Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
17.44 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
75
Dose descriptor starting point:
NOAEL
Value:
530 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
1 308 mg/m³
Explanation for the modification of the dose descriptor starting point:
Reliable repeated dose data via the oral route are available.
AF for dose response relationship:
1
Justification:
DNEL is based on a NOAEL
AF for differences in duration of exposure:
6
Justification:
Exposure duration (subacute to chronic)
AF for interspecies differences (allometric scaling):
1
Justification:
Correction of respiratory volume was applied for calculation of the starting point.
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
5
Justification:
for worker
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
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:
2.47 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
300
Dose descriptor starting point:
NOAEL
Value:
530 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
742 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Reliable repeated dose data via the oral route are available.
AF for dose response relationship:
1
Justification:
DNEL is based on a NOAEL
AF for differences in duration of exposure:
6
Justification:
Exposure duration (subacute to chronic)
AF for interspecies differences (allometric scaling):
4
Justification:
Species used: rat
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
5
Justification:
for worker
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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)
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:
medium hazard (no threshold derived)

Additional information - workers

No repeated dose toxicity studies were available for N-(3-(trimethoxysilyl) propyl) butylamine, but data were available for the analogue substance N-(3-(trimethoxysilyl) propyl) ethylenediamine. In an oral gavage study conducted similar to OECD 422 and according to GLP the NOAEL for N-(3-(trimethoxysilyl) propyl) ethylenediamine relating to repeated dose (systemic) effects and to developmental toxicity was at 500 mg/kg bw/day, as no significant adverse effects were observed up to the highest dose of 500 mg/kg bw/day tested in rats. Increased nasal sounds and squeaky vocalisation was observed in the treatment groups, and did not occur in the control groups. Reduction in weekly body weight gain was observed in males of the 25 and 125 mg/kg bw groups during week 4, but was not statistically significant. A statistically significant increase in platelet counts was observed in the female treatment group. As the values were within historical control data no toxicological significance was attributed to these effects. No treatment-related pathology or histopathology findings were observed.

 

Repeated-dose toxicity – systemic effects – dermal route – worker:

The DNEL for systemic effects via the dermal route is determined on the basis of route-to-route extrapolation from an oral OECD 422 toxicity study. In this study a NOAEL of 500 mg/kg bw was derived, which was the highest concentration tested.

The following corrections were made:

Based on the different molecular weights of N-(3-(trimethoxysilyl) propyl) butylamine (235.4 g/mol) and the analogue substance N-(3-(trimethoxysilyl) propyl) ethylenediamine (222.4 g/mol), the NOAEL was adapted to 530 mg/kg bw (MW correction target/source = 235.4 g/mol/ (222.4 g/mol) =1.06; 500 mg/kg bw/day×1.06= 530 mg/kg bw/day).

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 was set to 1.

Correction for number of exposures per week: 7d/5d

The corrected NOAEL is therefore:

530 mg/kg bw×1×(7/5) =742 mg/kg bw

The following assessment factors were applied to the corrected NOAEL:

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

Interspecies differences (toxicodynamics): 2.5 (ECHA default)

Interspecies differences (toxicokinetics, rat/human): 4 (ECHA default)

Intraspecies differences (worker): 5 (ECHA default)

Total AF:6×2.5×4×5=300

The overall DNEL (repeated-dose – systemic – dermal - worker) is therefore:

742 mg/kg bw/day/300=2.47 mg/kg bw/day.

 

Repeated-dose toxicity – systemic effects – inhalation route – worker:

The DNEL for systemic effects via inhalation is determined on the basis of route-to-route extrapolation from an oral OECD 422 toxicity study. In this study a NOAEL of 500 mg/kg bw was derived, which was the highest concentration tested.

The following correction was made to the NOAEL:

Based on the different molecular weights of N-(3-(trimethoxysilyl) propyl) butylamine (235.4 g/mol) and the analogue substance N-(3-(trimethoxysilyl) propyl) ethylenediamine (222.4 g/mol), the NOAEL was adapted to 530 mg/kg bw (MW correction target/source= 235.4 g/mol/ (222.4 g/mol) =1.06; 500 mg/kg bw/day×1.06=530 mg/kg bw/day).

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 number of exposures per week: 7d/5d

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

530 mg/kg bw×1/0.38 m³/kg bw×(6.7 m³/10 m³) ×(7/5) =1308 mg/m³

The following assessment factors were applied to the corrected NOAEC:

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

Interspecies differences (toxicodynamics): 2.5 (ECHA default)

Intraspecies differences (worker): 5 (ECHA default)

Total AF: 6×2.5×5=75

The overall DNEL (repeated-dose – systemic – inhalation - worker) is therefore:

1308 mg/m³/75=17.44 mg/m³.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.07 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
150
Dose descriptor starting point:
NOAEL
Value:
530 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
460.87 mg/m³
Explanation for the modification of the dose descriptor starting point:
Reliable repeated dose data via the oral route are available.
AF for dose response relationship:
1
Justification:
DNEL is based on a NOAEL
AF for differences in duration of exposure:
6
Justification:
Exposure duration (subacute to chronic)
AF for interspecies differences (allometric scaling):
1
Justification:
Correction of respiratory volume was applied for calculation of the starting point.
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
10
Justification:
for general population
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
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:
0.88 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
600
Dose descriptor starting point:
NOAEL
Value:
530 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
530 mg/kg bw/day
AF for dose response relationship:
1
Justification:
DNEL is based on a NOAEL
AF for differences in duration of exposure:
6
Justification:
Exposure duration (subacute to chronic)
AF for interspecies differences (allometric scaling):
4
Justification:
species used: rat
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
Justification:
for general population
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
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:
0.883 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
600
Dose descriptor starting point:
NOAEL
Value:
530 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
530 mg/kg bw/day
AF for dose response relationship:
1
Justification:
DNEL is based on a NOAEL
AF for differences in duration of exposure:
6
Justification:
Exposure duration (subacute to chronic)
AF for interspecies differences (allometric scaling):
4
Justification:
species used: rat
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
10
Justification:
for general population
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

No repeated dose toxicity studies were available for N-(3-(trimethoxysilyl) propyl) butylamine, but data were available for the analogue substance N-(3-(trimethoxysilyl) propyl) ethylenediamine. In an oral gavage study conducted similar to OECD 422 and according to GLP the NOAEL for N-(3-(trimethoxysilyl) propyl) ethylenediamine relating to repeated dose (systemic) effects and to developmental toxicity was at 500 mg/kg bw/day, as no significant adverse effects were observed up to the highest dose of 500 mg/kg bw/day tested in rats. Increased nasal sounds and squeaky vocalisation was observed in the treatment groups, and did not occur in the control groups. Reduction in weekly body weight gain was observed in males of the 25 and 125 mg/kg bw groups during week 4, but was not statistically significant. A statistically significant increase in platelet counts was observed in the female treatment group. As the values were within historical control data no toxicological significance was attributed to these effects. No treatment-related pathology or histopathology findings were observed.

Repeated-dose toxicity – systemic effects – dermal route – general population:

The DNEL for systemic effects via the dermal route is determined on the basis of route-to-route extrapolation from an oral OECD 422 toxicity study. In this study a NOAEL of 500 mg/kg bw was derived, which was the highest concentration tested.

The following corrections were made:

Based on the different molecular weights of N-(3-(trimethoxysilyl) propyl) butylamine (235.4 g/mol) and the analogue substance N-(3-(trimethoxysilyl) propyl) ethylenediamine (222.4 g/mol), the NOAEL was adapted to 530 mg/kg bw (MW correction target/source= 235.4 g/mol/ (222.4 g/mol) =1.06; 500 mg/kg bw/day×1.06=530 mg/kg bw/day).

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 was set to 1.

The corrected NOAEL is therefore 530 mg/kg bw.

The following assessment factors were applied to the corrected NOAEL:

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

Interspecies differences (toxicodynamics): 2.5 (ECHA default)

Interspecies differences (toxicokinetics, rat/human): 4 (ECHA default)

Intraspecies differences (general population): 10 (ECHA default)

Total AF: 6×2.5×4×10=600

The overall DNEL (repeated-dose – systemic – dermal - general population) is therefore:

530 mg/kg bw/day/600=0.88 mg/kg bw/day.

 

Repeated-dose toxicity – systemic effects – inhalation route – general population:

The DNEL for systemic effects via inhalation is determined on the basis of route-to-route extrapolation from an oral OECD 422 toxicity study. In this study a NOAEL of 500 mg/kg bw was derived, which was the highest concentration tested.

The following correction was made to the NOAEL:

Based on the different molecular weights of N-(3-(trimethoxysilyl) propyl) butylamine (235.4 g/mol) and the analogue substance N-(3-(trimethoxysilyl) propyl) ethylenediamine (222.4 g/mol), the NOAEL was adapted to 530 mg/kg bw (MW correction target/source= 235.4 g/mol/ (222.4 g/mol) =1.06; 500 mg/kg bw/day×1.06=530 mg/kg bw/day).

No correction for relative absorption oral vs. inhalation: 1

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

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

530 mg/kg bw×1/1.15 m³/kg bw=460.87 mg/m³

The following assessment factors were applied to the corrected NOAEC:

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

Interspecies differences (toxicodynamics): 2.5 (ECHA default)

Intraspecies differences (general population): 10 (ECHA default)

Total AF: 6×2.5×10=150

 

The overall DNEL (repeated-dose – systemic – inhalation - general population) is therefore:

460.87 mg/m³/150=3.07 mg/m³.

 

Repeated-dose toxicity – systemic effects – oral route – general population:

The DNEL for systemic effects via the dermal route is determined on the basis of route-to-route extrapolation from an oral OECD 422 toxicity study. In this study a NOAEL of 500 mg/kg bw was derived, which was the highest concentration tested.

The following corrections were made:

Based on the different molecular weights of N-(3-(trimethoxysilyl) propyl) butylamine (235.4 g/mol) and the analogue substance N-(3-(trimethoxysilyl) propyl) ethylenediamine (222.4 g/mol), the NOAEL was adapted to 530 mg/kg bw (MW correction target/source= 235.4 g/mol/ (222.4 g/mol) =1.06; 500 mg/kg bw/day×1.06=530 mg/kg bw/day).

The corrected NOAEL is therefore 530 mg/kg bw.

The following assessment factors were applied to the corrected NOAEL:

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

Interspecies differences (toxicodynamics): 2.5 (ECHA default)

Interspecies differences (toxicokinetics, rat/human): 4 (ECHA default)

Intraspecies differences (general population): 10 (ECHA default)

Total AF: 6×2.5×4×10=600

 

The overall DNEL (repeated-dose – systemic – oral - general population) is therefore:

530 mg/kg bw/day/600=0.88 mg/kg bw/day.