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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1974
Reference Type:
review article or handbook
Title:
Calcium Chloride, SIDS Initial Assessment Report For SIAM 15
Author:
OECD
Year:
2002
Bibliographic source:
OECD SIDS Initial Assessment Report For SIAM 15, Boston, USA, 22-25th October 2002

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
no
Remarks:
study reported before establishment of GLP guidance
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Calcium chloride
EC Number:
233-140-8
EC Name:
Calcium chloride
Cas Number:
10043-52-4
Molecular formula:
CaCl2
IUPAC Name:
calcium dichloride
Specific details on test material used for the study:
- Name of the test material used in the report: calcium chloride
- Batch No.: FDA 71-87
- Appearance: fine white granular material

Test animals

Species:
mouse
Strain:
CD-1
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: adult females

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on mating procedure:
Virgin adult female albino outbred mice were mated with young adult males, and observation of the vaginal sperm plug was considered Day 0 of gestation.
Duration of treatment / exposure:
gestation day 6 to 15
Frequency of treatment:
daily
Duration of test:
until gestation day 17
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Negative Control
Dose / conc.:
1.89 mg/kg bw/day (nominal)
Dose / conc.:
8.78 mg/kg bw/day (nominal)
Dose / conc.:
40.8 mg/kg bw/day (nominal)
Dose / conc.:
189 mg/kg bw/day (nominal)
Dose / conc.:
150 mg/kg bw/day (nominal)
Remarks:
Positive control (Aspirin)
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: all animals were observed daily for appearance and behaviour with particular attention to food consumption and weight.

BODY WEIGHT: Yes
- Time schedule for examinations: body weights were recorded on gestation day 0, 6, 11, 15 and 17

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 17
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes, after caesarean section under surgical anesthesia the numbers of implantation sites, resorption sites and live and dead fetuses were recorded.
Blood sampling:
n.a.
Fetal examinations:
The body weights of the live pups were recorded. In addition, all fetuses were examined grossly for the presence of external congenital abnormalities. One-third of the fetuses of each litter underwent detailed visceral examinations employing the Wilson technique. The remaining two-thirds were cleared in potassium hydroxide (KOH), stained with alizarin red S dye and examined for skeletal defects.
Statistics:
n.a.
Indices:
Numbers of implantation sites, resorption sites, live and dead fetuses, sex ratio
Historical control data:
n.a.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
See Table 1 in box " Any other information on results incl. tables".
Body weight and weight changes:
no effects observed
Description (incidence and severity):
See Table 5 in box " Any other information on results incl. tables".
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Endocrine findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
No adverse effects were observed/described.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Early or late resorptions:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Dead fetuses:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Other effects:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
> 189 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no adverse effects observed at the highest dose tested

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Changes in sex ratio:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
See Table 2 in box " Any other information on results incl. tables".
Anogenital distance of all rodent fetuses:
not examined
Changes in postnatal survival:
not examined
External malformations:
not examined
Skeletal malformations:
no effects observed
Description (incidence and severity):
See Table 3 in box " Any other information on results incl. tables".
Visceral malformations:
no effects observed
Description (incidence and severity):
See Table 4 in box " Any other information on results incl. tables".
Other effects:
not examined

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
> 189 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects observed at highest dose tested

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Any other information on results incl. tables

Table 1: Fate Summary
Group Material Dose Total Surviving at Term
mg/kg bw Mated Pregnant Total Pregnant*
341 Vehicle control 0 25 22 25 22
342 Aspirin** 150 25 19 25 19
347 CaCl2 1.89 25 22 25 22
348 CaCl2 8.78 25 21 24 20
349 CaCl2 40.8 25 21 25 21
350 CaCl2 189.0 25 23 25 23

*includes all dams examined at term

**positive control

Table 2: Reproduction data
Group 341 342 347 348 349 350
Dose (mg/kg bw) Neg Con Aspirin* 1.89 8.78 40.8 189.0
Pregnancies
Total No. 22 19 22 21 21 23
Died/aborted before Day 17 0 0 0 1 0 0
To term (Day 17) 22 19 22 20 21 23
Live Litters
Total No. 21 29 21 20 21 21
Implant Sites
Total No. 251 240 244 248 235 272
Average per dam 11.4 12.6 11.6 12.4 11.2 11.8
Resorptions
Total No. 19 8 12 7 5 35
Dams with 1 or more sites resorbed 6 5 8 6 4 13
Dams with all sites resorbed 1 0 1 0 0 2
% partial resorptions 27.3 26.3 36.4 30.0 19.1 56.5
% complete resorptions 4.55 0 4.55 0 0 8.70
Live Fetuses
Total No. 229 224 229 238 227 234
Average per dam** 10.4 11.8 10.4 11.9 10.8 10.2
Sex ratio (m/f) 1.16 1.07 0.80 0.84 0.89 0.93
Dead Fetuses
Total* 3 8 3 3 3 3
Dams with 1 or more dead 2 6 3 3 3 3
Dams with all dead 0 0 0 0 0 0
Per cent partial dead 9.09 31.6 13.6 15.0 14.3 13.0
Per cent all dead 0 0 0 0 0 0
Average Fetus weight (g) 0.89 0.87 0.90 0.93 0.91 0.90

*positive control

**includes only those dams examined at term

Table 3: Summary of Skeletal findings**
Group No. 341 342 347 348 349 350
Dose (mg/kg bw) Neg. Con. Aspirin* 1.89 8.78 40.8 189.0
Live fetuses examined (at term) 158/21 160/19 160/21 162/20 159/21 161/21
Sternebrae
Incomplete oss. 25/10 28/10 21/11 15/6 24/10 12/5
Scrambled  
Bipartie 11/9 9/7 3/3 12/8 13/10 7/6
Fused  
Extra  
Missing 9/7 11/5 16/10 12/5 10/6 12/5
Other            
Rids
Incomplete oss.            
Fused/split  
Wavy 1/1  
Less than 12  
More than 13 41/14 30/12 28/12 42/14 35/14 20/12
Other            
Vertebrae
Incomplete oss. 3/3 1/1 2/2     2/2
Scrambled  
Fused  
Extra crts. Oss.  
Scoliosis  
Tail defects  
Other            
Skull
Incomplete closure            
Missing  
Craniostosis  
Other: facial bones, inc 1/1            
Extremities
Incomplete oss. 1/1 1/1 1/1     2/2
Missing    
Extra            
Miscellaneous
Hyoid, missing 23/14 23/11 33/14 26/11 20/10 30/13
Hyoid, reduced 23/13 4/4 22/14 12/9 23/12 12/9

*positive control

**numerator= number of fetuses affected, denominator= number of litters affected

Table 4: Summary of Soft Tissue Abnormalities
Group Material Dose (mg/kg bw) Dam No. Of Pups Description
342 Aspirin* 150.0 A6102 1 Gastroschisis
349 CaCl2 40.8 N5070 1 Umbilical hernia
350 Cacl2 189.0 N5112 1 Cleft palate

*positive control

Table 5: Average body weights (g)
Group Material Dose (mg/kg bw) Day 0 Day 6 Day 11 Day 15 Day 17
341 Neg. Con. 0.0 27.7 30.6 34.5 41.1 46.8
342 Aspirin* 150.0 28.7 31.9 35.0 43.4 50.2
347 CaCl2 1.89 29.3 31.3 35.4 43.6 49.2
348 CaCl2 8.78 28.7 30.7 35.2 45.2 51.5
349 CaCl2 40.8 29.0 30.9 35.8 44.1 50.2
350 CaCl2 189.0 30.9 33.6 37.4 45.4 50.4

*positive control

Applicant's summary and conclusion

Conclusions:
In this study conducted similar to OECD TG 414, oral administration of calcium chloride given once a day to CD1 mouse dams from Day 6 to 15 of gestation was well tolerated of up to the highest dose applied of 189 mg/kg bw/day. As no adverse results were observed in any examined parameter, the NOAEL for reproductive/developmental and maternal toxicity is considered to be greater than 189 mg/kg bw/day.
Executive summary:

In a developmental toxicity study conducted similar to OECD TG 414, calcium chloride was administered to groups of 25 pregnant adult female CD1 mice/dose by gavage at dose levels of 0, 1.89, 8.78, 40.8 and 189.0 mg/kg bw/day from day 6 through day 15 of gestation. The animals were sacrificed on gestation day 17.

No treatment-related effects were seen in maternal or offspring survival and no maternal/foetal toxicity was observed. In addition, no differences were seen in either soft or skeletal examinations of the fetuses. As no adverse results were observed in any examined parameter, the NOAEL for reproductive/developmental and maternal toxicity is considered to be greater than 189 mg/kg bw/day.