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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.7 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
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
123.4 mg/m³
Explanation for the modification of the dose descriptor starting point:

Please refer to " Additional information"

AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
6
Justification:
The standard assessment factor for time extrapolation from subacute to chronic duration was used.
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scalling is applied for inhalation as the inhalative data is standardized with reference to the respiratory rates. Respiratory rates depend directly on caloric demand, therefore inhalative study results are already extrapolated to humans on the basis of metabolic rate scaling (=allometric scaling).
AF for other interspecies differences:
2.5
Justification:
Recommended AF for other interspecies differences.
AF for intraspecies differences:
5
Justification:
The default value for the relatively homogenous group "worker" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
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
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.7 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
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 400 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Please refer to "Additional information"

AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
6
Justification:
The standard assessment factor for time extrapolation from subacute to chronic duration was used.
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
2.5
Justification:
Recommended AF for other interspecies differences.
AF for intraspecies differences:
5
Justification:
The default value for the relatively homogenous group "worker" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

General

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA, Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose-response for human health (Version: 2.1, November 2012). In view of the data used for evaluation, the "quality of whole database factors" and "dose-response factors" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.

 

Inhalation

Long term, systemic DNEL – exposure via inhalation (workers)

Using a conservative approach, a worker DNEL (long-term inhalation exposure) is calculated. This worker long-term DNEL is considered to ensure an appropriate level of protection with regard to acute inhalation exposure (no high peaks of exposure expected).

No repeated dose inhalation toxicity study with the target substance is available. Therefore, it will be necessary to obtain a long-term DNEL by route-to-route extrapolation:

The dose range finder for the combined repeated dose oral toxicity study OECD 422 is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral systemic NOAEL is 100 mg/kg bw/day. This DNEL is used as PoD.

PoD: NOAEL = 100 mg/kg bw/day

Step 1: Modification of PoD into correct starting point:

Standard respiratory volume, human (sRVhuman) for 8 hours: 6.7 m3

Standard respiratory volume of the rat (sRVrat) for 8 hours: 0.38 m3/kg bw/d

Worker respiratory volume (wRV) for 8 hours with light physical activity: 10 m3

Oral absorption of the rat/ inhalation absorption of humans (ABS oral-rat / ABS inh-human): 50%/100 % (default)

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker

Corrected NOAEC (inhalation) for workers:

= 100 mg/kg bw/day x 0.5 x 1/0.38 m3/kg bw/day x (6.7 m3/10 m3) x (7/5)

= 123.4 mg/m3

Step 2: Use of assessment factors

Intraspecies AF (workers): 5

Interspecies AF, remaining differences: 2.5

Exposure duration AF: 6 (default)

Remaining uncertainties AF: 1

Overall AF= 75

In conclusion, long term systemic inhalation DNEL, workers = 1.7 mg/m3

Acute, systemic DNEL- exposure via inhalation (workers)

No data for the classification and labelling of the test substance for acute inhalation toxicity is available. The substance is not classified for acute oral toxicity, therefore no adverse result for inhalation toxicity is expected (in accordance with "Guidance on information requirements and chemical safety assessment", chapter R8). Furthermore, due to the extremely low vapour pressure (3.93E-4 Pa at 20°C and 5.9E-4 Pa at 25°C) of Reaction product of Hexamethylene diisocyanate, oligomers with Mercaptopropyltrimethoxysilane, inhalation exposure is not considered as relevant. The substance is unlikely to be available as a vapor. As the substance is a liquid no generation of dust is assumed. Therefore, no DNEL was derived.

Long term & acute, local DNEL- exposure via inhalation (workers)

The substance is not classified for skin irritation/corrosion according to Regulation EC No 1272/2008 and in conclusion local mucosal irritation of the respiratory membranes is not expected.

Dermal

Long term, systemic DNEL- exposure via dermal route (workers)

No repeated dose dermal toxicity study with the target substance is available. Therefore, it will be necessary to obtain a long-term dermal DNEL by route-to-route extrapolation.

The dose range finder for the combined repeated dose oral toxicity study OECD 422 is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral systemic NOAEL is 100 mg/kg bw/day. This DNEL is used as PoD.

PoD: NOAEL = 100 mg/kg bw/day

Step 1: Modification of PoD into correct starting point:

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker

Oral absorption of the rat / dermal absorption of humans (ABSoral-rat/ ABSdermal-human): 100%/10%

From physic-chemical properties of Reaction product of Hexamethylene diisocyanate, oligomers with Mercaptopropyl-trimethoxysilane a low dermal absorption is predicted because of its low water solubility, a molecular weight above 500 g/mol and an estimated log Pow value of 7.11. In cases were the molecular weight is above 500 and log Pow values outside the range of -1 to 4 are observed a value of 10% skin absorption can be assumed.

Corrected NOAEL (dermal) for workers:

= 100 mg/kg bw/day x (7/5) x (100%/10%)

= 1400 mg/kg bw/day

Step 2: Use of assessment factors

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

Exposure duration AF: 6

Remaining uncertainties AF: 1

Overall AF= 300

In conclusion, long term systemic dermal DNEL, workers = 4.7 mg/kg bw/day

Acute, systemic DNEL- dermal exposure (workers)

The test material is not classified and labelled for acute dermal toxicity, according to Regulation (EC) No 1272/2008 (CLP). Thus, no DNEL is required.

Long term & acute, local DNEL- dermal exposure (workers)

Reaction product of Hexamethylene diisocyanate, oligomers with Mercaptopropyltrimethoxysilane is classified for skin sensitization Cat 1A. Therefore the substance is allocated to the high hazard band (according to "Guidance on Information Requirements and Chemical Safety Assessment Part E: Risk Characterisation", May 2016). A qualitative risk assessment is conducted.

Hazard to the eye-local effects (workers)

The test item is not classified for eye damage according to Regulation (EC) No 1272/2008 (CLP). Therefore, no hazard has been identified.

References

ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2.1, November 2012

ECHA (2016). Guidance on information requirements and chemical safety assessment. Part E: Risk Characterisation, Version 3.0, May 2016

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.3 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
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
43.5 mg/m³
Explanation for the modification of the dose descriptor starting point:

Please refer to " Additional Information"

AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
6
Justification:
The standard assessment factor for time extrapolation from subacute to chronic duration was used.
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scalling is applied for inhalation as the inhalative data is standardized with reference to the respiratory rates. Respiratory rates depend directly on caloric demand, therefore inhalative study results are already extrapolated to humans on the basis of metabolic rate scaling (=allometric scaling).
AF for other interspecies differences:
2.5
Justification:
Recommended AF for other interspecies differences.
AF for intraspecies differences:
10
Justification:
The default value for the relatively homogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
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
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.7 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
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Please refer to "Additional Information"

AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
6
Justification:
The standard assessment factor for time extrapolation from subacute to chronic duration was used.
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
2.5
Justification:
Recommended AF for other interspecies differences.
AF for intraspecies differences:
10
Justification:
The default value for the relatively homogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.2 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
Dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
AF for dose response relationship:
1
Justification:
The dose response relationship is considered unremarkable, therefore no additional factor is used.
AF for differences in duration of exposure:
6
Justification:
The standard assessment factor for time extrapolation from subacute to chronic duration was used.
AF for interspecies differences (allometric scaling):
4
Justification:
The default allometric scaling factor for the differences between rats and humans is used.
AF for other interspecies differences:
2.5
Justification:
Recommended AF for other interspecies differences.
AF for intraspecies differences:
10
Justification:
The default value for the relatively homogenous group "general population" is used.
AF for the quality of the whole database:
1
Justification:
The quality of the whole data base is considered to be sufficient and uncritical.
AF for remaining uncertainties:
1
Justification:
The approach used for DNEL derivation is conservative. No further assessment factors are required.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
acute toxicity
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

General

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA, Guidance on information requirements and chemical safety assessment, Chapter R.8: Characterization of dose-response for human health (Version: 2.1, November 2012). In view of the data used for evaluation, the "quality of whole database factors" and "dose-response factors" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.

Inhalation

Long term, systemic DNEL – exposure via inhalation (general population)

No repeated dose inhalation toxicity study with the target substance is available. Therefore, it will be necessary to obtain a long-term DNEL by route-to-route extrapolation:

The dose range finder for the combined repeated dose oral toxicity study OECD 422 is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral systemic NOAEL is 100 mg/kg bw/day. This DNEL is used as PoD.

PoD: NOAEL = 100 mg/kg bw/day

Step 1: Modification of PoD into correct starting point:

Standard respiratory volume of the rat (sRVrat) for 24 hours: 1.15 m3/kg bw

Oral absorption of the rat/ inhalation absorption of humans (ABS oral-rat / ABS inh-human):50%/100 % (default)

Corrected NOAEC (inhalation) for general population:

= 100 mg/kg bw/day x 0.5 x 1/1.15 m3/kg bw/day

= 43.5 mg/m3

Step 2: Use of assessment factors

Intraspecies AF (General population): 10

Interspecies AF, remaining differences: 2.5

Dose response relationship AF: 1

Exposure duration AF: 6

Remaining uncertainties AF: 1

Overall AF: 150

In conclusion, long term systemic inhalation DNEL, general population = 0.3 mg/m3

Acute, systemic DNEL- exposure via inhalation (general population)

No data for the classification and labelling of the test substance for acute inhalation toxicity is available. The substance is not classified for acute oral toxicity, therefore no adverse result for inhalation toxicity is expected (in accordance with "Guidance on information requirements and chemical safety assessment", chapter R8). Furthermore, due to the extremely low vapour pressure (3.93E-4 Pa at 20°C and 5.9E-4 Pa at 25°C) of Reaction product of Hexamethylene diisocyanate, oligomers with Mercaptopropyltrimethoxysilane, inhalation exposure is not considered as relevant. The substance is unlikely to be available as a vapor. As the substance is a liquid no generation of dust is assumed. Therefore, no DNEL was derived.

Long term, local DNEL- exposure via inhalation (general population)

The substance is not classified for skin irritation/corrosion according to Regulation EC No 1272/2008 and in conclusion local mucosal irritation of the respiratory membranes is not expected.

Dermal

Long term, systemic DNEL- exposure via dermal route (general population)

No repeated dose dermal toxicity study with the target substance is available. Therefore, it will be necessary to obtain a long-term dermal DNEL by route-to-route extrapolation.

The dose range finder for the combined repeated dose oral toxicity study OECD 422 is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral systemic NOAEL is 100 mg/kg bw/day. This DNEL is used as PoD.

PoD: NOAEL = 100 mg/kg bw/day

Step 1: Modification of PoD into correct starting point:

Correction for difference between human and experimental exposure conditions: 7 d rat, 24 h/7 d, 24h general population

Oral absorption of the rat / dermal absorption of humans (ABSoral-rat/ ABSdermal-human): 100%/10%

From physic-chemical properties of Reaction product of Hexamethylene diisocyanate, oligomers with Mercaptopropyl-trimethoxysilane a low dermal absorption is predicted because of its low water solubility, a molecular weight above 500 g/mol and an estimated log Pow value of 7.11. In cases were the molecular weight is above 500 and log Pow values outside the range of -1 to 4 are observed a value of 10% skin absorption can be assumed.

Corrected NOAEL (dermal) for general population:

= 100 mg/kg bw/day x (100%/10%) x (7/7)

= 1000 mg/kg bw/day

Step 2: Use of assessment factors

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Dose-response relationship AF: 1

Exposure duration AF: 6

Remaining uncertainties AF: 1

Overall AF: 600

In conclusion, long term systemic dermal DNEL, general population = 1.7 mg/kg bw/day

Acute, systemic DNEL- dermal exposure (general population)

The test material is not classified and labelled for acute dermal toxicity, according to Regulation (EC) No 1272/2008 (CLP). Thus, no DNEL is required.

Long term & acute, local DNEL- dermal exposure (general population)

Reaction product of Hexamethylene diisocyanate, oligomers with Mercaptopropyltrimethoxysilane is classified for skin sensitization Cat 1A. Therefore the substance is allocated to the high hazard band (according to "Guidance on Information Requirements and Chemical Safety Assessment Part E: Risk Characterisation", May 2016). A qualitative risk assessment is conducted.

Oral

Long term, systemic DNEL- exposure by oral route (general population)

The dose range finder for the combined repeated dose oral toxicity study OECD 422 is selected for DNEL derivation as it is the relevant repeated dose study performed in accordance to OECD guideline and GLP. In this study, the oral systemic NOAEL is 100 mg/kg bw/day. This DNEL is used as PoD.

PoD: NOAEL = 100 mg/kg bw/day

Step 1: Use of assessment factors

Interspecies AF, allometric scaling (rat to human): 4

Interspecies AF, remaining differences: 2.5

Interspecies AF, remaining differences: Interspecies differences are fully covered by the allometric scaling

Intraspecies AF (general population): 10

Dose-response relationship AF: 1

Exposure duration AF: 6

Remaining uncertainties AF: 1

Overall AF: 600

In conclusion, long term systemic oral DNEL, general population= 0.2 mg/kg bw/day

Acute, systemic DNEL- exposure by oral route (general population)

According to ECHA Guidance on information requirements and chemical safety, Chapter R.8, Appendix R. 8-8, „a DNEL for acute toxicity should be derived if an acute toxicity hazard (leading to C&L) has been identified. The substance has low acute dermal toxicity with the LD50 of >2000 mg/kg. Therefore, the DNEL is not required.

Hazard to the eye-local effects (general population)

The test item is not classified for eye damage according to Regulation (EC) No 1272/2008 (CLP).

 

References

ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8:

Characterization of dose [concentration]-response for human health. Version 2.1, November 2012

ECHA (2016). Guidance on information requirements and chemical safety assessment. Part E: Risk Characterization, Version 3.0, May 2016

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