Trimethoxy(methyl)silane

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

In the key Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test with trimethoxy(methyl)silane, conducted according to OECD Test Guideline 422 and in compliance with GLP, the NOAEL for reproductive toxicity was concluded to be at least 1000 mg/kg bw/day based on no adverse effects (Dow Corning Corporation, 2005).

In line with ECHA Final Decision No. TPE-D-2114453632-51-01/F for trimethoxy(methyl)silane, an extended one-generation reproductive toxicity study in rats, will be conducted according to OECD Test Guideline 443 and in compliance with GLP, and the study results will be submitted when available.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

19.11.2003 to 19.05.2005

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)

Qualifier:

according to guideline

Guideline:

other: USEPA OPPTS 870.3650

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: Crl:CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: No data
- Age at study initiation: Nine weeks
- Weight at study initiation: Males: 294.2-351.5; Females: 200.2-260.2 g
- Fasting period before study: None
- Housing: individually housed in suspended wire-mesh cages (pregnant rats in shoebox cages)
- Diet (e.g. ad libitum): Ad libitum (except during FOB)
- Water (e.g. ad libitum): Ad libitum (except during FOB)
- Acclimation period: Six days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.2-22.5
- Humidity (%): 36.0-62.0
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 09.02.2004 To: 19.04.2005

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Conducted over nitrogen atmopshere. Test substance was placed into a volumetric flask and corn oil added to achieve the desired volume. The weight of the test substance added to the flask was used to calculate nominal dose solution concentrations. Dosing solutions were prepared at least once every two weeks consistent with the previously determined 15-day stability. The concentration, homogeneity and stability of the test substance in vehicle for at least 15 days.

VEHICLE
- Justification for use and choice of vehicle (if other than water): No data
- Concentration in vehicle: Various
- Amount of vehicle (if gavage): Up to 3 ml/kg
- Lot/batch no. (if required): 122K0131
- Purity: Considered 100%

Details on mating procedure:

A 1:1 mating ratio was used. After dosing on study day 14, the animals were paired by placing the lowest numbered ear tag reproductive group female within each group in the home cage of the male with the lowest numbered ear tag from the same group. Female animals were housed continuously with the same male until evidence of copulation was obtained. Females were evaluated daily for evidence of copulation, as indicated by either a vaginal copulatory plug or sperm in the vaginal smear. Day 0 of gestation was defined as the day evidence of copulation was obtained, at which time the female was returned to her home cage (shoebox cage).

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The concentration of methyltrimethoxysilane (MTMS) in corn oil dosing solutions was determined prior to the beginning of the definitive study.

Duration of treatment / exposure:

Toxicity group females and males were treated for 28 and 29 days, respectively. Reproductive group females were treated for 14 days prior to the mating period, during the mating period, and then up to and including post partum day 3, for a total of up to 51 days.

Frequency of treatment:

Daily, seven days/week

Details on study schedule:

No further relevant details.

Dose / conc.:

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

Dose / conc.:

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

Dose / conc.:

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

Dose / conc.:

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

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Based on a range-finding study

Parental animals: Observations and examinations:

Mortality/Morbidity: Animals were observed at least twice daily in their cages for moribundity and mortality throughout the in-life phase of the study.
Clinical observations:
Daily Observations: General clinical examinations were made at least once a day and were conducted immediately after dosing. The examinations included, but were not limited to, changes in the skin, fur, eyes, mucous membranes, respiratory, circulatory, autonomic and central nervous system functions, motor activity and behavior patterns. Findings were recorded for individual animals. General clinical examinations were not performed on days when detailed physical examinations were performed.
Detailed Physical Examinations: All animals received a detailed physical examination once before the first dose administration (to allow for within-subject comparisons), and weekly thereafter. Examinations were made outside the home cage in a standard arena at approximately the same time each day. Observations were detailed and carefully recorded. Examinations included, but were not limited to, changes in skin, fur eyes, mucous membranes, occurrence of secretions and excretions, and autonomic activity. Changes in gait, posture and response to handling as well as the presence of clonic or tonic movement, stereotypies, difficult or prolonged parturition or bizarre behavior were recorded. The presence or absence of findings was recorded for individual animals.

Body weights and food consumption were recorded weekly. Additional body weights for reproductive group females were obtained on gestational day 0, 7, 14, and 20, and within 24 hours of parturition, and on postnatal day 4. Individual food consumption was determined for each group following group specific schedules. In addition, detailed clinical observations (functional observational battery [FOB] conducted out of the home cage) and locomotor activity were evaluated for all adult male and toxicity phase females once prior to the start of test article administration (baseline evaluations) and again during the last week of the test article administration. Blood samples were collected from males and toxicity group females on the day of scheduled termination for analysis of hematology and serum chemistry parameters.

Litter observations:

All reproductive phase females were allowed to deliver and rear their offspring to lactation day 4; surviving dams and pups were euthanized and examined on lactation day 4.On the day parturition was initiated (PND 0), the pups were sexed and examined for gross malformations, and the numbers of still born and live pups were recorded. Individual gestation length was calculated using the date delivery started. Abnormal behavior of the offspring was recorded. The dam and litter remained together until PND 4.

Mean measured parameters were calculated for:
Days of gestation
Undetermined sex
Male pups/litter
Female pups/litter
Males/Females per litter
Total pups/litter
Viable (live) pups/litter
Viable/Total pups per litter

Initial litter weight at parturition (g)
Initial average pup weight at parturition (g)
Final litter weight at PND 4 (g)
Final average pup weight at PND 4 (g)

Total number of implants
Corpora counts

Postmortem examinations (parental animals):

Clinical pathology assessments (hematology and serum chemistry) and macroscopic and microscopic examinations (including organ weights) were also performed on the appropriate groups of adult males and toxicity phase females. For females that delivered or had macroscopic evidence of implantation, the numbers of former implantation sites and corpora lutea were recorded. Recognizable fetuses for the females euthanized in extremis were examined externally and preserved in 10% neutral-buffered formalin. For females that failed to deliver, a pregnancy status was determined. Uteri with no macroscopic evidence of implantation were opened and subsequently placed in a 10% ammonium sulfide solution for detection of early implantation loss.

Postmortem examinations (offspring):

Intact offspring dying from PND 0 to 4 were necropsied. Cannibalized pups were discarded without necropsy. Tissues were preserved in 10% neutral-buffered formalin for possible future histopathologic examination only as deemed necessary by gross findings. The carcass of each pup was then discarded.

Statistics:

Reproductive parameters with the exception of litter size were analyzed using an ANCOVA (Analysis of Covariance) with liter size as the covariate. Litter size was analyzed using an ANOVA.

Reproductive indices:

Male (Female) Mating Index (%)
Male Fertility Index (%)
Male Copulation Index (%)
Female Fertility Index (%)
Female Conception Index (%)

Offspring viability indices:

On the day parturition was initiated (PND 0), the pups were sexed and examined for gross malformations, and the numbers of still born and live pups were recorded.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Thirty percent of the animals in the 50 mg/kg bw/day dose group and 100 % of the animals in the 250 and 1000 mg/kg bw/day dose groups exhibited a transient period of salivation and/or abnormal inactivity at least once over the course of treatment immediately after dosing.

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No statistically significant differences in treatment group maternal body weight relative to control group animals.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No statistically significant differences in treatment group maternal food consumption relative to control group animals.

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:

not examined

Histopathological findings: non-neoplastic:

not examined

Description (incidence and severity):

Histopathology was not assessed in the reproductive/developmental group animals.

Histopathological findings: neoplastic:

not examined

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Description (incidence and severity):

There were no treatment-related effects apparent for any of the reproductive endpoints. All females bred successfully and delivered live litters. Litter sizes were comparable for all groups. Differences in group mean values for the treated groups relative to the control group were small and none were found to be statistically significant.
"Number pregnant per dose level: 10
"Number aborting: 0
"Number of resorptions, early/late if available: None detected.
"Number of implantations: Group Mean (standard deviation): Control: 15 (2.2); 50 mg/kg bw/day bw/day: 16 (2.0); 250 mg/kg bw/day: 16 (1.4); 1000 mg/kg bw/day: 16 (1.9)
"Number of corpora lutea: Group Mean (standard deviation): Control: 19 (4.7); 50 mg/kg bw/day: 19 (3.1); 250 mg/kg bw/day:18(2.0); 1000 mg/kg bw/day: 17 (3.9)
"Duration of Pregnancy: Group Mean (standard deviation): Control: 21 (0.5); 50 mg/kg bw/day: 21(0.5); 250 mg/kg bw/day: 22(0.5); 1000 mg/kg bw/day: 22 (0.5)

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects on reproduction observed

Critical effects observed:

no

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

No gross abnormalities were found for any of the pups, with the exception of a single runt in the 50 mg/kg/day group.

Histopathological findings:

not examined

Behaviour (functional findings):

not examined

Developmental immunotoxicity:

not examined

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

>= 1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects observed in F1 pups.

Critical effects observed:

no

Reproductive effects observed:

no

Result: Exposure to methyltrimethoxysilane was not associated with reproductive  toxicity. The findings support a NOAEL of 1000 mg/kg/day.

NOAEL (NOEL) (maternal toxicity): >1000 mg/kg/day
NOAEL (NOEL) (reproductive toxicity):>1000 mg/kg/day
LOAEL (LOEL):  N/A

Conclusions:

In the key Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test with trimethoxy(methyl)silane, conducted according to OECD Test Guideline 422 and in compliance with GLP, the NOAEL for reproductive toxicity was concluded to be at least 1000 mg/kg bw/day based on no adverse effects.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

In the key Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test with trimethoxy(methyl)silane, conducted according to OECD Test Guideline 422 and in compliance with GLP, the NOAEL for reproductive toxicity was concluded to be at least 1000 mg/kg bw/day based on no adverse effects (Dow Corning Corporation, 2005). Thirty percent of the animals in the 50 mg/kg bw/day dose group and 100 % of the animals in the 250 and 1000 mg/kg bw/day dose groups exhibited a transient period of salivation and/or abnormal inactivity at least once over the course of treatment immediately after dosing. There were no statistically significant differences in treatment group maternal body weight and food consumption relative to control group animals. There were no treatment-related effects apparent for any of the reproductive endpoints. All females bred successfully and delivered live litters. Litter sizes were comparable for all groups. Differences in group mean values for the treated groups relative to the control group were small and none were found to be statistically significant.

The Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test with the structural analogue triethoxy(methyl)silane, conducted according to OECD Test Guideline 422 and in compliance with GLP (Bozo Research Center, 2012), has been included to the dossier to support the read-across approach used for developmental toxicity in first species.

Exposure to triethoxy(methyl)silane at doses of 0, 30, 150 and 750 mg/kg bw/day did not demonstrate any test substance-related effects on reproduction or development. The NOAEL for reproductive and developmental toxicity was at least 750 mg/kg bw/day, the highest dose tested, based on no adverse effects.

Effects on developmental toxicity

Description of key information

There are no developmental toxicity data available for the registered substance trimethoxy(methyl)silane. Therefore, data are read-across from the structural analogue triethoxy(methyl)silane (CAS 2031-67-6).

In the key prenatal developmental toxicity study with the structural analogue triethoxy(methyl)silane (CAS 2031-67-6), conducted according to OECD Test Guideline 414 and in compliance with GLP, the NOAEL for developmental toxicity in rats was concluded to be at least 1000 mg/kg bw/day based on no adverse effects on development of offspring observed up to and the highest dose tested (Covance Laboratories, 2020).

In line with ECHA Final Decision No. TPE-D-2114453632-51-01/F for trimethoxy(methyl)silane, a prenatal developmental toxicity study in a second species (rabbits), to be conducted according to OECD Test Guideline 414 and in compliance with GLP, has been planned and the dossier with be updated with the study results when available.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

August 2019 through November 2019

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Version / remarks:

25 June 2018

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

Department of Health of the Government of the United Kingdom

Limit test:

no

Species:

rat

Strain:

other: Crl:CD(SD)

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Ltd.
- Age at study initiation: 70 to 79 days old
- Weight at study initiation: 231 to 294 g
- Fasting period before study:
- Housing: Housed up to 4 animals per cage during acclimazation; housed one stock male and one female during mating; individually housed during gestation. Cages comprised of a polycarbonate body with a stainless steel mesh lid. Solid (polycarbonate) bottom cages were used during the acclimatization and gestation periods.
- Diet: SDS VRF1 Certified pelleted diet (manufactured in Witham, Essex, England), available ad libitum
- Water: Water from the public, available ad libitum
- Acclimation period: Six days before commencement of pairing

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 40-70
- Air changes (per hr): at least 15 air changes/hour
- Photoperiod (hrs dark / hrs light): 12 hours light : 12 hours dark

Route of administration:

oral: gavage

Vehicle:

other: Dried and de-acidified corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: The required amount of test item was added to the required volume of vehicle. The formulation was stirred using a magnetic stirrer under a fume hood until uniformly mixed and then transferred to final containers, via syringe, while magnetically stirring. A series of formulations at the required concentrations were prepared by dilution of individual weighing of the test item in ascending order of concentration.

VEHICLE
- Preparation of vehicle: 50% silica, 25% aluminum oxide neutral and 25% aluminum oxide activated acidic (40g, 20g and 20g respectively per liter of oil) were mixed. The dry mixture was placed in a vented oven set to 250 ºC overnight or for at least eight hours. The oil and dry materials were mixed in a suitable container, using a stir bar on a magnetic stirring plate, for at least two hours under a nitrogen purge and then allowed to dry to room temperature. The oil and dry materials mix was allowed to settle for a minimum of 30 minutes. The oil was filtered with 0.22 µm cellulose acetate filter system with vacuum to remove the alumina and silica.
- Amount of vehicle (if gavage): 4 mL/kg body weight.

Analytical verification of doses or concentrations:

yes

Remarks:

The mean concentrations of formulation samples taken from the first and last preparation were within 3% of the nominal concentration, confirming the accuracy of formulation. The difference from mean remained within 3%, confirming precise analysis.

Details on analytical verification of doses or concentrations:

Before commencement of treatment, the suitability of the proposed mixing procedures was determined and specimen formulations at 1 and 250 mg/mL were analyzed to assess the stability and homogeneity of the test item in the liquid matrix. Stability was confirmed as one day at ambient temperature (15 to 25 ºC) and fifteen days at refrigerated temperature (2 to 8 ºC).

Samples of each of the first and last preparation formulations were analyzed for achieved concentration of the test item.

Details on mating procedure:

- Impregnation procedure: cohoused
- M/F ratio per cage: 1:1
- Verification of same strain and source of both sexes: yes; a colony of stud males was maintained specifically for the purpose of mating; these animals were not part of the study and were maintained as stock animals.
- Proof of pregnancy: evidence of vaginal plug and sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

From Day 6 to Day 19 (inclusive) after mating

Frequency of treatment:

Daily

Dose / conc.:

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

Dose / conc.:

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

Dose / conc.:

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

No. of animals per sex per dose:

20 females per dose

Control animals:

yes, concurrent no treatment

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals were inspected visually at least twice daily for evidence of ill-health or reaction to treatment. Cages were inspected daily for evidence of animal ill-health amongst the occupant(s).

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Detailed observations were recorded daily during the treatment period at the following times in relation to dose administration: pre-dose observation; one to two hours after completion of dosing; as late as possible in the working day. A detailed physical examination was performed on each animal on Days 0, 5, 12, 18 and 20 after mating to monitor general health.

BODY WEIGHT: Yes
- Time schedule for examinations: The weight of each adult was recorded on Days 0, 3 and 6-20 after mating.

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

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: See Table 1

OTHER: A thyroid hormone analysis was performed on all animals, which occurred at scheduled termination. Animals were not fasted. Samples were analysed for serum thyroxine (T4) and triiodothyronine (T3) levels, as well as thyroid-stimulating hormone (TSH).

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

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

Statistics:

The following sequence of statistical tests was used for body weight, gravid uterus weight, food consumption, corpora lutea, implantations, pre/post implantation loss, live young, sex ratio - percentage male, placental, litter and fetal weights and organ weight data:

A parametric analysis was performed if Bartlett's test for variance homogeneity was not significant at the 1% level. For pre-treatment data, analysis of variance was used to test for any group differences. Where this was significant (p<0.05) inter group comparisons using t-tests, with the error mean square from the one-way analysis of variance, were made. For all other analyses the F1 approximate test was applied. If the F1 approximate test for monotonicity of dose-response was not significant at the 1% level, Williams' test for a monotonic trend was applied. If the F1 approximate test was significant, suggesting that the dose response was not monotone, Dunnett's test was performed instead.

A non-parametric analysis was performed if Bartlett's test was still significant at the 1% level following both logarithmic and square-root transformations. Forpre-treatment data, Kruskal-Wallis’ test was used to test for any group differences. Where this was significant (p<0.05) inter group comparisons using Wilcoxon rank sum tests were made. For all other analyses the H1 approximate test, the non-parametric equivalent of the F1 test described above, was applied. If the H1 approximate test for monotonicity of dose-response was not significant at the 1% level, Shirley's test for a monotonic trend was applied. If the H1 approximate test was significant, suggesting that the dose-response was not monotone, Steel's test was performed instead.

For organ weight data, analysis of covariance was performed using terminal body weight as covariate, unless non-parametric methods were applied.

Indices:

Pre-implantation loss (%) = ((Number of copora lutea - Number of implantations)/Number of corpora lutea) X 100
Post-implantation loss (%) = ((Number of copora lutea - Number of implantations)/Number of implantations) X 100

Historical control data:

Historical Control data was included and used for the evaluation of both fetal and litter incidences.

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

effects observed, non-treatment-related

Description (incidence and severity):

At 1000 mg/kg bw/day group mean food consumption was slightly lower, and attained statistical significance, during Days 6-18 of gestation when compared with the group mean food consumption of the control group.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

The mean gravid uterine weight for females treated with triethoxy(methyl)silane was comparable to the mean gravid uterine weight from the control females, as was adjusted body weight gain.

The weight of the liver was higher in females treated with 1000 mg/kg bw/day when compared with the controls (136% of the controls, respectively) and slightly higher in females receiving 300 mg/kg bw/day (109% of the controls, respectively). The weight of the thyroids and parathyroids were higher in females receiving 1000 mg/kg bw/day triethoxy(methyl)silane (129% of the controls, respectively). The weight changes stated above all attained statistical significance.

Gross pathological findings:

no effects observed

Neuropathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

In the thyroids, minimal/slight follicular cell hypertrophy was seen in all treated groups, with a clear relationship to dose. The hypertrophy was considered to account for the statistically significant higher than control group mean bodyweight adjusted thyroid weights for females that received 1000 mg/kg bw/day. This effect is likely secondary to the increase in TSH, which is a compensatory feedback mechanism to increase thyroid hormone production by the thyroid gland and part of a homeostatic response by the hypothalamic-pituitary-thyroid axis.

Histopathological findings: neoplastic:

not examined

Other effects:

effects observed, treatment-related

Description (incidence and severity):

The analysis of serum TSH concentrations performed at scheduled termination on Day 20 of gestation revealed that the TSH level at 1000 mg/kg bw/day was found to be statistically significantly higher compared to the control group at the 0.1% (p < 0.001) level.

There was a decrease in T4 and T3 concentration in females receiving 1000 mg/kg bw/day triethoxy(methyl)silane, both were found to be statistically significantly lower compared to the control group at the 0.1% (p < 0.001) level.

It was concluded that there was an effect of triethoxy(methyl)silane on serum T3, T4 and TSH concentrations in pregnant rats at a dose level of 1000 mg/kg bw/day, administered via oral gavage. It is possible that the change in TSH and thyroid hormones were secondary to liver enzyme induction and enhanced metabolism and clearance of thyroid hormones, which is consistent with increased liver weights.

Number of abortions:

no effects observed

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

no effects observed

Early or late resorptions:

no effects observed

Dead fetuses:

no effects observed

Changes in pregnancy duration:

no effects observed

Changes in number of pregnant:

no effects observed

Other effects:

not examined

Key result

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Basis for effect level:

other: No adverse effects observed

Key result

Abnormalities:

no effects observed

Fetal body weight changes:

no effects observed

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

no effects observed

Changes in postnatal survival:

no effects observed

External malformations:

no effects observed

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

At 1000 mg/kg bw/day there was a slight increase in incidence of cranial interparietal fissure(s) compared to concurrent control and was outside historical control data range. In isolation and at such low incidence this was not considered adverse.

Visceral malformations:

effects observed, non-treatment-related

Description (incidence and severity):

At 1000 and 300 mg/kg bw/day there was a slight increase in the incidence of partially undescended thymus compared to concurrent control but was within historical control data range and therefore considered unrelated to treatment. This is a transient stage in fetal development and therefore not considered adverse.

Other effects:

not examined

Key result

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects observed

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

Conclusions:

Based on the results of this study, no adverse effects on development of offspring were observed up to and including 1000 mg/kg bw/day, the highest dose tested.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

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

There are no developmental toxicity data available for the registered substance trimethoxy(methyl)silane. Therefore, data are read-across from the structural analogue triethoxy(methyl)silane (CAS 2031-67-6). See attachment to Section 13 for justification of read-across.

In the key prenatal developmental toxicity study with the structural analogue triethoxy(methyl)silane (CAS 2031-67-6), conducted according to OECD Test Guideline 414 and in compliance with GLP, 0, 100, 300 and 1000 mg/kg bw/day triethoxy(methyl)silane in corn oil were administered daily via oral (gavage) to 20 pregnant female rats per group from gestation days (GD) 6 to 19 (Covance Laboratories, 2020).

The animals were inspected visually at least twice daily for evidence of ill-health or reaction to treatment.  Cages were inspected daily for evidence of animal ill-health amongst the occupant(s). Detailed observations were recorded daily during the treatment period at the following times in relation to dose administration: pre-dose observation; one to two hours after completion of dosing; as late as possible in the working day. A detailed physical examination was performed on each animal on GDs 0, 5, 12, 18 and 20 after mating to monitor general health. The weight of each adult was recorded on GDs 0, 3 and 6-20 after mating. Food consumption was also determined for each animal. A thyroid hormone analysis was performed on all animals at scheduled termination. Samples were analysed for serum thyroxine (T4) and triiodothyronine (T3) levels, as well as thyroid-stimulating hormone (TSH). The animals were sacrificed on GD 20 and gravid uterine weight was recorded and uterine content was examined for number of corpora lutea, implantations and, early and late resorptions. All fetuses were examined for external abnormalities, while half of the fetuses were examined for visceral, skeletal and head malformations.

There were no treatment-related deaths observed during the course of the study and there were no treatment-related clinical signs of toxicity. At 1000 mg/kg bw/day group mean food consumption was slightly lower, and attained statistical significance, during Days 6-18 of gestation when compared with the group mean food consumption of the control group. There were no effects on body weight gain.

The mean gravid uterine weight for females treated with triethoxy(methyl)silane was comparable to the mean gravid uterine weight from the control females, as was adjusted body weight gain.

The weight of the liver was higher in females treated with 1000 mg/kg bw/day when compared with the controls (136% of the controls) and slightly higher in females receiving 300 mg/kg bw/day (109% of the controls).  The weight of the thyroids and parathyroids were higher in females receiving 1000 mg/kg bw/day triethoxy(methyl)silane (129% of the controls).  The weight changes stated above all attained statistical significance.

The analysis of serum TSH concentrations performed at scheduled termination on Day 20 of gestation revealed that the TSH level at 1000 mg/kg bw/day was found to be statistically significantly higher compared to the control group at the 0.1% (p < 0.001) level.  

There was a decrease in T4 and T3 concentration in females receiving 1000 mg/kg bw/day triethoxy(methyl)silane, both were found to be statistically significantly lower compared to the control group at the 0.1% (p < 0.001) level.

It was concluded that there was an effect of triethoxy(methyl)silane on serum T3, T4 and TSH concentrations in pregnant rats at a dose level of 1000 mg/kg bw/day, administered via oral gavage. It is possible that the change in TSH and thyroid hormones were secondary to liver enzyme induction and enhanced metabolism and clearance of thyroid hormones, which is consistent with increased liver weights.

There were no effects observed at gross necropsy. In the thyroids, minimal/slight follicular cell hypertrophy was seen in all treated groups, with a clear relationship to dose.  The hypertrophy was considered to account for the statistically significantly higher than control group mean bodyweight adjusted thyroid weights for females that received 1000 mg/kg bw/day. This effect is likely secondary to the increase in TSH, which is a compensatory feedback mechanism to increase thyroid hormone production by the thyroid gland and part of a homeostatic response by the hypothalamic-pituitary-thyroid axis.

There were no treatment-related effects on abortions, number of implantations, resorptions, live and dead fetuses, pregnancy duration and number of pregnant rats.

There were no treatment-related effects on litter parameters such as fetal body weight changes, number of live fetuses, sex ratio and litter size. There were no external malformations noted for any of the fetuses. At 1000 mg/kg bw/day there was a slight increase in incidence of cranial interparietal fissure(s) compared to concurrent control that was outside historical control data range.  In isolation and at such low incidence this was not considered adverse. At 1000 and 300 mg/kg bw/day there was a slight increase in the incidence of partially undescended thymus compared to concurrent controls but within historical control data range, and therefore considered unrelated to treatment.  This is a transient stage in fetal development and therefore not considered adverse.

The NOAEL for developmental toxicity in rats was concluded to be at least 1000 mg/kg bw/day based on no adverse effects on development of offspring were observed up to and the highest dose tested.

In a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test with trimethoxy(methyl)silane, conducted according to OECD Test Guideline 422 and in compliance with GLP, the NOAEL for reproductive toxicity was concluded to be at least 1000 mg/kg bw/day based on no adverse effects (Dow Corning Corporation, 2005). There were no treatment-related effects apparent for any of the reproductive endpoints. All females bred successfully and delivered live litters. Litter sizes were comparable for all groups. Differences in group mean values for the treated groups relative to the control group were small and none were found to be statistically significant. Developmental toxicity was not apparent at any dose level. There were no grossly visible abnormalities, external, soft tissue and skeletal abnormalities. No gross abnormalities were found for any of the pups, with the exception of a single runt in the 50 mg/kg bw/day group.

The Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test with the structural analogue triethoxy(methyl)silane, conducted according to OECD Test Guideline 422 and in compliance with GLP (Bozo Research Center, 2012), has been included to the dossier to support the read-across approach used for developmental toxicity in first species.

Exposure to triethoxy(methyl)silane at doses of 0, 30, 150 and 750 mg/kg bw/day did not demonstrate any test substance-related effects on reproduction or development. The NOAEL for reproductive and developmental toxicity was at least 750 mg/kg bw/day, the highest dose tested, based on no adverse effects.

Justification for classification or non-classification

Based on the available data for trimethoxy(methyl)silane and read-across data, the registered substance does not require classification for reproductive or developmental toxicity according to Regulation (EC) No. 1272/2008.