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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

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1963
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

Constituent 1
Chemical structure
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 / concentrationsopen allclose all
Dose / conc.:
413 mg/kg bw/day (nominal)
Remarks:
cited as 0.4 mL/kg bw/d
Dose / conc.:
826 mg/kg bw/day (nominal)
Remarks:
cited as 0.8 mL/kg bw/d
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

open allclose all
Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Effect level:
826 mg/kg bw/day
Sex:
male
Basis for effect level:
mortality
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.

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