Tris(2-hydroxyethyl)methylammonium methyl sulphate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1991-03-19 to 1991-05-06

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP and guideline compliant study.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1991

Report date:

1991

Materials and methods

Objective of study:

distribution

excretion

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

no

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Tris(2-hydroxyethyl)methylammonium methyl sulphate

EC Number:

249-655-6

EC Name:

Tris(2-hydroxyethyl)methylammonium methyl sulphate

Cas Number:

29463-06-7

Molecular formula:

C7H18NO3.CH3O4S

IUPAC Name:

1,5-dihydroxy-3-(2-hydroxyethyl)pentan-3-aminium methyl sulfate

Details on test material:

- Name of test material 1: N-Tris-(2-hydroxyethyl)-methylammonium-methosulfate- Substance type: organic- Physical state: yellow solution in water- Analytical purity: about 98 %- Lot/batch No.: 1072321- Storage condition of test material: at room temperature in the dark- Name of test material 2: N-Tris-(2-hydroxyethyl)-14C-methylammonium-iodide- Substance type: organic- Physical state: yellow solution in oil- Lot/batch No.: CFO 6020- Radiochemical purity (if radiolabelling): > 98 %- Specific activity (if radiolabelling): 7.3 mCi/mmole- Storage condition of test material: stored at -20 °C in the dark

Radiolabelling:

yes

Remarks:

(N-Tris-(2-hydroxyethyl)-14C-methylammonium-iodide is almost identical to the test substance and was therefore used in a mixture application with the test substance.)

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS- Source: Charles River Wega Ltd., Sulzfeld, Germany- Age at study initiation: 8 - 10 weeks- Weight at study initiation: 200 - 300 g- Fasting period before study: no- Housing: individually- Individual metabolism cages: yes- Diet: ad libitum, Altromin diet- Water: ad libitum, tap water- Acclimation period: yesENVIRONMENTAL CONDITIONS- Temperature (°C): 21±2- Humidity (%): 55±15- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: solution in 0.9 % NaCl

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:The test substance N-Tris-(2-hydroxyethyl)-14C-methylammonium-iodide was prepared as a solution in 0.9 % NaCl. In the main study one group was given a dose calculated to yield final concentration of about 1 mg of undiluted N-Tris-(2-hydroxyethyl)-14C-methylammonium-iodide per kg body weight. The doses actually achieved were about 0.9 mg/kg body weight for the female and about 0.6 mg/kg body weight for the male animals. The other group received amounts of radioactivity (N-Tris-(2-hydroxyethyl)-14C-methylammonium-iodide diluted 1:5 with the non radioactive test substance) expected to result in final doses of about 100 mg/kg body weight. The doses achieved had means of about 100 mg/kg body weight for the female animals and about 97 mg/kg body weight for the males.

Duration and frequency of treatment / exposure:

Single oral dose was administered to the rats. They were kept in metabolism cages 24 hours before dosing and 72 hours afterwards.

Doses / concentrations

Remarks:

Doses / Concentrations:100 mg/kg bw

No. of animals per sex per dose / concentration:

4

Control animals:

no

Positive control reference chemical:

no

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)- Tissues and body fluids sampled: urine, faeces, blood, cage washes, expired CO2 of two animals- Time and frequency of sampling: 8, 24, 48 and 72 hours after administration- Other: The following organs were collected after sacrifice: brain, heart, lung, liver, kidney, urinary bladder and gastrointestinal tract

Results and discussion

Preliminary studies:

After a single intravenous administration of radioactive N-Tris(2-hydroxyethyl)-methylammonium-iodide to two female rats and one male the total recovery of radioactive material in urine was 96.1±1.1 %. The excretion of the radioactivity with the urine was fast. During the first 24h about 90 % of the administered radioactivity was excreted with the urine. The total recovery of radioactive material in feces was low, about 1.31±0.12 %. Most of this was excreted in the first 48h. In all organs examined (heart, lung, liver kidneys, urinary bladder, gastro-intestinal tract) the amount of radioactivity detected was very low, in total about 0.27 % of the administered dose. The organs with the highest amount of radioactive material were the liver (about 0.1 %) followed by the gastro-intestinal tract (about 0.07 %) and the blood (about 0.05 %). The radiochemical dose found in the expired air was low (about 0.6 %). The overall recovery, without the residual carcasses was about 99.4 + 0.60 % of the radiochemical dose. The preliminary study supports the hypothesis that the biliary excretion of the test substance is of no importance.

Main ADME results

Main ADME results 1

Type:

distribution

Results:

relevant recovery levels only seen in liver, gastrointestinal tract and blood

Main ADME results 2

Type:

excretion

Results:

mainly in urine and faeces

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:

In all organs examined (heart, lung, liver kidneys, urinary bladder, gastro-intestinal tract) the amount of radioactivity detected was very low, in total about 0.39 % of the administered dose. Only the liver (female: 0.07 %, male: 0.17 %), the gastro-intestinal tract (female: 0.13 %, male: 0.18 %) and the blood (female: 0.07 %, male: 0.07 %) contained relevant amounts of radioactivity.The overall recovery, without the residual carcasses was about 93.1 ± 1.7 % for the female animals and 94.6 ± 1.5 % for the male.

Details on excretion:

After the oral administration of 100 mg/kg of a mixture of N-Tris(2-hydroxyethyl)- C-methylammonium-iodide and the unlabelled test substance to four female rats about 65.5 ± 8.8 % of the radioactive material was recovered in the feces after 72 h. In the four male rats the recovery in the feces was about 57.6 ± 15.3 % of the administered dose. Most of the radioactive material was eliminated in both sexes within the first 48h. The mean total recovery of radioactive material in the urine was 23.5 ± 7.8 % for the female and 33.2 ± 13.9 % for the male rats. Most of the radioactive material was eliminated during the first 24 h.

Metabolite characterisation studies

Metabolites identified:

not measured

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study resultsMost of the radioactive material was excreted with the feces (about 61 %) within the first three days. 28 % was excreted via urine, most being eliminated within the first 24 hours.