N-(1,1-dimethyl-3-oxobutyl)acrylamide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1981

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Publication in a recognised journal.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1981

Materials and methods

Objective of study:

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The in vitro biotransformations of acrylamide and ten related compounds in the hepatic enzyme system of the mouse were studied in order to learn more about their toxic actions in vivo.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

diacetone acrylamide

IUPAC Name:

diacetone acrylamide

Details on test material:

Supplier: Tokyo Kasei Co.

Radiolabelling:

no

Test animals

Species:

mouse

Strain:

other: ddY

Sex:

male

Details on test animals or test system and environmental conditions:

- Age at study initiation: 5-6 weeks- Weight at study initiation: 29 +- 2.2 g

Administration / exposure

Details on exposure:

Animals received i.p. injections of sodium phenobarbital at a 50 mg/kg dose level for five successive days, up until a day before they were killed.

Results and discussion

Main ADME results

Type:

metabolism

Metabolite characterisation studies

Metabolites identified:

no

Details on metabolites:

In vitro metabolism of acrylamide analogues in hepatic microsomal systems:In order to assess whether the test compounds underwent metabolism by hepatic microsomal enzymes, the reaction mixtures were subjected to g.l.c. at 0, 30, 60, and 90 min of incubation. A decrease in the substrate concentration was visible with time under the NADPH-generating system for diacetone acrylamide. Two metabolites were detected with retention times of 12.8 and 16.6 min; the retention time of diacetone acrylamide was 7.38 min. The metabolites could not be identified.Kinetic constant of diacetone acrylamide for hepatic microsomal enzymes: Km = 3.83 mM; Vmax = 2.79 nmol metabolized/mg protein/min.Effect of phenobarbital pretreatment on the rate of metabolism in the mouse hepatic microsomal enzyme system:Vmax without PB: 2.97 nmol metabolized/mg protein/min; Vmax with PB: 6.93 nmol metabolized/mg protein/minGlutathione S-transferase activity (nmol glutathione decreased/h/mg protein) in mouse liver cytosol for diacetone acrylamide as substrate, with and without PB treatment:Without PB: 11.5; with PB: 18.0

Applicant's summary and conclusion

Conclusions:

Diacetone acrylamide is metabolised in vitro by hepatic microsomal enzymes and by a glutathione conjugation reaction. The metabolites could not be identified. The metabolic reactions are enhanced by phenobarbital pretreatment, but none of the compounds investigated seems to be bioactivated by the metabolic inducer.

Executive summary:

The in vitro biotransformations of acrylamide and ten related compounds in the hepatic enzyme system of the mouse were studied in order to learn more about their toxic actions in vivo.

Diacetone acrylamide is metabolised in vitro by hepatic microsomal enzymes and by a glutathione conjugation reaction. The metabolites could not be identified. The metabolic reactions are enhanced by phenobarbital pretreatment, but none of the compounds investigated seems to be bioactivated by the metabolic inducer.