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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
1972
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
For reproductive/developmental toxicity a prenatal developmental toxicity / teratogenicity study (hamster) with amorphous calcium silicates (read across with Crystalline silicic acid, calcium salt) is included. No developmental effects were observed in this study.
Cross-reference
Reason / purpose:
reference to other study
Reference
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
1972
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
For reproductive/developmental toxicity a prenatal developmental toxicity / teratogenicity study (rats) with amorphous calcium silicates (read across with Crystalline silicic acid, calcium salt) is included. No developmental effects were observed in this study.
Reason / purpose:
reference to other study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
no gross pathological examination of the organ dams other than the urogenital tract; statistical evaluation is missing.
GLP compliance:
no
Remarks:
Study performed prior to GLP adoption
Limit test:
no
Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: young adult
- Housing: individually in mesh bottom cages
- Diet: ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): controlled
- Humidity (%): controlled
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Oral gavage

PREPARATION OF DOSING SOLUTIONS: the substance was given as a water solution

DIET PREPARATION no data

VEHICLE
- Amount of vehicle (if gavage): 1 mL/kwg bw
The sham-exposed group received anhydrous corn oil.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Details on mating procedure:
- Impregnation procedure: mated
-Observation of the vaginal sperm checked on Day 0 of gestation
Duration of treatment / exposure:
Gestation Day 6 to Day 15
Frequency of treatment:
daily
Duration of test:
All dams were sacrificed after Cesarian section on gestation Day 17
No. of animals per sex per dose:
21-23
Control animals:
yes, sham-exposed
other: positive control aspirin (given at 250 mg/kg bw)
Details on study design:
- Dose selection rationale: no data
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes (appearance, behaviour)
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:

BODY WEIGHT: Yes
- Time schedule for examinations: Day 0, 6, 11, 15 and 17 of gestation

FOOD CONSUMPTION: Yes, daily

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 17
- Organs examined: urogenital tract examined macroscopically

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:
- Mortality reported: Yes
- External examinations: Yes, all per litter
- In general congenital abnormalities: Yes, all per litter
- Detailed visceral examinations: Yes, 1/3 per litter
- Skeletal examinations: Yes, 2/3 per litter
- Average fetuses weights and sex were recorded.
Statistics:
No data
Indices:
Not reported
Historical control data:
No data
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
No effects observed up to the highest dose applied.
Dose descriptor:
NOAEL
Effect level:
> 1 600 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
> 1 600 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No effects observed up to the highest dose applied.
Dose descriptor:
NOAEL
Effect level:
1 600 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Embryotoxic / teratogenic effects:
Abnormalities:
not specified
Developmental effects observed:
not specified

Table 1. Reproduction data

 

Dose mg/kg bw/day

Sham-exposed

Aspirin

250

16

74

350

1600

PREGNANCIES

 

Total No

21

25

21

21

20

22

Died or aborted

0

0

1

0

0

0

To termination

21

25

20

21

20

22

CORPORA LUTEA

 

Total No

271

284

324

269

283

292

Average/dam mated

11.8

10.1

11.6

11.7

12.9

12.2

LIVE LITTERS

 

Total No*

21

21

20

21

20

21

IMPLANTATION SITES

 

Total No

214

249

234

216

230

251

Average/dam*

10.2

9.96

11.7

10.3

11.5

11.4

RESORPTIONS

 

Total No*

4

62

3

3

1

13

Dams with ≥1 resorption sites

4

14

3

2

1

2

Dams with all sites resorbed

0

3

0

0

0

1

% partial resorptions

19.0

56.0

15.0

9.52

5.0

9.09

% complete resorptions

-

12.0

-

-

-

4.55

LIVE FETUSES

 

Total No*

210

175

231

212

229

238

Average/dam*

10.0

7.0

11.6

10.1

11.5

10.8

Sex ratio M/F

1.08

1.22

1.14

1.12

0.88

1.14

DEAD FETUSES

 

 

 

 

 

 

Total No*

-

12

-

1

-

-

Dams with ≥1 dead fetuses

-

7

-

1

-

-

Dams with all dead fetuses

-

0

-

0

-

-

% partial dead

-

28.0

-

4.7

-

-

% all dead

-

-

-

-

-

-

AVERAGE FETUS WEIGHT (g)

3.77

2.38

4.04

4.01

3.90

4.06

*Includes only dams examined at termination

Table 2. Skeletal findings

 

Dose mg/kg bw/day

Sham-exposed

Aspirin

16

74

350

1600

Live Fetuses examined

146/21

127/21

157/20

149/21

158/20

166/21

STERNEBRAE

 

Incomplete Oss.

39/16

89/21

38/14

37/15

36/11

43/15

Scrambled

 

 

 

 

 

 

Bipartite

1/1

23/14

 

 

 

 

Fused

 

 

 

 

 

 

Extra

 

 

 

 

 

 

Missing

2/2

119/21

16/5

2/2

12/6

10/6

RIBS

 

Incomplete Oss.

 

 

 

 

 

 

Fused/split

 

 

 

 

 

 

Wavy

3/1

10/5

11/7

11/9

16/5

5/5

Less than 12

 

 

 

 

 

 

More than 13

6/4

24/11

5/5

10/7

8/4

 

VERTEBRAE

 

Incomplete Oss.

 

99/20

4/2

1/1

5/2

3/2

Scrambled

 

 

 

 

 

 

Fused

 

 

 

 

 

 

Extra ctrs. Oss.

 

 

 

 

 

 

Scoliosis

 

 

 

 

 

 

Tail defects

 

 

 

 

 

 

SKULL

 

Incomplete closure

4/2

53/14

16/8

3/2

16/12

25/13

Missing

 

 

 

 

 

 

Extra

 

 

 

 

 

 

EXTERMITIES

 

Incomplete Oss.

 

2/2

 

 

 

 

Missing

 

 

 

 

 

 

Extra

 

 

 

 

 

 

MISCELLANEOUS

 

Hyoid; missing

1/1

17/7

15/8

9/8

19/8

15/8

Hyoid; reduced

9/2

12/5

23/13

7/4

21/9

45/13

-nominator: No of fetuses affected, denominator: No of litters affected

Soft tissue abnoramilites such as exncephaly. spina bifida, and umbilical hernia were seen in several pups from dams treated with the positive control aspirin. No soft tissue abnormalities were seen in the sham exposed controls or in the test item treated animals.

Conclusions:
Oral administration by gavage of hydrated calium silicate to female Wistar rats, during gestation days 6-15, did not result to any maternal or developmental toxicity, at doses up to 1600 mg/kg bw.
Executive summary:

In a developmental toxicity study, hydrated calcium silicate (FDA 71-4, fine white powder) was administered by gavage to groups of female pregnant Wistar rats, during gestation, from Day 6 to Day 15, at dose levels of 16, 74, 350 and 1600 mg/kg bw. Sham-exposed animals were used as negative control and aspirin was given at 150 mg/kg bw to an additional group, as a positive control. Bodyweights were recorded on Days 0, 6, 11, 15 and 17 of gestation. Clinical observations and food consumption were recorded daily. Caesarean sections were performed to all dams on Day 17, and the number of dead, live or resorbed fetuses, sex ratio and number of implantation sites were recorded. All fetuses were weighed and examined for external congenital abnormalities. One-third of the fetuses/litter was examined for visceral malformations, and the other two-thirds for skeletal malformations.  The ovaries and uterine content of all dams were examined.

No adverse effect related to the treatment with hydrated calcium silicate was detected. Malformations recorded in the fetuses were comparable to sham-exposed controls. Treatment with the teratogen aspirin resulted in several malformations of the pups. Under the conditions of this test, the NOAEL for both maternal and developmental toxicity for the test item was considered to be 1600 mg/kg bw/day, the highest dose applied.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1972
Report Date:
1972

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
no gross pathological examination of the organ dams other than the urogenital tract; statistical evaluation is missing from the report.
GLP compliance:
no
Remarks:
Study performed prior to GLP adoption
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Name of test material (as cited in study report): FDA 71-41 (Silene EF; hydrated calcium silicate)
- Physical state: solid, fine powder

Test animals

Species:
hamster, Syrian
Strain:
other: outbred
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: young adult
- Housing: individually in mesh bottom cages
- Diet: ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): controlled
- Humidity (%): controlled

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Oral gavage

PREPARATION OF DOSING SOLUTIONS: the substance was given as a water solution

DIET PREPARATION no data

VEHICLE
- Amount of vehicle (if gavage): 1 mL/kwg bw
The sham-exposed group received anhydrous corn oil.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Details on mating procedure:
- Impregnation procedure: mated
-Observation of the vaginal sperm checked on Day 0 of gestation
Duration of treatment / exposure:
Gestation Day 6 to Day 10 (5 days)
Frequency of treatment:
daily
Duration of test:
All dams were sacrificed after Cesarian section on gestation Day 14
No. of animals per sex per dose:
21-23
Control animals:
yes, sham-exposed
other: positive control aspirin (given at 250 mg/kg bw)
Details on study design:
- Dose selection rationale: no data

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes (appearance, behaviour)
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:

BODY WEIGHT: Yes
- Time schedule for examinations: Day 0, 8, 10, and 14 of gestation

FOOD CONSUMPTION: Yes, daily

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 14
- Organs examined: urogenital tract examined macroscopically

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:
- Mortality reported: Yes
- External examinations: Yes, all per litter
- In general congenital abnormalities: Yes, all per litter
- Detailed visceral examinations: Yes, 1/3 per litter
- Skeletal examinations: Yes, 2/3 per litter
- Average fetuses weights and sex were recorded.
Statistics:
No data
Indices:
Not reported
Historical control data:
No data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
No effects observed up to the highest dose applied.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
> 1 600 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
> 1 600 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No effects observed up to the highest dose applied.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
1 600 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Embryotoxic / teratogenic effects:

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Table 1. Reproduction data

 

Dose mg/kg bw/day

Sham-exposed

Aspirin

250

16

74

350

1600

PREGNANCIES

 

Total No

21

23

21

22

19

21

Died or aborted

0

0

1

0

0

0

To termination

21

23

20

22

19

21

CORPORA LUTEA

 

Total No

330

345

297

319

289

291

Average/dam mated

15.0

13.3

14.1

14.5

13.1

13.2

LIVE LITTERS

 

Total No*

21

22

20

22

19

21

IMPLANTATION SITES

 

Total No

267

273

232

256

229

250

Average/dam*

12.7

11.9

11.6

11.6

12.1

11.9

RESORPTIONS

 

Total No*

8

25

10

12

6

6

Dams with ≥1 resorption sites

7

10

7

10

5

4

Dams with all sites resorbed

-

-

-

-

-

-

% partial resorptions

33.3

43.5

35.0

45.5

26.3

19.0

% complete resorptions

-

-

-

-

-

-

LIVE FETUSES

 

Total No*

259

237

221

242

221

243

Average/dam*

12.3

10.3

11.1

11.0

11.6

11.6

Sex ratio M/F

0.53

0.51

0.63

0.56

0.47

0.66

DEAD FETUSES

 

 

 

 

 

 

Total No*

-

11

1

2

2

1

Dams with ≥1 dead fetuses

-

3

1

2

2

1

Dams with all dead fetuses

-

-

-

-

-

-

% partial dead

-

13.0

5.0

9.09

10.5

4.76

% all dead

-

-

-

-

-

-

AVERAGE FETUS WEIGHT (g)

1.77

1.63

1.81

1.76

1.80

1.80

*Includes only dams examined at termination

Table 2. Skeletal findings

 

Dose mg/kg bw/day

Sham-exposed

Aspirin

250

16

74

350

1600

Live Fetuses examined

182/21

165/22

155/20

169/22

155/19

175/21

STERNEBRAE

 

Incomplete Oss.

117/20

114/21

95/20

99/22

89/17

96/21

Scrambled

 

 

 

 

 

 

Bipartite

16/9

17/11

22/6

21/12

15/9

12/7

Fused

 

 

1/1

1/1

 

1/1

Extra

 

 

 

 

 

3/2

Missing

17/10

29/14

12/7

20/14

14/7

14/7

RIBS

 

Incomplete Oss.

 

 

 

 

 

 

Fused/split

 

 

 

 

 

 

Wavy

 

 

 

 

 

 

Less than 12

 

 

1/1

 

 

 

More than 13

14/10

41/6

37/19

20/11

17/12

30/17

VERTEBRAE

 

Incomplete Oss.

 

1/1

 

 

1/1

 

Scrambled

 

 

 

 

 

 

Fused

 

 

 

 

 

 

Extra ctrs. Oss.

 

 

 

 

 

 

Scoliosis

 

 

 

 

 

 

Tail defects

 

 

 

 

 

 

SKULL

 

Incomplete closure

 

 

 

 

 

 

Missing

 

 

 

 

 

 

Extra

 

 

 

 

 

 

EXTERMITIES

 

Incomplete Oss.

 

1/1

 

 

 

 

Missing

 

 

 

 

 

 

Extra

 

 

 

 

 

 

MISCELLANEOUS

 

Hyoid; missing

 

1/1

 

 

 

 

Hyoid; reduced

1/1

1/1

 

1/1

1/1

 

-nominator: No of fetuses affected, denominator: No of litters affected

No soft tissue abnoramilites were seen in any of the animals.

Applicant's summary and conclusion

Conclusions:
Oral administration by gavage of hydrated calium silicate to female pregnant golden hamsters, during gestation days 6-15, did not result to any maternal or developmental toxicity, at doses up to 1600 mg/kg bw.
Executive summary:

In a developmental toxicity study, hydrated calcium silicate (FDA 71-4, fine white powder) was administered by gavage to groups of female pregnant golden hamsters, during gestation, from Day 6 to Day 15, at dose levels of 16, 74, 350 and 1600 mg/kg bw. Sham-exposed animals were used as negative control and aspirin was given at 150 mg/kg bw to an additional group, as a positive control. Bodyweights were recorded on Days 0, 8, 10 and 14 of gestation. Clinical observations and food consumption were recorded daily. Caesarean sections were performed to all dams on Day 14, and the number of dead, live or resorbed fetuses, sex ratio and number of implantation sites were recorded. All fetuses were weighed and examined for external congenital abnormalities. One-third of the fetuses/litter was examined for visceral malformations, and the other two-thirds for skeletal malformations.  The ovaries and uterine content of all dams were examined.

No adverse effect related to the treatment with hydrated calcium silicate was detected. Malformations recorded in the fetuses were comparable to sham-exposed controls. Under the conditions of this test, the NOAEL for both maternal and developmental toxicity for the test item was considered to be 1600 mg/kg bw/day, the highest dose applied.