Disodium disilicate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: No tables provided with report; results only discussed qualitatively. Therefore, limited amount of information available. For justification of read across see endpoint summary.

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Safety of the metal scavengers sodium metasilicate and sodium polyphosphate.

Author:

Saiwai, K. et al.

Year:

1980

Bibliographic source:

Internal Report Toho University

Reference 2

Reference Type:

secondary source

Title:

Unnamed

Year:

2004

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Application of Na-metasilicate via gavage from day 0 to 18 of gestation. Examination of fetuses and and newborns.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Disodium metasilicate

EC Number:

229-912-9

EC Name:

Disodium metasilicate

Cas Number:

6834-92-0

IUPAC Name:

disodium oxosilanediolate

Details on test material:

SOURCE: not reported
PURITY: not reported
IMPURITY/ADDITIVE/ETC.: not reported
ANY OTHER INFORMATION: the test substance was sodium metasilicate, 20% aqueous solution.

Test animals

Species:

mouse

Strain:

other: JLC-TCR

Details on test animals or test system and environmental conditions:

Well developed males and females 8-13 weeks of age and  27-35 g/animal.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

1 male was caged with each female until a vaginal plug was observed, at which time the female was housed in a separate cage.

Duration of treatment / exposure:

17-18 days

Frequency of treatment:

daily

Duration of test:

18 days

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

12.5 mg/kg bw/day (nominal)

Remarks:

low dose

Doses / concentrations 2

Dose / conc.:

50 mg/kg bw/day (nominal)

Remarks:

medium dose

Doses / concentrations 3

Dose / conc.:

200 mg/kg bw/day (nominal)

Remarks:

high dose

No. of animals per sex per dose:

33 and 27 animals respectively

Control animals:

yes

Details on study design:

10 animals/cage were raised until mating. Mating was performed with 1 female and 1 male. Males were kept individually beginning 1 week before mating. After mating, animals were kept individually. The gestation period was determined by identifying the vaginal plug as day "zero" of pregnancy. The pregnant animals were randomly divided into 4 groups receiving volumes of 10 ml/kg bw of water (control), 12.5, 50 and 200 mg/kg bw sodium metasilicate by gavage. Treatment was repeated daily from day "zero" until day "seventeen". The living fetuses of 5 mothers, randomly chosen from each group, were fixed with Bouin's fixative for examinations of inner organs. The living fetuses of the other mothers were fixed using  95% ethanol followed by staining with Alizarin Red S for examination of skeleton anomalies.10 pregnant mice were allowed to deliver their young naturally. After parturition, neonates were arranged in groups of 8 randomly chosen neonates born by the same mother (if possible four male and four  female/group) and nursed for 30 days. The weight of the main organs was determined in both mothers and neonates.  Running Test: animals were placed on their backs on a plane inclined at  45° and their reaction classified into four patterns: animal fell down  immediately; stayed motionless on the center; turned 90° and moved to the  right or to the left; turned and moved to the top. Rod Grasping Test: the animals were gently held by their tails and lowered until their forefeet touched a fixed rod, when they were  released. The time was measured from touching the rod until the animals fell from the rod. This test was conducted three times with each animal on the 6th, 8th, 10th and 14th day after birth. 

Examinations

Maternal examinations:

- body weight
- Clinical observations: registered daily

ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC): 
- Organ weights P and F1: reported for F1 individuals only, 30 days after birth 
- Histopathology P and F1: on day 30 after birth the offspring were necropsied and the skeletons stained and examined for 

Ovaries and uterine content:

counting of nidations, corpi lutei and living/dead fetuses

Fetal examinations:

STANDARDIZATION OF LITTERS: 
after parturition the neonates were counted, and arranged into groups of 8 randomly chosen individuals born by the same mother (preferably 4 males and 4 females), for an unknown number of females from each group.

weighing of living fetuses and important organs, sex determination, examination of integument anomalies, naked eye  examination of other changes
Parameters evaluated were: number of neonates, parturition failures, body weight gain, behavioral development in the Running and Rod Grasping Testand skeletal development. The running test on an inclined plane and the rod grasping test were conducted on day 6, 8, 10 and 14 after birth, to assess development.

ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC): 
- Organ weights P and F1: reported for F1 individuals only, 30 days after birth 
- Histopathology P and F1: on day 30 after birth the offspring were necropsied and the skeletons stained and examined for 
anomalies.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Parental data and F1: 
- Body weight: no treatment-related effects were observed in either mother animals, fetuses delivered by hysterectomy or neonates. 
- Fertility index: see table below
- Duration of gestation: 18 days
- Mortality: 2/27 females administered 50 mg/kg and 2/33 females administered 200 mg/kg died during the exposure period. In one female of  the highest dose group all fetuses died at an early stage. No parturition  fatalities were observed when mothers were allowed to deliver their young  naturally. 
- Gross pathology incidence and severity: observed skeletal malformations  in neonates like cervical vertebrae, tail vertebrae and vomer adhesion  occurred in the controls, too, and did not show a dosage correlation. No  malformations of the skeleton or the inner organs of fetuses delivered by hysterectomy were observed; the frequency of malformations and  abnormalities of the external integument, like opened eyes, cleft palate  and exencephaly showed a slight tendency toward dose dependance, but it  was lower than in the control. No effects on main organs of both mothers  and neonates as compared to controls.
- Number of corpora lutea: No significant differences between control and  test groups, but actual numbers not reported.
- Organ weight changes: No treatment-related effects of organ weights of  mother animals and neonates; not reported for fetuses delivered by hysterectomy.

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

12.5 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects: no effects

Details on embryotoxic / teratogenic effects:
- Litter size and weights: There was a dose-related, but not statistically significant decrease in litter size.
- Post natal survival until weaning: no treatment-related effects on body weight gain. 
- Effects on offspring: a dose-related, but not statistically significant decrease in embryo weight and delayed ossification process was observed.
- Postnatal growth, growth rate: no treatment related effects
- Other observations: no treatment-related effects in the Running Test and the Rod Grasping Test.

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

> 200 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects oberserved at the high dose

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

- Fertility index: 
Dose [mg/kg bw/d] pregnancies/mated female    % pregnancies
---------------------------------------------------------------
     0 (control)             20/26                   77%
    12.5                      22/24                   92%
    50                        20/31                   65%
   200                        21/25                   84%


- Offspring toxicity F1:
Dose [mg/kg bw/d]    average no. of neonates/litter
-----------------------------------------------------
     0 (control)            14.7 +- 2.4
    12.5                      13.8 +- 2
    50                        12.9 +- 2
   200                        12.8 +- 2

Applicant's summary and conclusion

Conclusions:

No developmental effects were observed in this study up to and including 200 mg/kg bw/day. The NOAEL for developmental toxicity was determined to be > 200 mg/kg bw. The NOAEL for maternal toxicity was 12.5 mg/kg bw/day.

Executive summary:

In a developmental toxicity study by Saiwai et al. (1980), pregnant mice were administered 12.5, 50 or 200 mg/kg bw/day sodium metasilicate in aqueous solution from day 0 until 17/18 of gestation by daily gavage. Among the mother animals 2 fatalities occurred both in the 50 and 200 mg/kg group (total number of animals: 33 and 27, respectively); body and organ weights and dissection findings were not affected. On day 18 of gestation fetuses were delivered by hysterectomy and examined. No differences to controls were observed for the following parameters: number of pregnancies and living or dead fetuses, body weight and malformations of inner organs and the skeleton. 10 mother animals were allowed to deliver their young naturally. The neonates were observed for 30 days. Litter size and fertility index were not significantly affected up to and including 200 mg/kg bw/day. Body weight gain, organ weights and behavioural development did not reveal any differences to the control. Skeletal malformations did not exhibit a correlation with dosage. The NOAEL for developmental toxicity was determined to be > 200 mg/kg bw/day. The NOAEL for maternal toxicity was 12.5 mg/kg bw/day.