Silicic acid, aluminum sodium salt

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Description of key information

There is no study on the test substance Silicic acid, aluminum sodium salt (CAS 1344-00-9, NAS) available, but an expert's review concludes that extended one-generation reproductive and toxicity studies are predicted to be without a toxicological relevant response. Details see also below in 'Additional information' resp. attached PDF within the IUCLID endpoint in section 7.8.1.

Oral administration of the structurally related read-across substance silicon dioxide up to 1000 mg/kg body weight had no adverse effect on the reproductive performance of rats or on the growth and development of the offspring into adulthood for two consecutive generations.

Link to relevant study records

Reference

Reference 1

Endpoint:

extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Reference 2

Endpoint:

two-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Jan. 5, 2011 - Feb. 27, 2012

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Qualifier:

according to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

Version / remarks:

2001-01-22

Deviations:

yes

Remarks:

minor ones (s. attachement)

GLP compliance:

yes

Specific details on test material used for the study:

NM-200 (Synthetic Amorphous Silica)

Species:

rat

Strain:

Wistar

Details on species / strain selection:

obtained from. Charles River, Deutschland, Sulzfeld, Germany
The Wistar strain was used because of their general acceptance and suitability for this type of studies.

Sex:

male/female

Details on test animals or test system and environmental conditions:

ca. 5 weeks old, 4 animals/cage, feed: Rat & Rat No. 3 Breeding Díet RM3 and tap-water ad libitum, 22 +/- 2 °C, 45-65 % humidity, 12 h light/dark
Upon evidence of copulation the females were caged individually for the birth and rearing of their pups.

Route of administration:

oral: gavage

Vehicle:

other: MHPC (0.5% w/v)

Details on mating procedure:

At the end of premating each female was caged with one male from the same group. Animals were caged together until mating occurs or 2 weeks elapsed. ln case a male died before successful copulation it was replaced by another male from the same dose group (a male that already had successfully mated with another female). A rest period of at least 2 days was taken between the mating period of that male.
Mating pairs were clearly identified. Every consecutive morning during the mating period, vaginal smears were made for determination of the presence of sperm to determine whether mating had occurred.
The day on which a sperm-positive smear was detected was considered as gestation day 0.

Duration of treatment / exposure:

Male animals were dosed during a 10-week premating period and during mating and up to the day before sacrifice. The female animals were dosed with the test item during a 10-week premating period and during mating, gestation and lactation up to postnatal day 21. Selected F1-generation pups were dosed by gavage from postnatal day 22 until the day prior to sacrifice.

Dose / conc.:

100 mg/kg bw/day (nominal)

Remarks:

group B

Dose / conc.:

300 mg/kg bw/day (nominal)

Remarks:

group C

Dose / conc.:

1 000 mg/kg bw/day (nominal)

Remarks:

group D

No. of animals per sex per dose:

28

Control animals:

yes, concurrent vehicle

Details on study design:

The objective of this study was to provide data on the possible effects of the test item on reproductive performance of Wistar rats and on the development of pups consequent to daily oral administration of the test item by gavage to male and female rats during a premating period of at least 10 weeks and during mating (2 weeks), gestation and lactation until postnatal day 21.
At weaning, pups were selected for the F1-generation and were dosed at the same concentrations as their parents during their growth into adulthood.

On or shortly after postnatal day 21, the F1-pups were weaned and 28 males and 28 females were selected at random from as many litters as possible in each group to rear the next generation.

Parental animals: Observations and examinations:

- Each animal was observed daily in the morning hours by cage-side observations and, if necessary, handled to detect signs of toxicity.
- Body weights of male and female rats were recorded shortly before the start of the treatment at randomization and at the start of the study (premating).
Males were weighed weekly until sacrifice. Females were weighed weekly during the premating and mating period. Mated females were weighed on days 0, 4, 7, 10, 14, 17 and 21 during presumed gestation and on days 1, 4, 7, 10, 14, 17 and 21 of lactation.
- Food consumption of male rats were measured weekly, except during the mating per¡od. Food consumption of female rats were measured weekly during the premating period. Food consumption of mated females were recorded during pregnancy over successive periods (day 0-4, 4-7,7-10,10-14,14-17 and 17-21), and during lactation on days 1-4, 4-7, 7-10, 10-14, 14-17, 17-21.
- At the end of the gestation period (gestation day 21), females were examined twice daily for signs of parturition. Any difficulties occurring during parturition were recorded.
- During the last part of the lactation period of the FO-generation females, milk of ca. 12 lactating females per group was collected in order to obtain insight in the exposure of the F1-generation pups during lactation.

Oestrous cyclicity (parental animals):

Vaginal smears to evaluate the estrus cycle length and normality were made daily for about 3 weeks prior to mating. Smears were made and stained of all females but only the smears of the control group and the high-concentration group were evaluated.

Sperm parameters (parental animals):

At scheduled necropsy, epididymal sperm was derived from the left cauda epididymis of all males of all groups. For this purpose the cauda epididymis was dissected, weighed and thereafter minced in M199 medium containing 0.5% bovine serum albumin. Sperm motility and, after sonification and DNA staining, the cauda epididymal sperm reserves (sperm count) were measured for all males of all groups, using the Hamilton Thorne lntegrated Visual Optical System (IVOS). ln addition, a smear of the sperm solution was prepared and stained for all males, but only the smears of the control and the
high-dose group males were examined for morphology. lf treatment-related changes were observed in the high-dose group, the examination of sperm morphology was extended to the intermediate-dose groups in consultation with the sponsor's monitor.

Litter observations:

- To keep nest disturbance to a minimum the litters were examined only once daily for dead pups.
- The total litter size and numbers of each sex as well as the number of stillbirths, live and dead pups and grossly malformed pups were evaluated on days 1,4,7,10, 14, 17 and 21 of lactation. The pups were weighed individually on days 1, 4,7, 10, 14, 1T and 21 ot lactation. Mean pup weíghts were calculated per sex and both sexes combined.

Postmortem examinations (parental animals):

- Males were sacrifìced after successful mating and females were sacrificed at or shortly after weaning on postnatal day 21.
- Microscopic examination was performed on the following organs of all rats of the control and high-dose groups: epididymides, ovaries, pituitary gland,
prostate, seminal vesicles and coagulating qlands, spleen, testes, uterus, vagina

Postmortem examinations (offspring):

- All stillborn pups and pups found dead during the study were stored in a freezer (<-18.C) for macroscopical examination for structural and pathological changes. Gross necropsy was also performed on pups of dams that died during lactation (these pups were sacrificed at the time of the dam's death) and on pups that showed external abnormalities at weaning.
- After selection of the pups for the next generation, from the remaíning pups 1 male and 1 female pup of each litter was subjected to a thorough necropsy. Special attention was paid to the organs of the reproductive system.
- At scheduled necropsy, epididymal sperm was derived from the left cauda epididymis of all males of all groups. For this purpose the cauda epididymis was dissected, weighed and thereafter minced in M199 medium containing 0.5% bovine serum albumin. Sperm motility and, after sonification and DNA staining, the cauda epididymal sperm reserves (sperm count) were measured for all males of all groups, using the Hamilton Thorne lntegrated Visual Optical System (IVOS). ln addition, a smear of the sperm solution was prepared and stained for all males, but only the smears of the control and the
high-dose group males were examined for morphology. lf treatment-related changes were observed in the high-dose group, the examination of sperm morphology was extended to the intermediate-dose groups in consultation with the sponsor's monitor.

Statistics:

The resulting data were analyzed using the methods given below. p < 0.05 was considered as the level of significance.
- Clinical findings were evaluated by Fisher's exact probability test.
- Body weight, body weight gain, food consumption and organ weights data were subjected to one-way analysis of variance (ANOVA) followed by Dunnett's multiple comparison tests.
- Fisher's exact probability test was used to evaluate the number of mated and pregnant females, the number of pregnant females with ímplants but no pups, females with live pups, females with stillborn pups, live and dead fetuses or pups and the numbers of litters lost entirely.
- Pre-coital time (mean number of days), the duration of gestation, the number of corpora lutea and implantation sites, the total number of pups delivered (mean), the mean number of live pups per litter and pre- and post-implantation loss (%) were evaluated by Kruskal-Wallis nonparametric analysis of variance and by the Mann-Whitney U test.
- Mortality data and data of the pathology of parent animals were evaluated by the Fisher's exact probability test.
- Sperm parameters were evaluated by one-way analysis of variance followed by Dunnett's multiple comparison test (epididymal and testicular sperm count and numerical sperm motility parameters) or by Kruskal-Wallis non parametric analysis of var¡ance and by Mann-Whitney U test (motility parameters expressed as a percentage and sperm morphology).
- Estrus cyclic¡ty was evaluated by Fisher's exact test (number of acyclic animals and number of animals with prolonged estrus per¡od), ANOVA followed by Dunnett's multiple comparison tests (number of cycles per animal) and Kruskal-Wallis nonparametric ANOVA followed by Mann-Whitney U test (length of the longest cycle).
- Sexual developmental parameters (preputial separation, vaginal opening and testes descending) were subjected to one-way analysis of variance (ANOVA) followed by Dunnett's multiple comparison tests.

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

The clinical findings observed in the animals of the F0-generation are common findings in rats of this strain and age or occurred as individual fortuitious findings. The distribution of all findings was equally amongst the various groups or occurred in only one or a few animals. Therefore, they were not considered to be related to treatment.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

Animal B98 was killed in moribund condition on Day 58. Macroscopical findings were a intra-abdominal nodule of 5x3 cm. At sacrifice it was shown that this nodule originated from the right kidney. Microscopically, the nodule appeared to be a nephroblastoma
Animal A21 was killed in moribund condition during the first week of the lactation period. This animal showed a prolaps of the uterus. Moreover, some other animals were sacrificed during the first week of the lactation because they lost their complete litters.

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

Mean body weight changes of the male animals of all treatment groups of the F0-generation were stat¡stically significant different from the control group during several intervals. However, the effects were inconsistent. ln the low-dose group, mean body weight changes were decreased between days 7-14, 28-35 and 49-56 and increased between days 21-28 and 42-49. ln the mid-dose group, mean body weight changes were decreased between days 7-14, 28-35,49-56 and increased between days 0-7, 14-21,35-42 and 56-63. ln the high-dose groups, mean body weight changes were decreased between days 21-28 and 42-49. No statistically significant effects on overall body weight changes were observed between the various groups during the entire period.
Mean body weight changes of the female animals of all treatment groups of the F0-generation were statistically significant different from the control group during several intervals of th epremating period. However, the effects were inconsistent: ln the low-dose group, mean body weight changes were decreased between days 28-35 and 49-56 and increased between days 42-49. ln the mid-dose group, mean body weight changes were decreased between days 28-35, 49-56 and 63-70 and increased between 35-42 and 56-63. ln the high-dose groups, mean body weight changes were decreased between days 21-28 and 63-70. No statistically significant effects on overall body weight changes were observed between the various groups during the entíre period (day 0-70).

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

Microscopic examination of the sampled organs and tissues did not reveal treatment related histopathological changes. The histopathological changes observed were about equally distributed amongst the different treatment groups or occurred in one or a few animals only. They are common findings in rats of this strain and age or occurred as individual chance findings. Therefore, they were not considered to be related to treatment.

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

Description (incidence and severity):

No statistically significant effects were observed on the mating-, female fecundity, male fertility-, female fertility and gestion indices. There was no statistically significant difference between post-implantation loss in the control group and treatment groups.

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

clinical signs

mortality

body weight and weight gain

food consumption and compound intake

organ weights and organ / body weight ratios

gross pathology

histopathology: non-neoplastic

reproductive function (oestrous cycle)

reproductive function (sperm measures)

reproductive performance

Key result

Critical effects observed:

no

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

Description (incidence and severity):

No statistically significant effects were observed on the mating-, female fecundity, male fertility-, female fertility and gestion indices. There was no statistically significant difference between post-implantation loss in the control group and treatment groups.

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

The clinical findings observed in the animals of the F1-generation are common findings in rats of this strain and age or occurred as individual fortuitious
findings. The distribution of all findings was equalty amongst the various groups or occurred in only one or a few animals. Therefore, they were not considered to be related to treatment.
Undistended lungs as is observed in many pups of the control, mid-and high-dose groups indicates that these pups were still born.

Mortality / viability:

mortality observed, non-treatment-related

Description (incidence and severity):

Animal C653 was killed in moribund condition at the end of the gestation period. This female was in labour but was unable to deliver the pups. The dystocia exhausted the animal and it was therefore humanely killed. The uterus contained I dead fetuses.
Animal D673 was found dead on gestation day 12, The main macroscopical findings were incompletely collapsed lungs with a firm appearance
Moreover, some other animals were sacrificed during the first week of the lactation because they lost their litters completely

No statistically significant effects were observed on liveborn index and on pup mortality

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

Mean body weight changes of the male animals of all treatment groups of the F1-generation were statistically significant different from the control group during several intervals. However, the effects were inconsistent: ln the low-dose group, mean body weight changes were decreased between days 35-42 and 56-63 and increased between days 14-21, 28-35, 49-56 and 70-76. ln the mid-dose group, mean body weight changes were decreased between days 35-42 and 56-63 and increased between days 7-14,42-49 and 63-70. ln the high-dose groups, mean body weight changes were increased between days 70-76. No statistically significant effects on overall body weight changes were observed between
the various groups during the entire period (day 0-76).
Mean body weight changes of the female animals of all treatment groups of the F1-generation were statistically significant different from the control group during several intervals of the premating period. However, the effects were inconsistent: ln the low-dose group, mean body weight changes were decreased between days 35-42 and 56-63 and increased between days 49-56. ln the mid-dose group, mean body weight changes were decreased between days 0-7, 35-42 and 56-63 and increased between 42-49 and 63-70. ln the high-dose groups, mean body weight changes were decreased between days 14-21 and increased between days 21-28. No statistically significant effects on overall body weight changes were observed between the various groups during the entire period (day 0-76).

Food consumption and compound intake (if feeding study):

effects observed, non-treatment-related

Description (incidence and severity):

Food consumption (expressed as g/animal/day) of the male animals of the mid- and high-dose groups was statistically significantly increased between days 21-28 and 70-76. No statistically significant effects were observed on food consumption of the male anlmals of the F1-generat¡on when expressed as g/kg/day.
Food consumption (expressed as g/animal/day) of the female animals of the mid-dose group was statistically significantly decreased between days 28-35, 42-49,56-63 and 63-70 of the premating period. ln the high-dose group, food consumption (expressed as g/animal/day) was statistically significantly increased between days 14-21 and 21-28. Food consumption (expressed as g/kg/day) of the female animals of the mid-dose group was
statistically significantly decreased between days 28-35, 4249 and 63-70 of the premating period. No effects were observed in the high-dose group.
During the gestation and lactation periods of the F1-generation, no statistically significant effects were observed on food consumption (both
expressed as g/animal/day and g/kg/day). ln conclusion, no treatment-related effects on food consumption were observed.

Sexual maturation:

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

Except for a statistically significant decreased relative weight of the thyroid of the male animals of the mid-dose group, no statistically significant differences were observed between absolute and relative organ weights of male and female animals of the various groups.

Gross pathological findings:

no effects observed

Histopathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Microscopic examination of the sampled organs and tissues did not reveal treatment related histopathological changes. The histopathological changes observed were about equally distributed amongst the different treatment groups or occurred in one or a few animals only. They are common findings in rats of this strain and age or occurred as individual chance findings. Therefore, they were not considered to be related to treatment.

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

>= 1 000 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

viability

sexual maturation

clinical signs

mortality

body weight and weight gain

organ weights and organ / body weight ratios

gross pathology

histopathology: non-neoplastic

Key result

Critical effects observed:

no

Key result

Reproductive effects observed:

no

Conclusions:

ln conclusion, in this study, oral administration of NM-200 Synthetic Amorphous Silica up to 1000 mg/kg body weight had no adverse effect on the reproductive performance of rats or on the growth and development of the offspring into adulthood for two consecutive generations.

Executive summary:

The toxicity potential of NM-200 (a SAS) to reproduction was assessed in rats.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Study duration:

chronic

Species:

rat

Quality of whole database:

reliability 1

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Details on Expert's review:

A weight of evidence analysis shows that the already available information on the developmental and reproductive toxicity of Al3+ and Si(OH)4/SiO2 cover all relevant aspects that are investigated in an EOGRTS for Silicic acid, aluminum sodium salt (CAS 1344-00-9, NAS). Therefore, performing an EOGRTS for Silicic acid, aluminum sodium salt (CAS 1344-00-9, NAS) is not warranted and should not be performed due to animal welfare reasons. Moreover, an increase in Al3+ tissue concentrations is not expected under the conditions of an EOGRTS due to the very low bioavailability of Al3+. Therefore, an EOGRTS with Silicic acid, aluminum sodium salt (CAS 1344-00-9, NAS) will generate uninterpretable results.

Effects on developmental toxicity

Description of key information

The administration of up to 1600 mg/kg bw of the test substance Silicic acid, aluminum sodium salt (CAS 1344-00-9, NAS) to pregnant rats, mice, hamsters, or rabbits for 5 to 13 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

no data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Qualifier:

no guideline followed

Principles of method if other than guideline:

Virgin female rats were mated with young males. Beginning on day 6 of gestation, the females were dosed orally with the test compound (4 dose levels) for 10 days. On day 20 of gestation all dams were sacrificed and examined.

GLP compliance:

no

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as quoted in study report): synthetic silica sodium silicoaluminate (FDA 71-45), from the study report it cannot be ascertained wether a crystalline or amorphous form was used
- Physical state: fine white powder
- Analytical purity: no data

Species:

rat

Strain:

Wistar

Remarks:

albino

Details on test animals or test system and environmental conditions:

- Housing: disposable plastic cages in temperature and humidity-controlled quarters
- Diet and water: ad libitum
- Water (e.g. ad libitum): tap water; ad libitum

Route of administration:

oral: gavage

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

Virgin female rats were mated with young adult males, and observation of the vaginal sperm plug was considered day 0 of gestation.

Duration of treatment / exposure:

exposure from day 6 to day 15 of gestation (10 days)

Frequency of treatment:

daily

Duration of test:

on day 17 all dams were sacrificed

Dose / conc.:

16 mg/kg bw/day

Dose / conc.:

74.3 mg/kg bw/day

Dose / conc.:

345 mg/kg bw/day

Dose / conc.:

1 600 mg/kg bw/day

No. of animals per sex per dose:

not specified

Control animals:

yes, sham-exposed

Details on study design:

positive control: Asperin (250 mg/kg bw/d)

Maternal examinations:

daily for appearance, behavior and food consumption
body weights on GD 0, 6, 11, 15, 20
on GD 20: implantation sites, resorption sites, live and dead fetuses, urogenital tract

Fetal examinations:

body weight, grossly for congenital abnormalities
visceral examination in one third of animals, skeletal defects in the other two third

Mortality:

no mortality observed

Other effects:

no effects observed

Description (incidence and severity):

nidation: no clearly descernible effect

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 600 mg/kg bw/day (nominal)

Basis for effect level:

mortality

other: nidation

Abnormalities:

not examined

Fetal body weight changes:

not specified

Reduction in number of live offspring:

effects observed, non-treatment-related

Description (incidence and severity):

no clearly descernible effect

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

did not differ from the number occuring spontaneously in the sham-treated control

Visceral malformations:

effects observed, non-treatment-related

Description (incidence and severity):

did not differ from the number occuring spontaneously in the sham-treated control

Other effects:

effects observed, non-treatment-related

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 600 mg/kg bw/day (nominal)

Basis for effect level:

reduction in number of live offspring

skeletal malformations

visceral malformations

Abnormalities:

effects observed, non-treatment-related

Key result

Developmental effects observed:

no

The administration of up to 1600 mg/kg (body weight) of the test material to pregnant rats for 10 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.

Conclusions:

Test item showed no maternal or developmental toxicity up to 1600 mg/kg bw/d.

Executive summary:

Female rats were orally administered Sodium silicoaluminate from GD 6 to GD 15 to examine tetratologic effects.

Reference 2

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

no data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Qualifier:

no guideline followed

Principles of method if other than guideline:

Virgin female rabbits were inseminated artificially on day 0. Beginning on day 6, the females were dosed orally with the test compound (4 dose levels) for 13 days. On day 29 all dams were sacrificed and examined.

GLP compliance:

no

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as quoted in study report): synthetic silica sodium silicoaluminate (FDA 71-45), from the study report it cannot be ascertained wether a crystalline or amorphous form was used
- Physical state: fine white powder
- Analytical purity: no data

Species:

rabbit

Strain:

Dutch

Details on test animals or test system and environmental conditions:

- Housing: disposable plastic cages in temperature and humidity-controlled quarters
- Diet and water: ad libitum
- Water (e.g. ad libitum): tap water; ad libitum

Route of administration:

oral: gavage

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

Virgin female rabbits were inseminated artificially with 0.3 ml of diluted semen from a proven donor buck using appr. 20 x 10^6 motile sperm. This was considered day 0.

Duration of treatment / exposure:

exposure from day 6 to day 18 (13 days)

Frequency of treatment:

daily

Duration of test:

on day 29 all dams were sacrificed

Dose / conc.:

16 mg/kg bw/day

Dose / conc.:

74.3 mg/kg bw/day

Dose / conc.:

345 mg/kg bw/day

Dose / conc.:

1 600 mg/kg bw/day

No. of animals per sex per dose:

not specified

Control animals:

yes, sham-exposed

Details on study design:

positive control: 6-aminonicotinamide (2.5 mg/kg on day 9)

Maternal examinations:

daily for appearance, behavior and food consumption
body weights on days 0, 6, 12, 18, 29
on day 29: implantation sites, resorption sites, live and dead fetuses, urogenital tract

Fetal examinations:

body weight, grossly for congenital abnormalities
visceral examination in one third of animals, skeletal defects in the other two third

Mortality:

mortality observed, non-treatment-related

Description (incidence):

no clearly descernible effect

Other effects:

no effects observed

Description (incidence and severity):

nidation: no clearly descernible effect

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 600 mg/kg bw/day (nominal)

Basis for effect level:

mortality

other: nidation

Abnormalities:

not examined

Fetal body weight changes:

not specified

Reduction in number of live offspring:

effects observed, non-treatment-related

Description (incidence and severity):

no clearly descernible effect

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

did not differ from the number occuring spontaneously in the sham-treated control

Visceral malformations:

effects observed, non-treatment-related

Description (incidence and severity):

did not differ from the number occuring spontaneously in the sham-treated control

Other effects:

effects observed, non-treatment-related

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 600 mg/kg bw/day (nominal)

Basis for effect level:

reduction in number of live offspring

skeletal malformations

visceral malformations

Abnormalities:

effects observed, non-treatment-related

Key result

Developmental effects observed:

no

The administration of up to 1600 mg/kg (body weight) of the test material to pregnant rabbits for 13 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.

Conclusions:

Test item showed no maternal or developmental toxicity up to 1600 mg/kg bw/d.

Executive summary:

Female rabbits were orally administered Sodium silicoaluminate from GD 6 to GD 18 to examine tetratologic effects.

Reference 3

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

no data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Qualifier:

no guideline followed

Principles of method if other than guideline:

Virgin female mice were mated with young males. Beginning on day 6 of gestation, the females were dosed orally with the test compound (4 dose levels) for 10 days. On day 17 of gestation all dams were sacrificed and examined.

GLP compliance:

no

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as quoted in study report): synthetic silica sodium silicoaluminate (FDA 71-45), from the study report it cannot be ascertained wether a crystalline or amorphous form was used
- Physical state: fine white powder
- Analytical purity: no data

Species:

mouse

Strain:

CD-1

Details on test animals or test system and environmental conditions:

- Housing: disposable plastic cages in temperature and humidity-controlled quarters
- Diet and water: ad libitum
- Water (e.g. ad libitum): tap water; ad libitum

Route of administration:

oral: gavage

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

Virgin female mice were mated with young adult males, and observation of the vaginal sperm plug was considered day 0 of gestation.

Duration of treatment / exposure:

exposure from day 6 to day 15 of gestation (10 days)

Frequency of treatment:

daily

Duration of test:

on day 17 all dams were sacrificed

Dose / conc.:

16 mg/kg bw/day

Dose / conc.:

74.3 mg/kg bw/day

Dose / conc.:

345 mg/kg bw/day

Dose / conc.:

1 600 mg/kg bw/day

No. of animals per sex per dose:

not specified

Control animals:

yes, sham-exposed

Details on study design:

positive control: Asperin (150 mg/kg bw/d)

Maternal examinations:

daily for appearance, behavior and food consumption
body weights on GD 0, 6, 11, 15, 17
on GD 17: implantation sites, resorption sites, live and dead fetuses, urogenital tract

Fetal examinations:

body weight, grossly for congenital abnormalities
visceral examination in one third of animals, skeletal defects in the other two third

Mortality:

mortality observed, non-treatment-related

Description (incidence):

no clearly descernible effect

Other effects:

no effects observed

Description (incidence and severity):

nidation: no clearly descernible effect

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 600 mg/kg bw/day (nominal)

Basis for effect level:

mortality

other: nidation

Abnormalities:

not examined

Fetal body weight changes:

not specified

Reduction in number of live offspring:

effects observed, non-treatment-related

Description (incidence and severity):

no clearly descernible effect

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

did not differ from the number occuring spontaneously in the sham-treated control

Visceral malformations:

effects observed, non-treatment-related

Description (incidence and severity):

did not differ from the number occuring spontaneously in the sham-treated control

Other effects:

effects observed, non-treatment-related

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 600 mg/kg bw/day (nominal)

Basis for effect level:

reduction in number of live offspring

skeletal malformations

visceral malformations

Abnormalities:

effects observed, non-treatment-related

Key result

Developmental effects observed:

no

The administration of up to 1600 mg/kg (body weight) of the test material to pregnant mice for 10 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.

Conclusions:

Test item showed no maternal or developmental toxicity up to 1600 mg/kg bw/d.

Executive summary:

Female mice were orally administered Sodium silicoaluminate from GD 6 to GD 15 to examine tetratologic effects.

Reference 4

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

no data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Qualifier:

no guideline followed

Principles of method if other than guideline:

Virgin female hamsters were mated with young males. Beginning on day 6 of gestation, the females were dosed orally with the test compound (4 dose levels) for 5 days. On day 14 of gestation all dams were sacrificed and examined.

GLP compliance:

no

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as quoted in study report): synthetic silica sodium silicoaluminate (FDA 71-45), from the study report it cannot be ascertained wether a crystalline or amorphous form was used
- Physical state: fine white powder
- Analytical purity: no data

Species:

hamster

Strain:

other: Golden

Details on test animals or test system and environmental conditions:

- Housing: disposable plastic cages in temperature and humidity-controlled quarters
- Diet and water: ad libitum
- Water (e.g. ad libitum): tap water; ad libitum

Route of administration:

oral: gavage

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

Virgin female hamsters were mated with young adult males, and observation of the vaginal sperm plug was considered day 0 of gestation.

Duration of treatment / exposure:

exposure from day 6 to day 10 of gestation (5 days)

Frequency of treatment:

daily

Duration of test:

on day 14 all dams were sacrificed

Dose / conc.:

16 mg/kg bw/day

Dose / conc.:

74.3 mg/kg bw/day

Dose / conc.:

345 mg/kg bw/day

Dose / conc.:

1 600 mg/kg bw/day

No. of animals per sex per dose:

not specified

Control animals:

yes, sham-exposed

Details on study design:

positive control: Asperin (250 mg/kg bw/d)

Maternal examinations:

daily for appearance, behavior and food consumption
body weights on GD 0, 8, 10, 14
on GD 14: implantation sites, resorption sites, live and dead fetuses, urogenital tract

Fetal examinations:

body weight, grossly for congenital abnormalities
visceral examination in one third of animals, skeletal defects in the other two third

Mortality:

no mortality observed

Other effects:

no effects observed

Description (incidence and severity):

nidation: no clearly descernible effect

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 600 mg/kg bw/day (nominal)

Basis for effect level:

mortality

other: nidation

Abnormalities:

not examined

Fetal body weight changes:

not specified

Reduction in number of live offspring:

effects observed, non-treatment-related

Description (incidence and severity):

no clearly descernible effect

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

did not differ from the number occuring spontaneously in the sham-treated control

Visceral malformations:

effects observed, non-treatment-related

Description (incidence and severity):

did not differ from the number occuring spontaneously in the sham-treated control

Other effects:

effects observed, non-treatment-related

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 600 mg/kg bw/day (nominal)

Basis for effect level:

reduction in number of live offspring

skeletal malformations

visceral malformations

Abnormalities:

effects observed, non-treatment-related

Key result

Developmental effects observed:

no

The administration of up to 1600 mg/kg (body weight) of the test material to pregnant golden hamsters for 5 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.

Conclusions:

Test item showed no maternal or developmental toxicity up to 1600 mg/kg bw/d.

Executive summary:

Female hamsters were orally administered Sodium silicoaluminate from GD 6 to GD 10 to examine tetratologic effects.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Study duration:

subchronic

Species:

other: rat, mouse, hamster, rabbit

Quality of whole database:

reliability 2

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

As neither developmental toxicity with the test substance Silicic acid, aluminum sodium salt (CAS 1344-00-9, NAS) in studies in rats, mice, hamsters, and rabbits nor toxicity to reproduction with the read-across substance silicon dioxide (SAS) was observed, there is no need for classification. This is also confirmed by an expert's review which concluded that extended one-generation reproductive and toxicity studies are predicted to be without a toxicologically relevant response.