1-ethylpyrrolidin-2-one

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

16.75 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

6

Dose descriptor starting point:

NOAEC

Value:

200 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

100.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

corrected NOAEC = 200 mg/m3 (NOAEC) x  6h/8h x 6.7 m3/10m3 (for workers in case of 8h exposure/d) = 100.5 mg/m3

AF for dose response relationship:

1

Justification:

NOAEC for systemic toxicity in inhalation study

AF for differences in duration of exposure:

2

Justification:

Extrapolation from subchronic (90 days) to chronic exposure.

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling not applied for derivation of inhalation DNEL

AF for other interspecies differences:

1

Justification:

No systemic toxicity observed at the high conc. (200 mg/m3) in the 90d inhalat. study. The local irration in the resp. tract is the dose limiting factor for inhalation studies with NEP. A theoretical NAEC (5d/w, 6h) for syst. toxicity can be calculated from the (human relevant) NOAEL of 100 mg/kg bw/d for females in the oral 90d study. Based on this extrapolation, a NAEC (90d, 5d/week, 6h/day) would be expected at a much higher value in the range of 570 mg/m3/ (=(100 mg/kg bw/d x 0.5 kg)/(6h x 20.5l/h) x 7d/5d) x 1000), a dose level where distinct resp. irritation was observed in repeated dose studies. From this it follows that the DNEL calculation for systemic effects based on the 90d inhalat. study is a conservative approach.
For comparison the inhalat. DNEL (systemic effects) can also be extrapolated from the available oral study. After feeding NEP in a 90d study the only relevant findings at the low doses was a centrilobular hypertrophy of hepatocytes and a slight liver weight increase starting from 100 mg/kg bw/d onwards in males indicative for enzyme induction of the cytochrome P450 system. This was considered a detoxifying adaptive effect as no cytotoxicity was recorded. The kidney findings in male animals was shown to be a related to the induction of alpha 2u globuline (a toxicological mechanism known to be not relevant for humans). At the mid dose (300 mg/kg bw/d), decreased food consumption, decrease in bw and bw gain and a decrease in grip strength forelimbs in males were observed as additional findings (=LOAEL).
If the DNEL is now derived from the oral NOAEL and if ECHA's standard AFs are applied, a conc. of ca 10 mg/m3 is obtained (100 mg/kg bw/d/0.38 mg/m3) x 7d/5d x (6.7m3/10 m3) x 1/2 x 1/2.5 x 1/5). This is in line with the above calculated DNEL (systemic effects, long-term). An AF of 1 for other interspecies differences is therefore considered to be sufficiently conservative when using the NOAEC of the 90d inhalat. study as a point of departure.

AF for intraspecies differences:

3

Justification:

Variability between workers. The local irration in the resp. tract is the dose limiting factor for inhalation studies with NEP. A theoretical NAEC (5d/w, 6h) for syst. toxicity can be calculated from the (human relevant) NOAEL of 100 mg/kg bw/d for females in the oral subchronic study. Based on this extrapolation, a NAEC (90d, 5d/week, 6h/day) would be expected at a much higher value in the range of 570 mg/m3/ (=(100 mg/kg bw/d x 0.5 kg)/(6h x 20.5l/h) x 7d/5d) x 1000) which is a dose level where distinct resp. irritation was observed in repeated dose experiments. From this it follows that the DNEL calculation for systemic effects based on the 90d inhalat. study is a conservative approach.
For comparison the inhalat. DNEL (systemic effects) can also be extrapolated from the available oral study. After feeding NEP in a 90d study the only relevant findings at the low doses was a centrilobular hypertrophy of hepatocytes and a slight liver weight increase starting from 100 mg/kg bw/d onwards in males indicative for enzyme induction of the cytochrome P450 system. This was considered a detoxifying adaptive effect as no cytotoxicity was recorded. The kidney findings in male animals was shown to be a related to the induction of alpha 2u globuline (a toxicological mechanism known to be not relevant for humans). At the mid dose (300 mg/kg bw/d), decreased food consumption, decrease in bw and bw gain and a decrease in grip strength forelimbs in males were observed as additional findings (=LOAEL).
If the DNEL is now derived from the oral NOAEL and if ECHA's standard AFs are applied, a conc. of ca 10 mg/m3 is obtained (100 mg/kg bw/d/0.38 mg/m3) x 7d/5d x (6.7m3/10 m3) x 1/2 x 1/2.5 x 1/5). This is in line with the above calculated DNEL (systemic effects, long-term). An AF of 3 for intraspecies differences is therefore considered to be sufficiently conservative.

AF for the quality of the whole database:

1

Justification:

Klimisch 1 study

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:

10.05 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

3

Dose descriptor:

NOAEC

Value:

60 mg/m³

AF for dose response relationship:

1

Justification:

NOAEC for local toxicity in inhalation study

AF for differences in duration of exposure:

1

Justification:

There was no increase in irritation effects in the respiratory tract between the 28d subacute and the 90d subchronic study, which indicates that there is no additional assessment factor necessary for chronic exposure.

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling not applied for derivation of inhalation DNEL

AF for other interspecies differences:

1

Justification:

Default factor of 1 for local effects considered sufficiently conservative.
In the publication by Brüning et al. (Arch Toxicol. 88, 1855-1879, 2014), it was suggested that an interspecies Extrapolation Factor (iEF) of 3 should be applied for extrapolation from animal data for all those substances with indication of local irritating effects as the most sensitive response in animal studies. In case the target structure in the animal experiment is the olfactory epithelium (OE), it should be considered to reduce the default iEF to 2 because of the higher physiological sensitivity of rats in the OE (twofold higher airflow along the OE resulting in twofold higher tissue burden in rats). This scheme can be used for setting OELs from data regarding sensory irritation. If adequate animal data are available, the iEFs may be applied as default factors for the derivation of OELs. Using this concept, an overall factor of 3 for intra- and interspecies extrapolation can now be applied.
Similarly, the German MAK Commission on Occupational Health and Safety has recently set an OEL for NEP of 23 mg/m3 (5 ppm; vapor) based on the results of the 90d inhalation study in rats and using the approach suggested by Brüning et al. (2014).

AF for intraspecies differences:

3

Justification:

In the case of local irritation in the upper respiratory tract, an interindividual variability factor of 3 between workers is considered sufficient (see also above justification for interspecies differences).

AF for the quality of the whole database:

1

Justification:

Klimisch 1 study with 90d inhalation of NEP

AF for remaining uncertainties:

1

Justification:

Not needed (local sensory irritation in OE of rats), see also above

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

20.1 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

DNEL extrapolated from long term DNEL

Workers - Hazard via dermal route

Systemic effects

Long 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

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

24

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

extrapolation from oral to dermal exposure considered appropriate

AF for dose response relationship:

1

Justification:

NOAEL in 90 d study for females

AF for differences in duration of exposure:

2

Justification:

extrapolation from subchronic to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

allometric scaling

AF for other interspecies differences:

1

Justification:

At the LOAEL in females pathological findings were centrilobular hypertrophy in the liver considered to be the result of an adaptive, detoxifying process, no further AF needed.
LOAEL for males is based on alpha 2u nephropathy which is considered not to be relevant for humans

AF for intraspecies differences:

3

Justification:

variability within workers

AF for the quality of the whole database:

1

Justification:

Klimisch 1 study

AF for remaining uncertainties:

1

Justification:

covered by allometric scaling and AF for intraspecies differences. At the LOAEL in females pathological findings were centrilobular hypertrophy in the liver considered to be the result of an adaptive, detoxifying process, no further AF needed.
LOAEL for males is based on alpha 2u nephropathy which is considered not to be relevant for humans.

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

Acute/short-term exposure - systemic effects

N-Ethyl-2 -Pyrrolidone (NEP) has a low acute toxicity by all relevant routes of exposure as indicated by the LD₅₀/LC₅₀values of 3200 mg/kg bw, >52000 mg/kg bw and >5100 mg/m³(Aerosol) determined in rats for oral, dermal and inhalation exposure, respectively. Therefore, NMP is not subject to classification and labelling for acute toxicity and consequently no DNEL for acute/short-term exposure - systemic effects has to be established. This is in line with ECHA guidance on information requirements and chemical safety assessment, Chapter R.8 (2008).

Acute/short-term and long term exposure - local effects

Skin irritation/corrosion: NEP is not irritating to skin

Eye irritation: NEP causes irreversible damage to the eye (Category 1, H318). A quantitative assessment of eye irritation is not possible because only qualitative data from the relevant studies are available. Risk minimization measurements (goggles) have be applied when handling the concentrated substance. Concentration limits as provided by the CLP Regulation (EU GHS: EU Regulation 1272/2008 ) may serve as approximation for a eye irritation DNEL.

Respiratory irritation: No irritating effects on the respiratory tract in humans are known. Minimal to moderate signs of local irritation in the nasal cavity were observed in a 90d inhalation study in rats.

Skin sensitisation: Based on available animal data NEP is not supposed to be a skin sensitising substance and no DNEL concerning skin sensitising potential has to be established. This is in line with ECHA guidance on information requirements and chemical safety assessment, Chapter R.8 (2008).

Long term exposure - systemic effects

NEP may be an inducer of developmental toxicity / teratogenicity and is suspected of damaging fertility (Category 1B, H360Df).

Inhalation exposure: Inhalation exposure of rats to N-ethyl-2-pyrrolidone vapors for 90 days (65 exposures) did not lead to any exposure-related effect in clinical chemistry of the blood and hematological examinations. Clinical signs of toxicity indicated local irritation in the nasal cavity of the test substance at 200 mg/m3. In concordance with the clinical observation, histological examination revealed some effect in nasal cavity. These effects were observed in a concentration-related manner. Under the current test conditions, the NOAEC for local effect in nasal cavity was 60 mg/m3 and is used for DNEL derivation. No signs of systemic toxicity occurred up to the highest tested concentration of 200 mg/m3.

Dermal exposure: In order to derive a DNEL for dermal exposure, the NOAEL of 100 mg/kg bw/day assessed in the oral repeated dose toxicity study in rats is used. A route to route extrapolation from oral to dermal toxicity studies is in accordance with ECHA guidance on information requirements and chemical safety assessment, Chapter R.8 (2008).

Oral exposure: In a 90-day study according to OECD 408 groups of 10 male and 10 female Wistar rats received doses of 0, 100, 300 and 1000 mg N-Ethyl-2 -pyrrolidone/kg body weight/day over a period of 3 months via their diet. The study included FOB examinations and additional reproductive toxicity parameters. Substance-related adverse effects at 1000 and 300 mg/kg bw/day in both sexes and 100 mg/kg bw/day in males. The target organs identified in this study were liver and kidneys. The kidney effects were considered to be initial stages of an alpha 2u nephropathy in the male rat as substantiated by immunohistochemical staining. Alpha 2u nephropathy is assessed to be not relevant to humans as it is induced by a rat-specific mechanism. The effects on the liver may be considered to be a detoxifying, adaptive effect because no signs for cytotoxicity were recorded. In addition, sperm analysis revealed an increased number of sperms with abnormal heads in males at 1000 mg/kg. Therefore the no observed adverse effect level (NOAEL) under the conditions of this study was 100 mg/kg bw/day in females based on body weight effects and the liver findings considered to be the result of an adaptive, detoxifying process. The NOAEL in males was < 100 mg/kg bw/day (alpha 2 u nephropathy).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor starting point:

NOAEC

Value:

200 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

50 mg/m³

Explanation for the modification of the dose descriptor starting point:

corrected NOAEC = 200 mg/m3 (NOAEC) x  6h/24h (for general population in case of 24/d) = 50 mg/m3

AF for dose response relationship:

1

Justification:

NOAEC for systemic toxicity in subchronic inhalation study

AF for differences in duration of exposure:

2

Justification:

extrapolation from subchronic (90 days) to chronic exposure

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling not applied for derivation of inhalation DNEL

AF for other interspecies differences:

2.5

Justification:

ECHA Guidance

AF for intraspecies differences:

10

Justification:

ECHA Guidance, variability in the general population

AF for the quality of the whole database:

1

Justification:

Klimisch 1 study, good/standard quality of the database

AF for remaining uncertainties:

1

Justification:

covered by applied inter- and intraspecies AFs

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:

1.2 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor:

NOAEC

Value:

60 mg/m³

AF for dose response relationship:

1

Justification:

NOAEC in subchronic inhalation study

AF for differences in duration of exposure:

2

Justification:

subchronic (90 days) to chronic exposure

AF for interspecies differences (allometric scaling):

1

Justification:

Allometric scaling not applied for derivation of inhalation DNEL

AF for other interspecies differences:

2.5

Justification:

ECHA Guidance

AF for intraspecies differences:

10

Justification:

ECHA Guidance, variability in the general population

AF for the quality of the whole database:

1

Justification:

Klimisch 1 study, good/standard quality of the database

AF for remaining uncertainties:

1

Justification:

covered by applied inter- and intraspecies AFs

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.2 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

DNEL extrapolated from long term DNEL

Dose descriptor starting point:

NOAEC

Value:

50 mg/m³

General Population - 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):

200

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

Systemic toxicity after subchronic exposure was most sensitive endpoint.

NOAEL dermal = NOAELoral x (ABS oral / ABS dermal) = 100 mg/kg/d x (100%/100%) = 100 mg/kg bw/d;  NOAELoral = 100 mg/kg bw/d (OECD 408; oral; rat)

AF for dose response relationship:

1

Justification:

NOAEL

AF for differences in duration of exposure:

2

Justification:

subchronic (90 days) to chronic exposure

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA Guidance (extrapolation from rat to human)

AF for other interspecies differences:

2.5

Justification:

ECHA Guidance

AF for intraspecies differences:

10

Justification:

ECHA Guidance, variability within general population

AF for the quality of the whole database:

1

Justification:

Klimisch 1 study

AF for remaining uncertainties:

1

Justification:

covered by applied inter- and intraspecies AFs. The overall no observed adverse effect level (NOAEL) under the conditions of this study was 100 mg/kg bw/day based on body weight effects and the liver findings considered to be the result of an adaptive, detoxifying process. This value was used for DNEL derivation.

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

General Population - Hazard via oral 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):

200

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

AF for dose response relationship:

1

Justification:

NOAEL from an oral subchronic study

AF for differences in duration of exposure:

2

Justification:

extrapolation from subchronic to chronic

AF for interspecies differences (allometric scaling):

4

Justification:

ECHA Guidance, extrapolation from rat to human

AF for other interspecies differences:

2.5

Justification:

ECHA Guidance

AF for intraspecies differences:

10

Justification:

ECHA Guidance, variability within general population

AF for the quality of the whole database:

1

Justification:

Klimisch 1 study

AF for remaining uncertainties:

1

Justification:

The overall no observed adverse effect level (NOAEL) under the conditions of the 90d study was 100 mg/kg bw/day based on body weight effects and the liver findings considered to be the result of an adaptive, detoxifying process. This value was used for DNEL derivation. 

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

high hazard (no threshold derived)

Additional information - General Population

Acute/short-term exposure - systemic effects

N-Ethyl-2 -Pyrrolidone (NEP) has a low acute toxicity by all relevant routes of exposure as indicated by the LD₅₀/LC₅₀values of 3200 mg/kg bw, >52000 mg/kg bw and >5100 mg/m³(Aerosol) determined in rats for oral, dermal and inhalation exposure, respectively. Therefore, NMP is not subject to classification and labelling for acute toxicity and consequently no DNEL for acute/short-term exposure - systemic effects has to be established. This is in line with ECHA guidance on information requirements and chemical safety assessment, Chapter R.8.

Acute/short-term and long term exposure - local effects

Skin irritation/corrosion: NEP is not irritating to skin

Eye irritation: NEP causes irreversible damage to the eye (Category 1, H318). A quantitative assessment of eye irritation is not possible because only qualitative data from the relevant studies are available. Risk minimization measurements (goggles) have be applied when handling the concentrated substance. Concentration limits as provided by the CLP Regulation (EU GHS: EU Regulation 1272/2008 ) may serve as approximation for a eye irritation DNEL.

Respiratory irritation: No irritating effects on the respiratory tract in humans are known. Minimal to moderate signs of local irritation in the nasal cavity were observed in a 90d inhalation study in rats.

Skin sensitisation: Based on available animal data NEP is not supposed to be a skin sensitising substance and no DNEL concerning skin sensitising potential has to be established. This is in line with ECHA guidance on information requirements and chemical safety assessment, Chapter R.8.

Long term exposure - systemic effects

NEP may be an inducer of developmental toxicity / teratogenicity and is suspected of damaging fertility (Category 1B, H360Df).

Inhalation exposure: Inhalation exposure of rats to N-ethyl-2-pyrrolidone vapors for 90 days (65 exposures) did not lead to any exposure-related effect in clinical chemistry of the blood and hematological examinations. Clinical signs of toxicity indicated local irritation in the nasal cavity of the test substance at 200 mg/m3. In concordance with the clinical observation, histological examination revealed some effect in nasal cavity. These effects were observed in a concentration-related manner. Under the current test conditions, the NOAEC for local effect in nasal cavity was 60 mg/m3 and is used for DNEL derivation. No signs of systemic toxicity occurred up to the highest tested concentration of 200 mg/m3.

Dermal exposure: In order to derive a DNEL for dermal exposure, the NOAEL of 100 mg/kg bw/day assessed in the oral repeated dose toxicity study in rats is used. A route to route extrapolation from oral to dermal toxicity studies is in accordance with ECHA guidance on information requirements and chemical safety assessment, Chapter R.8.

Oral exposure:In a 90-day study according to OECD 408 groups of 10 male and 10 female Wistar rats received doses of 0, 100, 300 and 1000 mg N-Ethyl-2 -pyrrolidone/kg body weight/day over a period of 3 months via their diet. The study included FOB examinations and additional reproductive toxicity parameters. Substance-related adverse effects at 1000 and 300 mg/kg bw/day in both sexes and 100 mg/kg bw/day in males. The target organs identified in this study were liver and kidneys. The kidney effects were considered to be initial stages of an alpha 2u nephropathy in the male rat as substantiated by immunohistochemical staining. Alpha 2u nephropathy is assessed to be not relevant to humans as it is induced by a rat-specific mechanism. The effects on the liver may still be considered to be a detoxifying, adaptive effect because no signs for cytotoxicity were recorded. In addition,sperm analysis revealed an increased number of sperms with abnormal heads in males at 1000 mg/kg. Therefore, the overall no observed adverse effect level (NOAEL) under the conditions of this study was 100 mg/kg bw/day in females based on body weight effects and the liver findings considered to be the result of an adaptive, detoxifying process. The LOAEL in males was < 100 mg/kg bw/day (alpha 2u nephropathy).