N-[3-({[2,2-dimethyl-3-(morpholin-4-yl)propylidene]amino}methyl)-3,5,5-trimethylcyclohexyl]-2,2-dimethyl-3-(morpholin-4-yl)propan-1-imine

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

11.67 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

Modified dose descriptor starting point:

NOAEC

Value:

875 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:

6

Justification:

The recommended time extrapolation factor for a subacute toxicity study is used.

AF for interspecies differences (allometric scaling):

1

Justification:

No allometric scaling factor is applied because an oral-to-inhalation route extrapolation is performed.

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

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

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:

13.33 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

Modified dose descriptor starting point:

NOAEL

Value:

4 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated dermal exposure. Taken into account the physico-chemical properties of the substance, dermal absoption is anticipated to be low (25 % of oral absorption). For details 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:

6

Justification:

The recommended time extrapolation factor for a subacute toxicity study is 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

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:

low hazard (no threshold derived)

Additional information - workers

General

DNEL derivation for the substance Sika Hardener MI is performed under consideration of the recommendations of ECHA. 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.

 

Workers – Hazard via inhalation route

 

Long term systemic inhalation DNEL, worker

Calculation of dose descriptor

 

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

For risk characterisation a inhalation NOAEC was derived by route to route extrapolation.

The oral NOAEL of 1000 mg/kg bw/day, obtained from chronic repeated dose toxicity testing in rats was considered as key value for the chemical safety assessment and therefore, most relevant starting point.

 

Step 2: Modification into a correct starting point:

In a first step the oral NOAEL was transferred to humans with a factor of 4 for allometric scaling from rats. For worker a NOEC long-term, inhalation was calculated assuming 70 kg per person, 8h light activity (10 m³ breathing volume), 50 % absorption via oral routes and 100 % absorption via inhalatory routes. NOEC (Worker) inhalation = 1000 mg/kg bw/day * 1/4 *70 kg * 1/10 m³ * 50 % Abs, (oral) / 100 % Abs, (inhal) = 875 mg/m³

 

Step 3: Use of assessment factors: 75

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

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

time extrapolation AF: 6

In conclusion the long term systemic inhalation DNEL workers was calculated to be 11.67 mg/m³ bw/day.

 

Short term acute inhalation DNEL, worker

Based on the uses of the substance, exposure is not expected (see section 3.5). Furthermore, the test material is not classified and labelled for acute dermal and oral toxicity, according to Regulation (EC) No 1272/2008 (CLP). Thus, in accordance with “Guidance on information requirements and chemical safety assessment chapter R8: Characterisation of dose (concentration)- response for human health” no DNEL is required.

 

Workers – Hazard via dermal route

 

Long term systemic dermal DNEL, worker

Calculation of dose descriptor

 

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

For risk characterisation a dermal NOAEL was derived by route to route extrapolation.

The oral NOAEL of 1000 mg/kg bw/day, obtained from chronic repeated dose oral toxicity testing in rats, was considered as key value for the chemical safety assessment and therefore, most relevant starting point.

 

Step 2: Modification into a correct starting point:

Based on the physical chemical properties of the substance (molecular mass 476.74 g/mol, log Pow value =5.71 which is outside the range [-1, 4]), dermal uptake of the substance is assumed to be low (according to “Guidance on information requirements and chemical safety assessment chapter R7c: Endpoint specific Guidance”). But, as the molecular mass is still <500 and water solubility is 1008 mg/L and therefore favours dermal uptake, absorption through skin can not be excluded and an absorption rate of 25 % was deduced. In conclusion, dermal NOAEL = oral NOAEL x [ABS oral rat/ABS dermal human] = 1000 mg/kg bw/day x (100/25) = 4000 mg/kg bw/d.

 

Step 3: Use of assessment factors: 300

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

Interspecies AF, remaining differences: 2.5

Intraspecies AF (worker): 5

Exposure duration AF (subacute exposure period): 6

In conclusion the long term systemic dermal DNEL workers were calculated to be 13.33 mg/kg bw/day.

 

Local effects, long term dermal exposure

The test item is classified as a skin sensitizer, cat. 1 according to Regulation (EC) No 1272/2008 (CLP). Thus, a qualitative risk assessment is conducted.

 

Acute short term dermal DNEL, worker

Local dermal effects are covered by the long term local risk assessment and no quantitative acute local dermal assessment is required.

 

Worker – Hazard for the eyes

The substance is classified for eye irritation (cat. 2) according to Regulation (EC) No 1272/2008 (CLP) and is, therefore, allocated to the low hazard band. A qualitative risk assessment is conducted (according to “Guidance on information requirements and chemical safety assessment part E: risk characterization”, Nov. 2012).

 

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. November 2012.

- ECHA (2012). Guidance on information requirements and chemical safety assessment.Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics. November 2012.

- 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:

2.5 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

Modified dose descriptor starting point:

NOAEC

Value:

375 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:

6

Justification:

The recommended time extrapolation factor for a subacute toxicity study is used.

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 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:

low hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

low hazard (no threshold derived)

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:

6.67 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

Modified dose descriptor starting point:

NOAEL

Value:

4 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

There are no relevant experimental data on repeated dermal exposure. Taken into account the physico-chemical properties of the substance, dermal absoption is anticipated to be low (25 % of oral absorption). For details 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:

6

Justification:

The recommended time extrapolation factor for a subacute toxicity study is 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:

1.67 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

Modified dose descriptor starting point:

NOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation is required.

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 recommended time extrapolation factor for a subacute toxicity study is 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:

low hazard (no threshold derived)

Additional information - General Population

General

DNEL derivation for the substance Sika Hardener MI is performed under consideration of the recommendations of ECHA. 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.

 

General population – Hazard via inhalation route

Long term systemic inhalation DNEL, general population

Calculation of dose descriptor

 

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

For risk characterisation a inhalation NOAEC was derived by route to route extrapolation.

The oral NOAEL of 1000 mg/kg bw/day, obtained from chronic repeated dose toxicity testing in rats was considered as key value for the chemical safety assessment and therefore the most relevant starting point.

 

Step 2: Modification into a correct starting point:

In a first step the oral NOAEL was transferred to humans with a factor of 4 for allometric scaling from rats. For general population a NOEC long-term, inhalation was calculated assuming 60 kg per person, 24h light activity (20 m³ breathing volume), 50 % absorption via oral routes and 100 % absorption via inhalatory routes.

NOEC (General population) inhalation = 1000 mg/kg bw/day * 1/4 *60 kg * 1/20 m³ * 50%Abs, (oral) / 100 % Abs, (inhal) = 375 mg/m³

 

Step 3: Use of assessment factors: 150

Interspecies: Respiratory interspecies differences are fully covered by the modification of the NOAEC

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Exposure duration AF: 6 (subacute study)

In conclusion, long term systemic inhalation DNEL, general population = 2.5 mg/m3

 

Short term acute inhalation DNEL, general population

The test material is not classified and labelled for acute oral and dermal toxicity, according to Regulation (EC) No 1272/2008 (CLP). Thus, in accordance with “Guidance on information requirements and chemical safety assessment chapter R8: Characterisation of dose (concentration)- response for human health” no DNEL is required.

Local effects

No data on respiratory irritation is available. As the substance is not classified as skin and eye irritating also no adverse effects on respiratory system is expected (in accordance with "Guidance on information requirements and chemical safety assessment, chapter R8"). Additionally, based on the uses of the substance (see section 3.5), exposure to the substance and its hydrolysis products is not expected. Thus, no DNEL is required.

 

General population – Hazard via dermal route

Long term systemic dermal DNEL, general population

Calculation of dose descriptor

 

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

For risk characterisation a dermal NOAEL was derived by route to route extrapolation.

The oral NOAEL of 1000 mg/kg bw/day, obtained from chronic repeated dose oral toxicity testing in rats, was considered as key value for the chemical safety assessment and therefore, most relevant starting point.

 

Step 2: Modification into a correct starting point:

Based on the physical chemical properties of the substance (molecular mass 476.74 g/mol, log Pow value =5.71 which is outside the range [-1, 4]), dermal uptake of the substance is assumed to be low (according to “Guidance on information requirements and chemical safety assessment chapter R7c: Endpoint specific Guidance”). But, as the molecular mass is still <500 and water solubility is 1008 mg/L and therefore favours dermal uptake, absorption through skin can not be excluded and an absorption rate of 25 % was deduced. In conclusion, dermal NOAEL = oral NOAEL x [ABS oral rat/ABS dermal human] = 1000 mg/kg bw/day x (100/25) = 4000 mg/kg bw/d.

 

Step 3: Use of assessment factors: 600

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

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Exposure duration AF: 6 (subacute study)

In conclusion, long term systemic dermal DNEL, general population = 6.67 mg/kg bw/day

 

Local effects, long term dermal exposure

The test item is classified as a skin sensitizer, cat. 1 according to Regulation (EC) No 1272/2008 (CLP). Thus, a qualitative risk assessment is conducted.

 

Acute short term dermal DNEL, general population

Local dermal effects are covered by the long term local risk assessment and no quantitative acute local dermal assessment is required.

 

General population – Hazard for the eyes

The substance is classified for eye irritation (cat. 2) according to Regulation (EC) No 1272/2008 (CLP) and is, therefore, allocated to the low hazard band. A qualitative risk assessment is conducted (according to “Guidance on information requirements and chemical safety assessment part E: risk characterization”, Nov. 2012).

 

General population – Hazard via oral route

Long term systemic oral DNEL, general population

 

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

A chronic study in rats 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 NOAEL in rats is 1000 mg/kg bw/day.

 

Step 2: Modification of the starting point:

Not required.

 

Step 3: Use of assessment factors: 600

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

Interspecies AF, remaining differences: 2.5

Intraspecies AF (general population): 10

Exposure duration AF: 6 (subacute study)

In conclusion, long term systemic oral DNEL, general population = 1.67 mg/kg bw/day

 

Acute short term oral DNEL, general population

The acute oral systemic DNEL is not required as the substance is not classified for acute oral toxicity.

 

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. November 2012.

- ECHA (2012). Guidance on information requirements and chemical safety assessment.Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics. November 2012.

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