Registration Dossier

Diss Factsheets

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
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
370 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
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
80.4 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Dose descriptor:
NOAEC
Value:
1 500 mg/m³
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:
1
Justification:
No time extrapolation factor is needed since a chronic toxicity study is available.
AF for interspecies differences (allometric scaling):
2.5
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 normally 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

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.4 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
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
840 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 a two times lower absorption via the dermal route (end route) as compared to the oral route (starting route) is used.

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
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:
low hazard (no threshold derived)

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).

Acute/short-term, systemic effects

Short-term DNELs are not required as the acute toxicity of Incozol 4 is low. The substance is not classified and labelled for acute systemic toxicity, according to Regulation EC 1272/2008 (CLP), based on the test data for acute oral and dermal toxicity.

 

Acute/long-term, local effects

Exposure by inhalation

During use of the test item as hardener the test substance hydrolyses completely into the degradation products 1,6 hexanediyl-bis-carbamic acid bis(N-hydroxyethyl-2-aminoethyl) ester and Isobutyraldehyde (CAS 78-84-2). 1,6 hexanediyl-bis-carbamic acid bis(N-hydroxyethyl-2-aminoethyl) ester reacts with other components of the product within seconds forming a solid matrix. Therefore, no emission from product is expected. Further, its estimated vapour pressure is very low. Therefore, no likelihood of exposure other than covered by the exposure estimations of isobutyraldehyde is assumed and DNEL derivation is based on the NOAEC obtained in a subchronic inhalation study with Isobutyraldehyde.

 

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

The NOAEC of 1500 mg/m³, stated in the publication (Abdo et al., 1998) is identified as the relevant dose descriptor and starting point. According to the ECHA disseminated Dossier of Isobutyraldehyde the local NOAEC after 90 -days and 2 years were identical.

 

Step 2: Modification into a correct starting point:

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:

= 1500 mg/m3 x 0.67

= 1005 mg/m3  

 

Step 3: Use of assessment factors: 12.5

Intraspecies AF (worker): 5

Other interspecies differences AF: 2.5

Exposure duration AF: 1

 

In conclusion, long term local inhalation DNEL, workers = 80.4 mg/m3

 

Skin and eye exposure

Skin irritation/corrosion: Based on the available study Incozol 4 is not classified for skin irritation.

Skin sensitization: As Incozol 4 is a weak sensitizer in the LLNA and no dose-response relationship is available a qualitative risk assessment is conducted.

Eye irritation: Incozol 4 is classified for eye irritation based on the results of the eye irritation study available. As no dose-response relationship is available a qualitative risk assessment is conducted.

 

Long term, systemic effects

Occupational exposure to Incozol 4 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 (2017) 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/d

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

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

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/d × 0.5 × (1 / 0.38 m3/kg bw/d) × (6.7 m3/10 m3) x 7/5

= 370 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

 

Dermal exposure

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

The OECD TG 408 study (2017) 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 is 300 mg/kg bw/day.

 

Step 2: Modification of the starting point:

Using a conservative approach, a worker DNEL (long-term dermal exposure) is derived. Based on the physico-chemical properties of Incozol 4 (log Kow: 2.9 and water solubility: 30 mg/L) dermal absorption is assumed to be half of oral absorption. The corrected NOAEL and starting point is therefore 600 mg/kg bw/day.

Correction for difference between human and experimental exposure conditions: 7 d rat/5 d worker (=1.4)

Corrected NOAEL (dermal) for workers:

= 600 mg/kg bw/day x 1.4

= 840 mg/kg bw/day

Step 3: Use of assessment factors: 100

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

Intraspecies AF (worker): 5

Other interspecies differences AF: 2.5

Exposure duration AF: 2

 

In conclusion, long term systemic dermal DNEL, workers = 8.4 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, 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:
2.6 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
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
130.4 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:
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
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
60 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Dose descriptor:
NOAEC
Value:
1 500 mg/m³
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:
1
Justification:
No time extrapolation factor is needed since a chronic toxicity study is available.
AF for interspecies differences (allometric scaling):
2.5
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 normally 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 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

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3 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
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
600 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 a two times lower absorption via the dermal route (end route) as compared to the oral route (starting route) is used.

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
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
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
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 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) 

Acute/short-term, systemic effects

Short-term DNELs are not required as the acute toxicity of Incozol 4 is low. The substance is not classified and labelled for acute systemic toxicity, according to Regulation EC 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 study Incozol 4 is not classified for skin irritation. Therefore, no qualitative risk assessment is required.

Skin sensitization: As Incozol 4 is a weak sensitizer in the LLNA and no dose-response relationship is available a qualitative risk assessment is conducted.

Eye irritation: Incozol 4 is classified for eye irritation based on the results of the eye irritation study available. As no dose-response relationship is available a qualitative risk assessment is conducted.

 

Exposure by inhalation

During use of the test item as hardener the test substance hydrolyses completely into the degradation products 1,6 hexanediyl-bis-carbamic acid bis(N-hydroxyethyl-2-aminoethyl) ester and Isobutyraldehyde (CAS 78-84-2). 1,6 hexanediyl-bis-carbamic acid bis(N-hydroxyethyl-2-aminoethyl) ester reacts with other components of the product within seconds forming a solid matrix. Therefore, no emission from product is expected. Further, its estimated vapour pressure is very low. Therefore, no likelihood of exposure other than covered by the exposure estimations of isobutyraldehyde is assumed and DNEL derivation is based on the NOAEC obtained in a subchronic inhalation study with Isobutyraldehyde.

 

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

The NOAEC of 1500 mg/m3, stated in the publication (Abdo et al., 1998) is identified as the relevant dose descriptor and starting point. According to ECHA disseminated Dossier of Isobutylaldehyde the local NOAEC after 90 -days and 2 years was identical.

 

Step 2: Modification into a correct starting point:

Modification of the starting point is not necessary.

 

Step 3: Use of assessment factors: 25

 

In conclusion, long term local inhalation DNEL, general population = 60 mg/m3

 

Long term, systemic effects

Consumer exposure to Incozol 4 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/d, assessed in the 90-day repeated dose oral toxicity study (2017) 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

Body weight: 70 kg

Default respiratory volume of general population (wRV) for 24 hours: 20 m3person

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

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 × 1/1.15 m3/kg/d *(7/7)

= 130.4 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 = 2.6 mg/m3

 

Dermal exposure

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

The NOAEL of 300 mg/kg bw/d, assessed in the 90-day repeated dose oral toxicity study (2017) is identified as the relevant dose descriptor and starting point.

 

Step 2: Modification of the starting point:

Using a conservative approach, a general population DNEL (long-term dermal exposure) is derived. Based on the physico-chemical properties of Incozol 4 (log Kow: 2.9 and water solubility: 30 mg/L) dermal absorption is assumed to be half of oral absorption. The corrected NOAEL and starting point is therefore 600 mg/kg bw/day.

 

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 = 3 mg/kg bw/day

 

Oral exposure 

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

The NOAEL of 300 mg/kg bw/d, assessed in the 90-day repeated dose oral toxicity study (2017) is identified as the relevant dose descriptor and starting point.

 

Step 2: 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, November 2012

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