1-methyl-2-pyrrolidone

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

14.4 mg/m³

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

12.5

Dose descriptor starting point:

NOAEC

Value:

360 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

180 mg/m³

Explanation for the modification of the dose descriptor starting point:

The NOAEC has to be corrected for the differences in respiratory volume of animal and worker (6.7/10) and for the duration of daily exposure (6/8) of workers according to 'Reach guidance on information requirements and chemical safety assessment, Chapter R.8, November 2012'.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

No time extrapolation is required for developmental toxicity as increasing exposure duration does not increase the incidence or severity of adverse effects.

AF for interspecies differences (allometric scaling):

1

Justification:

The AF has already been handled within the correction of the modification of the dose descriptor.
Therefore, no additional factor has to be applied.

AF for other interspecies differences:

2.5

Justification:

The default AF for other interspecies differences, i.e. toxicokinetic/-dynamic differences is used.

AF for intraspecies differences:

5

Justification:

The default factor of 5 for workers is set in line with the REACH guidance.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

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:

40 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

other: The health-based occupational exposure limit (OEL, 8-hour TWA) provided in: "Recommendation from the Scientific Committee on Occupational Exposure Limits for N-Methyl-2 -Pyrrolidone" (SCOEL, 2007) is used as worker DNEL for long-term inhalation exposure.

Overall assessment factor (AF):

2

Dose descriptor:

NOAEC

Value:

80 mg/m³

AF for dose response relationship:

1

AF for differences in duration of exposure:

1

AF for interspecies differences (allometric scaling):

1

AF for other interspecies differences:

1

AF for intraspecies differences:

1

AF for the quality of the whole database:

1

AF for remaining uncertainties:

2

Justification:

SCOEL describes an AF of 2 as adequate to account for identified and remaining uncertainties.

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

4.8 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

50

Dose descriptor starting point:

NOAEL

Value:

237 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

237 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation is necessary since a developmental toxicity study via dermal route is available.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

No time extrapolation is required for developmental toxicity as increasing exposure duration does not increase the incidence or severity of adverse effects.

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

2.5

Justification:

The default AF for other interspecies differences, i.e. toxicokinetic/-dynamic differences is used.

AF for intraspecies differences:

5

Justification:

The default factor of 5 for workers is set in line with the REACH guidance.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

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

 
NMP has a low acute toxicity by all relevant routes of exposure as indicated by the LD50/LC50 values of 4150 mg/kg bw, > 5000 mg/kg bw and > 5100 mg/m³ determined in rats for oral, dermal and inhalation exposure, respectively. Therefore, NMP is not subject to classification and labelling.

Inhalation exposure:

The RAC value of 14.4 mg/m³ is considered to represent the appropriate worker DNEL (long-term inhalation exposure).

NMP is considered to be an inducer of developmental toxicity / teratogenicity (Category 1B, H361).

There are no relevant effects/hazards reported for an acute/short-term inhalation exposure.

 
Dermal exposure:

The RAC value of 4.8 mg/kg is considered to represent the appropriate worker DNEL (systemic effects from combined exposure).

Apart from accident reports under occupational conditions, there are no relevant effects/hazards reported for an acute/short-term dermal exposure.

NMP is considered to be an inducer of developmental toxicity / teratogenicity (Category 1B, H361).

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

Inhalation exposure:

The SCOEL 8 -hour TWA value of 40 mg/m³ (10 ppm) is considered to represent the appropriate worker DNEL (long-term inhalation exposure).

[For comparison: Considering the NOAEC from the key repeated dose inhalation toxicity study (BASF SE, 1994) in the rat as relevant dose descriptor and taking the starting point modification and assessment factors into account, the worker DNEL can be calculated as follows:
Relevant dose descriptor (NOAEC): 125 ppm (0.5 mg/L/ 500 mg/m3)
Modification of the starting point factor (to light work): not necessary as a dose response is not considered for the effect
Exposure duration factor (sub-chronic to chronic): 2
Interspecies factor (rat-to-worker): 5
Intraspecies factor (no toxicokinetic/-dynamic differences expected due to local irritational effects): 1
Extrapolation factor (NOAEC): 1
Quality of database factor: 1
worker DNEL (long-term inhalation exposure) = 500 mg/m3 /(2 × 5) = 50 mg/m3 (12 ppm)]

The SCOEL STEL value of 80 mg/m³ (20 ppm) is considered to represent the appropriate worker DNEL (acute/short-term inhalation exposure).

Skin irritation/corrosion:

NMP is irritating to skin (Category 2, H315). Dermal irritation is not reliably quantifiable based on the available dataset. Accordingly, no worker DNEL for skin irritation is derived.
 
Eye irritation:

NMP is a mild eye irritant (Category 2, H319). A quantitative assessment of eye irritation is not possible because only qualitative data from the relevant studies are available.
 
Respiratory irritation:

NMP is irritating to the respiratory system (Category 3, H335). Based on the lack of dose-response information, no DNEL is derived for this endpoint. However, the health-based occupational exposure limits of 80 mg/m³ (20 ppm; 15-min STEL) and 40 mg/m³ (10 ppm; 8-hour TWA) provided in the "Recommendation from the Scientific Committee on Occupational Exposure Limits for N-Methyl-2-Pyrrolidone" (SCOEL) are considered to adequately protect against respiratory irritation following acute / short-term and long term exposure, respectively.
 
Skin sensitisation:

NMP is not considered to be a skin sensitising substance and no DNEL for a possible skin sensitising potential has to be established.
 
This is in line with ECHA guidance on information requirements and chemical safety assessment, Chapter R.8 (2012).

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.6 mg/m³

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

By inhalation

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

25

Dose descriptor starting point:

NOAEC

Value:

360 mg/m³

Modified dose descriptor starting point:

NOAEC

Value:

90 mg/m³

Explanation for the modification of the dose descriptor starting point:

The NOAEC has to be corrected for the differences of the experimental exposure conditions compared to the duration of exposure for the population:

(animal study: 6h/d, 7d/w general population: 24 h/d, 7d/w) = (6/24)*(7/7)

according to ‘Reach guidance on information requirements and chemical safety assessment, Chapter R.8, November 2012’.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

No time extrapolation is required for developmental toxicity as increasing exposure duration does not increase the incidence or severity of adverse effects.

AF for interspecies differences (allometric scaling):

1

Justification:

No route to route extrapolation is needed and the dose of the animal study is assumed to be already scaled according to the allometric principle, since ventilation rate (dose expressed as concentration: mg/m3) directly depend on the basal metabolic rate.

AF for other interspecies differences:

2.5

Justification:

The default AF for other interspecies differences, i.e. toxicokinetic/-dynamic differences is used.

AF for intraspecies differences:

10

Justification:

The default factor of 10 for the general population is set in line with the REACH guidance.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

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:

4.5 mg/m³

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

20

Dose descriptor:

NOAEC

Value:

500 mg/m³

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

The standard factor for local tissue damage in the respiratory tract to correct for differences in the experimental exposure duration and the duration of exposure for the population and scenario under consideration for a sub-chronic study is used.

AF for interspecies differences (allometric scaling):

1

Justification:

Local effects are independent of the basal metabolic rate and allometric scaling is not applied.

AF for other interspecies differences:

1

Justification:

It is assumed that in terms of dynamics that animals and humans will respond to the insult in the same way. The default factor for remaining uncertainties of 2.5 is reduced to 1.

AF for intraspecies differences:

10

Justification:

The default factor of 10 for the general population is set in line with the REACH guidance.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

irritation (respiratory tract)

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.4 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

100

Dose descriptor starting point:

NOAEL

Value:

237 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

237 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation is necessary since a developmental toxicity study via dermal route is available.

The pregnant animals were exposed 8 h/d, hence an assessment for experimental exposure conditions does not need to be performed.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

No time extrapolation is required for developmental toxicity as increasing exposure duration does not increase the incidence or severity of adverse effects.

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

2.5

Justification:

The default AF for other interspecies differences, i.e. toxicokinetic/-dynamic differences is used.

AF for intraspecies differences:

10

Justification:

The default factor of 10 for the general population is set in line with the REACH guidance.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.85 mg/kg bw/day

Most sensitive endpoint:

neurotoxicity

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:

169 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

169 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The NOAEL (and the doses fed in th study) are given as ppm/animal in the original study. The most relevant effect with a conservative NOAEL was 3000 ppm observed in male rats and calculated by the study authors to equal 169 mg/kg bw/male rat.

No route to route extrapolation is necessary since an oral feedind study is available.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

2

Justification:

The standard factor for differences in the experimental exposure duration and the duration of exposure for the population and scenario under consideration for a sub-chronic study is used.

AF for interspecies differences (allometric scaling):

4

Justification:

The default allometric scaling factor for the differences between rats and humans is used.

AF for other interspecies differences:

2.5

Justification:

The default AF for other interspecies differences, i.e. toxicokinetic/-dynamic differences is used.

AF for intraspecies differences:

10

Justification:

The default factor of 10 for the general population is set in line with the REACH guidance.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

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

 
NMP has a low acute toxicity by all relevant routes of exposure as indicated by the LD50/LC50 values of 4150 mg/kg bw, > 5000 mg/kg bw and > 5100 mg/m³ determined in rats for oral, dermal and inhalation exposure, respectively. Therefore, NMP is not subject to classification and labelling.

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

Inhalation exposure:

The derived DNEL for local effects after long term exposure of 4.5 mg/m3 is considered to represent the appropriate general population DNEL.