Bis(trimethoxysilylpropyl)amine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

32.91 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:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

2 468.42 mg/m³

Explanation for the modification of the dose descriptor starting point:

NOAECcorr = NOAELoral*(1/0.38 m³/kg bw/day)*(ABSoralrat/ABSinhhuman)*(6.7 m³ (8h)/10 m³ (8h)) * (7 days expsoure rat/5days exposure worker) = 1000 mg/kg bw/day*(1/0.38 m³/kg bw/day)*(1/1)*0.67*1.4 = 2468.42 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: ABSoralrat = oral absorption rate in rats, ABSinhhuman = 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

AF for intraspecies differences:

5

Justification:

Default AF for workers

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:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.67 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:

84 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 400 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The NOAEL of 1000 mg/kg bw/day obtained for systemic toxicity after oral application in the subacute OECD 407 study with the registered substance was considered to be the most suitable dose descriptor for systemic toxicity. The dermal systemic DNEL after repeated exposure will therefore be derived from the oral NOAEL of 1000 mg/kg bw/day on the basis of route to route extrapolation.

Dermal NOAEL = oral NOAEL*ABS(oral)/ABS(dermal) * (7 days exposure rat/5 days exposure worker) = 1000 mg/kg bw/day *(1/1) * 1.4 = 1400 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:

Default AF

AF for other interspecies differences:

2.5

Justification:

Default AF

AF for intraspecies differences:

5

Justification:

Default AF for workers

AF for the quality of the whole database:

1

Justification:

The DNEL is absed 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:

no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

For assessment of long-term effects of bis(trimethoxysilylpropyl)amine an OECD 407 (subacute oral toxicity; Chemical Evaluation and Research Institute, Japan, 2014) is available with the submission substance.

In the repeated dose oral gavage study (conducted according to OECD 407 and in compliance with GLP) male and female Crl:CD(SD) rats were treated with 100, 300, and 1000 mg/kg bw/day with the test substance. Taken together, as no adverse effects were observed with respect to general/detailed clinical observations, haematological/clinical chemistry/neurobehaviour examination, body weights, organ measurements or urinalysis, the NOAEL (systemic) was considered to be 1000 mg/kg bw/day. Gross and histopathological examinations revealed edema (submucosal layer), slight hyperplasia of the surface epithelial cells (fundic mucosa) and slight necrosis (pyloric mucosa) in 1/5 males of the 1000 mg/kg bw/day group. In the recovery group, slight hyperplasia of the surface of epithelial cells in the pyloric mucosa and slight focal necrosis of the fundic mucosa related to the macroscopic findings in the glandular stomach were also observed in 1/5 male animals of the 1000 mg/kg bw/day dose group. Slight hyperplasia of the surface epithelial cells in the pyloric mucosa in the glandular stomach was observed in 1/5 females of the 1000 mg/kg bw/day dose group. Additionally, these effects were also noted in 1/5 females of the 1000 mg/kg bw/day dose group of the recovery group. Since local adverse effects on gross pathology and histopathological examination following treatment with the test material at 1000 mg/kg bw/day were recorded in 1 male and female animal each a NOAEL (local) of 300 mg/kg bw/day was derived.

The NOAEL of 1000 mg/kg bw/day obtained for systemic toxicity after oral application in the OECD 407 study with the registered substance was considered to be the most suitable dose descriptor for systemic toxicity. The dermal systemic DNEL after repeated exposure was therefore derived from the oral NOAEL of 1000 mg/kg bw/day on the basis of route to route extrapolation.

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 407 toxicity study with the submission substance. 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.

In this study a NOAEL of 1000 mg/kg bw was derived.

The following correction was made to the NOAEL:

No 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 (7 days/exposure rat, 5 days exposure worker): 7/5

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

1000 mg/kg bw/day×1/0.38 m³/kg bw×(6.7 m³/10 m³)×1.4= 2468.42 mg/m³/day

The following assessment factors were applied to the corrected NOAEC:

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

Interspecies differences (toxicodynamics): 2.5 (default)

Intraspecies differences (worker): 5 (default)

Total AF: 6×2.5×5=75

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

2468.42 mg/m³/day/75=32.91 mg/m³/day.

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

As no adverse systemic effects were observed in the dermal subacute toxicity study the DNEL for systemic effects via the dermal route is determined on the basis of the systemic NOAEL of 1000 mg/kg bw observed in the OECD 407 oral toxicity study (repeated dose, subacute). The following correction was made to the NOAEL:

No correction for relative absorption oral vs. dermal: 1 (default)

Correction for exposure duration (7 days exposure rats, 5 days exposure workers): 7/5

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

1000 mg/kg bw/day×1×1.4=1400 mg/kg bw/day

The following assessment factors were applied to the systemic NOAEL:

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

Interspecies differences (toxicodynamics): 2.5 (default)

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

Intraspecies differences (worker): 5 (default)

Total AF: 6×2.5×4×5=300

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

1400 mg/kg bw/day/300=4.67 mg/kg bw/day.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.8 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:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

869.57 mg/m³

Explanation for the modification of the dose descriptor starting point:

NOAECcorr = NOAELoral*(1/1.15 m³/kg bw/day)*(ABSoralrat/ABSinhhuman = 1000 mg/kg bw/day* (1/1.15 m³/kg bw/day) = 869.57 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: ABSoralrat = oral absorption rate in rats, ABSinhhuman = 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

AF for intraspecies differences:

10

Justification:

Default AF for general population

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:

no hazard identified

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.67 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:

84 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The NOAEL of 1000 mg/kg bw/day obtained for systemic toxicity after oral application in the OECD 407 study with the registered substance was considered to be the most suitable dose descriptor for systemic toxicity. The dermal systemic DNEL after repeated exposure was therefore derived from the oral NOAEL of 1000 mg/kg bw/day on the basis of route to route extrapolation.

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:

Default AF

AF for other interspecies differences:

2.5

Justification:

Dafault AF

AF for intraspecies differences:

10

Justification:

Default AF for general population

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:

no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.67 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:

1 000 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

NOAECcorr = NOAELoral*(ABSoralrat/ABSoralhuman) = 1000 mg/kg bw/day*(1/1) = 1000 mg/kg bw/day.It is assumed that oral absorption rate in rats and human is 100%. ABSoralrat = ABSoralhuman.

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:

Default AF

AF for other interspecies differences:

2.5

Justification:

Default AF

AF for intraspecies differences:

10

Justification:

Default AF for general population

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

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

For assessment of long-term effects of bis(trimethoxysilylpropyl)amine an OECD 407 (subacute oral toxicity; Chemical Evaluation and Research Institute, Japan, 2014) is available with the submission substance.

In the repeated dose oral gavage study (conducted according to OECD 407 and in compliance with GLP) male and female Crl:CD(SD) rats were treated with 100, 300, and 1000 mg/kg bw/day with the test substance. Taken together, as no adverse effects were observed with respect to general/detailed clinical observations, haematological/clinical chemistry/neurobehaviour examination, body weights, organ measurements or urinalysis, the NOAEL (systemic) was considered to be 1000 mg/kg bw/day. Gross and histopathological examinations revealed edema (submucosal layer), slight hyperplasia of the surface epithelial cells (fundic mucosa) and slight necrosis (pyloric mucosa) in 1/5 males of the 1000 mg/kg bw/day group. In the recovery group, slight hyperplasia of the surface of epithelial cells in the pyloric mucosa and slight focal necrosis of the fundic mucosa related to the macroscopic findings in the glandular stomach were also observed in 1/5 male animals of the 1000 mg/kg bw/day dose group. Slight hyperplasia of the surface epithelial cells in the pyloric mucosa in the glandular stomach was observed in 1/5 females of the 1000 mg/kg bw/day dose group. Additionally, these effects were also noted in 1/5 females of the 1000 mg/kg bw/day dose group of the recovery group. Since local adverse effects on gross pathology and histopathological examination following treatment with the test material at 1000 mg/kg bw/day were recorded in 1 male and female animal each a NOAEL (local) of 300 mg/kg bw/day was derived.

The NOAEL of 1000 mg/kg bw/day obtained for systemic toxicity after oral application in the OECD 407 study with the registered substance was considered to be the most suitable dose descriptor for systemic toxicity. The dermal systemic DNEL after repeated exposure was therefore derived from the oral NOAEL of 1000 mg/kg bw/day on the basis of route to route extrapolation.

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 407 toxicity study with the submission substance. 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.

In this study a NOAEL of 1000 mg/kg bw was derived.

The following correction was made to the NOAEL:

No 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:

1000 mg/kg bw/day/1.15 m³/kg bw = 869.57 mg/m³/day

The following assessment factors were applied to the corrected NOAEC:

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

Interspecies differences (toxicodynamics): 2.5 (default)

Intraspecies differences (general population): 10 (default)

Total AF: 6×2.5×10=150

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

869.57 mg/m3/day/150=5.80 mg/m³/day.

 

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

As no adverse systemic effects were observed in the dermal subacute toxicity study the DNEL for systemic effects via the dermal route is determined on the basis of the systemic NOAEL of 1000 mg/kg bw observed in the OECD 407 oral toxicity study (repeated dose, subacute). The following correction was made to the NOAEL:

No correction for relative absorption oral vs. dermal: 1 (default)

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

1000 mg/kg bw/day×1=1000 mg/kg bw/day

The following assessment factors were applied to the systemic NOAEL:

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

Interspecies differences (toxicodynamics): 2.5 (default)

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

Intraspecies differences (general population): 10 (default)

Total AF: 6×2.5×4×10=600

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

1000 mg/kg bw/day/600=1.67 mg/kg bw/day.

 

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

The DNEL for systemic effects via the oral route is determined on the basis an oral OECD 407 toxicity study (repeated dose, subacute) with the registered substance. In this study a NOAEL of 1000 mg/kg bw was derived.

No correction for relative absorption oral vs. oral: 1 (default)

Therefore the corrected NOAEL for repeated-dose systemic effects via the oral route is:

1000 mg/kg bw/day×1=1000 mg/kg bw/day

The following assessment factors were applied to the NOAEL:

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

Interspecies differences (toxicodynamics): 2.5 (default)

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

Intraspecies differences (general population): 10 (default)

Total AF: 6×2.5×4×10=600

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

1000 mg/kg bw/day/600=1.67 mg/kg bw/day.