose of either 0, 3.5, 7.0 and 14.0 mg/kg bw. Administration volume was 0.1 mL/100 g bodyweight. Females used for breeding were treated 7 d/wk from the beginning of mating until weaning of their young at the age of four weeks.
Statistics:
Kolmogorov-Smirnov test: check for normality of data
multivariate ANOVA/ Kruskall-Wallis ANOVA: to test treatment effectson behavioural outcomes
univariate ANOVA: to analyze electrophysiological data
LSD testing: for post hoc analysis of group differences

Results and discussion

Effect levels

open allclose all
Dose descriptor:
LOAEL
Effect level:
3.5 mg/kg bw/day
Sex:
male
Basis for effect level:
other: developmental neurotoxicity
Dose descriptor:
NOAEL
Basis for effect level:
other: developmental neurotoxicity
Remarks on result:
not determinable
Remarks:
no NOAEL identified
Dose descriptor:
NOAEL
Basis for effect level:
other: maternal
Remarks on result:
not determinable
Remarks:
no NOAEL identified

Observed effects

Behavioral outcomes were: increased vertical exploration activity (rearing) and increased exploration of an open-field center.

LOAEL (neurotoxic effects) : This study suggests a developmental neurotoxicity of cadmium. The behavior testing with effects on exploratory open field behavior, and on rearing are considered relevant in this report. This effect was significant for the three dose arms. This means that 3.5 mg/kg bw/d was sufficient to induce adverse effects. This is shown in figure 1, panel B on page 694 of the article. Therefore, it is not possible to calculate a NOAEL from this study. LOAEL is 3.5 mg/kg bw/d.

Any other information on results incl. tables

None

Applicant's summary and conclusion

Conclusions:
LOAEL for developmental neurotoxicity in rats is 3.5 mg/kg bw/d Cadmium
Executive summary:

A study was conducted to evaluate the behavioural neurotoxicity of the test material in rats.

Three consecutive generations of Wistar rats were orally treated by gavage with 3.5, 7.0, or 14.0 mg Cd/kg bw/d (as cadmium chloride diluted in distilled water) over the period of pregnancy, lactation, and 8 weeks after weaning. Behavioral (open field behavior) andelectrophysiological (spontaneous and evoked cortical activity, etc.) parameters of male rats from each generation were investigated at the age of 12 wk.

The main behavioral outcomes were increased vertical exploration activity (rearing) and increased exploration of an open-field center. The spontaneous and evoked electrophysiological variables showed dose- and generation-dependent changes (increased frequencies in the electrocorticogram, lengthened latency and duration of evoked potentials, etc.) signaling a change in neural functions. The results indicate that low-level, multigeneration exposure of rats to inorganic cadmium can affect nervous system function.