1-methyl-2-pyrrolidone

Endpoint summary

Description of key information

The LD50/LC50 values derived from the key studies were:
LD50 (oral, rat) 4150 mg/kg bw, similar to OECD 401, Ansell and Fowler, 1988;
LC50 (inhalation, rat) > 5100 mg/m³, OECD 403, 1988;

LD50 (dermal, rat) > 5000 mg/kg bw, OECD 402, 1984.

Based on these results, NMP is of low acute toxicity.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1988

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

The test parameters documented do not totally comply with the specific testing guideline.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

1987-02-24

Deviations:

not specified

Remarks:

No test doses are given, only LD50 discussed.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

- Source: GAF Chemicals Corporation, Wayne, NJ, USA
- Purity: >= 98%, with less than 0.5% of water

Species:

rat

Strain:

Sprague-Dawley

Remarks:

albino rats

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: young adult
- Weight at study initiation: 200 - 300 g
- Fasting period before study: 18 - 24 h
- Diet: ad libitum
- Water: ad libitum

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

None

Doses:

Not indicated, LD50 is given

No. of animals per sex per dose:

5 (No. of groups as described in the publication: 6)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations: daily
- Necropsy of survivors performed: not specified, but animals that died were observed for gross necropsy
- Other examinations performed: clinical signs, pharmacological activity

Statistics:

The oral LD50 including 95 % confidence limits was calculated using the method of Litchfield and Wilcoxon (1949).

Sex:

male/female

Dose descriptor:

LD50

Effect level:

4 150 mg/kg bw

Based on:

test mat.

95% CL:

3 100 - 5 560

Mortality:

Mortality is only given as LD50 value.

Clinical signs:

other: Ataxia and diuresis at high but sublethal doses (1/8 LD50).

Gross pathology:

Irritation of the pyloric and/or gastro-intestinal mucosa was typically noted with darkening of kidneys, liver and lungs in non-survivors.

Other findings:

No data

Interpretation of results:

GHS criteria not met

Conclusions:

NMP is of low toxicity and the oral LD50 was 4150 mg/kg bw (95 % confidence limits: 3100 - 5560 mg/kg bw).

Executive summary:

The acute oral toxicity of NMP was investigated in male and female Sprague-Dawley rats. The animals were administered graded doses of the neat test substance and observed for 14 days. Clinical signs at high but sublethal doses included ataxia and diuresis (at 1/8 LD50). The oral LD50 was 4150 mg/kg bw (95 % confidence limits: 3100 - 5560 mg/kg bw). NMP is of low toxicity based on the oral LD50 and will not be classified under Regulation (EC) No. 1272/2008 but it has to be considered that a classification for low acute toxicity category 5 defined under UN GHS might be applicable.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

4 150 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1988

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

concentration x time method

Limit test:

yes

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: BASF AG

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: tightly closed container
- Stability under test conditions: guaranteed at least for the test period by the sponsor

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: no special pre-treatment performed

FORM AS APPLIED IN THE TEST: aerosol

Species:

rat

Strain:

Wistar

Remarks:

SPF-Wistar/Chbb:THOM

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Dr. K. Thomae, 7950 Biberach, Germany
- Age at study initiation: about 8-9 weeks old
- Weight at study initiation: 282 g (males, mean value), 187 g (females, mean value)
- Housing: groups of 5 animals in type DIII cages (Becker, Germany) without bedding material
- Diet: conventional laboratory diet (Kliba laboratory diet rat/mice 24-343-4, 10 mm pellet, Klingenthalmuehle AG, Kaiseraugst, Switzerland), ad libitum
- Water: drinking water, ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose/head only

Remarks:

System INA 20 (BASF AG, Germany)

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

4.6 µm

Geometric standard deviation (GSD):

2.1

Remark on MMAD/GSD:

- Particle size distribution: 87 % capable of entering alveoli
- MMAD50% = 4.6μm (geometric standard deviation = 2 .1)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: INA 20 head-nose inhalation system
- Exposure chamber volume: 55 L
- Method of holding animals in test chamber: animals were placed in tubes with their snouts extending into the inhalation space
- Source and rate of air: compressed air, 1500 L/h
- System of generating particulates/aerosols: continuous infusion pump (INFU, Indigel, Switzerland) and a dual nozzle (model 970, Schlick)
- Method of particle size determination: gas chromatography
- Temperature in air chamber: 19 - 25 °C

TEST ATMOSPHERE
- Brief description of analytical method used: For a test group, a sample for particle size analysis was taken at the earliest 30 min after the beginning of the test. Before sampling, the impactor was fitted with metallic collection disks and a filter for residual particles. The impactor was connected to the pump and the test apparatus, and a sample (9 L) was taken. The impactor was taken apart. The collection disks and the residual particle filter were rinsed with 2-propanol. The samples thus obtained were analyzed by a gas-chromatographic method. The contents of the preimpactor and the amounts of material deposited on the impactor walls (wall losses) were also determined quantitatively.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

From the analytical data and the volume of the inhalation atmosphere sample, the concentrations were calculated in mg/L.

Duration of exposure:

4 h

Concentrations:

5.1 mg/L

No. of animals per sex per dose:

5 rats

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations were performed at least once per working day, weekly body weight determination.
- Necropsy of survivors performed: yes

Statistics:

Statistical evaluation of the dose-response relation was performed based on the binomial test (Wittig H, 1974. Mathematische Statistik, p. 32-35).
Particle size distribution was calculated based on mathematical evaluation methods for particle measurements (Silverman L, 1971. Particle size analysis in industrial hygiene, p. 235-259).

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.1 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No mortality.

Clinical signs:

other: Accelerated, irregular breathing, slightly reddish nasal secretion and reduced pain sensitivity during exposure. Accelerated breathing, fur on head reddish coloured (blood test positive) and urine yellow coloured (metabolite effect) after exposure. There

Body weight:

Over the entire follow-up period, the body weight gain of the females in the test group remained unchanged relative to that in a historic control group. The body weight gain of the males in the test group relative to that in a historic control group was slightly retarded during the first follow-up week, but became normal during the second week.

Gross pathology:

Reddish-brown foci were noted in all lobes of the lungs (probably caused by aspiration).

Interpretation of results:

GHS criteria not met

Conclusions:

There was no mortality observed and therefore the LC was >5.1 mg/L.
Apart from local effects, such as slightly reddish nasal secretion and reddish-brown foci in all lobes of the lungs no further effects were observed which were not reversible.

Executive summary:

The acute inhalation toxicity of NMP was investigated at a single concentration of 5.1 mg/L in a group of 5 male and 5 female Wistar rats following head-nose exposure for 4 hours of a vapour/aerosol mixture with a mass median aerodynamic diameter (MMAD) of 4.6 µm. The respirable fraction was 87 %. Observation period was 14 days. No animal died and all gained body weight. The LC50 was >5.1 mg/L after 4 hours. NMP is classified as being of low toxicity based on the LC50 in males and females.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating conc.

Value:

5 100 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1984

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

not specified

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 196 - 237 g

Type of coverage:

occlusive

Vehicle:

not specified

Details on dermal exposure:

TEST SITE
- % coverage: approximately 20 - 25 % of the body surface
- Type of wrap if used: occlusive dressing, elastic adhesive bandage backed with aluminium foil

REMOVAL OF TEST SUBSTANCE
- Washing: yes
- Time after start of exposure: following bandage removal after 24 hours

TEST MATERIAL
- Amount(s) applied: 2 mL at maximum

Duration of exposure:

24 hours

Doses:

1300, 2500, 5000, 10000 mg/kg bw

No. of animals per sex per dose:

2 rats

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

1/2 males and 2/2 females treated at 10000 mg/kg bw died within 48 hours.

Clinical signs:

other: Hunched posture was noted at 2500 and 10000 mg/kg bw, lethargy was observed at 5000 and 10000 mg/kg bw

Gross pathology:

No data

Interpretation of results:

GHS criteria not met

Conclusions:

The LD50 value was >5000 mg/kg bw.

Executive summary:

The acute dermal toxicity of NMP was investigated in each 2 male and 2 female Sprague-Dawley rats. The rats were exposed to the undiluted test substance on shaved skin under an occlusive dressing for 24 hours. The animals were observed for 14 days for mortality and signs of toxicity. The LD50 value was >5000 mg/kg bw. NMP is of low toxicity based on the LD50 value determined for males and females.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

5 000 mg/kg bw

Additional information

NMP has a low acute toxicity by oral, dermal, inhalation, intraperitoneal, and intravenous routes of exposure.

An oral LD50 value was determined to be 4150 mg/kg bw and the dermal LD50 value was above 5000 mg/kg bw in rats. Reliable inhalation exposure studies were generally conducted with a vapor/aerosol mixture. The valid LC50 was > 5100 mg/m³. Based on these results, NMP has a low acute toxicity.

Oral route (Ansell and Fowler, Fd. Chem. Toxicol. 26, 1988):

The acute oral toxicity of NMP was investigated in male and female Sprague-Dawley rats. The animals were administered graded doses of the neat test substance and observed for 14 days. Clinical signs at high but sublethal doses included ataxia and diuresis (at 1/8 LD50). The oral LD50 was 4150 mg/kg bw (95 % confidence limits: 3100 - 5560 mg/kg bw). NMP is of low toxicity based on the oral LD50 and will not be classified under Regulation (EC) No. 1272/2008 but it has to be considered that a classification for low acute toxicity category 5 defined under UN GHS might be applicable.

Inhalation route (BASF, 1988):

The acute inhalation toxicity of NMP was investigated at a single concentration of 5.1 mg/L in a group of 5 male and 5 female Wistar rats following head-nose exposure for 4 hours of a vapour/aerosol mixture with a mass median aerodynamic diameter (MMAD) of 4.6 µm. The respirable fraction was 87 %. Observation period was 14 days. No animal died and all gained body weight. The LC50 was >5.1 mg/L after 4 hours. NMP is classified as being of low toxicity based on the LC50 in males and females.

Dermal route (Clark et al., Int. Res. Comm. System Med. Sci. 12, 1984):

The acute dermal toxicity of NMP was investigated in each 2 male and 2 female Sprague-Dawley rats. The rats were exposed to the undiluted test substance on shaved skin under an occlusive dressing for 24 hours. The animals were observed for 14 days for mortality and signs of toxicity. The LD50 value was >5000 mg/kg bw. NMP is of low toxicity based on the LD50 value determined for males and females.

Justification for classification or non-classification

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. As a result the substance does not need to be classified and labelled for acute toxicity (oral, dermal and inhalation) under Regulation (EC) No 1272/2008, as amended for the sixth time in Regulation (EC) No 605/2014.