Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.6 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
Value:
190 mg/m³
Explanation for the modification of the dose descriptor starting point:
The NOAEC for long-term inhalation is based on the dietary NOAEL of 30 mg/kg bw/day for dogs in a 90-day study with the analogue N-(n-octyl)-2-pyrrolidinone. Correction for molecular weight is 1.28. Extrapolation formula: corrected oral NOAEL for dog in mg/kg bw/d : 38.5/AS (1.4) * 70 (kg bw)/ 10 (m³/person/day)= 193 mg/m³
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
AF for sub-chronic to chronic.
AF for interspecies differences (allometric scaling):
1
Justification:
Not applicable
AF for other interspecies differences:
2.5
Justification:
Default
AF for intraspecies differences:
5
Justification:
Default
AF for the quality of the whole database:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
12.5
Modified dose descriptor starting point:
other: NOAEL
Value:
176 mg/m³
Explanation for the modification of the dose descriptor starting point:
Extrapolation formula: NOAEL inhalation human= NOAEL oral: 100 mg/kg / 0.38 m³/kg bw x 0.67
AF for dose response relationship:
1
AF for other interspecies differences:
2.5
AF for intraspecies differences:
5
AF for the quality of the whole database:
1

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.1 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
35
Modified dose descriptor starting point:
NOAEL
Value:
38.5 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
NOAEL is based on the dietary NOAEL of 30 mg/kg bw/day for dogs in a 90-day study with the analogue N-(n-octyl)-2-pyrrolidinone. Absorption through skin is considered as being equal to absorption after oral uptake. Correction for molecular weight is 1.28.
AF for dose response relationship:
1
Justification:
At the LOAEL of 90 mg/kg bw/day only minor effects were observed in the dog study.
AF for differences in duration of exposure:
2
Justification:
AF for sub-chronic to chronic.
AF for interspecies differences (allometric scaling):
1.4
Justification:
dog-human
AF for other interspecies differences:
2.5
AF for intraspecies differences:
5
AF for the quality of the whole database:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Extrapolation formula: NOAEL dermal acute = NOAEL oral: 100 mg/kg x 0.5 (sub-acute to acute), suggesting absorption by skin is equal to absorption after oral uptake.
AF for dose response relationship:
1
AF for interspecies differences (allometric scaling):
4
Justification:
rat to human
AF for other interspecies differences:
2.5
AF for intraspecies differences:
5
AF for the quality of the whole database:
1

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low 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:
1.9 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEC
Value:
96.5 mg/m³
Explanation for the modification of the dose descriptor starting point:
The NOAEC for long-term inhalation is based on the dietary NOAEL of 30 mg/kg bw/day for dogs in a 90-day study with the analogue N-(n-octyl)-2-pyrrolidinone. Correction for molecular weight is 1.28. Extrapolation formula: corrected oral NOAEL for dog in mg/kg bw/d : 38.5/AS (1.4) * 70 (kg bw)/ 20 (m³/person/day)= 96.5 mg/m³
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
sub-chronic to chronic
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
AF for the quality of the whole database:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
Value:
88 mg/m³
Explanation for the modification of the dose descriptor starting point:
Extrapolation formula: NOAEC inhalation human= NOAEL oral: 100 mg/kg / 0.38 m³/kg bw x 0.335
AF for dose response relationship:
1
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
AF for the quality of the whole database:
1

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.55 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
70
Modified dose descriptor starting point:
NOAEL
Value:
38.5 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The dermal NOAEL is based on the dietary NOAEL of 30 mg/kg bw/day for dogs in a 90-day study with the analogue N-(n-octyl)-2-pyrrolidinone. Absorption through skin is considered as being equal to absorption after oral uptake. Correction for molecular weight is 1.28.
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic
AF for interspecies differences (allometric scaling):
1.4
Justification:
dog to human
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
AF for the quality of the whole database:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Extrapolation formula: NOAEL dermal acute = NOAEL oral: 100 mg/kg x 0.5 (sub-acute to acute), suggesting absorption by skin is equal to absorption after oral uptake.
AF for dose response relationship:
1
AF for interspecies differences (allometric scaling):
4
Justification:
rat to human
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
AF for the quality of the whole database:
1

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.55 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
70
Modified dose descriptor starting point:
NOAEL
Value:
38.5 mg/kg bw/day
AF for dose response relationship:
1
AF for differences in duration of exposure:
2
Justification:
Sub-chronic to chronic
AF for interspecies differences (allometric scaling):
1.4
Justification:
dog to human
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
AF for the quality of the whole database:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Value:
200 mg/kg bw/day
AF for dose response relationship:
1
AF for interspecies differences (allometric scaling):
4
AF for other interspecies differences:
2.5
AF for intraspecies differences:
10
AF for the quality of the whole database:
1

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

Based on available date, the most relevant reproducible effect, liver related changes in dogs, was identified as the basis for establishing the long-term DNELs. The NOEL for repeated exposure of rats in the 28 -day study was used for estimation of the acute DNELs. These data are more conservative than those identified in association with local and/or acute effects. The route-to-route extrapolation of DNELs is performed according to the ECHA Guidance Document R.8, Characterization of Dose [Concentration]-Response for Human Health dated November 2012.