Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14.8 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):
25
Dose descriptor starting point:
NOAEL
DNEL value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
370.26 mg/m³
Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation. A conservative approach is used assuming a two times higher absorption via the inhalation route (end route) as compared to the oral route (starting route).

 

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:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
1
Justification:
Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.
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:
DNEL (Derived No Effect Level)
Value:
2.7 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.7 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.2 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):
100
Dose descriptor starting point:
NOAEL
DNEL value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
420 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated dermal exposure. Due to physico-chemical properties the same  absorption via the dermal route (end route) as compared to the oral route (starting route) is used. For details, please refer to the discussion.

 

 

 

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:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).
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:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

General

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA (2010).  

Acute/short-term, systemic effects

Short-term DNELs are not required as the acute toxicity of Hardener LH is low. The substance is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute oral and dermal toxicity.  

Acute/long-term, local effects

Skin irritation/corrosion: Based on the available acute skin irritation study Hardener LH is not classified for skin corrosion/irritation according to Regulation (EC) No 1272/2008.  

Eye irritation/corrosion: Based on the corrosive properties of one of the degradation products of Hardener LH the test item is considered to cause severe eye damage. Hardener LH is therefore classified as H318 according to Regulation (EC) No 1272/2008.  

Respiratory irritation/corrosion:

SIKA Hardener LH hydrolyses very fast and one of the degradation products (hexamethylendiamine (HMD), CAS 124-09-4, see disseminated dossier published on the ECHA homepage), is known to cause respiratory irritation and a local long-term DNEL of 0.54 for the inhalation route is provided in the dossier. This DNEL was used as starting point for the DNEL-derivation of SIKA Hardener LH:  

As the available DNEL was assessed for 100 % HMD, it has to be modified according to the HMD concentration present in a solution after hydrolysis of SIKA Hardener LH. During manufacture of HMD, the substance amount never exceeds 25 % and the substance purity accounts for 50 - 80 %. Assuming a purity of 80%, 25 % therefrom leads to an endconcentration of 20 % HMD. Therefore the DNEL has to be modified as follows:  

 

5 * 0.54 mg/m3 leads to a DNEL local, long-term (inhalation) of 2.7 mg/m3.

 

Skin sensitization: Based on the results of the GMPT the test item is classified for skin sensitisation, cat. 1B. In the absence of a dose-response relationship a qualitative risk assessment is conducted.  

Long term, systemic effects

Occupational exposure to SIKA Hardener LH occurs mainly by dermal route, and may also occur by inhalation route. Therefore two long-term DNELs are calculated for workers. In view of the data used for evaluation, the "quality of whole database factor" and "dose-response factor" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.  

 

Exposure by inhalation

 

Step 1: Selection of the relevant dose descriptor (starting point): The NOAEL of 300 mg/kg bw/day, assessed in the 90-day repeated dose oral toxicity study (ToxiCoop, 2016) is identified as the relevant dose descriptor and starting point.  

Step 2: Modification into a correct starting point: Using a conservative approach, a worker DNEL (long-term inhalation exposure) is derived. This worker DNEL is considered to ensure an appropriate level of protection with regard to acute inhalation exposure (no high peaks of exposure expected).  

Relevant dose descriptor (NOAEL): 300 mg/kg bw/day

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

Oral absorption of the rat / inhalation absorption of humans (ABSoral-rat / ABSinh-human): 0.5 (50%/ 100%)

Standard respiratory volume of humans (sRVhuman) for 8 hours: 6.7 m³

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

Frequency of exposure used in study: 7 days/week

Frequency of exposure of the worker: 5 days/week

Corrected inhalatory NOAEC for workers = 300 mg/kg bw/day × 0.5 × (1 / 0.38 m³/kg bw/d) × (6.7 m³/10 m³) x (7/5) = 370.26 mg/m³  

Step 3: Use of assessment factors: 25

Interspecies: no allometric scaling factor is applied because an oral-to-inhalation route extrapolation is performed.

Other interspecies differences AF: 2.5

Intraspecies AF (worker): 5

Exposure duration AF: 2

 

 

In conclusion, long term systemic inhalation DNEL, workers = 14.8 mg/m3  

 

Risk Assessment for long-term inhalation is based on the acute local long-term DNEL (see above), as it represents a worst case value as compared to the DNEL long-term, systemic.  

 

Dermal exposure

 

Step 1: Selection of the relevant dose descriptor (starting point):

The NOAEL of 300 mg/kg bw/day, assessed in the 90-day repeated dose oral toxicity study (ToxiCoop, 2016) is identified as the relevant dose descriptor and starting point.  

Step 2: Modification of the starting point: Assuming that dermal absorption is the same as oral absorption, a worker DNEL (long-term dermal exposure) is derived.  

Frequency of exposure used in study: 7 days/week

Frequency of exposure of the worker: 5 days/week

ABS (oral rat): 100%

ABS (dermal human):100%

Corrected dermal NOAEL for workers:

= 300mg/kg bw/d x 100%/100% x 7/5 = 420 mg/kg bw/d

Step 3: Use of assessment factors: 100

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

Other interspecies differences AF: 2.5

Intraspecies AF (worker): 5

Exposure duration AF: 2 

 

In conclusion, long term systemic dermal DNEL, workers = 4.2 mg/kg bw/day  

 

References

(not included as endpoint study record)  

- ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2.1. ECHA-2010-G-19-EN.

 

- ECHA (2014). Guidance on information requirements and chemical safety assessment.Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics. ECHA-14-G-06-N.

 

- ECHA (2012) Practical Guide 15: How to undertake a qualitative human health assessment and document it in a chemical safety report, November 2012.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.22 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):
50
Dose descriptor starting point:
NOAEL
DNEL value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
111.1 mg/m³
Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated exposure by inhalation. A conservative approach is used assuming a two times higher absorption via the inhalation route (end route) as compared to the oral route (starting route).

 

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:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).
AF for interspecies differences (allometric scaling):
1
Justification:
Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.
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 more heterogenous 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:
DNEL (Derived No Effect Level)
Value:
2.7 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.7 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.5 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):
200
Dose descriptor starting point:
NOAEL
DNEL value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated dermal exposure. Due to physico-chemical properties the same  absorption via the dermal route (end route) as compared to the oral route (starting route) is used. For details, please refer to the discussion.

 

 

 

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:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).
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 more heterogenous 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:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
medium 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:
1.5 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):
200
Dose descriptor starting point:
NOAEL
DNEL value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No route to route extrapolation is necessary since a repeated dose oral toxicity study is available.

 

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:
2
Justification:
The default extrapolation factor for exposure duration is used: subchronic (starting point) to chronic (end point).
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 more heterogenous 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:
medium hazard (no threshold derived)

Additional information - General Population

General

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA (2010).

 

Acute/short-term, systemic effects

Short-term DNELs are not required as the acute toxicity of Hardener LH is low. The substance is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute oral and dermal toxicity.

 

Acute/longterm, local effects

Skin irritation/corrosion: Based on the available acute skin irritation study Hardener LH is not classified for skin corrosion/irritation according to Regulation (EC) No 1272/2008.

 

Eye irritation/corrosion: Based on the corrosive properties of one of the degradation products of Hardener LH the test item is considered to cause severe eye damage. Hardener LH is therefore classified as H318 according to Regulation (EC) No 1272/2008.

 

Respiratory irritation/corrosion: SIKA Hardener LH hydrolyses very fast and one of the degradation products (hexamethylendiamine (HMD), CAS 124-09-4, see disseminated dossier published on the ECHA homepage), is known to cause respiratory irritation and a local long-term DNEL of 0.54 for the inhalation route is provided in the dossier. This DNEL was used as starting point for the DNEL-derivation of SIKA Hardener LH:

 

As the available DNEL was assessed for 100 % HMD, it has to be modified according to the HMD concentration present in a solution after hydrolysis of SIKA Hardener LH.

During manufacture of HMD, the substance amount never exceeds 25 % and the substance purity accounts for 50 - 80 %. Assuming a purity of 80%, 25 % therefrom leads to an endconcentration of 20 % HMD. Therefore the DNEL has to be modified as follows:

5 * 0.54 mg/m3 leads to a DNEL loacal, long-term (inhalation) of 2.7 mg/m3.

Skin sensitization: Based on the results of the GMPT the test item is classified for skin sensitisation, cat. 1B. In the absence of a dose-response relationship a qualitative risk assessment is conducted.

 

Long term, systemic effects

Consumer exposure to SIKA Hardener LH occurs mainly by dermal route, and may also occur by oral and inhalation route. Therefore long-term DNELs are calculated for the general population. In view of the data used for evaluation, the "quality of whole database factor" and "dose-response factor" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.

 

Exposure by inhalation

Step 1: Selection of the relevant dose descriptor (starting point):

The NOAEL of 300 mg/kg bw/day, assessed in the 90-day repeated dose oral toxicity study (ToxiCoop, 2016) is identified as the relevant dose descriptor and starting point.

 

Step 2: Modification into a correct starting point:

Using a conservative approach, a general population DNEL (long-term inhalation exposure) is derived.

 

Relevant dose descriptor (NOAEL): 300 mg/kg bw/day

Oral absorption of the rat / inhalation absorption of humans (ABSoral-rat / ABSinh-human): 0.5 (50%/100%)

Body weight: 60 kg

Default respiratory volume of general population (wRV) for 24 hours: 20 m³/person

Standard respiratory volume of the rat (sRVrat) for 24 hours: 1.35 m³/kg bw/d

Frequency of exposure used in study: 7 days/week

Frequency of exposure of the general population: 7 days/week

 

Corrected inhalatory NOAEC for general population

= 300 mg/kg bw/day × 0.5 x 1/1.35 m3/kg/d x (7/7)

= 111.1 mg/m³

 

Step 3: Use of assessment factors: 50

Interspecies: no allometric scaling factor is applied because an oral-to-inhalation route extrapolation is performed.

Other interspecies differences AF: 2.5

Intraspecies AF (general population): 10

Exposure duration AF: 2

 

In conclusion, long term systemic inhalation DNEL, general population = 2.2 mg/m3

 

Dermal exposure

Step 1: Selection of the relevant dose descriptor (starting point):

The NOAEL of 300 mg/kg bw/day, assessed in the 90-day repeated dose oral toxicity study (ToxiCoop, 2016) is identified as the relevant dose descriptor and starting point.

 

Step 2: Modification of the starting point:

Assuming that dermal absorption is the same as oral absorption, a general population DNEL (long-term dermal exposure) is derived.

 

Frequency of exposure used in study: 7 days/week

Frequency of exposure of the general population: 7 days/week

ABS (oral rat): 100%

ABS (dermal human):100%

 

Corrected dermal NOAEL for general population:

= 300 mg/kg bw/d x 100%/100% x 7/7 = 300 mg/kg bw/d

Step 3: Use of assessment factors: 200

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

Other interspecies differences AF: 2.5

Intraspecies AF (general population): 10

Exposure duration AF: 2

 

In conclusion, long term systemic dermal DNEL, general population = 1.5 mg/kg bw/day

 

Oral exposure

Step 1: Selection of the relevant dose descriptor (starting point):

The NOAEL of 300 mg/kg bw/day, assessed in the 90-day repeated dose oral toxicity study (ToxiCoop 2016) is identified as the relevant dose descriptor and starting point.

 

Step 2: Modification of the starting point: Not required.

Step 3: Use of assessment factors: 200

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

Other interspecies differences AF: 2.5

Intraspecies AF (general population): 10

Exposure duration AF: 2

 

In conclusion, long term systemic oral DNEL, general population = 1.5 mg/kg bw/day

 

References

(not included as endpoint study record)

 

- ECHA (2012). Guidance on information requirements and chemical safety assessment. Chapter R.8: Characterisation of dose [concentration]-response for human health. Version 2.1. ECHA-2010-G-19-EN.

 

- ECHA (2014). Guidance on information requirements and chemical safety assessment.Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics. ECHA-14-G-06-N.

 

- ECHA (2012) Practical Guide 15: How to undertake a qualitative human health assessment and document it in a chemical safety report, November 2012.