Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

In a good quality one-generation reproductive toxicity study (RCC, 2004) conducted to OECD Test Guideline 415 and in compliance with GLP, the parental toxicity and reproductive NOAELs for 3-(2,3-epoxypropoxy)propyltrimethoxysilane were 500 and = 1000 (the highest dose tested) mg/kg bw/day, in rats. Treatment with the test substance resulted in signs of discomfort after dosing (noted for P females from early /mid gestation onwards), decreased body weight gain of males, and increased absolute and relative liver and kidney weights in P males and females. Histopathology revealed effects on livers and kidneys of males.

Link to relevant study records
Reference
Endpoint:
one-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
13.10.2003 to 30.04.2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: RCC Ltd., Laboratory Animal Services, Switzerland
- Age at study initiation: (P) x 6-8 wks
- Weight at study initiation: (P) Males: 144-184 g; Females: 162-190 g
- Fasting period before study: None
- Housing: During the pre-pairing period, males and females were housed individually. During the pairing period, the rats were housed two females/one male in Makrolon pairing cages. After positive mating or at the end of the pairing period, the males and females were housed individually again; males until necropsy and the females for the birth and rearing of young. On the day of weaning, the dam was separated from its litter.
- Use of restrainers for preventing ingestion (if dermal): yes/no
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: Seven days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22± 3
- Humidity (%): 30-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 20.10.2003 To: 30.04.2004
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The test substance was administered in dried corn oil. Mixtures of the test substance in the vehicle (weight:volume) at the appropriate concentrations were freshly prepared once per week using a magnetic stirrer.
Details on mating procedure:
- M/F ratio per cage: 1:2
- Length of cohabitation: 21 days maximum
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
- After 21 days of unsuccessful pairing replacement of first male by another male
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): individually
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Verification analyses of the actual test substance concentrations, stability during administration (2 hours) and over seven days, and homogeneity in the prepared mixtures were performed on the prepared mixtures on three days (one during pre-pairing, one during gestation and one during the lactation period). On the day of preparation, samples of each dose concentration were taken before dosing. Samples from before dosing were taken from the top, middle and bottom of the container. Later, samples were taken from the middle of the container for verification of stability at room temperature for two hours and for seven days. Analysis was performed using gas chromatography.
Duration of treatment / exposure:
Exposure period: Males: Exposed for a 70-day pre-pairing period, during pairing and until the last litter reached day 7 post-partum. Females: Exposed during pairing and until the last litter reached day 7 postpartum. Premating exposure period (males): 70 days. Premating exposure period (females): 14 days . Duration of test: until the last litter reached day 7 postpartum.
Frequency of treatment:
once daily
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Dose / conc.:
500 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:
12 male and 24 female
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose levels were selected in conjunction with the sponsor, based on the results of preceding prenatal developmental and repeated dose toxicity studies.
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were examined at least twice daily for mortality and signs of a reaction to treatment and/or symptoms of ill health.

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: Daily from start of treatment until necropsy. Organs weighed were: pituitary gland, liver, kidneys, testes, prostate, seminal vesicles with coagulating glands, epididymides, ovaries and uterus with cervix and oviducts.

FOOD CONSUMPTION:
- Food consumption for females was recorded weekly from start of treatment to delivery (except mating period). During lactation, food consumption was recorded on days 1, 7 and 14 post-partum. Since pups begin to consume material feed on or about lactation day 14, food consumption was not recorded after this day. For males, food consumption was recorded weekly from treatment start until necropsy, except during mating.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
Oestrous cyclicity (parental animals):
Daily determination of the estrous cycle stage beginning at pairing start until evidence of positive mating.
Sperm parameters (parental animals):
Parameters examined in P male parental generations: testes weight, epididymis weight, prostate weight, epididymides weight, histopathology of testes, prostate, seminal vesicles and epididymides.
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 8 pups/litter (4/sex/litter as nearly as possible); excess pups were killed and examined macroscopically.

PARAMETERS EXAMINED
The following parameters were examined in offspring on day 21 post-partum: number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross external and internal abnormalities, weight gain, physical or behavioural abnormalities.

GROSS EXAMINATION OF DEAD PUPS: yes, they were autopsied and/or preserved in fixative for possible further examination.
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals when the last litter was at least seven days old.
- Maternal animals: All surviving animals after the last litter of each generation was weaned.

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera. Special attention was directed to the reproductive organs. Implantation sites were counted for all dams (uteri placed in solution of ammonium sulphide).

HISTOPATHOLOGY / ORGAN WEIGHTS
- All adults, including those that died before scheduled sacrifice, or were killed in a moribund condition. The tissues histopathologically examined in all animals of the control and high dose groups were as follows: pituitary glands, liver, kidneys, testes, prostate, seminal vesicles, epididymides, ovaries, uterus, cervix and vagina. In addition, the following organs were histopathologically examined in all groups: ovaries, uterus, cervix and vagina in non-pregnant positively mated females (with day 0 post coitum); tested, epididymides, seminal vesicles with coagulating glands and prostate in males that failed to mate.
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring not selected at standardisation were killed and examined macroscopically.
- After weaning at post-partum day 21, all pups were sacrificed and examined internally and externally for abnormalities.
Statistics:
The following statistical methods were used to analyse body weights, food consumption, reproduction and pup data:
- means and standard deviations.
- if the variables could be assumed to follow a normal distribution, the Dunnett t-test, based on a pooled variance estimate, was used for intergroup comparisons (i.e. single treatment groups against the control group).
- The Steel test (rank test) was applied when the data could not be assumed to follow a normal distribution.
- Fisher's Exact test for 2x2 tables was applied if the variables could be dichotomized without loss of information.

For pup data, the litter was the appropriate unit for statistical comparison.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
No clinical signs that were attributable to treatment with the test item were noted. All females survived until scheduled necropsy. At 1000 mg/kg bw/d, starting during early/mid gestation, all females displayed signs of discomfort after dosing (pushing head through bedding). This behaviour was noted as long as the females were dosed (i.e., one day prior to scheduled necropsy).
Mortality:
no mortality observed
Description (incidence):
All males survived until scheduled necropsy.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
At 1000 mg/kg bw/d, mean body weight gain of males during the pre-pairing period was slightly decreased, resulting in a slightly lower mean body weight at the end of the pre-pairing period (375 g compared with 409 g in the vehicle control).  Although statistical significance was only reached on single days, this reduction was considered to be test item related.  During the pairing and after pairing period, lower absolute body weights at 1000 mg/kg bw/d persisted, while body weight gain was similar to that of the vehicle control. Body weight development of females was not affected by treatment with the test item.
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
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
In the liver of males, the severity of glycogen deposition was slightly increased at 1000 mg/kg bw/d. This finding was considered in relation with the nutritional state of the animals and of no adverse character. Kidneys A slightly increased severity of tubular hyaline change occurred in males of Group 4 (1000 mg/kg bw/d) mainly in the outer cortex. The grade was 2.5 versus 2.0 in the controls.  Probably this change reflects an increased accumulation of alpha-2-microglobulin which is a male rat specific phenomenon of no toxicological relevance for humans. 
Other effects:
not examined
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Description (incidence and severity):
For both generations, the fertility rate was high resulting in at least 23 litters per group for evaluation of reproduction data.  At all dosages, there were no treatment related effects on mean or median pre-coital time, fertility indices, mean duration of gestation and number of implantations, post-implantation loss, pup survival or litter size from birth through to weaning.
Dose descriptor:
NOAEL
Remarks:
parental toxicity
Effect level:
500 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Decreased body weight gain of males, and increased absolute and relative liver and kidney weights in P males and females. Histopathology revealed effects on livers and kidneys of males.
Key result
Dose descriptor:
NOAEL
Remarks:
reproductive effects
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed
Critical effects observed:
no
Clinical signs:
no effects observed
Description (incidence and severity):
No test-item related findings or clinical signs were noted at first litter check on day 0 postpartum or during the lactation period. 
Mortality / viability:
no mortality observed
Description (incidence and severity):
No effect on pup survival.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Pup weights at birth and during lactation were unaffected by treatment with the test item.  
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:
no effects observed
Description (incidence and severity):
No test-item related findings were noted at macroscopic examination of pups.
Histopathological findings:
not examined
Other effects:
no effects observed
Description (incidence and severity):
No treatment-related effects on sex ratios were noted.
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: There were no effects on any reproductive parameters.
Critical effects observed:
no
Reproductive effects observed:
no

In a good quality one-generation reproductive toxicity study (reliability score 1) conducted to OECD Test Guideline 415 and GLP, the parental and reproductive NOAELs for [3-(2,3-epoxypropoxy)propyl]trimethoxysilane were = 1000 mg/kg bw/d, in rats. Treatment with the test substance resulted in signs of discomfort after dosing (noted for P females from early /mid gestation onwards), decreased body weight gain of males, and increased absolute and relative liver and kidney weights in P males and females. Histopathology revealed effects on livers and kidneys of males.

Please see attached document for result tables.

Conclusions:
In a good quality one-generation reproductive toxicity study (reliability score 1) conducted to OECD Test Guideline 415 and GLP, the parental and reproductive NOAELs for [3-(2,3-epoxypropoxy)propyl]trimethoxysilane were 500 and = 1000 mg/kg bw/d, in rats. Treatment with the test substance resulted in signs of discomfort after dosing (noted for P females from early /mid gestation onwards), decreased body weight gain of males, and increased absolute and relative liver and kidney weights in P males and females. Histopathology revealed effects on livers and kidneys of males. Based on these data a NOAEL for parental animals was established at 500 mg/kg bw/d. A NOAEL for reproductive effects was established at 1000 mg/kg bw/d.
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
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

A one-generation reproductive toxicity study conducted according to OECD Test Guideline 415 and in compliance with GLP, reports the parental toxicity and reproductive NOAELs for 3-(2,3-epoxypropoxy)propyltrimethoxysilane of 500 and =1000 mg/kg bw/day respectively, in rats (RCC, 2004). Treatment with the test substance resulted in signs of discomfort after dosing (noted for P females from early/mid gestation onwards), with decreased body weight gain seen in male rats, and increased absolute and relative liver and kidney weights in parental generation males and females. Histopathology revealed effects on livers and kidneys of males; the severity of hepatic glycogen deposition was slightly increased at 1000 mg/kg bw/day. A slight increase in tubular hyaline was evident in the outer renal cortex at 1000 mg/kg bw/day. The effects were not deemed to be adverse or of toxicological relevance to humans. Based on these data a systemic toxicity NOAEL for parental animals was established at 500 mg/kg bw/day. A NOAEL for reproductive effects was established at 1000 mg/kg bw/day.



Effects on developmental toxicity

Description of key information

In a good quality study with reliability score 1 (BRRC, 1993), conducted using a protocol similar to OECD Test Guideline 414 and in compliance with GLP in rabbits, the NOAELs for maternal toxicity and developmental toxicity were 200 and =400 (the highest dose tested) mg/kg bw/day, respectively, in rabbits. No developmental effects were observed at the highest dose, in the presence of maternal toxicity.

In a good quality developmental toxicity study with reliability score 1 (BRRC, 1990), conducted using a protocol similar to OECD 414 and in compliance with GLP in rats, the test material exhibited maternal toxicity at 3000 mg/bw kg/day and evidence of developmental delay at 3000 mg/kg/day, which is far in excess of the limit dose. The NOAEL for maternal and developmental toxicity (minimal fetotoxicity) was therefore 1500 mg/kg bw/day in rats.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
04.12.1990 to 22.11.1993
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
Dosing during organogenesis only.
GLP compliance:
yes
Limit test:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazleton Dutchland Laboratories, Inc
- Age at study initiation: 5.5 months old
- Weight at study initiation: 3.0 to 4.0 kg
- Fasting period before study: No data, but probably not
- Housing: Individually in stainless steel, wire mesh cages
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 16 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 61-70 (16-21°C)
- Humidity (%): 40-60
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 04.12.1990 To: 22.11.1993
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The appropriate amount of A-187 was dissolved with Mazola corn oil. Solutions were mixed manually by repeated inversions and then transferred to a glass Erlenmeyer flask and mixed for at least 10 minutes. Dosing solutions were prepared based on the selected dose and administration of a constant dose volume of 2ml/kg/day. Target concentrations of solutions for the 50, 200 and 400 mg/kg/day dose levels were 25, 100 and 200 mg/ml, respectively. Dosing solutions were prepared three times during the study and were stored at room temperature. Dosing solutions were stirred using a magnetic stirrer for at least 10 minutes prior to each daily dosing period.

VEHICLE
-No details on vehicle.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentrations of the dosing solutions were verified prior to use in the study using gas chromatography. Homogeneity of A-187 in each solution was established. Homogeneity and stability of the dosing solutions were initiated prior to the onset of actual dosing.
Details on mating procedure:
- Impregnation procedure: No data. Report states that "females were mated to proven males from the BRRC breeding colony. Following successful copulation, the animals were returned to their respective cages"
- If cohoused:
- M/F ratio per cage: No data
- Length of cohabitation: No data
- Further matings after two unsuccessful attempts: No data
- Verification of same strain and source of both sexes: No data
- Proof of pregnancy: Date of copulation referred to as day 0 of pregnancy
Duration of treatment / exposure:
Test substance exposure occurred during the primary period of organogenesis, i.e., gestation days 6-18.
Frequency of treatment:
Once per day on gestation days 6-18
Duration of test:
25 days (animals sacrificed on gestational day 29)
Dose / conc.:
50 mg/kg bw/day
Dose / conc.:
200 mg/kg bw/day
Dose / conc.:
400 mg/kg bw/day
No. of animals per sex per dose:
22 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on the results from three developmental toxicity range-finding studies of Union Carbide Organofunctional Silane A-187 in pregnant New Zealand white rabbits.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Observations for mortality and clinical condition were performed daily (twice daily during the dosing period).


DETAILED CLINICAL OBSERVATIONS: No data


BODY WEIGHT: Yes
- Time schedule for examinations: Maternal body weights were measured on gestational days 0, 6, 12, 15, 18 and 29.


FOOD CONSUMPTION: Yes, food consumption was measured daily throughout gestation (gestation days 0-29).
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes


WATER CONSUMPTION: No


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
- Organs examined: Uterus, ovaries (including corpora lutea), cervix, vagina and abdominal and thoracic cavities. Liver was weighed.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes, each uterus was externally examined for signs of haemorrhage, removed from the peritoneal cavity, weighed and dissected longitudinally to expose the contents.
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 unit of comparison was the pregnant female or the litter.  Data collected for non-pregnant females were not included in the statistical analyses.  Results of the quantitative continuous variables (e.g., maternal body weights, organ weights, etc.) were intercompared for the three exposed groups and the vehicle control group by use of Levene's test for equal variances (Levene, 1960), analysis of variance (ANOVA), and t-tests with Bonferroni probabilities for pairwise comparisons.  The t-tests were used when the F value from the ANOVA was significant.   When Levene's test indicated homogeneous variances and the ANOVA was significant, the pooled t-test was used.  When Levene's test indicated heterogeneous variances, all groups were compared by an ANOVA for unequal variances (Brown and Forsythe, 1974) followed, when necessary, by the separate variance t-test.  Nonparametric data obtained following laparohysterectomy were statistically treated using the Kruskal-Wallis test (Sokal and Rohlf, 1969) followed by the Mann-Whitney U test (Sokal and Rohlf, 1969) when appropriate.  Incidence data were compared using Fisher's Exact Test (Sokal and Rohlf, 1969).  For all statistical tests, the fiducial limit of 0.05 (two-tailed) was used as the criterion for significance.
Indices:
No data
Historical control data:
No data
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
One dam from the 400 mg/kg bw/day group was found dead on gestation day 29. This animal exhibited gasping, and laboured and audible breathing. No significant clinical signs were observed in any other treatment group.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, treatment-related
Description (incidence):
One dam from the 400 mg/kg bw/day group was found dead on gestation day 29. This animal exhibited gasping, and laboured and audible breathing. No significant clinical signs were observed in any other treatment group.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Details on maternal toxic effects:
One dam from the 400 mg/kg bw/day group was found dead on gestation day 29. This animal exhibited gasping, and laboured and audible breathing. No significant clinical signs were observed in any other treatment group. No statistically significant, treatment-related differences in body weight/body weight gain or food consumption were observed. There were no significant findings in the necropsy of the dam that died. There were no treatment-related findings from the necropsy of the surviving animals.
Dose descriptor:
NOAEL
Remarks:
maternal toxicity
Effect level:
200 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
mortality
Dose descriptor:
NOAEL
Remarks:
maternal developmental toxicity
Effect level:
>= 400 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: no maternal developmental toxicity was observed.
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:
no effects observed
Visceral malformations:
no effects observed
Other effects:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
There were no effects of the treatment on the number of ovarian corpora lutea, on the number of total, viable or non-viable (early and late resorptions and dead fetuses) implantations per litter or on sex ratio (% males). Percent pre-implantation and post-implantation losses were equivalent across groups. Fetal examination indicated no evidence of embryotoxicity or malformations in any of the treatment groups.  There were no effects on mean fetal body weight and no treatment-related differences in the incidences of external, visceral or skeletal variations.
Dose descriptor:
NOAEL
Effect level:
>= 400 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: teratogenicity
Abnormalities:
no effects observed
Developmental effects observed:
no

Please see attached tables in attachments.

Conclusions:
In a well conducted study (reliability score 1), conducted using a protocol similar to OECD Test Guideline 414 and GLP, the NOAEL for maternal toxicity and developmental toxicity were 200 and =400 mg/kg bw/day, respectively, in rabbits.
Executive summary:

In a well conducted study (reliability score 1), conducted using a protocol similar to OECD Test Guideline 414 and GLP, the NOAELs for maternal toxicity and developmental toxicity were 200 and =400 mg/kg bw/day, respectively, in rabbits.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
400 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
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

The key developmental toxicity study, conducted according to a protocol similar to OECD Test Guideline 414 and in compliance with GLP, reports the NOAEL for maternal toxicity and developmental toxicity of 200 and =400 mg/kg bw/day, respectively, in rabbits (BRRC, 1993). The doses tested were 50, 200 and 400 mg/kg bw/day. One dam from the 400 mg/kg bw/day group was found dead on gestation day 29. This animal exhibited gasping, and laboured and audible breathing. No significant clinical signs were observed in any other treatment group. No statistically significant, treatment-related differences in body weight/body weight gain or food consumption were observed. There were no significant findings in the necropsy of the dam that died. There were no treatment-related findings from the necropsy of the surviving animals. No embryotoxic or teratogenic effects were reported; there were no effects on the number of ovarian corpora lutea, on implantations per litter or on the sex ratio. No effect on foetal body weights, external, visceral or skeletal variations were reported. There was no evidence of embryotoxicity or malformations in any of the treatment groups.

The second developmental toxicity supporting study was conducted according to a test protocol that is comparable to the appropriate OECD test guideline, and in compliance with GLP (BRRC, 1990). The test material was administered orally at 500, 1500 and 3000 mg/kg bw/day during the primary period of organogenesis, i.e., gestation days 6-15. There was no treatment related maternal deaths, and no dams aborted.  Gestational weight gain was significantly reduced at 3000 mg/kg bw/day during the dosing period, with concomitant reduced food consumption. Clinical signs present at 3000mg/kg bw/day included hypoactivity, audible respiration and unkempt appearance. At the time of sacrifice on gestation day 21 there were no effects on maternal or foetal body weights or any other gestational parameters. One skeletal variation, unossified anterior arch of the atlas, was significantly increased at 3000 mg/kg bw/day, indicating minimal fetotoxicity. There were no other variations. The NOAEL was concluded to be 1500 mg/kg bw/day, which is in excess of the limit dose for this type of test.

One additional supporting study for developmental toxicity is also available.

A developmental toxicity study in rat conducted to a protocol similar to OECD 414 and in compliance with GLP reports no adverse effects on the maternal animals or the offspring (Dow Corning Corporation, 1982). The test material was administered orally at 50, 500 and 1000 mg/kg/day, during the primary period of organogenesis, i.e., gestation days 6-15. The NOAEL for maternal and developmental toxicity was concluded to be =1000 mg/kg bw/day. There were no test substance-related mortalities.  There were no test substance-related effects on clinical condition, behaviour, body weight, body weight gain or food consumption.  No effects on liver or gravid uterine weight or on the number of implantation sites or corpora lutea per dam were observed. The incidence of pregnancy was not affected by treatment with the test substance; all rats were confirmed to be pregnant at gestation day 20. There were no adverse effects on the number of live foetuses per litter, mean litter size, sex ratio or foetal body weight. There was no evidence of embryotoxicity or malformations in any of the treatment groups.



Justification for classification or non-classification

Based on the available data, 3-(2,3-epoxypropoxy)propyltrimethoxysilane does not require classification for reproductive or developmental toxicity according to Regulation (EC) No. 1272/2008.