Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.76 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:
132 mg/m³
Explanation for the modification of the dose descriptor starting point:
long term 28 day repeated dose toxicity is chosen
AF for dose response relationship:
1
Justification:
not a LOAEL
AF for differences in duration of exposure:
6
Justification:
28 day subacute study to chronic study
AF for interspecies differences (allometric scaling):
1
Justification:
there is no need for the species-specific allometric scaling factor for inhalation exposures (ECHA, 2010, table R.8-4)
AF for other interspecies differences:
2.5
Justification:
remainder
AF for intraspecies differences:
5
Justification:
individual variability
AF for the quality of the whole database:
1
Justification:
full data set
AF for remaining uncertainties:
1
Justification:
no others
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.28 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):
0.33
DNEL extrapolated from long term DNEL
Modified dose descriptor starting point:
NOAEC
Value:
132 mg/m³
Explanation for the modification of the dose descriptor starting point:
One simple and well-established method used to estimate an acute threshold limit value (TLV) is multiplication of the long-term DNEL by a factor of 3 (Guidance R.8, Appendix R.8.8, 2010)
AF for dose response relationship:
1
Justification:
not a LOAEL
AF for interspecies differences (allometric scaling):
1
Justification:
there is no need for the species-specific allometric scaling factor for inhalation exposure
AF for other interspecies differences:
2.5
Justification:
remainder
AF for intraspecies differences:
5
Justification:
individual variability
AF for the quality of the whole database:
1
Justification:
full data set
AF for remaining uncertainties:
1
Justification:
no others

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
ECHA REACH Guidance

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 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:
150 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
long term 28 day repeated dose toxicity is chosen
AF for dose response relationship:
1
Justification:
not a LOAEL
AF for differences in duration of exposure:
6
Justification:
28 day subchronic study to chronic study
AF for interspecies differences (allometric scaling):
4
Justification:
rats to human
AF for other interspecies differences:
2.5
Justification:
remainder
AF for intraspecies differences:
5
Justification:
individual variability in response
AF for the quality of the whole database:
1
Justification:
full data set
AF for remaining uncertainties:
1
Justification:
no other
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.5 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):
0.33
DNEL extrapolated from long term DNEL
Modified dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
long term 28 day repeated dose toxicity is chosen
AF for dose response relationship:
1
Justification:
not a LOAEL
AF for interspecies differences (allometric scaling):
4
Justification:
rats to human
AF for other interspecies differences:
2.5
Justification:
remainder
AF for intraspecies differences:
5
Justification:
individual variability in response
AF for the quality of the whole database:
1
Justification:
full data set
AF for remaining uncertainties:
1
Justification:
no other

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
ECHA REACH Guidance

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

The overall assessment factor for chronic oral/dermal exposure for workers is 300, which is divided into the NOAEL of 150 mg/kg bw/day, for a final value of 0.5 mg/kg bw/day. The overall workers assessment factors is comprised of 4 independent AFs: - allometric scaling scaling factor of 4, - remainder factor of 2.5, - intraspecies factor of 5, - study duration factor of 6. It is dived into the NOEL of 150 mg/kg Bw/day from the following study: Envirogem AD01, H-104, in a 28-day gavage study in Hsd:WISnrats, at dose concentrations of 0, 15, 150, and 1000 mg/kg bw/d. The NOAEL in this study was 150 mg/kg bw/day.

For the longterm inhalation DNEL route-to-route extrapolation is used.

The NOAEL from the H-104 28 day repeated dose toxicity study in rats is chosen (150 mg/kg bw/d). The NOAEL is multiplied by an absorption factor of 0.5 (gastric absorption from the oral route is half that of inhalation exposure, as per an ECHA default value), and a modifier (0.75) to convert from a 6 h/day exposure to the 8 h/day exposure of a worker’s shift. This is also multiplied by another modifier (0.67) to reflect an increased respiratory volume (10.0 m3) during light exertion of a worker compared to the resting level typical of animal exposure (6.7 m3). This results in the dose descriptor being reduced to to 132.26 mg/ m3. There is no need for the species-specific allometric scaling factor for inhalation exposures (ECHA, 2010, Table R.8-4). The overall AF is 75, divided into the modified dose descriptor, resulting in a DNEL of 1.76 mg/ m3.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.43 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:
150 mg/m³
Explanation for the modification of the dose descriptor starting point:
long term 28 day repeated dose toxicity is chosen
AF for dose response relationship:
1
Justification:
not a LOAEL
AF for differences in duration of exposure:
6
Justification:
28 day subacute study to chronic study
AF for interspecies differences (allometric scaling):
4
Justification:
rats to human
AF for other interspecies differences:
2.5
Justification:
remainder
AF for intraspecies differences:
10
Justification:
individual varability in response
AF for the quality of the whole database:
1
Justification:
full data set
AF for remaining uncertainties:
1
Justification:
no other
Acute/short 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):
0.33
DNEL extrapolated from long term DNEL
Modified dose descriptor starting point:
NOAEC
Value:
150 mg/m³
Explanation for the modification of the dose descriptor starting point:
existing long term test on rats (oral)
AF for dose response relationship:
1
Justification:
not a LOAEL
AF for interspecies differences (allometric scaling):
4
Justification:
rats to human
AF for other interspecies differences:
2.5
Justification:
remainder
AF for intraspecies differences:
10
Justification:
individual varability in response
AF for the quality of the whole database:
1
Justification:
full data set
AF for remaining uncertainties:
1
Justification:
no other

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
ECHA REACH Guidance

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.25 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:
150 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
long term 28 day repeated dose toxicity is chosen
AF for dose response relationship:
1
Justification:
not a LOAEL
AF for differences in duration of exposure:
6
Justification:
28 day subacute study to chronic study
AF for interspecies differences (allometric scaling):
4
Justification:
rats to human
AF for other interspecies differences:
2.5
Justification:
remainder
AF for intraspecies differences:
10
Justification:
individual varability in response
AF for the quality of the whole database:
1
Justification:
full data set
AF for remaining uncertainties:
1
Justification:
no other
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.75 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):
0.33
DNEL extrapolated from long term DNEL
Modified dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
long term 28 day repeated dose toxicity is chosen
AF for dose response relationship:
1
Justification:
not a LOAEL
AF for interspecies differences (allometric scaling):
4
Justification:
rats to human
AF for other interspecies differences:
2.5
Justification:
remainder
AF for intraspecies differences:
10
Justification:
individaual varability in response
AF for the quality of the whole database:
1
Justification:
full data set
AF for remaining uncertainties:
1
Justification:
no other

Local effects

Long term exposure
Hazard assessment conclusion:
DMEL (Derived Minimum Effect Level)
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information
DNEL derivation method:
ECHA REACH Guidance

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.25 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
Explanation for the modification of the dose descriptor starting point:
long term 28 day repeated dose toxicity is chosen
AF for dose response relationship:
1
Justification:
not a LOAEL
AF for differences in duration of exposure:
6
Justification:
28 day subacute study to chronic study
AF for interspecies differences (allometric scaling):
4
Justification:
rat to human
AF for other interspecies differences:
2.5
Justification:
remainder
AF for intraspecies differences:
10
Justification:
individual variability in response
AF for the quality of the whole database:
1
Justification:
full data set
AF for remaining uncertainties:
1
Justification:
no other
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.75 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):
0.33
DNEL extrapolated from long term DNEL
Modified dose descriptor starting point:
NOAEL
Value:
150 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
long term 28 day repeated dose toxicity is chosen
AF for dose response relationship:
1
Justification:
not a LOAEL
AF for interspecies differences (allometric scaling):
4
Justification:
rat to human
AF for other interspecies differences:
2.5
Justification:
remainder
AF for intraspecies differences:
10
Justification:
individual variability in response
AF for the quality of the whole database:
1
Justification:
full data set
AF for remaining uncertainties:
1
Justification:
no other

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

The overall assessment factor for chronic oral/dermal exposure for the population is 600, which is divided into the NOAEL of 150 mg/kg bw/day, for a final value of 0.25 mg/kg bw/day. The overall population assessment factor is comprised of 4 independent AFs: - allometric scaling scaling factor of 4, - remainder factor of 2.5, - intraspecies factor of 10, - study duration factor of 6. It is dived into the NOEL of 150 mg/kg Bw/day from the following study: Envirogem AD01, H-104, in a 28-day gavage study in Hsd:WISnrats, at dose concentrations of 0, 15, 150, and 1000 mg/kg bw/d. The NOAEL in this study was 150 mg/kg bw/day.

For the longterm inhalation DNEL route-to-route extrapolation is used. The NOAEL from the H-104 28 day repeated dose toxicity study in rats is chosen (150 mg/kg bw/d). The NOAEL is multiplied by an absorption factor of 0.5 (gastric absorption from the oral route is half that of inhalation exposure, as per an ECHA default value), and a modifier (0.87) to convert from a 6 h/day exposure to the 24 h/day exposure for the population. The final dosedescriptor is 64.22 mg/m³. Three AFs are applied: remainder 2.5, intraspecies 10, duration 6. There is no need for the species-specific allometric scaling factor. The overall AF is 150, divided into the modified dose descriptor, resulting in a DNEL of 0.43 mg/ m3.