N-methylacetamide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Meets scientific standards with acceptable restrictions (one dose; partly limited documentation, e.g. no details about the test substance).

Data source

Reference

Reference Type:

publication

Title:

An investigation on the relationship between the hepatotoxicity and the metabolism of N-alkylformamides

Author:

Kestell P, Threadgill MO, Gescher A, Gledhill AP, Shaw AJ, Farmer PB

Year:

1987

Bibliographic source:

J Pharmcol Exp Therap 240: 265-270

Materials and methods

Objective of study:

metabolism

Principles of method if other than guideline:

Metabolism in mice after i.p. injection

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

N-methylacetamide

EC Number:

201-182-6

EC Name:

N-methylacetamide

Cas Number:

79-16-3

Molecular formula:

C3H7NO

IUPAC Name:

N-methylacetamide

Details on test material:

Source: Aldrich Chemical Co.
no further details

Radiolabelling:

no

Test animals

Species:

mouse

Strain:

other: CBA/CA

Sex:

male

Details on test animals or test system and environmental conditions:

Body weight: 18-25 g
no further details

Administration / exposure

Route of administration:

intraperitoneal

Vehicle:

physiological saline

Details on exposure:

injection volume: 0.2 ml per animal

Duration and frequency of treatment / exposure:

Single application

Doses / concentrations

Remarks:

Doses / Concentrations:
400 mg/kg bw

No. of animals per sex per dose / concentration:

6

Control animals:

no

Details on study design:

- Dose selection rationale: comparison with other amides in this study using the same dose level; no toxic effects of the test substance even at a dose level of 3000 mg/kg bw (41.1 mmol/kg; liver enzymes measured and body weight gain)

Details on dosing and sampling:

Urine collected 0-24 h after i.p. injection.

Results and discussion

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

2.0 +- 2.0% (mean +- standard deviation) of the applied dose were excreted unchanged in urine.
54 +- 10% were excreted as N-hydroxymethylacetamide (n=5).

Applicant's summary and conclusion

Conclusions:

Idendification of N-hydroxymethylacetamide as the main metabolite in urine of mice treated with N-methylacetamide.

Executive summary:

Meets scientific standards with acceptable restrictions (one dose; partly limited documentation, e.g. no details about the test substance).

Mice received i.p. 400 mg/kg bw and metabolites in the 24 -h urine were determined. Only 2.0 +-2.0% of the applied dose were excreted unchanged but 54 +-10% as N-hydroxymethylacetamide. The metabolic pathway is clearly different from that of N-methylformamide and these differences are paralleled by differences in hepatotoxicity (no hepatotoxicity of N-methylacetamide even at a dose level of i.p. 3000 mg/kg bw but hepatotoxic effects of N-methylformamide at >=200 mg/kg bw)

Conclusion: Idendification of N-hydroxymethylacetamide as the main metabolite in urine of mice.