Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10.75 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):
200
Dose descriptor starting point:
NOAEL
Value:
1 220 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
2 151 mg/m³
Explanation for the modification of the dose descriptor starting point:

Relevant dose-descriptor; Value: NOAEL: 1220 mg/kg; Remark: This is the concentration where no significant adverse effects were seen in a sub-chronic oral toxicity study.

 

Modification of starting point for rat respiratory volume (Allometric scaling); Value: 0.38 m3/kg bw (rat 8-hour respiratory volume); Remark: A modification of starting point for rat respiratory volume was applied per REACH guidance R.8.4.2. 

 

Modification of starting point for differences in respiratory volumes; Value: 0.67 (6.7 m3/10 m3); Remark: A modification was applied to account for the increased respiratory volumes in active workers as compared to individuals at rest per REACH guidance R.8.4.2. 

Correction Factor: NOAEL of 1220 mg/kg/d / 0.38 m3/kg = 3211 * [6.7 m3/ 10 m3] = 2151 mg/m3  

AF for dose response relationship:
1
Justification:
A factor of 1 is appropriate since the dose descriptor is a NOAEL.
AF for differences in duration of exposure:
2
Justification:
This is a default assessment factor for a sub-chronic study per REACH Guidance R.8.4.3.1.
AF for interspecies differences (allometric scaling):
1
Justification:
A factor of 1 is appropriate since the adjusted start point was via mg/m3 (inhalation) and thus this assessment factor is not applicable per REACH guidance R.8.4.3.1.
AF for other interspecies differences:
2.5
Justification:
A default factor of 2.5 is appropriate per REACH guidance R.8.4.3.1.
AF for intraspecies differences:
5
Justification:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1.
AF for the quality of the whole database:
4
Justification:
No repeat dose inhalation studies available that are reliable or reached MTDC (maximum tolerated dose).
AF for remaining uncertainties:
2
Justification:
Route–to-route extrapolation: A factor of 2 is appropriate per REACH guidance R.8.4.2 (oral to inhalation).
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:
12.2 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:
1 220 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

This is the concentration where no significant adverse effects were seen in a subchronic oral toxicity study.

AF for dose response relationship:
1
Justification:
A factor of 1 is appropriate since the dose descriptor is a NOAEL.
AF for differences in duration of exposure:
2
Justification:
This is a default assessment factor for a sub-chronic study per REACH Guidance R.8.4.3.1.
AF for interspecies differences (allometric scaling):
4
Justification:
A factor of 4 is appropriate since the adjusted start point was via mg/kg per REACH guidance 8.4.3.1.
AF for other interspecies differences:
2.5
Justification:
A default factor of 2.5 is appropriate per REACH guidance R.8.4.3.1.
AF for intraspecies differences:
5
Justification:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1.
AF for the quality of the whole database:
1
Justification:
A high quality, robust toxicity database exists for this substance.
AF for remaining uncertainties:
1
Justification:
Route–to-route extrapolation: A factor of 1 is appropriate since the animal exposure was via ingestion.
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:
high 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:
2.65 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):
400
Dose descriptor starting point:
NOAEL
Value:
1 220 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
1 061 mg/m³
Explanation for the modification of the dose descriptor starting point:

Relevant dose-descriptor; Value: NOAEL: 1220 mg/kg; Remark: This is the concentration where no significant adverse effects were seen in a sub-chronic oral toxicity study. 

Modification of starting point for rat respiratory volume (Allometric scaling); Value: 1.15 m3/kg bw (rat 24-hour respiratory volume); Remark: A modification of starting point for rat respiratory volume was applied per REACH guidance R.8.4.2.

AF for dose response relationship:
1
Justification:
A factor of 1 is appropriate since the dose descriptor is a NOAEL.
AF for differences in duration of exposure:
2
Justification:
This is a default assessment factor for a sub-chronic study per REACH Guidance R.8.4.3.1.
AF for interspecies differences (allometric scaling):
1
Justification:
A factor of 1 is appropriate since the adjusted start point was via mg/m3 (inhalation) and thus this assessment factor is not applicable per REACH guidance R.8.4.3.1.
AF for other interspecies differences:
2.5
Justification:
A default factor of 2.5 is appropriate per REACH guidance R.8.4.3.1.
AF for intraspecies differences:
10
Justification:
This is a default assessment factor for the general population per REACH Guidance R.8.4.3.1
AF for the quality of the whole database:
4
Justification:
A factor of 4 is appropriate because of the lack of repeat dose inhalation data warrants an uncertainty factor of greater than 1.
AF for remaining uncertainties:
2
Justification:
Route-to-route extrapolation: A factor of 2 is appropriate per REACH guidance R.8.4.2 (oral to inhalation).
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:
6.1 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):
200
Dose descriptor starting point:
NOAEL
Value:
1 220 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

This is the concentration where no significant adverse effects were seen in a sub-chronic oral toxicity study.

AF for dose response relationship:
1
Justification:
A factor of 1 is appropriate since the dose descriptor is a NOAEL.
AF for differences in duration of exposure:
2
Justification:
This is a default assessment factor for a sub-chronic study per REACH Guidance R.8.4.3.1.
AF for interspecies differences (allometric scaling):
4
Justification:
A factor of 4 is appropriate since the adjusted start point was via mg/kg per REACH guidance 8.4.3.1.
AF for other interspecies differences:
2.5
Justification:
A default factor of 2.5 is appropriate per REACH guidance R.8.4.3.1.
AF for intraspecies differences:
10
Justification:
This is a default assessment factor for the general population per REACH Guidance R.8.4.3.1.
AF for the quality of the whole database:
1
Justification:
A high quality, robust toxicity database exists for this substance.
AF for remaining uncertainties:
1
Justification:
Route-to-route extrapolation: A factor of 1 is appropriate since the animal exposure was via ingestion.
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:
6.1 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):
200
Dose descriptor starting point:
NOAEL
Value:
1 220 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

This is the concentration where no significant adverse effects were seen in a sub-chronic oral toxicity study.

AF for dose response relationship:
1
Justification:
This is a default assessment factor for a sub-chronic study per REACH Guidance R.8.4.3.1.
AF for differences in duration of exposure:
2
Justification:
This is a default assessment factor for a sub-chronic study per REACH Guidance R.8.4.3.1.
AF for interspecies differences (allometric scaling):
4
Justification:
A factor of 4 is appropriate since the adjusted start point was via mg/kg per REACH guidance 8.4.3.1.
AF for other interspecies differences:
2.5
Justification:
A default factor of 2.5 is appropriate per REACH guidance R.8.4.3.1.
AF for intraspecies differences:
10
Justification:
This is a default assessment factor for the general population per REACH Guidance R.8.4.3.1.
AF for the quality of the whole database:
1
Justification:
A high quality, robust toxicity database exists for this substance.
AF for remaining uncertainties:
1
Justification:
Route–to-route extrapolation: A factor of 1 is appropriate since the animal exposure was via ingestion.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - General Population

The DNEL for general population long-term dermal and oral exposure is derived as follows:

Step 1) Relevant dose-descriptor; Value: 1220 mg/kg (NOAEL); Remark: This is the concentration where no significant adverse effects were seen in a sub-chronic oral toxicity study. |

Step 2) Assessment Factors (AF):

Route–to-route extrapolation; Value: 1; Remark: A factor of 1 is appropriate since the animal exposure was via ingestion.

Animal-to-man scaling factor (Allometric scaling); Value: 4; Remark: A factor of 4 is appropriate since the adjusted start point was via mg/kg per REACH guidance 8.4.3.1.

Interspecies; Value: 2.5; Remark: A default factor of 2.5 is appropriate per REACH guidance R.8.4.3.1.

Intraspecies; Value: 10; Remark: This is a default assessment factor for the general population per REACH Guidance R.8.4.3.1.

Exposure duration; Value: 2; Remark: This is a default assessment factor for a sub-chronic study per REACH Guidance R.8.4.3.1.

Dose response; Value: 1; Remark: A factor of 1 is appropriate since the dose descriptor is a NOAEL.

Quality of database; Value: 1; Remark: A high quality, robust toxicity database exists for this substance.

DNEL general population long term dermal and oral: Value: 1220 mg/kg bw/day; Remark: 1220 / (1 x 4 x 2.5 x 10 x 2 x 1 x 1) = 2.24 mg/kg bw/day

The DNEL for general population long-term inhalation exposure is derived as follows:

Step 1) Relevant dose-descriptor; Value: NOAEL: 1220 mg/kg; Remark: This is the concentration where no significant adverse effects were seen in a sub-chronic oral toxicity study.

Step 2) Modification of starting point for rat respiratory volume (Allometric scaling); Value: 1.15 m3/kg bw (rat 24-hour respiratory volume); Remark: A modification of starting point for rat respiratory volume was applied per REACH guidance R.8.4.2.

Step 3) Assessment Factors (AF)

Route–to-route extrapolation; Value: 2; Remark: A factor of 2 is appropriate per REACH guidance R.8.4.2 (oral to inhalation).

Animal-to-man scaling factor (Allometric scaling); Value: 1; Remark: A factor of 1 is appropriate since the adjusted start point was via mg/m3(inhalation) and thus this assessment factor is not applicable per REACH guidance R.8.4.3.1.

Interspecies; Value: 2.5; Remark: A default factor of 2.5 is appropriate per REACH guidance R.8.4.3.1.

Intraspecies; Value: 10; Remark: This is a default assessment factor for the general population per REACH Guidance R.8.4.3.1

Exposure duration; Value: 2; Remark: This is a default assessment factor for a sub-chronic study per REACH Guidance R.8.4.3.1.
Dose response; Value: 1; Remark: A factor of 1 is appropriate since the dose descriptor is a NOAEL.

Quality of database; Value: 4; Remark: A factor of 4 is appropriate because of the lack of repeat dose inhalation data warrants an uncertainty factor of greater than 1.

DNEL general population long term inhalation: Value: 2.65 mg/m3; Remark: 1220 / 1.15 / (2 x 1 x 2.5 x 10 x 2 x 1 x 4) = 2.65 mg/m3