Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.29 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):
12
Modified dose descriptor starting point:
LOAEC
DNEL value:
15.5 mg/m³
Explanation for the modification of the dose descriptor starting point:
No inhalation toxicity data are available. The LOAEL from the 26-week repeated-dose oral toxicity study is used for derivation of the DNEL-long-term for the inhalation route. For intestinal absorption a figure of 20% has been estimated (based on rat data). Inhalation absorption was estimated to be 100% (no data). Corrected inh NOAEL = oral NOAEL x [1/sRV(rat) ] x [absorption (oral-rat) / absorption (inh-human) ]. This will be: 43 x 1/0.38 m3(8h) x 20/100 = 23 mg/m3. Further correction for respiratory volume = x [sRV(human) / wRV]. This will be: 23 mg/m3x [6.7 m3(8h) / 10 m3(8h) = 15.5 mg/m3
AF for dose response relationship:
1
Justification:
no additional assessment factor is needed
AF for differences in duration of exposure:
2
Justification:
sub-chronic to chronic exposure
AF for interspecies differences (allometric scaling):
1
Justification:
not applicable as this has already been done at route to route extrapolation
AF for other interspecies differences:
1
Justification:
rats and dogs showed similar NOAELs following 26 weeks of exposure; mice showed a 2-times higher NOAEL at a 2-times shorter duration (13 weeks), indicating that interspecies effect concentrations are small if at all
AF for intraspecies differences:
3
Justification:
for workers a factor 3 is generally considered to be sufficient
AF for the quality of the whole database:
1
Justification:
no additional assessment factor is needed
AF for remaining uncertainties:
2
Justification:
LOAEL to NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6 940 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
7.5
Modified dose descriptor starting point:
NOAEC
DNEL value:
1 627 mg/m³
Explanation for the modification of the dose descriptor starting point:
No inhalation toxicity data are available. The NOEL from the acute oral toxicity study is used for derivation of the DNEL-acute for the inhalation route. Based on the particle size distribution normally obtained after nebulizing, it is expected that 90% of the inhaled substance will be deposited in the upper respiratory tract, which will finally be taken up orally. Of this, only 20% will be absorbed in the gastrointestinal tract and become available systematically, i. e. 0.9 x 0.20 = 0.18. The other 10% may reach the alveoli and it is assumed that this will be absorbed completely (worst case). Therefore, the total inhalation absorption factor will be 0.18 + 0.10 = 0.28. Corrected inh NOAEL =oral NOAEL x [1/sRV(rat) ] x [absorption (oral-rat) / absorption (inh-human) ]. This will be: 1294 x 1/0.38 m3(8h) x 20/28 = 2432 mg/m3. Further correction for respiratory volume =x [sRV(human) / wRV]. This will be: 2432 mg/m3x [6.7 m3(8h) / 10 m3(8h) = 1627 mg/m3
AF for dose response relationship:
1
Justification:
no additional assessment factor is needed
AF for interspecies differences (allometric scaling):
1
Justification:
not applicable as this has already been done at route to route extrapolation
AF for other interspecies differences:
2.5
Justification:
systemic effects
AF for intraspecies differences:
3
Justification:
for workers a factor 3 is generally considered to be sufficient
AF for the quality of the whole database:
1
Justification:
no additional assessment factor is needed
AF for remaining uncertainties:
1
Justification:
no additional assessment factor is needed

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.74 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
87.5
Modified dose descriptor starting point:
NOAEL
Justification:
no additional assessment factor is needed
AF for differences in duration of exposure:
1.7
Justification:
lifetime study but exposure for 3 days a week rather than 5 days a week
AF for interspecies differences (allometric scaling):
7
Justification:
difference in bodyweight
AF for other interspecies differences:
2.5
Justification:
default assessment factor
AF for intraspecies differences:
3
Justification:
for workers a factor 3 is generally considered to be sufficient
Justification:
no additional assessment factor is needed
Justification:
no additional assessment factor is needed
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
36 µg/cm²
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
36
Dose descriptor:
other: LOAEL
Justification:
no additional assessment factor is needed
AF for differences in duration of exposure:
6
Justification:
sub-acute to chronic exposure
AF for interspecies differences (allometric scaling):
1
Justification:
no allometric scaling needed because of local effects
AF for other interspecies differences:
1
Justification:
local effects
AF for intraspecies differences:
3
Justification:
for workers a factor 3 is generally considered to be sufficient
Justification:
no additional assessment factor is needed
AF for remaining uncertainties:
2
Justification:
LOAEL to NOAEL
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)

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:
0.38 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):
20
Modified dose descriptor starting point:
LOAEC
DNEL value:
7.4 mg/m³
Explanation for the modification of the dose descriptor starting point:
No inhalation toxicity data are available. The LOAEL from the 26-week repeated-dose oral toxicity study is used for derivation of the DNEL-long-term for the inhalation route. For intestinal absorption a figure of 20% has been estimated (based on rat data). Inhalation absorption was estimated to be 100% (no data). Corrected inh NOAEL = oral NOAEL x [1/sRV(rat) ] x [absorption (oral-rat) / absorption (inh-human) ]. This will be: 43 x 1/1.15 m3(24h) x 20/100 = 7.4 mg/m3.
Justification:
no additional assessment factor is needed
AF for differences in duration of exposure:
2
Justification:
sub-chronic to chronic exposure
AF for interspecies differences (allometric scaling):
1
Justification:
not applicable as this has already been done at route to route extrapolation
AF for other interspecies differences:
1
Justification:
rats and dogs showed similar NOAELs following 26 weeks of exposure; mice showed a 2-times higher NOAEL at a 2-times shorter duration (13 weeks), indicating that interspecies effect concentrations are small if at all
AF for intraspecies differences:
5
Justification:
for the general public a factor 5 is generally considered sufficient
Justification:
no additional assessment factor is needed
AF for remaining uncertainties:
2
Justification:
LOAEL to NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 071 mg/m³
Most sensitive endpoint:
acute toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Modified dose descriptor starting point:
NOAEC
DNEL value:
804 mg/m³
Explanation for the modification of the dose descriptor starting point:
No inhalation toxicity data are available. The NOEL from the acute oral toxicity study is used for derivation of the DNEL-acute for the inhalation route. Based on the particle size distribution normally obtained after nebulizing, it is expected that 90% of the inhaled substance will be deposited in the upper respiratory tract, which will finally be taken up orally. Of this, only 20% will be absorbed in the gastrointestinal tract and become available systematically, i. e. 0.9 x 0.20 = 0.18. The other 10% may reach the alveoli and it is assumed that this will be absorbed completely (worst case). Therefore, the total inhalation absorption factor will be 0.18 + 0.10 = 0.28. Corrected inh NOAEL =oral NOAEL x [1/sRV(rat) ] x [absorption (oral-rat) / absorption (inh-human) ]. This will be: 1294 x 1/1.15 m3(24h) x 20/28 = 804 mg/m3.
AF for dose response relationship:
1
Justification:
no additional assessment factor is needed
AF for interspecies differences (allometric scaling):
1
Justification:
not applicable as this has already been done at route to route extrapolation
AF for other interspecies differences:
2.5
Justification:
systemic effects
AF for intraspecies differences:
5
Justification:
for the general public a factor 5 is generally considered sufficient
AF for the quality of the whole database:
1
Justification:
no additional assessment factor is needed
AF for remaining uncertainties:
1
Justification:
no additional assessment factor is needed

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.32 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):
204
Modified dose descriptor starting point:
NOAEL
Justification:
no additional assessment factor is needed
AF for differences in duration of exposure:
2.3
Justification:
lifetime study but exposure for 3 days a week rather than 7 days a week
AF for interspecies differences (allometric scaling):
7
Justification:
difference in bodyweight
AF for other interspecies differences:
2.5
Justification:
default assessment factor
AF for intraspecies differences:
5
Justification:
for the general public a factor 5 is generally considered sufficient
Justification:
no additional assessment factor is needed
Justification:
no additional assessment factor is needed
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEL
AF for dose response relationship:
1
Justification:
no additional assessment factor is needed
AF for interspecies differences (allometric scaling):
4
Justification:
difference in bodyweight
AF for other interspecies differences:
2.5
Justification:
default assessment factor
AF for intraspecies differences:
5
Justification:
for the general public a factor 5 is generally considered sufficient
AF for the quality of the whole database:
1
Justification:
no additional assessment factor is needed
AF for remaining uncertainties:
1
Justification:
no additional assessment factor is needed

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.56 mg/cm²
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
11.7
Dose descriptor:
other: NOAEL
Justification:
no additional assessment factor is needed
AF for differences in duration of exposure:
2.3
Justification:
lifetime study but exposure for 3 days a week rather than 7 days a week
AF for interspecies differences (allometric scaling):
1
Justification:
no allometric scaling needed because of local effects
AF for other interspecies differences:
1
Justification:
local effects
AF for intraspecies differences:
5
Justification:
for the general public a factor 5 is generally considered sufficient
Justification:
no additional assessment factor is needed
Justification:
no additional assessment factor is needed
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.29 mg/cm²
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
5
Dose descriptor starting point:
other: NOAEL
AF for dose response relationship:
1
Justification:
no additional assessment factor is needed
AF for interspecies differences (allometric scaling):
1
Justification:
no allometric scaling needed because of local effects
AF for other interspecies differences:
1
Justification:
local effects
AF for intraspecies differences:
5
Justification:
for the general public a factor 5 is generally considered sufficient
AF for the quality of the whole database:
1
Justification:
no additional assessment factor is needed
AF for remaining uncertainties:
1
Justification:
no additional assessment factor is needed

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.53 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):
80
Modified dose descriptor starting point:
LOAEL
AF for dose response relationship:
1
Justification:
no additional assessment factor is needed
AF for differences in duration of exposure:
2
Justification:
sub-chronic to chronic exposure
AF for interspecies differences (allometric scaling):
4
Justification:
difference in bodyweight
AF for other interspecies differences:
1
Justification:
rats and dogs showed similar NOAELs following 26 weeks of exposure; mice showed a 2-times higher NOAEL at a 2-times shorter duration (13 weeks), indicating that interspecies effect concentrations are small if at all
AF for intraspecies differences:
5
Justification:
for the general public a factor 5 is generally considered sufficient
AF for the quality of the whole database:
1
Justification:
no additional assessment factor is needed
AF for remaining uncertainties:
2
Justification:
LOAEL to NOAEL
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
26 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEL
AF for dose response relationship:
1
Justification:
no additional assessment factor is needed
AF for interspecies differences (allometric scaling):
4
Justification:
difference in bodyweight
AF for other interspecies differences:
2.5
Justification:
default assessment factor
AF for intraspecies differences:
5
Justification:
for the general public a factor 5 is generally considered sufficient
AF for the quality of the whole database:
1
Justification:
no additional assessment factor is needed
AF for remaining uncertainties:
1
Justification:
no additional assessment factor is needed

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - General Population