Bis(triethoxysilylpropyl)amine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

11.2 mg/m³

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):

33

Dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

370 mg/m³

Explanation for the modification of the dose descriptor starting point:

The long-term DNEL for systemic effects via the inhalation route is determined on the basis of the subacute oral NOAEL observed in a combined repeated dose oral toxicity study with the reproduction/developmental toxicity screening test (OECD 422; 2022) on the registration substance itself.

 

To correct the interspecies difference between rat and human the no observed effect level has to be corrected as follows:

Corrected starting point for the inhalative route for workers:

= NOAEL(oral) * (1/0.38 m³/kg bw/day) * (ABSoral-rat/ABSinh-human) * 6.7 m³ (8h) /10 m³ (8h)* (7 days exposure rat/5 days exposure worker)

= 150 mg/kg bw/day * (1/0.38 m³/kg bw/day) * (1/1) * 0.67 m³ * 1.4 = 370 mg/m³

 

In contrast to the recommendations of the ECHA Guidance, a factor of 1 (equal absorption of 100% assumed for the oral and the inhalative route for animals and humans) was included for the extrapolation from oral to inhalation absorption, as there is no valid data suggesting that inhalation leads to higher absorption than oral ingestion (recommendation of the VCI Working group "Toxicology", 2008). Molecules with a molecular weight <500 and a log Kow between 0 and 4 can be assumed to be well absorbed equivalently by the oral and inhalation route. Oral absorption may be reduced for acids and bases depending on their pKa value and their electric charge in the GI tract. More lipophilic substances may be better absorbed in the GI tract due to solubilisation with bile acids, and thus oral absorption may be higher than inhalation absorption (VCI Working group "Toxicology", 2008). Unless valid data suggest that inhalation leads to higher absorption than oral ingestion, equal absorption will be assumed when extrapolating from oral to inhalation route.

 

(ABSoral-rat = oral absorption in rats, ABSinh-human = inhalation absorption rate in humans)

 

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):

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

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.6 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 the discussion section)

Overall assessment factor (AF):

132

Dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

210 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Dermal NOAEL = oral NOAEL*ABS(oral)/ABS(dermal) * (7 days exposure rat/5 days exposure worker) = 150 mg/kg bw/day *(1/1) * 1.4 = 210 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

Route of original study:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

low hazard (no threshold derived)

Additional information - workers

The long-term DNEL for systemic effects via the inhalation and dermal route is determined on the basis of route-to route extrapolation from the OECD 422 oral study on the registration substance, which showed a NOAEL of 150 mg/kg bw/day. The following correction was made to the NOAEL:

 

Inhalation route – worker:

Correction for relative absorption oral vs. inhalation: 1

Correction for respiratory volume (rat/worker): 0.38 m³/kg bw (8 h)

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

Correction for exposure duration (exposure duration rat / exposure duration worker): 7 days / 5 days

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

150 mg/kg bw x (1/0.38 m³/kg bw) x (6.7 m³/10 m³) x 1 x (7 days/5 days) = 370 mg/m³

 

The following assessment factors were applied to the corrected NOAEC:

Exposure duration (sub-chronic to chronic): 6 (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: 33

 

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:

370 mg/m³ / 33 = 11.2 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 are considered (7 days exposure for rat and 5 days exposure for workers).

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

150 mg/kg bw/day x 1 x (7 days / 5 days) = 210 mg/kg bw/day

 

The following assessment factors were applied to the corrected NOAEL:

Exposure duration (subchronic 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:

210 mg/kg bw/day / 132 = 1.6 mg/kg bw/day

 

 

Acute toxicity

Acute oral and dermal toxicity studies performed with the registered substance 3-(triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine (CAS 13497-18-2) conducted according to OECD 401 and 402 and in compliance with GLP revealed LD50 values of 4580 and >2000 mg/kg bw for males and females, respectively.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.72 mg/m³

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):

48

Dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

130.4 mg/m³

Explanation for the modification of the dose descriptor starting point:

The long-term DNEL for systemic effects via the inhalation route is determined on the basis of the subacute oral NOAEL observed in a combined repeated dose oral toxicity study with the reproduction/developmental toxicity screening test (OECD 422; 2022) on the registration substance itself.

To correct the interspecies difference between rat and human the no observed effect level has to be corrected as follows:

Corrected starting point for the inhalative route for general population:

= NOAEL(oral) * (1/1.15 m³/kg bw/day) * (ABSoral-rat/ABSinh-human)

= 150 mg/kg bw/day * (1/1.15 m³/kg bw/day) * (1/1) = 130.4 mg/m³

In contrast to the recommendations of the ECHA Guidance, a factor of 1 (equal absorption of 100% assumed for the oral and the inhalative route for animals and humans) was included for the extrapolation from oral to inhalation absorption, as there is no valid data suggesting that inhalation leads to higher absorption than oral ingestion (recommendation of the VCI Working group "Toxicology", 2008). Molecules with a molecular weight <500 and a log Kow between 0 and 4 can be assumed to be well absorbed equivalently by the oral and inhalation route. Oral absorption may be reduced for acids and bases depending on their pKa value and their electric charge in the GI tract. More lipophilic substances may be better absorbed in the GI tract due to solubilisation with bile acids, and thus oral absorption may be higher than inhalation absorption (VCI Working group "Toxicology", 2008). Unless valid data suggest that inhalation leads to higher absorption than oral ingestion, equal absorption will be assumed when extrapolating from oral to inhalation route.

(ABSoral-rat = oral absorption in rats, ABSinh-human = inhalation absorption rate in humans)

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):

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

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.78 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 the discussion section)

Overall assessment factor (AF):

192

Dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Dermal NOAEL = oral NOAEL*ABS(oral)/ABS(dermal) = 150 mg/kg bw/day *(1/1) = 150 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:

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:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.78 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 the discussion section)

Overall assessment factor (AF):

192

Dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No route-to-route extrapolation is required.

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:

low hazard (no threshold derived)

Additional information - General Population

There is no potential for exposure of consumers via any route to 3-(triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine, nevertheless, where applicable, the respective DNELs have been calculated.

 

The long-term DNEL for systemic effects via the inhalation and dermal route is determined on the basis of route-to-route extrapolation from the OECD 422 oral study on the registration substance, which showed a NOAEL of 150 mg/kg bw/day. The following correction was made to the NOAEL:

 

Inhalation route – general population:

Correction for relative absorption oral vs. inhalation: 1

Correction for respiratory volume (rat/general population): 1.15 m³/kg bw (24 h)

 

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

150 mg/kg bw x (1/1.15 m³/kg bw) x 1 = 130.4 mg/m³

 

The following assessment factors were applied to the corrected NOAEC:

Exposure duration (sub-chronic to chronic): 6 (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: 48

 

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:

130.4 mg/m³ / 48 = 2.72 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, no correction for differences in absorption is required and the NOAEL for repeated dose systemic effects via dermal route is 150 mg/kg bw/day.  

The following assessment factors were applied to the corrected NOAEL:

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 – dermal – general population) is therefore:

150 mg kg bw/day / 192 = 0.78 mg/kg bw/day

 

Oral route – general population:

The long-term DNEL for systemic effects via the oral route is determined on the basis of the OECD 422 oral study on the registration substance, which established a NOAEL of 150 mg/kg bw/day.

The following assessment factors were applied to the NOAEL:

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:

150 mg/kg bw/day / 192 = 0.78 mg/kg bw/day.

 

Acute toxicity

Acute oral and dermal toxicity studies performed with the registered substance 3-(triethoxysilyl)-N-[3-(triethoxysilyl)propyl]-1-propanamine (CAS 13497-18-2) conducted according to OECD 401 and 402 and in compliance with GLP revealed LD50 values of 4580 and >2000 mg/kg bw for males and females, respectively.