Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.612 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: substance-specific, see discussion
Overall assessment factor (AF):
11
Modified dose descriptor starting point:
NOAEC
DNEL value:
6.734 mg/m³
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
subchronic to chronic (default)
AF for interspecies differences (allometric scaling):
1
Justification:
substance-specific, see discussion
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
2.2
Justification:
substance-specific, see discussion
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
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:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.567 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: substance-specific, see discussion
Overall assessment factor (AF):
33
Modified dose descriptor starting point:
NOAEL
DNEL value:
84.7 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No dermal study available.
AF for dose response relationship:
1
AF for differences in duration of exposure:
6
Justification:
subacute to chronic (default)
AF for interspecies differences (allometric scaling):
1
Justification:
substance-specific, see discussion
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
2.2
Justification:
substance-specific, see discussion
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
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:
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

Triethoxysilane is a volatile liquid that hydrolyses rapidly in water, with a predicted half-life of 1 hour at pH 7. The hydrolysis products are ethanol and silanetriol. Over longer timescales, the Si-H bond may also be unstable with respect to hydrolysis; the expected hydrolysis product is silicic acid, Si(OH)4. Triethoxysilane is acutely toxic following inhalation of vapour, and is irritating to skin. Indications of systemic toxicity were observed in acute studies using the inhalation and oral routes, but not via the dermal route. There are no repeated dose toxicity data on triethoxysilane or its hydrolysis product, so good quality data for the related substances trimethoxysilane (CAS 2487-90-3) and trimethoxy(methyl)silane (CAS 1185-55-3) have been used to assess the general systemic toxicity of triethoxysilane. In repeat-dose inhalation studies, the respiratory tract was identified as the potential target organ, and no other systemic effects were observed. At high concentrations effects were observed in a number of organs following oral and dermal exposure, including the lungs, kidney, liver, spleen, pancreas, adrenals, and gastrointestinal tract, but it is not possible to determine if these were secondary to irritation or independent systemic effects.

Toxicity data after repeated exposure via inhalation is available for the structural analogue trimethoxysilane (CAS 2487-90-3). This read-across was chosen as a very conservative read-across and a higher NOAEL in repeated inhalation test and a corresponding higher DNEL could be expected if triethoxysilane was tested. This assumption is based on the fact that trimethoxysilane is acutely very toxic and is also corrosive, whereas triethoxysilane is acutely toxic and irritating to the skin.

Both analogues have similar physicochemical properties (log Kow 0.2 and 1.7 for trimethoxysilane and triethoxysilane respectively; predicted water solubility 54000 and 5600 mg/l). In contrast, the vapour pressure differs in a magnitude of approximately 10 trimethoxysilane having the higher vapour pressure (113 hPa) than triethoxysilane (9.21 hPa). At neutral pH, the hydrolysis rate of trimethoxysilane is slower than that of the registered substance, triethoxysilane (half-lives ca. 2 hours and 1 hour respectively). It is therefore considered valid to read-across from trimethoxysilane to triethoxysilane in order to determine a DNEL for systemic effects via the inhalation route.

Repeated exposure of rats to trimethoxysilane (CAS 2487-90-3) vapour in a 9-day range finding study resulted in lethal effects at 5 ppm (0.025 mg/l), attributed to respiratory tract injury. The LOAEC in this study was 1 ppm, and the NOEC was 0.2 ppm. In a subsequent 90-day vapour inhalation study in the rat, there were no effects at the highest dose level tested, 0.5 ppm. The NOAEC for both local and systemic effects was therefore at least 0.5 ppm.

The choice of such a low exposure concentration for the repeat-dose studies was determined by the need to minimise suffering of the test animals due to severe respiratory tract injury following exposure to vapour. However, the low concentrations used were not suitable to properly assess potential systemic toxicity. The 90-day NOAEC of 0.5 ppm is therefore considered to be the most appropriate starting point to determine a DNEL for systemic effects after a long term exposure via the inhalation route.

No repeated-dose studies are available for neither for triethoxysilane (998-30-1) itself, via the oral and dermal routes nor for the hydrolysis product, silanetriol. Therefore, a read-across to trimethoxy(methyl)silane (CAS 1185-55-3) was performed for the oral route.

An oral OECD 422 combined repeat-dose and reproductive/developmental toxicity screening test in rats is available for the substance trimethoxy(methyl)silane (CAS 1185-55-3). Both analogues have similar physicochemical properties (log Kow 0.7 and 1.7 for trimethoxy(methyl)silane and triethoxysilane respectively; predicted water solubility 29000 and 5600 mg/l). At neutral pH, the hydrolysis rate of trimethoxy(methyl)silane is slower than that of the registered substance, triethoxysilane (half-lives ca. 2 hours and 1 hour respectively), but under low pH conditions in the stomach, both substances hydrolyse very rapidly. It is therefore considered valid to read-across from trimethoxy(methyl)silane to triethoxysilane in order to determine a DNEL for systemic effects via the oral route.

No studies have been conducted with trimethoxysilane for reproductive or developmental toxicity. Since the 90-day inhalation study tested very low concentrations of trimethoxysilane which would be unlikely to lead to manifestation of effects in the reproductive organs, it is appropriate to read-across from the structural analogue, trimethoxy(methyl)silane, for which there is an oral OECD 422 study as described above. In this study no reproductive or developmental effects were observed up to a dose of 1000 mg/kg bw/day. In addition, there is a 90 day inhalation study on trimethoxy(methyl)silane that did not show any adverse treatment-related effects on the reproductive organs up to an exposure concentration of 8900 mg/m³ in rats.

 

Workers

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 NOAEL of the oral OECD 422 study in rats, conducted with the analogue substance trimethoxy(methyl)silane (CAS 1185-55-3).

The following corrections were made:

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

Correction for exposures per week: 7 d/5 d

Correction for molecular weight difference: 164.28/136.22=1.21

The corrected NOAEL (dermal) is therefore:

50 mg/kg bw/day×1×(7/5)×1.21= 84.7 mg/kg bw/day.

 

The following assessment factors were applied to the corrected NOAEL:

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

Interspecies differences (toxicodynamics): 2.5 (default)

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

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

Total AF: 6×2.5×1×2.2=33

 

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 for triethoxysilane on the following grounds:

  1. The silanol hydrolysis product of the substance (and many other related substances (PFA, 2013f)) shows no biodegradation in a ready biodegradation test 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 triethoxysilane 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 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 (repeated-dose – systemic – dermal) is therefore:

84.7 mg/kg bw/day/33=2.567 mg/kg bw/day.

 

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

TheDNEL for systemic effects via the inhalation routeis determined on the basis of the NOAEC of 2.5 mg/m³ from the 90-day inhalation study in rats, performed with the analogue substance to trimethoxysilane (CAS 2487-90-3). The following corrections were made:

Correction for lower human breathing rate: 4

Correction for exposure duration: 6 h/8 h

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

Correction for molecular weight: 164.28/122.20=1.34

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

2.5 mg/m³×4×(6/8)×(6.7/10)×1.34=6.734 mg/m³

 

The following assessment factors were applied to the corrected NOAEC:

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

Interspecies differences (toxicodynamics): 2.5 (default)

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

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

Total AF: 2×2.5×1×2.2=11

 

The overallDNEL (repeated-dose – systemic – inhalation)is therefore:

6.734 mg/m³/11=0.612 mg/m³.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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:
no hazard identified
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

General Population - Hazard via oral route

Systemic 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 for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

There is no contact of the general population with triethoxysilane.