Reaction mass of chlorodifluoroacetic acid and trifluoroacetic acid

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

No data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well conducted study although no guideline followed. Excretion only studied.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1989

Materials and methods

Objective of study:

excretion

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The extent of production of aerobic metabolite of halotane, trifluoroacetic acid and the mode of its elimination were studied in the rabbit.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Trifluoroacetic acid

EC Number:

200-929-3

EC Name:

Trifluoroacetic acid

Cas Number:

76-05-1

Molecular formula:

C2HF3O2

IUPAC Name:

trifluoroacetic acid

Test material form:

liquid

Details on test material:

Name of test material (as cited in study report): trifluoroacetic acid

Radiolabelling:

no

Test animals

Species:

rabbit

Strain:

not specified

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hiroshima Jikken Dobutsu Co., Ltd.
- Weight at study initiation: 2.5 - 3.5 kg.

ENVIRONMENTAL CONDITIONS: no data

IN-LIFE DATES: no data

Administration / exposure

Route of administration:

other: Inhalation for halothane, intravenous and enteral administrations for TFA

Vehicle:

other: Inhalation gases with 1 % halothane. Solution of TFA in saline for enteral and intravenous administrations.

Details on exposure:

- Method of holding animals in test chamber: rabbits were initially anesthetized with phenobarbital sodium as 25 mg/kg intravenously, and supplemented as required to maintain a stable anesthesic state. After tracheostomy the rabbit was ventilated by a Harvard animal respirator. Femoral artery and vein were cannulated for arterial blood sampling and for continuous infusion of lactated Ringer's solution. The rabbit was ventilated and the physiological level of arterial CO2 tension was maintained by adjusting the volume and rate of the respirator. PO2, PCO2 and pH were measured by ABL4 (Radiometer, Copenhagen, Denmark). The urinary bladder was cannulated with a 10F Foly's balloon catheter for urine sampling. Body temperature was maintained with a warming blanket.

The animals were divided into 4 groups. The animals in groups 1, ,2 and 4 underwent bile duct drainage under intravenous pentobarbital anesthesia. A duodenal catheter was inserted 2 cm caudal from the papilla duodeni to the animals in group 4 for administration of TFA.

Group 1: Inhalation exposure to Halothane
- Exposure apparatus: vaporizer (VaporR, Drager, West Germany)
- Rate of air: 2 L/min
- End-tidal halothane concentration was monitored using a gaschromatography (Shimazu, Kyoto, Japan) before and after the experiment.
- Pentobarbital infusion was continued for 24 hours after halothane inhalation was ceased, and then the animals were allowed to feed ad lib in their cage.

Group 2: Intravenous administration of TFA + bile duct drainage
- 100 µmol TFA with 5 mL saline
- animals were kept anesthetized with continuous intravenous infusion of phenobarbital sodium at the rate of 2 mg/kg/hour.

Group 3 : Intravenous administration of TFA
- 100 µmol TFA with 5 mL saline
- animals were kept anesthetized with continuous intravenous infusion of phenobarbital sodium at the rate of 2 mg/kg/hour.

Group 4: Administration via duodenal catheter + bile duct drainage
- 100 µmol TFA with 5 mL saline
- animals were kept anesthetized with continuous intravenous infusion of phenobarbital sodium at the rate of 2 mg/kg/hour.

Duration and frequency of treatment / exposure:

Group 1: 2 hours, one exposure.
Group 2, 3, 4: one injection

Doses / concentrations

Remarks:

Doses / Concentrations:
Group 1: 1% halothane
Group 4: 100 µmol TFA

No. of animals per sex per dose / concentration:

Group 1: 8 animals
Group 2, 3, 4: 5 animals

Control animals:

no

Positive control reference chemical:

No

Details on study design:

No details

Details on dosing and sampling:

Measurements of TFAA in the bile, urine and blood samples: samples were diluted 10-fold by deionized water, deproteinized using an ultrafiltration device and centrifuged at 1500 g for 45 minutes. After deproteinization, samples were filtrated through a cation exchanger filter in order to remove excess cation. After these preparations, 100 µL samples were injected into an ionchromatographic analyzer.

Statistics:

The plasma concentration-time data obtained for TFAA were analyzed using compartment analysis. Bi-exponential functions were fitted to the data using least-square non-linear regression analysis.

Results and discussion

Preliminary studies:

Not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:

No details

Details on distribution in tissues:

No details

Details on excretion:

In group 1 TFAcould be detected in the bile immediately after halothane inhalation was started, and the amount of TFA excreted in each hour reached its peak twelve hours after inhalation was started. TFA was detected in the bile for more than 84 hours after halothane administration was ceased. The total amount of TFA excreted in the bile was 108 +/- 8.32 µmol, and that in the urine was 61.9 +/- 11.2 µmol.
The elimination half-life of the TFA plasma concentration is significantly longer in the rabbits without bile fistula (Group 3) than with bile fistula (Group 2). These findings suggest the existence of the enterohepatic circulation of TFA.
In group 4, TFA appeared immediately in the plasma after enteral administration and plasma concentration of TFA reached the peak in one hour following enteral administration.
See Table 7.1.1/1 for details on results.

Metabolite characterisation studies

Metabolites identified:

not measured

Any other information on results incl. tables

Table 7.1.7/1: Pharmacokinetic data charcaterizing the elimination of TFA following intravenous (group 2 and 3 ) and enteral (group 4) administration

Group	Volume of distribution (L)	Distribution half-life (hours)	Elimination half-life (hours)	1st order elimination coefficient	Biliary excretion rate (%)	Urinary excretion rate (%)
2	0.91 ± 0.13	0.64 ± 0.23	15.6 ± 2.13	0.16 ± 0.01	51.8 ± 7.93	14.5 ± 3.09
3	0.66 ± 0.05	0.31 ± 0.05	34.3 ± 7.44	0.04 ± 0.007	0	58.0 ± 3.98
4	0.42 ± 0.12	0.59 ± 0.15	16.7 ± 4.32	0.13 ± 0.27	20.7 ± 4.30	22.0 ± 4.94

Applicant's summary and conclusion

Conclusions:

The most important mechanism of long lasting excretion of TFA after halothane anesthesia seems to be the enterohepatic circulation of TFA.

Executive summary:

The extent of production of aerobic metabolite of halotane, trifluoroacetic acid (TFA) and the mode of its elimination were studied in the rabbit. Animals were divided into 4 groups:

- Group 1 (8 animals): Inhalation exposure to Halothane (2 hours, 1 %) with bile duct drainage

- Group 2 (5 animals): Intravenous administration of TFA (100 µmol with 5 mL saline) with bile duct drainage

- Group 3 (5 animals): Intravenous administration of TFA (100 µmol with 5 mL saline) without bile duct drainage

- Group 4 (5 animals): Enteral administration (duodenal catheter) of TFA (100 µmol with 5 mL saline) with bile duct drainage.

The average amount of TFA excreted in the bile and urine for 72 hours after halothane inhalation was 108 µmol and 61.9 µmol, respectively, in the rabbit with bile fistulae. The present finding confirms that the bile was the major channel of elimination of TFA.

The elimination half-life of TFA was shorter in Group 2 (with bile fistulae) than in the Group 3 (without bile fistulae).

After enteral administration, TFA appeared rapidly in the circulatory blood and a considerable amount of TFA was reabsorbed in the gastrointestinal tract and then excreted into the urine and the bile.

 

Based on these observations, the most important mechanism of long lasting excretion of TFA after halothane anesthesia seems to be the enterohepatic circulation of TFA.