Silicic acid, aluminum magnesium sodium salt

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Sep. 14, 2000 - 2002

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

Test material ist different from reference substance but comparable, see chapter 13, attachment 'Analogue Approach Justification'

Cross-reference

Reason / purpose for cross-reference:

read-across: supporting information

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2015

Report date:

2015

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Version / remarks:

2001-01-22

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)

Version / remarks:

Aug. 1998

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

Silicon dioxide

EC Number:

231-545-4

EC Name:

Silicon dioxide

Cas Number:

7631-86-9

Molecular formula:

O2Si

IUPAC Name:

Silicon dioxide

Test material form:

solid: nanoform, no surface treatment

Details on test material:

Precipitated, CAS-No.: 112926-00-8, Surface area / BET [m2/g]: 160

Specific details on test material used for the study:

NM-200 (synthetic amorphous silica (SAS))

Test animals

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

supplied by Charles River Laboratories, Research Models and Services, Germany GmbH; 10-12 weeks old, individually caged, feed: Kilba and bottled drinking water ad libitum, 20-24 °C, 30-70 % humidity, 12 h light/dark

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: highly deionized water containing 10% FBS

Details on exposure:

To prepare the dose formulations, the specific amount of test substance (1, 3 and 10 g) was weighed and placed into a calibrated glass beaker, topped up to 90 ml with highly deionized water and gently homogenized manually.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The analyses of the test-substance preparations were carried out at Competence Center Analytics, BASF SE, Ludwigshafen, Germany, not in full compliance with GLP under the supervision of Dr. W. Wohlleben.
The test substance is assumed to be stable in the formulation for at least the time of administration.
Samples of the test substance preparations were sent to the analytical laboratory twice during the study period (at the beginning and towards the end) for verification of the size stability of the test material in the vehicle.

Details on mating procedure:

After an acclimatization period of at least 5 days, 1 - 2 untreated female rats were mated with one untreated male animal of the same breed. The male mating partners were kept under the same conditions (air conditioning, feed, water) as the female rats of this study.
Mating took place from about 15:30 h to about 7:30 h on the following day. If sperm were detected microscopically in a vaginal smear in the morning, the female was considered impregnated and transferred into the study. This day was referred to as gestation day 0 (GD 0, beginning of the experimental phase) and the following day as GD 1.

Duration of treatment / exposure:

GD 6-19

Frequency of treatment:

once daily

Duration of test:

until GD 20

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

100 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

300 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

1 000 mg/kg bw/day (nominal)

No. of animals per sex per dose:

25 (females only)

Control animals:

yes, concurrent vehicle

Details on study design:

The test substance was administered as an aqueous solution to groups of 25 presumed pregnant female Wistar rats by gavage at doses of 100; 300 and 1000 mg/kg body weight/day (mg/kg bw/d) on gestation days (GD) 6 through 19.

Examinations

Maternal examinations:

Food consumption and body weights of the animals were recorded regularly throughout the study period. The state of health of the animals was checked each day.

Fetal examinations:

On GD 20, all females were sacrificed and assessed by gross pathology (including weight determinations of the unopened uterus and the placentae). For each dam, corpora lutea were counted and number and distribution of implantation sites (differentiated between resorptions, live and dead fetuses) were determined. The fetuses were removed from the uterus, sexed, weighed and further investigated for external findings. Thereafter, one half of the fetuses of
each litter were examined for soft tissue findings and the remaining fetuses for skeletal (inclusive cartilage) findings.

Statistics:

DUNNETT-test: Food consumption, body weight, body weight change, corrected body weight gain (net maternal body weight change), carcass weight, weight of unopened uterus, number of corpora lutea, number of implantations, number of resorptions, number of live fetuses, proportions of preimplantation loss, proportions of postimplantation loss, proportions of resorptions, proportion of live fetuses in each litter, litter mean fetal body weight, litter mean placental weight
FISHER'S EXACT test: Female mortality, females pregnant at terminal sacrifice, number of litters with fetal findings
WILCOXON-test: Proportions of fetuses with malformations, variations and/or unclassified observations in each litter

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Maternal developmental toxicity

Number of abortions:

no effects observed

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

no effects observed

Early or late resorptions:

no effects observed

Dead fetuses:

no effects observed

Changes in number of pregnant:

no effects observed

Effect levels (maternal animals)

Key result

Dose descriptor:

NOAEL

Effect level:

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

Basis for effect level:

behaviour (functional findings)

body weight and weight gain

changes in number of pregnant

clinical signs

dead fetuses

early or late resorptions

food consumption and compound intake

gross pathology

mortality

number of abortions

organ weights and organ / body weight ratios

pre and post implantation loss

total litter losses by resorption

Maternal abnormalities

Key result

Abnormalities:

no effects observed

Results (fetuses)

Fetal body weight changes:

no effects observed

Changes in sex ratio:

no effects observed

External malformations:

effects observed, non-treatment-related

Description (incidence and severity):

External malformations were recorded for one fetus each in the low- and high-dose group (100 and 1000 mg/kg bw/d). Both fetuses concerned had multiple malformations. In one fetus the mandibular micrognathia mirrored the severely malformed skull bones found during skeletal examination; these findings are not considered independent of each other. Both findings were considered to be spontaneous in nature and without a relation to dosing. The total incidence of external malformations in treated animals did not differ significantly from that of the control group.

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

Skeletal malformations were noted in single fetuses of test groups 0, 1 and 3 (0, 100 and 1000 mg/kg bw/d). Although some of these findings are not in the historical control data, each of them affected individual fetuses and neither statistically significant differences between the test groups nor a dose-response relationship was observed. The overall incidences of skeletal malformations were comparable to those found in the historical control data.

Visceral malformations:

effects observed, non-treatment-related

Description (incidence and severity):

Three soft tissue variations, i.e. short innominate, enlarged atrial chamber of the heart and uni- or bilateral dilation of renal pelvis, were detected. These findings observed in 1 to 5 fetuses of 1 to 4 litters in test groups 0, 1, 2 and 3 (0, 100, 300 and 1000 mg/kg bw/d) showed no dose-response relationship. The observable differences between the groups reflect the usual fluctuation for this parameter and were clearly within the range of the historical control data

Effect levels (fetuses)

Key result

Dose descriptor:

NOAEL

Effect level:

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

Sex:

male/female

Basis for effect level:

changes in sex ratio

fetal/pup body weight changes

external malformations

skeletal malformations

visceral malformations

Fetal abnormalities

Key result

Abnormalities:

effects observed, non-treatment-related

Localisation:

external: eye

external: face

skeletal: skull

skeletal: pelvic girdle

visceral/soft tissue: cardiovascular

Overall developmental toxicity

Key result

Developmental effects observed:

yes

Lowest effective dose / conc.:

0 mg/kg bw/day (actual dose received)

Treatment related:

no

Relation to maternal toxicity:

developmental effects in the absence of maternal toxicity effects

Dose response relationship:

no

Relevant for humans:

no

Any other information on results incl. tables

No treatment related devopmental toxicity was observed. The observed effects were also seen in the control group (0 mg/kg bw/d).

Applicant's summary and conclusion

Conclusions:

Under the conditions of this prenatal developmental toxicity study, the oral administration of NM-200 Synthetic Amorphous Silica to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) elicited no test substance-related adverse effects at any tested dose.
In conclusion, the no observed adverse effect level (NOAEL) for maternal toxicity and prenatal developmental toxicity is 1000 mg/kg body weight/day. No adverse maternal and fetal findings of toxicological relevance were evident at any dose.

Executive summary:

The developmental toxicity of NM-200 was evaluated in rats.