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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Sep. 14, 2000 - 2002
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'
Reason / purpose for cross-reference:
read-across: supporting information

Data source

Reference Type:
Report date:

Materials and methods

Test guidelineopen allclose all
according to guideline
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
according to guideline
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Version / remarks:
Aug. 1998
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Chemical structure
Reference substance name:
Silicon dioxide
EC Number:
EC Name:
Silicon dioxide
Cas Number:
Molecular formula:
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

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
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:
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 / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
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.


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.
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
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:
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
number of abortions
organ weights and organ / body weight ratios
pre and post implantation loss
total litter losses by resorption

Maternal abnormalities

Key result
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:
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Basis for effect level:
changes in sex ratio
fetal/pup body weight changes
external malformations
skeletal malformations
visceral malformations

Fetal abnormalities

Key result
effects observed, non-treatment-related
external: eye
external: face
skeletal: skull
skeletal: pelvic girdle
visceral/soft tissue: cardiovascular

Overall developmental toxicity

Key result
Developmental effects observed:
Lowest effective dose / conc.:
0 mg/kg bw/day (actual dose received)
Treatment related:
Relation to maternal toxicity:
developmental effects in the absence of maternal toxicity effects
Dose response relationship:
Relevant for humans:

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

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.