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

Endpoint summary

Description of key information

There are no acute oral toxicity studies available for [3-(2,3-epoxypropoxy)propyl]dimethoxy(methyl)silane (CAS 65799-47-5). Reliable data have therefore been read across from structural analogues.

An acute oral toxicity study conducted according to a protocol similar to OECD 401, but not in compliance with GLP, reported an LD50 of 8025 mg/kg bw for [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (Dow Corning corporation, 1976).  

An acute oral toxicity study for [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane was conducted according to appropriate OECD guidelines and in compliance with GLP. The acute oral LD50 value was concluded to be >2000 mg/kg (Dow Corning Corporation, 2008).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

5 June to 3 July 2008

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

Study was conducted in accordance with an appropriate guideline and in compliance with GLP.

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

other: Crl:CD (SD) IGS BR VAF/Plus

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories Inc., USA
- Age at study initiation: 8 weeks
- Weight at study initiation: 154.4 to 181.2g
- Fasting period before study: yes
- Housing: individually in wire mesh cages
- Diet (ad libitum): LabDiet 5002, PMI
- Water (ad libitum): municipal water
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.81 to 22.09
- Humidity (%): 40 to 66
- Air changes (per hr): 14.5
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 17 June 2008 To: 3 July 2008

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: not stated

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: not stated

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

6 female

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: twice daily
- Frequency of weighing: day of dosing, weekly thereafter including the day of necropsy
- Necropsy of survivors performed: yes

Statistics:

Body weight was reported as groups means and standard deviations, computed by Provantis v6.5

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

None

Clinical signs:

other: None

Gross pathology:

No findings

Interpretation of results:

GHS criteria not met

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

In a study conducted according to an OECD test guideline and in compliance with GLP, administration of [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane to female rats at 2000 mg/kg bw did not result in any remarkable findings and the LD50 was considered to be greater than 2000 mg/kg bw.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

No data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Not GLP. Weighing and necropsy of animals were not performed.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

No necropsies and no weighing of animals.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: No data
- Age at study initiation: No data
- Weight at study initiation: 200 ± 2 g
- Fasting period before study: Overnight
- Housing: Grid floor cages (segregated according to sex and dose)
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: No data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: No data

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 12.6 ml/kg bw

Doses:

3.9, 5.0, 6.3, 10.0 and 12.6 ml/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observed daily. Animals do not appear to have been weighed.
- Necropsy of survivors performed: no

Statistics:

LD50 and 95% confidence limits calculated using the method of Litchfield, J.T. and Wilcoxon, F. (1949) J. Pharm Exp Therap. 96. 99.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

7.5 mL/kg bw

95% CL:

>= 6 - <= 9.37

Remarks on result:

other: assuming a density of 1.07g/cm3 this gives an LD50 of 8025 mg/kg bw

Mortality:

See Table 1.

Clinical signs:

other: Piloerection and lethargy within one hour of administration, followed by coma and death. All deaths occurred within 48 hours of administration and all survivors were generally asymptomatic after this time.

Gross pathology:

Not examined.

Other findings:

None reported.

Table 1 Summary of mortality data.

Dose ml/kg	Cumulative deaths by day (/10)						Percentage mortality
	1	2	3	4	7	14
12.6	5	8	8	8	8	8	80
10.0	7	7	7	7	7	7	70
6.3	3	3	3	3	3	3	30
5.0	3	3	3	3	3	3	30
3.9	1	1	1	1	1	1	10

Interpretation of results:

GHS criteria not met

Conclusions:

In an acute oral toxicity study (reliability 2), that was conducted using a protocol similar to the now deleted OECD 401 (animals not weighed and no necropsies performed), but not in compliance with GLP, the LD50 for [3-(2,3-epoxypropoxy)propyl]trimethoxysilane was 7.5 ml/kg bw (assuming a density of 1.07 g/cm3 this gives an LD50 of 8025 mg/kg bw).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Additional information

Data are read across from an acute oral toxicity study for [3-(2,3-epoxypropoxy)propyl]trimethoxysilane which was conducted using a protocol similar to OECD 401, but not in compliance with GLP. The study reported an LD50 of 7.5 ml/kg bw (equivalent to 8025 mg/kg bw) (Dow Corning Corporation, 1976). Clinical signs included piloerection and lethargy within one hour of administration, followed by coma and death. All deaths occurred within 48 hours of administration and all survivors were generally asymptomatic after this time. Effects on body weight were not recorded and no necropsy was carried out.

 

A second acute oral toxicity study is read across from [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane. The study was conducted according to an OECD test guideline and in compliance with GLP (Dow Corning Corporation, 2008). The test substance was administered to five female Crl:CD rats at 2000 mg/kg bw and resulted in no remarkable findings, with an LD50 of >2000 mg/kg bw. There were no deaths, no clinical findings and no adverse changes to body weight reported in the study.

 

Read-across justification

There are no available measured data [3-(2,3-epoxypropoxy)propyl]dimethoxy(methyl)silane (CAS 65779-47-5) for acute toxicity. Therefore, the Annex requirements are fulfilled with data on structurally analogous substances. This document describes the analogue approach for fulfilling this endpoint by read-across from two source substances, [3‑(2,3‑epoxypropoxy)propyl]trimethoxysilane, (2530-83-8), and [3‑(2,3‑epoxypropoxy)propyl]diethoxy(methyl)silane, (2897-60-1), according to the Read-across Assessment Framework (RAAF)[1].

Read-across is proposed in accordance with RAAF Scenario 2: “This scenario covers the analogue approach for which the read-across hypothesis is based on different compounds which have the same type of effect(s). For the REACH information requirement under consideration, the effects obtained in a study conducted with one source substance are used to predict the effects that would be observed in a study with the target substance if it were to be conducted. The same type of effect(s) or absence of effect is predicted. The predicted strength of the effects may be similar or based on a worst case.”

The read-across justification is presented (Table 5.6.4) according to RAAF scenario 2 assessment elements (AE) as outlined in Table B1 of the RAAF1:

Table 1: RAAF scenario 2 assessment elements (AE) as given in Appendix B (Table B1) of the RAAF1

AE A.1	Characterisation of source substance
AE A.2	Link of structural similarity and differences with the proposed Prediction
AE A.3	Reliability and adequacy of the source study
AE 2.1	Compounds the test organism is exposed to
AE 2.2	Common underlying mechanism, qualitative aspects
AE 2.3	Common underlying mechanism, quantitative aspects
AE 2.4	Exposure to other compounds than to those linked to the prediction
AE 2.5	Occurrence of other effects than covered by the hypothesis and Justification
AE A.4	Bias that influences the prediction

 

1.  AE A.1 Identity and characterisation of the source substance

The first source substance, [3-(2,3-epoxypropoxy)propyl]trimethoxysilane, (2530-83-8) is a trimethoxysilane with a 3-(2,3-epoxypropoxy)propyl side-chain. It hydrolyses to [3-(2,3-epoxypropoxy)propyl]silanetriol (1 mole) and methanol (3 moles). Its measured hydrolysis half lives are: 0.15 hours at pH 5, 6.5 hours at pH 7, 0.13 hours at pH 9 and 24.5°C (OECD 111). At 37°C, close to physiological temperature, half-lives of 0.087 hours at pH 5, 3.3 hours at pH 7 and 0.053 hours at pH 9 were determined for the substance. At physiological temperature 35ºC and pH 2 (relevant for conditions in the stomach following oral exposure), the hydrolysis half- life is approximately 5 seconds.

At 37.5ºC and pH 5.5 (relevant for dermal exposure), the hydrolysis half-life will be in between the half-lives at pH 5 and pH 7 at 37.5ºC, i.e. between 0.087 hours and 3.3 hours. The hydrolysis half-life at pH 7 and 37.5°C (relevant to the lungs and blood) is predicted to be 3.3 hours. The products of hydrolysis are [3-(2,3-epoxypropoxy)propyl]silanetriol (1 mole) and methanol (3 moles). The source substance has log Kow of 0.5 at 20°C (estimated), predicted water solubility of 1.1E+05 at 23°C and predicted vapour pressure of 1.1 Pa at 25°C.

The second source substance [3‑(2,3‑epoxypropoxy)propyl]diethoxy(methyl)silane, (2897-60-1) is a diethoxysilane with methyl and 3-(2,3-epoxypropoxy)propyl side-chains. It has estimated hydrolysis half-lives at 20-25°C 0.4 hours at pH 4, 0.5 hours at pH 5, 11.7 hours pH 7 and 0.2 hours at pH 9. The calculated half-life at pH 2 and 35°C (relevant for conditions in the stomach following oral exposure) is approximately 5 seconds. At 37.5ºC and pH 5.5 (relevant for dermal exposure), the hydrolysis half-life will be less than 0.5 hours. The hydrolysis half-life at pH 7 and 37.5°C (relevant to the lungs and blood) is predicted to be 4.4 hours. The products of hydrolysis are [3-(2,3-epoxypropoxy)propyl]methylsilanediol (1 mole) and ethanol (2 moles). The source substance has log Kow of 2.7 at 20°C (estimated), predicted water solubility of 1200 and measured vapour pressure of 0.42 Pa at 25°C.

2.  AE A.2 Link of structural similarities and differences with the proposed prediction

The target substance, 3-(2,3-epoxypropoxy)propyl]dimethoxy(methyl)silane (CAS 65779-47-5) is a dimethoxysilane with a methyl and a 3-(2,3-epoxypropoxy)propyl side-chains.

The first source substance, [3-(2,3-epoxypropoxy)propyltrimethoxysilane], (2530-83-8) is a trimethoxysilane with a 3-(2,3-epoxypropoxy)propyl side-chain.

The second source substance, [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane, (2897-60-1) is a diethoxysilane with a methyl and a 3-(2,3-epoxypropoxy)propyl side-chains.

The target and source substances are all alkoxysilanes with a 3-(2,3-epoxypropoxy)propyl side-chain. They have the general structural formula shown in Figure 1 (attached).

For the target substance:                         R1 is methyl,      R2 is methyl.

For the source substance 2530-83-8:        R1 is methoxy,  R2 is methyl.

For the source substance 2897-60-1:        R1 is methyl,      R2 is ethyl.

Therefore, all structural features of the target substance (3-(2,3-epoxypropoxy)propyl side-chain, dialkoxy(methyl)silane, methoxysilane) are present in one or both of the source substances.

The target substance and the source substance 2530-83-8 are both methoxysilanes with a 3-(2,3-epoxypropoxy)propyl side-chain. The difference between these substances is that one of the three methoxy groups in the source substance is replaced by a methyl group in the target substance.

The target substance and the source substance 2897-60-1 are both dialkoxysilanes with methyl and 3-(2,3-epoxypropoxy)propyl side-chains. The difference between these substances is that the two alkoxy groups are ethoxy for the source substance and methoxy for the target substance.

The three substances all have similar moderate molecular weight (220-248) and low vapour pressure (0.4-3 Pa at 25°C). They all have low log Kow (0.5-2.7) and moderate to high water solubility (1200 – 110000 mg/l), with the target substance being in between the two source substances. All the substances hydrolyse rapidly, with half-lives of <12 hours at pH 7 and 25°C and 5 s at pH 2 and 37.5°C.

Table 2: Physico-chemical properties

Property	Target substance	Source substance	Source substance
CAS	65799-47-5	2530-83-8	2897-60-1
Type	Dimethoxy	Trimethoxy	Diethoxy
Name	[3-(2,3-epoxypropoxy)propyl]dimethoxy(methyl)silane	[3-(2,3-epoxypropoxy)propyl]trimethoxysilane	[3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane
Hydrolysis products	[3-(2,3-epoxypropoxy)propyl]methylsilanediol (1 mole) and methanol (2 moles)	[3-(2,3-epoxypropoxy)propyl]silanetriol(1 mole) and methanol (3 moles)	[3-(2,3-epoxypropoxy)propyl]methylsilanediol (1 mole) and ethanol (2 moles)
MW	220.34	236.34	248.4
WS / mg/l	1.2E+04	1.1E+05	1200
Log Kow	1.7	0.5	2.7
Hydrolysis half-life at pH 7 and 25°C	1.6 hours	6.5 hours (measured)	11.7 hours
Hydrolysis half-life at pH 7 and 37.5°C	0.6 hours	3.3 hours (measured)	4.4 hours
Hydrolysis half-life at pH 2 and 37.5°C	5 s	5 s	5 s
VP at 25°C / Pa	3.0	1.1	0.42 (measured)
HP MW	192.29	194.26	192.29
HP WS / mg/l	1E+06 (limited to around 1000 mg/l by condensation reactions)	1E+06 (limited to around 1000 mg/l by condensation reactions)	1E+06 (limited to around 1000 mg/l by condensation reactions)
HP Log Kow	-0.7	-2.6	-0.7
HP VP at 25°C / Pa	2.8E-04	1.7E-05	2.8E-04

 

3.  AE A.3 Reliability and adequacy of the source study

The acute oral study for [3-(2,3-epoxypropoxy)propyl]trimethoxysilane (CAS 2530-83-8) was conducted according to a protocol similar to OECD 401, but not in compliance with GLP (Reliability 2) (Dow Corning Corporation, 1976). In the study, the test substance was administered to male and female Wistar rats (5 male and 5 female animals per dose) at doses of 3.9, 5.0, 6.3, 10.0 and 12.6 ml/kg bw. Clinical signs included piloerection and lethargy within one hour of administration, followed by coma and death. All deaths occurred within 48 hours of administration and all survivors were generally asymptomatic after this time. Effects on body weight were not recorded and no necropsy was carried out. The study reported an LD50 of 7.5 ml/kg bw (equivalent to 8025 mg/kg bw).

The acute oral study for [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane, (2897-60-1) was conducted according to OECD 423 and in compliance with GLP (Reliability 1) (Dow Corning Corporation, 2008). In the study, the test substance was administered to female Crl:CD rats (5 animals) at a dose of 2000 mg/kg bw. There were no mortalities, no effect on body weight and no remarkable findings. It was concluded that the LD50 was > 2000 mg/kg bw.

4.  AE A.4 Bias that influences the prediction

Data on the source substances [3-(2,3-epoxypropoxy)propyl]trimethoxysilane and [3‑(2,3‑epoxypropoxy)propyl]diethoxy(methyl)silane were read across to the registered (target) substance [3‑(2,3-epoxypropoxy)propyl]dimethoxy(methyl)silane. The source substances and the target substance have similar chemical structure and physico-chemical properties. All three substances hydrolyse at comparable rates and produce similar silicon-containing hydrolysis products. One source substance gives the same silanol hydrolysis product as the target substance, [3-(2,3-epoxypropoxy)propyl]methylsilandiol and a different non-silanol hydrolysis product, ethanol. The other source substance gives a similar silanol hydrolysis product as the target substance, [3-(2,3-epoxypropoxy)propyl]silanetriol, and the same non-silanol hydrolysis product as the target substance, methanol. All structural features of the target substance (3-(2,3-epoxypropoxy)propyl side-chain, dialkoxy(methyl)silane, methoxysilane) are present in one or both of the source substances. All substances show similar predicted toxicity profiles using the OECD QSAR Toolbox v. 4.1, and have the same structural alerts. Therefore, their toxicological properties are expected to be similar, with similar acute toxicity. No other data for relevant substances were available. These substances are the closest structural analogues to the target substance.

5.  AE A.2.1 Compounds the test organism is exposed to

The source substances as well as the target substance hydrolyse at similar rate in contact with water under conditions relevant for oral exposure. Therefore, the test organism could possibly be exposed to the parent substances and their hydrolysis products, [3-(2,3-epoxypropoxy)propyl]silanetriol or [3-(2,3-epoxypropoxy)propyl]methylsilanediol and methanol or ethanol. The source and target substances have been profiled using the OECD QSAR Toolbox v. 4.1. The three substances and their silanol hydrolysis products show similar profiles for all toxicological endpoints. They are all predicted to be Class III High hazard.

6.  AE A.2.2 and A.2.3 Common underlying mechanism, qualitative and quantitative aspects

No toxicity data are available for the target substance [3-(2,3-epoxypropoxy)propyl]dimethoxy(methyl)silane, therefore data are read-across from the structurally analogous substances [3-(2,3-epoxypropoxy)propyl]trimethoxysilane, (2530-83-8) and [3‑(2,3‑epoxypropoxy)propyl]diethoxy(methyl)silane, (2897-60-1). These three substances hydrolyse at comparable rates 1 moles of a [3-(2,3-epoxypropoxy)propyl silanol The non-silanol hydrolysis products are methanol and ethanol, which are of known toxicity and not expected to contribute to the effects observed for this endpoint. Moreover, they have similar predicted physico-chemical properties, and are predicted by QSAR Toolbox to be subject to similar metabolic processes. Thus, all three substances are expected to have similar toxicity profiles.

7.  AE 2.4 Exposure to other compounds than to those linked to the prediction

The registration substance, [3-(2,3-epoxypropoxy)propyl]dimethoxy(methyl)silane has a purity of 98 %.

Neither the target substance nor the source substances have impurities of toxicological concern.

The purity of test substance in the study with the source substance, [3-(2,3-epoxypropoxy)propyl]trimethoxysilane, was not reported. However, the Substance Identity Profile for the REACH Registration of this substance indicates that it has a purity of >98% and no impurities are present at >1%.

The test substance in the study with the second source substance [3‑(2,3‑epoxypropoxy)propyl]diethoxy(methyl)silane, has a purity of >98%.

8.  AE 2.5 Occurrence of Other Effects than Covered by the Hypothesis and Justification

The difference between the source studies is the clinical observations. This is not a concern because the clinical effects observed in the study on [3-(2,3-epoxypropoxy)propyl]trimethoxysilane were seen at doses far in excess of those tested in the acute test for [3‑(2,3‑epoxypropoxy)propyl]diethoxy(methyl)silane.

 

[1]European Chemicals Agency (ECHA) (2015) Read-across Assessment Framework. Appendix B, Scenario 2.

Justification for classification or non-classification

Based on the available read-across information for [3-(2,3-epoxypropoxy)propyl]dimethoxy(methyl)silane, no classification is required for acute oral toxicity according to Regulation (EC) No. 1272/2008.