[3-(2,3-epoxypropoxy)propyl]triethoxysilane

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

There are no reproductive toxicity data on [3-(2,3-epoxypropoxy)propyl]triethoxysilane or its ultimate hydrolysis product, 2,3 -dihydroxypropoxypropylsilanetriol, so good quality data for the related substance [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8) have been used to assess the reproductive toxicity of [3-(2,3-epoxypropoxy)propyl]triethoxysilane.

In a one-generation reproductive toxicity study with the read-across test substance [3-(2,3-epoxypropoxy)propyl]trimethoxysilane, conducted according to OECD 415 and in compliance with GLP, a reproductive NOAEL was concluded to ≥1000 mg/kg bw/day. This was based on that no toxicologically significant effects relevant to humans were observed (RCC, 2004).

Link to relevant study records

Reference

Endpoint:

one-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

13.10.2003 to 30.04.2004

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

The study was conducted according to an appropriate OECD test guideline, and in compliance with GLP, and is therefore considered to be reliabillity 1.

Qualifier:

according to guideline

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 or test system 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 post partum. Premating exposure period (males): 70 days. Premating exposure period (females): 14 days . Duration of test: until the last litter reached day 7 post partum.

Frequency of treatment:

once daily

Remarks:

Doses / Concentrations:
0, 250, 500 and 1000 mg/kg bw/d
Basis:
actual ingested

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 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 sulfide).

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

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Other effects:

not examined

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS):All males survived until scheduled necropsy and 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 behavior was noted as long as the females were dosed (i.e., one day prior to scheduled necropsy).

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): Mean food consumption of males and females was not affected by treatment with the test substance. At 1000 mg/kg bw/d, mean body weight gain of males during the prepairing period was slightly decreased, resulting in a slightly lower mean body weight at the end of the prepairing 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. The author of this summary concludes that the effect on body weights in the prepairing period, although possibly related to treatment is not toxicologically significant. This is because mean body weights in the treated groups were not reduced by more than 10% compared with controls. Also, the reduction appeared to be transient, as body weight gain was similar to controls for the pairing and after pairing period. Body weight development of females was not affected by treatment with the test item.


REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): 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 precoital time, fertility indices, mean duration of gestation and number of implantations, post-implantation loss, pup survival or litter size from birth through to weaning.


ORGAN WEIGHTS (PARENTAL ANIMALS): At 1000 mg/kg bw/d, statistically significant increased mean relative liver and kidney weights were noted for males and females.


GROSS PATHOLOGY (PARENTAL ANIMALS): No test-item related findings were noted at macroscopic examination of parental males or females.


HISTOPATHOLOGY (PARENTAL ANIMALS): 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 male rat specific phenomenon of no toxicological relevance for humans. 

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: There were no toxicologically significant, adverse effects relevant to humans.

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day

Sex:

male/female

Basis for effect level:

other: No adverse effects on reproductive parameters.

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

VIABILITY (OFFSPRING): No effect on pup survival.


CLINICAL SIGNS (OFFSPRING): No test-item related findings or clinical signs were noted at first litter check on day 0 post partum or during the lactation period. 

BODY WEIGHT (OFFSPRING): Pup weights at birth and during lactation were unaffected by treatment with the test item.  


GROSS PATHOLOGY (OFFSPRING): No test-item related findings were noted at macroscopic examination of pups.


OTHER FINDINGS: No treatment-related effects on sex ratios were noted.

Dose descriptor:

NOAEL

Generation:

F1

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 on offspring.

Reproductive effects observed:

not specified

Conclusions:

In a good quality one-generation reproductive toxicity study (reliability score 2; read-across) conducted according to OECD 415 and in compliance with GLP, the parental and reproductive NOAELs for [3-(2,3-epoxypropoxy)propyl]trimethoxysilane were ≥ 1000 mg/kg bw/d, in rats. There were no adverse effects on reproductive parameters. Mean body weights of males in the mating period were sporadically reduced, but body weight gain during mating and after mating was similar for treated and control groups. Therefore effects on body weight are not considered toxicologically significant. There were also some species-specific effects on the kidneys and non-toxicological effects on the liver. Therefore there were no toxicologically significant effects relevant to humans and the NOAEL for general toxicity in the parent animals was therefore ≥ 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

There are no reproductive toxicity data on [3-(2,3-epoxypropoxy)propyl]triethoxysilane or its ultimate hydrolysis product,2,3-dihydroxypropoxypropylsilanetriol, so good quality data for the related substance [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8) have been used to assess the reproductive toxicity of [3-(2,3-epoxypropoxy)propyl]triethoxysilane.

The study was conducted according to an appropriate OECD test guideline, and in compliance with GLP, and is therefore considered to be reliability 1.

Justification of read-across is provided in the document attached in Section 13.

Justification for selection of Effect on fertility via oral route:
The selected study is the only study of reproductive toxicity available for a relevant surrogate substance. It was conducted in accordance with an appropriate OECD test guideline and in compliance with GLP.

Effects on developmental toxicity

Description of key information

There are no developmental toxicity data on [3-(2,3-epoxypropoxy)propyl]triethoxysilane or its ultimate hydrolysis product,

2,3-dihydroxypropoxypropylsilanetriol, so good quality data for the related substance [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8) have been used to assess the developmental toxicity of [3-(2,3-epoxypropoxy)propyl]triethoxysilane.
In a well conducted study (BRRC, 1993), conducted using a protocol similar to OECD 414 and GLP, 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.

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:

guideline study

Remarks:

The study was conducted according to an appropriate OECD test guideline, and in compliance with GLP, and is therefore considered to be reliability 1.

Qualifier:

equivalent or similar to guideline

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 or test system 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)

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 (gd 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 haemorhage, 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 nonpregnant 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

Details on maternal toxic effects:

Maternal toxic effects:yes

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

Effect level:

200 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

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 nonviable (early and late resorptions and dead fetuses) implantations per litter or on sex ratio (% males). Percent preimplantation and postimplantation 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

Basis for effect level:

other: teratogenicity

Abnormalities:

not specified

Developmental effects observed:

not specified

Conclusions:

In a well conducted study (reliability score 2; read-across), conducted using a protocol similar to OECD 414 and in compliance with GLP, the NOAEL for maternal toxicity and developmental toxicity were 200 and ≥400 mg/kg bw/day, respectively, in rabbits.

Executive summary:

.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

400 mg/kg bw/day

Study duration:

subchronic

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 on [3-(2,3-epoxypropoxy)propyl]triethoxysilane or its ultimate hydrolysis product,2,3-dihydroxypropoxypropylsilanetriol, so good quality data for the related substance [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8) have been used to assess the developmental toxicity of [3-(2,3-epoxypropoxy)propyl]triethoxysilane.

The study was conducted using a protocol similar to OECD 414 and in compliance with GLP, and is therefore considered to be reliability 1.

Justification of read-across is provided in the document attached in Section 13.

Justification for selection of Effect on developmental toxicity: via oral route:
The selected study is the only study of developmental toxicity available for a relevant surrogate substance. It was conducted in accordance with an appropriate OECD test guideline and in compliance with GLP.

Justification for classification or non-classification

The available data do not suggest that [3 -(2,3 -epoxypropoxy)propyl]trimethoxysilane should be classified for reproductive or developmental toxicity under Regulation (EC) No 1272/2008.