Registration Dossier

Administrative data

Key value for chemical safety assessment

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:
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 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
Developmental Screening Test : 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
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:
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 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.
Effect on developmental toxicity: 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 OECD test guideline 422, 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 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 anallogue 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.  

An OECD 414 study with triethoxy(phenyl)silane has been commissioned and once the study is available it will be read across to trimethoxyphenylsilane (CAS 2996-92-1) based on an analogue approach, 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.