Trimethoxypropylsilane

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

25.6 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: substance-specific (for further details please refer to discussion section)

Overall assessment factor (AF):

11

Dose descriptor starting point:

NOAEC

Value:

560 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

281.4 mg/m³

Explanation for the modification of the dose descriptor starting point:

The following correction is made to the NOAEC (inhalation): Correction for experimental exposure duration (6 h/d to 8 h/d), Correction for respiratory volume (worker): 6.7 m3/10 m3. Therefore, the corrected NOAEC for repeated-dose systemic effects via the inhalation route is: 560 * (6 h/ 8 h) * (6.7 m3/10 m3) = corrected NOAEC 281.4 mg/m3.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEC

AF for differences in duration of exposure:

2

Justification:

The DNEL is based on a subchronic study

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route

AF for other interspecies differences:

2.5

Justification:

Default AF according to ECHA REACH Guidance

AF for intraspecies differences:

2.2

Justification:

Substance-specific (for further details please refer to the discussion section)

AF for the quality of the whole database:

1

Justification:

DNEL is based on a high quality study

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

insufficient hazard data available (further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.53 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: substance-specific (for further details please refer to discussion section)

Overall assessment factor (AF):

132

Dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

70 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The systemic DNELs for the dermal route are based on the NOAEL of 50 mg/kg bw/day from a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test on the structural analogue substance trimethoxy(methyl)silane (CAS RN 1185-55-3), conducted according to OECD Test Guideline 422 and in compliance with GLP (Dow Corning Corporation, 2005). The following modifications of the dose descriptor starting point have been made:

Dermal NOAEL = oral NOAEL * ABS(oral)/ABS(dermal) * (7 days exposure rat/5 days exposure worker) = 50 mg/kg bw/day * (1/1) * 1.4 = 70 mg/kg bw/day.

 It is assumed that oral and dermal absorption rates are equal.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL

AF for differences in duration of exposure:

6

Justification:

The DNEL is based on a subacute study

AF for interspecies differences (allometric scaling):

4

Justification:

The experimental animal was rat (default AF according to ECHA REACH Guidance)

AF for other interspecies differences:

2.5

Justification:

Default AF according to ECHA REACH Guidance

AF for intraspecies differences:

2.2

Justification:

Substance-specific (for further details please refer to the discussion section)

AF for the quality of the whole database:

1

Justification:

The DNEL is based on a high quality study

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

The long-term DNEL for systemic effects via the inhalation route is determined from an OECD 413 study on the structural analogue substance trimethoxy(methyl)silane (CAS RN 1185-55-3), which showed a NOAEC of 560 mg/m³.

The long-term DNEL for systemic effects via the dermal route is determined from an OECD 422 (oral) study on the same analogue substance, which showed a NOAEL of 50 mg/kg bw/day.

The following correction to the dose descriptor starting points have been made:

 

Inhalation route – worker:

Correction for respiratory volume (worker, light physical activity): 6.7 m³ / 10 m³

Correction for exposure duration (exposure duration rat / exposure duration worker): 6 h / 8 h

Therefore, the corrected NOAEC for repeated dose systemic effects via inhalation is:

560 mg/m³ x (6.7 m³ / 10 m³) x (6 h / 8 h) = 281.4 mg/m³

 

The following assessment factors were applied to the corrected NOAEC:

Exposure duration (sub-chronic to chronic): 2 (default)

Interspecies differences (toxicodynamics): 2.5 (default)

Interspecies differences (toxicokinetics, rat/human): 1 (not used for inhalation route)

Intraspecies differences (toxicodynamics, worker): 2.2 (substance-specific, see below)

Intraspecies differences (toxicokinetics, worker): 1 (substance-specific, see below)

Total AF: 11

 

Intraspecies differences

The intraspecies assessment factor accounts for the variability in sensitivity between individuals. The human population is far more diverse than experimental animals that are bred to be as similar as possible, and unhealthy animals are not allowed to start the study. This AF also covers differences between ethnic groups and age groups. The default intraspecies factors are typically broken down into equal factors accounting for toxicodynamic and toxicokinetic differences, respectively. Accordingly, an interspecies factor of 10 is composed of two identical factors of √10 = 3.2. Likewise, the default for workers (AF = 5) can be split into AFs of √5 = 2.2. As discussed in the TK assessment, the conversion of alkoxysilanes to silanols and their excretion proceeds without enzymatic involvement. Individual genetic dispositions and other factors affecting xenobiotic-metabolizing enzymes are therefore without effect on these processes. As a result, the toxicokinetic components (3.2 and 2.2 for general population and workers, respectively) can be eliminated from the intraspecies AF for substances that hydrolyse fast into the ultimate excretion product.

The overall DNEL (long-term – systemic – inhalation - worker) is therefore:

281.4 mg/m³ / 11 = 25.6 mg/m³

 

Dermal route – worker:

As no reliable information is available from acute dermal or dermal repeated dose toxicity tests regarding dermal absorption, a conservative approach is applied, and thus the relative dermal absorption as compared to the oral absorption is set to 1. A correction based on different exposure times between experimental animal and worker is considered (7 days exposure for rat and 5 days exposure for workers).

Therefore, the corrected NOAEL for repeated dose systemic effects via the dermal route is:

50 mg/kg bw/day x 1 x (7 days / 5 days) = 70 mg/kg bw/day

 

The following assessment factors were applied to the corrected NOAEL:

Exposure duration (subacute to chronic): 6 (default)

Interspecies differences (toxicodynamics): 2.5 (default)

Interspecies differences (toxicokinetics, rat/human): 4

Intraspecies differences (toxicodynamics, worker): 2.2 (substance-specific, see above)

Intraspecies differences (toxicokinetics, worker): 1 (substance-specific, see above)

Total AF: 132

 

The overall DNEL (long-term – systemic – dermal - worker) is therefore:

70 mg/kg bw/day / 132 = 0.53 mg/kg bw/day

 

Testing proposals are included in the dossier for OECD 413 (rat) and OECD 414 (oral, rat) studies, therefore, the DNELs for trimethoxy(propyl)silane will be re-evaluated when this data becomes available.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

6.25 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

other: substance-specific (for further details please refer to discussion section)

Overall assessment factor (AF):

16

Dose descriptor starting point:

NOAEC

Value:

560 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

100 mg/m³

Explanation for the modification of the dose descriptor starting point:

The following correction is made to the NOAEC (inhalation): Correction for exposure duration (6 h/d to 24 h/d), Correction for dosing frequency: 5 days/7 days. Therefore the corrected NOAEC for repeated-dose systemic effects via the inhalation route is: 560*(6 h/ 24 h)* (5/7) = corrected NOAEC 100 mg/m3.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL

AF for differences in duration of exposure:

2

Justification:

The DNEL is based on a subchronic study

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route

AF for other interspecies differences:

2.5

Justification:

Default AF according to ECHA REACH Guidance

AF for intraspecies differences:

3.2

Justification:

Substance-specific (for further details please refer to the discussion section)

AF for the quality of the whole database:

1

Justification:

DNEL is based on a high quality study

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

insufficient hazard data available (further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.26 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: substance-specific (for further details please refer to discussion section)

Overall assessment factor (AF):

192

Dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The systemic DNELs for the dermal route are based on the NOAEL of 50 mg/kg bw/day from a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test on the structural analogue substance trimethoxy(methyl)silane (CAS RN 1185-55-3), conducted according to OECD Test Guideline 422 and in compliance with GLP (Dow Corning Corporation, 2005).

It is assumed that oral and dermal absorption rates are equal, therefore, no modification of the dose descriptor is neccessary.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL

AF for differences in duration of exposure:

6

Justification:

The DNEL is based on a subacute study

AF for interspecies differences (allometric scaling):

4

Justification:

The experimental animal was rat (default AF according to ECHA REACH Guidance)

AF for other interspecies differences:

2.5

Justification:

Default AF according to ECHA REACH Guidance

AF for intraspecies differences:

3.2

Justification:

Substance-specific (for further details please refer to the discussion section)

AF for the quality of the whole database:

1

Justification:

The DNEL is based on a high quality study

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.26 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: substance-specific (for further details please refer to discussion section)

Overall assessment factor (AF):

192

Dose descriptor starting point:

NOAEL

Value:

50 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The systemic DNEL for the oral route is based on the NOAEL of 50 mg/kg bw/day from a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test on the structural analogue substance trimethoxy(methyl)silane (CAS RN 1185-55-3), conducted according to OECD Test Guideline 422 and in compliance with GLP (Dow Corning Corporation, 2005). No modifications of the dose descriptor starting point are necessary.

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL

AF for differences in duration of exposure:

6

Justification:

The DNEL is based on a subacute study

AF for interspecies differences (allometric scaling):

4

Justification:

The experimental animal was rat (default AF according to ECHA REACH Guidance)

AF for other interspecies differences:

2.5

Justification:

Default AF according to ECHA REACH Guidance

AF for intraspecies differences:

3.2

Justification:

Substance-specific (for further details please refer to the discussion section)

AF for the quality of the whole database:

1

Justification:

The DNEL is based on a high quality study

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - General Population

The long-term DNEL for systemic effects via the inhalation route is determined from an OECD 413 study on the structural analogue substance trimethoxy(methyl)silane (CAS RN 1185-55-3), which showed a NOAEC of 560 mg/m³.

The long-term DNEL for systemic effects via the dermal and oral routes is determined from an OECD 422 (oral) study on the same analogue substance, which showed a NOAEL of 50 mg/kg bw/day.

The following correction to the dose descriptor starting points have been made:

 Inhalation route – general population:

Correction for exposure duration (exposure duration rat / exposure duration general population): 6 h / 24 h

Correction for exposure frequency (exposure frequency in rat / exposure frequency general population): 5 d / 7 d

Therefore, the corrected NOAEC for repeated dose systemic effects via inhalation is:

560 mg/m³ x (6 / 24) x (5 / 7) = 100 mg/m³

 

The following assessment factors were applied to the corrected NOAEC:

Exposure duration (sub-chronic to chronic): 2 (default)

Interspecies differences (toxicodynamics): 2.5 (default)

Interspecies differences (toxicokinetics, rat/human): 1 (not used for inhalation route)

Intraspecies differences (toxicodynamics, general population): 3.2 (substance-specific, see below)

Intraspecies differences (toxicokinetics, general population): 1 (substance-specific, see below)

Total AF: 16

 

Intraspecies differences

The intraspecies assessment factor accounts for the variability in sensitivity between individuals. The human population is far more diverse than experimental animals that are bred to be as similar as possible, and unhealthy animals are not allowed to start the study. This AF also covers differences between ethnic groups and age groups. The default intraspecies factors are typically broken down into equal factors accounting for toxicodynamic and toxicokinetic differences, respectively. Accordingly, an interspecies factor of 10 is composed of two identical factors of √10 = 3.2. Likewise, the default for workers (AF = 5) can be split into AFs of √5 = 2.2. As discussed in the TK assessment, the conversion of alkoxysilanes to silanols and their excretion proceeds without enzymatic involvement. Individual genetic dispositions and other factors affecting xenobiotic-metabolizing enzymes are therefore without effect on these processes. As a result, the toxicokinetic components (3.2 and 2.2 for general population and workers, respectively) can be eliminated from the intraspecies AF for substances that hydrolyse fast into the ultimate excretion product.

The overall DNEL (long-term – systemic – inhalation – general population) is therefore:

100 mg/m³ / 16 = 6.25 mg/m³

 

Dermal route – general population:

As no reliable information is available from acute dermal or dermal repeated dose toxicity tests regarding dermal absorption, a conservative approach is applied, and thus the relative dermal absorption as compared to the oral absorption is set to 1. Therefore, the corrected NOAEL for repeated dose systemic effects via the dermal route is:

50 mg/kg bw/day x 1 = 50 mg/kg bw/day

 

The following assessment factors were applied to the corrected NOAEL:

Exposure duration (subacute to chronic): 6 (default)

Interspecies differences (toxicodynamics): 2.5 (default)

Interspecies differences (toxicokinetics, rat/human): 4

Intraspecies differences (toxicodynamics, general population): 3.2 (substance-specific, see above)

Intraspecies differences (toxicokinetics, general population): 1 (substance-specific, see above)

Total AF: 192

 

The overall DNEL (long-term – systemic – dermal – general population) is therefore:

50 mg/kg bw/day / 192 = 0.26 mg/kg bw/day

 

Oral route – general population:

No modification of the dose descriptor starting point was necessary. The following assessment factors were applied to the NOAEL of 50 mg/kg bw/day:

Exposure duration (subchronic to chronic): 6 (default)

Interspecies differences (toxicodynamics): 2.5 (default)

Interspecies differences (toxicokinetics, rat/human): 4

Intraspecies differences (toxicodynamics, general population): 3.2 (substance-specific, see above)

Intraspecies differences (toxicokinetics, general population): 1 (substance-specific, see above)

Total AF: 192

 

The overall DNEL (long-term – systemic – oral – general population) is therefore:

50 mg/kg bw/day / 192 = 0.26 mg/kg bw/day.

 

Testing proposals are included in the dossier for OECD 413 (rat) and OECD 414 (oral, rat) studies, therefore, the DNELs for trimethoxy(propyl)silane will be re-evaluated when this data becomes available.