Silicic acid, calcium salt

Developmental toxicity / teratogenicity

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 for cross-reference:

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 for cross-reference:

reference to other study

Qualifier:

equivalent or similar to guideline

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 or test system 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

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

Test material information

Constituent 1

Reference substance name:

hydrated calcium silicate (amorphous)

IUPAC Name:

hydrated calcium silicate (amorphous)

Constituent 2

Reference substance name:

Amorphous silicic acid, calcium salt

Molecular formula:

CaSiO3.nH2O

IUPAC Name:

Amorphous silicic acid, calcium salt

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 or test system 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)

1

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

2

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.