Trimethoxyphenylsilane

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Description of key information

Reproduction Screening Test: according to OECD TG 422 in rat:
NOEL reproductive toxicity = 500 mg/kg bw/day.
LOAEL parent systemic = 100 mg/kg bw/day.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

14 Jan - 20 Oct 2009

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: Han Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Labs Ltd., Wölferstrasse 4, 4414 Fuellinsdorf, SWITZERLAND
- Age at study initiation: 11 wk
- Weight at study initiation: 294-330 g (m), 178-213 g (f)
- Housing: 1/Makrolon type 3 cage
- Diet: standard diet ad libitum
- Water: drinking water ad libitum
- Acclimation period: 6 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3
- Humidity (%): 20-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 2009-01-14 To: 2009-04-06

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Prepared weekly. Homogeneous suspension maintained with magnetic stirrer during dosing.
VEHICLE
Dried deacidified corn oil
- Justification for use and choice of vehicle (if other than water): none given
- Concentration in vehicle:
- Amount of vehicle (if gavage): dose volume 5 ml/kg bw
- Lot/batch no.: 37899577

Details on mating procedure:

- M/F ratio per cage: 1:1
- Length of cohabitation: 2 wk
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

GC-FID. Stability and homogeneity verified at start of study and during 2nd last week of dosing.

Duration of treatment / exposure:

toxicity males: from 2 weeks prior to mating for at least 4 wk
toxicity/reproductive females: from 2 weeks prior to mating for at about 7 wk

Frequency of treatment:

daily, 7/days/wk

Dose / conc.:

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

Dose / conc.:

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

Dose / conc.:

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

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: prior range finding study (Harlan B88762)
- Rationale for animal assignment (if not random): random with consideration for body weight

Positive control:

no

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: daily

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined weekly

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: just prior to sacrifice
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes (18 h)
- How many animals: 5

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: just prior to sacrifice
- Animals fasted: Yes (18 h)
- How many animals: 5

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION/FOB: Yes
- Time schedule for examinations: 1 or 2 days prior to sacrifice (males) or postpartum day 3/4 (females)
- Dose groups that were examined: 5/sex, all groups
Cage-side observations: unusual body movements (e.g. tremors, convulsions), abnormal behavior (e.g. circling, stereotypy) and posture as well as resistance to removal.
Hand-held observations: palpebral closure, pinna reflex, lacrimation, pupil size, pupil reactivity, salivation, muscle tone, extensor thrust response, righting reflex and reaction to handling.
Open field observations: level of ambulatory activity including rearing (one minute evaluation), responsiveness to sharp noise, paw pinch, gait evaluation, quantity of urine and fecal pellets voided.
Categorical observations (can be made any time during the FOB): hair coat, behavior, respiration, muscle movements, eyes, hearing ability (Preyer’s reflex), urine or feces, soiling, general abnormalities, posture.
Measurements / Counts: hind limb / fore limb grip strength, landing foot splay, rectal temperature.
Locomotor activity (low beam counts)

Oestrous cyclicity (parental animals):

not recorded

Sperm parameters (parental animals):

not recorded

Litter observations:

The litters were examined for litter size, live births, still births and any gross anomalies. The sex ratio of the pups was recorded. Pups were weighed individually (without identification) on days 0 (if possible), 1 and 4 postpartum.

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals day 28/29
- Maternal animals:PND 4/5


GROSS NECROPSY
All parent animals were examined macroscopically for any structural changes, either at the scheduled necropsy or during the study if death occurred. For the parent animals, special attention was directed at the organs of the reproductive system. The number of implantation sites and corpora lutea was recorded for all dams with litters. The uteri of non-pregnant females were placed in a solution of ammonium sulfide to visualize possible hemorrhagic areas of implantation sites.


HISTOPATHOLOGY / ORGAN WEIGHTS
Tissues indicated in OECD 422 were prepared for microscopic examination and weighed.

Special emphasis was made on the stages of spermatogenesis and histopathology of interstitial cell structure.
Histological examination of ovaries was carried out on any females that did not give birth. In addition, microscopic examination of the reproductive organs of all infertile males was made, ifnecessary.

Postmortem examinations (offspring):

All pups were examined macroscopically for any structural changes

Statistics:

Means and standard deviations of various data were calculated. The Dunnett-test (many to one t-test) based on a pooled variance estimate was applied if the variables could be assumed to follow a normal distribution for the comparison of the treated groups and the control groups for each sex. The Steel-test (many-one rank test) was applied instead of the Dunnett test when the data could not be assumed to follow a normal distribution. Fisher's exact-test was applied to breeding data and the macroscopical findings.

Reproductive indices:

Gestation time, precoital time, corpora lutea count, implantation rate, post implantation loss.
Percentage mating = (Females mated / Females paired) * 100
Fertility index = (Females achieving a pregnancy / Females paired) * 100
Conception rate = (Females achieving a pregnancy / Females mated) * 100
Gestation index = (Number of females with living pups / Number of females pregnant) * 100

Offspring viability indices:

Litter size: Birth index = (number of pups born alive / number of implantations) * 100
Post-natal loss (PND 0-4): Viability index = (number of alive pups on day 4 p.p. / number of pups born alive) * 100

Clinical signs:

no effects observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

500 mg/kg bw: reduced body weight and body weight gain

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

500 mg/kg bw: reduced body weight and body weight gain

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

100, 250, 500 mg/kg bw: hyperplasia, dilatation in the urinary bladder

Other effects:

not examined

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Mean precoital time, fertility and gestation indices and conception rate were not affected by the treatment with the test item.
Implantation rate and post-implantation loss were also not affected by the treatment with the test item.

CLINICAL SIGNS AND MORTALITY
No treatment-related effects.

BODY WEIGHT AND WEIGHT GAIN
In males: at 500 mg/kg bw/day mean body weight gain was statistically significantly reduced during the pre-pairing period. This resulted in a statistically significantly decrease in body weight throughout the whole study. In females: at 500 mg/kg bw/day mean body weight gain was statistically significantly reduced between days 8 and 14 of the gestation resulting in a decrease of mean body weight between days 11 and 20 of gestation.

FOOD CONSUMPTION
500 mg/kg bw: reduced food consumption in the pre-pairing period (male/female), increased food consumption in the after-pairing period (male)
HAEMATOLOGY
No treatment-related effects.

CLINICAL CHEMISTRY
In males, at 250 and 500 mg/kg bw/day, the concentration of urea was statistically significantly increased in dose-dependent manner. The concentration of bile acids was statistically significantly increased but without showing a dose-dependent pattern. At 500 mg/kg bw/day, the concentration of cholesterol was also statistically significantly increased.

NEUROBEHAVIOUR/FOB
No treatment-related effects.

ORGAN WEIGHTS
The report highlights that at 500 mg/kg bw/day, absolute and relative weight of the kidneys was statistically significantly increased in males. In addition, in females at this dose, thymus weight was reduced (absolute, relative to body and relative to brain), although these values were within the range of historical controls. Female liver and kidney weights (relative to body) were also increased at the top dose; again within the range of historical controls. [The report incorrectly notes increased thymus and reduced liver weights for this group.]

GROSS PATHOLOGY
The urinary bladder was thickened in all treated groups (100 mg/kg bw/day 6/10 m, 2/10 f; 250 mg/kg bw/day 7/10 m, 6/10 f; 500 mg/kg bw/day 9/10 m, 7/10 f). This finding in the urinary bladder was said mainly to correlate with transitional cell hyperplasia observed at microscopic level.

HISTOPATHOLOGY: NON-NEOPLASTIC
Microscopically, the test item-related lesions recorded were:
Kidneys: At 500 mg/kg bw/day, multifocal tubular degeneration/regeneration was noted in all males and two females, and in one male this was associated with minimal hyaline casts. Tubular simple dilation was noted in four males and all females. Increased incidence of focal tubular degeneration/regeneration was observed in females. Transitional cell hyperplasia was noted in all males and females. At 250 mg/kg bw/day, multifocal tubular degeneration/regeneration was observed in three males. Transitional cell hyperplasia was noted in all males and females. The hyperplastic lesions were accompanied by an increased incidence of renal pelvic dilation in six/six males and five/five females and correlated the hyperplastic findings in urinary bladders.
Urinary Bladder: Perivascular lymphoid cell infiltration was noted in ten/ten males and six/seven females at 100 mg/kg bw/day, in ten/ten males and seven/eight females at 250 mg/kg bw/day and in seven/ten males and ten/ten females at 500 mg/kg bw/day. At all dose levels, minimal to moderate transitional cell hyperplasia was observed in all males and females. These hyperplastic lesions were accompanied by minimal to slight dilation in each eight/ten males at 100 and 250 mg/kg bw/day, and ten/ten males at 250 mg/kg bw/day. In females, dilation in three/seven at 100 mg/kg bw/day, four/eight at 250 mg/kg bw/day, and ten/ten at 500 mg/kg bw/day. Minimal to moderate bladder congestion in all males at all dose levels. In females, six/seven at 100 mg/kg bw/day, seven/eight at 250 mg/kg bw/day, and ten/ten at 500 mg/kg bw/day, in each one male and one female at 250 mg/kg bw/day associated with slight hemorrhage.
Jejunum: At 500 mg/kg bw/day, multifocal lymphangiectasis of villi was noted in all males and females and in two males and one female at 250 mg/kg bw/day.
Liver and Thyroid: At 500 mg/kg bw/day, the liver cell hypertrophy noted in two/five females and consequent increase of follicular cell hypertrophy in the thyroid gland was considered to be an adaptive effect and therefore, not adverse.

Dose descriptor:

LOAEL

Effect level:

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

Sex:

male/female

Basis for effect level:

other: urinary bladder effects at lowest dose tested

Critical effects observed:

yes

Lowest effective dose / conc.:

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

System:

urinary

Organ:

bladder

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

Clinical signs:

not examined

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

not examined

The mean number of pups at first litter check was not affected by the treatment with the test item. The sex ratio was also not affected. No abnormal pups were noted at any dose level. During the lactation period, pup weight gain at 500 mg/kg bw/day was reduced compared to the controls, but did not attain statistical significance. The reaction was due primarily to lower weight gain which occurred in two litters. Excluding the lower pup weight which occurred in these two litters at 500 mg/kg bw/day, mean pup weight gain was not considered to be affected by the treatment with the test item.

At necropsy of the pups, the incidence of pups with no milk in the stomach did not give any indication of a test item-related effect.

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

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

Sex:

male/female

Basis for effect level:

other: No adverse reproductive effects at highest dose tested

Critical effects observed:

no

Reproductive effects observed:

no

Conclusions:

A well reported oral combined repeated dose/reproductive and developmental screening study, conducted according to the current guideline and in accordance with GLP, reported a NOAEL for reproductive effects at the highest tested dose of 500 mg/kg bw/day. General systemic parental effects were reported at the lowest tested dose of 100 mg/kg bw/day.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

500 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The study was conducted according to the appropriate OECD test guideline, and in compliance with GLP.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Studies were chosen as key when the available study was of relevance and of sufficient quality for classification, labelling and for risk assessment.

A key reliable OECD 422 combined repeated dose/reproductive and developmental screening study is available by the oral route for trimethoxyphenylsilane. Mean precoital time, fertility and gestation indices and conception rate were not affected by the treatment with the test item. Implantation rate and post-implantation loss were also not affected by the treatment with the test item. The NOEL for reproduction toxicity was considered to be 500 mg/kg bw/day, since no effects were noted in all parameters investigated. However, based on microscopic findings noted in the urinary bladder at all dose levels (see Section 5.6), it is not possible to establish a general systemic NOAEL (SEHSC, 2009).

Furthermore, a reliable OECD combined repeated dose/reproductive and developmental screening study is available by oral route for triethoxy(phenyl)silane (CAS 780 -69 -8). The test substance was administered in corn oil as vehicle at dosages of 40, 120, and 360 mg/kg body weight/day, and controls received the vehicle only. Two recovery groups were included which were treated with vehicle only or 360 mg test substance/kg bw/day. 

Treatment-related effects were observed in body weight and food consumption in the high dose group. One male rat from the high dose group with 360 mg/kg bw/day was sacrificed moribund on day 15. The death was considered treatment-related as a consequence of backflow nephrosis. At necropsy adverse effects in kidneys and urinary bladder were observed at 120 and 360 mg/kg bw/day. The systemic toxicity is described in detail under the chapter “repeated dose toxicity”.

There were no effects on estrous cyclicity, litter data, litter weight data, precoital interval and duration of gestation, reproductive indices, anogenital distance and nipple retention, pup thyroid weight and thyroid hormone analysis in parental males and pups sacrificed on PND 13 and male sacrificed at the end of recovery period in all groups up to 360 mg/kg bw/day.

A very slight and dose-dependent tendency towards lower a serum thyroxine hormone (T4) level was observed in PND 13 pups of the dose groups when compared to controls. A relation to treatment with the test item cannot be excluded.

Histopathologically, no specific lesions were noted in the reproductive system organs from males and females.

Based on the findings in the urinary tract, the NOAEL for triethoxy(phenyl)silane in this study for general toxicity is considered to be 40 mg/kg bw/day. As no effects were observed in any reproductive toxicity aspects, the NOAEL for reproductive toxicity is considered to be 360 mg/kg bw/day.

Comparing the findings in the screening study with both substances it can be seen that their target organ is the same and their toxicity is in the same range. Thus, read across between both substances can be justified.

Effects on developmental toxicity

Description of key information

OECD TG 414 (GLP, RL1, rat, oral) study on the structural analogue substance triethoxyphenylsilane (CAS: 780-69-8):

NOAEL systemic toxicity = 120 mg/kg bw/day

NOAEL developmental toxicity = 400 mg/kg bw/day

 

Developmental Screening Test on the registration substance: according to OCED TG 422 in rat: 

NOEL developmental = 500 mg/kg bw. 

LOAEL maternal = 100 mg/kg bw.

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Remarks:

screening study

Type of information:

experimental study

Adequacy of study:

key study

Study period:

14 Jan - 20 Oct 2009

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: Han Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Labs Ltd., Wölferstrasse 4, 4414 Fuellinsdorf, SWITZERLAND
- Age at study initiation: 11 wk
- Weight at study initiation: 294-330 g (m), 178-213 g (f)
- Housing: 1/Makrolon type 3 cage
- Diet: standard diet ad libitum
- Water: drinking water ad libitum
- Acclimation period: 6 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3
- Humidity (%): 20-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 2009-01-14 To: 2009-04-06

Route of administration:

oral: gavage

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Prepared weekly. Homogeneous suspension maintained with magnetic stirrer during dosing.
VEHICLE
Dried deacidified corn oil
- Justification for use and choice of vehicle (if other than water): none given
- Concentration in vehicle:
- Amount of vehicle (if gavage): dose volume 5 ml/kg bw
- Lot/batch no.: 37899577

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

GC-FID. Stability and homogeneity verified at start of study and during 2nd last week of dosing.

Details on mating procedure:

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

Duration of treatment / exposure:

toxicity males: from 2 weeks prior to mating for at least 4 wk
toxicity/reproductive females: from 2 weeks prior to mating for at about 7 wk

Frequency of treatment:

daily, 7 days/wk

Dose / conc.:

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

Dose / conc.:

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

Dose / conc.:

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

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: prior range finding study (Harlan B88762)
- Rationale for animal assignment (if not random): random with consideration for body weight

Maternal examinations:

The number of implantation sites and corpora lutea was recorded for all dams with litters. The uteri of non-pregnant females were treated to visualize possible hemorrhagic areas of implantation sites.

Histological examination of ovaries was carried out on any females that did not give birth. In addition, microscopic examination of the reproductive organs of all infertile males was made, if necessary.

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: daily

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined weekly

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: just prior to sacrifice
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes (18 h)
- How many animals: 5

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: just prior to sacrifice
- Animals fasted: Yes (18 h)
- How many animals: 5

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION/FOB: Yes
- Time schedule for examinations: 1 or 2 days prior to sacrifice (males) or postpartum day 3/4 (females)
- Dose groups that were examined: 5/sex, all groups
Cage-side observations: unusual body movements (e.g. tremors, convulsions), abnormal behavior (e.g. circling, stereotypy) and posture as well as resistance to removal.
Hand-held observations: palpebral closure, pinna reflex, lacrimation, pupil size, pupil reactivity, salivation, muscle tone, extensor thrust response, righting reflex and reaction to handling.
Open field observations: level of ambulatory activity including rearing (one minute evaluation), responsiveness to sharp noise, paw pinch, gait evaluation, quantity of urine and fecal pellets voided.
Categorical observations (can be made any time during the FOB): hair coat, behavior, respiration, muscle movements, eyes, hearing ability (Preyer’s reflex), urine or feces, soiling, general abnormalities, posture.
Measurements / Counts: hind limb / fore limb grip strength, landing foot splay, rectal temperature.
Locomotor activity (low beam counts)

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: No data
- Number of late resorptions: No data

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: No
- Skeletal examinations: No
- Head examinations: No

The litters were examined for litter size, live births, still births and any gross anomalies. The sex ratio of the pups was recorded. Pups were weighed individually (without identification) on days 0 (if possible), 1 and 4 postpartum.

Statistics:

Means and standard deviations of various data were calculated. The Dunnett-test (many to one t-test) based on a pooled variance estimate was applied if the variables could be assumed to follow a normal distribution for the comparison of the treated groups and the control groups for each sex. The Steel-test (many-one rank test) was applied instead of the Dunnett test when the data could not be assumed to follow a normal distribution. Fisher's exact-test was applied to breeding data and the macroscopical findings.

Indices:

Litter size (birth index), post-natal loss (PND0-4) (viability index).

[Also gestation time, gestation index, precoital time, conception index, corpora lutea count, implantation rate, post implantation loss.]

Historical control data:

provided and relevant to comment on organ weight changes (below)

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
ORGAN WEIGHTS
In females at 500 mg/kg bw/day, thymus weight was reduced (absolute, relative to body and relative to brain), although these values were within the range of historical controls. Female liver and kidney weights (relative to body) were also increased at the top dose; again within the range of historical controls. [The report incorrectly notes increased thymus and reduced liver weights for this group.]
GROSS PATHOLOGY
The urinary bladder was thickened at all doses. This finding in the urinary bladder was said mainly to correlate with transitional cell hyperplasia observed at microscopic level.
HISTOPATHOLOGY: NON-NEOPLASTIC
Kidneys: At 500 mg/kg bw/day, multifocal tubular degeneration/regeneration was noted in all males and 2 females, and in 1 male this was associated with minimal hyaline casts. Tubular simple dilation was noted in 4 males and all females. Increased incidence of focal tubular degeneration/regeneration was observed in females. Transitional cell hyperplasia was noted in all males and females. At 250 mg/kg bw/day, multifocal tubular degeneration/regeneration was observed in 3 males. Transitional cell hyperplasia was noted in all males and females. The hyperplastic lesions were accompanied by an increased incidence of renal pelvic dilation in 6/6 males and 5/5 females and correlated the hyperplastic findings in urinary bladders. Renal pelvic dilation was also observed in the 100 mg/kg bw dose group (4/5 females).
Urinary Bladder: Perivascular lymphoid cell infiltration was noted in 10/10 males and 6/7 females at 100 mg/kg bw/day, in 10/10 males and 7/8 females at 250 mg/kg bw/day and in 7/10 males and 10/10 females at 500 mg/kg bw/day. At all dose levels, minimal to moderate transitional cell hyperplasia was observed in all males and females. These hyperplastic lesions were accompanied by minimal to slight dilation in each 8/10 males at 100 and 250 mg/kg bw/day, and 10/10 males at 250 mg/kg bw/day. In females, dilation in 3/7 at 100 mg/kg bw/day, 4/8 at 250 mg/kg bw/day, and 10/10 at 500 mg/kg bw/day was observed. Minimal to moderate bladder congestion occurred in all males at all dose levels. In females, congestion was observed in 6/7 at 100 mg/kg bw/day, 7/8 at 250 mg/kg bw/day, and 10/10 at 500 mg/kg bw/day. In each one male and one female at 250 mg/kg bw/day it was associated with slight hemorrhage.
Jejunum: At 500 mg/kg bw/day, multifocal lymphangiectasis of villi was noted in all males and females and in 2 males and 1 female at 250 mg/kg bw/day.
Liver and Thyroid: At 500 mg/kg bw/day, the liver cell hypertrophy noted in 2/5 females and consequent increase of follicular cell hypertrophy in the thyroid gland was considered to be an adaptive effect and therefore, not adverse.

Dose descriptor:

LOAEL

Remarks:

maternal toxicity

Effect level:

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

Basis for effect level:

other: effects to urinary bladder at lowest dose tested

Abnormalities:

effects observed, treatment-related

Localisation:

other: urinary system

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
The mean number of pups at first litter check was not affected by the treatment with the test item. The sex ratio was also not affected. No abnormal pups were noted at any dose level. During the lactation period, pup weight gain at 500 mg/kg bw/day was reduced compared to the controls, but did not attain statistical significance. The reaction was due primarily to lower weight gain which occurred in two litters. Excluding the lower pup weight which occurred in these two litters at 500 mg/kg bw/day, mean pup weight gain was not considered to be affected by the treatment with the test item.

At necropsy of the pups, the incidence of pups with no milk in the stomach did not give any indication of a test item-related effect.

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

Abnormalities:

no effects observed

Developmental effects observed:

no

Conclusions:

A well reported oral combined repeated dose/reproductive and developmental screening study, conducted according to the current guideline and in accordance with GLP, reported a NOAEL for developmental effects at the highest tested dose of 500 mg/kg bw/day. General systemic parental effects were reported at the lowest tested dose of 100 mg/kg bw/day.

Reference 2

Endpoint:

developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

Please refer to the attached justification below

Reason / purpose for cross-reference:

read-across source

Species:

rat

Strain:

Wistar

Remarks:

Crl: WI(Han)

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

Abnormalities:

effects observed, treatment-related

Localisation:

other: ureter

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

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

Conclusions:

On the basis of this prenatal developmental toxicity study in Wistar pregnant female rats with the source substance 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.
The same NOAELs are estimated for trimethoxy(phenyl)silane. As explained in the justification for type of information, the differences between the target and the source substance are unlikely to lead to differences in developmental toxicity that are higher than the typical experimental error of the test method.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

400 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The study was conducted with the source substance according to the OECD test guideline 414 and in compliance with GLP.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Studies were chosen as key when the available study was of relevance and of sufficient quality for classification, labelling and for risk assessment.

A reliable prenatal developmental toxicity study according to OECD 414 is available for the source substance triethoxy(phenyl)silane (CAS 780 -69 -8) (Eurofins, 2020). The test substance was administered in corn oil (vehicle) at dosages of 40, 120, and 400 mg/kg body weight/day, and controls received the vehicle only during gestation day (GD) 5 to 19.

No test item-related mortality was observed during the treatment period and all animals survived until the end of the study. There was no test item-related or adverse clinical signs of toxicological relevance observed in the females of any treatment group. None of the females showed signs of abortion or premature delivery prior to the scheduled necropsy. The mean body weight remained unaffected by the test item and increased with the progress of the study in the control, LD (40 mg/kg bw/day) and MD (120 mg/kg bw/day) groups. However, lower mean body weights were observed in HD (400 mg/kg bw/day) females with statistical significance seen on GDs 5-8 and GDs14-20. Bodyweight gain was also reduced in the HD group when compared to the control (20% below control) and statistically significant from GD 5 to 20. This was considered be a test item-related effect. In correlation to lower mean body weight and bodyweight gain, statistically significantly lower food consumption was observed in the HD group on GDs 5-8, 8-11, 11-14 (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 consumptions of the LD and MD groups were comparable to control animals. No test item-related effects of toxicological relevance were noted for any prenatal parameters including; terminal body weight, adjusted maternal weight (carcass weight), uterine weight, net weight change from GD 0, number of corpora lutea, implantation sites, early and late resorptions, number of live foetuses, anogenital distance, number of male and female foetuses, sex ratios and percent pre- and post-implantation loss in treatment groups when compared to the controls. No dead foetuses were noted in any of the groups. However, statistically significant reduction in mean carcass weight (7% below control) and Net weight change (g) from Gestation day 0 (33% below control) were observed in HD groups.

Successful mating resulted in 22/23 pregnancies in the LD group, 20/23 in the MD group and 22/23 in the HD group compared to 21/23 pregnancies in the control group. In all terminally sacrificed females, no toxicologically relevant effect was observed on group mean T3, T4 and TSH hormone levels and values were comparable to the controls. Statistical analysis of post-fixed thyroid/parathyroid weights from all dams revealed no statistically significant differences in the absolute and relative (to body weight) thyroid/parathyroid weights of the dose groups when compared to the control group. No test item-related gross pathological changes were observed during the macroscopic examination in the LD and MD groups. However, in the HD group there were test item related gross pathological findings observed in the ureter, abnormal shape (thick) in 1/23 females and dilation in both sides in 11/23 females, and urinary bladder thickened wall in 2/23 females. There were no test item-related findings at histopathological evaluation of the thyroid gland in any of the treated groups. 

In male and female foetuses, weight and cube root of foetal weight were comparable to control and no test item-related findings were observed. In males and females, the relative anogenital distance (AGD) in the LD and HD groups, respectively, was statistically significantly lower when compared to the control. There was no dose dependency, as this was observed in the LD and HD groups but not in the MD group. However, all these 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 checked for indication of incomplete testicular descent/cryptorchidism and evaluation revealed completion of testicular descent (abdominal) in all male foetuses from all groups. There were no test item-related effects of toxicological relevance observed for the mean foetal weight, as male and female foetal weights on a per litter basis (group mean of individual litter mean) were not different in any of the treatment groups when compared with the controls. There were no test item-related external abnormalities observed in any of the dose groups. 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 controls. As the observed findings were minor variations and/or lacked dose dependency and consistency, no toxicological significance can be attributed to these findings and they were considered to be spontaneous in nature. All litter incidences from dose groups were well within the historical control data range and statistically insignificant when compared with the control. Craniofacial examination by razor blade serial sectioning technique revealed incidences of head, subcutaneous hematoma in all treated groups (45%, 50% and 45% in the LD, MD and HD groups, respectively) when compared to control (25%). Lower litter incidences of mid brain subdural oedema were observed in all treated groups (50% in each LD, MD and HD groups, respectively) when compared to control (65%). Higher litter incidences of increased subcutaneous space in head were observed in the LD and MD 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 the LD, MD and HD 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 and within the historical control range. Statistical analysis of the data revealed no statistical significance for any of these findings. 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 group. Statistically significantly higher foetal incidences were observed at 4th sternebra in the LD group (8%) when compared to 2% in control and at 3rd sternebra in the LD group (5%) when compared to control (0%). Statistically significantly higher foetal incidences were observed in skull supraoccipital with small hole in the HD group (60% compared to 34% in the control). All these findings were observed without dose dependency or consistency and therefore they were not considered to be test item-related. Without achieving statistical significance, the observed incomplete ossification of some bones and other incidental skeletal findings in the HD group were either marginally lower or higher than concurrent controls or within the historical control data range. Generally, delayed ossification is not regarded to persist post-natally and is not associated with longterm 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 In conclusion, the NOAELs for maternal and foetal toxicity of the source substance triethoxyphenylsilane in this study were considered to be 120 mg/kg bw/day and 400 mg/kg bw/day, respectively.

A key reliable OECD 422 combined repeated dose/reproductive and developmental screening study is available by the oral route for trimethoxyphenylsilane. The mean number of pups at first litter check was not affected by the treatment with the test item. The sex ratio was also not affected. No abnormal pups were noted at any dose level. During the lactation period, pup weight gain at 500 mg/kg bw/day was reduced compared to the controls, but did not attain statistical significance. The reaction was due primarily to lower weight gain which occurred in two litters. Excluding the lower pup weight which occurred in these two litters at 500 mg/kg bw/day, mean pup weight gain was not considered to be affected by the treatment with the test item. At necropsy of the pups, the incidence of pups with no milk in the stomach did not give any indication of a test item-related effect. General systemic parental effects were reported at the lowest tested dose of 100 mg/kg bw/day (SEHSC, 2009).

Also, a reliable combined repeated dose/reproductive and developmental screening study according to OECD 422 is available for the structural analogue triethoxy(phenyl)silane (CAS 780 -69 -8) (Eurofins, 2019). The test substance was administered in corn oil as vehicle at dosages of 40, 120, and 360 mg/kg body weight/day, and controls received the vehicle only. Two recovery groups were included which were treated with vehicle only or 360 mg test substance/kg bw/day. 

Treatment-related effects were observed in body weight and food consumption in the high dose group. One male rat from the high dose group with 360 mg/kg bw/day was sacrificed moribund on day 15. The death was considered treatment-related as a consequence of backflow nephrosis. At necropsy adverse effects in kidneys and urinary bladder were observed at 120 and 360 mg/kg bw/day. The systemic toxicity is described in detail under the chapter “repeated dose toxicity”.

There were no effects on litter data, litter weight data, pre and post-natal data, pup survival data, anogenital distance and nipple retention, pup thyroid weight and thyroid hormone analysis in parental males and pups sacrificed on PND 13 and male sacrificed at the end of recovery period and pup external findings in all groups up to 360 mg/kg bw/day.

A very slight and dose-dependent tendency towards lower a serum thyroxine hormone (T4) level was observed in PND 13 pups of the dose groups when compared to controls. A relation to treatment with the test item cannot be excluded. Based on the findings in the urinary tract, the NOAEL for triethoxy(phenyl)silane in this study for general toxicity is considered to be 40 mg/kg bw/day. As no effects were observed in any developmental toxicity aspects, the NOAEL for developmental toxicity is considered to be 360 mg/kg bw/day.

Based on the above mentioned results, read across between trimethoxyphenylsilane and triethoxy(phenyl)silane can be justified in accordance with Annex XI, 1.5, Regulation (EC) No. 1907/2006 to avoid tests in terms of animal welfare.

Justification for classification or non-classification

The available data on reproduction and developmental toxicity of the test substance do not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.

No information is available on effects via lactation.