Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.234 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:
37 mg/m³
Explanation for the modification of the dose descriptor starting point:
No repeated dose toxicity study by inhalation is available. Therefore an oral-to-inhalation extrapolation is done. The default factor of 2 was included.
AF for dose response relationship:
1
Justification:
default value
AF for differences in duration of exposure:
6
Justification:
default value for time extrapolation from subacute to chronic study
AF for interspecies differences (allometric scaling):
4
Justification:
default value for correction for differences in metabolic rate (rat to humans)
AF for intraspecies differences:
5
Justification:
default value (worker)
AF for the quality of the whole database:
1
Justification:
GLP Guideline study
AF for remaining uncertainties:
1
Justification:
Toxicodynamic differences between humans and rats are not assumed. Therefore the assessment factor for remaining differences is set to 1.
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.35 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:
42 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No repeated dose toxicity study with dermal application is available. Therefore an oral-to-dermal extrapolation is done.
AF for dose response relationship:
1
Justification:
default value
AF for differences in duration of exposure:
6
Justification:
default value for time extrapolation from subacute to chronic study
AF for interspecies differences (allometric scaling):
4
Justification:
default value for correction for differences in metabolic rate (rat to humans)
AF for intraspecies differences:
5
Justification:
default value (worker)
AF for the quality of the whole database:
1
Justification:
GLP Guideline study
AF for remaining uncertainties:
1
Justification:
Toxicodynamic differences between humans and rats are not assumed. Therefore the assessment factor for remaining differences is set to 1.
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
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)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

DNEL Derivation - Worker

General considerations

The primary route of anticipated industrial exposure to N4-amine is via skin contact. Given its low vapour pressure at room temperature, inhalation of N4-amine is not likely to be high. However, exposition to aerosols or droplets of an inhalable size cannot be ruled out. 

 

The N4-amine is harmful after single ingestion (BASF AG, 1977), toxic after single skin contact (BASF AG, 1977), corrosive after single skin (BASF AG, 1977) and causes serious eye damage after contact (BASF AG, 1977). Furthermore, it is highly sensitizing after skin contact (BASF SE, 2008) and damages certain organs after repeated exposure (BASF SE, 2012). It is not possible to derive a local DNEL based on the available data. Because of its sensitizing potential however, the N4-amine should be attributed to a high hazard class according to the ECHA Guidance on information requirement and chemical safety assessment, Part E: Risk Characterisation. Appropriate qualitative risk management measures and operational conditions should therefore be implemented when developing exposure scenarios.

The N4-amine did not show any adverse effects regarding mutagenicity.

 

Inhalation long-term exposure – systemic effects:

The NOAEL from a combined 28-day oral repeated dose toxicity study with the reproduction /developmental toxicity screening test in rats conducted according to OECD TG 422 (BASF SE, 2012) was identified as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. The NOAEL for general, systemic toxicity of the test substance was 30 mg/kg bw/day for rats based on damages of spleen, adrenal gland, kidneys, stomach, eyes and lung at the next higher dose levels of 100 mg/kg bw/day and 300 mg/kg bw/day.

This point of departure was modified to get the corrected starting point for DNEL derivation. As a first step, route-to-route extrapolation was performed as recommended in the "Guidance on information requirements and chemical safety assessment, Chapter R.8, p. 20 f.":

The oral rat NOAEL was converted into the inhalative human NOAEC corrected for differences between the 8-hour standard inhalation volume of rats versus humans, and for differences between the 8-hour inhalation volume of workers in rest versus workers in light activity, by multiplying with the corresponding factors and by adjusting the time of exposure (rats were exposed 7 days/week and worker is exposed 5 days per week) (x 1/0.38 m³/kg/d x 6.7 m³/10 m³ x 7/5). Furthermore, it is proposed, thus, in the absence of route-specific information on the starting route, to include a default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) in the case of oral-to-inhalation extrapolation. The resulting corrected starting point for inhalation DNEL derivation for workers is equal to 37.0 mg/m³.

Dermal long-term exposure – systemic effects:

The NOAEL from a combined 28-day oral repeated dose toxicity study with the reproduction /developmental toxicity screening test in rats conducted according to OECD TG 422 (BASF SE, 2012) was identified as the appropriate starting point for DNEL derivation for long-term exposure following dermal application. The NOAEL for general, systemic toxicity of the test substance was 30 mg/kg bw/day for rats based on damages of spleen, adrenal gland, kidneys, stomach, eyes and lung at the next higher dose levels of 100 mg/kg bw/day and 300 mg/kg bw/day.

This point of departure was modified to get the corrected starting point for DNEL derivation based ona route-to-route (oral -> dermal) extrapolation with the assumption that the dermal absorption will not be higher than oral absorption (factor of 1). The starting point was further corrected by a factor of 1.4 since rats were exposed 7 days per week and the worker is exposed 5 days per week (7/5). This results in a corrected starting point of 42 mg/kg bw/day.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.217 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:
13 mg/m³
Explanation for the modification of the dose descriptor starting point:
No repeated dose toxicity study by inhalation is available. Therefore a oral-to-inhalation extrapolation is done. The default factor of 2 was included.
AF for dose response relationship:
1
Justification:
default value
AF for differences in duration of exposure:
6
Justification:
default value for time extrapolation from subacute to chronic study
AF for interspecies differences (allometric scaling):
4
Justification:
default value for correction for differences in metabolic rate (rat to humans)
AF for intraspecies differences:
10
Justification:
default value (consumer)
AF for the quality of the whole database:
1
Justification:
GLP Guideline study
AF for remaining uncertainties:
1
Justification:
Toxicodynamic differences between humans and rats are not assumed. Therefore the assessment factor for remaining differences is set to 1.
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.125 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:
30 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
No repeated dose toxicity study with dermal application is available. Therefore a oral-to-dermal extrapolation is done.
AF for dose response relationship:
1
Justification:
default value
AF for differences in duration of exposure:
6
Justification:
default value for time extrapolation from subacute to chronic study
AF for interspecies differences (allometric scaling):
4
Justification:
default value for correction for differences in metabolic rate (rat to humans)
AF for intraspecies differences:
10
Justification:
default value (consumer)
AF for the quality of the whole database:
1
Justification:
GLP guideline study
AF for remaining uncertainties:
1
Justification:
Toxicodynamic differences between humans and rats are not assumed. Therefore the assessment factor for remaining differences is set to 1.
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
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)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.125 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:
30 mg/kg bw/day
AF for dose response relationship:
1
Justification:
default value
AF for differences in duration of exposure:
6
Justification:
efault value for time extrapolation from subacute to chronic study
AF for interspecies differences (allometric scaling):
4
Justification:
default value for correction for differences in metabolic rate (rat to humans)
AF for intraspecies differences:
10
Justification:
default value (consumer)
AF for the quality of the whole database:
1
Justification:
GLP guideline study
AF for remaining uncertainties:
1
Justification:
Toxicodynamic differences between humans and rats are not assumed. Therefore the assessment factor for remaining differences is set to 1.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

Inhalation long-term exposure – systemic effects:

The NOAEL from a combined 28-day oral repeated dose toxicity study with the reproduction /developmental toxicity screening test in rats conducted according to OECD TG 422 (BASF SE, 2012) was identified as the appropriate starting point for DNEL derivation for long-term exposure following inhalation. The NOAEL for general, systemic toxicity of the test substance was 30 mg/kg bw/day for rats based on damages of spleen, adrenal gland, kidneys, stomach, eyes and lung at the next higher dose levels of 100 mg/kg bw/day and 300 mg/kg bw/day.

This point of departure was modified to get the correct starting point for DNEL derivation. As a first step, route-to-route extrapolation was performed as recommended in the "Guidance on information requirements and chemical safety assessment, Chapter R.8, p. 20 f.":

The oral rat NOAEL was converted into the inhalative human NOAEC corrected for differences between the 24-hour standard inhalation volume of rats versus humans by multiplying with the corresponding factor (x 1/1.15 m³/kg/d). Furthermore, it is proposed, thus, in the absence of route-specific information on the starting route, to include a default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) in the case of oral-to-inhalation extrapolation.

The resulting corrected starting point for inhalation DNEL derivation for the general population is equal to 13.0 mg/m³.

Dermal long-term exposure – systemic effects:

The NOAEL from a combined 28-day oral repeated dose toxicity study with the reproduction /developmental toxicity screening test in rats conducted according to OECD TG 422 (BASF SE, 2012) was identified as the appropriate starting point for DNEL derivation for long-term exposure following dermal application. The NOAEL for general, systemic toxicity of the test substance was 30 mg/kg bw/day for rats based on damages of spleen, adrenal gland, kidneys, stomach, eyes and lung at the next higher dose levels of 100 mg/kg bw/day and 300 mg/kg bw/day.

This point of departure was not modified to get the corrected starting point for DNEL derivation because it isassumed that the dermal absorption will not be higher than oral absorption (factor of 1). This results in a corrected starting point of 30 mg/kg bw/day.

 

Oral long-term exposure – systemic effects:

In addition, the DNEL for oral long-term exposure was derived from the no observed adverse effect level obtained in a gavage study conducted with the substance in rats according to OECD TG 422 (BASF SE, 2012). The NOAEL for general, systemic toxicity of the test substance was 30 mg/kg bw/day for rats based on damages of spleen, adrenal gland, kidneys, stomach, eyes and lung at the next higher dose levels of 100 mg/kg bw/day and 300 mg/kg bw/day.

A correction of the starting point is not necessary since an oral study is available.