Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.18 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
Dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
88.16 mg/m³
Explanation for the modification of the dose descriptor starting point:

Extrapolation oral to inhalation:2, difference in respiratory volumes: 0.38x(10/6.7)=0.567

AF for dose response relationship:
3
Justification:
There are low incidences of adverse testicular pathology in the animals from the 30 and 100 mg/kg/day treatments which were statistically not different from controls. Therefore a AF of 3 is used for dose response relationship.
AF for differences in duration of exposure:
2
Justification:
The dose descriptor was obtained from a 13 week subchronic study in the rat. AF for exposure duration to extrapolate from subchronic to chronic is 2.
AF for interspecies differences (allometric scaling):
1
Justification:
Derivation of a inhalation DNEL therefore there is no need to apply a allometric scaling factor
AF for other interspecies differences:
2.5
Justification:
There are no data for NTO to quantify other differences between animals and humans that could affect interspecies extrapolation. On this basis a default factor of 2.5 to account for other species differences will also be applied.
AF for intraspecies differences:
5
Justification:
There are no data to quantify variability in susceptibility to the effects of long-term exposure to NTO in the human population. The default factor of 5 for workers will therefore be used to take account of intraspecies differences.
AF for the quality of the whole database:
1
Justification:
The key study was part of a series of rat studies conducted to methods equivalent to modern regulatory standards. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
No other uncertainties
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:
irritation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
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:
0.33 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
Dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No correction as there are no known differences in bioavailability of NTO in animal and human, the route to route extrapolation is from oral-dermal =1 and differences in exposure conditions between animal and human are not applicable

AF for dose response relationship:
3
Justification:
There are low incidences of adverse testicular pathology in the animals from the 30 and 100 mg/kg/day treatments which were statistically not different from controls. Therefore a AF of 3 is used for dose response relationship.
AF for differences in duration of exposure:
2
Justification:
The dose descriptor was obtained from a 13 week subchronic study in the rat. AF for exposure duration to extrapolate from subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
The dose descriptor is obtained from a subchronic study in the rat. It is therefore necessary to apply an allometric scaling factor of 4 to take account of differences in basal metabolic rates between rats and humans.
AF for other interspecies differences:
2.5
Justification:
There are no data for NTO to quantify other differences between animals and humans that could affect interspecies extrapolation. On this basis a default factor of 2.5 to account for other species differences will also be applied
AF for intraspecies differences:
5
Justification:
There are no data to quantify variability in susceptibility to the effects of long-term exposure to NTO in the human population. The default factor of 5 for workers will therefore be used to take account of intraspecies differences.
AF for the quality of the whole database:
1
Justification:
The key study was part of a series of rat studies conducted to methods equivalent to modern regulatory standards. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
No other uncertainties
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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.59 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
DNEL value:
88.16 mg/m³
Explanation for the modification of the dose descriptor starting point:

Extrapolation oral to inhalation:2, difference in respiratory volumes: 0.38x(10/6.7)=0.567

AF for dose response relationship:
3
Justification:
There are low incidences of adverse testicular pathology in the animals from the 30 and 100 mg/kg/day treatments which were statistically not different from controls. Therefore a AF of 3 is used for dose response relationship.
AF for differences in duration of exposure:
2
Justification:
The dose descriptor was obtained from a 13 week subchronic study in the rat. AF for exposure duration to extrapolate from subchronic to chronic is 2.
AF for interspecies differences (allometric scaling):
1
Justification:
Derivation of a inhalation DNEL therefore there is no need to apply a allometric scaling factor
AF for other interspecies differences:
2.5
Justification:
There are no data for NTO to quantify other differences between animals and humans that could affect interspecies extrapolation. On this basis a default factor of 2.5 to account for other species differences will also be applied.
AF for intraspecies differences:
10
Justification:
There are no data to quantify variability in susceptibility to the effects of long-term exposure to NTO in the human population. The default factor of 10 for the general population will therefore be used to take account of intraspecies differe
AF for the quality of the whole database:
1
Justification:
The key study was part of a series of rat studies conducted to methods equivalent to modern regulatory standards. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
No other uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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:
0.17 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
Dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No correction as there are no known differences in bioavailability of NTO in animal and human, the route to route extrapolation is from oral-dermal =1 and differences in exposure conditions between animal and human are not applicable

AF for dose response relationship:
3
Justification:
There are low incidences of adverse testicular pathology in the animals from the 30 and 100 mg/kg/day treatments which were statistically not different from controls. Therefore a AF of 3 is used for dose response relationship.
AF for differences in duration of exposure:
2
Justification:
The dose descriptor was obtained from a 13 week subchronic study in the rat. AF for exposure duration to extrapolate from subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
The dose descriptor is obtained from a subchronic study in the rat. It is therefore necessary to apply an allometric scaling factor of 4 to take account of differences in basal metabolic rates between rats and humans.
AF for other interspecies differences:
2.5
Justification:
There are no data for NTO to quantify other differences between animals and humans that could affect interspecies extrapolation. On this basis a default factor of 2.5 to account for other species differences will also be applied
AF for intraspecies differences:
10
Justification:
There are no data to quantify variability in susceptibility to the effects of long-term exposure to NTO in the human population. The default factor of 10 for the general population will therefore be used to take account of intraspecies differences.
AF for the quality of the whole database:
1
Justification:
The key study was part of a series of rat studies conducted to methods equivalent to modern regulatory standards. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
No other uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.17 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
Dose descriptor starting point:
NOAEL
DNEL value:
100 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No extrapolation

AF for dose response relationship:
3
Justification:
There are low incidences of adverse testicular pathology in the animals from the 30 and 100 mg/kg/day treatments which were statistically not different from controls. Therefore a AF of 3 is used for dose response relationship.
AF for differences in duration of exposure:
2
Justification:
The dose descriptor was obtained from a 13 week subchronic study in the rat. AF for exposure duration to extrapolate from subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
The dose descriptor is obtained from a subchronic study in the rat. It is therefore necessary to apply an allometric scaling factor of 4 to take account of differences in basal metabolic rates between rats and humans.
AF for other interspecies differences:
2.5
Justification:
There are no data for NTO to quantify other differences between animals and humans that could affect interspecies extrapolation. On this basis a default factor of 2.5 to account for other species differences will also be applied
AF for intraspecies differences:
10
Justification:
There are no data to quantify variability in susceptibility to the effects of long-term exposure to NTO in the human population. The default factor of 10 for the general population will therefore be used to take account of intraspecies differences.
AF for the quality of the whole database:
1
Justification:
The key study was part of a series of rat studies conducted to methods equivalent to modern regulatory standards. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
No other uncertainties
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population