Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.88 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
Modified dose descriptor starting point:
NOAEC
Value:
440.79 mg/m³
Explanation for the modification of the dose descriptor starting point:

As the NOAEL was obtained on rats using the oral route, it must be corrected for an inhalation exposure of workers, taking into account that workers are considered to be working 8h/d, with inhalative volumes for 8h/d defined in the ECHA Guidance at 6.7m3 for base level activity and 10m3 for light activity.

Corrected NOAEC(inhalation) = NOAEL(oral-rat) * (1 / sRV(rat)) * ((ABS(oral-rat) / ABS(inhalation-human))) * (sRV(human) / wRV)

Where ABS = Absorption, sRV = standard Respiratory Volume, and wRV = worker Respiratory Volume. Absorptions by inhalation and oral route are not known, therefore in order to propose a conservative approach and as no actual absorption values are available, it was considered that oral absorption in the rat was 50% less effective than the human absorption by inhalation in accordance with ECHA Guidance.

Corrected NOAEC(inhalation) = NOAEL(oral-rat) * (1 / sRV(rat)) * ((ABS(oral-rat) / ABS(inhalation-human))) * (sRV(human) / wRV)

Corrected NOAEC(inhalation) = NOAEL(oral-rat) * (1 / sRV(rat)) * 0.5 * (sRV(human) / wRV)

Corrected NOAEC(inhalation) = 500 mg/kg bw * (1 / 0.38m3/kg) * 0.5 * (6.7m3 / 10m3)

Corrected NOAEC(inhalation) = 440.79 mg/m3

AF for dose response relationship:
1
Justification:
ECHA REACH Guidance
AF for differences in duration of exposure:
6
Justification:
Subacute exposure to chronic exposure
AF for interspecies differences (allometric scaling):
1
Justification:
ECHA REACH Guidance
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
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:
DNEL (Derived No Effect Level)
Value:
5.88 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
75
Dose descriptor:
NOAEC
Value:
440.79 mg/m³
AF for dose response relationship:
1
Justification:
ECHA REACH Guidance
AF for differences in duration of exposure:
6
Justification:
Subacute exposure to chronic exposure
AF for interspecies differences (allometric scaling):
1
Justification:
ECHA REACH Guidance
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
AF for remaining uncertainties:
1
Justification:
ECHA REACH Guidance
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:
1.67 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
Modified dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

In accordance with the ECHA Guidance, in order to derive DNELs for the dermal route for systemic effects from a repeated-dose toxicity study by the oral route, a conversion must be made in order to take into account the differences between the routes.

Corrected NOAEL(systemic-dermal) = NOAEL(oral-rat) * ((ABS(oral-rat) / ABS(dermal-rat)))

Absorptions by dermal and oral routes are not known. On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral-to-dermal extrapolation.

Corrected NOAEL(systemic-dermal) = NOAEL(oral-rat) * ((ABS(dermal-rat) / ABS(oral-human)))

Corrected NOAEL(systemic-dermal) = NOAEL(oral-rat) * 1

Corrected NOAEL(systemic-dermal) = 500 mg/kg/day * 1

Corrected NOAEL(systemic-dermal) = 500 mg/kg/day

AF for dose response relationship:
1
Justification:
ECHA REACH Guidance
AF for differences in duration of exposure:
6
Justification:
Subacute exposure to chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
Rats to Humans
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
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:
DNEL (Derived No Effect Level)
Value:
0.04 mg/cm²
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
75
Dose descriptor:
other: NOAEL = 2.81 mg/cm2
AF for dose response relationship:
1
Justification:
ECHA REACH Guidance
AF for differences in duration of exposure:
6
Justification:
Subacute exposure to chronic exposure
AF for interspecies differences (allometric scaling):
1
Justification:
ECHA REACH Guidance
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
AF for remaining uncertainties:
1
Justification:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
AF for remaining uncertainties:
1

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

The only effects observed were in a sub-acute oral toxicity / reproduction screening study with transient effects at 500 mg/kg. This was used as a NOAEL. Inhalation exposure is unlikely; figures estimated from oral study appear very high (using ECHA defaults). The dermal systemic DNEL generated using ECHA defaults appears low and provides a conservative assessment of the value.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.44 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
Modified dose descriptor starting point:
NOAEC
Value:
217.39 mg/m³
Explanation for the modification of the dose descriptor starting point:

As the NOAEL was obtained on rats using the oral route, it must be corrected for an inhalation exposure of the general population, taking into account that the general population is considered as being exposed 24h/d. A sRV(rat) of 1.15m3/kg is used in order to consider this 24h/d exposure.

Corrected NOAEC(inhalation) = NOAEL(oral-rat) * (1 / sRV(rat)) * ((ABS(oral-rat) / ABS(inhalation-human)))

Where ABS = Absorption and sRV = standard Respiratory Volume. Absorptions by inhalation and oral route are not known, therefore in order to propose a conservative approach and as no actual absorption values are available, it was considered that oral absorption in the rat was 50% less effective than the human absorption by inhalation in accordance with ECHA Guidance.

Corrected NOAEC(inhalation) = NOAEL(oral-rat) * (1 / sRV(rat)) * ((ABS(oral-rat) / ABS(inhalation-human)))

Corrected NOAEC(inhalation) = NOAEL(oral-rat) * (1 / sRV(rat)) * 0.5

Corrected NOAEC(inhalation) = 500 mg/kg bw * (1 / 1.15m3/kg) * 0.5

Corrected NOAEC(inhalation) = 217.39 mg/m3

AF for dose response relationship:
1
Justification:
ECHA REACH Guidance
AF for differences in duration of exposure:
6
Justification:
Subacute exposure to chronic exposure
AF for interspecies differences (allometric scaling):
1
Justification:
ECHA REACH Guidance
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
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:
DNEL (Derived No Effect Level)
Value:
1.44 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
150
Dose descriptor:
NOAEC
Value:
217.39 mg/m³
AF for dose response relationship:
1
Justification:
ECHA REACH Guidance
AF for differences in duration of exposure:
6
Justification:
Subacute exposure to chronic exposure
AF for interspecies differences (allometric scaling):
1
Justification:
ECHA REACH Guidance
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
AF for remaining uncertainties:
1
Justification:
ECHA REACH Guidance
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:
0.83 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
Modified dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

In accordance with the ECHA Guidance, in order to derive DNELs for the dermal route for systemic effects from a repeated-dose toxicity study by the oral route, a conversion must be made in order to take into account the differences between the routes.

Corrected NOAEL(systemic-dermal) = NOAEL(oral-rat) * ((ABS(oral-rat) / ABS(dermal-rat)))

Absorptions by dermal and oral routes are not known. On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral-to-dermal extrapolation.

Corrected NOAEL(systemic-dermal) = NOAEL(oral-rat) * ((ABS(dermal-rat) / ABS(oral-human)))

Corrected NOAEL(systemic-dermal) = NOAEL(oral-rat) * 1

Corrected NOAEL(systemic-dermal) = 500 mg/kg/day * 1

Corrected NOAEL(systemic-dermal) = 500 mg/kg/day

AF for dose response relationship:
1
Justification:
ECHA REACH Guidance
AF for differences in duration of exposure:
6
Justification:
Subacute exposure to chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
Rats to Humans
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
AF for remaining uncertainties:
1
Justification:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
AF for remaining uncertainties:
1

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.02 mg/cm²
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
150
Dose descriptor:
other: NOAEL = 2.81 mg/cm2
AF for dose response relationship:
1
Justification:
ECHA REACH Guidance
AF for differences in duration of exposure:
6
Justification:
ECHA REACH Guidance
AF for interspecies differences (allometric scaling):
1
Justification:
ECHA REACH Guidance
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
AF for remaining uncertainties:
1
Justification:
ECHA REACH Guidance
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:
0.83 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:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The NOAEL derived from the subacute oral toxicity study by does not need to be modified for the purpose of DNEL calculation for the oral route

AF for dose response relationship:
1
Justification:
ECHA REACH Guidance
AF for differences in duration of exposure:
6
Justification:
Subacute exposure to chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
Rats to Humans
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
AF for remaining uncertainties:
1
Justification:
ECHA REACH Guidance
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

The only effects observed were in a sub-acute oral toxicity / reproduction screening study with transient effects at 500 mg/kg. This was used as a NOAEL. Inhalation exposure is unlikely; figures estimated from oral study appear very high (using ECHA defaults). The dermal systemic DNEL generated using ECHA defaults appears low and provides a conservative assessment of the value.