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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
172.88 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: substance-specific (for details see discussion)
Overall assessment factor (AF):
33.6
Modified dose descriptor starting point:
NOAEC
DNEL value:
5 809 mg/m³
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 (for details see discussion)
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
2.2
Justification:
substance-specific (for details see discussion)
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
24.94 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 (for details see discussion)
Overall assessment factor (AF):
33.6
Modified dose descriptor starting point:
NOAEL
DNEL value:
838.1 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 are available for the inhalation route.
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 (for details see discussion)
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
2.2
Justification:
substance-specific (for details see discussion)
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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

As described in the data waiver for repeated dose toxicity an OECD 422 study with trimethoxy(2,4,4-trimethylpentyl)silane (CAS 34396-03-7) will be conducted to support read-across of higher tier mammalian toxicity data from the source substance, triethoxy(2,4,4-trimethylpentyl)silane (CAS 35435-21-3). As soon as a decision is made that higher tier data from the source substance are reliable to use as read across the DNELs will updated accordingly.

In the available key study (Hoechst, 1986) the test item was tested for repeated dose toxicity after subacute inhalative treatment. The test was conducted according to the OECD TG 412 and in compliance with GLP. Groups of ten male and ten female Wistar rats were exposed to a respirable aerosol of the test item at concentrations of 0.32, 1.54 and 2.89 mg/l (mean actual concentration) for 28 days (6 h/day, 5 days/week). After the exposure period five male and five female rats of each group were kept during a 14 d recovery period before necropsy. Following exposure each animal of the high dose group had a staggering gait, which was resolved by the next day. In the mid dose group, animals that showed a lack of coordination following exposure were recovered within two hours after exposure. There were sporadic changes to body weights in comparison to the controls. The low dose and control group animals did not have any clinical signs. There were no treatment-related effects on haematology, clinical chemistry, urinalysis, organ weights, and gross pathology. There were signs of minimal intense alveolar irritation (isolated and small clusters of foam cells) in several high dose animals, which is considered to be the predominant effect. Overall, the NOAEC for this study was considered to be 2.89 mg/l.

 

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

The DNEL for systemic effects via the inhalation route is determined on the basis of a 28-day inhalation toxicity study. In this study a NOAEC of 2890 mg/m³ was derived, which was the highest concentration tested.

 

The following correction was made to the NOAEC:

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

Therefore, the corrected NOAEC for long-term systemic effects via the inhalation route is:

2890 mg/m³×4×(6 h/8 h)×(6.7 m³ /10 m³)=5809 mg/m³

 

The assessment factors were selected on the following basis:

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

Interspecies differences (toxicodynamics): 2.5 (default)

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

Intraspecies differences (toxicodynamics, worker): 2.24 (i.e. √5, substance-specific, see below)

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

Total AF: 6×2.5×1×2.24×1=33.60

 

Allometric scaling factor (Toxicokinetics)

The allometric scaling factor accounts for metabolic differences between the test species and humans based on the caloric demand of the relevant species. The rat is thereby thought to have the ability for a faster detoxification by metabolic and excretion processes. On the other hand, any metabolism leading to more toxic molecules makes the rat more susceptible. The default allometric scaling factor is not considered to be relevant for trimethoxy(2,4,4-trimethylpentyl)silane on the following grounds:

1. The silanol hydrolysis product of the substance (and many other related substances) 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 (please see section 4.1).

2. Hydrolysis of the methoxy groups is seen as the major, rate determining step in detoxification as the resulting silanols have an increased urinary clearance based on the decreased molecular weight and the increased water solubility and have only a low tendency to migrate into potential target cells. Subsequent enzymatic metabolism steps are unlikely and would be of limited relevance for a rapid excretion of the substance.

3. Differences in excretion may also scale according to the allometric principle. However, for a small water soluble molecule with a strong affinity to aqueous compartments and without indications for specific organ toxicity, the role of the excretion step is seen as minimal.

4. Toxicokinetic arguments (see also Section 5.1) 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.

Conclusion

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 the major deal of the uncertainty on toxicokinetic interspecies differences. Since the metabolism of trimethoxy(2,4,4-trimethylpentyl)silane by humans and rats does not involve enzymes, the interspecies toxicokinetic differences are reduced from 4.0 to 1.0. Likewise, there is no basis for intra-human variability of the hydrolysis step. The default intraspecies factor of 10 or 5 for consumers and workers, respectively, is reduced to √10 = 3.2 and √5 = 2.2, respectively. Only the toxicodynamic differences remain to be considered.

 

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

5809 mg/m³/33.60=172.9 mg/m³.

 

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 28-day inhalation toxicity study. In this study a NOAEC of 2890 mg/m³ was derived, which was the highest concentration tested.

 

The following corrections were made:

Based on the physical and chemical properties, the QSAR calculation for dermal uptake of trimethoxy(2,4,4-trimethylpentyl)silane is believed to be about 50%. As no information is available from acute dermal or dermal repeated dose toxicity tests, a conservative approach is applied, and thus the relative dermal absorption was set to 1.

Correction for the respiratory volume for the rat: 0.29 m³/kg bw (6 h)

The corrected NOAEL is therefore 2890 mg/m³×1×0.29 m³/kg bw=838.1 mg/kg bw

 

The following assessment factors were applied to the corrected NOAEL:

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

Interspecies differences (toxicodynamics): 2.5 (default)

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

Intraspecies differences (toxicodynamics, worker): 2.24 (i. e. √5, substance-specific, see above)

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

Total AF: 6×2.5×1×2.24×1=33.60

 

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

838.1 mg/kg bw/day/33.6=24.941 mg/kg bw/day.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
43 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: substance-specific (for details see discussion)
Overall assessment factor (AF):
48
Modified dose descriptor starting point:
NOAEC
DNEL value:
2 064 mg/m³
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 (for details see discussion)
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
3.2
Justification:
substance-specific (for details see discussion)
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
12.47 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 (for details see discussion)
Overall assessment factor (AF):
48
Modified dose descriptor starting point:
NOAEL
DNEL value:
598.6 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 are available for the inhalation route.
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 (for details see discussion)
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
3.2
Justification:
substance-specific (for details see discussion)
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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
12.47 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 (for details see discussion)
Overall assessment factor (AF):
48
Modified dose descriptor starting point:
NOAEL
DNEL value:
598.6 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No data are available for the oral route. However, reliable data are available for the inhalation route.
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 (for details see discussion)
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
3.2
Justification:
substance-specific (for details see discussion)
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
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

As described in the data waiver for repeated dose toxicity an OECD 422 study with trimethoxy(2,4,4-trimethylpentyl)silane (CAS 34396-03-7) will be conducted to support read-across of higher tier mammalian toxicity data from the source substance, triethoxy(2,4,4-trimethylpentyl)silane (CAS 35435-21-3). As soon as a decision is made that higher tier data from the source substance are reliable to use as read across the DNELs will updated accordingly.

In the available key study (Hoechst, 1986) the test item was tested for repeated dose toxicity after subacute inhalative treatment. The test was conducted according to the OECD TG 412 and in compliance with GLP. Groups of ten male and ten female Wistar rats were exposed to a respirable aerosol of the test item at concentrations of 0.32, 1.54 and 2.89 mg/l (mean actual concentration) for 28 days (6 h/day, 5 days/week). After the exposure period five male and five female rats of each group were kept during a 14 d recovery period before necropsy. Following exposure each animal of the high dose group had a staggering gait, which was resolved by the next day. In the mid dose group, animals that showed a lack of coordination following exposure were recovered within two hours after exposure. There were sporadic changes to body weights in comparison to the controls. The low dose and control group animals did not have any clinical signs. There were no treatment-related effects on haematology, clinical chemistry, urinalysis, organ weights, and gross pathology. There were signs of minimal intense alveolar irritation (isolated and small clusters of foam cells) in several high dose animals, which is considered to be the predominant effect. Overall, the NOAEC for this study was considered to be 2.89 mg/l.

 

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

The DNEL for systemic effects via the inhalation route is determined on the basis of a 28-day inhalation toxicity study. In this study a NOAEC of 2890 mg/m³ was derived, which was the highest concentration tested.

 

The following correction was made to the NOAEC:

Correction for lower human breathing rate: 4.0

Correction for 5-days/week treatment: 5 d/7 d

Correction for exposure duration: 6 h/24 h

Therefore the corrected NOAEC for long-term systemic effects via the inhalation route is:

2890 mg/m³×4×(5 d/7 d)×(6 h/24 h)=2064 mg/m³

 

The assessment factors were selected on the following basis:

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

Interspecies differences (toxicodynamics): 2.5 (default)

Interspecies differences (toxicokinetics, rat/human): 1 (substance-specific, see discussion for workers)

Intraspecies differences (toxicodynamics, gen. pop.): 3.2 (i.e. √10, substance-specific, see discussion for workers)

Intraspecies differences (toxicokinetics, gen. pop.): 1 (substance-specific, see discussion for workers)

Total AF: 6×2.5×1×3.2×1=48

 

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

2064 mg/m³/48= 43.00 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 28-day inhalation toxicity study. In this study a NOAEC of 2890 mg/m³ was derived, which was the highest concentration tested.

 

The following corrections were made:

Based on the physical and chemical properties, the QSAR calculation for dermal uptake of trimethoxy(2,4,4-trimethylpentyl)silane is believed to be about 50%. As no information is available from acute dermal or dermal repeated dose toxicity tests, a conservative approach is applied, and thus the relative dermal absorption was set to 1.

Correction for the respiratory volume for the rat: 0.29 m³/kg bw (6 h)

Correction for weekly exposure duration: 5 d/7 d

The corrected NOAEL is therefore

2890 mg/m³×1×0.29 m³/kg bw×(5 d/7 d)=598.6 mg/kg bw

 

The following assessment factors were applied to the corrected NOAEL:

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

Interspecies differences (toxicodynamics): 2.5 (default)

Interspecies differences (toxicokinetics, rat/human): 1 (substance-specific, see discussion for workers)

Intraspecies differences (toxicodynamics, gen. pop.): 3.2 (i.e. √10, substance-specific, see discussion for workers)

Intraspecies differences (toxicokinetics, gen. pop.): 1 (substance-specific, see discussion for workers)

Total AF: 6×2.5×1×3.2×1=48

 

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

598.6 mg/kg bw/day/48=12.47 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 of route-to-route extrapolation from the 28-day inhalation toxicity study. In this study a NOAEC of 2890 mg/m³ was derived, which was the highest concentration tested.

 

The following corrections were made:

Correction for relative absorption oral vs. inhalation: 1

Correction for the respiratory volume for the rat: 0.29 m³/kg bw (6 h)

Correction for 5-days/week treatment: 5 d/7 d

The corrected NOAEL is therefore

2890 mg/m³×0.29 m³/kg bw×(5 d/7 d)=598.6 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): 1 (substance-specific, see discussion for workers)

Intraspecies differences (toxicodynamics, gen. pop.): 3.2 (i.e. √10, substance-specific, see discussion for workers)

Intraspecies differences (toxicokinetics, gen. pop.): 1 (substance-specific, see discussion for workers)

Total AF: 6×2.5×1×3.2×1=48

 

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

598.6 mg/kg bw/day/48=12.47 mg/kg bw/day.