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Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Well documented publication

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
The Urotoxic Effects of N,N'-Dimethylaminopropionitrile
Author:
Mumtaz M.M. et al.
Year:
1991
Bibliographic source:
Toxicol. and Appl. Pharmacol., 110, 61-69 (1991)
Reference Type:
publication
Title:
STUDIES ON THE MECHANISM OF UROTOXIC EFFECTS OF N,N'-DIMETHYLAMINOPROPIONITRILE IN RATS AND MICE. 1. BIOCHEMICAL AND MORPHOLOGIC CHARACTERIZATION OF THE INJURY AND ITS RELATIONSHIP TO METABOLISM
Author:
Mumtaz M.M. et al.
Year:
1991
Bibliographic source:
J. of Toxicology and Environm. Health 33, 1-17 (1991)

Materials and methods

Objective of study:
excretion
metabolism
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The metabolism and excretion of N,N'-Dimethylaminopropionitrile was studied in vitro and in vivo in rats and in vivo in mice.
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
3-dimethylaminopropiononitrile
EC Number:
217-090-4
EC Name:
3-dimethylaminopropiononitrile
Cas Number:
1738-25-6
Molecular formula:
C5H10N2
IUPAC Name:
3-(dimethylamino)propanenitrile
Details on test material:
- Name of test material (as cited in study report): DMAPN
- Analytical purity: 98%
Radiolabelling:
no

Test animals

Species:
other: rats and mice
Strain:
other: Sprague-Dawley and ICR
Sex:
male
Details on test animals or test system and environmental conditions:
Animals were obtained from Timco Laboratories (Houston, TX). The animals were acclimatized in an animal facility for a week prior to experimentation and allowed free access to food and water.

Administration / exposure

Route of administration:
oral: gavage
Duration and frequency of treatment / exposure:
in vivo: twice on one day
Doses / concentrations
Remarks:
Doses / Concentrations:
in vivo: 175, 350, or 525/700 mg DMAPN/kg body wt
No. of animals per sex per dose / concentration:
in vivo: 5
Control animals:
yes

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on excretion:
Animals treated with 525 mg DMAPN/kg or equimolar doses of commercially available potential DMAPN metabolites showed varying levels of urinary retention. About 44% of the administered dose of DMAPN was excreted unchanged in 5 days, while mice excreted only about 6% of the dose.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
in vivo: ß-Aminopropionitrile and cyanoacetic acid were identified as urinary metabolites. The urinary excretion of cyanoacetic acid was nonlinearly proportional to the volume of urine retained in the bladders.

Any other information on results incl. tables

In vitro the metabolism of DMAPN to cyanide, formaldehyde and cyanoacetic acid was localized mostly in the microsomal fraction of liver, kidney and urinary bladders.

Other findings (enzyme modulation tests with activators and inhibitors of the CYP-450 system) indicate that DMAPN is primarily metabolized via a cytochrome P450-dependent mixed-function oxidase system and that the urotoxic effects of DMAPN may be related to this metabolism.

 

The biochemical effects of DMAPN included depletion of glutathione and increased lipid peroxidation in target organs, including urinary bladder and kidney. These studies indicate that there are species differences in DMAPN toxicity. The differences

may be due to differences in the formation of reactive metabolic intermediates of DMAPN.

Applicant's summary and conclusion