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

Endpoint summary

Description of key information

There are no skin irritation studies available for [3-(2,3-epoxypropoxy)propyl]dimethoxy(methyl)silane (CAS 65799-47-5). Therefore data were read-across from the structurally analogous substances, [3-(2,3-epoxypropoxy)propyl]triethoxysilane and [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane. An in vitro/ex vivo eye irritation study is available for the registered substance, from which it was not possible to conclude on classification. In vivo eye irritation studies are available for the structural analogue substances, [3-(2,3-epoxypropoxy)propyl]trimethoxysilane and [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane.

[3-(2,3 -Epoxypropoxy)propyl]triethoxysilane was found not irritating to rabbit skin in a study conducted according to a protocol similar to OECD 404, but not in compliance with GLP (Allied Corporation, 1982). The test material was found corrosive to rabbit eye and the study was conducted according to OECD 405 Test Guideline and in compliance with GLP (IFREB, 1982).

[3-(2,3 -Epoxypropoxy)propyl]diethoxy(methyl)silane was found not irritating to rabbit skin or eye in studies conducted according to current OECD guidelines and in compliance with GLP (WIL 2000b, 2000c).    

In the Bovine Corneal Opacity and Permeability Study, conducted according to OECD 437 Test Guideline and in compliance with GLP, reported an in vitro irritation score of 18.76 which falls between the range of > 3 and < 55 and no prediction on the irritancy potential can be made (Eurofins, 2018). Therefore, the read-across data for the structural analogue substance, [3-(2,3-epoxypropoxy)propyl]trimethoxysilane were selected as a worst-case approach to determine the classification of [3-(2,3-epoxypropoxy)propyl]dimethoxy(methyl)silane.

   

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

The study was conducted according to an appropriate OECD guideline and in compliance with GLP.

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS

- Age at study initiation: young adult
- Weight at study initiation: 3475-3602g
- Housing: Individually suspended wire mesh cages
- Diet: ca. 150 g of a commercial feed was offered per day
- Water: ad libitum
- Acclimation period: minimum of 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 66.1-66.9
- Humidity (%): 57.7-64.1
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 ml

Duration of treatment / exposure:

4 hours

Observation period:

72 hours

Number of animals:

3 females

Details on study design:

TEST SITE
- Area of exposure: backs and flanks
- Type of wrap if used: gauze, gauze binder, secured with tape

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The site of administration was wiped with a disposable paper towel moistened with deionized water
- Time after start of exposure: 4h

SCORING SYSTEM: Draize

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.33

Max. score:

4

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.33

Max. score:

4

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritant / corrosive response data:

The test article induced very slight erythema on all animals, which subsided within 48 hours. No edema or other dermal findings were noted during the test period.

Other effects:

There were no deaths during the study, nor remarkable body weight changes.

Interpretation of results:

GHS criteria not met

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

The test material was found not irritating to rabbit skin in a study conducted according to an appropriate guideline and in compliance with GLP. The test article induced very slight erythema on all animals, which subsided within 48 hours. No edema or other dermal findings were noted during the test period.

Reference 2

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

07.09.1981 to 11.09.1981

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Remarks:

the test was non-GLP and a 24 hour exposure was used.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

24 hour exposure

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Buckshire Corporation, Perkasie, Pennsylvania.
- Age at study initiation: No data
- Weight at study initiation: No data
- Housing: Individually in suspended steel wire mesh cages
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 12 days.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ±2
- Humidity (%): 50± 5
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 07.09.1981 to 11.09.1981

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 ml

Duration of treatment / exposure:

24 hour(s)

Observation period:

72 hours

Number of animals:

6

Details on study design:

TEST SITE
- Area of exposure: No data
- % coverage: No data
- Type of wrap if used: No wrap used. The treated patch of gauze was secured on two opposing edges with narrow strips of surgical tape.


REMOVAL OF TEST SUBSTANCE
- Washing (if done): Not done


SCORING SYSTEM: Draize

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Time point:

other: 24, 48 and 72 hours

Score:

1.94

Max. score:

8

Reversibility:

fully reversible within: 8 days

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1.7

Max. score:

4

Reversibility:

fully reversible within: 5 days

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 5 days

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1.7

Max. score:

4

Reversibility:

fully reversible within: 8 days

Irritation parameter:

erythema score

Basis:

animal #4

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 6 days

Irritation parameter:

erythema score

Basis:

animal #5

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 6 days

Irritation parameter:

erythema score

Basis:

animal #6

Time point:

24/48/72 h

Score:

1.6

Max. score:

4

Reversibility:

fully reversible within: 6 days

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

animal #4

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

animal #5

Time point:

24/48/72 h

Score:

0.7

Max. score:

4

Reversibility:

fully reversible within: 4 days

Irritation parameter:

edema score

Basis:

animal #6

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritant / corrosive response data:

All six animals developed well-defined erythema (grade 2) 24 or 48 hours after application, which remained in all animals to 96 hours. One animal had persistent erythema (grade 1) to 168 hours. There was no oedema.

Other effects:

None reported.

No irritation was observed at the untreated sites of all animals. Significant irritation was observed in the positive control animals which had a PII score of 5.22

Interpretation of results:

Category 3 (mild irritant) based on GHS criteria

Remarks:

Not classified according to Regulation (EC) No. 1272/2008.

Conclusions:

In a skin irritation study (reliability score 2) conducted using a protocol similar to OECD 404, but not to GLP, [3-(2,3-epoxypropoxy)propyl]trimethoxysilane was mildly irritating to the skin of rabbits following 24 hours exposure. Based on the available information, the substance does not meet the current EU criteria for classification as a skin irritant.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Reference 1

Endpoint:

eye irritation: in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

28 February 2018 to 28 February 2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 437 (Bovine Corneal Opacity and Permeability Test Method for Identifying i) Chemicals Inducing Serious Eye Damage and ii) Chemicals Not Requiring Classification for Eye Irritation or Serious Eye Damage)

Version / remarks:

2017

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Specific details on test material used for the study:

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature
- Stability under test conditions: stable
- Solubility and stability of the test substance in the solvent/vehicle: The test item was used as provided by the sponsor.
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: not applicable

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: not applicable
- Preliminary purification step (if any): not applicable
- Final dilution of a dissolved solid, stock liquid or gel: not applicable
- Final preparation of a solid: not applicable

Species:

cattle

Strain:

not specified

Details on test animals or tissues and environmental conditions:

- Justification of the test method and considerations regarding applicability: The Bovine Corneal Opacity and Permeability (BCOP) test method is an in vitro test method that can be used to classify substances as “ocular corrosives / severe irritants” and “non-irritants”. The BCOP is recommended for use as part of a tiered-testing strategy for regulatory classification and labelling within a specific applicability domain. Test substances can be classified as ocular corrosives / severe irritants or non-irritants without further testing in rabbits.

- Description of the cell system used, incl. certificate of authenticity and the mycoplasma status of the cell live: The assay uses isolated corneas obtained as a by-product from animals freshly slaughtered at an abattoir in Germany. On the test day, fresh eyes were collected from the slaughterhouse and were transported on ice to the laboratories. Immediately after arrival of the eyes, cornea preparation was initiated. The eyes were carefully examined for defects and any defective eyes were discarded. The tissue surrounding the eyeball was carefully pulled away and the cornea was excised leaving a 2 to 3 mm rim of sclera. The isolated corneas were stored in a petri dish containing HBSS (Hanks’ balanced salt solution with Ca++ and Mg++ containing penicillin/ streptomycin). Before the corneas were mounted in corneal holders with the endothelial side against the O-ring of the posterior chamber, they had been visually examined for defects and any defective cornea had been discarded. The anterior chamber was then positioned on top of the cornea and tightened with screws. The chambers of the corneal holder were then filled with RPMI (without phenol red) containing 1% FBS and 2 mM L-glutamine (complete RPMI). The corneas were incubated for one hour at 32°C.

Vehicle:

unchanged (no vehicle)

Controls:

yes

yes, concurrent positive control

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 750 µL
- Concentration (if solution): not applicable

Duration of treatment / exposure:

10 minutes incubation at 32°C

Duration of post- treatment incubation (in vitro):

2 hours incubation at 32 +/- 1 °C

Details on study design:

SELECTION AND PREPARATION OF CORNEAS: The assay uses isolated corneas obtained as a by-product from animals freshly slaughtered at an abattoir in Germany. On the test day, fresh eyes were collected from the slaughterhouse and were transported on ice to the laboratories. Immediately after arrival of the eyes, cornea preparation was initiated. The tissue surrounding the eyeball was carefully pulled away and the cornea was excised leaving a 2 to 3 mm rim of sclera. The isolated corneas were stored in a petri dish containing HBSS (Hanks’ balanced salt solution with Ca++ and Mg++ containing penicillin/ streptomycin). Before the corneas were mounted in corneal holders with the endothelial side against the O-ring of the posterior chamber, they had been visually examined for defects and any defective cornea had been discarded. The anterior chamber was then positioned on top of the cornea and tightened with screws. The chambers of the corneal holder were then filled with RPMI (without phenol red) containing 1% FBS and 2 mM L-glutamine (complete RPMI). The corneas were incubated for one hour at 32°C.

QUALITY CHECK OF THE ISOLATED CORNEAS: The eyes were carefully examined for defects and any defective eyes were discarded.

NUMBER OF REPLICATES: triplicate corneas per group

NEGATIVE CONTROL USED: Yes, physiological saline 0.9% NaCl

SOLVENT CONTROL USED (if applicable): Not applicable

POSITIVE CONTROL USED: Yes, ethanol 100%

APPLICATION DOSE AND EXPOSURE TIME: 750 µL test substance for 10 minutes incubation at 32°C

TREATMENT METHOD: [closed chamber / open chamber] not specified

POST-INCUBATION PERIOD: yes, 2 hours incubation at 32 +/- 1 °C

REMOVAL OF TEST SUBSTANCE
- Number of washing steps after exposure period: washed at least three times with MEM (containing phenol red)

- POST-EXPOSURE INCUBATION: yes, 2 hours incubation at 32 +/- 1 °C

METHODS FOR MEASURED ENDPOINTS:
- Corneal opacity: Each cornea was observed visually and pertinent observations were recorded.
- Corneal permeability: passage of sodium fluorescein dye measured with the aid of UV/VIS spectrophotometry0)

SCORING SYSTEM: In Vitro Irritancy Score (IVIS)

DECISION CRITERIA: please specify if the decision criteria as indicated in the TG was used. Yes

Irritation parameter:

in vitro irritation score

Run / experiment:

treatment with 750µL test substance

Value:

18.76

Vehicle controls validity:

not applicable

Negative controls validity:

valid

Positive controls validity:

valid

Interpretation of results:

study cannot be used for classification

Conclusions:

In the Bovine Corneal Opacity and Permeability Study, conducted according to OECD 437 Test Guideline and in compliance with GLP, reported an in vitro irritation score of 18.76 which falls between the range of > 3 and < 55 and no prediction on the irritancy potential can be made.

Reference 2

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Age at study initiation: no data available
- Weight at study initiation: ca. 2.5 kg
- Housing: individual polystyrene cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20
- Humidity (%): 30-70
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12

Vehicle:

unchanged (no vehicle)

Controls:

other: the other eye

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 ml

Duration of treatment / exposure:

4 hours

Observation period (in vivo):

21 days

Number of animals or in vitro replicates:

6 males

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes
- Time after start of exposure: not stated in report

SCORING SYSTEM:

TOOL USED TO ASSESS SCORE: hand-slit lamp

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

not fully reversible within: 21 days

Remarks on result:

other: All animals demonstrated grade one iridial scores, with 3/6 animals not recovering by day 21.

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

not fully reversible within: 21 days

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

not fully reversible within: 21 days

Irritation parameter:

iris score

Basis:

animal #4

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

not fully reversible within: 21 days

Irritation parameter:

iris score

Basis:

animal #5

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

not fully reversible within: 21 days

Irritation parameter:

iris score

Basis:

animal #6

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

not fully reversible within: 21 days

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

not fully reversible within: 21 days

Remarks on result:

other: All animals had corneal scores of >=2, four animals not having recovered by day 21.

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

3

Max. score:

4

Reversibility:

not fully reversible within: 21 days

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

not fully reversible within: 21 days

Irritation parameter:

cornea opacity score

Basis:

animal #4

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

not fully reversible within: 21 days

Irritation parameter:

cornea opacity score

Basis:

animal #5

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

not fully reversible within: 21 days

Irritation parameter:

cornea opacity score

Basis:

animal #6

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

not fully reversible within: 21 days

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

2.33

Max. score:

3

Reversibility:

not fully reversible within: 21 days

Remarks on result:

other: all animals had conjunctival scores of >2, one animals not having recovered by day 21

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

2

Max. score:

3

Reversibility:

not fully reversible within: 21 days

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

24/48/72 h

Score:

3

Max. score:

3

Reversibility:

not fully reversible within: 21 days

Irritation parameter:

conjunctivae score

Basis:

animal #4

Time point:

24/48/72 h

Score:

2

Max. score:

3

Reversibility:

not fully reversible within: 21 days

Irritation parameter:

conjunctivae score

Basis:

animal #4

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

not fully reversible within: 21 days

Irritation parameter:

conjunctivae score

Basis:

animal #5

Time point:

24/48/72 h

Score:

2

Max. score:

3

Reversibility:

not fully reversible within: 21 days

Irritation parameter:

conjunctivae score

Basis:

animal #6

Time point:

24/48/72 h

Score:

2

Max. score:

3

Reversibility:

not fully reversible within: 21 days

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

2.33

Max. score:

4

Reversibility:

not fully reversible within: 21 days

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

3.33

Max. score:

4

Reversibility:

not fully reversible within: 21 days

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

3.67

Max. score:

4

Reversibility:

not fully reversible within: 21 days

Irritation parameter:

chemosis score

Basis:

animal #4

Time point:

24/48/72 h

Score:

3

Max. score:

4

Reversibility:

not fully reversible within: 21 days

Irritation parameter:

chemosis score

Basis:

animal #5

Time point:

24/48/72 h

Score:

3.33

Max. score:

4

Reversibility:

not fully reversible within: 21 days

Irritation parameter:

chemosis score

Basis:

animal #6

Time point:

24/48/72 h

Score:

2.67

Max. score:

4

Reversibility:

not fully reversible within: 21 days

Irritant / corrosive response data:

All animals demonstrated effects of irritancy, the study report concluding the test substance to be a severe irritant/corrosive in 4/6 rabbits.

Interpretation of results:

Category 1 (irreversible effects on the eye) based on GHS criteria

Conclusions:

The test material was found corrosive to rabbit eye in a study conducted according to OECD TG 405 and in compliance with GLP.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Data are read across from an in vivo skin irritation study on [3-(2,3-epoxypropoxy)propyl]trimethoxysilane. The study was conducted according to a test protocol that is comparable to the appropriate OECD test guideline, but was not compliant with GLP (Allied Corporation, 1982). The test material was found to be mildly irritating to the skin of rabbits following 24 hours exposure. Based on the available information, the substance does not meet the current EU criteria for classification as a skin irritant.

A second in vivo skin irritation study is read-across from [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane. The study was conducted according to an appropriate guideline and in compliance with GLP (WIL, 2000b). The test article induced very slight erythema in all animals, which subsided within 48 hours. No edema or other dermal findings were noted during the test period. It was concluded that the test material was not irritating to rabbit skin.

An in vitro/ex vivo eye irritation study is available for the registered substance. In the Bovine Corneal Opacity and Permeability Study (BCOP), conducted according to OECD 437 Test Guideline and in compliance with GLP, reported an in vitro irritation score of 18.76 which falls between the range of > 3 and < 55 and no prediction on the irritancy potential can be made (Eurofins, 2018).

Isolated corneas obtained as a by-product from animals freshly slaughtered at an abattoir were treated with 750µL undiluted test material, physiological saline or positive control substance (ethanol 100%) for 10 minutes at 32±1 °C. After incubation either the test substance or the control substance was removed and the epithelium washed at least three times with MEM (containing phenol red). Once the medium was free of test substance, the cornea was rinsed with complete RPMI (without phenol red). The anterior chamber was refilled with complete RPMI and an illuminance measurement was performed after 2 hours incubation at 32±1 °C. Also, each cornea was observed visually and pertinent observations were recorded. After the illuminance measurement was performed, the medium was removed from both chambers of the holder. The posterior chamber was refilled with fresh complete RPMI. 1 mL of a 4 mg/mL sodium fluorescein solution was added to the anterior chamber and the corneas were incubated for 90 minutes at 32±1 °C. Then the medium from the posterior chamber was removed and its optical density at 490 nm (OD490) was determined, using a spectrophotometer (Jenway 6405 UV/VIS).

Since no conclusion could be made on eye irritancy potential of the registered substance, existing in vivo data for the structural analogues, [3-(2,3-epoxypropoxy)propyl]triethoxysilane and [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane have been considered.

In the in vivo eye irritation study available for [3-(2,3-epoxypropoxy)propyl]trimethoxysilane, the substance was concluded to be a severe irritant to rabbit eye, based on irreversibility of effects. The study was conducted according to OECD 405 Test Guideline and in compliance with GLP (IFREB, 1982).

An in vivo eye irritation study is available for [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane, conducted according to an appropriate OECD guideline and in compliance with GLP (WIL 2001c). Minor (grade 1) conjunctival irritation was noted for all animals at the one hour post instillation observation. The eyes of all animals appeared normal by 48-hours postinstillation. There were no corneal or iridial findings. No animals vocalized upon instillation of the test article. There were no remarkable body weight changes, and there were no deaths during the study.

As  the BCOP study did not allow prediction of the eye irritancy potential of the registered substance, the conclusion on eye irritation classification has been based on the study for [3-(2,3-epooxypropoxy)propyl]trimethoxysilane. The substance [3-(2,-epoxypropoxy)propyl]diethoxy(methyl)silane is the closer structural analogue (dialkoxy) and has the more recent data, a more conservative approach has been followed and classify the substance as a severe eye irritant based on adverse outcome in a read-across study and no conclusion in an in vitro test for the registered substance.

Read-across justification

There are no available measured data [3-(2,3-epoxypropoxy)propyl]dimethoxy(methyl)silane (CAS 65779-47-5) for skin irritation The only available data on eye irritation for [3-(2,3-epoxypropoxy)propyl]dimethoxy(methyl)silane (CAS 65779-47-5) are from a BCOP study from which it was not possible to conclude on classification. Therefore, the Annex requirements are fulfilled with data on structural analogous substances. This document describes the analogue approach for fulfilling this endpoint by read-across from two source substances, 3‑(2,3‑epoxypropoxy)propyltrimethoxysilane, (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 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 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. Its 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. At 37.5ºC and pH 5.5 (relevant for dermal exposure), the hydrolysis half-life is predicted to be less than 0.5 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)propyl]trimethoxysilane, (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: Physicochemical 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

Data are read-across from an in vivo skin irritation study on [3-(2,3-epoxypropoxy)propyl]trimethoxysilane. The study was conducted according to a test protocol that is comparable to the appropriate OECD test guideline, but not compliant with GLP (Allied Corporation, 1982) (Reliability 2). The test material was found to be mildly irritating to the skin of rabbits following 24 hours exposure. Based on the available information, the substance does not meet the current EU criteria for classification as a skin irritant.

A second in vivo skin irritation study is read-across from [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane. The study was conducted according to an appropriate guideline and in compliance with GLP (WIL, 2000b) (Reliability 1). The test article induced very slight erythema in all animals, which subsided within 48 hours. No edema or other dermal findings were noted during the test period. It was concluded that the test material was not irritating to rabbit skin.

An in vitro/ex vivo eye irritation study is available for the registered substance. In the Bovine Corneal Opacity and Permeability Study (BCOP), conducted according to OECD 437 Test Guideline and in compliance with GLP, reported an in vitro irritation score of 18.76 which falls between the range of > 3 and < 55 and no prediction on the irritancy potential can be made (Reliability 1) (Eurofins, 2018).

Data are read-across from an in vivo eye irritation study on [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane, conducted according to an appropriate OECD guideline and in compliance with GLP (Reliabilty 1) (WIL 2001c). Minor (grade 1) conjunctival irritation was noted for all animals at the one hour post instillation observation. The eyes of all animals appeared normal by 48-hours post-instillation. There were no corneal or iridial findings. No animals vocalized upon instillation of the test article. There were no remarkable body weight changes, and there were no deaths during the study.

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 physicochemical 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]diethoxy(methyl)silane 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 potential to cause irritation. The results for skin irritation show agreement between the two source substances. For eye irritation, data for [3‑(2,3‑epoxypropoxy)propyl]trimethoxysilane, (2530-83-8) indicate that the substance causes severe eye damage based on the irreversibility of effects seen in the study.

A Bovine Corneal Opacity and Permeability Study is available for the target substance, which reported an in vitro irritation score of 18.76. This result falls between the range of > 3 and < 55 and no prediction on the irritancy potential can be made. The conclusion for eye irritation is based on the severe eye damage result for [3-(2,3-epoxypropoxy)propyl]triethoxysilane as a conservative approach. 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 substance 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 havebeen 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 undefined for eye irritation by the OECD QSAR Toolbox v. 4.1.

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

No skin or eye irritation 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 physicochemical 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 skin and eye irritation studies 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 purity of test substance in the skin and eye irritation studies with the source substance, [3-(2,3-epoxypropoxy)propyl]diethoxy(methyl)silane, was not reported. However, the Substance Identity Profile for the REACH Registration of this substance indicates that it has a purity of >95% and no impurities are present at >1%.

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

Not relevant.

[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 and in vitro information for [3-(2,3-epoxypropoxy)propyl]dimethoxy(methyl)silane, no classification is required for skin irritation and Category 1, serious eye damage/eye irritation "H318: Causes serious eye damage." is required for eye irritation according to Regulation (EC) No. 1272/2008.