Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
11.75 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):
75
Modified dose descriptor starting point:
NOAEC
Value:
881.58 mg/m³
Explanation for the modification of the dose descriptor starting point:
Justification for NOAEC ( mg/m3) calculation attached to technical dossier.
AF for dose response relationship:
1
Justification:
Table R8-6
AF for differences in duration of exposure:
6
Justification:
Table R8-6
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is accounted for in NOAEL extrapolation
AF for intraspecies differences:
5
Justification:
intraspecies – workers Table R8-6
AF for the quality of the whole database:
1
Justification:
Table R8-6
AF for remaining uncertainties:
2.5
Justification:
Table R8-6
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:
3.33 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
300
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
AF for dose response relationship:
1
Justification:
Table R8-6
AF for differences in duration of exposure:
6
Justification:
Table R8-6
AF for interspecies differences (allometric scaling):
4
Justification:
Table R8-3
AF for intraspecies differences:
5
Justification:
Table R8-6
AF for the quality of the whole database:
1
Justification:
Table R8-6
AF for remaining uncertainties:
2.5
Justification:
Table R8-6
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:
1.03 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
other: Extrapolation from animal and human data
Overall assessment factor (AF):
5
Dose descriptor:
other: NOAEL
AF for dose response relationship:
1
Justification:
human data
AF for differences in duration of exposure:
1
Justification:
human data
AF for interspecies differences (allometric scaling):
1
Justification:
human data
AF for intraspecies differences:
5
Justification:
Table R8-6 workers
AF for the quality of the whole database:
1
Justification:
human data
AF for remaining uncertainties:
1
Justification:
human data
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

The short term exposure dermal systemic DNELs is based on sensitisation data in humans.

 

Acute systemic dermal DNEL = Dermal sensitisation DNEL:

The following database assessment factors were used.

·        Interspecies variation = 1x (human data)

·        Intraspecies (human-human inter-individual variation) = 5x (for workers)

·        Exposure Duration = 1x (not applicable for sensitisation)

·        LOAEL to NOAEL = 1x ( NOAEL/SCL used)

·        Quality of Dataset = 1x for multiple reliable K1 and K2 studies)

The final assessment factor is 5x.

DNEL Calculation:

·        NOAEL/SCL = 10% (w/v)

·        Amount applied to skin = 0.2 ml x 0.932 g/ml (density) x 10% (NOAEL/SCL concentration) = 0.01864 g or 18.64

·        Amount applied per unit surface area = 18.64 mg÷3.63 cm2skin (based on ¾” x ¾” patch noted in a number of studies) = 5.13 mg/ cm2

Adjusted dose descriptor = 5.13 mg/cm2skin÷ 5 (total AF) = 1.03 mg/cm2

 

The long term exposure DNELs have all be derived based upon the NOAEL(C) values observed from repeated dose exposure with Assessment Factor based adjustment to make the DNELs appropriate to workers, based on Table R. 8 -6. The dermal DNEL is estimated directly from the available 28 -day repeated dose dermal toxicity data. As the inhlataion data are considered unsafe, however, due to a high proportion of mineral oil mist in the exposure concentration the NOAEL(C) is calculated from the 28 -day repeated dose oral toxicity data.

 

Based on formulae in R. 8-3, as a worst case it is assumed 100% adsorption orally to rats and by inhalation to human. Due to the presence of mineral oil changing the physical state of the substance, granulometry data are not available and deposition in the lungs cannot be determined. Target endpoints are also assumed to be equivalent.

 

For workers (8h exposure/d)

NOAEC (inhal) = 500 * 1/0.38 m3/kg/d * 100/100 * 6.7m3/10m3

NOAEC (inhal) = 881.58 mg/m3

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.9 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:
434.78 mg/m³
Explanation for the modification of the dose descriptor starting point:
Justification for NOAEC (434.78 mg/m3) calculation attached to technical dossier.
AF for dose response relationship:
1
Justification:
Table R8-6
AF for differences in duration of exposure:
6
Justification:
Table R8-6 subacute to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is accounted for in NOAEL extrapolation
AF for intraspecies differences:
10
Justification:
Table R8-6 general population
AF for the quality of the whole database:
1
Justification:
Table R8-6
AF for remaining uncertainties:
2.5
Justification:
Table R8-6
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:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
600
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
AF for dose response relationship:
1
Justification:
Table R8-6
AF for differences in duration of exposure:
6
Justification:
Table R8-6
AF for interspecies differences (allometric scaling):
4
Justification:
Table R8-3
AF for intraspecies differences:
10
Justification:
Table R8-6 general population
AF for the quality of the whole database:
1
Justification:
Table R8-6
AF for remaining uncertainties:
2.5
Justification:
Table R8-6
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:
0.513 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
other: Extrapolation from human and animal data
Overall assessment factor (AF):
10
Dose descriptor:
other: NOAEL
AF for dose response relationship:
1
Justification:
human data
AF for differences in duration of exposure:
1
Justification:
human data
AF for interspecies differences (allometric scaling):
1
Justification:
human data
AF for intraspecies differences:
10
Justification:
Table R8-6 general population
AF for the quality of the whole database:
1
Justification:
human data
AF for remaining uncertainties:
1
Justification:
human data
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.833 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
AF for dose response relationship:
1
Justification:
Table R8-6
AF for differences in duration of exposure:
6
Justification:
Table R8-6
AF for interspecies differences (allometric scaling):
4
Justification:
Table R8-3
AF for intraspecies differences:
10
Justification:
Table R8-6 general population
AF for the quality of the whole database:
1
Justification:
Table R8-6
AF for remaining uncertainties:
2.5
Justification:
Table R8-6
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 short term exposure dermal systemic DNELs is based on sensitisation data in humans.

Acute systemic dermal DNEL = Dermal sensitisation DNEL:

The following database assessment factors were used.

·        Interspecies variation = 1x (data available on humans)

·        Intraspecies (human-human inter-individual variation) = 10x (for general population)

·        Exposure Duration = 1x (not applicable for sensitisation)

·        LOAEL to NOAEL = 1x ( NOAEL/SCL used)

·        Quality of Dataset = 1x for multiple reliable K1 and K2 studies)

The final assessment factor is 10x.

DNEL Calculation:

·        NOAEL/SCL = 10% (w/v)

·        Amount applied to skin = 0.2 ml x 0.932 g/ml (density) x 10% (NOAEL/SCL concentration) = 0.01864 g or 18.64

·        Amount applied per unit surface area = 18.64 mg÷3.63 cm2skin (based on ¾” x ¾” patch noted in a number of studies) = 5.13 mg/ cm2

Adjusted dose descriptor = 5.13 mg/cm2skin÷ 10 (total AF) = 0.513 mg/cm2

The long term exposure DNELs have all be derived based upon the NOAEL(C) values observed from repeated dose exposure with Assessment Factor based adjustment to make the DNELs appropriate to workers, based on Table R. 8 -6. The dermal DNEL is estimated directly from the available 28 -day repeated dose dermal toxicity data. As the inhlataion data are considered unsafe, however, due to a high proportion of mineral oil mist in the exposure concentration the NOAEL(C) is calculated from the 28 -day repeated dose oral toxicity data.

Based on formulae in R. 8-3, as a worst case it is assumed 100% adsorption orally to rats and by inhalation to human. Due to the presence of mineral oil changing the physical state of the substance, granulometry data are not available and deposition in the lungs cannot be determined. Target endpoints are also assumed to be equivalent.

For general population (24h exposure/d)

NOAEC (inhal) = 500 * 1/1.15 m3/kg/d * 100/100

NOAEC (inhal) = 434.78 mg/m3