[3-(triethoxysilyl)propyl]urea

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

28.87 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

Modified dose descriptor starting point:

NOAEC

Value:

2 165 mg/m³

Explanation for the modification of the dose descriptor starting point:

For derivation of long-term DNELs the results from a reliable 28-day repeated dose study, conducted according to OECD TG 407, were used. No further long-term toxicity data were are available.

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

Justification:

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:

ECHA default

AF for intraspecies differences:

5

Justification:

for workers

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.1 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

Modified dose descriptor starting point:

NOAEL

Value:

1 228 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

For derivation of long-term DNELs the results from a reliable 28-day repeated dose study, conducted according to OECD TG 407, were used. No further long-term toxicity data were are available.

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

Justification:

based on a subacute study

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA default

AF for other interspecies differences:

2.5

Justification:

ECHA default

AF for intraspecies differences:

5

Justification:

for workers

AF for the quality of the whole database:

1

AF for remaining uncertainties:

1

Acute/short term exposure

DNEL related information

Additional information - workers

In the absence of any significant findings relating acute toxicity the critical health effect is considered to be repeated-dose toxicity.

No experimental data is available for the registered substance; however, reliable data is available for the closely related substance ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters (CAS 116912-64-2). The silicon-containing products of hydrolysis are close structural analogues: both [3-(triethoxysilyl)propyl]urea (CAS 23779-32-0) and ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters (CAS 116912-64-2) hydrolyse to ureidopropyl silanetriol. Both substances hydrolyse very rapidly: hydrolysis is expected to occur during testing and following exposure. The further products of hydrolysis are methanol and ethanol, respectively. It is therefore considered appropriate to read-across the results from ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters (CAS 116912-64-2) to the registered substance and DNEL calculation can be based on the results of the read-across substance. No correction for molecular weight was performed, as ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters (CAS 116912-64-2) is a multiconstituent substance without a defined molecular weight. Its molecular weight, however, is slightly higher than that of [3-(triethoxysilyl)propyl]urea (CAS 23779-32-0). Therefore, correction would result in a higher NOAEL and is not necessary.

A 28-day repeated dose study for the oral route is available for assessment of long-term toxicity of ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters (NOTOX, 2000b). The study was conducted according to OECD 407 and in compliance with GLP. Five male and female Wistar rats were dosed once daily (7 days/week) by oral gavage with 61, 184, 1228 mg/kg bw of the test substance. No treatment-related clinical signs have been observed. Slightly lower body weight gain was observed in the mid and high dose males, but was not statistically significant. Decrease of RBC, HB, relative number of lymphocytes and an increase of relative number of neutrophils in the female mid-dose group were considered to have occurred by chance, as there was no dose-response relationship and the values were within the historical control data. In two females of the mid-dose group the total motor activity was increased. Moreover, in one of these females the ratio between upper and lower sensor recordings was reverse to what is expected. These effects were considered to have occurred by chance because no corroborative findings in the animals and no dose-response relationship was observed. A decrease in the thymus/body weight ratio of high dose males was not supported by histological examination of the thymus. In view of the very small variation in the thymus weights of the male high dose group and the fact that all thymus weights were within the range of the historical control data, the toxicological significance of this effect was doubted. Thickening of the limiting ridge was observed in the stomach of 2/5 females of the high dose group. Microscopically a minimal squamous hyperplasia was observed. These effects were rather attributed to an irritative effect of the substance and are also commonly seen in gavage studies. In conclusion, as no treatment-related effects were observed at all the NOAEL was identified as 1228 mg/kg bw, which was the highest dose applied.

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

The long-term DNEL for systemic effects via the dermal route is determined on the basis of route-to-route extrapolation from the OECD 407 oral study on ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters, which identified a NOAEL of 1228 mg/kg bw/day. The following corrections were made:

As no differences were observed in the acute oral and dermal toxicity studies and no further information is available for evaluation of dermal absorption, a correction factor of 1 was applied accounting for the differences in oral and dermal absorption.

The corrected dermal NOAEL is therefore: 1228 mg/kg bw/day × 1 = 1228 mg/kg bw/day.

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: 6x2.5x4x5300

 

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

1228 mg/kg bw/day/300=4.1 mg/kg bw/day.

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

The long-term DNEL for systemic effects via the inhalation route is determined by route-to-route extrapolation from the OECD 407 oral study on ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters, which identified a NOAEL of 1228 mg/kg bw day. The following corrections were made:

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 factor for different absorption: 1

As shown in Section 2.4.1, Guidance Document R8 (ECHA, 2012b) suggests that a default correction factor of two be applied when performing extrapolation from oral to inhalation route. This is meant to reflect a two times higher absorption following inhalation compared to oral ingestion. This is thought to be too unrealistic an assumption to serve as default for human hazard characterisation. Whereas the GI tract is a flow-through system anatomically designed to absorb ingested molecules, the respiratory tract is a cul-de-sac designed for absorbing oxygen and desorbing CO2. There are no active mechanisms for taking up molecules other than O2 through the alveolar membrane into the surrounding capillary bed. For molecules that are acid-hydrolysable, the ratio of oral vs. inhalation absorption should be even more in favour of oral absorption: alkoxysilanes are acid labile and are rapidly hydrolysed in the gastric milieu. This gives rise to smaller, more hydrophilic molecules. For these molecules, gastrointestinal absorption may be higher than for the parent molecule. In contrast, some of these molecules can be expected to be relatively stable in the respiratory tract at near-neutral pH values. Thus, there are several factors in favour of higher oral absorption compared to inhalation absorption. If no experimental data are available to quantify absorption via these routes, it can be conservatively assumed that absorption via both routes is equally effective.

Therefore, the corrected NOAEC for long-term systemic effects via the inhalation route is:
1228 mg/kg bw/day/0.38 m³/kg×(6.7/10)×1=2165 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 (long-term - systemic - inhalation - worker) is therefore:

2165 mg/m³/75=28.87 mg/m³

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

7.12 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

Modified dose descriptor starting point:

NOAEC

Value:

1 068 mg/m³

Explanation for the modification of the dose descriptor starting point:

For derivation of long-term DNELs the results from a reliable 28-day repeated dose study, conducted according to OECD TG 407, were used. No further long-term toxicity data were are available.

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

Justification:

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:

ECHA 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

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.05 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

Modified dose descriptor starting point:

NOAEL

Value:

1 228 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

For derivation of long-term DNELs the results from a reliable 28-day repeated dose study, conducted according to OECD TG 407, were used. No further long-term toxicity data were are available.

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

Justification:

based on a subacute study

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA default

AF for other interspecies differences:

2.5

Justification:

ECHA 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

DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.05 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

Modified dose descriptor starting point:

NOAEL

Value:

1 228 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

For derivation of long-term DNELs the results from a reliable 28-day repeated dose study, conducted according to OECD TG 407, were used. No further long-term toxicity data were are available.

AF for dose response relationship:

1

AF for differences in duration of exposure:

6

Justification:

based on a subacute study

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA default

AF for other interspecies differences:

2.5

Justification:

ECHA 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

DNEL related information

Additional information - General Population

In the absence of any significant findings relating acute toxicity the critical health effect is considered to be repeated-dose toxicity.

No experimental data is available for the registered substance; however, reliable data is available for the closely related substance ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters (CAS 116912-64-2). The silicon-containing products of hydrolysis are close structural analogues: both [3-(triethoxysilyl)propyl]urea (CAS 23779-32-0) and ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters (CAS 116912-64-2) hydrolyse to ureidopropyl silanetriol. Both substances hydrolyse very rapidly: hydrolysis is expected to occur during testing and following exposure. The further products of hydrolysis are methanol and ethanol, respectively. It is therefore considered appropriate to read-across the results from ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters (CAS 116912-64-2) to the registered substance and DNEL calculation can be based on the results of the read-across substance. No correction for molecular weight was performed, as ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters (CAS 116912-64-2) is a multiconstituent substance without a defined molecular weight. Its molecular weight, however, is slightly higher than that of [3-(triethoxysilyl)propyl]urea (CAS 23779-32-0). Therefore, correction would result in a higher NOAEL and is not necessary.

A 28-day repeated dose study for the oral route is available for assessment of long-term toxicity of ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters (NOTOX, 2000b). The study was conducted according to OECD 407 and in compliance with GLP. Five male and female Wistar rats were dosed once daily (7 days/week) by oral gavage with 61, 184, 1228 mg/kg bw of the test substance. No treatment-related clinical signs have been observed. Slightly lower body weight gain was observed in the mid and high dose males, but was not statistically significant. Decrease of RBC, HB, relative number of lymphocytes and an increase of relative number of neutrophils in the female mid-dose group were considered to have occurred by chance, as there was no dose-response relationship and the values were within the historical control data. In two females of the mid-dose group the total motor activity was increased. Moreover, in one of these females the ratio between upper and lower sensor recordings was reverse to what is expected. These effects were considered to have occurred by chance because no corroborative findings in the animals and no dose-response relationship was observed. A decrease in the thymus/body weight ratio of high dose males was not supported by histological examination of the thymus. In view of the very small variation in the thymus weights of the male high dose group and the fact that all thymus weights were within the range of the historical control data, the toxicological significance of this effect was doubted. Thickening of the limiting ridge was observed in the stomach of 2/5 females of the high dose group. Microscopically a minimal squamous hyperplasia was observed. These effects were rather attributed to an irritative effect of the substance and are also commonly seen in gavage studies. In conclusion, as no treatment-related effects were observed at all the NOAEL was identified as 1228 mg/kg bw, which was the highest dose applied.

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

The long-term DNEL for systemic effects via the oral route is determined on the basis of an OECD 407 oral study on ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters, which identified a NOAEL of 1228 mg/kg bw/day.

The following assessment factors were applied to the 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:

1228 mg/kg bw/day/600=2.05 mg/kg bw/day.

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

The long-term DNEL for systemic effects via the dermal route is determined on the basis of route-to-route extrapolation from the OECD 407 oral study on ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters, which identified a NOAEL of 1228 mg/kg bw/day. The following corrections were made:

As no differences were observed in the acute oral and dermal toxicity studies and no further information is available for evaluation of dermal absorption, a correction factor of 1 was applied accounting the differences of oral and dermal absorption.

The corrected dermal NOAEL is therefore: 1228 mg/kg bw*1=1228 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:

1228 mg/kg bw/day/600=2.05 mg/kg bw/day.

 

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

The long-term DNEL for systemic effects via the inhalation route is determined of route-to-route extrapolation from the OECD 407 oral study on ureidopropyltrialkoxysilane, mixed methoxy and ethoxy esters, which had a NOAEL of 1228 mg/kg bw/day.

The following corrections were made:

Correction for respiratory volume (rat/human): 1.15 m³/kg bw (24 h)
Therefore, the corrected NAEC for long-term systemic effects via the inhalation route is: 1228 mg/m³/1.15 m³/kg=1068 mg/m³
 
The assessment factors were selected on the following basis:
Exposure duration (sub-acute 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 (long-term – systemic – inhalation) is therefore:
1068 mg/m³/150=7.12 mg/m³