Triethoxypropylsilane

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

12 May - 20 Aug 2020

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:

2018

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

Bayerisches Landesamt für Gesundheit und Lebensmittelsicherheit, Schwabach, Germany

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Triethoxypropylsilane

EC Number:

219-842-7

EC Name:

Triethoxypropylsilane

Cas Number:

2550-02-9

Molecular formula:

C9H22O3Si

IUPAC Name:

triethoxy(propyl)silane

Test animals

Species:

rat

Strain:

Wistar

Remarks:

Crl:WI (Han)

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, Sulzfeld, Germany
- Age at study initiation: female: approx. 11-12 weeks old; male: between 12 weeks and not older than 24 weeks
- Weight at study initiation: males: 316 - 370 g, females: 197 - 256 g
- Fasting period before study: no
- Housing: individually in IVC cages (type III H, polysulphone cages) on Altromin saw fibre bedding (except during the pre-mating period when females will be kept in groups of two animals and during mating period when two females will be paired with one male); the pregnant females were provided with nesting material towards the end of the pregnancy (e.g. at GD 18).
- Diet: Altromin 1324 maintenance diet for rats and mice, ad libitum
- Water: tap water, sulphur acidified to a pH of approximately 2.8, 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:

corn oil

Remarks:

dried and deacidified

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: The test item was weighed into a tared plastic vial on a suitable precision balance and the vehicle will be added to give the appropriate final concentration of the test item. The formulation was vortexed and/or stirred until visual homogeneity is achieved. After homogenization the formulation was overlaid with argon to prevent instability caused by repeated contact of the test item formulation with air.
Based on the results of stability testing (Eurofins Munich Study No. 192760), the test item formulations were prepared fresh at least once every 11 days (within the stability time frame). The prepared formulations were stored protected from light and air at room temperature.

VEHICLE
- Justification for use and choice of vehicle: The vehicle was selected as suggested by the sponsor based on the test item’s characteristics and testing guideline.
Corn oil was filtered through a mixture of activated silica gel 60 and aluminium oxide (1:1, volume/volume), which had been filled into a glass chromatography column to three quarters of its height. For filtering, a vacuum of 75 mbar was applied. The dried and deacidified vehicle was overlaid with argon and stored until usage.
- Concentration in vehicle: 25, 75 250 mg/mL
- Amount of vehicle (if gavage): 4 mL/kg bw
- Lot/batch no.: MKCK6411

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Before the beginning of the treatment period, formulation samples were prepared and analysed in order to obtain knowledge about their stability and homogeneity of the test item in the selected vehicle at Eurofins Munich as part of a separate GLP study (Eurofins Munich Study No. 192760).
Study pre start stability analysis was included on the samples from high-dose and low-dose groups and the investigation was made for 0 h, 6 h (RT), 10 days (RT), 10 days (2-8 °C) and 10 days (-15 to -35 °C).
A prestart homogeneity investigation was carried out on the samples collected from various levels (top, middle and bottom) of high-dose and low-dose groups.
As the test item was shown to be homogenous according to Eurofins Study No. 192760 (after 30 min without stirring), additional samples were not collected during the study for the investigation of homogeneity and only samples were taken for confirming substance concentration only during the first and last weeks of the study for all doses (8 samples in total).
The mean recoveries observed for the low-dose group were between 97.8% and 98.0% of the nominal value, between 99.6% and 100.2% for the mid-dose group and between 99.0% and 100.4% of the nominal value for the high-dose group. The mean recoveries observed in the low-, mid- and high-dose groups were 97.9%, 99.9%, and 99.7% of the nominal concentration, respectively.
Nominal concentrations were confirmed for all dose groups, as measured concentrations were within the acceptance criterion of 10%.

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:2
- Length of cohabitation: not reported
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

Day 5-19 of gestation

Frequency of treatment:

daily, 7 days/week

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

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

Remarks:

low dose (LD)

Doses / concentrations 2

Dose / conc.:

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

Remarks:

mid dose (MD)

Doses / concentrations 3

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

Remarks:

high dose (HD)

No. of animals per sex per dose:

control group: 25
low-, mid- and high-dose group: 23

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Dose levels are based on a dose range finding study (Eurofins Study No. 192757). In this study, pregnant Wistar rats were treated with the test item triethoxy(propyl)silane at dose levels of 100, 300 and 1000 mg/kg bw/day administered on GD 5 to 19 and results indicated that the test item did not have any treatment related maternal and fetal toxicological effects up to the highest dose tested at 1000 mg/kg bw/day.The highest dose level is chosen with the aim of inducing toxic effects, but not death or severe suffering. Thereafter, a descending sequence of dose levels is selected with a view to demonstrate any dose-related response and a NOAEL.

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: General clinical observations were made at least once a day, preferably at the same time each day, except for animal nos. 61 (300 mg/kg bw/day), 93 (control) and 94 (control), for which the clinical signs were not made on GD 0, on GD 4 and on GDs 4 and 11, respectively. Twice daily all animals were observed for morbidity and mortality except on weekends and public holidays when observations are made once daily.
- Cage side observations checked: 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: Prior to the start of the mating a detailed clinical observation was made outside the home cage.

BODY WEIGHT: Yes
- Time schedule for examinations: All animals were weighed once before initiation of pairing to ensure that the body weights were within ± 20% variation. The sperm positive females were weighed on GD 0, 5, 8, 11, 14, 17 and 20. Males were not be weighed in this study except once before initiation of pairing.

FOOD CONSUMPTION: Yes
- Food consumption of sperm positive females was measured on GD 5, 8, 11, 14, 17 and 20. Food consumption was not measured for males during the entire study or for both male and females during the mating period.


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: At the time of termination or death during the study, the dam (presumed pregnant female) was examined macroscopically for any structural abnormalities or pathological changes which may have influenced the pregnancy. Any macroscopic findings were preserved in 4% neutral-buffered formaldehyde.
Immediately after the termination or as soon as possible after death, the uteri (with cervix) 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.
Thyroid/parathyroid glands from all dams were preserved in 4% neutral-buffered formaldehyde. The weight of thyroid/parathyroid glands was measured after 24 hours fixation.

OTHER: Thyroid hormones levels from samples from all dams were assessed at the end of the treatment prior to or as part of the sacrifice of the animals. At termination, blood samples were collected from the abdominal aorta in serum separator tubes and obtained serum were stored under appropriate conditions. Serum samples were assessed for thyroid hormone levels (T3, T4, TSH) using ELISA.

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:

Blood from the abdominal aorta of the animals was collected in serum separator tubes for evaluation of thyroid hormones.

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter

Statistics:

A statistical assessment of the results of the body weight and food consumption will be performed by comparing values of dosed animals with control animals using a one-way ANOVA and a post-hoc Dunnett Test. Results of absolute and relative organ weights, thyroid hormones and fetal evaluation parameters like external, visceral, craniofacial and skeletal parameters will be statistically analysed by comparing values of dosed with control animals using either a parametric one-way ANOVA and a post-hoc Dunnett Test or a non-parametric Kruskal-Wallis Test and a post-hoc Dunn’s Test, based on the results of homogeneity and normality tests. The statistics will be performed with GraphPad Prism V.6.01 software or Ascentos 1.3.4 software (p<0.05 is considered as statistically significant).

Historical control data:

Historical control data were used to analyze anogenital distance.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Overall, the clinical signs were observed in 1/25 females of the control, 2/23 females of the LD, 3/23 females of the MD and 12/23 females of the HD groups.
Females of the control, LD and MD group showed hairless area and scratches/cuts as clinical signs (control female no. 19: hairless area; LD females nos. 24, 34: hairless area; MD female no. 55: hairless area, female no. 58: scratches/cuts, female no. 67: hairless area and scratch/ cut). Also, one HD female (no. 91) showed a hairless area. These clinical signs are found to be incidental in nature and not test item-related.
Animal no. 72 (HD), showed slight piloerection on GDs 14-15. Slight to moderate piloerection was observed in female no. 86 (HD) on GDs 19-20. On GD 17-19, animal no. 80 (HD) showed moderately reduced spontaneous activity. Slightly to moderately increased salivation was observed in females of the HD group towards the end of the treatment period (females nos. 74, 75, 76, 77, 87, 88 and 89). Moving the bedding occasionally occurred in 3 animals of the HD group (females nos. 74, 89 and 92) for 1-2 days each. These clinical signs
occurred in timely relation to dose administration. Thus, they were considered to be local effects of the test item formulation and/or attributed to discomfort of the animals during the oral administration.
The clinical signs of moving the bedding, increased salivation, reduced spontaneous activity and piloerection were only observed in the HD group. These are considered to be test-item related local effects.

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

No test item-related mortality was observed during the study period and all females survived until the end of the study.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

The mean body weight was not affected by the test item treatment and all pregnant females gained body weight during the progress of the study.

There were slight decrease or increase in mean body weight gain in the treated groups during the treatment period when compared to control without any dose dependency or statistical significance. HD females showed slight decrease in mean body weight gain on days 5-8 (27.45% below control) and on days 14-17 (11.13% below control) when compared to the control. Overall, during the treatment period on GDs 5-20, there were no test item related effects on mean body weight gain.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Food consumption was comparable between test item-treated groups and the control group throughout the study period. Mean food consumption was not affected by treatment with the test item. No statistical significance was observed in any of the treated groups when compared to control.

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:

effects observed, non-treatment-related

Description (incidence and severity):

Statistical analysis of post-fixed thyroid/parathyroid weights from all dams revealed no statistically significant or toxicologically relevant effect on the absolute and relative (to body weight) thyroid/parathyroid weights of the dose groups when compared to the control.

No significant differences in uterine weight were observed between the control and the treatment groups. The slightly lower uterine weight of MD and HD females (compared to the control [%]: MD: -6.223, HD: -10.207) might result from a slightly reduced mean foetus number per female (control 11.5, LD 11.6, MD 10.8, HD 11.0) and a reduced mean foetus weight (control 3.8 g, LD 3.7 g, MD 3.6 g, HD 3.4 g).

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

No test item-related macroscopic finding was observed at necropsy. One low-dose animal showed a dilatation of the left renal pelvis and a dilatation of the left ureter which are considered to be incidental.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

There were no test item-related findings at histopathological evaluation of the thyroid glands and parathyroid in any of the treated groups.

Histopathological findings: neoplastic:

not examined

Other effects:

no effects observed

Description (incidence and severity):

In all terminally sacrificed females, no statistically significant or toxicologically relevant effect was observed on group mean T3, T4 and TSH hormone levels and values were comparable to the control.

Maternal developmental toxicity

Number of abortions:

no effects observed

Description (incidence and severity):

No female showed any signs of abortion or premature delivery prior to the scheduled sacrifice.

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

Treatment with the test item had no toxicologically relevant effect on prenatal data including pre- or post-implantation loss when comparing test item-treated groups to the control group.

Total litter losses by resorption:

no effects observed

Description (incidence and severity):

Treatment with the test item had no toxicologically relevant effect on prenatal data including total litter losses by resorption when comparing test item-treated groups to the control group.

Early or late resorptions:

no effects observed

Description (incidence and severity):

Treatment with the test item had no toxicologically relevant effect on prenatal data including early or late resorptions when comparing test item-treated groups to the control group.

Dead fetuses:

no effects observed

Description (incidence and severity):

Dead fetuses were not observed 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 18/25 pregnancies in the control group, 19/23 pregnancies in the LD group, 18/23 pregnancies in the MD group and 18/23 pregnancies in the HD group.

Other effects:

not examined

Effect levels (maternal animals)

Key result

Dose descriptor:

NOAEL

Remarks:

maternal

Effect level:

>= 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: No adverse effects observed.

Maternal abnormalities

Key result

Abnormalities:

no effects observed

Results (fetuses)

Fetal body weight changes:

effects observed, treatment-related

Description (incidence and severity):

The mean male (10.7% below control) and female (9.4% below control) fetal weights were statistically significantly reduced in the HD group when compared to the control (male fetal weight: control 3.81 g, HD 3.40 g; female foetal weight: control 3.63 g, HD 3.29 g). No statistical significant changes were observed in the LD and MD groups. The slight and statistically significant reduction in the foetal body weight in HD groups (on foetal basis) are considered to be test item related effects.

Reduction in number of live offspring:

no effects observed

Description (incidence and severity):

There was no test item-related reductions in the number of live offspring in any dose group.

Changes in sex ratio:

no effects observed

Description (incidence and severity):

No statistically significant effect was observed on the sex ratio of foetuses.

Changes in litter size and weights:

no effects observed

Description (incidence and severity):

No statistically significant effect was observed on the number of male and female foetuses per pregnant female.

Anogenital distance of all rodent fetuses:

effects observed, non-treatment-related

Description (incidence and severity):

There was no statistically significant difference of the anogenital distance (AGD) and relative AGD of male fetuses of the LD and HD groups and in female fetuses of the all dose groups observed when compared to the control group.

Male fetuses of the mid-dose group showed a statistically significantly higher AGD and relative AGD compared to the control (Males: AGD: control 2.61 mm; MD 2.74 mm; relative AGD: control 1.68; MD 1.77). There was no dose dependency, as this was only observed in male fetuses of the mid-dose group. All values were within the historical control values of this strain. Hence, this was not considered to be a test item-related effect.

All male foetuses were analysed for indication of incomplete testicular descent/cryptorchidism and the evaluation revealed completion of testicular descent (abdominal) in all male foetuses from all groups.

Changes in postnatal survival:

not examined

External malformations:

effects observed, non-treatment-related

Description (incidence and severity):

There was no test item-related external abnormalities observed in any of the fetuses of treated groups.

One fetus of the mid-dsoe group showed a hematoma at the hind limb and one fetus of the high-dose group showed a generalized edema. These were considered to be incidental.

Skeletal malformations:

effects observed, treatment-related

Description (incidence and severity):

Skeletal examination of the Alizarin red stained foetuses revealed a range of findings in all groups including the control.
As usual for foetuses at the stage of GD 20 incomplete ossification or unossified bones were seen in several bones of several litters in all experimental groups including the control. Mostly bones of the skull, sternum, limbs, and vertebra were affected by variations in the status of expected ossification in terms of incomplete ossification, irregular ossification, unossification or increased ossification distributed throughout all groups. However, in this study a trend towards a test item-related incomplete ossification and unossification of several bones was observed which resulted in statistically significantly higher foetal incidences of incomplete ossification and unossification of numerous bones in the HD group. In many findings, also the incidences for MD and/or LD litters were slightly, but not statistically significantly higher than in the control litters. This indicates a dose-dependency. The test item-related effects found in the skeletal examination are considered to be a secondary effect to the lower foetal weight observed in this study.
Bones showing statistically significantly higher litter incidence of incomplete ossification in the HD compared to the control group were 2nd sternebra (affected litters: 13 compared to 4; affected foetuses per litter [%]: 24.91 compared to 4.58), humerus of the forelimb (upper extremity; affected litters: 13 compared to 2; affected foetuses per litter [%]: 37.04 compared to 1.72), sacral arch(es) of the vertebra (lower extremity; affected litters: 9 compared to 1; affected foetuses per litter [%]: 21.33 compared to 0.79), caudal arch(es) of the vertebra (affected litters: 9 compared to 1; affected foetuses per litter [%]: 20.40 compared to 0.79), frontal skull (head-neck; affected litters: 13 compared to 2; affected foetuses per litter [%]: 45.58 compared to 1.90), parietal skull (head-neck affected litters: 16 compared to 2; affected foetuses per litter [%]: 65.29 compared to 6.30), hyoid body of the skull (head-neck; affected foetuses per litter [%]: 12.37 compared to 0.00), right squamosal skull (head-neck; affected foetuses per litter [%]: 5.94 compared to 0.00),
zygomatic arch (head-neck affected litters: 11 compared to 1; affected foetuses per litter [%]: 18.74 compared to 2.22), left squamosal skull (head-neck; affected foetuses per litter [%]: 6.93 compared to 0.00), interparietal skull (head-neck; affected foetuses per litter [%]: 85.59 compared to 23.64), left zygomatic arch of the skull (head-neck affected foetuses per litter [%]: 10.49 compared to 1.11), supraoccipital skull (head-neck; affected foetuses per litter [%]: 98.15 compared to 77.94), 5th sternebra, trunk (bone) (lower extremity; affected foetuses per litter [%]: 71.34 compared to 42.74), femur(/ora) of the hind limb (lower-extremity; affected litters: 18 compared to 3; affected foetuses per litter [%]: 46.51 compared to 2.83), zygomatic arch of the skull (head-neck; affected litters: 11 compared to 1; affected foetuses per litter [%]: 27.19 compared to 2.22), nasal skull (head-neck; affected foetuses per litter [%]: 13.00 compared to 1.11), squamosal skull (head-neck; affected litters: 11 compared to 1; affected foetuses per litter [%]: 37.22 compared to 2.22) and basisphenoid skull (head-neck; affected foetuses per litter [%]: 5.15 compared to 0.00).
Bones showing statistically significantly higher litter incidence of unossification in the HD compared to the control group were the hyoid body of the skull (head-neck; affected foetuses per litter [%]: 5.85 compared to 0.00), metacarpal(s) of the forelimb (upper extremity; affected litters: 18 compared to 6; affected foetuses per litter [%]: 73.09 compared to 7.51), cervical centrum/(tra) of the vertebra (head-neck; affected foetuses per litter [%]: 97.35 compared to 68.61 and in MD group, affected foetuses per litter [%]: 96.85 compared to 68.61) and the 6th sternebra (trunk; affected litters: 15 compared to 4; affected foetuses per litter [%]: 51.20 compared to 4.37).
Irregular ossification was found statistically significantly more often in HD group compared to control litters in bones of the thoracic centrum/(tra) of the vertebra (trunk; affected foetuses per litter [%]: 30.20 compared to 12.25).
In HD litters, when compared to the control litters a statistically significantly higher incidence for (a) bent scapular spine(s) was observed (upper extremity; affected foetuses per litter [%]: 6.85 compared to 0.00).
The MD group showed a statistically significantly higher incidence for an incomplete ossification of the parietal skull (head-neck; affected litters: 13 compared to 2; affected foetuses per litter [%]: 27.83 compared to 6.30) when compared to the control litters.
Wavy ribs were observed at an incidence of affected foetuses per litter of 17.06% (affected litters: 9) in the control group, 25.65% (affected litters: 10) in the LD group, 25.85% (affected litters: 12) in the MD group and statistically significantly higher incidence of 67.64% (affected litters: 17) in the HD group. In general, wavy ribs are typically classified as transient and reversible post-natally and thus may be considered as variations but not malformations [11].
HD group litters showed a statistically significantly lower incidence compared to the control for increased ossification of the orbital socket region of the skull (head-neck;affected litters: 0 compared to 10; affected foetuses per litter [%]: 0.00 compared to 23.94) and for incomplete ossification of the 6th sternebra (trunk; affected foetuses per litter [%]: 44.11 compared to 80.03).
There were statistically significantly less foetuses found with fused caudal and vertebral central arches in LD, MD and HD litters compared to the control (affected foetuses per litter [%]: LD 0.88, MD and HD 0.00, control 15.05 and 13.31, respectively).

Visceral malformations:

effects observed, non-treatment-related

Description (incidence and severity):

Statistically significantly higher litter incidences of a supernumerary liver lobe were observed in the MD group (7 affected litters, 9.35% per litter) compared to the control group (0 affected litters). There were statistically significantly higher litter incidences of a bilateral azygous vein in the MD group (4.07% per litter) compared to the control group (0% per litter). In LD litters, a statistically significantly higher incidence for internal haemorrhage of the abdomen was observed when compared to the control group (control: 3.11% per litter; LD 18.05% per litter). The incidence for a long thymus per litter was statistically significant higher in the MD group (MD 2.96% per litter) compared to the control litters (control: 0% per litter).
Internal observation of the foetal viscera by free hand microdissection technique revealed a range of visceral findings in all groups including the control group. 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 the concurrent controls. As the observed findings were either minor variations and/or due to a lack of dose dependency and consistency, no toxicological significance could be attributed to these findings and they were considered to be spontaneous in nature.

Other effects:

effects observed, non-treatment-related

Description (incidence and severity):

Craniofacial examination by a razor blade serial sectioning technique revealed a range of visceral findings in all dose groups at similar frequencies or in some cases in slightly lower or higher frequencies than in litters of the concurrent control group. A statistically significant higher litter incidence was observed for red material in the perimeningeal space of the brain in MD litters compared to the control litters (control: 0% per litter; MD: 2.78% per litter). As there was no dose-dependency, these findings were not considered test item-related and therefore not toxicologically relevant, but incidental in nature.

Effect levels (fetuses)

Key result

Dose descriptor:

NOAEL

Remarks:

fetal toxicity

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

fetal/pup body weight changes

Fetal abnormalities

Key result

Abnormalities:

no effects observed

Description (incidence and severity):

A trend towards a test item-related incomplete ossification and unossification of several bones (mostly skull, sternum, limbs, and vertebra) was observed which resulted in statistically significantly higher fetal incidences of incomplete ossification and unossification of numerous bones in the high-dose group. This is considered to be a secondary effect to the lower fetal weight observed in this study.

Overall developmental toxicity

Key result

Developmental effects observed:

yes

Lowest effective dose / conc.:

1 000 mg/kg bw/day (actual dose received)

Treatment related:

yes

Relation to maternal toxicity:

developmental effects in the absence of maternal toxicity effects

Dose response relationship:

yes

Relevant for humans:

not specified

Applicant's summary and conclusion

Conclusions:

In an oral prenatal developmental toxicity study, conducted according to OECD 414 and to GLP (reliability score 1) the maternal NOAEL for the test substance triethoxy(propyl)silane (CAS 2550-02-9) was ≥1000 mg/kg bw/day in rats and the developmental NOAEL was 300 mg/kg bw/day based on the reduction in mean fetal weight.