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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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: (1) Reliable without restriction
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1995

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Qualifier:
equivalent or similar to
Guideline:
other: EC TM B31 Dir. 87/302/EEC 30/05/88
Deviations:
not specified
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes
Remarks:
in compliance with United States FDA GLP regulations (21 CFR, Part 58)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Name of test material-CdO
SOURCE: Lot 110383 from Johnson Matthey Aesar Group (Seabrook, NH)
PURITY: 99.4 %
Impurities : 400 ppm chlorine, all other impurities detected totaled less than 263 ppm

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Simonsen Laboratories (Gilroy, CA)
- Age at study initiation: 14 wk
- Weight at study initiation: Female : 92-94 (mean body weight per group)
- Housing: in individual cages within the exposure chambers
- Diet : NIH-07 Open Formula Diet (Zeigler Brothers, Inc., Gardners, PA) in pellet form
- Water : City water (Richland, WA), ad libitum
- Acclimation period: 12-15 d


ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
Particle size: MMAD = 1.1 - 1.6 µm, GSD : 1.7-1.8
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No information
Details on mating procedure:
2 to 3 females were cohoused overnight with each males. On the first day of vaginal plug or sperm detection (gestation d 0), positively mated females were assigned to exposure groups by weights. Breeding was conducted for 3 consecutive nights.
Duration of treatment / exposure:
Gestation Day 4-19
Frequency of treatment:
6h and 16 min/d; 7 d/wk
Duration of test:
Sacrifice on Gestation Day 20
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 0.05, 0.5 or 2 mg/m3
Basis:
nominal conc.
No. of animals per sex per dose:
32 positively mated females/ exposure group
Control animals:
yes
Details on study design:
No information

Examinations

Maternal examinations:
PARAMETERS ASSESSED DURING THE STUDY
Clinical observations performed and frequency: recorded twice daily rats were weighed on gestation Days 0, 4, 6, 10, 14, 17 and on the day of necropsy
Parameters assessed during study (maternal):
- Maternal livers, kidneys and uteri were weighed.
- Corpora lutea, implantation sites, resorptions were counted.        
- Extra-gestational weight change was calculated by subtracting the gravid uterine weight from the maternal body weight.       
- Uteri with no visible implantation sites were stained with ammonium sulfide to detect very early resorptions.       
- Placentas were examined and discarded unless abnormal.       
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes

Fetal examinations:
Parameters assessed during study (maternal):
- Live and dead fetuses were counted
- Live fetuses were weighed and examined for gross defects and then killed and sexed.       
- Half of the fetuses from each litter as fetuses wth gross external abnormalities were examined for visceral defects using methods adapted from Staples (1974). The other half of the fetuses were decapitated; heads were fixed in Bouin's fixative, sectioned and examined for soft-tissue craniofacial defects. All carcasses were double stained with Alcian blue and alizarin Red S and examined for skeletal malformations.
Statistics:
Exposure-related trends in pregnancy indices were determined by the Cochran-armitage test (Armitage, 1971). Each exposed group was compared 
to the control group with a chi-square test (Conover, 1971).  Organ and bosy weight data, which have approximately normal distributions, were analyzed with the parametric multiple comparisons procedures of Williams (1971, 1972) and Dunnett (1955).  Exposure group means for data with skewed distributions were analyzed using the nonparametric multiple comparisons methods of Shirley (1977) or Dunn (1964).  Jonckheere's test (1954) was used to assess the significance of dose-response trends and to determine whether a trend-sensitive test (William' or Shirley's test) was more
appropriate for pairwise comparisons than a test that does not assume a monotonic dose response (Dunnett's or Dunn's test). Trend-sensitive tests were used when Joncheere's test was significant at a P-value less than 0.1. The significance of the dose-response trend for extra-gestational weight
change was tested with the SAS General Linear Models Procedure (SAS, 1985). For fetal malformations and variations, the arc sine transformation of 
each proportional incidence was analyzed against the class variable, "treatment", using a one-way analysis of variance test. A Tukey's t-test (two-tailed) was used to assess statistically significant differences between control and exposed groups. If appropriate, the dose-response relationship was
determined by an orthogonal trend test (Winer, 1971).
Indices:
No information
Historical control data:
No information

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
TOXIC RESPONSE/EFFECTS BY DOSE LEVEL: 
Maternal data : One female rat in the highest exposure group died on gestation Day 17. Pregnancy index were respectively  81%, 88 %, 91 % and 97 % in the control, low, medium and high dose groups. Clinical signs of toxicity included dyspnea in all exposed groups ; the incidence, duration and severity being dose-related. In addition, hypoactivity was noted in most rats at 2 mg/m3.  Mean body weight and body weight gain of pregnant females from the highest exposure group were significantly lower than those of the control group (respectively 87 % and 59 % of the control). In addition, at this  dose level, absolute and relative liver weights and absolute kidney weight were significantly lower than in the controls (respectively 82 %, 95 % and 91 % of the controls), while relative uterine and kidney weights were significantly greater than the controls (respectively 110 % and 105 %).

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
0.5 mg/m³ air
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
2 mg/m³ air
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
0.5 mg/m³ air
Basis for effect level:
other: developmental toxicity
Dose descriptor:
LOAEL
Effect level:
2 mg/m³ air
Basis for effect level:
other: developmental toxicity

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
Foetal data : No effect on the number of implantations per dam, litters with resorptions or resorptions per litter were noted. In addition, no statistically significant differences in fetal mortality, number of live fetuses per litter or sex ratios were observed.  Mean body weights of male and female fetuses from the highest exposed group were significantly lower than those of the controls (84 % of the control for M and 83 % of the control for F).  No significant increase of the incidence of total fetal malformations or of the mean percent of malformed fetuses per litter. In addition, no statistically significant differences were observed between the control and exposed groups in the overall incidence of fetal variations (14.6 %, 21.7 %, 20.6 % and 28.3 %) or the mean percent of fetuses per litter with variations (14.3 %, 21.2 %, 20.6 % and 27.8 %). However, the mean percent of fetuses per litter with reduced ossifications of the pelvis (2.4 %, 2.3 %, 3.4 % and 12 %) and sternabrae (4.4 %, 7.5 %, 8.4 % and 24.7 %) dose-relately increased, with both parameters being significantly greater at 2 mg/m3.

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:
Maternal toxicity was observed in rats exposed to 2 mg/m3 CdO as evidenced by a decrease in body weight and body weight gain and presence of clinical signs of toxicity. There was no evidence of embryolethality at any exposure level. However, in rats exposed to 2 mg/m3, developmental toxicity was evidenced by lower fetal weights and a significant increase in the incidence of reduced skeletal ossification.
Executive summary:

A study was conducted to evaluate the teratogenic effects of the test material in SD rats.

Sperm-positive female Sprague-Dawley rats were exposed to 0, 0.05, 0.5, or 2 mg/m3 cadmium oxide 6 h/d, 7 d/wk, from gestation Day 4 through 19.

Maternal toxicity was observed in Sprague-Dawley rats exposed to 2 mg/m3 cadmium oxide and included body weights lower than those of the controls and clinical signs of toxicity (dyspnea and hypoactivity). There was no evidence of embryolethality in rats at any exposure level. However, in rats exposed to 2 mg/m 3, developmental toxicity was evidenced by lower fetal weights and a significant increase in the incidence of reduced skeletal ossifications.