Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.7 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
Value:
346 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
427 mg/m³
Explanation for the modification of the dose descriptor starting point:

There are no adequate experimental data on the inhalation route available. Therefore, the worker-DNEL long-term for inhalation route - systemic is derived from the NOAEL of 346 mg/kg bw/day, obtained in the key subacute oral repeated dose study in Wistar rats. The NOAECcorr. is calculated as follows:

- standard respiratory volume rat = 0.38 m³/kg/8h

- standard respiratory volume human = 6.7 m³/8h

- worker respiratory volume = 10 m³/8h

- absorption (oral, rat) = 50 % (default)

- absorption (inhalative, human) = 100 % (default)

--> modified dose descriptor (corrected inhalatory NOAEC) = 346 mg/kg bw/day * (1/0.38 m³/kg/d) * (6.7 m³ (8h)/10 m³ (8h)) * (0.5/1) * (7 exposure days/week; rat/5 exposure days/week; worker) = 427 mg/m³

AF for dose response relationship:
1
Justification:
ECHA REACH Guidance (starting point for the DNEL calculation is a NOAEL)
AF for differences in duration of exposure:
6
Justification:
ECHA REACH Guidance (subacute --> chronic)
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation.
AF for other interspecies differences:
2.5
Justification:
ECHA REACH Guidance
AF for intraspecies differences:
5
Justification:
ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
ECHA REACH Guidance (good/standard quality of the database)
AF for remaining uncertainties:
1
Justification:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.7 mg/m³
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:
8.1 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):
300
Dose descriptor starting point:
NOAEL
Value:
346 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
2 420 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

There are no experimental data on repeated exposure by the dermal route available. Therefore, the worker-DNEL long-term for dermal route - systemic is derived from the NOAEL of 346 mg/kg bw/day, obtained in the key subacute oral repeated dose study in Wistar rats. The NOAELcorr. is calculated as follows:

- absorption (oral, rat) = 50 % (default)

- absorption (dermal, human) = 10 % (assumed as worst case)

--> modified dose descriptor (corrected dermal NOAEL) = 346 mg/kg bw/day * (0.5/0.1) * (7 exposure days/week; rat/5 exposure days/week; worker) = 2420 mg/m³

AF for dose response relationship:
1
Justification:
ECHA REACH Guidance (starting point for the DNEL calculation is a NOAEL)
AF for differences in duration of exposure:
6
Justification:
ECHA REACH Guidance (subacute --> chronic)
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA REACH Guidance (rat --> human)
AF for other interspecies differences:
2.5
Justification:
ECHA REACH Guidance
AF for intraspecies differences:
5
Justification:
ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
ECHA REACH Guidance (good/standard quality of the database)
AF for remaining uncertainties:
1
Justification:
ECHA REACH Guidance
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)

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:
1 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:
346 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
150.4 mg/m³
Explanation for the modification of the dose descriptor starting point:

There are no adequate experimental data on the inhalation route available. Therefore, the general population-DNEL long-term for inhalation route - systemic is derived from the NOAEL of 346 mg/kg bw/day, obtained in the key subacute oral repeated dose study in Wistar rats. The NOAECcorr. is calculated as follows:

- standard respiratory volume rat = 1.15 m³/kg/24h

- absorption (oral, rat) = 50 % (default)

- absorption (inhalative, human) = 100 % (default)

--> modified dose descriptor (corrected inhalatory NOAEC) = 346 mg/kg bw/day * (1/1.15 m³/kg/d) * (0.5/1) = 150,4 mg/m³

AF for dose response relationship:
1
Justification:
ECHA REACH Guidance (starting point for the DNEL calculation is a NOAEL)
AF for differences in duration of exposure:
6
Justification:
ECHA REACH Guidance (subacute --> chronic)
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation.
AF for other interspecies differences:
2.5
Justification:
ECHA REACH Guidance
AF for intraspecies differences:
10
Justification:
ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
ECHA REACH Guidance (good/standard quality of the database)
AF for remaining uncertainties:
1
Justification:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 mg/m³
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:
2.8 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:
346 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1 730 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

There are no experimental data on repeated exposure by the dermal route available. Therefore, the general population-DNEL long-term for dermal route - systemic is derived from the NOAEL of 346 mg/kg bw/day, obtained in the key subacute oral repeated dose study in Wistar rats. The NOAELcorr. is calculated as follows:

- absorption (oral, rat) = 50 % (default)

- absorption (dermal, human) = 10 % (assumed as worst case)

--> modified dose descriptor (corrected dermal NOAEL) = 346 mg/kg bw/day * (0.5/0.1) = 1730 mg/m³

AF for dose response relationship:
1
Justification:
ECHA REACH Guidance (starting point for the DNEL calculation is a NOAEL)
AF for differences in duration of exposure:
6
Justification:
ECHA REACH Guidance (subacute --> chronic)
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA REACH Guidance (rat --> human)
AF for other interspecies differences:
2.5
Justification:
ECHA REACH Guidance
AF for intraspecies differences:
10
Justification:
ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
ECHA REACH Guidance (good/standard quality of the database)
AF for remaining uncertainties:
1
Justification:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.8 mg/kg bw/day
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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.58 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:
346 mg/kg bw/day
AF for dose response relationship:
1
Justification:
ECHA REACH Guidance (starting point for the DNEL calculation is a NOAEL)
AF for differences in duration of exposure:
6
Justification:
ECHA REACH Guidance (subacute --> chronic)
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA REACH Guidance (rat -->human)
AF for other interspecies differences:
2.5
Justification:
ECHA REACH Guidance
AF for intraspecies differences:
10
Justification:
ECHA REACH Guidance
AF for the quality of the whole database:
1
Justification:
ECHA REACH Guidance (good/standard quality of the database)
AF for remaining uncertainties:
1
Justification:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.58 mg/kg bw/day
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population