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Toxicological information

Basic toxicokinetics

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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: Study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Effect of dietary intake of trimethylamine on human metabolism of the industrial catalyst dimethylethylamine
Author:
Lundh T, Akesson B, Skerfving S
Year:
1995
Bibliographic source:
Occup Environ Med. 52(7):478-83.

Materials and methods

Objective of study:
metabolism
Principles of method if other than guideline:
metabolism of dimethylethylamine (DMEA) in human
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): DMEA
- Supplier: Janssen Chemical, Geel, Belgium
Radiolabelling:
no

Test animals

Species:
human
Sex:
male
Details on test animals and environmental conditions:
The participants were five healthy male volunteers (subjects A, B, C, D, and E), mean age 40 (range 25-55) years, body weight 81 (70-88) kg, and height 1.81 (1.75-1.91) m, all non-smokers. They were instructed not to eat fish or drink alcohol during the 24 hour period preceding the experiments, and to fast overnight (> 8 hours) before being given the amines.

The study design was approved by the ethics committee of Lund University, and all five subjects gave their informed consent to participate in the study.

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Duration and frequency of treatment / exposure:
once a week for six weeks
Doses / concentrations
Remarks:
Doses / Concentrations:
25 mg, pH adjusted to 7
No. of animals per sex per dose:
5 volunteers
Control animals:
no
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: blood samples (20 ml) were collected by venepuncture,
- Time and frequency of sampling: before and one hour after the doses of amines

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine was collected in polyethylene bottles,
- Time and frequency of sampling: before the start of the experiments, and 2, 4, 6, 8, and 24 hours after the doses of amines
- From how many persons: 5
- Method type(s) for identification: GC

Results and discussion

Preliminary studies:
Before amines were given, the median plasma concentrations of TMA and TMAO were 11 and 32 µmol/l, respectively. There were only minor
variations within and between the volunteers in the TMA concentrations (range 6-15 µmol/l). The range of TMAO concen trations was wider, 4-97 µmol/l, corresponding to TMAO fractions of 20% to 91% (median 72%). In all experiments the plasma DMA concentration was below the detection limit of our method (0·6 µmol/l). Neither DMEA nor DMEAO were found in plasma or in urine collected before the experiments, or in the
experiments where no DMEA was given. One hour after the start of control experiments without amines, the median plasma concentrations of TMA and TMAO were about the same as the baseline values (11 and 9 µmol/l, respectively; table 1). The median TMAO fraction was 50%. Median 24 hour urinary excretions of TMA and TMAO were 3·4 and 390 µmol, respectively, the TMAO fraction being 99%. There were only minor variations within and between the volunteers in urinary excretion of TMA and TMAO during the four two-hour periods with standardised diet and in the eight to 24 hour period (table 1).
Main ADME resultsopen allclose all
Type:
distribution
Results:
The median plasma DMEAO concentration was 1 µmol/l, and the DMEAO fraction 100%.
Type:
excretion
Results:
Median urinary excretion (0-24 hours) of DMEA was 1 0 µmol and that of DMEAO 275 µmol/l. 81% of the dose was excreted in urine
Type:
excretion
Results:
During the period, two to eight hours after the dose of DMEA, the half lives were 1.2-2.0 hours for DMEA, and 2.7-3.5 hours for DMEAO
Type:
excretion
Results:
Urinary DMA excretion to have increased during the first two-hour period after the dose from 0.7 to 5.6 µmol for 25 mg of DMEA

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
In only one subject (A), did the plasma DMEA concentration at one hour after the dose of DMEA exceed the detection limit of 0.04 µmol/l (table 1). The median plasma DMEAO concentration was 11 µmol/l and the DMEAO fraction 100%.
Details on excretion:
Median urinary excretion (0-24 hours) of DMEA was 1.0 µmol and that of DMEAO 275 µmol. The median Sum-DMEA value represented 81% of the DMEA dose given (table 2). The DMEAO fraction was 100% in all cases except subject A, where it was 1-2% lower.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
Dimethylethylamineoxide (DMEAO)

Applicant's summary and conclusion

Executive summary:

DMEA (0/25 mg) was given once weekly for six weeks to five healthy volunteers. Plasma was collected before and one hour after the doses, and urine 0-2, 2-4, 4-6, 6-8, and 8-24 hours after the doses. Specimens were analysed by gas chromatography with a nitrogen sensitive detector. DMEA was readily absorbed from the gastrointestinal tract and excreted in urine within 24 hours (81%) (Lundh et al., 1995).