Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information
No other studies are availabe.
Link to relevant study records

Referenceopen allclose all

Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Data waiving:
other justification
Justification for data waiving:
other:
Reproductive effects observed:
not specified
Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
19.11.2003 to 19.05.2005
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was carried out in accordance with an appropriate OECD test guideline and in compliance with GLP. Reliability was set to 2, as it was used as a read-across.
Justification for type of information:
Please refer to the attached justification below and the overall justification for grouping of substances attached in IUCLID Section 13.
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Qualifier:
according to
Guideline:
other: USEPA OPPTS 870.3650
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals 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.
Remarks:
Doses / Concentrations:
0 (corn oil), 50, 250, and 1000 mg/kg/day
Basis:
actual ingested
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
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Gross pathological findings:
no effects observed
Reproductive performance:
no effects observed
"Mortality and day of death:         None.
"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: 16 (2.0);    250 mg/kg: 16 (1.4);  1000 mg/kg: 16 (1.9) 
"Number of corpora lutea: Group Mean (standard deviation): Control: 19(4.7); 50 mg/kg: 19(3.1); 250 mg/kg:18(2.0); 1000 mg/kg:  17(3.9)
"Duration of Pregnancy:  Group Mean (standard deviation):        Control: 21  (0.5); 50 mg/kg: 21(0.5); 250 mg/kg: 22(0.5);   1000 mg/kg: 22(0.5)
"Body weight:  No statistically significant differences in treatment group maternal body weight relative to control group animals.
"Food/water consumption:  No statistically significant differences in treatment group maternal food consumption relative to control group animals.
"Description, severity, time of onset and duration of clinical signs:  Thirty percent of the animals in the 50 m/kg/day dose group and 100 % of the animals in the 250 and 1000 mg/kg/day dose groups exhibited a transient period of salivation and/or abnormal inactivity at least once over the course of treatment  immediately after dosing.
"Gross pathology incidence and severity:  Gross pathology of the  reproductive/developmental group animals was not an endpoint for this study.
"Organ weight changes, particularly effects on total uterine weight:   Organ weight was not assessed in the reproductive/developmental group animals.
"Histopathology incidence and severity:  Histopathology was not assessed in the reproductive/developmental group animals. No treatment-related effects were observed in any of the reproductive parameters evaluated. All females bred successfully and delivered live litters. 

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.
Key result
Dose descriptor:
NOAEL
Remarks:
reproduction
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed
Clinical signs:
no effects observed
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:
no effects observed
Histopathological findings:
not examined
No gross abnormalities were found for any of the pups, with the exception of a single runt in the 50 mg/kg/day group.
Key result
Dose descriptor:
NOAEL
Remarks:
reproduction
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
Reproductive effects observed:
not specified

Result: Exposure to trimethoxy(methyl)silane was not associated with reproductive toxicity. The findings support a NOAEL of 1000 mg/kg/day.

NOAEL (maternal toxicity): 50 mg/kg/day
NOAEL (reproductive toxicity): 1000 mg/kg/day
LOAEL (maternal toxicity): 250 mg/kg bw/day

Conclusions:
Exposure to trimethoxy(methyl)silane was not associated with reproductive toxicity. The findings support a NOAEL of 1000 mg/kg bw/day.
Endpoint:
toxicity to reproduction
Remarks:
other: Sub-acute
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Study period:
No data
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: 4b The result is sourced from secondary literature (IUCLID 2000 data set). The original reference was not available for review and no further information is available. The study is a read-across from a structural analogue substance.
Justification for type of information:
Please refer to the attached justification below and the overall justification for grouping of substances attached in IUCLID Section 13.
Qualifier:
equivalent or similar to
Guideline:
other: OECD Guideline 412 (Repeated Dose Inhalation Toxicity: 28/14-Day)
Deviations:
yes
Remarks:
Range-finding study only
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
inhalation
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on mating procedure:
Not applicable
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
Exposure period: 9 days
Duration of test: 9 days
Frequency of treatment:
6 hr/day, 5 day/wk
Details on study schedule:
Not applicable
Remarks:
Doses / Concentrations:
0.2, 1 and 5 ppm
Basis:

No. of animals per sex per dose:
10/sex/group
Five additional animals/sex were in the control and 5 ppm groups for a 14-day recovery group. 
Control animals:
yes, concurrent no treatment
Details on study design:
Three groups, consisting of 10 male and 10 female Sprague Dawley. rats, were exposed 6 hours/day, 5 days/week, for 9 days to trimethoxysilane vapor at target concentrations of 0.2, 1, and 5 ppm. A control group was exposed to filtered air alone. Five additional animals/sex were in the control and 5 ppm groups for a 14-day recovery group. 
Reproductive indices:
Testes weights were collected.
Dose descriptor:
NOAEC
Effect level:
1 ppm
Sex:
male/female
Reproductive effects observed:
not specified

The one surviving male animal exposed to 5 ppm for 9 days
was observed to have increased testes weight (absolute and relative to  

body weight); the relative testes weight (as a percentage of brain  

weight) for this one animal was decreased.  Interpretation of these  

findings must be performed with caution due to the small number of  

animals (one) and its moribund condition.

Conclusions:
In a IUCLD 2007 summary of an inhalation range-finding study (reliability score 4) conducted using a protocol similar to OECD 412, and to GLP, trimethoxysilane vapor at 5 ppm was lethal, with death probably being a consequence of respiratory tract injury. Based on the body weights, organ
weights, the clinical pathology, and the necropsy and histopathologic observations, the NOAEL for trimethoxysilane in rats exposed for 9 days was 0.2 ppm. The reproductive toxicity NOAEL was a cautious 1 ppm based on effects on testes weight in one surviving animal at 5 ppm.
Executive summary:

In a IUCLD 2007 summary of an inhalation range-finding study (reliability score 4) conducted using a protocol similar to OECD 412, and to GLP, trimethoxysilane vapor at 5 ppm was lethal, with death probably being a consequence of respiratory tract injury. Based on the body weights, organ weights, the clinical pathology, and the necropsy and histopathologic observations, the NOAEL for trimethoxysilane in rats exposed for 9 days was 0.2 ppm. The reproductive toxicity NOAEL was a cautious 1 ppm based on effects on testes weight in one surviving animal at 5 ppm.

Endpoint:
toxicity to reproduction
Remarks:
other: subchronic
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Study period:
19.08.1993 to 06.01.1995
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
2b The study was conducted according to an appropriate OECD test guideline, with acceptable restrictions. The restrictions were that low exposure concentrations were used, an exposures were only on five days per week. The study is a read-across from a structural analogue substance.
Justification for type of information:
Please refer to the attached justification below and the overall justification for grouping of substances attached in IUCLID Section 13.
Qualifier:
equivalent or similar to
Guideline:
other: OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
inhalation
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on mating procedure:
No mating, this is a repeated dose study
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
Exposure period: 90 days
Duration of test: 90 days
Frequency of treatment:
6 hr/day, 5 day/wk
Details on study schedule:
Not applicable
Remarks:
Doses / Concentrations:
0.2, 0.1, and 0.51 ppm
Basis:

No. of animals per sex per dose:
Three groups, consisting of 10 male and 10 female Sprague Dawley® rats with an additional 5 rats/sex in the control and high exposure groups
Control animals:
yes, concurrent no treatment
Details on study design:
Three groups, consisting of 10 male and 10 female Sprague Dawley® rats with an additional 5 rats/sex in the control and high exposure groups, were exposed 6 hours/day, 5 consecutive days/week, for 13 weeks to trimethoxysilane Y-4398 (trimethoxysilane, CAS No. 2487-90-3) vapor at target concentrations of 0.02, 0.1, and 0.5 ppm. The control group (0 ppm) was exposed to filtered air alone. Five animals/sex in the control and 0.5 ppm groups were maintained for a 4-week recovery period. 
Reproductive indices:
Reproductive organs (testes, epididymis, prostate, seminal vesicles, ovaries, vagina and uterus) were evaluated.
Histopathological findings: non-neoplastic:
no effects observed
Dose descriptor:
NOAEC
Effect level:
> 0.51 ppm
Sex:
male/female
Reproductive effects observed:
not specified

Result: There were no test article related effects in any of the reproductive organs at the highest concentration tested (0.51 ppm) after 90 days exposure.

Conclusions:
In a good quality 90-day inhalation study (reliability score 2) conducted in a study comparable to OECD 413 and GLP, the NOAEL for trimethoxysilane was greater than 0.51 ppm (the highest dose tested) in rats exposed six hours/day, five days/week, followed by a four-week recovery period. There were no test substance-related effects in any of the reproductive organs up to the highest concentration tested.
Executive summary:

In a good quality 90-day inhalation study (reliability score 2) conducted in a study comparable to OECD 413 and GLP, the NOAEL for trimethoxysilane was greater than 0.51 ppm (the highest dose tested) in rats exposed six hours/day, five days/week, followed by a four-week recovery period. There were no test substance-related effects in any of the reproductive organs up to the highest concentration tested.

No reproductive toxicity studies have been conducted with trimethoxysilane; this substance is a highly reactive
toxicant, it is unlikely to reach the reproductive organs or the embryo/fetus and result in toxicity.  In repeated dose
toxicity studies, the NOAEL were identified as >0.51 ppm (after 28 or 90 days exposure) and 0.2 ppm (after 9 days exposure).
These repeated dose studies indicated that a maximum concentration of 0.5 ppm would be required for a
reproduction study in order to avoid death or obvious suffering due to respiratory damage.  The data provided in
the repeated dose toxicity studies indicate a practical and humane dose range for reproductive toxicity studies is below
the limit of toxicological significance. Furthermore, trimethoxysilane is a site limited chemical intermediate
that is not transported from the site of manufacture. Trimethoxysilane is produced in closed systems that are hard
piped.  Final products generally contain less than 0.001 %, but may contain up to 0.2% trimethoxysilane.

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
Quality of whole database:
OECD guideline study in compliance with GLP. Results are sufficient to assess the endpoint "Toxicity to reproduction".
Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
2.55 mg/m³
Study duration:
subchronic
Species:
rat
Quality of whole database:
OECD guideline study in compliance with GLP. Used concentrations were lower as proposed in the respective OECD guideline due to the irritating effects of the test substance. The NOAEC rather describes local than systemic effects.
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

There are no reliable studies that investigate the potential for trimethoxysilane to cause adverse effects on fertility; therefore a reliable oral OECD 422 study on the structural analogue, trimethoxy(methyl)silane, has been used. In addition there is a 90 day rat inhalation study on trimethoxysilane that did not show any adverse treatment-related effects on the reproductive organs up to an exposure concentration of 2.55 mg/m³.

In the OECD 422 study male and female rats were dosed with 50, 250, and 1000 mg/kg bw/day with trimethoxy(methyl)silane for up to 29 and 51 days, respectively. No mortality was observed and no difference in body weight gain was observed within the treatment and control group animals. No effects on the reproductive endpoints and no maternal toxicity have been observed. Gross pathology and organ weight were not assessed in the study. In conclusion a NOAEL of 1000 mg/kg bw was deduced for both, maternal and reproductive toxicity.

In a good quality 90-day inhalation study (reliability score 2) conducted in a study comparable to OECD 413 and in compliance with GLP, the NOAEC for trimethoxysilane was greater than 0.51 ppm (the highest dose tested; 2.55 mg/m³) in rats exposed six hours/day, five days/week, followed by a four-week recovery period. There were no test substance-related effects in any of the reproductive organs up to the highest concentration tested. The repeated dose studies indicated that a maximum concentration of 0.5 ppm would be required for a reproduction study in order to avoid death or obvious suffering due to respiratory damage (LOAEL in the range-finder was 1 ppm, based on local corrosive effects). 


Short description of key information:
No studies have been conducted with triethoxysilane for reproductive toxicity. Since the 90 day inhalation study tested very low concentrations of trimethoxysilane, it is appropriate to read-across from the structural analogue, trimethoxy(methyl)silane, for which there is an oral OECD 422 study. In this study reproductive effects were not observed up to a dose of 1000 mg/kg bw/day.

Effects on developmental toxicity

Description of key information
A study similar to a OECD 414 is available for the analogue substance disodium metasilicate (CAS 6834-92-0), where the NOAEL for maternal toxicity was 12.5 mg/kg bw for maternal toxicity and 200 mg/kg bw (highest dose tested) for developmental toxicity.
Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No tables provided with report; results only discussed qualitatively. Therefore, limited amount of information available.
Justification for type of information:
Please refer to the attached justification below and the overall justification for grouping of substances attached in IUCLID Section 13.
Principles of method if other than guideline:
Application of Na-metasilicate via gavage from day 0 to 18 of gestation. Examination of fetuses and and newborns.
GLP compliance:
no
Limit test:
no
Species:
mouse
Strain:
other: JLC-TCR
Details on test animals and environmental conditions:
Well developed males and females 8-13 weeks of age and  27-35 g/animal.
Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
17-18 days
Frequency of treatment:
daily
Duration of test:
18 days
Remarks:
Doses / Concentrations:
12.5, 50 or 200 mg/kg bw/d
Basis:
nominal conc.
Control animals:
yes
Details on study design:
Sex: male/female
Maternal examinations:
body weight
Ovaries and uterine content:
counting of nidations, corpi lutei and living/dead fetuses
Fetal examinations:
weighing of living fetuses and important organs, sex determination, examination of integument anomalies, naked eye  examination of other changes
Parameters evaluated were: number of neonates, parturition failures, body weight gain, behavioral development in the Running
and Rod Grasping Test (see below) and skeletal development.
Key result
Dose descriptor:
NOAEL
Effect level:
12.5 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Key result
Dose descriptor:
NOAEL
Effect level:
> 200 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Abnormalities:
not specified
Dose descriptor:
NOAEL
Effect level:
> 200 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Abnormalities:
no effects observed
Developmental effects observed:
no

TOXIC RESPONSE/EFFECTS BY DOSE LEVEL: 
- Parental data and F1: 
- Body weight: no treatment-related effects were observed in either mother animals, fetuses delivered by hysterectomy or

neonates. 

- Fertility index: 
Dose [mg/kg bw/d] pregnancies/mated female    % pregnancies
---------------------------------------------------------------
     0 (control)             20/26                   77%
    12.5                      22/24                   92%
    50                        20/31                   65%
   200                        21/25                   84%

- Duration of gestation: 18 days

- Mortality: 2/27 females administered 50 mg/kg and 2/33 females administered 200 mg/kg died during the exposure period. In

one female of  the highest dose group all fetuses died at an early stage. No parturition  fatalities were observed when mothers

were allowed to deliver their young  naturally. 
- Gross pathology incidence and severity: observed skeletal malformations  in neonates like cervical vertebrae, tail vertebrae

and vomer adhesion  occurred in the controls, too, and did not show a dosage correlation. No  malformations of the skeleton or

the inner organs of fetuses delivered by  hysterectomy were observed; the frequency of malformations and  abnormalities of theexternal integument, like opened eyes, cleft palate  and exencephaly showed a slight tendency toward dose dependance, but it  was lower than in the control. No effects on main organs of both mothers and neonates as compared to controls.
- Number of corpora lutea: No significant differences between control and  test groups, but actual numbers not reported.
- Organ weight changes: No treatment-related effects of organ weights of  mother animals and neonates; not reported for

fetuses delivered by hysterectomy.


- Offspring toxicity F1: 
- Litter size and weights: There was a dose-related, but not  statistically significant decrease in litter size.
Dose [mg/kg bw/d]    average no. of neonates/litter
-----------------------------------------------------
     0 (control)            14.7 +- 2.4
    12.5                      13.8 +- 2
    50                        12.9 +- 2
   200                        12.8 +- 2

- Post natal survival until weaning: no treatment-related effects on body  weight gain. 
- Effects on offspring: a dose-related, but not statistically significant  decrease in embryo weight and delayed
ossification process was observed.
- Postnatal growth, growth rate: no treatment related effects
- Other observations: no treatment-related effects in the Running Test  and the Rod Grasping Test.

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Study period:
19.11.2003 to 19.05.2005
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study was carried out in accordance with an appropriate OECD test guideline and in compliance with GLP. Since this is a read-across from a structural analogue substance, the reliability was set from RL1 to RL2.
Qualifier:
according to
Guideline:
other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Qualifier:
according to
Guideline:
other: USEPA OPPTS 870.3650
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals 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%
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.
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).
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, 7 days/week
Duration of test:
51 days
Remarks:
Doses / Concentrations:
0 (corn oil), 50, 250, and 1000 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
No further relevant details.
Maternal 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.

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.

WATER CONSUMPTION: No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #
- Organs examined:

OTHER:
Ovaries and uterine content:
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.
Fetal examinations:
Each litter was examined following delivery to determine the number and sex of the pups, stillbirths, live births, runts, sex ratio, and the presence of any gross abnormalities. Litter weights were taken within 24 hours of parturition and on day 4 postpartum.
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.
Statistically significant probabilities are reported at either the p<0.05 or p<0.01 levels.
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.
Details on maternal toxic effects:
Details on maternal toxic effects:
"Body weight: No statistically significant differences in treatment group maternal body weight relative to control group animals.
"Food/water consumption: No statistically significant differences in treatment group maternal food consumption relative to control group animals.
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No gross abnormalities were found for any of the pups, with the exception of a single runt in the 50 mg/kg/day group.
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: teratogenicity
Developmental effects observed:
no

Result: Maternal toxicity was not apparent at any dose level.  NOAEL = 1000  mg/kg/day.  Developmental toxicity was not apparent at any dose level.   

NOAEL = 1000 mg/kg/day.

Grossly visible abnormalities, external, soft tissue and skeletal abnormalities:  None.

Litter sizes were comparable for all groups.  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.

Conclusions:
Exposure to trimethoxy(methyl)silane was not associated with developmental toxicity. The findings support a NOAEL of 1000 mg/kg/day.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
200 mg/kg bw/day
Study duration:
subacute
Species:
mouse
Quality of whole database:
Reliable study performed with an analogue substance with limited amount of information. Sufficient for assessment of developmental toxicity as discussed in the OECD SIDS (Soluble Silicates).
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

A study similar to an OECD 414 is available for an analogue substance disodium metasilicate (CAS 6834-92-0), where the NOAEL was 12.5 mg/kg bw for maternal toxicity and 200 mg/kg bw (highest dose tested) for developmental toxicity. The NOAEL of 12.5 for parental toxicity was probably based on the mortality of 2/27 females in the 50 mg/kg bw group. No further information is given regarding the dead females. Thus, it can not be excluded, that substance-related systemic parental toxicity would be observed only at higher doses.

In the study by Saiwai et al. (1980), pregnant mice were administered 12.5, 50 or 200 mg/kg bw/d sodium metasilicate in aqueous solution from day 0 until 17/18 of gestation by daily gavage. Among the mother animals 2 fatalities occurred both in the 50 and 200 mg/kg group (total number of animals: 33 and 27, respectively); body and organ weights and dissection findings were not affected. On day 18 of gestation fetuses were delivered by hysterectomy and examined. No differences to controls were observed for the following parameters: number of pregnancies and living or dead fetuses, body weight and malformations of inner organs and the skeleton. 10 mother animals were allowed to deliver their young naturally. The neonates were observed for 30 days. Litter size and fertility index were not significantly affected up to and including 200 mg/kg bw/d. Body weight gain, organ weights and behavioral development did not reveal any differences to the control. Skeletal malformations did not exhibit a correlation with dosage. A dose-related decrease in the number of neonates was observed, however, this was not statistically significant.

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.