Registration Dossier

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

Constituent 1
Chemical structure
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.