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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally scientific accepted principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Experimental study on the metabolism of dimethylethylamine in man
Author:
Stahlbom B, Lundh T, Akesson B
Year:
1991
Bibliographic source:
Int. Arch. Occup. Environ. Health, 63, 305-310

Materials and methods

Objective of study:
absorption
excretion
metabolism
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Experimental study on the absorption, excretion and metabolism of dimethylethylamine after inhalation administration in man.
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
Ethyldimethylamine
EC Number:
209-940-8
EC Name:
Ethyldimethylamine
Cas Number:
598-56-1
Molecular formula:
C4H11N
IUPAC Name:
N,N-dimethylethanamine
Details on test material:
Purity: 99%
Source: JanssenChemical, Beerse, Belgium
Radiolabelling:
no

Test animals

Species:
human
Sex:
male
Details on test animals or test system and environmental conditions:
4 men were studied
respective ages: 33, 53, 35, 53 years old
respective weights: 75, 82, 75, 88 kg

Administration / exposure

Route of administration:
inhalation: vapour
Vehicle:
unchanged (no vehicle)
Details on exposure:
TYPE OF INHALATION EXPOSURE: whole body

Fresh air stream by an evaporizer, ie an electrically heated part of an air-stream tube, dose with DMEA through a motor-driven syringe with constant flow. The concentration of DMEA in the chamber was continuously monitored by an infrared spectrometer and by eight 1-h air samples obtained in impinger vessels.
Duration and frequency of treatment / exposure:
8 hours
Doses / concentrations
Remarks:
Doses / Concentrations:
10, 20, 40 and 50 mg/m3
No. of animals per sex per dose / concentration:
4 men in total
Control animals:
no
Positive control reference chemical:
none
Details on dosing and sampling:
Blood samples were obtained before the start of the exposure, 4h and 8h after., and six-times during the 16 h after the end of exposure.
Urine samples were collected before start, during the 2-h exposure periods, and after the end of exposure overnight up to 40h.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
DMEA uptake was readily absorbed by inhalation. The DMEA uptake calculated as the difference between the test-chamber amine concentration and the DMEA concentration in exhaled air was 87% (81-94%; all 14 experiments). There was no difference between individuals or between various exposure levels in the exhaled air concentration. Nor was there any systematic trend over the 8-h exposure.

The plasma concentration of DMEA increased during the first 4h. From 4h to 8h, there was no increase of the DMEA concentration. The DMEAO plasma concentration increased during 8h exposure for all subjects and seemed not to reach a steady state level. After the end of exposure, the plasma concentration in DMEA and DMEAO decreased. At 24hafter the start of exposure, the plasma concentration of DMEA ranged from below the detection limit to 0.08µmol/l and the concentration of DMEAO from 0.13 to 0.84µmol/l.
Details on excretion:
The major part of the inhaled DMEA was biotransformed into dimethylethylamine-N-oxide (DMEAO). Even in the urine sampling period 0-2 h, the DMEAO fraction of the combined DMEA and DMEAO was 76% (range 63-85%; all 14 experiments). The average DMEAO fraction in plasma at the end was 90% (range 85-94%). No DMEA or DMEAO was found in the preexposure samples.

After the end of exposure, there was only minor elimination of DMEA by exhalation. The concentration in exhaled air (percentage of exposure level) in the four subjects at 1h and 2h after exposure ranged from 0.2% to 1.2% and from 0.1% to 0.4%, respectively.

Urinary excretion
The urinary DMEA increased during the first 6h. In the exposure period from 6h to 8h, there was no further increase in DMEA urinary excretion.
The DMEAO excretion increased throughout the 8h-exposure period and did not reach a steady state.
The total amount of DMEA and DMEAO excreted into the urine during 24h after exposure accounted for 100-140% of the calculated DMEA uptake.
The average DMEAO fraction as calculated over a 24-h urine-sampling period, was 90%. Two subjects displayed considerably lower DMEAO fraction, 75 and 81%, respectively. In these experiments the CLr was high in both subjects: 39 and 29l/h.
Toxicokinetic parametersopen allclose all
Toxicokinetic parameters:
other: half life (DMEA)=1.3h
Toxicokinetic parameters:
other: half life (DMEAO)=3.0h

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
N-oxidation (dimethylethylamine-N-oxide, DMEAO) but no dealkylation was found.

Any other information on results incl. tables

Plasma concentrations and urinary excretion of dimethylethylamine (DMEA) and dimethylethylamine-N-oxide (DMEAO), and pharmacokinetics in four volunteers exposed (inhalation for 8 h) to four different levels of DMEA
Subject (no.) Exposure level (mg/m3) Plasma concentrations  Urine Clearance Distribution volume (l)
DMEA (µmol/l) DMEAO (µmol/l)  Half-life b Recovery c (mmol/l) DMEAO fraction d (%)  Renal Non-renal
DMEA (h) DMEAO (h) DMEA (l/h) DMEAO (l/h) DMEA (l/h)
1 8.4 0.3 3.7 1.3 (7) 2.4 (6) 0.44 95 7.4 10 130 290
21 0.9 8.5 1.4 (4) 2.5 (6) 0.98 90 13 10 110 220
38 1.6 18.5 1.9 (11) 2.7 (7) 2.3 94 9.2 11 150 300
51 1.9 21.8 1.4 (9) 2.3 (e) 2.9 92 15 18 170 340
2 7.8 0.3 3.9 1.3 (6) 2.7 (5) 0.49 90 17 11 180 260
42 1.6 14.1 1.2 (5) 2.5 (10) 2.3 75 39 11 140 310
53 1.9 19.4 1.5 (11) 2.9 (10) 2.8 89 21 13 170 290
3 8.4 0.3 3.2 3.2 (4) 2.1 (8) 0.43 93 11 11 160 310
21 0.7 7.6 1.1 (4) 2.0 (7) 0.77 94 7.5 8.6 120 240
38 1.4 20.4 1.3 (12) 2.3 (10) 1.6 90 14 7.4 130 310
51 1.7 18.4 1.3 (4) 2.4 (9) 1.9 92 10 10 120 260
4 7.8 0.3 3.7 1.6 (e) 3.3 (7) 0.55 89 12 12 190 480
42 1.4 12.9 1.5 (8) 2.8 (8) 2.3 81 29 14 160 370
53 1.7 21.1 1.0 (8) 2.1 (10) 3.5 92 22 14 260 410
a At end of exposure
b First phase, second phase in parenthesis
c The sum of DMEA and DMEAO excreted during and 24 h after the end of the exposure
d DMEAO as percentage of DMEA and DMEAO combined
e No certain second phase

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Executive summary:

During 8 h, four healthy volunteers were exposed to four different DMEA air concentrations (10, 20, 40 and 50mg/m3; 20mg/m3, two subjects only). DMEA was biotransformed into dimethylethylamine N-oxide (DMEAO). On average, DMEAO, accounted for 90% of the combined amount of DMEA and DMEAO excreted into the urine. The half-lives of DMEA and DMEAO in plasma were 1.3 and 3.0 h, respectively. The urinary excretion of DMEA and DMEAO followed a two-phase pattern. The half-lives in the first phase were 1.5 h for DMEA and 2.5 h for DMEAO. In the second phase, which started about 9 h after the end of exposure, half-lives of 7h for DMEA and 8 h for DMEAO were recorded. The combined concentration of DMEA and DMEAO, in both plasma and urine, showed an excellent correlation with the air concentration of DMEA. Thus, both urinary excretion and plasma concentration can be used for biological monitoring of exposure to DMEA. An 8-h exposure to 10 mg DMEA/m3 corresponds to a post-exposure plasma concentration and 2-h post-exposure urinary excretion of 4.9 µmol/1 and 75 mmol/mol creatinine, respectively.