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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
22.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: substance-specific (for further details please refer to discussion section)
Overall assessment factor (AF):
11
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
247 mg/m³
Explanation for the modification of the dose descriptor starting point:

The long-term DNEL for systemic effects via the inhalation route is determined on the basis of the 90-day oral NOAEL on the registration substance itself.

To correct the interspecies difference between rat and human the no observed effect level has to be corrected as follows:

Corrected starting point for the inhalative route for workers:

= NOAEL(oral) * (1/0.38 m³/kg bw/day) * (ABSoral-rat/ABSinh-human) * 6.7 m³ (8h) /10 m³ (8h)* (7 days exposure rat/5 days exposure worker)

= 100 mg/kg bw/day * (1/0.38 m³/kg bw/day) * (1/1) * 0.67 m³ * 1.4 = 247 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.

(ABSoral-rat = oral absorption in rats, ABSinh-human = inhalation absorption rate in humans)

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEC.
AF for differences in duration of exposure:
2
Justification:
based on a subchronic 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:
2.2
Justification:
substance-specific (for further details please refer to the discussion section)
AF for the quality of the whole database:
1
Justification:
The 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
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
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:
3.2 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: substance-specific (for further details please refer to the discussion section)
Overall assessment factor (AF):
44
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
140 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The calculation of the DNEL is based on an oral NOAEL observed in a subchronic repeated dose oral toxicity study (OECD 408; 2020).

Corrected starting point for the dermal route for workers:

Dermal NOAEL = oral NOAEL*ABS(oral)/ABS(dermal) * (7 days exposure rat / 5 days exposure worker) = 100 mg/kg bw/day *(1/1) * (7/5) = 140 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:
2
Justification:
based on a subchronic study
AF for interspecies differences (allometric scaling):
4
Justification:
The experimental animal was a rat.
AF for other interspecies differences:
2.5
Justification:
ECHA default
AF for intraspecies differences:
2.2
Justification:
substance-specific (for further details please refer to the discussion section)
AF for the quality of the whole database:
1
Justification:
The 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
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Based on all available data the critical health effect is considered to be repeated-dose toxicity.

Workers

The long-term DNEL for systemic effects via the dermal route is determined on the basis of route-to route extrapolation from the OECD 408 oral study on dimethoxy(dimethyl)silane, which showed a NOAEL of 100 mg/kg bw/day. The following correction was made to the NOAEL:

No correction for relative absorption oral vs. dermal: 1 (worst case). A correction based on different exposure times between experimental animal and worker are considered (7 days exposure for rat and 5 days exposure for workers)

The corrected NOAEL is therefore: 100 mg/kg bw/day * (7/5) = 140 mg/kg bw/day.

The following assessment factors were applied to the corrected NOAEL:

Exposure duration (subchronic to chronic): 2 (default)

Interspecies differences (toxicodynamics): 2.5 (default)

Interspecies differences (toxicokinetics, rat/human): 4

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

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

Total AF: 44

Intraspecies differences

The intraspecies assessment factor accounts 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 in the TK assessment, 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.

Dermal DNEL = 140 mg/kg bw / 44= 3.2 mg/kg bw/day

The long-term DNEL for systemic effects via the inhalation route is determined on the basis of the 90-day oral NOAEL.

The following corrections were made:

Correction for metabolic rate: 1 / 0.38 m³/kg bw/day

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

Correction for exposure duration (exposure duration rat / exposure duration worker): 7 days / 5 days

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

100 mg/kg bw/day × (1/0.38 m³/kg bw/day) × (6.7 m³/day /10 m³/day) × (7days / 5 days) = 247 mg/m³

The following assessment factors were applied to the corrected NOAEC:

Exposure duration (sub-chronic to chronic): 2 (default)

Interspecies differences (toxicodynamics): 2.5 (default)

Interspecies differences (toxicokinetics, rat/human): 1 (not used for inhalation route)

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:

247 mg/m³/11= 22.5 mg/m³

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.44 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: substance-specific (for further details please refer to discussion section)
Overall assessment factor (AF):
16
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
87 mg/m³
Explanation for the modification of the dose descriptor starting point:

The long-term DNEL for systemic effects via the inhalation route is determined on the basis of the 90-day oral NOAEL on the registration substance itself.

Corrected starting point for the inhalative route for general population:

= NOAELoral * (1/1.15 m³/kg bw/day (24h)) * (ABSoral-rat / ABSinh-human)

= 100 mg/kg bw/day * (1/1.15 m³/kg bw/day) * (1/1) = 87 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.

(ABSoral-rat = oral absorption in rats, ABSinh-human = inhalation absorption rate in humans)

Thus, the corrected starting point for general population was 87 mg/m³ for inhalation.

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEC.
AF for differences in duration of exposure:
2
Justification:
based on a subchronic 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:
3.2
Justification:
substance-specific (for further details please refer to the discussion section)
AF for the quality of the whole database:
1
Justification:
The 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
Most sensitive endpoint:
acute toxicity
Route of original study:
By inhalation
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:
1.56 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: substance-specific (for further details please refer to discussion section)
Overall assessment factor (AF):
64
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The calculation of the DNEL is based on an oral NOAEL observed in a subchronic repeated dose oral toxicity study (OECD 408; 2020).

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:
2
Justification:
based on a subchronic study
AF for interspecies differences (allometric scaling):
4
Justification:
The experimental animal was a rat.
AF for other interspecies differences:
2.5
Justification:
ECHA default
AF for intraspecies differences:
3.2
Justification:
substance-specific (for further details please refer to the discussion section)
AF for the quality of the whole database:
1
Justification:
The 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
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.56 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):
64
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No route-to-route extrapolation is needed as an adequate and reliable subchronic repeated dose oral toxicity study performed with rats (OECD 408) is available DNEL (oral) derivation. The basis for the DNEL is the NOAEL = 100 mg/kg bw/day.

AF for dose response relationship:
1
Justification:
The dose descriptor starting point is based on a NOAEL.
AF for differences in duration of exposure:
2
Justification:
based on a subchronic study
AF for interspecies differences (allometric scaling):
4
Justification:
The experimental animal was a rat.
AF for other interspecies differences:
2.5
Justification:
ECHA default
AF for intraspecies differences:
3.2
Justification:
substance-specific (for further details please refer to the discussion section)
AF for the quality of the whole database:
1
Justification:
The 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
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Based on all available data the critical health effect is considered to be repeated-dose toxicity.

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 408 oral study on dimethoxy(dimethyl)silane, which showed a NOAEL of 100 mg/kg bw/day. The following correction was made to the NOAEL:

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

The corrected NOAEL is therefore: 100 mg/kg bw/day * 1 = 100 mg/kg bw/day.

The following assessment factors were applied to the corrected NOAEL:

Exposure duration (subchronic to chronic): 2 (default)

Interspecies differences (toxicodynamics): 2.5 (default)

Interspecies differences (toxicokinetics, rat/human): 4

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

Intraspecies differences (toxicokinetics, gen. pop.): 1 (substance-specific, see below)

Total AF: 64

Intraspecies differences

The intraspecies assessment factor accounts 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 in the TK assessment, 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 - general population) is therefore:

100 mg/kg bw / 64=1.56 mg/kg bw/day

The long-term DNEL for systemic effects via the inhalation route is determined on the basis of the 90-day oral NOAEL.

The following corrections were made:

Correction for metabolic rate: 1 / 1.15 m³/kg bw/day

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

100 mg/kg bw/day × (1/1.15 m³/kg bw/day) = 87 mg/m³

The following assessment factors were applied to the corrected NOAEC:

Exposure duration (sub-chronic to chronic): 2 (default)

Interspecies differences (toxicodynamics): 2.5 (default)

Interspecies differences (toxicokinetics, rat/human): 1 (not used for inhalation route)

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

Intraspecies differences (toxicokinetics, gen. pop.): 1 (substance-specific, see above)

Total AF: 16

The overall DNEL (long-term – systemic – inhalation - general population) is therefore:

87 mg/m³ / 16=5.44 mg/m³

The long-term DNEL for systemic effects via the oral route is determined on the basis of the OECD 408 oral study on dimethoxy(dimethyl)silane, which established a NOAEL of = 100 mg/kg bw/day.

The following assessment factors were applied to the NOAEL:

Exposure duration (subchronic to chronic): 2 (default)

Interspecies differences (toxicodynamics): 2.5 (default)

Interspecies differences (toxicokinetics, rat/human): 4

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

Intraspecies differences (toxicokinetics, gen. pop.): 1 (substance-specific, see above)

AF = 64

The overall DNEL (long-term – systemic – oral – general population) is therefore:

100 mg/kg bw/day / 64 = 1.56 mg/kg bw/day.