Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.024 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:
1.5 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
1.85 mg/m³
Explanation for the modification of the dose descriptor starting point:

The NOAEL of 1.5 mg/kg was the concentration where no significant adverse effects were seen in a 4-week drinking water study.

Modification of starting point for oral rat to human inhalation: 0.5

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.8.4.3.1.

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.8.4.3.1.

Modification of starting point for differences in experimental/human exposure conditions: 1.4

AF for dose response relationship:
1
Justification:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1.
AF for differences in duration of exposure:
6
Justification:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1.
AF for interspecies differences (allometric scaling):
1
Justification:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1.
AF for other interspecies differences:
2.5
Justification:
This is a default assessment factor for workers 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:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1.
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:
0.007 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:
1.5 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
2.1 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The NOAEL of 1.5 mg/kg was the concentration where no significant adverse effects were seen in a subchronic oral toxicity study. A modification of starting point of 1.4 for differences between experimental and human exposure conditions was applied per REACH guidance R.8.4.3.1.

AF for dose response relationship:
1
Justification:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1.
AF for differences in duration of exposure:
6
Justification:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1.
AF for interspecies differences (allometric scaling):
4
Justification:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1.
AF for other interspecies differences:
2.5
Justification:
This is a default assessment factor for workers 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:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1.
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

In a GLP drinking water study according to OECD Guideline 407, groups of male and female Wistar rats received 20, 100 or 600 ppm of the test substance for 4 weeks, followed by a recovery period of 2 weeks. The 20, 100 and 600 ppm values correspond to 1.5, 7.3 and 38.9 mg/kg bw in males and 1.9, 9.2 and 84.0 mg/kg bw in females, respectively. In high dose treatment, following effects were observed: impairment of the food and water consumption and of the food efficiency; reduced body weight, mild anaemia, leucocytosis, slight impairment of hepatocellular and renal function, increased synthesis rate of serum proteins and cholesterol, substance-related changes in thyroid and spleen. In the mid dose, slight impairment of water consumption in males, increases in total protein, albumin, globulins and cholesterol in the males, increases in platelets and thyroid stimulating hormone (TSH) in the females, decreases in haemoglobin and triglycerides in the females and increased extramedullary haematopoiesis in the spleen of male and female rats were observed. In the low dose, no substance related effects were observed. In the recovery period, the effects were not fully reversible in animals of the high dose treatment. Therefore, the NOAEL is identified as 20 ppm corresponding to 1.5 mg/ kg bw in males and 1.9 mg/kg in females.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.089 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:
1.5 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
13.33 mg/m³
Explanation for the modification of the dose descriptor starting point:

The NOAEL of 1.5 mg/kg was the concentration where no significant adverse effects were seen in a 4-week drinking water study.

Modification of starting point for oral rat to human inhalation: 0.5

Modification of starting point for rat respiratory volume (Allometric scaling); Value: 0.05625m3/kg bw (rat 1-hour respiratory volume); Remark: A modification of starting point for rat respiratory volume was applied per REACH guidance R.8.4.3.1.

AF for dose response relationship:
1
Justification:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1.
AF for differences in duration of exposure:
6
Justification:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1.
AF for interspecies differences (allometric scaling):
1
Justification:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1.
AF for other interspecies differences:
2.5
Justification:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1.
AF for intraspecies differences:
10
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:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1.
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:
0.003 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:
1.5 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
1.5 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The NOAEL of 1.5 mg/kg was the concentration where no significant adverse effects were seen in a subchronic oral toxicity study. No further modifications for starting point were applied.

AF for dose response relationship:
1
Justification:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1.
AF for differences in duration of exposure:
6
Justification:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1.
AF for interspecies differences (allometric scaling):
4
Justification:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1.
AF for other interspecies differences:
2.5
Justification:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1.
AF for intraspecies differences:
10
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:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1.
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:
0.003 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:
1.5 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The NOAEL of 1.5 mg/kg was the concentration where no significant adverse effects were seen in a subchronic oral toxicity study. No further modifications for starting point were applied.

AF for dose response relationship:
1
Justification:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1.
AF for differences in duration of exposure:
6
Justification:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1.
AF for interspecies differences (allometric scaling):
4
Justification:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1.
AF for other interspecies differences:
2.5
Justification:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1.
AF for intraspecies differences:
10
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:
This is a default assessment factor for workers per REACH Guidance R.8.4.3.1.
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

In a GLP drinking water study according to OECD Guideline 407, groups of male and female Wistar rats received 20, 100 or 600 ppm of the test substance for 4 weeks, followed by a recovery period of 2 weeks. The 20, 100 and 600 ppm values correspond to 1.5, 7.3 and 38.9 mg/kg bw in males and 1.9, 9.2 and 84.0 mg/kg bw in females, respectively. In high dose treatment, following effects were observed: impairment of the food and water consumption and of the food efficiency; reduced body weight, mild anaemia, leucocytosis, slight impairment of hepatocellular and renal function, increased synthesis rate of serum proteins and cholesterol, substance-related changes in thyroid and spleen. In the mid dose, slight impairment of water consumption in males, increases in total protein, albumin, globulins and cholesterol in the males, increases in platelets and thyroid stimulating hormone (TSH) in the females, decreases in haemoglobin and triglycerides in the females and increased extramedullary haematopoiesis in the spleen of male and female rats were observed. In the low dose, no substance related effects were observed. In the recovery period, the effects were not fully reversible in animals of the high dose treatment. Therefore, the NOAEL is identified as 20 ppm corresponding to 1.5 mg/ kg bw in males and 1.9 mg/kg in females.