1-methyl-2-pyrrolidone

Repeated dose toxicity: dermal

Administrative data

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1963

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1963

Reference 2

Reference Type:

other company data

Title:

Unnamed

Year:

1986

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)

Deviations:

yes

Remarks:

only 2 animals per dose group and sex instead of 5 as required by guideline

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

1-methyl-2-pyrrolidone

EC Number:

212-828-1

EC Name:

1-methyl-2-pyrrolidone

Cas Number:

872-50-4

Molecular formula:

C5H9NO

IUPAC Name:

1-methylpyrrolidin-2-one

Test material form:

liquid

Specific details on test material used for the study:

Methyl pyrrolidone - tested as supplied.

Test animals

Species:

rabbit

Strain:

other: albino

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: approx. 1.8 - 2.3 kg
- Acclimation period: 2 weeks

Administration / exposure

Type of coverage:

not specified

Vehicle:

not specified

Details on exposure:

Route of Administration: dermal

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

20 days

Frequency of treatment:

5 days/week

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

413 mg/kg bw/day (nominal)

Remarks:

cited as 0.4 mL/kg bw/d

Doses / concentrations 2

Dose / conc.:

826 mg/kg bw/day (nominal)

Remarks:

cited as 0.8 mL/kg bw/d

Doses / concentrations 3

Dose / conc.:

1 653 mg/kg bw/day (nominal)

Remarks:

cited as 1.6 mL/kg bw/d

No. of animals per sex per dose:

2 rabbits with intact skin
2 rabbits with abraded skin

Control animals:

not specified

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes

DERMAL IRRITATION (if dermal study): Yes

BODY WEIGHT: Yes
- Time schedule for examinations: Twice weekly

FOOD CONSUMPTION:
- No data

FOOD EFFICIENCY:
- No data

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At the beginning and at the end of the study
- Anaesthetic used for blood collection: No data
- Animals fasted: No data

CLINICAL CHEMISTRY: Yes

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Mild local skin irritation was noted after repeated dosing.
At 0.4 and 0.8 mL/kg bw/day (corresponding to 413 and 826 mg/kg bw/day), no systemic signs of toxicity substantiated by clinical examinations.

Dermal irritation:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Description (incidence):

At 1.6 mL/kg bw/day (corresponding to 1,653 mg/kg bw/day) 1/4 animals died (abraded skin). 

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Description (incidence and severity):

At 0.4 and 0.8 mL/kg bw/day (corresponding to 413 and 826 mg/kg bw/day), no systemic signs of toxicity substantiated by hematological examinations.

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

At 0.4 and 0.8 mL/kg bw/day (corresponding to 413 and 826 mg/kg bw/day), no systemic signs of toxicity substantiated by histopathological examinations.

Histopathological findings: neoplastic:

not specified

Details on results:

No further findings occurred in the surviving animals.

Effect levels

1

Dose descriptor:

NOAEL

Remarks:

systemic toxicity

Effect level:

826 mg/kg bw/day

Sex:

male

Basis for effect level:

mortality

2

Dose descriptor:

LOAEL

Effect level:

1 653 mg/kg bw/day

Sex:

male

Basis for effect level:

mortality

Target system / organ toxicity

Critical effects observed:

no

Applicant's summary and conclusion

Conclusions:

The NOAEL for local irritation was <413 mg/kg bw/day (cited as 0.4 mL/kg bw/day) due to mild local skin irritation noted at all dose levels tested.

Executive summary:

The subacute dermal toxicity of NMP was investigated in male albino rabbits. Groups of two rabbits each received concentrations of 0, 413, 826 or 1653 mg/kg bw/day (cited as 0, 0.4, 0.8 or 1.6 mL/kg bw/day) on the intact or abraded skin, applied once a day, 5 days per week, for a total period of 4 weeks. Mild local skin irritation was noted after repeated dosing at 413 mg/kg bw/day and above. Beside the death of one rabbit with abraded skin after one week of treatment out of four in total, which received 1653 mg/kg bw/day, no further signs of systemic toxicity was noted by clinical, hematological and histopathological examinations.

Thus, the NOAEL for systemic toxicity was 826 mg/kg bw/day, while for local irritation no NOAEL could be obtained after repeated application due to missing effects.

This toxicity study in the rabbit is acceptable and satisfies the general guideline requirements for a repeat-dose dermal toxicity study (OECD 410) in rabbits with some restrictions due to the fact that the study was performed prior to the date of guideline publication.