1,3-Cyclohexanedimethanamine, N1,N3-bis(2-methylpropylidene)-

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

17.9 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):

30

Modified dose descriptor starting point:

NOAEC

Value:

539.9 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 default extrapolation factor for exposure duration is used: subacute (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:

1

Justification:

Interspecies differences including toxicokinetics are fully covered by the allometric scaling. There is no additional evidence for species differences including toxicodynamics. Therefore, no additional factor is used.

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)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

10.15 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):

120

Modified dose descriptor starting point:

NOAEL

Value:

1 218 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 50 % of oral absorption.

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 default extrapolation factor for exposure duration is used: subacute (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:

1

Justification:

Interspecies differences including toxicokinetics are fully covered by the allometric scaling. There is no additional evidence for species differences including toxicodynamics. Therefore, no additional factor is used.

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:

medium hazard (no threshold derived)

Additional information - workers

General

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA (2012).

 

Acute/short-term, systemic effects

Short-term DNELs are not required as the acute toxicity of Incorez 397 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 Incorez 397 is classified as corrosive to skin, cat. 1C (H314) according to Regulation (EC) No 1272/2008. A qualitative risk assessment is conducted.

 

Eye irritation: Based on data for skin irritation, the test item is considered to cause severe eye damage. Incorez 397 is therefore classified as H314 according to Regulation (EC) No 1272/2008. A qualitative risk assessment is conducted.

 

Skin sensitization: The test item is classified for skin sensitisation, cat. 1 based on the results of the LLNA with the Incorez 397. A qualitative risk assessment is conducted.

 

Long term, systemic effects

Occupational exposure to Incorez 397 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 609 mg/kg bw/day, assessed in the 28-day repeated dose oral toxicity study (Toxi Coop, 2011) 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 considering a two times higher absorption by inhalation in comparison to oral absorption. 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): 609 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

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

 

Corrected inhalatory NOAEC for workers

= 609 mg/kg bw/day × 0.5 × (1 / 0.38 m³/kg bw/d) × (6.7 m³/10 m³)

= 536.9 mg/m³

 

Step 3: Use of assessment factors: 30

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

Intraspecies AF (worker): 5

Exposure duration AF: 6

 

In conclusion, long term systemic inhalation DNEL, workers = 17.9 mg/m3

 

Dermal exposure

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

The NOAEL of 609 mg/kg bw/day, assessed in the 28-day repeated dose oral toxicity study (Toxi Coop, 2011) is identified as the relevant dose descriptor and starting point.

 

Step 2: Modification of the starting point:

A worker DNEL (long-term dermal exposure) is derived. Based on physico-chemical properties (log Pow 5.13, water solubility: 0.98 mg/L) dermal penetration of Incorez 397 is assumed to be 50 % of oral absorption.

NOAEL (dermal) = NOAEL (oral) / 0.5 = 609 mg/kg bw/day / 0.5 = 1218 mg/kg bw/day.

 

Step 3: Use of assessment factors: 120

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

Intraspecies AF (worker): 5

Exposure duration AF: 6

 

In conclusion, long term systemic dermal DNEL, workers = 10.15 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. ECHA-2010-G-19–EN.

- ECHA (2017). Guidance on information requirements and chemical safety assessment. Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics. June 2017.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.81 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):

60

Modified dose descriptor starting point:

NOAEC

Value:

228.4 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 default extrapolation factor for exposure duration is used: subacute (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:

1

Justification:

Interspecies differences including toxicokinetics are fully covered by the allometric scaling. There is no additional evidence for species differences including toxicodynamics. Therefore, no additional factor is used.

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

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.1 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):

240

Modified dose descriptor starting point:

NOAEL

Value:

1 218 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 50 % of oral absorption.

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 default extrapolation factor for exposure duration is used: subacute (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:

1

Justification:

Interspecies differences including toxicokinetics are fully covered by the allometric scaling. There is no additional evidence for species differences including toxicodynamics. Therefore, no additional factor is used.

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:

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:

2.5 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):

240

Modified dose descriptor starting point:

NOAEL

Value:

609 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation is required 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:

6

Justification:

The default extrapolation factor for exposure duration is used: subacute (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:

1

Justification:

Interspecies differences including toxicokinetics are fully covered by the allometric scaling. There is no additional evidence for species differences including toxicodynamics. Therefore, no additional factor is used.

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:

high hazard (no threshold derived)

Additional information - General Population

General

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA (2012).

 

Acute/short-term, systemic effects

Short-term DNELs are not required as the acute toxicity of Incorez 397 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 Incorez 397 is classified as corrosive to skin, cat. 1C (H314) according to Regulation (EC) No 1272/2008. A qualitative risk assessment is conducted.

 

Eye irritation: Based on data for skin irritation, the test item is considered to cause severe eye damage. Incorez 397 is therefore classified as H314 according to Regulation (EC) No 1272/2008. A qualitative risk assessment is conducted.

 

Skin sensitization: The test item is classified for skin sensitisation, cat. 1 based on the results of the LLNA with the Incorez 397. A qualitative risk assessment is conducted.

 

Long term, systemic effects

Consumer exposure to Incorez 397 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 609 mg/kg bw/day, assessed in the 28-day repeated dose oral toxicity study (Toxi Coop, 2011) 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 considering a two times higher absorption by inhalation in comparison to oral absorption.

 

Relevant dose descriptor (NOAEL): 609 mg/kg bw/day

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

Allometric scaling: 4

Body weight: 60 kg

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

 

Corrected inhalatory NOAEC for general population

= 609 mg/kg bw/day × 0.5 / 4 × 60 kg / 20 m³/person

= 228.4 mg/m³

 

Step 3: Use of assessment factors: 60

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

Intraspecies AF (general population): 10

Exposure duration AF: 6

 

In conclusion, long term systemic inhalation DNEL, general population = 3.8 mg/m3

 

Dermal exposure

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

The NOAEL of 609 mg/kg bw/day, assessed in the 28-day repeated dose oral toxicity study (Toxi Coop, 2011) is identified as the relevant dose descriptor and starting point.

 

Step 2: Modification of the starting point:

A general population DNEL (long-term dermal exposure) is derived. Based on physico-chemical properties (log Pow 5.13, water solubility: 0.98 mg/L) dermal penetration of Incorez 397 is assumed to be 50 % of oral absorption.

NOAEL (dermal) = NOAEL (oral) / 0.5 = 609 mg/kg bw/day / 0.5 = 1218 mg/kg bw/day.

 

Step 3: Use of assessment factors: 240

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

Intraspecies AF (general population): 10

Exposure duration AF: 6

 

In conclusion, long term systemic dermal DNEL, general population = 5.1 mg/kg bw/day

 

Oral exposure

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

The NOAEL of 609 mg/kg bw/day, assessed in the 28-day repeated dose oral toxicity study (Toxi Coop, 2011) is identified as the relevant dose descriptor and starting point.

 

Step 2: Use of assessment factors: 240

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

Intraspecies AF (general population): 10

Exposure duration AF: 6

 

In conclusion, long term systemic oral DNEL, general population = 2.5 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. ECHA-2010-G-19–EN.

- ECHA (2017). Guidance on information requirements and chemical safety assessment. Chapter R.7.12: Endpoint specific guidance: Guidance on Toxicokinetics. June 2017.