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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
No information
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non standard test. Well documented publication.
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1990

Materials and methods

Principles of method if other than guideline:
To examine the effect of cadmium exposure on maternal and foetal zinc metabolism, rats were exposed to cadmium chloride in drinking water on Days 6 through 20 of pregnancy.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
-Name of test material-CdCl2

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Holtzman Company (Madison, WI)
- Housing: cages
- Diet: ad libitum, Purina 5002 Certified Rodent chow (containing 75 ppm Zn and < 0.01 ppm Cd)
- Water (e.g. ad libitum): no information


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 +/- 1.5
- Photoperiod (hrs dark / hrs light): 12/12


Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
not specified
Details on exposure:
No information
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Cd concentrations were determined by AAS with a graphite furnace (Perklin -Elmer Zeeman/3030) at a wavelenght of 228.8 nm and a slit wiidth of
0.7 nm.
Details on mating procedure:
no data available
Duration of treatment / exposure:
Days 6 to 20 of gestation
Frequency of treatment:
Daily through drinking water
Duration of test:
Dasy 6 to 20 of gestation
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 5, 50 and 100 ppm
Basis:
nominal conc.
Actual mean Cd intakes resp. 0, 220, 1650 and 2860 µg/d
No. of animals per sex per dose:
0 ppm: 66; 5 ppm: 64; 50ppm: 42; 100ppm: 48
Control animals:
yes
Details on study design:
No information

Examinations

Maternal examinations:
PARAMETERS ASSESSED DURING THE STUDY:
PARENTS:
- Clinical observations performed and frequency: appearance, behaviour, daily water intake were checked but no further details are given.
- Bodyweights: maternal body weight was measured in all rats on Day 6 and Day 20 of gestation. Maternal weight gain and net weight gain (i.e. weight gain of the mother minus total fetal and placental weight) between Days 6 and 20 of pregnancy.
- Autopsy: microscopic and macroscopic examination

FETUSES
- Clinical observations performed and frequency: appearance, gross defects, behaviour (response to tactile stimuli) were checked but no further details are given.
- Bodyweights: measured on Day 20 of gestation

ADDITIONAL EXAMINATIONS: DISTRIBUTION STUDIES: in mother and fetuses
Ovaries and uterine content:
no information
Fetal examinations:
no information
Statistics:
all statistical comparisons were done using analysis of variance. Intergroup comparisions were made with Scheffe’s test for multiple comparisons at an alpha level of 0.1 (Zar, 1974).
Indices:
no information
Historical control data:
no information

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Details on maternal toxic effects:
- Mortality and time to death: no death occurred in any of the test groups
- Clinical signs: exposed dams did not differ from controls
- Body weight gain: maternal weight gain and net maternal weight gain of dams of the mid and top dose differed significantly from the controls. A dose-effect relationship is seen.
- Water consumption: decreased in all exposure groups (cfr actual mean intake of Cd), in the top dose group significantly different from the controls
- Organ weights: not determined
- Gross pathology: not determined
- Average litter size: no significant difference occurred in the exposed groups vs. control.

Zinc concentrations in maternal organs were not significantly altered.

Alkaline phosphatase in maternal serum was substantially decreased in the top dose group (activity level of approx. one-fourth that of the controls). In the other exposure groups while also lower, however not significantly different. Delta-ALAD activity in maternal whole blood was markedly decreased in all Cd exposure groups. Maternal liver delta-ALAD was slightly elevated in the low and mid-dose groups. A similar trend was seen for maternal kidney delta-ALAD although this finding was not statistically significant. Thus these increase occurred in organs that had sequestered zinc in response to Cd administration.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
5 ppm
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
5 ppm
Basis for effect level:
other: developmental toxicity
Dose descriptor:
LOAEL
Effect level:
50 ppm
Basis for effect level:
other: developmental toxicity
Dose descriptor:
LOAEL
Effect level:
50 ppm
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
- Clinical signs: no differences between the groups
- Weight: significant lower in the mid and the top dose. Multiple regression analysis was performed to determine whether the effect of Cd on fetal weight was independent of its effect on maternal weight. In the top dose group the adjusted fetal weight (i.e. adjusted for maternal weight) did not differ from control weight, indicating that the decreased fetal weight was indeed secondary to decreased maternal weight. However, in the mid-dose group the adjusted fetal weight was significantly different from the control weight, indicating that the effect of Cd on fetal weight in this group was not solely a consequence of decreased maternal weight.

Fetal liver zinc concentrations were reduced by 56 and 55% in the mid- and the top dose respectively when compared to controls. These reductions are proportionally much greater than the decrease in fetal weight suggesting that Cd exposure exerts specific effects on zinc disposition.
 
Overall, fetal Cd concentration showed a significant negative correlation with fetal weight (r = -0.43, p<0.01, n=442). This association was strongest in the top dose group (r= -0.67, p<0.01, n=109). There was also a strong negative correlation between fetal Cd and fetal zinc concentrations (r= -0.41, p<0.01, n=442).

In the fetal liver, which was deprived of zinc in response to Cd, delta -ALAD was substantially decreased in the 50- and 100 -ppm Cd groups.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

none

Applicant's summary and conclusion

Conclusions:
Oral Cd exposure in the pregnant rat is associated with alterations in the maternal and fetal disposition of zinc. The authors hypothesize that these
changes, which are accompanied by reductions in the activities of zinc metalloenzymes in both maternal and fetal tissues, may be responsible in part
for the adverse reproductive outcomes commonly associated with Cd exposure during pregnancy in animals.
Executive summary:

To examine the effect of cadmium exposure on maternal and foetal zinc metabolism, rats were exposed to cadmium chloride in drinking water on Days 6 through 20 of pregnancy.

Maternal weight and weight gain during exposure period were significantly decreased in the 50- and 100-ppm exposure groups (but not in the 5-ppm group). At the highest concentration tested, decrease of fetal weight appeared to be largely secondary to the decreased maternal weight gain and presumably water and food intake. However, in the 50-ppm group the adjusted fetal weight (for maternal weight) was significantly different from control weight, indicating an effect that was not solely a consequence of decreased maternal weight. At this concentration, cadmium caused a substantial Zn retention in maternal liver and kidney, considered to be partially responsible for the decreased concentration of Zn in the foetal liver. The changes in the maternal and foetal disposition of Zn, accompanied by a modification in the activities of Zn metalloenzymes in both maternal and foetal tissues (delta-aminolevulinic acid dehydratase) support the author's hypothesis that the Cd-induced maternal zinc retention is responsible for an impaired foetal growth.