Triethylamine

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

January 1988

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well-documented publication, which meets basic scientific principles

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

publication

Title:

Experimental study on the metabolism of triethylamine in man

Author:

Akesson B., Skerfving S. et al.

Year:

1988

Bibliographic source:

Br. J. Ind. Med. 45,|262-268, (1988)

Materials and methods

Objective of study:

metabolism

Principles of method if other than guideline:

no data

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Triethylamine

EC Number:

204-469-4

EC Name:

Triethylamine

Cas Number:

121-44-8

Molecular formula:

C6H15N

IUPAC Name:

triethylamine

Details on test material:

- Name of test material (as cited in study report): Triethylamine
- Substance type: organic
- Stability under test conditions: stability of urine samples with respect to TEA and triethylamine-N-oxide (TEAO) was excellent; no loss of TEA or TEAO was found at storage at 25'C with or without additions for three weeks and not in acidified samples stored at 4°C for one year.
- Storage condition of test material: at 4 °C in polyethylene bottles for acidified 82 ml concentrated HCl per 100 ml) urine samples or at 4°C for acidified (0.5 ml 1 M HCl) 2ml plasma samples

Radiolabelling:

no

Test animals

Species:

human

Strain:

other: not applicable

Sex:

male

Details on test animals or test system and environmental conditions:

Five healthy male volunteers,
age 46-52 (mean 49)
body weight 78-84 (mean 82) kg,
height 1.075-1.84 (mean 1.81) m

Administration / exposure

Route of administration:

inhalation

Vehicle:

other: air

Details on exposure:

TEA vapour was administered to the air stream entering the chamber and concentration in the chamber was continuously monitored by infrared spectrometry and at intervals by air sampling. The amine level in the chamber was stable, with a deviation of less than 4% from the target value.
Each individual was exposed on different occasions to air concentrations of TEA in the chamber of about 10 (range 8.9-9.9) and 20 (range 18.5-20.2) mg/m3. The exposure lasted eight hours. In addition, two subjects were exposed to 34 mg/m3, and one to 53 mg/m3, for four hours.

Duration and frequency of treatment / exposure:

4 or 8 hours

Doses / concentrations

Remarks:

Doses / Concentrations:
10; 20; 35 and 50 mg/m3

No. of animals per sex per dose / concentration:

5 humans

Control animals:

not specified

Positive control reference chemical:

not applicable

Details on study design:

- Dose selection rationale: also higher doses as found in industrial workers (>20 mg/m3)
The total experience indicates that the time weighted average (TWA) exposure in the workroom should not exceed 10 mg/m3.

Details on dosing and sampling:

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, venous blood, expiratory air
- Time and frequency of sampling: see below
- Method type(s) for identification: gas liquid chromatography
- Limits of detection and quantification: 0.01 mg/m3 for air samples (15 liter sample), 0 .1 µmol TEA/I urine and plasma

Urine was sampled at the start of exposure and then for periods of two hours during the exposure period, during four successive two hour periods after the end of exposure, and then during an additional seven hours, and at least during two additional four hour periods.
On four occasions, venous blood was sampled during exposure, as well as one and two to three hours after the end of exposure.
In one subject, at two different exposure concentrations, expiratory air was sampled during the final 10 minutes ofeach two hour exposure period and one and two hours after the end of exposure. Expired air was collected with a Douglas bag from all subjects while sitting in the chamber (reading) to determine the respiratory rate.

Statistics:

no data

Results and discussion

Preliminary studies:

TEA may cause visual disturbances (Akesson, 1986 and 1985)

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Using the respiratory rate in combination with the air TEA concentrations, the mean amounts of inhaled TEA were calculated. In the 20 mg/m3 experiments the average was 929 µmol, in the 10 mg/m3 experiments 433 µmol. The corresponding mean amounts of U-TEA were 655 and 337 1smol during the exposure period and 23-32 hours after.
The concentrations of TEA in exhaled air are about 20% of those in inhaled air, with no trend during the exposure. This corresponds approximately to the difference between pulmonary ventilation and alveolar ventilation at rest. The exhaled amount corresponds to the fraction of the tidal volume occupied by the dead space. It is thus probable that the absorption of the TEA which reaches the alveolar region is complete. This is in agreement with the extreme water solubility of TEA.

Details on distribution in tissues:

24% of the exposure concentration was measured on the average in plasma and urine as a Triethylamine-N-Oxide.
The distribution was dependent upon the measured concentration in the urine, the half life amounted to 3.2 hours.
The plasma concentrations of TEA (P-TEA) increased in the four hour exposure sample on the four occasions studied (in three subjects). There was a further increase in the eight hour samples.

Details on excretion:

The plasma and urinary concentrations of TEA and TEAO decreased rapidly after the end of exposure
24% of the exposure concentration was measured on the average in plasma and urine as a Triethylamine-N-Oxide.
The distribution was dependent upon the measured concentration in the urine, the half life amounted to 3.2 hours.

The present data indicate that the major part of the absorbed TEA is excreted in the urine as such. If it is assumed that the absorption of the inhaled amount is 80% (vide supra) the median excretion in different experiments was 93%. The efficient excretion in urine is not surprising, considering the h gh water solubility of the compound.

During an eight hour exposure, the urinary concentration of TEA (U-TEA) was increased in the two hour period after onset of exposure, at exposure of 20 and 10 mg/m3. A continuous further increase followed and a steady state was not reached during the exposure as there was an increase between the 4-6 hour and the 6-8 hour samples. One subject showed an increase of U-TEA at both 20 and 10 mg/m3 0-2 hours after exposure. Another subject displayed a corresponding increase in the 20 mg/m3, but a decrease in his 10 mg/m3, experiment. In the other six experiments in three subjects there was a decrease. Later on, U-TEA decreased. During the 23-32 hours surveyed after the end of exposure, nobody reached the detection limit. The half lives of TEA excretion in urine after end of exposure at 10 mg/m3 averaged 3 1 (range 2 7-3-6) hours, and at 20 mg/m3, 3-4(2 5-45) hours. The fits to the exponential decay curves were good.

One hour after the end of exposure, Plasma TEA decreased in all experiments. The concentrations were still well above the dectection limit after 2-3 hours in all experiments.

The amounts of UTEAO were 219 and 103 µmol. The TEA and TEAO excreted in urine corresponds to an average of 97% (range 81-117) of the calculated inhaled amount of TEA.

In subject No 1 the exhalation of TEA was measured. The concentration before exposure was below the detection limit. Measurements were also made during the final 10 minutes in each two hour period of exposure. At an air TEA concentration of 20.1mg/m3, the level in exhaled air was 3.6-4.2 mg/m3 (18-21% of the concentration in inhaled air). One hour after end of exposure, the level was 0.2 mg/m3 and two hours after it was 0.1 mg/m3. At an air concentration of 9.9 mg/m3, the concentrations in exhaled air were 1.6 - 2.2 mg/m3 (18-20% of concentrations in inhaled air). After the end of exposure, the concentrations were 0.2 (1 h) and 0.1 (2 h) mg/m3, respectively. So only a minor excretion through exhalation.

Toxicokinetic parameters

Toxicokinetic parameters:

half-life 1st: mean 3.2 hours

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Triethylamine-N-Oxide (TEAO)

Any other information on results incl. tables

VISUAL DISTURBANCES: The subject who was exposed to a TEA air level of 53 mg for four hours developed visual symptoms (blue haze), as did both subjects exposed to 35 mg/m3 for four hours and four of the five subjects exposed to 20 mg/m3 for eight hours. None had such symptoms at 10 mg/m3 for eight hours.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results
continously inhalation of TEA ends in a akkumulation in the human body

Executive summary:

Urinary determination is feasible for biological monitoring of TEA exposure.

It seems that determination of U-TEA, corrected for dilution of urine by use ofthe creatinine concentration, in urine sampled during the first two hours after the end of work is a useful index.

There was an excellent association between air levels of TEA and the urinary concentrations in samples obtained within two hours of the end ofexposure. Thus the urinary level of TEA taken in this period is useful as a biological monitoring of exposure. An air concentration of 10 mg/m3 corresponds to an average urinary concentration of about 40 mmol/mol creatinine (at sedentary work).

Considering the extreme water solubility of the compound, it is probable that the absorption is proportional to ventilation. At moderately heavy work (ventilation 10 cm3/8h), an Air-TEA of 40 mg/ m3 would then correspond to an U-TEA of 320 mmol/ mol creatinine. Data on visual disturbances presented here and earlier,23 however, indicate that 40 mg/m3 is too high a TLV; 10 mg/m3 would be more reasonable. This would correspond to an average U-TEA of about 40 mmol/mol creatinine in a resting worker and 80 mmol/mol creatinine in moderately heavy industrial work.