Triethoxy(phenyl)silane

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

31 March 2020 to 28 May 2020

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2020

Report date:

2020

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:

GLP-Landesleitstelle Bayern, Bayerisches Landesamt für Gesundheit und Lebensmittelsicherheit

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Triethoxy(phenyl)silane

EC Number:

212-305-8

EC Name:

Triethoxy(phenyl)silane

Cas Number:

780-69-8

Molecular formula:

C12H20O3Si

IUPAC Name:

triethoxy(phenyl)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, 97633 Sulzfeld, Germany
- Age at study initiation: approx. 11-12 weeks
- Weight at study initiation: males: 324.3 – 429.5 g; females: 195.8 – 254.9 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 were kept in groups of two animals and during mating period when two females were paired with one male)
- Diet: ad libitum to Altromin 1324
- Water: ad libitum to tap water, sulphur acidified to a pH of approximately 2.8 (drinking water,municipal residue control, microbiological controls at regular intervals)
- 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

IN-LIFE DATES: From: 17 March 2020 To: 28 May 2020

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: 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 de-acidified vehicle was overlaid with argon and stored until usage.
The test item was weighed into a tared plastic vial on a suitable precision balance and the vehicle was added to give the appropriate final concentration of the test item. The formulation was vortexed and/or stirred until visual homogeneity was 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. 178274), the test item formulations were prepared at least once in 10 days at room temperature. The prepared formulation was stored protected from light and at room temperature.


VEHICLE
- Justification for use and choice of vehicle: The vehicle was selected in consultation with the sponsor based on the test item’s characteristics and testing guideline.
- Concentration in vehicle: 0, 10, 30, 100 mg/mL
- Amount of vehicle (if gavage): 4 mL/kg bw

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Before beginning of the treatment period, formulation samples were prepared and analysed in order to obtain knowledge about 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. 178274). The formulations (10, 25 and 250 mg/mL) were stable for 6 h and for 10 days at room temperature and at -15 to -35 °C. Therefore, it was decided to store prepared formulations at room temperature and use them within 10 days after preparation.
Since the test item was shown to be homogenous (after 30 min without stirring), samples were not collected during the study for the investigation of homogeneity. Samples were only taken for determining the substance concentration in the first and last week of the study for all doses (8 samples in total).
Each sample taken during the study was retained in duplicate (sample A, sample B, each of at least 3 mL). The A-samples were analysed at Eurofins Munich (Eurofins Munich Study Phase No. 193040) and until then stored under appropriate conditions based on available stability data. The B-samples were retained at below -15 °C at BSL Munich (test facility) and discarded after completion of the final study report.

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:2
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

GD 5 to GD 19

Frequency of treatment:

daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

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

Doses / concentrations 2

Dose / conc.:

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

Doses / concentrations 3

Dose / conc.:

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

No. of animals per sex per dose:

23

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Dose levels are based on two 14-day oral dose range finding studies (BSL Munich Study Nos. 178272 and 180703) and OECD 422 oral toxicity study (BSL Munich Study No. 178271). In the first 14-day study male and female Wistar rats were treated with the test item at 100, 300 and 1000 mg/kg bw/day for a period of 14 days. Test-item related mortality (3/3 males and 2/3 females) and clinical signs indicating toxicity such as paresis, ataxia, lethargy/stupor, apathy, dehydration, abnormal breathing and haematuria were observed at the highest dose of 1000 mg/kg bw/day.
In the second 14-day study male and female Wistar rats were treated with the test item at doses of 100, 250 and 500 mg/kg bw/day for a period of 14 days. Mortality occurred in 1/3 males at the highest dose of 500 mg/kg bw/day. Also, at that dose level, animals showed signs of renal toxicity, such as a thickened wall of the urinary bladder, dilated ureters and dilated kidneys, increased weights of kidneys and clinical biochemistry markers. A thickened wall of the urinary bladder was also observed at the two lower dose levels of 250 and 100 mg/kg bw/day.
In the OECD 422 study, male and female Wistar rats were treated at doses of 40, 120 and 360 mg/kg bw/day (treated for 28 days in males and 63 days in females). In this study, test item-related lesions were observed in the kidneys, ureters and the urinary bladder at 120 and 360 mg/kg bw/day. The NOAEL for general toxicity in this study was considered to be 40 mg/kg bw/day and for reproductive toxicity screening is considered to be 360 mg/kg bw/day.
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 assess any dose-related response and establish a NOAEL.

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations: morbidity, mortality

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: GD 0, 5, 8, 11, 14, 17 and 20

FOOD CONSUMPTION: Yes
- Food consumption measured on GD 5, 8, 11, 14, 17 and 20

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
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.

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 sampled from the abdominal aorta and collected in serum separator tubes. The obtained serum was stored under appropriate conditions. Serum samples were assessed for serum levels for thyroid hormones (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
- Other: The position and number of foetuses in each uterine horn was also recorded.

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 was 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 foetal evaluation parameters like external, visceral, craniofacial and skeletal parameters were 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 were performed with GraphPad Prism V.6.01 software or Ascentos 1.3.4 software (p<0.05 is considered as statistically significant).

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Clinical signs observed on a few days during the treatment period included skin and fur, hairless area (hind limb/abdomen/inguinal) in one female on GD 14-20 and increased salivation on GD 19 and hairless area (fore limb/hind limb/neck) in another female on GD 9, 10, 13-20 of the high dose group. A third female showed deviations in skin and fur, namely hairless area at right hind limb on GD 17-19. These findings are considered to be of incidental in nature.
Animals nos. 75, 77, 79 and 80 showed moderate increased salivation on GD 18-19, 16 17, 15-16, 12/17-19 respectively in the high dose group. This was observed transiently after dose administration and considered as a clinical sign elicited by local effects of the test item formulation and/or attributed to discomfort of the animals due to oral administration.

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Description (incidence):

No mortality was observed during the treatment period and all females survived until the end of the study.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

The mean body weight remained unaffected by the test item and increased with the progress of the study in the control, low dose and mid dose groups. However lower mean body weights was observed in high dose females with statistical significance seen on GD 14 - 20 (5-6 % below control).
Moderate, but statistically significantly lower mean body weight gain was observed on GD 5-8 and GD 11-14 in the high dose group. The group mean body weight gain of low dose and mid dose groups were comparable to control. However, slightly lower mean body weight gain was observed on GD 0-5 in low dose females and GD 11-14 in mid dose females (19 % and 16 % respectively) without achieving statistical significance.
Overall, statistically significant lower mean body weight gain was observed on GD 5-20 in high dose females when compared to the control (20 % below control), this is considered be a test item-related effect.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

In correlation to lower mean body weight and bodyweight gain, statistically significant lower food consumption was observed in the high dose group on GDs 5-8, 8-11, 11-142 (15-19 % below control). The overall mean food consumption on GDs 5-20 was found to be statistically reduced in the HD group (13 % below control) when compared to control.
The group mean food consumption of LD and MD groups were comparable to control animals

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):

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.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Animals no. 30 and 76 showed lungs with abnormal red spotted colour in the low dose group and abnormal red/mottled in the high dose group, respectively. Uteri with abnormal red colour in animal no. 59 and both sides dilated in animals no. 49 and, 61 were observed in the mid dose group and a 2.5 cm mass was observed in ovaries of animal no. 30 of the low dose group. These are considered to be incidental findings and not toxicologically relevant.
Predominant findings of dilated ureter on both sides were observed in animals no. 83, 72, 73, 79, 85, 86, 87, 89, 92; on the right side only in animals no. 84, 88; abnormally shaped, thick ureter in animal no. 75 and thickened wall, urinary bladder in animal no. 79, 92 was observed in the high dose group. All these findings are considered to be test item-related effects.

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 gland 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 toxicologically relevant effect was observed on group mean T3, T4 and TSH hormone levels and values were comparable with the controls.

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:

not examined

Changes in number of pregnant:

no effects observed

Description (incidence and severity):

Successful mating resulted in 22/23 pregnancies in the lo dose group, 20/23 in the mid dose group and 22/23 in the high dose group compared to 21/23 pregnancies in the control group.

Other effects:

effects observed, treatment-related

Description (incidence and severity):

Net weight change (g) from GD 0 showed a slight trend towards lower mean weight in the HD group compared to the control group (32.8 % below control). As there is no dose-dependency, it is not considered toxicologically relevant. Carcass and uterine weight were found to be comparable to control except for a slight but statistically significant reduction in mean carcass weight in the high dose group (7 % below control).

Effect levels (maternal animals)

Key result

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Basis for effect level:

body weight and weight gain

food consumption and compound intake

gross pathology

Maternal abnormalities

Abnormalities:

effects observed, treatment-related

Localisation:

other: ureter

Results (fetuses)

Fetal body weight changes:

no effects observed

Description (incidence and severity):

There were no test item-related effects of toxicological relevance observed for the mean foetus weight, male and female foetus weight on litter basis (group mean of individual litter mean) in any of the treatment groups when compared to control.

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

not examined

Changes in litter size and weights:

no effects observed

Changes in postnatal survival:

not examined

External malformations:

no effects observed

Description (incidence and severity):

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

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

Skeletal examination of the 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.
Statistically significantly higher foetal incidences were observed at 4th sternebra in the low dose group (8 %) when compared to 2 % in control and at 3rd sternebra in the low dose group (5 %) when compared to control (0 %). Statistically significantly higher foetal incidences were observed in skull supraoccipital with small hole in high dose group (60 % compared to 34 % in control). All these findings were observed without dose dependency or consistency; hence they are not considered to be test item-related.

Higher or lower litter incidences, but without achieving statistical significance, were observed as mentioned below.
Higher or lower litter incidences of unossified forelimb phalanx (low dose, mid dose and high groups, 100% each) were observed compared to 95 % in control. Higher or lower litter incidences of pelvic girdle, caudal shift were observed (30 %, 25 % and 20 % in low dose, mid dose and high dose groups, respectively) when compared to 20% in control. Higher or lower litter incidences of incomplete ossifications of 2nd sternebra were observed (40 %, 15 % and 50 % in low dose, mid dose and high dose groups, respectively) when compared to 45 % in control. Higher litter incidence of incomplete ossification of forelimb humerus and frontal skull (left) was observed in the high group (15 % compared to 5 % in control). Higher or lower litter incidence incomplete ossification of skull parietal (bone) was observed in treated groups (35 %, 40 % and 55 % in the low dose, mid dose and high dose groups, respectively) when compared to control group (35 %).
Higher litter incidence of incomplete ossification of skull frontal (bone) was observed in high groups (15 % compared to 10 % control). Litter incidence of vertebra thoracic centrum, irregular ossification was observed in treated groups (65 %, 70 % and 65 % in the LD, MD and HD groups, respectively) when compared to control group (70 %). Higher or lower litter incidence of forelimb metatarsal, unossified was observed in treated groups (40 %, 25 % and 65 % in the low dose, mid dose and high dose groups, respectively) when compared to control group (45 %). Higher litter incidence of forelimb radius, incomplete ossification-upper extremity (bone) was observed in treated groups (25 % in high dose compared to control (5 %). Higher litter incidences incomplete ossification of skull supraoccipital was observed in treated groups (95 %, 95 % and 100 % in the low dose, mid dose and high dose groups, respectively) when compared to control group (90 %).
Higher litter incidence of 14th Rib, rudimentary was observed in treated groups (45 %, 60 % and 50 % in the low dose, mid dose and high dose groups, respectively) when compared to control group (40%). Higher or lower litter incidence of sternebra (5th) incomplete ossification was observed in treated groups (75%, 65% and 80% in the low dose, mid dose and high dose groups, respectively) when compared to control group (75%). Higher litter incidence of hind limb femur incomplete ossification was observed in treated groups (60 %, 55 % and 75 % in the low dose, mid dose and high dose groups, respectively) when compared to control group (40 %). Higher or lower litter incidence of vertebra cervical centrum, unossified was observed in treated groups (100 %, 90 % and 100 % in the low dose, mid dose and high dose groups, respectively) when compared control group (95 %).
Higher or lower litter incidence of skull orbital socket region, increased ossification was observed in treated groups (65 %, 70 % and 45 % in the low dose, mid dose and high dose groups, respectively) when compared to control group (75 %). Higher or lower litter incidence of skull parietal (right), increased ossification was observed in treated groups (35 %, 20 % and 35 % in the low dose, mid dose and high dose groups, respectively) when compared to control group (30 %). Higher or lower litter incidence of skull parietal (left), increased ossification was observed in treated groups (0 %, 30 % and 20 % in the low dose, mid dose and high dose groups, respectively) when compared to control group (10 %). Higher litter incidence of skull basisphenoid, increased ossification was observed in treated groups (25 % in the mid dose group) when compared to control group (5 %). Higher or lower litter incidence of 14th rib (right), rudimentary was observed in treated groups (50 %, 45 % and 45 % in the low dose, mid dose and high dose groups respectively) and control group (50 %).
Litter incidence of incomplete ossification of 6th sternebra was observed in treated groups (100 % in the low dose and high dose groups and 95 % in mid dose group) when compared to control group (95 %). Higher or lower litter incidence of ribs, wavy was observed in treated groups (30 %, 70% and 65 % in the low dose, mid dose and high dose groups, respectively) when compared to control group (70 %). Higher or lower litter incidence of vertebra cervical arches, irregular ossification was observed in treated groups (35 %, 40 % and 15 % in the low dose, mid dose and high dose groups, respectively) when compared to control group (35 %).
Litter incidence of vertebra sacral centrum and arches fused was observed in treated groups (20 %, 20 % and 5 % in the low dose, mid dose and high dose groups, respectively) when compared to control group (20 %).
Higher or lower litter incidence of vertebra caudal centrum and arches fused was observed in treated groups (25 %, 10 % and 10 % in the low dose, mid dose and high dose groups, respectively) when compared to control group (15 %). Higher or lower litter incidence of pelvic girdle caudal shift (right) was observed in treated groups (20 %, 10 % and 30 % in the low dose, mid dose and high dose groups, respectively) when compared to control group (20 %). Higher or lower litter incidence of vertebra lumbar arches increased ossification was observed in treated groups (5 %, 20 % and 15 % in the low dose, mid dose and high dose groups, respectively) when compared to control group (10 %).
The observed incomplete ossification without achieving statistical significance of a few bones and a few other skeletal findings in the treated groups were either marginally lower or higher or within the historical control data range. Generally delayed ossification is not regarded to persist postnatally and is not associated with long-term consequences on survival, general growth and development and therefore is not considered to be adverse.
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, non-treatment-related

Description (incidence and severity):

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 concurrent controls. As the 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.
Higher litter incidences of testes, malpositioned in the high dose group were observed (45 %) when compared to control (30%). There were lower litter incidences of umbilical artery malpositioned (30 %, 25 % and 30 % in the low dose, mid dose and high dose groups, respectively, compared to 45 % in control) observed. There were lower litter incidences of liver, lobe supernumerary (20 %, 30 % and 25 % in low dose, mid dose and high dose groups, respectively, compared to 40% in control) observed. There were lower litter incidences of azygos vein (bilateral) (55 %, 70 % and 40 % in the low dose, mid dose and high dose groups, respectively, compared to 80 % in control observed. There were higher litter incidences of abdomen, internal haemorrhage (55 %, 80 % and 80 % in low dose, mid dose and high dose groups, respectively, compared to 55 % in control) observed. Lower litter incidence of discoloured kidney, thoracic internal haemorrhage and long thymus was observed in the low dose group (5 % each). All these findings are considered to be incidental in nature.

Other effects:

no effects observed

Description (incidence and severity):

In male and female foetuses weight and cube root of foetus weight were comparable to control group and no test item-related findings were observed.
In males and females, the relative anogenital distance (AGD) in low dose and high dose groups, respectively, was statistically significantly lower when compared to the control. There was no dose dependency, as this was observed in low dose and high dose but not in mid dos group. However, all these values are within the historical control values of this strain. Hence, this is not considered to be a test item-related effect.
All male foetuses were checked for indication of incomplete testicular descent/ cryptorchidism and evaluation revealed completion of testicular descent (abdominal) in all male foetuses from all groups.

Craniofacial examination by razor blade serial sectioning technique revealed incidences of head, subcutaneous hematoma in all treated (45 %, 50 % and 45 % in low dose, mid dose and high dose groups) when compared to control (25%). Lower litter incidences of mid brain subdural oedema were observed in all treated (50% in each low dose, mid dose and high dose groups, respectively) when compared to control (65 %). Higher litter incidences of increased subcutaneous space in head was observed in low dose and mid dose groups (10 % and 5 %, respectively) when compared to control (0 %). Higher or lower litter incidences of increased perimeningal space were observed in all treated groups (10 %, 20 % and 10 % in low dose, mid dose and high dose groups, respectively) when compared to control (15 %). All 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 for any of these findings.

Effect levels (fetuses)

Key result

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed up to the highest dose tested

Fetal abnormalities

Key result

Abnormalities:

no effects observed

Overall developmental toxicity

Key result

Developmental effects observed:

no

Applicant's summary and conclusion

Conclusions:

On the basis of this prenatal developmental toxicity study in Wistar pregnant female rats with triethoxyphenylsilane (CAS 780-69-8) at dose levels of 40, 120, and 400 mg/kg bw/day administered on GD 5 to GD 19, the following conclusions can be made:
No test item-related mortality and clinical signs were observed during the treatment period of this study. Test item-related and statistically significant reductions in mean body weight gain and mean food consumption were observed at the high dose group. No test item-related effects on prenatal and litter data parameters or, thyroid hormone and thyroid/parathyroid organ weights of dam were observed. Test item-related effects on gross pathology of terminally sacrificed high dose females was observed which included dilated ureter on both sides, abnormally shaped and thick ureter and thickened wall of urinary bladder. There were no test item-related findings at histopathological evaluation of the thyroid gland in any of the treated groups. Furthermore, no test item-related and toxicologically relevant external, visceral or craniofacial findings were observed in the treatment groups. However, there were a few skeletal findings including incomplete ossification of some bones and other incidental skeletal findings observed which were not of statistical significance in the high dose group. These findings were either marginally lower or higher or within the historical control data range and not considered to be adverse.
The NOAELs for maternal and foetal toxicity of triethoxyphenylsilane in this study are considered to be 120 mg/kg bw/day and 400 mg/kg bw/day, respectively.