Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
16.33 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:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
2 450 mg/m³
Explanation for the modification of the dose descriptor starting point:

Per REACH Guidance 8.4.2 the different exposure time (7 days/week in the experiment; 5 days/week for workers) were corrected by multiplying a factor of 7/5. According to Example R. 8-2 Workers, this time correctet oral NOAEL of 1400 mg/kg/day (28 days Repeated Dose Toxicity Test) was converted to an inhalation equivalent: 1400 mg/kg/day ÷ 0.38 m3/kg bw (8 h exposure – rat) × 6.7 m³ (8 h exposure – human) ÷ 10 m³ (worker respiratory volume [wRV] - 8 h) = 2450 mg/m³

AF for dose response relationship:
2
Justification:
According to REACH Guidance (R.8.4.2), in the case of oral-to-inhalation extrapolation, and in the absence of route-specific information on the starting route, a default factor of 2 should be included (i.e. the absorption percentage for the starting route is half that of the end route). The inclusion of factor of 2 means that 50% (instead of 100%) absorption is assumed for oral absorption, and 100% for inhalation. A default factor of 2 is appropriate per REACH Guidance R.8.4.2.
AF for differences in duration of exposure:
6
Justification:
A factor allowing for differences in the experimental exposure duration and the duration of exposure for the population and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. A default factor of 6 (sub-acute to chronic exposure) is appropriate per REACH Guidance R.8.4.3.1.
AF for interspecies differences (allometric scaling):
0
Justification:
The default allometric scaling factor of 4 (rat to human) per REACH Guidance R.8.4.3.1 is already included in the calculation of the modified dose descriptor starting point.
AF for other interspecies differences:
2.5
Justification:
The standard procedure for threshold effects would be, as a default, to correct for differences in metabolic rate (allometric scaling) and to apply an additional factor of 2.5 for other interspecies differences. A default factor of 2.5 is appropriate per REACH Guidance R.8.4.3.1.
AF for intraspecies differences:
5
Justification:
For workers, as standard procedure for threshold effects a default assessment factor of 5 is to be used, based on the fact that this sub population does not cover the very young, the very old, and the very ill. A default factor of 5 is appropriate per REACH Guidance R.8.4.3.3.
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:
4.667 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:
1 000 mg/kg bw/day
AF for differences in duration of exposure:
6
Justification:
A factor allowing for differences in the experimental exposure duration and the duration of exposure for the population and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. A default factor of 6 (sub-acute to chronic exposure) is appropriate per REACH Guidance R.8.4.3.1.
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling extrapolates doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight. A default factor of 4 (rat to human) is appropriate per REACH Guidance R.8.4.3.1.
AF for other interspecies differences:
2.5
Justification:
The standard procedure for threshold effects would be, as a default, to correct for differences in metabolic rate (allometric scaling) and to apply an additional factor of 2.5 for other interspecies differences. A default factor of 2.5 is appropriate per REACH Guidance R.8.4.3.1.
AF for intraspecies differences:
5
Justification:
For workers, as standard procedure for threshold effects a default assessment factor of 5 is to be used, based on the fact that this sub population does not cover the very young, the very old, and the very ill. A default factor of 5 is appropriate per REACH Guidance R.8.4.3.3.
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
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:
2.917 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:
1 000 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
970 mg/m³
Explanation for the modification of the dose descriptor starting point:

Per REACH Guidance 8.4.2 (Example R. 8 -1 General Public), the oral NOAEL of 1000 mg/kg/day (28 days Repeated Dose Toxicity Test) was converted to an inhalation equivalent: 1000 mg/kg/day ÷ 1.15 m3/kg bw (24 h exposure – rat) = 970 mg/m³.

AF for dose response relationship:
2
Justification:
According to REACH Guidance (R.8.4.2), in the case of oral-to-inhalation extrapolation, and in the absence of route-specific information on the starting route, a default factor of 2 should be included (i.e. the absorption percentage for the starting route is half that of the end route). The inclusion of factor of 2 means that 50% (instead of 100%) absorption is assumed for oral absorption, and 100% for inhalation. A default factor of 2 is appropriate per REACH Guidance R.8.4.2.
AF for differences in duration of exposure:
6
Justification:
A factor allowing for differences in the experimental exposure duration and the duration of exposure for the population and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. A default factor of 6 (sub-acute to chronic exposure) is appropriate per REACH Guidance R.8.4.3.1.
AF for interspecies differences (allometric scaling):
0
Justification:
The default allometric scaling factor of 4 (rat to human) per REACH Guidance R.8.4.3.1 is already included in the calculation of the modified dose descriptor starting point.
AF for other interspecies differences:
2.5
Justification:
The standard procedure for threshold effects would be, as a default, to correct for differences in metabolic rate (allometric scaling) and to apply an additional factor of 2.5 for other interspecies differences. A default factor of 2.5 is appropriate per REACH Guidance R.8.4.3.1.
AF for intraspecies differences:
10
Justification:
For general population, as standard procedure for threshold effects a default assessment factor of 10 is to be used, based on the fact that humans differ in sensitivity to toxic insult due to a multitude of biological factors such as genetic polymorphism affecting e.g. toxicokinetics/metabolism, age, gender, health status and nutritional status. A default factor of 10 is appropriate per REACH Guidance R.8.4.3.3.
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:
1.667 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:
1 000 mg/kg bw/day
AF for differences in duration of exposure:
6
Justification:
A factor allowing for differences in the experimental exposure duration and the duration of exposure for the population and scenario under consideration needs to be considered taking into account that a) in general the experimental NOAEL will decrease with increasing exposure times and b) other and more serious adverse effects may appear with increasing exposure times. A default factor of 6 (sub-acute to chronic exposure) is appropriate per REACH Guidance R.8.4.3.1.
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling extrapolates doses according to an overall assumption that equitoxic doses (when expressed in mg/kg bw/day) scale with body weight. A default factor of 4 (rat to human) is appropriate per REACH Guidance R.8.4.3.1.
AF for other interspecies differences:
2.5
Justification:
The standard procedure for threshold effects would be, as a default, to correct for differences in metabolic rate (allometric scaling) and to apply an additional factor of 2.5 for other interspecies differences. A default factor of 2.5 is appropriate per REACH Guidance R.8.4.3.1.
AF for intraspecies differences:
10
Justification:
For general population, as standard procedure for threshold effects a default assessment factor of 10 is to be used, based on the fact that humans differ in sensitivity to toxic insult due to a multitude of biological factors such as genetic polymorphism affecting e.g. toxicokinetics/metabolism, age, gender, health status and nutritional status. A default factor of 10 is appropriate per REACH Guidance R.8.4.3.3.
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
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:
no hazard identified
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