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Diss Factsheets

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018

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
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
449-160-7
EC Name:
-
Cas Number:
116912-64-2
Molecular formula:
C7H18N2O4Si C8H20N2O4Si C9H22N2O4Si C10H24N2O4Si
IUPAC Name:
[3-(ethoxydimethoxysilyl)propyl]urea; [3-(trimethoxysilyl)propyl]urea; {3-[diethoxy(methoxy)silyl]propyl}urea

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River, 97633 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: 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:
A dose formulation analysis was not performed in this study as test item was administered as it is.
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
- 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

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least once a day, preferably at the same time each day

BODY WEIGHT: Yes
- Time schedule for examinations: Mean body weights were recorded on gestation days 0, 5, 8, 11, 14, 17, and 20.

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: The uteri were removed, weighed with the cervix, 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. 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
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
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.
Indices:
Pre-implantation loss (%); post-implantation loss (%); early, late, and total resorptions
Historical control data:
Historical control data were included for uterine data, litter weight, and external, visceral, skeletal, and cranofacial fetal findings.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
Low incidences of alopecia were noted in isolated females from all dose groups including the control group (2 controls, 1 each from low- and high-dose group and 2 from the mid-dose group). There was also crust on snout and abnormal breathing observed in one each mid- and high-dose group female. Moving the bedding in one low-dose, 2 high-dose and increased salivation in 2 high-dose group females on a few treatment days were observed. Moving the bedding was a transient sign and was considered to be a 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.
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
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
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
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

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 pregnancy duration:
no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
not examined

Effect levels (maternal animals)

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

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
The following statistically significant findings were noted in litter indicence: decreased supernumerary rib cartilage (14th) (L) and 14th full rib (L) at 100 mg/kg bw/day; and increased hindlimb phalanges ossification at 100 and 1000 mg/kg bw/day. These changes 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.

In the high-dose group, slightly higher litter incidences, but without achieving statistical significance were noted 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).

The observed reduced ossification without achieving statistical significance of few bones at 1000 mg/kg bw/day that normally exhibit rapid ossification during the last days of gestation indicates a slight generalised skeletal delay at 1000 mg/kg bw/day. 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.

Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
There was statistically significantly higher litter incidence of umbilical artery transposed in low- and high-dose groups when compared to the control group; however, values were well within historical control data range. An increased incidence either for litters and/or for individuals were observed for a few of the visceral findings including renal pelvis dilated (R) at the high dose, ureter (L) convoluted at all doses, and ureter (B) dilated at the low and high dose; these increases occurred at high numbers but did not achieve statistical significance when compared to controls and were 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.
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.

Effect levels (fetuses)

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

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
In an OECD 414 study conducted in compliance with GLP, no effects of ureidopropyltrialkoxysilane on females were found at dose levels up to 1000 mg/kg body weight/day. Regarding developmental toxicity no adverse effects were observed in foetuses up to the highest dose tested. The NOAEL for maternal toxicity and embryo-foetal toxicity of ureidopropyltrialkoxysilane in this study is considered to be 1000 mg/kg body weight/day.