Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.47 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
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
370.26 mg/m³
Explanation for the modification of the dose descriptor starting point:

A NOAEL of 300 mg/kg bw /day was the lowest NOAEL determined for the source substances in repeated-dose studies. This NOAEL was derived in a sub-acute repeated dose oral toxicity study in rats (Longobardi 2013). This value was converted into the corrected inhalatory NOAEC taking into account the standard respiratory factor of 1/0.38 m³/kg/day, the absorption rates (oral 50 %, inhalation 100 %; in accordance with ECHA Guidance R.8 the absorption rate of the starting route is half that of the end route), the standard respiratory volume in humans/ worker respiratory volume (6.7 m³ (8 h) / 10 m³ (8 h)) and the correction factor between human and experimental exposure conditions of workers (5 working days vs. 7 days continuous exposure) of 1.4.

NOAEC corrected = 300 mg/kg bw/day * 1/0.38 m³/kg/day * 50/100 * (6.7 m³/10 m³) * 1.4 = 370.26 mg/m³

AF for dose response relationship:
1
Justification:
Default
AF for differences in duration of exposure:
6
Justification:
sub-acute (28 d) to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling should be applied in case of oral-to-inhalation extrapolation
AF for other interspecies differences:
2.5
Justification:
default; no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans
AF for intraspecies differences:
5
Justification:
default for workers
AF for the quality of the whole database:
2
Justification:
due to read across
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

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7 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
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
other: NOAEC
Value:
4 200 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

A NOAEL of 300 mg/kg bw /day was the lowest NOAEL determined for the source substances in repeated-dose studies. This NOAEL was derived in a sub-acute repeated dose oral toxicity study in rats (Longobardi 2013). This value was converted into the corrected dermal NOAEC taking into account the absorption rates (oral 100 %, dermal 10 %) and the correction factor between human and experimental exposure conditions workers (5 working days vs. 7 days continuous exposure) of 1.4.

NOAEC corrected = 300 mg/kg bw/day * 100/10 * 1.4 = 4200 mg/kg bw/day

AF for dose response relationship:
1
Justification:
Default
AF for differences in duration of exposure:
6
Justification:
sub-acute to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
rat to human
AF for other interspecies differences:
2.5
Justification:
default; no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans
AF for intraspecies differences:
5
Justification:
default for workers
AF for the quality of the whole database:
2
Justification:
due to read across
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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.43 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):
300
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
130.43 mg/m³
Explanation for the modification of the dose descriptor starting point:

A NOAEL of 300 mg/kg bw /day was the lowest NOAEL determined for the source substances in repeated-dose studies. This NOAEL was derived in a sub-acute repeated dose oral toxicity study in rats (Longobardi 2013). This value was converted into the corrected inhalatory NOAEC taking into account the standard respiratory factor of 1/1.15 m³/kg/day, the absorption rates (oral 50 %, inhalation 100 %; in accordance with ECHA Guidance R.8 the absorption rate of the starting route is half that of the end route).

NOAEC corrected = 300 mg/kg bw/day * 1/1.15 m³/kg/day * 50/100 = 130.43 mg/m³

AF for dose response relationship:
1
Justification:
Default
AF for differences in duration of exposure:
6
Justification:
sub-acute (28 d) to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling should be applied in case of oral-to-inhalation extrapolation
AF for other interspecies differences:
2.5
Justification:
default; no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans
AF for intraspecies differences:
10
Justification:
default for general population
AF for the quality of the whole database:
2
Justification:
due to read across
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:
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):
1 200
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
other: NOAEC
Value:
3 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

A NOAEL of 300 mg/kg bw /day was the lowest NOAEL determined for the source substances in repeated-dose studies. This NOAEL was derived in a sub-acute repeated dose oral toxicity study in rats (Longobardi 2013). This value was converted into the corrected dermal NOAEC taking into account the absorption rates (oral 100 %, dermal 10 %).

NOAEC corrected = 300 mg/kg bw/day * 100/10 = 3000 mg/kg bw/day

AF for dose response relationship:
1
Justification:
Default
AF for differences in duration of exposure:
6
Justification:
sub-acute to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
rat to human
AF for other interspecies differences:
2.5
Justification:
default; no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans
AF for intraspecies differences:
10
Justification:
Default for general population
AF for the quality of the whole database:
2
Justification:
due to read across
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:
0.25 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):
1 200
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

An oral NOAEL of 300 mg/kg bw /day was the lowest NOAEL determined for the source substances in repeated-dose studies. This NOAEL was derived in a sub-acute repeated dose oral toxicity study in rats (Longobardi 2013).

AF for dose response relationship:
1
Justification:
Default
AF for differences in duration of exposure:
6
Justification:
sub-acute to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
rat to human
AF for other interspecies differences:
2.5
Justification:
default; no substance and route specific information on toxicokinetic and toxicodynamic is available for animals and humans
AF for intraspecies differences:
10
Justification:
Default for general population
AF for the quality of the whole database:
2
Justification:
due to read across
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