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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
05 Sep - 08 Nov 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2021
Report date:
2021

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
22 January, 2001
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
Bayerisches Landesamt für Gesundheit und Lebensmittelsicherheit, Schwabach, Germany
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
449-160-7
EC Name:
-
Cas Number:
116912-64-2
IUPAC Name:
ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River, Sulzfeld, Germany
- Age at study initiation: approx. 11-12 weeks old
- Weight at study initiation: males: 318 - 361 g; females: 194 - 238 g
- Housing: The animals were kept individually in IVC cages (type III H, polysulphone cages) on Altromin saw fibre bedding (except during the pre-mating period when females were kept in groups of two animals and during mating period when two females were paired with one male). During the pre-mating period and after mating, males were housed in groups (2 animals / cage) in IVC cages.
- Diet: Altromin 1324 maintenance diet for rats and mice provided ad libitum
- Water: tap water, sulphur acidified to a pH of approximately 2.8 (drinking water, municipal residue control, microbiological controls at regular intervals) provided ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 55 ± 10
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Dose volume of test item (mL/kg) was calculated as follows:
Test item volume = mL/kg = Dose (g/kg) / density of test item (1.1 g/mL).
Thus, test item volume for the 100, 300 and 1000 mg/kg bw/day dose groups were 0.091, 0.27 and 0.91 mL/kg bw, respectively.
For each animal the individual dosing volume was calculated on the basis of the body weight most recently measured.
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
A dose formulation analysis was not performed in this study as test item was administered as it is.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: Mating was performed using a ratio of 1:2 (male to female).
- Further matings after two unsuccessful attempts: no; after getting 100 sperm positive females, the remaining females and males were discarded without any observations.
- Proof of pregnancy: sperm in vaginal smear referred to as gestation day (GD) 0
Duration of treatment / exposure:
The female animals were treated with the test item or control item between gestation day 5 until gestation day 19.
Frequency of treatment:
daily
Duration of test:
15 days
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
25 females/group
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: Doses were selected based on a dose-range finding study. The highest dose level was chosen with the aim of inducing toxic effects, but not death or severe suffering. Thereafter, a descending sequence of dose levels was selected with a view to demonstrate any dose-related response and a NOAEL.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once a day, preferably at the same time each day; twice daily for mobidity and mortality except on weekends and public holidays when observations were made once daily
- Cage side observations included: spontaneous activity, lethargy, recumbent position, convulsions, tremors, apnoea, asphyxia, vocalisation, diarrhoea, changes in the skin and fur, eyes and mucous membranes (salivation, discharge), piloerection and pupil size. Changes in gait, posture, response to handling as well as the presence of clonic or tonic movements, stereotypes, difficult or prolonged parturition or bizarre behaviour

BODY WEIGHT: Yes
- Time schedule for examinations: Mean body weights were recorded on gestation days 0, 5, 8, 11, 14, 17, and 20 except for one female of the control group (no. 23), which was weighed on GDs 0, 6, 9, 12, 15, 17 and 20.

FOOD CONSUMPTION: Yes
- Food consumption was measued on gestation days 5, 8, 11, 14, 17 and 20.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #20
- Organs examined: The uteri were removed and the pregnancy status of the dams was confirmed. Uteri that appeared non-gravid were further examined by staining with 10% ammonium sulphide solution to confirm the non-pregnant status. Each gravid uterus with the cervix was weighed. The number of corpora lutea was counted for pregnant animals. The uterine contents were examined for embryonic or foetal deaths as well as the number of viable foetuses. The degree of resorption (late and early) was confirmed in order to help estimate the relative time of death of the conceptus. The position and number of foetuses in each uterine horn was also recorded.
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 early resorptions: Yes
- Number of late resorptions: Yes
Blood sampling:
- Plasma: No
- Serum: No
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: Craniofacial examination of the heads of the foetuses used for the soft tissue examination of the first 20 litters per group were performed or internal structure including the eyes,
brain, nasal passage and tongue by razor blade serial sectioning technique
Statistics:
A statistical assessment of the results of the body weight, food consumption was performed by comparing values of dosed with control animals using a one-way ANOVA and a post-hoc Dunnett Test. Foetal evaluation parameters like external, visceral, craniofacial and skeletal parameters were analysed using Fisher’s exact test.
Historical control data:
Historical control data were included for uterine data, litter weight data, and external, visceral, skeletal, and cranofacial fetal findings.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Low incidences of alopecia on various body parts were noted in isolated females of thel dose groups and the control group (2 control, 1 each from LD (low dose) and HD (high dose) and 2 from MD (mid dose). There was also crust on snout in one female of the LD and abnormal breathing observed in one female of the MD group. Moving the bedding in one MD and 2 HD and increased salivation in 2 HD group females on a few treatment days were observed. As the moving the bedding was noted mainly immediately after administration and just for a short period, this transient sign was considered to be a sign of local reaction to the test item rather than a systemic adverse effect. All clinical signs observed in terminally sacrificed females were incidental or non adverse in nature.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
No mortality occurred during the treatment period of this study and all animals survived until terminal sacrifice.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The mean body weight remained unaffected and increased with the progress of the study in the control, LD, MD and HD groups. There was no effect on body weight gain (GDs 0-20) observed in the treatment groups when compared to the controls. The group mean body weight and body weight gain of the treatment groups was comparable to the control group throughout the study period and was within the normal range of variation for this strain.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
In correlation to the body weight and body weight gain, food consumption in the LD, MD and HD groups was comparable to the controls. There was no statistically significant effect observed on food consumption in treatment groups throughout the study period when compared with the controls.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Endocrine findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No test item-related effects of toxicological relevance or statistical significance were noted for gravid uterus weight.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No gross pathological changes of toxicological relevance were observed during the macroscopic examination of the females of the control, LD, MD and HD groups.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
None of the females showed signs of abortion prior to the scheduled sacrifice.
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
No test item-related effects of toxicological relevance or statistical significance were noted for percent pre-and post-implantation loss.
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Description (incidence and severity):
No test item-related effects of toxicological relevance or statistical significance were noted for early and late resorptions.
Dead fetuses:
no effects observed
Description (incidence and severity):
No dead foetuses were noted in any of the groups.
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
Successful mating resulted in 24/25 pregnancies in the MD and HD group compared to 25/25 pregnancies in the control and LD group. The marginally low pregnancy rates (no.of pregnancies / no. of females mated or sperm-positive x 100) of 96% in the MD and HD
group compared to 100% in the LD and control group was considered to be a biological variation and well above standard pregnancy rate of minimum 80% in rat.
Details on maternal toxic effects:
No test item-related effects of toxicological relevance or statistical significance were noted for any of prenatal data parameters like terminal body weight, gravid uterus weight, adjusted maternal weights, number of corpora lutea and implantation sites.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: no adverse clinical signs, no treatment-related effect on body weight, food consumption, prenatal data parameters and gross pathology

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
There were no test item-related effects of toxicological relevance or statistical significance observed for any litter data parameters like mean foetus weight (individual and litter basis), male and female foetus weight (individual basis), the total, male and female litter weight (litter basis) in any of the treatment groups when compared with the controls.
Reduction in number of live offspring:
not examined
Description (incidence and severity):
No test item-related effects of toxicological relevance or statistical significance were noted for live foetuses and number of male and female foetuses.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
No test item-related effects of toxicological relevance or statistical significance were noted for sex ratio.
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
There were no test item-related effects of toxicological relevance or statistical significance observed for any litter data parameters like mean foetus weight (individual and litter basis), the total, male and female litter weight (litter basis) in any of the treatment groups when compared with the controls.
Anogenital distance of all rodent fetuses:
not examined
Changes in postnatal survival:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
There were no external abnormalities considered to be of toxicological relevance in any of the dose groups. Statistical analysis of data revealed no significant differences compared to the control group.
Low incidences of red spot on snout and lower mandible (1 in Control) and haematoma on tail (1 in MD) were noted in isolated females of the control group and MD group without dose dependency. As these findings were observed in single foetuses, they were considered to be incidental in nature and unrelated to the treatment.
Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
Skeletal examination of the Alcian blue and Alizarin red stained foetuses revealed a range of findings which occurred at an incidence generally comparable to or slightly lower or higher in the dose groups when compared to the control group. Most of the skeletal
findings observed in HD group were within the historical control data range.
A statistically significant decrease in litter incidence for supernumerary rib cartilage (14th) (L) and 14th full rib (L) in LD, hindlimb phalanges increased ossification in LD and HD, compared to the control group were considered to be incidental as frequencies were even less in numbers compared to the controls. Therefore, these findings are not to be considered as treatment-related and solely spontaneous in nature.
Slightly higher litter incidences, but without achieving statistical significance for incomplete ossification of frontal (B) (25% compared to 15% in controls), interparietal (85% compared to 65% in controls), parietal (B) (55% compared to 30% in controls), squamosal (B and R) (15-25% compared to 0-5% in controls), zygomatic arch (B) (15% compared to 5% in controls), femur (B) (15% compared to 5% in controls), basioccipital with small hole (15% compared to 5% in controls), scapula bent (B) (5% compared to 0% in control), scapula bent (R) (20% compared to 0% in control), branched xiphoid cartilage (65% compared to 55% in control), left 14th rudimentary rib (65% compared to 50% in control), wavy ribs (65% compared to 55% in controls), rudimentary 7th cervical rib (5-15% compared to 0% in control) misshapen humerus (20% compared to 5% in controls), unossified forelimb metacarpals (55% compared to 30% in controls) and pelvic girdle (B) caudal shift (20% compared to 10% in control) were observed in the HD group when compared to the concurrent control group.
The observed reduced ossification without achieving statistical significance of few bones in the HD group that normally exhibit rapid ossification at the last days of gestation indicates a generalised skeletal delay in the HD group. Generally slightly delayed ossification is not regarded to persist postnatally and not associated with long-term consequences on survival, general growth and development and therefore is not considered to be adverse.
Rudimentary/short ribs are considered as transient abnormalities. In contrast, full/long ribs are considered permanent and may cause health effects in humans; however, postnatal consequences in rats are unknown but are assumed to be minimal.This finding
was not considered to be treatment-related but spontaneous in nature.
Wavy ribs and bent scapulae are common findings in rodent studies and are considered to be postnatally reversible. Thus, wavy ribs are classified as variations and were not considered as an adverse effect of the treatment with the test item.
There was no statistical significance and no indication of a test item-related trend in the type and/or incidences of other skeletal findings and they were therefore considered to be spontaneous in nature.
Visceral malformations:
effects observed, treatment-related
Description (incidence and severity):
Visceral findings observed in the dose groups were at frequencies generally comparable to or in some cases slightly higher or lower in frequency compared to controls. As observed findings were either minor variations and/or due to a lack of dose dependency
and consistency, no toxicological significance can be attributed to these findings and they were considered to be spontaneous in nature.
There was statistically significantly higher litter incidence of umbilical artery transposed in LD and HD groups when compared to the control group. However, values were well within historical control data range (85.71%).
Few visceral findings like renal pelvis dilated (R) in HD, ureter (L) convoluted in all treatment groups and ureter (B) dilated in LD and HD group litter and or individual incidences were observed in higher numbers without achieving statistical significance when compared to controls but well within historical control data range (renal pelvis dilated (R)- 47.37%, ureter (L) convoluted- 73.91%, ureter (B) dilated- 87.50%). There was discolouration of organs like liver and adrenal gland observed in few foetuses of treatment and control group without dose dependency. Discolouration of organs was considered likely to reflect the consequence of a functional disorder and thus not strictly as developmental anomalies. Due to lack of dose dependency and consistency, these discolouration findings were not considered as toxicologically relevant.
Dilated/convoluted ureter and dilated renal pelvis are common finding in rodent studies and is classified as a variation as it is transient and likely to be postnatally reversible. Furthermore, values were within the historical control data so that no toxicological relevance was attributed to it.
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
Craniofacial examination by razor blade serial sectioning technique revealed few predominant findings (subcutaneous edema of head, retinal fold, slightly dilated 3rd ventricle and dilated lateral ventricle) at low frequencies generally comparable to or in some cases slightly higher or lower in frequency in the dose groups compared to the controls. These findings were considered to be spontaneous in nature and not related to the treatment with the test item. Statistical analysis of the data revealed no statistical significance of any of the findings.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no treatment-related and toxicologically relevant effect on litter weight data, external, skeletal, visceral or craniofacial foetal findings

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
In an OECD 414 study conducted in compliance with GLP, no treatment-related effect on body weight, food consumption, prenatal data parameters and gross pathology of terminally sacrificed females was observed up to highest dose tested (1000 mg/kg bw/day). No mortality occurred during the treatment period of this study and all clinical signs observed in terminally sacrificed females were incidental or non adverse in nature. Furthermore, no treatment-related and toxicologically relevant effects on litter weight data, external, visceral or craniofacial foetal findings were observed in the high dose group. The NOAEL for both maternal toxicity and foetal toxicity of the test substance in this study is considered to be >=1000 mg/kg bw/day.