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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
123.82 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: Substance-specific
Overall assessment factor (AF):
11
Modified dose descriptor starting point:
NOAEC
Value:
1 361.98 mg/m³
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
based on a subchronic study
AF for interspecies differences (allometric scaling):
1
Justification:
Substance-specific
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
2.2
Justification:
Substance-specific
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:
17.86 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: Substance-specific
Overall assessment factor (AF):
11
Modified dose descriptor starting point:
NOAEL
Value:
196.5 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No data are available for the dermal route, however, reliable data from a structural analogue substance are available for the inhalation route.
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
based on a subchronic study
AF for interspecies differences (allometric scaling):
1
Justification:
Substance-specific
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
2.2
Justification:
Substance-specific
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

There are no repeat dose toxicity studies available for trimethoxy(propyl)silane (CAS 1067-25-0), however, reliable data for the oral and inhalation route are available for the structural analogue substance trimethoxy(methyl)silane (CAS 1185-55-3).

Both substances will ultimately hydrolyse to produce structurally similar silanol molecules, propylsilanetriol and methylsilanetriol. The Si-C bond is stable under physiological conditions; the propyl and methyl moieties are thus firmly bound to the silanol group. The latter renders both molecules very polar and ready for rapid excretion via urine. It is therefore considered that read-across between the substances is appropriate.

In the absence of any significant findings relating to reproductive or developmental endpoints in appropriate and guideline compliant tests, the critical health effect is considered to be repeated-dose toxicity.

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 the NOAEC for the structural analogue substance trimethoxy(methyl)silane (560 mg/m³) from a 90-day inhalation study in rats. The following corrections were made:

Correction for respiratory volume: 0.29 m³/kg (rat, 6 hour)

Correction for route to route extrapolation (relative absorption inhalation vs. dermal): 1

The molecular weight difference between target and source chemical is 164.27/136.22 = 1.21

The corrected NOAEL (dermal) is therefore:

560 mg/m³ × 0.29 m³/kg bw/day × 1 × 1.21 = 196.5 mg/kg bw/day

The following assessment factors were applied to the corrected NOAEL:

Extrapolation of exposure duration (sub-chronic to chronic): 2 (default)

Interspecies differences (toxicodynamics): 2.5 (default)

Interspecies differences (toxicokinetics, rat/human): 1 (substance-specific, see below)

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

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

Total AF: 11

 

Allometric scaling factor (Toxicokinetics)

 

The allometric scaling factor accounts for metabolic differences between the test species and humans. This factor is not considered to be relevant fortrimethoxy(propyl)silaneon the following grounds:  

  1. The silanol hydrolysis product of the substance (and many other related substances) shows no biodegradation in a ready biodegradation test (PFA, 2013f) other than can be accounted for by degradation of non-silanol hydrolysis products; this suggests that the substance and its silanol hydrolysis product are not recognised by biological systems containing all the mammalian enzymes and metabolic systems.
  2. Toxicokinetic arguments show that the silanol hydrolysis product has low log Kow and hence low uptake, rapid excretion via urine, which would be true in all mammals, with minimal interspecies differences.

3.     Higher enzyme expression levels, stronger inducibility, higher substrate affinities and co-factor levels are factors that are potentially in favour of a more rapid xenobiotic metabolism, including elimination, by rodents compared to humans. Enzymes are not involved in the abiotic hydrolysis of the alkoxysilanes, and the silanols are rapidly excreted as such without prior enzymatic conjugation. This knowledge eliminates a great deal of the uncertainty on toxicokinetic interspecies differences.Since the metabolism of trimethoxy(propyl)silane by humans and rats does not involve enzymes, the toxicokinetic differences (both inter- and intraspecies) are reduced from 4.0 to 1.0. Only the toxicodynamic differences remain to be considered.

 

 

Intraspecies differences

 

The intraspecies assessment factor takes account 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 above, the conversion of siloxanes 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 – dermal - worker) is therefore:

196.5mg/kg bw / 11 = 17.86mg/kg bw/day

 

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

The DNEL for systemic effects via the inhalation route is determined on the basis of the 90-day inhalation NOAEC for the structural analogue substance trimethoxymethylsilane (560 mg/m³). The following corrections were made:

Correction for lower human breathing rate: 4.0
Correction for experimental vs. occupational exposure duration: 6 h/8 h

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

The molecular weight difference between target and source chemical is 164.27/136.22 = 1.21.

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

560 mg/m³ × 4.0× (6 h/8 h) × (6.7 m³ /10 m³) × 1.21 = 1361.98 mg/m³

The assessment factors were selected on the following basis:

Extrapolation of exposure duration (sub-chronic to chronic): 2 (default)

Interspecies differences (toxicodynamics): 2.5 (default)

Interspecies differences (toxicokinetics, rat/human): 1 (substance-specific, see above)

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

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

Total AF: 11

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

1361.98 mg/m³ /11= 123.82 mg/m³

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
30.25 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: substance-specific
Overall assessment factor (AF):
16
Modified dose descriptor starting point:
NOAEC
Value:
484 mg/m³
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
based on a subchronic study
AF for interspecies differences (allometric scaling):
1
Justification:
substance-specific
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
3.2
Justification:
substance-specific
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
154.17 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
24
Modified dose descriptor starting point:
LOAEC
Value:
3 700 mg/m³
AF for dose response relationship:
3
Justification:
no NOAEC was determined
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for inhalation route
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
3.2
Justification:
substance specific
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1

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:
8.77 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: substance-specific
Overall assessment factor (AF):
16
Modified dose descriptor starting point:
NOAEL
Value:
140.36 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No data are available for the dermal route, however, reliable data from a structural analogue substance are available for the inhalation route.
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
based on a subchronic study
AF for interspecies differences (allometric scaling):
1
Justification:
substance-specific
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
3.2
Justification:
substance-specific
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:
1.26 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: substance-specific
Overall assessment factor (AF):
48
Modified dose descriptor starting point:
NOAEL
Value:
60.5 mg/kg bw/day
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:
substance-specific
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
3.2
Justification:
substance-specific
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

General Population

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

The DNEL for systemic effects following single exposures via the inhalation route is determined based on results from a key acute inhalation study in rats (TNO, 1990). In this study, the LC50 was >22 200 mg/m³; the only dose tested. Following acute inhalation exposure there were signs of narcosis, therefore 22 200 mg/m³ is a LOAEC, which is chosen as point of departure for an acute DNEL.

The following corrections were made: Modification for experimental exposure duration (4 h in the study in rats to 24 h in consumers): 1/6

Therefore the corrected LOAEC for single-dose systemic effects via the inhalation route is:  22 200 × 1/6 = 3700 mg/m³.

The following assessment factors were applied to the corrected LOAEC:                                 

Assessment factor for use of a LOAEC: 3 (default)

Interspecies differences (remaining differences): 2.5(default)

Assessment factor for intraspecies differences: 3.2 (substance-specific, see above)

Total AF: 24

 

The overall DNEL (acute – systemic – inhalation – general population) is therefore:

3700 mg/m³ / 24 =154.17 mg/m³

 

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 the NOAEC for the structural analogue substance trimethoxy(methyl)silane (560 mg/m³) from a 90-day inhalation study in rats.

The following corrections were made:

Correction for number of exposures per week: 5 per week/7 per week (study data): 5/7 Correction for respiratory volume: 0.29 m³/kg (rat, 6 h)

The molecular weight difference between target and source chemical is 164.27/136.22 = 1.21

Correction for route to route extrapolation (relative absorption inhalation vs. dermal): 1

Therefore, the corrected NOAEL for systemic effects via the dermal route is:
560 mg/m³ × 5/7 × 0.29 m³/kg bw/day × 1 × 1.21 = 140.36 mg/kg bw/day

The following assessment factors were applied to the corrected NOAEL:

Extrapolation of exposure duration (sub-chronic to chronic): 2 (default)

Interspecies differences (toxicodynamics): 2.5 (default)                                              

Interspecies differences (toxicokinetics, rat/human): 1 (substance-specific, see above)

Intraspecies differences (toxicodynamics, general population): 3.2 (i.e. √10) (substance-specific, see above)

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

Total AF: 16

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

140.36 mg/kg bw/day / 16 =8.77 mg/kg bw/day

 

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

The DNEL for systemic effects via the inhalation route is determined on the basis of the 90-day inhalation NOAEC for structural analogue substance trimethoxymethylsilane (560 mg/m³).

The following corrections were made:

Correction for lower human breathing rate: 4.0

Correction for experimental exposure duration (6 h/d to 24 h/d): 6/24

Correction for number of exposures per week: 5 per week/7 per week (study data): 5/7.

The molecular weight difference between target and source chemical is 164.27/136.22 = 1.21

Therefore the corrected NOAEC for repeated-dose systemic effects via the inhalation route is: 560 mg/m³ × 4.0 × 6/24 × 5/7 × 1.21 = 484 mg/m³

The assessment factors were selected on the following basis:

Extrapolation of exposure duration (sub-chronic to chronic): 2 (default)

Interspecies differences (toxicodynamics): 2.5 (default)

Interspecies differences (toxicokinetics, rat/human): 1 (substance-specific, see above)

Intraspecies differences (toxicodynamics, general population): 3.2 (i.e. √10) (substance-specific, see above)

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

Total AF: 16

 

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

484 mg/m³ / 16 =30.25 mg/m³

 

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

The DNEL for systemic effects via the oral route is determined on the basis of the 28-day oral NOAEL for structural analogue substance trimethoxymethylsilane (50 mg/kg bw/day).

The molecular weight difference between target and source chemical is 164.27/136.22 = 1.21.

Therefore the corrected NOAEL is: 50 mg/kg bw/day × 1.21 = 60.5 mg/kg/day.

The assessment factors used to determine the DNEL (oral) were selected on the following basis:

Extrapolation of exposure duration (sub-acute to chronic): 6 (default)

Interspecies differences (toxicodynamics): 2.5 (default)

Interspecies differences (toxicokinetics, rat/human): 1 (substance-specific, see above)

Intraspecies differences (toxicodynamics, general population): 3.2 (i.e. √10) (substance-specific, see above)

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

Total AF: 48

 

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

60.5 mg/kg bw/day/ 48=1.26 mg/kg bw/day