TCA

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Test method similar to OECD guideline 417. No data on GLP.

Data source

Reference

Reference Type:

publication

Title:

Metabolism and Lipoperoxidative Activity of Trichloroacetate and Dichloroacetate in Rats and Mice

Author:

Larson JL, Bull RJ

Year:

1992

Bibliographic source:

TOXICOLOGY AND APPLlED PHARMACOLOGY 115, 268-277

Materials and methods

Objective of study:

metabolism

toxicokinetics

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

no

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

TCA

EC Number:

211-479-2

EC Name:

TCA

Cas Number:

650-51-1

Molecular formula:

C2HCl3O2.Na

IUPAC Name:

trichloroacetic acid

Details on test material:

- Name of test material (as cited in study report): Trichloroacetate, TCA
- Analytical purity: > 99 %

Radiolabelling:

yes

Remarks:

[14C]TCA; The sodium acetate was labeled in both carbon positions and had a specific activity of 55 mCi/mmol.

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Simonsen Laboratories (Gilroy, CA)
- Weight at study initiation: The average weight ± standard deviation was 331 ± 24.
- Fasting period before study: Prior to treatment, rats were fasted for 24 hr.
- Diet (e.g. ad libitum): The animals were maintained on Purina rodent chow provided ad libitum.
- Water (e.g. ad libitum): The water was provided ad libitum.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ºC
- Humidity (%): 40-60%
- Photoperiod (hrs dark / hrs light): A 12-hr light-dark cycle

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

The doses were given in a constant volume of 3 mL/kg to rats.
Each individual dosing solution of TCA was prepared by dissolving test substance in HPLC grade water and adjusting the pH to 7 by addition of sodium hydroxide.

Duration and frequency of treatment / exposure:

A single dose.

Doses / concentrations

Remarks:

Doses / Concentrations:
20, or 100 mg/kg [14C]TCA
Each animal was dosed with 5-20 µCi of [14C]TCA.

No. of animals per sex per dose / concentration:

36 male rats per dose

Control animals:

not specified

Positive control reference chemical:

No data

Details on dosing and sampling:

Blood samples (200-300 µL) were taken serially from the tail vein of rats at 0.25, 1, 3, 5, 10, 16, 24, 32, and 48 hr. The number of rodents sampled at each time point was four.
Radioactivity in plasma was determined in plasma before proteins were precipitated and in protein-poor plasma following precipitation and removal of protein. The resultant protein-poor plasma samples were chromatographed on a 25-cm X 4.6-mm high-pressure liquid chromatography column (Alltech C18, 10 µm Econosil). Fractions were colIected after elution and assayed for radioactivity by liquid scintillation counting. The recovery of radioactivity from the column was always greater than 90%.
Blood concentration of parent compound and metabolites over time curves were constructed for TCA at the 20 and 100 mg/kg doses.
All kinetic parameters were estimated from the analyses of TCA and metabolites in the protein-poor plasma fraction of the blood: the terminal half-life (t1/2), the volume of distribution (Vd) and clearance (CL).

Statistics:

Statistical analyses were first made using ANOVA. With a significant ANOVA, the significance between two groups, a control and treatment group was assessed by Student's t tests, with p < 0.05 chosen as the minimum level of significance.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Toxicokinetic parameters

Toxicokinetic parameters 1

Toxicokinetic parameters:

Cmax: 230 ± 10 nmol/mL (low dose)

Toxicokinetic parameters 2

Toxicokinetic parameters:

Cmax: 1200 ± 100 nmol/mL (high dose)

Toxicokinetic parameters 3

Toxicokinetic parameters:

AUC: 2530 ± 70 nmol/mL/h (low dose)

Toxicokinetic parameters 4

Toxicokinetic parameters:

AUC: 10000 ± 600 nmol/mL/h (high dose)

Toxicokinetic parameters 5

Toxicokinetic parameters:

half-life 1st: 7.0 h (low dose)

Toxicokinetic parameters 6

Toxicokinetic parameters:

half-life 1st: 5.8 h (high dose)

Toxicokinetic parameters 7

Toxicokinetic parameters:

other: Volume of distribution: 365 mL/kg (low dose)

Toxicokinetic parameters 8

Toxicokinetic parameters:

other: Volume of distribution: 485 mL/kg (high dose)

Toxicokinetic parameters 9

Toxicokinetic parameters:

other: Clearance: 36 mL/kg.h (low dose)

Toxicokinetic parameters 10

Toxicokinetic parameters:

other: Clearance: 58 mL/kg.h (low dose)

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Concentrations of DCA in the plasma of rats when the 100 mg/kg dose of TCA was given was 30 nmol/mL. It was also detected GOG as a TCA metabolit. The AUC values for GOG were 25 and 120 nmol/mL/hr in rats given 20 and 100 mg/kg, respectively. The Cmax for GOG was proportional to dose The KE for GOG was between 0.2 and 0.5 hr(-1).

Any other information on results incl. tables

Following an oral dose of 20 mg/kg, the Cmax was 230 ± 10 nmol/mL; the AUC was 2530 ± 70 nmol/mL/h; the half-life was 7.0 h; the volume of distribution: 365 mL/kg; and the Clearance: 36 mL/kg.h. After an oral dose of 100 mg/kg, the Cmax was 1200 ± 100 nmol/mL; the AUC was 10000 ± 600 nmol/mL/h; the half-life was 5.8 h; the volume of distribution: 485 mL/kg; and the Clearance: 58 mL/kg.h.

Concentrations of dichloroacetate in the plasma of rats when the 100 mg/kg dose of test substance was given was 30 nmol/mL. It was also detected GOG as a trichloroacetate metabolite.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results
Following an oral dose of 20 mg/kg, the Cmax was 230 ± 10 nmol/mL; the AUC was 2530 ± 70 nmol/mL/h; the half-life was 7.0 h; the volume of distribution: 365 mL/kg; and the Clearance: 36 mL/kg.h. After an oral dose of 100 mg/kg, the Cmax was 1200 ± 100 nmol/mL; the AUC was 10000 ± 600 nmol/mL/h; the half-life was 5.8 h; the volume of distribution: 485 mL/kg; and the Clearance: 58 mL/kg.h.
Concentrations of dichloroacetate in the plasma of rats when the 100 mg/kg dose of test substance was given was 30 nmol/mL. It was also detected GOG as a trichloroacetate metabolite.

Executive summary:

Trichloroacetate has been shown to be hepatocarcinogenic in mice when administered in drinking water. To identify potential mechanisms involved in the liver pathology, the biotransformation of sodium trichloroacetate was investigated in male Fischer 344 rats. Rodents were administered 20 or 100 mg/kg [14C]trichloroacetate as a single oral dose by gavage in water. Blood samples (200-300 µL) were taken serially from the tail vein of rats at 0.25, 1, 3, 5, 10, 16, 24, 32, and 48 hr. The number of rodents sampled at each time point was four.

Following an oral dose of 20 mg/kg, the Cmax was 230 ± 10 nmol/mL; the AUC was 2530 ± 70 nmol/mL/h; the half-life was 7.0 h; the volume of distribution: 365 mL/kg; and the Clearance: 36 mL/kg.h. After an oral dose of 100 mg/kg, the Cmax was 1200 ± 100 nmol/mL; the AUC was 10000 ± 600 nmol/mL/h; the half-life was 5.8 h; the volume of distribution: 485 mL/kg; and the Clearance: 58 mL/kg.h.

Concentrations of dichloroacetate in the plasma of rats when the 100 mg/kg dose of test substance was given was 30 nmol/mL. It was also detected GOG as a trichloroacetate metabolite. The AUC values for GOG were 25 and 120 nmol/mL/hr in rats given 20 and 100 mg/kg, respectively. The Cmax for GOG was proportional to dose. The KE for GOG was between 0.2 and 0.5 hr(-1).